/
Author: Katritzky A.R. Rees C.W.
Tags: chemistry organic chemistry chemical technology heterocyclic compounds
Year: 1997
Text
Comprehensive
Heterocyclic
Chemistry
in
8
volumes
(CD
-
ROM version)
Editors in Chief:
Alan R. Katritzky, F.R.S.
Charles W. Rees, F.R.S., C.B.E.
Volume
5
©
1997 Elsevier Science Ltd.
Full Contents
VOL
UME
1
1.01
Introduction
1.02
Nomenclature of Heterocyclic Compounds
1.03
Review Literature of Heterocycles
1.04
Biosynthesis of Some Heterocyclic Natural Products
1.05
Toxicity of Heterocycles
1.06
Application as Pharmaceuticals
1.07
Use as Agrochemicals
1.08
Use as Veterinary
Products
1.09
Metabolism of Heterocycles
1.10
Importance of Heterocycles in Biochemical Pathways
1.11
Heterocyclic Polymers
1.12
Heterocyclic Dyes and Pigments
1.13
Organic Conductors
1.14
Uses in Photographic and Reprographic Techniques
1.15
Heter
ocyclic Compounds as Additives
1.16
Use in the Synthesis of Non
-
Heterocycles
1.17
Heterocyclic Rings containing Phosphorus
1.18
Heterocyclic Rings containing Arsenic, Antimony or Bismuth
1.19
Heterocyclic Rings containing Halogens
1.20
Heterocyclic Ri
ngs containing Silicon, Germanium, Tin or Lead
1.21
Heterocyclic Rings containing Boron
1.22
Heterocyclic Rings containing a Transition Metal
Volume 1
References
VOLUME
2
2.01
Structure of Six
-
membered Rings
2.02
Reactivity of Six
-
membered Rings
2.03
Synthesis of Six
-
membered Rings
2.04
Pyridines and their Benzo Derivatives: (i) Structure
2.05
Pyridines and their Benzo Derivatives: (ii) Reactivity at Ring Atoms
2.06
Pyridines and their Benzo Derivatives: (iii) Reactivity of Substituents
2.07
Pyridines
and their Benzo Derivatives: (iv) Reactivity of Non
-
aromatics
2.08
Pyridines and their Benzo Derivatives: (v) Synthesis
2.09
Pyridines and their Benzo Derivatives: (vi) Applications
2.10
The Quinolizinium Ion and Aza Analogs
2.11
Naphthyridines, Pyridoqui
nolines, Anthyridines and Similar Compounds
Volume 2 References
VOLUME
3
2.12
Pyridazines and their Benzo Derivatives
2.13
Pyrimidines and their Benzo Derivatives
2.14
Pyrazines and their Benzo Derivatives
2.15
Pyridodiazines and their Benzo Derivativ
es
2.16
Pteridines
2.17
Other Diazinodiazines
2.18
1,2,3
-
Triazines and their Benzo Derivatives
2.19
1,2,4
-
Triazines and their Benzo Derivatives
2.20
1,3,5
-
Triazines
2.21
Tetrazines and Pentazines
2.22
Pyrans and Fused Pyrans: (i) Structure
2.23
Pyrans and
Fused Pyrans: (ii) Reactivity
2.24
Pyrans and Fused Pyrans: (iii) Synthesis and Applications
2.25
Thiopyrans and Fused Thiopyrans
2.26
Six
-
membered Rings with More than One Oxygen or Sulfur Atom
2.27
Oxazines, Thiazines and their Benzo Derivatives
2.28
Pol
yoxa, Polythia and Polyaza Six
-
membered Ring Systems
Volume 3 References
VOLUME
4
3.01
Structure of Five
-
membered Rings with One Heteroatom
3.02
Reactivity of Five
-
membered Rings with One Heteroatom
3.03
Synthesis of Five
-
membered Rings with One Hetero
atom
3.04
Pyrroles and their Benzo Derivatives: (i) Structure
3.05
Pyrroles and their Benzo Derivatives: (ii) Reactivity
3.06
Pyrroles and their Benzo Derivatives: (iii) Synthesis and Applications
3.07
Porphyrins, Corrins and Phthalocyanines
3.08
Pyrroles
with Fused Six
-
membered Heterocyclic Rings: (i) a
-
Fused
3.09
Pyrroles with Fused Six
-
membered Heterocyclic Rings: (ii) b
-
and c
-
Fused
3.10
Furans and their Benzo Derivatives: (i) Structure
3.11
Furans and their Benzo Derivatives: (ii) Reactivity
3.12
Furan
s and their Benzo Derivatives: (iii) Synthesis and Applications
3.13
Thiophenes and their Benzo Derivatives: (i) Structure
3.14
Thiophenes and their Benzo Derivatives: (ii) Reactivity
3.15
Thiophenes and their Benzo Derivatives: (iii) Synthesis and Applica
tions
3.16
Selenophenes, Tellurophenes and their Benzo Derivatives
3.17
Furans, Thiophenes and Selenophenes with Fused Six
-
membered Heterocyclic Rings
3.18
Two Fused Five
-
membered Rings Each Containing One Heteroatom
Volume 4 References
VOLUME
5
4.01
S
tructure of Five
-
membered Rings with Two or More Heteroatoms
4.02
Reactivity of Five
-
membered Rings with Two or More Heteroatoms
4.03
Synthesis of Five
-
membered Rings with Two or More Heteroatoms
4.04
Pyrazoles and their Benzo Derivatives
4.05
Pyrazoles wi
th Fused Six
-
membered Heterocyclic Rings
4.06
Imidazoles and their Benzo Derivatives: (i) Structure
4.07
Imidazoles and their Benzo Derivatives: (ii) Reactivity
4.08
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
4.09
Purines
4.10
Other Imidazoles with Fused Six
-
membered Rings
4.11
1,2,3
-
T
riazoles and their Benzo Derivatives
4.12
1,2,4
-
Triazoles
4.13
Tetrazoles
4.14
Pentazoles
4.15
Triazoles and Tetrazoles with Fused Six
-
membered Rings
Volume 5 References
VOLUME
6
4.16
Isoxazol
es and their Benzo Derivatives
4.17
Isothiazoles and their Benzo Derivatives
4.18
Oxazoles and their Benzo Derivatives
4.19
Thiazoles and their Benzo Derivatives
4.20
Five
-
membered Selenium
-
Nitrogen Heterocycles
4.21
1,2,3
-
and 1,2,4
-
Oxadiazoles
4.22
1,2,5
-
Oxadiazoles and their Benzo Derivatives
4.23
1,3,4
-
Oxadiazoles
4.24
1,2,3
-
Thiadiazoles and their Benzo Derivatives
4.25
1,2,4
-
Thiadiazoles
4.26
1,2,5
-
Thiadiazoles and their Benzo Derivatives
4.27
1,3,4
-
Thiadiazoles
4.28
Oxatriazoles and Thiatriazoles
4.29
Five
-
membered Rings (One Oxygen or Sulfur and At Least One Nitrogen Atom)
Fused with Six
-
membered Rings (At Least One Nitrogen Atom)
4
.3
0
Dioxole
s and Oxathioles
4.31
1,2
-
Dithioles
4.32
1
,3
-
Dithioles
4.33
Five
-
membered Rings containing Three Oxygen or Su
lfur Atoms
4.34
Dioxazoles, Oxathiazoles and Dithiazoles
4.35
Five
-
membered Rings containing One Selenium or Tellurium Atom and One Other
Group VI Atom and their Benzo Derivatives
4.36
Two Fused Five
-
membered Heterocyclic Rings: (i) Classical Systems
4.37
Two Fused Five
-
membered Heterocyclic Rings: (ii) Non
-
classical Systems
4.38
Two Fused Five
-
membered Heterocyclic Rings: (iii) 1,6,6a
4
-
Trithiapentalenes
and Related Systems
Volume
6
References
VOLUME
7
5.01
Structure of Small and Large Rings
5.02
Reac
tivity of Small and Large Rings
5.03
Synthesis of Small and Large Rings
5.04
Aziridines, Azirines and Fused
-
ring Derivatives
5.05
Oxiranes and Oxirenes
5.06
Thiiranes and Thiirenes
5.07
Fused
-
ring Oxiranes, Oxirenes, Thiiranes and Thiirenes
5.08
Three
-
memb
ered Rings with Two Heteroatoms and Fused
-
ring Derivatives
5.09
Azetidines, Azetines and Azetes
5.10
Cephalosporins
5.11
Penicillins
5.12
Other Fused
-
ring Azetidines, Azetines and Azetes
5.13
Oxetanes and Oxetenes
5.14
Thietanes, Thietes and Fused
-
ring Der
ivatives
5.15
Four
-
membered Rings with Two or More Heteroatoms and Fused
-
ring Derivatives
5.16
Azepines
5.17
Oxepanes, Oxepins, Thiepanes and Thiepins
5.18
Seven
-
membered Rings with Two or More Heteroatoms
5.19
Eight
-
membered Rings
5.20
Larger Rings except
Crown Ethers and Heterophanes
5.21
Crown Ethers and Cryptands
5.22
Heterophanes
Volume
7
References
VOLUME
8
Physical Data Index
Author Index
Subject Index
Ring Index
References
EXPLANATION OF THE REFERENCE SYSTEM
Throughout this work, references are designated by a number-letter coding of which the
first two numbers denote tens and units of the year of publication, the next one to three
letters denote the journal, and the final numbers denote the page. This code appears in the
text each time a reference is quoted; the advantages of this system are outlined in the
Introduction (Chapter 1.01). The system is based on that previously used in the following
two monographs: (a) A. R. Katritzky and J. M. Lagowski, 'Chemistry of the Heterocyclic
N-Oxides', Academic Press, New York, 1971; (b) J. Elguero, C. Marzin, A. R. Katritzkyand
P. Linda, 'The Tautomerism of Heterocycles', in 'Advances in Heterocyclic Chemistry',
Supplement I, Academic Press, New York, 1976.
The following additional notes apply:
1. A list of journals which have been assigned codes is given (in alphabetical order)
together with their codes immediately following these notes. Journal names are abbreviated
throughout by the CASSI (Chemical Abstracts Service Source Index) system.
2. A list of journal codes in alphabetical order, together with the journals to which they
refer, is given on the end papers of each volume.
3. Each volume contains all the references cited in that volume; no separate lists are given
for individual chapters.
4. The list of references is arranged in order of (a) year, (b) journal in alphabetical order
of journal code, (c) part letter or number if relevant, (d) volume number if relevant, (e) page
number.
5. In the reference list the code is followed by (a) the complete literature citation in the
conventional manner and (b) the number(s) of the page(s) on which the reference appears,
whether in the text or in tables, schemes, etc.
6. For non-twentieth century references the year is given in full in the code.
7. For journals which are published in separate parts, the part letter or number is given
(when necessary) in parentheses immediately after the journal code letters.
8. Journal volume numbers are not included in the code numbers unless more than one
volume was published in the year in question, in which case the volume number is included
in parentheses immediately after the journal code letters.
9. Patents are assigned appropriate three letter codes.
10. Frequently cited books are assigned codes, but the whole code is now prefixed by the
letter 'B-'.
11. Less common journals and books are given the code 'MI' for miscellaneous.
12. Where journals have changed names, the same code is used throughout, e.g. CB refers
both to Chern. Ber. and to Ber. Dtsch. Chern. Ges.
Journals
Acc. Chern. Res.
Acta Chern. Scand., Ser. B
Acta Chim. Acad. Sci. Hung.
Acta Crystallogr., Part B
Adv. Phys. Org. Chern.
Agric. BioI. Chern.
ACR
ACS(B)
ACH
AX(B)
APO
ABC
References
Angew. Chern.
Angew. Chern., Int. Ed. Engi.
Ann. Chim. (Rome)
Ann. N.Y. Acad. Sci.
Arch. Pharm. (Weinheim, Ger.)
Ark. Kemi
Arzneim.- Forsch.
Aust. J. Chern.
Biochem. Biophys. Res. Commun.
Biochemistry
Biochem. J.
Biochim. Biophys. Acta
Br. J. Pharmacol.
Bull. Acad. Pol. Sci., Ser. Sci. Chim.
Bull. Acad. Sci. USSR, Div. Chern. Sci.
Bull. Chern. Soc. Jpn.
Bull. Soc. Chim. Belg.
Bull. Soc. Chim. Fr., Part 2
Can. J. Chern.
Chern. Abstr.
Chern. Ber.
Chern. Heterocycl. Compd. (Engl. Transl.)
Chern. Ind. (London)
Chern. Lett.
Chern. Ph arm. Bull.
Chern. Rev.
Chern. Scr.
Chern. Soc. Rev.
Chem.-Ztg.
Chimia
Collect. Czech. Chern. Commun.
Coord. Chern. Rev.
C.R. Hebd. Seances Acad. Sci., Ser. C
Cryst. Struct. Commun.
Diss. Abstr. Int. B
Dokl. Akad. Nauk SSSR
Experientia
Farmaco Ed. Sci.
Fortschr. Chern. Org. Naturst.
Gazz. Chim. Ital.
Helv. Chim. Acta
Heterocycles
Hoppe-Seyler's Z. Physiol. Chern.
Indian J. Chern., Sect. B
Inorg. Chern.
Int. J. Sulfur Chern., Part B
Izv. Akad. Nauk SSSR, Ser. Khim.
J. Am. Chern. Soc.
J. BioI. Chern.
J. Chern. Phys.
J. Chern. Res. (S)
J. Chern. Soc. (C)
J. Chern. Soc., Chern. Commun.
J. Chern. Soc., Dalton Trans.
J. Chern. Soc., Faraday Trans. I
J. Chern. Soc., Perkin Trans. I
J. Gen. Chern. USSR (Engl. TransI.)
J. Heterocycl. Chern.
J. Indian Chern. Soc.
J. Magn. Reson.
AG
AG(E)
AC(R)
ANY
AP
AK
AF
AJC
BBR
B
BJ
BBA
BJP
BAP
BAU
BCJ
BSB
BSF(2)
CJC
CA
CB
CHE
CI(L)
CL
CPB
CRY
CS
CSR
CZ
C
CCC
CCR
CR(C)
CSC
DlS(B)
DOK
E
FES
FOR
G
HCA
H
ZPC
IJC(B)
IC
IJS(B)
IZV
JA
JBC
JCP
JCR(S)
JCS(C)
CC
JCS(D)
JCS(FI)
JCS(PI)
JGU
JHC
JIC
JMR
References
J. Med. Chern.
J. Mol. Spectrosc.
J. Mol. Struct.
J. Organomet. Chern.
J. Org. Chern.
J. Org. Chern. USSR (Engl. Transl.)
J. Pharm. Sci.
J. Phys. Chern.
J. Prakt. Chern.
Khim. Geterotsiki. Soedin.
Kristallografiya
Liebigs Ann. Chern.
Monatsh. Chern.
Naturwissenschaften
Nippon Kagaku Kaishi
Nouv. J. Chim.
Org. Magn. Reson.
Org. Mass Spectrom.
Org. Prep. Proced. Int.
Org. React.
Org. Synth.
Org. Synth., Coli. Vol.
Phosphorus Sulfur
Phytochernistry
Proc. Indian Acad. Sci., Sect. A
Proc. Nat!. Acad. Sci. USA
Pure Appl. Chern.
Q. Rev., Chern. Soc
Recl. Trav. Chim. Pays-Bas
Rev. Roum. Chirn.
Russ. Chern. Rev. (Engl. Transl.)
Spectrochim. Acta, Part A
Synth. Commun.
Synthesis
Tetrahedron
Tetrahedron Lett.
Ukr. Khim. Zh. (Russ. Ed.)
Yakugaku Zasshi
Z. Chern.
Zh. Obshch. Khim.
Zh. Org. Khim.
Z. Naturforsch., Teil B
Book Series
'Advances in Heterocyclic Chemistry'
'Chemistry of Heterocyclic Cornpounds' [Weissberger-Taylor series]
'Methoden der Organischen Chernie (Houben- Weyl)'
'Organic Compounds of Sulphur, Selenium, and Tellurium' [R. Soc.
Chern. series]
'Physical Methods in Heterocyclic Chemistry'
Specific Books
Q. N. Porter and J. Baldas, 'Mass Spectromety of Heterocyclic Com-
pounds', Wiley, New York, 1971
T. J. Batterham, 'NMR Spectra of Simple Heterocycles', Wiley, New
York, 1973
JMC
JSP
JST
JaM
JOC
JOU
JPS
JPC
JPR
KGS
K
LA
M
N
NKK
NJC
OMR
OMS
OPP
OR
as
OSC
PS
P
PIA(A)
PNA
PAC
QR
RTC
RRC
RCR
SA(A)
SC
S
T
TL
UKZ
YZ
ZC
ZOB
ZOR
ZN(B)
AHC
HC
HOU
SST
PMH
MS
NMR
References
'Photochemistry of Heterocyclic Cornpounds', ed. O. Buchardt, Wiley, New
York, 1976 PH
W. L. F. Arrnarego, 'Stereochernistry of Heterocyclic Compounds', Wiley,
New York, 1977, parts I and 2 SH
Patents
Belg. Pat.
Br. Pat.
Eur. Pat.
Fr. Pat.
Ger. (East) Pat.
Ger. Pat.
Neth. Pat.
lpn. Pat.
lpn. Kokai
S. Afr. Pat.
U.S. Pat.
BEP
BRP
EUP
FRP
EGP
GEP
NEP
JAP
JAP(K)
SAP
USP
Other Publications
All Other Books and Journals ('Miscellaneous')
All Other Patents
Personal Cornrnunications
Theses
Unpublished Results
MI
MIP
PC
TH
UP
Foreword
Scope
Heterocyclic compounds are those which have a cyclic structure with two, or more,
different kinds of atom in the ring. This work is devoted to organic heterocyclic compounds
in which at least one of the ring atoms is carbon, the others being considered the heteroatoms;
carbon is still by far the most common ring atom in heterocyclic compounds. As the number
and variety of heteroatoms in the ring increase there is a steady transition to the expanding
domain of inorganic heterocyclic systems. Since the ring can be of any size, from three-
membered upwards, and since the heteroatoms can be drawn in almost any combination
from a large number of the elements (though nitrogen, oxygen and sulfur are the most
common), the number of possible heterocyclic systems is almost limitless. An enormous
number of heterocyclic compounds is known and this number is increasing very rapidly.
The literature of the subject is correspondingly vast and of the three major divisions of
organic chemistry, aliphatic, carbocyclic and heterocyclic, the last is much the biggest.
Over six million compounds are recorded in Chemical Abstracts and approximately half of
these are heterocyclic.
Significance
Heterocyclic compounds are very widely distributed in Nature and are essential to life;
they playa vital role in the metabolism of all living cells. Thus, for example, the following
are heterocyclic compounds: the pyrimidine and purine bases of the genetic material DNA;
the essential amino acids proline, histidine and tryptophan; the vitamins and coenzyme
precursors thiamine, riboflavine, pyridoxine, folic acid and biotin; the B 1 2 and E families
of vitamin; the photosynthesizing pigment chlorophyll; the oxygen transporting pigment
hemoglobin, and its breakdown products the bile pigments; the hormones kinetin,
heteroauxin, serotonin and histamine; together with most of the sugars. There are a vast
number of pharmacologically active heterocyclic compounds, many of which are in regular
clinical use. Some of these are natural products, for example antibiotics such as penicillin
and cephalosporin, alkaloids such as vinblastine, ellipticine, morphine and reserpine, and
cardiac glycosides such as those of digitalis. However, the large majority are synthetic
heterocyclics which have found widespread use, for example as anticancer agents, analeptics,
analgesics, hypnotics and vasopressor modifiers, and as pesticides, insecticides, weedkillers
and rodenticides.
There is also a large number of synthetic heterocyclic compounds with other important
practical applications, as dyestuffs, copolymers, solvents, photographic sensitizers and
developers, as antioxidants and vulcanization accelerators in the rubber industry, and many
are valuable intermediates in synthesis.
The successful application of heterocyclic compounds in these and many other ways, and
their appeal as materials in applied chemistry and in more fundamental and theoretical
studies, stems from their very complexity; this ensures a virtually limitless series of struc-
turally novel compounds with a wide range of physical, chemical and biological properties,
spanning a broad spectrum of reactivity and stability. Another consequence of their varied
chemical reactivity, including the possible destruction of the heterocyclic ring, is their
increasing use in the synthesis of specifically functionalized non-heterocyclic structures.
Aims of the Present Work
All of the above aspects of heterocyclic chemistry are mirrored in the contents of the
present work. The scale, scope and complexity of the subject, already referred to, with its
vii
viii
Foreword
correspondingly complex system of nomenclature, can make it somewhat daunting initially.
One of the main aims of the present work is to minimize this problem by presenting a
comprehensive account of fundamental heterocyclic chemistry, with the emphasis on basic
principles and, as far as possible, on unifying correlations in the properties, chemistry and
synthesis of different heterocyclic systems and the analogous carbocyclic structures. The
motivation for this effort was the outstanding biological, practical and theoretical importance
of heterocyclic chemistry, and the absence of an appropriate major modern treatise.
At the introductory level there are several good textbooks on heterocyclic chemistry,
though the subject is scantily treated in most general textbooks of organic chemistry. At
the specialist, research level there are two established ongoing series, . Advances in
Heterocyclic Chemistry' edited by Katritzky and 'The Chemistry of Heterocyclic Com-
pounds' edited by Weissberger and Taylor, devoted to a very detailed consideration of all
aspects of heterocyclic compounds, which together comprise some 100 volumes. The present
work is designed to fill the gap between these two levels, i.e. to give an up-to-date overview
of the subject as a whole (particularly in the General Chapters) appropriate to the needs
of teachers and students and others with a general interest in the subject and its applications,
and to provide enough detailed information (particularly in the Monograph Chapters) to
answer specific questions, to demonstrate exactly what is known or not known on a given
topic, and to direct attention to more detailed reviews and to the original literature. Mainly
because of the extensive practical uses of heterocyclic compounds, a large and valuable
review literature on all aspects of the subject has grown up over the last few decades.
References to all of these reviews are now immediately available: reviews dealing with a
specific ring system are reported in the appropriate monograph chapters; reviews dealing
with any aspect of heterocyclic chemistry which spans more than one ring system are
collected together in a logical, readily accessible manner in Chapter 1.03.
The approach and treatment throughout this work is as ordered and uniform as possible,
based on a carefully prearranged plan. This plan, which contains several novel features, is
described in detail in the Introduction (Chapter 1.01).
ALAN R. KA TRITZKY
Florida
CHARLES W. REES
London
Contributors to Volume 5
Professor R. N. Butler
Department of Chemistry, University College, Galway, Eire
Professor J. Elguero
Instituto de Quimica Medica, Juan de la Cierva 3, Madrid 6, Spain
Dr J. V. Greenhill
Department of Pharmaceutical Chemistry, University of Bradford, Bradford, West Yorkshire
BD7 lOP, UK
Professor M. R. Grimmett
Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
Professor A. R. Katritzky, FRS
Department of Chernistry, University of Florida, Gainesville, FL 32611, USA
Professor J. M. Lagowski
Department of Zoology, University of Texas, Austin, TX 78712, USA
Dr J. A. Montgomery
Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255, USA
Dr J. B. Polya
Departrnent of Chemistry, University of Tasmania, Box 252 C, GPO Hobart, Tasrnania,
Australia
Professor K. T. Potts
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, NY 12181, USA
Dr J. A. Secrist III
Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35255, USA
Professor S. W. Schneller
Departrnent of Chemistry, University of South Florida, Tampa, FL 33620, USA
Professor G. Shaw
School of Studies m Chemistry, University of Bradford, Bradford, West Yorkshire
BD7 lOP, UK
Professor Dr I. Ugi
Organische-Chemisches Institut, Technische Universität München, Lichtenberstrasse 4,
0-8046 Garching, Federal Republic of Germany
Professor Dr H. Wamhoff
Institut für Organische Chemie und Biochernie, Universität Bonn, Gerhard-Domagk-
Strasse 1,0-5300 Bonn 1, Federal Republic of Germany
ix
4.01
Structure of Five-membered
Rings with Two or More
Heteroatoms
A. R. KA TRITZKY
University of Florida
and
J. M. LAGOWSKI
The University of Texas at Austin
4.01.1 SURVEY OF POSSIBLE STRUCTURES
4.01.1.1 Aromatic Systems without Exocyclic Conjugation
4.01.1.:? Aromatic Systems with Exocyclic Conjugation
4.01.1.3 Non-aromatic Systems
4.01.2 THEORETICAL METHODS
4.01.2.1 The MO Approximation
4.01.2.2 Electron Densities
4.01.2.3 Frontier Electron Densities
4.01.2.4 Localization Energies
4.01.2.5 Semiempirical Methods
4.01.2.6 Other Applications of Theory
4.01.3 STRUCTURAL METHODS
4.01.3.1 X-Ray Diffraction
4.01.3.2 Microwave Spectroscopy
4.01.3.2.1 Molecular geometry
4.01.3.2.2 Partially and fully saturated ring systems
4.01.3.3 1 H NMR Spectroscopy
4.01.3.4 I3 C NMR Spectroscopy
4.01.3.5 Nitrogen NMR Spectroscopy
4.01.3.6 UV Spectroscopy
4.01.3.6.1 Parent compounds
4.01.3.6.2 Benzo derivatives
4.01.3.6.3 Effect of substituents
4.01.3.7 IR Spectroscopy
4.01.3.7.1 Aromatic rings without carbonyl groups
4.01.3.7.2 Azole rings containing carbonyl groups
4.01.3.7.3 Substituent vibrations
4.01.3.8 Mass Spectrometry
4.01.3.9 Photoelectron Spectroscopy
4.01.4 THERMODYNAMIC ASPECTS
4.01.4.1 Intermolecular Forces
4.01.4.1.1 Melting and boiling points
4.01.4.1.2 Solubility of heterocyclic compounds
4.01.4.1.3 Gas-liquid chromatography
4.01.4.2 Stability and Stabilization
4.01.4.2.1 Thermochemistry and conformation of saturated heterocycles
4.01.4.2.2 Aromaticity
4.01.4.3 Conformation
4.01.5 TAUTOMERISM
4.01.5.1 Annular Tautomerism
4.01.5.2 Substituent Tautomerism
4.01.5.2.1 Azoles with heteroatoms in the 1,2-positions
4.01.5.2.2 Azoles with heteroatoms in the 1,3-positions
2
2
2
4
5
5
5
6
6
7
7
8
8
8
8
8
13
15
16
16
16
21
24
24
24
24
24
30
30
31
31
31
31
32
32
32
32
34
35
35
36
36
37
1
2 Structure of Five-membered Rings with Two or More Heteroatorns
4.01.1 SURVEY OF POSSIBLE STRUCTURES
We classify cornpounds as arornatic, if there is continuous conjugation around the ring,
or non-arornatic. Arornatic cornpounds are further subdivided into those without exocyclic
double bonds and those in which irnportant canonical forrns containing exocyclic double
bonds contribute.
4.01.1.1 Aromatic Systems without Exocyclic Conjugation
The neutral aromatic azole systerns (without exocyclic conjugation) arc shown in Scherne
1; throughout, Z is 0, S or NR. There are, thus, 24 possible systerns; however, for NR = NH,
tautornerisrn renders (3) == (5), (4) == (6), and (7) == (8). Ring-fused derivatives without a
bridgehead nitrogen atorn are possible for systerns (1), (2), (3) and (5). Ring-fused derivatives
with a bridgehead nitrogen atorn can be derived frorn all except (5) and (8).
O
/N
Z
(1) Pyrazole (Z = NH)
Isoxazole (Z = 0)
Isothiazole (Z = $)
I/
t.:.... /N
Z
1,2,3-
" /N
Z
1,2,4-
(3
Z
(2) Imidazole (Z = NH)
Oxazole (Z = 0)
Thiazole (Z = $)
n
N, /N
Z
1,2,5-
N-N
()
Z
1,3,4-
,
Triazoles, Oxadiazoles, Thiadiazoles
(3)
N-N
II II
" /N
Z
1,2,3,4-
(7)
(4)
(5)
(6)
I/ ] Tetrazoles (Z = NH)
N,z/N Oxatriazoles (Z = 0)
Thiatriazoles (Z = $)
1,2,3,5-
(8)
Scheme 1 Neutral aromatic azoles (no exocyclic double bonds) (Z = 0, $ or NR)
The five possible azole monoanions are shown (one canonical forrn only) in Scherne 2;
all heteroatoms are now nitrogens.
ÇN () ( N N-N
Z Z II
N Ñ"N N Ñ"N
(9) (10) (11) (12) (13)
Scheme 2 Monoanionic aromatic azoles
The arornatic azole rnonocations are given in Scherne 3; here Z and Yare both 0, S or
NR; there are therefore three rnixed sets. If Z = Y, then (16) == (18), (20) == (21), (22) == (24),
and (25) == (26). Hence there are (3 x 14) + (3 x 10) = 72 possible systerns.
4.01.1.2 Aromatic Systems with Exocyclic Conjugation
Each of the arornatic monocationic systems (14)-(27) can be converted into a neutral
systern by substitution of an anionic 0, S or NR group on to a ring carbon atorn. However,
(14) and (15) each give three such systerns, (16)-(21) two 'each, and (22)-(27) one each.
The resulting 24 systems can be divided into two groups: 12 systerns for the azolinones
and related cornpounds (Scherne 4) and 12 systerns for the rnesoionic (betaine) compounds
(Scherne 5).
Of the rnesoionic systems, (40) and its aza derivatives (43), (44) and (49) have been
designated as Class B by Ollis (76AHC(19)1), including cornpounds with X = CRR'; there
Structure of Five-membered Rings with Two or More Heteroatorns
3
Pyrazolium (Z = Y = NH) + Imidazolium (Z = Y = NH)
Q Isoxazolium (Z = 0, Y = NH) (') Oxazolium (Z = 0, Y = NH)
Isothiazolium (Z = S, Y = NH) Thiazolium (Z = S, Y = NH)
/Y 1,2-Dioxolylium (Z = Y = 0) 1,3-Dioxolylium (Z = Y = 0)
Z Z
(14) 1,2-Oxathiolylium (Z = 0, Y = S) (15) 1,3-0xathiolylium (Z = 0, Y = S)
1,2-Dithiolylium (Z = Y = S) 1,3-Dithiolylium (Z = Y = S)
+ N-Y +
( Z n ( () J)
+y +y N, :'Y /N
z/ z/ Z Z Z 'z
(16) (17) (18) (19) (20) (21)
1,2,3- 1,2,4- 1,2,5- 1,3,2- 1,3,4- 1,3,5-
Triazolium, Oxadiazolium, Thiadiazolium, Dioxazolium, Oxathiazolium, Dithiazolium
N-N
( \\
+y
Z/
(22)
I!
N, ;;'Y
Z
(23)
N
II
N, ;;'Y
Z
(24)
+
N-Y
II II
" /N
+
Y
II II
N, /N
Z
(26)
+
N-Y
II )
N,
Z
(27)
(25)
Tetrazolium, Oxatriazolium, Thiatriazolium, Dioxadiazolium, Oxathiadiazolium, Dithiadiazolium
Scheme 3 Monocationic azoles
x
d x .J::;y [Y
zAx
Z/ Z
(28) (29) (30)
N-i X X
J:.N N\ iii N-Y 11\
X Z/ I!...z"y x-Ä... z "Y N, "Y I!...z.A x N, X
Z Z
(31) (32) (33) (34) (35) (36)
X
N=N -{ N-Y
xJ...z/y II A
N, /Y N,z X
Z
(37) (38) (39)
Scheme 4 Azolinones and related compounds (X = 0, azolinones; X = S, azolinethiones; X = NR, azolinimines)
x X +
Q+ t1 -L1
Z"y Z X Z
(40) (41) (42)
X X X X +
h \ Y + +
t L N-Y r)
[\\ - J!.. )
z"y+ N, "y+ /N X Z/N N,Z
Z Z X Z
(43) (44) (45) (46) (47) (48)
X + X +
r + N-Y r
.J!.. \1
N, /Y _ /N N, /N
Z X Z Z
(49) (50) (51)
Scheme 5 Mesoionic compounds (Z = 0, S or NR; X = 0, S, NR or CRz)
are 88 total systerns. Class A mesoionic compounds include (41), (42) and their aza
derivatives (45)-(48), (50) and (51), giving a total of 144 systems. Members of the latter
group contain 1,3-dipoles, often reflected in their pronounced ability to undergo cycloaddi-
tion reactions.
4
Structure of Five-membered Rings with Two or More Heteroatorns
These are subdivided into: (a) compounds isomeric with aromatic compounds in which
the ring contains two double bonds but also an sp 3 - hybridized carbon (7 systems; Scheme
6) or a quaternary nitrogen atom (9 systems; Scheme 7).
R R R
r+ R R / R R t N
(ýN __;N _.A )\
N N N R N
(52) (53) (54) (55)
4.01.1.3 Non-aromatic Systems
R t R N
II
....N
N
(56)
R
N-\-R
I/.. 'iN
N
(57)
R N=N
>Z. 'i'N
R N
(58)
Scheme 6 Isomers of aromatic CíJmpounds with an Sp3 - hybridized carbon atom
CN
N
If 'R
(59)
CJ
N
Ii 'R
(60)
r
. ....N
N
Ii 'R
(61)
N\ R
( N./
N "R
R"
N
R.//
" ....N
N
(64)
(65)
Scheme 7 Isomers of aromatic compounds with a quaternary nitrogen atom
(67)
e N R
\ ./
">. "N"
N R
'" + .....N
N
R/ 'R
(63)
(62)
N-N
II \\
"-+....N
N
R/ 'R
(66)
N=N R
I \./
;;N"
N R
(b) Dihydro cómpounds in which the ring contains one double bond (66 systems; Scheme
8).
ÇNH ÇN H ÇN (NH ç) C)
z)
z
(68) 2,3- (69)2,5- (70) 4,5- (71) 2,3- (72) 2,5- (73)4,5-
NH eN N N\ N\ HN
(\ zJIH C \\ I/.. NH (Z....NH (Z;N
Z....NH Z....N Z....
(74) 2,3- (75) 2,5- (76) 4,5- (77) 2,3- (78) 2,5- (79) 4,5-
n F\ N-NH N=N
N.... Z ....NH HN....Z"NH I/.. ) (z)
Z
(80)2,3- (81) 2,5- (82) 2,3- (83) 2,5-
N-NH N=N HN-N I/N.,H FN., r
I/.. \ (. ....f.m ( \I
Z....NH ....N N.... ....NH HN NH HN N
Z Z Z ....Z.... ....Z....
(84) 2,3- (85) 2,5- (86) 4,5- (87) 2,3- (88) 2,5- (89) 4,5-
Scheme 8 Dihydroazoles (Z = 0, S or NR)
(c) Tetrahydro compounds in which the ring contains no double bonds (24 systems;
Scheme 9).
CNH C NH NH HN\
z) C ....'NH ( ....NH
Z Z Z
(90) (91) (92) (93)
n HN-NH HN-NH tN.,H
HN.... ....NH (z) ( ....'NH HN, NH
Z Z Z""
(94) (95) (96) (97)
Scheme 9 Tetrahydro compounds (Z = 0, S or NR)
Structure of Five-membered Rings with Two or More Heteroatorns
5
4.01.2 THEORETICAL METHODS
4.01.2.1 The MO Approximation
In the simpler MO approximations the 1T- electrons are assumed to move independently
in MOs that can be represented as linear combinations of the atomic p-orbitals. When
these MOs are used as the basis for an approximate wave mechanical calculation, the energy
of the MOs and the distribution of the 1T- electrons in each depend on the values of certain
integrals. These integrals are of two types, termed Coulomb integrals and resonance
integrals; both are negative and have the dimensions of energy. The Coulomb integrals are
characteristic of an atomic 1T- orbital in a given molecular environment and are a measure
of the effective electronegativity of that atom toward 1T-electrons. The resonance integrals
are characteristic of a 1T- bond between two atoms and are a measure of the stability that
a localized 1T- bond would have if formed between them. Neither the Coulomb integrals
nor the resonance integrals are usually directly evaluated by integration; the calculations
are based on certain simplifying assumptions concerning the relative values of the different
Coulomb integrals and the relative values of the different resonance integrals.
For unsubstituted aromatic hydrocarbons all the carbon atoms are assigned the same
Coulomb integral (a) and all C-C bonds are assigned the same resonance integral (ß).
In heteroaromatic molecules the approximate Coulomb integral for the heteroatom is
expressed in terms of a and ß, the standard integrals associated with the carbocyclic aromatic
hydrocarbons. There has been considerable variation in the Coulomb integral used for the
neutral nitrogen atom as typified by that in pyridine; the values used have ranged from
a + 2.0ß to a + 0.2ß, the lower values being the more recent. The Coulomb integral for
nitrogen is considered to depend considerably on the chernical environment, and the
approximate values are discussed under the compounds concerned. It has been suggested
that a different Coulomb integral should be used for the nitrogen atom of pyrrole in simple
Hückel-type MO calculations, giving a value of a + 1.9ß. Non-empirical calculations indicate
that the 1T-electrons of the pyrrole anion are almost evenly distributed over all five atoms,
so the carbon and nitrogen atoms should be assigned the same Coulomb integrals in the
simple MO treatment.
The Coulomb integral (ac) of the carbon atoms adjacent to the heteroatom (more
electronegative than the carbon atoms in benzene because of the inductive effect of the
heteroatom as relayed through the 0'- bonds) is accommodated by making the appropriate
Coulornb integrals more negative than a. This increases the agreement between the simple
MO calculations and those based on elaborate, non-empirical treatments. It is convenient
to e press the value of ac in terms of a and ß, and so the Coulomb integrals used for the
heteroatom and for the adjacent carbon atoms may be defined by two parameters hand
h' according to equations (1) and (2).
Heteroatom
Adjacent carbon atoms
ax==a +hß
ac==a+h'ß
(1)
(2)
The resonance integral of the 1T- bond between the heteroatom and carbon is another
possible parameter in the treatment of heteroatomic molecules. However, for nitrogen
compounds more detailed calculations have suggested that this resonance integral is similar
to that for a C-C bond and moreover the relative values of the reactivity indices at different
positions are not very sensitive to change in this parameter.
Theoretical reactivity indices of heteroaromatic systems distinguish reactivity toward
electrophilic, nucleophilic and homolytic reactions.
4.01.2.2 Electron Densities
The 1T-electron density refers to the electron density at a given carbon atom obtained
by summing the contributions from all the filled molecular orbitals. Electrophilic attack
occurs where this density is highest, and nucleophilic attack where it is lowest; 1T-electron
densities are not dominant in determining the orientation of homolytic substitution.
Values for the 1T-electron densities in imidazole and two related ions are given in Figure
1. The 1T-electron densities in the conjugate acid of imidazole are greater at the 2-position
ó
Structure of Five-membered Rings with Two or More Heteroatorns
than at the 4-position and thus bear no relation to the chemical reactivity, as nucleophiles
attack at the 2-position and electrophiles at the 4-position. The res'!lts for the neutral
molecule and the conjugate base are more satisfactory; however, the uncertainty in these
values, estimated as 0.02 units, exceeds the difference between the 7T-electron density at
the 2-position and that at the more reactive 4(5)-positions in all three reactive forms of
imidazole.
t
1113 [ 7 N 1.1U1 0'990 ( NH 1 20( N 1 08DI ()31
r r 'r 'r
1.112 )1.100 )0,997 _ )1.207 1.109 "N1.162
N N N N
H H 1.197 H
I ó50 1,512 1.656
Fif-lure 1 The 1T-electron densities in imidazole, its conjugate acid and base, and pyrazole
Results for the neutral pyrazole molecule show a considerable spread. The 71'- electron
and total (71' + (J') densities predict electrophilic substitution at the 4-position as found.
Results for thiazole also agree with experimentally determined electrophilic and nucleophilic
reactivity.
The 7T-electron distribution in benzimidazole favors substitution at the 4-position in the
conjugate acid, at the 4- and 5-positions in the neutral molecule, and at the 2-position in
the conjugate base. These results do not explain the apparently exclusive substitution at
the 5-position in nitration. There is thus no general agreement between the 7T-electron
distribution and the chemical reactivity.
Values for 7T-electron density on nitrogen atoms generally indicate the position of
electrophilic attack, e.g. at the 3-position of 1,2,3-thiadiazoles.
The net (J'-charge on ring hydrogen atoms can also be significant; for thiazole the order
of decreasing acidity of the hydrogens is H-2 5 > 4, consistent with experiment.
4.01.2.3 Frontier Electron Densities
An alternative approach is in terms of frontier electron densities. In electrophilic substitu-
tion, the frontier electron density is taken as the electron density in the highest filled MO.
In nucleophilic substitution the frontier orbital is taken as the lowest vacant MO; the
frontier electron density at a carbon atom is then the electron density that would be present
in this MO if it were occupied by two electrons. Both electrophilic and nucleophilic
suhstitution thus occur at the carbon atom with the greatest appropriate frontier electron
density.
The significance of frontier electron densities is limited to the orientation of substitution
for a given aromatic system, but this approach has been developed to give two more cornplex
reactivity indices termed superdelocalizabilities and Z values, which indicate the relative
reactivities of different aromatic systerns.
4.01.2.4 Localization Energies
Localization energies refer to the difference between the 71'- electron energy in the isolated
molecule and that in the related system where the carbon atom at the point of substitution
has been rernoved from the cyclic conjugation by bonding with the reagent. The Wheland
structure, originally considered to be a suitable model of the transition state, generally
corresponds to an intermediate. Nevertheless, the relative stabilities of the different transi-
tion states in the same molecule appear to be in the same order as the calculated localization
energies, and this reactivity index is probably the best guide to the orientation of substitution
in aromatic and heteroaromatic systems.
The localization energies for the neutral diazoles were originally calculated on the
assumption that the Coulomb integrals for the two nitrogen atoms are equal; for the neutral
diazoles these results may therefore require sorne modification. For the neutral molecule
and conjugate acid of pyrazole the orientation of electrophilic attack is correctly assigned
to the 4-position. For the neutral molecule and conjugate acid of imidazole the orientation
of electrophilic attack is correctly assigned to the 4(5)-positions. If the Coulornb integral
Structure of Five-membered Rings with Two or More Heteroatorns
7
of the nitrogen atoms in the conjugate base of irnidazole is set equal to that for the carbon
atoms, then the localization energies for the 2- and 4,5-positions become equal. In reactions
of the conjugate base of imidazole the orientation appears to depend on the reagent, but
there is probably little difference between the reactivity of the 2- and 4-positions.
The localization energies for electrophilic substitution in benzimidazole predict that all
three reactive forms should undergo substitution in the 4-position. This does not explain
the formation of the 5-nitro compound or that of the 2-deutero compound. It is doubtful
whether any electrophilic substitution occurs preferentially in the 4-position.
The calculation of localization energies in heteroaromatic systems derived from alternant
hydrocarbons has been simplified by Dewar and Maitlis (57JCS2521). This approach has had
considerable success; the results provide a somewhat empirical index of reactivity.
4.01.2.5 SemiempiricaI Methods
The simple, or Hückel based, molecular orbital theory described above frequently
provides useful quantitative insights but cannot be used reliably in a quantitative sense.
For this purpose it is necessary to use a method which takes account of all the electrons
as well as their mutual repulsions. This is usually done within the framework of a formalism
developed independently by Roothaan (51MI40100) and Hall (51MI40101). Procedures
of this kind are variously known as RH, non-empirical or, rnost frequently, ab initio
molecular orbital calculations. Here, once the forms of the atomic orbitals, i.e. basis sets,
are specified, no further approximations are made. While numerous alternative basis sets
are possible, most practical applications of ab initio MO theory now utilize one of the
carefully optimized expansions of Gaussian functions introduced by Pople and his co-
workers (74MI40100). The simplest (and least accurate) is designated STO-3G, while the
most complex in comrnon use is designated 6-31G. Fortunately, even the simplest basis
sets seem to give excellent descriptions of the electron distribution, especially when
expressed in terms of integrated spatial populations (80MI40101). Palmer, in particular, has
presented electron distribution data in many heterocyclic systems (78JST(43)33). Unfortu-
nately, apart from those special cases in which species having the same numbers of each
tÿpe of bond are cornpared, the quantitative estirnation of relative energies in ab initio
theory usually requires a basis set of at least 3-21G quality. Moreover, for reliable results
the geometries of the species being compared must be calculated at the ab initio level. The
expense inherent in the use of the more complex basis set, as well as that of geometry
optimization, has tended to limit the most detailed studies to rather small heterocyclic ring
systerns (77JA7806, 78JA3674, 83JA309).
The major bottleneck in ab initio calculations occurs in the computation and storage of
the enormous number of electron-repulsion integrals involved. Early efforts by Pople and
co-workers to reduce this problern led to the CNDO, INDO and NDDO approximations
(70MI40100). Although once popular, these methods in their original forms are now largely
superseded. Dewar has implemented modifications of the two latter approximations which
have proven to be very successful. The most recent versions are designated MINDO /3
(75JA1285) and MNDO (77JA4899) respectively. Since their inception these methods have
been somewhat controversial since they were parameterized to reproduce not the results
of the ab initio methods from which they are derived (as was done in CNDO/2 and INDO),
but experimental geometries and energies. These semi empirical MO procedures therefore
appear to involve several theoretical inconsistencies which have yet to be fully resolved
(B-77MI40100). Nevertheless, judged on purely empirical criteria, they seem to work well.
Indeed they are frequently comparable in accuracy (relative to experiment) to ab initio
calculations using moderately sized basis sets and much better than those using minimal
basis sets (79JA5558). Semiempirical procedures of this kind have been used to study the
reactions of various five-rnembered heterocyclic systems (77JCS(P2)724).
4.01.2.6 Other Applications of Theory
Applications of MO methods to such diverse problems as aromaticity, tautomeric structure,
dipole mornents, and UV, NMR and PE spectroscopy are discussed in various monograph
chapters.
8
Structure of Five-membered Rings with Two or More Heteroatorns
4.01.3 STRUCTURAL METHODS
4.01.3.1 X-Ray Diffraction
Details of bond lengths and bond angles for all the X-ray structures of heterocyclic
compounds through 1970 are listed in 'Physical Methods in Heterocyclic Chemistry', volume
5. This cornpilation contains many examples for five-membered rings containing two
heteroatorns, particularly pyrazoles, imidazoles, isoxazoles, oxazoles, isothiazoles, thiazoles,
1,2-dithioles and 1,3-dithioles. Further examples of rnore recent rneasurements on these
heterocyclic compounds can be found in the rnonograph chapters.
For compounds with three or four heteroatoms in the ring the number of rneasurements
is much fewer, and these are summarized in Table 1.
4.01.3.2 Microwave Spectroscopy
Microwave spectra provide a rich source of rninute details of molecular structures. They
tell us about the rnolecular geometry because the spectra are primarily analyzed in terms
of the accurate average values of the reciprocals of the three moments of inertia. This
generally gives at once the general molecular conformation and sorne precise structural
features may emerge. To obtain a cornplete structure it is necessary to rneasure the changes
in moments of inertia which accompany the isotopic replacements of each atorn in turn
(74PMH(6)53).
From accurate measurements of the Stark effect when electrostatic fields are applied,
inforrnation regarding the electron distribution is obtained. Further information on this
point is obtained from nuclear quadrupole coupling effects and Zeeman effects (74PMH(6)53).
Microwave studies also provide important information regarding molecular force fields,
particularly with reference to low frequency vibrational modes in cyclic structures
(74PMHl6)53).
4.01.3.2.1 Molecular geometry
Structural parameters in aromatic five-membered rings are shown in Table 2. All the
C-H distances are near 107.5 pm, close to the C-H link in ethylene. With heteroatoms
at adjacent ring positions, the C-H groups are displaced frorn the bisector of the ring
angles toward the adjacent heteroatorn (74PMH(6)53).
The N - H bond lengths in pyrazole and imidazole (99.8 pm) are a little shorter than
those found in dimethylarnine. Delocalization in pyrazole, imidazole, 1,2,3-triazole and
1,2,4-triazole is sufficient to bring the hydrogen attached to nitrogen into the plane of the
other atorns. The N - H bond in pyrazole does not lie in the bisector of the ring angle (as
is required by syrnmetry in pyrrole), but is displaced by around 50 toward the second
nitrogen (74PMHl6)53).
The ring angles at C and N are usually 108:1::5 0 , but drop nearer to 90 0 at sulfur and
seleniurn.
Minor variations in the bond lengths reflect variations in the double bond character and,
for exarnple, suggest larger de localization in 1,3,4-thiadiazole than in 1,3,4-oxadiazole
(74PMHl6)53). In thiazole the geometry of the SCN part of the ring resembles the
corresponding part of 1,3,4-thiadiazole, while the remaining part of the ring resembles the
corresponding thiophene.
Microwave spectroscopy distinguishes readily between possible tautomeric forms of 1,2,3-
and 1,2,4-triazole, which are both in the IH-form. In tetrazole both the IH-and 2H-forms
are detected (74PMH(6)53).
Dipole rnoments can also be obtained from the microwave spectral data (74PMH(6)53) and
available values are given in Table 2.
4.01.3.2.2 Partially and fully saturated ring systems
Relatively few such heterocyclic systems have been studied by rnicrowave spectroscopy;
sorne data are included in Table 2. In 1,3-dioxolane the bent form is more stable than the
Structure of Five-membered Rings with Two or More Heteroatorns
9
Table 1 X-Ray Structures of Compounds with Five-membered Rings and Two, Three or Four Heteroatoms'
Ring
C 3 N z
C Z N 3
CN 4
C 3 NO
C 3 NS
C 3 NO
C 3 NS
CzNzO
CzNzS
CN 3 0
CN 3 S
C 3 0 Z
C 3 0S
C 3 S Z
C Z 0 3
C Z S 3
CzOzS
CzNS z
CzNS z
CzNOS
Ring position
2 3 4 5
N N
1
N N
N N N
N N N
N N N N
o N
S N
o N
S N
o N N
o N N
o N
o N N
S N N
S N N
S N
S N N
o N N N
S N N N
S N N
o 0
o S
o S
S S
S S
000
S S S
o S 0
S S N
S S N
o S N
o S N
o N S
o S N
Examples of compounds studied
Pyrazole;b substituted pyrazoles; ð. 1 _ and ð. z -pyrazolines; pyrazolinones;
pyrazolidines; pyrazolidinones
lmidazole;b 4,5-di-t-butylimidazole; histamine dihydrochloride; 2-thio-
hydantoin
1,3-Dimethyl-4-( 1 ,2,3-triazolyl) sulfide; 3-methyl-2-phenyl-1,2,3-triazol-
1-ine-4-thione
1,2,4- Triazole b
5-Amino-2-methyltetrazole;b 5-aminotetrazore monohydrate;b sodium
tetrazolate monohydrateb
5,5' - Biisoxazole;b 3-hydroxy-5-phenylisoxazole;b 3,3' -bi-2-isoxazoline;h
3-hydroxy- 5 -phenylisoxazole; D 3-phenylisoxazolin- 5-ont;b
Methyl 3 - hydroxy-4-phenylisothiazole-5 -sulfonate; dehydromethionine
2,2' -p-Phenylenebis(5-phenYloxazole) 2-(4-pyridyl)oxazo!e;h 2,4-
dimethyl-5 -( p-nitrophenyl)oxazole; 2-oxazolidinone b
Thiamine hydrochloride monohydrate;b rhodanine;b 2-imino-5-phenyl-4-
thiazolidinone b
N- (p-Bromophenyl)sydnone;b 4,4'-dichloro-3,3'-ethylenebis(sydnone)
3 -(2- Aminopyridyl)-5-methyl-1 ,2,4-oxadiazole
N 3-(p-Bromophenyl)-4-methyl-1,2,5-oxadiazole 2-oxide;b 3-( p-bromo-
phenyl)-4-methyl-1 ,2,5 -oxadiazole 5-oxide; b 3,4-diphenyl-1,2,5-
oxadiazole
Monoaryl-1,3,4-oxadiazoles c
5-Acylamino-3-methyl-1,2,3-thiadiazole; 5-phenyl-1,2,3-thiadiazole 3-
oxide
5-lmino-4- phenyl-3 -phenylamino-4 H - 1,2,4-thiadiazoline d
N 3,4- Diphenyl-1 ,2,5 -thiadiazole; 1,2,5 - thiadiazole-3 ,4-dicarboxamide
1,3,4- Thiadiazole; 2,5-diphenyl-1,3,4-thiadiazole b
Mesoionic 3-phenyl-1,2,3,4-oxatriazole-5-phenylimine; mesoionic 3-
phenyl-1 ,2, 3,4-oxatriazol-5 -one
5- Phenyl-1 ,2,3 ,4-thiatriazole; 5 -amino-1 ,2,3 ,4-ihiatriazole; 5-phenyl-
1,2,3,4-thiatriazole 3-oxide
N 2-Acetyl-5-chloro- 2H -1 ,2,3,5-thiatriazolo[ 4,5-a ]isoquinoline 5-oxide
Bis(dioxolane); ethylene carbonate; cís-2+butyl-5-carboxymethyl-1,3-
dioxolan-4-one; 2-methyl-1,3 -dioxolan-2-ylium perchlorate
3,3-Diphenyl-1,2-oxathiolane 2,2-dioxide; 5H-1,2-benzoxathiole 2,2-
dioxide
Ch oles tan -4-0 ne- 3 -spiro(2,5 -0 xa thiolane)
1,2-Dithiolanc-4-carboxylic acid;b 3-phenyl-1,2-dithiolylium iodide;b 4-
methyl-l,2-dilhiole-3-thione b
Bis-1 ,3-dithiol-2-Yl 4,5-dioxo-2-thioxo-1,3-dithiolane;b 1,3-dilhiolane-
2-thione 5-oxide; tetrathiafulvalene c
trans- 5 -Anisyl-3 -methoxycarbonyl-l ,2,4-trioxolane!
1,2,4- Trilhiolane-3,5-dione diphenylhydrazone g
1,3,2-Dioxathiolane 2,2-dioxide;h 1,3,2-dioxathiole 2,2-dioxide h
2,4,6- Tri-t-butyl-7 ,8,9-dithiazabicyclo[ 4.3 .O]nona-l (9),2,4-triene i
5-Amino-1,2,4-dithiazolin-3-one ('Rhodan hydrate');; 5-amino-l,2,4-
dithiazoline-3-thione ('Xanthane hydride');k 3,5-diamino-1,2,4-
dithiazolium chloride ('Thiuret hydrochloride')1
2,4-Dioxo-2-( 4-methylphenyl)-1 ,2,3-oxathiazoline;m 1,2,3-oxathiazolo-
[5,4-d][1,2,3]oxalhiazole 2,2,5,5-telraoxide n
6,1 Ob- Dihydro-3 -(2,2,6,6-telramethylcyclohexyliden)-1 ,2,4-oxathiazolo-
[5,4-a ]isoquinoline o
4- Phenyl-1,3 ,2-oxathiazolin -5 -one P
2- Trichloromethyl-5-phenyl-ð. 4 -1,3,4-oxathiazoline Q
· Unless otherwise indicated data are taken from the appropriate chapter of 'Comprehensive Heterocyclic
Chemistry'. b Data taken from (nPMH(5)1), which gives references to the original literature. c X-Ray powder
data; cf. Chapter 4.23. d (78CC652). e (71CC889). ! (70ACS2137). g (7IJCSlBJ415). h (68JA2970). i (80AX(B)1466). j (66ACS754).
k (63ACS2575, 63AXI157). I (66ACSI907). m (71TL4243). n (80MI40100). 0 (78AO!E)455). P (72023). Q (8IJCSlPI)2991).
Table 2 Structure Parameters in Five-membered Rings from Microwave Spectra ......
a
4 ! 0 3
'\
, ....., "-" b
V)
...
....
::::
Bond lenf{th (pm).'" Anf{le (0)" Dipole moment <".\
...
::::
Compound a b c d e a ß y Ô ê (10 -3() C m)a
c :!1
0 141.6 133.1 134.9 135.9 137.3 111.9 104.1 113.1 106.4 104.5 7.37
/N c:;
N I
H
[) d
c::r-
(137.8) (132.6) (134.9) (136.9) (135.8) (105.4) (111.3) (107.2) (106.3 ) (109.8) 12.8
N \:).,
H
S.
[
c OQ
'"
/N 5.97
.
N ...
H ;:s-<
N c
Z
c
135.9 132.3 135.9 133.1 132.4 114.6 102.1 110.2 llO.1 103.0 9.07 c
/N ....
N
H
f
I!
N.... /N 135.1 128.4 132.4 133.4 131.0 7.31
N
H
s::.
...
N-N g c
\\ (134.5) (l28.3) (134.7) (135.1) (129.0) {I 12.2) (106.9) (105.3) 17.05 '"
/N
N
H
h
0 9.21
/N
0
0
ON 8.67
S/
() 0
139.5 129.3 135.7 137.0 135.3 103.9 115.0 103.9 108.1 109.1 5.00
0 (J}
() 0 >:::
137.2 130.4 172.4 171.3 136.7 110.1 115.2 89.3 109.6 115.8 5.37
S
+ í :!1
J:. Me
(133.4) (131.3 ) (138.9) (111.3) (103.8) (114.4) 21.12
Õ O/N I
N . <:::t'
Z J
O (138.0) (130.3) (141.8) (106.1) (103.2) (114.2) 5.44
n c .
N.... ,.,N 142.1 130.0 138.0 138.0 130.0 109.0 105.8 110.4 105.8 109.0 11.28 '"
0 s.
...
n 0
141.7 132.7 163.0 163.0 132.7 113.8 106.5 99.4 106.5 113.8 5.27
N, /N c
S c
...
N-N c
I() 139.9 129.7 134.8 134.8 129.7 105.6 113.4 102.0 113.4 105.6 10.14
0
(
...
136.6 129.0 169.2 168.9 136.9 114.0 111.2 92.9 107.8 114.2 11.98 c
/N
S ë
N I '"
I( 136.6 131.7 164.9 170.7 131.3 120.1 107.1 92.8 112.3 107.7 1.5
/N
S
fi) c
N, 142.0 132.8 163.1 163.1 132.8 113.8 106.4 99.6 106.4 113.8 5.24 ......
S ......
Table 2 (continued)
Compound
Bond length (pm)".h
b c d
ê
Dipole moment
(10- 30 C m).
Angle (O)h
Y
ß
ô
a
e
a
N-N
()
S
112.2
10.94
130.2
86.4
114.6
130.2
172.1
172.1
112.2
114.6
137.1
Ç5 <
3.97
Co
o
142.8
105.1
105.1
101.7
156.3
156.3
142.8
0\ n
(. /0
o
143.6
99.2
106.2
99.2
3.64
139.5
106.2
99.2
139.5
147.0
143.6
N-S
oAo
135.6
128.6
110.8
121.1
107.9
169.0
176.6
140.2
93.8
106.3
a 1 Å = 100 pm; 1 D = 3.336 X 10. 311 C m. h X-Ray diffraction data are enclosed in parentheses. C Dala taken from (74PMH(6153), which see for references to the original literalure.
d Dipole momenl is concenlration-dependent (cf. Section 4.06.3.2). e Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'. f No bond lengths or angles
given in (74JSP(49)423); calculated values taken from Chapter 4.13. g Bond lengths and angles for 5-bromotetrazole; dipole moment for tctrazole in dioxane. h Measured in benzene;
cf Section 4.16.1.4.1 (i). ' Bond lengths and angles from X-ray data for 4,4' -dichloro-3,3' -ethylenebis(sydnone) (67JA5977); calculated dipole moment for 3-methylsydnone (7lJST(9)32 I).
j Bond lengths and angles from X-ray data for 3-(2-aminopyridyl)-I,2,4-oxadiazole (79AX(B)2256); dipole momenl for 3-methyl-5-phenyl-l ,2,4-oxadiazole (35GI52). k Dipole moment
from (76MI40100). I (74TH40100). m Values calculated from experimentally derived rotational constants; cf Section 4.30.1.3.2. n (nJA6337). 0 Values for 1,3,4-oxathiazolin-2-one
determined from electron diffraction measurements and refined using rotational parameters from microwave spectra; cf Section 4.34.2.3.2.
IV
....
::::
<">
...
::::
::n
c:::
I
c::r-
;:::'
()Q
'"
:ê.
...
;:s-<
c
c
....
õ:)
c
'"
Structure of Five-membered Rings with Two or More Heteroatorns
13
twisted, and pseudorotation occurs. In 1,2,4-trioxocyclopentane the equiljbrium conforma-
tion is twisted, and there is a barrier of 6.3 kJ mol-I opposing pseudorotation (74PMH(6)53).
4.01.3.3 lH NMR Spectroscopy
Proton chemical shifts and spin coupling constants for ring CH of fully aromatic neutral
azoles are recorded in Tables 3-6. Vicinal CH-CH coupling constants are small; where
they have been measured (in rather few cases) they are found to be 1-2 Hz.
Table 3 t H NMR Spectral Data for Ring Hydrogens of Nitrogenous Azoles: (a) NH Derivatives
I H Chemical shifts Coupling
(8, p.p.m.) constants,
Compound H-2 H-3 H-4 H-5 1(Hz) Solvent Ref.
Pyrazole 7.61 7.31 7.61 2.1 71PMH(4)121,
B-73NMR
Imidazole 7.86 7.25 7.25 1.0 CDCl 3 71PMH(4)121,
B-73NMR
1,2,3-Triazole 7.75 7.75 CDCl 3 "
1,2,4- Triazole 7.92 8.85 HMPT 71PMH(4)121,
B-73NMR
Tetrazole 9.5 DzO
a Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
Table 4 t H NMR Spectral Data for Ring Hydrogens of Nitrogenous Azoles: (b)
N(l)-Methyl Derivatives
t H Chemical shifts" (8, p.p.m.)
Compound H-2 H-3 H-4 H-5
Pyrazole h . c 7.49 6.22 7.35
Imidazole h 7.47 7.08 6.88
1,2,3- Triazole b 7.74 7.59
1,2,5-Triazole b 7.75 7.75
1,2,4- Triazole h 7.94 8.09
1,3,4-Triazole b 8.23 8.23
1,2,3,4- T etrazole d 8.98
1,2,3,5- Tetrazole d 8.60
a Spectra measured in CDCI 3 .
b Data taken from (B-73NMR) which contains references to the original literature.
c Coupling constants are h 4 = 2.0 Hz; 13 5 = 0.7 Hz; 14 5 = 2.3 Hz.
d ...
Value for N-methyl derivative; cf. Chapter 4.13.
Table 5 t H NMR Spectral Data for Ring Hydrogens of Azoles Containing Oxygen
Compound
t H Chemical shifts (8, p.p.m.)
H-2 H-3 H-4 H-5 Solvent
8.14 6.28 8.39 CS z
7.95 7.09 7.69 CCl 4
8.2 8.7 C 6 H 6
8.19 8.19 CHCl 3
8.73 8.73 CDCl 3
Isoxazole"
Oxazole b
1,2,4-0xadiazole c
1,2,5-0xadiazole d
1,3,4-0xadiazole c
: Coupl!ng constants: 1 3 . 4 = 1. 78 Hz; 13.5 = 0.27 Hz; 14.5 = 1.69 Hz (74CJC833).
Couplmg constants: 1 Z . 4 = 0 Hz; lz.5 = 0.8 Hz; 1 4 . 5 = 0.8 Hz.
c (76AHC(2ü)65, 64HCA942).
d Section 4.22.1.3.1.
c Section 4.23.2.2.1.
For the NH azoles (Table 3), the two tautomeric forms are usually rapidly equilibrating
on the NMR timescale (except for triazole in HMPT). The N-methyl azoles (Table 4) are
'fixed'; chemical shifts are shifted down field by adjacent nitrogen atoms, but more by a
'pyridine-like' nitrogen than by a 'pyrrole-like' N-methyl group.
14
Structure of Five-membered Rings with Two or More Heteroatorns
Table 6 I H NMR Spectral Data for Ring I Iydrogens of Azoles Containing Sulfur
Compollnd
1 H Chemical shifts (8, p.p.m.)
2 3 4 5
Solvent
Isothiazole"
Thiazole b . c
1,2,3- Thiadiazolé
8.54
7.26 8.72
7.98 7.41
(AB multiplet
centered at 8.80)
9.90'
CCl 4
CDCI 3
CCl 4
8.88
1,2,4- Thiadiazole
1,2,5-Thiadiazole h
1,3,4- Thiadiazole f
8.66 d
8.70
8.70
7.55
7.55
CC1 4
CDCl 3
Coupl ng constants: J 3 . 4 = 11.66 Hz; J 3 ,5 = 0.15 Hz; J 4 ,5 = 4.66 Hz.
Couphng constants: J 2 ,4 = 0 Hz; J 2 . S = 1.95 Hz; J 4 ,5 = 3.15 Hz.
" (79HCI34-1167, 79HCI34-1173).
Ù Value given for 5-phenyl derivative (SOJOC3750).
C Value given for 3-phenyl derivative (74JOC962).
I (7 IJAP2 1). g (7SJOC2487). b (64DlS2690).
Cornparison of the relevant data shows that an adjacent oxygen (Table 5) and especially
a sulfur atom (Table 6) induce lower field shifts than either type of nitrogen atom.
The effects of anion and cation formation on l H chemical shifts can be assessed from
data in Tables 7 and 8. Anion formation always results in shifts to higher field; however,
the effect is relatively modest except for the 4-position of pyrazole because in all other
cases the adjacent nitrogen lone pair partially cancels the shift. Conversely, in the cations
(Table 8), the down field shift is especially large for the CH groups next to nitrogen. The
coupling constants appear to be significantly greater in the cations.
CompO!wd
Table 7 IH NMR Spectral Data for Ring Hydrogens of Azole Anions
1 H Chemical shifts (8, p.p.m.)
2 3 4 5
Solvent
Ref.
eN
N
7.35
6.05
7.35
KOD/D 2 0 68JA4232
eJ
N
7.80
7.21
7.21
71PMH(4)121
I/
:-,
N
7.86
7.86
NaOD/D 2 0 "
N
L(
N
8.19
8.19
NaOD/D 2 0 7lPMH(4)121
N-N
(-;
N
8.73
71PMH(4)121
" Data taken from Chapter 4.11.
Relatively few data are available on the IH NMR spectra of azolinones and related
thiones and irnines (Table 9).
Some available data on I H NMR spectra of non-aromatic azoles containing two ring-
double bonds are given in Table 10. Here there is no ring current effect and the chemical
shifts are consequently more upfield.
Tables 11 and 12 give some available chemical shifts for azolines and azolidines, respec-
tively. Unfortunately data for many of the parent compounds are lacking, often because
the compounds themselves are unknown.
Structure of Five-membered Rings with Two or More Heteroatorns
15
Table 8 I H NMR Spectral Data for Ring Hydrogens of Azole and Related Cations: Two Heteroatoms
1 H Chemical shifts (8, p.p.m.) Coupling constants, J (Hz)
Compound H-2 H-3 H-4 H-5 Solvent 2,4 2,5 3,4 3,5 4,5
Pyrazolium a . b 8.57 6.87 8.57 DMSO-d 6 2.9 2.9
Imidazolium c 8.6 7.5 7.5 H 2 SO 4 1.4 1.4 2.4
Isoxazolium i 9.18 7.26 9.01 D 2 S0 4 2.8 1.9
Isothiazolium a 9.1 7.9 9.6 H 2 SO 4 2.7 0.6 5.6
Thiazolium d 9.55 8.23 7.93 0.70 1.55 3.10
1,2-0xathiolylium e 7.64
1,2-Dithiolylium C 6.71 1.44 -0.26 4.9 4.9
1,3- Dioxolylium f 10.4
1,3-0xathiolylium g 8.12
1,3-Dithiolylium b 11.65 9.67 9.67 2.0 2.0
a Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
b Values given for 1,2-dimethylpyrazolium.
C Data taken from (71PMH(4)\21) and (B-73NMRl) which see for references to the original literature.
d (66BSF3524).
e Value given for 5-methyl-3-(2-oxo-1-propyl)-I,2-oxathiolylium perchlorate.
f Value given for 1,3-benzodioxolylium fluorosulfonate.
g Value given for 2,5-diphenyl-l,3-oxathiolylium perchlorate.
h (74JOC3608). i (83PC40100).
Table 9 IH NMR Spectral Data for Ring C-H of Azolinones
I H Chemical shifts (8, p.p.m.)
Compound H-2 H-3 H-4 H-5
Pyrazolin -3 -one b 5.45 7.22
Imidazolin-2-one c 6.50 6.50
Pyrazoline-3-thione b 6.23 d
1,2,4- Triazoline-3-thione 8.20
Pyrazolin-3-imine f 5.46
1,2,4- Triazolin - 5 -imine 2.05
å 2 -1,3 ,4-0xadiazqline- 5 -thione g 8.88
Isothiazolin-3-one ' 6.05 7.98
1,3- Thiazolin-2-one j . k -1.14 3.21 3.7
Isothiazoline- 3 - thio n e I.m 6.90 8.25
1,3- Thiazoline-2-thione k . n 6.68 2.7 3.05
1,3- Thiazolin-2-imine o . P 3.03 3.37
Solvent
CDCl 3
DMSO
CDCl 3
CDCl 3
DMSO-d 6
DMSO-d 6
C 3 D 6 0
CDCl 3
a Values given for 1,2-dimethylpyrazolin-3-one; J II . 5 = 3.5 Hz. b (76AHC(SI)\). C Data taken from (B-73NMR) which
contains references to the original literature. d Values given for 1,5-dimethyl-2-phenylpyrazoline-3-thione.
e Values given for 1,5-dimethyl-2-phenylpyrazolin-3-imine. f (nBsF2807). g Section 4.23.2.2.1. h Values given for
2-melhylisothiazolin-3-one; J 4 . 5 = 6.0 Hz. i (71JHC571). jCoupling constants: J 3 . 4 = 2.5 Hz; J 3 . 5 = 1.1 Hz; J 4 . 5 =
5.3 Hz. k (79HC(34-2)385). I Values given for 2-methylisothiazoline-3-thione; J 4 . 5 = 6.0 Hz. m (80CPB487). n J 4 . 5 =
4.6 Hz. 0 Values given for 2-ethoxycarbonylimino-3-ethyl-å 4 -1,3-thiazoline. P (79HC(34-2)26).
Proton-proton coupling constants of benzo rings of benzazoles can illuminate the bonding
in such compounds. Thus, comparison of the J values for naphthalene with those for
benzotriazoles of different types (Table 13) shows evidence of bond fixation, particularly
in the 2-methyl derivative (98) (71PMH(4)121).
o: :Y\
NMe
::::,... ,..., /
N
(98)
4.01.3.4 13e NMR Spectroscopy
Chemical shifts for aromatic azoles are recorded in Tables 14-17. As for the proton
spectra, fast tautomerism renders two of the chemical shifts equivalent for the NH derivatives
(Table 14). However, data for the N-methyl derivatives (Table 15) clearly indicate that the
16 Structure of Five-membered Rings with Two or More Heteroatorns
Table 10 IH NMR Spectral Data (8, p.p.m.) for Ring Hydrogens of Non-aromatic Azoles with Two Ring Double
Bonds (83UP40100)
4H-Imidazoles
Me 1.3S Ph Me 1.40
6.3Ö Me 7.30 Ph 5n Me
7.35 r N 1. N r N+
7.48 /.
N N" Me N '0-
2.22
1.16 2 IS 1.63 2.35 EtJ.M"."
M'tr.. MD'
;N +;N +;N
Me Me N Me N
3.00 I 1.93 I
Me 4.16 O.
Ph Ph
t N Me 23t Me t N Me
8.38 X 1.56 + X 2.0
N Me N CH 2 CH 3 Ph Me
1.88 0.72 Me 4.0
Me 1.58 H 5.17 1.31 Me
NCt N Et2NtN MX N
) 7.60 ;\ +;\
H 2 N N Et 2 N N NEt2 Me N Me
2.20 I
O.
3H-Pyrazoles
4H-Pyrazoles
2H-Imidazoles
carbon adjacent to a 'pyridine-like' nitrogen shows a chemical shift at lower field than that
adjacent to a 'pyrrole-like' N-methyl group (in contrast to the H chemical shift behavior).
In azoles containing oxygen (Table 16) and sulfur (Table 17), the chemical shifts are
generally at lower field than those for the wholly nitrogenous analogues, but the precise
positions vary.
Azolinone derivatives and the corresponding thiones and imines are listed in Table 18;
only substituted derivatives have been measured frequently. The 13C chemical shifts of
non-aromatic azole derivatives are given in Tables 19-21; relatively few data are available
and these are generally for substituted derivatives rather than for the parent compounds.
4.01.3.5 Nitrogen NMR Spectroscopy
Available data are recorded in Table 22. In azoles the chemical shift of a 'pyridine-like'
nitrogen atom is around -125 p.p.m. in N- methylimidazole or oxazole. Additional nitrogen
atoms in the ring cause small upfield shifts if they are non-adjacent, but sizable down field
shifts for adjacent nitrogen atoms. Adjacent ring oxygen gives a large downfield shift, but
the effect of ring sulfur is less if adjacent.
A 'pyrrole-like' nitrogen in a ring N-methyl group gives a peak around -220 p.p.rn. if
adjacent to two carbon atoms; one or two neighboring nitrogens shift the peak down field
by about 40 and 90 p.p.m., respectively.
4.01.3.6 UV Spectroscopy
4.01.3.6.1 Parent compounds
In general, aza substitution (replacement of cyclic CH by N) has little effect on UV
spectra (Table 23). Typically, aza analogs of pyrrole show Åmax at 217 nm or lower with
log ê ca. 3.5, whereas aza analogs of thiophene show Åmax at 230-260 nm with log ê ca. 3.7
(Table 23); insufficient data are available for aza analogs of furan to generalize but these
compounds appear to have maxima below 220 nm.
Table 11 IH NMR Spectral Data for Ring Hydrogens of Azolines (Non-aromatic Azoles with One Ring Double Bond)
1 H Chemical shifts (8, p.p.m.) Coupling constants,
Compound Substituents H-1 H-2 H-3 H-4 H-5 Solvent J(Hz)
Pyrazole ..,
::::
2,3-Dihydro- a 1,2,3-trimethyl- 2.55 2.60 1.71 4.60 3.65 CDCl 3 3,5 = 1.8; 4,5 = 1.8 r'\
12'
4,5-Dihydro-3H- a 4.27 1.46 4.27 Neat
4,5-Dihydro- a 5.33 6.88 2.65 3.31 CDCl 3 3,4 = 1.4; 4,5 = 9.8
1,2,3-Triazole :!1
4,5-Dihydro- b.d 5.35 4.77 4,5 = 2.0 <::
c.d 5.73 4.60 '"
4,5 = 7.5 I
2i
1,2,4-0xadiazole '"
2,5-Dihydro- . 2,5-dimethyl-3-phenyl- 6.0 2i
4,5-Dihydro- f 5-ethyl-3-phenyl- 5.38 5.64 4,5 = 4.5 '"
1,3,4-0xadiazole
2,3-Dihydro- a 3-benzoyl-5-phenyl- 5.9
-.
Thiazole ()Q
'"
2,5-Dihydro- : 4.79& 3.03& 6.12&
4,5-Dihydro- J 2.26 5.83 6.84 2,4 = 2.2; 4,5 = 8.6
1,3,4- Thiadiazole
2,3-Dihydro- k 2,3,5-triphenyl- 6.38 c
1,2,4-Dioxazole c
..,
2,3-Dihydro- a 3 -carboxymethyl-5 -phenyl- 6.39 I CDCh
1,3,4-Dioxazole
2,3-Dihydro- a 2-benzyl-5-phenyl- 6.20 CDCl 3
1,3,4-0xathiazole
2,3- Dihydro- a 5-methyl- 2-trichloromethyl- 6.30 I CDCl 3 Ii:'
è3
1,2,4-Dithiazole
...
2,3-Dihydro- a 5-phenyl- 5.70 I CCl 4 C
2i
'"
a Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'. b Values given for trans-5-propyloxy-4-methyl-l-(4-nitrophenyl) derivative. c Values given
for cis isomer of compound named in footnote b. d (65CB 1153). e (73BSF2996). f (77JOCI55S). g Value taken from 5,5-dimethyl-â 3 -thiazoline. h Value taken from 2,2,4-trimethyl-â 3 _
thiazoline. i (66BSF3524). j (64MI40100). k (Sl1CS(P1)360). 1 Substituent in this position.
....
-.J
18 Structure of Five-membered Rings with Two or More Heteroatorns
Table 12 'H NMR Spectral Data for Ring Hydrogens of Azolidines (Non-aromatic Azoles without Ring Double
Bonds)
'H Chemical shifts (8, p.p.m.)
Compound Substituents H-2 H-J H-4 H-5 Solvent
Tetrahydro
-pyrazole a 1,2-dimethyl-3-phenyl- 6.51 7.85 6.76 CDCl 3
-thiazole D ,< 5.9 8.2 6.8 7.2
-1,2,4-oxadiazole d 2+butyl- 3,4-diphenyl-5 -thioxo- 5.93
-1,3,4-oxadiazole e 3,4-dimethyl- 4.27 4.27
-1 ,2,4-dioxazole e 3,5-di-n-propyl- 4.63 4,63
-1,3,2-dioxazole e N-alkyl- 3.97 3.97
-1,3,4-dioxazole" 2,5 -di -t-butyl-4-phenyl- 4.96 I 4.58
-1,2,4-dithiazole e 3,4-dialkyl-3 -phenyl- I 4,72
-1,3,2-dithiazole" 2-methyl- I 3.58 3.58
8 (71Tl33), DJ4.5 values are J A . B ,=JA',B=7.61 Hz; J A . B =J A '.B,=4.71 Hz; J s . s =-13.7Hz; J 4 . 4 =-7.2Hz.
c (74JA1465). d (74JOC957). e Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
I Substituent in this position.
Table 13 Proton-Proton Coupling Constants (Hz) in Benzotriazoles 8
(JC N (XN, CD
NMe
/ "",/ Q
N N
H
Compound J 4 . S J S . 6 J 4 ,6
Benzotriazole b 8.3 6.7 1.4
2-Methylbenzotriazole 9.4 3.6 0.5
Naphthalene 8.6 6.0 1.4
a Data taken from (71PMHt4J141) which contains references to the original
literature.
D Rapid tautomerism between 1- and 3-positions occurs.
Table 14 DC NMR Chemical Shifts for Nitrogenous Azoles: (a) NH Derivatives
DC Chemical shifts (p.p.m.)a
Compound C-2 C-J C-4 C-5 Solvent Ref.
Pyrazole 134.6 105.8 134.6 CHzClz
Imidazole 135.9 122.0 122.0
1,2,3- Triazole 130.4 130.4 MezCO
1,2,4-Triazole 147.8 147.8
Tetrazole 144.2
a All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
D Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
C Data taken from (71PMHt4JI21), which contains references to the original literature.
Table 15 Uc NMR Chemical Shifts for Nitrogenous Azoles: (b) NO )-Methyl Derivatives
Compound
DC Chemical shifts (p.p.m.)a
C-2 C-J C-4 C-5 Solvent Ref.
138.7 105.1 129.3 CDCl 3
138.3 129.6 120.3 74JOC357
134.3 125.5 DMSO-d ó D
142.1 DMSO-d ô 74JOC357
151.9 DMSO-d 6 74JOC357
Pyrazole
Imidazole
1,2,3-Triazole
1,2,3,4- Tetrazole
1,2,3,5- Tetrazole
. All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
D Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
Structure of Five-membered Rings with Two or More Heteroatorns
19
Compound
Table 16 l3C NMR Chemical Shifts for Azoles Containing Oxygen"
l3C Chemical shifts (p.p.m.)b
C-3 C-4
C-2
C-5
Solvent
Oxazole
1,3,4-0xadiazole c
1,2,5-0xadiazoles d
150.6
159.5
125.4
138.1
166.3
CDCI 3
139-160
"Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
b All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
C Values given for 5-methoxy-2-methyl derivative.
d 3 -Substituted 4-phenyl derivatives.
Table 17 l3C NMR Chemical Shifts for Azoles Containing Sulfur
l3C Chemical shifts (p.p.m.)"
Compound C-2 C-3 C-4 C-5 Solvent Ref.
Isothiazole 157.0 123.4 147.8 CDCh b
Thiazole 153.4 143.7 119.7 79HC(34-1)76
1,2,3-Thiadiazole 147.3 135.8 CDCh b
1,2,4- Thiadiazole 170.0 187.1 8IJPR279
1,3,4- Thiadiazole
3 -amino-5 -methyIthio- 152.7 152.7 CDCI 3 78BAP291
1,2,3,4- Thiatriazole
5-phenyl- 178.5 CDCh b
" All chemical shiflS expressed in p.p.m. from TMS (original values converted where necessary).
b Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
Table 18 l3C NMR Chemical Shifts for Azolinones
13 C Chemical shifts (p.p.m.)"
Compound C-2 C-3 C-4 C-5 Solvent Ref.
2-Pyrazolin-5-one b
3-methyl-l-phenyl- 156.2 43.0 170.6
3-Pyrazolin-5-one b
2,3-dimethyl-l-phenyl- 156.0 98.1 165.7
Imidazolin-2-one 183.8 44.4 44.4 DMSO-d 6 80CS(15)193
Imidazoline- 2 - thione 164.8 40.3 40.3 DMSO-d 6 80CS(15)193
Tetrazolin-5-one
I-phenyl- 148.7 b
T etrazoline-5 - thione 162.9 b
ð, 4 - Thiazoline-2-thione 118.4 128.9 114.0 CHCI 3 79HC(34-1)388
1,2,3-0xadiazolin-5-imine
3-methyl- 97.3 170.4 80RCR28
ð, 2 -1,3,4-0xadiazolin-5 -one 145.7 155.7 820MR(18)159
ð,2 -1,3,4- Thiadiazoline-
5-thione 157.2 186.4 77JOC3725
1,3 ,4-0xathiazolin - 2-one b
5-methyl- 174.2 158.7
1 ,2,4-Dithiazoline-3 -lhione b
5 -anilino- 209.3 179.1
" All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
b Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
Table 19 l3C NMR Chemical Shifts for Non-aromatic Azoles with Two Ring Double Bonds
(83UP40100)
l3C Chemical shifts (p.p.m.)
Compound C-2 C-3 C-4 C-5
4H-Pyrazoles 178-182 63-68 178-182
3H-Pyrazoles 93-110 125-150 130-170
2H-Imidazoles 101-119 158-165 158-165
4H-Imidazoles 163-181 66-115 180-190
Table 20 DC NMR Chemical Shifts for Azolines (Non-aromatic Azoles with One Ring Double Bond)
DC Chemical shifts (p.p.m.)a
2 G3 4 G5
Compound
Ref.
ð/ -Pyrazoline
A 2 - Imidazoline
I -methyl- 2-methylthio-
A 4 -Imidazoline- 2- thione
I-methyl-
A 2 - Thiazoline
1,3,4- Thiadiazoline
2- benzylamino- 5 -phen yl-5 - tosyl-
A 2 -1 ,3,4-0xathiazoline
2-phenyl- 5 - trichloromethyl-
1,2,4- Dithiazoline
142.9 33.2
165.3 b
161.3
229.4 321.7
151.5
95.9
146.36 d
45.4 80TH40100
54.3 76TL3313
119.8 76TU313
354.7 70CR(CH270)1688
149.5
157.6
156.19< 0
· All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
h No C-4 shift reported.
"Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
d lIe F = 275.7 Hz.
<"Ie:F=15.9Hz.
Table 21 l3C NMR Chemical Shifts for Azolidines (Non-aromatic Azoles without Ring Double Bonds)
l3 C Chemical shifts (p.p.m.J"
2 G3 G4 GS
Compound
Ref.
Imidazoline- 2-thione, I-methyl-
Oxazolidine, cis-4-methyl-5-phenyl-
Thiazole. tetrahydro-
1,3.4- Thiadiazolidine, 2,2-dimethyl-4-phenyl-
5-phenylimino-
1 ,3,2-Dioxazole, tetrahydro-N-alkyl-
1,2,3-0xathiazole, dihydro-N-phenyl, S-oxide
183.2 b 50.4 76TL3313
85.4 60.3 80.3 79MI40100
248.4 245.9 226.9 74CR(C)(279)717
79.2 176.3 80JCS(PI )574
67.6 67.6 0
45.9 70.9 c
· All chemical shifts expressed in p.p.m. from TMS (original values converted where necessary).
b C-4 shift not reported.
C Data taken from appropriate chapter, 'Comprehensive Heterocyclic Chemistry'.
3,4-Diaza
Table 22 ISN NMR Chemical Shifts for Nitrogenous Azoles.. h
Positions of ring lSN Chemical shifts with heteroatom in I-position (p.p.m.)
nitrogen NH NMe 0 S
1 -135 -181
2 -135 -76 +3 -82
1 -173 -221
3 -173 -125 -124 -57
1 -128 -144
2 -60 -15 _35 c
3 -60 -28 -106 d
1 -174 -173 -106
2 -84 -20 -186'
4 -132 -130 -140 -70
1 -128 -132
2,5 -60 -53 +33 -35
1 -222
3,4 -82 -82 -10
1 -106 -159
2 -15 -14
3 -25 +9
4 -106 -54
1 -99
2 -4
3 -43
5 -69
Nitrogen
position (s)
2-Aza
3-Aza
2,3-Diaza
2,4-Diaza
2,5-Diaza
2,3,4-Triaza
2,3,5- Triaza
· Chemical shifts expressed in p.p.m. referred to internal MeN0 2 .
h Data taken from (B-73MI40100) or (SIMI40100), which contain references to the original literature.
C Value for 3-methylsydnone (SOOMR(13)274).
d Value for 5-acetyl-3-methylsydnonimine (SOOMRI13)274).
· Value for 2-amino-5-methyl-l,3,4-thiadiazole (7SH(11)121).
Structure of Five-membered Rings with Two or More Heteroatoms
21
Relatively few data are available for protonated cationic species, but from what there
are it appears that protonation has little effect on the position and intensity of the absorption.
4.01.3.6.2 Benzo derivatives
Benzo derivatives show at least two, and up to seven, maxima in the range 200-320 nm
(Table 24). The longest wavelength maximum occurs at 275-315 nm and generally at rather
longer wavelengths for the sulfur derivatives than for their N or 0 analogues, and also for
the benzo[c] compared with the benzo[b] derivatives.
Table 23 UV Absorption Maxima for Azoles a
4 3
S02
Z
1
Additional Z=NH Z=O Z=S
nitrogen atoms Åmax (nm) (log e) Åmax (nm) (log e) Åmax (nm) (log e)
2 210 (3.53) 211 (3.60) 244 (3.72)
3 207-208 (3.07) 240 207.5 (3.41),233 (3.57)b
end absorption
2,3-di 210 (3.64) 211 (3.64),249 (3.16), 294 (2.29t
2,4-di 216.5 (3.66) 229 (3.73)
2,5-di 220 250 (3.86), 253 (3.87),257 (2.83), 260 (3.68)d
3,4-di 200 e 220
2,3,4-tri 205 280 (4.03)1
a Unless otherwise indicated data taken from (71PMH(3J67) which contains references to the original literature.
b Measured in ethanol.
C Measured in cyclohexane.
d Measured in isooctane; cf. Section 4.26.2.4.
e 2-Melhyl-l,3,4-oxadiazole exhibits a maximum at 206 nm (log e 2.62) in MeOH; cf. Section 4.23.2.2.2.
15-Phenyl-l,2,3,4-thiatriazole.
Table 24 UV Absorption Maxima for Benzazoles a
(X I X
:::::,.. l
Z=NH
X Y Åmax (nm) (log e)
N CH 250 (3.65), 284 (3.63),
296 (3.52)
CH N 242 (3.72), 265 (3.58),
271 (3.70),277 (3.69)
N N 259 (3.75), 275 (3.71)
S+ N
Z=O
Åmax (nm) (log e)
Z=s
Åmax (nm) (log e)
235 (4.00),243 (3.91), 205 (4.20), 222 (4.37), 252 (3.56), 261 (3.39),
280 (3.46) 297 (3.58), 302 (3.57), 3.08 (3.56)b
231 (3.90),263 (3.38), 217(4.27),251(3.74),285(3.23),295(3.13)
270 (3.53), 276 (3.51)
C
213.5 (4.20), 266 (3.72), 312.5 (3.40)
238 (3.91), 350 (4.35), 425 (3.29)d
o: -----y'z
:::::,.. "',(
Z = NMe
X y Åmax (nm) (log e)
N CH 275 (3.80), 292 (3.79),
295 (3.78)
N N 274 (3.96), 280 (3.98),
285 (3.97)
Z=o Z=S
Åmax (nm) (log e) Åm.. (nm) (log e)
203 (4.16), 221 (4.21), 288s (3.88), 298
(3.46), 315s (3.60)e
310 (3.5), 275 (3.6) 221-222 (4.16), 304(4.14), 310 (4.14), 330s
(3.39)
a Unless otherwise indicated data taken from (7IPMH(3)67) which contains references to the original literature.
b (73JHC267).
C Unknown; see Scheme 2 in Section 4.21.1.
dIn concenlrated H 2 S0 4 (69Z0RI53).
e f) t t 1<I.n frnm p('tinn d 17 "I h
tv
tv
Table 25 Effects of Substituents on UV Absorption Maxima (nm)".b
4 3
502
Z
I
Z=NH Z=O Z=S
Substituent position Substituent position Substituent position
Substituent Aza positions 2 3 4 5 2 3 4 5 2 3 4 5
Me 2 213 220 (=3) 217 221 213 246.5 251 c 243 c
3 210 215 (=4) 235 241 239
2,3 216 (=4) 213 217
2,4 <220 (=3)
2,5 (=3) 257 m (=3)
3,4 206 (=2) <230 (=2)
Ph 2 248 250.5 (=3) 239 260 270,291 266 d 266 d
3 271 260 (=4) 263 243 267 287 252 275
2,3 245 (=4) 310.
2,4 241.5 (=3) 238. 250.
2,5 (=3) 280 m (=3)
3,4 247.5 (=2) 268 (=2)
2,3,4 241
Br (Cl) 2 221 (=3) (244l 256 c 241 c
3 220* 217 (=4) 245 246 247
OMe (OH) 2 (=3) 220 255 g
3 (=4) 239
2,3 234* (=4)
2,5 (=3) 273 (=3)
2,3,4 213*
NH z (NMez) 2 228 (=3) 228.5 245.5 278 h 286 c (258)
3 230* (=4) 254.4*
2,3 228 (=4)
2,4 <220 (=3) 247;
3,4 (=2) 251 (=2)
2,3,4 218
COzMe (COzH, CHO) 2 217 (=3) 216; 244 256 (250l 263 c
3 285 256.5 (=4) 230
2,5 (=3) (=3) 263 m (=3)
3,4 243 k (=2) (=2)
NO z 2 261 275 (=3) 239 272
3 325 298 (=4)
2,4 215,245 1 (=3)
2,5 (=3) (=3)
a Unless otherwise indicated, data taken from (71PMH(3)67), which contains references to the original literature. A dash indicates that a substituent cannot be in lhat posilion; a blank means that lhe
value has not been reported. b Asterisk (*) indicates, exceptionally, acidified or basified solvenl; for details, see references quoted in (71PMH(3)67). c (64JCS446). d In cyc10hexane (66T2119). e (64HCA942).
f Value based on 'average increment' observed for a large number of compounds; cf Chapter 4.17. g (70T2497). h Perchlorate salt in MeOH (71JHC657). j (54CB57). ; 2-Benzyl-5-methyl derivative.
k 2-Benzyl-5-methyl derivative. I In water. m cf Section 4.26.2.4.
IV
W
24
Structure of Five-membered Rings with Two or More Heteroatorns
4.01.3.6.3 Effect of substituents
Although UV spectra have been rneasured for a large nurnber of substituted azoles, there
has been no systernatic attempt to explain substituent effects on such spectral maxima.
Readily available data are sumrnarized in Table 25, and sorne rnajor trends are apparent.
However, detailed interpretation is hindered by the fact that different solvents have been
used and that in aqueous rnedia it is not always clear whether a neutral, cationic Or anionic
species is being measured. Furtherrnore, values below 220 nrn are of doubtful quantitative
significance.
4.01.3.7 IR Spectroscopy (71PMH(4)265, 63PMH(2)161)
4.01.3.7.1 Aromatic rings without carbonyl groups
For rnany of the parent cornpounds, cornplete assignrnents have been rnade (71PMH(4)265).
For substituted derivatives, group frequencies have been derived. In the ring systerns under
discussion, IR bands rnay be placed in the following categories. (a) CH stretching rnodes
near 3000 crn- 1 which are of little diagnostic utility. (b) Ring stretching rnodes at 1650-
1 00 crn- 1 (Table 26), four or five bands generally being found which lie in well-defined
regions. The intensities of these bands vary according to the nature and orientation of
substituents. (c) CH and ring deforrnation rnodes at 1300-1000crn- 1 (Table 27) and at
1000-800 crn.. 1 (Table 28). The forrner are largely in-plane CH and the latter out-of-plane
CH and in-plane ring deforrnation rnodes. (d) Substituent vibrations: these are discussed
later.
4.01.3.7.2 Azole rings containing carbonyl groups
The carbonyl group is found in a wide variety of situations in five-rnernbered rings
accornmodating diverse heteroatorns. Carbonyl frequencies to be discussed range frorn
about 1800 to below 1600 crn- 1 ; sorne such frequencies are so low that they often fail to
be recognized as carbonyl absorptions at all, e.g. carbonyl joined to a heterocyclic ring via
an exocyclic double bond as in structure (99). Low frequency v(C=O) bands are widespread
because five-rnernbered heterocyclic rings are inherently 'IT-electron donors. The transfer of
electrons into the exocyclic double bond [v(C=Z) of 99] is likely to be extensive when both
X and Yare electron donor atoms.
C:>=ZCOR
(99)
In Table 29 the v(C=O) and other characteristic bands are given for sorne saturated
five-mernbered heterocycles, and cornpared with the corresponding absorption frequencies
for cyclopentanone. Adjacent NH groups and sulfur atorns have the expected bathochrornic
effect on v(C=O), whereas an adjacent oxygen atorn acts in the reverse direction. The
CH z vibrations of cyclopentanone are repeated to a considerable extent in the heterocyclic
analogs.
Table 30 reports v(C=O) for a variety of azolinones containing ring double bonds. The
hypsochrornic effect of an oxygen atom or CR z group versus the bathochromic effect of
NR, S or C=C can readily be traced.
4.01.3.7.3 Substituent vibrations
In general, substituent frequencies in azoles are consistent with those characteristic of
the sarne substituents in other classes of cornpounds. Sorne characteristic trends are found,
and these have been used to rneasure electronic effects. Thus, for exarnple, the frequencies
of v(C=O) in 3-,4- and 5-alkoxycarbonylisoxazoles lcf. 100) are respectively 9-12, 2-8
and 17-18 cm- 1 higher than those of the corresponding alkyl benzoates, indicating the
Structure of Five-membered Rings with Two or More Heteroatorns
25
Table 26 Azoles: IR Ring Stretching Modes in the 1650-1300 cm -I Region a
Compound Stretching modes (cm I)
Isoxazoles 1650-1610 1580-1520 1510-1470 1460-1430 1430-1370
Isothiazoles 1488 1392 1342
Pyrazoles 1600-1570 1540-1510 1490-1470 1380-1370
Oxazoles 1650-1610 1580-1550 1510-1470 1485 1380-1290
Thiazoles 1625-1550 1550-1470 1440-1380 1340-1290
Imidazoles 1605 1550-1520 1500-1480 1470-1450 1380-1320
1,2,4-0xadiazoles 1590-1560 1470-1430 1390-1360
1,2,5-0xadiazoles 1630-1560 1530-1515 1475-1410 1395-1370
1,3,4-0xadiazoles 1680-1650 1630-1610 1600-1580 1430-1410
1,2,4- ThiadiazoJes 1590-1560 1540-1490
1,2,3- ThiadiazoJes 1650-1590 1560-14Z0 1350-1325 1260-1180
1,2,5- Thiadiazoles b 1461 1350
1,2,3,4- Thiatriazoles 1720-1690 1610-1530 1300-1260
1,2,3- Triazoles 1650-1615w 1530-1485 1440w 1420-1400w
1,2,4- Triazoles 1545-1535 1470-1460 1365-1335
Tetrazoles 1640-1615 1450-1410 1400-1335 1300-1260
a Data taken from (71PMHI41265), which contains references to the original literature; w = weak.
b Dala taken from Section 4.26.2.5.
Table 27 Azoles: Characleristic IR Bands in the 1300-1000 cm - I Region a
Compound ß(CH) modes (cm I) Ring breathing (cm -I)
Isoxazoles 1218m 1155-1130 1088s 1028-1000
Isolhiazoles 1070m 1060m 980s
Pyrazoles 1310-1130 1160-1090 1090-990 1040-975
Thiazoles 1240-1230 1160-1075 1105-1055 1040
Imidazoles 1285-1260 1140 1100 1060
1,2,4-0xadiazoles 1070-1050
1,2,5-0xadiazoles 1360-1175 1190-1150 1160-1150 1035-1000
1,2,4- Thiadiazoles 1270-1215 1185-1170 1160-1080 1050
1,2,3- Thiadiazoles 1150-950
1,2,5- Thiadiazoles b 1251-1227 1041
1,3,4- Thiadiazoles 1230-1165 1190-1120 1075-1045 1040
1,2,3,4- Thiatriazoles 1235-1210 1120-1090 1060-1030
1,2,3- Triazoles 1300-1275 1150-1070 1095-1045 1005-970
Tetrazoles 1210-1110 1170-1035 1060 995-900
a Dala laken from (71PMHI41265), which contains references to the originallileralure; s = strong,
m = medium, w = weak.
b Data taken from Section 4.26.2.5.
Table 28 Azoles: Characteristic IR Bands below 1000 cm 1 a
Compound CH modes (?) (cm I) ß-Ring (?) (cm -I) CH modes (?) (cm- I )
IsoxazoJes 970-920 899 945-845 774
Isolhiazoles 915w 810s 740vs
Pyrazoles 960-930 860-855 805-790 765-750
Thiazoles 980-880 890-785 800-700 745-715
Imidazoles 970-930 895 840 760
1,2,4-0xadiazoles 915-885 750-710
1,2,5-0xadiazoles 980-900 890-825 715-700
1,2,3- Thiadiazoles 910-890
1,2,4- Thiadiazoles 1030-935 890 860-795 750-740
1,2,5- Thiadiazoles 860-800 780 h
1,3,4- Thiadiazoles 975-905 905-875 850 775-750
1,2,3,4- Thiatriazoles 960-930 910-890
1,2,3- Triazoles 855-825 970-700
1,2,4- Triazoles 865-855(?)
Tetrazoles 960 810-775
a Dala laken from (71PMHI41265) which contains references 10 the original literature; VS = very
strong, s = strong, w = weak.
h Data taken from Seclion 4.26.2.5.
tv
'"
VJ
-
....
Table 29 IR Absorption Assignments for 2,5-Dihetero Derivatives of Cyclopenlanone a s::
I")
-
s::
C=X: C=O C=O C=S C=O C=O C=S C=S C=O C=S C=O C=S
2-Position: CH 2 CH 2 CH 2 0 S S 0 0 S NH NH
5-Position: 0 N N 0 S S NH NH NH NH NH :!1
Vibration type (em-I) (em-I) (em-I) (em-I) (em-I) (em-I) (em-I) (em-I) (em-I) (em-I) (em-I)
<I>
I
v(C=X) 1770 1695 1109 1795 1638 1058 1171 1724 1047 1661 1208
"'
CH 2 scissors 1490 1494 1478 1483 1434 1416 1464 1485 1458 1488 1459
1466 1440 1458 1422 1422 1370 1402 1412 1432 1449 1368 "'
....
1426 1426 1420 1394 1380 "'
1379 1378 :;.;,
CH 2 wag 1284 1270 1309 1226 1275 1275 1319 1333 1250 1200 S.
D1:)
1242 1230 1215 1254 1243 1230 1230 1203 ""
CH 2 twist 1192 1169 1168 1175 1158 1148 1203 1160 :ê.
-
CH 2 rock 990 995 970 1005 983 983 969 967 998 988 980
v ring 1166 1285 1290 1140 888 882 1290 1250 1294 1270 1273 c
1037 1068 1059 1071 826 831 1035 1077 1080 1103 1042 c
....
890 915 915 971 677 670 942 1021 650 1037 1003 g:
929 887 880 894 939 946 914 918 927 933 919
l' ring 800 805 493 773 457 770 768
a Data taken from (63PMH(2i16J), whieh contains references to the originalliterature.
:::::.
-
c
""
Structure of Five-membered Rings with Two or More Heteroatoms
27
Table 30 v(C=O) Frequencies for Some Azolinones'
Ring system
substituent(s) Z =NH (em-I) Z = 0 (em-I) Z =8 (em-I)
R =HorMe
R
O';::N 1705-1695 b
R'
O ';:;;N R 1680-1630
0
ÔR 1660.
z/
ÇNR 1684-1677 d 1780-1750 1640'
Ao
0
Rt) 1770-1740 1780-1700
R Z
R
N
o z) ca. 1820 1725 1
· Unless olherwise indicated, data taken from appropriate chapter, 'Comprehensive
Heterocyclic Chemistry'.
b Z = NR', R' = alkyl, aryl.
C R = Me (64TLI477).
d Data taken from (63PMH(2)161) which contains references to the original literature.
. (79HC(34-2)421).
1 (79HC(34-2)430).
following order of electron donor power: phenyl> 4- > 3- > 5-position of isoxazole. Sirnilar
work has been reported for other ring systerns and substituents (63PMH(2)161).
N
o [;) ()
N N I
I II C
R/C,::-O R/C,O- if 'Ox
(100) (101) (102) (103)
Otting (56CB1940,57MI40100) has shown that the v(C=O) for acetylazoles (ct. 101)
increases with the nurnber of cyclic nitrogen atoms (Table 31). Additional nitrogen atorns
in the ring act as powerful electron-withdrawing substituents and decrease the importance
of forrns such as (102). Staab et at. (57MI40100) give data for benzo analogs (Table 31) and
Et0 2 C O
7
/N
o
Table 31 Carbonyl Frequencies for N-Acetylazoles'
N-Acetylazole v(C=O) (em-I) N-Acetylazole v(C=O) (em-I)
Pyrrole 1732 Indole 1711
Imidazole 1747 Benzimidazole 1729
1,2,4- Triazole 1765 Benzotriazole 1735
Tetrazole 1779
. Data taken from (S6CBI940) and (S7MI40100) which contain references to the original
literature.
N
00
VJ
-
....
s::
""
-
s::
:!1
"'
I
Table 32 Melting and Boiling Points.. h . c ;::
"'
;::
Ring system H Me Et COMe COzH COzEt CONH z CN NH z OH OMe SH SMe Cl Br
"'
Benzene 80 111 136 212 122 211 130 190 184 43 154 168 187 131 155
:;.;,
Pyrrole-l 130 114 129 180 95d 180 166 S.
Pyrrole-2 130 148 181 90 205d 39 174 83 g D1:)
Pyrrole-3 130 158 179 115 148 78d 152 208-14 ""
Furan-2 31 64 92 31 133 34 142 147 68 80 110 78 103 .
Furan-3 31 65 54 122 179 168 58 80 103 ;;.
Thiophene-2 84 113 133 214 129 218 180 196 214 217 156 166 128 150
Thiophene-3 84 115 135 57 138 208 178 179 171 136 157 (;;)
Pyrazole-l 70 127 137 234 103 213 141 37 (;;)
Pyrazole-3 70 205 209 101 214d 160 148 150 40 166 >370 d 40 70 ....
Pyrazole-4 70 207 244 114 278 79 92 81 118 62 77 97
Isoxazole-3 95 118 139 16 149d 134 168 ....
Isoxazole-4 95 127 130 ""
Isoxazole-5 95 121 52 149 174
Imidazole-l 90 199 226 102 218 -
"'
Imidazole-2 90 141 80 80 164d 250d 227 139 165 207 ....
(;;)
Imidazole-4 90 56 275d 157 215 130 I:>
-
Oxazole-2 69 87 97 (;;)
;::
Oxazole-4 69 142 48 ""
Thiazole-2 118 128 158 226 102d 48 118 31 92 164 79 230 145 147
Thiazole-4 118 133 56 196 52 150 60 165 190
Thiazole-5 118 141 142 218 217 186 53 83 176 222 140 192
1,2,3- Triazole-l 206 228 238 51
1,2,4- Triazole-l 121 20 199 40-2 230 138 81-2d 136-8d
1,2,4- Triazole-3 121 95 65-6 137 178 312 187 159 234 oil 216 105 167 189
1,2,4- Triazole-4 121 90 oil 76-7
Tetrazole-5 156 148 86 234 99 203 260 154 205 151 73 148
Tetrazole-1 156 39 265 >370
Tetrazole-2 156 147 163 >370
Isothiazole-3 113 134 32 135 290 154 60 33 74 147 160
Isothiazole-4 113 146 161 174 192 94 45 143 34
Isothiazole-5 113 142 250 201d 172 47 112 149 150
1,2,3-0xadiazole (sydnone) 36 340
1,2,4-0xadiazole-3 87 105
1,2,4-0xadiazole-5 87 104
1,3,4-0xadiazole-2 150 164 174.5 255 156 120 89-91
1,2,3- Thiadiazole-4 160 87-9 140 227-8 86 220-2 62-3 44-6 170
1,2,3-Thiadiazole-5 160 104-6 222 145-7
1,2,4- Thiadiazole-3 121 132 32
1,2,4- Thiadiazole-5 121 119 120 93 220 122
1,2,3,4- Thiatriazole-5 128-30 44-5d e 50-65d 34 expl.f
1,3,4- Thiadiazole 43 201d 221 193 143 33 73
1,3-Dioxole-4 51 76
1,2- Dithiol- 3-one-4 >370 >370 >370 79.5-80.5 62-3
1,2-Dithiol-3-one-5 >370 214-6 >370 223
1,2,4- Trioxolane-3,3-di 116 88
1,2,4- Trioxolane-3,5 -di 116 90 140 42
1,2,4- Trilhiolane-3,5 -di 78 >200 >230
a Melting points above 30 oC are given in bold; melting poinls below 30 oC are not included.
b Boiling points are given at almospheric pressure to facilitate comparison; those reported al other than atmospheric pressure were converted using a nomogram (S7MI40101).
C A dash indicates that the compound is unstable, unknown, or the data are not readily available.
d Value given for EtS derivative.
e Value given for EtO derivative.
f Explodes.
g Value given for the monohydrate.
V)
::::
:!1
<::t'
1::1..
:::ö
s.
O'Q
""
.
-
;::;-
....
-
a
c
8
""
N
\D
30 Structure of Five-membered Rings with Two or More Heteroatorns
show that v(C=O) values for substituted benzoyl-irnidazoles (103) and -triazoles follow the
Hamrnett equation. For N -acylpyrazoles, see reference (S9MI4olon).
Substituent vibrations in IR spectra have been extensively used to determine tautorneric
structure, particularly C=O, NH, OH and SH stretching modes. For exarnple, 3-hydroxy-
isoxazoles show broad v(OH) at 2700 cm- 1 (dirners). Boulton and Katritzky developed a
technique for determining the structure of potentially tautorneric arnino cornpounds by
partial deuteriurn exchange. If the cornpound under investigation contains an amino group,
the change frorn NH 2 to, NHD produces a new single v(NH) at a frequency between those
of the original doublet for asyrnrnetrical and syrnrnetrical v(NH 2 ). If the cornpound does
not contain an arnino group and the two bands are derived frorn two separate NH groups,
there should be no new band between the original two in the partially de ute rated derivative.
The rnethod was applied to aminoisoxazoles (6IT(l2)SI).
4.01.3.8 Mass Spectrometry (66AHû7)301, B-7IMS)
Arnong the rnost irnportant fragrnentation pathways of the molecular ions of azoles are
the following. (a) Loss of RCN or HCN; this occurs particularly readily for systems containing
(104), i.e. irnidazoles and thiazoles. It does not occur so readily for oxazoles, but is found
again in the 1,2,4-oxadiazoles (105) and also for pyrazoles (106). (b) Loss of RCO+; this
is irnportant for systerns (107) in oxazoles and in 1,3,4-oxadiazoles. It is also found in
isoxazoles, where it probably occurs after skeletal rearrangernent of the isoxazole via (108)
into an isomeric oxazole. (c) Loss of NO+ and/or NO' occurs for furazans (109) and
sydnones (110). (d) Loss of N 2 frorn triazoles and tetrazoles (but not pyrazoles). (e) Whenever
the structural element (111) occurs, a McLafferty rearrangernent can take place (111 112).
(f) Isothiazoles are rather stable and show intense rnolecular ions with sorne HCN loss,
probably via rearrangernents analogous to (108) to give thiazoles.
(-1.N R' :N : R !-N
:')R ) 0 ,')"
N, '. R '.....N I" R
.......x '. 0" N '. :0
R
II04JX=S or NR' (105) (106) (107)
I I
ij/1 R R' R' NR C C
n.. L.I N .......N-::::- 'CR 2 ....... N/ ':::::-CR 2
N rf R N' ,..N I -. H +
:'0 -0 .' 0.... H, .....CR2
X R2C=X
(108) (109) (110) (111) (112)
There are correlations between rnass spectral fragrnentations and therrnal and photo-
chernical fragrnentations and rearrangernents; see Sections 4.02.1.2.1 and 4.02.1.2.2.
4.01.3.9 Photoelectron Spectroscopy (74PMH(6)1)
In this rnethod, photons of an energy well in excess of the ionization potential are directed
onto a molecule. The photoelectron spectrurn which results allows assessrnent of the energies
of filled orbitals in the rnolecule, and thus provides a characterization of a rnolecule.
Comparisons between photoelectron spectra of related compounds give structural inforrna-
tion, for example, on the tautomeric structure of a compound by cornparison of its spectrurn
with those of models of each of the fixed forms.
Photoelectron spectra have been discussed and assigned in the following series: pyrazole
(Section 4.04.1.4.9), 1,2,3-triazole (Section 4.11.3.2.9), isothiazole (Section 4.17.2.2),1,3,4-
oxadiazole (Section 4.23.2.2.5), 1,2,5-thiadiazole (Section 4.26.2.2), 1 ,3,4-thiadiazole (Sec-
tion 4.27.2.3.10), 1,3-dioxolane (Section 4.30.1.4.5), 1,2-dithiole (Section 4.31.1.4), and
1.2,4-trioxolane and 1,2,4-trithiolane (Section 4.33.2.2.5).
Structure of Five-membered Rings with Two or More Heteroatorns
4.01.4 THERMODYNAMIC ASPECTS
4.01.4.1 Intermolecular Forces
31
4.01.4.1.1 Melting and boiling points
In the parent unsubstituted ring systerns (ef. first colurnn of Table 32) replacernent of a
-CH=CH - group with a sulfur atorn has little effect, and replacernent of a -CH=CH-
group with an oxygen atorn lowers the boiling point by ca. 40 o C.
Introduction of nitrogen atoms into the ring is accornpanied by less regular changes.
Substitution of either a -CH=CH - group by an NH group or of a =CH - group by a
nitrogen atorn increases the boiling point. When both of these changes are rnade sirnul-
taneously the boiling point is increased by an especially large arnount due to the possibilities
of association by hydrogen bonding.
The effect of substituents on rnelting and boiling points can be surnrnarized as follows.
(a) Methyl and ethyl groups attached to ring carbon atorns usually increase the boiling
point by ca. 20-30 and ca. 40-60 o C, respectively. However, conversion of an NH group
into an NR group results in large decreases in the boiling point (e.g. pyrazole to 1-
methylpyrazole) because of decreased association. (b) The acids and arnides are all solids.
Many of the amides melt in the range 130-180 o C; the rnelting points of the acids vary
widely. (c) Cornpounds containing a hydroxy, rnercapto or arnino group are usually relatively
high-rnelting solids. For rnany hydroxy and rnercapto cornpounds this can be attributed to
their tautornerisrn with hydrogen-bonded 'one' and 'thione' forrns. However, hydrogen
bonding can evidently also occur in arnino cornpounds. (d) Methoxy, rnethylthio and
dimethylarnino derivatives are often liquids. (e) Chi oro corn pounds are usually liquids which
have boiling points sirnilar to those of the corresponding ethyl cornpounds. Brorno corn-
pounds boil approxirnately 25 oC higher than their chloro analogs.
4.01.4.1.2 Solubility of heterocyclic compounds (63PMH(1)177)
In general, the solubility of heterocyclic cornpounds in water (Table 33) is enhanced by
the possibility of hydrogen bonding. 'Pyridine-like' nitrogen atorns facilitate this (compare
benzene and pyridine). In the sarne way, oxazole is rniscible with water, and isoxazole is
very soluble, rnore so than furan.
The effect of arnino, hydroxy or mercapto substituents is to increase hydrogen bonding
properties. However, if stable hydrogen bonds are found in the crystal, then this can decrease
Table 33 Solubilities of Some Five-membered Heterocycles in Water at 20 0 C a
Compound
Parts soluble
in 1 part
of water
Compound
Furan
Isoxazole
Oxazole
Benzoxazole
Sydnone
3-methyl- c
1,2,4-0xadiazole d
Thiophene
Isothiazole
Thiazole
2-methyl-
2-amino-
1,2,3- Thiadiazole
1,3,4- Thiadiazole
0.03
0.02
Misc. b
0.008
Pyrrole
Pyrazole
2-amino-4-hydroxy-
Imidazole
2,S-dihydroxy-
I-methyl-
1,2,4- Triazole
3-amino-
3-hydroxy-
Tetrazole
Benzimidazole
Indazole
3-hydroxy-
Purine
Misc.
Misc.
0.001
0.03
Misc.
0.05
0.03
Misc.
Parts soluble
in 1 part
of water
0.06
0.40
0.009
1.8
0.02
Misc.
1
0.3
0.05
1
0.002
0.0008
0.002
0.5
a Unless otherwise indicated, data taken from {63PMHI1I177) or from appropriate chapter, 'Comprehensive
Heterocyclic Chemistry', which contain references to the original literature.
b Misc. = miscible.
CAt 40 0 C {80JCS(P2)553).
d {65MI40100).
32
Structure of Five-membered Rings with Two or More Heteroatorns
their solubility in water (63PMH(1)177), e.g. indazole and benzimidazole are less soluble than
benzoxazole.
Other solvents can be divided into several classes. In hydrogen bond-breaking solvents
(dipolar aprotics), the sirnple amino, hydroxy and mercapto heterocycles all dissolve. In
the hydrophobic solvents, hydrogen bonding substituents greatly decrease the solubility.
Ethanol and other alcohols take up a position interrnediate between water and the hydro-
phobic solvents (63PMH(!)177).
4.01.4.1.3 Gas-liquid chromatography (71PMH(3)297)
Gas-liquid chromatography has been widely used for the identification of reaction
rnixtures and for the separation of heterocycles. Sorne typical conditions are shown in Table
34.
Table 34 Operating Conditions for GLC Separation of Five-membered
Heterocycles with More Than One Heteroatom a
Compound
Conditions
Pyrazolines
Imidazoles
Thiazoles
Oxadiazoles
1- Phenylpyrazoles
Purines
Dioxolanes
Oxazolines
10% Cyanethylated mannite on Celite 545.
5% OV-17 on Chromosorb W, AW-DMCS (H.p.).h
Carbowax 4000, dioleate on firebrick. 190 oc.
Silicone grease on Chromosorb P.
Apiezon L on firebrick C-22, 220 oC.
15% Hallcomid M-18 on firebrick.
Carbowax 20M on Gas-Chrom P.
Ethyleneglycol succinate on Diatoport-S.
a Data taken from (71PMHI31297), which contains references to the original literature.
h Simple alkyl- and aryl-imidazoles. N-Unsubstituted compounds are N-acylated
prior to injection.
4.01.4.2 Stability and Stabilization
4.01.4.2.1 Thermochemistry and conformation of saturated heterocycles (74PMH(6)l99)
Calculation of group incrernents for oxygen, sulfur and nitrogen cornpounds has allowed
the estirnation of conventional ring-strain energies (CRSE) for saturated heterocycles frorn
enthalpies of formation. For 1,3-dioxolane, CRSE is about 20 kJ mol-I. In 2,4-dialkyl-l,3-
dioxolanes the cis forrn is always therrnodynarnically the more stable by approxirnately
1 kJ rnol- 1 .
For 1,3-dithiolanes the ring is flexible and only srnall energy differences are observed
between the diastereoisorneric 2,4-dialkyl derivatives. The 1,3-oxathiolane ring is less
mobile and pseudoaxial 2- or 5-alkyl groups possess conformational energy differences (cf.
113 114); see also the discussion of conforrnational behavior in Section 4.01.4.3.
H
d Me
S---....o
o
H+==:S
Me
(113) 13% (a)
(114) 87% Ie)
4.01.4.2.2 Aromaticity
This subject has been dealt with in (74AHCl17)255), which should be consulted for further
details and references to the original literature.
(i) Imidazole, pyrazole, thiazole, isothiazole and oxazole
ERE (ernpirical resonance energy) and 'conjugation energy' data (Table 35) suggest that
pyrazole is rnore arornatic than both irnidazole and pyrrole. LCAO-SCF calculations on
Structure of Five-membered Rings with Two or More Heteroatoms
33
various azoles, however, lead to the conclusion that the stability of azoles decreases on
increasing substitution of nitrogen atorns for carbon atorns, with the stabilities of pyrazole
and irnidazole being cornparable.
Table 35 Empirical Resonance Energy Data (kJ mol-I) for Azoles.. b
Compound Method A C Method B d Method C.
Pyrazole 173.6 112.1 136.8
Imidazole 134.3 53.1 74.1
1,2,4-Triazole 205.8 83.7 151.5
Tetrazole 231.0 264.0
Indazole 309.2 246.9 248.9
Benzimidazole 287.9 203.8 204.2
Benzotriazole 346.9 312.5
. Adapted from (74AHC(17)2SS) which contains further details and references to
the ori nalliterature.
b 1 x 10- J = 2.3901 X 10- 8 cal.
C Results obtained using Pauling's bond energy terms.
d Using lhe bond energy terms reported by Cottrell.
· Using Coates and Sutton's bond energy terms.
Data relevant to the aromaticity of these cornpounds have been obtained by a variety
of other techniques, rnany of which are discussed elsewhere in this chapter. Arornaticity
implies planarity; X-ray and microwave data support planarity. The NMR rnethod has been
extensively applied; thus l H NMR shifts for imidazoles, pyrazoles and pyrroles are compar-
able; 13C NMR spectral data for imidazole show appreciable ring current anisotropy. The
ring protons of thiazoles and th rnethyl protons in methylthiazoles are deshielded relative
to signals frorn the corresponding imidazoles. Elvidge has interpreted these NMR data as
evidence that the thiazole ring has the same degree of aromatic character as benzene
(65PC40100).
The precise geometrical data obtained by microwave spectroscopy allow conclusions
regarding bond delocalization and hence arornaticity. For exarnple, the rnicrowave spectrurn
of thiazole has shown that the structure is very close to the average of the structures of
thiophene and 1,3,4-thiadiazole, which indicates a sirnilar trend in aromaticity. However,
different methods have frequently given inconsistent results.
l H NMR data for 4-methyloxazole have been compared with those of 4-methylthiazole;
the data clearly show that the ring protons in each are shielded. In a cornprehensive study
of a range of oxazoles, Brown and Ghosh also reported NMR data but based a discussion
of resonance stabilization on pK and UV spectral data (69JCS(B)270). The weak basicity of
oxazole (pKa 0.8) relative to 1-methylimidazole (pKa 7.44) and thiazole (pKa 2.44) demon-
strates that delocalization of the oxygen lone pair, which would have a base-strengthening
effect on the nitrogen atom, is not extensive. It rnust be concluded that not only the
experimental measurernent but also the very definition of aromaticity in the azole series is
as yet poorly quantified. Nevertheless, its importance in the interpretation of reactivity is
enorrnous.
(ii) Diheterolyliurn ions and related compounds
The 1,2-dithiolylium and 1,3-dithiolylium ions (115) and (116) are iso-7T-electronic with
the tropylium ion, from which they may be formally derived by replacing double bonds by
sulfur atoms. Various calculations and structural data dernonstrate that the rings are
stabilized by 7T- electron delocalization.
+ CS --.
S
(11Sa)
0 \+
S/
(11Sb)
S s+
[)+-+f)
S S
(116a) (116b)
0+
[)OH
o
(117)
The NMR spectrurn of the 2-hydroxy-l,3-dioxolyliurn cation (117) (68JA1884) shows a
significant ring current. The arornaticity of vinylene carbonate was pointed out by Balaban
(S9MI40100).
34 Structure of Five-membered Rings with Two or More Heteroatorns
(iii) Compounds containing three heteroatorns
The arornatic character is critically dependent upon the position of the heteroatorns in
the ring, and oxygenated cornpounds have rnarked diene character. Various ERE deterrnina-
tions of 1,2,4-triazole have given values ranging between 83.7 and 205.8 kJ rnol- 1 (Table
35). LCAO-SCF calculations, however, suggest that the ring is substantially less stable than
the diazoles but more stable than tetrazole.
Microwave spectra of 1,3,4-thiadiazole (118), thiophene (119), 1,2,5-thiadiazole (120)
and 1,2,5-oxadiazole (121) yield the following order of decreasing arornaticity based on
bond lengths: (120), (119), (118), (121), (122). 1,2,5-0xadiazole is planar with a C=N
bond length of 130.0 prn, interrnediate between that of forrnaldoxine t127.0 prn) and
pyridine (134.0 prn), suggestive of a high degree of 'diene' character. Comparison with
cyclopentadiene indicates that 1 ,2,5-oxadiazole has sorne srnall degree of arornatic character.
(J
S
(118)
o
S
(119)
n
N, /N
S
(120)
N
//
" /N
o
(122)
n
N, /N
o
(121)
The sydnones rnay be represented by structures t123a-d), of which the zwitterionic
structure (123a) most clearly irnplies an arornatic sextet. The diarnagnetic susceptibility
exaltation for N-phenylsydnone of 11.0 X 10- 6 crn 3 rnol- 1 is cornparable with the corre-
sponding value for pyrrole (10.2 x 10- 6 ). 3-p- Bromophenylsydnone (123; R = H, R' =
p- brornophenyl) is essentially planar; however, the O-N bond and O( 1)-C(5) bond lengths
are not very different frorn norrnal single bond distances.
+ +
J: R - NR' J: R _NR'
+--I> \\ +--I> \ +--I>
o O/N 0 O/N-
(123b) (123c)
R NR'
JC \\
-0 O/N
(123a)
R NR'
"1/ \
õ...z.(f' N
(123d)
(iv) Benzo derivatives
In the series 1,3-benzoselenazole (124; X = Se), -benzothiazole (124; X = S) and -benz-
oxazole (124; X = 0) the deshielding effect on the rnethyl protons on changing the
heteroatorn X is in the opposite sense to the electronegativity of the atorn. This has been
explained in terrns of decreasing aromaticity in the order (124; X = Se), (124; X = S), (124;
X=O).
(X I X)Me 'x S (X 1 N
N NI 6 Xl
(124) (125) (126)
In 2,1,3-benzoselenadiazole (125; X = Se), 2, 1,3-benzothiadiazole (125; X = S) and 2,1,3-
benzoxadiazole (125; X = 0) the effect of the heteroatom X on the ring is sirnilar to that
in the previous systern; thus a decreasing scale of arornatic character (125; X = Se), (125;
X = S), (125; X = 0) is again suggested. The ortho proton-proton coupling constants (5,6),
and hence bond fixation and arornatic character, decrease in the order t126; X = S), (126;
X = NMe), (125; X = NMe), (125; X = S), (125; X = 0). The ratios of J 5 ,6 :hs for these
cornpounds are 0.859, 0.824, 0.781, 0.748 and 0.706, respectively.
4.01.4.3 Conformation
Saturated five-membered heterocyclic cornpounds are non-planar, existing in half-chair
or envelope conformations. The far-IR spectra of THF and 1,3-dioxolane (127) show both
to have barriers of ca. 0.42 kJ rnol- 1 .
ç)
(127)
COHO]
o 0
(128)
ç O
(129)
o
[)OR
o
(130)
Structure of Five-membered Rings with Two or More Heteroatorns
35
1,3-Dioxolane also pseudorotates essentially freely in the vapor phase. 2,2'-Bi-l,3-
dioxolane (128) has been shown by X-ray crystallography to have a conformation midway
between the half-chair and envelope forms. The related compound 2-oxo-l;3-dioxolane
(129) shows a half-chair conformation. This result is confirmed by microwave spectroscopy
and by 13C NMR data. Analysis of the AA'BB' NMR spectra of the ring hydrogen atoms
in some 1,3-dioxolane çlerivatives is in agreement with a puckered ring. Sorne 2-alkoxy-l,3-
dioxolanes (130) display anti and gauche forms about the exocyclic C(2)-0 bond.
The 1,2,4-trioxolane ring prefers a half-chair conformation (131); the C-O-C portion
of the ring forrns the reference plane, and alkyl substituents prefer the equatorial positions.
o
H, / \ /H
c- \ o- / c,
H/ 0 R
(131)
S
ç)
(132)
1,3-Dithiolane (132) derivatives also possess non-planar skeletons; the most irnportant
conformation is probably of symmetry C 2 (half-chair). The dithiolane ring rnay be quite
flexible and a minirnurn energy ,conformation is only well defined if there is a bulky
substituent at the 2-position.
4.01.5 TAUTOMERISM (76AHC(Sl)1)
4.01.5.1 Annular Tautomerism
Annular tautomerism (e.g. 133 134) involves the movernent of a proton between two
annular nitrogen atoms. For unsubstituted irnidazole (133; R = H) and pyrazole (135; R = H)
the two tautomers are identical, but this does not apply to substituted derivatives. For
triazoles and tetrazoles, even the unsubstituted parent compounds show two distinct
tautomers. However, interconversion occurs readily and such tautorners cannot be separ-
ated. Sometimes one tautomeric form predominates. Thus the rnesornerism of the benzene
ring is greater in (136) than in (137), and UV spectral cornparisons show that benzotriazole
exists predominantly as (136).
R N tjH R R
ç) ------'" ç O H
.....N
H H
(133) (134) (135)
(X \N Cr N , EWS EWS
NH Q+ +---+ ÇN H
N "-/ .....NH
N
H H H
(136) (137) (138)
Table 36 summarizes the known annular tautomerism data for azoles. The tautomeric
preferences of substituted pyrazoles and irnidazoles can be rationalized in terms of the
differential substituent effect on the acidity of the two NH groups in the conjugate acid,
e.g. in (138; EWS = electron-withdrawing substituent) the 2-NH is more acidic than 1-NH
and hence for the neutral form the 3-substituted pyrazole is the rnore stable.
Table 36 Annular Tautomerism of Azoles'
Azote
Parent
Substituted compounds
Pyrazole
Imidazole
v- Triazole
s- Triazole
Telrazole
Equivalent
Equivalent
1,2,5> 1,2,3
1,2,4> 1,3,4
1,2,3,4> 1,2,3,5
Electron-withdrawing group prefers 3-position
Electron-withdrawing group prefers 4-position
· Data taken from (76AHC(Sl)296) which contains references to the original literature.
36
Structure of Five-membered Rings with Two or More Heteroatorns
The situation is rnore cornplex for triazoles and tetrazoles where qther effects such as
lone-pair repulsions intervene; see discussion in (76AHClSIJ296).
4.01.5.2 Substitnent Tautomerism
4.01.5.2.1 Azoles with heteroatoms in the 1,2-positions
3-Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms
(139, 140; Z = 0, N or S; Table 37). Amino compounds exist as such as expected, and so
do the hydroxy corn pounds under most conditions. The stability of the OH forms of these
3-hydroxy-1,2-azoles is explained by the weakened basicity of the ring nitrogen atom in
the 2-position due to the adjacent heteroatom at the I-position and the oxygen substituent
at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen
atorn causes these compounds to exist mainly in the OH forrn.
XH
d
/N
Z
(139)
X
riH
/(z)
(140)
Table 37 Tautomerism of 3-Substituted Azoles with Heteroatoms-I,2 a
Substituent
Ring
Phase(s J
Conclusions
OH
I-Substituted pyrazole
C 6 H 12 , CHCl 3 , H 2 0, xtal.
OH except in H 2 0 where OHjNH
coexist
Mainly OH in aU media
OH
NH 2
NH 2
NH 2
SH
NH z
Isoxazole
Isothiazole
I-Substituted pyrazole
Isoxazole
Isothiazole
Isothiazole
C 6 H 12 , CHCl 3 , H 2 0, xtal.
MeOH, xtal.
MeOH, KBr
CHCI 3 , H 2 0
CCl 4
CCl 4
SH
. For further details and original references see (70C134) and (76AHC(Sl)1).
The 4-substituted analogs can exist in two uncharged tautorneric forrns (141) and (142)
and, in addition, in the zwitterionic forrn (143), but all the evidence shows that the cornpounds
all exist predorninantly in thé NH 2 or OH forrn (141).
HX
h
(;N
z
(141)
X ON
z/
(142)
----"
..--
x
h+
/(_;NH
z
(143)
For 5-substituted isoxazoles, pyrazoles and isothiazoles, three uncharged tautomeric
forrns are possible: (144), (145) and (146). Some conclusions are recorded in Table 38.
Again, the arnino derivatives exist as such. In the case of the hydroxy cornpounds, the
hydroxy form is of little irnportance (except in special cases where a suitable substituent in
the 4-position can forrn a hydrogen bond with the 5-hydroxy group). The relative occurrence
of the 4H-oxo form (145) and 2H-oxo tautorner (146) depends on the substitution pattern
and on the solvent. Tautorner (146) is considerably rnore polar than (145), with a large
contribution frorn the charge-separated canonical structure (147). Hence, it is not unexpec-
ted that the 2H-oxo tautorner (146) is strongly favored by polar media. A substituent at
the 4-position also tends to favor forrn (146) over (145) because of conjugation or hypercon-
jugation of the 4-substituent with the 3,4-double bond.
f/lI
HX z/N
(144)
----"
..--
XJ:)N
(145)
----"
..--
J:J
NH
X z/
(146)
..-.
J[J +
- NH
X z/
(147)
Structure of Five-membered Rings with Two or More Heteroatorns
37
Table 38 Tautomerism of S-Substituted Azoles with Heteroatoms-i,Za
Substituent Ring Phase (s ) Conclusions
OH i-Substituted pyrazole C 6 H12' CHCI 3 , EtOH, H 2 0, xtal. CH in non-polar;
Isoxazole C 6 H 12 , CHCI 3 , EtOH, H 2 0, xtal. Increasing NH in polar;
NH favored by 4-substituent
NH 2 i-Substiluted pyrazole CCl 4 NH 2
Isoxazole CHCI 3 , H 2 O NH 2
Isothiazole CCl 4 NH 2
SH Isoxazole C 6 H 12, CCI 4 , MeOH, xtal. SH
a For further details and original references see (70CI34) and (76AHC(Sljl).
Complex tautomerism for azoles with heteroatoms in the 1,2-positions occurs for
pyrazoles which are not substituted on nitrogen. Scheme 10 shows the four important
tautomeric structures (148)-(151) for 3-methylpyrazolin-5-one, and (152) and (153) as
examples of other possible structures. A detailed investigation of this system disclosed that
in aqueous solution (polar medium) the importance of the tautomers is (149) > (151) >>(150)
or (148), whereas in cyclohexane solution (non-polar medium) (151) > (148) >>(149) or
(150).
J:)Me N : Me Me Me Me
HOÇN HO ÇN H HOÇN HO CN
o N N
H H H
(148) (149) (150) (151) (152) (153)
Scheme 10
4.01.5.2.2 Azoles with heteroatoms in the 1,3-positions
The tautomerism of 2-substituted 1,3-azoles -(154 155) is summarized in Table 39.
Whereas amino compounds occur invariably as such, all the potential hydroxy derivatives
exist in the oxo form, and in this series the sulfur compounds resemble their oxygen analogs.
There is a close analogy between the tautomerism for all these derivatives with the
corresponding 2-substituted pyridines.
( NH I/N
r A ,,
Z X Z XH
(154) (155)
Table 39 Tautomerism of Z-Substituted Azoles with Heteroatoms-i,3 a
Substituent Ring Phase (s ) Conclusions
OH i-Substituled imidazole KBr disc NH, C=O
Oxazole MeOH, CCl 4 NH, C=O
Thiazole Alcohol, CS 2 NH, C=O
NH 2 i-Substituted imidazole O.iN aq. KCI, EtOH/aq. KCl NH 2
Oxazole MeOH NH 2
Thiazole EtOH, CDCl 3 NH 2
SH i-Substiluted imidazole Liquid film, MeOH, EtOH NH, C=S
Oxazole CCI 4 , MeOH NH, C=S
Thiazole CCI 4 , EtOH NH, C=S
a For further details and original references see (70CI34) and (76AHC(SI)I).
4-Substituted 1,3-azoles exist in two non-charged tautomeric forms (156) and (157)
together with the zwitterionic form (158). 5-Substituted 1,3-azoles also exist in forms (159)
and (160) together with the zwitterionic forms (161). Some results are summarized in Table
38
Structure of Five-membered Rings with Two or More Heteroatorns
40; for the potential hydroxy forms, the non-arornatic tautorners of types (157) and (160)
clearly can be of importance.
HX
t)
Z
(156)
x
t)
Z
(157)
X
t3 H
Z
(158)
I/N
HX z)
(159)
!:)
X z
(160)
Substituent
Table 40 Tautomerism of 4- and 5-Substituted Azoles with Heleroatoms-l,3 a
Conclusions
4-0H
5-0H
5-NH 2
Ring
Oxazole
Thiazole
Oxazole
Oxazole
Phase(s)
EtOH, xtal., MezSO
MezSO, MezCO
Xtal.
CHCI 3 , xlal.
CH
OH and CH
CH
NHz
a For further details and original references, see (70C134) and (76AHCIS!)\).
.
I/ H
x z)
(161)
4.02
Reactivity of Five-membered
Rings with Two or More
Heteroatoms
A. R. KA TRITZKY
University of Florida
and
J. M. LAGOWSKI
The University of Texas at Austin
4.02.1 REACTIONS AT HETEROAROMATIC RINGS
4.02.1.1 General Survey of Reactivity
4.02.1.1.1 Reactivity of neutral azoles
4.02.1.1.2 Azolium salts
4.02.1.1.3 Azole anions
4.02.1.1.4 Azolinones, azolinethiones, azolinimines
4.02.1.1.5 N-Oxides, N-imides, N-ylides of azoles
4.02.1.2 Thermal and Photochemical Reactions Formally Involving No Other Species
4.02.1.2.1 Thermal fragmentation
4.02.1.2.2 Photochemical fragmentation
4.02.1.2.3 Equilibria with open-chain compounds
4.02.1.2.4 Rearrangement to other heterocyclic species
4.02.1.2.5 Polymerization
4.02.1.3 Electrophilic Attack at Nitrogen
4.02.1.3.1 Introduction
4.02.1.3.2 Reaction sequence
4.02.1.3.3 Orientation in azole rings containing three or four heteroatoms
4.02.1.3.4 Effect of azole ring structure and of substituents
4.02.1.3.5 Proton acids on neutral azoles: basicity of azoles
4.02.1.3.6 Proton acids on azole anions: acidity of azoles
4.02.1.3.7 Metal ions
4.02.1.3.8 Alkyl halides and related compounds: azoles without a free NH group
4.02.1.3.9 Alkyl halides and related compounds: compounds with a free NH group
4.02.1.3.10 Acyl halides and related compounds
4.02.1.3.11 Halogens
4.02.1.3.12 peracids
4.02.1.3.13 Aminating agents
4.02.1.3.14 Other Lewis acids
4.02.1.4 Electrophilic Attack at Carbon
4.02.1.4.1 Reactivity and orientation
4.02.1.4.2 Nitration
4.02.1.4.3 Sulfonation
4.02.1.4.4 Acid-catalyzed hydrogen exchange
4.02.1.4.5 Halogenation
4.02.1.4.6 Acylation and alkylation
4.02.1.4.7 Mercuration
4.02.1.4.8 Diazo coupling
4.02.1.4.9 Nitrosation
4.02.1.4.10 Reactions with aldehydes and ketones
4.02.1.4.11 Oxidation
4.02.1.5 Attack at Sulfur
4.02.1.5.1 Electrophilic attack
4.02.1.5.2 Nucleophilic attack
41
41
41
42
42
43
43
44
44
45
46
46
47
47
47
48
48
49
49
50
51
51
53
54
54
55
55
55
55
55
57
57
57
58
58
59
59
59
59
60
61
61
61
39
40
Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.1.6 Nucleophilic Attack at Carbon
4.02.1.6.1 Hydroxide ion and other O-nucleophiles
4.02.1.6.2 Amines and amide ions
4.02.1.6.3 S-Nucleophiles
4.02.1.6.4 Halide ions
4.02.1.6.5 Carbanions
4.02.1.6.6 Reduction by complex hydrides
4.02.1.6.7 Phosphorus nucleophiles
4.02.1.7 Nucleophilic Attack at Hydrogen Attached to Ring Carbon or Ring Nitrogen
4.02.1.7.1 Metallation at a ring carbon atom
4.02.1.7.2 Hydrogen exchange at ring carbon in neutral azoles
4.02.1.7.3 Hydrogen exchange at ring carbon in azolium ions and dimerization
4.02.1.7.4 C-Acylation via deprotonation
4.02.1. 7.5 Ring cleavage via C-deprotonation
4.02.1.7.6 Proton loss from a ring nitrogen atom
4.02.1.8 Reactions with Radicals and Electron-deficient Species; Reactions at Surfaces
4.02.1.8.1 Carbenes and nitrenes
4.02.1.8.2 Free radical attack at the ring carbon atoms
4.02.1.8.3 Electrochemical reactions and reactions with free electrons
4.02.1.8.4 Other reactions at surfaces (heterogeneous catalysis and reduction reactions)
4.02.1.9 Reactions with Cyclic Transition States
4.02.1.9.1 Diels-Alder reactions and 1.3-dipolar cycloadditions
4.02.1.9.2 Photochemical cycloadditions
4.02.2 REACTIONS OF NON-AROMATIC COMPOUNDS
4.02.2.1 Isomers of Aromatic Derivatives
4.02.2.1.1 Compounds not in tautomeric equilibrium with aromatic derivatives
4.02.2.1.2 Compounds in tautomeric equilibrium with aromatic derivatives
4.02.2.2 Dihydro Compounds
4.02.2.2.1 Tautomerism
4.02.2.2.2 Aromatization
4.02.2.2.3 Ring contraction
4.02.2.2.4 Other reactions
4.02.2.3 Tetrahydro Compounds
4.02.2.3.1 Aroma tiza tion
4.02.2.3.2 Ring fission
4.02.2.3.3 Other reactions
4.02.2.3.4 Stereochemistry
4.02.3 REACTIONS OF SUBSTITUENTS
4.02.3.1 General Survey of Substituents on Carbon
4.02.3.1.1 Substituent environment
4.02.3.1.2 The carbonyl analogy
4.02.3.1.3 Two heteroatoms in the 1,3-positions
4.02.3.1.4 Two heteroatoms in the 1,2-positions
4.02.3.1.5 Three heteroatoms
4.02.3.1.6 Four heteroatoms
4.02.3.1.7 The effect of one substituent on the reactivity of another
4.02.3.1.8 Reactions of substituents not directly attached to the heterocyclic ring
4.02.3.1.9 Reactions of substituents involving ring transformations
4.02.3.2 Fused Benzenoid Rings
4.02.3.2.1 Electrophilic substitution
4.02.3.2.2 Oxidative degradation
4.02.3.2.3 Nucleophilic attack
4.02.3.2.4 Rearrangements
4.02.3.3 Alkyl Groups
4.02.3.3.1 Reactions similar to those of toluene
4.02.3.3.2 Alkylazoles: reactions involving essentially complete anion formation
4.02.3.3.3 Reactions of alkylazoles involving traces of reactive anions
4.02.3.3.4 C-Alkyl-azoliums, -dithiolyliums, etc.
4.02.3.4 Other C-Linked Substituents
4.02.3.4.1 Aryl groups: electrophilic substitution
4.02.3.4.2 Aryl groups: other reactions
4.02.3.4.3 Carboxylic acids
4.02.3.4.4 Aldehydes and ketones
4.02.3.4.5 Vinyl and ethynyl groups
4.02.3.4.6 Ring fission
4.02.3.5 Aminoazoles
4.02.3.5.1 Dimroth rearrangement
4.02.3.5.2 Reactions with electrophiles (except nitrous acid)
4.02.3.5.3 Reaction with nitrous acid: diazotization
4.02.3.5.4 Deprotonation of aminoazoles
4.02.3.5.5 Aminoazolium ions/neutral imines
61
62
64
66
66
66
68
69
69
69
69
70
71
71
72
72
72
72
73
74
75
75
77
77
77
77
78
78
78
78
79
79
80
80
80
80
81
81
81
81
82
82
83
83
83
83
84
84
85
85
86
86
86
87
87
88
88
89
91
91
91
92
93
94
94
94
94
95
96
97
97
Reactivity of Five-membered Rings with Two or More Heteroatorns 41
4.02.3.6 Other N-Linked Substituents 98
4.02.3.6.1 Nitro groups 98
4.02.3.6.2 Azidoazoles 98
4.02.3.7 O-Linked Substituents 98
4.02.3.7.1 Tautomeric forms: interconversion and modes of reaction 98
4.02.3.7.2 2-Hydroxy, heteroatoms-1,3 99
4.02.3.7.3 3-Hydroxy, heteroatoms-1,2 100
4.02.3.7.4 5-Hydroxy, heteroatoms-1,2 100
4.02.3.7.5 4- and 5-Hydroxy, heteroatoms-1,3 and 4-hydroxy, heteroatoms-1,2 101
4.02.3.7.6 Hydroxy derivatives with three heteroatoms 101
4.02.3.7.7 Alkoxy groups 102
4.02.3.8 S-Linked Substituents 102
4.02.3.8.1 Mercapto compounds: tautomerism 102
4.02.3.8.2 Thiones 102
4.02.3.8.3 Alkylthio groups 103
4.02.3.8.4 Sulfonic acid groups 104
4.02.3.9 Halogen Atoms 104
4.02.3.9.1 Nucleophilic displacements: neutral azoles 104
4.02.3.9.2 Nucleophilic displacements: halogenoazoliums 105
4.02.3.9.3 Other reactions 105
4.02.3.10 Metals and Metalloid-linked Substituents 106
4.02.3.11 Fused Heterocyclic Rings 107
4.02.3.12 Substituents Attached to Ring Nitrogen Atoms 107
4.02.3.12.1 N-Linked azole as a substituent 107
4.02.3.12.2 Aryl groups 107
4.02.3.12.3 Alkyl groups 108
4.02.3.12.4 Acyl groups 109
4.02.3.12.5 N-Amino and N-nitro groups 109
4.02.3.12.6 N-Hydroxy groups and N-oxides 110
4.02.3.12.7 N-Halogeno groups 110
4.02.1 REACTIONS AT HETEROAROMATIC RINGS
4.02.1.1 General Survey of Reactivity
In this initial section the reactivities of the major types of azole aromatic rings are briefly
considered in comparison with those which would be expected on the basis of electronic
theory, and the reactions of these heteroaromatic systems are compared among themselves
and with similar reactions of aliphatic and benzenoid cornpounds. Later in this chapter all
the reactions are reconsidered in more detail. It is postulated that the reactions of azoles
can only be rationalized and understood with reference to the cornplex tautomeric and
acid-base equilibria shown by these systems. Tautomeric equilibria are discussed in Chapter
4.01. Acid-base equilibria are considered in Section 4.02.1.3 of the present chapter.
4.02.1.1.1 Reactivity of neutral azoles
Replacing a CH group of benzene with a nitrogen atorn gives pyridine (1); replacing a
CH=CH group of benzene with NH, 0 or S gives pyrrole, furan or thiophene (3),
respectively.
O O Q
(1) (2) (3)
()
Z
(4)
0 '\
....N
Z
(5)
The azoles (4) and (5) may be considered to be derived from benzene by two successive
steps, one of each of these types. Hence, the chemistry of five-membered aromatic rings
with two or more heteroatoms shows similarities to both that of the five- and that of the
six-membered aromatic rings containing one heteroatom. Thus, electrophilic reagents attack
lone electron pairs on multiply bonded nitrogen atoms of azoles (cf. pyridine) (see Section
4.02.1.3), but they do not commonly attack electron pairs on heterocyclic nitrogen atoms
in NR groups or on heterocyclic oxygen or sulfur atoms (cf. pyrrole, furan, thiophene) (for
example, see Section 4.02.1.5.1).
42 Reactivity of Five-membered Rings with Two or More Heteroatorns
The carbon atorns of azole rings can be attacked by nuclcophilic (Section 4.02.1.6
electrophiIic (Section 4.02.1.4) and free radical reagents (Section 4.02.1.8.2). Sorne systern:
for example the thiazole, imidazole and pyrazole nuclei, show a high degree of arornati
character and usually 'revert to type' if the arornatic sextet is involved in a reaction. Other
such as the isoxazole and oxazole nuclei are less arornatic, and hence rnore prone to additio
reactions.
Electron donation frorn pyrrole-like nitrogen, or to a lesser extent frorn analogous sulft:
or oxygen atorns, helps electrophilic attack at azole carbon atorns, but as the nurnber (
heteroatorns in the ring increases, the tendency toward electrophilic attack at both C an
N decreases rapidly.
Just as electron displacement toward the nitrogen atom allows nucleophilic reagents t
attack pyridines at the a-position, similar displacements toward the nitrogens of the azolE
also facilitate nucleophilic attack at carbon. As in similar reactions with pyridine, forrnatio
of the initial adduct involves dearornatization of the ring. The subsequent fate of the addU(
depends in part on the degree of arornaticity. Those derived frorn highly arornatic azolE
tend to rearornatize, whereas those of lower arornaticity can take alternative reaction path
For rnost neutral azoles, nucleophilic attack at a ring carbon atorn is only possible wit
very strong nucleophiles,
Where azoles contain ring NH groups, this group is acidic and nucleophiles can rernov
a proton. Nucleophilic species can also remove ring-hydrogen atorns, particularly thos
which are a to a sulfur or oxygen atom, as in base-catalyzed hydrogen exchange an
metallation reactions (Section 4.02.1. 7).
4.02.1.1.2 Azolium salts
All neutral azoles possess positively charged azolium counterparts. In addition, as &
cussed in Chapter 4.01, certain 'olylium' species exist which have no neutral counterpart
for example dithiolylium salts.
Azoliurn systerns show rnuch lower reactivity than the corresponding neutral azoles towar
electrophiles at ring carbon. Even if an azoliurn ion contains an additional unquaternize
pyridine-like nitrogen, this nitrogen is hardly basic in character. By contrast, azoliurn catior
show a great reactivity toward nucleophiles: at ring carbon atorns, at the hydrogen of rir
CH and NH groups, and even at ring sulfur atoms.
In all these azoliums, oxolyliums and thiolyliurns the positive charge facilitates attack t
nucleophilic reagents at ring carbon atoms a or l' to the charged heteroatorn (Sectic
4.02.1.6). Hydroxide, alkoxide, sulfide, cyanide and borohydride ions, certain carbanion
amines and organornetallic compounds react under rnild conditions, usually at a positic
a to the quaternary center as in (6), to give initial non-arornatic adducts (7) which can t
isolated in certain cases but undergo further reaction with alacrity. The rnost irnportant (
these subsequent reactions include: (i) oxidation, e.g. the formation of cyanine dyes in tI-
thiazole series (Section 4.02.1.6.5(ii)); (ii) ring opening with subsequent closure, e.g. tt
reaction of dithiolyliurn salts with amines (Section 4.02.1.6.2); (iii) ring opening with01
subsequent closure, e.g. the reactions of oxazoliums with hydroxide ion (Sectic
4.02.1.6.5(ii)).
H Nu
\ c/ \ C H
\\ + Nu \
.....N- R ----+ .....N-R
(6) (7)
Ring hydrogen atorns can be abstracted from the a-carbon atorns of azolium ions b
strong bases, as demonstrated in base-catalyzed hydrogen exchange (Section 4.02.1.7.2
4.02.1.1.3 Azole anions
Azole anions are derived from imidazoles, pyrazoles, triazoles or tetrazoles by proto
loss frorn a ring NH group. In contrast to the neutral azoles, azole anions show enhance
reactivity toward electrophiles, both at the nitrogen (Section 4.02.1.3.6) and carbon atorr
(Section 4.02.1.4.1 (i)). They are correspondingly unreactive toward nucleophiles.
Reactivity of Five-membered Rings with Two or More Heteroatorns 43
4.02.1.1.4 Azolinones, azolinethiones, azolinimines
These compounds are usually written in the unionized forrn as in (8; Z = NH, NR, 0,
S). Canonical forms of types (9) or (10) are important, i.e. these compounds can also be
considered as betaines formally derived from azolium ions. Many compounds of this type
are tautorneric and such tautomerism is discussed in Section 4.01.5.2.
+
ß ( N\H I[ \H f/ H
z/ O z/'--.O- 'z9^--o-
(8) (9) (10)
Reactions of these compounds follow logically from the expected electron displacements
in the molecules. Their very varied chemical reactivity includes four main possibilities for
heterolytic reactions: electrophilic attack at a ring carbon atom ß to a ring heteroatom (e.g.
Section 4.02.1.4.2), or at a carbonyl oxygen atom (Section 4.02.3.7), a thiocarbonyl sulfur
atom (Section 4.02.3.8.2) or an imine nitrogen atom (Section 4.02.3.5.5). Nucleophilic
attack to remove hydrogen from an NH group (Section 4.02.1.3.6) or at a ring carbon atom
a to a ring heteroatom (Section 4.02.3.12.3) also needs to be considered.
The mode of attack of electrophilic reagents (E+) at ring carbon atoms is ß to the
heteroatoms as shown, for example, in (11) and (12); the interrnediates usually revert to
type by proton loss. Halogenation takes place more readily than it does in benzene (Section
4.02.1.4.5). Nitration and sulfonation also occur; however, in the strongly acidic environ-
ment required the compounds are present mainly as less reactive hydroxyazolium ions, e.g.
(13).
NH
z O
(11)
NH
z O
(12)
+
flNH
_)OH
Z
(13)
The reactions of electrophilic reagents at a carbonyl oxygen atom, a thiocarbonyl sulfur,
and an imino nitrogen atom are considered as reactions of substituents (see Sections 4.02.3.7,
4.02.3.8.2, 4.02.3.5.4 and 4.02.3.5.5).
The removal of a hydrogen atom from a heterocyclic nitrogen atom of azolones by
nucleophiles acting as bases, e.g. (14) (15), gives rnesomeric anions, e.g. (15) (16)
(17), which react exceedingly readily with electrophilic reagents, typically: (i) at nitrogen,
e.g. with alkyl halides (Section 4.02.1.3.9); (ii) at oxygen, e.g. with acylating reagents (Section
4.02.3.7); (iii) at the ß-carbon atoms, e.g. with halogens (Section 4.02.1.4.5), and in the
Reimer- Tiernann reaction (Section 4.02.1.4.6).
[ NI-i [ Ñ fiN e N
-+ --./!.._ -.---
sO SO sO SO
(14) (15) (16) (17)
4.02.1.1.5 N-Oxides, N-imides, N-ylides of azoles
Azole N-oxides, N-imides and N-ylides are formally betaines derived from N-hydroxy-,
N-amino- and N-alkyl-azolium compounds. Whereas N-oxides (Section 4.02.3.12.6) are
usually stable as such, in most cases the N-imides (Section 4.02.3.12.5) and N-ylides (Section
4.02.3.12.3) are found as salts which deprotonate readily only if the exocyclic nitrogen or
carbon atom carries strongly electron-withdrawing groups.
The reactivity of these compounds is somewhat similar to that of the azolonium ions,
particularly when the cationic species is involved. However, although the typical reaction
is with nucleophiles, the intermediate (20) can lose the N-oxide group to give the simple
a-substituted azole (21). Benzimidazole 3-oxides are readily converted into 2-chloroben-
zimidazoles in this way.
/\ E-
CH --.
I
0-
(18)
Nu-
-
<X:U -+ <;,ÀNU
I
OE
(20)
(21)
rÇbH
I
OE
(19)
44 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.1.2 Thermal and Photochemical Reactions Formally Involving No Other Species
We consider here fragrnentations and rearrangernents which involve only the azole
rnolecule itself, without the vital involvernent of any substituent or other rnolecule. Many
fragmentations of azoles can be surnmarized by the transforrnation (22) ..... (23) + (24), where
(23) represents a stable fragrnent, particularly N 2 , but also CO 2 , N 2 0, COS or HCN.
I/ \
,_/B
Z
(22)
--+ AB + . +--+ ( --+ Products
(23) Z Z
(248) (24bl
4.02.1.2.1 Thermal fragmentation
Therrnal and photochernical fragrnentation are often related to the rnass spectroscopic
breakdown of azole rnolecules (see Section 4.01.3.8), the latter often providing an indication
of the behavior of a given rno1ecule under such stirnuli. Such fragrnentations are facilitated
in the polynitrogenous azoles, and azoles containing several nitrogen atoms undergo ring
fission with loss of nitrogen. This is particularly noticeable when two adjacent pyridine-like
nitrogen atorns are present. Therrnolysis of (25) to give N 2 and a 1,3-dipole, such as
+ -
PhC = N-O, is a useful and general reaction. Azoles containing only two heteroatorns, such
as the pyrazole and thiazole systerns, are therrnally very stable.
Ph Ph
n
N, /N
S
O 2
(26)
Z-N
II \\
Y, /N
X
(25)
Although un substituted 1,2,5-thiadiazole is stable on heating at 220 o C, 3,4-diphenyl-
1 ,2,5-thiadiazole 1, I-dioxide (26) decornposes into benzonitrile and sulfur dioxide at 250 oC
(68AHC!9) 1 07).
Therrnal reactions of 1,4,2-dioxa-, 1,4,2-oxathia- and 1,4,2-dithia-azoles are surnrnarized
in Scherne 1. The reactive interrnediates generated in these therrnolyses can often be
trapped, e.g. the nitrile sulfide dipole with DMAD.
N ] Y R
RNCY +- RC/ u / RC=NS ---+ RCN
Y ZAX/ N
Scheme 1
1,2,3,4- Thiatriazoles readily decornpose therrnal into nitrogen, sulfur and an organic
fragrnent, usually a cyanide, e.g. (27) ..... BuiOCN + L N 14 N + S (76AHC<Z0)14S).
N-rN
Z ; \\
Bu'O .....I
s"...
(27)
Ph NPh Ph...... -::::-NPh (X N
[" 'N --+ ---+ I )Ph + PhN=C=NPh
'N :N: N (31)
H
(28) (29) (30)
Ph N Ph
1/\
N,O/S O
(32)
Ph NPh
1/\
N, /PPh 3
o
(33)
N-N
II \\
N'N/N
Ph
(34)
Other classes of heterocycles undergo thermolytic fragrnentation to give irnidolylnitrenes.
As typified by the therrnolysis of 1,5-diphenyltetrazole (28), the interrnediates (29) can
either cyclize on to arornatic rings to forrn benzirnidazoles (30) or undergo a Wolff-type
rearrangernent to carbodiirnides (31) (81AHC<Z8JZ31). Cornpounds (32) and (33) therrnolyze
to give rnainly the carbodiirnides (31) (79JA3976). Pentazoles (34) spontaneously forrn azides,
usually below 20 oc.
Reactivity of Five-membered Rings with Two or More Heteroatorns 45
4.02.1.2.2 Photochemical fragmentation
Photolysis of 1,2,3-thiadiazole (35) gives thiirene (36) which can be trapped by an alkyne
(70AHC(1l)1). 4,5-0iphenyl-l,2,3-thiadiazole (37) is photolyzed at low temperatures to the
thiobenzoylphenylcarbene triplet (38). Oiphenylthioketene (39) is formed on warming
(81AHC(28)231).
CF J
N I
1/ I lì's + ill
"s/ -N 2 C
(35) (36) F
J
CF J
--+ O CF
S J
Ph N
Ph( ;
S
(37)
Ph
Î:..
77K
Ph S
(38)
t!.
--+
Ph
>=C=S
Ph
(39)
3-Phenylthiazirine (40) can be isolated as an intermediate in the photolysis of 5-phenyl-
1,2,3,4-thiatriazole and also from other five-membered ring heterocycles capable of losing
stable fragments; see Scheme 2 (81AHC(28)231). Photolysis of 5-phenylthiatriazole in the
presence of cyc10hexene yields cyc10hexene episulfide (60CB2353) by trapping the sulfur atom.
N-N
Ph 1/ ''N
's....
N-S
Phl!..oAo
:7
Ph f
S
Y (40)
+/0-
N-N
PhI!.. ;'N
S
It!.
+ -
PhC:=N-S
It!.
PhCN + S
Scheme 2
o
r O
Ph(:w'N
S
Oiaziridine derivatives (42) can be obtained from tetrazoles of type (41).
RN-N
r II
X-0.,.N/N
R
(41)
hv =< N R
--+x I
NR
(42)
Mesoionic compounds undergo a variety of photochernical fragrnentations. Examples are
shown in which CO 2 or PhNCO is extruded (Schernes 3 and 4, respectively) (76AHC(19)1).
R 2 ÑRl R 2 NR '
1/ I f'.:.', -Ä R 2\,\'" fR 1
-O o;N --+ O O;N N
0-
PhN--(
/1 N--+
"N....
Ph
Ph
"
N=N +-
."
Ph
Scheme 3
I
N-f.O
I( ....NPh
N
Ph
Scheme 4
R'N-N
.J... ;\R2 R 1 -Ñ-N:=C-R 2
00 cO 2
o
PhN-f
(N"' N
Ph
\
N
+ PhNCO
Ph
46 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.1.2.3 Equilibria with open-chain compounds
Azoles of types (44) and (46) are isorneric with the open-chain compounds (43) and (45),
respectively. Rearrangernent between the two pairs is rapid and the therrnodynamically
stable isorner is encountered. Thus diazoketones (43; X = 0) exist as such, but
diazothioketones (43; X = S) spontaneously ring-close to thiadiazoles (44). 1,2,3-Triazoles
generally exist as such unless the nitrogen carries a strong electron-withdrawing substituent.
Thus l-cyano- and 1-arenesulfonyl-l,2,3-triazoles (47) undergo easy, reversible ring-
opening to diazo-imine tautorners (74AHC(16)33).
Stable for X = 0
Can be stable for X = NR
..0::: X
R-C::>"
I
CH=N 2
(43)
R X
--"" 1/ \\
'__...N
N
H
(44)
R X
--"" II I
...-- N, 'l' N
N
Stable for X = S
Can be stable for X = NR
R-C=X
I
N J
(45) (46)
R'
( N
II
R 2 N ....N
N
S02 Ar
(47)
--""
...--
R'X N2
R 2 N S02Ar
HOAc
IR'=Mel
H2CX.H
R 2 N NS0 2 Ar
A similar situation exists for rnolecules containing an azide group bonded to a doubly
bound carbon atorn as in (45). When X is oxygen, the acyl azide exists in the acyclic forrn
(45), but when X is sulfur the cyclic thiatriazole (46) predorninates. When X is nitrogen,
as in tetrazoles, the irnidoylazide (45) or the tetrazole (46) rnay predorninate, or both may
exist in equilibriurn. The position of the tetrazole-irnidoylazide equilibriurn depends on the
following factors: (1) electron-withdrawing substituents favor the azide forrn; (2) higher
ternperature favors the azide forrn; and (3) polar solvents tend to favor the tetrazole forrn,
and non-polar solvents the azide form. Ring strain is also irnportant and two fused five-
mernbered rings are in general avoided. For exarnple, in the tetrazolothiadiazole equilibriurn
(48) (49), the systern exists in the bicyclic forrn in the solid state and in the azide forrn
in carbon tetrachloride solution (77AHC(21)323). Fusion with six-rnernbered rings generally
is rnore favorable to a bicydic tetrazole form. For exarnple, pyridine fusion gives essentially
all tetrazole (50) (69TL2S9S).
N-N-N1\ N-N
R(' I N Rtf \\N 3
S N "s/
(48) (49)
o
I( ..- I N 3
N===N
(50)
4.02.1.2.4 Rearrangement to other heterocyclic species
Many exarnples are known of rearrangernent of azoles involving scrarnbling of the ring
atorns to give a new isorneric azole rnolecule. Different rnechanisrns are involved.
For isoxazoles the first step is the fission of the weak N -0 bond to give the diradical
(51) which is in equilibriurn with the vinylnitrene (52). Recyclization now gives the
substituted 2H-azirine (53) which via the carbonyl-stabilized nitrile ylide (54) can give the
oxazole (55). In sorne cases the 2H-azirine, which is forrned both photochernically and
therrnally, has been isolated; in other cases it is transforrned quickly into the oxazole
(79AHC<2S)147).
The photorearrangernent of pyrazoles to irnidazoles is probably analogous, proceeding
via irninoylazirines (82AHC(30)239); indazoles sirnilarly rearrange to benzirnidazoles
(67HCA2244). 3-Pyrazolin-S-ones (56) are photochernically converted into irnidazolones (57)
and open-chain products (58) (70AHC(11)1). The 1,2- and 1,4-disubstituted irnidazoles are
interconverted photochernically.
Reactivity of Five-membered Rings with Two or More Heteroatorns 47
[ R 3 R 3 R 4
R 3 R 4
sP +--+ ï.'
l:;)R Ìf5Rs RS
(51)
\
P
R 3 R 4 J
ì==(
:N: CORs
(52)
N J R4 R3C:=N-ë-cORs R3 CORS
R ß RS P R I 4 P 7
"0 N
(55) (54) (53)
A hv
MeN,j --+
N 0
Ph
(56)
h
MeN NPh + MeCOCH 2 -N-C0 2 Me
Y J,h
o
(57) (58)
Irradiation of isothiazole gives thiazole in low yield. In phenyl-substituted derivatives an
equilibrium is set up between the isothiazole (59) and the thiazole (61) via interrnediate
(60) (nAHC(14)1).
ri: r : l F\
's/ L \/ V
+
(59) (60) (61)
Iminobenzodithioles (62) and benzisothiazolethiones (63) therrnally equilibrate
(nAHC(14)43).
NR
CC I s
::::,..,. I
S
(62)
S
NR
Sl
(63)
Mesoionic compounds of the type designated (76AHC(19)1) as 'A' are capable of isomerisrn.
In one case in the 1,2,4-triazole series, isornerisrn of the pair (64) (65) has been
demonstrated (67TL4261).
+
N-NR HN-NR HN-NR HN-NR
/1 \\ EtOH / \ I \\ / \
-.A.... X ?-.... XOEI c,_ x, Y ?-.... ....XOEt
z y.... Z y.... Z Y OEt Z
(64)
..---
N-ÑR
/1 \\
ÿ.A.... z / X
(65)
4.02.1.2.5 Polymerization
Imidazoles and pyrazoles with free NH groups form hydrogen-bonded dimers and
oligomers (66AHC(6)347).
4.02.1.3 Electrophilic Attack at Nitrogen
4.02.1.3.1 Introduction
Reactions of this type can be related to the chemistry of simple tertiary aliphatic amines.
Thus the lone pair of electrons on the nitrogen atom in trimethylamine reacts under mild
conditions with the following types of electrophilic reagents: (i) proton acids give salts; (ii)
Lewis acids give coordination compounds; (iii) transition metal ions give complex formation;
(iv) reactive halides give quaternary salts; (v) halogens give adducts; and (vi) certain oxidizing
agents give amine oxides. The analogous reactions of pyridines with these electrophilic
48 Reactivity of Five-membered Rings with Two or More Heteroatorns
reagents at the lone pair on the nitrogen atorn are well known. All neutral azoles contain
a pyridine-like nitrogen atorn and therefore sirnilar reactions with electrophiles at this
nitrogen would be expected. However, the tendency for such reactions varies considerably;
in particular, successive heteroatorn substitutions markedly decrease the ease of reaction.
One convenient quantitative rneasure of the tendency for such reactions to occur is found
in the basicity of these cornpounds; this is treated in Section 4.02.1.3.5.
In azoles containing at least two annular nitrogen atorns, one of which is an NH group
and the other a multiply-bonded nitrogen atorn, electrophilic attack occurs at the latter
nitrogen. Such an attack is frequently followed by proton loss frorn the NH group, e.g.
(66) -+ (67). If the electrophilic reagent is a proton, this reaction sequence sirnply rneans
tautorner interconversion (see Section 4.01.5), but in other cases leads to the product.
E+
NE NE
() -(\\-()
N N'" N
H H (67)
(66)
4.02.1.3.2 Reaction sequence
n
Me<':"N;N,
H
(6S)
Me ÇN H
t
(69)
Since the electrophilic reagent attacks the rnultiply-bonded nitrogen atorn, as shown for
(68) and (69), the orientation of the reaction product is related to the tautorneric structure
of the starting material. However, any conclusion regarding tautorneric equilibria frorn
chernical reactivity can be rnisleading since a rninor cornponent can react preferentially and
then be continually replenished by isornerization of the rnajor component.
In addition to reaction sequences of type (66) -+ (67), electrophilic reagents can attack
at either one of the ring nitrogen atorns in the rnesorneric anions forrned by proton loss
(e.g. 70 -+ 71 or 72; see Section 4.02.1.3.6). Here we have an arnbident anion, and for
unsyrnrnetrical cases the cornposition of the reaction product (71) + (72) is dictated by steric
and electronic factors.
()_().-() () or
N N N N
H E
(70) (71)
( NE
)
N
(72)
4.02.1.3.3 Orientation in azote rings contqining three or four heteroatorns
Such cornpounds contain two or three 'pyridine-like' heteroatorns. For the syrnrnetrical
systerns (73) and (74), no ambiguity occurs, but for systerns (75)-(78) there are at least two
alternative reaction sites. It appears that reaction takes place at the nitrogen atorn furthest
away frorn the 'pyrrole-like' heteroatorn, as shown in (75)-(77) where evidence is available
frorn reactions with alkylating reagents (Section 4.02.1.3.8).
N-N . 0Ñ
II \\ [ II II \\
"x./ x.... N "x.... N
(74) (75) (76)
n
N, ....N
X
(73)
N- N"')
II II
"x.... N
(77)
Sirnilar arnbiguities arise in the reactions of azole anions. At least as regards alkylation
reactions in the 1,2,3-triazole series (79), the product appears to depend on the reagent
used. In the 1,2,4-triazole series (80) a single product is forrned, whereas tetrazole (81)
gives rnixtures.
N (N ( N-N
f/ II II ( II
N, ....N Ñ.... N '\ -....N)
X .) Me Nt N J N)
(7S) Me!
(SO) /S1)
(79)
Reactivity of Five-membered Rings with Two or More Heteroatorns 49
4.02.1.3.4 Effect of azole ring structure and of substituents
The ease of attack by an electrophilic reagent at the nitrogen atom. of any azole is
proportional to ÁE between the ground state and transition state energies. However, ground
state structure largely controls the variation in these differences, which hence depend on
the electron density on the basic nitrogen atom and the degree of sterk hindrance. The
number, orientation and type of heteroatoms are very irnportant in deterrnining electron
density. Additional 'pyridine-like' nitrogen atoms always reduce the electron density at
another 'pyridine-like' nitrogen (compare the reduced basicities of diazines relative to
pyridine). Unshared electron pairs on two 'pyridine-like' nitrogen atorns can interact, but
the effect on reactivity appears to be small (78AHC(22)71). In the case of 'pyrrole-like'
nitrogen, oxygen and sulfur there are two rnutually opposed effects: base-strengthening
rnesomeric electron donation and base-weakening inductive electron withdrawal. The latter
is particularly strong for heteroatoms in the a-position and in fact for oxygen and sulfur
always dominates over the base-strengthening effect.
The effects of substituents rnay be rationalized as follows. (i) Strongly electron-with-
drawing substituents (e.g. NO z , COR, CHO) rnake these reactions more difficult by decreas-
ing the electron density on the nitrogen atorn(s). The effect is largely inductive and therefore
is particularly strong frorn the a-position. (ii) Strongly electron-donating substituents (e.g.
NH 2 , OR) facilitate electrophilic attack by increasing the electron density on the nitrogen.
This is caused by the mesorneric effect and is therefore strongest from the a- and ,,-positions.
(iii) Fused benzene rings, aryl and alkyl groups, and other groups with relatively weak
electronic effects have a relatively small electronic influence.
The foregoing electronic effects are illustrated by the pKa values given in Section
4.02.1.3.5. Reactions other than proton addition are hindered by all types of a-substituents.
However, steric hindrance is less in these five-rnernbered ring heterocycles than that in
pyridines because the angle subtended between the nitrogen lone pair and the a-substituent
is significantly greater in the five-mernbered ring cornpounds and thus the substituent is
held further away frorn the lone pair.
4.02.1.3.5 Proton acids on neutral azoles: basicity of azoles
Mesorneric shifts of the types shown in structures (82) and (83) increase the electron
density on the nitrogen atorn and facilitate reaction with electrophilic reagents. However,
the heteroatom Z also has an adverse inductive effect; the pKa of NHzOH is 6.0 and that
of N2 is 8.0, both considerably lower than that of NH 3 which is 9.5.
[J
ZJ
(82)
n;;
)
(83)
Gas-phase pKa values for azoles are unavailable except for imidazole and 1-methyl-
imidazole. Imidazole is ca. 75 kJ mol-I more basic than amrnonia, i.e. approximately the
same as pyridine; I-methylimidazole is about 29 kJ rnol- I more basic than irnidazole
(82PC40200).
Tetrazoles are preferentially protonated at N-4.
The basicities of the parent azole systems in water are shown in Table 1. When both
heteroatoms are nitrogen, the rnesorneric effect predorninates when the heteroatoms are
in the 1,3-positions, whereas the inductive effect predorninates when they are in the
1,2-positions. The predorninance of the rnesomeric effect is illustrated by the pKa value of
imidazole (82; Z = NH), which is 7.0, whereas that of pyrazole (83; Z = NH) is 2.5 (cf.
pyridine, 5.2). An N-rnethyl group is base-strengthening in imidazole, but base-weakening
in pyrazole, probably because of steric hindrance to hydration. When the second heteroatom
is oxygen or sulfur the inductive, base-weakening effect increases; the pKa of thiazole (82;
Z = S) is 3.5 and that of isoxazole (83; Z = 0) is 1.3.
Substituents are expected to alter the electron density at the rnultiply-bonded nitrogen
atorn, and therefore the basicity, in a rnanner similar to that found in the pyridine series.
The rather lirnited data available appear to bear out these assurnptions. The additional ring
nitrogen atoms in triazoles, oxadiazoles, etc. are quite strongly base-weakening; this is as
50 Reactivity of Five-membered Rings with Two or More Heteroatoms
Table 1 pKa Values for Proton Addition (63PMH,III. 71 PMH,31 I. B. 76MI40200. B-76MI402" I)
X Ring systems
() ( \ N n
n Z
/N /N /N N, ,--N
X X X X X
NH 2.52 6.95 1.17 2.45 11.17)
NMe 2.06 7.33 1.25 3.20 <1
0 -2.97 0.8
S -0.51 2.53 -4.9
(ÇN ()::) (XN>
::::,.. "'N l
::::,.. I ::::,.. X
X
NH 1.31 5.53
NMe 0.42 2.02 5.57
0 -4.7 -2.20 -0.13
S -0.05 1.2
expected since diazines are weaker bases than pyridine. As regards C-substituents, their
effects on the pKa of the parent cornpounds are as follows. (i) Methyl groups are weakly
base-strengthening due to their rnesorneric and inductive electron donor effect: thus in the
methylthiazoles the base strengths decrease in the order 2> 4 > 5. (ii) Phenyl groups are
weak resonance donors, but inductive acceptors. Phenyl groups are therefore expected to
reduce the basicity of azoles. (iii) Amino groups are strong resonance electron donors and
hence base-strengthening, particularly if directly conjugated with the basic center. (iv)
Methoxy groups are resonance donors but inductive acceptors. The inductive effect would
be expected to be dorninant for azoles. (v) Halogen atorns are inductive acceptors (and
weak resonance donors); they are expected to cause a rnarked decrease in basicity, especially
frorn a-positions. (vi) Fused benzene rings usually have little effect; cf. the pKa values of
irnidazole and benzirnidazole. Substituents on the benzene ring in benzazoles should have
little effect on the basicity.
Annular nitrogen atorns can forrn hydrogen bonds, and if the azole contains an NH
group, association occurs. Imidazole (84) shows a cryoscopic rnolecular weight in benzene
20 tirnes that expected. Its boiling point is 256 0 C, which is higher than that of I-methyl-
imidazole (198 oc).
{ , ß:::::::.,
N".HN I
/ N"'HN N"'H-N/ }
\.d '
(84)
4.02.1.3.6 Proton acids on azote anions: acidity of azotes
The acidities of the five parent corn pounds are compared with that of pyrrole in Table
2. The acidity of the ring systern increases as the nurnber of nitrogens increases, the acidity
of pyrrole increasing by approximately 2, 4.5 and 5 pKa units for each successive addition
of a nitrogen atom. 1,2,3-Triazole is slightly rnore acidic than 1,2,4-triazole, but the effect
on NH acidity of nitrogen orientation is rnuch less than the effect of the total nurnber of
nitrogens (71PMH(3)1).
Table 2 pKa Values of Azoles for Proton Loss (B-7bMI40200.
B-76MI40201)
Nitrogen Nitrogen
positions pKa positions pKa
1 16.5 1,2,3 9.26
1,2 14.21 1,2,4 10.ü4
1,3 14.44 1,2,3,4 4.89
Reactivity of Five-membered Rings with Two or More Heteroatorns 51
Ring substituents can have a considerable effect on the acidity of the systern. In the
1,2,4-triazole series a 3-arnino group decreases the acidity to 11.1, a 3-methyl group to
10.7, whereas a 3-phenyl group increases the acidity to 9.6, and 3,5-dichloro substitution
to 5.2 (71PMH(3)1).
4.02.1.3.7 Metal ions
(i) Simple complexes
Many exarnples are known of cornplexes between rnetal cations and both neutral azoles
and azole anions. Overlap between the d-orbitals of the rnetal atorn and the azole 7T-orbitals
is believed to increase the stability of rnany of these complexes.
Despite the weak basicity of isoxazoles, cornplexes of the parent methyl and phenyl
derivatives with numerous rnetal ions such as copper, zinc, cobalt, etc. have been described
(79AHC(2S)147). Many transition rnetal cations form cornplexes with irnidazoles; the coordina-
tion number is four to six (70AHC(12)103). The chernistry of pyrazole complexes has been
especially well studied and coordination cornpounds are known with thiazoles and 1,2,4-
triazoles. Tetrazole anions also forrn good ligands for heavy rnetals (77AHC(21)323).
Isothiazoles react with hexacarbonyls M(CO)6 to give N -coordinate M(CO)s derivatives.
(ii) Chelate complexes
Chelate rings can be forrned by azoles containing a-substituents such as carbonyl or
CH=NH groups. An irnportant bidentate chelating agent is histidine (85), and many
pyrazoles with substituent groups are known which forrn bis and tris complexes with rnany
metals, e.g. (86). Similarly, 2- and 4-a-pyridylthiazoles are bidentate chelating agents.
Complex forrnation of this type has analytical applications; thus 1,3,4-thiadiazole-2,5-
dithione has been used as a spot test for bisrnuth and other rnetals (S8MI40200).
+
J:.NH
-02C-CH-CH2 N;\
I H
H3
(85)
(86)
4.02.1.3.8 Alkyl halides and related compounds: azoles without a free NH group
Pyrazoles and imidazoles carrying a substituent on nitrogen, as well as oxazoles, thiazoles,
etc., are converted by alkyl halides into quaternary salts. This is illustrated by the preparation
of thiarnine (89) frorn cornponents (87) and (88).
Me Me + .......CH 2 L N
I/ \ BrCH2 C N I/N I I
HOCH 2 CH/,S/ + H 2 N )Me -+ HOCH 2 CH/,S;\ H 2 N Me
(87) (88) (89)
Azoles having heteroatoms in the 1,3-orientation are rnore reactive than those in which
the arrangement is 1,2. However, the rnagnitude of the factor varies. Thus oxazole is 68
times rnore reactive than isoxazole, whereas benzoxazole quaternizes 26 tirnes faster than
does 1,2-benzisoxazole (78AHC(22)71).
These reactions are of the S N 2 type and are sensitive to steric effects of substituents in
the azole ring. However, these steric effects are significantly less than, for example, in the
analogous pyridine derivatives because the angle subtended by the nitrogen lone pair and
an a-substituent is about 70 0 in an azole as opposed to 60 0 in pyridine. Thus the rate
constant for methylation of 2-t-butylthiazole by rnethyl iodide is only 40 times less than
that for the corresponding 2-methyl compound. By comparison, in the pyridine series the
retardation factor is over 2000 in the same solvent (nitrobenzene). As in six-mernbered
rings, the kinetic consequences of the steric effects of o-alkyl groups are related to the Es
parameter. However, buttressing groups can cause special effects as has been investigated
extensivelv in the thiazole series.
52 Reactivity of Five-membered Rings with Two or More Heteroatorns
Annulation of a five-membered aza ring to a benzo ring generally leads to rate retardation
in N-quaternization reactions similar in rnagnitude to that for six-rnernbered rings. Excep-
tions are known: 2, I-benzisoxazole undergoes N-rnethylation faster than isoxazole, and in
2,1,3-benzoxadiazole and 2,1-benzisothiazole the rates are little changed frorn the corres-
ponding rnonocyclic rings; however, here we are dealing with o-quinonoid structures. The
more usual situation is rate retardation by a rnoderate arnount. This is probably caused not
by steric effects, but by electronic effects, as is shown by the corresponding influence on
the pK" values (78AHC(22)71).
Satisfactory Brønsted correlations for a-substituted azoles offer further evidence of the
lesser irnportance of steric effects in the azole series (78AHCl22)71).
For both azole and benzazole rings the introduction of further heteroatorns into the
ring affects the ease of quaternization. In series with the sarne nurnber and orientation
of heteroatorns, rate constants increase in the order X = 0 < S < SMe (d. Table 3)
(7SAHC(22)71). The quaternization of triazoles, thiadiazoles and tetrazoles requires stronger
reagents and conditions; rnethyl fluorosulfonate is sornetirnes used (78AHC<22)71). The l-
or 2-substituted 1 ,2,3-triazoles are difficult to alkylate, but rnethyl fluorosulfonate succeeds
(71 ACS2(87).
Table 3 Heteroatom and Benzo-fusion Effects on Relative
Rate Constants for N-Mcthylation (78AHC!22J71)
k,",
Hl!rl!roc 'C!1! 0 S NMe
0 6.9 120
/N
X
() r 912)
X 61
N \2 56 )
:::::,... I
X 2.8
cç ( .6 33 )
:::::,... :--'N} 9.2
(XN> ( .3 708)
:::::,... X 76
():N,X 2.8
:::::,... :--. I
N
Oxadiazoles are difficult to alkylate, unless the ring contains a strong electron donor group
such as an amino substituent.
1,2,3- Thiadiazoles are quaternized to give 3- or rnixtures of 2- and 3-alkyl quaternary
salts. In 5-arnino-l,2,4-thiadiazole, quaternization takes place at the 4-position (90)
(MAHC(3)I). I-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-
substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) (64AHC(3)1).
I'.:l.Me
"
\\
H1N( /N
S
(90)
"N
II \\
" /N
N
R
(91)
N\\
/N
N.)
(92)
Reactivity of Five-membered Rings with Two or More Heteroatorns 53
5-Substituted 1,2,3,4-thiatriazoles (93) are alkylated only under very forcing conditions
with triethyloxonium fluoroborate, but then give the expected products (94) (75JOC431).
+
N-N O . F . N-NEt
II \\ Et, B.) II \\ BF;
X's/N X'S/N
(93) X = SEt, SMe, Ph (94) X = SEt, SMe, Ph
I-Alkyl-S-phenyltetrazoles are converted into 2-alkyl isorners on heating with alkyl
iodide, presurnably by quaternary salt forrnation followed by elirnination of alkyl iodide to
give the therrnodynarnically rnore stable isorner (Scheme 5) (77AHC(21)323).
+
RN-N N-N N-NR N-NR
\\ II \\ II \\ II \
Ph ",-+/N RI Ph, /N ...-- Ph, /N ...-- Ph, N
N N r- N
R r R R
Scheme 5
1,2,4-Thiadiazole with Me30+BF; gives the diquaternary salt (95); diquaternary salts
are also known in the 1,2,4-triazole series. 1,3-Disubstituted 1,2,4-triazoliurn salts can be
further alkylated to diquaternary derivatives.
+
Me ,,+
( ....NMe
S
(95)
4.02.1.3.9 Alkyl halides and related compounds: compounds with a free NH group
Pyrazoles and imidazoles with free NH groups are readily alkylated, e.g. by MeI or
MezS04' A useful procedure is to use the alkyl salt of the azole in liquid arnmonia
(80AHC(27)241). However, alkylation can also occur under neutral conditions, particularly
with imidazoles.
Unsyrnmetrical imidazoles and pyrazoles usually give a rnixture of products, the composi-
tion of which rnay depend on the reaction conditions. Thus the ethoxycarbonylpyrazole
(97) gives predorninantly the isorneric N-rnethyl derivatives (96) and (98) under the
conditions indicated. The difference in orientation can be related to the stabilization of the
tautorneric structure (97) by hydrogen bonding (possibly intrarnolecular), which rneans that
alkylation of the free base gives (98). The isorner (96) is forrned via the anion. Benzylation
of (97) gives mainly the analogue of (98) (80JHC137).
Me
j[J
EtOC N....N
\\ /
o-"H
(97)
Me
n
Et02C _ .;N
N
Me
(96)
i,Na
ii,Mel
Mel
Me
Et0 2 C (;N Me
N
IOO'C
(98)
The differential effects of steric hindrance and tautomeric content in the irnidazole series
are illustrated in Scherne 6 (80AHC(27)241).
Ph [ NMe
)Me
N
(15%)
Me,S? Ph N Ph NH
c (ScZ1ij" [
slow ../Me"'-- )Me
N N
H (minor tautomer)
(major tautomer)
Scheme 6
Mc,SO. Ph N
fS,.Z'J t .r"
fast .,/Me
N
Me
(85%)
N-Unsubstituted 1,2,3-triazoles are rnethylated rnainly in the I-position with methyl
iodide and silver or thalliurn salts, but rnainly in the 2-position by diazornethane. There is
also sorne sterk control. For exarnple, 4-phenyl-l,2,3-triazole with dimethyl sulfate gives
the 2-methyl-4-phenyl (38%) and I-rnethyl-4-phenyl isorners (62%), but none of the more
hindered I-methyl-S-phenyltriazole (74AHC(16)33). N-Unsubstituted 1,2,4-triazoles are gen-
erally alkylated at N-l.
54 Reactivity of Five-membered Rings with Two or More Heteroatorns
Alkylation of tetrazoles as the anions gives mixtures of 1- and 2-alkyl isorners. In general,
electron-donating substituents in the 5-position slightly favor alkylation of the I-position
and electron-withdrawing 5-substituents slightly favor the 2-position.
Azolone anions are readily alkylated at nitrogen, e.g. 2-triazolone with methyl iodide
gives the I-methyl derivative.
N-Arylation of azoles is achieved either by using arynes, activated halobenzenes (e.g.
dinitro) or under Ullmann conditions. Thus benzyne reacts with irnidazoles to give N-
arylirnidazoles (70AHC< 12)103), and these compounds have also been prepared under rnodified
Ullmann conditions.
N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael
reactions, for exarnple acetylenecarboxylic esters and acrylonitrile readily form the expected
addition products. Styrene oxide gives rise, for example, to 1-styrylirnidazoles (76JCS(P1 )545).
Benzirnidazole reacts with formaldehyde and secondary amines in the Mannich reaction to
give 1-aminornethyl products.
4.02.1.3.10 Acyl halides and related compounds
Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-
pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) (67)
or type (70) (71) or (72). Such reactions have been carried out with benzoyl halides,
sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under
Schotten-Baumann conditions or in inert solvents. When two isomeric products could result,
only the thermodynamically stable one is usually obtained because the acylation reactions
are reversible and the products interconvert readily. Thus benzotriazole forms I-acyl
derivatives (99) which preserve the "Kékulé resonance' of the benzene ring and are therefore
more stable than the isorneric 2-acyl derivatives. Acylation of pyrazoles also usually gives
the more stable isomer as the sole product (66AHC<6)347). The imidazole-catalyzed hydrolysis
of esters can be classified as an electrophilic attack on the rnultiply bonded imidazole
nitrogen.
(X I \N
I
N
COR
(99)
Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of,
for example, imidazoles to give the sterically less favored derivative. This principle is
illustrated in Scheme 7 (80AHC<27)241).
N
Me[)R
N
H
or AcCI: Mt'Cl\'; Et:;N
AC20lrcfluxJ
Me N
[)R
N
COMe
PhCH,Br
MeCN
Mt-NCH Ph
(. JR 2
N Br-
COMe
Olr
-----+
Me [ NCH 2 Ph
)R
N
Scheme 7
1,2,3- Triazoles are acylated with acyl halides, usually initially at the I-position, but the
acyl group may migrate to the 2-position on heating or on treatment with base. Thus
acetylation with acetyl chloride often gives I-acetyl derivatives, which rearrange to the
2-isomers above 120 oC (74AHC< 16)33).
Whether tetrazoles are acylated in the 1- or 2-position depends on the 5-substituent.
2-Acyltetrazoles are unstable (see Section 4.02.3.12.4) (77AHC<21)323); 1-alkylsul-
fonyltriazoles are also unstable (see Section 4.02.1.2.3).
4.02.1.3.11 Halogens
At room temperature, N-unsubstituted azoles react with halogens and interhalogens (e.g.
lei) to give N-halogenoazoles, probably via unstable adducts. Thus imidazoles with halogens
forrn N-halogeno compounds, which easily rearrange to form C-halogenoimidazoles
(70AHC<12)103). N-Halogenopyrazoles are unstable and act as halogenating agents. N-
Reactivity of Five-membered Rings with Two or More Heteroatorns 55
Halogeno-l,2,4-triazoles are more easily isolated, especially when the 3,5-positions are
substituted.
4.02.1.3.12 Peracids
Pyridine I-oxides are formed in good yield on treatment of pyridines with peracids,
although pyridine reacts less readily than do aliphatic tertiary amines. Azoles generally
react even less readily, and N-oxides of azoles can rarely be formed in this way. However,
some exarnples are known. Thus l-rnethylpyrazole gives the 2-oxide, 2,4-dimethylthiazole
(100) the 3-oxide (101) (B-71MI40200) and 1,2,3-thiadiazoles the 3-oxides. 5-
Phenylthiatriazole (102) gives the 3-oxide (103) with peroxytrifluoroacetic acid (75T1783).
More frequently, attempted N-oxide formation affords azolones or ring-cleaved derivatives,
probably by nucleophilic attack of a peroxide anion on the azolium ion (cf. Section
4.02.1.6.1). Thus attempted conversion of oxazoles into N-oxides fails and leads to ring
opening (74AHC(17)99), and rnost thiazoles are extensively degraded.
Mer N
!C)Me
S
(100 )
CF,CO,H
þ
0-
N-Ñ/
Ph II \\
"S/N
(103)
perphthalic
acid
o-
M +/
e N
[)Me
S
(101)
N-N
Ph II \\
"S /N
(102)
4.02.1.3.13 Aminating agents
Amination at an azole ring nitrogen is known for N-unsubstituted azoles. Thus 4,5-
diphenyl-l,2,3-triazole with hydroxylarnine-O-sulfonic acid gives approximately equal
amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords
(106) and indazole gives comparable amounts of the 1- and 2-amino derivatives.
Me
+
I N-NH 2
:::::,... I
N
Me
(107)
Ph N
Ph'f/ \\
Z.../N
N
I
NH 2
(104)
Ph _N
Phr=/
N 'NH 2
(105)
n
z. ;N
N
I
NH 2
(106)
Azoles without a free NH group are also aminated, giving N -aminoazolium salts, e.g.
(107) (81AHC(29)71).
4.02.1.3.14 Other Lewis acids
Azoles can form stable compounds in which metallic and metalloid atoms are linked to
nitrogen. For example, pyrazoles and imidazoles N-substituted by B, Si, P and Hg groups
are made in this way. Imidazoles with a free NH group can be N-trimethylsilylated and
N-cyanated (with cyanogen bromide). Irnidazoles of low basicity can be N-nitrated.
4.02.1.4 Electrophilic Attack at Carbon
4.02.1.4.1 Reactivity and orientation
(i) Ease of reaction
Replacing a CH=CH group in benzene with a heteroatorn (Z) increases the susceptibility
of the ring carbon atorns to electrophilic attack noticeably when Z is S, more when Z is 0,
and very markedly when Z is NH (cf. Chapter 3.02). Replacing one CH group in benzene
with a nitrogen atom decreases the ease of electrophilic attack at the remaining carbon
atoms (cf. Chapter 2.02); replacement of two CH groups with nitrogen atorns decreases it
further (cf. Chapter 2.02). Such deactivation is very strong in nitration, suIfonation and
56 Reactivity of Five-membered Rings with Two or More Heteroatorns
Friedel-Crafts reactions, which proceed in strongly acidic media, i.e. under conditions in
which the nitrogen atorn is largely protonated (or cornplexed). The effect of a protonated
nitrogen atom is considerably greater than, for exarnple, the two nitro groups in m-
dinitrobenzene. The deactivating effect is less pronounced in reactions conducted under
neutral or weakly acidic conditions, where a large proportion of unprotonated free base
exists, i.e. as in halogenation and mercuration reactions.
In azote chemistry the total effect of the several heteroatoms in one ring approximates
the superposition of their separate effects. It is found that pyrazole, irnidazole and isoxazole
undergo nitration and sulfonation about as readily as nitrobenzene; thiazole and isothiazole
react less readily (ca. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles,
etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration
or sulfonation. Strong electron-donor substituents help the reaction.
Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic
solution. Under these conditions they react with electrophilic reagents almost as readily as
phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased
reactivity of pyrrole anions over the neutral pyrrole species).
eN
N
(108)
N
()
N
(109)
W) Orientation
A rnultiply bonded nitrogen atorn deactivates carbon atorns a or y to it toward elec-
trophilic attack; thus initial substitution in 1,2- and 1,3-dihetero cornpounds should be as
shown in structures (110) and (111). Pyrazoles (110; Z = NH), isoxazoles (110; Z = 0),
isothiazoles (110; Z=S), irnidazoles (111; Z=NH, tautornerism can rnake the 4- and
5-positions equivalent) and thiazoles (111; Z = S) do indeed undergo electrophilic substitu-
tion as expected. Little is known of the electrophilic substitution reactions of oxazoles (111;
Z = 0) and compounds containing three or rnore heteroatoms in one ring. Deactivation of
the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable
double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of
imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112).
E'
(_)-1
fJ.
(110)
E-tj
Z
(111)
E+
R z/
(112)
Ç E+
(113)
The above considerations do not necessarily apply to reactions of electrophilic reagents
with pyrazole and imidazole anions (108, 109). The imidazole anion is sometimes substituted
in the 2-position (113) and the indazole anion in the 3-position (cf. Section 4.02.1.4.5).
Wi) Effect of substifl/ents
Just as in benzene, substituents can strongly activate (e.g. NH 2 , NMe2, OMe), strongly
deactivate (e.g. N0 2 , S03H, C0 2 Et) or have relatively little effect on (e.g. Me, Cl) the ring
toward further substitution. Further electrophilic substitution generally will not take place
on an azole which carries a strongly deactivating substituent unless the azole ring is also
carrying a strong electron-donor group or is strongly activated, as it is in the azolone forrn.
However, these considerations can be affected by basicity considerations: thus a strongly
deactivating group can also increase the amount of rnore reactive neutral molecule cornpared
with a less reactive cation.
When the preferred substitution position (cf. 110 and 111) is occupied, activating sub-
stituents can facilitate substitution in other positions (cf. exarnples in Sections 4.02.1.4.2
and 4.02.1.4.5); ipso attack can also occur if the substituent is itself easily displaced.
In benz- and phenyl-azolones, electrophilic substitution often occurs in the benzene ring;
such reactions are considered as reactions of substituents (see Sections 4.02.3.2.1 and
4.02.3.4.1 L
Reactivity of Five-membered Rings with Two or More Heteroatoms 57
4.02.1.4.2 Nitration
Nitration of rnonocyc1ic compounds is surnmarized in Table 4. Substitution occurs in the
expected positions. The reaction conditions required are more vigorous than those needed
for benzene, but less than those for pyridine. Ring nitration of oxazoles is rare, but (114)
has been obtained in this way (74AHC(17)99).
Ph N
[ )NMe l
o
H 2 S0 4 + HNO,.
-4'C
P- O lNC 6 H ( N
r \\
OlN /,NMel
o
(114)
Table 4 Nitration and Sulfonation of Azoles
Heterocycle
Position
substituted
Reaction conditions
Sulfonation Nitration
Pyrazole
Imidazole
3-Methylisoxazole
Isothiazole
Thiazole
4-MethyIthiazole
2,5- Dimethylthiazole
4
4(=5)
4
4
5
5
4
H 1 S0 4 /S0 3 ,100 0 C
H l S0 4 /S0 3 , 160 oC
HS0 3 Cl, 100 oC
H l S0 4 /S0 3 , 150 oC a
H l S0 4 /S0 3 /Hg, 250 oC
H l S0 4 /S0 3 , 200 oC
H l S0 4 /S0 3 , 200 oC
HN03/HzS04/S03,100oC
HN0 3 /H z S0 4 ,160 o C
HN0 3 /H z S0 4 /S0 3 , 70 oC
HN0 3 /H z S0 4 , 230 oC
HN0 3 /H 1 S0 4 /S0 3 , 160 oC
HN0 3 /H z S0 4 /S0 3 , 160 oC
a (66GEP1208303).
.,
Substituents are sometimes displaced: thus chloroimidazoles are nitrated normally, but
iodo analogues suffer nitro-deiodination.
Pyrazoles can undergo nitration at several positions: 4-brorno-l-rnethylpyrazole yields
the 3,5-dinitro product. I-Methylpyrazole 2-oxide yields the 5-nitro derivative.
As expected, nitration is facilitated by activating groups such as an arnino group; for
exarnple, nitration of (115) occurs at about 20 0 C (HN0 3 /H z S0 4 ). Sydnones (116) are
nitrated readily. The pyrazolinone (117) is nitrated as indicated, and 1,2,4-triazolinones
have also been ring nitrated.
[ \NH
/' S/ 1
(115)
4.02.1.4.3 Sulfonation
JC Ar
o ....N
o
(116)
2nd
'" Me
O N H
Ó
t
1st
(117)
Sulfonation conditions are given in Table 4. The orientation is as expected. Azolinones
react as readily as the corresponding azoles; sulfonation of (117) occurs at the positions
indicated (H Z S0 4 /S0 3 at 100 o C). Imidazoles are readily chlorosulfonated at C-4.
4.02.1.4.4 Acid-catalyzed hydrogen exchange
Acid-catalyzed hydrogen exchange is used as a rneasure of the cornparative reactivity of
different aromatic rings (see Table 5). These reactions take place on the neutral molecules
or, at high acidities, on the cations. At the preferred positions the neutral isoxazole,
isothiazole and pyrazole rings are all considerably more reactive than benzene. Although
the 4-position of isothiazole is sornewhat less reactive than the 4-position in thiophene, a
similar situation does not exist with isoxazole-furan ring systerns.
Imidazoles, because of their high basicity, are very unreactive unless electron-withdrawing
substituents are present.
58 Reactivity of Five-membered Rings with Two or More Heteroatoms
Table 5 Reactivities Toward Acid-catalyzed Deuterodeprotonation
(79AHCtZ51147)
Heterocycle
2
log (partial rate factor)"
Ring positions
3 4
5
Isoxazole
Isothiazole
Furan
Thiophene
1-Methylpyrazole
8.2
8.6
ca. 4.5
5.0
5.6
4,3
3.6
ca. 4.5
5.0
9.8
8.2
8.6
5.6
a Relative to position 1 of benzene = 1.
4.02.1.4.5 Halogenation
Imidazoles and pyrazoles containing an unsubstituted NH group are easily chlorinated
(CUHzO or N-chlorosuccinimide/CHCh), brominated (Brz/CHCI3; KOBr/HzO), and
iodinated (l z /HI0 3 ). Substitution generally occurs first at the 4-position, but further reaction
at other available nuclear positions takes place readily, especially in the irnidazole series.
When halogenation of the nucleus involves electrophilic attack on anions of type (109),
the 4-position of imidazole is again initially substituted (earlier work suggested a different
orientation). The benzimidazole anion is iodinated at the 2-position; other halogenation
generally occurs in the benzene ring.
Isoxazoles can be halogenated in the 4-position (63AHCI2)365). Ring bromination of
oxazoles with bromine or NBS occurs preferentially at the 5-position and, if this is occupied,
at the 4-position (74AHOI7)99). Aminooxazoles are readily halogenated.
Isothiazoles with electron-releasing substituents such as arnino, hydroxy, or alkoxy in the
3- or 5-position are brorninated in high yield in the 4-position. Alkylisothiazoles give lower
yields, but 3-rnethylisothiazole-5-carboxylic acid has been brorninated in 76% yield
(72AHO 14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position
are brominated at the 5-position (79HC(34-1)5).
1,2,3- Triazoles are brorninated at the 4- or 5-positions, but only if there is no N-substituent
(74AHC( 16)33). This also applies to 1,2,4-triazoles. N-Halogeno derivatives are frequently
isolated as intermediates (81H037)289).
3-Amino-l,2,5-thiadiazole is chlorinated or brominated at the 4-position at 20 0 C in
acetic acid. 3-Methyl-l,2,5-thiadiazole can also be chlorinated in the 4-position
(6RAH09)107). Bromination of 2-arnino-l,3,4-thiadiazole succeeds in the 5-position
(65ACS2434).
Azolidinones are very easily halogenated, e.g. (118) gives (119) (79AHC<25)83); similar
reactions occur in the isothiazolidinone series.
o
t NPh
sAo
(118)
o
t NPh
+ Br 2 --+ Br sAo --+
o
BrtNPh
Br S Ao
(119)
4.02.1.4.6 Acylation and alkylation
Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation,
several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes
Friedel-Crafts acetylation and Vilsmeier forrnylation at the 4-position, and the 5-alkylation
of thiazoles by carbonium ions is known.
Heating N-substituted pyrazoles with benzoyl chloride at 200 0 C gives quite high yields
of 4-benzoylpyrazoles, even in the absence of catalysts. Benzylation of N-substituted
pyrazoles proceeds similarly in the 4-position (66AHCI6)347).
+
L Ph
_ 0 N
0'-
(120)
+
N-NCOPh
Ph()\ CI-
S
(121)
--+
N-N
Ph( )\COPh
s
(122)
Reactivity of Five-membered Rings with Two or More Heteroatorns 59
Heating 2-phenyl-4-benzoyl-1,3,4-thiadiazoliurn chloride (121) at 200 0 C causes the
benzoyl group to move to the 2-position as in (122) (68AHC(9)16S), probably via deproton-
ation.
For the C-acylation of imidazoles via deprotonation, see Section 4.02.1. 7.4.
4-Aminotriazole is carboxylated at the 5-position by heating with aqueous sodium
bicarbonate in a Kolbe-type reaction (7IJCS(C)lS0I). 2- Thiazolinones undergo the Gatter-
mann and Reirner- Tiemann reactions at the 4-position, and 3- and 4-pyrazolinone anions
on alkylation give 4-alkyl as well as 0- and N-alkyl derivatives.
4.02.1.4.7 Mercuration
While there appears to have been no general study of the rnercuration of azoles, the
reaction seems to proceed readily in several systerns. Thus pyrazoles are 4-chloromercurated
by HgCh. Oxazoles are mercurated in acetic acid: the ring positions react 5> 4 > 2
(74AHC(17)99). Thiazoles react under the sarne conditions and show the same order of ring
position reactivities. Isoxazoles can be easily mercurated in the 4-position with rnercury(II)
acetate (63AHC(2)36S). Oxadiazoles have been rnercurated, e.g. (123) gives (124) (64HCA838).
1-Phenyltetrazole is rnercurated in the 5-position, and 3-arylsydnones at the 4-position.
N-{h
If. N + HgCl 2 --+
0""
(123)
N---,.Ph
II \\
CIHg" ....N
o
(124)
N Ph
II
Cl" ....N
o
4.02.1.4.8 Diazo coupling
Diazo coupling is expected to occur only with highly reactive systems, and experiment
bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the
2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other
azoles react only when they contain an arnino, hydroxyl, or potential hydroxyl group, e.g.
the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all
these reactions occur on the corresponding anions).
t --+
N
(125)
C)N=NPh
N
H
(126)
[;+ /Ar
N
N/
(Xi I N
1:"'/
N
(127)
HO n
H( ;N
N
Ph
(128)
O):/ H
H
(129)
o
t NPh
s....Ä-o
(130)
+ PhN 2 CI
o
-'J-NPh
--+ N S....Ä-O
I
PhNH
4.02.1.4.9 Nitrosation
Under alkaline conditions, alkyl nitrites nitrosate imidazoles which possess a free NH
group in the 4-position (70AHC(12)103). Nitrosation of 3,5-dimethylpyrazole gives the 4-
diazonium salt by further reaction of the nitroso compound with rnore NO+. 5-Pyrazolinones
are often nitrosated readily at the 4-position. 3-Alkyl-5-acetarnidoisothiazoles undergo
4-nitrosation.
4.02.1.4.10 Reactions with aldehydes and ketones
Imidazoles are hydroxyrnethylated by CHzO at the 4-position; 1-substituted imidazoles
react at the 2-position. Isoxazoles can be chlorornethylated in the 4-position (63AHC(2)365).
60 Reactivity of Five-membered Rings with Two or More Heteroatorns
Aldehydes and ketones react with azolinones. The reaction between aldehydes and
2-phenyl-5-oxazolinone (131; Y = H), forrned in situ frorn PhCONHCH 2 C0 2 H and AczO,
gives azlactones (131; Y = RCH). Similar reactions are given by 4-thiazolidinones, e.g. (132)
gives (133) (79AHCl2S)83), and 4-irnidazolinones. In pyrazolin-5-ones the 4-position is
sufficiently activated for condensation to occur with ketones in acidic media (Scheme 8)
(66AHCl6J347).
y
O )Ph
o
(131)
Me Me
Me C Me
r1 N" 0 Q'j"N;'N
Ph Ph
4.02.1.4.11 Oxidation
O t NH
S NPh
(132)
or NH
H S NPh
Ph
+ PhCHO --+
(133)
n Me
ow -Ä-...;N
o N/
Ph
Me
I
C
Me"'" - Me
OÁN;N
Ph
Me;!CO
H"
Scheme 8
The pyrazole ring is generally stable to oxidation and side chains are oxidized to carbonyl
groups (66AHCl6)347). l-Aryl-3-rnethylpyrazoles (134) react with ozone to yield 1,3,4-
oxadiazolinones (135) (66AHCl7)183).
O 0 N-NAr
, II \
Me N"NAr ----- Me"o O
(134) (135)
Irnidazole rings also survive rnost oxidation conditions, but photosensitized oxidation of
irnidazoles can give diarylbenzarnidines through a hydroperoxide (136) (70AHC(12)103).
HOO
0,.1," Ph t N Ph C.....NHCOPh
MeOH ' Ph::,., )\Ph --+ - '::-NCOPh
N
Ph N
Ph[ .)Ph
N
H
(136)
The thiazole, triazole and tetrazole rings are resistant to oxidation (e.g. by KMn04, Cr03).
Isoxazoles are more susceptible (e.g. 137 138, benzil a-rnonoxirne benzoate). The oxazole
ring is relatively readily cleaved by oxidizing agents such as perrnanganate, chrornic acid
or hydrogen peroxid#Q give acids or arnides. Oxidation of 4,5-diaryloxazoles with chlorine
or bromine gives the êorresponding benzils in high yield (74AHC( 17)99).
Ph
/
Ph-C-C
I; 0 '::-N
o II /
Ph-C-O
11381
Ph Ph
(J -2L.
Ph N
0"
1137)
Oxidation of azole anions can give neutral azole radicals which could, in principle, be 1/'
(139) or (J" (140) in nature. ESR spectra indicate structure (141; hyperfine splittings in G)
for imidazolyl radicals, but both 1/'- and (J"-character have been observed for pyrazolyl
radicals. Tetrazolyl radicals (142 143) are also well known (79AHCl2S)20S). Oxidation of
2,4,5-triarylimidazole anions with bromine gives l,l'-diimidazolyls (144) which are in
equilibrium with the dissociated free radical (145) (70AHCl12)103).
Q)
{ 'N<1D
/0
(139)
@
{ 'N<D
""'0
(140)
lO,55ij 2.()O
"') 1362
N
(141)
...-
N-NAr
II \+.
R" - /NAr
N
(143)
N-NAr
II \
R" . /NAr
N
(142)
Reactivity of Five-membered Rings with Two or More Heteroatorns 61
Ph N
Ph )Ph
N
Na+
---.
Ph Ph
N::::::'\ ß::::, N
I N-I'{ I
Ph,-,::::::::/ Ph
Ph Ph
(144)
->0.
....--
Ph N
Ph [)Ph
N
(145)
4.02.1.5 Attack at Sulfur
4.02.1.5.1 Electrophilic attack
In contrast to thiazoles, certain isothiazoles and benzisothiazoles have been directly
oxidized to sulfoxides and sulfones. 4,5-Diphenyl-1,2,3-thiadiazole is converted by peracid
into the trioxide (146). Although 1,2,5-thiadiazole 1,1-dioxides are known, they cannot be
prepared in good yield by direct oxidation, which usually gives sulfate ion analogous to the
results obtained with 1,2,4- and 1,3,4-thiadiazoles (68AHC(9)107).
Õ
Ph I /
PhC"
S
O-:::::- O
(146)
O t NR O t NR
S NPh ---. s NPh
O 2
Scheme 9
When a hydroxyazole can tautornerize to a non-aromatic structure, oxidation at an
annular sulfur atom becomes easy, e.g. as in Scherne 9 (79AHC(25)83).
Thiazoles are desulfurized by Raney nickel, a reaction probably initiated by coordination
of the sulfur at Ni. The products are generally anions and carbonyl corn pounds (see Section
4.02.1.8.4 ).
4.02.1.5.2 Nucleophilic attack
Isothiazoles and isothiazolium cations are attacked by carbanions at sulfur and on
recyclization can give thiophenes, illustrated by (147) -.. (148). 2-Alkyl-3-isothiazolinones
(e.g. 149) are also vulnerable to nucleophilic attack at sulfur (72AHC(14)1).
o
êNEt
s
(149)
O + PhCOCHCO,EI Þ
R' NR
S'"
(147)
R,OCOPh
S
(148)
o
CH,lCO,EtI, Þ rNHEt
NaOEI Z_ _..
SCH(C0 2 Et) 2
Nucleophilic attack at sulfur is implicated in rnany reactions of 1,2,4-thiadiazoles; gener-
ally, 'soft' electrophiles attack at sulfur, cf. (150) (151). n-ButylIithiurn with 4,5-
diphenyl-1,2,3-thiadiazole yields PhC == CPh, probably by initial nucleophilic attack at
sulfur.
N-fh
Ph( SiMe
S
(150)
CW
--+
N-fh
Ph( NMe
S
I
CN
(151)
4.02.1.6 Nucleophilic Attack at Carbon
Because of the increased importance of inductive electron withdrawal, nucleophilic attack
on uncharged azole rings generally occurs under rnilder conditions than those required for
analogous reactions with pyridines or pyridones. Azoliurn rings are very easily attacked by
nucleophilic reagents; reactions similar to those of pyridiniurn and pyryliurn corn pounds
are known; azolium rings open particularly readily.
62 Reactivity of Five-membered Rings with Two or More Heteroatorns
Nucleophilic attack on the ring carbon atoms of azoles occurs readily with oxazole and
aza analogues. Such reactions are generally facilitated by additional ring heteroatorns and
by electron-attracting substituents, and hindered by electron-donating substituents. A fused
benzene ring aids nucleophilic attack on azoles, azolium ions and azolones; this rnay be
rationalized because the loss of aromaticity involved in the formation of the initial adduct
is less than that in monocyclic cornpounds. The orientation of attack is generally between
two heteroatorns, as in (152).
(z) 'ÛH
(152)
4.02.1.6.1 Hydroxide ion and other O-nucleophiles
(i) Neutral Azoles
Uncharged azoles not containing oxygen or sulfur are often resistant to attack by hydroxide
ions at temperatures up to 100 oC and above. However, neutral azoles react with hydroxide
ions under extreme conditions, e.g. I-substituted irnidazoles such as (153) at 300 0 C give
the corresponding irnidazolinone (154) (SOAHCl27)241).
K K
Ph N Ph Ñ Ph Ñ Pt NH
Ph[) KOH [ -H -H, ph(Ao HCI
---+ Ph . - Ph NAO
N N CH
R R R R
(153) (154)
Imidazoles and benzirnidazoles (155) react with acid chloride and alkali to give compounds
of type (157), but these are reactions of the cation (156). 1,2,4-Triazoles and tetrazoles
sirnilarly undergo ring opening.
(X i N)
N
H
(155)
COPh
- (X I N5
N
COPh
(156)
-
0 1 NHCOPh
NHCOPh
RCH-NH
I I
RCO COR
(158)
(157)
Isoxazoles are also rather stable to nucleophilic attack by OH- at carbon. For reactions
with base at a ring hydrogen atom, leading, for exarnple, to ring opening of isoxazoles, see
Section 4.02.1.7.1.
Oxazoles give acylamino ketones (158) by acid-catalyzed ring scission, although they are
sornewhat more stable than furans. The oxazole ring is also rnoderately stable to alkali
(74AHCl17)99); as expected, reaction with hydroxide ions is facilitated by electron-with-
drawing substituents and fused benzene rings.
Oxazoles are easily cleaved. 2,5-Dialkyl-l,3,4-oxadiazoles (159) in aqueous solution with
acid or base give hydrazides (if suitable substituents are present, further reaction can occur;
see Section 4.02.3.5.1). 3-Methyl-l,2,4-oxadiazole (160) is easily hydrolyzed to
acetamidoxime (61CHL)292).
N-N
R )R' H' orOH . RCONHNHCOR'
o
(159)
N--;\Me
1/ \\ HCI
,,/N HOH
o
(160)
-;:::-NOH
Me-C
'NH 2
Isothiazoles and thiazoles are rather stable toward nucleophilic attack. Both 5- and
6-nitrobenzothiazole (161) add methoxide at C-2; the initial adduct undergoes ring opening
to give (162) (79AHCl25)1). Unsubstituted 1,2,4-thiadiazole is sensitive to alkali. Substituents
stabilize the ring sornewhat, but ring-opening reactions are still cornrnon, e.g (163) ---. (164).
5- Alkylarnino-l,2,3,4-thiatriazoles are cleaved by alkali to azide ion and an isothiocyanate;
in addition, a Dirnroth rearrangement occurs to give a mercaptotetrazole (64AHCI3)263).
Reactivity of Five-membered Rings with Two or More Heteroatoms 63
X 0= ' \.
Y 1/
N
X=H, Y=N0 2
X=N0 2 , Y= H
X S)<H
Y Ñ OMe
X o s-
I ....-H
Y N=C,
OMe
(162)
(161)
NH 2
/
N---;\NH 2 - N=C
II \\ / \
H 2 N" /N /C NH 2
S H 2 N 0
(163) (164)
(ii) Azoliurn ions
Azolium ions (165) react reversibly with hydroxide ions to form a small proportion of
the pseudo base (166). The terrn 'pseudo' is used to designate bases that react. with acids
measurably slowly, not instantaneously as is normal for acid-base reactions. Fused benzene
rings reduce the loss of resonance energy when the heteroring loses its' aromaticity, and
hence pseudo bases are forrned even rnore readily by benzothiazolium cations than by
thiazoliurn ions. Pseudo bases carrying the hydroxyl group in the a-position are usually
formed preferentially. As expected, pseudo base forrnation for S-containing azoliums is
easiest with the dithiolyliurn and least easy with the thiazoliurn (79AHC(25)1).
Me Me Me
{ " / { " / { " /
CH CH C
/ /" /'\.
OH 0
(165) (166)
pKRT values for pseudo base forrnation are defined by equation (1),
K R + = [H+][QOH]/[Q+]
(1)
where Q+ and QOH denote the azolium cation and pseudo base, respectively. Some pKRT
values are given in Scheme 10.
+ /CH 2 -( N
Mt) N
o
5.8
+
t3 Me
s
10.8
Ph S+
t)
S
2.2
Scheme 10 pKR. values for azolium cations
Some pseudo bases are stable. 1,3-Dithiolyliurn adds alkoxide ions at the 2-position to
give stable adducts which regenerate the starting salts with acids (80AHC(27)15l). Pseudo
bases can also lose water to give an ether (e.g. 167 168).
O=:>Ph [o=:
(167) (168)
+
cJ;Me
X
(169)
Oxidation to an azolone is an expected reaction for a pseudo base, but little appears to
be known of such reactions. Most cornrnonly, pseudo bases suffer ring fission. Estirnated
rates of ring-opening of (169) are in the ratio 10 9 : 10 4 . 5 : 1 for X = 0, Sand NMe, respectively'
(79AHC(25)1).
Thus quaternized thiazoles (170) consume two equivalents of OH on titration because
the pseudo bases (171) ring open to (172), which forrn anions (173). Quaternized oxazoles
(174) are readily attacked by hydroxide to give open-chain products such as (175)
(74AHC(17)99), and quaternized 1,3,4-oxadiazoles behave similarly. Quaternary isothiazoles
(e.g. 176) are cleaved by hydroxide (nAHC(14)1), as are 1,2,4-thiadiazolium salts
(177 178).
64 Reactivity of Five-membered Rings with Two or More Heteroatoms
+
[ NR
r )
s
(170)
[NR H
sX OH
[ NR
r _ tHO
s
..--
[ NR
r tHO
s
H
(172)
(173)
(171)
+
[ NMe
R,r )R
o
(174)
011
---+ R'COCH 2 N(Me)COR
(175)
Me0 2 C O Me
r .
/NMc
S
(176)
011
----+
Me C0 2 Me
>=<
McNH CHO
N ----{h
Ph ;NMe
S
(177)
Ph
/
HN-C
--+ / \\
/C NMe
Ph 0
(178)
1,2-Dithiolylium ions undergo ring opening and degradation with hydroxide (Scheme
11) (66AHCI7)39,80AHC(27)151). 1,2-Dimethylpyrazolium is degraded to HC0 2 H and
MeNHNHMe.
R 1 R'
R3CS'
S/
011
-----+
[ R2 R' J
R' R '
H ., l:!
R 2 R 1
R 3 1:;:-S -
Scheme
Reclosure to form a new heterocyclic or hornocyclic ring can occur in azolium ions
carrying suitable substituents; these reactions are considered under the appropriate sub-
stituents.
Anthranils are readily cleaved by nitrous acid, presumably by attack of water on N- nitroso
cations. The first product that can be observed is the nitrosohydroxylamino compound
(179), which becomes reduced to the diazonium salt (180) (67AHC(S)277).
R R
I I
ryC.::::,.o --+ ryC.::::,.o
N OH N;
I
NO (180)
(179)
(iii) Azolinones
Although imidazolinones are usually resistant to hydrolysis, oxazolinone rings are often
easily opened. In acid-catalyzed reactions of this type, water converts azlactones (181) into
a- acylamino-a,ß- únsaturated acids (182) (77 AHC(21)175). 1,3,4-0xadiazolinones are
readily opened by hot water to give hydrazine carboxylic acids which undergo decarboxy-
lation.
R 'HC}-- H
OAolR'
:C)Hl
(181)
II'
------+
H 2 0
[ R1HC ]
..,);;L R 2
HO O H
--+ R'CH=C-NHCOR 2
I
C0 2 H
(182)
4.02.1.6.2 Amines and amide ions
(i) Azoles
Oxygen-containing rings can be opened by arnines; frequently this is followed by reclosure
of the intermediate to form a new heterocycle. Thus isoxazoles containing electron-with-
drawing substituents give pyrazoles with hydrazine, q;. (183; Z = 0) --.... (183; Z = NH), and
Reactivity of Five-membered Rings with Two or More Heteroatoms 65
(184) --.... (185) (66AHC(6)347). In the benzo series a rather different reaction can occur:
6-nitroanthranil (186) is converted by amines into 2-indazoles (187) (61J0C3714). Oxazoles
heated at 180 0 C with formamide are transformed into imidazoles (74AHC(17)99). With
2,4-dinitrophenylhydrazine in HCl, oxazoles form hydrazones by ring fission (Scheme 12)
(74AHC(17)99). Benzoxazole with hydroxylamine gives 2-aminobenzoxazole by elimination
of water from the initial adduct. 1,3,4-0xadiazoles react readily with ammonia and primary
amines to give 1,2,4-triazoles.
[J C0 2 H
Ph r N
z/
(183 )
O 2 Nf\\Me
Me!!... ;N
0/
(184)
PhNHNH 2
02 N [J Me
r
Me /N
N
Ph
(185)
02 N O::- O -+
(186)
o::- c:;:;--
NR
02 N N'
(187)
R 4 N
R S [ )R'
o
DPN, HCl
Þ
room temp.
R 4 CH-NH-CO-R 2
5 I
R C=N-NH-C 6 H 3 (N0 2 h
DPN, HCl þ R 4 ý=N-NH-C 6 H 3 (N0 2 h
IOO.C R 5 C=N-NH-C 6 H 3 (N0 2 h
Scheme 12
Amines are insufficiently nucleophilic to react with most azoles which do not contain a
ring oxygen, and the stronger nuc1eophile NH z - is required. When treated with amide ions,
thiazoles can be aminated in the 2-position by NaNH 2 at 150 o C. Only N-substituted
condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions.
Imidazoles are aminated by alkaline NH 2 0H.
(ii) Azolium ions
Most azolium ions are sufficiently reactive to be attacked by amines. Sometimes the initial
adducts are stable: ammonia and primary and secondary amines add to 1,3-dithiolylium
salts at the 2-position to give compounds of the types NT 3 , RNTz and RzNT, respectively,
where T=the 1,3-thiol-2-yl group (SOAHC(27)151).
Some azoliums give open-chain products: primary and secondary amines with 1,2-
dithiolyliums generally give (188) (SOAHC(27)151).
+
s-s
ArZ) + RR'NH -+
S H
ArÿNRR'
H
(188)
+ S + H+
In other cases, reclosure to a new ring occurs: 1,2-dithiolylium ions with ammonia give
isothiazoles according to the mechanism shown in Scheme 13 (SOAHC(27)151). Treatment
of quaternary isothiazoles with hydrazine or phenylhydrazine gives pyrazoles (Scheme 14)
(72AHC(14)1), and 1,2,4-thiadiazoliums similarly yield 1,2,4-thiazoles. Oxazolium ions react
with ammonium acetate in acetic acid to give the corresponding imidazoles (Scheme 15)
(74AHC(17)99).
R'
RO+
S
NH 3
--
-H'
R' R'
r- NH2 -+ rl
R( _)ì R - 'NH
S S
I
SH
Scheme 13
R'
-+ RnN + H 2 S
(S)
PhONE!
S
PhNHNH 2
þ Ph O N
N/
Ph
Scheme 14
66 Reactivity of Five-membered Rings with Two or More Heteroatoms
R 4 NR 3
R S [)R 2
o
AcONH 4
AcOH
R 4 NR 3
R S ()R 2
N
Scheme 15
Where an N- methoxy group is present, as in 1-methyl-3-methoxybenzimidazole, elirnina-
tion of MeOH can give an arornatic product.
4.02.1.6.3 S-Nucleophiles
Data on reactions of sulfur nucleophiles with azoles are sparse. Oxazoles are transformed
in low yield into the corresponding thiazoles over alumina with H 2 S at 350 oC (74AHC(17}99).
Sulfur nucleophiles such as SH- or RS- add to 1,3-dithiolylium salts at the 2-position
(80AHl.(27)1S1).
4.02.1.6.4 Halide ions
Chloride ions are comparatively weak nucleophiles and do not react with azoles. In
general, there is also no interaction of halide ions with azolium compounds.
Benzirnidazole 3-oxides, e.g. (189), react with phosphorus oxychloride or sulfuryl chloride
to form the corresponding 2-chlorobenzimidazoles. The reaction sequence involves first
forrnation of a nucleophilic cornplex (190), then attack of chloride ions on the complex,
followed by rearomatization involving loss of the N-oxide oxygen (191--....192).
0- OPOC1 2 c...OPOCl,
I I I .
N+ CXN OCN H OC N
OC) --+ . I yo- --+ --+ . I )Cl
"'" N "'" N '"", N Cl "'" N
Me Me Me Me
(189) (190) (191) (192)
4.02.1.6.5 Carhanions
U) Organometallic compounds
In contrast to pyridine chemistry, the range of nucleophilic alkylations that can be effected
on neutral azoles is quite limited. Lithium reagents can add at the 5-position of 1,2,4-
oxadiazoles (Scheme 16) (70CJC2006). Benzazoles are attacked by organometallic com-
pounds at the C=N a- position unless it is blocked.
N--r e Bu"U
Ph ;N
o
Li+
Ñ Me
BU)(
Ph 0/
Scheme 16
i.CO,
Ii. H 2 0
H
N Me
Bun \
Ph 0/
Azolium rings react readily with organometallic cornpounds. With a Grignard reagent,
conversion (193) --.... (194) is known in the benzothiazoliurn series, and 1,3-benzodithioly-
liurns give products of type (195).
Me Me H
H I
OC N ) OC N H OC S R Me N Me-C-NH-CO-Ph
--+ I )<Ph I S'><R' o )Ph --+ I
Ph-C-OH
S 0 I
(193) (194) (195) (196) Ph
(197)
4-Methyl-2-phenyl-5-oxazolinone (196) with phenylmagnesium bromide gives (197)
(6SAHCl4)7S).
Reactivity of Five-membered Rings with Two or More Heteroatoms 67
(ii) Activated methyl and methylene carbanions
The mesorneric anions of activated rnethyl and rnethylene compounds react with azolium
ions. Thus 1,2-dithiolylium ions with a free 3- or 5-position react with various carbon
nucleophiles to give products which are oxidized in situ to rnesomeric anhydro-bases
(198 199 200). Dimethylaniline gives an intermediate which is oxidized to a new
dithiolyliurn salt (Scherne 17) (66AHC(7)39). However, if the 3,5-positions are substituted,
an alternative ring scission can occur (199 201 202) (80AHC(27)151). In this sequence,
(198) can be ArCOCH 2 CS 2 Me, NCCH 2 CSNH or NCCH 2 CO z Et. The conversion in the
1,2,4-thiadiazole series of (203) into (204) is analogous.
R 2
X , RI
-- Y, R3>( CS
'c Cs
R 4 /1
H
(199)
H \ R2 R 1
C 0
y/ "---"" R 3 S
CH\. S /
I +
R 4
(198)
R 2 R 1
R 3 =H X ;0
---+ II '
............ h /S
R4 C S
I
R 3
(200)
1 R 3 ;éH
R 3
H ß R2
"N
R 4 \.
x ç.r R I
Y
(201)
-- YH +
R 3
R4 R2
)Rl
X S
(202)
N-lh
II \\
Ph, .....NMe
S
(203)
CH<CN)2
.
N
Ph Ç 'ì Ph
NC NMe
NH
(204)
R 1 H
R 2 0 \+ --
S"'"
ff ÑR2
H .ó
R 1 H
2 r S
R S"'"
R HC6H4NR2
-- R2 _ ;5+
s"'"
Scheme 17
Anhydro bases can attack the a-position, e.g. of thiazoliurn cations, with the formation
of adducts capable of oxidation to cyanine dyes, e.g. Scheme 18 (see Section 4.02.3.3.4).
Active rnethylene cornpounds can add to 1,3-dithiolylium ions to give 2-substituted
1,2-dihydro-l,3-dithioles (206). Again, addition is often followed by oxidation (to 207).
Alternatively, further addition can occur (to 208) (80AHC(27)151). In this reaction, (205)
can be CH 2 (CNh, CH 2 (COMeh or even MeCOMe. Somewhat sirnilar reactions are shown
by 1,3-diarylirnidazolium ions.
Me Me Me
(X w N (X N H Me
I s> + H2C=<S -- I S)<CH2-f
S
/ZH
(X I CH-1
s S
Scheme 18
68 Reactivity of Five-membered Rings with Two or More Heteroatoms
R I ( S R 3
2H + 21
R /--"-R 4
S / (207)
R! ( )< H R3
R 21 /
S C
H/ 'R 4
(206) R1 ( S H H S 1
W + I X)( J R
R 2 S /C, S I R 2
R 3 R 4
(208)
RI (
R2 .Y
S
R 3
+ H 2 C/ --+ H+ +
'R 4
(20S)
Wi) Cyanide ions
Cyanopyrazoles are formed by irradiation of pyrazoles in the presence of cyanide ions
in photosubstitution reactions.
4.02.1.6.6 Reduction by complex hydrides
Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic
products have been reported from the reductions with complex rnetal hydrides of oxazoles
(e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and
benzoxazolinones (e.g. 215, 216 214). Reductions of 1,2,4-oxadiazoles always involve
ring scission. Lithium aluminum hydride breaks the C-O bond in the ring (Scheme 19)
(76AHCt20)6S).
Ph[)Ph
o
(209)
PhCHCH 2 NHCH 2 Ph
--+ I
OH
(210)
ryN> --+
O
(213)
0 1 NHMe
""" OH
(214)
N R'
R(\
: 0/
LiA1H4
Ph
n PhCHCH 2 CHPh
Ph _;N --+ I I
0/ OH NH 2
(211) (212)
+--
o=
I )=x
""" 0
{2IS) X=O
(216) X = S
""NOH
R'-C Y
'NHCH 2 R
Scheme 19
Nitrogen azoles are less easily reduced: benzimidazole with lithiurn alurninum hydride
gives dihydrobenzimidazole (S2CB390).
Cationic rings are readily reduced by complex hydrides under relatively mild conditions.
Thus isoxazoliurn salts with sodium borohydride give the 2,5-dihydro derivatives (217) in
ethanol, but yield the 2,3-dihydro compound (218) in MeCN/HzO (74CPB70). Pyrazolyl
anions are reduced by borohydride to pyrazolines and pyrazolidines. Thiazolyl ions are
reduced to 1,2-dihydrothiazoles by lithiurn aluminum hydride and to tetrahydrothiazoles
by sodium borohydride. The tetrahydro compound is probably formed via (219), which
results from proton addition to the dihydro derivative (220) containing an enarnine function.
1,3-Dithiolylium salts easily add hydride ion from sodiurn borohydride (Scherne 20)
(80AHCl27)lSl).
R'
R" CN R
0/
(217)
R'
R,,'CNR
0/
(218)
R'
R" Q NR
so'"
(219)
R'
R" O R
S
(220)
Reactivity of Five-membered Rings with Two or More Heteroatoms 69
Rl ( , Rl ( S H (or D)
21 '..)R X- + W (orD-) - 21 )<
R S R S R
R = H, SMe, NR 2 , aryl, cyclohexyl
Scheme 20
+ X-
4.02.1.6.7 Phosphorus nucleophiles
Trialkyl- and triaryl-phosphines react with 1,3-benzodithiolylium ions to give a phos-
phonium salt which is deprotonated by n- butyllithium to give (221) (76TL3695).
cr s
I >= PR 3
S
(221)
N
--f n
2nd H X H 1st
(222)
-0 ".:
r\.H ....N
X
(223)
4.02.1.7 Nucleophilic Attack at Hydrogen Attached to Ring Carbon or Ring Nitrogen
Hydrogens attached to ring carbon atorns of neutral azoles, and especially azolium ions,
are acidic and can be rernoved as protons by bases. Reaction follows the orientations shown
in (222) and (223). The anions from neutral azoles can be stabilized as lithiurn derivatives,
except in isoxazoles where ring cleavage occurs. Typically, the anion adds a proton again
and hydrogen isotope exchange can result. The zwitterions from azoliurn rings can react
as carbenes.
4.02.1.7.1 Metallation at a ring carbon atom
Neutral azoles are readily C-lithiated by n- butyllithiurn provided they do not contain a
free NH group (Table 6). Derivatives with two heteroatoms in the 1,3-orientation undergo
lithiation preferentially at the 2-position; other cornpounds are lithiated at the 5-position.
Attempted rnetallation of isoxazoles usually causes ring opening via proton loss at the 3-
or 5-position (Section 4.02.2.1.7.5); however, if both of these positions are substituted,
norrnallithiation occurs at the 4-position (Scherne 21).
Table 6 Lithiation of Azoles by n-Butyllithium
Heterocycle Position lithiated Temperature (oC) Ref
3-Methyl-1- phenylpyrazole 5 66AHC(6)347,52JA3242
3,5-Disubstituted isoxazoles 4 -70 to -65 79AHC(25)147,70CJC1371
3,5-Disubstituted isothiazoles 5 -70 65AHC(4)75,72AHC(14)1
I-Substituted imidazoles 2
I-Substituted oxazoles 2 'low' 74AHC(17)99
I-Substituted thiazoles 2 -60
2-Substituted thiazoles 5 -100
I-Phenyl-I ,2,3 -triazoles 5 -60 to -20 74AHC(16)33,7ICJCI792
I-Butyltetrazole 5 -60 77AHC(21)323
OMe Lì OMe
PhON - PhON
o 0
Scheme 21
4.02.1.7.2 Hydrogen exchange at ring carbon in neutral azoles
Base-catalyzed hydrogen exchange has been sumrnarized for five-mernbered rings
(74AHC(16)1). In many reactions of this type the protonated azole is attacked by hydroxide
70 Reactivity of Five-membered Rings with Two or More Heteroatoms
ion to form an ylide in the rate-determining step, e.g. for imidazole (Scherne 22) (74AHC(16)1).
Deuteration of imidazole is fast at the 2-position and much slower at the 4- and 5-positions.
Rates fall off for N-unsubstituted irnidazoles at high pH values because of the formation
of unreactive anions. In the case of 1-rnethylbenzimidazole the rate of hydrogen exchange
in the 2-position is independent of the acidity over a wide range, in agreernent with the
mechanism shown in Scheme 22 (SOAHC(27)241).
D N
D[)D
N
Me
+
D NH
D[)D
N
Me
slow
ow
Scheme 22
+
D NH
D[)-
N
Me
-+
D NH
D[.)H
N
Me
Under strongly basic conditions oxazoles undergo fast 2-deuteration and slower 5-
de ute ration (74AHC(l7)99). The hydrogen in the 5-position of isothiazoles exchanges rapidly
under basic conditions (69JHC199). Neutral thiazoles exchange by two competitive mechan-
isrns: at pO 0-11 the conjugate acid exchanges the 2-H via the ylide (224), whereas at
higher pO exchange is at the 2- and 5-posítions via the carbanions (225) and (226). The
1,2,4- (227), 1,3,4- (228) and 1,2,3-thiadiazoles (229) all undergo rapid exchange at the
5-, 2- and 5-positions, respectively (74AHC(l6)1).
+
[)
S
(224)
N
[)-
S
(225)
N
-f)
S
(226)
",,, o"'N
S
(227)
N-N
(s),
(228)
If
./Z. _ o"'N
S
(229)
I-Substituted tetrazoles readily exchange the 5-hydrogen for deuteriurn in aqueous
solution. A major rate-enhancing effect is observed with copper(II) or zinc ions due to
(T- cornplexation with the heterocycle. The rate of base-induced proton-deuteriurn exchange
of I-methyltetrazole is 10 5 times faster than 2-rnethyltetrazole (77AHC(21)323).
4.02.1. 7.3 Hydrogen exchange at ring carhon in azolium ions and dimerization
Hydrogen atoms in azolium ions can be removed easily as protons (e.g. 230 --+ 232);
exchange with deuterium occurs in heavy water. The intermediate zwitterion (e.g. 231) can
also be written as a carbene, and in sorne cases this carbenoid form can be trapped or
isolated as a dimer.
+
MenNMe
H _)H
S
(230)
+
M]"-NMe
H _)-
S
(231)
--. [) e
S
(232)
The relative rates of H-isotope exchange in 0 2 0/00- for oxazolium, thiazoliurn and
imidazolium are shown in formulae (233)-(235), respectively (71PMH(4)55). The interrnediate
carbene can forrn a dimer (236) or be trapped with azides (237) (74AHC(16)1). Hydrogen
atoms in positions 3 and 5 of 1,2-dithiolylium ions undergo deprotonation and can be
replaced by deuterium (SOAHC(27)151). Thiadiazolium salts (238) and (239) (74AHC(16) I},
and especially tetrazolium salts (e.g. 240) (74AHC(16)1), exchange particularly quickly.
MenNMe
_)1O"
o
(233)
Me NMe
[)IO"
S
(234)
+
Me n NMe
(.)1
N
\1<:
(235)
Relative rates of H-isotope exchange in D 2 0/OD-
R R
((>==<:=0
(236)
(( NMe
I )=N-N=NR
S
(237)
+
r: NEt
r \\ BF-
N 4
so'"
(238)
+
N-NEt
() CI-
S
(239)
+
N-NEt
II \\
N, ./
N
R
(240)
Reactivity of Five-membered Rings with Two or More Heteroatoms 71
Base-catalyzed hydrogen exchange occurs at the 3- and 5-positions of 1,2-dirnethyl-
pyrazoliurn salts. 2-Unsubstituted 1,3-dithiolyliurn salts are easily deprotonated by
nucleophilic attack of hydrogen. The interrnediate carbene easily undergoes dimerization.
Hydrogen exchange can also occur (Scherne 23) (SOAHC(27)151).
H [ -H+ H ( S +D+
R I :)H C +H + · R I ): c þ
S S -D+
H ( ,
R I :.)D
S
Scheme 23
4.02.1. 7.4 C-Acylation via deprotonation
l-Substituted irnidazoles can be acylated at the 2-position by acid chlorides in the presence
of triethylarnine. This reaction proceeds by proton loss on the N-acylated intermediate
(241). An analogous reaction with phenyl isocyanate gives (242), probably via a sirnilar
mechanism. Benzimidazoles react sirnilarly, but pyrazoles do not (SOAHC(27)241) (cf. Section
4.02.1.4.6).
+
fiNCOAr
( }>H
N
R CI-
(241)
Et 3 N
--+
-HCI
+
fiNCOAr
(- )- --+
N
R
N
f:)COAr
N
R
L)CONHPh
N
R
(242)
4.02.1. 7.5 Ring cleavage via C-deprotonation
Isoxazoles unsubstituted in the 3-position react with hydroxide or ethoxide ions to give
ß-keto nitriles (243) -+ (244). This reaction involves nucleophilic attack at the 3-CH group.
1,2-Benzisoxazoles unsubstituted in the 3-position sirnilarly readily give salicylyl nitriles
(67AHC(S)277), and 5-phenyl-1,3,4-oxadiazole (245) is rapidly converted in alkaline solution
into benzoylcyanarnide (246) (61CI(L)292). A sirnilar cleavage is known for 3-unsubstituted
pyrazoles and indazoles; the latter yield o-cyanoanilines.
Hic)R
Rd --+
0:5
(243)
CH -c
I 2 \II
RCO N
(244)
N
Ph( /N
o
(245)
orOH-
Ph -C- NHCN
II
o
(246)
standing
Þ
H[ß
RCÑR'
0/
(247)
3-Unsubstituted isoxazoliurn salts (247) lose the 3-proton under very mild conditions,
e.g. at pH 7 in aqueous solution, to give intermediate acylketenimines (248) which convert
carboxylic acids into efficient acylating agents (249) (79AHC(25)147).
R
/
HC-C
;(J II,
R'NH/C",;:,P J
o-c=o -+
I
R"
Hf=C=N-R' R"CO H
R ÑR' -+ /C 2 I
00 R 0
(248)
R
/
HC-C
;.7 to
/C'" I
R'NH C=O
/\ -
R" '-Nu
(249)
Isoxazoles substituted in the 3-position, but unsubstituted in the 5-position, react under
more vigorous conditions to give acids and nitriles (Scheme 24). Anthranils unsubstituted
in the 3-position are similarly converted into anthranilic acids by bases (Scherne 25)
(67AHC(S)277). Atternpted acylation of anthranils gives benzoxazine derivatives via a similar
ring opening (Scherne 26) (67 AHC(S)277).
R'
R R I
ow CR C
rir ---+ \II + III --+ R'CH 2 C0 2 H
- ojN N C
I
0-
Scheme 24
72 Reactivity of Five-membered Rings with Two or More Heteroatoms
o
c
aw
o
II
(X I C,o-
NH 2
Scheme 25
N'O
Ac"
C >>
to'-
H
;(? --
Ac
o: C O
7'
COR
::-- /
N
O
-+ U )R
N
Scheme 26
For ring-opening reactions of C-metallated azoles, see Section 4.02.3.8.
4.02.1.7.6 Proton loss from a ring nitrogen atom
Pyrazoles, irnidazoles, triazoles and tetrazoles are weak acids. They form metallic salts
(e.g. with NaNH 2 , RMgBr) which are extensively hydrolyzed by water. The resulting anions
react very readily with electrophilic reagents on either ring nitrogen or carbon atoms, as
discussed in Sections 4.02.1.3 and 4.02.1.4. For exarnple, proton loss from a ring nitrogen
atom gives the highly nucleophilic irnidazole anion. This anion can be formed with sodium
hydroxide or sodiurn alkoxide; good results are obtained with sodamide in liquid arnmonia
(70AHCt 12)103).
Azolinones are weak to rnedium strong acids of pKa 4-11. They forrn mesorneric anions
which react very readily with electrophilic reagents at the nitrogen, oxygen or carbon atorns,
depending on the conditions; see Section 4.02.1.1.4.
4.02.1.8 Reactions with Radicals and Electron-deficient Species; Reactions at Surfaces
4.02.1.8.1 Carhenes and nitrenes
Few reactions of azoles with these reagents have been reported. 2-Methylimidazole reacts
with :CCl 2 to give 5-chloro-2-methylpyrirnidine in poor yield. Pyrazoles react with HCCh
at 550 oC (with :CClz formation) to give 2-chloropyrirnidines in good yields. l-Alkyl-1,2,4-
triazoles react with nitrenes forrned by the irradiation of azides to give N- imines (Scheme
27) (74AHC!l7)213).
N
II + MeCON 3
'" /N
N
CH 2 Ph
hv
_ /COMe
N"
N
+/N
N
CH 2 Ph
>>
CH,CI,
Scheme 27
4.02.1.8.2 Free radical attack at the ring carhon atoms
Despite some recent discoveries, free radical reactions are still very much less cornmon
in azole chernistry than those involving electrophilic or nucleophilic reagents. In sorne
reactions involving free radicals, substituents have little orienting effect; however, rather
selective radical reactions are now known.
(Í) Aryl radicals
Phenyl radicals attack azoles unselectively to forrn a rnixture of phenylated products.
Relative rates and partial rate factors are given in Table 7. The phenyl radicals rnay be
prepared from the usual precursors: PhN(NO)COMe, Pb(OCOPhk (PhC0 2 h or
PhI(OCOPhh. Substituted phenyl radicals react sirnilarly.
Reactivity of Five-membered Rings with Two or More Heteroatoms 73
Table 7 Relative Rates and Partial Rate Factors for the Homolytic Phenylation a of Five-membered
Heterocycles (74AHC{i6)123)
Relative Partial rate factors
Heterocycle rates 2 3 4 5
Thiazole 1.6 6.2 1.0 2.S
2-Methylthiazole 0.6 1.0 2.4
4-Methylthiazole 1.2 2.9 4.3
5-Methylthiazole O.S 3.S 1.0
Isothiazole 0.95 2.7 0.5 2.5
I-Methylpyrazole 0.6 0.18 0.03 3.4
I-Methylimidazole 1.2 2.7 0.5 2.5
a Benzoyl peroxide is the source of the phenyl radicals, except for the first entry, where it is
nitrosoacetanilide.
(ii) Alkyl radicals
Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic
and attack protonated azoles at the most electron-deficient sites. Thus irnidazole and
1-alkylirnidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly,
thiazoles are attacked in acidic rnedia by rnethyl and propyl radicals to give 2-substituted
derivatives in moderate yields, with smaller arnounts of 5-substitution. These reactions have
been reviewed (74AHC(i6)123); the mechanism involves an intermediate O"-cornplex.
Sirnilar reactions occur with acyl radicals, for exarnple with the CONH 2 radical from
formamide (74AHC(16)123).
4.02.1.8.3 Electrochemical reactions and reactions with free electrons
Neutral rings are reduced by the uptake of an electron to form anion radicals (SOAHC(27)31).
In isoxazole and oxazole this can be achieved in an argon rnatrix, but normally ring fission
occurs; reduction of 1,2,4-thiadiazoles also usually results in ring cleavage. Thiazoles
containing electron-withdrawing groups, 1,3,4-oxadiazoles, 1,2,5-oxadiazoles and 1,2,5-
thiadiazoles on electrochemical reduction yield transient anion radicals which can be
characterized by ESR, e.g. (250) and (251). Anion radicals from benzazoles can be more
stable, e.g. (252).
N-N MenMe CX N
Ph(O)Ph N'Oo"'N- ' N'o
(250) (251) (252)
Cationic rings are reduced with the uptake of one electron (e.g. electrochemically) to
give neutral radicals (SOAHC(27)31). Examples of radicals which have been detected by ESR
are (253) and (254). Such radicals, e.g. those from benzothiazolium ions, can dimerize (to
255) or undergo further reduction (to 256). 3-Methylbenzothiazolium (257) is reduced in a
two-electron wave. The preparative reduction gives a mixture of the dihydro derivative
(258) and the dimer (259) (70AHC(12)213). Benzofurazan is reduced polarographically in a
six-electron reaction to 0- phenylenediarnine (59MI40200).
o
( )SEt
o
(253)
Ph
PhCS
so'"
(254)
(cx:;t
(255)
Me
CX N
I s>
(256)
Calculations indicate that 1,2-dithiolyl radicals have large spin densities at the 3,5-
positions and that 1,3-dithiolyl radicals have large spin densities at the 2-position. In
agreement, radicals of these types unsubstituted at such positions dimerize very readily;
when the position is substituted, the radical is more stable (253 and 254). Reduction of
tetrazolium salts gives tetrazolyl radicals which show appreciable spin density on all four
ring nitrogen atorns (77 AHC(21)323).
74 Reactivity of Five-membered Rings with Two or More Heteroatorns
Me
)
S
(257)
e
---+
Me
ex N H
1'/
S
e-+H"
I
e
)
(258)
1
(ex:><1,
(259)
Electron-withdrawing substituents stabilize such neutral radicals considerably. Mero
stabilization is found, for exarnple, in the pyrazolyl derivative (260) - (261)
(74JCS(P1)1422).
C0 2 Me
Me0 2 CCNEt .-.
N
Me
(260)
0-
I
Û C'-OMe
r t
Me02C ..;.NEt
N
Me
(261)
4.02.1.8.4 Other reactions at surfaces (heterogeneous catalysis and reduction reactions)
(i) Catalytic hydrogenation and reduction by dissolving metals
In general, azoles containing a cyclic oxygen atorn are readily reduced, those with cyclic
sulfur with rnore difficulty, and wholly nitrogenous azoles not at all.
Pyrazoles are very resistant to catalytic reduction, resisting hydrogenation over nickel at
150 oC and 100 atrn (66AHC(6)347). Imidazoles are generally resistant to reduction.
Isoxazoles are readily reduced, usually with concornitant ring fission (e.g. 262 ---. 263).
They behave as rnasked 1,3-diketones (79AHC(25)147). 1,2-Benzisoxazoles are easily reduced
to various products (Scherne 28) (67 AHC(8)277). Chernical or catalytic reduction of oxazoles
invariably cleaves the heterocyclic ring (Scherne 29) (74AHC(17)99). For sirnilar reactions
of thiazoles, see Section 4.02.1.5.1.
Me
MeCN
o
(262)
CH=CMe
--. I I
MeCO NH 2
(263)
Ph
I
U CH ,-
NH 2
I OH H Ph
N
d
0 , CH2Ph
OH
a:: Ph
OH
Ph
I
C':::-NH
VOH
Scheme 28
PhCH - NH
I I
PhCH CH 2 R
I
OH
R=aryl
Ph N
Ph[)R
o
R = alkyl
I
PhCH-NH
I I
PhCH 2 OCR
Scheme 29
Reactivity of Five-membered Rings with Two or More Heteroatorns 75
N-c. Ph
II \
HlNl..:... !(N
0..
(264)
Catalytic reduction of 1,2,4-oxadiazoles also breaks the N-O bond; e.g. (264) gives
(265). Benzofuroxan can be reduced under various conditions to benzofurazan (266), the
dioxime (267) or o-phenylenediamine (268) (69AHC(1O)1). Reduction by copper and hydro-
chloric acid produced o-nitroanilines (Scheme 30) (69AHC(1O)1).
o
II
N-C-NH l
Pd/C Þ Ph-C-7
2[Hj 'NH z
(265)
o: O
:::::.... "'- /
N
(266)
NOH
NOH
(267)
O INH l
NHz
(268)
Me O: N'o
:::::.... "'- /
N
I
0-
Cu
-----+
HCl
Me O NO l + Me O I NHz
:::::.... I NH l :::::.... NO z
(39%)
(61%)
Scheme 30
Isothiazoles are reductively desulfurized by Raney nickel, e.g. as in Scheme 31
(nAHC(14)1). 1,2,5-Thiadiazoles are subject to reductive cleavage by zinc in acid, sodium
in alcohol, or Raney nickel, e.g. Scheme 32 (68AHC(9)107).
Meo "':::::
MeO ð - i, Raney Ni
MeO Ij S ii, Ac,O/py
0
OH
Schenie 31
HOlCr.--;'ICOlH
II \\
N, /N
S
l HOlC COlH J
--. H --.
HlN NH l
HOlC N
HOlCC)
H
Scheme 32
4.02.1.9 Reactions with Cyclic Transition States
4.02.1.9.1 Diels-Alder reactions and 1,3-dipolar cycloadditions
The distinction between these two classes of reactions is semantic for the five-membered
rings: Diels-Alder reaction at the F /B positions in (269) (four atom fragrnent) is equivalent
to 1,3-dipolar cycloaddition in (270) across the three-atorn fragrnent, both providing the
47T- electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza
analogues show reduced aromatic character and will undergo rnany cycloadditions, whereas
fully nitrogenous azoles such as pyrazoles and irnidazoles do not, except in certain isolated
cases.
E-D E=D
II \\ I \
F B .-. -F B+
'A/ 'A/
(269) (270)
Isoxazolium salts react with enamines to give pyridinium salts (Scheme 33) (69CPB2209).
o- N
Me ey Ph /Í "--.J
r + Þ
o/NMe
Me w r\
I + PhCOCH(Me)CON 0
Ph + ....,;: \.......J
N
Me
Scheme 33
76 Reactivity of Five-membered Rings with Two or More Heteroatorns
Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 34)
(74AHClI7)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles
has indicated that rates decrease with the following substituents: alkoxy> alkyl> acyl >>
phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienes is
probably due to steric crowding. In certain cases, bicyclic adducts of type (271) have been
isolated and characterized (74AHCl17)99); they can also decompose to yield furans (Scherne
35). Oxazoles react with singlet oxygen to give bicyclic adducts of type (272) which
subsequently decornpose (e.g. to 273) (74AHCl17)99).
R' N
R"[ \\R +
0/
o l: o]
o (271)
C0 2 H
R" O C0 2 H
-- R' "" I R
N
Scheme 34
RI/N
EtO(( )
o
CO,Me
I -
C
+ III
C
I
COzMe
[ 0 J
;g c0 2 Me
N/
-- 1 Ii
R OEt C0 2 Me
Me0 2 C O C0 2 Me
-- y OEt + RC=N
o
Scheme 35
Pht:t Ph
0-0
(272)
--
PhC=N
+
Ph-C -O-C-Ph
II II
o 0
(273)
1,2,3,4- Thiatriazolin-5-imines undergo a variety of cycloaddition reactions with the elimi-
nation of N 2 . 1,3-Dithiolylium-4-o1ates undergo cycloaddition reactions, e.g. as in Scheme
3t'i (HOAHC\27)151). Scheme 37 gives an example of cycloaddition in the oxathiazole series.
s R
R'C=CR 4 , 0 / R'
s -
R 4
R2 s.
_XS>RI
o
R 4 R 3
.-..-.. COS + R 1 0R 2
S
Scheme 36
O t 0
Ph . 'N
s
DMAD Me0 2 C O C02 Me
, Ph Y '\
,....N
S
Scheme 37
+ C02
Enarnines and enolate anions react with benzofuroxan to give quinoxaline di-N-oxides
(Scherne 38) (69AHCllO)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275)
(76AHClI9)1), and frorn (276) the intermediate adduct (277) can be isolated (73JA8452). This
is one of the few instances in which such primary cycloadducts have been isolated in the
oxazole series of rnesoionic cornpounds.
X=NR ,O-
Scheme 38
0-
I
CX ) R'
I R "
::::,... .
N
I
0-
(J: N
"'\
o +
::::,... o--;{
I
0-
R' X
'c"""
II --
H"""C'R"
Reactivity of Five-membered Rings with Two or More Heteroatorns 77
ij Ph
- o -'Z.._ N
0/
(274)
+ PhNCO --.
0-
PhN-i
I( N
N/
Ph
(275)
m
1 iPh
HN
(276)
+ PhC=C-C0 2 Et --.
:0 h
NH U \
C0 2 Er
(277)
4.02.1.9.2 Photochemical cycloadditions
Photochernical additions to give four-rnernbered rings are known. Thus the reactions of
imidazoles across the 4,5-bond with benzophenone and acrylonitrile are illustrated by
(278) -+ (279) and (280) -+ (281), respectively (80AHC(27)241). Oxazolin-2-one undergoes
acetone-photosensitized photochemical addition to ethylene (80CB1884).
Ph
Ph-!--LN
O _\\
) N/
Ph 2 CO. ben2ene H I
C=O
I
R
(279)
C5>
N
I
C=O
I
R
(278)
hv
Ph N
Ph[) Ph
N
Me
(280)
R tt 1 Ph N
hv R 2
CH 2 =CHCN ) N)Ph
Ph Me
(281) R' = H, R 2 =CN
R 1 =CN,R 2 =H
4.02.2 REACTIONS OF NON-AROMATIC COMPOUNDS
Discussion of these compounds is divided into isorners of arornatic cornpounds, and
dihydro and tetrahydro derivatives. The isorners of aromatic azoles are a relatively little-
studied class of cornpounds. Dihydro and tetrahydro derivatives with two heteroatoms are
quite well-studied, but such compounds become more obscure and elusive as the number
of heteroatoms increases. Thus dihydrotriazoles are rare; dihydrotetrazoles and tetrahydro-
triazoles and -tetrazoles are unknown unless they contain doubly bonded exocyclic sub-
stituents.
S- Oxides of sulfur-containing azoles cornprise another class of non-arornatic azoles.
4.02.2.1 Isomers of Aromatic Derivatives
4.02.2.1.1 Compounds not in tautomeric equilibrium with aromatic derivatives
The 3H- and 4H-pyrazoles and 2H- and 4H-irnidazoles (83UP40200) contain two double
bonds in the heterocyclic ring, but in each case the conjugation does not include all the
ring atorns; hence the cornpounds are not arornatic.
The quaternization of 5H-irnidazoles occurs at the I-position (Scherne 39) (64AHC(3)1).
4H- Pyrazoles are also readily rnonoquaternized.
Me )C s N
M -
e )Me
Me N
RX Me >c s _N _
----+ Me \ X
+.p'Me
Me N
R
Scheme 39
78 Reactivity of Five-membered Rings with Two or More Heteroatorns
Dichloropyrazolinones with alkali give alkynic acids (Scheme 40) (S8JAS99).
CI
C 'b I,Ph
I aq. NaOH þ PhC = CC
o /N 5 'C. 2-3 min - 02 H
N.
H
Scheme 40
Migrations of C-linked substituents around the ring, on to carbon or nitrogen atoms, are
common arnongst these compounds. This is the van Alphen-Huttel rearrangement and by
it 3H- pyrazoles are converted into lH- pyrazoles, and 2H- irnidazoles are therrnally iso-
rnerized into lH-irnidazoles.
3H- Pyrazoles are photochemically converted into cyclopropenes, and 3H-indazoles react
similarly, e.g. (282) --+ (283) (70AHC(1l)1). If a 3-aryl group is present, an indene can be
formed, e. . (284) --+ (285) (83UP40200).
0N hI'
M O cCJ-- t! --+
(282)
Ph
Meo n c C 02Me hv OQ
Ph _ I C0 2 Me
N :::::....
Ph N H CO,Me
(284) (258)-
Addition of nucleophiles to C=N bonds is comrnon in these compounds.
Meo 2 cÜ1><
(283)
4.02.2.1.2 Compounds in tautomeric equilibria with aromatic derivatives
Compounds of types (286) and (287) are in tautorneric equilibria with 4- or 5-
hydroxyazoles. However, the non-arornatic forrn is sornetimes by far the most stable. Thus
oxazolinone derivatives of type (287) have been obtained as optically active forrns; they
undergo racernization at measurable rates with nucleophiles (77AH021)17S). Reactions of
these derivatives are considered under the aromatic tautorner.
Dihydroazoles can exist in at least three forms (cf. Section 4.01.1.3), which in the absence
of substituents are tautomeric with each other. The forrns in which there is no hydrogen
on at least one ring nitrogen normally predorninate because irnines are generally rnore
stable than vinylarnines in aliphatic chernistry. Thus for dihydropyrazoles the stability order
is,12 (hydrazone) (288)>.:1 1 (azo) (289)>.:1 3 (enehydrazine) (290).
CN H
N
H
(290)
o
R';tJR
H X
(286)
4.02.2.2 Oihydro Compounds
4.02.2.2.1 Tautomerism
ON
N
H
(288)
R' H
1: R
o X'/
(287)
CN
N
(289)
4.02.2.2.2 Arornatization
il 4 -Imidazolines, -oxazolines and -thiazolines (291), and their benzo derivatives (292),
are very easily arornatized (292 --+ 293), and syntheses which might be expected to yield
such dihydro compounds often afford the corresponding arornatic products.
Dehydrogenation of .:1 2 -imidazolines (294; Z = NR) gives imidazoles, but requires quite
high ternperatures and a catalyst such as nickel or platinum. Alternatively, hydrogen
acceptors such as sulfur or seleniurn can be used (70AHC(12H03).
Reactivity of Five-membered Rings with Two or More Heteroatoms 79
H
I
I/NH r'YN )< H
z) z R
(291) (292) (293) (294)
,:l2-Pyrazolines are converted into pyrazoles by oxidation with bromine or Pb(OAc)4 and
they can also be dehydrogenated with sulfur. 3,5-Diphenylpyrazoline (295) on heating with
platinum disproportionates to the pyrazole (296) and the pyrazolidine (297) (66AHC(6)347).
Q N
--. I >R
:::::,... Z
c)
z
Ph
Ph O '
w... N
H
(295)
Ph
--. PhON
N
H
(296)
Ph
+ Ph O NH
N/
H
(297)
4.02.2.2.3 Ring contraction
I-Pyrazolines undergo photochemically-induced nitrogen elirnination and ring-contrac-
tion to cyclopropanes, e.g. (298) -.. (299). This is particularly useful for the preparation of
strained rings, e.g. (300) -. (301) (70AHC(11)1). .::l2-Pyrazolines unsubstituted in the 1-
position lose nitrogen on pyrolysis to give cyclopropanes (e.g. 302; Z = NH -.. 303), probably
via .::l1 - pyrazolines.
R
R-t-l C0 2 Me
o
N
(300)
Photodecornposition of .::l2 -1,2,3-triazolines gives aziridines. In cyclohexane the cis deriva-
tive (304) gives the cis product (305), whereas photolysis in benzene in the presence of
benzophenone as sensitizer gives the sarne ratio of cis- and trans- aziridines frorn both
triazolines and is accounted for in terrns of a triplet excited state (70AHC(11)l). .::l2-Tetrazo-
lines ar photolyzed to diaziridines.
H
hv
H C0 2 Me
Ilrnrl' lIIullll
(. N
N
(298)
R
R CO'M'
(301)
hv
--
H C0 2 Me
''''''', '',"m
(299)
acetone
eN
z
(302)
H, .......H
H.......C "/C 'H
C"
H/ H
(303)
--. H '- j- H
N
I
Ph
(305)
Fragmentation of ,:l3- 1 ,3,5-thiadiazoline derivatives is sumrnarized in Scherne 41.
II/h" N
Ph II hv
1//1/// N---+
N/
H Ph
(304)
H r ..... H
N.
ptf
R 2 C=N-N=CR 2
hv
--
N=N
Rl, )R 2
X
X=S, SO, S02
Scheme 41
II.
--
R R
R X;-!R
X
4.02.2.2.4 Other reactions
Dihydro cornpounds show reactions which parallel those of their aliphatic analogues
provided that the arornatization reactions just discussed do not interfere.
80 Reactivity of Five-membered Rings with Two or More Heteroatorns
Ll 2 -Irnidazolines (294; Z = NH) arc cyclic amidincs and exhibit the characteristic resonance
stabilization and high basicity. Ll 2 -Oxazolines (294; Z= 0) are cyclic imino ethers, and
Z-thiazolines (294; Z=S) are imino thioethers; both are consequently easily hydrolyzed
by dilute acid.
Ll z -Pyrazolines and Ll z -isoxazolines (302; Z = NH, 0) are cyclic hydrazones and oximes,
respectively. 2-Pyrazolines are quaternized at the 2-position (306 --. 307) (64AHC!3Jl).
1,3,4-0xadiazolines (e.g. 308) are very easily ring-opened (66AHCi7)183).
H
H+- t
R")(;N
H N/
I
R 1
(306)
H R 2
R -t--(
)(.;N
H N
/ "-
R R'
x-
RX
---+
(307)
N-NPh
Ph( )(H
a Ph
(308)
MeOH/H,O þ
PhCONHNHPh + PhCHO
Reduction of dihyro cornpounds to the tetrahydro derivatives is sometimes possible. For
exarnple, thiazolines are reduced to thiazolidines by aluminurn arnalgarn.
4.02.2.3 Tetrahydro Compounds
4.02.2.3.1 Arornatization
Sorne tetrahydro azoles can be arornatized, but this is more difficult than in the correspond-
ing dihydro series. Thus the conversion of pyrazolidines into pyrazoles is accornplished with
chloranil. Imidazolidines are aromatized with great difficulty.
4.02.2.3.2 Ring fission
Cleavage of the heterocyclic ring is usually accornplished using degradative procedures
which are also applicable in the aliphatic series. Thus a nitrogen-containing ring can be
opened by Hofrnann exhaustive rnethylation (e.g. 309 --. 310). Pyrazolidines also undergo
reactions of the Fischer indole synthesis type (311--.312). The sulfur-containing ring of
thiazolidines can be opened by Raney nickel desulfurization.
ONca 2 Et
N
/ "-
Ph Et
(309)
(CH1)PEt
I
NCa 2 Et
I
N
/ "-
Ph Et
(310)
NaOEt
CNH 0
Ó : +a
I
CH,CH,NH,
I
H2 (sD C'-.
--. N
I:
(312)
(311)
Cornpounds of types (313; R = H) and (314; R = H) are in equilibrium with open-chain
forms (315); such tetrahydro compounds are readily hydrolyzed by dilute acid (R 'I' H).
/NR
"J)
R
(3131
(NR
a)
(314)
H 2 C-N
I
H 2 C, CH,
X .
(315)
Isoxazolidines sornetirnes undergo retro 1,3-dipolar cycloaddition to give back alkenes
and nitrones (77 AHCi2l)207).
4.02.2.3.3 Other reactions
These compounds lIsuaJ1y show the typical reactions of their aliphatic analogues. 1,3-
Dioxolanes (316), tetrahydroimidazoles (313), tetrahydrooxazoles (314) and tetrahydro-
thiazoles (317) are somewhat less easily ring-cleaved than their acyclic analogues (ef.
previous section), but their properties are otherwise similar.
Reactivity of Five-membered Rings with Two or More Heteroatoms 81
o
ç)
(316)
C NR
s)
(317)
R' R R' R
O :J::;NH Me H ' PNHPh
N/ 0
Ph
(318) R= H, R'= Me
R = Me, R' = H
l-Aryl-5-pyrazolidinones (318) are photochemically ring-contracted to ß-lactams
(70AHC(ll)1).
4.02.2.3.4 Stereochemistry
Whereas the arornatic systerns are planar, fully reduced five-rnernbered rings have
non-planar envelope conforrnations, as is discussed in Section 4.01.4.3.
4.02.3 REACTIONS OF SUBSTITUENTS
Substituents attached to carbon are considered by classes; substituents linked to ring
nitrogen are considered separately because of their differing character.
4.02.3.1 General Survey of Substituents on Carbon
If the reactions of the sarne substituents on heteroarornatic azoles and on benzene rings
are cornpared, the differences in the reactivities are a rneasure of the heteroatorns' influence.
Such influence by the mesomeric effect is srnaller when the substituent is ß to a heteroatorn
than when it is a or y. The influence by the inductive effect is largest when the substituent
is a to a heteroatom.
4.02.3.1.1 Substituent environment
The electronic environrnent of an a-substituent on pyridine (319) approaches that of a
substituent on the corresponding imino corn pound (320) and is interrnediate between those
of substituents on benzene and substituents attached to carbonyl groups (321,322) (ef.
discussion in Chapter 2.02). Substituents attached to certain positions in azole rings show
sirnilar properties to those of a- and y-substituents on pyridine. However, the azoles also
possess one heteroatorn which behaves as an electron source and which tends to oppose
the effect of other heteroatorn(s).
o
,J"')Y
N
(319)
R
I
J'""C
HN 'y
(320)
R
I
0.:;;-C,
o Y
(321)
O
th Y
Z,)
(322)
N ----;\M e
II \\
Me" /N
o
(323)
Substituents cannot directly conjugate with ß-pyridine-like nitrogen atorns. Azole sub-
stituents which are not a or y to a pyridine-like nitrogen react as they would on a benzene
ring. Conjugation with an a-pyridine-like nitrogen is rnuch rnore effective across a forrnal
double bond; thus the 5-rnethyl group in 3,5-dimethyl-l,2,4-oxadiazole (323) is by far the
rnore reactive.
In azolium cations, the electron-pull of the positively charged heteroatorn is strong, and
substituents attached a or y to positive poles in azoliurn rings show correspondingly
enhanced reactivity.
Azolinones and azole N-oxides possess systerns which can act either as an electron source
or as an electron sink, depending on the requirernents of the reaction.
82
Reactivity of Five-membered Rings with Two or More Heteroatorns
In aliphatic corn pounds, reactions of functional groups are often modified very significantly
by an adjacent carbonyl group. As would be expected frorn the discussion in the preceding
section, the reactions of certain substituents a and y to pyridine-like nitrogen atorns in
azole rings are sirnilarly influenced. Such effects on substituents can be classified into six
groups. (i) Substituents which can leave as anions are displaced by nucleophilic reagents
(324). (ii) ai-Hydrogen atorns are easily lost as protons (325). (iii) As a consequence of
(ii), tautornerism is possible (326 327). (iv) Carbon dioxide is readily lost frorn carboxy-
rnethyl (328) and carboxyl groups (329). (v) These effects are transferred through a vinyl
group, and nucleophilic reagents will add to vinyl and ethynyl groups (330) (Michael reaction).
(vi) Electrons are withdrawn frorn aryl groups (331). Examples of these are listed for both
carbonyl and heterocyclic compounds in Table 8.
R R
I I r\
.ýc." Nu t".ýC "">,H Nu
o (.y 0 Y
(324) (325)
4.02.3.1.2 The carbonyl analogy
R 0
I II
QC -..r>C,,-..
o C "0-
/ "-
R R
(328)
R
): ((Y-
o"" C
II
o
(329)
R
I
""C, /H
0"" Y
(326)
R
I
C
HO/ ':::-y
(327)
r--
0""C.,,,--,,,, C R 2
0"" C""
I
R
(330)
R
f}?
(331)
Reaction type
Table 8 Reactivity of Substituents: The Carbonyl Analogy (B-68MI4020t))
Group Q- or y-groups Compare with
Nitro Are displaced readily
Halogen Are displaced Acid chloride
AlkOXYI} Are displaced when additionally Ester
Amino activated Amide
Hydroxyl Are acidic Carboxylic acid
Amino Are less basic Amide
Alkyl Become 'active' Ketone
Hydroxyl Exist largely in the oxo form Carboxylic acid Itwo
equivalent struc-
turesl
Amino Exist to a small extent only in the Amide
imine form
Mercapto Exist largely in the thione form Thiocarboxylic acid
Carboxyl Decarboxylate at ca. 200 0 C Q- Keto acids
Carboxymethyl Decarboxylate at ca. 50 0 C ß- Keto acids
Vinyl } Undergo Michael additions readily Q,ß- Unsaturated
Ethynyl ketones
ß- Hydroxyethyl Undergo reverse Michael reaction ß- Hydroxy ketones
readily (lose H 2 O)
Phenyl Undergo electrophilic substitution Phenyl ketones
in the meta and para positions
Ica. 1: 11
Nucleophilic displacement
Proton loss
Tautomerism
Decarboxylation
Michael reactions
Electrophilic attack on
phenyl groups
4.02.3.1.3 Two heteroatorns in the 1,3-positions
The 2-position in imidazoles, thiazoles and oxazoles is electron deficient, and substituents
in the 2-position (332) generally show the sarne reactivity as a- or y-substituents on
pyridines. 2-Substituents in azoliurns of this type, including 1,3-dithiolyliums, are highly
activated.
[)
Z
(332)
t3 R
Z
(333)
Reactivity of Five-membered Rings with Two or More Heteroatoms 83
Substituents in the 4-position of these compounds are also a to a rnultiply-bonded
nitrogen atom, but because of bond fixation they are relatively little influenced by this
nitrogen atom even when it is quaternized (333). This is similar to the situation for
3-substituents in isoquinolines, cf. Chapter 2.02. In general, substituents in the 4- and
5-positions of irnidazoles, thiazoles and oxazoles show rnuch the same reactivity of the
same substituents on benzeneoid corn pounds (but see Section 4.02.3.9.1).
4.02.3.1.4 Two heteroatoms in the 1,2-positions
Substituents on pyrazoles and isoxazoles, regardless of their positions, generally show
reactivity closer to that of the sarne substituent on a benzene ring rather than to that of a-
or y-substituents on pyridine. The (electron-releasing) mesomeric effect of the 'pyrrole-type'
NH group and 'furan-type' oxygen atorn appears to be rnore irnportant than their (electron-
withdrawing) inductive effect in pyrazole and isoxazole (334). However, som reactions of
these types are known (see e.g. Section 4.02.3.3.3) and halogen atorns and rnethyl groups
in the 3- and 5-positions of pyrazoles and isoxazoles (334) becorne 'active' if the ring is
quaternized (335).
V
yeN
z/
(334)
V
VCÑR
Z
(335)
Substituents on the isothiazole ring are a little rnore reactive, especially in the 5-position.
In cationic rings reactivity is rnuch higher, e.g. for substituents in 1,2-dithiolylium salts.
4.02.3.1.5 Three heteroatorns
In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than
at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example,
approach the reactivity of 4-halogenopyrirnidines. The 1,2,4-oxadiazole ring shows a similar
difference between the 3- and 5-positions.
Substituents in 1,3,4-thiadiazoles are quite strongly activated, as in the 2-position of
pyridine.
In contrast, substituents in 1,2,4-triazoles are usually rather similar in reactivity to those
in benzene; although nucleophilic substitution of halogen is sornewhat easier, forcing
conditions are required.
4.02.3.1.6 Four heteroatorns
Alkyl groups and halogen atorns in tetrazoles are not highly activated unless the ring is
quaternized.
4.02.3.1. 7 The effect of one substituent on the reactivity of another
The effect of one substituent on the reactivity of another is generally similar to that
observed in the corresponding polysubstituted benzenes. However, the partial bond fixation
in an azole can lead to differential effects in the mutual interactions of substituents, similar
to those found in naphthalene where the benzene ring fusion induces bond fixation. A good
example is in the comparison of methyl group reactivity in (336); the 5-rnethyl group
condenses with aldehydes easily, the 3-methyl group does not. However, quaternization at
nitrogen renders the 3-methyl group reactive.
02N O Me
7
Me /N
o
(336)
84 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.3.1.8 Reactions of substituents not directly pttached to the heterocyclic ring
In general, substituents removed from the ring by two or rnore saturated carbon atorns
undergo norrnal aliphatic reactions, and substituents attached directly to fused benzene
rings or aryl groups undergo the sarne reactions as do those on norrnal benzenoid rings.
4.02.3.1.9 Reactions of substituents involving ring transformations
Several classes are known. Dirnroth-type rearrangements occur by ring opening and
reclosure so that one ring atorn changes places with an exocyclic atorn. The rearrangernent
of 5 -phenylarninothiatriazole to I-phenyl-5 -rnercaptotetrazole in basic solution is reversible
(Scherne 42). As the anion it is the tetrazole systern which is the stable one, whereas the
neutral species is the thiatriazole (76AHC(20)14S).
N-N
II " i
N 'N"'-^-S-
Ph
OH 1l H-
N-N
II "SH
N'N/
Ph
:.
N-N
II "
N'S"'-^-ÑPh
H-1l oH
ð
N-N
1'/ "NHPh
's/
Scheme 42
A different type of rearrangernent occurs when suitable side chains are a to a pyridine-like
nitrogen atorn. In the rnonocyclic series this can be generalized by Scherne 43. For a given
side chain the rate of rearrangernent is 1,2,4-oxadiazoles>isoxazoles> 1,2,5-oxadiazoles.
Typical side chains include hydrazone, oxime and arnidine. Some exarnples are shown in
Table 9 (79AHC(2S)147). Sirnilar rearrangernents for benzazoles are discussed in Section
4.02.3.2.4.
Table 9 Examples of Rearrangements Involving Three-atom Side
Chains of Azoles (79AHCt251147)
Starting material
Product
R
I
C
R ß N
r I
R 5 O/N NHR 1
R
I
r('C N
R5 _\;r )H
o
{1 -....
r H
Me /N NR
o
H
{1 N-....
N
r II
Me /N NR
o
H
{1 N,
r NHPh
Me /N S
o
R 4
R 5 )-.....
\Ì/l.
HO N, /N
N
R 1
R R
\\ II \\
o N, /N
o
MeCOCH 2 r,-N
II "
N'"N/
R
MeCOCH 2 ijN
N "
'N/
R
MeCOCH2ij
N, /NHPh
S
Reactivity of Five-membered Rings with Two or More Heteroatorns 85
X---:<",A""B Y?'r---A
1/ \\ I _ II \\
y, /N c- N, /B
Z C
Scheme 43
A sornewhat sirnilar type of ring interconversion involving attack on sulfur has been
postulated in the 1,2,4-thiadiazole series, e.g. (337) -.. (338). Such reactions are cornrnon
in the 1,2,4-dithiazoliurn series, e.g. (339) - (340).
./ NHPh
C
/ NH
PhN
NJ..
ArHN /s
N
PhN-fHPh
NJ.-s;N
HN NH
I
Ar
(337)
---+
(338)
R
N
7--( '1 02
R II s+ CH R'
s/ 2
(339)
---+
R
N N
I -I 'S02
R S
S R'
(340)
Cycloadditions including a cyclic S atorn and an exocyclic C=X bond are known in the
dithiazole series, e.g. as shown in Scherne 44.
R'
x_ I X
N--1 ---c J R'
R S 1// ---+ Jl=< I R'
s"'" ---.c RC S
I S
R'
Scheme 44
4.02.3.2 Fused Benzene Rings
4.02.3.2.1 Electrophilic substitution
In cornpounds with a fused benzene ring, electrophilic substitution on carbon usually
occurs in the benzenoid ring in preference to the heterocyclic ring. Frequently the orientation
of substitution in these cornpounds parallels that in naphthalene. Conditions are often
sirnilar to those used for benzene itself. The actual position attacked varies; cornpare
forrnulae (341)-(346) where the orientation is shown for nitration; sulfonation is usually
sirnilar for reasons which are not well understood.
minor.... N>
major;t o
(341)
minor
... N
. O=>
major t S
minor
(342)
2nd H
0= ...
I )=0
lst 0
(345)
...
(X =--ti. z
/
N
(346)
lst,
I N
/
t
2nd H
(343)
.... N>
N
H
(344)
...
s/N
(347)
Indazoles show rnost of the typical benzene electrophilic substitution reactions. Anthranil
is halogenated and nitrated in the benzene ring at position 5 (67AHC(8)277). Nitration of
1,2-benzisothiazole gives a rnixture of the 5- and 7-nitro derivatives (347) (nAHC(14)43).
2,1-Benzisothiazole undergoes electrophilic brornination and nitration in the 5- and 7-
positions (nAHC(14)43). Nitration of benzofuroxan gives the 4-nitro and then the 4,6-dinitro
cornpound (69AHC(1O)1).
Substituents on the benzene rings exert their usual influence on the orientation and ease
of electrophilic substitution reactions. For example, further nitration (H2S04/S03/HN03)
86 Reactivity of Five-membered Rings with Two or More Heteroatorns
of 4-nitrobenzofuroxan (348) gives the 4,6-dinitro derivative, the first nitro group directing
meta as expected. Strong electron-donating groups enhance electrophilic substitution and
direct ortho/para. Thus dirnethylarninobenzofuroxans can be nitrosated and diazo-coupled
(69AHC(tO)1); brornination of 4-, 5-, 6- and 7-aminobenzothiazoles occurs ortho and para
to the arnino group.
6 r10
I
0-
(348)
HO NN
7 H
(349)
S ex , N)
CH 2 0 S Me
I 7
CH
"
CH 2
(350)
A heterocyclic ring induces partial double-bond fixation in a fused benzene ring. Hence,
for exarnple, diazo coupling occurs at the 7 -position of 6-hydroxyindazole (349), and Claisen
rearrangernent of 6-allyloxy-2-methylbenzothiazole (350) gives the 7 - and 5-allyl products
in a ratio of 20: 1.
4.02.3.2.2 Oxidative degradation
Vigorous oxidation (e.g. with KMn04) usually degrades fused benzene rings in preference
to rnany azole rings, especially under acidic conditions. Thus benzimidazoles are oxidized by
chrornic acid or 30% hydrogen peroxide to imidazole-4,5-dicarboxylic acid (70AHC(t2)103),
and 2,1 ,3-benzothiadiazole is oxidized by ozone or potassiurn perrnanganate to the dicar-
boxylic acid (351) (68AH09)107).
CC =--N,S
::::,.., :::--/
N
H0 2 Ctï\\C0 2 H
KMnO. II \\
N'S/N
(351)
H0 2 CII1.
H 2 N CJ--;N ---+ H0 2 C(s;N
(352) (353)
As expected, oxidative degradation of a fused benzene ring is facilitated when it carries
electron-donating groups and is hindered by electron-withdrawing substituents. 5-
Arninobenzisothiazole (352) with potassiurn permanganate gives the carboxylic acid (353)
(59JCS3061).
4.02.3.2.3 Nucleophilic attack
Most fused benzene rings are stable toward nucleophilic attack, but exceptions are known
for highly electron-deficient benzazoles. Thus aniline and benzofuroxan at 150 oC give the
anil (354) (45HCA850).
N,
N"O
I
0-
PhNH,
.:.
PhN NHPh
PhHN NPh
(354)
Halogen atorns on benzazole rings can be activated toward nucleophilic displacement by
electron-withdrawing groups. Thus azide ion displaces chlorine frorn 5-chloro-4-nitro- and
4-chloro-7 -nitro-benzofuroxan (65JCS5958).
4.02.3.2.4 Rearrangements
In the benzazole series, reactions of the type discussed for rnonocyclic derivatives in
Section 4.02.3.1.9 are generalized by Scherne 45 and exarnples are given in Table 9.
4-Nitrobenzofuroxan (355) undergoes a rearrangernent (recognizable as an isornerization
in unsyrnrnetrically substituted derivatives) which is an exarnple of this general rearrange-
ment (Scherne 45) (64AG(E)693); see Table 10.
Reactivity of Five-membered Rings with Two or More Heteroatorns 87
.,::::-B
A
6: -- N \
D
::-../
C
6 t -:'N
I D
#' C.,::::-
õ + hO
'N
ò: N
7" __ \
::-..t/O
I
0-
(355)
-
0-
6 "7- 0 ,
.ó N
I#, N=O
I
0-
Scheme 45
Table 10 Benzazole Rearrangements (71JCS{CI1193)
Examples of involvement of two-atom side chains
/-NAr
N'"
MeZN ò: --N'o
"'+/
N
I
0-
6 - Ar
#N
_ MezN I
#,NO z
MeCO
N\
;l
I
0-
é( Mv 0,
#N
-I
ßNO z
Q:5 Me
7" ,;;...-
"'N P
N
O
-+ COMe
N
N-d
Photolysis of anthranils (356) in rnethanol or arnines gives 2-methoxy- or 2-arnino-3H-
azepines (357) by ring expansion of interrnediate nitrenes (81AHC(28)231). Photolysis of
2-alkylindazoles probably also goes through a nitrene interrnediate, which either abstracts
hydrogen from the solvent to give (359) (81AHC(28)231) or ring expands to yield (358).
R!
R! OC R! CJ RZ c!: O R 2
R2 o:J ,;;...- hv R 2 7" -"'::::0 R 3 O NuH R 3 COR'
O---Þ I - ---
R 3 ::-.. / R .....-: Nu
N 3 N: N N
(356) (357)
R 1 = Ph or Me; R 2 , R 3 = H or CI; NuH = MeOH, EtzNH or PhNHz
NR
N 0
H
(358)
hv
+------
H,O'
W
NR
::-..
hv
-+
77 K
m NR
NH2
(359)
4.02.3.3 Alkyl Groups
4.02.3.3.1 Reactions similar to those of toluene
Alkyl groups attached to heterocyclic systerns undergo rnany of the sarne reactions as
those on benzenoid rings.
(i) Oxidation in solution (KMn04, Cr03, etc.) gives the corresponding carboxylic acid
or ketone; for exarnple, alkyl groups on pyrazoles are oxidized with perrnanganate to
88 Reactivity of Five-membered Rings with Two or More Heteroatorns
carboxylic acids ((j6AHC(6)347), 3-rnethylisothiazoles are converted by chrorniurn trioxide
into the 3-carboxylic acids (72AHC(l4)1), and rnethylthiazoles with SeOz give thiazole-
carbaldehydes.
(ii) Free radical brornination with N-brornosuccinirnide often succeeds. Thus 2,5-disub-
stituted 4-rnethyloxazoles on brornination give the 4-brornornethyl cornpounds
(74AHCi 17)99), and rnethyl groups in the 4- and 5-positions of isoxazole (360) and (361)
have been brominated with NBS (63AHCi2J36S).
C o I Me
Me /N
o
(360)
NBS
Cl Me
O
BrH 2 C /N
o
M'l/i
R _;N
o
(361)
NBS BrH 2 C O R
þ 7
Bz 2 0 2 R N
0/
Bz,O,
Wi) A fused cyclohexeno ring can be converted into a fused benzene ring, e.g.
(362) -+ (363).
(iv) A trichlorornethyl group has been converted by antirnony trifluoride into a
trifluoromethyl group in the 1,2,4-thiadiazole series (Scherne 46).
Q)N
H
(362)
Pd/C
--
I'\:N
I
N
H
(363)
CI 3 C r N
N )CI
5
ShF F 3 C r N
1500 Þ NY "Cl
'5/
Scheme 46
4.02.3.3.2 Alkylazoles: reactions involving essentially complete anion formation
In addition to the reactions described in the preceding section, alkyl groups in the
2-positions of irnidazole, oxazole and thiazole rings show reactions which result frorn the
easy loss of a proton frorn the carbon atorn of the alkyl group which is adjacent to the ring
(see Section 4.02.3.1.2).
Additional nitrogen atorns facilitate such reactions, particularly if they are a or y to the
alkyl group, and, if a, act across a forrnal double bond. Thus, the 5-methyl group in
3,5-dirnethyl-l,2,4-oxadiazole is much rnore reactive than the 3-rnethyl group in this
cornpound or the rnethyl groups in 2,5-dirnethyl-l ,3,4-oxadiazole (76AHCi20)6S).
The strongest bases, such as sodarnide (N aNH2/NH 3 , 40 OC) or organornetallic cornpounds
IBuLijEtzO, 40 0 C), convert, for exarnple, 2-rnethyl-oxazole and -thiazole and 1,2-
dimethylirnidazole essentially cornpletely into the corresponding anions (e.g. 364), although
sorne ring metallation also occurs (d. Section 4.02.1.7.1). These anions all react readily
even with mild electrophilic reagents; thus the original alkyl groups can be substituted in
the following ways. (i) Alkylation, e.g. MeI -+ CHzMe for the forrnation of (365). Iii)
Acylation, e.g. the oxadiazole (366) undergoes Claisen condensation with ethyl oxylate
(76AHCi20)6S). Wi) Carboxylation, e.g. CO 2 -+ CH 2 CO z H in the tetrazole series. (iv) Reac-
tions with aldehydes, e.g. MeCHO -+ .CHzCH(OH)Me in the 1,2-dirnethylimidazole series.
Mt)Me
5
MerN Mel
(_)CH2L
5
(364)
Me N
[)CH 2 Me
5
(365)
N Ar
Me("} + (COzEth
o
(366)
i,NaOEt
-
ii. MeCO,H
o 0 N Ar
II II //
EtO-C-C -HzC" /N
o
4.02.3.3.3 Reactions of alkylazoles involving traces of reactive anions
In aqueous or alcoholic solution, certain alkylazoles react with bases to give traces of
anions of type (367). With suitable electrophilic reagents, these anions undergo reasonably
rapid and essentially non-reversible reaction.
Reactivity of Five-membered Rings with Two or More Heteroatorns 89
N N
f)Me (\\
FelC0 2 J 2
[ Ñ 6 NO ' ' Ò'k
Ç CHl 1#
z ëHl
(367a) (367b) (368) (369)
(i) A nitro so group gives an imine, as in the probable rnechanisrn of the conversion of
(368) into (369).
(ii) Aliphatic aldehydes can form monoalcohols, e.g. (370) gives (371) (79HC(34-1)S).
N N OH
[ \\ CCl,CHO. [ \\ I
/Me /CH 1 -CH-CC1 3
S S
(370) (371)
(iii) Aromatic aldehydes give styryl derivatives (e.g. 372) by spontaneous dehydration
of the intermediate alcohol (cf. Section 4.02.3.1.2). 5-Methyl-3-phenyl-l,2,4-oxadiazole
(373) reacts thus with benzaldehyde in the presence of zinc chloride (76AHC(20)6S). Benz-
aldehyde has not been condensed with any of the methylisothiazoles, but 3-nitrobenzalde-
hyde reacts with the 5-rnethyl derivative (6SAHC(4)7S). The 4- and 5-rnethylthiazoles are
unreactive.
N
[)CH=CHPh
N
H (372)
N Ph
M II + PhCHO
c" /N
o
(373)
ZnCI N h
2 . PhCH=CH /I
"O/N
(iv) Halogens displace hydrogen atorns, e.g. 3,4,5-trirnethylpyrazole (374) is converted
into (375) (S6LA(S98)186).
Me f/l....Me
Me( ;N
N/
H
(374)
--+
Me n CCl 3
r
CI)C /N
N
H
(375)
OlN()Me --+ OlN()TIH
Me Me CH
(376) N 1 M
el
(377)
(v) Forrnarnide acetal gives dirnethylarninovinyl derivatives, as in (376) -+ (377).
(vi) Pyridine and iodine give pyridinomethyl cornpounds, e.g. (378) yields (379)
(80AHC(27)241).
N
( ')Me
OlN N
Me
(378)
/2.0
) ( N)-CHl -N Q +
OlN N -
Me r-
(379)
ZnCll
()Me
S
(380)
Reactions of types (i)-(vi) can be catalyzed by alkoxide or hydroxide ions, or amines.
Alternatively, an acid catalyst forms a complex of type (380) frorn which proton loss is
facilitated.
4.02.3.3.4 C-Alkyl-azoliums, -dithiolyliurns, etc.
Proton loss frorn alkyl groups a or y to a cationic center in an azoliurn ring is often easy.
The resulting neutral anhydro bases or rnethides (cf. 381) can sornetimes be isolated; they
react readily with electrophilic reagents to give products which can often lose another
proton to give new resonance-stabilized anhydro bases. Thus the trithione methides are
anhydro bases derived frorn 3-alkyl-l,2-dithiolyliurn salts (382 383) (66AHC(7)39). These
methides are stabilized by electron-acceptor substituents such as CN or C0 2 R (66AHC(7)39).
90 Reactivity of Five-membered Rings with Two or More Heteroatorns
{ .......N/ Me
/L::;'CH 2
(381)
R 2 F=\
,,/S
.S
R 3
w
, )
R 1 R
R 3 R 2 HCCS+
S/
(382)
(383)
Both ex- and y-alkylazoliurn ions, analogously to the 2- and 4-alkylazoles thernselves,
can also react with electrophilic reagents without initial cornplete deprotonation. They
undergo the same types of reactions as the alkylazoles but under rnilder conditions, and
these reactions are often catalyzed by piperidine. Thus in quaternized pyrazoles, 5-rnethyl
groups react with benzaldehyde to give styryl derivatives and can be chlorinated
(66AHC!6)347). The rnethyl groups in quaternized isoxazoles are also reactive, and here
piperidine is sufficient as catalyst (Scheme 47) (63AHC(2)36S).
Me
MeCÑR 1-
o
CH= CHAr
2ArCHO ) n. 1-
C,H",NH ArCH=CH, _ /:NR
o
Scheme 47
Sorne weak electrophilic reagents, which are usually inert toward azoles, also react with
quaternized azoles. Diazoniurn salts yield phenylhydrazones (Scherne 48) in a reaction
analogous to the Japp-Klingernann transformation of ß-keto esters into phenylhydrazones;
in the dithiolyliurn series illustrated the product has bicyclic character. Cyanine dye prepara-
tions fall under this heading (see also Section 4.02.1.6.5). Monornethine cyanines are forrned
by reaction with an iodo quaternary salt, e.g. Scherne 49. Tri- and penta-rnethinecar-
bocyanines (384; n = 1 and 2, respectively) are obtained by the reaction of two rnolecules
of a quaternary salt with one molecule of ethyl orthoforrnate (384; n = 1) or ß-ethoxyacrolein
acetal (384; n = 2), respectively.
Me
n+
'S;S
N
PhN; I V I
/S-NPh
S
Scheme 48
( NMe Q
V + I --
S CH2 MeS ::,....
Et
.
NMe I
C CH ::,...+
EI
Scheme 49
+
( NMC MeN ]
sACH(CH=CH). J!..s
(384)
R
R-h:N
S.....S-O'
(385)
R S R
RXS>-< HAr
(386)
+
Me (X S
I )-CH=CHNMe 2
S
(387)
3-Methyl-1,2-dithiolyliums react with aldehydes to give styryl derivatives, with DMF to
give Vilsrneier salts, and on nitrosation forrn the bicyclic products (385) (SOAHC!27JlSl).
2-Alkyl groups in 1,3-dithiolyliurn ions also react with arornatic aldehydes to give (386),
with DMF to give (387), and with other electrophiles (SOAHC!27)lSl).
In general, methyl groups in the 4- and 5-positions of irnidazole, oxazole and thiazole
do not undergo such deprotonation-rnediated reactions, even when the ring is cationic.
Compounds which can forrnally be considered as an hydro bases can sornetimes react
with nucleophiles. Thus unsaturated azlactones with Grignard reagents give saturated
azlactones (Scheme 50) (6SAHC(4)7S).
Reactívity of Five-membered Rings with Two or More Heteroatoms 91
ArHC
O )Ph + RMgX
R
I
ArHC H
olJPh
Scheme 50
4.02.3.4 Other C-Linked Substituents
4.02.3.4.1 Aryl groups: electrophilic substitution
Electrophilic substitution occurs readily in C-aryl groups, often predominantly at the
para position. Thus nitrations of phenyl-thiazoles, -oxazoles and -imidazoles (HN0 3 /H 2 S0 4
at 100 o C) all yield the corresponding p-nitrophenyl derivatives. This is to be contrasted
with the situation for a-phenylpyridine, where a rnixture of rnainly m- and p-nitrophenyl
derivatives is forrned. Although in strongly acidic media a C-linked aryl group is generally
rnore readily substituted than the ring, the orientation often changes when C-phenylazole
derivatives are nitrated under less acidic conditions. Thus 3- and 5-phenylpyrazoles can
give under such conditions the 4-nitro derivatives. Such orientation changes have been
dernonstrated to result frorn changes in the species undergoing reaction from the azoliurn
ion to the neutral azole.
3-Methyl-5-phenylisoxazole undergoes nitration as the conjugate acid at the para position
of the phenyl group. 5-Methyl-3-phenylisoxazole is nitrated as a conjugate acid at the meta
position but as the free base at the para position of the phenyl group (79AHC(25)147). Phenyl
groups attached to oxazole rings are nitrated or sulfonated in the para position, with relative
reactivities of the phenyl groups in the order 5> 4 > 2 (74AHC(17)99).
3-Phenylisothiazole is nitrated predorninantly in the meta position of the phenyl group,
whereas 4-phenylisothiazole is nitrated ortho and para in the phenyl group (nAHC(14)1).
Nitration of 3-phenyl-l,2,4-oxadiazole gives a rnixture of rn- and p-nitrophenyl derivatives
(63Gl196).
In the 1,2-dithiolyliurn ion systern, 3- and 5-phenyl groups on nitration give rnixtures of
para and meta orientation, whereas nitration of a 4-phenyl group gives para substitution
only (61JA2934).
4.02.3.4.2 Aryl groups: other reactions
3-Arylanthranils (388) on therrnolysis give acridones (389) (SlAHC(2S)231). 3-Phenylan-
thranils (390) also forrn acridones (391) on treatrnent with nitrous acid (67 AHC(S)277).
Related rearrangernents are found with 3-heteroarylanthranils (e.g. 392 -+ 393)
(SlAHC(2S)231).
D.
cÇð o OMe
I I
d- N: d- OMe
--
o
OMe
UNN
I OMe
H
(389)
(388)
HNO,
Q
C
OC o
::::,., I ......OH
I
NO
-
o
UNN
H
(391)
92 Reactivity of Five-membered Rings with Two or More Heteroatorns
N:'ì
o:) N
Me
CI c:;;- 0
:::::,... "" /
N
l392)
ChH,Cl'Þ t C1 o:Jc l 0 r NM J _ CI O: I" J e
:::::,... ..N') :::::,... N #
N: N/+
(393)
Methyl groups on C-linked phenyl attached to oxazoles, isoxazoles and oxadiazoles react
with benzylidineaniline to give stilbene derivatives (Scherne 51) (78AHC(23)171).
N
Ph l o>-O Me
N Ph
PhCH=NPh þ ( If If
KOH Ph 0 -
Scheme 51
4.02.3.4.3 Carboxylic acids
Azolecarboxylic acids can be quite strongly acidic. Thus 1,2,5-thiadiazole-3,4-dicar-
boxylic acid has first and second pKa values of 1.6 and 4.1, respectively (68AHC(9)!07).
The acidic strengths of the oxazolecarboxylic acids are in the order 2> 5 > 4, in agreernent
with the electron distribution within the oxazole ring (74AHC( 17)99). Azolecarboxylic acids
are arnino acids and can exist partly in the zwitterionic, or betaine, forrn (e.g. 394).
+
[ NH
o)COi"
(394)
+
-co, þ [)
o
(395)
The relatively easy decarboxylation of rnany azolecarboxylic acids is a result of inductive
stabilization of intermediate zwitterions of type (395) (cL Section 4.02.1.7.1). Kinetic
studies have shown that oxazole-2- and -5-carboxylic acids both decarboxylate through the
zwitterionic tautorners (71JA 7045). Thiazole-2-carboxylic acids, and to a lesser extent -5-
carboxylic acids, decarboxylate readily; thiazole-4-carboxylic acids are relatively stable.
Isothiazole-5-carboxylic acids decarboxylate readily, the 3-isorners less so while the 4-
isorners require high ternperatures. The 1,2,4-, 1,2,5- and 1,3,4-thiadiazolecarboxylic acids
are also easily decarboxylated; their stability is increased by electron-donating substituents
(68AHCt9J165). Most 1,2,3-triazolecarboxylic acids lose carbon dioxide when heated above
their rnelting points (74AHCt 16)33).
Azoleacetic acids with a carboxyrnethyl group also decarboxylate readily, e.g. all three
thiazole isorners, by a mechanisrn sirnilar to that for the decarboxylation of ß-keto acids;
d. Section 4.02.3.1.2. The rnechanisrn has been investigated in the oxazole case,
(396) ---. (397) ---. (398) (72JCS(P2)1077).
Ar + 0
I/ð,H II _
Z C,,,,,
o CH 2 0
(396)
Ar NH Ar N
(\ - [)Me
O/'::'CH 2 0
(397) (398)
In most other reactions the azolecarboxylic acids and their derivatives behave as expected
(d. Scherne 52) (37CB2309), although sorne acid chlorides can be obtained only as hydro-
chlorides. Thus irnidazolecarboxylic acids show the norrnal reactions: they can be converted
into hydrazides, acid halides, arnides and esters, and reduced by lithiurn alurninurn hydride
to alcohols (70AHCtI2)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show
the norrnal range of reactions.
However, in sorne cases carboxylic acid-derived groups can participate in ring fission-
reclosure reactions. Thus photolysis of 1,5-disubstituted tetrazole (399) gives nitrogen and
appears to involve the arnino-nitrene interrnediate (400), which reacts further to give (401)
(77 AHCt21 )323).
Reactivity of Five-membered Rings with Two or More Heteroatorns 93
CIOC
t3
H
Me,NH
Me2NOC
t3
H
MeOzC
(:)
H
IH4
HOH 2 C
(:)
H
EtNH,
EtHNOC
(:3
H
H0 2 C
t3
N
H
he, s
11100e
MeOH
160 0 e
165-175 0 C
H2 NH NOC t N
r )\
N
H
Scheme 52
N-N
(! \1
Me0 2 C "N.....N
CO 2 Me
(399)
hv
-N,
N: 0
Me02C OMe
(400)
N-O
-- Me0 2 C( )OMe
N
(401)
4.02.3.4.4 Aldehydes and ketones
In general, the properties of these cornpounds and those of their benzenoid analogs are
sirnilar. Thus isothiazole aldehydes and ketones behave norrnally and forrn the usual
derivatives (72AHC(14)1). Imidazole-2-carbaldehyde exists as a hydrate in aqueous solution.
4-Acetyloxazoles are oxidized to the corresponding acids with sodiurn hypobrornite
(74AHC(17)99). Thiazole aldehydes undergo the benzoin and Cannizzaro reactions. However,
corn pounds with aldehyde groups a to an NH group sornetirnes forrn dirners, e.g. as in the
1,2,4-triazole series (402) (70TL943).
r Me O COMe
N OH r morpholine
l , .....N
HO \\,N'N
J (403)
( 402)
s; :.
Me n CH 2 CSNC 4 H H O
r
.....N
N
R
(404)
The Willgerodt reaction can proceed norrnally. Thus the 3-acetylpyrazole (403) is con-
verted into the morpholide (404) (57JCS2356).
Deacylations are known. C-Acyl groups in 1,3,4-thiadiazoles are cleaved by sodiurn
ethoxide in ethanol (68AHC(9)165). Irnidazole-2-carbaldehyde behaves sirnilarly, yielding
irnidazole and ethyl forrnate; this reaction involves an ylide interrnediate. 3-Acylisoxazoles
(405) are attacked by nucleophiles in a reaction which involves ring opening (79AHC(25)147).
R 2 R2 Nu
\,( Nu- " I
C C
O GO 0) "0- .R'eONu
r -- r I ÕC(R1)=C(R)CN
R'.....N R ' .....N
o 0.)
(405)
Sornetirnes ring opening and reclosure can occur with participation of a C-acyl group.
Thus oxazole derivatives of type (406; X == H, Cl or NH 2 ; Y == OH or OEt) rearrange on
heating to 255 oC by ring opening and recyclization (74AHC(17)99). 3-Acylanthranils (407)
rearrange to benzoxazinones (408) on heating (67AHC(8)277).
XOC YOC
Yt)R -- Xt)R
o 0
(406) R = alkyl or aryl
W COPh
o
:::::,... "'-/
N
(407)
:.
--
O
U , Ph
N
(408)
94 Reactivity of Five-membered Rings with Two or More Heteroatoms
4.02.3.4.5 Vinyl and ethynyl groups
Such groups a to a pyridine-like nitrogen atom are expected to undergo Michael additions.
Examples are known in the imidazole series.
4.02.3.4.6 Ring fission
Certain a-substituted alkyltetrazoles on pyrolysis yield nitrogen and an alkyne by the
mechanism shown in Scheme 53 (77AH02U323).
X N N
I ....N HX ""N -"i
RR'C--< II .....::...- RR'C =< I RC= CR'
N--N ::::::-N
,_ H N
X - halogen, OH, NH, S h 53
- c erne
When an azoIe carbene is formed, spontaneous ring fission can occur. The prototypes
for these reactions are shown: (409) (410), (411) (412).
O-ëR
(409)
OC
Z " CR
(410)
-
4.02.3.5 Aminoazoles
ëR
0-
Z
(411)
H .::::;CR
C C Y
III + I
C ""CH
H ZY
(412)
4.02.3.5.1 Dimroth rearrangement
The thermal acid- or base-catalyzed interconversion of 5-amino-1-phenyItriazoles (413)
and 5-anilinotriazoles (415) was discovered by Dimroth. It is an example of a general class
of heterocyclic rearrangements (416 417) now known by the name Dimroth rearrange-
ments (74AHO 16)33). The original Dimroth rearrangement probably involves a tautomeric
diazoimine intermediate (414) (74AH016)33). Electron-attracting and large groups tend to
favor the tautomer in which they are on the exocyclic nitrogen. Alkyl groups tend to prefer
to reside on the cyclic nitrogen (74AHC(16)33). 5-Aminotetrazoles similarly rearrange via
azidoamidines (418).
There are many related examples which are now known as the general Dimroth rearrange-
ment. For example, 3-ethylamino-1,2-benzisothiazoIe (419) is in equilibrium in aqueous
solution with the 2-ethyl-3-imino isomer (420) (72AHCí14)43). Dimroth rearrangements are
known in the 1,2,4-thiadiazole series (421 422), and in the 1,3,4-thiadiazole series as
products of reactions of halogeno-1,3,4-thiadiazoles; see Section 4.02.3.9.1 (68AHCtY)16S).
For a similar example in the 1,2,3,4-thiatriazole series, see Section 4.02.3.1.9.
NH
NEt'HC1
V-s/
(420)
N
R (
I N
R'HN I
N
Ph
(413)
R):N,
R'HN =---NPh
1414a)
y ) X )
(416) (417)
NHEt
mN'HCl
Sl
(419)
--"
..-
R N,
PhHN):N '
(4140)
N
R (
--" N
..-- PhHN I
N
R'
(415)
+ -
N=N=N
RNAN
H I
Ar
(418)
MeN R
HN--ZS;N
(421)
N---;\R
II \\
MeHN'-. /N
S
(422)
--+
Reactivity of Five-membered Rings with Two or More Heteroatorns 95
2-Amino-1,3,4-oxadiazoles (423) ring-open and the products immediately recyclize to
triazolinones (424) (66AHC(7)183).
N-N
H 2 N(O)R
(423)
H,O
----=--+ NH 2 CONHNHCOR
-H 2 0
--
N-NH
R( ,
N O
H
(424)
4.02.3.5.2 Reactions with electrophiles (except nitrous acíd)
In aminoazoles with the amino group ex or y to C=N, canonical forms of type (425b)
increase the reactivity of the pyridine-like nitrogen atom toward electrophilic reagents, but
decrease that of the amino group. Even when the amino group is ß to C=N there is still
a smaller electron flow in the same sense. Consequently, protons, alkylating agents and
metal ions usually react with aminoazoles at the annular nitrogen atom (d. Section 4.02.1.3).
There are exceptions to this generalization, e.g. 4-aminoisothiazole is methylated to the
4-trimethylaminoisothiazole and both 3- and 4-dimethylaminopyrazoles are alkylated at
the NMez group.
N N
II" --. II' +
Z?--NH2 Z/::-NH2
(425a)
(425b)
Other electrophilic reagents form products of reaction at the amino group. This occurs
when initial attack at the pyridine-like nitrogen atom forms an unstable product which
either dissociates to regenerate the reactants or undergoes rearrangement inter- or intra-
molecularly. In reactions of this type, carboxylic and sulfonic acid chlorides and anhydrides
give acylamino- and sulfonamido-azoles, respectively. Thus 3-, 4- and 5-aminothiazoles
form acetyl derivatives, sulfonamides and ureas. The 3- and 5-amino-1,2,4-thiadiazoles
(6SAHC(S)119) can be acylated and sulfonylated; 3-amino-l,2,5- (68AHC(9)107) and 2-amino-
1,3,4-thiadiazoles (68AHC(9)16S) also behave normally on acylation.
3-Amino-2,1-benzisothiazole (426) is acylated both at the cyclic and exocyclic nitrogen
atoms to give (427) (71AJC240S). 5-Aminotetrazoles with nitric acid give nitramines. Sulfona-
tion of the 5-aminopyrazole (428) gives first the expected product, (429), then a disulfonyl
derivative (430), which rearranges on heating to the more stable (431). Aminothiazoles
react with aldehydes to give Schiff bases.
:2
(426)
ROC!
(C I N:OR
I
N
COR
(427)
n__
H2N ;N
N
Me
(428)
RS0 2 N0N
H N
Me
(429)
--+
F\ --+ O
RS02N N/NS02R (RS0 2 JzN N/N
Me Me
(430)
(431)
In still other cases, the product of reaction of an electrophile with an aminoazole is from
electrophilic attack at a ring carbon. This is electrophilic substitution and is the general
result of nitration and halogenation (see Section 4.02.1.4). In such cases, reactions at both
cyclic nitrogen and at an amino group are reversible.
In a rather different reaction, aminotetrazoles treated with bromine lose nitrogen and
give isocyanide dibromides (77AHC(21)323); probably the mechanism is as shown in
Scheme 54.
7!- \ r- N --+ RNC RN= CBr 2
RHN"N/N RN -
H N
Scheme 54
96 Reactivity of Five-membered Rings with Two or More Heteroatoms
4.02.3.5.3 Reaction with nitrous acid: diazotization
Prirnary amino groups attached to azole rings react normally with nitrous acid to give
diazonium cornpounds via primary nitroso compounds. However, the azole series shows
two special characteristics: the prirnary nitroso compounds can be stable enough to be
isolated, and diazo anhydrides are formed easily from azoles containing ring NH groups.
(i) Primary nitroso compounds
Attempted diazotization in dilute acid sometimes yields primary nitroso cornpounds.
Reactions of 3- and 5-amino-l,2,4-thiadiazoles with sodiurn nitrite and acid give primary
nitrosarnines (e.g. 432.......433) (6SAHC(S)119) which can be related to the secondary
nitrosamines (434) prepared in the normal way. 1-Substituted 5-arninotetrazoles with nitrous
acid give stable primary nitrosamines (435). Primary nitrosarnines have been isolated in
the irnidazole series.
R
H 2 N" /N
S
(432)
R
ONHN( /N
S
(433)
CH,N,
------+
R
ONMeN( /N
S
(434)
R
c HNO,
MeHN( /N
S
N-N
ONN( ;
H N
R
(435)
(ii) Diazo anhydrides
Oiazotization of aminoazoles with free cyclic NH groups can give diazo anhydrides which
show rnany of the normal reactions of diazoniums (67AHC(8)1). In the pyrazole series these
diazo anhydrides are particularly stable.
3-Diazopyrazole (436) undergoes gas-phase thermal extrusion to form an azirine, prob-
ably by the mechanism shown (81AHC(28)231); 4-diazopyrazoles show normal diazonium-type
reactions (Schemes 55 and 56) (67AHCl8)1). Analogous diazoirnidazoles and diazopurines
are known (67AHCl8Jl).
N 2
Merf
PhZ__ N
N
(436)
[ Me. Me CN J Me CN
PhCN -- X"' -- Ph N
N Ph N,
N"
+
NHH2Ph
Ph _ j'N
N
N
H N H '" Ph
MeCO,H
,
IOO'C
Ph ;NH
N
Scheme 55
N
+
N Ü OPh
Ph N
No"
h,'
henzene
Ph n COPh
Ph r
/N
N
H
'IV
----
benzene
P'ì=\C OPh
_.....,Ñ __ N
N-- N
N=N
A N
N 2
(437)
Scheme 56
Diazotetrazole (437) has been prepared; on pyrolysis it yields carbon atoms and nitrogen
(79JAD03).
Wi) Diazoniurn salts
Pyridine-2- and -4-diazonium ions are far less stable than benzenediazoniurn ions.
Azolediazonium salts generally show intermediate stability; provided diazotization is carried
out in concentrated acid, many of the usual diazonium reactions succeed. Indeed,
azolediazoniurn salts are often very reactive in coupling reactions.
2-Nitroimidazoles and 2-azidoimidazoles are available via the diazoniurn fluoroborates,
and photolytic decomposition of the fluoroborates gives 2-fluoroimidazoles (80AHC(27)241).
Reactivity of Five-membered Rings with Two or More Heteroatoms 97
3-Amino-2, I-benzisothiazole is readily diazotized to (438), which gives coupling products
and the cyanide (439) (72AHC(14)43). Diazonium salts from 3-, 4- and 5-aminothiazoles
undergo Sandmeyer reactions (to give halogenoisothiazoles), reductive deaminations and
Gomberg-Hey reactions (72AHC(14)1). 5-Aminooxazoles can be satisfactorily diazotized,
but the 2-amino compounds cannot (74AHC(17)99).
+
s
(438)
CuCN/KCN
N
N's
(439)
Cl-
The 4- and 5-amino-1,2,3-triazoles are diazotizable, e.g. the diazonium salt from 4-
aminotriazole-5-carboxamide with potassium iodide gives the 4-iodo derivative, and that
from 4-amino-1,5-diphenyltriazole gives 1,5-diphenyltriazole in ethanol (74AHC(16)33).
In strong acid the 1,2,4-thiadiazole-3- and -5-diazonium salts have been prepared; the
5-derivatives are very reactive in coupling reactions and undergo Sandmeyer reactions.
Diazonium salts from 3-amino-1,2,4-thiadiazoles are less reactive with coupling reagents
(6SAHC(S)119). Amino-1,3,4-thiadiazoles undergo diazotization smoothly provided the solu-
tion is sufficiently acidic. The diazonium salts (440) show remarkably strong coupling activity
and will even couple with mesitylene (68AHC(9)16S). 3-Amino-1,2,5-thiadiazole on attempted
diazotization forms only the diazoamino compound (441) (68AHC(9)107).
N-N
R!.(S)Ni
(440)
N-N M
II \\ e
-- R"-S/'N=N -D Me
Me
NHN=N
rl h
N, /N N, /N
S S
(441)
4.02.3.5.4 Deprotonation of aminoazoles
Canonical forms of type (442b) facilitate proton loss from the amino groups; the anions
formed react easily with electrophilic reagents, usually preferentially at the exocyclic
nitrogen atom (e.g. 443....... 444) (79HC(34-2)9).
[)NHEt
S
(442a)
[ N
SAÑHEt
(442b)
LiNH,
---+
[
S ÑEt
(443)
PhCH,CI
I
[)NEt
S I
CH Ph
(444) 2
4.02.3.5.5 Aminoazolium ions/neutral imines
Amino groups on azolium rings can lose a proton to form strongly basic azolinimines,
e.g. (445) yields (446). 2-lminobenzothiazoline with acrylic acid yields (447).
Ph NMe
Ph()NH 2
Me
(445)
--
Ph N NM e
PhIL .ANH
N
Me
(446)
Me
a N
I )=NCH 2 CH,C0 2 H
S
(447)
In the 1,2-dithiole series such imines are readily isolated; they can be alkylated or
protonated, e.g. (448) (449) (66AHC(7)39).
R}---(Rl
R 3 _ ,s
S....
(448)
R 4 X
-----+
+-----
R 2 NR 1 R 4
R 3 CS+
S/
(449)
98 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.3.6 Other N-Linked Substituents
4.02.3.6.1 Nitro groups
Nitro groups on azole rings are often smoothly displaced by nucleophiles even rnore
readily than are halogen atoms in the corresponding position. Thus 2,4,5-trinitroimidazole
(450) is converted by HCl successively into (451) and (452) (80AHC(27)241).
O,N N 02 N [ N 02N [ N
02 [)N02 02N r N)Cl -- Cl r N)CI
H H
(450) (451) (452)
Nitro groups are easily reduced, catalytically or chemically, to give amino compounds,
e.g. 4-nitroisothiazoles give the corresponding 4-amino derivatives (72AHC(!4H). In the
pyrazole series, intermediate nitroso cornpounds can be isolated. Nitrosoirnidazoles are also
relatively stable.
4.02.3.6.2 Azidoazoles
The most important chernistry of azidoazoles is the fragmentation of derived nitrenes of
which the prototypes are (453)....... (454) and (455)....... (456). Thus 5-azido-l,4-
diphenyItriazoIe (457) evolves nitrogen at 50 oC (70JOC2215). 4-Azido-pyrazoles and -1,2,3-
triazoles (458) undergo fragrnentation with formation of unsaturated nitriles (81AHc(28)231).
Gi
Ô'-+
W
(455)
('. --
QzðN:
(453)
CC
Z N
(454)
H N
C c:;'-
III + \
C
H Z
( 456)
:I l \
I l N
+ - J
N 2 -N Ph
(457)
Ph
'rN'N
C q
ø N
N Ph
N) X
R[; 40-IIO'C Þ
N
R'
(458) X = N or CR
CN
/
N=C
/ "
R' R
N
O )-+
N.--N
H
(459)
3-Azidopyrazoles exist as such (459), but their anions
tetrazole anions (461) which can be trapped as (462).
N:,...+
d '.;:N Ñ
-/N
N
(460)
--->.
Ó N N
-I
-N
V
(461)
-+
r=( N N
_)-J-
N Me
(462)
(460) are in equilibrium with
4.02.3.7 O-Linked Substituents
4.02.3.7.1 Tautomeric forms: interconversion and modes of reaction
As discussed in Section 4.01.5.2, hydroxyl derivatives of azoles (e.g. 463, 465, 467) are
tautomeric with either or both of (i) aromatic carbonyl forrns (e.g. 464, 468) (as in pyridones),
and (ii) alternative non-arornatic carbonyl forms (e.g. 466, 469). In the hydroxy 'enolic'
form (e.g. 463, 465, 467) the reactivity of these compounds toward electrophilic reagents
is greater than that of the parent heterocycles; these are analogs of phenol.
--->.
o
t)
Z
(466)
[ --->. [ NH
z;lOH z O
(463) (464)
HO
t)
Z
(465)
Reactivity of Five-membered Rings with Two or More Heteroatorns 99
n
HO...zZ;N
(467)
O N H
Z
(468)
OJ:)N
(469)
Interconversion of the hydroxyl and carbonyl forms of these heterocycles proceeds
through an anion (as 471) or a cation (as 472), just as the enol (474) and keto forms (477)
of acetone are interconverted through the ions (475) or (476). Reactions of the various
species derived from the heterocyclic compounds are analogous to those of the corresponding
species from acetone: hydroxyl forms react with electrophilic reagents (478) and carbonyl
forms with nucleophilic reagents (479). In addition, either form can lose a proton (480,
481) to give an anion which reacts very readily with electrophilic reagents on either oxygen
(482) or carbon (483).
OH 0-
d -->. d Me-C-OH Me-C-Õ
" -->. "
Z Z CH 2 CH 2
(470) (471) (474) (475)
II II II II
+
OH 0 Me-C=ÕH
d d Me-C=O
-->. I -->. I
Me Me
Z Z
(472) (473) (476) ( 477)
-CL'OH r Nu - n -C -C-O\ E' -C
-C=O -C-O-H Nu
II IV II I :-:\ t')- 11 II
-CH E + -CH 2 -CH -CH- H Nu -CH -CH E+
(478) (479) (480) (481) (482) (483)
The completely conjugated carbonyl forms are usually quite stable and highly aromatic
in that after reaction they revert to type (Section 4.02.1.1.4). An overall treatment of their
reactivity is given in Section 4.02.1.1.4. Electrophilic attack on the oxygen atom of the
carbonyl group, and nucleophilic attack at the carbonyl carbon atom, in reactions which
lead to substitution rather than ring opening are discussed in this section. Electrophilic
attack at ring carbon (Section 4.02.1.4) and ring nitrogen (Section 4.02.1.3) and nucleophilic
attack at ring carbon (Section 4.02.1.6) (other than C=O replacement) are discussed in
the sections indicated.
4.02.3.7.2 2-Hydroxy, heteroatoms-l,3
2-Hydroxy-imidazoles, -oxazoles and -thiazoles (484; Z = NR, 0, S) can isomerize to
2-azolinones (485a). These compounds all exist predominantly in the azolinone form and
show many reactions similar to those of the pyridones. They are mesomeric with zwitterionic
and carbonyl canonical forms (e.g. 485a.... 485b; Z = NR, 0, S).
[ N
z OH
(484)
-.
+
[ H
O-
Z
(485b)
[ NH [ N
-- )OMe
S 0 S
(486) (487)
---"
[NH
z O
(485a)
(i) Electrophilic attack on oxygen
2-Azolinones are protonated on oxygen in strongly acidic media. a-Alkylation of 2-
azolinones can be effected with diazomethane; thiazolinone (486) forms (487). Frequently
0- and N-alkylation occur together, especially in basic media where proton loss gives an
ambident anion.
100 Reactivity of Five-membered Rings with Two or More Heteroatoms
(ii) Nucleophilic displacements
2-Imidazolinones, 2-oxazolinones and 2-thiazolinones behave as cyclic ureas, thiocarb-
mates and carbamates, and predictably do not normally react with nucleophilic 'ketonic
reagents' such as HCN, RNH 2 , NaHS0 3 , NHzOH, N z H4' PhN 2 H 3 or NH z CON z H3'
Stronger nucleophilic reagents, i.e. those of the type that attack amides, generally also react
with azolinones. Thus they can be converted into chloroazoles with POCl 3 or PCl s , e.g.
(489) (488). Similarly, bromoazoles may be prepared using PBrs. Alkyl substituents on
the azole nitrogen atom are usually lost in reactions of this type. Phosphorus pentasulfide
converts carbonyl groups into thiocarbonyl groups (e.g. 489 490).
[)CI tOCl,
S
(488)
4.02.3.7.3 3-Hydroxy, heteroatoms-l,2
[ NH
s o
(489)
[ NH
s s
P 1 S,
--
(490)
Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491;
Z = NR, 0, S) could isomerize to 3-azolinones (492). However, these compounds behave
as true hydroxy derivatives and show phenolic properties. They give an intense violet color
with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated
by alkyl halides (to give 494; R = alkyl) and acylated by acid chlorides (to give 494; R = acyl).
OH 0
d d
Z/N Z/NH
(491) (492)
0-
d
Z/N
(493)
O OR
r
/N
Z
(494)
Sometimes compounds which exist predominantly in the hydroxyl form give products of
N-methylation with diazomethane, for exarnple 3-hydroxy-5-phenylisothiazole
(63AHC!2)24S); of course, the arnbident anion (493) is an intermediate. 3-Hydroxypyrazoles,
under rather severe conditions, can be converted into 3-chloropyrazoles with POCl 3
(66AHC!6)347).
4.02.3.7.4 5-Hydroxy, heteroatoms-l,2
5-Hydroxy-isoxazoles and -pyrazoles can tautornerize in both of the ways discussed in
Sections 4.02.3.7.3 and 4.02.3.7.5 (495 496 497). The hydroxy form is generally the
least stable; the alternative azolinone forms coexist in proportions depending on the
substituents and the solvent, with non-polar media favoring the CH forrn (497) and polar
media the NH form (496). The derived ambident anion can react with electrophiles at N,
C or 0 depending on the reagent and conditions.
n
HO Z;N
(495)
O .J::';N H
Z
(496)
H
H
O-;:(_;N
z
(497)
--0.
The hydroxyl groups of 5-hydroxypyrazoles (498) are readily replaced by halogens by
the action of phosphorus halides.
Me
HO n
N;N
H
(498)
POCl.,
140-200 'C
Me
c, n
N;N
H
Reactivity of Five-membered Rings with Two or More Heteroatoms 101
4.02.3.7.5 4- and 5-hydroxy, heteroatoms-l,3 and 4-hydroxy, heteroatoms-l,2
The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-
pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl
form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes
and -pyrroles is possible (499 500; 503 504; 501 502), as well as a zwitterionic
NH forrn (e.g. 505). Most 4- and 5-hydroxy compounds of types (500) and (502) exist
largely in these non-aromatic azolinone forms, although the hydroxyl form can be stabilized
by chelation (e.g. 506). The derived ambident anions react with electrophiles at 0 or C.
Replacement of the hydroxyl group is sometimes possible provided electron-withdrawing
groups are present as, for example, in 5-substituted 4-hydroxypyrazoles.
HO 0 H
l3 Ht3 J:.N Hk N
---->. ---->. o z)
..-- HO Z) ..--
Z H Z
(499) (500) (501) (502)
R
HO 0 at. /
O::::=-C
b HU NH &'o-t5 R
---->. r )
..--
Z/N H Z/N
Z 0
(503) (504) (505) ( 506)
4-Hydroxy derivatives of type (503) show more phenolic character; thus 4-hydroxy-
isothiazoles are normally O-methylated and O-acylated (72AHC(14)1).
Ring fission occurs readily in many of these compounds. For example, azlactones, i.e.
4H-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydro-
lyzed to a-benzamido-a,ß-unsaturated acids (509), further hydrolysis of which gives a-keto
acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis
of a-amino acids (e.g. 508 507).
H
I
Ph-C
PhCHzCHNH z ol=3Ph PhCH=C-NH PhCHzCO
I - ---. I I ---. I
COzH 0 HOzC COPh COzH
( 507) ( 508) (509) (510)
4.02.3.7.6 Hydroxy derivatives with three heteroatoms
These compounds generally exist in carbonyl forms. The oxygen function can be converted
into halogen by phosphorus halides. Reactions with electrophiles are quite complex. Thus
urazole (511) reacts with diazomethane quickly to yield (512), which is more slowly
converted into (513). 1-Phenylurazole gives (514); however, 4-phenylurazole yields (515).
Oxadiazolinones of type (516) can be alkylated at both 0- and N-atoms.
0 MeN OMe
HN-i HN OMe
oJ. /NH ---. OJ.N;N ---. OJ.N;N
N
H H Me
(511) (512) (513 )
0
MeN OMe PhN-i HN-N
oJ.N;N oJ.N/NMe OJ. )Ar
0
Ph Me
(514) (515) (516)
102 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.3.7.7 Alkoxy groups
The alkoxy groups in alkoxyazoles undergo easy de alkylation to the corresponding
hydroxyazoleazolinone when several nitrogen atoms are present or when they are addi-
tionally activated by another substituent. Thus pyrazolyl ethers are cleaved under vigorous
conditions, or more easily if a nitroso group is present. Nucleophilic displacement of alkoxy
groups on cationic rings occurs readily, e.g. in quaternary 1,2,3-triazole ethers.
Azoles with alkoxy groups ex to nitrogen can rearrange to N-alkylazolinones on heating;
thus 2-alkoxy-l-methylirnidazoles give 3-alkylimidazolin-2-ones and 2-methoxythiazoles
behave similarly. O-Allyl groups rearrange considerably rnore readily, e.g. 2-allyloxybenz-
imidazole (517) gives l-allyl-2-benzimidazolinone (518) at 180 0 C (67AHC(8)143). 5-Allyl-
oxypyrazoles undergo Claisen rearrangement of the allyl group to the 4-position.
H
(( N
I )-0,
N CH 2
/
H,C=CH
(517)
---+
H
((:>=0 /-CH 2
CH 2 CH""
(518)
Aryl tetrazolyl ethers (519) are reduced by palladium on charcoal to give the arene and
the tetrazolinone (520) (77AHCl21}323); this reaction is used for the removal of phenolic
functionality.
N-N K,CO, N-N Pd/C HN-N
ArOH + ( \1 . ( \1 -. O N + ArH
CI /N acetone ArO /N
N N
Ph Ph Ph
1519) (520)
4.02.3.8 S-Linked Substituents
4.02.3.8.1 Mercapto compounds: tautomerism
Many rnercaptoazoles exist predorninantly as thiones. This behavior is analogous to that
of the corresponding hydroxyazoles (cf. Section 4.02.3.7). Thus oxazoline-, thiazoline- and
imidazoline-2-thiones (521) all exist as such, as do compounds of type (522). However,
again analogously to the corresponding hydroxyl derivatives, other mercaptoazoles exist as
such. 5-Mercaptothiazoles and 5-mercapto-l,2,3-triazoles (523), for example, are true SH
compounds.
NH
As
(521)
N-NH
(zAs
(522)
HS[;
N
I
R
(523)
The pattern of reactivity is sirnilar to that discussed for the azolinones in Sections
4.02.1.1.4 and 4.02.3.7.1. A difference is the greater nucleophilicity of sulfur, and thus
rnore reaction of the ambident anion with electrophiles occurs at sulfur.
4.02.3.8.2 T/riones
Many azolinethiones show reactions typical of thioamides; in particular, they react with
electrophiles at the sulfur atorn.
0) Alkyl halides give alkylthio derivatives, e.g. in the imidazoline-2-thione, thiazoline-2-
thione and l-arylpyrazoline-5-thione series.
Oi) Thiones are oxidized, e.g. by iodine, into disulfides. Thus 5-mercapto-1,2,3,4-
thiatriazole is converted into the disulfide (524) (64AHCl3)263); similar behavior is known
in the tetrazole series.
Reactivity of Five-membered Rings with Two or More Heteroatorns 103
N-N N-N
II \\ II \\
N, s/'S-S--"--S/N
(524)
Mn-- NH
:ZN S
H
H,O,
--.
Me N
C)SO,H
H
(525)
( 526)
(iii) Thione groups can often be eliminated by oxidation; probably the sulfinic acid is
the intermediate. Sometimes the sulfinic acid can be isolated (e.g. 525....... 526), but rnore
usually it spontaneously loses SOz. In this way, thiazoline-2-thiones give thiazoles, 1,2-
dithiole-3-thiones (527) are converted into 1,2-dithiolylium salts (528) and 1,3-dithiole-2-
thiones (529) into 1,3-dithiolylium salts (530) (66AHC(7)39). In the pyrazole series (531)
also loses an N-rnethyl group to yield (532).
1 s
R 'O
S
(527)
R 1
AcO,H. 'n -
R'z:.._;S+ X
S
R 2 !ÍS,- AcO,H. R2rS\
R' S;-S RIl.
(iv)
(528) (529)
Me Me
D AcO,H 0 "
. I ,
S N/ NMe N/N
Ph Ph
(531) (532)
However, aryl-l ,2,4-dithiazoline-3-thiones are oxidized to the 3-ones (533 -+ 534).
S 0
A -- A
r" /S r" /S
S S
(533) (534)
(530)
(v) Strong oxidation forms a sulfonic acid or betaine as, for example, in the pyrazole
(535....... 536), thiazole and tetrazole series.
Me Me
S NMe -- O)S -QNMe
Ph Me
(535) (536) (537) (538)
(vi) Cyc1oaddition across the C=S bond can lead to spiro derivatives, e.g. (537) ....... (538).
S\\"h
S S;N
ArCNO N"'-O X S ìJ Ph
· l I
Ar S S...-N
4.02.3.8.3 Alkylthio groups
2-Alkylthiothiazoles rearrange thermally into the 3-alkylthiazoline-2-thiones; in the
imidazole series a thermal equilibrium is reached.
Alkylthio groups are oxidized to sulfoxides by H z 0 2 and readily by various oxidizing
reagents to sulfones, e.g. in the imidazole series. The SR group is replaced by hydrogen
with Raney nickel, and de alkylation is possible, e.g. of 3-alkylthio-1,2-dithiolyliums to give
1,2-dithiole-3-thiones by various nuc1eophiles (SOAHC(27)151).
Alkylthio groups are replaced in nucleophilic substitutions. Such reactions are easy in
cationic derivatives; for example, in the 1,2-dithiolylium series (539), substituted cyclopen-
tadienyl ion gives fulvene derivatives (540) (66AHC(7)39). 2-Methylthio groups in
1,3-dithiolylium ions are substituted by primary amines or secondary amines (SOAHC(27)151),
and similar reactions are known for 2-alkylthiothiazoles.
R' SM, À R Rr R S
R,QS + gR -- RJ S [)SR
S/ R R S/ S
1,3-Dithiole-2-thiones trap radicals to give neutral stabilized radicals (541) (SOAHC(27)31).
104 Reactivity of Five-membered Rings with Two or More Heteroatorns
4.02.3.8.4 Sulfonic acid groups
Azolesulfonic acids frequently exist as zwitterions. The usual derivatives are formed, e.g.
pyrazole-3-, -4- and -5-sulfonic acids all give sulfonyl chlorides with PCls. The sulfonic
acid group can be replaced by nucleophiles under rnore or less vigorous conditions, e.g. by
hydroxyl in irnidazole-4-sulfonic acids at 170 o C, and by hydroxyl or arnino in thiazole-2-
sulfonic acids.
4.02.3.9 Halogen Atoms
4.02.3.9.1 Nucleophilic displacements: neutral azoles
As discussed in Section 4.02.3.1, nucleophilic replacernents of halogen atorns are facili-
tated by rnesorneric stabilization in the transition state for sorne halogenoazoles, depending
on the nurnber and orientation of the ring heteroatorns and halogen. Additional to this,
and just as in benzene chernistry, all types of halogen atorns are activated toward nucleophilic
displacernent by the presence of other electron-withdrawing substituents. Halogen atorns
n the 4- and 5-positions of irnidazoles, thiazoles and oxazoles and those in all positions of
pyrazoles and isoxazoles are norrnally rather unreactive, but are labilized by an ex or y
electron-withdrawing substituent. Reactions of N-unsubstituted azoles containing a ring
NH group are often difficult because of the formation under basic conditions of unreactive
anions.
Halogen atorns in the 2-position of imidazoles, thiazoles and oxazoles (542) undergo
nucleophilic substitution reactions. The conditions required are rnore vigorous than those
used, for exarnple, for ex- and y-halogenopyridines, but rnuch less severe than those required
for chlorobenzene. Thus in cornpounds of type (542; X = Cl, Br) the halogen atorn can be
replaced by the groups NHR, OR, SH and OH (in the last two instances, the products
tautornerize; see Sections 4.02.3.7 and 4.02.3.8.1).
N
[)x
Z
(542)
The 4- and 5-halogenoirnidazoles and 4- and 5-halogenooxazoles are less reactive toward
nucleophilic substitution than the 2-halogeno analogs, but still distinctly rnore reactive than
un activated phenyl halides. Thus a brornine atorn in the 4- or 5-position of 1-rnethyl-
irnidazole requires lithiurn piperidide to react, whereas the 2-brorno analogue is converted
into 2-piperidinoirnidazole by piperidine at 200 o C. The chloro group of 5-chloro-4-
nitroirnidazole can be replaced by an alkylrnercapto group (70AHC(12) 1 03). The relative
reactivities with respect to nucleophilic displacernent increase in the order Cl < Br < I; fluoro
cornpounds have been little studied but 4-fluoroirnidazoles are relatively unreactive. 5-
Halogenothiazoles react unexpectedly rapidly with rnethoxide, the 4-halogenothiazoles less
readily.
3-Chloro-5-arylisoxazoles undergo nucleophilic displacernent with alkoxide ion. Haiogen
atorns in the 5-position of the isoxazole nucleus are readily displaced if an activating group
is present in the 4-position (63AHC(2136S).
Halogen atorns at the various positions of isothiazoles show considerable differences in
reactivity. 5-Halogens, particularly when activated by an electron-withdrawing group such
as nitro in the 4-position, readily undergo nucleophilic displacernent to give hydroxy, alkoxy,
alkylthio, arnino and cyano derivatives. However, a 3-halogen atorn, even when activated,
is less reactive than a halogen in the 5-position, and replacernent is often accornpanied by
ring cleavage, e.g. Scherne 57 (nAHC(14)1). 4-Halogenoisothiazoles are still less reactive,
but can react with copper(l) cyanide to give the corresponding nitrile (6SAH04)107).
NC O CI
Cl
S/N
Na,S
NC SMe
Mel Þ MesON
S
MeS CN
" /
+ C=C
/ "
MeS CN
Scheme 57
Reactivity of Five-membered Rings with Two or More Heteroatoms 105
Halogens attached to the pyrazole nucleus are norrnally very inert. If there is an electron-
withdrawing group in the 4-position, then the halogen atorn in the 5-position of a pyrazole
ring becornes activated, for exarnple Scherne 58 (66AHC(6)347). However, such an electron-
withdrawing group in the 4-position only activates the chlorine atorn in the 5-position and
not one in the 3-position because of the influence of partial bond fixation (66AHC(6)347)
(see discussion in Section 4.02.3.1).
PhN=N O Me E s- PhN=N O Me
c,1 E S 1
N/N t N/N
Ph Ph
Scheme 58
5-Halogeno-l-methyl-l,2,3-triazoles undergo substitution reactions with arnines, but the
4-halogeno analogs do not. 5-Chloro-l,4-diphenyl-l,2,3-triazole with sodiurn cyanide in
DMSO gives the cyano derivative (63JCS2032). i-Substituted 3-chloro- and 5-chloro-l,2,4-
triazoles both react with arnines.
5-Chlorine atorns in 1,2,4-oxadiazoles can be replaced by arnino, hydroxy or alkoxy
groups (76AHC(20)6S). 5-Halogeno-l,2,4-thiadiazoles are also quite reactive: silver fluoride
gives the fluorides, in concentrated hydrochloric acid a 5-hydroxy group is introduced, and
thiourea reacts, as do various arnines. Sodiurn sulfite gives sulfonic acids, and reactive
methylene cornpounds give the expected substitution products (6SAHC(S)119). By contrast,
halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents:
thus 3-chloro-5-phenyl-l,2,4-thiadiazole resists arninolysis and thiourea; however, a 3-
alkoxy group is introduced by sodiurn alkoxide (65AHC(S)119).
Halogens on the 1,2,5-thiadiazole ring are highly reactive and easily converted into ethers
by refluxing with alkoxides (68AHC(9)107). 2-Chloro-l,3,4-thiadiazole and benzylamine give
a rnixture of (543) and (544) (68AHC(9)16S), the latter resulting frorn a Dirnroth rearrange-
ment (see Section 4.02.3.5.1). With hydrazine, (545) is sirnilarly forrned (68AHC(9)16S).
N-N N-NH N-N N,H. N-NH
S)NHCH2Ph ---I' N S R S)CI · R N S
CH 2 Ph NH 2
(543) (544) (545)
Halogen atorns at the 5-position of tetrazoles are reactive and easily replaced by
nucleophiles. 5-Brorno-l-rnethyltetrazole is significantly rnore reactive than the 2-rnethyl
isorner (77 AHC(21)323).
4.02.3.9.2 Nucleophilic displacements: halogenoazoliurns
Halogen atorns in cationic oliurn rings are very reactive. The halogen atorn in the
quaternary salts of 3- and 5-halogeno-l-phenylpyrazoles is replaced at 80-100 o C by
hydroxyl, alkoxyl, thiol, arnino or cyano groups (66AHC(6)347). 3-Halogeno-l,2-dithiolyliurns
are converted into 1,2-dithiol-3-ones by water and react readily with other nucleophiles
(80AHC(27)lSl). Displacernent of brornine frorn triazoliurn salts takes place easily, e.g. as in
Scherne 59 (74AHC(16)33).
Me
N
[ "N+
Br I
N
Me
Na,S
Me
N+
r :N
-J-. N
S Me
Scheme 59
4.02.3.9.3 Other reactions
Nuclear halogen atorns also show rnany of the reactions typical of aryl halogens. (i) They
can be replaced with hydrogen atorns by catalytic (Pd, Ni, etc.) or chernical reduction (HI
or ZnjH 2 S0 4 ). For exarnple, halogenopyrazoles with HI and red phosphorus at 150 0 C
106 Reactivity of Five-membered Rings with Two or More Heteroatorns
give pyrazolcs (66AHC(6)347), and 5-brorno-1,2,4-thiadiazole is reduced by Raney nickel to
the parent heterocycle. 2-Bromothiazole can be reduced electrochernically. (ii) They give
Grignard reagents; however, in the preparation of these it is sornetimes necessary to add
ethyl bromide to activate the rnagnesiurn ('entrainment rnethod'). Pyrazolyl Grignard
reagents have been obtained by the entrainrnent reaction (66AHC(6)347). 4-Iodoisoxazoles
give Grignard reagents (63AHC(2)36S). The 4- and 5-halogenooxazoles undergo halogen-
metal exchange with n-butyllithium to give 4- and 5-lithiooxazoles (74AHC(17)99).
Halogenothiazoles give Grignard reagents and lithio derivatives.
4.02.3.10 Metals and Metalloid-linked Substituents
Metalloid azoles frequently show expected properties, especially if not too rnany
heteroatorns are present. Thus Grignard reagents prepared frorn halogen-azoles (see Section
4.02.3.9.3) show norrnal reactions, as in Scherne 60. 2-Lithioirnidazoles react norrnally,
e.g. with acetaldehyde (Scherne 61) (70AHC(12)103); 5-lithioisothiazoles (see Scherne 62)
(72AHC(14)1) and 2-lithiothiazoles undergo rnany of the expected reactions.
H0 2 C O Me C02 IMg o I,Me PhCOR PhRClOH O r Me
M r +-- Me I I N · Me /N
e O/N 0/ 0
Scheme 60
N
[)
N
I
CH 2 Ph
N
i, BuLi . [)CHMe
ii, MeCHO N I
I OH
PhH 2 C
Scheme 61
R R 1
R 2 CN
S/
R R 1
O
H0 2 C /N
S
R R 1
O
OHC S/N
r IC02
R R '
L'U
1 S/N
( R2C 7 1 Br, HO
R R ' R R ' R R '
R 2 0CCN BrQN R 2 (OH)HCUN
s/ S S
Scheme 62
However, as the nurnber of heteroatorns increases, the stability decreases: the 5-lithio
derivatives of 1,2,3-triazoles (546) ring-open spontaneously (74AHC(16)33). 1-Methyl-
tetrazol-5-yllithium de corn poses to nitrogen and lithium rnethylcyanarnide above -50 o C,
although it gives the expected Grignard-like reactions with brornocyanogen, esters, ketones
and sulfur at lower ternperatures (77AHC(21)323).
Li
I
-+ PhC=C=NPh+N 2
Ph C
L ,I N
I I
Ph
(546)
Reactivity of Five-membered Rings with Two or More Heteroatorns 107
Acetoxymercurioxazoles (74AHC(17)99) and acetoxyrnercuriothiazoles with halogens give
the corresponding halogenooxazoles in good yield. 4-Acetoxyrnercuriopyrazoles show many
of the reactions of phenylrnercury(II) acetate: removal by HCl, conversion to Br by bromine,
and to SCH 2 Ph by (SCNh/PhCH 2 Cl.
4.02.3.11 Fused Heterocyclic Rings
A wide variety of such derivatives is known; their properties are usually those of the
individual ring systems. However, sorne unique reactions arise from the special juxtaposition
of the two rings, e.g. pyridotetrazoles (547) on photolysis yield cyanopyrroles (548)
(81AHC(28)231).
o
flN N
\ I
N=N
(547)
150'C(gas)
C )
-10 'C (solid)
o .. -- O CN
fl. .A N ' N
N .
H
(548)
4.02.3.12 Substituents Attached to Ring Nitrogen Atoms
4.02.3.12.1 N-Linked azole as a substituent
It is instructive to consider N-substituted azoles in reverse, i.e. the azole ring as the
substituent linked to some other group. Harnrnett and Taft u-constant values for azoles as
substituents are given in Table 11. The values show that all the azoles are rather weak net
resonance donors, imidazole being the strongest. They are all rather strong inductive
acceptors, with pyrazole considerably weaker in this respect than imidazole or the triazoles.
Table 11 Hammett and Taft u- Constants for Azoles as Substituents
in a Benzene Ring (SIJCR(S)364)
Z-y
\\
/X
N
Ó
Azote
X y Z UI UR'
3 N 0.30 -0.06
2 N 0.51 -0.15
7 N N 0.53 -0.10
5 N N 0.53 -0.12
4 N N 0.66 -0.10
N-Linked azole rings behave as good leaving groups, the rnore so the rnore nitrogen
atorns contained in the ring (cf. Section 4.02.3.12.4).
4.02.3.12.2 Aryl groups
Electrophilic substitution occurs readily in N-phenyl groups, e.g. 1-phenyl-pyrazoles,
-imidazoles and -pyrazolinones are all nitrated and halogenated at the para position. The
aryl group is attacked preferentially when the reactions are carried out in strongly acidic
media, where the azole ring is protonated.
The azole ring can activate rnetallation at the ortho position of an N-phenyl group, as in
1-phenylpyrazoles.
IOH Reactivity of Five-membered Rings with Two or More Heteroatoms
If the N-aryl group is strongly activated, then it can be rernoved in nucleophilic substitution
reactions in which the azole anion acts as leaving group. Thus 1-(2,4-dinitrophenyl)pyrazole
reacts with N 2 H 4 or NaOMe.
On pyrolysis, l-arylirnidazoles rearrange to 2-arylirnidazoles. In other systerns pyrolysis
causes rnore deep-seated changes. l-Arylbenzotriazoles (549) on pyrolysis or photolysis
give carbazoles (550) via interrnediate nitrenes (81AHC(28)231). I-Phenyl-1,2,4-triazole
(551) pyrolyzes to isoindole (552) via a carbene interrnediate (81AHCI28)231) and another
exarnple of participation of N-phenyl groups is found in the forrnation of benzirnidazoles
frorn tetrazoles (see Section 4.02.1.2.1). In the oxadiazolinone series (553), a nitrene
interrnediate (554) is also probably forrned, which then ring closes (70AHO 11)1).
ex , I N
I
N
Ph
(549)
.1 0 "
----+ -
NPh
Cd:)
N
H
(550)
çr _:.' :3<:J Q)H
15511
- NH
(552)
hv
----+
N:
Ph--<
N
Ph
(554)
N
- Ph\NV
H
N-. O
Ph< ---l
h 0
(553)
4.02.3.12.3 Alkyl groups
N-Alkyl groups in azoliurn salts can be removed by nucleophilic SN2 reactions; soft
nucIeophiles such as PPh 3 and r are effective. Sornetirnes there is cornpetition; for exarnple,
in (555) the rnethyl group is the rnore readily rernoved to give rnainly N-ethylirnidazole
(556) (80AH027)241). This reaction has been studied quite extensively in the irnidazoliurn
series. The 1,2- and 1 ,3-dialkyltriazoliurn salts undergo nucleophilic displacernent on heating
(74AHO 16)33), and 2-alkylisothiazoliurn salts are reconverted into isothiazoles.on distillation
(72AHOI4)1). Pyrazoliurn salts sirnilarly give pyrazoles. The benzyl group in l-benzyl-1,2,3-
triazoles is rernoved by reduction with sodiurn in liquid arnrnonia or catalytic reduction.
+
[3ce
N I
M.:..-/
(555)
.1
---+
[ NEt
)
N
(556)
+ [1
N
Me
N-Alkyl groups in neutral azoles can rearrange therrnally to carbon. For example,
2-alkylirnidazoles can be prepared in this way in a reaction which is irreversible, uncatalyzed,
intrarnolecular and does not involve radicals (80AH027)241). N- Vinyl and N-alkyl groups
in irnidazoles also rearrange therrnally to the 2- and 4-ring positions.
Deprotonation can occur at the a-CH of azole N-alkyl groups: treatrnent of l-rnethyl-
pyrazole with n-BuLi followed by aldehydes gives products of type (557). Such proton loss
is facilitated in cationic azido rings, and the ylides so forrned sornetirnes undergo rearrange-
ment. Thus quaternized 1,2-benzisoxazoles (558) lose a proton and then rearrange to
1.3-benzoxazines (559) (67AHC(8)277). Quaternized derivatives of benzofuroxan forrned
in situ undergo rearrangernent to hydroxybenzirnidazole N-oxides (560) (69AHC(10)1).
Reactions of this type are also known for N-alkylazolinones.
O
/N
N
CH 2 CmOH)R
(557)
Reactivity of Five-membered Rings with Two or More Heteroatoms 109
Ph
NEt
ó
(558)
-H+
-----+
Ph
o=d +-
I NCHMe----'
d
ct : hN
/I
::"'0 CHMe
----.
Ph
(Ç;Me
H
(559)
0-
I
(X I )
N
OH
(560)
0: :o- N ,
::--Ñ P
\
0-
MeOTs
Me
(X , N,
I +p
N
II
o
-H+
--+
CH 2
II
(('O-
Il
o
---+
4.02.3.12.4 Acyl groups
An azole ring is quite a good leaving group, far better than NR 2 . Hence N-acylazoles are
readily hydrolyzed. Their susceptibility to nucleophilic attack gives rise to the synthetic
utility of cornpounds such as carbonyldiirnidazole (561) which have been used, for example,
in peptide syntheses. N-Acylazoles offer mild and neutral equivalents of acid chlorides.
The leaving group ability of the azole ring increases with the nurnber of nitrogen atoms it
contains.
kJ-r
(561)
Acyl derivatives of azoles containing two different environments of nitrogen atorns can
rearrange. For exarnple, l-acyl-l,2,3-triazoles are readily isornerized to the 2H-isomers in
the presence of triethylarnine or other bases; the reaction is intermolecular and probably
involves nucleophilic attack by N-2 of one triazole on the carbonyl group attached to
another (74AHC(16)33).
2-Acyltetrazoles lose nitrogen spontaneously to give oxadiazoles, and thiadiazoles can
be prepared similarly from 2-thioacyltetrazoles (Scherne 63) (77AHC(21)323).
R'
I
/c
N-N x
II \
R'-. 7 N
N
X=O,S,N
-No + _ N-N
---+ RC=N-N-C-R' -- II \\
II R'-. .?R'
x X
Scheme 63
4.02.3.12.5 N-Amino and N-nitro groups
N-Amino groups are replaced by hydrogen on treatrnent with nitrous acid (e.g. 562 563)
(80AHC(27)241) or phosphorus trichloride (1,2,4-triazole-4-acylimines are converted into
triazoles (74AHC(17)213)).
R N
[)SMe
N
NH 2
(562)
HONO
-
R N
[JSMe
N
H
N-Aminoazoles can be oxidized to nitrenes which then fragment or ring expand in various
ways. l-Ami 0-1,2,3-triazoles (564) lose two rnoles of nitrogen to give alkynes
(74AHC(16)33). N-Arnino-triazoles (565) and -tetrazoles on oxidation with lead tetraacetate
fragrnent to benzonitrile or benzyne (81AHC(28)231); however, the interrnediate nitrene can
be trapped as an aziridine (566). Sirnilarly, the N-aminopyridazinotriazoles (567) undergo
110 Reactivity of Five-membered Rings with Two or More Heteroatorns
oxidative fragrnentation to give open-chain compounds (568) (81AHC(28)231). N-
Arninopyrazoles can ring expand to 1,2,3-triazines.
R
N I
R ( N -+ m
R / C
N I
NH 2 R
(564)
N-N
Ph( )Ph -+
N
NH 2
(565)
/
N-N
Ph )Ph
N
I
N:
R
N ::t =--N,
I NNH 2
N;:,... :0- /
R N
(567)
Pb<OAcI 4
N 2 + 2PhCN
N-N
Ph )Ph
N
I
N
A
1566)
R
I ..-;N
N C:::::-
I
Nyc N
R
(568)
I-Nitropyrazoles rearrange to 4-nitropyrazoles in H 2 S0 4 and to 3-nitropyrazoles ther-
rnally. Sirnilar rearrangernents are known for N-nitro-l,2,4-triazoles.
4.02.3.12.6 N-Hydroxy groups and N-oxides
Cornpounds of this type are tautomeric: in general, the N-oxide forrn (e.g. 570) is favored
by polar rnedia, the N-hydroxy forrn (e.g. 569) by non-polar rnedia.
N
[)
N
OH
(569)
NH
[)
N
I
0-
(570)
..--
N-Hydroxy groups can be acetylated (AC20) and O-alkylated in basic rnedia by rnethyl
iodide. l-Hydroxypyrazole 2-oxides are quite strong acids.
Azole N-oxide groups are readily removed by reduction with ZnjHOAc, HI or PCh,
e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isornerize on irradiation to the
corresponding 2-oxides.
Oxidation of N-hydroxyazoles can give cyclic nitroxyls (e.g. 571-573) (79AHC(2S)20S).
0-
(X
I + Me
+./
N
I
0-
(571)
(X N
?"
I t
I
0-
(572)
4.02.3.12.7 N-Halogeno groups
0-
I
(X I
+.{
N
I
0-
(573)
Generally these derivatives are rather unstable and behave as oxidizing and halogenating
agents. 1- Iodoirnidazoles are rnore stable than other analogs.
4.03
Synthesis of Five-membered Rings with
Two or More Heteroatoms
K. T. POTTS
Rensselaer Polytechnic Institute, New York
4.03.1 INTRODUCTION 112
4.03.2 SYNTHESES USING ALDOL-TYPE CONDENSATIONS 112
4.03.2.1 Intramolecular Condensations 112
4.03.2.1.1 Ring systems with two heteroatoms 112
4.03.2.1.2 Ring systems with three heteroatoms 115
4.03.2.1.3 Ring-fused systems 116
4.03.2.2 Intermolecular Condensations 118
4.03.2.2.1 Ring systems with two heteroatoms 118
4.03.2.2.2 Ring-fused systems 119
4.03.2.2.3 Ring systems with two adjacent heteroatoms 121
4.03.3 SYNTHESES UTILIZING INTERMOLECULAR NUCLEOPHILIC DISPLACEMENTS 122
4.03.3.1 Classification of Reaction Types 122
4.03.3.2 Design of the Appropriate Bielectrophile 123
4.03.3.2.1 1,1-Bielectrophiles 123
4.03.3.2.2 1,2-Bielectrophiles 123
4.03.3.2.3 1,3-Bielectrophiles 124
4.03.3.2.4 1,4- and higher bielectrophiles 125
4.03.3.3 Syntheses Using 1,1-Bielectrophiles 125
4.03.3.3.1 Ring systems with two heteroatoms 125
4.03.3.3.2 Ring systems with three or more heteroatoms 126
4.03.3.3.3 Ring-fused systems 128
4.03.3.4 Syntheses Using 1,2-Bielectrophiles 129
4.03.3.4.1 Ring systems with two heteroatoms 129
4.03.3.4.2 Ring systems with three or more heteroatoms 130
4.03.3.4.3 Ring-fused systems 131
4.03.3.5 Syntheses Using 1,3-Bielectrophiles 131
4.03.3.5.1 Ring systems with two heteroatoms 131
4.03.3.5.2 Ring systems with three or more heteroatoms 132
4.03.3.5.3 Ring-fused systems 133
4.03.4 INTRAMOLECULAR RING CYCLIZATIONS 133
4.03.4.1 Oxidative Ring Closure Reactions 133
4.03.4.1.1 C-N bond formation 133
4.03.4.1.2 N -N bond formation 134
4.03.4.1.3 C-S bond formation 135
4.03.4.1.4 N -S bond formation 135
4.03.4.1.5 O-C bond formation 136
4.03.4.1.6 O-N bond formation 137
4.03.4.1.7 S-S, S-Se and Se-Se bond formation 137
4.03.4.2 Electrophilic Ring Closures via Acylium Ions and Related Intermediates 138
4.03.4.3 Ring Closures via Intramolecular Alkylations 139
4.03.4.4 Ring Closures via Nucleophilic Additions 139
4.03.4.5 Ring Closures via Radical Intermediates 141
4.03.5 SYNTHESES INVOLVING CONJUGATE ADDITION REACTIONS 142
4.03.6 RING FORMATION VIA CYCLOADDITION REACTIONS 143
4.03.6.1 1,3-Dipolar Cycloadditions 143
4.03.6.1.1 Monocyclic systems with two or more heteroatoms 146
4.03.6.1.2 Ring-fused systems 147
4.03.6.1.3 Cycloadditions using mesoionic ring systems 149
4.03.6.2 1,4-Dipolar Cycloadditions 150
4.03.6.3 1,5-Dipolar Cycloadditions 151
111
112 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.7 HETEROCYCLIC RING INTERCONVERSIONS
4.03.7.1 Small Rings as Dienophiles or Dipolarophiles
4.03.7.2 Small Rings as a Source of Ylides
4.03.7.3 Small Rings as Substrates for Ring-opening Reactions
4.03.7.3.1 Three-membered rings
4.03.7.3.2 Four-membered rings
4.03.7.4 Interconversion of Five-membered Rings
4.03.7.5 Interconversion of Six- and Five-membered Rings
4.03.7.6 Ring Interconversions Involving Side Chains
4.03.8 PHOTOCHEMISTRY IN HETEROCYCLIC SYNTHESIS
4.03.8.1 Elimination Processes
4.03.8.1.1 Loss of nitrogen
4.03.8.1.2 Loss of carbon dioxide
4.03.8.2 Photochemically Induced Isomerizations
4.03.8.3 Carbon-Carbon Bond Formation
4.03.8.3.1 Intramolecular reactions
4.03.8.3.2 Intermolecular reactions
4.03.9 REACTIVE, ELECTRON-DEFICIENT INTERMEDIATES
4.03.9.1 Carbenes
4.03.9.2 Nitrenes
4.03.10 USE OF YLIDES IN HETEROCYCLIC SYNTHESIS
4.03.10.1 Sulfonium Ylides
4.03.10.2 Phosphonium Ylides
4.03.10.3 Sulfimides
153
153
153
154
154
155
156
157
158
159
159
159
159
160
161
161
162
162
162
163
164
164
165
166
4.03.1 INTRODUCTION
Synthetic procedures leading to five-rnembered rings containing two or rnore heteroatorns
have been reported in the literature for over a century, and the developrnent of these
syntheses in many ways reflects the developrnent of organic chernistry. The vast nurnber
of five-rnernbered ring systerns that incorporate two or rnore heteroatorns, together with
their ring-fused derivatives, presents a considerable challenge for a systernatic treatrnent
of their synthesis as the rnethods utilized ernbrace the rnajority of the reaction processes
used in organic chernistry.
The synthesis of these five-rnembered ring systerns has classically been discussed in terrns
of the ring system forrned. In recent years rnany synthetic procedures have been classified
in terrns of the bonds being forrned and the position and nature of the heteroatorns involved.
Both rnethods have their advantages, and also their drawbacks.
In this general chapter on the synthesis of the ring systems described in Volurnes 5 and
6 of this work, attention is focused on the reactions involved in forrning the bonds involved
in rnaking up the heterocycle. This rnethod has rnany advantages and provides a convenient
frarnework for discussion of not only the heterocycles described in these two vol urnes, but
also of those in the cornpanion vol urnes in the series. Although the classification of the
reaction types is somewhat arbitrary and occasional overlap occurs, this approach ernphasizes
that heterocyclic synthesis is a vital part of organic synthesis in general, and it is particularly
useful as a basis for devising new synthetic approaches to a ring systern with a desired
substituent pattern. It was initially developed by the author as part of a successful short
course on heterocyclic synthesis that was presented at rnany locations in the United States
over the past few years.
4.03.2 SYNTHESES USING ALDOL-TYPE CONDENSATIONS
4.03.2.1 Intramolecular Condensations
4.03.2.1.1 Ring systems with two heteroatorns
Modification of reaction schernes leading to furans, thiophenes and pyrroles by incorpor-
ation of a heteroatorn into the substrate provides ready access to irnidazoles, thiazoles,
oxazoles, dithioles, oxathioles, etc. Incorporation of two heteroatorns into the substrates
Synthesis of Five-membered Rings with Two or More Heteroatorns 113
enables triazoles, thiadiazoles, oxadiazoles, etc. to be obtained. These general reaction
schernes are shown in Scherne 1.
H-t-X\H + HzY -- -(Y ir
Á'o oA J-x
HX-XH
'o á
+ HzY --
Y
-<'ìí
x-x
Scheme 1 General reaction schemes for the synthesis of five-membered heterocycles containing two or more
heteroatoms by aldol-related reactions
Oxazoles rnay be readily prepared in this rnanner in good yields and under relatively
mild conditions. Thus, 5-ethoxy-4-methyloxazole (3) was obtained by treating ethyl 2-
forrnarnidopropionate (2), itself prepared frorn alanine (1) by forrnylation and esterification,
with phosphorus pentoxide in chloroforrn at 55 oC (72JCS(Pl)909,914). Known collectively
as the Robinson-Gabriel synthesis, these cyclodehydrations can be effected by a variety of
acidic ring closure reagents, including sulfuric acid, phosphorus pentachloride, phosgene
or anhydrous hydrogen fluoride. a-Acylarninoketones and related systerns undergo sirnilar
ring closures, and exarnples illustrating the variety of substituents which rnay be introduced
into the oxazole nucleus are discussed in Chapter 4.18.
MeCHNH 1 MeCHNHCHO M ( e N
t01H --. t01Et -- EtO )
o
) ) ß)
These a-acylarninoketones also provided a convenient synthesis of thiazoles on treatment
with phosphorus pentasulfide (Gabriel's rnethod). Although yields range frorn 45 to 80%,
substituents are usually restricted to alkyl, aryl and alkoxy derivatives. Thus, reaction of
the a-acylaminoketone (4) with P4SlO gave the thiazole (5), and thiazole (7) itself was
prepared in this rnanner in 62% yield frorn forrnylaminoacetal (6) (14CB3163). The corres-
ponding 5-ethoxy compound was obtained frorn the a-forrnamidoester and phosphorus
pentasulfide in an inert solvent.
R 1
ps ( N
RCOCHR1NHCOR 1 T R )R 1
S
(4) (5)
PS ( N
(EtOhCHCH1NHCHO )
S
(6) (7)
Nurnerous variations of this reaction have been studied, principally those involving a
prior inclusion of the nuclear sulfur atom in a thioacylarnino compound. Thus, thiobenz-
ami do acetaldehyde diethyl acetal (8) underwent ring closure to 2-phenylthiazole (9) on
gentle heating (57JCS1556). Similarly, N-thioacyl a-arnino acids also undergo ready ring
closure to thiazoles.
PhCSNHCH1CH(OEt)z ()Ph
S
(8) (9)
This reaction rnay also be used to introduce other substituents into the thiazole ring, and
exarnples are described in Chapter 4.19 and in (69CC818) and (72MI40300). In contrast, this
reaction sequence has not been used to prepare selenazole derivatives, these being more
readily available by the reactions described in Section 4.03.2.2.2.
a-Acylaminoketones on heating with an arnrnonia source such as arnmoniurn acetate are
converted into imidazoles. 2,4,5-Triarylirnidazoles (11) were prepared in this way from
(10) (73CB2415), and the reaction is capable of numerous variations. Forrnamide on heating
at 175 oC with chloroacetaldehyde diethyl acetal in the presence of arnmonia resulted in a
60% yield of imidazole.
Ph
\
PhCOCHNHCOAr
(10)
Ph
NH.OAc ijN
AcOH,.l ) Ph, )Ar
NH
(11)
114 Synthesis of Five-membered Rings with Two or More Heteroatorns
An alternative method involves reaction of an a-acylarninoketone (12) with a prirnary
amine and subsequent ring closure of the resultant Schiff's base (13) with phosphoryl
chloride. This enables the introduction of a 1-substituent as in (14) to be carried out
efficiently, and if the arnine were replaced with a rnonosubstituted hydrazine, the irnidazole
derivative (15) resulted (78LA1916).
R 1
R 2 ()R
N
NHR 4
(15)
Both nitrogen atorns of the imidazole ring rnay be incorporated in the initial I ,4-dicarbonyl
or thiocarbonyl systern. Thus, diphenylglycine thioarnide (16) on heating with alurninum
chloride in toluene gave a rnixture of the irnidazole derivatives (17) and (18) together with
the thiazole (19) (80AHC(27)241). Other variations of this approach are discussed in Chapter
4.08 and provide opportunities for diversifying the substituent pattern in the resultant
irnidazoles.
R 1 R 1
I R'NH I
RCONHCHCOR 2 --4 RCONHCHCR 2
II
NR'
R 1
R 2 ()R
N
R 3
(14)
(12)
(13)
Ph 2 Ph 2 Ph
Ph 2 CNHCOR r \ + r \ + ( \
I toluene S ;>R HN _/R Ph ;>R
CSNH 2 NH S NH
(16) (17) (19) (18)
Analogous open-chain precursors also lead readily to 1,3-dithiolyliurn salts. S-a-Oxoalkyl
thioesters such as (20) on treatrnent with perchloric acid in glacial acetic acid and HzS
undergo ready cyclization to the 1,3-dithiolyliurn perchlorate (22) (66AHC\7)39). The
oxoalkyl dithioesters (21) are probably interrnediates in this cyclization as they thernselves
undergo cyclization with warrn 70% perchloric acid or sulfuric acid (80AHC\27)lSl).
R 1 R 1 I
I IRS
RCOCHSCOR 2 AC 'S) RCOCHSCSR 2 -- R()R 2
S+ 10-
(20) (21) (22) C 4
Several variations of this general procedure have been described. The functionalized
dithiocarbarnate (23) on heating with a rnixture of phosphorus pentasulfide and
tetrafluoroboric acid gave the 2-arnino-substituted 1,3-dithiolyliurn tetrafluoroborate (24)
in rnoderate to good yield (69CPBI924).
R 2 N n SCH 2 COR P ' 4 I R()NR 2 BF 4 -
S S+
(23) (24)
Use of the ß-thiodithiocarbonates (25) and acid results in ring closure to the 1,3-dithiol-2-
one (26). Methyl, ethyl and isopropyl groups have been utilized in (25) (76S489), and when
R Z = t-butyl, ring closure occurred in the presence of perchloric acid with extreme ease
(74JOC9S). Other variations of this synthetic route to 1,3-dithiole derivatives are described
in Chapter 4.32.
R 1
I 2
RyCHSyOR
S S
R 1
R(
S 0
(25) (26)
2,5-Diaryl derivatives of the 1 ,3-oxathiolyliurn systern (29) are prepared by acid-catalyzed
cyclization of the ß-keto thioesters (28) which are readily prepared frorn thioacid salts (27)
Synthesis of Five-membered Rings with Two or More Heteroatorns 115
and phenacyl brornides (7SH(3)217). The difficulty encountered in preparing representatives
of this five-rnernbered heterocyclic systern is readily apparent from the examples illustrated
in Chapter 4.30.
Ph 0
ArCOSK+PhCOCHzBr ArCOSCHzCOPh H, S0 4) ()Ar CIO;
S+
(27) (28) (29)
Application of the above principles to the synthesis of 1,3-diselenolyliurn ions has been
successful. N,N-Dialkyldiselenocarbarnates as their oxo esters (30) undergo acid-catalyzed
cyclization and dehydration to give the cation (31) in nearly 90% yield (7SJOC746, 77CCSOS,
SOCCS66, SOCCS66).
R R R
I . I ( se+
MezNCSeCHCOR 1 ....!:!..... MezNCSeCHCR 1 R 1 \\ M x-
II II II /N ez
Se Se +OH Se
(30) (31)
4.03.2.1.2 Ring systems with three heteroatorns
Incorporation of two heteroatorns into the open-chain 1,4-dicarbonyl systerns and sub-
sequent ring closure enables a variety of five-rnernbered rings containing three heteroatorns
to be prepared in a relatively straightforward rnanner. 2,5-Disubstituted 1,3,4-oxadiazoles
(33) containing alkyl and aryl substituents in the 2,5-positions are rnost conveniently
prepared by the therrnal or acid-catalyzed cyclization of 1,2-diacylhydrazines (32). 1-
Substituted 1,2-diacylhydrazines (33a) in acetic acid in the presence of a strong acid HX
undergo cyclization in a sirnilar fashion. However, in this instance 2,3,5-trisubstituted
1,3,4-oxadiazoliurn salts (34) were forrned (70JCS(C)1397).
N-N
RCONHNHCOR t R( )R 1
o
(32) (33)
R Z
I
RCONHNCOR 1
R Z
+/
HX N-N _
R( )R1 X
o
(34)
(33a)
Acylhydrazine derivatives of this general type provide one of the rnost convenient routes
to a variety of 1,3,4-oxadiazoles, and the scope and lirnitations of this method are discussed
in Chapter 4.23.
Both 1,3,4-thiadiazoles and 1,2,4-triazoles rnay be prepared from derivatives of 1,2-
diacylhydrazine by the choice of the appropriate cyclization agent. The rnajority of 1,3,4-
thiadiazole syntheses are based on cyclizations of thiosernicarbazide derivatives or corn-
pounds incorporating this basic structural pattern. The sirnple diacylhydrazines lead to
2,5-disubstituted 1,3,4-thiadiazoles when treated with phosphorus pentasulfide. Alkyl, aryl
and heteroaryl groups may be introduced in this way. Cyclization of the acyl thiosemicarb-
azide (35) with sulfuric acid, polyphosphoric acid or phosphorus halides gave the 5-
substituted 2-arnino-1,3,4-thiadiazole (36). Methanesulfonic acid has also been used for
this cyclization and resulted in high yields of pure products (SOJHC607). Numerous variations
of this general route to 1,3,4-thiadiazoles have been devised enabling the 2,5-substituents
to be varied over a wide range of functional groups. These variations are discussed in
Chapter 4.27.
N-N
RCONHNHCSNHR 1 R( )NHR 1
S
(35) (36)
1,2-Diacylhydrazines (32) on heating with a primary arnine undergo cyc1ization to the
1,2,4-triazole derivative (38). It is assurned that the arnidrazone (37) is an intermediate in
the reaction. Most practical syntheses of 1,2,4-triazoles now utilize an arnidrazone or a
derivative of this alicyclic interrnediate containing three nitrogen atorns, and these variations
are discussed in Chapter 4.12.
116 Synthesis of Five-membered Rings with Two or More Heteroatorns
/NHR 2 N-N
RCONHNHCOR 1 +R 2 NH 2 RC ---+R'I( )R
NNHCOR 1 N
R 2
(32) (37) (38)
Ring closure of diacylhydrazines (32) with phosphorus pentaselenide also provides entry
into the 1,3,4-selenadiazoles (39). Alkyl and aryl groups rnay be introduced into the
2,5-positions by this procedure (04JPR(69)509). The corresponding 1,3,4-oxadiazole (33) is
the rnajor product of this reaction, and as a consequence, attention has focused on variations
of this approach using seleniurn analogs of sernicarbazide. Reaction of carboxylic acids with
selenosernicarbazide (40) yielded the 2-acylarnino-l,3,4-selenadiazole (42), probably via
the interrnediate diacyl derivative (41). Hydrolysis of the acylarnino group in (42) occurred
readily giving (43) (71JHC835, 73JPS839). Other variations are described in Chapter 4.20.
p s N-N N-N
RCONHNHCOR' RI( )R ' + RI( ,;)R '
Se 0
(32) (39) (33)
Reo H N-N N-N
H,NCSeNHNH, RCONHCSeNHNHCOR -- /1 \\ R -- /1 \\
-. R" /NHCO R" /NH 2
Se Se
(40) (41) (42) (43)
4.03.2.1.3 Ring-fused systems
(i) [5,5J fused systems
Annulation of a second ring to a five-rnernbered heterocycle by an aldol-related reaction
requires a l,4-arrangernent of two carbonyl groups or related functional groups in one of
the heterocyclic cornponents. This can be achieved in several ways, and syntheses involving
vicinal arrangernents of the two carbonyl functions are illustrated by the conversion of the
1,3-disubstituted 4,5-diaroylpyrazole (44) into the tetrasubstituted thieno[3,4-d]pyrazole
(45) on heating with phosphorus pentasulfide in an inert solvent (731OCI769). However,
with the diaroyl substituents in the 3,4-positions of the pyrazole nucleus as in (46), reaction
with phosphorus pentasulfide in boiling pyridine gave the nonclassical heteropentalene
thieno[3,4-c]pyrazole (47) (74JA4276). Other syntheses of this type are described in Chapter
4.37.
R 2 CO R' R ' R 2 R 2 CO COR 2
0 \ p.s,,, X c;:;.- 0 \
R 2 CO N N S R'.N
'" \ ,.
N N R 2 N
R R R
(44) (45) (46) (47)
An alternative approach involves an endocyclic-exocyclic arrangernent of the 1,4-dicar-
bònyl functions which also can result in C-C points of ring fusion. Again using phosphorus
pentasulfide as the thiation agent, reaction with the a-acylarninocarbonyl systern contained
in (48) led to thieno[2,3-d]thiazoles (49) (70CHE1515), pyrazolo[5,4-d]thiazoles, (50)
(74CHE813) and pyrazolo[ 4,5-d]thiazoles (51) (65CHE165).
R 1 R 2
RN S+
.l \..,
N R 2
X NH Me S N
I I Y p.s,,, a
\ A 0 lWC. R /Me
Z 0 R S
(48) (49)
R
N N
NQC )Me
R S
(50)
R N
N8: )Me
N S
R (51)
Ring-fused systerns involving ring junction nitrogen atorns and additional heteroatorns
can also be prepared in this rnanner. Reaction of an arnino-substituted heterocyclic thiol
such as (52) with an acylating agent gave (53), which on heating with phosphorus oxychloride
underwent ring closure to give, for exarnple, irnidazo[2,1-b][1,3,4]thiadiazoles (54)
(63LAI663)J 13).
Synthesis of Five-membered Rings with Two or More Heteroatorns 117
H
N N 5 N 5
/ 5H RCOX / ---v- 0 POCl, \
a I -+ a I -----"+ I qlR
\_NNH2 \_N, ^ N-N
N R
H
(52) (53) (54)
Variations of these approaches to [5,5] ring-fused systerns are found in Chapter 4.36.
(ii) [5,6} fused systems
Reaction processes of this type used to form [5,6] ring-fused systerns usually involve
formation of the five-rnernbered ring. Those in which the six-rnernbered ring is formed
have C-C fusion points and are illustrated by the reaction of vicinal dicarbonyl cornpounds
such as (55) with hydrazine forming [1,2,3]thiadiazolo[4,5-d]pyridazine (56) (76JHC301).
Other applications of this approach are described in Chapter 4.29, and an interesting
variation is the reaction of the vicinal dicarbonyl cornpound with a prirnary arnine having
a methylene group adjacent to the arnino group in the presence of DBU. Frorn the
1,2,5-oxadiazole derivative (57), the [1 ,2,5]oxadiazolo[3,4-c ]pyridine (58) was obtained
(805842,795687).
R R
N :X 5 RCO l N '0 R'CH,NH, R,O::N,
RCO l 'N NH,NH, N I \
I N · 0
RCO 51 N II RCO =-N ' DBU N::,.. I
N
R R
(55) (56) (57) (58)
Other C-C fused systerns are also available by utilization of 1 ,4-dicarbonyl-type systerns.
The substituted pyrimidinethione (59) on treatrnent with polyphosphoric acid readily forrned
the thiazolo[5,4-d]pyrimidine systern (60) without any of the alternative ring closure product
(65JOC1916).
NH 2 Ph NH 2
N Y N-7'ýN
l_j 0 pp;;:-+ __3-- )Ph
N 5 N 5
H
(59) (60)
Systerns with a nitrogen atorn at the ring junction are also readily available by this
procedure, a reflection on the case of forrnation of the requisite 1,4-dicarbonyl cornpound.
The 1-phenacyl-2(1H)-pyridinone (61) underwent ring closure to the oxazolo[3,2-
a]pyridinium salt (62) on treatrnent with sulfuric acid/perchloric acid (67JHC66). If the
possibility exists for the loss of a proton, then the neutral product is obtained, as in the
conversion of (63) into the ring-fused systern (64) (7IJOC222). Additional heteroatorns may
also be included in the ring-fused systerns and exarnples illustrating these syntheses are
discussed in Chapter 4.29.
0 0 HClO. . QO
NJ. H,SO. JR
R + CIO-
(61) (62) 4
Ph Ph Ph
O O O Ph
F\
a NH ((yM' C(f 0::/
Ac,O. I
I C0 2 H I 0 -- -- I
C0 2 Ac
0 0
(63) (64)
118 Synthesis of Five-membered Rings with Two or More Heteroatoms
4.03.2.2 Intermolecular Condensations
4.03.2.2.1 Ring systems with two heteroatorns
As shown in Scheme 2, two heteroatorn-carbon bonds are constructed in such a way
that one cornponent provides both heteroatorns for the resultant heterocycle. By variation
of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the
use of the appropriate oxidation level in the carbonyl-containing corn pone nt, further
oxidized derivatives of these ring systerns result. These processes are analogous to those
utilized in the forrnation of five-rnembered heterocycles containing one heteroatorn, involv-
ing cyclocondensation utilizing enols, enarnines, etc.
o HO X
xl - <1)- - Ht. 1-i
:(
Scheme 2 General reaction scheme for the synthesis of five-membered heterocycles containing two or more
heteroatnms by aldol-related reactions
The rnost widely used rnethod for the synthesis of thiazoles (see Chapter 4.19) is of this
type and involves the reaction of a-halo cornpounds (Y = halogen in Scherne 2) with a
reactive cornponent containing an :::N -C(=S)- structural entity. Reaction of the a-
brornoketone (65) with the prirnary thioamide (66) in hot benzene gave the interrnediate
hydroxy cornpound (67), which could be isolated in certain instances but in rnost cases
underwent dehydration to forrn the thiazole (68). The diversity in the substituents capable
of being introduced into the resultant thiazole by this procedure is illustrated in Chapter
4.19. Especially noteworthy in this respect is the reaction of the brornopyruvaldehyde oxirne
(69) with thiourea in methanol at room ternperature. Neutralization with sodium carbonate
resulted in the isolation of the 2-arninothiazole-4-carbaldehyde oxirne (70) in 39% yield
(73JOC806).
R 2 R 2
yN"""'R3 -H 2 0 f/
R 1 COCHBrR 2 +R 3 CSNH 2 HO' L I ---"--+ R'(_)R 3
R' S S
(65) (66) (67) (68)
HON=CH N
BrCH 2 COCH=NOH+NH 2 CSNH 2 ()NH 2
S
(69) (70)
Thiazolines and thiazolidines rnay also be prepared in this fashion, the structure of the
final product deterrnining the substitution pattern to be chosen in the reaction cornponents.
Reaction of ethyl brornoacetate with the substituted thioarnide (71) resulted in forrnation
of the thiazolidin-4-one (72) (70KGS1621).
o
t NRI
BrCH 2 C0 2 Et+R 1 NHCSCHR 2 CN CN
S R 2
(71) (72)
The cornparatively ready accessibility of selenocarboxarnides has encouraged the use of
this procedure for the synthesis of selenazoles (1889LA(250)294). Reaction of the a-chloro-
carbonyl cornpound (73) with the selenocarboxarnide (74) provided a ready synthesis of
a variety of substituted selenazoles (75). Useful variations of this general procedure are
described in detail in Chapter 4.20, and particularly attractive is the reaction of hydrogen
selenide with a rnixture of a nitrile and the a-halogenoketone to afford the selenazole
(48YZ191,79S66).
(73)
(74)
R N
Rtf )R 2
Se
(75)
RCOCHR t CI + R 2CSeNH 2 --+
Synthesis of Five-membered Rings with Two or More Heteroatorns 119
Arnidines and related systerns such as guanidines react with a-halogenoketones to forrn
irnidazoles. a-Hydroxy ketones also take part in this reaction to form imidazoles, and a
variety of substituents can be introduced into the imidazole nucleus by these procedures.
Reaction of the a-halogenoketone (73) with an alkyl- or aryl-substituted carboxarnidine
(76) readily gave the imidazole (77) (OlCB637, 48JCS1960). Variation of the reaction corn-
ponents that successfully take part in this reaction process is described in Chapter 4.08.
NH R1
RCOCHR1Cl+R2 NH2 __ ![
R .:>R 2
NH
(73) (76) (77)
Oxazoles are also obtained by the reaction of a-halogenoketones (7S) with primary
amides (the Blümlein-Lewy synthesis), and this method is particularly appropriate for
oxazoles containing one or more aryl groups as in (79). Forrnarnide rnay also be used in
this process, resulting in a free 2-position in the oxazole, and when a urea derivative (SO)
is used, 2-arninooxazoles (S1) are forrned (80Z0R2185, 78IJC(B)1030, 78JIC264). Numerous
applications of these procedures are described in Chapter 4.18.
Ar N
R(')NR 1 R 2
o
(81)
NH 2 CONR1R2
{SO)
Ar N
ArCOCHRX+R 1 CONH 2 -- R(')R 1
o
(78) (79)
a-Halogenoketones also undergo ready reaction with an excess of thioacids (S2) or
thioesters in the presence of halogen or perchloric acid (7IJPR722). 1,3-Dithiolylium salts
(S3) are forrned, and replacernent of the thioacid with a gern-dithiol system as in (S4) leads
readily to 1,3-d-ithiole derivatives (S5) (64JHC163, 65JOC732). Other aspects of this reaction
type are described in Chapter 4.32.
R S
RJ[ AyCOR 2
S 3
(85) R
SH
/
R 2 COC=C
I "
R' SH
(S4)
RCOCHR 1 Cl+R 2 COSH
R 1 S+
-4 R(')R 2
S
(83)
(82)
In a reverse of the usual role of the a-dibrornoketone, (S6) undergoes reaction with
potassium O-ethyldiselenoxanthate (S7) to give the 1,3-oxaselenol-3-one (SS; 61 % yield)
and the 1,2-oxaselenole (S9; 30% yield) (78,cZ361).
Se R 1 R l
II Se Se
RCOCBr2Rl+2KSeCOEt -- R( O + R( )(Rl
o 0 COR
(86) (87) (88) (89)
4.03.2.2.2 Ring-fused systems
(i) [5,5] fused systems
Many of the acyclic functional groups used for the synthesis of the five-rnernbered system
discussed in Section 4.03.2.2.1 rnay also be incorporated into five-mernbered heterocyclic
systerns, thus providing a convenient means of annulation of a second ring.
Scheme 3 illustrates two general annulation procedures, one with the a-halogenoketone
moiety incorporated in a cyclic systern leading to C-C fused systems. The other, with the
heteroatoms already incorporated in a heterocycle, results in a product with a heteroatorn
at a fusion point.
Z
g o /I c-t-- z
(CH 2 )n + RCYH -- (C )n /l >
X Y
H
z
{ y + RCOCHXR 1
/YH
Z
--C( )Rl
\l R
Scheme 3 Ring annulations using (!- halogenoketones
120 Synthesis of Five-membered Rings with Two or More Heteroatoms
The latter approach is illustrated by the conversion of the 2-thiazolethione (90) into the
thiazolo[2,3-b ]thiazolylium salt (92) by reaction with the a-halogenoketone. The interrnedi-
ate (91) rnay be isolated, and strong acid was required to effect the final cyclization
(77HCl30-1)1). A wide variety of [5,5] fused systerns are prepared in this way, and variations
of this approach are discussed in Chapter 4.36.
s S
R 1H
R'
(90)
S S
+ R 2 COCHR 3 Br --. R YJR3
R' + R 2 X-
(92)
S S
R Y )R 3
R' O-::S(
(91) R 2
(ii) [5,6] fused systems
Ring-fused systerns with C-C fusion points have been prepared by reaction of 2-
chlorocyclohexanone (93) with an appropriate thioarnide (94) in boiling chloroforrn over
24 hours, giving the hexahydrobenzothiazole (94a) in rnodest yield (68BRPl112128). The
structural variations in this reaction are the nature of the group R in (94), and incorporation
of heteroatorns into the carbocyclic ring or increasing the size 'Of the ring. Exarnples of all
variables have been reported. Thus, reaction of 3-brorno-4-piperidone hydrochloride (95)
with thiourea for three days at 20 0 C gave 2-arnino-4,5,6,7-tetrahydrothiazolo[5,4-
c]pyridine (96) (79HC(34-1)230). Increase in ring size such as in the forrnation of the benzocyc-
loheptathiazoles (98) by the reaction of 6-bromo-l-benzosuberone (97) with a thioarnide in
boiling ethanol for four hours (35% yield) was also successful by this route (79HC(34-1)200).
s (X s
Cl II
00 + R'CNH z --. I )R'
(93) (94) (94a)
HNJO + NH 2 CSNH z --. H0 >NHz
Br
I ) 1%)
8 0 + RCSNH, ex>
Sr 0
(97) (98)
Reaction of a-chlorocyclohexanone (93) with selenourea has been reported to yield
2-arnino-4,5,6,7-tetrahydrobenzoselenazole (99) (43RTC580. 51JA1864).
('lCI e (X S
O + NH 2 CNH 2 --. I N'/NH z
(93) (99)
In contrast to the above, the reaction of a heterocyclic thione with an a-halogenoketone
(Scherne 3) has been widely exploited as a route to [5,6] ring-fused systerns with a heteroatorn
at a ring fusion point.
2( 1H )-Pyridinethione (100) reacts readily with an a-halogenoketone to give the 2-ß-
oxoalkylthiopyridine (101) which undergoes ring closure with strong acids such as sulfuric,
phosphoric or polyphosphoric to give the thiazolo[3,2-a]pyridiniurn systern (102) in good
Synthesis of Five-membered Rings with Two or More Heteroatorns 121
yield. Chloro or nitro substituents in the pyridine ring do not hinder the reaction (66JHC27).
The 3-hydroxypyridine analog (103) also cyclized in a sirnilar rnanner to give (104).
O S
+ RCOCHBrR I
:::::,... NH
-
S
O)RI
(101) R
-
a s
JRI
+ R
(102)
(100)
h-- s
O)RI
R
0-
a s
- ' J RI
::::,... N /J
+
R
(104 )
(103)
This reaction procedure has also been used for the synthesis of oxazolo[3,2-a]pyridine
and imidazo[1,2-a]pyridine derivatives, and the nurnerous variations studied, allowing
changes of the substituent pattern and the nurnber and position of the nitrogen atorns in
the six-rnembered ring, are described in Chapters 4.10 and 4.29.
4.03.2.2.3 Ring systems with two adjacent heteroatorns
Scherne 4 shows in a general rnanner cyclocondensations considered to involve reaction
mechanisms in which nucleophilic heteroatorns condense with electrophilic carbonyl groups
in a 1,3-relationship to each other. The standard rnethod of preparation of pyrazoles involves
such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity
in the condensation does not occur. However, with a rnonosubstituted hydrazine such as
methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained: the
1,3-dirnethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 rep-
resents this type of reaction as a relatively straightforward process, it is considerably rnore
complex and an appreciable effort has been expended on its study (77BSF1163). Details of
these reactions and the possible variations of the procedure rnay be found in Chapter 4.04.
o XH t o HO \ x 'Ç
+I XH I X
....- 1""- YH ....- I
-0 YH HO YH -Y
HO
Scheme 4 General reaction scheme for the synthesis of five-membered heterocycles containing two or more
heteroatoms by aldol-related reactions
Me
MeCOCHzCH(OMeh + MeNHNH z N
N
Me
(105)
+ Me 0 N
'N)
Me
(107)
(106)
Scherne 4 also represents the classical route to isoxazoles, first studied in 1888 by Claisen
and his coworkers (1888CB1149). Reaction of a 1,3-diketone with hydroxylarnine gives, via
the isolable rnonoxirne (108) and the 4-hydroxyisoxazole (109), the isoxazole (110). Unsym-
rnetrical 1,3-diketones result in both possible isorners (110) and (111), but the ratio of the
isorneric products can be controlled by the right cornbination of the 1,3-dicarbonyl com-
ponent and the reaction conditions used. These irnportant considerations are described in
Chapter 4.16, along with the variations possible in the 1,3-dicarbonyl component designed
to yield diverse substituents in the resultant isoxazole.
RCOCHzCOR 1
H 2 NOH
R
) RCCHzCOR 1 -. HO n N
\I Ì'--n) o /
NOH t
(108) R (109)
R
-R t0 N
'0)
(110)
R 1
R 0 N
'0)
(111)
122 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.3 SYNTHESES UTILIZING INTERMOLECULAR NUCLEOPHILIC
DISPLACEMENTS
4.03.3.1 Classification of Reaction Types
Reactions considered in this section have, as their guiding principle, bond formation
occurring via reaction of a binucleophilic cornponent with an electron-deficient bielec-
trophilic counterpart. As the number of available binucleophiles containing two heteroatoms
is comparatively small, the principal ernphasis is placed on the bielectrophilic cornponent
of the reaction. Reagents under consideration rnay be arbitrarily classified into three general
groups:
Group 1:
Group 2:
Group 3:
Binucleophiles (BNu)
Bielectrophiles (BE)
Reagents containing both a nucleophilic and
an electrophilic center (NuE), e.g. HSCH 2 C0 2 H
A convenient classification scherne for reactions of this general type expressed below
focuses attention on the nurnber of atorns separating the two reactive centers in each
component.
BNu+BE -+ Heterocycle
Number of atoms Resultant
separating reactive heterocyclic
centers in ring system
BNu BE
2 + 1 -+ 3-rnernbered
2 + 2 -+ 4-membered
2 + 3 -+ 5-rnernbered
3 + 1 -+ 4-rnernbered
3 + 2 -+ 5-mernbered
3 + 3 -+ 6-rnembered
4 + 1 -+ 5-rnernbered
4 + 2 -+ 6-membered
4 + 3 -+ 7 -membered
3 + 4 -+ 7 -rnembered
Thus, reaction of a 1,2-binucleophile with a 1,3-bielectrophile would lead to a five-
mernbered heterocycle, as would the reaction of a l,4-binucleophile with a 1,1-bielec-
trophile. Considering the reactions in this rnanner has several advantages and provides a
convenient frarnework for considering synthetic approaches to target heterocycles.
Table 1 Some Examples of Commonly Encountered Binucleophiles
1,2-Syslems 1,3-Syslems 1,4-Syslems 1,2-Syslems 1,3-Syslems 1,4-Syslems
S NH S
II II II
H 2 NNH 2 RCNH 2 H 2 N(CH 2 hNH 2 H 2 NOH RCNH 2 RCNHNH 2
S NH Se
II II II
RNHNHR RCNHR H 2 N(CH 2 hOH RNHOH RCNHR RCNHNH 2
Se NH NH
II II II
H 2 NNR 2 RCNH 2 H 2 N(CH 2 hSH R 2 NOH H 2 NCNH 2 RCNHNH 2
ONH 2 S NH
Se II II
II RCH=NNH 2 H 2 NCNH 2 RCNHOH
RNHNR 2 RCNHR XH S
Se
II II
RCH=NOH H 2 NCNH 2 H 2 NCNHNH 2
Synthesis of Five-membered Rings with Two or More Heteroatoms 123
Table 1 lists sorne of the cornmon binucleophiles utilized in heterocyclic synthesis, the
numerical prefixes referring to the relative positions of the nucleophilic centers to each
other. Higher order binucleophiles, e.g. 1,5-systerns, come readily to rnind and the above
illustrative exarnples rapidly increase in scope when the incorporation of these structural
elements into heterocyclic systerns is considered. This last group offers rnany opportunities
for ring annulations.
4.03.3.2 Design of the Appropriate Bielectrophile
A convenient classification of the bielectrophilic cornponent also relies on the number
of atoms separating the reactive centers, resulting in 1,1-bielectrophiles, 1,2-bielectrophiles,
1,3-bielectrophiles and higher order systerns. Each group rnay be further subdivided accord-
ing to the atoms cornprising the bielectrophilic cornponent and, for those involving electron-
deficient carbon centers, by the hybridization of the carbon atorns. A further subdivision
is that of a bielectrophile equivalent, i.e. a reaction cornponent that by virtue of its reaction
behaves as a bielectrophile.
4.03.3.2.1 1,1-Bielectrophiles
This group includes many of our cornrnon reagents such as the carboxylic acid chlorides,
phosgene, thiophosgene, phosgene iminium salts, ortho esters, thionyl chloride, phosphorus
oxychloride, isocyanide dichlorides, etc. All these reagents have the cornrnon feature of at
least two electron-withdrawing substituents attached to the same atorn, and these sub-
stituents also have good leaving group characteristics.
4.03.3.2.2 1,2-Bielectrophiles
By definition, members of this group have a vicinal arrangement of their electron-deficient
centers. They rnay be conveniently considered according to their atom composition and
the hybridization state of any carbon atorns involved.
Type 1: Contains two Sp2 hybridized
carbon atorns
2 C . 2 d 3
Type: ontams an sp an an sp
hybridized carbon atorn
Type 3: Contains at least one heteroatom
Type 4: Bielectrophilic equivalents or
a 'rnasked' bielectrophile
0 0 RN NR 0 0 RN 0
'\. ,f' '\. ,f' '\. ,f' '\. ,f' '\. ,f'
Type1: C-C C-C C-C C-C C-C
/ '" / '" / '" / '" ./ '"
CI CI CI CI CI OEt CI CI
H 0 H 0
Type 2: '" ,f' '" ,f' '" ,f'
-C-C Ph-C-C EtOCO-C-C
/ '" / '" / '"
Br CI Br CI
NR 0 CI
,f' / ,f' ,f' /
Type 3: -X-C -X-C- CI-S-C CI-S-C Cl-S-C-CI
'" '" "'CI "'CI '"
CI
CI CI
/ /
CI-S-C-H CI-S-CCONR z
'" '"
CI CI
I I H 0 CN OSOzPh
Type 4: -C-C= I
/ R CN Ph-CHC:::=N
Scheme 5 Illustrative 1,2-bieIectrophiIes classified by structural type
124 Synthesis of Five-membered Rings with Two or More Heteroatorns
Representative rnernbers of these four groups of 1,2-bielectrophiles are shown in
Scherne 5.
4.03.3.2.3 1,3-Bielectrophiles
The possible variations arnong the three atorns cornprising this reactive cornponent rnake
this the largest group and the one with the rnost potential for further developrnent. They
are particularly useful in the synthesis of five-, six- and seven-rnernbered ring systerns. They
also rnay be conveniently considered according to their atorn cornposition, and the hybridiz-
ation state of any carbon atorns involved.
Type 1: Contains three Sp2 hybridized
carbon atorns
Type 2: Contains an Sp3 and two Sp2 or sp
hybridized carbon atorns
Type 3: Contains at least one heteroatom
Scherne 6 shows representative rnernbers of these three groups. Other cornbinations are
possible and the design of an appropriate bielectrophile for use as a versatile synthon
presents a considerable synthetic challenge, as by virtue of the structural entities involved
they are extrernely reactive.
Type I:
I
, 'lC' 'l
C C
I I
R
R2N O
CI CI
R
R O
CI H
I
C
Type 2: '::';'C""" I 'C'l
I I
R H
oyXyo
CI CI
Type 3:
, 'lX, 'l
C C
I I
RyNyO
Cl CI
R
OyNyO
CI CI
OVN
I "c
CI '::';'0
'::';'C......C.::,;,C
I .::,;,
R
R2N S
CI CI
R
R O
CI OEt
I
/C,
C I C
R H
RNyXyNR
CI CI
I
hC'
'c 7 X
I I
R N S
YI
CI CI
R
OyNyNR
CI Cl
o N
Y "C.::,;,
EtO 0
R
R2N NR
CI CI
R
0, Ac
'] ''::';'0
CI
R H
OyXyNR
Cl CI
X
.::,;, ...... .::,;,
C C.::,;,
I
X
.2::-c""" 'c'l
I I
R
R NR
Cl CI
R
O SMe
CI SMe
R H
cXc
III \\\
N N
R 2 N y N y r'JR 2
CI CI
R R
R-l"'NyO
Cl CI
OyN-ySMe
EtO SMe
Scheme 6 Illustrative 1,3-bielectrophiles classified by structural type
RyNyNR
CI CI
R
RNyNyO
Cl CI
Ov N .::,;,
I C.::,;,
EtO S
R
R ÑR2
CI CI
R H
CX o
III T
N X
OyN-ySMe
R SMe
Synthesis of Five-membered Rings with Two or More Heteroatorns 125
4.03.3.2.4 1,4- and higher hielectrophiles
Extension of the approach discussed above suggests several structural types which rnay
be classified under this category, the rnain variable being the nature and hybridization of
the electrophilic centers and the nature of the atorns joining these two centers. They rnay
be conveniently divided into two groups:
Type 1: Systerns containing all carbon atorns
with two Sp2 hybridized carbon atorns,
two 'benzylic' carbon atorns or a
cornbination of these types
Type 2: Systerns containing two Sp2 hybridized
carbon atorns with one or rnore hetero-
atorns joining these two centers
Representative exarnples of these types are shown in Scherne 7. The range of structural
types is greatly extended when acyl halides attached to any ring systern in a vicinal
relationship are considered.
R R
o=f1ro
CI Cl
0 =0= =0- >0<
o 0
000 0=0-
Cl Cl CI Br
R R
O H
Cl Br
R R
R2N NR2
Cl 0 CI
Type 1:
Type 2:
yX'v^
o
RN<::::,./S..... ^
I N CI
CI
()
N O
c! Cl
I;
o
Scheme 7 Illustrative 1,4- and higher order bielectrophiles classified by structural type
4.03.3.3 Syntheses Using l,l-Bielectrophiles
4.03.3.3.1 Ring systems with two heteroatoms
The role of the 1, I-bielectrophile in ring closures of this type is to provide a one-carbon
unit (or heteroatorn) to close the cycle. Thus, the synthesis of the four-atorn precursor with
two nucleophilic centers 1,4 to each other is an appreciable challenge, especially to obtain
a heterocycle at the desired oxidation level. The exarnples below illustrate the way this
approach to synthesis rnay be gainfully utilized.
The methylhydrazone of acetophenone (112) underwent ready reaction with n-butyl-
lithium giving the dianion (113); reaction with acid derivatives such as acid chlorides or
esters resulted in pyrazole (114) forrnation whereas with aldehydes, pyrazolines were
obtained (76SC5). With dichlorornethyleneirniniurn salts (115), 5-dirnethylaI?inopyrazoles
-
Ph Me Ph CH z
CI >=NMe l "- / "- /
R R C C Ph
![J CI o- Il Bu"Li II 2Lt RCN
MezN N (115) N N
N; "- "- N;
Me NHMe W Me
Me
(116) (112 ) (113) (114)
126 Synthesis of Five-membered Rings with Two or More Heteroatorns
(116) resulted (74AGIE)79). Other related ring closures involve the reaction of the Vilsrneier-
Haack reagent (POCh-DMF) with ketone sernicarbazones or ketazines. Two rnoles of the
reagent are used and the resultant pyrazoles contain a 4-forrnyl substituent after reaction
work-up (70JHC25, 70TL4215). Additional reactions of this type are described in Chapter 4.04.
Ethylenediarnine derivatives undergo reaction with a wide variety of 1,I-bielectrophiles
leading to partially reduced irnidazole derivatives (Chapter 4.08). When a dehydrogenation
agent is present irnidazoles are forrned. It is particularly useful for the synthesis of irnidazoles
with a definitive substitution pattern, illustrated by the preparation of rnethyl l-rnethyl-
irnidazole-4-carboxylate (119) frorn 2-arnino-3-rnethylarninopropionic acid (117) with
triethyl orthoforrnate. The initial irnidazoline (118), after esterification and subsequent
oxidation with activated rnanganese dioxide, gave (119) in very good yield (70AHCI 12)103).
H0 2 C N Me0 2 C N
HCiOEtl, · C )\ -- ( )\
N N
Me Me
(117) (ilS) (119)
A sirnilar utilization of two heteroatorns is illustrated by the reaction of the ethylenedithiol
(120) with forrnic acid in the presence of perchloric acid. 4,5-Diphenyl-l,3-dithiolyliurn
perchlorate (121) was forrned in 45% yield (69MI40300). Introduction of a 2-oxo or 2-thioxo
substituent as in (123; X = 0, S) is illustrated by the reaction of the disodiurn salt (122)
with phosgene and thiophosgene, respectively (76S489).
Ph SH Ph S + NC S- CI NC S
)[ HH · Ph(') CI0 4 - :1 2 Na+ + >=X -- Ncf ):,
Ph SH S NC S- Cl S X
(120) (121) (122) (123)
H0 2 CCHNH 2
I
CH 2 NHMe
The 1,3-dithiolane ring systern rnay also be prepared in an analogous fashion. Reaction
of a carbonyl cornpound with 1,2-ethanedithiol (124) in the presence of BF3 or p-toluenesul-
fonic acid readily gave the saturated ring systern (125) (74S32). Use of dirnethylforrnarnide
dirnethyl acetal provided for the introduction of a 2-dirnethylarnino substituent as in (126),
and phosgene in ether at 20 0 C gave the corresponding 2-oxo substituent as in (127)
(41 RTC(60)453).
C \ COCl, HSC H CH SH
2 2 BF,
S 0 (124) .
(127) !Me,NCHIOEtI,
[)yR
S Rt
(125)
[\-H
S NMe 2
(126)
Other applications of this conceptual approach are found throughout the various chapters,
and the range of potential 1,1-bielectrophiles, e.g. ethyl chloroforrnate, will be readily
apparent.
4.03.3.3.2 Ring systems with three or more heteroatoms
Nurnerous exarnples of the ring closure of a binucleophilic systern with ai, 1-bielectrophile
leading to five-rnernbered heterocycles with three or rnore heteroatorns have been described,
the popularity of this route nO doubt reflecting the cornparative ease with which the
penultirnate product rnay be obtained.
Reaction of a hydrazide (128) with phosgeneirniniurn chloride (115) led to the 2-
dirnethylarnino-1,3,4-oxadiazole (129) in 90% yield (75AG(E)806). The 1,3,4-thiadiazole
systern was also obtained in an analogous reaction in which the dithioirnidate (130) underwent
reaction with the thiohydrazide (131). Depending on the nature of X in (131), the 2-
substituent in the resultant 1,3,4-thiadiazole (132) rnay be varied (80ZC413). Although (130)
Synthesis of Five-membered Rings with Two or More Heteroatoms 127
also has an electrophilic center ß to the C(SMeh function, reaction of the binucleophile
occurs at the latter function to forrn the five-rnernbered ring (see Section 4.03.3.5).
+ CI
RCONHNH 2 + Me 2 N=<
CI
(128) (115)
N-N
Cl- -+ RI( )NMe2
o
(129)
/SMe N-N
MeOCON=C" + H 2 NNHCX -+ MeOCONHI( )x
SMe S
(130) (131) (132)
This approach is particularly suited to the forrnation of nonclassical systerns such as
rnesoionic compounds in the 1,3,4-thiadiazole systern. Reaction of the thiohydrazide (133)
containing a substituent on N' with phosgene, thiophosgene or an isocyanide dichloride
leads to ready ring closure and forrnation of the rnesoionic 1,3,4-thiadiazole (134; X = 0,
S, NR, respectively) (B-79MI40300). 3,3-Dichloroacrylonitrile (135) and (133) gave the
corresponding rnesoionic 2-rnethylene derivative (136) (70TLS083).
+
R1N-N
Rl(s CN
CN
CI CN
>=<
CI CN
(
(135)
l CI
RCNNH 2 + x=< -+
II CI
S
(133 )
R 1 Ñ-N
I( )x-
S
(136)
(134)
The isocyanide dichlorides are particularly attractive 1, 1-bielectrophiles, and the N-
sulfonyl derivative (138) underwent reaction with the N-hydroxythioarnide (137) to give
the 1,3,5-oxathiazole derivative (139) (71AP763). Yields varied frorn 62% for R = Me and
were slightly less for R = Ph (57%) and R = p-MeOC 6 H 4 (50%).
CI Ph S
>= reflux I
PhCSNHOH + NS0 2 R toluene N 0 R
Cl '0 NS 2
(137) (138) (139)
The above exarnples illustrate reactions at an electron-deficient carbon atorn. Other
1,1-bielectrophiles allow the direct introduction of a heteroatorn into the resultant
heterocycle. The rnost widely applicable and versatile rnethods for the synthesis of 1,2,5-
thiadiazoles and 1,2,5-selenadiazole rely on this approach.
It has been found that an acyclic NCCN systern in which the N-C groups rnay be sp,
Sp2 or Sp3 hybridized reacts with sulfur rnonochloride or sulfur dichloride to forrn the
appropriately substituted 1,2,5-thiadiazole (68AHC(9)107, 67JOC2823). This reaction is illus-
trated by the reaction of cis-diarninornaleonitrile (140) with sulfur dichloride, which gave
3,4-dicyano-1,2,5-thiadiazole (141) in 93% yield (72JOC4136). Tables 16 and l,;\in Chapter
4.26 list the various substituted systerns which rnay be rnade in this rnanner. Seleniurn
monochloride has been used as the cyclization agent in the preparation of 1,2,5-
selenadiazoles; however, this series has not been as thoroughly investigated as their sulfur
analogs (79S979).
HN CN NC CN
X n
+ SCI 2 -+ N N
/- , ,..
HN CN S
(140) (141)
4,5-Dicyano-1,2,3-trithiole 2-oxide (143) has been prepared frorn the silver salt of
2,3-dimercaptornaleonitrile (142) and thionyl chloride (66HC(21-1)67). Sirnilarly, the reaction
of ethylene glycol (144) with thionyl chloride gave 1,3,2-dioxathiolane 2-oxide (145), the
parent corn pound of saturated five-rnernbered cyclic sulfites (see Chapter 4.33).
NC SAg NC S
1: + SOCI 2 -+ NC(),-..
NC SAg S 0
(142) (143)
HOCH 2 CHpH + SOCI 2 -+ Cs
ó -"0
(144) (145)
128 Synthesis of Five-membered Rings with Two or More Heteroatorns
A nurnber of 1,2,3-oxathiazole S-oxides are prepared frorn the reaction of thionyl chloride
with various ethane derivatives having vicinal oxygen- and nitrogen-containing groups.
Reaction of the 2-arninoethanol derivative (146) with SOCh gave (147) (see Chapter 4.34).
R2 R3 R 2 N R4
H--t--+R1 SOCl,þ R: r S
R 4 NH OH R 7"0/ -0
(146) (147)
Applications of these ring closure sequences to the synthesis of 1,2,3,5-thiatriazolines
are described in Chapter 4.28.
4.03.3.3.3 Ring-fused systems
The syntheses of ring-fused systerns with both C-C and C-N fusion points are par-
ticularly suited for cyclocondensations of this type. Treatrnent of the 4,5-diarninopyrazole
(148) with thionyl chloride under reflux gave the pyrazolo[3,4-c ][1,2,5]thiadiazole S-oxide
(149) (68JMCl164), and when (148) was treated with sulfur rnonochloride, the arornatic
systern (150) was obtained (81J0C406S). The corresponding 1,2,5-selenadiazole was isolated
when (148) was heated with seleniurn dioxide (52% yield).
Me N H 2 N Me
N..ç--y 's (s,o, SOCl,þ
'...-1:::. I H2N _ jN .:.
N N N
Ph Ph
(150) (148)
Me N
N I S O
, I
N NH
Ph
(149)
As appropriately substituted o-disubstituted benzene derivatives are teadily available,
this procedure has found widespread application in the synthesis of benzo-fused five-
rnernbered heterocycles. Exarnples abound in the various chapters in these volurnes and
the following few exarnples illustrate the general trend.
o-Substituted anilines (151) react readily with phosgeneirniniurn chloride (115) to give
benzoxazoles, benzothiazoles and benzirnidazoles (152) containing a 2-dirnethylarnino sub-
stituent in yields ranging frorn 60 to 97% (73AGIE)806). Sirnilar vicinally substituted
heterocycles also react in a sirnilar way, providing entry into a large nurnber of ring-fused
systerns. An interesting variation of this reaction is the forrnation of the irnidazole (154)
frorn 1,1-diphenylhydrazine (153). Here a carbon atorn of the benzene ring acts as the
second nucleophilic cornponent.
O NH Cl + (r x
I 2 + >=NMe 2 I JNMe 2
XH Cl N
Cl-
(151) IllS) (152) X=O,S,NR
Ph Ph
O NH cr; N,
I 2 + (115) I N
,9
NMe
(153) (154) 2
The above procedure is also of rnajor irnportance for the synthesis of ring-fused systerns
with a nitrogen atorn at the ring junction. Several rnethods are available for the synthesis
of the four-atorn precursor. Arnination of 2-arnino-4-rnethylthiazole occurs on the ring
nitrogen and base treatrnent leads to the free base (155). Reaction with phosgeneirniniurn
chloride (115) gave the thiazolo[3,2-b ][1,2,4 ]triazole derivative (156) in good yield
(73AGIE)806). The isorneric ring systern thiazolo[2,3-c][1,2,4]triazole (158) rnay be prepared
frorn the corresponding hydrazine (157) with a variety of 1,I-bielectrophiles such as
carboxylic acids, ortho esters, carbon disulfide and cyanogen brornide (71J0C10).
S S N
l' )NHNH 2 / Y 'NH
LN '\..-N....j
R R ì\
S
(157) (158)
S NH Cl S N
< r + >=NMe 2 < 'Y JNMe 2
'--.-NNH 2 Cl '--.- 'N
Me Cl- Me
(155) (115) (156)
This rnethod of ring closure is the rnost convenient for the synthesis of ring-fused
1,2,4-triazoles with this arrangernent of nitrogen atorns. It has been used extensively to
forrn the analogous [5,6] ring-fused systerns, and structural arnbiguity is only encountered
Synthesis of Five-membered Rings with Two or More Heteroatoms 129
when the six-rnernbered ring is capable of undergoing ring opening-ring closure in a Dirnroth
rearrangernent (see Chapter 4.15).
4.03.3.4 Syntheses Using 1,2-Bielectrophiles
4.03.3.4.1 Ring systems with two heteroatoms
As the bielectrophile contains two atorns of the five-rnernbered ring, reactions to be
considered under this category require a 1,3-binuc1eophile (see Table 1). An appreciable
nurnber of applications have been reported in the literature and illustrative exarnples are
described below. One should also consider reactions discussed in Section 4.03.2.2 above
as extensions of this concept.
Because of the structural requirernents of the bi lectrophile, fully arornatized heterocycles
are usually not readily available by this procedure. The dithiocarbarnate (159) reacted with
oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and
the same reagent reacted with N-alkylbenzarnidine (161) at 100-140 oC to give the 1-alkyl-2-
phenylimidazole-4,5-dione (162) (see Chapter 4.08). Irninochlorides of oxalic acid also
react with N,N-disubstituted thioureas; in this case the 2-dialkylaminothiazolidine-2,4-dione
bis-irnides are obtained. Thiobenzarnide generally forrns linear adducts, but 2-thiazolines
will form under suitable conditions (70TL3781). Phenylirninooxalic acid dichloride, prepared
frorn oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded
thiazolidine derivatives on reaction with thioureas (71KGS471).
I O.:::(S,-?S
H5CNHR + CICOCOCI )_ JR
o
(159) (160)
R
NH N
II O '-..,Ph
PhCNHR+CICOCOCI )..-ri
o
(161) (162)
a-Halo acyl halides (Type 2, Scherne 5) are particularly reactive bielectrophiles well suited
for the synthesis of mesoionic ring systerns. Reaction of the secondary thioarnide (163)
with a-brornophenacetyl chloride (164) in the presence of triethylarnine readily gave the
anhydro-4-hydroxythiazolium hydroxide systern (165). Similarly substituted arnidines (166)
and dithioic acids (168) with the sarne reagents forrned the corresponding irnidazolium
(167) and dithiolyliurn (169) rnesoionic systerns (77JOC1633, 77JOC1639). 2-Brorno-2-ethoxy-
carbonylacetyl chloride was also especially useful in reactions of this type.
I r S
RCNHR1+PhCHCOCI Ph(-)R
)'-NR 1
-0 +
(163) (164) (165)
R 1
NR 2 N
II Ph( '-..,R
RCNHR!+(164) J.-riRl
-0 +
(166) (167)
Ph 5+
R<:SH+(164) -O--()R
S
(168) (169)
Several reactive species which may be considered 'bielectrophilic equivalents' (Type 4,
Scheme 5) have been utilized in cyclocondensations. The aryl-substituted dicyanooxirane
(170), prepared frorn arornatic aldehydes, rnalononitrile and subsequent oxidation, is a
particularly interesting application of this idea. It undergoes ready reaction with a 1,3-
binucleophile such as a thioarnide to give the 4-thiazolinone (173). Interrnediates such as
(171) and (172) may be involved in this reaction (765261, 76CC23, 78JOC3732, 73CR(C)(277)1153).
Thiourea may be used in the condensation giving the 2-arninothiazolin-4-one, and if a
secondary thioarnide were used, the rnesoionic systern (174) was obtained.
S 5
"-. R l I 2 0 II 5 /5,
R I 1/ l NHR R,j \....CN + R1CNH R1C/ 'CHR R1C CR
\1 NR 2 ;---\ 2 II I II II
-0 + H CN HN CO HN C
I II
(174) (170) R=aryl (171) CN (172) 0
o
Rt)R 1
5
(173)
130 Synthesis of Five-membered Rings with Two or More Heteroatorns
A variation of this idea utilizes the glycidic estcr (175). This underwent condensation
with thioureas and phenyl dithiocarbarnate to give (176; R 1 =NR 2 , SPh, respectively)
(71BSF4021).
S H S
o II HO ""R 1
R / \ ",C0 2 Et + R'CNH --+ 1/
1\ 2 R R N
RHo
(175) (176)
The reactions of the benzenesulfonyl ester of rnandelonitrile (177) provide another
illustration of the 'rnasked' bielectrophile approach. On reaction with a prirnary thioarnide
the 4-arninothiazole (178) was obtained and this is a convenient route to these derivatives.
With a thiourea, the thiazoline (179) was the initial product, and this on treatrnent with
water gave the thiazolidin-4-one (180) (6lJOC271S).
S
PhCHCN S Ph ( ""Ph
1+11 --+ 1/
PhSOP RCNH 2 H 2 N N
(177) (178)
1 s
II
RNHCNHR
S NR
Ph( 'r . PhSO)H
H 2 N NR
(179)
S
Ph( 'rNR
}-NR
o
(180)
4.03.3.4.2 Ring systems with three or more heteroatoms
Ring systerns of this nature are rnost readily prepared frorn 1,2-bielectrophiles already
containin"g one of the desired heteroatorns. As sulfur can be readily converted into sulfenyl
chlorides, substrates containing this functional group have found considerable use. The
reaction of trichlorornethanesulfenyl chloride (181) with arnidines (182) in the presence
of base under rnild conditions is a general method for the preparation of 5-chloro-l,2,4-
thiadiazoles (183) (6SAHC(S)1l9). Variation of (181) to contain one or two chlorine atorns
attached to carbon greatly extends the usefulness of these reagents, and these aspects are
discussed in Chapter 4.25.
H
RCNH 2 + CI)CSCl
(182) (181)
N R
--+ /1
CI" ,.. N
S
(183)
Several related derivatives have also been utilized in this type of synthesis. Irnino-
chlorornethanesulfenyl chlorides (184), prepared by the controlled addition of chlorine to
isothiocyanates, react with arnidines (161) to give 1,2,4-thiadiazolines (185) (7lT4117).
Chlorocarbonylsulfenyl chloride (186), prepared by the hydrolysis of trichlorornethanesul-
fenyl chloride with sulfuric acid, reacted with ureas, thioureas and guanidines to give
1,2,4-thiadiazolidine derivatives (187) (70AG(E)S4, 73CB3391).
R þlH
"-./
S
/'\.
R NH
(186)
o 0
Et N H
+ClCOCOCl N..... ,<;N
's'"
/'-.
R R '
(189)
x
RN-i
CICOSCl+RNHCNHR --+ J NR
0"""- S,..
(187)
H R'N Ph
RN=CSCl+PhCNHR' --+ J
I RN"""- ,..
Cl S
(184) (161) (185) R = aryl, ArCO
(188)
Synthesis of Fiue-membered Rings with Two or More Hete.roatoms 131
Of particular interest is the reaction of S,S-disubstituted sulfur diirnides (188) with oxalyl
chloride in dilute solution in the presence of triethylarnine. The 1,2,5-thiadiazole-3,5-dione
(189) was forrned in alrnost quantitative yield (72LA(759)107).
4.03.3.4.3 Ring-fused systems
Ring-fused systerns with C-C points of fusion cannot be prepared by this approach.
However, numerous syterns with a nitrogen atorn at the fusion point have been synthesized,
reflecting incorporation of the above binucleophiles in a heterocyclic ring. Reaction of
2-arninobenzothiazole (190) with (phenylirnino)oxalic acid dichloride (191) gave 3-(phenyl-
irnino)-2-oxoirnidazo[2, 1-b ]benzothiazole (192), and 2-mercaptobenzirnidazole (193)
afforded 2-phenylirnino-3-oxothiazolo[3,2-a]benzirnidazole (194) (71KGS471). These
authors based their assignrnent of the direction of ring closure on spectral data.
s 1 1 S N
0- JNHz + CICOC=NPh 6 T >=0
N (191) ,, -(
'\'\ NPh
(190) I NH (192)
r:>SH
(193)
NyS
Ó: {NPh
(194)
Bielectrophiles containing a heteroatorn are equally effective in ring annulations of this
type. Both [5,5] and [5,6] ring-fused systems rnay be readily prepared by reaction of the
appropriate 2-arnino heterocycle containing an arnidine function with trichlorornethanesul-
fenyl chloride (181). Reaction of 2-arninopyridine (195) with (181) in chloroforrn gave the
interrnediate sulfenirnide (196) which with an arornatic arnine in the presence of triethyl-
amine underwent ring closure to (198), probably via the interrnediate (197). Treatrnent of
(195) with the irninochlorornethanesulfenyl chloride (184) led to (198) directly (70JOC1965,
7ÌJOC1846, 73JOC3087, 75JOC2600).
O NH Z
::::::,.. + ClSCC1 J
(195) (181)
! SCi
/
RN=C
11841 "CI
a NH ,
I S
::::::,.. ÒCl
(196) J
jRNH 2 /Et 3 N
(r N\
S c
::::::,.. N--{
(198) NR
a NH...
I S
::::::,.. N C1--lNR
(197)
4.03.3.5 Syntheses Using 1,3-Bielectrophiles
4.03.3.5.1 Ring Systems with Two Heteroatoms
Although the wide diversity of structural types illustrated in Scherne 6 suggests that
numerOUS exarnples of their application to five-rnernbered heterocycles would be known,
132 Synthesis of Five-membered Rings with Two or More Heteroatoms
their utilization has been restricted because of the cornparative shortage of 1,2-binu-
cleophiles. However, they are rnore suited to the synthesis of six-rnernbered systerns, and
it is in this area that their potential application lies.
The irnoniurn salt (199), obtained frorn ynarnines and phosgeneirnoniurn chlÓ'ride, under-
went ready reaction with rnonosubstituted hydrazines to give the 3,5-bis(dirnethyl-
arnino)pyrazole (200) (68T4217, 69T3453). Sirnilarly, the adduct (201), resulting frorn the
addition of phosgene to ynarnines, likewise reacted with syrn-disubstituted hydrazines to
give pyrazoles (202). With hydroxylarnine derivatives the isoxazolinone (203) was obtained.
R
Me2N NMe2 CI- R'NHNH,.
CI CI
(199)
R
R2N O
CI CI
(201)
R'NHNHR'
.
R 0
RNOR 1
2 N"
R 1
(202)
R NMe2
o
Me2N "N
N
R 1
(200)
R NR 2
O .J:;;N R
(203)
a-Functionalized ketene dithioacetals (Type 3, Scherne 6) and thioacetals are also useful
synthons for five-rnernbered rings. Thus, the a-oxoketene dithioacetal (204) reacted with
a rnonosubstituted hydrazine on heating in n-butanol to give the pyrazole (205) in greater
than 62% yield (76ZC398). The dithioacetal (206), derived frorn ethyl cyanoacetate, reacted
with hydrazine to give products dependent on the reaction conditions. With hydrazine in
a 5: 1 ratio the pyr.azole '(207) was forrned; heating in a 1: 1 ratio in ethanol resulted in
condensation at the cyano group giving the pyrazole (208) in 66% yield (76ZC16).
RCO
SMe
SMe
:1
N-
R'NHNH, R
.
MeS '/ N
N
R 1
(204)
(205)
Et0 2 C NH,
n N,H.
MeS "N
NH
(208)
Et0 2 C SMe
>=< N,H. .
NC SMe
(206)
NC OH
MesCN
NH
(207)
4.03.3.5.2 Ring systems with three or more heteroatoms
To forrn a five-rnernbered ring in this rnanner, the 1,3-bielectrophile rnust contain a
heteroatorn, and several systerns such as the aza analog of (204) are known (68T4217, 69T3453).
Dirnethyl N-ethoxycarbonylthiocarbonirnidate (209) reacted readily with a rnonosubstituted
hydrazine to give the 1,2,4-triazolinone (210), and with hydroxylarnine the 1,2,4-
oxadiazolinone (211) was obtained (73JCS(Pl)2644).
HN OMe
/
O N"
R
(210) (209) (211)
An interesting illustration of a bielectrophile contributing two heteroatorns to the resultant
five-rnernbered ring is the 2-alkyl-2-chloro- (or fluoro-) sulfonylcarbarnoyl chlorides (212).
With rnethylhydrazine initial attack by the more basic nitrogen occurred on the carbarnoyl
chloride, and this was followed by base-induced cyclization to 1,2,3,5-thiatriazolidine
derivative (213) (77JCR(S)238, 77JCR(M)2813). Other reactions of this type are discussed in
Chapter 4.28.
SMe
RNHNH, /
-- EtOCON=C
"-
SMe
NH,OH.
HN OMe
/
O O"N
Synthesis of Five-membered Rings with Two or More Heteroatoms 133
R 0
\ J-NMe
CICONS0 2 Cl + MeNHNH 2 -+ RN NH
's6 2
(212) (213)
4.03.3.5.3 Ring-fused systems
1,3-Bielectrophiles have found appreciable applications in the synthesis of ring-fused
systerns, especially those involving [5,6] fused systerns. The following serve to illustrate
these applications. Reaction of pyrazole with (chlorocarbonyl)phenyl ketene (214) (Type
1, Scherne 6) readily forrned the zwitterionÎc pyrazolo[1,2-a ]pyrazole derivative (215)
(80JA3971). With 1-methylirnidazole-2-thione (216), anhydro-2-hydroxy-8-rnethyl-4-oxo-3-
phenyl-4H-irnidazo[2, 1-b ][1,3]thiazinium hydroxide (217) was obtained (80JOC2474).
0- 0 s Me
N '-- H N--.,/ ) S 0-
{ N Ph PhC , =C=O t / ." I
'\.-- {2161 \.-- Ph
o 000 0
(215) (214) (217)
The 3-chloroacrylaldehyde (218) (Type 1, Scherne 6) reacted readily with 2-arnino-l,3,4-
selenadiazole (219). The final product was the [1,3,4]selenadiazolo[3,2-a]pyridinium salt
(220) (76ZC337).
R R N-N se"Y." ) N""
>=< + ( )NH 2 -+ <
Cl CHO Se N - + R
R
(218) (219) (220)
4.03.4 INTRAMOLECULAR RING CYCLIZATIONS
4.03.4.1 Oxidative Ring Closure Reactions
4.03.4.1.1 C -N bond formation
Oxidative procedures have been utilized for the synthesis of both mono cyclic five-
rnernbered heterocycles and their ring-fused analogs, although the ease of synthesis of the
precursors for the latter ring closures results in wider application of this procedure. A
variety of oxidizing agents have been used and the conversion of the benzylidene
hydrazidines (221) into the 4-arylarnino-1,2,4-triazole (222) was effected with rnercury(II)
oxide (77BCJ953).
N-NH
I; \
PhCH lMe
N
I
NHAr
(221)
N-N
Ph( )Me
N
I
NHAr
(222)
Al 0 N=N
C C:3) Mel.. S
N
Ar
(225) (223) (224)
The direction of ring closure can often be influenced by the nature of the dehydrogenation
agent. The substituted thiosernicarbazone (223) with Alz0 3 in chloroforrn forrned the
N=N
Mel.. NAr
S
MnO,
( benzene
Me HNAr
"C >=
/ \\ S
Me N-NH
134 Synthesis of Five-membered Rings with Two or More Heteroatorns
1,2,4-triazoline-3-thione (224) but if manganese dioxide in benzene were used, the
thiadiazoline (225) resulted (70JCS(C)63).
Lead tetraacetate is often used as the oxidizing agent for the conversion of hydrazones
into ring-fused systems.
Oxidation of the hydrazone of 2-hydrazinopyrazole (226) with Pb( OAC)4 in CH 2 Ch
is a two-step reaction. The azine (227) was formed as an intermediate and this underwent
ring closure to the 3H-pyrazolo[5,l-c][l,2,4]triazole (228) (79TL1567). A similar reaction
applied to the benzal derivative of 2-hydrazinobenzothiazole (229) gave 3-phenyl-
[1,2,4 ]triazolo[3,4-b ]benzothiazole (230) together with a by-product (231) (nJCS(pl)1519).
R 2 NH
\
Rl ! IH N
N --- 'f..
R 3 R 4
(226)
R 2 N R 2 N
-- Ria \ -- Rl(1: 'N
N""N N_N
R/'R 4 R3 R 4
(227) (228)
S N (r s COMe
-- Ó -----r N + :::? I >- NHCOPh
If '\ N......j' ::::,... N
Ph
(230) (231)
(r s
I >NHN=CHPh
::::,... N
(229)
4.03.4.1.2 N -N bond formation
Oxidative processes leading to N -N bond formation have been utilized to form a variety
of five-membered heterocycles and also in ring annulations. The bis-hydrazone (232)
underwent ready ring closure to the l-amino-l,2,3-triazole derivative (233) with mercury(I)
acetate or manganese dioxide (67TL3295, 71JPR882, 71ZC179). In a related oxidative ring
closure, the osazone (234) with potassium ferricyanide gave the deeply colored zwitterionic
I ,2,3-triazole derivative (235) (74T445).
Ar X NNH 2 HgOAc Ar N ArXNNHPh K,FetCN'b . Ar N
--- (II (11+
N...N Ar ...NPh
H NNHz Ar NNHPh N
I I
NHz -NPh
(232) (233) (234) (235)
Formation of ring-fused systems via N-N bond formation can occur in several ways,
depending'on the structure of the particular precursor. A variety of oxidizing agents have
been employed and the following reactions illustrate the various possibilities. Oxidation of
the hydrazone (236) with NBS gave v-triazolo[5, l-b ]-thiazolylium and -imidazolylium salts
(237; X = Sand NH, respectively). The imidazolylium salts readily lost HBr in the presence
of pyridine to form the free base (67AG(E)261). A precursor amidine (238) with Pb(OAc)4
underwent facile ring closure to s-triazolo[1,5-a ]pyridine derivatives (239) and a wide
variety of amidines will undergo related ring closures (see Chapter 4.15) (66JOC260).
Ring closure to give C-C fusion points in the resultant ring-fused system is also possible.
Lead tetraacetate in glacial acetic acid effects closure between the primary amino group
and the azo group of (240) giving the v-triazolo[ 4,5-d]pyrimidine (241). It is possible that
this closure involves a nitrenoid-type intermediate (see Section 4.03.9.2) (ncPB605).
x- X N NBS x
Rl ì( 'I 20 o c'EIOA/ Rl IN Br-
'--N NHR) '-- + 'NR3
R R
(236) (237)
NH R 1
R -o l y
::::::,.. N NH honzene
(238)
fY-Y
R N_N')RI
(239)
N
R( J NH2
N ß N=NPh
NHz
(240)
Pb,OAc,.
-.
gl.AcOH
N
Rr- :;: N\
N '- ,NPh
:::,.... N
NH 2
(241)
Synthesis of Five-membered Rings with Two or More Heteroatorns 135
4.03.4.1.3 C -S bond formation
This process is not as common as the other oxidative procedures and usually involves
ring closure onto an aromatic or heteroaromatic ring. The following examples illustrate the
structural types required for this cyclocondensation.
It is particularly appropriate for the synthesis of benzothiazoles (the Jacobson-Hugershoff
synthesis) and an example among many is the oxidative ring closure of the thioanilide of
diethyl methanetricarboxylate (242) with bromine in polar solvents. Sulfenyl bromides (243)
most likely function as intermediates yielding the benzothiazole derivative (244) (73ZC176).
A variety of oxidizing agents will effect ring closures of this type, including thionyl chloride
(70BCJ2535).
I Br 9 Br (X s CO Et
ArNHCCH(COzEth ArN=CCH(COzEth __ I >=< 1
:::::,.. NH COlEt
(242) (243) (244)
The 2-thienylthiourea (245) on oxidation with bromine in acetic acid gave the thieno[3,2-
d]thiazole (247). It has been suggested that the intermediate electrophilic sulfenyl bromide
adds to the 2,3-bond of the thiophene ring to form (246) when then loses HBr to give
(247) (71AJC1229, 78JHC81). Pyrazolo(3,4-d]thiazoles are formed in a similar fashion
(76GEP2429195).
S S
R1 Q- NH Br RI(.'-yN
h \ 2 -4 U }-NHR l
R sr NHR R SBr
(245)
--
l N
RI'\---J- >NHR l
R H S
(246)
-HBr
--
S N
Ria >NHR:
R S
(247)
4.03.4.1.4 N-S bond formation
Numerous examples of N -S bond formation using oxidative conditions have been
described in the literature. A convenient synthesis of isothiazoles involves the direc1
oxidation of y-iminothiols and numerous variations have been studied (see Chapter 4.17).
The oxidation of the amidine (248) to give the 3-aminoisothiazole (249) illustrates the
reaction scheme (65AHC(4)107, nAHC(14)1), which has been extended to the syntheticall)
useful 5-amino-4-cyano-3-methylisothiazole (251) obtained by oxidation of (250) witb
hydrogen peroxide (75JHC883).
NH z R NH NH l S NC Me
I 0 1 I II H 0 !J
HN=C?HCSR 1 -- R I '/ 'N MeC=?-CNH 2 HlNz( 'N
R S/ CN S/
(248) (249) (250) (251)
1,2,4- Thiadiazoles are conveniently prepared from thioamides or substrates containing
an analogous functional group on treatment with a variety of oxidizing agents including
halogens, hydrogen peroxides, sulfur halides, etc. (see Chapter 4.25). The mechanism of
the conversion is still uncertain and the reaction is illustrated by the conversion of the
thioamide (252) into (253; Hector's base) on oxidation with hydrogen peroxide
(65AHC(5)1l9). Variation of the thiourea substitution pattern as in (254) allows for a different
substitution pattern in (255) which was readily formed in 90-95% yield on bromine oxidation
of (254) (nzc13o).
[ Ar ]
S I NH
II H,O, ArNH ìí N y NH 2 ArN
ArNHCNH 2 I /I __ J N
NH S HN S/
(252) (253)
Ph S
I II
PhN=CNHCNH 2
(254)
Ph
Br N
J \
HN NPh
S/
(255)
136 Synthesis of Five-membered Rings with Two or More Heteroatorns
This procedure is equally successful in the formation of ring-fused systems. Hydrogen
peroxide oxidation of the vicinal aminothioamide (256) readily gave 3- minoisothiazolo[3,4-
b ]pyridine (257) (73CJC1741), and the same oxidant readily converted (258) into 3-
aminonaphtho[1,2-c ]isothiazole (259) (77JPR6S). Oxidative ring closure onto a ring nitrogen
atorn also occurs readily as in the formation of the [1,2,4]thiadiazolo[2,3-a]pyridine (261)
frorn the 2-pyridylthiourea (260). This ring closure was equally successful with aza analogs
of (260) (7SJHC1l91). Bromine oxidation of 2-thiazolylthiourea (262) gave the 2-
aminothiazolo[3,2-b ][1,2,4]thiadiazolylium brornide (263) (71JPR1148), and the action of
the same oxidant on the cyclic thiourea (264) resulted in formation of the interesting
2,3,5 ,6-tetrahydroimidazo[ 1,2 -d][ 1,2,4 ]thiadiazol- 3 -ones (265) (73JPRS39 >.
N-S
NH 2 cxY NH
CO I CSNH2__ I # 2
# #
(258) (259)
N N
O CSNH 2 H,O, (- Y'\
I fiNH 2 S
N NH 2
(256) (257)
0 1 NHCNHC02Et
N II
S
(260)
(t N"- S
-+ )==NC0 2 Et
"-N
(261)
S
1-{NHR Br,.CHCl'l
o
(264)
S NH S N
\ ì( }-NH 2 -. \ ì( )NH 2
'\.-N S '\.- --S Br-
(262) (263)
N S
C y '
N NR
--{
o
(265)
4.03.4.1.5 o-c bond formation
A variety of oxidizing agents can be utilized for O-C bond formation leading to both
five- and six-mernbered rings. Lead tetraacetate has been used for hydrazone cyclization
onto a carbonyl oxygen atom as in the conversion of the hydrazone (266) into the 1,2,4-
oxadiazolyl ether (267) (76NKK782). The sernicarbazones (268) also were converted into
the 2-amino-5-benzoyl-l,3,4-oxadiazoles (269) (72AC(R)11, 76MI40300). a,ß-Unsaturated
ketoximes such as (270) undergo oxidative ring closure with bis-triphenylphosphinepal-
ladium dichloride to give 3,5-diphenylisoxazole (271) in 92% yield (73TLS07S) (see also
Chapter 4.16).
RCH=NNHC0 2 R 1
PÞIOACJ 4 )
N-N
R( )OR 1
o
(267)
PhCOCH=NNHCONHR )t \
PhCO" /NHR
o
(268) (269)
(266)
W OH
PhCCH=CHPh+(PPh:;hPdCI 2 NaOPh) Ph n N
'(0)
(270) (271)
Formation of ring-fused systems by this procedure is not as common. If the vicinally
substituted hydroxyamino derivative is available, then Pb(OAc)4 treatment will lead to a
ring-fused oxazole as in the conversion of (272) into (273) (71JCS(C)1482). In a different
approach the CH=N - functional group is generated in situ. The 2-{1-pyrrolidinyl)ethanol
Ar
. EtO'CW
o
(273)
o N=CHAr
EtO'C(DOH
o
(272)
PÞlOAcI 4
Synthesis of Five-membered Rings with Two or More Heteroatoms 137
ON:j "OA.". Q:j cr
(274) R (275) R (276)
(274) on oxidation with mercury(II) acetate is ultirnately converted into the pyrrolidino[2, 1-
b ][1,3]oxazolidine derivative (276). The intermediate imoniurn salt (275) is considered to
undergo nucleophilic attack by the hydroxy group (60JA5148).
4.03.4.1.6 O-N bond formation
In comparison to N-S bond formation, O-N bond formation by essentially oxidative
procedures has found few applications in the synthesis of five-membered heterocycles. The
1,2,4-oxadiazole system (278) was prepared by the action of sodium hypochlorite on
N-acylarnidines (277) (76S268). The N-benzoylamidino compounds (279) were also conver-
ted into the 1,2,4-oxadiazoles (280) by the action of t-butyl hypochlorite followed by base.
In both cyclizations N-chloro cornpounds are thought to be intermediates (76BCJ3607).
NH
II
RCNHCOR 1
NaOCI
---
R
N\\
RIll N
"'0....
(278)
NH
II Bu'OCI
RCNHCOPh ---
N R
Ph II
"0....
(280)
(277)
(279)
R = Ph, MeO, C s H ION
o 0
R CORI R O
YNH z YN)
o 0
(281) (282)
Ring-fused systems have also been prepared using this bond formation approach. Treat-
ment of the ß-arninoketone (281) with lead tetraacetate gave the isoxazole system (282)
(74S30).
4.03.4.1. 7 S -S, S -Se and Se -Se bond formation
A general route to 1,2-dithiolanes (284) involves the direct oxidation of the 1,3-dithiol
(283) with hydrogen peroxide at 75 oC in acetic acid containing potassiurn iodide. Iron(III)
chloride or lead tetraacetate may be used as the oxidizing agent but the instability of the
product makes the H 2 0 2 rnethod the one of choice (69JOC36) (see Chapter 4.31). ß-Dithio
compounds such as (285) undergo oxidation in acid medium to yield the 1,2-dithiolylium
salt (286) (76JCS(Ð)455).
[O] Q
\ I -+ S
SH SH s""-
(283) (284)
MezN Y"{ NMe z !(J NMez
[OJ '/
I I W- Me N S+ X-
S S z S""-
(285) (286)
In an analogous fashion the oxidative coupling of 1,3-diselenols is used for the preparation
of 1,2-diselenolanes, the precursors being obtained by a variety of methods (see Chapter
4.35). Similar reactions have been used for the preparation of 1,2-thiaselenolanes. Sub-
stituted propane-1,3-diselenones (287) are oxidized by halogen to the corresponding 3,5-
diarnino-l,2-diselenolylium chloride (288) (67AJC1991).
(287)
NHz
HzNCse+ X
S;;-
(288)
HzN NHz
/I 1/
Se Se
138 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.4.2 Electrophilic Ring Closures via Acylium Ions and Related Intermediates
Ring closures considered under this heading are essentially intramolecular cyclodehydra-
tions (or their equivalent) and bear many resemblances to the intermolecular processes
discussed in Section 4.03.3. They are more suited to the synthesis of ring-fused systems
because of the ease of access to the requisite precursors.
Acyl or thioacyl a-amino acids and their derivatives undergo cyclization to oxazole and
thiazole derivatives with a variety of cyclodehydration agents. Reaction of an amino acid
with thioacetic acid under controlled conditions gives the N-thioacetyl derivative (289). If
the reaction is carried out at 100 0 C Over 16 hours, then cyclization occurs to the thiazole
(290) (69CC818). This process has been developed as a step-wise process for the degradation
of polypeptides (69MI40301). Numerous variations of this reaction have been described (see
Chapter 4.19), an interesting variation being the use of thiocarbonyl amino acid silyl esters.
Treatment of the trimethylsilyl ester (291) with phosphorus tribrornide gave the thiazolidine-
2,5-dione (292) in high yield and purity (71CB3146). This procedure offers considerable
advantages over previous ones. If trifluoroacetic acid is used as the cyclodehydration agent
for (289), then 2-thiazolin-5-ones are obtained (69JCS(C)1117).
R 1
MeCSNHCHR 1 C0 2 H -+ MeCOS()Me
S
(289) (290)
R 1 NH
ROCSNHCHRIC02SiMe3 0.1::):=:0
S
(291) (292)
Substitution of the nitrogen atom in (289) and subsequent ring closure of (293) under
acid cyclodehydration conditions gave the mesoionic systern anhydro-5-hydroxythiazolium
hydroxide (294). These reactions are analogous to the cyclodehydration of the N-nitrosogly-
cines (295) with acetic anhydride to give the sydnones (296) (see Chapter 4.21).
l R 2 NR1 J( RI NR
RCSNCHR 2 C0 2 H -+ _ ij \\R RNCHR 1 C0 2 H -+ Y \I
O S/ O -0 O/N
(293) (294) (295) (296)
Various ring annulations are possible using reactions analogous to those described above.
2-Acetamido-5-thiazolylthioglycolic acid (297) on heating with phosphorus oxychloride
underwent ring closure to 2-acetamidothieno[3,2-d]thiazolin-4-one (298) (S6AC(R)27S).
Corresponding ring closures in the thiophene series result in isornerization occurring in the
final product (62ACS(B)lSS). Ring closure onto a ring junction heteroatorn, as in the ready
conversion of (l-methylimidazol-2-yl)thioglycolic acid (299) into the ring-fused meso ionic
system (300), occurred with acetic anhydride (79JOC3803). Acylations of this type are
characteristic of reactive mesoionic systems without a substituent adjacent to the carbonyl
group.
fiN POC),
H0 2 CCH 2 S(_)NHCOMe ---'+
S
(297)
S S
ÇI)NHCOMe
o
(298)
(299)
Me Me
N S N
T-rCOCH2S<'NJ
0-
(300)
W S
lìî)
V C0 2 H
The cyano group is also a suitable precursor for an analogous intramolecular cyclization.
Reaction of the thioacetonitrile derivative (301) with HBr resulted in ready ring closure
to form the 3-amino-2-ethoxycarbonylthiazolo[3,2-a ]pyridinium bromide (302)
(78JCR(S)407). This is a general reaction and is a. successful procedure for the annulation of
a 3-aminothiazole function to a variety of five- and six-membered heterocycles containing
an analogous relationship of cyano and nitrogen functions. It may also be applied to the
synthesis of amino-substituted rnonocyclic systems, such as 4-arninoimidazoles (see Chapter
4.08).
Synthesis of Five-membered Rings with Two or More Heteroatorns 139
SyC02El S
CN JCOzEt _
NHz Br
(301) (302)
4.03.4.3 Ring Closures via Intramolecular Alkylations
This synthetic process is rnore suited to the preparation of ring-fused syterns as the
precursors are more readily available than their alicyclic counterparts. The pyrazoline (303)
with a hydroxy group appropriately situated to form a ring underwent ring closure to the
pyrazoliniurn salt (304) on heating with thionyl chloride (68JOC3941). Related ring closures
can be effected in alternative ways, e.g. the alcohol (305) on heating with sulfuric acid or
other reagents such as SOCh, POCh or PCl s underwent ring closure to the racemate of
tetramisole (306) (66JMC545, 68JOC1350).
R R
r- ) SO 12þ r- ) _
N OH N a
R R +
(303) (304) (305) (306)
Sulfur may also be alkylated under appropriate conditions. On forrnation, the N-ß-
chloroethylthiazolidine-2-thione (307) underwent spontaneous ring closure to the tetrahy-
drothiazolo[2,3-b]thiazolylium chloride (308) (71CHE1534) and a sirnilar reaction occurred
io the imidazole series.
2-Chloromethylpyrrolidine (309) when treated with CS 2 in DMF in the presence of
potassium carbonate readily formed the dithiocarbamate (310). In the presence of base,
intramolecular alkylation on sulfur occurred to give (311) (63JOC981).
J:>-Ph -+ Ph('-)
S Hz OH X-
I __/SYS\ Cl __ Cl -- (C s
\ S' '\.-.t;:I-I a- \.-.NH . \-N1(SK N--{
(307) (308) (309) (310) S (311) S
Similar alkylations may be effected on oxygen. 1-(2-Chloroethyl)imidazolidin-2-one (312)
when treated with potassium hydroxide or sodium hydride underwent ring closure to the
tetrahydroimidazo[2, 1-b ]oxazole (313) (571 A5276). This approach can be used for the prepar-
ation of bicyclic hydantoins and the corresponding dihydro derivatives of (313) using the
rnesylate of (312) and NaH (77JHC511, 79JMCI030).
t1 x -- (,-)
(312)
(313)
4.03.4.4 Ring Closures via Nucleophilic Additions
The addition of nucleophiles to double and triple bond systems is often a convenient
way of effecting an intrarnolecular ring closure. Addition to cyano groups has received
considerable attention, as in addition to ring formation it provides a convenient method
for the introduction of an amino group. Reaction of methyl N-cyanodithiocarbirnidate with
N-methylaminoacetonitrile resulted in displacement of methanethiol and forrnatÎon of (314).
Sodium ethoxide treatment in DMF converted (314) into a 4-amino-5-cyanoimidazole
NCN
II H N
RC NaOEt 2 fiN
"NCH 2 CN NC )Me
I N
Me Me
(316) (317)
SMe H N
I 2 N
NCCH 2 N(Me)C=NCN N t Þ NC()SMe
N
Me
(315)
(314)
140 Synthesis of Five-membered Rings with Two or More Heteroatorns
(315) (70AHCl12)103). A sirnilar ring closure involving a carbanion occurred when an
N-cyanoamidine such as (316) was treated with sodium ethoxide in ethanol to give (317)
in rnoderate to good yields (7SHCA2192).
Five-membered ring formation in this way occurs with an appreciable number of suitably
substituted substrates. Reaction of 1,3-oxathiolylium salts with cyanamide gave the ring-
opened product (318). When this reaction was carried out in the presence of sodiurn
hydroxide, (318) underwent a facile ring closure to afford the arninobenzoylthiazole (319)
in good yield (71ZC421, 73JPR497). Opening of the oxathiolylium nucleus with a variety of
carbonyl-stabilized carbanions and subsequent ring closure in this fashion lead to arnino-
substituted thiophenes.
R 2 N
\.-NCN S
,- -+ PhCO('ìì NR2
LCOPh H 2 N N
(318) (319)
N-Nucleophiles also add readily to a cyano group, the product depending on the degree
of substitution of the nucleophilic arnino group. Conversion of an amidine into its N-chloro
derivative (320) with sodium hypochlorite and addition of potassium thiocyanate in ethanol
at 0 oC resulted in good yields of 5-amino-1,2,4-thiadiazoles (322), the interrnediate (321)
undergoing ready ring closure under the reaction conditions. This is a rnild rnethod for
producing 5-amino-l,2,4-thiadiazoles and is discussed further in Chapter 4.25 (6SAHClS)119).
-.C;'
NSC=N N R
R .J -- II
O'C NH H 2 N"-.. /N
2 S
NCI
RC:í' + KSCN
"-
NH 2
(320)
(321)
(322)
R 1 NHR 2 R 1 2
ìí ( NR
J -- RCO 'I
RCO SCN S)::,NH
(323) (324)
A related ring closure is also successful in the thiazole series. Treatment of a ß-arnino-a,ß-
unsaturated ketone with thiocyanogen gave the intermediate thiocyano cornpound (323)
which underwent ring closure to the 2-iminothiazoline derivative (324) (83MI40300). Related
reactions are described in Chapter 4.19, and for those involving potassium selenocyanate
see Chapter 4.20.
Oxygen nucleophiles rnay also add to cyano groups, in rnany instances providing entry
into the isoxazole systern (Chapter 4.16). These reactions are illustrated by the conversion
of the 2-arylhydrazono-3-oxonitrile (325) into a 5-aminoisoxazole (327). Treatment of
(325) with hydroxylarnine in the presence of sodium ethoxide gave the oximino derivative
(326) which then underwent base-catalyzed ring closure to (327) (7SJOC2604). If the
hydroxylamine addition is carried out in refluxing ethanol, the 3-aminoisoxazole is formed
via an intermediate amidoxime.
WNHAr
RCOCC:=N
WNHAr
H,NOH, RC-CCN
NaOMe II
NOH
(326)
ArN=N R
-- H 2 N n N
'(0)
(327)
(325)
Exarnples are known of nitrogen, oxygen and sulfur nucleophiles adding to unsaturated
carbon-carbon systems to provide ready syntheses of five-membered ring systems with two
heteroatoms. The nucleophile supplies one of the heteroatorns, the other being incorporated
into the precursor at sorne suitable stage in its synthesis. Reaction schemes utilizing this
synthetic approach are illustrated by the reaction of the a-aminoacetylene (328) with carbon
disulfide. The interrnediate dithiocarbamic acid (329) underwent ring closure to the thiazole
(330) which with sulfuric acid underwent a prototropic rearrangement to (331) (49JCS786).
This addition of CS 2 is, however, sensitive to the degree of substitution at the arnino group,
3-t-octylarnino-1-butyne not undergoing reaction (63JOC991).
Propargyl alcohol (332) and (328) react readily with isocyanates in the presence of a
basic catalyst to give 4-methylene-2-oxazolidinones (334) and 4-methylene-2-
imidazolinones (336), respectively (63JOC991). In the absence of sodium methoxide the
interrnediate methanes (333) and ureas (335) were obtained and on treatrnent with sodium
methoxide underwent ring closure. Moderate to excellent yields were obtained.
Synthesis of Five-membered Rings with Two or More Heteroatoms 141
RI
H 2 C r N
)=0 ,NaOMe
Me N
R
(336)
MeCHC:=CH
I R1NCO
N
R/ "- CONHR 1
MeCHC:=CH cs MeCHC:=CH
I -4 I
RNH RNC=S
I
SH
(328) (329)
(335)
S S
H2C 7S Me( ys
Me NR Me NR
(330) (331)
? H CONHR 0
H2C 0
MeCHC:=CH + RNCO Me HC:=CH r
Me NR
(332) (333) (334)
Ring-fused systems may also be prepared by this synthetic approach. Reaction of 2-
mercaptobenzimidazole with 3-brorno-1-phenyl-l-propyne gave the thioether (337). Addi-
tion of the ring nitrogen to the triple bond is controlled by the reaction conditions. In
alcohol with sodium ethoxide the 3-benzylthiazolo[3,2-a ]benzimidazole (338) was obtained.
On heating (337) in acetic acid with mercury(I) acetate and sulfuric acid the 4-phenyl-2H-
thiazino[3,2-a]benzimidazole (339) was forrned. In contrast the thioether (340), obtained
from 2-mercaptobenzimidazole and propargyl bromide, under the latter conditions gave
3-methylthiazolo[3,2-a]benzimidazole (341) (76S189). Other ring closures of this general
type are described in Chapter 4.36.
N :::::-,----S\ NaOEt
rt : I --f' , EtOH
o N tH 2 Ph
(338)
(X N
I >SCH 2 C:=CPh
NH
AcOH, A
Hg,( OAc),
H 2 S0 4
NY J S
ó--:
(339)
(337)
(X N
I >SCH 2 C:=CH
NH
AcOH, A
Hg,(OAc),
H, S0 4
NyS
þ r<::;
Me
(341)
(340)
In contrast to the above additions N-allyl- and substituted N-allyl-arnides, -urethanes,
-ureas and -thioureas undergo intramolecular cyc1ization only in 60-96% sulfuric acid to
give the corresponding oxazolinium and thiazoliniurn salts. Treatment of these cations
with base yields 2-oxazolines and 2-thiazolines in moderate to good yields. The reaction
is illustrated by the conversion of N- 2-phenylallylacetamide (342) into 2,5-dimethyl-5-
phenyl-2-oxazoline (343) in 70% yield (70JOC3768) (see also Chapter 4.19).
II Me 0 Me 0
Ph NHCOMe H, S0 4 þ Ph :e HSO'; Ph>C= Me
(342) - (343)
In this group of intramolecular additions the reaction apparently proceeds via an inter-
mediate carbocation whose presence was established by NMR data.
4.03.4.5 Ring Closures via Radical Intermediates
Although sorne of the oxidative ring closures described above, e.g. reactions with lead
tetraacetate (Section 4.03.4.1.2), rnay actually involve radical intermediates, little use has
been made of this reaction type in the synthesis of five-membered rings with two or more
heteroatoms. Radical intermediates involved in photochernical transformations are
described in Section 4.03.9. Free radical substitutions are described in the various mono-
graph chapters.
142 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.5 SYNTHESES INVOLVING CONJUGATE ADDITION REACTIONS
Conjugate addition reactions leading to five-membered heterocycles with two or rnore
heteroatorns are predominantly intermolecular in nature, and a variety of nucleophiles have
been added to alkynes conjugated with electron-withdrawing groups. Dimethyl acety-
lenedicarboxylate has found extensive use, both for monocyclic ring forrnation and for ring
annulation reactions in which six-mernbered rings are usually forrned.
Hydrazine and its mono- and di-substituted derivatives all undergo addition to acetylene
mono- and di-carboxylic acid esters. Hydrazine hydrate and diethyl acetylenedicarboxylate
forrned ethyl 5-oxopyrazoline-3-carboxylate (344) (1893CB1719). Phenylhydrazine and
DMAD forrned a 1 : I adduct (345) that under basic conditions gave the N-phenylpyrazol-
inone (346) (1889CB2929). 1,2-Dimethyl- and 1,2-diphenyl-hydrazines gave analogous
pyrazolinones. In ether solution 1,2-dimethylhydrazine and ethyl propiolate formed (347)
but in ligroin a dicondensation product was obtained (65LA(686)134). Reaction conditions
also control product forrnation in the reaction of hydrazobenzene with DMAD. In glacial
acetic acid the pyrazolinone (349) was obtained, but in xylene methyl indole-2,3-dicarboxy-
late was produced on heating the intermediate enarnine (348). In pyridine a quinoline
derivative was isolated (34LA(Sll)16R).
C0 2 Et
OJ::N
N
H
(344)
o .J:';N Me
N
"-1.:
(347)
CO Me C0 2 Me
PhNHNf' 2 ---. o.J:)N
C0 2 Me Ph
(345) (346)
H ìí C0 2 Me Ff 0 2 Me
1 ---. o /NPh
PhNHN C0 2 Me N
I Ph
Ph
(348)
(349)
Ring annulations can be effectively carried out using a reaction of this type. As one of
the unsaturated groups attached to the triple bond is usually also involved in the reaction,
six-membered rings result. Reaction of 3-aminobenzisoxazole (350) with methyl propiolate
gave a rnixture of regioisorners (351) and (352) (nCB794). With 2-aminoselenazoles (353)
only one cyclized product, 7 H-selenazolo[3,2-a ]pyrimidin-7 -one (354), was obtained, but
it was accompanied by the uncyclized product (355) and a 1 : 2 adduct (356) (75JHC675).
(351) (352)
C0 2 Et C0 2 Et
F F
()NH 2 IIC=CCO,E', tT O + t NH t N
Sc R Se Se '-co Et
(353) (354) (355) (356) 2
In contrast, 2-amino-5-ethyl-l,3,4-selenadiazole (357) and ethyl propiolate gave the
ring-closed product 2-ethyl-7 H- [1,3,4 ]selenadiazolo[3,2-a]pyrimidin-7 -one (358) together
with 2- or 3-ethoxycarbonyl-5H-selenazolo[3,2-a ]pyrirnidin-5-one (359), apparently
formed as the major product in a ring opening-ring closure sequence (75JHC67S). With
DMAD (357) gave (360) as the principal product. Amino-1,3,4-oxadiazoles (Chapter 4.23
and 4.29) form analogous products as do the 1,3,4-thiadiazoles (Chapter 4.29).
se :J N 0 sey :) N
Et\ I + i I
wN A-N
Et0 2 C
o
CX; NH 2
-;:? I '\:N
::::,.., d
(350)
Se N 0
,/ :J MeO,CC=CCO,Me
Et I .
N_N
C0 2 Me
(360)
Q-r N .;;;N 0
HC=CCO,Me, j ::'/") + ["'1
O_N O_N
o
N-N _
II \\ HC=CCO,Et.
Et"-. /NH 2
Se
(357)
(358)
(359)
Synthesis of Five-membered Rings with Two or More Heteroatorns 143
4.03.6 RING FORMATION VIA CYCLOADDITION REACTIONS
4.03.6.1 1,3-Dipolar Cycloadditions
A versatile rnethod for the synthesis of a variety of five-membered heterocycles and their
ring-fused analogs involves the reaction of a neutral 47T-electron-3-atorn systern with a
27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available
evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity
exerting only a rnoderate influence on the reaction, indicates that the cycloaddition proceeds
via a concerted rnechanism (63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in
general terms by the expression in Scheme 8.
+ /b,_
a c
+ --
d=e
/b,
a c
\ /
d-e
Scheme 8 A 1,3-dipolar cycloaddition reaction
Table 2 illustrates 1,3-dipoles with a double bond and with internal octet stabilization,
commonly referred to as the propargyl-allenyl anion type. These are all reactive dipoles
and a large number of five-membered heterocycles can be constructed from these readily
available dipoles, especially when the dipolarophile is varied to include heterocumulenes, etc.
Table 2 1,3-Dipoles with a Double Bond and Internal Octet Stabilization; Propargyl-allenyl Anion Type
å=b-ë ++ a=:b-ë
i i
- + - +
a=b-c ++ a=b=c
Sextet Octet
structures structures
+ -/ + -/ /
Nitrile ylide -C=N-C ++ -C=:N-C in situ from -C=N-CH
, , tl '
+ - +
Nitrile imine -C=N-N- ++ -C=:N-N- in situ from -C=N-NH-
I
Cl
+ - + -
Nitrile oxide -C=N-O ++ -C=:N-O in situ from -C=NOH
I
Cl
+ - +
Nitrile sulfide -C=N -S ++ -C=:N-S Thermal fragmentation of an
oxathiazolone
Diazoalkane ,+ - , + - Usually stable
C-N=N ++ C=N=N
/ /
+ - + -
Azide -N-N=N ++ -N=N=N Usually stable
+ - + -
Nitrous oxide -N=N-O ++ -N=:N-O Stable
1,3-Dipoles without a double bond but with internal octet stabilization, referred to as
the allyl anion type, are shown in Table 3. A third group, 1,3-dipoles without octet
stabilization such as vinyl carbenes, irninonitrenes, etc., is known, but these are all highly
reactive interrnediates with only transient existence. Reference is made to this type where
appropriate and in Table 4 (p. 146).
Dipolarophiles utilized in these cycloadditions leading to five-membered heterocycles
contain either double or triple bonds between two carbon atoms, a carbon atom and a
heteroatorn, or two heteroatorns. These are shown in Scheme 9 listed in approximate order
of decreasing activity from left to right. Small rings containing a double bond (either C=C
or C=N) are also effective dipolarophiles, but these result in six- and seven-rnernbered
ring systerns.
144 Synthesis of Five-membered Rings with Two or More Heteroatorns
Table 3 1,3-Dipoles Without a Double Bond but With Internal Octet Stabilization; Allyl Anion Type
Azomethine ylide
Azomethine imine
Nitrone
Azimine
Azoxy compound
Nitro compound
Nitroso imine
Nitroso oxide
Carbonyl ylide
Carbonyl oxide
Carbonyl imine
Ozone
Thiocarbonyl ylide
Selenocarbonyl ylide
b
+/ ".-
a c
i
b
-/ ".+
a c
Sextet
structures
I
N
+/ ".-
-C C-
I I
I
N
+/ ".-
-C N-
I
+
-/ ,
-C 0
I I
N
+/ ".-
-N N-
I
N
+/ ".-
-N 0
I
N
+/ ".-
o 0
o
+/ ".-
-N N-
O
+/ ".-
-N 0
o
+/ ".-
-C C-
I I
o
+/ ".-
-C 0
I
o
+/ ".-
-C N-
I
o
+/ ".-
o 0
S
+/ ".-
-C C-
I I
Se
+/ ".-
-C C-
I I
#
+
b
/ ".-
a c
i
+
#
b
-/ ,
a c
Octet
structures
#
+
/ ".-
-C C- in situ from
I I
I X-
N+
". / ,
-C C- or aziridines
I I
H
.-.
+
/ ".-
-C N - in situ from
I
I X-
N+
/".
-C NH-
I
#
+
/ "...
-C 0 Stable
I I
N+
/ ".-
-N N- From heterocycles
+
/ ".-
-N 0 Stable
+
/ "...
o 0 Stable
0+
/ ".-
-N N-
0+
/ ".-
-N 0
0+
/ ".-
-C C- From oxiranes or heterocycles
I I
0+
/ ".
-C 0 From carbene + O 2
I
#
#
#
#
#
#
#
#
0+
/ ".-
-C N-
I
0+
/ ".-
o 0 Stable
S+
/ "..
-C C- From heterocycles
I I
Se+
/ ".-
-C C- From heterocycles
I I
#
#
#
Several five-rnernbered ring systerns readily available by 1,3-dipolar cycloadditions are
shown in Scherne 10. The dotted line indicates how the systern was constructed, the line
bisecting the two new bonds being forrned in the cycloaddition. The rnajority of chapters
in these vol urnes rnake sorne reference to 1,3-dipolar cycloadditions.
Synthesis of Five-membered Rings with Two or More Heteroatorns 145
Alkynic dipolarophiles
NCC=CCN, CF 3 C=CCF 3 , ROzCC==:CCOzR, benzyne, R1COC=CCOR, HC=CCOzR, R 2 C=CCO z R,
RZC=CR z , RZC=CH (R = Me, Et; R 1 = alkyl, aryl; R Z = aryl, heteroaryl)
Alkenic dipolarophiles
o
o
NR
o
R=Me, Et, Ph
CHz=CHCN, CHz=CHCOMe, CHz=CHCOzEt, CHz=CMeCOzMe, EtOzCN=NCOzEt, PhCH=CHNO z ,
PhCCI=CHNO z , PhCH=CH z , PhCH=CHPh
Heterocumulenes
R1CONCO, R1CONCS, RNCO, RNCS
R I = aryl, CCI 3 ; R = alkyl, aryl
N
tr
Imidazoles
>(;+.
Pyrazolines
, I
N'N
AN
I
"N
/, 'N
\\'v
N,
/ "
I
"N
(-. 'w-
N
1,2,4- Triazolines
\O,
, N
\ /,
-20, --
AI-
Isoxazoli nes
NC H
H 1 CN
Me0 2 C H
1
H C01Me
Scheme 9 Frequently used dipolarophiles
---N'XfrO ---N'XfrS
\ / N \ iN
--r;;; " \T "
Imidazolidines
I
): "'N,
" NH
, I
-';"N
\ '
" N
.. /,
" N
' 'N--
" I
-';"N
1,2,3- Triazoles
I
"N
xY" N
N'" II
/\\
X=O,S,NR
o .'
-ç)'ìr
.J-N
Oxazoles
-*O,
%f---
Isoxazolidines
o
X ':f
--PN
Oxazolines
>iM \ s,
" N
... I.
Isothiazolines
I
r
"' '
, N
" II
" N
1,2,3- Triazolines
I
',N
iJ
I
t-
NR
Pyrazolidines
I
'N
X '
\', N--
N' + ,
I ..
X=O,S,NR
1,2,4- Triazolidines
o
(
Oxazolidines
O
M N
H C01Me
1
H C0 2 Me
--
Pyrazoles
I
i-
o
, I
",N'N
'<\ II
N";-\
1 ,2,4- Triazoles
I
" N
)(.. 'N--
N.... I
IV
I
"N
-..,/., 'N
\\ \ II
N",:N
Tetrazoles
Isoxazoles
"0
i'V<
0r. 0 ,
/\ \ N
N,
/ ..
1,2,4-0xadiazolines
iÇ( \ s,
I" N
II \ /,
1,2,4-0xadiazoles
\ S,
--(.... Ir
N-'.;-\
1,2,4- Thiadiazoles
Isothiazoles
Scheme 10 Some five-membered ring systems available by 1,3-dipolar cycloadditions
146 Synthesis of Five-membered Rings with Two or More Heteroatorns
Table 4
1,3-Dipoles Without Octet Stabilization
Ketocarbenes
I I
C c
+/ ".- ../ '\.
-C C- -C C-
I I
I I
C C
-/ ".- ../ '\.
-C N- -C N-
I I
C c
+/ ". - ../ '\.
-c 0 -C 0
Vinylcarbenes
lminocarbenes
Vinylnitrenes
I
C
+/ ".-
N C-
I
I
C
.. / '\.
N C-
I
lminonitrenes
I
C
+/ ".-
N N-
I
C
+/ ".-
N 0
I
C
.. / '\.
N N-
I
C
.. / '\.
N 0
Ketonitrenes
These are all highly reactive intermediates with only transient
existence
4.03.6.1.1 IKonocyclic systems with two or more heteroatoms
(i) Generation of the 1,3-dipole from alicyclic precursors
Nitrilirnines (361) are generally generated in situ frorn hydrazonyl halides by dehy-
drohalogenation with an organic base such as Et3N. Trapping with alkynic dipolarophiles
leads readily to 3,4,5-trisubstituted pyrazoles (362) and with activated nitrUes 1,3,5-trisub-
stituted 1,2,4-triazoles (362a) result. Applications to the synthesis of pyrazoles and 1,2,4-
triazoles are discussed in Chapters 4.04 and 4.12, respectively. A wide variety of exarnples
of this type of reaction utilizing nitrile ylides, nitrile oxides, diazoalkanes, azides, azornethine
ylides, azornethine irnines and related 1,3-dipoles generated frorn alicyclic precursors are
described in the various rnonograph chapters.
R' R
R 3 CN
N/
T l R'C=Y R'
RC=NNHR' RC=NÑR' (362)
(361) R'C R
N\\
Rd( N
N/
R'
(362a)
(ii) Generation of the 1,3-dipole by thermal elimination of nitrogen
Generation of a 1,3-dipole in this rnanner rnay be expressed in general terrns as shown
in Scherne 11. Nitrilirnines, thiocarbonyl ylides and carbonyl ylides rnay all be generated
in this fashion frorn the appropriate heterocycle and trapped by the dipolarophUe.
/Y, +
X 4 'lY,- +-+ +/Y,- +N 2 t
N=N X Z X Z
Scheme 11 Generation of a 1,3-dipole by thermal elimination of nitrogen
(a) Tetrazoles -. nitrilimines (61CB2S03, 76T261S). 2,5-Diphenyltetrazole (363) on heating
at 160 0 C gives the diphenylnitrilirnine (364) which can undergo cycloaddition to alkynes,
Synthesis of Five-membered Rings with Two or More Heteroatoms 147
alkenes, irnines and nitriles. With a nitrile the 1,2,4-triazole (365) was obtained. This general
reaction adds irnportance to tetrazoles as synthetic precursors, and it is described fully in
Chapter 4.13. Intrarnolecular reactions of this type leading to ring-fused systerns are
described in Section 4.03.6.1.2.
Ph N
f/ I'
N N
'N/
Ph
(363)
IWC, N 2 t + PhC:::=NÑPh
RCN
-----+
N Ph
Phl!....
N'"
Ph
(365)
(364)
Ph 2 C
R 2 r o R 4
.
R1 S R 3
(369)
(b) ..1 3 -1,3,4- Thiadiazolines thiocarbonyl ylides (72JOC4045, 73JOC844). Therrnolysis of
the 2,5-dialkyl-6?-1,3,4-thiadiazoline (366) in a hydrocarbon solvent in the presence of
diethyl azodicarboxylate (excess) gave the thiadiazolidine (368) in good yield. When the
pyrolysis was carried out in the presence of diphenylketene (equirnolar arnount), the
trans- 2,4-disubstituted 5-diphenylrnethylene-1,3-oxathiolane (369) was obtained indicating
that the trans-thiocarbonyl ylide (367) added suprafacially in a 1,3-rnanner over the carbonyl
function of diphenylketene.
R1 N=N R 3
'1.....)(
R2 S R 4
(366)
t>
R 1 S R 3
)()(
R 2 N-N R 4
/ "-
Et0 2 CN=NC0 2 Et./' EtO]C C0 2 Et
, /' (368)
R 2 S R 4
yy
R 1 R 3
(367) Ph2C=C=
(Ui) Generation of the 1,3-dipole by thermal elimination of carbon dioxide (78JOC3736)
5-Phenyl-l,3,4-oxathiazol-2-one (370), prepared frorn prirnary arnides and tri-
chlorornethanesulfenyl chloride, undergoes a ready therrnal elirnination of carbon dioxide
with the forrnation of the nitrile sulfide ylide (371). This can be trapped by a wide variety
of unsaturated dipolarophiles, and with an alkyne provides a ready route to isothiazoles
(372) (see Chapter 4.17). Applications to 1,2,4-thiadiazole synthesis are described in
Chapter 4.25. Therrnolysis of 1,3,4-oxadiazolin-5-ones (500 oC/10- 2 rnrnHg) results in the
loss of CO 2 and generation of the corresponding nitrilirnine (78JOC2037).
o E R
Ph\\, yO [RC:::=ÑS-] EC='CE, ECN
N-S S'"
(370) (371) (372)
E = C0 2 Me
4.03.6.1.2 Ring-fused systems
Cycloadditions resulting in ring-fused systerns rnay be classified in two principal groups:
intrarnolecular and interrnolecular cycloadditions. As the synthesis of the requisite precursor
for an intrarnolecular cycloaddition is often rnore involved, rnore ernphasis has been placed
on those of an interrnolecular nature.
(i) Intramolecular 1,3-dipolar cycloadditions
The synthetic strategy in this reaction class is the fabrication of a precursor in which the
1,3-dipole rnoiety is separated frorn the unsaturated linkage by a suitable chain of sufficient
length and flexibility for the reaction centers to adopt an appropriate conforrnation for
orbital overlap to occur with subsequent bond forrnation. It is expressed in general terrns
in Scheme 12. This concept of intrarnolecular 1,3-dipolar cycloaddition has been extended
148 Synthesis of Five-membered Rings with Two or More Heteroatorns
to include nitrones, azides, nitrilc oxides, nitrilimines and azornethine irnines, and in rnany
instances the cycloaddition results in products accessible only with difficulty by other rneans.
d ..... X e__ d .....X
e=, I ,
Y --+a I Y
a'b...... -Z' \b......c-Z '
Scheme 12 Intramolecular 1,3-dipolar cycloaddition
The reaction is illustrated by the intrarnolecular cycloaddition of the nitrilirnine (374) with
the alkenic double bond separated frorn the dipole by three rnethylene units. The nitrilimine
(374) was generated photochernically from the corresponding tetrazole (373) and the
pyrrolidino[1,2-b ]pyrazoline (375) was obtained in high yield (82JOC4256). Applications of
a variety of these reactions will be found in Chapter 4.36. Other aspects of intrarnolecular
1,3-dipolar cycloadditions leading to cornplex, fused systerns, especially when the 1,3-dipole
and the dipolarophile are substituted into a benzene ring in the ortho positions, have been
described (76AG(E)123).
N-N(CH z )3 CH =CH z + _ / N
Arl( N ArC=N-N-(CH z )3 CH =CH z --+ \.-......l-ÌAr
N
(373) (374) (375)
Ui) Intermolecular 1,3-dipolar cycloadditions
Forrnation of ring-fused systerns by reactions of this type can be achieved in two ways:
in one the heterocycle to which ring annul at ion is to occur acts as the dipolarophile; the
alternative rnode utilizes incorporation of the 1,3-dipole into the heterocyclic ring for
reaction with the dipolarophile. Both approaches have been investigated intensively.
2,3-Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give
furo[2,3-d]isoxazoles (378) and furo[3,4-d]isoxazoles (379), respectively, as cycloadducts.
The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is
generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-rnethyl-2-
oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions
are discussed in Chapter 4.36.
O:(;N
Ph
(379)
Q +-
-- PhC=N-O
13771
o 0 0
o CO
;,;N
Ph
(378)
CCN
o Ph
(380)
0,0,
N .....j'N
Ph
(381)
In the alternative approach .the 1,3-dipolar systern can be constructed in several ways.
Treatrnent of a:-chloroacylhydrazones of diary I ketones and certain aralkyl and dialkyl
ketones (382) with NaH in anhydrous THF gives l-(disubstituted rnethylene)-3-oxo-l,2-
diazetidiniurn inner salts (383). Reaction of (383) with DMAD in rnethylene chloride gave
(384), a 2: 1 adduct with loss of CO. Double bond migration in (384) occurred on heating
to give (385). The interrnediate in the cycloaddition was found to be (386), which on heating
lost CO to forrn a new ylide systern which in turn underwent reaction with rnore DMAD
(8IJA7743).
Ph
Ph
NaH Me Ñ r Ph Me N )
PhzC=NNHCOCHMeCI -- J= - --+ J= N J E
o 0 E
(383) (386)
-co/"
Me Ph 2 Me Ph 2 ,/'
E(ZJE E(ZJE
E E E E
(385) (384)
(382)
E=COzMe
Synthesis of Five-membered Rings with Two or More Heteroatoms 149
As the Sp2 nitrogen atorn in rnany heterocycles can be alkylated and arninated, the
construction of an azornethine ylide or azornethine irnine dipole is readily attainable as
shown in Scherne 13. These ylides are very reactive and undergo cycloaddition with a
{ n
N+
./ 'CH R
2
X-
H R 1
{)+ _ - { )+ _ { ./t\Rl
'CHR ./ 'CHR ,N'f
H R
R '
{ Y\RI
./NJ
R
/'
{)
{ n
N+
./ 'NH
X- 2
H R 1
{ )+ _ { 'X { nRl
./ ,- ./ , - ./ .....NH
NH NH .
R 1
{ Y)Rl
./N'N
Scheme 13 Azomethine ylides and azomethine imines incorporated in heterocyclic systems
variety of alkynic dipolarophiles. Oxidation of the intermediate dihydro product to the
aromatic systern usually occurs during the reaction work-up. The reaction is illustrated by
the conversion of pyridine into its pyridinium salt (387) with hydroxylarnine O-sulfonic
acid. Treatrnent with base generated the ylide (388) which underwent cycloaddition with
DMAD to give as the final product the pyrazolo[1,5-a ]pyridine (389). These reactions have
been applied to a variety of azines and are described in Chapter 4.15.
0 "":: O "":: O ""::
+ h DMF + h +
N 1- N N
I I I
NH 2 -NH -NH
(387) (388)
Oj C0 2 Me
MeO,CC=CCO,Me , M
N,'l CO 2 e
:::::,.. 'N
(389)
However, depending on the nature of the initial heterocycle, rearrangernents are possible.
Alkylation of thiazole to forrn the thiazoliurn salt (390) and generation of the ylide (391)
with triethylarnine in the presence of DMAD gave not (392) but the isorneric product (393)
by the rearrangement indicated (76JOC187). Rearrangernents of these types are described
in Chapters 4.07 and 4.19.
( S d X- S
I Et 3 N C "
\ + \ 1/_
\\ NCH COR 1 ----"--+ \\ +NCHCOR 1
R 2 R
R'C=CR'
---
(N:;4R'
RICO H
(392)
---+
R 2
Q R10H
R N # R 2
l s _jOR l ---+R 2 Ù......)
R
(393)
(390)
(391)
4.03.6.1.3 Cycloadditions using rnesoionic ring systems
Use of rnesoionic ring systerns for the synthesis of five-rnernbered heterocycles with two
or rnore heteroatorns is relatively restricted because of the few readily accessible systerns
containing two heteroatorns in the 1,3-dipole. They are particularly suited for the unarn-
biguous synthesis of pyrazoles as the azornethine irnine is contained as a 'rnasked' 1,3-dipole
in the sydnone systern. An attractive feature of their use is that the precursor to the
rnesoionic systern rnay be used in the presence of the cyclodehydration agent and the
dipolarophile, avoiding the necessity for isolating the rnesoionic systern.
Reaction of the N-nitrosoglycine (394) with acetic anhydride gave the anhydro-5-
hydroxy-l,2,3-oxadiazoliurn hydroxide (395). Reaction with DMAD resulted in forrnation
of the interrnediate1: 1 cycloadduct (396) which was not isolated and which lost CO 2 under
the therrnal reaction conditions to give dimethyl1-phenylpyrazole-3,4-dicarboxylate (397)
(83MI40300). This reaction is capable of considerable variation in terrns of the substituents
150 Synthesis of Five-membered Rings with Two or More Heteroatorns
attached to the 1,2,3-oxadiazole ring and in the nature of the dipolarophile, especially as
alkenic dipolarophiles rnay also be utilized (see Chapter 4.21).
+ NPh
NPh 0 vl
Ph7CH2C02H AC20 Þ- O ) ---+ C02Me
NO 0 0 C0 2 Me
(394)
(395)
(396)
Me0 2 C C0 2 Me
-co, Þ CN
N/
Ph
(397)
A similar product is obtained from the reaction of anhydro-4( 5 )-hydroxy-1 ,2,3 - triazolium
hydroxide (398). In this case reaction with DMAD occurred in 1 hour in boiling benzene.
Extrusion of rnethyl isocyanate frorn the initial 1: 1 cyc10adduct (399) occurred during the
reaction giving (400).
Me
/
NMe 0 N 1 ) Me02C C0 2 Me
- r- IN ---+ rN I C0 2 Me ---+ n N
o / N.... II )
Me Me C0 2 Me e
(398) (399) (400)
Thiocarbonylirnines are present as the 'masked' 1,3-dipole in the anhydro-5-hydroxy-
1,3,2-oxathiazolyliurn hydroxide systern (402) which rnay be prepared by the cyc1odehydra-
tion of S-nitroso-a:-phenyl-a:-rnercaptoacetic acid (401). Under therrnal conditions reaction
with DMAD occurred to give an interrnediate1: 1 cycloadduct (403) which lost CO 2 under
these reaction conditions forrning dirnethyl 2-phenylisothiazole-3,4-dicarboxylate (404)
(nCB 196). In the cycloaddition of ethyl propiolate the addition was not regiospecific, the
4-ester being obtained in greater arnount (56%). However, under photochernical conditions
an isorneric product was obtained via the interrnediacy of the nitrile sulfide dipole. Irradi-
ation in neat DMAD has been postulated to result in forrnation of the valence tautorner
(405) which lost CO 2 to give the thiazirene (406) which underwent rearrangernent to the
nitrile sulfide dipole (371). Reaction with DMAD led to dirnethyl 3-phenylisothiazole-4,5-
dicarboxylate (372) (72CBI88, 75JA6197) (see also Chapter 4.17).
PhCHC0 2 H
I
SNO
(401)
Ph S+
---+ JC II
_ 0 N
0/
o I h Me02C C01Me
---+ -.JC02Me -co 2 Þ PhCN
o C0 2 Me S
(403) (404)
(402)
lhV
Ph S S, + _
"N ---+ Ph!:::;N ---+ PhC=N-S ---+
O O
(405) (406) (371)
Me0 2 C Ph
0 ,
Me02C N
S....
(372)
Use of rnesoionic systerns in the synthesis of [5,5] ring-fused systerns has received little
attention. However, they are useful for the synthesis of [5,6] ring-fused systerns where the
six-mernbered ring is constructed via the dipolar cycloaddition process. Annulation of a
pyridone ring to the irnidazole, 1,2,4-triazole (79JOC3803), thiazole and 1,3,4-thiadiazole
ring systerns (79JOC3803) has been achieved via cycloadditions with the appropriate bicyclic
mesoionic ring systern.
Anhydro-3-hydroxy-2-phenylthiazolo[2,3-b ]thiazolyliurn hydroxide (407) underwent
ready therrnal reaction with alkynic and alkenic dipolarophiles in refluxing toluene. With
the former dipolarophile sulfur was lost frorn the interrnediate1: 1 cyc10adduct (408) to
give the substituted 5H-thiazolo[3,2-a ]pyridin-5-ones (409). With the latter, the interrnedi-
ate (410) lost H 2 S, also forrning (409).
Synthesis of Five-membered Rings with Two or More Heteroatoms 151
s S
)-T-(Ph
o
(407)
R lC=CR 1
I
S Ph R'
/);Rl-4 /- X) IR'
N \-N Ph
I SRI R
R 0
(408) (409)
"R'CH=CHR'
/-H 2 S
O s PhR!
J: H
N R'
RVH
(410)
4.03.6.2 l,4-Dipolar Cycloadditions
Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-rnernbered
rings. Their principal use in five-rnernbered heterocycles is for ring annulations giving [5,6]
ring-fused systerns.
Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangernents
which may be encountered. Thiazole or 2-rnethylthiazole (411; R=H and Me, respectively)
in DMF reacted with DMAD to give an initial l,4-dipolar species (412). Reaction with a
second DMAD gave the 1: 2 rnolar adduct, presurnably (413). Ring opening to (414),
followed by cyclization in the alternative rnode, resulted in the forrnation of (415), the
structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also
Chapter 4.19).
S S S E S ESE E
( j;R ( j;R I - E __ ( R O E __ ( E
N +N \-tI ,9 E t-- ,9 E '\.--N E
. E E R
E E
(411) (412) (413) (414) (415) E=C0 2 Me
Solvent has an irnportant influence on the course of this cycloaddition, and in the reaction
of 2,5-dimethylthiazole with DMAD in DMF the product analogous to (415) was obtained.
However, in DMSO or acetonitrile a thiazolo[3,2-a ]azepine was forrned in addition to this
product, whereas with THF, dichlorornethane or nitromethane, only the thiazoloazepine
was isolated.
l,4-Dipoles can also be built into heterocyclic systerns, and though of lirnited use, they
may also be utilized for the synthesis of [5,6] ring-fused systerns. Reaction of 2(3H)-
benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave
the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic
pyridinone (418) was obtained, presurnably by elirnination of cas frorn the interrnediate
cycloadduct (417) (80JOC2474).
(416)
o
O Ph E
J:: E 6 s ,E
N II 'N Ph
h SE '/
o 0
(417) (418)
6 sySyo-
f , yPh
- 0
Ethyl propiolate reacted with (416) in boiling benzene giving ethyll-oxo-2-phenyl-1H-
pyrido[2, 1-b ]benzothiazole-4-carboxylate in 83 % yield, and no trace of the other possible
isorner was found.
152 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.6.3 1,5-DipoIar Cycloadditions
The concept of a 1,5-dipolar cyclization gives rise to a general rnethod for the synthesis
of an appreciable nurnber of heterocyclic systerns. 1,5-Dipoles are derived frorn 1,3-dipoles
by conjugation with different double bond systerns, and it is possible to derive 98 theoretically
possible 1,5-dipolar systerns. The general expression for a 1,5-dipole and sorne possible
combinations of double bond systerns are shown in Scherne 14.
Octet structure
Sextet structure
.,...... .... + .. .. +
ã-b=c-d=e ++ ã-b=c-d=e ++ a=b-c-d=e
+ .. - ....., "-
a=b=c-d=e ++ a-b=c-d=e
Ib -a -:;::-b.....
c ;) ---'" c a
+....-- \ /
'd.,::;e d=e
Possible combinations for d=e
/ /
/C=C< /C=N-, /C=O, /C=S, -N=C< -N=N-, -N=O
Scheme 14 1,5-Dipoles
1,5-Dipolar cyclizations leading to rnonocyclic and ring-fused systerns are known. The
2,5-disubstituted tetrazole (419; X=O, S, N-) on heating underwent ring opening to the
1,5-dipolar species (420) which readily lost N 2 to give the conjugated nitrilirnine (421).
1,5-Dipolar cyclization of (421) through X leads to oxadiazoles, thiadiazoles and triazoles
{70CB1918. 65CB2966) (see also Chapter 4.13).
XPh Ph
,." + I - N + - +
\ IN + .). N=N-C=N-NCXPh =-4 PhC=N-NCXPh ..... PhC=N-N=?Ph ...
N Ph X-
(419) (420) (421)
X
Ph\\" JPh
N-N
(422)
X=O,S,N-
The thermal conversion of I-substituted 5-aminotetrazole (423) into a 5-substituted
arninotetrazole (424) can be rationalized by a sirnilar 1,5-dipolar cyclization.
R
N
H 2 N\\" ):
N-N
(423)
NH 2
+ /
N=NN=C
'--
NHR
---'"
....--
NH NH
+ - RNHc"" 'N
N=N-N-C -+ \\ II
'- N-N
NHR (424)
Reaction of l-chloroisoquinoline with 5-phenyltetrazole gave 3-
phenyl[1,2,4]triazolo[3,4-a]isoquinoline (428). It has been suggested that the initial 2-
tetrazolylisoquinoline (425) underwent ring opening to (426) which readily lost N 2 giving
(427). This nitrilirnine is a 1,5-dipole, and on cyclization the [1,2,4]triazolo[3,4-a]isoquino-
line (428) is forrned {70CB1918).
Ph N
II II PhC + .,:::-
N N "::N, IY N
'N/ N
N rrN
VV VV
(425) (426)
-N 2
-+
Ñ"éCPh
\N
CÒ
(427)
N-N
oj )Ph
?" I N
#
(428)
The reaction of l-aminopyridiniurn iodide (429) with dirnethyl chlorofurnarate in
ethanol/K 2 C0 3 to forrn, ultirnately, a pyrazolo[I,5-a]pyridine also occurs via a 1,5-dipolar
rnechanisrn. The initially forrned 1: 1 adduct (430), stabilized by delocalization of the
negative charge, underwent disrotatory ring closure as shown to give (431) in which the 3
Synthesis of Five-membered Rings with Two or More Heteroatoms 153
and 3a hydrogens are cis to each other. Pd dehydrogenation gave dirnethyl pyrazolo[1,5-
a ]pyridine-2,3-dicarboxylate (432) (nJOC3106). This reaction also occurs with the corres-
ponding alkylated pyridiniurn salt (73JCS(P1)2089).
O CI )[ cozMe
I ,- + I K,CO..
+ó M 0 C EtOH
Nez H
I
NHz
(429)
a MeozC 1 H
k I
+ 'Ñ COzMe
(430)
I
J6 0 zMe a _(COzMe
N""ÑAcozMe +--+ ""N'AcozMe
l
H
d) H ....COzMe
fi COzMe
N'N
( 431)
W cozMe
Pd c:::? ::0-
-- fi COzMe
N'N
(432)
4.03.7 HETEROCYCLIC RING INTERCONVERSIONS
4.03.7.1 Small Rings as Dieitophiles or Dipolarophiles
Srnall unsaturated rings are usually very reactive undergoing ring opening in a number
of ways, and this characteristic has been utilized in heterocyclic synthesis. In their role as
dienophiles or dipolarophiles, the initial cycloaddition is usiIally followed by a valence
tautornerisrn resulting in a six-rnernbered or larger ring systern. Several exarnples exist,
however, where this does not occur, and these are described below.
The therrnal reaction of 2-phenyl-1-azirine (433) with carbon disulfide (sealed tube,
100 o C, 3 hours) gave 2-rnethylthio-5-phenylthiazole (435). It has been suggested that this
reaction occurred via a regioselective cycloaddition of carbon disulfide to the 7T-bond of
the 1-azirine by either a concerted [.".2 s + .".2a] or stepwise rnechanisrn to give the interrnediate
(434). Ring opening and hydrogen shift would result in (435) (75JOC1348). Sirnilar results
were obtained with 3-rnethyl-2-phenylazirine.
S S
Iþ s-f -+ Ph()Me
Ph Ph N N
Ph
(433) (437) (435)
A similar regiospecific [2 + 2] cycloaddition across a C=S group occurred when benzoyl
isothiocyanate (436) and 2,3-diphenyl-1-azirine were heated in refluxing benzene for 12
hours. The product obtained was shown to be (438) and an interrnediate such as (437)
could also be involved in this cycloaddition (74JOC3763). In contrast, thiobenzoyl isocyanate
added in a [4 + 2] fashion, and after ring expansion gave a thiadiazepine derivative.
N NCOPh (.'S"
PhCON=C=S + þPh -+ sf -+ Ph L //NHCOPh
Ph Ph N Ph N
(436) Ph (437) (438)
Although in its reactions with several rnesoionic systerns diphenylthiirene dioxide (439)
does not lose S02 frorn the cycloadducts, in its reactions with pyridiniurn, quinoliniurn and
isoquinoliniurn phenacylides it behaves as an acetylene equivalent. Thus, reaction of (439)
154 Synthesis of Five-membered Rings with Two or More Heteroatorns
with the pyridinium phenacylide (440) gave the indolizine (441) with elimination of S02
and loss of hydrogen (73BCJ667).
Ph
S02 0 W =--
Phbàph + I + ---+ N /, Ph + S02 + H 2
N,_ //
CHCOPh COPh
(439) (440) (441)
4.03.7.2 Small Rings as a Source of Ylides
Photolysis of 2,3-diphenyl-Ll 1 -azirine (442) generates benzonitrile ylide (443). Irradiation
in the presence of ethyl cyanoformate resulted in a mixture of the oxazoline (444) and the
imidazole (445) by 1,3-dipolar cycloaddition to the carbonyl and nitrile group, respectively
(72HCA919).
N N 0 Ph N
Ph Ph "'v'H Ph-=.r -....v H EtO CN EtO ?( O", 1/ )
Ph<í! I +-+ I >> lh + Et02C _, Ph
N Ph Ph NC -N
Ph H
(442) (443) (444) (445)
Azomethine ylides (Section 4.03.6.1.1) have been generated from a wide variety of
aziridines using both thermal and photochemical methods. With carbon-carbon unsaturated
dipolarophiles, pyrrolines or pyrrolidines are obtained. With hetero double bonds, however,
ring systems of interest to this discussion result.
Thermolysis of the aziridine (446) in the presence of diphenylketene gave a rnixture of
the pyrrolidone (447; rninor product) and the oxazolidine (448; major product). In this
instance the preferential addition to the C=O bond is explained in terrns of steric effects
(72CC199). Similar addition to diphenylacetaldehyde takes place with the sarne orientation
and the oxazolidine (448a) was obtained. When the reaction of the aziridine with the
aldehyde )Vas carried out in the presence of hydrogen selenide a selenazolidine was obtained
(72BSB29S).
Ph
N
PhÖ(CO,Meh
112'C
Ph
+ N ' Ph,C=C=O
>>
,/' ".-
PhCH C(C0 2 Me)2
Ph 2 ) 0 0
C Ph,C"{'-)Ph
Ph (CO,Meh + L NPh
h (Me0 2 Ch
(447) (448)
(446)
o
Ph,CHC)Ph
(Me0 2 Ch NPh
(448a)
These therrnal or photochemical ring openings of aziridines when applied to ring-fused
aziridines generate ylides which may be trapped, leading to structures of considerable
interest which are difficult to obtain by other means. As an illustration in five-membered
ring chemistry, the ring-fused aziridine (449) underwent ring opening in refluxing xylene
to the azomethine ylide (450). In the presence of diethyl acetylenedicarboxylate the
3H-pyrrolo[1,2-c ]irnidazole (451) waS- obtained. With maleic anhydride the ylide was
equally readily trapped giving the 1: 1 cycloadduct (452) (68JOCI097). Similar adducts are
forrned with diethyl fumarate, cis or trans-dibenzoylethylene, diethyl azodicarboxylate and
N-phenylrnaleimide.
o
H h
o N
H N ...,J
R Me,
G:
o
Ph - Ph
R .i n
N N ---+ + r N N
"'-/ "'-/
Me 2 R Me 2
EtO,CC=CCO,Et
(452)
(449)
(450)
R = P-N0 2 C 6 H 4
EtO
Et0 2 C'\--N...,JN
R Me 2
(451)
Synthesis of Five-membered Rings with Two or More Heteroatoms 155
4.03.7.3 Small Rings As Substrates for Ring-opening Reactions
4.03.7.3.1 Three-membered rings
Three-membered rings, especially oxiranes and aziridines, are susceptible to nucleophilic
ring opening and form five-membered rings with a variety of nucleophiles. Chloromethyl-
oxirane (453) and a hydrazine derivative at -25 oC readily gave the 4-hydroxypyrazolidine
(454). A variety of nucleophiles is effective in ring opening and the reaction has been
adapted for the synthesis of ring-fused systems. Reaction of the oxazoline (455) with the
oxirane (456) gave the oxazolidino[2,3-b ]oxazolidine (457) (66LA(698)174). Imidazoline and
thiazoline formed the analogous ring-fused systems. Oxiranes containing 1, 1-dicyano
substituents undergo nucleophilic ring opening with ease. Treatment of 1,1-dicyano-2-
phenyloxirane with potassium selenocyanate gave 2-N-acylimino-1,3-oxaselenoles
(78CC447).
-25 0 C
HO
CNR!
N-'
R 1
(454)
R
o 0 0-1...-0
C t + ÖRI -- Ct)R 1
o
Cl CH2 Ö
R1NHNHR 1
,
(453)
(455)
(456)
(457)
Aziridines represented by the general structure (458; X = 0, S, NR) undergo a facile
ring opening and subsequent closure on heating with sodium iodide in acetone or acetonitrile.
For (458; X = 0) the oxazoline (460) was formed, presumably via the intermediate (459)
(66JOC59).
On heating the fused aziridine (461) at temperatures greater than 250 o C, the resultant
product was the furo[3,4-d]oxazole system (462).
R 1
" .......x
CXR I c.- - 0",-
N - x=o, C fjR l
RÖ R R N
I
(458) (459) (460)
H
O NCOR
H
(461)
H
oct>
H
(462)
This aziridine ring-opening reaction is a particularly attractive route to imidazolines and
ring-fused imidazolines. The 1-substituted aziridine (463), prepared from the imino ether
and aziridine, on treatment with iodide ion or thiocyanate ion gave (464) (62JOC2943,
60JOC461). The 2-(1-aziridinyl)quinoxaline (465) under related conditions formed the tricyc-
lic system (466), and (467) with iodide ion underwent two ring-opening reactions to give
initially (468) and then (469).
R
RC=NR' R' (X) 2:1)
_ N
N C:/
Ö
N N V 1#
(463) (464) (465) (466) R=CI, OMe
L\ N6. \)NJ:) r:f)
'c""'"
II r --
N -- 6NO' 6NO'
ON0 2
(467) (468) (469)
156 Synthesis of Five-membered Rings with Two or More Heteroatorns
Aziridines also undergo ring enlargernent when treatrnent with thiocyanic acid. cis- and
trans- 2,3-Dimethylaziridine (470) with thiocyanic acid gave exclusively trans- and cis- 2-
arnino-4,5-dirnethyl-2-thiazoline (471) (72JOC4401).
H
Me N H
H Me
(470)
HSCN
--
Me S
H "dNH2
H"7- N
Me
(471)
4.03.7.3.2 Four-membered rings
Azetidines under analogous reaction conditions to those above result in six-membered
ring forrnation. However, diketene (472), an oxetan-2-one, offers considerable prornise for
five-rnernbered heterocycle formation. With hydroxylamine the 3-methylisoxazolin-5-one
(473) was forrned. Phenylhydrazine gave the corresponding 3-rnethyl-l-phenylpyrazolin-5-
one.
Me
't-9 NH,OH þ N
4 000 /
(472) (473)
4.03.7.4 Interconversion of Five-membered Rings
Interconversion of five-membered heterocycles rnay be effected in numerous ways, and
in general, oxygen in a five-membered ring rnay be readily replaced by sulfur and by
nitrogen. Sirnilarly, sulfur rnay be replaced by nitrogen with an appropriate reagent. Ring
opening with subsequent ring closure is usually involved.
Heating oxazoles with a source of nitrogen leads to imidazoles. Thus, the oxazole (474)
when heated under reflux with formam ide gave the imidazole (475) with a variety of alkyl
and aryl groups substituted in the nucleus. Using a prirnary arnine with the oxazole-4-
carboxylic acid (476) in an aqueous environment at 150 0 C gave the imidazole (477) with
accornpanying decarboxylation (S3CB88, S3CB96, 48JCS1960) (see Chapters 4.07 and 4.18).
H
o N
R 2 ( "R 1 HCONH, R 2(.'" '''R I
1/ .l þ L 1/
R3 N R 3 N
(474) (475)
H
N
( "R ,NH"H,O
1/ lS0'C
N
(477a)
R 1
(d R + R 1 NH 2 H O þ ()R
H0 2 C N
(476) (477)
Isoxazoles (478) in the presence of base undergo ring opening to a-ketonitriles (479).
When the reaction was carried out in the presence of hydrazines, 5-aminopyrazoles (480)
were obtained. The reaction is also a convenient source of irnidazoles. For exarnple, when
the 1,2-benzisoxazole (481) was treated with phenylhydrazine, decarboxylation initially
occurred with subsequent ring closure to (482) (see Chapter 4.16).
o '
RI O N
/, NaOH
R
(478)
[ 0 ] RI 0
R1GN --. r
R - R CN
(479)
R'NHNH, [ RI '-C=NNHR J
þ I --.
/CHCN
R
R 1 R 1
H 2 NCN
2
(480)
R
O\
0--fN
C0 2 H
(481)
R N
PhNHNH, (X) ::;.-- \
þ NPh
::::--
NH 2
(482)
1,2-Dithiolylium salts (483) may be converted into pyrazoles, pyrazoliurn salts and
isothiazoles depending on the type and degree of substitution of the nitrogen source.
Synthesis of Five-membered Rings with Two or More Heteroatoms 157
4-Phenyl-1,2-dithiolyliurn salt (483) with hydrazine, methylhydrazine or phenylhydrazine
yielded the corresponding pyrazole (485) via the intermediates (484a-c). The ring-fused
systern (486) is a convenient source of the ring-fused pyrazole (487) when treated with
hydrazine (see Chapter 4.31).
RNHNH SSH Ph Ph
n+ RNHNH,;+H 1 n -s, -H,S !(J
PhZ_;S Ph(jS - - HSS,;N ------'--+ /N
S S/ Ph CH=NNHR N N
R R
(483) (484a) (484b) (484c) (485)
;---r-S's [O SMe ] _ OC N\
'\.-l0 NHNH 2 ,9
SMe SH
(486) (487)
3,4-Dimethyl-l,2-dithiolylium perchlorate (488) when treated with amrnonia at -5 0 C
underwent nucleophilic ring opening to (489). Subsequent ring closure with loss of H 2 S
gave 4,5-dimethylisothiazole (490) in 85% yield (see Chapter 4.17). This reaction involved
an initial attack of the ammonia at the unsubstituted 3-position. A srnall amount of the
3,4-dimethylisothiazole (491; 15%) indicated that sorne attack of the amrnonia also occurred
at the 5-position.
Me Me Me Me Me Me
MeC NH M MeC 0 [J
"'-S/ S CIO; _50 Þ H S_ SSH- Me /N /N
S'I "'-NH S S
+ C+H
(488) (489) (490) (491)
H
4.03.7.5 Interconversion of Six- and Five-membered Rings
Ring expansion of five- to six-rnernbered rings such as oxazole pyridine derivatives
via a Diels-Alder reaction is a well-established procedure. However, the conversion of a
six-membered heterocycle into a five-membered ring systern has not been exploited to any
great extent, and those systems that have been studied usually involve a cationic species.
pyrylium salts are susceptible to nucleophilic ring opening by attack at the 2-position.
When treated with hydroxylamine, the pyrylium salt (492) underwent ring opening to an
intermediate oxime of a 1,5-enedione (493). Conjugate addition of the oxime group to the
a,ß-unsaturated ketone gave (494) which in the presence of acid gave the isoxazole (495).
A sirnilar reaction with a monosubstituted hydrazine resulted in the pyrazoline (496).
R
0 1 NH,OHþ
R::,... R
9
(492)
R
RaOH
(493)
R
RD H O'
-
/N
RCOCH 2 0
(494)
R
RCN
0/
(495)
R
RCOCH 2 , n
^_jN
R N
R
(496)
1,3-0xazinium salts (497) and hydrazine undergo an analogous reaction giving pyrazoles
(498) (69CB269, 65CB334, 62CB937). 1,3,5-0xadiaziniurn salts (499) reacted with hydroxyl-
arnine to give the 1,2,4-oxadiazoles (500) and with hydrazines to form the 1,2,4-triazole
derivatives (501). The substituents in these cationic species are usually aryl, restricting the
appeal of these ring interconversions (65CB334, 67CB3736).
R R
C Ph N Ph N N N Ph
I; 0 ( NH,OH RNHNH, Ph(
R 0.& R Ph N'N Ph N +----'--- Rl+)R ,
0/ N
+ H 0 R
(497) ( 498) (500) ( 499) (501)
158 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.7.6 Ring Interconversions Involving Side Chains
This type of ring interconversion is represented by the general expression shown in
Scheme 15. Analogous rearrangernents occur in benzo-fused systerns. The known conver-
sions are limited to D = 0 in the azole system, i.e. cleavage of the weak N-O bond occurs
readily. Under the reaction conditions, Z needs to be a good nucleophile in its own right
or by experimental enhancernent (base catalysis, solvent, etc.) and Z is usually 0, S, N or
C.
A X
á ' ì( ''y
'O_N Z'
I
H
(502)
--.
A X
á ' ìí ''y
'0 N....Z'
I
H
(503)
E
if' 6 9 - E \
N N
---,
Ò:l I Þ ë A
Scheme 15 General expression for mononuclear heterocyclic rearrangements
The reaction is illustrated by the conversion of the 1,2,4-oxadiazole oxime (504) into
the 3-acylamino-l,2,5-oxadiazole (505). This irreversible rearrangement occurred on heat-
ing (504) in hydrochloric acid (81AHC(29)141). Isoxazoles also undergo this rearrangernent
and these are discussed in Chapter 4.16.
N H+
R < N I -'-'--+
0"" OH
(504) (505)
Arnong ring-fused systerns, the 3-(0-aminoaryl)benzisoxazole (506) underwent rearrange-
rnent on refluxing in THF with sodiurn hydride or lit hi urn aluminum hydride. In this case
the 3-(0-hydroxyphenyl)benzimidazole (506a) was obtained.
x
H
R'VN 2
II II \\
o N, /N
o
OH
N
I
N
H
1506a)
.J.THF
(506)
Tahle 5 Heterocyclic Rearrangements Involving Side Chains (Mononuclear
Heterocyclic Rearrangements)
lnitial ring Final ring
system (502) ABD XYZ System (503)
1,2,4- Oxadiazole NCO CNO 1,2,5-0xadiazole
Isoxazole CCO CNO 1,2,5-0xadiazole
1,2,5 -Oxadiazole CNO CNO 1,2,5-0xadiazole
1,2,4-0xadiazole NCO NCO 1,2,4-0xadiazole
Isoxazole CCO NCO 1,2,4-0xadiazole
1,2,4-0xadiazole NCO CCO Isoxazole
1,2,5-0xadiazole CNO CCO Isoxazole
1,2,4-0xadiazole NCO CNN 1,2,3- Triazole
Isoxazole CCO CNN 1,2,3- Triazole
1,2,5 -Oxadiazole CNO CNN 1,2,3- Triazole
1,2,4-0xadiazole NCO NCN 1,2,4- Triazole
Isoxazole CCO NCN 1,2,4- Triazole
1,2,5-0xadiazole CNO NCN 1,2,4- Triazole
1,2,4-0xadiazole NCO NCS 1,2,4- Thiadiazole
Isoxazole CCO NCS 1,2,4- Thiadiazole
1,2,5-0xadiazole CNO NCS 1,2,4- Thiadiazole
Isoxazole CCO NNN Tetrazole
1,2,4-0xadiazole NCO NCC Imidazole
1,2,4-0xadiazole NCO CCN Pyrazole
Isoxazole CCO CCN Pyrazole
Synthesis of Five-membered Rings with Two or More Heteroatoms 159
The various combinations of XYZ and ABD in the monocyclic system in Scherne 15
which illustrate the scope of the rearrangement are shown in Table 5.
4.03.8 PHOTOCHEMISTRY IN HETEROCYCLIC SYNTHESIS
4.03.8.1 Elimination Processes
4.03.8.1.1 Loss of nitrogen
A nurnber of five-membered heterocycles undergo ready fragrnentation into a reactive
segment and a stable molecule, a process usually induced by heat or light. Loss of nitrogen
frorn compounds containing an azo function often occurs on photolysis, generating a
1,3-diradical which undergoes ring closure to a third species. The loss of nitrogen from
pyrazolines to form cyclopropanes and from 1,2,3-triazolines to form aziridines are well
established exarnples of this rnethodology.
To form ring systems of the type under discussion in this volume, two heteroatoms must
remain in the reactive fragment. Although 2,5-diphenyltetrazole undergoes photochernical
fragmentation to the 1,3-dipole, diphenylnitrilimine (see Section 4.03.6.1.1(ii)), 1,5-
diphenyltetrazole (507) underwent fragmentation to (508), which by an intrarnolecular
trapping process formed (509) (67JA5958, 67JA5959).
A similar intrarnolecular trapping of the interrnediate (511) frorn the photolysis of the
corresponding methyl tetrazole-l,5-dicarboxylate (510) gave rnethyl 5-methoxy-l,2,4-
oxadiazole-3-carboxylate (512).
N-N
II II hv
Ph"N"N
Ph
( 507)
Ph-\ 0 --. (X I N>Ph
N NH
(508) (509)
N' N C0 2 Me
-';;'2 þ Me0 2 C-{ 0 --. MeO \
0/
OMe
(510) (511) (512)
4-Phenyl-l,2,3-thiadiazole (513) as well as the 5-phenyl isomer (514) both lose N z on
photolysis. The 1,3-dithiole derivative shown was formed from both thiadiazoles
(58LA(614)4).
Me02C[
N/
C0 2 Me
s..... Ph ( S Ph ( S.....N
<r I _ Þ I )=CHPh (_h II
LN 2 S 2 N
Ph
(513)
(514)
4.03.8.1.2 Loss of carbon dioxide
Photochemical elimination of carbon dioxide from suitable precursors has given a variety
of reactive intermediates at low ternperatures where they are often stable and can be studied
further. This approach has been utilized in attempts to generate new 1,3-dipolar species,
and photolysis of (515) gave an azomethine nitrene intermediate (516) (see Section 4.03.6)
O-N
o-Á. )Ph
N hv ..
Ph -....::;. N: ÇY N
(515) Ph-{ -0 --. (X >Ph
!;:Y' N IÍ NH
1/ NPh \\
Ph'-O) O (516) (509)
(517)
160 Synthesis of Five-membered Rings with Two or More Heteroatorns
which was trapped intrarnolecularly to yield (509) (68TL32S). A small arnount of (509) was
also obtained frorn photolysis of the oxathiadiazole 2-oxide (517) which apparently lost
S02 to give (516) as an intermediate (68TL32S).
A number of mesoionic compounds also lose a srnall, stable fragment on photolysis.
N-Phenylsydnone (518) on irradiation gave 4-phenyl-1,2,4-oxadiazolin-5-one (522). When
labelled carbon dioxide was passed through the solution during irradiation, it was incorpor-
ated into (522) (66TL4043, 71J0ClS89). These results were rationalized in terrns of an initial
valence isornerization to (519), and loss of CO 2 to give (520) which underwent ring opening
to the 1,3-dipole (521). This dipole subsequently reacted with carbon dioxide to give (522).
o-
ro.. o.. -CO'Þ N -+PhÑ-N=:CH ?
9N N N..... O?-..N"N
+Ph Ph Ph Ph
(518) (519) (520) (521) (522)
4.03.8.2 Photochemically Induced Isomerizations
The systems discussed here are aromatic systems which undergo a variety of isornerizations
on irradiation. Irradiation of imidazoles led to a scrarnbling of substituents, whereas such
scrambling has not been observed in the pyrazoles which undergo photoisornerization to
imidazoles.
Irradiation of the substituted pyrazole (523) gave the imidazoles (524) and (525). The
arnount of each isorner forrned is solvent dependent. In ethanol 7% of (524) was forrned
together with 2% of (525). In cyc1ohexane, however, isornerization was rnore efficient, the
percentages of the two isorners being 20% and 10%, respectively.
ßjN t>-+
I I I
(523) (524) (525)
Mechanisrns which explain these isomerizations are shown in Scherne 16, and by the use
of deuterated l,4-dimethylimidazole it was concluded that pathway (a) in Scherne 16 was
the rnain one (69T3287) (see Chapter 4.04).
X X
y C) z -+ RNDz --
N y
R
v()z
N ,
R X N
vrc;z --
N
R
Z N
Y()X
N
R
X z
D z N Z N
N -- V/(SX -- y( )X
À N N
V NR R R
Scheme 16 Mechanistic pathways for the photoisomerization of imidazoles
Indazole benzirnidazole photoisomerization involves a singlet state and has been deter-
rnined to be rnonornolecular and rnonophotonic. The UV spectrurn of an interrnediate with
a lifetime of the order of seconds was recorded. Irradiation of the indazole (526) resulted
in a 96% yield of the 1-methylbenzirnidazole (528) probably via the interrnediate (527)
(70PA024)495,69CI09).
NMe __ mNMe -+ N>
k N
Me
(526) (527) (528)
Synthesis of Five-membered Rings with Two or More Heteroatoms 161
Irradiation of IH-indazoles under non acidic conditions resulted in isomerization to
benzimidazoles and also ring opening to isorneric benzonitriles. With I-substituted benz-
imidazoles and sensitized irradiation, nitriles were formed, but these are only rninor
products with other substitution patterns (67HCA2244, 64TL2999). Irradiation of benz-
irnidazoles leads to oxidative dirnerization.
Isoxazoles largely undergo photochernical isomerization to azirines, which sornetimes
undergo a further therrnal or photochemical reaction. 3,4,5- Triarylisoxazole (529) forrned
the 2,3-diphenyl-3-benzoylazirine (530) which underwent further reaction to the oxazole
(531) (nJAI199). A small amount of the corresponding benzoyl ketenirnine was also obtained.
Ph Ph Ph Ph N
pi[ N -. Ph7 \ -. Ph( )Ph
0/ PhCO 0
(529) (530) (531)
4.03.8.3 Carbon-Carbon Bond Formation
4.03.8.3.1 Intramolecular reactions
With an appropriately substituted precursor, photochemical carbon-carbon bond forma-
tion is a convenient method for the synthesis of ring-fused systerns of the type under
discussion.
N-Bridgehead corn pounds have been obtained from the photochemical cyclization of
cis-I-styrylirnidazoles. For exarnple, irradiation of the irnidazole (532) in rnethanol in the
presence of Iz resulted in cyclization at the 2-position of the irnidazole ring with the
formation of an irnidazo[2,I-a]isoquinoline (533) (76JCSCPI)7S). Isomerization of the trans-
to the cis-styrylimidazole was followed by photodehydrocyclization.
trans-1-Styrylbenzimidazole (534) was isomerized under Pyrex-filtered light in the pres-
ence of one molar equivalent of Iz, The resulting cis isorner on irradiation through quartz
gave the benzimidazo[2,I-a]isoquinoline (535) in 53% yield.
R Z R Z N
/IN N R N/
R3 )Rl 06 , )>R3 Ö
I #
Ph #
(532) (533) (534) R (535)
Oxidative cyclization of the fully methylated 6-(benzylidenehydrazino)uracils (536) pro-
vides a 90% yield of the pyrazolo[3,4-d]pyrirnidines (537) (7SBCJ1484).
OÓ 7 V .
R::::'" I N
#
o 0
MeN 1 {R MeN 1 'IN
..Jl N benzene J... .Jl,,;
o N N/ 0 N N
Me Me Me Me
(536) (537)
Ring contraction and intramolecular cyclization constitute a convenient route to ring-fused
systems that would be difficult to synthesize in other ways. IH-I,2-Diazepines (538) undergo
electrocyclic ring closure to the fused pyrazole system (539) (71CC1022). Azepines also
undergo similar valence bond isornerizations.
Ph
PhUPh ..!:!:...
N-N
R
(538)
Ph
Ph
I N
/
N
Ph R
(539)
162 Synthesis of Five-membered Rings with Two or More Heteroatorns
4.03.8.3.2 Intermolecular reactions
Unusual heterocyclic systems can be obtained by photodirnerizations and for five-
rnernbered heterocycles with two or rnore heteroatorns such dirnerizations need be effected
on their ring-fused derivatives. Cyclobutanes are usually obtained as in the photodirneriz-
ation of the s-triazolo[ 4,3-a ]pyridine (540) to the head-to-head dirner (541). These ther-
mally labile photodimers were formed by dirnerization of the 5,6-double bond in one
rnolecule with the 7,8-double bond in another (77Tl247). Irradiation of the bis(1,2,4-
triazolo[ 4,3-a]pyridyl)ethane (542) at 300 nm gave the cisoid-fused cyclobutane dimer (543).
At 254 nrn the 'cage-like' structure (544) was forrned (77Tl253).
N "f N-N
-Ù N M N I )R'
I 7" "'" \ hv N
R N ---+
N...J
R 2 R 1 R 1
(540) (541)
N N
I --\ /-- \
NyN) (NyN
V
(542)
300 nm )
N N
I -\ H H /- \
NyNHNyN
H H
54 nm 254 nm/
--?J
(544)
4.03.9 REACTIVE, ELECTRON-DEFICIENT INTERMEDIATES
4.03.9.1 Carbenes
Utilization of carbenes in the synthesis of five-membered heterocycles with two or more
heteroatorns has not been featured prorninently in the synthetic strategies developed for
these ring systems. The following illustrations show their considerable promise.
Thermolysis of the 1,2,3-thiadiazoles (545) in the presence of carbon disulfide leads to
the thiocarbonyl carbene (546) adduct, the ring-fused 1,3-dithiole-2-thione (547)
(76JOC730).
@: N g: s
-N . CS >=
(CH 2 )n I IN (CH 2 )n ----4 (CH 2 )n I S
S S S
(545) (546) (547)
ëH ( N
R 1 0COCHN 2 --. .R10-{ RIO ï ;>R
o 0
(548) (549) (550)
Decomposition of the diazoacetic ester (548) to the keto carbene (549) is prornoted by
copper(II) trifluoromethanesulfonate. In the presence of nitriles, 1,3-dipolar addition to
the nitrile occurred giving the oxazole (550) (75JOM(88)115) (see also Section 4.03.8.1).
Decornposition of the diazoimide (551) by heating in the presence of copper acetylaceton-
ate also generated a ketocarbene (552). This undergoes an intrarnolecular condensation to
give the anhydro-4-hydroxy-3-methyl-4-p-nitrophenyl-2-phenyloxazolium hydroxide
(553), which cannot be prepared by more classical means (75CL499).
Synthesis of Five-membered Rings with Two or More Heteroatorns 163
Me
I
PhCONCOCC 6 H 4 N0 2 -p --.
II
N 2
(551)
R,. OyPh R(O)Ph
J.---NMe --. J-NMe
o -0 +
(552) (553)
R = P-N0 2 C 6 H 4
4.03.9.2 Nitrenes
Nitrenes have enjoyed appreciable application in the synthesis of a wide variety of
heterocyclic systems, and the majority of the methods used for generating nitrenes have
been utilized in these syntheses.
ß-Nitrovinylazides (554), prepared by nitration of vinyl azides with nitryl fluoroborate,
undergo spontaneous cyclization to the furoxan (555) with loss of N 2 (75AG(E)775), the Z
isomer being irnplicated in the ring closure onto the nitro group. The E isorner, on heating
or photolysis, gives the corresponding nitroazirine (see Chapter 4.22).
R" /C0 2 Et
C=C
/ "-
02N N 3
(554)
----+
R C0 2 Et
>=< -.
N N
-0""'" + ..
o
R C0 2 Et
in
.......N, /N
-0 0
(555)
The behaviour of ß-oxovinylazides is quite similar to those above. The Z isomer (556),
formed from the ß-halo carbonyl compound and sodium azide, is unstable losing N 2 and
forming the isoxazole (557) in an anchirnerically assisted concerted reaction (75AG(E)775,
78H(9)1207). At moderate temperatures (50-80 oc) the E isorner formed acylazirines which
at higher temperatures rearranged to oxazoles and isoxazoles.
R 1 R 2
>=< NaN,.
RCO Cl
R 1 R 2
R -.(=< N 3 --'
o
(556)
R 1 R 2
R 0 N
l.:..0)
( 557)
The synthetic potential of nitrenes is more readily apparent in the synthesis of ring-fused
systerns (81AHC(28)309), which can be accornplished by cyclization onto a heteroatom or
onto an adjacent ring, the latter having the possibility of reaction at carbon or at a
heteroatorn.
Heating of the O,O'-diazidoazobenzene (558) at 58 0 C resulted in formation of (559);
raising the temperature to 70 oC resulted in a second ring closure to the tetraazapentalene
(560) (62JA2453, 67JA2618).
N 3 0
)---ff 58 'C
0 =N
(558)
N N 3 Ñ
\N -o h
j -ND
(559) (560)
Triethyl phosphite is an effective reagent for the deoxygenation of appropriate nitro (or
nitroso) aromatic systems. Free nitrenes or some 'nitrenoid-like' species rnay be involved,
and the use of this reagent is illustrated by the examples below. It has the advantage over
the azide approach in that two steps in the synthesis can be avoided.
Treatrnent of the substituted azobenzene (561) with triethyl phosphite gave the triazapen-
talene (563). It is likely that the 2-substituted benzotriazole (562) was initially formed
which then underwent deoxygenative cyclization to (563) (74CL951).
0 COPh
N=N
O'NÒ
(561) #
(EIO),P)
0 COPh
N/ :O
\
N-
--=:
'''0,,', V
(IN-N
(562)
(563)
164 Synthesis of Five-membered Rings with Two or More Heteroatorns
A similar trcatmcnt of the Schiff's base derived from 3-nitro-2-thienylcarbaldehyde (564)
with triethyl phosphite gave the thieno[3,2-b ]pyrazole (565) (78CC453):
NO, N
- };JAr IEtO'3 P (X ::-,
( )---i >> NAr
S S "-N/
(564) (565)
Cyclization onto a heterocyclic ring also readily occurs, as when the 2-substituted pyridine
(566) was treated with triethyl phosphite. In this case the pyrrolopyrazole (567) was obtained
(79JOC622).
.& R
N :;::;--
NMe
0, ::::-..
CO,Me
(566)
__ Q=è /Í :;::;--R
N NMe
+\ ::::-..
CO 2 Me
(567)
4.03.10 USE OF YLIDES IN HETEROCYCLIC SYNTHESIS
As in organic synthesis in general, ylides have been applied in the synthesis of heterocycles
with increasing frequency. In five-membered ring chernistry they are more suited to the
synthesis of systems with one heteroatorn, but applications to ring systems with two or
rnore heteroatoms are known, as well as to ring-fused systerns. Two approaches have
evolved: the ylide may be an acyclic synthon used to bring a particular functional group
into construction of the heterocycle; or a heterocycle may be rnodified to incorporate an
ylidic function. This latter approach is useful for functional group rnodification or for ring
annul at ions.
4.03.10.1 Sulfonium Ylides
The dimethylsulfonium ylide (568) added readily to aroyl isocyanates to give the inter-
mediate addition product (569). This on heating underwent ring closure with loss of dirnethyl
sulfide to form the 4-hydroxyoxazole (570) (73T1983). This normal C-acylation of the
sulfoniurn ylide also leads to thiazoles with thiobenzoyl isocyanate; in this case the initial
acylation product was not isolated, the thiazole being obtained directly.
o
Me2S=CHCOzEt + ArCONCO --> MezS=CCONHCOAr Il, -Me,S Et0 2 C ( 'ì;Ar
I N
COzEt HO
(568) (569) (570)
A convenient route to /12 -isoxazoline N-oxides has been developed from nitrostyrenes
using dirnethylsulfoxoniurn rnethylide. The addition of the ylide (572) to the nitrostyrene
(571) was greatly facilitated by the presence of copper(1) salts, the isoxazoline N-oxide
(573) being obtained in excellent yield (76JOC4033).
0- 0
NO ? - I: I Ph Me
I 2 NaH Me!STCH ':N-O 11.+
PhCH=CMe+ Me 2 S =CH, ---+ :VH H -- "-_;N,
+ - DMS? I \ 0 0-
Cu Ph Me
(571) (572) (573)
Dimethylsulfonium phenacylide (574) underwent C-alkylation with a-chloronitroso com-
pounds such as (575). The intermediate (576) irnrnediately cyclized to the isoxazoline (577).
With a more basic ylide such as dimethylsulfonium methoxycarbonylmethylide the initial
alkylation product underwent elirnination of the sulfonium group to an alkene rather than
its displacernent (72T3845).
Modification of functional groups incorporated in a heterocycle is possible via ylide
reactions. The 5-rnethylisoxazole (578) on reaction with n-butyllithium and methanesulfenyl
Synthesis of Five-membered Rings with Two or More Heteroatoms 165
R R 1 R R1
RCH-CHRl+R2CH=SMe2 -. M c Ä ( H-. 0
I I e 2 \ 1/ PhCO ,N
Cl NO PhCO '0 0
(575) (574) (576) (577)
chloride in THF readily formed the sulfide (579). Alkylation followed by treatrnent of the
resultant salt with n-butyllithium gave the dirnethylsulfonium ylide (580). This undergoes
the norrnal reactions of sulfonium ylides: with aldehydes, the oxiranes (581) were obtained;
with aroyl chlorides, the C-acylation products (582) were isolated; and with a,ß-unsaturated
ketones the cyclopropane (583) formed with displacernent of dimethyl sulfide (77JHC37).
n
Ov 'O/N
R I (581)
7
R R R R
(J i, Bu"Li (J n PhCOCI ÆJ
Me ,N' ii,CH 3 SCI . MeSCH 2 ,N -. Me2S=CH _;N -+ N
o THF 0 0/ Me 2 S=C 0/
(578) (579) (580) PhtO
"" (582)
PhCOCH=CHP R
Ph N
COPh
(583)
4.03.10.2 Phosphonium Ylides
Although widely applied in functional group modification in a variety of heterocyclic
systems, phosphorus ylides have only been ernployed sparingly in heterocyclic ring construc-
tion with two or more heteroatoms in the nucleus. Their potential is shown in the applications
illustrated below.
The isoxazoles (585) were formed regioselectively from the (dioxoalkyl)phosphoniurn
salts (584) with hydroxylarnine hydrochloride, the direction of cyclization being different
frorn that of the nonphosphorus-containing 1,3-dioxo compound (see Chapter 4.16).
Aqueous sodiurn hydroxide converted (585) into the isoxazole (586) and triphenylphosphine
oxide. TreatmÞnt of (585) with n-butyllithiurn and an aldehyde gave the alkene (587).
With hydrazine or phenylhydrazine analogous pyrazoles were formed (80CB2852).
Ph 3 PCH R ICOCHR 2COR
Cl-
(584)
NH 2 0H.HCI
NaOH/",
R 2 R /'
+ N
Ph 3 P-CH 0/
I " Bu"Li
R' Cl- ii, PhCHO
(585)
R 2 R
R 'CH [J N
. 2 0/
(586)
R 2 R
PhCH=CHCN
o
(587)
Reaction of the keto ylide (588) with cyanazide (589) provided a convenient route to
the 1,2,3-triazole-1-carbonitrile (590). On heating, (590) lost N z readily to forrn the a-
cyanoirnino carbene (591) (81AG(E)113).
166 Synthesis of Five-membered Rings with Two or More Heteroatoms
Ph Ph N
I f \\
Ph 3 P=CCOMe + N 3 CN - Me N
N-:-
CN
(588) (589) (590)
Ph Me
,-N,)
NCN
(591)
An interesting application of a phosphorus ylide in heterocyclic synthesis is in a ring
annulation. The diazopyrazole (592) when treated with various phosphorus ylides gave the
3H-pyrazolo[5, l-c ][1,2,4]triazole derivatives (593) with elimination of triphenylphosphine
(79TL1567).
Ñ-N I
Rt = R N
_ + Ph 3 P=CR 2 R 3 - R<y N
R jN' N_N-J
N í'R 3
R 2
(592) (593)
4.03.10.3 Sulfimides
Sulfirnides have been utilized extensively for the synthesis of rnonocyclic ring systems as
well as ring annulations.
Formation of the imine (594) by reaction of the phenyl thioether with mesitylsulfonylhy-
droxylarnine and treatrnent with base provided a reactive substrate that could be halogenated
with NBS or NCS, acylated with a variety of acylating agents, and was sufficiently reactive
to add to benzoylalkynes forming the irnine (595), which on heating underwent cyclization
to isoxazoles (596). With the vinyl ether (597), substitution occurred giving (598), which
then cyclized to the isoxazole (598a) (73JOC4324).
MeCO
n
Mei(_;N
o
McCO
(MeCOhC=CH
" McCO OEt
N- c
I 1597)
RPhS+
Ph
"
S=NH
/
R
(594)
PhCOC:=CR I
.
1598a)
(598)
R'
/
PhCOCH=C
,,-
N
+/
RPhS
(595)
R
CHCI,, ) n
90% Phi( _ ;N
o
(596)
Sulfirnides have been key synthons in a variety of ring annulations, reacting readily with
ketenes, nitrile oxides and electron-withdrawing alkenes. These reactions are illustrated by
the conversion with diphenylketene of the sulfirnide (599) derived frorn 2-aminopyridine
by N-chlorination, reaction with rnethyl sulfide and treatment with base. The imidazo[1,2-
a ]pyridin-3-one (600) was formed in good yield (77H(8)109). Reaction of (599) with a nitrile
oxide led to the [l,2,4]triazolo[l,5-a]pyridine 3-oxide (601), also in good yield. This method
provides an unambiguous route to this N-oxide and is also applicable to analogous
pyrirnidines and pyrazines (76JCS(Pl)2166, 78BCJ563).
a --'\ RC=N-Ò
;R .
N-N+
"0-
O N=SMe 2 cr N
I + (PhhC=C=O - Ph 2
N N
o
(601)
(599)
(600)
4.04
Pyrazoles and their Benzo Derivatives
J. ELGUERO
Instituto de Química Medica, Madrid
4.04.1 STRUCTURE
4.04.1.1 Survey of Possible Structures
4.04.1.1.Ì Aromatic systems withoUt exocyclic conjugation
4.04.1.1.2 Aromatic systems with exocyclic conjugation
4.04.1.1.3 Non-aromatic systems
4.04.1.2 Theoretical Methods
4.04.1.2.1 Structure and reactivity of neutral pyrazole, its anion and its cation
4.04.1.2.2 Structure and reactivity of substituted pyrazoles
4.04.1.2.3 Structure and reactivity of indazoles
4.04.1.2.4 Dipole moments
4.04.1.3 Structural Methods
4.04.1.3.1 X-Ray diffraction
4.04.1.3.2 Microwave spectroscopy
4.04.1.3.3 IH NMR spectroscopy
4.04.1.3.4 B C NMR spectroscopy
4.04.1.3.5 Nitrogen NMR spectroscopy
4.04.1.3.6 UV spectroscopy
4.04.1.3.7 IR spectroscopy
4.04.1.3.8 Mass spectrometry
4.04.1.3.9 Photoelectron spectroscopy
4.04.1.3.10 Electron spin resonance spectroscopy
4.04.1.4 Thermodynamic Aspects
4.04.1.4.1 Intermolecular forces
4.04.1.4.2 Stability and stabilization
4.04.1.4.3 Conformation and configuration
4.04.1.5 Tautomerism
4.04.1.5.1 Annular tautomerism
4.04.1.5.2 Substituent tautomerism
4.04.2 REACTIVITY
4.04.2.1 Reactions at Aromatic Rings
4.04.2.1.1 General survey of reactivity
4.04.2.1.2 Thermal and photochemical reactions formally involving no other species
4.04.2.1.3 Electrophilic attack at nitrogen
4.04.2.1.4 Electrophilic attack at carbon
4.04.2.1.5 Nucleophilic attack at carbon
4.04.2.1.6 Nucleophilic attack at hydrogen
4.04.2.1.7 Reaction with radicals and electron-deficient species; reaction at surfaces
4.04.2.1.8 Reactions with cyclic transition states
4.04.2.2 Reactions of Non-aromatic Compounds
4.04.2.2.1 Isomers of aromatic derivatives
4.04.2.2.2 Dihydro derivatives
4.04.2.2.3 Tetrahydro compounds
4.04.2.3 Reactions of Substituents
4.04.2.3.1 General survey of substituents on carbon
4.04.2.3.2 Indazoles
4.04.2.3.3 Other C-linked substituents
4.04.2.3.4 N-Linked substituents
4.04.2.3.5 O-Linked substituents
4.04.2.3.6 S-Linked substituents
4.04.2.3.7 Halogen atoms
4.04.2.3.8 Metals and metalloid-linked substituents
4.04.2.3.9 Fused heterocyclic rings
4.04.2.3.10 Substituents attached to ring nitrogen atoms
4.04.2.4 Pyrazoles, Indazoles, and their Derivatives as Starting Materials for the Syntheses of
Fused Ring Systems
167
169
169
170
170
171
171
171
173
175
176
178
178
181
182
190
193
197
199
202
205
206
206
206
208
208
210
211
213
217
217
217
218
222
236
243
245
246
247
249
249
253
256
257
257
258
260
261
264
265
266
267
267
268
271
168
Pyrazoles and their Benzo Derivatives
4.04.3 SYNTHESIS
4.04.3.1 Ring Synthesis from Non-heterocycles
4.04.3.1.1 Formation of one bond
4.04.3.1.2 Formation of two bonds
4.04.3.1.3 Formation of three bonds
4.04.3.2 Ring Synthesis from Heterocycles
4.04.3.2.1 Ring opening
4.04.3.2.2 Ring transformations
4.04.3.3 Best Practical Methods
4.04.3.3.1 General methods
4.04.3.3.2 Nucleosides
4.04.3.3.3 Labelled compounds
4.04.4 APPLICATIONS AND IMPORTANT COMPOUNDS
4.04.4.1 Synthetic Products
4.04;.4.1.1 Pharmaceuticals
4.04.4.1.2 Agrochemicals
4.04.4.1.3 Dyestuffs and analytical applications
4.04.4.1.4 Plastics
4.04.4.2 Metabolism and Toxicity
4.04.4.3 Natural Products
273
274
274
277
284
285
285
286
288
288
288
289
291
291
291
297
298
300
301
302
Pyrazoles belong to the family of azoles, i.e. five-membered rings containing only nitrogen
and carbon atorns, ranging from pyrrole to pentazole. According to Albert's classification
(B-59MI40400) they are 7T-excessive N-heteroaromatic derivatives, and according to
Kauffmann's arenology principle (71AG(E)743) as a substituted carbon they are analogues
of amines (Section 4.04.2.3.1(iii)) and as a substituted nitrogen they are analogues of
halogens, i.e. pseudohalogens. These two arene analogies will be discussed later in the
reactivity sections.
The pyrazole ring is particularly difficult to cleave and, amongst the azoles, pyrazoles
together with the 1,2,4-triazoles are the most stable and easiest to work with. This qualitative
description of pyrazole stability covers the neutral, anionic and cationic arornatic species.
On the other hand, the saturated or partially saturated derivatives can be considered as
hydrazine derivatives; their ring opening reactions usually involve cleavage of the N-C
bond and seldom cleavage of the N-N bond. It should be noted, however, that upon
irradiation or electron impact the N-N bond of pyrazoles can be broken.
In contrast to pyrrole, imidazole, indole and benzimidazole, pyrazole, indazole and their
derivatives are of little biological significance. This is probably due to the difficulty for living
organisms to construct an N - N bond. On the other hand, the compounds discussed in this
chapter have interesting pharmacological properties (Section 4.04.4.1.1) and for this reason
they have had application in drug synthesis despite the recent tendency to suppress com-
pounds containing an N-N bond in human medicine.
Several books and their revisions on pyrazoles and their derivatives have appeared, the
rnost recent being that of Grimmett in 'Cornprehensive Organic Chemistry' (B-79MI40415).
Jacobs' review (B-57MI40400) was the leading reference for rnany years and a permanent
source of research ideas due to its critical presentation. The work of von Auwers, probably
the chemist who contributed the most to the developrnent of pyrazole chemistry, is clearly
described there. About 10 years later, two of the most prolific workers in this field, Kost
and Grandberg, published a chapter on pyrazoles (66AHC(6)347) that it is still useful because
it contains an authoritative summary of the Russian school's results. At about the same
time a volume on pyrazoles appeared in the Weissberger series (67HC(22)1) and this is still
the most irnportant source of information on these compounds, containing a comprehensive
chapter on pyrazoles but less detailed and critical chapters on pyrazolines and pyrazolidines,
as well as on indazoles and condensed types. In a narrower field, a different point of view
and an up-to-date bibliography can be found in the book on hydrazones by Kitaev and
Buzykin (B-74MI40407). In the excellent book on azoles (B-76MI40402), pyrazoles are discussed
in a comparative fashion with other azoles, and there are numerous very useful tables of
physical properties. The book concentrates on pyrazoles with the exclusion of reduced and
benzo derivatives.
A nurnber of general reviews related to the topics covered in this chapter have appeared
(Table 1) and others will be discussed in the section dealing with synthetic aspects (Section
4.04.3.1). The Sokolov review is particularly noteworthy since it is quite recent and complete,
containing 304 references to pyrazoles and isoxazoles.
Pyrazoles and their Benzo Derivatives
Table 1 Reviews on Pyrazoles and Related Topics
169
Main author
Huisgen
Busev
Wagner
Grandberg
Elguero
Trofimenko
Lablache-Combier
Trofimenko
Katritzky
Elguero
V olkov
Bouchet
Baiocchi
Sokolov
Bonati
Tisler and Stanovnik
Dorn
Title
Cycloaddition reactions of alkenes
Pyrazolones as analytical reagents
Pyrazolines as optical brighteners
Ring opening reactions of pyrazolines
Reaction of hydrazines with l,3-difunctional compounds
Polypyrazolylborates
Photoisomerization of aromatic five-membered rings
Coordination chemistry of pyrazole ligands
Tautomerism of heteroaromatic compounds
Synthesis and reactivity of pyrazolinium salts
Pyrazole chemistry
Fluoroazoles
Synthesis, properties and reactions of indazolones
Chemistry of pyrazoles and isoxazoles
Pyrazole metallic derivatives
Heterocyclic diazo compounds
Pyrazolidones, iminopyrazolidines, amino- and hydroxy-pyrazoles
Ref.
B-64MI40400
6SRCR237
66AG(E)699
66RCR9
70BSF2717
71ACRl7
71 BSF679
nCRV497
76AHC(Sl)l
76MI40403
77RCR374
77BSFl71
78S633
79RCR289
80MI40402
80CHE443
80CHEl
In addition to the authors quoted above, the names of Boyd, Finar, Habraken, Jacquier,
Lynch, Reimlinger, Schrnid and Sucrow are all associated as rnain contributors to pyrazole
chemistry over the past three decades.
4.04.1 STRUCTURE
4.04.1.1 Survey of Possible Structures
The most rational way to classify structures related to pyrazole is to take into account
the number of double bonds present, either endo- or exo-cyclic. An endocyclic double
bond can forrnally be considered part of a benzene ring in this context.
Three double bonds. The most fully oxidized pyrazoles, the typical non-aromatic rep-
resentatives of which are the pyrazoline-4,5-diones (1) and the pyrazolidine-3,4,5-triones
(2), should be included here.
O'J---t
0-::(- J"
N,
R
(1)
o 0
oDR2
N
R'
(2)
Two double bonds. This is the most important class which includes the aromatic compounds
pyrazole (3), indazole (4) and isoindazole (5), their non-aromatic isomers, pyrazolenines
(or 3H-pyrazoles; 6), isopyrazoles (or 4H-pyrazoles; 7) and 3H-indazoles (8), and the
carbonyl derivatives of pyrazolines with the endocyclic double bond in positions 1, 2 or 3,
i.e. (9), (10) and (11), respectively. The indazolones (12) and the pyrazolidinediones (13)
and (14) also belong to this group.
R 4 R 3 4 R3 cG R 3 R 4 R 3 R 3 '
RSCN s()j Rd R3 ' Rt:/ N
6 I? NR 1 R s1 N
N' :;;,..../ RS N
R 1 7 R 1
(3) (4) (5) (6) (7) (8)
R 4 R 3 R 4 0 R tJO RtJ
RJ:jR3' R D R 3 R 4 R 3 ((5NR'
0 .J::;N R 2
o N o ....N I , ,NR 2 o ....NR 2
N N N N R S N N 1
R 1 R 1 R 1 R' R
(9) (10) (11) (12) (13) (14)
170
Pyrazoles and their Benzo Derivatives
One double bond. The three pyrazolines, ,:l1. (15), ,:l2_ (16) and ,:l3-pyrazoline (17), and
the carbonyl derivatives of pyrazolidines like (18), are the most representative compounds
of this group.
R 4 R 3 R 4 R 4 R 3 iJ R 4 R 3
R4ÜR3' Rb R3 R S ;(:;N R 2 :s R2 R4 D R 3'
RS R S R S NR 2
, N N s' N'
, N' R I s' N s' N'
R S R S R I R R R 1 R R 1
(15) (16) (18) (19)
(17)
Without double bonds. Pyrazolidines (19) are the only representative of this group.
This natural classification, with the number of substituents R increasing regularly from
two to eight (the unsubstituted I-pyrazoline-3,4,5-trione is unknown), is useful for redox
studies, but in order to be consistent with other parts of this work the following classification
will be used throughout the chapter.
4.04.1.1.1 Aromatic systems without exocyclic conjugation
Only three systems belong to this group: pyrazole (3), IH-indazole (4) and 2H-indazole
(isoindazole; 5). The fused carbon atoms in indazoles are numbered 3a and 7a. When
R 1 = H, annular tautomerism (76AHC(Sl)1) makes the 3- and 5-positions of pyrazoles
equivalent and thus the narne 3(5)-R-pyrazole means that the compound is a rnixture of
tautorners with the substituent R in position 3 and in position 5. The same applies to
N-unsubstituted indazoles; however, the nurnbering is identical in both tautomers and thus
3-R-indazole means either (4) or (5) (R 1 or R 2 = H). Since the indazole tautorner is largely
predorninant (Section 4.04.1.5.1), indazoles are usually represented by the formula (4).
Only one monoanion and one monocation are possible for each of structures (20), (21),
(22) and (23). In spite of the localized representation, when R 1 = R 2 and R 3 = R 5 , the anion
(20) and the cation (22) are fully delocalized structures of C 2v symmetry. Thus in rnany
publications they are represented as shown in (20')-(23').
R 4 R 3 R3 R 4 R 3 R 3
RSCN N R S 'CÑR 2 (X)ÑR 2
N N' N
R 1 R t
(20) (21) (22) (23)
R 4 .......R 3 R3 R 4 ... R 3 R 3
RSÇN r:zJ OONR 2
OON R5 ". .: NR 2 ..../
"' f;( N i
R 1 R
(20') (21') (22') (23')
4.04.1.1.2 Aromatic systems with exocyclic conjugation
Formally, these are derived from the rnonocationic structures (22) and (23) by replacing
one of the CR groups by a negatively charged heteroatom (generally 0-, S- or RN-). Two
groups of unequal importance are included here: the pyrazolinones and the betaines.
The pyrazolinones (11) (pyrazolinethiones and irninopyrazolines) correspond to the
replacement of R 3 or R 5 in (22) by 0-, and are norrnally represented by their neutral
structure, but it is important to bear in mind their dipolar formula (26) when discussing
their reactivity. Sirnilarly, the indazolinones (12) (27) result from the indazolium salts (23).
R 4 R 3 -0 -0 R 3
-OCNR 2 (X;NR 2 R S CNR 2
N/+ r-r N/+
R 1 R 1 R 1
(26) (27) (28)
Pyrazoles and their Benzo Derivatives
171
The rnesoionic compounds are derived from pyrazolium salts (22) when R 4 is replaced
by a negatively charged heteroatom, like the anhydro-4-hydroxypyrazolium hydroxide (28).
According to Ollis and Rarnsden (76AHC(19)1) they belong to the mesoionic class B type.
4.04.1.1.3 Non-aromatic systems
Following the classification of Chapter 4.01, three classes will be considered. (a) Com-
pounds isomeric with aromatic compounds: (6), (7) and (8). The quaternary, non-aromatic
salts (Scheme 7, Chapter 4.01) will be discussed only in connection with protonation studies
which lead to the conclusion of their non-existence. The carbonyl derivatives (9), (10), (13)
and (14) will also be included here because it is possible to write an aromatic tautomer for
each one, (9')-(14'), even if it is energetically unfavoured. (b) Dihydro compounds. In this
class not only pyrazolines (15), (16) and (17) but also pyrazolidinones (18) and
pyrazolinediones like (1) are included. (c) Tetrahydro compounds. Besides the pyrazolidines
(19), the pyrazolidinetriones (2) are included here.
R 4 R 3
HOCN
N
H
(9') R 3 ' = R 4 ' = H
R 4 R 3
HOCN
N
R I
(10') R 4 ' = H
HO O OH
R 5 r N
N/
R I
(13') R 2 = R S ' = H
R 4 OH
HOCN
N
R I
(14') R 2 = R 4 ' = H
4.04.1.2 Theoretical Methods
Theoretical methods ranging from the now obsolete HMO studies to ab initio calculations
have been used extensively on pyrazoles. Although not emphasized in earlier reviews
(66AHC(6)347, 67HC(22)1), the most recent publications (B-76MI40402, 79RCR289) contain several
references to theoretical studies. Some publications related to structural studies are to be
found in the following sections, especially in connection with 13C NMR spectroscopy (Section
4.04.1.3.4), UV spectroscopy (Section 4.04.1.3.6), PE spectroscopy (Section 4.04.1.3.9)
and tautomerism {Section 4.04.1.5).
In this section, reactivity studies will be emphasized while in those devoted to synthesis
(Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles
(mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the
theoretical treatrnent of reactivity is a very complicated problern and for this reason, most
of the calculations have been carried out on aromatic compounds, as they are the easiest
to handle. In general, solvents are not taken into account; thus, at the best, the situation
described theoretically corresponds to reactions taking place in the gas phase.
4.04.1.2.1 Structure and reactivity of neutral pyrazole, its anion and its cation
Burton and Finar published a comparative table of calculations on pyrazole (29)
(70JCS(B)1692). That table, updated with recent references and extended to the pyrazole
anion (30) and cation (31), is the present Table 2.
H 4 H 3
HS)jN
N
'I
H
(29)
HW H3
HS a'l
(30)
H (3
H 5 :+:' N
N 'H 2
I
HI
(31)
Concerning the 7r- framework a considerable spread of results is observed, the most
reliable ones being those of Roche and Pujol (69BSFI097) and Olivella and Vilarrasa
(8IJHC1189) who optimized the geometry and used, respectively, the Julg irnproved LCAO
method and the Dewar MNDO method. Figure 1 contain the optimized geometries used
by the last authors; for pyrazole (29) there is good agreernent with the geornetrical structure
obtained from microwave spectroscopy (see Section 4.04.1.3.2) (74PMH(6)53), all bond
-...J
tv
Table 2 Calculated Electron Densities of Pyrazole, its Anion and its Cation
Molecule Method Densities' N-I N-2 C-3 C-4 C-5 H-I H-3 H-4 H-5 Ref
Pyrazole HMO 7T 1.64 1.38 0.93 1.11 0.94 51MI40400
Pyrazole VESCF 7T 1.656 1.162 1.031 1.042 1.1 09 60AJC49
Pyrazole HMO 7T 1.776 1.045 0.930 1.137 1.108 62T985
Pyrazole HMO 7T 1.700 1.269 0.975 1.107 0.949 66CHE413
Pyrazole EHT {: 1.57 1.54 0.89 1.11 0.90 67MI40401
Pyrazole EHT 3.49 4.28 2.85 3.12 2.89 0.708 0.888 0.890 0.888 67MI40401
Pyrazole VESCF 7T 1. 745 1.139 1.015 1.066 1.035 67MI40400 i3
Pyrazole HMO 7T 1.453 1.293 1.064 1.150 1.040 68JCS(B)725 N
Pyrazole ILCAO {: 1.75 1.18 0.97 1.11 0.99 69BSFI097 0
rï;-
Pyrazole SCF 3.43 4.01 3.06 3.00 3.03 0.81 0.90 0.89 0.88 70BSF273 '"
Pyrazole CNDO/2 {: 1.596 1.279 0.994 1.105 1.026 7OJCS(B)1692
Pyrazole CNDO/2 3.444 3.867 2.951 2.968 2.911 0.885 0.989 0.992 0.994 7OJCS(B)1692 ::!
Pyrazole ab initio {: 1.626 1.093 1.104 1.101 1.077 B-70MI40401 ...
;:s-
Pyrazole ab initio 3.722 4.038 3.053 3.165 3.037 0.610 0.780 0.806 0.789 B-70MI40401
Pyrazole MNDO {: 1.599 1.228 1.003 1.125 1.044 81JHC1189 ::;.
Pyrazole MNDO 3.577 3.898 3.053 3.048 2.958 0.772 0.894 0.906 0.896 81JHC1189 Q:,
Pyrazole anion VESCF 7T 1.210 1.210 1.190 1.199 1.190 60AJC49 ::!
Pyrazole anion EHT {: 0.898 1.11 0.898 67T2513 N
0
Pyrazole anion EHT 2.80 3.05 2.80 67T2513 \J
Pyrazole anion ILCAO 7T 1.25 1.25 1.12 1.26 1.12 69BSFI097
::!.
Pyrazole cation VESCF 7T 1.618 1.618 0.913 0.936 0.913 60AJC49 <:;
Pyrazole cation EHT {: 0.898 1.11 0.898 67T2513
...
Pyrazole cation EHT 2.83 3.04 2.83 67T2513 ;:;.
Pyrazole cation HMO 7T 1.512 1.512 0.924 1.128 0.924 68JCS(B)725 '"
PyrazoIe cation ILCAO 7T 1.74 1.74 0.73 1.06 0.73 69BSFI097
PyrazoIe cation CNDO/2 {: 1.617 1.617 0.838 1.090 0.838 70JCS(B)1692
Pyrazole cation CNDO/2 3.394 3.394 2.973 2.971 2.973 0.788 b 0.908 0.905 0.908 70JCS(B)1692
Pyrazole cation CNDO/2 { 1.585 1.585 0.875 1.081 0.875 73T3469
Pyrazole cation CNDO /2 3.399 3.399 2.945 2.975 2.945 0.796 b 0.916 0.912 0.916 73T3469
Pyrazole cation MNDO 1.604 1.604 0.851 1.092 0.851 8IJHC1189
Pyrazole cation MNDO 3.531 3.531 2.973 3.063 2.973 0.709 b 0.833 0.844 0.833 8IJHC1189
. Total charges are not given but they can be easily calculated adding the 7T- and u-densities. b The same value for H-2.
Pyrazoles and their Benzo Derivatives
173
lengths [except N(1)-C(5)] and angles being :Í: 0.02 Å and :Í: 2 0 , respectively, within
experirnental values. The N(l)-C(5) bond length (1.398 Â) is somewhat longer than the
experirnental values obtained by neutron diffraction (1.356 Å) (70ACS3248) and by micro-
wave spectroscopy (1.360 Å) (74JST(22)401). The ILCAO N(1)-C(5) calculated distance
is 1.375 Å (69BSFI097). The CNDO force method has been used to calculate fully optimized
geometries for five-membered heterocycles including pyrazole (73MI40400).
H
H
H
109,5 129,0
\N(2L H
1.384 109' 5!J 1.014
N(1) 121,5
1.014r
H
Figure 1 MNDO optimized geometries for pyrazole (29) and pyrazole cation (31)
HMO calculations (66CHE413) showed a considerable localization of the 7T-system (bond
orders: N(1)N(2), 0.396; N(2)C(3), 0.765; C(3)C(4), 0.581; C(4)C(5), 0.770; C(5)N(1),
0.441). However, a more recent HMO calculation using new pararneters gave a rnore
'aromatic' picture (bond orders: N(1)N(2), 0.5045; N(2)C(3), 0.6712; C(3)C(4), 0.6709;
C(4)C(5), 0.6625; C(5)N(1), 0.6434) (70CB3289).
The most complete discussion of the electrophilic substitution in pyrazole, which experi-
mentally always takes place at the 4-position in both the neutral pyrazole and the cation
(Section 4.04.2.1.1), is to be found in (70JCS(B)1692). The results reported in Table 2 show
that for (29), (30) and (31) both 7T- and total (7T + u )-electron densities predict electrophilic
substitution at the 4-position, with the exception of an older publication that should be
considered no further (60AJC49). More elaborate models, within the CNDO approximation,
have been used by Burton and Finar (70JCS(B)1692) to study the electrophilic substitution
in (29) and (31). Considering the substrate plus the properties of the attacking species
(H+, Cl+), they predict the correct orientation only for perpendicular attack on a planar
site. For the neutral molecule (the cation is symmetrical) the second most reactive position
towards H+ and Cl+ is the 5-position. The activation energies (kJ mol-I) relative to the
4-position are: H+, C-3, 28.3; C-5, 7.13: ct, C-3, 34.4; C-5, 16.9.
The binding energy of pyrazole (0.309 a.u.) is slightly lower than that of imidazole
(0.335 a.u.) due to the vicinal position of the nitrogen atoms in the former, a situation that
parallels the heat of atornization (B-69MI4040l). The relative basicity of these two azoles
(Section 4.04.2.1.3(iv)) has been discussed on theoretical grounds (81JHC1189). After applica-
tion of the partitioning of energy in the MNDO rnethod, the authors concluded that the
greater basicity of imidazole in comparison with that of pyrazole can be primarily ascribed
to the extra destabilization of the 7T- bonding in the pyrazole after protonation. The
destabilization of the 7T- bonding for pyrazole is larger than for irnidazole because the 7T
lone pair on the N-1 atom of the former compound does not contribute appreciably to the
delocalization of the positive charge which appears after protonation at N-2. For a more
rigorous treatrnent of the basicity of pyrazoles, see (83H(20)1717, 83UP40400).
4.04.1.2.2 Structure and reactivity of substituted pyrazoles
Minkin et ai. (66CHE413) have used Stretwieser 'optimal' values of Coulomb and resonance
integrals to calculate the 7T-electron densities and bond orders of 1-phenylpyrazole (32;
Figure 2). From the values of the 7T-electron densities they concluded that a preferential
electrophilic attack takes place at the 4-position, as in pyrazole itself, and that pyrazole as
a substituent of the phenyl ring has an ortho-para directing effect (pseudohalogen character).
The low value of the N(1)-C(l) bond order in (32) shows that the interaction energy
between the two aromatic rings is small in the ground state.
However, the fundarnental contribution to the theoretical study of the structure of
substituted pyrazoles has been made by Finar (68JCS(B)725,70JCS(B)1692). Figure 3 shows
174
Pyrazoles and their Benzo Derivatives
1.1 05 0.977
0.957 eN 1.278
0' 0 7 : 1.649
1.026
I 0 999
1.019
11.579
0.76900.761
0.4 7 3 N'Í 89
ð'
(32)
Figure 2 LC AO MO calculations of 7T-electron densities and bond orders
the 1T-electron densities and bond orders of 1-phenyl- (32) and 1-rnethyl-pyrazole (33) and
their corresponding cations (34) and (35) calculated by the HMO rnethod (68JCS(B)72S).
Figure 4 shows the CNDO/2 calculations on (33) and (35) (70JCS(B)1692).
I 143 1.1)53
1.04ÓCN1.306
0' 0 7 : 1.403
1.028
I 0.999
1.021
1.1.11 0.9 3
O 1.526
II 74 N_
S N;.397- H
11988
('" 1.011
I 0.999
I.IHI
0.635
0.7000.691
0.581 No"O.498
ð'
(32)
0.689
0.661 0 0.614
N-- H
0.65 ð 4 N/\'0.438
0.24\
I
(34)
I 162 1.096
1.104 0 N1.334
No"
11.371
Me
0.934
1.135 1.1!29
Q 1.52ó
0.991 /I:"--H
I 1.396
Me
0.663
0.664 C .652
0.627 No"O.540
1 0 .204
Me
(33)
0.698
065t:] :...07
0.677 N1í.453 H
0.1061
Me
Figure 3 HMO calculations of 7T-electron densities and bond orders
(35)
1.102 0.996
11I41CN1288
N I 6
I ..
Me
0. 93 n.990
H H
2.97 .953
w ../ 3868
0.993 3.436
Me
(33)
1.085 0.862
O 1.619
0.871 N--- H
No".
1 1.556
Me
0.911 0914
H H
2.9 4 2.965
2.9681 N3.406
H "--H
0.914 3.389 0.795
Me
Figure 4 CNDO/2 calculations of 7T- and u-electron densities
(35)
The results obtained for 1-phenylpyrazole (32) and its conjugate acid (34) are consistent
with those of Minkin. The bond order between thé two rings decreases by protonation
(frorn 0.341 to 0.241) and this is in agreernent with the expected effect of the N-2 positive
charge on the de localization of the lone pair on N-1 over the phenyl ring.
The reactivities of 1-rnethylpyrazole (33) and pyrazole (29) are sirnilar and so are the
corresponding charges. The cornpetition between C-4 and C-4' in 1-phenylpyrazole depends
on the electrophile and on the experirnentaJ conditions (Section 4.04.2.3.10(i)). Thus in
an acidic rnediurn the reaction takes place on the conjugate acid (34) and considering the
calculated charge densities the attack on C-4 would always be favoured.
An alternative rnethod for studying electrophilic substitution is to calculate the energy
required to localize a pair of 1T- electrons at the site of substitution and to assurne that this
localization energy (Ed is a rneasure of the energy of activation. When the attacking reagent
is a cation (NO; or Br+), then besides E L (which represents the energy required to reorganize
the 1T- electrons in pyrazole), Finar (68JCS(B)72S) takes into account the electrostatic energy
required to bring the cation to the site of attack. The calculation of this potential energy
(P.E.) is carried out for each case where the unit positive charge was placed at a point
3 Å perpendicular to the site of substitution. Molecular brornine is treated as an uncharged
species (P.E. = 0). Another possibility is to calculate the polarization energies (ilE".) and
to correct thern with a P.E. terrn if the nucleophile carries a positive charge. By considering
Pyrazoles and their Benzo Derivatives
175
these different possibilities, Finar has succeeded in explaining the different experirnental
results.
Free valences and localization energies have been calculated for a series of pyrazoles
(neutral rnolecules and conjugate acids) for homolytic substitution. In all the cornpounds
the site with the lowest localization energy has the highest free valence index. This parallel
between the two indices of reactivity is maintained in pyrazole, l-rnethylpyrazole and their
conjugate acids, but not in l-phenylpyrazole and its conjugate acid. For the three cornpounds
exarnined experirnentally, (32), (33) and (35) (Section 4.04.2.1.8(ii)), only the predictions
for (33) are in agreement with the experimental results.
There is a rather poor agreernent between the basicities of pyrazoles (Section 4.04.2.1.3
(iv)) and either the difference in total 7T-energy between the free base and its conjugate acid
(ÄE 7T ) or the net charge on N-2 of the free base (68JCS(B)72S). The inclusion of the u-electrons
and the calculation of the proton affinities (P.A.) does not improve the results (70JCS(B)1692)
(see, however, (83H(20)1717, 83UP40400)). The lowering effect of N -rnethylation (Section
4.04.2.1.3(iv)) cannot be explained by indices unable to take solvation phenornena into
account. Only gas phase proton affinities can possibly correlate with Burton and Finar's
calculations.
The hydrogen-deuteriurn exchange rates for l,2-dimethylpyrazoliurn cation (protons 3
and 5 exchange faster than proton 4; Section 4.04.2.1.7(iii)) have been exarnined theoreti-
cally within the frarnework of the CNDO/2 approxirnation (73T3469). The final conclusion
is that the relative reactivities of isorneric positions in the pyrazoliurn series are deterrnined
essentially by inductive and hybridization effects.
4.04.1.2.3 Structure and reactivity of indazoles
Indazoles have been subjected to certain theoretical calculations. Karniya (70BCJ3344) has
used the serniernpirical Pariser-Parr-Pople method with configuration interaction for calcu-
lation of the electronic spectrurn, ionization energy, 7T- electron distribution and total
1T-energy of indazole (36) and isoindazole (37). The 1T-densities and bond orders are
collected in Figure 5; the molecular diagrarns for the lowest 1( 1T,7T*) singlet and 3( 7T,7T*)
triplet states have also been calculated; they show that the isornerization (36)..... (37) is
easier in the excited state.
0.990
1.008
1.029
0.737
1.022
0.747
0.590
0.529
N 1.340
18
N
\1.587
H
0.579
0.536
1.471
N-H
61
N
1.449
0.988
0.735
0.534
0.542 1.004
0.995
0.556
1.062
1.020
(36)
(37)
Figure 5 PPP calculations of 1T-electron densities and bond orders
The positional preference for electrophilic substitution in lH- indazole (36) and 2H-
indazole (37) is predicted to be 7> 5 and 3> 5> 7 > 4, respectively, although it is known
that experimentally substitution takes place at C-3 and C-5 (Section 4.04.2.1.4(i)). Since
in this study the rnolecular geornetry of indazoles was tentatively approxirnated as a regular
hexagon and pentagon with a bond length of 1.394 Å on account of a lack of experirnental
data, Faure et al. have used the X-ray structure of benzazoles (indazole, benzirnidazole,
benzotriazole) as a basis for CNDO/2 and CNDO/S calculations (74T2903). The electron
density diagram with the charges (1T and u) and the bond orders is shown in Figure 6. The
1T- electron densities seern rnore realistic, with the 3-position rich in electrons (7) 5> 3).
Nevertheless, no diagrarn of electron densities, however accurate, would correctly predict
the chemistry of a molecule like indazole, with rnany sites of comparable reactivity.
On the other hand, theoretical rnethods allow an insight into the structure of 'non-existent'
molecules like 2H-indazole (37) or the anion of indazole (38). INDO calculations have
been performed by Palmer et at. on the anion of indazole (38) (7SJCS(Pl)169S). The optirnized
geometry obtained by them is shown in Figure 7. The N-N bond distance is longer in the
176
Pyrazotes and their Benzo Derivatives
I.U13
H
1.01:1
1.008
H
2.974
0.974
1.056 0.755 0547
H
1.002
/3.945
N
\4.376
H
0.899
0.978
0.455
N 1.155
).362
N
\1712
H
H
1.010
0.559
0.594
LOtiO
(36)
Figure 6 CNDO/2 calculations of 7T-and CT-electron densities and bond orders
indazole anion than in the benzotriazole anion as a consequence of the charge repulsion
between the negatively charged nitrogen atorns (total net charges: N-1, -0.320; N-2,
-0.169). The correlation between N-methylation ratios and charge is less satisfactory; a
possible explanation could be that there is rnore than one rnechanisrn for the reaction
between the indazole anion and alkylating agents (Section 4.04.2.1.3(viii)).
1.434
1.407 1\1.5 N
106.4 Y
\08.2)11.33\
1.422 1.396 N
(38)
Figure 7 INDO optimized geometry for indazo[e anion
4.04.1.2.4 Dipole moments
Dipole rnornents seern to exert a sort of fascination on theoretical chernists, who often
check their calculations by cornparing their calculated values of the dipole rnoment with
the experimental ones. This is particularly startling since the experimental dipole rnornents
generally arise from dielectric data (63PMH(1)189) and thus only the rnodulus is known.
Experirnental values are collected in the McClellan book (B-63MI40400) and in a review
on dipole mornents and structure of azoles (71KGS867). Sorne selected values are reported in
Table 3. The old controversy about the dipole mornent of pyrazole in solution has been settled
by studying its permittivity over a large range of concentrations (7SBSF167S). These rneasure-
ments show that pyrazole forrns non-polar cyclic dimers (39) when concentration increases
and, in consequence, the perrnittivity value decreases.
C -fi,
N.. ;N\
H-N V
(39)
A selection of calculated dipole mornents are shown in Table 4. Except frorn the aberrant
EHT value, the others are quite sirnilar. CNDO/2 calculations using experimental
geornetries (74T2903, 7SBSF167S) provide better results than when ideal geornetries are used
(70JCS{ß)l692). Theoretically optirnized geornetries have been used in several cases
(67MI40400, 69BSFI097, 73MI40400, 81JHCl189). The papers by Palrner et at. (74JCS(P2)420,
78JST(43)203) contain an irnportant discussion on dipole and second rnornents of five- and
six-rnernbered heterocycles based on ab initio calculations and on the linear cornbination
of gaussian orbitals (LCGO) procedure.
Pyrazotes and their Benzo Derivatives 177
Table 3 Experimental Dipole Moments of Pyrazoles and Indazoles at 25 oC
Molecule Method" Solvent J.I. (D) Ref.
Pyrazole b M None 2.21 74PMH(6)53
Pyrazole D Benzene 1.92 75BSF1675
Pyrazole D Dioxane 2.32 75BSF1675
1-Methylpyrazole D Benzene 2.25 75BSF1675
3(5)-Methylpyrazole D Benzene 1.43 71KGS867
1- Phenylpyrazole D Benzene 2.00 71KGS867
3(5)- Phenylpyrazole D Benzene 2.26 71KGS867
3,5-Dimethylpyrazole D Benzene 2.31 71KGS867
3,4-Dibromopyrazole D Benzene 4.66 71KGS867
3,4,5- Tribromopyrazole D Benzene 2.48 71KGS867
3(5)-Azidopyrazole D Dioxane 3.73 78BSB189
1-Acetylpyrazole D Dioxane 1.55 77RRC471
Indazole D Benzene 1.60 75BSF1675
1-Methylindazole D Benzene 1.50 75BSF1675
2-Methylindazole D Benzene 3.40 75BSF1675
" Microwave spectroscopy (Stark effect). b (J, the probable approximate angle between the direction
of J.I. and the symmetry (or near symmetry) axis of the ring through atom N-1, in the molecular
plane, has the value 69 0 .
Table 4 Calculated Dipole Moments of Pyrazoles and Indazoles
Molecule
Experimental value"
Calculated values
Pyrazole
2.21 (G), 2.32 (D)
2.28 (VESCF) (67MI40400); 5.05 (EHT) (67MI40401); 2.50 (ILCAO)
(70BSF273); 2.52 (CNDOj2) (70JCS(B)1692); 2.21, (J = +400 (ab
initio) (B-70MI40401); 2.33 (CNDOj2) (73MI40400); 2.85, J.l.l. 2.23,
J.l.U 1.77 (ab initio LCGO) (74JCS(P2)420); 2.30 (CNDOj2)
(7SBSF167S); 2.11 (MNDO) (81JHC1189)
2.51 (CNDOj2) (70JCS(B)1692); 2.35 (CNDO/2) (7SBSF167S)
2.27 (HMO) (66CHE413)
1.67 (CNDOj2) (74T2903); 1.97 (ab initio LCGO) (78JST(43)203)
1-Methylpyrazole
1-Phenylpyrazole
Indazole
2.25 (B)
2.00 (B)
1.60 (B)
"G, gas phase; D, dioxane; B, benzene.
The comparison of the experimental mean values with the theoretically calculated ones
for individual tautomers (Section 4.04.1.5.1) (76AHC(S 1) 1) or conformers (Section
4.04.1.4.3) has been used in the literature to determine equilibriurn constants. Thus, the
experimental value for 1,1' -thiocarbonylbis(pyrazole) (40) is 3.19 0 and the vector sums
of the simple group rnoments after addition of the extra rnesorneric moments are shown
in Figure 8. From these values Carlsson and Sandström (68ACS1655) concluded that confor-
mation (40b) exerts the largest influence.
"s',
"
N /C..... ..
tf ' N_N
U
(40a) J.l.zz 5.79
,'s',
"
.. C
N'N/ ......N
o ,, J
(40b) J.l.ZE 3.23
:s',
"
/C......
rN N
h: . J
(40c) J.l.EE 0.38
Figure 8 Vectorially calculated dipole moments for the three planar conformations of 1,l'-thiocarbonyl-bis-
pyrazole
A similar approach has been used in the case of azolides (N- acylazoles). The experimental
dipole moment of 1-acetylpyrazole (1.550, Table 3) was compared with the CNDO/2
calculated values for the E and Z conformations, respectively 1.87 and 5.46 D. Fayet et
at. concluded that the E conformer (41) largely predominates (77RRC471).
R 2
R n
^__;N:
R 4 N
I
C
:Q'l- ......R 1
(42)
eN:
N
I
C
:g'l- ......Me
(41)
178
Pyrazoles and their Benzo Derivatives
The rnethod has also been applied to partially saturated systerns. For instance, the dipole
rnornents of a series of 1-acylpyrazolines (42) with R 1 = H, Me, Et and Ph have been
measured (72CHE445); they range frorn 3.46 to 4.81 D. When cornpared with values corn-
puted by the fragmentary calculation rnethod, the conclusion was reached that here also
the E forrn predorninates. In all these exarnples the lone pair-lone pair repulsions deterrnine
the most stable conforrnation.
The last exarnple is sornewhat rnore cornplicated since four isomers (two tautorners and
two conformations) are present at equilibriurn (Figure 9) (78BSB189). The experirnental
value (3.73 0, Table 3) establishes the predominance of the 3-azido tautomer but does not
allow the determination of the conforrnational equilibriurn; other rnethods (Section
4.04.2.3.4(v)) are necessary to establish definitely the Z conforrnation (43b).
N
III
N+
I
N;
0.:
H
(43a) ILE 3.81
O B'N
+ N
/N.
N/ .
H
(43b) ILz 3.56
N
111+
N
I
W
á
\'f
(43c) ILE 1.29
B,
r=d( N
(./ H
N
Figure 9 Vectorially calculated dipole moments for the four planar isomers of 3(5)-azidopyrazole
(43d) ILz 0.96
4.04.1.3 Structural Methods
4.04.1.3.1 X-Ray diffraction
The fact that only 11 structures were reported in (72PMH(5)1) whereas in Table 5, which
is non-exhaustive, 36 rnore have been added shows the great developrnent of X-ray structural
deterrninations in recent times. Sorne of these structures deserve brief cornrnent.
Table 5 X-Ray Structures of Pyrazoles and Indazoles
Type of struc ture
Pyrazole
Pyrazolone
Name"
Pyrazole
3- Meth yl-5-phenylpyrazole
3,5-Dimethyl-l-phenylpyrazolium nitrate
4- Bromo-1-(2,4-dinitrophenyl)pyrazole (10 J )
4-Chloro-l-(2,4-dinitrophenyl)pyrazole
4- Bromo-3-methyl-l-(4-nitrophenyl)pyrazole
1- Acetyl-4-bromopyrazole
3-Azido-4-phenylpyrazole (45)
3-Amino-4,5-dicyano-l-methylpyrazole
5 - Amino-4-cyano-3 -dimethylamino-l- phenylpyrazole
3 -Meth yl-(5-amino-3 -methylpyrazol- 1-yl)-3-acrylonitrile
I-Pyrazol-3-yl-pyrrole-2-carboxylic acid (46)
4-[4-( p-Chlorophenyl)-3-pyrazolyl]-4H- 1,2,4-triazole (47)
Phenylazo-5-diethylamino-4-methyl-l-phen ylpyrazole
1,9-Dihydro[1 ]benzothiopyrano[ 4,3-c ]pyrazole S,S-dioxide (48)
4-Ethoxycarbonyl-5-methoxy-l-phenyl-3-(a-
phthalimidoethyl)pyrazole (138)
1,1,1- Trimethylhydrazinium 3-methoxycarbonyl-5-pyrazolecar-
boxylate
4-Bromo-2,3-dimethyl-l-phenyl-5-pyrazolone (60)
3-Methyl-l-phenyl-5-pyrazolone (49)
3-Hydroxy-5-methyl-1-phenylpyrazole
4-Ethoxycarbonyl-5-hydroxy-1-phenyl-3-(a-
phthalimidoethyl)pyrazole
2- Bromo-l-methylbenzo[ c ]pyrazolo[ 1, 2-a ]pyrazole -3, 9-dione
4-( p-Chlorobenzal)-1,3-diphenyl-2-pyrazolin-5 -one
3 -Methyl-3-pyrazolin-5 -one
Antipyrine (2,3-dimethyl-l-phenyl-5 -pyrazolone)
Ref.
60AX946,
70AXIB)1880,
73ACS1845
74JCS(P2)1298
82CJC97
72PMH(5)1
70AX(B)380
72AX(B)791
72AXIB )3316
74CSC713
76AXIB)853
77AX(B)413
78JHC185,
75AX(ß)2119
81CPB3214
77JHC65
74CC339
77JHC387
80CSC1l27
74AX(8)2505
72PMH(5)1
73CSC469
73CSC473
80CSCl12l
73ACS661
nCSC253
71AX(B)1227
74AX(B)557,
73AX(ß)714
Pyrazoies and their Benzo Derivatives
Table 5 (continued)
179
Type of structure
Betaine
Pyrazoline A,z
Al
Salts
Pyrazolidine
Pyrazolidinone
Indazole
Indazolone
Indazoline
Name"
1,I-Dimethyl-3-phenylpyrazolium S-oxide (50)
A 2 -Pyrazoline hydrochloride (64)
3-p- Bromophenyl-l-nitroso- 2-pyrazoline
1,3-Diphenyl-A 2 -pyrazoline (89)
I-p-Iodophenyl-3-phenyl-A 2 -pyrazoline adduct of isocolumbin
acetone solvate (1303)
3- Benzoylamino-l-phen}'l-A 2 -pyrazoline
3-Acetamido-l-benzyl-A 2 -pyrazoline
3a,8b-Dihydro-l,3-diphenylindeno[1 ,2-c ]pyrazol-4( 1 H)-one
Dimers of 3-alkoxycarbonyl-S-formyl-S-methyl-A 2 -pyrazoline
9-0xo-2a,3,S,6, 7 ,8,8a,9-octahydroindolizino[I' ,2' :S,4]pyrazolo-
[1 ,S-a ]indole
1-(3,S,S- Trimethyl-l-pyrazolinyl) phthalazine hydro bromide
1-(4-Methyl-l-pyrazolin-3-yl)-S,S-bis(trifluoromethyl)-A 2 -1,2,3-
triazoline
3-Methoxycarbonyl-trans-3,S-dimethyl-A I-pyrazoline hydro-
bromide (72)
1,2,3,S,S-Pentamethyl-2-pyrazolinium perchlorate (94)
1 ,2,3,S,S-Pentamethyl-l-phenyl- 2-pyrazolinium perchlorate
2- Acetyl-S -(methoxycarbonylmethyl)-l-methyl-3,4,S-
pyrazolidinetricarboxylic acid, trimethyl ester
4' -Methylene-l,2-di-m-bromophenyl-l',2',6', 7'-
tetraphenylspiro{pyrazolidine-4,8' -[8' H,4' H]-benzo[I,2-c ;4,S-
c']dipyrazoline}-3,3',S ,S' -tetraone
4-n- B utyl-l ,2-diphenyl-3,S-dioxopyrazolidine (phenyl-
butazone) piperazine salt
Indazole
3-Diazoindazole (51)
Substituted pregn-4-en-20-one[3,2-c]- 2' -phenylpyrazole
2-Acetyl-3-indazolinone (896)
2,3,4,7 - T etrahydro-3a,4-bis(methoxycarbonyl)- 2,6-dimethyl-S-
phenylindazol-7 -one
Ref.
70JHC89S
72PMH(S)1
71AX(B)986
72PMH(S)1
72PMH(S)1
81MI40401
81MI40401
76AX(B)2314
7SAX(B)S48,
76AX(B)2216
8lHCA769
77CPB147
73CB288
72PMH(S) 1
72PMH(S)l
72CR(C)(274) 11 92
79CB 1719
74AX(B)273
74AX(B)S90
74AX(B)2009,
74T2903
78AX(B)293
71AX(B)S73
72PMH(S)l
74JOCI007
"Numbers in italic type are those used in (nPMH{SJ1).
The molecular structure of pyrazole was determined for the first time by Ehrlich (60AX946)
who noticed that there are two crystallographically independent molecules in the cell, both
with strong hydrogen bonds. This structure was later proved to be wrong, but Ehrlich
deduced from the bond lengths (C(4 )-C(5) longer than C(3)-C(4), Figure 10) that there
is a large contribution frorn the betaine form (44) to the resonance hybrid.
ÇN -
I
H
(44)
This conclusion and the experirnental geometry caused considerable confusion among
theoretical chemists, who, following a suggestion by Mighell and Reimann (67JPC237S), had
to exchange the assignrnent of the two nitrogen atorns to be consistent with their calculations.
This inverted Ehrlich geometry was used explicitly for calculations in several theoretical
papers (69BSF1097) but not in others (70CB3289). Mighell and Reimann's proposal was
sustained by X-ray structural data from coordinated pyrazole derivatives (Section 4.04.2.1.3
(vi)). In fact the correct structure of pyrazole is not the 'inverted-Ehrlich' structure but one
having a more regular geornetry compatible with the classical representation of pyrazole
(70AX(B)1880). The definitive structure of pyrazole was established by two important publica-
tions by Rasrnussen et ai. (70ACS3248,73ACSI84S), the first one dealing with a neutron
diffraction study and the second one with an X-ray diffraction study (at 295 and 108 K).
In Figure 10 the five structural determinations of pyrazole (29) are represented. They
have to be compared with the experimental microwave spectroscopic structure (Section
4.04.1.3.2, Figure 12) and wi th the theoretically optimized geornetries (for instance, Figure 1,
180
Pyrazoles and their Benzo Derivatives
Section 4.04.1.2.1). The spectroscopic and the diffraction results refer to rnolecules in
different vibrational quantum states.. In neither case are the. distances those of the
hypothetical minimum of the potential function (the optimized geornetry). Nevertheless,
the experimental evidence appears to be strong enough to lead to the conclusion that the
electron redistribution, which takes place upon transfer of a rnolecule frorn the gas phase
to the crystalline phase, results in experimentally observable changes in bond lengths.
H
105.5 N(2)
110 Á6
N(1)
11.10
H
(a)
H
H
H
H
104.5 N(2)
112 A35
N(1)
11.00
H
(b)
H
H
H
104.8 N(2)
1110,65
N(1)
11.036
H
(c)
H
H
103.7 N(2)
113.0^'52
N(1)
10.91
H
(e)
Figure 10 Mean values of bond lengths and bond angles of pyrazole structures: (a) Ehrlich (X-ray); (b) Berthou
et al. (X-ray); (c) Rasmussen et al. (neutron, corrected for rigid body motion); (d) Rasmussen et al. (X-ray, 295 K);
(e) Rasmussen et al. (X-ray, 108 K)
The indazole molecular structure (Figure 11) shows the tautorneric proton bonded to
N-l (lH-indazole, Section 4.04.1.5.1). A linear correlation between the bond lengths and
the bond orders calculated by the CNDO/2 rnethod was observed (74T2903).
1.358 119.5
120.6
Figure 11 Bond lengths and bond angles of indazole X-ray structure
1.431
105.8 N
{384
110.0/ 1 ..
N
H
For N- unsubstituted pyrazoles the tautomeric proton was generally located without
arnbiguity. 3-Substituted tautomers were favoured in the solid state: (45), (46) and (48)
(Table 5). For the pyrazolyltriazole (47) the authors (77JHC65) concluded that the X-ray
analysis indicates that the proton on the pyrazole ring populates either nitrogen atorn to
g=> ?i
0=8 J
r
....N
N
H
(48)
Ph O N3
r
....N
N
H
(45)
121.4
122.4 107.4
1.359
117.2
1.355
1.400
NC O R
r
....N
N
H
(46)
F
Ar N N
n
(. J-l
N
H
(47)
Pyrazoles and their Benzo Derivatives
181
an indistinguishable extent. This conclusion is doubtful, since other sirnilar claims have
been proved to be false (81CC1207).
. An interesting report on 1-phenyl-3-methyl-5-pyrazolone (49) shows that when two
tautomers are of comparable energy they could both be present in the crystal cell (73CSC469).
In this case NH and OH tautorners, (49a) and (49b) respectively, coexist in the crystal
(Section 4.04.1.5.2).
Me Me
O .J::;N H HOCN
N N
Ò Ò
(49a) (49b)
The structure of the unusual betaine (50) has been deterrnined (70JHC895). The bond
lengths and angles suggest that a significant contribution to the structure is made by a
resonance form (SOb) in which the N(1)-C(5) bond does not exist ('ketene' form).
H
'fi-lh
-o)f;)'N
/ "-
Me Me
(SOa)
..........
H Ph
\C-l
II \\
.--;C /N
0:;-' N
/ "-
Me Me
(SOb)
N:
+J!1
cQ i '\..........
/
N
(Sla)
N:
11/
+N
MN
V/
(SIb)
3-Diazoindazole (51) is one of the few heterocyclic diazo compounds whose structure
has been determined (78AX(B)293). The diazo group shows a substantial 'carbanionic'
character (51b).
4.04.1.3.2 Microwave spectroscopy
Since there is an excellent review by Sheridan (74PMH(6)53) referencing all the relevant
publications on this topic, only the microwave geometry of pyrazole determined by the
group at the University of Copenhagen (74JST(22)401) will be shown here (Figure 12).
H
Figure 12 Microwave structure of pyrazole
Quantum chemists refer now in their calculations of optirnized geornetries to this standard
geometry (73MI40400,81JHC1l89). Another conclusion of this study is that the N - N bond
is the weakest bond in pyrazoles and is one that is stretched in order to close the ring.
This is in accord with electron impact (Section 4.04.1.3.8) and photoinduced fragrnentations
(Section 4.04.2.1.2(i)). The sornewhat longer N-H bond in the crystal structure (0.03 Å,
Figure 10) was to be expected, as it had been shown that pyrazole forrns strong hydrogen
bonds in the crystal state. Structurally, there is no prototropy, at least in the gas phase on
the time scale of a microwave experiment. This allows the experimental deterrnination that
3(5)-D-pyrazole is a 50: 50 mixture of the 3-D and the 5-0 tautomers.
182
Pyrazoles and their Benzo Derivatives
4.04.1.3.3 1 H NMR spectroscopy
(i) Aromatic systems
The excellent book by the late Professor T. J. Batterharn contains all the available
inforrnation (up to 1973) on pyrazoles and their non-aromatic derivatives (B-73NMR16S)
and on indazoles (B-73NMR263). The bibliography for pyrazoles and pyrazolones has been
updated in (B-76MI40402). It should be emphasized that alrnost all the principal results about
the I H NMR spectra of these heterocycles were published at that tirne, and thus only a
surnrnary of the principal conclusions is needed here.
In the assignment of signals and the identification of isomeric pyrazoles by this technique,
one must bear in rnind that for 'symrnetrical' systerns, i.e. those for which R 3 = R S , which
are N -substituted (52) the problem is to assign the signals (protons or rnethyl groups) of
the 3- and 5-positions (those of the 4-position always appear at higher fields (lower
frequencies)). When R 1 = H, tautomeric equilibriurn usually rnakes the 3- and 5-positions
equivalent (Section 4.04.1.5.1). On the other hand, 'asymmetric' pyrazoles, Le. those for
which R 3 R 5 , the problern of distinguishing unambiguously between isomers (53) and (54)
is often a difficult one.
R 4 R 3 R 4 R 3
RS O N RSnN
N/ 'N)
R R
(52) (53) (54)
These two problerns are closely related and will be discussed together under the title of
assignrnent of signals since it is evident that if the signals are correctly assigned then the
isorneric structure of the pyrazole follows irnmediately. The main methods to assign signals
in pyrazoles employ the following:
(i) The fact that hs is always larger than J 3 ,4; the more the electron-withdrawing ability
of R 1 the rnore the difference between both 3 J constants as a consequence of the localization
of the 1T-system. This fact can be used for compounds having two adjacent protons like 3-
or 5-arnino- or hydroxy-pyrazoles (74JPR70S) or a proton and a rnethyl group (R 3 = R 4 =
H; R 3 's, = Me, R 4 = H; R 3 (S) = H, R 4 = Me). Caution rnust be exercised not to extend
rnechanically these rules to IH_ 19 F (77BSF171) or 19F_19F (79TL3179) coupling constants in
pyrazoles.
(ii) The fact that the signal of the proton in position 3 is broadened by the nuclear
quadrupole relaxation effect of N-2 (the broadening disappears by heteronuclear decoup-
ling). If the H-3 signal is a singlet (R 4 "i' H), it is srnaller than the H-5 signal; if it is a doublet
(R 4 = H), it is less well resolved than that of H-5.
(Hi) The fact that the signal of the substituent in position 5 is rnore sensitive to solvent
effects than that of the 3-substituent. This is true for protons and methyl groups, the best
solvents for these studies being benzene, CDCh, DMSO and HMPT. A beautiful illustration
of this method is provided by the establishrnent of the structure of the six 1, l'-dimethyl-
bipyrazolyl isorners (72JHC1373).
(iv) The appearance of the C- or N-phenyl signal when a substituent, generally a rnethyl
group, is in a vicinal position. In this case the phenyl group gives rise to a singlet (in CDCh);
if there is no substituent, the signal appears as two multiplets (ortho protons at low fields,
meta and para protons at high fields). The difference, 6.8, between ortho and meta-para
protons is characteristic of the position of a phenyl group in the azole ring (73CJC231S).
(v) Paramagnetic metals (71OMR(3)S9S,79CJC1186) associated with the N-2 lone pair
(Section 4.04.2.1.3(vi)). Consequently, the signal of the 3-position rnoves further than that
of the 5-position.
The mean chernical shifts of N- unsubstituted pyrazoles have been used to deterrnine the
tautorneric equilibriurn constant, but the method often leads to erroneous conclusions
(76AHCtS1J1) unless the equilibrium has been slowed down sufficiently to observe the signals
of individual tautomers (Section 4.04.1.5.1). When acetone is used as solvent it is necessary
to bear in rnind the possibility (depending on the acidity of the pyrazole and the ternperature)
of observing the signals of the 1: 1 adduct (55) whose formation is therrnodynamically
favoured by lowering the solution ternperature (79MI40407). A sirnilar phenornenon is
observed when SOz is used as solvent.
The IH chernical shifts shown in Table 6 for 3-substituted pyrazoles are rnean values of
3- and 5-substituted tautorners. Only in the case of the 3-azidopyrazole (56) have the
R 4 R3
RS ÇN R
Pyrazoles and their Benzo Derivatives
183
R 4 R 3 H 4 Ñ, + 0
RSCN n N N H8.62
7/ HS---ZN;N 9.91 H/ );;J
Melll / ""C, Ál 8.12 H \,;j'
00 H
(55) (56) (57)
couplings with the N(1)-H proton been observed, demonstrating the presence of the azido
group in position 3 exclusively. In the spectrum of 4-formylpyrazole (57) at low ternperature
the signals of protons H-3 and H-5 are different. This is not related to the annular
tautornerism but is the consequence of a slow rotation about the C-C(4) forrnyl-pyrazole
bond (LlG = 36.7 kJ rnol- 1 ).
The chernical shifts have been discussed using ernpirical additive rules (B-73NMR165).
Several authors have tried to correlate l H chemical shifts and charge densities of the carbon
atom to which the proton is bound. The success has only been moderate due to the fact
that the underlying hypothesis is an oversimplification of the theory of the chemical shift
(67MI40402). Much better results are obtained with 13C chernical shifts (Section 4.04.1.3.4).
However, sorne significant papers rnust be quoted in this respect. An old paper by Lynch
and Dou (66TL2627) correlates lH chemical shifts rneasured in TFAA with HMO 1T-electron
densities of 1-methyldiazoles. They found an ernpirical equation: 8 = 7.98 -7.90(1- Q1T)'
Adam and Grimison (67T25 13, 67MI40401) cornpare the total electron densities calculated by
the EHT method (Section 4.04.1.2.1) with the lH chemical shifts of a series of five-rnembered
rings, including pyrazole. A reasonable correlation was obtained. Finally, all-electron ab
initio calculations (B-70MI40401) show that proton chernical shifts do not correlate with
the 1T-electron densities but with the u- and total-electron densities (however H-3(5) of
pyrazole clearly deviates). All the studies quoted above suffer frorn using the mean signals
of N -substituted azoles.
The results in Table 7 show that the chemical shift of H-5 is very sensitive to the nature
of the R 1 substituent. The ratio hs :J 3 ,4 also varies with R \ frorn 1.0 (R 1 = NHz) to 1.82
(R 1 = N0 2 ). One publication (78MI40403) describes the chernical shifts of twenty N-
substituted derivatives of pyrazole (rnainly R 1 = alkyl). Table 8 is a selection of pyrazoles
substituted both on the nitrogen atom and on the carbon atorns. The srnall coupling constant
between the N- rnethyl group and H-5 could be used to assign isorneric structures (it
disappears in 5-substituted derivatives). When the substituent on the nitrogen atorn or the
carbon atorns has a lone pair in a position ortho to it (as in 2'-pyridyl or 3'-pyridazinyl), a
deshielding effect is observed on the opposite proton (70BSF1345, 70BSF1346, 81JHC9). The
isorners (58) and (59) clearly illustrate this phenomenon (80JHC137). The N-methyl chernical
shifts of 22 pyrazoles have been gathered and cornpared with those of other azoles; they
are characteristic of the azole ring (73CJC2315).
í: 1 :
6.83 H H 7.95
Me V ;N.
N .
I
CH 2 5.20
I
Ph
(59)
Work on indazoles has the drawback of having to employ computer procedures to analyze
the ABCDX systern of C- unsubstituted indazoles. The first five exarnples in Table 9
correspond to LAOCOON-analyzed spectra and the last two to simpler systems for which
the first-order analysis gives acceptable chemical shifts.
The rnost characteristic coupling constant in indazoles is the 'cross-ring' 5 J 3 ,7 present
both in indazoles and in isoindazoles unsubstituted in positions 3 and 7. 2-Methyl isomers
show an additional 4J Me ,H coupling which can serve to identify an isoindazole unsubstituted
in position 3. In 3-azidoindazole, as in 3-azidopyrazole (56), the prototropic exchange is
slowed down sufficiently to allow the measurement of a 'zig-zag' 5 J 1,4 coupling constant.
The deshielding effects observed in N -acetyl derivatives, e.g. I-acetyl (60) on H -7 and
2-acetyl (61) on H-3, are related to a preferred E conforrnation (Section 4.04.1.4.3).
00
Table 6 I H NMR Spectral Data for N-Unsubstituled Pyrazoles'
S(I H ) (p.p.m.) Coupling constants; (Hz)
Pyrazole R J R 4 R 5 Solvent H-I H-3 H-4 H-5 3,4 4,5 3,5 Others
Pyrazole H H H CCl 4 12.64 7.61 6.31 7.61 2.0 2.0
3-Methyl Me H H CDCI 3 2.32 6.06 7.48 1.7
4-Methyl H Me H CDCI 3 7.36 2.09 7.36
3+Butyl Bu' H H CDCI 3 1.37 6.06 7.44 1.9
3,5-Dimethyl Me H Me CDCI 3 2.21 5.76 2.21
3,4-Dimethyl Me Me H CDCI 3 2.20 1.98 7.26
N
3,4,5- Trimethyl Me Me Me CDCI 3 2.20 1.87 2.20 c
3-Phenyl Ph H H CDCI 3 7.77 6.53 7.52 2.2
'"
4-Phenyl H Ph H DMSO-d 6 8.00 7.3-7.6 8.00 !::>
3-Fluoro b F H H CDCI 3 5.83 7.39 (6.0) 2.7 (2.7) ;:s
4-Fluoro c H F H CDCI 3 12.40 7.49 7.49 (4.5) (4.5) ....
3-Chloro Cl H H CDCI 3 6.24 7.53 1.9
4-Chloro H Cl H CDCI 3 12.75 7.53 7.53 :;;.
4-Bromo H Sr H CDCI 3 12.23 7.60 7.60 I:1:J
4-Iodo H I H CDCl 3 7.65 7.65 ;:s
3-Nitro d NO z H H DMSO-d 6 7.69 7.00 8.02 2.6 N
c
4-Nitro d H NO z H DMSO-d 6 11.20 8.54 8.54 tJ
3-Nitroso. NO H H CDCI 3 14.3 5.97 7.99 2.8 <1>
4-Nitroso' H NO H DMF-d 7 13.1 8.68 8.68 ::I.
3-Azido f N 3 H H CDCI 3 3.34 6.01 7.55 2.35 1 1 .4 2.10,11.5 1.45 k !::>
....
3-Amino NH z H H (CD 3 hCO 5.12(b) 5.52 6.30 2.2 .
4-Ethoxy H OEt H CDCI 3 10.96 7.25 3.92, 1.36 7.25 '"
4-Formyl2 H CHO H TIfF (163 K) 8.12 9.91 8.62
3-Ethoxycarbonyl COzEt H H CDCI 3 5.51,1.40 6.86 7.80 2.3
3-Cyano CN H H CDCI 3 12.37 6.80 7.81 2.5
3- Trimethylsilyl' Me3Si H H CCI 4 13.78 0.30 6.37 7.62 1.9
4- Trimethylsilyl' H SiM e 3 H CCI 4 14.78 7.50 0.22 7.50
· Unless otherwise indicated, data taken from (B-73NMR165) and (B-76MI40402), for which see references to the original literature. b (75MI40403). c (75LA470). d (79MI40407). . (71CB3(J{j2). f (74JHC921).
2 (75BS8499). h (71JCS(CI2147). j (nCB1759). j Values in parentheses are IH_ 19 F coupling constants. k Couplings with NH -1 are observed only in DMSO.
Pyrazoles and their Benzo Derivatives 185
Table 7 I H NMR Spectral Data for N-Substituted Pyrazoles'
SeH) (p.p.m.) Coupling constants (Hz)
Pyrazole Solvent H-l H-3 H-4 H-5 3,4 4,5 3,5
1-Methyl CD0 3 3.88 7.49 6.22 7.35 2.0 2.3 0.7
1-Ethyl CDCl 3 4.18,1.47 7.50 6.23 7.38 2.0 2.3
1-Phenyl CDCh 7.2-7.6 7.72 6.46 7.87 1.9 2.5 0.7
1-(2' ,4' ,6' - Trinitrophenyl) CDCl 3 8.92 7.85 6.60 7.74 1.9 2.6
1-Acelyl CDCl 3 2.70 7.71 6.44 8.25 1.6 2.9 0.6
1-Ethoxycarbonyl CDCl 3 4.54, 1.46 7.77 6.44 8.18
1-Carboxamido CDCl 3 7.66 6.40 8.26 1.6 2.7 0.7
1-Tosyl DMSO-d 6 Me: 2.36 7.88 6.58 8.45 1.7 2.8 0.6
1-Nitro b Acetone-d 6 7.77 6.66 8.65 1.7 3.1 0.9
1.Amino b CDCl 3 6.3(b) 7.30 6.06 7.30 2.2 2.2
1- Trimethylsilyl CCl 4 0.41 7.63 6.21 7.53 1.5 2.4
1- Trimethylgermyl CCl 4 0.63 7.57 6.19 7.42 1.6 2.2
1-P( NMe zh CDCl 3 2.66 7.70 6.30 7.53 1.9 2.2
· Unless otherwise indicated, data taken from (B-73NMRI65) and (B-76MI40402) which see for references to the
original literature. b (81UP40400).
OZN N
N
H 7 I
C
O-? 'Me
H 3
OzN (r) -;;.- ....,;0
N-C:;/
::::,... 'Me
(60)
(61)
H 6 . 05
7.35 HOH 7.35
N'.:..::N
(62)
The chemical shifts of the pyrazolate anion (62) represented an up field effect of 0.3 p.p.m.
compared with pyrazole itself (68JA4232).
The l H NMR spectra of pyrazolium and indazolium ions have been widely studied (Table
10), including both the conjugate acids and the quaternary salts. The spectra obtained in
sulfuric acid prove unquestionably that the protonation of these species takes place at
position 2 (Section 4.04.2.1.3(iv)).
The N-methyl chemical shifts of quaternary pyrazolium and indazolium salts have been
discussed in connection with the resonance effect of the heterocycle (74JHC1011).
The spectra of pyrazolinones have been used in tautomeric studies (Section 4.04.1.5.2).
The l H chemical shifts shown in Table 11 are representative of the three classes of fixed
derivatives [OR (63) and (64), NR (65) and CR (66)], and many others are discussed in
(76AHC(Sl)1). Some tautomeric compounds are also included in Table 11.
O OMe
M r
e /N
N
Ph
(63)
Me
EtOCN
N
Ph
(64)
Me
o .J::;N Me
N
Ph
(65)
Me 2 n Me
O _.;N
N
Ph
(66)
(ii) Non-aromatic systems
Sparse data on the pyrazole isomers, pyrazolenines and isopyrazoles, are presented in
Table 12. Besides the obvious upfield effect on the chemical shift due to the suppression of
the ring current, these compounds behave normally. Data on pyrazolidinones and their
salts show the behaviour of cyclic hydrazides (66T2461, 67BSF3502).
Considerable effort has been devoted to the NMR study of pyrazolines. The results shown
in Table 13 represent a minute part of the literature values, and more can be found in
(B-73NMR165).
NMR studies of ill -pyrazolines, mainly due to Crawford, McGreer and Carrié, cover
two main topics: determination of the stereochemistry of carbon atoms C-3, C-4 and C-5
(cis-trans pairs) and calculation of the ring puckering. For the latter purpose, chemical
shifts and coupling constants via the Karplus equation have been used. A reasonable
estimation of the (j angle of il 1 -pyrazolines (67) is 30 0 (73T1135,76BSB545). When the
substituents on the 4-position are different, the equilibrium constant between the two
envelope conformations (67a) and (67b) may be determined by lH NMR (730MR(5)453).
.-
00
0\
Table 8 I H NMR Spectral Data for N,C-Substituted Pyrazoles'
R 1 R 3 R 4 R 5 8(I H ) (p.p.m.) Coupling constants (Hz)
Pyrazole Solvent H-I H-3 H-4 H-5 3.4 4,5 3,5 Others
1,3-Dimethyl Me Me H H CDCI] 3.80 2.23 5.95 7.22 2.0 4 J (NMe-H(5)) 0.4<
l,4-Dimelhyl Me H Me H CDCI] 3.80 7.28 2.04 7.12
1,5-Dimethyl Me H H Me CDCI] 3.73 7.36 5.98 2.22 2.0
1,3,5- Trimethyl Me Me H Me CDCI] 3.66 2.17 5.78 2.17
1,3,4,5 - T etramethyl Me Me Me Me CDCI] 3.68 2.14 1.89 2.12
I-MethyI-3-phenylb Me Ph H H CDCI] 3.85 7.4-7.8 6.50 7.75 2.0 4 J (NMe-H(5)) 0.4<
I-Methyl-5-phenylb Me H H Ph CDCI] 3.82 7.50 6.30 7.40 1.5
N
1,3-Dimethyl-5-phenyl Me Me H Ph CDCI] 3.80 2.30 6.09 7.43 c
1,5-Dimethyl-3-phenyl Me Ph H Me CDCI] 3.80 7.78 6.30 2.30
'"
3-Methyl-1-phenyl Ph Me H H CDCI] 7.2-7.7 2.35 6.23 7.78 2.6 !::>
5-Methyl-1-phenyl Ph H H Me CDCI] 7.43 7.56 6.19 2.34 1.5 ;:s
.....
. Unless otherwise indicated, data taken from (B-73NMRI6S) and (B-76MI40402). b (69BSF3306). < (SOM77S).
::;.
I:1:J
;:s
Table 9 IH NMR Spectral Data for Indazoles N
c
8(I H ) (p.p.m.) tJ
Indazole Solvent NR H-3 H-4 H-5 H-6 H-7 Other data Ref. ::!.
Indazole DMSO-d 6 13.04 8.08 7.77 7.11 7.35 7.55 J 3.7 1.11,14.5 8.12, J 4 . 6 0.96,14.7 1.05, 770MR(9)235 (3'
J 5 . 6 6.89,15.7 0.78, h.7 8.46 '"
3-Methyl CDCI] 2.63 7.64 7.10 7.32 7.40 Coupling constants 75JCS(P1)1695
I-Melhyl CDCI] 3.95 7.94 7.71 7.10 7.34 7.59 Coupling constants 75JCS(Pl) 1695
2-Methyl CDCI] 3.80 7.67 7.56 7.02 7.26 7.68 J(Me-H(3)) 0.5-0.6 75JCS(P1 )1695,
80M775
3-Azido DMSO-d 6 12.92 7.58 7.13 7.41 7.51 J 1.4 0.65 770MR(9)235
1-Acetyl-5-nitro CDCh 2.83 8.30 8.70 8.42 8.57 Coupling constants 66BSF2075
2-Acetyl-5-nitro CDCI] 2.95 9.05 8.75 8.15 7.80 Coupling constants 66BSF2075
Table 10 IH NMR Spectral Data for Pyrazole and Indazole Cations
SCH) (p.p.m.)
Compound N(1)-R N(2)-R Solvent H-l H-2 H-3 H-4 H-5 Other data Ref
Pyrazole H H H 2 SO 4 ]2.5 ]2.5 8.]8 6.90 8.]8 11.3 =12,3 2.25, 1 2 .4 2.0,1 3 .4 2.8 8JUP40400
1-Phenylpyrazole Ph H H 2 SO 4 12.2 7.75 6.50 7.75 12,3 =h.5 2.0,1 2 . 4 1.6, 740MR(6)272
13.4 =1 4 . 5 2.95
Indazole H H H 2 SO 4 11.35 12.11 8.13 11.3 0, h.3 2.3 740MR(6)272
1,2-Dimethylpyrazolium Me Me DMSO-d 6 4.20 4.20 8.57 6.87 8.57 1 3 . 4 = 1 4 . 5 3.0:1: 0.],1 3 . 5 0.9:1: 0.1 B-73NMR165,
69BSF1687
2-Melhyl-1-phenylpyrazolium Ph Me DMSO-d 6 7.82 3.99 8.95 7.18 8.88 13.4 =1 4 . 5 3.0:1:0.1,1 3 . 5 0.9:1:0.1 B-73NMR165,
69BSF1687
1,2,3,4,5 -Pentamethylpyrazolium Me Me DMSO-d 6 3.96 3.96 2.37 2.01 2.37 B-73NMR165
1,2-Dimethylindazolium Me Me DMSO-d 6 4.34 4.49 9.28 69BSF1687
Table 11 IH NMR Spectral Data for Pyrazolinones'
sCH) (p.p.m.)
Compound Solvent H-l H-2 H-3 H-4 H-5
3 -Methylpyrazolin -S-one DMSO 10.94 2.12 5.31
3- Methyl-1-phenylpyrazolin -5-one CDCl 3 7.3-7.8 2.12 3.37 b
3- Hydroxy-5-methyl-1-phenylpyrazole CHCl 3 7.33 11.1 5.54 2.16
3-Methoxy-5-methyl-1-phenylpyrazole Neat 7.37 3.87 5.66 2.10
5- Ethoxy-3-methyl-1-phenylpyrazole CHCl 3 7.0-7.9 2.26 5.50 4.14,1.41
2,3- Dimethyl-1-phenyl-3-pyrazolin -5 -one CHCI 3 7.30 3.07 2.20 5.37
3,4,4- Trimethyl-l-phenyl-2-pyrazolin-S-one CDCI 3 7.2-7.9 1.94 1.18 e
. Data taken from (B-73NMRI65), which see for references to the original literature. bCH 2 . eCMe2'
;::
N
'"
$::I
:::s
!::I..
-
:::s-
""
:;.
""
:::s
N
t1
""
....
(:;'
(:;'
""
""
>-'
00
-J
Table 12 'H NMR Spectral Data for Pyrazolenines and Isopyrazoles
S('H) (p.p.m.) ......
Compound Solvent H-l H-3 H-3' H-4 H-4' H-5 Ref 00
00
5 - Methoxycarbonyl-3 ,3,4-trimethylpyrazolenine CDCI 3 1.39 1.39 2.31 3.98 69JCSrC) I 065
4-Methoxycarbonyl-3,3,5 -lrimethylpyrazolenine CDCl 3 1.52 1.52 3.86 2.69 69JCS(C) 1065
3,3,5- Trimethylpyrazolenine I-oxide CCl 4 1.38 1.38 7.10 2.08 62JOC1309"
3,3,5-Trimethylpyrazolenine 2-oxide CClt 1.40 1.40 5.90 2.12 62JOC1309"
3,4,4,5- Tetramethylisopyrazole CDCl 3 2.16 1.17 1.17 2.16 68BSF3866
4- Benzyl- 3,4,5 -trim ethylisopyrazole CDCl 3 2.15 1.24 (Me) 2.97 (CH 2 Ph) 2.15 70JA6218
3,5 - Dimethyl-4-hydroxy-4-phenylisopyrazole CDCl 3 2.03 7.33 (Ph) 7.73 (OH) 2.03 76JOC2874
1- Ethyl-3 ,4,4,5 -tetramethylisopyrazolium iodide CDCi) 4.44, 1.63 2.35 1.63 1.63 3.00 68BSF3866
"See also (B-73NMRI65).
Table 13 I H NMR Spectral Data for Pyrazolines and their Salts
N
c
S('W (p.p.m.)
'"
Pyrazoline Solvent H-l H-2 H-3 H-3' H-4 H-4' H-5 H-5' Other data Ref
;:s
Unsubstituted-b. I Neat 4.27 4.27 1.46 1.46 4.27 4.27 65JA3023
....
3-Acetyl-3,4-dimethyl-b. I (E) CCl 4 3.60 (Ac) 1.26 (Me) 2.15 (H) 0.87 (Me) 4.57 3.95 Coupling constants B-73NMR165
3-Acetyl-3,4-dimethyl-b.' (Z) CCl 4 3.70 (Ac) 1.53 (Me) 0.90 (Me) 1.72 (H) 4.68 3.98 Coupling constants B-73NMR165 ::;.
3,5-Dimethyl-b.' (E) CCl 4 1.29 (Me) 4.57 (H) 1.27 1.27 4.57 (H) 1.29 (Me) B-73NMR165 I:1:J
3,5-Dimelhyl-b. 1 (Z) CCl 4 4.20 (H) 1.54 (Me) 2.08 0.48 4.20 (H) 1.54 (Me) B-73NMR165 '"
;:s
3,3-Dimelhoxycarbonyl-4-methyl-b. 1 CDCi) 3.81 3.86 2.82 4.82 4.27 Coupling constanls 730MR(5)453 N
C
Unsubstituted-b. 2 CDCi) 5.33 6.88 2.65 2.65 3.31 3.31 Coupling constants 70UP40400 0
'"
1,3-Dimethyl-b. 2 CDCi) 2.74 1.95 2.96 2.96 3.58 3.58 Coupling constants" 70UP40400 .....
.
1-(2,4-dinitrophenyl)-3-methyl-b. 2 CDCl 3 2.12 3.01 3.01 3.79 3.79 Coupling constants" 70UP40400
....
1-Formyl-3-methyl-b. 2 CDCiJ 8.81 2.05 2.88 2.88 3.90 3.90 Coupling constanls".b 70BSF3466 .
3,5,5- Trimethyl-b. 2 CDCiJ 4.4 1.99 2.42 2.42 1.25 1.25 Coupling constants 70UP40400
'"
3,4,4.5,5- Pentamethyl-1-phenyl-b. 2 CDCi) 1.95 0.91 1.03 3.55 (H) 1.02 (Me) Coupling constants 68BSF3866
1,3-Diphenyl-b. 2 CDCi) 3.12 3.12 3.76 3.76 Coupling constant{ B-73NMR165
3,5-Diphenyl-b. 2 CDCiJ 2.89 3.35 4.02 Coupling constants d 74MI40401
1,2,3- Trimethyl-b. 3 CDCl 3 2.55 2.60 1.71 4.60 3.65 3.65 Coupling constants. 69BSF3316
1 ,2,3,5,5-Penlamethyl-b. 3 CDCl 3 2.47 2.56 1.80 4.53 1.17 1.17 70BSF3147
2.3.5- Trimethyl-1-phenyl-b. 3 CDCl 3 7.2 2.70 1.80 4.69 4.20 (H) 1.37 (Me) Coupling constants 70BSFl129
I H-Ll'-Pyrazoline (70) CDCi) 4.96 4.17 rCH) 1.80 1.80 'H_ 19 F Coupling 79T389
constants
1,1 ,3,5,5-Pentamethyl-b. 2 -pyrazolinium DMSO-d ó 3.16 2.15 3.28 3.28 1.48 1.48 67BSF3516
1,2,3,5,5-Pentamethyl-b. 2 -pyrazolinium CDCl 3 2.92 3.78 2.57 3.23 3.23 1.35 1.35 67BSF3516
"1 3 .4 = 1.0 ( 7MI40402). h 11.5 = 1.0 (70BSF3466). /4.4 (gem ) = - ?O: hs(trans) = 8.7, 1 4 . S (cis) = 12.0, 1 s . s (gem) = -10.0 (B-73NMR16S). d 1 4 .4(gem) = -16.32, 1 4 . S (trans) = 8.74, 1 4 .s(cis) = 10.68
(74MI40401). 13.4 =h.i;=1 4 . S = 1.8 (69BSF3316). endo-exo eqUlhbnum of the double bond (70BSF3147).
Pyrazoles and their Benzo Derivatives
189
N
/JI
R4 .N
R
R4'
__ __r. ;_
. N
(67a) (67b)
The work on 2 -pyrazolines of the Montpellier group is well summarized in (B-73NMR
165) except for some unpublished results (70UP40400) covering about 100 compounds. The
2-pyrazoline ring is also puckered (68) and a method based on the Karplus equation that
uses the ratio of the vicinal coupling constants (74MI40401) has been used for the calculation
of the puckering angle (20 0 < 8 < 400) and the conformation populations. An X-ray study
(quoted in 76BSB545) gives a value of 8 = 27 0 for the 5-methoxycarbonyl-4,5-diphenyl-2-
pyrazoline.
,Z./H.
;--i l
R 3
(68)
The Eu(dprnh shift reagent has peen used to assign the cis-trans configuration of
3,4-dimethoxycarbonyl-1-phenyl-2-pyrazolines since the value of the 3 14 . 5 coupling constant
is almost the same for both compounds (74CB1318). Eu(fodh has also been used in connection
with bicyclic pyrazolines (79JOC2513). The results in Table 13 show that for 1,3-diphenyl-
and 3,5-diphenyl-2-pyrazolines leis > Itra s> but this criterion could be misleading since it
depends on the nature of the substituent on N-1 (74MI40401). Another criterion for the
assignment of pairs of cis-trans isomers, when R 4 = R 5 = Me, uses the McConnell anisotropy
effect of the methyl group on the vicinal proton (68BSF4403, 74CJC2296).
Chemical shifts for some representatives of the less common class of 3 -pyrazolines are
shown in Table 13. These cyclic enehydrazines are also probably puckered (69); however,
no X-ray determination nor conformational study has been carried out to solve this problem.
Compound (70) is representative of the rare N(l)-unsubstituted 3 -pyrazolines prepared
by Burger et al. (79T389).
"N R Z
R'/ ' / ('
8 ""N
_____t. -,------ ' 4
(69)
Me Me
(F 3 C) C'N CH(CF 3 )z
N
H
(70)
The salts (71) and (72) are both 2-pyrazoline derivatives. However, the first one is
obtained by quaternization of a 2 -pyrazoline and the second one by protonation of a
3 -pyrazoline (Section 4.04.2.2.2(v)). Several 2 -pyrazolinium salts (72) and their NMR
spectra are described in (69BSF3292, 71T123) and for 3 -pyrazolinium salts (73) see (69BSF3316).
0.15 Mer-tri 1.22
z....+.;N
N
/" { 8 A =4.98
H ZT THz 8 B =5.99
Ph Ph J AB = 12.2
(74)
When the N-1 atom of salts of type (71) bears two prochiral groups an anisochrony of
protons analogous to that of diethyl acetals is observed. For instance in compound (74) the
benzylic protons show chemical shifts at 8 4.98 and 5.99 p.p.m. with JA.B = 12.2 Hz
(690MR(1)249) .
The fully saturated pyrazolidines have been utilized as models for the study of the nitrogen
inversion of hydrazines. For instance, (75), a 2,3-diazabicyc10[2.2.1]heptene derivative,
presents a consecutive inversion process at two nitrogen atoms with an activation barrier
of 59 kJ mol- 1 determined by proton line-shape measurements (67JA81). Monocyclic
Me
MeQN
N
/ "
Me Me
Me
MeO N ; '
I Me
Me
(72)
(71)
R 4 R 3
R s:r=\
R s'X-.Ñ;NR Z
1/ " M
R e
(73)
190
Pyrazoles and their Benzo Derivatives
pyrazolidines are discussed in (B-73NMR16S). It has been shown by 1 H NMR data that the
tetrarnethyl derivative (76) exists in a conforrnation such that the steric effects are rninimized
(690MR(1 )249).
(75b)
Me
M,;::i" M
I e
Me
(76)
J:-:<' -
I
Me
(750)
J:-rx M '
N Me
4.04.1.3.4 13e NMR spectroscopy
In contrast to the previous section, there is little inforrnation available on 13C NMR
spectra of pyrazoles and indazoles in books or reviews. Consequently, this section will treat
the literature results in some detail, giving the principal references and sorne illustrative
examples.
Pyrazole itself (Table 14) has been studied several times, the most remarkable conclusion
being that, depending on the solvent and the ternperature, one or two signals are observed
for carbons C-3 and C-5. This is comrnon for all the N-unsubstituted pyrazoles with not
too different tautomer populations. It has become quite comrnon to observe broad signals
for these carbons in spectra run in polar aprotic solvents, like DMSO. The factors that
influence the prototropic exchange rate have been discussed (79JAS4S,79MI40407); in the
solid state the proton is firrnly bound to the nitrogen atorn (81CC1207).
For N- substituted pyrazoles, Table 14 shows a regular trend in the effect of the R 1
substituent; when the electron-withdrawing properties of the substituent increase all the
signals shift to lower fields and, sirnultaneously, the 1J coupling constants increase. Figure
13 represents the variation of the 1J coupling constants at the three carbon atoms for 11
R 1 substituents (first-order analyzed spectra). It appears that it could be dangerous to assign
C-3 and C-5 signals frorn the 1J value, unless R is an electron-withdrawing substituent,
d h f 1 J 1 J 1 J
an t ere ore C-S.H-S > C-3. -3 > C-4.H-4.
For 'asyrnmetric' pyrazoles, C NMR data, both chemical shifts and coupling constants,
prove superior to 1 H NMR data for identifying isorneric structures and even for deciding
the major tautorner in solution (Section 4.04.1.5.1). For instance, values in Table 14 for
3(5)-nitropyrazole and its two derived nucleosides clearly show the 3-nitro tautorner
preponderance. The C-Me signal is characteristic of its position on the pyrazole ring
(3-Me -13.5, 5-Me -11 p.p.m.), and the N-Me signal is sensitive to the presence or
absence of a substituent in the 5-position. The difference, Á8 = 8 0 - 8m, is related to the
torsion angle between the two aromatic rings in N-phenylazoles (73ACS3101), and it has
been used to calculate a dihedral angle of 25 0 for I-phenylpyrazole (Section 4.04.1.4.3)
(78Tl139). However, Á8 depends not only on steric factors but also on the electronic
properties of the azole (8IUP40400).
Linear relationships between chemical shifts and the total charge densities in azoles,
including pyrazole, have been described several times (67JA6835, 67T2513. 68JA4232. B-
70MI40401). However, a careful study with a large set of data on N-methylazoles shows that
if a general trend is actually observed (8 = -216q7T+O- +988, R = 0.919 (780MR(11)234)), the
possibility of assigning carbon signals using calculated charge densities is presently excluded.
Table 15 contains the 13 C chemical shifts of some selected indazoles. The major difference
between indazoles and isoindazoles lies in the chernical shifts of carbons C-3 and C-7a.
The substituent chemical shift (SCS) induced by the substituent in position 3 have been
discussed using an empirical model (noMR(9)716). The rnodel that gives the best results,
Á8 = afli + bÇfJl + c22 * (fli and ÇfJl are the Swain-Lupton pararneters and 22 * is the Schaefer
pararneter), has been used with succesS to correlate SCS (780MRClI)617). However, the
tendency today is to apply the principal component analysis to the data without making
any assumption (8lJCSCP2)403). The benzo condensation effect, i.e. the effect on the hetero-
cyclic carbon chernical shifts when pyrazole and indazole are compared, has been discussed
in connection with other such pairs (780MR(11)617).
Other pyrazole derivatives have not been the subject of systematic studies. Owing to the
variety of structures involved, figures instead of tables are used to describe chernical shift
Table 14 13C NMR Chemical Shifts for Pyrazoles P
8( 13 C) (p.p.m. from TMS)
Compound Solvent C-l C-2 C-3 C-4 C-5 Other data Ref.
Pyrazole CH 2 Cl 2 134.6 105.8 134.6 74JOC357
Pyrazole Acetone 133.4 104.6 133.4 Coupling constanls a 76JCS(P2)736
Pyrazole HMPT (-17 O C) 138.1 103.9 127.6 77JOC659
Pyrazole DMSO-d 6 (29 OC) 138.6 104.5 128.2 Coupling constants b 79JA545
Pyrazole DMSO-d 6 (34 OC) 133.7(b) 104.8 133.7(b) 790MR(12)587
Pyrazole Solid slate 138.7 107.0 128.8 81CC1207 ï::1
3 (5)-Methylpyrazole CH 2 Cl 2 144.4 (CMe) 105.3 135.8 CMe 12.6 74JOC357 N
3-Methylpyrazole C HMPT (-17 OC) 146.05 103.2 128.3 3-Me 13.7 77JOC659
5-Methylpyrazole c HMPT (-17 O C) 137.2 103.2 138.6 5-Me 10.55 77JOC659 ""
3,5-Dimethylpyrazole CH 2 Ch 145.3 104.8 145.3 74JOC357 $::I
:::s
3(5)-Nitropyrazole Acetone-d 6 d 102.4 132.6 Coupling constants 79MI40407
4-Nitropyrazole Acetone-d 6 132.5 135.6 132.5 Coupling constanls 79MI40407 ....
:::s-
3-Azidopyrazole e Acetone-d 6 146.8 (CN 3 ) 95.3 131.1 Coupling constants! 79MI40407
:::;.
3(5)-Aminopyrazole DMSO-d 6 154.0 (CNH 2 ) 91.5 132.0 790MR(12)587 b:J
3 (5)-Amino-5 (3 )-Methylpyrazole DMSO-d 6 155.1 (CNH 2 ) 92.9 142.9 5(3)-(Me) 11.9 790MR(12)587
1-Methylpyrazole CDCI 3 38.4 138.7 105.1 129.3 Coupling constants 78JCS(P2)99 :::s
N
1-Elhylpyrazole CDCI 3 15.6 (Me), 46.8 (CH 2 ) 139.0 105.3 128.1 79MI4041O
1-t-B ulylpyrazole CDCI 3 29.9 (Me), 58.1 (C) 138.9 104.7 125.3 Coupling constants 8lUP40400 tJ
1- Allylpyrazole CDCl 3 139.2 105.7 128.9 g 79MI4041O ....
1-Benzylpyrazole CDCI 3 55.8 (CH 2 ) 139.4 105.7 129.1 79MI40410 (:;'
$::I
1-Phenylpyrazole CDCl 3 140.7 107.3 126.2 Coupling constants g 73ACS3101 ....
(:;'
1-p-Nitrophenylpyrazole CDCI 3 142.7 109.3 128.8 8lUP40400
1-(2,4-Dinitrophen yl)pyrazole DMSO-d 6 143.8 109.6 131.0 g 8lUP40400 ""
1-Acetylpyrazole CDCl 3 21.3 (Me), 169.2 (CO) 143.6 109.3 127.8 Coupling constants h 78JCS(P2)99
1- Elhoxycarbonylpyrazole DMSO-d 6 149.1 (CO) 144.4 109.3 131.2 g 8lUP40400
1-Carboxamidopyrazole DMSO-d 6 142.3 108.6 128.8 8lUP40400
1- Tosylpyrazole DMSO-d 6 21.1 (Me) 145.8 109.6 132.4 8lUP40400
1- Triftuoromethylsulfonylpyrazole CDCh 119.3 (CF 3 ) 148.4 111.9 134.1 8lUP40400
1-Nitropyrazole DMSO-d 6 141.6 109.8 126.8 8lUP40400
1-Aminopyrazole DMSO-d 6 136.9 104.2 129.2 8OJCR(M)0514
continued overleaf
>-'
\0
>-'
\C
IV
Table 14 13C NMR Chemical Shifts for Pyrazoles (continued)
8(13C) (p.p.m. from TMS)
Compound Solvent C-l C-2 C-3 C-4 C-5 Other data Ref.
1- Trimethylsilylpyrazole CDCh -0.8 (Me) 143.5 106.3 134.0 81UP40400
1,3-Dimethylpyrazole CH 2 Cl 2 39.1 148.8 105.6 131.0 3-Me 13.9 74JOC357
1,5-Dimethylpyrazole CH 2 Ch 36.7 138.7 105.9 139.1 5-Me 11.9 74JOC357
1,3,5- Trimethylpyrazole CH 2 Ch 36.3 147.5 105.4 139.8 3-Me 14.0, 5-Me 11.7 74JOC357
5- Amino-l ,3-dimethylpyrazole DMSO-d 6 33.9 146.2 88.9 147.9 3-Me 13.9 790MR(12)587'
3-Amino-l-methylpyrazole DMSO-d 6 38.0 155.7 92.2 131.5 790MR(12)587
5 -Amino-3,4-dicyano-l-methylpyrazole DMSO-d 6 38.0 126.5 78.9 155.1 75JOC1815
N
3- Amino-4,5-dicyano-l-methylpyrazole k DMSO-d 6 41.8 160.3 84.6 120.6 75JOC1815 c
1,5- Dimethyl -3,4-diphenylpyrazole CDCI 3 36.2 5-Me 9.9 1 790C1186 '"
5-Acetyl-4-ethoxycarbonyl-l,3 -dimethylpyrazole CDCl 3 38.2 149.3 110.6 143.0 3-Me 13.6 í . m 78JOC2665 !::>
3-Bromo-1-phenylpyrazole CDCl 3 127.9 110.4 128.4 Coupling constants R 73ACS3101 ;:s
4-Bromo-1-phenylpyrazole CDC1 3 141.3 95.5 126.8 Coupling constants g 73ACS3101 ......
5-Bromo-1-phenylpyrazole CDCh 141.1 110.2 112.5 Coupling constants R 73ACS3101 ;:s-
3- Ethoxycarbonyl-4-methyl-1-phenylpyrazole CDCI 3 142.7 122.1 127.7 4-Me 9.9 R 790MR(12)205 ::;.
5- Ethoxycarbonyl-4-methyl-l-phenylpyrazole CDCI 3 141.1 123.7 130.7 4-Me 10.31 g 790MR(12)205 I:1:J
i '"
3-Nitro-1-(ß- D-ribofuranosyl)pyrazole n 156.8 103.4 131.9 79MI40402 ;:s
5-Nitro-1-(ß- D-ribofuranosyl)pyrazole n 139.6 108.0 146.5 79MI40402 N
C
Pyrazolate anion (potassium pyrazolale) H 2 O 138.7 103.6 138.7 68JA4232 b
.....
Pyrazolium cation (pyrazole hydrochloride) H 2 O 135.2 109.1 135.2 68JA4232 .
1,2-Dimethylpyrazolium iodide DMSO-d 6 36.9 36.9 137.6 106.9 137.6 Coupling constants n 780MR(11 )234
1,2,3- Trimelhylpyrazolium iodide DMSO-d 6 37.2 34.1 146.2 106.7 136.2 Coupling constanls 780MR(11)234 .
'"
2,3-Dimethyl-1-phenylpyrazolium iodide CDCI 3 35.4 148.4 108.2 137.3 3-Me 12.5 R 82UP40400 '"
2,5-Dimethyl-1-phenylpyrazolium iodide DMSO-d 6 37.6 138.2 107.6 147.7 5-Me 12.1 g 82UP40400
a At low temperature (-40 0 C) the signals of the acetone adduct (55) were observed (75T1463. 76JCS\P2)736). b At room temperature in acetone C-3 and C-5, IJ = 185.5, 2J = 3 J = 6.6, C-4,
1J ó= 176.7, 2J = 9.9 (76JCSIP21736); in DMSO-d 6 at 10 oC, C-3, 1J = 185.9, C-5, 1J = 186.1, C-4, IJ = 175.1, 2J = 10.1 (79JA545). C Separated signals for each tautomer were observed in
HMPT at -17 oc. d Not observed. . As discussed in Section 4.04.1.3.3(i) only the 3-azido tautomer is present in DMSO-d 6 solution. f Coupling of the three carbons with the proton linked
to nitrogen is observed. g Chemical shifts of the N(l)-substituted compound are also given in the quoted reference. h C-3, I J = 187.1, 2J = 9.2, 3 J = 6.1, C-4, 1 J = 178.7, J = 11.8 and
8.8, C-5, 1 J = 190.3, 2 J = 8.8, 3J = 4.4. i See also (7911.2991) j Chemical shifts of the carbons at the 3-, 4- and 5-positions are also given in the quoted reference. k Isomeric structure
established by X-ray crystallography. I Its isomer, 1,3-dimethyl-4,5-diphenylpyrazole shows a signal at 12.7 p.p.m. corresponding to 3-Me. m Its isomer, 3-acetyl-4-ethoxycarbonyl-l.5-
dimethylpyrazoIe shows a signal at 10.4 p.p.m. corresponding to 5-Me. n 2',3',5'-tri-O-acetyl derivatives. 0 C-3, C-5, 1 J = 195, C-4, 1 J = 188. P For the spectra in the solid state see (83Ht20J1713).
Pyrazoles and their Benzo Derivatives
193
(Hz)
IJ(C(3)-H(3)) _ 204
I J (C(5)-H(5)) 0 11 IJ
202 10/
H(4) H(3)
200
)j
H(5) N....N
198 R 1
196
194
11-
192
190
188 -
9
186
184
182
178 180 182
I J (C(4)-H(4)) (Hz)
1, SiMe3; 2, Me; 3, Bu'; 4, Ph; 5, NH 2 ; 6, 4'-N0 2 C 6 H 4 ; 7, Ac; 8, 2',4'-(N0 2 hC 6 H 3 ; 9, C0 2 Et; 10,S02CF3; 11, N0 2
Figure 13 Variation of the IJ coupling constant in pyrazole with the nature of R 1
180
172
174
176
effects. Some values for pyrazolinones, pyrazolinethiones and pyrazolidinediones are shown
in Figure 14. These 13C chemical shifts have been used with success in tautomeric studies
(Section 4.04.1.5.2). As in l H NMR studies, the CH tautomer is easily identified but both
NH and OH tautomers give rise to mean signals; the NH/OH exchange rate is still too
fast on the NMR time scale. However, even the mean signals are useful for tautomeric
studies since the C-5 signal is quite different in the oxo derivatives and very different in
the thio derivatives for the NR and OR fixed forms.
A large amount of data on 2 -pyrazolines has been collected but not completely published.
Some values can be found in Figure 15.
4.04.1.3.5 Nitrogen NMR spectroscopy
The possibility offered by new instruments to obtain IsN NMR spectra using natural
abundance samples has made 14 N NMR spectroscopy a method which holds no interest for
the organic chemist, since the chemical shifts are identical and the signal resolution incompar-
ably better with the IS N nucleus (I =!) than with 14N (I = 1). l H _ 1S N coupling constants
could be obtained from natural abundance samples by IsN NMR and rnore accurately from
IsN-labelled compounds by l H NMR. Labelled compounds are necessary to measure the
13C_1SN and IS N _15 N coupling constants.
In the corning years, one can expect a great development in nitrogen NMR spectroscopy
for the study of azoles (for recent work see (82JOC5132, 83HCA1537)). At this moment most
Table 15 13 C NMR Chemical Shifts for Indazoles
Õ(DC) (p.p.m. from TMS)
Compound Solvent C-3 C-4 C-5 C-6 C-7 C-3a C-7a Other data Ref
Indazole DMSO-d 6 133.4 120.4 120.1 125.8 110.0 122.8 139.9 Coupling constants. 76CJC1329
3-Methylindazole DMSO-d 6 140.9 119.8 119.3 125.8 109.9 122.1 140.8 nOMR(9)716
3-Fluoroindazole DMSO-d 6 156.8 118.2 121.0 128.0 111.1 107.7 141.8 b 770MR(9)716
3-Azidoindazole DMSO-d ó 139.6 118.5 120.4 127.2 110.7 114.0 141.6 Coupling constants. nOMR(9)235
I-Methylindazole CDCI 3 132.4 120.8 120.2 125.9 108.6 123.8 139.7 Coupling constants C 78JCS(P2)99 d
2-Methylindazole CDCh 123.1 119.6 121.2 125.4 116.8 121.8 148.7 Coupling constants. 78JCS(P2)99 d
l-Acelylindazole CDCh 139.4 120.6 124.1 129.2 115.3 126.1 139.4 Coupling constants f 78JCS(P2)99
2-Acetylindazole CDCh 122.1 124.0 121.4 129.0 118.8 122.1 150.7 Coupling constants S 78JCS(P2)99
1,2-Dimethylindazolium iodide DMSO-d 6 132.6 122.7 124.7 132.6 111.1 118.6 139.9 Coupling constants h 780MR(1l)234
. For a rigorous determination of the coupling constants see (79MI4041l). b 13C_ 19 F coupling constants: C-3, I J "" 224, C-4, 3 J "" 4, C-3a, 2 J "" 25.5. cNMe 35.2. d See also (770MR(9)716).
· NMe 39.7. f NAc 22.7 (Me), 170.7 (CO). &NAc 21.8 (Me), 170.8 (Co). hi-Me 33.9, 2-Me 38.5.
16.8 13.9 12.9 Ph IS.8
Me Me Me e NH ' Me CH 2 R
;oS6.2 Jj J:j ""
V 148.4 158.8 103.S 147.8 :)j
170.6 '\ O V '\ 141.6
o N"N IS4.6 N 165.7 N 169.8 N : I N 160.7 N
HO W' o / --Me 3S.3 o N/ H, N/ HO N/
Ph Ph Ph Ph o 161.4 ph H
CDCr 3 DMSO-d6 CDCl 3 DMSO CDCl, DMSO-d ó
(77JCStPZilO24) (77JCS,P2ilO24) (74ACSIB)61) (70JCSICI184Z) (8IJCSIPI i697)
17.6 17.5 11.9 55.0 16.0
Me Me Me Et OMe Et 0 02 N Me
;;J:j ;;J:J C E Et D 73.S pr
V 143.8 143.2 _ 146.5 166.9 156.0
15H N 153.5 r N 170.5 173.S N o N
MeS N/ HS N" S /N'M o N/ o N/N-- Me 29.8 163.5 N"
N e 34 . 6
21.7 Ph Ph Ph Me 30.7 Me C ó H 3 (N0 2 )2- 2 ' ,4'
CDCl 3 CDCl 3 CDCl, CDCl 3 CDC1 3 Acetone-d ó
(74JHCI35) (74JHCI35) (74JHCI3S) (80CB3910) (80CB3910) (XIAP532)
Figure 14 13 C chemical shifts (p.p.m.) of pyrazolinones, pyrazolinethiones and pyrazolidinediones
......
\C
.þ..
ì3
N
o
$::)
;::
$::).
-
;:;-
.
tIJ
;::
N
o
;:!.
$::)
....
;:;.
""
15.4
54 [j 1 Me
177.7
62.2 + N
N/
./\
Me Me
'-.--'
39.2
DMSO-d 6
(SOTH40400)
I3 C chemical shifts (p.p.m.) of ð. 2 -pyrazolines and their salts
45 3 :'0. 9
H
DMSO-d 6
(SOTH40400)
33.1 142.2
46.2 O N
N/
Ph
DMSO-d 6
(790MRtI2)579)
Figure 15
Pyrazoles and their Benzo Derivatives
16.0
jj 9.6 Me
Not obs.
27.1 {M e 1 N/N
61.5 H
DMSO-d 6
(SOTH40400)
35.6 153.7
47.6 O N
N/
C 6 H z (NO z h-2',4',6'
DMSO-d 6
(790MRl12)579)
195
15.6
Me
37 0 2 1513
.
56.1 N
N/
Me 43.5
DMSO-d 6
(SOTH40400)
r
of the work on 14N NMR spectra has been done by Witanowski, Stefaniak and Webb
(B-73MI40401, 780MR(11)27, 780MR(1l)38S) and will not be discussed here. Study of 15N NMR
spectra owes a lot to the pioneering work of Roberts, whose publications on pyrazoles and
indazoles (791OC176S) will be examined in detail. The 14N nuclear quadrupole coupling
constants (measured either by pure quadrupole resonance or by microwave spectroscopy)
of heterocycles including the pyrazoles are discussed in (71PMH(4)21, 71MI40401, 81ZN(A)34).
All the chemical shifts in this section are from nitromethane as external reference; the
values for recalculating data from other external and internal standards are to be found in
(77JMR(28)217,77JMR(28)227). In particular, Roberts' positive values (reference: 1M nitric
acid) have been transformed by the following equation: ô(MeN0 2 ) = -ÔRoberts -4.43 p.p.m.
according to the general agreement that negative values denote shifts to higher magnetic
field from the reference.
Most available literature results on pyrazoles and indazoles are shown in Tables 16 and
17.
Since nitrogen atoms are directly involved in exchange processes, the best way to study
tautomerism, isomerism and protonation is to observe the nitrogen signals. In pyrazoles,
protons H-3 and H-5 are separated by 0.15 p.p.m. (Table 7), carbons C-3 and C-5 by
10.5 p.p.m. (Table 14) and nitro gens N-1 and N-2 by 93 p.p.m. (Table 16). Thus two 15 N
signals are observed for pyrazole in DMSO at room temperature and a broad signal for
N-2 of 3-methyl-1-phenylpyrazolone under the same conditions. This broad nitrogen signal
corresponds to a slow exchange rate between the OH and NH tautomers (77JCS(P2)1024),
whereas the corresponding lH and 13 C NMR spectra show only mean narrow signals.
Isomerism is easily determined by 15 N NMR; for example, the absolute difference in p.p.m.
between the pyridine and pyrrole nitrogen atoms is 146 for the indazole N- methyl structure
and 70 for the isoindazole structure. Finally, protonation produces dramatic changes in the
chemical shifts, so much so that it is pos ible to use them to determine accurate pKa values:
pyrazole, 2.63 (thermodynamic value, 2.52 (68BSFS009)), N-methylpyrazole, 2.15 (thermo-
dynamic value, 2.09 (68BSFS009)).
Nitrogen chemical shifts of nitrogen heterocycles, including pyrazole, N- methylpyrazole
and indazole, have been compared with calculated nitrogen screening constants
(780MR(1l)27) and a fairly good correlation (ô exp = 1.18ô calc - 104.2, correlation coefficient
0.901) is obtained. The results in Table 16 show the great sensitivity of N-1 chemical shifts
to the nature of R 1 (R 1 = Me, Ph, CMe20H, N0 2 ).
The coupling constants are very rich in structural information. For the sake of comparison,
indazole and isoindazole have been numbered like pyrazoles (Figure 16).
n
sQNZ
11
R
Figure 16 Numbering of indazole and isoindazole as substituted pyrazoles
3
æ 4
I N2
::::,...,s
I
R
Table 16 IS N NMR Chemical Shifts for Pyrazoles and Indazoles
å('S N )
(p.p.m. from MeNO z )
Compound Solvent N-l N-2 Other data
Pyrazole CHCI 3 -132.9 -132.9
Pyrazole DMSO -171.3 -78.3
Pyrazole HCI (pH 0.45) -183.5 -183.5
3 (5)-Methylpyrazole CHCI 3 -138.2 -132.5 3 J N(1)-H(4))-6,
J(N(1)-H(5))-14
3 (5)-Methylpyrazole HCI (pH 0.45) -189.0 -185.5 3 J(N(1)-H(4)) 4.6, 2 J(N(l)-H(5)) 6.6,
3 J(N2)-H(4))=3 J(N(2)-H(5))=3.4
3,5-Dimethylpyrazole CHCI 3 -138.0 -138.0
3,5- Dimethylpyrazole HCI (pH 0.45) -190.1 -190.1
I-Methylpyrazole CHCI 3 -179.0 -74.7
I-Methylpyrazole HCI (pH 0.06) -188.1 -174.6
1,2- Dimethylpyrazolium iodide H 2 O -183.9 -183.9
1- Phenylpyrazole CDCI 3 -164.2 -78.2 'SN_'SN, 13C_lsN and IH_1sN coupling constants
Pyrazole-acetone adduct (55) Acetone (-50 0 C) -140.4 -80.6 ISN_1SN, 13C_ISN and 'H_IS N coupling constants
I-Nitropyrazole Acetone -107.8 -82.9 ISN_1SN, 13 C _'S N and IH_Is N coupling conslanls
3-Methyl-l-phenyl-2-pyrazolin-5-one CDCI 3 - 186.4 -54.5 ISN_1SN, I3 C _IS N and IH_Is N coupling constants
Indazole DMSO-d 6 -194.4 -65.6 13C_lsN and 'H_1SN coupling constants
I-Methylindazole DMSO-d 6 - 202.8 -56.6 I3 C _ ls N and 'H_'sN coupling constants
2-Methylindazole DMSO-d 6 -91.2 -161.0 13C_ISN and 'H_'sN coupling constants
Ref.
79JOC1765
79JOC1765
79JOCI765
79JOC1765
79JOC1765
79JOC1765
79JOC1765
79JOC1765
79JOC1765
79JOC1765
77JCS(P2) 1024
82UP40401
82UP40401
77JCS(P2)1024
820MR(18)10
820MR(18)10
820MR(18)10
Table 17 Coupling Constants for Pyrazoles and Indazoles
Coupling constants (Hz)
N(/I-N(2) N( 1)-C(3) N(/ )-C<5/ N(1/-C(4) N(2/-C(3J N(Z/-C(51 N(21-C(4/ N(/)-H(3) N(/ /-H(51 N(1)-H(4) N(2)-H(3) NIZ)-H(5) N(Z)-H(4)
3.4" 8.9" 4.3" 8.9" 3.4" 4.3"
13.4 13.4 7.5 4.0 5.2 12.9 0 1.1
12.8 1.2< 12.1 6.2 1.2< 0 2.1 7.4 4.4 6.0 14.2 0 1.0
14.7 d 11.6 7.9 d 0 2.0 10.6 3.1 7.6 14.4 0.9 0.9
0 13.6 5.9 0 1.1 1.8 7.4 12.8
0 15.0 6.6 0 0.8 1.8 7.6 12.8
1.3 13.2 5.0 1.8 0.7 4.3 <0.5
6.4 1.9
Compound
Ref.
Pyrazole-I- lSN
Pyrazole-acetone adduct (55)
l-Phenylpyrazole-I,2- lS N
1- Nitropyrazole-I.2- I 'N
Indazole-I- or -2- t'N
I-MethylindazoJe-l- or -2-"N
2-MethylindazoJe-l- or -2- "N
l-Phenyl-3.5-dimethylpyrawle-l,2-' 'N
73JMR(10)130
82UP40401
77JCS(P2)1024
82UP40401
820MRil8)10
820MR118)10
820MRil8)\0
800MRil3)\97
. Mean values. b Blocked exchange. C' Not assigned; a coupling of 1.2 Hz is observed on the C-3 resonance of the doubly labelled I-phenylpyrazole. d Nonmeasurable on a broadened SÌgnal.
-
\0
0\
.)
N
o
ëi>
'"
$::)
;::
$::).
...
;:s-
::;.
OJ
;::
N
o
tJ
....
.
.
""
Pyrazoles and their Benzo Derivatives
197
The values of Table 17 are remarkably coherent. As Begtrup has pointed out (74CC702)
coupling constants are less sensitive to substituent effects than chemical shifts, and for this
reason are preferable for tautomeric studies. For instance, the mean value of the lH_ 1s N
coupling constants measured in the acetone adduct (55) is close to the values measured in
CC1 4 for the monolabelled pyrazole (rapid exchange situation; Figure 17). These last values
have been compared with CNDO /2 and INDO calculated spin-spin coupling constants
(73JMR(10)130).
H(4) H(3)
)j
H(5) N/N 2
,I
Mt l'OH
Me
N(2)-H(3) = 12.9 }
N(1)-H(5) = 4.0
N(2)-H(4) = 1.1 }
N(1)-H(4) = 5.2
N(2)-H(5) = 0 }
N(1)-H(3) = 7.5
2 .j, 3 2 .j,
J=8.45 J=3.4 J=8.9
t H W'
3 l 3 H
J=3.15 J=(3.......... H-Z 15
3J=3.75
Figure 17 IH_ 15 N coupling constants in pyrazole
The coupling constants measured in the IsN NMR spectrum of 3(5)-methylpyrazole
(Table 16) are probably inaccurate. Since the equilibrium constant is almost 1 (Section
4.04.1.5.1), the expected values are 3 I N - 1 ,H-4 = 3 to 4 Hz and 2 JN _ 1 ,H_S = 8 to 9 Hz, instead
of 6 and 14 Hz respectively. Significant differences are observed in 1 H_ 1S N coupling constants
determined from lH and IsN NMR spectra. For example, the l J CH_ 1s N) coupling constant
in indazole is 106.4 Hz by lH and 104.8 Hz by lsN NMR (S20MR(18)10). Incidentally, the
existence of this coupling proves the 1H structure of indazole e S N-2 is not coupled with
H-l).
Axenrod et at. have used lH_ 1S N (790MR(12)476) and 13C_1SN (SOOMR(13)197) coupling
constants, measured by l H and 13 C NMR spectroscopy respectively, to assign pyrazole
isomeric structures. For a pyrazole of general structure (77), only the isomer (77a) (prepared
from PhNH- 1s NH 2 ) shows a 3 JCH- 1S N) coupling constant of 2.2-3.0 Hz and a 2 J e 3 C_ 1S N)
coupling constant of 8.2-8.8 Hz.
CH R I
R2 0 N152
N/
Ph
(77a)
R 2
R1H C O N15
2 N/
Ph
(77b)
4.04.1.3.6 UV spectroscopy
Electronic absorption spectroscopy, UV and visible, has been covered extensively by
(63PMH(2)1) and (71PMH(3)67). Table A2 of (B-76MI40402) contains UV absorption data for
nearly 70 pyrazoles and pyrazolones.
The use of UV spectroscopy as an identification method is continuously decreasing in
relative importance compared to the use of NMR or mass spectrometry. However, due to
the general validity of Beer's law, it continues to be an appropriate method for quantitative
studies such as the measurement of ionization constants (Section 4.04.2.1.3(iv) and (v)) and
the determination of tautomeric equilibrium constants (Section 4.04.4.1.5).
Discussion of the UV spectra of heteroaromatic molecules has changed with time, from
the classical way illustrated by the Italian publications (56G797) to the modern quantum
mechanical calculations.
(i) Pyrazole
Absorption maxima for pyrazole itself and for monosubstituted pyrazoles are shown in
Table 18.
The only observed transition for pyrazole is a 7r 7r* one of the C Al l B1 ) class;
n 7r* bands have not been reported. The 7r 7r* band occurs at 211 nm (47 390 em-I)
in ethanol and at 203.2 nm (49210 cm -1) in the vapour phase, corresponding to ÅE of
5.88 and 6.10 eV.
198 Pyrazoles and their Benzo Derivatives
Table 18 UV Spectral Maxima (nm) for Pyrazoles in Ethanol
Substituent at position
Pyrazole 1 3 4 5 Amax (log e) Ref.
Unsubstituted H H H H 211 (3.49)" 66BSF3744 b . c
3(5 )-Methyl H Me H H 213 (3.57) 66BSF3744 c
4-Methyl H H Me H 219 (3.67) 66BSF3744 c
3(5 )-Phenyl H Ph H H 248 (4.14) 66BSF3744 c
4-Phenyl H H Ph H 250.5 (4.18) 66BSF3744 c
4-Chloro H H CI H 220 (3.46) 66BSF3744
4-Bromo H H Br H 221 (3.47) 66BSF3744
4-lodo H H I H 227 (3.38) 66BSF3744
3(5)-Amino H NH 2 H H 228 (3.28)
3(5)-Nitro H N0 2 H H 261 (3.79)d 73JHC1055
4-Nitro H H N0 2 H 275 (3.91) 71PMH(3)67
3(5 )-Methoxycarbonyl H C0 2 Me H H 217 (3.94) 71PMH(3)67
I-Methyl Me H H H 217(3.61) 66BSF3744 c
I-Acetyl MeCO H H H 239 (4.06) 7lPMH(3)67
I-Carboxamido CONH 2 H H H 233 (3.98) 66BSF3744
I-Phenyl Ph H H H 255 (4.15) 68JCS(B)725 c
I-p-Nitrophenyl C 6 H 4 N0 2 H H H 313 (4.24) 66BSF3744
1-12,4-Dinitrophenyi) C 6 H 3 (N0 2 h H H H 308 (4.07) 66BSF3744
1-( 2.4,6- Trinitrophenyl) C 6 H 2 (N0 2 h H H H 305 (3.81) 66BSF3744
I-Tosyl MeC 6 H 4 S0 2 H H H 240 (4.25) 66BSF3744
I-Nitro N0 2 H H H 265 (3.69)
a 203 (vapor phase) (70TH40400). b Theoretical calculations (70BCJ3344). c Theoretical calculations (68JCS!B)72S). d n
(L05N HC!.
W) Indazoles
The UV spectra of indazole and its two N -methyl derivatives can be seen in Table 23
(Section 4.01.3.6). Calculated values for the absorption maxima of indazole agree fairly
well with the experimental ones (Table 19).
Table 19 Experimental and Calculated UV Spectral Data for Indazole
Experimental UV maxima PPP calculation a (70BCJ3344) CNDOjS calculation" (?4T2903)
Am"x (nm) loge ð.E (eV) ð.E (eV) { (cgs) a (0) ð.E (eV) {(cgS) 0(0)
296 3.52 4.19} 4.47 0.18 84 {4.32 0.045 23
284 3.63 4.37 4.87 n.... 71'*
250 3.65 4.95 4.88 0.13 -48 5.10 0.124 -76
221 5.60 6.11 0.94 7 5.79 0.754 59
6.22 0.56 18 5.81 0.544 -61
5.99 n.... 71'*
6.53 0.36 -16 6.27 0.427 -41
d n = polarization direction measured counterclockwise to the x- axis, f = oscillator strength.
(iii) Effect of substituents on aromatic compounds
A publication by Elguero et al. (66BSF3744) discusses UV spectra of 170 pyrazoles
determined in 95% ethanol. Rigorously, the UV substituent effects must be discussed using
wavenumbers, since only wavenumbers (in em-I) are proportional to transition energies,
!J..E. However, in order to have rnore farniliar values, data on 1-(2,4-dinitrophenyl)pyrazoles
(6óBSF3744) have been transforrned frorn wavenumbers to wavelengths (in nm) (Table 20).
Substituents in positions 3 and 4 produce bathochromic shifts whereas substituents in
position 5 produce hypsochromic shifts, which becorne more pronounced as the bulk of
Table 20 Substituent Effects in the UV Spectra of 1-(2,4-Dinitrophenyi)pyrazoles
(68BSF707)
Unsubstituted 308, 4-CI +4, 4-Br +4, 4-Me + 14, 3-CI +4, 3-Br +8, 3-Me + 16,
3-Et + 16, 3-Pr' +20, 3-Bu' +20, 5-CI -30,S-Me -16, 5-El -17, 5-Pr' -18,
5-Bu' -39
Pyrazoles and their Benzo Derivatives
199
the 5-substituent increases (steric inhibition of the resonance). When another substituent
is introduced into position 4, the steric effect produced by the substituent in position 5
increases (buttressing effect) by about 8 nm (4-Clj5-Me, 4-Br/5-Me, 4-Br/5-Cl). Braude's
law, used with discretion, allows the calculation of a dihedral angle of 55 0 between pyrazole
and phenyl for I-phenyl-5-methylpyrazole (78T1139).
From UV studies of 4-phenyl-, 4-nitro- and 4-nitroso-pyrazoles, Habraken et at.
(67RTC1249,72JHC939) conclude that the 4-pyrazolyl group acts as an electron-donating
group. UV spectra of pairs of 1-aryl- and 2-aryl-indazoles and their utility in the deterrnina-
tion of isomeric structures are discussed in (67BSF2619); many other UV data on indazole
derivatives can be found in (71PMH(3)67).
Simple HMO calculations (68JCS(B)72S) satisfactorily account for the UV spectra of a
great number of pyrazoles substituted by methyl and phenyl groups. The spectra of
pyrazolium and indazolium salts (free bases in 1N HCl) have been compared with calculated
transitions (Pariser-Parr-Pople method) (74MI40403).
(iv) Non-aromatic derivatives
Neither (71PMH(3)67) nor (B-76MI40402) contains information on non-aromatic derivatives
of pyrazole. Table 21 gives some references to these compounds, including aromatic
pyrazolones.
Table 21 Some References to UV Studies of PyrazoIe Derivatives
Pyrazolones
Prrazolidones
8 -Pyrazolines'
8 2 -Pyrazolines'
8 3 - Pyrazolines'
Pyrazolidines
Ref.
76AHC(Sl)1, B-76MI40402, 78JPRS21
67BSF3S02
78JAS122
66BSF610, 67BSF3S16 b , 80CHE66 c
69BSF3316,70BSF1l29
70CHE744
Pyrazole derivatives
. See also (67HCl22J1). b Pyrazolinium salts. C Fluorescence.
4.04.1.3.7 IR spectroscopy
IR and Raman studies of heterocycles today cover two different fields. For sirnple and
symmetrical molecules very elaborate experiments (argon rnatrices, isotopic labelling) and
complex calculations lead to the complete assignment of the fundamentals, tones and
harmonics. However, the description of modes ought to be only approximate, since in a
molecule like pyrazole there are no pure ones. This means that it is not correct to write
that the band at 878 cm- 1 is y(CH), and the only correct assertion is that the y(CH) rnode
contributes to the band. On the other hand, IR spectroscopy is used as an analytical tool
for identifying structures, and in this case, bands are assigned to v(CO) or ô(NH) on the
basis of a simple Nujol rnull spectrurn and conventional tables. Both atttitudes, almost
antagonistic to each other, are discussed in this section.
(i) Aromatic rings without carbonyl groups
IR spectroscopy of pyrazoles has been reviewed twice by Katritzky et al.
(63PMH(2)161,71PMH(4)26S), where much qualitative information is to be found. Recently,
several groups of workers have begun an exhaustive study of pyrazole, the two rnost
important studies being those of Tabacik and Pellegrin (78MI40400, 79SA(A)10SS) and
Troitskaya and Tyulin (74CHE471, 74CHE121S, 74MI4040S). The first study involved eight
molecules: pyrazole-d o , pyrazole-1-d 1> pyrazole-4-d 1, pyrazole-1,4-d 2 pyrazole-3,5-d 2 ,
pyrazole-l ,3,5-d 3, pyrazole-3,4,5-d 3 and pyrazole-d 4 ; it employed IR (gas and argon rnatrix)
and Raman (crystal, CCl 4 and gas) procedures. The second study utilized pyrazole-d o ,
pyrazole-1-dJ, pyrazole-4-d}, pyrazole-l,4-d z , pyrazole-3,4,5-d 3 , pyrazole-d 4 and 15Nz_
pyrazole, with IR (gas, solution and crystal) and Raman (crystal, H 2 0 and CCI 4 ) procedures;
they also made use of the CdClz: pyrazole complexes. Both groups have identified the 21
normal modes of pyrazole (point syrnmetry group C s ; Table 22). Although for the a" group
and the four high-frequency at there is complete agreement, some discrepancies persist for
200 Pyrazoles and their Benzo Derivatives
Table 22 Pyrazole-d o : Assignment of Vibrational Spectra (21 Normal Modes) (em-I)
Argon' Remarks concerning the approximate Assignment b Gas b
Gas a matrix Assignment description of modes a
515 525 V21 (a") The six vibrations of the a" class V21 (a") 515
612 V20 (a") include two r (ring bending out-of- V20 (a") 612
673 677 VI9 (a") plane), three y(CH) (CH bending V19 (a") 670
744 748 VI8 (a") out-of-plane) and one y(NH) (NH VI8 (a") 746
833 834 VI7 (a") bending out-of-plane). V17 (a") 833
879 878 VI6 (a") V21 (a") ""y(NH) VI6 (a") 880
VIS (a') 865
909 909 VIS (a') The 11 low-frequency vibrations of the V14 (a') 910
1008 1015 VI4 (a') a' class include three 8(CH) (CCH VI3 (a') 1010
bending in-plane), one 8(NH) (CNH VI2 (a') 1010
1054 1063 VI3 (a') bending in-plane), two ß (ring bending VII (a') 1060
1121 1127 V12 (a') in plane), one BR (ring breathing) and V10 (a') 1125
(1156)" VII (a') four w (ring stretching in plane). V9 (a') (1155)<
1254 1256 VIO (a') VII (a') "" BR (it appears only in the V8 (a') 1255
1343 1345 V9 (a') Raman spectrum)<
1358 1357 V8 (a') V7 (a') 1360
1395 1393 V7 (a') V6 (a') 1400
1449 1449 V6 (a')
Vs (a') 1470
1535 1530 Vs (a')
(3115)< 3116 V4 (a') The four high-frequency vibrations of V4 (a,)f (311 0)<
3130< V3 (a') the a' class include three v(CH) (CH V3 (a')! (3135)d
(3148)< V2 (a')< stretching) and one v(NH) (NH V2 (a')! (3155)d
3524 3507 VI (a') stretching). VI (a') "" v(NH) VI (a')! 3525
. (79SAIA)IOSS). b (74MI4040S). < Raman. d CdCh complex. < V2 (a') "" II(CH-4) (78MI40400). I Respectively, v(CH-5),
v(CH-3), v(CH-4) and v(NH) (74MI4040S).
the low frequency a': the 1345, 1449 and 1530 cm- 1 bands determined by the French group
and the 865, 1010 and 1470 cm- l bands of the Russian group.
Pyrazole, in all possible states, either free or complexed, shows C. symmetry, with positions
3 and 5 clearly differentiated, even if it is not possible to assign individual bands to these
positions, for exarnple v(CH) or '}I(CH). Both research groups carried out norrnal coordinate
calculations using different potentials. In spite of the large amount of data obtained, the
problem is not definitively settled and rnore experimental work and quantum rnechanical
calculations are to be expected in the next few years.
(ii) Pyrazole rings containing carbonyl groups
In this subsection compounds with a pyrazole C-O bond will be discussed independently
of their arornatic character. In solution the tautorners of pyrazolinones, e.g. (78a), (78b)
and (78c), are easily identified by their IR spectra (Figure 18) (76AHC(Sm).
R' R 3 R 3
O.J::)N HOQN O N H
R ' R ' R I
(78a) (78b)' (78c)
V(CO) { 1695 (R: = alkyl) v(CH(4)) 3150 v(CO) 1630-1680
1705 (R = aryl) v(ring) 1560 v(C=C) -1590
Figure 18 lR characteristics of pyrazolone tautomers
In the solid state the CH tautorner (78a) is always readily identified, but the OH and
NH tautomers (that, in some cases, coexist in the crystal (73CSC469)) are difficult to
differentiate due to the strong hydrogen bonds that shift the v(CO) band to the region of
pyrazole vibrations. This source of complications is not present in the 'fixed forrns' that
can always be identified by their IR spectra, both in solution and in the solid state.
The spectra of pyrazolidinones have often been described (63PMH(2)161, 67BSF3502,
70CHEI568). In the l-aryl-3-pyrazolidones (79), both the v(CO) and v(NH) bands changed
considerably between the crystal (cyclic dimer) and the solution spectra. Typical values for
v(CO) range from 1700 to 1730 cm- 1 in solution. For the 1-aryl-5-pyrazolidones (80),
Pyrazoles and their Benzo Derivatives
201
o
dH
N
Ar
(79)
R 3
r--(NR 2
O N)
Ar
(80)
ri R 3 R 2
O N N '"
Ar H
(81)
r-! Me
O N N(
Ar Me
(82)
1690 em -1 is often the frequency of the carbonyl band, moving to 1730 em -1 in the conjugate
acids and to 1740 em -1 in the quaternary salts, these frequencies being compatible only
with an electrophilic attack on N-2, (81) and (82) respectively.
The fundamental vibrations of 1,2-dimethyl-3-pyrazolidinethione (83), a cyclic thiohy-
drazide, have been tentatively assigned (81ACS(A)767). The X-ray structure of the 5-p-
chlorophenyl derivative has been determined in order to have an experirnental geometry
for (83) suitable for normal coordinate analysis. 3,5- P rrazolidinediones (84) show two
carbonyl absorptions at 1715-1725 and 1745-1755 cm- and these are probably coupled
modes. Finally, the mesoionic anhydro-4-hydroxy-l,2-dimethyl-3,5-diphenylpyrazolium
hydroxide (85) shows no CO stretching vibration in the usual carbonyl region (73CC402),
but a band at 1546 cm- 1 in DMSO has been assigned to v(CO) because it is the band
exhibiting the largest shift in changing from aprotic to protic solvent (the UV band also
shifted from 447 nm in C 6 H 6 to 325 nrn in H 2 0). In its IR characteristics, compound (85)
differs markedly from other mesoionic compounds, like the sydnones (v (CO) 1750-
1770 em-I), and this has been explained by the fact that compound (85) belongs to rnesoionic
heterocycles of type B (76AHC(19)1). On reduction of the hydrochloride of (85) by means
of LAH (73TH40400) the 4-pyrazolidone (86) was obtained; this compound showed a carbonyl
vibration at 1750 cm-t, similar to those of cyclopentanone (1744 cm-\
s 0 -001h o Ph
C"5NMe ODR 2 Ph "M'
. + .
Ph .....;.NMe
N N N
R 1 Me j
Me Me
(83) (84) (85)
(86)
(iii) Substituent vibrations
Substituent vibrations are discussed in (71PMH(4)26S). The C=O frequencies of some
methylpyrazoles containing in the 3-, 4- or 5-position a formyl, acetyl or ethoxycarbonyl
group have been reported (69JHCS4S). A comparison of these frequencies shows that with
the exception of the ethoxycarbonylpyrazoles, they are 2 to 35 em -1 lower than their
corresponding parent benzene derivative (benzaldehyde, acetophenone, ethyl benzoate),
indicating that, in general, the pyrazole ring donates electrons rnore readily than the phenyl
ring. The 4-position appears to have the highest electron-releasing capacity (ð.v = -12 to
-35 em-I). This conclusion agrees with the observation of a slow rotation about the C-C
bond in 4-forrnylpyrazole (57) (Section 4.04.1.3.3) and shows that resonance structures
like (87) are important in these compounds. When both phenyl rings of benzophenone are
replaced by 4-pyrazolyl rings (88) the v(CO) band shifts from 1665 to 1610cm- 1 (ð.v =
-55 cm- 1 ) (78M337). 0
R/b ÇN ò N...,N
+ N (J HJ, ) I
N N O ' M e
R 1 H NHz
(87) (88) (89) (90)
The characteristic absorption at 1746 crn- 1 of l-acetylpyrazole (89) has been related to
the pseudohalogen behaviour of the I-pyrazolyl substituent (O'p = 0.23) by the equation
O'p = 0.0103v(CO) - 17.7 (74JCS(P2)449). The O'p value was calculated from the vas (NH) band
of 1-p- aminophenylpyrazole (90) measured in CCl 4 (O'p = 3.11 x 1O- 2 ð.v as -12.6 x 10- 2 ).
The two NH 2 stretching vibrations of aminopyrazoles follow the Bellamy-Williams
relation [vs(NH) = 345.5-0.876v as (NH)] (76AHC(SI)I) establishing the arnino tautomeric
structure of (91). Azidopyrazoles also show the V s and Vas bands of the azido group. The
202
Pyrazoles and their Benzo Derivatives
last absorption is very strong and appcars at 2110-2190 ern -1 depcnding on thc substitucnt
and the sample state. The band at 2130cm- 1 of 3-azido-5-methylpyrazole (92) in ethanol
shifts to 2120 em -1 in basic rnedium, corresponding to the anion (93), and subsequently
disappears since in the end the cornpound is exclusively in the tetrazole form (94) (74JHC921).
The intensity of the Vas N 3 band has been used to rneasure the rate of the transforrnation
(93) (94).
R 4 R 3 ON3 :.....N3 cf'
0 Me r ;N Me(;[N Me r _/N-t
H 2 N /N
N N N N
R 1 H
(91) (92) (93) (94)
(iv) Non-aromatic derivatives
The three isomeric pyrazolines can be identified by their IR spectra. ð. 1 -Pyrazolines show
the v(N=N) vibration at 1545:1:5 cm- 1 (the cornplete assignment for ð. 1 -pyrazoline itself
has been published, v(N=N) occurring at 1552cm- 1 ), and in ð. 2 -pyrazolines the v(C=N)
band occurs at 1590-1625 cm- 1 depending on the substituents in positions 1 and 3
(71PMH(4)265). ð. 3 -Pyrazolines substituted in the 3-position by hydrogen or an alkyl group
have only the C=C band at 1665-1675 crn- 1 (69BSF3316). IR spectroscopy has been used
in a careful study of the protonation of ð. 2 -pyrazolines (71 PMH(4)265, 75AP0(11)267). The
cation (95) was fully characterized by the V (C=N) band at 164 em -1 (in the free base it
occurred at 1624 cm- 1 ) and the group of bands belonging to the NH 2 group.
Me
Me 2 ÇN
/ "-
H H
(95)
4.04.1.3.8 Mass spectrometry
An introductory cornment should be made concerning this section. The structures
represented in the following fragrnentation schernes are rnore mnernonic devices than
structural forrnulae in the meaning they have in the ground state. It is necessary to rernernber
that the ions generated in a mass spectrorneter have a large excess of energy. In the rnost
recent publications the tendency is to represent the ions by their rnolecular forrnulae unless
the structure has been established definitively. Often this structure corresponds to an
open-chain compound, which is more stable than the cyclic one.
A book (B-71MS) and a review by Nishiwaki (74H(2)473) contain much inforrnation about
the behaviour of pyrazoles under electron impact. The Nishiwaki review covers mainly the
hydrogen scramblings and the skeletal rearrangements which occur. One of the first con-
clusions reached was that pyrazoles, due to their aromatic character, are extremely stable
under electron irnpact (67Z0R1540). In the dissociative ionization of pyrazole itself, the
rnolecular ion contributes about 45% to the total ion current; thus, the rnolecular ion is
the most intense ion in the spectrum.
A series of papers by van Thuijl et al. (700MS(3)1549, 7lJHC311, 71OMS(5JI101, 730MS(7)1165,
790MS577) constitutes the fundarnental work on the mass spectrornetry of pyrazole and its
derivatives. For pyrazole itself the fragmentation pattern shown in Scherne 1 was proposed,
based on extensive isotopic labelling. The loss of H. from the molecular ion [(96) (97)]
comes predorninantly from H-3 and H-5 (92%); H-4 and H-l contribute little to this loss.
Analogously, elirnination of HCN [(96) (98)], involves mainly H-3 and H-5 (86%).
Another interesting fact is that hydrogen scrarnbling, i.e. randomization of the ring
hydrogens of pyrazole to lose positional identity on electron impact, has not been observed
to any significant extent (see however 780MS575).
For N -rnethylpyrazole (99), the molecular ion of which is less intense than pyrazole (a
common feature for rnethyl-substituted pyrazoles (67Z0R1540)), the fragmentation pattern
involves the rnethyl group (Scheme 2). These results were established using 2H, DC and
15N labelling studies.
Pyrazoles and their Benzo Derivatives
203
H 4 H 3 l;
sH
H --ZN;N
II
H
(96) m/e 68
-HCN 1 *
-H, -N z
-- C 3 H 3 N 2 -
(97) m/ e 67
v
-H.
--+
C3H2;
m/ e 38
m/e 39
-HC+
\I T
N
H
(98) m/e 41
_ -ý \HZ
-H'
C 2 HN; ----;;;- C 2 N+
m/e 39 m/e 38
m
'<,'.f
m/e 40
Scheme 1
H HT
H
H --Z_ _;N
N
I
CH 3
(99) m/ e 82
\l l t
N
I
CH 3
m/e 55
H D H
-H, I,S-cleavage H-.hifl :t)N
---+ (J 0
+/N H -9N
N H N
II
CH 2 m/e 81 m/e 81
m/e 81 1- N '
eavage
C,XH H-shifl CN
+) C 4 H;
H N
m/e 81 H m/ e 53
m/e 81
-H j
VNH
N
III
/C
H
m/e 81
C 3 H 4 N+
m/ e 54
Scheme 2
A mass spectrometric study of indazole and its nitro derivatives has been carried out by
the Mons group (750MS558, 77BSB281, 780MS518, 790MS114, 790MS117, 800MS144). In indazole
itself, the loss of HCN and DCN from indazole-l-d (100) and indazole-3-d (101) in a near
unity ratio leads to the assumption that a molecular ion isomerization occurs prior to the
fragmentation (Scheme 3) (750MS558).
A small preference for the involvement of the N-l nitrogen is observed in the loss of
HCN from the molecule of 1sN-labelled indazole (800MS533). In addition, there is a srnall
isotope effect (1.08).
The structure of the radical cation [C 6 H s Nr (102) has been established by mass-analyzed
ion kinetic energy spectrometry (MIKE) (780MS518). From structure (103), structures (104)
and (105) are formed (Scheme 4).
Although the conventional mass spectra of the five C- nitro derivatives of indazole are
nearly identical, the corresponding metastable peak shapes associated with the loss of NO.
can be used to differentiate the five isomers (790MS114). The protonation and ethylation
occurring in a methane chemical ionization source have been studied for a variety of
arornatic amines, including indazoles (800MS144). As in solution (Section 4.04.2.1.3), the
N-2 atom is the more basic and the more nucleophilic (Scheme 5).
204
Pyrazoles and their Benzo Derivatives
H
Oj l N
/
N
I
D
(100)
C N T
Nß
I
D
(103)
C b H 4 DN 1 :
7 m/e92
Oj l N
/
N
I
H
(01)
-e /'"
/
. CbHsN l:
(102) m/e 91
Scheme 3
. NHT
O c
(103) -----+
NH
.
ONHT
(104)
O=ë=NH T
(105)
Scheme 4
N
N
H
oc
I N-Et
/+
N
H
[H+] (C c::::-
-- NEt
I
N
Jr
NH
N
[EI]"
-
NH
N+
I
Et
Scheme 5
N
N
Et
Substituted pyrazoles fragment following pathways that are strongly dependent on the
nature of the substituent. Thus N- and C -phenylpyrazoles lead to N -phenylaziridinium,
-cyclopropenium and benzodiazepinium ions (68Z0R689, 78CHE1123), C -diphenylpyrazoles
to the fluorenium ion (m/ e 165) (690MS(2)739), and I-phenylpyrazol-4-yl oximes to the
1-phenylpyrazolium ion (m/e 144) (69JCS(C)2497).
The behaviour under electron impact of N - and C- trimethylsilylpyrazoles (mono-, di-
and tri-substituted) has been studied by Birkofer et al. (740MS(8)347). Loss of a methyl
radical followed by loss of HCN is the most common fragmentation feature of these
compounds. When more than one trimethylsilyl group is present, a neutral fragment C 3 H s Si
is expelled. Mass spectrometry of pyrazolium salts has been studied by Larsen et al. (81OMS377,
830MS52).
Amongst the non-aromatic derivatives, 3,4,4,5-tetramethylisopyrazole has a molecular
ion of low intensity (7%) in contrast to aromatic pyrazoles. It loses one of the 4-methyl
groups leading to a pyrazolium ion and after than the fragmentation is similar to that of
trimethylpyrazole (67Z0R1540). This tendency towards aromatic structures is also found in
the mass spectrometry of 2-pyrazolines (67JCS(B)583, 690MS(2)729, 73KGS64, 76BSF869). In the
last paper, Aubagnac et at. have proposed a retro-dipolar cycloaddition to explain the
formation of ethylene from 1,3-disubstituted pyrazolines (Scheme 6), an observation pre-
viously noted by Hammerum (72JOC3965).
Pyrazoles and their Benzo Derivatives
205
R 3 l t
QN
R 1
CH 2
II
CH 2
R 3 l t
C""-
+ III
N+
- ....-
N
I
R 1
Scheme 6
Finally, d l-pyrazolines lose N 2 (73KGS64) but it is possible that this takes place thermally
before ionization, since thermolysis of d 1 -pyrazolines usually gives cyclopropanes (Section
4.04.2.2.2(iv)).
4.04.1.3.9 Photoelectron spectroscopy
Results on the PE spectroscopy of pyrazoles are few. After a preliminary paper by Baker
et at. (70CC286) in which the lowest ionization energies of pyrazole are given (9.5, 10.1 and
10,8 eV) and briefly discussed, the fundamental contribution of Palmer et al. appeared
(73T2173). The PE spectrum of pyrazole in the gas phase using a He-I source consists of a
series of bands belonging to three regions, A, Band C (Table 23). Only region A shows
a resolved vibrational structure, probably involving an in-plane deformation mode
(660 cm- 1 )i' a 'breathing vibration' (900 em-I) and a symmetrical skeletal stretching
(1050 cm- ). However, the complete assignment of the vibrational spectra of pyrazole
(Table 22; Section 4.04.1.3.7) proves that these bands must be assigned to V19 (a"), VIS (a')
and V13 (a'), respectively.
Table 23 Experimental and Calculated Vertical Ionization Energies (eV) in Pyrazole
Experimental Assigned Principal Centres! bond
Regions values levels Eigenvalue character orbitals
9.15 3 a" -11.32 2pz N(I)N(2)-C(2)C(3)
A 9.88 2a" -13.01 2pz N(2)C(3 )C(4 )-N (1)C(5)
10.7 15a' -13.84 Sp2 N(2)
13.6 {14a' -17.58 2p, ISH C(4)C(5)-C(3)C(4)
13a' -18.59 2p, ISH C(4)H-C(5)H
B 14.7 1 a" -19.15 2pz N(1),C
15.1 12a' -19.24 2p, lsH NH-C(3)H
C 17.5 11 a' - 22. 79 2p, lsH C(5)N(1), C(4)H + C(5)H
The assignment of bands has been carried out using ab initio calculations, unfortunately
using the erroneous Ehrlich geometry (Section 4.04.1.3.1). There is a linear relationship
between the calculated energy levels (eigenvalues) and the experimental ones: IE exp ==
0.37 +0.75IE calc , (C.C.)2 == 0.994.
The same group has published two articles on indazoles [indazole (36), 1-methyl- (106)
and 2-methyl-indazole (107)]. The He-I and He-II spectra have been obtained and satisfac-
torily interpreted by means of ab initio LCGO calculations (78JST(43)33, 78JST(43)203). The
PE spectra support the conclusion (Section 4.04.1.5.1) that the IH-tautomer is by far the
more stable. X-Ray photoelectron spectra of some pyrazole and pyrazoline derivatives have
been reported (83MI40400).
Experimental and calculated (CNDOjS) vertical ionization energies have been measured
for pyrazol-3-ine-5-thiones (108; R = H, Me). These compounds exhibit an intense low-
energy band (7.55-7.60 eV) corresponding to the ionization of both a thiocarbonyl 7T-
electron and the sulfur n electron (78JAI275).
(107)
R
s J::;N Me
N
Me
(108)
N
N'
Me
(106)
NMe
/
N
206
Pyrazoles and their Benzo Derivatives
4.04.1.3.10 ESR spectroscopy
ESR spectroscopy of heterocyclic radicals has been reviewed (74PMH(6)9S) and two
publications are briefly reported in the appendix to this reference. Kasai and McLeod
(73JA27) generated radical anions in argon matrices at 4 K by reaction of the parent
heterocycles with sodium atoms. Subsequently the matrix was irradiated with 'yellow' light
(A > 5500 Á). The photoinduced radical anion of pyrazole shows an ESR spectrum with
the characteristic triplet-of-doublets feature; this excludes a 7T-type radical anion possessing
the original structure. The authors assigned the spectrum to a non-aromatic tautomeric
form (109). The triplet feature with a spacing of -50 G is attributed to the two protons at
C-5, and the doublet with a spacing of -15 G to proton 4. INDO-calculated values for the
two isotropic hyperfine coupling constants are 52 and 9 G, respectively. The calculated
coupling constant with H-3 is 1 G. The radical formed by the reaction of OH. with pyrazole
has the structure (110) according to the ESR spectrum (hyperfine constants (G): H-3, H-1,
1.5: H-4, 10; H-5, 31) (73JPC1629).
H H
HijN
H
(109)
H H
H/:;)
HO N
H
(110)
Janssen and co-workers prepared t-butyl1-pyrazolecarboxylate (111) via I-pyrazolecar-
bonyl chloride (7SJOC91S). The thermolysis of this compound in benzene solution at -140 oC
led to I-phenylpyrazole. The N -pyrazolyl radical (112), which is proposed as an intermedi-
ate, proved elusive and neither CIDNP nor ESR signals were observed.
Since the authors did not succeed in obtaining an ESR spectrum, they were unable to
decide whether the N -pyrazolyl radical is of the (J' (112a) or the 7T (ll2b) type. Ab initio
calculations indicate that the radical has B 1 (7T) symmetry (76T1SSS). However, the radical
is formed from (111) as a (J' radical and is able to react as such in its lifetime. This is in
agreement with the experimental results (7SJOC91S), no C -phenylated pyrazoles being
detected.
O
....N
N
I
/,c
0"" 'O-Bu'
(111)
Solutions of colourless pyrazolidinediones give highly coloured solutions of radicals (113)
when treated with lead dioxide. The ESR spectra of these radicals have been recorded
(78JOC808). They dimerize to tetrazenes (114) which appear to be indefinitely stable.
R42rlO
O ....N.
Nt
R
(113)
4.04.1.4 Thermodynamic Aspects
W N . --. Q N
.;! . 1 .
N
8 ' 5e :
. 'N'
J.;,..... .
(112a)
(ll2b)
R42rlO Oh R42
0-::( ....N-N,_ .Ào
N N
R 1 R 1
(114)
4.04.1.4.1 Intermolecular forces
(Í) Melting and boiling points
A large collection of melting and boiling points of pyrazoles may be found in (67HC(22)1,
B-76MI404(2); for pyrazolines, pyrazolidines and indazoles see (67HC(22)1), and for
pyrazolones and pyrazolidones see (64HC(20)1). Pyrazole itself melts at 69-70 oC; it is very
stable to heat and can be distilled at atmospheric pressure without decornposition (b.p.
186-188 0 C at 757.9 rnmHg, 96 0 C at 16 mmHg). The general conclusions (Section
Pyrazoles and their Benzo Derivatives
207
4.01.4.1.1) still hold for pyrazoles; for instance, when the hydrogen bonds are suppressed
(N- or O-methylation) the boiling (melting) point decreases. A point worthy of note is that
3(5)-substituted pyrazoles are mixtures of tautomers and the boiling point may possibly
correspond to an azeotrope. Melting and boiling points for some monosubstituted pyrazoles
are collected in Table 24.
Table 24 Melting and Boiling Points (oC) of Monosubstituted Pyrazoles.. b
Me Et But Ph CHO COMe COzH COzMe
i-Substituted 127/760 137/760 80/30 246/760 Ic'?), e 234/760 103 d 35
4-Substituted 207/760 122/16 e 230 83 114 278 137
3(5)-Substituted 205/760 209/760 53 78 150 101 214 d 141
COzEt CON Hz CN NHz N 3 NO NO z OH
i-Substituted 213/760 141 37 IC?), e Ie?). e 93
4-Substituted 79 e 92 81 234 164 118
3(5)-Substituted 160 148 150 40 56 161 175 166
OMe SEt S03 H F Cl Br I SiMe3
i-Substituted Ic?), e IC,?), e (c?), e 152/760
4-Substituted 62 345 38 77 97 109 64
3(5)-Substituted e 103/0.5 257 78/12 40 70 73 80
. Melting points above 30 0 C are given in bold; melting points below 30 0 C are not included. b Boiling poinls
are given in oC/mmHg. C Unstable. d Decomposes. e Unknown.
The melting point of indazole has been reported at various temperatures in the range of
145 to 149 oc. Indazole boils at 269-270 oC at 743 mmHg and 146 oC at 15 mmHg, can be
readily sublimed on a water bath and is also steam-volatile. Its two N -methyl derivatives
have similar melting points: 1-methyl (106), m.p. 61 oC, 2-methyl (107), m.p. 56 0 C, but
they are easily separated by fractional distillation [(106), 120/15; (107), 141/15].
(ii) Solubility of pyrazoles and indazoles
From the data reported in (63PMH(I)I77) it was concluded that hydrophobic substituents
reduce the solubility of pyrazole in water (at 20 o C: pyrazole, 1 part in 2.5; 3,5-dimethyl-
pyrazole, 1 part in 52). Another determination gives the following values for the solubilities
of pyrazole at 25 oc in water, benzene and cyclohexane (expressed as g/100 g of solvent):
130, 18 and 3 (66AHC(6)347). Indazole is soluble in hot water and most organic solvents,
but less so in cold water.
The partition coefficient P, defined as the equilibrium concentration of the compound in
n -octanol divided by that in the aqueous phase, has been measured for pyrazole and
indazole (B-79MI40416). It was found that log P = 0.13-0.26 for pyrazole and 1.82 for
indazole, clearly showing the greater hydrophobicity (lipophilicity) of the indazole ring, due
to the benzenoid moiety.
(iii) Chromatography
In addition to the two references, one dealing with pyrazoles and the other with pyrazolines,
given in (71PMH(3)297), other references describing the gas chromatography (GC) of pyrazo-
lines, pyrazolidines and pyrazolidones can be found in (66T2461, 67BSF3502, 69BSF3306,
70BSF1129). It has been shown (69BSF3306) that  3 -pyrazolines are partially pyrolyzed on
the column (an SE 30 silicone) to pyrazoles. The proportion of pyrazoles increases when
the column temperature rises and the flow diminishes.
An important publication by Kost et al. (63JGU525) on thin-layer chromatography (TLC)
of pyrazoles contains a large collection of R f values for 1: 1 mixtures of petroleum ether-
chloroform or benzene-chloroform as eluents and alumina as stationary phase. 1,3- and
1,5-disubstituted pyrazoles can be separated and identified by TLC (R f 1,3> Rf 1,5). For
another publication by the same authors on the chromatographic separation of the
aminopyrazoles, see (63JGU2519). N- Unsubstituted pyrazoles move with difficulty and it is
necessary to add acetone or methanol to the eluent mixture. Other convenient conditions
for NH pyrazoles utilize silica gel and ethyl acetate saturated with water (a pentacyanoamine
ferroate ammonium disodium salt solution can be used to visualize the pyrazoles).
208
Pyrazoles and their Benzo Derivatives
4.04.1.4.2 Stability and stabilization
(i) Thermochemistry
Two now classical papers (61MI40400, 62JCS2927) contain almost all the experimental
thermochemical data on pyrazole and indazole. Heats of combustion determined by
Zimmerman (61MI40400) have been used by Dewar to calculate the heats of atomization
(Table 25) (69JA796). Quantum mechanical calculations, carried out by Dewar (69JA796) or
Olivella (81JHC1189), gave accurate empirical values.
Table 25 Experimental and Calculated Thermochemical Data of Pyrazole and Indazole (kJ mol-I)
Heat of Heat of - (Heat of - (Heat of Heat of Heat of
combustion combustion atomization) atomization) formation formation
Compound (crystal)8 (gas)" b calc. b c calc. d
expo expo
Pyrazole 1858.5 1926.3 3632.4 3638.1 181 :1:9 190.0
Indazole 3763.5 3860.6 6721.6 6744.0
8 (61MI40400). b (69JA796). c (62JCS2927). d (8IJHCI189).
(ii) Arornaticity
Since aromaticity is, at best, a relative value, the problem of the aromaticity of pyrazole,
compared to other azoles, is to be found in Section 4.01.1.2, in which the authoritative
review by Cook et al. (74AHC(17)255) is summarized.
From a qualitative viewpoint there is no doubt that the compounds classified as aromatic
in Section 4.04.1.1 (pyrazoles, indazoles, isoindazoles, pyrazolones, indazolones, mesoionic
derivatives) indeed have aromatic properties to a greater or lesser extent. Dihy-
drobenz[cd]indazole (115) is also formally an aromatic compound since it has an odd
number of electron pairs (n = 7). However, due to the presence of two adjacent nitrogen
atoms the 'aromatic' tautomer (115a) is not stable, and the compound exists as the 1,5- or
1,3-dihydro tautomers (l1Sb) or (l1Sc) (72JCS(P2)68). The 'antiaromatic' benz[cd]indazole
(116), although unstable, has been fully characterized by 15N, l H and l3C NMR spectroscopy
(82CC86)
ó3 H ' .pm
'<::::
:::::". I #
(115a)
N-NH
Çò
H H
!1l5b)
H éò -N:
H I
:::::". #
(115c)
(116)
4.04.1.4.3 Conformation and configuration
Considerable information is available on this topic which will be discussed according to
the classification shown in Scheme 7.
Aromatic compounds
(planar)
Non-aromatic compounds
(non-planar)
{ Isomerism about a formal CSp2 -CSp2 double bond
Isomerism about a formal { C-C: C-aryl and C-aeyl derivatives
Sp2_Sp2 single bond C-N: N-aryl and N-aeyl derivatives
Conformation about a Csp -CSp3 single bond
{ Conformation of the ring
Nitrogen inversion
Scheme 7
The configuration of pairs of isomeric 4-arylidene-5-pyrazolones, (2)- and (E)-(117),
was determined by IH NMR data (72G491). When R 3 is H, the E configuration is preferred;
when it is a methyl or a phenyl group, the 2 configuration predominates. The presence of
an exocyclic sulfur atom as in (118) lowers the interconversion barrier and the products
Pyrazoles and their Benzo Derivatives
209
are equilibrium mixtures in solution at room temperature (an X-ray determination shows
that (Z)- and (E)-(118; R 3 =Ph, R=Bu t ) are present in the crystalìn an 87:13 ratio)
(76BSB697).
H
t R3
xV O N;N
Ph
(Z)-(117)
Q
H/C R3
O N;N
Ph
(E)-(117)
H
I
C
RS/ R3
O N;N
Ph
(Z)-(118)
SR
I
C
H/ R3
O N;N
Ph
(E)- (118)
Another example of the influence of a heteroatom on the barrier to rotation about a
formal C-C double bond is provided by Mannschreck (B-7SMI40404). In compound (119)
the rotation about the C-N bond (process 1) is more hindered than the rotation about
the C=C bond (process 2), the free energies of activation being 89.1 and 80.3 kJ mol-t,
respectively. Other activation energies are given in Figure 19. Compound (120) exists in
the Z configuration, as it has been represented in Figure 19. The effect of the bulky
substituents in (121b) on the barrier results in an increase of the dihedral angle between
the pyrazole ring and the thiocarbamoyl group, thus reducing their resonance interaction.
For compound (122) Sandström has calculated the entropy and enthalpy of activation using
a very accurate bandshape analysis.
jJ
Me'N Me'N C'" Me
I NPh I N
Me h / Me J..-.. /
o NON
Ph Ph
(119) AO: = 89.1 (120) AO: = 77.8
(B-75MI4U4U4) (77JP.R9I I)
S
II
Me'N/C r Me
I I N
Me Me N
R
(122) R = Me, AO: = 72.0
(770MR(9)1)
R
R O
/N
N
I 1
-;;:-C.,:;> /Me
S N
I
Ml'
(121a) R = H, AO: = 64.0
(12Ib) R=Bu',AO: =88.7
(nAcs21)
Barriers to internal Iotation (in kJ mo!-I) for pyrazole derivatives
Figure 19
In addition to the dynamic study of compound (120), Freyer (77JPR89S) has used 15N_
labelled compounds eH_ 15 N coupling constants) to assign the configuration of compounds
(123) and (124). For the latter, a l J ctH_ 15 N) coupling constant of 92 Hz establishes the
tautomeric structure as (124) (78JPRS08).
Ph,15
N
II
C
H/ )=.,M e
O N} Me
Ph
(123)
H
R I
"-15 C Me
N/ ;C
I N
H.. // N
o Ph
(124)
From studies reported in the references in Table 5 (Section 4.04.1.3.1) the dihedral angle
between a phenyl and a pyrazole ring in the crystalline state, falls between 4 0 and 22 0 when
the phenyl group is in the 3- or 4-position. The planar conformation of C -formylpyrazoles
(57) and the resonance interaction between them (87) has already been discussed in
connection with l H NMR (Section 4.04.1.3.3(i)) and IR studies (Section 4.04.1.3.7(iii)).
Considerable effort, with both N -aryl and N -acyl derivatives, has been devoted to
studying the rotational isomerism and equilibrium dihedral angles of N -substituted azoles.
The results obtained with N -acylazoles and azolides (Sections 4.04.1.3.1 and 4.04.1.3.3(i))
are summarized in (81RCR336). N-Acetyl-pyrazole (41), -indazole (60) and -isoindazole
(61) are planar or almost planar compounds with an E configuration. As in other azoles,
the predominant structure is that in which the carbonyl oxygen atom and the pyridine-type
peripheral nitrogen atom are as far apart as possible. If a pyrrolic (NH) nitrogen atom is
present in the a-position, as in compound (125) (see Table 5, Section 4.04.1.3.1), then
the hydrogen-bonded Z -isomer is found in the crystal (69AX(B)2355).
210
Pyrazoles and their Benzo Derivatives
,N_C/M'
N) II
" .0
H'"
(125)
The atropoisomerism of N -phenylazoles, i.e. an isomerism of the type shown b'y biphenyl
derivatives, has been studied by several authors. Some torsional angles, measured by X-ray
crystallography (Section 4.04.1.3.1) are shown in Table 26.
Table 26 Dihedral Angles Between the Pyrazole and the Phenyl Ring in N- Phenylpyrazoles Determined by
X-Ray Crystallography (for References see Table 5)
Compound
2-Substituent
S-Substituent
6 (0)
4- Bromo-3-methyl-l-p- nitrophenylpyrazole
5-Hydroxy-3-methyl-l-phenylpyrazole (78b, R I = Ph)
3-Methyl-l-phenyl-.i 3 -pyrazolin-5-one (78, R 1 = Ph)
3-Hydroxy-5-methyl-l-phenylpyrazole
5 - Amino-4-cyano-3-dimethylamino-l-phenylpyrazole
3,5-Dimethyl-l-phenylpyrazolium nitrate
H
H
OH
=0
Me
NH z
Me
20
38"
23"
33-44 b
60
48<
H+
"Calculated torsional angles of minimum energy (method HMO-NBI), 15 and 20 0 , respectively (75MI40401). b Two
independent molecules in the unit cell. < The calculated dihedral angle corresponding to the conformation of
minimum intramolecular van der Waals energy was 60 0 (82CJC97).
Theoretical calculations on the conformation of I-phenylpyrazole (126) and 5-methyl-l-
phenylpyrazole (127) (extended Hückel method) have been compared with experirnental
(including X-ray) values for the dihedral angle of minimum energy (78T1139). The authors
conclude that values of () of 26 and 55 0 , respectively, are a reasonable estimation for the
molecule in solution. Fong has calculated the dihedral angles of a large nurnber of azole
derivatives, including many N -phenylpyrazoles (80AJC1763). For the 5-methyl derivative, a
value of () of 53 0 was found, but the author assumed that compounds (126) and (128) are
planar, a highly improbable hypothesis. The rates of quaternization of N -arylpyrazoles
have been discussed on the basis that steric interactions are more important in the products
(128) than in the reactants (126) (phenyl substituted in the 3'- and 4'-positions) and result
in twisting of the aryl ring away from coplanarity with the pyrazole nucleus (75AJC1861).
MeCN CN
6 6'M'
(127) (128)
O
/N
Ó N
I
(126)
The syn-anti conformational problem of ex- and ß-pyrazofurins (756; one of the rare
naturally occurring pyrazole compounds, see Section 4.04.4.4.3), which involves a rotation
around a pyrazolic Sp2 carbon atom and a sugar Sp3 carbon atom, has been studied
theoretically using the PCILO method (81MI40403). In agreement with the experimental
observations, the ß anomer is energetically more favourable than the ex anomer, the
preferred conformations being anti and syn, respectively.
The conformation of heteroethylenic rings, D. 1_ and D. 2 -pyrazolines, and the nitrogen
inversion and preferred orientation of the N -methyl groups in pyrazolidines (71T123) have
been discussed in connection with their l H NMR spectra (Section 4.04.1.3.3).
4.04.1.5 Tautomerism
After the publication of a book on the prototropic tautomerism of aromatic heterocycles
(76AHC(Sl)1) which covered the literature up to 1975, the study of the tautomerism of
pyrazoles has not made great strides. In this section the main conclusions of this earlier
review will be summarized and comments on a few recent and significant references added.
Pyrazoles and their Benzo Derivatives
211
An account of non-prototropic tautomerism (mainly annular metallotropy) and non-
aromatic functional tautomerism will also be included.
From a general point of view, the tautomeric studies can be divided into 12 areas (Figure
20) depending on the migrating entity (proton or other groups, alkyl, acyl, metals. . .), the
physical state of the study (solid, solution or gas phase) and the thermodynamic (equilibrium
constants) or the kinetic (isomerization rates) approach.
Vapour Solution Solid
x
Proton
Quantum
mechanical
calculations
Figure 20 The 12 areas of tautomeric studies
About 90% of all the studies on tautomerism refer to the determination of prototropic
equilibrium constants in solution. Most probably in the next years there will be further studies
in the remaining areas, some of them alrnost a desert at the present time.
4.04.1.5.1 Annular tautomerism
All the N -unsubstituted pyrazoles (129) in solution (and probably in the gas phase) are
mixtures of annular tautomers in different proportions, depending on the nature of the
substituents R 1 and R 2 . In the majority of cases the difference of free energy between both
tautomers is low enough for the chemical reactivity to be unrelated to the equilibrium
constant.
R 1
R2QN
H
(129a)
When R 2 = H, in all the known examples, the 3-substituted tautomer (129a) predominates,
with the possible exception of 3(5)-methylpyrazole (R 1 = Me, R 2 = H) in which the 5-methyl
tau to mer slightly predominates in HMPT solution at -17 0 C (54%) (77JOC659) (Section
4.04.1.3.4). For the general case when R 2 = or ;éH, a dependence of the form 10gK T =
a L3,5 Uj + b L3,5 UR, with a > 0, b < 0 and a > Ib I, has been proposed for solutions in dipolar
aprotic solvents (790MR(12)587). The equation predicts that the 5-trimethylsilyl tautomer is
more stable than the 3-trimethylsilylpyrazole, since Uj and UR for Me3Si are -0.12 and
0.07, but more experimental work has to be done to understand the influence of the
substituents on the equilibriurn constant which is solvent dependent (78T2259). There is no
problem with indazole since the IH tautúmer is always the more stable (83H(20)1713).
The observation of individual tautomers by 13C and 15N NMR spectroscopy (Sections
4.04.1.3.4 and 4.04.1.3.5) avoids the complication of interpolation methods. As line
intensities in 15 N NMR spectra are strongly influenced by spin-lattice and spin-spin relaxa-
tion times, relaxation mechanism and experimental conditions, special care has to be taken
in using 15N spectra for quantitative purposes (800MR04)129). However, interpolation
methods continue to be used, sometimes without sufficient attention to the implicit assump-
tions. For example, (75JOC1815) contains a study on the tautomerism of pyrazoles. Using
averaged 13C chemical shifts without taking into account any corrective term (effect of the
N -methyl group on the chemical shifts), these authors calculated some tautomer predomin-
ances that are in contradiction with reliable literature results. From other authors' data
(74JOC357) they concluded that the 3-methylpyrazole tautomer (129a; R 1 = Me, R 2 = H) is
definitely the preferred one.
R 1
R 2 CN H
N
(129b)
K T = [(129a)]/[(129b)]
212
Pyrazoles and their Benzo Derivatives
The 'magic spinning angle' (MAS) technique gives the possibility of recording high
resolution NMR spectra of nuclei other than the proton, thus extending the study of
tautomerism in the solid state to non-crystalline solids (Section 4.04.1.3.4). Since the method
gives clear results in the case of pyrazole itself, it would be interesting to reexamine those
X-ray studies in which the tautomeric proton seems non-localized (Section 4.04.1.3.1), as
in the case of 5(3)-methyl-3(5)-phenylpyrazole (130) (74JCS(P2)1298).
A large programme utilizing temperature-jump relaxation methods for the study of
tautomerism in aqueous solution has led the Dubois group to determine the kinetic and
thermodynamic parameters of the equilibrium (130a) (130b) (78T2259). The tautorneric
interconversion involves two successive intermolecular proton transfers.
Ph
MeeN
N
H
(130a)
Ph
Me ÇN H
(130b)
A well-known example of non-prototropic tautomerism is that of azolides (acylotropy).
The acyl group migrates between the different heteroatorns and the most stable isomer
(annular or functional) is obtained after equilibration. In indazoles both isomers are forrned,
but 2-acyl derivatives readily isomerize to the 1-substituted isomer. The first order kinetics
of this isomerization have been studied by NMR spectroscopy (74TL4421). The same publica-
tion described an experiment (Scheme 8) that demonstrated the intermolecular character
of the process, which has been called a dissociation-recombination process.
Ph
PhCI CCI '>::
, N +
132'C /
N
COEt
cr5 h o::
NCOMe + NCOEt
"'- / 02 N "'- /
N N
Ph
r
N'''
COMe
+ N
02N N/
COEt
(Xjl '>::
+ N
02 N N'
COMe
Cç
+ NCOMe
02 N "'-N'
Scheme 8
2-Acylindazoles are good acylating agents, particularly the 2-acetyl-7 -nitro derivative
(131). The acetylation of pyrazole by this compound proceeds quickly in chloroform and
more slowly (about 15 min) in DMSO (66BSF3041).
r!COMe
N0 2 N
(131)
Although the thermodynamic aspects of acylotropy are well documented, there have
been few kinetic studies of the process. The activation barrier is much higher than for
prototropy and only Castells et at. (ncc709) have succeeded in observing a coalescence
phenomenon in l H NMR spectra. At 215 oc in 1-chloronaphthalene the rnethyl groups of
N -phenyl-3,5-dimethylpyrazole-l-carboxamide coalesce. The mechanism of dissociation-
cornbination explains the reversible evolution of the spectra (Scheme 9).
Men Me [ Me0; Me l
N-N N-NH
O=C/ +
'NHPh O=C=NPh
T c =195 0 C,ð-O: =100kJmo!-1
Me0;Me
N-N
'C=O
/
PhHN
Scheme 9
Many other groups migrate with activation energies low enough to determine equilibrium
constants. In the absence of strong steric and hydrogen-bond effects the position of the
equilibrium is independent of the nature of the N -substituent (78JCS(P2)99). Groups other
Pyrazoles and their Benzo Derivatives
213
than protons are sensitive to steric effects; for this reason, the major tautomers of 7-
nitroindazole are the HI and the 2-acetyl (131). Table 27' includes several activation
energies for pyrazolic annular tautomerism.
Table 27 Kinetic Data for Autolrope Rearrangements in Pyrazoles
Coalescence Activation
temperature energy
NR 1 pyrazoles R 1 NMR (oC) (kJ mol-I) Ref.
Unsubstituted H 13C -100 46" 75T1461
Unsubstituted H 13 C 47 63 b 77JOC659
Unsubstituted H 13C 64 62 0 79JA545
3,5-Dimethyl Me3Ge I H 95-100 83 72MI40400
3,5-Dimethyl Me3Ge 13C 84 74JOM(70)347
Unsubslituted Me3Ge I H 150-160 92 72MI40400
3,5-Dimcthyl Me3Si I H 104 117 7IJOM(27)185
3,5-Dimethyl Me3Si I H l3 C 96 74JOM(70)347
3,5-Dimethyl Et 3 Si I H 'l3 C 96 74JOM(70)347
3,5-Dimethyl (EtOhSi I H ' l3 C 106 74JOM(70)347
U nsubstituted Me3Si I'H 165 -134 7IJOM(27)185
3,4,5-Trimethyl Me3Si I H 90 100 7IJOM(27)185
3,5 -Bis( trifluoromethyl) Me3Si I H 170 7IJOM(27)185
Un substituted MezGa I H <30 8IJOM(215)157
3,5-Dimethyl-4-R PhHg I H --110 71MI40400
Un substituted B U 3 Sn I H 13C << -80 77JOM(132)69
I'
Un substituted (CO}zCIRh H low temp. 74JOM(65)C51
3,5-Dimethyl (CO}zCIRh IH low temp. 74JOM(65)C51
3,5-Dimethyl (PriTPP)(CO)Ru d IH 100 71 72JOM(39)179
"In a mixture of.ether and tetrahydrofuran. b In HMPT the same barrier is obtained for the 3,5-dimethylpyrazole.
o In DMSO. d Pr'TPP = tetrakis(p-isopropylphenyl)porphinate dianion.
Dipolar aprotic solvents raise dramatically the coalescence temperature (other factors
are also important; Section 4.04.1.3.4) but the phenomenon is insensitive to steric effects
(no differences between pyrazole and 3,5-dimethylpyrazole). The metallotropy activation
energies are independent of the solvent and the concentration but are sensitive to steric
and to electronic effects of substituents in 3,5-positions. It has been concluded that metal-
10tropy, contrary to prototropy and acylotropy, .follows an intramolecular mechanism with
a cyclic symmetric transition state (132). The migratory aptitude of R 1 in pyrazoles is in
the following order: Me < COR < SiR 3 < GeR3 < H = HgR < SnR 3 . For the tin derivatives
the transition state is probably pentacoordinated and this aptitude to expand the valency
stabilizes the transition state (reactional intermediate?). In the case of the rhodium derivative
(133), there is a concomitant prototropy and metallotropy of the ligand (133a) (133b).
In another fluxional process involving ruthenium instead of rhodium, it has been shown
that the rate-controlling step is the complex dissociation and that the ligand exchanges
between the two annular nitrogen atoms by an intermolecular process.
R--{)-R
N..
M
(132)
Rn R
HN-NRhCHcOh
(133a)
R0 R
(CObC1RhN-NH
(133b)
4.04.1.5.2 Substituent tautomerism
Together with pyridones, the tautomerism of pyrazolones has been studied most intensely
and serves as a model for other work on tautomerism (76AHC(Sl)1). 1-Substituted pyrazolin-
5-ones (78) can exist in three tautomeric forms, classically known as CH (78a), OH (78b)
and NH (78c). In the vapour phase the CH taut orner predominates and in the solid state
there is a strongly H-bonded 'mixture' of OH and HN tautomers (Section 4.04.1.3.1).
However, most studies of the tautomerism of pyrazolones correspond to the determination
of equilibrium constants in solution (see Figure 20).
214
Pyrazoles and their Benzo Derivatives
Non-polar solvents resemble the vapour phase and the CH tautomer is favoured. In
dipolar aprotic solvents the NH form changes into the OH form; the dielectric constant
and the dipole moment of the solvent do not play an important role in this transformation.
In protic solvents the amount of the CH form is low, but as the acidity of the solvent
increases, the percentage of the NH form present increases to the detriment of that of the
OH form. These qualitative conclusions can be converted into quantitative terms by applying
the scaled Palm-Koppel equation (log K = log Ko + Y Y + pP + eE + bB, Ko, Y, P, E and B
being the equilibrium constant in the vapour phase, the polarity, the polarizability, the
acidity and the basicity of the solvent, respectively) to the percentage of the CH tautomer
of 1,3-dimethylpyrazolin-5-one in 16 solvents. The following result was obtained: log Ko =
2.2:!: 0.2, e = -1.4:!: 0.2, b = -1.9:!: 0.1, y and p not significant. The value of log Ko, 2.2
(K o = 160), corresponds to the predominance of the CH tautomer in the vapour phase.
Only the acidity E and the basicity B of the solvent are important, and as they increase
the percentage of the CH form decreases (75BSB1189). A 13 C NMR study of 26 4-substituted
3-methyl-1-phenylpyrazolin-5-ones (81JPR188) shows that in non-polar solvents like CDCh,
where the CH form is preferred at room temperature, cooling shifts the tautomeric equili-
brium to yield a higher amount of the NH form.
The effect of the substituent in the 1-position on the tautorneric equilibrium has received
little attention. However, it is known that the change from the N-Me to the N-Ph series
increases the percentage of the CH form to the detriment of the NH form. The effect of
the substituent in the 3-position has been thoroughly studied and the percentage of the
CH forrn decreases in the order: NH 2 > OEt > Me > Ph > H > C0 2 Et. The study of the
effect of the 4-substituents shows that the percentage of the CH form decreases as the
electronegativity of R 4 increases (81JPR188). The fact that 4-fluoro-5-hydroxypyrazole (134)
exists as such in DMSO ctH and 19 F NMR data) has been attributed to hydrogen bond
formation between the hydroxy group and the fluorine atom (81BCJ3221). However, the
high electronegativity of the fluorine atom is probably sufficient to justify the observed
tautomer.
Hydrogen bonding plays a major role in pyrazolone tautomerism, and the formation of
a chelate structure can shift the equilibrium towards the chelated form. Structures (135)
and (136) are two representative examples of such stabilized tautomers. Structure (137) is
a hypothetical example of stabilization of the NH tautomer.
R 3
n
O^N;N
h(x)
(136)
R 3
F
H r
o N
R'
R 3
n
O^N;N
I I
H. /;C-Me
'0'
(134)
(135)
R 3
O J:;N '.
)"
(137)
4-Acyl-, 4-alkoxycarbonyl- and 4-phenylazo-pyrazolin-5-ones present the possibility of
a fourth tautomer with an exocyclic double bond and a chelated structure. The molecular
structure of (138) has been determined by X-ray crystallography (Table 5). It was shown
that the hydroxy group participates in an intramolecular hydrogen bond with the carbonyl
oxygen atorn of the ethoxycarbonyl group at position 4 (80CSC1121). On the other hand,
the fourth isorner is the most stable in 4-phenylazopyrazolones (139), a chelated phenyl-
hydrazone structure.
OEI 3
C R
0-7 X;
: I N
H I
'0 N
Ph
(138)
N R 3
ArN/ "
I N
H. h N
'0 R'
(139)
The problem of tautomerism is simpler in the case of 1-substituted pyrazolin-3-ones
since only two forms, the OH (140a) and the NH (140b), are possible. The OH form is
the more stable and is the only one present in the crystal (Section 4.04.1.3.1). In protic
solvents, like water or methanol, the equilibrium position is much more evenly balanced
between the OH and NH forms. Finally, 4-hydroxypyrazoles (141) exist as such. A CNDO/2
calculation justifies the result that 4-hydroxy tautomers are relatively more stable than
Pyrazoles and their Benzo Derivatives
215
OH
RS O N
N/
R'
(140a)
o
RSUH
N
R'
(140b)
HO R3
S O N
R N/
R'
(141)
5-hydroxy tautomers and used as an analogy the fact that ketones are easier to enolize
than amides (76CJC1752).
The N -unsubstituted pyrazolones constitute a complex case of tautomerism, with no less
than eight tautomers being possible. However, there are only four probable tautomers
(142a)-(142d). The equilibrium between (142b) and (142c) is a case of annular tautomerism
and, generally (Section 4.04.1.5.1), the 3-0H tautomer (142b) is the more stable. The
problem thus can be reduced to the study of the equilibria between three forms: the CH
(142a), the 3-0H (142b) and the NH (142d). In non-polar solvents there is an equilibrium
between the CH and the 3-0H tautomers, in aprotic dipolar solvents the 3-0H tautomer
predominates, and in protic solvents there is a mixture of the 3-0H and the NH tautomers.
R 4 R 3
OJ:YN
N
H
(142a)
R 4 OH
3 0 N
R N/
H
(142b)
R 4 R J
HO O N
N/
H
(142c)
R 4 R J
O N H
N
H
(142d)
1-Substituted indazolones exist in the OH form (143b) and 2-substituted indazolones
exist in the NH form (144a), whereas the structure of N -unsubstituted indazolones varies
with the physical state. This difference of behaviour, depending on the position of the N-R
substituent, corresponds to the 'aromatic' structure of the indazole derivatives compared
with the 'quinonoid' structure of isoindazoles.
NH
V--N 1
R
(143a)
OH
N
NI
R
(143b)
NR
V--N 1
H
(144a)
CQ ::;-OH
NR
"-N'
(144b)
When the oxygen atom is replaced by a sulfur atom as in pyrazoline-5-thiones, the CH
form (145a) never occurs, and the tautomerism implies only the SH (145b) and the NH
(145c) forms (77BSB949).
R 4 R J
SJ:YN
N
R'
(145a)
R 4 R 3
HSCN
N
R'
(145b)
R 4 R 3
S N H
N
R'
(145c)
For amino derivatives, the problem of tautomerism is clear cut; all the derivatives exist
in the amino form (3-,4- and 5-aminopyrazoles, aminoindazoles and 3,5-diaminopyrazoles).
IR spectroscopy and especially the Bellamy-Williams relationship (Section 4.04.1.3.7(iii))
are useful for the study of amino tautomerism.
A theoretical, comparative study of the tautomerism of 56 five-membered heterocyclic
rings announced in (76AHC(Sl)1) has appeared (81MI40402). The stabilities of the three forms
for 5-pyrazolones, 5-pyrazolethiones and 5-aminopyrazoles have been calculated by a
simple Hückel ú) iterative method. The relative energies and the substituent and solvent
effects are in agreement with the experimental results.
The tautomerism of bifunctional derivatives is quite complicated. Figure 21 represents
the most stable tautomer for some 3,5-disubstituted pyrazoles such as 3-amino-2-pyrazolin-
5-ones (146), 5-amino-3-hydroxypyrazoles (147a), 3-hydroxy-2-pyrazolin-5-ones (148)
and 1,2-disubstituted 3,5-pyrazolidinediones (149). The structure of (147a) has been ques-
tioned (81CHE375); the authors consider the tautomer (147b) to be the more stable on the
basis of a band at 1640 cm- 1 in the IR spectrum, this band previously being assigned to a
8(NH 2 ), but no clear proof was given. Recently (82JOC295) it was concluded from IR and
UV data that the dihydroxy form (150) is the predominant tautomer when the substituent
at position 4 is aromatic.
216
Pyrazoles and their Benzo Derivatives
0
J:5 H l çOH -" d
o N"N H1N r N H1N N"NH
R ' R 1 R 1
(146) (147a) (147b)
0 R 4 OH
OH O Rl
O;::)N HOCN
N
R ' R ' H
(148) (149) (150)
Figure 21 Structure of the most stable tautomers of difunctional pyrazoles
The 1-hydroxypyrazoles exist as the neutral structure (151a) and not in the N-oxide
forrn (151b), although in water there is a small percentage of the latter present. For
tautornerisrn of 2-hydroxyindazole see (82JOC4323).
R 4 R 3
R S O N
N/
I
OH
(151a)
R 4 R
RS QN H
I
0-
(151b)
An exarnple of non-aromatic tautomerisrn has already been quoted (Table 13, Section
4.04.1.3.3(ii)); the equilibrium between the two enamines (152a) and (152b) is solvent and
tern perature dependent (70BSF3147).
Me
Mez ÇN Me
Me
(152a)
CH 1
MezVNMe
Me
(152b)
ð.. J -Pyrazolines unsubstituted on both nitrogen atorns (153a) are unknown. ð.. 1 -Pyrazolines
(153b) undergo thermal isomerization to the ð,.2 derivatives (153c), and there is only one
report of the reverse therrnal isomerization (153c) ---. (153b) involving the 5,5-dimethyl-ð.. 2 _
pyrazoline (65CHE375) (in the presence of hydrazine hydrochloride the equilibrium is
reversed). Thus, the normal order of stability for the three pyrazoline tautomers is: ð,. 2 > ð,.1 >
ð,.3. However, when strong electron-attracting groups are present in both positions 1 and
4, the ð,.3 tautorner (154a) is rnore stable than the ð,.2 tautomer (154b) (63YZ373, 65YZ158).
N ÇN H HNt
R; Ç: H R lJ H R;Ç ' 6 NO ' 6 NO '
H H NO z N0 1
(153a) (153b) (153c) (154a) (154b)
A study of the tautomerisrn of aminopyrazolines (70BSF1571, 70BSF1576, 71TH40400) has
led to the conclusion that the imino structure (155a) of 5-aminopyrazolines and the amino
structure (155b) of 3-aminopyrazolines are the predorninant tautomers. However, in the
last case a broadening of the signals in the IH and 13C NMR spectra points to a solvent
dependent dynarnic phenomenon, the origin of which is not yet clearly understood (in
CDCh-TFAA mixtures the broadening is so appreciable that the IH NMR spectra show
no signals, even those of the phenyl group disappearing in the base line).
R 3
HN Z:;N H
N
R 1
(155a)
O NH 2
R S N
N/
R '
(155b)
Pyrazoles and their Benzo Derivatives
217
4.04.2 REACTIVITY
4.04.2.1 Reactions at Aromatic Rings
4.04.2.1.1 General survey of reactivity
Aromatic pyrazoles and indazoles, in the broad sense defined in Sections 4.04.1.1.1 and
4.04.1.1.2, will be discussed here. Tautomerism has already been discussed (Section
4.04.1.5) and acid-base equilibria will be considered in Section 4.04.2.1.3. These two topics
are closely related (Scheme 10) as a common anion (156a) or a common cation (156b) is
generally involved in the mechanism of proton transfer (e.g. 78T2259 . For aromatic pyrazoles
with exocyclic conjugation there is also a common anion (157) for the three tautomeric forms
;....>:R
eN
/' N ,
(156a)
R R R
CN H J:J
0 . .
/N 0": ;N
N N
H , /' R 1
._. R (157)
8
",-;':-NH
N
H
(156b) Scheme 10
(i) Reactivity of neutral pyrazoles and indazoles
The pyrazole molecule resembles both pyridine (the N(2)-C(3) part) and pyrrole (the
N(1)-C(5)-C(4) part) and its reactivity reflects also this duality of behaviour. The
'pyridinic' N-2 atom is susceptible to electrophilic attack (Section 4.04.2.1.3) and the
'pyrrolic' N-1 atom is unreactive, but the N-1 proton can be removed by nucleophiles.
However, N-2 is less nucleophilic than the pyridine nitrogen atom and N(l)H more acidic
than the corresponding pyrrolic NH group. Electrophilic attack on C-4 is generally preferred,
contrary to pyrrole which reacts often on C-2 (a attack). When position 3 is unsubstituted,
powerful nucleophiles can abstract the proton with a concomitant ring opening of the anion.
Having its pyrazolic 4-position substituted, electrophilic attack on indazoles takes place
in the 3-position and in the 'homocycle' (the 5- and 7-positions). The condensation of a
benzene ring results in a decrease of the 'aromaticity' of the pyrazole moiety, as in
naphthalene compared to benzene, and therefore basic ring cleavage is easier in indazoles
than in pyrazoles (Section 4.04.2.1.7(v)).
Finally, it should be mentioned (Section 4.04.2.1.9) that pyrazole never reacts as an
alkene towards a diene or a 1,3-dipole nor as an azadiene towards a dienophile.
(ii) Pyrazolium and indazolium cations
Figure 22 represents the main consequences on pyrazole reactivity when a positive charge
is present at the 2-position of the nucleus. A similar situation occurs in the indazolium
salts, which thermally decompose into an alkylindazole and an alkyl halide, a reaction
sequence described by von Auwers.
Attack by hydrides
More difficult, but ! Acidity of the
still possible, electrophilic methyl hydrogens
attack at C-4 j
CH 3
Enhanced reactivity of 8 -- x-
halogen atoms toward, : + ';N
nucleophiles -4 Y 'N::- .....CH)
. . / R --Dequaternization by
RIng openIng by attack of nucleophiles
alkali fusion (including X-)
Figure 22 Reactivity of pyrazolium cations
218
Pyrazoles and their Benzo Derivatives
Uîi) Pyrazole and indazole anions
Pyrazole and indazole anions, in a rnanner similar to other azole anions, show the expected
inversion of reactivity when compared with the cations. They are more reactive towards
electrophiles, both at the nitrogen and carbon atorns, and less reactive towards nucleophiles
than the corresponding neutral molecules. For practical purposes rnost of the N -alkylated
pyrazoles and indazoles are prepared from the corresponding anions.
(iv) Pyrazolones, pyrazolethiones, pyrazoleimines and their benzo derivatives
The tautomerism of these compounds has already been discussed (Section 4.04.1.5.2).
Owing to the extra functionality they have a complex reactivity, and to the reactions of the
substituent must be added those of the pyrazole ring itself (Section 4.04.2.3), which are
different for each tautorner. In addition to the three neutral tautomers, one has to bear in
mind that the NH and OH tautomers of 5-pyrazolones can be written as betaines as in
forrnula (158) which is important in understanding their reactivity.
R 3
-O-CNH
N +
R 1
(158)
-O d R3
r NH
N/+
R 1
(159)
In the case of 4-hydroxypyrazole, tautomer (159), although not abundant in the equili-
briurn rnixture (Section 4.04.1.5.2), must be considered when discussing their reactivity.
The mesomeric anion (157; Scheme 10) reacts readily with electrophilic reagents such
as alkyl or acyl halides at N-2, C-4 and the exocyclic oxygen atorn. The percentages of the
different products formed are controlled by the HSAB principle. The acyliurn ion (hard)
attacks preferentially at oxygen (hard), whilst the softer alkylating agents attack the nitrogen
atom.
(v) N-Oxides, N-irnides and N-ylides of pyrazoles and indazoles
The tautomerisrn of N -hydroxypyrazoles (Section 4.04.1.5.2) is displaced towards the
neutral structure (ISla), but for reactivity studies the N -oxide tautorner (151b) must be
considered. The reactions at the oxygen atom will be discussed in Section 4.04.2.3.10, and
in other aspects they behave like pyrazolium ions. Quaternary salts (160) can be obtained
by amination of N -alkylpyrazoles and by alkylation of N -aminopyrazoles. However, the
corresponding N -imides (161), as the N -ylides (162), are unknown.
R 3
R5 0 NNH
N/+ 2
R'
(160)
R 3
R 5 0 NNHR
N/+
R'
(161)
R 3
R5 0 NëR,
N/ + .
R 1
(162)
4.04.2.1.2 Thermal and photochemical reactions formally involving no other species
In addition to fragrnentation on electron impact (Section 4.04.1.3.8), rnost of the referen-
ces in this section involve photochemical studies and an excellent account of these has been
given by Lablache-Cornbier (B-76PH123).
(i) Fragmentation
The photochemistry of antipyrine derivatives (Scherne 11) involves, depending on the
substituent in position 4, ring opening fragmentations and rearrangernents. In all cases the
N-N bond is cleaved. Irradiation of the 4-unsubstituted derivative (163; R 4 = H) in alcohols
leads to transposition of the ring atorns to yield 1,5-dirnethyl-3-phenyl-4-imidazolin-2-one
(164) plus several ring-opened fragments (69JCS(C)2624). Similar results are obtained when
irradiation is carried out in the presence of diethylarnine (73AP155).
Irradiation of 4-hydroxy- and 4-alkoxy-3-pyrazolin-5-one derivatives (163; R 4 = OH,
OR) leads to ring cleavage with the forrnation of ß -diamides (165) (69TL271). The rnethylene
blue sensitized rearrangement of the sarne pyrazolinone (R 4 = H) to the oxindole (166) also
Pyrazoles and their Benzo Derivatives
hV/
OH or Et 2 NH
RÎ=\M e
O . ./NMe
N
Ph
(163)
hv
MeOH
hv
sens.
Scheme 11
219
F\M e
PhNyNMe
o
(164)
Me
I
) PhNHCOCCONHMe
I
OR
(165)
Me
C- Me
/; ,.... ,H
O'
N
H
(166)
involves an initial nitrogen-nitrogen bond cleavage (73CB2070). Finally, the 4-amino deriva-
tive (163; R 4 = NH 2 ) behaves similarly to the 4-hydroxy derivative giving cornpound (165;
R = H) together with other ring-opened products (74AP21l). Flash therrnolysis of 3,5-
dimethylpyrazole affords 1,3-pentadiene and nitrogen (82JOC2221).
(ii) Rearrangement
The azido/tetrazole rearrangement of pyrazole and indazole derivatives will be discussed
in the corresponding section (4.04.2.3.4(v)).
(a) Ring opening without fragmentation. Ring opening to 2-alkylarninobenzonitriles (167)
occurs when N-l-alkylated indazoles (168) are irradiated (67HCA2244).
R 3
CN R3 N
N N/
I R 1
(167) R 1 (168)
A new type of rearrangernent has been reported for certain l-(o-nitrophenyl)pyrazoles
(169), giving cis- and trans-benzotriazole l-oxides (170; Scheme 12) (73TL891). The reaction
was rationalized in terms of an intermediate azo compound (171), formed in turn either
from the diradical species (172) or from the intramolecular l,4-adduct (173). Subsequently
R 4 R 3
RJC N
N/
02N Ò
I
(169) X
hv 1
R4RS
R 3 0"
hv O-N
N 'N
(173) X
R 4 R 3
R S C
N"
o N/
'o/J
U
X
(172)
R 4
R:. À _R3
lí
o N
N
o' 'Ó
X
(171 )
Scheme 12
1
R 3 R 4
o: I I
NC=CCOR s
X::::,... ::::-.. /
N+
I
0-
(170)
220
Pyrazoles and their Benzo Derivatives
the radical rnechanism was preferred (76BSF184), both for o-nitrophenyl and 2,4-dinitro-
phenyl derivatives. Only nitro group reduction products are obtained frorn the corresponding
1-( p- nitrophenyl)pyrazoles (76BSF19S).
Cyclodehydrogenation of 1,4,5-triphenylpyrazole (174) to give I-phenyl-1H-
phenanthro[9,10-c]pyrazole (175) has been observed (Scherne 13), but in the presence of
benzophenone ring opening to 3-anilino-2,3-diphenylacrylonitrile (176) was preferred
(77JCS(Pl )2096).
I,
Ph
PhrN
N'"
Ph
(174)
(175)
Ph,CO
NC NHPh
>=<
Ph Ph
(176)
Scheme 13
(b) Ring contraction. There are no examples of light-induced ring contractions of.aromatic
pyrazoles (pyrazoles, indazoles and pyrazolones) similar to those described for
pyrazolidinones (Section 4.04.2.2.2(iv)).
(c) Ring isomerization. One of the most important photochemical reactions of pyrazoles
is their transformation into imidazoles. Discovered independently by Schmid (67HCA2244),
Beak (67TL531S) and Ege (67CC488), this reaction generally involves the exchanges of
positions N-2 and C-3 of the pyrazole with positions C-2 and N-3 of the irnidazole.
Van Tamelen and Whitesides (71JA6129; see also 71BSF192S) have proposed a general
mechanism to account for the rearrangement products of five-mernbered heteroarornatic
systerns. It involves initial cleavage of the weakest single bond (in pyrazoles (177) the
NO)- N(2) bond) followed by cyclization of the resulting diradical intermediate (178) to
forrn the azirine (179; Scheme 14). They also propose that species (179) is in equilibrium
with valence bond isomers (180), (181) and (182), thus accounting for the formation of
irnidazoles (183) and (184), the latter being the one rnost frequently obtained. The rnechan-
isrn is equally valid for the isornerization of isoindazoles (177; R 3 _R 4 = C 4 H 4 ) to benz-
irnidazoles (183; R 3 -R 4 =C 4 H 4 ).
R 4 R 3
R 4 R 3 11
R s![ N hv
.-. R S '.: N
N/ N .
R 1 I
(177) R 1
ì (178)
hv If
R 4 R 3 R 3 R 4 N
RS Q ---" R4 ---" R S QR 3
..--- ..---
N R S :
R 1 R 1
(180) I (181)
II R 1 II
(179)
R 4 R 3 R 3 N R 4 N
RIN N R 4 1[)R S R J [)R 3
N N
R S R 1 R 1
(182) (183) (184)
Scbeme 14
Pyrazoles and their Benzo Derivatives
221
In this pioneering work Schmid (67HCA2244) studied a large collection of examples of
the transformation (177) --. (184), with R 1 = H, Me, Bz and Ph, and R 3 , R 4 , R 5 = H or Me.
The reaction was conveniently carried out in DME in the presence of benzophenone, and
the yields were in the range 20-30%. In ethanol solution, 1,3,5-trimethylpyrazole (177;
R 1 = R 3 = R 5 = Me, R 4 = H) yielded (183) and (184) (69T3287). In contrast with the pre-
viously observed sensitized photorearrangements (67HCA2244, 67CC488), this last reaction
was not sensitized by acetophenone or benzophenone.
In addition to reduction, ring transposition of the type (177) --. (184) is observed in the
conversion of (185) into 1,2-bis(1-phenylimidazol-4-yl)ethane-1,2-diol (186) by irradiation
at 254 nm (74JCS(Pl)1871).
o
Ph^n
(.;
N
Ph
(185)
OH OH
I I
N----(T-T:?;-N
(J Ph Ph(J
N N
Ph Ph
(186)
The phototransposition reaction in the isoindazole series (187) to give benzimidazoles
(188) has been carefully investigated when R 1 = Me, Et, Pr\ Bu\ Bz and Ph (67HCA2244).
The reaction is sensitive to steric effects; thus for R 1 = But and R 4 = Me, the l-t- butyl-7-
methylbenzimidazole is not formed.
M
Rl
(187)
R 4 NR 1
(X)R3
(188)
R 3
NRI
(189)
In the case of 2-alkylindazoles (187; R 3 = R 4 = H) the reaction has been studied with
regard to variations of quantum yield with exciting wavelength, solvent, temperature and
concentration (69CI09). It has been assumed from theoretical considerations based on the
change in bond orders upon excitation that the reaction occurs frorn the lowest excited
singlet state. The most likely structure for the intermediate forrned in quantitative yield at
-60 oC is the tricyclic compound (189), the indazolic counterpart of (180). The temperature
dependence of the quantum yields of fluorescence, intersystem crossing and photoreactions
has been measured for several neutral and protonated 2-alkylindazoles (78HCA234). Based
on kinetic and photochernical data, the authors conclude that the very efficient radiationless
deactivation process that takes place at 150 K proceeds via a hypersurface crossing in the
course of the photochemical rearrangernent (187) --. (189).
N- Unsubstituted indazoles (R 1 = H) behave like a mixture of N(l)H and N(2)H tautomers
giving rise to o-aminobenzonitriles (190) similar to 1-substituted isorners and to benz-
irnidazoles (191) like the isoindazoles (67HCA2244, 74JA201O, 74JA2014).
-o CN
R I NH 2
(190)
-o= NH
R I >
N
(191)
(d) Ring enlargement. In dilute sulfuric acid (pH 2-4) rearrangement of isoindazoles into
benzimidazoles (1874188) is suppressed and the dihydroazepinones (192) and (193) are
obtained (76HCA2632), whereas in strongly acid solution the o-aminoacetophenones (194)
are formed. The mechanism of formation of compounds (194) has been elucidated
(78HCA618). It occurs via arylnitrenes formed directly in their triplet ground state from the
triplet state of the isoindazoles.
o
VH
o
(192)
æ : O
I 0
NH
R 3
O
V NH 2
(193)
(194)
222
Pyrazoles and their Benzo Derivatives
Uii) Polymerization and disproportionation
Pyrazoles with free NH groups form hydrogen-bonded cyclic dimers (195) and trimers
(196) as well as linear polymers, depending on the substituents at positions 3 and 5. For
R = H, Me or Et, the oligomers are preferred, but for R = Ph, the cyclic dimer and the
linear polymers exist. The cyclic trimer (196; R = Ph) is) is not forrned because of steric
hindrance (B-76MI40402).
R
R N"H
I I
H., /N R
N
R
(195)
R
h
R ..N'......,>--R
H' 1'1
J:r f
Y'. H , :
R N--N
jJ-R
R
(196)
There are no known examples of pyrazole or indazole disproportionation.
All the examples quoted in this section concerning fragmentations or rearrangements
involve photochemistry. An interesting therrnal reaction has been described (72TL223S) in
which the pyrolysis of indazole between 700 and 800 0 C leads to a mixture of (197) and
(198; Scheme 15). A mechanism involving the 3H tautomer and the carbene seems
reasonable.
H H
OQN o=}
H
H
er"
OC=CH 2 + 0- C =CH
(197) (198)
Scheme 15
4.04.2.1.3 Electrophilic attack at nitrogen
U) Introduction
The reactivity of the pyridine-like N-2 atom of pyrazoles and indazoles follows the general
trends indicated in Section 4.02.1.3 for azoles. Since this part belongs to the classical
chemistry of pyrazoles, earlier results in (66AHC(6)347, 67HC(22)1, B-76MI40402, 79RCR289) will
be sumrnarized and occasionally updated.
(ii) Reaction sequence
In a neutral azole, the apparent rate of formation of an N-substituted derivative depends
on the rate of reaction of a given tautomer and on the tautorneric equilibriurn constant.
For example, with a 3(5)-substituted pyrazole such as (199), which exists as a rnixture of
two tautorners (199a) and (199b) in equilibrium, the product composition [(200)]/[(201)]
is a function of the rate constants k A and k B , as well as of the composition of the tautomeric
rnixture (Scheme 16) (76AHC(Sl)1).
R
eN
N
H
(199a)
1 k A
R
CN R 1
N
(200)
R
CN H K T = [(199a)]/[(199b))
N
(199b)
1 ks
O ï R [(200)]/[(201)] = k A K T
/N k B
N
R 1
(201)
Scheme 16
Pyrazoles and their Benzo Derivatives
223
Two points must be stressed: that a 3-R-pyrazole (199a) gives a 1,5-disubstituted
derivative (200) and that often the less abundant tautomeric species (Section 4.04.1.5.1)
is the more reactive. It is theoretically possible to use the tautomeric composition to direct
the synthesis towards one or another derivative. For instance, if (199a) is the more abundant
tautomer, the condition to obtain a large proportion of (200) is that k A >> k 1 . The factors
influencing the tautomeric exchange rates have already been described (Section 4.04.1.3.4)
and the reaction rates k A and k B will be discussed later (Section 4.04.2.1.3(vii)). Thus it
will be possible to direct the synthesis by slowing down the exchange rate (lowering the
temperature in a dipolar aprotic solvent or changing the proton by another group) and by
using powerful alkylating reagents (like Meerwein's oxonium salts).
Often electrophilic reagents can attack both nitrogen atorns of the mesomeric pyrazolate
and indazolate anions. In this case there is no simple relationship between the tautomeric
constant and the product composition.
(iii) Effect of substituents
The steric and electronic effects of substituents on the electrophilic attack at the nitrogen
atom have been discussed in the general chapter on reactivity (Section 4.02.1.3). All the
conclusions are valid for pyrazoles and indazoles. The effect on equilibrium constants will
be discussed in detail in the sections dealing with pKa values (Sections 4.04.2.1.3(iv) and
(v)) and the kinetic effects on the rates of quaternization in the corresponding section
(4.04.2.1.3( vii)).
(iv) Proton acids on neutral compounds: bas city of pyrazoles and indazoles
The basicity of pyrazole and its relation with imidazole basicity (due both to enthalpy and
entropy changes (77MI40403)) have been discussed on theoretical grounds (Section 4.04.1.2.1).
The pKa values of 90 pyrazoles have been determined by Gonzalez et al. (68BSF707, 68BSF5009)
and it is essentially his work that will be discussed below. A selection of pKa values are shown
in Table 28. The pKa values for some other pyrazoles have been measured in connection with
nitration studies (Section 4.04.2.1.4(ii)) (7IJCS(B)2365).
Table 28 pKa Values for Proton Addition (in Water at 20 oc)
Pyrazole
pKa (:t:0.04)
2.52
3.32
3.30
3.30
3.09
4.12
4.63
-1.96
0.60
0.64
0.82
-0.48
2.13
2.09
2.00
1.95
0.44
-0.65
-1.40
-2.0.
Unsubstiluted
3(5)-Methyl
3(5)-Elhyl
3(5)-t- Butyl
4-Methyl
3,5-Dimethyl
3,4,5- Trimethyl
4-Nitro
4-Chloro
4-Bromo
4-Iodo
3(5)-Chloro
3(5)-Phenyl
I-Methyl
I-Ethyl
1-t-Butyl
I-Phenyl
1-p- Nitrophenyl
1-(2,4- Dinitrophenyl)
1-(2,4,6- Trinitrophenyl)
a :t:O.1.
The pKa values are approxirnately additive and a linear relationship of the type
pK alc == pK + L pK holds for the whole set (pK is the pKa of pyrazole itself and
pK is the effect of a substituent rn at position n). Deviation from the additivity is found
when two bulky substituents are in contiguous positions. Instead of discussing pKa values,
the authors consider pK which are mean values and thus more significant since they
correspond to several pairs of compounds.
224
Pyrazoles and their Benzo Derivatives
The electronic effect of the substituents in N- unsubstituted pyrazoles roughly follows a
Hammett relationship, -ll pK ;:' = 6.57u m , without tak into account the tautomeric
equilibrium. The N-methyl group is base-weakening (llpK a = -0.45) and considering the
statistical factor (76AHC(Sl)l), the real effect is -0.75 pKa units (83UP40400). Since in imi-
dazoles the experimental value lies between 0.05 and 0.30, it was concluded that the effect
on the pKa of a methyl group in position 1 is due to a steric hindrance to cation solvation,
which is larger in N-ethyl- and N-t-butyl-pyrazole (Table 28). Steric effects of the 3-
substituents are discussed in (68BSF707). It is well known that they do not hinder the proton
approach but the stabilizing solvation of the conjugate acid.
The basicities of indazole (1.31), I-methyl (0.42) and 2-methyl (2.02) derivatives and
of eight other substituted indazoles have been measured (67BSF2619). The effect of sub-
stituents in the 3-position is similar in pyrazoles and indazoles with Il pK values as follows:
Me, 0.80 and 0.86; Cl, -3.01 and -2.98; Br, -2.85 and -2.82, respectively. A nitro group
in the homocycle has an expected base-weakening effect of -2 pKa units, whether it is at
the 5- or the 6-position.
pKa values for pyrazolones and alkoxypyrazoles (B-76MI40402) have been used as a tool
in tautomeric studies (76AHOSUl). Pyrazolone itself has a pKa of 2.32. The OH forrn is
rnore basic than the NH form (for N-Ph derivatives the pKa values are 2.5 and 1.3,
respectively) and the CH form is a very weak base (pK a - -4). The structures involved in
acid-base equilibria in 5-pyrazolones are shown in Scheme 17. The OH (202b) and NH
(202c) forrns yield a common cation with a structure of type (203) whilst the CH form
(202a) gives a different cation, probably having structure (204). The protonation constants
of 4-hydroxy-pyrazoles have been determined in the course of studies of their tautomerism
(7óAHnSl)l). R4
H R3
0-::(. .;N
N
R '
(202a)
y
R 4 R J
O z;." H
N
R'
(202c)
II K.
R 4 R 3
HO N
N
R '
(202b)
R 4
H tJ R 3
NH
o N/+
R'
(204)
.
(v) Proton acids at anionic compounds: acidity of pyrazoles and indazoles
Pyrazole and indazole are very weak acids (Table 29) and -R, -[ groups considerably
increase the acidity (3,5-dinitropyrazole has a pKa of 3.14 (73JHCI055), i.e. it is a stronger
acid than formic acid). However, when in the 3- and 4-positions the acids are the same
strength. Habraken has pointed out the importance of resonance forms like (205), (206)
and (207) in the stabilization of nitro- and nitroso-pyrazole anions. Bulky substituents in
the 3- and 5-positions considerably decrease the acidity of these compounds, because they
prevent the coplanarity of the nitro or nitroso group at the 4-position (72JHC939, 73JHCI055).
o
1- 0
RH-
R5 þ
N
(205)
II K,
R4.___. R 3
HO:C:;"H
N
R'
(203)
Scheme 17
o
I
0--= N j'--lt
R 5 \)N
(206)
-0
I
N'J-r
R5 ;
(207)
Pyrazoles and their Benzo Derivatives
225
Table 29 pK. Values for Proton Loss'
Compound
pK.
Pyrazole
3-Acetylpyrazole
Pyrazole-3-carboxylic acid
4- Hydroxy-l-phenylpyrazole
4-Nitropyrazole
3,5 - Dimelhyl-4-nitropyrazole
3-Nitropyrazole d
3,5 - Dim thyl-4-nitrosopyrazole e
Indazole
Pyrazolone
14.21
11.85
3.74 b
9.05 c
9.67
10.65
9.81
9.14
13.80
7.94
. From (B-76MI4040Z), which see for references to the original
literature. b Involves the C0 2 H function. C Involves the 4-0H
function. d (73JHClOSS). e (nJHC939). f (67T28SS).
A Hammett relationship of the form IlpKa = 5.80'rn has been proposed for 4-substituted
pyrazoles (74TL1609) in order to explain the effect of 4-nitro (llpK a = 4.5, 0' rn = 0.71) and
4-diazo groups (llpK a = 10.0, O'rn = 1.76). The acidity constants of a series of pyrazolidine-
3,5-diones have been determined (75AJCI583) and the 4-n- butyl-1,2-diphenyl derivative
phenylbutazone has a pKa of 4.33.
(vi) Metal ions
(a) Ionic compounds of electropositive metals. Pyrazoles and indazoles form sodium,
potassium, magnesium and silver salts which are hydrolyzed to a large extent by water.
The resulting anions react very readily with electrophiles (Section 4.04.2.3.1O(viii)). The
sodium salts, prepared from the metal itself, are probably ionic, pz- Na+, but the insoluble
silver salt AgPz is probably polymeric as in (208). The silver derivative of 4-i-C 3 F 7 -pyrazole
is soluble in acetone where it is tetrameric (nCRv497).
Ô
N-=-=-N
" /"
Ag Ag Ag
Ö "($
(208)
(b) Simple complexes. The neutral and anionic pyrazoles are excellent ligands, and the
coordination chemistry of pyrazoles has been extensively studied. Two comprehensive
reviews deal with this topic: the one by Trofimenko (nCRv497) stresses the importance of
poly(pyrazol-1-yl)borates as ligands, while that of Bonati (80MI40402) covers all the metallic
derivatives of pyrazolès. Addition of the name of Reedijk to those of these two important
authors completes the list of main contributors to the chemistry of pyrazole complexes.
Bonati has classified the pyrazole complexes into two groups: compounds containing
neutral pyrazoles (HPz), called 2-monohaptopyrazoles since it is the N-2 pyridinic nitrogen
lone pair which confers on them the ligand properties; and compounds containing pyrazole
anions (pz) which can act as monodentate or, more often, as exobidentate ligands (nCRv497).
Pyrazole and its C-methyl derivatives acting as 2-monohaptopyrazoles in a neutral or
slightly acidic medium give M(HPz)nXrn complexes where M is a transition metal, X is the
counterion and m is the valence of the transition metal, usually 2. The number of pyrazole
molecules, n, for a given metal depends on the nature of X and on the steric effects of the
pyrazole substituents, especially those at position 3. Complexes of 3(5)-methylpyrazole
with salts of a number of divalent metals involve the less hindered tautomer, the 5-
methylpyrazole (209). With pyrazole and 4- or 5-monosubstituted pyrazoles M(HPz)6X z
0ì Me
Br, , -1'(
/ n'B{H
(209)
226
Pyrazoles and their Benzo Derivatives
cornplexes are obtained when X is an anion of low coordination potency, such as NO;-,
BF'; or CIO';. When X is a halide or an NCS- ion, complexes M(HPz)4X 2 are formed in
which the anion is coordinated as in (209). 3,5-Disubstituted and 3,4,5-trisubstituted
pyrazoles form complexes of the type M(HPz)4X2 with low coordinating potency anions
and of the type M(HPzhX 2 with halide ions.
Both Bonati and Trofimenko include in the group containing pyrazole anions compounds
like (210) and (211), which contain an N-C bond, and compounds like (212), which are
reported in Section 4.04.2.1.3(xv).
()
H.. }'I-N, /Cl
'c Cl-Ni
", I ".
H N-N " 'Cl
V
(210)
Me
Me C'N Ph Ph
N
0...... I O N Me
N-O-Cu-N I
0/ I
o Me
I
N
0/ ......0
(211)
n
N-N
Me I , ..Me
Ga Ga'"
M '" I 'Me
e N-N
V
(212)
Bonati considers that due to the spatial disposition of lone pairs in the pz - anion, it could
be a good exobidentate ligand but not a chelating agent. However it was found recently
that the uraniurn complex (213) has an endobidentate structure which was attributed to
the highly ionic character of the U-N bond. There are many examples of pyrazole anion
complexes and their study goes beyond the limits of this chapter. Some highly symmetrical
complexes, e.g. (214) (79IC65S), which resembles the pyrazole N -H, . . N trimer (196),
and (215) of C 3V symmetry, are shown.
o
N\jsQ
LQS
(213)
ð
N:.c::N
A/ 'Au
/ "-
O N.\. - U ...
;' ':N-Au-N:. ;
...... ....
(214)
CZ Q
I , l \
H-B q" Ô "'co :"7,:-:-' \ B-H
\,q, , ,,'í \0/
\ , \ I
N-N N-Ñ
V 0
(215)
The only structures definitely established are those obtained from X-ray measurements.
Some of these are shown in Table 30, from which a large number of aromatic pyrazole
geometries can be found.
Studies on metal-pyrazole cornplexes in solution are few. The enthalpy and entropy of
association of Co(II), Ni(II), Cu(II) and Zn(II) with pyrazole in aqueous solution have been
determined by direct calorimetry (SlMI40406). The nature of the nitrogen atom, pyridinic
or pyrrolic, involved in the coordination with the metal cannot be determined from the
available thermodynamic data. However, other experiments in solution (Section
4.04.1.3.3(i)) prove conclusively that only the N-2 atom has coordinating capabilities.
(c) Chelate complexes. Apart from the uranium derivative (213), the other chelate
complexes involving endobidentate ligands are derived from pyrazoles bearing functional
groups containing heteroatoms. Trofimenko (nCRv497) has described several examples of
chelates, the endobidentate ligands of which are either N-substituted pyrazoles (216) and
(217) or C-substituted pyrazoles such as (218) and (219).
ON:
N
I
c
s ......s-
(216)
eN:
N
I
F 3 C'."C
, ......0-
F 3 C
(217)
(}-Q-O
-1'!' .]'I 1':I. .]'1-
(218)
W """ Me
I N
::::,.., N ':. .--J.
" .N Me
0- .
(219)
Copper salt (220; Table 30) involves the nitrogen atom of the carbamoyl group, but in
the complex (221) the ligand is coordinated to the divalent metal ions through the nitrogen
atom of the pyrazole ring and the oxygen atom of the carbamoyl group (SOMI40403).
Table 30 X-Ray Structures of Pyrazole Complexes
Metal Ligand Formula Ref.
Cr(II) 3(5)-Methylpyrazole (HMPz) [Cr(HMPz)4 F Z](BF 4 ) 79JCR(S)374
Mn(II) 3(5)-Methylpyrazole (HMPz) Mn(HMpz)4Brz (209) 71IC2594
Co(II) 3,5-Dimethylpyrazole (HDMPz) [CoF(HDMPzhh(BF 412 78IC1990
Co (II) 3,5-Dimethyl-l-phenylpyrazole (DMPPz) Co(NCS12(DMPPz12 80AX(B)159
Co(II) Hydrobis(pyrazol-l-yl)borale [BHz(pzh] Co[BHz(pzh]z 73IC508
Co (II) Hydrotris(pyrazol-l-yl)borate [BH(Pzh] Co[BH(Pzhh (215) 70IC1597
Ni(II) Pyrazole (HPz) Ni(HPz)6(N0 3 12 70AX(B)521
Ni(II) Pyrazole (HPz) Ni(HPz)4 C1 Z 67 AX135
Ni(II) Pyrazole (HPz) Ni(HPz)4 Br Z 69AX(B)595
Ni(II) 3,5- Diethyl-4-methylpyrazole (HDEMPz) Ni(HDEMPz)4 Cl z 79MI40413
Ni(II) 3,5- Diethyl-l-phenylpyrazole (DEPPz) Ni(DEPPzh(N0 3 12 79MI40403 N
c
Ni(II) Bis(3,5 -dimethylpyrazol-l-yl)methane [CHz(D Mpz12] {Ni[CHz(DMPz12]Clzh (210) 80IC170
Ni(II) Dimethylbis(pyrazol-l-yl)gallale [GaMez(pz12] Ni[GaMez(pz12h 75JCS(D)176
Ni(II) Dimethylbis(3,5 -dimethylpyrazol-l-yl)gallate [GaMez(DMpzh] Complicated structure' 80CJC 109 1
;::s
Cu(II) 3,5-Diethyl-4-methylpyrazole (HDEMPz) Cu(HDEMPz12Cl z 79MI40412
Cu(I) l-AllyI-3,5-dimelhylpyrazole (ADMPz) [Cu(ADMPz)CI]z 76BCJ143 ....
Cu(II) 3,5-Dimelhyl-l-phenylpyrazole (DMPPz) Cu(DMPPz12Cl z 80MI40401
.
Cu(II) 3,5- Dimethyl-l-phenylpyrazole (DMPPz) Cu(DMPPz12(N0 3 12 (211) 79AX(B)1468 tJ::J
Cu(II) l-Carboxamido-3,5-dimethylpyrazole (CD MPz) Cu(CDMPz12 (220) 79JCS(D)1867
Cu(II) Hydrotris(pyrazol-l-yl)borate [BH(Pzh] Cu[BH(pzh]z 79JCS(D)1646 ;::s
N
Cu(I) Hydrolris(pyrazol-l-yl)borate [BH(Pzh] {Cu[BH(Pzh]h 76JA71 1 c
Cu(II) Dimethylbis(pyrazol-l-yl)gallate [GaMez (pz12] Cu[GaMez(pz12]z 75JCS(D)718 0
Cu(II) Dimethylbis(3,5-dimethylpyrazol-l-yl)gallate [GaMez (DMpz12] Cu[GaMez(DMPz)z]z 75JCS(D)718
Cu(II) Dimethylbis(3-methylpyrazol-l-yl)gallate [GaMez(MPz)z] {CuO[G aMe z(MPz)z](3MPz)h 76CJC343 (;.
Cu(II) Antipyrine (APy) Cu(APyh(N0 3 h. form I b 74AX(B)2246
(;.
Cu (II) Anlipyrine (APy) Cu(APyh(N0 3 h, form lIb 74AX(B)2500
Mo(lI) Dimethylbis(pyrazol-l-yl)gallate [GaMez(Pz)z] Complicated structure' 80CJCI080 '"
Mo(II) Dimethylbis(3,5-dimethylpyrazol-l-yl)gaIIate [GaMez (DMPzh] Complicated structure' 80CJCI080
Mo(lI) Methylbis(3,5-dimethylpyrazol-l- yl)hydroxygallate [GaMe(OH)(DMPz)z] MO(COh(7j3_ C4H7 ) [GaMe(OH)(DMPz12] 79CJC139
Mo(II) Hydrobis(3,5-dimethylpyrazol -l-yl)borate [BH z (D MPz12] Mo(CO)z(7j3 -C3HS) [BHz(DMPz12] 71AX(B)1859
Mo(V) Hydrotris(3,5-dimethylpyrazol-l- yl)borate [B H(DMPz)3] MoOCl z 'C 6 H s CI[BH(DMPzh] 82JCR(S)6
Rh(I) Pyrazole (HPz) [Rh(CO)P(OPhh(HPz)]z 8IJOM(205)247
Pd(II) 3,5- Dimethylpyrazole (HD MPz) [PdCl(PEt 3 h(HDMPz)](BF 4) 81IC1545
Ag(I) 3,5-Dimethyl-l-phenylpyrazole (DMPPz) [Ag(DMPPZ)3](N0 3 ) 79AX(B)177
Pt(II) Pyrazole (HPz) [P1Cl z (C Z H 4 Jz (HPz) ]Cl 81IC1519
U(IV) Pyrazole (HPz) U(Cp)3(HPz)C (213) 81IC1553
'Due to the presence of a second, more complex pyrazole ligand. b Cu-O=C(5) bonds. C Cp = cycIopentadienyI. N
N
--.}
228
Pyrazoles and their Benzo Derivatives
2...
O Me H 0
Me V N I 0 V N
N/ '" /N_ C 7 N/ "'M
1 Cu I HI",
7 C --r-f & U ..- N ..... /C O
o I I I Me N
H Me'l /I A
(220) (221)
Ligands like (222) are useful analytical reagents for Cu(II) (64HC(20)1), whilst ligands
(223) and (224) are used as dyes (Section 4.04.4.1.3). In dyes such as (223), which are
applied to wool, the usual metal employed is chromium; for cotton dyes like (224) it is
more common to use copper.
Ar
o 'N
" "
..N )d Ph a N=N Jd Me . )j N Me
_ 0 V N I V V
N/ 02N OH -0...N -0 N...N
R h Ph
(222) (223) (224) (225)
The 15N, 13C and t H chemical shifts and the corresponding coupling constants have been
determined for the chelate (225; M = Zn(II)) (81MlOS).
(d) Azocrown ethers and porphyrinogens. In an interesting series of papers, Tarrago (e.g.
see 81T991) has shown that polypyrazolic macrocycles (226), (227) and (228) are excellent
complexing agents for the alkali metal cations due to the electronegative cavity formed by
the Sp2 lone pairs. The hexapyrazolic derivative (227) is an exceptional cornplexing agent
for Cs+. Compound (226) also forms classical complexes with Hg 2 +, Ag+ and Cd 2 + salts.
Me Me
ó N?-N
;I N Me
I N N I
Me N 1
C jJ N ' Me
M I IN
e N
-(;
Me Me
o :
N R 2
R 21 N'N N ]
L-rN'w J
WRJ
(226)
Me
MoQ-N
-\:N ì1 MO
Mel)N N;-l
t N N-N
...........vMe
Me
(227)
Ar,!S Me
N "
,/ I 'N
M/2..... 0 N'
Ph
(228)
(vii) Alkyl halides and related compounds: compounds without a free NH group
Alkylating agents transform pyrazoles and indazoles into the corresponding quaternary
salts (229) and (230); in some instances, e.g. in the reaction of pyrazole with methyl iodide,
the quaternary salt is formed directly from the N-unsubstituted compound. The situation
is more complicated for hydroxypyrazoles (S-76MI40402). At 60 0 C both the N-alkyl and
the O-alkyl derivatives yield the quaternary salt (231; X = 0). Experiments at higher
temperatures produce more complicated results, including C- alkylation at the 4-position.
4-Hydroxypyrazoles lead to the quaternary salts (232), the precursors of mesoionic deriva-
tives (28) (S-76MI40402).
R 4 R J RJ RJ HO RJ
R S CNR 2 I NR2 RXCNR 2 RSCNR2
N/+ N'+ N/+ N/+
R J R! Rl R J
(229) (230) (231) (232)
Amino and sulfur analogues of pyrazolones also yield the 'arornatic' quaternary salt (231;
X = NH or S). If the pyrazole bears a substituent with a second pyridine-like nitrogen atom,
an intramolecular bridge can be formed by reaction with a dihalogenoalkane. Thus pyrazol-
1'-ylpyridines react with 1,2-dibromoethane to form (233) (8IJHC9).
Pyrazoles and their Benzo Derivatives
229
R 4 R 3
RSCN+
Ò N / N}
I
(233)
The kinetic aspects of the SN2 quaternization (the Menschutkin reaction) have been
covered by Zoltewicz and Deady (78AHC(22)72), the latter author having done most of the
experimental work related to pyrazoles and indazoles. In C- unsubstituted N- methyl deriva-
tives a Brønsted relationship (log krel = 0.43pK a - 2.75) is followed, and therefore the
quaternization rate can be predicted from the pKa value (Section 4.04.2.1.3(iv)). The point
corresponding to 2-methylindazole deviates from the regression line by a factor of 2.7,
corresponding to a rate-retarding steric effect. Even if there are no experimental results
on the effect of C-substituents on the reaction rate in the case of pyrazoles and indazoles,
an equation of the form log k/ k H = 85 0 + PPI + PR(7R derived for pyridines can be equally
valid for ortho-substituted pyrazoles (50 is an ortho-steric pararneter (80JCS(P2)1350). As
commented on in Section 4.04.1.4.3, the rates of N-methylation of N-arylpyrazoles (log
k/ k H = -1.10(7) show that steric interactions cause the aryl group to rotate out of the plane
of the heterocyclic ring in the transition state.
(viii) Alkyl halides and related compounds: compounds with a free NH group
Although N- alkylation is one of the most important and most studied reactions of
pyrazoles, its quantitative (orientation ratios) and qualitative (mechanism) aspects are still
unclear. All the classical results are reported in (67HC(22)1, B-76MI40402) and can be summar-
ized as follows.
(1) Alkylations have been carried out on the pyrazole ring using alkyl halides (usually
iodides and bromides), dialkyl sulfates, arenesulfonates and diazomethane as alkylating
agents. Trialkyl phosphates give excellent yields (80-90%) of N-alkylpyrazoles
(73JCS(Pl)2506). With neutral pyrazoles and alkyl halides the alkylation yields salts of the
corresponding acids liberated in the reaction.
(2) In the formation of monoalkyl derivatives from 'unsymmetrical' pyrazoles, not even
empirical rules can predict the orientation of the entering alkyl group on the basis of the
nature of the existing substituents. For the same reactant, the position taken by an entering
alkyl group may be dependent on the nature of the alkylating agent and on experimental
conditions. In Scheme 18 some orientation ratios are shown.
Me
(;:-:_;N
N '" 35%
Î
65%
Dimethyl sulfate
in basic medium
(82JOC536)
.'. C0 2 Et
MeWN
( 65%
35%
Ph
O+-- 25%
75'10/' H
Methyl iodide in a
sealed tube
(82JOC536)
uB I
'"
N
Me ".._.;N
(N 40%
60%
NO
2
(;:-:.',:N
N '" 26%
Î
74%
Methyl iodide in aqueous
ethanolic potash
(B-76MI40402)
OHCtf-::fH 0
z:::: : .;N
N "'55%
Î
45%
Dimethyl sulfate in
basic medium
(74CB2l27)
CH 2 Ph
Mea
r H 40%
60%
Q Me
.-.
Me :,:
( H 67% Me
33%
Benzyl bromide in DMF in the presence of KI (80JHCI37?
Scheme 18
The more recent results of Scheme 18 can be summarized as follows: the less hindered
isomer is formed unless the substituent has a lone pair, the electrostatic field of which
enhances the nucleophilicity of the adjacent nitrogen atom. This is true not only for pyridine
and pyrazole, but probably also for CHO and C0 2 Et.
230
Pyrazoles and their Benzo Derivatives
Studies of the alkylation of indazoles (67HC(22)1) have been updated by Nunn
(73JCS(PIJ2371) and Palmer (7SJCS(Pl)169S). The ratio of methylation at positions 1 and 2 is
relatively sensitive to the steric effect of substituents at positions 3 and 7 as shown by the
results obtained in basic medium for unsubstituted indazole (55: 45) and its 3-phenyl (74: 26)
and 7 -nitro derivatives (29: 71).
Phase transfer catalysis has been used with success to prepare N-substituted pyrazoles
(78MI40403, 79MI4040S, 70JHC1237, SOJOC3172) and this procedure can be considered the
simplest and most efficient way to obtain these compounds. Experimental design
methodology has been used to study the influence of the factors on the reaction between
pyrazole and n- butyl bromide under phase transfer conditions (79MI4040S).
When polyhalogenoalkanes are used as alkylating agents, poly-N-pyrazolylalkanes are
obtained. In this way, compounds (234), (235; R == H) and (236) have been prepared from
pyrazole anions and methylene iodide (70JASllS), chloroform (B-76MI40402), and carbon
tetrachloride (70JASllS), respectively. Phase transfer catalysis is a better way to obtain
azolylmethanes (S2JHC1141, S3BSF(2)S).
Me
MeCN
N
I
CH 2
I
/N
NQMe
Me
(234)
R
R n
;N
N N
R C \ I
N-CH
"'- I
R O N
N /, R
R
Q
C "Z I
N-C-N
"'- I \---
N
N O N
/,
(236)
(235)
Another possibility is that both nitrogen atoms react with a double alkylating agent. In
this way fused pyrazole derivatives (pyrazolo[1,2-a ]pyrazoles) like (237) can be obtained
by reaction of 3,5-dimethylpyrazole with 1,3-dichloropropane or 1-chloro-3-propanol
(69BSF2064). More surprising is the reaction with (X- chlorocarbonylphenylketene which yields
the paraionic compound (238) (SOJA3971) which can also be obtained from 3,5-dihydroxy-4-
phenylpyrazole and ß-dicarbonyl compounds (S2JOC29S).
Me
+N Q Me
O +-+
Ph 0
Me
+N'0Me
a
(237)
Me.....
P:\
O \\' ;;Me
R-,
Ph 0
(238)
A parallel exists between the results of protonation and alkylation of pyrazolones since
there is an alkyl derivative for each tautomer. The main difference is that the percentage
of the different tautomers is thermodynamically controlled whereas that of alkyl derivatives
is kinetically controlled. One has to remember that the alkyl derivatives thus obtained are
the 'fixed' compounds used in tautomeric studies.
Scheme 19 contains all the reactions observed in different examples, none being so
complex (B-76MI40402). Most studies deal with the methylation of 3-methyl-1-phenyl-
pyrazolone, since in this case one of the products obtained is antipyrine (2,3-dimethyl-l-
phenyl-3-pyrazolin-5-one), one of the classical antipyretic agents (Section 4.04.4.1.1).
Only the anion (239) is susceptible to C-alkylation in the 4-position. The two other
anions (240) and (241) can only give rise to 0- and N-substituted derivatives which result
in the asymmetry of Scheme 19.
R 3 R3 R 3
O ..DN..... ROUN..... O N R
... ) N/ ... -'N
R t t
(239) (240) (241)
In the alkylation of 1-phenylpyrazole-3,5-diones both carbon and oxygen compete
successfully with nitrogen (B-76MI40402). Phenylbutazone (Section 4.04.4.1.1) can be pre-
pared by reaction of 1,2-diphenylpyrazole-3,5-dione with n- butyl halides and alkali, even
if the industrial procedure uses n-butyl malonic diesters and hydrazobenzene (Section
4.04.3.1.2(ii)).
Pyrazoles and their Benzo Derivatives 231
R 3 R 3 R R 3
ROCN --. ROCN ROCN
N N N
H R R
/ \ \ \
R 3 R 3 R3 R R 3 D R3
RO ÇN R OJ:3N --. oJ:3N --.D --.
o .....N o /N
N N N N
H R R R
\ / I /
R 3 R 3 R R 3
o N R --. J:;N R O .J.:;N R
o N/ N
H R R
Scheme 19
(ix) Aryl halides and related compounds
The SNAr reaction of pyrazoles with activated halogenated benzenes has been mainly
studied by the Montpellier group (Scheme 20) (66BSF619, 66BSF775, 66BSF2832, 66BSF3727,
67BSF289, 68BSF707, 68BSF5019, 70BSF231).
R 4 R 3 R 4 RS
SCN Rl:YN
R .....
N N.....
H Ar
Jf (243)
+
R 4 R 3
R 4 R3 RSO
RS VN H
N
Ar
(242) (244)
Scheme 20
The principal conclusions from these studies are as follows.
(1) Only N-unsubstituted pyrazoles react, thus no 1,2-disubstituted quaternary salts can
be obtained in that way.
(2) Only activated halogenated benzenes react (p-fluoronitrobenzene, 1-fluoro-2,4-
dinitrobenzene, picryl chloride). 3,6-Dichloropyridazine reacts with two moles of pyrazole
to yield (245), an excellent chelating agent (70BSF1346). With non-activated halogenated
benzenes (bromobenzene for instance), the Ullmann condensation should be used
(70MI40400). Using this method polymeric pyrazoles were prepared from 1,4-diiodobenzene
and 4,4' -bipyrazolyl (69RRC1263).
êN-Q-N(J
(245)
)
80% 20%.
( 246)
OMe
Me>:k
20% 80%
(247)
(3) Concerning the orientation of the reaction, i.e. the ratio (243): (244) when asym-
metrical pyrazoles are used (242; R 3 '" R S ), the tendency of a substituent R 3 to occupy the
3-position (isomer 244) follows in the order: COzEt> Ph> ::::C=C:::::: > Et > Me;3 Br > Cl >
H. Other experiments prove that Me> OMe and But> H. Finally, the methylene group of a
fused saturated ring> H, except in the case of the 3(5),4-trimethylenepyrazole (246).
The results obtained with methoxypyrazole (247) are attributed to an electronic effect,
whereas those obtained with (246) can be explained by taking into account the angular
strain in the minor isomer. Reaction of 3(5)-nitropyrazole with 1-fluoro-2,4-dinitrobenzene
affords exclusively 1-(2,4-dinitrophenyl)-3-nitropyrazole (70JHC1237).
232
Pyrazoles and their Benzo Derivatives
(4) Concerning the reaction rate, a considerable decrease is observed qualitatively when
R 3 = C0 2 Et or Ph. The presence of two But groups in the 3- and 5-positions (242;
R 3 = R 5 = But) completely inhibits the reaction. Structure (248) for the transition state has
been established from a kinetic study of the reaction between pyrazole and 1-fluoro-2,4-
dinitrobenzene (72JCS(P2)1420).
Y..:.)j
;, N"N 'H
I :..J ----N'o, ,.
, .
NO,
(248)
The reaction has been extended to indazole (67BSF2619) from which both isomers have
been obtained, and to pyrazolones (68BSFS019). In the latter system N-, 0- and C-aryl and
even diaryl derivatives have been isolated from the reaction with 1-fluoro-2,4-dinitroben-
zene.
(x) Acyl halides and related compounds
Since N-acylpyrazoles have been fully described in (B.76MI40402) only a summary and
some new references will be discussed here. Only neutral pyrazolides have been described,
but a cationic intermediate (249) is involved in the Olofson and Kendall method of obtaining
minor N-alkylated isomers (70JOC2246).
N- Acetylated pyrazoles are obtained from N- unsubstituted pyrazoles by treatment with
acetyl chloride (alone or in the presence of pyridine) or acetic anhydride. N- Trimethylsilyl-
(80JOM(188)141) and N- dimethylgallyl-pyrazoles (81JOM(21S)349) (Section 4.04.2.3.10(viii))
are also useful precursors. From an asymmetric pyrazole two acylated derivatives can be
obtained, but only one, the less hindered, is often isolated. This happens because the less
stable isomer is transformed in the reaction medium into the more stable one (acylotropy;
Section 4.04.1.5.1). The same behaviour is observed in indazoJes. The unstable 2-acylin-
dazoles can be prepared working at low temperature (76JMC839) or using the indazole silver
salt. In the case of pyrazolones the situation is more complicated and N-, 0- and C- acyl
derivatives are obtained, the first two being subject to acylotropy (no C-C bond breaking
has been observed) (64H020)1, 74CPB207, 74CPB214). Indazolone (250) yields two N-acetyl
derivatives (251) and (252), and a diacetyl derivative (253). The unstable isomer (252), the
structure of which has been determined by X-ray crystallography (Table 5; Section
4.04.1.3.1), is transformed into the stable isomer (251) in basic mediurn (S7AG732).
NH NH NAC NAC
NI N J N
H Ac H Ac
(250) (251) (252) (253)
The fact that the isomeric structure of azolides is thermodynamically controlled has been
used by Olofson and Kendall to prepare l-alkylazoles regioselectively (70JOC2246). An
asymmetric pyrazole yields two alkylated derivatives (Scheme 21; see Section 4.04.2.1.3
(viii)), but the alkylation with a powerful alkylating agent of the acetylated derivative leads
to the less abundant isomer via the salt (249), which is too unstable to be isolated.
R XR I R j9R
ÇN ÇN + /NRI
H R minor
Jr major
R
R eN
VN H IRjOISF.
XCOR' N or
COR' R'FSO,
Scheme 21
Î H 2 0
[ (:> RI X- ]
COR'
(249)
Pyrazoles and their Benzo Derivatives
233
In addition to the N- acylated derivatives described above, N- COzR, N- CONR lR 2 ,
N-C(=NR 1 )R 2 (81JMC1521), N-CN (70CB1954), N-SOzR\ etc. derivatives have also been
prepared from pyrazoles and indazoles. Some of these compounds are biologically active:
the N-carbamoylindazoles are anthelmintic agents (76JMC839) and the N-benzimidoyl-
pyrazoles are hypoglycemic agents (81JMC1521).
When pyrazolecarboxylic acids (Section 4.04.2.3.3(iii)) are treated with thionyl chloride
instead of the acid chloride, compound (254) is isolated. This corresponds to a double
N-acylation (67HC(22)l).
. n R
:XI:
u'
R
(254)
(xi) Michael addition on double and triple bonds
N- Unsubstituted pyrazoles and indazoles add to compounds containing activated double
and triple bonds (67HC(22)1, B-76MI40402). Amongst C-C double and triple bonds, maleic
anhydride, acrylic acid esters and nitriles, acetylene-carboxylic and -dicarboxylic esters
(78AHC(23)263), quinones, and some a,ß-unsaturated ketones have been used with succeSS.
Phenylacetylene reacts with pyrazole in the presence of Na/HMPT as catalyst to yield the
Z isomer of I-styrylpyrazole in a highly stereoselective reaction (78JHC1543).
With an activated C-C triple bond two successive additions can occur if the intermediate
alkene is reactive enough. DMAD and 3,5-dimethylpyrazole give an initiaJ fumarate (255)
which reacts further at the other end to form regioselectively the succinates (256). On the
other hand, methyl ethynyl ketone reacts twice at the same carbon atom with pyrazole to
form 1,1-pyrazolylbutanone (258) (68ZC458). The probable intermediate, a pyrazolide
vinylogue (257), can be prepared from methyl ß- chlorovinyl ketone and pyrazole, in a
reaction which is similar to acetylation (Section 4.04.2.1.3(x)).
n Me n Q
Me __;N ç M e Me _.;N /N
N O N I
I Me"" /N, ......N:-h' Me I
/C ......C0 2 Me CH-CH N H ......C C ......H /CHCH2COMe
Me0 2 C C I I I N-N
I Me0 2 C C0 2 Me / 1 \
H COMe "-./
(255) (256) (257) (258)
Indazole adds to acrylonitrile and 4-vinylpyridine giving 1- or 2-substituted derivatives
depending on the 7-substituents (69BSF2064). It also reacts with epoxystyrene to form (259).
Addition of pyrazole to C-X double bonds is also common. Formaldehyde gives stable
adducts (260) and (261) (69BSF2064), but in the addition to ketones, (262) is only observed
at low temperatures (Section 4.04.1.3.3(i)). However, hexafluoroacetone forms a stable
adduct (262; R = CF 3 ) that has been used as a chelating agent (Section 4.04.2.1.3(iv)).
Addition of pyrazoles to aryl isocyanates affords (263); the addition is also reversible, but
it requires high temperatures to dissociate the adduct (Section 4.04.1.5.1).
R 3
O
/N
N
I
RUIIIIIIC
, 'OH
R
(260)
R 3
n
_;N
N
CH 2 0H
(261)
R 3
O
/N
N
I
C,
o NHAr
N
J
CH 2 CHOHPh
(259)
OC I'\:N
:::::,... /
N
CH 2 0H
(262)
(263)
(xii) Halogens
N - Halogenated pyrazoles are unstable compounds (Cl> Br > I) that are seldom isolated.
1-Bromopyrazoles resemble NBS and may be important in the process of C-1:iromination,
not because of an N to C rearrangement but by acting as a source of the powerfully
electrophilic brominium ion (Section 4.04.2.1.4(v)). 4-Substituted pyrazoles can form
234
Pyrazoles and their Benzo Derivatives
per bromides which are formulated as (264). Such compounds readily lose hydrogen bromide
to give I-bromopyrazoles, the corresponding 1-brorno cornpound (265) frorn 4-
nitropyrazole having been isolated (B-76MI40404).
(265)
[M9'] ,-
(266)
R 4 R J
R5 0 N
N/
r
(267)
[ R4 R 3 ]
R;CNBr Br-
N/+
H
(264)
02N O
7
/N
N
Br
With iodine in carbon tetrachloride, 4-rnethylpyrazole affords a deep-red oil for which
the structure (266) has been proposed. Nitric acid, silver nitrate and iodine together convert
pyrazole into 1,3,4-triiodopyrazole (267; R 3 = R 4 = I, R 5 = H). The N-iodopyrazoles are
quite stable and well-characterized derivatives, several having been prepared by Hüttel and
by Reirnlinger (70CBI949) (267; R 3 = R 4 = Me, R 5 = H; R 3 = R 4 = Me, R 5 = I; R 3 = R 4 = R 5 =
Me; R 3 = R S = Me, R 4 = halogen).
(xiii) Peracids
Surprisingly, there are very few exarnples of successful N-oxidation of pyrazoles. Simple
N- alkylpyrazoles generally do not react with peracids (B-76MI40402, 77JCS(P1)672). The only
two positive results are the peracetic acid (hydrogen peroxide in acetic acid) transforrnation
of 1-rnethylpyrazole into l-rnethylpyrazole 2-oxide (268) in moderate yield and the peroxy-
trifluoroacetic acid (90% hydrogen peroxide in trifluoroacetic acid) transforrnation of
5-arnino-1-rnethylpyrazole into l-rnethyl-5-nitropyrazole 2-oxide (269).
RÇ ,O- 02NÇ ,O_
Me Me
(268) (269)
Forrnation of an N,N' -linked bipyrazole was observed during the oxidation of 5-arnino-3-
anilino-4-ethoxycarbonylpyrazole by rneans of dibenzoyl peroxide (82ZC56).
(xiv) Aminating and nitrating agents
The powerful arninating agents hydroxylarnine 0- sulfonic acid and 0- rnesitylenesulfonyl-
hydroxylarnine have been used to prepare cornpounds (270)-(274) (80JCR(M)0514, 76CPB2267).
ÇN OCN O:)NH, M,D H, T,,- oë;NH' T,,-
NH 2 NH Me Me
(270) (271) 2 (272) (273) (274)
N- Arnination of indazole affords a rnixture of 60% (271) and 40% (272), which corn pares
with the 55: 45 ratio obtained in rnethylation (Section 4.04.2.1.3(viii)). A carnphopyrazole
derivative (a rnixture of tautorners 275 and 276) when treated with hydroxylarnine 0-
sulfonic acid yields exclusively the (4S, 7 R )-4,7 - methano-2-arnino-7 ,8,8-trirnethyl-4,5,6, 7-
tetrahydro-2H- indazole (277) (79YZ699).
](71= ](
?NoN ?N:;NH
N N
(275) H (276) (277)
The N- nitration of pyrazoles discovered by Hüttel and extensively studied by Habraken
is a reaction of considerable interest (B-76MI40402). Using solutions of acetyl nitrate, or by
adding nitric acid and then acetic anhydride to a solution of the pyrazole in acetic acid, a
wide range of N-nitropyrazoles (278) have been prepared (82S844). cine-Substitution and
isornerization to 3(5)-nitropyrazoles will be discussed later (Section 4.04.2.3.100v)), but it
should be noted here that a synthesis of forrnycin (Section 4.04.4.2.1) proceeds through an
N -nitropyrazole (279) (80CC237). In this case and in other examples of unsymmetrical
pyrazoles, the less hindered isomer is isolated (278c, d). With an equivalent of acetyl nitrate
IeN NH'
N
Pyrazoles and their Benzo Derivatives
235
a' R 3 =R 5 =H R 4 =alkyl
b; R'=R'=H:R'=NO, O,N r :,0 OA, OA,
c; R 3 =Bu' R 4 =R s =H N
d' R 3 =NO R 4 =R s =H N/
, 3 2, 4 5 N0 2
e; R 3 = M,f. R = l} = H
(278) f; R = R = H. R = Me (279)
the 3(5)-rnethylpyrazole gave a rnixture of 3-rnethyl- (278e) and 5-rnethyl-1-nitropyrazoles
(278f), but with a large excess of the reagent only the 1,3-cornpound (278e) was obtained.
Depending on the reaction conditions both N- nitroindazoles (280) and (281) have been
isolated (7IJOC3084, 820MR(19)22S) and their structures were established by lH and 13C NMR
data. They will be discussed in Section 4.04.2.3.10(vi).
R 4 R 3
RS O N
N/
N0 2
::o--
02 N NN0 2
/
N
(280)
02N N
N
NO
(281) 2
(xv) Other Lewis acids
In the preceding parts of Section 4.04.2.1.3 the electrophilic attack on pyrazolic nitrogen
with the concomitant forrnation of different classes of N-R bond has been exarnined:
N-H (iv, v), N-rnetal (vi), N-C( Sp 3) (vii, viii, xi), N-C(spZ) (ix, x, xi), N-SOzR (x),
N-halogen (xii), N-O (xiii) and N-N (xiv). In this last part the reaction with other Lewis
acids leading to the forrnation of pyrazole N-rnetalloid bonds will be discussed, and the
study of their reactivity will be dealt with in Section 4.04.2.3.10(viii).
Pyrazoles, and sorne indazoles, substituted on the nitrogen by B, AI, Ga, In, Si, Ge, Sn,
P and I-Ìg are known. Poly(pyrazol-l-yl)borates have been studied by Trofimenko (ncRv497)
who found that they were excellent ligands (Section 4.04.2.1.3(vi)). The parent ligands
(282), (283) and (284) are available by the reaction of an alkali rnetal borohydride with
pyrazole, the extent of substitution depending on the reaction ternperature (Scherne 22).
BH:ï + 2 O N
N/
H
HPz
-120'C
OL HJ -
(282)
HPZ 180'C
Oj, J O t-BHr
(284)
Scheme 22
(283)
The three ligands are still widely used to prepare cornplexes, for instance of gold
(80AJC949), palladium (80BCJ961) and platinurn (references cited in 8IJOM(21S)131). Neutral
pyrazol-1-ylboranes generally exist in the dirneric pyrazabole structure (285) while cations
may have the trimeric D 3h structure (286). Recently rnonorneric N- borylated pyrazole
derivatives (287) have been synthesized (8IJOM(20S)147).
Ô --
. ,
, ,
, .
N ::::N
R / \ R
'B B/
R" \ / 'R
N-N
0 _-
. ,
. -'
Ô -- +
, ,
, ,
N::::Ñ
Jr
EtB BEt
\ /
N-N
F--':\
(285)
(286)
O
N/N
I
B
MeCNMe
(287)
236
Pyrazoles and their Benzo Derivatives
Analogously, pyrazolyl-aluminate and -indate ligands have been prepared (75JCS(D)749)
and their chelating properties evaluated with cobalt, nickel, copper and zinc. Gallyl deriva-
tives of pyrazoles and indazoles have been extensively studied by Storr and Trotter (e.g.
75CJC2944) who deterrnined several X-ray structures of these cornpounds. These derivatives
exist in the solid state as dirners, such as (212) and (288). A lH NMR study in acetone
solution showed the existence of a slow equilibriurn between the dirner (212) and two
identical tautomers (289) and (290) (Section 4.04.1.5.1) (SIJOM(215)157).
Yn
N-N R
R, I \;
"Ga Ga"
\\\\\\ \ / . 1í'11
R N-N R
Ô
N-N
"
Ga-R
/
R
n
N-N
/
R-Ga
"R
(290)
(288)
(289)
I-Silyl-, I-gerrnyl- and I-stannyl-pyrazoles and -indazoles are known cornpounds
(SOMI40402), the rnost irnportant being the silylated derivatives (SOZOBS75) since they are
useful starting rnaterials for other N-substituted derivatives (Section 4.04.2.3.10(viii)).
Several reagents can be used to introduce the rnetalloid on the nitrogen atorn including
R 3 MNMez (transarnination), Me3MCl, Me3MzO (6SCR(C)(266)44) and HN(MMe3h
(SOZOBS75) (M = Si, Ge, Sn).
Phosphorus derivatives of different structures have been prepared including pyrazol-l-
ylphosphines PPz 3 , PhPPzz and PhzPPz (pz for pyrazolate anion (ncRv497,SOMI40402)). By
transamination with tris(dirnethylarnino)phosphine, pyrazoles and indazole are converted
into (291) and (292), respectively (67CR(C)(265)1507). 3,S-Dimethylpyrazole reacts with
arnidodichlorophosphates to yield triarnides (293) whereas 1-substituted pyrazolones yield
arnidophosphates (294) (71LA(750)39).
R 4 R 3
R5 0 N
N/
I
P
/"
Me,N NMe,
oc l N
/
N
I
p
/"
Me2N NMe2
(291)
(292)
O 0 X Me
MCtMe O- t
Me CN -p- N r==; MC N O-p-O-Z..;N Me(..;N
N' I I...N-:P N I N N/
NR 2 R! NR 2 R 1 HgPh
(293) (294) (295) X = CI. Br or NO,
3,5-Dirnethylpyrazole (L) reacts with rnercury(II) chloride to give cornplexes of the
structure Lz(HgClzh. In connection with rnetallotropy (Section 4.04.1.5.1) the behaviour
of cornpounds (295) has been described. These phenylrnercury derivatives were synthesized
by the action of phenylmercury hydroxide on the appropriate pyrazole (71MI40400).
4.04.2.1.4 Electrophilic attack at carbon
(i) Reactivity and orientation
The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should
be consulted as some of the conclusions reported therein are gerrnane to this discussion.
Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral rnolecule it reacts
as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation,
etc.). Pyrazole cations, formed in strong acidic rnedia, show a pronounced deactivation
(nitration, sulfonation, Friedel-Crafts reactions, etc.). For the sarne reasons quaternary
pyrazoliurn salts norrnally do not react with electrophiles.
Pyrazoles and their Benzo Derivatives
237
As discussed in the theoretical section (4.04.1.2.1), electrophilic attack on pyrazoles takes
place at C-4 in accordance with localization energies and 1T-electron densities. Attack in
other positions is extremely rare. This fact, added to the deactivating effect of the substituent
introduced in the 4-position, explains why further electrophilic substitution is generally
never observed. Indazole reacts at C-3, and reactions taking place on the fused ring will
be discussed in Section 4.04.2.3.2(i). Reaction on the phenyl ring of C- and N-phenyl-
pyrazoles will be discussed in Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i), respectively. The
behaviour of pyrazolones is quite different owing to the existence of a non-arornatic
tautomer.
The effect of the substituents on the reactivity of pyrazoles towards electrophiles follows
the general pattern discussed in Section 4.02.1.4.1.
(ii) Nitration
Pyrazole is very stable in acid media and even under rnore vigorous nitration conditions
neither ring opening nor ring oxidation was observed (for oxidation to pyrazolones with a
mixture of brornine and nitric acid see Section 4.04.2.1.4(v)).
The principal results on the nitration of pyrazoles are shown in Scherne 23. If the
substituent is a phenyl group, it can compete with the pyrazole ring and para- nitration is
often observed (Sections 4.04.2.3.3(ii) and 4.04.2.3.10(i)).
HN0 3 /H 2 S0 4
'"
O
N....N"
H HN03/Ac20
(Section 4.04.2.1.3!xiv))
HN0 3 /H 2 S0 4 or HN03/Ac20
'"
(J
....N
N
k
Scheme 23
R O N
N.... "
H HNOJ/ Ac 2 0
(Section 4.04.2.1.3lxiv))
1st
R j('
n
?,Z,_ _;N
2nd N
I
R (HN0 3 /H 2 S0 4 )
The mechanism of the reaction is now well known due to a series of kinetic studies by
Katritzky et al. (Table 31). The nature, free base or conjugate acid, of the substrate depends
on the substituents in the pyrazole ring and on the acidity of the nitrating rnixture.
Nitration of pyrazolones and alkoxypyrazoles takes place at the 4-position (or in the para
position of the 1-phenyl substituent) (B-76MI40402). Treatrnent of propyphenazone (296)
with fuming nitric acid results in at least 27 products (81AP532), amongst them (297) which
was identified by lH and 13C NMR data. .
Pr i
02N Me
O ;N
Ó NO ,
N0 2
(297)
Pr i Me
o :J:;N Me
N
Ó
(296)
4-Bromopyrazoles (298) react with fuming nitric acid in 80% sulfuric acid to give
4-nitropyrazoles (ipso nitration; Section 4.04.2.3.7). When R was an alkyl group, nitration
took place at C-3 giving (299) (a srnall amount of the dinitro derivative (300) was also
obtained) (79AJCl727). Nitrodebrornination proceeds from the protonated pyrazolium ion
whereas 3-and 5-nitration were expected to involve the free base.
Br a
V
....N
N
R
(298)
B U r N02
V
....N
N
R
(299)
B U r N02
V
02N ....N
N
R
(300)
238 Pyrazoles and their Benzo Derivatives
Substrate
Table 31 Kinetic Nitration Studies on Pyrazoles and Aromatic Pyrazolones (Reagent: HNûJ/H z Sû4)
Conclusions
Ref.
7IJCS(ß)2365
1,3,5- Trimethylpyrazole
1,2,3,5- Trimethylpyrazolium
3- Methyl-l-phenylpyrazolone
and its N- and O-methyl
derivatives
1- Phenylpyrazoles and their 2-
methyl quaternary salts
Different pyrazoles
3-Hydroxy-l-phenylpyrazoles
Methylpyrazoles
1,4-Dimethylpyrazole
1.4-Dimethyl-3-nitropyrazole
Nitration occurs on the conjugate acid at the 4-position
Nitration occurs at the 4- and para-positions on the
conjugate acid at high acidities. At low acidity some
react as free bases
Nitration occurs at the 4- and para-positions; nitro
derivatives react as free bases. A methyl group in the
2-position has a high deactivating effect (selective para
attack)
Calculation of standard ko values at 25 oc and Ho -6.6.
Thermodynamic parameters for P1razole itself: ilH t =
69kJmol-I,ilSt=-109Jmol- K- 1
The 4-nitro derivative nitrates in the para-position and
the para-nitro derivative in the 4-position. At low
acidity the reaction occurs on the free base and at high
acidity on the conjugate acid
Comparison of standard rates for nitration: benzene, log
ko = 0.45, I-methylpyrazole, log ko = -7.60, 1,3,5-
trimethylpyrazole, log ko = -4.79
The attack at the 3- and 5-positions occurs on the free
base." Standard rates: 1,4-dimethylpyrazole (attack at
the 3-position). log ko = 3.55, 1,4-dimethyl-3-
nitropyrazole (attack at the 5-position), log ko = -4.73
(deactivating effect of the nitro group)
74JCS(P21382
74JCS(P2)389,
72JCS(P2)1654
75JCS(P2)1600
75JCS(P2) 1609
75JCS(P2)1624
75JCS(P2)1632
"The difference in the susceptibility of the 3- and 4-positions in the free-basI! form of pyrazole towards nitration
is a relatively small factor in favour of the 4-position (ca. 1 log unit). Doubtless for the more usual nitration via
the conjugate acid the difference is considerably greater.
Nitration of 4-(2-thienyl)- (301) and 4-(3-thienyl)-pyrazoles (302) rnainly occurs on the
thiophene ring, but when acetyl nitrate is used as the nitration agent srnall quantities of
products nitrated on the pyrazole ring are isolated (position of the nitro group uncertain)
(80CS(\5) 1 02). Pyrazol-1' -ylpyridines (303) undergo electrophilic reactions (brornination,
chlorination and nitration) preferentially in the pyrazole ring. Thus, the nitration of (303;
R = R 4 = R S = H) either with a rnixture of nitric acid and sulfuric acid at 10-15 oC or with
acetyl nitrate at 0-5 0 C yields the 4'-nitro derivative (8IJHC9). When the 4'-position is
substituted by bromine, ipso nitration and nitration on the pyridine ring are observed.
R 4 R J
R5 0 N
N....
Ó
s
....N
N
Me
S
....N
N
Me
(301) (302) (303)
With mixed acid I-methylpyrazole 2-oxide (268) gives high yields of I-methyl-5-
nitropyrazole 2-oxide (269) (S-76MI40402). The form undergoing the reaction is the
base, for which first-order kinetics are observed in the Ho range frorn -5 to -6.5; a
dinitro derivative is also forrned under slightly different conditions. The reaction of
indazole with furning nitric acid affords a nearly quantitative yield of 5-nitroindazole
(Section 4.04.2.3.2(i)).
riii) Sulfonation
Direct sulfonation of the pyrazole ring is a rather difficult reaction due to cation forrnation
and takes place only on prolonged heating with 20% oleum. The sulfonic acid group enters
at position 4 of pyrazole, 3(5)-methyl- and 3,5-dimethyl-pyrazole (67HC(22)1). Under the
vigorous reaction conditions required, phenyl groups, if present, also undergo sulfonation
(66AHC(6)347). Indazole can be sulfonated by heating it with 20% oleurn for 1! hours. The
product is indazole-7-sulfonic acid (Section 4.04.2.3.2(i)) (67HC(22)1).
Pyrazoles and their Benzo Derivatives
239
Sulfonation of 2- and 3-pyrazolin-5-ones occurs at position 4. Thus 3-methyl-l-phenyl-
pyrazolin-5-one with 20% oleum at 10-15 oC yields the corresponding 4-sulfonic acid (304)
(64HC(20)1). Higher ternperatures cause suIfonation not only of the heterocycle but also of
the phenyl group. Antipyrine treated with sulfuric acid and acetic anhydride yields (305).
H0 3 S 0 Me H0 3Sj=\M e
HO r N O - jNMe
N/ N
Ph Ph
(304) (305)
(iv) Acid-catalyzed hydrogen exchange
Progress in this field is due rnainly to the work of Katritzky et al. reported in two
fundamental papers (73JCS(P2)1675, 75JCS(P2)1624). Qualitatively (B-76MI40402) it was observed
that in D 2 S0 4 exchange in 1-rnethylpyrazole occurred initially at C-4 and then simul-
taneously at C-3 and C-5, and in 1,2-dimethylpyrazolium it occurred only at C-4. Other
methylated pyrazoles and pyrazolium ions have been examined, and for all the compounds
studied with unsubstituted 4-positions, exchange occurred there preferentially (pyrazoles)
or exclusively (pyrazoliums). Rate profiles (70-90 o C) for 4-exchange revealed a change
from reaction via the free base to reaction via the cation at Do = -5 to -6, a conclusion
confirrned by the behaviour of the quaternary salts. At higher temperatures (140-222 oc)
exchange occurred at C-3 and C-5 on the free base without mechanistic changeover.
Rates of exchange are collected in Table 32. Methyl groups invariably increase the rate
of exchange, but their quantitative effect depends on the position at which reaction is
occurring, the position of the rnethyl group, and the species undergoing reaction. The effect
of a methyl group in the 5-position is slightly larger (+ 1.6 log units) than one in the
3-position (+0.9 log units) upon hydrogen exchange at C-4 in the free base; in the cation
the situation is reversed, the effect being + 1.0 and + 1.5 log units, respectively. The reactivity
of protonated pyrazoles is greater than predicted by additivity; this happens when both an
electron-donating and an electron-withdrawing group are present in the molecule.
Table 32 Logarithms of the Partial Rate Factors Calculated According to the Standard Conditions
(pD = 0, 100 0 C)
Pyrazole
Species
3
5.6
-2
I-Methyl
I-Methyl
1,2-Dimethyl
1,3-Dimethyl
1,3-Dimethyl
1,5-Dimethyl
1,5-Dimethyl
1,2,3-Trimethyl
1,3,5- Trimethyl
1,3,5- Trimelhyl
1,2,3,5- Tetramethyl
1,4-Dimethyl
1,2,4- Trimelhyl
1,3,4- Trimethyl
1,4,5- Trimethyl
1,2,3,4- Tetramethyl
Free base
Conjugate acid
Pyrazolium cation
Free base
Conjugate acid
Free base
Conjugate acid
Pyrazolium cation
Free base
Conjugate acid
Pyrazolium cation
Free base
Pyrazolium cation
Free base
Free base
Pyrazolium cation
5.0
4 5
9.8 5.6
3.4 -2
3.0
10.7 5.8
4.9
11.4
4.4
3.4
13.4
6.0
5.6
6.8
a
7.5
6.8
7.2
a Exchange did not occur at any measurable extent.
If the reactivity of the 4-position alone in pyrazolium cations is considered, there is a
linear relationship between standard rates for nitration (k 0 2 ) (Section 4.04.2.1.4(ii)) and
hydrogen exchange (k O ) (75JCS(P2)1624): log k 0 2 = 0.89 log k O - 0.88, (c.c.f = 0.98.
(v) Halogenation
Halogenation is one of the most studied electrophilic substitutions in the pyrazole series
(67HC(22)1, B-76MI40402). The results concern chlorination, bromination and iodination since
there is no report on direct fluorination of pyrazoles (fluoropyrazoles are prepared by other
240
Pyrazoles and their Benzo Derivatives
ways, Sections 4.04.2.3.4(v) and 4.04.3.1.2(ii)). The main results can be summarized as
follows: halogenation of neutral and anionic C(4)-H pyrazoles always occurs at C-4;
halogenation of anionic C(3)-H indazoles (silver salts) occurs at C-3; polyhalogenation of
pyrazoles is observed in N- unsubstituted derivatives and generally occurs via N- halogena-
tion (Section 4.04.2.1.3(xii)); aminopyrazoles, 3-pyrazolin-5-ones (like antipyrine) and
3-hydroxypyrazoles behave norrnally and are halogenated at C-4. On the other hand,
2-pyrazolin-5-ones yield 4,4-dihalogeno derivatives (306). It was also reported that 4-
hydroxypyrazoles are dichlorinated at position 5 to give (307).
x
X R3
od-.... .;N
N
R 1
(306)
Oh R3
0/,. .;N
N
R 1
(307)
R R R
NN-cr-N\N:::::l
H
(308)
Many reagents are able to chlorinate arornatic pyrazole derivatives: chlorine-water,
chlorine in carbon tetrachloride, hypochlorous acid, chlorine in acetic acid (one of the best
experimental procedures), hydrochloric acid and hydrogen peroxide in acetic acid, sulfuryl
chloride (another useful procedure), etc. N- Unsubstituted pyrazoles are often used as silver
salts. When rnethyl groups are present they are sornetirnes chlorinated yielding CCh groups.
Forrnation of dirners and trimers (308; R = CO has also been observed.
Brornine in chloroforrn and brornine in acetic acid are the reagents used most often to
brorninate pyrazole. When nitric acid is used as a solvent, both brornine and chlorine
transforrn pyrazoles into pyrazolones (Scherne 24). Thus 3-methyl-1-(2,4-dinitrophe-
nyl)pyrazole is brominated at the 4-position (309). The product reacts with chlorine and
nitric acid to give the pyrazolone (310). The same product results frorn the action of brornine
and nitric acid on (311). The electrophilic attack of halogen at C-4 is followed by the
nucleophilic attack of water at C-5 and subsequent oxidation by nitric acid.
Br
CI Me
H)( J'1
HO N""
Ar
SI'/7
O Me
'\
....N
N
Ar
SO'CI2/
B a r Me
'\
....N
N
Ar
(309)
""- CI,/HNO,
Br
CI Me
H _. N
N
Ar
;/
! HNO,
NO'
Br
CI Me
O . .;N
N
Ar
(310)
C n l Me
'\
/N
N
Ar
(311)
Scheme 24
To effect polybromination of pyrazoles the use of iron as catalyst is necessary; only the
3-trifluorornethyl derivative when treated with two equivalents of brornine in aqueous
sodium acetate gave 3,4-dibrorno-5-trifluorornethylpyrazole. N- Unsubstituted 4-methyl-
pyrazoles behave abnormally in brornination reactions. Closs was the first to show that
3,4,5-trirnethylpyrazole is transformed by brornine into the 4-brornoisopyrazole (312)
(B-76MI40402). The reaction was extended to other polyalkylpyrazoles (69CR(C)(269)570).
Bromination of 4-rnethylpyrazole was studied by Hüttel who observed the forrnation of
dirners (313) and trirners (308; R = Me) (69CR(C)(269)570). Reirnlinger et al. described the
forrnation of the cyclic dirner (314) from the reaction between bromine and the silver salt
of the 3,4,5-trirnethylpyrazole (70CB1949). It was later shown (82UP40402) that the correct
structure of the product is (315), a structure which accounts for the anisochrony of the
rnethylene protons ('crown' conformation).
Aqueous brornination of indazole shows the relative order of reactivity for various
positions to be 5> 7 >>others, 5 > 3 > 7 >>others, and 3 >>others for reactions of cationic,
Pyrazoles and their Benzo Derivatives
241
Br
Me Me
Me( . ;) N
N/
(312)
M ;f) e
V
,...N
e N N
Me f I H
--==N
(313)
;ç Me Me
V
N/N
,) , )
NLf
Me Me
(314)
Me
;eN
N-N LMe
Mel/---r()Me
Me N
(315)
neutral and anionic species, respectively (74AJC2343). This may account for the variable
substitution patterns found in other reactions, viz. 3- brornination in dioxane and 3-azo
coupling; 3-, 3,5- and 3,5,7-halogenation in acetic acid; 5- and 5,6-nitration; and 7-
substitution (sulfonation in oleum) (Section 4.04.2.3.2(i)).
Pyrazole does not react with iodine although pyrazolylsilver is converted into 4-
iodopyrazole. 3-lodoindazole can be obtained by the reaction of iodine with the silver salt
of indazole. Kinetic studies on pyrazole iodination have been carried out by Vaughan et
al. (71PMH(4)55, B-76MI40402). Coordination of pyrazole by nickel(II) in aqueous solution
increases the rate of iodination by factors of two at pH 6 and eight at pH 7.2 (nJA246o).
(vi) Acylation and alkylation
1-Substituted pyrazoles are formylated (Vilsmeier-Haack reaction) and acetylated
(Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in
positions 3 and 5 facilitate the reaction (80ACH(105)l27, 80CHEl), but the heteroatoms compete
with the C-substitution. For instance, when the amino derivative (91; R 1 = R 3 = Ph, R 4 = H)
was submitted to the Vilsmeier-Haack reaction, the 4-formyl-5-dimethylaminomethylene
derivative was isolated.
C- Alkylation of pyrazoles was a rather uncommon reaction until Grandberg and Kost
found the experimental conditions necessary to obtain high yields of 4-benzylpyrazoles
(66AHC(6)347). With N-unsubstituted pyrazoles a large excess of aluminum chloride is
necessary to accomplish alkylation at C-4.
(vii) Mercuration
Pyrazoles were chlorornercurated at C-4 giving (316) by reaction with rnercury(II) chloride
(B-76MI40402, 66AHC(6)347). The mercury group in (316) behaves in a variety of
reactions just as phenylrnercury chloride. 1-Phenylpyrazole reacts with mercury(II) acetate
to yield the 4-acetoxyrnercury derivative (317). The sarne reactions with 3(5)-phenylpyrazole
also introduce the acetoxyrnercury group at position 4 and not on the nitrogen atom.
CIH t] R 3
R5 V N
N/
R 1
(316)
ACOH t]
V
,...N
N
Ph
(317)
(viii) Diazo coupling
Generally, pyrazoles do not react with diazoniurn salts. The literature (B-76MI40402)
reports only one such example, the coupling between 3,5-dimethylpyrazole and diazotized
3-arninopyrazole. When an activating group (hydroxy, alkoxy, arnino) is present at position
3 or 5, the reaction proceeds easily at position 4. Thus 5-arninopyrazoles give the azo
derivatives (318) and (319) by reaction with the appropriate diazonium salt (78HCA108,
80CHEll60).
R
,...N
; )NH 2
MK
N=N (j Me
V
H 2 N /N
N
R
(318)
N
Me(')'!R
Br
N=N (j Me
V
H 2 N /N
N
(319) R
242
Pyrazoles and their Benzo Derivatives
The reaction is very common in pyrazolonc chemistry. Since alkoxypyrazoles and
tautomerizable pyrazolones undergo this reaction and 3-pyrazolin-5-ones, like antipyrine,
do not, it is assumed that the reaction takes place at C-4 of the OH tautorner. Pyrazolone
diazo coupling is an important industrial reaction since the resulting azo derivatives are used
as dyestuffs. For instance, tartrazine (Section 4.04.4.1.3) has been prepared this way.
3,5-Pyrazolidinediones react with aryldiazonium salts resulting in the introduction of a
4-arylazo group. As has been described in Section 4.04.2.1.4(v), diazoniurn salts couple in
the 3-position with indazole to give azo cornpounds.
(ix) Nitrosation
The behaviour of pyrazoles towards nitrosation is sirnilar to their behaviour described
above towards diazo coupling, i.e. arninopyrazoles and pyrazolones readily react with
nitrosation agents, like alkyl nitrites (81FES1019), to afford stable nitroso derivátives. Sorne
sirnple nitrosopyrazoles have been isolated, for exarnple the blue-green 3,S-dirnethyl-4-
nitrosopyrazole, and rnany others have been proposed as reactive interrnediates in the direct
conversion of pyrazoles into diazoniurn or diazo derivatives (Scherne 25) (B-76MI40402).
R 3
RS O 'N
N....
H
NaNO,
HCl
r N R 3 ] N=N
LR'9 N R' '
--.
+
N=N hR3
R5( t)N
Scheme 25
(x) Reaction with aldehydes and ketones
N- U nsubstituted pyrazoles and indazoles react with aldehydes and ketones to give
N- hydroxyalkyl compounds (260)-(262) (Section 4.04.2.1.3(xi)). N- Substituted pyrazoles,
even those containing a CH 2 0H group, react with paraforrnaldehyde in the presence of
acids to give a variety of products (B-76MI40402, 68JHC407, 82UP40403) depending on the
pyrazole and the experirnental conditions. Cornpounds (320) to (323) have been isolated
and identified.
(323)
RCH 3
ob:
N
R 1
(324)
HOCH R>
RS'n N
ZN)
R 1
(320)
R Q;)d R3
N R s R s r 'N
'N N....
R 1 Rl
(321)
R tç O :rJ R3
N R S R s r 'N
'N N....
R 1 R 1
(322)
?d R3
EtO r,
R S N
N....
R 1
Pyrazolones show a great variety of reactions with carbonyl compounds (B-76MI40402).
For instance, antipyrine is 4-hydroxyrnethylated by formaldehyde and it also undergoes
the Mannich reaction. Tautornerizable 2-pyrazolin-5-ones react with aldehydes to yield
cornpound (324) and with acetone to forrn 4-isopropylidene derivatives or dimers (Scheme
8; Section 4.02.1.4.10).
(xi) Oxidation
N-Oxidation with peracids (Section 4.04.2.1.3) and the transformation of pyrazoles into
4,4-dihalogeno-2-pyrazolin-5-ones (Section 4.04.2.1.4(v)) have already been discussed.
Transforrnation of non-aromatic 2-pyrazolin-5-ones into the 4-oxo derivatives will be
examined in Section 4.04.2.2.1 (ii).
C- Oxidation of pyrazoles and indazoles disrupts the azole ring. Potassiurn permanganate
transforrns C-rnethylpyrazoles into pyrazolecarboxylic acids (Section 4.04.2.3.3(i)), and
under more drastic conditions indazole is cornpletely destroyed (67HC(22)1). Open-chain
cornpounds (glyoxal, benzoic acid, phenylazocrotonitrile, hydrazine, etc.) are isolated by
oxidation of pyrazoles with ozone or peracids (B-76MI40402). In sorne instances ring transfor-
rnations are observed; 1-aryl-3-rnethylpyrazoles react with ozone to yield 1,3,4-
oxadiazolinones (325; Section 4.02.1.4.11), 3,5-diphenylpyrazole reacts with peracetic acid
to yield 2,5-diphenyl-l,3,4-oxadiazole (326), and 1,4-dihydroxy-3,5-diphenylpyrazole
reacts with peracids to give an entry into the 1,3,4-oxadiazin-6-one 4-oxides (327). Hydroly-
sis of (327) was accompanied by a facile rearrangernent to the corresponding oxadiazole
(326).
Pyrazoles and their Benzo Derivatives
243
N -NAr
Me( o
o
(325)
N-N
Ph( )Ph
o
(326)
0-
I
+N
w" '1Ph
Phl
o 0
(327)
4.04.2.1.5 Nucleophilic attack at carbon
Very little is known about nucleophilic attack on an unsubstituted carbon atom of
pyrazoles and their aromatic derivatives (pyrazolones, pyrazolium ions). The SNAr reaction
of halogenopyrazoles will be discussed in Section 4.04.2.3.7. Sulfur nucleophiles do not
attack the ring carbon atorns of pyrazolium salts but instead the substituent carbon linked
to nitrogen with concomitant dequaternization (Section 4.04.2.3.10(ii)). The ring opening
of pyrazolium salts by hydroxide ion occurs only if carbon C-3 is un substituted; the exact
mechanisrn is unknown and perhaps involves an initial attack of OH- on C-3.
Only two topics are of importance for this section: the reduction of pyrazolium salts and
3-pyrazolin-5-ones by complex hydrides, and the nucleophilic photosubstitution of pyrazoles
and indazoles.
(i) Reduction by complex hydrides
A 2 -Pyrazolines are obtained by the reduction of pyrazoles with sodium and alcohol, by
catalytic hydrogenation on palladium or by electrochernical rneans (B-76MI40402). In sorne
cases the reduction proceeds further yielding pyrazolidines and open-chain compounds.
A 3 -Pyrazolines and pyrazolidines are isolated frorn the lithium aluminurn hydride reduc-
tion of 3-pyrazolin-5-ones and pyrazolium salts. Tautornerizable 2-pyrazolin-5-ones are
not reduced (Section 4.04.2.2.1(ii)). A large number of publications by the Montpellier
group dealing with this topic are sumrnarized in (B-76MI40402). Three papers
(69BSF4466, 69BSF4469, 69BSF4474) describing thiopyrine, pyrarnidon and thiopyrarnidon
reduction should also be consulted.
A mechanism has been proposed to rationalize the results shown in Figure 23. The
relative proportion of the A 3 -pyrazolines obtained by the reduction of pyrazolium salts
depends on steric and electronic effects. When all the substituents are alkyl groups, the
hydride ion attacks the less hindered carbon atorn; for exarnple when R 3 = But only C-5 is
attacked. The srnaller deuterohydride ion is less sensitive to steric effects and consequently
the reaction is less selective (73BSF288). Phenyl substituents, both on the nitrogen atorn and
on the carbon atorns, direct the hydride attack selectively to one carbon atorn and the
isolated ?-pyrazoline has the C-C double bond conjugated with the phenyl (328; R 1 or
R 5 = Ph). Open-chain compounds are always forrned during the reduction of pyrazolium
salts, becoming predorninant in the reduction of arnino substituted pyrazoliurns.
1-Isopropyl-3-phenylindazole is cleaved when it reacts with phenyllithium, followed by
hydrolysis (73KGS138) giving, after acetylation, 0- benzoyl-N- isopropylacetanilide.
(ii) Nucleophilic photosubstitution
The research carried out at Leiden by Cornelisse and Havinga and at Montpellier by
Bouchet and Lazaro has opened the way for the introduction of different nucleophiles into
the pyrazole and indazole ring. Reactions unknown in the ground state are possible in the
singlet excited state. Upon irradiation, not only halogens or a nitro group but also the
hydrogen atorn can be replaced by the nucleophile. Irradiation of pyrazoles (329; R 1 = Me,
p-NO Z C 6 H 4 , R 3 = N0 2 , Br, Me) (78RTC35, 79T1331) in the presence of cyanide ions yields
4-cyanopyrazoles (330); if the 4-position is substituted as in (331), the cyano group enters
in the 5-position (332; R 1 =p-NO z C 6 H 4 ). Analogously, irradiation in the presence of
methanolic sodium acetate or potassiurn cyanate gives the 1-p-nitrophenylpyrazoles forrny-
lated in positions 4 and 5, respectively, in moderate yields (79T1331).
R 3
O
/N
N
R 1
(329)
NC R 3
O
/N
N
R 1
(330)
02N O R3
7 N
N/
R 1
(331)
02N O Me
NC 7 N
N/
R!
(332)
tv
R 4 Me R 4 Me R 4 Me R 4 Me
X N Me --. CNMe + UMe + xDMe
N N N
Ph Ph Ph Ph
X = 0, R 4 = H (antipyrine) yes yes yes
X = S, R 4 = H (thiopyrine) yes yes yes
X=NPh, R 4 =H no yes yes
X = 0, R 4 = NMez (pyramidon) no yes yes
X = S, R 4 = NMez (thiopyramidon) no yes yes
N
C
'"
5::1
::!
...
;:s-
<':>
::t.
R 4 R 4 R 4
R 4 R J Rd R 4 R J R 4 R 3 R 4 R J R R3 R50R3 R R3
-R S eNR 2 --. R 5 N: 2 + + R 5 ÇNR 2 + 0 NR2 + + +
R\J:j H N o ....N ....N
NR 2
N N/ N/ R' R' HN/ 'R 2 HN '2 HN 'R 2
R' R' H R' I I R I
(328) R' R' R'
R 5 =alkyl yes yes yes no yes no no
R 5 = aryl yes no yes no yes no no
R 5 =NR 2 no no yes yes no yes yes
Figure 23 Reduction by complex hydrides of pyrazolones, thiopyrazolones, iminopyrazolines and pyrazolium salts
tJ:j
<':>
::!
N
C
b
('II
...
;:;.
f?
;:;.
<':>
'"
Pyrazoles and their Benzo Derivatives
245
Similarly, the hydrogen atom at the 3-position of the indazole ring has been replaced by
NHz, NHMe, NMez and NEt z upon irradiation in the presence of the appropriate
nucleophile (80T3523).
4.04.2.1.6 Nucleophilic attack at hydrogen
(i) Metallation at a ring carbon atom
Lithiation of pyrazoles has been studied as a synthetic route to pyrazolecarboxylic acids,
n-butyllithium being more effective than phenyllithium. N-Substituted pyrazoles are metal-
lated at C-5 (B-76MI40402,79RCR289) (Table 6 in Section 4.02.1.7.1); with a substituent on
C-5, lithiation occurred at the N-methyl group (333; X = Li). I-Methylindazole reacted
with butyllithium at -15 oC to form 1-lithiomethylindazole (334; X = Li) whereas 2-methyl-
indazole gave the corresponding 3-lithio derivative (335; X = Li) (70CHE1339). Treatment
of these lithio derivatives with carbon dioxide gave the respective acids (333)-(335)
(X = COzH).
R 3
R5 0 N
N/
CH 2 X
(333) R 5 = Me or OMe
oc l N
N
CH 2 X
(334)
(X) ,;;--X
NMe
,,-I
(335)
(ii) Hydrogen exchange at ring carbon in neutral pyrazoles
The base-catalyzed hydrogen exchange of pyrazoles has been studied by Vaughan and
conveniently summarized in (74AHC(16)1) and (B-76MI40402). The method has been used to
prepare the isotopic species necessary to assign the fundamental vibration of pyrazole
(Sections 4.04.1.3.7(i) and 4.04.3.3.3).
(iii) Hydrogen exchange at ring carbon in pyrazolium cations
The base-catalyzed deuteration of the 1,2-dimethylpyrazolium ion has been studied by
l H NMR spectroscopy. Exchange occurs at positions 3 and 5, and position 4 does not
exchange. A complementary situation arises under acid-catalyzed (D 2 S0 4 ) conditions where,
for the same salt, only H-4 exchanges (Section 4.04.2.1.4(iv)). Other quaternary azolium
salts exchange at a faster rate than do pyrazolium salts (B-76MI40402), for example, H-2 of
1,3-dimethylimidazolium exchanges 3 x 10 4 times faster. The presence of a bromine atom
on C-4 significantly increases the acidity of nuclear hydrogen atoms in pyrazolium salts.
(iv) C-Acylation via deprotonation
Neither pyrazoles nor pyrazolium salts react by this mechanism which has been described
for imidazoles and imidazolium salts (Section 4.01.1.7.4). As exchange rates show (Section
4.04.2.1.7(iii)), it is considerably more difficult to generate an ylide from a pyrazolium salt
than from an imidazolium salt (at C-2).
(v) Ring cleavage via C-deprotonation
3-Unsubstituted pyrazoles and indazoles are cleaved by strong bases. Indazoles undergo
ring opening more readily than pyrazoles since the fused benzene ring enhances the ease
of removal of the C-3 proton in the initiating step.
Potassium t- butoxide in t- butyl alcohol requires powerful electron-attracting substituents
at C-4 to effect ring opening of pyrazoles but sodamide does not (Scheme 26) (B-76MI40402).
As the key to the transformation is the generation of the anion, similar results were obtained
by heating some pyrazole-3-carboxylic acids with quinoline.
H
n
z'H;N
N
R
NH,
------+
H:Y
Z, ON
N
R
A
--+
( C=N
N-
I
R
- RNHCH=CHCN
Scheme 26
246
Pyrazoles and their Benzo Derivatives
Similar rnechanisrns explain the ring opening of 1-alkyl- and 1-aryl-indazoles by sodamide
to o-cyanoanilines (65CHE531) and the ring opening of 1-arylindazole-3-carboxylic acid
during decarboxylation in boiling quinoline (Scheme 27) (73AJC2683). The presence of
electron-withdrawing substituents in the 1-aryl group favours the ring opening during the
formation of 1-arylindazoles.
CC C02H
7'" I N
I
N
Ar
base
CO 2
CX! -co,
1-
I
N
Ar
0> 1 -;
I
N
Ar
.1
--
IH"
O (=N
NH
I
Ar
Scheme 27
(vi) Proton loss from a ring nitrogen atom
Pyrazoles are weak acids unless they carry powerful electron-withdrawing groups (Section
4.04.2.1.3(v)). They form metallic salts which are readily hydrolyzed by water (Section
4.04.2.1.3(vi)).
4.04.2.1.7 Reaction with radicals and electron-deficient species; reaction at surfaces
(i) Carbenes and nitrenes
3,4,5-Trimethylpyrazole (336) adds dichlorocarbene generated under basic conditions
(CHCh-EtONa) to give 10% of 4-dichloromethyl-3,4,5-trimethylisopyrazole (337; Scheme
28) (bromine also transforms (336) into an isopyrazole (312); Section 4.04.2.1.4(v)).
Treatrnent with sodium ethoxide results in ring expansion of (337) into an ethoxymethyl-
pyridazine (338) (B-76MI40402).
Me O Me
EtOH 2 C I N
N
(338)
EtON.
CHCl 2
Me-J---,Me
Me(;
N
(337)
:CCl, Me O Me
Me N
N/
H
(336)
Scheme 28
:CCI,
Me
'Cl O Me
I +
Me:,... .....N
N
(339)
Me
MerN
Me )C1
N
(340)
With dichlorocarbene in neutral, aprotic conditions (frorn sodium trichloroacetate), a
large arnount (71 %) of starting material (336) was again recovered, together with very
small amounts (-0.5%) of 4-chloropyridazine (339) and 2-chloropyrimidine (340). Using
phase-transfer catalysis (76S798) the yield of (339) was increased to 3% but the main
product was tris(3,4,5-trimethylpyrazol-1-yl)methane (63%). 3,5-Dimethylpyrazole reacts
with chloroforrnjNaOH under phase-transfer conditions to give 33% of the
tris(pyrazolyl)methane (235; R = Me) and 1 % of 2-chloro-4,6-dimethylpyrimidine
(79LA1456).
Better results were obtained when a mixture of chloroform and either pyrazole or
C-rnethylpyrazoles was heated at 555 0 C in a continuous-flow vapour phase reactor
(79JCSrpl)2786). 2-Chloropyrimidines were obtained in high yields (51-89%). Indazole
similarly gave only 2-chloroquinazoline (68%).
An interesting exarnple of photolytic nitrene cyclization, (341) (342), has been described
by Tsuge and Samura (7lJHC707). This method has often been used to prepare azapentalenes
with two ring junction nitrogen atoms (78AHC(22)184, 81AHC(28)232, 81CL331) from l-aryl-
pyrazoles and indazoles.
N
N/
ON,
(341)
hv
->
(ÇI
N+
8-
(342)
Pyrazoles and their Benzo Derivatives
247
(ii) Free radical attack at the ring carbon atoms
Methyl radicals generated by the decarboxylation of acetic acid with ammonium peroxy-
disulfate and pyrazole gave about 10% of 3(5)-methylpyrazole (B-76MI40402). Another
highly selective alkylation takes place when pyrazole is treated with t- butyl radicals
(730PP10S), 3(5)+ butylpyrazole being the only product.
Radical phenylation of N-substituted pyrazoles has been studied by Lynch et al. (B-
76MI40402). The most significant results are shown in Figure 24.
1 5
94 0
N'
Me
40.5
59.5CNH
N +
Me
30
O
/N
Ò N I"
6
10
Figure 24 Percentages of radical phenylation attack
Clearly, the proportion of substitution occurring adjacent to the 'pyridinic' nitrogen atom
is increased by protonation. Also noteworthy are the high proportion of ortho substitution
product and the selective attack at C-3 in the N-phenyl derivative.
(iii) Electrochemical reactions and reactions with free electrons
Electrochemical oxidation of 3-methyl-l-phenylpyrazole gave the 3-carboxylic acid
whereas electrochemical reduction (Section 4.04.2.1.6(i)) of 1,5-diphenyl-3-styrylpyrazole
produced the z -pyrazoline (B-76MI40402) with concomitant reduction of the exocyclic double
bond (343).
Ph O CH1CHZPh NC O O
N....N N....N NC N....N
Ph Me Me
(343) (344) (345)
Anodic oxidation of I-methylpyrazole in the presence of cyanide ions yielded 33% (344)
and 6% (345); no 3-cyano derivative was formed (78RTC3S).
(iv) Catalytic hydrogenation and reduction by dissolving metals
As reported in Section 4.04.2.1.6(i), pyrazole and 1-phenylpyrazole under reduction with
Hz palladium give the pyrazolines or, under more drastic conditions, the pyrazolidines.
l-Substituted pyrazoles are also reduced with sodium and alcohol (B-76MI40402).
4.04.2.1.8 Reactions with cyclic transition states
(i) Diels-Alder reactions and 1,3-dipolar cycloadditions
In theory, a pyrazole could react towards dienophiles or dipolarophiles as an azadiene
(A) or as a 1,3-dipole of the azomethine imine category (B), both situations being identical
with regard to the number of 7T-electrons involved (Figure 25) (see also Section 4.02.1.9.1).
There is also the possibility that it may react as an alkene (C) or as an imine (D) towards
dienes or 1,3-dipoles. In the case of ethenylpyrazoles a final possibility of a Diels-Alder
reaction involving an exo- and endo-cyclic double bond must be considered.
4 3
sn
C Nl
(A)
Sc Ñl
+....
NI
R
(B)
4C
5,1'
C
(C)
C 3
'\. z
N
(D)
All these six reactions are theoretically allowed, since they have aromatic transition
states; however all of them destroy the 'aromaticity' of pyrazole, and for this reason they
are almost unknown at the present time.
248
Pyrazoles and their Benzo Derivatives
R 4 R 3 R!
/ R 4 R 3
D N (mb"'
R 5 t N/ Ia) ill (b) N
- ...... r -
\ R 1 i r h R : R 5 N/N
: + i
RC=CR R 4 R 5 R R 1 R 5 R 1
tf) R 4 R 3 R R R 4 R"
/ R 4
R5 r N4-..."":::: R5W :Jr:)R 3 Idl Ræ N
l r -
N/ w.. N N/N ....:;; /
N
R 1 R 1 R! R'
)d.' R 3 Rtk R 4
\.." r æN R (Ii R\(Ú
\\\ R 5 l' N/N R5 r w.-V -
,\ .: R! R""'" N N/ R/ w- N ....:;;
R'.' R R 5 R! R! R!
Figure 25 Pericyclic reactions involving the pyrazole nucleus
In 1973 two papers appeared almost simultaneously (73T101, 73CPB2026) describing the
formation, as a minor product, of 3,4,5-trimethoxycarbonyl-l-phenylpyrazole (346) in the
reaction between benzaldehyde phenylhydrazone and DMAD (EC = CE). To account for
the formation of (346) George et al. (73T101) proposed a tentative rnechanisrn (Scheme 29)
involving a Diels-Alder reaction of type (a; Figure 25), followed by a retro-Diels-Alder
elimination of methyl phenylpropiolate (347).
/Ph
N
Ph ...IN....E --.
t+J
E E E
lal
E E
E O "N
N'"
Ph
(346)
+ PhC=CE
(347)
Eri h
E( ;N
N/
Ph
E = Me02C
EC=CE
Scheme 29
Further evidence showed this mechanism to be incorrect, especially the fact that it was
rnethyl cinnamate and not (347) which was isolated from the reaction (73CPB2026). Also
I-phenylpyrazoles did not react with DMAD under the reaction conditions (74BSF2547).
The origin of (346) remains obscure, but in no circurnstances does it imply a Diels-Alder
reaction of a pyrazole. For Ogura et al., it has its origin in an intermediate 3 -pyrazoline
(73CPB2026).
At about the sarne time a paper frorn Abjean appeared (74CRiC)(278)359) describing the
sequence of reactions shown in Scherne 30.
lal
Ar
N/
MeJ N.... E
U.J
MeE
(349)
Me
H+ O E
---+ I
Me '" + E
N
NHAr
BF;
O Me 2BF O Me
Me r 'IN ----4 Me r N . 2BF 3
N/ N'"
Ar Ar
(348)
EC=CE
E = Me02C
Scheme 30
These interesting results have been quoted by Sokolov (79RCR289) and by Acheson and
Elrnore (78AHC(23)263). However, they proved to be erroneous, as to both structure (348)
(a fluoroborate, not a complex) and structure (349) (for which (350) represents the correct
structure established by X-ray crystallography (83T2193)).
O \1e
Mer \N+ E HF -
N' ......C=c.....
Ar / ......
E H
(350)
Pyrazoles and their Benzo Derivatives
249
The conclusion is that there are no known examples of behaviour of type (a) for pyrazoles.
The same negative conclusion could have been extended to the other reaction pathways
of Figure 25 until very recently when an example of type (e) was described (Scheme 31
(82PC40400). Other dienophiles do not take part in this reaction.
H
I
H, ?-C b
C r
ß
N
I
Ph
E = Me02C
(e)
CQ N
E I
N
E Ph
EC=CE
Scheme 31
In the indazole series an example of a type (c) reaction (Figure 25) has been described
utilizing a 1,3-dipole instead of a diene (Scheme 32) (76H(4)1655). The cycloadduct (351)
is transformed into the triazole (352) on reaction with hydrochloric acid.
Ph Ph
I I
H N__ N__N
AeC=N-ÑPh OJ J H cd J
) ?' N Ac ?' N lAC
(e) N NH
Me I
Me
(352)
00 1 N
I
N
Me
(351)
Scheme 32
(ii) Photochemical cycloadditions
[2 + 2] photochemical additions to give four-membered rings (Section 4.02.1.9.2) are
unknown in the pyrazole series.
4.04.2.2 Reactions of Non-aromatic Compounds
4.04.2.2.1 Isomers of aromatic derivatives
(i) Compounds not in tautomeric equilibrium with aromatic derivatives
This important section deals with pyrazolenines, isopyrazoles and 4,4-disubstituted 2-
pyrazolin-5-ones whose thermal and photochemical reactions will be discussed in this order.
A thermal rearrangement, the so-called Van Alphen-Hüttel rearrangement (Scheme 33),
relates pyrazolenines (353), isopyrazoles (354) and pyrazoles (355) by a series of [1,5]-
sigmatropic rearrangements (73TL3781, 79CJC1186). If R 4 is an alkyl or aryl group, the
isopyrazole (354) obtained from (353) is stable; if R 4 = H, it undergoes isomerization into
an NH-pyrazole; finally, if R 4 is an ester group, under drastic conditions of heating or
acidity the isopyrazole loses this substituent from the 4-position affording the NH-pyrazole.
When R 3 R 3 ', the migration tendency depends on the experimental conditions (neutral
or acidic). In the un catalyzed rearrangement the relative rates are: Me (1), Et (23), PhCH 2
(157), Ph (530), C0 2 Me (19000) (80TL1417). Thermal isomerization of tetramethyl-
isopyrazole (354) into tetramethylpyrazole (355; R 3 ' = R 3 = R 4 = R S = Me) occurs at 400 oC
(76CRV187); a mechanism involving the tetramethylpyrazoline is possible, although there is
evidence that a competing radical pathway is also involved.
R 4 R 3 '
RsN, 3
- N R
N-
/' (353)
R 3 '
RS R3
N-N
(354)
- - - - -- - - - -- -- - -- -----.----+
Scheme 33
R 4
R \( JR 3
N-NR 3 '
(355)
250
Pyrazoles and their Benzo Derivatives
4-Hydroxyisopyrazoles (354; R 3 ' = alkyl or phenyl, R 4 ' = OH) rearrange to 4-hydroxy-
pyrazolenines (353; R 4 = OH) which in turn tautomerize to the rnore stable 2-pyrazolin-4-
ones (356) (76JOC2874). Finally, some pyrazolenines (357) undergo a ring expansion to the
3H-l,2- benzodiazepines (358) rather than a therrnal Van Alphen rearrangernent (75CC128).
R'ft. R ;: M';:).,
N-NH N=N Me N=N
(356) (357) (358)
Diazoalkanes and ynamines react with the electrophilic C(4)-C(5) double bond of
pyrazolenine (359) to afford the cycloadducts (360) and (361), respectively, whereas
diphenylketene yields the bicyclic diazetidinone (362) by reaction with the cís-azo systern
of (359) (79CC568).
O Me 2
MeOzC ",N
N
8 R H Me,
N" qN
N N
C0 2 Me
H
MeIT---lMe z
EtzN N N
C0 2 Me
(361)
Mez
MeOzcCN
Ny Ph 2
o
(362)
(359) (360)
The tetrahydropyrazolo[3,4-c ]pyrazole (360) is unstable and, by loss of N 2 , leads to
3- R -4-isopropyl- 5-methoxycarbonylpyrazole.
Isopyrazole quaternary salts (363) are key intermediates leading to the highly substituted
2 -pyrazolines. Lithium aluminum hydride gives the pentasubstituted derivatives (364;
R = H) and Grignard reagents provide access to the fully substituted 2-pyrazolines (364;
R;i: H) (68BSF3866, 70BSF1121).
R 4
R4' R3
RS +.;
N
R'
(363)
R 4
R4 1j R3
R S ï
N....N
R R'
(364)
Two reactions of the non-aromatic 4,4-disubstituted pyrazolones are worthy of rnention.
Carpino discovered that 4,4-dihalogenopyrazolones (365) and 4-substituted 4-
halogenopyrazolones (366) when treated with bases yield a,ß-alkynic and -alkenic acids,
respectively (66JOC2867). The reaction proceeds through an oxopyrazolenine (2,3-diazacyc-
lopentadienone; (367) (B-74MI40408). A modification of the experirnental procedure trans-
forrns (365) into birnanes (368) (82JOC214), which are forrned frorn (367; R = X).
X R 4 0 0
X R3 X R3 R R 3 }--. .-l\
O . .;N O . .;N 0 0N X JX
N R) R 3
(365) (366) (367) R = X or R 4 (368)
2-Pyrazolin-5-ones with an exocyclic double bond at the 4-position (369; X = CMe2)
react as heterodienes towards alkyl vinyl ethers (77G91). The kinetics of this Diels-Alder
reaction giving pyrazolopyrans (370) have been studied.
Me, R. 1
RO N
i'o)L N
Ph
X 3
oh:
N
Ph
(369)
(370)
Progress in the photochemistry of pyrazolenines and isopyrazoles is largely due to the
studies of Dürr and Franck-Neumann. Since this subject has not previously been treated
systematically, a relatively detailed account will be given here.
Considerable effort has been devoted to studying the photolysis of pyrazolenines since
it still constitutes the best way to obtain cyclopropenes. An irnportant publication by Closs
Pyrazoles and their Benzo Derivatives
251
(68JA173) illustrates this possibility (Scheme 34). Thus 3,3,5-trimethyl-3H-pyrazole (371;
R 4 = H) on irradiation in pentane solution gives 1,3,3-trimethylcyclopropene (372; R 4 = H);
the intermediate diazoalkene (373) has been characterized. The tetramethyl derivative
(371; R 4 = Me) when irradiated at -50 oC in methylene chloride leads to a species believed
to be a 1,2-diazabicyclo[2.1.0]pent-2-ene (374). This isomerization is thermally reversible,
the 3H- pyrazole being regenerated at room temperature.
Me
R 4 Me, Ri=<
MeO - --. -(:: Me
N Me 2
(371) (373)
--.
R 4 Me
)=< Me
Me .
(375a)
R 4 Me
Me
Me..J '
(375b)
Itv Jf
1
R4 Me 2
MeOZ
N
(374)
R 4
þ Me 2
Me
(372)
Scheme 34
The mechanism involves the cleavage of the N(2)-C(3) bond of pyrazolenine (371) with
formation of the isomeric diazoalkene (373) (in some cases they are stable for hours at
room temperature in benzene solutions (74JA3708)). Loss of nitrogen yields a carbene (375a)
which in turn cyclizes to the cyclopropene (372) (B-77MI40402). Acyl- (77T751) and sulfinyl-
cyclopropenes (77AG(E)323) have been prepared by photolysis of the corresponding
pyrazolenines.
The cyclohexylpyrazole (376) and the azirine (377) are formed by irradiation of 3-diazo-4-
methyl-5-phenylpyrazolenine (378) in cyclohexane (Scheme 35) (77JA633). The former is
the result of carbene insertion into cyclohexane followed by a [1,5] hydrogen shift, whereas
the latter arises by ring cleavage of nitrene (379) or by a concerted pathway.
rP
N
H
(376)
M d N2
Ph hN
N>-'
(378)
Itv Me O "
-N 2 ' Ph 7 N
N
o
M
PhZN N V
1
Mex =N
Ph !'J.
(379)
Me C=N
--'Ph
N
( 377)
Scheme 35
The prospect of obtaining new ring systems of unusual structure has led to much work
on the photolysis of cyclopentadiene-spiropyrazolenines and related compounds. The results
obtained have justified the expectations. Figure 26 contains some structures prepared in
this way.
()x l R
::::,.... R
(77T2677)
0>0
(75AGIE)647)
(74LAl132)
(74AG(E)646)
x=O,S,CO
(77 CC843)
Figure 26 Cyclopropenes obtained by photolysis of spiropyrazolenines
252
Pyrazoles and their Benzo Derivatives
A radical pathway has been proposed to account for the isolation of (381)-(383) frorn
the irradiation of the 3H-indazole (380) (73T1833). Results of sensitization and quenching
experirnents suggest that the reaction proceeds from the excited singlet state.
W EI02C Me Me Et0 2 C
I Ox , Me 00 , C0 2 Et )=CH 2
:' N IÍN '- 0 Ph
"''' "''' C0 2 Et
(380) (381) (382) (383)
Photolysis of spiro[fluorene-9,3'-indazole] (384) to the tribenzopentalene (385) has been
rationalized in terrns of the initial formation of triplet diradical (386) (76JOC2120). The
spiroindazole (387) behaves differently and on irradiation in THF is converted into the
dirner (388) and the stable N-ylide (389) (76CB2596).
(387)
(385)
l{)
(388)
(386)
(389)
In contrast to pyrazolenines, there are only a few publications on the photochernistry of
isopyrazoles and they concern exclusively their N-oxides (390). Irradiation of (390) affords
the N-oxides of pyrazolenine (391) (70CC289). Bicyclic interrnediates (392) and (393;
Scherne 36) are believed to be implicated in this reaction (75MI40400). The final step is sirnilar
to that reported frorn studies of the valence bond isornerization of pyrazolenines (68JA173).
Çr J2jRl R 1 R 1 R 1
hv Rl-f> R CN
-----to --. --.
R ",,-+/N + 'iN +/
R 1 N R 2 N N
I I 2 I I
0- 0- 0- 0-
(390) (392) (393) (391)
Scheme 36
The photolysis of the diazopyrazolone (369; X = N 2 , R 3 = Me) in methanol yields two
isomeric forms of methyl 3-phenylazo-2-butenoate (394) (80CC1263). The azo esters rnay
arise via protonation of the carbene (395) with a concurrent opening of the ring by the
nucleophilic solvent.
OEt Me
I I
O=CCH=CN=NPh
(394)
.' Me
O;ç)N
Ph
(395)
(ii) Compounds in tautomeric equilibrium with aromatic derivatives
The non-aromatic CH tautomers of pyrazolones have a malonic-like reactivity due to
the fact that the hydrogen atoms of the CH 2 group at position 4 are acidic because the
conjugate anion (239) is fully delocalized. Figure 27 illustrates some classical reactions of
3 -rnethyl-l-phenyl- 2-pyrazolin -5 -one (396) (64HC(20) 1).
Pyrazoles and their Benzo Derivatives 253
1)M H+c
M t r ) e ( X R
o ....N 7J Me R2t]Me
Ph ---+
o .....N o ....N R,NH o .....N
N )HNO' N N
Ph Ph Ph
, (306)b
X=CI,Br
R RHJj
RtJMe Me Me
o N;N XR oJ:5N
RCHO o N.....N
N
Ph Ph Ph
(Scheme 19) (396)" (324)
Michael
addition d
\HNO'
R 1
J:)j e
N
/
R h
HON Me
OJ:jN
Ph
OM'
Me 2ChMe
O ;N
Ph
(369) X = CMe2
a LiAIH4 did not reduce 2-pyrazolin-S-ones (70BSFI974). b See also formulae (365) and (366). c (68M2157).
d (80CHEI80).
Figure 27 Some reactions of 2-pyrazolin-S-ones
If the pyrazolone is unsubstituted on position 1, there is still another possibility: lead
tetraacetate oxidation of (397) yields the oxopyrazolenine (398) (73CRV93) which is a very
reactive azadienophile (73JCS(P1)221).
R 4 R 3
oJ:YN
N
H
(397)
R 4 R 3
O J:]N
N
(398)
Hydrazinolysis of the ethoxypyrazolone (399) leads to the hydrazino derivative (400)
(70ZC224). A probable mechanism involves intermediates (401; R = OEt) and (401; R =
NHNH 2 ).
nOEl
oÄ--N'N
Ph
(399)
nNHNH2
o-d.....__)-I
N
H
(400)
R
O N"
I NHPh
NH 2
(401)
PhN=NnMe
o-d....._j.N
N
Ph
(402)
C-N bond homolysis may be the initial step in the conversion of (396) into the
phenylazopyrazole (402), a product which is believed to arise by interaction of ground-state
pyrazole with a photochemically generated phenyldiazonium ion (76CC68S).
4.04.2.2.2 Dihydro derivatives
According to the classification of Section 4.04.1.1.3 this section deals with 1_(15), 2 -(16)
and 3 -pyrazolines (17), and with pyrazolidones (18) and aminopyrazolines. The number
of publications dealing with these compounds is so large that only the most relevant results
and most important references will be described. The Jarboe review on pyrazolines
(67HC(22)1) contains information up to 1963 and fortunately the chemistry of pyrazolidones
and aminopyrazolines is covered by an excellent review by Dorn in 1980 (80CHE1).
254
Pyrazoles and their Benzo Derivatives
(i) Tautomerism and isomerization
Tautomerisrn has been discussed in Section 4.04.1.5.2. It concerns prototropic tautorner-
ism and the decreasing order of stability is A 2 (hydrazone) >A 1 (azo)>A 3 (enehydrazine).
The isomerization A 2 - A 3 occurs via a A1-pyrazoline (6SBSF769). Pyrazolidones and arnino-
A 2 -pyrazolines exist as such. The only exarnple of non-prototropic tautornerisrn deals with
the isornerization (403) - (404) (74CJC3474). This intrarnolecular process is another exarnple
(Section 4.04.1.5) of the therrnodynarnic analogy between prototropy'and rnetallotropy.
Rl/\
.. N
R 3 Si N
(403)
R IQNSiR3
(404)
(ii) Arornatization
A variety of oxidizing agents transforrn pyrazolines into pyrazoles: sulfur, bromine,
chloranil, potassiurn perrnanganate, lead dioxide and rnercury(1I) acetate are all effective
(66AHC(6)347). The use of lead tetraacetate is well docurnented (73CRV93). Photooxygenation
(79CRV447) of 1,3-disubstituted 2-pyrazolines yields pyrazoles and open-chain cornpounds.
If a 2-pyrazoline is disubstituted at position 5, as in (405), the oxidation is accornpanied
by rnigration of a rnethyl group and a 3,4,5-trisubstituted pyrazole such as (406) is obtained.
R 4 R 4
Me Me O Me 1;j R3 H ;Lj R3 R4 R 3
M 0 M 7 5 O
e 2 N e N R.' N () 5 I N
N" N" - J N" R S "'N{N R N"
H H HzX R ' R ' R '
(405) (406) (407) (408) (409)
2-Pyrazolines substituted at position 4 or 5 with hydroxy or arnino groups readily elirninate
a rnolecule of water or arnine yielding pyrazoles. The 4-substituted derivatives are relatively
rnore stable than the 5-substituted ones, because for the last group the lone pair at N-1
assists the elirnination (407) -.. (408) -.. (409). The sulfonyl group at position 1 is also easily
elirninated and this property is taken advantage of in Dorn's elegant synthesis of 3-
arninopyrazole (Section 4.04.3.3.1).
A 3 - Pyrazolines such as (410) are oxidized by iodine, rnercury(II) acetate and trityl chloride
to pyrazoliurn salts (411), and compound (410) even reduces silver nitrate to AgO (69JOU1480).
Electrochernical oxidation of 1,3,5-triaryl-2-pyrazolines has been studied in detail
(74BSF768, 79CHEllS). They undergo oxidative dirnerization and subsequent transforrnation
into the pyrazole derivative (412).
Ph Ph 4 Ph Ph
CN Me CNMe RrN u N l4
N N + Ph '..--J . N -= Ph
Me Me
(410) (411) (412)
Photooxidation has also been used to transforrn pyrazolines into pyrazoles (74AJC2267)
and 3-pyrazolidones into 3-hydroxypyrazoles (76CC68S).
(iii) Reduction
All three isorners of pyrazolines have successfully been reduced to pyrazolidines, the Al
catalytically (65JA3768), the A 2 polarographically (6SJOU9S) and the A 3 by means of sodiurn
borohydride (68JOU692). 1,2-Disubstituted pyrazoliniurn salts (229) are reduced to
p razolidines by cornplex hydrides (69BSF3302) and 3-pyrazolidinones forrn rnixtures of
A -pyrazolines and pyrazolidines (70BSF1936). Norrnally A 2 -pyrazolines are not reduced by
cornplex hydrides unless an electron-withdrawing group is present at N-l. Thus, alurninurn
hydride reduces 1-acetylpyrazolines to 1-ethylpyrazolidines through prior cornplexing at
the N-2 atorn of the pyrazoline ring (80CHE936).
(iv) Thermolysis and photolysis
The fundarnental subject of this section is the transforrnation of A l-pyrazolines into
cyclopropanes (Buchner-Curtius and Kishner cyclopropane syntheses). The cyclopropane
is often accornpanied by alkenes (67HC(22)1). When applied to A 2 -pyrazolines the reaction
occurs via the Al isorners (Scherne 37).
Pyrazoles and their Benzo Derivatives
255
R 4 R 3
RS O N
N....
H
R 4 R 3 R 4
-- 0 -- t:>R 3
R S I'fN R S
Scheme 37
The therrnal and photolytic processes have been extensively studied in connection with
the mechanisrn (concerted or diradical) and the stereochernistry of the decornposition. For
a classical paper see (66JA3963) and for more recent studies, Table 33.
Table 33 Thermolysis and Photolysis of I-Pyrazolines
1- Pyrazoline
ð.
hv
Conclusions
Ref.
Methoxycarbonyl and acetyl deriva-
tives
*
Relative rates of decomposition 7SJCS(P2)1791
into cyclopropanes and alkenes
One-step process mechanism 7SLA449
Methoxycarbonyl and cyano
derivatives
Cis- and trans-3,S-diphenyl
derivatives
*
*
*
1,3-Diradical mechanism
76T619
3-Ethyl-S-methyl (3R, SR) and
(3R, SS) derivatives
*
Elucidation of the stereochemistry 77JA2740
of the pyrazoline.... cyclopropane
reaction
Bicyclic derivatives
*
Rate constants for nitrogen 78JAS122
extrusion
4-Methylene-l-pyrazoline
*
Secondary deuterium isotope 81CJC2SS6
effects on the reaction rate
Simple derivatives
*
*
Barriers to decomposition
82JA1698
Ring contraction to cyclopropanes (413) with the forrnation of azo side-chains is observed
in the photolysis of 5-phenylpyrazolines (71BSF192S) and to azetidinones (414) in the
photolysis of 5-pyrazolidones (69JCS(C)2624, 83JCS(P2)1111).
R 4 R 3
-n R 2
,?-NN/
o 'Ph
( 414)
^ß=N
Ph "R 1
R 3
( 413)
(v) Other reactions
Other significant reactions of tl- and .6. 3 -pyrazolines are shown in Figures 28 and 29,
respectively.
Z eN
eN
N N
R 1 R 1
ì z+c Î B- 1
QN XR 1b eN XR C ON
x-
N N
H R 1 )/ "
R R
1 acetone a 1 HX d Ip
O x-
+.....N
N
II
/C"
Me Me
a (76MI40403). b R 1 = COR or NO (67HC(22)1), R 1 = nitrophenyl (66BSF61O). C Enamine behaviour (Z = Br, CHO,
PhN 2 , etc.) (67BSF47I6). d Protonation (75APO(lI)267, 76MI40403); R 1 = H, X-ray structure (Table 5). e Quaternization
(76MI40403). f Dequaternization (76MI40403). g Aminonitrile rearrangement (66RCR9, 80ZC167).
Figure 28 Some reactions of ð. 2 -pyrazolines
O X-
+.....N
N
1/ "
R H
/1"
----+
CC=N
N
1/ "
R R
256
Pyrazoles and their Benzo Derivatives
1 y = OH<
R 3
R 3 r--4
CN R 2 C..)'
W N/ R)
/ " R I
R' R 1
"Protonation (75APOIl \)267. 76MI40403); X-ray structures of the salts (Table 5). b Quaternization (76MI40403).
c (75APOI I 1 1267). d Nucleophilic attack (Y = CN, OH, H, R, Ar) (76MI40403). e Ring opening (76MI40403).
Figure 29 Some reactions of /13 -pyrazolines
R 3 R 3
O XHa o
I
NR 2 NR 2
; XRh ; t
ì R=H'
y-d
R 3
(N/ :2
R'
For a discussion of the reactivity of pyrazolidones and arninopyrazolines see (80CHEl).
(vi) Stereochemistry
The stereochernistry of pyrazolines and pyrazolidines has already been discussed (Section
4.04.1.4.3). Optically active Ll 1 - and Ll 2 - pyrazolines have seldorn been described (77 JA2740,
79CJC360), but cis-trans isorneric pairs are cornrnon. The C-4 acid-catalyzed epirnerization
involves the rnechanisrn shown in Scherne 38 (70TL3099), but in spite of sorne inconclusive
argurnents the C-5 epirnerization has never been established with certainty.
R R3
RSÁN;r.J
R 1
)j R4 R3
---.
R 5 N.... '
I H
R
R 4 R3
s J::;N H
R N
H/ "R 1
H
R jj "" R3
---. ---.
N
R S N....t'H
R 1
)j R4 R3
R 5 N;N
R 1
Scheme 38
4.04.2.2.3 Tetrahydro compounds
Pyrazolidines are cyclic hydrazones and their reactivities are comparable, the rnain
difference being found in the oxidation of pyrazolidines to pyrazolines and pyrazoles.
(i) Arornatization
Analogous to the oxidation of hydrazones to azo cornpounds, N- unsubstituted
pyrazolidines are oxidized to Ll 1 -pyrazolines. For exarnple, the bicyclic pyrazolidine (415)
when treated with silver oxide yields the pyrazoline (416) (6SJA3023). Pyrazolidine (417)
is transforrned into the perchlorate of the pyrazoliurn salt (411) by reaction with rnercury(II)
acetate in ethanol followed by addition of sodiurn perchlorate (69JOU1480).
The pyrazole (420) is forrned when the pyrazolidine (418) is heated with chloranil and
the interrnediate Ll 3 -pyrazoline (419) (one of the rare N (1)- unsubstituted derivatives) can
be isolated (78TL4S03).
.li NH
A H
(415)
çQN
(416)
Ph
OMe
N
Me
(417)
Me0 2 C O Me 2
....NH
N
Ph
(418)
Me0 2 C O Me
7 NH
N....
Ph
( 419)
Me0 2 C O Me
7
....N
N
Ph
(420)
(ii) Ring fission
Formation of a 1,2-disubstituted hydrazine by acid hydrolysis of an appropriately
substituted pyrazolidine has been noted (67HC(22)1), but the rnost interesting ring fission of
pyrazolidines involves the N(1)-N(2) bond of I-phenylpyrazolidines (421). If, instead of
phenylhydrazone, cornpound (421) is used in the Fischer indole synthesis, N- arninopropylin-
doles are forrned (73T404S). Scherne 39 shows the reaction with cyclohexanone.
Pyrazoles and their Benzo Derivatives
257
CNH
N
Ó
--.
Ó )D C 2? N NH C '{P NN:'
I I I
(421)
Scheme 39
Eberle has explored the synthetic possibilities of (421); with aldehydes it leads to hexa-
hydropyrirnido[1,2-a ]indoles (73T4049). Its 5-oxo derivative (1-phenyl-5-pyrazolidinone)
has a cornparable reactivity (76JOC377S).
Kost et al. . have studied related reactions of 2-acyl-1-phenylpyrazolidines (422) and
1-phenyl-2-thiocarbarnoylpyrazolidines (423). The forrner are converted on reaction with
phosphorus oxychloride into tetrahydropyrirnido[1,2-a]indoles (424) (nCHEs7) and the
latter into tetrahydropyrimido[2, 1-b ]benzothiazoles (425) under the influence of acidic
agents (SOCHE169).
:: R3
R 4 R 4 R 3 RC
R S CNCOCH 2 R! R)(J N
R 5 ,
, /NCSNHR 1 R 5' N)\
N R'ò N R'
Ò ç7\ OS
I :::::-..
(422) (423) (424) (425)
(Ui) Other reactions
Reaction of 2-ethoxycarbonyl-l-phenylpyrazolidine with Meerwein's salt (boron
trifluoride etherate) yields the quaternary arnmoniurn salt (426) which is not stable and
undergoes ring opening to the hydrazine (427) with sodiurn ethoxide (76JOC1244).
O Me
+ /NC0 2 Et /\N Me, h O NMe
N" EtO/ N)" W" 'Me N'
() E' U 'E' CO,E< eFt, Ph O)'Ph
(426) (427) (428) (429)
The reactivities of benzoyltrirnethylhydrazine (428) and I-benzoyl-2-rnethylpyrazoline
(429) towards rnethyl iodide have been discussed in connection with the corresponding
geornetries deterrnined by X-ray crystallography (SlJOC2490).
(iv) Stereochemistry
The stereochernistry of pyrazolidines has briefly been discussed in Section 4.04.1.4.3.
The pyrazolidine ring in (429) in the crystal state is not planar and the configuration about
the arnide bond is E as represented.
4.04.2.3 Reactions of Substituents
4.04.2.3.1 General survey of substituents on carbon
The general discussion in Section 4.02.3.1 is valid for pyrazoles and therefore only minor
points will be discussed here.
(i) Substituent environment
In pyrazoles the sirnplest way to characterize the three ring carbon atorns is to consider
that C-3 is sirnilar to the pyridine a-position, C-4 to the pyrrole ß-position and C-5 to both
the y-pyridine and the a-pyrrole positions. In indazoles C-3 corresponds to pyrazolic C-3
and in isoindazoles to pyrazolic C-5.
258
Pyrazoles and their Benzo Derivatives
(ii) The carbonyl analogy
The analogy between a substituent linked to a carbonyl group and a substituent in an a
or, to a lesser extent, a y-position to a pyridinic nitrogen has been discussed in Section
4.02.3.1.2). The conclusions hold for pyrazoles and indazoles.
(iii) Pyrazoles and indazoles
As indicated in the introduction to this chapter, Kauffmann (71AG(E)743) rernarked on
the fact that 7T-electron-rich arenes, like 1-rnethylpyrazoles, are cornparable with functional
groups that have a +R and a -1 effect, such as the arnino group. As an exarnple of this
analogy (the arenology principle) he quotes the fact that the hydrogen atorns of C-
rnethylazoles are not acidic just as the hydrogen atorns of N-methylarnines are not acidic.
This analogy is particularly valid for substituents at position 4. As has been discussed
before (Sections 4.04.1.3.6(iii) and 4.04.1.3.7(iii)), the pyrazole ring donates electrons to
substituents like COR, NO or N0 2 attached to the 4-position.
(iv) The effect of one substituent on the reactivity of another
In pyrazoles the two rnost important effects are produced by nitro groups and by
quaternization (Section 4.02.3.1.7). Both enhance considerably the reactivity of a second
substituent, for exarnple, that of a methyl group towards aldehydes or of a chloro substituent
towards arnines.
(v) Reactions of substituents not directly attached to the heterocyclic ring
According to Section 4.02.3.1.8 substituents rernoved frorn the pyrazole ring by two
or rnore saturated carbon atorns and substituents on the benzene ring of indazoles are
sirnilar in reactivity to the corresponding arornatic derivatives. For instance, chlorornethyl-
pyrazoles are corn parable to benzyl chlorides and 5-hydroxyindazoles to ß-naphthols in
their reactivity.
(vi) Reaction of substituents involving ring transformations
Reaction of substituents of other azoles leading to pyrazoles and indazoles will be discussed
in the corresponding preparative section (4.04.3.2.2). Azido-tetrazole isomerisrn, an inter-
esting property cornrnon to all heterocycles having an azido substituent a to a pyridinic
nitrogen atorn, will be exarnined in Section 4.04.2.3.4(v). It has been established (78MI40402)
that by heating 4-acetyl-3-methyl-1-phenylpyrazol-5-one phenylhydrazone (430) in the
presence of an acid 3,5-dimethyl-l-phenyl-4-a-phenylhydrazidopyrazole (431) is
obtained. This constitutes a new exarnple of the Boulton-Katritzky rearrangernent, now
widely found in oxygen heterocycles (Section (4.04.3.2.2) but still rare in pyrazoles.
o Me
PhN N
\.J Me /
N .
H 'N,
I Ph
H
(430)
o M
PhN e
\ , Mel.?
. N
N' Ph
/1
H H
(431)
4.04.2.3.2 lndazoles
This section deals with reactions taking place at positions 4, 5, 6 and 7 of the indazole
ring. The reactivity of position 3 has already been discussed with that of pyrazoles.
(i) Unsubstituted indazoles
The ring enlargernent of indazoles to yield dihydroazepinones (192) and (193) has already
been described (Section 4.04.2.1.2(ii)). Another reaction that destroys the arornatic ring is
catalytic hydrogenation. Unexpectedly, it is the hornocyc1ic six-rnernbered ring and not the
heterocyclic five-rnernbered ring which is slowly reduced by platinurn and hydrogen in acetic
acid (67HC(22)1). 4,5,6,7-Tetrahydroindazole (3,4-tet arnethylenepyrazole) and its two N-
rnethyl derivatives have been prepared by this rnethod.
Pyrazoles and their Benzo Derivatives
259
In the section dealing with electrophilic attack at carbon sorne results on indazole
homocyclic reactivity were presented: nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-
ation at position 7 (Section 4.04.2.1.4(iii)) and brornination at positions 5 and 7 (Section
4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the
indazole. Protonation, for instance, deactivates the heterocycle and directs the attack
towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2,
3, 5 or 7 has been published by Habraken (7IJOC3084) who described the synthesis of several
dinitroindazoles (5,7; 5,6; 3,5; 3,6; 3,4; 3,7). The kinetics of the nitration of indazole to forrn
the 5-nitro derivative have been deterrnined (nJCS(p2)632). The rate profile at acidities below
90%' sulfuric acid shows that the reaction involves the conjugate acid of indazole.
All these results are represented schernatically in Figure 30.
1st
(Br, N0 2 1 's (X)
I N-H
Nit
t I
2nd H
(Br, N0 2 )
1st
( S0 3 H )
Indazole reactivily towards electrophilic reagents
(ii) Substituted indazoles
Substituents in the indazole ring rnay direct a given reaction towards another position
either by their R and I electronic properties or simply by protecting the rnost reactive
position. Exarnples of both types are found in sulfonation studies (67HC(22)1). As indicated
before (Section 4.04.2.3.2(i)), sulfonation takes place at position 7. However, the presence
of an arnino group at positions 5 or 7 directs the attack towards the 4-position (Scherne
40). To obtain the indazole-5-sulfonic acid a rnore cornplicated procedure has been used
but it is still based on the sarne ideas.
S03H S03H
H2N N N __
N/ N
H NH 2 H
(Section 4.04.2.1.4.(v))
W
I -.';N
-I
N
(Section 4.04.2.1.4(v))
2nd
Ist (r) "
's
I N
N
t I
3rd H
Figure 30
N
N
NH 2 H
H03S N __ __
N
H
NH 2
H03S N
NI
AcH N H
H03S T __
i'
AcH N H
Scheme 40
---.
N0 2
---' N
NI
AcHN H
1
NH 2
--
N
AcH N H
Indazole substituents can be engaged in a variety of reactions. Those at position 3 react
in a similar rnanner to pyrazolic 3(5)-substituents and will be discussed in the following
sections. Substituents in the fused benzene ring have a naphthalene-like reactivity (Section
4.04.2.3.1 (v)). Several classical exarnples are described in (67HC(22)1): NO z --.. NH 2 (PdjHz);
NH z -.. condensed pyridines (Skraup reaction); NH z -.. N z + -.. H, Cl, I, CN,...;
COzH -.. Br (Hunsdiecker reaction); Br -.. H (NajHg); etc. As a rnatter of fact, the whole
spectrum of arornatic reactivity can be transferred to indazoles substituted at the fused
benzene ring. Cornpare, for exarnple, the reactions described by Suschitzky et al.
(68JCS(C)1937) for 2-azidonaphthalene (432) and for 5-azidoindazole (433). Pyrolysis of
these compounds in a rnixture of acetic and polyphosphoric acid yields (434) and (435),
respectively.
N3 C0 1
#
(432)
N3 N
NI
H
(433)
Me
(434)
Me
I/O
N I N
I
N
(435) H
260
Pyrazoles and their Benzo Derivatives
4.04.2.3.3 Other C-linked suhstituents
c- Linked substituents behave in pyrazoles and indazoles as in other azoles (Section
4.02.3.3). The classical arornatic chernistry of these compounds has given rise to a great
nurnber of publications (66AHC(6)347, 67HC(22)1, B-76MI40402), but not to a specific pyrazole
chernistry. For this reason, only a brief survey will be given here.
(i) Alkyl groups
We have already noted (Section 4.04.2.1.4(xi)) that alkyl groups on pyrazoles are
oxidized with perrnanganate to carboxylic acids. Silver nitrate and arnmonium persulfate
transforrn 4-ethyl-l-methylpyrazole (436) into the ketone (437) (72JHC1373). The best
yield was obtained starting with the alcohol (438) and using an acid dichromate solution
as oxidizing agent.
OH
CH 3 CH z I
CH 3 CO O CH 3 Clh C)ÇN
b 7 7
/N /N /N
N N N
Me Me Me H
(436) (437) (438) (439)
The synthesis of indazoles frorn their 4,5,6,7-tetrahydroderivatives (439) by rneans of
sulfur or, better, by catalytic dehydrogenation over palladiurn on charcoal (67HC(22)1) can
also be included here.
The acidic character of the hydrogen atorns of C- rnethyl groups linked to the pyrazoliurn
ring (Figure 22; Section 4.04.2.1.1(ii)) facilitates a nurnber of reactions difficult to carry
out with neutral pyrazoles. Since efficient rnethods of de alkylation have been described
(Section 4.04.2.3.10(ii)), the synthesis via the pyrazoliurn salt is a useful alternative. The
same behaviour is observed for indazoliurn salts, for exarnple, nucleophilic addition to
arornatic aldehydes (78JOC1233).
(iO Aryl groups
C- Aryl groups carrying hydroxy or arnino substituents can be oxidized without affecting
the pyrazole nucleus (B-76MI40402). In the discussion of electrophilic reactions the fact that
the p- position cornpetes with the pyrazolic 4-position has been mentioned (Sections
4.04.2.1.4(i) and (ii)); for example, nitration occurs on the phenyl ring under conditions in
which the pyrazole nucleus is protonated (B-76MI40402). Nitration and brornination of (301)
and (302) (Section 4.04.2.1.4(ii)) have been studied in order to evaluate the directing effect
of a 4-pyrazolyl group in electrophilic substitution in the thiophene series (80CS(1S)102).
(iiO Other carbon-linked functionality
Pyrazolecarboxylic acids (pKa (66RTC119S)) are readily decarboxylated and this provides
a rnethod for introducing a deuteriurn atorn into the pyrazole ring. 3-Deuteroindazole has
also been prepared in this way (76CJC1329). Lithiurn alurninurn hydride reduces 3-ethoxycar-
bonyl-3'(5'),5-dirnethyl-5'(3')-pyrazol-1-ylpyrazole (440; R = C0 2 Et) to the corresponding
alcohol (440; R = CH 2 0H) (8IT987).
Me M O C
R
N, , #
N N
H
(440)
COCI
ClOCCN
N
Ph
(441)
Acid chlorides are useful reagents, but when the pyrazole is N- unsubstituted a dirneriza-
tion occurs and the diketopiperazine (254) is isolated (Section 4.04.2.3.3(x)). However,
(254) reacts with rnany cornpounds as an acid chloride would, for example with arnines to
yield arnides (67HC(Z2)1). The difunctional pyrazole derivative (441) affords polymers by
reaction with diphenols (69RRC763). Cyanopyrazoles can be hydrolyzed to the corresponding
carboxylic acids (68CB829).
Owing to the nurnber of different reactions in which they can be used, pyrazole aldehydes
and ketones are the rnost interesting group of C-linked substituents. Transforrnations of
the CHO group into C0 2 H, CH(ORh, CH=CHR, etc., and of the COR group into
Pyrazoles and their Benzo Derivatives
I
261
C(OH)RR', oximes (Semrnler-Wolf and Beckmann rearrangements (76CB1898)) and rnany
other functional groups have been mentioned in the literature (67HC(22)1, B-76MI40402). As
an example, the aldehyde (442) yields the alcohol (438) when treated with rnethylrnagnesiurn
iodide, and the ketone (437) affords the rnalonylaldehyde sodiurn salt (443) by formylation
(72JHC1373). Compound (443) treated with rnethylhydrazine affords a rnixture of 1,1'-
dimethyl-3,4'-bipyrazolyl (444) and 1,I'-dirnethyl-4,4'-bipyrazolyl (445).
Na+
H
I
H, -::/C b
T
H /N
N
Me
OHC (J OHCëHCO O
1/\\ 1/\\
N/N N/N N/N N/N
Me Me Me Me
(442) (444) (445) (446)
Pyrazolecarbinols can be dehydrated to vinylpyrazoles, (438) -+ (446) (72JHC1373), or
transforrned into chlorornethyl derivatives (81T987). Cornpound (440; R = CH 2 Cl) thus
prepared is the starting rnaterial for the synthesis of the rnacrocycles (226)-(228) (Section
4.04.2.1.2(vi)). Vinyl- and ethynyl-pyrazoles have been extensively studied (B-76MI40402)
and many vinylpyrazoles are polymerized by free radical initiators.
4.04.2.3.4 N-Linked substituents
Most of these substituents are interrelated as shown in Scherne 41.
ON-eN ---. H 2 N-1=l-N ---. N;-H N
N/ 'N) 'N)
I I I X-
R 1 R! R!
(451) X (iT X (T
02N- N3-
'N/N 'N;N
I I
R 1 R!
(449) (455)
Scheme 41
Me 3 N-eN
N/ X-
I
R'
(450)
R'=H
N 2h
)
N
( 453)
N2
or d
N
N
( 454)
-- HzNHN-H
,__;N
N
I
R 1
(452)
(i) Arnino-pyrazoles and -indazoles
Arninopyrazoles do not undergo the Dirnroth rearrangernent, since rnore heteroatorns
are necessary for this rearrangernent to occur (Section 4.02.3.1.9, 4.02.3.5.1). 3-
Aminopyrazole itself (447; R 1 = H) can react with electrophiles at four positions: both ring
nitrogen atoms, the arnino group and the 4-position. Dorn, for example, has studied its
reaction with toluene-p-sulfonyl chloride (B-76MI40402, 80CHE1) and has identified mono-,
di- and tri-substituted derivatives on nuclear and arnino nitrogen atorns. A similar situation
is found in acylation studies, but in this case the nuclear acyl groups (azolides; Section
4.04.2.3.10(iii)) are very readily hydrolyzed. Other reactions of arninopyrazoles, like
diazotization (forrnation of 448), peracid oxidation (forrnation of 449) and perrnethylation
(forrnation of 450) are well docurnented (B-76MI40402, 80CHEt).
Dirnethylaminopyrazoles react with alkylating agents to afford quaternary salts
(72BSF2807). The nitrogen atorn of the dirnethylarnino group is the rnost reactive in the case
of 3-dimethylarnino- and 4-dirnethylarnino-pyrazoles (forrnation of 456 and 457 salts,
respectively) whereas 5-dirnethylarninopyrazoles yield arninopyrazoliurn salts (458).
+ + Me
NMe3 Me3N TsN I
d h TSN O Me
N X- Z;N X- MezNCNMe M h :e Me N
N/ N/ N + (N/\ N/
R 1 R 1 R I X- Me Me
(456)
,(457)
(458)
(459)
(460)
262
Pyrazoles and their Benzo Derivatives
The chernical behaviour of the rnesoionic pyrazole (459) has be n studied by Boyd et at.
(74JCS(P1\I02S). Protonation and alkylation take place on the exocyclic nitrogen atorn and
a therrnal rearrangernent of a rnethyl group is observed when (459) is boiled in benzonitrile
for several hours giving (460).
(ii) Arninopyrazoliurn ions
Besides the salts (458) and (459) previously described, arninopyrazolium salts can be
obtained from the reaction between arnines and chloropyrazoliurn salts (Section
4.04.2.3.70i)) or by quaternization of irninopyraz9lines as in (461) -+ (462) (nBSF2so7).
The lithiurn alurninurn hydride reduction of the salt (462) affords mixtures of reduced and
open-chain pyrazoles (Figure 23; Section 4.04.2.1.6(i)).
R 3
R 5 N .J::)N R'
R 1
(461)
R 3
R5N O R'
I N/'"
R R 1
1462)
(iii) [mines
In addition to (461), Dorn has described the irnine (463) isolated frorn 5-arnino-l-
rnethylpyrazole and arenesulfonyl chloride (SOCHE1). Upon heating, or in the presence of
triethylarnine, it undergoes rearrangernent to the rnore stable 5-bis(arylsul-
fonamido)pyrazoles (464). 5-Irninopyrazolines (461) react with acyl chlorides at the exocyc-
lic nitrogen atorn to afford arnidopyrazoliurn salts (B-76MI40402).
RO,SN -VN SO,R
Me
(463)
(RO,S),N O N
N/
Me
(464)
(iv) Nitro and nitroso groups
4-Nitropyrazoles are prepared by direct nitration of pyrazoles (Section 4.04.2.1.4(ii))
whereas the 3-nitro derivatives are derived from the rearrangernent of N-nitropyrazoles
(Section 4.04.2.3.10(vi)). Partial reduction of 4-nitropyrazoles (449) to the corresponding
nitroso cornpounds (451) is possible with alkali stannites (B-76MI40402), but the most
irnportant reaction of the nitro corn pound is the cornplete reduction to arnino derivatives
(447). This reduction rnay be achieved using zinc and acetic aciò (this rnethod has been
used in one step of the synthesis of the C-nuc1eoside antibiotic forrnycin (SOCJC2624)), tin
and hydrochloric acid, sodiurn hydrosulfite, alurninurn arnalgarn with rnoist ether or alcohol,
catalytically, and with red phosphorus and hydriodic acid (B-76MI40402). The nitro so (451)
to arnino group (447) conversion has principally been accornplished using hydrazine and
alcohol, but tin and hydrochloric acid and zinc and acetic acid are also effective. This is
one of the best methods of synthesis of 4-arninopyrazoles from pyrazoles (67HC(22)1).
Oxidation to nitropyrazoles, e.g. (451).... (449), has been carried out with potassiurn per-
manganate or nitric acid. 4-Nitrosopyrazoles (451) can also react with 3-arninopyrazoles
(447) to yield azopyrazoles, for exarnple (465).
N=N
r( M:n: e
ZN;N eZN/'ì
H H
(465)
ArN=N R 3
R5 0 N
N/
R 1
(466)
(v) Azo-, diazo- and azido-pyrazoles
4-Arylazo-5-pyrazolones are very comrnon products (139; Section 4.04.1.5.2) readily
converted into 4-arylazopyrazoles (466; RS=H) via the 5-chloro derivatives (466; R S = Cl)
(67HC(22)1). Other azopyrazoles (318) and (319) have been described in Section
4.04.2.1.4(viii). These cornpounds can be reduced to amines (zinc and acetic acid) or to
arylhydrazines (zinc in alkaline rnediurn) (67HC(22)1).
Pyrazoles and their Benzo Derivatives
263
Pyrazole- and indazole-diazoniurn salts are cornpounds of exceptional thermal stability.
Their chernistry has been studied rnainly by Reirnlinger, and their application to the synthesis
of heterocyclic systerns by TiSler and Stanovnik who have reviewed this topic (80CHE443).
As in classical arornatic chernistry, the pyrazolediazoniurn salts (448) have been used as
starting materials for the synthesis of chloro-, brorno-, cyano- and nitro-pyrazoles (B-
76MI40402). The transforrnation of (448) into fluoropyrazoles using the Balz-Schiernann
procedure yields only insignificant arnounts of 3(5)-fluoropyrazole (77BSF171), but irradiation
of the diazonium fluoroborate salt (Kirk and Cohen rnethod) can be used to prepare
relatively large quantities of fluoroazoles. 3-Fluoroindazole (77BSF171), rnono- (78JHC1447)
and di-fluoropyrazoles have been prepared (79TL3179) by this procedure.
Pyrazolediazonium salts (448) couple with activated arornatic rnolecules, like naphthols
(79KGS80S), and can be reduced to hydrazines (452) with tin (II) chloride (74MI40406).
The most interesting property of diazoniurn salts (448; R 1 = H) is their conversion into
4- or 5-diazopyrazoles, (453) and (454). 3-Diazoindazole (467) was the first heterocyclic
diazo cornpound to have its structure deterrnined by X-ray diffraction analysis (Section
4.04.1.3.1). In addition to the reactions discussed in Section 4.01.3.4.1, it should be stressed
that diazopyrazoles are useful synthons for rnany condensed heterocyclic systems, such as
azapentalenes (78AHC(22)184, 80CHE443). Other reactions of diazopyrazoles are their reduc-
tion to pyrazoles with titaniurn(I1I) and iron (II) salts (79S194) and their cycloaddition with
ylides (79TLtS67) and with electron-rich alkenes (81TLt199) to afford 5,5- and 5,6-fused
heterocycles, respectively. There is evidence frorn rnass spectrornetry that the forrnation of
3-azidoindazole by the action of azide ion on 3-diazoindazole (467) involves a spectacular
intermediate, the indazolylpentazole (468) (80CHE443).
N 2
OjN
(467)
N:::::-N
I \
N ,1N
---
OÓ ' N N
I
N
H
(468)
Azidopyrazoles (455) exist as such even when the azido group is at the 3-position where
an azido-tetrazole equilibriurn is possible (469) (470) (77AHC(21)72, 78AHC(22) 184).
However, when the rnolecules are converted into their anions, the cyclic pyrazolo[I,5-
d]tetrazole (471) forrn predorninates. It is possible to 'trap' the cyclized anions such as
(471) by rnethylation and to obtain stable azapentalenes (472) and (473).
N
R U 'N
r II
R S N-N
N/
H
(470)
Therrnolysis of 4- and 5-azidopyrazoles has been studied by Srnith (B-70MI40402,
81AHC(28)232). These cornpounds undergo fragrnentation with forrnation of unsaturated
nit riles via the nitrenes (474a) and (474b; Scherne 42).
R 4 N
RS O N3
N/
H
(469)
N 3 R 3
RS O N -+
N....
R 1
R 4 R 3
O
N 3 ....N
N
R 1
N
R O 'N
II
R S N-N
/
(471)
Me
N
R Ö 'N
II
R S N/N-N
N
Rf=(
RS N/ N- Me
(472)
(473)
ç:J
R 1
(474a)
NC
I
......C':::-
R S N + R 3 C:N
I
R 1
-+
-+
r R 4 R J
[ N
(474b)
Scheme 42
R 4 R 3
"C=C/
/ \
NC N
N
I
R 1
264
Pyrazoles and their Benzo Derivatives
4.04.2.3.5 O-Linked substituents
The fact that an OH or OR group in position 3 or 5 enhances the reactivity of the
pyrazolic 4-position towards electrophiles has already been discussed (Section 4.04.2.1.3).
Likewise, the non-aromatic reactivity of 2-pyrazolin-5-ones has been examined in Section
4.04.2.2.1 (ii).
(i) lnterconversion and modes of reaction of tautomeric forms
The tautornerism of pyrazolones has been discussed in Section 4.04.1.5.2 and their
multiple reactivity in Sections 4.04.2.1.1 (iv) and 4.04.2. 1. 3 (viii). Interconversion of the
different tautorners proceeds readily through the anion (157; Scheme 10) or the cations
(203) and (204; Scheme 17), thus providing pyrazolones with exceptional possibilities of
reaction.
(ii) 3-Hydroxy-pyrazoles and -indazoles
From the results quoted in Section 4.04.2.1.3(x) the stability of acetyl derivatives of
indazolone decreases in the order N(1)-acetyl>N(2)-acetyl>O(3)-acetyi. The reactivity
of 3-hydroxypyrazoles is covered by Dorn's comprehensive review (SOCHEl). Amongst the
results reported there are the Claisen rearrangement of allyloxypyrazoles (475a) -+ (475b)
and a method for transforming 3-hydroxy- into 3-chloro-pyrazoles via the pyrazolone (476)
and the chloropyrazolium chloride (477). Methylation of 3-hydroxypyrazole (478; X = OH)
affords the pyrazolone (476), which in turn is transformed into the salt (477) by reaction
with phosphorus oxychloride. The final step is the therrnolysis of (477) that yields the
3-chloropyrazole (478; X = Cl)
OCHi'H =CH
R J- 'N
'N"
R'
(475a)
H>C=CHCH O OH
RS r N
N"
R'
(475b)
o
R s(}NMe
N
R'
o
R S O NMe 0-
N"+
R'
x
S O
R "N
N
R'
(478)
Thermolysis of the betaine (479) affords the aromatic 3-methoxypyrazole (480) (SOCHEl)
(476)
( 477)
0-
[:!N
N
/ "-
Me Me
(479)
O OMe
r
"N
N
Me
(480)
R 3
Rn
'ìf"tI;N
o R 1
(481)
:)j H R3
<;>:7 I ":N
H /
' 0 N
R'
(482)
(iii) 5-Hydroxypyrazoles
The title cornpounds also undergo the Claisen rarrangement (5-allyloxypyrazoles -+ 4-
allyl-5-pyrazolones) and are readily transforrned into 5-chloropyrazoles by means of phos-
phorus oxychloride (SOCHEl). In the presence of aluminum chloride 5-acyloxypyrazoles
(481) undergo the Fries rearrangement affording 4-acyl-5-hydroxypyrazoles (482).
The acetyl transfer reactions of acetylated pyrazolones (acylotropy) have been carefully
studied by Arakawa and Miyasaka (74CPB207, 74CPB2l4) (Section 4.04.2.1.3(x)). Methylation
of 3-methyl-l-phenyl-4-phenylazo-5-pyrazolone (402) yields, depending on the experi-
mental conditions, the N- and the O-methylated derivatives (483) and (484) (66BSF2990).
These derivatives have been used as model compounds in a study of the tautomerism of
(402) (structure 139; Section 4.04.1.5.2).
PhN- Jj N
I Me
Me
o N"N
Ph
(483)
PhN=N hMe
MeO( J\j
N
Ph
(484)
(iv) 4-Hydroxypyrazoles
4-Hydroxypyrazoles are amphoteric cornpounds which form salts with alkalies and with
rnineral acids (B-76MI40402). The 4-hydroxy group directs electrophilic substitution towards
Pyrazoles and their Benzo Derivatives
265
the 5-position (diazo coupling, chlorination, nitrosation). Alkylation of 1-substituted 4-
hydroxypyrazoles (485; R = H) takes place on the oxygen atorn giving (485; R = Me) or
on the nitrogen atorn giving (486), depending on the experirnental conditions (B-77MI40402,
79CJC904). The salts (486) on deprotonation yield the mesoionic pyrazoles (28; Section
4.04.1.1.2). Oxidation of N-unsubstituted 4-hydroxypyrazoles (485; R = R 1 = H) affords
3,4-diazacyclopentadienone (487) which behaves either as a diene or as a dienophile towards
a wide variety of cycloaddition reagents (79CJC904).
RO R 3
R S O N
N/
R'
(485)
HO R 3
R SCNMe X-
N +
R'
(486)
OhR 3
R ;) N
N/
(487)
(v) Alkoxy groups
An alkoxy group may be replaced by chlorine upon treatment of a suitably substituted
pyrazole with phosphorus oxychloride (67HC(22)1). Heating at 230-300 oC results in a methyl
group rearrangernent from the oxygen atorn in (488) to the nitrogen atorn at position 2
giving (489; R = Me). Quaternary salts like (490) lose an alkyl halide molecule upon heating
to yield pyrazolones (489; R = Et) and not alkoxypyrazoles (488) (67HC(22)1).
a te Me
eO N/N O N R
Ph Ph
(488) (489)
Me
MeoCNEt Cl-
N +
Ph
(490)
4.04.2.3.6 S-Linked substituents
(i) Mercapto compounds: tautomerism
5-Mercaptopyrazoles exist as a rnixture of the SH and NH tautomers (Section 4.04.1.5.2).
1-Substituted 3-rnercaptoindazoles exist as such whereas 2-substituted derivatives exist as
thiones (NH tautorner) (76AHC(Sl) 1).
(ii) Thiones
Most of the reactions described in Section 4.01.3.6.2 have their counterpart in
thiopyrazolones (67HC(22)1, B-76MI40402): S-methylation (491; R S = Me), S-acylation (491;
R S = COR), oxidation to disulfides (492) or, with a stronger oxidizing agent, to sulfonic
acids (493). Oxidative desulfurization is also known and of particular interest is the reaction
of thiopyrine (494) with hydrogen peroxide which yields 3-rnethyl-1-phenylpyrazole with
loss of sulfur and the 2-methyl group (67HC(22)1).
R 3
RsS O N
N/
R'
(491)
R 3 R3
n n
N...._ _/.... S-S Ä..._ _;N
N N
R 1 R'
(492)
_ R 3
O
H0 3 S /N
N
R'
(493)
Me
s J;N Me
N
Ph
(494)
(iii) Alkylthio groups
Derivatives like (491: R S = Me) can be de-S-methylated by Raney nickel in ethanol or
concentrated hydrochloric acid. Acid hydrolysis of (491; R S = acyl) also affords 5-mercap-
topyrazoles, whereas alkaline hydrolysis of the pyrazoliurn salt (495) furnishes methanethiol
and antipyrine.
Methylation of (494) with rnethyl iodide affords the salt (495) which on distillation loses
the N-methyl group yielding the 5-rnethylthiopyrazole (491; R 1 = Ph, R 3 = R S = Me). The
direct transformation (494) --+ (491) occurs by sirnple heating (67HC(22)1), although the
quaternary salt is probably the catalyst for the N- to S- rearrangement. This reaction has
been thoroughly studied by Maquestiau et al. (77BSB961). Alkylthio derivatives (491) can
be readily oxidized to sulfones (496).
266
Pyrazoles and their Benzo Derivatives
Me
O X-
MeS ...NMe
N
Ph
(495)
R 3
, O
R-0 2 S N...N
R!
( 496)
R 3
-O,SÇ H
R 1
(497)
(iv) Sulfonic acid groups
Pyrazolesulfonic acids, like (493), have high melting points (Table 24) and probably exist
as the zwitterions (497). They are very stable to hydrolysis and only afford pyrazolones at
high temperatures. The replacement of the S03H group by bromine has also been reported
(B-76MI40402). Pyrazole-3-, -4- and oS-sulfonic acids react with phosphorus pentachloride
to form sulfonyl chlorides.
4.04.2.3.7 Halogen atoms
(0 Nucleophilic substitution reactions: neutral pyrazoles and indazoles
Halogeno-pyrazoles and -indazoles are quite unreactive cornpounds. For instance 3-
brorno-5-methylpyrazole does not react with hydrazine nor with sodiurn azide, even in
DMSO or HMPT (74MI40406). Neither 3-chloro- nor 3-brorno-indazole reacts with
hydrazine (78MI40401) whilst the 3-iodo derivative is reduced to indazole. These cornpounds
need an electron-withdrawing group in the a (pyrazoles) or 'Y (indazoles) position for the
halogen atom to be reactive. Thus S-chloropyrazoles (498; X = Cl) bearing an electron-
withdrawing group Y at the 4-position react with secondary arnines to afford S-
arninopyrazoles (B-76MI40402). The reactivity depends on the nature of Y and decreases in
the order N0 2 > PhN 2 :> PhCO>> Br>> H. 3- Bromo-5-nitroindazole (499: X = Br) also reacts
with secondary arnines to afford the 3-amino derivatives (78MI40401). Nucleophilic photosub-
stitution of both (498; Y = N0 2 , X = Cl) and (499; X = Br) has been studied (79Tl331, 80T3523)
and in this way 5-cyanopyrazoles (498; Y = N0 2 , X = CN) and 3-arninoindazoles (499;
X = NR 1 R 2 ) have been prepared.
Reaction of the pyrazole anion with (498; Y = N0 2 , X = Cl) in DMSO yields the pyrazolyl-
pyrazole (500) (81M675).
y Me
X O N
N'"
Ar
(498)
X
02N N
N
H
(499)
02N Me
...Jf. j
N--'N N...N
U Ph
(500)
(iii) Nucleophilic displacements: halogenopyrazolium salts
The 3- or S-halogenopyrazoliurn salts such as the chloro or brorno derivatives (477) are
reactive compounds. Their halogen atorn can easily be replaced by nuc1eophiles, for exarnple
by amines to yield aminopyrazoliurn salts (462), and the chlorine atom can be replaced by
bromine or iodine (67HC(22)1). A nurnber of brornopyrazolium salts (501)-(503) have been
studied by Begtrup (73ACS2051). On hydrolysis they give 3- or S-pyrazolones by an
'anornalous' addition (OH-)-elirnination (HBr) mechanism.
Br Br
CNMe CNMe
N + N +
R 1 R 1
(501) (502)
n
Br . .....NMe
N +
R 1
(503)
Nitration in 80% sulfuric acid of 4-bromopyrazoles gives rise to considerable nitro-
debromination (formation of 4-nitropyrazoles) (79AJCl727). The reaction takes place on
the protonated pyrazolium ion (Section 4.04.2.1.4(ii)).
(Ui) Other reactions
Reduction of the halogen substituent has been carried out by different procedures such
as catalytic hydrogenation using palladium-carbon or Raney nickel, red phosphorus and
hydroiodic acid, and zinc and sulfuric acid (66AHC(6)347). 3-Deuteropyrazole has been
Pyrazoles and their Benzo Derivatives
267
prepared by ZnjCu-AcOD reduction of 3-brornopyrazole (70BSFI974). Grignard reagents
are only forrned frorn bromopyrazoles when promoted by active alkyl halides (B-76MI40402).
Two irnportant problerns in this section still remain unsolved. The first one concerns the
relative leaving group ability of the four halogen atorns. As is well known the experimental
order of reactivity of halogenonitrobenzenes in the S NAr reaction is F>> Cl > Br > 1. This
order has also been observed for 2-halogeno-6-nitrobenzothiazoles (77BSFI71). In pyrazoles
and indazoles no clear-cut conclusion can be drawn from the scattered literature results.
It has been clearly established that in pyrazolium salts chlorine can be replaced by the rnore
nucleophilic brornine and iodine (Section 4.04.2.3.7(ii)) but not by fluorine (77BSFI71). On
the other hand, fluoropyrazoles (Section 4.04.2.3.4(v)) are quite stable cornpounds.
The second problem is the relationship between the position of the substituent in the
pyrazole nucleus and its mobility. In the 1-phenylpyrazole series in their reactions with
Grignard reagents, the brornine reactivity decreases in the order 5-Br> 4-Br > 3-Br (B-
76MI40402). When an electron-withdrawing group is present at the 4-position, the 5-
chloropyrazole is more reactive than 3-chloropyrazole, but this has been attributed to bond
fixation (Section 4.02.3.9). Thus, this problern needs further clarification.
4.04.2.3.8 Metal and metalloid-linked suhstituents
In different sections of this chapter, pyrazoles and indazoles C-linked to a rnetal or a
rnetalloid have been described or they will be described in the preparative sections,
including lithio derivatives (Section 4.04.2.1.7), pyrazolylmagnesium reagents (Section
4.04.2.3.7 (iii)), chlorornercury derivatives (Section 4.04.2.1.4( vii)) and silylpyrazoles
(Section 4.04.3.1.2(ii)). All these corn pounds are useful intermediates and some of their
rnost characteristic reactions will be discussed here.
Lithiated pyrazoles prepared from ë H or preferably frorn C- Br pyrazoles (B-76MI40402)
can be transforrned into carboxylic acids. In this way pyrazole-4-carboxylic acids (504;
R 1 == H or Me) have been prepared frorn the corresponding 4-bromopyrazoles.
N-NPh
Ph Y H
N 0
N-NPh
( 507)
H0 2 C O
/N
N
R'
BrMg o
/N
N
Ph
(504)
(505)
(I)
....N N/
Ph Ph
(506)
Finar and coworkers (B-76MI40402) have rnade a detailed study of the pyrazolyl Grignard
reagent (505). In addition to alcohols and ketones, the hydrocarbons (506) and (507) could
be isolated, the first by heating the Grignard reagent (505) and the second by reaction with
diethyl carbonate.
4-Chlorornercurypyrazoles (316) react like phenylmercury(II) chloride (B-76MI40402). The
group is rernoved by dilute hydrochloric acid and replaced by brornine in the reaction with
bromine in acetic acid. C- Trimethylsilylpyrazoles have been studied by Birkofer and
coworkers (nCB 1759, B-76MI40402). Sodium hydroxide selectively desilylates the Me3Si group
at the 3-position, while sulfuric acid removes the 4-SiMe3 substituent. The 3- and 4-
nitrosopyrazoles, difficult to obtain by direct nitrosation (Section 4.04.2.1.4(ix)), are readily
prepared by nitroso-detrirnethylsilylation (B-76MI40402).
4.04.2.3.9 Fused heterocyclic rings
There are rnany representatives of fused pyrazoles. By far the rnost intensively studied
are the [5.6] bicyclic derivatives which include indazoles and azaindolizines (77HC(30)1l7,
77HC(30)179) (see also Section 4.04.2.4). Less studied but still well known are the [5.5]
bicyclic systems, the azapentalenes (77HC(30)1, 77HC(30)317, 78AHC(22)184). Pyrazoles fused
to a seven-membered ring have few representatives. Cornpound (508) when irradiated
affords 3-phenylindazole amongst other products (78H(1l)293). The cycloheptapyrazoles
268
Pyrazoles and their Benzo Derivatives
c)j o Ph ÖÓ o Ph R 4 R 3
I N fj I N Rill
=-- N =-- N N-N
I I I
Ph Ph R 1
(508) (509) (510) (511) (512)
(509) and (510) are the rnajor constituents of the reaction rnixture obtained in the reaction
of diphenylnitrilimine with tropone (77JCS(Pl)939).
The 1,2-diazepine ring system is related, thermally and photochemically, to two pyrazole
[4.5] bicyclic systerns (511) and (512). A large nurnber of publications by Moore, Sharp,
Snieckus and Streith deal with these isomerizations (72CCS27. SOCC444).
Ph
OGN
H
4.04.2.3.10 Substituents attached to ring nitrogen atoms
R4 R 3
JJjN
R N
I
R'
This is a rnost original situation in azoles since there is no equivalent in either arornatic
or six-rnernbered ring heterocyclic chemistry, at least in neutral molecules. With a substituent
on the nitrogen atorn, pyrazoles behave as halogens (71AG(E)743); thus N-acetylpyrazole
can be regarded as the arenologue of acetyl chloride.
(0 Aryl groups
Spectroscopic rneasurernents of N- arylpyrazoles have been used to calculate the Harnrnett
and Taft parameters of pyrazole and some of its derivatives (74JCS(P2)449. SOAJC1763.
SIJCR(S)364). In the last reference a critical exarnination of the literature values is given.
Typical values are as follows: pyrazole, 0'1 = 0.300, O'R o = -0.061; indazole, 0'1 = 0.361,
O'R 0 = -0.154; isoindazole, 0'1 = 0.420, O'R 0 = -0.126. A typical pseudohalogen substituent,
NCS, has 0'1 = 0.42 and O'R o = -0.07 (B-79MI40416).
Fong (SOAJC1763) assurnes that (O'R 0)0 (the substituent constant for the conforrnation where
the azole is coplanar with the benzene ring) is the same for all the pyrazoles. Frorn the
experirnental value of O'R 0 he calculated the dihedral angle (Section 4.04.1.4.3) assurning
that (O'RO)O = (O'RO)OCOS 2 e. If instead of -0.165 we assume that (O'RO)O is equal to -0.20 then
e for 1-phenylpyrazole and 5-rnethyl-1-phenylpyrazole is 25 0 and 57 0 , respectively.
In the section dealing with electrophilic substitution on the carbon atorn (Section
4.04.2.1.4) it has been pointed out that the para-position of the 1-phenyl ring cornpetes
with the pyrazolic 4-position. For instance, brornination of 1-phenylpyrazole affords 4-
brorno-l-p-brornophenylpyrazole (B-76MI40402). In a strong acid medium, the I-phenyl-
pyrazoliurn cation is nitrated exclusively on the para-position (72JCS(P2)1654). In this respect
pyrazoles also behave like pseudohalogens (chlorine is an ortho-para directing substituent,
30-70), but steric hindrance prevents the ortho attack. The reactivity of the 1-thienyl-
pyrazoles (513) and (514) has been studied by Gronowitz et at. (7SCS( 13)157). Reactions occur
at the thiophene ring and the pyrazole ring behaves as a +R substituent.
Ph Ph
r
(J ò N'N N,N
I
(513) (514) (515) (516) (517)
Another example of the analogy between pyrazole and chlorine is provided by the alkaline
cleavage of 1-(2,4-dinitrophenyl)pyrazoles. As occurs with l-chloro-2,4-dinitrobenzene,
the phenyl substituent bond is broken with concomitant formation of 2,4-dinitrophenol
and chlorine or pyrazole anions, respectively (66AHC(6)347). Heterocyclization of N- aryl-
pyrazoles involving a nitrene has already been discussed (Section 4.04.2.1.8(i)). Another
example, related to the Pschorr reaction, is the photochernical cyclization of (515) to (516)
(SOCJClSS0). An unusual transfer of chlorine to the side-chain of a pyrazole derivative was
observed when the arnine (517; X = H, Y = NH 2 ) was diazotized in hydrochloric acid and
subsequently treated with copper powder (72TL3637). The product (517; X = Cl, Y = H) was
isolated.
ON
N
s6
O
,N
sd
ç C0 2 Et
XCH 2 r N
Vò
Pyrazoles and their Benzo Derivatives
269
(ii) Alkyl groups
Lithiation on the N-methyl group of (334) has previously been discussed (Section
4.04.2.1.7(i). N- Vinylpyrazoles are polymerized by free radical initiators (B-76MI40402).
However, the rnost irnportant reactions of this section are the dequaternization reactions
of pyrazoliurn and indazolium salts (67HC(22)1, B-76MI40402), which have been extensively
studied by von Auwers. Pyrolysis of pyrazole quaternary iodides results in the loss of one
of the nitrogen substituents as alkyl iodide. The groups rnost readily cleaved are benzyl>
allyl> methyl> ethyl> propyl> phenyl. The therrnal decornposition of indazoliurn salts
produces mixtures of 1- and 2-alkylindazoles, the 1-isomer being generally predorninant.
These thermal dealkylations require reaction ternperatures of 200 0 C or higher and are
often accornpanied by extensive degradation and isomerization. Recently, several less drastic
methods of dequaternization have been described involving reagents such as triphenylphos-
phine, the thiophenolate anion under phase transfer catalytic conditions (78CR(C)(287)439),
and piperidine or 3-methylpyridine (80JHC905).
(iii) Acyl groups
The solvolysis of 1-acetyl-pyrazoles and -indazoles has been tudied by Staab et al.
(B-76MI40402) in connection with other azolides, specially l-acetylirnidazole. These corn-
pounds, for exarnple (131; Section 4.04.1.5.1), are useful acylating agents. N-Alkoxycar-
bonylpyrazoles (518) on heating in a polar, aprotic solvent yield N-alkylpyrazoles. The
mechanisrn of this alkylative decarboxylation (74JOC1909) involves the pyrazole anion and
a nuc1eophile such as r as catalyst. Butyl isocyanate transforrns the 2-ethoxycarbonylin-
dazole (519) into (520) with migration of the C0 2 Et group (77S804). 1-Cyanopyrazoles
(521) are relatively unstable compounds, readily hydrolyzed with formation of the car-
boxarnides (522) (70CB1954).
O
....N
N
I
/-C,
O/' OR
(518)
F3C ():J H2
NC0 2 Et
:::::,.., "'N/
(519)
OC NH2
F 3 C
I N
:::::,.., /
N
CONBuC0 2 Et
(520)
R 4 R 3
RSÇN
CN
(521)
R 4 R3
S O
R ...N
N
CONH 2
(522)
(iv) N-Oxides
The N-hydroxypyrazoles (523; R = H) and the pyrazoleN-oxides (268; Section 4.04.2.1.3
(xiii)) have been reduced to pyrazoles by rneans of zinc in acetic acid and catalytic hydro-
genation, respectively (75MI40402).
The OH group of (523; R = H) can be rnethylated (73JCS(P2)164), acetylated and tosylated
(74JOC2663). The reaction of the 2-hydroxyindazole (524) with diazomethane affords a
mixture of 0- and N-rnethylated products, (525) and (526) (81BSB645). Jones and coworkers
have studied the rearrangements of 1-methoxypyrazoles (523; R = Me) (73JCS(Pl)170).
R 4 R 3
RS O N
N....
OR
(523)
o:: Me
::;:.-
NOH
:::::,.., /
N
Me
OC ' N-O-
:::::,.., /+
N
H
o:: Me
::;:.-
NOMe
:::::,.., "'/
N
Me
N-O-
N/+
Me
(526)
(v) N-Amino groups
N-Aminopyrazoles (Section 4.04.2.1.3(xiv)) have been used for the synthesis of N,N'-
linked biazoles (527; R 5 = H, OH, OMe, Cl) and (528) (SOJCR(M)0514, 8IJHC957).
Vapour phase pyrolysis of sulfoxirnides (529) results in the formation of the nitriles (530)
(75JCS(Pl)41). The tosylate (273), when treated with acetic anhydride, rearranges to (531)
RSÇN ÇN R Me
I I R 3 CR 3 -n
N N cr5 ( c4 H2C-'-N;N
0 1 < N ' _ Ì7 N /' ::;:.- NN=SOMe I Me
II II :::::,.., "'N/ :::::,.., C N C0 2 Me
(528) (529) (530) (531)
(527)
---->.
..---
(524)
(525)
>
N-N
(532)
270
Pyrazotes and their Benzo Derivatives
(76CPB2267) and the oxidation of (277) with lead tetraacetate results in ring expansion to
give the 1,2,3-triazine (532) (79YZ699).
(vi) N -Nitro groups
The chernistry of N -nitro-pyrazoles and -indazoles has been developed by Habraken
and coworkers (B-76MI40402). I-Nitropyrazoles (Section 4.04.2.1.3(xiv)) rearrange to 4-
nitropyrazoles in sulfuric acid and thermally to 3(5 )-nitropyrazoles, rnaking these last
compounds readily accessible. All experimental data (76JOC1758) on the N - to C -isorneriz-
ation are cornpatible with a rate deterrnining [1,5] shift of N0 2 to give a pyrazolenine as .
an intermediate, which subsequently isomerizes to the 3(5)-nitropyrazole (Scherne 43).
R 4 R 3
O
/N
N
N0 2
[1.5I.NO,
R 4 R 3
02N 'F\
^_:1- N
H N
fast
R 4 R 3
O
02N ....N
N
H
Scheme 43
2-Nitroindazoles rearrange to 3-nitro derivatives on heating (7IJOC3084). Another impor-
tant property of N- nitropyrazoles was also discovered by Habraken (77JOC2893) who showed
that l,4-dinitropyrazoles undergo 'cine' substitution with secondary amines to give
arninonitropyrazoles (Scheme 44). Using pyrazoles as nucIeophiles this reaction affords
3(5)-(pyrazol-1-yl)pyrazoles (79JOC4156) and tripyrazoles (8IJHC559).
02 N
{
r _ _t;N
.. N
R 2 NH I
eN0 2
02 N
-NO, R D
. 2 N - --+
-w ""N
H N
02N O
R 2 N 7 ;N
N
H
Scheme 44
This reaction has been used as the key step in an original synthesis of formycin (80CJC2624).
Bya sirnilar rnechanisrn, via a 3H -indazole, the 2,5-dinitro derivative reacts with secondary
arnines to afford 3-amino-5-nitroindazoles (SOMI40404, 81JOC2706, 82PNA4487).
As Olah et at. have reported (8IJOC2706), N- nitropyrazole in the presence of Lewis or
Brønsted acid catalysts is an effective nitrating agent for aromatic substrates. The greater
lability of the N - N0 2 bond in N -nitropyrazole compared with aliphatic nitrarnines was
discussed on the basis of its rnolecular structure as deterrnined by X-ray crystallography.
(vii) Halogens
N -Chloro- and N -brorno-pyrazoles are unstable compounds, whilst N -iodopyrazoles are
stable (Section 4.04.2.1.3(xii)). These last cornpounds readily yield the iodoniurn ion, which
in turn acts as an iodinating agent. Thus, the forrnation of 3-iodo-4,5-dirnethylpyrazole
from l-iodo-4,5-dirnethylpyrazole (B-76MI40402) is explained. The different steps in the
chlorination of 3,5-diphenylpyrazole have been characterized (Scheme 45). The N -chloro
derivative (533) was fairly stable when stored at low ternperatures, but it was converted
into the isopyrazole (534) on standing for several hours at room ternperature (80JOC76,
82S844).
Ph
Ph O N
N/
H
--+
C o I Ph
Ph 7
N"N
H
--+
C O I Ph
Ph 7 N
N/
CI
(533)
--+
C1 2n Ph'
Ph . .;N
N.
(534)
Scheme 45
(viii) N -Metallic derivatives
Sodiurn and silver pyrazole salts (Section 4.04.2.1.3(vi)) are often used instead of neutral
pyrazoles to facilitate electrophilic attack on the ring nitrogen atorns. For exarnple, pyrazolyl-
rnethanes (234)-(236) have been prepared frorn pyrazole anions (Section 4.04.2.1.3(viii)).
Unstable 2-acetylindazoles are obtained from the reactive silver salts of indazoles (Section
4.04.2.1.3(x)). Electrophilic attack on the ring carbon atorns also occurs rnore readily in
Pyrazoles and their Benzo Derivatives
271
the anion than in the neutral molecule. For exarnple, brornination is often carried out on
pyrazole and indazole silver salts (Section 4.04.2.1.4(v)).
Pyrazoles bearing metalloid groups on the nitrogen atorn (Section 4.04.2.1.3(xv)) such
as SiMe3, GeMe3, SnMe3, GaMe2, etc., readily react with alkylating and acylating agents
to afford N -alkyl- and N-acyl-pyrazoles (80Z0B875, 8IJOM(215)349), respectively. Aldehydes
and ketones yield cornpounds (535) when treated with I-trirnethylsilylpyrazole
(8IJOM(208)309).
O
....N
N
I
R 1 -COS iMe 3
I
R 2
(535) (537)
The decomposition of (536) with hydrogen sulfide yields pyrazole (76T1909). The 1-
phosphorylpyrazoles (537) are suitable reagents for the phosphorylation of alcohols, arnines,
hydrazines and azides (76AG(E)378).
O
....N
N
HgCI
(536)
R 3
RSCN
N....
I
P-R'
0-::::' 'R 2
4.04.2.4 Pyrazoles, Indazoles and their Derivatives as Starting Materials for the Syntheses
of Fused Ring Systems
Fused ring systerns containing a pyrazole unit can be prepared either frorn the heterocyclic
moiety by forrnation of a pyrazole ring or from the reaction between a pyrazole derivative
and a suitably functionalized reagent. The ring systerns thus obtained are discussed in detail
in other chapters (Chapters 4.05, 4.35, 4.36) but it is of interest to discuss here those
methods which start from a pyrazole derivative as the reactions involved can be considered
as examples of the reactivity of pyrazoles. The most widely studied fused ring systerns are
the [5.6] systerns and the examples described in this section will be chosen from this group
and, occasionally, frorn [5.5] and [5.7] systerns.
The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic
ring is created between the arnino group and the I-position (if unsubstituted) or between the
amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-
difunctional corn pounds to afford pyrazolo[I,5-a]pyrirnidine derivatives (538) (Table 34).
Aminopyrazolinones (R 3 = OH) can be used instead of aminopyrazoles. Sirnilarly 3-arninoin-
dazole yields pyrirnido[l ,2-b ]indazoles (539).
RI c NnRÒ N J RI
N-N _Jk #
R2 N.... R 2
(538) (539)
This reactivity of N -unsubstituted arnino-pyrazoles and -indazoles which can be regarded
as 1,3-diarnino derivatives has been used to build a great variety of fused six-mernbered
heterocycles such as the 1,2,4-triazine derivatives (540) and (541), the 1,3,5-triazine
derivatives (542) and (543), and benzothiadiazines (544).
N
N.,;:/
I I ,IR3
N-d
N N R,(N n N ' (X i n
/kJR2 N N-J J JN S....N-N
N/ R! R 2 N.... R 2 O 2
(540) (541) (542) (543) (544)
When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon
atom, the reactivity of which is enhanced by the arnino group. Thus pyrazolo[3,4-b ]pyridines
(545) are obtained either by the Skraup synthesis or from 1,3-difunctional cornpounds.
Here also arninopyrazolinones have been used instead of arninopyrazoles to prepare (545;
R 3 = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of ß-ketoesters,
pyrazolo[3,4-b ]azepinones (546) are obtained.
When the pyrazole ring bears two adjacent functional substituents, it reacts like
an o-substituted benzene. For example, 4,5-diaminopyrazoles behave similarly to
272
Pyrazoles and their Benzo Derivatives
Table 34 Synthesis of Fused Ring Systems from Pyrazoles and Indazoles
Pyrazolo[ 1 ,5 -a lpyrimidine (538)
Ring system
2- Hydrox pyrazolo[1 ,5-a ]pyrimidine
(538; R = OH)
Pyrimido[ 1 ,2-b ]indazole (539)
Pyrazolo[ 1 ,5-c][ 1 ,2,4 ]triazine (540)
[1,2,4]Triazino[3,2-c ]indazole (541)
Pyrazolo[ 1 ,5-a][ 1 ,3,5]triazine (542)
[1,3,5]Triazino[1,2-b ]indazole (543)
Pyrazolo[1,5-b ][1 ,2,4]benzothiadiazine (544)
Pyrazolo[3,4-b lpyridine (545)
3-Hydrox pyrazolo[3,4-b ]pyridine
(545; R = OH)
Pyrazolo[3,4-b ]azepinone (546)
Pyrazolo[3,4-b ]pyrazine (547)
Pyrazolo[3,4-b ]quinoxaline (548)
Pyrazolo[3 ,4-b ][ 1 ,4 ]diazepine (549)
Pyrazolo[3,4-d][ 1 ,2,3 ]lriazole (550)
Pyrazolo[3,4-d]pyrimidine (552)
Pyrazolo[2,3-e ]diazepinone (553)
Pyrazolo[ 4,3-d]pyrimidine (554)
Pyrazolo[3,4-d]pyridazine (555)
Pyrazolo[3,4-e][ 1 ,2,4]lriazine (556)
Ref.
67CB2577, 70BCJ849, 70JHC247, 74JHC423, 77JHC155,
78JHC185, 79FES898, 80JCS(Pl)481, 8lJHC163,
81KGS1554
70CB3252, 79JHC773
76T493
76JOC3781
74JOCI833,76H(4)1115
73JHC885,76JHC1305
76T493
76JHC395
68AHC(6)347, 67AG981, 68CB3265, 70JHC247,
72JHC235, 75JHC517, 78JHC319, 79JPR881,
80JCS(Pl)938
79JHC773,80BSB51
79CJC3034
67TL2029
62JGU1876
77JHCI013
62JGU1876,75JHC279
70TL4611, 73JCS(Pl)1903, 75JHC1199, 76JOC3781,
79AP610
75MI40402
68LA(713)149,69TL289
69BSF2061, 69JPRI058, 70TL4611, 77JHC375, 77T45,
78JHC813
70JCS(C)1313
o-phenylenediarnine, yielding pyrazolo[3,4-b ]pyrazines (547) and the corresponding
pyrazolo[3,4-b ]quinoxalines (548). The last ring system can also be obtained frorn 0-
phenylenediarnine and 4,5-pyrazolinedione (68M2157). Sirnilarly, pyrazolo[3,4-b ][1,4]-
diazepines (549) have been prepared.
OQ Me R3
I N
o 1
(546)
However, there are differences between o-phenylenediarnine and 4,5-diarninopyrazoles
in the synthesis of [5.5] systerns. For exarnple, the forrnation of pyrazolo[3,4-d]-
[1,2,3]triazole (550) is sirnilar to that of benzotriazole, but all atternpts to extend the
synthesis of benzirnidazoles to the preparation of the irnidazo[ 4,5-c ]pyrazole system (551)
have failed (78TH40400).
H
N
R2/ Me
\\ y
N ...N
Ph
(551)
W R2 ...R3
.. \N
R 4 :>.. ."":)(
N N R 1
(545)
NH
N/ )1 Me
\\ y
N ...N
N
Ph
(550)
R I ( N )C N
R 2 I I
:>"N N
H
(547)
R 2 R J
N
R4 )l t
N H
(552)
N R 3
'ì0N
...J!--,J
N l
(548)
o Ph
(553)
t 4 __N R 3
)Q '\:N
/
-- N
R5 R1
(549)
N
R4r' "'ì0N
N N'
R 2 R 1
(554)
The pyrazole analogues of anthranilic acids or anthranilonitriles are a convenient source
of [5.6] fused systerns (for a general review see (80T2359)). Thus 5-arnino-4-cyanopyrazoles
(in sorne exarnples an ester or a hydrazido group replaced the cyano group) have been
transforrned into pyrazolo[3,4-d]pyrirnidines (552) and into pyrazolo[2,3-e ]diazepinones
(553), and 4-arnino-5-rnethoxycarbonylpyrazoles have been converted into pyrazolo[4,3-
d]pyrirnidines (554).
Pyrazolo[3,4-d]pyridazines (555) can be prepared readily frorn hydrazines and pyrazoles
substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups.
4,5-Pyrazolinediones have been used as starting rnaterials for the synthesis of the quinoxaline
derivatives (548) (see above) and of pyrazolo[3,4-e ][1 ,2,4 ]triazines (556)
Pyrazoles and their Benzo Derivatives
273
R 2 R 3
1'f N
N N
R 4 R!
(555) (556)
Pyrazolopyridines isorneric to those described previously have been obtained by other
methods. Thus, the derivative (558) was formed by Raney nickel reduction of the 4-
nitrosopyrazole (557) (7lJHC103S), and the pyrazolo[3,4-c ]pyridine derivative (560) was
prepared from the azide (559) (79CC627).
H
Me ON Me Me çq N e Et0 2 C æ Me
'I I I N I N
N.... O N....N N N 3 Me N '
H 0 H Me
(557) (558) (559) (560)
A heterocyclization involving the N-2 atom of indazole affords [1,2,4]triazino[4,5-b]-
indazoles (561) frorn the 3-carbohydrazinoindazole (78JHCl159, 79JHCS3). The corresponding
pyrazolo[1,S-d][1,2,4]triazine (562) has been prepared by the same procedure (8lJHC1319).
N Me
N?
R2 )L.N/N
Ph
Me
Et02C OC
N I N
I
N
Me
R 4 R 3 R 3
XJ rQ
a:t NH 0 :\5 LÒ
N.... NJ'N NH R 2 :
I
N_N N
(561) (562) (563) (564)
Some tricyclic systems have been prepared by intrarnolecular cyclization from N -aryl-
pyrazoles carrying substituents both in the pyrazole ring at C-S and in the phenyl ring at
the o-position. Tþus pyrazolo[l,S-a]quinazolines (563) (69JHC947) and pyrazolo[1,5-a]-
[1,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable pre-
cursors.
The Pschorr reaction has been ernployed successfully in the preparation of a pyrazolo[3,4-
c ]isoquinoline derivative (565) (78JHC1287).
Finally, some results obtained frorn indazoles substituted in the carbo cycle are of interest,
even though in these cases the reaction does not involve the heterocyclic moiety (Section
4.04.2.3.2(ii)). For exarnple, pyrazolo[3,4-f]- (566) and pyrazolo[ 4,3-f]-quinolines (567)
have been obtained from aminoindazoles by the Skraup s nthesis (76JHC899). Diethylethoxy-
methylenernalonate can also be used to give (566; R = C0 2 Et, R 2 = OH) (77JHC117S).
Pyrazolo-[ 4,3-f]- and -[ 4,3-g ]-quinazolones (568) and (569) have been obtained frorn the
reaction of formarnide with 5-arnino-4-rnethoxycarbonyl- and 6-amino-5-carboxyindazole,
respectively (81CB1624).
2): = R3
I N
I
o N N
Me Ar
(565)
.""
N 7"
I N
:::,.., I
N
H
( & 0
N 7"
I N
:::,.., N '
H
( 567)
(568)
o
HN :):)ç 1 N
:::,.., I
N N
H
(569)
4.04.3 SYNTHESIS
The synthesis of pyrazoles, indazoles and their derivatives generally follows classical
methods, the two most irnportant rnethods for practical purposes being the reaction between
hydrazines and ß-difunctional cornpounds, and 1,3-dipolar cycloadditions (Section
4.04.3.1.2). Both procedures are well docurnented (64HC(20)1, 66AHC(6)327, 67HC(22)1) and
thus the length of the sections in this part of the chapter reflects not only the number of
publications dealing with a particular method but also its interest and novelty.
274
Pyrazoles and their Benzo Derivatives
4.04.3.1 Ring Synthesis from Non-heterocycles
The different possibilities for the creation of the pyrazole ring according to the bonds
formed are shown in Scheme 46. It should be noted that this customary classification lacks
mechanistic significance; actually, only two procedures have mechanistic irnplications: the
formation of one bond, and the simultaneous formation of two bonds in cycloaddition
reactions (disregarding the problern of the synchronous vs. non-synchronous rnechanisrn).
One bond
-1-
CN ' COO\
b '
/N C N
N\ N N/
+, .j.
0'.N ("""k' -.,..:u.\
ii N : iii N
J'N\ N/ "N/
.j.
(:'.. C:,"\ ...... , k"
, ... ,
11 N ' 111
, /N " /N
IN N' N
Scheme 46
] 4+ 1
Two bonds
3+2
4.04.3.1.1 Formation of one hond
(i) Between two heteroatorns
The creation of the N - N bond as the last step of the ring synthesis is common in indazoles
and very rare in pyrazoles. In indazoles this method is well known (type B synthesis
(67HC(22)1), for example, the dehydration of oximes (570) with acetic anhydride yields
l-acetylindazoles (571), and in basic rnedium the indazole I-oxides (573) are formed from
the nitro derivatives (572).
a: Me (é Me (( CH CN Ar
r-' 1 '" NOH ;/ I N r-' I NHAr N:
:::,.., NH, :::,.., N :::,.., NO, b-
0\,
(570) (571) (572) (573)
The photochernical cyclization of anthranilonitriles (190; Section 4.04.2.1.2) yields
indazoles (ncc126). Reduction of o-benzonitrile with lithium alurninurn hydride yields
indazole (75ACS(B) 1089). 2-Arninoindazole (576) has been prepared in 94% yield from (574)
via the o-phthaloyl derivative (575; R 2 = o-phthaloyl) (72JOC2351). Sirnilarly, treatrnent
of the o-azidobenzanilide (577) with thionyl chloride affords 2-aryl-3-chloroindazole (578)
(79S308).
o
H II
0: ;:;:.- ((I CNHAr cç ;1
I "'NNR, NNR, NNH, NAr
" N :::,.., 0-..1 ,,0-..1 :::,.., 0-..1
........... 3 N.......... N . N 3 N
(574) (575) (576) (577) (578)
The 1,3-dioxime (579) with thionyl chloride yields the isopyrazole N -oxide (580)
(66CB618). A general method of pyrazole synthesis involving the creation of an N -N bond
has been described by Barluenga and coworkers (81JCS(PJ) 1891, 83JCS(P1)2273). Rigorously it
should be classified in Section 4.04.3.2.2(iii) since it involves a ring transforrnation. However,
the overall reaction goes from the l-azabutadiene (581) to the tetrasubstituted pyrazole via
the interrnediate 1,2,6-thiadiazine S-oxide (582) which loses sulfur rnonoxide therrnally.
R Me
RrN-OH
Me N
I
OH
(579)
(581)
R 4
R 5 ri/" : t 3
N, /NR 1
S
o
(582)
R' Me
Me0N
N+
I
0-
(580)
R 4
R50YR3
HN NHR I
Pyrazoles and their Benzo Derivatives
275
(ii) Adjacent to a heteroatorn
This ring closure is the final step of the reaction of hydrazines with 1,3-difunctional
compounds (Section 4.04.3.1.2(ii)), and nurnerous exarnples in the literature of pyrazoles
have been described. In sorne cases the N -C ring closure occurs by a concerted mechanism,
classified by Huisgen (80AG(E)947) as 1,5-electrocyclizations.
Sucrow, studying the chernistry of the enehydrazines (83CB1520), has found several methods
for the synthesis of pyrazoles. For example, he has described (79CB1712) the cyclization of
rnonornethylhydrazones of dialkyl oxalacetates to 5-pyrazolones via an enehydrazine
(Scherne 47).
ROzC COzR
ì=<
H NMe
/
HzN
---+
COzR
rl
ROzC N
HN/
I
Me
Scheme 47
---+
n COzR
Od-.,N;N
Me
The azine (583) of hexafluoroacetone adds the ynamine (584) to give the azetine (585).
On heating (585) in the presence of triethylamine it is converted into the pyrazole (586)
as indicated in Scherne 48 (75ZN(B)622).
",ex;'
F 3 C y CF 3 Me (F 3 Ch O Me I NEtz
C Me; I
...N + III ---+ ...N NEt z ---+ ...N
N C N N
NEtz )l )l
F 3 C CF 3 (584) F 3 C CF 3 F 3 C CF 3
(583) (585) 1
(CF 3 )zHC NEt z (CF 3 )zHC NEt z CF 3 hHC NEt 2
Hfl
d H D
/N ...- H r:r W ...- HN.....N
N
I )L )L
CH(CF 3 )z
(586) F 3 C CF 3 F 3 C CF 3
Scheme 48
Hart and Brewbaker have described the cyclization of 1,3-bis(diazopropane) to pyrazole
(Scherne 49) by a concerted, intrarnolecular 1,3-dipolar cycloaddition (69JA711).
HzC-CH:
NzCHCHzCHN z ---+ HJ- N ---+
' ..
---+ o
/N
N
H
Scheme 49
In indazoles there are two possibilities for ring closure by creation of an N -C bond,
depending on whether the bond is the N(2)-C(3) or the N(1)-C(7a) bond. Both are
classical methods of indazole synthesis (types A and C (67HC(22)1)). An exarnple of each
class is shown in Scheme 50 (785633).
C02H
.......NHz
N
H
---+
OH
?
H
NH
Vx kH
"-
Ph
---+
OH
(X) I N
I
N
Ph
x = halogen
Scheme 50
276
Pyrazoles and their Benzo Derivatives
Recently (82CC450) the conversion of aromatic hydrazides into indazolones in good yield
when treated with three equivalents of n- butyllithiurn has been described. For example,
benzoylhydrazine afforded indazolone in an 80% yield (Scheme 51).
a
H __
V NH 2
kid [q)l [CX; 1
a
-- JJH
N
H
Scheme 51
(iii) ß to a heteroatorn
The important synthesis of pyrazoles and pyrazolines frorn aldazines and ketazines belongs
to this subsection. Formic acid has often been used to carry out the cyclization (66AHC(6)347)
and N -formyl-il 2 -pyrazolines are obtained. The proposed mechanism (70BSF4119) involves
the electrocyclic ring closure of the intermediate (587) to the pyrazoline (588; R I == H)
which subsequently partially isomerizes to the more stable trans isorner (589; R I == H)
(Section 4.04.2.2.2(vi)). Both isomers are forrnylated in the final step (R' == CHO).
R 4
r:, I 3
"C R
w" C/
H \
("... C===;:(N'H
/
R' I
H
(587)
)j R4 R3
5 )N
R' R 1
(588)
)j R4 R3
5 )N
R R 1
(589)
Cl
X N
N/
I
CHCICC1=CXCI
(590)
The synthesis of 1,2-dimethylpyrazoliniurn salts from dirnethylhydrazine and carbonyl
compounds is thought to involve a rnechanism of the sarne type (71BSF1925). Pyrazoles (590)
have been obtained by thermal cyclization of azines derived from di- and tri-halogeno-
acroleins (77T2069). The dianion of benzyl phenyl ketazine, generated by treating the ketazine
with two equivalents of lithium diisopropylarnide, rearranged to 3,4,5-triphenylpyrazole
(78JOC3370). A new synthesis (7ITL1591) of 4-hydroxypyrazole-5-carboxylic acids (592)
entails cyclization of the hydrazones (591).
HO R 3
" /
O ,,:::.c-c
\\
ROlCCHl'M'N
I
R!
(591)
HO R 3
ROlC N
N
R '
(592)
Although forrnally it could be classified with the ring transformations (Section 4.04.3.2.2),
conversion of 2,4-diphenyl-1,3,4-oxadiazol-2-one (593) by flash vacuurn pyrolysis at 500 oC
into 3-phenylindazole (595) involves a C(3)-C(3a) ring closure of the diphenylnitrilirnine
(594) (79AG(E)721).
P O .....Ph oj
\\ Qm ?'" I \::N
N'N"'O """ .....N+ """ N
Ph l:-! H
(593) (594) (595)
The Frasca method for obtaining 1-arylindazoles also involves a C(3)-C(3a) ring closure
(67CJC697). It consists in the cyclization of p-nitrophenylhydrazones of ketones and aldehydes
with polyphosphoric acid. The Barone cornputer-assisted synthetic design program has
found several new rnethods for preparing indazoles (79MI40409). The selected method
involves the transforrnation of N' ,N' -diphenylhydrazides (596) into 1-phenylindazoles
(597) by means of trifluoromethanesulfonic anhydride. The yields vary frorn 2% (R 3 == H)
to 50% (R 3 =Ph).
Pyrazoles and their Benzo Derivatives
277
R 3
Q O"::-C/
I I
""" N.....NH
I
Ph
(596)
(XJ 3
I N
""" I
N
Ph
(597)
4.04.3.1.2 Formation of two honds
(i) From 4 + 1 atom fragments
The reactions described here are not synchronous and accordingly can be divided into
two successive steps, the last step belonging to one of the three classes of Section 4.04.3.1.1.
However, several syntheses of pyrazoles result from the reaction of two cornpounds, one
component contributing four atoms to the ring and the other the fifth atom. There are
three possibilities for 4 + 1 reactions shown in Scherne 46, but only those represented by
(ii) are described in the literature.
The synthesis of pyrazolines and pyrazoles of the [CCNN + C] type with the creation of
. two bonds, N(2)-C(3)+C(3)-C(4) (or N(1)-C(5)+C(5)-C(4)), has been studied by
several groups. Bearn and coworkers have published a series of papers on the synthetic
utility of lithiated hydrazones. Thus, the rnethylhydrazone of acetophenone (598) is conver-
ted by butyllithium into the dianion (599), which in turn reacts with methyl benzoate to
afford the pyrazole (600) (76SCS). In earlier publications Bearn et al. have used aldehydes
and acyl chlorides to obtain pyrazolines and pyrazoles by the same method.
Me, /Ph LiCH 2 , /Ph
C C
II II Ph
/N N PhON
HN LiN/
I I N/
Me Me Me
(598) (599) (600)
The stabilized phosphonium ylide (601) reacts with arornatic aldehydes to give N-
phenacylpyrazoles (602) in good yields (73CC7). Ketone semicarbazones and ketazines react
with two moles of phosphorus oxychloride-DMF, the Vilsrneier-Haack reagent, with the
formation of 4-formylpyrazoles (603; R 1 = H or PhC=CH 2 ) (70JHC2S, 70TL421S).
Ph 3 P=CH, Me Me OHC O R 3
C/
II An 7
/N r /N /N
N N
N CH 2 COPh R'
II
CHCOPh (602) (603)
(601)
R 4 R 3 eXr
Cl, + Me 0 I N
C=N...... Cl- Me 2 N /N """ N '
N
CI/ 'Me R 1 Ph
(604) (605) (606)
Viehe and coworkers have used dichloromethylenearnmonium salts (604) to obtain
5-dimethylaminopyrazoles (605) from N -rnethylhydrazones (74AG(E)79). The same reagent
(604) affords 3 -dimethylaminoindazoles (606) by reaction with N,N- diphenylhydrazine
(73AG(E)40S).
(ii) From 3 + 2 atom fragments
(a) [CCC + NN]. The standard method of synthesis of pyrazoles consists in the con-
densation of a 1,3-difunctional cornpound with hydrazine or its derivatives (Scheme 46;
[3 + 2], i). A review has been published on this subject (70BSF2717) and many exarnples rnay
be found in (64HC(20)1, 66AHC(6)347, 67HC(22)1, SOCHE1). A typical experiment is the forrnation
of 1,3- and 1,5-dimethylpyrazoles frorn the reaction between rnethylhydrazine and 4,4-
dimethoxy- 2-butanone (Scheme 52). The structure of both isomers has aroused much interest
278
Pyrazoles and their Benzo Derivatives
in the past (see Appendix 1 of B- 76MI40402) and the reaction has been studied using the
rnethodology of design of experirnents (nBsFl163) which has allowed the deterrnination of
the effect of seven factors on the yield and selectivity of this reaction.
w
MeCOCH 2 CH(OMe)2 + MeNHNH 2 -
O Me
V
/N
N
Me
+ MeCN
N
Me
Scheme S2
Although rnost syntheses of the pyrazole ring use hydrazines and hundreds of publications
have been devoted to this method, it must be acknowledged that the mechanisrn of the
reaction is still only partially known and the structural reasons that favour one or the other
isomer are not clearly understood. The complexity of the problern appears when considering
that a 1,3-dicarbonyl compound, for exarnple, can react in six different ways with a
nucleophile (taking into account both carbon atorns of the ß-diketo tautomers and the two
enols) and that hydrazines have two nucleophilic centers. Thus, there are 12 different
possibilities to initiate a reaction which finally ends in only two different compounds. Under
neutral or acidic conditions and if the nucleophilicity of the two nitrogen atoms of the
hydrazine is very different as in 2,4-dinitrophenyl, tosyl and acetyl derivatives, the most
abundant isorner corresponds to the 1,2-addition at the terrninal NH 2 group of the hydrazine
to the most reactive carbonyl group of the ß- dicarbonyl compound (CO C0 2 R > CO R >
COAr).
Phenylhydrazine reacts in basic rnedium at the N-1 atorn of the conjugate base, PhNNH 2 ,
with a,ß -unsaturated ketones, esters, acids and nitriles. In neutral or acidic rnedium it
reacts at the N-2 atorn of the neutral rnolecule, PhNHNH 2 (70BSF2717). This proprty has
been used to obtain a specific isomer, for exarnple, of pyrazolidones. The rnechanism of
the fl2 -pyrazoline ring formation from a,ß -unsaturated carbonyl cornpounds and hydrazines
has been examined with regard to the stereochernistry of the 4- and 5-positions in the
product (73JCS(P2)936). There is no relationship between the E/ Z configuration of the alkene
and the stereochernistry of the resulting pyrazoline (73BSF3401), since the configuration at
C-4 results frorn the protonation of a common intermediate, the fl3 -pyrazoline (607; Scheme
53).
R S
\ I
C=C
I \
H C-R 3
II
o
(E)
R 4 .
R 4
R)'-_l3
R S,,(N;N
R 1
+
R'NHNH,
R S
\ I
C=C
HI 'c- R 3
II
R1NHN
+
--+
R 4 R 3
--/\NH
RS^N)
R 1
(607)
w
-
+
H R 4
\ I
C=C
I \
R S I. C - R3
Ó
(2)
H R 4
\ /
C=C
I \
R S C-R 3
I;
R1NHN
R R3
R sÁN;N
R 1
Scheme S3
From the large arnount of data available in the literature on this reaction, the most
significant references are reported in Table 35; for references before 1970 see (70BSF2717).
Owing to their particular interest two individual reactions will now be discussed separately.
The reaction of rnethoxycarbonylhydrazine and 3-brorno-2,4-pentanedione affords, in addi-
tion to the expected pyrazole (608), a pyrazolium salt (609), the structure of which was
established by X-ray crystallography (74TL1987). Aryldiazonium salts have been used instead
of arylhydrazines in the synthesis of pyrazolines (610) and pyrazoles (611) (82JOC81). These
compounds are formed by free radical decomposition of diazonium salts hy titanium(II)
chloride in the presence of a,ß-ethylenìc ketones.
Me
Me['JN+
N/ 'NH
I I
/NH C0 2 Me
McO,C
(609)
B Q Me
Me V N
N/
CO,Me
(608)
Br-
A U r Me2
MeV NH
N/
Ar
Ar R J
Me O N
N/
Ar
(610)
(611)
Table 35 Syntheses of Pyrazoles from Hydrazines
1,3-Difunctional compound (a) NH 2 NH 2 (b) R INHNH2 (c) R INHNHR2 (d) R 1 R 2 NNH 2
"- I / I I I CNH CNH ÇN'R 2
L C=C-C=C , Br-C-C-C-Br
/ I "- I I I N N
H I I
R' R I
CH 2 -
"- "- QN
2. C=C-C::=C-, -C-C::=C-
/ I / N
CI c
H
""
"- I ON ON [9 N l Q 'R 2 QN
;:s
3. C=C-C=O s::...
/ I N N .....
N I I /'-. ';:S-
H R' R 1 R I R 2
:;;.
0 0 d:, 0
0
dH dH ç5N H ;:s
"- ,f' O NH N
4. C=C-C c
/ I "- 0
OR N N N N R2
H I , I 1/ 2 .
R' R' R' R R
d:., c::;'
oNH 2 Û H2 CS H2
"- HN NH ""
5. C=C-C::=N
/ I N/N /N +/N
N N N
H 'I , I /'-.
R R' R' R I R 2
CH 2 - CH 2 -
6. -C::=C-C::=C- ON ON -H CDN
N/ N 2 N
H I I
R' R 1
N
-.}
1.0
tv
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0
Table 35 (continued)
1,3-Dífunctíonal compound (a) NH 2 NH 2 (b) R 1 NHNH 2 (c) R 1 NHNHR 2 (d)R'R 2 NNH 2
I "- I I
-C:=C-C=O, C=C-C=O Q 0 0 [ 9 N ]
/
7. X /N /N N/ '
0 N R 2
H I I
/ "- / R 1 R 1 R 1 R 2
-C:=C-C-C . X = Cl, SMe, NMe2 i:$
I "- N
0 c
OH H (\)
0 RO /0 oDN 0 O--C)N o .J:;;N "- '"
,;- !::>
8. -C:=C-C , C-C:=C-C N/N ;:s
N
"- ,;- "- H I I I R 2 1/ , 2 ...
OR 0 OR R 1 R 1 R I R R ;:s-
<1>
:::;.
f b::J
"- <1>
cfHl ;:s
-C:=C-C:=N, C=C-C:=N H 2 NO N
/ 0 r \ c
9. X H 2 N "N /N 0
N N <1>
, I , I H I I ;:';.
C=C-C:=N, C=C=C-C:=N R 1 R 1 <::
/ / !::>
...
C:;'
0 <1>
I 0 0 '"
10. -C-C-C- N/N N/N N/ 'Rl
II I II
0 0 H I I
R 1 R 1
I ,;-0 OI;)N OH oDN o -:ÇN , -o-QN
0
11. -C-C-C N"N
II I "- N R l
0 OR H I I I /,
R 1 R 1 R 1 R1 R l
Table 35 (continued)
1,3-Difunctional compound
(a) NH 2 NH 2
(b) R 1 NHNH 2 (c) R 1 NHNHR 2 (d) R J R 2 NNH 2
ONH 2 H 2 NCN [H'NQN J
r \
N.....N N
I] ,] )/ " 2
R R R R
0 0
o.;:;5NH o.;:;5N, 2
I I R N
C
R! R 1 -
"'
""
J:JNH2 dO
J:JNH2 ::!
s::...
o 'N H 2 N r NH ...
o N/N'R 2 ;:s-
N/ N/ "'
I I I :;0'
R! R 1 R!
"'
::!
QNH 2
r \ 0
H 2 N /N "'
;:!.
I <::
!:?
R! (:;'
<1>
""
12.
I
-C-C-C:=N
II I '
o
CN
"C=C/
/ "
X CN
X = OEt, NHAr
0 '
H 2 N /N
N
H
13.
o 0
I ..f'
C-C-C
/ I "
RO OR
o
oDH
N
H
14.
o
I
C-C-C:=N,
/ I
RO
o S
I ..f'
C-C-C
/ I "
RS NR 2
NH2
O N;N
H
15.
I
N:=C-C-C:=N,
I
EtO EtO
" I
C-C-C:=N
Þ I '
HNf'
O NH 2
r \
H 2 N /N
N
H
NH
" I ..f'
C-C-C
..f' I "
HN OEt
1. Most synlheses start from 1,3-dibromopropanes (67HC(22Jl). 1a. The pyrazolidine obtained from dienes is further oxidized. Ic. (75JHCI233). 2a. A 2 -Pyrazolines from chloroalkynic compounds
(70Z0R90S). 3b. The A 4 -pyrazoline is not isolated since it is oxidized to pyrazole (74AJC2041). 3d. (76BSF476). 4. (SOCHE1). 4d. (76BSF476, 7SBSF(2)602. SOAJCI365). 5. (SOCHEI). 5d. (76BSF476). 7a.
(75S79S, 76JHC455). 7b. (73CB3092. 76JHC257. 76JHC455. 79H(12)657, 79JCR(M)2921). 7 d. The non-aromatic pyrazolium salt has never been isolated, since il decomposed to 1-substiluted pyrazoles by
loss of R 2 X (70CHEI32I) or to open-chain compounds (79JCR(M)2921). 8. (SOCHEI). 8b. 3-Methoxycarbonylpyrazolones have been prepared from acetylenedicarboxylic esters (74JCS(P1)297). 8d.
(75AG(E}560. S3CCI144). 9a. (76S52. 79TL299I. SIJCS(P1)2997). 9b. (75JOCISI5, 76S52). 10. Reactions of 1,3-cyclohexanedione with hydrazines (73CB745). lOa. For Reichardt's synthesis of 4-fluoro- and
4-t-butyl-pyrazoles from substituted malonic aldehydes, see (75LA470, 75AG(E}S6); for synthesis of bis-pyrazoles by this method, see (7SM337). lOb. 4-Fluoro- and 4+butyl-pyrazoles (74CB3454,
75AG(E)S6}. 10c. 4-Fluoropyrazolium salts (75LA470, 75AG(E}S6); for the synthesis of bicyclic compounds by this method, see (S2JOC295); for the reaction of diazetidinone as 1,2-disubstituted
hydrazine, see (SIJA7660). 10d. Formalion of mono- and di-substituted hydra zones. 11. (SOCHEI). lId. (70JHC923. S2JHCI215). 12. (SOCHEI). 12a. The aminopyrazole reacts further with the
ketonitrile to afford condensed pyrazoles (7SJHCIS5); for the synthesis of aminopyrazoles from enaminonitriles, see (SIMS75). 12b. (SOJHCI527). 12d. A I-substituted 5-aminopyrazole has been
isolated by dequaternization of the 1,I-disubstituted salt (7ICB2053). 13b. (75AJCI33). 14. Dialkylaminopyrazolones have been prepared from thioamides (70LA(734)I73). 15. Malononitrile itself
yields 5-amino-4-cyano-3-cyanomethylpyrazoles, the iminoethers being necessary to obtain 3,5-diaminopyrazoles (64JOC942, 6SJOC2606); 3,5-dimethylaminopyrazoles have been prepared from
dichloromalonyl cyanines (74JOCI233).
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282
Pyrazoles and their Benzo Derivatives
Indazoles can also be prepared by the [CCC+ NN] method. For instance indazolones
have been obtained rather simply by the action of hydrazine hydrate on 2-halobenzoic
esters (7SS633).
(b) [CCN + NC]. No definite exarnples of this way of forrning the pyrazole nucleus are
described in the literature. The closest example is the transformation of N -substituted
anilines (612) into I-substituted indazolones (613) via the carbamoyl azides (614) or the
isatin (615) (7SS633).
(613)
R -o l /CONJ
:::".. N
I
R'
(614)
R O
V--N r
R'
R-o NH
I
R'
(612)
-oc H
R I N
:::".. N '
R'
(615)
(c) [CNN + CC]. This section is second in irnportance to the use of hydrazines for
preparative purposes, but it is the rnore important one from the theoretical and mechanistic
point of view. More diversified than the section dealing with hydrazines, it has the advantage
of having been treated in several comprehensive reviews and books (Table 36) to which
the reader should refer for the original literature references. Most of these syntheses of
pyrazoles and pyrazolines have been known for a long time and many exarnples are described
in (67H022)1).
Table 36 General References to Pyrazole Syntheses of the [CNN + CC] Class
Title
Ref.
B-64MI40400
B-7 SMI40404
B-7 SMI40405
74AG{E)47
74AG(E)627
76S349
79AG(E)721
SOJHCS33
1,3-Dipolar cyc1oadditions to alkenes
1 ,3-Dipolar cyc1oadditions to alkynes
Synthetic applications of diazoalkanes
Thermal pericyc1ic reactions
1,3-Anionic cyc1oadditions
Reactions of azines and imines (including 'criss-cross' cyc1oadditionJ
1,3 - Dipolar cyc1oreversions
Hydrazoyl halides
Diazo compounds react with alkenes to afford il 1 -pyrazolines, which in turn izomerize
to il 2 -pyrazolines if there is a hydrogen atorn ex to the N =N bond (Scheme 54). In those
cases where two possible ways of isornerization exist, the rnore acidic hydrogen migrates
preferentially. The alkene configuration is conserved on the il 1 -pyrazoline (stereospecificity)
but the regioselectivity depends on the substituents of both the alkene and the diazo
cornpound.
Me'C/COzMe
II + CHzN z
H/C'COzMe
MeOzC COzMe
H+-\-Me
(_ N
N
MeOzC COzMe
--+ H++Me
_jNH
N
MeOzC COzMe
Me++H
( N
N
MeOzC COzMe
--+ MeH
(__;N
N
H
Scheme 54
Pyrazoles are formed when the diazo cornpounds react with alkynes or with functionalized
alkenes, viz. the enols of ß-diketones. Pyrazolenines (353; Section 4.04.2.2.1) are isolated
from disubstituted diazornethanes. Many pyrazoles, difficult to obtain by other methods,
have been prepared by this procedure, for example 3-cyanopyrazole (616) is obtained frorn
cyanoacetylene and diazornethane (7IJCS(C)2147), 3,4,5-tris( trifluorornethyl)pyrazole
(617) frorn trifluorodiazoethane and hexafluoro-2-butyne (SlAHC(2S)1), and 4-phenyl-3-
triflylpyrazole (618; R 1 =H) from phenyltriflylacetylene and diazomethane (82MI40402). An
excess of diazomethane causes N -methylation of the pyrazole (618; R 1 = H) and the two
isomers (618; R 1 = Me) and (619) are formed in a ratio of 1: 1.
Pyrazoles and their Benzo Derivatives 283
OCN F3bCF3 PbS02CF3 Ph Et 2u C0 2 Me
y . y y 0 Me y N
....N l-3 C ....N ....N CF 3 S0 2 ....N
N N N N N....
H H R! Me H
(616) (617) (618) (619) (620)
Since 1,3-dipolar cycloadditions of diazornethane are HOMO (diazornethane)-LUMO
(dipolarophile) controlled, enarnines and ynarnines with their high LUMO energies do not
react (79JA3647). However, introduction of carbonyl functions into diazornethane makes
the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylarninopropyne
furnished the aminopyrazole (620) in high yield.
The theoretical interest that these reactions aroused was enorrnous. Presently 1,3-dipolar
cycloadditions are one of the cornerstones of theoretical chernistry and many references
are to be found in the publications quoted in Table 36. For sorne recent publications related
to this chapter see (78JA5701, 79TL2621, JST(89)147).
Nitrilirnines (621) are another class of 1,3-dipoles which provide a useful entry into the
pyrazole ring. They are often generated by cycloreversion (79AG(E)721) of tetrazoles,
triazolopyridines and oxadiazolones (79JOC2957) (Scheme 55). Pyrazolines of known
stereochernistry, pyrazoles and indazoles (Section 4.04.3.1.1(iii)) have all been prepared
from nitrilimines.
R 3 R 3
N'N....N NN
R' ,H,Nj R'
o R 3
/
O ....N
N
R 1
- + - +
R 1 N-N=CR 3 R!N-N=CR 3
(621)
1 R4C=C ' = Ph
Ph
(Xj l
ì'
N
H
(595)
R 4 CH=7
R 4
R 3
R s.J:)N
R 1
R 4 = R S = C0 2 Me (trans)
R 4 = H, R S = CN, C0 2 Me
R 4 R 3
RS O N
N....
R!
R 4 = R S = C0 2 Me
R 4 = C0 2 Me, R S = Ph
Scheme 55
Azomethines add with great ease and stereospecificity to carbon-carbon double bonds
affording pyrazolidines. They also add to carbon-carbon triple bonds with the formation
of pyrazolines. Benzirnidazolium N -imines, e.g. (622), are a special case of azornethines.
Its reaction with DMAD yields 1-(2-methylaminophenyl)pyrazole (624), which is forrned
by cleavage of the initial adduct (623) (75JHC225).
Me
MeN Ñ-ÑH
Ö
Me C!./\C 02Me
Me J
Me-N if 'H
Ö
(623)
(622)
Me0 2 C O C0 2 Me
y
Me ....N
N
MeNH ò
I
(624)
Burger's 'criss-cross' cycloaddition reaction of hexafluoracetone-azine (76S349) is also a
synthetic rnethod of the [CNN + CC] class. In turn, the azornethines thus produced, (625)
and (626) (79LA133), can react with alkenes and alkynes to yield azapentalene derivatives
(627) and (628), or isornerize to fl4 -pyrazolines (629) which subsequently lose HCF 3 to
afford pyrazoles (630; Scheme 56) (82MI40401).
284
Pyrazoles and their Benzo Derivatives
(CF 3 ) 2
Me 2 ÇN-
II
C
F 3 C/ 'CF 3
(625)
Me
H,C=< /
y
F 3 C, /CF 3
C
II
/N
N
II
C
F 3 C / 'CF 3
R R
, /
C=C
H/ 'H
)
R (CF 3 )2
ROW
N
II
C
F 3 C/ 'CF 3
MC-C=C
MH CF ) 2
EtO(+,...N-
N
II
C
F 3 C/ 'CF 3
(626)
Scheme 56
Me
/
H,C=C,
Me
(CF 3 )2
Me 2 Q O N
Me 2
(F 3 C)2
(627)
R O ( CF 3) 2
-----. R ,...NH
N
I
/C
F]C CF 3
(629)
RC::CR
R (J CF 3
-----. R ,...N
N
I
/CH
F 3 C 'CF 3
(630)
Me o (CF 3 ) 2
EtO O N
N //
(F 3 C)2 R
(628)
Hydrazoyl halides are useful reagents for the synthesis of pyrazolines and pyrazoles
(SOJHCS33). The elirnination of HX, usually with triethylarnine, is now the preferred rnethod
for the generation of the nitrilirnine (621) in situ. Although in sorne cases it is not clear if
the rnechanisrn involves a nitrilirnine (621) (as for exarnple in the Fusco rnethod in which
sodiurn salts of ß-diketones are used), in other reactions it is the rnost reasonable possibility.
For exarnple, the synthesis of pyrazolobenzoxazine (633) frorn the hydrazoyl halide (631)
probably occurs via the nitrilirnine (632). Trifluorornethylpyrazoles (634) have been pre-
pared by the reaction of a hydrazoyl halide and an alkynic compound in the presence of
triethylarnine (S2H(19)179).
Ph
I Ct..... /C0 2 Et
C C
III II
C .....N
[J:
U
(631)
Ph
I .....C0 2 Et
C +C
III II
(C Ñ/ N
0.......... 6
I
(632)
(ÿ Ph COlEt
1
,N
N
o
U
(633)
(J CF 3
Ph 1 N
6
(634)
Monosubstituted hydrazones react with alkenes and alkynÎc cornpounds to yield
pyrazolidines and pyrazolines, respectively (71LA(743)50. 79JOC21S). Oxidation often occurs
during the reaction and pyrazoles are isolated as the end product.
4.04.3.1.3 Formation of three honds
Pyrazolines can be prepared frorn the reaction between a hydrazine and two carbonyl
cornpounds, one of thern having at least one hydrogen atorn a to the carbonyl group.
Forrnally, these reactions correspond to the [NN + C + CC] class. However, if one considers
the different steps in the ring forrnation, they rnore properly belong to the [CNN + CC]
(Section 4.04.3.1.2(ii)), the [CCNN + C] (Section 4.04.3.1.2(i)), or the forrnation of one
bond (Section 4.04.3.1.1) classes.
The synthesis of ß3-pyrazolines by reaction of a 1,2-disubstituted hydrazine, formalin and
a carbonyl compound, known as the Hinrnan synthesis, probably proceeds by the rnechanisrn
shown in Scherne 57 (69BSF3300).
Pyrazoles and their Benzo Derivatives
285
R1NHNHR Z
HCHO
-.
H C=Ñ-NHR 2 X-
Z I
R 1
R'COCH,R 4
)
R 4 R 3
O NR Z X
N/+
R 1
-XH
----+
R 4 R 3
G N R 2
N/
R 1
Scheme 57
When two moles of a carbonyl compound are used instead of formalin, the mechanisrn
is different (Scherne 58) (70BSF3147). In one exarnple (80CCC2417) the product of the
nucleophilic addition of the hydrazine to the pyrazolinium salt (635; R 1= R 2 = Ph, R 3 = R 4 =
H) has been isolated (636). With monosubstituted hydrazines and aldehydes, D.? -pyrazolines
(637) are forrned (69CHE80S).
R 1 NHNHR 2
R'COCH,R 4
R 4 H C
2" +
C=N-NHR 2 X-
R / I
R 1
-XH
R 4 CH
\;-NNHR z
/ I
R' R 1
R 4 R 3
R 3 ";:;N R 2
4 N/
R HzC R 1
-XH
+-
R 4 R 3
R 3 -n
.;N X-
R4H z C / + 'R z
R 1
(635)
1 R'COCH,R 4
R 4 HC CHzR4
- -N-N=C/
/ I I " x-
R' R 1 R 2 R 3
Scheme 58
Ph
I
NNHPh
Me d NPh
N/
Ph
(636)
R
RCHl:]N
N
R 1
(637)
4.04.3.2 Ring Synthesis from Heterocycles
4.04.3.2.1 Ring opening
Pyrazoles can be prepared by ring opening reactions of fused systerns already containing
the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been
opened to substituted pyrazoles, usually in basic mediurn. In general, the rnethod has little
preparative interest since another pyrazole derivative has usually been used to build the
ring-fused system. However, due to the unexpected structures obtained, two publications
are worthy of notice. 6H -Cyclopropa[5a,6a]pyrazolo[1,5-a]pyrirnidine (638) was readily
obtained frorn the corresponding pyrazolopyrirnidine by the action of diazomethane at
room ternperature (Scherne 59) (81H(lS)26S). When (638) was treated with potassiurn
hydroxide, the pyrazole (640) was forrned, probably via the diazepine (639).
NC N
Ç(JAC
C0 2 Et
a :, Jç() , ]
EtOzC l HO CO 2
(638) (639)
Ac
MeO
N
---+ 0 C02H
NC r
/N
N
H (640)
Scheme 59
Other still rnore unusual structures were obtained in the reaction of the 3a,6a-diazapen-
talenes with DMAD (78CLl093). Depending on the substituents on the diazapentalene (641;
R 1 =R 2 =H or R 1 =COAr, R 2 =Ar), the rearranged 1:2 adducts (642; E=C0 2 Me) and
(643; E = C0 2 Me), respectively, were obtained.
286
Pyrazoles and their Benzo Derivatives
R'
CtJR 2
+ -
(641)
E N,N
E H
E E
(642)
B Ar COAr
H
E ;N
E
E' II
E
(643)
4.04.3.2.2 Ring transformations
The transforrnations between pyrazole derivatives of different oxidation levels, i.e.
between pyrazolones and pyrazolines, will not be discussed here since they have been
exarnined in the reactivity sections (Section 4.04.2).
The richness and cornplexity of the present section is considerable. Alrnost any heterocycle
conveniently substituted can be transforrned into another chosen ring systern, and this is
shown in the two excellent volurnes of van der PI as ('Ring Transforrnations of Heterocycles')
(B-73MI40402). The arrangernent of the aforernentioned book (frorn the starting heterocycle
point of view) does not suit this section and for the purposes of this chapter an alternative
classification has been selected. When no explicit references are given, the rnaterial has
been taken frorn (B-73MI40402).
(î) Masked ß-difunctional compounds
Pyrazoles have been prepared by the action of hydrazines on heterocyclic derivatives
which react as rnasked functional groups of a 1,3-difunctional derivative (Section
4.04.3 .1.2(ii)).
(a) One functional group. A carbonyl group can be replaced by a three-mernbered ring,
usually an oxirane (73BSF3159) or an aziridine (74JHCI093), or by a ß-substituted pyrrole or
indole derivative (67HC(22)1). In Scherne 60 two classical exarnples are shown.
HO
CNH-
N
R'
C1CH z \7
o
R 'NHNH,
O
N/N
R 1
00 coMe
7' I '
N
H
NH,NH,
Scheme 60
(b) Both functional groups. Most of the ring interconversions forrning pyrazoles involve
the action of hydrazine upon heterocycles which function as rnasked 1,3-difunctional
corn pounds (B-73MI40403). These include 1,2-dithioliurn salts, isoxazolinones, oxazoles
(77JCR(S)140), furoxans, pyryliurn salts, benzopyryliurn salts, dehydroacetic acid, 1,3-oxazine-
2,4-diones (82JCS(P1)473), pyrirnidines (76JCS(P2)315), thymine, cytosine, uracil (81CPB3760)
and 1,7- and 1,8-naphthyridines.
(in Bimolecular reactions
In this section forrnation of pyrazoles from the reaction of heterocycles with cornpounds
other than hydrazines will be discussed.
(a) Sydnones. Owing to their preparative and fundarnental irnportance, sydnones have
been classified separately. Mesoionic anhydro-5-hydroxy-1,2,3-oxadiazolium hydroxides
(sydnones) (76AHC(19)1, 81CB2450) react with alkenes and alkynes to afford pyrazolines and
pyrazoles with evolution of carbon dioxide (Scherne 61). With benzyne, 2-substituted
indazoles are forrned. Isosydnones react sirnilarly (76AHC(19)1).
(b) Others. Therrnolysis of 2,5-diphenyltetrazole yields, with nitrogen evolution,
diphenylnitrilimine (621; R 1 = R 3 = Ph), a useful source of pyrazolines and pyrazoles (Sec-
tion 4.04.3.1.2(ii)). The following interesting reaction belongs to this section. Anthranils
react with anilines to yield 2-arylindazoles. Hydrazine behaves as a diarnine this reaction,
affording a 2,2-diindazolyl derivative (Scherne 62).
Pyrazoles and their Benzo Derivatives
287
(R 4 CH=CHR '
R5 _-+-/N -
N
R 1
I O
) (r) ;S
NR 1
"'- I
N
Uii) Monomolecular rearrangements
This section includes therrnal and photochernical rearrangernents of heterocycles to
pyrazoles without using any other reagent. It is probably the most interesting part but also
the rnost diversified and difficult to summarize. Two exarnples have already been rnentioned:
the rearrangernent of 1,2-diazepines (Section 4.04.2.3.9) and sulfur rnonoxide extrusion
from thiadiazine S -oxides (Section 4.04.3.1.1 (i)). Other exarnples are shown in Figure 31.
They include the isornerization of vinylaziridines (644) to pyrazoles (645) and of 5-
arninoisoxazoles (646) to pyrazolones (647). The anion (648) derived frorn 6H -1,3,4-
thiadiazine undergoes sulfur extrusion at low ternperatures yielding the pyrazole (649)
(75TL33). Photolysis transforms dipolar irnines (650) into N -ethoxycarbonylpyrazoles (651)
(76CC250). 1-Cyanopyrazole (653) has been obtained in 62% yield frorn 2-azidopyrirnidine
(652), via the 2-pyrirnidylnitrene (81AHC(28)232).
N R 3 R 3 R 3
XCH=CH2 ---. eN H 2 NCN ---.
N 0
H
(645) (646)
R 4 R 3
O
R S N
N/
R 1
CH2=.: C
(ChIOr7
CN
RSnN
N)
R 1
(C) :::o-
o + NH 2 NH 2
02 N r.{
(644)
R 4 C",CR'
R 4 R 3
RS O N
N/
R 1
Scheme 61
(ç :::o- I C;() '" N0 2
---. N-N
02 N "'- I .-::;
N
Scheme 62
R 3
O N H
H
(647)
R4 C - R3 R4 R 3
:-:'1 2. 7
R S "'N;N RSCN
H
(648) (649)
CH=NR 1
N R 4 R 3 CN O:N, 0::
R( )R4 hv -N,
---+ (J ::>-'N JN3 -- 0 "...2 ---. NR I
.Q R 3 -RCN N/N N/N R ".../
Ñ R N0 2 N
_I C0 2 Et CN
NCOzEt (651) (652) (653) 0-
(650) (654) ( 655)
---. I k Ho l .....?
NH2 N,O N/
H
(656) (657)
(X) NHCOPh
I
N
Me
(659)
R ) ---.
N R Z
'0
(662)
Synthesis of pyrazoles and indazoles by ring transformation
X Me
N ":N-N.....
Phil .......Ph
"- /N
o
(658)
R 1 NH
J ) R'
'0
(660)
---.
HCOR'
z..... ;N
N
R 1
(661)
Figure 31
o; NHCOR 2
I N
/
N
R 1
(663)
288
Pyrazoles and their Benzo Derivatives
A series of rearrangements involving oxygenated azoles (however, see 430 ----.431, Section
4.04.2.3.l(vi)) related to the BouIton-Katritzky rearrangernent yielded pyrazoles and
indazoles, for example, the transforrnation of benzofurazan oxides (654) into indazoles
(655) (SOJOCI653). The treatrnent of 3-(0-aminophenyl)-1,2-benzisoxazole (656) with
lithiurn alurninurn hydride affords the hydroxyphenylindazole (657) (74JHCSS5). The N-
rnethyl-N -phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (658) undergoes a
rearrangement to (659) with loss of benzonitrile (S2JCS(P1)165). The transforrnation
(660) ----. (661) can be used to prepare 3-acylamino-Ll 2 -pyrazolines and the related reaction
(662) ----. (663) affords 3-acylarninoindazoles (S2JCS(P1J759).
4.04.3.3 Best Practical Methods
4.04.3.3.1 General methods
In the synthesis sections (4.04.3.1 and 4.04.3.2) the rnore useful rnethods to obtain the
heterocycles which this chapter covers have been described. Table 37 contains a list of
cornpounds described in Organic Syntheses.
Table 37 Pyrazole and Indazole Derivatives Described in Organic Syntheses
Compound
Ref.
51OS(31)43
6S0S(4S)S
4S0S(2S)S7
490S(29)54, 590S(39)27,
620S(42)69
400S(20)73
6S0S( 4S)113
3,5- Dimethylpyrazole
3-Aminopyrazole
3-Amino-1-phenyl-5-pyrazolone
Indazole
5-Nitroindazole
2-Phenylindazole
Most of these cornpounds, for instance pyrazole itself, are today cornmercially available,
so there is only a rninor interest in detailing the experirnental procedures used. The best
way to prepare pyrazole is the Protopopova rnethod (Section 4.04.3.3.2) and a rnodification
using hydrazine hydrate instead of a hydrazine salt has recently been patented
(SOGEP2922591).
4.04.3.3.2 Nuc/eosides
Arnongst the N -substituted azoles, the nucleosides constitute a special class both for
their biological significance (S-SlMI40407) and for the particular synthetic methods involved
in their preparation. Pyrazoles and indazoles react with suitable sugar derivatives to give
the corresponding N -glycosides. These glycosidations' have been carried out by conventional
rnethods.
Glycosidation of syrnrnetrical pyrazoles leads to a unique N -substituted pyrazole.
However, depending on the glycosidation rnethod used and on the starting rnaterials, one
or two isorners (anorners) which differ only in the configuration of the C-1 carbon of the
sugar rnoiety can be obtained. Thus, the reaction of 3,5-dirnethylpyrazole and 2,3,5-tri-O-
acetyl-D-ribofuranosyl chloride, in the presence of rnercury(n) cyanide as a hydrogen halide
acceptor, yields the nucleoside (664) of ß-anorner configuration (SOJHC1l3). However, the
fusion reaction of another syrnrnetrical pyrazole, the 4-nitro derivative, with 1,2,3,5-tetra-
O-acetyl-D-ribofuranose, in the presence of iodine as a catalyst, gives a rnixture of both
anorners, represented by (665) and (666) (74MI40400).
Me
eÇN
A'00
AcO OAc
(664)
02 N ffX\
(j
A,o-(1N
AcO OAc
(665)
A'O-Ö
AcO AcO N
(. :N
U
02 N
(666)
Pyrazoles and their Benzo Derivatives
289
The reaction between asyrnrnetrically substituted pyrazoles (74MI40400, 74MI40404,
74Z0R1787, 79JMC807, 80JMC657) or indazoles (70JHC117, 70JHC1329, 70JHC143S, 73TL4619,
74MI40402, 76BSF1983, 76MI40401) with sugar derivatives leads to glycosyl derivatives on N-1
and N-2, or to rnixtures of both derivatives, depending on the glycosidation rnethod, the
experirnental conditions and the structure of the starting rnaterials.
The fusion reaction between 3(5)-ethoxycarbonyl-5(3)-brornopyrazole and penta-O-
acetyl-ß-o-glycopyranose in the presence of p-toluenesulfonic acid as a catalyst gives a
rnixture of the two possible isorners (667a) and (668a). The sarne reaction, but with
tetra-O-acetyl-ß-o-ribofuranose or tetra-O-acetyl-ß-D-ribopyranose, yields only the 5-
ethoxycarbonyl derivatives (667b) and (667d) (79JMC807). The fusion of 3(5)-ethoxycar-
bonylpyrazole with peracylated sugars in the presence of iodine gives preferentially the
3-ethoxycarbonyl derivatives (669a), (669b) and (669d) (74MI40404, 74Z0R1787).
O CHlBr
EtOlC N
N/
R!
(667)
COlEt
[J
BrCH 2 /N
N
R 1
(668)
ç C0 2 Et
7
/N
R 1
(669)
a; R 1 = 2,3,4,6-tetra-O-acetyl-ß-o-glucopyranosyl
b; R 1 = 2,3,S-tri-O-acetyl-ß-o-ribopyranosyl
c; R 1 = 2,3,4-tri-O-acetyl-ß-o-ribopyranosyl
d; R 1 = 2,3,S-tri-O- benzoyl-ß-o-ribofuranosyl
In the case of indazoles the reaction of indazole, 5-nitroindazole or 6-nitroindazole with
glycosyl halides and mercury(n) cyanide gives exclusively 2-g1ycosylindazoles (670), (673)
and (675) (70JHC143S). Sirnilarly, the reaction of 1-trirnethylsilyl derivatives of indazole,
3-cyanoindazole, 4-nitroindazole, 5-nitroindazole and 6-nÎtroindazole with 2,3,5-tri-O-
acetyl-o-ribofuranosyl bromide gives only, or preferentially, the 2-ribofuranosyl derivatives
(670)-(674) (70JHCl17, 70JHC1329).
: N y
N' OAc
o
OAc
(670) R 1 =R l =R 3 =R 4 =H OAc
(671) R 1 =CN,R l =R 3 =R 4 =H
(672) Rl=R3=R4=H,Rl=NOz
(673) Rl=Rz=R4=H,R3=NOz
(674) Rl=Rz=R3=H,R4=N02
oc
I N
I
Mod
AcO OAc
(675)
1-Glycosylindazoles (675) are obtained by fusion of peracylated sugars with indazoles in
an iodine-catalyzed reaction (73TL4619). However, by changing the catalyst or its amount,
rnixtures of 1- and 2-(ß-o-ribofuranosyl)indazoles are obtained (74MI40402, 76BSF1983).
Another way to obtain 1-substituted indazoles is by the nucleophilic addition of an indazole
(indazole, 3-brornoindazole, 5-chloroindazole, 5-nitroindazole, 6-nitroindazole) to an ex,ß-
unsaturated cyclic ether, such as 2,3-dihydrofuran or 2,3-dihydro-4H -pyran in the presence
of an acid as catalyst (76MI40401). Thus the deoxy analogues of nucleosides are obtained.
The other general method of obtaining pyrazoles, the reaction of hydrazines and ß-
dicarbonyl cornpounds (Section 4.04.3.1.2(ii)), has also been applied to pyrazologluconu-
cleosides (81LA2309).
4.04.3.3.3 Labelled compounds
In the structure sections, labelled cornpounds have often been used to solve a spectroscopic
problern involved in rnicrowave (Section 4.04.1.3.2), nitrogen NMR (Section 4.04.1.3.5),
IR (Section 4.04.1.3.7(i)) or rnass spectrornetry (Section 4.04.1.3.8). The synthesis usually
involves non-radioactive compounds eH, 15 N ) by classical methods that rnust be repeated
several tirnes in order to obtain good yields.
The synthesis of the 11 deuterated derivatives of pyrazole (676) is described in (70BSF1974).
Seven can be obtained by HID exchanges making use of the fact that the exchange rates
290
Pyrazoles and their Benzo Derivatives
decrease in the order 1-position > 4-position > 3(5)-position (Figure 32). The four others
have been prepared by reduction of the 3(5)-bromopyrazole (677) followed by HID
exchanges.
o
n
N;N
H
!Ia')
o
O
/N
N
o
O
/N
N
o
I,a)
O
N/N
H
(676)
Ibl
--
o
OeN
W'"
o
leI
-
o 0
O O
/N
N
H
Ila'l
o 0
On
N;N
D
lib')
o
o
N/N
H
(678)
O U O I" O a O
r
N/N N/N
H 0
} b"
Ibl
O OH
r
/N
N
H
Idl
----.
o
O
N/N
H
+
O U O
/N
N
H
Î lei
Sr
O
N/N
H
(677)
The isotopic purity on the carbons was about 95%; the experirnental conditions, found
ernpirically, are near the theoretical conditions deduced from the exchange rates of Wu
and Vaughan (70JOCI146, 79SA(A)10SS). Sorne authors have used sirnilar conditions to prepare
deuteropyrazoles (71JHC311, 71JST(9)46S) and others, using slightly different procedures such
as perdeuterated acetone in a sealed tube at 190 oc (74JST(22)401) or a solution of D 2 S0 4
in 0 2 0 at 100 oC (74CHE471) have prepared pyrazole-1,4-d 2 . Decarboxylation of 3,5-
pyrazoledicarboxylic acid-d 3 has been used to obtain a rnixture of (678) and (679)
(74JST(22)40I). Decarboxylation of 1-rnethylpyrazole-5-deuterocarboxylic acid yields 1-
methylpyrazole-5-d 1 with a 50-60% labelling with apparently no scrambling (690MR( I )431),
but it is known that this rnethod leads generally to compounds labelled not only on the
ipso carbon atorn but also on the ortho one. The five C -rnonodeuterated indazoles have
been prepared (76CJC1329), the 3-d 1 by decarboxylation and the others frorn arninoindazoles
by nitrous acid deamination using deuterated hypophosphorous acid.
15N-Labelled (mono and di) pyrazole has been prepared several times (73JMR( 10)130,
74CHE471, 74JST(22)401, 82UP40401), always using the Protopopova rnethod (reaction between
a hydrazine salt and tetrarnethoxypropane) (S7Z0BI276). Pellegrin has cornpared Jones'
(49JA3994) and Protopopova's procedures and found that the second one gives better results
(82UP40401). In a typical experirnent a solution of hydrazine sulfate ( 15 N 2 ) (1 g) in (1.5 crn 3 of
water and 0.4 crn 3 of 1N HCl was treated with 2 crn 3 of 1 ,1,3,3-tetraethoxypropane (rnalonic
aldehyde dirnethyl acetal) during 1 h at 50 oC. The volurne was reduced by evaporation to
1-1.5 crn 3 and 2.5 crn 3 of 30% NaOH was added. The rnixture was extracted with ether
(5 tirnes 10 ern). The ethereal solution was dried over sodiurn sulfate and evaporated. The
residue, 500 rng (96% yield), was chrornatogra hically pure pyrazole. The labelling of the
hydrazine (95%) is conserved in the pyrazole. sN-Labelled phenylhydrazine (rnono- and
di-labeIled) has been used to prepare several1-phenylpyrazoles (77JCS(P2)l024, 790MR( 12)476,
800MR(13)197). An original synthesis of 1-benzylpyrazole 15N-labelled at N-2 has been
reported recently (Scheme 63) (810PP371).
OO ON
I
CH 2 Ph
o
O
N/N
D
a t
o N/N
H
(679)
(a) Three 3 h exchanges in D 2 0 at room temperature
(a') Three 3 h exchanges in H 2 0 at room temperature
(b) Two 12 h exchanges in an autoclave at 200 oC with D 2 0
(b') Two 12 h exchanges in an autoclave at 200 oC with H 2 0
(c) Two 12 h exchanges in an autoclave at 200 oC with IN NaOD
(d) 12 h in an autoclave at 180 oC with POBr3
(e) Reduction by Zn-Cu in AcOD at reflux
Figure 32 Synthesis of deuterium labelled pyrazoles
\a)
--
Q H
N
I
CH 2 Ph
i, PhCH 2 NH 2 ; ii, lsNH20S03H; iii, CH 2 [CH(OMehh/H-
Scheme 63
iii
-
nlS
..;N
N
CH 2 Ph
Pyrazoles and their Benzo Derivatives
291
Indazole-I- 15 N has been prepared frorn 2-nitrotoluene- 15 N (Table 37) in 51 % yield.
Indazole-2- 15 N has been Rrepared frorn 2-rnethyl-4-nitroaniline and sodiurn nitrite- 15 N,
through 5-nitroindazole-2- 15 N, in three steps (overall yield 45%) (81MI4040S).
4.04.4 APPLICATIONS AND IMPORTANT COMPOUNDS
4.04.4.1 Synthetic Products
4.04.4.1.1 Pharmaceuticals
Some of the rnost irnportant arornatic pyrazoles with biological activity are shown in
Table 38. Pyrazole itself and several N -unsubstituted pyrazoles are inhibitors and deac-
tivators of liver alcohol dehydrogenase (79JMC3S6, 79ACS(B)483, B-79MI40414, 82ACS(B)101).
The analgesic activity of difenarnizole (680) was cornparable with those of arninopyrine
and aspirin and less than that of mefenarnic acid. Its antiinflarnrnatory activity was greater
than that of aspirin (B-76MI40404). 1-(4-Fluorophenyl)-4-(4-chlorophenyl)-3-pyrazolylacetic
acid (Pirazolac) has recently'been reported (82MI40400) to have antiinflamrnatory activity, and
the advantageous relationship between activity and gastric tolerance led to detailed biological
investigations (83APS88, 83AP608). Interest in the effect of the CF 3 substituent on the activity
of pyrazole derivatives prornpted sorne authors to investigate compounds (681) and (682).
3- Trifluorornethyl-4,5-trirnethylenepyrazole (681) was about 0.3% as effective as an amebi-
cide compared with ernetine, and 5,5-dirnethyl-3-trifluorornethyl-4,5-dihydroindazole (682)
had 0.5 to 1 % the trichornonacidal activity of metronindazole (71JMC997).
CF 3
(JCN
N
H
(681)
OC CF3
Me 2
I N
I
N
H
(682)
Betazole (683) has been used as a chemical control substance for pharrnacological
characterization of histamine receptors (B-80MI40406), and shows a relative selective activity
towards the Hz-receptor. Betazole hydrochloride is used to diagnose impairrnent of the
acid-producing cells of the stomach.
Sulfaphenazole (684) and sulfazamet (685) are both exarnples of relatively short acting
sulfonarnides (B-80MI40406) and their antibacterial activity has been tested against
Escherichia coli, the forrner being rnore effective than the latter. Sulfaphenazole also
displaces sulfonyl ureas from protein binding sites on hurnan serum albumin and con-
sequently increases the concentration of the free (active) drug and produces a rnore intense
reaction that rnay result in hypoglycernia.
3,5-Dirnethylpyrazole possesses hypoglycernic activity in glucose prirned and diabetic
rats because of its rnetabolism to the corresponding 5-carboxylic acid. This rnetabolisrn
product acts primarily on adipose tissue by inhibiting lipolysis, promoting the conversion
of glucose to triglyceride, and stimulating glycogenesis (B-76MI40404). Salts of 5-rnethyl-
pyrazole-3-carboxylic acid with basically substituted adenine derivatives (686) which have
significantly rnore lipolysis inhibitory activity than the free acid itself have been described
recently (81AF2096).
NH 2
N.ç-yN
_. > Me
N N IT
CH 2 CHOHCH 2 NCH 2 CH 2 0H
I
H
( 686)
A nurnber of 4-pyrazolylpyridinium salts (687) have been found to have hypoglycernic
activity in several animal rnodels (68JMC981). The possibility that the corresponding 4-
pyrazolylpyridine I-oxides rnight also exhibit this type of activity was investigated without
success (69JMC94S).
I-Methyl-4-[3(5)-pyrazolyl]quinoliniurn iodides (688) also failed to depress blood sugar
levels significantly (69JMC1124). Neuroleptic-like effects of sorne ß-arninoketones (689)
containing a pyrazole nucleus have been described in the literature (B-80MI40406). The
CO-
MeCN 2
N
H
IV
\0
IV
Table 38 Some Selected Pyrazole Derivatives with Biological Activity
Substituents
N
Generic name No. 1 3 4 5 Activity Ref. c
'"
Difenamizole (680) Ph Ph H NHCOCH(Me) NMe 2 Analgesic-anliinflammatory-antipyretic B-76MI40404
:::
(681) H CF 3 -(CH 2 h- Amebicide 71JMC997 !::I..
(682) H CF 3 -CH 2 C(MehCH=CH- Trichomonacidal 71JMC997 ...
Betazole (683) H CH 2 CH 2 NH 2 H H Diagnostic aid (gastric secretion) B-76MI40404 ""
Sulfaphenazole (684) Ph H H NHS0 2 C 6 H 4 NH 2 -p An tibacterial-antimicrobial B-76MI40404 ::;.
t:ö
Sulfazamet (685) Ph Me H NHS0 2 C 6 H 4 NH 2 -p Antibacterial B-76MI40404 t';)
H Me H Me Hypoglycemic B-80MI40406 :::
N
H C0 2 H H Me Hypoglycemic B-76MI40404 c
(687) H C S H 4 NMe H Me Hypoglycemic 68JMC981 t1
""
(689) Ph H COCH2NC4HgNC6H4Me-o Me Antipsychotic B-80MI40406 ;:So
(690) H CH= CMe 2 H H Sedative-hypnotic 79MI40400 <::
EMD-16923 (691) H (CH2hNC4HgNCóH4CI-m H Me Sedative-hypnotic 80MI40400 ...
;::;.
""
eo,
Pyrazoles and their Benzo Derivatives
293
Me
Me Ñ g-v '" N H o- í\
N/ _ N'---IN(CH2)2COÌïl\
Me Me(J-j
N
(687) (688) (689) Ph
pyrazole (690) potentiates hexobarbital-induced sleep time (79MI40400) and EMD-16923
(691) was shown to be clinically effective in anxiety, producing an EEG-pattern in rabbits
indicative of drowsiness (SOMI40400).
R 2 R t
Me Ñ -()N H
N/J
R 3
n CH =CMe 2
1(_ J'N
N
H
(690)
(CH2)2-N -o
á '---1-
Me a
N/N
H
(691)
Research for an antidepressant arnong non-tricyclic cornpounds with pharrnacological
effects qualitatively different frorn those of the conventional tricyclic cornpounds led to the
preparation and testing of a series of indazole derivatives for reserpine-like activity in rnice.
1-[3-(Dirnethylarnino)propyl]-5-rnethyl-3-phenyl-l H -indazole (FS-32; 692) antagonizes
reserpine-induced effects and potentiates arnphetarnine-induced self-stimulation and L-
Dopa-induced increase in rnotor activity. FS-32 produces an anticholinergic action rnainly
on the central nervous systern, while the action of irniprarnine occurs centrally as well as
peripherally (79AF511).
Ph
MemN
N
(CH 2 h NMe 2
(692)
R 3 ()::) :::;- 2
N R
"'N1 RI
VR
(693)
Most of the pharmacologically active indazole derivatives are useful as antiinflamrnatory
drugs, e.g. bendazac or [(1-benzyl-lH-indazol-3-yl)oxy]acetic acid (LDso in rnice and rats
of 355 and 388 rng kg- 1 i.p., respectively) and benzydarnine or 1-benzyl-3-[3-(dirnethyl-
arnino)propoxy]-lH -indazole (LDso in rnice and rats of 110 and 100 rng kg-I i.p., respec-
tively). The last cited cornpound also has analgesic and antipyretic properties (B-76MI40404).
Recently, Picciola et al. (SlFESI037) prepared some 2H -indazole derivatives containing
a phenylalkanoic acid residue with potential antiinflamrnatory activity (693). M.G. 18755
(R = CHMeCOzH, R 1 = R Z = R 3 = H) and its lysine salt, M.G. 18334, showed greater activity
than ibuprofen, and the hornologous butyric acid derivative M.G. 18860 showed good
activity as a platelet aggregation inhibitor.
Antiarthritic effects on prirnary or secondary arthritis have been shown by the ethyl ester
of 1-(p-chlorobenzoyl)-5-rnethyl-1H -indazole-3-carboxylic acid (694) (SlFES315).
W C02EI
Me I N
/
N
O -o o
(694)
H
H
(695)
Finally, a new class of antisperrnatogenic agents containing the sarne fundarnental struc-
ture cited above has been described (76JMC77S). 1-Halobenzyl-lH-indazole-3-carboxylic
acids are potentially useful for birth control, and because they act after a single adrninistration
they are of interest for the physiological study of the rnale reproductive systern.
In 1959 Clinton and coworkers reported the first synthesis of sorne pyrazole fused
androstane derivatives and described their biological activity (B-76MI40404). Stanazolol (695)
or 17-rnethyl-2H-5a-androst-2-eno[3,2-c]pyrazol-17ß-ol was 10 tirnes as active as 17a-
methyltestosterone in irnproving nitrogen retention in rats (B-SOMI40406), and its rnyotrophic
activity was only twice that of 17a -rnethyltestosterone. It is used as an anabolic steroid
with no lasting adverse side eflects.
294
Pyrazoles and their Benzo Derivatives
IIß, 17.21- Trihydroxy-6, 16a -dimethyl-2' -phenyl- 2' H -pregna- 2,4,6-trieno[3,2 - c]-
pyrazol-20-one-21-acetate, commonly named cortivazol (696), has been used since 1962 by
Merck & Co. as a glucocorticoid (B-76MI40404). Tricyclic pyrazoles (697) have been found to
possess antiarrhythrnic and antiinflarnmatory activities (76JHC545).
CH 2 0COMe
I
co
Me ,,,,,,,OH
1I1""Me
X A CONHR
1/
N R = Me or (CHz)zNEtz
Ò A = CH z , (CHz)z, (CHzh
.
I
y
Me (696) (697)
Tricyclic pyrazole derivatives (698) are described by Hashem et al. as inhibitors of the
growth of Bacillus subtilis, Pseudomonas fluorescens, Staphylococcus aureus and KB cells at
moderate concentrations (76JMC229).
cxÇÇ "
I N
I
""" N
RO I þ H
(698) (699) (700)
Steroid-type systems (399) (77 JMC664) and 1 ,4-dihydro[ 1 ]benzothiopyrano[ 4,3-c]-
pyrazole (700) also have antirnicrobial activity (77JMC847).
In the pharrnaceuticalliterature some pyrazoles fused to the prostaglandin structure are
cited. Thus, 9,II-azo-PGE 2 (701), a stable endoperoxide analogue that is eight tirnes as
potent as PGG 2 , is a cornpound that specifically blocks TXA 2 synthetase (79MI40401).
N"\ " "" " CO H
II z
N,I"""'llil
OH
(701)
Methoxy-pyrazole and -indazole derivatives constitute a family of interesting phar-
rnaceutical agents. Thus, 4-rnethoxy-2-(5-rnethoxy-3-rnethylpyrazol-l-yl)-6-rnethyl-
pyrirnidine (rnepirizole), prepared by Naito et al. in 1968, is about twice as effective as
arninopyrine (see later) by intraperitoneal injection and about as effective as arninopyrine
by oral adrninistration in analgesic tests. Its antipyretic activity is low cornpared with
arninopyrine, but its antiinflarnrnatory activity is cornparable. This fact suggests that the
introduction of a rnethoxy group into the 5-position of the pyrazole rnoiety is irnportant in
irnproving activity (B-76MI40404). The search for a drug containing a pyrazole ring with both
antiinflarnrnatory, analgesic and antipyretic activities afforded the 3-carbarnoyl-l-(m-
chlorophenyl)-5-rnethoxypyrazole derivatives (703) (76MI40400). The rnost potent and least
toxic derivative of this series was PZ-I77 in which the side chain at the 3-position was an
N,N-disubstituted arnide (R 1 = R 2 = Me).
O fONR1R2
MeO ....N
N
ÒCI
N"'\ j---( CO zH
"ml
(702)
(703)
In the search for new structures with antiinflarnrnatory activities sorne I-substituted
3-dirnethylarninoalkoxy-IH -indazoles (704) have been synthesized and pharrnacologically
tested (66JMC38). Doses of 20-40 rng g -I i.p. produced sedation, rnuscle relaxation and rnotor
incoordination, whereas doses of 80-100 rng kg -1 produced depression. Toxicity was fairly
constant in all series, varying frorn 120 to 150 rng kg-I i.p., with the exception of cornpounds
possessing a nitro group or an amino group in the indazole nucleus, which provoked cyanosis.
Pyrazoles and their Benzo Derivatives
295
Sorne of these indazoles showed analgesic activity greater than that of aspirin and several
possessed significant antiinflarnrnatory action. Both properties were the rnost striking and
characteristic ones of the series. In a few cases the authors isolated the corresponding
indazolones (705) which were less active than (704) in terrns of analgesic and antiinflarnrna-
tory properties.
-o=; O(CH2)nNMe2
R 'N
""" N'
R 1
(704)
o
R -Cj , N(CH2)nNMe2
""" I
N
R 1
(705)
Probably the best known class of pharrnacological agents derived frorn pyrazole are the
5-pyrazolones. They are useful as analgesics, antipyretics and antiinflarnrnatories (B-
76MI40404, B-80MI40406, B-80MI40407). Antipyrine, l-phenyl- 2,3 -dirnethyl-3 -pyrazolin - 5 -one,
was one of the first synthetic compounds used in rnedicine (1884) and its analgesic, antipyretic
and antirheumatic activities are sirnilar to those of aspirin and sodium salicylate (B-
80MI40407). It is also administered as antipyrine salicylate which is prepared by fusing
antipyrine and salicylic acid. Some other 5-pyrazolones (B-76MI40404) are listed in Table 39,
but because of their toxicity their use is steadily diminishing. Arninopyrine and dipyrone are
no longer official drugs in the United States due to their tendency to cause fatal
agranulocytosis, but they are still available in other countries (B-80MI40407). Aminopyrine
has been used as a sedative hypnotic cornbined with chloral hydrate (under the narne
dichloralphenazone) to avoid the unpleasant taste, odor and gastric irritation of chloral
hydrate itself. However, the cornbination did not achieve much popularity (B-80MI40406).
Table 39 Some Active 3-PyrazoIin-S-ones
Substituents
Generic name 1 2 3 4
Antipyrine Ph Me Me H
Propyphenazone Ph Me Me Pr i
Ampyrone Ph Me Me NH 2
Aminopyrine Ph Me Me NMe2.
Isopyrine Ph Me Me NHPr'
Pidylon Ph Me Me NHCOCH 2 OCOMe
N
Nifenazone Ph Me Me NHCo D
Dipyrone Ph Me Me NMeCH 2 S0 3 Na
Dibupyrone Ph Me Me N(CH 2 Pr')CH 2 S0 3 Na
Piperylon -C NMe H Ph Et
Forbisen, 2,2' ,3,3'-tetrarnethyl-l ,l'-diphenyl-4,4'-bi-3,3' -pyrazoline-5,5'-dione (706)
(B-76MI40404), a by-product obtained in the rnanufacture of antipyrine, has been used in
bovine anaplasmosis.
Me _ e
':vIe':'.J ( N "'A. o o J:. N/NMe
Ph Ph
(706)
R 4 R 3
O :J:;N H
N
eN
R 4 R 3
o :J:;N Me
6
(707)
(708)
Some active 5-pyrazolone derivatives (707) and (708) in which the l-phenyl substituent
of antipyrine was replaced by 2'-, 3'- and 4'-pyridyl groups have been prepared (66HCA272).
A series of aminoesters substituted at the nitrogen atom of the ester grouping with an
antipyryl residue (709) were found to possess local anesthetic properties (69MI40400).
296
Pyrazoles and their Benzo Derivatives
R'
(CH ) OCO -o R 1
Mer=( 2 .
\4el'<. , O
'J
Ph (709)
n = 2 or 3
R 1 = H, OMe, OEt, OPr n , OPr\ N0 2 , NH 2
R 2 = Me, Et
Finally, benzpiperylon or 1-(1-rnethyl-4-piperidyl)-3-phenyl-4-benzyl-2- (or 3-)
pyrazolin-5-one has been utilized by Sandoz as an investigational agent in connective tissue
disorders (B-76MI40404).
Muzolirnine (710), a l-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic,
differing frorn the structures of other diuretics since it contains neither a sulfonarnide nor a
carboxyl group. It has a saluretic effect sirnilar to furosernide and acts in the proxirnal
tubule and in the rnedullary portion of the ascending lirnb of the loop of Henle. Phar-
rnacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show
that the cornpound is readily absorbed after oral adrninistration (B-80MI40406).
H2
O _-/N
N
I
CHMe
ÒCI
CI
(710)
The 3,5-pyrazolidinedione derivatives are an irnportant class of antiinflarnrnatory agents.
The rnost widely used are listed in Table 40.
Table 40 Some 3,S-Pyrazolidinedione Derivatives with Biological Activity
Substituents
Generic name No. 1 4 4' Ref.
Phenylbutazone (711) Ph Bun H B-80MI40406
Oxyphenbutazone (712) C 6 H 4 OH-p Bun H B-80MI40406
Sulfinpyrazone (713) Ph CH 2 CH 2 S0 2 Ph H B-80MI40406
Mofebutazone (714) H Bun H B-76MI40404
Kebuzone (715) Ph CH 2 CH 2 COMe H B-76MI40404
Prenazone (716) Ph CH 2 CH= CMe 2 H B-76MI40404
Suxibuzone (717) Ph Bun CH z OCOCH 2 CH 2 C0 2 H B-76MI40404
Pipebuzone (718) Bun 1\
Ph CH 2 N NMe B-76MI40404
"----I
Phenylbutazone (711) has been extensively studied. It was synthesized in 1946 in Switzer-
land and showed analgesic and antipyretic properties but without any advantage over
antipyrine and arninopyrine. The antiinflarnmatory activity in rnan was not discovered until
1949. It is also a prostaglandin-synthetase inhibitor. Its acidity is cornparable to that of
carboxylic groups (pK a == 4.5) and it is possible to prepare the corresponding sodiurn salt that
solubilizes a nurnber of sparingly soluble drugs. The long half-life of phenylbutazone (72 h
in rnan) is due to the slow rate of glucuronide conjugation. Its two phenyl groups provide
the lipophilic characteristics for protein binding and tissue distribution. Phenylbutazone
cornpetes for the sarne binding sites on hurnan plasrna alburnin as cournarin, anticoagulants,
sulfonarnides, tolbutarnide, indornethacin and glucocorticoids.
Oxyphenbutazone (712), 1'- hydroxyphenylbutazone and kebuzone (715) are rnetabolites
of phenylbutazone in liver. The first cited is an equally potent antiinflarnrnatory agent but
slightly less toxic. Cornpounds (711) and (712) are rarely used as analgesics and antipyretics
because of their toxicities. The first one is used in therapy of rheurnatoid disorders character-
ized by a lack of detectable antiglobulin and antinuclear antibodies in the serurn. The
1'- hydroxyphenylbutazone has rnarked uricosuric activity but little antirheurnatic effect.
Kebuzone (715) is an antiinflarnrnatory agent still widely used in Europe.
Pyrazoles and their Benzo Derivatives
297
Sulfinpyrazone (713) has enhanced uricosuric activity but lacks the antiinflarnrnatory and
analgesic properties of phenylbutazone. This rnodification of the biological activity has been
ascribed to the increased acidic character of (713) (pKa = 2.8) corn pared to (711). In
contrast, the half-life of sulfinpyrazone in rnan is only 2 h. It is known that increasing the
acidity of phenylbutazone derivatives decreases the antiinflarnrnatory activity, half-life and
sodium retaining potency but increases their uricosuric activity. The uricosuric action of
(713) is by inhibiting secretion and is additive to that of prebenecid and phenylbutazone
but antagonizes that of salicylates. Sulfinpyrazone also displaces organic anions bonded to
plasrna protein, thus alternating their tissue distribution and renal excretion.
Although sorne authors propose that an enolizable ß- dicarbonyl systern is essential for
inflamrnatory activity, two analogues in which this hydrogen atorn at carbon 4 has been
substituted, suxibuzone (717) and pipebuzone (718), are used as antiinflammatory agents,
and the latter also possesses antipyretic and analgesic properties. However, these cornpounds
are probably not active per se and their activity is due to rnetabolisrn to phenylbutazone.
Prom the various modifications that have been rnade on the phenylbutazone structure
in order to increase activity and reduce toxicity it has been found that the activity persists
when methyl, chloro, hydroxy or nitro groups are introduced into the para position of one
or both benzene rings (see oxyphenbutazone (712) as an example). Mofebutazone (714)
has also been used in Europe for several years as an antirheurnatic drug.
Some exarnples of Ll 1 -pyrazoline derivatives with biological activity, (701) and (702),
have been described earlier. BW-755C (719), a Ll 2 -pyrazoline derivative, has been shown
to inhibit cyclooxygenase and lipooxygenase enzymes. It also inhibits leucocyte rnigration
into the site of inflarnrnation in rats (81MI40404). Only a very few exarnples of drugs containing
a pyrazolidine nucleus without exocyclic oxo substitution are known. These pyrazole
derivatives have found application as new local anesthetics in the forrn of esters of
1,2-diethyl-3-hydroxyrnethylpyrazolidine (720), which bear structural resemblances to pro-
caine, piperocaine and other synthetic local anesthetics. The structure-activity relationship
results obtained parallel findings previously reported for benzoate esters (66JMC493).
O NH 2
\ 0 R 2
Ò N o"' N Ò N/N'CONH -ð
I RC0 2 CH 2 CNEt ;...-
: CF 3 t """ I
(719) (720) R I (721)
The synthesis of 1-phenyl-2-(phenylcarbarnoyl)pyrazolidines (721) afforded a new series
of anticonvulsant agents (79JPS377).
4.04.4.1.2 Agrochernicals
Some pyrazole derivatives have found application in the agrochernical field as insecticides.
Two organophosphate insecticides (722) and (723) containing a pyrazole ring constitute a
good exarnple of how rnolecular rnodification, based on a sound understanding of the
chemistry and pharrnacology of the compound, can lead to safer and rnore useful insecticides
and therapeutic agents (B-76MI40404).
x n,Me
EtO,1I )!...;r../
P-O No'" (722) X = 0
EtO""" H (723) X = S
O,O-Diethyl O-(3-methyl-5-pyrazolyl) phosphate (722) and O,O-diethyl O-(3-rnethyl-
5-pyrazolyl) phosphorothioate (723) were prepared in 1956 by Geigy and they act, as do
all organophosphates in both insects and marnrnals, by irreversible inhibition of acetyl-
cholinesterase in the cholinergic synapses. Interaction of acetylcholine with the postsyn-
aptic receptor is therefore greatly potentiated. O-Ethyl-S-n-propyl-O-(1-substituted
pyrazol-4-yl)(thiono)thiolphosphoric acid esters have been patented as pesticides
(82USP4315008).
Dimetilan (dimethylcarbarnic acid 1-[( dirnethylamino )carbonyl]-5-methyl-1H- pyrazoI-3-
yl ester; 724) and isolan (dirnethylcarbarnic acid 3-methyl-l-isopropyl-1H -pyrazol-5-yl
298
Pyrazoles and their Benzo Derivatives
ester; 725) also have useful insecticidal properties, exerting their toxic action on insects by
reversibly inhibiting cholinesterase. The carbamoylated enzyrne reacts with water rnuch
rnore slowly than does the acetylated enzyrne (B-76MI40404).
R 4 R'
R, O N
No'"
O R'
if 'N
I II
R 1
(726)
o
II
[J OCNMe,
M
e N
N"
I
/- CNMe 2
0;0-
(724)
I-Phenylcarbarnoyl-2-pyrazolines (726) were synthesized and studies on their biological
activities dernonstrated a high insectidal action for this class of cornpound. 3,4-Diphenyl
substitution in the heterocyclic ring increased the potency of this new class of insecticides
corn pared with 3-phenyl or 3,5-diphenyl substitution by a factor of 3 to 100. The phenornena
observed after poisoning are sirnilar in all cases, these derivatives being active against larvae
and adult insects (79MI4040S).
o J:J Me
II r
Me,NCO No"'N
Pr i
(725)
4.04.4.1.3 Dyestuffs and analytical applications
5-Pyrazolone derivatives have found rnany applications as cotton azo dyes because, even
if they were rnore expensive interrnediates, they irnproved qualities such as brightness and
light fastness. Rosanthrene Orange (727) and Pyrazol Orange (728) are two representative
exarnples.
Nao,c 0 N ==N -O ::::,... I CONH N==NhC02Na
N JOH V HO(J"
6 6
NH, NH,
(727)
PhN==N tt e
H O
o"'N
N
6
::::,...1
SO.lNa
HO N=N --O-O- fj N=N
-- -- d C02Na
Na02C
HO o"'N
6
(728) SO.lNa
Tartrazine, 4,5-dihydro-5 -oxo-l-(4-sulfophenyl)-4-[ (4-sulfophenyl)azo ]-IH -pyrazole-
3-carboxylic acid trisodiurn salt was discovered by Ziegler in 1884 and is used as a dye for
wool and silk. It is used as a colour additive in foods, drugs and cosrnetics, and is an
adsorption-elution indicator for chloride estirnations in biochernistry (B-76MI40404).
Other azopyrazolone acid dyes covering a range of bright yellows have been prepared
and arnong the rnost irnportant ones are Fast Light Yellow 36 (729) (B-70MI40403), Xylene
Light Yellow (730) (B-70MI40403) and Polar Yellow (731) (B-76MI4G404).
Na03s0-N=N Me0- 0 ,so-Q-N=N
-- Me -- -- h Me
HO( ;N HO( J"
N N
6 1 C1 6 'S03Na
Cl::::,... ::::,...
S03Na CI
(729)
(730)
(731)
Pyrazoles and their Benzo Derivatives
299
Hagenbach used 5-hydroxy-3-methyl-l-phenylpyrazole as a coupling cornponent and
made Eriochrome Red B (732), an important chrorne dye (B-70MI40403).
OH
V N=N Me
SOlNH 1 hI
HO( -/\
N
ÒSO'NH'
OH
NaOJs g N=N
. d Me
- V
\ j HO N/N
Ph
(732)
(733)
The use of prechrorned cornplexes instead of chrorning the dye on the fiber is advan-
tageous; one of the rnore frequently used ones is Neolan Orange R (733) (B-70MI40403).
Pigrnents derived frorn pyrazolones include Hansa Yellow R, 1-phenyl-3-methyl-4-[(2,5-
dichlorophenyl)azo ]-5-hydroxypyrazole and Pigrnent Chrorne Yellow, l-phenyl-3-rnethyl-
4-[(o-tolylazo]-5-hydroxypyrazole, as exarnples of rnonoazo cornpounds.
Vulcan Fast Red GF (734), a bisazopyrazolone pigrnent, has been developed prirnarily
for the coloration of rubber (B-70MI40403).
N=N N=N
Me t) ,. Ö e
VleO OMe V
N OH HO N
Ò 6
Me Me
(734)
Anthra[1,9]pyrazol-6(2H)-one (735) dyes have also been described in the literature
(B-70MI40403). These compounds result by acid ring closure of 1-anthraquinonyl hydrazine
or its N -sulfonic acid.
3-Methyl-1-phenyl-3-pyrazolin-5-one gives a green-black dye (736) with 4-nitroso- or
4-arnino-dimethylaniline and silver chlorides in the presence of light, a process of great
irnportance in colour photography (B-76MI40403).
Other pyrazole derivatives (737) suitable as coupling cornponents for diazotype printing
have been prepared by Pett et al. (79MI40406).
<<:ò _NH
I I
o
(735)
Me N o- N
2 .h M
- 0-;:(- J" e
N
Ph
(736)
M a::H e
Ò N Ò N R=S03H,S03-,H1NMel+
I I
R R
(737)
Phenidone, l-phenyl-3-pyrazolidone (738) (B-76MI40404), has been used as a non-
staining, high contrast photographic developer. New optical brighteners containing 2-
pyrazolines (739) and pyrazoles (740) have been synthesized recently and their properties
and applications reviewed (7SAG(E)66S).
0
0 R Me N"N
VNH ÇN t6
Ò
Ò Q 0
0
S02(CH 1 hNMe 1 Ph
(738) (739) (740)
300
Pyrazoles and their Benzo Derivatives
Optical brighteners are colourless fluorescent dyestuffs that absorb in the near UV
(350-390 nrn) and fluoresce in the violet to blue region of the spectr'um (425-445 nrn).
Analytical applications of pyrazolones have been reviewed by Busev et al. (65RCR237).
Organic bases are easily characterized by forrnation of highly crystalline salts with picrolonic
acid (l-(4-nitrophenyl-3-rnethyl-4-nitro-5-hydroxypyrazole). The last-narned compound is
used as a reagent for alkaloids, tryptophan, phenylalanine and for the detection and
estirnation of calciurn (B-76MI40404).
4.04.4.1.4 Plastics
Polyrners with a backbone of five-rnernbered heterocyclic rings have been developed in
the new area of therrnally stable rnaterials during the last 10 years (B-80MI40408). The sirnple
polypyrazole (741) is prepared by condensation of polydiethynylbenzene with hydrazine in
pyridine with yields of 60-97%.
104
N-N
: CH 2 r # n
(741)
N-Substituted polypyrazoles can also be obtained by using N -alkylhydrazines, and it
should be noted that these polymers consist of a randorn rnixture of head-to-head and
head-to-tail structures. Other syntheses of polypyrazoles have been described in the
literature. Thus polyphenylene pyrazoles (742) and (743) occurred when rn- or p-diethynyl-
benzene (DEB) reacted with 1,3-dipoles such as sydnones or bis(nitrilimines) (Scherne 64).
Cl
I
Cl . C=NNHPh
PhNHN= ß
lIDEB)
O-N N-O
1(:".:\ 1(:'::\ _
-O N N O
lIDEB)
[eN r-LN:l l
1 ì{
(742)
(743)
Scheme 64
In these types of 1,3-dipolar cycloaddition only one of two possible isorners is obtained
and the pyrazole functions have different orientations by the two rnethods. Another classical
synthesis of pyrazoles (Section 4.04.3.2.1(ii)), the reaction between hydrazines and ß-
diketones, has been used with success to prepare high molecular weight polypyrazoles
(Scherne 65) (81 MI40400). N -Arylation (Section 4.04.2.1.3(ix)) of 4,4' -dipyrazolyl with
1,4-diiodobenzene also yields polyrneric pyrazoles (69RRC1263).
RCOCH 2 COCOCH 2 COR + H 2 NNH O- x -o NHNH 2
x = S02' CH 2
R R -at
- N N . r-Lx If
N N -
n
Scheme 6S
Tetrazoles (744), as bis(nitrilimine) (745) generators (Section 4.04.3.1.2(ii)), afford poly-
pyrazoles when reacted with diynes. Benzoquinone has also been condensed with bis-
sydnones to incorporate a fused pyrazole nucleus (746).
Pyrazoles and their Benzo Derivatives
301
N N
Phl'( 'j-Ar-( 'rPh
N=N N=N
(744)
PhÑ-N=CArC=N-ÑPh
(745)
1 *N-Al
(746)
Finally, using divinyl cornpounds instead of diynes, surprisingly stable polypyrazolines
(747) can be obtained.
iG N -Q- N 6-Ot
(747)
Properties of ferrocene-containing polyrners have been improved by inclusion of pyrazole
systems in the backbone. The synthesis of (748) was achieved by condensation of bis( ß-
diketoferrocenes) with arornatic dihydrazines to give polyhydrazones that were later cyclo-
dehydrated (B-SOMI4040S).
@JÇN
+Á \,-
(748)
4.04.4.2 Metabolism and Toxicity
Drugs and other chemicals such as food additives or insecticides foreign to the body
undergo enzymatic transforrnations that result in loss of pharrnacological activity
(detoxification), or lead to the formation of rnetabolites with therapeutic or toxic effects
(bioactivation ).
One exarnple of bioactivation is found in active 3,5-pyrazolidinedione derivatives (Section
4.04.4.1.1). Thus, phenylbutazone is rnetabolized alrnost cornpletely by liver rnicrosornal
enzymes to oxyphenbutazone and y-hydroxyphenylbutazone, which have approximately
the sarne activity (B-SOMI40406). Detoxification of phenylbutazone and sulfinpyrazone (Sec-
tion 4.04.4.1.1) in man occurs by forrnation of the corresponding C -glucuronide rnetabolites
(749) and (750). The glucuronyl moiety with its ionized carboxyl group and polar hydroxyl
groups imparts the water solubility required for ready excretion, and the glucuronides are
pharmacologically inactive (B-SOMI40406).
H H O O R: ('49) RoBu"
H 0 N/ 'Ph
I (750) R = CHzCHzSOPh
Ph
Several other studies on metabolism of pyrazole derivatives with biological activity have
been reported in the literature. 2-Norantipyrine, 4-hydroxyantipyrine and 3-hydroxy-
methylantipyrine were identified as metabolites of antipyrine in the rat by action of three
hepatic rnonooxygenases (SOMI4040S). The rnajor rnetabolite of pyrazole in male rats was
found to be 4-hydroxypyrazole (77MI40401). In another study (77MI40400) seven metabolites
were identified, including hydroxylated and conjugated derivatives. Two rnetabolites were
conjugated with a pentose sugar, perhaps indicating that pyrazole serves as a substrate in
the salvage pathway of purines and pyrirnidines, forrning pyrazole ribosides.
The rnetabolic fate of - 1-(4-rnethoxy-6-rnethyl-2-pyrirnidinyl)-3-rnethyl-5-methoxy
pyrazole, rnepirizole, has been investigated in rats, rabbits and man. Three metabolites,
(751), (752) and (753), were identified in human urine (76CPBS04).
302
Pyrazoles and their Benzo Derivatives
O CH 2 0H
7
MeO ....N
N
N N
MeO JMe
(751)
O C0 2 H
7
MeO ....N
N
N N
MeoVMe
(752)
Me
O
MeO ....N
N
N N
MeoVC0 2 H
(753)
In rnan, the rnetabolic pathways of rnepirizole were distinct frorn those in experirnental
anirnals, since hydroxylation on each of the aromatic rings did not occur in rnan. Cornpound
(752) was obtained by oxidation of the 3-rnethyl group to the carboxylic acid (a similar
process occurs with 5-rnethylpyrazole-3-carboxylic acid, an active rnetabolite of 3,5-
dirnethylpyrazole). However, the carboxylic acid rnetabolite of rnepirizole had no analgesic
activity and did not decrease blood glucose.
Many azo dyes, such as tartrazine (Section 4.04.4.1.3), are susceptible to reduction by
bacterial reductases in the intestinal flora. Azo reduction is believed to proceed through a
hydrazo interrnediate that undergoes subsequent reductive cleavage of the nitrogen-nitrogen
bond to yield the arylarnine derivatives (B-80MI40406).
Organophosphates and carbarnates containing a pyrazole ring, useful as insecticides as
discussed earlier (Section 4.04.4.1.2), are rnetabolized rnainly through hydrolysis of the
ester function (B-80MI40406).
As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatornegaly,
atrophy of the testis, anernia and bone rnarrow depression in rats and rnice (72E1198). The
4-rnethyl derivative is well tolerated and may be rnore useful than pyrazole for pharrnacologi-
cal and metabolic studies of inhibition of ethanol rnetabolisrn. It has been shown (79MI40404)
that adrninistration of pyrazole or ethanol to rats had only rnoderate effects on the liver,
but cornbined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact
that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the
enzyrnes involved in alcohol oxidation (Section 4.04.4.1.1).
Several cornrnents about the toxicity of pharrnaceutical, agrochernical and azo dye
pyrazoles have been rnade previously in Section 4.04.4.1. Sorne LDso values frorn the
literature are shown in Table 41 (B-76MI40404).
Generic name
Table 41 50% Lethal Dose of Pyrazole Derivatives
Section
LDso (mgkg- 1 )
Difenamizole
Sulfaphenazole
Mepirizole
Antipyrine
Aminopyrine
Phenylbutazone
Kebuzone
Prenazone
Bendazac
Benzydamine
Phosphate.
Dimetilan
103 Lv. in mice
5800 orally in mice
970-1020 orally in mice
1800 orally in rats
1700 orally in rats
525 orally in mice
650 orally in mice
1065 orally in mice
11 05 orally in mice
515 orally in mice
4 orally in mice
25 orally in rats
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.1
4.04.4.1.2
4.04.4.1.2
.0.0- Diethyl-O- (3-methyl-5-pyrazolyl) phosphate.
4.04.4.3 Natural Products
There are very few exarnples of naturally occurring pyrazoles. As indicated in the
introduction to this chapter, cornpounds containing the N-N bond are rare in higher plants
and the biosynthesis and rnetabolisrn of N-N bonds is still unknown. Withasornnine,
4-phenyl-1,5-trirnethylenepyrazole (754), was isolated frorn the roots of Indian rnedicinal
plants, Withania sornnifera Dun, and its structure established by physical rnethods and total
synthesis (68TL5707, 82H(19)1223).
Pyrazoles and their Benzo Derivatives
303
Q
....N
I
CH 2 CHC0 2 H
I
NH 2 HO OH
(754) (755) (756)
L-ß-Pyrazolylalanine (755) and y-L-glutamyl-ß-pyrazol-L-alanine are found in the seeds
of rnany species of Cucurbitaceae (65P933). It was subsequently dernonstrated that free
pyrazole occurs in waterrnelon seeds in concentrations of 280 to 410 J.Lg g -\ depending on
the variety (75P2512). Biosynthetic studies implicate 1,3-diarninopropane as a precursor of the
pyrazole moiety of (755) (S2PS63).
An azole C-nucleoside, 4-hydro-3-ß-D-ribofuranosylpyrazolo-5-carboxarnide, pyrazo-
furin or pyrazomycin (756), was isolated in 1969 frorn the ferrnentation broth of Streptomyces
candidus. This antibiotic has broad spectrum antiviral activity and high cytotoxicity. It is now
being evaluated as an antiturnor agent and has been the object of various syntheses
(SIJCS(Pl)2374). On standing in aqueous solutions the inactive a-anomer is forrned. The
antiviral activity of pyrazofurin was reversed by uridine and uridine 5'-rnonophosphate, and
pyrazofurin 5' -rnonophosphate, an apparent rnetabolite, inhibits orotidylic acid decarboxy-
lase. Activity against Friend leukernia virus infection in mice was shown by acyl derivatives
of pyrazofurin (B-SOMI40406). Syntheses of pyrazofurin analogues have been reported in the
literature (70HCA64S).
The influence of pyrazole derivatives on 'Pre biotic Condensation Reactions of a-Amino
Acids' induced by polyphosphates in aqueous solution has been studied in cornparison with
other azoles (SlC59). In the case of triglycine forrnation the presence of pyrazole did not
increase the yield significantly.
a Ph
7
....N
N
HO
4.05
Pyrazoles with Fused Six-membered
Heterocyclic Rings
J. v. GREENHILL
University of Bradford
4.05.1 INTRODUCTION
4.05.2 STRUCTURE
4.05.2.1 Theoretical Methods
4.05.2.2 NMR Spectroscopy
4.05.2.3 UV Spectroscopy
4.05.2.4 Tautomerism
4.05.3 REACTIVITY
4.05.3.1 Electrophilic Attack at Nitrogen
4.05.3.2 Electrophilic Attack at Carbon
4.05.3.3 Nucleophilic Attack at Carbon
4.05.3.4 Reduction
4.05.3.5 Reactions of Substituents
4.05.4 SYNTHESIS
4.05.4.1 From Non-heterocyclic Compounds
4.05.4.2 Six-membered Ring Synthesis by Formation of One Bond
4.05.4.2.1 a to a heteroatom
4.05.4.2.2 'Y to a heteroatom
4.05.4.3 Six-membered Ring Synthesis by Formation of Two Bonds
4.05.4.3.1 From [5 + IJ atom fragments
4.05.4.3.2 From [4+2J atom fragments
4.05.4.3.3 From [3+3J atom fragments
4.05.4.4 Five-membered Ring Synthesis by Formation of One Bond
4.05.4.4.1 Between the heteroatoms
4.05.4.4.2 a to a heteroatom
4.05.4.4.3 ß to a heteroatom
4.05.4.5 Five-membered Ring Synthesis by Formation of Two Bonds
4.05.4.5.1 From [4+1J atom fragments
4.05.4.5.2 From [3 +2J atom fragments
4.05.4.6 By Transformation of Existing Heterocycles
,
4.05.5 IMPORTANT COMPOUNDS
305
306
306
308
308
308
309
309
311
312
313
315
316
316
318
318
321
322
322
326
331
334
334
336
337
338
338
339
342
343
4.05.1 INTRODUCTION
There appears to be a fundamental law of heterocyclic chemistry that the greater the
ratio of heteroatoms to carbon atoms the more likely the final compound in the synthetic
scheme is to be formed by ring closure. When the references for this chapter were finally
assembled, more than 80% dealt only with synthesis by cyclization methods. Much of this
work has been stimulated by the discovery of potent antibiotic and antineoplastic compounds
(Section 4.05.5).
Most of the compounds reported contain only nitrogen heteroatoms. Under modern rules
of nomenclature they are properly called pyrazolopyridines, pyrazolopyrimidines,
pyrazolotriazines, etc. The literature abounds with other, often more elegant terms; a few
examples are given here. Pyrazolo[1,5-a]pyridine (1) may be called 1,7a-diazaindene,
305
306
Pyrazoles with Fused Six-membered Heterocyclic Rings
3,4-diazaindene or 3-azaindolizine. Pyrazolo[1,5-a]pyrimidinc (2) may be 3,8-diazain-
dolizine. Pyrazolo[3,4-b]pyridine (3) may be 1,2,7-triazaindene ot 7-azaindazole.
Pyrazolo[5,I-c ][1,2,4]triazine (4) has been called 3,4,7,8-tetraazaindene or even
pyrazolo[3,2-c ]-as- triazine. The older literature uses pyrrocoline for indolizine.
5 Qj 4 3
;} 2
6 -N
7 t
4
5 c N y\
6 _;)2
7 8
(1)
(2)
4.05.2 STRUCTURE
4.05.2.1 Theoretical Methods
4 3
5 N2
6 _)l_j
N Nt
7 H
(3)
I
N 8
2N'l
3 _/7
4 5 6
(4)
The results of various electron density calculations for pyrazolo[1,5-a ]pyridine are col-
lected in Table 1. All successfully predict the observed electrophilic attack at C(3). The
CNDO/2 \'alues (b) lead to a theoretical dipole rnornent of 2.60 and those of n to 2.5 D.
These compare favourably with the experimental value (2.18 D). The values are also con-
sistent with delocalization of the bridgehead nitrogen lone pair over the 107T-electron system.
Table 1 Electron Density Calculations for Pyrazolo[1,5-a]pyridines
m
5
6 _; 2
7 I
N(1) C(2) C(3) C(3a) C(4) C(5) C(6) C(7) N(B) Ref.
(i) 1.426 0.939 1.189 0.988 1.040 0.980 1.052 1.012 1.372 71JAI887"
(ii) 5.166 3.939 4.067 3.896 4.026 3.966 4.031 3.896 4.894 72CB388 b
(iii) 5.191 3.853 4.162 3.856 4.059 3.933 4.040 3.902 5.034 74JHC223 b
(iv) 5.043 3.824 4.124 3.803 4.046 3.898 4.016 3.877 4.928 74JHC223<
(v) 1.42 1.01 1.14 0.98 1.01 0.98 1.02 0.95 1.49 65JHC410 d
(vi) 0.61 0.02 0.46 0.04 0.26 0.18 0.10 0.33 0.01 65JHC4W
"7T-Electron densities, CNDO/2. h-[otal electron densities, CNDO/2. <Total electron densities, CNDO/2 for
Ñ(I)- H. d 7T _ Electron densities, frontier electron density calculation. <Frontier electron densities.
Other available electron densities are shown in Scheme 1. Compound (2) shows CNDO/2
calculations (75CJCI19), compounds (3) and (5a) show HMO calculations (69CJCI129), and
(5b) and (6) show the results of LCAO calculations (58JCS2973).
3.7R8
5. 216 1
N 4166
3.882 C
I ;)3.875
4.07\ N-N
3.881 i 5.214
4.947
0.942 1.062
1.046 Cél
N 1.213
0.919 ::,... N 1
N I 1.544
1.248
H
0.848 1.050
I.2 39N :C1 N
I 1.2\1
O.859!.::::::-N rf
1.252 I
H
(2)
1.01
0.73 1 0.87
1.34N 1
I N 1.35
O.7S!.::::::- N 1
N 1.71
1.36 I
H
(5b)
(3)
(5a)
0.92
1.35 1
N 0.90
0.78(' 'rN 1.29
1.33N N: T N I
O 6 1.70
.7 I
0.97 H
(6)
Scheme 1 Electron density calculations for other fused pyrazoles
Table 2 lH NMR Spectral Data for Fused-ring Pyrazole Derivatives
4
5 ( X
I ;)2
6:::'" ....N-N
)' I
Ring atoms Chemical shifts (p.p.m.) Coupling constants (Hz)
X y Solvent 8(2) 8(3) 8(4) 8(5) 8(6) 8(7) J 2 . 3 J 3 . 7 J 2 . S J 4 . S J 4 . 6 J 4 . 7 J S . 6 J S . 7 J 6 . 7 Ref.
CH CH CCl 4 7.80 6.38 7.44 6.97 6.62 8.39 2.18 0.9 0.5 8.94 1.17 1.02 6.79 1.00 6.93 64AJC1128
N CH CDCl 3 8.13 6.72 8.69 6.80 8.47 2.0 5.0 2.0 7.0 75CJC119
N CH TFA-d 8.75 7.32 9.88 7.72 9.20 3.0 5.0 2.0 7.0 75CJC119
CH N CDCl 3 8.02 6.62 7.95 6.95 8.25 3.0 10.0 2.0 4.8 74CC941
Table 3 UV Spectral Data for Fused-ring Pyrazole Derivatives
X R 2
yr
I I ;)Rl
Z"" N_r:
Ring atoms Substituents
X y Z R 1 R 2 Solvent Åmax (nm) (log e) Ref.
CH CH CH H H H 2 O 219 (4.59) 286 (3.65) 64JCS4226
CH CH CH H H aq. H 2 SO 4 214 (4.51) 218 (4.42) 292 (3.77) 64JCS4226
CH CH CH H H C 6 H 12 223 (4.56) 227 (4.54) 289 (3.52) 310 (3.25) 340 (2.72) 57JCS4510
CH CH CH Me Me MeOH 227 (4.68) 234 (4.65) 287 (3.80) 298 (3.83) 320 (3.43) 68JOC3766
CH CH CH Me COMe MeOH 223 (4.63) 226 (4.66) 252 (4.08) 260 (4.10) 310 (4.15) 68JOC3766
N CH CMe H H EtOH 230 (4.60) 280 (3.30) 320 (3.20) 62CPB620
CH CH N H H a 224 (4.57) 276 (3.08) 317 (3.15) 74CC941
N N CMe H H 226 (4.50) 287 (3.28) 350 (3.41) 66JCS(C)1127
aSolvent not given.
N
C
""
.
-
:;:s-
VJ
.
I
CJ'o
C">
'<
C">
""-
c:;.
::ö
Sf
w
o
--..J
308
Pyrazoles with Fused Six-membered Heterocyclic Rings
4.05.2.2 NMR Spectroscopy
Many of the published l H NMR spectra have not been unequivocally assigned. Some
that have are given in Table 2. An interesting comparison between a l-alkyl- and a
2-alkyl-pyrazolo[ 4,3-c ]pyridine is shown in Scheme 2 (73T441). The 13C chemical shifts for
pyrazolo[I,5-a ]pyridine are shown in Scheme 3 (81JHC1149, 74HCA873) and 13C chemical
shifts (DMSO) for two pyrazolopyrimidinones (7) and (8) are noted in their formulae
(73JHC431 ).
9.1 8.15
N
8.37 NI
7.21 \
5.55.......
Ph 7.25
h77 Hz h7 0.6; J 6 . 7 7 Hz
Scheme 2 tH NMR chemical shifts (8, p.p.m., CDCI 3 ) for l-alkyl- and 2-alkyl-pyrazolo[l,5-a]pyridines
tX 9 . 15 05
N---\.59
8.26 :--"N/ Ph
7.52 7.33
140.41139.51
1117.37) J
118.3 96.9196.25)
1112.35) 123.3 w ::::--
IÍ 142.1 1141.291
1110.8311'11.8 N-N
128.8
1128.08 )
Scheme 3 l3C NMR chemical shifts (p.p.m.) for pyrazolo[I,5-a]pyridine (1) in CDCI} (neat liquid)
(7)
139.14
N 1133.81
143'00( :;ç; N
HN \ r/
/' H
153.36 0 126.81
(8)
105.63
157.91,0 J
34'14
HN I N
147.57 N i i
154.45
4.05.2.3 UV Spectroscopy
UV spectra in this series show typical aromatic, multipeak, envelopes. Sorne absorption
maxima for simple b -fused pyrazoles are shown in Table 3.
4.05.2.4 Tautomerism
Available examples of compounds carrying oxo substituents in the six-membered ring
all have the carbonyl group a and l' to a pyridine-type nitrogen and, as expected, strongly
favour the keto forrn. Scheme 4 gives some typical spectroscopic results in support of this
generalization; none of the compounds shows a hydroxy band in the IR spectrum (70CB3252)
(but see Scheme 45, Section 4.05.4.2.2 for a special case).
H Me
o NON
X) X)
Am.. (MeOH) 230 nm (log E 4.30),
268 (3.8})
IR (KBr) 1738,1672, 1578cm-'
Scheme 4
H
N
ç'r)
o
Am.. (MeOH) 210 nrn (log E 4.37), Am.. (MeOH) 211 nm (log E 4.39),
215 (4.27), 250 (3.57), 271 (3.64) 257 (3.88), 297 (3.79)
IR (KBr) 1678 cm- 1 IR (KBr) 1682, 1624, 1583 cm- 1
UV and IR absorptions fOi pyrazolo[I,5-a]pyrimidines
Allopurinol (9; X = 0) has an IR absorption (solid) at 1695 crn- 1 (C=O) and thiopurinol
(9; X = S) at 1195 crn- 1 (C=S), both being strong bands with no OH or SH absorption.
Similarly (10; X = 0) shows 1680 and 1210 cm- 1 bands, and when X = S, absorptions occur
at 1210 and 1200 cm- 1 (69CR(C)(268)1798).
Pyrazoles with Fused Six-membered Heterocyclic Rings
309
x X 0
H H N / N H N
- _.J-,,! s -.J-"( N N N NI
N H H Me
D
Strong carbonyl bands are shown by the pyrazolopyridazines (11) and (12) at 1670 and
1680 em -1, respectively. The IR spectra are little changed by methylation at N(5) (73T43S).
2-Hydroxypyrazolo[1,5-a ]pyridine (13) has been examined carefully and shows no
evidence for a carbonyl tautomer. The IR s ectrum (CHCh) has an OH band at 3000 cm- 1
and a band assigned to C=N at 1635 cm- . The UV spectrum with Åmax (MeOH) at 232
(log e 4.59), 281 (3.09) and 310 nm (3.10) is very sirnilar to that of the O-methyl derivative
(14) which shows Åmax at 234 (log e 4.57), 282 (3.30) and 307 nm (3.31). The N-methyl
derivative (15) is clearly different, with an IR band at 1660 cm- I (C=O), and Åmax (MeOH)
at 242 (log e 4.47), 281 (3.89), 288 (3.88) and 341 nm (3.32) (Scheme 5) (76BCJ1980).
HN ):: O ,;;:..-
I NMe
N '"-N/
OMe CCH2N2 OH
N_: N_:
(14) (13)
Me2S0. ) (14)
Na2C03
co
+ 0
:::::,... N-N
(15) Me
Scheme 5
3-Hydroxy derivatives of pyrazolo c-fused compounds give conflicting results. For
example, there is evidence for the carbonyl form in 3-hydroxypyrazolo[ 4,3-c ]pyridine
but the II(C=O) absorption seems to be absent in I-substituted 3-hydroxypyrazolo-
[3,4-b ]pyridines and in pyrazolo[3,4-d]pyrimidines (B-76MI40S00).
4.05.3 REACTIVITY
Electrophilic attack at carbon always occurs at C(3) of the pyrazole ring but if a bridgehead
nitrogen is present, a second attack on the six-mernbered ring may follow almost as rapidly.
A bridgehead nitrogen apparently donates its lone pair to complete a 107T- aromatic system
so it is not surprising that both rings are activated towards electrophiles.
The conditions used for nucleophilic attack on pyridine and the diazines are probably
too severe and would cause decomposition of the fused systems considered here. Further,
the b -fused pyrazoles would clearly be deactivated to nucleophilic attack and in the c -fused
pyrazoles, electron withdrawal by the pyrazole ring would make attack on the six-membered
ring difficult. However, displacement of a suitably positioned halide or other good leaving
group is often possible.
4.05.3.1 Electrophilic Attack at Nitrogen
The 107T-electron system (1) is very weakly basic (pK a 1.43), but in strong acid it
protonates at N(1) to give the 107T ++ 67T resonance system (Scheme 6) (71JOC3087).
However, the UV spectrum is little changed so presumably the 107T-system makes the
majór contribution (64JCS4226).
Cú H+ (Q CO I'
8 8-
:::::,... N-N :::::,... N_Ñ :::::,... -N
(1) H H
Scheme 6
The pyrazolopyrirnidine (16; R = H) has pKa 2.84
R = NH 2 ) has I'Ka 5.00 (S8JCS2973).
N
f.''rN
N N'
R
(16)
and its 7-amino derivative (16;
N :J:j NH 2 N :t NH2
1 I N 1 NR
/ :::::-./
N N N -1''1
R
(17) (18)
310
Pyrazoles with Fused Six-membered Heterocyclic Rings
4-Aminopyrazolo[3,4-d]pyrimidine is a tautomeric system with a calculated (from tem-
perature jump l3C NMR relaxation studies) AH(tautomerism) of 3.8 kJ mol- 1 at 10 0 C
giving K(18; R=H)/(17; R=H) of 0.1. The interconversion is catalyzed by acid (via the
common cation) or base (via the anion). The parent system has pKa 4.61 (for anion
formation, pKa 11.03) and the derivatives (17; R = Me) pKa 4.30 and (18; R = Me) pKa
5.11. The sites of protonation have been investigated for the isopr pyl derivatives by 13C
NMR; compound (17; R = Pr') protonates at N(5) but (18; R = Pr') proto nates equally at
N(5) and N(7) (77JA7257). 4-Aminopyrirnidine has pKa 5.7, showing that the pyrazole ring
of (17) and (18) exerts, as expected, a net electron-withdrawing effect.
The pyrazolopyrimidinone (19) gives the product of N(4)-methylation with dimethyl
sulfate and sodium hydroxide, but diazomethane produces a mixture of N(1)- and O-methyl
derivatives (Scheme 7) (78FES14).
H
N N N
Me ç Me c CH2N2 Me ç
lPh + , jPh +-- I jPh
N-N N-N N-N
o Me OMe 0
(19)
Scheme 7
Me
N
Me2S0., NaOH Me ç
j , jPh
N-N
o
The 3-nitropyrazolopyridine (20; R = H) is alkylated at N(1) by methyl iodide to give
(20; R = Me) (73JCS(Pl)2901), but the 7-aminopyrazolopyrimidine (21) alkylates in the
six-membered ring while acylation followed by reduction provides a route to the secondary
amine (22; Scheme 8) (65CPB142). It is interesting that one of the three entering methyl
groups when (23) is treated with excess dimethyl sulfate goes to N(2) rather than N(1)
(Scheme 9) (58HCAI052). With the pyrazolo[ 4,5-d]pyrimidine (24; R = H), dimethyl sulfate
gives a mixture of products (25) and (26), but for (24; R = Me) only compound (25) is
produced (Schern@ 10) (65JOC199) (see Section 4.05.4,3.1 and Scheme 5, Section 4.05.2.4).
(20)
El
ç N EtI C N
I jMe (acetone ,jMe
N-N N-N
NH 2
NH (21)
i, AC20, PY j
ii,LiAIH.
C Ny)Me
N-N
NHEt
(22)
N N0 2
Me (JÇ 1 N
/
N
R
Scheme 8
o
HN N
O NJ-N
H H
(23)
o
Me2S04, NaOH MeN
I NMe
A 0-/
o N N
Me
Scheme 9
R Me Me
o NON 0 N
Y N Me2S04j Y N + Y =;t: NMe
RN / MeN / MeN 0- /
N N N
o HOMe 0
(24) (25) (26)
Scheme 10
The useful intermediate (29) is formed when the pyrazolopyrimidine (27) is treated with
the hydroxylamine (28) at room temperature (see Section 4.05.3.5) (81JCS(P1)2387).
NH
H2NN N
- .jl (
N N
R
N 0
_ .J-- (N + 02 N IÍ ONH 2 -+
N N0 2
(27) R = protected ribosyl (28)
(29)
Pyrazoles with Fused Six-rnfrnbered Heterocyclic Rings
311
Acylation of a pyrazolopyridine has been shown to be temperature dependent. In the
cold, benzoyl chloride and pyridine give the 2-acyl derivative (30), but at reflux the sarne
mixture gives the 1-acyl compound (31; Scheme 11) (73JCS(Pl)2901).
(X) N ::;-- (Ç N
NCOPh -- I N --
"-,,.../ /
......." N N
H
(30)
N
(Ç I N
/
N
COPh
(31)
Scheme 11
4.05.3.2 Electrophilic Attack at Carbon
Generally, C(3) of the five-membered ring is the position of electrophilic attack, but the
rate of reaction and the possibility of a second substitution in the six-membered ring depend
on the fusion system. The b-fused pyrazolopyridine (1) is readily nitrated at C(3) at ice
bath temperature, but a dinitro derivative (33) is produced at roorn temperature. Use of
fuming nitric acid in acetic anhydride gives a mixture of two C(3) derivatives (Scheme 12).
Alternatively, nitrous acid converts (1) to the 3-nitroso compound which may be oxidized
to (32) with peracetic acid (74JHC223). Derivatives of (1) carrying electron-donating groups
at C(2) substitute very readily at C(3). For example, (34; R = Me) gives the 3-acetyl derivative
with acetyl chloride and pyridine at room temperature (68JOC3766). Compound (34; R = OH)
gives 3-nitroso (with HNO z ) and 3-nitro (with fuming HN0 3 at OOC) derivatives and, with
1 mole of bromine (in acetic acid-sodium acetate), the 3-bromo compound. With a second
mole of bromine the unusual 1,3-dibromo derivative (35) is obtained. The hydroxy group
of (34; R = OH) shows pyrid-2-one character in being replaced by chlorine with phosphorus
oxychloride to give (34; R = Cl) (76BCJ1980).
r --N
(32) + +N=O C HNO;:t 20 (1)
N0 3 -
N_t
HN0 3 . H 2 S0 4
Q'C Þ
z
N_I
(32)
HN0 3 . H 2 S0 4 Þ
25'C
z
N_/
(33)
Scheme 12
R
N_I N_rrO
(34) (35) Br
Pyrazolo[1,5-a]pyrimidine (2) gives the 3-brorno, followed by the 3,6-dibromo, deriva-
tives. Several attempts failed to find conditions to give the 6-monobromo compound.
'Normal' nitration conditions gave the 3-nitro derivative (36) but nitric acid in acetic
anhydride gave exclusively the 6-nitro product (38). It has been suggested that this results
from rapid formation of (37), followed by loss of acetic acid on work-up (Scheme 13)
(75CJC119). The 5,7-dimethyl derivative (39) of (12) gives exclusively 3-substitution with
electrophiles. A nitration mixture at 10 oc gives (40; E = N0 2 ). N -Bromosuccinimide and
N NO z N N N
( . HN0 3 . H 2 S0 4 ( HNO".AC20þ OzN,JÝ" __ (
N_j Q'C N_t O'C H N_/ OzN N_t
H OAc
(36) (2) (37) (38)
Scheme 13
Me ( NY)
N-N
Me
(39)
N E
Me ( Y)
N-N
Me
(40)
4 3
Me
_ )Me
N N_N
(41)
N 8
(Y)
N N_N
NHPr
(42)
312
Pyrazoles with Fused Six-membered Heterocyclic Rings
N -chlorosuccinimide give (40; E = Br, Cl) and iodine monochloride gives (40; E = I).
Friedel-Crafts acylation (acetyl chloride-tin(IV) chloride-dichloromethane) gives (40; E =
Ac) and the Mannich reaction gives (40; E = CH2NMe2) in acetic acid at room ternperature
(74JMC64S). The pyrazolo[1,5-c ]pyrimidine (41) gives first the 3-bromo then the 3,4-dibromo
derivatives (72CB388). The pyrazolotriazine (42) brorninates in the five-membered ring at
C(8) on brief boiling with N -bromosuccinimide in chloroform (74JHC199).
4.05.3.3 Nucleophilic Attack at Carbon
Despite the significant arnount of work that has been done on pyrazolopyridines and
pyrazolopyrimidines, there seerns to be no report of direct nucleophilic substitution on
these systems. The pyrazolotriazine (43) reacts with 0.5M sodium hydroxide solution at
room ternperature. One carbon is removed to give a useful intermediate (44; Scheme 14)
(74JHC199).
N
MeSr n
N N_
/'
-OH
(43)
O.5M NaOH þ
r.t.
N N
MeSr n -+ MeSr n
-NXN_N HN N_N
H OH H
1
N
MeS"::::' <EtOt,CMe
I I;J ·
N N-N
Me
N
MeSr . O.5M NaOH
H 2 N H -N') Lt.
(44)
MeSyNT)
H 2 N OHCN_ N
Scheme 14
When the six-membered ring is strongly activated, e.g. by a 6-nitro substituent, nucleophilic
attack by alcoholic alkali may lead to rearrangement as in Scheme 15 (81T3423). These
reactions are analogous to those occurring in the corresponding 1,2,4-triazolo-pyridine
and -pyrirnidine systems.
þN n CN::t) Q'N-'y"\ií'> Q,N
02N N_ -+ 02 N b N_ -+ l.. "l -+ . .J--"l
\ N N N
-OH H OH H
Scheme 15
Many reports of nucleophilic displacement of halogens and methylthio groups have
appeared. A few examples will serve to summarize this work.
Scherne 16 illustrates the ease of displacement of chlorine from the C(4) position of (45).
In the pyrazolopyrimidine derivative, disubstitution can generally be achieved by the use
of higher temperatures and longer reaction tirnes. Only dimethylamine has been found to
disubstitute too rapidly for the monosubstitution product to be isolated. For the products
(46; R = OMe or SMe), aqueous methylamine at 80 0 C gives (46; R = NHMe) without
replacing the chlorine atom, but with (46; R = SH) the chlorine rather than the thiol group
is replaced. Similarly for (46; R = OH) the chlorine atorn is replaced by ethanolic amrnonia
at 200 o C. In contrast to the dichloro compound (45), the methoxymethylthio derivative
(47) or the dimethylthio cornpound gives the 4-dimethylamino derivative (48) without
displacing the 6-methylthio group. These nucleophilic reactions probably take place on the
anions of the pyrazolopyrimidines. If the 1-methyl derivative of (45) is employed, the C(6)
aq NaOH
Cl
N
Cl . .J--N'N
N H
(45)
NaSH, o'c
KSMe. 0 'C
R
N
Cl _ .J-- t
N H
NaOMe, 0 'C
RNH"
aq. EtOH
RO'C
146) R = OH, SH, SMe, OMe, NHR
Scheme 16
Pyrazoles with Fused Six-membered Heterocyclic Rings
313
OMe NMe2
N N
Mesl.NJL. t -- Mesl.NJL. t
H H
(47) (48)
chlorine atom is rnuch more readily displaced (57JA6407). Further examples of nucleophilic
attack at C(4) are shown in Scheme 17 (8lJCS(Pl)2387).
N g CN
'::N N .i- N N -'+ N N N
. .J-- ; . .J-.- ! ..J-.J ..J-- ;
N N N N N N N N
R R R R
R = triacetylribosyl
i, UN 3 , acelone, 25 oC; ii, ethyleneimine; iii, NaI, acetone, reflux
Scheme 17
Difficulties encountered in nucleophilic displacement at the C(6) position of pyrazolo-
[3,4-d]pyrirnidines are illustrated in Scheme 18. Compound (49; R = H) shows no carbonyl
absorption in its IR spectrurn. Electron release from its hydroxy group deactivates the
pyrimidine ring so that the methylthio group is not displaced by any of the cornmon
nucleophiles. Oxidation with chlorine water gives the sulfone, a much better leaving group,
which is displaced by ammonia to give (51). Conversion to the 3-chloro compound (50)
allows attack at C(6). The 3-chloro substituent slightly activates the pyrimidine ring. For
(50; R = Me) the methylthio group can be replaced by OH (NaOH), OEt (NaOEt) or NH 2
(NaNH 2 ). Position C(3) is not attacked; the chlorine atom rernains in position even after
24 h at 200 0 C with ethanolic ammonia. Strong base converts (50; R = H) into its anion
and no nucleophilic attack occurs (6lJOC451).
CI OH OH OH
N N CPOCI, N N CI 2 .H 2 0) N N NH,) N N
MeS . .J-.-'''/ N NI MeS _ .J-.-NI Me02Sl.. .J-.-N' H2N _ .J-.-NI
R N R N H N H
(50) (49) (51)
Scheme 18
4.05.3.4 Reduction
The usual hydrogenolysis of aromatic halogen derivatives over palladium or platinum
usually succeeds in these fused-ring systems. For example, the brornine is removed from
3-bromo-5,7-dimethylpyrazolo[1,5-a]pyrimidine (75JMC460). In the example of Scheme 19
the halogen is lost after five minutes at room temperature. Within 2 h the six-membered
ring is reduced as well (65CPB1207). Partial reduction of (52) with sodiurn borohydride gives
(53) (79FES751). Reduction of a pyrazolopyridine is accompanied by decarboxylation
(Scheme 20) (75JHC517).
e N 'f)M e
::::,.. N--N
Cl
H
H 2 Pd e N C N
, Me -- , Me
::::,.. N--N N--N
Scheme 19
e N
, Ph
Et0 2 C::::,.. N--N
Me
(52)
H
N Sr
NaSH.) C n Ph
El0 2 C N--N
Me
(53)
314
Pyrazoles with Fused Six-membered Heterocyclic Rings
Me Me
H0 2 C (C 1 N LC N
M I I
e N N N N
Me Me H Me
Scheme 20
The 3-hydroxypyrazolopyrazine (54) undergoes reductive ring-opening with Raney
nickel. A lower reaction temperature suffices for its i-methyl derivative (Scherne 21)
(58JA421). This reaction often succeeds with cyclic hydrazides of this type.
N N OH N OH N
r ) CONH 2 Ä r JC N --1L. r JC N r ) CONH 2
NH N 1 N 1 NHMe
N 2 N N N
(54) H Me
i, Raney Ni, NH 2 CHO, 115-120 oC; ii, Mel, NaOH; iii, Raney Ni, EtOH, reflux
Scheme 21
The pyrazolo[1,2-a ]pyridazine (55) reacts with sodium methoxide in boiling methanol,
presumably via preliminary deprotonation at benzylic carbon. After 8 h a mixture of (56;
72%) and the Hofmann-type elimination product (57; 12%) is obtained, but after 25 h
only (57; 75%) is isolated. The imino bond (v 1640 em-I) of (57) may be saturated with
sodium borohydride. With potassium t-butoxide in t-butyl alcohol at reflux, the rearranged
isoindole (58) is obtained (Scheme 22) (74CPB2142). Scheme 23 shows a rearrangernent
similar to (55) (56) for which a radical mechanism has been suggested. However, here,
both radicals from N-N bond homolysis are resonance stabilized. Ring closure is to the
thermodynamically more stable system (59) (ncPB69).
H
OC I %0 J N
Me ,- ;_
(55) (56)'
'
N NHMe
(58)
Scheme 22
-+ OC =>
Me
(57)
cç Me
: I ) -OM.)
o ,-
cç l - ) e -. rY' ) e
N N
o 0
1
Me
cç ) Cç()
o 0
(59)
Scheme 23
ArH Ar Ar
C:=> (Na,NH, C +=> NaOM. ) C D
Me Me í
(62) (60) (61)
Scheme 24
Pyrazoles with Fused Six-membered Heterocyclic Rings
315
Compound (60), which lacks only the benzo fusion of (56), follows a different reaction
path with boiling sodium methoxide in methanol (Scheme 24). Deprotonation of the methyl
group has been suggested as the first step in the production of the diazabicyclodecane (61).
Reduction of (60) splits the N-N bond to give the diazacyc1ononane (62) (69JOC2720).
4.05.3.5 Reactions of Substituents
The hydrazino cornpound (63) (from nucleophilic displacement of chlorine with
hydrazine) reacts with triethyl orthoformate under rnild conditions to give the fused triazole
(64). Heating in a neutral solvent gives the thermodynamically more stable, isomeric fused
triazole (65) which can also be obtained from (63) directly. The 5-amino derivative (29;
see Section 4.05.3.1) is readily converted into (65; Scheme 25) (81JCS(P1)2387).
N-N
NHNH 2 (
CCI' -4 tJl)
N N N N
R R
(63) (6;:
NH 1/ 2c 7
H2NN N N'N I '\:IN
NJ--N N N
R R
(29) R = protected ribosyl (65)
i, (EtOhCH, 70 o C, 45 min; ii, MeO(CH 2 hOH, reflux; iii, (EtOhCH, reflux, 12 h or TsOH, 25 0 C; iv,
MeC0 2 CH(OEth
Scheme 2S
Catalytic hydrogenation of 3-nitro or 3-nitroso ring-fused pyrazoles (see Section 4.05.3.2)
gives the 3-amino derivatives which on diazotization often give stable diazo compounds.
For exarnple, compound (66) heated with hydrobromic acid gives the 3-bromopyrazolo-
pyridine as expected (Sandmeyer reaction) (73JCS(P1)2901). However, photolysis in benzene
produces the phenyl derivative (67), or treatment with 2,5-dimethylfuran in methanol gives,
after rearrangernent, the 3-pyrazolyl derivative (68). A salt of (66) rapidly undergoes a
Diels-Alder reaction to give the 3-pyridazinyl salt (69; Scheme 26) (78JHC1175).
rlOMe
Me/(_ _;N
N
N
_ _Jl')
N N
H
(68)
_ J ,)
N N
H
(67)
Ä-
N 2
CC N
N N
(66)
Liii
Me
Me O
+/.N
N'" -
OJ BF4
I N
::,... /
N N
H
(69)
i, C6H6, hv; ii, 2,5-dimethyIfuran, MeOH, 0 oC; iii, for BF; salt, 2,3-dimethylbutadiene, ooC
Scheme 26
316
Pyrazoles with Fused Six-membered Heterocyclic Rings
The diazoniurn salt (70) is prepared frorn the amine with sodiurn nitrite in tluoroboric
acid. Photolysis of the resulting solution gives the 3-tluoro derivative (71) (77JMC386).
+
Me ( Ny)
% N.....N
Me
(70)
BF- N
4 Me ( n
N.....N
Me
(71)
4.05.4 SYNTHESIS
4.05.4.1 From Non-heterocyclic Compounds
In neutral solution, cyanoacetohydrazine (72) reacts with acetylacetone to give the
enaminone derivative (73) which, under carefully controlled alkaline conditions, cyclizes
to the pyrazolopyrirnidine (74). The hydrazine (72) also reacts with diketene to give (75;
Scheme 27) (61LA(647)116). The aldehydo nitrile (76) and hydrazine hydrate in refluxing
toluene give (77; 30-54 % depending on conditions) along with a sirnple pyrazole (71AP121).
The enol ether (7S) and hydrazine give the hydrogen bonded bis-enarninone (79) which on
heating collapses to the fused heterocycle (SO). The reactive substituents are removed by
standard rnethods to give the dirnethylpyrazolopyrirnidine (SI; Scherne 28) (70BCJ849).
H N
N 0 t ill
Me ç iii U N i I "0 1 ii
q>OH H NNH.......'-..../ -- --
N..... 2
N N-N 0
o H H
(75) (72) (73)
Me ( N
';OH
% N-N
Me
(74)
i, pentane-2,4-dione; ii, NaOH (2.4 eq.); iii, diketene
Scheme 27
(78)
N
Phý NH ( NT)
Ph% N.....rt
NH 2
(76) (77)
H
o N CO 2 Me
N;cr)Me
Me
(80)
iii, iv, v, VI
( N DMe
N-N
Me
(81)
NC CO 2 Me O"'H M N
:1 MeO-f -N\ rOMe Ä
OMe ....T');=< H'''O
C
(79)
i, N 2 H 4 , EtOH, CsHsN, 2S oC; ii, EtOH, reflux; iii, aq. NaOH; iv, Ä; v, POCI 3 ; vi, H2' catalyst
Scheme 28
Irnportant syntheses of allopurinol (85; R 2 = H) and oxyallopurinol (S7; R 2 = H), both
used in the treatrnent of gout (see Section 4.05.5), are shown in Scheme 29. Cyanoacetic
acid and formamide react in hot acetic anhydride to give (S2; R 1 = H) which is treated,
without isolation, with triethyl orthoformate to give the enol ether (S3). This is converted
into the hydrazine (S4). Heating (S4; R 1 = H, OEt; R 2 = H) for a few rninutes gave the
pyrazolopyrirnidines (S5) and (87) directly, but for (S4; R 2 = Me, Ph) gentle heating during
recrystallization from nitromethane gave the isolatable pyrazoles (S6) which closed the
second ring on stronger heating. A further elaboration of this general approach is shown
in Scherne 30. The dithiocarbarnate (SS) can be converted directly into the
pyrazolopyrimidine (S9) or taken via the substituted pyrazole as before. The product (S9)
is hydrolyzed to (S7; R = Ph) by warm aqueous chloroacetic acid (71JCS(C)1610).
2,3,5-Tri-O-benzyl-D-ribose condenses with hydrazine in rnethanol at roorn tern-
perature to give the derivative (90). This reacts as shown to give the protected nucleosides
(91; Scheme 31) (81S92S).
Pyrazoles with Fused Six-membered Heterocyclic Rings
317
N 0 0 N 0 0
i li r A ii li r A
--. N R 1 --. N R'
1 H 1 H
EtO (83) RZHNHN (84)
o I m
HN N ÄR'^ HN N
O JlN HzN( ; dJlN
N R z N N R z
H R Z
(87) (86) (8S)
N 0 0
III U A
"""N R'
H
(82)
i, (EtOhCH, AczO; ii, RZNHNH z ; iii, for R 1 = R Z = H, 150 o C, 15 min; iv, for R 1 = H, R Z = Ph; or R 1 = OEt,
R Z = Me, Ph, warm; v, for R 1 = H, R 1 = Ph, ß; vi, for R 1 = OEt, R Z = Me, Ph, ß; vii, for R 1 = OEt, R Z = H, 140 0 C
Scheme 29
CN 0
rY
S N
SEt
m 0 Å
PhNHNH 2 Þ 0 1 N H SEt--4
EtOH J
PhNHNH
o
HN N
S NJlN
H Ph
(89)
The pyrazoloquinazolines (92) and (93) are available in high yield as shown in Scheme
32. The reactants are boiled with dilute hydrochloric acid (69JHC947).
N
III
+ EtO
L COzEt
Scheme 30
CN
BzO 0 NHNH z A (a)
u'-) + EtO or CN
H CN
A (b)
EtO ì;- NHCHO
o
BzO OBz
(90)
Scheme 31
N
I III
H2N
0 1 NHNH2
COzH
+
1
(88)
--.
R
N :)J
I I /
N
B'O
BzO OBz
(91a) R = NH 1
(91h) R = OH
H
0 0 NT)Me
--N
I Q
(92)
H
0 0 Nn2Et
--N
I Q
(93)
Scheme 32
Nitrilimines (94), which are reactive 1,3-dipoles, undergo [3 + 2] cycloadditions with
alkenic and alkynic dipolarophiles. Their use in the preparation of benzopyrazolooxazines
and benzopyranopyrazoles, often in high yields, is illustrated in Scheme 33. The reactive
interrnediates, e.g. (96), are generated by elimination of hydrogen chloride from suitable
substrates (95) and (97) (74TL269), or by photolysis of tetrazoles (98) (78JOC1664). Pyrazoles
Rl_C=N=N-Rl R 1 -C:=N-Ñ-R 2 R 1 -C=N-Ñ-R 2
(94)
318
Pyrazoles with Fused Six-membered Heterocyclic Rings
of type (99) can be prepared by rnild oxidation (DDQ or chloranil (77HCA303S)) or directly
from the appropriate alkyne. These intramolecular 1,3-dipolar cycloadditions provide entry
into fused-ring systerns not readily available by other routes.
./'-..- ./'-..-
& 0 J & 0; + & 0 N:;;-'fiC02Et
I 'N"<: C0 2 Et I 'N-:0-C02Et -+ I ....N
d- (95) d- (96) d-
O
CI NPh
" " I
NNHPh ..,N, I: N
(97)
6z : N
I I II
d- N" "N
N
(98) Me
hv
--
c;:;--
NMe NMe
I: "N I I: "N I
(99)
Scheme 33
A general method for the preparation of fused pyrazoles with a bridgehead nitrogen
atorn is the [2 + 3] cycloaddition of an alkyne to a diazoketone. A spontaneous 1,5 sig-
matropic rearrangernent completes the reaction. For exarnple, diazocyclopentanone and
dirnethyl acetylenedicarboxylate give the unstable adduct (100) which rapidly changes into
the pyrazolopyridine (101) (73JOCS2S). The diazoketone (102) reacts with benzyne (frorn
diazotized anthranilic acid) in refluxing dichlorornethane (73TL1417), and the diazoben-
zopyrazole (103) reacts with the ynamine by a similar rnechanism (Scherne 34) (7SCB22SS).
Even diazanorbornanone and diazacamphor react in this way (73AG(E)240).
YN 2
o
DMAD
-+
[ C02Et ]
yçr'Et
(100)
ÇQ C0 2 Et
:- fi C0 2 Et
....N
o
(101)
N z
0 benzyne.
V-Nr
H
(102)
N 2 Me N
OJ I U( N
N + III -+
I II I " ..-N Me
N NEt l N NEt 2
(103)
Scheme 34
4.05.4.2 Six-membered Ring Synthesis by Formation of One Bond
4.05.4.2.1 a to a heteroatom
An elegant synthesis of pyrazolo[1,5-a]pyridine (1) in 47% yield is shown in Scherne 35.
Sodium rnethoxide in diglyrne at 180 oC catalyzes the rearrangement of the bis-hydrazone
(104) and evidence is available for the indicated mechanism. The same technique also
allows the preparation of the fused cyclopropane derivative (105) (74HCA12S9).
Hot aqueous sodium carbonate is sufficiently basic to catalyze the ring closure of (106)
to (107), where the amino group attacks the nitrile carbon atom (60JCS2S36). Dinitriles like
(108) are ring closed under acid catalysis. The reaction usually occurs in one step, but the
intermediate acid amide can be isolated if necessary (Scherne 36). Protonation of the
carbonyl oxygen atorn of the acid group allows attack by the amide nitrogen (S9JA24S2).
Pyrazoles with Fused Six-membered Heterocyclic Rings
319
H _
TsN TsN
......N ......N N+
<> <> <Q <Q
N...... N...... _ N 2 + N 2 +
NTs NTs I
(104) H
(0--
(1)
(t)
N 2 +
Scheme 35
NNHTs N O o 0
<(P
N.N to H 2 N ...NPh aq. Na 2 C0 3 . (r3NPh
-- n
N-N H 2 N N/
N N Ph
NNHTs Ph H
(105) (106) (107)
o
N NC NH 2 H ?;} NH2
\ n NaOH. 2
...N H 2 0 ...N MeOH
N HO N
H ", 0 H /
(108) '" c. HCI, reflux
Scheme 36
üÇ o NH2
HN I }
o N
H
The appropriate aldehyde treated with nitromethane (NaOEt) and reduced (H 2 /Ni) gives
the amino alcohol (109). Triethylamine catalyzes lactam formation and further elaboration
gives the fully aromatic pyrazolopyridine (110; Scheme 37) (73T441).
o
C0 2 Et tç
H J-Ç -.!... HN :;:;.- NMe ii, iii. iv. N o::; :;:;.- NMe
NMe ,... / ,... /
N/ N N
H 2 N (109) OH (110)
i, Et 3 N; ii, KHS0 4 , mell; iii, POCI 3 ; iv, H 2 , Pd
Scheme 37
Sodium hydrosulfide hydrolyzes the nitrile group of (111) to the thioamide which spon-
taneously undergoes ring closure to thiopurinol (112) in 97% yield (66AG(E)308). Alkaline
peroxide hydrolyzes the nitrile (113) and allows attack on the neighbouring acetyl group
to give (114). This is a general rnethod for the preparation of fused pyrimidines (S8JOC191).
NC
El0 NnN
N)
H
(111)
---. H' f J HN:X>
Et NJLN: N N
H H
(112)
NC
MeCONHCN
N'"
H
(113)
H 2 0 2 , KOH.
o
HN N
Me .JlN
N H
(114)
320
Pyrazoles with Fused Six-membered Heterocyclic Rings
In Scherne 38 an isoxazole is used to generate the vinylogous urea which ring closes with
alcoholic hydrogen chloride (72JHC9S1). In the sarne way the isoxazolyl carboxarnide (115) is
changed, via the substituted enarninone, into (116) (74JHC623).
2R
Ph H 2 N Ph Þ ì Hl
n F\ 'Ç h
N,_)- O N, _ ;;
N N
o
Scheme 38
H
N
Ph Ç
reflux I N h
-N
o
H
N Me Ph 0 N
/", n H,.Ni '1'.
Ov>-CONH-i.:-..N....N ----=-+ Meoc N_jPh
Me H Me
(115) (116)
The conditions for the general method of formation of pyrazolo[ 1 ,5-a ]pyrimidines shown
in Scherne 39 seern to be critical. In one r port (77ZN(B)307), prolonged reflux of (117a) in
glacial acetic acid gave only (118a, 75%). In another (70BCJ849), the use of alcoholic
hydrogen chloride produced a rnixture (117a to 118a, 30% + 118b, 63%). Clearly there is
little difference between the activation energies for attack at nitrile and ester. For (117b)
only the keto group reacts to give (118c) (81JHC163).
H
N
)HU
Et0 2 C R -N
(117a) R = CN
(117b) R=COC0 2 Et
N
-+ R2('Q
R 1
(118a) R 1 = NH 2 ; R 2 = C0 2 Et
(118b) R 1 = OH; R 2 = CN
(118c) R 1 = R 2 = C0 2 Et
Scheme 39
3-Amino-5-phenylpyrazole reacts with aqueous nitrous acid to give the stable (rn.p.
168 OC) diazonium salt (119). With active rnethylene cornpounds, this gives the derivatives
(120; R = CN, C0 2 Et) which are isolated and dissolved in concentrated sulfuric acid to
produce the pyrazolotriazines (121; R = NH 2 , OH) (76JOC3781). Two further exarnples
illustrate this widely used procedure. The diazonium salt (122) gives the derivatives (123;
R = Me, OEt) with acetylacetone and ethyl acetoacetate, respectively, and compound (124)
with 2-naphthol (81M24S). The stable diazo cornpound (125), prepared with isopentyl nitrite
and fluoroboric acid followed by sodium carbonate, reacts with cyc1ohexane-1,3-dione to
give first the hydrazone and, on acid treatrnent, the tetracycle (126) which is arornatized
to the corresponding phenol by strong heating (Scherne 40) (78JHCl17S).
+ H
N 1 N'N Ü ...N
0- N n Ph -+ II N 1 Ph -+ .'" UPh
I'N/ ^, NC':: ......N-N
H NC R R
(119) (120) R = CN, C0 2 Et (121) R = NH 2 , OH
+ N
...N Ph N 1 Ph N-::-
N'" c;;;-- 0- I IMe
R. 1--... T)Me -- N Me -+ W ::::,... N-N
Y -N 'N I
o Me H::::,... Q
(123) R= Me, OEt (122) (124)
Base-catalyzed ring closure of the isothiocyanate derivative (127) gives the pyrazolo-
[1,5-a][1,3,5]triazine (128; Scheme 41) (74JHC199). The sulfur may be removed with Raney
nickel in arnmonium hydroxide. Another example of this versatile route is the forrnation
of (130) in Scherne 42. However, the starting material (129) also has a hydrazone group
Pyrazoles with Fused Six-membered Heterocyclic Rings
321
+ N
cct;\ CÀJh o
N H-GV U
(125) (126)
Scheme 40
NH 2
(;N
N/
H
S=C=NC0 2 El þ
H
nN'fS
Z)I NH
N I
H C0 2 Et
(127)
Scheme 41
2M NaOH
Þ
25'C
H
r==Y'N 'fS
" N NH
N- Y
o
(128)
/N :C O
PhN" c H so
NH
o N """N /
H
(131)
PhNHN H NNHPh
O=<-rN'fS o=<-T-N'fS
N_N 7 H N_N'-.;7N
H co Ph H Ph
(129) (130)
Scheme 42
which, in acid, takes part in the ring closure. Elimination of benzamide occurs to give the
pyrazolo[3,4-e][1,2,4]triazine (131) (77ZN(B)430).
The ketone (132) gives the pyranopyrazole (133) on heating with strong acid, but under
reducing conditions the tetrahydro derivative (134) forms (Scheme 43) (81KGS403). The
8- keto acid (135) gives the a- pyranone (136) with thionyl chloride. Treatment with
hydrazine reopens the ring and the resultant hydrazone/hydrazide (137) may be reclosed
either to a pyrazolodiazepine (138) or to a pyrazolopyridine (139) according to the reaction
conditions (Scheme 44) (8IJHC271).
Ph M o Ph
e Ph Me
PPA \
PhCX-:;N (gO'C 0 N....N
o Ph Ph
(133) (132)
Et 3 SiH. CF 3 C0 2 H
BF3
Ph Me
þ N
Ph"-oAN/
Ph
(134 )
Scheme 43
o NNH2
Ph SOCl 2 þ Ph ÇÇ I N N 2 H 2þ Ph
\ 0 N/ \
H0 2 C ....N H H 2 NNHOC N
N 0
(135) H (136) (137) H
Ph ;/
NrrN --.!:!f4 PhmN
b--l'-1 H2NN i
H 0 H 0 H
(138) (139)
Scheme 44
4.05.4.2.2 'Y to a heteroatom
3-Aminopyrazoles react with diethyl ethoxyrnethylenemalonate to give derivatives such
as (140). Strong heating in an inert solvent gives the hydroxy ester (141), from which the
322
Pyrazoles with Fused Six-membered Heterocyclic Rings
valuable chloro compound (142) can be obtained. Alternatively, the diester (140) will go
directly to (142; Scheme 45). Compound (141) is a member of a series which shows no
py'ridone carbonyl bands but v(OH) appears at 3400 cm- 1 and the ester v(CO) is lowered
to 1660-1680 cm- 1 by hydrogen bonding. The chloro compound (142) has a norrnal ester
carbonyl absorption at 1730 em -1. The hydroxy tautomer (141) is stabilized by the hydrogen
bond and by the aromatic nature of the ring systern (72JHC23S).
Et0 2 C, S?e t
t. '- \
N^ )
H Et
(140) \
.H
l '0 Cl
Ph,O þ EtO ?" pon, Et02C 1
230-260 'C I N ----"--+ N
,/ :::,.. /
"N N N
N B B
(141) (142)
POCl,
Scheme 45
/'
The standard preparation of a new pyridine ring by treatment of a suitably substituted
anthranilic acid with phosphorus oxychloride has exarnples which are relevant here. The
acid (143) gives the chloro-substituted tricyclic derivative (144), but the isorneric systern
(145) rif!-g closes on to nitrogen rather than carbon and the pyrazoloquinazoline (146)
results (76JMC262). Exarnples of the sarne ring closure from aminopyrazolecarboxylic acids
are also available (76JHClSS). The triarylpyrazole (147) on photolysis cyclizes with loss of
hydrogen chloride to (148) in 100% yield (Scheme 46) (80CJC1880).
0 C02H rl e
N^N;N
H Me
Cl Me
I N
" h /
............ N N
Me
a 1C0 2H e
:::::,... A jNMe
N N/
H
(143)
(144)
(145)
cç l NnMe
:::::,... N-N
Me
o
(146)
hv
--
(147)
Scheme 46
4.05.4.3 Six-membered Ring Synthesis by Formation of Two Bonds
4.05.4.3.1 From [5+ 1/ atom fragments
The acid arnide (149), prepared as in Scheme 36 (Section 4.05.4.2.1), reacts with triethyl
orthoformate to give the pyrazolqpyridine (150) (S9JA24S2). Diazotization of the arnine
(151) leads to immediate insertion into the methyl ketone to give the pyrazolopyridazine
(152) (SOHCA1183).
o
H NH2
2 ï 'I tEtOI,CH. Ac,O
/N
N
HO H
o
(149) (150) (151) (152)
The arnine (153) and triethyl orthoformate give the imine (154) which with arnrnonia is
converted via the amidine into the pyrazolopyrirnidine (155; R = CN). Hydrolysis of the
remaining nitrile group (aq. NaOH) gives (155; R = C0 2 H) which readily decarboxylates
when sublimed to form (155; R = H) (66JOC342). By the sarne route, rnethylarnine and the
cr; NH 2
N::;-'
þ I N
:::::,... N/
H0 2 C H
o
HÆ;:Ph
N
Me
HNO,. 0 'C þ
o 0
NPh
'NJ-- N 1
H Me
Pyrazoles with Fused Six-membered Heterocyclic Rings
323
appropriate irnine give (156). On warming in water, however, this readily undergoes Dirnroth
rearrangernent as shown in Scheme 47 (60JA3147).
NC CN NC CN NH 2 R
n (EtO"CH. n NH, N I
H2N __;N FN ;N -----"-+ l...J--"l
EtO N
(153) (154) (155)
NH tc H NH2 NHMe
MeN N -+ H N I N ---+ MeN X I N -+ N :C 1 N
/' 1;:0, I 0 I "'" I I I
HO- N N Ñ N HO' "N N l.::::N N
(156) Me H Me Me Me
Scheme 47
Acid-catalyzed addition of thioacetarnide to the aminonitrile (157) in ethanol gives an
intermediate pyrazolothiazine (158), but basic treatrnent during work-up catalyzes the
Dirnroth rearrangement to the pyrazolopyrimidine (159). Other thioamides react similarly.
A by-product (160) from this reaction, believed to arise by an exchange mechanism, provides
a route to the 6-unsubstituted derivative (162). Hydrogen chloride in DMF gives (161)
which ring closes under the reaction conditions (Scheme 48) (6IJA248).
N)
b l Me S NV
ï 'I EtOH. G :t \: -+
.0 / N NH2 J:J
H 2 N N .. 'I
H H 2 N N/N
H
(157)
1
(157a)
+
NH 2 NH NH
Me N f N
Jl; Me .J--N
H 2 N N
H H
(158)
1
s s S
H2N N H2N N -+ HN N
H 2 N N OHCN N l.NJ--
H H H H
(160) (161) (162)
S
HN N
Mel.NJ--NI
H
(159)
Scheme 48
The last step in Scheme 48 provides a useful way to form a pyrimidine ring by the reaction
of a formarnide with a vicinal aminoamide. The amine is forrnylated and ring closure occurs
under the conditions of the reaction. For example, the preparation of pyrazolo[3,4-d]-
pyrimidine (5; Scheme 49) (S6JA784) and of the adenine analogue (165; Scheme 50)
(S6JA2418) illustrate this approach. Recent work has provided evidence that the reaction
goes via an arnidine (167) which is attacked by the neighbouring amide nitrogen atorn. The
substituted amides (166) gave (168) in good yield as the sole product when boiled with
formamide (Scherne 51) (81S727).
H 2 NCO
n
H2N ..;N
N
H
(163 )
o
H,HCHq H'l)lX)
N N
H
i.POCI,
ii. H 2 . Pd/C
I t N
N N
H
(5)
Scheme 49
Less cornmonly, formic acid or a homologue is used. Presumably the conversion of the
amine to an amide is the first step. The aminoamide (169) gives (170; R = H) in refluxing
formic acid or (170; R = Me) with acetic acid at 185 0 C (76USP3939161). With rnethyl
isocyanate, (169) gives (171) (70JHC863).
324
Pyrazoles with Fused Six-membered Heterocyclic Rings
I-I,N N
n i ( :;ç
H,NCO ;N ----. HN I IN
N N
H H
(164) 0
ii, iii. iv
N
("rN
N NI
H,N H
(165)
i, H 2 NCHO; ii, P 2 S S , CsHsN; iii, Mer, NaOH; iv, NH 3 , 200 oc
Scheme 50
[ H'N ]
H 2 N Me '=N Me N Me
RHNOC n N ----. ( :)Ç N ----. ( :;ç N
N) RN N RN N
H
H 0 H 0 H
(166) (167) (168)
R = Pr, Bu, CsH II \ Bz, PhCH 2 CH 2
Scheme 51
H
o N Me
Y N
HN N I
Me
o
(171)
H 2 N Me N Me
.MeNCO n RCO,H) R( N
H,NCO . .;N HN I
N N
Me Me
o
(169) (170)
Fusion of aminoamides with urea or thiourea leads to pyrazolopyrimidinediones or the
corresponding one-thiones (Scherne 52) (56JA2418). This method yvas ernployed (65JOC199)
to establish the structure of the trimethylated cornpound (26; Scheme 53) (Section 4.05.3.1).
o H
:.:c H,N 0 N
HN I /N 0 \ Y N
I H 2 NCO .,/N HN I
y N N N N
H H H 0 H
(164)
H 2 NCO
0 \
H 2 N ....N
N
H
(163)
ì'í
H,NCNH,
Y=O,S
H 2 N CONH 2
0 \
N fuse
N/
Me
Scheme 52
H Me
o NON
Y"rNMe Me,S04) y'rNMe
HN NI MeN NI
o 0
(26)
Scheme 53
The nitrile group of (172) reacts with hydroxylarnine to give the hydroxyarnidine (173).
Reduction of the nitro to an arnino group and then treatrnent with trirnethyl orthoforrnate
gives the arninopyrazolopyrirnidine N -oxide (174) which, with care, can be hydrolyzed to
the cyclic hydroxarnic acid (175; Scherne 54) (70JHC863).
O,N Me 02 N Me H 2 N Me N Me N Me
NCON --4 H ONyÇ 'I.J4 YQ 'I r: CQ N ...!4 ( :;ç N
N/ /N HON /N ......N:::". I HON N I
H N N -0 N
NH 2 H NH, H NH 2 H 0 H
(172) (173) (174) (175)
i. NH 2 0H, EtOH, reflux; ii, H 2 , Pd; iii, (MeOhCH, reflux; iv, H20, AcOH, DMF, 55 oc
Scheme 54
The pyrazolylaniline (176) condenses with benzaldehyde to give the pyrazolo[I,5-c]-
quinazoline (177). It also reacts in low yield with forrnaldehyde but other aliphatic
aldehydes fail to react. With forrnic acid or acid chlorides, it gives the fully arornatic
derivatives (178; Scherne 55) (63JOC1336).
Pyrazoles with Fused Six-membered Heterocyclic Rings
325
9u
#
:::-- ,
+-'--
H N"'-,/ N _ j
Ph
(177)
9n
1#
" :::--
Ó
N,:::/N_N
R
(178)
(176)
i, PhCHO; ii, HC0 2 H (R = H) or RCOCl, NaOH, H 2 0 (R = Me, Et, Ph, etc.)
Scheme 55
3-Arnino-5-phenylpyrazole and ethyl acetirnidate give the pyrazolylarnidine (179). This
reacts with different reagents to give derivatives of pyrazolo[1,5-a][1,3,5]triazine (Scherne
56) (74JHC691) (cf. Section 4.05.3.2).
N
Merr IEIOJ CH
I j Ph ----.L-
N,:::/N_J
N
Merr X)
I Ph
H 2 N HN_J
(179)
IEtO"CO
- )
NaOEI
H
N
Me (
I jPh
NyN_N
o
lBrcN
N
Mer
jPh
N,:::/N_N
NH 2
Scheme 56
The thiourea (180) rapidly cyclizes with diethoxyrnethyl acetate to the thione (181) frorn
which derivatives can be rnade via nucleophilic displacement of methanethiol (e.g. 182;
Scherne 57) (74JHC991).
Ph
0 '1
H 2 N /N
N
I
C=S
I
NH 2
(180)
N N
r UPh r UPh
HN y N-N N N_N
NH 2 NH
S
(181)
(182)
i, MeC0 2 CH(OEt)2, reflux 5 min; ii, Me!; iii, N 2 H 2
Scheme 57
(183)
N/. N ::;;--Me
I NBz
H N -N 1
o
(184 )
H 2 N CONH 2
n HNO, )
Me ;N
N
Bz
Diazotization of the arnine (183) is followed by ring closure on to the arnide nitrogen to
give the pyrazolotriazinone (184) which can be extracted frorn its salt with potassium
bicarbonate (8IJCS(Pl)2374). The pyrirnidine ring of (65) (see Section 4.05.3.5) is opened
and the resulting forrnyl group hydrolyzed by sodiurn hydroxide to give (185). NitrQus acid
produces a new 1,2,3-triazine ring (Scherne 58) (8IJCS(Pl)2387).
r :x;
"
N '\:
1
N N
R
NaOH)
rN ::o
'N
H ï 'IN
H 2 N /'
R
(185) R = ribosyl
Scheme 58
r :r
NaNO, . " I '\:N
HOAc N /
<:::- N
N R
(65)
326
Pyrazoles with Fused Six-membered Heterocyclic Rings
4.05.4.3.2 From [4+2/ atom fragments
The Friedlander synthesis can be applied to the preparation of pyrazolopyridines. For
exarnple, the aminopyrazole (186) undergoes Friedel-Crafts acylation to give the amino
ketone (187), two rnolecules of which condense together to give the pyrazolopyridine (188)
(78T117S). The Vilsmeier reaction converts (186) into the amino aldehyde (189) which
reacts with ethyl acetoacetate in pyridine to give (191), presurnably via (190). At high
ternperature (192) is produced, possibly via (190), but rnore likely through interrnediate
arnide forrnation (Scherne 59) (7SJHCSI7).
Me [ O Me ]
ï '\ -.!..... ï '\ -
H 2 NÇN H 2 N N/N
Me Me
(186) (187)
}i
Me
Meo N
o N N
H Me
(192)
OHC Me
iv n Hi
H2N N,N --+
Me
(189)
N
N NH
" 2
N
Me (188)
[ MeOC Me ] Me
N ---+ Et02C N
EtOi ..Jl-../ Me .J--.../
H 2 N M N N N
e Me
(190) (191)
i, AC20, H 2 S0 4 ; ii, POCl 3 , DMF; iii, EAA, py, reflux; iv, EAA, 160-170 o C
Scheme 59
The diketone (193) condenses with ethylglycine hydrochloride to give a rnixture of the
pyrazolopyridines (194; 8%) and (195; 37%), which are separated by colurnn chrorna-
tography (Scherne 60) (8IJHC1073).
PhOC CO Ph
CN
N'
Ph
(193)
Ph Ph
Et0 2 C O::; c;:;.--- N (X: c;:;.---
NPh + NPh
N::,... -N 1 Et0 2 C::::::,.. -N 1
Ph Ph
(194) (195)
-.!.....
i, H 2 NCH 2 C0 2 Et . HCl, butanol, reflux
Scheme 60
Vicinal dicarbonylpyrazoles react with hydrazines to give pyrazolopyridazines. For
exarnple, the diketone (196) gives (197) (nJHC37s) and the aldehydo esters (198) and (199)
both give pyrazolopyridazones (Scherne 61) (73T43S).
MeOC COPh
MeCN -.!.....
N
Ph
(196)
Me Me
NPh
N NI
Ph
(197)
o
Et0 2 C O X CHO , R2N
N -24 I NR 1
N' N -N 1
R 1
(198)
o
, R 2N
I I N
N::,... N 1
R'
Et0 2 C
OHCnN
N)
R 1
(199)
i, N 2 H 4 ; ii, for R 1 = Me, Bz, R 2 NHNH 2 (R 2 = H, Me)
Scheme 61
Mild oxidation of the pyrazolone (200) with lead tetraacetate gives the transient species
(201) which is trapped by the cyclopentadienone (202) in a [41T + 21T] cycloaddition. The
product (203) loses carbon dioxide on sublirnation to give the 107T-arornatic systern (204;
Scherne 62) (73JCS(P1)221). A rnechanism for this interesting rearrangernent involving loss
of carbon dioxide from the two non-adjacent carbonyl groups has been suggested by the
authors.
Pyrazoles with Fused Six-membered Heterocyclic Rings
327
(200)
(201)
P O
O t Ph ZIO.C,O.lmmHg
- \ -co, )
Ph N Ph Ph
Ph
(203)
Ph Ph
Ph (ö ==--
Ph
Ph:::::,.. N....J
Ph
(204)
o
Ph Ph Ph Ph Ó
N LTA. ";:;N + Ph h Ph
o N" 0 Ph Ph
H
(202)
Scheme 62
The bis-diazo ketone (205) refluxed in 2,3-dimethylbuta-l,3-diene gives the
pyrazolopyridine (207), presurnably via (206) (71CCS37). A Diels-Alder reaction gives the
pyrazolo[1,2-a]pyridazine (208) which can be further elaborated to the aromatic salt (209;
Scheme 63) (71JHC2S). An alternative preparation of (201), carried out in the presence of
buta-l,3-diene, gives (210), which is also obtained when the tetrahydropyridazine (211) is
heated with the ß -keto ester (212; Scherne 64) (66JOC2867).
o 0,.. Ph 0
Ph, Å ,Ph å Ph X Me W
ìí ìr -=-+ \ Ph ----+ I ð Ph
N 2 N 2 N....N Me N....N
(205) (206) (207)
( HN--\
+ HNJ
Me
. ( NJZ .. ( NJZ
I NJ :::::,.. NJ
Me Me
(208)
OEt
(
N.::J
+ Me
(209)
BF;
+
i, LTA; ii, PdjC, PhCI, boil; iii, Et 3 0 BE,
Scheme 63
Ph
CIH h
od......)
N
H
Ph Ph ( ( NJZ
:: ) O ";:;N + - I NJPh
N Ph
(201) (210)
( N 1 H
+ PhCOCHPhC0 2 Me
NH
(211)
(212)
Scheme 64
The Diels-Alder 'ene' (213) is also prepared in situ by rnild oxidation (lead tetraacetate
or t-butyl hypochlorite). It forrns many adducts, two of which are shown in Scherne 65.
HN-\ N-\ i ( N-\
HN "Et 2 - "Et2 - I N "Et 2
o 0 0
(213) (214)
lii. iii
o 0 y
ð::t
(216) 0
1v
C )Et2
(215)
Hf:J E " J: M1E"
(217)
i, buta-l,3-diene; ii, Hz, Pd; iii, LAH; iv, tropone; v, hv; vi, MeOH
Scheme 65
328
Pyrazoles with Fused Six-membered Heterocyclic Rings
With butadiene it gives (214), which can be reduced to (215) (nJHC41). Tropone gives the
bridged ring systern (216) which on photolysis in rnethanol is converted into (217). In
refluxing ethanol this reaction goes thermally to give the ethyl ester equivalent to (217;
Scherne 65) (nJCS(pl)783).
Diesters, diacid chlorides and dihaloalkanes react with suitable cyclic hydrazines to give
saturated or partially unsaturated pyrazolo[1,2-a ]pyridazines (62HCA37). For example,
tetrahydropyrazole and diethyl succinate give the dione (218) which under standard arnide
reduction conditions gives (219; Scherne 66). As with rnost saturated pyrazolo[l ,2-a]-
pyridazines, catalytic hydrogenation splits the N-N bond of (219) (nJHC41).
0
ICH,CO,EtI, ( ) LAH CZ)
CNH I ---
N'
H 0
(218) (219)
Scheme 66
Aminopyrazolonitriles react with sirnple nitriles to give arninopyrazolopyrimidines, e.g.
as in Scherne 67 (6IJOC4967). The arnino ester (220) reads with phenylacetonitrile via
nucleophilic attack of the deprotonated arnine on the nitrile carbon atorn to give (221). A
minor by-product (222) arises due to the benzyl carbanion attacking the ester group (Scherne
68) (62HCA1620).
NC
H1NCN
N'
R 1
R 1 = H, Me, Ph; R,l = Me, Bz, Ph, subst. Ph
Scheme 67
NHz
R'CN.NH 3 .200'C N :CI
I 'I N
R Z <.:::::,. I
N I
Et01C
H1NCN
N.
Pr'
(220)
BzCN. Na I
Ph Me
o 0
HN N + Ph N
Bzl-. .JL N ; H1Nt ,JL N ;
N . N '
Pr' H Pr'
(221) (222)
Scheme 68
Forrnarnidine acetate is a useful reagent because it can provide a C-N unit to synthesize
a pyrirnidine ring, e.g. as in Scherne 69 (74JOC2023). Another irnportant exarnple is seen in
a synthesis of the antibiotic forrnycin (223; Scherne 70) (80CJC2624).
N Me OlN R I N Me
( NMe RZCN ii,iii,;v l ("rN
N NI N' N NI
NH 1 Me NH 1 Me
i, R 1 =CN, R1=Me; ii, R 1 =Me, R1=CN; iii, Na 1 S104; iv, NH1CHNH 1 ÕAc
Scheme 69
NO z H H NH
N N l
J CN J CN i H,/Pd I '<::N NaOMc
N N ' I N . I
I N0 1 I N0 1 ii, NH,CHÑH, ÕAc I ) I dcprotecllonl HO
R R R N
H NHz
IN ""N
N I J
N
o
R = tri-O-acetylribosyl
HO OH
(223)
Scheme 70
Pyrazoles with Fused Six-membered Heterocyclic Rings 329
Guanidine or guanidine carbonate can also provide a C- N unit, but the resulting
pyrirnidine carries an additional arnino group (Scheme 71) (6IJCS2S89).
Nh + X 2 ] C02- 1 2 N
H2N jN ,/ '- 3 H N _ .3--,)
N H 2 N NH 2 2 2 N N
H H
Scheme 71
With arninonitriles, forrnarnides and ureas provide two-atom units to give pyrimidines
(Scheme 72). With the derived aminoamides these reagents provide one-atorn units (see
Section 4.05.4.3.1) (S6JA784).
NH 2 NC NH2
XN Ä- H 2 NCN l N
N N N X N N
H H H H
i, HCONH 2 , boil; ii, NH 2 CXNH 2 , fuse (X=' 0, S)
Scheme 72
The pyrazole (224) is readily available frorn tetracyanoethylene and rnethylhydrazine. It
reacts with refluxing N-alkylforrnarnides to give the pyrazolopyrimidines (e.g. 225, 62 %)
after spontaneous Dimroth rearrangernent (73JCS(Pl)1903). Forrnarnides with amino esters
such as (226) give pyrazolopyrirnidones (227) (S6HCA986).
NHMe 0
NC CN N Et02C Jc
-n HCONHMe N '<::::: n HCONH 2þ HN I N
H N . ./N þ 1I JJ H2N jN I"",
2 N/ "'N""" N N ":::::N N
Me Me H H
(224) (225) (226) (227)
Fusion of arnino esters such as (228) with urea (200 o C) or thiourea (180 o C) gives
pyrazolopyrimidines (229), and with alkyl isocyanates, N -alkylated derivatives (230) are
obtained (Scheme 73) (S9HCA349).
o
HN !, ,"H,CX"H,
X N N' å
H Me
(229) X='O,S
Et0 2 C
H 2 NCN
N
Me
MeNCO
--+
NaOH
o
MeN N
O N N'
H Me
(230)
(228)
Scheme 73
Carbon disulfide reacts with the arnine (231) and cyclizes on to the neighbouring nitrile
group to give the isolable pyrazolothiazine (232). This readily rearranges in alkaline solution
(Scherne 74) (66AG(E)308).
NC
H 2 NCN
N
H
(231)
[ l NH
CS 2 .C s H S N þ sl' 1 N _ S N
reflux .3--) J-",:
S N N S N N
H H H H
(232)
S
HN::CJJ
S N N
H H
Scheme 74
Glyoxal (233) and the diaminopyrazole (234) react to give 3-hydroxypyrazolo-
[3,4-b ]pyrazine (235) (S8JA421). 1,2-Diketones also react to give 5,6-disubstituted deriva-
tives of (235) (61AG1S).
CHO H 2 N OH
I + n_
CHO H2N _ jN
N
H
(233) (234)
N OH
( :CJJ
N N
H
(235)
330
Pyrazoles with Fused Six-membered Heterocyclic Rings
3-Arninopyrazolediazoniurn chloride (236) reacts with ethyl acetoacetate to give the
interrnediate (237) which ring closes to the pyrazolotriazine (238). Other 1,3-diones also
react in a sirnilar rnanner. The reduction of the diazoniurn salt to the hydrazine (239)
followed by treatrnent with a 1,2-diketone gives a sirnilar fused heterocycle (240; Scherne
75) (66JCS(C)1127).
Cl- N n N
zL:.... )
N
H
(236)
i
-...
N
N
19 ;)
EtOzC I -N
(237)
Ä
N
N T)
EtOzC N_J
Me
(238)
"N T)
ï \ iv N'" :;;--
HzNNH N -... R 1 , N Ii
N -N
H R
(239) (240) R = Me, Ph
i, EAA, HzO, NaAc, 25 oC; ii, MeOH, reflux; iii, SOz, EtOH; iv, RCOCOR
Scheme 7S
Another diazoniurn salt (241) reacts with 3-chloropentane-2,4-dione, or 3-
chloroacetoacetic ester, with loss of two carbon atorns to give (242) which hydrolyzes and
cyclizes under carefully controlled conditions to the hydroxypyrazolotriazine (243). The
free diazo cornpound (244) gives the adduct (245) with dirnethyl acetylenedicarboxylate
(Scherne 76) (77JHC227).
Ph CI
N n N + MeCOCH/
zL:.....) "-
Cl- R
(241)
ii
H
"N N
-4 0 N ;)Ph.i4 (UPh
CI H.....N HO .....N
Me
R = COMe, COzEt (242) (243)
N=N 'lN
.t" ;)Ph Ä N ;)Ph
-N..... MeOzC N.....
COzMe
(244)
(245)
i, NaAc, HzO, EtOH, 25 oC; ii, KCN, HzO, reflux; iii, base; iv, DMAD
Scheme 76
Michael addition of the anion"frorn rnalononitrile to the conjugated system (246) results
in the pyranopyrazole (247) (74AP444). For (246; R 1 = Ph) adducts forrn with vinyl ethers
at 70-80 o e. With extra activation (246; R 1 = PhCO or MeCO) the adducts forrn at roorn
ternperature. The reaction is regiospecific but gives a rnixture of cis (248; ca. 80%) and
trans (249; ca. 20%) isorners (Scherne 77) (80JPR711).
ct R RI CN
7 CH(CNh NaOMe if I
N -'----+ N ..0 -...
\ \ r-.C=N
NON 0- ·
Ph Ph
(246) \loR
No2l '\ N
'N 0 OR Z N-lOÁORZ
Ph Ph
(248) (249)
1 2 i t
R = Ph, MeCO, PhCO; R = Me, Et, Pr, Bu
Scheme 77
R 1
Nm CN
'W- 1( 0)NHz
Ph
(247) R I = Me, Ph
Pyrazoles with Fused Six-membered Heterocyclic Rings
331
4.05.4.3.3 From [3+3J atom fragments
The 4-arninopyrazole (250) reacts under Skraup conditions to give a useful synthesis of
the pyrazolo[4,3-b]pyridine (251; 19%) (58JCS3259). 1,3-Diketones (252) react with 3-
arninopyrazoles (e.g. 253) to give simple pyrazolo[1,5-a]pyrirnidines (254). If the two R
groups are different, mixtures result, but these can be treated with N -bromosuccinirnide
to give the 3-brorno derivatives, purified, and the hydrocarbons regenerated by reduction
(75JMC460).
H 2 N
n
N/N
Ph
R 'Ç O R ( N
h O + H 2 N(N;N - --j
H R
R
(250) (251) (252) (253) (254)
The rnalonaldehyde acetal (255) reacts with arninopyrazoles (256; R = H, CN, COzH)
to giv the derivatives (257) unsubstituted in the pyrirnidine ring. The acid (257; R = COzH)
decarboxylates in high yield on pyrolysis, but, surprisingly, a mixture results. Only 14%
yield of the expected pyrazolo[1,5 -a ]pyrirnidine (258) is obtained along with 71 % of the
rearranged pyrazolo[3,4-b ]pyridine (259). Hydrolysis and decarboxylation of the nitrile
(257; R = CN) by prolonged boiling in 85% sulfuric acid gives only the rearranged product
(259; 80%; Scherne 78) (70JHC247).
/'-. h '/ 'I . ( rA .. ( CJCI
(EtOhCH CH(OEth + H N _ .;N I il N ,? I il N ,? + IN
2 N/ :::::,.. -N -N N N
H H
(255) (256) (257) (258) (259)
N
Skraup þ I ":N
:::::,.. I
N
Ph
i, ZnCI 2 , EtOH, reflux; ii, R = C0 2 H, 290-300 oC; R = CN, 85% H 2 S0 4 , reflux
Scheme 78
The reactions of 3-arninopyrazole (253) with various esters and nitriles are sumrnarized
in Scherne 79 (62CPB620, 70CB3252, 74AP177, 81JMC61O). In most cases it is clear that initial
alkylation of the arnine nitrogen is followed by ring closure on to N(1) or in a strongly
protic solvent for (261) on to C(4) (70CB3252). The mechanisrns of forrnation of compounds
(260) and (262) are uncertain (70CB3252, 62CPB620). 3-Arninopyrazoles carrying substituents
on C(4) and/or C(5) react sirnilarly (70BCJ849, 79FES478) (see Section 4.05.4.2.1).
H H 0
'Q R(p ÓO
(260) 0 N N
" J Y 'oriii. H(261)H
I,ll v iv
H H
O N n Eto c ç N
:::::,.. _ il H2N _ ,;N I ;)
N N N-N
NH 2 H
("') NCZ (' j 5 o "
/ OEt H
( NY) ( Y) ç NY)
NC:::::,.. N-4 Et0 2 C:::::,.. N_J Et0 2 C N-4
NH 2 Me 0
i, HC=CC0 2 Me'; ii, THF, 25 oC; iii, EtOCH=CHC0 2 Et; iv, HOAc, reflux; v, for R = H, NaOCH=CHC0 2 Et;
for R = Me, EAA; vi, NCCH 2 C0 2 Et; vii, DEAD
Scheme 79
332
Pyrazoles with Fused Six-membered Heterocyclic Rings
3-Amino-5-phenylpyrazole (263) forrns an arnide (265) with ethyl benzoylacetate at
160 o C. The ring closes under acid catalysis to (266) but on strong heating it rearranges to
give (264; Scherne 80) (nJHC951).
Ph
n
H2N jN
N
H
(263)
PhCOCH,CO,Et, 220 'c)
H
Ph ç N
I I ,fPh
N-N
o (264)
PhCOCH,CO,Et
160'C
lphc=cco,Me
j220 'C
H
o l o N
l: HCl,EtOH H -' ' il N ;,;Ph
I JPh 0 -N
N-N
Ph Ph
(266) (265)
Scheme 80
The arninopyrazolinone (267; R = Me) reacts with pentane-2,4-dione to give (268;
R = Me) (79JHC773), but for (267; R = H) alkaline conditions are needed for the reaction
to take this course, giving (268; R = H). The pyrazolone carbanion ensures that ring closure
is to C(4) and not N(1). In acid (aqueous HCl) the pyrazolopyrirnidine (269) is obtained.
Cornpound (267; R = H) reacts with ethyl acetoacetate and diethyl rnalonate to give
pyrazolopyridines (60CBl106), but with diketene a pyrirnidine ring forrns (Scherne 81)
(6JLA(647)J16). The aminopyrazolone (270) reacts with 1,3-diketones to give
pyrazolopyridines (271) (79JHC773).
Me 0
NH ( i,IMeCO),CH,
Me ..3--.../ ii, NaOH
N N
R
(268)
o
H 2 NêNH
N
R
(267)
i, tMeCO),CH,
ii,HCI
Me c N
· I JO H
N-N
Me
(269)
1: aOY
ii,E
1 diketene
.
,(CO,Et),
OH 0
{X;NH
o N N
H H
Me 0
t)jNH
o N N
H H
H
o N
Y'Y)OH
N-N
Me
Scheme 81
H 2 N
H N o
Ph
(270)
R 0
CH,ICOR),. NPh
R _ .3--.../
N N
H
(271) R = H, Me, Ph
Ethyl acetoacetate converts the arnine (272) into the isolable enarninone (273). On strong
heating in an inert solvent this cyclizes to (274) which is deoxygenated to (275) by standard
means. If the enarninone is heated in glacial acetic acid, it rearranges and ring closes to
the alternative pyrazolopyridone (276). Deoxygenation gives the trirnethylpyrazolopyridine
(277), which is also available by independent syntheses (Scherne 82). Both (275) and (277)
are converted into tetrah dro derivatives by hydrogen over platinurn, only the pyridine
ring being reduced. The 3C chernical shifts for the carbonyl groups of (274) and (276),
178.5 and 163.2 p.p.m. respectively, provide a sensitive rnethod for the assignrnent of
sirnilar structures (75JHC517).
When the arninopyrazole (272) reacts with another 3-keto ester (278) an unexpected
dehydrogenation occurs to give (279) (75JHC523). The extra double bond gives an enarninone
systern, for which the rnesorner has arornatic stabilization.
Pyrazoles with Fused Six-membered Heterocyclic Rings
333
Me
n
H 2 Nz:... .;N
N
Me
(272)
1 v ;
r o: t Me te o Me
-4 I on...i4 I I N
Ã..;N Me I
Me N N/ N N
H Me H Me
(273) (274)
1 v
1 iii . iv
e Me Me Me
(DN LeN
N NON N
Me H Me
(277) (276)
Me
e rN
Me "'NY---N 1
Me
(275)
i, EAA; ii, Dowtherm, reflux; iii, POCI 3 ; iv, H2' Pd; v, HOAc, reflux; vi, MeCH=CHCHO or MeCOCH=CH z
Scheme 82
Me 0 Bz 2r
n 0 C0 2 Et ::::::0-.. Me
H2Nz:... .;N + - "
N/ 'N
M N I
e Bz 0 N N
(272) (278) (279) Me
Several enarninones have been shown to react like (280) with the arninopyrazolone (281)
to give pyrazolopyridines (282; Scheme 83). For one enarninone (283), a rnixture of the
norrnal product (284; 80%; v(CO) 1610 crn- 1 ) and the pyrazolopyrirnidine (285; 18%;
v(CO) 1620 em-I) was obtained (Scherne 84) (69M1250).
Ph 0 Ph 0 0
.BNH C8CNH GCNH
Me2N H 2 N N N N N N
H H H H
(280) (281) (282)
Scheme 83
t P o C O (jC Ph 0 Me C N
I + I NH - I NH + I;=O
H N I Me '" N 1 N_ N
Me NH 2 2 N H Ph H
(283) (281) (28 ) (285)
Scheme 84
Hydrazine and 3-arninocrotononitrile (286) give the pyrazole (287), which can be reacted
with a second rnolecule of starting rnaterial or with acetoacetonitrile to give the
pyrazolopyrirnidine (288; Scherne 85). A similar reaction sequence is shown in Scherne 86
(74JHC423).
Me N
N H n 1286, Me c
Me9=CHCN ---3.....4 H 2 N z:.. N ;N orMcCOCH,Cr! ::::::0-.. _jMe
NH z H NHz
(286) (287) (288)
Scheme 85
Ph N
PhCHCN N,H4) O C
I H 2 N N/N Ph::::::o-.. k;)
CHO H NH N
( z
Scheme 86
334
Pyrazoles with Fused Six-membered Heterocyclic Rings
Scherne 87 illustrates two potentially useful routes to the pyrazolo[3,4-d]pyrirnidine
systern. In (290) the usual higher reactivity of the halogen at C(4) is seen (see Section
4.05.3.3). Ethylarnine monosubstitutes at roorn ternperature, but disubstitution requires a
tern perature of 100 oC (75S645). Cyanoguanidine converts the arninopyrazole (263) into the
pyrazolotriazine (291) on heating at 160 oC (570597).
CI Me
N N ( CI,CN=CCI,
C1 NJ-N'
Ph
(290)
Me
n
H 2 NZ, .;N
N
Ph
ClCONCO
):3 0 Me
HN I N
O N N
H Ph
Scheme 87
Ph
NCN N
H 2 N(".;N + H 2 N-C-/' 160'C, H 2 N( UPh
N H "NH N N_N
2 NH 2
(263) (291)
Aminopyrazoles (292) carrying ribosyl groups are used to prepare potential antineoplastic
cornpounds (Scherne 88). The arninopyrazolotriazine (293) is readily hydrolyzed (see Section
4.05.3.3) to (294). After deprotection of the sugar residue, both derivatives showed activity
against leukernic cells (B-78MI40500).
H
N R N R R x...',./ N R
( Hi ( ? n 1
HN I ;) N /J +-- N I ;) N /J H 2 NZ. .;N HN r ;) N /J
Y -N -N N Y -N
NH 2 H
o 0
(294) (293) (292)
R = prolected ribosyl
ì, X = 0, PhOCONCO, X = S, SCNC0 2 Et; ii, EtOCH=NCN; iii, K 2 C0 3
Scheme 88
Benzoylhydrazine reacts with ethyl acetoacetate at 130 0 C in the absence of solvent to
give first the pyrazolone (295; R = PhCO). Water frorn the reaction hydrolyzes the benzoyl
group and a second molecule of the ester reacts to give the pyranopyrazolone (296)
(63BSF2742). The aminopyrazolones (297) and carbon disulfide give the zwitterionic
pyrazolothiazines (298) which S,S -dialkylate with diazornethane or alkyl iodides (78FES799).
Me
O -ÇN H
R
(295)
Me Me
EAA,130'C, N
o 0 N
H
(296)
o J: s OH
CS,. KOH S ==--
H N d NR ' I NR
2 N / I
S N N
H H
(297) (298)
R:: H, Me, Ph
4.05.4.4 Five-membered Ring Synthesis by Formation of One Bond
4.05.4.4.1 Between the heteroatoms
Mild oxidation converts the pyridylethylarnine (299) into pyrazolo[1,5-a]pyridine (1)
(57JCS4510). The useful ring closure of the arnine on to the nitro group of (300) proceeds
as shown in Scheme 89. Sirnilar procedures provide the pyridopyrazolobenzirnidazole (301)
and the pyrazolopyridines of Scheme 90 (73JCS(Pl)319). However, under different conditions
N NH 2
(299)
K,FelCNJ 6
CQ :;;.--
, /J
::::,... N-N
(1)
Pyrazoles with Fused Six-membered Heterocyclic Rings
335
the nitroamines (302) give the hitherto difficult to obtain N -oxides (303). The N -oxide
groups can be reduced (H 2 /Pd/C) (77CC556).
,.,.0 O +ÇOH ?l
((:1 N,""" H+ o; N,+ -H+,-H 0 -..,. -!
). --+ NHPh 2 þ '<" NPh-
NHPh :::--
N N N
(300) H H
o
N NPh
o
II
PhNH 2 Þ CX ' N -H 2 0 þ N\NPh
NHPh .,
N N NH
NHPh
Reagents: TsOH, PhNH 2 . El0H, reflux
Scheme 89
N02
l::,N NH O
H 2 N ð
TsOH) o--N\N J)
::::-- I
N #
N
(301) H
0:;
:-- \ HCl
NAr 'EtOH
:::--
N Cl
H
o: NO H 0 oÇ N\
I NAr H A! I NAr
N h N
o
Scheme 90
0-
00 1
MeN N02 Me \NR
O N NHR O N
Me Me
(302) R = Me, Pri, Bz, PhCH 2 CH 2 (303)
The azide (304; R = N 3 ) ring closes in boiling decalin to give the pyrido[1,2-b ]indazole
(305; 60%) as the only product. Surprisingly, (304; R = N0 2 ) gives the same product (305)
on treatment with iron (II) oxalate at 300 o C, probably also via the nitrene intermediate.
This reaction succeeds even if the pyridine ring of (304) is quaternized or converted into
its N -oxide, when the extra group is lost before ring closure (61CJC2516). In contrast, the
nitrene from (306) gives a rnixture of the pyrrolopyridine (307) and pyrazolopyridine (308)
in approximately equal amounts (73JOC3995).
- NßJ
(305)
R J
(304) R = N 3 , N0 2
--A..
+
(306)
Nitrene generation frorn nitroso and nitro compounds with triethyl phosphite can also
be used. For example, (304; R = NO) and TEP give (305) in 98% yield (63JCS42). The
pyrrole (309) and TEP, refluxed in xylene (7 d), give the mesomerically stabilized heteropen-
talene derivative (310) which undergoes cycloaddition reactions (Scheme 91) (79JOC622).
336
PyrQzoles with Fused Six-membered Heterocyclic Rings
Ph
Me
Nr-vC02Et
02 N
(309)
Ph
Me
N::',:)-=.JC02Et
N
1 3101
: O,M'
N'N C02Me
C0 2 Et
Ph
CI Jt M e
N -
:::::,.. 'N""" C0 2 Et
etc.
Scheme 91
The hydrazine (311; R = NHNHz) heated at 300 oC without solvent gives the triazinoin-
dazole (312), but the azide (311; R = N 3 ) gives the same product at 200 0 C (70JCS(C)2298).
N N
NH2 -+ U ( NH2
R NvN :::::,... ...NvN
NH 2 N NH 2
(311). R = NHNH 2 . N 3 (312)
4.05.4.4.2 (){ to a heteroatom
4-Hydrazinonicotinic acid or its N -oxide cyclizes to pyrazolo[ 4,3-c ]pyridin-3-one in
refluxing hydrochloric acid (65AJC379). The phenylhydrazone (313) and cyanoacetamide
react in the presence of base to give a rnixture of the substituted pyridines (314) and (315).
After separation these can be cyclized to the pyrazólopyridines (316) and (317). The
protonated 'benzylic' methoxy group is displaced in a nucleophilic attack by the hydrazone
nitrogen (Scheme 92) (62LA(657)156).
OMe
r (CN
PhNHN 0 + A
H 2 N 0
o
(313)
OMe
"0". 'C jlN NPh
HOC .JMe
N
Me
+ NC I N=NPh
HO::,...
N
OMe
(315)
r AC (314)
McOH
reflux
CN
HO (X; C;:;--
N NPh
::,... ,-I
N
Me
r AC
McOH
reflux
(316)
N
HO ü::) C;:;--
NPh
NC :::::,... '-N 1
Me
(317)
Scheme 92
Several hydrazones like (318) are converted by aldehydes in refluxing DMF into
pyrazolopyrimidines (320). By using ethanol as solvent, the interrnediate (319) can be
isolated (Scheme 93) (77JCS(Pl)765).
o Ph
MeN I { PhCHO þ
I N EtOH
O N N'
Me H
(318)
M'N h (Ph OM'. M' N'
O NÀN' O N N Ph
Me Me
(319) (320)
Scheme 93
Pyrazoles with Fused Six-membered Heterocyclic Rings
337
The phenylhydrazone (321) cyclizes in hot hydrochloric,acid, presurnably via nucleophilic
attack on the protonated quinoxaline, to (322) (71MI40500).
(( N N
ç/ I (( I :C N
N, ...,; I
N NPh N N
(321) H (322) Ph
4.05.4.4.3 {J to a heteroatom
The N -iminopyridine (323) ring closes and decarboxylates in refluxing xylene to give
(324) (73JCS(Pl)2580). The imine (325) similarly cyclizes in boiling toluene to give the ketone
(326; lI(CO) 1665, lI(C=C) 1630 em-I) (72T21).
O + Cf 02Et -+ Oj C:'Et M'A 1 M'
' N -) N"N N 0 -+ '''r
N N
(323) (324) (325) (326)
N-Iminopyridines (327) react with diketene to give pyrazolo[I,5-a]pyridines (328)
and (329) as shown in Scheme 94. Methyl iodide and sodium ethoxide convert (328) into
a mixture of its N - (329) and O-methyl (330) derivatives (75CPB452). Similar cyclizations
where ester and nitrile groups stabilize the intermediate carbanion are known (78BCJ251).
0 1 0 1
+ +
N N
1- I I
NHR W
(327) X ..R=Me... Y&
111
1 26 %
COMe
01 " o:? :::o-"
....!4 0
+ N-N
Me
MeNìf"ì( (329)
o 0
Oj COMe
ç/ =--
h OH
N"N
(328)
t ;,m
36%
OJ =--COMe
N hOMe
"N
(330)
i, K 2 C0 3 , diketene; ii, NaOEt; iii, Mel
Scheme 94
The hydrazone (331; R::: H) is converted into (332) on heating above its melting point
for a few minutes (73S300). The derivative (331; R = Me) is not cyclized in this way but
refluxing in thionyl chloride (77H(6)945) or photolysis (75BCJ1484) gives (332; R = Me). In
:\ 0 Ph
MeN I {-+ MeN, Jl,, N
O N N..-N O N N '
Me R Me R
(331) (332)
:Jt o Ph
MeN N0 2 (
I I I -+
O ...N
N N
Me Me
(333)
T
MeN,. . Jl,,} + MeN, Jl N
O N N O N N
Me Me Me Me
(334) (335)
338
Pyrazoles with Fused Six-membered Heterocyclic Rings
each case the reaction is accornpanied by an oxidation, presumably by air. The nitro-
hydrazone (333) is ring closed either thermally or photolytically to 'give a rnixture of the
pyrazolopyrimidine (334; 40%) with loss of the nitro group and the triazolopyrirnidine
(335; 35%) with loss of benzaldehyde (74CPB1269).
4.05.4.5 Five-membered Ring Synthesis by Formation of Two Bonds
4.05.4.5.1 From [4+1J atom fragments
Pyrazole rings are formed from 2-alkylpyridine-N -irnines and acid chlorides under basic
conditions. For example, the 1-aminopyridinium salt (336) gives first (337) but this is very
reactive and is acetylated under the reaction conditions to (338; Scherne 95) (68JOC3766).
The 2-hydroxyrnethylpyridine (339) shows similar reactions (Scheme 96) (73CPB2146).
0 1 Me
+N C,H,N
'NH 1-
(336) 2
((1M' [COMj CQ :
I (337) (338)
OH
Scheme 95
N_N'/
i
-
d OH OAc
?" I OJ ?' Me
"- +N "- N
'-'-, '-'--N
NH 2
ct-
(339)
Liii
(r) ?,OH
N Ph
-N
i. (EtOhCH. HOAc, NaOAc; ii, Ac 2 0, NaOAc; iii, PhCOCl, K 2 C0 3 , H 2 0
Scheme 96
The hydrazine (340) and acetic anhydride give the pyrazolopyrimidine (341; R = Me).
With mixed forrnic-acetic anhydride the unsubstituted derivative (341; R = H) is obtained
(58LA(615)42). The pyridylacetic ester (342) reacts with hydroxylamine-O-sulfonic acid in
water at roorn ternperature to give the phenolic compound (13) (see Section 4.05.2.4)
(76BCJ1980).
o )j o R
MeN I -+ MeN I N
O N NHNH 2 O N N '
Me Me H
(340) (341)
OJ
OEt
H,NOS0 3 0H
þ
CO ?'
N /, OH
-N
(342)
(13)
Pyrimidines with alkyl and primary arnine groups on neighbouring carbon atoms can be
converted into pyrazolopyrimidines with nitrous acid. Cornpound (343) treated with nitrous
acid at 20 0 C followed by warming gives (344). Rernarkably, the 2-arnino group does not
seem to be affected by these conditions (52JCS3448). The arnine (345) gives a trace of
pyrirnidotriazine (346), which can be filtered off, and the diazoniurn salt (347) which only
cyclizes in 20% sodiurn hydroxide (Scheme 97) (65JOC199) (d. Section 4.05.4.6).
N N
H 2 N( :J Me HN02 I H2Nr :xJ N
N:::-.. NH 2 N:::-.. I
N
Me Me H
(343) (344)
Pyrazoles with Fused Six-membered Heterocyclic Rings
339
Me Me Me
ON O N N O-ON
Y I Me HNO,þ y 1 /' + Y' I Me
MeN'y,mH 2 MeN N N MeNyN CI-
000
(345) (346) (347)
Scheme 97
The amide of 3-amino-2-rnethylpyridine (348) gives the nitroso cornpound (349) which
dehydrates in boiling benzene without purification to give the 1-acetylpyrazolopyridine
(350). Hydrolysis gives the base (351) which under rnild conditions is reacetylated at N(2)
to forrn (352). It is noteworthy that the carbonyl group of (350) has v(CO) 1710 em -1, but
that of (352) has v(CO) 1740 em-I. This high figure presurnably reflects the contribution
of the dipolar rnesorner for which the pyridine ring is a 67T-systern (Scheme 98)
(73JCS(Pl)2901).
NaOH
-----+
Me
OyN
MeN N
o H
N
0 1 Me NOCI þ
::::"., NHAc
(348)
a N Me
"- I NO
............ N/'
(349) Ac
N
C 6 H 6 f' - I
reftux þ N/N
Ac
(350)
115%HCI
lreflux
OJ + cç i.AgNO,
NAc +------. NAc c
:: Ñ' :: -N' ;;,,",,,",0,."..
(352)
N
f-'rN
NI
H
(351)
Scheme 98
4.05.4.5.2 From [3 + 2J atom fragments
Activated alkynes add to N -iminopyridines to provide a simple, general route to
pyrazolo[1,5-a ]pyridines. Oxidation is usually spontaneous under the reaction conditions
and decarboxylation occurs at moderate temperatures (Scheme 99) (68JOC2062). Sub-
stituents at position 3 of the pyridine ring generally lead to mixtures of products, but in
high total yields (75JCS(Pl)406). N - Iminopyridine also reacts with dimethyI2-chloro-furnarate
or -maleate to give in both cases the trans product (353) which is a stable solid. In solution
at room temperature it srnoothly ring closes to (354), which can be oxidized by palladium
at room tern perature, by heating in benzene, or photochernically (Scherne 100) (72JOC3106).
Ethyl acetoacetate and acetylacetone also undergo useful [2 + 3] cycloadditions with N-
irninopyridines (73JHC821). N -Iminoquinoline and N -iminoisoquinoline react similarly, the
latter to give only pyrazolo[3,2-a ]isoquinoline (62TL387). Pyrazolo[1,5 a ]quinoxalines and
pyrazolonaphthyridines are also available (75JHC119). N- Iminopyridazine can be used for
the preparation of pyrazolo[1,5-b ]pyridazine and derivatives (Scheme 101) (74CC941).
O . 0 .. W ::o--C02Et.... 00 ::0--
1 I I IJ m,IV
--'-+ --+ ---'---+ N ú
::::-...+ ::::-...+ ::::"., N.....N ::::".,.....N
N 1 - N
I I
NH 2 H
i, K 2 C0 3 , DMF, 25 oC; ii, ethyl propiolate; iii, KOH, MeOH, 25 oC; iv, distil
Scheme 99
O Meoco Oj C02Me W co2Me
Il '?-" ..?-"::o--
+ N I N ß C0 2 Me ....!4 N ß C0 2 Me
::::"., 'N C0 2 Me -N -N
(353) (354)
i, CH 2 CI 2 , 25 oC; ii, Pd, C 6 H 6 , 25 oC; or C 6 H 6 , boil; or hv
Scheme 100
340
PyrQzoles with Fused Six-membered Heterocyclic Rings
CO 2 Me 0 eõ C02Et
-:? :;;.- . -:? -.. -:? ==---.. .
C02Me.-!- + I Mes /J
. .....N_J ::,... /N, /N-N
N N NH 2 N
OJ ==---
F
N/N_N
i, DMAD, py; ii, ethyl propiolate; iii, KOH, MeOH; iv, 57% HI
Scheme 101
Sorne interesting cyc1oadditions to 3-pyridyne (355) are illustrated in Scheme 102.
N -Phenylsydnone (356) gives (357), which spontaneously loses carbon dioxide to give the
pyrazolopyridine (358). Benzaldehyde phenyl hydrazone is oxidized by lead tetraacetate to
the nitrilimine dipole (359), which also reacts with 3-pyridyne to give a pyrazolopyridine
(360) (71BCJ858).
H
N
Ph N' 'Ph
cr H2 O\-,
-:? 'LTA THF 0 /:' '..\
N I lN 2;'C þ N II + O ;NPh
'i :::"'. PhC=N-ÑPh )35'1 j (356)
(359) I
Ph /0
(JC) N, I N, co,
I N NPh O---=-Þ
N /J N::,...
Ph
(360) (357)
cc -- N ,
NPh
N ::,... ::0-.
(358)
Scheme 102
The ester (361) is the first product formed when the corresponding acid is treated with
diazomethane. However, it reacts further to give, as the major product of a rnixture, the
pyrazolopyridone (362; 54%), probably by the mechanism shown in Scheme 103
(76CPB1870).
0C02Me l N J --+ N QÇI N ÇÇI N
'l..A MeN N Il MeN II MeN I MeN I
NON N N
Me 0 Q 0 0 HOMe
(361) 0 0 Me (362)
Scheme 103
Hydrazine and its derivatives react with readily available chi oro aldehydes, ketones,
esters and nitriles to give a variety of fused systems. A few typical exarnples are shown in
Schemes 104 (77H(6)727), 105 (a preparation of allopurinol in 74% yield) (7IGEP1950076),
106 (64CB3349) and 107 (8IJHC333).
Cl
R N,H.,reßux Þ
\ Ä N .)
R = CN, C0 2 Et
Scheme 104
aY HN- R
f I ":::
S N.&
R=NH 2 ,OH
CI
N ) CHO
II .& C1
N
Cl
N,H. N
-lS'C Þ ll__.J--N/N
N H
2M NaOH
Þ
lOO'C
o
HN N
..J--",:
N N
H
Scheme 105
Pyrazoles with Fused Six-membered Heterocyclic Rings
341
0C02Et POCl,þ 0C02Et N,H4 Þ :
N,_ j O N, )Cl N ",J-",t N 1
N N N
H 7 H
O lCH 2 0H N,H41 CC I NH HNO,þ CD I N
N . Cl N", N 1 N", N 1
N N H N H
Scheme 106
o 0
(Y I R
N N,H,
N/
Ph
Scheme 107
Pyridazine and its fused derivatives react readily with diphenylcyclopropenethione to
give pyrazolo[1,2-a ]pyridazines. The derivatives of diphenylcyclopropenone are sometimes
also available (Scheme 108). The proximity of the sulfur or oxygen atom to one of the
aromatic protons causes a considerable downfield shift, as shown in Scheme 108 (71CJC3119).
S Ph 0 Ph
88.8 H 0 89.4 H h
ArN'N Ph _ 00 1 N N -4 ArN'N Ph
ð
N Ph
PhN ():) '.:::: R = Ph
N-
::::,... "'N 1 N,H,
o
PhN (X; N'.::::
NH
::::,... "N 1
Ph Ph
i, I])=s, CHC1 3 ; ii, 1])=0, MeOH, reflux
Ph Ph
Scheme 108
A standard pyrazolone preparation applied to piperidone esters is shown in Scheme 109
(34JA700). Standard procedures for the preparation of saturated and partially unsaturated
pyrazolo[1,2-a]pyridazines are shown in Schemes 110 (68BSF4222), 111 (70CPB1526) and
112 (65CR(261)1872).
o 0
AC0 2 Et R cr5
l) + PhNHNH 2 -+ '" I NPh
N N
R
R = Me, Et, Pr, Bu
Scheme 109
(: : + (C] rS
o 0
Scheme 110
o 0 0
H+(I
NH II N-I
o 0
Scheme 111
000
c): + CH,(COC]), <>=>
000
Scheme 112
The benzopyran (363) and diazornethane give the benzopyranopyrazole (364). The
chlorohydrazone (365) loses HCl in the presence of a weak base to give an azomethine
342
Pyrazoles wíth Fused Six-membered Heterocyclic Rings
irnine which undergoes a 1,3-dipolar cycloaddition with (363) to give (366; Scherne 113)
(81BCJ217).
PhN-N
cry; H Ph
I H
::::::,.. 0
(366)
Cl
Et,N /' "-
+--"-- Ph N Ph
+
co l '::::
::::::,.. 0
(363)
N-:::N
CH 2 N,þ
U o )
(364)
(365)
Scheme 113
Scherne 114 shows the preparation of benzothiopyranopyrazolones (367) and their further
oxidation to (368). Both series contain potent immunosuppressants (81JMC830).
o
(X)CO'MO
S
HN-NR
RNHNH 2 0:)>1 '-'::::: 0 a-chlor.nil
----+ þ
::::::,.. s
(367)
R = H, Me, Ph, substituted Ph
Scheme 114
o:J _NR 0
Ç/ I I
::::::,.. s
(368)
4.05.4.6 By Transformation of Existing Heterocycles
Oxidative rearrangement of the pyrimidinopyridazine (369) gives a pyrazolopyrirnidine
(370) which can be transforrned into the unsubstituted aromatic system (Scherne 115)
(74TL3893).
o CO H
N ::xJ1 C02H N N2 ii,Hi. N N
MeS ..-N H MeS ß-.N' Nß-.N'
N N H H
H
(369) (370)
i, KOH, KMn04; ii, 300 0 C (-C0 2 ); iii, Raney Ni
Scheme 115
H
N J N N
OC I " ' __'
::::::,.. N N--NN
(371) H (372)
The azide (371) dirnerizes on photolysis to the pentacycle (372; 85%) (71JHC78S). The
N -oxide (373), available in good yield in this case (ct. Section 4.05.4.5.1), is transforrned
into a pyrazolopyrirnidine (374) under reductive conditions (Scheme 116) (6SJOC199).
H H H
o N 0 N /0- 0 N
Y ) Me Y I ':!';I SnCl, þ Y A
HN NH 2 HN 'iN HN N '
N
o 0 0 H
(373) (374)
Scheme 116
N -Substituted isatoic anhydrides react with anions from pyrazolones to give
pyrazoloquinazolinones. A large number of fused pyrazoles has been prepared by this route,
e.g. as in Scherne 117 (81JHC117, 81JMC73S).
Dehydroacetic acid (375) reacts with some ketone reagents to give the
pyrazolopyrirnidines in Scherne 118. A study of the UV spectra of alkyl derivatives showed
that the predominant tautomers are as indicated (nCB388).
Pyrazoles with Fused Six-membered Heterocyclic Rings
343
0(1 0 + oJ:) ' ;. XìM'
Me 0
Scheme 117
iiMe
-- H )Me
Y -N
X
X=O,S
i, N -aminoguanidinium chloride; ii, NH 2 CONHNH 2 or NH 2 CSNHNH 2
Scheme 118
cr H 0
Me j 1 '-':::
. )Me +-'-
N N_N Me 0
NH . 0
2 (375)
Contraction of the pyrazolothiazepine (376) on treatrnent with sodiurn hydride and methyl
iodide in DMF or DMSO probably follows the mechanism shown in Scheme 119 (75JHCl137).
H Me Ph
t : . t)
O N Me . O N Me
H Me
(376)
(? e
-- - )LN:N
O }-N
Me
Me
Ph I
Ph Me s Me
{):3N -H I N
o N NON
Me Me Me Me
i
Scheme 119
4.05.5 IMPORTANT COMPOUNDS
Most of the work discussed in this chapter has been stirnulated by the discovery of a few
biologically active cornpounds. As is usual in medicinal chemistry, only a few out of rnany
thousands of compounds synthesized have found their way on to the rnarket.
Perhaps the most widely used at present is allopurinol (85; R 2 =H) in the treatment of
gout. This and its congeners oxyallopurinol (87; R 2 = H) and thiopurinol (112) inhibit
xanthine oxidase and so inhibit the oxidation of xanthine and hypoxanthine to uric acid,
the causative agent of gout. This group of compounds also shows some antineoplastic
activity (71JCS(C)1610).
Much effort has been expended on the search for antiturnor and antiviral corn pounds
based on the antibiotic forrnycin (223). No derivative seerns to have reached the rnarket
yet, but exciting research results continue to appear (S-70MI40500, 81JCS(Pl)2387).
O h pr
OH
(( N,-
Me;.r I N
N)NMe z
(377)
Azapropazone (377) has found some use in the treatment of rheumatic disease and other
musculoskeletal disorders (71AF1532).
4.06
Imidazoles and their Benzo Derivatives:
(i) Structure
M. R. GRIMMETT
University of Otago
4.06.1 INTRODUCTION
4.06.2 THEORETICAL METHODS
4.06.3 STRUCTURAL METHODS
4.06.3.1 X-Ray Diffraction
4.06.3.2 Dipole Moments
4.06.3.3 1 H NMR Spectroscopy
4.06.3.3.1 Aromatic systems
4.06.3.3.2 Non-aromatic systems
4.06.3.4 13C NMR Spectroscopy
4.06.3.4.1 Aromatic systems
4.06.3.4.2 Non-aromatic systems
4.06.3.5 NMR Involving Other Nuclei
4.06.3.6 Ultraviolet Spectroscopy
4.06.3.6.1 Aromatic systems
4.06.3.6.2 Non-aromatic systems
4.06.3.7 Infrared Spectroscopy
4.06.3.7.1 Aromatic systems
4.06.3.7.2 Non-aromatic systems
4.06.3.8 Mass Spectrometry
4.06.3.8.1 Aromatic systems
4.06.3.8.2 Non-aromatic systems
4.06.3.9 Electron Spin Resonance Spectra
4.06.3.10 Photoelectron Spectra
4.06.4 THERMODYNAMIC ASPECTS
4.06.4.1 Intermolecular Forces
4.06.4.1.1 Melting and boiling points
4.06.4.1.2 Solubilities
4.06.4.1.3 Gas-liquid chromatography
4.06.4.2 Thermochemistry; Aromatic Stability
4.06.5 TAUTOMERISM
4.06.5.1 Annular Tautomerism
4.06.5.2 Ring-substituent Tautomerism
4.06.5.3 Ring-Chain Tautomerism
4.06.5.4 Betaines
345
346
350
350
351
352
352
353
354
354
355
355
355
355
357
357
357
358
358
358
360
361
361
362
362
362
362
362
362
363
363
365
371
372
4.06.1 INTRODUCTION
Imidazole (1) is a planar, five-membered ring system with three carbons and two nitrogen
atoms in the 1- and 3-positions. The systematic name for the compound then is 1,3-diazole.
One of the annular nitrogens bears a hydrogen atom and can be regarded as a pyrrole-type
nitrogen; the other resembles the nitrogen in pyridine. For this reason it is possible to look
upon imidazole as a molecule which has overlapping properties of both pyrrole and pyridine.
Contributions of one 7T-electron from each carbon and the 'pyridine' nitrogen and two from
the 'pyrrole' nitrogen make up an aromatic sextet.
345
346
Imidazoles and their Benzo Derivatives: (i) Structure
Benzimidazole (2) has a benzene ring fused in the 4,5-positions of an imidazole ring.
The rnolecules (1) and (2) are nurnbered as depicted on the structures.'
4 3
N
5(}2
H
(1)
4 3
sr YN}
6 N
7 HI
(2)
ç) ç) C)H ()H
H H H H
(3) (4) (5) (6)
The partially and fully reduced derivatives of irnidazole are variously designated as
2-irnidazoline (3), 3-irnidazoline (4), 4-imidazoline (5) and imidazolidine (6). Such com-
pounds are no longer planar and lack the arornatic character of irnidazole and benzirnidazole.
The great bulk of the published material relates to the fully unsaturated cornpounds.
4.06.2 THEORETICAL METHODS
As has been mentioned earlier (Section 4.01.2), many of the theoretical studies applied
to the azoles have endeavoured to achieve comparisons within the series. Thus calculations
of electron densities, dipole rnornents, and energies of forrnation give values which reflect
the decrease in azole stability as the numbers of nitrogen atorns increase. Irnidazole,
therefore, stands near the head of a decreasing stability series.
A survey of quantum mechanical studies shows that the HMO method (which is not of
great current interest) has been used mainly in connection with dipole rnornents, while the
VESCF method has been ernployed likewise in such calculations (B-76MI40600, 74JCS(P2)420,
nCHE1131,78JCS\P2)865).
Values calculated for 7T-electron densities at various positions in the irnidazole molecule
are, at tirnes, contradictory (66RCR122, 70AHC(12)103, 80AHC(27)241), but this rnerely reflects
the gradual development of the computational technique by the MO LCAO rnethod. When
the LCAO-SCF rnethod was used, taking into account the differences between N-l and
N-3, it showed that in the imidazole neutral molecule the electron density at C-4 (or C-5)
is greater than at C-2 between the two nitrogens; in the corresponding anion and cation
the electron density is higher at C-2 (Section 4.01.2.2). Earlier calculations, which did not
take into account the differences between the two nitrogen atorns, had shown qualitatively
the sarne trends. Table 1 gathers together the results of a number of these theoretical studies.
More recent calculations of u-complex energies and total electron densities for the
irnidazole cation, anion and neutral molecule demonstrate that, where electrophilic attack
is believed to involve a u-cornplex, good agreement can be obtained with the experirnentally
observed site of substitution. SCF calculations of 7T-electron distributions for the ground
0.432 0.567
'\0.526 /'
0. 774 C N \0.639
N 0.453
Neutral molecule or cation (55AlCJOO)
0590 7 )425
0436(..
N 0.532
Anion (55AlCIOO)
1.013
1.350
0.974 f
o 457 N . 727
--+ 0947
0.587
0422 N
15Jk
000 :;: 37 0.5575 /.1709
N
08007 0.7821
-00853 ): 0.0216
. 0.521 N
I '" 0.2308
H
1.015
1.018
I 055
Neutral molecule (ó2T985) Neutral molecule (70B(13344)
Figure 1 Bond locåIization energies, 7T-densities and/or free valencies for imidazole and benzimidazole
Table 1 7T-Electron Densities in Imidazole
Neutral molecule Anion Cation
N-l C-2 N-3 C-4 C-5 N-l(3) C-2 C-4(5) N-l(3) C-2 C-4(5) Ref
1.502 0.884 1.502 1.056 1.056 0.903 1.429 1.323 54JCS2701
1.479 0.907 1.479 1.067 1.067 0.835 1.458 1.436 55AJCI00
1.650 1.100 1.101 1.037 1.112 1.197 1. 207 1.200 1.512 0.997 0.990 59AJC543
0.2308 0.0216 -0.1709 0.0370 -0.0853 62T985
1.347 0.991 1.286 1.104 1.072 B-63MI40600
0.833 1.06 1.06 0.833 1.06 0.833 1.06 66T835,67T2513
1.525 1.012 1.315 1.006 1.142 70BCJ3344
0.225 -0.139 -0.150 -0.066 -0.350 78JCS(P2)865
0.031 -0.458 0.289 73CHE88
0.298 0.094 -0.287 -0.068 -0.037 79CHE939
is::
N
C
-
t.,
;::
.....
;::00
:::t.
;::
N
C
t:J
....
C;.
C;.
t.,
-.
'-"
...
s:::
w
.þ"
-...,J
348
Imidazoles and their Benzo Derivatives: (i) Structure
state of irnidazole have predicted the order of electrophilic substitution as 5> 2 > 4, but
these calculations did not take into account the tautomeric equivalence of C-4 and C-5
(see Section 4.06.5.1.1) (70BCJ3344, 78JCS(P2)86S). The results of calculations (SSAJCI00,
62T98S) of bond orders and free valences for imidazole are collected in Figure 1.
While the 7T-densities predict greater reactivity to electrophilic attack at C-2 in the
irnidazole anion, localization energies suggest an order of reactivity of C-4 > C-2. Use of
the CNDO/2 method predicts the order of electrophilic substitution in benzimidazole to
be 5'"'" 7 > 6 > 4 > 2, whereas the observed order (for aqueous bromination) is 5> 7 > 6,4,2
(78JCS(P2)86S). Predictions of preferential nucleophilic attack at C-2 are confirmed by
experiment. Table 2 lists 7T-electron densities in benzimidazole.
Semi-empirical LCAO calculations for all azoles, introducing O'-electrons, indicate that
charges are weak except those on NH nitrogen atoms, and that the O'-dipolar moments are
close to those of lone pairs. It is therefore inappropriate to take O'-polarity into account in
the approxirnations used in 7/'-calculations for these heterocycles. A nurnber of other
quantum mechanical calculations have been applied to reactions of imidazoles
(80AHC(27)241), while the nucleophilic substitution reactions at C-2 of benzimidazoles, and
diazo coupling at C-2 of uncondensed imidazoles have been discussed from theoretical
points of view.
Several workers have examined the electronic spectra of the azoles using Pariser-Parr-
Pople type calculations, while even more interest has centred On NMR spectroscopy. Using
EHT calculations it has proved possible to obtain good correlation between total electron
densities and lH and 13C chemical shifts, but the rnethod does not work for spin-spin
coupling constants (B-76MI40600). The generalized free electron MO rnethod (G-FEMO)
gives a good description of the ground state properties of irnidazole, and yields results
equivalent to Hückel MO calculations. Calculations (LCAO-SCF) of the 7/'-energies of
protonation of irnidazole free bases indicate that rnethyl substituents exert a purely inductive
electronic effect. The electronic natures of both irnidazole and benzirnidazole have been
computed taking into account both 0'- and 7/'-electrons. The energies of bonds between
hydrogen atoms and the hetero ring provide inforrnation which has been used to explain
changes in stability which had been noticed in pyrolysis experirnents. Correlation of therrnal
stabilities with resonance energies and, in particular, with the energies of HOMO was
possible.
Further applications of MO treatments to studies of protonation, hydrogen bonding,
tautornerisrn and conforrnation have been discussed earlier (80AHCf27)241, B-76MI40600); ab
initio SCF calculations have, for exarnple, shown that irnidazole is a stronger proton-donor
to water than pyrrole, and as proton-acceptors the two are quite different. Thus, while
irnidazole forrns a strong hydrogen bond with water through the N pair of O'-electrons,
pyrrole forrns a relatively weak and flexible 7T-cornplex. Good agreernent with experiment
is found in theoretical studies of isornerisrn and conforrnation of azolides.
The valence bond approach allows resonance structures to be drawn for irnidazole (7-12;
Scherne 1), arnong which are a nurnber of dipolar structures. Certainly such dipolar
contributors will be rnuch rnore irnportant than in the case of benzene. They correctly
cornpute the arnphoteric nature of the rnolecule and its susceptibility to electrophilic attack
at N-3, C-4 and C-2. When tautornerisrn is taken into account, electrophilic attack at C-5
could also be expected. There is also an indication in structure (11) that nucleophiles will
be attracted to C-2. A structure such as (12) can have real rneaning only in the presence
of very strong bases.
()
H
(7)
--
_N -N W W N
C)- .-. CJ -- () -- ()+ -- ()
H W
(8) (9) (10) (11) (12)
Scheme 1
A set of reSOnance structures drawn for benzirnidazole show sirnilar features as far as
arnphoteric nature is concerned, but irnply that electrophilic attack will be either at N-3 or
in the benzene ring; nucleophilic attack at C-2 is predicted (see Scheme 2). Qualitatively
the sarne trends can be noted as are obtained by applications of MO methods.
Table 2 7T-Electron Densities in Benzimidazole
Neutral molecule Anion Cation
N-l C-2 N-3 C-4 C-5 C-6 C-7 C-2 C-4 C-5 C-2 C-4 C-5 Ref
0.228 0 -0.121 -0.005 -0.016 -0.011 -0.030 78JCS(P2)865 a
-0.021 0.174 -0.225 -0.015 -0.024 -0.006 -0.035 - 78JCS(P2)865 a
-0.013 0.170 -0.237 -0.010 -0.015 -0.012 -0.015 - 78JCS(P2)865 a
0.168 0.391 0.380 - 73CHE88
1.40 0.96 1.03 1.04 1.39-1.73 0.99-1.02 1.14-1.35 0.81 1.03 1.02 56JCS4288
1.569 0.947 1.350 1.013 1.015 1.018 1.055 70BCJ3344
0.256 0.170 -0.312 -0.024 -0.024 -0.021 -0.029 - 79CHE939
a Values quoted from top to bottom used VESCF /BJ, CNDO/2 and CNDO/S respectively.
is.:
N
<::>
t.,
;::::
...
;::::00
:::;.
b:1
;::::
N
<::>
t:J
....
ë'
ë'
t.,
-.
'-'
V)
:::;
:;::
E'
w
\0
350
Imidazoles and their Benzo Derivatives: (i) Structure
(X I N> __ (X I :> __ :)- __ (X I N)+_
N tf N N
H H H H
0::> -- 0:;> -- -0:> -- -0:)
- H H H H
Scheme 2
There has been sorne success in the application of Harnrnett treatrnents to reactions and
reactivity of irnidazoles (80AHC(27)241, B-76MI40600), but the cornplications of tautornerisrn
and the different natures of the ring nitrogen atoms have created difficulties. Nevertheless,
the use of Urn and U o values of -0.34 and 0.42, respectively, for the ring NH group (replacing
a CH=CH group) in conjunction with the Harnrnett relationship for pyridines has permitted
the prediction of reasonably accurate pKa values for imidazoles. Fairly successful correlation
of pKa values for 1-, 2- and 4-substituted irnidazoles is obtained using Urn and u/ values;
rneta- and para-substituted I-phenylirnidazoles have also proved amenable to Harnmett
treatrnent. Calculated u-constants for the irnidazole ring in benzirnidazole suggest that it
is electron releasing, or conversely that the fused benzene ring is electron withdrawing.
This is borne out by experirnental observations, and indeed follows the predictions of the
reSOnance structures (Scheme 2). Calculations of Taft u*-values for alkyl groups have been
rnade frorn rate constants for N- acylimidazole hydrolysis and irnidazole-catalyzed N-
acylirnidazole hydrolysis in water. The steric effect was found to be the same in both acid-
and base-catalyzed reactions, and the range of u e' values (u::" = U kY'/ U thYI) for prirnary,
secondary and tertiary alkyl groups dernonstrates nO dependence on the degree of branching.
The corrected (or 'true') U kY' values were calculated frorn the rate constants for C-
substituted ester hydrolysis, and show that, in this instance, the steric effects in acid- and
base-catalyzed hydrolysis are not the sarne. This means that the Taft CT*-values probably
give a measure of steric effects. Other applications of Harnrnett treatrnents to specific
problerns such as tautornerisrn and quaternization studies will be discussed in the appropriate
section.
4.06.3 STRUCTURAL METHODS
4.06.3.1 X-Ray Diffraction
The results of a low-ternperature study (Figure 2) show irnidazole to be a planar molecule
with considerable double-bond character in all bonds. The dirnensions for 4,5-di+butyl-
irnidazole are essentially sirnilar, but the 4,5-bond is sornewhat stretched as might be
expected. In irnidazole the presence of NHmN bonds with the exceptionally short length
of 286 prn can be demonstrated. Such chains of rnolecules give the crystals a fibrous
appearance. A sirnilar X-ray study of a supercooled rnelt of 4-methylirnidazole revealed
that in this case the associated rnolecules in the polyrner structure have linear NH---N bonds
with a bond length of about 300 prn (B-76MI40600, 80AHC(27)241).
02 N
\'"
N
/14.1.2
NO!
Figure 2 X-ray structures for imidazole and l,4-dinitroimidazole (bond lengths in pm)
Imidazoles and their Benzo Derivatives: (i) Structure
351
More recently there has been some interest in the structures of the N-nitration products
of 4-nitroirnidazoles. Both 4-nitro- (SlUP40600) and 2-isopropyl-4-nitro-irnidazole
(nCJC34n) have been shown to N-nitrate with such an orie!1 t ation that the 1,4-dinitro
corn pound results (see Figur 2).
While irnidazolidine-2-thione has been shown to be a fairly planar molecule with only
slight distortions caused by crystal forces (S3AX369), there is evidence for folded (envelope-
type) structures in the 3-aryl-5-benzylhydantoins. Such deviations from the plane may be
a consequence of non-bonded arornatic-arnide attraction (79JCS(P2)6S3).
4.06.3.2 Dipole Moments
There has been considerable interest in the rneasurernent of the dipole mornents of
irnidazole and its derivatives since the values obtained should provide valuable information
about the structures of the rnolecules (70AHC(12)103, SOAHC(27)241, 66RCRI22).
The high values (16-20 x 10- 30 C m) obtained by early workers for imidazole resulted in
the postulation of a dipolar ion for its structure; even ionic salt-like structures were suggested
for imidazole (13) and benzirnidazole in aqueous solution. Subsequent experirnent, however,
has dernonstrated that these high values were probably obtained as a consequence of their
being made in relatively concentrated solutions in which interrnolecular association would
be significant. The present accepted value for the dipole rnornent of imidazole is nearer to
13 X 10- 30 C m, a value which reflects considerable polarization of the ring, but insufficient
to yield an ionic structure or even a dipolar structure. The dipole rnornent is concentration
dependent, a property typical of corn pounds containing an NH group and forrning inter-
molecular hydrogen bonds of the type N-H.--N. At high concentrations in non-aqueous
media the association coefficient reaches values between 5 and 20 (14), and not 2 as would
be expected for an ionogenic structure (13).
+
()H
H
()
N
N---H-N N----
f) N.--.H-NV
I
----.H
(14)
(13)
Dipole rnornent data indicate that the line of action of the mornent in irnidazole rnakes
an angle of _13 0 with the A-axis (where the proposed A-axis rnakes an angle of -28 0
with the N-H bond and intersects the N(1)-C(2) bond). The molecule is planar, as is
benzirnidazole, but the application of dipole moment studies to conformational studies has
shown that N- and C-aryl, and N- and C-furyl, cornpounds are not planar, even though
planar bicyclic fragments do exist in polyarylimidazoles. In l-arylirnidazoles the dipole is
towards the aryl substituent, a finding which is in agreernent with the observed reactivity
towards electrophilic reagents (Section 4.07.3.2.2). Substituent effects on dipole moments
are as expected; non-polar groups and condensed carbocyclic rings have little influence,
but polar groups may change rnatters to a rnajor extent. A selection of dipole rnornents is
listed in Table 3.
Table 3 Dipole Moments for Imidazoles and Benzimidazoles (71CHE809)
Compound
p (C m x 1030) Compound
p (C mX 1030)
Imidazole
1-Phenyl-
1-Propyl-
1-Methyl-
4,S-Diphenyl-
2-Formyl-l-methyl-
1,2-Dimethyl-
1,2- Dimethyl-S -bromo-
2-Formyl-1-phenyl-
2,4,5- Triphenyl-
12.S Benzimidazole
10.5 1-Methyl-
13.7 1-Benzyl-
12.1 1-Phenyl-
14.5 S-Nitro-
12.6 l-Ethyl-4,S-dimethyl-
12.5 2-Methyl-S-nitro-
11.2 2-Formyl-l-methyl-
l1.S 2-Acetyl-
13.1
13.3
13.5
11.6
11.2
19.9
13.7
21.9
11.2
6.4
352
Irnidazoles and their Benzo Derivatives: (i) Structure
4.06.3.3 1 H NMR Spectroscopy
4.06.3.3.1 Aromatic systems
The proton rnagnetic resonance spectrurn of irnidazole shows a one-proton triplet at
87.64 p.p.rn. (assigned to the 2-H) and a two proton doublet at 8 7.01 p.p.rn. (assigned to
the 4- and 5-H atoms). The coupling constants are of the order of 1.0 Hz. Because of the
rapid interchange of the N -H proton (see Section 4.06.5.1) there are no spin-spin splittings
observed due to interaction with the I-H. In fact, this NH proton gives rise to a broad
signal only in concentrated solutions in aprotic solvents such as benzene, chloroforrn or
acetone; the positions and half-widths of these signals depend very rnuch on the concentra-
tion. As the concentration increases the signal shifts to lower field with a relatively large
shift (> 10 p.p.rn.) corn pared with that observed for other such hydrogen bonded cornpounds.
One of the rnajor difficulties encountered in attempting to obtain NMR spectra of
irnidazoles unsubstituted on a ring nitrogen is a consequence of their poor solubility in
non-polar solvents (Section 4.06.4.1.2). Spectra in 0 2 0 are frequently obtained, but where
there are exchangeable hydrogens present (e.g. as in hydroxyalkyl- or arninoalkyl-
imidazoles), incornplete or poorly-defined spectra may often be obtained. In the case of
imidazole quaternary salts the 2-proton is frequently labile enough to exchange with
deuteriurn. Some workers have recornrnended conversion of irnidazoles into their N-acetyl
derivatives, which are readily soluble in CDCl 3 or (CD 3 hSOjCDCh mixtures. Irnidazoles
substituted on ring nitrogen (and benzimidazoles) are, of course, usually quite soluble in
the standard NMR solvents.
In concentrated acid solution there is a reduction in the exchange frequency of the N - H
proton to the extent that CH-NH spin splitting rnay becorne apparent, and the 4- and
5-protons rnay nO longer be equivalent. The irnidazoliurn ion can be shown by its proton
NMR spectrurn to have the symmetrical structure (15).
H H
H
N. + N--- H
H.......'''t 3
H
(15)
^ study has been rnade of the effects of solvent On the chernical shifts in the neutral
rnolecule and cationic species of 1-methylimidazole. The shifts induced by protonation,
obtained by direct cornparison of spectra in CDCh and CF 3 C0 2 H, are consistent with
stabilization of the cations by an amidiniurn-type resonance such as that shown in (15).
When N-3 is protonated the signal for H-2 shifts down field by 1.26 p.p.rn., whereas those
shifts for H-4 and H-5 move only 0.52 and 0.64 p.p.m. respectively. Such a result is only
to be expected since H-4 and H-5 are adjacent to only part of the positive charge; H-2 is
rnuch rnore fully involved. Sirnple quaternary salts of l-rnethylirnidazole resernble the
protonated species. The process of quaternization deshields the ring protons (H-4, 6.8 =
+0.95 p.p.rn.; H-2, 6.8 = +1.45 p.p.m.) and rnay result in the 2-H signal being broadened.
Often it is, as rnentioned above, so decidedly acidic that its signal rnay be absent from a
spectrum taken in 0 2 0. In the case of I-methylirnidazole rnethiodide it has proved possible
to split the methyl signal into a doublet with a coupling constant, J(N-CH 3 , H-2) = 0.45 Hz,
while the magnetically equivalent 4- and 5-protons are coupled to H-2 with J(H-4,5, H-2) =
1.8 Hz. The spectra of 4(5)-brornoirnidazole in concentrated acid solutions have perrnitted
inferences to be rnade as to the tautomeric nature of the cornpound (Section 4.06.5.1).
Table 4 1 H NMR Solvent Shifts (M) for I-Methylimidazole (78JOC3565)
Solvent 1:18 (p.p.m,)
CDC/., Me2S0-d6 D 2 0 J 1 J 2
7.41 7.55 7.57 -0.14 -0.16
7.03 6.88 6.99 +0.15 +0.04
6.87 7.08 7.07 -0.21 -0.20
Position
H-2
H-4
H-5
. l = ÔMe,SO-dn - ÔCDCI1; ß 2 = ÔD,O - ÔCDCI1'
Imidazoles and their Benzo Derivatives: (i) Structure
353
In 1-alkylirnidazoles the ring protons adjacent to an N-rnethyl group can be differentiated
frorn other ring protons by a characteristic shift in 0 with variation in solvent. In non-polar
solvents H-5 appears at higher field than H-4, with the order being reversed in polar
solvents (see Table 4).
The exarnination of coupling constants has permitted differentiation of 1,4- and 1,5-
disubstituted imidazoles and, when electronegative substituents are present (e.g. as in
4-nitroirnidazoles), the H-2 signal rnay not necessarily appear at lowest field. It would
appear that a nurnber of assignrnents in the literature rnay require revision in the light of
these observations. A selection of chernical shift data for imidazoles is listed in Table 5.
Table 5 A Selection of I H NMR Data for Imidazoles.. b
Ring protons (p.p.m.) Methyl protons (p.p.m.)
Compound H-2 H-4 H-5 Me-l Me-2 Me-4 Me-5
Imidazole 7.73 7.14 7.14
I-Me 7.47 7.08 6.88 3.70
2-Me 6.96 6.96 2.36
4-Me 7.47 6.81 2.23
1,2- Me z 6.79 6.73 3.52 2.30
1;4-M e z 7.20 6.53 3.49 2.15
1,5- Me z 7.27 6.68 3.42 2.10
2,4-Mez 6.54 2.21 2.04
4,5- Me z 7.45 2.19 2.19
2,4,5- Me 3 2.23 1.98 1.98
2-Br-l-Me 7.04 7.04 3.64
5-Br-l-Me 7.59 7.07 3.63
I-Me-4-NO z 7.54 7.87 3.90
I-Me-5-NO z 7.64 8.09 4.05
1,2- Me z-5-NO z 7.76 3.90 2.42
2-Br-l-Me-4-NO z 7.91 3.80
5-Br-l-Me-4-NO z 7.68 3.79
. Data largely taken from (70AHC(12)103, B-76MI40600).
b Solvents are CDCl 3 or CCl 4 for N-substituted imidazoles: DzO for others.
In addition to its utility for structure elucidation, and in tautornerism studies, l H NMR
has found applications for analysis in kinetic studies, in conformational studies (e.g. 1-
arylirnidazoles and reduced irnidazoles), for the deterrnination of product ratios in isomeriz-
ation reactions, and in reaction mechanism studies. Thus the technique was able to show
that deuteriurn exchange at the 2-position of irnidazoles can occur either in the presence
or absence of added base (Section 4.07.1.6.2).
Considerable use has also been rnade of the technique in the study of benzirnidazoles
(77JHC1321, 74JCS(Pl)903, nCHE1533, 74CRV279) and quaternary salts (73LA380, 74CRV279).
Although an interpretation of the A 2 B 2 portion of the spectrurn of benzirnidazole has been
reported, as yet there has been no detailed, specific analysis of the chernical shifts of protons
in unsyrnrnetrically substituted derivatives. As with imidazole, rapid N-1-N-3 proton
exchange takes place in neutral solutions of benzimidazoles, and in dilute acids fast exchange
between solvent protons and the NH is possible. This is severely retarded in concentrated
sulfuric acid, when the cornpound is protonated at N-3. The H-2 appears as a triplet with
J1,2 = J 2 ,3 = 2.5 Hz under these conditions demonstrating the position of protonation
unequivocally. The use of NMR has led to the conclusion that the transrnission of substituent
effects frorn C-2 to C-5(6) is about 20% less effective than in the opposite direction
(81OMR(15)219). Lanthanide shift reagents, which cornplex at N-3, cause a large pararnagnetic
shift of the C-4 proton in l-rnethylbenzirnidazoles.
4.06.3.3.2 Non-aromatic systems
Although the arnount of systematic published rnaterial is not great, there have been a
nurnber of l H NMR studies relating to conformations and configurations of irnidazolines
and imidazolidines, along with their oxo and thione derivatives (B-77SH(1)113). Most interest
has been concentrated on the 2-irnidazolines and imidazolinones. In rnany instances, nearby
bulky substituents prefer to take up a trans relationship. Thus when 1,2-diarninoalkanes
354
Irnidazoles and their Benzo Derivatives: (i) Structure
react with aldehydes the products are frequently th cis-2,4-disubstituted imidazolidines,
but when phenyl groups are present on the nitrogen atoms the trans isorners begin to
predorninate. In 4,5-di(substituted amino)-1,2-disubstituted 2-imidazolines the amino
groups are also trans to each other (81JHC921). With the 2,4-disubstituted 1,3-dibenzyl-
irnidazolidines, however, the 2- and 4-substituents adopt the cis configuration (7IT2453,
79JCSIP1J2289). Proton rnagnetic resonance studies have allowed differentiation of such
geornetrical isorners as in the 5-methyl-l ,2-diphenylimidazolidines (73BSF2676), and have also
provided evidence (in accord with dipole moment studies) for the envelope conformations
of sorne irnidazolidines (B-77SH(1)113, 73BSF2676). Such studies have been of value in determin-
ing the configurations of compounds with chiral centres. Evidence for the symrnetrical cation
of irnidazolinium comes from IH NMR studies of 2-irnidazolines in trifluoroacetic acid
(76CHE9l7).
The 4- and 5-methylene protons of 2-imidazolines resonate in the region 8 3-4, depending
on the substituents present; in irnidazolidines the corresponding resonances are usually
around 3 p.p.m. with the 2-protons at lower field (-4 p.p.m.). The proxirnity of an oxo or
thione function shifts the signals to even lower field, e.g. in 1,3-dimethylimidazolin-2-one,
the methylene protons give a singlet at 3.27 p.p.rn. in CDCl 3 (8IJCS(P2)317), while in
2-rnethyl-2-irnidazolin-5-one the H-4 resonance in DMSO-d 6 appears at 83.88 (7IBSFI040).
4.06.3.4 13C NMR Spectroscopy
4.06.3.4.1 Aromatic systems
The increasing interest in 13C NMR spectroscopy has resulted in considerable use of the
technique, although no detailed study of the whole range of imidazoles and benzirnidazoles
has been reported. Chernical shifts for a few simple cornpounds of this type are listed in
Table 6. As expected, in the absence of electron-withdrawing substituents, C-2 resonates
at lowest field because of its situation between the two annular nitrogen atoms. As long as
the neutral molecule is the substrate, the 13C chernical shifts rnight be expected to provide
an indication of the likely sites for electrophilic (and nucleophilic) attack in the imidazole
ring. Thus C-5 would appear to be the site of choice for electrophilic attack in I-methyl-
irnidazole, while in the benzimidazoles C-2 should be prone to nucleophilic attack; elec-
trophiles are more likely to favor the fused benzene ring. Studies of 13C NMR have been
only of limited value in ascertaining positions of tautorneric equilibriurn for rapidly equili-
brating tautomers, but there have been some useful conforrnational studies made using the
technique. In particular, the relationships between 13C chemical shift and dihedral angle
in phenyl substituted imidazoles have been noted (73ACS3101). In the relatively unhindered
I-phenylimidazole (where there is considerable interannular conjugation), there is a rela-
tively large difference (BC-3' - BC-2' = 9.4 p.p.m.) between the ortho- and meta-carbon
chemical shifts. The C-phenyl cornpounds have the ortho-carbons (C-2') rnore shielded than
in the N-phenyl isorners, and in the rnore hindered l-rnethyl-2-phenylimidazole the signal
for the ortho-carbon is shifted appreciably downfield cornpared with the corresponding
Table 6 l3 C NMR Chemical Shifts (p.p.m.) for Imidazoles and Benzimidazoles
Compound C-2 C-4 C-5 C=O Me C-l' C-2' C-3' C-4' Ref
Imidazole 136.2 122.3 122.3 76CJC617,
73JMR(12)225
l-Ac 136.2 130.5 115.9 166.3 22.3 78JCS(P2)99
I-Me 138.7 130.2 121.0 34.2 74JOC357
I-Ph 135.0 129.9 117.8 136.7 121.0 129.4 128.0 73ACS3101
2-Ph 146.7 122.7 122.7 130.0 125.2 128.4 128.3 73ACS3101
I-Me-2-Ph 147.2 127.8 121.9 34.4 130.1 128.0 128.0 128.0 73ACS3101
l-Me-4-Ph 141.7 137.4 122.2 133.6 124.3 128.1 126.2 73ACS3101
C-2 C-4 C-5 C=O Me C-6 C-7 Ref
Benzimidazole 144.4 110.1 122.7 121.9 119.4 790MR(12)95
I-Me 143.1 119.7 121.5 30.4 122.4 108.9 78JCS(P2)99
l-Ac 141.2 120.2 124.7 166.9 23.3 125.5 115.1 78JCS(P2)99
Imidazoles and their Benzo Derivatives: (i) Structure
355
carbon atom in 1-methyl-4-phenylimidazole. Changes in solvent affect the chemical shifts,
and lanthanide shift reagents have found application (74JOC357).
4.06.3.4.2 Non-aromatic systems
l3C Chemical shifts for imidazoline- and imidazolidine-thiones have been compared
(76TL3313). Additionally, it has been shown that in 1-methyl-3-phenyl-4-imidazolin-2-ones
there is extensive interannular conjugation, but the larger sulfur atom in the analogous
2-thiones pushes the phenyl group out of the plane of conjugation (74ACS(B)61). Related
studies have been applied to 1-aryl-3-phenyl-2-thioxoimidazolidin-4-ones (820MR(19)27),
and to a series of 4-mono- and 4,5-di-substituted imidazolidine-2-thiones with a variety
of alkyl substituents on nitrogen. In the latter group it was found that the increase in steric
interactions between N-methyl and N-ethyl compounds caused deformations of the ring
and variation in the valence angle of the substituted nitrogen atom (80CS(15)193).
On the basis of 13C satellite observations and iterative computer calculations it has proved
possible to make tentative assignrnents of conformation for 1,3-dimethylimidazolidines. At
about -150 o C it was possible to detect both cis (15a) and trans (15b) isomers; the free
energy barrier to rotation is approximately 6.2 kJ moC I . In such compounds typical shifts
are 41.8 (CH 3 ), 55.0 (CHz-CH z ) and 80.2 (NCH 2 N) p.p.m. (790MR(12)362, 7IT2453).
Table 6a lists some typical 13C NMR shifts for irnidazolinones and imidazolidinones.
N
Me.... ""-../ ... Me
r ,
H H
(15a)
N
Me'" ""-../ '1 4# M
_r e
H H
(15b)
Table 6a 13C NMR Chemical Shifts (p.p.m.) for Some Non-aromatic Derivatives of Imidazole
Compound Solvent CH 3 C-2 C-4,5 Ref
2-Imidazolidinone HzO 169.4 43.4 81JCS(P2)317
1,3 -Mez-2-imidazolidinone CDCl 3 29.5 160.1 43.3 81JCS(P2)317
4,5-Mez-4-imidazolin- 2-one CF 3 CO z H 8.7 151.2 119.5 81JCS(P2)310
4.06.3.5 NMR Involving Other Nuclei
Studies involving 14N, 15 N and 19 F nuclei have appeared (80AHC(27)241). The 15 N shifts
for imidazole and 1-methylimidazole in dichlorornethane relative to those in aqueous
solution are prirnarily due to strong hydrogen bonding between 15 N _ 3 and water protons.
Both hydrogen bonding and protonation result in upfield shifts, but the magnitudes of the
protonation shifts far exceed those associated with hydrogen bonding. In non-aqueous
rnedia tne imidazolium ions show less than normal shifts, suggesting that there is ion-pair
formation resulting from interior hydrogen-bonding. In solvents of higher dielectric constant
(and greater solvating power for salts) these effects diminish.
4.06.3.6 Ultraviolet Spectroscopy
4.06.3.6.1 Aromatic systems
Imidazole and its simple alkyl derivatives have little absorption in the near-UV, and this
can be attributed to their high arornatic stability. Alkyl groups in any ring position produce
a small bathochromic shift of the absorption band at 207-208 nrn. When, however, there
is an aryl group attached to a ring carbon or nitrogen, new intense bands appear between
250-300 nm as a consequence of conjugation between the arornatic and heteroaromatic
systerns. Bands of this type are also present in the spectra of 2-arylbenzimidazoles
356
Imidazoles and their Benzo Derivatives: (i) Structure
(70AHC(12)I03, 66RCRI22). In instances where steric hindrance to coplanarity is present, then
these absorption bands may be appreciably shifted.
Other groups conjugated with the irnidazole ring rnay profoundly affect the spectrurn.
Thus imidazole-2-carbaldehyde has Amax 285nm (loge 4.10) and imidazole-4-carbaldehyde
(as the neutral rnolecule) has Amax 256 nm (log e 4.07). For the latter isomer the correspond-
ing anion has Amax 280nm (loge 4.17); the cation absorbs at Amax 237nm (loge 3.85)
(B-7óMI40600). The spectra of nitroimidazoles display features which are altered characteristi-
cally by substituents and by pH and which, in consequence, are useful for the purposes of
orientation. Some exarnples are listed in Table 7. A rnethod of sirnultaneous analysis of
N- substituted and N- unsubstituted nitroirnidazoles depends largely on their spectroscopic
properties. The latter forrn yellow nitro imidazole anions in alkaline medium, and difficulty
of reduction of these anions together with the shift in the absorption rnaximurn to longer
wavelengths rnakes the analysis possible.
Table 7 Ultraviolet Absorption Spectral Data for Nitroimidazoles'
Imidazole
Basic medium
Amax (nm) (I0g1u 1')
H 2 0
Amax (nm) (I0g10 1')
Acid medium
Amax (nm) (I0g10 1')
2-N0 2
4-NO
2,4-(N0 2 )2
4,5-(NO )
I-Me-2-N0 2
l-Me-4-N0 2
I-Me-5-N0 2
2- Br-I-Me-4-N0 2
2-Br-l-Me-5-N0 2
5-Br-l-Me-4-N0 2
5-I-4-NO z
5-0Me-4-N0 2
325 (3.95)
298 (3.80)
304 (4.05)
284,221
325 (3.93)
225 (3.55), 301 (3.83)
227 (3.53), 305 (3.91)
3090.86)
316 (3.96)
221 (3.68),314 (3.85)
240 (3.66), 325 (3.83)
237 (3.57), 330 (4.12)
298 (3.91)
267 (3.85)
372 (4.13)
227 (3.52), 352 (4.01)
354 (4.09)
255,370
300 (3.89)
268 (3.85)
367 (3.80)
220 (3.76), 280 (3.88)
223 (3.73), 282 (3.83)
221 (3.69),288 (3.87)
307 (3.80)
225 (3.54), 307 (3.90)
273 (3.53), 363 (3.97)
237 (3.60), 285 (3.53), 366 (4.15)
· Most of these data are from (B-76MI40600).
The absorption spectrurn of benzimidazole is much rnore cornplicated than that of
imidazole, with absorption maxima appearing at 244 (log e 3.74), 248 (3.73), 266 (3.69),
272 (3.71) and 279 (3.73) nm. The short wavelength band (244-248 nm) is attributed to
electron transitions localized in the imidazole ring, while the longer wavelength absorption
is regarded as a displaced B-band of benzene (255 nm). As seems characteristic of the
spectra of other benzazoles, there appears to be no band which corresponds with an
interaction between the benzene and azole rings. When rnore than one ring is fused to
irnidazole (as in the naphthirnidazoles) the spectra become even more complex. There are
rnarked bathochromic shifts in the series imidazole, benzimidazole, angular naph-
thirnidazole, linear naphthirnidazole.
UV spectroscopy has been applied to studies of 2,4,5-triarylirnidazole radicals, imi-
dazolones and various thioirnidazoles. In addition, the rates of hydrolysis, alcoholysis and
aminolysis of irnidazolides such as 1-acetylirnidazole can be determined readily since such
azolides show characteristic intense absorptions at wavelengths longer than those of the
imidazole products. In the C-acyl- and C-aroyl-imidazoles, those which have the carbonyl
group attached at C-2 exhibit a bathochrornic shift of about 20 nm, while in rn- and
p-substituted 2-aroylirnidazoles intense absorptions (lOgiO e 3.5-4.3) appear in the 295-
309 nm region, with slightly less intense peaks at about 233-266 nm (74CRV279).
Applications of UV studies to the determination of the tautomeric natures of imidazoles
will be discussed later (Section 4.06.5).
In recent years there has been intensive research into the luminescence and photo-
chemistry of irnidazoles. While aspects of this will be discussed in Sections 4.07.1.1 and
4.07.1.4,. the spectral characteristics of the cornpounds will be treated at this stage. The
types of cornpound involved are polyphenyl- or polyaryl-substituted imidazoles such as
1,2,5- or 2,4,5-triphenylimidazole (lophine). It has been established that the introduction
of substituents into the 1-phenyl group of 1,2,4-triphenylimidazole has little effect either
on the absorption spectrurn (A max 290 nm) or the spectral-luminescence characteristics (A max
370 nm, 1/1 = 0.4-0.5). The effects of substituents in other phenyl rings lead to a batho-
chromic effect frorn electron acceptors in the 2-position or from electron donors in the
Irnidazoles and their Benzo Derivatives: (i) Structure
357
5-position. The luminescence, however, is not affected to any extent except in special cases
(e.g. Br or N0 2 substitutent) in which there is a substantial decrease in the quantum yield
due to intensification of the intercornbination conversion.
Benzimidazole derivatives absorb at 300-400 nrn and fluoresce intensely in solution at
320-450 nm. In 2-substituted benzirnidazoles the substituent group causes substantial
changes in the spectral characteristics of the absorption and fluorescence. Aryl substituents
with acceptor groups cause hypsochromic shifts whereas donor groups shift the spectra
bathochrornically. Such a substituent effect suggests that the nature of the long-wave electron
transition is associated with redistribution (during excitation) of the electron density in a
direction away from the C- aryl ring.
Chernilurninescence, which is a low-intensity luminescence which develops as a result of
conversion of a portion of the chemical energy into energy of electronic excitation of
rnolecules and subsequent deactivation by the emission of light, was first detected in 1877
when lophine was oxidized by molecular oxygen in 1M ethanolic KOH. In fact this
chernilurninescence (broad band at 465-660 nm, Åmax 545 nm) actually develops during
deactivation of excited peroxide rnolecules forrned in the reaction of lophine free radicals
with rnolecular oxygen (77CHE1160).
4.06.3.6.2 Non-aromatic systems
Only in the presence of such chromophores as C=O and C=S do the non-arornatic
derivatives show any marked UV absorption. The 7T-7T* transitions of the N-C(=S)-N
chromophore in imidazolidine-2-thiones give rise to absorptions in methanol solution at
about 240 nrn (log e -4.2) (79T511).
4.06.3.7 Infrared Spectroscopy
4.06.3.7.1 Aromatic systems
Assignments of the absorption bands of irnidazoles fall into three main regions: (i)
ring-skeletal (-1550, 1490, 1325 cm -1), (ii) ring-breathing and C-H in-plane deforrnations
(-1260, 1140, 1060 crn- 1 ), and (iii) C-H out-of-plane deforrnations (-940, 840,
760 cm- 1 ). When the irnidazoles are unsubstituted on nitrogen, the N-H bond stretching
frequencies appear in the region 2200-3600 crn -1; association generally rnakes this band
a very broad one. Many of the fundarnental frequencies associated with C-H bonds have
been assigned through studies of deuterated irnidazoles, and sirnilar assignrnents have been
rnade for 1-methylirnidazole in the solid, liquid and gaseous states and in solution. A
cornparison of such spectra in different states suggests that there is sorne interaction between
ring C-H groups and the 'pyridine-type' nitrogen of another irnidazole nucleus. Perhaps
this may account in part for the rather high boiling points of cornpounds such as 1-
rnethylirnidazole.
The very strong hydrogen-bonding between imidazoles with free NH groups leads
to linear associates of molecules, absorption at frequencies lower than usual, and
concentration-dependent spectra. Similar absorption characteristics are evident in the IR
spectra of benzirnidazoles, and a wide range of substituted irnidazoles and condensed
imidazoles.
N- Acylazoles have interesting IR characteristics in that their carbonyl stretching bands
appear at frequencies which are usually slightly higher than those norrnally associated with
aliphatic ketones (1765-1725 cm- 1 ), and rnuch higher than those for disubstituted arnides
(1650 cm- 1 ). Thus 1-acetylimidazole has a carbonyl stretching frequency of 1747 cm-t,
illustrating the rninor importance in these cornpounds of conjugation between the heteroaro-
matic ring nitrogen and the acyl group (see structure 16). This results in a carbonyl carbon
which is very susceptible to nucleophilic attack, and hence to the extremely facile hydrolysis
of such cornpounds. They are, in fact, powerful acylating agents (Section 4.07.3.8.4). It
should be noted, though, that a shift in the carbonyl band towards higher wavelengths (i.e.
increase in the C-O force constant) can, however, also be attributed to increased electron
attraction by the heterocyclic ring.
358
Irnidazoles and their Benzo Derivatives: (i) Structure
>'ì. C-R
(g
(16)
NOi
N-f' K+
Y)--N0 2
(17)
In general, IR spectroscopy has neither been a particularly valuable structural tool in
imidazole chernistry, nor has it found particular application in tautomerisrn studies. The
IR spectra of nitroimidazoles and their salts have been clairned to indicate that the salt
formation involves only the nitro function, with the formation of an isoirnidazole ring (17).
In polynitroirnidazoles only one of the nitro functions appears to be involved in such salt
formation (70AHC(12)103, 74CRV279, 80AHC(27)241).
4.06.3.7.2 Non-aromatic systems
The ring stretching frequencies for 4H-irnidazoles appear in the regions 1625-1650 and
1567-1575 crn- 1 (75JHC471). In 2-irnidazolines there is a strong band for C-N between
1585 and 1625 crn- 1 (76CHE917, 77LA1183), shifted to 1670 crn- 1 in 2-amino derivatives
(77JHC607). The 2-irnidazolones show a strong carbonyl absorption at -1680 crn- 1 with the
C=C stretch appearing near 1650 cm- 1 , while 1-hydroxyimidazolin-5-ones show their
principal bands at 3250 (OH) and 1690-1700 (C=O) crn- 1 (70JHC439).
4.06.3.8 Mass Spectrometry
4.06.3.8.1 Aromatic systems
The high stabilities of irnidazoles give rise to pronounced molecular ions in their rnass
spectra which are also notable for their characteristic fragrnentation patterns (but few
skeletal rearrangernents). The rnajor fragmentations in rnany of the compounds are those
due to successive losses of HCN and hydrogen atorns by competing pathways. Thus the
mass spectrurn of irnidazole shows a strong ion at m/e 40 m.u. assigned to an aziriniurn
cation (18; see Scherne 3). Deuteriurn labelling experiments indicate that the loss of hydrogen
atorns is specifically from the 4(5)-positions, but the HCN loss is less specific, originating
in order of preference from positions 2> 4(5) > 1. The rnanner in which HCN is lost can
be profoundly affected by the substitution pattern; it can come frorn the 2,3-positions (l-
and 4-rnethylirnidazole), orfrom the 1,5- or 3,4-positions (2-methylimidazole). The observa-
tion that both 1,2-dimethylimidazole and 2-mercapto-1-methylimidazole show very little
loss of HCN frorn the rnolecular ions is an indication that such a fragrnentation does not
readily involve the 3,4-positions (70AHC(12)103). At energies above the range 17-26 e V the
aziriniurn cation (18) loses a hydrogen rnolecule to give C 2 N+ (Scheme 3).
[ ç> r - '. m!: ?';HW
'j-HCH .
[ IT r -H,. [ 1 r -H'
W / 40
) N me
(18)
. j-H.
) 'Ç7
t':
m/e 41
* denotes metastable observed
Scheme 3
For a nurnber of specifically-labelled l-rnethylimidazoles the early stages of the rnass
spectral fragmentation have been exarnined in some detail. The relative losses of labelled
and unlabelled HCN frorn the Mt and [M - 1t species show that there is an insignificant
arnount of hydrogen-randornization in the rnolecular ions prior to fragmentation. Sub-
Irnidazoles and their Benzo Derivatives: (i) Structure
359
sequent elimination of HCN, as rnentioned above, involves C-2 and N-3. The rnolecular
ions eject hydrogen radicals largely from the rnethyl group (Scheme 4), but there is sorne
rninor contribution to this process frorn H-5. The resultant [M -It ions exhibit extensive,
but incornplete, hydrogen-randomization, and subsequent loss of HCN frorn these ions is
consistent with the interrnediate forrnation of ring-expanded ions.
N N
() = () 1,2-cl vage)
N N
I II
CH 3 CH z
Hz N Hshift
N)
\."' .
H 7 ):: ::r ) r
HzC, .rJ "" +
N N
H
N H
( y
"" ...-CH z
N
hifl
r-N X H
Ñ H
H
r'N 'CH z
N H
Scheme 4
The mass spectral fragmentation pattern of benzirnidazole parallels that of irnidazole.
Again, the rnolecular ion is frequently the most intense ion which loses HCN to forrn an
azirinium radical cation by a non-specific process. Further consecutive losses of HCN and
a hydrogen atorn lead to an ion, C s H3 + (Scherne 5). In 2-methylbenzimidazole the loss of
MeCN is not a rnajor process; rather, the initial fragrnentation is loss of a hydrogen atorn
(probably from the methyl group) with concornitant ring expansion to give a stable quin-
oxalinium cation (19). Subsequent loss of consecutive molecules of HCN gives rise to the
phenyl cation (Scheme 6) (74CRV279, 68T1875, 78M379, 77JHC1321). In l-methylbenz-
irnidazoles, competitive losses of CH 3 ', CH 3 NC and HCN are possible from the molecular
ion.
[ ex:> r
-HCN
(): +. -H'
) "- I NH ' -HCN) C H +
............. --+ 5 3
Scheme 5
ex N
I }-C H 3
:::::,.... N
H
+
. (X I N )
:::::,.... +h'
N
,H
(19)
H - c
-HCN) 0-J C 6 H S +
Scheme 6
On electron irnpact the 4-rnethyl-5-nitroirnidazole rnolecular ion loses H 2 0. Such a loss
seems to require an NH group adjacent to the nitro group, i.e. loss of H 2 0 cornes frorn
the least dorninant tautorner (80AHC(27)241). However, an adjacent CH group may be
irnplicated. Loss of ,OH by the norrnal 'ortho' process also takes place (Scheme 7). In
1-alkyl-5-nitroirnidazoles there is a similar hydrogen transfer which is followed by an
unusual rearrangernent, resulting ultirnately in the loss of an aldehyde or ketone fragrnent
from the molecular ion (Scheme 8). In 1-(o-nitrophenyl)imidazoles the 2-H proton is
involved in the loss of 'OH, a related 'ortho effect' (780MS(13)575). The rnass spectrurn of
1-methyl-4-nitroimidazole-5-carboxarnide shows elimination of water by electron impact
as distinct from the normal thermal process. Most nitro-irnidazoles and -benzimidazoles,
though, have rnass spectra which display the usual characteristic losses of N0 2 " NO and
0, fragments. Thus fragments arising frorn the losses of 0" NO, N0 2 , and ,OH appear in
the spectrum of 1,2,5-trirnethyl-4-nitroimidazole. In addition, there is evidence of loss of
CHO, a fragmentation which appears to be uncommon in azoles but which has been
observed with sorne other nitroarornatics.
360
Irnidazoles and their Benzo Derivatives: (i) Structure
H HO
C ';, -O. \+ +
CH, N-O' CH, N=O
-. H -'OH I H
N ND N ND NVD
m/e 12R 1 ?) m/e 111
CH z CW CH 2 N=O
K(oH -HDO I H
N D
V v N
m/e 109
Scheme 7
O=Ñ-C)
1 I
O' ";-C ,
H I R
R'
N
O=Ñ1;.) --)
'0\1
I C-- R
H k'
Nl-:-
ON-c)
H t
'O'/J'R
R'
R'-C-R
II
o
N 1-:-
ON-cP
H
Scheme 8
The rnass spectra of 1-benzylirnidazoles are dorninated by the tropyliurn (C 7 H/) ion.
Azolides tend to elirninate ketene, giving rise to 'molecular ions' of the corresponding
unsubstituted azoles. Other fragrnentation pathways, though, rnay compete with this. When
1-acetylimidazoles lose CO the resultant ions do not have N- or C- methylirnidazole
structures. In 2-aroyl-irnidazoles and -benzirnidazoles a hydrogen atorn is cornrnonly elirni-
nated frorn the molecular ion, while CO loss from either the Mt or [M -It species is
also characteristic; p-rnethoxybenzoyl derivatives lose either formaldehyde or consecutive
CH 3 . and CO fragrnents frorn the [M - 29t ion (80AHCi27)241). 2-Formylirnidazole, 2-
forrnyl-1,4,5-trirnethylimidazole 3-oxide and 2-forrnyl-l,5-dirnethylirnidazole 3-oxide all
lose CO frorn the rnolecular ions. The two principal fragrnentation sequences, though, are
loss of O. followed by the forrnyl function and the alternative order of fragmentation.
Whereas loss of a hydrogen atorn is observed frorn 2-forrnyl-1-rnethylimidazole, this is not
the situation with the N-oxides presumably because the hydrogen atom is lost in the 'OH
fragrnent. Loss of ,0 and 'OH fragments from most irnidazole N-oxides is cornrnon. In
2-formyl-l,4,5-trimethylirnidazole 3-oxide, HCN is elirninated frorn the m/ e 109 rn.u.
species, the molecular ion having first lost 'OH and CO in this particular instance; in
2-forrnyl-l,5-dimethylimidazole the process differs in that the HCN loss frorn the rnl e
95 m.u. fragrnent follows prior loss of O. and CO frorn the molecular ion. In the trirnethyl
cornpound, not only can a hydrogen radical be rernoved frorn the forrnyl group but it can
also originate frorn the 4-methyl group. In the corresponding 2-carboxylic acid the rnost
striking loss is CO 2 , but losses of 0., .OH and HCN are also present as with the forrnyl-
substituted N-oxides (B-76MI40600). While 2-arylbenzimidazole 3-oxides display the charac-
teristic losses of 16 and 17 rn.u., the most intense ion is invariably an RCO+ ion which
rnust result frorn sorne rearrangernent (78JCR(S)366).
In the rnass spectra of a number of rnethylated histamine derivatives the base ions arise
frorn ß-cleavage, usually with concornitant hydrogen rearrangernent. This results in ions of
the general forrn [M - CHR=NRt, where R = Me, H.
^ variety of fragrnentations has been noted in the rnass spectra of benzirnidazoles
substituted by ketone functions at C-2. Some of these involve rearrangernents such as those
illustrated in Scherne 9.
4.06.3.8.2 Non-aromatic systems
The rnost significant ions in the rnass spectra of 4,5-dihydroimidazoles arise from 0)
elirnination of the C-4 substituent, Oi) cleavage of the 1,2 N-C and 4,5 C-C bonds with,
or without, hydrogen rnigration, and Oii) cleavage of the 1,5 and 2,3 N-C bonds with
charge retention on the N-I-C-2 species (780MS(l3)319). In the rnass spectrurn of 4-
Imidazoles and their Benzo Derivatives: (i) Structure
361
Reo
o 1 +
(( N II'
I }-CH 2 -C-R
:::::,.... N
H
----"
N 1 1:
N r-R
H OH
IR=Me C.1H4
-0
(X I N)-cH2CO
N
H
-co
(X N
) I }-CH 2
:::::,.... N
H
N>-OHl:
N
H
j
R = Me, Ph
* denotes metastable ion observed
+
(D" C()
H
(( N + (( N
I 2 1. -CH2=C= I r Ph
:::::,.... N\'-.::C=o N
H / H
Ph
Scheme 9
substituted 2-imidazolones the base peak is the molecular ion, which loses such fragments
as CO and RNCO (where R is the N-substituent or hydrogen) (79JHC983). Mass spec-
trornetry has been used in the deterrnination of the trans configuration of 4,5-dirnorpholino-
2-irnidazoline (8IJHC921).
4.06.3.9 Electron Spin Resonance Spectra
The free radicals produced at roorn ternperature by X-irradiation of crystalline irnidazole,
benzimidazole and their 2-rnethyl derivatives are shown to be alrnost identical (1: 2 : 1
triplet (a = 45 G) with each line displaying further, poorly-resolved, hyperfine splitting).
The radical produced from irnidazole, therefore, must have coupling with two identical
protons as in structure (20). Exarnination of the ESR spectra of 2,4,5-triphenylirnidazolyl
radicals using partially and completely deuterated species has been supplemented by the
application of simple MO calculations to demonstrate that the radicals are not planar. There
is, nevertheless, some arnbiguity since ESR shows the radicals to be of the 7T-type; INDO
calculations point to a o--radical. Oxidation of I-hydroxybenzirnidazole 3-oxides with silver
oxide or lead tetraacetate gives syrnrnetrical nitroxide radicals, and irnidazole anion radicals
are believed to exist in the tautomeric a-pyrrolenine forrn (21) rather than (22). A CNDO
study has criticized this conclusion (80AHC(27)241, 74CRV279).
H
/
C H
N
I
H
(20)
/N
:^N)
Ç N
. X:
(21)
(22)
4.06.3.10 Photoelectron Spectra
Comparisons have been made arnong benzimidazole, benzoxazole and benzoselenazole
using MO calculations and PE spectra. The theoretical calculations agree with the observed
relative band intensities for the He(I) and He(II) spectra (78MI40600). Application to
imidazoles of He(I) PE spectroscopy demonstrates that the lone pair levels are heavily
localized on nitrogen, while the other MOs of the valency shell are strongly delocalized
(73T2173).
362
Irnidazoles and their Benzo Derivatives: (i) Structure
4.06.4 THERMODYNAMIC ASPECTS
4.06.4.1 Intermolecular Forces
4.06.4.1.1 Melting and boiling points
As a general rule the boiling points of imidazoles are relatively high, probably because
of the high degree of intermolecular association. When there is a substituent other than
hydrogen on an annular nitrogen, there is no longer any chance of such association. As a
result there is a considerable lowering of boiling point (e.g. irnidazole, 256 0 C; 4-rnethyl-
irnidazole, 264 0 C; 1-methylimidazole, 198 0 C; 1,4-dirnethylirnidazole, 200 OC). There is a
similar pattern associated with the melting points (e.g. imidazole, 90 oC; 4-methylirnidazole,
56 0 C; l-rnethylirnidazole, -6 0 C; benzirnidazole, 171 0 C; 1-rnethylbenzirnidazole, 66 o q.
4.06.4.1.2 Solubilities
The solubilities of irnidazoles, too, are affected in a striking fashion by substituents on
an annular nitrogen. Those with a free NH group are usually highly soluble in polar, protic
solvents such as water and have poor solubility in non-polar solvents. These solubility
characteristics are reversed in i-substituted imidazoles. There are occasional exceptions to
this general rule of thurnb. The compound 2-acetylirnidazole is quite soluble in chloroforrn
and only poorly soluble in water. It appears that intramolecular hydrogen bonding (between
the NH and carbonyl oxygen) competes with the normal intermolecular hydrogen bonding
cornrnon to the series. Such quantities as association energy, dielectric relaxation time,
ionization energy and dissociation constant in aqueous rnediurn have been deterrnined for
irnidazole. An IR exarnination has been rnade of the association of 4-rnethylirnidazole in
carbon tetrachloride and in 1,1 ,2,2-tetrachloroethane (64MI40600). The concentration depen-
dence of the rnaxirnurn extinction coefficient of the free NH valency bond allowed deterrnina-
tion of the rnonorner content, the rnean viscosity and the equilibriurn constants K 12 and
K 13 . Frorn the tern perature dependence of these values the mean heat of addition (34:f:
2 kJ rnol- 1 ) and the heats of forrnation of the dirners (42.7 kJ rnol- 1 ) and trirners
(33.9 kJ rnol- 1 ) were obtained. Although this rnean heat of addition was rather higher than
had been obtained by an earlier worker, both results were not contradictory to the
assumption that irnidazoles form chain-like associations with angled structures.
When one endeavours to apply such separation techniques as solvent extraction and the
various forrns of chrornatography to irnidazoles, one must be aware of the significant
influence that the substituents (and their positions) have on molecules which have a
well-developed polar nature and a tendency to forrn associates.
4.06.4.1.3 Gas-liquid chromatography
The polar natures of imidazoles with a free NH group have rnade their separation by gas
chrornatography difficult (70AHC(12)103). The 1-substituted cornpounds are rnuch rnore
susceptible to the separation technique, and it is often advantageous to convert N-unsub-
stituted cornpounds into their N- acetyl derivatives before separation. A set of conditions
which has proved effective for sirnple alkyl- and aryl-substituted imidazoles cornprised a
glass colurnn packed with Chrornosorb W, AW-DMCS (H.P.), 80-100 rnesh coated with
5% OV-17, and using nitrogen as carrier gas (nMI406o0).
4.06.4.2 Thermochemistry; Aromatic Stability
That imidazoles and benzirnidazoles have high stability has been known for many years.
Resistance to acids,' bases, heat and oxidation or reduction are cornmon traits of these
corn pounds, which display considerable arornatic character. Thus treatment of benz-
irnidazole with perrnanganate leads to irnidazole-4,5-dicarboxylic acid; irnidazoles, in gen-
eral, are not easily oxidized or reduced (Sections 4.07.1.4.11, 4.07.1.5.6, 4.07.1.7.4).
Therrnal stability too is evidenced by the resistance of the irnidazole nucleus to ring fission
Imidazoles and their Benzo Derivatives: (i) Structure
363
during thermal rearrangernents of 1-alkyl- and 1-aryl-irnidazoles at temperatures above
600 oc (Section 4.07.1.2.2). The planar natures of the molecules (as shown by X-ray studies),
the lack of ring strain, the typical, low-field chernical shifts of the ring protons in the
l H NMR spectra of the rnolecules, and the appreciable ring current anisotropy in the l3C
NMR spectra are all diagnostic of aromatic character. The importance, cornpared with
benzene, of dipolar resonance contributors to the hybrids has been comrnented on earlier
(Section 4.06.2).
Frorn the enthalpy of forrnation of crystalline irnidazole (61:f: 3 kJ mol-I), the heat of
sublirnation (67:f:4kJrnol- 1 ) and the heat of forrnation of gaseous imidazole (128:f:
8 kJ rnor\ a resonance energy value of 59 kJ mol- 1 can be calculated. While this is
considerably lower than that of benzene, it still indicates considerable stabilization.
4.06.5 TAUTOMERISM
4.06.5.1 Annular Tautomerism
Although it is not possible to separate 4- and 5-rnethylirnidazole isorners, rnethylation
gives an approxirnately 50: 50 rnixture of the 1,4- and 1,5-dirnethylimidazoles. In addition,
the l H NMR spectrum of imidazole shows but a single peak for the 4- and 5-hydrogen
atorns, indicating that they rnust be rnagnetically equivalent. Such observations can be
explained in terrns of a rapid proton exchange between the -NH- and the =N- nitrogen
atoms. In neutral, organic solvents this can be an interrnolecular process involving two or
more imidazole molecules (Scheme 10), while in protic solvents such as water the solvent
itself is involved. The NH proton of irnidazole can be shown to exchange with deuteriurn
very rapidly in 0 2 0. The rate equation for the tautomerism of irnidazole has been shown
to contain kinetic terrns which correspond to catalysis by H+, OH- and imidazolium cations.
There is also an uncatalyzed term which seerns to be unexpectedly large and may involve
the bifunctional participation of water (Scherne 10) (76JA3737). Certainly, the large associates
of imidazoles, unsubstituted on the NH nitrogen, in organic solvents are hydrogen-bonded
in such a way that fast proton exchange is possible. It is this rapid exchange which is
responsible for the absence of spin-spin splittings with the NH proton in the l H NMR
spectrurn, and for the observation that this proton gives rise to a broad, distinct signal only
in concentrated solutions in such solvents as benzene, chloroforrn and acetone. Thus this
prototropy makes the 4- and 5-positions rnagnetically and chernically equivalent.
,f'-N-H H..
r""N-H .....:N?7- H ...: N V C h ) .... /o'H)n
1'10 .
\\ W
Scheme 10
The presence of proto tropic tautornerisrn can also be demonstrated when an atternpt is
rnade to synthesize the two individual tautomers of a pair. Both synthetic pathways (Scheme
11) lead to the 'same compound', or to a product rnixture which behaves as if it was a
single cornpound. The ultirnate product (23) (in reality it is a tautorneric mixture which
acts as a single corn pound) can be narned 4(or 5)-ethyl-5(or 4)-rnethylirnidazole, but it is
now accepted practice to assurne that workers in the field are aware of the irnplications of
the simpler form of nornenclature, 4-ethyl-5-rnethylirnidazole. When the NH group is
Me
\ Me NH Me NH
HC-NH 2
I KCNS Et()SH Ete)
/C
Et 0 1'1 1'1
Jf Raney Ni ) Jf (23)
Et
\ Et NH Et NH
HC-NH 2 KCNS
I MeQSH Me()
......C,,-
Me "0 1'1
Scheme 11
364
Irnidazoles and their Benzo Derivatives: (i) Structure
substituted by, for example, an alkyl group, then prototropic tautomerism is no longer
possible. Thus methylation of 4-methylimidazole gives a mixture of two quite distinct
compounds, 1,4- and 1,5-dimethylimidazole, in about equal quantities.
To this stage we have only considered imidazoles which have simple alkyl groups at C-4
or C-5. It would not be unreasonable to expect that other groups might favour one tautorneric
form at the expense of the other. A case in point is 4(or 5)-bromoimidazole (24, 25; Scherne
12), which exists mainly as the 4-bromo form (24). Evidence for this comes from exarnination
of the NMR spectra of deuterated derivatives in concentrated acidic medium. Such a
medium converts imidazole into the cation which is able to undergo proton exchange only
very slowly; coupling with the NH proton can be observed in consequence. When 2-deuterio-
4(5)-bromoimidazole (26) was treated with concentrated D z S0 4 , the product had a coupling
constant of 2.7 Hz. 1,2-Dideuterio-4(5)-bromoimidazole (27) in concentrated H 2 S0 4
showed a smaller coupling constant of 1.9 Hz. On the basis of the assurnption that a larger
coupling constant is due to adjacent protons, and the smaller one is due to distant protons
(cross-ring coupling), it could be concluded that the compound exists as 4-bromoimidazole
(70AHC(12)103). The results of this study could also be interpreted as indicating that the
4-brorno tautorner protonates faster, but in view of the known electronic characteristics of
the bromo substituent this is an unlikely state of affairs. The observation that the coupling
constants for 4(5)-fluoroimidazole correspond closely with those of 4-fluoro-l-methyl-
imidazole suggests that in solvents of low polarity the 4-fluoro form is the dominant tautomer
(78JHC1227).
D, S0 4 ) f1 D
H
J S _ H . 1 _ H =2.7Hz
Scheme 12
Br N
()
N
H
(24)
Br NH
()D
N
-"
...---
Br N
()D
N
H
(26)
Br NH
Q
(25)
Br ND
()D
N
Br N
f)D
D
Br NH
H, S0 4 J?:.': \
) /D
D
J._ H . 1 _ H = 1.9 Hz
(27)
Another way to study tautomerisrn is through pKa measurements. A comparison of the
basic pKa values for 4(5)-nitroimidazole with those of 1-methyl-4- (29) and 1-methyl-5-
nitroimidazole (30) leads one to the conclusion that the 4-nitro tautomer (28) predorninates
(Scheme 13); in fact the 4-nitro:5-nitro ratio has been computed as about 400:1. In this
experirnent the methylated compounds serve as 'fixed models' in which the nitro substituent
is fixed in each of the two possible orientations. The influence of the methyl group can be
shown to be small by comparison of the pKa values for imidazole (-7.0) and 1-rnethyl-
imidazole (-7.1), and hence I-methyl-4-nitroimidazole resembles the major tautomer.
02 N () 02NrNH
N )
H
(28) pK. = -0.05
02 N ()
N
Me
(29) pK. = -0.53
Scheme 13
02 N ( NMe
)
N
(30) pK. = 2.13
The K T values have been summarized for a variety of 4(5)-substituted imidazoles (Table
8) (76AHC(S1)280), and these, along with Charton's application of the Hammett equation
to heteroaromatic tautomerism (65JOC3346, 69JCS(8)1240), have suggested qualitatively that
electron-donating groups (u m <0) will favour the 5-substituted tautomer, while electron-
attracting groups (u m > 0) will favour the 4-isorner. It is possible to predict the position
of tautomeric equilibrium for any unsymmetrically substituted imidazole (provided that t::.p
is known) using the relationship log K T = pK B - pK A = (PB - P A)U m (where A and B refer
to the 4- and 5-tautomers). A relatively recent attempt (70JHC227) to the correlate pKa
values of imidazoles with the sum of the Hammett coefficients, LU*, in which the u-values
of the substituents were expressed as !(u o -Um), made the inadmissible assumption that
K T = 1 in each case. Although the available experimental evidence tends to support the
view that electron-withdrawing groups favour the 4-substituted tautomer and the converse
Irnidazoles and their Benzo Derivatives: (i) Structure
365
is true for electron donors, as yet the range of substituents on which this is based is very
limited. In fact, calculated heats of combustion show that in the 4-aminoimidazole
5-aminoimidazole equilibrium there is a slight predominance of the 4-amino form, a
conclusion at variance with the foregoing since (T m (NH 2 ) :::: -0.161.
Table 8 K T Values for Imidazole Annular Tautomerism (76AHClSl)280)
Imidazole
K T
Imidazole
K T
Unsubstituted
2-Br
4-Br
4-Cl
4-NO z
1
1
63-152
447
320-500
4-Ph
5-CI-4-NO z
2-Br-4-NO z
2,4-(NO z h
10-37
118-186
210
1.1-3.1
. K T = [4-NO z J/[5-NO z J.
It should be emphasized that none of the tautomerism studies discussed here relies on
chemical reactivity, a notoriously misleading measure of tautomeric structure.
X- Ray crystallography has been employed to demonstrate that, in the solid state,
histamine is 5-(2-aminoethyl)imidazole, a result which contrasts with the structure deter-
mined for its cation. However, from determinations of pKa values of histamine and its two
possible N-methyl derivatives, a K T value of 4 (4-:5-substituted isomer) has been found.
In fact, in aqueous solution histamine exists largely as the protonated form (31) which
reverts to (32) on neutralization. Electron-withdrawing groups in the imidazole ring of
histamine cause the 4-isomer to predominate, but methyl groups have little effect
(80AHC(27)241). The 4-substituted zwitterionic form for histidine is preferred in basic
medium; this form is maintained in a number of histidine derivatives (e.g. the polypeptide
bacitracin).
(31)
CH 2 CH 2 NH z
F\
NVH
(32)
R O: N
I Me
R N
\ Me
H...O""C"
(33) OEt
CH z CH 2 NH 3
F\
HN-V N
Although, as mentioned above, the prototropy between N-1 and N-3 of imidazole is
normally very rapid, as it is with benzimidazole, it is possible to prepare benzimidazoles
(of general structure 33) in which the rate of prototropy has decreased to the extent that
the two forms can be demonstrated. The retarding effect described in this instance can be
ascribed to intramolecular hydrogen bonding between the NH and the carbonyl oxygen.
Ring-chain tautomerism can be eliminated as an explanation because of the low energy
barrier to rotation, and the strong carbonyl band in the IR spectrum (75TL4085). Of course,
when there is a benzene ring fused in the 4,5-positions of imidazole the prototropic
tautomerism makes the 4- and 5-positions equivalent to the 7- and 6-positions, respectively
(Scheme 14). K T is near unity for most benzimidazoles.
R 5 * R4 3 R 5 JQ= R4
",,4 N 7 NH
I 19 5 I þ
R6 >--7 N R6 >--4 N
H
R7 R7
Scheme 14
4.06.5.2 Ring-substituent Tautomerism
As discussed in the General Chapter (Section 4.01.5), imidazoles with potential hydroxy,
thiol and amino substituents can exist in a variety of tautomeric forms. In contrast to the
'hydroxypyrazoles' which have been studied in detail, comparatively little is known about
the corresponding 1,3-diazoles. Many of the imidazoles are not easily accessible syntheti-
cally, and they may not be particularly stable (e.g. 4-hydroxyimidazoles). Amino derivatives
366
Irnidazoles and their Benzo Derivatives: (i) Structure
have also received little attention for similar reasons. The most valuable source material
relating to ring-substituent tautomerism is to be found in (76AHC(Sl)266). The 1-substituted
imidazolin-5-ones can exist in four possible forms (34-37; X = 0) in tautomeric equilibrium
(Scherne 15), and the same could be said for the corresponding sulfur (X = S) and amino
(X = NH) compounds (76AHC(S1)280). Certainly both 1,2,4-trimethyl- and 1,4-dimethyl-2-
phenyl-imidazolin-5-one exist in the form corresponding to (34; X = 0) under a wide variety
of conditions. Evidence came from UV studies in methanol, IR studies in the solid state,
NMR data in a variety of solvents, and comparison with 4,4-dimethyl model compounds.
However, the 4-phenyl analogues do not exist in the form (34; X = 0), but the experimental
data available do not adequately define the true structure; the authors suggest that the enolic
form (35; X = 0) predominates.
:f , = HX1= , =. ')-r., =
N N N
R 1 R 1 R 1
(34) X = 0, S, NH (35) (36)
R 4
)::\
R' R-
(37)
Scheme 15
I-Methylimidazolin-4-ones can exist in three possible forms (38-40; X = 0) (Scheme
16). In the solid state, 1,2-dimethyl-5-phenylimidazolin-4-one exists in the OH form (39;
X = 0), but insolubility precluded studies in solution. Compounds stated to be 1-acyl-
irnidazolin-4-ones have been formulated as the 4-oxo forms (analogous to 38; X = 0) on
IR evidence. Where possible, it seems that a non-conjugated carbonyl form (e.g. 34, 42;
X = 0) is preferred to the conjugated version (e.g. 37, 41; X = 0), but although substituents
may have a marked effect, the nature of the solvent is not of particular importance in
deterrnining the position of tautomeric equilibriurn for these compounds.
HX
R S Jç)R 2
Me
(39)
Scheme 16
In the N-unsubstituted imidazolin-4(5)-ones the number of possible structures is greatly
increased. Although there are only three possible forms (41-43; X = 0) for the 5,5-
disubstitufed compounds, there are eight alternative forms (44-51; X = 0) for the 2,4-
disubstituted imidazolin-5-ones (Scheme 17). 2-Methyl-5,5-diphenyl- and 2,5,5-triphenyl-
imidazolin-4-one both have IR spectra in the solid state which show absorptions belonging
X
H):)R 2
RS N
Me
(38) X = 0, S, NH
..--
-X)--NH
R S JZ....)R 2
N
Me
(40)
.,.t ., = .,t;\:, =
R S R5 N
H
(41) X = 0, S, NH (42) (43)
H+- H+- H R - H R)-
X N/'-R2 X rR2 XAN^- 2 HX--(N,)'--R 2
H H R H
HXì= N
R S ;(.,)R 2
R S N
144) X = 0, S, NH
(45)
(46)
(47)
R 4
'rim
-X-Z.)-R2
H
(48)
-->-
..--
H+ N
HX ..)-R2
N
(49)
Scheme 17
R N R)-NH
HX N)ç HX--Z R2
(50) (51)
Irnidazoles and their Benzo Derivatives: (i) Structure
367
to individual tautomers (41) and (42) and it is even possible to separate both 'desmotropic'
forms as crystalline solids. However, in solution each form contributes to the same equilib-
rium mixture with identical spectra. In such compounds the hydroxy form (43; X = 0) does
not seem to be a significant contributor. In non-polar solvents the 5,5-diphenyl and
5-spirocyclohexyl derivatives of imidazolin-4-one exist as the less polar, less conjugated
tautomer resembling (42), but as the solvent polarity increases the rnore polar tautomer of
type (41) increases in importance (72JHC363), particularly when electron-donating groups
are present at C-2.
In a recent study (798S8289) of the prototropy of imidazolin-5(4)-ones, two methods were
used: (i) an energetic analysis of the molecular entities with consideration of the solvation
term, and (ii) examination of the protonation sites of the common anion. In agreement
with the experimental results it was shown that in the vapour phase, as well as in solution,
the major tautomeric form is the non-conjugated carbonyl form (42; R S = H, X = 0);
methylation at positions 1, 2 and 5 leads to the predominant form (38; R 2 = R S = Me,
X = 0). Until recently, work on the 2,4-disubstituted imidazolin-5-ones was not particularly
definitive, but the use of spectroscopic studies allied with CNDO/2 calculations has proved
of great value. The summarized conclusions (76AHC(Sl)280, p. 374) are (i) in the absence of
4- or 5-substituents, the CH form (44; X = 0) predominates; (ii) if there is a 4-phenyl
group present, one or both hydroxy forms (47, 51; X = 0) predominates in the solid state
or in solution; in CF 3 C0 2 H the CH form (44; X = 0) is also present; (iii) of the CH forms
(44, 45; X = 0) the former is always favored; (iv) 2-substituents have less influence than
4-substituents on the position of equilibrium; and (v) solvents do not greatly affect the
equilibrium.
If one excludes zwitterionic structures which appear to have less stability than the other
forms, there are four possible structures for the imidazolin-2-ones (52-55; X = 0) (Scheme
18). IR evidence points to a carbonyl form (53; X = 0) in the solid state, while the
characteristic absorption in the UV region supports their designation in solution as the
carbonyl forms. If their melting points are compared with imidazoles (e.g. imidazole, 90 oC;
imidazolin-2-one, 250 o C), the high values may point to the presence in the solid state of
salt-like structures. Benzimidazolinones, and other fused-ring imidazolin-2-ones, appear
to exist and react as the ketone forms (66RCR122).
r NH ->0 IjNH ->0 F N
'-NAxH .- '-N X'- HÄNAxH
H H
(52) X = 0, S, NH (53) (54)
Scheme 18
->0
.-
H
H t NH
AX
N
(55)
Critical summaries of what is known about the tautomeric natures of imidazolinones
have appeared earlier (B-76MI40600, 76i\HC(Sl)280, 70ZC338, 80AHC(27)241).
The best known of the potential mercaptoimidazoles are the imidazoline-2- and benz-
imidazoline-2-thiones, which resemble imidazolin-2-ones in that the tautomeric form (53;
X = S) is the preferred form. The crystal structure and the l H NMR spectrum of 1,3-
dimethyl-3H-imidazoline-2-thione have been interpreted as showing partial double bond
character in the N-C-N system, but no aromaticity (70CC56). However, the preference
for a betaine structure (56) rather than (57) or (58) should be accepted with caution since
it is really only a resonance structure similar to others which undoubtedly contribute to the
overall structures of oXO-, thio- and amino-imidazoles. Measurement of the pKa values for
a series of imidazoline-2-thiones substituted variously on C-4, C-5, N-1 and N-3 by
hydrogen, phenyl or methyl shows that all of the values are similar. Approximate K T values
calculated show that these compounds exist even more in the thione forms (53, X = S; 58)
than do the corresponding thiazoline-2-thiones and oxazoline-2-thiones. The UV spectra
in aqueous solution support thione structures, as do dipole moment and X-ray studies
(76AHC(Sl)280, p. 400).
s-
Me ÑMe
\d
(56)
s-
MeNÅNMe
\;. + .: I
(57)
S
^
MeN NMe
U
(58)
368
Irnidazoles and their Benzo Derivatives: (i) Structure
Imidazolidine-2-thiones (or 2-ones) have been shown by 13C NMR studics to cxist entirely
in these forrns rather than as the possible 2-mercapto-(or 2-hydroxy- )2-imidazolines
(80CS(15)193). The thione structure for benzirnidazolinethiones is supported by UV, IR and
dipole moment measurements. In addition, an X-ray study of l-(ß-D-ribofuranosyl)benz-
imidazoIine-2-thione confirms its thione (59) rather than the thiol (60) structure (Scheme 19).
(r NH
I >=S
N
R
(59) R = ß-D-ribofuranosyl
(r N
\ }-SH
N
R
(60)
Scheme 19
Compounds with a potential thiol group at C-4 or C-5 are not at all well known, but
might be expected to display behavior analogous to the related oxygen cornpounds. Seern-
ingly only the 4,4-diphenyIimidazoIine-5-thiones (together with their N- and S-rnethyl
derivatives) have been described, but no study of their tautomerism has been reported.
Aminoimidazoles rnight be expected to prove more complicated than the analogous
'hydroxy' and "mercapto' derivatives because of the possibility that an R group on NHR
could have a marked effect on the position of tautomeric equilibrium, particularly if R is
an acyl or sulfonyl function. However, amines are much weaker acids than hydroxy or
rnercapto compounds and so it should not be necessary to consider zwitterionic structures
to any extent; an NH- group is not at all likely.
The bulk of the evidence available points to these compounds existing mainly in the
arnino (NHz) rather than the imino (=NH) forms (71CHE752). With 2-amino-l-methyl-4,5-
diphenylimidazole the UV (in methanol), IR (in the solid state) and pKa values of the two
corresponding fixed derivatives (63) and (64) demonstrate clearly that the cornpound exists
largely as the arnino tautomer (61) with K T = (61)/(62) = 3 x 10 4 (Scheme 20). An amino
structure in which 2,4,6-trinitrophenyl groups replace the methyl functions in (64) has been
incorrectly assigned to the reaction product of 2-aminoimidazole and picryl fluoride
(70JHCI391).
Ph N Ph NH Ph N r h NMe
Ph(>-- Ph( PhC NHMe Ph( NH
N NH z N NH N
Me Me Me Me
(61) (62) (63) (64)
Scheme 20
4-Aminoimidazoles are rather unstable and have not been studied extensively, but despite
the absence of a specific study of their tautornerism it is possible to gather some evidence
in favour of the amino tautomer of types (35; X = NH) (39; X = NH) or (47; X = NH).
Imino structures (e.g. 34, 38, 44; X = NH) require the appropriate CH signals in the NMR
spectrum: these are absent, and the IR spectra display characteristic bands for NHz. The
X-ray structure for 4-acetarnido-2-bromo-5-isopropyl-1-methylimidazole confirms the
structure (65) rather than the tautomer (66) (Scheme 21). On the basis of 13C NMR
evidence, 2-arylamino-2-imidazolines prefer to exist in the arylirnino forms (B-77MI40600).
MeCONH MeCON
,)c\\Br H - r)Br
Pr N"" pr
Me Me
(65) (6
Scheme 21
Like the uncondensed compounds, 2-aminobenzirnidazoles exist in the amino forms.
Evidence comes from the NH z bands in the IR (solid state) and comparison of the UV
spectra with those of fixed rnodels. A K T value of 160 in 50% aqueous ethanol has been
calculated for 2-amino-1-methylbenzirnidazole. Calculations of the 1T-energies of each
tautomer also favour the amino form for this compound and for linear and angular
2-aminonaphthirnidazoles. Even in the structure (67), where hydrogen bonding rnight be
expected to favour an imino tautorner (68), the amino form persists (Scheme 22).
Imidazoles and their Benzo Derivatives: (i) Structure
369
"' Vy N}-NH' --=- M' VY rNH
N N
(67) Me (68) Me
Scheme 22
There is a tautomeric equilibrium between N- oxides and N- hydroxyazoles and their
benzo derivatives. The equilibrium shown in Scheme 23 has a K T (70/69) value of about
3, but the UV spectrum bears most resemblance to the hydroxy model (71). The authors
admit, though, that steric hindrance between the N-methyl and adjacent phenyl groups in
the oxide model (72) renders it less than perfect and the best conclusion (albeit irnprecise)
may be that in aqueous solution K T is about 1. In less polar solvents (ethanol, cyclohexane,
chloroform, dioxane) UV comparisons still favor the OH form but the foregoing limitations
of (72) as a model still apply (7lJCS(B)2350). In general, such a study of the UV spectra
using 'fixed models' when allied with pKa determinations (which allow one to know with
certainly whether an anion, cation or neutral molecule is being studied) provides an
excellent example for tautomerism studies. Both hydroxy and oxide forms of 1-hydroxy-4,5-
dimethylimidazole are present in chloroform, dioxane and acetonitrile solutions. In the
solid state, mass spectrometry favors a polymorphism of a single tautomer. However, mass
spectral data on gaseous molecules might not be expected to provide unequivocal evidence
for the existence of structures in the solid state, in which only an X-ray crystallographic
study can be expected to be completely definitive.
Ph N Ph NH Ph N Ph NMe
Ph ()Ph -->- pJ[;)Ph Ph() Ph Pi[;)>Ph
....---
N
I I 6Me ,
OH 0- 0-
(69) (70) (71) (72)
Scheme 23
One of the common properties of imidazole N- oxides is their strong association even in
dilute solution, and in the solid state such association can mask distinction in the IR between
NH and OH bands. Thus IR studies of such compounds in the solid state may give rise to
confusing results. Careful UV studies of 1-hydroxybenzimidazoles show that with a variety
of substituents (e.g. 6-nitro, 2-alkyl or 2-aryl) the hydroxy form (73) is favoured in organic
solvents, and the more polar oxide form (74) in water (there is a mixture of both in aqueous
ethanol). With 1-hydroxybenzimidazole the N-methyl model (75) is not sterically hindered,
and the value of K T (74/73) = -12 deduced from the pKa values of the models (75/76) in
water should be much more reliable than that for the hydroxyimidazoles (Scheme 24). In
other solvents (benzene, chloroform, acetonitrile, dioxane), UV results show that the OH
form (73) predominates; in 75% aqueous ethanol K T ::: 1.
ex) ex:> ex)
\ \ \
OH 0- OMe
(t NMe
I +>
N
\
0-
(73)
(74)
(75)
(76)
Scheme 24
On the basis of UV measurements it has been shown that 1-hydroxy-2-imidazolines exist
in equilibrium with 2-imidazoline 3-oxides (76CHE1280).
In the 1-hydroxyimidazole 3-oxides a single signal is observed in the NMR spectrum for
the 4- and 5-methyl groups of (77). This requires an autotropic form of rearrangement
(Scheme 25).
0- OH
Me ;:( Me rf
Me('JMe MeQMe
6H (77) 6-
Scheme 25
370
Irnidazoles and their Benzo Derivatives: (i) Structure
Cases in which more than one tautomerizable substituent are present in the imidazole
ring are common, but tautomerism studies of such compounds are less so. Work on the
hydantoins (imidazolidine-2,4-diones) is not at all definitive; UV and IR studies suggest
the dioxo form (78), but evidence for the existence of other tautomeric structures (79,80)
is not convincing (Scheme 26). Imidazolidine-4,5-diones also exist as the dioxo forrns. NMR
studies show that the 2-benzyl derivatives must exist in solution as the NH forrn (81;
R = H, Me), and the rnethoxy derivatives, similarly, are NH (82) rather than OH (83)
derivatives (Scheme 26).
o
O CH2Ph
R
tJ:o =
H
(78)
O)- H
O N HPh
R
(81) R=H,Me
H O'!= N
(.AOH
N
(79)
HO
'ç O
H
(80)
O t NH
MeO "'" CHPh
N
H O t N
MeO "" A--CHPh
N
(82)
(83)
Scheme 26
In contrast to the 2,4-dioxoimidazoles (and such compounds as 5-phenyl-2-thiohydan-
toin), there is convincing evidence (UV, IR, NMR data) that imidazolidine-2,4-dithiones
exist mainly in the thione-thiol forms (84; Scheme 27). The two tautorners (85,86) have
been separated in 5,5-diphenylimidazolidine-2,4-dithione; in KBr the C=N bands appear
at 1495 and 1575 cm -I, respectively. In the 5,5-spiropentane analogues the structure related
to (85) increases in importance as the solvent polarity increases. As rnentioned above, the
oxo-thione structures for imidazolin-4-one-thiones is supported by IR spectra in the solid
state, and by UV spectra in ethanol. The partially fixed derivatives (87,88; Scherne 28)
can be crystallized separately, but give identical spectra in solution. Both X-ray crystal
structures and solid state IR spectra confirm the existence of two structures (87; y(C=O)
1690, y(C=N) 1510-1490 cm- I ) and (88; y(C=O) 1720, y(C=N) 1590-1575 cm- I ). As
with the dithiones, the irnportance of the cross-conjugated form (88) increases with decrease
in solvent polarity.
S t NH HS t NH
Ph S Ph As
N N
H H
(84)
S
Ph )SMe
Ph N
H
(85)
s NH
Ph )SMe
Ph
(86)
Scheme 27
Phl)sM, = Pht) M'
Ph N PhN
H
(87) (88)
Scheme 28
Studies of the aminoimidazolinones have also been limited. However, in the I-substituted
2-aminoirnidazolin-4-ones the NMR evidence that C-5 is close to Sp3 in nature limits the
possible tautorners to three (89-91), with the third (91) not being at all likely (Scheme 29).
Of the other two, the available evidence is equivocal, but the pKa of 4.55-4.80 rules out
(90) (expected pKa - 8-9) leaving the probable form as the arnino-oxo structure (89).
Similar evidence for 2-amino-1-methylimidazolin-5-ones, while not definitive, suggests that
both arnino and imino forms have significant contributions to the equilibrium. The added
cornplication in unsubstituted 2-aminoimidazolin-4(5)-ones of annular tautornerisrn
increases the number of possible tautomeric forms (Scheme 30). The UV absorption in
ethanol at 213-225 nm, pKa of -4.5-4.8 and NMR spectrum showing an sp3_ type C-5
still leave five possible structures, and the problem is as yet unresolved. The distinction
between 4-amino and 4-imino forms in 4-aminoimidazolin-2-ones has also not been made.
Imidazoles and their Benzo Derivatives: (i) Structure
371
O t N O t NH
HR NR
Me Me
(89)
(90)
HO
'ç NR
Me
(91)
000
t t NH t NH ---...
NJ--NHR NANHR NR ..--
H
Scheme 30
The selective UV absorption of imidazole-4-carbaldehyde has been referred to resonance
structures such as (92), which are improbable in the cation. In addition, a hydroxymethylene
forrn can be excluded.
H O t N
N)-NHR
HO
'ç NR
H
Z-JH-O-
N
H
(92)
4.06.5.3 Ring-Chain Tautomerism
Probably the best-known examples of this type are of azide-tetrazole tautomerisrn. Under
basic conditions, 2-azidoimidazoles (93) isomerize to the tetrazole (94); both compounds
are probably in the anionic forms (Scheme 31). The recently developed MNDO semi-
empirical SCF-MO method has been used to study this problem. Calculations suggest that
the bicyclic anion is more stable than the neutral bicyclic molecule (94) by 70 kJ mol-I.
Such a shifting of the equilibrium towards the tetrazole form in the anion can be attributed
to delocalization of the negative charge on the tetrazole moiety of the bicyclic system
(79JHC68S). In dimethyl sulfoxide, 1-acetyl-2-azidoimidazole gives a 3: 2 mixture of azido
and tetrazole forms (80AHC(27)241). Apparently the azide form is more prevalent in azoles
than in azines or thiazoles, but substituent effects are similar, viz. resonance electron-
withdrawal shifts the equilibrium towards the tetrazole form. That steric factors can also
be important is indicated by the observation that in a series of 1-acyl-2-azidoimidazoles,
a t-butyl group in the acyl group is more effective in promotion of the tetrazole tautomer
than is a rnethyl group in the same situation (76TL417S).
H H
N
eN ( N
N AN 3 N I
'N"",N
(93) (94)
Scheme 31
The dyes formed when imidazoles couple with diazonium salts (Section 4.07.1.4.8) in
alkaline medium could exist as the usually accepted azo form (95; R = H) or the hydrazone
form (96). Comparison of the UV and visible spectra of the dyes with a non-tautomeric
model (95; R = Me) demonstrated unequivocally that if such an equilibrium as shown in
Scheme 32 exists, then the azo structure predominates (79BAP249).
R
()-N -N-Q- X ()=N- -Q- X
(95) R = H, Me (96)
Scheme 32
372
Irnidazoles and their Benzo Derivatives: (i) Structure
4.06.5.4 Betaines
There have been many occasions on which betaines have been suggested as being involved
in tautorneric equilibria. In fact, the high melting points of imidazolin-2-ones and -2-thiones
have been ascribed to dipolar character. The high energies of such forms compared with
the forms which have no formal charge separation probably mean that they will not usually
have a large contribution to the tautomeric equilibrium.
Reactive betaine intermediates are alrnost certainly involved in many reactions of imi-
dazoles, e.g. base catalyzed deuteriurn exchange, acylation at C-2, etc. Begtrup (B-76MI40600.
p. 143) has implicated betaines in his studies of the nucleophilic hydroxylation of triazolium
salts, and one rnight expect an extension of these researches into the imidazolium series.
Me
R()Ph
)-NPh
-0 +
(97)
Sorne mesoionic imidazoles quaternized on ring nitrogen (97) have been studied. The
5-acyl derivatives are quite stable because the negative charge can be delocalized, but the
unsubstituted compound (97; R = H) is very susceptible to electrophilic attack (71JOC3368).
Similar compounds can be generated by the action of 2-bromoacetyl chlorides on benz-
amidines. The 4-formyl derivatives of I-phenyl-5-hydroxy (or -mercapto) imidazoles are
rather strong acids which appear to exist in mesoionic forms in a variety of rnedia (79CHES44).
4.07
Imidazoles and their Benzo Derivatives:
(ii) Reactivity
M. R. GRIMMETT
University of Otago
4.07.1 REACTIONS AT AROMATIC RINGS
4.07.1.1 General Survey of Reactivity
4.07.1.1.1 Reactivity of neutral imidazoles
4.07.1.1.2 Imidazolium ions
4.07.1.1.3 Imidazole anions
4.07.1.1.4 Imidazolinones, imidazolinethiones and imidazolinimines
4.07.1.1.5 N-Oxides
4.07.1.2 Thermal and Photochemical Reactions Formally Involving No Other Species
4.07.1.2.1 Fragmentation
4.07.1.2.2 Rearrangement
4.07.1.2.3 Polymerization and disproportionation
4.07.1.3 Electrophilic Attack at Nitrogen
4.07.1.3.1 Introduction
4.07.1.3.2 Reaction sequence
4.07.1.3.3 Effects of substituents
4.07.1.3.4 Proton acids at neutral azoles: basicity ofimidazoles and benzimidazoles
4.07.1.3.5 Proton acids at imidazole anions: acidity of imidazoles
4.07.1.3.6 Metal ions
4.07.1.3.7 Alkyl halides and related compounds: compounds without a free NH group
4.07.1.3.8 Alkyl halides and related compounds: compounds with a free NH group
4.07.1.3.9 Acyl halides and related compounds
4.07.1.3.10 Halogens
4.07.1.3.11 Other electrophiles
4.07.1.4 Electrophilic Attack at Carbon
4.07.1.4.1 Reactivity and orientation
4.07.1.4.2 Nitration
4.07.1.4.3 Sulfonation
4.07.1.4.4 Acid-catalyzed hydrogen exchange
4.07.1.4.5 Halogenation
4.07.1.4.6 Acylation
4.07.1.4.7 Mercuration
4.07.1.4.8 Diazo coupling
4.07.1.4.9 Nitrosation
4.07.1.4.10 Reactions with aldehydes and ketones
4.07.1.4.11 Oxidation
4.07.1.5 Nucleophilic Attack at Carbon
4.07.1.5.1 Hydroxide ion and other O-nucleophiles
4.07.1.5.2 Amines and amide ions
4.07.1.5.3 S-Nucleophiles
4.07.1.5.4 Halide ions
4.07.1.5.5 Carbanions
4.07.1.5.6 Reduction by complex hydrides
4.07.1.5.7 Azide ions and nitrite ions
4.07.1.6 Nucleophilic Attack at Hydrogen
4.07.1.6.1 Metalation at a ring carbon atom
4.07.1.6.2 Hydrogen exchange at ring carbon in neutral azoles
4.07.1.6.3 Hydrogen exchange at ring carbon in imidazolium ions
4.07.1.6.4 C-Acylation via deprotonation
4.07.1.6.5 Proton loss from a ring nitrogen atom
4.07.1. 7 Reactions With Radicals and Electron-deficient Species
4.07.1.7.1 Carbenes
4.07.1. 7.2 Free radical attack at the ring carbon atoms
373
374
374
374
375
375
375
376
376
376
376
380
382
382
382
383
383
385
386
386
387
390
393
393
394
394
395
397
397
398
402
403
403
404
404
405
406
407
409
413
413
414
415
415
415
415
416
417
417
417
418
418
418
374
Imidazoles and their Benzo Derivatives: (ii) Reactivity
4.07.1.7.3 Electrochemical reactions and reactions with free electrons
4.07.1.7.4 Catalytic hydrogenation and reduction by dissolving metals
4.07.1.8 Reactions With Cyclic Transition States
4.07.1.8.1 Diels-Alder reactions and 1,3-dipolar cycloadditions
4.07.1.8.2 Photochemical cycloadditions
4.07.2 REACTIONS OF NON-AROMATIC COMPOUNDS
4.07.2.1 Isomers of Aromatic Derivatives
4.07.2.1.1 Compounds not in tautomeric equilibrium with aromatic derivatives
4.07.2.1.2 Compounds in tautomeric equilibrium with aromatic derivatives
4.07.2.2 Didhydro Compounds
4.07.2.2.1 Tautomerism
4.07.2.2.2 Aromatization
4.07.2.2.3 Other reactions
4.07.2.3 Tetrahydro Compounds
4.07.2.3.1 Aromatization
4.07.2.3.2 Ring fission
4.07.2.3.3 Other reactions
4.07.3 REACTIONS OF SUBSTITUENTS
4.07.3.1 Benzenoid Rings
4.07.3.1.1 Fused benzene rings: unsubstituted
4.07.3.1.2 Fused benzene rings: substituted
4.07.3.2 Other C-Linked Substituents
4.07.3.2.1 Saturated alkyl groups
4.07.3.2.2 Aryl groups
4.07.3.2.3 Other C-linked functionality
4.07.3.3 N-Linked Substituents
4.07.3.3.1 Amino compounds
4.07.3.3.2 Aminoazolium ions
4.07.3.3.3 Imines
4.07.3.3.4 Nitro groups
4.07.3.3.5 Nitroso groups
4.07.3.3.6 Azidoazoles
4.07.3.4 O-Linked Substituents
4.07.3.4.1 Hydroxy compounds
4.07.3.4.2 Alkoxy and aryloxy compounds
4.07.3.5 S-l.inked Substituents
4.07.3.5.1 Thiones
4.07.3.5.2 Disulfides
4.07.3.5.3 Thioethers
4.07.3.5.4 Sulfinic and sulfonic acids and derivatives
4.07.3.6 Halogen Atoms
4.07.3.7 Metals and Metalloid-linked Substituents
4.07.3.8 Substituents Attached to Ring Nitrogen Atoms
4.07.3.8.1 Aryl groups
4.07.3.8.2 Alkyl groups
4.07.3.8.3 Alkenyl and alkynyl groups
4.07.3.8.4 Acyl and aroyl groups
4.07.3.8.5 Nitrogen functions
4.07.3.8.6 Halogen atoms
4.07.3.8.7 Silicon, phosphorus, sulfur and related groups
4.07.3.8.8 N-Oxides and N-hydroxy compounds
4.07.3.8.9 N- Ylides
419
419
419
419
420
421
421
421
424
424
424
425
425
427
427
427
427
428
428
428
429
430
430
432
434
438
438
441
441
441
441
442
442
442
443
443
443
445
446
447
447
448
448
448
449
450
451
454
454
454
455
4%
4.07.1 REACTIONS AT AROMATIC RINGS
4.07.1.1 General Survey of Reactivity
4.07.1.1.1 Reactivity of neutral imidazoles
Irnidazole (1) can be considered as having properties sirnilar to both pyrrole and pyridine.
In consequence, one would expect that electrophilic reagents would attack the unshared
electron pair on N-3, but not that on the 'pyrrole' nitrogen since it is part of the arornatic
sextet. The ring carbons, too, are prone to attack by electrophilic, radical and nucleophilic
species to a greater or lesser extent; substitution reactions which do not destroy the aromatic
character are predorninant. While the imidazole ring is rather susceptible to electrophilic
attack on an annular carbon, it is much less likely to becorne involved in nucleophilic
Imidazoles and their Benzo Derivatives: (ii) Reactivity
375
substitution reactions unless there is a strongly electron-withdrawing substituent elsewhere
in the ring. In the absence of such activation the position rnost prone to nucleophilic attack
is C-2. Although such reactions do not take place with any great facility with irnidazoles,
the fused benzene ring in benzimidazoles provides sufficient electron withdrawal to allow
a variety of nucleophilic substitution reactions at C-2.
When the imidazole ring is considered to be sornething resernbling a pyrrole-pyridine
combination (1) it would appear that any electrophilic attack should take place preferably
at C-5 (pyrrole-a, pyridine-ß). Such a model, though, fails to take account of the tautorneric
equivalence of C-4 and C-5 (Section 4.06.5.1). The overall reactivities of irnidazole and
benzimidazole can be inferred from sets of resonance structures in which the dipolar
contributors have finite importance (Section 4.06.2) or by mesorneric structures such as
(2). These predict electrophilic attack in irnidazole at N-3 or any ring carbon atorn,
nucleophilic attack at C-2 or C-1, and also the arnphoteric nature of the rnolecule. In
benzimidazole the acidic and basic properties, the preference for nucleophilic attack at C-2
and the tendency for electrophiles to react at the fused benzene ring can be readily
rationalized.
pyrrole ß } .'
pyridine a ( N.(baSIC)
pyrrole a } ) { pYITo,le a
pyridine ß N pyndme a
I (acidic)
H
(1)
$
N
I
H
(2)
4.07.1.1.2 Imidazolium ions
When the rnultiply bonded nitrogen becornes quaternized either by a proton or sorne
other group it loses its basic properties. The ring now becomes rnuch less susceptible to
electrophilic attack, and conversely shows an increasing inclination to react with
nucleophiles. The C-2 hydrogen atom between the two quaternary nitrogens rnay becorne
appreciably acidic, and nucleophilic attack at C-2 becornes rnore facile, often resulting in
ring opening. Since many of the cornrnon electrophilic substitution reactions occur in acid
medium, they often involve the imidazolium species as substrate. Thus, such reactions as
nitration and sulfonation occur with difficulty, and Friedel-Crafts reactions are virtually
absent. In the benzirnidazolium ion too the reactivity of C-2 with nucleophiles is enhanced
compared with the neutral rnolecule.
4.07.1.1.3 Imidazole anions
In contrast to the neutral molecule of imidazole, the conjugate base is highly susceptible
to electrophilic attack, particularly on one or other of the annular nitrogen atorns. Thus,
alkylation occurs very rapidly in basic medium. There are also sorne electrophilic substitution
reactions at ring carbon atorns which involve the heterocyclic anion, e.g. diazo coupling
and iodination.
4.07.1.1.4 Imidazolinones, imidazolinethiones and imidazolinimines
The tautornerisrn (Section 4.06.5.2) and general reaction types (Section 4.02.1.1.4) of
these compounds have been discussed earlier. Although the rnajor tautorners are usually
written in the unionized forms, there is undoubtedly polar character, i.e. the rnolecules
could be considered as betaines of general structure (3) or (4). With the exceptions of
irnidazolin-2-ones and -thiones (and the corresponding benzo derivatives) cornpounds of
these classes are not particularly well known. 2-Aminobenzirnidazoles have been studied
but amino, hydroxy and thiol groups at position 4 or 5 of irnidazole often seern to give rise
to unstable cornpounds. In fact, rnany of the reactions typical of azolinones, azolinethiones
and azolinimines are uncommon among the irnidazole analogues. The 2-imidazolinones are
weakly basic and acidic compounds in line with their tautorneric character, while nucleophilic
376
Imidazoles and their Benzo Derivatives: (ii) Reactivity
displacernents occur readily at positions adjacent to an oxo function. 2-Phenyl-2-irnidazolin-
5-ones have an active rnethylene group at C-4 capable of undergoing condensations with
aldehydes (76TL571). Arnong the hydantoins (irnidazolidine-2,4-diones; 5) the 5-rnethylene
group is acidic enough to forrn benzylidene derivatives very readily. Such hydantoins are
fairly acidic with rnuch of this acidity deriving frorn the NH group flanked by the carbonyl
functions. Parabanic acid (6) is a fairly acidic molecule with only negligible basic character.
Both 2-irnidazolidinones and the corresponding thiones readily forrn the anions by loss of
an NH proton when treated with such reagents as sodiurn hydride.
( NH
ï _
N Z
H
(3) Z=NH, 0, S
!/NH
z ;
H
(4) Z= NH, 0, S
i NH
O-Ä."NA.O
H
(5)
O}-NH
O NA.O
H
(6)
Both 4,4-diaryl- and 5,5-diaryl-2-imidazoline-5- and -4-thiones are rearranged by
alurninurn chloride in benzene to 4,5-diarylirnidazoles; 5,5-diphenyl-4-irnidazolidine-
thiones, though, only give benzo[b ]thiophenes under these conditions (76T2421).
4.07.1.1.5 N-Oxides
Since the direct N -oxidation of imidazoles has not yet been achieved, the synthetic
rnethods available start with acyclic precursors. In consequence the range of cornpounds is
not extensive, and their reactivity is not well known as yet. Since rnost of the published
chernistry relates to the reactivity of the oxide function, it has been considered preferable
to discuss all of the reactions of irnidazole N -oxides in Section 4.07.3.9.8.
4.07.1.2 Thermal and Photochemical Reactions Formally Involving No Other Species
4.07.1.2.1 Fragmentation
Irnidazoles in general are very stable to heat. The parent rnolecule is said to decornpose
at 590 oC by an unknown process which rnay be sirnilar to the mass spectral fragrnentation
(Section 4.06.3.8) since HCN has been identified arnong the reaction products. The reported
stabilities of the therrnal rearrangernent products of 1-substituted irnidazoles at temperatures
as high as 650 0 C cast sorne doubt on the above decornposition temperature, but contact
tirne is doubtless important (Section 4.07.1.2.2). .
When irnidazole 3-oxides are photolyzed the products are unsyrnrnetrical benzil diirnines
(78CC857). This reaction is believed to proceed via a fused oxaziridine interrnediate (7;
Scheme 1). In an analogous process 1-hydroxy-2-rnethylbenzirnidazole 3-oxide (8; R = Me)
is transforrned photolytically into o-nitrosoacetanilide (9; R = Me). When there is no
substituent at C-2 (8; R = H) the product isolated is 0 -nitroforrnanilide, presurnably an
oxidation product of (9; R = H) (78TL4581). The UV irradiation of 2,2-dirnethyl-2H-
benzirnidazole 1,3-dioxide (10) gives rise to (11) by an analogous process. In view of the
foregoing results it seerns likely that the photosensitized oxygenation of irnidazoles to
benzarnidines may follow a similar process, although a hydroperoxide interrnediate has
been irnplicated (68TL3277). Thus, 2,4,5-triphenylirnidazole reacts with singlet oxygen to
give (12; R = H), while a 97% yield of N,N'-dibenzoyl-N -phenylbenzarnidine (12; R = Ph)
is derived frorn 1,2,4,5-tetraphenylirnidazole (Scherne 2).
4.07.1.2.2 Rearrangement
The equilibriurn between azidoirnidazoles and the bicyclic tetrazole tautorners has been
discussed earlier (Section 4.06.5.3).
Although the reverse reaction is well known, the photochernical conversion of irnidazoles
into pyrazoles and benzimidazoles into indazoles does not take place. However, 1,4- and
1,2-disubstituted imidazoles are interconverted in t-butanol, while 1,4,5-trirnethylirnidazole
gives the 1,2,5-isorner (40%) in ethanol, t-butanol or cyclohexane. In the last-narned
Imidazoles and their Benzo Derivatives: (ii) Reactivity
377
o-
J
Ph N Ph N-O Ph NCOAr 2
Ph ( +\\ Ph( \/ ---+ X
N/"'--Ar 2 N/'Ar 2 >-.. 1
Ar1 Ar 1 Ph NAr
(7)
OH
I OH /OH
>-R ---+ NN ---+ O INO R=H O lN0 2
N N CR NHCOR ---+ NHCHO
I II
_0 0
(8)
(9)
0-
I
N
)Me2
b-
(10)
ihv Ol N0 2
, þ
ii,oxidation ON=CMe 2
(11)
Scheme 1
Ph [ OOH l
NOh N Ph NCOPh
PhÇ)Ph M 'o Þ PhI( jPh ---+ PhC
H N COPh
(12)
Scheme 2
solvent, 1,2,5-trimethylimidazol gives less than 5% of the 1,4,5-isorner, being largely
destroyed. When 1,2,4-trirnethylimidazole is photolyzed in t-butanol it is hardly affected,
and though it undergoes a photoreaction in cyclohexane no isorneric imidazoles are formed
{69T3287). The above interconversions rnay involve a disrotatory valence bond isornerization,
followed by a [1,3]-sigmatropic shift and another disrotatory isornerization (Scherne 3).
Evidence for such a pathway is derived frorn the observation that 2-deutero-1,4-dirnethyl-
imidazole undergoes photoconversion into 4-deutero-1,2-dirnethylirnidazole. When
2,4,5,5-tetraphenyl-4H -irnidazole is heated it rearranges to 1,2,4,5-tetraphenylirnidazole.
X N N X N Z N
y( \\z yQz ---+ R-N:JJ] ---+ y()x
N"" N YZ N
R R R
X=Me, H; Y=H, Me;
Z=Me, H, D; R=Me
Scheme 3
In 1883 Wallach discovered that when 1-methylimidazole was heated he obtained
2-methylirnidazole and sorne HCN. The reaction now appears to be rnuch more general
{73AJC2435) and of sorne synthetic irnportance since it can give rise to a fairly wide variety
of 2-substituted irnidazoles. The reaction can be shown to be irreversible, uncatalyzed and
intramolecular, with no radical involvernent. The irnplication of [1,5]-sigmatropic shifts
(Scherne 4) seerns likely. Although the 2-substituted product (13) predorninates, srnall
quantities of the 4- or 5-isorner (14) are also formed. Previous reports of related reactions
included the isornerization on rnelting of I-trityl- to 2- and 4-trityl-imidazoles, but more
recent results {8lH(15)943) report that at 230 0 C 1-tritylirnidazoles rearrange in a rather
different fashion; no migration to the 2- or 4-positions was noted and the product proved
to be (15; Scherne 5). Groups such as isopropyl, n-propyl and p-tolyl at 600-650 o C give
products which show no rearrangement of the 'rnigrating group', but some cracking of the
alkyl groups can lead to decreased yields and rnixtures of products. That a 1-allyl group
migrates with equal facility to both the 2- and 5-positions suggests that a Cope-type
378
Imidazoles and their Benzo Derivatives: (ii) Reactivity
rearrangernent may also be involved in the case of this group (73AJC2435). In the presence
of '}'-alumina 1,2,4- and 1,2,5-trirnethylirnidazoles are thermallÿ rearranged to 2,4,5-
trimethylimidazole, while the therrnal transforrnation of 1- to 2-alkylbenzimidazoles appears
to proceed norrnally.
N
R()
N
H
(14)
5:)
R N
() 00-6S0'C. C3<H [1,S]H Þ ()R
N N R N
R H
(13)
Scheme 4
() ()
N
N Q
I 230'C 10 h
PhCPh I
N,
6 C1
1,9 HCPh
6 0
(15)
Scheme 5
In view of the importance of 2-nitroimidazoles as antibiotics (e.g. 2-nitroirnidazole;
'azornycin') and the problems involved in their synthesis (usually via the 2-arninoirnidazole)
it seerned worthwhile to atternpt to prepare these compounds by therrnal rearrangernent
of the N -nitro cornpounds (by analogy with the well-known reactions of 1-nitro-pyrazoles
and -indazoles) (Chapter 4.04). Thus, when 1,4-dinitroirnidazole (16) is heated at 140 0 C
in chlorobenzene, benzonitrile or anisole there is conversion into 2,4- and 4,5-
dinitroirnidazoles, but considerable denitration can also occur, giving 4-nitroimidazole
(Scherne 6). 2-Methyl-1,4-dinitroimidazole rearranges srnoothly to 2-rnethyl-4,5-
dinitroirnidazole, but 5-methyl-1,4-dinitroirnidazole appears to denitrate in prefer nce to
any other reaction. Further study of these reactions is indicated.
02 N N 02 N N 02 N N O,N N
ç) 140'C Þ ç) + O,NC) + f)NO,
NO, H H H
(16)
Scheme 6
Under irradiation at 300 nm, trans -l-styrylimidazoles are transformed into the cis isorners
(17) which subsequently undergo photocyc1ization to (18; Scherne 7). That this is probably
a radical cyclization onto the imidazole ring gains credence both frorn the position of attack
at C-2 and frorn an apparently analogous reaction in which the diazoniurn salt of (19) reacts
in the presence of H 3 P0 2 (Scheme 7) (80AHC(27)241).
N CO,Me N CO,Me
CD Z)CO'Me 06 1 )co,Me
I N I
:::::,.,,9 ,9
(17) (18)
N N
'=.I
MeO,C CO,Me
(19)
i, NaN0 2 /HCl Þ
ii.H,P0 2
Scheme 7
Imidazoles and their Benzo Derivatives: (ii) Reactivity
379
N [ N ] *
ç) ç) ç'.) + RCO'
COR COR O%
B) ROC() + ()COR
N N
H H
r CN . F;,N l ÂO%
( H HÌ'-' .)
'C-R R-C- N * =. or t
I I 1m = 2- or 4-imidazol y l
0* 0*
hv
----.
hv or A1 2 0 3 ,
hv
\H/
'C'
I "OH
(20)
(21)
Scheme 8
The photo-Fries rearrangernent of N -substituted imidazoles, where the substituent on
nitrogen is an acyl group, to give 2- and 4-substituted isomers could involve either a
dissociative path (A) or an intrarnolecular process (B). The excited species could be a radical
or a radical cation (Scherne 8). More complex acyl groups, e.g. stearoyl, tend to undergo
cleavage in the side-chain, but the 1-acylirnidazole (20), derived from de hydro abietic acid
appears to be subject only to rnigration, perhaps via a cyclobutanol intermediate, to give
2- and 4-acyl derivatives (21; Scheme 8) {SOAHC(27)241). The photo-Fries rearrangernent
of N -acyl- or -aroyl-benzÎrnidazolinones (23) in benzene or alcohol solution gives rise to
products of deacylation in addition to so-called ortho- and para- transposition products (24
N H COR H H
(X I )COR (X i >=0 (X I >=0 + Roc (X 1 N)=O
N N N :::::,.., N
'_ COR H H
(22) 0 (23) (24) (25)
0-
I
(X i )Et via eXcit: triplet)
:::::,.., N state
CH 2 Ph
(26)
,. : L.I (X} , ] (X o
L CH 2 Ph CH 2 Ph
/ (30) (27)
[ (X/:, ]
CH 2 Ph
(X i )Et
N
CH 2 Ph
-- 0 1 NHCOEt or 0 1 NHCOEt
N=CHPh NHCH 2 Ph
(28) (29)
Scheme 9
380
Imidazoles and their Benzo Derivatives: (ii) Reactivity
and 25; Scherne 9). The initial N -acyl compounds (23) can be obtained by photolysis (or
therrnolysis) of 2-acylbenzimidazole I-oxides (22) (78JHC625). The initial photorearrange-
rnent to the benzimidazolinone occurs also with irnidazole N -oxides and often involves
displacernent of an alkyl group frorn C-2 to a ring nitrogen. For instance, 1-benzyl-2-
ethylbenzirnidazole 3-oxide (26) gives 1-benzyl-3-ethylbenzirnidazolinone (27) as the rnajor
product. There is evidence of sorne deoxygenation of (26) (particularly in the presence of
aceto- or benzo-phenone) and, depending on the solvent, products of fragrnentation (28,
29) are fOund (Scherne 9). The products can be rationalized in terms of two different
pathways. Deoxygenation of an excited triplet state is enhanced by acetophenone or
benzophenone, or the excited singlet state can form an oxaziridine intermediate (30) which
can either undergo ionic rearrangernent in a protic solvent to forrn (27) or via a diradical
yield the fragrnentation products (70CPB964). It does not seem entirely necessary to postulate
the diradical interrnediate since an ionic mechanism such as that described in Section
4.07.1.2.1 could equally well account for the products. These foregoing reactions bear
striking sirnilarities to the effects of an acyl halide (particularly tosyl chloride) in the presence
of hydroxide ions on 2,3-polyrnethylenebenzimidazole l-oxides (31). The ben-
zirnidazolinone products (33) could arise either frorn a 1-tosylate interrnediate (32) (which
could follow the farniliar process of ring opening of benzimidazoles in the presence of
hydroxide ion and acyl halides) or by way of an oxaziridine interrnediate (34; Scherne 10)
(73JCS(PI )705).
r(CH 2 is
cr;V
I
0-
(31)
j
r fCH2 )s
losyl chloride \ J
OW þ 0-- )éOH
OTs '"
(32) "'" r(CH 2 )s
cr
/ 'ÓTs -OH
-. N H2is
N---./
(33)
r(CH 2 is
cr
(34)
Scheme 10
In the remarkable forrnation of 2-benzoyl-6-nitrobenzirnidazole (40) on irradiation of
1-(2,4-dinitrophenyl)-4-phenylirnidazole (35), either a dipolar cycloaddition or a radical
process could lead to the proposed ortho-nitrosoimine interrnediates (36, 37). Certainly the
ortho- nitro group could take part in a 1,3-cycloaddition at C-2 and C-5, and subsequent
rupture of the 1,2- or 1,5-bonds could lead to these intermediates. Recyclization would
give rise to (38) and (39); after hydrolysis and deoxygenation the forrner would forrn (40),
while (39) would be expected to produce a 2-arninobenzirnidazole product (Scherne 11)
(76BSFl92).
4.07.1.2.3 Polymerization and disproportionation
When irnidazoles and benzirnidazoles have free NH groups, interrnolecular hydrogen
bonding gives rise to linear associates of rnolecules in the crystals and in non-protic solvents.
Early deterrninations of molar rnasses and dipole mornents gave anornalous results because
of this phenomenon, particularly when concentrated solutions of the azoles were used. In
fact, linear associates of as rnany as 20 molecules of irnidazole are possible at high
concentrations in solvents such as benzene. This interrnolecular hydrogen bonding gives
rise to broad NH signals in NMR spectra, and in solvents capable of exchange, e.g. 0 2 0,
no signal at all for NH. The high rnelting and boiling points of irnidazoles have been
discussed (Section 4.06.4.1.1). N-Oxides of the series which also contain hydroxy groups,
e.g. 1-hydroxy-2,4,5-trirnethylirnidazole 3-oxide, are also capable of forrning association
cornplexes; even at high dilutions these cornplexes exist as trirners.
Imidazoles and their Benzo Derivatives: (ii) Reactivity
N 4Ph
:!(Js
IN
6 NO ,
N0 2
(35)
H,C....N ;r Ph
II
o N..&
ÓN O
N0 2
(36)
j
N H
02N ÑXC=NCHO
I I
0- Ph
(38)
H 2 0 f
Cl N
I ')COPh
02 N ::::::'" N
H
(40)
Scheme 11
381
or
Ph
N)......C-H
l II
"N 0
ÓN=O
N0 2
(37)
\
o: N H
02 N ::::::,.. =ÑXN=CCHO
ó- h
(39)
In the absence of hydrogen sources the thermolysis of 2,4,4-triaryl-5-methylthio-4H-
imidazoles (41) produces 1,l'-biirnidazolyls (42), probably by way of a free radical pathway
(Scheme 12).
Ar2 SMe Ar Ar
A Ar r:::::::\ N
N N -- I 'N-N. I
Y N '\:;:::::'-'Ar
Ar Ar Ar
(41)
(42)
Scheme 12
A nurnber of photochernical processes give rise to dimeric products in which hydrogen
is lost, sornetimes by concurrent oxidation. Thus, benzimidazole photodehydrodirnerizes in
1 % ethanol to give a mixture of isomers (43 and 44). This reaction probably proceeds
through the intermediacy of a 2-benzimidazolyl radical which substitutes the benzene rnoiety
of another benzirnidazole rnolecule {78AJC2675). About 50% of the substrate rernains
unchanged (Scherne 13). In contrast, 2-alkylbenzirnidazoles do not give dirners; rather,
mixtures of 1-, 4- and 5-acetylbenzirnidazoles are produced through oxidation of transient
benzirnidazoline intermediates.
(X N (X rQ (X
::::::,.. I N') 1% E J ::::::,.. I; _ +::::::,.. I : N')
H' N
NyNH H
(43) 16% (44) 25%
Scheme 13
Great interest has centered on the involvernent of 2,4,5-triphenylimidazole (lophine) and
sirnilar compounds in the phenomenon of chemiluminescence {77CHE1160). The
phenomenon was first observed in 1877 by Radziszewski who noted the ernission of light
when 10phine was decornposed with alcoholic potash in the presence of light. Sorne aspects
of this are discussed elsewhere (Seç:tions 4.07.1.2.1 and 4.07.1.4.11), but sorne of the
dimerization reactions will be treated under this present heading. In the presence of
potassium ferricyanide lophine gives rise to a piezochrornic dirner (45) which gives an
intensely violet solution of the radical (46) in organic solvents. Other dimeric species (47,
382
Imidazoles and their Benzo Derivatives: (ii) Reactivity
48) have also been reported (ncHE116o, B-76MI40701). In a nurnber of instances the photooxi-
dation of the arylimidazoles leads to products of fragmentation, e.g. dibenzoylbenzarnidine.
Ph
N rhPf-=
Ph N )Ph
Ph N
(45)
(46)
(47)
Ph N
Ph F .\
F N N Ph
Ph .Y Ph
N Ph
(48)
Ph N
Ph( )Ph
N
Ph Ph
N0N-N N
bJ bJ
Ph Ph Ph Ph
4.07.1.3 Electrophilic Attack at Nitrogen
4.07.1.3.1 Introduction
The range of reactions which are possible at the ring nitrogens of imidazole and ben-
zirnidazole has been outlined (Section 4.02.1.3). As they are the rnost basic of the azoles,
irnidazoles are particularly prone to such reactions as protonation, alkylation and acylation,
and they readily become involved in complex forrnation with transition rnetals. Ben-
zimidazoles, too, are reactive, but less so than the non-condensed species.
4.07.1.3.2 Reaction sequence
In theory, electrophilic attack on irnidazole at a ring nitrogen can involve the neutral
species, the conjugate base or the conjugate acid. This would lead to four possible transition
states (49)-(52) for the reaction. While either nitrogen of the neutral rnolecule could be
attacked by the electrophile, reaction is norrnally confined to the rnultiply bonded nitrogen
which has an unshared electron pair orthogonal to the ring. Reaction with the NH nitrogen
would require the use of two electrons from the 67T system to form a bond, disrupting the
arornaticity. For this reason the transition state (49) would be energetically rnore favorable
than (50) and, in consequence, reactions with the irnidazole neutral rnolecule follow the
sequence shown in Scherne 14, an S E 2 ' process. When the irnidazole already has a group
other than hydrogen at N-1 a quaternized product results. Such a reaction sequence is
typical of the classical rnethod of alkylation of irnidazoles which involved heating the azole
with excess alkylating agent, perhaps in a sealed tube. Yields are not high and side reactions
corn plicate the process. For exarnple, either the HI produced or excess Me I can react with
irnidazole or l-rnethylirnidazole (Scherne 14). The resulting salts forrned are irnpurities and
()--E [) c-) r;:NH
::.-- )
N N - - N,
H / \ ',' /
H E E+ H E+
(49) (SO) (51) (52)
N:--->E+ Ñ-E NE
ç) ç [) +W
H V N
H
[)
N
H
lHI
NH
0) I-
N
H
Mel
( NMe
) ï); + HI
N
"tel
,NMe E:,NMe
< .) 1- < ) I-
N N
H Me
Scheme 14
Imidazoles and their Benzo Derivatives: (ii) Reactivity
383
are also resistant to methylation. In spite of these limitations the reaction has found
considerable utility in the synthesis of 1-substituted irnidazoles. Attack at either nitrogen
of the irnidazole anion (51) will be a highly favored reaction. Such a .reaction sequence
applies- when imidazoles are alkylated in basic medium, conditions which lead usually to
good yields of 1-alkylirnidazoles with none of the problems of quaternization which can
accompany alkylation of the neutral rnolecule. Any reaction involving a transition state of
type (52) would not be favored and such electrophilic substitutions of imidazolium appear
to be absent.
4.07.1.3.3 Effects of substituents
When the irnidazole ring already has a substituent at C-4 or C-5 then there will be a
directional effect irnposed on electrophilic attack at annular nitrogen. As outlined earlier
(Section 4.02.1.3) this orientation may be related to the tautorneric nature of the substrate.
In spite of the inherent pitfalls in equating tautorneric nature with chernical reactivity there
are exarnples which seern only to be explicable in terrns of a major tautorner reacting, e.g.
rnethylation of 4-nitroimidazole. Substituents at C-2 can only affect the rate of a reaction
at ring nitrogen.
The usual substituent effects apply in the series: electron-withdrawing groups decrease
the rate of substitution and, if possible, direct it to the more rernote nitrogen atorn. This
is particularly evident in reactions of the imidazole anion which cannot be subject to
complications engendered by tautomerism. Such electron withdrawal is largely inductive.
Mesorneric electron-releasing groups will usually be expected to direct electrophilic attack
to a nitrogen ex or l' to the substituent. In the case of such a 4- or 5-substituted irnidazole,
however, both annular nitrogens can only be in ex or l' positions. Thus inductive and steric
effects (or the tautomeric nature) are more likely to determine the orientation of substitution.
Since imidazoles with OH, OR, NH z or SH groups at the 4- and 5-positions are not well
known (in sorne instances they appear to be unstable), it is not possible to rnake firm
generalizations based on experirnental results. Certainly steric effects can be important;
electrophilic substitutions leading to N -acylimidazoles are reversible reactions which, in
consequence, are subject to therrnodynarnic control and give the sterically least-hindered
isorner (Section 4.07.1.3.9). Steric effects, however, would have less importance in the
protonation of irnidazoles and benzirnidazoles in which the pKa values of the parent
rnolecules are only rnodified by the nature and position of the substituent-electronic effects
here predominate.
4.07.1.3.4 Proton acids at neutral azoles: basicity of imidazoles and benzimidazoles
Imidazole is the rnost basic of the azoles and forrns salts with a wide variety of acids,
both organic and inorganic. Thus, hydrochloride and nitrate salts are well defined, although
they rnay be hygroscopic. Salts of organic acids, e.g. oxalates and picrates, forrn readily and
their relatively low solubilities in aqueous rnedium have made thern extremely useful for
the isolation and purification of irnidazoles. Picrates, for example, can be decornposed by
sulfuric acid and the resulting irnidazoliurn hydrogen sulfate yields the irnidazole after
sequential neutralization with BaC0 3 , filtration of the BaS04 and ether extraction of the
aqueous filtrate.
The stability of an imidazole salt is a function of the syrnrnetrical irnidazoliurn cation
(53) which is resonance stabilized.
/\ + +-+ + /\
HNvNH HNvNH
(53)
One rnajor consequence of the basicity of irnidazole is that at physiological pH (-7.4)
substantial quantities of both the free base and protonated imidazole species are present
in the histidine units of a protein. This allows histidine to act as either a proton acceptor
or a proton donor according to the demands of its irnmediate environrnent. It seerns likely
that histidine units in a number of enzyrnes such as ribonuclease, aldolase and sorne proteases
may have this role. The buffering action of histidine in the hemoglobin-oxyhemoglobin
384
lrnidazoles and their Benzo Derivatives: (ii) Reactivity
Table 1 Basic pKa Values of Imidazoles (B-76MI40701. 70AHC\12IlO3. 80AHCl271241)
Compound pKa Compound
Alkylimidazoles Arylimidazoles
Imidazole 7.00,7.25 I-Ph
I-Me 7.30,7.33 2-Ph
2-Me 7.85,7.56 4-Ph
4-Me 7.56 2,4-Ph z
1,2- Me z 7.85 4,5-Ph z
1,4-Mez 7.20 I-Me-4-Ph
1,5- Me z 7.70 l-lp- HOC 6 H 4 J
2,4-Mez -8.5 l-lm-HOC 6 H 4 )
2,4,5-Me" 8.92 1-(p-BrC 6 H 4 )
l-Et 7.30 l-lp-COMeC 6 H 4 )
2-Et 8.00 l-lp-NO z C 6 H 4 )
l-CH z Ph 6.10
Halogenoimidazoles Halogenonilroimidazoles
2-F 2.40 4-CI-5-NO z
4-F 2.44 4-CI-I-Me-5-N0 2
2-F-1-Me 2.30 5-CI-I-Me-4-NO z
4-F-1-Me 1.90 2-Br-l-Me-4-NO z
5-F-1-Me 3.85 2-Br-l-Me-5-NO z
4-Cl-I-Me 3.10 5-Br-2-Me-4-NO z
5-CI-1-Me 4.75 5-Br-1-Me-4-NO z
2-Br 3.85 2-I-4-NO z
4-Br 3.88, 3.60 2-I-I-Me-4-NO z
2-Br-1-Me 3.88 2-I-I-Me-5-NO z
5-Br-1-Me 5.26
Nitroimidazoles Aminoimidazoles
2-NO z -0.81 2-NH z
4-NO z -0.05, -0.16 2-NHz-I-Me
I-Me-2-NO z -0.48 2-NH z -4,5- Me z
1-Me-4-NO z -0.53 2-NH z -4,5-Ph z
I-Me-5-NO z 2.13 4-NH z -l,2- Me z-5-NO z
2-Me-4-NO z 0.50 5-NH z -1,2- Me z-4-NO z
2,4-INO z )z -7.33
I-Me-2,4-iNO z Jz -7.47
Acylimidazoles A lkoxyimidazoles
4-CHO 2.90 2-0Me-5-NO z
I-COMe 3.6 2-0Me-l-Me-4- NO z
4-CO z H 6.08 2-0Me-l-Me-5-NO z
4-CO z Et 3.66 4-0Me-l,2- Me z-5-NO z
4,5-ICO z HJz -1.55
2-Me-4,5-(CO z HJz 4.25 Miscellaneous imidazoles
2-Ph-4,5-iCO z H)z 3.00 4-CH z OH
4,5-iCNJz 5.2 4-CH z CH z OH
4-CH z OAc
Imidazole I-oxides 4-CH z NH 2
2,4,5-Ph 3 3.28 4-(CHzJ z NHz
I-Me-2,4,5-Ph 3 3.32 4-CF 3
1-0Me-2,4,5-Ph 3 3.78 2-(2-imidazolyl)
4-l2-pyridyl)
pK.
5.10
6.40
6.10
5.64
5.90
5.78
5.35
5.23
4.91
4.54
3.96
-3.62
-1.42
-3.49
-3.07
-0.75
-0.55
-1.77
-0.85
-1. 70
-0.14
8.46
8.65
9.21
7.04
2.50
0.33
-0.90
-0.44
-1.03
2.65
6.54
7.'26
6.20
9.68, 5.88
9.8,6.0
2.28
4.53
5.42
systern is a further consequence. The cornrnent has been made (76MI40700) that the irnidazole
groups of histidine units in a polypeptide are the strongest bases present in any quantity
at physiological pH. Furthermore, the irnidazolium cations are the strongest acids present
in substantial arnount, with variations in pKa induced by local environrnent.
The effects of substituents on the basic nature of imidazole are summarized in Section
4.02.1.3.4. Tables 1 and 2 list the basic pKa values of sorne representative irnidazoles and
benzirnidazoles. Frorn these it can be seen that rnethyl and other alkyl substituents exert
a weak, base-strengthening inductive effect which is additive. Aromatic substituents decrease
basic strength, while groups attached to these aryl rings exert their norrnal behavior. In
fact, Harnrnett studies have permitted prediction with reasonable accuracy and correlation
of pK" values for a variety of irnidazoles. In a study of rneta- and para-substituted
I-phenylirnidazoles Pozharskii (70CHEI94) has shown not only that I-phenylimidazole is a
Imidazoles and their Benzo Derivatives:' (ii) Reactivity
385
Table 2 Basic pK. Values of Benzimidazoles (53HC(6-11. 65JCS5590)
Compound pK. (HzO)" Compound pK. (50% EtOH)
Benzimidazole 5.53 (4.98) 2-NH z 3.37
l-Et-6-Me 5.07 5-CI 3.92
I-Me 5.57 (4.88) 5,6-Cl z 3.26
2-Me 6.19 (5.77) 4-0Me 4.98
4-Me 5.67 (5.16) 5-0Me 5.07
5-Me 5.81 (5.32) 2-0Me-1-Me 4.07
5-NH z 6.11 2-0Et-1-Me 4.36
4-0Me-l-Me 5.25 2-0Me-1-Me-5-NO z 2.10
5-0Me-1-Me 5.78 2-Ph 4.51
1-CH z Ph-5-0Me 5.38 4-NO z 3.33
6-0Me-1-Me 5.65 5-NO z 2.67
5-0H-1-Me 5.94 2-Me-5-NO z 4.37
5-NH z -1-Me 6.21 2-Me-5,6-(NO z h -0.7
. Values in parentheses are in 50% EtOH.
weaker base than irnidazole, but also that the phenyl substituents have their usual effects.
The p value for correlation between these substituents on the benzene ring and the ionization
constants is +0.753. This is an indication that the electron transfer effects from the aryl
substituent to the imidazole basic nitrogen are weak. It was observed that strongly electron-
attracting groups (viz. p-NO z , p-COMe) behave as though their (T values are greater than
normal (i.e. + 1.25 and +0.65, respectively). These values are, in fact, close to the (T-
constants (+ 1.27, +0.87). Such a result implies that there is significant polar conjugation
between the 7T-systems of the heterocycle and the substituent.
The fused benzene ring of benzirnidazole decreases the basicity of irnidazole by about
the sarne arnount as a 1-phenyl or a 5-chloro or -bromo substituent, and the groups attached
to that benzene ring (e.g. Cl, NO z ) can enhance this base-weakening effect. The marked
difference in basicity between 1- and 2-methylbenzimidazoles rnay be a consequence of
the more syrnrnetrical cation (54) forrned by the latter (Scherne 15).
rYi N )
N
Me
-.
NH
)
Me
(r +NH (r NH
I ')Me -. I .}Me
N N
H H
(54)
Scheme 15
There is cornrnonly a sharp contrast between the pKa values of 4- and 5-substituted
irnidazoles. This contrast can only be evident when a ring nitrogen is substituted with
consequent definition of the position of the 4- or 5-substituent. Thus 1-methyl-5-
nitroimidazole is a rnuch stronger base than the 1-methyl-4-nitro isorner. Certainly an
electron-withdrawing substituent a to the basic nitrogen atorn has a much greater effect
than a ß substituent. This observation, which appears to be general, has been utilized in
some tautomerism studies (Section 4.06.5.1), and the resulting generalization that electron-
withdrawing substituents favor existence rnainly as the 4-isorner, and vice versa, is valid.
4.07.1.3.5 Proton acids at imidazole anions: acidity of irnidazoles
The NH proton in sirnple irnidazoles and benzirnidazoles is weakly acidic. Thus, the
cornpounds are able to forrn salts with a nurnber of rnetals (Section 4.07.1.6.5). The anion
which forrns on loss of the proton is again syrnrnetrical and is highly susceptible to attack
by electrophiles. Use is rnade of this property when irnidazoles are alkylated in basic rnedium
(Section 4.07.1.3.8). That substituents can rnodify considerably the weakly acidic nature
of imidazole is evident frorn the values quoted in Table 3.
A detailed study of fluorinated irnidazoles (related to relative reactivities in nucleophilic
dehalogenation reactions) has shown that whereas 2-fluoroirnidazole dissociates to the anion
with pK = 10.45, the 4-fluoroisorner shows no sign of such dissociation up to pH 11.7
(pK = 11.92). Such results parallel those for the corresponding bromo analogues; the greater
acidities of the 2-substituted isorners can be attributed to the syrnrnetrical anions that they
386 Irnidazoles and their Benzo Derivatives: (ii) Reactivity
Table 3 Acidic pKa Values for Imidazoles and Benzimidazoles ( UAHCI271241, 7UAHCi121103)
Compound
pKa Compound pKa Compound pKa
14.90 2-Br 11.03 2,4,5-Ph I-oxide 8.4
15.10 4-Br 12.32 Benzimidazole 13,2, 11.26
15.10 2-F 10.50 2-Me 11.65
13.32 2-F-4-Me 10.70 2-Ph I 1.4 I
13.42 4-F 11.92 2-( 2- Pyridyl} 10.17
12.53 4-NO z 9.30 2-(4-Pyridyl) 10.27
13.43 4-CHO 10.7 Naphth[ 1.2- d]imidazole 12.52
Imidazole
2 - '.1e
4-Me
2-Ph
4-Ph
2,4-Ph z
4.5-Ph z
forrn. That the fluoroimidazoles are stronger acids (and weaker bases) than their brorno
counterparts is an indication that the inductive effect of halogen overshadows its resonance
effect.
4.07.1.3.6 Metal ions
There are rnany examples of cornplexes which form between transition rnetal ions and
irnidazoles; the coordination number is four or six (70AHC(12)103). Thus, coordination
between the pyridine-type nitrogen and rnetal ions such as Cd(I1), Co(ll), Zn(Il), Pt(II),
MnOI), Cu(Il) or Cu(l) has been reported on rnany occasions, giving rise to complexes such
as CoCI 2 .2L and CoCh'4L (where L = imidazolyl ligand). It is also likely that a nurnber of
old reports in the literature of 'rnetal salts of imidazoles' really refer to complexes. One
very irnportant exarnple of such coordination occurs in hernoglobin where Fe(ll) coordinates
with a histidine unit of the protein. Methylrnercury(II) complexes with imidazole in solution
usually have a coordination nurnber of two. Under equilibrium conditions tetraam-
minerutheniurn(I1) cornplexes bind to irnidazoles rnainly at N-3, but there are one or two
instances in which binding rnay occur at C-2 (e.g. in 4-rnethylirnidazole and benzirnidazole).
Equilibriurn constants for the forrnation of six-coordinate complexes of general structure
trans-Ru NH3)4(S03)L L = 1-methylirnidazole, irnidazole and histidine) are >4.6 x 10 3 ,
11.8 x 10' and 0.76 x 10 , respectively (78JA2767).
4.07.1.3.7 Alkyl halides and related compounds: compounds without a free NH group
The quaternization of 1-substituted irnidazoles is a facile reaction which leads to a stable
quaternary salt via an SN2 reaction (Scherne 16) which may be affected by steric factors.
It has been shown (78AHC(22)71) that the effects of N -aryl substituents on rate constants
for the quaternization of irnidazoles can be correlated using a Harnmett equation. The
value of p (-0.45) for the ethylation of imidazoles shows little sensitivity to substituent
effects, but this is to be expected since the basic pKa values of the N -aryl compounds do
not vary widely, and the rate of alkylation must depend on the basicity of the nitrogen
being quaternized. Certainly the expected sequence of reactivities, l-rnethyl> I-benzyl>
I-phenyl, is observed in the ethylation of 1-substituted irnidazoles with iodoethane in
ethanol or acetone, and although only qualitative observations are available, 1-methyl-4-
and -5-chloroimidazoles react less readily than 1-methylirnidazole. Considerable experi-
rnental difficulty is experienced in quaternizing nitro-substituted imidazoles.
f/ N:--Me..ex p.!'I Me _
)\ --+ (:.) X
N N
Me Me
Scheme 16
There are nurnerOus examples of quaternizing alkylations of imidazoles using such diverse
reagents as alkyl, alkenyl or aralkyl halides, ethyl chloroacetate, phenacyl brornide or dirnethyl
sulfate. Since water is frequently held very tenaciously by irnidazole quaternary salts the
compounds are often best prepared in anhydrous conditions (e.g. dry benzene solvent in a dry
nitrogen atrnosphere) even though the reaction is cornrnonly slower in non-polar solvents.
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
387
Reports of quaternization at the already substituted nitrogen should be viewed with
suspicion, and one of the products of the reaction of imidazole with 2,2-dichlorodiethyl
sulfide (mustard gas) designated as (55) is more likely to be (56) or (57). The observations
of Pinner and Schwarz in 1902 that the quaternary salt obtained frorn I-methylimidazole
and 1-bromopentane could be decomposed by alkali to give both arninomethane and
1-aminopentane was the first piece of evidence (rnore recently confirrned by NMR studies)
to support the accepted view that quaternization takes place at the unsubstituted ring
nitrogen.
()
N Cl-
/' ,
HzC CH z
I I
HzC, CH z
"s/
(55)
+ ......CH z ,
[) 1 Hz
N S
" /
CHz-CH z
Cl-
[ ()CHZ)ZS(CHZh"- ] + ct-
(CHzhS(CHzh-"
(56)
(57)
4.07.1.3.8 Alkyl halides and related compounds: compounds with a free NH group
As mentioned above (Section 4.07.1.3.2) imidazoles are readily alkylated in neutral or
basic medium following either an S E 2 ' or an S E 2cB mechanisrn. The rnethod of choice now
commonly involves alkylation of the heterocycle in basic rnedium (Scheme 17) since these
conditions do not suffer frorn side reactions which produce the irnidazoliurn species. Thus,
the reaction of an imidazole with an alkyl halide (or related cornpound) is carried out in
the presence of the oxide or hydroxide of an alkali rnetal or alkaline earth element, with
sodium ethoxide or sodamide, in solvents such as ethanol, dioxane, acetone or liquid
ammonia. The use of sodium in liquid arnmonia gives excellent yields (>70%) in many
instances. Other workers have obtained high yields of N -alkylimidazoles by heating the
potassiurn imidazolate with an alkyl halide either in a sealed tube or under reflux in xylene,
benzene or toluene.
() () + x-
N N
R
Scheme 17
Related reactions which utilize the imidazole anion include alkylations of the silver salts
or an imidazolyl Grignard reagent. The forrner reaction has been ernployed specifically for
the introduction of trityl and carbohydrate residues. Condensation of either the rnercury
complex or silver salt of 4-aminoimidazole-5-carboxamide with protected carbohydrates
provides a route to imidazole-1-g1ycosides (80AHC(27)241). The first example of such a
synthesis was the preparation of l-g1ucopyranosyl-5-methylirnidazole frorn the silver salt
of 4-methylimidazole and (X- acetobromoglucose. Many alkylations involving unsaturated
compounds, too, probably proceed via the irnidazole anion. 1-Allylimidazole is accessible
by reaction of the heterocycle with 3-chloro-1-propene in the presence of sodiurn hydroxide
in acetonitrile, while the reaction of 4,5-dicyanoimidazole with ethylene oxide in sodium
hydroxide solution gives 4,5-dicyano-1-vinylirnidazole. Vinyl halides give the same products,
and even alkynes in the presence of bases can alkylate imidazoles.
Alkaline rnedium, however, is not always suitable since branched-chain alkyl halides are
subject to elimination, and there are striking changes in orientation of substitution with
unsyrnmetrically substituted irnidazoles. Only low yields of 1-(1-imidazolyl)-2-rnethyl-
propane are obtained in the reaction of irnidazole with 1-iodo-2-rnethylpropane in sodiurn-
liquid ammonia.
The use of phase-transfer catalysis in the alkylation of imidazoles and benzimidazoles
has already proved its value; in ether, 18-crown-6 catalysis gives 64-86% yields of N-rnethyl
products with basic aqueeus solutions of the heterocycles and alkyl halides (79TL4709,
76BSF1861,80JOC3172).
There are a multitude of exarnples which involve alkylation of the irnidazole neutral
molecule in spite of the problerns of side products which cornrnonly accornpany the
388
lrnidazoles and their Benzo Derivatives: (ii) Reactivity
procedure. The process is of the S E 2 ' variety (Scheme 14) and involves reagents as diverse
as triphenylmethyl chloride or fluoroborate, alkyl esters of phosphonic or phosphinic acids,
various carbonyl compounds, oxiranes, unsaturated compounds and diazomethane. The
N -alkylation reactivity of trialkyl phosphates decreases with increase in size of the alkyl
groups. High yields of N -alkylirnidazoles result on treatrnent of irnidazole at 180 0 C with
dirnethyl oxalate, while the sealed-tube reaction of imidazole and formaldehyde at 120-
130 0 C gave a liquid (described as 1-hydroxyrnethylirnidazole) which formed irnidazole
when boiled with water. Dirnethyl sulfoxide reacts at elevated ternperatures with 1-
trirnethylsilylirnidazole in a Purnrnerer reaction to produce l-(methylthio)methyl-
imidazoles. The vapor phase rnethylation of imidazole with methanol in the presence of
alurnina is accompanied by catalytic rearrangernent of an N -rnethyl group to C-4 or C-5
followed by remethylation at N-t. Such a reaction seems unlikely to involve an electrophilic
substitution rnechanisrn and may indeed be a radical process (70AHC{12)103). In the alkylation
of 2-amino-1-rnethylimidazole with a-bromocarbonyl reagents, an N,N-dialkylated imi-
noirnidazole (58) is formed at low temperatures; when the temperature is raised above
66 0 C, a bicyc1ic dehydration product (59) results (Scherne 18). The use of trimethyl
orthoforrnate to give 1-dialkoxymethyl products, which are readily hydrolyzed in acidic or
neutral rnedium at room temperature, has been recornmended for protection of imidazoles
during forrnation of the 2-lithiated derivatives (Section 4.07.1.6.1) (SOJOC403S).
R
/
/CH
( N OR'
N
Me (58)
- H 2 0 1>66 o c
BrCHIR)COR'
R
I/ N 7 R '
)=N
N
Me
(59)
[)NH 2
N
Me
Scheme 18
As intimated earlier, the alkylation products of 'unsymmetrical' imidazoles may vary
according to reaction conditions. The product orientation depends not only on the mechan-
isrn, but also on such factors as substituent and steric effects, and even the tautomeric
nature of the azole cannot be neglected. In basic rnediurn the mechanisrn (S E 2cB) involves
the anion, and the two possible products (60, 61; Scheme 19) are obtained in a ratio which
reflects the electronic and steric effects of the substituent group R and those of the reagent.
A large R group tends to direct substitution to the rnore remote nitrogen. An electron-
withdrawing group R reduces the basic nature of the adjacent nitrogen rnore than that of
the rernote nitrogen and gives the same orientation (61); conversely, an electron-releasing
group leads to a preponderance of (60). Thus, the alkaline benzylation of 2,4-dialkylated
irnidazoles gives the least sterically-hindered product (1,2,4), and also in basic medium the
methylation of 4-nitroirnidazole gives a 9: 1 ratio of 1-methyl-4-nitro: l-rnethyl-5 nitro
products (electronic effect). Under sirnilar conditions dimethyl sulfate converts 2-chloro-4-
nitroirnidazole into rnainly 2-chloro-1-rnethyl-4-nitroirnidazole.
R N R , R N
R'X (NR
C) .) + [)
.. .
N N N
R'
(60) (61)
Scheme 19
Matters be corne rnore cornplex still in neutral conditions because now tautorneric effects
can be superirnposed upon steric and electronic effects. In an S E 2 ' process 2-methyl-4-
phenylimidazole is methylated by dirnethyl sulfate to give a mixture of the 4-phenyl and
lmidazoles and their Benzo Derivatives: (if) Reactivity
389
5-phenyl isomers in the ratio 5.7: 1 (Section 4.02.1.3.8). The phenyl group has
some steric effect, besides being electron withdrawing; both of these combine to result in
a preference for the formation of the l,4-product in spite of the fact that this necessarily
involves methylation of the minor tautorner. There are, however, a number of instances in
which the products can only be accounted for in terms of alkylation of a rnajor tautomer.
4-Nitroirnidazole and 4-bromoirnidazole both give mainly the 1,5-substituted compounds
when methylated with dimethyl sulfate, while 2-methyl-4-nitroimidazole can be fused with
alkyl tosylates to give rnainly the 1,2,5-substituted products. Table 4 lists alkylation results
from the literature, but it would be valuable to check and arnplify the data using rnethods
of analysis currently available since the total yields quoted are often less than quantitative.
Table 4 Ratios' of Isomers Formed in Alkylation of Imidazoles (S.76MI40701, 79H(l2ll86)
Imidazole
Me!
Me z S04
Reagents
CHzN z MezS04/0H- Ag+ salt/MeI
4-Br
4-CN
4-CHO
4-CO z Me
4-Me
4-NO z
4-Ph
1:34
2.9: 1
mixture
2:1
b
b
b
1:350
5:1
1 :45
1:2
2.2: 1
9:1
· l,4-Isomer: 1,5-isomer. b 1,5-Isomer only. c l,4-Isomer only.
Ridd and his co-workers (60JCS1352, 60JCS1363) have provided a sound basis for the
interpretation of the results of methylation of 4-nitroirnidazole, the results of which have
been discussed elsewhere (B-76MI40701). The kinetic results are summarized in Figure 1. It
is evident that the conjugate base reacts about 10 3 times faster than the neutral rnolecule,
and that in imidazoles with electron-withdrawing groups the changeover frorn the SE2cB
to S E2 ' mechanisrns should occur somewhere in the pH range 6-11.
OzN N O.22x 10- 2
[)
N
1.78 x 10- 2
OzN N l.4x 10- 4
[')
N
H
--->.
...----
OzN NH
[)
N
<5.6 X 10- 3
SE2cB (in HzO at 25 oc)
SE2' (in HCOzH at 50 o C)
Figure 1 Rate coefficients (dm 3 mol- l S-I) for methylation of 4-nitroimidazole with dimethyl sulfate
The orientation of rnethylation using diazomethane is not easy to explain since the
mechanisrn is in doubt. One interpretation of the preferential formation of 5-substituted
1-methylimidazoles (with a 'highly electron-dense' potential 5-substituent) is via the initial
formation of an ion pair [Irn-MeN 2 '1-] in which the cationic portion is situated near to the
nitrogen adjacent to the substituent. This may be true, but the results obtained with
unsymmetrical pyrazoles (79AJC2203) cannot be explained entirely in this way.
Benzimidazoles, too, are readily alkylated either in neutral Or basic mediurn. As with
the uncondensed compounds, the former conditions are complicated by salt forrnation, but
to a lesser extent since benzimidazoles are less basic. It is often valuable to vary the initial
amounts of alkali and alkyl halide in order to improve yields. The best yields of 1-
alkylbenzimidazole (76-83% for prirnary and 50-60% for secondary alkyl and aralkyl
bromides) result with two moles of brornide and 1.5 moles of alkali per mole of ben-
zimidazole (66RCR122). There is severe steric hindrance to the alkylation of 2-arylben-
zimidazoles in alkaline rnedium, but reactions with the silver salts seem more successful.
The rapid and almost quantitative reaction between a benzimidazole and dimethylphenyl-
alkylarnrnonium chlorides in aqueous sodium hydroxide provides a very convenient rnethod
of introducing a primary aralkyl group (benzyl, a-naphthylmethyI). There has been little
systematic study of the alkylation of unsymmetrical benzimidazoles, though rnuch the sarne
criteria should apply as in the uncondensed cornpounds. In this respect the observation
that 1-bromopropane reacts with the anion of 2,6-dirnethyl-4-nitrobenzimidazole to give
390
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
2,6-dimethyl-4-nitro-1-propylbenzirnidazole is not unexpected. With diethyl sulfate, alkyla-
tion of 5-nitrobenzimidazole gives a higher proportion of the 1,6-isomer, but with dirnethyl
sulfate in basic rnedium the ratio of 1,5: 1,6 is close to 1: 1. Alkyl halides, however, e.g.
rnethyl iodide and benzyl chloride, in basic conditions give rnainly the 1,5-isomer (74CRV279).
1,3-Polymethylenebenzirnidazoles are formed when suitable dibromoalkanes react with
benzimidazolinone in strongly basic rnedium (Scheme 20). When n = 10-12 yields are high,
but reduction of chain length (n = 5-8) gives rise to dirners and trirners, and with n = 3 and
4 N -0- bridged products appear (76TL79). Other reactions in which there is corn petition
for alkylation between an annular nitrogen and an exocyclic group such as amino, hydroxy
or mercapto will be discussed with the appropriate functional group.
(X N
-;:? BrlCH 2 )n Br
:::::,.. I N>- liH/DMF/90-95'C
CH2).
H
(X I N>=O
:::::,.. N
H
BrICH,lnBr (XI N >= :-\
NaH/DMF/20'C) 0 (CH z ).
:::::,.. N,-/
n =3,4
n = 10-12
Scheme 20
There are a few examples of intramolecular alkylation and related processes involving
N-l. Base-catalyzed cyclization of the appropriate 2-substituted thioacid derivatives have
given (62) and (63). In addition cyclization of a series of ketones (64) gives the tertiary
alcohols (65) which are subject to dehydration (Scherne 21) (74CRV279).
o
(X:Þ
(62)
(X :tì
I Ií S
:::::,.. N
(63)
(X I N)-S
:::::,.. N >-R
HO=<
(64) R'
--.>.
..---
(X I N')-S -H,O. (X I N')-S
:::::,.. N :::::,.. N I
R '\::;:::"'R
R'
HO R'
(65)
Scheme 21
Benzimidazoles, benzimidazolinones and benzimidazolinethiones react with forrnal-
dehyde and secondary amines in a Mannich reaction to forrn N -arninomethyl derivatives.
The conversion of benzimidazoles into 1-(2-hydroxyethyl) derivatives with ethylene oxide
is well known.
Arylation at a ring nitrogen is not a particularly simple procedure for aryl halides are
not usually susceptible to nucleophilic displacement of the halogen group. Nevertheless, a
rnodified Ullrnann reaction using the aryl halide in nitrobenzene in the presence of potassium
carbonate and copper(I) brornide catalyst gives reasonable yields of 1-arylimidazoles
(66KGSI43). When there are strongly electron-withdrawing groups associated with the aryl
halide less vigorous conditions are needed; 1-fluoro-2,4-dinitrobenzene reacts with irni-
dazoles in benzene containing a little triethylamine to give 77-92% yields of the N- aryl
derivatives. The kinetics of the reactions of irnidazole with either the above aryl fluoride
or picryl chloride are third order overall, and second order with respect to imidazole at
low irnidazole concentrations. Sorne leveling off of rates has been interpreted as indicating
an addition-elimination rnechanism with the decornposition into products being fast for the
chloro and slow for the fluoro compound (80AHCC27)241). The use of benzyne leads to the
direct N -arylation of imidazoles.
4.07.1.3.9 Acyl halides and related compounds
Reactions leading to N -acylirnidazoles have excited considerable interest in recent years
in view of the importance of N -acylimidazoles in certain biological processes. In addition
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
391
they are arnong the more useful of the 'azolides' which have found synthetic utility in a
variety of acylation reactions (Section 4.07.3.8.4). When one adds to these facets the
probable intermediacy of N -aroylimidazoles in 2-aroylimidazole formation, and the value
of l-acylimidazoles in the regiospecific alkylation of the heterocycles there is ample reason
for the upsurge of interest in these compounds.
As long as there is only a hydrogen on the ring nitrogen of imidazole the N -acyl compounds
can be prepared using such diverse reagents as acyl halides and anhydrides, alkyl chlorocar-
bonates, isocyanates (at elevated temperatures), cyanates, ketene, isopropenyl acetate,
acetyladenosine monophosphate, phosphoryl halides and chlorides of sulfonic acids. For
simple N -acyl compounds the most common rnethods of synthesis are, however, reaction
of a 1: 2 molar mixture of acid chloride and irnidazole in an inert solvent at roorn
temperature, or reaction of free carboxylic acids with 1,l'-carbonyldiimidazole at room
temperature. With phosgene the latter reagent forms the 1-carbonyl chloride (66) which
is in turn converted into the amide (67) by piperidine (Scheme 22) (79LA1756). Note though
that 1-acetyl derivatives of imidazole-2-thiols (or -2-ones) must be prepared by heating
with acetic anhydride in pyridine; in a reaction mediurn of ethanol the S -acyl product is
forrned preferentially. Acid chlorides also react with I-trimethylsilylimidazoles to give
azolides. Trifluoromethylsulfonation forms an imidazolide which is a convenient reagent
for the introduction of a 'triflate' group. In the cases of highly basic 1-substituted irnidazoles,
acid halides can give rise to quaternized products, and in the presence of antimony chloride
1-acetylimidazole is even quaternized by acetyl chloride (70AHC(12)103, 80AHC(27)241).
r=\ r=\ COCl 2þ r=\ HNJ r=\ . O .
NyN-CO-N N NyNCOCl ---=+ NyN-CO-N
(66) (67)
Scheme 22
Benzimidazoles, too, are readily acylated and rnay also be converted by acylating agents
into quaternary salts. In one such reaction the benzimidazole is eventually partially
dearomatized to (68) on reaction with bis(l-chloroformyl)diphenylarnine (Scherne 23)
(76CC48). Under similar conditions imidazole is only acylated.
N COCl COCl
+rJr Y')--
N
H
or\)
NX-N
0-N
o
(68)
Scheme 23
At elevated temperatures imidazole-2-carbanilide is acylated by phenyl isocyanate. The
initial reaction product (69) gives rise to the bicyclic cornpound (70) in the presence of base
(Scheme 24).
()CONHPh
N
H
Ph:CO) ( C/NHPh (\
N N' yO
}-NPh
o NHPh 0
(69) (70)
Scheme 24
With phosphoryl chloride in alkali, irnidazole gives the diphosphoryl imidazole (71) while
1-methylimidazole gives an analogous product. Such N -phosphorylirnidazoles play an
irnportant role in enzymic transphosphorylation. When two moles of irnidazole (or ben-
zimidazole) react with one mole of dialkyl (or diary!) phosphoric acid chloride, the com-
pounds (72) are formed, and di- and tri-imidazolides of phosphoric acid (e.g. 73) can be
obtained similarly from phosphoric acid dichloride or from phosphoryl chloride (Scheme
392
Imidazoles and their Benzo Derivatives: (ii) Reactivity
25) (66RCR122, 7SZN(B)1033). The derivatives of I-phosphorylimidazolé in which the phos-
phoryl residue is cornbined with an organic radical are relatively stable and readily phos-
phorylate amines, alcohols and carboxylic acids at roorn ternperature.
RO"
p=o
/1
RO CI
N
[)
N
PO(ORh
(72)
pNH
+ (. ) Cl-
N
H
P0 3 H
./
N
[)
N
P0 3 H z
o
N II N
I ,N-P-N I
L.::::::::::I I
N
)
(73)
(71)
Scheme 25
Kinetic studies of the reactions of irnidazoles with benzoyl and sulfonyl halides have been
carried out. In acetonitrile the reaction of benzoyl fluoride with irnidazole is a rnixed third-
and fourth-order process, which means that the rate-determining step contains the acid
fluoride and two or three molecules of imidazole. With benzoyl chloride in benzene a
second-order equation, sirnilar to the aroylation of aniline, is followed. The reactions are
subject to steric hindrance, and even a methyl group on an adjacent carbon rnakes the
N -acylation rnore difficult. Because of this, and because of the reversible nature of the
reaction, it has been possible to devise a rnethod of regiospecific alkylation of imidazoles
to give the sterically least-favored product (SOAHC(27)241). A typical reaction scherne is
shown in Section 4.02.1.3.9. When ethyl chloroformate is used as the acylating reagent,
high yields of N -alkoxycarbonyl corn pounds result. For example, 2-ethyl-4-rnethylimidazole
gave greater than 95% of 1-ethoxycarbonyl-2-ethyl-4-methylirnidazole with little or none
of the 5-rnethyl isorner. These 1-acyl derivatives can lose carbon dioxide to give the
l-alkylirnidazoles, but the decarboxylation process is unfortunately accornpanied by some
isomerization. The above product gave a 3: 1 mixture of 1,2-diethyl-4- and -5-methyl-
irnidazoles (SOAHCl27)241).
Acylation reactions which lead ultimately to 2-acylirnidazoles will be discussed as elec-
trophilic substitutions at ring carbon atoms (Section 4.07.1.4.6) in spite of the almost certain
interrnediacy of the N -acyl cornpounds.
Considerable effort has been applied to studies of ester hydrolysis catalyzed by irnidazoles
(76MI40700, SOAHC(27)241). Certainly, 1-acetylimidazole can be made enzymically, probably
by the sequence: acetyl phosphate + coenzyrne A acetylcoenzyrne A + phosphate, acetyl-
coenzyrne A+irnidazole 1-acetylirnidazole+coenzyrne A. In addition, the imidazolyl
group of histidine appears to be implicated in the mode of action of such hydrolytic enzyrnes
as trypsin and chymotrypsin, thereby engendering further interest in the process of irnidazole
catalysis. The two pathways which have been found to be involved are general base catalysis
and nucleophilic catalysis. In the forrner (Scherne 26) a basic irnidazole rnolecule can activate
a water molecule to attack the ester at the carbonyl carbon, this being followed by the
usual sequence of steps as in sirnple hydroxide ion hydrolysis. At high irnidazole concentra-
tions the imidazole rnolecules rnay be involved directly.
o
11 -0
R - -c,.o II R'
......0,
H H\
(N 1
L H
o
11 -0
R-5.-c.P II R'
N
L J
'.( r=\
H"-...:NVNH
Scheme 26
In nucleophilic catalysis the catalytic properties are a result of the intermediate forrnation
of a l-acylirnidazole (Scherne 27). When the ester has a good leaving group, e.g. p-
nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases
in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester
has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and
general base catalysis predominates. Thus, for irnidazoles with pKa::;; 4 catalysis by the
anion is the rnain reaction. Irnidazole is a much more effective nucleophile than other
amines in this type of reaction since it is a tertiary arnine with little steric hindrance, and
it is able to delocalize the positive charge which results frorn the nucleophilic addition to
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
393
the ester carbonyl group. Additionally, 1-acylimidazoles are much more reactive in aqueous
solution than other substituted amides, a facet which will be discussed with the reactions
of the azolides (Section 4.07.3.9.4). The irnidazole-catalyzed isomerization of penicillin into
penicillenic acids probably involves an initial nucleophilic attack of the heterocycle on the
pencillin (B-76MI40701).
N:
(J R-C-OR'
N d'
H 0
---'-
..--
R
+ I _
ij -?-O
i( ;> OR'
N
H
---'-
..--
( COR ()COR ()
N N N
H H
Scheme 27
+ RCOzH
4.07.1.3.10 Halogens
Examples exist in which some azoles are able to react reversibly with halogens and
interhalogen compounds to give unstable adducts which are probably n,CT charge transfer
complexes (77JOU1S72). A few N -halogenated azoles have been isolated - N-
iodoimidazoles would appear to have reasonable stability in some instances. During the
C -halogenation of imidazoles there is probably a transhalogenation process occurring since
there is evidence for the initial formation of the N -halogen isomers. In a situation where
subsequent rearrangernent of the N -halogen atom cannot occur, e.g. in the reaction between
the sodium salts of 2,4,5-triarylimidazoles and bromine in anhydrous ether, the operation
of a radical process is indicated by the formation of 1,l'-biirnidazolyls.
4.07.1.3.11 Other electrophiles
There are no known examples of direct N -oxidation of imidazoles or benzimidazoles by
peracids. With hydrogen peroxide imidazole is cleaved to give oxarnide, while perbenzoic
acid destroys the ring giving ammonia and urea.
Trimethylsilylation of N -unsubstituted compounds is common and the derivatives formed
have synthetic and analytical applications.
Direct N -cyanation is possible when cyanogen bromide reacts with an irnidazole or
benzimidazole having a free NH group (Scheme 28) (SOH(14)1963).
Ph N
Phl[)\
N
H
BrCN
----+
Ph N Ph NH
Ph()\ + Ph(J
N N
CN H
Br-
Scheme 28
Reactions of alkynes with benzimidazole are also electrophilic processes. Thus, 1-vinyl-
benzimidazole and 1 ,3-divinylbenzirnidazolinone are formed by the addition of acetylene in
aqueous dioxane at 160 and 200 oC to benzimidazole and benzimidazolinone, respectively.
There is rather rnore complication involved in the reactions of such alkynes as dimethyl-
acetylene dicarboxylate (DMAD) (see Section 4.07.1.8) with not only products of
N -alkylation, but also the formation of tricyclic products involved.
Although imidazole is too basic to form the 1-nitro derivative when treated with nitric
acid-acetic anhydride (indeed, the nitrate salt forms in preference), less basic imidazoles
can be N -nitrated under these conditions. Thus, 4-nitroimidazole gives l,4-dinitroimidazole
(SlUP40700, SOAHC(27)241), and the corresponding 2- and 5-methyl-4-nitroimidazoles react
in the sarne way. Of interest is the orientation of N -nitration which parallels that of
methylation of the anion. Whether the anion reacts in the nitronium acetate medium or
whether steric factors control the site of attack is not known.
With tetracarbonyliron, rnercury tetracarbonylferrate(II), ferrocene or dicarbonyl-
cyclopentadienyliron, imidazole forms iron(II) cornplexes of the general form
Fe(C 3 H 3 N 2 h or Fe(C3H3N2h'0.5(C3HtN2). Iron(I1I) complexes have also been described.
394
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
4.07.1.4 Electrophilic Attack at Carbon
4.07.1.4.1 Reactivity and orientation
(Í) Ease of reaction
Irnidazole varies considerably in its reactivity with electrophiles depending on the type
of reagent and the reaction conditions. Reactions which can involve the irnidazole neutral
rnolecule or the anion occur with sorne facility, e.g. halogenation and diazo coupling, but
when highly acidic conditions are ernployed the azoliurn ion is the substrate. In consequence
it is considerably deactivated. Such reactions as sulfonation and nitration occur with
difficulty. Imidazole is nitrated in rnixed acids 10 9 tirnes slower than benzene, but 10 10
tirnes faster than pyridine (which also reacts as the protonated species). Friedel-Crafts
reactions will only take place if there is strong activation frorn a substituent. The rneasure-
rnents and MO calculations of 7T-electron densities for irnidazole and benzirnidazole predict
a reactivity with electrophiles sirnilar to that of benzene, and rnuch greater reactivity in the
case of the irnidazole anion, but the carbon atorns are less prone to attack than the
rnultiply bonded nitrogen atorn. A nurnber of reactions which result in ultirnate C-substitu-
tion rnay proceed via an initial N -substitution, e.g. halogenation and acylation, and others
rnay involve an addition-elirnination process, e.g. brornination of l-rnethylirnidazole with
cyanogen brornide.
(ii) Orientation
In reactions of the irnidazole neutral rnolecule or cation, attack by electrophiles at C-5
is preferred. However, when there is a free NH in the ring, tautornerisrn rnakes the 4- and
5-positions equivalent. Conditions in which the irnidazole anion exists are reported to be
characterized by electrophilic substitution at C-2. There would appear to be exceptions to
this generalization, e.g. halogenation (Section 4.07.1.4.5). When the preferred positions
are blocked it is usually possible to induce electrophiles to enter alternative ring positions
and rnultiple substitution is cornrnonly possible. In fact it is difficult to prepare rnono-
brornoirnidazole, and irnidazole can be dinitrated. More than one benzeneazo group can
couple when imidazole reacts with diazoniurn salts.
Atternpts to correlate reaction rnechanisrns, electron density calculations and experi-
rnental results have rnet with only lirnited success. As rnentioned in the previous chapter
(Section 4.06.2), the predicted orders of electrophilic substitution for irnidazole (C-5 > -2 >
-4) and benzirnidazole (C-7 > -6 > -5 > -4>> -2) do not take into account the tautorneric
equivalence of the 4- and 5-positions of irnidazole and the 4- and 7-, 5- and 6-positions
of benzirnidazole. When this is taken into account the predictions are in accord with the
observed orientations of attack in irnidazole. Much the sarne predictions can be rnade by
considering the irnidazole rnolecule to be a cornbination of pyrrole and pyridine (74) - the
rnost likely site for electrophilic attack is C-5. Furtherrnore, while sets of resonance structures
for the irnidazole and benzirnidazole neutral rnolecules (Schernes 1 and 2, Section 4.06.2)
suggest that all ring carbons have sorne susceptibility to electrophilic attack, consideration
of the stabilities of the expected u-interrnediates (Scherne 29) supports the cornrnonly
observed preference for 5- (or 4-) substitution. In benzimidazole attack usually occurs first
at C-5 and a second substituent enters at C-6 unless other substituent effects intervene.
. t l pyridine a
deactivated pyrmle ß (: N
. . t 3 \ ..
. d{ pyrldme ß 5 1;;> pYrIdme a } deactivated
activate pyrroIe a N pyemIe a
H
(74)
(Íii) Effects of substituents
Norrnal substituent effects operate in irnidazoles and benzirnidazoles. Thus, if a nitro
group is already present in the ring it is extrernely difficult to introduce a second or a third
one. Furtherrnore, when there is a phenyl ring either fused or attached to imidazole,
electrophiles rnay prefer to attack this benzene rnoiety, particularly electrophiles generated
in acid rnediurn. Although rnethyl groups have little activating effect they rnay exert an
apparent directing effect if they are responsible for a change in reaction rnechanisrn, e.g.
halogenation of I-methylirnidazole (Section 4.07.1.4.5).
Imidazoles and their Benzo Derivatives: (ii) Reactivity
395
2-substitution
.,.
ff H -. C H - +C H
N N
H E H E H E
4-substitution
E H
+t)
N
H
E H
)
H
5-substitution
+
H'ìC) - H ;:;; _ H !:: )+
E E E
Scheme 29
In an endeavor to study the transmission of substituent effects in imidazoles Noyce
(73JOC3762) exarnined the solvolysis rates of a series of l-(1-rnethylimidazolyl)ethyl p-
nitrobenzoates (75-77; OPNB = p-nitrobenzoate). The relative rates (75: 76: 77 =
1: 13 : 15) parallel the relative electron densities in 1-rnethylimidazole as deduced frorn
chernical shift data. By comparison with other heteroarylethyl p -nitrobenzoates the effective
replacernent constants, u;." were deterrnined as Ur-Im = -0.82, U -Im ='-1.01 and U;-Im =
-1.02. The effects on the 2-substituted compound of alkyl, aryl and halogen substituents
at the 4- and 5-positions were exarnined, but though the rates for the 5-substituents could
be represented satisfactorily by u;, u;;' failed to account properly for the observed reac-
tivities of the 4-substituted compounds. It is not surprising that the distorting effects of
annular heteroatorns make it difficult to superimpose the substitution behavior of benzenoid
corn pounds into this series.
Ç Me
Me OPNB
(75)
OPNB
M' )
N
Me
/IN
Meý" )\
OPNB Me
(77)
(76)
OPNB = p-nitrobenzoate
In the benzimidazoles a powerful electron-releasing group at C-5 will direct subsequent
substitution to C-4; electron-withdrawing substituents lead to subsequent attack at C-4 or
C-6.
4.07.1.4.2 Nitration
When imidazole is treated with a rnixture of concentrated nitric and sulfuric acids the
4-nitroirnidazole is forrned by nitration of the irnidazole conjugate acid. There is no
substitution at C-2 and so the irnportant antibiotic 2-nitroirnidazole (azornycin) cannot be
prepared by direct nitration. Variations in reaction conditions such as heating irnidazole
nitrate with sulfuric acid or addition of sodium or potassiurn nitrates to irnidazole give the
sarne 4-nitro product. Exhaustive nitration in 'rnixed acids' gives successively 4-nitro- and
4,5-dinitroirnidazoles, but not 2,4,5-trinitroirnidazole. The last-narned cornpound can,
however, be prepared by nitration of 2,4-dinitroirnidazole (73CHE465). A chloro substituent
is no hindrance to the nitration process: both 1-rnethyl- 4- and 1-rnethyl-5-chloroirnidazoles
are readily nitrated in sulfuric acid. While nitric acid in acetic anhydride (nitroniurn acetate)
seerns to form only the nitrate salt in rnany instances, dinitrogen tetroxide in acetonitrile
is reported to convert 4-substituted irnidazoles bearing electron-withdrawing substituents
into a mixture of 5- and 2-nitro derivatives. Such nitrations at C-2 are unexpected. With
396
Irnidazoles and their Benzo Derivatives: (ii) Reactivily
nitric-sulfuric acid rnixtures 1-rnethyl- and 1,2-dirnethyl-irnidazoles give rnixtures of the 4-
and 5-nitro isorners in the approxirnate ratios of 5: 2 and 2: 1, respectively.
The kinetics of nitration of irnidazole have been studied in sulfuric acid rnedium. The
yields of 4-nitroirnidazole are dependent on the acidity, e.g. %H z S0 4 , yield (%): 83.7,46;
89.6, 26; 93.8, 19; 98.8, 19; 1% S03, 90. Ring opening accornpanies the process giving
rise to arnrnonia and, presurnably, oxidation products. The kinetic results which could be
separated indicate that the species being nitrated is the irnidazole cation, but side reactions
cornplicate rnatters. The suggested rnechanisrn is outlined in Scherne 30 (S-76MI4070i).
OzN
N , _ NH N0 2 . )-NH OzN NH
[) 0) H(.z,+) /[;)
N N N N
H H H H
Scheme 30
Both benzirnidazoles and aryl-substituted imidazoles are cornmonly substituted by nitro
in the aryl rings, and consequently such reactions will be treated as reactions of substituents
(Sections 4.07.3.1 and 4.07.3.2). On occasions, though, reaction can occur in the heterocyclic
nucleus. Thus, when 2-(p-fluorophenyl)irnidazole is nitrated under mild conditions an 80%
yield of the 4-nitro product (78) results. Yet a further nitro group can be introduced by
the use of nitric and acetic acids at 95 oC. More acidic nitrating agents tend to attack the
benzene ring or rnay result in oxidation. The observation that nitric acid in 20% oleum at
-10 oC still nitrates (presurnably) the deactivated irnidazoliurn species in preference to the
electron-deficient fluorophenyl group rnust reflect the relative stabilities of the Wheland
interrnediates (Scherne 31) (79JHC1153).
r=\
HN (S N
I
F
HNO,-Ac,O !low yield) )
or HNOJ-oleum t20%) at -lOoC
180% yield)
70% HNo' l
H 2 S0 4
OMOH
N O :H
lð
F
H 0'
HOzC N
F,
N O O
I":::
#
F
NO z
r=\
HNXN
U
F
(78)
1 70% HNO,/H2S04
or
90% HNO,/oleum
OzN NO z
r=\
HN 6 N
I":::
#
F
90%
HNO, )
HOAc, 95 'C
NO z
F\
HN ó :
#NO z
F
Scheme 31
Attention is also drawn to the conditions under which N -nitration (Section 4.07.1.3.11)
and NN0 2 CNO z rnigrations (Section 4.07.1.2.2) take place.
'ipso'- Nitration of iodoirnidazoles has been reported (80AHC(27)241), but recent studies
(79CC523, 81JOCi781) have dernonstrated that some cornpounds, reported to be 2-iodo
derivatives, are in fact 4-iodoirnidazoles. Accordingly, when the results reported earlier are
arnended in the light of these findings it can be seen that iodo groups in the 4- and 5-positions
of irnidazole may be replaced by the nitro group (Scherne 32). It had been reported earlier
that 4,5-dibrornoirnidazole could not be nitrated, but that 4-chloro- and 4-brorno-irnidazoles
undergo nitration at the vacant C-5 (or -4) position. The forrnation of 2,4,5-trinitroirnidazole
(80) frorn 2,4,5-triiodoirnidazole (79) is unexpected as it involves nitration at C-2. An
analogous nitration (in 50% HN0 3 ) of 4,5-diiodoirnidazole to give 5-iodo-2,4-
dinitroirnidazole rnust be viewed with suspicion since the authors thought their starting
rnaterial was 2,4-diodoirnidazole. Furtherrnore, the suggestion (76JCS(P2)1089) that the facility
of nitrodehalogenation decreases with an increase in acid strength (because water is needed
Imidazoles and their Benzo Derivatives: (ii) Reactivity
397
to rernove the halogen cation frorn the Wheland interrnediate) is not in accordance with
the use of 100% nitric acid for the conversion of (79) into (80). Repetition of this sequence
of reactions will be required to clarify the anornalies.
I N
I[)
N -..... .::?3-H2S0.
H 20' 0 N
2 N
I N HN i:; )
ç) H
H
02 N N
HN0 3 -H 2 SO., [ \\
180'C 02N ./
N
H
02 N N
l:)I
H
( HNO r H 2 SO.
20'C
I N 02 N N
( \\ 100% HN0 3 , ( \\
I ./1 02N ./N0 2
N N
H H
(79) (80)
Scheme 32
4.07.1.4.3 Sulfonation
The sulfonation of irnidazole occurs at the 4-position when the heterocycle is treated
with 50-60% oleurn at 160 oC. As with nitration, attack is on the irnidazoliurn species. The
2-rnethyl, 4-methyl, 4-brorno and 4-brorno-2-methyl cornpounds are all sirnilarly sulfonated
at C-4 (or C-5), and under severe conditions 2-rnethylirnidazole gives sorne of the 4,5-
disulfonÎc acid. Sulfur trioxide in the presence of air also appears capable of sulfonating
imidazole.
Chlorosulfonation of 4-brorno-, 4-chloro-1-rnethyl-, 5-chloro-1-methyl- and a series of
2-aryl-imidazoles occurs also at C-4 (or C-5), but only decornposition products were isolated
frorn the reaction with 4-acetamidoirnidazole.
4.07.1.4.4 Acid-catalyzed hydrogen exchange
While rnost hydrogen exchange reactions of irnidazoles appear to involve a base-catalyzed
process (Section 4.07.1.6.2), the relative rates of hydrogen-deuteriurn exchange at the 2-,
4- and 5-positions of 1-methylirnidazole (Path 1, Scherne 33) are quoted as 1: 73 : 120.
This reaction involves an SEAr pathway through the conjugate acid species. In such an
acid-catalyzed process involving a Wheland interrnediate the relative reactivities of the
various species arising frorn the heterocycle are conjugate base> neutral rnolecule>
conjugate acid (SOAHC(27)241, B-76MI40701). Acid-catalyzed ring proton exchange in 1-
rnethylirnidazole occurring by electrophilic attack on the irnidazolium ion has significant
reaction rates only at high ternperatures and in rnoderately strong acid rnedia, e.g. -160 oC
in 1M DCl in D 2 0. If the irnidazole has a low enough pK value, then an alternative
rnechanisrn can apply involving electrophilic attack at C-4 or C-5 in the neutral rnolecule.
Substituents rnust be present which are capable of stabilizing a carboniurn ion. Under these
circurnstances the exchange is rnuch more rapid. For exarnple, in 0.1-3M DCl at 50 o C,
tl/2=9 h for 4-fluoro-2-rnethyl-, 12 h for 4-fluoro-1-rnethyl-, 16 h for 2-fluoro-4-rnethyl-
and 54 h for 4-fluoro-imidazole. No exchange at C-2 was noted. In 1M DCl at 50 0 C
exchange of H-4 in 1-rnethylirnidazole was estimated to occur with tl/2 approaching 84
years. To date, a fluorine substituent appears to be the only one capable of providing the
necessary corn bin at ion of electro negativity and resonance overlap to perrnit facile exchange
by this alternative pathway (Path 2, Scherne 33). As a corollary of this, 2-fluoroirnidazole
resists nitration at 100 o C, but 2-fluoro-4-methylimidazole can be nitrated even at -60 o C.
This rernarkable behavior is consistent with the observed effect of the 4-rnethyl group in
prornoting isotope exchange in 2-fluoro-4-rnethylirnidazole: the carbonium ion (81) is
stabilized (79JOC4240).
398
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
Path 2
F H
H
NyNMe
H H H H D H+H
\-I + \-I D+---LY
/ - \ J2..- +/ - \ +/ \
NyNMe ..--- DNyNMe ..--- DNyNMe
H
.
D H
F H ì=\
J---YD NyNMe
NyNMe
F H
D+ D
NyNMe-
Path]
HoC H
);\D
N NH
c;F
(81)
Scheme 33
9.07.1.4.5 Halogenation
The results of halogenations of irnidazole and its derivatives have provided a host of
cornplicated but rnechanistically interesting results.
(0 Chlorination
It is only in the past 15 years that reports of imidazole chlorination have be corne at all
cornrnon. With chlorine, irnidazole gives 'undesired products containing carbonyl groups'
or 'poor yields of undescribed chloro cornpounds'. It has been suggested (76CBI62S) that
the rnajor product is 2,2,4,5-tetrachloro-2H-imidazole. Sulfuryl chloride, too, appears to
be incapable of forrning sirnple chloroirnidazoles. When, however, sodiurn hypochlorite is
ernployed under carefully defined conditions the product is 4,5-dichloroirnidazole. The
behaviour is sirnilar with 2-ethyl-, 2-rnethyl-imidazole and irnidazole-2-carboxylic acid,
while 4-brornoirnidazole gave the 4-brorno-5-chloro product. There is sorne evidence that
small quantities of 2,4,5-trichloroirnidazole are forrned in the further chlorination of 4,5-
dichloroirnidazole. In boiling chloroform N-chlorosuccinimide or N-chlorophthalirnide
converts irnidazole into the 4-chloro- (13 %) and 4,5-dichloro- (25 %) irnidazoles. 2-Methyl-
irnidazole behaves in a similar fashion, and 2,4-dirnethylirnidazole gives a 60% yield of
5-chloro-2,4-dirnethylirnidazole (B-76MI40701). In such halogenations, though it rnust be
adrnitted that the initial reaction probably involves radical species; once the reaction has
been initiated electrophilic chlorination can take over. Irnidazole anions are rnonochlori-
nated by hexachloroethane. When subjected to chlorination at 100-200 o C the 1-rnethyl-
2,4,5-trichloroirnidazole ring opens forrning perchloro-2,5-diazahexa-l,5-diene. When the
2-lithio derivative of 1-triphenylrnethylirnidazole is treated with chlorine a 39% yield of
the 2-chloro derivative is obtained (78JOC4381).
(ii) Bromination
By far the greatest arnount of study has been applied to the brornination and iodination
of irnidazoles and the benzologues. It is, however, becorning apparent that sorne of the
definitive results may have been based on earlier incorrect assignment of structure, par-
ticularly in the case of 2-iodoimidazole. Subsequent discussion here will endeavour to
exarnine sorne of these earlier results in the light of the presently available structural
inforrnation.
Irnidazole brorninates very readily; with brornine in aqueous solution or organic solvents
2,4,5-tribornoirnidazole is formed. With 1-alkylirnidazoles, too, it is difficult to prevent
brornination of all vacant ring positions. A feature of these reactions is the ease with which
a brornine will enter the 2-position, in sharp contrast to the situation in nitration. With
brornine in chloroforrn at -10 oC 4-methylirnidazole gives the dibrorno derivative along
with 34% of 4-brorno-5-rnethylirnidazole, but even under these mild conditions imidazole
Imidazoles and their Benzo Derivatives: (ii) Reactivity
399
gives the tribromo product along with traces of 4,5-dibromoirnidazole. Complete C-brorni-
nation occurs with a variety of substituted imidazoles: 2-rnethyl-, 4-rnethyl-5-nitro-, 2- and
4-ethoxycarbonyl- and 4-ethoxycarbonyl-5-methyl-. In aprotic solvents irnidazole is also
tribrorninated by NBS. It has proved possible to achieve direct rnonobrornination of
imidazole and 1-methylimidazole using the reagent 2,4,4,6-tetrabrornocyclohexa-2,5-
dienone; the brornine enters at C-4. A similar result is achieved when the anion of imidazole
reacts with carbon tetrabrornide. Using the former reagent the reaction products (Scherne
34) also include some 4,S-dibrorno- and 2,4,S-tribromo-irnidazoles. That these polybrorni-
nated species are forrned when only one rnolar proportion of the tetrabrornodienone is
used is a consequence of the equilibrium set up between irnidazole and 4-brornoirnidazole,
producing a conjugate base species susceptible to further bromination. Such an explanation
accounts for the cornparative resistance of 1-rnethylirnidazole to polybrornination. With
2,4,4,6-tetrabrornocyc1ohexa-2,5-dienone (1 rnole) a 60% yield of 5-bromo-l-methyl-
imidazole is obtained; with 2 moles of brorninating agent 65% of 4,5-dibrorno-1-methyl-
imidazole forrns, and only traces of other products can be detected (72JCS(P1)2567).
4-Arylirnidazoles are brominated at C-S and dibrorninated at C-2 and C-5;
4,5-diphenylimidazole gives the 2-brorno derivative.
o
/IN B O B Br N Br N Br N
_ ) + r I I r -- ( \\ + Brl[ \\ + Brl[)Br
N Br Br N/ N/ N
H H H H
o
41% 28% 27%
N Br N NH Br N
()+() I[) +()
N N N N
H H H -
Scheme 34
With bromine in chloroform imidazole forms a cornplex, (C 3 H 4 N 2 hBr+ Br3 -, in which
two imidazoles are joined to a bromoniurn cation through the N-3 atorns; 1-rnethylirnidazole
behaves in the sarne way. During the bromination of imidazoles there can be considerable
ring degradation which is enhanced by an increase in acidity of the rnediurn. Such reactions,
which are initiated by electrophiJic brornination, will be further discussed as oxidations
(Section 4.07.1.4.8)
As with the un substituted cornpounds, 1-alkylirnidazoles are so readily brorninated that
it is difficult not to obtain tribrornoirnidazoles. Again the 2-position brorninates with
rernarkable facility, although 1,5-dirnethylimidazole reacts less readily than the l,4-isorner.
When 1,4,5-trirnethylirnidazole is warrned with brornine in carbon disulfide a 22% yield
of the 2-brorno product is isolated. It may be that the reaction proceeds via an initial
N- bromination (or an addition-elimination reaction) as shown in Scherne 35. Such a
hypothesis is supported by the reaction of irnidazole with cyanogen brornide in which
2-bromoirnidazole and HCN are formed (but see Section 4.07.1.3.11). The involvement
of the ylide in this process is contraindicated since the second stage of the pathway would
have to be attack by Br+, a species which could not originate frorn BrCN. Whilst the
brornination of 4,5-diarylirnidazolin-2-ones leads ultirnately to ring opening, one of the
Me N
Me/[)
N
Me
r" CS" A,
[ yBr J
Me NB Me N Me N
!/ú.,\ r ---" f/ \'yH I[ \\
Mei(_ .kJ- H ..- Mei(/\ Me /Br
N ".. N Br N
Me Br- Me Me
l + yCN J
I[) /[ N H -HCN þ /[)Br
N N \..H "-N Br N
H H Br- H H
Scheme 35
400
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
initial processes is brornination of the aryl rings. In the case of 4,5-di(p-brornophenyl)irni-
dazolin-2-one the first product forrned appears to be (82; Scherne 36) (B-76MI40701,
70AHC(l2)103,80AHC(27)241).
Br qp ,,::: I ":::Br
ð ð
I \
NyN
o
Br,. HOAr Þ
+
HNVNH
OH
(82)
Schème 36
Deterrnination of the rate laws and isotope effects provides evidence that irnidazole is
brorninated via a rate-deterrnining birnolecular process which leads to the forrnation of a
Wheland interrnediate (78JCS(P2)865) between the neutral irnidazole rnolecule and rnolecular
brornine. The studies carried out by Coller's group ernployed halogenation by instalrnents
with coulopotentiornetric rnonitoring. In irnidazoles all three hydrogens were found to be
replaced with the order of reactivity 5> 4 > 2 (in agreernent with MO calculations). There
is still unexpectedly high reactivity at C-2, and it rnay be that an addition-elirnination process
is occurring. Rate constants, calculated using literature values of Ka, are listed in Table 5.
It appears that the relative rates of successive brorninations are pH dependent and it rnay
be possible to design conditions to obtain optirnum yields of partially brominated irnidazoles.
The lirnited effect of N-methylation (only fourfold across the 1,2- or 1,5-bond) contrasts
sharply with the effect of a 2-rnethyl group (180-fold between C-2 and C-5). Such differences
ernphasize the irnportance of bond fixation effects in heterocyclic compounds. Again, the
greater reactivity of C-5 towards electrophiles is evident frorn the relative reactivities of
the 4- and 5-brorno-1-rnethylirnidazoles.
Table 5 Bimolecular Rate Constants for Neutral Monobromination of Imidazoles and Benzimidazoles
(78JCSiP21865.74AJC2331)
kbix 10- 4 (dm 3 mol-! S-I)
Substrate C-2 C-4 C-5 C-7
Imidazole 20 40 50
I-Methylimidazole 80 170 230
2-Methylimidazole 9000 9000
5-Bromo-l-methylimidazole 4 36
4- Bromo-l-methylimidazole <10 460
2- Bromo-l-methylimidazole -240 -240
2,4(5)-Dibromo-l-methylimidazole 5 5
4,5-Dibromo-l-methylimidazole 0.16
Benzimidazole <0.0004 0.0935 0.004
I-Methylbenzimidazole 0.0879
2-Methylbenzimidazole 0.63
5 - B romobenzimidazole 0.004
The fused benzene ring in benzirnidazole deactivates C-2 to electrophilic brornination
by a factor of about 5000. However, rnost brornination occurs in the fused benzene ring
with the preferential order in rnultiple brorninations being 5> 7> 6, 4> 2, an order which
closely parallels that predicted by MO calculations. These reactions will be discussed in
rnore detail as substituent reactions (Section 4.07.3.1).
UU) Iodination
In aqueous alkali iodine reacts with irnidazole to give 2,4,5-triiodoirnidazole and sorne
of the 4,5-diiodo cornpound (the latter cornpound had been incorrectly designated as
2,4-diiodoirnidazole). The products isolated by Pauly on iodination of 4-rnethylirnidazole
are alrnost certainly 4-iodo-5-rnethyl- and 2,4-diiodo-5-rnethyl-irnidazole. Imidazole-4-
carboxylic acid gives 2,4,5-triodoirnidazole, but 1,4- (or 1,5- ?)-dirnethylirnidazole is not
susceptible to iodination. In alkaline rnediurn a nurnber of irnidazoles and benzirnidazoles
are subject to iodination on a ring nitrogen, giving rise to 1-iodo products, and it is these
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
401
which rnay be precursors to the ultirnate C-iodo products. In addition, it is possible that
the cornplexes forrned between rnolecular iodine and azoles could have sorne involvernent
in the process. The overall reaction rnechanism still has sorne regions of uncertainty, but
it seems clear that the rate-limiting step is nucleophilic attack by a base on the hydrogen
being abstracted from the u-cornplex (83). Such acceleration follows the nucleophilicity of
the base rather than its basicity. It seems likely that the initial step involves rnolecular
iodine (or perhaps 13") reacting with the irnidazole anion (Scheme 37). The involvement of
imidazole anions even at pH = 7 accounts for the failure of 1-substituted irnidazoles to
react. Iodination of 2,4,5-trideuteroimidazole showed a large kinetic isotope effect (k H / k D =
4.5), present also for 4,5-dideutero- but not for 2-deuteroirnidazole. The relative reaction
rates for the above three deuterated substrates proved that the initial substitution occurs
at C-4. Even in the presence of a large excess of irnidazole the rnajor product is still a
diiodoimidazole (alrnost certainly 4,5-diiodo-) (B-76MI4070l, SOAHC(27)24l). In fact, the
rnonoiodination of irnidazole has proved to be a difficult process. With iodine and iodic
acid, 5-chloro-1-methylirnidazole was converted into a rnixture of 27.5% of the 4-iodo and
12.7% of the 2,4-diiodo compounds. More recently the previously undescribed 2-
iodoimidazole (85) (Pauly's '2-iodoirnidazole' has been shown to be the 4-isorner) was
prepared in low yield (-5%) via the lithiation of l-benzenesulfonylirnidazole (84; R=
S02Ph) and in higher yield (40%) using the 1-trityl analogue (84; R = CPh 3 ; Scherne 38)
(7SJOC43Sl).
.N H t N
1 2 + ( ..) I ) + I-
N N
(83)
510!/
I N
r;;:) + BH
N
Scheme 37
[) BuLi Þ ()Li
N N
R R
(84) R = S02Ph, CPh 3
ii,H'"
) [)l
N
H
(85)
i,l"THF
Scheme 38
A detailed study of the kinetics of iodination of 2- and 4-rnethylirnidazole (SOJOC3l0S)
showed that, like the iodination of irnidazole, the reactions are base catalyzed, but whereas
2-rnethylirnidazole (and irnidazole) also undergoes uncatalyzed iodination, 4-rnethyl-
irnidazole does not. The relative rates for uncatalyzed iodination (irnidazole: 2-rnethyl-
irnidazole: 4-rnethylirnidazole) were 1: 28: 0; those for base-catalyzed iodination were
1: 34: 667. Further conclusions about the process of 2-iodination drawn from this study
have been rendered dubious in the light of the reassignrnent of 2,4- as 4,5-diiodoimidazole
(SUOC17Sl).
When histidine is iodinated, attack is again by iodine on the anionic species, and it occurs
at C-4; proton removal is again the rate-deterrnining step. With histidine and some of its
derivatives there is the added cornplication of hydrogen bonding being possible between
the side-chain and the nucleus, hence deactivating the anion. A nurnber of bases, including
imidazole, have been found to catalyze the iodination of irnidazoles, such catalysis depending
on the nucleophilicity of the bases in question. In the iodination of the Ni(II) cornplex of
irnidazole there is a negligible catalytic terrn since the base catalysis is elirninated by Ni-N
coordination. Rather, the reaction involves molecular iodine reacting with Ni(C 3 H 4 N 2 )2+ and
Ni(C 3 H 3 N 2 t species (B-76MI4070l).
In alkaline solution benzirnidazole iodinates at C-2. 1-Alkoxy-2-iodobenzimidazole is
forrned when the corresponding Grignard reagent reacts with iodine.
402
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
4.07.1.4.6 Acylation
It is a general rule that irnidazoles and benzirnidazoles are resistant to Friedel-Crafts
reactions. This is not surprising since such basic cornpounds rnust be rnarkedly deactivated
in the presence of Lewis acids. Imidazolin-2-ones appear to be an exception and apparently
possess sufficient activation to react. Reactions between irnidazoles and N- rnethylfor-
rnanilide and phosphoryl chloride are also unproductive. With 4,5-diphenylirnidazole,
phenyl isocyanate at 80 0 C gives products of both N- and C-substitution, but in boiling
nitrobenzene only the latter (86) is forrned. 2-Methyl-4-phenylirnidazole gives (87) under
the sarne conditions, and 1,3-diphenylirnidazoliurn perchlorate is transforrned by potassiurn
t-butoxide into a ylide which reacts at C-2 with phenyl isothiocyanate. Sufficient activation
is present in 1-methyl-2-phenyl-4-phenylarninoirnidazole for it to react by substitution at
C-5 with acetic anhydride (71JOC3368).
Ph Ph
F\
NyNH
CONHPh
(86)
Ph CONHPh
F\
NyNH
Me
(87)
Perhaps the rnost interesting exarnples of C-acylation or C-aroylation are those in which
a l-substituted imidazole reacts with an acyl or aroyl halide in acetonitrile in the presence
of triethylarnine (80AHC(27)241). The reaction rnay follow the sequence of Scherne 39.
Certainly the rnechanisrn has been shown to involve an initial N- acylation or -aroylation,
and electron-withdrawing groups in the acid halide assist the reaction. The process by which
the N- acyl intermediate rearranges appears to be intrarnolecular. Benzirnidazoles react
sirnilarly, as does 1-benzyl-5-rnethylirnidazole, but an exocyclic C-aroyl product is obtained
when there is a rnethyl group blocking C-2. When imidazole itself is subjected to the sarne
reaction conditions the product is a triacylirnidazolinylirnidazole (88). In order to prepare
2-acyl- or 2-aroyl-imidazoles with no ring nitrogen substituent, the acylation can be carried
out either on 1-rnethoxyrnethylirnidazole (here the N-substituent can later be rernoved
under conditions which do not affect the entering ketone function) or by a rnodification of
Regel's original conditions. Irnidazole reacts readily with two equivalents of aroyl chloride
in pyridine containing two equivalents of triethylarnine to give 2-aroylirnidazoles in 60-80%
yields (788675). Since 1-benzoylirnidazole (89; R = H) gives 2-benzoylirnidazole under the
sarne conditions it seerns likely that the powerful benzoyl chloride-pyridine adduct is the
acylating agent in this instance (Scherne 40). Apart frorn a large nurnber of aroyl halides
other acyl cornpounds such as ethyl chloroforrnate, phosgene and trifluoroacetyl chloride
(but not acetyl chloride) take part in the reaction. The presence of strongly electron-
withdrawing groups at C-4 of irnidazole prevents the reaction, probably by failing to assist
the initial N- acylation. Reactions of imidazoles at elevated ternperatures with isocyanates
show sorne resernblance to the foregoing. Irnidazolium ions, deprotonated by sodiurn
hydride, react with acetic anhydride to give 2-acyl products.
t N ço- ] N
[yc, -- [')COAr
N Ar N
R
[)
N
R
...NCOAr NCOAr
ArCOCI þ r;: ':\ [ \\
N'./"-..H -HCI N/- --
R cr R
Scheme 39
COR
N H
lNKfJ
COR N
COR
(88)
There has been scant attention paid to the carboxylation of irnidazoles. Irnidazole-4,5-
dicarboxylic açids can be prepared by the reaction of carbon dioxide with irnidazole (or
2-alkylirnidazoles) at 260 0 C under pressure in the presence of potassiurn carbonate and
cadrnium fluoride. 5-Arninoirnidazole, and sorne of its 1-substituted derivatives, and aqueous
bicarbonate are in equilibriurn with the 4-carboxylate (90). In acid rnediurn decarboxylation
occurs, but in the presence of excess bicarbonate carboxylation takes place (Scherne 41).
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
403
çr; + R O COCI
H
Et 3 N
pyridine
(r;
N
I
C=O
Ò
R
(89)
R O COCI. Et 3 N
pyridine
[)CO O R
H
Scheme 40
?
O-C
: - Ii NH
HmO '--If \\
. /
H 2 N N
R
-02 C NH
H N() +H 2 0
2 N
R
(90)
Scheme 41
Both carbon dioxide and potassiurn carbonate are ineffective in prornoting the reaction
(S-76MI40701).
4.07.1.4.7 Mercuration
References to rnercuration of irnidazole are notable for their scarcity. The ylide obtained
from 1, -diphenylirnidazolurn perchlorate is said to react at C-2 with rnercury(I1) chloride.
4.07.1.4.8 Diazo coupling
Diazo coupling is an electrophilic substitution reaction which occurs readily only with
activated substrates. Thus, N-unsubstituted irnidazoles react via the conjugate base species,
N- substituted irnidazoles fail to react, and irnidazoles with electron-withdrawing substituents
present in the ring are resistant to a greater or lesser extent. The interesting facet of this
reaction is that coupling, which takes place in alkaline mediurn, occurs preferentially at
C-2, although other ring positions are also reactive, e.g. 4-rnethylirnidazole gives approxi-
mately equal amounts of the 2- (91) and 4- (92) isorners and sorne 2,4-bis cornpound (93)
(Scherne 42). With irnidazole itself sorne tris coupling has been observed. The azo products
of the reactions are red, orange or yellow dyes which are of value for the detection of
N-unsubstituted irnidazoles on chromatographs, and for their spectrophotometric analysis
(70AHC(12)103). Diazotized sulfanilic acid is the coupling agent of choice in what has corne
to be referred to as the Pauly reaction. Irnidazole-4-carboxylic acid couples readily, but
derived esters and anilides do not; nitroirnidazoles will not couple, and imidazole-4,5-
dicarboxylic acids couple with the loss of one carboxyl group. Imidazolin-4-ones couple at
C-5.
Me N. Me N Me N Me N
() ArN,. ow ) [)N=NAr + ArN=N() + ArN=N()N=NAr
N N N N
H H H
(91) (92) (93)
Scheme 4
In the pH range 7-11 the coupling of irnidazole with diazotized sulfanilic acid is a
bimolecular reaction involving the irnidazole anion. For the corresponding reaction with
2,4,5-trideuteroimidazole there is a negligible isotope effect which shows that proton
rernoval is not involved in the rate-limiting step. This is one noteworthy difference frorn
the iodination reaction, while the observation that initial substitution is at C-2 constitutes
another. A possible explanation is that the charge density at C-2 in the anion is greater
404
Imidazoles and their Benzo Derivatives: (ii) Reactivity
than that at C-4; the localization energies, however, predict that clectrophiles should attack
C-4 (or C-5). In iodination the rate is determined by proton loss from the <T-complex, and
this follows the predictions of localization energies. Diazo coupling occurs preferentially at
the site defined by the electron density. The reactions are, however, complicated and the
above rationalization may be an oversimplification (S-76MI40701).
The rate of coupling of imidazole has been reported to be even greater in DMSO than
in water, but since the reactions involve the imidazole anion results are complicated by the
different acidities of the solvents.
Intramolecular diazo coupling occurs with 0-(imidazol-1-yl)phenyl diazoniurn salts (94)
which substitute at C-5 at pH 5-6 to give the irnidazo[5,I-c][1,2,4]benzotriazine (95;
Scherne 43). If the 5-position is blocked, coupling can occur (with greater difficulty) at C-2.
In these reactions the coupling does not take place at pH values of less than 4, and
consequently the unprotonated imidazole ring participates. The driving force for the reaction
could be the tendency for ring closure to produce the irnidazotriazine system (70AHC( 12)103).
()R NJ:)R
N --. II N
',6 N'Ò
(94) (95)
Scheme 43
4.07.1.4.9 Nitrosation
To date, there has been no report of the nitrosation of imidazole itself. There are, however,
a nurnber of examples of nitrosation of substituted irnidazoles in basic medium. The
observation that such reactions do not occur with N-substituted irnidazoles irnplicates the
imidazole anion as the likely substrate. Substitution generally occurs at C-4 or C-5 and
may be accompanied by sorne nitration. In the presence of sodium ethoxide, pentyl nitrite
nitrosates 4-phenyl-, 2-methyl-5-phenyl- and 2,5-diphenyl-imidazoles at the vacant 4- or
5-positions. The reaction apparently failed with 5-methyl-2-phenyl- and 4,5-diphenyl-
imidazoles (SSG463).
4.07.1.4.10 Reactions with aldehydes and ketones
When imidazoles substituted on nitrogen are treated with formalin, either neat or in a
solvent such as DMSO, hydroxymethylation takes place at C-4 (or C-5); I-substituted
irnidazoles react at C-2. Thus, 4-methyl- and 4-bromo-imidazoles give the 5-hydroxymethyl
derivatives (96): 1-methyl-, 5-halo-I-methyl-, I-benzyl-, I-aryl- and 1,5-dimethyl-
imidazoles give the 2-hydroxymethyl products (97; Scheme 44). 1,4-Dimethylimidazole,
however, is converted into the 5-hydroxymethyl derivative, but a number of imidazoles
with electron-withdrawing substituents, e.g. l-methyl-2- and -4-nitro-, fail to react.
Nevertheless, I-methyl-5-nitroimidazole undergoes hydroxymethylation at C-2 (79JHC871).
When heated in a sealed tube imidazole is hydroxymethylated by formaldehyde not only
at C-2, but also (in low yield) at the other vacant ring positions (Scherne 44). 1,2,4-
Trialkylimidazoles react at the 5-position. A change in reaction conditions to weakly acid
rnediurn (e.g. forrnate buffer) with 1,2-dimethylimidazole gives a 25-50% yield of a rnixture
of the 5- and 4,5-dihydroxymethylimidazoles; sealed tube reaction gives a low yield of the
forrner product. The reaction mechanism could involve either direct attack by forrnaldehyde
at the ring carbon or N- hydroxymethylation followed by rearrangement. The interrnediacy
of a quaternary salt would have to be conceived for I-substituted irnidazoles (and perhaps
also for N-unsubstituted cornpounds), but this is not too dissimilar to the acylation reactions
in acetonitrile with triethylamine (Section 4.07.1.4.6). Thermal condensation of N-
substituted imidazoles with other aldehydes (except acetaldehyde) or reaction of aldehydes
with 2-lithio- or 2-trimethylsilyl-imidazoles also results in the production of 2-hydroxy-
rnethylimidazoles (SOAHC(27)241).
Imidazoles and their Benzo Derivatives: (ii) Reactivity
405
R 4 R 4
[ N CHO [ N
I N) HOCH 2 I N)
H H
(96)
R S [)
N
R'
CH 2 0) R S Ç)CH 2 0H
R 1
(97)
N HOCH [ N
CH 2 0 [ \\ 1 \\
sealed tube ) /CH 2 0H + HOCH 2 /CH 2 0H
N N
H H
Scheme 44
The related Mannich reaction is not cornrnon. Under the usual acidic reaction conditions
N-substitution occurs, but this is a reversible reaction in the presence of base. Therefore,
in basic rnedium, C-substituted products accumulate, and all positions can be substituted.
2-Methylirnidazole gives 1,4,5-tri, 4,5-di- and 4-rnono-substituted products. The observa-
tion that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with
the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it
is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain
activating substituents they are not very susceptible to reaction with aldehydes (except
HCHO) and ketones. An exception appears to be the product (99) of interaction between
imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-
thione gives the 5-dimethylamino compound (100); imidazoline-2-thione gave only the
N- hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a
free 5-position readily form benzylidene derivatives (B-76MI40701).
[)
N
H
(X N N MeN
HRN I N> (ÑJ Me 2 NCH 2 ()SH
H Me H
(98) R = H, COzH (99) (100)
Both benzimidazole and l-acetylbenzimidazole react with diketene to form products of
N- 3 and C- 2 acetylation.
4.07.1.4.11 Oxidation
The imidazole ring is not at all susceptible to oxidation, although the parent compound
can be degraded by permanganate to formic acid and carbon dioxide, as can sorne derivatives.
An exception to the usual resistance to chromic acid oxidation is the conversion of
4,5-diphenylimidazoline-2-thione into dibenzoylurea; nitric acid converts the same com-
pound into benzil. While hydrogen peroxide has been reported to oxidize some imidazoles
to oxamide, under alkaline conditions it transforms 4-ethyl-2-phenylimidazole into 5-ethyl-
3-phenyl-l,2,4-oxadiazole along with some carbonate, benzoate and propanoate. Although
this appears to be a general reaction for a number of 2,4-disubstituted imidazoles, 4,5-di-
and 2,4,5-triphenylimidazoles are unaffected, and both 2- and 4-phenylimidazoles forrned
only benzoic acid, perhaps via the oxadiazoles. Perbenzoic acid transforms imidazole into
ammonia and urea; direct N-oxidation of imidazoles does not occur and the synthesis of
imidazole N- oxides can be a difficult procedure.
Benzimidazole (but not l-methylbenzimidazole) is oxidized by permanganate, dichromate
or hydrogen peroxide to imidazole-4,5-dicarboxylic acid, while napth-[1,2-d]- and -[2,3-d]-
imidazoles also form products in which the heterocyclic ring remains intact, hence demon-
strating its stability to these conditions. With lead peroxide benzimidazole is subject to an
unusual oxidation as it forms (101), also the reaction product of lead dioxide and 2,2'-
bibenzimidazolyl. In dioxane, selenium dioxide oxidizes 2-methylbenzimidazole to 0-
hydroxyacetanilide (66RCR122).
o: o--N>=<N-- :O
::::::,... o--.N N--" #
(101)
406
Imidazoles and their Benzo Derivatives: (ii) Reactivity
Oxidative degradation of the imidazole ring can accompany certain electrophilic substitu-
tion reactions such as bromination, and perhaps nitration. When NBS reacts in aqueous
rnedium with imidazole and its 4-substituted derivatives, arnmonia, glyoxal (or the appropri-
ate 1,2-dicarbonyl compound) and formamide can be detected among the reaction products.
The aqueous conditions suggest that this ring degradation may be initiated by nucleophilic
attack. In boiling acetic acid 4,5-di(p-brornophenyl)imidazolin-2-one reacts with bromine
to give (82; Scheme 36). Hydrolysis of this product forms urea and 4,4'-dibrornobenzil,
while reaction of the urea with 4,5-diacetoxy- or 4,5-dihydroxy-4,5-di(p-brornophenyl)-2-
imidazolidinone from (82) gives rise to glycouril (102). Histidine is degraded to iodoforrn
and oxalate during iodination.
#
Br
(102)
The oxidation reactions of 2,4,5-triphenylirnidazole (lophine) have received considerable
attention. With chromic acid it gives benzarnide and benzanilide, but even rnore interest
has centred on its involvernent in the phenomenon of chemiluminescence. Some of this
rnaterial has been discussed earlier (Sections 4.06.3.6, 4.07.1.2.1 and 4.07.1.2.3). The
oxidative decomposition of lophine in the presence of air is accompanied by the ernission
of light, and it is the excited singlet state of the diaroylarylamidine (12; Scherne 2) which
is the light emitter. The radical (46) derived from oxidation of lophine with aqueous
ferricyanide and ethanolic KOH forms a hydroperoxide with hydrogen peroxide with
consequent luminescence. When 2,4,5-tri- and 1,2,4,5-tetra-phenylimidazoles are oxidized
in dilute methanol solution in the presence of methylene blue, the dibenzoylbenzarnidine
is also formed under circumstances in which hydroperoxides cannot be interrnediates
(B-76MI40701).
When phenylimidazoles react with singlet oxygen, although there is some evidence that
2,5-endoperoxides or zwitterionic intermediates may be formed initially, the products which
are isolated (Scheme 45) appear to arise from the decomposition of hydroperoxides or
dioxetanes (8IT(S9)191).
Ph[)
N
H
o 0
hv 0 Ph -}-NH II
M:O . )(..A + H0 2 CNHCNHCOPh
MeO N 0
H
15% 2%
Ph[)Ph
N
H
o
: O . Ph1:)Ph
MeO N
H
29%
Scheme 45
Reactions of the sodiurn salts of 2,4,5-triarylimidazoles with bromine and oxidations of
N- hydroxybenzimidazoles to cyclic nitroxyls have been discussed elsewhere (Section
4.02.1.4.11).
4.07.1.5 Nucleophilic Attack at Carbon
Nucleophilic reactions on imidazoles are not at all facile unless the ring is activated to
such attack by an electron-withdrawing group or in some other way such as in the reactions
Imidazoles and their Benzo Derivatives: (ii) Reactivity
407
of the quaternized compounds. Furtherrnore, a fused benzene ring (as in benzimidazole,
benzimidazolium and benzimidazolinone) aids such reactions since any loss in aromaticity
during the reaction is minimal compared with the monocyclic analogues.
MO calculations predict that in unsubstituted imidazoles and benzimidazoles the 2-
position should be the most susceptible to nucleophilic attack and quaternization of the
heterocycle should enhance this orientation. The presence of electron-withdrawing groups
elsewhere in the molecule can modify this preferred site of attack.
Some of the reactions described below lead to products of nucleophilic displacement;
others result in ring opening.
4.07.1.5.1 Hydroxide ion and other O-nucleophiles
(i) Neutral imidazoles
As rnentioned earlier (Section 4.02.1.6.1) 1-substituted 4,5-diphenylimidazoles react at
300 oC with hydroxide ion to give the imidazolin-2-one. The reaction of a neutral imidazole
with hydroxide ion, however, rarely leads to hydroxylation. Both 1,2-dimethyl-4- and
-5-nitroimidazoles show signs of reacting with hydroxide ion, and arnmonia is produced on
prolonged heating. Bis(1-benzimidazolyl)alkanes (103) are hydroxylated to (104) by
potassium hydroxide as long as the linking hydrocarbon chain is at least three carbon atoms
long (Scheme 46). Compounds with n = 1 or 2 decompose under the influence of KOH.
The reason is probably not steric but rather a function of the greater pKa values of the
cornpounds in which n = 3-5 allowing easier reaction with the K+ ion (nCHE12S0). At high
temperatures (-250 oc) 2-alkyl and 2-aryl groups of benzimidazoles can be replaced by
hydroxy groups (Scheme 46) (76CHE437). Whereas bulky groups at N-1 do not significantly
hinder amination (Section 4.07.1.5.2), they exert a much greater influence on hydroxylation.
Thus, whilst 1-isopropylbenzimidazole gives a 33% yield of the benzimidazolone at 250-
290 oC with potassium hydroxide, the l+butyl compound resinifies. Groups such as nonyl
and decyl with no branching provide little steric hindrance to the reaction.
H
N>=O
N
I
(CHz)n
I
N>=O
N
(104) H
N)
N
I
(CHz)n
I
(X)
(103)
N)R
N
Me
(X
þ 1)=0
N
Me
KOH
250'C
R = alkyl, phenyl
Scheme 46
There are a few examples of displacement of groups other than hydrogen by hydroxy.
Halogen atoms, particularly at C-2, are replaced by hydroxyl, as are sulfo groups. However,
hydroxide ion (or thiolate anion) often causes decomposition. The cleavage of a 5-
nitroimidazole derivative by hydroxide has been ascribed to nucleophilic attack at C-4.
Recently, this instability of 1-alkylnitroimidazoles has been examined and it was found that
the rate of decomposition increases sharply with the base concentration and temperature
(SOAHC(27)241). Under comparable conditions it can be demonstrated that 1-methyl-4-nitro-
and 1-methyl-2-nitro-imidazoles are 50-150 times more stable than the 1-methyl-5-nitro
isomer. In view of the postulate that the first step in the breakdown of the 4- and 5-nitro
compounds is ß-addition of hydroxide ion to the 4,5-bond leading to (105) and (106),
respectively, the greater stability of the 4-nitro compound may be a function of the fact
that (105) cannot form so readily-it is subject to an adjacent lone pair effect not present
in (106) (7SJûC3570). However, this argument may have less validity if the negative charge
resides on the nitro group (Section 4.06.3.7).
NO z H OH
K
:NyNMe
(105)
HOJ-<._NO Z
:NyNMe
(106)
408
Imidazoles and their Benzo Derivatives: (ii) Reactivity
When the mild fluorinating agent, xenon difluoride, reacts with 2,4,5-tribromo-l-methyl-
imidazole the product is I-methyl-2,4,5-imidazolidinetrione, formed by successive fluorina-
tion and hydrolysis steps (79JGUl251). There are frequent references to the replacement of
a halogen atorn by alkoxy, hydroxy or aryloxy groups, particularly in irnidazoles which
already carry a nitro (or adjacent formyl) group. The developrnent of blue-green colours
during the reaction of alkoxide with 4-brorno-1,2-dimethyl-5-nitroirnidazole has been
attributed to the formation of the interrnediate complex. However, the corresponding
5-brorno-4-nitro cornpound failed to react under the sarne conditions.
The forrnation of I-benzyl-4,5-dimethylirnidazolin-2-one (107) when acetic anhydride
reacts with I-benzyl-4,5-dirnethylirnidazole 3-oxide parallels sirnilar reactions in the
pyridine series (Scherne 47).
0-
Me +/
I/N
Me'N)
CH 2 Ph
[ ÇOAC ]
Me N Me N Me NH
AC20 1/ H -HOAc [ " H'/H 2 0. [ ,
--=-+ Me'_.A Me /OAc..--- Me O
N OAc N N
CH 2 Ph CH 2 Ph CH 2 Ph
(107)
Scheme 47
One important point regarding relative reactivities of N-unsubstituted and N-substituted
2-chloroimidazoles with powerful nucleophiles such as alkoxide is that in the former there
is competition between proton abstraction from N-l (which severely harnpers any
nucleophilic attack at C-2) and the nucleophilic substitution at the 2-position. Thus, chloride
is not displaced from 2-chlorobenzimidazole by alkoxide ions, whereas 2-chloro-l-methyl-
benzimidazole reacts readily. That steric effects can also be important is evidenced by the
lack of reactivity of 2-chloro-l-methylbenzimidazole with t-butoxide, and similar resistance
to nucleophilic attack of 2-chloro-1-isopropylbenzirnidazole. Alkoxide readily displaces
chloride from 2-chloro-l-isopropenylbenzimidazole, and the N-substituent may be removed
subsequently by oxidative cleavage (74CRV279).
There appear to be no examples of displacement of amino or diazonium by hydroxy
groups.
(ii) Azoliurn ions
The forrnation of pseudo bases when N- methylazoliurn ions react with hydroxide has
been discussed earlier (Section 4.02.1.6.1). Alkalies convert imidazoliurn and ben-
zirnidazolium species (via these pseudo bases, e.g. 108) into alkenes or o-disubstituted
benzene derivatives (Scheme 48) by attack at the 2-position. Such a process is responsible
for the Bamberger degradation reaction in which benzoyl chloride in alkaline rnedium
cleaves the irnidazole ring to forrn a 1,2-dibenzamidoethylene (109; Scherne 48). The
interrnediate formation of a 1,3-dibenzoyl quaternary salt, readily attacked by hydroxide
ion, is assumed. It is this reaction which prevents the employment of Schotten-Baurnann
conditions for the acylation of imidazoles. The reaction is also general for benzirnidazoles
which are converted into amides of o-phenylenediamine. When a non-hydroxylic base is
used, 2-acylimidazoles can be prepared (Section 4.07.1.4.6). A kinetic study of the Barnber-
ger cleavage of imidazole and histidine derivatives by diethyl pyrocarbonate in aqueous
solution has indicated that at low concentrations of the acylating agent, the carboxyethylation
t-N '>ï-NCOPh NCOPh
)(J Ph 11 )() J(X H
N N N rOH
H COPh COPh\y
(108)
1
rN,H weak alkali
.J(_ . stow
N 0
COPh
XNHCOPh
NHCOPh
(109)
Scheme 48
ìíNHCOPh
.H 2 0 J
NCHO
I
COPh
Imidazoles and their Benzo Derivatives: (ii) Reactivity
409
is rate deterrnining; at higher concentrations the breakdown of an intermediate resembling
(108) becomes the slow step. If the solution is only weakly alkaline the diacyl- or diaroyl-
alkene (109) can recyclize slowly to give a 2-imidazolinone (81TL2431).
There have been a number of studies of the behaviour of benzirnidazolium species with
nucleophiles, and ring opening is especially easy when there is a 1-(2,4-dinitrophenyl)
substituent. Even weak bases such as aniline or pyridine can effect the transforrnations.
Under the influence of benzoyl chloride in aqueous alkali, 1,2-disubstituted benzimidazoles
are cleaved in a rather complex reaction. Provided that a methylene or rnethyl group is
present at C-2, compounds of type (110) result (Scheme 49) (74CRV279).
(XI N PhCOCI 0 1 NHCOPh (XI N _ /Ph
/Me NOH + /CH-C
:::::,.... N a NCOMe N "OCOPh
Ph Ph Ph
(110)
Scheme 49
In what appears to be a related reaction, benzirnidazole N-oxides give rise to ben-
zirnidazolinones as by-products when treated with an acyl halide in the presence of alkali.
With tosyl chloride the sole product is the benzimidazolinone (111) which rnay be formed
as in Scherne 50. The C - N rearrangement could also take place via the oxaziridine
(112) (73JCS(P1)70S).
R(X:;:;' '. R(X R (YZH R (YN):)H,),
N N N -OH N----..-/
6- 6Ts 'ÒTS (111)
r(CHz)n
R(X
(112)
Scheme 50
In addition to products of ring opening, the alkaline hydrolysis of 1,3-dimethyl-4-
nitrobenzimidazoliurn salts gives the benzimidazolinone and 4,4' -azoxybis( 1 ,3-dimethylben-
zimidazolin-2-one). The Wheland intermediates (113) formed in the arnination of imi-
dazolium and benzimidazoliurn species are also subject to hydrolysis reactions which
ultirnately lead to the formation of pseudo bases (Scherne 51).
R R
N\/H N'vH 0 1 NHR
Nj\.NHz Nj\.OH -. NCHO
R R R
(113)
Scheme 51
4.07.1.5.2 Arnines and amide ions
(i) Azoles
Usually amines are too weakly nucleophilic to react with imidazoles and benzimidazoles
unless there are activating groups present elsewhere in the molecule. For this reason, rnost
successful ami nations have utilized the NHR- anionic species. Imidazole itself cannot be
directly aminated at C-2, nor do 1-alkyl-4,5-diphenylimidazoles react with sodamide. In
reaction with alkaline hydroxylamine, 1,2-dimethyl-4- and 1,2-dimethyl-5-nitroimidazole
give respectively the 5- and 4-amino derivatives, with replacernent of H-4 seemingly more
facile than H-5. It is only condensed imidazoles which will enter the Chichibabin reaction
(74CRV279). Thus, the reaction of sodamide in xylene with 5-methoxy-1-methylben-
zimidazole gives a good yield of the 2-amino product (114; Scheme 52), a reaction which
410
Imidazoles and their Benzo Derivatives: (ii) Reactivity
can be cxtcndcd to a widc varicty of N-substitutcd bcnzirnidazolcs and naphthirnidazoles.
Benzimidazoles react more readily than pyridine as long as the ring nitrogen is substituted.
When it is not, the anion formed initially frorn the heterocycle cannot be subject to
nucleophilic attack, and so the reaction fails. The comparison with pyridine was deduced
frorn the reactions of (115) and (116) with sodamide. On the basis of NMR data for the
two bases, it was concluded that the reason for the greater reactivity of benzimidazole is
the greater polarizability of the C=N bond in benzimidazole during coordination with the
sodarnide (ncHEl131).
Meo N NaNH2 Meo N NH2
N N
Me (114) Me
N
N
I
ò'
N
N
I
(CH 2 )n
Ò
N
(116)
(115) n = 0, 2
Scheme 52
When l-arylbenzimidazoles take part in the reaction there is often an accornpanying ring
opening of the imidazole moiety, and reductive debenzylation of a I-benzylirnidazole or
I-benzimidazole can also occur with sodamide. The arnination of N-alkylbenzimidazoles
is affected by a substituent at C-5; thus, while 5-alkyl and 5-alkoxy derivatives are arninated,
those with halogen, hydroxy, nitro and carboxy groups at C-5 are resistant (66RCR122).
When there are two methoxy groups in the fused benzene ring the situation becomes rnore
cornplex. Cornpounds with two rnethoxy groups ortho to each other (viz. I-benzyl-5,5-,
-6,7- and -4,5-dimethoxybenzirnidazole) fail to react with sodarnide with the exception that
all experience some demethylation, and the last named, surprisingly, gives a 75% yield of
benzirnidazole. The other dimethoxy compounds (substituted 4,7, 4,6 and 5,7) substitute
norrnally to give the 2-amino product (71CHE1036). The process of arnination is also affected
to some extent by the substituent on N-!. If there is some branching at the a-carbon of
this substituent (e.g. isopropyl, a-phenylethyl) the retarding effect is only rninimal and good
yields are obtained as long as excess sodamide is used and the reaction time is lengthened.
Reaction, however, is much more difficult when there is a I-t-butyl group present. Although
at first glance steric factors may appear to be responsible there is sorne evidence that the
basicity of the heterocycle rnay be the controlling factor. Amination of cornpounds (103;
Scheme 46) parallels the hydroxylation behaviour.
Under vigorous conditions (NaNHz, 250 OC) a 2-alkyl or 2-aryl group in l-rnethylbenz-
irnidazole can be replaced by amino, although other products are also forrned (Scheme
53) (76CHE437).
N R NaNH2 N NH2 + 0 1 NH2 + NH2
N/ -RH N/ NHMe H2
Me Me
Me
+ cr:}-< J)
Me
R = alkyl, Ph
Scheme 53
In contrast to the limited range of examples of replacement of a hydrogen atorn by amino,
the replacement of halogen is much more cornmon. In the non-condensed imidazoles
difficulty rnay still be experienced, but electron-withdrawing groups on adjacent ring carbons
usually ensure the successful outcome of such reactions. Thus l-alkyl-4-halogeno-5-nitro-
and l-alkyl-5-halogeno-4-nitro-imidazoles react with ammonia and amines, 2-brorno-l-
rnethyl-5-nitroimidazole reacts with boiling piperidine and l-alk'yl-2-bromo-4,5-diphenyl-
imidazole reacts by displacement of brornine with arnrnonia and a variety of alkyl- and
aryl-amines in an autoclave or in DMF. In a sealed tube at 80 0 C 4-chloro-1-rnethyl-5-
Imidazoles and their Benzo Derivatives: (ii) Reactivity
411
nitroimidazole reacts with cyclic secondary amines to give some 4,5-diamino product. The
behaviour of 5-bromo-4-sulfonamidoimidazole is interesting; arnmonia replaces the
bromine by amino, while ethanolic ammonia at 180 ot (or diethylamine) also displaces the
sulfonamido group. Nitro groups are particularly efficient in promoting such nucleophilic
substitutions as the above, in fact more effective than an extra annular nitrogen. When
treated with piperidine both 2-bromo-1-methyl-5-nitro- and 5-bromo-1-methyl-4-
nitro-irnidazoles are rnuch more reactive than 5-bromo-1-methyl-l,2,4-triazole. Although
2-bromo-1-methylimidazole is fairly resistant to reaction with piperidine (1-methyl-2-
piperidinoirnidazole is forrned after 60 hours at 200 OC), the 5-chloro and 5-bromo isomers
(117) are even less reactive and require the much more nucleophilic lithium piperidide for
any substitution to be achieved (B-76MI40701). The 4-halo isomers are so unreactive that
they give no trace of either the 2- or 4-piperidino compounds. The following reaction
products were reported from reaction of 5-chloro- and 5-bromo-1-methylimidazole (117)
with lithiurn piperidide in ether (71RTC594): from (117; X = Cl), 5-chloro-l-rnethylimidazole
(70%), 4-chloro-l-methylimidazole (trace), l-rnethyl-5-piperidinoimidazole (15-20%), 1-
methyl-2-piperidinoimidazole (118) (3-5%); the yields of the corresponding four com-
pounds from (117; X = Br) were 49, 30, 25 and 16%, respectively. The possibility that a
hetaryne-type mechanism might be operating is negated by the absence of any 4-piperidino
product, while the 4-halo products are probably a r sult of normal base-induced isomeriz-
ation of (117). The formation of (118) may be accounted for in terms of the pathway shown
in Scheme 54.
Li
xl[) U+pip- Þ H. :C3< % H
N N_)(PIP N pIP H N Me
Me Me Me Me
(117)
X=Cl, Br
PiP=NJ
..:.!:!.+ I[ .
/PIP
N
Me
(118)
Scheme 54
The reaction of 5-bromo-1-methylimidazole with potassium amide in liquid ammonia
does not result in nucleophilic substitution, but rather in migration and elimination of
halogen producing a rnixture of I-methyl- and 4-bromo-1-methyl-imidazole. Usually, a
2-chloroimidazole will be quite unreactive in the presence of an amine, and even the
corresponding 2-bromo derivatives need very forcing conditions to effect substitution.
2-Chlorobenzimidazoles, too, only react sluggishly. A study of the effects of benzo-annula-
tion on the amination of compounds (119)-(122) gave relative rates of 383: 12: 1 : 0 for
displacernent of chlorine. It is noteworthy that in the Chichibabin reaction, which involves
replacement of the much more tightly bonded hydrogen, the order of reactivity is quite
different with (121) > (120) > (119); compound (122) does not react (79CHE218). However,
in the presence of copper salts the reactions are assisted to the extent that 2-chloroben-
zimidazoles (121) and 2-chloroimidazoles (122), albeit less readily, undergo nucleophilic
substitution. The reaction may be accompanied by some dehalogenation (Scheme 55).
N>Cl
N
Me
C(x ":::
-;:?' N
I >Cl
N
Me
(119)
(120)
(X N
I >Cl
N
Me
(121 )
N
![)CI
Me
(122)
Ph N
Phl[)Cl
N
Me
Ph N Ph N
Me2NH,7.5h þ I[ \\ + I[ \\ +
CU2Br2 Ph /Cl Ph /
N N
Me Me
11 % 60%
Ph N
Ph![)NMe z
Me
25%
Scheme 55
412
Imidazoles and their Benzo Derivatives: (ii) Reactivity
The 2-halo-substituted benzimidazoles, then, rnore or less readily react with arnmonia,
arnines and hydrazines (SOAHC(27)241, 70AHC(12)103, 74CRV279). It is likely that the forrnation
of the 2-pyridinium compound (123) when cycloheptimidazolin-2(lH)-one reacts with
phosphoryl chloride in pyridine occurs via the 2-chloro interrnediate (Scheme 56). The
sulfur function of benzimidazole-2-sulfonic acid can be displaced by arnino or alkylamino
groups.
N
N>=O
H
POCI, ) N,\ N Q + Cl-
pyridine :r _
(123)
Scheme 56
(m Irnidazoliurn and benzimidazoliurn ions
In the cationic forms the compounds are more readily attacked by arnines, particularly
the benzimidazoles. Thus, benz- and naphth-[1,2-d]imidazoliurn salts substituted at N-l
by a 2,4-dinitrophenyl group substitute at C-2 even with bases as weak as aniline and
pyridine. Less activated salts such as 4,5-diphenylirnidazolium require rnore severe condi-
tions. In the reactions of potassium amide with 1,3-dimethyl-irnidazolium and -benz-
irnidazolium salts the difficulties of arornatization of the adducts (113; Scheme 51)
mean that they tend to undergo a variety of alternative transformations, the chief of which
is hydrolysis to pseudo bases (76CHE304). However, the fundarnental possibility of amination
of such cations by KNH z is demonstrated in the case of 1-methoxybenzirnidazolium (124;
Scheme 57). The general scope of the reaction of (124; R = Me) with nucleophiles has been
studied. Yields are generally very high, and the process is useful in the preparation of
2-alkylarninobenzirnidazoles. It is likely, though, that the reaction mechanisrn cannot be
described in terms of a simple addition-elimination process. Rather, it rnay involve carbene
interrnediates. When treated with triethylamine in acetonitrile (124; R = Me) gave a 64%
yield of the bibenzirnidazolyl 3-oxide (Scherne 57) (74CRV279).
OMe
OMe '-I
(X I )H KNH,) (X I NXH (X I N NH2
N 1- N NH 2 N
R R R
(124)
X-jfI-
r9 Me
(X 2 Me (X (X N
I + - + HX +-+ I 7? --+ I X
N N N
Me Me Me
1
[ OMe l
OMe OMe q
(X >-{X) (X >=\X)
Me Me Me Me
'\-
0-
(X N X)
I +X I
N N #
Me Me
Scheme 57
Methylthio groups at C-2 of imidazoliurn have been displaced by arnines.
Imidazoles and their Benzo Derivatives: (ii) Reactivity
413
4.07.1.5.3 S-Nucleophiles
5-Halogeno-4-nitro- (and -4-formyl-) imidazoles, whether or not substituted at N-l by
methyl, react with ammonium sulfite or thiols to give the corresponding sulfur derivatíves.
Other successful reagents have been sodium or amrnoniurn sulfide and thiourea. Conversion
of halogen-substituted irnidazoles into the sulfonic acids by treatment with sulfite succeeds
only when extra activation is present in the ring; otherwise the sulfur compound merely
reduces the halogen compound. For this reason sodium sulfite produces only a small quantity
of 5-bromoimidazole-4-sulfonic acid when it reacts with 2,4,5-tribromoimidazole. When
there is a nitro group present as in 5-bromo-4-nitro- or 5-chloro-1-methyl-4-nitro-imidazole
(but not 2-bromo-l,5-dimethyl-4-nitroimidazole) the sulfonic acids can be prepared by
halogen displacement. A carboxyl group is much less effective in assisting these reactions.
Nucleophilic displacement of halogen by thiophenol occurs in 1-substituted 2-
halogenobenzimidazoles and in 1,3-diakyl-2-chlorobenzimidazolium tetrafluoroborates.
The reactions of 4-haloimidazolium salts with sulfide or methanethiolate ions are accom-
panied by some replacement of halogen, but reduction and ring cleavage to give N-methyl-
thioamides can also take place.
While the fluoro group in 4-fluoroimidazoles is stable in the presence of nucleophiles, a
2-fluoro group is labile under fairly mild conditions. The ease of displacement by thiol is
doubtless due to the interrnediate formation of the symrnetrical2-fluoroimidazolium cation
(125) which is subject to addition-elimination processes (Scheme 58) (SOAHC(27)241,
B-76MI40701).
r==\ RSH A RS- A -F- F\
NVNH ===' HN0-NH -- HN ' NH HN0-NH
F F SR
(125) RS F
Scheme 58
4.07.1.5.4 Halide ions
While nucleophilic replacement of hydrogen by halogen is unknown in these compounds
there are a number of examples of other groups which are displaced by halide and related
nucleophiles.
The most common is the conversion of imidazolinones and benzimidazolinones into the
halo compounds. Phosphoryl chloride transforms 4,5-diphenylimidazolin-2-one (126) into
the 2-chloro compound, and the reaction is even more rapid with benzirnidazolinones
(66RCR122). The same reagent will convert imidazole N-oxides into 2-chloroimidazoles
(Scheme 59) (see Section 4.02.1.6.4).
Ph NH Ph N
Ph(A Ph[.')Cl
NON
H H
(126)
0-
Me ( MeN
[ \\ POC], ( \\
Me / ----'-+ Me /Cl
N N
CHzPh CHzPh
Scheme 59
Halogen replacement by another halogen is also quite common. At 150 0 C 2,5-
dibromoimidazole-4-carboxylic acid reacts with hydrochloric acid to give a rnixture of chloro
compounds, but 2,4,5-tribromo- and 2-bromo-4,5-dichloro-imidazoles in boiling HCI gave
2,4,5-trichloroimidazole. With potassium iodide in DMF 1-alkyl-4-chloro- (or bromo-)
5-nitroirnidazole gives the 4-iodo analogue. Replacement of bromine by fluorine has been
reported; xenon hexafluoride converts 2,4,5-tribromoimidazole into the trifluoro compound
(79JGU1251), but 4-fluoroimidazoles could not be prepared by halogen exchange (using KF,
CsF, AgF) on 4-bromø-5-nitro- or 4-bromo-5-ethoxycarbonyl-imidazoles. Nor can a
chlorine atom be displaced in this way (SOAHC(27)241).
Sulfo and hydrazine functions at C-2 of benzimidazoles can be replaced by chloro. The
decomposition of imidazolediazonium fluoroborates might be expected to lead to
fluoroimidazoles, but such diazonium salts are remarkably stable to heat. However, UV
414
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
irradiation of the cornpounds leads to 30-40% yields of the corresponding fluoroirnidazoles.
The reaction works well for 2- and 4-fluoro- and 2-chloro-imidazoles, but fails for the
brorno- and iodo-azoles (78JOC4381). The forrnation of stable diazo compounds rnay also
account for the reluctance of the Sandrneyer reaction to operate when ethyl 5-
arninoirnidazole-4-carboxylate is diazotized in the presence of copper(l) chloride; only low
yields of the 5-chloro products are obtained. However, 1-substituted 5-arninoirnidazoles
give diazoniurn salts which are rnuch rnore reactive giving good yields of the 5-
chloroirnidazoles (80JCS(PI )2310).
When there is more than one nitro group present in an irnidazole ring, halogenodenitra-
tions are possible with the displacement order being 2-N0 2 > 5-N0 2 > 4-N0 2 (Scherne 60).
Phosphoryl chloride in pyridine or DMF is successful for 4,5-dinitro cornpounds, but only
the latter solvent is suitable for 2,4-dinitroirnidazoles (80AHC(27)241).
02 N N
Ç)N0 2
H
HBr
-
02 N N
()Br
N
H
02 N N
ij \\ POCI, )
02N,_ /N0 2
N
H
02 N N
Cl()Cl
N
H
02 N N 02 N N
ij \\ ij \\
02 N 'N./ Br<':"N./
Me Me
Scheme 60
4.07.1.5.5 Carhanions
(i) Activated methyl and methylene carbanions
Few exarnples of this type of reaction exist, but the chlorine atorn of 5-chloro-l-rnethyl-4-
nitroirnidazole is replaced in reaction with sodiomalonic ester. The reactions of 1,3-
diacylirnidazolium at C-3 of a 1,2-disubstituted indole provides a further exarnple of this
type; such reactions are used in the synthesis of arornatic aldehydes. The reactive arornatic
cornpound (pyrrole, indole, thiophene, anisole) reacts with 1,3-diacyl-irnidazoliurn or
-benzirnidazoliurn to give the 2-substituted 1,3-diacyl-4-irnidazoline. Alkaline hydrolysis
of this gives the aldehydes (Scheme 61) (80T2S0S).
r=\ NH r=\ 0
I \ I \ ow
CF 3 0CN-(;;-NCOCF 3 --- CF3CON >ö NCOCFJ - y CHO
H N
H N H
Scheme 61
(ii) Cyanide ions
In 1-rnethylirnidazoles, nitro and rnethoxy groups, especially at C-5, can be replaced by
cyanide in nucleophilic photosubstitution reactions. The following products and yields have
been reported: l-rnethyl-5-nitroimidazole gives 5-cyano-1-rnethylirnidazole (65%); 1-
rnethyl-4-nitroirnidazole gives 4-cyano-1-methyl-(3%) and 5-cyano-1-rnethyl-4-nitro-
irnidazole (1.5%); I-methyl-2-nitroimidazole gives no stable products; l-rnethyl-5-
rnethoxyirnidazole gives 2-cyano-5-rnethoxy-1-methylimidazole (13 %); 1-rnethylirnidazole
gives 5-cyano-1-rnethylimidazole (3 %). The final two listed reactions show that the replace-
rnent of hydrogen by cyanide is not impossible in the series, and indeed the reaction has
also been noted with irnidazole quaternary salts such as (127), in which instance the reaction
is probably of the SN 1 type (Scherne 62). In the corresponding N-oxide the Reissert reaction
failed to introduce a cyanide group at C-2. With potassiurn cyanide in ethanoll,2-dirnethyl-
4-nitroirnidazole gives (128); the conversion of a nitro function into azoxy is not peculiar
to this series.
[ R NOMe R N
Me ) Me()CN
N N
CH 2 Ph CH 2 Ph
(127)
Scheme 62
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
415
N CN NC N
Mel(3-Ñ=N-I[.,)Me
N I N
Me 0- Me
(128)
02 N N
NC/[,)
N
Me
(129)
Displacement of halogen by cyanide is much more comrnon, occurring in preference at
C-5. Thus, while 1-alkyl-5-chloro- (or bromo-) 4-nitroimidazoles react with potassium
cyanide in ethanol to give the 5-cyano product, the 1-alkyl-4-chloro- (or bromo-) 5-nitro
isomers would not react. Under much more forcing conditions though (20 h, 120-130 o C
with KCN and KI in DMF) the earlier unreactive isomers gave (129). This surprising
transforrnation does not take place in the absence of iodide and may involve transmethylation
giving at first 5-cyano-1,3-dimethyl-4-nitroimidazolium which would decompose preferen-
tially to (129) (B-76MI40701).
4.07.1.5.6 Reduction by complex hydrides
Sodium borohydride converts 4H-imidazole N-oxides into 1-hydroxy-imidazoline or
-irnidazolidine derivatives. Under the same conditions 1,3-dioxides forrn 1,3-dihydroxy-
imidazolidines (76CHE1280).
Unless the NH of imidazole or benzimidazole is substituted, the preferential reaction
with a complex hydride will be salt formation which leaves a negative charge on the ring
nitrogen. In consequence the species becomes resistant to reduction. Thus, at room tem-
perature or below, benzirnidazole forms only a salt with lithium alurninurn hydride, but in
benzene-ether as solvent the benzimidazoline (130) results. Benzimidazoline-2-thione does
not react, but hydantoins (irnidazolidine-2,4-diones) give a variety of products depending
on the reaction conditions. With lithiurn aluminum hydride at room temperature 1-methyl-4-
phenylirnidazolidine-2,5-dione gave 1-methyl-4-phenylirnidazolin-2-one (131) which could
be reduced further to (132) and (133) (66AHC(6)45).
H
N)R
N
H
(130) (131) (132) (133)
2,4,5- Tris(diethylarnino)imidazoliurn chloride is reduced by sodium
ethanol to the 1,3-diazacyclopentadiene (134; Scheme 63) (8ITL2973).
Ph NH
(Ao
Me
Ph N
()
N
Me
Ph NH
()
N
Me
borohydride in
Et 2 N "" Et 2 N
r: ":\ NaSH.. EtOH " - F N
Et 2 N<":::N,;)NEt 2 -70'C-->r.t. · Et 2 N)'-1o.,)NEt 2
H Cl- H N
(134 )
Scheme 63
4.07.1.5.7 Azide ions and nitrite ions
Both 2-azido- and 2-nitro-imidazoles are accessible by nucleophilic displacement of the
2-diazonium fluoroborate.
4.07.1.6. Nucleophilic Attack at Hydrogen
4.07.1.6.1 Metalation at a ring carbon atom
N-Alkyl-irnidazoles and -benzimidazoles react with lithium or butyllithium at low
temperatures to give the 2-lithio derivatives. It has been reported, though, that in the
metal at ion of I-methylimidazole a small arnount of the 5-substituted compound is also
416
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
forrned. Reagents such as phenyllithium or phenylsodium are also effective, but 5-brorno-1-
ethylbenzimidazole would not react with phenyl- or pentyl-sodium.
These metalation reactions require an N-protected imidazole (otherwise the reagent
would preferentially deprotonate the NH to give an unreactive anion), and the protecting
group should be capable of subsequent removal. Benzyl can be rernoved reductively or by
oxidation, but it does suffer from the deficiency that deprotonation can occur at the benzyl
methylene group rather than in the heterocyclic ring. A trityl group is rernoved by strong
acid hydrolysis as is benzenesulfonyl. The most useful N- protecting group would appear
to be alkoxymethyl (Section 4.07.1.3.8) which is easily hydrolyzed under acidic or neutral
conditions. The 1-ethoxymethylimidazoles lithiate readily at -40 o C in THF. While earlier
reports suggested that C-5 metalation is difficult, 1-ethoxymethyl-2-phenylthioirnidazole
(135) is lithiated at C-5 in 83% yield by butyllithiurn in THF at -78 0 C. The 5-methylthio
analogue of (135) failed to metalate at C-4 with butyllithium, but potassiurn diisopropy-
lamide-lithium t-butoxide at -78 OC was successful (Scheme 64). It has proved possible to
replace successively all bromine atorns by lithiurn in 1-ethoxymethyl-2,4,5-
tribrornoimidazole (81CCI095, 80JOC4038).
[)SPh
N
CH 2 0E!
(135)
i, BuLi, THF, -78 'C I [
ii, MeS- MeS .?SPh
N
CH 2 0E!
potassium
diisopropylamide I
Li t-butoxide
Li N D
MeS[)SPh
N
CH 2 0E!
OHC N
MeS[)SPh
N
CH 2 0E!
H0 2 C N
MeS[)SPh
N
CH 2 0E!
Scheme 64
Thus, when the 2-position of imidazole is blocked it is possible for alternative metalation
to take place at C-5. The process does not occur particularly readily, especially at low
temperatures, and an alternative lateral metalation of the 2-methyl group rnay take place.
Butyllithium reacts with 1-methylbenzirnidazole at room temperature to forrn the 2,2'-
dibenzimidazolyl (136) via its dihydro derivative (Scheme 65).
o= N o= N o= N JO i '<::::
I >Li + I > -+ I I -+
N N NHN
Me Me Me Me
H
N Nì0
NH N
Me Me
0,
-H,OI
NxNì0
N N
Me Me
(136)
Scheme 65
4.07.1.6.2 Hydrogen exchange at ring carbon in neutral azoles
The basic features of hydrogen and deuteriurn exchange have been summarized in the
general chapter (Section 4.02.1.7.2). In the parent irnidazole molecule the proton attached
to nitrogen exchanges in 0 2 0, while H-2 is exchanged at 37 0 C with tl/2 -700 minutes.
At 150 0 C the reaction is virtually cornplete in two hours with or without added base; in
acid rnedium exchange does not take place. Thus exchange at C-2 did not take place over
a period of days at 37 0 C in D 2 S0 4 or MeC0 2 D, but complete exchange of all imidazole
protons occured at 250 oC in 0 2 0.
Two parallel processes appear to be occurring: rate-determining proton abstraction frorn
the irnidazolium ion by D 2 0 and by 00- to give the ylide at C-2 (137) followed by
deuteration there (Scheme 66). The pO profile for 4-substitution can be accounted for by
an additional path involving proton abstraction frorn the irnidazole neutral rnolecule. In
strongly alkaline mediurn imidazoles with no nitrogen substituent exchange more readily
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
417
at C-4 or C-5 by a carbanion process which involves deprotonation of the free base. There
is a further mechanistic possibility involving u-intermediates at high pO values. In the ylide
mechanism shown here the conjugate acid is naturally more reactive than the neutral
molecule, while the conjugate base is unreactive. In any process via a Wheland interrnediate
the opposite reactivity sequence applies, viz. copjugate base> neutral molecule> conjugate
acid.
+
ND
[) + OD-
N
D
ND fast ND
( \\ [ \\
..----- ",r + HOD ..----- /D
N N
D D
(137)
Scheme 66
1-Methylimidazole is deuterated at C-2 by 0 2 0 with the rate of the reverse reaction
being virtually independent of pH, as long as conditions do not becorne too acidic when
the rate rapidly falls to zero. Again an ylide mechanism applies (Scheme 9; Section
4.01.1. 7 .2). The relative rates of exchange at the 2-, 4- and 5-positions of 1-methylimidazole
are 54.5 x 10 3 : 1.6: 1 (base-catalyzed exchange) for the ylide mechanism, and 1: 73: 120
(acid-catalyzed exchange) for an SEAr process involving a conjugate acid species. Even in
basic conditions, then, 1-methylimidazole acts as the cation which loses a proton to forrn
an ylide in the rate-determining step (80AHC(27)241, B-76MI40701). The resistance of H-4 to
exchange in these cornpounds has been attributed to the adjacent lone-pair effect, i.e.
electrostatic repulsion between the lone pairs of the spz orbitals at N-3 and C-4.
Substituted imidazoles, too, can be deuterated: 4-bromoimidazole with 0 2 0 for 7.5 hours
at 100 oC gave the 1,2-dideutero compound, and 4-nitroimidazole at 100 oC for 13.5 hours
gave the 2- and 5-deutero compounds in the ratio 5: 3. When sodiurn deuteroxide is present
the exchange of all ring hydrogens is complete in 12 hours at roorn temperature. 4-
Methylimidazole gave the 2,5-dideuterated species after two exchanges of 4-5 hours at
100 0 C in D 2 0-NaOD, but exchange waS slow at 37 0 C, and in acid only H-5 exchanged.
Under identical conditions 1-rnethyl-4- and -5-nitroimidazoles behave quite differently. In
the former, after 12.5 hours at 100 0 C in 0 2 0 exchange at C-5 was 90% complete, and
that at C-2 was 50% cornplete. With the latter, exchange at C-2 was 100% complete, but
only 10% complete at C-4. If the reaction is assumed to depend on a rate-limiting
proton abstraction at each site, then these results are in line with the IH NMR shifts (p.p.m.)
quoted for the molecules, viz. 1-methyl-4-nitroimidazole: H-5 8.30, H-2 7.54 (CDCh),
H-5 8.94, H-2 8.38 (CF 3 CO z D); 1-methyl-5-nitroimidazole: H-4 7.64, H-2 8.09 (CDCh),
H-4 8.54, H-2 9.03 (CF 3 C0 2 D) (80AHC(27)241, B-76MI40701).
Hydrogen exchange at C-2 in 1-methylbenzirnidazole has been discussed earlier (Section
4.02.1.7.2).
4.07.1.6.3 Hydrogen exchange at ring carbon in irnidazolium cations
The observation that 1 H NMR spectra of imidazole quaternary salts in 0 2 0 show relatively
rapid loss of the H-2 signal is evidence for facile exchange at that position.
The base-catalyzed deuteration at C-2 of imidazole quaternary salts proceeds via an
ylide. Exchange at C-2 in 1,3-dimethylimidazolium is 3 X 10 4 times as fast as 3- (or 5-)
deuteration in 1,2-dimethylpyrazoliurn.
4.07.1.6.4 C-Acylation via deprotonation
The acylation reactions at C-2 of imidazoles and benzimidazoles are discussed elsewhere
(Section 4.07.1.4.6).
4.07.1.6.5 Proton loss from a ring nitrogen atom
The salts formed when imidazoles and benzimidazoles react with metallic reagents such
as alkali rnetal ami des and Grignard reagents are very easily hydrolyzed. The resulting
418
Imidazoles and their Benzo Derivatives: (ii) Reactivity
anions, though, are very strong nucleophiles, a property which is utilized in such reactions
as alkylation. The weakly acidic nature of the cornpounds has been discussed in Section
4.7.1.3.5, and pKa values are listed in Table 3.
The sodium salts of imidazoles are so readily hydrolyzed that they are only stable in such
rnedia as ethanol or liquid amrnonia. Sparingly soluble salts, e.g. silver salts, are stable in
aqueous rnedium, and have been utilized for isolation of irnidazoles and in the formation
of some I-substituted derivatives, e.g. 1-trityl, 1-g1ycosyl (Section 4.07.1.3.8). Mercury salts
of imidazole are believed to adopt a linear polyrneric structure, and results of studies of
thallium and tin derivatives suggest that they, too, are polyrneric, at least in the solid state.
Stable organotin derivatives of imidazoles are non-explosive and often stable in boiling
water.
4.07.1.7 Reactions with Radicals and Electron-deficient Species
4.07.1.7.1 Carbenes
When irnidazole, or 1- and 2-substituted imidazoles react with chloroforrn at 550 0 C the
products include 5-chloro- (138) and 4-chloro-pyrirnidines, and 2-chloropyrazines. Carbene
insertion from the chloroforrn into either a C-C or C- N bond accounts for the products
among which (138) predominates (Scheme 67). With hexachloroacetone at roorn tem-
perature 2-methylirnidazole gives a 5-7% yield of (138; R = Me) (SOJCS(P1)1427).
[ \ CHCl3
.?R 550'C Þ
N
H
Cl e N e CI N rN ) Cl
)R + )R + R
N N N
(138) R = Me; 11 : 1 : S
R= H; 9:0: 1
Scheme 67
4.07.1.7.2 Free radical attack at the ring carbon atoms
(i) Aryl radicals
A study of the phenylation of 1-methylimidazole using N- nitrosoacetanilide or
diazoarninobenzene as the sources of phenyl radicals gave about 10-20% conversion to
phenylimidazoles with a relative rate compared with benzene of 1.2. Most substitution was
at C-2 (radicals follow the substitution patterns of nucleophiles largely) with partial rate
factors relative to benzene: fz:::: 4.8, f4 = 0.14, fs = 2.2. Later experirnents using benzene
diazonium fluoroborate with 1-methylirnidazole gave phenylated products with isomeric
proportions sirnilar to the foregoing, but which depended on the concentration of the salt.
There is a suggestion that some of this radical substitution might be occurring with the
more reactive quaternized substrate (139). When phenylation, using the decomposition of
benzoyl peroxide at 118 0 C, was studied under two sets of conditions, one in which
l-rnethylirnidazole itself acted as the solvent, and the other in acetic acid, there was no
change in the overall yield. In acetic acid, however, only 1-methyl-2-phenylirnidazole was
formed; with excess heterocycle 1-methyl-2-phenyl- and -5-phenyl-imidazoles were isolated
in the ratio 29:21. The values of the relative rates (9.0 in acetic acid, 5.7 in 1-rnethyl-
irnidazole) are much higher than those quoted above, but this may be a function of the
reagent, since the quaternized species (140) may be responsible for the values obtained.
+ +
[JN1Ph ()COPh
N N
Me Me
(139)
(140)
(ii) Alkyl and other carbon radicals
The nucleophilic radicals formed by the silver-catalyzed, oxidative decarboxylation of
carboxylic acids by peroxydisulfate ions attack protonated imidazoles mainly at the 2-
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
419
position, the most electron-deficient site. The catalytic action of the silver salt follows the
reaction sequence shown.
2Ag + + S20/- -. 2Al+ + 2S0/-
RC0 2 H+Al+ -. R.+C0 2 +H+ +Ag+
The rnediurn has no specific oxidative action towards the alkyl radicals, and in the presence
of protonated base the rnajor reaction is a substitution. Thus, irnidazoles and 1-substituted
imidazoles are alkylated exclusively at C-2, albeit in rather low yields. The use of isopropyl
and t-butyl radicals gives irnproved yields (80-90%) but benzyl and allyl radicals tend to
dimerize in preference. Benzimidazoles are also alkylated at C-2, and with isopropyl and
t-butyl radicals yields of 50-80% can be achieved (80AHC(27)241, 74AHC(16)123).
Under UV irradiation 1-(p-nitrophenyl)-4-phenylimidazole reacts with cyanide ion to
give the 2-cyano substitution product (80%); the corresponding 2-methyl analogue gave a
rnixture of 4-cyano (30%) and 4-hydroxyrnethyl (20%) products (79T1331).
4.07.1. 7.3 Electrochemical reactions and reactions with free electrons
In the electrochernical reduction of 5-bromo-1-rnethyl-4-nitroirnidazole sorne cleavage
of the C-Br bond is evident giving rise to the debrominated product (79JGU1877). Irnidazole
itself is not reducible cathodically in aqueous rnedia, but electrons have been attached to
irnidazole and histidine in aqueous solution; the rate of oxidation depends on pH. Protonated
or quaternized irnidazoles form the neutral conjugate acids of the true anion radical, and
a number of anion radicals have been rnade frorn nitroirnidazoles under various radiolytic
conditions (79AHC(25)205). The electrochemical reduction of 2-cyanobenzirnidazole 3-oxide
gives sequentially 2-cyanobenzimidazole and 2-aminornethylbenzirnidazole (80ZC263).
4.07.1.7.4 Catalytic hydrogenation and reduction by dissolving metals
Imidazoles and benzimidazoles are generally quite resistant to such reduction reactions.
Catalytic reduction of aryl- and furyl-substituted imidazoles affects only the aryl and furyl
rings, but there has been an isolated report that 2-methyl-4,5-diphenylimidazole can be
reduced over palladium to give the corresponding irnidazolidine (70AHC(12)103). In the
presence of palladiurn, platinum and rhodium catalysts in acid media, benzimidazoles were
found to be reduced only in the fused benzene ring (73MI40700).
4.07.1.8 Reactions with Cyclic Transition States
4.07.1.8.1 Diels-Alder reactions and 1,3-dipolar cycloadditions
Reactions of imidazoles with dienophiles such as DMAD usually lead not to norrnal
Diels-Alder adducts, but to products of N-alkylation (Scheme 68; see also Section
4.07.1.3.11) (78AHC(23)265, 79JCS(P1)1239).
MeN
()
N
H
MeO,CC",CCO,Me, MoCN )
reflux
Me N
[)
N
Me02C C02Me
Scheme 68
(XN>-S
N C02Me
Me0 2 C
9-17%
(X N
I )SCH 2 CN
N
H
MeO,CC=CCO,Me )
There are instances, nevertheless, in which some forrn of addition takes place. For
exarnple, 1,2-dimethylimidazole gives the adduct (141), and 2-phenacylimidazole forrns the
420
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
imidazopyridine (144), presumably via (142) which cyclizes to (143) before undergoing a
Stobbe-type ring opening under the influence of solvent (Scheme 69). The mesoionic
irnidazole (145) gives the pyrrole (146) alrnost quantitatively in what appears to be a typical
1,3-dipolar cycloaddition reaction (Scherne 69).
::;xyo
"Jc02Me
N N
\d
(143)
[ Ph N j
o MeOzC C0 2 Me
Meo 2 cc""CC0 2 Me) a P 0 \1
MeOzC :-. NPh --+ I \
',\ Ph Ph
MeOzC Ph h
(146)
Meo: n
MeozC NJ
C0 2 Me
(141)
Ph 0-
[ N - COzMe
N)CHzCOPh --+ A- .)COzMe --+
H N N
\d
(142)
-0 +
li-NPh
Ph(. JPh
N
Ph
( 145)
Ph
0 C02H
A..)C0 2 Me
N N
bJ
(144)
Scheme 69
Most of the reactions with benzimidazoles have been sumrnarized (78AHC(23)265.
74CRV279). Benzimidazoliurn ylides (147) react with 1,3-dipolarophiles to give the tricyclic
products (148) in low yield (Scheme 70).
CHCOR
1+
N>
N
Me
(147)
HC""CC0 2 Et )
r,t.
COR
9C02Et
N
Me
(148) 4%
Scheme 70
Imidazole reacts very slowly with singlet oxygen to forrn the imidazolidinone (150)
through an elirnination reaction which involves proton loss and cleavage of the oxygen-
oxygen bond of the cyclic peroxide (149). Under sirnilar conditions 4-phenylirnidazole forms
the hydantoin derivative (151) and N-benzoyl-N'-rnethoxycarbonylurea (Scheme 71).
Apparently more than one rnole of oxygen per mole of substrate is taken up in this latter
instance, which is a parallel with the oxygenation of histidine during the photooxidative
inactivation of some enzymes (70AHC(12)103). Other photooxidation reactions have been
discussed earlier (Section 4.07.1.2).
N 0-0 N MeO NH
f) t1 --+ HoÇA o MeOH) MeoÇA o
H t1 H H H
(149) (150)
Scheme 71
4.07.1.8.2. Photochemical cyc1oadditions
o
HN^NH
HPh
o OMe
(151)
Many of these reactions give rise to four-mernbered rings. Additions across the 4,5-bond
with benzophenone and acrylonitrile have already been referred to briefly (Section 4.02.1.9).
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
421
In the photoaddition of acetone and other ketones to 1-, 2- and 1,2-di-methylirnidazoles
the products are a-hydroxyalkylirnidazolcs (153) which are derived frorn the selcctive attack
of excited carbonyl oxygen at C-5. In the case of 2-methylimidazole the products are the
4-mono- (8%) and 4,5-di- (14.5%) substituted cornpounds, but irnidazole itself does not
react. The suggestion that it is not a sufficiently electron-rich substrate is not particularly
convincing. The reaction rnechanisrn (Scherne 72) rnay reflect the greater radical reactivity
at C-5, and the cornparative stabilities of the radical intermediates derived from carbonyl
attack at this position. Hückel calculations of radical reactivity indices show that, indeed,
C-5 is more reactive, and the radical interrnediate at C-5 is more stable than that at C-4,
but a concerted cydoaddition could also give rise to the oxetane (152). Such an oxetane
can be isolated in the photochernical addition of benzophenone to 1-acetylimidazole.
R OH
I H R H I
N R-C. r- N R+f-N RzC N
()Me R O') 6-f-,,)Me -+ .JMe -+ ()Me
N N H N N
Me H Me Me Me
(152) (153)
Scheme 72
Benzophenone reacts differently with 1,2-dimethylimidazole. While acetone gives (153),
the diarylketone adds at the 2-rnethyl group, and with I-benzylirnidazole reaction is at the
exocyclic methylene (Scheme 73) (SOAHC(27)241, SOJHCl777).
f)Me
Me
N OH
Ph,CO, hv ij \\ I
benzene ) Zu/,CHz-C-Ph
N I
Me Ph
ij \ Ph,CO,hv) ij \
_ ./ benzene _ ./
N N
CHzPh I
.Ph-C-C(OH)Ph z
H
Scheme 73
When acrylonitrile adds across the 4,5-bond of 1-methyl-2,4,5-triphenylimidazole a
four-mernbered ring is also formed, but the reaction is very sensitive to substituents and
to solvents. While 2,4,5-triphenylirnidazole reacts in both ethanol and acetonitrile to give
(154), the 1-methyl analogue gives the [2+2]-cycloaddition products (155) in ethanol, but
(156) when the solvent is acetonitrile.
Ph N
PhCX:;Me
CN
(154)
Ph
N +ï 1
Ph{
N R Z
Me Ph
(155) R 1 =H,R 2 =CN
R 1 =CN,R 2 =H
Ph z
O )Ph
Me
(156)
It has been concluded that encounter complexes (or exciplexes) and ion-pairs are the
key intermediates in these reactions. Addition of acrylonitrile to N- unsubstituted imidazoles
gives the N-substitution product, while the N-substituted cornpounds undergo cycloaddition
(SOAHC(27)241).
4.07.2 REACTIONS OF NON-AROMATIC COMPOUNDS
4.07.2.1 Isomers of Aromatic Derivatives
4.07.2.1.1 Compounds not in tautomeric equilibrium with aromatic derivatives
These compounds inClude the 2H- (157) and 4H- (158) irnidazoles ('isoimidazoles'), the
isoimidazolones (159, 160) and such derivatives as 5,5-disubstituted hydantoins (161). There
will also be a nurnber of other possibilities in which the exocyclic oxygens of (159)-(161) are
replaced by S, NH or CR 2 .
422
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
(159)
o H
t)R 2
N
(160)
R H
0 10
H
(161 )
(157)
R 2 C)
N
(158)
R 2 H
00
V R2
Some of the properties such as salt forrnation and alkylation to quaternary salts have
already been mentioned for the 2H- and 4H- imidazoles (Section 4.02.2.1.1), e.g. 5H-
irnidazoles quaternize at N-t. If, however, the 4-substituent is thiol, then methylation with
methyl iodide in basic rnediurn gives the S- rnethyl cornpound before subsequent methylation
leads to quaternization. There are a number of examples of such exocyclic alkylation and
acylation (69T4265, 75M1461). The spiro 1-substituted 2-imidazolin-5-ones (162) alkylate
readily to form the quaternary salts (61J0C4480), while sirnilar methylation in basic mediurn
of 2-substituted 4,4-diphenyl-4H-irnidazolin-5-one (or its other isorner) gives the N- rnethyl
derivative (163; Scheme 74) (69T4265). Hydantoins unsubstituted on nitrogen can be
alkylated there by a variety of reagents.
Me
rYN rY 1-
)rNMe ),rNMe
o 0
(162)
PH O
NVNH
R
p O
Mer / \
NaOEt) NVNMe
R
(163)
Scheme 74
The acylation of 3-irnidazoline-4-thiones gives 1-acylimidazoline-5-thiones which rear-
range on heating to the 'isoimidazoles' (164; Scheme 75) (75M1461).
R
F N R'
S N)(R2
COR 3
R N
140"C F \/R 1
R3COS _.^
N R 2
(164)
Scheme 75
There are a nurnber of therrnal reactions whích transform 'isoirnidazoles' into the fully
aromatic compounds, e.g. the rearrangement of 2,2-dialkyl-2H-imidazoles (165) to the
1,2-dialkyl isorners proceeds by a concerted process. In the absence of hydrogen sources
thermolysis of 2,4,4-triaryl-5-methylthio-4H-irnidazoles gives 1,l'-biirnidazolyl products
(166) by a radical process (80AHC(27)241). Catalytic hydrogenation of the 4H-imidazole
(167) leads to aromatization, and the cornpound is indeed unstable enough for treatment
with concentrated hydrochloric acid at roorn ternperature also to give an irnidazole product
(Scheme :t6) (75JHC471).
P N Ph N
Ph()R 2 -4 Ph[YÆ
N N
R
-4
Ar Ar
F\ F\
NVN-NVN
Ar Ar
Ar2 SMe
n
N /ß
Ar
Ar Ar
(165)
( 166)
OH
PJl...i.....Me Ph CH 2 Cl
II \ c,HO F\
NVN -----+ HNVN
NR 2 NR2
(167)
Scheme 76
Sorne imidazolinones can be hydrated when heated under reflux with water which adds
across the 2,3-double bond. Catalytic hydrogenation also operates at the same site indicating
high double-bond character at that site (Scherne 77) (61J0C4480). On the other hand, the
4H-imidazole (168) is transformed into a 3-acyl-5-amino-1,2,4-oxadiazole when heated in
aqueous solution (Scheme 77).
When heated under reflux with anhydrous AICb in an aromatic hydrocarbon solvent,
5,5-diphenyl-2-irnidazoline-4-thiones are both arornatized and desulfurized (69T4265).
Ph Me
F\ H 2 /Pt
HNVN +-=--
NR2
Imidazoles and their Benzo Derivatives: (ii) Reactivity
423
H
IVNì c H 2 /Pd
\....J\-NH
R
QÇ1
o
R H
oç --+OH
IOO'C NH
o
HON t COR
R JNH 2 'HCI H O H2N >
(168)
Scheme 77
The isoimidazole species can sornetirnes be reduced to imidazoline, e.g. 2,2-
pentamethylene-2H- benzimidazole (169) is reduced by sulfinic acids under mild conditions
at the same tirne as being substituted at C-5 (Scherne 78) (77J0U1817).
0::>0 "'0,", 0:=>0
(169) H
Scheme 78
Nucleophiles attack 2,4,5-trichloro-2H-irnidazoles or 2,4-dichloro-4H-imidazoles with
displacernent of halogen (Scherne 79) (76CB1638).
N I Ph ): CI
CI C X C PhNH2 N t N
Ph ) PhNH2
CI ::-- Ph "Ph Ph ::-.. Cl----+
N PhNH /
Scheme 79
5,5-Disubstituted thiohydantoins can be oxidized by permanganate to 5H- 2-imidazolin-
4-ones.
The N-oxide derivatives of compounds of this class are subject to a variety of typical
reactions. As with the fully aromatic irnidazoles the oxide function can be rernoved:
hexachlorodisilane induces deoxygenation of 2,2-dimethyl-4-phenyl-2H- irnidazole 3-oxide
(78JOC2289). Such compounds act as nitrones with reagents like LiAIH 4 , Grignard reagents
and DMAD. Thus the compounds can be reduced to the irnidazolines by the hydrides
(Scheme 80) (80CHE628). Depending on the position of the N-oxide group sirnilar NaBH4
reduction of 4H-irnidazole N-oxides can give 1-hydroxyirnidazolines or irnidazolidine
derivatives, and under the sarne conditions 4H-irnidazole 1,3-dioxides give 1,3-dihydroxy-
irnidazolidines (76CHE1280). The N-oxide functions can be alkylated and acetylated. Some-
times the ring is cleaved by nucleophiles such as Grignard reagents or alkali (Scheme 80).
NHPh
Ph.}-N
Ph )NHPh
0-
R' 1+ R' OH
e N e N
LiAIH4
R VPh2 R )Ph2
0-
1+
():N) Me2
N+
I
0-
OH
I
NaBH4 C): Me2
I
0-
Q NOH
MeMgI
NBu'
Me \
OH
Me 2 N Me Y NHCOR'
í \\ NaOH
R -I;)R' ----+ Me C
N R/ NOH
I
0-
Scheme 80
424
Imidazoles and their Senzo Derivatives: (ii) Reactivity
4.07.2.1.2 Compounds in tautomeric equilibria with aromatic derivatives
Cornpounds of this type include sorne of the irnidazolinones or irnidazolinethiones which
can be in equilibriurn with the fully arornatic hydroxy or thiol forrns (Section 4.06.5.1).
The non-arornatic forrns may be quite stable in sorne instances, but rnay also react in the
arornatic forrn. Thus, 5H -irnidazolin-4-ones (170) are acylated under Schotten-Baumann
conditions on the exocyclic oxygen. When the reaction conditions are altered it is possible
to obtain products of N -acylation and N,O-diacylation (71CHE746). With the sarne corn-
pound a Mannich reaction takes place at the 5-position, and phosphoryl chloride gives
products of 0- and N -phosphorylation rather than nucleophilic chlorination (Scherne 81).
N OCOPh
Ar/()Me
N
H
o
Ar(jMe
N
COMe
aOH
O O/PhCOCl
/1 -f AcC!
ArZ, ,)Me dry pyridine ·
N
H
(170)
N OCOMe
Ar )Me
N
COMe
HCIIO
R,NH
HC)
C)3
o=p ( -O-(:?t +O=P ( -N N )
Me 3 O 3
o
ArtZ1cH2NR2
N Me
H
Scheme 81
Irnidazolin-2-one (see Scherne 18, Chapter 4.06) has enamine reactivity and dirnerizes in
dilute acid, rather like a pyrrole, by protonation at C-4 (Scherne 82). Such irnidazolinones
are weakly acidic cornpounds as well as being basic by virtue of their tautorneric character.
With phosphoryl chlorides they give 2-chloroirnidazoles, and the cornpounds rnay also be
dialkylated. Brornine adds across the 4,5-bond, while treatrnent with perrnanganate yields
the glycol. They can also undergo Friedel-Crafts reactions with acyl halides and Lewis acids
to forrn 4-acyl derivatives. The cornpounds are therefore characterized by a rnixture of
arornatic and non-arornatic behaviour. The sarne is true for the 4-irnidazolinones which
can couple with diazoniurn salts as well as the active rnethylene adjacent to the carbonyl
function being involved in the forrnation of benzylidene derivatives (B-57MI40700).
HN,
oJ...;f:)Yi NH
H .À
N 0
H
HCI, aq. EtOH
.
600(', 2 days
?t
oÄ..N
H I À
N 0
H
Scheme 82
4.07.2.2 Dihydro Compounds
4.07.2.2.1 Tautomerism
Irnidazolines can exist as three possible structures: 2-irnidazolines (171), 3-irnidazolines
(172) or 4-irnidazolines (173) (Scherne 83,. The first-narned can exist as a pair of tautorners,
but any proton shift in (172) will give (173) by rearrangernent. In fact the hydrolysis of
N -unsubstituted 3-irnidazolines to a-arninoketones occurs presurnably via the 4-irnidazo-
line. 2-Irnidazolines are cyclic arnidines, and as such exhibit the characteristic resonance
stabilization and strongly basic natures of these cornpounds. Protonation occurs on the
unsubstituted nitrogen to give a resonance-stabilized irnidazoliniurn ion. Exarnples of pKa
Imidazoles and their Benzo Derivatives: (ii) Reactivity
425
values, which dernonstrate that the 2-irnidazolines are slightly weaker bases than the
corresponding arnidines, are: 2-methyl 11.09, 2-ethyl 11.05, 2-phenyl 9.88, 1,2-diphenyl
9.26 (69BSF4075, 73JCS(P2)1371).
c)
N
H
(171)
ç )
H
(172)
Scheme 83
( NH
N)
H
(173)
Positions 4 and 5 are equivalent as in the fully arornatic imidazoles, but when these
positions are occupied by the sarne substituent groups meso and racernic forrns are possible.
4.07.2.2.2 A rom a tiza tion
Both 3- and 4-imidazolines (and benzirnidazoline) are converted very readily into the
fully aromatic compounds (Section 4.02.2.2.2). The 2-irnidazolines, though, are much rnore
resistant to dehydrogenation. Arnong the reagents and rnethods which have proved effective
are Raney nickel at 170-200 oC, rnetals such as Pt or Pd at high ternpel atu"e and hydrogen-
acceptors such as S, Se, CuO or cyc1ohexanone. Even rnild oxidation with active rnanganese
dioxide has given high yields of the arornatic cornpounds from substituted 2-imidazolines
(70AHC(12)103, 80AHC(27)241).
4.07.2.2.3 Other reactions
The strongly basic 2-imidazolines dissolve in water to give basic solutions and forrn salts
with acids. Although the hydrochlorides tend to be hydroscopic the pic rates are well-
developed crystalline cornpounds. 3-Imidazolines, too, forrn hydrochloride salts readily in
anhydrous medium, but these are hydrolyzed with sorne facility to ring-opened products.
The picrates are rnore stable.
Alkylation can lead to several products. When heated in a variety of solvents with alkyl
halides, 2-imidazolines give low yields (30-40%) of 1-alkyl-2-irnidazolines, accornpanied
by sorne 1,3-dialkyl quaternary salts. If water is present these salts are readily hydrolyzed
to aliphatic secondary diamines. In the presence of reducing agent, e.g. H 2 /Ni, 1-benzyl-2-
imidazoline is rnethylated at N-1 by forrnaldehyde. When 2,2,4-triethyl-5-rnethyl-3-
imidazoline (174) is treated with dimethyl sulfate in aqueous alkali the 1-rnethyl product
is forrned (Scherne 84).
E N E N
MeÇ)Et 2 M:: 4þ MeÇ)Et 2 : þ Et 2 CO + EtCOCHMeNHMe
H Me 60% 40%
(174)
l AC 2 0
Et N N
MeC ) Et C þ Et 2 CO + EtCOCHMeNHMe + Et ( ) Me
N 2 2 Me Et
Ac N
H COR
C) N RCOX C
Q CH 2 NPh 2 N À CHNPh 2
COR
X=CI, Br (175)
Scheme 84
Acylation of imidazolines also occurs at a ring nitrogen (72JOC2158, 59M402, B-73MI4071).
As with irnidazoles, acylation under Schotten-Baurnann conditions brings about ring
426
lmidazoles and their Benzo Derivatives: (ii) Reactivity
cleavage to aliphatic diarnides. Under very rnild conditions, though, it is possible to forrn
N -acyl cornpounds in which the heterocyclic ring is intact, e.g. acylation of (174) with acetic
anhydride, and formation of the diacyl product (175), probably via the rnono-N -acyl
derivative (Scherne 84).
Imidazolines are rather susceptible to hydrolytic reagents which cause fission of the ring.
Aqueous acids and alkalies react with 2-irnidazolines to give N -acylated derivatives of
ethylenediamine (Scherne 85). The acid hydrolysis appears to involve a rate-lirniting attack
by water on the heterocyclic dication (B-73MI40701). Even heating in water can bring about
this transforrnation with the 2-aryl derivatives being rnore resistant than the 2-alkyl corn-
pounds (77LAl183). Hydrolysis of acylated 2-imidazolines takes place with cleavage of the
1,2-bond to give a diarnide (Scherne 85), while acylated 3-irnidazolines under sirniIar
conditions give an aldehyde (or ketone) and an a-arninoketone (Scherne 84) (nJOc2158).
H
e N
H,O
)Me H'orOH-'
N
CH 2 NHCOMe
I
CH 2 NH 2
Ph N
e HO'
Ph ;>Ph
N
COR
PhrNHCOPh
Ph NHCOR
Scheme 85
Exposure of 2-rnethyl-2-imidazoline to a mixture of nitric and acetic acids leads to both
oxidation and nitration, giving 1,3-dinitroimidazolidin-2-one (179). When 2-nitrarnino-2-
irnidazolines are further nitrated they give the I-nitro products (176) which are
dinitroguanidines. Addition of arnines and alcohols leads to (177) and (178), respectively,
while allylic rearrangernent followed by further nitration gives (179; Scheme 86).
7
NO z
e3<NHN0 2
N OR
H
(118)
N0 2 N0 2
C \ HNO, C) N RNH, e N NHN02
.,p'NHN0 2 h NHN0 2 -- 'v
N N""NHR
(176) H
1 (171)
NO z NO z
Ç1 NNoz HNO" [ o
H NO z
(179)
Scheme 86
It is not possible to forrn irnidazolidines by hydrogenation of irnidazolines. Hydroxylarnine
converts 2-rnethylthio-2-irnidazoline into 2-hydroxyirninoirnidazolidine. When heated at
170 0 C with sodium rnetal cis-2,4,5-triphenyl-2-irnidazoline rearranges to the trans forrn
(nJOC21587.
There are a few exarnples in which irnidazolines act as dienophiles in Diels-Alder reactions
(81 TL2063), while sorne related corn pounds can also react with monoalkenes in 'ene' reactions.
Nucleophiles rnay also add across the C=N bond (Schernes 86 and 87) (7OJOC3097).
Ac 0 k
N % Ac
çÀo 180 0 C,xylene' r 1
Ac N 0
Ac
c 0
r-r--T >= 0 I
N hv,Me,CO
Ac
Ph H Ph 0 o
Meotl 1:1 r Ni
o N 0 0 NOMe
Me Me Ph
o
1 Me,C=CMe,
Me z
MezCHC H
Ph)-N
O NÀO
Me
Scheme 87
Imidazoles and their Benzo Derivatives: (ii) Reactivity
427
4.07.2.3 Tetrahydro Compounds
4.07.2.3.1 A rom a tiza tion
Irnidazolidines are not particularly well known; they may be considered as aldehyde-
arnmonias, and can be converted into the arornatic irnidazoles only with extrerne difficulty
if at alL Quinones and azo compounds dehydrogenate 1,3-diphenylimidazolidine, but only
as far as the imidazoliniurn ion (B-77MI40700).
4.07.2.3.2 Ring fission
General methods of ring opening have been surnrnarized earlier (Section 4.02.2.3.2). A
variety of reagents are capable of cleaving the ring, e.g. acid chlorides and HCN, borane
in THF, and even cold dilute acid, which brings about rapid hydrolysis of irnidazolidines
to N,N'- disubstituted ethylenediamine salts and an aldehyde. The compounds are, however,
resistant to cold dilute alkali (B-77MI40700, B-74MI40700).
Ring-chain tautomerisrn of the type shown in Scherne 88 is well known, but the ring
forrn is generally dorninant (SOH(14)1313).
{\ "'- {\
HNXNMe ---,.. N'J\ NHMe
H Ar H Ar
Scheme 88
Aqueous permanganate converts 1,3-dibenzyl-2-phenylirnidazolidine into a mixture of
benzamide and benzoic acid. When l-alkyl-3-phenylirnidazolidines are subjected to N-
oxidation the unstable N-oxides rearrange to give tetrahydro-I,2,5-oxadiazines (180) via
the ring-opened product (Scheme 89) (77LA956).
R 2 R 2
Ä R 2 +/0- -1;:1 0- PhN O
PhN NR 1 ---+ PhN/'..N Ph-N'l" N/ I I
'---l '---l 'R 1 '---l 'Rl NRI
(180)
Scheme 89
4.07.2.3.3 Other reactions
Many of the reactions discussed here will be those of oxo and thio derivatives of
irnidazolidine, although such reactions might also be classified as those of irnidazolines or
properties of oxygen- and sulfur-linked functional groups.
Alkylation and acylation on ring nitrogen should occur readily with sirnple imidazolidines;
alkylation in particular occurs with sorne facility in the presence of strong bases.
When I-substituted 2-iminoimidazolidines are nitrated in acetic anhydride the initial
product is the nitrate salt (181). This can be further nitrated under the influence of chlorine
catalysis (Scherne 90).
R
Ç1 NH
H
R
AC20 Þ ç \ .
HN0 3 H2
N0 2 N0 3 -
C20 (181)
Cl 2 HN0 3 Cl 2 ÄC20
HN0 3
R
Ç 02
N0 2
Scheme 90
428
Imidazoles and their Benzo Derivatives: (ii) Reactivity
Treatrnent of 2-imidazolidinone with a carboxylic acid (and heat) gives a 2-alkyl-2-
irnidazoline. The corresponding 2-thione (182) undergoes nucleophilic displacernent by
prirnary arnines to form the 2-alkylarnino-2-irnidazoline; the sarne result is obtained using
a 2-rnethylthio-2-irnidazoline as substrate. In the presence of strong bases (182) can be
acylated on a ring nitrogen, but rnethylation occurs on the exocyclic sulfur atom (Scheme
91) (8IJCS!P1)2499).
H H
C)>NHR (RNH, C1 C1
N N S N"':'S
H H
(182)
/... BuLi
Iii. 'Mel. CS,
"\,
C)>SMe
N
I
C
s-7 .....SMe
H
ç 1 s
I
/-C
s"" 'S-
Scheme 91
The hydantoins (2,4-dioxoirnidazolidines) when unsubstituted at N-3 are fairly acidic
(K. = 7.6 x 10- 10 for the parent cornpound). The hydrogen atorns at C-5 are also acidic
enough to be able to form benzylidene cornpounds in alkaline solution. This lability of the
hydrogens at C-5, while present, is negligible when compared with that of the NH protons.
In b sic solution oxidation can take place at the 5-position, and the ring is cleaved by initial
hydroxide ion attack at C-4. Thus bariurn hydroxide hydrolysis gives hydantoic acids, with
the ease of hydrolysis dependent on substituents at C-5 (Scherne 92). Acetylation and
nitration of hydantoin give the 1-substituted products, but halogenation occurs at the
5-position to give products susceptible to facile nucleophilic displacernent.
H
H /N.....
iN, B.IOH)" H 2y y=O
O :J.....- .Ào -::-c NH 2
N 0 I
H OH
Scheme 92
Parabanic acid (2,4,5-trioxoirnidazolidine) has NH groups which are fairly acidic (K. =
3.7 x 10- 6 ) and have very little basic character. The compound acts as a dibasic acid which
forrns readily alkylated salts. There are a variety of analogues of parabanic acid in which
one or rnore of the ketone functions is replaced by =S or =NH. Such cornpounds revert
to the oxo cornpound when treated with peracetic acid. Even hydrolysis with aqueous
ethanolic rnineral acid serves to convert =NH into =0 (79JOC3858).
4.07.3 REACTIONS OF SUBSTITUENTS
Attention is drawn to the general survey of reactivities and reaction types in Chapter
4.02.3.1.
4.07.3.1 Benzenoid Rings
4.07.3.1.1 Fused benzene rings: unsubstituted
Electrophilic reagents preferentially attack benzirnidazoles in the fused benzene ring,
while nucleophiles react at C-2 which has enhanced nucleophilic activity because of the
electron-withdrawal effect of the benzene rnoiety. The fused aryl ring appears to exhibit
less arornatic stability than the heteroring as evidenced by the ready oxidation of ben-
zirnidazole to imidazole-4,5-dicarboxylic acid, and by its catalytic reduction over platinurn
Imidazoles and their Benzo Derivatives: (ii) Reactivity
429
oxide to 4,5,6,7 -tetrahydrobenzirnidazole. Benzimidazoles (but not 1-methylben-
zimidazoles) are also oxidized by chrornic acid or by 30% hydrogen peroxide.
The SCF calculations (Section 4.06,2) predict the sequence of electrophilic attack in
benzirnidazole as 7> 6 > 5 > 4, although positions 4 and 7, and 5 and 6 are tautomerically
equivalent in N -unsubstituted benzirnidazoles. Substitution appears to occur with greatest
facility in the 5- (or 6-) positions. Bromination in acetic acid of 2-arnino-1-rnethylben-
zimidazole occurs at C-6. It can be seen from Table 5 (Section 4.07.1.4.5) that aqueous
bromination of benzimidazole itself occurs most readily at C-5, followed by C-?, as it does
in the 1- and 2-rnethyl analogues (78JCS(P2)86S). Sorne of the experirnental results are
summarized in Scherne 93. Chlorination of both benzirnidazole and 2-rnethylbenzirnidazole
give the 4,5,6-trichloro product. Nitration and sulfonation, too, occur most readily at
position 5 with either sulfuric or chlorsulfonic acids being effective in the latter reaction.
N> Br N) + Br N)
N N N
R R Br R
R = H, Me
02N N) + 02N N) + 02N N>
N 02N N N
R R N0 2 R
(some)
er N B er N B er N
I Me r I >Me + r I )Me
N/ HOAc N N
H H Br H
IHOSOzCl
l excess
BIz
H03S N>Me
N
H
Br
Br er N B er N
I )Me + r I >Me
Br N Br N
Br H Br H
(some)
Scheme 93
In acetic anhydride at 30 0 C nitration of benzirnidazolinone gives 5-nitroben-
zimidazolinone; at 70 oC the 5,6-dinitro product is obtained, while furning nitric aciq. can
give 4,5,6-trinitrobenzimidazolinone (76M1307). In a Friedel-Crafts reaction ben-
zimidazolinone (and its 6-methyl and 1,3-dimethyl derivatives) reacted with phthalic anhy-
dride and AICh to form the 5-(2-carboxybenzoyl) derivatives (74CRV279).
4.07.3.1.2 Fused benzene rings: substituted
Substituents on the benzene ring can play some part in subsequent electrophilic substitu-
tion reactions, but the situation is not a sirnple one. As can be seen in Scherne 93 the
normal meta directirrg effect of a nitro substituent can be offset by the directional effect of
the fused imidazole ring, as can the usual ortho-para directing effect of brorno.
Under the influence of nitrosylsulfuric acid, 2-amino-5- and -6-brorno-1-methylben-
zirnidazoles (183) are converted, as a result of self-coupling, into the 2',5- (184) and 2',6-
(185) azobenzimidazoles. Even the 5,6-dibromo analogues can react in a similar way by
loss of one of the bromine atorns (Scherne 94) (nCHElS33). Coupling with diazonium salts
of 4-amino- and 2-rnethyl-4-arnino-benzimidazole occurs at C-7, while a protected 4-arnino
group (acetylated) directs nitration into both the 5- and 7-positions. A 4-fluoro substituent
likewise leads to 7-nitration (74CRV279).
Oxidation (with such reagents as iron(I1I) chloride, potassium dichromate, silver oxide
or nitrous acid) of 4,7-,6,7-, and 5,6-dihydroxy-, and 5,6-dimethoxy-benzirnidazoles gives
the corresponding quinones. A 5-methyl group is oxidized by perrnanganate to carboxy
(74CRV279). In the presence of copper(II)-piperidine or -dimethylarnine cornplexes oxygen
430
Imidazoles and their Benzo Derivatives: (ii) Reactivity
BrLyN)NH 2 : 2 , Br-éyN)N 2 ---+
N 24 N
Me Me
(183)
-û N B Ù N
Br I }-N=N ùl N -(XI N _ I )NH 2
::::,... N /NH 2 + Br r N - N ::::,... N
Me Br ::::,... N ::::,... N Me
(184) Me Me (185)
Scheme 94
converts 5-hydroxybenzirnidazoles in 70% yield into 4,5-dioxo products which have also
been arninated at C-8. No C-2-amination was noted (78CHE1366).
Attempts to carry out nucleophilic substitution of bromine by arylarnino failed for
5-brorno-, 5-bromo-6-nitro- or 6-brorno-5-nitro-l-ethylbenzimidazole, as it did likewise
for the corresponding benzirnidazoliurn salts (70CHE628).
4.07.3.2 Other C-Linked Substituents
4.07.3.2.1 Saturated alkyl groups
Alkyl groups can be oxidized under a variety of conditions either to the aldehydes or to
the carboxylic acids. Reagents such as permanganate or dichrornate yield carboxylic acids,
but rnilder conditions can lead to the aldehyde. A 4-hydroxyrnethyl group can be converted
into an aldehyde using seleniurn dioxide, lead tetraacetate, or active rnanganese dioxide,
with the last narned reagent being the one of choice. A 70% yield of irnidazole-2-aldehyde
was obtained from 2-hydroxyrnethylirnidazole using a sixfold excess of activated rnanganese
dioxide in anhydrous ether, acetone or carbon tetrachloride (70AHC(12)103). Periodate will
cleave polyhydroxyalkyl chains to aldehyde in the normal way.
Hydroxyalkyl groups can be converted by thionyl chloride into haloalkyl, or reduced to
alkyl.
Methyl groups in the 2-position of imidazole are subject to sufficient electron withdrawal
by the flanking nitrogen atorns to act as if they are 'active'. Proton loss in the presence of
strongly basic reagents is possible giving rise to the anions. Even in the cationic forrn of
the heterocycle rnethyl groups at C-4 or C-5 are unaffected; 2-alkyl groups, though, are
very prone to proton loss under these conditions, e.g. forrnation of stable an hydro bases
such as the diazafulvenes (186; Scheme 95). When there are strongly electron-withdrawing
groups at the 4- or 5- positions a C-4 (or C-5) rnethyl group becomes reactive, but in these
circumstances a 2-methyl group reportedly failed to condense with benzaldehyde.
F\
H N ',. +':NH
'V-' THF
CHPh 2
C\-
n
N N
):
Ph Ph
(186)
Scheme 95
Butyllithium reacts with 1,2-dirnethylimidazole at -80 oC to lithiate the 2-rnethyl group,
and at higher ternperatures sorne 5-rnetalation also occurs (74JOC2301). Reaction of
2-methyl-, 5-chloro-2-methyl- and 2-benzyl-benzimidazoles with two rnolar equivalents of
butyllithiurn in THF-hexane at 0 oC results in dilithiation, although subsequent reactions at
the side-chain carbanion centre also take place (Scherne 96) (73JOC4379).
In the presence of weaker bases than butyllithiurn or sodarnide active methyl groups are
still able to take part in a variety of èondensation reactions with carbonyl cornpounds. In
fact, only catalytic arnounts of the proton acceptor rnay be needed. Thus, 2-rnethylirnidazole
reacts with benzaldehyde to form the 2-styryl cornpound ((187), and 1,2-dirnethyl-5-
nitroirnidazole condenses with dimethylforrnarnide dicyclohexyl acetal to give an 86% yield
Imidazoles and their Benzo Derivatives: (ii) Reactivity
431
er N . er N .+ er N ?H
I )Me þ I _}-ëH 2 Me d I )CH 2 CHr-Æe
N N N
H Li+ H
()CH 2
N
Me
PhCHO ( N OH
Li+ -15.C Þ Y }CH tHPh
N 2
Me 60%
Scheme 96
of (188); with benzoyl chloride in the presence of a tertiary amine base the product is the
2-phenacyl derivative (189; Scheme 97) (SOAHC(27)241). An analogous reaction to the last
occurs with 1-benzyl-2-rnethylirnidazole, but with 1-benzyl-5-rnethylirnidazole the product
is 2-benzoyl-1-benzyl-5-methylimidazole as a result of substitution at C-2 (75JOC252)
(Section 4.07.1.4.6).
()Me
N
H
PhCHO ( N
ZnCl/ }CH=CHPh
N
H
(187)
( \ Me,NCH(OC.Hll)'
N0 2 /Me )
N
Me
R> PhCOCI
J;c
( N Ph H+ [ N
N0 2 Y }CH=C N0 2 }CH 2 COPh
e OCOPh e
(189)
(
N0 2 }CH=CHNMe 2
N
Me
(188)
Scheme 97
A recent study of the kinetics of base-catalyzed exchange of C-methyl protons in
C,N-dimethylnitroirnidazoles has shown that the most reactive isomer is 1,5-dirnethyl-4-
nitroirnidazole, and the 'least acidic' cornpounds are 1,2-dirnethyl-4-nitro- and 1,4-
dirnethyl-2-nitro-irnidazoles. These results parallel the reactivities in aldol condensations,
demonstrating low activity in compounds with nitro and rnethyl groups 'meta' to each other
(this orientation hinders resonance stabilization of the anion). There is a suggestion that in
1-substituted irnidazoles there may be significant localization of the 4,5-bond (SlJOC4717).
Related reactions include the forrnation of the 2-cyano compounds (190) when 1,2-
dimethyl-5-nitroimidazole is heated with nitrosyl chloride or an N -oxide, and when 2-
methyl-1-(o-nitrophenyl)irnidazoles (191) cyclize under the influence of iron(II) oxalate
(Scherne 98) (74JCS(P1)1970). The last reaction product is contarninated by a large arnount
of arnine reduction product (-64%) but there is also sorne cyclization with the 4-rnethyl
isomer of (191). In the presence of trirnethylarnine, 2-cyanornethylbenzirnidazole condenses
with acetone to give the unsaturated derivative (192; Scherne 99) (ncPB30s7). Neither
2-methylirnidazole nor 2-methylbenzimidazole reacts with formamide in the presence of
phosphoryl chloride.
[ \ NOCI Þ
N0 2 /Me
N
Me
N0 2 ()CN
N
Me
(190)
X0 N02 Me
N/-:::.N
(191) \d
N
Fe(IIJoxalate Þ X (X\
280.C Á
N "N
\d
13%
Scheme 98
432
Imidazoles and their Benzo Derivatives: (ii) Reactivity
(X N (X N CN
'" Me CO '"
I )CH 2 CN Et:N. I
::::::,... N ::::::,... N' Me
H H M
(192) e
Scheme 99
Exarnples of side-chain halogenation of alkyl groups are uncommon, but 1,2-dirnethyl-5-
nitroirnidazole reacts with io!iine and pyridine to forrn 30% of the pyridiniurn iodide (193),
presurnably via an initial lateral iodination of the Me group at the 2-position (Scheme 100)
(SOAHC(27)241).
[ \ [ \ + 1\ , -
N0 2 N/ Me O N N02 N/CH2N
Me II Me
(193)
Scheme 100
Substituted alkyl groups attached to an imidazole ring can take part in a wide variety of
typical reactions. The halornethyl cornpounds are subject to nucleophilic substitution reac-
tions forrning the corresponding alcohols, arnines, cyanides, etc. Investigations of the rnode
of action of 2-trichlorornethylbenzirnidazoles with nucleophiles have been initiated since
these rnay serve as model corn pounds in studies related to the possible involvernent of
benzirnidazoles in purine antirnetabolite behaviour. The benzirnidazoles rnay act biologically
by cornpetitive inhibition of nucleic acid synthesis. Thus, with aqueous arnrnonia, 2-
trichlorornethylbenzirnidazole forrns a mixture of 2-cyanobenzirnidazole (50%) and the
pyrazine diirnine (194) (30%). With anhydrous arnrnonia, only the cyano corn pound (86%)
is obtained (Scheme 101). Primary and secondary arnines also react to give arnidines and
anilides, respectively, but 1-rnethyl-2-trichloromethylbenzirnidazole is rnuch less reactive
in such substitution reactions, perhaps irnplying involvement of the benzimidazole anion
(74CRV279).
(X N NH
I CCI
/ 3 H 2 0
::::::,... N
H
rr-N')CN + rr-NM NH
N NN
H HN :O
(194)
Scheme 101
Alkaline hydrolysis of 2-trifluorornethylirnidazole to the 2-carboxylic acid occurs at 30 oc
in 0.1 M KOH with a half-life of 5.8 hours. The 4-methyl analogue is 12 times rnore reactive
than the parent. The rate-lirniting step in the reaction is the solvent-assisted, internal
elirnination of fluoride ion frorn the imidazole anion, to give a transient difluoroazafulvene
which can be trapped in reaction with other nucleophiles (Scherne 102) (79JOC2902).
R R R R
F\ OH: F\ n R'OH r=\
NyNH .---- NyW N N -- NyNH
CF 3 CF 3 Y CF 2 0R'
CF 2
R
r=\ H 2 0
N NH'-
Y
C0 2 H
H 2 0 1-HF
R
r=\
NyNH
""c,
0'" F
Scheme 102
4.07.3.2.2 Aryl groups
The rnajority of electrophilic substitution reactions of C -arylirnidazoles (involving acidic
reaction conditions) occur in the para position of the aryl ring. This is a consequence of
Imidazoles and their Benzo Derivatives: (ií) Reactivity
Table 6 Nitration of C-Arylimidazoles (B-76MI40701)
433
Imidazole
Conditions'
Products
2-Ph
A (100 oc)
1-Me-2-Ph
4-Me-2-Ph
4-C0 2 H-2-Ph
4,5-(C0 2 Hh-2-Ph
4-Br-2-Ph
4,5-Br2-2-Ph
4-Ph
4-Ph
1-Me-4-Ph
1-Me-5-Ph
2,4,5-Ph 3
50% 2-(p-N0 2 C 6 H 4 ),
1.5% 2-(o-N0 2 C 6 H 4 ),
0.2% 2-(m-N0 2 C 6 H 4 )
-43% 1-Me-2-(p-N0 2 C 6 H 4 )
4-Me-5 -N0 2 -2- (p-N 0 2C6H4)
52% 4-C0 2 H-2-(p-N0 2 C 6 H 4 ),
19% 4-C0 2 H-2-(m-N0 2 C 6 H 4 )
52% 4,5-(C0 2 Hh-2-(m-N0 2 C 6 H 4 ),
19% 4,5-(C0 2 Hh-2-(p-N0 2 C 6 H 4 )
31 % 4-Br-2-(p-N0 2 C 6 H 4 )
63% 4,5-Br2-2-(p-N02C6H4),
1.8% unidentified isomer
69% 4-(p-N0 2 C 6 H 4 ),
25% 4-(o-N02C6H4)
4-(p-N0 2 C 6 H 4 )
1-Me-4-(p-N0 2 C 6 H 4 )
1-Me-5-(p-N0 2 C 6 H 4 )
2,4,5-(p-N0 2 C 6 H 4 )3
A (l00 oc)
B
A
C
D
D
A
B orC
A
A
B
a Conditions: A, nitrate of base added to H 2 S0 4 ; B, fuming HN0 3 ; C, HNO r H 2 S0 4 ; D,
solution of base in H 2 S0 4 added to KN0 3 .
the substrate being the imidazolium species which is rather resistant to electrophilic attack,
but which is electron releasing to the aryl substituent. Table 6 lists results of nitration of
sorne aryl-substituted imidazoles. In contrast to the arylpyrazoles the preference for para
nitration is not nearly so clear-cut. Undoubtedly the nitration proceeds via the cationic
species in each case, and hence irnidazoliurn acts largely as an ortho,para director. The
introduction of electron-withdrawing groups into the imidazole ring can rnodify this direc-
tional effect to the extent that meta nitration becomes predorninant (Scherne 103)
(B-76MI40701).
[)Ph
N
H
H0 2 C [ N HNO
H0 2 C ))Ph H 2 S0 4
N
H
NH HNO, [ NH
(_ )Ph H2S 4Þ _; :
N N \
H H 1\ #' N0 2
H o.
major product
H0 2 C N H0 2 C N
H02C 02 + H02C
H V H VN0 2
52% 19%
Scheme 103
Substituents in the aryl ring, too, can exert their own directional effects: a p-nitro group
deactivates the benzene ring and directs further attack into the heterocyclic ring; in 4-(3,
4-dichlorophenyl)irnidazole nitration is rnainly at C-5; in 4-(p- rnethoxyphenyl)imidazole
. (195) subsequent nitration takes place adjacent to the methoxy function and then at C-5
(Scherne 104) (ncHE1110). The nitration of 2-(p-fluorophenyl)irnidazole has been discussed
earlier (Section 4.07.1.4.2).
Oxidation of aryl-irnidazoles and -benzimidazoles can give carboxylic acids, in sorne
instances with breakdown of the irnidazole ring. Thus, (196) is transformed by alkaline
permanganate into 4-methoxy-3-nitrobenzoic acid. The effects of oxidizing agents in alkaline
medium on triarylirnidazoles have been covered earlier in relation to lurninescence
phenornena (Sections 4.07..1.2.1, 4.07.1.2.3 and 4.07.1.4.8). The polarographic oxidation
of such cornpounds is facilitated by electron donor groups in the aryl rings.
Rearrangernent reactions of 3-(irnidazol-2-yl)anthranils have been described (Section
4.02.3.4.2).
Irradiation at 313 nm converts 4,5-diphenyl- and 2,4,5-triphenyl-irnidazoles into the
phenanthroirnidazoles (197) by a process which rnay involve hydrogen abstraction by the
solvent (Scheme 105) (nJPC3362).
434
lmidazoles and their Benzo Derivatives: (ii) Reactivity
M'O'
t)
Me 3MHNY
ê\-3
N03
Meo
+ N
02 N r ;\
N
H
Meo No2 MeO 2
!J 02 N
'\.'\. c.HNO, -""
O,N "%co, O,N 1 3 O,N 1 ;
MeO O C0 2 H (196)
(195)
Scheme 104
R = H, Ph
N
)R
N
H
Ph N
If"..!!!:..
Ph, /R
N
H
Scheme 105
Substituents attached to aryl groups on imidazole or its benzo derivatives have their
normal individual reactivities, e.g. reduction of nitro to amino, diazotization of amino, etc.,
although there may be some modification of these properties because of the particular
environment.
4.07.3.2.3 Other C-linked functionality
(i) Carboxylic acids and derivatives
Imidazolecarboxylic acids are stable, crystalline compounds which form salts with metals,
and which may exist in zwitterionic forms such as (198; Scheme 106). Such zwitterionic
forms have been implicated in the decarboxylation mechanisms of the compounds. The
carboxyl functions exert a pronounced base-weakening effect on the parent molecules, but
it is surprising that a 5-bromo substituent in imidazole-4-carboxylic acids is not subject to
ready nucleophilic displacement by CN- or SO/-.
-02C \,m H0 2 CfiN
((:.) (;\
N N
H H
(198)
Scheme 106
Decarboxylation can be achieved by heating the acids above their melting points, often
in the presence of a copper-chromium oxide catalyst, and it is possible to remove one
group at a time from imidazole-4,5-dicarboxylic acid by heating the monoanilide. Studies
of the kinetics of decarboxylation of 5-aminoimidazole-4-carboxylic acids implicate a
first-order decarboxylation of both the acid and the zwitterion; the anion is stable and not
Imidazoles and their Benzo Derivatives: (ii) Reactivity
435
decarboxylated. Some evidence exists for catalysis by hydrogen ions at low pH values, and
of general base or nucleophilic catalysis. The rate of loss of CO 2 is decreased by complex
formation with transition metal ions. When imidazolium-2- and -5-carboxylates are de car-
boxylated ylides are formed, presumably again through the dipolar tautomers. When
imidazole-4-carboxylic acid is treated with iodine in alkaline solution the product is 2,4,5-
triiodoimidazole (B-76MI40701). Benzimidazole-2-carboxylic acids decarboxylate readily
(75S703). When 1-methylimidazole-4,5-dicarboxylic acid is treated with PCl s in thionyl
chloride there is some decarboxylation and conversion of carboxyl functions into tri-
chloromethyl (73NKK996).
The usual range of carboxylic acid derivatives c'an be prepared and interconverted. Both
carboxylic acid and ester functions are capable of reduction by lithium aluminum hydride
to alcohols, or by controlled potential reduction to aldehydes. Attempts to form the
anhydride from imidazole-4,5-dicarboxylic acid by heating with acetic anhydride failed.
Instead, compound (199) is formed. This product forms the monoester (200) when heated
with methanol and the hydrazide (201) when treated similarly with hydrazine (Scheme 107)
(75S162). The corresponding 1-methyl-4,5-dicarboxylic acid loses the 4-carboxyl group
when heated with acetic anhydride, but in boiling aniline it is transformed into the 1-methyl-
4-carboxanilide (79H(12)186).
H iozMe
o N
^n MeOH / (200)
COzH å
HN Ac 2 0) NÇ"-N -- N
N -)COzH å '--d. -N......j'
ð NH2
(199) HN CONHNH z
J
N
(201)
Scheme 107
Imidazole-4-carboxamides do not take part in the Hofmann reaction. 5-Aminoimidazole-
4-carboxamide forms a fairly stable diazocarboxamide when treated with nitrous acid;
under acid, basic or neutral aqueous conditions this product cyclizes to a triazine. Amide
functions can be converted into thioamide which is then susceptible to methylation on the
sulfur atom.
Cyanoimidazoles have been of interest because of their utility as starting materials for
the synthesis of purines, e.g. 4-cyanoimidazole-5-carboxamide. The function reacts in most
normal cyanide transformations, e.g. with aqueous alkali it forms the amide or the acid,
and it can be reduced with LiAIH 4 , sodium in alcohol or by hydrogenation over Raney Ni.
In 1-substituted 4,5-dicyanoimidazoles (202) the two groups exhibit different reactivities.
Even with 4,5-dicyanoimidazole itself, partial hydrolysis to the monoamide requires 1M
NaOH, and stronger base at higher temperatures converts the remaining cyano group
Na 2 Moo.l H 2 0 2 /EtOH
NH
"
NÇ N MeOC N
ij \\ MeOH ( \\
NCZ /Ar 'Naõ"Mi NC /Ar
N N
CHzAr CHzAr
(202) (203)
I NH 3
HzNOC N
NC())Ar
N
CHzAr
(205)
MeOzC N
MeOH ( \\
NC >Ar
N
CHzAr
(204)
1 CatBH 4 )2
NC N
HzNOC())Ar
N
CHzAr
(206)
HOHzC N
NC( ))Ar
N
CHzAr
Scheme 108
436
Imidazoles and their Benzo Derivatives: (ii) Reactivity
(B-76MI40701. 80AHC(27)241). Regiospecific conversion of the cyano groups in (202) may
afford purines of unequivocal structure. Thus, methanol in sodium methoxide selectively
adds at the 4-cyano group to give the methyl imidate (203) which can be converted into
either the ester (204) or the amide (205); selective reduction of (204) to the hydroxymethyl
cornpound has been accomplished. On the other hand (202) can be directly hydrolyzed to
the 5-carboxamide (206), thus making the two different positional isomers of
cyanoirnidazolecarboxamide (205 and 206) available for purine synthesis (Scheme 108).
The zwitterion, or carbene, derived from 4,5-dicyano-2-diazoimidazole reacts with acetic
acid to give 4,5-dicyanoimidazolin-2-one (79JOC1717). Photolysis of 4-amino-5-
cyanoimidazole gives 1,6-dihydroimidazo[ 4,5-d]imidazole (207; Scheme 109) (74JA2010).
NC N
H N[')
2 N
H
N N
<x)
N N
H H
(207)
Scheme 109
(ii) Aldehydes and ketones
Acyl-substituted imidazoles have distinctive UV and IR spectra, and can exist as hydrates
in solution, e.g. imidazole-2-carbaldehyde. The aldehyde group is sufficiently electron
withdrawing to assist nucleophilic displacement of an adjacent halogen atom. The normal
aldehyde derivatives such as oximes, acetals and hydrazones can be formed, and the kinetics
of oxime formation with the 4-carbaldehyde have been studied. The tautomeric ratio
(zwitterion: uncharged aldehyde form) of 1-substituted imidazole- and benzimidazole-2-
aldoximes rises in parallel with an increase in basicity of the parent molecule (73CHEI074).
These compounds have been shown by NMR studies to adopt the syn configuration. With
hydrazine hydrate, imidazole-4,5-dicarbaldehydes give imidazo[ 4,5-d]pyridazines (208;
Scheme 110).
N-fHO H,NNH,'H,O
()CHO )
N
R
{=c
R
(208)
[ \ qEt __ ()_
NÆ:JC 0 N
R I R
H
(209)
H
I
+ H-C-O-Et
II +
o
Scheme 11 0
Scheme 111
When the 2-aldehyde of imidazole (209) is treated with ethanol some decarbonylation
takes place by way of a nucleophilic attack of the alcohol on the carbonyl carbon (Scheme
111). The products isolated are imidazole and ethyl formate. One would normally expect
that acetal formation would result under these conditions, but it appears that in the
acid-catalyzed formation of acetals from (209) the yield of acetal depends on the arnount
of catalyst. When the ratio of H+: imidazole is > 1, then the diethyl acetal is produced in
high yield. When this ratio falls to less than unity there is some decarbonylation, and in
the absence of acid only decarbonylation occurs. Electron-withdrawing groups in the
heterocyclic nucleus (or quaternization) assist this reaction which does not appear to occur
with 4- or 5-aldehyde functions (80AHC(27)241).
Both imidazole-2- and -4-carbaldehydes resist the Cannizzaro, Perkin and benzoin
reactions, but the I-substituted compounds react normally. I-Substituted 5-nitroimidazole-
2-aldehydes condense readily with alkyl aryl ketones. Examples of successful condensations
(X N (X N
Ph P=CHCO Me -:?
I )CHO 3 2) I )CH=CHC0 2 Et
N N
Me Me
N CHO r-It
() +N S--
N V
H SH
(210)
CH 0
N-(' H N CH 2 CH{NH 2 )C0 2 H
() N S r Ip) ()
N V N
H SH
Scheme 112
Imidazoles and their Benzo Derivatives: (ii) Reactivity
437
with carbanions, active methylene and similar compounds include reaction with nitroalkanes,
with Grignard reagents (73JOC349S), with phenyllithium in THF, and a number of Wittig
reactions (Scheme 112) (74CHE3S8). In the synthesis of histidine use is made of the reaction
of imidazole-4-carbaldehyde at the active methylene of 2-mercapto-5-thiazolone (210;
Scheme 112).
Hydroxylamine-O-sulfonic acid converts an imidazole-2-aldehyde into a mixture of the
carboximidamide and the 2-cyanoimidazole (79JHC871).
Most usual oxidizing agents act normally with imidazole aldehydes and ketones but
I-benzylimidazole-2-carbaldehyde is reportedly somewhat resistant to selenium dioxide
oxidation. Reduction of ketone functions under Clemmensen and Wolff-Kischner conditions
is usually successful. Zinc dust and acetic acid reduce acetyl groups to a mixture of secondary
alcohol and ethyl; borohydride gives the alcohol exclusively (B-76MI40701).
(iii) Unsaturated alkyl groups
Studies of alkenyl- and alkynyl-imidazoles in recent years have increased because of the
interest in the polymerization of these compounds under the influence of free radical
initiators.
Oxidation of the substituents usually gives carboxylic acids, or sometimes the aldehydes.
Thus, ozonolysis of 1-methyl-5-nitro-2-styrylimidazole gives the corresponding 2-aldehyde
(7SLA146S).
While addition reactions occur normally with some unsaturated derivatives, there are
instances in which this is not the case. 2- Vinylimidazole resists epoxidation and hydrobor-
ation, and this resistance is even more marked in the N -substituted compounds (Section
4.07.3.8.3).
The vinyl- and ethynyl-substituted compounds are able to participate in Michael addition
reactions with a variety of nucleophiles, particularly if the group is attached to C-2. When
the sodium salt of 2-ethynyl-1-methylbenzimidazole is treated in liquid ammonia with an
aliphatic alcohol, the vinyl ether (211) is produced, but KOH in ethanol surprisingly gives
1,2-dimethylbenzimidazole (Scheme 113) (7SJOU1130).
U N
I )Me
""" N
Me
KOH
----
EtOH
U N U N
I )C:=CH N :31 I )CH=CHOR
""" N """ N
Me Me
(211)
Scheme 113
A number of the condensation reactions of 2-ethynyl-1-methylbenzimidazole are sum-
marized in Scheme 114. The oxidative self-condensation of the compound can take two
courses depending on the reaction solvent (74CHE1491). Under Favorskii reaction conditions
(KOH in ether) the expected product (212) with acetone is not formed. Instead, further
U N
I )C:=CH
""" N
Me
N)c:=CCMe20H
N
Me
(212)
KOH l
Et20 Me2CO
Brc= CP 7
U N
I )CH=C Me 2
""" N 1\
o 0
pyridine Me '-.../
MeOH (213) Me2
U N
I )C:=C-C:=CPh
""" N
Me
U N N J()
I )C:=C-C:=C< I
""" N N #
Me Me
U N OMe N J()
I )t=CH-C:=C< I "'::
""" N N #
Me Me
Scheme 114
438
Imidazoles and their Benzo Derivatives: (ii) Reactivity
rapid condensation with another molecule of acetone gives the dioxolane (213) (7SCHEI23).
Some of these reactions are a function of the acidic nature of the ethynyl group, which is
a weak electron acceptor when attached to azoles and which is more acidic than acetylene
itself in these situations (7SCHE718).
Both acrylic and alkynic acids of imidazoles decarboxylate norrnally on heating, and
bromoacrylic acids in the series are dehydrobrominated under the influence of ethanolic
alkali (71 CHE 132).
4.07.3.3 N - Linked Substituents
4.07.3.3.1 Amino compounds
Aminoimidazoles are not particularly well-described compounds (Section 4.07.1.1.4).
There are synthetic difficulties involved, and 4-amino and 1-substituted 5-amino compounds
are often unstable; they are certainly much more labile than the 2-arninoimidazoles
(8IJOC4717).
(i) Dirnroth rearrangement
Very few examples of this reaction exist among the imidazoles. Nevertheless, treatment
of 4-amino-1-methyl-2,3-diphenylimidazolium chloride (214) with warm, dilute potassium
hydroxide solution gives 4-anilino-1-methyl-2-phenylimidazole (215; Scheme 115)
(7IJOC3368). The thermolysis of a 2-amino-1-aroyl-3-methylbenzimidazolium chloride,
which gives a 2-aroylarnino-1-methylbenzimidazole, provides another example (74CHE 1225).
Heating in concentrated aqueous ammonia converts ethyl 5-rnethylaminoirnidazole-4-
carboxylate into 5-amino-1-methylimidazole-4-carboxamide, again-via a Dimroth product
(79JCS(Pl)3107).
Me Me
N N
(. )Ph i.Ac,O ( )Ph
-L \ NaHCO, r.j Cl-
MeCON Ph H 2 N Ph
(216) (214)
Scheme 115
Me
N
aq. KOH (. '-.,Ph
--. L 1/
PhNH N
(215)
(ii) Reactions with electrophiles
Whereas 2-aminoimidazole is a mono acidic base which protonates on the annular
nitrogen, 4-aminoimidazole can form dihydrochlorides and dipicrates. In this respect 4-
aminoimidazoles resemble true aromatic amines. Even the salts of these compounds,
however, are relatively unstable in aqueous solution, and 4-aminoimidazole itself is deami-
nated and undergoes ring fission under the usual Van Slyke amino-nitrogen determination
conditions. Usually alkylation and acylation occur on a ring nitrogen atom, but if initial
reaction at this site gives rise to an unstable product the ultimate product may turn out to
be the exocyclically substituted one. Consecutive substitution at ring and exocyclic nitrogens
is possible. Thus, the imidazole quaternary salt (214) acetylates on the amino function and
subsequent treatment of the product with bicarbonate gives the rnesoionic system (216;
Scheme 115). 2-Aminoirnidazole and some of its derivatives give products of acetylation
and aroylation which are almost certainly 2-acylaminoimidazoles; 4-aminoimidazoles can
give 4-acylamino compounds and sometimes diacylated products (S-76MI40701).
The acylation of 2-amino-1-methylbenzimidazole with unsaturated acid chlorides gives
the 3-acyl quaternary salt (217). With triethylamine in acetonitrile at 10-15 oC this dehydro-
chlorinates to give the 2-imino derivative (218), and both (217) and (218) can rearrange
to give the exocyclic amide (219) which is capable of cyclization (Scheme 116) (78CHE73).
Other similar examples exist (74CHE122S) in which an increase in ternperature is generally
sufficient to promote the acyl rearrangement - treatment with base gives the imino product.
In the presence of sodamide the anionic form of 2-amino-1-ethylbenzirnidazole is sub-
stituted by alkyl halides on both the annular and exocyclic nitrogens. With butyl and
isopropyl iodides the proportion of dialkylated product is increased. The synthetic utility
of such nucleophilic reactions of 2-aminobenzimidazole is exemplified by reactions with
ethyl cyanoacetate, acetoacetic ester and ethyl benzoylacetate, when subsequent cyclization
of the initial products also gives pyrimidobenzimidazole derivatives (Scheme 117).
Imidazoles and their Benzo Derivatives: (ii) Reactivity
439
(X N
I >NH 2
:::::,..., N
Me
PhCH=CHCOCl
Þ
(X OCH=CHPh
I + }NH 2
:::::,..., N!/ CI-
Me
(217)
(X OCH=CHPh
Et,N >=
I NH
10-15'C:::::"'" N
(218) Me
Ph_
(X N- /0
I r N
:::::,..., N
Me
5'C
Et,N 1.5 h ÆHCl
MeCN J(""24 h '
(X N
EtN
(re:ux I )NHCOCH=CHPh
:::::,..., N
Me
(219)
Scheme 116
(X N (X :hMe
I )NH 2 MeCOCH,CO,E\ I )-N
:::::,..., N :::::,..., N
H
Scheme 117
(iií) Diazotization
Diazonium salts of both 2- and 4-aminoimidazoles have been prepared, with a strongly
acidic medium being preferred for the reactions. On occasion it is possible to isolate the
intermediate nitrosoamines which are resistant to the action of dilute acid on storage, but
which are subject to denitrosation when heated in alcohol solutions. The nitrosoamines can
be converted into the diazonium salts. Diazonium fluoroborates have proved synthetically
valuable for they can be transformed into the 2-nitro-, 2-azido- and 2-fluoro-irnidazoles
(80AHC(27)241). The derived diazonium salts are also capable of coupling reactions (Scheme
118) (ncHE1533).
(X N
I )NHNO
Br:::::,..., N
R
NaNO,
( H,P0 4
(X N
I >NH 2
Br:::::,..., N
R
NOHS0 4 Þ
(X N (X N
+ ow /'/ N
I ": N ----+ I rN=N:;.-
Br:::::,..., N> 2 HSO- Br:::::,..., N B:Y >NH 2
R 4 R Ir N
R
N)Ñ2 N>-N
6 ö
Scheme 118
(iv) Condensation reactions with carbonyl compounds
It has been reported that 2-aminoimidazoles do not react readily with aromatic aldehydes
to form Schiff's bases, and even though the 4-am\no compounds have more aromatic amine
character, their instability has meant that there have been few studies of these reactions.
Triethyl orthoformate reacts with 5-amino-4-cyano-1-methylimidazole to give (220) which
is cyclized by ammoniacal ethanol to 9-methyladenine (78JCS(Pl)1381). The cyclization of
2-amino-1-methylimidazole with an a-bromoketone provides another example. There are
also a number of examples of lactam formation as when polyphosphoric acid reacts with
5-afuino-1-imidazolylacetic acid, or when 2-aminobenzimidazole and propiolic esters inter-
act (Scheme 119) (73JCS(Pl)1588).
440
Imidazoles and their Benzo Derivatives: (ii) Reactivity
NC N
H 2 N())
Me
HC(OE0 3 I
NC N
EtOHC=N[ ;)
N
Me
(220)
[)NH 2
N
Me
BrCH(RICOR'
>70.C I
N R'
( yN
N
Me
U N
I )NH 2
N
H
RC=CCO,R
R
O
N r
>-- .
Scheme 119
(v) Oxidation
In the presence of atmospheric oxygen 2-arnino-1-benzylbenzimidazole reacts with two
equivalents of sodium metal to give 2-aminobenzimidazole and 2,2' -azodibenzirnidazole
(221; Scherne 120). When four equivalents of sodium are present the products are (221)
(55%) and 2-nitrobenzimidazole (45%) (70CHE1183). The proposed mechanism for such
oxidations, based on such circumstantial evidence as the unreactivity of I-alkyl analogues,
the requirement for the presence of atmospheric oxygen in the process, and the apparent
requirernent for a large excess of I-benzylbenzimidazole for the oxidation of 2-aminoben-
zimidazole, is shown in Scheme 120. The last requirement suggests that benzylsodium plays
a significant role in the process.
UN UN No uN
I )NH 2 I )NH 2 ---+ I Ñ NW Na+
N N +
CH 2 Ph Na Na+
1 No O,
ii,HCI
uN . UN [U )-NI
": 1,0, I Ñ)N 2 - 2Na+
I N>N0 2
H Na+
(221)
Scheme 120
1,2-Diamino-4-phenylimidazole is oxidized by manganese dioxide to a mixture of 4-
phenyl-l,2,3-triazole and 3-amino-5-phenyl-l,2,4-triazine (80AHC(27)241). A C -nitrene
interme.diate (222) is probably involved, although an N -nitrene intermediate cannot be
ruled out (Scheme 121).
N
Phf' Ì]NH 2
..-N
,/ N
()NH 2 r { . ] ---+ PhyNC:=N
N N N
NH 2 NH 2 .. NNH 2
(222)
Ph N
If \\
.,/N
N
H
H
H'NO'i-fÑ o 'N
NVN NVNH
(222a)
Scheme 121
Imidazoles and their Benzo Derivatives: (ii) Reactivity
441
4.07.3.3.2 Aminoazolium ions
5-Diazoimidazole-4-carboxamide is an explosive compound which cyclizes to 2-aza-
hypoxanthine (222a; Scheme 121) (67AHC(8)1).
4.07.3.3.3 [mines
Proton loss from cationic species of type (217; Scheme 116) can give rise to relatively
stable imines which can be alkylated or acylated with some facility. However, imines are
much more common in compounds which are not in tautomeric equilibrium with fully
aromatic imidazoles, and among the imidazolidines.
4.07.3.3.4 Nitro groups
IR studies have shown that strongly electropositive metals form salts with nitroimidazoles
in which the negative charge is largely associated with the nitro function (Section 4.06.3.7).
Nitroimidazoles dissolve in aqueous solutions of alkali metal hydroxides, carbonates or
ammonia to form yellow solutions containing the nitroimidazole anion (B-76MI40701).
While there are a number of examples of nucleophilic displacement of nitro groups
attached to imidazole rings (Section 4.07.1.5), the nitro groups themselves facilitate the
nucleophilic displacement of other functional groups, and also have a profound effect on
the orientation of such reactions as alkylation (Section 4.07.1.3). The strongly base-
weakening effects are well known and may even prevent the formation of salts with acids.
Reduction of nitro groups can be accomplished using either chemical or catalytic means.
Such reagents as zinc and acetic acid, tin and HCl, or hydrogen with Raney nickel, Adams
catalyst or palladium-carbon, in addition to hydrazine with the latter catalyst, usually reduce
a nitro group smoothly to the amino group. Problems which arise are often a function of
the instability of the reduction products. Thus, when 2-nitroimidazole is reduced with
Adarns catalyst an unstable reduction product is formed. Nitro groups attached to the
benzene ring of benzimidazole have been reduced with hydrazine and Raney nickel.
When ethylene oxide is used to alkylate 2,4-dinitroimidazole, 60% of the N -alkylated
product is formed, but 25% of the product is a bicyclic nitroimidazo[2,1-b]oxazole (223)
which must be formed as a result of intramolecular nucleophilic displacement of the 2-nitro
group (Scheme 122) (79JHC1499).
02 N N 02 N N
Ç 02 -- ç o
I -0 L-.J
H2C'C 2 (223)
Scheme 122
4.07.3.3.5 Nitroso groups
Although not particularly well known, nitrosoimidazoles appear to be quite stable com-
pounds. The nitroso function can be reduced to amino, or oxidized to nitro. When 5-nitroso-
2,4-diphenylimidazole is subjected to dropwise treatment with phenylhydrazine there is
some reduction, but ring modification with the formation of the oxadiazole (224) accom-
panies this reaction (Scheme 123) (60G831). The nÎtroso function is able to take part in
condensation reactions with compounds which possess active methylene groups, and related
species (B-76MI40701).
Ph N PhNHNH 2
[ (dropwise)
H 2 N )Ph EtOH
H
Ph N
ON(')Ph
N
H
PhNHNH 2 .HCI
100 'C. EtOH
o Ph
I
NyN
C
Ph"'-- NNHPh
(224)
heme 123
442
Imidazoles and their Benzo Derivatives: (ii) Reactivity
4.07.3.3.6 Azidoazoles
Azido-tetrazole tautomerism has been discussed earlier (Section 4.06.5.3).
Many of the compounds which are known are crystalline, but they can decompose (often
explosively) on melting. They exhibit an IR absorption band in the 2300 cm -1 region.
Reaction of sodium metal in liquid ammonia with 2-azidoimidazoles (or 2-azidoben-
zirnidazole) gives the N-dianions (225) which methylate very readily (Scheme 124)
(71CHE1156). Other reactions of 2-azido-1-methylbenzimidazole are also summarized in
this scherne.
U N
I NMe2
::::,... N
Me
N N -0
N NH2 + N')-NH ;J Me
Me Me
\zMel
U N
I ')-N 2 -2Na+
::::,... N
(225) Me
N:;.zNa
[AICl,
I PhMe
N N3 Ph 2 CS I N')-N=<Ph
N N Ph
Me Me
U N Br U N U N
I NH2 + I NH2 + I NH2
::::,... N ::::,... N Br::::,... N
Me Me Me
o + N NAC2 + N NHAC
N AcO N AcO N
Me Me Me
Scheme 124
4.07.3.4 O-Linked Snbstituents
The tautomerism of these compounds has been discussed in detail in the chapters on
structure (Sections 4.01.1.1 and 4.06.5.2), and general reactivities have been considered
in Chapter 4.02.3.7 wherein the relative reactivities and interconversions of the hydroxy
and carbonyl forms are summarized. Some of the reactions have also been covered in the
section dealing with non-aromatic derivatives of imidazoles (Section 4.07.2). Discussion
here will bt: limited to reactions which do not lead to ring fission.
4.07.3.4.1 Hydroxyl compounds
The 2-hydroxyimidazoles are acidic compounds which have lost the norrnal imidazole
basic properties. In dilute alkaline solution they form salts, and they are commonly stable,
crystalline cornpounds with high melting points. Stability to acid hydrolysis is typical and
there are few indications of phenolic properties, the compounds best being regarded as
imidazolinones (or benzimidazolinones). The imidazolin-4 (or 5) -ones, though, have both
amidine and keto-enol systems. Accordingly they are amphoteric compounds forming, for
example, both picrates and silver salts, and they are rather less stable than the 2-isorners.
Again the keto forms are preferred.
Imidazoles and their Benzo Derivatives: (ii) Reactivity
443
Resistance to reduction processes seems to be a general characteristic as most catalytic
methods (as well as sodium in ethanol) reduce only the ring. However hydantoin can be
reduced by diisobutylaluminum hydride to imidazolin-2-one (8ITL2063), and imidazoline-2-
thiones can be prepared from 2-thiohydantoins (70AHC(12)103). Oxidative procedures often
result in ring opening (B-76MI40701).
The oxygen function is strongly activating for electrophilic substitution. In consequence,
imidazolin-2-ones are readily substituted at C-4 and C-5, while imidazolin-4-ones couple
with diazonium salts. Nucleophilic displacement of the oxygen functions has been discussed
elsewhere (Section 4.07.1.5).
Both acylation and alkylation occur most readily on an annular nitrogen, but there are
examples of O-acylation which have been reported (albeit tentatively). The acetyl derivative
of 4-methyl-2-phenylimidazolin-5-one has been formulated as 4-acetoxy-5-methyl-2-
phenylimidazole because of its basic properties, and derivatives of 1-substituted imidazolin-
5-ones are also probably the O-acetyl compounds (70JHC961, 71CHE746). From the limited
results available it appears that alkylation of imidazolin-2-ones is confined to the annular
nitrogens; nucleophilic displacement of halogen is the most usual approach to the synthesis
of alkoxy-substituted imidazoles. 1-Acyl-2-imidazolidinones, however, are alkylated on the
exocyclic oxygen by oxonium fluoroborates (77JOC941). One of the most notable differences
in reactivity between the oxygen and sulfur derivatives of imidazoles is in their reactivity
with alkylating and acylating reagents.
4.07.3.4.2 Alkoxy and aryloxy compounds
When 2-alkoxy-1-methylimidazoles are heated they rearrange to alkylimidazolin-2-ones.
The reaction occurs also with 2-alkoxybenzimidazoles. The 2-allyloxy compounds undergo
a similar Claisen rearrangement but 15-20 times more rapidly (Section 4.02.3.7.7). At
150 0 C in the absence of light (in nitrobenzene with AICh) 2-aryloxybenzimidazoles give
no Fries-rearranged products, but photorearrangement leads to 2-(2- and 4-
hydroxyphenyl)benzimidazoles (226,227; Scheme 125) (73BCJ2600).
O)OPh -'"-. O :}-Ö + o: >-o OH
H H H
(226) (227)
Scheme 125
The kinetics and mechanism of the trans alkylation reaction between 2-alkoxy-l-methyl-
benzimidazoles and thiophenol have been studied. The results demonstrate a rapid proton-
ation of the azole followed by an SN2 reaction which forms the benzimidazolinone. The
basicity of the benzimidazole and the pH both affect the reaction rate (Scheme 126). The
corresponding sulfur analogue, 1-methyl-2-methylthiobenzimidazole, does not react with
thiophenol, probably because of the poor electron-donating ability of the sulfur atom of
thiophenate (71JCS(B)2299).
r
0: , N>OMe + ArSH (X I )-0-CH3 -- 0: 1 N>=O + ArSMe
N rÞ N
H H
Scheme 126
4.07.3.5 S - Linked Substituents
4.07.3.5.1 Thiones
Compounds with a potential SH group exist predominantly in the thione form (Sections
4.02.3.8 and 4.06.5.2). The UV maxima for the thiones lie in the range 260-270 nm, shifted
to shorter wavelengths in the quaternary salts. Imidazoline-2-thiones are high-melting solids
444
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
which form stable salts in aqueous alkali, but they are too weakly basic to form stable
picrate or hydrochloride salts. The compounds can indeed be quite strong acids, e.g.
5-rnercapto-l-phenylimidazole-4-carbaldehyde, pKa = 4.63 (admittedly the forrnyl group
is here exhibiting a strong effect).
In contrast to the oxy analogues, imidazolinethiones are much more subject to alkylation
on the exocyclic atom. Heating directly with an alkyl halide, or heating the sodium salt of
a thione with an alkylating agent both give S -alkyl products. Oialkylation giving N,S-
dialkylimidazoles can occur. Thus, methyl bromoacetate alkylates 1,3-dimethyI-
imidazoline-2-thione to give the exocyclic quaternized product (228), which forrns the
quasi-Wittig reagent (229) when treated with base (Scheme 127) (78JA6538). Under phase-
transfer conditions imidazolidine-2-thione is alkylated both on nitrogen and sulfur by
1,2-dibromoethane to give a bicyclic product. With 3-bromopropyne, benzimidazoline-2-
thione gives the S -propargyl product (230) (74TL2643), while S -alkenyl corn pounds can be
rnade by heating imidazoline- or benzirnidazoline-2-thiones with alkynes, either under
pressure or in the presence of heavy metal salts (74CHE1217, 76CHE433). Both N- and
S -products are produced. The addition of alkynic esters to benzimidazoline-2-thiones
provides yet another example of S -alkylation (Scheme 127) (79TL53).
Me
f/N
NAs
Me
BrCH,CO,Me
CH,Cl,. 30 'C
Me
(N
N A SCH,C0 2 Me
Me
(228) Sr-
MeCN
-30'C
Me
(N
NAS-ëHco,Me
Me
(229)
H
(X I N)=S
N
H
1 HCsCH
(X I >=s + (X I N SCH=CH,
N N
CH=CH 2 H
- (X N
HC=CCH,Br Þ I SCH2C=CH
N
H
(230)
(X N
I SCH=CH2
N
CH=CH,
H
(X I N)=S
N
H
MeO,CCsCCO,Mc
þ
(X N
I ;--s
Ny-lcHco 2 Me
o
Scheme 127
The reaction of 1,3-dimethylimidazolidine-2-thione with iodomethane follows second
order kinetics in polar solvents, and gives the S -methyl quaternary salt (81JCS(P2)414).
Selective alkylation of hydantoins is difficult unless one nitrogen is blocked during synthesis.
As long as N-3 is already substituted, alkylation at N-1 may be achieved using alkyl halides
or tosylates in anhydrous OMF (S-76MI40701). With 5,5-diaryl-2,4-dithiohydantoins (231)
boron trifluoride dimethyl etherate selectively methylates S-2 with concornitant extrusion
of S-4 and rearrangement to a 4,5-diphenyl-4-irnidazoline. With 2-thiohydantoins (232)
such S -rnethylation is not accompanied by any rearrangement (Scheme 128) (S-73MI40701).
S -Glycosides of imidazoles and benzirnidazoles have been prepared.
P S Ph Ph
/ \ BFJ'Mc,O r=\
R 3 N NR' ----+ RJN NR 1
Y e
S
(231)
Ph 2 0 P o
n BFJ'Mc,O / \
MeN NH -'-4 MeNVN
Y SMe
S
(232)
When benzirnidazoline-2-thiones react with a mixture of OMSO and acetyl chloride at
50-60 o C a profusion of products are formed (Scheme 129). Rationalization of these is in
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
445
terms of replacement reactions by benzimidazoline-2-thione on an intermediate sulfonium
acetate. At lower temperatures the products can also include the ylidc (233) in 20% yield
(74CRV279).
H CH 2 SMe
(X I N )= S (XI N )= S
AcCI "-
N "" N
H CH 2 SMe
+ Q Q
MeSCH 2 N y N-CH 2 -N y NH
S S
Me H
+ N)=S + N)=S + >-S=CH2
N N N
CH 2 SMe CH 2 SMe
(233)
Scheme 129
Removal of the mercapto (or thione) function is most commonly achieved using Raney
nickel, although concentrated HCl at high temperatures or nickel boride have been
employed. Thiohydantoins are transformed into imidazolidin-4-ones by sodium in amyl
alcohol (70JHC439). Oxidative desulfurization procedures too are often used; the reactions
probably proceed through the unstable sulfinic acid species which very readily eliminates
sulfur dioxide. The high resistance of sulfonic acids to acid hydrolysis renders unlikely the
possibility that they are reaction intermediates.
When thiones are exposed to oxidizing agents the reaction products can vary considerably
depending on conditions. Mild oxidation (e.g. air, iodine, hydrogen peroxide) converts them
into disulfides (234); more vigorous conditions occasionally allow the detection of a sulfinic
acid (235), e.g. carefully controlled oxidation with hydrogen peroxide of 4-methyl-
imidazoline-2-thione. The most common oxidation products (using hydrogen peroxide,
chlorine, bromine, chromic or nitric acids) are the sulfonic acids (236), while yet more
vigorous conditions can lead to cleavage of the C-S bond and desulfurization (Scheme
130). Chromic acid oxidation of 4,5-diphenylimidazoline-2-thione gives N,N' -dibenzoyl-
urea (B-76MI40701). With chlorine in the presence of HCl, 4-mercaptoirnidazole-5-
carboxamide is oxidized to the sulfonyl chloride derivative (76CHE924).
H
fiN fiN N ) N N
..A - ('Ls-s II - If "so H - If ''s
N S N" N N;> 2 N;> 03 H
H H H H H
(234) (235) (236)
Scheme 130
Hydrogen peroxide in acetic acid transforms a thione group to oxo (79JOC3858), and a
sulfur group may be replaced by chloro using aqueous chlorine.
When benzimidazoline-2-thiones are treated with the mercury salt of phenylacetylene
the products are mercury(II) benzimidazole-2-thiolates (237), which form the disulfides
when treated sequentially with sodium iodide and iodine. Such thiolates can be benzoylated
on nitrogen by benzoyl chloride (Scheme 131) (77LAI06). While the acylation of thiones
in general can take place, like alkylation, either on nitrogen or sulfur (or both), there is a
preference in favour of N -acylation.
H
R N>=S
R N
H
Hg{C=CPh)2 þ R N)-SHgS--<N X) ,,:::: R
R N N #R
H (237) H
Scheme 131
4.07.3.5.2 Disulfides
Besides their oxidation behaviour (Scheme 130) disulfides can be cleaved by hydrogen
sulfide and may be desulfurized by photochemical means (80AHC(27)241). With
446
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
dibenzoylmethane the disulfide (238), derived from benzimidazoline-2-thione, is alkylated
via (239) to (240), a product resulting from a benzoyl migration. Acetylacetone gives only
the S -alkylation product (241), and benzoylacetone gives a product which ultimately
rearranges to the N -acetyl derivative (242; Scheme 132) (74JA1957).
IPhCO"CH'L
/57%
( (X}-sl C ;.'" (X)SCHA"
H /2 H
(238) (241)
PhCOCH,Ac
100%
[ (X SCH(COPh)']
(239)
i
(X N
I SCH2COPh
N
CO Ph
(240)
(X N
I SCH(AC)COPh
N
H
i
(X I N SCH2COPh
N
Ac
(242)
Scheme 132
4.07.3.5.3 Thioethers
Alkyl- and aryl-mercaptoimidazoles are basic compounds which can be oxidized to
sulfones with a range of oxidizing agents, and to sulfoxides by careful treatment with
peroxide (77JHC889) or periodate (75JHC597). Removal of the sulfur function can be accorn-
plished with Raney nickel or by acids at elevated temperatures. The alkylthio group is
subject to cleavage by hydriodic acid, sodium in liquid ammonia, or aluminum bromide in
benzene, but not by butyllithium. An equilibrium is set up between SR- and NR-substituted
imidazoles (Scheme 133). Kinetic studies show that the process is an autocatalytic rearrange-
rnent in which there is reaction between the thioether (243) and the quaternary salt (244)
(79CJC813).
Me Me
f1N: N ( NMe N )
_. + MeR-( .) ï ; ) : SMe + /
N SMe N N SAN
R' R' R ' R'
(243) (244)
Scheme 133
The vinyl group of 2-vinylthiobenzimidazole can be reduced to ethyl by hydrogen in the
presence of a nickel catalyst (74CHE1217), while addition of an alkanethiol occurs under
radical conditions in an anti-Markownikov fashion (76CHE1278). 2-Propargylthioben-
zimidazoles (245) are subject to Claisen rearrangement in a similar way to S-alkyl corn-
pounds (Scheme 134; see Section 4.01.3.5.8) (74TL2643).
(X I )
N/--- S A[3,3]
H
(245)
::/ l
Y /-fCH 2 Me
(X{S (Xr S + (Xr S
Scheme 134
Imidazoles and their Benzo Derivatives: (ii) Reactivity
447
4.07.3.5.4 Sulfinic and sulfonic acids and derivatives
Sulfinic acids and sulfoxides are not particularly common, being readilÿ oxidized to the
sulfonic acids and sulfones, respectively. Sulfonic acids have high melting points and probably
exist as zwitterions. They are amphoteric, but mainly display the characteristics of weak
acids. The sulfonic acid group activates an adjacent halogen to nucleophilic displacement,
and may itself be displaced, e.g. reaction of alkylamines with benzimidazole-2-sulfonic acid.
Imidazolesulfonic acids resist esterification and acid chloride formation, and are only
hydrolyzed by concentrated hydrochloric acid at 170 o C; the 2-isomers are more resistant
than the 4- or 5-isomers. Aqueous alkali converts the free acids into hydroxy derivatives.
Sulfonyl chlorides are accessible via the thiols (Section 4.07.3.6.1) which react with ammonia
to form sulfonamides, or are reduced by tin (II) chloride to thiols (77JHC889).
4.07.3.6 Halogen Atoms
Reactions in which halogens are displaced by nucleophiles have been discussed earlier
(Sections 4.02.3.9 and 4.07.1.5) as have electrophilic nitrodehalogenations (Section
4.07.1.4.2).
Halogen substituents are electron withdrawing and decrease the basic strength of imi-
dazole. Conversely the acid strength is augmented by these atoms (Tables 1 and 3). Salts
formed with concentrated mineral acids often hydrolyze on dilution. The fluoroimidazoles
have become more well known in recent years and are weaker bases and stronger acids
than the corresponding bromo compounds. The inductive effect of the halogen atom
obviously overshadows any resonance effect (Section 4.07.1.3.5) (75JCS(P2)928). The effects
of a fluorine substituent on ring-hydrogen exchange have been outlined (Section 4.07.1.4.4).
Among the catalytic and other methods which have been used to replace a halogen atom
by hydrogen, reagents such as Pd-C and Raney Ni are generally successful, while red
phosphorus and HI, sodium and alcohols, and a variety of metal-acid combinations have
been employed with varying success (B-76MI40701) (see also Section 4.07.1.7.3). It is
frequently necessary to adjust the dehalogenation conditions in order to avoid modifying
other groups. For this reason hydrogenation of 1-benzyl-5-chloro-2-phenylimidazole over
Raney Ni was carried out at low temperature in order to prevent debenzylation and
conversion of phenyl to cyclohexyl (ncHE742).
Reactions of sulfite with haloimidazoles can take two courses. If sufficient activation is
present nucleophilic replacement will occur; if not the sulfite will merely reduce the halogen
function. For this reason the major reaction of 2,4,5-tribromoimidazole with sulfite is
reduction, although a little 4-bromoimidazole-5-sulfonic acid appears among the products
(Scheme 135), and even 2-bromo-1,5-dimethyl-4-nitroimidazole gave no sulfonic acid
product. The 2-sulfonic acid was, however, formed from the 2-bromo-1,4-dimethyl-5-nitro
isomer. Apparently the position of the activating group is important. When there is little
or no activation for nucleophilic substitution, then in N -unsubstituted imidazoles 2-bromo
and (with less facility) 4-bromo groups are easily replaced by hydrogen. In I-methyl-
imidazoles even a 2-bromo group is only slowly reduced. An earlier observation (B-
76MI40701) that in iodoimidazoles it is the 2-iodo substituent that is more resistant to sulfite
reduction should now be modified, since the conclusion was based on Pauly's incorrect
assignment of structure to 4,5-diiodoimidazole (Section 4.07.1.4.5). It would be of value
to attempt sulfite reduction of authentic 2,4-diiodoimidazole.
Br N Br N Br N N HOJS N
Br!Ç)Br :e :-, !Ç) + Br!Ç) + ç) + Br!Ç)
H H H H H
Scheme 135
The catalytic replacement of halogen atoms by alkynic groups is reported to take place
more readily with 2- than with 4-iodoimidazoles (B-76MI40701). Again, this observation
must be treated with suspicion.
1-Methyl-5-chloroimidazole reacts with naphthyllithium or naphthylsodium more quickly
than with butyllithium to give the 5-lithio (or -sodio)-l-methylimidazole along with the
2-metalated isomer. Bromine and iodine atoms are replaced with much more facility than
chlorine (75CHE343).
448
Imidazoles and their Benzo Derivatives: (ii) Reactivity
4.07.3.7 Metals and Metalloid-linked Substituents
The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly
novel. The compounds do, however, prove a means of introducing a variety of functional
groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can
only occur readily when there is no alternative site for the metal. Therefore, only N-
substituted imidazoles are of synthetic utility, and it may be necessary to select an N-
substituent which can be removed later. For this reason, benzyl (removed by reductive or
oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed
by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium)
groups have proved useful in this context. A typical reaction sequence is shown in Scheme
136 (78JOC4381, 77JHC517). In addition, reactions with aldehydes and ketones (to forrn
alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form
carboxylic acids) have found application (B-76MI40701).
(), ( F (Ju DMF I ()CHO
N N N
;/ CP 'cof CPh\ CPh,
C)C0 2 Et
CPh 3
N
(),
N
H
()N=NNHPh ..!:!9.... ij \NH
N N;> z
CPh 3 CPh 3
Scheme 136
While l-alkylbenzimidazoles readily form the 2-sodio and 2-lithio derivatives, 5-bromo-
l-ethylbenzimidazole does not react with phenylsodiurn or amylsodium. In addition, the
rnetalation of 1-arylbenzimidazoles is appreciably complicated by side reactions. Some of
these problems can be overcome by the use of o-anisylsodium (7ICHEI163).
Lateral metalation can be a complication, and this occurs in compounds such as 1,2-
dimethyl- and I-benzyl-imidazoles, and with 2-methyl- and 2-benzyl-benzimidazoles. Sub-
sequent reactions of these compounds take place at the side-chain carbanion centre
(73JOC4379, 74JOC2301).
4.07.3.8 Substituents Attached to Ring Nitrogen Atoms
4.07.3.8.1 -Aryl groups
N -Aryl substituents usually depress the basic properties of the imidazole or benzimidazole
nucleus. The effects of substituents on the aryl group are evident from the data listed in
Table 7 which also lists rate constants for quaternization with iodoethane, a reaction which
is dependent upon the nucleophilic character of the pyridine-type nitrogen (70CHE194). A
phenyl group withdraws electrons from the imidazole ring, but does so rather weakly. The
p value of +0.753 for the protonation process is in accord with weak electron transfer frorn
the phenyl substituent to the basic nitrogen.
Table 7 Basic pK. Values and Rate Constants for Ethylation of I-AryJimidazoles in Acetone (70CHE194)
i-Aryl
substituent
pK.
k X 10 6
(dm 3 mol-I S-I)
i-Aryl
substituent
pK.
k X 10 6
(dm 3 mor 1 S.I)
None
poOH
m-OH
p-Me
5.10
5.35
5.23
5.24
15.7
22.6
19.6
19.0
m-Me
p-Sr
p-Ac
p-NO z
5.24
4.91
4.54
3.96
16.9
11.0
10.8
7.8
In many instances the aryl and azole rings may not be completely coplanar. This state
of affairs becornes more common when there are other aryl groups present and where there
Imidazoles and their Benzo Derivatives: (ii) Reactivity
449
are substituents (even methyl) on adjacent carbon atoms. Both dipole moment and spectro-
scopic studies have demonstrated this. In the l H NMR spectra, the ortho protons of phenyl
are deshielded, and in instances in which there is considerable loss of coplanarity the phenyl
resonance often appears as a singlet.
Electrophilic substitution reactions of 1-phenylimidazoles frequently involve substitution
on the benzene rihg. When I-phenylimidazole is nitrated with a mixed nitric-sulfuric acid
reagent the major product is l-(p-nitrophenyl)imidazole. Such nitration has been shown
to involve the imidazolium species as substrate. Nitration in acetic anhydride yields only
the nitrate salt.
Oxidation and reduction procedures have little effect on 1-aryl substituents which are
also very difficult to remove. When, however, there are strongly electron-withdrawing
groups present in the benzene ring, nucleophiles are effective in promoting dearylation.
Thus, a 2,4-dinitrophenyl group at N-1 of histidine is cleaved by alkaline hydrolysis,
aminolysis or hydrazinolysis. On the other hand, 1-(2-pyridyl)imidazole is cleaved neither
by 2M sodium hydroxide nor by 2M hydrochloric acid.
The thermal rearrangemen t of N - to C -arylimidazoles has been discussed earlier (Section
4.07.1.2.2).
4.07.3.8.2 Alkyl groups
The N -alkyl compounds have lower boiling and melting points than their C -alkyl isorners,
as well as being much more soluble in non-polar solvents (Section 4.06.4.1).
While removal of an N -alkyl substituent is not always a feasible process benzyl groups
can be removed by reduction with sodamide or by catalytic hydrogenolysis. If such reductive
methods fail, an oxidation with chromium trioxide in acid may be successful. Other groups
are not so readily displaced, but a procedure involving transalkylation with benzyl chloride
followed by debenzylation can be employed to convert 1-methylimidazole into imidazole
(Scheme 137). The reaction is capable of extension and operates because the quaternary
salt is in equilibrium with both 1-alkylimidazoles and the alkyl halides. Under conditions
in which the more volatile alkyl halide can escape from the system the 1-benzylimidazole
builds up.
( N c; ..NCHPh ( NCHPh ( N
'I \\ ,PhCH 2 CI. :: + )\ 2 'I \ 2 'I \\
;> ..../ Cl - -MeCI Iiq NH ;>
N N . J N
Me Me H
Scheme 137
The dequaternization of imidazole quaternary salts is a process which has been known
for many years, but which has only recently been studied systematically (77 AJC200S). Pyrolysis
of imidazolium halides disubstituted on nitrogen by alkyl (or aryl) groups gives 1-substituted
imidazoles. Usually the reaction is carried out at about 240 0 C in vacuo so that the
1-substituted imidazoles can be distilled from the reaction vessel as they are formed. It is
likely that the process is of the SN2 type - this is evident from the behaviour of differing
alkyl groups, and from a study of the effects of different anions on the reaction. The facility
with which groups are cleaved from imidazolium diminishes in the order: allyl (2.8) > methyl
(1.0) > benzyl (0.6) > ethyl (0.14) > butyl, propyl (-0.04-0.09) > isopropyl (-0.01-0.03)>>
phenyl, vinyl (0). The values in parentheses refer to relative cleavage rates compared with
methyl. The reaction conditions are not typical of an SN1 reaction, and the above reactivity
sequence does not correspond with carbonium ion stability. In addition, non-nucleophilic
and very bulky anions (e.g. perchlorate, tetraphenylborate) will not promote the reaction.
In the decomposition of (246; R = Me, R' = Et, X = I, Br, Cl) the proportion of 1-methyl-
imidazole increases as the nucleophile becomes smaller (in the ratio r: Br -: Cl- =
1: 1.5: 2.3). The process can then be envisaged as competing SN2 attacks at Rand R' with
the least sterically hindered alkyl group being converted most readily into the alkyl halide
(Scheme 138). An SN2' process could account for the high reactivity of allyl, although some
SN1 character in this instance cannot be ruled out. Electron-withdrawing groups at C-4 of
imidazole favour cleavage of the adjacent N -alkyl bond. Conjugated groups such as vinyl
and phenyl are not cleaved.
450
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
R
(Y'\
/?:.N ) f/ NR f/ N
( :) X- 1.:....) + I.:....J + RX +R'X
} N ,
R'/
(246)
!?: "':lCH2- CH2 f/ N f/ NCH2CH=CH2
(, ) / I.:....J + 1.:....)
e )- e N
f
Scheme 138
Methyl and methylene groups attached to nitrogen are not normally regarded as 'reactive',
but sorne metalation experiments using 1-benzylimidazole as substrate indicate reaction at
the exocyclic methylene (S-76MI40701).
4.07.3.8.3 Alkenyl and alkynyl groups
UV studies suggest that in 1-vinyl-imidazoles and -benzimidazoles there is conjugation
with the heteroaromatic ring. Certainly the reactivities of such compounds would indicate
that they are not normal alkenes, nor are the alkynyl compounds typical of other alkynes.
They are very prone to polymerization processes, and electrophilic addition reactions are
often quite difficult to accomplish. When 1-styrylimidazoles are prepared, the trans com-
pound is rnuch more likely to eventuate as the more stable isomer (73CJC3765, 76JCS(P1)545).
1- Vinylimidazole does not react at low temperatures with hydrogen halides, but at 25 oc
it forms a hydrochloride when treated with HCl gas in carbon tetrachloride. Halogenation,
too, is resisted and can be achieved only partially. The reaction is believed to proceed
through initial complex formation followed by addition at the exocyclic double bond. The
vinyl function can, however, be reduced by catalytic hydrogenation over Raney nickel, but
not as readily as an exocyclic S-vinyl group (74CHE1217, 80AHC(27)241).
Oxidation sometimes gives the carboxylic acid, but the use of hydrogen peroxide (as with
other free radical initiators) causes polymerization. Under the influence of radical initiators
it is possible to induce thiols to add in an anti-Markownikov manner across an N -vinyl
group (Scheme 139), while ionic catalysts promote normal electrophilic addition (75CHE1416).
(X I N
N
I
CH
/ "-
RS Me
(X I N
RSH N/
CH=CH 2
,
Me20 CNIN= NO CN)Me2
RSH
(X i N
N
CH 2 CH 2 SR
Scheme 139
Therrnal rearrangement of 1-vinylimidazole gives a 7: 1 ratio of 2- and 4-vinyl isorners.
Sirnilar treatment of 1-allylimidazole gives about equal quantities of the 2- and 4-allyl
cornpounds. Irradiation at 300 nrn transforrns trans-1-styrylimidazole into the cis isorner
(247) which then photocyclizes to (248; Scheme 140) (76JCS(Pl)75).
() ()
N N
I 3Wnm I
......c":- ....H ......c":- ....Ph
H C H C
I I
Ph H
(247)
Scheme 140
With potassium hydroxide in THF at OoC 3-(2-amino-l-benzimidazolyl)propyne (249)
isomerizes to the allene (250; Scheme 141) (75CHE461).
hv
----+
C èo
N I
ß
(248)
Imi(1azoles and their Benzo Derivatives: (ii) Reactivity
451
(X I N)NHz T: oCI
N
CHzC=CH
(249)
(X N
I )NH z
N
CH=C=CH z
(250)
Scheme 141
4.07.3.8.4 Acyl and aroyl groups
Probably the most important property of these compounds is the propensity of N -acyl-
imidazoles and -benzimidazoles (as well as other azoles) to become involved in reactions
which result in acylation of an attacking nucleophile. The compounds are unlike other
tertiary amides in that there is little or no contribution from resonance structures of type
(251) to the hybrid (Scheme 142); hence the positive nature of the carbonyl carbon is
undiminished. The electron pair on the annular nitrogen is part of the aromatic sextet. The
compounds are known as 'azolides' generally, and more specifically as 'imidazolides'.
Because the annular nitro gens are not directly adjacent imidazolides are more reactive than
the corresponding pyrazolides.
/R 1 + /R 1 + /R 1
R-C-N +---+ R-C-N ..- R-C=N
II 'R z I 'R z I 'R z
o 0- 0-
(251)
Scheme 142
The azolides are able to participate in a wide variety of nucleophilic 'olysis' reactions
which form aldehydes, ketones, carboxylic acids, esters, amides, thiol esters, hydrazides
and anhydrides (Scheme 143). In addition, 1-trifluoroacetylimidazole (252) is a convenient
reagent for the conversion of aldoximes into nitriles (Scherne 144) (SlBCJ1579).
ImH + RCOR'
RCOzH + ImH ".....H 2 0 tR'MgBr RCHO + ImH
.--z I' LiA
f/ \ H NNHR'
R'O l(;> 2 I RCONHNHR' + ImH
RCOzR'+ImH OR' ...........R'C0 2 H
R'NH2/ "'-
I \ R'SH RCOzCOR' + ImH
RCONHR' + ImH \
RCOSR' + ImH
ImH = imidazole
Scheme 143
r==\ RCH=NOH
N V NCOCF 3 I RVN OCOCF 3
(252) r H
(,
L NH
/: + ",
- RC=N + HN", ':NH
"'V/
77-99% OCOCF 3 -
Scheme 144
Among the most useful of these azolides is 1, l'-carbonyldiimidazole (253). This compound
is extremely reactive towards nucleophilic reagents because the carbonyl group is subject
to electron withdrawal from both sides. Also, although it is very rapidly hydrolyzed by
water at room temperature with vigorous carbon dioxide evolution, the compound is
crystalline, and much more easily handled than phosgene which has similar reactivity. In
the formation of 1-acylimidazoles compound (253) reacts in equimolar proportions with a
carboxylic acid in an inert solvent to give practically quantitative yields. This reaction
comprises a two-step mechanism (Scheme 145) in which the carboxylic acid reacts initially
452
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
with the diazolide, and then an intermolecular transacylation, in which imidazole is released,
gives the 1-acylimidazole. Such transacylations render 1,l'-carbonyldiimidazole a valuable
synthetic reagent with applications in the synthesis of esters, amides (and peptides),
hydroxamine acids, hydrazides, anhydrides, acyl halides, diacyl peroxides, C -acyl
triphenylphosphine alkylenes and peracid esters. In peptide synthesis, the mild conditions
of the reaction minimize racemization (Scheme 145).
o
N N- -N N
\ d '-=-'
(253)
Ii. RCO,H
j ii.R'NH,
RCO,H þ [ N CO,CORJ
lImH
RCONHR' + CO, + ImH
N NCOR + CO 2 + ImH
bJ
Scheme 145
When (253) reacts with phosgene the I-acyl chloride product (254) can react with arnines
to give amides (79LA1756), while in a further transfer reaction with ketones the compounds
(255) and (256) are produced (Scheme 146) (80H(14)97). Acylation of aromatic hydrocarbons
using 1-acylimidazoles in the presence of trifluoracetic acid gives high yields provided that
the aryl compounds are electron rich, e.g. p-dimethoxybenzene, thiophene, anisole
(80BCJ1638).
Ph
(254)
HNJ F\ 0
---+ N N-C-N
Y II
o
o
II COCl, F\
N N-C-N N NyNCOCI
'==-' '-=-'
[)
N
I
Me-C-Ph
I
N
LJ
(255)
Ph, ""CH,
C
I
N
+ (J
(256)
Scheme 146
In addition to transacylations, imidazolides possess a number of other useful synthetic
applications. 1-Formylimidazole is an effective reagent for introducing an aldehyde group;
it decomposes above its melting point with evolution of carbon monoxide to reform
imidazole. The formation of aldehydes and ketones (in 50-95% yields) when lithium
aluminum hydride and Grignard reagents, respectively, react with imidazolides has been
comrnented on above. A further source of aldehydes is the reaction in which 1-acety-
limidazoles are treated by the slow addition of a reactive molecule such as indole in acetic
anhydride at 125 0 C. The major product (257), formed by electrophilic attack at C-3 of
indole by 1,3-diacetylimidazolium, can be hydrolyzed to the aldehyde (258; Scheme 147).
Further reactions analogous to those of phosgene are shared by 1,l'-carbonyldiimidazole.
In inert solvents ureas are formed with primary amines; secondary amines yield imidazole-1-
carboxamides. If the reaction conditions are controlled it is possible to achieve a 1: 1
reaction between the primary amine and (253) resulting in the formation of 1-carboxamides
which dissociate at low temperatures to isocyanates. With alcohols and phenols (253) forms
diesters of carbonic acid. Monoesters of phosphoric acid, and the acid itself, react with
(253) at room temperature with elimination of carbon dioxide and formation of the
imidazolium salts of imidazolides, (ImH 2 t (ROP0 2 Im)-, which are effective phosphorylat-
ing agents in solution. Furthermore, the reaction of (253) with water to produce carbon
dioxide has been recommended in preference to the use of PCI s for the microanalytical
estimation of carbon and hydrogen in organic compounds.
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
453
AC)
'Î-k o
U) N/
H H
(257) (258)
Scheme 147
Kinetic studies of the nucleophilic reactions of azolides have demonstrated that the
aminolyses and alcoholyses proceed via a bimolecular addition-elimination reaction
mechanism, as does the neutral hydrolysis of azolides of aromatic carboxylic acids. Aliphatic
carboxylic acid azolides which are subject to steric hindrance can be hydrolyzed in aqueous
medium by an SN1 process. There have been many studies of these reactions, and evidence
supporting both SN1 and SN2 processes leaves the impression that there are features of
individual 'olysis' reactions which favour either an initial ionization or a bimolecular process
involving a tetrahedral intermediate (80AHC(27)241, B-76MI40701).
The imidazole-catalyzed hydrolysis of esters has been described earlier (Section
4.07.1.3.9). In the uncatalyzed aminolysis of 1-acetylimidazole, strong bases react with the
azolide in a second order reaction (which is faster than general base catalysis of hydrolysis),
while weak bases simply act as general base catalysts of hydrolysis. The rate-determining
+
step is the dissociation of the ion-pair, RNHzAc' 1m - (Scheme 148). Usually the expulsion
of an amine anion from an amide in aqueous solution is very difficult without general
acid-base catalysis, and the fact that such reactions of 1-acylimidazoles with nucleophiles
occur at all is very largely a consequence of the much greater stability of an imidazole
anion compared with anions of other amines.
k I + k 2 +
RNH z + Adm RNHzAc. 1m - RNHzAc + Im-
.-. .-, If. H . II.H<
RNHAc ImH
Scheme 148
In a study of the kinetics of transfer of an acetyl group from 1-acetylimidazolium and
1-acetylimidazole to phenols the rate constants were found to be in close agreement with
those obtained for similar acetylation of thiols. As well as this, it was discovered that the
acetyl transfer reactions of the non-dissociating model, 1-acetyl-3-methylimidazolium
chloride, compared very closely with those of l-acetylimidazolium. This provided evidence
that many reactions of acetylimidazolium with reagents of type HY are merely acid-catalyzed
reactions of the anion Y- (B-76MI4070I).
Diimidazolides analogous to 1, l'-carbonyldiimidazole, e.g. 1, l'-thiocarbonyldiimidazole,
are similar to the oxy compounds but are rather less reactive; even so they are powerful
thioacylating agents.
Deacylation of azolides can be accomplished in weakly acidic or basic solutions, with
boiling water (or even a moist atmosphere) and by heating. Electron-withdrawing groups
elsewhere in the imidazole ring assist the process. A corollary of the decarbonylation by
heat of 1-acetylimidazole is the thermal decarboxylation of 1-alkoxycarbonylimidazoles
(259) to 1-alkylimidazoles (Scheme 149) (80AHC(27)241). When, however, the methyl ester
of 2-aminobenzimidazole-1-carboxylate is heated above its melting point in boiling anisole,
the ester function migrates to the exocyclic nitrogen. A cyano group at N-1 of imidazole
(l-cyanoimidazole can be prepared by the action of phosphoryl chloride on imidazole-1-
carboxamide) can be removed in aqueous solution (80H(14)1963).
f) * f)
N N
COzR R
(259)
Scheme 149
454
Imidazoles and their Benzo Derivatit'es: (ii) Reactivity
4.07.3.8.5 Nitrogen functions
(i) Nitro
The few 1-nitroimidazoles which are known are relatively stable, crystalline cornpounds
with characteristic UV and IR spectra (N-NO antisyrnrnetric vibration band in the region
-1640 ern -1). The thermolysis of these cornpounds has been mentioned earlier (Section
4.07.1.2.2).
(íi) Amino
l-Arninoirnidazoles can only be prepared by ring-synthetic rnethods. They are stable,
crystalliné corn pounds with rnelting points usually in excess of 100 o C. Rernoval of the
arnino group occurs on treatrnent with nitrous acid, but oxidation causes extensive
rnodification. Manganese dioxide converts 1,2-diarnino-4-phenylirnidazole into a rnixture
of 4-phenyl-l,2,3-triazole and 3-arnino-5-phenyl-l,2,4-triazine, while 1-arninobenz-
irnidazole sirnilarly gives 3-arnino-1,2,4-benzotriazines (80AHC(27)241, 77JOC542) (see also
Section 4.07.1.7). Oxidation of 1-arninoirnidazole quaternary salts gives azoirnidazoliurn
salts.
When ß-diketones and related carbonyl compounds react with 1,2- and 1,5-
diarninoirnidazoles, bicyclic products forrn after initial attack at the C- arnino function
(80AHC(27)241).
4.07.3.8.6 Halogen atoms
Most N -haloirnidazoles and their benzo analogues are rather labile cornpounds, but the
N -iodo corn pounds are stable probably because the iodoniurn cation is rnore stable than
other halogen cations. 1-lodoirnidazoles do not dissolve in acids or alkalies and decornpose
on heating with liberation of iodine. The rearrangernent of N - to C -halopyrazoles has been
observed and has also been postulated to occur with irnidazoles; N -iodoirnidazoles rnay be
interrnediates in the C-iodination process.
During the nitration of 1,2,4,5-tetraiodoirnidazole the N -iodo function is lost (B-
76MI40701).
4.07.3.8.7 Silicon, phosphorus, sulfur and related groups
1-Trialkylsilyl-irnidazoles and -benzirnidazoles are prepared by reaction of the bases with
trialkylsilyl chlorides or hexaalkyldisilazanes. The derivatives are therrnaUy stable but can
be cleaved by hydrolysis or alcoholysis. The cornpounds also react srnoothly in acylation
reactions. When treated at 180 0 C with DMSO, 1-trirnethylsilylirnidazole gives the N-
(rnethylthio)rnethylirnidazole (260) via a Purnrnerer reaction. The corresponding derivatives
of 2-rnethylirnidazole and benzirnidazole react likewise (Scherne 150) (79JHC415). Oxidation
of 1,1' -bis(trirnethylsilyl)-2,2' -bi(2-irnidazolinyl) with manganese dioxide gives 2,2'-
biirnidazolyl (74S815).
1Ý'-- S .
2 N N IMe 3
b.J
Me2S0 ,
180"C.6h
1Ý'--
N NCH 2 SMe + (Me 3 SihO + ImH
b.J
(260)
Scheme 150
Most 1-trirnethylstannylimidazoles are rnore stable towards hydrolysis than the foregoing
silylated derivatives.
Irnidazolides of phosphoric acid have proved very useful as phosphorylating agents. With
arnrnonia or arnines they forrn phosphorarnides, with alcohols phosphate esters result, and
with carboxylic acids the products are acyl phosphates. Adenosine diphosphate has been
prepared by converting the rnonophosphate into its irnidazolide (261; R = adenosyl) and
then treating this product with orthophosphate (Scherne 151). The irnidazolides of phos-
phoric acid are hydrolyzed very rapidly by water, the di- and tri-irnidazolides being
particularly susceptible to rnoisture. Greater than 80% conversions of aldoxirnes into nitriles
are possible using irnidazolides of phosphorus (78ZN(B)1033). Sulfur oxidizes 1-diphenylphos-
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
455
phinoimidazole to the phosphinato analogue (74CJC3981). When 1-dialkylphosphory-
limidazoles with short alkyl chains decompose below 80 0 C to give the 1-alkylimidazole,
trialkyl phosphate and 1,3-dialkylimidazolium polyphosphate, the reaction is considered
to result from nucleophilic attack of the pyridine nitrogen of one 1-dialkylphosphory-
limidazole on the a-alkyl carbon of another (78JOC4853).
o 0 0 0
II 1Ý'-- II II II
RO-P-N N + HO-P-OH --Þ RO-P-O-P-OH+lmH
ò- bJ 6- 6- 6-
(261) R = adenosyl
Scheme 151
4.07.3.8.8 N-Oxides and N-hydroxy compounds
The photolysis of imidazole and benzimidazole N -oxides has been described earlier
(Section 4.07.1.2) as has their tautomerism (Section 4.06.5.2).
The compounds are mostly crystalline, although hygroscopic, and are often light sensitive.
This hygroscopic nature may lead to their isolation as hydrates. Deoxygenation can occur
on heating, while some compounds of this type decompose above their melting points.
When there are both N -hydroxy and N -oxide functions in the same molecule inter- and
intra-molecular hydrogen bonds can form. Thus, 1-hydroxy-2,4,5-triphenylimidazole 3-
oxide is associated in chloroform solution and even exists as trimers at high dilutions.
The N -oxides and N -hydroxy compounds have acidic properties, but basic properties
are not suppressed to a great extent since salts with picric and hydrochloric acids can still
be formed.
Removal of an N -oxide function utilizes the usual reagents such as zinc and acetic or
hydrochloric acids, sodium borohydride, hydriodic acid, phosphoryl chloride, sodium
dithionite, phosphorus trichloride or hydrogenation over Raney nickel. When 1-hydroxy-2-
methyl-5-phenylimidazole (262) reacts with butyllithium and hexachlotodisilane this also
induces dehydroxylation (Scheme 152) (80AHC(27)241). At times, as with other heterocyclic
N -oxides, deoxygenation with phosphorus halides can introduce a halogen atom at C-2 of
imidazole (75JCS(Pl)275).
Me Me 0-
N1Ý'--NOH BuLi N1Ý'--N/
bJ bJ
Ph Ph
(262)
Me
Si2C16 N1Ý'--NH
bJ
Ph
Scheme 152
When 1-hydroxy-3-imidazoline 3-oxides (263) are treated with HCl they dehydrate
forming imidazole 3-oxides (Scheme 153) (73CHE1175). Reduction of 4H -imidazole N-
oxides with borohydride leads to either I-hydroxy-imidazolines or -imidazolidines, depend-
ing on the position of the oxide function. Under the same conditions 4H -imidazole
1,3-dioxides give 1,3-dihydroxyimidazolidines (76CHE1280). The 4H -imidazole N -oxides
are prepared by heating 5,5-disubstituted l-acyloxy-3-imidazoline 3-oxides in vacuo.
0-
'-+ Me
N\
Ph NOH ..!:!9....
Me
HN Me
P h i PCI,
V " - ----"-+
Me 0
N Me
Ph NH
Me
(263)
Scheme 153
Dehydrogenation of 1-hydroxyimidazoles and their 3-oxides with lead dioxide gives
N -oxides and N,N'-dioxides of imidazolyls. These short-lived radicals are also formed
when alkali salts of I-hydroxyimidazole 3-oxides react with halogen in polar organic solvents.
Hydroquinone converts the N,N'-dioxides back into 1-hydroxy 3-oxides.
Both the N -hydroxy compounds and the N -oxides which are in tautomeric equilibrium
with hydroxy compounds form O-acyl and O-aroyl compounds, and such esters can act as
456
Irnidazoles and their Benzo Derivatives: (ii) Reactivity
acyl transfer reagents. Methylation, cither with iodornethane in alkaline medium or with
diazomethane, converts imidazole N-oxides into the N-methoxy derivatives (B-76MI40701).
Alkaline cleavage of 2,4,4-trimethyl-5-phenyl-4H -imidazole 1-oxide gives oxirnes of
(X- acylaminoketones as products (SOAHC(27)241).
One of the difficulties in studying directional effects of an N -oxide group in irnidazoles
has been the synthesis of examples with free ring-carbon positions; few of these have been
described (74JHC615, 77JCS(Pl)672). Indeed, the 3-oxide function of 1,4,5-trimethylimidazole
3-oxide (264; R = Me) exerts a similar effect to that in pyridine N -oxide: nitration is directed
to C-2 via the free base species (Scheme 154) (77JCS(Pl)672). Although the Reissert reaction
failed to introduce a cyanide group into the ring, when the oxides are converted into
quaternary salts and treated with potassium cyanide, the 2-cyanoimidazoles result. As had
been found earlier with benzimidazole N -oxides, the imidazole 3-oxides can undergo
1,3-dipolar additions. With phenyl isocyanate (264; R = CH 2 Ph) gives N -(1-benzyl-4,5-
dirnethylirnidazol-2-yl)-N,N'-diphenylurea (266) via the cycloaddition product (265) which
is subject to ring cleavage, decarboxylation and reaction with further phenyl isocyanate.
Sirnilarly, with DMAD (267) is forrned (Scheme 154) (75JCS(Pl)275).
0-
Me +/
Me()NO z
N
Me 'H, 04
R=Me IN03
Me +
//NOMe
Me( ))
N
R
KCN
-
Me N
Me( ))CN
N
R
Me,sy
Me + /0-
ij \ PhNCO
Mei.:...'/ R=CH,Ph '
N
R
(264)
R=CH,Ph/
/MeO,CC=CCO,Me
Me
ij COzMe
Mei.:...N)-tHcoCOzMe
CHzPh
(267)
Me N/OyO
Me( kNPh
N H
CHzPh
(265)
P'hCNO l-co,
Me N
[ \\ Ph
Me N/-NCNHPh
CHzPh
(266)
Scheme 154
2,2-Disubstituted 2H -benzimidazole N,N'-dioxides (268), when treated with sodiurn
borohydride, are reduced in a stepwise manner to the mono-N-oxides and then to the
isobenzimidazoles (Scheme 155).
0-
o: ) > + NaBH o: --N > NaBH o: --N >
Rz Rz R 2
+
I I
0- 0-
(268) R = alkyl
Scheme 155
4.07.3.8.9 N- Ylides
A number of the reactions of imidazoles and benzimidazoles with dienophiles such as
DMAD appear to be reactions of the azole-N-ylides (see Section 4.07.1.8.1).
4.08
Imidazoles and their Benzo Derivatives:
(iii) Synthesis and Applications
M. R. GRIMMETT
University of Otago
4.08.1 RING SYNTHESIS FROM NON-HETEROCYCLIC COMPOUNDS
4.08.1.1 Formation of One Bond
4.08.1.1.1 Formation of the 1,2- (or 2,3-) bond
4.08.1.1.2 Formation of the 1,5- (or 3,4-) bond
4.08.1.1.3 Formation of the 4,5-bond
4.08.1.2 Formation of Two Bonds
4.08.1.2.1 From [4 + 1] carbon fragments
4.08.1.2.2 From [3 + 2] carbon fragments
4.08.1.3 Formation of Three or Four Bonds
4.08.1.3.1 From reactions of ammonia, amines or formamide with functionalized carbonyl
compounds
457
457
457
464
466
467
467
473
482
4.08.2 SYNTHESIS BY TRANSFORMATION OF OTHER HETEROCYCLES
4.08.2.1 Ring Expansions
4.08.2.2 Transformations of Other Five-membered Rings
4.08.2.2.1 Pyrazoles and indazoles
4.08.2.2.2 Formation of benzimidazoles from imidazoles
4.08.2.2.3 2-Imidazolines from cyclic ureas
4.08.2.2.4 From other five-membered heterocycles containing nitrogen only
4.08.2.2.5 From oxazoles and isoxazoles
4.08.2.2.6 From oxadiazoles
4.08.2.2.7 From five-membered rings containing sulfur
4.08.2.2.8 Imidazoles from condensed heterocycles
4.08.2.3 Ring Contractions
4.08.2.3.1 From pyrimidines
4.08.2.3.2 From pyrazines and quinoxalines
4.08.2.3.3 From other six-membered heterocycles
4.08.2.3.4 From seven-membered heterocycles
4.08.3 APPLICATIONS AND IMPORTANCE
482
487
487
489
489
489
490
490
491
492
493
493
493
494
495
496
496
497
In contrast to the pyrazoles, there is no single method of wide application for the synthesis
of imidazoles, although the use of o-phenylenediamine and related compounds in benz-
imidazole synthesis might merit such a description. The common synthetic rnethods are
divided into those which build up the imidazole ring frorn largely acyclic precursors, and
transformations of other heterocyclic species. Ring-synthetic procedures can entail the
formation of between one and four bonds.
4.08.1 RING SYNTHESIS FROM NON-HETEROCYCLIC COMPOUNDS
4.08.1.1 Formation of One Bond
4.08.1.1.1 Formation of the 1,2- (or 2,3-) bond
C-N
/ \
C f:
'N"
()
N
H
457
C-N
+-- / \
C'N. ß
458 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
The earliest example of this type of synthesis was probably the Wallach synthesis
(70AHC(12)103) in which an N,N'-disubstituted oxamide underwent ring closure with phos-
phorus pentachloride. The chloro-containing intermediate which forrned was reduced by
hydriodic acid to give a I-substituted imidazole. An adaptation of this reaction to the
synthesis of 5-chloro-l-methylimidazole is shown in Scheme 1.
r Cl NMe :') H
CONHMe PO, .....c,? Cl-CTN
I -----+ I ---4 / '-\\
CONHMe C Cl ......CH2
c(" "'NMe
Me
Scheme 1
Cl()
N
Me
There are a nurnber of syntheses which use an alkylene or arylene 1 ,2-diarnino compound
in which one of the amino groups is acylated or thioacylated. Functionalization of the
starting rnaterial rnust also be such that cyclization can give an aromatic product. Perhaps
the best-known example of this type is the forrnation of 2-substituted benzirnidazoles by
the cyclodehydration of o-aminobenzanilides (1) in mineral acid (Scheme 2). This reaction
can be adapted to the preparation of 2-aminobenzimidazoles if an alkyl halide is utilized
to induce cyclodesulfurization of an N-(2-aminophenyl)thiourea (2) (S-73MI40800,
75MI40800,74541). Such thioureas are available by condensation of phenyl isothiocyanate
with o-phenylenediarnines. Depending on the nature of the substitution, these thioureas
can be decomposed thermally to give benzirnidazoline-2-thiones (3); in some instances the
energy input required is only rninimal. For exarnple, when the o-phenylenediarnine is
substituted on nitrogen by a ß-dimethylarnino function, the reaction with phenyl isothiocyan-
ate leads directly to a I-substituted benzirnidazoline-2-thione. There is, of course, sorne
classification difficulty with these reactions since they could be considered to involve
forrnation of both the 1,2- and 2,3-bonds (Section 4.08.1.2.1). N,N' - Diacylated 0-
arylenediamines (4) cyclize in the rnelt to give 2-rnethyl- and 2-phenyl-benzirnidazoles in
a 3: 1 ratio (Scherne 2) (74JOU1542).
Ol NH 2 ' (el N
NHCOPh /Ph
N
(I) H
H
N>=S
N
H
(3)
.1
..-
O NH 2
I NHCSNHR
(2)
MeI/EtOH
(e N
I )NHR
N
H
R' O INHCOMe
R 2 NHCOPh
(4)
R' (e N
2 I >Me +
R N
H
RI N Ph
R2 1
H
Scheme 2
The reductive cyclization of o-benzoquinonedibenzimide (5) with triphenylphosphine
gives I-benzoyl-2-phenylbenzimidazole, perhaps by the mechanisrn outlined in Scherne 3
(74CRV279).
CX NCOPh (J( Ñ-COPh
"7 PhJP" . .
---- I Ph
>--NCOPh N
..T\ +
(5) O-PPh)
Scheme 3
COPh
\
(X N Ph
I X +
J O-PPh)
COPh
!
(I N
I )Ph
N
----+
-
In a study of the forrnation of benzimidazoles by the peroxy acid-catalyzed cyclization
of o-acylamino-N,N-dialkylanilines, it has been demonstrated that the reaction proceeds
via an N-oxide interrnediate, since it has proved possible to synthesize this N-oxide and
cyclize it under the reaction conditions (S-73MI40800). Both ortho-N-acylated and -N-
lmidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 459
aroylated arylamines and nitrobenzenes are able to be cyclized under suitable conditions
to give benzimidazoles. The tricyclic derivative (6) involves a skeletal rearrangement in
its formation (Scheme 4). In a reaction of the same class, sunlight converts quinone di-
benzenesulfonamides (7) into a number of products, arnong which are benzimidazoles
(8; Scheme 4).
((CHz)n
CX N I
I 'J PPA
NHCOR 145-150'C
Me
) QQ I (CHZ)n_1
. ,/
N
N
R
(6)
?)::,'
MezNY
NSOzPh
(7)
0HCOMe
. NOz
Sn/HOAc
A
er N
I )Me
N
H
Me
PhSOzNH \
MezN 1
(8)
Scheme 4
I
One of the amino functions in o-phenylenediamine can be functionalized in other ways.
Thus high yields of polychlorobenzimidazoles (9) are forrned when sulfuryl chloride reacts
with o-amino-N,N-dialkylanilines, while the Schiff base (10) eliminates methanol when it
cyclizes to the 2-substituted benzimidazole (Scheme 5) (75MI40800).
N(CHZRh
VNHz
S0202
CHzR
Cl I
) Cl N\R
Cl 1
Cl
(9)
H
f1(N
VNH z CN
OW
MeOH
N
rj( A N
NHz OMe ---+ 0--.N
O H
Scheme 5
The most useful method of synthesis of benzimidazole N-oxides seems to be the reductive
ring closure of N-acyl-o-nitroanilines with ammoniurn sulfide or sodiurn borohydride. Note,
however, that N-(2,4-dinitrophenyl)amino acids have been converted into compounds
designated as 6-nitrobenzimidazole l-oxides (B-73MI40800). Such methods, which involve
reduction in situ (or prior to cyclization) of a nitro group ortho to a functionalized amino,
have becorne relatively cornmon. Thus N-benzylidene-2-nitroaniline derivatives (11) can
be reductively cyclized to 2-phenylbenzimidazoles in yields rather higher than when 0-
arylenediamines and aldehydes (Section 4.08.1.2) are used (Scheme 6). In the absence of
oxygen, acids catalyze the formation of 2-substituted benzimidazoles from the aldehyde
o-aminophenylhydrazones, again available by reduction of the nitro compounds (12).
Although this rnethod is complicated it gives yields of 67-86% and provides a useful
alternative for benzimidazoles with sensitive groups at C-2. The reaction may proceed
through intermediate 1,2,3,4-tetrahydro-l,2,4-benzotriazines (13) which are formed by
addition of the amino group to the hydrazone double bond (Scheme 6) (79JHC1005).
Under reductive conditions an o-nitro-N;N-dimethylaniline (14; R = Me) is converted
into a benzirnidazolinone in a reaction which may involve transition rnetal complexes.
When, however, the N,N-diethylaniline (14; R = Et) is subjected to the same reaction
conditions, the product is the benzimidazole (15; Scheme 7).
In the forrnation of the l, I' -bibenzimidazole (16) the second benzimidazole ring is forrned
by cyclization of a rnonoacylated o-phenylenediamine (8lJCS(Pl)403), while thermolysis of
the anils (17) derived from 2-azidoaniline also gives good yields of 2-aryl-substituted
460 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
CX N h
R I
N0 2
(11)
NH
(X 'N
I H -R
N0 2
(12)
H,. Pd/C )
Benzolriazines
N)R
N
H
(C N
\ )CH 2 0AC (
N
EI
(15)
ZnCl,
Ac,O
(R=EO
(X N
R I N>Ph
H
R=H,47%
R=Me, 33%
(EtO),P, Bu'Ph
reflux
H
'NH2
I R
N H
H
(13)
I
NH 1
I )
N)<: rj(NH H2
N NHCHR
H
NH
(X 'N H+
\ II --.
HC-R
NH 2
Y
Scheme 6
rj(NR 2
N02
(14)
Scheme 7
ZnCl,
Ac,O
(R=Me)
Me
(C N
) I >=0
N
Ac
benzirnidazoles. Yields are in the range 48-96% (Scherne 8) (74CRV279). Rernarkably high
yields of benzirnidazolinones are obtained when aroyl azides (18) are heated in acetic
anhydride or xylene. The reaction is of unknown rnechanism, but that sorne of these
cycIizations which form benzimidazoles involve nitrene interrnediates is evident. The partici-
pation of such intermediates in, for exarnple, the therrnolysis of o-azidoanils and the
deoxygenation of o-nitroanils of arornatic aldehydes has been reviewed recently (79CHE467).
0 NH2
N=N
MeOCH=D
W
MeCHO
(X I N"::::vR
N)
(17)
R'
(C N
I >=0 (
N
Ac
R'=Ac ifR=H
R'=MeifR=Me
Ac,O..l
R=H,Me
(C N
I )Me
N
MeOCH=NV
.l
-)
N)R
N
H
PPA
-
(C N
\ )Me
N
J()
Me\. \
N #
(16)
0 1 CON) xylene
NHR .l
(18) R=H, Me, COPh
Scheme 8
R
N>=o
N
H
When an o-arylenediamine is treated with phosgene a polymer is formed which can be
degraded therrnally to produce the o-diisocyanate (19), a source of a range of benz-
irnidazolinones; the corresponding diisothiocyanates produce benzimidazolinethiones
when heated with alcohols (yields about 60%) (Scherne 9) (SOJCSfPl)260S).
lrnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 461
Me
0 l NH 2
NH 2
i, COClz
ii..å
Me
0 1 NCO HzO
) -
NCO
(19)
Me H
N>=O
N
H
H H
MeLyN>=o
N
I
C0 2 Me
O INCS
NCS
H
N>=s
N
I
C
S:7 'OR
Scheme 9
Although synthesis of the desired acyclic precursors may not always be a simple procedure,
there is a host of reactions of suitably functionalized 1,2-diaminoalkanes which give
uncondensed imidazole products. Many of these are related to some of the foregoing
preparations of benzimidazoles. For example, when the ß-glucopyranosylarnine (20) is
treated in sulfuric acid with an acetylating mixture, the imidazole product (21) is formed
in good yield (Scherne 10).
CH 2 0H
H 1'L-<? 0 HOAc/ AczO
HO' NH -;; Me H Z S04
NHCOMe
(20)
rN Ð Me
/Z... þ Me
(AcOHC)) N)
I
AcOH 2 C (21)
Scheme 10
Oxidation of the Schiff bases (22) of diarninomaleonitrile monoarnide gives 4-
cyanoirnidazole-5-carboxamides with a variety of 2-substituents. When diarninomaleonitrile
reacts with formamidine, the condensation product (23) can form imidazoles in two ways.
Direct loss of ammonia gives 4,5-dicyanoimidazole, but isomerization, followed by cycliz-
ation in which HCN is eliminated, gives 4-amino-5-cyanoirnidazole. With further for-
marnidine this latter product is converted into adenine (Scheme 11) (79JOC4532).
NC X N= CR 2
H 2 N-C NH 2
II
o
NC N
H2NOC >--R
H
(22)
NC X NH 2
NC NH 2
NC 1 NHCH=NH
HN=CHNH z
)
NC NH 2
(23)
N
-NH, NCf )
NClL.. N
H
Jf
NC NHCH=NH
X
H 2 N CN
Scheme 11
-HCN
N
NC ( )
H 2 N N
H
Diphenylimidazoles, along with 4H-imidazoline-5-thiones (24) and the iminothiazolines
(25), are formed when diphenylglycine thioamides are cyclized in boiling toluene by
aluminurn chloride (Scheme 12). Use of hydrogen chloride in hot dioxane gave only (24).
Rather similar treatment of N-formylsarcosine-N-methylthioamide with acid leads to 1,3-
dimethylimidazoliurn-4-thiols (80AHC(27)241).
462 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
Ph Ph
Ph 2 C-NH Pht N Pht N Ph N
I \ AICI, )R + HN )R + Ph()R
C C -
-9'\ II'R PhMe S N
S NH 2 0 S N
H H
(24) (25)
Scheme 12
Dry hydrogen chloride induces ring closure of PhCH=NCCCN)=C(R)SMe to
chloroirnidazoles, and N-(1-cyanoalkyI)alkylidenearnine N-oxides (26) can be converted
by way of nucleophilic attack by thiophenol into imidazoles substituted at C-5 by thio-
phenoxy (Scherne 13). This latter reaction is accelerated by small arnounts of piperidine,
but inhibited by temperatures above the melting point of the N-oxide. The action of cyanide
ion on sirnilar nitrones gives cyanoimines which cyclize to imidazoles in 40-90% yield
(80JCS(Pl )244).
Scheme 13
The Schiff bases, which can be formed by the reactions of prirnary arnines with a-acylarnino
ketones (27), cyclize in the presence of phosphoryl chloride or phosphorus pentachloride
to give I-substituted imidazoles. If a substituted hydrazine is used instead of a primary
arnine the reaction gives 1-aminoirnidazoles, añd the versatility of this reaction is such that
it can also be adapted to the synthesis of bicyclic products such as the irnidazopyridine (28;
Scheme 14). The starting a-acylamino ketones can be prepared quite readily frorn a-arnino
acids (78LA1916). Ring closure of forrnylglycine amidines (29; R 1 =R 2 =R 4 =H; R S =
NH-alkyl), either induced thermally or by the action of phosphoryl chloride, gives l-alkyl-5-
arninoimidazoles (70AHC(l2)103).
PhS-
Jf'<
C=N
R'-dH
\+
N=CHR 2
I
0-
(26)
R H }Ph
c-c
/ \\
N W
-0'- '- + .:;;
HC
I,
R-
R' SPh
W F\
) NyNH
R 2
-H 2 0
o 4 R 5
4 H II 5 R'NH 2 R,H / POO,
R -C-C-R C-C
I / benzene
NHCOR 2 NHCOR 2 NR'
(27) (29)
":'NHNH 2
R 4 R 5
F\
) NVRI
R'
R4 H R 5
'C-C/
/ I POCl,
NHCOR2 NNHR benzene
R 4 R 5
F\
N N
Y --NHR'
R'
NH
RC....
II
o
POCl,
benzene
.
R'=N
(28)
Scheme 14
Adaptation of similar functionality to the synthesis of imidazole N-oxides is illustrated
by the fluoride ion-promoted cyclization of the trimethylsilyl ether of the oxime (30)
derived from 1-(dichloroacetylphenyI)aminopropanone (Scherne 15) (80AHC(27)241).
The reaction of dimethylforrnarnide diethyl acetal with the carbanion which forms when
the isocyanide (31) is rnetalated gives an alkene (32) which reacts with methyl iodide to
give an imidazole product (79LA1444). In the presence of base, 2-isocyanoalkane nitriles
(33) react with alcohols, thiols or hydrogen sulfide to forrn imidazoles which have an oxygen
or sulfur substituent at C-5 (Scheme 16) (79LA1602).
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 463
PhN-CH 2
I \
CI 2 CH-C, CMe
1/
o N
I
OSiMe3
(30)
p-
--
PhN l
lCl'HC ('J
PhN
OHC JM-e
N
I
0-
Scheme 15
(31)
(32)
Me
MeN N
W
C0 2 R
BuLi Mer
MezNCH(OEt}z+CNCHzCOzR - MezNCH=C(CN)COzR -
NC NC N- [ #'...
I R'O- I /
RICH-CN _ RI-CH-C
(33) 'OR' R'f!.,
þ
ii, tautomerization
i,H+
N NH
'=f
R' OR 2
Scheme 16
In addition to the reactions of diaminomaleonitrile shown in Scheme 11 there are also
some examples of photochemical transformations which lead to imidazole products. The
initial reaction isomerizes the cis-dinitrile to the trans forrn which then forms a 5-
aminoirnidazole-4-carbonitrile via the iminoazetine (34). There are a number of related
reactions, although the photochemical isomerization of en amino nit riles (35) probably
involves an azirine interrnediate (Scheme 17) (81JOC2872).
H2 N )[CN NC.1 NH2 [ H2NnH ] H,:t"
H 2 N CN H 2 N CN NC NH NC)
(34)
NC)[H à H)(N [ HnH ] _ r
Me NH 2 Me NH 2 Me NH Me )
H CN hv H, óNH hv
HJNH2 H ; -D-.
(35)
Scheme 17
()
N
H
Sorne of the above synthetic procedures can be adapted for the synthesis of imidazolines.
If a 1,2-diamide is heated alone, or in the presence of aluminum or magnesium, ring closure
brings about the formation of a 2-alkyl- or -aryl-irnidazoline. Better results are obtained
when the diamide and the corresponding diamine hydrochloride are heated at about 300 oc,
and good yields (85-95%) of 1,2-diaryl-2-imidazolines result when polyphosphoric acid is
used to cyclize N-aryl-N'-benzoylethylenediamines (Scheme 18) (7OJHC791). When
monoacylated 1,2-diamines carry sorne substituent other than hydrogen on the arnino
function, it is normal to obtain imidazolines rather than imidazoles, and a further exarnple
is provided by the cyclization of the oxirninoisocyanate to an imidazoline N-oxide
(Scheme 18).
H
(()
X HN
I
COAr
ry-N:)
.
X Ar
+<
H 2 N N.......
OH
COCl,
Et,N
þ 't-{ __ 'i-{
NCO N-" OH HN'-.../' -..O-
Scheme 18
Usually the 2- or 4-imidazolines that are formed in the cyclization of 3- or 2-aza-l,3-
butadienylnitrenes are dehydrogenated under the reaction conditions to imidazoles. There
are, however, some cases in which the hydrogenated diazoles can be isolated in moderate
yields (79CHE467).
464 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
N;--Ph er N
/.
Ph-C;', + ---) I ì Ph
N-NMe) N
(36) H
Scheme 19
Above 170 0 C the amidrazone ylide (36) decomposes with loss of triethylamine and
concurrent cyclization to give an 85% yield of 2-phenylbenzimidazole (Scheme 19)
(B-75MI40S00). Poorer yields (-40%) are obtained when N-benzyl-o-nitroaniline is pyrolyzed
in the presence of iron oxalate. No doubt this last reaction is similar in many respects to
the reactions shown in Scheme 2. Both 2-phenyl-imidazoles and -benzimidazoles (as well
as other 2-substituted analogues) can be obtained as a result of thermal rearrangement of
the I-substituted isomers (Section 4.07.1.2.2), by radical substitution methods (Section
4.07.1.7) or via the 2-lithio derivatives (Sections 4.07.1.6, 4.07.3.7).
4.08.1.1.2 Formation of the 1,5- (or 3,4-) bond
C-N N
(/, t --(')-
N/ N
H
Compounds related to amidines are frequently involved in syntheses of this class. Thus
methyl 3-hydroxypropionimidate condenses with the acetal of an aminoaldehyde to give
an amidine salt (37) which ring closes in acid solution to the imidazole (Scheme 20). This
reaction has been applied to the synthesis of 2-phenylimidazole and a number of its
4-substituted derivatives, and to 'isohistamine' [2-(2-aminoethyl)imidazole (70AHC(12) 1(3)].
Ring closure in the same way of a cyanide carbon on to an imidic nitrogen allows access
to a series of mesoionic imidazoles (40) via the 4-aminoimidazolium salts (38, 39)
(SOAHCl27)241). Should stronger base treatment (e.g. aqueous KOH) be applied to (38), it
is likely to undergo a Dimroth rearrangement (Section 4.07.3.3.9), and concentrated alkali
causes ring fission (Scheme 21).
NH NH z CI-
,f' HCI \I HCI
HO(CHz)zC + RNHCHz(OEt)z -- HO(CHz)z-C CHzCH(OEth-
'" '" /
OMe N
R
(37)
C---N
I \
C C
'N/
HO(CH 1 12Z)
N
R
Scheme 20
Me
Ph-C-N -CH,CN
\I -
NPh
dry H CI
Me
N
(Ì!Ph Cl-
HzN Ph
(38)
l i,Ac 2 o
ii. NaHCO,
1 MeCOCI
Me Cl-
N
(Ì!Ph
MeCOHN Ph
(39)
NaHCO,
Me
N
('Ì!Ph
}-N Ph
MeCON +
(40)
Scheme 21
An electron-deficient trifluoromethyl carbon becomes part of an imidazole ring when
(41) is heated with tin(ll) chloride (Scheme 22).
F)C,
C=N
F co"'" \ 2 SnCl,
3 I/R
N
R 1
(41)
F)C N
F()R 2
N
R 1
Scheme 22
Irnidazoles and their Benzo Derivatives: Ciii) Synthesis and Applications 465
There is one example in which part of the amidine system is a C-N bond in a heterocyclic
ring. The enamino ketone condensation products (42) of 3-amino-1,2,4-oxadiazoles and
1,3-dicarbonyl compounds cyclize in basic medium to form 60-80% yields of imidazoles.
The driving force for this reaction is provided by the well-established, general attack of a
nucleophilic centre in the side-chain at N-2 of the heterocyclic ring, but it is unusual in
that a carbon nucleophile (rather than an oxygen or nitrogen species) is implicated (Scheme
23).
H
N
N ---("" 'CR I
/( \\ II
R 3 INCH
0/ I
COR z
(42)
[ N ]
NaOEt N---(' ':\C-R 1
DMF. IIOOC ) R 3 /(0/N '{H
COR z
H
---+ R 3 COHN(lR '
N COR z
Scheme 23
Claisen rearrangement of the adduct (43) formed when a propiolate ester and an aryl
aldoxime combine leads to imidazole-4-carboxylates in 61-72% yields. This reaction also
proceeds by ring closure of an amidine (44; Scheme 24) (80AHC(27)241).
H
C
III
+ C
I
COzR
NOH
Are!
NHz
-
o '
N"" 'CH
II II
ArC CH
\ I
NHz COzR
--'"
..--
(43)
o
HN/'--""CH
I II
ArC..} /CH
\\ I /
NH COzR
1 . PhzO
[1.3]-shift
N J -H 0
Ar( ï COzR
N
H
OH
HH roo
N N: 'c"'"
Art( H Ar ---t-H
N COzR 'No"'" \
H H C R
(44)
Scheme 24
The formation of benzimidazoles by cyclization of aryl amidines can be accomplished in
a number of ways, but is usually carried out under anhydrous conditions in the presence
of a base. Thus cyclizations of (45; R = OH) induced by benzenesulfonyl chloride in pyridine
or triethylamine generally give yields of greater than 60%. The more direct process of
oxidizing the parent compounds (45; R = H) with sodium hypochlorite under basic conditions
gives even higher yields (70-98%). Intermediates in these reactions are the N-haloamidines
(45; R = Cl); a nitrene intermediate may be involved or merely dehydrochlorination with
concomitant cyclization (Scheme 25). Alternative cyclization procedures include oxidation
of the parent amidines (45; R = H) by manganese dioxide or lead tetraacetate and thermal
RI -E) N Ph PhSO,CI.Et.1 N ) RI (X I N Ph
#,f IR=OHI " /
N " N
'R H
- NaOCI. ow '/"
(45)R=OH,H,CI /
1 (R=H)
OEt- (R=CI)
[R'-o}-P
-a N
R 1 Ph
N
H
Me
N'
R -o- <'hR'
M-;V
(46)
Me
R o--<J J()RI
Me NOi
(47)
Scheme 25
II.
--
-s
0- /;NMe NO z
R C fI _
J 'N-S M R,
Me
(48)
466 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
and photochemical methods. The substituted benzamidine (46), which has a nitro group in
the ortho-position of the N-phenyl ring, undergoes thermal cyclization via a nucleophilic
substitution reaction, giving the benzimidazolium nitrite (47). The sulfenamide (48) in which
the nitrophenyl moiety is linked through sulfur gives the same product with extrusion of
the sulfur atom (Scheme 25) (77TL3453, 80AHC(27)241).
Reactions of imidoylaziridines (49) (amidine-type compounds), which ring open and
cyclize in the presence of such reagents as oxalyl chloride or ethanolic HCl, provide further
examples of 1,5-bond formation (Scheme 26). The products, though, are reduced imidazoles,
being triketoimidazolidines (50) and 2-imidazolines (51), respectively (77JOC847).
o
Y orN -Q
---{ N0 2
Cl 0
[>1=N -Q
X N0 2
COCll
þN-C=NPh
I
CHR 2
HCI
CHR,
N h
U
EtOH
(49) X=CI, OMe
(50) 80-90%
Scheme 26
(49)
(51) -100%
3-Butynylthiourea and 3-butynylurea are cyclized in sulfuric acid to 4,5-dimethyl-
imidazoline-2-thione and the corresponding imidazolin-2-one, respectively (Scheme 27),
while the imidazolin-2-ones are also accessible when suitable urea derivatives are cyclized
thermally (79JHC983). The use of urea derivatives for the synthesis of 2-imidazolidinones
and hydantoins is relatively common (Scheme 27) (79JHC607, B-75MI40800).
HC:::C NH 2 Me NH 0- /CH2C02Et il 0- /--(0
M HC ! t H 2 S0 4 M r \ /, N /, N NR
e 'N/ ""'X e /,::::::X \\ II tONHR EtOH \\ II Y
H H 0
(X=O, S) (60-84%)
Scheme 27
Thermal ring-closure of enecarbamoylazides (52) gives rise to 4-imidazolin-2-ones
(Scheme 28) (71JHC557).
Me
2 2 CH 2 CH=CH 2 n
dl: H i.H + UN)'NH
(52) 0
(minor product) (major product)
Scheme 28
4.08.1.1.3 Formation of the 4,5-bond
C-N
; \
c, /c
N
-- ()
N
H
Synthetic methods of this class are uncommon and are limited largely to examples in
which an active methylene group, in basic medium, cyclizes on to the carbon of a nitrile
function. The acyclic precursors required for the reactions can be made by alkylation of
arylaminomethylene cyanamides (53), or cyanoimidothiocarbamates, with a-halogen-
substituted carbonyl compounds (76M1413), or by the condensation in the presence of
triethylamine of 2-aminonitriles (or glycine esters) with N-cyanoacetimido esters (54)
(75HCA2192). Subsequent base-catalyzed cyclization gives 4-aminoimidazoles in yields
between 40 and 90% (Scheme 29). Such 4-aminoimidazoles substituted at C-5 by nitrile
or carbonyl functions are useful intermediates for purine synthesis.
A further example of a similar sequence of reactions is provided by the reactions of
N-cyaniminodithiocarbonic esters (55) with a-cyanoammonium salts. The initial condensa-
tion product (56) cyclizes when heated with sodium ethoxide in DMF, again giving a
4-amino-5-cyanoimidazole. Related is the reaction of (55) with the hydrochloride salt of
ethyl methylaminoacetate, which gives imidazoles directly; perhaps this might be classified
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 467
R1NHC(R1)=NCN + BrCH COR 3 K,co J )
1 DMF
(53)
/C==:N
N
II CHzCOR3
Rl N/
R'
N NHz
NaOEt R Z (]COR 3
EtOH
N
R 1
NaOEt N NH 1
) RZ)CN
EtOH
Me
CN
R)loMe
(54)
+ MeNHCH1CN . HC!
C=N
EtJN N'"
-
EtOH CH1CN
R N/
Me
Scheme 29
SMe
/
N=C-N=C
"-
SMe
(MeNHCH,CN), SO -
)
EtOH, Et,N
SMe
I
N=C-N=C-N-CH 2 CN
Me
(56) 45%
1 tEt
H1N N
NC()SMe
N
Me
(55)
EtJN l +
DMF MeNHCH,CO,Et CI-
H1N N
EtOzC()SMe
N
Me
Scheme 30
more correctly as a cyc1oaddition leading to the formation of the 1,2- and 1,5-bonds (Scheme
30) (70AHC(12)103).
In the presence of a catalytic amount of a metal carbonyl, benzylamine reacts with carbon
tetrachloride to form a mixture of 2,4,5-triphenylimidazole and 2,4,5-triphenyl-2-imidazo-
line. The reaction is probably of the free radical type involving, ultimately, cyclization of
a species such as (57). When hydrobenzamide (58) is treated with an acid chloride in the
presence of triethylamine the product is an N-acyl-3-imidazoline (59). When, however,
(58) is heated and subsequently reacts with an acid chloride in the presence of triethylamine,
the isomeric 2-imidazoline is formed (Scheme 31) (72JOC215S).
(58)
Ph
F-fH
N'X"ß-COCH1N3
H Ph
(59)
NHCH1Ph
/
Ph--cH
\
NHCH1Ph
(57)
N=CHPh
Ph-éH N,CH,COCI
N=CHPh Et 3 N
Scheme 31
4.08.1.2 Formation of Two Bonds
4.08.1.2.1 From [4 + 1J carbon fragments
(i) Formation of the 1,5- and 1,2-bonds
T- Q
C, .C ï \
. "N'"
H
Alkyl N-cyanoalkylimidates (60) react with primary amines to form 1-substituted 5-
aminoimidazoles. This reaction has been applied tó the synthesis of 5-aminoimidazole
nuc1eosides (Scheme 32). The reaction appears to be quite general for a wide variety of
such imidates with not only primary alkyl- and aryl-amines, but also hydrazines (not
1,2-disubstituted hydrazines) and semicarbazides. Hydrazines lead to 1-aminoimidazole
products: thus 1,5-diaminoimidazole (61) can be prepared from hydrazine and N-
cyanomethylformimidate (SOAHC(27)241, 66RCR122, SOJCS(Pl)2310).
In the presence of phosphorus trichloride, phenacylbenzamides react with primary aryl-
amines with the formation of 1,2,5-triarylimidazoles (62), albeit in less than 10% yields
468 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
E<O'CO H'+
a a
y
a
H-C=N-CH-COR
I I
OEI CN
(60)
O
HO - i>H1
N
\\ )NH 2
NCaR
OEI
/
HC
NCH2CN
H,N'NH,
--=-
Z)NH Z
N
I
NHz
(61)
R = NH 2 . OEt
Scheme 32
(Scheme 33) (ncHE1l42). Both 1,2,4,5-tetraarylimidazoles and the pentaarylimidazolium
salts are formed when compounds of type (63) react with either ammonia or primary
aromatic amines; in the latter instance a follow-up treatment with thionyl chloride is required
to produce the quaternary compound (Scheme 33) (70AHC(12)103).
Ar J
HI.
, ì N Ar
Ar + I
CI
Ar' a CI-
(63)
ArICOCH2NHCOA
ArNH,
Ar'()A
N
Ar
(62)
NH,
Ar 2 NAr 3
Arll[ M
N
H
PhO, po,
Scheme 33
When l-substituted N-formylglycine esters take part in a carbanion condensation reaction
with formate esters in the presence of base, the resulting N-alkenylformamides (64) can
be cyclized with ammonia to give 1-substituted imidazole-4,5-dicarboxylates (strictly speak-
ing, it is the 2,3- and 3,4-bonds which are being formed in this instance). The reaction
products, after reduction to the dialdehydes, can be converted by reaction with hydrazine
into imidazo[ 4,5-d]pyridazines (SOAHC(27)241). In a further reaction which shows some
similarities, 4-acylimidazoles (65) can be prepared from 1,3-dicarbonyl compounds which
are nitrated in their enolic forms. Reduction of the nitroalkene gives an intermediate
N-alkenylformamide which is cyclized by formamide in formic acid (Scheme 34) (79HCA497).
R
N
() C0 2 Et
N COzEt
HCON(R)C(C0 2 Et)=CHC0 2 Et
(64)
OH
/
R'CCH=C
II " 2
o R
N,O.
NO z OH
I /
) R ICC=C
II "z
o R
Pd/C. H, )
MeCO,CHO
NHCHO
/
R ICC OH
II' /
o C,
R"
HCONH,
")
HCO,H
H
N
RICO
R Z
(65)
Scheme 34
From the interaction at low temperatures in basic medium of an aldehyde or ketone and
tosylmethyl isocyanide ('tosmic'), N-( I-tosyl-l-alkenyl)formamides are formed. When these
are dehydrated they produce 1-isocyano-l-tosylalkenes (66) which react with primary
amines to form imidazoles in high yields (Scheme 35) (79RTC25S).
R NHCHO R
ROT Bu'OK "C=C/ POO,/Et,N ) "C=C/
CH + osCHzNC /" -H,O / "
H Tos H (66) Tos
N=C
R'NH,
R(;
N
R'
Scheme 35
When heated with a primary amine hydrochloride in DMF, 4-amino-2-azabutadienes
(67), formed by the interaction of dimethylformamide diethyl acetal and an azomethine,
cyclize to imidazoles (Scheme 36) (SlAG(E)296). Imidazolidin-4-ones are formed when
a-(N-acylhydroxyamino) esters react with ammonia (B-77MI40S00).
N SMe
Me2N
CO 2 Me SMe
(67)
Me02C
RNH'O-
, ) N NR
A, DMF V
SMc
Scheme 36
Irnidazoles and their Benzo Derivatives: (Ui) Synthesis and Applications 469
(ii) Formation of the 1,2- and 2,3-bonds
C-N N
<N): - ()
H
Reactions which involve variations on the cyclization of a 1,2-diaminoalkene are among
the most common methods leading to the formation of the imidazole nucleus, and by far
the most common approach to the syntheses of benzimidazoles, benzimidazolinones and
2-imidazolines. The cyclization of such compounds in which one of the amino groups is
already acylated has been discussed earlier (Section 4.08.1.1).
High yields of 2-alkylimidazoles (68) are obtained when a 1,2-diaminoalkene is treated
with an alcohol, aldehyde or carboxylic acid at high temperatures, and in the presence of
a dehydrogenating agent such as Pt/ Ah03 (Scheme 37). In the absence of dehydrogenating
agents the products are imidazolines, which are also available from the interaction of the
diamines with imino ether hydrochlorides, amidine hydrochlorides, thioamides or nit riles
(B-57MI40800). One of the problems associated with this general synthetic method is the
purification of the reaction products. The compounds can be azeotropically distilled with
an alkylaromatic hydrocarbon possessing a boiling point about 10-40 o C lower than the
imidazoles. Thus 2-methylimidazole is purified by distillation with 1- or 2-methylnaph-
thalene and then isolated by washing with toluene or pentane, solvents in which the azole
is only very sparingly soluble.
r (Pt/AI 2 0" H 2
H/R 400'C
N
H
(68)
CHlNH 1
I + RCOlH
CHlNH l
HCI
--I>
.1
C)R
N
H
H
HOlC-C-NH l
I
CHlNHMe
HOlC N
HCIOEI)\ C
HCI ;>
N
Me
MeOH
HCI
MeO?C N
C)
N
Me
(69)
Mn0 2
Me01C N
f)
Me
Scheme 37
The specific synthesis of 1,4- and 1,5-disubstituted imidazoles in 70% yields has been
achieved by cyclizing 2-amino-3-methylaminopropionic acid with triethyl orthoformate.
The products are isolated after dehydrogenation with active manganese dioxide of the
2-imidazoline (69; Scheme 37) (70AHC(12)103).
When an o-diaminobenzene is substituted for ethylenediamine this provides the most
important synthetic method for benzimidazoles. In fact, an 83% yield of benzimidazole is
produced when o-phenylenediamine and formic acid are maintained at room temperature
for five days. At 100-110 o C only two hours are required to achieve this yield, testifying
to the ease of the reaction (Scheme 38), which is applicable to a wide spectrum of
2-substituted benzimidazoles (70AHC(12)103, 66RCR122). Usually the reaction is carried out
in the presence of hydrochloric acid, and the yields can depend not only on the natures of
the diamine and carboxylic acid but also on the mineral acid concentration. Almost
quantitative yields of 2-benzyl- and 2-(2-phenylethyl)-benzimidazoles can be obtained
under the optimum conditions. The 2-arylbenzimidazoles can also be formed in 75-95%
yields from o-phenylenediamine and benzoic acid or its derivatives (e.g. esters, nitriles,
amides, imidates, selenoamides) (see Scheme 40). Much more vigorous reaction conditions,
however, are required than for the 2-alkyl derivatives. Thus a 95% yield of 2-phenyl-
imidazole can be obtained if the diaminobenzene and benzoic acid are heated for 40 minutes
in a sealed tube at 180 0 C in the presence of 25% hydrochloric acid. Much poorer yields
are obtained in the absence of the mineral acid and with halogen-substituted benzoic acids.
In place of the carboxylic acids it is quite common to employ aldehydes in the presence of
oxidizing agents. For the synthesis of benzimidazoles using aryl carboxylic acids it is
preferable to use polyphosphoric acid in place of hydrochloric acid as the reaction medium.
The diamine often competes successfully for the proton of the acid catalyst and this can
inhibit attack at the carbonyl carbon. This problem can be overcome by replacing the
carbonyl oxygen with the much more basic imino group; thus imino ethers (imidates) have
proved very successful in the reaction (Scheme 38) (74CRV279).
470 Irnidazoles and their Benzo Derivatives: (iÜ) Synthesis and Applications
Ü( N
I ')CH 2 CO z Et (
:::::,... N
H
EtO,CCH'-jì-OMe
NH
HCI
O NH 2
I + RCOzH
:::::,... NH 2
HCI
--
rrN>R
N
H
Scheme 38
With dicarboxylic acids, bis{2-benzimidazolyl)alkenes are obtained, and benzimidazoles
substituted at C-2 by heterocyclic groups use the heterocyclic carboxylic acid in the presence
of a cation exchange resin. As can be seen in Scheme 39, the general reaction can be
modified to prepare 1-substituted benzimidazoles by use of an N-substituted o-diamine;
the use of two moles of formaldehyde in boiling ethanolic HCI also gives moderate yields
of 1-methylbenzimidazoles (74JCS(Pl)903). When, however, an N,N-disubstituted o-phenyl-
enediamine reacts with chloral hydrate and hydroxylamine, semicarbazide or phenyl-
hydrazine, benzimidazoles substituted in the 2-position by oxime, semicarbazone and
hydrazone groups are formed in about 60% yields. A reaction sequence similar to that
shown in Scheme 39 may apply, proceeding via the chlorimine intermediate (70) (74CRV279).
O l NH 2
:::::,... NHR
NH
II
EtO-C-CH,Ar
HCI, EtOH
) rr N > CH 2Ar
N
R
Cl-
OJ 7 0H
--. å N
::9'\
:::::,...
-+
0:: 0
CCI,CHO
NH,OH
rY O
) 91
kNOH
(70)
(CH 2 )5 C1
\ CH=NOH
N---(
C("
ò3
::9' N
I )CH=NOH
:::::,... N
PPA
---
Scheme 39
The great diversity of reagents which can react with o-arylenediamines to give 2-
substituted benzimidazoles is exemplified in Scheme 40 (66RCR122). It should be noted
that in addition to these ring-synthetic methods, 2-substituted benzimidazoles can also be
obtained from benzimidazoles by nucleophilic substitution reactions (Section 4.07.1.5),
from the 2-lithio derivatives (Section 4.07.1.6) or by thermal rearrangement of I-substituted
benzimidazoles (Section 4.07.1.2).
rrN>H
N
R
Ar
O N=C/
:::::,... I NHR "NH 2
' r Ar ;H2
EtOH
Ü( N
) I )Ar
:::::,... N
R
Ü( NH
I >==0
:::::,... N
R
COCI,
CS, ) rrN\.SH
SalOH" /
or INH",CS N
- R
j "C-CH,Ar
EtOH, H .
R'COR' Ü( N
I >CH 2 Ar
H :::::,... N
Ü( N R' R
I )<R 2 Ü(N
:::::,... N ::9'
R -R'Hor > I Rt (or R2)
-R'H :::::,... rI
R
O l NH 2
:::::,... NHR
or urca
140-180 ,('
Ü( N
I >NH 2
N
R
/'
Nßr
or
NH,CN
Scheme 40
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 471
When there is no dehydrogenating agent present, the reactions of 1,2-diamines and
derivatives with carbonyl compounds will lead to reduced imidazoles, either imidazolines
or imidazolidines (Scheme 41). Conventional preparation of 2-imidazolines normally
requires nitriles or imino ethers, and only in selected cases can carboxylic acid esters be
used directly with 1,2-diamines (similar limitations apply to benzimidazole formation).
However, when coupled with trimethylaluminum, reagents (71) are formed which react
quite readily with esters to give high yields of 2-imidazolines (8IJOC2824). Imidazolidin-2-
ones (72) are readily obtained from diamines and urea (or diethyl carbonate) heated together.
If the diamine is treated with nitroguanidine, the product is the 2-nitraminoimidazoline
(73; Scheme 41) (80CB2823, 8IJCS(P2)317, 80JHC1789, 79JCS(P1)2289, 8IJOC2824).
H R
C)R 1 H (-70%)
N '- -OEt R R'
R=H H'
R'CHO
H CH 2 NHR H
e N I NH,CONH, e N
jAr R =: CH,NHR N Ao
R=H NH'-f- NHNO , H
ArNH OEt R=H MH (72)-75%
S KÒH H
C NAr R H Ric=c=CHCN QNHNO,
H (73)
(70-100%) H
C -RI
N "; ,
(40-98%)
Me2A1NH(CH2hNH, + OCO,Et
(71) S
----- o-<N J
S N
H
(92%)
Scheme 41
The reaction between o-phenylenediamine and an equimolar amount of an aromatic or
heterocyclic aldehyde has been shown to proceed by initial formation of a monoanil (74).
In the presence of oxidizing agents (e.g. nitrobenzene, which also acts as the solvent) this
can form the 2-substituted benzimidazole. With two moles of aldehyde the bis-anil (75)
forms, giving rise to a 1,2-disubstituted benzimidazole (Scheme 42). This aldehyde route
to benzimidazoles is particularly suited to the synthesis of compounds with a heterocyclic
group (e.g. 2-thienyl-, 2-pyridyl-) at C-2. Reaction of 2,2,4,4-tetrakis(trifluoromethyl)-1 ,3-
dithietane with o-phenylenediamine gives 2,2-bis(trifluoromethyl)benzimidazoline
(74BCJ78S).
O INH'
NH 2
ArCHO O N=CHAr ArCHO O N=CHAr
) I -----+ I
NH 2 N=CHAr
(74) ;/ (75)
/ -H, \ ArCHO
./ -H, \;
(X I N Ar >Ar (Ç I N ) Ar H
N N Ar
H C M M
Scheme 42
ß-Keto esters react with arylenediamines when heated in neutral solvents to give benz-
imidazolinones in a reaction which is capable of extension to the ß-keto esters derived
from cyclic ketones. Under acidic conditions, o-phenylenediamine gives a 78% yield of
472 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
2-methylbcnzimidazole when treatcd with acctoacctic ester, but the oenzimidazolinone (76)
predominates in neutral medium (Scheme 43). The compounds can be obtained even more
efficiently by heating the nitroamines in sand at 240 oC (74CRV279).
CI H'
- + MeCOCH 2 C0 2 EI
NH 2
H .1 xykno
(( N
I )Me
N
H
178%1
0::: + EIO Ú
H 'r=
xyh:nL' oc: ((N>=O
+
.1 N
H
(35%) 176126%
xylene)
.1
H
N>=O + N)<CH2)5C02Et
N N
Ò ''''
(53%)
Scheme 43
Such use of o-nitroanilines in place of o-phenylenediamines has found increasing favour
in the field, the cyclization and reduction processes usually being combined into one. Thus
in the presence of a suitable reducing agent (e.g. metal oxalates, iron pentacarbonyl, triethyl
phosphite, titanium (III) chloride, hydrazine hydrate in ethanol with Raney nickel, or
hydrogenation using palladium and carbon) the compounds can be cyclized to give high
yields of benzimidazoles. In connection with the interest in vitamin B 12, much work has
been done on the preparation of 5,6-dimethylbenzimidazole and its 1-glycosyl derivative
since such compounds have high physiological activity. The acetylated glycosyl compound
(77) can be prepared by the sequence of reactions in Scheme 44 (66RCR122). The mechanism
of benzimidazole formation, which involves the electrochemical reduction of o-nitroanilines
which have an alkyl substituent on the amino group, involves a nitroso compound. This is
formed in a redox reaction and takes part in the cyclization process (74BSF673).
Me O I NO) Me O I NO) H,NNH,) Me O I NH2 HC<OEtJ.,)
Me NH) Me NHR !\Ii Me NHR
R= Aco CH)O C
AcO
AcO
Me N>
Me N
R
(77)
Scheme 44
Although the direct oxidation of the parent compounds with organic peracids has not
proved fruitful, benzimidazole N-oxides can be made by the action of boiling hydrochloric
acid on o-nitro-N, N-dialkylanilines, although prolonged treatment results in the formation
of a chloro-substituted benzimidazole (B-73MI40800).
Some of the reactions of diaminomaleonitrile have already been outlined (Schemes 11
and 17), Reactions of this versatile compound which lead to the formation of the 1,2- and
2,3-bonds of imidazole have also been described. When heated in alcoholic solution with
an alkyl orthoformate, 4,5-dicyanoimidazole is formed; with forrnic acid in refluxing xylene,
4-cyanoimidazole-5-carboxamide results; with cyanogen chloride the product is 4,5-
dicyanoimidazolin-2-one. With catalytic amounts of acid present; diaminornaleonitrile
reacts with acetone to give an 80% yield of 4,5-dicyano-2,2-dimethyl-2H-imidazole.
Diiminosuccinonitrile (78) reacts with acetone and isopropylamine to form the 3-imidazolin-
5-one (79), while with phosgene the imidazolidinone (80) results. The trimethylsilylimine
(st) gives 4,5-diphenyl- 2H-imidazolinone (Scheme 45) (72JOC4136).
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 473
Cl
NC+-
NC
Cl H
(80)
COCl,
NCXNH
HN CN
(78)
Me2CHNH==N
+ Me2CHNH2 + Me2CO ----+ O ÅMe
H Me
(79)
Ph SiMe3
A. COCl,
Ph NSiMeJ
Ph N
Ph CA o
N
Scheme 45
A reaction restricted to the synthesis of 2,4-disubstitued imidazoles is that between
2-aminonitriles and aldehydes (71CB1562), and 4,5-dichloroimidazoles, previously not
accessible by general synthetic methods, can be obtained in 36-72 % yields when aldehydes
react with cyanogen in the presence of HCl. Aldehydes which can enolize undergo aldol-type
side reactions, while basic heteroaromatic aldehydes merely form salts under the reaction
conditions (80AG(E)130). The condensation of 2-azidoanilines with aromatic aldehydes in
the presence of fluoroboric acid gives phenylogous azido-iminium salts (82) which cyclize
to N-diazonium ions and then eliminate nitrogen to give 2-arylbenzimidazoles (Scheme 46)
(80H( 14) 725).
NHMe
/
Ph-CH + PhCHO
\
CN
Me
PhL) Ph
C=N
I
C=N
RCHO
HCI
Cl N
CIÇ)R
H
N3
VNHR
ArCHO
HBF.
+
(( : :
BFi
(82)
.1
-.
+
N=N
I
rjíN><r
N H
R BFi
-H' 'N,)
.1
(X N
I )Ar
N
R
Scheme 46
At 180 0 C acetic anhydride reacts with 1,2-dibenzoylaminoethylene to give 2-methyl-
imidazole. Although some other anhydrides can take part in this reaction it is not successful
for the synthesis of a wide range of 2-substituted irnidazoles (70AHC(12)103).
The reactions of a-aminooximes and a-dioximes with aldehydes to form imidazole
N-oxides are discussed with related synthetic methods in Section 4.08.1.2.2.
4.08.1.2.2 From [3 + 2J carbon fragments
()
N
H
The earliest method of this type, developed by Marckwald, employed the reaction of
a-aminocarbonyl compounds (or their acetals) with cyanates, thiocyanates or isothiocyanates
to give 3H-imidazoline-2-thiones. These compounds can be converted readily into imi-
dazoles by oxidation or dehydrogenation. The major limitations of this synthetic procedure
are the difficulty of synthesis of a wide variety of the a-aminocarbonyl compounds, and
the limited range of 2-substituents which are introduced. The reduction of a-amino acids
with aluminum amalgam provides one source of starting materials. The method has been
applied to the preparation of 4,5-trimethyleneimidazole (83) from 2-bromocyclopentanone
(70AHC(12)103), and to the synthesis of pilocarpine (84; Scheme 47) (80AHC(27)241). If esters
of a-amino acids react with cyanates or thiocyanates, the products are hydantoins and
2-thiohydantoins, respectively.
If cyanamide is used in place of isocyanate or thiocyanate, the cycloaddition reaction
with an a-aminocarbonyl compound gives a 2-aminoimidazole (80AHC(27)241). Alkylation
of the sulfur atom of ethyl 2-thiooxamate gives products (85) which contain nucleophilic
(i) Formation of the 1,5- and 2,3-bonds
C-N
/ \
C .-----+
"'N"'c
474 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
R 1 NH R 1
N
R ICH(NHz)COR z . HCI RNCS RZ( Raney N, RZ()H
EI,N N S or
IINO, N
R R
(orR z ) (-70%)
&.,
K phthalimide
Me,NCHO
' &-N
o
I
to'yl chloride
,CH,OHI,
n 0
O--N
o
N
<X)
H
(83)
H;-Äd)JJ
H 0
(Raney Ni <XN)=s &:r J
N
H
CHzCOCH,NH,
o ..
MeNCS
[ J:f'COCH'NHM"HM]
i,HOAc,.l
Ii, RanC')' NI
)
Et
f\:CHzT: Me
O O/ l(N)
(84)
)
K,CO" THF
Scheme 47
nitrogen atoms and good leaving groups. Treatment with aminoacetone gives good yields
of ethyl 4-methylimidazole-2-carboxylate in what appears to be a useful, general synthetic
approach to imidazole-2-carboxylic acids (73JOC1437). The exothermic reaction of a-
oxothionamides with aldimines gives imidazole-4-thiols. Cyclization of the isonitroso-
chromanone (86) with irnines gives a 4-aroylirnidazole (Scheme 48) (76TL4333).
S SR N
II Et I O'BF. + / NH,CH,COMe ()
NH ceo E or ) NHz=C, - - ) Me C0 2 Et
2 Z t ' CO - Et SaOAc N
FSO,OMe" H
(85) R = Et. Me 177%)
I 0 NOH PhCH=NAr I ü:.:tl 0 1/ N
l )''r..)Ph 0 Ph I Y Ph
o H N
(86) Ar
Scheme 48
Usually such an oximino ketone would react with an aldimine to form either an N-
hydroxyimidazole or an imidazole N-oxide. In aqueous ammonia, butane-2,3-dione
rnonoxime reacts with aldehydes to give I-hydroxyimidazoles by the pathway shown
(Scheme 49). The tautomeric equilibrium between N-hydroxyirnidazoles and irnidazole
N-oxides has been discussed earlier (Section 4.06.5.2). Since direct N-oxidation of the
imidazole ring has not been successful, ring-synthetic methods have, of necessity, become
important. Most of these will be discussed at this stage even though some do not conform
strictly to the classification implied by the heading. The interactions of 1,2-dioximes with
aldehydes, or oximino ketones with aldirnines, aldehydes and ammonia or amines, or
aldoximes give I-hydroxyimidazoles, imidazole N-oxides and I-hydroxyimidazole 3-oxides.
In addition, a-hydroxyaminooximes give I-hydroxy-3-imidazoline 3-oxides which can be
dehydrated readily to imidazole N-oxides (SOAHC(27)241. 73CHE117S).
Cyclohexanedione- and cycloheptanedione-1,2-dioxirnes react with ketones in acid
medium to give 2H-imidazole 1,3-dioxides; a-aminooximes give 3-imidazoline 3-oxides
under similar conditions (Scheme 50) (SOCHE62S).
The cyclization of anti-(E)-a-arninooxirnes (87) to 3-imidazolin-2-one 3-oxides (89;
Scheme 51) can be induced by phosgene (or by the hydrolysis of the urethanes 88). In
instances in which (87) has an a-hydrogen atom (R' == H), then the product forrned is the
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 475
RCHO
NH RCH=NH
U)
Me-C-C-Me
(II II
o NOH
Me Me
1\ +
HN /.N--. -
0
R
(C OH
OH
n =2,3
0-
1
g: N
R,CO + R
(CH 2 )n -';;<R
\
0-
Me
HI/Me
RCH=N-C-C
+ I II
0- N
'. 'OH
HO /Me
(Jf/c,c/ Me
II II
/C :N-OH
R H
L--
---..
L--
---..
l-OW
Me Me
1\ -H+ MeÇTCMe
N N ----- 11./ \+
.......OH N".....,..N.......OH
R \/\
H R
Scheme 49
R'
'C=NOH
I
.....C
R 2 ! 'NH
Me 2
o
R' +/
R N\ _ R
HC! ^_
Me R
H
(-100%)
Scheme 50
1-hydroxy-4-imidazolin-2-one (90). It is of interest that while both anti- and syn-cr.-
arninooxirnes react with acetirnidic ester to generate 2-methylirnidazoles, orthoacetic ester
only reacts with the anti isorner to form the dimeric 4H-imidazole N-oxide; the syn-
aminooxirnes are converted instead into pyrazine N-oxides. Although the majority of
reactions of cr.- ketooximes lead to imidazoles with N-oxygen substituents, there are excep-
tions such as with (86), and the formation of 4-acetyl-5-methyl-2-phenylirnidazole frorn
benzylarnine and 3-oximinopentane-2,4-dione (80AHC(27)241). In fact, yields of 2-
arylirnidazoles of 30-80% result frorn such interaction of benzylarnines with cr.-
oximinoketones in solvents such as DMSO, toluene and acetonitrile (80JHCl723).
R' R3
R 2 \ /
--'C-C
/ \\
NH 2 N....... OH
(87)
1 EtOCCI
R' R 3
R 2 \ /
.......c-c
1 \\
NH N-- OH
I
c,
o OEt
(88)
COCJ,
R' R 3
R 2 \ /
'C-C
/ II
N::,.. N-- OH
C
O
!
i.NaOH
ii, H
R'
R 2 ,\ R 3
+
) HN N-- O -
Y
o
(89)
R'=H
H"
H
R 2 \ \
HN N
y.......OH
o
R 2 R 3
-H+ F\
-----+
HN N-- OH
Y
o
(90)
Scheme 51
A 40% yield of 5-hydroxy-l-isopropyl-2-methyl-4-propylimidazole (91) has been
obtained from the interaction of norvaline methyl ester and N-isopropylacetonitrilium
tetrachloroferrate (Scheme 52).
MeC=N-Pr i FeCI;;- + PrCH(NHz)COzMe -..
N Pr
MeZ OH
Pr'
Scheme 52
(91)
Dirnerization of ethyl 2-amino-2-cyanoacetate gives diethyl 5-aminoimidazole-2,4-dicar-
boxylate (92) as in Scheme 53. At reflux temperatures in propanol, 1,I-dimethyl-1-phenacyl-
hydrazinium bromide is converted into 2-benzyl-4-phenylimidazole (93). Again the cycliz-
ation is a dimerization process (Scheme 53) (80AHC(27)241).
Among other reactions which fall under this heading and lead to imidazoles are the
synthesis of 4-formylirnidazoles frorn 5-aminopyrimidine and N-alkyl (or -aryl) imidoyl
476 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
HN=C=C-COzEt
I
NH z
1
EtOzC-C-CH=NH
(II
NH
HN'Q,C=C-COzEt HzN COzEt HzN COzE!
r.-'" I f\ F\
--. HzN NH --+ HN NH - HN N
"c/ X V
/ " EtOzC CH=NH COzEt
EtOzC CH=NH (92)
+ -HBr
PhCOCHzNMe2NHz -
2 moleo;
Ph()COPh
N
H
(93)
rhCOCH'6 'J -'-+ PhCOCH,NHNM"
Scheme 53
chlorides in the presence of phosphoryl chloride. These reactions proceed by cyclization
of arnidines (94) on to the pyrimidine ring and subsequent opening of the six-rnernbered
ring (Scherne 54) (81JOC608).
Br-
Nr NHZ
..)
N
R'N=CR ICI
N:y N'::-CR I
I H'J
I :NRz
N
(94)
H,O
o
OHC N
()R 1
N z
R
(25%)
Scheme 54
When 3-aminobut-l-yne is refluxed for 5 hours with acetarnide, 2,4,5-trimethylirnidazole
is forrned in a reaction which is capable of application to the synthesis of other C-
alkylirnidazoles (70AHC(12)103). The reaction of Schiff bases with diazenedicarboxylic esters
leads, in the presence of phenyllithium or sodiurn hydride, to 1,3-disubstituted 2-
irnidazolinones (95) in 58-88% yields (81S563). The rnost general method for preparing
2-irnidazolin-4-ones (96) consists of reaction between imidates and a-arnino acid esters
(B-57MI40800). In the presence of potassium thiocyanate in methanol, a-chloroaldirnines give
20-90% yields of 2-imidazolidinethiones (97), while 1,3-diarylimidazolidinones (98) are
sirnilarly forrned from aryl isocyanates and 2-chloroarnines (Scherne 55).
Ph "",NR z
'c9'
I
/CH z
R'
N-CO,Et
+ II .
N-COzEt
Ph N z
Ph(io
!
NHCOzEt
(95)
NHz
I; Cl-
R-C
\
OEt
CO,Et
/ .
+ CH, --
I .
NH z
H
o4 R
(96)
NR
>H
CI H
KSCN
McOH
s
^
HN NR
Meot+-
(97)
ArNH(CHzhCl
ArlNCO
o
)l
ArN NHAr l
I
(CHzhCl
OH í\
---. ArN NAr l
EtOH Y
o
(98) 4ó-84' ;>
Scheme 55
(if) Formation of the 1,2- and 4,5-bonds
()
N
H
One of the rnore useful developments in imidazole synthesis in recent years has been
the use of the reagent 'tosrnic', or toluene-p-sulfonylmethyl isocyanide (99), which enters
into base-induced cycloaddition reactions with aldirnines in pro tic media. Toluene-p-sulfinic
acid is eliminated to givel,5-disubstituted irnidazoles (100; R 4 = H). In analogous reactions
with irnidoyl chlorides, hydrogen chloride is elirninated giving, in these cases, toluene-p-
sulfonyl derivatives (100; R 4 =p-tosyl) (Scherne 56). In a sirnilar way, a-tosylbenzyl and
a-tosylethyl isocyanides react with aldirnines to give 1,4,5-trisubstituted imidazoles. The
natures of the substituent groups on the aldirnine play an important part and, under aprotic
conditions, the prirnary cycloadducts are imidazolines (which ultimately arornatize to irni-
dazoles). The use of sodium hydride in anhydrous DMSO converts 'tosrnic' into its sodiurn
C-N
: \
C C
'N'-
Imidazoles and their Benzo Derivatives: (Ui) Synthesis and Applications 477
Me O SOzCHZN=C
(99)
R 4
R'C!I=NR' e N
) 5/
orR'CCI=NR' R ;>
N 1
R
(100) R 4 = H, p-tosyl
Scheme 56
salt which is now a suitable nucleophile for reaction with the irnidoyl compounds. Groups
such as t-butyl and cyclohexyl on the aldirnine render it very prone to hydrolysis and in
consequence, even if very dry conditions are employed, only the amide (e.g. ButCONH-
cyclohexyl) is obtained. 'Tosmic' can also be used as a source of N-tosylmethylimidic esters
or thioesters (101), which react with Schiff bases to give 1,2,5-trisubstituted imidazoles
(Scherne 57), while the use of nit riles in place of aldimines with 'tosmic' itself leads to the
forrnation of high yields of 4-substituted imiòazoles with no nitrogen substituent. This
reaction is an example of a [47T + 27T] cycloaddition, and both reactions in Scherne 57 are
capable of extension to other isocyanides (e.g. thiomethyl) which can be a-metalated
(SOAHC(27)241).
....ß
TosCHzN=C +ArCH=NAr'--jo
'x
Ar()R
Ar'
R
B L' ( NH
TosCHzN=C + RCN Tos / )
N
(101) X = OMe, SMe
Scheme 57
Should the aldimine have two substituents (other than hydrogen) on the carbon atorn
then the reaction product, which cannot aromatize, is a 2-irnidazoline (102; Scherne 58)
(77LAllS3). A further extension of this type of reaction utilizes dilithiotosylmethyl isocyanide
(i.e. the dicarbanion of 'tosmic') (103), which reacts with carbon-nitrogen multiple bonds
with much more facility than does the rnonoanion. Even such weakly reactive aldimines as
isoquinoline will react (albeit in only 44% yield) (Scheme 58) (SOTL3723).
Na+ R'
RëHN=C + "C=NRJ--jo
R Z /
N
RH NR3
R1 R Z
(102)
p-MeC 6 H 4 SO z CH z NC
2 BuLi
THF
-70'C
- + Phr
MeQ-SOz-C:-N=C
(103) u+
iSOqUinOIi
Tos N
Ph()
N
H
(33%)
Scheme 58
cç
I N
>
N
Tos
(44%)
Similar to the above reactions is the isocyanide cycloaddition which leads to the regio-
specific synthesis of ethyl 5-aminoirnidazole-4-carboxylates (104, 105; Scherne 59).
SMe
b
R1NH/ Rz
+ EtOzC" /N=C
CH
HMPT
-----+
CuCI
EtOzC N
R1NH()
N z
R
(104)
EtOzC N
+ R 2 NH()
R'
(105)
K+
Scheme 59
Treatrnent of the irnidoyl chloride (106) with triethylarnine yields the nitrile ylide (107),
which undergoes cycloaddition with a variety of reagents giving imidazole products. With
ethyl cyanoforrnate a mixture of esters is obtained; with 2,4-xylyl cyanate the 4-aryloxy
478 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
product (108) results; with benzylidenernethylarnine the initially formed 2-irnidazoline
dehydrogenates to the fully aromatic tetrasubstituted imidazole (109; Scherne 60)
(80AHC<27)241). The rnesoionic oxazole (110) undergoes a 1,3-dipolar cycloaddition with
an electron-deficient nitrile to form, after decarboxylation of the interrnediatel: 1 cycload-
duct (111), a cornpound of type (109) (71CB1562). The electron-deficient nitrile can be
alkyl- or aryl-substituted (Scheme 60).
PhC=NCH 2 Ar Ft,r\ Ph-C=N-ëH-Ar
I
CI (107)
Me
Me O OCN
)
H
Ph{)Ar
Me )-N
Me Q- o
(108)
(106)
EtO:CY
CH=NMe
H
N
Ar()Ph
N C0 2 Et
H
N
+ Phf)Ar
N C0 2 Et
N H
Ph{''Y-Ar
MeN+ Ph
H
o j-H:
Ph Ph Phf]Ar
N MeN Ph
A\I11) (109)
-O t o
ArCN
Ph .)Ph-
N
Me
(110)
Scheme 60
In the presence of potassiurn cyanide the N-rnethyl-C-phenylnitrone (112) takes part in
yet a further cycloaddition reaction to give I-methyl-4,5-diphenylirnidazole. With lithiurn
metal the aldirnine (113) forms a delocalized carbanion which will cyclize with aryl cyanides
(Scheme 61) (SOAH027)241). See also Section 4.08.1.1.3.
o
-/
PhCH=N
"'-
(112) Me
C=N CN
CN I hase I
---I> Ph-C=NMe ---I> Ph-C=NMe
-H' ) \
Ph-C=N-CH 2
I
(CN
--
NC t Ph
NMe - HC",
Ph:::"')
N
Ph NM
Ph() e
N
L CH., - , CH
PhCH=NCH 2 Ph Ph/' 'ì,t" 'Ph
(113) Lï
í.ArCN
II.H,O
Ar N
Ph(')Ph
N
H
Scheme 61
N
-f)
H
The reactions of arnidines or guanidines with a-functionalized carbonyl compounds is a
cornrnon rnethod of imidazole synthesis. Formarnidine will react with a-hydroxy or a-
halogeno ketones to forrn mixtures of oxazoles and irnidazoles. Usually, the formarnidine
is liberated frorn its hydrochloride by the addition of sodiurn butoxide in butanol. When
a-hydroxy ketones becorne involved in this synthetic procedure the aliphatic rnernbers give
rnainly irnidazoles (35-70% yields) while benzoins give oxazoles (67-80%) in preference.
The competing reaction pathways are shown in Scherne 62. Unlike forrnamidine, both
acetamidine and benzarnidine react with arornatic and aliphatic a-hydroxy ketones to give
imidazoles exclusively. It has been suggested that aryl groups favor the enolic form (115)
of the tautorneric mixture, resulting in the formation of oxazoles as the major reaction
products; aliphatic groups favor the keto form (114) frorn which imidazoles are derived.
Formation of the 1,5- and 3,4-bonds
C..N
/ \
C. /c
N
Wi)
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 479
That amidines more complex than forrnarnidine give irnidazoles exclusively may be a
consequence of steric hindrance to the reaction of the enolic oxygen with the amidine
carbon atorn. The reaction has been widely used to prepare such cornpounds as 4,5-
dipropylimidazole [from tris(formylamino)methane and 5-hydroxyoctan-4-one], and a
variety of irnidazolin-2-ones and 2-aminoimidazoles.
NH
He!
'NH z
RCOCH'OH,R'
OH OH
R-t-tHR I -H,O
I
HN ..?JH
'CI-f
-NH 3
<--
R R 1
" /
C=C
/ \
N H OH
c.;'
I
NHz
(115)
Scheme 62
(
R-CH-C-R 1
I "--;0.
N"" /NH z
"'CH
/' (114)
l-H,o
R R 1
F\
N o
R R 1
F\
NyNH
Reaction of an N-alkylbenzarnidine with oxalyl chloride gives a l-alkyl-2-phenyl-
irnidazole-4,5-dione (116), while benzarnidine with 3-bromobenzo-4-pyrones can yield both
irnidazoles and pyrimidines; the forrner are the favored products in non-polar solvents
(Scheme 63). Ethoxyforrnamidine reacts with 2-rnethoxycycloheptatrienone to give the
irnidazole (117), which hydrolyzes in acid medium to give the cycloheptirnidazolin-2(1H)-
one. With forrnarnidine acetate, arninornalonitrile gives 4-amino-5-cyanoirnidazole. Di-N-
substituted amidines and guanidines cannot, of course, give fully arornatic products, and
therefore they provide a route to irnidazolidines. At reflux ternperatures aromatic aldehydes
condense with benzarnidine hydrochloride and ethyl chloroacetate in the presence of bicar-
bonate to give 2-phenyl-2-irnidazolin-5-ones (118) (76TL571). Amidines also react with
haloacetonitriles or a-bromoacetyl chlorides to give salts of rnesoionic 4-arnino- or 4-
hydroxy-irnidazoles (119), while N-acetylamidrazones (120) give l-arninoimidazoles on
reaction with phenacyl chloride (Scherne 64).
NH
I]
Ph-C-NHR.HCl
o
(COCII, II-f
ItJO-llO'C Ph _.ÀO
N
R
(116)
o 0
c6 B < ..rr:",\ c6
Ph
CÓ N H
?'"
I
0
Ph
NH N N
Ph NH, )
UOH
0: NH Q Ct
0 EtO- -NH,) _N - _N
OMe )OEI O
N N
(117) H
Scheme 63
An interesting corollary of these reactions is the formation of 2-aminoirnidazoles frorn
guanidines and suitably substituted ketones. At -10 DC in methanol, I-phenylpropane-l,2-
dione reacts with 1,l-disubstituted guanidines to give 2-(disubstituted amino)-4-hydroxy-4-
methyl-4H-imidazoles (121) which, on catalytic hydrogenation, give excellent yields of
480 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
CICH 2 C0 2 Et
+
H 2 N-c=;m, Cl-
I "
Ph
o
rl ArCHO
, N :: ..) H
Ph
NaHCO,. PrOH
ArCHHO
NVNH
Ph
(118) 30-55'1'0
-0 R1
H
R 2 N+ NR 2
Ph
(119)
NH
R- -NHNHAC
(120)
PhCH,COCI
- ,
N Ph
RZ)
N
I
NHAc
NHR 2
R1CH(Br)COCI + Ph-C/
'\R'
N Ph
RZJ
N
I
NH,
Scheme 64
4-methylirnidazoles. Treatment of (121) with concentrated hydrochloric acid gives the
chlorornethylirnidazoles (122) which take part in normal S N 2 displacernents to form hydroxy-
methyl and alkoxyrnethyl analogues (Scheme 65) (80AHC(27)241). These reactions work
equally well with guanidine itself.
NH
/I
PhCOCOMe + R IR 2 N-C-NH 2
MeOH
-IO'C
OH
Me
' N N
V
NR'R 2
(121)
Ph Me
F\
H,.P NV H
-------- NR I R'
onc. HCI
Ph CH,CI
F\ "
NVNH
NR 1 R 2
(122)
Scheme 65
A rnodification of this method, which produces 2-arninoimidazoles in up to 90% yield,
utilizes benzoins and diguanylhydrazine. The 2,2'-azoimidazoles (123) can be catalytically
hydrogenated to the 2-arnino cornpounds (Scherne 66) (66RCR122). When the disubstituted
guanidine (124) is treated with phenacyl bromide the first product forrned is the expected
2-( I-pyrazolyl)irnidazole (125), but subsequent hydrolysis of this occurs to give a 57% yield
of l-isopropyl-4-phenylirnidazolin-2-one (Scherne 66) (70AHC(12)103). Benzamidine hydro-
chloride reacts with monosubstituted glyoxals to form 2-imidazolin-4-ones.
Ar
'CHOH
2 I
......C=O
Ar
HN NH Ar N N Ar
+ ;c-NHNH-c!' -+ Ar()-NHNH-()Ar
H 2 N 'NH 2 N N
H H
1 0 ,
Ar N
2 Ar(J>NH2
N
H
H,.Pd/C
<< -
prc'ò"òun."
Ar N N Ar
Ar()-N=N-(JAr
N N
H H
(123)
Me
N O Me
'N
),
HN NHPr'
(124)
PhCOCH,Br
,
o
Me Me ^
OMe N Me + H pri
'N 'N
A H Ph
NP' NPr'
U
Ph
(125)
Scheme 66
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 481
Instead of using substituted ketones in reaction with amidines, it is possible to functionalize
alkenes in such a way that they can participate. In particular, N-chloro-N'-phenylamidines
react with enamines derived from aldehydes to give, in the first place, 2-imidazolines. These
deaminate readily to give the fully arornatic irnidazoles, especially when heated with
pyridinium or triethylammonium chlorides (Scheme 67). A disubstituted enamine will, of
course, give a 2-imidazoline disubstituted at the 5-position and such an irnidazoline will
not be capable of arornatization. Enarnines derived from ketones (or from aldehydes with
two ß-alkyl groups) will not give imidazoles; rather, chlorinated enarnines [or N-(2-amino-
2,2-dialkyl)ethylidene amidines] are observed (SOAHC(27)241). The method is further cornpli-
cated by the difficulty of synthesis of the starting vinylamines in the pure state, and the fact
that only arylenamines give good yields.
r-\ R\
o N-CH=CHAr + C=NCI
'LJ Ar1Nrt
pyridine
CHCI 3
0)
CN
H-1- N
H7\r)R
Ar Ar l
6. Q N
+ ) I
R.,NH CI- Ar R
Ar l
Scheme 67
If silyl enol ethers (126) are used instead of enarnines, some of these problems can be
overcome. The regiospecific synthesis of 5-alkylimidazoles (127) provides an example of
the use of these compounds (Scheme 68). In a sirnilar reaction, acylvinylphosphonium salts
can be condensed with amidines to give imidazolylphosphonium salts (129), presumably
via (128) (SOAHC(27)241). A recent improvement of this method uses, instead of the
enamines, the corresponding immonium salts which react with amidines in the presence of
triethylamine to give high yields (85-97%) of 2-irnidazolines (130). In all cases the trans-
imidazoline results (Scheme 68) (SOJHC97).
SiMe3
6
tH
II
CH
I
R
(126)
ClN
+ }-Ph
HN
I
Ar
CHCI 3
pyridine
) R()Ph
N
Ar
(127)
l +
""NH PPh 3
R'C'"
R Ph3 'NH 2 R,C
8 x- ) ß II x-
H 2 N/'...R 1
(128)
F=(' PPh 3
-- N, NH
V X -
R 1
(129)
o
II HN.
HC \\
I 2Br- + C-R
HC /
C ) H l
(R = alkyl, aryl, OMe, SMe;
o R 1 = aryl, acyl)
OH
Et 3 N ) Ht)R
()"
(130)
Scheme 68
When urea (or thiourea) reacts with a-hydroxy ketones or a-diketones the products are
imidazolin-2-ones (or -thiones) (70AHC(12)103,66RCR122). The reaction is lirnited to the
preparation of 4,5-alkyl(or aryl)- or 1,4,5-trialkyl(or triaryl)-imidazoles since an oxygen
or'sulfur function appears at C-2. Benzoin condenses with N-phenylthiourea in hexanol in
the presence of catalytic quantities of HCl to give 1,4,5-triphenylirnidazoline-2-thione (131)
in 50-60% yield (Scheme 69). While 1-methylurea can also take part in the reaction,
482 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
1,3-dimethylurea and imidazolidin-2-one fail to give simple products (81JCS(P2)310).
Cyanourea reacts in a similar way with a-halo ketones to give l-cyanoimidazolin-2-ones
which can be hydrolyzed to the corresponding I-carbamoyl compounds or to the 1-
unsubstituted imidazolin-2-ones (Scheme 69).
Ph,
C=O
I
HCOH
Ph/
S
II
+ PhNHCNH 2
Ph NH
Ph( S
Ph
(131)
R NH
CN R/(Ao
R N/ OH H
R1CAo H,OÎOW
N -......!:,O CONH,
H w---" Rrf "
RIC O
H
HCI
R H
'c -Br
=0 + NH 2 CONHCN
R 1 /
Scheme 69
4.08.1.3 Formation of Three or Four Bonds
C..-N N
"N'} ---. () --
H
4.08.1.3.1 From reactions of ammonia, arnines or formam ide with functionalized carbonyl
compounds
C',.N
/ ...
C C
"'N'"
The earliest synthesis of irnidazole was achieved by Debus frorn glyoxal, formaldehyde
and ammonia (Scheme 70), and rnany of the classical rnethods of imidazole synthesis were
based on this general type of reaction. Initially, most syntheses utilized a-diketones, but
in the 1930s it was shown that a-hydroxy ketones could serve equally well provided that
sorne oxidizing agent (e .g. arnrnoniacal copper(II) acetate, citrate or sulfate) was incorporated
in the reaction rnixture. Further irnprovement used arnrnoniurn acetate in acetic acid as the
nitrogen source.
H
'c=o
/ =O +
H
NH 3
-2H,O
()
N
H
NH 3
O C,.....H
I
H
Scheme 70
Although all of these methods suffered frorn deficiencies (difficulties of synthesis of
starting rnaterials, low yields, and rnore often than not the forrnation of mixtures of products
requiring tedious separation procedures), they still find arnple application for the preparation
of rnany C-substituted imidazoles (e.g. 4-alkyl, 4,5-dialkyl, 2,4,5-trialkyl). The old Debus
(or Radziszewski) method is still useful for preparing such cornpounds as 4-rnethyl- (132)
and 2,4-dimethyl-irnidazoles (133) using pyruvaldehyde (Scherne 71). However, alkaline
fission of the pyruvaldehyde can result in a mixture of products. When pyruvaldehyde is
treated alone with aqueous arnmonia there are three main products: (132), (133) and
2-acetyl-4-methylimidazole. Reversed aldol condensations cause degradation of the
pyruvaldehyde, and subsequent cyclization of the fragrnents as in Schemes 71 and 72 accounts
for the products.
Me N
()Me
N
H
(133)
MeCHO
2NH,
MeCOCHO
MeN
HCHO , r \\
2NH, <(.N/
H
(132)
Scheme 71
Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 483
Scheme 72
Me N
2MeCOCHO 2 ()COMe
N
H
NH
MeCOCHO MeCHO+HCONHz+HCHO+MeCONH z
OH
Some of the problems associated with the synthesis of a-dicarbonyl starting rnaterials
have been alleviated by the use of propane-1,3-dithiol, which reacts with aldehydes to give
cyclic thioacetals. With butyllithium the resulting stable dithiane anions (134) can be
transformed into a-diketones or a-hydroxy ketones (Scheme 73). A further approach to
such cornpounds is found in the reaction of a-ketonitrate esters with sodium acetate (Scherne
73), while aryl a-diketones are also available from a-ketoanils (prepared from the cyanide-
ion-catalyzed transformation of aromatic aldirnines) (70AHC(12)103).
RCHO+HS(CH 2 hSH -- C SX H C )=-R
S R S
HgCl,
RCOCOR! (
R1COr
C s R
ICOR!
( 134 )
,R'CHO
OH
I
C:X: HR1
HgCl,
) RCOCH(OH)R 1
o 0
NaOAc
R ;, COCHzONO z ) R ;, COCHO + HOAc + NaNO z
\\ II DMSO, Z5.C \\ II
Scheme 73
Examples of reactions which have used 1,2-diketones and ammonia wÌth or without
added aldehyde include the isolation of good yields of lophine (2,4,5-triphenylimidazole)
from benzil and ammonia, a rather elegant synthesis of 4,5-di-t-butylimidazole (135), and
the preparation of a series of 2-aryl-5-trifluoromethyl-4-phenylimidazoles (136) frorn 3,3,3-
trifluoro-1-phenylpropane-l,2-dione monohydrate (Scheme 74). Additionally, the forma-
tion of 1-hydroxyirnidazole 3-oxides (137) from a-diketones, hydroxylamine and aldehydes
(74CI(L)38), and the preparations of 2,2'-bis- (138) and 2,2' ,2"-tris-imidazolyls (139) frorn
benzil, ammonia and polyformyl aromatics provide further examples of this versatile reaction
(Scheme 74). There is yet some doubt about the pathway or pathways involved in these
(Ç Me Me 0
Na
) S
xylene H
OH
Me Me
CICH 2 C(MehCO z H
i, Na,S )
ii, H' /EtOH
S(CHzC(MehCOzEth
Q o
Pb(OAc)4
.. .
pyndlOc S 0
HCHO) Q= N\,
ZNH S /
3 N
H
Raney Ni
dioxane
Bu'
BU t ()
N
H
(135)
OH
SeO, I
PhCH z COCF 3 PhC-C-CF 3
II I
o OH
ArCHO
)
NH 4 0Ac
Ph CF 3
!\
NV H
Ar
(136)
Ph Ph
F-.
]l.T' N
-O........' """OH
R
NH OH
(137) RCHO '
PhCOCOPh
OHC -tot -!J CRO N ., NH40Ac
AcOH
n
NaBH,
Ph Ph
!\
N V """ OH
R
>tok H
Ph - N Ph
phl", Þ . ",J.h
(138) n = 0-3
Ph Ph
NH.OAc F\
CHO AcOH HN N
OHCOCHO Å
N I #'
PhG J.JPh
Ph H (139) Ph
Scheme 74
484 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
reactions; current ideas as to the mechanism have been discussed in detail elsewhere
(70AHC! 12)103).
Before the turn of the century, Maquenne had prepared imidazole-4,5-dicarboxylates
from tartaric ester dinitrates with either an aliphatic aldehyde or precursor in the presence
of ammonium ions at pH values 3.5-6.5. Hydrolysis, especially with bromoacetic acid, of
the resulting dicarboxylate esters gives imidazole-4,5-dicarboxylic acid (Scherne 75)
(70AHC(l2)103).
COzBu
I
HCONO z
I
HCONOz
I
COzBu
BuOzC N
AcONH 4 ( \\
AcOH ) BuOzC ,/
hexamine
(45-65% )
Scheme 7S
When Windaus discovered that a-hydroxycarbonyl compounds (acyloins) could be oxid-
ized in situ in the presence of ammonia and aldehydes to give imidazoles, he opened up a
wide variety of imidazole precursors, including reducing sugars, alicyclic and aromatic
ketols, and ketol acetates. Provided that an excess of the acyloin is used in an alcoholic
solution of copper(II) acetate and ammonia, the ring closure can give 2-imidazolyl ketones.
Thus benzoylmethanol gives a 32% yield of 2-benzoyl-4-phenylimidazole (140), and the
method has also been employed in the synthesis of histamine analogues and potential
histidine decarboxylase inhibitors. Even in the absence of copper(II) salts, acyloins still
seem able to react with ammonia to give imidazoles. 1,4-Dihydroxybutan-2-one gives
I-hydroxy-2-(4-imidazolyl)ethane (141; R = OH), while I-hydroxybutan-2-one gives 4-
ethylimidazole (141; R = H) in low yield (Scheme 76).
Ph N
CUlOAcl,2 ()\
2 PhCOCH 2 0H I \ COPh
2NH" McOH N
H
(140)
RCHzCHzç--N
HOCH 2 COCH 2 CH z R Z_ j)\
N
H
(141) R = H, OH
Scheme 76
It is usual for the reaction of a-acyloxy ketones with ammonium acetate to give mixtures
of oxazoles and imidazoles, with the result that the method may not be the one of choice
if the product mixture complexity can become too great (Scheme 77) (70AHC(l2)103). Excess
ammonia may help depress oxazole formation, although the oxazoles can be converted into
irnidazoles (Section 4.08.2.2).
R, 9'0
Y
RICH CR 2
....0.....
NH.OAc
AcOH
R NH 2
'C...... 0
) J II II R z
R C, ......C
o
-H,O 1
R N
RJ[)\R Z
o
--'"
..-
R,C.....NHCOR2
II
C
R I / 'OH
NH40Ac l
AcOH
"'--
---.,.
R, ......NHCOR 2
CH
I
......c:::,..,
R' ""0
R N
R 1 ()R 2
N
H
Scheme 77
As mentioned above, reducing carbohydrates are a readily available source of acyloins,
and glucose, fructose, etc. have been used to prepare both 4-methyl- and 4-hydroxymethyl-
imidazoles. The reactions, thollgh, are very cornplex, giving low yields along with many
other products including pyrazines. Besides the two imidazoles mentioned above (best
prepared with added formaldehyde), glucose and ammonia have yielded srnall quantities
of 2-hydroxymethyl-4-methyl and other 4-substituted imidazoles with hydroxyethyl, dihy-
droxypropyl and trihydroxybutyl side chains. From rhamnose and amrnonia, 4-ethyl- and
a 4-(dihydroxybutyl)-imidazole have been isolated. When lactose, cellobiose, sucrose and a
number of starches react with ammonia at high temperatures and pressures, conditions
which cause extensive degradation of any polyhydroxyalkyl side chain, a number of simple
alkylirnidazoles (and pyrazines) are isolated. Other carbohydrate-type sources which have
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 485
been used include glycolaldehyde, glyceraldehyde, hydroxypyruvaldehyde and even wood.
In only a few instances, however, have the results merited classification as useful organic
syntheses. Identification of the imidazoles forrned frorn the interaction of ammonia and
reducing oligosaccharides or periodate-oxidized polysaccharides has led to methods of
linkage determination in the sugars (70AHC(12)103, 80AHC(27)241), and the field has been
reviewed (6SMI40800). The reaction of periodate-oxidized glucosamine with ammonium
acetate and forrnaldehyde in the presence of a copper(II) salt provides a route to L-erythro-ß-
hydroxyhistidine (79JA3982).
Probably the most useful extension of the foregoing synthetic rnethods was developed
by Bredereck and Theilig in 1953. Their 'forrnamide synthesis' reacts a-diketones, a-
hydroxy, a-halogeno or a-arnino ketones, a-ketol esters or (under reducing condtions)
a-oximino ketones with forrnamide. Yields of imidazoles can approach 90% and are seldom
less than 40%. Although the reaction has been reviewed earlier (S9AG7S3,70AHC(12)103,
B-64MI40800) the major features will be sumrnarized here. The general reaction sequence
can be formulated as in Scheme 78.
R R
'c=o 'c=o
t=o or Ht-X
R 1 / R'/
R N
HCONH, ) RI()
N
H
Scheme 78
(X'" OH, NHz, halogen, OCOR)
Applicability of the reaction sequence to the preparation of 2-substituted imidazoles
rests on the use of more cornplex amides than formamide. This constitutes a severe limitation
to the process since it has only proved possible to substitute acetamide in a few cases, with
the formation of 2-methylimidazoles. Nevertheless, the method still has many applications
in the preparation of 4- and 5-substituted imidazoles. Best results are obtained if a large
excess offormamide is used at 180-200 oC, or passage of a stream of arnmonia at 150-175 oC
for 4-6 hours is maintained. The use of sulfuric acid as a condensing agent is also of value.
Should these conditions not be adhered to then oxazoles may be formed preferentially.
One of the simplest methods of carrying out the reaction is to brominate the ketone in
the presence of formamide; where unsymmetrical ketones are involved, careful control of
solvent rnay allow selective orientation of such bromination. Irnidazole itself can be prepared
in 60% yield by reaction of bromoethanal (as the glycol acetal), formamide and ammonia
at 180 oc. Apparently, the initial step in the reaction is acyloin forrnation followed by attack
of formamide at the carbonyl carbon (Scheme 79). The a-formamido ketone (142) is an
isolable intermediate which reacts with formamide to give the imidazole (143). The alterna-
tive possibility that the imidazoles might be formed by the action of formamide on oxazoles
formed from (142) has been dicounted since it can be shown that a-forrnamido ketones
give oxazoles only to a minor extent if heated in the absence of a condensing agent, and
oxazoles are not converted into irnidazoles at temperatures as low as that of the reaction.
OH
R /
'C-NHCHO -H,O
I
HCOH
R'/
R
.......C=O
I
HCOH
R 1 /
HCOKH,
R
'C-NHCHO
II
C-OH
1/
R
----'"
...---
R
'CH - NHCHO
I
c=o
1/
R (142)
j HCONH,
H
R()
R 1 N
(143)
-HC0 2 H
(
R ,NHCHO
.......C,.
11
C
R'/ 'NHCHO
-H,O
--
R ,,-NHCHO
'CH
I/OH
C
R 1 / 'NHCHO
Scheme 79
When a-diketones react with a mixture of formamide and formaldehyde at 180-200 o C
it is not possible to detect a-hydroxy ketones during the reaction. It seems, therefore, that
the formaldehyde cannot be acting as a reducing agent, and that imidazole formation must
be a consequence of generation of ammonia from formamide, and subsequent reaction
between the diketone, ammonia and formaldehyde. The major advantage here over earlier
methods lies in the reduced decomposition of the a-diketone, which normally results in
reduction in yields and mixtures of products.
486 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
Whereas a-amino ketones readily form imidazoles with formamide, they are often not
easy to prepare. Accordingly, they can be replaced by precursors, a-oximino ketones, which
can be reduced either by dithionite or using catalytic me hods in formamide at 70-100 oc.
Ring closure can then be achieved by raising the temperature (Scheme 80). When a-ketol
esters are used it appears that the imidazole formation may in this instance proceed by way
of the oxazole. A further special case is the formation of 4,5-disubstituted imidazoles from
l-chloro-l,2-epoxides and forrnamide. One recent example of an application of Bredereck's
method is the synthesis of the imidazolepropanol (144) from 3-brorno-2-rnethoxytetra-
hydropyran (Scheme 81) (SOAHC<27)241).
R-C-C-R '
II II
o N
\
OH
H 2 /PI0 2
or Na2S204
70-1()()'C
R-C-CH-R 1
/I I
Ö NH 2
HCONH,
lXII'C
R R'
F\
NyNH
Scheme 80
O Br
OMe
o
HCONH 2 UN
OH N
H
(144 )
Scheme 81
A reaction which is applicable to the synthesis of imidazoles substituted at C-4 by sulfur
substituents is the interaction of a-chloro-a-phenyl thioketones (prepared frorn the corre-
sponding diazoketones) with ammonia and carboxylic acids. Although the detailed reaction
course is yet uncertain, it bears a close resemblance to the reactions of a-chloro ketones
with amides. The method has been used to prepare 2-ethyl-4-methyl-5-phenylthioimidazole
(145) using ammonia, propanoic acid and 1-chloro-l-phenylthiopropanone (Scheme 82).
Cl
MeCOCHN 2 MeCOC
"-
SPh
Scheme 82
E,CO, NH )
FtCO,H
PhS N
Me()EI
N
H
1145) 32%
Yet a further reaction which forms three bonds is the use of imidic esters with suitably
functionalized ketones (e.g. a-hydroxy, a-bromo). This rnethod is exemplified by the
synthesis of a new irnidazole alkaloid (146), which had been isolated from a member of
the Urticaceae family (SOAHC<27)241), and by the more general synthesis of 4-alkyl-5-
methoxymethylimidazole (147) (79API07). The cyclization process, which takes place in
liquid arnrnonia, may be complicated by 2-alkylbutanamide by-products which result frorn
Favorskii rearrangement of the bromomethoxy ketones (Scheme 83).
H
() (CH2h -c-CMe
MeO I """ Br
MeO #'
dH' CI -
hq. NH,
Me NH
0 < CH 2)'..... 1/ \
MeO;::? I - N"'/"-<CH2hCH20H
MeO
(146)
Br,
R-C-CH=CH 2 R-C-CH-CH 2 0Me
II HglOAcJ 2 II I
o 0 Br
OEt
HC/
"'NH
NH,
N CH 2 0Me
)R
H
(147) R = Et, Pr, Bu
Scheme 83
In the reaction of ammonia, sulfur and o-hydroxyacetophenone the rnethyl group of the
ketone is so functionalized that the 2H-imidazoline-5-thione (149) is formed. The reaction
proceeds best in the presence of pyridine, and involves formation of a phenylglyoxylic
thioamide (148) in the first instance (Scheme 84). The ring closure of (148) resernbles
sirnilar reactions discussed earlier (Section 4.08.1.2.2(i)).
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 487
O OH S O OH S O OH
I OCH 3 I COCH 2 SH NH; I COCH(SHh
Ü): ,OH
::=-N (Sj Me ( !'IHJ
17 OH
S Hol .# OCOMe
(149)
NH/-H 2 S
O IOH
C-C-NH z
II II
o S
(148)
Scheme 84
Under UV irradiation, aqueous solutions of formaldehyde and amrnonium salts produce
imidazoles (Scheme 85). It is conceivable that the irradiation has catalyzed a 'formose'
reaction, yielding trioses and glycolaldehyde, and that reaction of these species with arnrnonia
could account for the products isolated. Such a reaction might be classed as a 'primitive-life'
synthesis, as might the observation that hydrogen cyanide and liquid ammonia react to
form 4,5-dicyanoirnidazole and adenine (70AHC(12)103).
HCHO + (Nt4hC0 3
Itv r N
254 om ) "N)
H
(23
Me N
+ ç)
H
5
HOCHy-N
+ (.)
N
H
1)
Scheme 85
There have been reports of a number of other processes which lead to imidazoles, but
which may have only limited synthetic utility. For example, the preparation of 2,4,5-
triarylimidazoles by the rhodium ion-catalyzed combination of alkenes with carbon
monoxide and ammonia; 50-60% yields are obtained. Benzylamine and derivatives react
with carbon tetrachloride in the presence of catalytic quantities of metal carbonyls to give
2,4,5-triarylirnidazoles and some of the corresponding irnidazolines through a process in
which radical species which coordinate with the rnetal carbonyl are implicated. Catalytic
conversion of acetylene, ammonia and ethyl en imine at 45-50 o C produces acetonitrile,
2-rnethylimidazole and 2-methylirnidazoline. The heating of monoamide resins has been
reported to give low yields of imidazoles (SOAHC(27)241).
4.08.2 SYNTHESIS BY TRANSFORMATION OF OTHER HETEROCYCLES
Syntheses of imidazoles which involve dehydrogenation of imidazolines have been dis-
cussed in Section 4.07.2.2.2, as have oxidations of benzimidazoles (Section 4.07.3.1.1).
4.08.2.1 Ring Expansions
There are a few examples of irnidazole formation from azirines and aziridines. 2-
Phenylirnidazole has been obtained in 25% yield from the reaction in ethanol of ammonium
carbonate with I-benzoyl-2-cyanoaziridine (150; Scheme 86). The reactions of 2H-azirines
(151) or their salts with nitriles likewise lead to imidazoles, a process which is prornoted
by perchloric acid or boron trifluoride, and which is a 1,3-dipolar cycloaddition to the
azaallyl cationic intermediates (152). When the azirine is disubstituted at C-3, then
perchloric acid and acetonitrile convert it into an imidazolium salt. Thus 3,3-dirnethyl-2-
phenyl-l-azirine (153) gives a 77% yield of the 4-hydroxy-2,5,5-trimethyl-4-phenyl-
imidazolidinium perchlorate (154). Results from labelling the nitrile nitrogen are consistent
with the possible mechanisms included in Scheme 87. It is likely that there is 1,3-bond
cleavage and ring enlargement at the cleavage site, since there were no products which
would have been obtained as a result of nucleophilic attack at the 1,2-bond (70AHC(12)103).
488 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
Cl
/
CH 2 -CH
I \
HNCOPh CN
NH CH 2 -CH-CN
\/
N
I
CO Ph
(150)
Ph Ph Ph
Ph BF3'Et,O) _ W
N H F3B- "-+ "'H
(151) (152)
INH 4 "CO, ç)\
- > 1 \ Ph
EtOH
H
RCN
-H+
Ph Ph
>O H
R
(30-82% )
Scheme 86
Me
N +A
Ph Me + MeCN* HCl0 4 > HO* CIO;
Me Pl1l-"""'M
(153) (N* denotes 15 N ) Me e
\
H C
I N ( N*
) either
Me
Ph Me
Me
HÑ *
4Me
Me
Scheme 87
or
Me
Hr(0- 1H
tl CIO;
Ph Me
H Me
(154)
\
C
IN) (N*
Me
Ph Me
Photolysis, too, of such azirines (155) generates benzonitrile ylides (156), and in the
presence of ethyl cyanoformate a mixture of oxazoline (158) and imidazole (159) is the
consequence of 1,3-dipolar cycloaddition to the carbonyl and nitrile groups respectively.
When there is no dipolarophile present, the ylide adds to the ground state azirine, giving
firstly the geornetrically isorneric 1,3-diazabicyclo[3,1,0]hex-3-enes (157), and then a
mixture of 2-rnethyl-4,5-diphenyl-1-vinylimidazole and 2,4-dimethyl-5,6-diphenyl-
pyrirnidine (Scherne 88). The photolysis of a formylazirine (which rearranges therrnally to
a pyrazole) gives a I-phenylimidazole (80AHC(27)241).
R 2 + R I
R\f-H R">=-'
N
(155)
H j-R t
>+-N
R 2
,1551
IR'=Me, >
R'=Phl
H Ph Ph
Me
XMe
(157)
!hP
(156)
.!, I
(R' = R' = Pi EtOâCN
CN
EtO h
Ox N
H Ph
(158)
Et0 2 C Ph
F\
+ HNVN
Ph
(159)
Ph Ph
F\
NV
II Me
CH 2
Ph
+ Me('ìt h
NV
Me
Scheme 88
There have also been a few exarnples of ring expansions involving azetines. One such
instance, which follows a pericyclic rnechanism, is the thermolysis of 4-cyano-l-t-octyl-3-t-
octylamino-2-t-octyliminoazetine (160), producing the 4-arnino-5-cyanoirnidazole (Scheme
89). Such azetine species have been implicated as intermediates in the photolysis of
enarninonitriles to irnidazoles (Section 4.08.1.1.1; Scherne 17). In strongly basic medium
the azetidinone (161), which possesses a lactarn group, is ring expanded to the 4H-
imidazolinone (163), probably via the anionic acylic species (162; Scheme 89)
(80AHCf27)241).
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 489
RNH)1ç
1:\ JH
Bu'CH 2 -C-CH 2
1
CH)
(160) R = t-octyl
t;
--
RHN N
CN(J>
R
H Ph
ë=N+--t- Ph
_)- Ph
o
(161)
I&Ni phl
lo NPhJ
(162)
Ph
Ph N
--. O )
Ph
(163)
Scheme 89
4.08.2.2 Transformations of Other Five-membered Rings
4.08.2.2.1 Pyrazoles and indazoles
Photolysis of N- and C-substituted pyrazoles and indazoles gives irnidazoles and benz-
irnidazoles, respectively, in moderate to high yields (20-90%). Thus 3-methylpyrazole
gives a rnixture of 2- and 4-rnethylimidazoles, and 4-aroyl-1-arylpyrazoles give the
biimidazol-4-yl derivatives (164). The reaction is potentially of synthetic importance in
view of the often greater ease of synthesis of pyrazole derivatives. Reactions are carried
out in 1,2-dimethoxyethane in the presence of benzophenone; although the sensitizer is
not absolutely necessary it improves the yield. Electron-attracting groups inhibit the reac-
tion, which goes through a ring opening to form an azirine (Scheme 90). The consequence,
allowing for tautomerism in the case of N-unsubstituted pyrazoles, is interchange of N-2
and C-3 in the pyrazole. 2-Methylindazole sirnilarly gives I-methylbenzimidazole when
irradiated, probably via the intermediate (165; Scheme 90). The courses of these reactions,
which can give yields as high as 96%, are markedly dependent on the nature and position
of substitution in the heterocyclic ring. In the absence of a substituent, benzimidazole (27%)
is forrned, and whilst 2-alkylindazoles give 1-alkylbenzimidazoles, 1-alkylindazoles only
give 2-alkylaminobenzonitriles (B-76MI40S00, SOAHC(27)241, 76HCA1512). Two pathways have
been suggested for the photo transposition of cyanopyrazoles to cyanoimidazoles, a reaction
which gives about 30% yields of isomeric imidazoles (SlCC604).
Me N MeN
ÇN (J>Me + (J>
H H H
COAr'
O
N'N
Ar
(X)
NMe
r/
hV\t;
R 3 R 2 R2
O hv R)
R 4 I N--
N/
R 1 R 4 R'
-.
R 3
R 4 ()R 2
N,
R
hv
-..
OHOH
NTt-tTN
I(N) År' Ar l ()
Ar (164) Ar
CX)
Me
Me
H +N
NMe ce
/ N-
(165)
Scheme 90
4.08.2.2.2 Formation of benzimidazoles from imidazoles
An unusual reaction which consists of building the fused benzene ring on to a preformed
imidazole nucleus utilizes the reaction of a 5-formylimidazole with a Grignard reagent,
then cyc1ization of the resulting alcohol (Scheme 91) (73JOC349S).
490 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
OHC()R
N
I
C 7 H 7
i, BrMgICH,I,cHOICH,J,O
ii,NH.CI
O Çz N å<;"
H N
1 )\R
N
H OH I
C 7 H 7 ,S04
rjíN)R
N
\
C 7 H 7
HOAc, H,O r NaOAc
Scheme 91
:+-q fiN
N)\R
I
C 7 H 7
4.08.2.2.3 2-lmidazolines from cyclic ureas
A convenient method for the synthesis of 2-imidazolines with long-chain alkyl or aralkyl
substituents at C-2 involves heating a carboxylic acid with a suitable <.:yclic urea (or thiourea)
(Scherne 92) (B-57MI40S00).
H H H H
N N J N N
C \ + HOzC(CHz)nCOz H + C }-(CHz>'-{ J
N O 0 N N N
H H
Scheme 92
4.08.2.2.4 From other five-membered heterocycles containing nitrogen only
Therrnolysis of ß-substituted a-(1-tetrazolyl)acrylamides (166) in the presence of copper
gives 2,4-disubstituted irnidazole-5-carboxamides. Since, however, the side chain is incor-
porated in the new ring, this might be better classified as a reaction in which the 1,5- or
3,4-bond is formed (Scheme 93) (SOAHC(27)241).
N-N
Rill \\
"'NN
I
C=CHR z
I
CON Hz
(166)
.1
Cu
R Z
R 1 ZJ CONH 1
N
H
Scheme 93
Thermal decomposition of 1,5-diaryltetrazoles gives low yields (8-20%) of benz-
irnidazoles (66RCRI22, 74CRV279). Photolysis, too, of tetrazoles can give rise to benz-
irnidazoles in a reaction which may have some synthetic utility. A 42% yield of
2-phenylbenzirnidazole was obtained from 1,5-diphenyltetrazole (167; R = Ph), while
5-phenoxy-l-phenyltetrazole (167; R = OPh) gave 2-phenoxybenzirnidazole (36%). Other
products, however, were also formed. These reactions can be accounted for in terms of an
initial loss of nitrogen, followed by partial secondary decornpositÌon of 2-phenoxybenz-
imidazole (Scheme 94) (74CRV279).
N-N
II \\
R", /N
N
Ph
(C N (C N OH
Izv :or 7" N
IR=OPh, ) I )R + I N + (Y )Ph+ PhPh
H J N 00-15%)
06%) (22%) H
(25%)
<1671 R = Ph, OPh
Scheme 94
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 491
,/
4.08.2.2.5 From oxazoles and isoxazoles
Oxazoles have long provided sources of imidazoles through oxygen-nitrogen exchange.
The oxazole can be heated with ammonia, formamide, hydrazine (gives l aminoirnidazoles)
or amines, often in the presence of a Brønsted acid. The use of formamide in place of
ammonia has been recommended to improve yields, which generally lie in the range 50-90%.
The reaction has been reported to fail with 2,4,5-triethyloxazole and with benzoxazole;
thus the employment of this transformation in benzimidazole synthesis seems to be pre-
cluded. Aliphatic groups at C-2 and C-5 of oxazole may cause steric hindrance to the
reaction since such compounds react only with difficulty with formamide, but even such
recalcitrant oxazoles can be converted into imidazoles using formamide and ammonia in
an autoclave at 200-210 oc. Aromatic and halogenoalkyl substituents, particularly at C-4
of oxazole, facilitate the reaction, presumably by lowering the electron density at the annular
oxygen. The proposed reaction course is outlined in Scheme 95 (66RCR122, 70AHC(12)103).
R 4
RS( R2 --
\
NH 3
R 4
\H
J- N C-N
// R 2 / 2 NH3
V 'c- C C-R-----.
R S I R S / \\ I
OH NH 2 0 NH 2
R 4
R 4
\H
C-N
/ -NH
RS-C 'C-R 2 -----,::...
/ \ I -H,O
NH 2 OH NH 2
R 4
N
R S ()R 2
N
H
Scheme 95
A novel oxazole to imidazole transformation occurs when the oxazole (168) reacts with
the imidoyl chloride (169) in the presence of phosphoryl chloride. The process probaoly
involves an initial quaternization of the oxazo1e with subsequent ring opening of the
oxazolium salt to form a ketimine (170). Intramolecular nucleophilic attack then leads to
the irnidazole product (Scheme 96).
PhCH2 )Me
o
(168)
o
II
+ Me-C=NCH 2 CNCH 2 Ph
I I
CI Me
(169)
POCI.,
16 h, r.t.
Me
PhCH 2 NCCH 2 N=C-Me
II I
o N+
.(.). ro;Me
PhCH2 O' t
Me '-J
1
Me
Me N
PhCH 2 NC-CH 2 -N y
II
o
PhCH 2 NMe
H 2 0
PhCH2N CH2
Me I
N+
PhCHt()Me
Me NCOMc
o
II
PhCH 2 NCCH 2
Me I
.N
r ""CMe
+-:\ I
PhCH 2 N=C" .....N-CMe
Me C II
H 0
(170)
Scheme 96
Oxazolium salts can be converted into imidazoles under much the same conditions as
oxazo1es are, and in the transformations of 3-phenyloxazolium salts into I-phenylimidazoles
the remarkable stabilities of the non-aromatic intermediates, and the forcing conditions
required to dehydrate them, have been remarked upon. Related reactions include conver-
sions of 2-oxo-4-oxazoline-3-carboxamides with strong acid into 4-irnidazolin-2-ones, and
of isoxazolin-5-irnines into related compounds. 2-Substituted 4-methyloxazole N-oxides
are attacked at C-2 by phenyl isocyanate with cleavage of the ring which then reforms,
yielding 1,2,5-trisubstituted 5-hydroxy-4-methylene-2-imidazolines (not imidazole N-
oxides as reported earlier). With ethyl a-amino-a-cyanoacetate, a 2-isoxazoline has
been converted into a derivative of l-(D-xylofuranosyl)imidazole (171; Scheme 97)
(SOAHC(27)241). Therrnolysis, photolysis and hydrogenation reactions have also proved of
value in effecting ring transformations of isoxazo1es into imidazoles. Thus heating 5-arnino-
3,4-dialkylisoxazoles at 180-190 o C gives 4,5-dialkylimidazolin-2-ones in 40-65% yields
(Scherne 98). Extensions of this work have revealed that 4-methyl-5-propyl-, 4-butyl-5-
propyl- and 5-benzyl-4-methyl-imidazoles can be prepared from 3,4-disubstituted 5-amino-
isoxazoles only if urea is present and the reaction is carried out in the condensed phase.
Arylamines such as aniline are also effective in promoting this transformation (75520).
492 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
1 ,5-Diphenyl-4-aryl(or alkyl)-4-imidazolin-2-ones are formed in yields greater than 70%
by the photolysis of 5-imino-2,3-diphenyl-4-aryl(or alkyl)-3-isoxaiolines in ethanol or
benzene with a high-pressure rnercury lamp.
In the presence of ammonia, amines or heterocyclic bases, sorne oxadiazolium salts form
1,2-diaminoimidazoles (Scheme 99) (see also Section 4.08.1.1.2) (67CB3418).
NHCOR
/
RJNH ( \
Ar I ;NRí
(51-95%)
Scheme 99
LY N)
Me'1 " 0
Me
4.08.2.2.6 From oxadiazoles
( CH2COAr
R 0)\NH2 Br-
NH,
I 0-CH 2
NC- C -CO,Et _ / \;0
H Me N NH 2
Me JC02Et
OH N
(171)
Scheme 97
R 1 R 2 R 1 R'
O .\ F\
N,O NH, --) HNÿH
o
Scheme 98
H' H 0 r NNH ,
-R O:H Ar,,)NRí
I-Hydroxybenzimidazoles and their 3-oxides can be prepared from 2,1,3-benzoxadiazole
I-oxides (172). Nitroalkane carbanions can accomplish the transforrnation by nucleophilic
attack at a ring nitrogen, while barbituric acid and 2,4,6-trialkylhexahydro-l,3,5-triazines
can effect similar transformations (Scherne 100) (77JCS(P1)470, 75S703).
-(r N
X I )C0 2 Na
N Na+
\
0-
!H3 0 '
-(e N
X I )CO,H
N
\
OH
t}o
o H
(
NaOH, MeOH, H,O
R 1
,
R 2 / Ç )NO,
xLì1\
NI
\
0-
O'
XfY >R
Ù :::::::N\ -CH I,.Et,N - N
X 0 . \
N +I OH
\ MeOH/H,O
O . R
W/'N
Rl. )R
N
(60-70%)
(172)
OH
-EX
X I >=NR
N
\
OH
(31-67%)
R 1
'0 0-
R 2 ' f C-N , I
e N02
_ X Np _ X0N\ R'
N'-J N: \,
'b'/ 1,
o' 0- o-
f I I
(X I >Rl xLY o: :XR:
N- 1 """'R N R
\ I' \
OH 0-
Scheme 100
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 493
The thermal decomposition of 2,4-diaryl-l,2,4-oxadiazolin-5-ones gives benzimidazoles
in high enough yields to rnake this a worthwhile synthetic method. The starting materials
are easy to prepare (Scheme 101). Modification of this thermolytic procedure by using
peroxide initiators, or by refluxing in dioxane, has also proved of value. For example,
when the analogous oxadiazolinethiones are heated, 2-(4-thiazolyl)benzimidazoles (197;
Scheme 113) are formed (74CRV279).
Ar
N Ar
ö-{
o
R
KyN)Ar+ C0 2
V--N
H
(70-90% )
Scheme 101
4.08.2.2.7 From five-membered rings containing sulfur
When 2,5-diamino-l,3,4-thiadiazole is treated with an a-halo ketone in ethanol, the
product is a 2-imino-3-(2-oxoalkyl)-5-amino-l,3,4-thiadiazoline hydrohalide (173). Direct
treatrnent with excess hydrazine hydrate, or such treatment subsequent to reaction with
aqueous ammonia, gives 1-aminoirnidazoline-2-thiones (Scherne 102) (70AHC(12)103).
FH 2 COR
N-N
II \ .HCl
H 2 N"'-. /""NH
S
(173). "-.....
N,H."-..,.
I.H,O
ii. aq. NH 3
N -..w""
H 2 N( I _ JR
S N
H4
H 2 N
\.
N\.
S t/R
H
Scheme 102
The dithiazole (174) is converted into the imidazodithiazole (175) and the imi-
dazolinethione (176) by a photochernical process of unknown mechanism (Scheme 103)
(SOAHC(27)241). However, the similarity of this last scheme to Scheme 103 suggests that
(176) rnay well be a breakdown product of (175). Treatment of 2,5-diaminothiazoles with
alkali gives imidazoline-2-thiones.
F N =< S N
S \ PhCN I )Ph
's II S..-N-ß'
S Ph
(174) (175)
Scheme 103
H
N
+ SYlPh
HN Ph
(176)
4.08.2.2.8 Imidazoles from condensed heterocycles
Examples exist of ring fission of purines to give 4,5-disubstituted imidazoles (Scheme
104) (7STL5007). The conversion of benzirnidazoles into irnidazoles has been discussed as
an exarnple of oxidation (Section 4.07.3.1).
NH NOR I
l :x II
R 0" N H2NC X N
ll) I>
N 2 OHC- 2
Scheme 104
4.08.2.3 Ring Contractions
There has been considerable literature pertaining to imidazole formation from
pyrimidines, pyrazines and triazines (70AHC(12)103, SOAHC(27)241, B-73MI40S01).
494 Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
4.08.2.3.1 From pyrimidines
When 5-amino-4-chloro-2-phenylpyrimidine (177) reacts with potassium amide in liquid
ammonia, the product is 4-cyano-2-phenylimidazole. Under the same conditions, (178)
gives 4-ethynyl-2-phenylimidazole (Scheme 105). A pyridine analogous to (177)
(3-amino-2-bromopyridine) rearranges when subjected to the same conditions, giving
3-cyanopyrrole, but 2-bromo-3-methylpyridine fails to give a pyrrole product. Whereas in
the pyridines only the 2,3-bond cleavage can account for the reaction products, with the
pyrimidines (177) and (178) either the 4,5- or 5,6-bonds could be broken. The situation
has been clarified by 14 C -l a belling, which demonstrates unequivocally that it is the 5,6-bond
of the pyrimidine which is subject to cleavage. This information permits the writing of a
feasible mechanism to account for the products (Scheme 106). There is still uncertainty as
to whether ring closure proceeds through a carbenoid species (180), or directly from (179)
(SOAHC(27)241).
Cl CN
N I H2 !/ )
Ph ..) Nil., Ph"
N
(177) H
CI
N I Me K H,. l! J C=CH
Ph ..) NH, Ph"
N N
H
(178)
Scheme 105
:r CI C - H2
(178) N I
-BH' Ph
N
H'
--
H
CI IbH
N:6'Y
Ph ..fJ
N
H'
--
CI
N C=CH
Jl H2
Ph N
(179)
1 -Cl-
---'"
H /CI
......c/
N/ .......c=c
J......
Ph N=CH 2
1
1 CI-
Cl CH
N 2
Ph ..)-
N
N C=CH
PhZ)
N
H
o
H
';:I C
Ph J.......N=CH2
(180)
Scheme 106
l-Cyanoimidazoles (185) are formed in high yield (80-90%) when 4- or 6-
azidopyrimidines are pyrolyzed. The azido compounds are readily prepared from the
corresponding chi oro compounds by reaction with potassium azide, and probably exist
largely as the tetrazolo tautomers (181). When (181) is labelled as in Scheme 107 (by
reaction of the 4-chloropyrimidine with K 15 NH 2 ), the subsequent pyrolysis gives a product
(185) in which only a ring nitrogen carries the label. Such a result is explicable only in
terms of the formation of a nitrene intermediate (182), which rearranges via the triazepine
(183) irreversibly into the pyrazinyl nitrene (184). This then undergoes ring contraction
(SOAHC(27)241). Certainly, thermal (or photochemical) nitrene generation from the
tetrazolopyrazine (186) also leads to 1-cyanoimidazoles (Section 4.08.2.3.2). Similar
thermolysis in benzene at 125 oC of 4-azido-6-methyl-2-methylthiopyrimidine gives a 50%
yield of l-cyano-4-methyl-2-methylthioimidazole.
N N N
Me N)N3 Mel N:-- Me NÀ * -.
*N=r-! (182)
(181) *N= I'N
Me
N N* __
Me N +--*-
(183)
* ..
( Ny N Me
Me"" )Me -- Me(Ñ/
N I
(184) CN
(185)
Scheme lØ7
(N 1
N N
\ /
N=N
(186)
Imidazoles and their Benzo Derivatives: (Ui) Synthesis and Applications 495
There are examples of photochemically induced transformations of pyrimidines into
imidazoles. In benzene or methanol solution, substituted pyrimidine I-oxides give low
yields of imidazoles (Scheme 108). Such reactions have been explained by invoking
oxaziridines, 1,2,4-oxadiazepines and zwitterionic species as intermediates.
R R
C """N hv r N
+)OMe ---. MeOC ..)\OMe
N N
! H
0-
Scheme 108
4.08.2.3.2 From pyrazines and quinoxalines
Both pyrazine N-oxides and 2,3-dihydropyrazines rearrange photochemically to imid-
azoles. Irradiation of the 2,5-disubstituted oxides (187) gives mixtures of the imidazole
products (188, 189), probably through the intermediacy of oxaziridine intermediates
(Scheme 109).
R N )
+ R
N
I
0-
(187) R = Me, Ph
( N
R R . R N R N
I R-- ( / R- Ck- H -()COR
Nq jÔ N COR
(188)
r N ) N N R N
R'?' I R -- R Ii..... jR -4 R -I.-.) R Q R
;N N OHC N
o H
(189)
Scheme 109
In a transformation which parallels those of azidopyrimidines (Section 4.08.2.3.1)
2-azidopyrazine l-oxide (190) on thermolysis forms 2-cyano-l-hydroxyimidazole;
2-azidopyrazines at 220 0 C give l-cyanoimidazoles via the nitrene interrnediate (Scheme
110) (80H(14)1963).
C)CN
N
I
OH
(83%)
Scheme 110
Certain quinoxaline N-oxides (191), too, are converted into l-acetyl-3-aroylbenz-
imidazolinones (193) when they are heated in acetic anhydride. The reaction proceeds by
an initial acetylation at N-3, and this is succeeded by formation and rearrangernent of an
intermediate oxaziridine (192; Scheme 111). Apart from their involvement in other reactions
discussed earlier, such intermediates have also been invoked to explain the formation of
1,3-dibenzoylbenzimidazolinone (70%) when quinoxaline 1,3-dioxide is exposed to sunlight
(74CRV279).
Ac Ac
(X Nyo (X N::rO
I +)Ar I Ar
<'0
0- (192)
Scheme 111
When treated with potassium amide in liquid ammonia, chloropyrazines undergo ring
contraction to imidazoles. The reaction has synthetic importance and resembles similar
reactions of pyridines and pyrimidines (Section 4.08.2.3.1). As before, labelling experiments
have been utilized to establish the origins of the nitrogen atoms in the products, and complex
N
(Ñ1 N3
I
0-
(190)
H
(X Nyo
I Ñ)Ar
I
0-
.1.
N=N
I \
(1 N
N
( \\
HOAc ;;
N
I
CN
(70%)
. )
benzene
Ac,O
reflux
Ac
-- rPYNrO
N
COAr
(193)
496 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
rnechanisrns have been proposed (Scherne 112). One factor which stands out is that the
products seldorn arise frorn a simple nucleophilic attack at the carbon atorn bearing the
halogen. The reaction products obtained frorn 2-chloropyrazine are 2-arninopyrazine (13-
15%), irnidazole (14-15%) and 2-cyanoimidazole (30-35%). Benzimidazoles are the rnajor
products of similar reaction sequences with 2-chloroquinoxalines (80AH027}241, 72RTC8S0).
N H \: t H NH 2
( )Cl NH,- -(y l :N
N /N
N
() -HCN C H -H, ()CN
N N CN N
H H H
Scheme 112
4.08.2.3.3 From other six-membered heterocycles
When the dihydro-1,2,4-triazinone (194) is heated at 180 0 C under reducing conditions
there is rupture of the 1,2-bond followed by ring closure, producing 4,5-diphenyl-
irnidazolinone (195). Such reductive ring closures of benzotriazine l-oxides (196) can give
benzimidazoles, in particular 2-(4-thiazolyl)benzirnidazoles (197) ('thiabendazole'). Sirnilar
reactions take place with 1,3,5-triazines. In fact, primary amines cleave the compounds
cornpletely with evolution of ammonia and formation of N,N'-disubstituted forrnarnidines.
With suitable primary amines, though, this reaction can be designed to produce irnidazolines
or benzirnidazoles (Scherne 113).
P yo
Hph , /NH
N
(194)
P/B!
Ph NH
PhCAo
N
H
(195)
R O: NTÖ
+;:::,N
N
I
0-
(196)
Zn/HOAc
or PtO,/EtOH
N N
N>--O
H
(197)
NH,
Me
(JC)
(SO%)
O INHMe
"" NH,
(
N N
llJ
N
CH,NH,
CH 2 NH,
c)
N
H
(47%)
Scheme 113
Treatment of 4H-1,3,5-thiadiazines (198) with aliphatic arnines at roorn ternperature
gives 2,4,5-triarylimidazoles. These may be forrned through the 871' 1,3,5-thiadiazine anion
(199), which could lose sulfur via a thia-a-homoimidazole (200; Scheme 114).
s S Ar S Ar
M Ar Ar
Ar( )Ar RNH, Ar("\1Ar w F\
, -, --.
N N -w N0 N N-_ -.N -s NVNH
ì( -..:.v
H Ar Ar Ar Ar
(198) (199) (200)
Scheme 114
4.08.2.3.4 From seven-membered heterocycles
Few exarnples are known in which heterocyclic rings containing rnore than six atorns
contract to forrn imidazoles. However, the acid-catalyzed contraction of 1,5-benzodiazepines
(201) into benzirnidazoles is well documented. When heated in water, (201) forrn benz-
Imidazoles and their Benzo Derivatives: (iii) Synthesis and Applications 497
irnidazoles and ketones (Scheme 115). Both the salts and free bases decompose on standing
in aqueous solution at arnbient temperatures, while dry distillation of the benzodiazepinium
salts has the sarne result.
H
(( 7" IN ) ::)
W
H R
(201)
.1 o= ' )
) I +': R + RCOMe
H 2 0 "::::,.. N
H
Scheme 115
If 5-benzyl-3,7-diaryl-4,6-dihydro-l,2,5-triazepines (20 ) are treated with bromine or
N-bromosuccinimide, a process involving consecutive halogenation and dehalogenation has
been proposed. The reaction sequence (Scheme 116) has been postulated to pass through
bicyclic intermediates (80AHC(27)241).
CH 2 Ph CH 2 Ph
\ \
( N)A Br2 PrAr
Ar ""'N- r Arl. N )
(202)
CH 2 Ph
\
M()A'
1
-ArCN
CH 2 Ph
Q \ '\ Ar
Ar " ')
N-
N Ar
zJ
N
I
CH 2 Ph
Scheme 116
4.08.3 APPLICATIONS AND IMPORTANCE
The imidazole nucleus appears in a number of naturally occurring products, among which
the rnost important are the amino acid histidine (203) and the purines, which cornprise
many of the important bases in nucleic acids. These purines, of which adenosine (204) is
an example, are fused imidazopyrimidines. Their chemistry is discussed in Chapter 4.09.
H0 2 C
\ H N
N{HCHf) (X)
H NH 2
(203) (204)
Histidine can be prepared from imidazole as in Scheme 117. It is a basic amino acid, the
biosynthesis of which appears to involve adenosine 5 ' -phosphate, ribose phosphate and
glutamine (which supplies a nitrogen for the imidazole ring) (Scheme 118). Histidine is
one of the most important amino acids and has involvement in such biological processes
as ester hydrolysis, acylation and (by virtue of its cornplexing power with iron) oxygen
()
N
H
PhCH 2 CI
N HOCH 2 N
) (') ()
N N
CH 2 Ph CH 2 Ph
rl o
HN+ s
y
s
N-< O
) HN S
H Y
S
HOCH 2 N
Na/NH, ) ()
N
H
/HN0 3
OHC N
(')
N
H
(203)
AcOH
Scheme 117
498 Irnidazoles and their Benzo Derivatives: (iii) Synthesis and Applications
transport (in haernoglobin). Several mamrnalian degradation routes of histidine are known,
of which decarboxylation to histamine (205) is well known. Histarnine is an amine which
has powerful biological properties, including stimulation of glands and smooth muscle and
dilation of capillaries. Release of histamine in the body is believed to be responsible for
certain allergic manifestations such as asthma and urticaria. This connection with allergies
has stimulated the synthesis of a large number of 'antihistarnines' to act as antagonists to
the effects of histarnine in biological systerns. Related (and degradation) products are
urocanic acid (206) and ergothionine (207).
RP
\
N JC N H OH
<. I N \<--(CHOHhCH 2 0P0 3 H 2
N .......c!
NH 2 I .......OH
H
CO,H
/ -
NH,COICH"2 CH "
NH,
R (CHOHhCH20P03H2
N NH 2 N-(
3CONH2 + (J
N N
;"H
(203)
RP
\ N
<Ny'-
N N
NH 2
[RP = ribose 5' -phosphate]
H2 N ( CH 2i[)
N
H
(205)
Scheme 118
Z)CH=CHCOZH
N
H
(206)
HN CH 2 CHCOi
s J Me3
N
H
(207)
Among other naturally occurring compounds with an imidazole or reduced irnidazole
nucleus are biotin (208), the essential growth factor, the hydantoin (209) which occurs in
beet sap, and allantoin (210) which is related to uric acid.
o
^
HN NH
U(CH2)4C02H
S
(208)
o
^
HN NH.
o}--l
(209)
o
1\ H
H 2 N-C- N 'r-- NH
O N>==O
H
(210)
C)cH2Ph
N
H
(211)
In view of the obvious importance of naturally occurring irnidazoles in biological systerns,
it is not surprising to find that a vast number of synthetic imidazoles have been prepared
as potential pharrnacological reagents. Of these, a number of nitroirnidazoles appear to be
finding considerable application. 2-Nitroimidazole (azornycin) and 1-(2-hydroxyethyl)-2-
methyl-5-nitroirnidazole (metronidazole) are antibacterial agents with particular applica-
tions as trichomonacides. Along with rnetronidazole, other nitroirnidazoles (misonidazole,
rnetrazole and clotrirnazole) are important anticancer drugs. They are prornising radio-
sensitizers which sensitize hypoxic tumour cells to the lethal effects of ionizing radiation.
Two irnidazolines, prisco I (211) and privine, are valuable vasodilating and vasoconstricting
drugs, while there are also a number of antagonists to histamine, such as antisine, rnethiarnide
and cirnethidine, which are also imidazolines.
Benzirnidazoles have been applied rather rnore as herbicides, and in veterinary problerns.
There are, for example, rnany benzimidazole fungicides and herbicides, and the antihelirnin-
thics thiabendazole (197; R = H) and cambendazole (197; R = NHC0 2 Pr') are of proven
efficiency both for human and veterinary use. There are also sorne fungicides known among
the 2- rninoirnidazolines.
A host of other applications of irnidazoles and benzirnidazoles is listed in the literature
with functions as widely divergent as dyestuffs, catalysts, polyrnerizing agents, drugs,
herbicides and fungicides.
4.09
Purines
G. SHAW
University of Bradford
4.09.1 INTRODUCTION
4.09.2 NOMENCLATURE OF PURINES
4.09.2.1 Nomenclature of Purine Bases
4.09.2.2 Nomenclature of Purine Nucleosides and Nucleotides
4.09.3 BIOSYNTHESIS OF PURINES
4.09.4 STRUCTURE
4.09.4.1 Theoretical Methods
4.09.4.2 Structural Methods
4.09.4.2.1 X-ray diffraction
4.09.4.3 Molecular Spectra
4.09.4.3.1 lH NMR spectra
4.09.4.3.2 l3C NMR spectra
4.09.4.3.3 lSN NMR spectra
4.09.4.3.4 UV spectra
4.09.4.3.5 UV photoelectron spectra
4.09.4.3.6 IR spectra
4.09.4.3.7 Mass spectra
4.09.4.3.8 ESR spectra
4.09.4.4 Tautomerism in Purines
4.09.4.4.1 Introduction
4.09.4.4.2 Dipole moments and purine bases
4.09.4.4.3 Dipole moments and purine nucleosides
4.09.4.4.4 Magnetic circular dichroism
4.09.4.4.5 Ionization constants
4.09.5 REACTIVITY AT THE RING ATOMS
4. 09.5.1 Introduction
4.09.5.2 Reactions with Electrophiles
4.09.5.2.1 lH, 2 H and 3H exchange reactions
4.09.5.2.2 N-Alkylation
4.09.5.2.3 N-Glycosylation
4.09.5.2.4 C-Alkylation and -arylation
4.09.5.2.5 Nitration
4.09.5.2.6 Reaction with diazonium ions
4.09.5.2.7 Oxidation of ring atoms
4.09.5.2.8 Halogenation
4.09.5.3 Reactions with Nucleophiles
4.09.5.3.1 Reduction
4.09.5.3.2 Amination
4.09.5.4 Reactions with Free Radicals
4.09.5.4.1 Alcohols
4.09.5.4.2 Amines
4.09.5.4.3 Ethers
4.09.5.4.4 Acyl radicals
4.09.5.4.5 Aryl radicals
4.09.6 REACTIVITY OF SUBSTITUENTS
4.09.6.1 Introduction
4.09.6.1.1 Nucleophilic displacement reactions
4.09.6.1.2 Substituent modification
4.09.6.2 N- and C-Alkyl Derivatives
4.09.6.3 Purine Aldehydes
4.09.6.4 Purine Ketones
4.09.6.5 Cyanopurines
501
502
502
503
505
505
505
506
506
510
511
514
515
516
517
518
519
520
520
520
521
522
523
523
525
525
526
526
528
536
536
538
538
539
540
540
540
541
543
545
545
545
546
546
547
547
547
547
547
547
548
548
CHC VOL 5-Q
499
500
Purines
4.09.6.6 Purinecarboxylic Acids 549
4.09.6.7 Purinecarboxylic Acid Esters 550
4.09.6.8 Purinecarboxamides 550
4.09.6.9 Nítropurines 550
4.09.6./0 Aminopurines 551
4.09.6./0./ Introduction 551
4.09.6./0.2 Acylation 551
4.09.6.10.3 Alkylation 551
4.09.6./0.4 Displacement reactions 552
4.09.6.// Hydrazínopurines 553
4.09.6./2 Purine N-Oxides 554
4.09.6./3 Hydroxyaminopurines 555
4.09.6./4 Oxopurines 556
4.09.6./4.1 Introduction 556
4'(J9.6.14.2 Oxo- to halogeno-purines 556
4.09.6./4.3 Thiation 557
4.09.6./4.4 Miscellaneous displacement reactions 557
4.09.6.15 Alkoxypurines 557
4.09.6./6 Thioxopurines 558
4.09.6./6./ Dethiation 558
4.09.6./6.2 Alkylation and acylation 559
4.09.6./6.3 Halogenation 559
4.09.6./6.4 Amination 560
4.09.6./6.5 Hydrolysis 560
4.09.6./6.6 Oxidation 560
4.09.6./7 Halogenopurines 561
4.09.6./8 Purines with a Fused Heterocyclic Ring System 564
4.09.6./8./ Introduction 564
4.09.6./8.2 Five-membered fused rings 564
4.09.6.18.3 Six-membered fused rings 566
4.09.6./9 Benzopurines 567
4.09.7 SYNTHESIS 567
4.09.7./ Introduction 567
4.09.7.2 Synthesis from Acyclic Precursors 567
4.09.7.3 Synthesis from Diaminopyrimidines 570
4.09.7.3./ Introduction 570
4.09.7.3.2 C(8)-Unsubstituted purines 571
4.09.7.3.3 C(8)-Substituted purines 573
4.09.7.4 Synthesis from Other 4,5-Disubstítuted Pyrimidines 579
4.09.7.4./ Synthesis from 5-amino-4-oxopyrimidines 582
4.09.7.4.2 Synthesis from 4,5-dioxopyrimidines 582
4.09.7.4.3 Synthesis from 4-aminopyrimidine-5-carboxamides 582
4.09.7.5 Purine Synthesis from Imidazoles 583
4.09.7.5./ Introduction 583
4'(J9.7.5.2 02)-Unsubstituted purines 583
4.09.7.5.3 2-Alky/-, ary/- and g/ycosy/-purines 587
4.09.7.5.4 2 -Oxopurines 587
4.09.7.5.5 2- Thioxopurines 589
4.(19.7.5.6 2-Aminopurines 590
4.09.7.6 Synthesis from Ring-fused Pyrimidine Heterocycles 591
4.09.7.7 Best Practical Methods for Specific Purine Synthesis 592
4.09.7.7./ Introduction 592
4.09.7.7.2 Purine 592
4.09.7.7.3 C-Línked purines 593
4.09.7.7.4 N-Línked purines 593
4.09.7.7.5 O-Linked purines 596
4.09.7.7.6 S-Linked purines 596
4.09.7.7.7 Se-Linked purines 597
4.09.7.7.8 Halogenopurines 597
4.09.8 NATURALLY OCCURRING PURINES-BIOCHEMISTRY AND APPLICATIONS 598
4.09.8./ Biosynthesis 598
4.09.8././ De novo biosynthetic pathways 598
4.09.8. /.2 Salvage pathways 598
4.09.8.2 Naturally Occurring Purines 598
4.09.8.2./ Methylated purines 598
4.09.8.2.2 Cytokinins 601
4.09.8.3 Nucleoside Antibiotics and Related Compounds 602
4.09.8.4 Miscellaneous 604
Purines
501
4.09.1 INTRODUCTION
The purine ring system is undoubtedly arnong the most ubiquitous of all the heterocyclic
compounds. This arises not only from the universal occurrence of adenine and guanine in
DNA and RNA and of additional modified derivatives in the various tRNAs but also frorn
the subsidiary uses of the ring systern' in very many biochernical systerns; Indeed across the
whole spectrum of biochemical reactions in living systerns there is hardly a reaction sequence
which does not involve in some way a purine derivative such as the adenosine or guanosine
rnono-, di- and tri-phosphates, associated cyclic phosphates and nucleotide coenzymes.
In addition to the nucleic acid bases and the long-known rnethylated purines such as
caffeine, in recent years modified purine structures both of natural and synthetic origin
have been a rich source of a wide variety of biologically active materials. Such compounds
generally include structural modifications in the carbohydrate moiety of ribose or
deoxyribose derivatives as with arabinosides, simple changes in known purines including
cytokinins, which are 6-N-alkylated adenines, and rnore deep seated changes in the purine
skeleton as with deaza and aza purines which involve carbon to nitrogen skeletal changes.
Table 1 Purines and Derivatives: Bibliography of Important Publications
Publication
Subject type Author(s) Ref
Major chemical review Book Lister 71HC(24-2)1
Chemistry and biology Book Wolstenholme and B-57MI40900
O'Connor (eds.)
Early review Chapter Lister 66AHC(6)1
Early general review Chapter Robins B-67MI40900
Syntheses Book Zorbach and Tipson (eds.) B-68MI40901
Physicochemical aspects Book Zorbach and Tipson (eds.) B-73MI40902
Physicochemical aspects Chapter Lister 79AHC(24)215
Purine N-oxides and cancer Paper Brown 68MI40903
Purine N-oxides Book Katritzky and Lagowski B-71MI40902
Chemistry of guanine Review Shapiro 68MI40902
Uric acid: chemistry and Book Hitchings B-78MI40900
synthesis
Nucleophilic and electrophillic Chapter Bergman, Lichtenberg, B-74MI40901
reactions Reichman and Neiman
Tautomerism and prototropy Chapter Elguero, Marzin, Katritzky 76AHClSl)502
and Linda
Electronic aspects and Chapter B. Pullman and A. Pullman 7lAHC(13)77
structure
Literature July 1978-J une Chapter Ellis and Sma1\ey B-80MI40903
1979
6-Mercaptopurine review Paper Benezra and Foss 78MI40906
Chemistry of purines and Chapter Lunt B-79MI40905
analogs
Recent chemical developments Paper Y oneda 75MI40901
General chemistry Chapter Shaw B-80MI40901
Ring opening and closing of Paper Fujii, Itaya and Saito 77H(6)1627
adenine
X-Ray data Chapter Ringertz B-72MI40902
X-Ray data Book Katritzky (ed.) 72PMH(5)1
X-Ray crysta1\ography Chapter Rao and Sundaralingham B-73MI40902, p. 399
X-Ray data Paper Taylor and Kennard 82JST(78) 1
X-Ray data Paper Taylor and Kennard 82JA3209
Gas-phase analysis Chapter Pierce B-73MI40902, p. 125
Dipole moments Chapter Bergmann and Weiler- B-73MI40901
Feilchenfeld
IR spectra Chapter Tsuboiand Kyogoku B-73MI40902, p. 215
EPR of irradiated single Chapter Herak B-73MI40901, p. 127
crystals
Metal complexes Chapter Kistenmacher and Marzilli B-77MI40901. p.7
Chromatography Chapter Radrazil B-73MI40902, p. 533
Charge transfer interactions Chapter Slifkin B-73MI40901, p. 67
Mass spectra Chapter Dejongh B-73MI40902, p. 145
UV spectra Chapter Albert B-73MI40902, p. 47
Ionization constants Chapter Albert B-73MI40902, p. I
H-exchange Chapter Jones and Taylor 81MI40900, p. 329
502
Purines
The subsidiary uses of purines, together of course with associated pyrimidines, can hardly
be accidental and serve to illustrate the economy shown by nature in its use of available
and appropriate feedstock chemicals, and also points to sorne deeper significance in the
original choice of purines for the specific biological functions they possess. In either case
the purines assume a philosophical importance possessed by few other heterocyclic com-
pounds in considerations related to the organization of organic matter and the origin of
living systerns. It is hardly surprising therefore that the purine ring systern has been the
object of intense study by every relevant physicochemical technique, and syntheses and
reactions of purines have been exarnined in great detail. Sorne important general reviews
of purine chernistry and physical chernistry are collected in Table 1.
4.09.2 NOMENCLATURE OF PURINES
The system was first narned by Fischer (1899CB435) but the correct ring structure was
proposed much earlier (1875LA(175)243) in a forrnula for uric acid. In the general literature
purine nornenclature has been to a large extent affected by the abundance of trivial names
for cornpounds which were isolated before their structures were known and by variation
in description of tautomeric forrns.
4.09.2.1 Nomenclature of Purine Bases
The naturally occurring purines fall into 4 rnain groups. (1) Sirnple substituted derivatives
of purine (1) such as adenine (2) and various 6-N-substituted derivatives. (2) Monoxo-
dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). (3) Dioxotetra-
hydropurines such as xanthine (6) and rnethylated derivatives including the 3,7 -dirnethyl
derivative theobrornine (7), 1,3-dirnethylxanthine or theophylline (8), and 1,3,7-
trirnethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10).
0 0
ÛN NH 2 HN:j:N "N:j:N NH 2
ÛN H N I l N
N
N N N N N H 2 N N o N N
H H H H H
(1) (2) (3) (4) (5)
0 M' o H o Me o H
"N N Hr-\ I N) MeN N> MeN N> H!\ N>=o
O N N O N N O N N O N N O N N
H H Me Me Me H H
(6) (7) (8) (9) (10)
Because purine and its derivatives have been drawn in the 9H forrn (1), it rnust not be
assurned that this necessarily specifies the precise location of that proton in all circurnstances.
The proton may in fact occupy different positions in the ring systern according to the state
of the molecule and its particular environrnent. This leads to different tautomeric forms
and to rnany canonical structures. Thus, in the crystal purine exists in the 7 H forrn (11)
(ó5AX573) and its relatively high melting point (214 OC) compared with, for exarnple, indene
(-1.8 0 C), indole (52 0 C) and benzimidazole (170 o C) might suggest contributions frorn
polarized forrns. For a discussion of tautomerisrn in purines see Section 4.09.4.4 and also
(76AHOSl)502). The numbering system adopted is as shown (12) -and is in accordance with
IUP AC rule B-2.11.
H
N N
uJ- >
N N
:r 7
IN r 5 N
H N 14 N:s H
J I
H
(11)
(12)
Purines
503
It will be appreciated that it is also possible to write oxo-nH- purines in different ways,
i.e. in the lactarn (oxo-nH) forrn as with (13) and in a lactim (hydroxy forrn) as with the
alternate structure for hypoxanthine (14). However there is little doubt (see later) that both
in the solid state and in solution, except at high pH, these particular derivatives exist alrnost
exclusively in the oxo-nH forms.
o H
HNQN>
N N
(13)
OH
Ù N >
N N
H
(14)
4.09.2.2 Nomenclature of Purine Nucleosides and Nucleotides
In addition to the free bases outlined in Section 4.09.2.1 many purines also occur as
N- glycosides or nucleosides. Of special irnportance are the 9-ß- D-ribofuranosyl and 2 ' -
deoxy-9-ß-D-ribofuranosyl derivatives of adenine and guanine, adenosine (15), guanosine
(16), inosine (17), xanthosine (18), 2 ' -deoxyadenosine (19) and 2 ' -deoxyguanosine (20).
The nucleosides also occur in various phosphorylated forrns or nucleotides which include
5 ' -phosphates such as adenosine 5 ' -phosphate (AMP, 21), guanosine 5 ' -phosphate (GMP,
22) inosine 5 ' -phosphate (IMP, 23) and corresponding pyro- (di-) and tri-phosphates
including ADP (24) and A TP (25). These last compounds rnay be regarded as the monorner
units of the nucleic acids which can thus be regarded as polynucleotides. The nurnbering
systern adopted is outlined in structure (26). It will be noted that nucleoside structures are
presented in the normally correct anti form. See however Section 4.09.4.4.3.
N NH 2
<:eN
O'yN I N)
HO u
HO OH
(15)
ti NH
O'yNJl- )NH 2
HO u N
HO OH
(16)
o
('i^NH
O'yNJlN)
HO U
HO OH
(17)
N :C O
< I NH
HO"ÛN ),o
HO OH
(18)
N :C O
< I NH
o N )NH 2
HO N
HO
(20)
N :C O
< I NH
HO _o O'yN N)NH 2
II U
o HO OH
(22)
N NH 2
<-r N
O'yNÁN)
HO U
HO
(19)
N NH 2
HO < -r7
I 0 NÁ_.
HO-P-O 'y N
II U
o HO OH
(21)
N JL O NH
HO < I I
I o N
HO-P-O N
II
o HO OH
(23)
504
Purines
N NH 2
<I N
NJlN)
HO-P-O-P-O.c ö o
I I 2
OH OH
OH OH
J
o 0 0 \ À..
II II II N N)
HO-P-O-P-O-P-O.c öo
I I I 2
OH OH OH
OH OH
(24)
(25)
7 JÓ O
f 5 6 lNH
5' 0 8< 14 3 JJ
HO ?:y
3U2'
HO OH
(26)
The irnportance to science of the nucleic acids has currently reached awesorne proportions
and the literature is now very substantial indeed. It is therefore beyond the scope of this
article to give rnore than the briefest rnention of purine nucleoside, nucleotide and nucleic
acid chernistry. However, Table 2 lists sorne useful reviews on the subject.
Table 2 Purine Nucleosides and Nucleotides: Bibliography of Important Publications
Publication
Subject Type Author(s) Ref.
General Book Robins and Townsend B-79MI40902
(eds.)
Preparation of nucleosides and Book Zorbach and Tipson (eds.) B-68MI40901
n ucleotides
Syntheses Books Townsend and Tipson (eds.) B-78MI40901,
B-78MI40903
General Book Harmon, Robins and B-78MI40908
Townsend (eds.)
Purine nucleosides from Paper Yamazaki and Okutsu 78JHC353
imidazoles
Nucleosides Paper Galankiewicz 78KGS723
Nucleosides and nucleotides Chapter Davies 76MI40900
Nucleosides and nucleotides Chapter Shaw B-79MI40903
Nucleosides and nucleotides Chapter Shaw 80MI40902
Nucleosides, nucleotides and Chapter Jones B-80MI40901, p. 117
nucleic acids
Nucleoside analogues Book Walker, De Clercq and B-79MI40901
Eckstein (eds.)
Photochemistry Review Rufalska and Wenska 80MI40907
tRNA-modified nucleosides Paper McCloskey and Nishimura 77ACR403
C-Nucleosides Paper Sato and Noyori 78MI40907
Nucleoside antibiotics Book Suhadolnik B-70MI40900
Nucleoside antibiotics Chapter Bloch B-78MI40903, p. 962
Cyclic nucleotides Book George and Ignarro (eds.) B- 78MI40905
Cyclic nucleotides Book Brooker, Greengard and B-79MI40907
Robinson
Cyclic nucleotides (mainly Book Cramer and Schultz (eds.) B-77MI40900
biological)
Biosynthesis of purine Chapter Flaks and Lukens B-63MI40902
nucleotides
Purine nucleotide biosynthesis. Chapter Buchanan and Hartman 59MI40900, 59MI40901
Purine arabinosides- Paper Yamanaka and Utagawa 80MI40904
physiological action and
enzyme synthesis
Arabinofuranosyl purines Review Kaneko and Shimizu 79MI40904
Antitumour nucleosides Chapter LePage B-75MI40900
ORD Chapter Ulbricht B-73MI40902, p. 177
Purines
505
4.09.3 BIOSYNTHESIS OF PURINES
The oxo-nH-purines are frequently end products of adenine or guanine catabolisrn but
are also concerned in the biosynthesis of the purine skeleton. Biosynthetic routes to purines
fall into two rnain categories. (1) De novo biosynthesis: this operates at the nucleotide level
and involves the elaboration of new adenine and guanine ring systerns around the prirnary
arnino group in 5-phosphoribosylarnine in an enzyrne-controlled sequence of reactions
involving eleven steps (for further details see references in Tables 2 and Section 4.09.8.1).
(2) Salvage pathways: these do not involve forrnation of new ring systerns but can control
the ratios of existing nucleotides in the biochemical pool (see Section 4.09.8.1).
4.09.4 STRUCTURE
4.09.4.1 Theoretical Methods
The evolution of rnolecular biology has stirnulated interest in the quanturn theory of
purines which were the first rnolecules of specific biological irnportance to be investigated
quantitatively by the rnethods of quanturn chernistry. Indeed, it has been suggested that
these particular studies inaugurated the advent of quantum biochernistry (B-72MI40902). The
major stages in the developrnent of the calculations on purines and base pairs and appropriate
references are briefly set out in Table 3.
Table 3 Stages in the Development of Theoretical Calculations on Purines
Year
Ref.
Method
1956-63
1961-6
1965
1968
1969-81
7r-Electron calculations. Hückel-type molecular orbital (HMO)
method:
Bases-first calculations
Base pairs-first calculations
7r-Eleclron calculations. Self-consistent field MO without (SCF MO)
and with (SCF CI MO) configuration interaction:
First calculations
a-Electron calculations. Del Re's Hückel-type method:
First calculations
All valence electron (AVE) calculations (simultaneous treatment of
a- and 7r-electrons)
Three treatments:
(i) EHT (extended Hückel theory)
(ii) IEHT (iterative extended Hückel theory)
(iii) CNDO treatment (an SCF MO type)
All-electron calculations
Ab initio calculations using a Gaussian atomic basis set:
First calculations
56CR(243)380
59BBA(36)343
63MI40901
65MI40905
68MI40908
68MI40907
69MI40907
69MI40906
69MI40901
The theoretical calculations have been of undoubted value to the chernist in successfully
predicting several physicochemical properties of purine rnolecules such as dipole rnoments
and ionization potentials (see Tables 4 and 5) and providing inforrnation about the various
tautorneric forrns.
Unfortunately, the results of the rnathematical treatrnent normally only reflect ground-
state values of the rnolecules (75IJC668) since it is difficult to find forrnulae which include
all the various intrinsic environrnental and extraneous factors such as solvent effects. Thus
in the case of purine, CNDO calculations suggest that the 7 H tautorner should have a
slightly lower energy value than the 9H forrn. In the solid state this appears to be the case
(65AX573) but in solution there is arnple chernical evidence of the equivalence of the 7 H
and 9H forms. Thus alkylation of purine with vinyl acetate leads to equal arnounts of the
7- and 9-vinylpurines (27) and (28), respectively, but with other purines the reaction is
kinetically rather than therrnodynarnically controlled and norrnally only one alkylated purine
is produced (75JOC3296) (see also Section 4.09.5.2.2).
506
Purines
Table 4 Calculated Dipole Moments of some Purine Nucleosides' (B-73M1409<H)
anti syn
Glycoside torsion Glycoside torsion
Compound Pucker endo angle (0) /k(D) angle (0) /kID)
Adenosine C-3' 20 5.6 240 1.9
280 2.8
Adenosine C-2' 70 8.2 260 4.4
Guanosine C-3' 35 4.6 280 10.0
2' -Deoxyguanosine C-2' 60 5.9 230 6.3
a Orientation at C(4')-C(5') gauche-gauche.
Table 5 Experimental and Calculated Ionization Potentials leV) of some Purines
Compound
Experimental
Calculated
SCF CNDO
Non-empirical
Purine
Xanthine
Hypoxanthine
Adenine
Tetramethyluric acid
Guanine
9.68:t:0.l
9.3:t: 0.2
9.17:t:0.l
8.91 :t:O.l
7.87
8.82
8.0
7.92
=7
7.59
10.08
9.06
9.41',9.99 0
9.09 0
,\ (h9M140906). 0 (h9MI40901).
CH=CH 2
(XN)
N N
(27)
t N)
N N
CH=CH 2
(28)
Electronic structures of purines in their ground and lower excited singlet (1T7T*) and
triplet (n?T*) states carried out using the AVE approxirnation CNDO/2 rnethod have
allowed both identification of rnost photoreactive sites and consideration of the dependence
of site locations on the. ionic states of the molecules to be rnade (79MI40906). Net electron
charges in the rnajor tautorners of purine, adenine, guanine and hypoxanthine are outlined
in Figure 1 (71AHC(13)77). Inforrnation about other tautorners is given in the sarne publication.
4.09.4.2 Structural Methods
4.09.4.2.1 X ray diffraction
X-Ray crystallographic studies of purine and its various substituted derivatives have been
of special value in providing (a) fine structural details of the ring systern of simple rnolecules
in their various neutral and protonated, and to a lesser extent, deprotonated forrns; (b) a
source of molecular geometries for theoretical calculations and related purposes; and (c)
inforrnation about the precise arrangement of purine (and pyrimidine) bases in the various
nucleic acids, and the way in which interaction of such bases with extraneous rnaterials
including intercalated or absorbed cornpounds occurs.
The studies have necessarily been lirnited by the availability of appropriate crystalline
derivatives, and the sparsity of crystalline anionic species is of special note since inforrnation
about the latter cornpounds would be of special value to the synthetic organic chernist. The
localization of protons in a given cornpound is to a large extent governed by the stacking
and interaction of units in die crystal lattice and hence the structure which eventually
ernerges rnay have little relationship to that which rnay dorninate in a reactive environrnent
as in solutions of varying polarities. Consequently, crystal structure data rnust be accepted
with care if the airn of the investigation concerns the prediction of reaction sites under the
norrnal conditions of hornogeneous or heterogeneous chernical reactions.
-0.00
H
-0.Q7
- :::N
+0.05
H
-0.02 N
-0.07
-0.14
Purine
+0.08
-0.45
o
+0.12
H
- N
+0.30
+0.11
-0.20
+0.12 +0.19
H +0.19
N -0.40
I +0.16
H
+0.14
+0.16
+0.05
N
+0.06
-0.40
Guanine
-0.01
N -0.20
H "m
N -0.49
\ +0.34
H
+0.13
-0.01
-0.16
7 '17 H
-0.05
-0.02
N -0.50
\ +0.38
H
+0.12
Purines
507
+0.11 +0.12
H________H
N -0.38
+0.14
-0.04
: ?l ":N
+0.10
H
-0.03 N
-0.04
-0.22
-0.01
-0.23
'15 H
+0.02
-0.02
N -0.48
\+0.37
+0.12
Adenine
+0.08
-0.45
o
+0.17
+0.13 +0.18
H
-0.51 N +0.09
+0.35 -0.15
+0.00
-017
: '17 H
-0.03
-0.01
N -0.51
\ +0.39
H
+0.12
+0.12 +0.17
+0.11 +0.00
H
-0.01 N
-0.01
-0.24
Hypoxanthine
Figure 1 Net electronic charges in some purine N(9)H tautomers evaluated by the CNDO/2 method. Upper
numbers: u-charges; lower numbers 7r-charges
(i) Purine bases
The first recorded X-ray crystal structures of purines were those of adenine (1948) and
guanine (1951) derivatives. Data for the!;e and related purines are recorded in Table 5.1
and additional exarnples are collected in a publication (72PMH(5)1). Recentl'y, results derived
frorn precisely-determined X-ray crystal structures of 24 adenine and 10 guanine derivatives
in both neutral and protonated forms have been published (82JST(78)1, 82JA3209).
The average standard deviations for bond lengths and angles assigned to this latter set
of data are 0.011 Å and 0.67 0 in adenine (neutral form), 0.011 Å and 0.81 0 in adenine
(protonated forrn), 0.78 Å and 0.48 0 in guanine (neutral form), and 0.015 Å and 0.83 0 for
guanine (protonated form). See also (B-72MI40902, p. 61) and Table 1 for further publications
devoted to bond lengths and bond angles in various purine derivatives.
Oddly enough, it is difficult to find accurate X-ray crystal structure determination of pure
anhydrous adenine or guanine. The arnount of experimental data available has clearly been
lirnited by the ability of workers to produce appropriate crystalline derivatives. This in
general means that published material almost exclusively is concerned with substituted
derivatives, frequently at N-9, including nucleosides and nucleotides or protonated forms
and hydrates which are found to produce good crystals. Unfortunately, literature abstracts
and titles of papers generally fail to make these distinctions, and reviews often quote a
structure for say, adenine, close exarnination of which reveals it to be for perhaps the
hydrochloride or other derivative. Also structures, especially tautomeric structures, have
frequently been assigned by assuming the existence of close relationships between bond
lengths and angles of, say, an aglycone and corresponding nucleoside derivative. Such
assurnptions are probably reasonable, but are nevertheless assumptions and to some extent
must cloud the accuracy of the reported assignments.
In contrast to adenine and guanine the structure of purine in the crystal is well character-
ized as the N(7)H tautomer (65AX573). However even this is to some extent unexpected
since calculations indicate that the N(7)H and N(9)H forms have similar stabilities.
508
Purines
Table .5.1 X-Ray Bond Lengths (Å); and Bond Angles (0) of Some Purines
6 7
lJ, N>B
N 4 N
3 9
Adenine Guanine Hypoxanthine
Bond length hydrochloride hydrochloride hydrochloride
(angle) Purine" hemihydrate b dihydrate C monohydrated
4-5 (4-5-6) 1.404 (118.2) 1.37 (118) 1.377 (119.9) 1.368 (120.9)
5-6 (5-6-1) 1.389 (119.0) 1.40 (114) 1.414 (110.8) 1.415 (110.2)
1-6 (2-1-6) 1.330 (118.0) 1.38 (123) 1.390 (125.6) 1.382 (124.9)
1-2 (1-2-3) 1.349 (128.2) 1.37 (124.5) 1.374 (123.4) 1.356 (125.4)
2-3 (2-3-4) 1.331 (113.2) 1.30 (112.5) 1.318 012.8) 1.297 (112.1)
3-4 (3-4-5) 1.337 (123.5) 1.36 (128) 1.345 027.6) 1.352 (126.5)
5-4 (5-4-9) 1.404 (109.6) 1.37 (107) 1.377 006.2) 1.368 (106.3)
4-9 (4-9-8) 1.374 004.2) 1.36 (105) 1.375 008.6) 1.375 (108.3)
8-9 (7-8-9) 1.312 (114.6) 1.33 (115) 1.335 (109.6) 1.333 (110.0)
7-8 (5-7-8) 1.332 (106.4) 1.35 (102) 1.322 (108.2) 1.318007.8)
5-7 (4-5-7) 1.374 005.3) 1.37 (111) 1.378 (107.4) 1.376007.7)
Sodium
Bond length 9-Methyladenine xanthinate Caffeine Theophylline
(angle) dihydrobromide c tetrahydrate f Uric acid& monohydrate h monohydrate'
4-5 14-5-6) 1.40 (120) 1.37 (118.2) 1.360 021.2) 1.32019.9) 1.37 (122.6)
5-615-6-1) 1.38 (111) 1.41 (113.0) 1.411 (111.3) 1.44 (115.8) 1.41 012.5)
1-612-1-6) 1.39 (124) 1.37 (125.7) 1.397 (128.8) 1.361127.6) 1.38 (126.0)
1-2 (1-2-3) 1.36 (127) 1.38 (120.5) 1.367 (116.0) 1.42 (112.9) 1.40(117.8)
2-3 (2-3-4) 1.35 (107) 1.33 (114.7) 1.382 (118.4) 1.35 (122.8) 1.35 (119.4)
3-4 (3-4-5) 1.37 (129) 1.36 (127.7) 1.356 (124.1) 1.42 (121.4) 1.37 (121.8)
5-4 (5-4-9) 1.40 (100) 1.37 (105.5) 1.360 (107.5) 1.32 (110.9) 1.37 (! 12.7)
4-9 (4-9-8) 1.37 (116) 1.41 (106.0) 1.360 (109.2) 1.31 (105.7) 1.33 (102.01
8-9 (7-8-9) 1.35 (04) 1.37 (115.0) 1.376 (107.1) 1.34 (112.3) 1.31 (! 14.3)
7-8 (5-7-8) 1.33 (109) 1.30 (101.9) 1.359 (108.1) 1.32 (103.4) 1.31 (106.7)
5-7 (4-5-7) 1.37 (111) 1.41 (111.7) 1.387 (108.0) 1.41 (107.2) 1.34 (104.2)
"(ó5AX573). b (51AXS1). C (65MI40903). d (69AXIBJ160S). e (62AXl179). f (69BCJ3099). & (66AX397). h(58AX453).; (58AX83).
An explanation for the existence of the N(7)H tautorner rnay reside in the fact that the
calculated dipole rnornent of the N(7)H forrn is rnuch greater than that of the N(9)H forrn
and the stabilization energy for interaction (as in the crystal lattice) of two N(7)H forrns
is hence greater than that for two N(9)H tautomers. In the gas phase however, the N(9)H
tautorner is the dorninant form (see Section 4.09.4.3.5).
A surnrnary with references of published X-ray structural data in the solid state of purines
other than adenine and guanine has been corn piled (B-72MI40902. p. 61).
In alrnost all cases the irnidazole ring systern is found to be planar whereas the pyrirnidine
ring has out-of-plane features. Bond lengths vary with the ionic state. Thus studies of
various adenine salts which contain the adeninium (protonated adenine) ion indicate that
protonation occurs firstly at N-1 in 9-substituted derivatives, which have been rnost studied
(see 71CRV439 for a discussion of protonation sites), followed by a second protonation at
N-7 (62AXI179). Differences in the imidazole ring bond angles between the rnono- (29)
(74AX(B)166) and the di-cation (30) (74AX(B)1528, 74CL409) of adenine similarly confirrn that
in the latter, protonation occurs initially at N-7.
NH 2 +
Na:
N H
(29)
+ :): NH 2 +
HNr I '>
l. N
N H
(30)
A study of 9-methyladenine at 126 K (81AX(B)1584), which reduces atornic vibrations,
has shown that the charge density on nitrogen is in the order N-1>N-7>N-3 with N-l
and N-7 accordingly the preferred sites for protonation. In unsubstituted adenine the first
Purines
509
protonation rnost likely occurs at N-l (78AX(B)2229) but a proportion of the protonated
imine form (31) is also probably present (see Section 4.09.4.3.3). The adenine anion hQwever
is assigned the arnino structure (32) (73AX(B)1974).
+
NH 2
HN N)
L. .Jl N
N H
(31)
NH 2
N N
l..J--:)
N N
(32)
Crystal structures of several 9-substituted adenines including 9-methyladenine (63AX907,
77AX(B)253), adenosine (72AX(B)1982), and 2'-deoxyadenosine (65AX1l1) confirm the 6-arnino
structure. Additional references are given in a review (76AHC(S1)502).
The crystal structure of a zinc chloride:adenine adduct namely (adenineh; ZnCl 4 oH z O
contains adenine cations which exist in the unusual N(7)H form (81AX(A)C63) analogous to
the structure found in purine crystals (65AX573).
With diprotonated 7-methyladenine (e.g. the dihydrochloride) the protonation sites are
at N-3 and N-9 (75AX(B)21l). Hypoxanthine and the analogous 6-mercaptopurine
(69AX(B)1608) both exist in the 7H-lactam tautorneric forms (69AX(B)1338, 69AX(B)1330) and
the lactarn structure of inosine h'as been confirrned in the solid state (69MI40903). Sirnilarly,
rnonoprotonated hypoxanthine exists in the N(l)H, N(7)H form with the proton at the
charged N-9 position (69AX(B)1608).
Crystal structure deterrninations of guanine hydrochloride hydrate also indicate that it
too exists with protonation assumed to occur at N(7)H as in (33) (69AX(B)1608) and, on
the assumption that bond lengths and angles in guanine are analogous to derived structures
of guanosine and inosine which are very similar, the N(9)H tautorner is also favoured
(68BBR(33)436). In contrast the N(7)H tautomer dominates in 6-thioguanine (70JA7441) and
crystal structure analysis of 3-rnethylguanine (34) also indicates that it exists as the N(7)H
tautomer (76TL3483).
:): 0
HN I +)
H 2 Nl N N
H
(33)
HN :): O N
HNL I )
2 N N
Me H
(34)
Puckering or distortion of the pyrimidine ring is especially noteworthy in the case of
1,3,9-trimethylxanthine with the C(2)-O bond displaced out-of-plane (73ACS2757), and
similarly the C-S bond in 6-thioxo-(lH)-purine is 1.5 0 out of plane with a dihedral angle
of 1.16 0 between the rings.
In the anionic form of xanthine (as a sodiurn salt) no hydrogen appears at N-3 or N-7
and the data has been interpreted by assignrnent of the canonical structures (Scheme 1)
(69BCJ3099). It is interesting to note that in this case all the forms are assigned as 9H
tautomers, the imidazole proton in solution usually being assigned to N-7.
o 0 0-
HN N) +---+ HN N) +---+ HN N)
-OÀ.NJl N oÅÑJl N OÅNAN
H H H
Scheme 1
Et N
{ '1NHH'
,+ 0
HN :): O Z
HNL I )
2 N N
(35) Et
:): 0
N I +)
H 2 NL N N
(36) Me
510
Purines
The effect of close stacking in a crystal structure is illustrated by the hemihydrochloride
structure of 9-ethylguanine (35) in which one form is protonated and the other hydrogen
bonded between the N-7 positions by a bond (2.637 Á) which is the shortest so far observed
(75AX(B)2862). The hydro bromide of 9-methylguanine analogously has the 7 H+ structure
(36) (64AX126). There can be no certainty, of course, that such a structure would have any
relevance in solutions of the cornpound.
Generally, however, the specific stacking patterns found in crystals of purine derivatives
are surprisingly consistent, especially when the influences of additional factors such as
hydrogen bonding, van der Waals interactions and steric factors are taken into account.
(ii) Purine nucleosides and nucleotides
The purine nucleosides and nucleotides have sirnilar stacking patterns to the aglycones
(B-72MI40902, p. 178) and the purine stacking in double helical polynucleotides is sirnilar to
that in sirnple purine derivatives. The stacking patterns are ascribed to the polar regions
of one rnolecule interacting with the polarizable ring system of an adjacent rnolecule, the
rnost cornrnon type involving the C-N bond of one base interacting with the polarizable
ring of the adjacent base. The high dipole mornents of the purines ensure strong interactions.
The stacking patterns fall into two general types.
In the first type the irnidazole rings point roughly in the sarne direction as in purine and
guanine. The second type has the imidazole rings of adjacent bases stacked in opposite
directions as in guanosine dihydrate and in interstrand stacking between purines of
cornplernentary polynucleotide strands.
A crystal structure deterrnination of guanosine hydro bromide (B-72MI40902, p. 217) has
interesting features in that the bromide ions appear to reside over the pyrirnidine ring
portion of the cornpound implying a charge delocalization On the bases, in contrast to
guanine hydrobromide (64AX126) where there is close approach of the N-7 (presurnably
protonated in both nucleoside and aglycone) and the brornide ion.
4.09.4.3 Molecular Spectra
Molecular spectra have always played an important part in investigations of purine
structure and reactions, and recent irnprovernents, especially in the developrnent of 1 H,
Table 6 NMR Spectra of Purines: Bibliography of Important Publications
Publication
Subject Type Authar(s) Ref.
I;N NMR spectra of Paper Grenner and Schmidt nCB373
nllcleosides
General 1 'c NMR spectra Chapter Stothers B-72MI4090 1
General 13 C NMR spectra Book Levy and Nelson B-72MI40900
13C NMR spectra (purine and Paper Thorpe, Coburn and 74JMR( 15)98
26 substituted purines) Monlgomery
l3C NMR spectrum. of purine Paper Pugmire, Grant, Robins 65JA2225
and Rhodes
1 Hand 13 C NMR spectra Paper Cheng, Kan, P.O.P. Tso, 80JA525
Giessner-Prettre and B.
Pullman
NMR spectra in molecular Book Davies B-78MI40902, p. 509
p!ology Paper Markowski, Sullivan and nJA714
N NMR spectra of
nucleosides and nucleotides Roberts
General NMR spectra Book Batterham B-73NMRI
1 H NMR spectra of purines Chapter Townsend B-73MI40902, p.313
and nucleosides
' N NMR spectra-general Book Levy and Lichter B-79MI40900
I;N_1H coupling in lsN_ Paper Leonard and Henderson 75JA4990
labelled adenines
1 'N NMR spectra of Paper Buchner et at. 78JMR(29)45
nucleotides
General review-mainly Book Pullman (ed.) B-78MI40902, p. 509
nllcleosides and nucleotides
Purines
511
l3c and 15N NMR spectral techniques, have resulted in major advances being made in our
understanding of these rnolecules.
There have been many publications representing a large amount of e'xperimental work
on the purine systern. Table 6 lists sorne major reviews and reference articles.
4.09.4.3.1 1 H NMR spectra
The preparation of specific, deuterated derivatives has made it possible to assign correctly
chemical shifts for the C-2, C-6 and C-8 protons of purine (63TL1499, 65JCS623). It was
shown that in neutral aqueous solution purine has three sharp singlets corresponding to
H-8 at highest field, followed downfield by H-2 and H-6, and the order is rnaintained in
non-aqueous solvents although accompanied by changes in chemical shift to lower field
(65JOC1110, 64JOC1988, 68B3721).
The spectrum of purine and, for that matter, its derivatives is very dependent on pH,
solvent, temperature and added chernicals. Thus aniline in aqueous solution causes the
proton signals for purine to be shifted upfield (66ZPC(51)297), presurnably due to sorne weak
association cornplex formation. The purine anion (32) has a similar spectrum to that of the
neutral molecule but that of the cation (29) is shifted downfield. Measurernents of pKa
suggest that purine is largely protonated at N-l (B-57MI40900, p. 11) but the large shift of
H-8 in the cation suggests delocalization of the charge with contributions from the N(3)-
and N(7)-protonated forrns (65JOC1110). At pH < 2.4 spin-spin coupling between C(2)H
and C(6)H occurs suggesting N(1)H protonation (B-73MI40902, p. 313). No such coupling
occurs at pH> 2.4.
An alternative (to deuteration) method involves measurements on purines in which each
C-proton is systematically replaced by methyl groups, the C-methyl having little effect on
the chemical shifts of the rernaining protons. Spin-spin coupling also occurs as would be
expected in the neutral forrn of I-methylpurine where the N-1 site is methylated rather
than protonated but not with 3-, 7- or 9-methylpurine where the C(2)H, C(6)H and C(8)H
protons appear as sharp singlets with no evidence for spin-spin coupling (B-73MI40902, p. 313).
Data for other C-substituted purines are included in Table 7.
Table 7 IH NMR Spectral Data of Purine and Some Simple Derivatives
Compound
Solvent
Chemical shift (8, p.p.m.)"
H-2 H-6 H-8
Ref.
Purine
1-Methylpurine
3-Methylpurine
6-Methylpurine
6-Aminopurine
6-Melhylaminopurine
6-Dimethylaminopurine
2- Azidopurine
6- Azidopurine
6-Chloropurine
6-Iodopurine
2,6-Dichloropurine
6-Methoxypurine
6-Methyl1hiopurine
6-Phenoxypurine
6- Trimethylammonium
chloride
6-Cyanopurine
6-Chloro-9-ethylpurine
6-Bromo-9-ethylpurine
6- Iodo-9-ethylpurine
Hypoxanthine
6-Mercaptopurine
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
TFA
AcOH
TFA
AcOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CDCh
CDCh
CDCh
DMSO
D 2 0
8.99
9.07
9.1
8.80
8.2
8.2
8.19
9.19
9.2
9.0
8.68 65JOC1110
8.67 B-73MI40902, p.313
8.45 66JHC241
8.55 78JOC2587
8.17 78JOC2587
8.33 B-73MI40902, p. 313
8.07 78JOC2587
8.58 66JOC935, 66JOC2210
9.35 66JOC935, 66JOC2210
8.58 66JOC935,66JOC2210
9.13 66JOC935,66JOC2210
8.59 66JOC935, 66JOC2210
8.73 78JOC2587
8.60 78JOC2587
8.77 65JOC1110
8.40 78JOC2587
8.47 78JOC2587
8.66 78JOC2587
9.03 78JOC2587
8.93 78JOC2587
8.76 80JOC3969
8.70 80JOC3969
8.63 80JOC3969
7.97 66JOC1417,66JOC2202
8.2 B-72MI40902, p. 264
a TMS used as internal standard.
8.03
8.55
8.10
9.13
8.74
8.80
8.63
8.57
8.75
8.60
9.28
9.12
8.17
8.3
8.24
8.12
512
Purines
It is noteworthy that the chernical shift of C(8)H is affected by substituents at C-2 and
C-6. Electron donating groups (e.g. NMe2) have a shielding effect and an upfield shift to
srnaller 8 values is observed, whereas electron withdrawing groups (e.g. CF 3 ) result in a
deshielding effect with concomitant larger 8 values. An equation incorporating an elec-
trophilic substitution constant which enables predictions to be rnade of the chernical shift
of C(8)H in purines has been of value (58JA4979). In the case of nucleosides, the ribofuranosyl
group exerts a deshielding effect on the irnrnediately adjacent O-H protons.
Adenine has two sharp singlets (8 8.11 and 8.14 p.p.rn.) assigned to H-2 and H-8,
respectively (65JOC1114), whereas adenosine also has two singlets 8 8.27 (H-2) and
8.45 p.p.rn. (H-8), a down field shift occurring with both protons but rnostly with the adjacent
H-8 (B-73MI40902, p. 313).
Inforrnation on tautomerisrn, and sites of protonation of purines has been derived frorn
NMR spectral studies. Thus protonation of adenine is first suggested to occur at N-l with
no evidence for protonation of the arnino group (65JOC1110) although protonation of the
substituted amino group does occur in 6-dimethylamino-3-rnethylpurine (68CClO02).
An MO study of the protonation of adenine and guanine using the Hartree-Fock-
Roothaan SCF rnethod has suggested, however, that for guanine, and to a lesser extent
adenine, several protonated forms rnay coexist in acid solution (80MI40906). Other naturally
occurring methylated purines including caffeine, theophylline and theobromine have sirnilarly
been exarnined and assignments of the methyl protons rnade (64JPS962, 65T3435, 64JA4721).
Table 8 lists sorne 1 H NMR spectral data for oxo- and thioxo-purines and Table 9 for charged
purine species.
Table 8 'H NMR Spectral Data of some Oxo and Thioxopurines (B-72MI40902. p. 264, 65T343S)
Compmmd
Solvent
Chemical shifts (8, p.p.m.jO
H-Me(1) H-Me(3) H-Me(7)
H-B
Xanthine
DMSO (9):D 2 0(1)
D 2 0
TFA
PhN0 2
D 2 0
TFA
PhN0 2
D 2 0
TFA
PhN0 2
D 2 0
2.15
2.05
Theophylline
( 1,3-dimethylxanthine)
3.65
3.27
Caffeine! 1,3,7-
trimethylxanthine)
3.59
3.23
3.86
3.45
2.12
3.75 4.28
3.35 3.81
2.12
3.8 4.33
3.38 3.82
1.61
2.05
Theobromine
\3,7 -dimethylxanthine)
2-0xo-!3H)-purine
6-Thioxanthine
o TMS used as internal standard.
NMR spectral studies of purine nucleosides have been rnuch concerned with assignrnent
of anomeric structure. The dihedral angle between vicinal protons in the cis H(1')-H(2')
configuration, as with a-o-ribofuranosyl derivatives, and the trans H( 1')-H(2') configuration,
as with ß-o-ribofuranosyl derivatives, rnay vary from 0-45 0 and 75-165 0 , respectively
(ó2JA62).
Coupling constants, J(l'-2'), vary from 3.5-8.0 Hz for cis protons in the a-D cornpounds
and from 0.0-8.0 Hz for trans protons in ß-o-ribofuranose derivatives. Hence the ß-J)-
configuration can be assigned when the J(l'-2') values fall within the range 0-3.5 Hz.
However subsequent work has indicated that the coupling constants rnust be .:;; 1 Hz before
acceptance of the trans configuration can be rnade with confidence. Sornetirnes however a
suitable derivative rnust be exarnined before assignrnent is possible. Thus adenosine has
J(l'-2') = 5.2 Hz (63JA2026) which is dirninished to 2.9 Hz in the 2',3'-O-isopropylidene
derivative (37) and this is sufficiently srnall to indicate the ß-configuration. Further reduction
of the J value is observed in the rigid N(3)-C(5') anhydro derivative (38) where the
anomeric proton now occurs as a singlet (B 6.8 p.p.rn.). It has also been shown that the
anorneric proton signal of aldofuranosyl nucleosides with cis H(l')-H(2') configurations
norrnally appears at a lower field than the signal for the shielded (by the [C(2')-OH])
Purines 513
Table 9 I H NMR Spectral Data of some Charged Purine Species
Chemical shift (8, p.p.m.t
Species Solvent H-2 H-6 H-8 Ref.
Purine D 2 0 8.82 8.96 8.60 66JCS(B)433
(neutral molecule)
Purine cation 1N DCl 9.39 9.56 9.12 66JCS(B)433
Purine anion 1N NaOD 8.74 8.93 8.53 63TL1499
Purine anion NH3/KNH2 8.58 8.79 8.12 79JOC3140
[6- 2H]Purine anion NH 3 /KNH 2 8.62 8.15 79JOC3140
6-Methylpurine anion NH 3 /KNH 2 8.48 8.06 79JOC3140
[8- 2 H]6-Methylpurine NH3/KNH2 8.48 79JOC3140
anion
2-Methylpurine anion NH 3 /KNH 2 8.68 8.05 79JOC3140
[6- 2 f:I]8- Methylpurine NH 3 /KNH 2 8.4 79JOC3140
amon
6,8- Di-t-butylpurine CDCl 3 9.0 79JOC3140
(neutral molecule)
Hypoxanthine
(neulral) DMSO 8.01 8.15 79JOC1450
(cation) D 2 0/CF 3 C0 2 D [2: 1] 8.61 9.44 79JOC1450
3-Methylhypoxanthine
(neutral) DMSO 8.31 8.21 79JOC1450
(cation) D 2 0/CF 3 C0 2 D [2: 1] 9.32 8.60 79JOC1450
a TMS used as internal standard.
NH 2 N_NH 2
<N rN ):N
HO)::tÄ \5N J
0)(0 HO OH
(37) (38)
anomeric proton of the corresponding trans H(1')-H(2') anomer, and this has proved a
valuable empirical rule for assignment of anomeric configurations. Another useful rule
involves examination of 2',3'-O-isopropylidene-D-ribofuranosyl derivatives. This (Imbach's)
rule proposes (73JHC417, 74TL129, 75ANY(255)177) that the difference in chemical shifts AS
for the endo and exo methyl group is >0.15 p.p.m. for ß-anomers and <0.15 p.p.m. for
a-anomers (Figure 2).
exo
M \: ,
endo 0 Aö 'V' OH
Base H
a-anomer
exo
M'\- ,
endo : ö OH
Base
ß-anomer
aM<0.15
ßM>0.15
Figure 2 Imbach's rule
For a rnore detailed discussion of notation see (B-78MI4.o902, p. 509).
The variation of spectra in different solvents and under differing conditions can rnake
assignments difficult. However tautomer compositions can be used to explain the rnechanism
of line broadening in spectra. Thus for guanine, guanine nucleosides and nucleotides, the
H-8 line widths were found to be strongly pH and temperature dependent (B-72MI40902,
p.277). However, sharp H-8 resonances were observed with I-methylguanosine (39) and
6-rnethoxypurine riboside over a wide range of temperatures and pH values. In the former
compound the guanine base can only exist in the lactam tautomeric form and in the latter
514
Purines
the purine exists solely in the enol (lactim) form. The line broadening is ascribed to chemical
exchange between tautomeric lactam-lactim structures for the guanine base. The alternative
amino-imino tautomerism is considered to be unlikely since H-8 broadening was still
observed in N 2 -dimethyl-1-methylguanosine (40) where this type of tautomerism is not
possible. The ratio of the normal (lactam) to abnormal (lactim) tautomers was approximately
17: 3 at roorn temperature in neutral aqueous solution.
N J:: O
r I NMe
--yOy\ JNR 2
HO u N
HO OH
(39) R = H
(40) R=Me
4.09.4.3.2 13C NMR spectra
Reviews and major papers dealing with the 13C NMR spectra of purines and derivatives
are collected in Table 6.
The 13C chernical shifts are normally reported relative to the peak in carbon disulfide,
benzene, DMSO or similar compounds. The first results on purine (65JA2225) indicated that
the relative positions of the peaks for the carbon atoms were in the sequence C-4 > C-2 >
C-8 > C-6 > C-5; the assignment of C-5 to the highest field was based on theoretical
predictions that it would have the highest 7T-electron density. It is noteworthy that IH NMR
spectra indicate a different order namely 6> 2 > 8 for the corresponding hydrogen atorns,
suggesting that in the use of chernical shifts for predicting charge densities care should be
exercised (B-73MI40902, p. 313).
Comparison of purine in the neutral, anionic and cationic forms indicated that the cation
is protonated at N-1 but in the anion, N-7 and N-9 could not be distinguished as a site of
protonation (71JA1880).
However, use of 7- and 9-methylpurine as reference compounds and extrapolation of
the results to the 7 H- and 9H-purines by application of a- and ß-substituent parameter
corrections indicated 40% of the 7 H tautomer in DMSO (75JA4627) and 58% in water
(75JA4636). Data for adenine in DMSO indicates about 15% of the 7 H form (75JA4627) and
this is in fair agreement with a figure of 22% for the 7 H form derived from a temperature-
jump relaxation technique in aqueous solution (75JA2369). Use of I H and 13C NMR spectra
in DMSO-d 6 has indicated that in 3-substituted adenine derivatives protonation occurs at
N-7 (81CPB2403). The assignments for adenine in the direction of increasing field were found
to be in the order of C-6 < C-2 > C-4 > C-8 > C-5 (7OJA4079) and this was confirmed in later
work (74JMR(15)98).
Table 10 13 C NMR Spectral Data of some Purines
Chemical shifts (8, p.p.m.)a
Compound Solvent C-2 C-4 C-5 C-6 C-B Ref.
Purine DMSO 152.1 154.77 130.46 145.5 146.09 74JMR(15)98
2-Aminopurine DMSO 160.59 155.11 125.52 147.69 141.02 74JMR(15)98
6-Aminopurine (adenine) DMSO 152.37 151.30 117.61 155.30 139.29 74JMR(15)98
6-Methylpurine DMSO 151.76 153.87 129.59 155.67 144.51 74JMR(15)98
9-Ethylpurine CDCI 3 152.5 149.9 134.2 148.6 144.8 80JOC3969
6-Chloro-9-ethylpurine CDCI 3 151.9 151.0 131.7 149.2 144.7 80JOC3969
6- Bromo-9-ethylpurine CDCI 3 151.7 150.5 134.2 144.8 143.0 80JOC3969
6- Iodo-9-ethylpurine CDCI 3 151.8 148.0 122.1 144.2 138.7 80JOC3969
6-Chloropurine DMSO 151.50 154.16 129.23 147.78 146.18 74JMR( 15)98
6-Bromopurine DMSO 151.52 152.98 131.97 140.12 145.94 74JMR( 15)98
6-Iodopurine DMSO 151.72 150.02 120.18 136.53 145.02 74JMR(15)98
2- Ethyl-6-chloropurine DMSO 165.01 155.11 127.70 147.59 145.99 74JMR(15)98
9 -ß- D- Ribofuranosylpurine D 2 0 152.6 151.2 134.4 148.7 146.6 80JOC3969
(nebularine)
a TMS used as internal standard.
Purines
515
The last authors also record the 13C NMR spectra of purine and 26 substituted purines
(three 2-substituted, twelve 6-substituted and eleven 2,6-disubstituted) and in most cases
proton-coupled in addition to decoupled spectra were obtained. Data for some of these
compounds are presented in Table 10 and for some purine species in Table 11. 13C spin
lattice relaxation data have also been used to assign a major structural form to the marine
sponge nucleoside 1-methylisoguanosine (80CC339) (see Section 4.09.8.2.1). See also
(74T3941) for a study of 13C chemical shifts of 6-substituted purines.
Recently the assignments, concentration dependence of chemical shifts in aqueous sol-
ution and solvent effects of all eight l H and 13C resonances of purines have been determined
(80JA525).
Table 11 13c NMR Spectral Data of some Purine Species (79J0C3140)
Chemical shifts (8, p.p.m.t
Compound Solvent C-2 C-4 C-5 C-6 C-8
Purine (neutral) CDCl 3 152.2 154.4 130.5 145.6 146.1
Purine (anion) NH3/KNHz 149.5 160.7 134.5 143.7 156.9
2-Methylpurine (neutral) CDCl 3 161.0 155.0 128.8 145.3 145.3
2-Methylpurine (anion) NH 3 /KNH z 156.7 164.5 134.5 143.3 158.4
8-Methylpurine (neutral) CDCl 3 151.5 155.9 131.2 143.3 156.2
8-Methylpurine (anion) NH 3 /KNH z 148.4 165.2 138.5 140.7 168.2
6,8-Di-t-butylpurine (neutral) CDCl 3 149.7 153.8 132.5 163.0 168.5
a TMS used as internal standard.
Table 12 shows the values of C-H coupling constants (Hz) of 1.0M purine at 25 oc.
Natural abundance 13C NMR spectra of purine nucleosides show a clean separation
between peaks for the aglycone (-36 to +33 p.p.m.) and the carbohydrate (+37 to
+89 p.p.m.) moieties (70PNA(65)27) with a benzene reference.
Table 12 Carbon-Proton Coupling Constants (Hz) of 1.0M Purine
(80JAS2S)a
C-2
C-4
C-5
C-6
C-8
H-2
1J = 206.5
3 J = 10.8
4J = 1.2
3 J =10.3
H-6
H-8
Carbon
3 J = 10.5
3 J = 4.9
zJ=5.9
1J = 187.3
4 J =0
3 J = 9.3
3 J = 8.4
1 J =212.9
a In DzO at pH 7, 25 oC.
4.09.4.3.3 lS N NMR spectra
N-H coupling has been used to investigate the rearrangement of 3-benzyladenine (41)
to N 6 - benzyladenine (42; Scheme 2), the data indicating that the mechanism involves ring
opening of both the imidazole and pyrimidine rings (75JA4990) since the 15 N label at the
6-NH 2 position of 3-benzyladenine appears at N-3 and N-9 in the product.
NHz NHCHzPh
Cì N ) Nl,j()
N N N N*
CHzPh * H
(41) (42)
Scheme 2
The mechanism of adenine formation under presumed abiotic conditions (see Section
4.09.7.2) from hydrogen cyanide and formamide has also been investigated in an elegant
series of experiments by detection of 15N_13C coupling contants (78JA4617). Thus when
516
Purines
doubly' enriched HCN was heated with normal formamide at> 160 oc the adenine produced
had a l3C NMR spectrum in which only the resonances of C-4, C-5 and C-6 were split by
15N nuclei. By cornparison, using normal HCN and doubly enriched formamide, in the
13C NMR spectrum of the adenine produced the C-2 and C-8 atoms alone are labelled and
there is no 15 N _ l3 C coupling. The derivation of the adenine atoms could accordingly be
assigned as in Scherne 3. The absence of C-N coupling using enriched formamide was
explained in a separate experiment (78CC485) when it was shown that the C- N bond is
cleaved and then recornbined as shown in Scheme 4.
.
:j: N.H2 .
.. Nor N
3HCN + 2HCONH 2 ---.. I .1 ')
. N
H
Scheme 3
H12C014NH2+H13C015NH2 -+ H12C015NH2+H13C014NH2
Scheme 4
15 N NMR spectra have also been useful in predicting the presence or absence of complex-
ing between nucleoside bases and metal atoms. Thus A TP shows a very broad peak assigned
to the 6-NH z nitrogen, N-9 is a singlet and N-7 a doublet (coupling to H-8) at lowest field.
N-l and N-3 produce doublets by coupling to H-2 with N-1 at highest field. Addition of
Mg z + causes no change in chemical shifts, suggesting a lack of complex formation between
Mg and N, whereas Zn2+ gives evidence which suggests complex interaction at N-7 and
the 6-amino group {66JA2077, B-73MI40902, p. 353).
High resolution 15 N NMR spectra of six nucleosides and six nucleotides including adenine,
guanine and hypoxanthine derivatives has enabled all nitrogen resonances to be assigned
by comparison with related compounds (77JA714). The assignments are confirmed in a
related study with adenosine and guanosine 3'-phosphates (3' AP and 3' GP) (78JMR(29)45,
B-78MI40906). On protonation a drastic up field shift of the N-1 resonance of 3' AP is
interpreted as conversion of a pyridine type nitrogen to a pyrrole type. The other five
resonances of 3' AP shift down field on protonation. This suggests that the aromatic character
of the adenine ring increases, consequently inducing a deshielding of all the nitrogen atoms
except N-t. There is also a strong down field shift of the 6-NH 2 nitrogen atom suggesting
that its partial double bond character (C=NH) increases during protonation. With 3' GP
the 15N(3)_15NHz coupling constant is 6.0 Hz suggesting that the lone pair is on N-3 and
no change was observed over the pH range 2.2-10.
Table 13 contains 15N NMR spectral data of purine and some cornmon nucleosides and
nucleotides.
Table 13 15 N NMR Spectral Data of Purine and Some Purine Nucleosides and Nucleotides (77JA714)
Chemical shifts (p.p.m)"
Compound Solvent N-l N-3 N-7 N-9 NH 2
Adenosine DMSO 139.6 152.7 134.7 205.6 293.8
Guanosine DMSO 228.0 209.5 128.5 205.3 302.0
Inosine DMSO 200.7 161.2 126.7 200.7
2' - Deoxyadenosine DMSO 139.1 152.1 134.3 202.1 293.7
Purine DMSO 94.5 113.6 187 187
(broad) (broad)
Adenosine '-phosphate H 2 O 152.1 16Q.4 144.8 207.0 297.0
ATP H 2 O 151.7 160.3 145.0 207.2 297.0
ATP (pH 2.5) H 2 O 214.3 154.4 139.5 200.1 288.8
GMP H 2 O 229.1 211.3 141.2 207.2 303.5
"Upfield from D 15 N0 3 .
4.09.4.3.4 UV spectra
The characteristic UV absorption spectra of purine derivatives have made the technique
widely used for identification, structure determination and tautomerism studies and have
Purines
517
resulted in a very large literature. Accordingly it is not possible to give more than a brief
account of the subject here. Full details and lists of absorption maxima are given in various
publications including (B-73MI40902, 7IHC(24-2)1, 72PMH(S)l, 77MI40902).
The absorption spectra of purines fall generally into the following groups. (1) n -)> 77'*;;;.
300 nm. These tend to be weak bands (8 103) which arise from 'forbidden transitions' and
show bathochromic shifts in passing from polar to non-polar solvents (63JOC130S). (2)
77' -)> 77'* transitions: (a) 230-300 nm. Strong bands with high extinction coefficients (8 2000
to 20000) which show hypsochromic shifts in passing from polar to non-polar solvents.
(b) >230 nm with high extinction coefficients (8 >20000). The absorption maxima may
lie below the limit of most UV spectrometers in normal use (ca. 210 nm).
In purine the first band (294 nm) is out-of-plane polarized (n -)> 77'* transition) probably
localized at N-3 (69JCP(Sl)1862, 77JA3934).
The second band (263 nm) is in-plane polarized at 48 0 from the C( 4)-C(5) axis (towards
C-6).
The weak band (250 nm) is out-of-plane polarized and assigned to a second n -)> 77'*
transition probably located at N-1.
A strong absorption band at 200 nm is polarized parallel to the 263 nm band and the
identity of an out-of-plane band (190 nm) is not established.
n -)> 77'* transitions in purines have also been calculated by the CNDO-CI method
(74MI40903, 77MI40902).
Since many purines exist in lactam and lactim forms (cf. Section 4.09.2.1) the position
and intensity of the peaks are often affected by pH and this can be used for pKa determina-
tions. In addition the position of substituents affects the spectra by increasing the intensity
and causing bathochromic shifts usually in the order 6 < 8 < 2 and of increasing hypsochromic
effect 2> 6 > 8 for the longer wavelength band. The effects of the substituents in polysub-
stituted derivatives are not, however, additive.
Differentiation of tautomers by the use of UV spectra has not been too rewarding. Thus
whereas hypoxanthine almost certainly exists as the lactarn form (13) as indicated by IR
and other spectral studies, its UV absorption spectrum (À max 249 nm, pH 5.6) is similar to
that of 6-methoxypurine (À max 252 nm, pH 5.2), a derivative of the lactim form of hypoxan-
thine, and 1,7-dimethyl-6-oxo-1(H),6(H)-purine (43) (S-73MI40902), a definite lactam
derivative. On the other hand, the UV spectrum of 8-oxo-7 (H),8(H)- purine (44) is closer
to that of its 7- and 9-monomethyl and 7,9-dimethyl (oxo or lactam) derivatives than to
8-methoxypurine (45) (B-73MI40902) implying the oxo structure. Even in basic solutions
where the lactim structure is expected, the results may be difficult to interpret. Thus the
spectrum of the anion of hypoxanthine is similar to that of the neutral species of adenine,
(À max 258 and 260 nm, respectively) whereas this is not true of the 2- and 8-oxopurines
when compared with the corresponding aminopurines.
o
MeN NMe
l..JL >
N N
(43)
H
N N
l,jL )=0
N N
H
(44)
N N
l. .JLN>OMe
N H
(45)
On the other hand, there is a close correlation in the spectra of the rnonoaminopurines
with those of the corresponding N- dimethyl derivatives. This at least does not conflict with
the primary amino (as distinct from an imino) structure assigned to the aminopurines which
is well characterized by, for example, X-ray crystallography and magnetic resonance studies.
However, full comparison with the various imino derivatives would be required before the
result could be considered meaningful.
4.09.4.3.5 UV photoelectron spectra
UV photoelectron spectroscopy has recently been used to study the electronic structure
and tautomerism in the gas Phase of purine, 6-, 7- and 9-methylpurines, adenine, 7- and
9-methyladenines, and 6-N-dimethyl- and N 6 ,9-dimethyladenines (80JA4627 and references
therein) .
Assignment of the photoelectron spectral data was aided by results from HAM/3 MO
calculations (77TL4627). The spectral data indicate that in purine (adenine) the three highest
518
Purines
occupied lone-pair orbitals have ionization potentials -9.6 (-9.6), -10.6 (-10.5) and
-11. 7 (-11.39) e V for the two bases, respectively, confirrning the similarity indicated by
the calculations. The four highest 7T-orbitals in both bases were also cornpared and shown
to differ significantly as a result of the planar exocyclic arnino group of adenine affecting
the 7T-structure of the rnolecule.
Comparison of the photoelectron spectra of purine, adenine and their 7- and 9-methyl
derivatives in the gas phase revealed that the spectra of purine and adenine are both much
more like the spectra of their 9-methyl rather than their 7 -methyl derivatives. This suggests
that in an isolated environment the N(9)H tautomers of both purine and adenine are more
stable than the N(7)H forms.
4.09.4.3.6 lR spectra
The insolubility of many of the naturally occurring purines has restricted the general
application of IR spectral studies as a useful routine procedure. Nevertheless there is a
substantial literature including reviews of the subject which contain lists of spectral data
(see Table 1).
(i) CH stretching bands
C(2)-H, C(6)-H and C(8)-N stretching frequencies for several purines including
purine, adenine, hypoxanthine and guanine are 3023, 3060 and 3098 ern-I, respectively
(B-73MI40902), and weak bands rnay be revealed in aminopurines by conversion of NH to NO.
(ii) OH stretching bands
In the solid form the oxohydropurines show no strong absorption in the OH (3650-
3590 em-I) or hydrogen bonded OH (3600-3200 em-I) regions, implying that they exist
as the oxo and not the hydroxy forms.
(iii) NH stretching bands
The NH stretching vibration of purine is broad (3000-2500 em-I) and similar broad
bands occur in the oxopurines centred at 3100 em -1.
(iv) NH 2 stretching bands
The aminopurines show bands in the 3400-3100 crn- I region with a strong characteristic
band at 3300 em -1.
(v) C=O, C=N and C=C stretching bands
The C=O absorption band in the oxohydropurines is in the region 1700-1620 em -1 and
the C=N and C=C bands at about 1600 em-I.
Adenine in the solid state, for example, has a band at 1672 cm- I assigned to the prirnary
arnino group (61JCSS04, 71HC(24-2)1, p. 71) and 9-ethyladenine in chloroform has two bands
separated by 100 crn- I which is characteristic of primary amines.
Adenine will dissolve in compounds such as antimony trichloride and IR and Rarnan
spectral data in this solvent are also consistent with the primary amino structure as are data
on polycrystalline adenine (74JCP(71)41S). Similarly, IR spectra of guanine in the solid state
support the oxoamino structure, and related work with thioxopurines shows a strong band
at 1323 cm- I and absence of bands at 2500 cm- I in the solid state which favor the thioxo
structures (55JA2S69).
(vi) CH deformation bands
Purine has three sharp bands at 1100, 804 and 790 em -1 which after deuteration at C(6)
are replaced by two bands at 770 and 760 em-I. The first three bands therefore are assigned
to C(6)-H deformation motions and the latter pair to C(6)-D deforrnations.
In the case of adenine a sharp band at 800 cm- 1 splits into two when de ute ration at
C-2 occurs and a band in hypoxanthine (600 em-I) only appears after C-8 deuteration
(B-73MI40902, p. 215).
With purine nucleosides the absorptions of the bases are in slightly different positions
and of slightly different intensity to those in the aglycone spectra. Thus inosine has bands
Purines
519
at 1690(s) and 1600(m) and 1560(m) cm- 1 compared to hypoxanthine with two bands in
this region. The carbohydrate portion of the rnolecules of course gives strong broad OH
stretching bands at 3400 cm- 1 normally distinguishable from NH z stretching bands.
4.09.4.3.7 Mass spectra
Simple purines at least are relatively stable compounds so that the highest intensity ion
in the rnass spectrum is due to the molecular ion. Subsequent fragmentation depends on
the nature of the substituents. Purine liberates two molecules of hydrogen cyanide derived
fromC(2)-N(3) and C(6)-N(1) and similarly 2-, 6- and 8-methylpurinesproduce hydrogen
cyanide and methyl cyanide (66NKK71) whereas adenine liberates three molecules of hydrogen
cyanide (67JA2719) with slight involvement of the arnino group, in contrast to the substituted
adenine, zeatin [46a, trans-6-( 4-hydroxy-3-methylbut-2-enyl)aminopurine]. This shows
initial fragmentation at the substituted amino group (64CC230, 66MI40904) in a manner
analogous to that of 6-methylaminopurine which eliminates firstly CHzN or CH 3 N followed
by elimination of three hydrogen cyanide units (67JA2719, 66MI40904). 6-Dimethylaminopurine
also eliminates CH 3 N (67JOC3856).
YCH 2
M
XCH 2 CH 2 NH
t N)
N N
H
(46a) X=H; Y=OH
(46b) X=OH;Y=H
The most intense ion in the mass spectrum of guanine is the molecular ion which fragments
to cyanarnide derived from N(I)-C(2) NH z (67JA2719) and an ion at m/e 109 which loses
CO and hydrogen cyanide.
Fragmentation of oxohydropurines such as hypoxanthine, xanthine and uric acid is similar
to that of guanine, the main route involving elimination of hydrogen cyanide from
N(1)-C(2), followed by ejection of CO and HCN. Xanthine and uric acid eject HCNO
followed by decarbonylation (67JA2719, 62M632). Also see (B-72MI40902, p. 402) for a mass
spectral study of N- and S-methylpurines.
Mass spectra of purine nucleosides give valuable information about both the base and
the attached carbohydrate. Thus adenosine produces a molecular ion which fragments to
produce base plus H, and base plus 2H units, the latter being more prominent in ribosides
than deoxyribosides (B-62MI40900, 62JA2005, B-73MI40901). A complete high resolution spec-
trum of adenosine has also appeared (67C226), and mass spectroscopy has been used to
deterrnine the site and extent of benzylation of eleven monobenzylated nucleosides
(79JHC585). A rnajor advantage of the mass spectral techniques is the small amount of
material required. The relative non-volatility of purine nucleosides, especially oxo deriva-
tives, and nucleotides can be improved by the use of trimethysilyl derivatives as with silylated
nucleosides (47) and (48) and the nucleotide (49).
NHSiMe 3
o (NX)
Me3Sio N N
Me3SiO OSiMe 3
(47)
OSiMe3
o (NX)
Me3Sio N N
Me3SiO OSiMe3
(48)
NHSiMe 3
N N
Me3SiO 0 (Å__J
I N N
Me3SiO-P-O
II
o Me 3 SiO OSiMe 3
(49)
520
Purines
4.09.4.3.8 ESR spectra
In recent years there has been much interest in the chemistry and biochemistry of
irradiated nucleic acids and their derivatives (B-76MI40901). ESR spectroscopy is concerned
with the structure of radical forms produced by high energy radiation and has been of value
in understanding the complex reactions which occur in the nucleic acids and their simpler
derivatives. A discussion of these last reactions is beyond the scope of this chapter and the
reader is referred to the bibliography in Table 2.
Guanine hydrochloride dihydrate was first examined for three different orientations of
the single crystal form in the magnetic field (67PNA(58)1279). The protonated radical observed
(50) is forrned by hydrogen atom addition at C-8 and the structure required hydrogen at
N-7 which has also been observed in the undamaged molecule by X-ray crystallographic
studies (65MI40903).
:): 0 H
HN N
H NI I :>
2 N N
H
(50)
NH 2 .
UN>
N N
H
(51)
In the case of adenine, analysis of hydrogen addition radicals was achieved with 2'-
deoxyadenosine monohydrate crystals (68PNA(60)450) and this suggested hydrogen addition
to C-2. However more recent experirnents involving selective deuteration at C-8 have
shown that in all adenine derivatives hydrogen addition to C-8 occurs as with (51) (71MI40908,
B-73MI40901, p. 214).
4.09.4.4 Tautomerisms in Purines
4.09.4.4.1 Introduction
There are various forms of tautomerism which operate in the different purine species.
( 1) Prototropy which involves attachment of the proton to anyone of the four ring nitrogen
atoms (Scheme 5). Corresponding CH tautomers, for example (52), seem to be of little
significance. (2) Amine-imine tautornerism which operates in the aminopurines such as
adenine (Scheme 6). (3) Lactam-lactim tautornerism as in the hydroxypurines such as
hypoxanthine (Scherne 7) and the related thioxo-thiol tautomerism (53) and (54) in the
biologically important mercaptopurines (Scheme 8). The subject has recently been discussed
in some detail (76AHC(Sl)502).
N N >
..A
N N
H
HN N N N N N N N
À ) l__À ) _J-- > uJL. )
N N N N N N N N
H H
(52)
(55)
(56)
Scheme 5
N NX:--
_ _3-- > _jL >
N N N N
H
:jc o OH
'7 N '7 N
H I ) r )
NH Jl-NH
Scheme 6
Scheme 7
S
:\ H SH H
HN N N0yN
I > __3-- >
N N N N
(53) (54)
Scheme 8
Purines
521
Information about the precise nature of the tautomeric forms of the various purines is
of special and practical irnportance.
Thus the transfer of genetic information during DNA replication and RNA transcription
for protein synthesis depends on the accuracy of base-pairing of the cornplementary nucleic
acid bases. Imperfect pairing of minor base tautorners could lead to genetic mutation. Thus
the lactim form of guanine is electronically superimposable with normal adenine and could
possibly be misread and paired with thymine to produce an abnormal G- T base pair instead
of the normal Watson-Crick G-C pair which involves the lactam forrn of guanine (Figure
3).
H
\
H N-H. 0 N H
H N"'H-K-XR
l-\H_ r N
\
H
H H
\ /
H-C O'H-O N H
H--<:N-H(}-1:
jN-{ F N R
R O."H-N
\
H
C-G
T-G
Figure 3 Normal C-G base pair and abnormal T -G base pairs
The comrnent by Pullman that investigations of the chemical and physicochemical proper-
ties of purine tautomers are still in a primitive form (71AHC(13)77) may still be a fair cornment
on the current state of the subject.
The distribution of negativity in the purine ring system was originally considered (B-
68MI40900) to be a function of the annulation of a 7T-electron excessive imidazole ring with
a 7T-electron deficient pyrimidine ring. Of the four possible NH tautomers, calculated heats
of formation (MINDa method) show exothermic values for the 7 H (11) and 9H (1)
tautomers and endothermic values for the 1H (55) and 3H (56) forms (Scheme 5). Together
with charge distribution calculations (CNDO type), this suggests that in the 7H and 9H
forms a remarkable flow of negative charge has occurred so that the net result is that the
pyrimidine ring is 7T-electron excessive and the imidazole ring is 7T-electron deficient, and
that the original concept only applies to the 1H and 3H tautomers (7SE996).
CNDO calculations also indicate that the 9H and the 7 H tautomer pairs should be more
stable (ca. 170 kJ mol-I) than the 1H and 3H forms (71AHC(13)77) and that orders of
stability are 9H < 7 H < 3H < 1H (73CPB1470, 72JCS(PZ)S8S).
Calculations also predict that the 1H and 3H tautomers should be bathochromic by about
10 nm compared with the 7H and 9H forms.
4.09.4.4.2 Dipole moments and purine hases
Both the CNDO and PPPCI procedures predict that the dipole moments of 1H and 7 H
tautomers should be higher (order of 5-7 D) than the tautomers 9H and 3H (about 3-4 D),
and measurements of three series of derivatives of the four purine protomers, narnely
9-methyl-8-phenyl-, N- methyl-6-thiomethyl- and N- methyl-6-thiomethyl-8-phenyl-pur-
ines, satisfactorily confirm the theoretical predictions (68CR(C)(Z67)1461, B-70MI4090Z).
However, such differences have not always been noted as with the dipole mornents of
9-benzyl- and 7-benzyl-6-chloropurines (69JOC973). The differences in the values and also
the direction of the dipole moments (Figure 4) of the purine protomers reflects their different
charge distributions (71AHC(13)77).
"N : ,"
lr---;t-- JLN(1)H
JLN(7)H
Figure 4 Relative magnitudes and the directions of the dipole moments in the four purine NH tautomers (PPPCI
method)
522
Purines
Dipole rnoments rnay also bc used to some extent to differentiate between tautomeric
forms of the monooxopurines (69JOC120S). The tautomers predicted by both the CNDO and
the SCF CI methods to be the rnost stable in the 6-oxo (57) and 8-oxo (58) series have
low mornents and the most stable form in the 2-oxo series (59) has a high rnoment.
HN
J->
N N
(57)
H
N0yN
J" )=0
N N
H
(58)
H
HN N>
O NÄN
(59)
In the case of xanthine (4) the 9H tautomer is predicted to have a higher rnornent than
the 7 H form. In the case of adenine the amine form is similar to the purine series with the
calculation indicating that the moment for the 7 H tautomer is greater than that for the 9 H
forrn and similarly IL 1H > IL 3H.
Table 14 lists experimentally-determined dipole moments of some purines. The com-
pounds exarnined are limited by their solubilities, hence the absence of the highly polar
compounds. Solubility in non-polar solvents is,' of course, increased by alkylation or
arylation.
Table 14 Dipole Moments of Some Purines
Compound
IL (D)
4.32
4.3
5.34
4.98
3.25
3.4, 3.94
3.70,4.6
5.43
3.04
6.47
Purine
9-n- Butylpurine
6-Chloropuri ne
3-Methyladenine
9-Methyladenine
Theophylline
Caffeine
2' ,3' -O-Isopropylideneinosine
2' ,3' -0- Isopropylideneadenosine
5' - Trityl-2' ,3' -0- isopropylidineguanosine
Ref.
B-72MI40902
67BSF1833
68MI40905
B-72MI40902
70JCS(B)596
68MI4090S
68MI4090S
B-72MI40902, p. 72
B-72MI40902, p. 72
B-72MI40902, p. 72
The experimental value for purine (4.32 D) lies between the calculated values for the
9H form (3.6 D) and the 7H form (5.5 D). It might therefore be assumed that a solution
of purine contains a mixture of the 7 Hand 9H tautomers in stark cornparison with the
7 H form found by X-ray crystal structure determinations (Section 4.09.4.2) and the 9H
form favoured in the gas phase (Section 4.09.4.3.5).
4.09.4.4.3 Dipole moments and purine nuc/eosides
Whereas simple N-alkylation or -arylation of purine does not rnarkedly affect the dipole
rnoment, e.g. 9-ethyl-, 9-phenyl- and 9-(2-phenylethyl)-6-chloropurines all have the same
dipole rnoment (67JCS(B)410), products of glycosidation as with purine nucleosides are rnore
complex because of the uncertainties surrounding the precise conformation of the sugar
relative to the base, the extremes being termed the syn (60) and anti form (61), respectively
(72BBR(46)12S). The anti forrn is the most common, the syn form dorninating when there
is a large substituent at C-8 as in the example given of 8-bromoadenosine. In the case of
guanosine however, whereas the anti forrn is preferred at neutral pH, at pH 1 conversion
to the syn form occurs (B-72MI40902, p. 297). Details of bond angles, bond lengths and the
NHz
N N
)LN')Br
N
HO
syn HO OH
(60)
N Z
Br __)
"^'ýOy N N
HO LJ
HO OH anti
(61)
Purines
523
various tautorneric forms of purine nucleosides have been recorded (73AG(E)591). The five
ring atorns in both the riboside and 2-deoxyribose moieties are in a half-chair conformation.
NMR data and X-ray crystal analysis (69MI40902, 70MI40901, 60JA222, 70JA4088) indicate that
one of the five atoms is displaced from the plane formed by the remaining four. The plane
is produced by C-1', C-4', 0-1' and either C-2' or C-3'. The out-of-plane atom is termed
endo if it is on the same side of the plane as the C-5' atom and exo if on the other side.
The most common forrns are C-2' and C-3' endo (Figure 5).
C S ' 0
I /.. v"-... I'
4'
2'
C(3')-endo
4 1'
3'
C(2')-endo
Figure 5 Endo configurations of ribofuranosyl derivatives
These various conformations influence the dipole moment so that theoretical values may
vary over a wide range and experimental values may agree with more than one conformation
(B-73MI40901).
Calculated values for the extreme syn and anti forms of a few purine nucleosides are
given in Table 14 and are derived from the PCILO [Perturbation Configurational Interaction
(using) Localized Orbitals] method. The data predict that with the gauche-gauche confor-
mation for the C(4')-C(5') bond, the ribosides of purine and xanthine (the 9H tautomer)
should have higher dipole moments in the anti form, the reverse being the case for the
hypoxanthine 1H-9H form (B-72MI40902, p. 21).
4.09.4.4.4 Magnetic circular dichroism
Differences between the two sets of pairs of the four isorneric purine types also arise
from magnetic circular dichroism measurements of the four N-methylpurines (73JHC419).
Thus the MCD bands for the 1-Me and 3-Me forms are of lower intensity and occur at
shorter wavelengths than the related bands for the 7 -Me and 9-Me isomers. Also protonation
results in wavelength shifts and changes in peak intensities and these variations could be
used to characterize a particular isomer. Thus peak heights of the bands for the 1-Me and
3-Me isomers after protonation increase by 0.25 and three times whereas those for the
7-Me and 9-Me isomers decrease by 0.25 and three times, respectively.
4.09.4.4.5 Ionization constants
Imidazole (basic pKa 7, i.e. N -)> NH+) is much more basic a molecule than pyrimidine
(basic pKa 1.31) and the combination of the rings in purine results in a basic pKa of 2.39.
Since the basicity of purine is depressed by electron-withdrawing groups such as
trifluorornethyl and since the decrease in basicity is greatest with the 6-substituted purine,
Table 15 pKa Values of Some C-Substituted Purines with Electron-
donating Substituents a -<:
pKa(basíc) pKa(acidíc)
Purine derivative N --+ NH+ NH --+N-
7-H 2.39 8.93
2-NH 2 3.80 9.93
6-NH 2 4.25 9.83
8-NH 2 4.68 9.36
2,6-Di-NH 2 5.09 10.77
2,6,8-Tri-NH 2 6.23 10.79
2- NMe 2 4.02 10.22
6-N Me 2 3.87 10.5
8-N Me 2 4.80 9.73
2-NHMe 4.01 10.32
6-NHMe 4.18 9.99
8-NHMe 4.78 9.56
a (54JCS2060). b{65JCS3770). c (60BJ(76)621).
524
Purines
it was suggested many years ago that the most basic centre in purine resides in the pyrimidine
ring especially at N-1 (B-57MI40900, p. 3). This has generally been confirmed by other
measurements although NMR data (ct. Section 4.09.4.3.1) suggests that protonation also
occurs at N-7 and N-9 to a modest degree.
Electron-donating groups increase the basic pKa values rnarkedly (Table 15), electron-
withdrawing groups decrease the pKa values especially when present in the pyrimidine ring
(Table 16), and N-substitution has relatively little effect (Table 17). The hydroxy and thiol
purines exist largely in the oxo- and thioxo-hydro forms which results in weakening of acidic
properties, and this was deduced by comparing pKa values, and UV and IR spectra of 0- and
N-methyl derivatives (Table 18), In all cases the thiol(thioxo) derivatives proved to be
stronger acids than the corresponding oxygen derivatives (Table 19).
Linear free energy (LEF) relations for rnonosubstituted purines relating pKa to the
Hammett constants Urn and Up have made calculations of pKa values possible (8lJPS425).
Tables of calculated and observed values are quoted for mono-, di- and sorne tri-substituted
purines. Generally good agreement between calculated and experirnental values are
obtained. Many additional values have also been recorded (B-73MI40902, p. I).
Table 20 records pKa values for sorne nucleosides and nucleotides.
Table 16 pK. Values of Some C-Substituted Purines wilh Electron-withdrawing Substituents
Purine derivative
pK. (basic)
N --. NH""
pK. (acidic)
NH --. N- Ref.
2-CI
6-CI
8-Cl
2,6-Di-Cl
2,6,8- Tri-Cl
6-CF J
8-CF 3
6-CN
0.69
0.45
1.77
-1.16
-3.1
<0
-1.0
-0.3
8.21 65JCS3017
7.88 65JCS3017
6.02 65JCS3017
7.06 65JCS30 17
3.96 65JCS3017
7.35 58JA3932, 58JA5744, 59JA2515
5.12 58JA3932, 58JA5744, 59JA2515
6.88 58JA3932, 58JA5744, 59JA2515
Table 17 pK. Values of Some N-Substituted Purines
Purine derivative
7-Me
9-Me
2-Cl-9-Me
6-Cl-9-Me
8-CI-9-Me
2-0Et-9-Me
6-0Et-9-Me
8-0Et-9-Me
pK. (basic)
N --.NH+
2.29
2.36
0.65
0.20
2.00
2.53
1.90
3.45
Ref.
54JA6073
54JCS2060
65JCS3017
65JCS3017
65JCS3017
67JCS(B)954
67JCS(B)954
67JCS(B)954
Table 18 pK. Values of Some Oxo(H)purines and Derivatives
Purine derivative
6-0H(oxo) (lactam)
6-0Me (lactim)
2-0H
2-0Me
8-0H
8-0Me
2-0H(oxo)-9-Me
6-0H-9-Me
8-0H-9-Me
2-NH r 6-0H (guanine)
2,6-Di-OH (xanthine)
2,6,8-Tri-OH (uric acid)
pKa (basic)
N --.NH+
1.98
2.21
1.69
2.44
2.58
3.14
<1.5
1.86
2.80
3.0
pK. (acidic)
NH --.N-
8.94,12.1
9.16
8.43, 11.90
9.2
8.24, >12
7.73
9.19
9.32
9.05
9.32, 12.6
7.7,11.94
5.4, 10.6
Ref.
54JCS2060
54JCS2060
54JCS2060
54JCS2060
54JCS2060
57JCS682
57JCS682
57JCS682
57JCS682
61LA(647)161
61LA(647)155,61LA(647)161
52B1(51 )133
Purines
525
Table 19 pK. Values of Some Thioxo(H)purines and Derivatives
Purine derivative
pK. (basic)
N --+NH+
pK. (acidic)
NH --+ N-
2-SH
2-SMe
6-SH
6-SMe
8-SH
8-SMe
8-SH-9-Me
8-SMe-9-Me
-0.5
1.91
<0
1.63
<0
2.95
<2.5
2.98
7.15,10.4
8.91
7.77,10.84
8.74
6.64, 11.16
7.67
7.48
Ref
54JCS2060
54JCS2060
54JCS2060
54JCS2060
54JCS2060
54JCS2060
57JCS682
57JCS682
Table 20 pK. Values of Some Purine Nucleosides and Nucleotides in Water at 20-25 oC
pK. (basic) pK. (acidic)
Compound N--+NH+ NH --+ N- Sugar OH P0 4 Ref.
Adenosine 3.63 12.35 51JBC(193)425,
60JA2641
AMP 3.74 13.06 6.05 51JBC(193)425,
60JA2641
ADP 4.2 7.0 62JPC(66)359
ATP 4.0 6.48 51JBC(193)425
dAMP -4.4 6.4 53JBC(204)847
Guanosine -1.6 9.33 -12.3 53B1(54)646
GMP -2.4 -9.4 -6.1 56MI40900
GDP -2.9 -9.6 -6.3 56MI40900
GTP -3.3 -9.3 -6.5 56MI40900
Inosine -1.5 8.82 53BJ(54)646
Xanthosine 5.67 53BJ(54)646
4.09.5 REACTIVITY AT THE RING ATOMS
4.09.5.1 Introduction
The purine ring system is capable of undergoing both electrophilic and nucleophilic
reactions at the ring atoms, but the products will often depend on the state of polarization
of the molecule and whether the reaction products examined result from kinetic or thermody-
namic control. Thus the anionic form of purine (62) is readily attacked by electrophiles
such as alkylating or glycosylating agents to produce normally, and usually exclusively, the
N-9 substituted derivatives. In the neutral form the products may vary. Thus kinetically-
controlled vinylation of purine (Section 4.09.4.1) produced a mixture of N(7)- and N(9)-vinyl
derivatives whereas normally (thermodynamic control) only one (9-substituted) product is
obtained. Once the ring proton has been replaced, further alkylation can occur to produce
quaternary salts at either the imidazole or pyrimidine ring nitrogen atoms. In the case of
oxo-, thioxo- and amino-purines the additional tautomeric forrns available enlarge the
possibility for attack by electrophiles at different ring nitrogen atoms. Thus alkylation of
adenine with alkyl bromide in dimethylacetamide produced 3-alkyl (55-66%), 9-alkyl
(10-14%), and 1-alkyl (7-13%) derivatives (63JA3719).
û:
N -
(62)
In addition to the ring nitrogen atoms the adjacent carbon atorns also show degrees of
electrophilic or nucleophilic character, the extent of which will depend on the state of
ionization of the molecule and the degree and type of substitution.
The large movement of negativity in purines from the 7T-electron excessive irnidazole
ring to the 7T-electron deficient pyrimidine ring systern (Section 4.09:4.4.1) results in the
C-8 atom becoming the rnost electron deficient in the unionized purine rnolecule and
526
Purines
substituents in this position are norrnally displaced first by nucleophiles. The order for
displacernent is C-8 > C-6 > C-2. On the other hand, purine anion formation appears to
cause a return of negativity to the imidazole half of the system with nucleophilic attack
now predorninating at C-6 in the pyrimidine ring, the order for replacement of appropriate
substituents being C-6 > C-2 > C-8.
In addition to its reaction with nucleophiles the C-8 atorn in purines rnay also achieve
sufficient electronegativity to permit attack by electrophiles. Such negativity, however, is
normally only achieved by the presence in the rin'g systern of one or more strongly
electron-donating groups. Thus, whereas purine only forms an adduct with bromine which
readily reverts to the free base, adenine produces the 8-bromo derivative. This type of
substitution is analogous to reactions at C-2 by electrophiles in imidazoles and is of special
interest to studies of the mechanism of oncogenesis in which 8-arylation, especially of
guanine rnoieties, may occur in DNA bases (80CC82, 70MI40904) by aryl cations. Other
reactions at C-8 by electrophiles include exchange reactions with 2 H +, 3 H +, reactions with
alkyl radicals, cations and diazoniurn ions.
4.09.5.2 Reactions with Electrophiles
Much of the earlier literature of purines was concerned with attack by nucleophiles but
rnore recently there has been a marked increase in studies of electrophile attack. This is
no doubt encouraged in part by work concerned with the rnechanism of oncogenesis which
involve arylation or alkylation of purines usually at C-8.
4.09.5.2.1 I H , zH and 3 H exchange reactions
Most purines readily undergo exchange of H -8 in the neutral or rnonoprotonated rnolecule
but not in the anionic forrn. Measurernent of the rates of exchange can be followed by
using an 8- 2 H labelled purine and noting the increase of the peak height of the NMR signal
due to the appearance of 8_ 1 H in the presence of the exchanging rnedium which is norrnally
water (73JCS(P2)1889, 73JCS(P2)2138, 74JCS(P2)174). Alternatively, using a 3H-labelled purine
the exchange reaction may be rnonitored by measuring the gain in radioactivity in the
exchange rnedium which again is normally water (73JCS(P2)1889). In all these reactions sorne
contarnination can occur due to exchange at other carbon atorns but this is usually small.
Thus in the case of adenine, exchange of the 2_ 3 H derivative is 2 X 10 3 times slower than
that for 8- 3 H-adenine (71CC394).
The rate of hydrogen exchange is increased by factors which increase the electron
deficiency of the imidazole ring. Thus adenosine with a weakly electron-attracting
ribofuranosyl group in the 9-position exchanges at about twice the rate of adenine (71CC394).
Sirnilarly, if a positive charge is introduced into the imidazole ring by quaternization of one
of the nitrogen atorns, e.g. (63), then a very rapid increase in exchange rate occurs and the
signal for 8-H rnoves strongly downfield (75JHC171, 69JA5625, 73JHC849). The sarne effect
can also be observed in a graduated fashion by reaction of inosine with rnethylrnercury(II)
chloride. When rnore than one molecular equivalent of the rnercury derivative has been
o Me
HNtr) x-
N I
R1
(63) R = ß-D-ribofuranosyl
o 0 0 HgCl
HN N) -+ CIHg N) _ C1Hg ) Cl-
-JLN .JlN -JLN
N I N I N I
R1 R1 R1
(64) (65)
Scheme 9
Purines
527
added, 8-H exchange readily occurs. This is explained by initial formation of the 1-
mercuriochloride derivative (64) which does not affect the rate, followed' by quaternization
at N -7 tp produce (65) with the second rnolecule (Scheme 9) (74CC9S7). Irtosine quaternized
at N-7 as in (65) has a rate exchange which is too rapid to be rneasured.
Substituents at C-2 and C-6, whether electron withdrawing or donating, have little effect
on the rate of exchange but N- alkylation affects the hydrogen exchange to a marked degree.
Thus 1-methylhypoxanthine (66) has a slightly enhanced rate of exchange at H-8 whereas
the 3-methyl derivative (67) shows a considerably reduced exchange rate (7SCC12S). Indeed
the decrease in exchange at H-8 is so large that exchange at C-2 takes preference.
'l\ >
N N
Me
(66) (67)
The exchange at C-2 rather than C-8 is explained by invoking dipolar forrns for the
1-methyl (68) and 3-methyl (69) derivatives, respectively. These aspects have been reviewed
recently (81MI40900).
a H
MeN N>
J-N
:x -a H
+ N
MeN r I >
J + N
N
H
(68)
:x -a H
HN r N
J + I >
N N
Me
(69)
(i) Effect of pH
Purines not substituted in the irnidazole ring have similar exchange rate curves with
variation in pH. In particular little exchange occurs at low (<2) and at high (> 12) pH
values. This suggests that the neutral form and the monocation exchange at roughly similar
rates whereas the anionic species and the dication do not exchange. In the case of the anion
the excess negative charge is localized in the five membered ring as in (70) and exchange
does not occur. However, when the ring proton is replaced as in 9-isopropylpurine the
exchange rate increases drarnatically at high pH (73JCS(P2)1889). In this form of course, a
norrnal anion cannot be formed.
N
N 3-- >
N
(70)
a NH
HN I >
a N N
Me
(71)
Almost identical bell-shaped rate-pH curves are produced by [8- 3 H]theophylline (1,3-
dimethylxanthine; 8), xanthine (77T803) and 1-rnethylxanthine (79T663) whereas the charac-
teristic curve shown by 9-isopropylpurine is also reproduced by [8- 3 H ]caffeine
(1,3,7 -trimethylxanthine) (77T803), [8- 3H]-theobrornine (3,7 -dimethylxanthine), 7-
methylxanthine and xanthosine (79T663) in which substituents also occur in the irnidazole
ring. 3-Methylxanthine (71) on the other hand shows a rate-pH profile which is exceptional.
The explanations for these various phenornena are by no means satisfactory. They have
to account for hydroxyl ion catalysis, and hydroxyl ion concentration being a rate determining
factor. The explanations which have been proferred generally fall into two separate
mechanistic categories: (a) hydrogen abstraction by hydroxyl ion; and (b) hydrogen
ion attack at a negatively charged C-8. The conclusions may be surnmarized as follows.
(1) At low pH prior protonation of the imidazole ring nitrogen occurs followed by abstraction
of hydrogen at C-8 by hydroxyl ions (Scheme 10) (nB123s). However, sirnple purines are
well known to undergo the first protonation in the pyrirnidine ring and this casts some doubt
on the scherne. (2) As the pH increases most compounds may participate in hydrogen
exchange in the neutral form. In the case of neutral species it is difficult to distinguish between
528
Purines
hydrogen abstraction or hydrogen ion attack, since rate-pH plots are the same for both
rnechanisms. (3) In strongly alkaline solution compounds may participate as mono- or
di-anions. The likely mechanism here, of course, involves hydrogen ion attack (Scherne 11).
(4) The increase in rates shown by purines substituted in the imidazole ring system which
cannot therefore form an anion in that ring is ascribed to hydrogen abstraction. This is not
very satisfactory since it is difficult to see why the rate should increase so drarnatically at a
given pH. The irnplication is that a new species is being formed by hydroxyl ion 'attack and
that this is the rate determining step. A species such as the azornethine ylide (72; Scherne 12)
might be an attractive possibility although such a structure would only be expected in very
small arnounts. A similar mechanism could be used, incidentally, to explain exchange in the
(correctly) protonated form (73). At the sarne tirne a methine intermediate could also possibly
explain the unusual rate-pH curve shown by 3-methylxanthine with protonation at N-7 as
in (74) followed by hydrogen abstractions as in (1) above.
+ + +
NH NH NH
X T -4 X - J4 X H
N N N
R R R
i, OH-, slow, rate determining; ii, H 2 0, fast
Scheme 10
N N T N
-:)-T+W -: -}-H +T+
N N H N
-N =N
T .?T b
-N =N
R R OH-
(72)
Scheme 11
=N =N
X T ... '"
# l H
=N H =N
R OW R
-N
H
-N
R
i, OH-, slow; ii, H 2 0 fast; iii, TOH; iv rearrange
HÙ: T
N R
(73)
4.09.5.2.2 N-Alkylation
Scheme 12
o
HN:XÑ
O N N
Me H
(74)
(i) Purine
Whereas reaction of purine with dimethyl sulfate in water, or with diazornethane, produces
only the 9-rnethyl derivative (75), vinyl acetate and purine give a rnixture of the 7 - and
9-vinylpurines (75JOC3297) (Section 4.09.4.1). Sirnilarly, rnethylation of the thalliurn salt
of purine with rnethyl iodide in DMF at room ternperature produces 9-rnethylpurine together
with the 7,9-dirnethylpuriniurn iodide (76). The latter is also forrned in better yield by
NCX:
N Me
(75)
Net)' r
N Me
(76)
Purines
529
reaction of purine with an excess of methyl iodide in methanol (69JOC1170) or from
7-methylpurine and methyl iodide (1898CB2550).
(ii) Halogenopurines
With electron-donating groups in the pyrimidine ring systern, however, sorne alkylation
may also occur there. Thus methylation of 6-methylpurine with dimethyl sulfate in
methanolic potassium hydroxide produced a mixture of 6,9-dirnethylpurine (77; 50%) and
3,6-dimethylpurine (78; 15%) (66Mr40905). In contrast, the presence of electron-with-
drawing groups in the pyrimidine ring system enhances alkylation in the imidazole moiety.
Thus glycosylation of 6-chloropurine with 2,3,5-tri-O-acetyl-ß -D-ribofuranosyl chloride
(79) gave the 9-substituted purine (80) (53JBC(204)1019). Generally however, alkylation of
mono-, di- or tri-chloropurines gives rise to a rnixture of the 7- and 9-alkylpurines, the
latter normally being produced in the highest amount although the use of thallium salts
results in exclusive 9-alkylation (69JOC1170). Table 21 gives further inforrnation with some
selected purine derivatives.
N
N JLN
N Me
Me
N
NÅN
Me
ACO Cl
AcO OAc
(77)
(78)
(79)
Cl
0yN
l_JL
N N
Ip
R f
(80)
Table 21 Alkylation of Purines
Alkylating
Compound agent So/vent Product Ref
Theophylline Etr NaOEt/EtOH 7-Et 07 AP(245)312
Theophylline Epichlorhydrin K salt/125 oc 7 - Dihydroxypropyl 56JCS3975
Theophylline Formaldehyde, HCl H 2 O/base 7 -CH 2 Cl 59JOC562
Theobromine PrI KOEt/EtOH 1-Pr 1897 AP(235)469
6-Chloropurine Me2S04 1N NaOH 7- and 9-Me 62JOC2478
6-Chloropurine Ed DMSO/K 2 C0 3 7-Me (5%) 61JA630
9-Me (50%)
6-Chloropurine BzCl DMSO/K 2 C0 3 7-Bz (15%) 61JA630
9-ßz (38%)
8-Chloropurine Mer DMSO/K 2 C0 3 7-Me (4%) 63JOC2310
9-Me (8%)
2-Chloropurine Mer DMSO/K 2 C0 3 7-Me (9%) 63JOC2310
9-Me (85%)
2,6-Dichloropurine CH 2 N 2 Et 2 0 7-Me (11 %) 63JOC2310
9-Me (20%)
6,8-Dichloropurine ßzCl DMF /K 2 C0 3 7-ßz (trace) 62JMC15
9-Bz (57%)
2,6,8- Trichloropurine Mer DMSO/K 2 C0 3 9-Me (50%) 63JOC1662
2- Amino-6-chloropurine BzCl DMSO/K 2 C0 3 7-Bz (24%) 62JMC25
9-Bz (40%)
6-Fluoropurine behaves similarly and with methyl iodide produces 7-rnethyl-6-
fluoropurine (81; 40%) and 9-methyl-6-fluoropurine (82; 60%). Base-catalyzed Michael
addition reactions leading to alkylated purines are also possible. Thus 6-chloropurine and
propenal in DMSO containing potassium carbonate readily gives the 9-(2-cyanoethyl)purine
(83) (65JOC2857) in 60% yield. Acid-catalyzed alkylations with appropriate cyclic ethers
occur, usually in ethyl acetate using toluene-4-sulfonic acid catalysts. Thus 6-chloropurine
N CI
F Me F :J:N
N:J:N :eN t I
I > t I t I
N N N N N N N t x
Me CH 2 CH 2 CN
(84) X=O
(81) (82) (83) (85) X=S
530
Purines
and 2,3-dihydrofuran at 70 o C, or 2,3-dihydrothiophene at higher ternperatures, produce
6-chloro-9-(tetrahydrofuran-2-yl)purine (84) or the analogous 6-chloro-9-(tetrahydro-
thiene-2-yl)purine (85), respectively (61JOC3837). Analogous 9-(tetrahydropyran-2-yl)-
purines were also produced frorn 2,6-dichloropurine (63JMC471) and 2,6,8-trichloropurine
(63JOC1662). Sirnilar cornpounds are furnished by 6-brorno- and 6-iodo-purines (61JA2S74).
(iií) Aminopurines
Introduction of amino groups into the pyrimidine ring system can result in substitution
by direct alkylation occurring in that ring. The'course of alkylation of adenine, for exarnple,
depends on several factors including the nature of the solvent and the presence or absence
of base or acid. Thus in acid media no alkylation occurs. In neutral aqueous solution or in
DMF or dirnethylacetamide with dirnethyl sulfate, the rnajor product is the 3-alkyladenine
plus srnaller amounts of the 1- and 9-alkyl derivatives (628SS8). Thus alkylation with alkyl
brornides in dimethylacetamide produced alkyladenines in yields of the degree, 3-alkyl-
(55-66%), 9-alkyl- (10-14%) and 1-alkyl- (7-13%) (63JA3719). Trimethyl phosphate
(7SJOC38S) or epichlorhydrin (7SJHCI04S) give similar products without use of solvents. By
contrast, in alkaline aqueous solutions or in aprotic rnedia with bases including potassiurn
carbonate, sodium hydride and sodium alkoxides, alkylation of adenine gives the 9-alkyl-
adenine as the rnajor product (64JHCllS, 6SJOC323S). An exception, however, includes the
reaction of the sodiurn salt of adenine in ethanol with 3-methylbut-2-enyl brornide to
produce the 3-alkyl derivative (86) (triacanthine) with only a srnall amount of the 9-
substituted isorner (62JA2148) being formed.
NHz PhCONH PhCONH
NJ:N) N:t N ) :eN
l l II N)
N N N N N CHzPh
CHzCH=CMe z CHzPh
(86) (87) (88)
Acylation of the exocyclic amino group appears to have little effect on the position taken
by the entering alkyl group. Thus benzyl at ion of 6-benzarnidopurine in DMF (6STL20S9) or
dimethylacetarnide (64JHCl1S) gave 3-benzyl-N 6 -benzoyladenine (87), whereas at higher
ternperatures increasing arnounts of the corresponding 9-benzyl derivative (88) are produced
(65TL20S9) in addition to the 3-benzyl derivative.
Further alkylation of an already alkylated aminopurine can be achieved usually by rnore
forcing reaction conditions or by use of a base. Thus 3,7-dimethyladenine (89) rnay be
produced by methylation of 3-methyladenine with rnethyl iodide in methanolic potassiurn
hydroxide or frorn 7-rnethyladenine in DMF at higher ternperatures (648494). Sirnilarly
benzylation of 3- or 7-benzyladenines using benzyl brornide (not chloride) gave 3,7-
dibenzyladenine (90) but benzylation in the presence of sodiurn carbonate produced N 6 ,3,7-
tribenzyladenine (91) (64JHCl1S) which is also forrned by benzylating the N 6 -benzyl com-
pound. The tribenzyl derivative was probably produced by a Dirnroth rearrangernent of an
interrnediate quaternary salt involving a ring opening and closing mechanism.
NH CH Ph
(xN;Z
N N
I
CH z Ph
(89) (90) (91)
It is noteworthy however that methylation of N 6 -benzyladenine with dimethyloxosul-
foniurn rnethylide afforded 9-rnethyl-N 6 -benzyladenine (70JOC3981). When a 9- or 1-
alkyladenine is further alkylated the 1,9-dialkylpurine is produced (64JHCllS). Conditions
used rnay vary.
Thus in dimethylacetarnide, methylation of 1-methyladenine with rnethyl p -toluenesul-
fonate to give 1,9-dirnethyladenine required 125 OCj2 h whereas benzylation of 1-benzyl-
adenine occurred at room temperature over 70 h (6SJHC291).
Since benzyl groups may be readily removed frorn N -benzyladenines, for exarnple by
hydrogenolysis, it is possible to prepare what rnight otherwise be difficultly available 1- or
7-alkyladenines by hydrogenolysis of an appropriate 1-alkyl-9-benzyl- Or 7-alkyl-3-benzyl-
N e
l..jL ;
N N
Me
NCHzPh
(i )H,Ph
N CHzPh
Purines
531
adenine. An alternative to the benzyl group in these reactions is 2-cyanoethyl which rnay
be removed by heating with rnethanolic potassium t-butoxide (68JHC863).
Imine formation in adenines is presumably a factor of sorne irnportance to reactivity
towards electrophiles since in N 6 -dialkylated derivatives where imine formation is not
possible, further alkylation becornes more difficult. Thus 6-diethylarnino-9-methylpurine
required prolonged heating with methyl iodide to produce the quaternary salt (92)
(65JOC3597) and similarly 6-dirnethylamino-9-benzylpurine required 3 days boiling with
benzyl brornide in acetonitrile to produce 3,9-dibenzyl-6-dimethylarninopurinium bromide
(93) (66JOC2202). Under these circumstances it is clearly difficult to control the alkylation
step and quaternization is the normal rule.
(X) N(X)
Me Me PhCH 2 CH 2 Ph
(92) (93)
Intramolecular alkylation can also occur. Thus the imidazolopurine (94) is produced from
N 6 -ethyl-N 6 -hydroxyethyladenine (95) and thionyl chloride (Scheme 13) (62JOC973) (see
Section 4.09.6.18). Although alkylation of adenines does not normally occur in acid media,
when N 6 -formylmethyladenine (96) is heated with dilute aqueous acid it rapidly produces
the bisimidazole (97) presumably via prior intramolecular alkylation at N-1 (Scheme 14)
(70JCS(C)2206).
CH 2 CH 2 0H
I
6)
N H
(95)
C NEt
N N
N
N
(94)
Scheme 13
CHOCH 2 NH r- NH
l ) l N N
N N
(96) H
Scheme 14
-HC0 2 H
H
N N
(t-f N
H
(97)
Alkylation of guanine in alkaline solution leads normally to the 9-alkyl derivative. Thus
in sodium hydroxide solution with methyl chloride the products forrned included the
9-methyl- (33%), 7-methyl- (18%), 3-methyl- (11 %) and 1-methyl-guanine (trace), together
with sorne N 2 -methylguanine (66B3007). Higher yields of 9-substituted guanines rnay also
be obtained by fusion of the base with a tetraalkylarnrnonium hydroxide and the sarne
rnethod also furnishes 9-alkyladenines (63JOC2087).
Alkylation of N(9)-blocked guanine derivatives such as nucleosides and nucleic acids,
results in N(7)-alkylation (71BJ841), and N(9)-blocking can also be achieved in xanthines
with cobalt complexes also leading to N(7)'-alkylation (75JA3351). Several 7-substituted
guanine derivatives have been prepared as potential antiprotozoal agents (SOJMC357). Further
alkylation of guanine or the 7- or 9-alkyl derivatives with alkylating agents in aprotic
solvents such as dirnethylacetamide furnishes 7,9-dialkylguanines. Thus rnethylation of 7-
or 9-methylguanine with dimethyl sulfate (62JA1914) or methyl p-toluenesulfonate (60CB1206)
gave the 7,9-dim,ethylguanine salt (98) convertible by arnrnonia into the betaine (99;
Scheme 15).
^r ; NH, . NJY ;
H 2 NlJ-. N H2N J-. N
Me N Me
(98) (99)
Scheme 15
532
Purines
(iv) Oxopurines
The increase in protonation sites in the oxopurines with' increasing oxygen functions
extends the possibilities for N -alkylation sites. Norrnally in the case of rnonooxo- and
dioxo-purines, with the exception of reactions with diazoalkanes, rnany of which are probably
free radical in nature, alkylating agents even in alkaline solutions produce only N -alkyl
derivatives. Trioxopurines such as uric acid derivatives are an exception. The nature of the
alkylation and the site(s) of attack nevertheless still vary according to the solvent, pH and
temperature.
(v) Monooxopurines
The rnost comrnon monooxopurine is hypoxanthine (3). Methylation with methyl iodide
in alcoholic sodium ethoxide solution produces 1,7-dimethylhypoxanthine (100) as a com-
plex with sodiurn iodide. 2-Methylhypoxanthine similarly affords 1,2,7-trimethylhypoxan-
thine (101) (I897CB2231). 7-Methylhypoxanthine may be obtained by rnethylation of N(l)-
blocked derivatives containing removable blocking groups such as 1-oxy-2-picolyl.
However, in contrast, hypoxanthine or its 7- or 9-methyl derivatives with dirnethyl sulfate
or rnethyl p-toluenesulfonate in dirnethylacetarnide produces a 7,9-methylhypoxanthiniurn
salt which with arnrnonia gives the betaine (102; Scherne 16) (62JA1914, 66CB944). Also
rnethylation of 9-rnethylhypoxanthine with dirnethyl sulfate in alkaline solution affords
1,9-dimethylhypoxanthine (103) (62JOC2478).
:]: 0 Me
MeN I N\
Rl 1/
N N
(100) R= H
(101) R=Me
o
MeN N
l..Jl N
N Me
(103)
o Me O. Me
HN > NJy >
lNJ-- N lNJ-- N
Me Me
(102)
Scheme 16
However benzylation of I-benzylhypoxanthine in DMF or dirnethylacetamide over 22 h
at 95 oC afforded 1,7-dibenzyl- (42%) and 1,9-dibenzyl- (21 %) hypoxanthines (66JOC2202).
On the other hand an improved yield (57%) of 1,7-dibenzylhypoxanthine was produced
by benzylation of the 7 -benzyl derivative with benzyl brornide. Sirnilarly benzylation of
3-benzylhypoxanthine gave as the main product (74%) 3,7-dibenzylhypoxanthine.
Benzylation of 3-benzylhypoxanthine with benzyl bromide in acetonitrile at 80 0 C over
16 h gave 1,3-dibenzylhypoxanthinium brornide but at higher ternperatures (110 OC) the
rnajor products were 1,7- and 1,9-dibenzyl derivatives obtained in roughly equal arnounts
and produced by rnigration from N-3, Evidence for the rnigration cornes from heating the
1,3-dibenzyl salt (104) with adenine in dimethylacetarnide at 120 0 C for 4 h when sorne
3-benzyladenine is produced (Scherne 17) (66JOC2202).
Scheme 17
o 0
Ot'Ì)
Non
(105) IJ
o oQ
Ot :(>
N N
o
tx H NH2
PhCH 2 1\! I N\ 120'C N N
l 1/ adonin? l..A /
N N N N
Br- I I
CH 2 Ph CH 2 Ph
(104)
(106)
Tetrahydropyranylation of hypoxanthine in DMSO occurs with acidic catalysis and
2,3-dihydropyran, to produce 1,9-bis(tetrahydropyran-2-yl)hypoxanthine (105) and the
corresponding 1,7 isorner (106) (66JOC268S). Alkylation studies of 2-oxodihydropurine have
been lirnited and no data are available for the 8-oxo isomer. Methylation of the 2-oxo
derivative with rnethyl iodide in alkaline solution at 80 0 C leads to the 7 -rnethyl, then the
3,7 -dirnethyl derivatives.
(vi) Dioxopurines
No doubt the commercial importance of the various rnethylated xanthines such as
theobrornine, theophylline and caffeine has contributed to the substantial literature on
Purines
533
alkylation of xanthine and its derivatives rnuch of which was carried out in the early part
of this century. It is not possible to cover all the reagents and conditions used and rnore
extensive data have been collected elsewhere (28JPR(118)198, 71HC(24-2)1).
In alkaline solutions, xanthine alkylates on nitrogen in the order N-3, N-7, N-1, i.e. in
decreasing order of acidity, and substitution is easier when the first position has been
alkylated so to this extent dialkyl derivatives tend to be rnost easily produced. Thus
3,7-dimethylxanthine (theobromine) is produced by rnethylation of xanthine or 3-
rnethylxanthine with methyl iodide and ba.riurn carbonate (33JCS662) or dimethyl sulfate in
potassiurn hydroxide at 60 oC (SOCB201). However when the oxygen functions are blocked
by trirnethylsilylation, alkylation occurs at N-7 (64CB934).
Further rnethylation of theobromine readily produces caffeine (31MI40900). Similarly,
I-methylxanthine is methylated by dimethyl sulfate in alkaline solution to furnish 1,3-
dimethylxanthine (theophylline) which is further converted into caffeine (31MI40900).
Scherne 18 outlines the rnajor stages of xanthine alkylation.
OH OH O R
N N H N
HN RX HN RX N
I> I> I>
ON N ON N ON N
H R R
IMeI ;x: lRX. ow
ow
0 o R o R
HN N HN N> RN N>
O N N O N N O N N
Me Me H R
o H 0 H
\1e 1 N\ Me,S04 MeN 1 N\ Me,S04 If .
A"J- 1/ ..J- 1/ ca eme
o N NON N
H Me
Scheme 18
Under acidic or neutral conditions rnethylation of xanthine proceeds at N-7 or N-9. Thus
with methyl iodide the 7,9-dirnethylxanthine betaine (107) results after heating in a sealed
tube at 150 0 C for 5 h. In solvents such a$ DMSO or dimethyl ace tarn ide using dirnethyl
sulfate or rnethyl p-toluenesulfonate, better yields may be obtained (62CB1812). The sarne
betaine is also produced by similar rnethylation of 9-rnethylxanthine (62JA1914, 61LA(647)161).
Further rnethylation of the betaine (107) produces 1,7,9-trirnethylxanthine (108;
Scherne 19) (64LA(673)78) and, analogously, 3,7-dirnethylxanthine affords 3,7,9-
trirnethylxanthine (109; Scherne 20) (62CB1812). When the fully rnethylated derivative
caffeine is further rnethylated with dimethyl sulfate in hot nitrobenzene solution, the
quaternary salt (110) is produced (21LA(423)200).
1 ; Ml ;
o N NON N
H Me H Me
(107) (108)
Scheme 19
"1 ; Hl )
o N NON N
Me Me Me
(109)
Scheme 20
o Me
MeN^r:>
OÀNJ- N
Me Me
(110)
534
Purines
The tendency to form 7 -substituted derivatives in acid media is exemplified by treatment
of 9-benzylxanthine with either hot benzyl bromide or hydrogen bromide when a rearrange-
ment to 7 -benzylxanthine occurs (79AJC387). Similarly 9-benzyltheophylline undergoes
acid-catalyzed rearrangement to 7-benzyltheophylline (77H(6)383). In somewhat analogous
fashion it might be noted that tetrahydropyranylation of xanthine in DMSO with 2,3-
dihydropyran and acid catalysis with hydrogen chloride produces the 7-tetrahydropyran-
2-ylxanthine directly (66JOC268S).
In contrast to xanthine the isomeric 2,8- and 6,8-dioxo compounds have been little
studied. However the presence of an oxo function in the imidazole ring ensures that
alkylation will very readily and rapidly occur in that ring, followed generally by alkylation
elsewhere. Thus in alkaline solution dimethyl sulfate converts 2,8-dioxo-l,2,7,8-tetra-
hydropurine into a mixture of the 1,7- and the 1,9-dimethyl derivatives (111) and (112),
respectively, in 10 minutes at room temperature, the former compound predominating
(14JBOI7>1). Further alkylation then affords the 1,7,9-trimethylpurine (113). Similar prod-
ucts are formed with methyl iodide under more forcing conditions (100oC, 1 h) and the
latter also produces the 3,7,9-trimethyl derivative (114) from the 3-methyl-2,8-dioxo
derivatives (1899CB2721).
Me H Me
MeNYN)=o MeNYN)=o MeNYN)=o
o N O N'-< N o N
H Me N Me
(111) (112) (113)
Me 0 0
M' :j:M<
l N)=o MeN I N)=O N N
l- N l I )=0
o N N N Me N N
Me Me Me Me
(114) (115) (116)
In a similar manner 6,8-dioxo-l,6,7,8-tetrahydropurine with methyl iodide and alkali
affords the 1,7,9-trimethyl derivative (115) and the 3,7-dimethyl-6,8-dioxo derivative also
produces the 3,7,9-trimethyl derivative (116) (1897CB1846).
A fuller account of the complex alkylation of 6,8-dioxopurines has appeared
(74JCSIPI )2229).
(vii) Trioxopurines
The major trioxopurine is uric acid (10). As with xanthines O-alkylation is rare, alkylation
normally occurring on nitrogen. From a study of the ionization constants of uric acid it was
shown (21CB1676) that the protons are most easily removed in the order N-3, N-9, N-l,
N-7. Accordingly, with methyl iodide in alkaline solution 3-methyluric acid is first formed
(1899CB43S), then further converted into 1,3,7-trimethyluric acid (1899CB2721) which may be
fully methylated to 1,3,7,9-tetramethyluric acid under more forcing conditions (100oC)
(1897CBSS9). Much of the early literature also records the alkylation of various metal salts of
uric acid under dry conditions. The pattern of products formed closely follows that produced
in alkaline solution with prior formation of the 3-alkyl derivative, followed by 9-alkylation,
and the degree of substitution could be modulated by the degree of metal content.
Occasionally O-alkylation products may be isolated. Thus ethylation at 100 0 C (with
ethyl iodide) of the silver salt of 1,3,7-trimethyluric acid initially gives 8-ethoxy-l,3,7-
trimethyluric acid (117) which subsequently rearranges to produce 1,3,7-trimethyl-9-
ethyl uric acid (1882LA(21S)316).
o Me
MeN N
..J- >OR
o N N
Me
(117) R=Et
(118) R=Me
o Me
MeN N
MeO NJ-N)=O
Me
(119)
Purines
535
Alkylation of uric acid with diazoalkanes has been reviewed (32JPR(134)310). With uric
acid 1,3,7,9-tetramethyluric acid is produced, presumably via an intermediate alkoxy
derivative (21ZPC(117)23) since 1,3,7-trimethyluric acid and 1,7,9-trimethyluric acid with
diazomethane at room temperature furnished 8-methoxy-1,3,7-trimethyl and 2-methoxy-
1,7,9-trimethyl derivatives (118) and (119), respectively (20CB2327).
Alkylation of the triethylsilylated uric acid (120) with methyl iodide is unusual in producing
1-methyluric acid but at 150 0 C with dimethyl sulfate the major products isolated were
1,7,9-trimethyl- (121) and 1,3,7,9-tetramethyl-uric acids (122; Scheme 21) (64CB934).
:x OSiEt3 :): 0 Me :): 0 Me
N"" N M so MeN N MeN N
. I I )OSiEt 3 l; OC 4, I I )=0 + I I )=0
Et 3 S10l.:::::- N N oAN N OAN N
SiEt 3 H Me Me Me
(120) (121) (122)
Scheme 21
(viii) Thioxopurines
Alkylation of the thioxopurines may lead to both S- and N -alkylation but in many
examples the S- alkyl derivative is probably first formed under mild conditions and then
rearranges to the N -substituted derivative under more forcing conditions. An exception
appears to be 6-thioxo-1,6-dihydropurine (123) which with dimethyl sulfate in alkaline
solution produces the relatively stable 6-methylthiopurine (124) (22LA(426)306). Similar
methylation of 6-thiotheobromine in alkali with methyl iodide at room temperature furnishes
the methylthio derivative (125) whereas, in contrast, the 6-thiocaffeine derivative (126) is
produced with dimethyl sulfate and alkali at 40 0 C (62JCS1863) and corresponding S- and
N -methyl derivatives are produced from the 6-thio analogue of theophylline.
:J= s Me
MeN I N>
O N N
Me
(126)
HN
..J- >
N N
(123)
SMe
aN)
N N
H
(124)
SMe Me
N N>
O Nß-N
Me
(125)
The site of alkylation may be modulated by solvent, temperature and the presence of
bases. Thus in DMF solution 6-thioxo-1,6-dihydropurine (123) with methyl iodide produces
some of the 3-methyl-6-methylthiopurine (127) (63MI40904) which in turn with methyl
bromide gave 3,7-dimethyl-6-methylthiopurinium bromide (128; Scheme 22).
SMe SMe Me
N N" MeBr N N\
lLuA / ---. t+.A 1/
N N N N
Me Me Br-
(127) (128)
Scheme 22
When the 1-position is blocked so that S-alkylation is not possible, alkylation usually
occurs at the 7- or 9-positions. Thus benzylation of 1-benzyl-6-thioxo-1,6-dihydropurine
with or without a base, afforded a mixture of the 1,7- and 1,9-dibenzyl derivatives (S9JOC320).
Methylation of the 2-thio analogue of xanthine (129) at 170 0 C gave a quaternary salt
which with ammonia afforded the betaine (130) in which both S- and N -methylation has
occurred. The analogous compound (131) is similarly produced as a toluene-4-sulfonate
salt from 2-amino-6-thioxo-1,6-dihydropurine and methyl toluene-4-sulfonate (62JA1914).
o H 0-
:)=M< SMe Me
HN:J=N j N::;-' I'! N:):N
MeS I +) I +)
S N N N N H2N N N X-
H
(129) (130) (131)
536
Purines
AlkyIthiopurines may also undergo Mannich and Michael addition reactions. Thus 6-
methyIthiopurine with formaldehyde and lpise gave 9-hydroxymethyl-6-methylthiopurine
(67JMCI04), and dihydrofuranylation of 2-acetamido-6-benzylthiopurine occurs in the pres-
ence of toluene-4-sulfonic acid and 2,3-dihydrofuran to give 2-acetamido-6-benzylthio-9-
(tetrahydrofur-2-yl)purine (63JMC471).
4.09.5.2.3 N-Glycosylation
The N -glycosylpurines or purine nucleosides include many naturally occurring com-
pounds, especially 9-ß -o-ribofuranosyl and 9-ß -o-2-deoxyribofuranosyl derivatives of
adenine and guanine which are of course major constituents of the various ribo (RNA) and
deoxyribo (DNA) nucleic acids. The literature on purine nucleoside chemistry is very
substantial and in this chapter it will only be possible to give a brief survey. However several
reviews exist (see Table 2).
Direct condensation of 2,3,5-tri-O-benzoyl-ß -o-ribofuranosyl bromide with adenine in
acetonitrile at 50 0 C leads after deblocking to the 3-ß-o-ribofuranosyladenine (132)
(B-68MI40901). Metal derivatives of purines tend to produce 7- or 9-g1ycosyl derivatives;
thus the silver salt of 2,8-dichloroadenine with 2,3,5-tri-O-acetylribofuranosyl chloride
produces the 9-ß-o-ribofuranosyl derivative (133) (48JCS967, 48JCSI68S). However similar
reactions with theobromine produce O-glycosides and with theophylline N-7 derivatives
(34JCS 1639).
(SEth
NH 2 NH 2
N:):N> N:):N OH
lL -- I >Cl
Cl"" N OH
N N N I
I ß R1
Rf OBz
(132) (133) (134)
With ribofuranosyl halides the major anomer produced is the ß-anomer which derives
from the neighbouring group (adjacent to the halogeno group) effect of the 2'-O-acyl group
which directs the incoming nucleophilic purine trans to the latter group. In contrast,
condensation of 3,5-di-O-acyl-ß -o-2-deoxyribofuranosyl halides with N 6 -benzoyladenine
in the presence of a molecular sieve produces a mixture of a - and ß -anomers of the
9-g1ycosides (B-68MI40901, p. 183). The same mixture of anorneric 2'-deoxyadenosines may
also be produced by glycosylating the mercuriochloride salt of adenine with 5-0-benzoyl-2-
deoxy-o-erythro-pentose diisopropyl dithioacetal (134) (B-68MI40901, p. 132).
If a cis- glycofuranosylpurine derivative is required, an appropriate sugar derivative
containing a non-participating neighbouring group may be used. Thus, condensation of
N 6 -benzoyladenine with 2,3,5-tri-O-benzyl-o-arabinofuranosyl chloride gave the corre-
sponding 9-(ß-o-arabinofuranosyl)adenine (135) after deblocking (B-68MI40901, p. 126).
NH 2
Ù:>
N I
AR1
(135) ARf = ß -o-arabinofural1osyl
OSiMe 3
0)
N SiMe 3
(136)
Silyl derivatives have proved valuable intermediates in purine glycosylation reactions.
Thus the trimethylsilyl derivative of hypoxanthine (136) with 2,3,4,6-tetra-O-acetyl-
a -o-glucosyl chloride produced, after deblocking, an anomeric mixture of the two 9-
glucosylhypoxanthines, and similar reactions with trimethylsilylated N 6 -benzoyladenine led
to a rnixture of 9-substituted anomers (B-68MI40901, p. 135).
4.09.5.2.4 C-Alkylation and -arylation.
Until recently only a few examples of C-alkylation or -arylation by ionic species had
been recorded, alkylation normally resulting in N -alkyl derivatives. However in perhaps
Purines
537
the first recorded example, theophylline in aqueous alkali with crotyl bromide at room
temperature produced 8-(but-2-enyl)theophylline (137) and no 7 -alkyl derivative was
detected (59CB1500, 76AJC891). The latter authors also confirmed an earlier (55FES733) claim
to have isolated 8-benzyltheophylline from a benzylation of theophylline under analogous
conditions. In this case however the 7 -benzyl derivative was also produced but it should
be noted that complete exclusion of radicals could not be achieved in this reaction.
o H :): OCH2CH=CMe2 :.x o
MeN N N?' N HN N
I I lCH 2 CH=CHMe I I I I CH2CH=CMe2
O N N H 2 N!.::::,.N N H 2 N!.::::,.N N
Me H H
(137) (138) (139)
Intramolecular rearrangement of 6-0-allyl-, 6-0-crotyl- and 6-0-2-methylbut-2-
enyloxy-2-aminopurine (138) occurs in good yield to produce the corresponding 8-alkenyl-
purines (139), especially when the anion is used (73JA7174, 74JA5894). The mechanism
proposed involves two anionic 3,3-sigmatropic shifts (Scheme 23), the first forrning a
C(5)-linked intermediate (140) and the second the substituted anion (141). When the
8-position is blocked the 3-[3,3] or 7 -[3,2] alkenyl derivatives are produced (76JOC568).
oP
N N
I I R-
H 2 N!.::::,. N
N H
p; '\:
H N h >R
2 'N N
(140)
[3 1
o R"M, RO: 1
H,:(X)M' H;(x)M'
jH
9
-. #
H':O:: H
(141)
j
(139)
Scheme 23
Recently, treatment of 2-methylthiopurine with diazomethane has been shown to give
9-methyl-2-methylthiopurine as the main product accompanied by the 7-methyl derivative,
and also by small but significant amounts of the 7,8- and 8,9-dimethyl-2-methylthiopurines
(142) and (143), respectively. Experiments showed that the 8-methyl group was introduced
prior to N-methylation (79AJC2771). With diazomethane, however, it is again not possible to
eliminate a free radical mechanism.
Me
N N
Mesl..JL lMe
N N
(142)
N :): N
I I Me
MeS!.::::,. N
N Me
(143)
Ionic alkylation of lithiated purine nucleosides has recently proved to be a successful
route to 8-substituted derivatives. Thus N 6 -dimethyl-5'-O-methyl-2',3',O-isopropyl-
ideneadenosine (144) with butyllithium followed by methyl iodide readily gave the 8-methyl
derivative (145) in good yield (88%) (79TL279). In a more extensive series of reactions
several 8-1ithiopurine trimethylsilylated nucleosides, e.g. the inosine derivative (146), were
reacted with a variety of electrophilic reagents to produce eventually, after desilylation,
good yields of the corresponding 8-substituted derivatives (147) (79TL2385). The lithio
derivatives were made by reacting several 8-bromo trimethylsilylated purine nucleosides
with butyllithium and the nucleosides used included inosine, adenosine, guanosine and
xanthosine. The electrophiles used included alkyl halides, ethyl chloroform ate, carbon
dioxide, benzaldehyde, benzonitrile and acetone to produce a wide variety of ppropriate
538
Purines
8-substituted derivatives. In the case of adenosine and guanosine derivatives, N 6 -alkylation
also occurred.
N NMe 2
OR<=C;
Meo H N N
OX O
(144) R=H
(145) R=Me
o
R<N NSiMeJ
o Jl..J
MeJSio N N
MeJSiO OSiMe J
(146) R = Li
(147) R = Me, COzH, COzEt, PhCHOH, PhCO, MezCHOH, (CHzhCOzEt
Silylated 8-bromoadenosine has similarly been converted into various 8-aryladenosines
by reaction with arylmagnesium halides in the presence of dichlorobis(triphenylphos-
phine)palladium (79TL3159),
Similarly, adenosine, inosine and 2'-deoxyinosine have been converted into their 8-
trifluoromethyl derivatives by reaction with the copper complex formed from trifluorornethyl
iodide and copper in hexamethylphosphorotriamide (SOJCS(Pl)275S). N 6 -Trifluoromethyl-
purine riboside was also produced from 6-chloropurine riboside. Recently, guanosine has
been shown to give the C(8)-substituted derivative (148) by reaction with a
benz[a ]anthracene 5,6-dioxide at pH 9.5 over 4 days at 37 oC (SOCC82).
N 9' NR1
O =<; N
N3
H NHz
(148)
4.09.5.2.5 Nitration
Electron-releasing groups are required in the purine ring system before nitration can
occur. In this way 8-nitro-caffeine (149), -theophylline (150), and -theobromine (151) have
been prepared by nitration of the appropriate purine with nitric acid, neat or in acetic acid
(71Hc(24-2)1, p.402). Similarly, 9-methylxanthine, but not xanthine, undergoes nitration to
9-rnethyl-8-nitroxanthine (60JA3773).
MN W
..JL >NO z
o N N
Me
(149)
MN
..)L >NO z
o N N
Me
(150)
HN e
"J- >NO z
o N N
Me
(151)
4.09.5.2.6 Reaction with diazonium ions
Disubstituted oxo- or amino-purines will usually couple with diazoniurn ions to produce
8-arylazo derivatives. Thus xanthine with diazotized p-chloraniline gave the derivative
(152) (60JA3773). Theophylline similarly condenses with diazotized p-aminobenzenesulfonic
acid to furnish (153) (07ZPC(Sl)42S), but when alkyl groups are present in the imidazole
moiety as with theobromine and caffeine, coupling does not occur (07ZPC(Sl)42S) possibly
because anion formation is not possible in these species (63JOC1662). Guanine and isoguanine
Purines
539
(60JA2S87) both couple with diazotized 2,4-dichloroaniline and several other arylamines to
produce the 8-arylazo derivative, and 2,6-diaminopurine also furnishes the 8-arylazopurine
(154) with diazotized 2,4-dichloroaniline.
o
Hl'ÌN N O CI
o N N -
H H
(152)
o H
:l):> N O sO'H
Me
(153 )
NH 2
7 N>N=N O Cl
H2N ..)lN -
N Cl
H
(154)
Similar reactions of adenine with arenediazonium chlorides however afforded 8-
aryladenines but via an internal free radical process from an aryltriazene (see Section
4.09.5.4.5).
4.09.5.2.7 Oxidation of ring atoms
Ionic as distinct from free radical oxidation (see Section 4.09.5.4) of purines leads to
N -oxides. A major review of the chemistry of heterocyclic N -oxides including purine
derivatives has been published (see Table 1) and should be consulted for more detailed
information. Reagents most commonly used for direct ,oxidation of purines include hydrogen
peroxide and various peracids but especially peracetic acid.
Purine with perbenzoic acid slowly (two weeks) afforded the l-oxide (155) (62JOCS67),
whereas peracetic acid was used to convert adenine or adenosine (58JA27SS) into their
l-oxides, these reactions taking a few days. Similar compounds are produced from other
nucleosides (67JMC130) and from adenosine mono-, di- and tri-phosphates (S8AG571).
Hypoxanthine, however, did not readily yield the l-oxide (S8JA27SS) which is best obtained
from the adenine derivative by deamination.
o
HN N>
H 2 Nl-.+.J- N
7 H
0-
(155) (156)
Oxidation of guanine overnight with trifluoroperacetic acid produced the 3-oxide (156)
in 62% yield (69JOC978) and this may be hydrolyzed to xanthine 3-oxide. Similar 3-oxides
are produced from various 6-substituted purines including 6-chloropurine and 6-alkoxy-
purines with peracetic acid in ethanol (69BCJ7S0). The 1-,7-,8- and 9-monomethylguanines
and 1,7 -dimethylguanine with trifluoroperacetic acid also gave corresponding 3-oxides
(71J0C263S). Purine furnished the 3-oxide with m -chloroperbenzoic acid but 6-methylpurine
gave a mixture of the 1- and 3-oxides.
There appear to be no confirrned examples of the direct conversion of purines into 7-
or 9-oxides which have been prepared, however, by other methods from imidazole precur-
sors (Section 4.09.7.5).
Methylation of adenine l-oxide produces the 9-rnethyl1-oxide (157) via an intermediate
O-methyl derivative (Scheme 24) (71CPB161l).
"'0::)
N H
NH 2 NH 2
MeON N> __ -O-N N>
l-N)lN IN)lN
Me
(157)
Scheme 24
The purine 3-oxides (69JBC(244)40n, 70MI4090S) and 7-oxides (76JOC1889) have potent
oncogenic properties.
Thiation of purine, 6-methyl- or 2-amino-purines with hot sulfur leads to the 8-thioxo
derivatives (64JOC3209). The reaction failed with guanine, hypoxanthine and 6-chloropurine
but was successful with 1,9-dimethyl-, 7,9-dibenzyl- and 7,9-dimethyl-hypoxanthines
540
Purines
(68CC200). Thiation of the 2-position also occurred with 1,3,7-trimethylhypoxanthinium
nitrate (69CB3000).
4.09.5.2.8 Halogenation
Most halogenopurines are normally prepared by replacement of hydroxy or thio groups
by halogen but direct halogenation at an unoccupied 8-position is possible, especially when
the purine contains one or more electron-releasing, normally hydroxy or similar, groups.
The course of the halogenation is considerably affected by the nature of the solvent used.
In non-polar solvents the xanthines furnish corresponding 8-halogenoxanthines; thus theo-
bromine with chlorine in chloroform gave 8-chlorotheobromine (1882LA(21S)316) but in
acetic acid it produced 5-chloro-3,7-dimethylisouric acid (158) derived by prior addition
to the C(4)-C(5) bond (14LA(406)22).
o
:1 1 Me
HN N
I >=0
O N ""-N
Me
(158)
Theophylline and caffeine (17LA(413)lSS, lOCB3SS3) and thio analogues of these purines
chlorinate in a similar manner (28CB1409). 1,9-Dimethylxanthines on the other hand are
slowly converted into 8-chloropurines by sulfuryl chloride (60Z0B3339, 64Z0B 1137).
Bromination, in contrast, readily occurs even with monosubstituted purines. Thus
hypoxanthine and adenine (1890CB22S) both produced the corresponding 8-brorno derivatives
by direct bromination, and. disubstituted derivatives such as xanthine (63JOC2310) and
guanine (1883LA(221)336) very readily afforded the corresponding 8-bromo derivatives.
Purine nucleosides also may be directly halogenated. Thus 2',3',5' -tri-O-acetyladenosine
or 3',5'-di-O-acetyl-2'-deoxyadenosine with N -bromoacetamide gave, after deblocking,
8-bromoadenosine and 8-bromo-2'-deoxyadenosine, respectively (64JA1242), and 8-
bromoguanosine is similarly obtained from its tri-O-acetyl derivatives by bromination with
brornine in acetic acid followed by deblocking. Recently 8-chloropurine nucleosides have
been prepared by reaction of nucleoside with rn-chloroperbenzoic acid and hydrogen
chloride in aprotic solvents (8IJOC2819).
4.09.5.3 Reaction with Nucleophiles
Nucleophilic attack on purines, by replacement reactions involving halogens, alkoxy,
alkylthio and similar groups, is very common and offers a valuable route to many purine
derivatives and is discussed in Section 4.09.6. Direct attack on ring atoms by nucleophiles
on the other hand is relatively rare, but in recent years increasing numbers of examples of
these reactions have appeared.
4.09.5.3.1 Reduction
Since many purines may be reduced by hydride-producing agents it is convenient to
gather together chemical reduction of purines under the nucleophilic heading. A general
review of this topic has appeared (71HC(24-2)1). Reduced purines of the oxo-nH type,
however, are perhaps best regarded as special cases since they can at least formally be
written in aromatic (hydroxypurine or betaine) forms and are dealt with elsewhere.
Reduction of purine in acetic or hydrochloric acid at a mercury cathode produced the
labile 1,6-dihy'dropurine which has been isolated as a complex with sodium tetraphenylbo-
rate (62JA1412). Purine also afforded the 1,6-dihydro derivative by catalytic hydrogenation
using palladium or platinum catalysts in acid solution and the unstable compound may be
isolated as a 1,9-diacetyl derivative by carrying out the hydrogenation in acetic anhydride
(69LA(729)73). The same author claims the formation of 1,3,7,9-triacetyloctahydropurine by
continued hydrogenation under similar conditions. In a similar manner, N -acetyl-l,6-
Purines
541
dihydro derivatives of 2-chloro- and 2-chloro-9-methylpurine may be produced without
hydrogenolysis of the halogen atom, in contrast to 2,6,8-trichloropurine in which all the
halogen atoms are reported to be removed (S9JA3789).
Chernical reduction of purine with various metal-acid combinations generally results in
ring opening to imidazoles or pyrimidines.
Electrochemical reduction of oxo- and amino-purines tends to be more complex. With
a lead cathode in dilute sulfuric acid, caffeine was found to lose the 6-oxo function and
afford the 1 ,6-dihydro derivative (159) in 70 % yield (1899CB68); see also (B-71MI40903, p. 428) for
additional confirmatory comment.
MeN 5L ; MeNH Jc O \
I 1/ J. I I/CI
O?-...N NON N
Me Me
(159) (160)
Xanthine (OlCB116S) and its 1-, 3- and 7-methyl derivatives similarly produced 6-deoxy
derivatives using a lead cathode in 75% sulfuric acid solution, and in 30% sulfuric acid
theophylline afforded the 6-deoxypurine (07CB37S2). An intermediate product (160) has
bt;en detected by polarography in an electrolytic reduction of 8-chlorotheophylline
(S4MI40901,S4MI40902).
Under similar conditions hypoxanthine undergoes ring opening, and uric acid at low
temperatures (<8 oc) produced the labile substance 'purone' with the possible structure
(161), where the C(4)-C(5) bond has been reduced, and this undergoes ready ring opening
to give pyrimidines (OlCB2S8). In contrast, rnethylated uric acids afford the normal 6-deoxy
derivatives, as does guanine which gave 2-amino-1,6-dihydropurine (162) in 75% yield
(OlCB1170).
H
HN N>=
O NJ--N 0
H H
(161) (162)
Further reduction of 6-deoxytheophylline in acetic acid and acetic anhydride over pal-
ladium afforded the 7-acetylhexahydro derivative (163) whilst with a platinum catalyst in
acetic anhydride the 7,9-diacetyloctahydropurine (164) is formed (69LA(729)73). In contrast,
the same author was unable to reduce adenine, hypoxanthine, xanthine and 6-chloropurine
in this manner.
HN N
H2Nl..Jl.N
N H
Ac Ac
MeN N> MeN N>
OJ.NJ-- N O NJ--N
Me Me k
(163) (164)
N-Alkylated purines, especially compounds such as quaternized caffeine with a positive
charge in the imidazole ring, are readily reduced by sodium borohydride to produce dihydro
derivatives, reduction occurring in the charged imidazole ring (76TL1199, 76JOC2303).
Compounds which can be regarded as analogous to reduction products are 1,6-covalent
adducts produced by various weak acids including potassium hydrogen sulfite and purine
(165) and the 2-oxopurine (166) (7SJCS(Pl)2240).
KSOJ H
HN N
l IN
N H
(165)
4.09.5.3.2 Amination
KSO J H
HN><y-N
OJ.NJl N
H H
(166)
It has recently been found that purine in its anionic form undergoes a Chichibabin reaction
with potassiurn amide in liquid ammonia with formation of adenine as the sole product.
542
Purines
The reaction is slow and after 20 h about 30% of purine could be recovered, but after 70 h
the reaction conversion was quantitative (79JOC3140). Moreover when the reaction was
repeated using 15 N -labelled potassium amide, the label appeared exclusively in the exocyclic
amino group with no ring labelling. Evidence for the involvement of the purine anion (167)
and hence the intermediate adduct anion (168) in the reaction came from a study of the
I H and 13C NMR spectra of reaction mixtures. The mechanism proposed (Scheme 25)
involves addition of the amide ion to the purine anion in which the pyrimidine ring has
apparently been so depleted of electronegativity as to make it a readily achievable target
for anion attack. Finally a hydride ion is liberated.
N
t JL- -:)
N N
(167)
ö\
'N N
(168)
Scheme 2S
-w
---+
N
t J.- -:)
N N
A similar conversion of 2-methylpurine into the corresponding adenine was also achieved
although in lower yield (20%), and evidence for direct amination with no ring opening was
again obtained. With 6-methylpurine, however, no adenine derivative was obtained and
this is readily ascribed to dianion formation with excess negativity in both rings. l H NMR
spectroscopic evidence was obtained (Scheme 26) for the dianion (169). However with
6,8-di+ butylpurine which can only form a monoanion (170), not surprisingly there was
no reaction with potassium amide.
Me N :1 CH2 - N
N I -' N I -'
:/ :/
N N N N
(169)
CMe 3
N I'!
Me3c JL- >
(170)
Scheme 26
In the case of 8-methylpurine, a modest yield of 8-methyladenine was produced in spite
of the fact that the dianion could be detected in solution. The implication is that the reaction
solution contained insufficient dianion to inhibit the reaction of the potassium amide with
the monoanion which was also present.
Similar reactions have also been observed with 8-chloro- and 8-methylthio-purines which
produce 8-chloro- (10% yield after 20 h) and 8-methylthio-adenines (80% yield after 20 h),
respectively (SORTC267). In addition, however, 8-chloropurine produced adenine (30% yield)
as the major reaction product and use of 15N-labelling again indicated that no ring opening
had occurred. The proposed mechanism is a novel tele-amination involving prior ami nation
of the chloropurine to forrn the adduct (171) which then undergoes a 1,4-tele-elimination
to produce adenine directly or via the purine adduct (172; Scherne 27).
NH 2
Û:
N H
H NH 2 -
N N NH N N )< H
I I /Cl 11
N '" h Ñ CI
N H N "'-
(171) -CI '\.
i
:X: 2 N
t_J:j
N N
(172)
Scheme 27
Purines
543
4.09.5.4 Reactions with Free Radicals
Calculations suggest that free radical attack on purines should marginally favour the
6-position followed closely by C-8 (71MI40903). In support of this, reaction of purine with
hydroxyl radicals generated by Fenton's reagent or by ionizing radiations in queous
solutions produced hypoxanthine, 2-aminopurine afforded guanine, and adenine gave the
8-oxo derivative (61CR(253)687). The nature of the hydrogen addition radicals generated by
radiation has been considered elsewhere (Section 4.09.4.3.8).
Free radical alkylation procedures have proved a useful route to alkylpurines which are
not readily available by other methods. Thus 6-substituted purines including adenine and
hypoxanthine may be converted into 8-methyl derivatives with t-butyl hydroperoxide in
the presence of iron(I1) ions and acid (74T2677), although small amounts of 2-methyl and
2,8-dimethyl derivatives were formed simultaneously. Adenosine and guanosine similarly
furnished the corresponding 8-methyl derivatives with diacetyl peroxide (as a source of
methyl radicals) and iron(II) ions (76T337).
Replacement of iron(I1) ion as a catalyst by radiation and use of peracid esters leads to
more efficient production of radicals. Thus with a 1200 W source and t-butyl peracetate,
methylation of caffeine is 28 times faster than using t-butyl hydroxide (77JA5096). An alkaline
solution of theophylline containing benzyl bromide similarly gave with UV radiation both
the 8- and the 7-benzyl derivatives (76AJC891). Formation of alkyl radicals in these various
reactions are summarized in Scheme 28.
Me Me
I F 2+ I. .
(a) Me-C-O-OH Me-C-O(+Fe 3 + +OH-) -. Me+MezCO
I I
Me Me
{ MeCO; -. Me + CO z
Me
I uv Me
(b) Me-C-O-OzCMe --. I..
I Me-C-O-. Me+Me 2 CO
Me I
Me
Scheme 28
Irradiation of purines in different environments can, of course, lead to a variety of radical
reaction products. Recently the regioselective nature of radical methylation has been
observed in several purine derivatives.
Thus using at-butyl peracetate'and a 450 W mercury larnp as a source of methyl radicals
it was shown that in acid solution hypoxanthine, 6-methoxy- and 6-methylthio-purines gave
mainly the C-8 methyl derivative whereas 3-methylhypoxanthine, 3-methyl-6-methoxy-
purine and 3-methyl-6-methylthiopurine gave mainly the C-2 methyl derivatives. The results
tend to be reversed at higher pH (79JOC1450).
The selectivity has been correlated with the site of cation formation, methylation occurring
fastest on the carbon where the proton resonated at lowest field. Table 22 gives details of
Table 22 Free Radical Melhylation of some Purines (79JOC1450)"
Yield (%)
Compound pH C-2 C-8 Ratio C-8: C-2 (%)
Hypoxanlhine 1.1 <1 85.2 >85
7.0 9.9 24.6 2.5:1:0.3
3-Me-hypoxanthine 1.1 47.4 8.8 0.2:1:0.1
7.0 7.8 34.9 5.l:!: 0.3
6-MeO-purine 1.1 2.3 67.4 29.2:1:0.8
7.0 11.6 22.8 2.0:1:0.2
3-Me-6-MeO-purine 1.1 25.7 17.5 0.7:1:0.1
7.0 <1 24.2 >24
6-MeS-purine 1.1 3.1 53.6 16.8:1: 1.6
7.0 5.7 34.6 5.9:1:0.7
3 -Me-6-MeS-purine 1.1 21.7 13.5 0.6:1:0.0
7.0 16.8 25.5 1.5:1:0.2
"t-Butyl peracetate: irradiation with a 450 W Hg lamp at room temperature.
544
Purines
reaction products and product ratios at different pH values and Table 23 gives rate constants
observed in these reactions. The proposed methylation routes for hypoxanthine and 3-
rnethylhypoxanthine are outlined in Schernes 29 and 30, respectively.
Table 23 Rate Constants for Free Radical Methylation of Purines (79JOCI4S0)a
Compound kC_2X 10 5 (s-I) kc_sx 10 5 (S-I) kC-B : kC_2
Hypoxanthine 0.05 (:1:0.01) 0.88 (:1:0.01) 17.6
3-Me-hypoxanthine 0.20 (:1:0.04) 0.06 (:1:0.01) 0.3
6-MeO-purine 0.07 (:1:0.01) 0.61 (:1:0.02) 8.7
3-Me-6-MeO-purine 1.33 (:1:0.01) 0.27 (:1:0.06) 0.2
6-SMe-purine 1.04 (:1:0.13)
3-Me-6-SMe-purine 1.94 (:1:0.19) 0.54 (:1:0.06) 0.28
a 1.7M in 0 2 0: CF 3 C0 2 0 (2: 1) and t-butyl peracetate (9 fold excess); irradiation with a 450 W
mercury lamp at room temperature.
HN N> HI:' N> "'" 2-M,
+JlN ,JlN
:X O V H H
HN I "-
I::,.., 1/
N N _
HN-\- > HN P> "'" 8-M'
--)LN JlN
N H N H
Scheme 29
, :) 0 N
HN I)
+ N
N
Me H
2-Me
:): 0
N I +)
+ N
N H
I
Me
8-Me
Scheme 30
The methylation of caffeine at C-8 using t-butyl peracetate in acid solution has also been
studied in detail (77JA5096) and rate constants were deterrnined (Table 24) over a wide
range of conditions including therrnal and irradiation production of rnethyl radicals. The
suggested pathway involves radical attack on either the neutral or N(7)-protonated forrns
of caffeine with eventual production in each case of a radical carbocation cr-cornplex which
then suffers loss of hydrogen (Scheme 31). In neutral solution the rate deterrnining step is
protonation which follows rnethylation, and in acid solution rnethylation of the protonated
purine is the controlling factor.
Table 24 Rate Constants for Thermal and Pholoinduced Radical Methylation of
Caffeine (77JAS096)a
Thermal
Thermal
Thermal
Thermal
Light
Light
Temp. (ac) (Hg lamp)
58
65
80
95
(450 W)
(1200 W)
Rate constant
(5 x 10 5 S-I)
Reaction conditions
No reaction after 21 h
0.40 (:1:0.01)
1.67 (:1:0.18)
7.61 (:1:0.37)
1.39 (:1:0.02)
6.67 (:1:0.36)
a 1.0M caffeine and 3M t-butyl peracetate in 0 2 0: CF 3 C0 2 0 (2: 1).
Purines
545
X N X Ñ Me X Me
I )H I )< I +X
N N H N H
R R R
/ lx.
H H
N N N
X ) Me' X -:> + Me+ XN)Me + HX
N
R R R
Scheme 31
The same authors have examined the free radical methylation of several "rluc1eosides in
the presence of t-butyl peracetate and shown that C-methylation occurs at pH 1-4 but at
pH 4-10 there is increasing N -methylation (SOJOC2373) as the electron availability on these
atoms builds up. C- Methylation is proposed to proceed via an addition rnechanisrn and
N -methylation via a radical extraction of hydrogen frorn NH followed by reaction with a
methyl radical. Irnplications of these reactions in radical oncogenesis are discussed.
4.09.5.4.1 Alcohols
UV irradiation of purine (6SJA2979), nebularine (7OJA47S1) and 2-arninopurine (71J0C3S94)
in methanol and ethanol gave 1,6-adducts. The ethanol adduct (173) with purine was
isolated in two diasteroisomeric forms.
Me :ç o,-
HN I 1)
N
N H
(173)
)= 0 TH2C(OH)Me2
MN N
J-..... I ;C(OH)Me 2
o N N
Me (174)
Not surprisingly, adenine and guanine have been a major focus of rnany studies in this
field and in alcohol solutions with irradiation at wavelengths >290 nm, 8-hydroxyalkyl
derivatives are produced. The yields are improved by use of sensitizers such as acetone
and di-t- butyl peroxide (73JOC3420). With substituted purines, attack may also occur at the
substituent group as with caffeine which in 2-propanol produced (174).
4.09.5.4.2 Arnines
Free radical reactions of purines with amines gave similar products to those produced in
alcohol solution although deamination may also occur, probably at the post- rather than
the pre-adduct stage. Whereas purine and n -propylamine afforded 6-n -propylpurine
(71MI40907), adenine and caffeine produced both the 8-aminoalkyl and corresponding 9-alkyl
derivatives (74MI40904). Also irradiation of 8-aminoalkylpurines in methanol furnished the
8-alkyl derivatives. Amino acids as an amine source are of special biochemical interest.
They also tend to produce 8-alkylpurines by concomitant deamination and decarboxylation
(69CC90S).
4.09.5.4.3 Ethers
With more complex substances such as ethers the nature of free radical attack becomes
more difficult to forecast. Thus in the presence of an acetophenone sensitizer, caffeine and
diethyl ether gave a 3: 1 mixture of the 8-(1-ethoxyethyl) and 8-ethyl derivatives
(Scheme 32) (70CJC1716). The first formed ether radical, presumably (175), is apparently
too unstable to produce a reaction product prior to rearrangement (Scheme 33). With
546
Purines
unsyrnrnetrical ethers, mixtures of products are inevitably produced. Thus, tetrahydrofuryl
alcohol and caffeine gave a mixture of the two 8-substituted derivatives (176) and (177) in
a ratio of 2.5 : 1.
o Me
MeN N>
O NJ-.N
Me
Et A MeN N\ MeN N\
--'---> I 0 I M CHOEt + I 0 I M;Et
O N N Me O N N
Me Me
Scheme 32
MeCH 2 0CH 2 CH 2 . MeCH 2 0èHMe
(175)
Scheme 33
o Me
MeN N H
O NJ-r:>--Ö--CH20H
Me
(176)
o M
MeN N >-tj e CH20H
_.J- b 0
o N N
Me
(177)
4.09.5.4.4 Acyl Tadicals
In the presence of substances capable of producing acyl radicals, purines gave 8-acyl
derivatives. Thus guanosine and ethanol give 8-acetylguanosine (178a), and similar products
were produced from other aldehyde sources and from inosine (75B1490). However adenosine
was unreactive under the conditions used, namely iron(II) persulfate initiation. Guanosine
also produced the 8-carbamoyl (178b) and 8-(N,N-dimethylcarbarnoyl) (178c) derivatives
with formamide and DMF, respectively, as sources of the appropriate carbamoyl radicals
(74T2677).
o
H N')COR
H 2 NI.:::::,. Jl N
N I
R1
(178a) R=Me
(178b) R=NH 2
(178c) R = NMe2
4.09.5.4.5 Aryl Tadicals
8-Aryladenines have recently been produced in an intermolecular free radical process
by heating coupling products (179) derived frorn benzenediazonium chloride at 60-90 o C
(Scherne 34) (8IJOC2203). The reaction is seen to proceed by formation of a phenyl radical
which attacks C-8. Evidence for this includes (a) the corresponding p -brornophenyltriazene
decornposed in the presence of 2,5-diaminopurine to give a rnixture of 8-aryladenine and
8-aryl-2,6-diaminopurine; (b) when adenine is added to a solution of the phenyltriazene
NHN2 :r NH2 N
N I ') N I ')Ph
N N
N H N H
(179)
Scheme 34
Purines
547
an increased yield of the 8-aryladenine is obtained after heating. The intermediate triazene
may also be reduced by sodium dithionite to afford 6-hydrazinopurine.
4.09.6 REACTIVITY OF SUBSTITUENTS
4.09.6.1 Introduction
4.09.6.1.1 Nucleophilic displacement reactions
Much of the early published chemistry of purines was concerned with nucleophilic
displacement reactions of halogen, alkylthio and sirnilar substituted purine derivatives. The
ease of displacement varies according to the substitution pattern in the ring system and the
particular neutral, cationic or anionic forrn of the purine. Thus in both the neutral and
protonated forms ensuing movement of electro negativity frorn the imidazole to the
pyrirnidine ring system tends to favour nucleophilic displacernent of groups at the C-8
position. On the other hand when anion formation is possible, electro negativity is drawn
into the imidazole ring systern resulting in preferential nucleophilic attack at C-2 or C-6
in the pyrimidine half of the molecule.
4.09.6.1.2 Substituent modification
Modification of substituents in purines generally follows patterns which are sirnilar to
substituent modification in typical aromatic systerns. These include interconversion of
hydroxyl, thiol, halogeno, amino and similar groups, and Sandmeyer type reactions involving
primary amines although isolation of stable diazonium salts is rarely possible. In addition,
transformations and reactions of carboxylic acid derivatives follow standard patterns.
4.09.6.2 N - and C- Alkyl Derivatives
Although all the simple alkyl, especially rnethyl, purines have been prepared there has
not been a great deal of interest in their chemistry. 6-Methylpurine shows weak acidic
properties and reacts with chloral to produce the adduct (180). The cornpound may also
be oxidized to 6-formylpurine (181) and to purine-6-carboxylic acid in various ways, and
it undergoes successive halogenation with either halogens, especially chlorine, or with
N -halogenosuccinimides or sulfuryl chloride. 8-Methylpurines rnay also be halogenated
and stable compounds isolated, especially when the nitrogen atoms are blocked as with the
various methylated xanthines, although 8-methyl theophylline is unreactive. 6-Alkylpurine
l-oxides undergo exceptional reactions via O-acyl rearrangements. Thus 6-methylpurine
l-oxide and rnethane sulfonyl chloride produced 6-chloromethylpurine (182) via an 0-
mesyl derivative. These reactions are examined in more detail in Section 4.09.6.12.
CH 2 CHOHCCl 3
l N)
N N
H
(180)
CHO
erN)
N N
H
(181)
CH,CI
(iN)
N N
H
(182)
There are only a few recorded reactions of N -alkylpurines which result in preservation
of the purine ring system, since ring opening generally occurs and pyrimidines or imidazoles
are produced. Halogenation may, however, lead to N -chloromethyl derivatives as with
2,7 -dimethyl purine which can be chlorinated to form 7 -chlorornethyl-2-methylpurine.
Details of reaction products derived from some alkylpurines are collected in Table 25.
4.09.6.3 Purine Aldehydes
A few 6- and 8-formylpurines have been prepared and their reactions investigated. They
tend to behave like typical aromatic aldehydes and produce stable anils with aromatic
548 Purines
Table 25 Reactions of Alkylpurines
Purine Product Conditions Ref.
6-Me 6-CHO SeOz/DMF 6SCB611
6-Me 6-CH=NOH NaNOz/HOAc 6SCB611
6-Me 6-CO z H (S%) KMn04/0W (SO oc) 6SCB611
6-CH z OH 6-CO z H (51 %) KMn04 (cold) 6SCB611
6-CH z CI 6-CO z H (77%) via Pyridinium 59JA2515
salt/K Mn0 4
6-CH z CI 6-CO z H KMn04 63Z0B3342
6-CH z Cl 6-CHO pyridinium salt + 59JA2515
NOC6H4NMez + acid
6-Me 6-CC1 3 (SO%) SOzClz/TF A 62JOC3545
2-NH z -6-Me 2-NH z -6-CCI 3 SOzCIz/TFA 64MI40900
S-CF 3 -6-Me S-CF 3 -6-CCI 3 SOzCIz/TFA 64MI40900
2-MeNH-6,S- Me z 2-MeNH-6-CCI 3 -9-Me SOzClz/TFA 64MI40900
6-Me 6- CHBr z N-Bromosuccinimide 62JOC3545
1,7 -Etz-S-Me-xanthine S-CCI 3 -1, 7 -Etz-xanthine CIz/POCI 3 45JCS751
SoMe-theobromine S-CCI 3 -theobromine AICI 3 /CH z CIz (60 0 C) 5SMI40901
(S%)
SoMe-caffeine S-CCI 3 -caffeine Clz/PhCl (<7 oc) 5SMI40900
SoMe-caffeine 7 -CICH z -S-CCI 3 -caffeine Clz/PhCl (>7 OC) 5SMI40900
SoMe-caffeine S-CHzBr-caffeine N- Bromosuccinimide 66AF541
(PhCOzh. UV
S-Me-isocaffeine S-CCI 3 -isocaffeine N-Chlorosuccinimide 60Z0B3332
S-Me-isocaffeine S-CCI 3 -3-CICH z -isocaffeine N-Chlorosuccinimide 60Z0B3332
6-Me 6-CH z CHOHCCI 3 Chloralj AcOH 61LA(649)131
SoMe-caffeine S-CHC1z-caffeine SOzCl z /CHCI 3 62Z0B2015
S-CHzCl-caffeine
6-Me I-oxide 6-CH z Cl MeSOzCI 62JOC3545
6-Me I-oxide 6-CH z OAc AczO 62JOC567
2,7-Mez 2-Me-7-CH z Cl Cl z /CI 3 CMe 7lHC(24-2)1, p. 131
amines. They undergo Perkin type reactions with malonic acid and will condense sirnilarly
with other active rnethylene derivatives and also undergo benzoin condensation. In addition
they give the usual aldehyde derivatives including oximes, hydrazones, semicarbazides,
reaction with Wittig reagents, and undergo oxidation to the carboxylic acids and reduction
to alcohols. Table 26 lists some of the more important reaction products, most of which,
it will be noted, are concerned with highly alkylated compounds. The paucity of exarnples
of highly polarized purine derivatives undoubtedly results from their insolubility in cornrnon
solvents.
4.09.6.4 Purine Ketones
Even fewer purine ketones have been prepared than aldehydes. They have been reduced
to alcohols either by hydrogenation or use of Meerwein-Pondorff rnethods. Table 27 outlines
information on the few compounds examined.
4.09.6.5 Cyanopurines
A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile
addition reactions rather readily. Thus, alkaline hydrolysis produces carboxarnides, then
carboxylic acids, alcoholysis leads to irnidates, amrnonolysis to amidines, hydrazinolysis to
amidhydrazines, hydroxylamine to arnidoximes, and hydrogen sulfide to thioarnides. Acid
hydrolysis tends to give the de carboxylated acid derivative. Reduction either by sodiurn-
ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition
of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, rnost of
the compounds examined have been relatively non-polar derivatives. Table 28 lists some
reactions and relevant literature.
Purines 549
Table 26 Reactions of Purine Aldehydes
Purine Product Conditions Ref.
6-CHO 6-CH=NOH NHzOH 66JOC4239
6-CHO 6-CH=NNH z NHzNHz 66JOC4239
6-CHO 6-Me NHzNHz/heat 64JOC3209
6-CHO 6-CH=NNHCONH z NHzCONHNH z 59JA2515
6-CHO 6-COzH KMn04(cold) (82% yield) 59JA2515
6-CHO 6-CH z OH Pt/Hz 68CB611
8-CHO-theophylline 8- CO zH-theophylline Aqueous KMn04 62CB414
8-CHO-theobromine 8-CO z H-theobromine Aqueous KMn04 62CB414
8-CHO-caffeine 8-CO z H-caffeine Aqueous KMn04 48Z0B2129
8-CHO-theobromine 8-CH=NOH-theobromine NHzOH 66JOC4239
8-CHO-theophylline 8-CH=NOH-theophylline NHzOH 66JOC4239
8-CHO-caffeine 8-CH=NOH-caffeine NHzOH 48Z0B2129
8-CHO-6-NEt z 8-CH=NOH-6-NEt z NHzOH 58JCS4069
2-Me-6-CHO 2-Me-6-anil PhNH z 60Z0B1878
8-CHO-theophylIine 8-CH=NPh PhNH z 62CB403
8-CHO-caffeine 8-CH=NPh PhNHz 62CB403
8-CHO-isocaffeine 8-CH=NPh PhNH z 62Z0B2015
8-CHO-theophylIine 8-CH=CHCO z H CHz(COzHh/pyridine 62CB414
8-CHO-theophylIine 8-CH=C(CO z Eth CHz(COzEt)z/pyridine 62CB414
8-CHO-caffeine 8-CH=C(CO z Eth CHz(COzEth/pyridine 52Z0B2220
8-CHO-theophylIine 8-CH=C(COR lRz)z CHz(COR l R z )z
R1=Rz=Me R1=Rz=Me
R 1 = Me, RZ=Ph R 1 =Me,R z =Ph 62CB414
Pyridine/piperidine
8-CHO-theobromine 2(8-CH=CH)PyMe+r 2-Methylpyridine methiodide 63Z0B3205
8-CHO-caffeine 2(8-CH=CH)PyMe+r- 2-Methylpyridine methiodide 62Z0B452
8-CHO-isocaffeine 2( 8-CH =CH) PyMe +r- 2-methylpyridine methiodide 63Z0B2942
8-CHO-theobromine 8-CH(OH)PO(ORh Pyridine methiodide
(RO)zHPO, 61Z0B3406
R=Me, Et, Pr, Bu
8-CH O-caffeine 8-CH(OH)PO(ORh (RO}zPO, R = Me, Et, Pr, Bu 60Z0B2427
8-CHO-theophylIine 8-CH=CHCO z Et Ph 3 P=CHCO z Et 62CB414
(hot dioxane)
8-CHO-isocaffeine 8-CHCl z SOCIz/CHCI 3 62Z0B2015
8-CHO-caffeine 8-COCHOH-8 KCN/DMF /EtOH 62CB414
8-CHO-theophylIine 8-COCHOH-8 KCN/DMF /EtOH 62CB414
8-CHO-lheobromine 8-COCHOH-8 KCN/DMF/EtOH 62CB414
Table 27 Reactions of some Purine Ketones (56AP453. 63JOC1379)
Purine
Product
Conditions
6-(p-OHC 6 H 4 CO)
6-(p-OHC 6 H 4 CO)
6-(p-OHC 6 H 4 CO)
6-(p-OHC 6 H 4 CO)
8-COMe-caffeine
8-COMe-caffeine
8-COCH z Br-caffeine
8-COMe-caffeine
6-(p-HOC 6 H 4 CHOH)
6-(p-HOC 6 H 4 C=NNH z )
6-CO z H
6-0H
8-CHOHMe-caffeine
8-C( OH)(Ph)Me-caffeine
8-CHOHCH z Br-caffeine
8-COCH z Br-caffeine
Pd/Hz/charcoal
NHzNHz
HzOz/OH-
HzOz/H+
Al(OPrih . HOPr i
PhMgBr
Al(OPr i )3 H . OPr i
Dioxane/Br z
4.09.6.6Purinecarboxylic Acids
Several 6- and 8-carboxypurines have been prepared. They readily undergo decarboxyla-
tion when heated, the 8-carboxyl group being liberated the most easily. Thus caffeine-8-
carboxylic acid loses carbon dioxide in hot water. The acids also readily form esters
normally using the Fischer-Speiers method and a few acid chlorides have been prepared
using phosphorus pentachloride or, preferably, thionyl chloride. Table 29 lists several typical
reactions of the acids.
550 Purines
Table 28 Reactions of some Cyanopurines
Purine Product Conditions Ref.
6-CN 6-CONH 2 2N NaOH 1 h 56JA3511
6-CN 6-C0 2 H 2N NaOH (hot) 56JA3511
6-CN 6-CSNH 2 H 2 S/NH 3 /EtOH 56JA3511
6-CN 6-C(=NH)NH 2 NH 3 /EtOH/pressure 56JA3511
6-CN 6-C(=NH)OEt EtOH 56JA3511
6-CN 6-C( =NH)NHNH 2 NH 2 NH 2 59JA2515
6-CN 6-C(=NH)NHNHPh PhNHNH 2 59JA2515
6-CN 6-C(=NH)NOH NH 2 0H 59JA2515
6-CN 6-0H 2N H 2 SO 4 59JA2515
6-CN 6-CH=NNHCONH 2 H 2 /Ni/NH z NHCONH 2 59JA251S
(low yield)
6-CN 6-CH z NH 2 H 2 /Pd/ charcoal 58JA3932
2-NH z -6-CN 2-NH 2 -6-CONH 2 NaOH/HzOz 63JMC289
2-NH 2 -6-CN 2-NHz-6-CSNH 2 H 2 S/NH 3 /EtOH 64USP3128274
8-CN-caffeine 8-CH 2 NH 2 -caffeine Na/EtOH 1895MI40900
8-CN-isocaffeine 8-CH 2 NH 2 -isocaffeine H 2 /Ni 63Z0B1650
8-CN-caffeine 8-COMe-caffeine MeMgI 56AP453
8-CN-caffeine 8-COE1-caffeine EtMgI 56AP453
Table 29 Reactions of some Purinecarboxylic Acids
Purine
6-CO z H
8-C0 2 H
8-CO z H-caffeine
3-Me-8-CO z H-xanthine
8-CO z H-caffeine
6-C0 2 H
8-CO z H -theophylline
Product
Conditions
Ref.
56JA3511
60JCS4705
48Z0B2129
23LA(432)266
1895MI40900
58JA3932
62CB414
Purine
Purine
Caffeine
3-Me-8-C0 2 Et-xanthine
8-C0 2 Me-caffeine
6-COCI
8-COCI-theophylline
Heat
Heat
Hot water
HCI/EtOH
Ag salt/MeI
PCls
SOCl 2
4.09.6.7 Purinecarboxylic Acid Esters
Several purine esters have been prepared, especially 6- and 8-derivatives. They readily
arninate to amides and may be reduced with lithium aluminurn hydride to the corresponding
alcohols. Table 30 lists several reactions of typical esters.
Table 30 Reactions of some Purine Esters
Purine
9- Me-8-CO z Et -xanthine
6-(CH 2 hC0 2 Et
8-C0 2 Et-theobromine
8-COSBu-caffeine
9-Me-6-CCI( COzEt}z
8-CCI( C0 2 Et)z-caffeine
Product
Conditions
Ref.
64Z0B1137
61LA(649)131
66Z0B816
52Z0B2225
63Z0B3342
61Z0B2645
9- Me-8-CONH 2 - xanthine
6-(CH 2 hOH
8-CH 2 0 H -theobromine
8-CH 2 0H-caffeine
6-CH 2 CI-9-Me
8-CH z O H -caffeine
NH 3
LiAIH4
LiAIH4
Ni/H2
HCl/EtOH
HCl/H 2 0
4.09.6.8 Purinecarboxamides
A few carboxamides have been prepared. They rnay be hydrolyzed to carboxylic acids,
dehydrated to nitriles, and homoamides also undergo the Hoffman reaction with alkaline
sodiurn hypobrornite to produce aminoalkylpurines. Table 31 lists reaction products of some
typical purinecarboxamides.
4.09.6.9 Nitropurines
The nitropurines rnay be reduced in various ways to provide corresponding arninopurines.
Table 32 records some reaction conditions for this process. In addition, nitro groups may
Purines
Table 31 Reaction of Some Purinecarboxamides
551
Purine
Product
Conditions
6-CONH 2
8-CONH 2 -caffeine
8-CONH 2 -caffeine
8-CONH r caffeine
6-CH 2 CONH 2
6-CONH 2
9-Me-6-CONH 2
6-C0 2 H
8-C0 2 H -caffeine
8-CN -caffeine
8-CN-caffeine
6-CH 2 NH 2
6-C(=NH)NH 2
9-Me-6-C( =NH)NH 2
2N'NaOH
N 2 0 3 , 50% H 2 S0 4
P 2 0 S
POCl 3
NaOBr/OH-
NH 2 NH 2
NH 2 NH2
Ref.
56JA3511
1895MI40900
1895MI40900
56AP453
61LA(649)131
58JA3932
63JMC289
Table 32 Reactions of Some Nitropurines
Purine
Product
Conditions
2-Nitroinosine
8-Nitrotheophylline
8-Nitrotheophylline
8-Nitrotheobromine
8-Nitrohypoxanthine
Guanosine
8-Aminolheophylline
8-Aminotheophylline
8-Aminotheobromine
8-Aminohypoxanthine
NaHS0 3
SnCI 2
NaSH
NH 4 SH
NaHS0 3
Ref.
64JA2948
57 AC(R)362
60JA3773
1897CB2584
60JA3773
occasionally undergo replacement by nuc1eophiles. Thus 8-nitrotheophylline gave the 8-
chloro and 8-bromo derivatives with hydrochloric or hydrobromic acids, respectively
(57 AC(R)366).
4.09.6.10 Aminopurines
4.09.6.10.1 Introduction
The biological importance of adenine and guanine and their derivatives has ensured that
there is a very substantial literature concerned with the aminopurines, and it will only be
possible to give a brief account of reactions undergone by the arnino group in such
compounds. Table 33 gives a representative list of typical reaction products but it is of
course far from complete. For rnore complete details see (71HC(24-2)1). The amino group
in aminopurines in the main undergoes most of the reactions of typical aromatic amines.
4.09.6.10.2 Acylation
Acetylation of adenine with acetic anhydride produced the N 6 -acetyl and the N 6 ,
N 9 -diacetyl derivatives, the N-9 group being readily rernoved by alcoholysis or by alkali.
Other aminopurines similarly may be acylated both on the exocyclic arnino group and on
ring atoms, the ring acyl groups being labile to both alcoholysis and alkaline hydrolysis. In
contrast, adenine with p-nitrobenzenesulfonyl chloride gave a ring sulfonylated derivative,
probably the N-9 derivative (66JMC373) which is usual in such acylations. On the other
hand, 2-arnino-9-methylpurine provides an exceptional case in which sulfonylation with
p- acetamidobenzenesulfonyl chloride in pyridine produced the 2-sulfonamido derivative
(66JMC373).
4.09.6.10.3 Alkylation
Alkylation of aminopurines normally leads almost exclusively to ring-substituted products
(see Section 4.09,5.2.2(iii)). However, alkylation of adenine with formaldehyde probably
produces the N 6 -hydroxymethyl derivative (183) (64JCS792), and the crystalline diadeninyl
derivative (184) is also obtained from a rnixture of equimolar arnounts of adenine and
forrnaldehyde in water, especially in acid solution (62MI40902).
552 Purines
Table 33 Reactions of Some Aminopurines
Purine Product Conditions Ref.
Adenine N 6 -Formyladenine HCOzH/ AczO 80JCS(PI)2728
Adenine N 6 -Acetyladenine AczO 5lJAI650
Adenine N 6 -Benzoyladenine PhCOCI 57JOC568
N 6 - Acetyladenine N 6 -Ethyl adenine LiAlH4 56JOCI276
N 6 -Benzoyladenine N 6 -Benzyladenine LiAIH4 65BSF26I7
Adenine 9-Allyladenine CHz=CHCHzCI/ 65JOC3235
K Z C0 3 /DMA
Adenine 9- Benzyladenine PhCH z CI/K z C0 3 64JHC1l5
Adenine 3-, 9- and I-Methyladenine Me Z S04/ DMF 62B558
Adenine 3- and 9-Alkyladenine Alkylation in neutral/alkaline 64JA5320
solution
Sodioadenine 3-(3-Methylbut-2- 3-Methylbut-2-enyl bromide 62JAI48
enyl)adenine (triacanlhine) in EtOH
plus trace of I-isomer
I-Methyladenine 1,9-Dimethyladenine Methyl p- 64B494
toluenesulfonate/DMA
3-Methyladenine 3, 7 -Dimethyladeni e MeI/KOH 64B494
N 6 -Benzoyladenine 3- and 9-Benzyl-N - PhCHzBr /DMF /80 oC 65TL2059
benzoyladenine
Adenine 8-Bromoadenine Brz I892ZPC329
Adenine Hypoxanthine HNO z 1886ZPC(10)258
Sodioadenine 9-Chloromercurioadenine HgCl z 66JOC1413
Adenine 5 (4 )-Aminoimidazole-4(5)- 6N HCI/150 o C 49JA3973
carboxamide
2-Aminopurine 2-Fluoropurine HNOz/HCI 60JA463
2-Aminopurine 2-Chloropurine HNOz/HCI 66JOC3258
Adenosine 6-Fluoroadenosine HNOz/HCI 69JOC1396
8-Aminocaffeine 8-Diacetylaminocaffeine AczO 59JOC1813
2,6-Diaminopurine N Z ,N 6 ,9- Triacetylpurine AczO 57JOC959
Guanine 7,9-Dimethylguanine Me z SOJ90 oC/DMA 62JA1914
Guanine 9-, 7- and 3-Methylguanine MeCI/NaOH/70 oC 66B3007
Guanine 9-Alkylguanines Tetraalkyl ammonium 63JOC2087
hydroxide/fusion
I-Alkylguanine 1, 7-Dialkylguanine 45JCS75I
N Z -Acetylguanine 7- and 9-Benzyl-N - PhCH z Br/90 'Cn h/ DMF 67CPBI066
acetylguanines
Guanine 8- Bromoguanine Brz I883LA(221)336
Guanine 8-Arylazoguanines Aryldiazonium salts 39JA351
Guanine Xanthine HNO z 1861LA(l18)151
Isoguanine Xanthine 25% HCl 48JA3109
Guanine Guanidine HCl/KClO 4 58LA(l29)141
Guanine 5(4 )-Aminoimidazole- 3.4N HCI/160 o C 36MI40900,
4(5)carboxamide 36MI40901
Alkylation at the 6-NH 2 group sirnilarly may also occur by Mannich reactions with an
amine and formaldehyde. Thus morpho line and adenine afforded the diarninomethylated
derivative (185) (67APIOOO).
(184)
1\
-N\.__l
t..J-
N N
I
CH z
( )
o
(185)
NHCHzOH
Cx)
N H
(183)
CH2 NH
ÙN
N N
I 2
4.09.6.10.4 Displacement reactions
The arnino group in adenine and substituted adenines is readily transforrned into hydroxyl
by nitrous acid to afford hypoxanthine and its derivatives, and guanine sirnilarly produces
Purines
553
xanthine, whereas isoguanine does not react but can be hydrolyzed to xanthine by long
heating with 25% hydrochloric acid. Amino derivatives resistant to nitrous acid may often
be dearninated with nitrosyl chloride and pyridine in DMF (72JOC39SS).
Replacement of the amino group in aminopurines by halogens has been achieved in
several ways. Thus 2,6-diamino-9-[(2,3,5-tri-O-benzyl)-D-arabinofuranosyl]purine with
fluoroboric acid and sodium nitrite in THF at -10 oC gave a 48% yield of the 2-fluoro-
adenosine derivative (186; R = 2,3,5-tri-O-benzyl-ß-D-arabinofuranosyl) (79JHC1S7),
and similar use of 2,6-diamino-9-ß -D-ribofuranosylpurine in hydrochloric acid solution
gave the 2,6-dichloropurine nucleoside (187) (60JA463).
CI
N N
Cl _ .Y- N ')
N I
RP
(186) (187) f
Recently several 9-substituted adenines including 2',3',5'-tri-O-acetyladenosine, with
pentyl nitrite in non-aqueous hydrogen atom donating solvents (especially THF) and
photolysis with a 200 W light source, were found to produce good yields (40-70%) of
9-substituted 6H -purines. The reaction is considered to proceed via homolysis of an
intermediate diazonium ion with formation of a purinyl radical which then extracts an
appropriate atorn from the solvent (Scheme 35). In halogen-donating solvents, especially
carbon tetrachloride, bromoforrn or methylene iodide, 6-chloro-, 6-bromo- and 6-iodo-
purines, respectively, are similarly produced (SOJOC3969).
NHz
UN')
N N
R
NHz N=NOR. X
UN') N') :t) r-N') r-N')
N jlN '-:" WJl--N )....N
R R R R
X==CI, Br,I, H
Scheme 35
In contrast to 6-arninopurines, several 8-aminopurines form stable 8-diazopurines with
nitrous acid, especially when dipolar forrns are possible. Thus 8-aminoxanthine and nitrous
acid at 5-10 o C gave the 8-diazo derivative (188) (60JA3773) and similar products are
produced frorn hypoxanthine, isoguanine and theophylline. In contrast 8-amino-9-
methylxanthine failed to produce a stable diazo derivative and this tends to favour the
particular ionic structure (188) which is further confirmed by the absence of imidazole
irnino groups in the IR spectra of these compounds.
o H
HN I +
..jl.:lNz
o N N
H
(188) (189)
The diazo group rnay be replaced by hydroxyl (water) and thiol (hot potassium hydro-
sulfide) groups (60JA3773) and also undergoes coupling reactions with amines to produce
triazenes including (189) from 8-diazohypoxanthine and dialkylamines (6IJAll13). Adenine
and arenediazonium chlorides also produce triazenes which when heated at 60-90 o C
produce 8-aryladenines by an interrnediate free (aryl) radical process (see Section
4.09.5.4.3).
HN N
J-N')N=NNRz
H
4.09.6.11 Hydrazinopurines
Several 2-, 6- and 8-hydrazinopurines have been prepared. The hydrazino group may
be replaced by hydrogen by aerial oxidation in alkaline solution or with iron(III) salts. On
the other hand, the srnall yield (6%) of 6-chloropurine first recorded frorn 6-hydrazinopurine
and iron(III) chloride (SSJA3932) has been markedly increased (67%) (B-78Ml40901, p. 19) (see
554
Purines
Section 4.09.7.7.8), and 8-chlorocaffeine is similarly obtained from 8-hydrazinocaffeine
(SSCB1932). 6-Hydrazinopurine is also. converted into 6-thioxo-1,6-dihydropurine in 60%
yield when heated with thiolacetic acid. The hydrazinopurines give azidopurines with
nitrous acid and undergo other reactions typical of arylhydrazines, including formation of
exocyclic pyrazole and triazole rings.
4.09.6.12 Purine N -Oxides
The chemistry of the heterocyclic N -oxides, including purine N- oxides, has been reviewed
extensively (B-71MI40902).
The N-oxides are readily converted into parent purines by reduction using platinum(IV)
oxide or Raney nickel catalysts with varying degrees of ease (S8JA27SS, 69JMC717, 69BCJ7S0,
69JOC978), or by deoxygenation processes involving heat, as in the conversion of 8-
phenyltheophylline 7-oxide into 8-phenyltheophylline by heating in DMF (64JA4721), irradi-
ation (64B880) or by the action of phosphorus halides or pentasulfide (6SJOC408) or amines
as in the conversion of 6-chloropurine 3-oxide into adenine derivatives (69JOC21S7). Enzymic
reduction using xanthine oxidase and an electron donor has also been used to reduce purine
N-oxides (69JBC2498). . .
Alkylation of many N -oxides affords correspónding N -alkoxypurines although xanthine
I-oxide produced the I-hydroxybetaine, and the 3-oxide behaves in a similar manner.
Alkylation often proceeds better in the presence of hydrogen peroxide (74CPB2466) as in
the conversion of adenine I-oxide into 1-methoxy-9-methyladenine with methyl iodide.
Similarly alkylation of adenosine l-oxide and its 2',3'-O-isopropylidene derivative ãfforded
the corresponding 1-alkoxy nucleosides (73CPB1676).
1-Alkoxy-9-alkyl-6-iminopurines undergo Dimroth rearrangements (involving ring open-
ing) in aqueous solution at 100 oC to produce 6-alkoxyamino-9-alkylpurines (71T241S). Also
7 -alkoxy-8-methyltheophyllines when heated produced 8-alkoxycaffeine derivatives
(Scheme 36) (66LA(693)233).
:Jc o OR
MeN I N>
O N N
Me
o Me
200'C MeN 1 N"
-.:l_.J- ,yOR
o N N
Me
Scheme 36
Acylation of N -oxides usually produces a reactive N,O-acyl derivative. Adenine I-oxide,
however, with acetic anhydride undergoes ring opening to afford an oxadiazole (Scheme 37)
(B-72MI40901, p. sso).
O.
NHz I H
N tl Ac 2 0) r II \
)l. I /NHz N, /Me
N N N 0
Scheme 37
In addition, migration of methyl groups in unsubstituted methylated N -oxides such as
I-methoxyadenine has been observed (Scheme 38) (71CPB1731) and kinetic studies have been
carried out (72CPB9S8, 7SCPB2643).
NHz
MeON N
. /
N N
NH
:x z MeONH H
MeON?' N N?' N
---... CHONH I > ---... (X >
N N N
H
Scheme 38
Xanthine 3-oxide on the other hand is readily converted into 3-acetoxyxanthine (190)
which reacts under very mild conditions with a wide variety of inorganic or organic
nucleophiles to produce 8-substituted xanthines (Scheme 39) in high yields (B-72MI40901,
p. sso). The mechanism has been extensively investigated by the same workers and it is
proposed that intermediate nitrenium (191) and carbo cations (192) are involved
(Scheme 40).
Purines
J= o H
HN N
-.:l I ;SMe
o N N
H
555
o H 0 H
HNJ=N; : þ HN N>-
O-.:lN N O-.:lNjlN
OAc H
(190)
Scheme 39
OH
CI
Br
N0 2
N J
SH
methionine
(
o 0
H.N ; HN N1
O NJ-N O-.:lN N
H H
(191) (192)
Scheme 40
Table 34 records some reactions of purine N -oxides.
Purine
Table 34 Reactions of Some Purine N-Oxides and Derivatives
Product
Conditions
Adenine 1-oxide
Adenine 1-oxide
Adenosine 1-oxide
Adenine 1-oxide
Adenine 1-oxide
2-Methyladenine 1-oxide
6-Methylpurine 1-oxide
Adenine 3-oxide
Guanine 3-oxide
Hypoxanthine 3-oxide
Hypoxanlhine 3-oxide
Hypoxanthine 3-oxide
Hypoxanthine 3-oxide
6-Bromo-, 6-iodo-,
6-methoxy-, 6-sulfo-
purines, 3-oxides
6-Chloropurine 3-oxide
6-Methoxypurine 3-oxide
Adenine (94%)
Adenine + isoguanine
Adenosine + isoguanosine
1-Methoxyadenine
1-Methoxy-9-methyladenine
1-Acetoxy- 2-methyladenine
6-Acetoxymethylpurine
Isoguanine
6- Amino- 2,8-dioxo-2,3, 7 ,8-
tetrahydropurine
Xanthine
Guanine
Hypoxanlhine
2,6-Dichloropurine + a little
6,8-dichloropurine
6-Bromo-, 6-iodo-,
6-methoxy, 6-sulfo-
purines
6-Chloropurine
6-Methyl-2-oxo-2,3-
dihydropurine
2- Thiohypoxanthine
Uric acid
8-Thiohypoxanthine (88%)
8-Aminoxanthine
7,9- Dimethylxanthine
6-Methoxypurine 3-oxide
Xanthine 3-oxide
Xanthine 3-oxide
Xanthine 3-oxide
7,9-Dimethylxanthine 1- and
3-oxides
Xanthine 7 -oxide" Xanthine
Theophylline 7-oxide 8-Acetoxytheophylline
Theophylline 7-oxide 1,3-Dimethyluric acid
8-Phenyltheophylline 7-oxide 8-Phenyltheophylline
8-Methyllheophylline 7 -oxide 8-Methyltheophylline
3-Acetoxyxanthine 8-Substituted xanthines
8-0xo-7,8-dihydropurine 2,8- Dioxo + 6,8-dioxo-
dihydropurines
Ni/H 2 /aq. NHJ
UVlight
UVlight
MeI/dimethylacetamide
MeI/H 2 02
AC20
AC20
AC20/(CFJCOhO
AC20
AC20/(CFJCOhO
pyridine/ AcOH (several
hours) +aq. NaOH
Ni/H 2 /aq. NH J (22 h)
POClJ/heat
Ni/H 2 /aq. NH J /1 h
Ni/H2/72 h
AC20/(CFJCOhO
MeCOSH
AC20
MeCOSH (4 h reflux)
Heat/aq. NaOH
Ni/H2
58JA2755
64B880
64B880
65MI40904
73CPB1676
60JA1148
62JOC567
69JOC981
69JOC981
69BCJ750
69BCJ750
69BCJ750
69BCJ750
69JOC2157
69JOC2157
69JOC981
69BCJ750
69JOC981
69BCJ750
69TL 785
69JOC978
Ni/H 2 /NaOH (slow) 65MI40904
AC20 66LA(693)233
Heat 66LA(691)142
Heat in DMF 64JA4721
Ni/H 2 /EtOH 65MI40904
Nucleophiles/H 2 0 pH-5 B-72MI40902, p. 550
Acetic anhydride 62JOC567
"The 1-oxides are very difficult to reduce.
4.09.6.13 Hydroxyaminopurines
Several 2-, 6- and 8-hydroxyaminopurines have been prepared and their chemistry
reviewed by the most active workers in this field (B-72MI40901, p. 478): Hydrogenation of
hydroxyaminopurines affords amino purines. Thus 6-hydroxyaminopurine with a palladium
556
Purines
catalyst gave adenine (58JA3932) and 2,6-dihydroxyaminopurine afforded 2,6-diaminopurine
(68JMC52). Acid hydrolysis of hydroxyaminopurines tends to produce oxopurines, an example
includes 6-hydroxyaminopurine which with nitric acid gives hypoxanthine (58JA3932)
whereas in TF A containing hydrogen peroxide 2-amino-6-hydroxyamino- and 6-
hydroxyamino-2-oxo-2,3-dihydropurines furnish guanine (68%) and xanthine (91%),
respectively (66B3057). In aerated alkaline solution however, 6-hydroxyaminopurine pro-
duced 6,6'-azoxypurine (B-57MI40900, p.3). Similarly 2- and 8-hydroxyaminopurines gave
2,2'- and 8,8'-azoxypurines and a 6-hydroxyaminopurine N-oxide was instantly converted
by alkali into 6,6'-azoxypurine 3,3'-dioxide (69JMC717) or by hydrogenation with a Raney
nickel catalyst into the 6,6'-bis(adenine) (193).
[ N&
N l rìl
(193)
With thioacetic acid 6-hydroxyaminopurine afforded 6-thioxo-1,6-dihydropurine
(64JOC3209) and oxidation of 6-hydroxyaminopurine with manganese dioxide afforded
6-nitrosopurine (66MI40901).
Table 35 collects data on some of the reaction products of various substituted
hydroxyaminopurines.
Table 35 Reactions of Some Hydroxyaminopurines
Hydroxyamino-
purine
6-NHOH
2,6-Di-NHOH
6-NHOH
6-NHOH
6-NHOH
2-NHOH
8-NHOH
2-F-6-NHOH
2- F -6-NH OH -9-ß- D-ribofuranosyl
2-NHOH
2-NHOH-6-NH 2
2-F-6-NHOMe
Product
Adenine
2,6-Di-NH 2
6-N(NO)OH
6-SH
6,6' - Azoxy
2,2' -Azoxy
8,8'-Azoxy
2-F-adenine
2-F-adenosine
2-NH 2
2,6-Di-NH 2
2-F-adenine
Conditions
Pd/H 2
Pd/H 2
HN0 2
MeCOSH
aq. NaOH
aq. NaOH
aq. NaOH
Ni/H 2
Ni/H 2
Ni/H 2
Ni/H 2
Ni/H 2
Ref.
58JA3932
68JMC52
70JHC75
64JOC3209
B-72MI40902, p. 478
B-72MI40902,p.478
B-72MI40902, p. 478
B-72MI40902,p.478
B-72MI40902, p. 478
B-72MI40902,p.478
B-72MI40902, p. 478
B-72MI40902, p. 478
4.09.6.14 Oxopurines
4.09.6.14.1 Introduction
The rnain reactions associated with the oxopurines, especially the enolizable derivatives,
involve their conversion into halogeno-, especially chloro-, and thioxo-purines.
4.09.6.14.2 Oxo- to halogeno-purines
The main agent used for the conversion of oxopurine into chloropurines is phosphoryl
chloride, either alone or with added water (which may produce pyrophosphoryl chloride),
phosphorus pentachloride, or with bases, usually tertiary amines and especially N,N-
dirnethyl- or diethyl-aniline. The use of bases, especially aliphatic amines, may however
lead to introduction of dialkyamino groups into the purine or formation of other byproducts
(74RCRI089). Other reagents which have been used include (a) thionyl chloride in DMF
(Vilsmeier-Haak reagents) which converts 2',3' ,5'-tri-O-benzoylinosine into the 6-
chloropurine nucleoside (64CPB639); and (b) chlorornethylenedimethylarnrnonium chloride
in chloroform.
Alkylated oxopurines in which no enolization is possible may also react but usually with
elimination of one or more alkyl groups; simultaneous halogenation at an unsubstituted
Purines
557
8-position may also occur. Thus theobromine with phosphoryl chloride and dimethylaniline
furnished 7-methyl-2,6-dichloropurine (60Z0B327) whereas when a mixture of phosphoryl
chloride and phosphorus pentachloride was used, 7-methyl-2,6,8-trichlbropurine was pro-
duced (1897CB2400, 1895CB2480). Similarly caffeine with the last mixture at 180 0 C gave the
same trichloropurine. Evidence for the intermediate formation of a dichlorodihydropurine
in these reactions has been obtained. For example, 1,9-dimethylxanthine after treatment
with phosphoryl chloride was condensed with ammonia to afford the imine (194)
(64Z0B2472).
NH
MeN^rN
O NjlN
H Me
(194)
Aminooxopurines may also produce corresponding halogeno derivatives although guanine
is resistant to chlorination. Thus 2-amino-6,8-dioxo-1,6,7,8-tetrahydropurine with phos-
phoryl chloride and phosphorus pentachloride afforded 2-amino-6-chloro-8-oxo-7,8-dihy-
dropurine (1898CB2619). .
Bromopurines have also 'been prepared from oxopurines and phosphoryl brømide. In
this way 6-bromopurine was produced in 40% yield from hypoxanthine (56JA3508) but
xanthine only furnished a low (10%) yield of 2,6-dibromopurine.
4.09.6.14.3 Thiation
Oxopurines, especially 6-oxo derivatives, are converted into corresponding thioxo deriva-
tives with phosphorus pentasulfide in hot pyridine over a few hours, the order of displacement
following the normal order of nucleophilic substitution. Thus hypoxanthine gave 6-thioxo-
1,6-dihydropurine in 73% yield (6IJA4038). The 2- and 8-oxopurines are less reactive than
the 6-oxo derivatives. Xanthine and the isomeric 6,8-dioxo-1,6,7,8-tetrahydropurine with
phosphorus pentasulfide give 2- or 8-oxo-6-thioxo-1,6,7,8-tetrahydropurines, respectively
(54JA5633, 6IJOC1660) and even after prolonged heating with phosphorus pentasulfide in
pyridine, uric acid could only produce 6-thiouric acid (59JA3039). Thiation to produce
polythioxopurines is possible if the starting materials have thioxo groups in the difficult
positions (prepared by other means-see Section 4.09.6.17). Thus 2-thioxo-2,3-dihydro-
hypoxanthine produced the corresponding 2,6-dithioxopurine (54JA5633), and 6,8-dioxo-2-
thioxo-1,2,3,6, 7,8-hexahydropurine afforded trithiouric acid (59JA5997). Aminooxopurines
may also be thiated. Guanine for example furnished 2-amino-6-thioxo-1,6-dihydropurine
(60JA2633) after long reflux in pyridine.
It is not essential to have enolizable oxy groups for thiation to succeed. Thus theophylline
and theobromine (62J<::S1863) furnished the corresponding 6-thioxo derivatives after 8 and
6 h heating in pyridine, respectively. Caffeine failed to react under these conditions, but
produced 6-thiocaffeine with phosphorus trisulfide in kerosine at 150 0 C (48Z0B2116) and
at higher temperatures (210 oc) 2,6-dithiocaffeine was obtained.
Purine nucleosides also readily undergo thiation. Thus 2',3',5'-tri-O-benzoylguanosine
gave the 6-thioguanosine derivative (58JA1669).
4.09.6.14.4 Miscellaneous displacement reactions
Examples of amination of oxopurines to aminopurines via silyl derivatives include
conversion of inosine into adenosine with catalysis by mercury ions (76LA745), and hypoxan-
thines have been converted directly into adenines with phosphoramides at 225-230 o C
(69IZV655).
4.09.6.15 Alkoxypurines
Unlike their thio analogs, the alkoxypurines have had relatively little application in purine
synthesis perhaps because their preparation is essentially limited to alkoxide displacement
of halogens in halogenopurines.
558
Purines
They are relatively stable to alkalis but undergo ready hydrolysis with aqueous acids.
Thus 6-methoxy-3-methylpurine furnished 3-methylhypoxanthine when set aside with 5N
hydrochloric acid over 12 h at 20 0 C (66JCS(C)10). More vigorous conditions (hydrochloric
acid at 100 0 C for 10 min) converted 8-ethoxycaffeine into 2,3,7-trirnethyluric acid
(1882CB253), but under these conditions ring opening may also occur to give irnidazoles.
Thus acid hydrolysis of 6-methoxy-9-methylpurine gave a mixture of products including
5-amino-1-methylimidazole-4-carboxamide (196; Scheme 41) (74JCS(Pl)1284).
N :): OMe N N
I I ') -- 0 H _ NlL ')
N N H 2 N N
Me Me
(196)
Scheme 41
It has sornetimes proved convenient to fix oxopurines in their lactim forrns by 0-
benzylation. The benzyl group in such derivatives may be removed by hydrogenolysis with
palladium catalysts. In this way 6-amino-2-benzyloxy-9-methylpurine furnished 9-methyl-
isoguanine with palladium and hydrogen in dilute acid (49JCS2490), and similarly in ethanol
solution 6-benzyloxy-2-fluoropurine produced 2-fluorohypoxanthine (67JOC3258). The tech-
nique has been applied to nucleosides, including 9-(ß -D-ribofuranosyl)-6-benzyloxy-2-
dimethylaminoinosine (65JA3752).
Rearrangernent of alkoxypurines to their N -alkyl isomers readily occurs on heating, as
with 8-methoxytheobrornine which gave 2,7,9-trirnethyluric acid when heated to 290 0 C
(30CB2876).
Many other examples exist (7lHC(24-2)1) including analogous rearrangements of dialkoxy-
purines such as 2,6-dimethoxy-7 -methylpurine which when heated at 210 oC for 15 min
afforded caffeine (35JCS955). The same authors were unable to isomerize a 2,6-dipropoxy-
purine.
Like their alkylthio analogs the alkoxypurines react with arnmonia and amines to produce
arninopurines but few exarnples have been reported. However 2-chloro-6-methoxy-9-ß -D-
ribofuranosylpurine gave 2-chloroadenosine with methanolic amrnonia at 80 oC (58JA3738).
N-Alkoxypurines have also been prepared and their reactions are recorded in Section
4.09.6.1.2 under N -oxides.
4.09.6.16 Thioxopurines
4.09.6.16.1 Dethiation
The thioxopurines undergo a wider variety of useful reactions than the corresponding
oxo derivatives. A major reaction is dethiation or desulfurization which enables replacement
of SH by hydrogen to be carried out. The dethiation step is commonly achieved by reaction
with Raney nickel. In this manner 6-thioxo-1,6-dihydropurine and 2,6-dithioxo-1,2,3,6-
tetrahydropurine may be converted into purine with nickel in aqueous ammonia (54JA5633).
Table 36 outlines some typical applications of the dethiation process. Oethiation rnay also
be achieved by the use of nitrous acid especially with 2- or 8-thio derivatives (21LA(423)200),
or by use of various oxidizing agents such as hydrogen peroxide, when the sulfinic acid is
an interrnediate (76MI40902). Even dilute nitric acid will sornetimes succeed, as in the
conversion of 2-thioxanthine into hypoxanthine (06AP(244)11). Similarly acidified hydrogen
peroxide converted 2-thioadenine into adenine (06AP(244)ll). When enolization of the thioxo
group is not possible because of ring substitution, dethiation may give dihydro derivatives,
as with 6-thiotheophylline which with nickel gave the 1,3-dirnethylpurine (195).
H
MeNr N >
oÅN)LN
Me
(195)
The Eschenmoser sulfur extrusion process has been applied to purines. Oethiation by
sulfur extrusion of 6-phenacylthiopurine nucleosides using triphenylphosphine and
Purines
559
Table 36 Reactions of Some Thioxopurines and Derivatives
Purine Product Conditions Ref
6- Thioxo-1,6-dihydropurine Purine Raney Nijaq.NH 3 54JA5633
1- Methyl -2-thioxo-2,3- 6-Methylpurine Heat, 2 h/Raney 64JOC3209
dihydropurine Ni/aq. NH 3
1-Methyl-6-thioxo-1,6- 1-Methylpurine Hot H 2 O/Ni 62JOC990
dihydropurine
6- ThiotheophyIIine 1,3-Dimethyl-2-oxo-1,2,3,6- Raney Ni, 1 h/heat B-65MI40902, p. 285
tetrahydropurine
6- Thiocaffeine 1,3,7 - Trimethyl-2-oxo- Raney Ni, 1 h/heat 66BSF3934
1,2,3,4-tetrahydropurine
2- Thioxo-2,3- Hypoxanthine aq. HN0 3 06AP(244)11
dihydrohypoxanthine
2-Thioxo-2,3- Adenine H 2 0 2 20% /H 2 S0 4 06AP(244)11
dihydroadenine
potassiurn t- butoxide, has led to 6-phenacylpurine nucleosides (76AG724) and similarly
6-phenacylthioinosine produced 6-phenacylpurine riboside (80CPB157).
4.09.6.16.2 Alkylation and acylation
CI SAc :ì s
7 N 7 N -----. HN I N
.J-- N .J-- N N
N H N H N Ac
(196)
Alkylation of thiopurines rnay produce both S- and N -alkyl derivatives in contrast to
oxopurines where O-alkylation is rare (Section 4.09.5.2.2). The S-alkyl derivatives are
favoured by carrying out the reaction below 40 oC in aqueous or aqueous alcoholic solutions
with equimolar equivalents of sodium hydroxide and either an alkyl halide or sulfate. At
higher temperatures the N -alkylpurine tends to be produced normally by S-N rearrange-
ment of the first formed S-alkyl derivative (65MI40906).
Interesting results which illustrate S-N migration arise when thioxopurines are acylated
with alkyl chloroformates. Thus 6-thioxo-1,6-dihydropurine or 8-thioxo-7,8-dihydropurine
with alkyl chloroformates produced 9-alkoxycarbonylpurines. On the other hand when the
imidazole ring is substituted as with 9-rnethyl-6-thioxo-1,6-dihydropurine, then S- alkylation
occurred with ethyl chloroform ate to produce the S-eìhoxycarbonyl derivative (64JMClO).
Evidence supporting the suggestion that the N -ethoxycarbonyl derivatives are produced
by rearrangement of a first forrned S-acyl derivative comes frorn formation of 9-acetyl-6-
thioxo-l,6-dihydropurine (196) from 6-chloropurine and potassium thiolacetate in DMF
(Scheme 42) (69JOC973), and successive treatment of 6-thiocyanatopurine (197) with sodium
ethoxide followed by acid (Scheme 43) gave the 9-ethoxycarbonyl derivative (198).
SCN S
(X) :'. Hlx:>
H N C0 2 Et
(197) (198)
Scheme 43
Scheme 42
Acetylation of thioxopurines with cyanogen bromides similarly produces thio-
cyanatopurines. Thus 2-, 6- and 8-thiocyanatopurines may be prepared from the correspond-
ing thioxopurines in sodium hydroxide solution at 0 oC with cyanogen bromide (67CPB909).
4.09.6.16.3 Halogenation
Thioxopurines may often be converted into halogenopurines by reaction with halogens.
For example 6-thioxo-1,6-dihydropurine with chlorine in cold ethanol afforded 6-
chloropurine. The use of chlorine in methanol or ethanol, especially on a large scale, has
been shown to be hazardous and acetonitrile or hydrochloric acid are proposed as alternative
and safer solvents (74JHC77). Methylthiopurines are often more suitable in these reactions,
and bromopurines may be prepared analogously and with advantage (62JOC986). 8-
Iodopurines have occasionally been obtained in a similar manner from 8-thioxopurines and
iodine.
560
Purines
The rnethod is especially valuable since it permits preparation of 2- and 8-chloropurines
which are not readily obtainable by chlorination of the coresponding oxopurines (B-
71M140901, p. 141). The mildness of the procedure makes it especially useful for analogous
syntheses of chloropurine nucleosides. Thus 6-thioxo- or 6-methylthio-purine-9-ß -D-
ribofuranosides with chlorine in rnethanol at -10 oC produced the valuable 6-chloropurine-
9-ß-D-ribofuranoside in 82% yield (60JA2654).
4.09.6.16.4 Arnination
Arnination of thioxopurines to aminopurines requires forcing conditions which may bring
about ring opening reactions and Dimroth rearrangements. However alkylthiopurines are
more reactive and many reactions with amines have been described. The order of replace-
ment is 8> 6 > 2 as predicted by the Fukui FMO superdelocalizability theory (B-74MI40901).
With weak amines such as aniline, mercury(II) chloride is recommended as a catalyst
(70IZV420). However alkylthio groups at C-2 normally fail to react (56JA217) although the
interesting conversion by aqueous amrnonia of 1-methyl-2-methylthio-6-thioxo-1,6-dihy-
dropurine (199) into 6-amino-2-methylaminopurine (200) is noteworthy (62JOC2478) but
probably involves ring opening prior to elimination of methanethiol (Scheme 44).
S NH 2
Mery_N> NH 4 0H, N r N >
MeSI..:::::-. .J- N MeNH )l'N
N H N H
(199) (200)
Scheme 44
4.09.6.16.5 Hydrolysis
Thioxo- and S-alkylthio-purines are readily converted into corresponding oxopurines
with various reagents including oxidizing agents such as nitric acid (25-50%) which converts
6-thioxo-1,6-dihydropurine into hypoxanthine (65MI40906). More readily hydrolyzed sulfinic
acids are likely intermediates in these reactions (74MI40902).
Hydrolysis of alkylthiopurines with acid readily occurs to give oxopurines, although
several hours heating may be required, especially with 2-methylthiopurines (62JA3008) which
may prove very difficult to hydrolyze when electron donors are present in the ring.
6-Amino-2-methylthiopurine, for example, failed to hydrolyze to any significant extent
with 6N hydrochloric acid (49JCS2490). On the other hand 2-rnethylthiohypoxanthine was
readily converted into xanthine (I3JBC(14)381) by acid hydrolysis. If an oxidizing agent is
included in the acid medium, then the reaction frequently readily proceeds to the oxopurine.
Thus 6-amino-2-methylthiopurine in the presence of hydrogen peroxide readily gave
isoguanine (59JA2442), again presumably via sulfinic acid intermediate. S-Carboxymethyl-,
purines which are conveniently prepared frorn thioxopurines in aqueous alkaline solution
with chloroacetic acid, have frequently been used as interrnediates in the conversion of
thioxo- into oxo-purines. In this rnanner hypoxanthine and 8-oxopurine derivatives may be
prepared from 6- or 8-carboxymethylthiopurines, respectively, by acid hydrolysis (58JA6265,
31CB752). However not all such derivatives, e.g. 2-carboxymethylthioadenine, undergo ready
hydrolysis (48JA3109).
4.09.6.16.6 Oxidation
With appropriate, i.e. enolizable, thioxopurines disulfides may be produced, often by
treatment with iodine in sodium iodide solution. 6-Thioxo-1,6-dihydropurine is oxidized
in this way (6IJOC3401). Other reagents include hydrogen peroxide in DMF (66LA(695)77)
or butyl nitrite in aqueous methanol (B-71MI40901, p. 291). Mixed purinyl disulfides including
n -butyI6-purinyl disulfide (201) have been prepared using the reagent (202) (70JAP7039709).
Benzyl purinyl disulfide (79CPB2518) has been ribosylated with ribofuranosyl tetra-G-
acetate and tin (IV) chloride.
Purines
561
SSBu
N N
I I )-
'-'::::- N
N H
(201)
NH
"
BuSSCNH z
(202)
Further aerial oxidation of dipurinyl disulfide in alkaline solution gave an excellent (90%)
yield of purine-6-sulfinic acid (61JOC3401) and the 2-amino derivative is produced in the
same way. More vigorous oxidation of thioxopurines or intermediate sulfinic acids with
potassium permanganate in alkaline solution afforded sulfonic acids (61JOC3401). The
purinesulfinic acids are readily hydrolyzed to oxopurines including 6-sulfinic acid which
immediately gave hypoxanthine with O.lN hydrochloric acid (61JOC3401), whereas the
corresponding sulfonic acid required brief heating to effect hydrolysis. Similar oxidation of
methylthiopurines produced methanesulfonyl derivatives which are reported to react with
nucleophiles as well as or even better than corresponding chloropurines (76JCS(P2)1176). The
methanesulfonyl groups in 2,8-dimethanesulfonyladenosine, for example, with cyanide were
replaced to produce 2- and 8-cyanoadenosines (79CPB183). Additionally 6-m thanesu1fonyl-
2' ,3' ,S'-tri-O -benzoyl-ß -D-ribofuranosylpurine reacted smoothly with ethyl acetoacetate
and sodium hydride in THF to afford 6-ethoxycarbonylmethylpurine nucleoside. Similar
reactions occurred with carbanions derived from diethyl malonate, ethyl cyanoacetate,
malononitrile and nitromethane (80CPB150).
The methanesulfonyl derivatives are more usually produced by reaction of appropriate
methylthiopurines with chlorine in aqueous or aqueous alcoholic solution at low tern-
peratures, or with N -chlorosuccinimide in methanol-DMF (62CPB1075). Gentle oxidation
of methylthiopurines, e.g. 6-methylthiopurine, with restricted amounts of hydrogen peroxide
can lead to intermediate methylsulfinylpurines. Thus 2-methylthioadenine gave 6-amino-2-
methylsulfinylpurine (203) (63JOC2560).
NHz
N N
Mesol.JL >
N N
H
(203 )
4.09.6.17 Halogenopurines
Nucleophilic displacement of halogen atoms in the halogenopurines, especially the readily
available chloropurines, has provided the major route to a wide variety of substituted
purines including nucleosides (B-71MI40901). The reaction of chloropurines with nucleophiles
has been found to be second order and bimolecular (65JCS3017, 67JCS(B)954). The ease of
replacement of halogen atoms from the 2-, 6- and 8-positions varies according to the state
of N-substitution.' Thus with unsubstituted 2,6,8-trichloropurine replacement by
nucleophiles decreases in the order 6> 2 > 8 and also in the various rnonohalogenopurines
a similar sequence is imposed. Thus 2-chloropurine is less reactive towards amines than
6-chloropurine (57JA2185). However when the pyrimidine ring is alkylated, nucleophilic
displacement occurs in the decreasing order 8> 6 > 2 (63JOC1662). These differences in
reactivity between N -substituted and unsubstituted halogenopurines does not accord with
the order predicted for N -substituted and unsubstituted derivatives by the Fukui FMO
superde10calizability theory (B-74MI40901).
The results have been explained by the 'anion theory'. Thus in unsubstituted
chloropurines, anion (204) formation is possible with the negative charge located in the
imidazole ring so inhibiting attack at C-8 by a nucleophile (Scheme 45). No such anion is
possible when the ring is alkylated and attack then tends to occur at the most polarized
CI H CI
N N -H+ N0y
Cll.JL >CI CIl:..JL -,:)CI
N N N N
(204)
Scheme 45
562
Purines
carbon-halogen bond, generally C-8. However, apparent exceptions inchide 2,8-
dichloropurine which with bases produced displacement at C-8 rather than C-2 (63CJCI807).
It has been suggested (B-71MI40901, p. 153) that this rnay be due to partial fixation of the
C(4)-C(5) double bond, leading to an increased electron density at C-2, possibly as in
Scheme 46, involving a mesomeric chlorine atom.
H H
rN>Cl N>Cl
Cl N N Cl N N
Scheme 46
Conversion of the halogenopurines into protonated forms should lead to a reversal of
the substitution order and this is generally but not always the case. Thus reaction of
6,8-dichloropurine (58JA6671) or 2,6,8-trichloropurine (1897CB2220) with hot acid gave
6-chloro- and 2,6-dichloro-8-oxodihydropurines, respectively. These variations in reactivity
of the anionic and cationic forms of halogenopurines have frequently been used to direct
nucleophiles into specific positions in the purine ring. Acid treatment however rnay also
lead to rearrangements occurring.
The ease of replacernent of a halogen atorn at a particular position in the ring system
also varies, not unexpectedly, according to the degree and type of sub titution. Thus whereas
8-bromocaffeine, where no anion is possible, is rapidly hydrolyzed by aqueous alkali,
8-brornoxanthine which can form an anion is stable at 100 0 C (1898CB3272). Similarly,
N -alkylation increases reactivity towards ammonia and amines. Thus, whereas 6-
chloropurine requires a forcing high pressure reaction with ammonia to produce adenine
(54JA6073), 6-fluoro-9-methylpurine reacts with aqueous ammonia under relatively rnild
conditions (62JMC1067) to give 9-methyladenine, and similarly 9-substituted 2,6-
dichloropurines react readily with alcoholic ammonia to produce 9-substituted 2-
chloroadenines (63JMC471). However, N-substituted, especially N 1 -alkylpurines are prone
to undergo Oimroth rearrangements in alkaline solutions. In contrast, aminochloropurines
tend to be relatively inert towards nucleophiles. Thus 2-amino-6-chloropurine barely reacted
with hot O.lN sodium hydroxide (60JOCI573), presumably due to anion formation. On the
other hand, 2,6-dichloropurine reacted readily enough with aqueous arnmonia to produce
2,6-diaminopurine (58JOC125) and in this case apparently the base is not strong enough to
achieve significant anion formation. However amination of 2,6,8-trichloropurine required
aqueous ammonia at 100 0 C over 6 h to form 6-amino-2,8-dichloropurine (1897CB2226),
the extra halogen presumably deactivating the ring system substantially. Fluorine tends to be
more reactive than chlorine, as with 6-chloro-2-fluoropurine riboside which produced
2-amino-6-chloropurine riboside with ammonia at room temperature (66JOC325S).
Similar reactions of halogenopurines occur with prirnary and secondary arnines and large
numbers of cornpounds have been rnade in this way, including several naturally occurring
substances many of which are 6-alkylaminopurines including the plant cytokinin zeatin
(66JCS(C)921) (Section 4.09.8.2). For more information see (B-71MI40901).
Halogenopurines will also react with tertiary amines. Thus 2,6,8-trichloropurine with
pyridine in ethanol gave, after neutralization, the betaine (205) (60AG708), and similarly
7-rnethyl-2-chlorohypoxanthine gave the betaine (206). 6-Chloropurine and trirnethylamine
afforded a quaternary salt (B-68MI40901, p.39) and the corresponding 9-ß -D-riboside has
also been reported (63JOC945). Some reactions and rearrangements of these quaternary
derivatives have been recorded (B-71MI40902, p. 504).
o
N
' Cl
Cl ..J- :/
N N
(205)
o
X)5
N N N
o
(206)
Halogen atoms in the halogenopurines rnay be replaced by hydrogen, the ease of
replacernent generally being 6> 8 > 2. The preferred method is usually hydrogenolysis with
palladium catalysts in the presence of magnesium oxide, or use of hydriodic acid alone or
Purines
563
with phosphonium iodide, but many other reducing agents have been used. Use of 2 H2 or
3H 2 provides a useful route to 2H_ or 3 H - pu rines (71MI4090S), complementing hydrogen
exchange reactions which are norrnally restricted to C-8 (see Section 4.09.5.2.1).
Hydrogenolysis is especially useful in that in polyhalogenopurines it may be possible to
control the reaction so as to remove only one halogen. Thus hydrogenolysis of 6-amino-2,8-
dichloropurine can be adjusted to produce either 6-amino-2-chloropurine (61LA(649)114) or
adenine (S9AG524). Hydrogenolysis is also possible in alkaline solution which makes it an
especially useful technique for reactions involving the oxopurines which are generally
insoluble in water but soluble in alkaline solution. Thus hydrogenolysis of 2,8-dichloro-
hypoxanthine in alkaline solution over palladium may be controlled to produce either
2-chlorohypoxanthine (61LA(649)114) or hypoxanthine (63CI(L)953).
Replacement of halogen atorns by alkoxy groups may be hindered in N(7)- and N(9)-
unsubstituted purines because of anion formation although this has been overcome to some
extent by use of antimony chloride followed by the alcohol (71MI40904). Aryloxypurines
have similarly been prepared from halogenopurines and hot alkaline phenol solutions. Since
alkylation of oxopurines tends to lead almost exclusively to N -alkyl derivatives (see Section
4.09.5.2.2(iv)), direct replacement of halogen atoms assumes special importance as a route
to the alkoxypurine derivatives.
Similarly, replacement of halogens by alkylthio or arylthio groups may be achieved using
appropriate metal sulfides in aqueous or alcoholic solution, generally under mild conditions.
This provides a useful route to those compounds which are, however, unlike their oxo
analogues, also available by alkylation (and occasionally arylation) of thioxopurines (Section
4.09.5.2.2(viii)). The biological activity of compounds such as 6-mercaptopurine and
azathiopurine (Section 4.09.8.4) has ensured that large numbers of thioxopurines and
derivatives have been prepared.
Replacement of halogens by thiol groups rnay also be achieved using alkali metal
hydrosulfides, thioacetates (64JOC3209), thiourea (54JA6073) or thioacetamide (65JMC667) in
ethanol solution. In these last reactions, intermediate thiouronium salts are formed which
readily hydrolyze or alcoholyze to the thioxopurine. Corresponding selenium derivatives
have been similarly prepared (7IJHC379).
In these last reaction types, selective replacement of halogens may be possible as with
2,8-dichloropurine where only the 8-chloro group is replaced to produce 2-chloro-8-thioxo-
7,8-dihydropurine (207), whereas with 6,8-dichloropurine thiourea may be used to furnish
either the 8-chloro-6-thioxo derivative (208) or the 6,8-dithioxopurine (209) according to
the amount of thiourea used (S8JA6671, S9JOC320).
H :r SH :r SH
N :C N >= HN N > HN I N >=S
I ' N I N h Cl I, N
Cl INS
N H N H
(207) (208) (209)
The halogenopurines react with many other nucleophiles including hydrazines, hydrox-
ylamine and alkoxyamines, sulfonic acids and thiocyanates, and compounds with active
methylene groups such as diethyl rnalonate furnish appropriate purine derivatives which
offer valuable routes to alkyl and substituted alkyl derivatives. Also aryl groups have been
substituted for halogen using aryllithiums (63N224).
Table 37 gives details of sorne of these miscellaneous reactions.
Displacement of chlorine atoms in selected chloropurines by other halogens, especially
fluorine and iodine, has been of value in the preparation of these derivatives. In particular
6-chloropurine and trimethylamine followed by potassiurn hydrogen fluoride produced
6-fluoropurine (69CC381), and several fluoropurines have been made by heating the corre-
sponding chloropurine with silver fluoride in high boiling solvents such as toluene or (for
2-chloropurines) xylene (63JOC2310). Relatively few iodopurines have been prepared and
then mostly by displacement of chlorine. Thus 6-chloropurine and hydriodic acid (47%) at
o oC gave 6-iodopurine (S6JA3S08). The C-2 chlorine in 2,6- and 2,8-dichloropurine is
resistant to reaction, however, and with hydriodic acid, 2-chloro-6-iodo- and 2-chloro-
8-iodo-purine (63CJC1807) respectively, were formed. In an analogous fashion, 2,6,8-
trichloropurine produced 2-chloro-6,8-diiodopurine (61LA(649)114). However when
phosphoniurn iodide was used in conjunction with hydriodic acid, 2,6,8-trichloropurine
underwent partial reduction with formation of 2,6-diiodopurine (S7Z0B1712).
564 Purines
Purine
Table 37 Miscellaneous Reactions of Some Halogcnopurines
2-CI
2-CI-6,NH 2
2-CI-6-oxo
6-CI
6-CI-7-Me
6-CI-9-Me
2,6-C1 2
2,6-Cl 2
6-CI
6-CI-9-Me
6-CI-2-F
6-CI
2-CI-hypoxanthine
2,6-CI 2
2,6,8-CI. 1
8-Br-adenosine
6-Cl
2-NH 2 -6-CI
6-Cl
8-Br-caffeine
6-Cl
6-CI-9-Me
2-Cl
2-CI-7-Me
6-CI
Product (purine)
2-NHNH 2
2-NHNH 2 -6-NH z
2-NHNH z -6-oxo
6-NHNH z
6-NHNH z -7-Me
6-NHNH z -9-Me
2-CI-6-NHNH z
2,6-(NHNH z h
6-NHOH
6-NHOH-9-Me
2,6-(NHOHh
6-NHOMe
2-N 1 -hypoxanthine
2,6-(N 3 h
2,6,8-(N 3 h
8-N,,-adenosine
6-S0 3 H
2-NH z -6-S0 3 H
6-SCN
8-CH(CO z Et)z-caffeine
6-CH(CO z Eth
6-CH(CO z Eth-9-Me
2-CH(CO z Et)z
2,7- Me z
6-Ph
Conditions
NHzNHz
NHzNHz
NHzNHz (91%)
NHzNHz (80%)
NHzNHz
NHzNHz
NHzNHz, room temp.
NHzNHz (80%)
NHzOH
NHzOH
NHzOH
NHzOMe
NaN 3
NaN 3
NaN 3
NaN 3 <75%)
Na Z S03 (3%)
Na Z S03
KCNS
NaCH(COzEt)z
NaCH(COzEt)z
NaCH(COzEth
NaCH(COzEth
MeMgI
PhLi
Ref.
57JA2185
57JA2185
57JA2185
57JA2185
57JA6401
57JA490
57JA2185
57JA2185
58JA3932
57JA490
68JMC52
66MI40901
66JOC221O
66JOC221O
64MI40901
65JA1772
6lJOC3401
6lJOC3401
59JA1898
35MI40900
63N224
63Z0B3342
64Z0B3254
49JAP49177355
63N224
4.09.6.18.1 Introduction
4.09.6.18 Purines with a Fused Heterocyclic Ring System
Many examples of compounds in which a heterocyclic ring is fused to a purine have been
recorded. These include the various types of cyclonudeosides such as (210). However in
this chapter a discussion of these compounds is not practical and for further details the
reader should consult works devoted to nucleoside chemistry. Appropriate references are
collected in Table 2.
o
/O,<-f'NH
H'C'("jNJlN)NH'
HO OH
(210)
The fused heterocyclic rings to be discussed here have normally been produced by an
intrarnolecular cyclization of an N(6)-, N(2)- or S-substituent onto a ring nitrogen atom
in the purine nucleus and are mainly five- or six-membered systerns; cyclonucleosides such
as (210) are of course notable exceptions and a few miscellaneous examples exist.
4.09.6.18.2 Five-membered fused rings
The imidazopurine (211) or 1,N 6 -ethenoadenine, obtained by cyclization of N 6 -formyl-
methyladenine (212), rapidly produced the bisimidazole (213) when heated for a short time
at 100 oC with hydrochloric acid (Scheme 47) (70JCS(C)2206). Analogous alkyl-substituted
adenines and adenosines have also been prepared and similarly were found to produce
bisimidazoles by acid treatment (80JA770). The corresponding dihydroimidazopurines (214)
have also been prepared (62JOC973).
The triazolopurine (215) is more resistant to ring opening but with strong hydrochloric
acid over 70 hours it produced the imidazolyltriazole (216) (6IJOC3446). The triazolopurine
(215) also isomerized to (217) when heated in formamide (Scheme 48) (65JOC3601). A
Purines
565
HNCH 2 CHO ( NH Ç-N
:I N :x \ 2
N N N__N N
I ) lOO'C I H \\
N N " N / H 2 N?
H N N
(212) (211) (213)
C NH
N N
. /
N N
(214)
Scheme 47
similar isomerization appears to occur with tetrazolopurines (218) and (219). These are
formed in equilibriulp both in the solid state or in solution with 2-azidopurine (220), and
the latter azido form is favoured in acid solution, the tetrazolopurines being favored in
neutral solution (Scheme 49) (66JOC93S).
ij
N, N HCONH 2
N _ .Jl N > ( 180'C
N H
(217)
N-NH
:x H2N N
N N r - )
,,) 'N)/"
N N H
(215) (216)
Scheme 48
H H H
N--rN-N N N N N
< A..AN N N ..JL- > < ..., I
N N 3 N N N N-"'\N
\ /
N':::-N
(218) (220) (219)
Scheme 49
The oxoimidazopurine (221), prepared from N 6 -chloroacetylpurine (222), has also been
implicated as an intermediate in the hydrolysis of N 6 -glycylpurine (223). With hot water
the imidazo derivative rapidly hydrolyzed to the carboxymethyladenine (224) via the
intermediate (225) (6682082) and a Dimroth rearrangement (Scheme 50).
NHCOCH 2 NH 2
t N)
N N
H
(223)
COCH 2 Cl
:j: NH H
N::'" N
I >
N N
(222)
o
(NH
N N
,/' ..À)
N N
(221)
:r NH N jc NHCH C02H
H0 2 CCH 2 N I ) -- N I )
N N
N H N H
(225)
(224)
Scheme 50
A somewhat different imidazopurine occurs in the naturally occurring nucleoside wyosinè
(226) which is a highly fluorescent compound found in the next position to the 3'-end of
the anticodon of yeast tRNA Phe and is very readily and characteristically (of 3-alkyl-
guanosines) hydrolyzed to the aglycone (78TL2S79) (see Section 4.09.8.3). Similar com-
pounds, namely wybutosine (227) and wybutoxosine (228) have been found in rat liver and
Lupinus luteus, respectively.
R SLN
Meet: JL:
N N N
Me I C- . -:bSH20H
r>/
o
(226) R=H
C0 2 Me
I
(227) R = CH 2 CH 2 CHNHC0 2 Me
(228) R = CH 2 CHCHNHC0 2 Me
I I
H0 2 C CO 2 Me
566
Purines
Several thiazolopurines have been prepared (Section 4.09.5.2.2(viii)) by simple cycIization
of thioxopurines. Such compounds, by dethiation, have proved to be a useful route to
alkylpurines. Thus 1-, 3-, 7- and 9-ethylpurines, respectively, are produced from the
thiazolopurines (229), (230), (231) and (232) by reaction with Raney nickel (Scherne 51)
(61JOC3446). Compound (229) also reacted readily with hydrogen sulfide to give the
thioxopurine (233). When the ring proton is substituted the thiazolopurines tend to exist
as quaternary forms, e.g. (234) (62JOC195). The unusual thiazolopurines (235) and (236)
are produced in 13% and 18% yields, respectively, from the corresponding 6-chloropurine
and thiourea (the 6-thioxo-1,6-dihydropurine is the main product) and when heated in acid
or alkaline solution they rearrange to produce the 8-amino-6-thioxo-l,6-dihydropurines
(237) and (238), respectively (Scheme 52) (66JOC1417).
C :\ S N J: N
N EtN
,,/ ,,/
N N N N
(229)
N)
S)lN N
U
(230)
Ni/H,
---+
N N
l )
N N
Et
Et
NrN\..,...-S Nr N \
__)l )l
N N N N
(231)
N:): N . :J: N
I }-S N I >
N I N
N \..---' N Et
(232)
Scheme 51
S
HSCH2CH2N N)
LN
N H
(233)
Ç N
NJlN)
(234) CH 2 Ph
NH 2
S--T-NH2 S
.l XN N > --+ H R QN)NH 2
N N N
H
(235) R = H (237) R = H
(236) R = Et (238) R = Et
Scheme 52
4.09.6.18.3 Six-membered fused rings
The pyrimidopurine (239), prepared from N 6 -isopentenyladenine (see Section
4.09.5.2.2(iii)) and TF A or fluoboric acid, rearranged when heated at 85 oC for 36 hours to
produce the isomeric pyrimidopurine (240; Scheme 53) (68JCS(C)1731). Recently methyl
7 -oxo-7 H -pyrido[2, 1-i]purine-9-carboxylate has been prepared (80RTC20) in addition
to a series of 7,8-purine derivatives with ring sizes up to seven atoms (79LA1872) and
purine[9,8-a ]quinolines and sorne related sulfur derivatives (70MI40903).
Me
Me2C=CHCH2NH H Me
:): N H :t N+
N I > N I ) heat þ
N N
N H N H
(239)
Scheme 53
X;e
NCxNS
N N
(240) H
Purines
567
Triazinopurines have also been prepared including (241) and (242) (53CR(236)2519,
56BSF888).
R
o
:]: N N
MeN I >- H
O N N
Me
(241) R = Me
(242) R = Ph
4.09.6.19 Benzopurines'
An interesting series of so-called stretched purines has been prepared in which a benzene
ring is interpolated between the imidazole and pyrimidine moieties of various purines. This
leads to three isomeric structures which have been narned Un- benzoadenine (243a), prox-
benzoadenine (244a) and dist- benzoadenine (245a) (75JOC356, 75JOC363),
:ú H2 N R
N r "':::
I
N
NH 2
N N)
.. N
N R
(243a) R = H
(243b) R = ß -D-ribofuranosyI
(244)
N :)0 NH 2 "':::
I I
N N
RN-Ý'
(245)
Corresponding ribofuranosyl derivatives (243b-245b) have also been prepared by stan-
dard methods (76JA3987) and these converted into 5 ' -phosphates. The Un- benzoadenosine
was found to hydrolyze to Un- benzoinosine in the presence of adenosine deaminase at a
rate comparable to that of the adenosine to inosine conversion. However Un- benzoadenine
unexpectedly was also converted by the same enzyme into Un- hypoxanthine but the prox
and dist isomers were refractory. Similarly Un- benzohypoxanthine with xanthine oxidase
produced Un -benzoxanthine, and Un- uric acid and Un- benzoinosine gave Un- xanthosine
with this enzyrne, the prox and dist isomers being less active in this system. A recent
publication (79JA1564) discusses some 'inter- and intra-molecular reactions of the Un-
benzoadenine ribonucleotides and should be consulted for a more detailed reference list
of earlier work.
4.09.7 SYNTHESIS
4.09.7.1 Introduction
Methods for the synthesis of purines rnay be conveniently separated into three groups.
(1) Synthesis from acyclic precursors: These normally consist of one step reactions although
they are often known to proceed via interrnediate imidazoles or pyrimidines. This group
also includes the so-called abiotic or abiogenic syntheses but the distinction of these frorn
the first type is blurred and to a large extent based on philosophical grounds. Perhaps the
main criteria for an abiotic synthesis is that it proceeds from the simplest molecules and
perhaps more importantly that it should occur under reaction conditions which might
reasonably have been expected to have existed on the primeval earth near the time of
emergence of organic molecules and living systems. Abiotic syntheses have provided a basis
for the so-called chemical evolutionary theories which have been used to account for the
first formation of life on earth from non-living precursors (B-73MI40900). (2) Synthesis from
pyrimidines by completion of an imidazole ring. (3) Synthesis from imidazoles by completion
of a pyrimidine ring.
4.09.7.2 Synthesis from Acyclic Precursors
There are relatively few examples of one-step syntheses of purines from acyclic precursors
and most of them in any case probably involve intermediate imidazoles or pyrimidines
568
Purines
which, however, have not necessarily been isolated in such reactions or their forrnation
confirmed.
Perhaps the earliest recorded example is the formation of uric acid by heating glycine
(1882M(3)796) or later by heating together tricWorolactic acid arnide and urea (Scheme 54)
(1887M(8)201,2SLA(441)21S).
CI 3 CCH(OH)CONH 2 urea þ uric acid
Scheme 54
Purine has also been obtained by heating formamide alone (ncPB623) and detected in
reactions involving hot formamide (77CPBl923). Interpretation of mechanisms of reactions
carried out in formamide solution must clearly be made with care. However the distribution
of 13C and IsN labels in purine derived from [ l3 C, IsN]HCN and formamide has suggested
the mechanism outlined (Scheme 55) (78TL4039).
2HCONH 2 NH 2 CH(OH)NHCHO NH 2 CH=NCHO
l ZH \3 C I5 N
J: *N
N I
/ -2NH,
N * N
H
:X; 7l2 J
. / NH2
NH 2
Scheme 5S
H OH *
N * NH
* NH
N *
H
Purine has also been produced in 40% yield by heating mixtures of N-cyanomethyl-
phthalirnide with either trisformamidomethane or formamidine acetate in formamide or
n-butanol (Scheme 56) (61AG163).
o
HC(NHCHO), + NCCH'N pwi" <-""'- HCONH,
o
Scheme S6
Several useful preparations of purine derivatives have been recorded from
cyanoacetamide and malononitrile derivatives. Thus hypoxanthine was obtained by heating
formamidomalonamidinecarboxamide with formamide (Scheme 57) (SOJBC(18S)439). In a
sirnilar rnanner a 75% yield of hypoxanthine was produced by heating ethyl
acetamidocyanoacetate, ethanolic ammonia, ammonium acetate and triethyl orthoforrnate
(S9TL9), and in like manner phenylazocyanoacetylurea gave xanthine and guanine whereas
the N'-methylurea produced 3-methylxanthine (76CPB1331).
HN O :S o N
OHC/ NH2 HN I
h N
HN NH 2 N H
Scheme 57
Analogous reactions of aminomalonamidinecarboxamide with ortho esters in DMF or
acetonitrile slowly afforded various 2,8-dialkylpurines (Scheme 58). Thus heating together
triethyl orthoformate and aminomalonamidinecarboxamide gave hypoxanthine after 5
minutes whereas triethyl orthoacetate required 10 hours to produce reasonable amounts
of 2,8-dimethylhypoxanthine, and triethyl orthopropionate 60 hours to give 2,8-diethylhy-
poxanthine (60JA3144). In a similar manner aminomalondiamidine and ortho esters furnished
H 2 NJ N
A. _. NH 2 RCiOEt\ HRN _ _ R
H 2 N NH N
Scheme 58
NH 2
H N t NH2 N
2 '<:NH ROOEt\ N R
H N "'NH R .)l.N
2 H
Scheme S9
Purines
569
2,8-dialkyladenines (Scheme 59). Purine syntheses from aminomalonamidine derivatives
appear to proceed by prior formation of an arninoimidazole followed by cyclization with a
second molecule, of ortho ester.
In constrast, high pressure hydrogenation of hydroxyiminomalononitrile or related aryl-
azomalononitriles, arnides or esters, using palladium or nickel catalysts in the presence of
ammonia and formamide, afforded purine derivatives including adenine, but in this case
intermediate nitrosopyrimidines are first produced (75CPB2401, 76CPB1331) where cyclization
has preceded reduction (Scheme 60). Guanidine carbonate, potassium hydroxy-
iminomalononitrile and sodium dithionite in formamide also afforded 2,6-diaminopurine
(246) in good yield (57JA1518), the reaction again proceeding through an intermediate
nitrosopyrimidine (Scheme 61). The use of arylamidines in this reaction has led to syntheses
of 2-phenyl- and 2-ß-pyridyl-adenines (59JA2442).
NH
NO NH2 NH 2
H 2 N HCONH" N ! NO ---. N I NH2
N H, . .)NH 2 . .)NH 2
H 2 N H N N
Scheme 60
N
tJ-
N N
H
NH 2
H 2 N NC N.,S,O. N N
)=NH + )=NOK HCONH,' H N .)1.. /
H 2 N NC 2 N
H
(246)
Scheme 61
Many of the so-called abiotic or abiogenic syntheses of purines have had as a basis,
pioneer experiments (53MI40902, 55JA2351) derived from theories which required the primeval
earth to have a reducing (hydrogen containing) atmosphere (B-52MI40900, B-53MI40900). In
these experiments mixtures of hydrogen, methane, ammonia and water vapour were subjec-
ted to a continuous spark discharge for several days. Many types of organic compounds,
especially amino acids, are produced but originally no purines were detected. However
later (63PNA(49)737) a 0.01 % yield of adenine was obtained by irradiation of gaseous mixtures
of the above type with a 4.5 MeV electron beam, and purines were also produced when
similar mixtures were exposed to a high frequency electric discharge (75CR(C)685). Adenine
had also been detected at an earlier date (60BBR(2)207) in heated, concentrated solutions
of ammonium cyanide. It was accornpanied by hypoxanthine (but no guanine) and at least
fifty other UV absorbing substances (63MI40905). When 0.1 % solutions of ammonium cyanide
were heated for 1 day at 90 0 C or 70 oC for 25 days, 0.1 % yields of adenine could be
obtained (61MI40900). In these experiments 5-aminoimidazole precursors such as the 4-
carbonitrile and 4-carboxamide were isolated in addition to formamidine (62MI40905) and
on the basis of these observations the route to adenine outlined in Scheme 62.was proposed.
(a) NH 3 + HCN H1NCH=NH
HCN NH H,NCH=NH
(b) 2HCN NH=CHCN - H1NCH(CN}z H1NCH[C(:NH)NH1Jl )
H
H N [ N
H cl )
1 II N
NH
H,NCH=NH,
(NyNH
N )
NH,
Scheme 62
In addition to adenine, guanine was also produced in yields of 1 % and 0.5%, respectively,
by UV radiation of dilute aqueous solutions of hydrogen cyanide over 7 days at room
temperature (B-65MI40901) and a biradical scheme has been proposed for this reaction
(Scheme 63) (62PNA(48)1300). When liquid ammonia was heated with liquid hydrogen cyanide
at 120 0 C in an autoclave over 20 hours, a 10-15% yield of adenine was obtained
(66JAP66101l4) by extraction of the residual solid with water.
An interrnediate in this reaction-.:using anhydrous hydrogen cyanide and ammonia was
diaminomaleonitrile (67MI40901) and the same compound was also obtained from
aminomalononitrile and hydrogen cyanide (66JA3829). UV radiation of the maleonitrile
570
Purines
.N
II -.
HC 'C
'::::-Ñ .....NH 2
< J '
N NH 2
H
N J CN
N NH 2
H
N J CN N J CN
< I NHCH=NH -. <N I N=CHNH 2 -.
H
N
toy>
N
NH 2
Adenine
Scheme 63
induced an isomerization via the trans-nitrile to give 5-aminoimidazole-4-carbonitrile in
80% yield (66JAI074, 69MI40904). The arninoimidazolenitrile with arnmonium cyanide solu-
tions further reacted at 30-100 o C to produce adenine, and extrapolation of the results to
- 20 oC allowed the authors to propose that molar solutions of adenine and similar heterocyc-
lic compounds could have been formed after 10 6 years in a prirnevallake which alternately
thawed in summer and froze in winter. In addition the aminoimidazole rut rile was readily
hydrolyzed to the corresponding carboxamide which with cyanogen or cyanate at 100 0 C
gave up to 20% yield of guanine (Scheme 64). If acetamide is used in place of hydrogen
cyanide then 2-methyl-, 8-rnethyl- and 2,8-dimethyl-adenines are produced, and liquid
rnethylarnine and hydrogen cyanide similarly furnished 7- and 9-methyl-6-rnethyl-
aminopurines (68JOC642).
HCN HCN
HCN -- HN=CHCN -- H 2 NCH(CNh
,Õi0.,. HN CHNH, \
N J CN +-
N NH 2
H
HN I : +- H 2 N 1 CN +- H 2 N 1 CN
HN P 2 NC NH 2 H 2 N CN
N
II
N J( CNH 2
I
N NH
oy H 2
o
N II
/I ] CNH 2 ICN),orHCNO
\ IOO'C
N NH 2
H
r :x N NH
N I >
::,-.. N
NH 2
o
HN NH
H N J-. >
2 N N
Scheme 64
4.09.7.3 Synthesis from Diaminopyrimidines
4.09.7.3.1 Introduction
The most widely used route to purines has undoubtedly involved the addition of an
imidazole ring to an appropriate pyrimidine. This particular route has probably dominated
the early literature because of the relative ease of synthesis of the requisite pyrimidines
cornpared with the lack, until recently, of useful routes to imidazole precursors. The synthesis
of pyrimidines has been exhaustively reviewed (62HC(16)l) and full details have been provided
of the synthesis of the specfic pyrimidines used in purine synthesis. The pyrimidine moiety
Purines
571
in such syntheses will of course include substituents in what will become the 1-, 2-, 3- and
6-positions in the resulting purine and the added imidazole ring will incorporate C(8)-
substituents whereas substitution at N-7 or N-9 could come from either moiety, but usually
from the pyrimidine, according to the precise intermediates used (Scheme 65).
6
Ncr+
N
7 6 H
N + >8 __ ;YN>8
N 3 J-- N 9
9 N
Scheme 65
It is therefore convenient to consider and classify variation in C-8 and N-7 or N-9
substitution in a synthesized purine resulting from different cyclization procedures when
applied to a given pyrimidine.
4.09.7.3.2 C(8)-Unsubstituted purines
The simplest example of the synthesis of a C(8)-unsubstituted purine frorn a pyrirnidine
is illustrated by the first general application, namely the formation of gu&nine by heating
6-oxo-2,4,5-triamino-1,6-dihydropyrimidine with formic acid (Scheme 66) (OOCB1371). This
and related reactions, frequently called Traube syntheses, proceed by forrnation of inter-
rnediate N-acyl or N-formyl derivatives (247) which can usually be isolated and cyclized
in other ways, e.g. by fusion or warming with aqueous alkali. The intermediate N-formyl
derivatives may be produced more readily by the use of formic-acetic anhydride, as in the
formylation of 4,5-diamino-2-methoxypyrirnidine (248) which is reluctant to react with
forrnic acid alone (Scheme 67) (S4JCS2060). That the site of acylation is usually at position
5 in the pyrimidine as in (247), can be shown by comparison with a known 5-
acylaminopyrimidine rnade by an unambiguous synthesis (48JCSllS7), or alternatively, by
reduction with lithium aluminum hydride to the alkylaminopyrirnidine, cyclization of which,
with formic acid, then produces a known 7-alkylpurine (Scheme 68) (S4MI40900).
o
HN NH2 HCO,H,
H2N JNH 2
N
o
HN NHCHO
H2N JNH2
N
(247)
Scheme 66
HN
-- H2N NJLN'>
:) :): N
N I NH 2 HCOOAc, N I )
MeO NH 2 MeO N
N N H
(248)
Scheme 67
N NH2
_ _)NHCOR
N
N NH2 N N)
_)NH J--N
N CH 2 R N CH 2 R
Scheme 68
The ease of cyclization of the 4-amino-5-formamidopyrimidines has been associated with
their acidity. Thus the weakly acidic methylated pyrimidine derivative (249) cyclized to
caffeine spontaneously (Scheme 69) (OOCB1371, OOCB303S), whereas the much more strongly
:] 0 Me :]: 0
HN I NCHO HN I >
O N NH 2 O N N
H H
(250)
:j o Me :x o e
MeN I NCHO MeN I >
O N NH 2 O N N
Me Me
(249)
Scheme 69
Scheme 70
572
Purines
acidic 4-amino-5-formamido-2,6-dioxo-1,6-dihydropyrimidine (250) was only converted
into xanthine by heating the sodium salt to 220 oc (Scheme 70).
In early preparations, forrnamide was commonly used as a solvent with formic acid, but
later it was shown that formamide alone is a useful formylating agent superior to forrnic
acid and its effectiveness is improved by the presence of an acid catalyst. It tends to give
better yields than formic acid as in a synthesis of adenine (92%) (62Z0B16SS) cornpared
with a 62% yield using formic acid. However, hot formamide tends to decompose slightly
to produce, arnong other things, ammonia (and to some extent adenine - see Section
4.09.7.2) and this restricts its use to pyrimidines with non-reactive substituents. Formamide,
like forrnic acid, with 4,5,6-triarninopyrimidines produces largely (75%) the 9-substituted
purine accompanied by some of the N 6 -substituted purine derivative (S8JCS4107). However,
the high ternperature normally associated with reactions in boiling formamide (160-180 oc)
may suffice to cause side reactions and also to displace any acyl groups which may be
attached to the aminopyrimidines. Thus the acetyl derivative (251) and formamide gave
xanthine (Scheme 71), not 8-methylxanthine as might have been expected
(SIJA4609,S8JOC2010), whilst 2,4,6-triamino-5-(p-chlorobenzamido)pyrimidine and for-
marnide gave a mixture of 2,6-diaminopurine and the 8-p-chlorophenyl derivative
(SIJAS23S).
o 0 H
HN NH.COMe HN N>
O N)NH2 O NJlN
H H
(251)
Scheme 71
Thioxopurines rnay similarly be produced by cyclization of appropriate thioxopyrimidines.
Thus 4,5-diamino-2-(or 6-)thioxodihydropyrimidines and formic acid gave 2-thioxo-2,3-
dihydropurine (S4JCS2060) and 6-thioxo-1,6-dihydropurine (S2JA411), respectively. However,
in the latter case especially, an alternative ring closure to produce a thiazolopyrimidine
(252) can also occur (see Section 4.09.6.1.8) (S6JA28S8) but this is less likely using formarnide
if only because intermediate thiazolopyrimidines rearrange to the corresponding
thioxopurines in the hot solvent (Scheme 72). Thioxopurine formation is improved by the
use of high pH and low temperatures. An alternative route to 6-thioxopurines which avoids
thiazolopyrimidine formation involves treatment of an aminooxoformamidopyrimidine with
phosphorus pentasulfide in a hot base such as pyrimidine. In this way thioguanine is produced
from 2,4-diarnino-5-formamido-6-oxo-1,6-dihydropyrimidine (60J A2633).
S S S
HN NH'CHO __ NJYN HN >
H2N .)NH 2 H2N J .Jl N
N N N
(252)
Scheme 72
The use of formic acid, as with formamide, as a cyclizing agent may be unsatisfactory
when the pyrimidine contains labile, easily hydrolyzed, or acid sensitive groups such as
halogens or sugars. Thus 4,5-diamino-6-chloropyrimidine with formic acid furnished
hypoxanthine (S4JA6073), and a 2-methylthiopyrimidine and formamide ultimately gave the
2-aminopurine derivative (62JOC2478). In such cases 1-carbon transfer agents have been
developed which will react with diaminopyrirnidines under milder conditions than forrnic
acid or forrnamide. These include dithioformic acid which was introduced during early
investigations into the synthesis of purine nucleosides. Thioforrnarnidopyrimidines are
produced in aqueous solution with this reagent and may be cyclized by heating in solvents
such as pyridine (43JCS383), as in the formation of 2-methyladenine (Scherne 73). The
method has also been used to prepare 9-g1ycosylpurines although, if aqueous or alcoholic
bases are used for the final cyclization step, the glycosyl derivative is always in the pyranose
form even if the original (blocked usually by acylation) sugar was in the furanose form.
However, 9-g1ycofuranosylpurines have been obtained in these reactions by heating the
intermediate N-glycosyl-N-formamidopyrimidine in an aprotic solvent such as acetonitrile
Purines
573
with added potassium acetate (46JCS852). However in the case of adenine precursors,
mixtures of 9- and N 6 -glycosyl derivatives may be obtained (4SJCS556). The various problems
associated with these nucleoside preparations, however, make them of little value today.
NH 2
N NHCHS N N
Me _)NH2 ----+ Me )l )
N N N
H
Scheme 73
Other cyclizing agents include the Vilsmeier-Haack reagent prepared from DMF and
phosphoryl chloride (27CB119) which permits the forrnylation and cyclization of 4,5-
diaminopyrimidines to be carried out at low temperatures (61JCSS048) and is especially
valuable for the preparation of chloropurines from chloropyrimidines. A modified
Vilsmeier-Haack procedure which involves cyclization of an intermediate azomethine (253)
at low temperatures in situ has also been applied to chloropurine synthesis (61JCSS048).
R 2
N N=CHNMe2
R 1 _)N=CHNMe 2
N
(253)
Triethyl orthoformate has proved to be a useful cyc1izing agent, especially when rnixed
with acetic anhydride which produces diethoxymethyl acetate (S6JA1928,56JOCS99,
B-78MI40903, p. 99S).
Whereas triethyl orthoformate will convert 4,5-diamino-2,6-dichloropyrimidine into 2,6-
dichloropurine (Scheme 74), many other 4,5-diaminopyrimidines including 4,5-
diaminopyrirnidine and 2- and 6-chloro-4,5-diaminopyrimidines fail to cyclize and instead
produce intermediate ethoxymethylene derivatives (Scheme 75) (60JOC39S).
CI CI CI Cl
N NH2 CH(OEt)3, N N> N NH2 CH(OEt h , N N=CHOEt
Cl _ _)NH 2 CI )lNH _)NH 2 )NH 2
N N N N
Scheme 74
Scheme 75
Diethoxymethyl acetate, on the other hand, permits r ady synthesis of chloropurines
under mild conditions and even 6-fluoropurines, although not 6-fluoropurine itself, have
been prepared by this method (62JMC1067). The reagent will also convert 4,5-
diaminopyrimidine into purine (60JOC39S). The method however is not readily adapted to
nucleoside synthesis since under the reaction conditions the sugar is usually lost. However
a l-(ß-D-ribofuranosyl)-substituted purine has been obtained using this reagent (61JOCS26).
4.09.7.3.3 C(S)-Suhstituted purines
(i) 8-Alkylpurines
8-Alkylpurines may in general be prepared by methods which closely parallel those used
for the unsubstituted derivatives although closure of the imidazole ring is more difficult to
achieve, and prolonged heating in acid solution is necessary. Normally, however, the
intermediate N-acyl derivative may be isolated and cyclized using aqueous alkali, fusion,
or similar heat treatment. Thus acetic acid and several hornologues with 4,5-diamino-1,3-
dimethylpyrirnidine gave intermediate 5-acylamidopyrimidines which could then be cyc1ized
to 8-alkyltheophylline derivatives (Scherne 76) (S3JA114). Use of hydroxy acids in these
o 0
MeN 1 NH2 i',RC02 , MeN 1 N R
nJNH II,OH 1/
o N 2 0 N N
Me Me
(254)
Scheme 76
574
Purines
reactions is also possible; thus lactic acid produced 8-a-hydroxyethylpurine (254; R =
CHOHMe) (S6AP4S3).
Alkanoic acid anhydrides and to a lesser extent acid chlorides have also been used and
interrnediate 9-acyl derivatives are then rnore readily produced. Using basic pyrirnidines
such as those which lead to adenines or alkylated purines, direct cyclization rnay be achieved
under these conditions. Thus acetic anhydride and 4,5-diarnino-1,3-dirnethyl-6-oxo-1 ,2,3,6-
tetrahydropyrirnidine alone produced 2,3,8-trirnethylxanthine (23LA(432)266) but the yield
is irnproved in the presence of pyridine (S3CB333). The interrnediate N-acetyl derivative
(255), however, when fused produced the betaine (256; Scherne 77) (S9CBS66).
Trifluoroacetic acid or anhydride have similarly been used to prepare 8-trifluoromethyl-
purines including 8-trifluorornethylpurine itself (S8JAS744) and 8-trifluorornethylguanine
(nCB1497).
o Me :): õ e
HN I NCOMe N r I .
I I +;Me
O N NHMe O N N
H H Me
(255) (256)
Scheme 77
With thioxopurines, thiazolopyrirnidines are usually obtained. Thus 4,5-diarnino-6-
thioxo-l ,6-dihydropyrirnidine with acetic anhydride rnainly afforded the thiazolopyrirnidine
(257; Scherne 78) (S9JA193) which unlike the unsubstituted derivative was stable to alkali
treatrnent and hence failed to produce the 6-thioxopurine by this route. However 5-
acetylamino-6-arninopyrirnidine-2-thione with phosphorus pentasulfide in pyridine gave
a rnixture of 6-oxo-2-thioxo- and 2,6-dithioxo-purines (Scherne 79).
Me
S S
HN/)NH 2 Ac,O, N N
JNH 2 J
N N
(257)
o O(S)
HN I NH.Ac HN I N
. .)NH pyridine Jl /Mc
S N 2 S N N
H H
Scheme 78
Scheme 79
Acid chlorides have proved to be rnainly of value for the preparation of di(purin-8-
yl)alkanes. Thus succinyl chloride with 4,5 -diarnino-6-oxo-l ,6-dihydropyrirnidine furnished
a diarnide which after cycIization gave a bispurine (Scheme 80) (61JOC1914).
[ 0 1
CH,COCI N
tH,COC! HN :X
' I /CH 2
<.:::::- N
N H 2
o
HN NH2
. J NH 2
N
Scheme 80
Ortho esters have also been used to prepare 8-alkylpurines, especially triethyl orthoace-
tate or orthopropionate (60JOC39S), but frequently, as with 4,5-diamino-6-chloropyrimidine,
only the interrnediate alkoxyalkylene pyrirnidine derivatives are obtained. These require
further treatrnent to produce the 8-alkyl-6-chloropurine (Scherne 81).
CI CI
N NH2 N N=c(OEt)R
)NH 2 .)N=c(OEt)R
N N
Scheme 81
Acid arnides have occasionally, like forrnarnide, been used to produce 8-substituted
purines. Acetarnide and 2,4,5-triamino-6-oxo-1,6-dihydropyrimidine afforded 8-methyl-
guanine (60JA2633) and 8-rnethyl- or ethyl-xanthines resulted frorn acetarnide or propion-
arnide and 4,5-diarnino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine (53CB333). Diamides such
Purines
575
as rnalonamide and succinamide similarly afforded bistheophylline derivatives (258; n = 1
or 2), respectively, when heated with the appropriate diarninopyrimidine.
l M1 + (CH1)"
o N N
Me 2
(258)
Acetamidine sirnilarly has been used to prepare 8-rnethylpurines, usually by fusing the
hydrochloride with the diarninopyrirnidine in the presence of sodiurn acetate (6IJCS4468).
The rnethod has also been used for making 8-rnethylthiopurines and 7-alkyl-8-rnethyl-
purines (67CB2280). A few 8-methylpurines have been prepared using an aldehyde, especially
as the bisulfite adduct, and an appropriate oxidizing agent (6SJHC4S3). Thus the
dioxopyrirnidine (259) and the adduct of ethanal with sodiurn hydrogen sulfite gave 1,3,8-
trimethylxanthine (260) under mild conditions (Scheme 82). In this exarnple the dihy-
dropurine interrnediate (261) is assurned to be oxidized by the hydrogen sulfite anion.
Acetylacetone and (259) sirnilarly gave the 8-methyl derivative (260) via the azornethine
(262). Me SO Na
o 0 y 3
MeN NHl MeN NH
O N)NHl O N)NHl
Me Me
o H
M1J=N>M<
o N N
Me H
(261)
1"
o H
M1'Ì N >M<
o N N
Me
(262) (260)
i, MeCH(OH)S03Na; ii, HS03"; iii, MeCOCH1COMe; iv, heat
Scheme 82
(259)
:j o Y'ìr
MeN IN 0
O N NH 1
Me
(ii) 8-Arylpurines
Several 8-arylpurines have been prepared using the Traube synthesis although little use
has been made of free aromatic acids as cyclization agents. However 8-phenylguanine has
been prepared frorn 4,5-diamino-6-oxo-1,6-dihydropyrirnidine with benzoic acid in poly-
phosphoric acid (67JMCI09), and phosphoryl chloride has also been used as a cyclization
agent (6SMI40900). With oxopyrirnidines, use of phosphoryl chloride rnay lead to
chloropurines and several 2-arnino-6-chloro(brorno)-8-(substituted phenyl)purines have
been prepared in this way (S2JA4897, SIJAS23S). It has been shown that halogenation precedes
cyclization in this reaction process.
In contrast to the sparse use of acids, aroyl chlorides, no doubt because of their availability
and greater reactivity, have been widely used to provide 8-arylpurines via interrnediate
aroylarnidopyrirnidines. These can usually be prepared by reaction of the appropriate
diarninopyrimidine with the aroyl chloride in aqueous alkali. The interrnediate arnides rnay
be cyclized by heating the free pyrirnidine or, on occasions, its sodiurn salt, and in sorne
cases, especially with methylated pyrirnidines, spontaneous cyclization can occur during the
acylation process.
Exarnples include 4-arnino-5-benzarnidopyrirnidine which gave 8-phenylpurine when
heated briefly at 200 oC (S4JCS2060) and 2-arnino-, 6-amino- or 2,6-diarnino-8-arylpurines
were made in a similar manner (S2JA4897, SIJAS23S). On the other hand, 8-phenyltheophylline
was readily forrned from the corresponding benzarnidopyrirnidine and aqueous alkali
(6SMI40900).
Arornatic amides have been rarely used for Traube cyclizations but exarnples do occur
including 2,4-diarnino-5-benzarnido-6-oxo-1,6-dihydropyrirnidine which furnished 8-
phenylguanine when heated with benzamide (SIJAS23S). Benzamidine has also been used
576
Purines
to produce 8-phenylpurines (66JCS(C)10), 8-phenyloxopurines (6lJCS4468), N -phenyl-N-alkyl-
purines (67CB2280) and sorne 8-(2- and 3-pyridyl)purines were obtained similarly frorn
corresponding nicotinarnidines (67JCS(C)12S4).
The use of an aldehyde and an oxidizing agent has been rnore generally applied to
arylpurine than to alkylpurine synthesis. In this rnanner, 8-phenyltheophylline is readily
obtained frorn the diarninouracil, benzaldehyde and oxygen plus a palladiurn catalyst
(Scherne 83) (54LA(S90)232). Intermediate 7,8-dihydropurines are probably involved in these
reactions. When an excess of aldehyde is used, an 8-aryl-7 -benzylpurine results (06CB227).
Keto esters have also been used to produce 8-phenyltheophylline frorn (263) via an
interrnediate azomethine (265) (S9CB2902) analogous to (264) obtained frorn benzaldehyde.
R Ph
o 0 ......C.....
MeN NH2 Ä MeN
O NJNH2 O NJNH2
Me Me
)
(263) (264) R = H
(265) R = CH 2 C0 2 Et
i, (a) PhCHO, (b) PhCOCH 2 C0 2 Et; ii 02/Pd, heat 230 oC
Scheme 83
o H
MeN N>Ph
O N N
Me
Alternative dehydrogenating agents have been used in these reactions. Thus 8-arylxan-
thines and 9-substituted 8-aryltheophyllines have been obtained by the hydrogenative
cyclization of 6-arnino-5-benzylidenearninouracils using diethyl azodicarboxylate
(78CPB290S) and thionyl chloride (78CPB3240). 8-Arylarninotheophyllines have also resulted
from 6-arnino-8-arylazouracils (78JHC64), and 9-aryltheophyllines were obtained in a similar
rnanner from 6-arylamino-5-arylazouracil (78H(9)1437).
(iii) 8-0xopurines
Synthesis of an 8-oxopurine by the Traube route requires the condensation of a 4,5-
diarninopyrirnidine with a carbonic acid derivative. Such derivatives include carbon dioxide
(rarely), alkyl chloroforrnates, carbonyl chloride, urea or substituted ureas and cyanic acid
derivatives.
Carbon dioxide has been used under pressure and at high ternperatures to convert the
silylated pyrimidine (266) into uric acid in good yield (60CB2810) (Scherne 84) but otherwise
it has found little application.
OSiMe3 0 H
N NHSiMe3 co,. H, HN N)=O
MeßiO . .JNHSiMe3 O JLN
N N H
(266) H
Scheme 84
In contrast alkyl chloroformates have been widely utilized and numerous exarnples have
been described especially in the early literature. Intermediate urethanes are usually obtained
as in the conversion of (267) with benzy1chloroformate in aqueous sodium hydrogen
carbonate into the 8-oxopurine (268) directly (Scheme 85) (6lJOC4961, 62MI40901).
BzO.CO.NBz 102Bz
ClCO,Sz, N I N )= O
NaHCO, _ _ JL
N N
H
(268)
NHBz
N NH2
_)NH2
N
(267)
Scheme 85
An even rnore reactive interrnediate for the introduction of an 8-oxo group is phosgene
which will frequently produce the desired cornpound by reaction of a diaminopyrirnidine
in aqueous sodiurn hydroxide solution at room ternperature. In this way 4,5,6-
triarninopyrimidine gave the 8-oxopurine (269; Scherne 86) (SOJA2587). Chloropurines
Purines
577
including 6-chloro-8-oxo-7,8-dihydropurine have also been made by this rnethod
(63JOC2677,68JOC530). On the other hand, 4,5-diaminouracil with phosgene failed to give
uric acid (60CB2810) but trimethylsilylated uracil with phosgene in toluene containing
triethylarnine furnished uric acid after subsequent deblocking of the silylated purine.
NH 2 NH 2 H
O :: coo, Þ l'):)=o
N N H
(269)
Scheme 86
Many 8-oxopurines have been produced by fusion of a 4,5-diaminopyrirnidine with an
excess of urea. In this manner 4,5-diaminouracil afforded uric acid (Scheme 87). It has
been established by 15N-labelling that the liberated ammonia in this reaction is supplied
wholly by the urea nitrogen atorns (48JA1240, 53HCA1324). Sirnilarly 8-oxo-7,8-dihydropurine
was produced from 4,5-diaminopyrirnidine and N,N' -dimethylurea (Scheme 88). When
reactive substituents, e.g. chlorine atoms, are present, the rnethod is usually unsatisfactory;
however 2-chloro-8-oxo-7,8-dihydropurine (60BBA(45)49) and 9-benzyl-6-chloro-8-oxo-
7,8-dihydropurine (68JHC679) have been prepared by the urea fusion method. Interrnediate
ureido derivatives are probably produced in all these reactions but not normally isolated
under the vigorous reaction conditions ernployed. However potassiurn cyanate and 4,5-
diaminouracil afforded a 5-ureido derivative which could be cyclized to uric acid by fusion
(23LA(432)266) or by heating with hydrochloric acid (16JBC(25)607).
o 0 H
HN NH2 HN N>=O
o JNH 2 o Jl N
N N H
H H
N NH2 COINHMe\
)NH2
N
H
N N
).... )=0
N N
H
Scheme 87
Scheme 88
Use of alkyl (or aryl) isocyanates in the sarne way offers a useful route to 9-alkyl (or
aryl)-8-oxopurines. 9-Phenyluric acid is produced in this way by the reaction of 4,5-
diaminouracil with phenyl isocyanate and cyclization of the intermediate phenyl-
ureidopyrimidine with hydrochloric acid (Scherne 89) (23LA(432)266). It is noteworthy that
the cyclization results in loss of ammonia and not aniline. In contrast to this reaction, fusion
of the N-methylphenylureidopyrirnidine (270) resulted in loss of aniline rather than arnrnonia
(Scherne 90) (66JCS(C)1o).
o
HN NH2
0 NJNH2
H
o H
HN):N>=O
O N N
H Ph
Me Me
N NCONHPh HN N
JNH 2 -- )=o
N N
(270)
Scheme 89
Scheme 90
Tetraethyl carbonate has also been used to give 8-ethoxypurines including 8-ethoxy-7-
methylpurine (74JCS(Pl)349).
(iv) 8-Thioxopurines
8-Thioxopurines have generally been prepared by Traube rnethods frorn a
diarninopyrimidine and either carbon disulfide, thiourea, thiophosgene or thiocyanic acid
derivatives. Carbon disulfide, in contrast to carbon dioxide, has been widely used in Traube
syntheses norrnally in conjunction with a base but it will also react directly. 4,5-
Diaminouracil and carbon disulfide under pressure gave 8-thiouric acid (02GEP142468), but
in pyridine reflux conditions were sufficient for reaction to occur (49JCS3001). Various
solvent combinations have been used according to the solubility of the intermediate
diaminopyrirnidine and these have included aqueous alkali (66JMC160), but reactions in
DMF are reported to give better yields (61J0C3386). The method is relatively rnild and
in solvents such as pyridine hydrolysis of labile substituents can often be avoided.
578
Purines
Thus 4,5-diamino-2-chloropyrirnidine produced 2-chloro-8-thioxo-7,8-dihydropurine
(63CJC1807). On the other hand 6-chloropyrimidines furnished thiazolopyrimidines, including
4,5 -diamino-6-chloropyrimidine which gave the thiazolopyrirnidine (271; Scherne 91)
(6lJOC3386). Such compounds rnay usually be isomerized to 8-thioxopurines with aqueous
alkali. When other leaving groups such as thiol or alkylthio are present in the 6-position
of the pyrimidine molecule, similar results are obtained (62JOC986). In contrast 4-amino-5-
methylarninopyrimidine failed to give an 8-thioxopurine with carbon disulfide, inhibition
of interrnediate dithiocarbarnate forrnation being held responsible (60JCS4347).
S
S
Cl NH
N NH2 N r I
_)NH 2 l NH 2
N N
(271)
Scheme 91
H
N NH2 NrN)=s N NH2
O N)NHMe O N)lN O N)NH2
H H Me Me
(272) (273)
Scheme 92
With readily hydrolyzed Ü enerally fully alkylated) pyrimidines Dirnroth rearrangements
are possible. Thus 9-methyl-8-thioxo-7,8-dihydropurine results, as expected, frorn the
pyrirnidine (272) but also from (273; Scherne 92) (63JCS1276).
Forrnation of 8-thioxopurines using thiourea parallels similar reactions with urea.
However, rnore drastic reaction conditions are required and there is rnore scope for
production of by-products. Thus the 2-thioxopyrimidine (274) gave the 2,8-dithioxopurine
(275) (l3JBC(14)299), guanidine thiocyanate being considered an interrnediate 1n such fusion
reactions (Scheme 93). This suggestion would açcount for the formation of the 8-
aminopurine (277) from the 2-alkyltltiopyrimidine (276; Scheme 94), and the sarne corn-
pound can be produced using guanidine thiocyanate directly (13JBC(14)381).
o 0 H
HN NH2 HN N)=S
S N)NH2 S N3--N
H H H
(274) (275)
Scheme 93
o
HN :J NH2 CSINH",
I or þ
MeS<.::::::,. NH 2 H,N"CiNH,J,SCW
N
(276)
HN :X O
I I jNH 2
MeS<.::::::,. N
N
(277)
Scheme 94
N;N'-Dirnethylthiourea also produced 8-thioxopurines at lower temperatures than
thiourea but the reaction may be cornplicated by S-rnethylation especially at higher tem-
peratures as in the formation of 8-methylthiotheophylline (Scheme 95) (65AFIO).
o H 0
MeN 1 N )= S .cSINH,J, MeN 1 NH2 CSINHMe\
_ _3-- 190 0 C _)NH 6IJOC
o N NON 2
Me H Me
MN
JL jSMe
o N N
Me
Scheme 95
Both alkyl and aryl isothiocyanates have been used to produce 9-substituted 8-
thioxopurines via intermediate thioureidopyrimidines. Thus the pyrimidine (278) and
methyl isothiocyanate gave the 9-rnethyl-8-thioxopurine (279) by loss of amrnonia (Scherne
96) (56JA5857), and phenyl isothiocyanate similarly afforded the corresponding 9-phenyl-8-
thioxopurine. However in the latter type of compound loss of aniline rather than arnmonia
rnay sornetimes occur as in the formation of the 6-oxo-8-thioxopurine (280) from the
phenyIthioureidopyrirnidine (281) (Scherne 97) (47JCS943). Also, in certain circumstances,
Purines
579
cyclization involving loss of hydrogen sulfide may occur to afford an 8-aminopurine as in
the conversion of (282) into (283) in the presence of mercury(II) oxide (Scheme 98)
(57CPB240).
o
MeN NHz MeNCS)
O NJNHz
Me
(278)
o CSNHMe
MeN H HC!)
O NJNHz
Me
o H
MeN N>=s
O N N
Me Me
(279)
Scheme 96
o 9SNHPh
HN I NH
Me NHz
N
(281)
:Jc o
heat H N
- PhNH, ) Me I N>=S
N H
(280)
Scheme 97
o
HN NHcs.NHMe HgO)
_ JNH z
N
(282)
o
HN N NHMe
l:. Jl N
N H
(283)
o
HN NHz CSCI, I
MeSl:. JNH z
N
HN
MeS jlLN>=S
N H
(284)
Scheme 98
Scheme 99
The use of thiophosgene in Traube reactions has probably been lirnited by its relative
inaccessibility but applications have been made under conditions analogous to those used
with phosgene as in the preparation of the 2-methylthio-6-oxo-8-thioxopurine (284; Scheme
99) (13JBC(15)515).
(v) 8-Aminopurines
Guanidine does not react too readily with diaminopyrimidines although a few examples
leading to 8-aminopurines have been recorded, including the 2- and 6-oxo and 6-thioxo
(but nót 2-thioxo) derivatives prepared from appropriate diarninopyrirnidines (63CJC1807)
(see also Section 4.09.5.2.2). Cyanogen bromide and 4,5-diaminopyrimidine gave a low
yield of 8-aminopurine (54JCS2060) whereas 4,5-diamino-6-thioxo-1,6-dihydropyrimidine
with cyanogen bromide gave a 35?/o yield of 8-amino-6-thioxo-1,6-dihydropurine (Scheme
100) (66JOC1417).
S S S
HN NHz BrCN) HN NHCN HN N NHz
JNHz JNH z J-N
N N N H
Scheme 100
Intermediate arylguanidinopyrimidines (285) produced from diphenylcarbodiimide and
5-alkyl( or aryl)amino-4-aminopyrimidines furnished 8-anilino- 7 -alkyl( or aryl)purines (286)
in hot DMF (Scheme '101).
N NHR C(NPh),)
_ .)NH z
N
PhNH
"-
C=NPh R
I
N :J NR N J N
I I I I jNHPh
'-.::::,. NHz '-.::::,. N
N N
(285) (286)
Scheme 101
4.09.7.4 Synthesis from Other 4,5-Disubstituted Pyrimidines
A minor extension of the Traube synthesis involves the reduction of a 4,5-
diaminopyrimidine precursor in the presence of an acylating agent such as formic acid.
580
Purines
Appropriate precursors which have been used include 4-arnino-5-nitroso-, 4-arnino-5-nitro-
and 4-amino-5-phenylazo-pyrimidines and 4-acylamino derivatives of these cornpounds.
Various reducing agents and conditions have been used and these are described in Table 38.
Table 38 Synthesis of Purines from Nitroso- or Nitro-pyrimidines by Reductive Acylation
Pyrimidine
Purine formed
Conditions
Ref.
62MI40903
62MI40903
54MI40903
55CB1306
57JAl518
65JA1976
65MI40907
60JCS1l13
67AG(E)2S8
4-NHz-5-NO
S-NH z -6-NO-uracil
5-NHz-6-NO-uracil
5-NH z -6-NO-uracil
Purine
Xanthine
Xanthine
Xanthine
90% HCOzH/Zn
Ni/Hz/NaOAc
HzS/HCONH z
HCONHz/NazSZ04
2-Ph-S- PhN z -4,6-di-NH z
4-NH z -S-NO z
4-Acetamido-6-p- acetamido-
styryl- 2-diethyl- 5 -nitro
2- Phenyladenine
Adenine
2-Diethylamino-8-
methyl-6-p-
acetamidostyryl
HzS/DMF /(EtOhCH/heat, 6 h
Ni/Hz
Ni/Hz
In addition to the simple extension of the Traube method attention has been turned in
recent years to the direct cyc1ization of purines from 4-alkylamino-5-nitrosopyrirnidines.
Thus the benzylarninonitrosopyrimidine (287) (which rnay be prepared directly frorn the
benzylaminopyrimidine and pentyl nitrite and used in situ) cyclized in hot xylene or
n-butanol to afford 8-phenyltheophylline (Scheme 102) (66LA(691)142), and the related
rnethylarninopyrimidine similarly cyclized to theophylline (64N137). The vigorous conditions
required for cyclization may be much reduced by employing O-acyl derivatives such as
(288) which cyc1ized in hot ethanol to give theophylline (67AG(E)258). Analogously, N-
methylation of the nitrosopyrirnidine gave, via the intermediate N-oxide (289), srnooth
cyc1ization to caffeine (66LA(698)14S).
o 0 R' /'
MeN NO heat I MeN N>R
O N) H O NJ.-N
Me CH 2 Ph Me "" Õ
o I
(287) N-Me
MeN " . +
O N NMe
Me
(289)
o
NOAC
MeN"
O N NMe
Me
(288)
Scheme 102
The use of 4-s-alkylarnino-5-nitrosopyrimidines can still produce purines as in the case
of the 4-isopropylarnino-5-nitrosopyrimidine (290) which afforded the 8,8-dirnethylpurine
(291). This readily isomerized to 8-methylcaffeine when melted (Scheme 103) (64ZC454).
The method rnay be modified in several ways; thus the 4-amino-S-nitrosopyrirnidine with
rnethylarnine or benzylamine gave theophylline or 8-phenyltheophylline, respectively
(66LA(691)142). Similarly the Vilsrneier-Haack reagent (DMF plus phosphoryl chloride) has
also been used to produce 8-dimethylarninotheophylline (Scheme 104) (73BCJ1836).
o 0 0 Me
MeN NO MeN N)<Me MeN N>Me
O N) H O NJ...Ñ Me O N N
Me CHMe z Me Me
(290) (291)
Schem(\ 103
Purines
581
o 0 H
MeN NO RNH,) MeNYyN)R
Ø::(N JNH2 Ø :lNJlN
Me Me
Scheme 104
A variation of these reactions includes introduction of the second nitrogen into a
monoalkylaminopyrimidine as in the reaction of the pyrimidine (292) with nitrosobenzene
which in acetic anhydride gave 7-phenyltheophylline directly (Scherne 105) (72JOC4464).
Similarly 6-benzylaminouracil and diethyl azodicarboxylate produced the purine (293) via
the interrnediate (294; Scheme 106) (75CC146), and the related urazolylpyrimidine (295)
gave 8-arylpurines with arornatic aldehydes (Scheme 107) (74CC551). In the sarne vein the
4-benzylaminopyrimidine (296) with pentyl nitrite followed by ethanolic hydrogen chloride
afforded 8-phenyltheophylline (Scherne 108) (66LA(691)142).
o
MeN DMF
I ) NMe 2 <<poC!,
o N N
Me
o 0 Ar
MeN I .. MeN N\
Å_ .JNHMe Ac,O . .jll/
o NON N
Me Me
(292)
Scheme 105
o
HN N,(CO,Et),)
OÅN!-NH
H I
CH 2 Ph
o NHC0 2 Et :]: 0 CO Et
I N 2
HN NC02Et __ HN I )Ph
0 NJ7H O N N
H CH 2 Ph H
(294) (293)
Scheme 106
o 0 æ
MeN N-NH MeN N)Ar
NJ o-Á. o NjlN
Ph
(295)
Scheme 107
o 0
MeN CsHIINOIH: MeN )Ph
Ø l.NJNHCH2Ph O NjlN
Me Me
(296)
Scheme 108
Benzaldehyde will also react with nitrosoaminopyrimidines but rnixtures of the 8-aryl-
purines and purine 7 -oxides are obtained. The latter can be avoided and good yields of
8-arylpurines obtained by the use of the aldehyde hydrazone (70CC1068) or N,N-dimethyl-
hydrazone (76JCS(Pl)1547). The Wittig reagent derived from benzyl brornide and triphenyl-
phosphine has also been .used to produce' 8-arylpurines directly (Scheme 109) (76CC155).
Phenylazopyrimidines behave like their nitroso analogues. Thus heating the derivative (297)
produced theophylline (Scheme 110).
o
MeN NO
0 N)NH2
Me
o
Ph 3 P=CHPh MeN 1 N\.\
) ..jl /Ph + Ph 3 PO
o N N
Me H
Scheme 109
582
Purines
o CI
MeN NC\J
I NHMe -Cl
a N
Me
(297)
o H Cl
heat MeN I N\ O
----+ 1/ + H 2 N
aNN -Cl
Me
Scheme 110
4.09.7.4.1 Synthesis from S-amino-4-oxopyrimidines
The rnethod has been largely confined to the synthesis of uric acid and its 7 - and 9-alkyl
derivatives by reaction of the appropriate 5-amino-4-oxopyrirnidine with urea or alkylureas,
cyanates or isocyanates. Thus 5-aminobarbituric acid when heated with urea gave uric acid
(4HJA1240). Potassiurn cyanate can replace urea and 9-substituted uric acids (298) resulted
from reaction with an alkyl or aryl isocyanate via the intermediate ureidopyrimidine (299;
Scherne 111) (21LA(423)242). 5-Alkylarninopyrirnidines similarly furnished 7-alkyluric acids
with urea or potassiurn cyanate (658650).
o 0
HN NH2 R'NCO HN NHCONHR'
O N O --+ O N O
H H
o
HN >=O
O NjlN
H R'
(299)
(298)
Scheme 111
Alkyl isothiocyanates also afford alkythioureidopyrimidines, usually by reaction in
aqueous alkali, and these rnay be cyclized by hydrochloric acid to produce 9-alkyl-8-
thioxopurines. In this manner 5-aminobarbituric acid furnished 9-alkyl-8-thiouric acids
(211A(423)242). 8-Thiouric acid (300) was also obtained by forrnation of a thioureido-
pyrimidine in situ frorn the cyanarnidopyrimidine (301; Scherne 112) (02C82563).
o 0 o 0
HN H,S HN
O N NCN -=-+ O N NCSNH 2
H H
(301)
o H
HN N>=S
O NJ-N
H H
(300)
Scheme 112
4.09.7.4.2 Synthesis from 4,S-dioxopyrimidines
Only a few examples have been "rec-orded using ureas as the irnidazole nitrogen source.
Thus isodialuric acid and urea afforded uric acid when heated in dilute acid and this is one
of the earliest recorded preparations of this compound (1889LA(251)235). N-Methyl and
N,N-dimethylureas similarly gave low (10%) yields of 7-rnethyl- and 7,9-dirnethyl-uric acid,
respectively (25LA(441)203).
4.09.7.4.3 Synthesis from, 4-aminopyrimidine-S-carhoxamides
Using a carboxarnide group as a source of an arnino group by applying Hoffman type
reactions, it has been possible to prepare several purines. Thus 4-aminopyrimidine-5-
carboxarnide and alkaline hypochlorite gave,a 60% yield of 8-oxo-7,8-dihydropurine (302)
(62C8956), and the same authors achieved a Curtius reaction with a 4-aminopyrirnidine-5-
carbohydrazide and nitrous acid (Scherne 113).
Purines
583
H
N CONHNH2 N CON3 --+ Njr-Nì=O
..)NH2 __)NH2 ..J--N
N N N H
(302)
Scheme 113
4.09.7.5 Purine Synthesis from Imidazoles
4.09.7.5.1 Introduction
The preparation of purines via an appropriate pyrimidine dominated the synthetic
chemistry of purine especially in the early pre Second World War literature. The reason
for this is undoubtedly connected with the difficulty of obtaining suitable imidazole, com-
pared with pyrimidine, precursors and additionally by the tendency of irnidazole precursors
to be rather labile and prone to aerial oxidation. To sorne extent these disadvantages have
been overcome in recent years and this particular route to purines including nucleosides
and nucleotides has been used increasingly. The method of course is of special significance
in that it is the route adopted in living systems for the de novo biosynthesis of purine
nucleotides, and interestingly it also appears to be the route favoured in the so-called abiotic
syntheses from simple acyclic precursors (see Section 4.09.8.1),
Alrnost all recorded purine syntheses frorn imidazoles involve the cyclization of 5(4)-
aminoimidazole-4(5)-carboxylic acid derivatives especially the carboxamides, thiocar-
boxamides, carboxarnidines, carboxamidoximes, nitriles and esters. The intermediates used
for completion of the purine ring are much the same as have been used for Traube qclization
of diaminopyrimidines (Section 4.09.7.3), especially formic and carbonic acid derivatives,
and cyclization generally occurs' under much milder conditions. This feature has been of
special value in the synthesis of purine nucleosides from imidazole nucleoside precursors.
The resultant purine will have variable substituents at C-2 and C-6 and it is convenient to
discuss and classify the various preparations largely in terms of the introduced 2-substituents.
The C-6 substituents largely reflect the type of carboxylic acid moiety used and do not vary
very much between arnino, oxo and thioxo.
4.09.7.5.2 C{2}-Unsuhstituted purines
Formic-acetic anhydride has been widely used with aminoirnidazoles to furnish an N-
formyl derivative which will cyclize by prolonged heating or better by treatrnent with a
weak base. In this manner 5-aminoirnidazole-4-carboxarnide produced hypoxanthine
(SOJBC(18S)439) via the N-formyl derivative (303) which readily cyclized when warrned with
aqueous sodium hydrogen carbonate (6SJHC253).
Similar methods have been used to prepare nucleosides including inosine (62JCS2937)
which results from the 1-ß-D-ribofuranosylimidazole (304; Scherne 114) and in a similar
manner, 7 -ß- D-ribofuranosylhypoxanthine (306) was obtained from the isomeric
aminoimidazole nucleoside (307; Scheme 115) (59JCS2893). 1-Benzylinosine has also been
prepared by cyclization of the aminoimidazolebenzylamide (305) with cold aqueous alkali
(S8JA3899). In like manner, 9-rnethyl- and 8,9-dirnethyl-6-thioxo-1,6-dihydropurine (308)
o
R 2 NHCO 2 :X N
[ NaHCO, R N I \.\
OHCNH ./ - /
N N N
I R 1
R 1
(303) R 1 =R 2 =H
(304) R 1 =Rf, R 2 =H
(305) R 1 =H, R 2 =PhCH 2
Scheme 114
584
Purines
and (309), respectively, were obtained by cyclization of the corresponding for-
mamidoimidazolethioamides (Scheme 116) (S9JCS4040).
R 0
H 2 NCO HN N
CHONH[) -- l-.,jL >
N N N
(307)
(306)
S
H 2 NCS N HN N
CHONH(>R -- NJ-N')R
Me Me
(308) R= H
(309) R = Me
Scheme 116
Scheme 115
In contrast to its application in Traube syntheses (Section 4.09.7.3.2) formamide has
been little used as a one-carbon cyclizing agent with aminoimidazoles. However 7 -methylhy-
poxanthine (310) was obtained by heating 4-amino-l-methylimidazole-S-carboxamide in
formamide (Scheme 117) (S7JA6401). 9-Benzylinosine was produced from (311) and for-
mamide (Scheme 118) (S8JA3899), thioinosine was similarly obtained from the corresponding
aminoimidazolethioamide (312; Scheme 119) (68CPB2172) and in an analogous reaction,
adenine was obtained from the aminoimidazolenitrile (313) and formamide (Scheme 120)
(S7JA6401).
o
H 2 NCO Me :X e
[ N HCONH,) HN I >
H 2 N ) N N
(310)
o
H 2 NCO N :X N
HN[\\ HN I ')
2 N/ N
CH 2 Ph N CH 2 Ph
(311)
Scheme 117
Scheme 118
S
H 2 NCS H :.x N
I/ HCONH,) H I
H 2 N,,_,9" I.:::::- N/
N' N H
(312)
NC H NH 2
H 2 NQ HCONH,) NCt:
N H
(313)
Scheme 119
Scheme 120
An excellent yield of adenine was also obtJiined by heating the aminoimidazolenitrile
(313) with formamidine acetate (6SJA4976, 66JA3829) and 3-methylhypoxanthine was similarly
produced from the corresponding aminoimidazole ester and formamidine acetate
(79JCS(P1 )3107).
Ethyl formate has also been used occasionally as a cyclizing agent as in a preparation of
hypoxanthine from 5-aminoimidazole-4-carboxamide in hot ethanolic sodium ethoxide
solution (67JOC32S8) but triethyl orthoformate has b en more widely used. Ring closure
may occur direètly with this reagent as in the preparation of 8-methylhypoxanthine from
the 2-methylimidazole (314) using triethyl orthoformate in DMF (Scheme 121) (60JA3144).
Hypoxanthine l-oxide was similarly produced from 4-amino-5-(N- hydroxy)carbamoyl-
imidazole (315; Scheme 122) (S9JOC2019).
o
H 2 NCO :.x N
[ \ CHIOEt\ HN I R
H 2 N .,9"R DMF l- /
N' N N
H
(314a) R = H
(314b) R=Me
Scheme 121
o
HOHNCO H _ +^ N
[ O-HN 'f
H 2 N l- /
N N N
H
(315)
Scheme 122
Glycosyl N-oxides have also been prepared from imidazole precursors. Thus the ethoxy-
methylidene derivatives (316) and hydroxylamine gave, presumably via the
hydroxyaminomethylene derivatives, isopropylideneadenosine (and 8 -methyladenosine) 1-
oxides (317) and (318), respectively, in 35% overall yield (Scheme 123) (69CPB1128).
Similarly (316) and methoxyamine furnished 9-( 2,3- O-isopropylidene- ß - D-ribofuranosyl)-6-
methoxyaminopurine (319).
Purines
585
NHR 2
N J CN N JC: N Õ
Rl( I NH 2 0H) R< I ,-
OyN N=CHOEt OyN N
HO HO
0)(0 0)(0
(316) (317) R I =R 2 =H
(318) R I =Me,R 2 =H
(319) R 1 = H, R 2 = OMe
Scheme 123
Similar cyclizations occur using mixtures of triethyl orthoformate and acetic anhydride or
diethoxyethyl acetate (61JCS484S), but in the absence of the anhydride the intermediate
ethoxymethyleneamino derivatives may sometimes be isolated. Thus 5-amino-4-cyano-1-
methylimidazole and triethyl orthoformate furnished the ethoxymethylene derivative (320).
Compounds of this type have proved to be useful intermediates for purine synthesis. Thus
(320) with ethanolic -ammonia readily furnished 9-methyladenine (Scheme 124) (S9JCS4040).
9-Cyclohexyladenine was similarly prepared (80JCS(Pl)2728) using cold alcoholic ammonia.
The reaction has been extended to include a glucopyranosylimidazole which produced
9-glucopyranosyladenine (7SCC964).
NC N
CH(OEt), [ \\
) EtOCH=N ,/
N
Me
(320)
Scheme 124
Several 8-glycosylpurines have similarly been prepared from appropriate imidazoles.
Thus 5 -amino-4-cyano-2-(2,3,5 -tri-O- benzoyl-D-arabinofuranosyl)imidazole (321) with
triethyl orthoformafe followed by ammonia gave, after deb locking, 8-arabinofuranosyl-
adenine. The 8-ribosyl derivative (322) underwent reaction in the same manner (Scheme
125) (76MI40902, 72MI40903, 72CR(C)(274)2192). An alternative successful route to 8-
ribofuranosyladenine involved reaction of 5-amino-4-cyanoimidazole and the ribosyl imi-
date (323; Scheme 126) (76TL4S). Analogous 8-(deoxyribosyl)purines have also been
prepared., Thus the 4-amino-2-(2-deoxyribosyl)imidazole-5-carbonitrile (324a) with
formamidine acetate followed by de acylation produced the 8-(2-deoxy-ß-D-ribosyl)adenine
(325c), and the related amide (324b) gave the 8-(2-deoxy-ß-D-ribosyl)hypoxanthine (326c)
after reaction with diethoxymethyl acetate and subsequent deblocking (Scheme 127)
(7ST2914). 7 -Methyladenine was prepared similarly from the isomeric 3-methylethoxy-
methyleneimidazole (60JA3147) which with methylamine also gave 1,9-dimethyladenine, and
with hydrazine 9-methyl-1-aminoadenine. Recently inosine was obtained in low yield
(15%) by reaction of the aminoimidazole riboside (327) with chloroform and sodium
methoxide, the proposed mechanism involvIng an intermediate carbene (Scheme 128)
(76MI40904).
NC N
H 2 NÇ5
Me
NH 2 N
NH,) Np ')
)l.N
Me
NC H NH 2
H 2 Nf)R -- N(ì:')R
N H
(321) R = 2,3,S-tri-O-benzoyl-D-arabinosyl
(322) R=2,3,S-tri-O-benzoyl-D-ribosyl
Scheme 125
o NH NH 2
NC HO H C :;'--- H1 f JC N
If \ + 'OEt HO I I
H 2 N((,.ð -- N N
N 0 0 H
>< 0 0
(323) ><
Scheme 126
586
Purines
o
X NH :): H
N N:7 2 N HN N
H N [ \\ ---+ I ')R 2 ---+ I I JR2
2 N.....-"-R 1 ..J--N N
H N H N
(324) (325) (326)
(aJ R 1 =3,5-di-O-p-toluoyl-2-deoxyribosyl, X = CN; (b) R 1 = 3,5-di-O-p-toluoyl-2-deoxyribosyl, X = CONH 2 ; (c)
R = 2-deoxyribofuranosyl
Scheme 127
H 2 NCO N H 2 NCO N
H 2 N[J :CCl 2 , H 2 N[)
N II N
I C \
R /" R1
(327) CI Cl
Scheme 128
o
---+ HN N')
..J-N
N I
Rf
Adenine was also obtained by formylation of the aminoimidazolecarboxamidine (328)
and cyclization of an intermediate which was postulated to be the formylamidine derivative
(Scheme 129) (50JBC(185)439). Recently this last compound has been shown to be N 6 _
formyladenine (329) and not the formylamidine indicating that cyclization of the intermedi-
ate occurs very quickly (80JCS(Pl)2728). C(2)-Labelled adenine has been prepared by this
method using labelled formic acid (S3JA5753). The antiviral agent (331) was similarly
produced directly by formylation of 5-amino-1-(2,3-dihydroxypropyl)imidazole-4-
carboxamidine (330) with formic/acetic anhydride and sodium formate and treatment of
the resulting N6-formyladenine derivative with sodium hydrogen carbonate (Scheme 130)
(80JCS(Pl)2728). Various 9-substituted adenines have also been obtained frorn 1-substituted
aminoimidazolecarboxamidines by similar cyclizing processes (78CPB1929).
NH
II
H 2 NC N
H 2 NÇ)
H
(328)
NHCHO
HC0 2 Ac , N N')
..J-N
N H
(329)
Scheme 129
NH
II
H 2 NC N
H2 )
CH 2 CHOHCH 2 0H
(330)
i. HC0 2 Ac
ii. H 2 0 '
NHCHO
N NH 2
l:.J- N > NaHCO" NOt:>
CH 2 CHOHCH 2 0H CH 2 CHOHCH 2 0H
(331)
Scheme 130
Useful syntheses of 3,9-disubstituted adenines have been achieved frorn appropriate
aminoimidazole precursors. In this way 3,9-dimethyladenine (332), isolated as a perchlorate,
was obtained in good yield from 5-formarnido-1-methylimidazole-4-methoxycarboxamidine
(333) by reduction with lithium aluminum hydride to the methylamino derivative (334).
Cyclization of (334) with triethyl orthoformate followed by hydrogenolysis of the alkoxy
group with a palladium catalyst afforded (332; Scheme 131) (73CC917). This route is
necessarily restricted to 3-methylpurine derivatives but it has been extended by alkylation
of the formamido derivative (333) with sodium hydride al)d an alkyl halide to give the
alkylformamido derivative (335) which may be cyclized directly to the alkoxyadenine (336)
(78TLS007). The alkylation has recently been found to proceed without added base
(8lH(16)909). The method has been applied to the synthesis of 9-(ß-D-ribofuranosyl)-3-
methyladenine (337). Hydrolysis of this very labile nucleoside with O.lM hydrochloric acid
proved to be a convenient route to 3-methyladenine in 92% yield (Scheme 132) (79CC135).
Purines
587
NOMe
II
H 2 NC N
CHONH[')
N
Me
(333 )
NOMe
"
H 2 NC N
MeNH[')
N
Me
ÄiAIH4 (334)
NOMe
"
H 2 NC N
OHCN[')
R N
Me
(335)
NOMe
N N
l..JL )
N N
Me Me
(336)
H,
----"-+
NH
NÄ.....N
l " )
N/--N
Me Me
(332)
/'
Scheme 131
PhCH 2 0N
"
H 2 NC N
OHCNH[')
N
I
RP
f
Mel
--
NaH
PhCH 2 0N HN
" II
H 2 NC N H 2 .NC N
OHCN[') OHCN[')
I N I N
Me I P Me I p
R f R f
NH
N I N O.lMHCl
l..Jl / <<
N N
Me H
1
aN;
N N
Me p
(337) f
Scheme 132
4.09.7.5.3 2-Alkyl-, aryl- and glycosyl-purines
Ethyl acetate and ethyl propionate in ethanolic sodium ethoxide with 5-aminoimidazole-
4-carboxamide and its riboside have provided a route to 2-methyl- and 2-ethyl-hypoxanthine
arid corresponding 2-alkylinosines, respectively (67JOC32S8,68JA2661). 2-Methylhypoxan-
thine has also been prepared from the same imidazole and ethyl orthoacetate via an
intermediate ethoxymethylene derivative which cyclized to the purine when heated
(60JA3144). The same method has been applied to the synthesis of 2,8-dimethyl- and
2,8-diphenyl-hypoxanthine from appropriate imidazole precursors.
Amides appear to have had little application as sources of C-2 purine substituents
but trifluoroacetamide when heated with the amino imidazole car box amide or the nitrile
afforded 2-trifluorornethylhypoxanthine or adenine, respectively (S8JAS744). The ribosyl-
amino imidazole ami dine cyclic phosphate similarly gave 2-trifluoromethyl cAMP with
trifluoroacetamide (74JA4962). The same authors also converted the imidazoleamidine into
2-alkyl(aryl) derivatives of cAMP in yields of 19-81% by reaction with an aldehyde and
a dehydrogenating agent which included palladium, chloranil in DMF, or aerial oxygen in
aqueous ethanol.
4.09.7.5.4 2-0xopurines
The first purine prepared from an imidazole was a 2-oxopurine, namely 7 -methylxanthine
(338), which was obtained from 4-amino-1-methylimidazole-5-carboxamide and diethyl
carbonate in a sealed tube (Scheme 133) (24HCA713).
588
Purines
H 2 NCO j:1e
H 2 N[)
N
COIOEt)2.
heat
o Me
HN N>
O NJlN
H
(338)
Scheme 133
Xanthine and xanthosine (74% yield), however, are more conveniently prepared frorn
diethyl carbonate and 5-aminoimidazole-4 carboxarnide or its riboside, respectively, in
refluxing ethanolic sodium ethoxide (67JOC3258). 6-Thioxanthosine was similarly obtained
frorn 5-aminoimidazole-4-thiocarboxamide riboside (68CPB2172, 73CPB692). However, fusion
of an aminoimidazole with urea has been more commonly used to prepare xanthine and
its derivatives including the parent (50JBC(185)439). 6-Thioxanthine was similarly produced
from the aminothioamide (339) by urea fusion (Scheme 134) (68CPB2172) and fusion of
the related aminoimidazoleamidine with urea furnished isoguanine (Scherne 135)
(50JBC(185)439). The amino ester (340) in hot pyridine with urea also gave xanthine
(50JCS1884), and 8-phenyl-, 8-benzyl- and 7-methyl-8-phenyl-xanthines were prepared in
the same way from the appropriately substituted imidazole esters.
HN
II
H 2 NC N NH 2 H
H 2 NÇ) l N>
H 0 N N
H
S
H 2 NCS H ): H
N N
r urea HN
H 2 N(.) Á I >
NON N
H
(339)
Et0 2 C N
H 2 N[)
N
H
(340)
Scheme 134
Scheme 135
Interrnediate ureido derivatives may be isolated in many of these reactions by working
at lower ternperatures as with 1-methyl-4-methylaminoimidazole-5-N-methylcarboxarnide
(341) which with urea at 140 0 C in the presence of hydrogen chloride gave the
ureidoimidazole (342). This then cyclized to theobromine with hot dilute acid (Scheme
136) (28CB1409). Potassium cyanate can sometimes replace urea, and with this reagent
(341) was readily converted into caffeine (Scheme 136) (28CB1409), but on the other hand
5-amino-2-methylthio-1-rnethylimidazole-4-carboxamide failed to react.
o Me
MeN N>
O NJlN
Me
o
MeHNCO j:1e MeHNCO j:1e ): j:1e
CNO- [ \ urea [ HCI HN I \
-- MeNH H 2 NCON .) I 1/
N I N 2 O N N
Me Me
(341) (342)
Scheme 136
The more reactive alkyl or aryl chloroformates can be used to produce 2-oxopurines
under rnilder conditions than those obtained in urea fusions. Xanthine for example resulted
frorn the aminoimidazolecarboxamide and ethyl chloroformate at 0 OC followed by cycliza-
tion of the intermediate urethane (343), either by fusion or by heating with aqueous ammonia
(Scheme 137) (50JBC(185)439).
H 2 NCO N
Et0 2 CNH[) xanthine
N
H
(343)
Scheme 137
An alternative route to xanthine involves prior reaction with phenylthiochloroformate
as in a synthesis of 9-methyl-8-methylthioxanthine (344; Scheme 138) (49JCS2329). Several
alkylated xanthines have been prepared from ethyl chloroformate and an appropriate
arninoimidazolecarboxamide in the presence of potassium carbonate, including 1,7-
dialkyl- (45JCS751), 7,8-dialkyl- (66RTC1254) and 1,3,8,9-tetramethyl-xanthines (63Z0B1650).
Purines
589
H 2 NCO N
H 2 N[)SMe
N
Me
PhSCOCI
.
H 2 NCO N
PhSCOHN[)SMe
N
Me
HN N
..J- )SMe
o N N
H Me
(344)
Scheme 138
In specific cases, cyc1ization to the 2-oxopurine may occur very readily as with the
trimethylimidazole (345; caffeidine) which with ethyl chloroformate in aqueous sodium
hydrogen carbonate readily furnished caffeine (Scheme 139) (28CB1409). In a similar manner,
phosgene and the aminoimidazolecarboxamidines (346) and (347) in aqueous alkali readily
afforded isoguanine and isoguanosine, respectively (Scheme 140) (49JA3973). Analogously
1,l'-carbonyldiimidazole has been used to convert the aminoimidazolecarboxamidine (348)
into 2-oxo cAMP (Scheme 140) (74JA4962), and also to give a 2-oxo-1,N 6 -etheno-cAMP
(349) from (350; Scheme 141) (76CPB1561).
MeNH CIC0 2 Et . MeN O I
M"HNIL 1/ NaHCO, Å 1/
e NON N
(345) Me
Scheme 139
HN
II NH
H 2 NC N :): 2 N
H 2 N[) C ;12. N?' I >
N COIm2 OÅN N
R H R
(346) R=H
(347) R = Rf
(348) R = Rcp
Scheme 140
H
[:
N N
H2N N)
(350) Rcp
COIm 2 .
c
l-):N
o N N
H Rcp
(349)
Scheme 141
Aminoimidazole esters have also been used as a source of 2-oxopurines, the additional
nitrogen being derived from urea, cyanates and similar compounds. In this manner
the amino ester (340) and potassium cyanate furnished a ureidoimidazole which
smoothly cyc1ized to xanthine with dilute alkali (Scheme 142) (42JCS232). Methyl iso-
cyanate similarly gave 1-methylxanthine and related derivatives have also been prepared
(49JCS1071,50JCS1884).
Et0 2 C N
[ \\ CNO-.
H 2 N ,/
N
H
Et0 2 C N
H 2 NCONH[)
N
H
ow .
-=--+ xanthme
Scheme 142
Uric acid and 1,7-dimethyluric acid were similarly produced from 2-hydroxyimidazoles
(imidazolin-2-ones) by reaction with potassium cyanate (Scheme 143) (62JOC4633).
R2NHCO R 1
[ N
V CNO- .
H 2 N À OH
N
R t 0
R 2 NHCO R [
N R2N N
NH 2 CONH[)OH ---+ I I >=0
N oAN N
(a) R 1 =R 2 =H H H
(b) R 1 =R 2 =Me
Scheme 143
4.09.7.5.5 2- Thioxopurines
Alkyl (or acyl) isothiocyanates have proved to be useful intermediates for thioxopurine
synthesis and can also be used to produce guanine derivatives. Methyl isothiocyanate and
590
Purines
5-amino-1-methylimidazole-4-carboxamide or the 2-methylthio derivative, for example in
hot pyridine, gave 9-methyl-2-thioxanthine and 9-methyl-8-rnethylthio-2-thioxanthine,
respectively (Scheme 144) (49JCS3001). Acetyl thiocyanate and the 2-methylthioimidazole
similarly afforded an intermediate thioureido derivative which readily cyclized to 8-methyl-
thio-2-thioxanthine after short treatment with aqueous sodium hydroxide (49JCS3001).
o
H 2 NCO N H 2 NCO N N
[ \\ [ \\ pyridine HN I I
H N )R 1 -- R 2 NHCSHN )R 1 heat >> I /R
2 N N SAN N
Me Me H Me
Scheme 144
Thiourea has also been used occasionally for 2-thioxopurine synthesis. 7-Methyl-2-
thioxanthine is formed by fusion of 4-amino-1-methylimidazole-5 -carboxamide and
thiourea (57JA6401). Other cyclization agents include carbon disulfide which converts the
arninoimidazole arnidoxime (351) into the 2-thioxopurine N-oxide (352) after 2 days in
pyridine at room temperature (Scheme 145) (63JOC2560), and sodium methylxanthate with
which 5-aminoimidazole-4-carboxamide riboside gave 2-thioxanthosine in almost quantita-
tive yield (67JOC3032, 68MI40903). 9-Methyl-2-thioxanthine and 9-methyl-2,8-dithiouric acid
have similarly been obtained using carbon disulfide and appropriate aminoimidazoles
(49JCS2329). Aminoimidazolenitriles furnished 2,6-thioxopurines including the 9-ribofurano-
side, probably via the intermediate (353) under similar conditions (75CPB759). The 7-
ribofuranosyl-2,6-dithioxopurine was obtained similarly (68JOC2828), and 1,l'-thiocarbonyl-
diimidazole and the aminoamidine (346) have been used to produce 2-thiocyclic iso-GMP
(74JA4962).
NOH
H2N N
H 2 NÇ5
H
(351)
CS,/pyridine >>
NH 2
õ-Ñr-- N >
SJ..NJl- N
H H
(352)
NH
IJ:N>
S N N
H Ip
(353) Rf
Scheme 145
4.09.7.5.6 2-Arninopurines
Cyclization of thioureidoimidazoles in the presence of sulfur-extracting agents such as
mercury salts may favour 2-aminopurine formation. Thus 5-aminoimidazole-4-(N-
rnethyl)carboxamide (354) and sorne 2-substituted derivatives with phenyl isothiocyanate
afforded the phenylthioureidoimidazole which when heated with mercury(II) salts produced
1 ,N 2 _ dimethylisoguanine and 8-substituted derivatives (355), respectively (Scheme 146)
(50JCS1888).
o
MeNHCO MeNHCO :j: H
r \ MeNCS r Hg" MeN N
H2N R ---- MeNHCSNH )R --+ MeNHlN I N'>R
(354) R = H, Ph, CH 2 Ph (355)
Scheme 146
The use of benzoyl isothiocyanate has led to a useful route to guanine and its derivatives.
Thus 5-aminoirnidazole-4-carboxamide and benzoyl isothiocyanate gave a thio-
ureidoimidazole which after S-methylation and amination of the S-methyl derivative readily
cyclized in alkaline solution to afford guanine (Scheme 147) (67JOC1825, 67JOC3032). 9-
Hydroxy-8-methylguanine has been made by the same route (72JOC1867). The methyl-
arninoimidazole ester (356) was similarly converted into 3-methylguanine (79JCS(Pl)3107),
and 1-methyl-5-methylaminoimidazole-4-carboxamide produced 3,9-dimethylguanine
(78TL1447) which was used in a synthesis of a wyosine base, 3-methylwye (see also Section
4.09.8.2). Similar reactions have led to syntheses of the potent coronary vasodilator,
2-phenylarninoadenosine from aminoimidazole nucleoside precursors (81CPB1870).
Purines
591
H 2 NCO_ NH
H 2 NÇ)
H 2 NCO
PhCONCS [ H
) HN'
I N
CSNHCOPh
Mel
-----.
H 2 NCO
HN[)
I N
C(SMe)=NCOPh
Scheme 147
H 2 NCO
HN[) guanine
I N
C(=NH)NHCOPh
EtOzC
MeHN[)
N
(356)
4.09.7.6 Synthesis from Ring-fused Pyrimidine Heterocycles
Several compounds exist which contain a pyrimidine ring fused to a heterocyclic system
and they are able to produce a purine, either by rearrangement or by reaction with an
appropriate reagent. Examples of the first type include the aminothiazolopyrimidines which
produce thioxopurines by heating or on treatment with alkali (see Section 4.09.6.16), and
the analogous 7-aminooxazolo[5,4-d]pyrimidine (357) which rearranged to hypoxanthine
or its 9-substituted derivatives with hot alkali (Scheme 148) (70BCJ3909). The related ethoxy
derivative (358) similarly afforded 3-substituted xanthines (Scheme 149) (73BCJS06), and
aminopurines are also produced by reaction with ammonia or amines. Thus the oxazolo
derivative (359) with methylamine gave a 9-methyladenine derivative (S2JA4897) (Scheme
150).
o
NHR N :I N
N r ') ow) HN I ')
Me ..)Lo Me N N
N R
(357)
Scheme 148
NHR 0
N r N ') HN N')
EtOl..)Lo O -.)LN
N N H
(358) R
Scheme 149
NHz NHz
N CI MeNH,) rN CI
N)LO/\.d NJ--N/\.d
(359) Me
Scheme 150
The somewhat analogous furazanopyrimidine (360) after reductive cleavage in the pres-
ence of an amine produced adenine (71J0C3211) and 9-substituted derivatives (Scheme 151).
The pyrimidino[5,4-c] [1,2,5]oxadiazine (361) similarly when heated to 200 0 C lost
formaldehyde with formation of 8-methyltheophylline (Scheme 152) (66LA(692)134).
o :): 0 H
N, N
MeN ?' 0 heat MeN I \
I I I Me
O N N/fMe -, O N N
Me Me Me
(361 )
NHz NHz
N J N" N :Jt N
I 0 RNH,þ I I ')R'
R ""'N/ R N
N N H
(360)
Scheme 151
Scheme 152
Tetrazolopyrirnidines can also act as' a source of a diaminopyrimidine and hence of
purines. Thus 8-amino-7 -chlorotetrazolo[1,5-c ]pyrimidine (362) when heated with
diethoxymethyl acetate furnished 6-chloro-8-ethoxypurine (Scheme 153) (62JOC1671) via
a nitrene intermediate and concornitant loss of nitrogen.
592
Purines
Cl
N NH2
lNAN
\ I
N=N
(362)
CI H
N N
IEtO) OAC þ NjL.)OEt
Scheme 153
Purines have also been obtained by transformations of appropriate pteridines
(75CPB2678, 73CB3203). Also the 6-azapteridine (363) on reduction produced 8-substituted
theophylline (Scherne 154) (69MI40900). Similarly the 7-azapteridine (364) with hot
forrnamide afforded 8-phenyltheophylline (Scheme 154) (76H(4)749), and the diazepinone
(365) with alkoxide also produced the 9-(2-propenyl)purine (366) by what is ultirnately a
Traube synthesis (Scheme 155) (70JHCI029).
o
MeN :J: N'N
I ::-.. ) R
O-?-.....N N
Me
(363)
Na,S,04
o H
MeN N>R
O NjlN
Me
HCONH,
--
o
MeN NÌ1R
o NAN/N
Me
(364)
Scheme 154
H MeC=CH 2
N 0 I
ex] N(XN)=O
N N Me N
H
(365) (366)
Scheme 155
4.09.7.7 Best Practical Methods for Specific Purine Synthesis
4.09.7.7.1 Introduction
Detailed preparations with full experimental details and additional references of a wide
variety of purines and purine nucleosides and nucleotides have been recorded in the
publication (B-68MI40901) and the more recent successors to this series (B-78MI40901,
B-78MI40903).
The purines are exceptional when compared to the majority of heterocyclic compounds
in that the most useful starting rnaterials for their preparation are often of natural occurrence.
This reflects of course the widespread occurrence of adenine and guanine and their nucleo-
sides as components of nucleic acids. Thus adenine and guanine may be obtained by acid
hydrolysis of nucleic acid (38CB718) and hypoxanthine is readily produced by deamination
of adenine with nitrous acid (38CB718) or by adenosine deaminase.
Caffeine occurs in both tea (3.5%) and coffee and is norrnally rnanufactured from coffee
and tea dust and similarly theobromine is the rnain purine of the cocoa bean frorn which
it may be prepared. Caffeine has also been manufactured from guanine by hydrolysis to
xanthine followed by methylation with methyl acetate or dimethyl sulfate (46USP2509084).
4.09.7.7.2 Purine
Purine is probably best prepared by the Traube route from 4,5-diaminopyrirnidine and
formic acid in an atmosphere of carbon dioxide (83% yield) (54JA6073), or, better, using
diethoxymethyl acetate as the cyclizing agent (82% yield) (60JOC395).
Purines
593
4.09.7.7.3 C-Linked purines
(i) C-Alkylpurines
C-Alkylpurines are usually best obtained by Traube syntheses as in the preparation of
6-methylpurine (6SJCS623) and 8-methylpurine (S4JCS2060), or by dehydrohalogenation
of a halogenoalkylpurine as in tile preparation of 2-methylpurine from 2-methyl-6-
chloropurine (S9JA193).
Recently a valuable route to 8-alkyl- or acyl-purine nucleosides has involved the reaction
of an unsubstituted or 8-halogenopurine with butyllithium and an appropriate alkyl or acyl
halide, including ethyl chloroformate, when excellent yields of the 8-substituted purine
nucleosides are produced (79TL238S).
(ii) Purinecarboxylic acids and derivatives
Purine-6-carboxylic acids are probably best prepared by hydrolysis, using 2N sodium
hydroxide, of 6-cyanopurine, itself prepared by heating 6-iodopurine (not chloropurine)
and copper{I) cyanide in pyridine over 2 hours (S6JA3Sl1). The nitrile may be used also as
a convenient source of purine-6-carboxamide and -thiocarboxamide. Homologous 8-, but
not 2- or 6-, purinecarboxylic acids are best prepared frorn 8-chloropurines and the sodium
derivative of diethyl malonate and its alkylated derivatives followed by hydrolysis as in the
preparation of 8-{a-alkyl)carboxymethylcaffeines from 8-bromocaffeine (S3MI40901), and
8-carboxymethylisocaffeine from 8-chloroisocaffeine (60ZOB3628). 8-Carboxy derivatives of
adenosine and guanosine may be conveniently prepared in good yield by reaction of
8-lithiopurine trimethylsilyl derivatives with ethyl chloroformate (79TL238S).
Purine aldehydes have only been prepared in recent years. The best route appears to be
the hydrolysis of a dichloromethylpurine which may be made from the methyl derivative
(62Z0B201S). Thus hydrolysis over several hours of 8-dichloromethylcaffeine produced
8-formy1caffeine (48Z0B2129). The corresponding 6-formylpurine may be prepared as an
oxime by reaction of 6-methylpurine with cold nitrous acid and this is converted by hydrazine
into the hydrazone (63N224). The hydrazone may be converted by nitrous acid into the
aldehyde (S9JA2S1S). Dehydration of the oxime with hot acetic anhydride over 5 hours also
afforded an alternative route to 6-cyanopurine (68CB611).
A few purine ketones have been prepared including 8-acetyl- or 8-propionyl-caffeine
from 8-cyanocaffeine and the appropriate Grignard reagent (S6AP4S3).
(iii) C-Aminopurines
2-Aminopurine is probably best obtained by a Traube synthesis from 2,4,5-
triaminopyrimidine and formic acid in boiling 4-formylmorpholine (S4JCS2060). 2-
Hydrazinopurine on the other hand is best prepared from 2-chloropurine and hydrazine
(S7JA218S). Adenine is best prepared in quantity by a modified Traube synthesis
(S3JA263,66MI40903). 2,6-Diaminopurine is also produced by the Traube method from
2,4,5,6-tetraaminopyrimidine, and material labelled with ls N in positions 1 and 3 has been
prepared in this way (SOJBC(18S)423, SOJBC(18S)43S).
8-Aminopurines have usually been prepared from 8-chloropurines as in the amination
of 8-chlorocaffeine to 8-aminocaffeine (1882LA(21S)26S), or alternatively from 8-methyl-
thiopurine as in the synthesis of 8-amino-, 8-methylamino- or 8-dimethylamino-purine from
8-methylthiopurine with ammonia, methylamine or dimethylamine, respectively (S4JCS2060).
A good yield of 8-amino-6-oxo-1,6-dihydropurine was obtained in a Traube synthesis from
4,5-diamino-6-oxo-1,6-dihydropyrimidine and guanidine at 200 oC (S8JA667I).
4.09.7.7.4 N-Linked purines
(i) N-Alkylpurines, nucleosides and nucleotides
The preparation of N-alkylpurine derivatives poses certain practical problerns. In the
case of the purine anion the normal site of alkylation is N-7 or N-9. Thus benzyladenine
may be conveniently prepared from sodium adenine and benzyl chloride (B-68MI40901, p. 3).
9-Ethylpurine is readily obtained in 68% yield from 9-methyladenine and pentyl nitrite
with illumination from a 200 W lamp (80JOC3969).
9-Substituted purine nucleosides which include most of the naturally occurring compounds
or their analogs are also produced by glycosylation of an appropriate purine anion derivative.
594
Purines
In this way 9-(ß-D-xylofuranosyl)adenine is obtained by reaction of 2,3,5-tri-O-acetyl-D-
xylofuranosyl bromide with the chloromercurio derivative of N 6 -benzoyladenine, followed
by deacylation with methanolic sodium methoxide (B-68MI40901, p. 139).
Silyl derivatives of purines are commonly used in the sarne way as in a synthesis
of 9-(a,ß- D-glucopyranosyl)adenine from N 6 - benzoyl-9-bis(trirnethylsilyl)adenine and
2,3,4,6-tetra-O-acetyl-a-D-glucosyl chloride at 150-160 oC over 4 hours to produce, after
deblocking, a mixture of anomeric nucleosides (B-68MI40901, p. 135). The hypoxanthine
nucleosides may be obtained in a similar fashion or by deamination of the adenine deriva-
tives.
2',3',5'-Tri-O-acetyladenosine is also usefully converted into 2',3',5'-tri-O-acetyl-
nebularine with pentyl nitrite and 200 W illumination in 45.8% yield (80JOC3969).
In a similar rnanner purine nucleotides including AMP and its a-anomer may be produced
directly by reaction of the N 6 -benzoyl-9-bis(trimethylsilyl)adenine with 2,3-di-O-benzoyl-
5-0-(diphenylphosphono)-D-ribofuranosyl bromide and deblocking the intermediate with
lithium hydroxide and a phosphodiesterase from Trirneresurus flavoviridis (B-78MI40903,
p. 821). This rnethod however gives a low yield and can hardly be recornrnended.
Purine nucleotides are probably best rnade by phosphorylation of the corresponding
nucleosides. In recent years phosphoryl chloride has proved most convenient for this purpose
and rnay be used with an unprotected nucleoside to give yields of about 50% (B-78MI40903,
p.827). Yields of purine nucleotides up to 60% may also be obtained using a phos-
photransferase and a suitable phosphate donor with the unprotected nucleoside. Typical
preparations of this type using an enzyrne frorn wheat shoots and p-nitrophenyl phosphate
as a phosphate donor have been described (B-78MI40903, p. 955).
The alternative fusion rnethod for nucleoside synthesis involves the reaction of a purine
with an acylated sugar in the presence of a suitable acid such as p-toluenesulfonic acid or
a compound such as tin(IV) chloride or antimony chloride. One of rnany exarnples includes
the preparation (48% yield) of 2,6-dibrorno-9-(ß-D-ribofuranosyl)purine by fusion at
130 0 C over 30 rninutes of 1,2,3,5-tetra-O-acetyl-ß-D-ribose with 2,6-dibrornopurine in
the presence of p-toluenesulfonic acid (B-68MI40901, p. 180).
The use of 2-deoxyribose derivatives tends to produce anorneric mixtures of nucleosides.
Thus 3,5-di-O-p-nitrobenzoyl-2-deoxY-D-ribofuranosyl chloride and N 6 -benzoyladenine
and molecular sieves gave, after deblocking with methanolic bariurn methoxide, a mixture
of the anomeric 2' -deoxyadenosines (B-68MI40901, p. 183). A variation to this technique
includes the condensation of N 6 -benzoy1chloromercurioadenine with 5-0-benzoyl-2-
deoxY-D-erythro-pentose diisopropyl dithioacetal in acetonitrile under reflux over 4 hours
to produce the same anomeric mixture of 2'-deoxyadenosines (B-68MI40901, p. 132).
I-Methylpurine is conveniently prepared by dethiation of 1-methyl-6-thioxo-(1H)-purine
with Raney nickel (62JOC990). An alternative route to 1-substituted purines involves
protection of the 9-position with a rernovable group followed by alkylation. Thus 9-
propenylhypoxanthine, prepared by a Traube synthesis, is readily rnethylated by methyl
p-toluenesulfonate to produce l-rnethyl-9-propenylhypoxanthine (367) frorn which
l-rnethylhypoxanthine rnay be obtained by oxidative removal of the propenyl group with
alkaline potassiurn perrnanganate (B-68MI40901, p. 22). I-Methyladenine has been prepared
similarly (65JOC3235). The benzyl group rnay also be used for protecting the 9-position in
such cornpounds and can subsequently be rernoved by hydrogenolysis.
o
MeN^yN)
jlN
CHzCH=CH z
(367)
In the case of nucleosides which contain a 9-g1ycosyl group, alkylation occurs at the
I-position. In this way, l-isopentenyladenosine is obtained by direct alkylation of adenosine
with isopentenyl brornide (B-68MI40901, p. 212).
In contrast to 9-substituted purines, direct alkylation of adenine with benzyl chloride in
DMA at 115 oC for 18 hours produced 3-benzyladenine (60% yield) which, when deami-
nated with nitrosyl chloride, afforded 3-benzylhypoxanthine (61 % yield) (B-68MI40901, p. 28).
Triacanthine (3-isopentenyladenine) was prepared sirnilarly frorn adenine and isopentenyl
brornide (B-68MI40901, p. 13).
Purines
595
In a similar fashion rnethylation of 6-methylthiopurine with rnethyl p-toluenesulfonate
in DMA at 95 oC over 1 hour afforded 3-methyl-6-rnethylthiopurine which could either be
de sulfurized with Raney nickel to give 3-rnethylpurine or reacted with primary arnines in
hot rnethanol over 12 hours to produce 3-methyladenine derivatives (B-68MI40901, p. 36).
Glycosylation of adenine with 2,3,5-tri-O-benzoyl-ß- D-ribofuranosyl brornide in
acetonitrile at 50 0 C over 36 hours also produced, after deblocking with rnethanolic
amrnonia, 3-(ß-D-ribofuranosyl)adenine (25% overall yield) (B-68MI40901, p. 160). In con-
trast 3-rnethylguanine is probably best prepared by a Traube synthesis frorn 2,5,6-triarnino-
1-methyl-4-oxo-3,4-dihydropyrirnidine in refluxing forrnarnide over 1.5 hours (80% yield),
and 3-rnethyluric acid rnay be usefully obtained by a sirnilar fusion reaction with urea at
150 o C, followed by alkaline hydrolysis of the interrnediate 2-arnino-3-rnethyl-6,8-dioxo-
1,9-dihydropurine. 3-Methylxanthine has also been prepared by alkaline hydrolysis of
3-methylguanine (84% yield) (B-68MI40901, p. 18).
7 -Substituted purines rnay arise in rnixtures with 9-substituted derivatives frorn direct
alkylation of purine anions. They are best prepared however by Traube syntheses. Thus
forrnylation of 4,5-diarnino-6-benzylthiopyrirnidine and ethylation of the forrnyl derivatives
gave a forrnarnidopyrimidine which readily cyclized to 6-benzylthio-7 -ethylpurine in the
presence of potassiurn carbonate (B-68MI40901, p. 31). The derivative is clearly a ready source
of 7-substituted adenines by reaction with arnmonia or arnines, or of 7-substituted purines
by dethiation with Raney nickel. 7-Methylguanine has also been obtained frorn 7-rnethyl-
guanosine, sodium borohydride and aniline at pH 4.5 (B-78MI40903, p. 615).
By reaction with appropriate nucleophiles, 6-chloropurine has been the rnajor inter-
rnediate for the preparation of 6-substituted purines. It has in particular been widely used
to prepare large nurnbers of 6-aminopurine derivatives. Thus with 3-methylbut-2-enylarnine
in 2-rnethoxyethanol, 6-chloropurine produces the cytokinin and tRNA constituent N 6 -(3-
methylbut-2-enyl)adenine (B-68MI40901, p. 11). This rnethod uses an excess of arnine to
rernove hydrogen chloride. Triethylarnine rnay be used for this purpose to conserve the
prirnary arnino cornpound, as in a synthesis of the cytokinin zeatin frorn 6-chloropurine
and trans-4-hydroxy-3-rnethylbut-2-enylarnine and triethylarnine in hot butanol
(66JCS(C)921). 6-Chloropurine riboside has been used sirnilarly to prepare zeatin riboside
(66JCS(C)921). The corresponding 6-chloro-9-(ß-D-ribofuranosyl)purine 5' -phosphate has
also been prepared by an irnproved process (68JCS(C)1516) and used to prepare zeatin ribotide
and other N 6 -substituted AMP derivatives by reactions with appropriate arnines.
(ii) N-Arninopurines
N-Aminopurines have been prepared frorn either pyrimidine or irnidazole precursors.
Thus 9-arninopurine rnay be obtained frorn 5-amino-4-hydrazinopyrimidine and formic acid
(6OJA4592). On the other hand 9-arnioo-8-rnethylhypoxanthine resulted frorn cyclization
of 1,5-diarnino-4-carbarnoyl-2-rnethylirnidazole with triethyl orthoforrnate and acetic
anhydride (6IJCS4845).
1-Aminoadenine is probably best obtained by arnination of adenine with rnesitylenesul-
fonylhydroxylarnine (74JOC3438) and the related 1-arninoinosine and guanosine were pre-
pared frorn the nucleosides and hydroxylarnine-O-sulfonic acid in aqueous sodium hydroxide
(69JOCI025). The sarne reagent is used in the preparation of 6,7 -diarnino-8-oxo-7,8-dihydro-
9-(ß- D-ribofuranosyl)purine frorn 8-oxo-7,8-dihydroadenosine (69JOC2157).
Substituted 3-arninopurines have also been best prepared by Traube syntheses frorn
3-(substit1;lted arnino)-4,5-diarninopyrirnidines and triethyl orthoforrnate (63JOC1162).
(iii) N-Oxides
Examples of all the four purine N-oxides are known. Purine l-oxide may be prepared
frorn purine and perbenzoic acid over two weeks (62JOC567), and adenine l-oxide is sirnilarly
prepared frorn adenine over 2 days (58JA2759). On the other hand hypoxanthine l-oxide
is best obtained by dearnination of adenine l-oxide (66JOC966). Reaction of 5-arnino-4-
hydroxyforrnarnidinoirnidazole with carbon disulfide rnay be used to rnake 2-thioadenine
l-oxide which with alkaline peroxide provides a useful route to isoguanine l-oxide
(67JOC1l51).
Purine 3-oxide has been prepared in good yield (64%) by hydrolysis of purine-6-sulfonic
acid 3-oxide with 90% formic acid (B-78MI40901, p. 33). Guanine 3-oxide rnay be obtained
directly frorn guanine and hydrogen peroxide in trifluoroacetic acid and when boiled with
6N hydrochloric acid it readily produced xanthine 3-oxide (69JOC978). 6-Chloropurine
596
Purines
3-oxide may be prepared similarly from 6-chloropurine and peroxyphthalic or peracetic
acid in ethanol (69BCJ750, 69JOC2153). Hydrolysis of the latter oxide with sodium hydroxide
is a useful route to hypoxanthine 3-oxide and to 6-methoxy, 6-brorno-, 6-iodo- and
6-sulfo-purine 3-oxides by reaction with appropriate nucleophiles (69BCJ750, 69JOC2157).
Purine 7 -oxides are generally rnost conveniently made by Traube syntheses from nitroso-
or nitro-pyrirnidines as with 7-hydroxytheophylline (66LA(691) 142, 66LA(693)233, 66LA(698)145,
66LA(699)145,72JOC1871).
Purine 9-oxides on the other hand are best rnade frorn irnidazole precursors. Thus
9-hydroxy-8-rnethylxanthine (368) and hypoxanthine (369) have been rnost conveniently
obtained by cyclization of 5-amino-1-benzyloxy-2-rnethylirnidazole-4-carboxarnide (370)
with carbonate or forrnate esters, respectively, and debenzylation of the interrnediate
benzyloxy derivatives with hydrogen brornide in acetic acid (Scherne 156) (72JOC1867).
o
H 2 NCO OCH 2 Ph :J=
( N HN N
H 2 N )Me - R I ')Me
N N N
OH
(370) (368) R = OH
(369) R=H
Scheme 156
4.09.7.7.5 O-Linked purines
Hypoxanthine is readily available frorn a Traube synthesis using triethyl orthoforrnate
and acetic anhydride in 95% yield (60JOC148) and an alternative one-step preparation frorn
arninornalonamidine, triethyl orthoforrnate in DMF gives an 85% yield. Sirnilarly,
xanthine is probably best prepared by acid hydrolysis or nitrous acid dearnination of guanine
(1861LA(118)151) or by Traube cyclization procedures. Guanine labelled at N-3 and N-l has
also been prepared by the Traube rnethod using IsN-Iabelled guanidine (44JBC(153)203).
Hypoxanthine is an irnportant primary feedstock intermediate for the synthesis of rnany
6-substituted purines especially the 6-thioxopurines and adenine derivatives.
Most of the other oxopurines have been prepared by Traube syntheses. Thus 2-oxo-2,3-
dihydropurine rnay be rnade frorn 4,5-diarnino-2-oxo-2,3-dihydropyrirnidine and forrnic
acid (12JBC(11)67), and 8-oxo-7,8-dihydropurine is best prepared frorn 4,S-diamino-
pyrirnidine and urea (54JCS2060).
. 2,8-Dioxo-2,3, 7 ,8-tetrahydropurine and 6,8-dioxo-1,6,7 ,8-tetrahydropurine ar.e sirni-
larly'prepared frorn 4,S-diarnino-2-oxo-2,3-dihydropyrirnidine and 4,5-diarnino-6-Q:!m-1,6-
dihydropyrirnidine and urea, respectively (54JCS2060).
Uric acid is probably best prepared frorn 4,5,6-triamino-2-oxo-2,3-dihydropyrirnidine
and urea, and rnateriallabelled at positions 1,3 and 9 by IsN has been made in excellent
yield by this procedure (48JA1240).
Alkoxypurines, especially 6-alkoxypurines, are norrnally best prepared by reaction of a
chloropurine with a sodiurn alkoxide as with 6-methoxypurine frorn 6-chloropurine and
sodiurn methoxide (57CB698). However Traube syntheses have also been used in the
preparation of 2-rnethoxypurine frorn 4,5-diarnino-2-rnethoxypyrirnidine and forrnic acid
(S4JCS2060) or 2,6-dirnethoxypurine frorn the corresponding dirnethoxypyrirnidine
(54JAS087). 8-Ethoxypurine has also been usefully prepared frorn 4,5-diaminopyrirnidine
and tetraethoxyrnethane (74JCS(Pl)349).
4.09.7.7.6 S-Linked purines
A major route to thioxopurines involves thiation of the corresponding oxopurine. Thus
a good yield of 6-thioxo-1,6-dihydropurine is obtained frorn hypoxanthine and phosphorus
pentasulfide (61JA4038). Thiation of an appropriate diarninopyrimidine and concornitant
cyclization to a thioxopurine is sornetirnes possible as in the preparation of 2-arnino-1-
rnethyl-6-thioxo-1,6-dihydropurine frorn 2,6-diarnino- 5 -forrnarnido-3-rnethyl-4-oxo-3,4-
dihydropyrirnidine and phosphorus pentasulfide in refluxing pyridine over 30 hours
Purines
597
(B-68MI40901, p. 44). Alternatively, Traube cyclizations with thiourea have provided a valuable
route to 8-thioxopurines as in the reaction of 2,5,6-triarnino-3 rnethyl-4-oxo-3,4-di-
hydropyrirnidine and thiourea at 200 0 C followed by 1N potassium hydroxide to give
8-rnercapto-1-rnethylguanine (B-68MI40901, p. 45). When the appropriate chloropurine is
readily available, the related thioxopurine may be obtained by reaction with various sulfur
derivatives including thiourea fusion as in the preparation of 9-benzyl-6-thioxo-1,6-dihy-
dropurine (94% yield) frorn 9-benzyl 6-chloropurine and thiourea in hot propanol over 2
hours (B-68MI40901, p. 47). Sodiurn hydrosulfide is also used as in the conversion of 2-
acetamido-6-chloro-9-(2-deoxy-3,5-di-O-p-toluoyl)purine into the 6-thioxo derivative (B-
68MI40901, p.272). S-Alkylation of thioxopurines including nucleosides is readily achieved
(in yields of 52-78%) by reaction with alkyl halides in DMF in the presence of potassium
carbonate and several examples may be found in the publication (B-68MI40901, p. 258).
The synthesis of purinesulfonic acids (yields 87-96%) rnay be successfully achieved by
oxidation of the corresponding thioxo derivatives with sulfite ions in the presence of oxygen
(74CB2284, B-78MI40903, p. 677). 6-Methylsulfonylpurines have, on the other hand, been pre-
pared from the methylthiopurine and chlorine, as in a synthesis of 6-rnethylsulfonyl-9-(ß- D-
ribofuranosyl)purine (50-75% yield) from chlorine in 90% ethanol solution at OOC over
10 minutes (B-78MI40903, p. 651).
Purine-6-sulfinic acid 3-oxide has been prepared in excellent yield (92%) from 6-thioxo-
1,6-dihydropurine 3-oxide and active manganese dioxide in aqueous sodiurn hydrogen
carbonate (B-78MI40901, p. 33).
4.09.7.7.7 Se-Linked purines
Related selenoxopurines have been prepared by replacement of the 6-amino group in
selected purines. Thus 9-(ß-D-ribofuranosyl)-6-selenoxo-1,6-dihydropurine (371) was con-
veniently prepared (56% yield) from adenosine in aqueous pyridine with hydrogen selenide
over 5 days at 65 oC. In a similar rnanner 2-arninoadenosine furnished 6-selenoguanosine
(21 %) (B-78MI40903, p. 673, 75CC319, 75JHC493). The latter compound rnay also be obtained
(58% yield) frorn 2-arnino-6-chloro-9-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)purine and
sodium hydrogen selenide. The rnethod adopted for the preparation of selenoxo derivatives
depends on the relative availability of thè appropriate chloro or aminopurine.
Se
(JLNH
/,,-..(,.oyN N)
H 0 L....J
HO OH
(371J.
4.09.7.7.8 Halogenopurines
2-Chloropurine is best rnade by the Traube process frorn 4,5-diamino-2-chloropyrimidine
and triethyl orthoforrnate (56JA1928) whereas 2-fluoropurine is better prepared (in 41 %
yield) frorn 2-aminopurine with sodiurn nitrite and 48% fluoroboric acid. Sirnilarly 2,6-
diaminopurine afforded 6-arnino- 2-fluoropurine in 22 % yield with sodiurn nitrite in liquid
hydrogen fluoride (69JOC7 4 7).
The valuable 6-chloropurine has been prepared from hypoxanthine by reaction with
phosphoryl chloride in the presence of dirnethylaniline (54JA6073), or better, N-ethyl-
piperidine (64ZC430). 6-Bromopurine is prepared in the same way using phosphoryl brornide
(56JA3508). An alternative synthesis of 6-chloropurine (67% yield) proceeds frorn 6-
hydrazinopurine and iron(III) chloride (B-78MI40901, p. 19). The hydrazinopurine rnay be
prepared frorn 6-rnethylthiopurine and hydrazine (58JA404). The (albeit hazardous) chlorina-
tion of thiohypoxanthine has also been recomrnended (62MI40904) as a route to 6-
chloropurine. 6-Iodopurine is best obtained frorn 6-chloropurine and hydrogen iodide
(56JA3508).
598
Purines
6-Chloro-9-(ß-D-ribofuranosyl)purine has similarly been prepared from inosine
(63JOC94S) by chlorination of 6-thioinosine (63MI40903) or, perhaps most success-
fully, by reaction of 2',3',5'-tri-O-acetylinosine with (chlorornethylene)dirnethylarnrnoniurn
chloride when yields of 70% are produced (B-78MI40903, p. 611). The latter reagent is obtained
from phosgene and DMF in chloroform solution (B-78MI40903, p. 989).
6-Bromo- or 6-iodo-9-(ß-D-2,3,5-tri-O-acetylribofuranosyl)purines have been prepared
in good yields (72.7% and 68.6%) from 2',3',5'-tri-O-acetyladenosine with pentyl nitrite
in brornoform or diiodomethane (as halogen sources), respectively, under 200 W illurnina-
tion (80JOC3969).
6-Fluoropurine is probably best prepared frorn 6-chloropurine. This was used to quatern-
ize trirnethylamine and the resultant quaternary salt on treatrnent with potassiurn hydrogen
fluoride in ethanol at 50 oC afforded 6-fluoropurine (69CC381) in good yield.
2,6-Dichloropurine rnay be prepared from xanthine with either phosphoryl chloride and
a trace of water (S6JA3508) or with phosphoryl chloride and phosphorus pentachloride
(S8JA27S1), and sirnilarly 2,6,8-trichloropurine resulted in 90% yield from heating uric acid
with an excess of phosphoryl chloride (SSMI40900).
8-Halogenopurines are generally rnost usefully prepared by direct halogenation of the
purine (62JOC986) with halogens or halogeno amides.
4.09.8 NATURALLY OCCURRING PURINES-BIOCHEMISTRY
AND APPLICATIONS
4.09.8.1 Biosynthesis
4.09.8.1.1 De novo biosynthetic pathways
New purine bases are produced, at the nucleotide level, by the de novo biosynthetic
route which cornmences with 5-phospho-a-D-ribosyl pyrophosphate and proceeds via
5-phospho-ß-D-ribosylamine to produce IMP in a sequence of enzyrne-controlled reactions
involving arninoimidazole intermediates. IMP is further converted into AMP and GMP by
separate pathways (Scherne 157).
4.09.8.1.2 Salvage pathways
The salvage pathway does not involve the formation of new heterocyclic bases but perrnits
variation according to dernand of the state of the base (B), i.e. whether at the nucleoside
(N), or nucleoside rnono- (NMP), di- (NDP) or tri- (NTP) phosphate level. The rnajor enzyrnes
and routes available (Scheme 158) all operate with either ribose or 2-deoxyribose derivatives
except for the phosphoribosyl transferases. Several enzyrnes involved in the biosynthesis of
purine nucleotides or in interconversion reactions, e.g. adenosine deaminase, have been
assayed using a rnethod which is based on the formation of hydrogen peroxide with xanthine
oxidase as a coupling enzyme (81CPB426).
4.09.8.2 Naturally Occurring Purines
4.09.8.2.1 Methylated purines
Methylation is an irnportant biochernical event and all the cornrnon purines and their
nucleosides occur naturally in rnono- or poly-methylated forrns. Sorne comrnon naturally
occurring purines are collected in Table 39.
1- MethylxantQine is the rnajor purine constituent of hurnan urine (3.1 g in 1000 1)
(1898ZPC(24)364). 3- and 7-Methylpurines are also rninor constituents of urine, especially
following large doses of caffeine or other methylated xanthines. 1,3-Dirnethylxanthine
(theophylline) occurs with caffeine in tea leaves and is a powerful diuretic and has been
used clinically for this purpose (generally as an adduct with salts of organic acids) and also
in the treatrnent of asthma. 1,7-Dirnethylxanthine (paraxanthine) is also an efficient diuretic
and, in addition, possesses antithyroid properties (4SJCS7S1). The rnain purine constituent
Purines
599
glutamine glutamic acid
HzO PP i
HO J HO
I 0 OH OH ION
HO-P-O I I HO-P-O Hz
II O-P-O-P-OH - ,;-- II
o II II Mg 0
HO OH 0 0 HO OH PRA
PRPP
}Jì
HO O=CH A
ION 0
HO-P-O H
II
o
HO OH FGAR
glutamine
ATP, HzO ,+
Mg
glutamic acid
ADP,Pi
H ATP
HO o= cC l
ION NH
HO-P-O H
II
o
HO OH FGAM
o íCOzH
N0 ...J-COzH
OH < Jl....
HO-Þ-O O N NHz
II
o
HO OH SAICAR
fumaric ì
acid 1
N10_formyl
THFA THFA
HO (p-CONH z U
I o N)LNHz
HO-P-O
II K+
o
HO OH AICAR
N JL O NH
OH < I I
ION -:::?
HO-P-O N
II
o
HO OH IMP
Scheme 157
glycine, A TP =ï
Mg'+
ADPP i
N 5 N 10 _melhenyl
THFA THFA HzN 1
U HO
ION 0
OH-P-O H
II
o
HO OH GAR
ADP, Pi, HzO N
\ J HO (1
"-- HO-Þ-O o N NHz
Mg'+, K+ II
o
HO OH AIR
COz,(HCOî)
1 Mg'+
ADP L-aspartic acid
P i J AT P HO (p-COzH
I o N)LNHz
_ - HO-P-O
Mg'+ II
o
HO OH CAIR
N
HO ( p-CONH z
I 0 N)LN-C=O
HO-P-O H H
II
o
HO OH FAICAR
/
HzO
600 Purines
(1) Phospho ribosyl transferases (ribose only)
B+RfTP --. NMP+(Pz);
(2) Nucleoside phosphorylases
B+I-R f MP <-+ N+P j
(3) Nucleoside kinases
ATP+N --. NMP+ADP
(4) 5'-Nucleotidases
NMP+HzO --. N+P,
(5) Nucleoside monophosphate kinases
N1MP+NzTP <-+ N1DP+NzDP
(6) Nucleoside diphosphate kinases
N)DP+NzTP --. N1TP+NzDP
Scheme 158
Table 39 Some Naturally Occurring Purines
Substitution at position
Trivial name 1 2 3 6 7 8 9
Adenine H NH z H H
Guanine NH z OH H H
Isoguanine OH NH z H H
Hypoxanthine H OH H H
Xanthine OH OH H H
Uric acid OH OH OH H
Theophylline Me OH Me OH H H
Theobromine OH Me OH Me H H
Caffeine Me OH Me OH Me H H
Isocaffeine Me OH Me OH H Me
Triancanthine H R 1 NH z H H
Eritadenine H NH z H R Z
Kinetin H NHR 3 H H
6-Methylaminopurine H NHMe H H
6-Dimethylaminopurine H NMez H H
6-Succinoaminopurine H NHR4 H H
Discadenine H R 5 NHR 1 H H
+
Herbipoline NH z 0- H Mez
R: = CHzCH=OMe)z; R Z = CHz(CHOHhCOzH; R 3 = furfuryl; R 4 = CH(COzH)CHzCOzH;
R' CHzCHzCH(NHz)COzH.
of the cocoa bean is 3,7-dirnethylxanthine (theobromine) (51AGSll) and smaller arnounts
of theophylline are also present (68N299). Theobromine is also strongly diuretic and like
theophylline it forrns soluble cornplexes with salts of various organic acids which aids oral
use. 1,2,7-Trirnethylxanthine (caffeine) is the major purine of the coffee bean and also
occurs in tea leaves (ca. 3.5%). It is a cardiac and respiratory stimulant and is frequently
used in headache powders. It has recently been shown that 7-rnethylxanthosine (372) is an
intermediate in caffeine biosynthesis (78P207S). Methylated adenines including 6-rnethyl-
arninopurine (S8JBC(230)717) and 6-dimethylarninopurine (S8MI40902) are of comrnon occur-
rence as constituents of yeast and other tRNAs.
NHz
MeN N')
O -AN
N R
(372)
2'-O-Methyladenosine (Am), 2'-O-methylguanosine (G m ) and 7 -rnethylguanosine (rn 7 G)
are also involved in capped 5'-terrnini of rnessenger RNA (rnRNA) produced by vaccinia
virus (7SPNA318,7SMI40903). Two types of termini are produced, narnely rn 7 G(5')_pppG m
and rn 7 G(5')-pppA m. Sirnilar caps occur in virus-specific rnRNA isolated from vaccinia-
Purines
601
infected HeLa cells where the terrnini also carry additional rnethyl groups on the N-6 atorn
of the penultirnate adenosine and the 2'-hydroxy group of the third nucleoside (77MI40904),
and the presence of such rnethylated 5'-ends (caps) appears to be a feature of eukaryotic
rnRNA, heterogeneous nuclear RNA and low rnolecular weight RNAs. Exceptions include
polio and other viruses. When the 7-rnethylguanosine cap is removed frorn the rnRNA of
vaccinia virus, significant loss of ability to bind to ribosornes and to stirnulate protein
synthesis in vitro occurs but this is recovered when the 7 -rnethylguanosine is replaced
(7SJBC(253)1710). In contrast, elirnination of the penultirnate 2'-O-methyl group appeared
to have only a rninor effect upon ribosome binding in vitro. Inhibition of the capping
rnechanisrn rnay be important as an explanation of antiviral activity with rnany com ounds.
7-Methylguanine or epiguanine (lS9SCB3272) also occurs in urine (3.4 g per 10 I) and
1-rnethylisoguanosine (doridosine) has been isolated frorn the marine sponges Tedania
digitata (SOMI40900) and Anisodoxis nobilis (SOMI40905). The latter compound has powerful
muscle relaxant and cardiovascular activity when administered orally in animals and since
it is resistant to adenosine deaminase it is thought to act as a long acting adenosine.
Adenosine of course is rapidly dearninated to inosine in vivo. The enzyrne which catalyzes
the dearnination, namely adenosine deaminase (aminohydrolase E.C. 3.5.4.4), is strongly
inhibited by transition state analogs (nACR10), i.e. cornpounds with enzyrne binding proper-
ties which resernble those of the highly reactive substrate intermediates approaching the
transition state (373). The naturally occurring cornpounds pentostatin (374)
(74JHC641, 77MI40903) and the ribose analog coformycin (375) (B-70MI40900) are two such
cornpounds which possess a tetrahedral carbon at what would be the analogous C-6 position
in adenosine and the transition state in the latter rnay be regarded as the tetrahedral state
(373). Isocoforrnycin (376) is a related inhibitor of adenosine deaminase (79MI4090S). These
compounds have been widely used to increase the efficacy of the antitumour drug
arabinofuranosyladenine by prolonging its action in vivo. Sirnple transition state analogs
including ethanol adducts presumably at C-6 have also shown enzyme-inhibiting activity
(70JA4751).
Enzyme
I
o NH 2
HN><y-N
-jlN
N I
(373) R
HO H
HNti: N >
'=N N
R
(374) R=dRf
(375) R = Rf
H OH
'(:X N >
N N
I
(376) R
4.09.8.2.2 Cytokinins
The cytokinins are plant growth substances which prornote cell division (B-71MI40900,
65MI4090S). They are adenine derivatives, the first of which to be isolated frorn a natural
source (Zea mays) was zeatin, trans-6-(4-hydroxy-3-methylbut-2-enyl)aminopurine (377a)
(63MI40900), 0.7 mg of which was isolated from 60 kg of corn. The structure (64CC230, 67T479)
was confirmed by synthesis (64CC231, 66JCS(C)921) frorn 6-chloropurine and trans-4-hydroxy-
3-methylbut-2-enylamine, the latter compound being obtained frorn methyl (E)-2-methyl-
crotonate. The cis isorner of zeatin also occurs naturally but was found to be 50 times less
active than the trans isorner in a standard tobacco callus bioassay (71JA3056). The cis forrn
(ns61s) has also been synthesized and occurs as a 9-ß-ribonucleoside in Nicotinia tabacurn
(7SMI4091O).
Other naturally occurring cytokinins include (- )dihydrozeatin (377b) frorn. irnrnature
seeds of Lupinus luteus (67TL1317). N 6 -lsopentenyladenine (377c) occurs as the free base
in Corynebacterium fasciens (66PNA(56)52,66PNA(56)60), as a 9-ß-D-ribofuranosyl derivative
in tRNA of yeast and calf liver (66JA2614,66AG392) and in spinach and garden peas
(67MI40902). Both zeatin (65PNA(54)1052) and the cis isorner (6SMI40906,70B3701) have also
been isolated as 9-ß-D-ribofuranosides. Various adenine derivatives related to zeatin have
also been isolated frorn Zea mays, including 6-(2,3,4-trihydroxy-3-methylbutyl-
arnino)purine (377d) (73P2445), and O-glucosylzeatin occurs in Populus species (79PS19).
602
Purines
R1NH
N N
J.-N R3
N R2
(377a) R ' =CH 2 CH=CMeCH 2 0H(trans); R 2 =R 3 = H
(377b) R 1 =CH 2 CH 2 CHMeCH 2 0H; R 2 = R J = H
(377c) Rl=CH2CH=CMe2;R2=R3=H
(377d) R 1 = CH 2 CH(OH)C(OH)MeCH 2 0H; R 2 = R J = H
(377e) R 1 = 2-furfuryl; R 2 = K' = H
(377f) R 1= PhCH 2 ' R 2 = R 3 = H
1 ' 2 3
(377g) R = o-hydroxybenzyl; R = glucofuranosyl; R = SMe
Perhaps the first cytokinin to be examined in detail was kinetin or 6-furfurylarninopurine
(377e), originally thought to be of natural occurrence but later found to be an artefact
produced in and isolated from autoclaved solutions of DNA (56JA1375). N 6 -Benzyladenine
(377f) has strong cytokinin activity and in rninute arnounts has been used cornrnercially
(verdan) to keep green vegetables such as lettuces fresh for extended periods. Substituted
benzyladenines have also been isolated frorn natural sources including the N 6 -0- hydroxy-
benzyl-8-rnethylthio-9-g1ucofuranosylpurine (377g) frorn Zantedeschia aethiopica (a
cuckoo pint) (80TL4387). A recent review of structure-activity relationships of 161 cytokinins
including synthetic cornpounds has appeared (80P2239).
4.09.8.3 Nucleoside Antibiotics and Related Compounds
Several glycosylpurines have been isolated frorn rnicroorganisrns (Table 40) and proved
to have substantial biological activity (B-70MI40900). They include substances such as 9-(ß-D-
arabinofuranosyl)adenine (Ara A) which is a powerful antiviral and antitumour agent and
Purine nucleoside
Table 40 Some Purine Nucleoside Antibiotics and Related Compounds
6- Dimethylamino-9-[ (3- p-methoxy-ß-
I.-phenylalan ylamino )-3-deoxy-ß- D-
ribofuranosyl]purine
3' -Deoxyadenosine
3' -Amino-3' -deoxyadenosine (plus 3' -N-
acetylhomocitrullyl and Iysyl)
6- Amino-9-(ß- D-psicofuranosyl)purine
9- ß-D-( 5 .6- Psicofuranosenyl) -6-aminopurine
9 -(ß - D- Ribofuranosyl)-2-methoxyadeni ne
9 -( ß- D- Arabinofuranosy I )adenine
9-[ß-(2'a,3'a-dihydroxy-4'ß-
(hydroxymethyl)cyclopentyl]adenine
4' ,5' -Dehydroaristeromycin
9-(F1uoro-5-0-
sulfamoylpentofuranosyl)adenine
N 6 -[Isopalmitoy Igi ycy 1-4-amino-4-deoxy- L-
glycero- L-glycoheptosyl]purine
9 -(ß-D- Ribofuranosyl)purine
2- H ydroxy-9-(ß- D-ribofuranosyl)adenine
9 - ß- D- Ribofuranosyl )hypoxanthine
N -(ß-D-Ribofuranosyl)-4,6-
dimethylimidazo[ 1 ,2-a ]purine
I-Methylisoguanosine
2 -Methylthio-N - carbonyl-[N-
threonyl]adenosine
Adenosine substituted on 5'-0 by a (-)chiro-
inositol L-gulosamine and L-serine unit
Trivial name (Origin)
Puromycin (S. alboniger)
Cordycepin (Cordyceps militaris and
Aspergillus nidulans)
(Helminthosporium. Cordyeeps militaris
and Aspergillus nidulans)
Psicofuranine (Angustmycin C)
(S. hygroseopicus var. deeoyieus)
Decoyinine (Angustmycin A)
(S. hygroseopieus)
Spongosine (c. trypta)
Spongoadenosine (S. antibiotieus)
Aristeromycin (S. citrie%r)
Neplanocin A (Aetinoplanaeea
ampullariella)
Nucleocidin (S. clavus)
Septacidin (S. fimbriatus)
Nebularine (Agaricus
(clitoeybe) nebularis and S.
yokosukanensis)
Crotonoside (Croton tiglium)
(S. antibiotieus)
Wyosine (Nucleoside YI) (Yeast
tRNA Phe )
Doridosine (Tedania digitata and
Anisodoris nobilis)
(Mammalian tRNA)
Adenomycin (S. griseoflavus)
Ref.
B- 70MI40900, p. 13
B-70MI40900. p. 50
B-70MI40900, p. 176
B-70MI40900. p. 98
B-70MI40900. p. 115
B- 70MI40900, p. 126
B-70MI40900, p. 128
B-70MI40900, p. 236
81CPB597
B-70MI40900, p. 246
B-70MI40900, p. 256
B-70MI40900, p. 261
B-70MI40900. p. 267
80JHC461
78TL2579
80TL567
80MI40905
79JA2224
80TL3203
Purines
603
is used clinically for these purposes (76MI4090S, 76MI40903, 76MI40906, 76MI40907). Activity of
the cornpound in vivo is severely reduced by its rapid dcamination with the enzyme adenosine
deaminase. However the activity may be prolonged by using the drug in the presence of
an adenosine deaminase inhibitor such as pentostatin (2'-deoxycoforrnycin) (77MI40903) or
by using a precursor (prodrug) of the cornpound such as the 2'-deoxy-2'-fluoro derivative
which produces Ara-A by slow hydrolysis (79JHC1S7).
Purornycin (378) has been extensively studied as an inhibitor of protein biosynthesis in
both bacterial and rnamrnalian cells. It is structurally similar to the aminoacyl end of
arninoacyl tRNA and functions by producing a codon-independent analog of arninoacyl
tRNA and so promotes the release of incornplete peptide chains frorn the ribosorne
synthesizing cornplex. It blocks peptide chain extension by reacting with the growing peptide
chain on the peptidyl-tRNA site on the ribosorne to produce a peptidylpurornycin derivative.
It is highly toxic to marnrnals and this restricts its use as an antibiotic. The aAalogous
homocitrullyarninoadenosine also inhibits protein synthesis apparently by inhibiting the
incorporation of leucine-tRNA (63BBA(72)62).
(=ð' <D
HO't} N H'NSO'OR:)' N
NHROH OH OH
(378) Puromycin; R = p-methoxy-L-phenylalanyl (379) Nucleocidin
Nuc1eocidin (379) which contains the first fluorosugar to be obtained frorn a natural
source is a more potent inhibitor of protein synthesis in vivo than purornycin but has similar
activity in vitro (66JBC(24)1091).
The ketosylpurines, psicofuranine and decoyinine, both have antimicrobial activity and
activity against adenocarcinorna in rats, and appear to operate by inhibiting XMP arninase
(60MI40900, 60BBR(3)S96).
Septacidin and nebularine has sorne activity against tumour cells (B-70MI40900) and
nebularine in addition has some antibacterial action. It is, however, very toxic to rnice
(S3JBC(204)1019,66MI40902).
Carbocyclic nucleoside analogs such as Aristeromycin (380) have also been isolated from
natural sources (Table 40) and have antirnicrobial activity. The 4',5'-dehydro derivative of
the latter, narnely Neplanocin A, also has antitumoU'r activity and has been synthesized
(81CPBS97).
N NH 2
<
HOt)--ZN J
OH OH
(380)
Both naturally occurring and synthetic nucleoside derivatives of several purines or purine
analogs have a broad spectrurn of biological activity (B-74MI40900). Generally rnost of the
cornpounds only become active after intracellular phosphorylation, usually catalyzed by
adenosine kinase to produce nucleotides. It has been concluded (7SMI40902) that necessary
but not sufficient conditions for substrate activity with this enzyrne are (a) the nucleoside
should have a 2'-hydroxy group which should be trans to the purine unit, (b) there should
be a considerable degree of freedom of rotation about the C(l')-N(9) bond. Given these
conditions the 3'-hydroxy and 4'-hydroxyrnethyl group could be either cis or trans to the
purine ring.
In recent years exceptional antiviral activity has been obtained with cornpounds which
show structural analogy to the comrnon purine nucleosides. In particular the substance
acycloguanine (381) (78MI40909) and 9-(5- 2,3-dihydroxypropyl)adenine (382) have high
604
Purines
antiviral activity and are undergoing clinical trials. The latter corn pound is active in the
early stages of viral replication but is not antibacterial since it does not penetrate the
bacterial cell wall. It rnay also be seen to be related to the naturally occurring cornpound
eritadenine (383) which was isolated from Len tin us edodes (74JMC846) and synthesized
(73JOC2887, 73JOC2891). This compound has high hypolipidernic activity which is, however,
surpassed by the synthetic analog 9-(4-chlorophenoxy-2-hydroxypropyl)adenine
(78JMC1073). Related 2,3-dihydroxypropylguanine derivatives have also been prepared
(78CCC3103). Details of the synthesis and properties of various rnodified nucleosides found
as rninor cornponents in DNA and RNAs have been recorded (B-71MI40901).
]c o N
HN I )
H2N N
N I ......0" ......CHzOH
CH 2 CH z
NH 2
t N)
N N
CH 2 CHCH 2
I I
HO OH
(381)
(382)
NH 2 N
UN)
N I H OH
H 1 C ;::2 "'
" " CO,H
H' OH -
(383)
4.09.8.4 Miscellaneous
6-Mercaptopurine (6-thioxo-I,6-dihydropurine) was one of the first purine derivatives
to find application in the treatment of leukaemia, especially in children. The drug inhibits
the biosynthesis of purine nucleosides, including the conversion of IMP to AMP (S4MI4090S,
B-66MI40900). The S-irnidazolyl derivative (384), azathiopurine or Irnvran, has also been of
value as a suppressor of the irnmune response.
NO z
t s
eN N
_J-. I
N N
H
o
II
NHzCO
(384)
R
(385a) R= H
(35gb) R=a-OH
(385c) R = ß-OH
Saxitoxin (385a) is an unusual derivative of tetrahydrodiarninopurine. It is produced by
various marine dinoflagellates such as Gonyaulax catanella which form the red tides off
the coasts of Canada and the USA. The compound tends to accurnulate in various edible
shell fish such as the Alaska butter clam (Saxidornus giganteus), toxic rnussels (Mytilus
californianus), and scallops. Saxitoxin is one of the most toxic, non-protein, cornpounds
known and its presence in shell fish has created serious health and econornic problerns
along the North Atlantic coast. The structure of the compound has been deterrnined
(7SJAI238, 7SJA6008) and it has been shown to exist as a hydrated cation (385a). Proton
relaxation rates and scalar coupling constants have been used to define the total absolute
stereochemistry of saxitoxin in solution and to give details of the overall and internal
rotation of the rnolecule (80JAlS13). The pKa values of the cornpound have been deterrnined
by potentiornetric titration and observation of the change in the BC NMR chernical shifts
with pH (80JA733S).
A stereospecific total synthesis of (:t)-saxitoxin has been achieved (77JA2818). Related
hydroxysaxitoxins Gonyaulax II (385b) and III (385c) have also been isolated from
Gonyaulax tarnarensis (76JAS414, 82TL321) and N-sulfo derivatives of these have been isolated
frorn Protogonyaulax clone PI07 (81JA6977). The latter compounds, reported as the first
N-sulfocarbarnoyl derivatives to be found in a natural source, are relatively non-toxic but
readily hydrolyzed to the toxic materials. Related diaminopurines such as 2,6-diarninopurine
are also toxic and the latter compound also has antileukaernic activity.
605
Saxitoxin can be regarded as a 3-substituted purine. The compound discadenine (386),
isolated frorn the cellular slirne mold Dictyosteliurn discoideurn, was the first recorded
naturally occurring purine to contain an amino acid residue in the 3-position. The compound
has pronounced spore germination inhibitory activity and in addition has cytokinin activity,
showing two thirds the activity of kinetin at 10- 7 mol in the standard tobacco pith test
(76TL3807). Discadenine minus the isopentenyl group has the same spore germination
inhibitory activity as the parent (80C82043).
NHCH 2 CH=CMe 2
()J
N N
I
CH 2CH 2CH(N H 2) CO 2H
(386)
One of the more unusual bases found in tRN As (next position of the 3' -end of the
anticodon of yeast tRNA Phe ) is wyosine (226) (see Section 4.09.6.18) or nucleoside Yt, a
3-rnethylguanine derivative (71TL2725, 768898) which is characterized by its strong fluores-
cence. In addition, the nucleoside bond is very readily hydrolyzed in weak acid (pH 4)
solution. Similar compounds, wybutosine (227) and wybutoxosine (228) have been also
found in baker's yeast tRNA Phe (67PNA(57)751,70JA7617), rat liver (71MI40906, 738188) and
Lupinus luteus (74JA7797). The lability of the sugar rnade assignrnent of its position difficult.
However the structure has been confirmed by synthesis (78TL2579).
4.10
Other Imidazoles with Fused
Six-membered Rings
J. A. MONTGOMERY and J. A. SECRIST 11/
Southern Research Institute, Birmingham, Alabama
4.10.1 INTRODUCTION
4.10.2 STRUCTURE
4.10.2.1 1midazo[1,2-c]pyrimidine
4.10.3 REACTIVITY
4.10.3.1 1midazo[1,2-a]pyridine
4.10.3.2 1m idazo[1, 5- a]pyridine
4.10.3.3 1midazo[4,5- b]pyridine
4.10.3.4 1midazo[4,5-c]pyridine
4.10.3.5 1midazo[1,2-a]pyrazine
4.10.3.6 1midazo[1,5-a]pyrazine
4.10.3.7 1m idazo[4, 5- b]pyrazine
4.10.3.8 1midazo[1,2-a]pyrimidine
4.10.3.9 1midazo[1,2-c]pyrimidine
4.10.3.10 1midazo[1,5-a]pyrimidine
4.10.3.11 1midazo[1,2- b]pyridazine
4.10.3.12 1midazo[4,5- c]pyridazine
4.10.3.13 1midazo[4,5-d]pyridazine
4.10.3.14 1midazo[4,5-d][1,2,3 ]triazine
4.10.3.15 1m idazo[1, 2- b][1,2,4 ]triazine
4.10.3.16 1midazo[1,5- b][1,2,4]triazine
4.10.3.17 1midazo[1,5-d][1,2,4]triazine
4.10.3.18 1midazo[2,1-c][1,2,4]triazine
4.10.3.19 1midazo[5,1-f][1,2,4]triazine
4.10.3.20 1midazo[1,2- a][1,3, 5]triazine
4.10.4 SYNTHESIS
4.10.4.1 1midazo[1,2- a]pyridine
4.10.4.2 1midazo[1,5-a]pyridine
4.10.4.3 1midazo[4,5- b]pyridine
4.10.4.4 1midazo[4,5- c]pyridine
4.10.4.5 1midazo[1,2- a]pyrazine
4.10.4.6 1midazo[1,5-a]pyrazine
4.10.4.7 1m idazo[4, 5- b]pyrazine
4.10.4.8 1midazo[1, 2- a]pyrimidine
4.10.4.9 1midazo[1,2-c]pyrimidine
4.10.4.10 1midazo[1,5- a]pyrimidine
4.10.4.11 1m idazo[1, 5- b]pyrimidine
4.10.4.12 1midazo[1 ,2- b]pyridazine
4.10.4.13 1midazo[1,5-b]pyridazine
4.10.4.14 1midazo[4,5- c]pyridazine
4.10.4.15 1midazo[4,5-d]pyridazine
4.10.4.16 1midazo[4,5-d][1,2,3]triazine
4.10.4.17 1midazo[1,2-b][1,2,4]triazine
4.10.4.18 1m idazo[1, 5- b][1,2,4]triazine
4.10.4.19 1midazo[1,5-d][1,2,4]triazine and 1midazo[1,2-d][1,2,4]triazine
4.10.4.20 1midazo[2,1-c][1,2,4 ]triazine
4.10.4.21 1midazo[4,5-e][1,2,4]triazine
4.10.4.22 1midazo[5, 1- c][1,2,4 ]triazine
4.10.4.23 1midazo[5,1-f][1,2,4]triazine
4.10.4.24 1midazo[1,2-a][1,3,5]triazine
4.10.4.25 Imidazo[1,5-a][1,3,5]triazine
608
610
610
610
610
614
615
619
624
625
626
627
627
628
628
628
629
629
630
630
630
630
630
631
631
631
634
635
639
642
644
645
647
648
649
649
650
651
651
651
652
653
653
654
654
655
656
656
657
659
607
608
Other Irnidazoles with Fused Six-membered Rings
4.10.4.26 Imidazo[1,2- b][1,2,4,5]tetrazine
4. [().4.27 lmidazooxazines
4.10.4.27.1 Im idazo[1 ,2- c][1,3]oxazine
4. W.4.27.2 Imidazo[1, 5- c][1,J ]oxazine
4.10.4.27.3 Imidazo[2,1- b][1,3]oxazine
4.10.4.27.4 Imidazo[4,5-d][1,3]oxazine
4. W.4.27.5 Imidazo[5,1- b][1,3]oxazine
4.10.4.27.6 I midazo[2, 1- c][1 ,4 ]oxazine
4.10.4.27. 7 I midazo[ 5,1- c][1 ,4 ]oxazine
4.10.4.28 lmidazooxadiazines
4.10.4.28.1 lm idazo[1 ,5- b][1,2,5]oxadiazine
4.10.4.28.2 Imidazo[2, 1- b][1,3,4]oxadiazine
4.10.4.28.3 Imidazo[2,1-c][1,2,4]oxadiazine
4.10.4.29 lmidazothiazines
4.10.4.29.1 Imidazo[2,l- b](l,3]thiazine
4.10.4.29.2 Imidazo[1,2-c][l,3]thiazine
4.10.4.29.3 Imidazo[4,5- d][1 ,3 ]thiazine
4. W.4.29.4 Imidazo[4, 5- e][1,3]thiazine
4.10.4.29.5 I midazo[2,l- c][1 ,4 ]thiazine
4. W.4.29.6 Imidazo[5, 1- c][1,4]thiazine
4.10.4.30 lmidazothiadiazines
4.10.4.30.1 Imidazo[4,5-c][1,2,6]thiadiazine
4.10.4.30.2 Imidazo[4,5-e][1,2,4]thiadiazine
4.10.4.30.3 Imidazo[2, 1- b][1,3,4 ]thiadiazine
4.10.4.30.4 Imidazo[2, 1- b][1,3,5]thiadiazine
4.10.4.30.5 Imidazo[4,5-d][1,2,3]thiadiazine
4.10.4.31 Imidazo[4,5-cl1 ,5,2]diazaphosphorine and Imidazo[4,5-d][1,3,2]diazaphosphorine
4.10.4.32 Imidazo[4,5-d][1,3,2]diazaborine
4.10.1 INTRODUCTION
Fifty-two ring systerns composed of an imidazole fused with six-membered heterocyclic
rings have been described in the literature, and are pictured below. The best known of
these is the imidazo[ 4,5-d]pyrimidine (purine) ring systern described in the preceding
chapter. The other 51, the topic of this chapter, include the various azaindenes and rings
containing oxygen, sulfur, phosphorus, boron and combinations of those heteroatorns in
rings with nitrogen. The major interest in most of these ring systems results frorn their
resernblance to the biologically important purine; sorne of them have been shown to function
as antirnetabolites with potentially useful activities. In addition, sorne are of interest as dyes
or because of other properties such as the bioluminescence of luciferins, the biological
activity of the streptothricin antibiotics, and the fluorescence of certain of the irnidazo[1,2-
c ]pyrirnidines.
The literature on these rings systems varies frorn fairly extensive in the case of the
irnidazopyridines (deazapurines) to as little as a single journal article in the case of the
irnidazodiazaphosphorines. In recent years rnany studies of these systerns have included
rather cornplete characterization by means of UV, IR and NMR spectroscopy and rnass
spectrometry, and these studies have provided rnuch useful information. Owing to space
limitations, we have spent very little time on the physical properties of the corn pounds
unless sorne feature warranted special note. Reviews are available on irnidazo[ 1,2-
a ]pyridines (61 HC(15-1)460, 77HC(30-2)117), imidazo[1 ,5-a ]pyridines (61 HC(15-1)643, 77HC(30-
2)117), irnidazo[I,2-c]pyrazines (61HC(15-Z)774, 79HC(35)365), irnidazo[I,5-a]pyrazines
(iiI H('(15-2)835, 79HC(35)370), irnidazo[ 4,5-b ]pyrazines (79HC(35)376), imidazo[I,2-
a ]pyrirnidines (6IHC(15-Z)80Z), irnidazo[1,2-c ]pyrimidines (61HC(15-Z)764, 84MI41000), imi-
dazo[1 ,2-b]pyridazines (73HC(27)801), irnidazo[ 4,5-c]pyridazines (73HC(Z7)818), imidazo[ 4,5-
d]pyridazines (73HC(Z7)807), irnidazo[ 4,5-d][1 ,2,3]triazines (8ZMI41000, 75ANY(255)Z9Z,
7RHC(33)! 18), irnidazo[1 ,2-b ][1 ,2,4]triazines (61HC(15-Z)903), irnidazo[2,I-c]-
[1,2,4 ]triazines (78HC(33)88Z), irnidazo[5, 1-/][1,2,4 ]triazines (78HC(33)885), irnidazo[ 1 ,2-a]-
[1,3,5]triazines (59HC(13)43Z, 61HC(15-Z)906), imidazo[1,S-a][1,3,5]triazines (61HC(15-2)916)
and irnidazo[2,I-b][ 1 ,3]thiazines (61HC(15-Z)80l).
, Qj S I
N2
6 N-.j
5 4 J
,iY N
6 -J2
5
6 (X ' 1\2
5 N
3
Imidazo[ 4,5-b ]pyridine
Imidazo[ 4,5-c ]pyridine
6 cr ' N
N )2
S N
. 3
Imidazo[ I,Z-a ]pyridine
Imidazo[l ,5-a ]pyridine
659
660
660
660
660
660
661
661
661
662
662
662
662
663
663
664
664
664
665
665
665
665
666
666
667
667
667
668
Other Irnidazoles with Fused Six-membered Rings
8 I
7Nl--N
6ly 2
Imidazo[ 1 ,2-a ]pyrazine
8 I
7f1N
6N"./' --f2
5
Imidazo[ 1 ,2-c ]pyrimidine
1
co 7 (N 2
6N
3
5 4
8 1
7N
I 1 N2
6 N--J
5 4 3
:cNx>
3
Imidazo[ 4,S -b Jpyrazine
Imidazo[l,S-a ]pyrazine
1
8 N
7 N /j :) 2
\..--N 3
6 5 4
8 1
7("!\N2
6 N "./' --J
5 3
Imidazo[l,S -a ]pyrimidine
Imidazo[l,S -c ]pyrimidine
609
8 1
7 c NyN 2
6 NJ
5 4 3
Imidazo[l ,2-a ]pyrimidine
7IY- N
6 N/ 2
5
Imidazo[1,2-b ]pyridazine
7 I
N =c N 'N 2
6< I
N N 3
5 4
Imidazo[l ,5-b ]pyridazine Imidazo[ 4,S-c ]pyridazine Imidazo[ 4,S-d]pyridazine Imidazo[ 4,S-d][1,2,3]triazine
1
)-- 8 /N
\ N ) 2
6 N --l-.. 3
5 N
4
Imidazo[1,2-b ][1 ,2,4]triazine
8 I
7N N
I I \2
6 N "./' N--J
5 4 3
Imidazo[l ,2-d][ 1,2,4 ]triazine
1
8 N
/--.,/ 'N 2
7N' I
\..-- N 3
6 5
4
Imidazo[S,l-c ][1 ,2,4]triazine
I
8 N
7 NI"'--( ì 2
\..--N N 3
6 5 "./'
4
Imidazo[l,S-a][ 1 ,3,S]triazine
8 1
7("!\N2
6 o"./' N--J
5 4 3
Imidazo[l ,S-c ][1,3 ]oxazine
I
8 0
7NI"'--( :J 2
\..--N 3
6 5
4
Imidazo[S,l-b ][1,3]oxazine
1
7 0
;-N/ ì 2
6J\! I
N3
5 4
Imidazo[l ,Sob ][ 1 ,2,S]oxadiazine
7 c yN 2
6 NJ
5 4 3
Imidazo[2, 1-b ][1,3]lhiazine
7 I
N D N'N 2
6<
N 3
5 4
6N ): 7 N
I )2
sN N
4 3
8 1
N
7N/'--( ) 2
\..-N, 3
6 5 N
4
Imidazo[l,S-b ][1,2,4]lriazine
8 I
N y N'N 2
7\-- 3
4
Imidazo[2, 1-c][ 1 ,2,4 ]triazine
1
J..-.. 8 /N
/ N ì 2
6N, I
N3
5 4
Imidazo[S,1-f][1,2,4]triazine
8 1
7 N-r-- N 'N 2
\-- 'N)3
4
Imidazo[1,2-b ][1,2,4,S]telrazine
8 I
7 c oyN 2
6 NJ
5 4 3
Imidazo[2, 1-b ][1,3 ]oxazine
70 N\2
6 N.J
5 43
Imidazo[2, 1-c ][1,4 ]oxazine
y6 ) 2
7\-- 'N 3
4
Imidazo[2, 1-b ][1,3,4]oxadiazine
8 1
rl-- N
6 S ...............NJ 2
5 4 3
Imidazo[l ,2-c ][1 ,3]thiazine
8 I
N2
7N' 1 I
\..-- '-...,/ N 3
6 4
Imidazo[ 1,5 -d][ 1 ,2,4 ]triazine
7 I
N x NN 2
6< )
N 3
5 N
4
Imidazo[ 4,S-e ][1,2,4 ]triazine
8 I
7 N yN ì2
\- '-...,/N 3
4
Imidazo[l ,2-a ][1 ,3,5]triazine
8 I
7f1N
60y --f2
Imidazo[1,2-c ][1,3 ]oxazine
6 /yN>
IN)-..N
4 3"
Imidazo[ 4,S-d][1 ,3]oxazine
8 I
70
I 1 'N2
6 N--J
5 4 3
Imidazo[S, 1-c ][1,4]oxazine
8 1
7(N y N'02
\--N 13
6 5
4
Imidazo[2, 1-c][ 1 ,2,4 ]oxadiazine
6Jj:N>
N N
4 3
Imidazo[ 4,S-d][1,3 ]thiazine
610
Other Irnidazoles with Fused Six-membered Rings
7 I
6t :>
3
Imidazo[ 4,S-e][ 1,3 ]thiazine
7 I
N =c N 'S2
6< I
N N3
5 4
Imidazo[ 4,S-c ][1,2,6]thiadiazine
8 I
7 NY S ì 2
\.- N'-.,/N 3
b 5 4
Imidazo[2, 1-b][ 1 ,3,S]thiadiazine
7 I
N =c N , p2
< I
N N3
5 4
8 I
7s N
6 N J>
5 4 3
Imidazo[2, l-c ][1,4 ]thiazine
7 I
<:xs:r
5
Imidazo[ 4,S-e][ 1 ,2,4 ]thiadiazine
7 I
6<NyN' 2
W S3
5 4
Imidazo[ 4,S-d][1,2,3 ]thiadiazine
Imidazo[ 4,S-d][ 1 ,3,2]diazaphosphorine
4.10.2 STRUCTURE
8 I
7S
I I N2
6 N--J
5 4 3
Imidazo[ 5, 1-c ][ 1,4 ]thiazine
yS ) 2
7\- 'N 3
4
Imidazo[2, 1-b][ 1 ,3,4 ]thiadiazine
7 I
6<N X P 'N2
N )3
5 N
4
Imidazo[ 4,S-c][ 1 ,S,2]diazaphosphorine
7 I
N =c N 'B 2
0( I
N N 3
5 4
Imidazo[ 4,S-d][ 1 ,3,2]diazaborine
Data on the structures of other ring systems covered in this chapter are available prirnarily
frorn IR, UV and NMR spectroscopy, but nothing deserves special comrnent. Much of this
rnaterial is discussed in the reviews cited in Section 4.10.1.
4.10.2.1 Imidazo[1,2-c]pyrimidine
The rnain irnidazo[1,2-c]pyrimidines whose structural characteristics have drawn interest
are the cornpounds prepared from cytidine, the e -cytidine derivatives such as (la). X-Ray
data on e -Cyd . HCl (la) indicate a slight deviation of the nitrogen heterocycle frorn
planarity, an anti conformation about the glycosidic linkage, and no base stacking within
the crystal (76JA740l). Cornpound (la) has a fluorescence ernission rnaxirnurn at 340 nrn,
with a quanturn yield of <0.01 and a fluorescence lifetirne of 30:1: 5 ps (nBBR(46)S97,
7óJA 740S). The quantum yield and fluorescence lifetirne can both be enhanced by the
preparation of substituted derivatives, such as (lb) (76JA740S). Although the protonated
forrns such as (la) are fluorescent, the neutral species are not.
N
I I \R 1
RN y NJ
R 2
o
(1)
4.10.3 REACTIVITY
a; R = ß-o-ribofuranosyl, R t = H, R 2 = H, HCl
b; R = ß-o-ribofuranosyl, R 1 = NHCOMe, R 2 = H
c; R = ß-o-ribofuranosyl, R 1 = H, R 2 = HgOAc
4.10.3.1 Imidazo[1,2-a]pyridine
The position of rnethylation of 2-methylirnidazo[1,2-a]pyridine (2) has been established
as N-1 by an ambiguous synthesis of 1,2-dimethylimidazo[1,2-a]pyridine (3) frorn (4)
(6SJHC331). This work was extended by others to protonation and to methylation of other
imidazo[1,2-a]pyridines (66JOC129S), and it verified earlier conjectures concerning the
position of quaternatization (SSCB1093, 26CB2048, 64JCS4226).
Other Irnidazoles with Fused Six-membered Rings
611
Me Me
N N O H
NJMe -- 2)Me +- IN
(2) (3) Br (4)
O=CMe
I
BrCH l
(5)
Imidazo[1,2-a]pyridines also react at N-2 with haloketones, especially phenacyl bromide,
to give quaternary salts, with the ease of reaction depending upon the basicity of N-1 and
steric factors as deterrnined by ring substituents (26CB204S, 55CBI093). These salts undergo
a variety of reactions with bases including cyclization with a methyl group at C-2.
Acid-catalyzed exchange of deuteriurn for hydrogen occurs at C-3 of imidazo[1,2-
a]pyridine (8) and a number of its rnethyl derivatives (6SJOCIOS7). The exchange rate of
the corresponding 1-methylimidazo[1,2-a]pyridiniurn halides is considerably slower,
suggesting hydrogen-deuteriurn exchange on the free base rather than the protonated
species. Base-catalyzed exchange also occurs readily, but in this case at both C-3 and C-5
to give (7), as predicted by resonance considerations. The 1-methyl cornpounds (10) undergo
catalyzed exchange at C-2 as well as C-3 and C-5 to give (11), which is also predictable.
N N N
NJ -- NJ +- NJ
X Y a (B D
(6) Y = D, X = H (8) (9)
(7) X=Y=D
e e
2) -- ::)D
. Br- D D
(10) (11)
Detailed studies have been carried out on the halogenation of imidazo[1,2-a]pyridine
(8) (65JOC40S5, 65JOC40S1, 77MI41000). In all cases where C-3 is unsubstituted, using bromine
water, N -brornosuccinimide, N -chlorosuccinimide or iodine, the 3-halo compound (9) is
obtained. Perchlorirnidazo[1,2-a]pyridine has been obtained in high yield by treatment of
irnidazo[1,2-a]pyridine with phosphorus pentachloride at 275 oC in a sealed tube (71JHC37).
The reaction of 3-methylimidazo[1,2-a]pyridine (12) with NBS gave products formed by
apparent nucleophilic substitution at C-2 (13 and 14) (SOJOC373S). A variety of electrophilic
substitution reactions have been shown to occur at C-3 (74Z0R2467, 77MI41000, 75JOC2916).
Bromination of 2-(2-furyl)imidazo[1,2-a]pyridine (15) occurs either at C-3 of the imi-
dazopyridine (16) or at C-5 of the furan ring (17) depending on the reaction conditions,
the reagents used or the position of substituents (nKGS691). On heating in DMF, the
3-bromo compound (16) disproportionates to give a mixture of 5'-bromo (17), 3,5'-dibromo
(18) and unbrorninated rnaterial (15) (77Z0R2626). 2-Phenylimidazo[1,2-a]pyridine l-oxide
(19) also undergoes electrophilic substitution at C-3 giving (20) (7SJOC65S).
N N Me N 0 )
NJ -- NJN D "!'N + NJN
Me Me I Me 0
(12) (13) Br (14)
N,\ n N,\ n __ \ n Br
N O/ N O/ N O/
Br
(15) (16) (17)
1
N,\ R Br
N O/
Br
(18)
612
Other Irnidazoles with Fused Six-membered Rings
0- 0-
1+ 1 +
N N
NJPh -- ;--./Ph
(19) (20) X
Imidazo[1,2,-a]pyridine (8) and several of its derivatives (21) were found to react smoothly
with nitrous acid to produce high yields of 3-nitroso products (22a) (25CB393, 77HC(30-2)117,
76JMC1352, 61HC(15-1)481). Nitration of imidazo[1,2-a]pyridine with cold nitric and sulfuric
acids gave a high yield of the 3-nitro derivative as did a number of rnonomethylimidazo[1,2-
a]pyridines (22b) (77HC(30-2)117). Other irnidazo[1,2-a]pyridines containing a variety of
substituents at C-2 and in the pyridine ring also give 3-nitro derivatives (78MI41003, 77KGS556,
79Z0R(15)2534). One study showed that nitration occurs prirnarily at C-3 of (23) but to a
lesser extent at C-S, giving in one instance a 3,5-dinitro derivative (25). Nitration of
5-ethoxyimidazo[1,2-a]pyridine (26) gave both the 3,6- (27) and the 3,8-dinitro (28)
derivatives (79BSF(2)529). These results were generally in agreement with the 13C NMR data
and estirnated CNDO 7T-charge densities.
N N
R ;--./Rl -- R :J-Rl
X
(21) (22) a; X = NO
b; X=N0 2
(r --N (r --N (r --N
- )C0 2 Et -- )C0 2 Et + )C0 2 Et
Me:::::".., N-.f Me:::::".., N-.f Me:::::".., N-.f
N0 2 N0 2 N0 2
(23) (24) 80% (25) 20%
N N N0 2 N
(;--./ -- 02 N (:--./ + (t--./
EtO OEt N0 2 RO N0 2
(26) (27) (28)
1,2-Dirnethylirnidazo[1,2-a]pyridinium perchlorate (29) underwent Friedel-Crafts acyla-
tion at C-3 with acetyl and benzoyl chloride to give (30a and b) (74Z0R2467). Imidazo[1,2-
a]pyridin-2(3H)-one (31) undergoes acylation at C-3 forrning (32) as well as on oxygen
giving (33) (24CB1381, 24CB2092, 25CB393).
n::
JMe -- JMe
COR
ClO-
4 X-
(29) (30) a; R = Me
b; R=Ph
N N N
:J=O -- ;J=O -- ;-Ì02CR
COR COR
(31) (32) R = Me, Ph (33)
Irnidazo[1,2-a]pyridine (8) and its derivatives (34) undergo the Mannich reaction
(65JOC2403) as well as reaction with acetaldehyde and chloral to give a variety of products
(35-41) (77JOC3377, 80KGS528). Aromatic aldehydes (but not acetaldehyde or phenylacetal-
dehyde) condense with irnidazo[1,2-a]pyridin-2(3H)-one (31) at C-3 to give (42), which
disproportionates to (43) (26CB2926, 49USP2481953). The anion of irnidazo[1,2-a]pyridine or
its 2-, 6-, 7- or 8-methyl derivatives (45), prepared from (44) by means of phenyllithium,
adds across the double bond of cylohexanone to give (46). 5-Methylimidazo[1,2-a]pyridine
(47) reacts at the methyl group affording (48) rather than at the ring (68JOC1638). Reaction
of 3-brornoirnidazo[1,2-a]pyridine (50) with strong bases leads to metal-halogen exchange.
Other Imidazoles with Fused Six-membered Rings
613
With methyllithium coupling at C-3 to give (49) occurs, but with metal amides debrornina-
tion, coupling at C-5 to give (51) and te/e-substitution at all positions of th pyridine ring
(52) take place (78JOC2900).
N N
NJR -- NJR
CH 2 NR I 2
(34) (35)
N\ _eY N\
Me N-J -- Me NJ + Me N-J
CH(OH)Me CH=CH 2
(36) \ (37) (38)
:( N N\
N_jMe + N-J
CH(OH)CCI 3 /TCHCI2
o
(40) (41)
é'Y N
+ Me N
(39) hCHMe
N N
(31) -- N:.rO -- : O
CHAr hCHAr
(42) (43)
Me Me J
Cr) -- (X)
(44)
Me
-- O: ð :
OH
(46)
(45)
X N N\ ?" ___N\
N_j +- N-{ -- N-J +
er N'"- ó ?" N
N >--.7
(47) (48) (49) (50) (51) (52)
The 5-chloro group is easily displaced from the imidazo[1,2-a ]pyridine ring with alkoxides,
but neither the 2-chloro nor the 7-chloro group is (65JHC53, 77HC(30-2)117). Sodium methoxide
displaces only the 5-chloro group of perchloroimidazo[1,2-a]pyridine (53) giving (54a), but
piperidine replaces two chlorines, presumably the 5- and 7-chloro groups (54b) (71JHC37).
The 2-chloro group can be displaced (56), however, when activated by a nitro group in the
3-position (55) (65JOC4085, 77AF82).
N N
NJ -- NJ
Me I
8"
RHN
0;)
Cl CI
CI U'J N Rl (r ;.--N
Cl -- - \0
o N j Cl N-J
Cl Cl R Cl
(53) (54) a; R = MeO, R 1 = CI
b; R=R 1 =CSHION
Oxidation of imidazo[1,2-a]pyridin-2(3H)-one (31) results in the forrnation of a red dye
(24CB2092, 23MI41000), which probably has the structure (57) (26CB2921).
Imidazo[1,2-a]pyridines (58) activated by a nitro group at C-6 or C-8 undergo the Dimroth
rearrangernent to (60) in aqueous base. Interrnediates of the rearrangement (59)were detected
and their structures investigated spectroscopically (73JHC755).
N N
NJC1 -- :--ÌR
N0 2 N0 2
(55) (56)
614
Other Irnidazoles with Fused Six-membered Rings
(31) --+ C! i N 0 --. a N 0-
o -t;' -0 -
N
(57)
N\ V .... . N
02N N..J' --+ 02 N .... 'J --+ 02 N NJ
R R R
OH
(58) (59) (60)
Dipyrido[1,2-a:3',3'-d]irnidazoles (62) have been prepared by the reaction of the
corresponding irnidazo[1,2-a]pyridines (61) with a -chloroacrylonitrile in nitrobenzene
containing alurninurn chloride (78CPB2924).
f"yN N
NJ + CH 2 =CCICN --+ N - D
NH 2 ;j
N
(61) (62) NH 2
There is little pu blished work on the catalytic hydrogenation of the irnidazo[ 1 ,2-a ]pyridines
(63), but what there is indicates that reduction of the pyridine ring takes place preferentially to
give the 5,6,7,8-tetrahydro derivatives (64) (77HC(30-2)117, 73JMCI272).
(r)R --+ (T)R
(63) (64)
The reactions of groups attached to the irnidazo[1,2-a]pyridine ring are unrernarkable
(61 He! 1 5-1 )460, 77He!30-2)117, 76JMC1352, 76JOC3549, 76FES209).
4.10.3.2 Imidazo[1,5-a]pyridine
The irnidazo[1,5-a]pyridine ring systern has been successfully functionalized with various
electrophilic reagents, metalated, and reduced in one case. No nucleophilic displacernents
of leaving groups have been reported on appropriate derivatives.
Acetylation (55JCS2834), forrnylation (75JHC379) and nitration (80JCS(Pl)959) all occur
rnainly at C-I, producing cornpounds (65a-c), respectively, although forrnylation also
produces sorne C-3 substitution. When C-l is blocked, electrophilic attack occurs at C-3
(55JCS2834, 80JCS(Pl)959). Thus, nitration of I-phenylirnidazo[1,5-a]pyridine (65d) produces
rnainly the 3-nitro cornpound (65e), although sorne dinitration (at C-3 and in the phenyl
ring) also occurs. Nitration of the I-nitro compound (65c) gives the 1,3-dinitro cornpound
(65f) (80JCS(Pl)959). Nitrosation also occurs at C-I, but the product tautornerizes, the ring
opens, and recyclization produces (66) (67JOC2430). Diazo coupling has also been carried
out on irnidazo[1,5-a]pyridines (78BRP1531752, 78BRP1528801). Irnidazo[1,5-a]pyridin-3-one
(67a) can be acylated, alkylated and arninomethylated at N-2 under standard conditions
(61AP404). The irnidazo[1,5-a]pyridin-3-one (67b) can be reduced with hydrogen and pal-
ladiurn on charcoal to the tetrahydro derivative (68) (75FES197).
I
N N )
o
(66)
l
N--t.
(65)
a; R 1 =COMe,R 2 =H
b; R 1 =CHO,R 2 =H
c; R 1 =N0 2 ,R 2 =H
d; R 1 =Ph,R 2 =H
e; R 1 =Ph,R 2 =N0 2
f; R 1 =R 2 =N0 2
cc
NR
N---(
o
(67) a; R = H
b:R=C0 2 Et
NR
N
o
(68)
Protonation (65JCS2778. 64JCS4226) and N -rnethylation of the parent heterocycle (77HC(30-
2)117) both occur at N-2. N -Arnination of irnidazo[I,5-a]pyridine and I-substituted deriva-
Other Irnidazoles with Fused Six-membered Rings
615
tives with either O-rnesitylsulfonylhydroxyJarnine or O-p-toluenesulfonylhydroxylarnine
produces (69). Oxidation of (69b) with saturated aqueous brornine resulted in irnidazole
ring opening and eventually produced (70) rather than a triazine, as seen with the corre-
sponding imidazo[1,2-a]pyridine (76JCS(Pl)1722). Oxidation with nitric acid results in either
irnidazole ring opening or C-1 nitration, depending upon the substitution pattern of the
heterocycle and the nitration reagent employed (79JCS(Pl)1833).
(C ::::o-R+
,NNH 2
::::,.. N---.j'
x-
(69) a; R=H
b; R = Ph
Metalation of the parent heterocycle with phenyllithiurn produced (71a) or (71b) after
quenching with cyclohexane or DMF (72JHC1157, 75JHC379), respectively, indicating metala-
tion at C-3. Treatment of (71c) with n -butyllithium followed by methyl iodide produced
the C-4 substituted cornpound (71d). The anion was also quenched with various carbonyl
compounds (80TL2195). Treatment with Raney nickel afforded 4-rnethylirnidazo[1,5-
a]pyridine (71e).
Ph
0+ , Br
N Br
+
Br
(70) X-
N--fN
R 2 R'
(71)
OH
a; Rl=D'Rl=H
b' R 1 =CHO R1=H
c.' R 1 =SEt R1=H
d" R 1 =SEt' R1=Me
, 1 '2 M
e; R = H, R = e
4.10.3.3 Imidazo[ 4,5-b]pyridine
Treatrnent of imidazo[4,5-b]pyridine or a number of its 5-,6- and 7-rnono- and 5,7-di-
substituted derivatives (72) with rnercury(II) chloride and aqueous sodiurn hydroxide gave
chloromercury derivatives of undefined structure that react with acylglycosyl halides to
give 3-g1ycosyl derivatives (73) (60MI41000, 63CPB265, 63IJC30, 63JOC1837, 66IJC403).
In sorne cases the 1-g1ycosyl derivatives (74) were also reported (65JOC4066) in considerably
reduced arnount, the ratio varying with the substitution on the irnidazo[ 4,S-b ]pyridine.
Fusion of a variety of 7- and 5,7-substituted imidazo[4,5-b]pyridines with tetra-O-acetyl-ß-
D-ribofuranose and an acid catalyst gave only substitution at N-3 (73), but frequently a
srnall amount of the a-anomer with the predominant ß form (66JMC354, 68IJC616, 71RTC654,
72JHC465, 75RTC153). The rnercury(II) cyanide method of glycosyJation has also been used
(75RTC153, 77H(8)433, 78JHC839), but in one case gave predorninantly 7-arnino-4-(tri-O-
benzoyl-ß -D-ribofuranosyl)irnidazo[ 4,5-b ]pyridine rather than the 3-isorner (72JHC465).
Reaction of irnidazo[4,5-b]pyridine with tetra-O-acetyl-ß-D-ribofuranose in the presence
of an equivalent of tin (IV) chloride for five hours gave 3-(tri-O-acetyl-ß -D-
ribofuranosyl)irnidazo[ 4,5-b]pyridine, but its trirnethylsilyl derivative (75) gave a 60-70%
yield of the 4-isorner (76), which on treatment with tin(IV) chloride gave a 40% yield of
the 3-isomer (77) and a 25% yield of the 1-isomer (78). If the initial ribosylation is run
for 30 hours, the predominant isorner is still the 4-, but significant amounts of the 1- and
3-isorners are forrned, whereas in the presence of 3.6 equivalents of tin(IV) chloride, the
major product is the 3-isomer, followed by the 1-isorner and a smaller arnount of the
4-isomer. These results indicate that the kinetically controlled product is the 4-isorner and
that the 3-isorner is the thermodynarnically rnost stable, followed by the 1-isorner (76H(5)285).
The trimethylsilyl derivative of 6-nitroirnidazo[ 4,5-b]pyridine produced only the 1- (11 %)
and 3-isomers (35%) indicating the decreased basicity of N-4 resulting frorn the nitro group
(77H(8)433). The trirnethylsilyl derivative (79) of imidazo[ 4,5-b ]pyridine 4-oxide yielded only
1-(tri-O-acetyl-ß-D-ribofuranosyl)imidazo[4,5-b]pyridine 4-oxide (80), perhaps due to a
steric effect (82MI41001). Reaction of 5-acetarnido-7-chloroirnidazo[4,5-b]pyridine with tri-
O-acetyl-D-ribofuranosyl chloride in the presence of rnolecular sieves gave substitution at
616
Other Imidazoles with Fused Six-membered Rings
N-3 (78JMCl12). Treatrnent of 7 -chloro-1-(tri-0-acetyl-ß -D-ribofuranosyl)imidazo[ 4,5-
b]pyridine with tetra-O acetyl-D-ribofuranose and HgBr2 produced the 3-isorner in 75.9%
yield with the indication that transglycosylation proceeds through the l,3-bis(glycosyl)
interrnediate to the therrnodynarnically rnore stable 3-isorner (82MI41001), confirrning the
relative stabilites rnentioned above.
RJ H R J R J Gly
R2 N R2 N R, N
R1l:-..J- > - R1l:-..J- N > + R1l:-.,J- N >
N N N N
(72) (73) Gly (74)
N 0îN N
l:-..J- - t.À -l:-..J- +
N N TMS N N :""N N
Ri(OAch Ri(OAcb
(75) (76) (77)
i(OAcb
l:-,.J- >
N N
(78)
(X (X ;OAd'
N+ N TMS N+ N
I I
0- 0-
(79) (80)
Alkylation of 6-haloirnidazo[4,S-b]pyridines (81) has been reported to occur at N-3 (82)
(60CPB539) and N-l (83) (63MI41001). Aminornethylation with forrnaldehyde and piperidine
or rnorpholine has also been reported but the position of attachment was not established
(60CPB539). Heating 3-(2,3-0 -isopropylidine- 5 -p -toluenesulfonyl-ß - D-ribofuranosyl)irni-
dazo[ 4,5-b]pyridine (84) in boiling acetone caused intramolecular alkylation to occur at
N-4 to give the anhydronucleoside (85) (63JOC3329). Reaction of prirnary arnines and excess
formaldehyde with 2-methoxycarbonylarninoimidazo[4,5-b]pyridine (86) occurred at N-3
and N of the urethane to give hexahydrotriazinoirnidazopyridines (87) (77ZC262).
H R
X N) _ X N + X N)
l:-N'jl N l:-NJ-- N l:-NJ-- N
R
(81) (82) (83)
N
l:-NJ-- N
no
OX O
Me Me
(84)
-
N>
l:-.,J-- N
N+
w-
OX O
Me Me
(85)
(X (X N
I )NHC0 2 Me - I '}-NC0 2 Me
N N N N )
(86) (87) NR
Alkylation of 3-rnethylimidazo[4,5-b]pyridine (88) with alkyl halides occurred at N-l to
give the quaternary salts (89) (68KGS954, 73KGS570, 73KGS1686), whereas rnethylation of the
l-rnethyl isorner (90) gave the 1,4-dirnethylirnidazo[ 4,5-b ]pyridinium chloride (91) or iodide
(91) (73KGS570, 73KGS1686). Alkylation of 3-substituted irnidazo[4,S-b]pyridin-2(1H)-ones
(92) with alkyl halides occurred at N-1 (93) (73JHC201, 78JMC965). Reaction of 3-amino (or
anilino) -7-methyl-2-phenylirnidazo[4,5-b]pyridin-5(4H)-one (94) with diazornethane or
rnethyl iodide took place at both N-4 and the carbonyl oxygen to given alrnost equal
Other Imidazoles with Fused Six-membered Rings
617
amounts of 3-arnino (or anilino) -4,7 -dimethyl-2-phenylimidazo[ 4,S-b ]pyridin-S(4H)-one
(95) and 3-amino (or anilino) -5-methoxy-7 -methyl-2-phenylirnidazo[ 4,5-b ]pyridine (96)
(78JHC937).
(X N (X
I -- I +:)
"" N "" N x-
N Me N Me
Me Me
(XN) __ Q>
N N N N
Me
(88)
(89)
(90)
X-
(91)
'
..,l )=0 -- ..,l )=0
N N N N
(92) R (93) R
Ü Me N Ü Me N (X Me N
I Ph -- I Ph + I Ph
o N NON N MeO ""N N
H NHR Me NHR NHR
(94) (95) (96)
Reaction of imidazo[ 4,S-b]pyridine (97), but not its S-amino derivative, with perphthalic
acid (49JA1885) or hydrogen peroxide in acetic acid (66IJC403) gave the N 4 -oxide (98).
Peracetic acid was used to prepare the N 4 -oxides of 6-brorno-, 6-chloro, 6-bromo-S- and
-7 -methyl-, and 5,7 -dimethyl-imidazo[ 4,S-b ]pyridine (98) (59JOC1455). The N -oxides can
be catalytically reduced to (97) (80JHC1757).
R 3 H R 3 H
R2 N R2 N
R' ",l ) RI , ,l >
N N N N
I
0-
(97) (98)
A number of imidazo[ 4,5-b ]pyridines have been acetylated on a nitrogen of the ring as
well as exocyc1ic groups (59JOC1455, 59JCS3157, 66IJC146, 78JMC1l2), but in only one instance
does the position of acylation appear to be established (78JHC937). These N -acetyl groups
are labile and can be removed by mild treatment in aqueous media. The N 3 -ethoxycarbonyl
group can be removed preferentially by treatment with aqueous ammonia (78MI41007). The
N 3 -isopropyl group is acid labile (69MI41003), and the N-arnino group can be removed by
diazotization (77KGS411, 78JHC937).
Reaction of l-(tri-O-acetyl-ß -D-ribofuranosyl)irnidazo[ 4,5-b ]pyridine 4-oxide (99) with
phosphorus oxychloride or the Vilsrneier reagent gave 7-chloro-1-(tri-O-acetyl-ß-D-
ribofuranosyl)imidazo[ 4,5-b]pyridine (100) (82MI41001).
Q 6= >
N N N N
I
0-
(99) (100)
R = tri-O-acetyl-ß-D-ribofuranose
Nitration or bromination of 1- or 3-rnethylirnidazo[ 4,5-b ]pyridines (102) occurs at C-6
giving (101) (68KGS953, 71KGS279), but nitration of imidazo[ 4,5-b]pyridine 4-oxide (104)
takes place at C-7 to give (105) (66IJC403), indicating the effect of the N -oxide on the
H H
X x __ X
NJ--N R NJ--N R NJ--N R
(101) (102) (103)
618
Other Irnidazoles with Fused Six-membered Rings
cx NOz H
Ç/ N
HI) -- .+.,L )
N N N N
0 1- I
0-
(104) (105)
electron distribution of the ring. On the other hand, hydroxylation or thiolation occurs at
C-2 (71KGS428, 76KGS1252). Oxidation at C-2 has also been used to prepare 1,3-disubstituted
imidazo[ 4,5-b ]pyridine-2(3H)-one (103) (68KGS954).
Radical rnethylation of 3-rnethylirnidazo[ 4,5-b ]pyridine (106) gave in 71 % yield a rnixture
of 2,3,5,7 -tetramethylimidazo[ 4,5-b]pyridine, 2,3, 7-trimethylirnidazo[ 4,5-b ]pyridine and
2,3-dimethylimidazo[ 4,5 -b ]pyridine (107) in a ratio of 1 : 9.3 : 14.7. Similar rnethylation of
the dirnethyl cornpound gave a 57% yield of the tetra- and tri-methyl cornpounds in a 1: 5
ratio. 1,2-Dirnethylimidazo[4,5-b]pyridine (108) was rnethylated simultaneously in the s-
and 7-positions (109), with the 7-position being more reactive than the 5-positions
(78MI41004).
rr N lY N
..,L ) -- R2 ..,L )R 1
N N N N
Me Me
(106) (107) (108) (109)
a-Alkylation of irnidazo[ 4,S-b]pyridin-2-ones (110) sometirnes occurs on treatrnent with
alkyl halides or diazornethane (78H(10)241, 78JHC937), and one instance of 0- as well as
N -acetylation as in (111) has been reported (the position of the N -acetyl group was not
firrnly established) (59JOC1455).
(X e (X Me e
I )Me -- I )Me
>--N N Me ""N N
Me H Me Ac
Br (X N B (X N
I >=0 __ r I )OAC
N "" N
N H N
(110) (111)
Chlorination of irnidazo[ 4,5 -b ]pyridinones (112) is norrnally accornplished by means of
phosphorus oxychloride (49RTCI013, 57 AP20, 58AP368); in one case phosphorus trichloride
was used additionally (70KGSl146) but that seems unnecessary. Chlorine at positions 5, 6,
and 7 and bromine at position 6 have been rernoved by catalytic hydrodehalogenation using
palladium catalysts (48RTC29, 49RTCI013, 49JA1885,<61RTC545, 71RTC654, 78JHC839, 57JA6421).
Phosphonium iodide and furning hydriodic acid have been used to remove chlorine at C-2,
(113) (114) (57AP20, 58AP368).
R 3 H R 3 H R 3 H
R2rrN R2n--N Rzrr N
RI ..,L >=0 -- Rl ..,L )-Cl -- Rl ..,L )
N N N N N N
H
(112) (113) (114)
The usual nucleophilic displacernent reactions of chlorine have been carried out with
arnrnonia and amines (49RTCI013, 52CBlO12, 61RTC545, 70KGS1146, 71RTC654, 71RTC1166,
75MI41001), hydrazine (nRTc65o, 78JHC839, 82MI41001), alkoxides (77JHC813, 78JHC839),
thiourea, sodium hydrosulfide and sodiurn rnethylmercaptide (115) -+ (116) (65JMC708,
66JMC354, 78JMC112); but, as in the case of the imidazo[4,5-c]pyridines, these displacernents
are rnore difficult than those in the purine series because of the lesser electron-withdrawing
power of one versus two ring nitrogens.
-a -a
X I )--R I)
""N N ""N N
(115) (116)
R = H, NH 2 , N 2 H 3 , NR'R", OR', =0, =S, SMe
Other Irnidazoles with Fused Six-membered Rings
619
Diazotization of 5- and 7-aminoimidazo[4,5-b]pyridines (118) in concentrated hydro-
chloric acid with or without opper(l) chloride gave the corresponding chloro compounds
(117), whereas in sulfuric acid the irnidazopyridinones (119) and (120) were formed (48RTC29,
49RTCI013, 57JA6421, 61RTC545, 65JMC708, 72RTC650, 78JHC839).
(117) x;>! Y = CI, H
(118) R 1 ;>!R z =NH z ,H
o H
Q>
N N
H
(119)
A-- ;y
x ..JL- > -- R, __JL- > ----
N N N N
1
Ü >
o N N
H
(120)
Aminoimidazo[ 4,5-b]pyridines (121) undergo normal acylation reactions (66IJC146,
681JC616, 74RTC160, 75P2539), and under forcing conditions with sodium benzylate, 5-
acetamido-7 -chloro-3-ß -D-ribofuranosylimidazo[ 4,5-b ]pyridine (l2tb) undergoes N -
benzylation along with displacement of the chloro group to give (122b) (78JHC839). The
benzyloxy group of (122a-c) has been catalytically hydrogenolyzed to give the imidazo[4,S-
b ]pyridin-7 -ones (123) (56JA4130, 74RTC160, 75RTC153, 78JHC839). Methyl or benzyl groups
on the imidazo[ 4,5-b ]pyridine ring undergo typical reactions such as oxidation (5QJOC1455,
75MI059, 75KGS1389) or reaction with aryl aldehydes (791JC(B)428). The resulting acids,
aldehydes or ketones are also typical.
ACNHCx)
N R
(121) a; R=H
b; R = ß-D-ribofuranose
OCH zPh
l\
I RINH ,.JL- )
N N
R
(122) a; R = R 1 = H
b; R 1 = PhCH z , R = ß-D-ribofuranose
c; R 1 = H, R = ß-D-ribofuranose
o
I fy
H 2 Nl N Jl N
H R
(123) R = H, ß-D-ribofuranose
4.10.3.4 Imidazo[ 4,5-c]pyridine
Treatment of imidazo[ 4,5-c]pyridine (124a) or its 4-chloro derivative (124b) with
mercury(II) chloride and aqueous sodiurn hydroxide gave chlorornercury derivatives of
undefined structure (125a) that react with glycosyl halides to give 1- and. 3-g1ycosyl-
irnidazo[ 4,5-c] pyridines (126) and (127) with the 1-isomer (126) usually predominating
(63JOC1837, 64JOC2611, 68CPB2011), although irnidazo[ 4,5-c]pyridine itself is an exception
with equal amounts of the two isorners being formed (65JQC4066). It is likely that, at least
in some cases, the 3-isomer (127) is formed by kinetic control whereas the 1-isomer (126)
is thermodynamically more stable. In keeping with this interpretation is the fact that the
fusion of (124b) or (124c) with tetra-O-acetyl-D-ribofuranose at elevated ternperatures
gave only traces of the 3-isorner (66JMCI05, 66B756, 77JHC195). Reaction of trimethylsilyl
derivatives of the imidazo[4,5-c]pyrimidines with glycosyl halides (75JCS(Pl)125, 75MI41000),
yo: 6\+ YO:N
N'x N N'x N Zoo": ßJ oo ßJ
(124) a; X=Y=H (125) a; Z=HgCI U U
b; X=CI, Y=H b; Z= Me 3 Si RO OR RO OR
c; X = Y = CI (126) (127)
620
Other Imidazoles with Fused Six-membered Rings
however, gave a significant amount of the 3-isomer, as well as a- and ß-anomers (77JHC195),
as did reaction of the base itself with 2,3,5-tri-O-benzyl-ß-o-arabinofuranosyl chloride in
a nonpolar solvent in the presence of molecular sieves (82JMC96). Methylation of 6-
chloroirnidazo[ 4,5-c]pyridine with diazomethane gave a mixture of the 1- and 3-rnethyl
derivatives (66JCS(B)285). Treatment of 1- or 3-rnethylimidazo[ 4,5-c]pyridine (128 or 130)
with alkyl halides gave 64-90% yields of quaternary salts (129) and (131), respectively.
. o=5 ()::) .0:)
X - Me Me
x-
(128) (129) (130) (131)
Preparation of 1,3-dimethylimidazo[ 4,5-c]pyrirnidinium iodide (133) was accornplished
by the lithiurn aluminum hydride reduction of 1,3-dimethylimidazo[ 4,5-c]pyridin-2(3H)-
one (132), prepared by the rnethylation of imidazo[ 4,5-c]pyridin-2(3H)-one with dil1).ethyl
sulfate (74KGS854), rather than by methylation of (128) or (130) (79MI41001).
(X e
N I >--
N
(X e (X e
N I )=0 -- N I +:) 1 -
N N
Me Me
H H +
(r N >-D H2N (r N >-Q N=1
Nib /Í -- N I h
N N -
(132) (133)
Michael addition of acrylonitrile to imidazo[4,5-c]pyridine-2(3HHhione (134) gave
1 ,3-bis(cyanoethyl)irnidazo[ 4,5-c]pyridine-3(3H)-thione (135) (79MI41000).
N >=S __ N :H2CN
V--N V--N
H CH 2 CH 2 CN
(134) (135)
N::::N
No: >-b + NO: >-o
N==N
(136) (137) (138) (139)
Diazotization of 2-(2-aminophenyl)imidazo[4,5-c]pyridine (136) resulted in attack by the
diazo group of (137) on both N-1 and N-3 giving a rnixture of (138) and (139) (800PP234).
Oxidation at N-4 (141) of the imidazo[ 4,5-c]pyridine ring systern (140) has been accorn-
plished with hydrogen peroxide in acetic acid and with perphthalic acid (64JOC2611, 80JHC1757,
64CPB866).
(X N (r N
J oJ
BZO BZO
BzO OBz BzO OBz
(140)
(141)
N)
ï
BzO U
BzO OBz
(142)
Chlorination of 3-ß-o-ribofuranosylimidazo[ 4,5-c]pyridine 4-oxide (141) resulted in
the expected reductive chlorination at C-4 to give 4-chloro-3-ß-o-ribofuranosylirnidazo-
[4,5-c ]pyridine (142), but the reaction failed with the 1-ribosyl derivative (64JOC2611).
4-Chloroimidazo[4,5-c]pyridine was prepared in the sarne manner from imidazo[4,5-
c]pyridine 4-oxide (64CPB866).
Nitration of imidazo[4,5-c]pyridin-2(3H)-one and its rnethyl derivatives (143) to give
the 4-nitro cornpound (144) has been reported (73KGS138, 78MI41005) but not confirrned
(80JHC1757).
Other Irnidazoles with Fused Six-membered Rings
621
ù:>=o (r:>=o ù > N(r >=S
R' N0 1 R 1 H
(143) (144) (145) (146)
The thiolation of imidazo[4,5-c]pyridine (145) by heating with sulfur at 230-260 oC for
15-60 minutes gave imidazo[ 4,S-c]pyridine-2(3H)-thiones (146), which can be desulfurized
by heating at 50-90 oC with dilute nitric acid (7IKGS42S).
Radical alkylation of 1-methyl-, 3-methyl- and 2,3-dimethyl-irnidazo[ 4,5-c]pyridine (147)
takes place at C-4 giving (148) with sorne dimethylation of monornethyl cornpounds
occurring, the second methylation being at C-2 (77KGS933, 7SMI41006).
N (X I N --+ N (X I N
::,., N Me ::,., N M
R ' e
(147) (148)
Imidazo[4,5-c]pyridin-4(5H)-one (150) has been chlorinated with phosphorus oxy-
chloride and thiated with phosphorus pentasulfide to give 4-chloroirnidazo[4,5-c]pyridine
(149) and imidazo[ 4,5-c]pyridine-4(5H)-thione (151), respectively (49RTCI013, 65JMC70S).
N(rM) HN fÎíM ) H,(ìr J )
CI N N N
o S
(149) (150) (151)
As expected, the chlorine of (149) is less susceptible to nucleophilic displacement reactions
than that of the corresponding purine, but nevertheless has been successfully displaced by
arnmonia (under drastic conditions) (49RTCI013), hydrazine hydrate (64MI41001), sodium
hydro sulfide (65JHCI96) and thiourea (65JMC70S). The chlorine of the 1-ribosyl derivative
(152; R = H) of (149) is somewhat more reactive as is also the case in the purine series,
presumably because there is no ionizable NH. It has been displaced by sodium hydrosulfide
(66JMCl'05), anhydrous hydrazine (66B756), water to give the oxo compound, and by amines
giving (153) or (154) (6SCPB2011, 75MI41001). Decornposition occurred with ammonia and
copper sulfate at elevated temperature and sodium azide failed to react (6SCPB2011). Oddly
enough the reaction of (152; R = H) with aqueous hydrazine resulted in dechlorination to
give (153; R = R Z = H) (6SCPB2011). Again, as in the purine series, a chlorine at C-6 activates
one at C-4 so that, in contrast to (152; R = H), (152; R = Cl) reacts with amrnonia to give
4-amino-6-chloro-1-ß-D-ribofuranosylimidazo[ 4,5-c ]pyridine (152; R = Cl, R Z = NH z ),
which can be hydrogenolyzed to 4-arnino-1-ß-D-ribofuranosylimidazo[ 4,5-c]pyridine (153;
R = H, R Z = NHz, 3-deazaadenosine) (75JCS(Pl)125). Other cases of hydrodechlorination
have been reported (66JCS(B)2S5). The bromine of 6-amino-4-bromoimidazo[ 4,5-c]pyridine
(155) has been displaced by thiourea and sodium hydroselenide, as has the bromine of the
corresponding I-ribosyl derivative by sodium hydrosulfide, to give (156; X = S, Se)
(74JHC233,77JHC195).
R (X I R (X I R çr 1
N I > --+ N I > or HN I >
::,., N ::,., N N
CI R 1
X
(152) (153) (154)
R 1 = (tri-O-acetyl)-ß-D- ribofuranose
R R
H1N N Ù l N> --+ H rrN>
::,., N N
Br X
(155) (156)
R = H or ß- D-ribofuranose
622
Other Irnidazoles with Fused Six-membered Rings
A nitro group at C-4 of rnethylated imidazo[ 4,5-c]pyridin-2(3H)-ones (157) can also be
displaced by nucleophilic attack, by halide ions (74KGS854) or alkoxide ions giving (158),
as well as being reduced to the amine (78MI41005).
Diazotization of the 4-amino group of (159) in concentrated hydrochloric acid resulted
in the norrnal displacement reaction to give the 4-chloro compound (160) (65JMC708).
o: >=o (X >=o (X > o: >
NO z R' X R' NHz N CI N
(157) (158) (159) (160)
Alkyl and substituted alkyl groups attached to carbon or nitrogen of the imidazo[ 4,5-
c]pyridine ring or through sulfur to carbon undergo the expected reactions. For exarnple,
rnethyl groups (161; R = H) react with benzaldehyde to form styryl derivatives (162) that
can be oxidized to the corresponding acids (163) which decarboxylate on heating to (164)
(62JPR(288)199). A rnethyl (161; R = H) or benzyl group (161; R = Ph) can be oxidized with
seleniurn dioxide to the aldehyde (165; R = H) or phenyl ketone (165; R = Ph), which rnay
be reduced with sodium borohydride to the alcohol (166) (72MIP41000, 73JMC1296). Treat-
ment of 2-(hydroxyrnethyl)imidazo[ 4,5-c]pyridine (166; R = H) with thionyl chloride gave
the chlorornethyl compound (167) (62JPR(288)199).
(X (X (X (X
I )CH 2 R --+ I )CH=CHPh --+ I )C0 2 H --+ I)
N", N N", N N", N N", N
(161) (162) (163) (164)
1
(X I )COR --+ (X I )CHOHR --+ (Y )CH2Cl
N", N N", N V-N
(165) (166) (167)
Thiones such as (168) or (170) are readily alkylated to (169) (66JMCI05, 66JCS(B)285,
79MI41000), and the resulting derviatives such as (171; R 1 = CH 2 C0 2 H or CHzCN, R = X =
H) undergo normal reactions (79MI41000). Treatrnent of the 2-rnethylthio cornpound (171;
R = H, R 1 = Me, X = Cl) with chlorine gas in rnethanolic HCl causes displacement of the
rnethylthio group by chloride giving (172) (66JCS(B)285).
Çl N (X N X (X N H X (X N CI (X N
HN I R) --+ N I R) N I S --+ N I R' --+ N I l
N '" N '" NR '" NR "" NR
MeS
S
(168) (169) (170) (171) (172)
Reduction of l-ß -o-ribofuranosyl-4-hydrazinoirnidazo[ 4,5-c ]pyridine (173) with Raney
nickel cleaved the N - N bond in typical fashion to give the adenosine analog 4-arnino-l-ß-o-
ribofuranosylimidazo[4,5-c]pyridine (174) (66B756), whereas l-aminoimidazo[4,5-
c]pyridin-2(3H)-one (175) was characterized by reaction with veratraldehyde to give the
hydrazone (176) (76JHC601).
Ri Ri
(X I N) --+ N (X I N)
'" N "" N
H 2 NHN HzN
(173) (174)
Ri = ß-D-ribofuranosyl
Reaction of 1-rnethylimidazo[4,S-c]pyridine-2(3H)-thione (177) with nitric acid, or that
of l-rnethylirnidazo[ 4,5-c]pyridine and its 2-methyl derivative with a mixture of nitrous
MeO
N=CH -o OMe
(X H2 (X -
N I )==0 --+ N I )==0
'" N '" N
H H
(175) (176)
Other Irnidazoles with Fused Six-membered Rings
623
and nitric acid, gave v-triazolo[4,S-c]pyridine (180). A mechanism involving hydration of
the imidazole ring to give (178), cleavage to an N-nitroso cornpound (179) and recyclization
was suggested (80KGS121). In another ring opening and reclosure, treatrnent of 7-
nitroimidazo[ 4,5-c]pyridin-4(5H)-one (181) with hydrazine hydrate gave 7-methylirni-
dazo[ 4,5-d]pyridazin-4(5H)-one (182) (82KGS70S).
Me Me Me Me
N N SH O H N,
NJ--N>=S -- NJ--N)<OH -- N I NHNO -- NJ--r: N
H NO
(177) (178)
(179)
IY N
HN ) -H )
o 0
(181) (182)
Partially saturated compounds. Only imidazo[ 4,5-c]pyridines saturated in the pyridine
ring have been studied. While reaction of histidine with equimolar arnounts of forrnaldehyde
gave 4,5,6,7-tetrahydroimidazo[4,S-c]pyridine-6-carboxylic acid (183), an excess gave an
insoluble methylol derivative but the position of the methylol group was not deterrnined
(184) (44BJ(38)309). When heated at 290 0 C (183) decarboxylated to give 4,S,6,7-tetrahy-
droimidazo[4,5-c]pyridine (187; R1_R3=H), whereas treatment of the silver salt of (183)
with ethyl iodide gave the ethyl ester (186) (13MI41000).
H
HO O) HO,CNÇ!)
(183) H CH 2 0H
I (184)
H
EtO CNCX >
(186)
R 3
HÇX)
R' R 2
(187)
/
1
H H
RrC'(N) +- MC 2 C=(lN>
N N
(188) a; R = CHMe2 (189)
b; R=EtCO
(180)
/
R 3
Çt N
N I)
R 4 C/ N
II R' R 2
X
(185) R 1 = R 2 = alkyl, R 3 = H
a; R 4 =Me,X=2H
b; R 4 =PhCH 2 ,X=0
c; R 4 = R 5 NH, X= 0, S, NH
H
H 2 0 N >
PhCH 2 N
(190)
The nitrogen of the saturated pyridine ring of (187) behaves like a norrnal aliphatic amine
since it reacts readily with ethyl bromide, benzyl chloroformate, isocyanates, isothiocyanates
and S-methyl thiouronium salts to give (185a-c) (77GEP2700012, 79USP4141899, 79BEP87198S).
It is likely that this nitrogen is the point of attachment of the methylol group of (184).
Catalytic reduction of (187; R 1 = Ph, R 2 = R 3 = H) with palladium-charcoal resulted in
cleavage of the pyridine ring to give the 4-benzylimidazole (190). The reaction is probably
lirnited to R 1 = aryl since the dimethyl compound (187; R 1 = R 2 = Me, R 3 = H) on heating
at 140 oC cleaved to (189), which was catalytically reduced to 4-(2-isopropylaminoethyl)imi-
dazole (188a), and boiling a solution of (187; R 1 = R 2 = Me, R 3 = H) in propionic acid gave
N -(2-imidazol-4-ylethyl)propionarnide (188b) (82JMCl168).
624
Other Irnidazoles with Fused Six-membered Rings
4.10.3.5 Imidazo[1,2-a]pyrazine
Treatment of imidazo[1,2-a]pyrazine (196) with methyl iodide resulted in quaternization
at N-7 (192) and N-1 (191) in a ratio of 1: 1.6 indicating the relative basicities of these
nitrogen atoms (77JOC4197). No reports of N -oxidation have appeared. Bromination with
NBS occurred at C-3 to give (195), and with bromine in glacial acetic acid reaction occurred
at both C-3 and C-5 (197a). No deuterium exchange took place in neutral or acid media,
but with sodium deuteroxide in DMSO exchange occurred at C-3 and C-5 (197b). The
pentachloroimidazo[1,2-a]pyridine (198) was prepared by treatment of the parent with
phosphorus trichloride at 265 oC (75JHC861). Methoxide displaced the chi oro groups from
C-5 and C-8 to give 2,3,6-trichloro-5,8-dimethoxyimidazo[1,2-a]pyrazine (199) which was
converted by catalytic hydrogenolysis to 5,8-dimethoxyimidazo[1,2-a]pyrazine (200). Treat-
ment of the 5,8-dibromo compound with methoxide gave 5-bromo-8-methoxyimidazo[1,2-
a]pyrazine, which was hydrogenolyzed to the 8-methoxy compound. Hydrazine hydrate
reacts with imidazo[1,2-a]pyrazine (196) by nucleophilic addition and subsequent cleavage
and reduction of the Wolff-Kishner type. Attack at C-5 gave 2-methylimidazole (193) and
at C-8 l-ethyl-2-methylimidazole (194) (76H(4)943). Oxidation of 2,8-dimethyl-6-phenyl-
irnidazo[1,2-a]pyrazin-3(7H)-one (201) in the presence of potassiurn t-butoxide in DMSO
caused cleavage of the imidazole ring with loss of CO 2 to give (202) (68TL3873).
Me H
N N MeN N MeríN\ + MerN\
NJ + N.) NJ' EtNJ'
1- 1-
(191) (192) / (193) (194)
N N\ N N\ N N
NJ - NJ -- NJ
fu X X
(195) / (196) (197) a; X'" Br
b; X"'D
OMe
N N
-- NJ
OMe
(200)
Cl OMe
N N N N
Cl NJCl -- Cl NJCl
Cl Cl OMe Cl
(198) (199)
Me Me M
HN N N N / e
I 'I Me -- I II 'è + CO
Ph N--{ Ph N -d 2
(201) 0 (202)
Renilla luciferin was converted to luciferyl sulfate (204) by treatment of the diacetate
(203) with sulfur trioxide in pyridine followed by removal of the acetyl group with ammonia
(77TL2685).
CH 2 Ph
}CH2 -o 0AC --
ACOV 0
(203)
CH 2 Ph
N )-CH1 -o OH
I S03- Na+
HO Q
(204)
ACN N\ ACN :n N 0
NJCONHl -- N f
NH 1 NH
N=/
(205) (206)
Treatment of (205) with triethyl orthoformate gave an 8,9-cyclic derivative of hypoxan-
thine (206) (67MI41000, 67MIP41000).
Other Irnidazoles with Fused Six-membered Rings
625
4.10.3.6 Imidazo[1,5-a]pyrazine
N
L 1- 'N--
N -f'
R
(207)
Oxidation of imidazo[1,5-a]pyrazine and its 3-methyl derivative (207) with MCPBA
occurred at N-7 giving (208) (73JOC2049). Reaction of these heterocycles with acid chlorides
and anhydrides resulted in addition rather than substitution, with the addition occurring at
the N-7,C-8 double bond to give (209), in a manner analogous to the Reissert reaction
(75JOC3376). Oxidation of the addition product followed by alcoholysis gave the correspond-
ing imidazo[1,5-a]pyrazin-8(7 H)-ones (211). Curiously, reaction of 3-(methylthio)imi-
dazo[1,5-a]pyrazine (212) with p-nitrobenzoyl chloride followed by quenching with water
gave a product (213) resulting from addition across the N-2,C-3 double bond (75JOC3379).
Me OH 0 0
R lCON X R lCON)l HN)l :;:::p
L "N -- L Y"N -- L Y"N
N-f' N-f' N-f'
R R R
(209) (210) (211)
-O,+
N r I
NJ
R
(208)
R = H, Me
N
rf -f'N + p-02NC6H4COCI
SMe
--
N
N/COC6H4N02-P
HO SMe
(213)
(212)
Aromatic substitution reactions on the imidazo[1,5-a]pyrazine ring system have been
studied using a variety of reagents (75JOC3373, 75JHC207). C-1, C-3 and C-5 are amenable
to attack. Chlorination of the parent ring system (214) furnished the 1-chloro-, 3-chloro-,
1,3-dichloro- and 1,3,5-trichloroimidazo[1,5-a]pyrazines (215a-d). Other reactions
studied include bromination, reaction with selenium dioxide, and the Mannich reaction; in
the latter case, substitution of 3-methylimidazo[1,5-a]pyrazine occurred at C-1 and C-5.
Reaction of nitrosonium fluoroborate with (216) provided 3-(methylthio)-1-
nitroimidazo[1,5-a]pyrazine (217) whereas aqueous nitrous acid resulted in pyrazine ring
cleavage (75JOC3379).
R'
N N
N-f'N -- N-f'N
R 3 R 2
(214) (215)
a; R 1 =CI,R 2 =R 3 =H
b; R 1 =R 3 =H,R 2 =CI
c; R 1 =R 2 =CI,R 3 =H
d; R 1 =R 2 =R 3 =CI
N02
N r N r
L N--L N
N-f' N-f'
SMe SMe
(216)
(217)
The bromine of 1-bromo-3-methylimidazo[1,5-a]pyrazine could not be displaced by a
variety of nucleophiles. This contrasts with the reactivity of the 8-chloro substituent of
(219; R = H or Me), prepared by the usual chlorination of the imidazo[1,5-a]pyrazin-8(7 H)-
ones (218), which was readily displaced by thiourea to give the thiones (220).
o
HN
NJ
R
(218)
--
Cl S
N HN)l ý
L 1- 'N -- L- Y--\
N-f' N-f'
R R
(219). (220)
Alkaline hydrolysis of (221) resulted in ring opening to give caffeidine (222) (61AC(R)1409).
Treatment of 1-bromo-3-methylimidazo[1,5-a]pyrazine (223) with bromine in water fol-
lowed by neutralization with excess dilute sodium hydroxide also resulted in destruction
of the pyrazine ring to give 4-bromo-3-methylimidazole-4-carbaldehyde (224) (75JOC3373).
o
)l HMe
MeN y--"
I . N
O N-f'
(221)
--
NHMe
MeNHCO N
MeN-f'
(222)
Br
N
N-f'N
Me
(223)
Br
OHC
-- I N
HN-f'
Me
(224)
626
Other Irnidazoles with Fused Six-membered Rings
The few studies that have been carried out indicate that substituents attached to the
imidazo[1,5-a]pyrazine nucleus react normally (61AClR)1409, 70JCS(C)1540, 75JOC3379).
4.10.3.7 Imidazo[4,5-h]pyrazine
Treatment of imidazo[ 4,S-b ]pyrazine (225; R = H) with hydrogen peroxide in glacial
acetic acid gave the 4-oxide (226; R = H) as the major product (50%) and the 4,7 -dioxide
(227; R = H) as the minor product. A 4-oxide was also obtained from the 1-methyl- and
the 1-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)-imidazo[4,5-b]pyrazine, in the latter case by
means of MCPBA (73JMC643). Other 4-oxides and 4,7-dioxides have been prepared
(75KGS690).
0- 0-
I I
N N N+ N N+ N
r X '> --( X '> +( X '>
N N + N
N R N R R
0-
(225) (226) (227)
Various imidazo[ 4,5-b ]pyrazin-2-ones (228) have been subjected to a number of different
reactions. Alkylation, acylation and the Mannich reaction all give 1,3-disubstituted deriva-
tives (229). Halogenation of the 2 oxo compound (230) with bromine or chlorine in acetic
acid or with sulfuryl chloride provided monohalo derivatives (231) (69FRP1578366,
71BRP1248146). The chlorine atom of (231) can be rernoved by catalytic hydrogenation.
H R'
N N N N
R(' X )=0 .-. R(' X )=0
R N R N
N H N R 1
(228) (229)
('N X X('N X
EtHN I N)=O =:! EtNH I N)=O
N H N H
(230) (231)
Nitration of 5-chloroimidazo[4,5-b]pyrazin-2-one (232) provides the 6-nitro derivative
(233), which can be reduced to the amino compound (234; R = H) or the substituted amino
compound (234; R == alkyl) if the reduction is carried out in the presence of an aldehyde
(71BRP1238105).
N H N N
Cl(' X N )= o __ CI( X )=0'-' CI( X )=0
OzN N RHN N
N N H N H
(232) (233) (234)
1,5,6-Trirnethylirnidazo[4,5-b]pyrazin-2(3H)-one (235) has been chlorinated to (236)
with phosphorus oxychloride and the resultant chlorine at C-2 displaced by ethoxides,
amines and diethyl malonate to give (237) (75MI41002, 76MI41001). The product of the diethyl
malonate reaction was chlorinated and decarboxylated to the 2-chloromethyl compound
(237; R = CH 2 Cl) which was aminated with a variety of arnines (76MI41001).
H
N N N N N N
Me( X )=0 .-. Me(' X )CJ .-. Me(' X )R
Me N Me N Me N
N Me N Me N Me
(n W
Cl ( N X N Cl ( N X N
I '>CCI 3 '-' I )COzEt.-.
Cl :::,.. N Cl '" N
N H N H
(238) (239)
N N
CI(' X )R
Cl N
N H
(240) R COzH, CONH z , CN
Other Irnidazoles with Fused Six-membered Rings
627
5,6-Dichloro-2-(trichloromethyl)imidazo[ 4,5-b ]pyrazine (238) was converted into the
2-carboxylic acid ethyl ester (239) by treatment with silver nitrate in ethanol (SOJHC3S1).
The ester was converted into the acid, amide and nitrile (240).
4.10.3.8 Imidazo[1,2-a]pyrimidine
As predicted by theoretical calculations (74JHCI013), the initial site of electrophilic attack
on imidazo[1,2-a]pyrimidines is C-3. Bromination of the parent compound (241a) with
NBS in chloroform produced (241b) (66JOCS09). As judged by NMR data, the most probable
site of protonation of (241a) is N-1 (750MR(7)455). As expected, the 2-substituted imi-
dazo[1,2-a]pyrimidines have a lower reactivity toward electrophiles than the corresponding
imidazo[1,2-a]pyridines. Nitration of 2-phenylimidazo[1,2-a]pyrimidine (241c) occurs
initially in the phenyl ring, and then at C-3 (70GllO, 70Gl106). Nitrosation of (241c) directly
produces (241d) (77H(6)929, 66LA(699)1l2). A properly substituted imidazo[1,2-a]pyrimidine
can undergo the Dimroth rearrangement (7IJHC643), as exemplified later.
a; R = X = H N N
Me C 1:)Ph
b; R=H,X=Br
a; X=CI
c; R = Ph, X = H
b; X=NMe2
d; R=Ph,X=NO X
(241) (242)
The 5-chlorine in (242a) is subject to displacement by various nucleophiles, including
amines and alkoxides. Treatment of (242a) with dimethylamine produces (242b). A chlorine
at C-S can be introduced in standard fashion from an oxo group with POCh (66LA(699)127).
Certain imidazo[l,2-a]pyrimidines undergo amination at N-l with O-p-toluenesulfonyl-
hydroxylamine (77JCS(Pl)7S).
N N
C 'Y\R
NJ
X
4.10.3.9 Imidazo[1,2-c]pyrimidine
The parent imidazo[l,2-c]pyrimidine (243a) has been found to protonate on N-l
(65JCS277S). Compound (la), as the neutral compound, protonates and alkylates on N-1
(76JA740S).
RrrN\R
N.::::::/..-NJ
R 1
(243) a; R=R 1 =H
b; R=R 1 =CI
c; R=CI, R 1 =NHMe
Mercuration of (la) with mercury(II) acetate in water affords the mercury derivative (lc)
(74BBA(361)231).
Treatment of 2,5,7-trichloroimidazo[1,2-c]pyrimidine (243b) with methylamine results
in preferential displacement of the 5-chloro group to produce (243c). Even a methylthio
group at C-5 is displaced preferentially to the chlorine at C-2 and C-7 (70JHC715).
Nucleosides such as (246) have been prepared by the coupling of the trimethylsilyl
derivative of (244) with 2,3,5-tri-O-acetyl-ß -D-ribofuranosyl bromide (245) followed by
deacetylation (75JOC370S). Arabinose derivatives substituted at N-1 have also been prepared
(76JMCS14).
ACOCH Z U O Br R
Cl J N i, (245) Cl N
I 1- AcO OAc "ï \
HNyN j ii,base Þ NyNJ
o 0
(244) (246) R = ß-D-ribofuranosyl
A Dimroth rearrangement in one particular system is mentioned in the synthesis section
(Section 4.10.4.9).
628
Other Irnidazoles with Fused Six-membered Rings
4.10.3.10 Imidazo[1,5-a]pyrimidine
As judged by NMR data, the parent heterocycle (247a) is protonated and quaternized
with methyl iodide at N-7. Bromination of (247a) with either NBS or bromine produces
the 6,8-dibromo compound, in agreement with theoretical calculations (72BSF2481).
R N
ry )
N N
R
(247)
a; R=H
b; R= Br
4.10.3.11 Imidazo[1,2-b]pyridazine
Electrophilic substitutions on imidazo[1,2-b ]pyridazines produced exclusively 3-
substituted products (67T387, 68T239). Treatment of imidazo[1,2-b]pyridazine (248a) with
either NBS or bromine in acetic acid produced 3-brornoirnidazo[1,2-b]pyridazine (248b).
Nitration and sulfonation have also been examined. Nitration of 2-phenylimidazo[1,2-
b]pyridazine (248c) resulted in initial nitration on the imidazole ring (3-position) followed
by para nitration of the phenyl group if excess reagent were present (68MI41000), producing
(248d). The parent ring system has a pKa of ca. 4.5 and undergoes protonation or
quaternization at N-1 (73HC(27)801).
N
_JNJR'
N R
(248)
Nucleophilic displacement of a chlorine atom in the 6-position is possible with hydroxide
(64CPB1351), alkoxides (64CPB1351, 67T2739, 65JAP6522265), thiophenolate (67T387), hydrazine
(67T387, 67T2739), amines (64CPB1351, 65JHC287) and azide (67T387, 68JHC351), but not with
amrnonia or KSH. Nucleophilic displacements at other positions have not been investigated.
Various other reactions have also been explored. Homolytic methylation of imidazo[1,2-
b ]pyridazine produced a mixture of 7 - and 8-methyl and 7,8-dimethyl derivatives, with the
latter predominating (68T2623), while homolytic phenylation produced 8-phenyl and to a
lesser extent 3-phenyl derivatives (74M834). N -Oxidation (hydrogen peroxide in PP A)
produces the 5-oxide (70JOC2478). A 2-methyl group is susceptible to oxidation and con-
densation reactions typical of a methyl group at a position adjacent to nitrogen in azines
(68JHC35, 67T2739).
a; R = R 1 = H
b; R=Br,R1=H
c; R = H, R 1 = Ph
d; R=N0 2 , R 1 =P-N0 2 C 6 H 4
4.10.3.12 Imidazo[ 4,5-c]pyridazine
The adenosine analog containing an imidazo[ 4,5-c]pyridazine (252) has been prepared
by the condensation of (249) with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide (250) to
produce (251). Removal of the benzoyl groups is readily achieved by methanolic ammonia
at room temperature, and then the chlorine is displaced with ethanolic amrnonia in an
autoclave at high temperatures to afford (252) (74JHC39).
SiMe) N R
N ìí - ,O NìíN ,
<ND + BZo Br · <'N
Cl BzO OBz Cl
(249) (250) (251)
R = 2,3,5-tri-O-benzoyl-ß-D-ribofuranosyl
R
N N
þ < X)
NHz
(252)
R = ß-D-ribofuranosyl
Displacernent or removal of chlorine is possible at both the 3- and 4-positions, and
desulfurization or alkylation on sulfur of compounds such as (253) has also been carried
out (67JHC555). Ring opening with base occurred at C-6 (67JHC555). Treatrnent of (254a)
with dihydropyran under acidic conditions produced only (254b). Compared to chlorine
displacement in (254a), it was found that the THP group in (254b) sornewhat facilitated
Other Irnidazoles with Fused Six-membered Rings
629
displacement of the chlorine with amines, producing, for example, (254c). The THP group
was readily removed with aqueous acid (68JHC13).
H
N JO N
s=< I
N #
H
(253)
R!
N N
<\JC)
R
(254)
a' R=Cl R 1 =H
b; R=Cl: R 1 =THP
c; R = NH(CHzhNEt z , R 1 = THP
4.10.3.13 Imidazo[ 4,5-d]pyridazine
Nucleophilic substitutions have been carried out most commonly with either chloro or
methylthio substituents. The order of reactivity is 4> 7> 2, with the 4- and 7 -positions
being distinguished by a group attached at N-1. The 4,7-dichloro derivatives are typically
prepared from the 4,7-dioxo compounds with phosphorus oxychloride (68JHC13, S8JA6083).
Selective displacement of one chlorine substituent is readily possible. For example, 1-benzyl-
4,7-dichloroimidazo[4,S-d]pyridazine (255a) when treated with ammonia or certain mono-
or di-alkylamines produced (255b) selectively (site of displacement inferred from steric
considerations) (S8JA6083). To replace both chlorines, quite vigorous conditions are required.
The bis-hydrazino compound (255d) is prepared by heating (255c) with 96% hydrazine
(64JHC182). Conversion of oxo or chloro groups to thioxo compounds is readily achieved
with phosphorus pentasulfide (64JHC182, 70CPB168S) or sodium hydrogen sulfide (S8JA6083).
The thioxo groups can be alkylated under standard conditions or removed with Raney
nickel (69JHC93, 64JHC182, 6SJHC247).
a; R=CH z Ph,R 1 =R z =Cl,R 3 =H
b; R = CHzPh, R 1 = NZ z (Z = H or alkyl), R Z = Cl, R 3 = H
c; R= H, R 1 = R Z = SMe, R 3 = Ph
d; R=H, R 1 =Rz=NHNH z , R 3 =Ph
e; R= ß-o-ribofuranosyl, R 1 =NH z , R 2 = R 3 = H
f; R = ß-o-ribofuranosyl, R 1 = H, R Z = NHz, R 3 = H
g; R=H,R 1 =R z =NH z ,R 3 =H
h; R=R 1 =R z =R 3 =H
Nucleosides relating to adenosine have been made by condensation of an imidazo[ 4,5-
d]pyridazine with a blocked carbohydrate. The chloromercury derivative of 4(7)-benzoyl-
aminoimidazo[ 4,5-d]pyridazine (256) was condensed with 2,3,5-tri-O-benzoyl-D-
ribofuranosyl chloride to give a rnixture of nuc1eosides. After removal of the blocking
groups and separation, the products were identified as (255e) and (255f) (S7JOC9S4).
:x R2
t;/ I )R 3
N::,.., N
R 1
(255)
NHCOPh
N J= N
I I "
N::,.., NRHgCl
(256)
4.10.3.14 Imidazo[ 4,5-d] [1,2,3]triazine
The 4-thiones can be readily S -methylated (2578 2588) (7SJOU902) or chlorinated to
the 4-chloro derivative, e.g. (257a 258b) (76CHE46S,74CHE376). The chlorine can then
be displaced with various amines (76CHE46S). Nucleophilic displacement of a 6-bromo
substituent is also possible (74JOC36S1). 7 -(ß- D- Ribofuranosyl)imidazo[ 4,5-d]-
[1,2,3]triazine nucleosides such as (261) can be prepared by direct condensation of the
nitrogen heterocycle (259) with an activated ribose derivative (245) in the presence of
mercury(II) cyanide (79CHE68S). Treatment of (258c) with hydrogen peroxide in acetic acid
affords several N -oxides, the major one being the 3-oxide (60JA3189).
R
N N
<\X; H
X
(257) a; X = s, R = H
b; X = 0, R = ß-o-ribofuranosyl
c; X=O,R=H
R
N X; N
) \ I "1
N fiN
X
(258) a; X = SMe, R = H
b; X=CI,R=H
c; X=NHz,R=H
d; X = NHz, R = ß-o-ribofuranosyl
630
Other Irnidazoles with Fused Six-membered Rings
fj :c N (OyB
\ I + ACOCH2"------l r.-.
N h N AcO OAc
SMe
(259) (245)
R N
\N JC
N h N
SMe
(261)
R = 2,3,5-tri-O-acetyl-ß-D-ribofuranosyl
4.10.3.15 Imidazo[1,2-h] [1,2,4 ] triazine
Several papers deal with the reactivity of this ring system. Brornination of 2,6-diphenyl-
imidazo[l,2-b][1,2,4]triazine (262a) produced (262b). Treatment of the parent ring system
with phenyliithium produced the 3-phenyl derivative (263) after air oxidation. Greater
stabilization of the intermediate anion leading to (263) is suggested as the reason for the
singular direction of addition (72JHC1157). Alkylation occurred at N-l (64MI41000).
N
Ph ,f-N; Ph
\ )R
N N
(262) a; R = H
b; R = Br
,f-N;N
\ )Ph
N N
(263)
4.10.3.16 Imidazo[1,5-h] [1,2,4]triazine
Brornination of (578a) with NBS afforded the 8-bromo derivative (578b) (74BSF1453).
4.10.3.17 Imidazo[1,5-d] [1,2,4]triazine
Corn pound (582a) can be S -rnethylated and the methylthio group then displaced with
various secondary amines (79JHC277).
4.10.3.18 Imidazo[2,1-c] [1,2,4 ]triazine
Oxidation of (264) with NBS or bromine produced the fully unsaturated corn pound (265)
(69C303).
H
Ph(:yN, .-. Ph(:"lN 1
,\--N Ph ,\--N Ph
(264) (265)
4.10.3.19 Imidazo [5,1-/][1,2,4 ]triazine
Protonation of (266a) occurred at N-6 (79JCS(P2)1327), although acylation occurred at the
exocyclic amino group (79JCS(Pl)1120). Reduction of (266b) with lithium aluminum hydride
produced (267a), which could be dehydrogenated to (268) with palladium-charcoal. Addi-
tion of methylmagnesium iodide to (268) occurred across the 3,4-double bond to produce
(267b) (80JCS(pl)1139).
PrO N
,r--N 'ì R
N NH
o
(266) a; R=NH 2
b; R=Me
PrO N
f"-N/ 'ì R
N NH
Me R
(267) a; R= H
b; R=Me
PrO N
f"-N/ 'ì Me
N N
Me
(268)
Other Irnidazoles with Fused Six-membered Rings
631
4.10.3.20 Imidazo[1,2-a][1,3,5]triazine
Bromination of (269a) (as the free base) with NBS produced (269b) in the only example
of an electrophilic substitution on a fully aromatic imidazo[1,2-a][1,3,5]triazine (70M724).
Ribosidation of (270) (as the bis-trimethylsilyl derivative) with 1-0-acetyl-2,3,5-tri-O-
benzoyl-ß -D-ribofuranose in 1,2-dichloroethane containing SnCl 4 produced the 8-
substituted isomer (271a), which was readily debenzoylated to (271b) (78JMC883).
(269) a; R = H
b; R=Br
H N R N
<ty )NH 2 ----. (ty )NH z
,\--NyN '\--NyN
o 0
(270) (271) a; R = 2,3,5-tri-O-benzoyl-ß-D-ribofuranosyl
b; R = ß-D-ribofuranosyl
N N
( Y SMe
,\--N N
R SMe
4.10.4 SYNTHESIS
4.10.4.1 Imidazo[1,2-a]pyridine
(i) Closure of the imidazole ring
The majority of imidazo[1,2-a]pyridines (275) have been prepared by the reaction of a
2-aminopyridine (272) with a a-halocarbonyl compound (273). 2-Aminopyridine and
cWoro- or bromo-acetaldehyde gave imidazo[1,2-a]pyridine itself (25CB1704), and this
reaction can be carried out under mild conditions (61HC(15-1)460). A variety of 2-
aminopyridines and a-halocarbonyl corn pounds have been used (26CB2048,5lJCS2411,
54JA4470, 53JA746, 55CBl117, 49YZ496, 79FES417, 79KGS643, 65JHC331), but failures have occur-
red, for example, with 2-amino-6-pyridinone, probably due to the decreased basicity of the
ring nitrogen (65JHC53). In some cases the intermediate onium bromides (274) cyclize slowly
in DMSO at room temperature with concomitant bromination at C-3 (78KGS258). 2,3-
Diaminopyridine reacts selectively with bromoacetaldehyde to give only 8-
aminoimidazo[1,2-a ]pyridine (78JOC2900). 1-Alkyl- 2-hydroxy- 2,3-dihydroimidazo[ 1 ,2-
a]pyridinium salts (278) were identified as isolatable intermediates in the synthesis of
1-alkylimidazo[1,2-a]pyridinium salts (279) from 2-alkylaminopyridines (276) (78JHC1149).
Methyl ketones in the presence of bromine or iodine give the corresponding 3-bromo- or
3-iodo-imidazo[1,2-a]pyridines (76KGS1396).
R 4
R3 0 NH O=CR6
I 2+ I ----.
R Z N XCHR 5
R 1
(272) (273)
R 4
R3 0 1 NHz ----.
R Z N:" ......CR 6
R 1 CH
I X-
(274) R 5
R 4
R3 N
R zl : ......) J R 6
R 1 R 5
(275)
RI
a N OH
I + Y ----.
N:J'Rz
R 3
Br - Sr-
(276) (277) (278) (279)
Condensation of 2-amino-N-phenacylpyridinium bromide (280) with p-dimethyl-
aminobenzaldehyde (281) (76IJC(B)551) and that of 2-acetoacetylaminopyridine (283) with
4-nitroso-N,N-dimethylaniline (284) gave the corresponding 2,3-disubstituted imidazo[1,2-
a]pyridines (282) and (285), respectively (44JA1805). 2-Aminopyridines react with a-chloro-
a -isonitrosoacetone to give 2-methyl-3-nitrosoimidazo[1,2-a)pyridines (78KGS1525)
whereas a-ketohydrazidoyl bromides give 3-(substituted phenyldiazo)imidiazo[1,2-
a]pyridines (80JHC877). 3-Hydroxyimidazo[1,2-a]pyridines can be prepared by the reaction
of 2-aminopyridine l-oxides with a-halomethyl ketones (79JHC187). 1-Benzyl-2-
aminopyridines (286) cyclized with difficulty in acid anhydrides to the corresponding
O NHR 2 OCRZ
I + I ----.
N BrCHR 3
I
JRZ
R 3
632
Other Imidazoles with Fused Six-membered Rings
3-arylimidazo[1,2-a]pyridines (287) (55CBI093}. Other carbonyl compounds such as dyp-
none (26CB1360}, diethyl oxalate (78CB2813}, benzoin (78HCA129} and isonitrosoflavanone
(80JCS(P1)354} have been substituted for the a-halo compounds.
O NH 0 a (r N
, 2 II Br- + OHC II NMe 2 ---+ N- )Ph
, /C, --{ a
CH 2 Ph CH II NMe 2
(280) (281) (282)
(r NH, a N
H + ON II NMe 2 -+ N >=
/ 2 --{f a
O=c, N II NMe 2
(283) Me (284) (285)
0 ,NH 2 + (R1COhO ---+ (r1) N hRl
N G N//
+,
CH 2 ).
X-
R #
(286) (287) R
Diphenyl ketone reacts with N -pyridin-2-yl-S,S-dimethylsulfilimine to give 3,3-di-
phenylimidazo[l,2-a]pyridin-2(3H)-one (79CPB2116}, whereas reaction of the 2-methyl-
pyridin-2-yl-S,S-dimethylsulfilimine with a variety of a-halocarbonyl compounds gave
3-substituted 5-methyl-2-methylthioimidazo[ 1 ,2-a ]pyridines (78YZ631}.
In a slight variation of the above synthetic approach, 2-phenylimidazo[1,2-a]pyridine
(290) was prepared by the reaction of 1-phenacyl-2-chloropyridiniurn brornide (288) with
ammonia (289) (55CB1117}. The use of primary amines (291) resulted in l-alkylimidazo[l,2-
a]pyridinium halides (292) (69JOC2129}, whereas hydroxylamine (293) gave imidazo[l,2-
a ]pyridine l-oxides (294) (78JOC658}.
O-
J
(YJPh ( H
(294)
O ,X 0 NH (r:; N
N II (28:' Þ N j Ph
+, /C,
CH 2 Ph
X-
(288)
(290)
l RNH 2
\291)
O .
:)Ph
X-
(292)
Cycloaddition of phenyl isothiocyanate (296) to pyridinium salts (295) produced
imidazo[1,2-a]pyridine-2(3H)-thiones (297) (77MI41001}. Reaction of l-aryl-2-
chloropyridin-6-ones with mono-N -substituted ethylenediamines provided dihy-
droimidazo[l,2-a]pyridin-5-ones (79CPB1207}. Another procedure involves the polyphos-
phoric acid cyclization of 2-(2-hydroxyethyl)aminopyridines (76AJCI039}. Treatment of
certain ß -aminoacrylic esters (298) with benzenediazonium fluoroborate (299) resulted in
h
+ PhN=C=S ---+ N->=S
CONHR
0 1
,
CH 2
X- I
CONHR
(295)
(296)
(297)
Other Irnidazoles with Fused Six-membered Rings
633
ring closure with loss of aniline to provide tetrahydroimidazo[1,2-a]pyridines (300)
(78H(9)757). The cyclodehydration of cyclic tertiary amines (301) c0ntaining aliphatic
neighboring groups capable of undergoing intramolecular Mannich reactions to (302) has
been accomplished with the mercury(II) EDT A complex (73APZ09).
R3 0
R 2 NCH=CHC0 2 Et + PhN/BF 4 ---'
R 1
(298)
R3 N
R2 NJC02Et + PhNH 2
R 1
(300)
O H2N a N
I --. Ph
N..... /CHPh NJ
CH 2
(301) (302)
(299)
(ii) Closure of the pyridine ring
The Horner-Wittig reaction of 1-substituted imidazole-2-aldehydes (304) gave intermedi-
ates (305) that cyclized to imidazo[1,2-a]pyridin-5-ones (306) (80LA54Z).
H
R0 2 C I R 1 R 1
"C::::,C ìí N RO C çr N
/ I '\ --. 2 I '\
C H N ....j' N ....j'
I 2
hC 0
0:;:'-- .....OR
(303) (304) (305) (306)
1-Methylimidazole-2(3H)-thione (308) and a-bromophenacetyl chloride (307) in the
presence of triethylamine gave anhydro-3-hydroxy-7 -methyl-2-phenylimidazo[2, 1-
b ]thiazolylium hydroxide (309), which with a variety of alkynic and alkenic dipolarophiles
(310) in refluxing benzene formed 1-methyl-6-phenyl-5H -imidazo[ 1 ,2-a ]pyridin-S-ones
(312) (79JOC3803).
R0 2 C
I R 1
CHP(O)(OEth OHC !Í N
I + I '\
CH 2 N....j'
I
R0 2 C
--.
R 2 Me
R' N
-=4 Ph NJ
o
(307) (308) (309) (311) (312)
Alky1cobaloximes (313) with acetic anhydride in pyridine gave an imidazo[1,2-a]pyridine
(314). A mechanism for the degradation of (313) involving formation of (314) prior to
cleavage of the cobalt complex has been proposed (75JCS(Pl)386).
o CH,CH(OH)Me
I I OH NOAc
Me C N , J'I ) Me U:) N "
Co --. CMe
Me:--' / I 'N"'-:: Me N Þ
H py I COMe
o
(313) (314)
Condensation of 1,2-dimethylimidazole (3ZLA(498)1) or 1-methyl-2-(methylthio)imidazole
(316) (74HCA750) gave a dihydroimidazo[1,2-a]pyridine (317), which in the case of the
methylthio compound rearranged to (318), and the latter compound could be desulfurized.
E
I
-""C
E-C:;:::'
Me Me
PhCHBr S N S N
+ I )> --. Ph ìí )>
O .....CI HN-JV r- -JV
-0
R R2
Ph Me
S N
oJ-NJ
R,C=CR, .
(310)
E-C C
I
E
(315) R = Me or MeS, E = C0 2 Me
Me
R f N
+ J--'
E (t E R e
E NJ
E
E e E0r- e
--. E NJ --. E NJ
E SMe E
(318) (319)
(316)
(317)
634
Other Irnidazoles with Fused Six-membered Rings
Derivatives of 8-phenyl-2,3-dihydroirnidazo[1,2-a]pyridin-7 -one (322) were prepared
by the condensation of a series of ß -keto esters (320) with 2-benzylirnidazoline (321)
(78JHCI021).
OEt H
O= PhCH ( N
I + 2{ \
RICH N---I
"C=O
R 2 /
(320) (321) (322)
In a related reaction, condensation of 1,3-dicarbonyl cornpounds (323) with rnethylene
bis-imidazolidine (324) gave substituted irnidazo[1,2-a]pyridines (325) (78LA1491). The
reactions of aldehydes (326) with ethyl 2-imidazolidinyleneacetate (327), or those of
aldehydes (326) and ß -dicarbonyl cornpounds with irnidazolidines (330) gave sirnilar struc-
tures (328) and (331) (78LA1476, 73GEP2210633).
-- R! NJ
R 1
R3
"-
c=o
I
R1-CH
I
c=o
/
R!
í\
N \; NH
+ H
N
J
í\
N::;,... NH
R':C N\
R1r:vrJ
R!
(323) (324) (325)
H Et01C H
Et01CCH N __ H R N\
RCHO+2 J C NyYNJ
N 0
H
(326)
(327)
(328)
R 2 CO
I
R1CHO+ CH 1 +
I
MeCO
H COR 3 H
R30CC N R! N
NJ -- R20C NJ
H Me
(326) (329) (330) (331)
Therrnal rearrangernent of 2,2-pentamethylene-4,5-diphenyl-2H -imidazole (332) gave
5,6,7,8-tetrahydro-2,3-diphenylimidazo[1,2-a]pyridine (333) in 66% yield (75JOC2562).
QN"Ph (r)Ph
N.:::J Ph
Ph
(332) (333)
There has been one report of the synthesis of the irnidazo[1,2-a]pyridine ring systern
(336) by the closure of both rings by the reaction of (334) and (335), but closure of the
pyridine ring probably occurs first (73Z0R2006).
Me ""CH
'C:Y 'CN C:=.CH e N
I I Me J
+ -- Me
C C H 1 N/ CH2 ::::;,.... N ,,7
I Me
Me
(334) (335) (336)
4.10.4.2 Imidazo[1,5-a]pyridine
(i) Closure of the imidazole ring
Synthetic procedures exist for both saturated and unsaturated irnidazo[1,5-a]pyridines.
All procedures forrn the five-rnernbered ring by forrnation of one bond adjacent to the
Other Imidazoles with Fused Six-membered Rinf{s
635
six-mernbered ring nitrogen in the last step of a sequence starting from a preformed pyridine
or piperidine ring.
All of the synthetic methods of this type are quite similar. A 2-substituted pyridine with
an a -amino substituent is treated with an appropriate reagent to generate a trigona) carbon
atom next to it, which is then closed in various ways to the imidazo[1,5-a]pyridine. As an
exarnple, formylation of a-2-pyridylbenzylamine produces (337), which cyclizes to 1-
phenylimidazo[ 1 ,5-a ]pyridine (65d) upon heating in benzene with phosphorus oxychloride
(73JCS(Pl)2595). Intermediates suitable for cyclization also have been prepared frorn a-2-
pyridylamines and isothiocyanates (80JHC555) and carboxylic acids (63AGllOl). Direct closure
has been achieved with cyanogen brornide (72JAP(K)7225190) and phosgene (75FES197). In
one example 2-pyridylacetohydrazide was treated with one equivalent of nitrous acid,
presumably generating after Curtius rearrangernent an a-2-pyridylisocyanate which closed
irnmediately to the imidazo[1,5-a]pyridine (77JHC993, 79JHC689). With aliphatic compounds,
cyclization has occurred by treating pipe colic acid (or an ester) with isothiocyanates (52JA4960,
60AP203, 63MI41000, 68RTCll), isocyanates (60JOC2108, 70JHC355) and by treatrnent of pipe-
colylamines with aldehydes or ketones (58N492).
0 1 CHPhNHCHO
---. (65d)
N
(337)
4.10.4.3 Imidazo[4,5-b]pyridine
(i) Closure of the imidazole ring
Almost all of the literature procedures for the preparation of the imidazo[ 4,5-b ]pyridine
ring systern, like the [4,5-c] system, involve closure to the irnidazole by rneans of a carboxylic
acid or some derivative thereof. The first reported synthesis involved boiling 2,3-
diaminopyridine or a chloro derivative (338) with acetic anhydride to give 2-methyl-
imidazo[ 4,5-b ]pyridine and a chloro derivative (340) (27CB766). The diacetamidopyridines
(339; R = Me) have been isolated by milder treatrnent with acetic anhydride and cyclized
to the imidiazopyridines (48JCS1389, 63MI41001), and other anhydrides have been used
(63MI41001). Cyclization in 98% formic acid to give irnidazopyridines unsubstituted at C-2
(340; R = H) has been employed extensively (48JCS1389, 49JA1885, 49RTC1013, 56JA4130,
57JA670, 57JA6421, 59CPB602, 59JOC1455, 60MI41000, 63JOC1837, 65JMC296, 72RTC650).
Isolation of the interrnediate formamido compounds followed by distillation frorn mag-
nesium has also been used (52CBlO12). A variety of other acids have been used (58CPB443,
67MI41001, 77JMC1l89), and polyphosphoric acid facilitates this ring closure (64JOC3403,
64M242, 78IJC(B)531, 79IJC(B)428, 80JHC1757). The aldehyde-oxidation procedure has also been
applied to this ring system (48RTC29, 61RTC545, 62JOC2163, 65IJC138, 66IJC403, 79IJC(B)428).
Application of this and other methods to 2,3,4-triaminopyridine results in ring closure
between the 3-amino group and both the 2- and the 4-amino groups to give a mixture of
the imidazo[ 4,5-c]pyridine and the imidazo[ 4,5-b ]pyridine (65JMC708, 69RTC1263). Nitroben-
zene, instead of copper(II) acetate, has served as the oxidant and the intermediate Schiff's
base (341) has been isolated and cyclized (79IJC(B)428). Formamidine, phenyl acetamidates
and the ethyl ester of phenylacetarnidic acid have also been used to close the imidazole
ring but seern to offer no particular advantage (63JOC1837, 75M1059, 65IJC138). Ortho esters,
primarily triethyl orthoformate, represent another variant (57JA6421, 77JHC813), and this
-() ú -(X
X I NHz ---. X I NHCOR ---. X I ì R
N NHz NHCOR ::""N J
(338) (339) / (340)
X/)N=CHR
)NHz
(341)
636
Other Imidazoles with Fused Six-membered Rings
cyclization is facilitated by the addition of a slight excess of concentrated hydrochloric acid
(relative to the diamine) (73JOC613, 73JMC292, 78MI41007).
Acetic anhydride has also been employed to enhance the ortho ester reaction (73UKZ277,
74RTC160) as has diethoxymethyl acetate (6SJMC708, 66JMC3S4, 76RTC127), the actual cycliza-
tion reagent resulting from the reaction of acetic anhydride and triethyl orthoformate.
Reaction of 2,3-diaminopyridine with tetraethoxymethane and with tetrapropoxymethane
gave 2-ethoxy- and 2-propoxyimidazo[ 4,5-c]pyridine (74JCS(Pl)349).
Other variations include formamide (S7JA6421), sodium dithioformate or phosphorus
oxychloride-DMF (69RTC1263), a thioamide (78MI41000) and acetylacetone (77JHC813).
Reduction of 2,6-dibenzamido-3-(2-butoxypyrid-5-ylazo)pyridine with iron and hydro-
chloric acid resulted in ring closure to 5-benzamido-2-phenylimidazo[ 4,5-b ]pyridine
(60AC(R)12S).
Ring closure to imidazo[ 4,5-b ]pyridin-2(3H)-ones (343; X = 0) has been accomplished
by fusion of 2,3-diarninopyridines (342) with urea (48JCS1389, S9JOC14SS, 6SJMC296, 80JHC17S7,
78JMC96S), by reaction with phosgene (49JA188S, 78JMC96S), or in one instance by means of
ethyl pyrocarbonate (76KGS1277). The imidazo[ 4,5-b]pyridine-2(3H)-thiones (343; X = S)
are most commonly prepared by closure with carbon disulfide (48JCS1389, 6SJMC296,
70MI41001, 77KGS411, 79AJC2713), but also by means of thiophosgene or thiourea (49JA1885,
80JHC17S7). 2,3-Diamino-5-nitropyridines, however, failed to react with urea or carbon
disulfide (6SJMC296). 3-Amino-2-hydrazinopyridine (345) closes with carbon disulfide and
triethylamine to give 3-aminoimidazo[ 4,5-b ]pyridine-2(3H)-thione (346), but under neutral
conditions closure occurs to give s-triazolo[ 4,3-a]pyridine-3(2H)-thione (344) (77KGS411).
Heating ethyl 1-aminopyridine-3-carbamate (347) at 160 0 C for 15 minutes gave imi-
dazo[ 4,5-c]pyridin-2(3H)-one (348), but the N-methyl carbamate required 200 0 C
(S7JCS442). An isomeric 3-aminopyridine-2-carbamate cyclized on reflux in n-propanol
(66JOC1890). Quaternary salts of 3-pyridylurea (349) cyclized on addition of alkoxides to
l,4-dihydroimidazo[ 4,5-b]pyridin-2(3H)-ones (350) (79ZN(B)1473).
R
R2 -o lNHR _ R2_ 1 N >= X
NHR 1 ..J.--.
N N N
R 1
(342) (343)
R R
0 1 C02Et -4 N>=O
NH 2 ..J.--. N
N N H
H
+-- 0 lNH 2 _ N>=S
NHNHz _ .J.--. N
N N NH 2
U H2
N N
J-r:
S H
(344) (345) (346)
H
ONHCONH 2 _ :>=O
+ X- H
R
(347) (348) (349) (350)
Derivatives of 2-aminonicotinamide (351) underwent an intramolecular Hofrnann rear-
rangement in which the intermediate isocyanate (352) reacted with the 2-amino group to
give imidazo[4,5-b]pyridin-2(3H)-ones (353) (S7AP20). Similarly pyridine-2- or -3-
carboxylic acid hydrazides undergo the Curtius reaction with cyclization on the adjacent
3- or 2-amino groups (S8AP368, S9JCS31S7). Treatment of 2-amino-N-hydroxynicotinamide
with tosyl chloride and aqueous base also resulted in cyclization to imidazo[ 4,5-c]pyridin-
2(3H)-one.
R 3 [ R3 J R3 H
R2 0 lCONHX _ R: 0 1N=C=O _ R: N>=O
R 1::'-" NH 2 R::'-" NH 2 R ,.J.--. N
N N N
H
(351) (352) (353)
The photocyclization of 3-nitro-2-pyridyl-DL-leucine (354) to 2-isobutyl-
irnidazo[ 4,5-b ]pyridine (355) has been studied spectrophotometrically and the quanturn
yield of the reaction determined as a function of pH (72JCS(P2)2218). 3-N -Methanesul-
fonamidopyridine l-oxide (356) is acyl aminated at C-2 by phenylbenzimidoyl chloride
(357) and the intermediate 2-acylaminated product (358) cyclized to 2,3-diphenyl-
imidazo[ 4,5-b ]pyridine (359) (74JOC1802).
Other Irnidazoles with Fused Six-membered Rings
637
0-
ñî k
--. .J- )CH 2 CHMe 2 + CO 2 + H 2 0
N
H
(354) (355)
0' NHS02Me PhC=NPh [0' NHS02Me ] (XI N
+ I - - /Ph + MeS0 3 H
'>-.Ñ CI NCOPh '>-.N N
I N I Ph
0- Ph
(356) (357) (358) (359)
Fusion of 2,3-diaminopyridine (360) with 2-(cyanoamino)-4-hydroxy-6-methyl-
pyrimidine (361) provided 2-[ 4-hydroxy-6-methylpyrimidin-2-ylamino]imidazo[ 4,5-
b]pyridine (362) (73JHC363). Reaction of tetra-O-acetyl glucopyranosyl isothiocyanate with
2,3-diaminopyridine gave 1-(2-aminopyridin-3-yl)-3-g1ucopyranosylthiourea (363), which
was S-methylated to (364) which cyclized on heating to 2-(tetra-O-acetylglucopyranosyl-
amino)imidazo[ 4,5-b ]pyridine (365) (79CPBllS3).
O NH j O (X N j O
I 2 + NCNH /, - I }-NH--{ /,
'>-.N NH 2 N II '>-.N N N II
Me Me
(360) (361) (362)
Q N0 2
I CHC0 2 H
/ "-
N NH CH 2 CHMe 2
H
O, NHC=NR (XI N
- \ - -'l"NHR
NH2 SMe '>-. N
N N
(364) (365)
AcOCH 2
R= t
AC
OAc
The reactions of ß-keto esters with 2,3-diaminopyridine (360) and derivatives thereof
are complex and dependent upon the substituents on both substrates and on the reaction
conditions. Thus, acetoacetic ester (366) reacted with 2,3-diaminopyridine (360) in xylene
to give the diazepinone (369) and 1-isopropenylimidazo[4,5-b]pyridin-2(3H)-óne (370);
without solvent the diazepinone (367), and 3-isopropenylimidazo[ 4,5-b ]pyridin-2(3H)-one
(368) were obtained. Heating both these diazepinones caused rearrangement to the corre-
spondingN-isopropenylimidazo[ 4,5-b ]pyridin-2-ones. Reaction of 2,3-diaminopyridine with
acetoacetic esters substituted on the a-carbon in xylene gave (373). The isomeric compound
could be prepared in this case by reaction neat to give (374) which cyclized to the diazepinone
(375) on treatment with sodium ethoxide in ethanol. The diazepinone rearranged on heating
to the imidazo[ 4,5-b ]pyridin-2-one (376) (73JHC201). On heating with acetoacetic ester in
xylene, 2,3-diaminopyridine substituted on the 2-amino group by a methyl or phenyl group
(377) gave 2-acetonyl-3-phenylimidazo[ 4,5-b ]pyridine (381) without the intervention of the
diazepinone. Reaction with the phenyl compound (377; R = Ph) neat at 70 0 C gave ethyl
3-(2-anilino-3-pyridyl)aminocrotonate (378; R = Ph), which on treatment with sodium
ethoxide in ethanol underwent a reverse Claisen reaction followed by cyclization to give
2-methyl-3-phenylimidazo[ 4,5-b ]pyridine (379; R = Ph) (68TL4811). 6,6-Diallyl-5, 7 -dioxo-
1,4,5,7 -tetrahydropyrido[2,3-b ][1,4 ]diazepine (382), prepared by the reaction of
2,3-diaminopyridine (360) with diethyl diallylmalonate, was hydrated to give a-2-(pyrido[2,3-
b ]imidazoly1)-a-allyl-y-valerolactone (383) (nMI41 000).
Distillation of 1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-2,4-dione (384) with zinc dust
caused a reductive rearrangement to imidazo[ 4,5-b ]pyridine (385) (S6JCS104S). Reaction
of 6-chloropyrido[2,3- b ]pyrazines (386) with potassium arnide in liquid ammonia resulted
in attack at C-2 giving (387), with ring contraction to (388) involving loss of chlorine to
give imidazo[ 4,5-b ]pyridine or 2-substituted derivatives thereof (389) (79JHC30S).
0 , NHCSNHR
NH 2
N
(363)
638
N
:I:
o u
^Ä
:I:Z Z
Cz
T
I "'1 I
On
:I:Z Z
Ö,
O
.'"
I \\
X Ö
+
N
:I:
o u
^Ä
:I:Z Z
Cz
Other Irnidazoles with Fused Six-membered Rings
N
r--
o
OZ^Z:I: G'
b
i
Ç\
Ö
i
q
:I: U
Z :I: N
Ö
/
ii:
Ö
f\
:i0 0
zt5: X
Ie
+
N
:I:
U 0
Ä^
.., Z Z:I:
Cz
..,
z-::f'.z
Cz
T
ûJ
N
o
U
:I:
U
.., II
-
Z Z
o
T
N
:I::I:
Ö &
1
..,
o
:I:
U
o
U
:I: :I:
Z Z
o
1
..,
o
l!..
:I:
U
Z-::f'. z
o
õC
r--
'"
:I:
U
II ..,
Õ
õF:
x 8
T
'"
:I:
U
II
:I:
U
i:
U
o
0
N
8:I:Z Z:I:
Ö
T
8
Ie
...
IX)
X 8
Î
(;
IX)
:I:
Z
II ex:
:I:
u s
o
T
i
'"
:I:
Z
:I:
IZ Z
Ö
o
IX)
T
8
o
G'
IX)
8 X
T
o :I:
r Z
:I:Z Ö O
_ IX)
f')
Z
II
Other Irnidazoles with Fused Six-membered Rings
639
(ii) Closure of the pyridine ring
Heating equimolar amounts of 5-amino-1-methylimidazole-2(3H)-thione (391) with
diethyl ethoxymethylenemalonate (390) gave the diethyl ester of [(5-amino-2,3-dihydro-1-
methyl-2-thioxo-1H-imidazol-4-yl)methylene]propanedioic acid (392), which cyclized in
10% aqueous sodium hydroxide to 6-ethoxycarbonyl-3-methyl-2(1H)-thioxoimidazo[4,5-
b ]pyridin-5( 4H)-one (393) (78H(10)241).
H H H
( N )= (E tO C) C - CH[ N )= Et0 2Ú' N )=S
(Et0 2 ChC=CHOEt + l. S ---. 2 2 - I S ---.
H 2 N N H 2 N NON N
Me Me Me
(390) (391) (392) (393)
Treatment of 1,5-diaminoimidazoles (395) with ethyl acetoacetate or propionate (394)
yielded imidazo[ 4,S-b ]pyridin-5(4H)-ones (397) and imidazo[1,5-b][1,2,4]triazepinones
(398). The relative yields of these isomeric compounds depend on the substituents on the
reactants and on the reaction conditions. Conversion of (398) into (397) occurred on
prolonged heating in water (78JHC937).
M,COCHRCO,Et + rí')Ph
rN')>Ph
R
)Ph
R7-\"""N
H 2 Nl. N O
N
N O
NY-N
, /N-ß
NHR 1 H NHR 1 H NHR 1 Me N Ph
(394) (395) (396) (397) (398)
The reaction of ß-aminocrotonamide and ethyl N-acylglycinates gave 2-
[(acylamino)methyl]-6-methylpyrimidin-4(3H)-ones (399), which cyclized to 5-methyl-
imidazo[4,5-b]pyridin-7(4H)-ones (402) when heated to 180-190 o C in polyphosphoric
acid. At 100-110 oC 2-methylimidazo[1,5-a]pyrimidin-4(lH)-ones (400) are formed, which
on heating to 180-190 OC (in polyphosphoric acid) rearrange via (401) to the imidazo[4,5-
b]pyridin-7(4H)-ones (402) (82JOC167). Attack by malononitrile on purine (403) occurs at
C-6 with ring opening (404) and reclosure (405) to give 5-amino-6-cyanoimidazo[4,S-
b]pyridine (406) (73JCS(Pl)1794).
N H
HN
? Me ---. N
) N I Me ---. N
NyMe ---.
OHN \--N \--NH
R R R C
000
(399) (400) (401)
o H
M,lJ)R
N N
H
(402)
(403)
(404)
---. NC
N') ---. NC
N')
-N
NY-N H2N
Y-N
I H N H
+/-CH
H N:;.-'
2 (405) (406)
rN') ---. (NChC=CHrN>
I.::::::-NY-N H2NHC=N
N
H H
4.10.4.4 Imidazo[ 4,5-c ] pyridine
(i) Closure of the imidazole ring
Imidazo[ 4,5-c]pyridine (408; R = R 1 = H) and a number of its 2-substituted and 1,2-
disubstituted derivatives have been prepared in moderate to good yields by the reaction
of the 3,4-diaminopyridines (407) with aliphatic, aromatic and heteroaromatic aldehydes
in aqueous alcohol solution in the presence of excess copper(II) acetate in a sealed tube at
130-150 o C (38CB2347, 42CB1936). The Schiff bases (409) are formed primarily in this syn-
thesis, and in many cases it is preferable to isolate the base (409) and effect the subsequent
oxidation in a separate operation in alcohol solution. Ring closure of 5-substituted, 6-
substituted and 2,6-disubstituted 3,4-diaminopyridines (410) to 7-substituted, 6-substituted
640
Other Irnidazoles with Fused Six-membered Rings
and 4,6-disubstituted imidazo[ 4,5-c]pyridines (411) has also been accornplished with sodiurn
dithioforrnate (not satisfactory), 98% formic acid (48RTC29, 49RTCI013), triethyl orthoforrnate
and acetic anhydride (6SJHC196, 66JCS(B)28S, 73UKZ3S0), diethoxymethyl acetate (6SJMC708,
66JMCIOS) and triethyl orthoforrnate and concentrated hydrochloric acid in dirnethyl-
acetamide (82JMC626). The use of triethyl orthoacetate and acetic anhydride (73UKZ703),
irninoesters (6S1JC138, 73JMC1296), urea and carbon disulfide (6SJMC296, 66JCS(B)28S) provided
2-methyl-, 2-benzyl-, 2-oxo- and 2-thioimidazo-[ 4,5-c ]pyridines with substituents in the
pyridine ring (413-416).
R
O NHR (X N
I + R1CHO ---. I >Rl
N:::,., NHz N:::,., N
(407) / (408)
O NHR
N:::,., I N=CHRI
(409)
R R
R 1 0 '<:::::: NH2 ---. R I (X I N')
N -9 NH 2 N:::,., N
R Z R 1 H
(410) (411)
R 2 R 3
RI (X N
RN+ I )=s
:::,., N
H
(416) '
R 1 R 3
RI (X N
+ I >Me
RN:::,., N
MeC(OEU 3 / (413)
/Ac,O
R Z
R1 0 NHR3
RN I NH,
(412)
NH,'
ç
nc' Cl-
OEt
R' R 3
Rl (X N
RW I >Bn
:::,., N
<H,N),
RZ R 3
RI (X N
RN+ I )=0
N
H
(415) (414)
Cyanogen bromide ring closure of (417) was used to prepare streptolidine lactam (418),
a guanidine-containing amino acid lactam moiety of the streptothricin antibiotic group
(77BCJ237S), that moiety being a 4,5,6,7 -tetrahydroimidazo[ 4,5-c ]pyridine.
O ---. N 0
H6 HO
NHz N
(417) (418) NH 2
Refluxing ethyl 2-(3-aminopyridin-4-yl)hydrazinecarboxylate (419) in 36% rnethanolic
hydrogen chloride for 8 hours gave 1-aminoimidazo[4,5-c]pyridin-2(3H)one hydrochloride
(423), rather than the expected pyridotriazinone (420), thought to be an intermediate in
the formation of (423) via (421) and (422) (76JHC60I).
[ H H
N N
0 1 NHNHC02Et ---. 'NH 1:!.:. H ---.
N:::,., NH, N N O\
NON Ow
(419) (420) H (421) H
N J NH2
\ !1 - (X i N)=O
N .A N:::,., N
NOH H
(422) H (423)
Other Imidazoles with Fused Six-membered Rings
641
The pyrolysis of 3-azido-4-dialkylaminopyridines (424) and (427) by heating in nitroben-
zene to generate nitrene intermediates (425) has also been used to form the imidazole ring
of imidazo[ 4,5-c]pyridines (426) and (428) (66JCS(C)80). In one instance the intermediate
dihydro compound (429) was trapped by carrying out the reaction in acetic anhydride
(63JCS1666).
0 1 NMe2 ---.
N:::,.. N 3
(424)
0 1 Me2 ---.
N:::,.. N:
(425)
Me
(r N
N I j
:::,.. N
(426)
(R (R
rjrNJ ---. Ny
N V N 3 N N
H
(427) (428)
(Xy
Ac
(429)
(ii) Closure of the pyridine ring
Treatment of both histidine (430; R = C0 2 H) and histamine (430; R = H) with diethoxy-
methane in hydrochloric acid solution forms a CH 2 bridge between the NH 2 group and
C-5 of the imidazole ring to give 4,5,6,7 -tetrahydroimidazo[ 4,5-c ]pyridine-6-carboxylic
acid (spinacine; 432; R = C0 2 H, R 1 = R 2 = H) (13MI41000, 44BJ(38)309) and 4,5,6,7-tetrahy-
droimidazo[ 4,5-c]pyridine (spinaceamine; 432; R = R 1 = R 2 = H) (20MI41000). This reaction
has been extended to other aldehydes (66JOC2380), including pyridoxal (48JA3429, 3669), and
ketones (65FES634, 67FES821, 76H(5)127, 77IJC(B)629). The cyclization has been carried out in
basic and neutral aqueous solution, in organic solvents, and neat. In one investigation the
corresponding Schiff bases (431) were formed under mild conditions and are presumably
intermediates in the cyclization (66JOC2380).
RýYN
H 2 N IN''
H
(430)
---. R0 N ') ---.
N IN
/C" H
R1 R 2
(431)
(OR')(N') ---. (X OH I N"
/N N RN N
R Bn Bn
(433) (434)
R Q N')
HN N
H
R1 R 2
(432)
R=Me, Bn
R'=Me, Et
Intramolecular cyclization of the imidazoles (433) also gave rise to 4,5,6,7-tetrahydro-
imidazo[4,5-c]pyridines (434) (75JHC1039).
4,6-Dihydroxyimidazo[ 4,5-c]pyridine (3-deazaxanthine; 436; R = H) and related 2-
substituted derivatives (436; R = C1) and (438) were prepared from the requisite imidazole
4-acetamide-5-carboxylic acid esters (435) and (437) by base-catalyzed cyclization to the
imide structure (63JOC3041).
:X)ÔR
o
(435) (436) (437) x = 0, S (438)
Treatment of 5-cyanoimidazole-4-acetonitrile (439; R = H) with anhydrous HBr gave
6-amino-4-bromoimidazo[ 4,5-c]pyridine (440; R = H, R 1 = Br) (74JHC233). Likewise, the
l-(tri-O-benzoyl-ß-D-ribofuranose) derivative of (439) gave (440; R = tri-
O-benzoyl-ß-D-ribofuranose, R 1 = Br), whereas treatment with liquid ammonia and with
H
H 2 NOCl- N jR
Me02ClN
H
H 2 NOCl- N )=X ---.
Me0 2 cl N
H
OYlí
HN N)=X
o H
642
Other Irnidazoles with Fused Six-membered Rings
hydrogen sulfide and triethylarnine gave the corresponding 4-amino and 4-thio compounds
(440; R I = NH 2 , SH) (78JOC289).
R
NC N
Ncl>
N
R
---+ H2 N (X 1 N>
N::,... N
R I
(440)
(439)
Similarly, reaction with liquid ammonia of 4-cyanomethylimidazole-5-carboxylic acid
methyl ester and a number of 1- and 3-substituted derivatives thereof (441) at 100 0 C for
8 days gave 6-aminoimidazo[4,5-c]pyridin-4(5H)-one (3-deazaguanine; 442; R = H) and
1- and 3-substituted derivatives (442; R = tri-O-acyl-ß-o-ribofuranose, di-O-acetyl-5-
deoxy-ß- o-ribofuranose, tetrahydropyranyl and tri -O-benzyl-ß-o-arabinofuranose)
(76JA1492, 78JMC1212, 79JMC958). Derivatives of 6-aminoimidazo[ 4,5-c]pyridin-4(5H)-one
substituted on the amino group have been prepared by ring closure of the corresponding
3,4-diarninopyridines, but attempts to convert thern into (442; R = H) itself failed (74RTC3).
In a variation of the ring closure described above, the cyano group of (441; R = H) was
allowed to react with hydroxylamine to give the carboxarnide-oxirne (443), which cyclized
on reduction with hydrogen and Raney nickel via (444; R = H) to (442; R = H) (79JHC1063).
H
---+ H2NnN1)R
HN N
o
(442)
NC N?)R
Meo 2 cl N
(441)
1 Î
HON:,... N R r HN N R ]
H'N :Xl lH,N ""cll
(443) (444)
4.10.4.5 Imidazo[1,2-a]pyrazine
(i) Closure of the imidazole ring
The rnajor rnethods for the preparation of this ring system involve forrnation of the
irnidazole ring by cyclization of appropriately substituted arninopyrazines or by the reaction
of bifunctional agents with 2-arninopyrazines. Cyclization of the pyrazin-2-ylarnino
acetal (445) in concentrated sulfuric acid gave irnidazo[I,2-a]pyrazine (196) in low yield
(65JCS2778). Treatrnent of pyrazin-2-ylaminoethanols (446) with thionyl chloride gave tars
and low yields of the 2,3-dihydroimidazo[1,2-a]pyrazines (447) (578S8136. 65JCS2778). Cyc-
lization of pyrazin-2-ylaminoacetic acids (448) by means of sodiurn alkoxides affords
irnidazo[ 1 ,2-a ]pyrazin-3(2H)-ones (449). Basic conditions are superior to acid for this
cyclization (67CC1011) (in one instance dicyclohexylcarbodiimide was ernployed) and esters
and arnides have also been used (68TL3873, 70YZ423). A number of irnidazo[I,2-a]pyrazin-
3(2H)-ones (450) including the luciferins have been prepared by reaction of 2-
arninopyrazines (451) with a-keto acids, usually followed by reduction of (452) to (453),
N NH......
N ?H2
CH(OEth
---+ (196)
N NH......
N ?H2
CHpH
(446)
---+
N N\
N--I
(445)
(447)
Nç-.,...... NH HN -{ N
I. II ......CH R ---+ I. R
N 1 2 N
COR I 0
(448) R 1= OH, O-alkyl, NH 2 (449)
Other Imidazoles with Fused Six-membered Rings
643
R2C7
R N
HN R2
RI N--{
o
(450)
R N R 2 R N R 2
N / __ HN /
RII::::".. N I RII NH I
C0 2 H C0 2 H
(452) (453)
R
N NH2 R 2 COC0 2 H.
Rl N
(451)
R2COCH R
N0yN\R 2
RII::::".. NJ
R 3
(454)
and treatment of (453) with dicyclohexylcarbodiimide or acetic anhydride (66TL3445,
69YZ1657, 70YZ441, 70YZ707, 80CL299).
Generally, better yields are obtained by the reaction of 2-aminopyrazines (451) with
a-keto aldehydes to give (450) (70YZ441, 70YZ707) or a-halocarbonyl compounds to give
(454), the latter being the rnost widely used reactants (65JHC287, 71JHC643, 75JHC861, 76H(4)943,
77JÒC4197,80EUP13914).
3-Aminoimidazo[1,2-a]pyrazine (456) has been prepared by the reaction of 2-
aminopyrazine (455) with sodium cyanide and the bisulfite addition compound from formal-
dehyde (68TL3873). Another 3-aminoimidazo[1,2-a]pyrazine (458) was made by the reaction
of the tetrahydropyrazine (457) with a-amino-a-cyanoacetamide (67MI41000, 67MIP41000).
N NH2
N
(455)
__ N N\
NJ
NH
(456) 2
HN
A N OEt 2 "-
C II + CHCONH--
I -I.'T / 2
" NC
(457)
AcN N
NJCONH2
NH 2
(458)
(ii) Closure of the pyrazine ring
The sodium salt of 2-benzoylimidazole (459) can be alkylated with bromoacetal in DMF
and the product (460) cyclized to 8-phenylimidazo[1,2-a]pyrazine (461) by refluxing in
acetic acid containing ammonium acetate (69MI41002).
Ph
I
o O=C J N NR.-- :) N
-- II I/,__ I I /,
HC...... /N // N //
CH 2
(459) (460) (461)
Various 1-alkylimidazo[1,2-a]pyrazine 7-oxide quaternary salts have also been synthe-
sized from imidazoles (71JCS(C)2748). Two approaches were used. Quaternization of the
oximes (462) with a-bromocarbonyl compounds gave salts (463) which cyclized in strong
acid to the 7-oxides (464), and quaternization of the acetals (465) with bromoacetaldehyde
oxime afforded salts (466) which were treated with concentrated sulfuric acid.
Studies on the trio, tetra- and penta-peptides of a-methylalanine (65T3209, 73ACS1509)
have shown that cyclization to the imidazo[1,2-a]pyrazine ring system occurs and a sequence
for its formation from the tripeptide suggested (467) --+ (468) --+ (469). Another tripeptide
cyc1izes to a piperazine and then to the bicyclic system (78TL1009).
(El0hCHCH 2 Br +
Ph
I
O.:::::-CyN
Na+ -NJ
644
Other Irnidazoles with Fused Six-membered Rings
R
HON=CH rí N
R ICOCH 2 Br + J
(462)
R
HON=CH'y-N
- L\
R 1 COCH 2 N:.t
(463)
COH
HON CHCH,B, + 0,\)
(465)
-
COH /'
O
HON=CHCH2 J
(466)
- R
O'Ñ N
RI
(464) Br-
Me Me
Me2 NH Me
HN..- N HN '-L
oJte o:{Me 2 - O H _e -
PhCH 2 C0 2 NH Me 0 Me2
(467) (468)
Me 2
HN N
o r-{Me2
Me 2 0
(469)
4.10.4.6 lmidazo[1,5-a]pyrazine
(i) Closure of the imidazole ring
The most useful synthesis of this ring system involves conversion of 2-aminomethyl-
pyrazines (470) by means of carboxylic acids or anhydrides into the amides (471), which
are cyclized to 3-substituted imidazo[1,5-a]pyrazines (472) (73JOC2049, 75JHC207, 75JHC211,
75JOC3379).
Reaction of (470; R = H, NH 2 ) with carbon disulfide gives 2,3-dihydro-3-
thioxoimidazo[1,5-a]pyrazine (473) and its 8-amino derivative instead of the 3,4-dihydro-
pteridines (70JCS(C)1540, 75JOC3379).
R R
N N I CH2NH2
I I NH +- L II -
N--{ N
S
(473) (470) (471) (472)
3-(Pyrazin-2-yl)imidazo[1,2-a]pyrazine (475) was obtained as a by-product (10%) in the
arnmonium chloride-catalyzed preparation of pyrazine carbaldehyde dimethyl acetal frorn
the aldehyde (474) and trimethyl orthoformate (71TL1441).
R R
N CH2NHCORI _ N N
N I N-J
R 1
N.ç-...."CHO N
+(MeOhCH/NH 4 CI - h-{N
Y"N
(474) (475) N
Reaction of 1,2-dihydropyrazines (476) and (478) with isocyanates gave the imidazo[1,5-
a]pyrazines (477) and (479) (79JOC4871).
H 2 NOC H 2 NOC NH NC N y O
N CN N N CONH2 N '-'::
Ar2 H + RNCO --. Ar2 ' 'NR Ar2 NH + RNCO - Ar2 N--{NR
Ar 1 Ar 1 Ar 1 Ar ' 0
(476) (477) (478) (479)
Hexahydroimidazo[1,5-a]pyrazines (481) have been prepared by closure of substituted
aminomethylhexahydropyrazines (480) with carbonyldiimidazole (75FES650). Other closures
have been performed using ethyl chlorocarbonate with sodium ethoxide and thiophosgene
Other Irnidazoles with Fused Six-membered Rings
645
(75IJC468, 78IJC(B)1015). Treatment of the piperazine ester (482) with phenyl isocyanate
followed by refluxing hydrochloric acid gave the dioxo derivative (483) (62HCA2383).
o
RN CH2NHR I RN MeN C02Et MeN ..-1<..
I I - I I 'NR I I I + PhNCO _ I T 'NPh
NH N--{ NH N--{
(480) (481) X (482) (483) 0
Other hexahydro derivatives (485) have been obtained by cyclization of anilinomethyl-
piperazines (484) with aldehydes (66JMC868, 70JMC77).
HN CH2NH -Q C02Et
I I +R'CHO-
NH
(484)
R
H7LN -Q C0 2 Et
R 1
(485)
(ii) Closure of the pyrazine ring
Prolonged heating of theophyllin-7-acetic acid (486) with barium hydroxide (55FES616)
or treatment with sodium hydroxide at room temperature (61AC(R)1409) resulted in fission
of the pyrimidine ring and reclosure to the imidazo[1,5-a]pyrazine (487).
o 0
^ ^ J:lHMe
MeN NMe MeN I"
O N - o N-.f'N
H02CCH2NJ
(486) (487)
4.10.4.7 Imidazo[ 4,5-b ]pyrazine
(i) Closure of the imidazole ring
In general, derivatives of this ring system have been synthesized by the formation of the
imidazole ring from 2,3-diaminopyrazines (52JA350, 56JA242), but alternative approaches
have been examined particularly for 2-oxo derivatives. The reaction of 2,3-diaminopyrazine
or its 5,6-disubstituted derivatives (488) with acetic anhydride gave the corresponding
2-methylimidazo[ 4,5-b ]pyrazines (489; R 1 = Me) (56JA242, 57BSB136, 66FES811). Acid
chlorides and carboxylic acids also provide 2-substituted derivatives (489) (52JA350, 56JA242,
75JHC1l27). Triethyl orthoformate has been used to prepare imidazo[ 4,5-b]pyrazines unsub-
stituted at C-2 (57BSB136, 52JA350, 56JA242). A pyrazine N-oxide (490) (73JMC643) and other
pyrazines with substituted amino groups such as (492) have also been used to form
imidazo[ 4,5-b]pyrazines (491) and (493) (73JMC643, 71JAP7133957, 71JAP7133956).
N N N N N Me
Rf" ) NH 2 _ R X }-RI f' ) NHMe _ X Nj
R NH 2 R N N + NH 2 + N
N H N N
I I
0- 0-
(488) (489) (490) (491)
N CH 2 CH 2 Ph
) NHCH2CH2Ph _ X NjEt
N NH2 N N
(492) (493)
Treatment of 2,3-diaminopyrazine (488) with a wide variety of reagents has been shown
to give 2-oxoimidazo[4,5-b]pyrazines (496): typical reagents that have been used are urea,
phosgene, diethyl carbonate, potassium cyanate, carbamoyl chlorides and methyl chlorofor-
mate (52JA350, 56JA242, 70USP3541093). 2-Aminopyrazine-3-hydroxamic acids (494) on treat-
ment with benzenesulfonyl chloride rearrange to give 2-oxo derivatives (496) (68JOC2543,
646
Other Irnidazoles with Fused Six-membered Rings
70USP3549633). This rearrangement takes place under basic conditions and it is possible to
isolate the benzenesulfonates (495). Other acid chlorides have also been used. Fusion of
the hydroxamic acid (494; R = Cl, R 1 = EtNH) resulted in ring closure (70USP3549633).
Rf'N ) CONHOH Rf'N ) CONHOS0 2 Ph
R' NH 2 Rl NH 2
N N
(494) (49S)
N N /
R (N) : HNH2 R (N) : 3
(497) (498)
The Curti us rearrangement of acyl azides (498) prepared by diazotization of the hydrazides
(497) also provides imidazo[4,5-b]pyrazine-2-ones (496) in good yield (73JMC537). Various
rnodifications of this approach have been described (69USP3461123, 69FRP1578366,
71BRP1248146, 71BRP1238105). Thermal cyclization of structures like (499) and (501) has been
utilized to prepare this type of structure (500) (70GEP1957711, 71BRP1232758).
-----.... H
RFN X N
(4911 Rl I )=0
N N
H
(496)
CN y N ) NH 2 CNyN X N CNyN ) NHCONMe2
ck N ICON9Me2 ck N I )=0 +- Cl N I NH2
CH 2 CHOHR H
(499) (SOO) (SOl)
(ii) Closure of the pyrazine ring
One of the few exarnples of forrnation of the pyrazine ring as the last step in the synthesis
of imidazo[ 4,5-b]pyrazines (504) involves the reaction of biacetyl with the diamine (503)
generated in situ frorn the 4-nitro-5-amino compound (502) (70TLl013). Another synthesis
involving the use of an imidazole is the condensation of ethylenediamine (505) with (506)
to give the perhydro derivative (507).
N N
02 N f H 2 Nf >
H N / H2N N
HO HO
HO OH
(S03)
HO OH
(S02)
Me C N X N
M I >
H
HO OH
(S04)
N + Ph
'fH 2 NH 2 + Phr-:' >=0 C >=0
CH 2 NH 2 Ph N N N
H Ph H
(SOS) (S06) (S07)
Another synthesis of the fully reduced ring system (510) results from the alkylation of
the nitrarnine salt of ethylenediamine (508) with 4,5-dichloro-1,3-diacetylimidazolidine
(509) (79IZV1618).
Ac
CH 2 ÑN0 2 Cl ( N )
I _ 2M+ +
CH 2 NN0 2 Cl N
Ac
(S08) (S09)
N0 2 Ac
CNX N )
N N
N0 2 Ac
(510)
Other Irnidazoles with Fused Six-membered Rings
647
4.10.4.8 lmidazo[1,2-a]pyrimidine
Although it has not been synthesized, one natural product containing an imidazo[1,2-
a]pyrimidine system, a1cocherneine, has been characterized (72T5207).
(í) Closure of the imidazole ring
By far the most common synthetic method for the preparation of imidazo[1,2-
a]pyrimidines involves the condensation of a 2-aminopyrimidine with an a-halocarbonyl
compound (39YZ97, 51 YZ760, 56CR(243)2090, 59CR(248)1832, 60JA1469, 63LA(663)108,
63BSF1000, 66BSF2529, 66JMC29, 71JPS74, 74CHE992). As an example, treatment of 2-amino-5-
methoxypyrimidine (511a) with phenacyl bromide (512) produces only (513) (66JMC29). In
all examples thus far the carbonyl carbon has become joined to the exocyclic amino group
of the 2-aminopyrimidine. When the pyrimidine moiety is unsymmetrical, two isomers are
possible, though apparently only one is seen in many cases. A condensation of a 2-
amino pyrimidine with glyoxal and glyoxalic acid has also been carried out (74GE.P2513864).
C N)NH z + HzBr _ C NyN\Ph
R N or ......Ph MeO N--.!
(5U) a; R = OMe (512) (513)
b; R=H
Several other synthetic routes starting with 2-aminopyrimidines are also known. The
reaction of 2-aminopyrimidine (511b) with (ß-acylvinyl)triphenylphosphonium salts such
as (514) under kinetic conditions produces (515a), while under thermodynamic conditions
the same reactants produce (515b). A Dimroth rearrangement of (515a) produces a mixture
of (515a) and (515b) (75LA1934).
o N
(5Ub) + Me CH=C PPh3 - cr)R 2
Br R1
(514) (515) a; R 1 =CH z P"'Ph 3 Br-,R 2 =Me
b; R 1 = Me, R z = CHzP"'Ph 3 Br-
PhHNN 0
(5Ua) + C-C HCl0 4 )
/ "-
Br H
N N
C y CI0 4 -
MeO ':'I--{
NNHPh
(517)
phenylhydrazone (516)
in perchloric acid
(516)
Treatment of (511a) with a-bromoglyoxal
affords (517) (76JOU929).
Displacement of the ethylthio group in (518) with 2-aminoethanol followed by treatment
with thionyl chloride and then cyclization with base and heat afforded a mixture of (519)
and (520) (70TLl411). Other similar sequences have been carried out at this oxidation level
or by closing cyclic guanidine acids (08CB176, 71JCS(C)679, 76CHE696, 56JA1618).
N N H H
Ç SEt Ç yN OyNyN
Me' NH - Me' NJ + Me NJ
o 0
(518) (519)
(520)
(ii) Closure of the pyrimidine ring
The other common synthetic method for imidazo[1,2-a]pyrimidines involves the con-
densation of a 2-aminoimidazole (or imidazoline) with a ß-dicarbonyl compound (50BSB573,
52DOK(87)783, 54JGUl045, 55JGU939, 72BSF3503, 73JHC1021, 73LA103, 76HCA1203, 76JMC512,
78GEP2806199, 80JMC1188, 80JHC337). For example, treatment of 2-aminoimidazole (521) with
diethyl methylmalonate (522) and ethoxide ion produces (523). Depending upon the
ß-dicarbonyl compound employed, a single isomer may be obtained, or a mixture of the
two possible isomers in an unsymmetrical case. As might be expected, a,ß-unsaturated
esters and acid chlorides also react with 2-aminoimidazoline to give imidazo[1,2-
a lpvrirnidines (73GEP2133998, 78AJC179).
648
Other Irnidazoles with Fused Six-membered Rings
HN HO ( -""""::::: J N
1_ ï + Et0 2 CCHC0 2 Et - I h
H 2 Nl.:::::-N I Me::::,... N //
Me OH
(521) (522) (523)
4.10.4.9 Imidazo[1,2-c]pyrimidine
Considerable recent interest has arisen in the synthesis of imidazo[1,2-c]pyrimidines due
to the ready conversion of cytosine- and cytidine-related compounds into this ring system,
and due to the attendant chemical, physical and biological properties of these derivatives
(84MI41000).
(i) Closure of the five-membered ring
The most cornmon and also the most versatile synthetic method for irnidazo[1,2-
c]pyrimidines is the condensation of a 4-aminopyrimidine with an a-halocarbonyl com-
pound. Treatment of 1-methy1cytosine (524a) with chloroacetaldehyde (525) produces
(526a) (71TLl993). Cytidine (524b) reacts similarly to produce (526b) (72BBR(36)597). A
substituted a-halocarbonyl compound such as phenacyl bromide (512) produces exlusively
the isomer represented by (526c) (78MI41010). The mechanism of this type of transforrnation
has been well studied (78MI41011, 78MI41008, 77DOK(234)343, 75IZV2766). Recently
bromoacetaldehyde has been recomrnended in place of chloroacetaldehyde since it reacts
faster and is apparently less mutagenic (80CPB932). Examples abound with other 4-
aminopyrimidines and a-halocarbonyl compounds (76MI41002, 76JCS(Pl)1991, 7IJHC643,
78JHC119, 80B3773, 64JHC34, 75CHE81). It is also possible to use a-haloacetals directly
(75JOC3708). Displacement of a 4-halogen with aminoacetaldehyde diethyl acetal results in
an intermediate which can be cyclized with acid (78JHC119, 65JCS2778). It is important to
note that not all 4-aminopyrimidines react with a-halocarbonyl compounds to produce
irnidazo[I;2-c]pyrimidines. With some compounds when C-5 is unsubstituted pyrrolo[2,3-
d]pyrimidines are formed, and some of the earlier literature has been found to be in error
in this regard (76JCS(Pl)1991).
NH 2 0 N
?" II 7"__
7 +CICH 2 CH _ - þ\R!
A...) RN y N..J
o N
R 0
(524) a; R = Me (525)
b; R = ß-o-ribofuranosyl
c; R=H
(526) a; R = Me, R 1 = H
b; R = ß-o-ribofuranosyl, R 1 = H
c; R=Me,R 1 =Ph
In a related synthesis, cytidine (524b) and some derivatives form irnidazo[1,2-
c]pyrirnidines (528) when treated with ß-acetylvinyltriphenylphosphonium bromide (527)
(72TL439, 73LA278, 75LA1934, 75M417). Compound (528a) undergoes the Dimroth rearrange-
rnent to produce (528b) (75LA1934).
o N
II + ,..... -- 1
(524b) + MeCCH=CNPPh 3 Br- - RN NJR
Y R 2
o
(527)
(528) a; R = ß-o-ribofuranosyl, R 1 = Me, R 2 = CH 2 P+Ph 3 Br-
b; R = ß-o-ribofuranosyl, R 1 = CH 2 P+Ph 3 Br -, R 2 = Me
Another common procedure involves treating 4-halopyrimidine with 2-chloroethylamine
to produce a 4-(2-chloroethyl)amino derivative which can be cyclized readily. Treatment
of 2,4-dichloro-5-nitropyrimidine (529) with 2-chloroethylamine affords (530). Reduction
with Raney nickel followed by cyc1ization gave the imidazo[1,2-c]pyrimidine (531)
(52JCS4410). Other similar cases are known (55JCS896, 58JCS2821, 57T(1)75, 7IJCS(C)675,
7IJCS(C)679) and the corresponding (2-hydroxyethyl)amino derivatives can be prepared and
cyclized using thionyl chloride (62JOC4080, 67T1297, 76CHE696).
Other Irnidazoles with Fused Six-membered Rings
649
CI NHCH 2 CH 2 CI NH 2
ON C N ON C N N
2 I I +CICH 2 CH 2 NH 2 _ 2 I I _ I 1--
CI CI N NJ
N N Cl
(529) (530) (531)
(ii) Closure of both rings
Condensation of the isothiocyanate (532) with ethylenediamine affords (533) (76M171).
Treatment of a-(5-bromouracil-1-yl)-a-alanine (534) with an amine such as piperidine
or morpholine results in the formation of (535) by an addition-elimination mechanism
(80CHE418).
Me 0
I II
Me-C-CH 2 CMe
I
N=C=S
NH,CH,CH,NH, )
MeH
Me2r't-N\
HNyN-J
S
(533)
(532)
o
Hl'JB'
o N NH
I I 2
CH 2 CHC0 2 H
(534)
O
- I 1 \C0 2 H
HNyN-J
o
(535)
4.10.4.10 Imidazo[1,5-a]pyrimidine
The imidazo[1,5-a]pyrimidine ring system has been formed in all examples thus far by
annulation of a 4-aminoimidazole with a three-carbon unit. In the first synthesis, a condensa-
tion of 5-amino-4-rnethylimidazole (536) with 2,4-pentanedione (537) produced (538)
(39YZ18S). Several other similar condensations have also been carried out (6SM741,
71BSF1031, 74JHC873). The 1-carboxyethylimidazole (539) has been cyclized to (540) by
heating in polyphosphoric acid (70JHC21l).
Me [ N J N--: Me
I ';t + MeCCH 2 CMe - N, I
H 2 N N N #
H Me
(536) (537) (538)
H
N0 2 N0 2 N 0
H2N PPA J
I 'N --+ N I
H0 2 C(CH 2 hN......f N
Me Me
(539) (540)
4.10.4.11 Imidazo[1,5-b ] pyrimidine
(i) Closure of the pyrimidine ring
Treatment of the methyl ester of L-histidine (541a) with phenylthiocarbonyl chloride
(542) results in the formation of (544) (S6M679). The same ring closure can be accomplished
with carbonyldiimidazole (543) and histidine or histamine (541b) (77BBA(491)2S3, 67T239).
Ring opening at the C-5 carbonyl group of (544) is readily achieved with amines (S6M679).
Conversion of histidine and histamine derivatives into (544) and various other substituted
derivatives of (544) has been used to achieve specific methylation both on the side-chain
nitrogen (78MI41002) and on a ring nitrogen (78RTC293). Compound (544c) can be readily
polymerized to oligohistidines in an aqueous buffer at 30 oC (77BBA(491)2S3).
o
II
PhSCCI (542)
or
o
N"""'N- -NA,N
\d (543) '=.J
R
) I r 'N
H Ny N......f
o
(541) a; R = COzMe
b; R=H
(544) a; R = COzMe
b; R=H
c; R=COzH
N
MeNyN......f
S
( 545)
' NH N
R NH
650
Other Irnidazoles with Fused Six-membered Rings
The sulfur-containing alkaloid zapotidine has been found to have the structure (545)
(6IJA2022). A synthesis of (545) has been achieved from (544b) by lithium alurninum hydride
reduction to N'" -rnethylhistamine followed by ring closure to (545) with thiocarbonyl-
diimidazole (67T239).
4.10.4.12 lmidazo[1,2-b ]pyridazine
(i) Closure of the imidazole ring
Direct syntheses of the bicyclic system have mainly employed the standard Tschitschibabin
cyclization between a 3-aminopyridazine and an a-halocarbonyl compound, or a closely
related sequence. For example, treatment of 3-amino-6-chloropyridazine (546) with a-
brornoacetophenone (512) in boiling ethanol produces (547a) (64CPBI351, 65JHC287). Typical
yields for this general type of cyclization are 30-60%. The parent ring system is best
prepared by condensation of (546) with bromoacetaldehyde to produce (547b), from which
the chlorine can be readily removed by catalytic hydrogenolysis (67T387). Substituents on
the imidazole ring can be varied just by selecting the appropriate a-halocarbonyl cornpound.
For example, condensation of (546) with ethyl 2-brornoacetoacetate produces (547c) in
37% yield (67T2739). Substituents on the pyridazine ring in imidazo[1,2-b]pyridazines are
either present on the starting 3-aminopyridazine or derivable from groups present on the
starting pyridazine.
0 1 NH2 Q::; N
+ PhCOCH 2 Br ---+ /, R
CI N R2 N Q
N N R'
(546) (512) (547) a; R = Ph, R 1 = H, R 2 = Cl
b' R = H R 1 = H R 2 = CI
c: R=Me. R 1 =C0 2 Et, R 2 =CI
d' R=Ph R 1 =R 2 =H
e; R=Rl'=H,R2=N 3
The mechanism of the ring formation appears to involve initial alkylation at N-2 followed
by cyclization to the exocyclic amino group. The evidence for this pathway is the isolation
of the salt (548) in the reaction of 3-aminopyridazine with (512) under rnild conditions.
Heating of (548) in aqueous solution results in the formation of (547d) (64CPB1351). All
cornpounds thus far isolated have substitution patterns consistent with this two-step rnechan-
isrn in which the intermediate is generally not isolated.
O lNH 2 0
N II
N + 'CH 2 CPh
Br- (548)
a
I 'CH 2 N
N N H2C1 ---+ (1.)
(549)
(550)
Formation of 2,3-dihydro cornpounds is possible either by generating a 3-(2-chloroethyl-
amino)pyridazine such as (549) and cyclizing it to (550) (65JCS2778) or by treating 3-
arninopyridazine directly with dibromoethane (69MI41001). The fully arornatized rnaterial is
then available by oxidation.
(ii) From a different ring system
An indirect preparation of the imidazo[1,2-b]pyridazine ring systern has also been
reported by valence isomerization of a tetrazolo[1,2-b]pyridazine (70JOC1138). Treatrnent
of 6-(2,2-dirnethoxyethylarnino)tetrazolo[1 ,5-b ]pyridazine (551) with polyphosphoric acid
produces a 45% yield of 6-azidoimidazo[1,2-b]pyridazine (547e).
Û N
--- \ PPA
MeO N ---+ (547e)
" H'>-. N /i
CHCH N N -N
/ 2
MeO
(551)
Other Imidazoles with Fused Six-membered Rings
651
4.10.4.13 lmidazo[1,5-b]pyridazine
Two reports exist on the synthesis of this ring systern. A double acid-catalyzed cyclization
of the semicarbazone (552) produced 2-phenyl-4-acetylimidazo[1 ,5-b ]pyridazine-
5,7(3H,6H)-dione (553a) in 70% yield (79JHCllOS). Several other examples are reported.
Methylation of (553a) with diazomethane afforded the 6-methyl compound (553b). The
other synthesis begins with the preparation of pyridazine (554) in several steps. Cyclization
of (554) with polyphosphoric acid followed by treatment with POCh produced the imi-
dazo[1,5-b ]pyridazine (555) (78GEP2804909).
COMe
I
/CH 2 CH t C0 2 Et
Ph-C NH 0 NH
N""" 'C...... 2
II
o
(552)
--+
o
ÇQ }-N....N'" Ph
RN
o COMe
(553) a; R=H
b; R = Me
H
U N 0
N i,PPA
I # ii, POCI:
Pr"CONHCH
I
Me
(554)
PrO N
Nr-'1..... . CI
Me
(555)
4.10.4.14 Imidazo[ 4,5-c]pyridazine
Unless the bonds are fixed by attachment of a group at N-5 or N-7, this ring system has
a mobile hydrogen which can reside at either site. For clarity, derivatives with this capability
are referred to only as (7 H)-imidazo[ 4,5-c ]pyridazines.
Syntheses of this ring system have been carried out exclusively by forming the imidazole
ring from a 3,4-diaminopyridazine. Substituents are incorporated by means of groups
attached to the pyridazine or by varying the precursor to C-6. Ring closure has been
accomplished with either triethyl orthoformate or formic acid to produce 6-unsubstituted
compounds. For example, when (556a) was treated with formic acid, (557a) was obtained
in 68% yield. Treatment of (556a) with cyanogen bromide produced the 6-amino compound
(557b), while treatment with carbon disulfide afforded the corresponding 6-thione
(67JHCSSS). Urea has also been used as a condensing agent (81AJC1361). The adenine analog
(557c) has been prepared by condensing (556b) with triethyl orthoformate to give (557d),
which was converted into (557c) by ethanolic ammonia in an autoclave at high temperature
(64JHC42). The parent heterocycle has been obtained by several routes, including the catalytic
dehalogenation of (557d) (67JHCSSS).
N H N
H 2 N Ü '::::-N R3/N ìí "'::::- '::::-N
H 2 N # R 1 \'N-_ "phl
R 2 R 2
(556) a; R 1 =R 2 =H (557) a; R 1 =R 2 =R 3 =H
b; R 1 =H,R 2 =Cl b; Rl=R2=H,R3=NH2
C' R 1 =H R 2 =NH 2 R 3 =H
d; R 1 =R 3 =H, R 2 ='CI
Derivatives substituted at N-5 or N-7 with methyl groups are available simply by ring
closure of the appropriate methylamino-substituted pyridazine (67JHCSSS).
4.10.4.15 lmidazo[ 4,5-d]pyridazine
The imidazo[ 4,5-d]pyridazine ring system has a mobile hydrogen which could give rise
to two isomers in an unsymmetrically substituted molecule.
Chemical synthesis of this ring system has been achieved by two basic methods. First,
imidazoles with groups at the 4- and 5-positions capable of undergoing condensation to
form the pyridazine ring have been employed. Second, 4,5-diaminopyridazines can be
condensed with an appropriate one-carbon synthon to produce imidazo[ 4,5-d]pyridazines.
(i) Closure of the pyridazine ring
As an example of the first method, treatment of dirnethyl imidazole-4,5-dicarboxylate
(558) with hydrazine at elevated temperatures results in direct forrnation of (559) (which
652
Other Irnidazoles with Fused Six-membered Rings
can be written in several tautomeric forrns). Carrying out the reaction at lowcr temperatures
results in formation of the dihydrazide, which can be further converted into (559) upon
heating (S6JA159). This process has also been accomplished with a nucleoside. Treatment
of (560a) with 85% hydrazine hydrate in boiling ethanol produced only (560b), which could
be converted into (561) by boiling in 97% hydrazine (76MI41000). Other examples sirnilar
to the two described are known (78JHCl, 73JPSlOll, 69JMC43, 68JHC13, 65JHC247, 64JHC182,
62JOC2500, 58JA6083, 58JOC1534). Recently 4,5-dicyanoimidazole has been converted with
hydrazine directly to the 4,7-diamino compound (255g) (78JHC1451).
o
"
RIC
-l;N
R IC ---ZN)
ROCHd
RO OR
(560) a; R = COMe, R 1 = OMe
b; R=H, R 1 =NHNH 2
(558)
(559)
H O
I N
HN h )
o N
HOCHd
HO OH
(561)
o
" H ) 0 H
,....,C N N
MeO X \+NH NH H I \
MeO, N I/ 2 2 HN 1/
C N
II 0
o
(ii) Closure of the imidazole ring
Many different 4,5-diaminopyridazines have been condensed with one-carbon fragrnents
to forrn imidazo[ 4,5-d]pyridazines. Treatment of (562) with formic acid at reflux produces
(255h) in 78% yield (70CPB1685).Other condensing agents have included triethyl orthofor-
rnate (81J0C2467, 60CPB999, 63AF878, 70CPB1685), triethyl orthoacetate and acetic anhydride
(60CPB999), formarnide (70CPB1685) and carbon disulfide (60CPB999, 63AF878, 70CPB1685).
\1NH2
NV NH 2
(562)
4.10.4.6 Imidazo[ 4,5-d][1,2,3]triazine
The impetus for research on this ring system comes frorn its close resernblance to the
purine ring. Various derivatives have been prepared as 2-aza analogs of purines and purine
nucIeosides and evaluated for biological activity (82MI41000, 75ANY(255)292).
Syntheses of irnidazo[ 4,5-d][1,2,3]triazines have been carried out exclusively by building
the triazine ring onto an existing, properly substituted imidazole ring. Treatment of 5-amino-
4-carboxarnido-l-(ß-o-ribofuranosyl)imidazole (563a) with sodium nitrite in aqueous
hydrochloric acid, resulting in diazotization of the 5-amino group and then cyclization to
the 4-arnide, produced (257b; 2-azainosine) (72JHC623, 72JMC841). Other irnidazo[ 4,5-d]-
[1,2,3]triazin-4-ones have been prepared in similar fashion (74JOC3651, 73JHC417,
5UBC(189)401, 60JA3189, 6UOC2396, 6IJCS4845). Similar diazotization-cyclization on 5-amino-
4-carboxarnidinoimidazoles such as (563b) produced (258d) (69CC458, 72JMC182). The 4-
thiones, such as (257a), are prepared from the corresponding thiocarboxamide (563c)
apparently by initial formation of imidazothiadiazines, which readily rearrange in amrnoniurn
hydroxide (75CHE995, 73CHEl173). Exposure of 4-(di-n -butyltriazeno)-5-carboxarnido-
imidazole (564) to light results in the formation of irnidazo[ 4,5-d][1,2,3]triazin-4-one
(2-azahypoxanthine; 257c) (62JOC2150). The starting imidazoles can be prepared by direct
synthesis or by one of several methods for the ring opening of a purine.
R H n
N X; H N X N= NNBu2
<- I 2 NH <- I NH
N 2 N C/ 2
X "
o
(563) a; X = 0, R = ß-D-ribofuranosyl (564)
b; X = NH, R = ß-D-ribofuranosyl
c; X = S, R = H
Other Irnidazoles with Fused Six-membered Rings
653
4.10.4.17 Imidazo[1,2-b ][1,2,4 ] triazine
(i) Closure of the imidazole ring
The most versatile method. for the preparation of this ring system is the condensation of
an a-halocarbonyl compound with a 3-amino-1,2,4-triazine. For example, treatrnent of
3-amino-5,6-dimethyl-1,2,4-triazine (565) with phenacyl bromide (512) produced only
(566) (65JHC287). In addition to a-halo ketones, a-haloaldehydes (nJHC1157, 55MI41000),
a-haloacetals (80MI41000) and a-haloesters (79CHE1255) have been used. The direction of
condensation is always as shown for the preparation of (566).
N/N ) Me ,f'N/N ) Me
II + (512) ---+ Ph\ _ I
H 2 N'N"'-;:: Me N N"'-;:: Me
6 6
The 6,7 -dihydro compounds can be prepared by a standard sequence such as the treatment
of (567) with 2-aminoethanol to produce (568a), which is converted into the chloro
cornpound (568b) with SOCh and cyclized with potassium t-butoxide to (569). Full arornati-
zation to (570) was carried out by heating with 10% palladium-charcoal (76JHC807).
N/N ) Ph N/N ) Ph /"N/ ) Ph N/N ) Ph
l NH2CH2CH20H ) l \ I '/
MeO ...-;:: Ph XCH 2 CH 2 NH ...-;:: Ph ---+ N ...-;:: Ph ---+ N A ...-;:: Ph
N N N N
(567) (568) a; X = OH (569) (570)
b; X=Cl
(ii) Closure of the triazine ring
Another useful synthetic method is the condensation of 1,2-diaminoimidazoles with
1,2-dicarbonyl cornpounds. Treatrnent of 1-acetylamino-2-amino-4-phenylimidazole (571)
with biacetyl (572a) under acid catalysis produced (573a) (70CB3533). The use of phenylgly-
oxal (572b) hydrate gave both (573b) and (573c), with (573c) predominating. The corre-
sponding aldoxime only resulted in (573b). Cyclization is also possible with a-ketoacids
(74JHC327).
o
"
Ç-NNHCMe
Ph\ .JNH 2
N
(571)
OyR
+ o l..R 1 ---+
(572) a; R = R 1 = Me
b; R=Ph,R 1 =H
N
Ph N/ R
NAN)R 1
(573) a; R = R 1 = Me
b' R=Ph R 1 =H
C : R=H'Rl=Ph
, ,
Other, less general syntheses have also been reported. Reaction of phenacyl bromide
(512) with amino guanidine produced dihydro cornpounds (574), which are readily oxidiz-
able to the fully aromatic compound (262) (68TL789). Cyclization of (575) with acid produced
the 3,6-dione (576) (69MI41000). When 3-amino-1,2,4-triazine was heated in concentrated
hydrochloric acid, a small amount of the parent compound imidazo[1,2-b][1,2,4]triazine
was isolated, presumably by degradation of the triazine to a two-carbon fragment which
condensed with the remaining triazine (76RTC74).
H
N
Ph(N/ ) Ph
N--l:. R
H N
(574) a; R=H
b; R = Br
o
"N N.
Bu n HNCCH 2 N/ Ph ---+ O N/. Ph
BUnNÅN'/ O N--l:.NAO
H I
(575) Bun (576)
4.10.4.18 Imidazo[1,5-b ][1,2,4]triazine
One synthesis of this ring system has been reported, the condensation of 1,5-
diaminoimidazoles with glyoxal or biacetyl. For exarnple, treatment of (577) with biacetyl
produced (578a) (74BSF1453).
654
Other Irnidazoles with Fused Six-membered Rings
N NHz
NNHz
Ph
(577)
Ph....N
MeC-CMe N Me
þ N Me
R N
(578) a; R=H
b; R = Sf
4.10.4.19 Imidazo[1,5-d] [1,2,4 ]triazine and Imidazo[1,2-d] [1,2,4 ] triazine
These new ring systerns are both prepared by annulation of the triazine ring onto an
irnidazole precursor. Treatment of irnidazole-4-carbaldehyde (579) with either methyl
dithiocarbazinate (580a) or ethyl carbazate (580b) produced (581a) or (581b), respectively.
Heating of either (581) derivative produced the corresponding bicyclic products (582)
(79JHC277).
CH N N
N I I -. N -I I
NH N y NH
RXCNH
II X
X
(581) a; X=S, R=Me (582) a; X=S
b; X = 0, R = Et b; X = 0
Similar treatrnent of irnidazole-2-carbaldehyde (583) produced the imidazotriazines
(584) (79JHC277).
CHO
N N
x
II
H,NNHC-XR (5801
a; X=S, R=Me
b; X=O,R=Et
(579)
OHCrN\ -. 0yN\
HNJ HNyNJ
X
(583) (584) a; X = S
b; X=O
4.10.4.20 Imidazo[2,1-c ](1,2,4]triazine
The rnoré general syntheses of this ring systern have all involved annulation of the triazine
ring onto a preforrned imidazole ring. A series of variations within this therne has been
developed.
(i) Closure of the triazine ring
Treatrnent of 2-rnethoxyirnidazoline (585a) with hydrazine produced the cyclic
arninoguanidine (586), which reacted with a-ketoesters (587) to give irnidazo[2, 1-c]-
[1,2,4 ]triazin-4(8H)-ones such as (588) (72LA(764)112)
N N
C ')XMe + NHzNHz -. C ')NHNH z
N N
H H
o 0
11 II
MeC-COR
15871
H
NyN'N
CNYMe
o
(588)
(585) a; X=O
b; X=S
Alkylation of (585b) with a phenacyl brornide produced (589), which can be cyclized
with hydrazine to (590) (77JHC59). Sirnilar cyclizations have been carried out on a 1-
phenacyl-2-brprnoirnidazole derivative (74UKZ99), a 1-phenacyl-2-rnethanesulfonyl-
irnidazole derivative (74CHE1492) and 1-(2-chloroethyl)-2-brorno-4,5-diphenylirnidazole
(75CHE371) to afford irnidazo[2, 1-c][ 1 ,2,4 ]triazines.
Treatrnent of (586) with DMAD (591) in rnethanol in the presence of triethylarnine
produced (593), presurnably via (592), which can be isolated under slightly different
conditions (74JCS(Pl )297).
(586)
Other Irnidazoles with Fused Six-membered Rings
655
N
e )SMe
N 0
CH2'
R
(589) Þ
H
NH2NH2 (-1 N'
I R
Þ
(590)
(591)
(592)
H N
NY'N
-. CN CH2C02Me
o
(593)
(586) + Me02CC===CC02Me -.
[e N H /,C01Me ]
)-NN=C"
N CH 1 C0 2 Me
H
The diazoniurn salt of 2-arninoirnidazole (594) when treated with ethyl cyanoacetate
produced the azo compound (595). Cyclization of (595) to (596) occurred on heating in
acetic acid (76JMCS17).
N
[ >N 2 +Cl-
N
H
(594)
NCCH 2 C0 2 Et
)
NC /C0 2 Et
"CH
N I
[ }-N N
N
H
(595)
(: ::::::ý"N'-
HOAc I "N
N C02Et
NH 2
(596)
(ii) Closure of the imidazole ring
The synthesis of (588) has also been reported by the cyclization of (597) (69MI41000).
This is the only reported synthesis of an imidazo[2,1-c][1,2,4]triazine starting frorn a triazine
derivative.
H
H ( N,
ClCH 2 CH 2 N 1 N
I -- (588)
Ny Me
o
(597)
(Ui) From other ring systems
Several other syntheses of this ring system were accornplished by annulation of the triazine
ring onto a five-mernbered ring, either oxazole (69C303) or thiazole (7IJCS(C)161S), with
concurrent ring opening and reclosure to forrn the imidazo[2,I-c][1,2,4]triazine system. For
exarnple, treatrnent of 2-arnino-3-phenacyl-5-phenyloxazoliurn brornide (598) with phenyl-
hydrazine produced (599).
+
[ NCH 2 COPh
I >NH 1
Ph 0
Br-
(598)
O NHNH 2
H
N::::::ý" N'NPh
) Ph I I
" N Ph
(599)
4.10.4.21 Imidazo[ 4,5-e ][1,2,4]triazine
Two basic synthetic approaches to this ring system have been developed recently. In one,
the irnidazole ring is appended onto a 5,6-diarninotriazine precursor. For exarnple, treatrnent
of 2-benzyl-5,6-diamino-l,2,4-triazin-3(2H)-one (600) with triethyl orthoforrnate in
nitrobenzene at reflux produced (601a) in 72% yield. Sirnilarly, benzaldehyde afforded
(601b). The tautorneric structure of the irnidazole ring is unknown (76CPB2274).
A second synthetic route involves the ring contraction of certain 7 -azapteridinones.
Treatment of 6-benzylidenehydrazino-3-rnethyluracils, for example (602a), with sodiurn
656
Other Irnidazoles with Fused Six rnernbered Rings
N X N ,
R( :;-' NCH 2 Ph
N N O
H
(601) a; R= H
b; R = Ph
nitrite in acetic acid produced the 5-nitroso compounds (602b), which underwent dehydra
tive cyclization to the azapteridine (603) with acetic anhydride. Treatrnent of (603) with
alcoholic sodiurn hydroxide followed by acidification resulted in the forrnation of
3-substituted 5 methyl-5H-imidazo[ 4,5-e][1,2,4]triazin-6(7 H)-ones such as (604)
(78CPB3154). 7-Azapteridine 5-oxides undergo a sirnilar conversion with either acetic anhy-
dride or alcoholic sodiurn hydroxide (76CC658, 76H(4)1503). Both reactions rnay occur by a
benzilic acid-type rearrangement with initial attack of hydroxide, for exarnple at the C-5
carbonyl group of (603).
H 2 Nf"N'NCH 2 Ph --
H2N w--l0
(600)
H H
oy =;\ N N'N
MeN I ßPh --
XH
o
(602) a; X=H
b; X=NO
H H
OY 0 N yN'N N X N .... N
MeN )Ph -- 0=\ )Ph
N M N
o e
(603) (604)
4.10.4.22 Imidazo[5,1-c][1,2,4]triazine
This ring systern has been prepared by the annulation of the triazine ring onto a substituted
imidazole. In the first reported synthesis, treatrnent of 4-hydrazino-2,5-di-t-butyl-2-rnethyl-
(2H)-irnidazole (605) with 3-brorno-4-rnethyl-2-pentanone (606) in the presence of base
produced a 44% yield of (607) (74M38). In a conceptually sirnilar sequence, alkylation of
2-rnethyl-4-nitro-5-brornoirnidazole (608a) with ethyl brornoacetate gave (608b), which
cyclized upon heating with 85% hydrazine hydrate in boiling DMF to (609a) in 78% yield
(79CHE1237). The 1-(2-bromoethyl) corn pound (608c) also cyc1ized 'upon heating with
hydrazine hydrate to forrn (609b). Forrnation of irnidazo[5,1-c][1,2,4]triazines has also
been accornplished frorn (608a) through initial alkylation with a-bromoketones (75CHE751,
81CHE622). H
J
N0 2 N0 2 N H
F'lBr A( 'N/
N NR -- N'\.-N
Me Me R
Bu' 0 Bu'
p--..,...-NHNH 2 II N""N
N-7 II + PriCHCMe __ N:t' I 1\
"-- N I "-- N '-./."Me
Me"\ Br Bu'/\ pr i
B Me
(60S)
(606)
(607)
(608) a; R=H (609) a; R=O
b; R = CH 2 C0 2 Et b; R = H 2
c; R = CH 2 CH 2 Br
In a different approach, treatrnent of the diazonium salt (610) with 4,6-nonanedione
produced azo compound (611), which could be cyclized to (612) upon heating in acetic
acid (76JMC517). Other active rnethylene compounds have also been ernployed
(8IJCS(Pl)1424).
H 2 NOC
L.....N + Cl-
(, 2
HN N
\;::::
o 0
II II
Pr"CCH 2 CPr" )
H 2 NOC H 2 NOC
./N N HOA ./N':::-N
HN T vY N' T
\;::::N O ",,0 d '\.-N Prn
Prn
Prn Prn 0
(611) (612)
(610)
4.10.4.23 Imidazo[ 5,1- f] [1,2,4 ]triazine
(i) Closure of both rings
Treatrnent of azodicarboxarnidine (613) with 1,3-dicarbonyl cornpounds such as (614)
resulted in the forrnation of (615) directly (73T1413, 73AP561, 73AP801). Acylation of (615)
Other Imidazoles with Fused Six-membered Rings
657
occurred at both exocyclic arnino groups (73AP730). The rnechanism of forrnation of (615)
involves initial addition of the active methylene group to the azo linkage followed by closure
of the triazine ring and then closure of the irnidazole ring (73AP697).
H1N N
f'N/ NHl
N N
Et Et
(615)
HN NH
" ,f'
CN=NC
/
H 2 N
+ EtCCH 2 CEt --.
"
NH 2
(613)
(614)
(ii) Closure of the imidazole ring
A different synthetic route to imidazo[5,1-f][1,2,4]triazines involves the condensation
of acy amino-a-ketoesters (616), available frorn N-acylarnino acids, with arninoguanidine,
(617a) or amidrazones, for exarnple (617b), to produce triazinones (618) (sOJCS(Pl)1l39).
Cyclization of (618) to (266) occurred with polyphosphoric acid or phosphorus oxychloride
(sOJCS(Pl)1l39, 79JCS(Pl)1l20). For exarnple, condensation of (616) with (617a) gave (618a),
which ring-closed to (266a), and likewise (617b) led to (618b) and then (266b).
o Me 0 NH ....N::::::,R PrO N
II I II II H N y "=l ,f"'N.... -::::::"R
Et0 2 CC-CHNHCPr"+RCNHNH 2 --. Pr"CNCH NH - N Wy I
II I ...--:: NH
o Me 0 0
(616) (617) a; R = NH 2 (618) a; R = NH 2 (266) a; R = NH 2
b; R=Me b; R=Me b; R=Me
4.10.4.24 Imidazo[1,2-a][1,3,5]triazine
Irnidazo[1,2-a][1,3,5]triazines have been prepared by annulation of the imidazole onto
an existing triazine as well as by annulation of the triazine onto an imidazole precursor.
Depending upon the desired substituent pattern, both routes allow effective preparation
of variously substituted heterocycles. Research on this ring systern has been minirnal until
recently, when several papers have focused on the synthesis of nucleoside derivatives, which
can be thought of as 5-aza 7-deazapurine nucleosides.
(i) Closure of the imidazole ring
An early synthesis involved the rearrangernent of aziridinyltriazines. For exarnple, heating
(619) with triethylarnine hydrochloride in acetonitrile produced (620). The same cornpound
was prepared by the condensation of potassium dicyanoguanidine with 2-chloroethylarnine
hydrochloride (SSJAS922). In a a similar vein, rearrangernent of (621) occurred upon heating
to produce (622) (77CHE210, SOCHE1l90, SlCHES3S).
<1 N L N
Ny )NH 2 _ C y NHl
N N N N
NH 2 NH 2
(619)
(620)
(621)
Me N
(Ny 'ò NHMe
\-NyN
o
(622)
N
MeHN( )NHMe
N N
OCH 2 CH 2 Cl
N
H 2 N( )SMe
N N
SMe
(623)
Treatment of 2-arnino-4,6-bis(rnethylthio)-1,3,5-triazine (623) with brornoacetaldehyde
afforded (269a) as the hydrobromide in 55% yield.
BrCH 2 CHO
) (269a)
(ii) Closure of the triazine ring
Recently, it has been found that the thermal rearrangement of (624) gave (625) and
(626). Treatrnent of (625) with base isornerized it cornpletely to (626) (SOTL4731).
658
Other Irnidazoles with Fused Six-membered Rings
Ph N Ph
(Ny 'ì1NHPh + <tyN'ì1NHPh
yN y N \..-N N
H C Me y
2 0 0
(624) (625) (626)
The guanine-related heterocycle (270) has been prepared by treatrnent of (627) with
aminoacetaldehyde dirnethyl acetal to produce (628), followed by deblocking and acid-
catalyzed cyclization (78JMC883).
N
PhHN( )NHPh
N N
OCH 2 C=CH
N
H 2 N( )CI
HNyN
o
(627)
Mea
"-
CHCH 2 NH 2 N NH
/ HN Y ,
MeO 2 I II T H2 --. (270)
HNyN CH(OMeh
o
(628)
Appending a triazine ring to an irnidazole ring to produce imidazo[1,2-a]-s-triazines has
been carried out in two ways. Treatrnent of 1,2-dimethylirnidazoline (629) with methyl
isothiocyanate gave (630) (7lGS69). Treatrnent of 2-(2,6-dichloroanilino)-2-irnidazoline
(631) with acid chloride (632) in the presence of base afforded (633) in 52% yield
(74GEP2314488). A rnuch more general route has been developed in connection with the
synthesis of certain nuc1eosides. Treatrnent of substituted 2-aminoirnidazoles such as (634)
and (636) with various aryloxycarbonyl isocyanates and their sulfur analogs produces
cornpounds (635a) and (637a). Rernoval of the benzoyl groups affords the nucleosides
(635b) and (637b). When X or Y is sulfur, amino groups can be incorporated by alkylation
at sulfur followed by displacernent of the rnethylthio group by arnrnonia or an arnine
(78JOC4774, 78JOC4784).
Me
N
C >Me
N
(629)
/NH
\ .,)NHR +
N
(631) R = 2,6,-dichlorophenyl
HYJ
ON N
BZOCH 2 (j H
BzO OBz
X
II
ArOCNC=Y
(634)
H 2 N()
.'OCH,d
BzO OBz
(636)
x
\I
ArOCNC=Y,
MeN=C=S
Me
M: I/Me
N I N'fS
CNyNMe
S
(630)
o
II
ClC, yÜ CI
N R I
II N
cr/ C Û --. e Ny I
I Cl NyN
o
(632) (633) R = 2,6-dichlorophenyl
R
I
NyN'fX
NyNH
Y
(635) a; R = 2,3,S-tri-O-benzoyl-ß-o-ribofuranosyl
b; R = ß-o-ribofuranosyl
R
NyN'fX
\-NyNH
y
(637) a; R = 2,3,S-tri-O-benzoyl-ß-o-ribofuranosyl
b; R = ß-o-ribofuranosyl
Other Irnidazoles with Fused Six-membered Rings
659
4.10.4.25 Imidazo[1,5-a][1,3,5]triazine
Although a corn pound containing this ring systern was prepared in 1934 during the
exploration of the chemistry of theobrornine (61HC(15-2)916), research has really only begun
recently.
(i) Closure of the imidazole ring
Treatment of 4,5-dihydro-5-methylpyrirnidin-4-ones such as (638a) with chlorotrirnethyl-
silane and hexarnethyldisilazane in pyridine produced the irnidazo[1,5-a][1,3,5]triazinone
(639a) (79JOC3835, 79JOC1740). 5-Allyl-substituted pyrirnidinones, exernplified by (638b),
undergo the sarne reaction to afford (639b) (81JOC3681). Although no rnechanisrn has been
established, the suggested rnechanisrn involves cyclization of a trirnethylsilylated (638a) to
an interrnediate (640) which might undergo carbon-carbon bond cleavage either heterolyti-
cally or electrocyclically to an interrnediate such as (641), which could reclose on the
adjacent irnidazole nitrogen to produce (639a).
o
II
NHz NHCR 1
N RZ
X NAo
R 1 N .
Nry X
}-NyNH
o
(639) a; X=SH,R=H,R1=Me
b; X = NH z , R = Me, R J = CHzCH=CH z
(638) a; X=SH,R1=H,Rz=Me
b; X = NH z , R 1 = Me, R Z = CHzCH=CH z
[ Hr;EJ] [o c:r:x)] (6 J
(640)
(641)
(ii) Closure of the triazine ring
Treatment of 5-arnino-4-cyano-4-rnethyl-4H-imidazole (642) with forrnarnidine under
rnild conditions resulted in the forrnation of (644), with 5-rnethyl-5H-adenine (643) postu-
lated as a transient interrnediate. Rearrangernent of (643) as suggested above would produce
(644). An independent synthesis of (644) was carried out by treatment of (645) with methyl
N-cyanomethanirnidate (646) (82JA235, 83JOC3).
N: N H :NH\ [ N ]
HzNlN N N
(642) (643)
N MeO
Me ( 'CH
HzN N/ +
H 'CN
(645) (646)
Me N
-+ Nry
N N
NHz
(644)
-- (644)
4.10.4.26 Imidazo[1,2-b ][1,2,4,5]tetrazine
Treatrnent of 3,6-dibenzyl-1,2,4,5-tetrazine (647) with rnethanolic potassiurn hydroxide
resulted in the forrnation of (648) by a cornplex rnechanism. Other alcohols did not give
the corresponding products (79JCS(Pl)333).
N-N N N N
PhCH z ( )CHzPh -+ Meo C ""-'j I
N=N N.... ;:::::JCHzPh
Ph N
(647) (648)
660
Other Irnidazoles with Fused Six-membered Rings
4.10.4.27 Imidazooxazines
The seven imidazooxazine systerns pictured in the introduction have been synthesized. With
a few exceptions the reaction schernes have little generality.
4.10.4.27.1 1m idazo[1, 2- cJ[1,3 Joxazine
Treatrnent of irnidazolylacetophenones such as (649) with phenyl isocyanate or
isothiocyanate afforded (650), which is stable with C-5 tetrahedral (75JOC252).
( N
I CH2CPh PhN=C=X
r-f x=o,S
H
(649)
Ph N\
OXN-ß
PhNH XH
(650)
4.10.4.27.2 Imidazo[1,5- c][1,3 Joxazine
A sirnilar type of product (652) was formed when the imidazole derivative (651) was
treated with acetyl chloride in pyridine under a specific set of conditions. The irnidazo[1,5-
c][1,3]oxazine was isolated as a stable solid (74JA2481, 73JA4452).
Me OH
H Me Me O.,X- e
o: ' Me -- ì r::NH
-0 S ""::: N CO H O'-../N ò "
3 I H 2 Me 2
# OH -.;:: OH
-a} #
(651) (652)
4.10.4.27.3 lrnidazo[2, 1- b J[1,3 Joxazine
Treatrnent of 2-rnethylthioirnidazoline (653) with ß-trichloromethyl-ß-propiolactone
(654) produced (655), pres urn ably by initial N-acylation and then cyc1ization to forrn the
oxazine ring (69JOU1790).
SMe
N 0 Cl C O+
C >S'" + a,cU 'ÇNJ
o
(653) (654) (655)
4.10.4.27.4 lrnidazo[ 4,5- d][1,3 Joxazine
H0 2 C N
H 2 N[)
d N
o C,H,N
AcOCH 2
AcO OAc
(656)
Heating the irnidazole ribonucleoside (656) with acetic anhydride and pyridine produced
(657). Propionic anhydride reacted cornparably (75JOC2920). The sarne ring systern can be
prepared by treating uric acid (658) with isobutyric anhydride. Cleavage and rearrangement
OZN
Me TÁ_ )
N N
ACOCH2d
AcO OAc
(657)
o H
HN N>=O
O NJ-N
H H
o
II
IMe,CHCH,C),O
>>
0 :.x 0
;1 I jpr'
Pr N N
(65111
(659)
Other Imidazoles with Fused Six-membered Rings
661
in both the irnidazole and pyrimidine rings resulted in the forrnation of (659) (77JOC3132).
With acetic or propionic anhydride, cleavage and rearrangerncnt occurred only in the
irnidazole ring.
4.10.4.27.5 lrnidazo[5,1- bJ[1,3Joxazine
Intrarnolecular ring closure of (660) with dicyclohexylcarbodiirnide produced the imi-
dazo[5, 1-b ][1 ,3]oxazine (661) (75CB372).
HO
RN OH COzH
),--N-J
o
(660)
HO 0 0
RN/-{-Y
),--N
o
(661)
N-N
R= l >-
Bu' S
4.10.4.27.6 lrnidazo[2,1- c J[1,4 Joxaz ine
The synthesis of irnidazo[2,1-c][1,4]oxazines has-been accornplished by several rnethods.
Several groups have closed the oxazine ring frorn an irnidazole derivative with an N-
hydroxyethyl group (79JHC871, 67USP3341549, 7IUSP3565892). For exarnple, treatrnent of (662)
with hydrochloric acid and ethanol afforded (663) (79JHC871).
N EtO
I. CHO O N
'\..-NCHzCHzOAc -+ NJ
OzN NO z
(662) (663)
In one report the imidazole ring has been closed frorn a preexisting l,4-oxazine derivative.
Treatment of (664) with 2-amino-2-cyanoacetarnide (665) under acidic conditions gave
(666) (66CHE134).
o
O II
C ) HN C N 0
z" ./" 0 -- II
+ CH NHz -+ I )CNH z
h OEt NC./ N-..f"
N NHz
(664) (665) (666)
4.10.4.27.7 lrnidazo[5,1- c][1,4Joxazine
Several different routes have been found which lead to irnidazo[5,1-c][1,4]oxazines.
Treatment of the imidazoledicårboxylic acid (667) with acetic anhydride afforded (668).
The initial steps of this transformation presurnably involve a modified Dakin-West reaction
(66JOC806).
(Me )zo) O N
Me N...-f
Ph
(667) (668)
Cyclization of the 2-chloroethyl ester (669) with base gave (670) (64JOC3707).
o
r::N NazCO, 6
HN, J OCHzCHzCl -----"--"+ N...-fN
lliY
o
(669)
Ph
I
E- ./CHCOzH
Nr N
WCOzH
(670)
662
Other Irnidazoles with Fused Six-membered Rings
Treatrnent of the diester (671) with styrene oxide and 0.1 rnole equivalent of potassiurn
resulted in the forrnation of (672). Larger quantities of potassiurn gave the irnidazole
derivative (673) via an irnidazo[5,1-c][1,4]oxazine interrnediate (75JCS(Pl)798).
(671)
(672)
Ph
,f'-N f
N C02H
Me02C
(673)
o
02Me
,f'-NH 0
N. I - I N
C02Me Ph N--þ
Me02C
4.10.4.28 Imidazooxadiazines
The three irnidazooxadiazines pictured in the introduction have been prepared, the first
two by annulation of the oxadiazine ring onto an irnidazole-related precursor, and the latter
by forrning both rings in the same reaction.
4.10.4.28.1 lrnidazo[I,S- b ][1,2,S]oxadiazine
Treatrnent of 3-hydroxyimino-2,4-pentanedione (674) with 4-rnethoxybenzaldehyde in
arnrnonia and ethanol afforded (675) (74LA1399).
/OH
o N 0
II II II
MeC-C-CMe
M O HO
I
NH 4 0H, EtOH
(je
't>fOOM'
N N -
OMe
(675)
(674)
4.10.4.28.2 1m idazo[2, 1- b ][1,3,4 ]oxadiazine
Treatrnent of 1-arnino-4-phenylimidazol-2-one (676) with a-haloketones, for exarnple
(677), produced (678). Ring opening of the oxadiazine occurred readily with aqueous HBr
(70CB272, 62ZC153).
þ-- O Ph
Ph\, X H2 + T/
0 CH 2 Br
(676) (677)
N 0
_ Ph< Y ì
'\-,-N, )Ph
N
(678)
4.10.4.28.3 lrnidazo[2,1- c][1,2,4 ]oxadiazine
Displacernent of the rnethylthio group frorn (679) with arninooxyacetic acid gave (680),
which cyclized to (681) upon atternpted esterification (70TLl879).
H H
" / N
N N+ N '0
C ')sMe- C )=NOCH 2 CO Z - - (J J
N N Y
H H 0
(679) (680) (681)
Other Irnidazoles with Fused Six-membered Rings
663
4.10.4.29 Imidazothiazines
Of the six irnidazothiazine systerns pictured in the introduction, by far the most cornrnon
is the irnidazo[2, 1- b ][1 ,3]thiazine.
4.10.4.29.1 Imidazo[2,1- b ]{1,3 ]thiazine
('rJ
o
(682) (683)
In a similar sequence, treatrnent of (684) with 3-brornopropionic acid produced (685),
which cyclized to irnidazo[2,1-b][1,3]thiazine (686) upon heating with acetic anhydride
(74JPR147).
(i) Closure of the thiazine ring
A nurnber of rnethods employ an imidazole-2-thione or related compound with a bifunc-
tional reagent to build the thiazine ring in one or two steps. Treatment of (682) with acrylyl
chloride directly produced (683) (64JOCl720). Substituting acrylic acid under catalysis allows
isolation of the S-alkylated interrnediate, which cyclized to (683) upon heating (64JOCl715).
H
N
C )=s CH 2 =CHCOCI)
N
H
o
II S N
(MeC)2 0 ) ç 'r-J Ph
Ph
o
(684) (685) (686)
Cyclization occurred readily to (688) when (682) was treated with rnethyl rnethylpropiolate
(687) (6SJCS(C)2510). Other alkynic esters also have been ernployed (6SJCS(C)2510, 67CJC953).
S N
(6821 +M,C"cco,M, M'Ç'r..J
o
(687) (688)
Alkylation of (684) with chloroketone (689) afforded (690a), which was converted into
the chloro corn pound (690b) in two steps. Cyclization of (690b) to (691) occurred upon
heating in basic solution (70MI41000). A chloroacetal has also been ernployed (79JMC237).
Ph ( N rr C S N
(684) +CICH 2 CH 2 CPh ---+ Ph I N)SCH 2 CH 2 CPh ---+ [-JPh
H Ph Ph
(689) (690) a; X = 0 (691)
b; X=H,Cl
H
N
Ph ( )=s
Ph N
H
BrCH 2 CH 2 C0 2 H
)
Ph ( N
I )S(CH 2 h C0 2 H
Ph N
Treatrnent of (684) with 1,3-dibrornopropane under the conditions of phase-transfer
catalysis (PTC) afforded a high yield of (692) (SOJHC393). Cyclization with 1,3-
dibromopropane and epibrornohydrin has been carried out under various reaction conditions
(73IJC747, 72JOC1464, SOTl079, 65JCS3456).
S N
(684) + Br(CH 2 hBr ':S ('r-JPh
Ph
(692)
When 2(3H)-irnidazolethione (693) was treated with (chlorocarbonyl)phenylketene
(694), the irnidazo[2,1-b][1,3]thiazinedione (695) was produced directly. Employrnent of
the N-methyl derivative of (693)" affords a heteroaromatic betaine (SOJOC2474).
664
Other Irnidazoles with Fused Six-membered Rings
o
H II
N Cl-C 0 S N
( )=s + 'c=c=o -- y-y )>
N Ph/ PhyN...J'
H 0
(693) (694) (695)
(ii) Closure of the imidazole ring
The synthesis of the imidazo[2,1-b][1,3]thiazine system also has been approached starting
with a thiazine. Treatment of (696) with an a-bromoketone such as phenacyl bromide (512)
produced an N-alkylated material, which could then be cyclized by heating to (697)
(70LA(742)85). An a-chloroketone has also been used in sirnilar fashion (69ZC27).
S S N
C)NH 2 +(512)--+ C1..)Ph
(696) (697)
4.10.4.29.2 Imidazo[1,2- cJ[1,3]thiazine
Ring expansion of the bicyclic isothiazole (698) occurred upon treatrnent with cyanide
ion to give the imidazo[1,2-c][1,3]thiazine (699). The mechanism involves initial ring
opening by attack on sulfur, and then ring closure. The anion of methyl propiolate also
causes the sarne type of rearrangernent (79TL1281).
H
N N
a \ 1:7' 1-- \
s'" + -J _ SyN--/
Br NH
(698) (699)
4.10.4.29.3 Imidazo[4,5- d][1,3]thiazine
Formation of imidazo[ 4,5-d][1,3]thiazines has been carried out in all cases from appropri-
ately substituted imidazoles. Treatment of a 5-amino-4-cyanoimidazole with either an
isothiocyanate or carbon disulfide directly affords this ring system (81CPB1870, 81JMC947,
75CPB759). For example, treatment of (700) with phenyl isothiocyanate produced (701),
which could be readily rearranged with base to the purine (702) (81CPB1870). Treatment
of a 4-amino-5-carboxamidoirnidazole with thiophosgene also resulted in an irnidazo[ 4,5-d]-
[1,3]thiazine after rearrangement (69CB3000).
",N C '. PhNH(XN) -"!!:..,
N
N
NCf ')
H1Nl.N
R
S
PhN:'ll()
N N
R
(700)
(701)
(702) R = ß-D-ribofuranosyl
4.10.4.29.4 Imidazo[4,5-e ][1,3]thiazine
In possibly the first synthesis of an imidazothiazine, treatment of (703) with potassium
isothiocyanate afforded (704), which upon heating in pyridine cyclized to 6-amino-2-bromo-
1,5-dihydroimidazo[4,5-e][1,3]thiazine (705) (34J1C867).
S
II
H!NCNHCH2fN')Br
Brl. N
H
(704)
N
H 1 NCH 2 f ')Br
Brl.N
H
(703)
N :): N
II I ')Br
H 2 N........ N
S H
(705)
Other Irnidazoles with Fused Six-membered Rings
665
4.10.4.29.5 1m idazo[2, 1- c][1,4]thiazine
Synthesis of imidazo[2,1-c][1,4]thiazines has been carried out from the lactam ether
(706) by treatment with an appropriate two-carbon fragment (68CHE322, 79JMC237). For
example, treatment of (706) with 2-amino-2-cyanoacetamide under acidic conditions gave
(707) (68CHE322).
CN
I
H 2 NCHCONH 2 Þ
(S)OEt
N
(706)
S N
JCONHz
NHz
(707)
4.10.4.29.6 1m idazo[5, 1- cJ[l,4]thiazine
When the thiazine ester (708) was treated with an isocyanate such as (709), an imidazo[5, 1-
c][l,4]thiazine (710) was produced (81JAP8161384). Treatment of certain penicillin sulfoxide
esters (711) with ethoxycarbonyl isocyanate results in a ring expansion of both rings to
afford an imidazo[S,1-c][1,4]thiazine (712) (81JOC3026).
r NH
S COzMe
Cl
O N=C=O
CI
(709)
o CI
N -o
N\<, _
o Cl
(710)
(708)
o
H V II
Rn S
o -)CO R 1
H z
(711)
o
/I
EtOCN=C=O
Y NHR 0
S -....;:
l. NH
XN
R tozc H
(712)
o
R=PhOCHzg-,R 1 = CHz O NOz
4.10.4.30 Imidazothiadiazines
Derivatives of the five imidazothiadiazines pictured in the intrQduction are known. The
most research has been carried out on 4,5-fused systems, where the impetus, at least partially,
has been their resemblance to the purine ring system.
4.10.4.30.1 lmidazo[ 4,5- cJ[l,2,6]thiadiazine
The imidazo[ 4,5-c][1,2,6]thiadiazine system has been synthesized from both imidazole
and thiadiazine precursors. Treatment of the thiadiazine dioxide (713) with potassium
dithioformate under mild conditions allowed the isolation of (714), which was readily
cyc1ized to (715a) upon heating. Direct conversion of (713) to (715a) also occurs, with an
improvement in yield over the two separate steps (76JHC793). This type of ring closure has
H
C N ......
HzN I ?oz
HzN ....;::N
NHz
S H R
/I H N C N....... N JC N......
HCS-K+ Þ 2 I ?02 < I ?OZ
HCNH....;::N N '....;::N
II
S NHz H NHz
(714) (715) a; R = H
b; R = 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl
(713 )
666
Other Imidazoles with Fused Six-membered Rings
also been used for other derivatives (78JHC221). Compound (715a) has pKa values of 0.28,
4.28 and 12.21, reflecting its unique structure (76JHC793).
Treatrnent of an appropriately substituted imidazole with sulfamoyl chloride results in
closure of the thiadiazine ring (77HCA521, 79JMC944). For exarnple, silylation of the imidazole
(716) with hexarnethyldisilazane followed by treatment with sulfamoyl chloride and then
base to cleave silyl groups produced (715a). The cyclization was greatly facilitated by amine
activation through silylation (79JMC944).
N
NCf
H2N N
H
(716)
i,IMe,SiJ,NH
ii, CISO,NH,
iii,NaOH
þ (715a)
Treatrnent of the silylated derivative of (715a) with 2,3,4,6-tetra-O-acetyl-ß-D-
glucopyranosyl brornide in the presence of mercury(II) cyanide afforded (715b). Synthesis
of (715b) was also possible by attaching the sugar to (713), and then closing the ring as
previously described (78MI41009).
4.10.4.30.2 lmidazo[ 4,5- e ][1,2,4]thiadiazine
All of the synthetic routes to imidazo[4,5-e][1,2,4]thiadiazines have used imidazole
Precursors. Ring closure of (717a) to (718a) can be carried out with forrnic acid, an ortho
ester, phosgene or thiophosgene (61JOC1861). It has been found that (717b) is unstable on
isolation, but it can be generated without isolation and converted directly into (718b) with
triethyl orthoforrnate (79JOC4046). Ribosylation of (718b) under a set of standard conditions
produced (718c).
o 0
R R
<N ] S02 NH 2 --+ <N X S.....NH
N NH 2 N.J
N
(717) a; R = Me (718) a; R = Me
b; R=H b; R=H
c; R = ß-D-ribofuranosyl
Heating the acyl azide (719) in an inert solvent induced rearrangement to the isocyanate
with loss of nitrogen followed by ring closure to (720) (76CHE924).
o 0
H H
N N X S .....
< ] S02 NH 2 --+ < I NH
N CN 3 N o
II N
o H
(719) (720)
4.10.4.30.3 1m idazo[2, 1- bJ{1,3,4]thiadiazine
Synthesis of the imidazo[2,1-b][1,3,4]thiadiazine systern has been carried out by the
action of a-halocarbonyl compounds upon either 2-amino-1,3,4-thiadiazines (72JHC1385,
75ZC482) or 1-amino-2-imidazolethione derivatives (70JMC164, 75ZC482). Treatment of the
readily available (721) with a-bromoketone (722) afforded (723) (72JHC1385).
S
H 2 N( ) Me
N,
N
Me
(721)
o Br N S
II I ) Me
PhC-CHPh Þ Ph I
(722) N
Ph 'N
Me
(723)
Cyclization of (724) with phenacyl bromide (512) gave imidazo[2,1-b][1,3,4]thiadiazine
(725) in good yield (75ZC482).
Other Irnidazoles with Fused Six-membered Rings
667
CI C\
I CI jNyS )
I)=S N'Nh Ph
N
NH
(724) 2 (725)
4.10.4.30.4 1m idazo[2, 1- b ][1,3,5]thiadiazine
Two quite specific methods have been employed for the synthesis of imidazo[2,1-b]-
[1,3,5]thiadiazines. In the condensation of 1,2-diphenylimidazoline-4,5-dione (726) with a
thiocarbonyl isocyanate such as (727), the isocyanate added to (726) in the manner of a
Diels-Alder diene to produce (728) (67CB2064).
Ph 0 Ph Ph
o N C r N:""L.....S OPh
r )Ph + 7-::/ ---+ O =<y T 'ì(
o N C N y N
P hO""" s
o 0
(726) (727) (728)
Treatment of imidazolidine-2-thione (729) with isothiocyanate (730) afforded (731) in
high yield (75S675).
CI-
H Cl H
e N I N s ì CH Cl
)=s + ......CHN=C=S ---+ C I 2
CICH 2 NyNH
S
(729) (730) (731)
4.10.4.30.5 lrnidazo[ 4,5- d][1,2,3]thiadiazine
Formation of the imidazo[4,5-d][1,2,3]thiadiazine system has been accomplished by
treating the thiocarbamoyl diazonium compound (732) with base, producing (733). Further
base treatment rearranges (733) into (734) (75CHE995, 73CHE1173).
S H H
N II N X; N N N
1:" ::;lCNH2 / I "" ---+ / X; ""
\'..:.IN + S NH
N 2 N. N
NH S
(732) (733) (734)
4.10.4.31 Imidazo[ 4,5-c ] [1,5,2]diazaphosphorine and Imidazo[ 4,5-d] [1,3,2]diazaphos-
phorine
Syntheses of the imidazo[ 4,5-c][1,5,2]diazaphosphorine system, oxidized at phosphorus,
was undertaken to prepare transition state analogs for adenosine aminohydrolase. Conver-
sion of imidazole derivative (735) to (736) required three steps. Treatment of (736) with
n-propylamine followed by either acidic or basic ring closure gave (737) (78MI41001). In
o 0
II N II N
(EtOhP [ ') ---+ CI 2 P [ ')
H 2 N N H 2 N N
CH 2 Ph CH 2 Ph
(735) (736)
o NHPr"
/
N X P ,
---+ < I NPr"
N .)
CH 2 Ph N
(737)
668
Other Irnidazoles with Fused Six-membered Rings
this sarne paper an imidazo[ 4,S-d][1,3,2]diazaphosphorine was also prepared in extrernely
low yield.
4.10.4.32 Imidazo[ 4,5-d][1,3,2]diazaborine
The irnidazo[ 4,5-d][1,3,2]diazaborine system was prepared as a boron-containing purine
analog. Treatment of (738) in hot ethanolic solution with phenylboronic anhydride gave a
high yield of (739) (61JA2708, 59JA6329).
o Me H
II N N !; N.,-
H2NCf) -+ < I Ph
H 2 Nl!....N N NH
Me
o
(738) (739)
4.11
1,2,3-Triazoles and their Benzo
Derivatives
H. WAMHOFF
Universitãt Bonn
4.11.1 INTRODUCTION AND NOMENCLATURE
4.11.2 HISTORY AND REVIEWS
4.11.3 STRUCTURE
4.11.3.1 Theoretical Methods
4.11.3.1.1 HMO methods
4.11.3.1.2 Electronic structure; 7r-electron distribution;
dipole moments
4.11.3.2 Structural Methods
4.11.3.2.1 X-Ray diffraction
4.11.3.2.2 Microwave spectroscopy and dipole moment measurements
4.11.3.2.3 1 H NMR spectroscopy
4.11.3.2.4 l3C NMR spectroscopy
4.11.3.2.5 14 N and IS N NMR spectroscopy
4.11.3.2.6 UV spectroscopy
4.11.3.2.7 IR spectroscopy
4.11.3.2.8 Mass spectrometry
4.11.3.2.9 Photoelectron spectroscopy
4.11.3.2.10 Polarography
4.11.4 REACTIVITY
4.11.4.1 Reactions at Aromatic Rings
4.11.4.1.1 General survey of reactivity
4.11.4.1.2 Thermal and photochemical reactions formally involving no other species
4.11.4.1.3 Electrophilic substitution and nucleophilic attack
4.11.4.1.4 Reactions with Cyclic Transition States
4.11.4.2 Dihydro Compounds (/!2-1,2,3-Triazolines)
,4.11.4.2
1 Stereochemical aspects
4.11.4.2.2 Aromatization reactions (dehydrogenation of /! 2 -1 ,2,3-triazolines)
4.11.4.2.3 Ring fission of /!2- 1 ,2,3-triazolines
4.11.5 SYNTHESIS
4.11.5.1 General Remarks
4.11.5.2 Triazoles from Non-heterocyclic Compounds
4.11.5.2.1 Formation of one bond
4.11.5.2.2 Formation of two bonds
4.11.5.3 Triazoles by Transformation of Other Heterocycles
4.11.5.4 Other Methods of Synthesis of 1,2,3-Triazoles
4.11.5.5 1H- and 2H-Benzotriazoles
4.11.6 APPLICATIONS OF 1,2,3-TRIAZOLES AND BENZOTRIAZOLES
4.11.6.1 Access to Compounds of Preparative Importance
4.11.6.2 Triazoles Utilized in Organic Synthesis
4.11.6.3 Triazoles in Medicinal Chemistry
4.11.6.4 Industrial Applications
4.11.6.4.1 Dyestuffs, fluorescent whiteners
4.11.6.4.2 Corrosion inhibition
4.11. 6.4.3 Photostabilizers
4.11.6.4.4 Agrochemicals
4.11.6.5 Important Natural Products
670
670
671
671
672
672
673
673
676
678
680
682
684
685
686
688
689
690
690
690
691
697
701
702
702
703
704
705
705
706
706
708
718
720
722
723
724
726
728
730
730
730
731
731
732
669
670
1,2,3- Triazoles and their Benzo Derivatives
4.11.1 INTRODUCTION AND NOMENCLATURE
1,2,3- Triazoles and their benzo derivatives have attracted considerable attention because
of their theoretical interest, and synthetic value, as well as for their nurnerous applications
in industry and agriculture due to their extensive biological activities and their successful
application as fluorescent whiteners, light stabilizers and optical brightening agents.
The 1,2,3-triazole system can be formally derived frorn pyrrole or indole by replacing
two carbons by two nitrogen atorns. The resulting parent compounds rnay be classified in
terrns of the constitutional forrnulae (1)-(3). In the literature this ring systern is still narned
'v-triazole', in order to distinguish it frorn 's-triazole'. While (1) and (2) can be considered
to depict heteroaromatic systerns, (3) is a non-aromatic compound and is rarely found in
the literature. In the older literature the term 'osotriazole' belongs to derivatives of (2),
particularly if these are derived frorn osazones.
"R N
5R[ 2
N,
R
(1) 1 H-l,2,3- Triazoles
J
N
4R ( ,
NR
5R 0- 12
N
,
J
N
4R2 ( \'
N2
5R 0- 1
N
I
(2) 2H-l,2,3- Triazoles
('osotriazole', l,2,5-triazole,
2,l,3-triazole)
(3) 4H-l,2,3- Triazoles
(l,2,3-isotriazole)
4 J
< (X N
I N2
I
N,
7 R
5 0: " ::;.--N,
NR
6 0-12
7 N
I
(4) lH- Benzo[d][l,2,3]triazoles
(azimidobenzene, benzene azoimine,
benzisotriazole, l,2,3-benzo-
triazole)
(5) 2H- Benzo[d] [l,2,3]triazoles
(pseudoazimidobenzene, 2,1,3-
benzotriazole)
The nornenclature of the potential benzotriazole derivatives (4) and (5) was chosen
analogously to that of the rnonocyclic systems.
4.11.2 HISTORY AND REVIEWS
The class of 1,2,3-triazoles and their benzo derivatives represents an overwhelming,
rapidly developing field in modern heterocyclic chernistry. This is impressively illustrated
by the large nurnber of excellent reviews which have been specially devoted to this class
of heterocycle and which are listed below.
As early as 1888 von Pechmann, assistant to von Baeyer, prepared the 1,2,3-triazole
cornpound (6) as well as some derivatives, and correctly characterized his newly invented
azole heterocycles as 1,2,3-triazoles (1888CB2751). In a 1950 review it was stated that rnore
than 1400 1,2,3-triazoles had been described in the literature, and in the period 1973-1980
Chemical Abstracts reported rnore than 9000 studies involving 1,2,3-triazoles.
Me C N ,
NPh
Me o-N
(6) 'Osotriazone' (v. Pechmann)
The following are the rnost irnportant reviews on 1,2,3-triazoles and their benzo deriva-
tives: (50CRV(46)1, B-57MI41l00, B-61MI41l00, B-71MI41l04, 74AHC(16)33, B-76MI41l03, B-
79MI41105, 80HC(39)l, B-80MI41l02). Further reviews (including syntheses, reactivities, etc.)
rnay be found in the following references: (67AG786, B-67MI41l01, B-70MI41l01, 69CRV345,
B-74MI41101).
1,2,3- Triazoles and their Benzo Derivatives
671
4.11.3 STRUCTURE
4.11.3.1 Theoretical Methods
Several types of molecular orbital calculation have been carried out on 1H - and 2H-l,2,3-
triazole structures, often in combination with predictions of the most reactive sites, and
studies of dipole moments, l H , l3C, 14 N and 15N NMR chemical shifts, proton exchange
rates, gas-phase tautomerism and PE spectroscopy.
4.11.3.1.1 HMO methods
Using CNDOj2 calculations, relative base strengths for IH- and 2H-l,2,3-triazole, as
well as for IH,2H- and IH,3H-triazolium ions, have been obtained and compared with
pKa values. From the E T values (i.e. total molecular energy), it was initially concluded that
1H-l,2,3-triazole is more stable than 2H-l,2,3-triazole; (7)....... (8) is the most likely
proton at ion step (6STL3727, 66JCP(44)759).
H+
--
+
[ H
/N
N
H
(8)
[
/N
N
H
(7)
Furthermore, LCAO calculations point towards significant differences between dipole
moments and primary 7T....... 7T* transitions of IH- and 2H-triazoles (69BSFI097). Calculated
geometries of IH- and 2H-l,2,3-triazoles are shown in Figure 1 (69BSFI097).
x <3) 1.42. eD
n / 109 109 ,
l.3ì_ 1\30
CD N 104.5 104.5 N @
1.3 12 (5)
1 y
CD
y
Q). 1.35(5) NeD
109.5 109\ \ 1
1.37 _ .32
CD 105 109 N@
137.5 108. .5
N
/0
Figure 1 Calculaled geomelries of IH- and 2H-l,2,3-triazoles
In turn, from the total energy E T it now follows that 2H-l,2,3-triazoles are more stable
than the 1H -tautomers, where E T = ErT + E. rr + ErT7r + Enucleus. This last calculation was
confirmed recently by PES spectra (see Section 4.11.3.2.10) and dipole mornent measure-
ments (see Section 4.11.3.2.2), comparing them with the corresponding N-methyl deriva-
tives. A refined and optimized molecular structure has also been given for both the 1H-
and 2H-tautomers (Figure 2) (SlZN(A)1246).
H
H
H
128.5
1.462
' ;:f ,
N 103.9 N
14.0400
N
11.035
H
H
1.087
130:ðlO;.:3 09 11
1.384f.n. i 338
1.094 105.1 106.8 N
122.4 _
1.407 IIOY 1416
128.7N 121.1
11.033
H
Figure 2 Final optimized molecular structures
In studying the relation between structure and reactivity in azole derivatives, CNDOj2
calculations have been carried out on heteroaromatic compounds includjng 1,2,3-triazoles
672
1,2,3- Triazoles and their Benzo Derivatives
(73T3463, 73T3469). This report deals with azolium ions representative of those studied
experimentally and with the zwitterions resulting from the deprotonation of these ions.
The correlation between calculated deprotonation energies and observed deprotonation
rates was exarnined, and the calculated charge distributions have been studied. The nature
of .the irnportant factors (solvent effects, delocalization of the added negative charge into
the O'-frarnework, coulombic effects) affecting deprotonation rates has been considered.
Some experimental results (H+ exchange rates) are in reasonable agreement with these
calculations (71ACS(B)249, 71ACS(B)2087).
HMO calculations were carried out on 5-chloro-1-methoxy-1,2,3-benzotriazole (9), and
the bond orders and '7T-electron charge densities were found to be as shown (78JHCI043).
A comparison of (9) with the unsubstituted 1-methoxy-1,2,3-benzotriazole showed a srnall
effect of the S-chlorine on the bond orders (76JHC509).
0.424
N
3 ,\73
2N
11 515
N
\0109
o
\0008
Me
0,586
0,608
(9)
4.11.3.1.2 Electronic structure; 'IT-electron distribution; dipole moments
All-electron calculations for azoles have shown that there are good correlations between
0' or total electron densities and l H and 13C chemical shifts (69MI41100). A good relationship
(correlation coefficient: 0.974) is found between '7T-electron densities calculated for 1,2,3-
triazole (and other azoles) by the simple MO method (B-61MI41101) and 13C chernical shifts
(68JA3543). Furtherrnore, the proton shifts show linear correlations with the MO 'IT-electron
densities (68CC1337).
Table 1 NMR and 1T-Electron Density Data (68CC1337)
4
S(IJ C )
(p.p.m.) 8
62.4
S(IR)
(p.p.m.)b
MO 1T-electron
density
Position on nucleus of
1,2,3-triazole
7.90
0.980
In comparison with other azoles
8 Up field from CS 2 . b Downfield from TMS; CF 3 C0 2 H solutions.
LCAO calculations of the 'IT-electron structures of 1H - and 2H-1,2,3-triazoles (cf.
69BSFI097) are found in (70BSF273); consideration is also given to the O'-skeleton with
extended Hückel iterations. '7T- Electron charge distribution diagrams have been given for
1,2,3-triazole, other azoles, their benzo homologs and the 1-vinyl derivatives (73MI41100).
14 N chemical shifts (cf. Section 4.11.3.2.6) of 1H -, 2H-, 1-rnethyl- and 2-methyl-
benzotriazoles correlate reasonably well with the SCF-MO-'lT-charge densities calculated
by the Pariser-Parr-Pople approximation using special pararneters for the rnethyl groups.
It is rather striking that a fairly linear correlation exists between such calculations of
'IT-charge densities (q ) and the experimental 14 N chernical shifts (72T637).
Using ab initio wave functions and the full operators, dipole and second rnornents (cf.
Section 4.11.3.2.2) as well as electronic charge distributions have been calculated for
1,2,3-triazoles and a number of other five- and six-mernbered heteroc:9'cles using the linear
cornbination of Gaussian orbitals (LCGO) procedure (Table 2) (74JCS(P2)420). Population
analyses for the corn pounds are found to be additive in bond contributions, and this assists
in the interpretation of the 0'- and 'IT-dipole rnoments. Some further calculations of the
dipole rnoments of 1H - and 2H-l,2,3-triazoles have been discussed using the vector additive
systern for the calculations (75Z0B1821, 75DOK(224)847).
1,2,3- Triazoles and their Benzo Derivatives
673
Table 2 Dipole Moments (D) and Vector Components in 1,2,3-Triazoles (74JCs(P2)420)
Jl.1I
cfz
l' \
Z, /y
-X--+JI..l
I
J.Ltotal JI..l Jl.1I /LO" JI.",
4.50 3.26 3.10 2.79 2.87
(+81.7 0 ) (+83.0 0 )
-3.24 -3.26 0.0
Compound
IH-l,2,3- Triazole
2H-l,2,3- Triazole
In the course of an N -methylation study and the analysis of the IH NMR spectra of
indazoles, INDO calculations of the charge distribution in the benzotriazole anion have
been determined (Figure 3). As the molecular geornetry was not known, the total energy
in the INDO semi empirical method was calculated for various geometric arrangements and
allowed to achieve an optimal value by a sequence of one-dimensional parabolic minimiz-
ations (75JCS(P2)1695). The large angle at N-2 (for comparison: indazole 111.5 0 ) is at first
surprising but is reasonable since much of the negative charge in the anion is localized at
N-1 and N-3. MO calculations carried out more recently by Servé et al. (78JHC127) give
different values but show that N-1 is a more nucleophilic site than N-2.
122.8
139.6
-0.025
-0.031
-0.031
-0.047
-0.323
N\
N + 0.059
I
N
1.388
N
,\07
ï
N
H
-0.077
-0.021
107.8
+0.057
121.2 1.407
H
-0.061
-0.326
N
\
/ -0.163
N
-0.326
+0.014
CI
-0.021
-0.019
-0.261
N\
IN -0.044
N +0.369
\
+ 0.0340
\
Me +0.002
-0.011
-0.024
(9)
Figure 3
However, the use of HMO calculations to elucidate 'IT-electron charge densities of
5-chloro-l-alkoxy-1,2,3-benzotriazole (9) led, as expected, to somewhat different results
(Figure 3) (78JHCI043). Following these results, positions 4, 6 and 7 are the most likely
sites of electrophilic attack carrying comparable '7T-charges.
4.11.3.2 Structural Methods
4.11.3.2.1 X-Ray diffraction
No measurements have been made to date on the parent compounds 1,2,3-triazole and
-benzotriazole. However, since 1975 several1,2,3-triazoliosulfide derivatives have had their
crvstal structures determined.
674
1,2,3- Triazoles and their Benzo Derivatives
The rnesoionic 1,3-disubstituted 1,2,3-triazolio-4-sulfides can be regarded as resonance
hybrids of several forms (A)-(E); 13C NMR data indicate a localization of charge on N-1
(74ACS(B)61).
S- S- S S
)=( )=( +rl +\rt H+
/N N/N"-.. /N'N N"-.. /N'Ñ/ N "-.. /N N/N"-.. /N'N N"-..
(A) (B) (C) (D) IE)
Some examples of differently substituted mesoionic 1,2,3-triazolio-4-sulfides are shown
in Figure 4, including interatornic distances (Á), bond angles (0), crystal systern and space
group. Analysis of the triazole rings in (10)-(14) shows that the heterocyclic ring is almost
planar. However, in (14) the methyl group, S atom and benzylic CH z group are significantly
out of plane.
S Me
1.7117 l .4 ì
125.0 126.8
1327 1370 N 119.3
120.3 113.9 \
1.3% 1.342
1.12 2 107.3 103.5 N
H 120.5 n /
0959 1.143 112.;.....-- 1.317
128 1 N 118.9
11.748
Me
(a) Monoclinic,
space group P2tfa,
R-value 0.034
S CH 2
1.695 1 465/, '>...1.4'
125.3 127.4 / 113.6 97
1.371 N Ph
132.0 102.7 113.9 \1 7.4
S 349
1028 N
1349 114 OO
1n6 N I180
11.482
Me
(d) Monoclinic,
space group P2Ifn,
R-value 0.063
S Me
1.699 1.455/
124.7 127.0 /
132.7 1.374 N 118.5
102.6 114.4 \
1.332
106.7 103.0 N
1.354 113.r18
N
127.4 1 119.4
1.442
Ph
(b) Triclinic,
space group PI>
R-value 0.05
S Me
1.691 1.499/
126.1 128.8/
130.7 1.365 N 122.8
103.2 108.2 \
1.411 1.361
125.2
111.3 111.1 N 1.445
. /120Me
1.329 106'YI316
N
(e) Orthorhombic,
space group P na 21>
R-value 0.04
S Ph
1.701 1.437/
126.9 128.3 /
131.7 1.387 N 117.8
101.4 113.8 \ ,
.\344
1087 102.8 N
H 0.91 . /
1.323 113.y 1.314
127.3N / 119.3
1.468
Me
(c) Monoclinic,
space group C e ,
R-vaIue 0.05 (12)
(There is a second modification (13):
monoclinic
space group P'2Ifa)
S Me
1685 1 50
12561274
1.352
131.3 103 0 108.6 \ 124 0
1 .408 1 360
1257
110.9 N 24
_ /1226 Ph
105.y 1.322
N
(f) Monoclinic,
space group P2tfq,
R-value 0.07
Figure 4 Some parameters of structure determinations of: (a) 1,3-dimethyl-4-(1,2,3-triazolio)suIfide (10)
(75A('SIA)647); (b) I-phenyl-3-methyl-4-(1,2,3-triazolio)sulfide (11) (79ACS(A)687); (c) I-methyl-3-phenyl-4-(1,2,3-
triazolio)suIfide (12, 13) (79ACSIA)687); (d) I-methyl-3-benzyl-4-(1,2,3-triazolio)sulfide (14) (79ACS(A)693); (e)
2,3-dimethyl-l,2,3-triazoI-l-ine-4-1hione (15) (79ACS(A)697); (f) 2-phenyl-3-methyI-l,2,3-triazol-l-ine-4-thione
(16) (79ACSIA)697)
A comparison of the geometry of the triazole nucleus in the above rnentioned
triazoliosulfides was carried out. The resulting bond lengths and angles for the average
triazole nucleus are shown in (17). Apparently methyl and phenyl substituents can be
interchanged with negligible effect on the geometry of the triazole ring. The almost identical
values for the angles at N-l and N-3 show that these are almost unaffected by the asymmetry
induced by the carbon substituents (79ACS(A)693). Calculation of the N(1)-C(5), N(1)-N(2)
and N(2)- N(3) bond characters was carried out in order to distinguish between the canonical
forms (A)-(E). This led to the conclusion that the resonance hybrid is made up predominantly
of forrn (A), and almost equal amounts of forms (B) and (C) (75ACS(A)647).
1,2,3-Triazoles and their Benzo Derivatives
675
5 4
c C 1.372 114.7 1.409 1.380 N
i 1073 102'2 108.8 6
1.342 1.375 122.7 123.3 105.0
1.400 1.376 109.8N
IN 113.4 114.0 N3 107.7 05
1. 03.042 122.7 121.0 108.7
N 1.388 N
2
(17) (18) Space group P2J,
R-value 0.056
Although the parent compound 1,2,3-triazole has not been studied, the crystal structure
of benzotriazole (18) has been determined (74AX(B)1490). Benzotriazole crystallizes in the
space group P2t. In association with its remarkable anticorrosion activity (Section
4.11.6.4.2) benzotriazole and its conjugate base form stable transition metal complexes
whose crystal structures have, in part, been studied. Some examples are presented in Figures
5-7, with special regard to the molecular dimensions of the benzotriazole rnoiety.
,
3.731 :
,
,
,
I
,
1.333
r
,
Ni(l)- _ _ _ _2.127 130.5
I -.
I '- 23 õNI05.5
126.4 N 112.7
- - í20. .7
2.06L ' 1.328 N
- 3
Ni(2)176.7
I .
I
,
I
I
I
I
I
I
o
I
I
,
/t,,-
Ph Ph Ph
,
,
-- C
- ---N"""'- --c
c
(19) Trigonal,
space group R3c,
R-value 0.129
Figure 5 Partial struclural details for hexakis(benzotriazolyl)hexakis(allylamine)trisnickel(II) triphenylphosphine
oxide complex (19; Ni[(BThNi(AAhJz . 2Ph 3 PO) (76AX(B)714)
Structure and bonding in transition metal triazenido complexes have attracted much
interest in recent years. The triazenido ligand (20), i.e. the conjugate base of benzotriazole,
represents a versatile group which may function as a bridging group between two metal
centers, a bidentate three-electron donor or a monodentate one-electron donor. Partial
structural details for an organometalic benzotriazenide complex are given in Figure 6. The
structures of other triazenido complexes, such as trans- bis(triphenylphosphane)car-
bonyl( 1 ,3-di-p-tolyltriazenìdo )hydridoruthenium(II) and cis- bis( triphenylphosphane)-
bis(1,3-diphenyltriazenido)platinurn(II), have been evaluated (76IC2788, 76IC2794).
((I . \
- :N
"::::". ï (
(20)
Additional benzotriazole transition metal complexes have been described recently,
e.g. di-p, -chloro-bis[bis(benzotriazole)chlorocopper(II)]monohydrate (22; Figure 7)
(81ACS(A)733). Coordination to copper has only a small effect on the geometry of the (nearly
planar) benzotriazole groups as shown by comparison with benzotriazole itself (74AX(B)1490).
676
1,2,3- Triazoles and their Benzo Derivatives
o=C
P
/ Z 074 121.8 :;::N
k . N I]M N
/ 178.4 130 I
P
Monoclinic,
space group C z .-P2i/n,
R-value 0.035
Figure 6 Partial structural details for bis(triphenylphosphane)carbonyl(triazenido)iridium(l) (21; Ir(8TA)(CO)-
(PPh 3 )z) (781C30Z6)
Triclinic,
space group Pi>
R-value 0.053
H
\060
N 1.338
47/ 11Z . 1
l.3í 104 9
1 5
:<JO\llO.Z
N 1.365
Iz.ozo
Cl- - .!7HCu-- - - --Cl
Iz.ooz
89.3 N 91.6 1 395
318/ 110 . 0
I.; 106.Z
N 106.6
1.3
>4 \IIZ.0
}'86
1.379
107.4
Figure 7 Partial structural details for di-lL-chlorobis[bis(benzotriazole)chlorocopper(Il)] monohydrate (22)
The structure consists of layers of Cu and Cl atorns separated by layers of alrnost parallel
benzotriazole ligands.
Furthermore, the crystal structures of benzotriazoliurn tetrachlorocobaltate(II)
[(BT AH 2 h(CoCI 4 )], bis(benzotriazole)dichlorozinc(II) [ZnCh(BT AHh] and polyrneric
tetrakis(benzotriazolato)dizinc(II) {[Zn2(BT AH)4]n} have been investigated by X-ray
diffraction techniques (BTAH = lH-l,2,3- benzotriazole; BTAH 2 = protonated form)
(SIACS(A)739). A surnmary of bond lengths (Â) and angles (0) for the (BTAH 2 h ligand is
shown in Table 3. The BTAH 2 ion is nearly planar and has nearly C 2v syrnrnetry, the H
atoms being bonded to N-l and N-3.
The crystal structure of a trinuclear nickel{II) benzotriazolate amine cornplex,
[Nb(BT A)6(NH 3 )6]' 2Me2CO. H 2 0 has also been determined (SlACS(A)747).
4.11.3.2.2 Microwave spectroscopy and dipole moment measurements
For an introduction to and general literature on, this topic see Section 4.01.3.2 as well
as (74PMH(6)53).
Magnetic susceptibility anisotropy (MSA) (measured from the Zeernan splitting of
rnicrowave absorption spectra) is defined for planar systerns in terms of the in-plane and
1,2,3- Triazoles and their Benzo Derivatives
677
Table 3 Some Bond Distances and Bond Angles for (BT AHzh in
(BT AH z )z[CoCI 4 ] a (SlACS(A)739)
a 4 +
I /
5 Nt
H
Bond distance (Â) Bond angle (0)
N(1)-N(2) 1.311 C(5)-N(1)-N(2) 113.4
N(2)-N(3) 1.313 N(1)-N(2)-N(3) 104.6
N(3)-C(4) 1.361 N(2)-N(3)-C(4) 112.7
C(4)-C(5) 1.390 N(3)-C(4)-C(5) 105.1
C(5)-N(1) 1.359 C(4)-C(5)-N(1) 104.1
a Monoclinic; space group C2/ c; R = 0.025.
out-of-plane total susceptibilities:
MSA = xJo P - (X )av
The diarnagnetic susceptibility anisotropy (DSA) is linearly related to the binding energy
(BE), the correlation being
x op-(xfp)av = 0.048Be+ 109
for azoles like 1,2,3-triazoles. DSA seerns not to be related to aromaticity (74TL253).
Furthermore, values of the diamagnetic susceptibility (X a) for 1H -1,2,3-triazole were
calculated to be -Xoop = 288.8 and (-XiP)av = 174.2 (74TL253).
The hyperfine structure in the microwave spectra of 1,2,3-triazole and N -deutero-l,2,3-
triazole was analyzed. The coupling constants derived from the analysis of each isotopic
species were combined and led to the principal nuclear quadrupole coupling constants at
the sites of the three non-equivalent 14 N nuclei (77JSP(65)313).
Experimental dipole moments of azoles are collected in (B-63MI41100); values for three
cornpounds are as follows: 1,2,3-triazole 1.79 (benzene, 25 oc), benzotriazole 4.10 (dioxane,
25 oc), 1-methylbenzotriazole 4.1 D (benzene, 25 oc). More recent rneasurements combined
with CNDOj2 calculations have been carried out by Mauret et al. (75BSF1675); the results
are shown in Table 4. The rneasurement of molecular polarizations represents not only a
valuable method for investigating autoassociation effects of azoles, but can also be widely
used for the determination of tautomerism in the azole field (75BSF1675, 76AHC(Sl)32,
76AHC(Sl)28I).
Table 4 Experimental Dipole Moments of Some 1,2,3-Triazoles in Benzene at 25 oC (75BSF1675)
Compound IX ß Pzoo RM D J,t(D)
1,2,3-Triazole 5.45 -0.38 86.56 16.70 1.85
1,2,3- Triazole (45 oc) 6.34 -0.48 100.02 16.70 2.08
I-Methyl-1H-l,2,3-triazole 26.24 -0.38 429.08 21.54 4.46
2-Methyl-2H-l,2,3-1riazole 0.19 -0.27 24.43 21.54 0.37
Benzotriazole 16.23 -0.45 388.42 35.55 4.15
Benzotriazole (45 oc) 14.68 -0.67 325.93 35.55 4.12
I-Methyl-1H- benzotriazole 13.08 -0.32 359.90 40.39 3.95
2-MelhyI-2H- benzotriazole 0.41 -0.26 45.41 40.39 0.49
By comparing the dipole moments of 1,2,3-triazole with its two l-methyl-1H (23) and
2-methyl-2H derivatives (24) in benzene at 25 oC, it was found that 83% of 1,2,3-triazole
existed as the symmetrical2H-form (2). From a second measurement at 45 oC the thermody-
namic parameters of the equilibrium were calculated (73MI41101). This result was confirmed
by another group (78MI41100). Further, dipole rneasurernents show similarly a large pre-
dominance of the 'asymmetric' 1H -benzotriazole tautomer in benzene at 25 and 45 oC
established by comparison with its 2-N -methyl derivatives (74MI41100).
678
1,2,3- Triazoles and their Benzo Derivatives
n
N, N
N/
H
(2) 83%
2H
..----
f/
../N
N
H
n
N, N
N/
Me
(23)
I/
_./N
N
Me
(24)
Dipole rnornent measurements have been used for structure determination and for
discussion of the probable conformation of two possible isomeric l-(a -aroyloxyary-
lidenearnino)-1,2,3-triazoles (25) formed by oxidation of bis-aroylhydrazones of a-dicar-
bonyl compounds (77JCS(P2)1779, 79JHC571). The probable conforrnation of these cornpounds
was deterrnined after theoretical calculation of the dipole rnornents by vector addition of
the rnoments of all polar groups, the results being very sirnilar to those of X-ray rneasure-
ments.
(1) 17%
1H
R 2 <!< R I <2. C H x-
I\. /64 P
N /NN=C"
N OCOC 6 H 4 X-p
(25)
4.11.3.2.3 1 H NMR spectroscopy
The first systernatic studies of lH NMR spectra of 1,2,3-triazoles and derivatives have
been reported by two groups (67JCS(B)516, 67BSF2998), and a review has appeared (B-
73NMR219); see also (71PMH(4)121).
Spectral parameters for a number of simple derivatives are listed in Table 5. The lH
NMR spectrum of the parent compound was first reported by Gold (65LA(688)205), who
assigned the signals at 87.9 p.p.m. to H-4 and H-5, and that at 15.9 p.p.rn. to the NH
proton. Furtherrnore, he showed that the symmetrically substituted N 1-(2-cyanoethyl)-
1 ,2,3-triazole gave a doublet at 8 -7.93 p.p.m., while the symrnetrical N 2 -(2-cyanoethyl)-
1 ,2,3-triazole gave a singlet at 8 8.15 p.p.rn.
Table 5 1 H NMR Spectral Data for Triazoles
Slibstitlients
Species
Cation
Anion
I-Me
Cation
I-Me,5-Br
Cation
2-Me
2-Me, 4-Br
1-Me,4-C0 2 H
I-Tosyl,5-Me
I-Ph,5-Me
Cation
Cation
Solvent
Neat
CDCI 3
DMSO
CóDó
TFA
NaOD
D2 0
MeCN
Neat
CDCl 3
DMSO
CóDó
HMPT
TFA
CDCI 3
TFA
CDCl 3
DMSO
CóDó
HMPT
CDCl 3
TFA
CDCl 3
TFA
CDCI 3
CDCl 3
õ(IH) (p.p.m.)
H-4 H-5 NR
7.86
7.75
7.91
7.30
8.60
7.86
8.00
7.80
7.89
7.74
7.72
7.40
7.63
8.44
7.88
8.48
7.57
7.77
7.32
7.75
7.20
7.30
7.86
7.75
7.91
7.30
8.60
7.86
8.00
7.80
8.12
7.59
8.08
6.90
8.37
8.49
7.57
7.77
7.32
7.75
7.55
7.80
8.25
8.81
2.30
2.21
Ref.
67BSF2998
67BSF2998
67BSF2998
67BSF2998
67JCS(B)516
67JCS(B)516
67JCS(B)516
67JCS(B)516
4.20 67BSF2998
4.10 67BSF2998
4.09 67BSF2998
3.37 67BSF2998
4.15 67BSF2998
4.48 67JCS(B)516
12
12.05
13.50
13.40
3.98 67JCS(B)516
4.42 67JCS(B)516
4.18 67BSF2998
4.18 67BSF2998
3.65 67BSF2998
4.20 67BSF2998
4.14 67JCS(B)516
4.40 67JCS(B)516
4.18 67JCS(ß)516
4.50 67JCS(B)516
7.50 60JA5007
7.30 60JA5007
1,2,3-Triazoles and their Benzo Derivatives
679
In the same way, in I-methyl-l,2,3-triazole (26) in CDCb H-4 and H-5 are not equivalent
and the assignment was made by comparison with 1-methyl-4-brorno-1,2,3-triazole (27)
(67BSF2998).
87'7 ( N
II
87.59 .....N
N
Me
(26)
Br N
Ï/II
8 7.57Z. ......N
N
Me
(27)
In their study of the stereochemistry of the 1,3-dipolar cycloaddition of azides to enol
ethers (cf Section 4.11.5.2.2), Huisgen and Szeimies (65CB1153) have reported 1 H NMR
spectral data for some Ll 2 -1,2,3-triazolines. On the basis of the chernical shifts and coupling
constants of H-4 and H-5, structural assignment of the stereoisomeric -triazolines (28) and
(29) was rnade as shown.
84.65
H
Me 1111111 N
II
85.23 HIP'II)' /N
BrO N
C 6 H 4 N0 2 -p
(28) 3 hs 2.0 Hz
Me
84.27 H'"'" N
II
85.40 HI/lilt! /N
BO N
r C 6 H 4 N0 2 -p
(29) 3hs 7.5 Hz
N 2 -Silylated 1,2,3-triazole (30) reacts with acetyl chloride to afford two isomeric acetyl
derivatives (31a) and (31b) (67CB3485), the assignrnent being made according to their lH
NMR spectra. Furthermore, at elevated temperatures (> 120 oc) 1-acetyl-l,2,3-triazoles
like (32) are capable of a reversible acyl group migration to (33). This equilibrium was
analyzed by means of l H NMR data (67CB3485), H-4 and H-5 resulting in One signal in (33).
Using temperature-dependent 1H NMR (in acetone) thermodynamic and kinetic
phenornena of the tautomerism in the azole series were studied. For 1,2,3-triazole at room
temperature a predorninance of the 2H-tautorner (singlet at 8 7.83 p.p.rn. for H-4 and H-5)
was found, and at -90 o C a 50/50 mixture of the IH- and 2H-tautomers (two additional
doublets at 8 8.32 and 7.83 p.p.m.) was evident (69TL495).
Me N,
r NSiMe J
l:::-/
N
82.38Me N
MoCDCI , [ II
J5 0 C 87.98 .....N
N
COMe
82.82
(31a) 75%
(30)
87.68
H [ N
H ' ..... \I N >120oC
( J
88.28 N
COMe
82.87
(32) hs 1.3 Hz
87.4 t N
+ II
Me N
82.53 N/
COMe
82.84
(31b) 25%
81.88 { HrN,
NCOMe
Hl:::-N' 82.76
(33)
In substituted triazoles (obtained, for exarnple, frorn phosphorus ylides and carbonyl-
azides) lH NMR is a valuable tool for determining the constituents and the progress of a
reaction, as in the acyl group migration (34) (35) (70TL5225). In the case of the isomeric
and regioisorneric triazoles (36, 37) with adjacent aroyl or ethoxycarbonyl substituents lH
NMR data can be successfully applied in structural determination (71T5623). l H NMR data
have also been used to assign the position of acyl groups in 4-substituted 5-amino-l,2,3-
triazoles (7IJCS(C)706).
8 2.36 8 2.60
M el\M e
N", ....-NCOC6H4N02-m
N
(34)
--+
82.40
r--^-----,
M e
Nï ï
" /N
N
COC 6 H 4 NO z -m
(35)
680
1,2,3- Triazoles and their Benzo Derivatives
88.0-7.3fmJ 88.36 87.67 87.44",
P hr=\H + Hr=\P h
PhC=CH + Et02 CN 3 I \ I \
N", ....NC0 2 Et N", ......NC0 2 Et
N N
(36) (37)
The NMR spectra of benzotriazole and its 1-rnethyl and 2-methyl derivatives have been
described. The l-rnethyl derivative shows strong coupling between the N-methyl group
and the benzene ring hydrogen. The coupling constants suggest also a quinone-type structure
for the 2-rnethyl compound (ct. compound (97a) and Table 12a, Section 4.01.3.3) (63JCS5556,
68JSP(26)139).
4.11.3.2.4 13e NMR spectroscopy
The 13C NMR spectrum of 1,2,3-triazole was first reported by Weigert and Roberts
(68JA3543). the solvent being acetone; 8( l3C) (p.p.rn.): C-4 = 130.4, C-5 = 130.4; ]C,H-4 =
205, ]C,H-5 = 13.4 Hz. This equivalence of both C-4 and C-5 points once again to the
symmetrical 2H -form.
The l3C shieldings for 1,2,3-triazole can be predicted by a four-parameter ernpirical
equation. Relative to the cylcopentadienyl anion, the carbon shifts are given by the equation
8..;:: No<C, + NßC ß + No<ßCo<ß + NßßC ßß (N; = number of nitrogen atorns in the ith position;
C; = shielding pararneter associated with those nitrogens) (68JA3543).
Ernpirical values: Co< = 15, C ß =4, Co<ß = 10, C ßß = -7 p.p.m.
For 1,2,3-triazole: 8 = Co< +C ß +c,"ß +C ßß = 26 p.p.rn.
8C 3 C)triazole = 103* +26 = 129 p.p.rn.
observed = 130.4 p.p.rn.
(* 8(13C) of a cyclopentadienyl anion)
In a systernatic study, the effects of substitution, lanthanide shift reagents, solvent changes
and tautomerisrn on the 13C NMR spectra of azoles were investigated (74JOC357). Sorne
results are given in Table 6.
Table 6 13C Chemical Shifts of 1,2,3- Triazoles (74JOC357)
Predominant
Ô( 13 C) (p.p.m.) tautomeric
Compound Solvent C-4 C-5 NMe form
1,2,3- Triazole Dioxane 131.6 131.6 2H
1,2,3- Triazole DMSO 130.3 130.3 2H
2- Methyl-l,2,3-triazole Dioxane 134.7 134.7 41.5 2H
2- Methyl-l ,2,3-triazole DMSO 133.2 133.2 2H
1- Methyl-l,2,3-triazole DMSO 134.3 125.5 35.7 lH
1- Methyl-l,2,3-triazole DMSO 132.6 124.8 35.2 IH
1- Methyl-l,2,3-triazole + Eu(fodh CDCh (1 M) 135.0 125.6 37.4 IH
Eu(fodh shift -6.6 +7.4 -5.7
As cornplexation of the shift reagent takes place predominantly on N-3, the carbon signal
of C-5 is accordingly shifted upfield. From the calculated charge densities (nT637), a reduced
affinity of N-3 for Eu(fodh and, thus, smaller shift effects can be expected. Furtherrnore,
sirnple chernical shifts are of lirnited value in ascertaining the positions of tautorneric
equilibria for rapidly interconverting azole tautomers. However, for this purpose l]e 3 C-H)
values, which are only slightly influenced by N- rnethylation, can be useful (74CC702). Thus,
in 1,2,3-triazole the l]e 3 C-H) value of 194.3 Hz for C-4 (i.e. C-5) falls within the range
of that for C-4 in 2-methyl-2H -1,2,3-triazole eJ( 13 C-H) 192.5 Hz). The average value for
the C-4 (194.3 Hz) and C-5 (196.6 Hz) methine groups in l-rnethyl-lH-l,2,3-triazole
irnplies that in CDCh solution at 32 oC, 1,2,3-triazole exists as a 2: 3 equilibrium mixture
of the 2H- and 1 H- tautomers. The interrnediacy of (38) or a cyclic dirner in the interconver-
sion of the tautomers seerns likely. The calculated l]( l3 C_H) value for the latter species
1,2,3- Triazoles and their Benzo Derivatives
681
1;I-
/N ] .
N'. 'N----H-N. ;
'''f.,r' ,--'
, N
-H
(38)
[(196.5 + 192.5 + 194.3 + 192.5)/4 = 194.0 Hz] is in good agreernent with the observed
vJ;!lue (74CC702). This is confirmed also by other physical characteristics. All the parent
azoles possess similar dipole moments (1.7-2.7 D) in the diluted gas phase according to
microwave spectroscopy; in solution however, pyrazole and 1,2,3-triazole exhibit low dipole
moments (1.6-1.8 D), whereas imidazole, 1,2,4-triazole and tetrazole have higher values
(3.2-5.1 D) (43MI41100, 76JCS(P2)736).
Table 7 13 C _ H Coupling Constants of 1,2,3-Triazoles (76JCS(P2)736)
{IJ(C-H)}
2 J (C-H) (Hz)
Compound Solvent C-4 C-5
1,2,3- Triazole CDCh 194.3 194.3
13.2 13.2
1,2,3-Triazole Acetone-d 6 193.9 193.9
13.6 13.6
1- Methyl-l ,2,3-triazole CDCl 3 194.3 196.6
11.7 15.6
2-Methyl-l ,2,3- triazole CDCl 3 192.5 192.5
12.8 12.8
4-Methyl-l,2,3-triazole CDCh 191.8
Acetone-d 6 a 191.2
1,4- Dimethyl-l ,2,3 -triazole CDCl 3 192.7
1,5-Dimethyl-l,2,3-triazole CDCl 3 191.3
2,4- Dimethyl-l ,2,3 -triazole CDCl 3 189.5
a 3 J(C-H) = 3.9 Hz.
Table 8 Conformer Distribution in N- Acetyl-l,2,3-triazole (39) and
-benzotriazole (40) in CDCl 3 (78JCS(P2)99)
%Zat34 0 C
Shift difference calculated
for position
(39)
(40)
o
100
C-5
C-7a
In Table 7 are shown some l3C-H coupling constants for a variety of substituted
1,2,3-triazoles. Furthermore, l3 C NMR spectral data of N-acetyl-azoles (39) and
-benzazoles (40) have been compared with data for the corresponding N- rnethyl compounds
in order to obtain information about the conformation of the acetyl compounds (78JCS(P2)99).
These results are given in Table 8.
J (X i N (X i N N
N/ 'N/ If N
oA o o ( o
Z (39) E Z (40) E
A l3 C NMR study of poly[ 4(5)-vinyl-1,2,3-triazole] in DMSO revealed that the spectrum
at room temperature displays three sets of two triazole carbon atoms corresponding to the
three tautomers: 1H (15-17%), 2H (66-70%) and 3H (15-17%), according to (41)
(76MI41101). While the monomer 4(5)-vinyl-l,2,3-triazole (42) showed only one set of four
signals in the same solvent, the two triazole carbon signals being slightly broadened, a 13C
NMR study at -55 oC allowed direct observation of the three separate tautomers, as shown
682
1,2,3- Triazotes and their Benzo Derivatives
-(CH-CH 2 ).-(CH-CH 2 )m-ICH-CH2 J p -
N N HN
-N 'N_N =N
H H
1H 2H 3H
(41)
Table 9 13C NMR Chemical Shifts of (42) (1.6M in DMF) (780MR!l!)578)
H
N
6 7
(42)
Õ(13 c ) (p.p.m.)
T(OC) C-4 C-5 C-6 C-7 % Tautorner
40 142-144 126-129 124.6 115 Averaged
-55 144 119.6 125.4 113.5 IH (20%)
145.1 130.2 125.4 115.7 2H (70%)
135 130.2 120.5 116.5 3H (10%)
in Table 9 (7S0MR(11)57S). The assignment of the absorptions is based on cornparison with
N- substituted derivatives (43)-(46).
HuN,-N N
WJ46.5
121.2 b
1265 - 115.6
(43)
N
N 'NBu
\1: 35.7
131.2
- 120.3
121.2
OH
I N
88.9 N / ' N
D 3 C-C-
I 45.8
CD 119.8
3 - 116.4
126.1
CD J
I
89.3
DJC-C-OH
I
N
N.... 'N
1.1467
131.6 .
-117.5
126.6
(44)
(45)
(46)
Townsend et at. (74JHC645) have reported 13C NMR data for some N-substituted 1,2,3-
triazole-4-carboxamides. These are presented in Table 10.
The structures of several N- (trialkylstannyl)-4,5-bis(alkoxycarbonyl)-1,2,3-triazoles
(47a-c) have been studied by means of l3C NMR spectroscopy. As the spectra measured
at room ternperature showed one singlet at 139.7 p.p.m. (C-4, C-5) and the two carbonyl
carbon atorns displayed a singlet at 161.9 p.p.rn. as well, compounds (47a-c) were assigned
a syrnmetrical structure, the tributylstannyl group being attached to N-2 of the 1,2,3-triazole
ring (77JOM(127)273) (see Table 11). lH NMR data, UV spectra and dipole rnoments also
confirm that the trialkylstannyl group is located at N-2 (nJOM(44)117).
N R N R
rJl J R' rJl J R'
'N 'N
NH 2 NHCOCH 2 Ar
(48) R, R' = Me, H, aryl (49)
Recently 4,5-unsymmetrically substituted l-amino- (48) and 1-(N-arylacetylarnino)-
1,2,3-triazoles (49) have been identified by their l3C NMR spectra (SOJHCl127). A signal
at 11:1:: 0.6 p.p.m. indicates a 4-methyltriazole derivative, whereas a signal at 7.9:1:: 1 p.p.m.
indicates a 5-methyltriazole. A signal at 120:1::5 p.p.m. (C-5) indicates a hydrogen atom in
the 5-position. Some values are given in Table 12.
4.11.3.2.5 14 N and 15 N NMR spectroscopy
14N and 15N NMR spectroscopy have been applied only recently to heterocyclic com-
pounds, and especially azoles. However, one must take into consideration the fact that the
1,2,3- Triazoles and their Benzo Derivatives 683
Table 10 13C NMR Chemical Shifts for Certain 1,2,3-Triazole-4-carboxamides (in DMSO-d 6 )
(74JHC64S)
Se 3 C) (p.p.m.)
Structure CON Hz C-4 C-5 8C-4 8C-5
J 130.4 130.4
N,
N
H
jONH2 161.65 141.78 129.93
N,
N
H
jONH2
.N, 161.64 142.96 127.28 -1.18 +2.65
N
Me
N J CONH2
II
161.53 143.34 125.01 -1.56 +4.92
N,
N
I
R
RNjONH 2
I
158.97 131.64 134.63 +10.14 -4.70
N
R = ß- D-ribofuranosyl
Table 11 Some Selected 13C NMR Data for 1,2,3-Triazoles (47a-c) (77JOM(127)273)
Rrl
'l
N, ..N
N
SnBuJ
S(13C) (p.p.m.)
Compound R TeC) C-4jC-5 c=o CH 3
(47a) COzMe r.t. 139.7 161.8 52.5
-50 137.7 161.5 52.8
(47b) COzEt Lt. 139.5 161. 7 14.1
-50 139.3 161.8 14.2
(47c) Et r.t. 146.8 14.2
-50 145.8 14.7
CH z
61.6
61.7
18.3
18.1
Table 12 13C NMR Chemical Shifts of Various SubstitUled Triazoles
(SOJHC1l27)
S(13C) (p.p.m.)
Compound R R' 4-Me 5-Me
(48) Me Me 10.6 7.4
(48) Ph Me 8.9
(48) Me Ph 11.5
(49) Me Me 10.4 6.9
(49) Ph Me 8.3
(49) Me Ph 11.1
684
1,2,3- Triazoles and their Benzo Derivatives
14N nucleus is inherently difficult to study, not only on account of its low relative sensitivity
but also because it has an electric quadrupole moment. Very often qu'adrupolar interactions
can dorninate the information available from a study of the 14N nucleus and other nuclei
spin-coupled to it. Two rnonographs have appeared in this field (B-73MI41103, B-79MI41103).
The first systematic 14 N NMR investigations of azoles and 1,2,3-triazoles and ben-
zotriazoles) was reported by Witanowski et al. (72T637). The I N chemical shifts are referred
either to MeN0 2 or Me 4 N+X-; some results are given in Table 13. Furthermore, it was
found that triazoles and benzotriazoles show a linear relationship between chemical shifts
and the SCF-PPP-MO 'IT-charge densities. In the case of unsubstituted 1,2,3-triazole, the
14 N spectra show that it exists 70-100% in the symmetrical 2H -form. However, due to
the appreciable quadrupole broadening of the signals, the results from 14 N NMR spectros-
copy are not always reliable, and in some cases are difficult to reproduce.
Table 13 14 N Chemical Shifts of 1,2,3-Triazoles and Benzotriazoles (nT637)
Compound
S(/4 N ) (p.p.m.)
Solvent MeN 0 2 · Me4N+ X- ·
Neat 60:1:8 (N, N) 272
132:1:4 (NH) 200
MeOH (1: 1) 60:1:8 (N, N) 272
128:1:6 (NH) 204
Neat 22:1: 1 (N, N) 310
143:1: 1 (NMe) 188
MeOH (1: 1) 28:1: 1 (N, N) 304
144:1: 1 (NMe) 188
Neat 51:1:1 (N,N) 282
130:1: 1 (NMe) 202
MeOH 53:1:2 (N, N) 280
132:1:2 (NMe) 200
Dioxane 81 :1:7 252
(satd.)
MeOH 89:1:7 244
Acetone (satd.) 40:1:6 (N, N) 292
148:1:5 (NMe) 184
Neat 50:1:8 (N, N) 282
118:1:2 (NMe) 214
1,2,3- Triazole
1-Methyl-1,2,3-triazole
2-Methyl-1,2,3-triazole
Benzotriazole
I-Methylbcnzotriazole
2-Methylbenzotriazole
. Internal reference.
Accordingly, nitrogen NMR spectroscopy turns rnore to the 15N isotope using liquid NH 3
at 25 0 C in a sealed tube as internal reference (80 p.p.m.); NH 4 N0 3 (in aqueous HN0 3 ,
821.6 p.p.m.), MeN0 2 (8379.60 p.p.m.) and NaN0 3 (8376.53 p.p.m. in saturated aqueous
solution) may also be used. The future technique with a signal enhancement factor of 10
is INEPT (Intensity uclei gnhancement by olarization Transfer); cf (80JA429),
usin sensitivity enhancement/polarization transfer with INEPT pulse sequence. Up to now
no I N NMR of spectra 1,2,3-triazoles have been published.
4.11.3.2.6 UV spectroscopy
The first UV spectra of 1,2,3-triazoles were reported in 1954 (54JA667), with the parent
cornpound showing a maximum at 210 nm (log e 3.6), being very similar to the spectrum
of pyrrole. Substitution of an alkyl group in the 4-position causes a slight bathochromic
shift to 215-216 nm.
More detailed studies on the UV spectra of 1,2,3-triazoles (and benzotriazoles) followed
in 1958 (S8G977, 58G1035), although benzotriazoles had been investigated rnuch earlier
(42CB1338). There exists a rich collection of the UV data for 1,2,3-triazoles and benzotriazoles
known today (71PMH(3)77, 103). Some additional and more recent data are presented in
Table 14.
Comparing the UV spectrum of benzotriazole in different solvents with that of benzene
and o-benzoquinone leads to the assumption that the principal contributing forrns of the
1,2,3-Triazoles and their Benzo Derivatives 685
Table 14 Some UV Speclral Data of 1,2,3-Triazoles in Ethanol (E) and 95% Ethanol (E*)
N R 4
II J 5
N..... R
N
R 1
R 1 R 4 R S Åmax (nm) log e Solvent Ref
Ph H H 209,244 4.24, 4.26 E 68JCS(C)1329
p-ClC 6 H 4 H H 201,232 4.20,3.99 E 68JCS(C)1329
p- N0 2 C 6 H 4 H H 295 4.47 E 68JCS(C)1329
Ph H OH 235 4.03 E* 58CJC1441
Ph H Cl 228 4.03 E* 58CJC1441
Ph Br H 253 3.96 E 55JA6532
Ph C0 2 H H 247 4.07 E 55JA6532
Ph C0 2 H Cl 231 4.03 E* 58CJC1441
Ph C0 2 H Me 226 4.07 E 68JCS(C)1329
214 4.22 E 58G977
Ph H C0 2 H 222 4.00 E 68JCS(C)1329
Ph H Me 207,230 3.67,3.84 E 68JCS(C)1329
P-N0 2 C 6 H 4 H Me 215,272 4.14,4.42 E 68JCS(C)1329
rnolecule in neutral, mildly acidic, acidic and basic solutions are, respectively, the neutral
species (A), the cation (B), and the anion (C) (73JA4360). UV spectroscopy has also been
employed for structure elucidation of 1-benzotriazolyl- and triazolyl-carbonyl moieties
(54JA4933).
0-JN
(A)
o: +
/"'\
NH
::::::,... ::-. /
N
(B)
o: o--
w
::::::,... ::-. /
N
(C)
4.11.3.2.7 IR spectroscopy
Complete assignments for the parent compounds have been reported (54JA667); see also
Section 4.01.3.7. From symmetry considerations the IR spectrum of 1,2,3-triazole in the
vapour and liquid states has been interpreted in terms of an asymmetric 1H -structure,
which is contrary to the results obtained with other spectroscopic methods (69JCS(B)307).
This interpretation has been disputed (64AC(R)735).
For 4-phenyltriazole the NH-stretching band was measured in all phases (cm- 1 ): 3522
(vap), 3470 (CCI 4 ), 2400-3300 (solid) (65CB4014).
Both 4- and 5-unsubstituted triazoles show C-H stretching at 3100-3410cm- 1
(70JHC361). Examination of the IR spectra of several 1,2,3-triazoles yields the following
pattern of bands appearing consistently in the ranges given (cm- 1 ): 1290-1150 (CH in-plane
deformation), 1130-1105 (CH in-plane deformation), 1090-1010 and 1000-900 (ring
breathing), 850-700 (CH out-of-plane deformation) (64CJC43). Furthermore, four different
triazoles studied showed the following approximate ring-skeletal vibrations: -1520, -1450,
-1410 cm- 1 (64CJC43).
It has been observed that among 16 azoles possessing the common feature of a benzoyl
group attached to a C atom of the heteroaromatic nucleus, the 1,2,3-triazoles (50) exhibit
a strong band in the region 895-920 cm- 1 with an intensity of the same order as that of
the benzoyl stretching band; for example, in (50; R = NHCOPh, COPh) there is a charac-
teristic band at 925 and 920 cm -t, respectively, in addition to lI( C=O) at 1645 crn -1. The
nature of this band has been established. The ratio of the apparent extinction coefficients
NH
R 1 = H, c.I'
"-
OAr
R 2 = H, C0 2 Et
PhOG -p: N
r \1
R .....N
N
H
(SO)
ArO f: N
r \1
R 2 N
N.....
R 1
(51)
686
1,2,3- Triazoles and their Benzo Derivatives
of the benzoyl band and that in the 920-895 cm- 1 region seerns to be useful as a diagnostic
aid in structural determination (62JOC2209).
In the course of cycloadditions of diazo compounds to cyanates the IR spectra of different
substituted 4-aryloxy-1,2,3-triazoles (51) have been measured. The absorptions between
957 and 990 crn- l have been attributed to the triazole nucleus while the y(CH) vibration
of the triazole-H (R 2 = H) is found in the range 1030-1045 cm- l and what is presumably
an N =N valence band occurs at 1720 cm- 1 (66CB317).
Raman spectra of several benzotriazoles were reported as early as 1940 (40CB162).
4.11.3.2.8 Mass spectrometry
No rnass spectra of 1,2,3-triazoles were described prior to 1968, when a series of highly
substituted triazoles, the oxidation products of 1,2-dicarbonyl-bis-benzoylhydrazones, were
investigated. The previously assigned structure of a dihydro-1,2,3,4-tetrazine could be
excluded in favor of the 1,2,3-triazole-isoirnide (52), which showed a low intensity molecular
ion Mt, but a prominent [M-28] ion corresponding to loss of N 2 giving (53) (68TL231).
The [M - 28] ion underwent further fragmentations as shown in Scherne 1.
(52) m/e 445
[ R R ] :
""" y OCQPh
=<Ph
(53) m/e 416
m/e311
P h;=f h OCOAr
N .....N-N=<
N Ar
Phv=? Ph
\+1 +
N
m/e 192
+ /OCOPh
N=C
'Ph
m/ e 224
----=:...... [PhC=N]: + PhCO/ -) Ph+
m/e 103' m/e 121 m/e 77
/
PhCO+
m/e 105
Scheme 1
Another study concentrated on the nitrogen elimination from diphenyl- and triphenyl-
1,2,3-triazoles upon electron irnpact (710MS(5)427). Differences in the rate of nitrogen
elimin3:tion were found, as some derivatives required a higher energy of activation. The MS
of 1,4-diphenyl-1,2,3-triazole (54) (and the 1,5-isomer 55) showed identical products due
to nitrogen extrusion leading to the azirine (56) (71OMS(5)427). This prirnary loss of nitrogen
seerns to be a special feature of 1H -1,2,3-triazole derivatives as the isomeric 2H -1,2,3-
triazoles do not undergo such an elimination. By this rneans 1H- and 2H -isorners can be
distinguished by MS (75JCS(P1)1). This was shown with the examples of 1- and 2-alkyltriazoles
(57) and (58). While the 1-alkyl derivatives (57) all show an ion [M+ - 28], this is absent
from the spectra of the 2-alkyl isorners (58) (75JCStPl )1).
pr N Ph þ + [ Ph N Phl
r II Ph[ NR
....N -) I NPh Ph N Ph '" /
N+ Ph N:;: N N
I' Ph R
Ph
(54) m/e 221 (56) m/e 193 (55) m/e 221 (57) (58)
However, unsubstituted 1,2,3-triazole eliminates nitrogen from both the 1H- and 2H-
tautorners (Scheme 2) (730MS(7)271). In addition, 1,2,4- and 1,2,3-triazoles behave similarly
upon electron irnpact, which is ascribed to the formation of cornmon ionic structures
(730MS(7)271).
In the gas phase the MS of 1,2,3-triazole is interpreted as being derived from a mixture
of both tautomers; the IH -triazole thereby eliminates one molecule of nitrogen and, on
the other hand, the 2H -form undergoes two other competitive reactions: M+ - HCN and
M+ - N 2 , the latter one being considered in terrns of a previous isomerization of the fragment
ion (Scherne 3) (730MS(7)271).
1,2,3- Triazoles and their Benzo Derivatives
687
H +
,.
N-N
,'.(.,,\\ '----
. N)<" --.......
.... ') -HCN HN::í!
'N' ......
;J )' ------ m/e 2
H/ '..N
-N.
--+
+
HN=CH
m/e 28
Scheme 2
N,
Path 1: HrJ",
N
A
HN-N
-r m/e42
N
.+/
H-N, h
N
\ It
N" ,.p>
N
^T
N'
Path 2:
J
N,
N
H
-e
-----+
J
N,
N+
H'
\l
N
H
m/e 41
Scheme 3
In addition, the MS of a wide variety of substituted 1,2,3-triazoles have been measured.
The molecular ion M t is usually strong and almost half the compounds in the group show
an [M+ + 1] ion. Subsequent fragmentation patterns are strongly dependent on the sub-
stitutents Rand R'. The cleavage of the triazole ring may begin with one or more accessible
cyclic (lH; 2H or 3H) or acyclic (a -diazo-ß -imino) molecular ions (79JCS(P1)1S).
The tautomerism of the 4- and 5-hydroxy-1,2,3-triazoles (59)-(61) in the gas phase has
been studied by comparison of their MS with those of the fixed dimethyl derivatives, e.g.
(62). These data suggest that (59) exists in the hydroxy form, and (60) and (61) exist as
tautomeric mixtures (76BSB795).
H OF\
N .....NMe
N
(59)
Oh
MeN, 1'N
N
H O/\
MeN, 1'N
N
(60)
HOr.--;\
1/ \\
N, .....N
N
Me
Oh
N, .....N
N
I
Me
OMe
Ì\
N N"'NMe
(61) (62)
A detailed mechanistic MS study of 1-phenyl-1,2,3-triazole and its D- and 13C-labelled
derivatives with regard to cornpeting decomposition pathways has been reported (780MSS71).
Sirnilarly, the mass spectra of some alkyl-, aryl- and acyl-benzotriazoles have been reported
and discussed on the basis of their thermolytic and photolytic fragmentation products
(67TL4379, 68CC1026). In the case of benzotriazole the molecular ion loses nitrogen, followed
by loss of HCN, to give a [C s H 4 ]t ion, the radical cation (A) being more stable by 1.7 eV
(Hückel MO calculations) than the azirine ion (D) (700MS(4)203).
(X N -N [0 + 0= +. CN; ]
I tJ -2.. I. C=NH U [C S H 4];
::::,." N ::::,." NH
H
m/e 119 (A) (B) m/e 91 (C) m/e 64 (D)
The most intense ion in the MS of 1-phenylbenzotriazole (63) at rn/e 167 is due to the
loss of nitrogen from the molecular ion and the subsequent fragmentations are quite similar
(PÑH
688
1,2,3- Triazoles and their Benzo Derivatives
to that of carbazole (65). Thus, after loss of nitrogen the radical cation (E) is forrned, which
cyclizes to give the rnolecular ion of a 4aH-carbazole (64). Isornerizåtion gives rise to the
rnolecular ion of carbazole (65) (700MS(4)203).
(X i N
:::::.... ,/
6
Q +
I --
:::::.... N'
Ó
0ðJ
N
+,
--
QSJ
N
H
(63) (E) (64) m/e 167 (65) m/e 167
More detailed studies of the behavior of benzotriazoles upon electron impact provided
evidence for the exclusive presence of the 1H -benzotriazole tautomer in the gas phase.
The Mt of 2H- benzotriazole is generated from 2-ethylbenzotriazole (66) by ethylene
elirnination; isomerization to the IH-tautorner precedes the fragmentation (730MS(7)1267).
N N T
0: ;;.- NCH2CH3 -=-=---. 'N
:::::.... "-N' N' ì.ì Y
(66) \" ': CH 2
m/e 64 (-HCN m/e 91 )
-C,H 4
\N,
(X I N
:::::.... .I
N
H
o: :---,N,
+--- NH
:::::.... "- /
N
m/ e 119
4.11.3.2.9 Photoelectron spectroscopy
The rnolecular energy levels of azoles and 1,2,3-triazole have been studied by gas phase
He(I) PE spectroscopy (Figure 8) and calculated by ab initio MO calculations. Thereby sets
of energy levels have been determined that correlate well with one another in the upper
valence shell region (73T2173).
10
14
18
eY
Figure 8 He(l) photoelectron spectrum of 1,2,3-triazole (731'2173)
Eigenvalues, principal character and c nters/bond orbitals are presented in Table 15.
The calculations provide in addition to eigenvalues (energy levels) a set of eigenvectors,
perrnitting analysis of the bonding characteristics of the levels and trends. The spectra relate
to a tautorneric mixture of the IH - and 2H- forms. In a subsequent reconsideration of this
topic a comparison was made of the PE spectra of the tautorneric 1,2,3-triazole with its
corresponding 1- and 2-methyl derivatives. 2H-l,2,3-Triazole has been identified as the
dominant tautomer in the gas phase (81ZN(A)1246).
1,2,3-Triazoles and their Benzo Derivatives
689
Table 15 Eigenvalues, Principal Character and Centers/Bond Orbitals of 1,2,3-Triazole
{73T2173)
Eigenvalue (eV)
Principal
character
a'
-429.4
-428.2
-427.0
-312.5
-311.5
-42.03
-34.69
-31.98
-25.18
-24.09
-22.85
-18.85
-18.47
-15.46
-12.81
-19.90
-13.71
-12.35
Is
Is
Is
Is
Is
2s ('A')
2s
2s
2s 2p ISH
2s 2p ISH
2p ISH
2p ISH
2p ISH
Sp2
2
sp
2pz
2pz
2pz
a"
Centers/bond orbitals
N 1
N 2
N 3
C 5
C 4
N 1 +N 2 +N 3
N 1 _N 3
N 2 _(C 4 +C 5 )
NH, N 3 C 4 , C 4 C 5
NN+CN C 4 H-C 5 H
CN, C 4 H'+C 5 H
c 4 C S , NH-C 5 H
C 4 H, CN
N 3 + N 2
N 3 _ N 2
N 1 + N 2 + N 3 +C 4 +C 5
N 3 C 4 _N 1 C 5
(N 1 +N 2 + N 3 )_(C 4 +c 5 )
Additionally, the final equilibrium geometries for the tautomeric pair have been cornputed
and are shown below. In agreement with the rnicrowave data (cf. Section 4.11.3.2.2) both
minimal and double zeta bases predict the 2H- tautomer to be more stable than the 1H -form
(81ZN(A)1246).
H
H
H
128.0
1.09j 1 .. 62 \
1.3: t . 9
14 OO
N
I 1.305
H
1.087
[30 i .5 [08[ 4 .1 \\ 1
1.348 .388
1.094 105.1 106.8 N
H 122.4 /.
1.407 / 1.416
128.7 N 121.1
11.033
H
The He(l) PE spectra of 4-(1,2,3-triazolio)sulfides have been recorded and assignments
made. An unusual stabilization effect obtained by methylation is discussed in terms of
perturbation theory (78JAI275).
4.11.3.2.10 Polarography
Substituent effects on the polarographic reduction of 1-arnino-4-aryl-1,2,3-triazoles and
1H-4-aryl-1,2,3-triazoles of the general forrnula (67) have been reported. Cathodic half-
wave potentials (E 1 / 2 ) determined in acetonitrile at 20 oC were between -2.1 and -2.6 V.
Linear relations were found between E 1 / 2 and the 'IT-electron density at C-5, as well as
Hamrnett u-values (76ZC280).
x
N"" .....NNH 2
N
(67) X=p-F,p-Cl,p-Br,p-Me
Benzotriazoles can take up four electrons in an irreversible reaction with subsequent ring
cleavage, whereas in basic rnediurn benzotriazoles are normally not reduced. However,
2-substituted benzotriazoles exhibit a reversible two-electron step yielding dihydro deriva-
tives (68MI41100).
690
1,2,3- Triazoles and their Benzo Derivatives
4.11.4 REACTIVITY
General aspects of the reactivity of azoles and 1,2,3-triazoles are discussed in Chapter
4.02. A more detailed discussion of these and other features of the chemistry of 1,2,3-
triazoles and benzotriazoles follows.
4.11.4.1 Reactions at Aromatic Rings
4.11.4.1.1 General survey of reactivity
In this section, the reactivity of the major types of aromatic 1,2,3-triazoles and ben-
zotriazoles is considered and compared with that which would be expected on the basis of
electronic theory and spectroscopic data presented in Section 4.11.3. Tautomeric equilibria
and ring-chain tautornerisms are discussed in Section 4.11.4.1.2(i), Dimroth rearrangernents
in Section 4.11.4.1.2(iii) and acid-base considerations are discussed in the section immedi-
ately following.
(i) Acid-base considerations; ionization constants
1,2,3- Triazole is both a weak base and a weak acid of cornparable strength to phenol.
The amphoteric properties may be deduced from examination of the mesomeric or resonance
structures (63PMH(I)98, 68JA6588). Some representative pKa values are listed in Table 16.
Table 16 pK. Values for Triazoles
Compound
Basic pK.
Acid pK. Ref.
2.27
9.4 63PMH(I)98
63PMH(I)98
63PMH(1)98
8.2 51JA4360
69JCS(C)2379
6.60 58JOC1916
7.91 58JOC1916
7.68 16G308
2.53 42MI41100
5.37 68JA6588
7.7 51JA4360
5.48 55JA5105
1,2,3- Triazole
I-Methyl-l,2,3-triazole
2-Methyl-l,2,3-triazole
Benzotriazole
5-Amino-l-phenyltriazole
4- Phenyl-5( p- nitrophenyl)amino-l ,2,3-triazole
4-Phenyl-5( p- methoxyphenyl)amino-l ,2,3-triazole
4-Phenyl-l,2,3-triazole
4,5 - Dicyano-I ,2,3-triazole
4,5-Dibromo-I,2,3-triazole
5-Chloroben:wtriazole
4,5,6,7 - Tetrachlorobenzotriazole
1.17
1.25
<I
1-Methyl-l,2,3-triazole shows a comparable basicity, but 2-methyl-1,2,3-triazole is a
much weaker base. That the N- alkyl groups show no base-strengthening effect can be
explained in terms of the formation of imidazolium-type cations (68) (I-methyl) and (69),
whilst 2-methyl-2H-1,2,3-triazole must achieve a pyrazolium-type cation (70).
G .. NH
. .\
:. + ':N
'N/
Me
(68)
f2 ..NH
:' + ';\
.....;..N
N
H
(69)
(f ..N
. .\
: + :
....;:-NMe
N
H
(70)
In the case of benzimidazole the. fused benzene ring is base-weakening and acid-
strengthening; substituents on the aromatic ring show predictable effects. 4,5-
Oibromotriazole is a much stronger acid than the parent compound (51JA4360).
Most derivatives with a ring NH are weak acids (58JOCI916), an exception being 4,5-
dicyano-1,2,3-triazole (42MI41100) in which resonance stabilization of the corresponding
anion plays a certain role. Benzotriazole shows an increased acidity after chlorine is
substituted in the benzene ring (51JA4360, 55JA5105).
(ii) Metalloid-linked substituents
4-Benzoyl- and 4-butyryl-triazoles form iron complexes when treated with iron(II)
chloride in THF under nitrogen. A Mössbauer spectrurn was measured with this complex
(fióDOK(l70)354). Similarly, Fe2(CO)9 reacts instantly with the above 4-aroyltriazoles to give
1,2,3- Triazoles and their Benzo Derivatives
691
red solutions of (PrCO-C 2 H 2 N 3 hFe and (PhCO-C 2 H z N 3 hFe which have been investi-
gated spectroscopically (68DOK(l81)1397).
On oxidation of 1,2-cyclooctanedione dihydrazone with HgO, cyclooctyne and Hg deriva-
tives of triazoles have been identified. The major product is C 32 H 42 N ó Hg, which was assigned
the structure shown (68LA(716)U). Cyclometallations of 2-aryl-4,5-dimethyl-1,2,3-triazoles
occur with Pd(II), Pt(II), Rh(II) and Ir(III) chlorides (78MI41 ios). The triazole acts as an
N -C-chelate ligand.
()
YM
,..N, .:
N N
U
Me Me
Q
cx: N, N
I :
4.11.4.1.2 Thermal and photochemical reactions formally involving no other species
(i) Tautomerism: ring-chain tautomerism
As has been pointed out often in the previous sections 1,2,3-triazole can exist in both
the 1H - and 2H-forms. Benzotriazole behaves in a sirnilar fashion (Scheme 4).
N R" R" R' (X N Cr:
rJl JR' n
N.... ,..N NH
....N N """- / """- /
R R N N
H
IH-form 2H-form IH-form 2H-form
Scheme 4
Considering the spectroscopic data known today leads to the conclusion that in the case
of 1,2,3-triazole the 'symmetrical' 2H -form predominates. More evidence is given in
(76AHC(Sl)281). Similarly, spectroscopic data indicate for benzotriazole that the 1H -form
is predominant (for more details see (76AHC(Sl)29S)).
Some features of the tautomerism of both 1,2,3-triazole and benzotriazole are summarized
in Table 17 (76AHC(Sl)296), where the tautomer with the highest dipole moment (and hence
the most likely to be associated) and that with the lowest basicity are listed.
Table 17 Annular Tautomerism of 1,2,3- Triazole and Benzotriazole (76AHC(SI)296)
Tautomer with
Azote Definition of K T Conclusion highest f.L Less basic
1,2,3-Triazole IH-l , 2 , 3-T 2H-l,2,3-T in solution; IH-l,2,3-T 2H-l,2,3-T
(l,2,3-T) 2H-l,2,3-T mixture of IH- and
2H-l,2,3-T in the gas phase
Benzotriazole IH-BT IH; K T >> 1 in solution IH-BT 2H-BT
(BT) 2H- BT and gas phase
Besides the annular tautomerism and the Diffiroth rearrangement (Section 4.02.3.5)
ring-chain tautomerism of certain 1,2,3-triazoles have been discussed and, in some cases,
shown by rneans of spectroscopic methods. Thus, cyanogen azide reacts with acetylene to
form a 1: 1 adduct, which was proved by means of IR, UV and temperature-dependent
692
1,2,3- Triazoles and their Benzo Derivatives
I H NMR data to exist as a ring-chain tautomeric mixture of 1-cyano-1,2,3-triazole (71a)
and a -diazo-N- cyanoethylideneimine (71b). The equilibrium is sensitive to temperature
and solvent (67JA4760).
N NC,
NCN/ N N N 2
N 3 CN+HC=CH -. W U
(71a) (71b)
Similarly, 1,3-dipolar cycloadditions of benzenesulfonyl azides to N,N-diethylaminoprop-
l-yne led to 1,2,3-triazoles (72a) and a-diazoamidines (72b). With the aid of IR and l H
NMR data these were shown to exist in a tautomeric equilibrium (70JOC3444). With IR and
1 H NMR data a 5-aminotriazole-diazoamidine equilibrium (73a) (73b) was established
(70TL2823, nCB2963, nCB2975). However, 4-arnino-1,2,3-triazole (74a) proved to be stable
and no ring-chain tautomerism could be identified (73TL1137).
N N2 NS0 2 Ph
N-7 'NS0 2 Ph ----"
'-=1 ..--- U
Me NEt 2 Me NEt2
(72a) (72b)
R' N R1XN2 N] N2:l
r\1 --'" II ( --ft+
Et 2 N .....N ..--- N, NH 2 H; NH 2
::,... 2
N Et 2 N NS0 2 R N
SOzR' H
(73a) (73b) (74a) (74b)
(ii) Thermal and photochemical reactions
Although the ring system of monocyclic 1,2,3-triazoles shows a remarkable stability
towards oxidation, reduction and hydrolysis, under forced conditions thermal extrusion of
nitrogen can be achieved at elevated temperatures. Some such reactions are reviewed in
(B-76MI41103). Similarly, photochemical extrusion of nitrogen can be effected, and this is
consistent with their behavior upon electron impact (ct. Section 4.11.3.2.8).
After extrusion of nitrogen the intermediate can be formulated in terms of three
mesomeric forms: an iminocarbene (A), a zwitterion (B) or a diradical (C). The potential
constitutions of (A), (B) and (C) follow from their reaction products involving, for example,
a photo-Wolff rearrangement (68JA1923), and a subsequent ring closure (with R = Ph, cf
(70CB3811)) to indoles, while (C) undergoes cyc1ization to give a 1 H-azirine which rearranges
in turn to the corresponding 2H-isomer, the latter process being more favorable than the
Wolff rearrangernent (Scheme 5) (71CC1519, 73JCS(P1)555).
R 3 R 3 R 3
R 3 N lJ.!hv R2 N J( RZJ(Ñ
e\1 þ
R 2 N -N 2
N..... R Z Ñ:
R 1 R 1 R 1 R 1
(A) (8) (C)
Ph (X) Ph
(A) -. >='=NPh + Ph f I
Ph N /-/
30% H
30%
Scheme 5
(C) -. [ ::þNR ] -. Ph X
Ph R
80%
Vapor phase pyrolysis of two unsymrnetrically substituted 1,2,3-triazole isomers, like (75)
and (76), involves the antiaromatic lH -azirine derivative (77) which rearranges to two
isomeric 2H-azirines (7S) and (79) (71CC1519, 73JCS(Pl)555) and other products. Irninocar-
benes (SO) are most likely involved as intermediates. Furthermore, nitrogen has been
extruded frorn severallH-1,2,3-triazoles by flash vacuum pyrolysis. l-Alkyl-1,2,3-triazoles
(SI) give nitriles (S2) and (S3) (via Wolff rearrangement) and (hydroxy)isoquinolines (S4)
and (S5) (by [l,4-H] transfer in the iminocarbene) (75JCS(Pl)1).
Both 4- and 5-phenyl-l-( l-phenylvinyl)-l ,2,3-triazoles are pyrolyzed at 575 oC to afford
rnixtures of 2,4- and 2,5-diphenylpyrrole; sirnilarly, l-phenyltriazoles (S6) react to give 2-
1,2,3- Triazoles and their Benzo Derivatives
Me N
Ph(" '
N.....
PhthI
(75)
o
PhthI"-N
o
Ph N
pJi \
"N.....
Me
(81)
600'C
þ
0.01 mmHg
Me\7Ph +-
N
Phth I
(77)
I \
Ph N
I/"
Me,,/N
N
Phth I
(76)
400-500 'C )
Ph
X N
Me Phth I
(78)
Ph
N2+ 1
Ph ::o...NMe
1
Ph 2 C=C=NMe
1
MeCPh 2 CN +- Ph2C_:: _=::.N
(82) Me.
Ph 2 CCN
I
Ph 2 CCN
(83)
Me
N
Ph Phth I
(79)
P\.......H
A ÇCH 2
Ph N
693
[) J
(80)
-.
Ph}
Ph N=CH 2
1
n
N:/
1
co Ph
I NH
tî
OH
m Ph + m Ph
N N
(85) (84)
and 3-phenylindoles (87), (88) (75JCS(Pl)1). Photolysis and pyrolysis of 4-phenyltriazole
lead mainly to phenylacetonitrile, and pyrolysis of 4,5-diphenyltriazole (89) in solution
gives 2,3,5,6-tetraphenylpyrazine (90) (nJHC87).
R 4 N
R sir \
N.....
6
(86)
R 4 =Ph, H
R 5 =H,Ph
Ph N
pJi \
"N.....
H
(89)
R 4
lû
R S N
n
::þN -Q
lî
R\, N
): V
R
rhl l
h NH J
-.
R 4
R S (0
\N
H
(87)
R S
-'R4
\N
H
(88)
Ph N ) Ph
Ph I Ph
N
(90)
694
1,2,3- Triazoles and their Benzo Derivatives
Gas phase pyrolysis of the unsubstituted 1H- and 2H-l,2,3-triazole mixturc rcsulted in
the formation of acetonitrile as the main product, and HCN and NH 3 occur as by-products.
At about 850 o C, an unexpectedly high pyrolysis temperature, 1,2,3-triazole was decom-
posed quantitatively. This is explained by the predorninance of the 2H-form in the gas
phase (78JCR(S)298).
Irradiation of 2H-l ,2,3-triazoles (91) in ether gives 22% MeCN, and in the presence of
excess cyclopentene it affords the adduct (92) (68CC977). 4H- Triazolines (93) bearing
rnethoxycarbonyl and alkyl groups at the ß -position give, on thermolysis, 2H-l,2,3-triazoles
(94) and/or 3-amino-2H-azirines; on photolysis, only azirines are formed (80CC940).
MeCN
M'l;-(e
N, ,.N MeH
N
Me Net>
(91) 0
Me H
(92)
R 1 NR 3 R' NR 3
R 1 N C 80'C R 2 H 2 n 2
NR3 0.1 Torr 0.1 Torr N'N'..-N
R 2 2 C hv N /N
CoHo R 2
(95) (93) (94)
On irradiation, 1-phenylbenzotriazole (96) loses nitrogen to give carbazole (98) in nearly
quantitative yield (cf. also the MS fragmentation in Section 4.11.3.2.8) (68JA1923). The
nature of the intermediate (97) was established as a diradical by photolysis of 5-chloro-l-
(4-chlorophenyl)benzotriazole (99) which gave (100) as the sole product (70CCI089). The
antiaromatic azirine (101) could b xcluded as a potential interrnediate (70CCI089). The
photochemical reactions of benzotriazoles have been the subject of a review (7SMI41100).
(X N hv 0.... -QD
I I N'
N
6 Ò N
H
(96) (97) (98)
Cl N N ICl ' I ' 0Cl ] _ C Cl
ò r-f MeCN L Ñ )J
Ç"I
::::,...
(99) CI
(C'(YN -o C
(100)
(101)
Upon photolysis at 254 nm 1-methoxy- and 1-cycloalkoxy 1,2,3-benzotriazoles (102)
show rather different photolytic pathways: homolytic cleavage of the N -0 - R bond occurs,
while a second path proceeds via nitrogen extrusion followed by an intrarnolecular H-
abstraction leading to phenylnitrene (103). The latter dimerizes to give an azobenzene
(104) (74JOC3788, 80JHC82S). I-Benzyloxy-l,2,3-benzotriazole shows a similar behavior
(80JHC1309).
(iii) Dimroth rearrangements
The Oimroth rearrangernent is frequently encountered in heteroaromatic chemistry and
was first recognized in the triazole series. General aspects of the rearrangement are described
1,2,3-Triazoles and their Benzo Derivatives
695
CI
I
(102) 0-0
hv
-.
-N 2
0=c8
CI 'H+ 8
U-i- O
,
CI Q
I _
N
'y / (103) -
I lvent
CI Q- N=N -Q CI
(104)
in Section 4.02.3.5 and several reviews have appeared on this subject (B-61MI41100, B-
68MI41101, 69ZC241, 74AHC(16)33).
The term Oimroth rearrangement was coined in 1963 as a convenient way of referring
to an isomerization proceeding by ring fission and subsequent recyc1ization, whereby a ring
nitrogen and its attached substitutent exchanged place with an imino (or potential imino)
group in the position a to it (63JCS1276).
The general reaction scheme for 1,2,3-triazoles is shown in Section 4.02.3.5 by formulae
(240)-(244). If the equilibrium reaction is carried out under thermal conditions, the position
of the equilibrium can be influenced by the solvent basicity. In general terms, the more
basic the solvent, the greater the proportion of the more acidic NH-triazole (106) which
exists in the equilibrium mixture (105) (106). Furthermore, electron-attracting groups
and bulky, rigid substituents tend to favor the tautomeric form in which they occur on the
exocyclic nitrogen; alkyl groups tend to favor the cyclic nitrogen atom. 5-Methylamino-
1,2,3 - triazole-4-carboxamide (107) rearranges to 5 -amino-1-methyl-1 ,2,3 - triazole-4-
carboxamide (108) when heated at 160 oC for one hour. Triazole (108) remains unchanged
even when heated with ethanolic ammonia at 180 oC (69JCS(C)152).
CI O
I NH1
[ N
7 \1
H1N /N
N
Ph
(105)
PhHN[
N
H
(106)
H1NOC [ N 160"C
7 \1 --+
HMeN /N
N
H
(107) (108)
However, the 1-benzyl derivative is rapidly isomerized in base, though the equilibrium
favors the ring-substituted isomers under neutral conditions (70JCS(C)230, 72JCS(Pl)461). These
reaction tendencies are generalized in Scheme 6.
H 2 NOC ( N
7 \1
H 2 N /N
N
Me
EtOH/NH,
'f- I
180"C
R 1 N
[ \1
H1N /N
N
R
R 1 N
'1/ II
..-- HRN . N
N/
H
Favored in neutral and
basic solution (R = Me), and
in neutral solution (R = CHzPh)
Scheme 6
Favored in basic solution
(R = Ar, CH1Ph)
Oimroth rearrangement also occurs between the 5-mercapto-l,2,3-triazoles (109) and
the 5-amino-1,2,3-thiadiazoles (110). If the thiadiazoles (110) are heated in basic solvents
they are converted into the triazoles, whereas the reverse reaction is observed in acidic
media (67LA(710)118, 69CB417, 72ACS1243). Thermal equilibria of thiadiazoles and triazoles,
with both isomers present, have been reported (62ACS(B)1800, 66CB1618).
696
1,2,3- Triazoles and their Benzo Derivatives
H+
P
B-
SH
I _ +
PhN=C-C-N=N
I
H
B HH'
S
" - +
PhNHC-C-N=N
I
H
B i!w
PhHN[
S
(110)
A detailed exarnination of the acylation of l-substituted 1,2,3-triazoles (09LA(364)183,
60CB2001, 68JCS(C)344, 69JCS(C)152) revealed that heating of 4-substituted 5-amino-l-phenyl-
1,2,3-triazoles in acetic anhydride afford acetyl derivatives of the isomeric 4-substituted
5-anilino-1,2,3-triazoles; in turn these anilino isomers and their acetyl derivatives retrogress
to acetyl derivatives of the amino compounds on prolonged refIuxing in acetic anhydride.
Acylation of 5-amino- or 5-anilino-1,2,3-triazoles at room temperature in the presence of
sulfuric acid yields unrearranged products (71JCS(C)706). Sorne yields of the various products
forrned are shown in Table 18. The appropriate triazole derivatives (111) or (115) (5
mmol) were refIuxed with acetic anhydride (10-20 cm 3 ).
HS[
N
Ph
(109)
0 0 0
" H " II
"'N-1(N ACN-JcN H 2 N-JcN
r \\ r \\ r \\
H 2 N ,.N Ac 2 N N/N Ph-N N/N
I I H I
(111) Ph Ph Ac
(112) (113)
0 0 NHAc
" II OC/
Ac-N-C H 2 N-JcN
H ):N Ac ): \
r \\ r \\
Ph-N N/N Ph-N N/N 'N /N
/' N
H I H H Ph I
Ac Ac
(114) (115) (116)
Table 18 Acetylation of Amino-l,2,3-triazoles (7IJCS(C)706)
Substrate Time of reflux Products Yield (%)
(111) 12 h (112) 56
(111) 20min (113) 70
(114) 15
(111) 3 or 6 h (113) 8
(114) 86
(115) 20min (113) 59
(114) 5
(115) 12 h (116) 63
CycIization of l-aryl-3-(cyanornethyl)triazenes (117) in protic media involves a Dimroth
rearrangernent to afford 5-(arylamino)-1,2,3-triazoles (118) (81JOC856). As found acciden-
tally, ethyI5-amino-l-phenyl-l,2,3-triazole-4-carboxylate (119) undergoes a Oimroth rear-
rangernent to (120) by simply refIuxing (119) in carbon disulfide (77UP41100). Furthermore
(119) proved to be stable under the conditions of direct irradiation. However, in the presence
of triphenylene as sensitizer, (119) rearranges to (120), this photorearrangement being the
1,2,3-Triazoles and their Benzo Derivatives
697
first example of a photoinduced Dimroth rearrangement (76ACH(19)26S). Some years later,
this photo-Oimroth rearrangement was also observed with 1,4-diphenyl-5-amino-1,2,3-
triazoles (77BCJ2S0S).
D N=NNHCHzCN
X -
(117)
d.EtOH
1-2h
H
(.'N,
x D- NHì N
(118)
EtOzC [ N
7 \1
HzN .....N
N
Ph
(119)
d. CS,. 18 h
or hv IÀ = 253.6 nm /
dioxane, senS.
EtOzC [ N
" \1
HN' N
I N.....
Ph H
(120)
(iv) Ring cleavage reactions: fragmentations
Besides ring-chain tautomerism (Section 4.11.4.1.2(i)) and the Oimroth rearrangement
(Section 4.11.4.1.2(iii)) cleavage reactions of some amino-, azido and diazo-methyltriazoles
have been reported. Thus, 5-azido-1,4-diphenyl-l,2,3-triazole (121) proved to be unusually
labile above 50 o C. Nitrogen is evolved with the formation of a conjugated nitrile (122)
(64JA202S, 70JOC221S). Similarly the diazomethyltriazole (123) decomposes to (124). Both
reactions can be explained in terms of concerted processes.
Ph NzHé
'-=N lf N I
>50'C Þ N z + N=.d -ó '--'CN --
N' Ph N.....
I I
Ph Ph
(122) (123)
Ph N
. "7f5 II
Ñ;lÑ'Ó-N<;'N
I
Ph
(121)
HC=.C
'\.
N z + C=NPh
/
Ph
(124)
1-Amino-1,2,3-triazoles undergo complete fragmentation with loss of two molecules of
nitrogen on decomposition. Thus, l-toluene-p- sulfonamidotriazoles (125) and iminophos-
phoranes (126) on photolysis, and l-aminotriazoles (127) upon oxidation, give alkynes.
This method has proved useful for the synthesis of strained alkynes (cf. Section 4.11.6)
(64AG144, 64AG(E)138, 68LA(711)46, 68LA(711)6S). This reaction type is completed by a frag-
rnentation reaction, which involves decarboxylation and ring cleavage. Treatment of 2-
phenyltriazole-4-carboxylic acid (128) with barium hydroxide at elevated temperatures
gives in a concerted process two ring-cleavage products (66TL4387).
R N
[ \1 hv/ox. . RC=.CR
R .....N
N
X
(125) X = NTs
(126) X=N=PPh 3
(127) X = NHz
J: N,
N-Ph
'" /.........
C N H
cÝ 0J -H
( 128)
SaIOH),
d
Þ PhNHN=CHCN +CO z + OH-
4.11.4.1.3 Electrophilic substitution and nucleophilic attack
In general, electrophilic substitution can take place at a ring nitrogen or at a ring carbon
atorn. Triazole offers three, and benzotriazole five H atoms which can be theoretically
replaced by other groups. Additionally, due to the tautomerism in unsymrnetrical 1,2,3-
triazoles three different positions of nitrogen substitution can be involved whereas sym-
rnetrical1,2,3-triazoles can result in two isomeric N-derivatives.
698
1,2,3- Triazoles and their Benzo Derivatives
Alkylation on nitrogen can be readily carried out with 1,2,3-triazoles (129) by means of
alkyl halides, dimethyl sulfate, diazoa,lkanes or methyl p-toluenesulfonate, or by the Mannich
reaction. Some of these electrophilic substitution reactions have been described (B-61MI41100,
74AHC(16)69, B-79MI4110S). Using methyl iodide and the silver or thallium salts of 1,2,3-
triazole, or using an alkaline solution, unsubstituted 1,2,3-triazole is in rnost cases preferen-
tially attacked on N-1 to give (132) (SSLA(S93)207, 6SLA(688)20S). However, the action of
diazornethane results in a high proportion of 2-methyl-2H-1,2,3-triazole (130) (7SJCS(Pl)l).
As soon as 1H-1,2,3-triazoles are N-1 substituted, they tend to form the 1,3-disubstituted
triazoliurn salts (133) (SSJA1703). The corresponding N-2-substituted 2H-l,2,3-triazoles can
be methylated only with powerful methylating agents, e.g. 'magic rnethyl', to give 1,2-
disubstituted triazolium salts (131) (71ACS(B)2087).
C
[ I
....N
N gsalt
H MeI
(129)
t Mel
N
r: '
NMe
0-/
N
(130)
MeSO,F I
Me
t . '
:: + ;NMe
..../
N
(131)
S02 F -
Me
( N
Mel 8'"
-----+ : + :N 1-
N....N .....>
N
Me Me
(132) (133)
Furthermore, the orientation of alkylation can be directed by the nature of the sub-
stituents. 4-Phenyl-1H -1,2,3-triazole (134) reacts with dirnethyl sulfate to give the 1-rnethyl
(135) and 2-methyl isomers (136) in 62% and 38% yield, respectively. The hindered
1-methyl-5-phenyl derivative was not forrned (67LA(707)147). C- Methylation of 1-phenyl-
1H -1,2,3-triazole can be carried out with butyllithiurn and methyl iodide at low tern-
peratures (71CJC1792).
Me,SO.
P + Ph C
tz.. ....N "" /NMe
N N
Me
(135) 62% (136) 38%
Ph [ N
7 II
....N
N
H
(134)
Sorne special examples follow. Recently phase-transfer-catalyzed alkylation has been
carried out on benzotriazole in benzene/aqueous NaOH ìn the presence of [PhCH2NEt3t
CL Both possible derivatives (137) and (138) were obtained (78MI41101).
(X I '\ o: --N'NR
JI ""-/
N N
I
R
(137) (138)
R = Me, Et, Pr, Bu, PhCH 2
1,2,3-Triazoles can be acylated in the usual manner, e.g. with acyl halides and anhydrides.
Isocyanates react with the formation of mixed ureas (139), which show characteristic
short-wave carbonyl absorptions (1745, 1788 crn- I ) (61LA(648m). Treatment of 1,2,3-
triazole with thiobenzoyl chloride in the presence of triethylamine yields a rnixture of
I-thiobenzoyl-1H- and 2-thiobenzoyl-2H-l,2,3-triazoles (73LA636).
( RNCO , ( I
....N THF, r.t. ....N
N N
H CONHR
R = Bu, Ph (139)
In some cases acyl group rnigration from the 1-position to the 2-position can be observed
when the prirnary 1-acyl derivative is heated above 120 oc (ct. 6SAG414, 6SAG(E)417, 66CB2S12).
2- Trimethylsilyl-1,2,3-triazole (140), easily obtained by silylation of 1,2,3-triazole
(67CB348S), can be srnoothly acylated in the 1-position to give (141) by rneans of acetic
1,2,3- Triazoles and their Benzo Derivatives
699
anhydride or acetyl chloride (67CB348S). This reaction has been studied intensively using
p-substituted monophenylacetylenes and TMS azide; contrary to normal observations, an
electron-releasing substitutent induces a higher yield (73T3271, 80MI41101).
N t J R I , AcCI ACN J RI >lZ0'C N J RI
þ / \\ C þ t
N, h'R IAc,O) N>- \R' Wor AcN... h'R'
TMS N "N <lZ0'C N
(140) (141) (142)
Acylation of benzotriazoles occurs in most instances on the 1- (or 3-)nitrogen atom.
Frorn 5-methylbenzotriazole and acetyl chloride or acetic anhydride, a rnixture of 1-acetyl-4-
and -5-methylbenzotriazoles is obtained (l3JCS1391). With acetic anhydride, benzoyl chloride
or benzenesulfonyl chloride and 5,6-dimethylbenzotriazole, acylation on N-l occurs
(52JA4917) and no N-2 substitution product could be observed. Analogously, benzotriazole
or 1-trimethylsilylbenzotriazole reacts 'with thiobenzoyl chloride to afford I-thiobenzoyl-
benzotriazole (73LA636). Similarly, with phenyl isocyanate 1-phenylcarbarnoylbenzotriazole
(143) is formed (49JA2297).
N
CONHPh
(143)
1,2,3-Triazole reacts with bromine to afford the 4,5-dibromo derivative and an excess
of hypobrornite leads to 1,4,5-tribromo-1,2,3-triazole. 2-Methyl-l,2,3-triazole shows in
comparison a decreased readiness towards halogenation. But in the presence of iron filings
as catalyst, the brornination affords 2-methyl-4,5-dibrornotriazole (144) and no monobromi-
nation product could be isolated (S5LA(593)207).
(X I N
J1
N
H
PhNCO
Br Br
Fen ZBr, þ 1/ \\
-ZHBr N, ,..N
N
Me
(144 )
1-lodo-1,2,3-triazoles have been reported to rearrange into the 4-isomers upon heating
(70ZC220). In contrast, brornination of 2-phenyl-lH-l,2,3-triazole in the presence of silver
sulfate affords the 2-p- bromophenyl derivative with a typical l H NMR pattern (A z B 2 of
the aromatic ring; singlet at 8 7.75 p.p.m.: two equivalent triazole-H) (63CJC2380). Similar
observations have been reported for the nitration of the same 2H -triazole: nitration occurs
firstly in the aromatic ring and then at C-4 of the triazole ring to give (145) and (146)
(48JOC815,63CJC274).
n
N, ,..N
N
Me
n
N, ....N
N
6
NO,
(145)
B M B r
N-::,. .....NH
N
(147)
amine
B r
N jN
(148)
1 Me,S04
NO,
1/ \\
N, ......N
N
6
NO,
(146)
o
Br N t
Br /
N
(149)
AH+
Me,CO
f
n + !\
N,.....N N-::,. ......NMe
N N
Me
(150) (151)
700
1,2,3- Triazoles and their Benzo Derivatives
The H-l atorn of 4,5-dibromo-1,2,3-triazole (147) (670109) is very acidic and forms
instantly the triazolide salt (148) when treated with dimethylamine (670109). The salt is
stable even when heated to 260 oC for 140 hours and reacts smoothly in a conjugate addition
reaction to give (149) (54JA4933). Methylation of (148) gives both the I-methyl-1 Hand
2-rnethyl-2H derivatives (150) and (151) (70JHC961).
Sirnilar results have been obtained with 4,5-dimethoxycarbonyl- and 4-phenyl-1,2,3-
triazolides, which displace chlorine from ethyl chloroacetate or ß -chloropropionate to give
both I-N- and 2-N-alkylated products. The highest 2-N to I-N selectivity was ca. 5:1
with the base triethylamine in DMF. Furthermore, triazolides add to alkynes to give Michael
adducts at the 2-position exclusively (73T3285, 73JOC2708).
1,3-Dirnethyl-1,2,3-triazolylium p-toluenesulfonate is brorninated in the 4-position (to
give 153) by means of bromine and NBS. When the 4-bromo salt (153) is dissolved in
base an equilibrium mixtu.r:e of (152)-(154) is obtained. Evidently, (153) is converted into
an ylide which is further brominated by (153). Subsequently, (153) and the dibromo
cornpound (154) undergo very much slower nucleophilic substitution to give 1,3-dirnethyl-
1,2,3-triazole 4-oxides (154a) (69ACS(B)2733, 71ACS(B)249). A similar mixture is obtained
frorn the 5-brorno derivative (155).
Me Me Me
N+ Ts- Br, Bt W TÇ base Bt W Ts-
f ll r II c · r II
/N INBS) /N Br /N
N N N
Me Me Me
(152) (153) (154)
+(152)
!OH
Me
[ + Ts-
Br N
N/
Me
(155)
R = H, Br
-0 +
Ì( NMe
r II
R /N
N
Me
(154a)
Chlorination of benzotriazole with aqua regia gives 4,5,6,7-tetrachlorobenzotriazole in
87% yield. The 1-methyl and 2-methyl derivatives have been obtained by alkylation and
chlorination of 1- and 2-methylbenzotriazole, respectively (SSJAS10S).
In contrast to various syntheses of 1,2,3-triazole nucleosides by cycloaddition of glycosyl
azides to substituted alkynes (see Section 4.11.5.2.2 and e.g. (70JHC1269)), the acid-catalyzed
fusion of rnethyl 1,2,3-triazole-4-carboxylate, 4-cyano-1,2,3-triazole and 4-nitro-1,2,3-
triazole (156) with an acylated ribofuranose provides the corresponding 4-substituted
2ß-D-ribofuranosyl-1,2,3-triazoles (157) along with the l-ß-D-isomers (158) (nJHC119s).
BZOH'W AC
OBz OB"
R
n
N, /N
N
BzO OBz
(157)
R N
//11
"-N/N
+ B,Otj
BzO OBz
(158)
R N
If II
(.__/N
N
H
(156)
R = COzMe, CN, NO z
R
n+
N N
'N/ '0-
Ph
(159)
Me,óB\
-
Rr.-c,X
II \1
N +N
'N/ '0-
Ph
(160)
R X
_1/1.
N N
'N/
Ph
(161)
R = H, Me
X = Cl, Br, OMe, SMe
R
n
N NOMe
'N/+
Ph BF;
(162)
x-
---+
X
R,r4-H
N, /NOMe
N
Ph
-H.
-OMe
R X
, \
N'N'N
Ph
(163)
1,2,3- Triazoles and their Benzo Derivatives
701
2-Aryltriazole l-oxides (159), readily availabe by various procedures (cf. Section 4.11.5),
undergo both electrophilic and nucleophilic substitution, being activated at C-5. The N-
oxides can be selectively halogenated and, in turn, the halogen can be replaced by strong
nuc1eophiles giving (160). On subsequent deoxygenation, the N-oxides yield halogeno-,
methylthio- and rnethoxy-triazoles (161) (81JCS(Pl)503). Methylation of the N-oxides with
trimethyloxonium tetrafluoroborate produces N-rnethoxytriazolium salts (162) in which
H-5 can be replaced by weak nucleophiles, e.g. fluoride ions and nurnerous other sub-
stitutents (to give 163) (81JCS(Pl)503).
Diazonium salts (165), derived from 4- or 5-aminotriazoles (164), undergo ready displace-
rnent of the nitrogen like other aromatic diazonium salts. Thus, 5-diazo-1,2,3-triazole-4-
carboxamide is rapidly converted into the corresponding iodide (166) (66JMC733).
N J CONH2
II II
N 'NH
, 2
N
H
(164)
HONO
N ) " CONH2
I . .
. .
N . '" N 2 +
N
H
(165)
1-
---..
N J CONH2
II
N, I
N
H
(166)
4.11.4.1.4 Reactions with cyclic transition states
(i) Cycloaddition reactions of heterocyclic ylides and mesoionic compounds containing a
1,2,3-triazole nucleus
By rneans of l H NMR studies Petersen and Heitzer have shown that upon oxidation of
2,3-butanedionebis(benzoylhydrazone) (168) the tetrazine (167) was not formed (OOCB644,
09CB659). Instead, an ylidic anhydro-2-benzoyl-1-benzoylimino-4,5-dimethyl-1,2,3-
triazolium salt (169) was obtained (70AG81, 70AG(E)67). The structure of (169) is in agreement
with its chemical properties. Some time earlier, anhydro-1,3-dimethyl-4-hydroxy-1,2,3-
triazolium hydroxide was obtained by rnethylation of 1-methyl-1,2,3-triazolin-5-one
(66ACS(B)1555, 69ACS(B)2733).
NR
N MeXNNHCOPh +/
N
Me( 'NCO H Mer: \
I 2 +-If- -. NR
Me:::,.., ....NC0 2 H Me"'-N'
N Me NNHCOPh
(167) (168)
I
NR NR NR
/ + /
Met Me(N Me (N\+
NR +---+ Me I _:NR +---+
Me "'- / Me R
N N N
(169)
e
X N
-0 N
Me
(170) X = H, Br
Cyclization (64CRV129) of ethyl N-methyl-N-phenylazoaminoacetate (171) with thionyl
chloride-pyridine readily gives anhydro-4-hydroxy-3-phenyl-l-methyl-1,2,3-triazolium
hydroxide (172) (70JOC3451) which reacts smoothly with DMAD, leading to the formation
of the pyrazole (174) via the trisazanorbornene (173). The intermediate cycloadduct (173)
easily aromatizes by loss of an aromatic isocyanate under the thermal reaction conditions
(70JOC3451). The polyaza adduct (175) obtained with ethyl azodicarboxylate is stable as
aromatization is irnpossible here. Both isocyanate and phenyl isothiocyanate gave 1: 1
cyc10adducts with (172), namely 1,2,6,7-tetraazabicyclo[2.2.1]heptanes (176) and (177)
(72JOC2049) .
702
1,2,3- Triazoles and their Benzo Derivatives
M .....CH2C02Et
e-N
I
N""NR
SOCI,-py
þ
+
I/ Me
-O N/N
R
(172)
(171)
Me
N
OyP"-NC0 2 Et
RN/ N ,r-fC0 2 Et
(175)
Me Me
NH N H
o / o Oy;/ s
MeN/N'NPh MeN/N'NPh
(176) (177)
Anhydro-1-phenylimino- 2,4,5-triphenyl-1 ,2,3-triazoliurn hydroxide (178), obtained by
oxidation of benzil bis-phenylhydrazone, affords 1: 1 cycloadducts with a wide variety of
alkynic and alkenic dipolarophiles, yielding pyrazolino[2,3-c]- and dihydropyrazolino[2,3-
c ]-[1,2,3]triazoles (179). The initial 1 : 1 cyc10adduct (180) obtained from (178) and carbon
disulfide undergoes therrnal fragrnentation to give 2,4,5-triphenyl-1,2,3-triazole (181)
(72T3987).
O,Me
III /""
to,M;./l4+2]
(172)
'NCO 4+2]
II ,_. "-.
EtO,CN
Me
N
Oy;/l--.. CO 2 Me
./N..J/
RN C0 2 Me
(173)
Me0 2 C O C0 2 Me
-RNCO 1/
Þ I ß
N
Me
(174)
ÑPh
/
N
Ph f \+
Phl. qNPh
N
CO,R C0 2 R
R02C f NPh
Ph
\
Ph ,...NPh
N
(179)
(178) s
\ cs, Si\NPh
Ph N
Ph N"' Ph
(180)
---+
N
Ph C \
. NPh +S+PhNCS
Ph N
(181)
4.11.4.2 Dihydro Compounds (å 2 -1,2,3-Triazolines)
4.11.4.2.1 Stereochemical aspects
Stereochemical interest has naturally concentrated on the .:1 2 -1,2,3-triazolines (review:
B-77SH(1)1l7), especially on the potential asymmetry at C-4 and C-5 and the orientation of
the R-N-N=N group with respect to it.
.:1 2 -1,2,3- Triazolines, e.g. (181a), are usually formed by 1,3-dipolar cyc1oaddition of azides
to alkenes (cf. 63AG604, 742, 63AG(E)565, 633, 68AG329. 68AG(E)321). The addition always occurs
cis and is usually regiospecific. Norbornene condenses with azides to form only the exo
H R 1
/f &...--J,."'\'"
R H
ArN,þ
R H
H""'H""'RI
ArN, 9N
N
(18la)
N
Ar
(181b)
1,2,3-Triazoles and their Benzo Derivatives
703
adduct (181b) (35LA(515)185, 65CB3992, 65JA306, 66CC352). Cycloaddition of cis- and trans-
enol ethers produces cis- and trans-substituted A 2 -1,2,3-triazolines, respectively, with high
stereospecificity (65CB1l53). .
From examination of the lH NMR spectra of 5-alkoxy- and 5-hydroxy-A 2 -1,2,3-triazo-
lines, an envelope conformation of the molecule was deduced with the 5-substituent being
in a pseudoaxial position at the flap and the 1-substituent being pseudo equatorial. This
preferred conformation can originate a type of anomeric effect (74ACS(B)42S). 5-Amino-1-(p-
nitrophenyl)-A 2 -1 ,2,3-triazolines have also been found to prefer the envelope conformation
(74ACS(B)425).
4.11.4.2.2. Arornatizatlon reactions (dehydrogenation of , /-1,2,3-triazo1ines)
The arornatization of triazolines can take place either by rearrangement reactions, by
direct oxidation or by an elimination reaction. A recent review discusses this topic
(78BSF(2)485). From the numerous reactions sorne illustrative examples are described below.
A 2 -1,2,3-Triazolines (182) can be srnoothly converted into the corresponding 1,2,3-
triazoles (183) with the aid of potassium permanganate (nJHC717, 66CB475). This oxidation
to a heteroaromatic system can be successfully performed with KMn04 using a two-phase
systern as well as a phase-transfer catalyst (78S694). In some cases, suitably substituted
open-chain diazo compounds can be cyclized directly to 1,2,3-triazoles by means of oxidizing
agents (0 2 , KMn04) (7 TL2823, 71BSF3642). Spirotriazolines like (184) isomerize spon-
taneously with cleavage of the spirocydopropane ring to afford (185) (75JOC2042, 75JOC2045,
75DIS(B)(36)1712).
-ARt R"
MeO"t N Meo"T r=0 R1
\\ KMn04 þ H 2 C -.
/N /N Ph N C0 2 R 3
N N PhN, 9 N C0 2 R 3
R R 'N 9 N
(182) (183 ) (184) (185)
Another example of the aromatization process is represented by the rearrangernent of
the indolospirotriazoline (186) upon treatment with a basic catalyst. The triazole (187) is
formed with cleavage of one u-bond (70LA(734)70). A 2 -1,2,3-Triazolines substituted in the
5-position with an arnino, alkoxy or hydroxy group and possessing at least one 4-H as in
compound (188) are capable of condensation reactions, eliminating RNH 2 , ROH or H 2 0
(-+ 189), when they are heated in the presence of acid or base (review: 78BSF(2)485). The
configurations at C-4 and C-5 playa decisive role in the facility of the elimination. Thus,
the elimination of an amine is much faster if the amino substituent at C-5 is in a trans
position with respect to H-4. Thus, the triazole (191) is obtained smoothly by heating of
the trans-substituted triazoline (190), while the corresponding cis-substituted isomer (192)
is stable under these conditions (73PC41l00).
CQc1 KOH (J(Xj
þ 'Nð
o EtOH
Me
I I
N0 2 N0 2
(186) (187)
Y H R 2 N Ph R 2 N H
Rn R -YH Rr=f PhIIH"IIIH P h h Ph '''''H'''''Ph A
þ ----/i---Þ
.....N, 9N d. H+ /OH- RN, 9N ArN, 9N ArN, /-N ArN, 9N
R N N N N'" N
(188) (189) (190) (191) (192)
Y = OR, NHR, OH
Triazolines which are formed as intermediates after the 1,3-dipolar cycloaddition of
azides to enamines cannot be isolated but directly undergo elimination to give triazoles.
704
1,2,3- Triazoles and their Benzo Derivatives
Enamines with ß-substituents such as an ester, ketone, cyano, nitro or sulfone group result
in compounds (193), which, possessing an a- hydrogen atom, behave in an analogous fashion
to give (194) (65CB1138, 65CB2715, 610849, 6201040, 65G1220, 67G304, 68G949).
[ R2NHC-CHY ] HC=CY
I \ _ R 2 NH + I \
RN, N RN, N Y=C0 2 R,COR,CN,N0 2 ,S02
N N
(193) (194)
q>
PhNH Ar
(195)
IC0 2 H)2 (r} + PhNH 2
Ar
(196)
Bicyc1ic triazolines can be readily aromatized, e.g. in the presence of oxalic acid compound
(195) gives (196) (65MI41l00).
One example has been reported where, after 1,3-dipolar cycloaddition of phenyl azide
to a heterocyclic ß-enaminoester to give compound (197) (cf. B-80MI41l03), no ß-hydrogen
atom is present for a regular elimination of ammonia. In this case a different arornatization
reaction is observed involving an elimination-ring cleavage process resulting in the formation
of the l,2,3-triazole carbonate (198) (71CB35IO). In some special cases HN0 2 can also be
eliminated from an initiall : 1 cycloadduct to form, for example, the triazole (199) (67CC918,
66JPR(305)199). Furthermore, l,2,3-triazoles are formed by the elimination of triphenylphos-
phine oxide from an appropriately substituted triazoline. This process is illustrated by the
conversion of (200) into (201), a sequence reminiscent of the Wittig reaction. (71T845,
71T5623, 69T5421, 69BSB14?).
[i}] ROC02 N
II
H 2 N /N
N
H 2 N f Ph
Ph
(197) (198)
( H R ] O-'PPh']
Rn N02 HN0 2 , Rf\R R1nR2 -Ph 3 PO R 1 R 2
!\
RN'N N RN, N RN, N RN, -::N
N N N
(199) (200) (201)
4.11.4.2.3. Ring fission of 11 2 -1,2,3-triazolines
While the photolysis and thermolysis of 1,2,3-triazoles are of considerable interest with
regard to mechanistic investigations and in the search for highly reactive intermediates, the
elimination of nitrogen from suitable triazolines provides an excellent synthetic entry to
aziridines (cf. Section 4.11.6). Several substantial reviews have been published on this topic
(B-76PH403, B-70MI41101, B-67MI41101).
Triazolines (202) obtained by 1,3-dipolar cycloaddition reactions lose nitrogen on pyroly-
sis or photolysis to give aziridines (203) in high yields. The isomeric imines (204) are also
formed (68T2757). A higher ratio of aziridines (203) to imines (204) results from thermal
reaction conditions than from the corresponding photolytic reaction (68T2757).
e N
II
Bu" /N
N
Ar
(202) (203) (204)
The decomposition of the diazo compounds (207) is 45 times slower than that of the
corresponding 1,2,3-triazoline (205). The exclusive generation of the enamino ester (209)
" Me
_Bu\? + >=NAr
N
Ar Bu"
1,2,3-Triazoles and their Benzo Derivatives
705
seems to exclude an equilibrium between (205) and (207) (66CB47S). However, the corres-
ponding cyano corn pound shows in the presence of a tertiary amine an equilibrium between
the triazoline and the diazo compound (66CB47S).
Meo 2 C C N
II
/N
N
Ph
(205)
1
Me0 2 C Me0 2 C Meo 2 c )
" + .. 100'C " I
C=N=N c: --.
/ .. -N 2 /
PhNHCH 2 PhNHCH 2 PhHN
(207) (208) (209)
Upon pyrolysis (315 oc) bicyclic triazolines like (210) afford various mixtures of imines
(211) and bicyclic aziridines (212), depending on the size of the condensed ring (see Table
19) (68T27S7). The aziridines formed can be considered as potential azomethine ylides, and
can also dimerize under the conditions of thermolysis (79BSF(2)633). The preparative aspect
of these extrusion reactions is discussed in Section 4.11.6.
8S'C
-N 2
Me0 2 C\7
N
Ph
(206)
Table 19 Pyrolysis of Bicyclic 1,2,3- Triazoles (68T27S7)
(C I (C + (C NAr
'-=(N/N NAr'
Ar
(210)
n
(211) (212)
(211) (%) (212) (%)
79 21
46 54
45 55
3
5
6
Treatment of 2-phenyItriazole-4-carboxylic acid (213) with barium hydroxide at elevated
temperatures gives two ring-cleavage products in a concerted process (66TL4387).
J: T'\
NPh
"- r-..
C N H..,...,...
or fo \QFH
(213)
Ba(OH)2 I
ð.
PhNHN=CHCN + cO 2 + OH-
4.11.5 SYNTHESIS
4.11.5.1 General Remarks
An extensive number of 1,2,3-triazoles and benzotriazoles are known today and numerous
syntheses have been reported. Most of the classical methods are well documented in excellent
reviews which describe the individual syntheses from different viewpoints and emphasize
different concepts. These reviews may be conveniently divided according to: (a) those
emphasizing different syntheses (74AHC(16)33, B-61MI41100, B-71MI411 04) and (b) those aiming
at different substitution products (50CRV(46)1, 80HC(39)1). As most of the major reaction
pathways involve azides, several reviews are devoted especially to aspects of forming
1,2,3-triazoles in this way (69CRV345, B-71MI41104).
In the following discussion the methods of ring formation are divided into a number of
principal synthetic routes according to Scheme 7.
The classical and well-documented pathways are described in more general terms, and
more emphasis is given to recent methods.
706
1,2,3- Triazoles and their Benzo Derivatives
Formation of one bond (N 1 ___N z )
4 3
C-N
I \
zC, .Nz
N'
1
Formation of two bonds (CsmN\ C 4 '_'N 3 )
4 3
CuN
I \
sC" .....NZ
N
1
(C 4 ___C S , N1u_N Z )
4 3
C-N
: \
sC, .NZ
N'
1
Scheme 7
4.11.5.2 Triazoles from Non-heterocyclic Compounds
4.11.5.2.1 Formation of one bond
In an intramolecular cyc1ization of adjacent groups 1-aminotriazoles (213b) and their
derivatives are prepared from bis-hydrazones and from substituted bis-hydrazones of
a-diketones in an oxidation step involving the formation of one bond. The bis-hydrazones
(213a) are more conveniently obtained frorn a-bromoketones than from a-diketones
(67TL3295, 71JPR882, 71ZC179). The oxidation reaction is carried out by means of Mn02 or
HgO, and the bis-hydrazone (213a) although being unsymmetrical, gave the 1-arnino-4-
phenyl-l,2,3-triazole (213b) as the only reaction product. The mechanism has been eluci-
dated ( ls N labelling studies) and the structure has been confirmed by X-ray analysis (71ZC179).
Overoxidation of the bis-hydrazones yielding alkyne compounds can be avoided by ernploy-
ing toluene-p-sulfonylhydrazones (52JCS4735, 68LA(711)46, 68LA(711)65).
O (OCHzBr '\ 1 ......... C\ I
:::::,... :::::,... NNHz :::::,...
" N
I \\
:::,.... ....N
H NNH 2 H
2
(213a) (213b)
Starting with the unsymmetrical bis-toluene-p-sulfonylhydrazone (214) both possible
triazoles (2l5a) and (21Sb) have been obtained (73JCStP1)555). Bis-semicarbazides (216)
react smoothly with lead tetraacetate to produce ureido-l,2,3-triazoles (217) (76S482).
Mercury(Il) acetate has also been used as the oxidizing agent (78JCS(Pl)881). The dianion
of a,ß- bistosylhydrazones (218) undergoes photochemical cyclization to give in excellent
yield sulfonamido-l ,2,3-triazoles (219) (69JOC1746).
MeXNNHTs
Ph NNHTs
(214)
H+
MefiN
Ph(_
N
NHTs
(21Sa)
Ph /[ N
+ I \\
Me ....N
N
NHTs
(21Sb)
RIXNNHCONH2
R 2 NNHCONH z
(216)
Pb{OAcl. ,
R 1 R Z
F\
N, "..NNHCONH 2
N
(217)
R NNTs-
RXNNTS-
(218)
hv
----+
RFf
N"" ....NNHTs
j-.l
(219)
1,2,3-Triazoles and 1H-triazoles (221) can be readily obtained by ring closure of a-
diazoimines (220), which may be prepared in situ frorn diazoketones and arnines (67CCC2155,
70T1393. 70LA(734)56). This very general reaction may also be applied to a-diazoarnides
(67CJCl727), which on ring closure with PCl s afford a 5-chlorotriazole (223) via an interrnedi-
ate imidoyl chloride (222) (67ACS(B)633).
1,2,3- Triazoles and their Benzo Derivatives
70'1
H
C=NPh
I
PhCOC
N 2
(220)
N
--+ PhCO(
N
(221) Ph
Me0 2 C C N
II II
CI I N
N/
CH 2 Ph
(222) (223)
Another synthetic pathway recently used is the cyclization of linear triazenes, like (224),
which in aprotic media with Lewis base catalysis yield 5-amino-l-aryl-l,2,3-triazoles (225).
However, in protic media Dimroth rearrangement affords the isomeric 5-(arylamino)-1,2,3-
triazoles (226) (70JOC2215, 81JOC856). The 2-tetrazene (227) gives methyl 1-benzyl-1,2,3-
triazolecarboxylate (228) by photochemically induced homolysis of a single N -N bond
(81TL227).
CH 2 Ph
I
CONH
I
Me02CC
N 2
Cl
I
C=NCH 2 Ph
I
Me0 2 CC,>>
N 2
PhN=NNHCH 2 CN --+
---+
H
N
PhNHL r
N
(224)
PhN/ N
H 2 N W
(225)
(226)
E = C0 2 Me
Bz = CH 2 Ph
E E E
l f r;
N-N=N-N N
I I Bz
Bz Bz
(227)
(228)
In an earlier publication the conversion of the 1,2-bis(benzeneazo)ethylene (229) into
the triazole derivative (230) by treatment with mild acid was described (62JOC4300).
PhJCN=N Ph Ph Ph
"=l 1\
í\ N"" /NNHCPh J
Ph N=NCPh J N
(229) (230)
H 2 C=NMe
\
H 2 C fIN
N
I
Ar
(231)
--+
G Me CIO:;
-:.-N
N
Ar
(232)
Azaallyl cations (231), formed from arenediazonium salts and 2-methylaminoethanol,
cyclize to the triazenium salts (232), a new class of heterocyclic cation (79CB445).
The cyclization of nitrogen derivatives of a,ß-dicarbonyl compounds represents a promis-
ing approach to substituted 2H-l,2,3-triazoles. Thus, glyoxal phenylosazone (233) is
converted by oxidation into the bis(benzeneazo)ethylene (234) which is smoothly cyclized
to (235) by the action of iron (III) chloride in dilute acid (26CB1742, 48JOC815). For further
examples of this synthetic approach, see (30G866, 46JA1799). Furthermore, manganese dioxide
and nickel dioxide have been found to give 1H-triazoles in poor-to-fair yields (67JOC2252,
75T1171). Activated a-dicarbonyl derivatives are converted into N-oxides of 2-phenyl-4-
hydroxy- (236) and 2,4,5-triphenyl-2H-1,2,3-triazoles (237) (60JOC313, 745198, 80AJC2447).
More recently, the oxidative ring closure has been effected with N-iodosuccinimide (NIS)
(80H(14) 1279).
5-Amino- and 5-hydroxy-4H-triazoles are formed by the reduction of a-azidonitriles
and esters, e.g. (238) (239) (58M557, 562, 588, 597).
708
1,2,3-Triazoles and their Benzo Derivatives
(NNHPh
NNHPh
(233)
N=NPh
(N=NPh
(234)
FeCI, Þ n
dilute N, /N
HCI N
Ph
(235)
OZN X NNHAr
7" HOAc
------+
::,.... H,O
H NOH
+ n OH
N, /N
_ 0 / N
Ph
(236)
Ph X NNHR
7" HgO
--
::,....
Ph NOH
Phr.-,lh
1/ \\
N, /N+
N " 0 -
Ph
(237)
Ph 2 CCN
I
N 3
Ph z N
/\\
__/N
N
(239)
(238)
4.11.5.2.2. Formation of two bonds
The most important syntheses in this group consist of the thermal1,3-dipolar cydoaddition
(6SCB4014. 67CB2494) of azides to alkynes, which is, of course, one of the most versatile
routes to lH-1,2,3-triazoles. A wide range of substituents can be incorporated into the
alkyne and azide components.
The parent compound, 1,2,3-triazole, has been obtained by several direct and indirect
synthetic approaches: the direct addition of hydrazoic acid to alkynes with electron-
withdrawing groups is the straightforward but also somewhat dangerous procedure
(S9ACS(B)888, 64MI41100); in the sarne way sodiurn azide can be used cautiously in the presence
of an acid. Alternatively, the addition of trimethylsilyl azide to the carbon-carbon triple
bond of the alkyne and subsequent removal of the silyl group provides a much safer
procedure (6SAG414. 6SAG(E)417). Furthermore, 1H-1,2,3-triazoles (240) can be produced
in a much safer way by cycloaddition of benzyl azide to DMAD and subsequent thermolysis
and hydrogenolysis of the benzyl group (S6JOC190. 6SLA(688)20S).
-co, þ r
N
H
/ (240)
/ H, S0 4
HC=CH + NaN J
Many of the different cyc1oadditions of azides to triple bonds have been reviewed
extensively (SOCRV(46)1. B-61MI41 100. B-71MI41104. 74AHC(16)33. 80HC(39)1). Some representa-
tive examples of triazole formation by cydoaddition of azides to triple bonds are given in
Table 20.
The addition of azides to terminal alkyl- or aryl-acetylenes often gives a good yield of
1,4-disubstituted products showing a high degree of regiospecificity (S2HCA167).
Intramolecular 1,3-dipolar cydoadditions lead to condensed triazolines (78ACS(B)683) and
an excellent review has been published on this subject (76AG131. 76AG(E)123).
TsN, [ : J - N + H,O.
' Ph(Na
N/
Ts
(241)
R 1 R 2
150-170 0 C F\
R 1 C=CR 2 + Me3SiN3 6-20h þ N /NSiMc3
N
(243)
HC=CCOzH +HN 3 ----+
HOZC 'F N
\\
/N
N
H
PhC=CNa
TsN J .
t'!a+ N
Phr \
",/
Ts
N 3 N
Ph}; \
N/
Ts
(242)
1,2,3-Triazoles and their Benzo Derivatives
709
Furthermore, cycloaddition reactions have been carried out between mðtal acetylides
and azides leading firstly to triazole triazene salts (241). On hydrolysis the corresponding
triazole azide (242) is obtained (S8JOCIOS1). The addition of trimethylsilyl azide to alkynes
occurs at higher temperatures, but due to the considerable thermal stability of the azide,
good yields of triazoles (243) can be achieved (80MI41101).
Similarly, silylated alkynes react with HN 3 to afford TMS-substituted 1,2,3-triazoles
(79CB2829). 1,2,3-Triazoles with alkenic side chains can also be synthesized from 1,3-enyne
hydrocarbons and their silane derivatives (78Z0870S).
Alkynes with a phosphonium substituent (244) cyc1ize with NaN 3 in DMF to (245), which
cleaves upon saponification to give 4-phenyl-1,2,3-triazole (246) (73JOC2708). Tropylium
azide can be considered in this reaction as a kind of protecting group (247) because of its
easy removal on hydrolysis to give (248) (6SJOC638). Cyanoacetylene gives 5-cyano-1,2,3-
triazole and a 2: 1 adduct with alumina azide (69JOC1l41).
Table 20 Triazoles from Azides and Acetylenes
Azide Acetylene Product Ref.
EF\E
RN 3 MeOzCC==:CCOzMe ßR 30JPR(125)498
HC==:CCOzH HOz C n 59ACS(B)888
HN 3 NyH
TsN 3 PhC==:CH P hF\ 65CB4014
N ßTs
N
PhC==:CH P h n 70CB1908
NaN 3 N .-NH
n h + P hf\
N 3 CO z Et PhC==:CH NyCOzEt N /NCOzEt 65CB2985
N 7IT5623
R R' R R'
N 3 C==:N RC==:CR' f\ 'C-C/ 67JA4760
NCN, ",N -r "-
N N N z
I
CN
0 P hrl h
PhC==:CPh N )"'O 69TL2589
N/- N 3 7lT5121
71JOC446
(EtOhC Hj\C H(OEt) 2
RN 3 (EtO)zCHC==:CCH(OEth N /NR 74CB715
N
HOCH zj\C HzOH
PhN 3 HOCHzC==:CCHzOH N ßPh 74CB715
N
n-F 13 C 6Ff h
PhN 3 n-C 6 F 13 C==:CPh N /NPh 75JOC81O
N
710
1,2,3- Triazoles and their Benzo Derivatives
PhC=CPPh 3 X-
NaN,
DMF
...
Ph PPh3
N::....:N
N....
(245)
NaOH
---
P h
N ....NH
N
(246)
(244)
---. E;=\E -0 Ft=\,E
N ....N \ Et,O N ....NH
N '"- N
(247) (248)
The cycloaddition of phenyl azide to the alkynic Grignard (249) provides an interesting
variant of this approach (67Z0R968), as the intermediate can in turn be carboxylated with
CO 2 to (250). Alkadiynes can serve in a successful approach to control mono- or di-addition
(S8CB1841). The products are (251) and (252).
O E
\ ....,;::; N 3 +
BrM gr={ h
PhC=MgBr + PhN 3 ---. N ....NPh
N
HOz Cr={ h
N ....NPh
N
(250)
(249)
MezCC=CC=CCMez
I I
OH OH
+0
NO z
---.
N...., NHOMezC
I, N
N N....
V CMezOH Ò
NO z I
(251) (252) NO z
2- Trialkyl-silicon- (253) and -tin-1,2,3-triazoles (254) are obtained readily frorn
organometallic azides and alkynes. These adducts are hydrolyzed smoothly in alrnost
quantitative yield to give (255) (66CB2512. 72JOM(44)1l7) (cf acylation via 2- TMS deriva-
tives, Section 4.11.4.5).
HOMez C(=f =cCMezOH
N ....N l)-
N "':::
I NO z
....-;:;
+
MO
RC=CR '
BU
R R 1
n
N" ....N
N
SiMe 3
(253)
....Ý
R R '
F\
N ....NH
N
(255)
R R 1
n
N'N....N
I
SnBu3
(254)
The cycloaddition of azides to alkynes is a generally applicable route to ò? -1,2,3-
triazolines, and most triazolines have been obtained by this rnethod. For brief reviews, see
(S4CRV41. B-64MI41l01, B-71MI141l04, 78BSF(2)48S).
In comparison with alkynes, cycloaddition of azides to alkenes proceeds at a much slower
rate. Ring strain and substitution of the double bond with electron-withdrawing groups
have been found to lead to enhancement of the cycloaddition rate (68T349. 2757). Double
bonds which are part of strained bicyclic systems are particularly reactive. Thus, the addition
of phenyl azide to norbornene leads in a very fast reaction to the triazoline (256), the
1,2,3-Triazoles and their Benzo Derivatives
711
addition occuring at the less hindered exo side (35LA(515)185). The stereospecificity of this
reaction has been established (65CB1153, 66JA4759, 68JA988) and mechanistic studies with
norbornene and substituted phenyl azides show that the reaction occurs in a concerted
manner (65JA306, 65CB3992). The direction of addition is controlled by electronic rather than
by steric factors. For a discussion of the regioselectivity of the addition of azides to
a,ß-unsaturated carbonyl compounds or nitriles see (66CB475).
)2) + PhN, -"
N/
(256) Ph
Me Ph
Ph Me + PhN 3 H --l =\" H
\=./ NyNPh
Ph
+PhN 3
Me
I;! h
Me í= \- H
N /NPh
N
Applying the frontier orbital method to the example of phenyl azide reacting with
electron-rich and conjugated dipolarophiles shows that the phenyl group is more effective
in raising the energy of the HOMO than in lowering the energy of the LUMO. From this
follows the orientation shown in (257). Phenyl azide reacting with electron-deficient alkenes
consequently shows the opposite regioselectivity giving 258); for literature on this topic
see (70MI41100, 75ACR361, B-76MI41104).
C?--Q
N' _
Ph ß ----------- x, C
LUMO HOMO
----.
N J
II ..
N..... X,C
N
Ph
(257)
, -__ z
-- 6
..........
N+
B--------
Ph
----. J Z
N.....
N
Ph
(258)
HOMO LUMO
More recently, the reactivity and regioselectivity of 1-azidoadamantane with various
alkenic and alkynic dipolarophiles have been described (8IJOC1800).
Azides with electron-withdrawing substituents add to allene (259) to produce triazoline
(260) (68JA2131). The cyc1oaddition of phenyl azide to cyanoallene affords 4-cyano-5-
methyl-1-phenyltriazole (64LA(678)9S).
N 3 MezC Me2
OzN O NO z / \ NO
I N N z
MezC=C=CMez + ----. y
NO z OzNVNO z
(259) (260)
Tetrachlorocyclopropene reacts with trimethylsilyl azide to yield a bicyclic triazole (261)
which rearranges to 4,5,6-trichloro-1,2,3-triazine (262) (79CB1529, 81CB1546).
Intramolecular cyc1oaddition of (263) in the presence of potassium and Alz0 3 leads to
4-phenyl-1,2,3-triazole (70CB1908). For the synthesis of 1-aryl-l,2,3-triazoles from aryl
azides and sodium ethoxide see (68JCS(C)1329).
Clz CI
Clz Mc 3 SiN 3þ CI A CI ----. Clrn C1 Ph KI AI 2 0 3 ) P h n
CI CI N ßSiMe3 N ....N >=CH z N ?H
N N 3
(261 ) (262) (263)
The base-catalyzed condensation of azides with activated methylene compounds is a
well-established route to 1H- triazoles. This is a regiospecific method ideally suited for the
synthesis of triazoles with a 5-amino or -hydroxy substituent, and an aryl or carbonyl
function at C-4. The general scheme is shown in Scheme 8. The stepwise character of the
reaction is best revealed by the anomerism of glycosyl azides during their reaction wÌth
712
1,2,3- Triazoles and their Benzo Derivatives
activated rnethylene compounds (72JA2530). The proposed intermediates have been detected
in solution or isolated while reacting azides with aliphatic ketones (68TL3805). Table 21
shows some typical examples.
R1CHCOR Z + N=N r ÑR3 ----+
o
:Y-R Z
N.::::,.
N-NR 3
----+
R 1 0-
Hf-tR Z
N /NR 3
N
Rl R Z
----+ F\
N /NR3
N
Scheme 8
With malonic esters and amides substituted at the central carbon atom, triazole formation
is accompanied by decarboxylation and 4-alkyl- or 4-aryl-5-hydroxytriazoles are isolated
(69ACS(B)1091). The 4-methoxybenzyl group has recently been found to be a versatile
N-protecting group for the synthesis of N-substituted 1,2,3-triazoles (82JCS(PI)627).
4-Phenyltriazole (265) is isolated in moderate yield from the reaction of aldehydes like
(264) and tosyl azide (68CB3734, 69CB2216). The reaction of azides with active rnethylene
corn pounds under basic conditions also represents a very widely used approach to the
versatile 1,2,3-triazole enamino esters and derivatives such as (266) (71T5873, B-80MI41103).
The first exarnple was described by Dimroth and Michaelis (27LA(459)39), and the reaction
has been found to proceed in a highly regiospecific manner. These compounds undergo in
part the Dimroth rearrangement (ct. Section 4.11.4.4.). Of special interest for the ring-chain
tautomerism (triazole-diazoamidine equilibrium (267a) (267b); cf. Section 4.11.4.1) is
the cycloaddition reaction of ynamines and sulfonyl azides (70TL2823, 70JOC3444).
o
II
o RzP 0-
" Phn H
RzPCHCHO + TsN3 ----+ N NT
I /' s
Ph N
(264)
----+
P ?\
N /NH
N
NC
" 1
CH 2 + R N 3
/
R
;C R N
NaOR r II
H2 /N
N
R 1
(265)
(266)
R N Etz 7 Etz
R1C=CNEt z + R 2 S0 2 N 3 ----+ / \ z N 2 C-C=NS0 2 R z
N /NS0 2 R I
N R1
(267a) (267b)
Electron-rich C=C double bonds have been observed to react very readily with azides
to afford 6. 2 -triazolines. With open-chain and cyclic enol ethers, triazolines are forrned in
regiospecific cycloadditions and nearly always in high yield (63AG742, 63AG(E)633).
Thus, with 2-ethoxy-1-propene and 4-nitrophenyl azide the 6. 2 -1,2,3-triazoline (268) is
formed in quantitative yield; at 150 0 C ethanol is eliminated to give in quantitative yield
the corresponding 1,2,3-triazole (269) (65CBl138). Cyclic enol ethers, like 2,3-dihydrofuran
or 3,4-dihydro-2H-pyran, afford similar adducts (270); however, upon heating nitrogen is
evolved to give the iminolactones (271) (65CB1138). For a discussion of the steric course
and stereoselectivity of the azide additions to enol ethers, see (65CBl153).
02N O N3 + Me>=CH 2
- EtO
0 N o- N....-N N
50'C 2 _ \--I
Me OEt
(268)
150'C
---+
02N o- N/N'::,.N
- '=I
Me
(269)
fi(CH 2 ).
RN 3 + (-)
o
X (CH2)'
N,7 >
N 0
R
(270)
Et,C=CHR+PhN, [R l) :t]
r(CH 2 ).
RN O)
(271)
Rf\O Et
N /NPh
1,2,3-Triazoles and their Benzo Derivatives 713
Table 21 Some Examples of Addition of Azides to Active Methylene Compounds
Actíve methylene
Azide compound Tríazole Ref.
Ph N
PhCH z N 3 PhCHzCN ![ II 59JOC134,
HzN /N
N 71JCS(C)2156
CHzPh
Ph N
PhN 3 PCHzCN [II 57JOC654,
HzN /N
N 570S(37)26
Ph
HzNCtN
V II
PhN 3 NCCHzCONH z H N N 60CB2001
2 N/
Ph
NC N
TsN 3 N=:CCHzC=:N HN[ 73BSF3442
Ts N
H
NC N
p-ClC 6 H 4 N 3 N=:CCHzC=:N [II 60CB2001
HzN /N
N
C 6 H 4 CI-p
PhCH z N 3 El0 z CCH z CO z Et EtOzt 1 56JA5832
HO /N
N
CHzPh
HOzt N
V II
ArN 3 MeCOCHzCOzEt Me N 61RTC1348
N/
Ar
HOzt N
V II
PhCH z N 3 PhCOCHzCOzEt Ph N 57CB382
N/
CHzPh
HOzt N
But V II
RCOCHzCOzEt R /N 7OJHC361
;d N
N 3
Bu '
N3 O NOz Ph N Ph N
PhCHzCN HzN[ 'N - HN[ I'N 27LA(459)39,
N I N/ 57JOC654, 59JOC134
p-NO z H 4 C 6 p-NO z H 4 C" H
0 0
0 " 1/
" (EtOht N (EtO)zÖ r
ArN 3 (EtOhPCHzCN V II + V ï 73LA578
HzN /N HzN /N
N 0
Ar
714
1,2,3- Triazoles and their Benzo Derivatives
An alternative approach is the cycloaddition of bis enol ethers (i.e. ketcne acetals), but
varying yields are obtained (600413, 63090). With temperature control and in the presence
of an excess of the ketene acetal, the intermediate triazoline can be obtained (680681.
76JHC20S). In this context it should be mentioned that benzyl azide was found to add even
to acetone with its rather small enol content to forrn at least 1-benzyl-5-methyl-1H-1,2,3-
triazole (273) and a trisubstituted product (274). The primary adduct (272) could be isolated
(73ACS(8)1987). For further examples, see (67JOC2022, 7STL2807).
OH
rl- Me ;=fi e . ì=fe
N /NCH 2 Ph -> N"'..,,,.NCH 2 Ph -> N /NCH 2 Ph
N N N
(272) (273) (274)
Triazolines which result from the addition of aryl azides to enamines are generally
isolatable, and a considerable number of these adducts have been prepared by Fusco,
Bianchetti and coworkers (610849, 933, 6201040. 63CB802, 72JCS(Pl)619, 769); for reviews, see
(B-69MI41101, 78BSF(2)48S). On heating the reagents together for 1-2 hours triazolines are
formed with an amino function in the 5-position. In some cases aromatization takes place
in situ, but more usually it is effected by heating the primary adducts to give (276). Two
characteristic reactions are shown, resulting in (277) and (278) (6SMI41100, 670109). The
high degree of regiospecificity, e.g. the formation of (279), in these cycloadditions has been
demonstrated (S8LA(614)1, 64JA2213), and many different enamines have been employed
(65TL2039.6S01220).
PhCH 2 N 3 + >=0
NaOBu'
R 2 R 2
"11 1 "r
^ R 2 N . .ß
R 2 N R' R' 3
(275)
WOH
--
R 2 N
R' If ''N
tz. N/
R 3
(276)
Et MePr n N1 0 NO,
"=< )
NHPr n
Me
EMNHPr n
N /N D
N ï
....::::. N0 2
(277)
í\ N,.QNEI'
CH 2 =CHN 0 )
LJ
("0
H N
r4
N ".N
N VN Et 2
(278)
C)H
R'++R2
ArN, ;::-N
N
(279)
In addition, ketenirnines have been used successfully leading to 1,2,3-triazolines of the
type (280) (670289.670304). The enamines can be generated in situ from ketones (6901131,
nOMR(4)247) and a,ß-unsaturated aldehydes (72JCS<Pl)619, 769) leading to adducts of type
(281). A stereochemical study has been reported (72JCSlPl)997) which leads to the following
conclusions:
(i) kinetic control produces trans-triazolines,
(ii) high temperature or acid leads to a cis-trans products rnixture,
C:::J + A,N,
h
R 1 R 2
-.
R ' R 2
F'í
-> ArN, ;::-N
N
1,2,3-Triazoles and their Benzo Derivatives
715
R
/
N
Rrl 'R 1
NvN
N02
(281)
The enamine-azide 1,3-dipolar cyc1oaddition has been found to be thermally reversible,
e.g. (282) (283) (7SJHCSOS). 4H- Triazoles (284), formed from sodium azide and a-
chloroenamines bearing methoxycarbonyl and alkyl groups at the ß-position, give on
thermolysis aromatic triazoles (285) and/or 3-amino-2H-azirines (286). On photolysis only
azirines (286) are obtained (80CC940).
(iii) the substituent size plays only a minor role,
(iv) a triazoline isomerization is possible.
RH 2 C
,
C=NR 2
/
R 1
NJ O N02
)
R R
)==0 + 'NH +
H R/
N3
o
N0 2
Me
/
R 2 NCH=C
,
CN
+ PhN 3
(282)
)=<Cl
R t NR 3 2
R 1 NR 3 2
R 2 H
N /N
N
(284)
NaN, ,
R'
Rft NHR 2
N""N/NY')
VN0 2
(280)
-.
Me
NCN R 2
6 N /NPh
N
(283)
R 1 NR 3
n 2
N, N
í
\ (285)
R' N
PNR 3 2
R 2
(286)
Good yields of l-aryl-4-nitrotriazoles (288, 289) are obtained on cyc1oaddition of 1-
morpholino-2-nitroethylene (287) (review: 81T14S3) with aryl azides (66TL6043, 68G949). The
spiro cyc1oaddition product from (290) and phenyl azide isomerizes to the triazole (291)
(7SJOC204S).
02Nr
__/N
N
H
(289)
01
N, /H
c TsN, c=c
/ ,
H NO z
(287)
N
Y
[ Y J::;:J
(290)
02N C N
7 'N
N/
Ar
(288)
->
>- HN-CH 2
F\
PhN, N
N
(291)
Similarly, (heterocyclic) ß-enamino esters substituted with an electron donor as well as
with an electron acceptor group ('push-pull') show a decreased cycloaddition tendency
towards 1,3-dipoles such as azides; see (71CB3SlO) and Section 4.11.4.7.
716
1,2,3- Triazoles and their Benzo Derivatives
An example of an azide cycloaddition to an open-chain enarnino ester (292) has also
been reported giving (293) (76BSF202S). 4-Acyl-1,2,3-triazoles (249) have been obtained
in fair yield by the reaction of the phenyl azide with a- keto vinyl chlorides (SSZOB 1366).
R 0
" /A RN, "N-HC- -A R Å
NCH=C - / I \ . M
/" RN, hN RCOCH=CHCl + PhN 3 --+ N.::,. / NPh
R N" N
(292) (293) (294)
A = C0 2 R, COR, CN R = H, Me
a- Acylphosphorous ylides represent another versatile structural type which reacts with
azides to give 1,2,3-triazoles. In a typical procedure the phosphorus ylides (295) and the
azide are heated to 80 0 C or left at room temperature. The intermediate triazolines (296)
eliminate spontaneously the phosphine oxide to give (297) (66JOC1587, 69T5421, 71T845,
71T5623, 72JOC3213). For a more detailed discussion of this reaction see (B-79MI41104).
Ph); R -I- R R
X R'NJ, P 3P-f-- -PhJPO, [
O-/--"T/N R' /N
-0 R 1 R' , 2
(295) (296) (297)
Another synthesis of 1,2,3-triazoles such as (299), through phosphorus-containing inter-
mediates (298), has been reported (73LAS78). Phosphorylated acetylenes (300) give 1,2,3-
triazoles containing phosphorus substituents as in (301) (73Z0B1683). Similar results have
been obtained from a- keto phosphorus ylides and ethyl azidoformate leading to a 2-
ethoxycarbonyl-2H-1,2,3-triazole (303) via the isolable 1H-isomer (302) (69TL63, 71T5623).
This method has been applied to the synthesis of 1,2,3-triazole nucleosides, e.g. (304), in
an elegant manner (80LA1455, 81CB316S).
o
II
o (EtOhP o-
Il ArN H..::.L-.!-Ph r=\P h
PhCOCH 2 P(OEt)2 / \ --+ / \ R 2 POC=CMe
N.::,. /N Ar N /NAr
N N
(298) (299) (300)
[ h3P-I- 0- ] [ ]
HHR r=\R
Ph.1P=CHCOR + Et02 C NJ --+ --+ I \
N /NC02Et N N"NC02Et
o
II
R 2 Pr=\M e
/ \
N"" /NPh
N
(301)
--+
R
n
N, /N
N
C0 2 Et
(303)
(302)
N R'
N 11 J R2
'N
PhC(O)O
PhClO)O OCOPh
(304)
Recently, the cycloaddition of cyanoazide to a-ketophosphorus ylides has been described
yielding (305), which upon thermolysis afforded reactive a- cyanimino-carbenes (306)
(81AGl18,81AG(E)113).
PhC(OJO Q O N3
R,P=CR'COR'
,
PhC(OJo OCOPh
Me 0
X NCN
Ph PPh3
MrNCN
Ph(.
N""
/CN
MeyN
Ph
_/CN
Me N
PhX
(306)
(305)
1,2,3-Triazoles and their Benzo Derivatives
717
Another promising route consists in the cycloaddition of acetyl azide to triethylphos-
phoranemethylenes (306a) and subsequent hydrolysis to (306b) with yields of 60% and
greater (69M1438). For further references see (70TL5225, 73T19S).
R' R 2
Ii.. ow
+ MeCON3 --. N/N;;.N --.
Ac
COR I
/
Ph 3 P=C"
R 2
(306a)
R I R 2
1\
N .....NH
N
(306b)
The cycloaddition of diazoalkanes to C=N double bond systems represents an additional
generally applicable route to 1,2,3-triazolines like (306c), and this regioselective reaction
can be formally regarded as a 1,3-dipolar cyc1oaddition. For reviews, see (B-70MI41l02,
78BSF(2)48S), and for some applications, see (54JCSI8S0, 71MI4I100. 72LA(7S7)9. 73S71. 76ZCI02).
The addition of diazomethane can be catalyzed by organoalanes (67LA(707)147). The
cycloaddition of diazomethane to various substituted benzylidene anilines provides a facile
synthesis of numerous 1,5-diaryItriazolines (306d) (S4JCS18S0. 66T24S3. 67JHC301, 69T30S3.
72LA(7S7)9.7SJHC143).
R'
)=N-R
R 2
R 3 CHN 2 Þ
20'C
R'
R2hR3
RN.... "",N
N
(306c)
ArCH=NAr
CH 2 N 2
20'C þ
An
Ar'N.... N
(306d)
The cyc1oaddition of diazo alkanes to heterocumulenes containing nitrogen preferably
takes place at the C=N bond. On adding ethyl diazoacetate to benzyl isocyanate triazoline
(307) is obtained. In the case of ketenimines and carbodiimides, with organometallic
diazoalkanes such as bis(trimethylstannyl)diazomethane, prirnary adducts isomerize spon-
taneously to give triazoles like (308) (64CB3476, 67JPR(308)82, 7IJCS(C)3910, 7SCCCl199).
RNCX
R 3 CHN 2 Þ
X H
MR 3 --.
RN.... "",N
N
(307)
HX
'r=t
RN.... "",N
N
(308)
In a somewhat related reaction type ('Umpolung' (cf. 69S17, 7SAGl. 7SAG(E)lS. 79AG2S9,
79AG(E)239)), the anion of N-nitrosomethylethylamine (309) gives with nitriles 1,2,3-
triazoles (310) in fair-to-good yields (72AG1187, 72AG(E) 1102). 2,4,5-Trisubstituted 1,2,3-
triazoles (311) are also obtained by 1,3-dipolar cyc1oaddition of nitrilimines to nitriles (in
addition to the isomeric 1,2,4-triazoles) (79CB163S).
NO
- /
MeCH-N
. "Me
(309)
R
RCN r=\
N .....NMe
N
(310)
PhC=N-Ñ-Ph
PhC=N
)
Ph Ph ( N Ph )
N n + Ph//
.....N/N "N.....N
Ph Ph
(311)
R = Ph, 4-MeC 6 H 4 , ß -C IO H 7
In a special reaction mode alkenediazonium hexachloroantimonate salts (312) are conver-
ted into 1,2,3-triazoles (313) with amines (8ILA7, 8ICB34S6).
OEt
N2CH=C/ SbCl ó ' RNH 2 )
bEt
(312)
n O Et
N':, /NR
N
(313)
In some cases mesoionic systems have proved to be valuable precursors for 1,2,3-triazoles
bearing latent functionalities. Thus, the oxatriazole derivative (314) decompsoes to an
intermediate azide, which can be intercepted, e.g. by tolane, forming triazole (315)
(68CB536). In a related photoreaction, the sydnone derivative (316) gives a 2H-l,2,3-triazole
(318), by way of an intermediate nitrilimine (317). The reaction rnechanism has been studied
by 1 N-labelling (*) (78HCA1477).
718
1,2,3- Triazoles and their Benzo Derivatives
Or
+N N-
L -co,. N, c.w
(314)
P h;={ h
N .....N?=::1
(315)
R 2 R 2
__ ì=\ hv
*N N*
I;
N N
/ \
(316) (317) R' R' (318)
Furthermore, vinyl azides (319) react with dimethylsulfoxonium ylide (320) at the azide
function to produce in high yield 1-vinyl-Ä 2 -1,2,3-triazolines (321) (6701411, 7SC1(L)278,
8lTLl863).
I R 2
R N' 2\ _" +
I: + : __ R2C=N-ÑR1
*N-:' C ( 0- *
R 2 R 2
*NnN*
'N"'"
R'
N 3
R
(319)
o
o t
t N=N-CH2-S e2
+ CH 2 -S+Me, -- -N/
(320) . R
-:;:::-N-N=CH 2
N
R
-DMSO
13201
-----+
N=N-CH 0
- N/ I 2 t
I CH 2 -cJ MC 2
R A
n
N, N
R N
(321)
4.11.5.3. Triazoles by Transformation of Other Heterocycles
In Section 4.11.4.4 sorne Dimroth rearrangements and equilibrium systems, e.g. 1,2,3-
thiadiazole (110) 1,2,3-triazole (109), were described. Some additional examples have
also been reported: 5-anilino-1,2,3-thiadiazoles (322) are converted under basic conditions
and in high yields into 1-aryl-5-rnercapto-1,2,3-triazoles (323) (62ACS(B)1800). Later corn-
pound (322) was suggested as an intermediate in the reaction of isothiocyanates with
diazomethane (74RTC317, 76CCC1551). This rearrangernent reaction has also been extended
to 1,2,3-thiadiazole-5-carbarnates (324) (325) (80GEP2852067, 79S470).
F"f HPh NaOH
N /s
N
(322)
S- Na+
f\
N .....NPh
N
(323)
N Mc
II ] C O NHNH
N, 2
S
i,NaNO,
ii,Bu'OH
N Me
( ]NHC0 2 BU t
S
H+
--Þ
N J Me
II SH
N'N
H
(325)
(324)
In a related, base-induced rearrangement the sydnone imines (326) are converted into
4-hydroxytriazoles (327) (62HCA2441). Arylazoaziridines (328) rearrange in the presence
of sodium iodide into l-aryl-1,2,3-triazolines (329) (62JA993).
R ÑPh )[NPh R NPh ArN=NN(j n
R ICOÑ!: \'N r \\ -- p:\
-0 .....N HO N ArN, ?N
0"'" N N N
COR'
(326) (327) (328) (329)
1,2,3-Triazoles and their Benzo Derivatives
719
A [6 5] ring contraction has been reported for diphenyltriazinone (330). Upon treat-
ment with chloramine, 4,5-diphenyl-l,2,3-triazole (332) is formed in high yield via the
2-carboxamido-2H- triazole (331) (73JCS(Pl)545, 66JOC3914). Furthermore, pyridine rings
undergo ring contraction under very mild conditions by diazotization of 3-aminopyridinium
salts (333) leading to IH-triazole-4-acroleins (334) (65JPR(30)96, 66JPR(305)54). This
mechanistically interesting ring contraction reaction can be understood in terrns of an
intramolecular cycloaddition of a diazo group to an imine. This ring contraction process has
also been successfully applied to 5-diazo-6-rnethoxyuracils (335), which upon thermolysis
gave 1,2,3-triazole derivatives (336) and other products (74JHC645, 77JHC647, 78JHC1349).
P IO NH,o. Pbf'N NH' Pbf"\CONH, Pb ( \N
Ph ...-NH Ph ;N -0: Ph N / Ph /
NON
H
(330) (331) (332)
H
O
( /N
N
R
(334)
N;
HOc->e Ñ )
R
(333)
-
O N2
HO +.&
N
R
-
h N2 _
oA ;)
H NR
o
) Ñ=Ñ
HN
O OMe
Me
(335)
o 0
ANA
, HOMe
N'N/
Me
(336)
Diazotization of 4-amino-3,5-dimethylisoxazole (337) affords triazole (338) via a linear
triazene (6ZJCSZ083). Two German groups have independently rearranged 4-azoisoxazole
derivatives into 2-substituted 2H-1,2,3-triazoles (339) and (340) (79GEPZ815956, 79ZC446).
Such 4-azoisoxazole 2H-1,2,3-triazole rearrangements had been observed earlier by
Wittig and coworkers, as well as by Freeman et al. (Z8CB1140, 65JCS331Z).
MeOC N
M 7 \\
i, HN0 2 e /N
ii,CN- N
iii, CUS04 h
Me -þ
N
(338)
Me O NH 2
ï
N, Me
o
(337)
07 0
C
R 1 R 2 R 1 N=N-R R',---( ' S R2
s- n 0 \\ Et30+ SF. -) II \\
N \ \ SR 2 N \
,/N N, O ' /N
N N
R R
(339) (340)
Thermal rearrangernent of 4-acylisoxazolearylhydrazones (341) in the presence of Cu
powder leads in high yields to 2H-l,2,3-triazoles (342) (71BCJ185). Another rearrangement
proceeds from 5-substituted 3-aroyl-1,2,4-oxadiazoles (342a) with hydrazone as well as
hydrazide side-chain substituents. Some of these rearrangements are carried out by heating,
e.g. of (342a), at the melting point, or refluxing with bases or acids. In all cases 4-acylamino-
2,5-diaryl-1,2,3-triazoles (342b) are forrned (review: 81AHC(Z9)141; 59G1654, 71BCJ185,
R 2
Rf-+N=NR
N oAo
ArHNN
/I
PhC
N O Ar'
'0
(341)
Cu powde !
o
/I ,
Ph tJ _{H 2 CAr
N
N
Ar 2
(342)
720
1,2,3- Triazoles and their Benzo Derivatives
7SJCS(P2)19). In a similar manner, 4,4-diazido-2-pyrazolin-5-ones (343) are converted into
2H-l,2,3-triazole-4-carboxylic acids (344) (SOZC437).
Ar
--
R" /N NH
o I
Ph
(342a) (342b) (343) (344)
A photochemical method involving a heterocyclic rearrangement is represented by the
tetrazole 2H-triazole conversion (345) (346) (69JOC411S). Similarly, the rearrange-
rnent of the hydrazones of 3-acyl-1,2,4-oxadiazoles provides a general route to 2-substituted
2H-1,2,3-triazoles (67JCS(C)200S, SlJHC723). This rearrangernent has been studied with
regard to its kinetics and rate (76MI41100, 78JCS(P2)19).
RCONHr.-\\Ar
II \\
N, /N
N
Ph
NJ
R N
r 3
N'N 0
R 1
NaOH þ
r.t.
Rh C02H
N
N
R 1
N-NMe
Ph 'N
N
(345)
Phr.-\\Ph
II \\
N, /N
N
Me
(346)
4.11.5.4 Other Methods of Synthesis of 1,2,3-Triazoles
The energy gained in producing the aromatic 1,2,3-triazole system facilitates the retro-
Diels-Alder reaction of appropriate triazolines formed previously by 1,3-dipolar cycloaddi-
tion to moieties which can act as suitable diene precursors upon thermolysis. Thus, on
therrnolysis of norbornadiene-phenyl azide adducts (347) a smooth retrodiene reaction
occurs forming the I-phenyl-1,2,3-triazole (348) as well as a substituted cyclopentadiene.
This reaction also occurs with the adduct from trimethylsilyl azide and norbornadiene
(50LA(ð66)58, 65CB3992, 72CJC3186, 76JOM(121)285). Furthermore, this decomposition reaction
can be extended to some heterocyclic tricyclic azide adducts, like (349). Dimethyl I-phenyl-
1 ,2,3-triazole-4,5-dicarboxylate (350) is produced in good-to-excellent yield on therrnolysis
of (349) (74TL2163, 76RTC67). Similarly, adduct (351) is cleaved at 70 oC into I-phenyl-l ,2,3-
triazole (348) and the isoindole (352) (63CB2S51).
R 2
N R 1 R 1
R 1 \ f'\ +0
--
/N ....N
N R 2
Ph
Ph
(347) (348)
X X
A:zE '; __ Ej\E
N ,...NPh
N? N
E E Ph
E = C0 2 Me, X = 0, NC0 2 Et (349) (350)
H
N
rr/ \ 70 0 C þ
/N
N
(351) Ph
[
/N
N
Ph
(348)
+ [(CH]
(352)
The cycloadduct of phenyl azide and tetrafluorobarrelene cannot be isolated, but instead
decornposes spontaneously into tetrafluoronaphthalene and 1-phenyl-l,2,3-triazole (348)
(691ZV144).
1,2,3-Triazoles and their Benzo Derivatives
721
M F [ F ] F
PhN - '/ F -....::::
F j J --4 F Þ. - F(X) +
F F N F
/
N
Ph
N
[ \\
/N
N
Ph
(348)
The 1,2,3-triazole moiety in benzotriazole has proved to be especially resistant to
oxidation. Thus, the permanganate oxidation of several substituted benzotriazoles yields
1,2,3-triazole-4,5-dicarboxylic acids (B-61MI41100). In more recent work, 1- and 2-phenyl-
benzotriazoles have been oxidized by means of permanganate to give 1- and 2-phenyl-1,2,3-
triazole-4,5-dicarboxylic acids (353a) and (353b) (27LA(4S4)164). For more examples of this
oxidation see (64CB3493, 67CB71),
o: N H02C""C02H
=-- \ KMn04 II \\
NPh '
H N ::- / N, "N
2 N N
Ph
(353a)
Furthermore, [1,2,3]triazolo[ 4,5-d]pyrimidines synthesized originally as purine analogs
cleave to monocyclic triazoles on acidic or basic hydrolysis (S9JAPS910468, 63JA2967). 6-
Methylthio-8-azapurine is rapidly degraded in boiling 1M HCl to 4-amino-5-(methyl-
thio)carbonyI-1,2,3-triazole (354) in almost quantitative yield. The 7-, 8- and 9-methyl as
well as the 9-benzyl derivatives behaved similarly (69JC (C)2379, 69CCSOO, 69AGllS,
69AG(E)132). Thus, the pyrimidine ring may be used as an intermediate carrier when the
1,2,3-triazole moiety is annulated to the pyrimidine ring. N-Alkyl-8-azapurines can be
hydrolyzed by cold aqueous 1M HCl to give 43-96% of the triazole aldehydes (355)
(77JCS(Pl)1819, 79MI41101). In the presence of hydrazine, bis(1,2,3-triazole-4-aldehyde)hy-
drazones (356) are obtained (73JCS(Pl)162S, 73JCS(Pl)1634).
H 2 NCX)'N
Ph
KMn04
Et0 2 Cf\C 0 2 Et
N /NPh
N
(353b)
SMe NjOSMe NjHO
fX) lMHCl If / lMHCl II
N, I J N, NH 2 N: I J , N, NH 2
r.t.
N N
N N H N N Me
H Me
(354) (355)
N :c
Nij I
, 7"R
N N
H
NH N J CH=N-N=CH C N
24, lf, 7\\
N, R 1 R t /N
N N
H H
(3S6)
R=H,OH,SH
R 1 = NH 2 , NHCONH z , NHCSNH2
1,2,3-Triazoles Can also be obtained from more complex molecules. On heating the
adduct (357), obtained from phenyl azide and morpholinopiperidine, in formic acid the
morpholine is eliminated while the piperidine ring is cleaved reductively with CO 2 evolution
to give the triazole (358) (64CB122S) (cf. also cleavage of (197) (71CB3S10)).
H N
M'Q:l
c)b
(357)
H'
--
N
7 \\
Me 2 N N/N
I
Ph
H
+ eN) + CO 2
o
(358)
In addition condensed heterocyclic systems formed by annulation can serve as valuable
sources of polyfunctional 1,2,3-triazoles. Triazolo[1,5-a]pyridines (360) are transformed
('trans-cyclization') into the 4-(pyrid-2-yl)-1,2,3-triazoles (361) upon heating with aniline
(70LA(734)S6).
722
1,2,3-Triazoles and their Benzo Derivatives
RDl
RltN Ph
o 0
(359)
N,H, , R W "-'::: 0
R 1
N Ph
\
N=N
(360)
PhNH 2 ,
"-':::
h- Ph
N _
N .....NPh
(361) N
4.11.5.5 IH- and 2H- Benzotriazoles
Benzo[d][1,2,3]triazole, usually known as benzotriazole, and many of its derivatives are
obtained from diazotized o-phenylenediamines or appropriately substituted derivatives.
The parent compound (362) is formed on treatment of o-phenylenediarnine with
NaN0 2 /MeC0 2 H (400S(20)16). Numerous examples illustrate the wide variety of ben-
zotriazoles available by this route; for reviews, see (SOCRV(46)1, B-61MI41100). lH-
Benzotriazole (362) is a very stable material, which can be converted in boiling aqua regia
into 4,5,6,7 -tetrachlorobenzotriazole (68JCS(C)1268).
NaNO,/MeCO,H (X,
, J1
N
H
(362) (363)
A useful preparative method of wide application for the synthesis of the 2H-isomer
is the cyclization of 1,2-azoaminobenzenes to give 2-phenyl-2H- benzotriazoles (363)
(22GEP338926, 21CB2191, 2201).
Sorne miscellaneous and classical cyclization methods of benzenes with 1,2-dinitrogen
functions are shown in Scherne 9 (1887CB1l76, 21071, 300644).
0 1 N=NPh
H 2 N NH 2
CuSO,. NH, ,
.90'C
o: =--N,
NPh
H 2 N ""N'
0 l NH 2
NH 2
o
t
O N=NPh
I NH2
c. H,SO,
-H,O
o: =--N, + O ::Ph
, NPh (
:::-"N' -H 2 0
AlN 2 r -PhNH 2
O NH
I 2 + PhN0 2
NH 2
0 1 NHNHPh
N= NPh
Scheme 9
Cyclization of an 0- nitrohydrazino derivative gives 1-hydroxy-6-nitrobenzotriazole (364)
(S4MI41101). 1-Hydroxybenzotriazole (365), a very versatile reagent in peptide synthesis
(cf. Section 4.11.6.2), is obtained by heating 2-chloronitrobenzene with hydrazine. The
cyclization is described in terms of an internal oxidation-reduction reaction (70CB788).
Another useful cyclization rnethod starts with o-nitroazobenzenes and reducing agents, like
(NH 4 hS or NaOH/Zn, to give (366) (78JAP(K)7898932). 2-Substituted benzotriazoles (368)
are obtained by the thermal decornposition of 0- azidoazobenzenes by refluxing in dioxane
(68JOC29S4).
0 1 NHNH2
02 N N0 2
NaOH
(X N
,y I
02 N /
OH
(364)
0 lN0 2
Cl
: · r d1 :'J
(X I N
/
N
OH
(365)
1,2,3-Triazoles and their Benzo Derivatives
723
N=N OH
0:02 D
Me
NaOH
er N HO
-7" =--- \ -
NN-QMe
(366)
Q- N=N -Q NMe 2 -. er:'N -Q NMe 2
(367) (368)
In a bimolecular cycloaddition reaction l-phenylbenzotriazole (369) is obtained from
dehydrobenzene (by diazotization of anthranilic acid) and phenyl azide (64JOC3733,
6SCB3142). The synthesis of l-g1ucosylbenzotriazole from glucosyl azides and dehydroben-
zene has been accomplished in this way, yielding, for example, 1-(2,3,4,6-tetra-O-acetyl-ß-
D-glucopyranosyl)benzotriazole (370) (68JHC699).
0 1 C02H -.
I:;J2
[O
cr N
/
N
Ph
(369)
(X I N
/
N
R
(370)
Heating 2,2'-diazidoazobenzene (371) at a temperature not higher than 58 oC leads to
2-(2-azidophenyl)-2H- benzotriazole (372), while above that temperature, e.g. at 170 o C,
the 1,3a,4,6a-tetraazapentalene (373) is formed in 93% yield (67JA2618). Most probably,
the second step also involves nitrene intermediates. Benzotriazoles are also accessible by
ring contraction reaction of bicyc1ic systems, like 1,2,4-benzotriazin-3(2H)-one (374). This
is converted into lH- benzotriazole on treatment with chlorarnine (an aminating oxidant)
in ether (71CCS32).
OI+RN3 -
H CH 2 0Ac
R= AcO q
ACO
H OAc H
:0 -7"
N I
ex "'"
IN; N
. (371)
. sS80C
N -D N3
ì
(372)
170 0 C
-
Ñ
o: NJJ
/
N
(373)
N'iO
/NH
N
(374)
Tricyclic heterocyclic betaines containing a benzotriazole moiety as one of its component
ring systems as in (375) are photolyzed in the presence of oxygen and Rose Bengal C02)
to give both 1H- and 2H- benzotriazoles (376a, b) (81CCI089). The products arise formally
from addition of 10 2 to the two mesomeric forms of (375).
0: N :J Me h ' 0 (X N, er =--N,
I I I v. , I "'N + NR
_ /N + sens. >- / /
N M lA>SOOnm) "N N
e R
(375) (376a) (376b)
NH 2 C1
ether
N
H
4.11.6 APPLICATIONS OF 1,2,3-TRIAZOLES AND BENZOTRIAZOLES
1,2,3-Triazoles (Ä 2 -1,2,3-triazolines) and benzotriazoles have found numerous applica-
tions in organic synthesis, as well as in medicine and industry as biologicallly active systems,
724
1,2,3- Triazoles and their Benzo Derivatives
as dyestuffs and fluorescent compounds, as corrosion inhibitors, as photostabilizers and as
agrochemicals.
4.11.6.1 Access to Compounds of Preparative Importance
As has been shown in Section 4.11.4.3, 1,2,3-triazole and A 2 -1,2,3-triazolines can be
converted either thermally or photochemically into three-membered 2H-azirines and
aziridines, respectively, with evolution of nitrogen (for reviews see B-67MI41101, B-70MI41101,
B-76PH403). In the following section some additional applications of greater preparative
interest are described.
In principle, elimination of nitrogen from A 2 -1 ,2,3-triazolines yields aziridines, imines
or isomeric irnines as shown in Scheme 10.
I I
-r- -
R/N, N
M
N
I
R
+ 'è-c + "c=c"""'-
N-Ý " HN/ "
R R
Scheme 10
Photolysis of the triazolines (A > 240 nm) leads to better yields of aziridines (66JA4759,
67JOC2022, 68JA988, 68T2757, 74JOC3739). The formation of the aziridines does not occur
stereospecifically, although a considerable retention of the configuration at C-4 and C-5 is
observed (70T4339, 66JA4759, 68JA988). A typical exarnple is presented in Table 22.
Table 22 Slereochemistry of Triazoline Photodecomposition (68JA988)
Triazoline
I"adiation
Ph Me
'--<"
\ I
N
H
(%)
Ph Me
'd
N
H
(%)
PhCEt
II
NPh
(%J
Me
-
\ Direct a 66 22 12
Ph N/N Sens. b 42 S4 4
Ph
Me
N Direct a 17 6S 18
\\ Sens. b 60 36 4
Ph N/N
Ph
a Å = 313 nm in benzene. b Å = 366 nm with benzophenone in benzene.
On thermolysis the formation of a betaine intermediate is postulated (Scheme 11) (cf
77CR(C)(284)509, 65CCS6, 6SJOC420S). This has alternative routes of stabilization by N 2
extrusion, either by irnine/ enamine forrnation or by cyclization to an aziridine.
I I
-C-C-
I \
N, N
R/ N
I I
-c-c-
I I
-N N
/
R
M
N
R
il
1<'
I /
-c-c
I /I
HN N 2
R
--. "c=c"""'-
fIN' "
R
" .......-
C-C-
RN-Ý "
Scheme 11
1,2,3- Triazoles and their Benzo Derivatives
725
Analogous to the pinacole rearrangement, bicyclic triazolines are transformed on heating
into aziridines, like (377), and the cyclic imines (378) or (379) depending on the nature of
the substituents (65JA749).
S<= M:-' N
II
R 1 N
ð.
----+
èp
R 1
(377)
Me
+ Q N
J. Me
Me
OMe
(378) R 1 = H
(379) R 1 = Me
The spiro-triazoline (380) can be converted into both the ketenimine (381) and the
cyclobutanimine (382) (74JOC63). Triazolines formed by cyc1oaddition of azides to norbor-
nene lead to numerous interesting norbornane derivatives (cf. 78BSF(2)48S). 5-Hydroxytriazo-
lines (383) afford the ring-contracted amide (384) by therrnal dehydration (67MI41100).
CH 2 =C = NPh
(381) 34%
P N [ [)(ëH2 -. 4 ]
N No NPh
/
(380) Ph
+
4 NPh
(382) 66%
Q} ÜyNHPb
HO Ph 0
(383) (384)
4-Cyano-1,5-diaryl-Ll 2 -1,2,3-triazolines (385), obtained by addition of diazo acetonitrile
to N- benzylideneanilines, have been decornposed to aziridines (386) and enarnines (387)
with migration of the 5 -aryl substituent (78T2229). Thermolysis of 4,4-dimethyl-1-(1-phenyl-
vinyl)-5-(1-pyrrolidinyl)-4,5-dihydro-1H- 1,2,3- triazole (388) gives 2-methyl-N- (1-
pheg,ylvinyl)-l-(pyrrolidinyl)-l-propanimine (389) which reacts like a 2-azabutadiene, e.g.
by [4 + 2] cycloaddition with electron-deficient dienophiles (81BCJ2779). In other solvents
(389) is formed in much lower yields. Instead an intermediate aziridine (390) is obtai!'}ed
which undergoes a ring enlargernent reaction to 2H-pyrroles (391) (81BCJ2779).
H
NCIIIIII/-
(ArJH-J-.. ./N
(H)Ar r
(385)
Ph
H2C 1 0
\, N
N e2
(388)
80"C
Ph O
/ N
(388) -. H 2 C=C I
'-.....CH
N
+ I
N 2 -CM e 2
-.
(H)Ar, CN
M
(Ar)H N H
Ar
(386)
NC Ar
+X
H NH Ar
(387)
Ph O
H C=C"/ N
2 \ /
N=C
"-
CHMe 2
-. e.g. Diels-Alder reactions
(389)
Ph O rlhO Ph
H 2 C=< N -+ N 'N CN
'\I 0 Me2 Me2
Me 2
(390) (391)
726
1,2,3- Triazoles and their Benzo Derivatives
The forrnation of pyrrole derivatives has been reported earlier. The triazoline (392) was
converted by heating at its rnelting point into the 4-oxazoline (393) which in turn gives the
2,5-dihydropyrrole (394) on reaction with ethyl acetylenedicarboxylate (70CR(C)(271)958).
A roM
A;---tCOzR ArN J COzR \1eO,CC:=CCO,Me þ r Q z e
ArN N A/ Me ArN COzMe
'N O
Ac COzR
(392) (393) (394)
A new ring transforrnation reaction of 4,5-dibenzoyl-1,2,3-triazoline (395) has been
reported, which appears to involve nitrogen expulsion followed by a C-NH proton shift.
This sequence opens a novel route to enarnino diketones (396) and tetraacylpyrrolidines
(and traces of aziridine 398) (76JHCl153).
PhOC O COPh
PhOC COPh
N
Ph
(397) (398)
Unusual pyrrole derivatives are formed by the photolysis of 1-vinyl-4,5-dihydro-1H-
1,2,3-triazoles (81CC1519).
Reaction of alkylidene cycloalkanes (399) with cyanogen azide (400) (64JA4506), followed
by hydrolysis, affords ring-expanded cyclic ketones (401), a reaction applicable to a wide
variety of ring sizes and to both saturated and a ,ß- unsaturated ketones (69J A3676, 73JOC2821).
Gas-phase pyrolysis of rnethyl- and fluoro-substituted benzotriazoles (402) yields
cyanocyclopentadienes (403) (67TL4379, 68CCI026).
c5 ,c". 8- CN ONCN
PhCOnCOzPh
PhN, N
N
(395)
PhCO NHPh
" ,.-
C
II
HC
.....COPh
(396)
+ PhOC\7COPh
N
Ph
0 0
(399) (400) (401)
CH z 0
II II
(C j --+ (c)
(CH,)" (CH 2 ),,+1
n 3 4 5 6 7 11
(%J yield 52 44 80 41 38 60
Ú!\ 500-800 'C [RÙ ÑH ] !Ç)CN
--+
R N' -N,
(402) H R
(403)
4.11.6.2 Triazoles Utilized in Organic Synthesis
A general reaction for preparing 6-amino-8-azapurines frorn 5-cyano-4-(dirnethyl-
arninornethylene)arnino-1,2,3-triazoles has been reported (B-78MI41104). When the triazole
1,2,3- Triazoles and their Benzo Derivatives
727
(404) is treated in DMF with POCh at 25 oC the ring-fused systern (405) is formed in 85%
yield.
N N NH 2
I J POCl / "' :0
MeN --4 MeN
'N..-:: N=CHNM e 2 'N--'
(404) (405)
Bromo-substituted quaternary 1,2,3-triazolium salts are strong brornination reagents in
basic solution (69ACS(B)2733).
1-Chloro-, 1-bromo- and (less) 1-iodo-benzotriazoles (easily accessible from 1-chloroben-
zotriazole (69JCS(C) 1474)) have proved to be powerful oxidants (69JCS(C)1478, nS259, 77JOC592,
78JCS(P1)909). Thus, cyclohexanol, 1-phenylethanol and benzyl alcohol are smoothly oxidized
to give cyclohexanone, acetophenone and benzaldehyde, respectively. By treatment with
1-chlorobenzotriazole and subsequent hydrolysis of the product, ethers are cleaved oxida-
tively to aldehydes (Scheme 12) (79AJC2787).
R lCH 2 0R 2 + (X i N N -- (X i \.r
rI j'
CI I
CHROR
H o.
R1CHO + R 2 0H +
r!í N
H
Scheme 12
5-Diazornethyl-1,4-diphenyl-1,2,3-triazole (406) gives products of typical carbene reac-
tions when thermolyzed slightly above roorn ternperature (i.e. 40-50 oc) in the absence of
a catalyst. Carbenes generated in this way show a higher selectivity than those frorn other
sources of rnethylene or ethoxycarbonylcarbene. In the case of aromatic derivatives triazolyl-
substituted cycloheptatrienes (407) are formed (68JOC1145, 74JOC1047, 81JOC679).
N Ph R
J Ph + O R 40-SOOC) r-( U\
N" CHN 2 _ N HC
N Ph
Ph --
(406) (407)
At 20 0 C 4-amino-5-aminornethyl-3-benzyl-l,2,3-triazole (408) gives with CS z the
dithiocarbamate (409), which upon heating affords the novel heterocyclic system 1,2,3-
triazolo[4,5-d][1,3]thiazine (410) (and not the expected 8-azapurine) (80AG319. 80AG(E)310,
80JCS(P1)2009).
S
II
N CH2NH2 N 3 CH2NHCS-
II II
N'N NH 2 N'N NH 2
CH 2 Ph CH 2 Ph
(408) (409) (410)
The ylidic 1-phenylimino-2,4,5-triphenyl-1,2,3-triazole (411) (ef Section 4.11.4.6) has
been shown to be an effective 1,3-dipolar system which can be reacted smoothly with CS 2 ,
PhNCS, alkynic esters, ethyl acrylate and acrylonitrile to give [3 + 2] cycloadducts, e.g.
(412). Upon photolysis or thermolysis the 2,4,5-triphenyl-2H-triazole (413) is formed
(71TL633).
Nr:('l
Ph H2 S
p:tr
Ph-c/ .
N
Ph
(412) (411) (413)
One of the most widely used benzotriazole derivatives is the 1-hydroxy compound (414),
which has proved to be a very valuable rnediator substance for activating carboxyl groups
/Ph
-N
I
Ph N
( \+
I IN - Ph
Ph /I
N
N
Ph r \
l:::. NPh
Ph"-N
728
1,2,3-Triazoles and their Benzo Derivatives
for peptide synthesis. Racemization is decreased, the forrnation of N-acylurea is avoided
and the yields of high purity peptides are improved (70CB788). Some recent examples of
coupling reactions in peptide, dipeptide and polypeptide synthesis, as well as protection of
carboxylic acids, are given in the following references: (74TL269S, 7SHCA688, 77TL199, 76TLl031,
78AG63, 78AG(E)67, 79CBI0S7, 79TLl72S, 81CB2649).
N N
OH
(414)
N N PF 6 -
I
O=P+(NMe2) .1
(415)
Furtherrnore, benzotriazolyl-N- hydroxytris( dimethylamino )phosphoniurn hexafluoro-
phosphate (415) has been used for coupling reactions in peptide synthesis (7STLl219). Very
recently, l-ethoxycarbonylbenzotriazole has been used successfully as a C- carboxylating
reagent (82AG139).
4.11.6.3 Triazoles in Medicinal Chemistry
Some 1,2,3-triazole derivatives have been reported to show significant biological activity,
such as 4-alkyl-1,2,3-triazoles which show some slight inhibition of rnicroorganisrns
(S4JA667). Furthermore, sorne triazole analogs of histarnine show antihistaminic and anti-
acetylcholine activities, while the 1,2,3-triazole ring is antagnostic to the imidazole ring in
triazole analogs of adenine and guanine (SIJA1207, 49JA1436). Ethanolamino derivatives of
1,2,3-triazoles show mydriatic action (SSFES23S).
In a rnore recent work sulfonyl hydrazides and their derivatives frorn 2-phenyl-l,2,3-
triazole-4-carboxylic acid (416) have been reported to inhibit the growth of Staphyllococcus
aureus, Escherischia coli and Salmonella typhi (76JIC833). In addition, 1,2,3-triazole-l,8-
naphthyridine derivatives have been synthesized; compounds (417) were found to have
twice the analgesic activity of phenylbutazone; both (417) and (418) showed sedative
activity; and cornpounds (418) were fungicidal (76FES797). Both 5- and 6-chloro-1-aroylben-
zotriazoles (419) and (420) revealed antiinflammatory activities (80JHClS0S).
N R
JR'
MOm
N N
(417)
R = Ph, C0 2 Et, Ac, CH 2 Ph, CONHPh
R' = NH 2 , Me, Ph, CH 2 C0 2 Et
N -o
---,
N R'
RC:N' /;
(416)
R = CONHN=CHR 2 , R' = H
R = C0 2 H, R' = S02NHN=CHR2
CH 2 X
r==<
Cl N l'\ 1 N At H ' i VN
CI OAc
COR COR AcO
(418) (419) (420) OAc
R = Ph, C0 2 H (420a) X = Br, I
In a recent East Gerrnan review some biological activities of triazoles (1,2,4- and 1,2,3-)
have been described (81MI41100). The virostatic, cytostatic, antirnicrobial and antirnycotic
activities of derivatives of 1,2,3-triazolecarbonarnides are discussed. Furtherrnore, 4- or
5-halornethyl-l,2,3-triazoles, e.g. (420a), can be used as radiomimetica and show cancero-
static activity (78MI41102, 79MIP41l01, 79MIP41l02).
The 1-tosyl-1,2,3-triazole (421) was found to possess bacteriostatic activity (78FESS43).
A typical example of an antibioticum carrying a 1,2,3-triazole ring in its side chain is
N J-
II
N'N NH
H
Me NY
1,2,3- Triazoles and their Benzo Derivatives
729
cefatrizin (422), which belongs to the class of cephalosporins currently in use and which
has activity against 342 different germs (76MI41102, 78MI41103). Another semisynthetic
penicillin from 2-phenyl-1,2,3-triazolecarboxylic acid (423) has recently been reported
(80MI41100).
Mer=\NEt z -0
I-I If'
N /NSO z R
N -
(421)
R=H,OMe
HO Q- CHNH'CONHJ=fJ
o C O HCHz
z I
S
h
N /NH
N
CONHn)Me
h 0 COH
N'N'N z
Ph (423)
N.1 and N-2 derivatives of benzotriazole with glycine and different sugar residues, like
ß-glucopyranose, ß-ribofuranose or polyacetylated furanoses, are found as cytostatica
(71MI41101, 71MI41102, 73MI41102) and several benzo-substituted benzotriazoles (424) are
cytostatically active against sarcomas and erythroleukomyelosis (77MI41101). Furtherrnore,
1H- and 2H-1,2,3-triazole nucleosides such as (425) and (426) have been found to possess
bactericidal activity (76USP3968103). Other nucleosides (427) and (428) were active in vitro
against herpes and measles virus (76usP3948885, 81MI41101). D-Arabinofuranosyl- and 2'.
deoxY-D-ribofuranosyl-1,2,3-triazolecarboxamides have been described in (77BCJ2689).
R N
(( , N
::::,.... /
N
H
(424) R = H, NHz, NHAc, CHNHzCOzH
(422)
R I
n
N.'N/N
RO ö
OR OR
(425)
H ZN O
N
II \\
HO I N
HOw
OH OH
(427)
R 3 N
Z !Ç \\
R N
ROw
OR OR
(426)
o
HzN OH
n
NyN
Hocd
OH OH
(428)
In two additional studies alkylated nucleosides have been investigated, and N-
glycosyl(halomethyl)-1,2,3-triazoles (429) and N-ribosylhalomethyl-1,2,3-triazole (430)
have been detected as a new type of alkylating agent showing cytostatic activity (79JMC496).
R = H, Ac, CHzPh
R I , R Z , R 3 = H, CN, NO z , COzMe, NHz, CNH z
II
S
J CHZX
N.....
ltJ
OBz OBz
(430)
I O C
ACO.A N
AcO R N: ::::
\;:::::::::.JR 1
R I
(429)
R = OAc, NHAc
R I =CHzX
X=CI, Sr, I, OH
730
1,2,3- Triazoles and their Benzo Derivatives
4.11.6.4 Industrial Applications
Besides their biological activity, some other important industrial applications of triazoles
and benzotriazoles are known, including dyestuffs, fluorescent compounds, optical bright-
eners, corrosion inhibitors, photostabilizers and agrochemicals. Some selected applications
are described in the following sections.
4.11.6.4.1 Dyestuffs, fluorescent whiteners
Numerous patents have appeared in the last few years which deal with 1,2,3-triazoles
and benzotriazoles as part of optical brightening rnolecules. These consist in rnost cases of
stilbene moieties with suitable heterocyclic chrornophores attached (B-64MI41102), and as a
consequence hundreds of brighteners are available today on the world rnarket. Special
applications are whitening of fibers [e.g. poly(ethyleneterephthalate), cellulose acetate and
poly(acrylonitrile)], lacquers and plastics. Several examples of the structural types involved
are shown in Scheme 13.
Meo O CH=CH o- N Me
- R - 'N,ø1COR
71GEP2129863
R 1
R O CH=CH o- N NH2
- - ' N ,ø1CONH 2
R 2 R 3
71GEP21298SS
Phr:N - O CH=CH o- N;NJPh
N SOzR SOzR N
72GEP2032172
0 \, N Ph
'( _ '\ CH=CH >\! ,....A
CI l:, / 0 0
N
72GEP2032088
:O:} -Q CH CH Q
76GEP2S39461 COzH
N
- ( ,
- N
R10CH=CHOCH=CH N
R
76JAP(K)7681826
(X N >-O D-:n
I j CH=CH j -
a
77USP4039S31 R
CH=CH C N
N.':Y\Í
79MIP41100 H
80MIP41100
Me 0
R N _ / :...i(
R1C N NMe
N OH N
Me 0
80GEP2848670
Scheme 13
A survey of the preparation of styryl and stilbenyl derivatives of 1H- benzotriazoles has
recently been published (81HCA662).
4.11.6.4.2 Corrosion inhibition
Benzotriazole and its derivatives have proved to be powerful corrosion inhibitors for
rnany rnetals and alloys, including copper, solder, brass, steel, cast iron and alurninurn, in
e.g. heat exchangers, heating systems or autornatic radiators. For sorne recent literature,
see (79MI41 102, 8lJAP(K)81l08882, 81JAP(K)81122884).
Associated with these above properties of corrosion inhibition is the readiness of triazoles
and benzotriazoles to forrn cornplexes with different rnetals. Benzotriazole and its 5-brorno
1,2,3- Triazoles and their Benzo Derivatives
731
derivatives can be used in quantitative determination of silver ion in the presence of copper,
nickel, bisrnuth, thalliurn, lead, cadmiurn, zinc, iron, cobalt and chloride ions (S4MI41100).
Benzotriazole also forms complexes with cobalt (SSMI41100) and palladiurn (SSJA6204,
S6MI41100). 4-Benzoyl- and 4-butyryltriazoles form iron complexes with iron (II) chloride
or nonacarbonyliron. The latter cornplexes possess two triazole molecules per iron atom,
which is 7r-bonded to the ring (66DOK(170)354, 68DOK(181)1397).
The synthesis and properties of chelate resins containing 1,2,3-triazole-4,5-dicarboxylic
acid as an anchor group have been described. The 2-vinyltriazole (431) was copolyrnerized
with divinylbenzene to yield crosslinked products and then saponified to give C0 2 H-
containing resins. These can be used for the complexation of heavy metals (79MI41100).
EtOzCnCOzEt
Ny
CH=CH z
(431)
Furtherrnore, the extraction of some complexes of manganese(II), iron(I1), iron (III) and
copper(II) by a chloroforrn solution of 1,2,3-benzotriazole has been reported (8IUKZI099).
4.11.6.4.3 Photostabilizers
1,2,3-Triazole and.benzotriazoles have been successfully applied as photostabilizers for
fibers, plastics or dyestuffs, for example, and for the protection of hurnan skin frorn harrnful
UV irradiation. For a brief surnrnary, see (B-71MI41103).
The wavelengths of available sunlight which affect the chemical bonds usually found in
polyrner backbones are in the region 300-400 nm. Benzotriazoles, e.g. (432), are widely
used absorbers (72PAC(30)13S). For further literature on this topic see (70JHC1113). The
stability of the benzotriazole series has been explained as involving a steric inhibition of
rotation of the o-hydroxyphenyl ring with respect to the triazole ring (72PAC(30)14S). The
2-phenyl-2H-1,2,3-triazoles (433) have proved to be UV absorbers, particularly for sunburn
protection (7IGEP2129864).
o: N HO
7" ;...- \N -o
""'- '" /
N Me-
(432) Åmax 340 nm
Mer.-FOzH
1/ \\
N'N"N
Ó '-':::::OH
R2
R
(433)
R = H, R Z = Cl, S03Na
R=Rz=Me
o: N OH -a But
7" ;...- \N U CH2 II OH
""'- '" / I But
N
Me
(434)
N\ SOJNa
/N
N I;IO
(435)
Several 2-phenylated 2H-1,2,3-benzotriazoles like (434) have been reported as light
stabilizers for organic materials, especially polymers (81EUP31302). Tetrazoles with aryl and
2-nitrophenyl residues in the 1- and 5-positions have been converted thermally into
2-arylbenzotriazoles (435) which are useful as UV absorbers, especially in retarding the
photo degradation of wool (81AJC691).
4.11.6.4.4 Agrochernicals
While 1,2,4-triazoles have found broad application as herbicides, fungicides and antibac-
terial agents, 1,2,3-triazoles have been detected only in the last decade to possess significant
biological activity, which rnakes them of interest in the area of agrochernicals (B-77MI41102).
732
1,2,3- Triazotes and their Benzo Derivatives
Thus, 5-anilino-lH-l,2,3-triazole-4-carboxylates (436) show al1'tihelrnintic activity
(70GEP2009134). Büchel et at. have claimed triphenyl-1,2,3-triazolyl-(1')-methanes (437) as
fungicides (7SGEP240730S).
R'H NF\C 0 2 Et
RN, N
I/
."..N
N
o- I X
" Þ 6 y
(436) (437) X, Y = H, alkyl, Hal, CN
1-( 3- Trifluorornethylphenyl)-5-phenyl-1 ,2,3-triazole and the corresponding 5-rnethyl
and 5-ethyl derivatives (438) show rnarked to strong but non-selective herbicidal activity
(77MI41 100). 1,2,3-Triazolecarboxylic acid amides of the type (439) have herbicidal,
defoliant, insecticidal, fungicidal and nematocidal activity (80GEP2834879). 1,2,3-
Benzotriazoles have been shown to possess varying degrees of biological activity. Chloro
substituents especially are known to increase the pesticidal activity of the rnolecule
(B75MI41101,80JHCl11S).
R
J:;N -o
N _
CF ò
(438)
R = Ph, Me, Et
Rh S OnR
N!N:;N
CONR 2 R 3
(439)
1,2,3-Triazoles of the type (440) are useful for regulating local plant growth (81MIP41100).
Trialkyl( 1,2,3-triazolyl)tin cornpounds (441) can be used as biocides (81GEP2936951).
R 1 N
1/\\
R NN
Ó
F 3 C # CF.,
(440)
J S(O)nR I
R3SnN,
(441)
4.11.6.5 Important Natural Products
Up to now and to our present knowledge no natural products have been isolated containing
1,2,3-triazole or benzotriazole moieties. Apparently it is difficult for nature, and thus
biochernical systerns, to produce rnolecules with three vicinal nitrogen atorns in an open-
chain or cyclic arrangement.
4.12
1,2,4- Triazoles
J. B. POLYA
University of Tasmania
4.12.1 INTRODUCTION
4.12.2 STRUCTURE
4.12.2.1 Constitutional Problems and Methods
4.12.2.2 Molecular Geometry and Dimensions
4.12.2.3 Molecular Spectra
4.12.2.3.1 UV spectra
4.12.2.3.2 IR spectra
4.12.2.3.3 NMR spectra
4.12.2.3.4 Mass spectrometry
4.12.2.4 Theoretical Studies
4.12.2.4.1 Thermochemistry
4.12.2.4.2 Acidity
4.12.2.4.3 Dipole moments
4.12.2.5 Betaines and Mesoionic Compounds
4.12.3 REACTIVITY
4.12.3.1 General considerations
4.12.3.2 Reactivity at the Ring Atoms
4.12.3.2.1 Stability of the ring
4.12.3.2.2 Electrophilic attack at nitrogen
4.12.3.2.3 Electrophilic attack at carbon
4.12.3.2.4 Nucleophilic attack at carbon
4.12.3.3 Reactivity of Substituents
4.12.3.3.1 C-Linked substituents
4.12.3.3.2 N-Linked substituents
4.12.4 SYNTHESIS
4.12.4.1 General Considerations
4.12.4.2 Synthesis of Triazole Rings from Acyclic Compounds
4.12.4.2.1 Methods employing hydrazine derivatives
4.12.4.2.2 Nitrilimine methods
4.12.4.3 Synthesis of Triazole Rings from Other Heterocyclic Systems
4.12.4.3.1 Destruction of non-triazole rings
4.12.4.3.2 Cleavage and recyclization of non-triazole rings
4.12.4.3.3 Nitrilimines derived from non-triazole rings
4.12.4.4 Introduction and Modification of Functions on the Triazole Ring
4.12.4.4.1 Alkyl and aryl groups
4.12.4.4.2 Halo groups
4.12.4.4.3 Nitrogen functions
4.12.4.4.4 Sulfur functions
4.12.4.4.5 Carbonyl functions
4.12.4.4.6 Metal complexes
4.12.4.4.7 Triazolidinediones
4.12.5 APPLICATIONS
4.12.5.1 Analytical and Synthetic Applications
4.12.5.1.1 Analytical uses
4.12.5.1.2 Synthetic uses
4.12.5.2 Industrial Uses of Triazoles
4.12.5.2.1 Biological activity
4.12.5.2.2 Dyes and photographic chemicals
4.12.5.2.3 Polymers
4.12.5.2.4 Other uses
734
736
736
738
739
739
739
740
741
742
742
742
742
742
743
743
744
744
746
752
753
755
755
760
761
761
762
762
768
770
771
771
779
781
781
782
782
782
783
784
784
784
785
785
786
787
787
788
788
790
733
734
1,2,4- Triazoles
4.12.1 INTRODUCTION
Sirnple 1,2,4-triazoles (those not forrning part of a fused polynuclear systern) are cyclic
hydrazidines with H or sorne other substituent on either a hydrazide nitrogen as in (1) or
an arnide nitrogen as in (2). The prefixes 1H and 4H are used to distinguish (1) and (2),
respectively. The narne 1,3,4-triazole for (2) appears in sorne theoretical papers but it is
deceptive when (1) and (2) are tautorners (with R 1 = R 4 = H): a catalogue of chernicals
offering 1,2,4-triazole and 1,3,4-triazole, the sarne substance, at different prices is an
exarnple of rnisapplied forrnalism. In order to list substituents in alphabetical order or deal
with rearrangernents between annular nitrogens sorne authors have used the narne '1,3,5-
triazoles' thus breaking one general rule of nornenclature in order to cornply with another.
R'
N
R S '/ 'N
\ \ --1J
N R,1
(1)
R'
N
R S ( 'ìJR3
N-N
(2)
The theoretically unlikely 'isotriazole' (3) is best understood as the acid (4a) consisting
of a proton balanced by the rnesorneric triazolate anion rnore cornpactly represented as
(4b) in Scherne 1 (81HCl37)l).
H R 3
X
N N
L/ -
R S N
(3)
[ R (Y -. R S (:'ìì R3 -. R3(y J W == rR\ ,'y J H+
N R3 N N N RS L N R3
(4a) (4b)
Scheme 1
In order to distinguish 1,2,3-triazoles (see Chapter 4.11) from 1,2,4-triazoles, the prefix
v- is used for the forrner and s- for the latter. If, as in this chapter, the context clearly
suggests 1,2,4-triazoles, the prefix 1,2,4- or s- rnay be ornitted.
Partially or fully reduced triazoles (triazolines and triazolidines, respectively) with
rnonovalent substituents are relatively unstable and of little current interest. They are not
treated separately here as in other chapters. Triazolines and triazolidines without exocyclic
double bonds, i.e. without ring-linked functions such as =0, =S, =NR'R", =CR'R", etc.,
are not arornatic. Few representatives of these classes have been prepared
(81 HC(37)1 p. 503, 516); sorne of those readily available rnay owe their stability to substitution
by, or fusion to, other heterocyclic rings. Like their aliphatic analogues, non-arornatic
triazolines and triazolidines are readily hydrolyzed in acidic rnedia; other electrophilic
reagents also open the ring. Those with substituents such as =0, =S or =NR rnay be
written as arornatic tautorners (Scherne 2) rernernbering, however, that graphical con-
venience rnust not be regarded as the solution of problems arising out of tautornerisrn or
rnesornerisrn. The sarne applies to the verbal or taxonornic convenience of terrns such as
'hydroxytriazole' or 'rnercaptotriazole' for cornpounds best regarded as triazolinones and
triazolinethiones, respectively. With such qualifications, the terrn 'triazole' rnay be used
generically, not only for 1,2,4-triazoles proper but also for triazolinones, etc. that are
H
N, N
X NR -'- HX( 'NR
N =./ ...--- N =./
H
N
x '
\ NR
HN-{
x 3
-'-
...---
H
X s N
'NR
N=./
x 3
N
HX S ( 'NR
HN-{
X3
N
-'- HX s <"", 'NR
...--- \ =./
N - X 3 H
t'Ct;.
--
x 3 , X S = 0, S or NR'
Scheme 2
1,2,4- Triazoles
735
potentially arornatic, and even for unarnbiguously non-arornatic triazolines, triazolidines
and other cornpounds forrnally derived frorn 1,2,4-triazoles.
A few trivial narnes for 1,2,4-triazoles are in comrnon use: 3,5-dioxo-1,2,4-triazolidines
(5) are called urazoles, and the corresponding 3,5-diarnino cornpounds (6) guanazoles.
H
o NrO
HN-NH
(5)
H
N
H 2 N( JNH2
N-N
(6)
A convenient shorthand representation of 1,2,4-triazoles illustrated by formally written
exarnples and their abbreviated equivalents (Scheme 3) rnay help those taking notes but
will not be used in this chapter.
(1) == R s IR3
RI
R 4
(2)==
(3) == Rsl- ß
3
Ph
Me(N'N == Me l N0 2
N -1J Ph.::.:r::
N0 2
H
N
S\" 'N
HN-1J
Me
H
==H
Scheme 3
The history of 1,2,4-triazoles is less than a century old and starts with the work of Bladin
(1885CB1544) who synthesized the first representatives and coined the narne for the class.
The alternative terrn 'pyrrodiazoles' is no longer in use. Well over 20000 'triazoles' (in the
most general sense as explained above) are known but practical applications have been
very few until recently. Although rnost triazoles are readily prepared and stored, expensive
starting materials or sensitive interrnediates appear to have discouraged industrial syntheses
and wide application. Thanks to improved preparative techniques the field of applications
has been so rapidly growing during the last two decades that its appreciation requires a
review beyond the size of this rnonograph.
The first studies of 1,2,4-triazoles were concerned with structural isornerisrn. Modern
instrurnental and theoretical rnethods achieved much success in dealing with tautomeric
problerns, the cornplexity of which is one of the enduring charms of the chernistry of
1,2,4-triazoles. However, sorne structural and rnany tautorneric problerns require further
study; kinetic and other quantitative rnechanistic studies are scarce; the stereochernistry
and photochernistry of 1,2,4-triazoles are virtually unexplored.
Few books on general organic chernistry deal with 1,2,4-triazoles beyond naming the
ring system. Even specialized texts of heterocyclic chernistry are not rnuch rnore inforrnative
with the exception of (B-67MI41200) which introduces the student to such properties of
triazoles that conforrn to the generalizable behaviour of kindred heterocycles.
Two reviews cover the first 70 years of the chemistry of 1,2,4-triazoles: (61CRV87) deals
not only with the sirnple triazoles discussed in this Chapter but also with their fused
polynuclear systerns (see Chapter 4.15); (B-61MI41200) considers both s- and v-triazoles (for
the latter see Chapter 4.11).
The most recent review (81CHC(37)1) lays stress on synthetic methods and provides an
extensive tabulation of 1,2,4-triazoles up to 1976; references to reactivity and applications
are nurnerous and interesting but subordinated to the rnain therne.
Another review (B-76M141200) treats the structure and reactivity of azoles with references
up to and including 1974, and contains valuable tables of physical properties of many
triazoles in various functional classes.
This rnonograph aims to present a cornposite picture of the chernistry of 1,2,4-triazoles
through examples chosen to display the variety of its problems and rnethods. It is also
intended to draw attention to some critical rnatters that tend to be overlooked by those
whose main concern is the ordering of a vast amount of material. Since the voluminous
controversy on some points of triazole chemistry is beyond the scope of this rnonograph,
it is hoped that readers irritated by seemingly dogmatic arbitration without full references
will consult the appropriate sections of the reviews quoted above.
736
1,2,4- Triazoles
4.12.2 STRUCTURE
4.12.2.1 Constitutional Problems and Methods
Identification of the 1,2,4-triazole ring and location of its substituents can be decided on
the evidence of synthesis and molecular formula in a few cases. However, the early literature
abounds in structural errors resulting frorn unjustified confidence in elernentary rnethods
and frorn the absence of instrurnental analysis that provides a variety of independent
structural proofs in our days. A few examples illustrate points to be kept in rnind by sceptical
triazole chernists.
Addition of phenylhydrazine to cyanogen affords 'dicyanophenylhydrazine' (7) or (8);
acylation and cyclization with acetic anhydride affords a triazole for which one rnust consider
structures (9) or (10) convertible into (11) or (12) respectively (Scherne 4). The first
assurnption of (7), and hence (9) and (11), was proved wrong by showing the correctness
of (8) (1893CB2385); cornpounds (10) and (12) were also obtained by alternative syntheses
frorn structurally unarnbiguous starting rnaterials.
NH 2
/ Ac,O
PhN --+
I
HN=C-CN
(7)
Ph
N
NC<"" 'N
\\ --1J .----+
N Me
(9)
Ph
N,
\\J
N Me
(11)
/
N
II
H 2 N-C-CN
(8)
NHPh
Ac,O M ("" , M ("" ,
--+ e\\ N m_.+ \\ f
N--1J N.....!!
CN
(10)
(12)
Scheme 4
Depending on substituents and solvents, the equilibriurn in Scheme 5 favours the acyclic
cornponent (13) or the triazolidinone (14) (78JHC806). The dirnerization of N-unsubstituted
1,2,4-triazolecarbaldehyde (15) (71AJC393) in Scherne 6 presents a sirnilar problern of
cycloisornerisrn (see Section 4.12.3.3). The possibility of hydrate or alcoholate forrnation
rnay rnask cyclization if the proof depends on elementary analyses alone; the usual rnethods
for the deterrnination of molecular weights are inadequate, and spectroscopic rnethods have
to be used with care since the solvent used for analytical purposes rnay affect equilibria
such as those presented in Schernes 5 and 6, and the sarne applies to the conditions irnplied
in rnass spectrornetry.
R 1
O N,
RCH=NNR1-CONHR4 \ NH
(13) R 4 N...J R
(14)
Scheme 5
H H ><y OH
N N -N N
OHC\\ 'N R< 0.- )R
N--1J -= N - N
R N
H OH
(15)
Scheme 6
Cyclizations of (16) as represented in Scherne 7 can afford triazole derivatives (17) or
isorneric triazoles (18) or other heterocycles (19). The clairned isolation of two stable
tautorners of (17) has been shown to be in error by dernonstration of the isornerization
involving (17) and (19; X = 0) (60LA(638)136).
Compounds originally thought to have the stereochernically strained structure (20) are
now understood to be rnesoionic compounds (S7QR1S) (see Section 4.12.2.5).
1,2,4- Triazoles
737
R'
N
R"í:r H
x
(17)
NH 2
/
+-- X=C + R"COY
"
NHNHR'
(16)
X
R'=H R"t" '-,NH
-- \\ II 2
N-N
(18) X=NR'"
(19) X = O,S
Scheme 7
Ph
N"
h I
PhN
(20)
The tautomerisrn of 1,2,4-triazoles (see Chapter 4.01 and (76AHC(Sl)1)) rnay involve one
or more of the following possibilities: annular prototropy, prototropy involving both the
ring and substituents and tautomerism restricted to the substituent. Only the first two of
these will be considered.
In N-unsubstituted triazoles (lor 2; R 1 , R 4 = H) prototropy between nuclear N centres
may occur. When R 3 and R S are different, the equilibriurn in Scherne 8 is not only of
theoretical importance but may affect alkylation, acylation, prototropy between ring and
substituents, ligand properties and so on. Most experimental and theoretical considerations
favour 1H (1) (or 2H (21)) as the predominant or only tautomer; the 4H tautomer may
playa comparable role. The paradox arises from the aU too common oversimplification of
the problem: the tautomeric status of a given triazole need not be the sarne in solution,
melt, solid or gas phase. Variation of substituents, solvents, temperature and the often
ignored variation of energy input by different analytical methods provide a field of results
rather than a unanimous decision for or against a certain tautomer.
H
N N
R S " 'N --'" R\ ' 'NH
N -.!J ...---- N d
R 3 R 3
(1) R 1 = H (21)
Scheme 8
Tautomerisrn involving 'isotriazoles' may be disrnissed on considering that (3) lacks the
aromaticityof (4), and the structures (3) and (4) are excluded by the rnolecular geornetry
derived from physical measurements. In addition, (4) exaggerates the acidity of unsubstituted
triazoles.
Prototropy in triazoles is particularly cornplex when substituents such as OH, SH and
NHR are available to donate protons to annular N. A detailed discussion of all possible
sub-cases of this type is beyond the scope of this chapter, but the main aspects of this
matter are reviewed in a broad critical context (76AHC(S1)1, p. 388, 414, 444) tabulating
generalizations and their levels of reliability. The section on reactivity (Section 4.12.3) gives
examples of the variability of tautomeric preference in some reactions.
Related to tautomeric problems of 1,2,4-triazoles are those concerned with hydrogen
bonding. N- Unsubstituted triazoles (1) or (2) with R 1 or R 4 = H may be linked by inter-
molecular bridges between 'pyrrole' NH and 'pyridine' -N=; if then R 3 = 2-pyridyl a
variety of intermolecular and intramolecular hydrogen bridges are possible.
Given the aromatic nature and small size of the 1,2,4-triazole ring, the relatively few
measurements on which the accepted notion of its coplanarity rests need not be questioned.
If puckering could be induced through the bonding or steric repulsion of substituents, one
would expect optical activity which has not been observed as yet. Triazole derivatives with
asymmetric substituents (22) can be obtained in optically active forrn and as a stereospecific
dienophile it has found extensive use in the resolution of hornocyclic dienes (SOJOCSlOS). A
little information is available on the conformation of some triazoles (81RCR336).
MeCHPh
N
0\,,';0
N=N
(22)
738
1,2,4- Triazoles
Polyrnorphism has been reported for a few triazoles (B-61MI41201). Application of rnodern
crystallographic rnethods to kinetic studies of the interchange and exclusion of structural
isornerization would be of interest.
Another irnperfectly understood molecular multiplicity is displayed by 3-hydroxymethyl-
1,5-diphenyl-1,2,4-triazole (23; R = Ph) (62TS39). The labile forrn 'A' (rn.p. 132-133 0 C)
changes into the stable forrn 'B' (rn.p. 153-154 0 C) in neutral solution and faster in the
presence of acid. In methanol the conversion is complete in 48 hours and is accompanied
by changes of the UV spectrurn. The IR spectra indicate isorners of similar chernical
behaviour; in fact 'A' and 'B' undergo the sarne reactions and yield identical derivatives.
The IR spectrurn indicates stronger hydrogen bonding of the alcoholic OH in 'A'. Polyrner-
ism and functional differences having been excluded, the rernaining alternatives include
buckling of the ring (which should have stereoisorneric consequences) and the doubtful
hypothesis of valence isomers. A similar isornerisrn is suggested in the case of (23; R =
4-C 6 H 4 0Me).
R
N,
Ph" _it
N CH 2 0H
(23) R = Ph, 4-C 6 H 4 0Me
The rnolecular geornetry of 1,2,4-triazoles has been studied rnostly in relation to annular
tautomerisrn, especially that of sirnple cornpounds in which 1H and 4H tatuorners have
different syrnrnetries.
Although crystallographic and related rnethods (see Section 4.12.2.2) have been used in
tautorneric studies, spectroscopic methods are most cornrnonly used for this purpose (see
Section 4.12.2.3). Theoretical methods (see Section 4.12.2.4) rely rnostly on therrnochernical
information, data on acidity and dipole rnornents to be considered in the sarne sub-section
(see Section 4.12.2.4).
Constitutional studies of rnesoionic cornpounds rnake use of all the rnethods rnentioned
above, and will be treated under Section 4.12.2.5.
4.12.2.2 Molecular Geometry and Dimensions
The intuitive statistical argument from two 'hydrazinic' N centres against one 'arnine' N
favours the less syrnmetricallH rather than the symrnetrical4H structure for 1,2,4-triazole.
On the evidence of X-ray diffraction analysis the solid parent triazole has a planar structure
with hydrogen bridges between N-1 and N-4 of neighbouring rings; of the two N-H bond
lengths irnplied, only that leading to N-1 is of the order required by covalent bonding
(65MI41200). Confirrnation frorn sirnilar studies carried out at -160 oC proves the rnolecular
dirnensions as shown in Table 1 for one unit of a pleated sheet linked by hydrogen bridges
(69AX(B)135). Slightly different values obtain at roorn ternperature or in substituted arornatic
triazoles.
Table 1 Molecular Geometry of 1,2,4- Triazole a at -160 oC (69AXIBI13S)
Angle (0) Bond Bond length (pm)
5-1-4 110.2 1-2 135.9
1-2-3 102.1 2--3 132.3
2-3-4 114.6 3-4 135.9
3--4-5 103.0 4-5 132.4
4--5-1 110.1 5--1 133.1
N(I)-H 103.0
C(3)-H 93.0
C(5)-H 93.0
a The numbering refers to annular centres in IH-l,2,4-triazole.
The microwave spectrurn of triazole in the vapour phase also supports the 1H structure
(7ICC873) for the rnonorner known to be the species present in the gaseous state (1892CB22S).
1,2,4- Triazoles
739
Triazole is monomeric or only slightly associated in polar solvents (in which it is soluble),
but solubility in non-polar solvents is slight and intermolecular bonds persist (40MI41200).
Further evidence in support of the 1H structure appears in Section 4.12.2.4.
Although 1,2,4-triazole is formally related to pyrazole and imidazole, it resembles the
latter. Its melting point (121 oc) and boílíng point (260 o C) are rnore similar to those of
imidazole than to those of pyrazole. However, in not too concentrated solutions pyrazole
is a closer analogue than imidazole. For a brief review see (69JCS(C)1056). Substitution on
N-110wers the melting point considerably, that on N-4 less so, but all known triazoles are
solid at room temperature.
Information on structure and molecular geornetry is of importance in pharmacodynamic
studies: work on 2-morpholinoethyltriazoles (77JHC439) is a good example of the combina-
tion of crystallographic and other analytical techniques for this purpose.
Semiconductive properties of imidazole have been derived frorn protonic rnigration or
proton tunnelling in an array of rotating heterocycles (6SMI41200). The model appears to
be applicable to 1,2,4-triazole which has a specific conductivity of about 10- 10 ohm -1 crn-\
of the same order as irnidazole.
4.12.2.3 Molecular Spectra
4.12.2.3.1 UV spectra
UV spectra of representative 1,2,4-triazoles have been tabulated (61CRV87, B-76MI41200,
p. 267). The parent triazole absorbs around 210 nm and lacks intensive n 'Tf bands at higher
wavelengths. Aryl substituents have a bathochrornic effect that varies with the site of
substitution in the order 3 (or 5) > 1 >4. The 3- or 5-aryltriazoles have non-ionic canonical
structures which are lacking for 1- and 4-isomers. The considerable bathochromic and
slight hypochrornic effects shown by 3-phenyl- and 3-m thyl-5-phenyl-l,2,4-triazoles in
the presence of alkali are sirnilarly explained, while changes of extinction observed when
N-1 is substituted by Me have been ascribed to steric effects (S4JCS42S6).
Hydroxytriazoles and tautomeric triazolinones have a cornmon mesorneric anion, hence
their spectra are affected in basic solvents. UV spectra have been used to demonstrate the
predominantly dioxo structure of 1-phenyl-1,2,4-triazolidine-3,5-dione (66T(S7)213) and the
thione structure of mercaptotriazoles (66ACSS7) utilized also in theoretical work.
The UV spectra of C-aminotriazoles are not affected by change from neutral to acid
solvents (67JCS(B)641). The considerable hyperchromic effects combined with hypochromic
or bathochromic shifts shown by 3-amino-5-(3-pyridyl)-1,2,4-triazole in aqueous solutions
containing varying concentrations of hydrochloric acid are due to the pyridine rnoiety
(S4JCS4S0S).
While N- acylation of the triazole nucleus results in a bathochromic shift, acylation of
substituent amino groups has a negligible spectroscopic effect (SSCR(241)1049).
4.12.2.3.2 IR spectra
IR spectra of N-acyltriazoles (61CRV87) show C-N stretching vibrations at 1208-
1212 cm- 1 and 1245-1266 cm- 1 ; the c=o stretching at 1756 cm- 1 is in excess of that for
carbonyl in Alk-COR and -CONR z . A detailed comparison of IR absorptions of triazole,
halotriazoles and their salts is found in (70KGS248).
Absorption in the region of 2400-3200 cm -1 characteristic for N-unsubstituted triazoles
has led to the parent triazole being regarded as a salt, triazolium triazolate, but this is
contradicted on all other experimental and theoretical evidence. However, a detailed study
of the IR spectra of N- unsubstituted triazoles in the region 1700-3000 cm -1 reveals a
difference between triazoles substituted on 3- (or 5- or 3,5-) by pyridyl and those with
substituents such as Br, Cl, Me, CHzOH, Ph and PhCH 2 . Both groups have two sets of
characteristic bands with the ratio of intensities in the range 1.6-9.6 for pyridyltriazoles
and 2.0-6.6 for others. Plots of intensity ratios against band maxima show a decreasing
parabolic pattern between 1700-1940 cm- 1 and a symrnetrical rise between 2473-
2800 cm- 1 for pyridyltriazoles, but such variations are not noted in the other group.
. Hydrogen bonding is involved in the explanation of these observations (71PMH(4)272). More
740
1,2,4- Triazoles
specifically, proton tunnelling has been suggested by analogy with other systerns containing
strong acidic and basic centres (69JCS(C)1056). For a cornplex case of this nature (24) see
(77AJC421).
Ph" t/.'
Ph N /N N +
,'iN ' ., R" a
N, ' ...o R'
"' "'O,, _N Ö Na+
r R "
(24)
Characteristic exarnples of the use of IR spectra are structural studies on urazoles and
triazolinones (66T(S7)213) and triazolinethiones (71JCS(C)1016). Tautomeric problerns of oxo-
hydroxy and thione-thiol systems are simplified by N-alkylation (73CPB1342). Although
earlier views in favour of oxo and thio rather than hydroxy and thiol forrns have been
confirrned, counter-exarnples have been found; 3-hydroxy-2-rnethyl-5-phenyl-1,2,4-
triazole (25) is preferred to the oxo tautorner (26) while the isorneric 4-rnethyl cornpound
(27) follows the general rule (Scherne 9).
Me Me
N O N,
HO( N "-::ÿ \ I.N
N --1Ph HN --1Ph
(25) (26)
Scheme 9
H
N
O 'N
MeN --1Ph
(27)
IR data and force constant calculations suggest that the 3-nitro structure (28) is preferable
to the 5-nitro structure (29) (73KGS707). Non-tautorneric substituents on C-3 and C-5 of
N-unsubstituted triazoles raise questions of annular prototropy. Although the location of
protons on N-1 or N-2 is favoured over the site at N-4, the choice between N-1 and N-2
is affected by solvents and substituents capable of imrnobilizing the proton through inter-
rnolecular bonding, e.g. furyl or 2-pyridyl (ncPB2096). The general rule (7SCPB9SS) clairns
that location of the proton on N-1 or N-2 is deterrnined according to whichever is nearest
to the best electron-donating substituent on C-3 and C-5. Preference for the 3-nitro structure
(28) over the 5-nitro (29) follows the rule but C-3 or C-5 functions capable of forrning
intrarnolecular hydrogen bonds with an annular N could prornote anomalous structures
such as (30) that would breach the general rule of preference for arnino over irnino groups.
However, acylation studies of arninotriazoles (80KGS1414) argue for regular arnino structures
with exceptions such as the bistriazole (31).
H
N,
( _It
N N0 2
(28)
H
N,
02 N ( N
N J
(29)
...0.
ON "H
t-r-!
N, NR
N
Me
(30)
4.12.2.3.3 NMR spectra
COR COR
HN N'N N N'rNH
HN--!( J-NH
(CH 2 )s
(31) R = Me, Ph
NMR spectra of representative triazoles have been tabulated (B-76MI41200, p. 277). Because
of rapid exchange, N - H signais of rnolten triazoles have been found in the range 10.88-
11.40 p.p.rn. down field frorn DMSO (69JCS(C)10S6), close to values for irnidazole but
substantially higher than those for pyrazole. On NMR evidence, association in
hexadeuteroacetone increases (69TL49S) but the bridged units of triazole do not share the
bridging protons equally: the pleated sheet structure discrirninates in favour of the 1H form.
One of the first successes of NMR analysis of triazoles was the until then rnuch debated
position of N-acyl groups: the protons on C-3 and C-5 are equivalent in 4-acyltriazoles
but different in 1-acyl isorners; the latter alternative has been proved by two signals occurring
in the ratio 1: 1 (62JOC2631).
1,2,4- Triazoles
741
The parent triazole shows a broad singlet in HMPT slightly above room tern perature
(88.03 at 37 oc) or slightly below it (8 8.17 at 10 OC); on cooling to -34 "C two signals are
obtained at 8 8.85 (H-5) and 8 7.92 (H-3). I-Methyltriazole behaves sirnilarly, but the single
band (8 8.20 at 37 oc) of 4-rnethyltriazole undergoes a slight shift to 8 8.34 on cooling to
-40 oC but is not split (68JOC2956). This paper estimates the half-life of a proton on N-! as
4 ns and provides thermodynarnic information on the process of coalescence. For sorne critical
rernarks on this rnuch quoted work see (76AHC(SI)I, p. 22).
The down field shift of the signal for the proton on C-5 in trifluoroacetic acid has been
used to establish the acidity of C-H in nitrotriazole (69AJC2251) and to dernonstrate proton-
ation at N-1 or N-4 according to whether N-4 or N-1 is substituted (67JCS(B)516). It was
shown by NMR spectroscopy that the C-H nearest to the nitrogen substituted by an
electron donor is most sensitive to solvent effects (67BSF2630) as confirrned by (75CPB955).
On the other hand, NMR spectroscopy is not suitable for the deterrnination of tautomeric
equilibrium constants by the interpolation rnethod as shifts of the tautorneric equilibrium
have little effect on chernical shifts (67TL2109).
The ratio 1H : 4H of the parent substance in concentrated methanolic solution has been
estimated as 1.5 by 14N NMR (72T637) but this result rnust be qualified by solvent effects
(73JA324). The use of 13C NMR does not appear to be more suitable for the assessrnent of
tautomeric equilibria (76AHC(Sl)49) or in Hückel calculations (68JA3543). However, 13C NMR
has been used to establish the fused structure (32) in a cornplex study instead of the
mechanistically rnore plausible (33) (81KGS694).
Ph Ph
/N N,
N N
L / -\--1/
Ph NyN Ph
o
(32)
Ph Ph
....N"-.- N
N II CO" 'N
LN N-.!J
Ph Ph
(33)
4.12.2.3.4 Mass spectrometry
Mass spectrometry of 1,2,4-triazoles has afforded many useful results, but some of its
interpretations have raised controversies that are not settled as yet. An elirnination pattern
of the parent substance (68CC727) postulates a 4H structure decomposed via an 'isotriazole'
and cleaved across the link between N-1 and N-2. A more substantial study of triazoles
(71JHC773) clairns elimination of nitrile leaving a diaziriniurn radical cation, which plausibly
suggests a reversal of triazole syntheses from nitriles and nitrilium reagents (see Section
4.12.4.2.2). Assumption of autotropy, involving the identical 1H and 2H tautorners leads
to an interpretation of data that assigns negligible weight to the 4H tautorner (720MS(6) 1139).
A careful rnajor study of alkyltriazoles (730MS(7)57) following on a dernonstration that the
complex rnass spectroscopic patterns of triazolinethiones require extensive labelling with
2 H and 15 N (72AJC335) cornes to the conclusion that observed decornpositions of the triazole
ring are consistent with 1H, 2H and 4H parent molecules. Mass spectroscopy of triazoles
(34) may tip the balance of argument in favour of interpretations based on the 1H form
(800MSI72) but the substituents of (34) may affect the tautornerism in a manner that does
not apply to 1,2,4-triazole and its simple alkyl hornologues.
H
N
Ph" 'N
NJ
SR
(34)
The equilibriurn between 1H- (or 2H-) and 4H-forms is expected to be different in
excited and unexcited molecules, hence interference with a rnolecule to a disruptive extent
rnay without paradox afford results at odds with those obtained by gentler rnethods on
quasi-static rnolecules.
At present the rnajor value of mass spectrornetry to structural triazole chemistry appears
to be in intricate heterocyclic reactions giving rise sirnultaneously not only to triazoles but
rnany other heterocycles at the same tirne (81KGS694). Identification of unstable triazolines
has been aided by mass spectrometry as well as by their NMR data (71BSF3296, 73BCJ1250).
742
1,2,4- Triazoles
4.12.2.4 Theoretical Studies
4.12.2.4.1 Thermochemistry
Early data on the heat of combustion of triazoles include sorne for cornpounds selected
for their exceptionally high nitrogen content (57JPC261). Resonance energy estirnates of
different authors vary in the range of 83.7-205.9 kJ rnol- 1 ; of these the highest value
appears rnost probable, and corn pares reasonably with that of pyrazole but less satisfactorily
with that of imidazole (61MI41202). Calculated energy differences between azole tautorners
support preference for the 1H over the 4H tautomer (69JA796). Sirnilarly, the usual
tautomeric preference for triazolinones over hydroxytriazoles and arninotriazoles over
triazolinirnines are supported on therrnochernical evidence (7OJA2929).
4.12.2.4.2 Acidity
It is rernarkable that acidity constants of triazoles as deterrnined for the first tirne
(06CB1831) require only srnall corrections for theoretical purposes (70JHC991). A representa-
tive selection of acidity data with rnethodical notes (B-76MI41200, p.284) has been drawn
rnainly frorn papers that consider the applicability of the Harnrnett treatrnent to the pKa
values of triazoles. The parent substance has pKa values of 2.19 (as base) and 10.26 (as
acid). The Harnrnett equation is rnore satisfactory for acidic than basic values of triazoles
(65ZC381). For triazoles without acidic groups other than the annular NH, p = 6.00; for 3-
(or 5-) 'hydroxytriazoles' the value is 7.62; in either case (J'm constants are rnost appropriate
(6SZC304) as for nitrotriazoles (70KGS558).
The strong basicity of 1,2,4-triazoles on cornparison with azoles other than irnidazole is
explained by the rnesorneric stabilization of the arnidiniurn ion formed on protonation
(67JCS(B)S16).
Acidity constants of 1,2,4-triazole and its 1-rnethyl and 4-rnethyl derivatives have been
used to calculate the equilibriurn constant for 1H and 4H tautorners as 10 in favour of
the forrner, but a rnore general treatrnent and other data suggest a lower value (76AHC(SI)1,
p.284).
On CNDO/2 calculations with pKa (as base) = 2.30 for triazole, the basicities of 1H and
4H tautorners are estirnated to be equal, and rnaxirnurn separation of protonated nitrogens
(i.e. N-1 and N-4 rather than N-1 and N-2) is predicted to afford the rnost stable cation
(68TL3727). Acidity constants of 1,2,4-triazoles correlate with total and 7T-electron densities
but not with the lone pair character of the pyridine-type N in MO calculations (70JCS(B)1692,
70BCJ3344).
4.12.2.4.3 Dipole moments
Early calculations of electron densities in 1,2,4-triazole and its anion, beginning with
(SlMI41201) provide qualitatively correct predictions of reactivity. Most of the rnodern
theoretical work is checked against dipole rnornents. Inforrnation surnrnarized in Table 2
shows preference for the 1H forrnulation. The dipole rnornents of N- un substituted
nitrotriazoles suggest 'fixation' of the proton on N-1 (71KGS275).
13C NMR spectroscopy used in conjunction with lanthanide shift reagents supports the
application of LCAO-SCF calculations to 1,2,4-triazoles (74JOC357).
4.12.2.5 Betaines and Mesoionic Compounds
Quaternization of the triazole amino acid (35) to (36) only superficially resernbles the
conversion of glycine into its betaine as in the forrner case the chernical systern includes
(37) which irnplies rnesorneric distribution of a negative charge in the heterocyclic ring
(Scherne 10). The betaine (38) (69MI41200) and its derivatives have attracted considerable
interest frorn crystallographers (73JCS(P2)1, 73JCS(P2)4, 73JCS(P2)9).
Of wider interest are rnesornerically-stabilized zwitterions of the general forrnula (39)
with R 1 and R 4 other than H. The charge on the nucleus arises without the intervention
1,2,4- Triazoles
743
Table 2 Dipole Moments (l0- 30 Cm) of some 1,2,4-Triazoles'
Parent compound
In dioxan
Dielectric constant
Microwave spectrum
of vapour
Dipole moment (10- 30 C m)
Found Calculated Method
IH 4H
10.57
10.98 10.81 17.81 Vectorial
9.07 10.24 CNDO/2
7.77 VESCF
10.24 19.12 LCAO-A
10.31 18.95 LCAO b
18.78 LCAO c
12.31 17.91 LCAO-SCF
10.07 CNDO/2 d
11.68
9.81"
18.78"
1,2,4-Triazole
Experimental
notes
I-Methyl
I-Phenyl
4-Phenyl
In dioxan
In benzene
In benzene
. Unless otherwise indicated, recalculated from (76AHCtSI J 1. p. 286). b + (J'- Electrons. C All electrons. d Fully optimized
geometry. e (43MI41200).
H H
""N, _ ""N,
HOzC \\ N OzC \\ N
N-.!J -- N-.!J+
NHz NMe
(35) (36)
N,
HOzC" N
N J
NMe3
(37)
NHz
_./N" +
S\\ //NHNH 3
N-N
(38)
t 371
N
HO Cc:f' 'N
+-+ z \ II
N--9+
- NMe3
Scheme 10
+-+ HOzC(N'N ]
N =.1+
NMe3
of tautomerisrn, and the negative charge is carried on 0-, S-, RN- or a carbanion. For
graphical convention one may write (40) or (41), the latter implying the notional addition
of water (81HC(37)1, p. S99).
[ Rl R' j Rl
N N N
R5(+'N +-+ R 5 ,,+ 'N etc. == R\1' ')N
R 4 N-{_ R4N _ R4!'Ì _
(39) (40)
R5( ;N ] OW
R 4 N 0
XH
(41)
The first syntheses of rnesoionic corn pounds included 1,2,4-triazoles and their oxa and
thia analogues. The structure postulated at first as (20) was rejected on stereochernical
grounds and on consideration of the large dipole mornent, to be replaced by a charged
monocyclic structure, defined as mesoionic and considerably extended to a great variety of
theoretically and practically important exarnples (S7QR1S, 76AHC(19)3).
Establishrnent of structures such as (40) requires care as the usual rnethods of preparation
do not exclude forrnation of non-triazolic isomers such as (42). Spectroscopic studies
(67AJCl779, 67JOC224S), an alternative synthesis of (40; Rt, R 4 = Ph, R 5 = H) (67TL4261) and
those of isorneric non-triazole heterocycles (42) provide conclusive proof.
R5( )ÑR4
R1!'Ì:':Í\j
(42) X= 0, S
4.12.3 REACTIVITY
4.12.3.1 General Considerations
On comparison of simple 1,2,4-triazoles with benzene, replacement of CH=CH in the
latter by NH enhances reactivity towards electrophilic reagents but two replacernents of
CH by N act in the opposite direction (see Section 4.02.1.1). Cornparison with other azoles
is of greater heuristic value still (B-76MI41200).
744
1,2,4- Triazoles
Deactivation against electrophilic attack accounts for the difficulty or failure of nitration,
sulfonation and N-oxidation of 1,2,4-triazoles proper. However, triazolate anions react
readily with electrophilic reagents: alkylation and acylation have received much attention
but halogenation and addition reactions less. Systematic study of the formation and reactions
of salts and metallic complexes is of recent origin.
Substituents on C are exchanged in nucleophilic reactions under mild conditions and in
the absence of activating groups. Reactivity of the ring towards nucleophiles is enhanced
in triazolium cations and rnesoionic triazole derivatives.
If in the absence of detailed mechanistic studies one cannot safely assign the site of the
initial attack to C or N, it is best to consider such reactions under the heading of ring
stability. The reactivities of ring atoms and those of the substituents they carry are inter-
linked, and it is a matter of convenience whether to regard certain reactions as chemical
properties of the former or of the latter. In general, reactions involving movement of
substituents to and from ring atoms will be considered under reactions of the ring atoms
concerned.
Tautomerism of compounds with formal substituents such as OH, SH and NHR allows
their classification not only as aromatic but also as reduced triazoles. As a rnatter of economy,
it is best not to duplicate reference to such materials even though some of their reactions
are characteristic of the aromatic tautomer while others are the outcome of the triazoline
or triazolidine structure.
Protonation of triazoles as bases or deprotonation to afford triazolates or rnesoionic
derivatives are aspects of reactivity but usually, also here, mentioned under acidity (Section
4.12.2.4.2).
4.12.3.2 Reactivity at the Ring Atoms
4.12.3.2.1 Stability of the ring
From syntheses of 1,2,4-triazoles at raised temperatures one may infer relative thermal
stability at about 300 oc. Although substituents and their location on the ring may undergo
changes on heating, the ring itself is unaffected. Triazolidines are less stable as shown by
the thermal cleavage of (43; Scheme 11) (73BCJ2215).
Ph
SV N , <l
\ NH -. H 2 N-CS-NPh-N=CMe 2
HN-!--Me
Me
(43)
Scheme 11
Insensitivity to photolysis is suggested by the formation of 1,2,4-triazoles frorn some
other heterocycles. However, mesoionic 4-aryl-1-phenyl-1,2,4-triazolin-3-ones (44) are
decomposed on photolysis as in Scheme 12 (ncc498); triazolinethiones lose sulfur only
(70AJC631).
Ph
N
R(.. N
Ar
0-
(44)
Ph
N
R-pN -.
ArN--{
o
Ph
r.'N,
R\\ NAr
N--{
o
!
ArN=NPh + ArNCO + (X I N')R
::::,.,. N
H
Scheme 12
The 1,2,4-triazole ring survives oxidative destruction of aromatic substituents and rings
fused to it but destabilization by a nitrene intermediate (45) permits the oxidative cleavage
of 4-arninotriazoles (46; Scheme 13) (70TL3851). Another instance of destabilization of the
ring by a nitrene substituent (Scheme 14) is the thermal decomposition of azides (47) to
1,2,4- Triazoles
745
NH 2 :N:
N'-.., PblOAc)4 N,
RÇ 1/ RÇ N -'N 2 +RCN
N-N NJ
R
(46) (45)
Scheme 13
NH 2 H
NH 2 NH 2 I N-N N-N
RçN)N3 RçN)B RyN p=N -. R( >=NH R( NH2
N-N N-N N=N N=N N=N
Scheme 14
tetrazines (48) (66TL5369). Triazolidines such as (43) are readily oxidized to acyclic com-
pounds (74M427).
Triazolinones are more sensitive to reduction than aromatic triazoles. Paradoxically,
reduction of the triazolinone (49) with lithium aluminum hydride (Scheme 15) affords the
more unsaturated triazole (50) (71BSF3296).
Me
Ov N, LiAIH4
\ N-----+
NJ
(49)
(H: 3N) í3N
(50)
Scheme 15
0-
OH I
N N
PhNH( )C0 1 Et -. (+)C0 1 Et
PhN-N PhN-N
(49a) (50a)
The drive to aromatization accounts for the elimination of water or amine from substituted
triazolines. Loss of water is illustrated in Scheme 15; aniline rather than water is lost from
(49a; Scheme 15) to give (50 a) (65CB642).
The first reported chemical cleavage of 1,2,4-triazoles subjected to the Schotten-Baumann
reaction has been refuted. However, 4-benzylaminotriazolyl arenesulfonates are easily
cleaved thanks to the loss of aromaticity in the triazolium salt (63JOC543). Another method
is quaternization followed by treatment with concentrated alkali (54CI(L)1458) as in
Scheme 16.
Me
....---N,
Me\\ t
NJ
Me
Me
N
Mel á--" N conc.aq.KOH
-+ Me{+\
3
Me Me
Scheme 16
MeNH 2
+
MeNHNH 2
It is easier to cleave triazolinones (Scheme 17) which may be regarded as cyclic amides
undergoing acid hydrolysis at rates qualitatively predictable from the electronic effects of
their substituents (65LA(682)123).
H
O N' N
dil. H,S04
HNJ ) NH 3 + NH 2 NH 1 + RC0 2 H + CO 2
R
Scheme 17
Ring expansion by reaction with dichlorocarbenes noted in the pyrazole and imidazole
series does not appear to occur with 1,2,4-triazoles but leads to the formation of tristriazole
(51) (69JCS(C)2251) or bistriazole (52; Scheme 18) (72BRP1269619). The first of these reactions
is induced by a free radical reagent but the mechanism of the second one is in doubt.
H [ Me í
ç N, :CCI, N?\
Me N ----+ INCH
J Me'-':::-N 1
N Me 3
(51)
H
ç N, Ph2CCI, N?\ r=:oN
N I N-CPh -N I
II Et)N '-':::- I 2 \-:=::=J
N ----2 N N
(52)
Scheme 18
746
1,2,4- Triazoles
4.12.3.2.2 Electrophilic attack at nitrogen
Alkylation and arylation including quaternization are well explored, and acylation has
also attracted much interest. The other classes of reactions to be considered here are
addition reactions involving annular NH as the addend, N- halogenation and reactions
involving metallic centres.
Alkylation of triazolic NH (61CRV87, B-76MI41200, p. 81), either by diazomethane or sources
of carbonium reactants, introduces substituents at N-1 rather than N-4. Although alkylation
of simple 1,2,4-triazoles at N-4 is rare and of little practical significance, it has been observed
(S4JCS141). The observed preference for N-1 agrees with a statistical consideration which
does not explain the rarity of 4-alkylation or follows from theory (70JOC2246). More difficult
is the prediction when substitution on 3- and 5- allows a choice between N-1 and N-2
(S4JCS3319) as in Scheme 19. Both of the expected products (53) and (54) are obtained in
ratios that vary with the alkylating agent; a theoretically unexplained 'thumb-rule' suggests
preference for methylation on the nitrogen adjacent to C-phenyl when diazomethane is
employed. Industrial alkylating agents include epoxides (68USP3394143, 74JAP74126679) and
ethylene carbonate (74JAP742017S).
H
N
R S "'" 'N
\\ ---1J
N R 3
Me Me
Mel-NaOH 5 N, N,
I R"'" N + R 3 "'" N
or CH,N, \\ ---1J \\ ---1J
N R3 N R S
(53) (54)
Scheme 19
N-Alkylation of 3-halotriazoles (75BSF647, 75EGPI11074) gives N-1, N-2 and N-4 isomers,
the last of which is obtained in a yield of up to 60% if methylation is carried out with
dimethyl sulfate in the absence of base.
In some cases the observed alkylation on N-4 does not lessen the validity of the
generalization that suggests preference for N-1. Thus 3-phenyl-5-ureido-1,2,4-triazole (55)
is methylated or benzylated to give (56; Scheme 20) because the internal hydrogen bridge
preempts the favoured N-l site.
H
OyN...
HN N,
\' N
N---1J
H Ph
(55)
R
N
---. \\ )NHCONH 2
N-N
(56) R = Me, PhCH 2
Scheme 20
Alkylation of triazolinones is rare. If either N-1 or N-4 is substituted, alkylation affords
1,4-disubstituted triazolinones (6SCB302S).
Nitrotriazoles are alkylated at N-1 or N-2 (70KGS26S, 70KGSSS8) but methylation occurs
at N-l or N-4 in the case of 5-nitro-1,2,4-triazolin-3-one (57) (69KGS1S9).
H
o N
)SMe
PhN-N
(58)
02 N (N y O
HN-NH
(57)
Triazolinethiones are preferentially alkylated on sulfur, but 3-rnethylthio-1-phenyl-
1,2,4-triazolin-5-one (58) is regularly substituted on N-4, although sorne a-methylation
occurs as well (B-76MI41200, p.94). 4,5-Diphenyl-l,2,4-triazoline-3-thione is acylated on S
in the presence of base but On N with acyl halides (74KGS851). The 4-phenyl-5-benzyl
analogue is acylated on N only (7SKGS844).
Generalizations based on alkylations with methyl, ethyl, benzyl and other hydrocarbon
groups are not safely extended to more complex alkylating agents. Thus
tetraacetylglucopyranosylation of 3-methyl-4-phenyl-1,2,4-triazoline-5-thione (59; Scherne
21) substitutes on S to give (60) which rearranges to the N-substituted isomer (61) on
treatment with mercury(II) salt (7SMI41200). Substitution on N rather than S takes place
1,2,4- Triazoles
747
Ph
N
RS( 'ì;Mc
N-N
(60) ) Hg2+
Ph Ph
S N SV N )
'ì;Me \ II
RN-N N-N
Scheme 21 (61) (62)
when the alkylation of 4-phenyl-1,2,4-triazoline-5-thione (62) is being carried out with
epoxide (71KGS700).
Methylation of 3-arnino-1,2,4-triazole does not afford the methylamino derivative but
all the three annular N-methyl derivatives are obtained in ratios that depend on the basicity
of the reaction mixture (73BSF1849). Similar results have been obtained in the case of
ribosylation and other instances (81HC(37)1 p.1S0). Alkylation of aminotriazoles on N-4
is rare.
Activated aromatic halides and 2- or 4-pyridyl halides can be used for the N-arylation
of 1,2,4-triazoles, best achieved by the Ullmann technique (70JCS(C)8S). Preference for
annular arylation on N-1 rather than N-4 is observed but arylations of 3-aminotriazoles
with picryl chloride are anomalous: the parent triazole itself is substituted on N-1 but in
3-aminotriazole the amino group is attacked first, then the adjoining ring NH. Since
4-aminotriazole lacks annular NH groups, picrylation affects the substituent amino group
only (68JHC199).
Triazoles with alkyl, aryl or acyl substituents on N-1 or N-4 can be quaternized. Because
of the mesomeric distribution of the positive charge on triazolium compounds, representa-
tions such as (63) are convenient but the equivalent formula (64) may be used to denote
the site at which quaternization has taken place (the mesomeric nature of (64) must be
kept in rnind of course). Trialkyloxonium tetrafluoroborates are powerful quaternizing
reagents (70JOC2246).
Ac
N
R\'t:')N
MN 0
e R 3
Ph
S N
Y 'ì;Me
HN-N
(59)
RBr
R = tetraacetylglucosyl
Ac
N
R 5,/' 'N
\\+---1J
MeN R 3
Me
N
R5( 'ì;R 3
N-N
(63)
(64)
(65)
Ac
N
R 5,/' 'N
\ \ ---1J
N R 3
(66)
Quaternization takes place so as to maximize the distance between substituents on annular
N. Thus a triazole substituted on N-1 is quaternized on N-4 and vice versa. However,
quaternization of triazolinones and triazolinethiones or diquaternization of aromatic
triazoles may involve N-1 and N-2. Structural proofs of quaternized compounds are simple
in cases such as that of (63): ready removal of the acetyl group from N-1 leaves (65).
If then (63) arose from the methylation of (66), the quaternized site is determined
unambiguously.
In early investigations, when none of the substituents on N could be removed by a
selective method, interpretation of the quaternized structure has led to errors. Thus quater-
nization of 1,3,5-trimethyl-1,2,4-triazole (67; Scheme 22) could afford either or both of
(68) and (69). Degradation as in Scheme 16 proves (69), but not quite conclusively as the
reported formation of ammonia and 1,2-dimethylhydrazine is consistent with either the
alternative structure of (68) or rearrangement between (68) and (69) under certain experi-
mental conditions. Conclusive proof is obtained from NMR spectroscopy which distinguishes
between symmetrical (68) and unsymmetrical (69) or from a chemical method (S9JCS3799)
based on the reactivity of a C-methyl situated between two substituted N-centres as in
(69): cyanine dye formation from the quaternized product of (67) establishes the structure
(69) for the latter.
Me
""N,
Me\\. N
MeÑ e
(69)
Me Me
Mel ,/'N, Me! ,/'N,+
- Me\\ N - Me\\ NMe
N ---1J N---1J
Me Me
(67) (68)
Scheme 22
748
1,2,4- Triazoles
Quaternization of 4-aminotriazoles at N-1 (66MI41200) or that of 5-arnino':1-methyl-l,2,4-
triazole at N-4 (63MI41200) follows the rule predicting attack on N-centres at maximum
separation. Much the same applies to the quaternization of azo dyes derived frorn triazole
(81HC(37)l, p.609) except that 1,4- and 2,4-patterns of substitution are equivalent under this
rule; even the 1,2-isorner may be formed.
Alkylation of 3-methyl-4-phenyltriazolin-5-one (70) with dirnethyl sulfate (Scheme 23)
affords not only the neutral I-methyl derivative (71) but also the mesoionic compound (72)
(66Ac(R)190). On the other hand the isomeric I-methyl-5-phenyltriazolin-3-one (73) affords
the rnesoionic compound (74) with methyl iodide but the rnethoxytriazole (75) with
diazomethane (76CPB1336).
(70)
(71)
(72)
Me Me Me
Ph ( " '\N Ph,/'N'NH CH,N,þ Ph,/'N'N
".. .:I \\ I \\ .JJ
MeN\O. N;O NOMe
(74) (73) (75)
Ph Ph Ph
OV N ", Me,SO. OV N ", -O.........::. 0,
\ lIMe ----. \ lIMe + \( + ':/ Me
HN-N MeN-N N':,:'NMe
Scheme 23
In the absence of NH and potential OH, 4-phenyl-l,2,4-triazoline-3,5-dione (76) is
converted into the unusual quaternary cornpound (77) on treatrnent with diphenyl-
diazomethane (Scheme 24) (65G33). Note that (77) is a triazolidinium zwitterion with both
charges accommodated on the nucleus, hence distinct from mesoionic compounds (40).
Ph Ph
o-yNyo O NyO
N=N /-N-N
Ph c""
(76) 2 (77)
Scheme 24
Quaternization of thiones or thiols proceeds successively through alkylation to methylthio
compounds to attack on annular N centres (59JCS3799, 61LA(641)94, 67JOC2245) to triazolium
salts or rnesoionic compounds. However, 3,5-bis(methylthio)-I-phenyl-l,2,4-triazole could
not be quaternized (S4CI(L)14S8).
Diquaternization is possible. The structure (78) implies rnesomeric distribution of two
charges over the ring. This structure is inferred from hydrolysis as shown in Scheme 25
(nJOC2259).
Me
,.,.-N,
.JJN
Et,O+SF';
Me
( ' > N Me,O+SF';
Þ : + : þ
EtN:.::J BF 4 -
dil.H7
Me
/ ,
V.2 :: NMe
EtN;:J (BF 4 -b
(78)
EtNH 2 + MeNHNHMe
Scheme 25
Although the mechanism of addition of triazolic NH or nucleophilic triazolate to polariz-
able 1T-systems is not known, one may regard such reactions as formally akin to alkylations.
Vinylation of 3-aminotriazole with acetylene in the presence of base affords mainly the
I-vinyl compound in addition to some of the 4-isomer (75MIP464584, 75JAP7504074).
Catalytic additions to acrylic acid and arylalkenes are thought to afford N-l derivatives
(S5JA2572). Acrylonitrile cyanoethylates 3,4-diphenyltriazoline-5-thione (79) on N-l
(75KGS844). Hydroxymethylation with formaldehyde (Scheme 26) also favours N-l
triazolinethiones such as (80) (75KGSI000), but similar reactions occur on N-4 if N-l is
substituted.
Ph
N
Ph\\, ys
N-NH
(79)
An important type of N- alkylation involves the addition of cyclic or acyclic C=CH to
reactive triazolinediones (76; Scheme 27) (81HC(37)1, p.530). However (76) may behave as
the 7T-system to which piperidine adds to yield (81) (76JHC673) or again it acts as a powerful
dienophile affording (82) in Scheme 27 (75JCS(P2)1325).
Ph
oyNyo
HN-NCNMe2
Me,C=CHNMe,/ C " Me
/ '
o
CHz=CHCH=CH, C N
) I NPh
N
o (82) 0
Except for hydroxymethylation (Scheme 26) and self-condensation (Scheme 6), 1,2,4-
triazoles do not give definable products on reactions with aldehydes but the resins formed
are worth closer investigation. Reactions of aminotriazoles with ß-diketo compounds are
used to prepare some fused triazoles (see Chapter 4.15).
All the general references cited devote much space to acylation, mostly performed by
reaction of anhydrides or acyl halides with triazolates or treatment of triazoles in inert
solvents with acyl halides including thiobenzoyl chloride, ethyl chloroformate and phosgene.
In the last mentioned case N,N-carbonylditriazole (83) is formed exothermally; acylation
at N-1 has been proved by NMR spectroscopy (62JOC2631). Carbonyldiazoles are acylating
agents: transacylation between (83) and benzoyl chloride affords 1-benzoyltriazole
(62CB1275). The preparation of 1-acetyl-1,2,4-triazole from the 1-trimethylsilyl derivative
and acetyl chloride (60CB2804) is another practical example of transacylation.
Acylation of triazolates is expected to occur at N-1 but transacylation by displacement
of an electrophilic substituent from N-1 might be predicted to proceed by attack of the
electrophile on N-4. The actual course of the reaction may be explained on the analogy of
isotopic studies on imidazole (66CB29SS) applied to triazole (Scheme 28): the first product
of the sequence is the mixed anhydride (84) that reacts with the liberated triazole at N-l
to afford benzoyltriazole (85) and the unstable carbamic acid (86).
,f
<..... /N
N
I
co
I
,...---N,
_l
(83)
1,2,4- Triazoles
749
H CH,OH
SyN'N CH,O) SyN'N
R 4 N -1J R 4 N -1J
R 3 R 3
(80)
Scheme 26
Ph
OyNyO
N=N
(76)
Scheme 27
Ph
oyNyO
N-N 0
H "N
(81)
CO,COPh
I H
PhCOCI ( N, ( N,
----+ N + N
-1J -1J
(84)
co,
y
1(84)
COPh
,...---N,
-1JN +
(85)
Scheme 28
[ ? Hl
-1J J
(86)
750
1,2,4- Triazoles
Acylation with potassium cyanate, phenylisocyanate and similar reagents gives ureides
(HIHC(37)1. p. 102). According to experirnental conditions, cyanogen affords the carboxamide
(87). The anomalous reaction with o-anisylisocyanate results in the isourea (88).
OMe
HN=T-O -o
N,
Ç. -1JN
N (88)
CONH 2
("'N,
J
(1.r7)
Notwithstanding controversies on 0- against N-acylation of triazolinones, modern views
favour the forrner. The substantial number of 1,2,4-triazole derivatives of phosphorus acids
(81HC(37)1, p.241, 247, 316. 357) are acylated on oxygen even when alternative N-acylation
would have been possible.
This generalization does not extend to 1,2,4-triazolidine-3,5-diones: both the 1-phenyl-
and 4-phenyl-urazoles (89) and (90) can be diacetylated to (91) and (92), respectively, as
in Scheme 29 (70JHC821, 66AP441); the first of these reactions occurs with a yield of 69%
while the yield in the second is almost quantitative. Phosgene does not afford carbonyl-
ditriazolidines but carbamyl chlorides such as (93) which are useful interrnediates in the
synthesis of areas and urethanes (74AP504).
H Ac
O NyO Ac,O þ O NyO
PhN-NH PhN-NAc
(89) (91)
Ph
O NyO
HN-NCOCI
(93)
Ph
O Nyo
HN-NH
(90)
Ph
O NyO
AcN-NAc
(92)
Scheme 29
Some unexpected N-acylations (Scheme 30) carne to light in studies of 4-phenyl-1,2,4-
triazoline-3,5-dione (76). Addition to vinyl acetate is followed by intrarnolecular acylation
to (94), finally yielding (95) (72JOC1454), while reaction with methanol resulted in a 1,2-
dicarboxylic acid (probably through NCH 2 0H formed by reaction with formaldehyde)
isolated as (96) (76CC326).
Ph Ph
O NyO .. O NyO CH,=CHOA\
PhNHCON-NC0 2 Me N=N
(96) (76)
l Ph 1
O Nyo Ph
N-N OVN o
roo -+ \ /
AC'B ) AcN-NCH 2 CHO
+ (95)
(94)
Scheme 30
Acylations of triazolinethiones by acyl halides, isocyanate or isothiocyanate under rnild
conditions take place on sulfur, but higher temperatures appear to favour N- acylation as
in Scheme 31 (74KGS851).
Ph Ph Ph
N S ß N N
PhÇ. Y ..- Ph\\, 'ì;SNa -+ Ph\\, 'ì;SCOPh
N-NCOPh N-N N-N
Scheme 31
The acylation of 3-aminotriazole (97) has received rnuch attention and generated rnuch
controversy (B-76MI41200, p. 120). The general pattern for N-1 or N-2 acylation (Scheme 32)
has heen substantiated (7OJHCI149) through the use of rnixed acylating agents: ordinary and
deuterated acetyl chloride produce (98)-(104), and action of trifluoroacetic anhydride on
acetylated aminotriazoles (98), (103) and (107; X = Ac) affords (105), whence (106).
Products of hydrolysis (107) are reacylated as shown. The results may be summarized in
noting the rapid exchange of acyl on annular nitrogen as against the slow acylation of the
substituent arnino group.
Acylation of guanazole (6) is complex (60RTC836); although acetylation on N-1 or N-2
has not been rigorously established, the assignments are in agreement with later findings
1,2,4- Triazoles
751
(103)
20
Ac Ac H
N ( N, H O N A " 0
,r'N N' ,r'N
\\ -1J -1J \\-1J
N NHz N NHAc" N NHAc"
(99) (105) (107) X = Ac"
H ì 4 :;ý
N N N H Ac'
('N f 'NAc t'/ 'NAc (.ß'N ....---N'N
N -1J N d \ d \\ -1J '""H;O \\ -1J
NHz NHz N NHAc N NHX N NHAc
(97) (98) O) (107) X = Ac (101)
49' 1 '
___ 29%""'" -----.
{ 101) + (37 ) + IÍ N + IÍ N -""è. (107) 50:;' X: A<,
\ N NHAc' N NHAc N NHAc' 50 Yo X - Ac
(102) (103) (104)
Ac=MeCO; Ac'=CD 3 CO; Ac"= CF 3 CO
Scheme 32
Ac"
N'N
(-1J
N NHAc"
(106)
H
N
,r 'N McNCS
\\ -1J --
N NHCSNHMe
H
N
....--- 'N
\\ -1J
N NH
z
(97)
CONHMe
....---N,
\\ -1JN
N NH
temperature 2
McNCO
1 r.t.
N
f 'NCONHMe
Nd
NHz
Scheme 33
such as those cited above, and partly with reactions of 3-aminotriazole with methyl isocyan-
ate and methyl isothiocyanate summarized in Scheme 33 (72JHC99, 73JCS(P1)1209).
Acylation of 4-amino-1,2,4-triazole occurs on the 4-NH z group (63JOC543); the result is
not trivial as alternatives such as triazolium salt forrnation are conceptually possible.
Benzoylation of hydrazinotriazoles (74AJC2447, 75AJC133) is in agreement with the general
behaviour of aminotriazoles.
In the industrially important reaction of bis(dimethylamino)phosphoryl chloride with
3-anilinotriazole (108) attack at the hydrazinic sites gives a rnixture of (109) and (110) as in
Scheme 34 (66RTC429). If R == H, the main product is (110), but for alkyl substituents the ratio
(109): (110) is 2-6, presumably for steric reasons.
H
N
R,r 'N CIPO(NMe,J,
\\ -1J - ,
N NHPh
(108)
PO(NMczh PO(NMczh
N N,
PhNH( 'N + R( /r
N -{ N----2 NHPh
(109) (110)
Scheme 34
A brief review (B-76MI41200, p. 125) does not resolve controversies on the annular arenesul-
fonation of 1,2,4-triazoles, only the substituent is acylated in the case of 4-aminotriazole
(6220B447). For a more extensive bibliography see (81HC(37)1, p. 260,284).
Although electrophilic halogenation of 1,2,4-triazoles is mostly intended as a preparative
method for C- halo triazoles, some N- halo derivatives can be isolated. Chlorination in
aqueous potassium hydrogen carbonate solution gives N-chloro-1,2,4-triazole, assumed to
be the 1-compound which rearranges on heating to the C-halo isomer (69KGSl114) by a
second order reaction in water to t- butyl alcohol (72JPR923). Excess of chlorine in alkaline
752
1,2,4- Triazoles
solution allows the reaction to proceed to 1,3-dichloro- and 1,3,5-trichloro-1,2,4-triazoles.
N-Chlorination occurs with 3-phenyltriazole (67ZC184).
Under moderate conditions, e.g. reacting potassiurn triazolate at OOC, bromine affords
N- bromotriazoles. If the triazole is 3,5-substituted, N- bromotriazole may be obtained
without special care; otherwise C- bromination occurs (67CB2250), presurnably through
N-bromo intermediates since 1,3-dichlorotriazole and 1,3,5-tribromo-1,2,4-triazoles may
be used for the halogenation of other triazoles (69ZC325). Brornination of the 1,2,4-triazole-
3-carboxylic acid has been shown to occur at N-1 (69ZC300).
In the absence of nuclear NH groups susceptible to N- bromination, as in the case of
4-phenyl-1,2,4-triazole, N-bromotriazolium bromide (111) is formed first. This decomposes
on heating to 3-bromo-4-phenyl-1,2,4-triazole (75BSF647).
Br
N
(:' N Br-
Ph N:.:::J
(111)
Iodination with iodine chloride in ethanol or aqueous alkali gives the relatively stable
N- iodotriazole which does not rearrange to the C- halo isorner on heating. This acts as an
iodinating agent when warrned with triazole (69ZC300).
For the somewhat analogous nuclear N-nitration, see Section 4.12.3.2.3.
Since nitrogen centres are responsible for the acidic and basic properties of 1,2,4-triazoles,
salt forrnation rnay be considered to involve reactions at such centres. A nurnber of inorganic
salts and corn pie xes have been noted (OOCB58) but their exact nature and reactivity are not
quite clear.
If we symbolize the parent 1,2,4-triazole as TrH (where H denotes the acidic proton),
TrH.HCl may be written as (TrH 2 tCl- and liberates the free base on treatment with
sodium hydroxide or sodiurn ethoxide in ethanol. This is not the case for TrH' HN0 3 which
on such treatrnent affords TrH'NaN0 3 or less likely TrNa.HN0 3 . Cornpounds such as
TrH.HN0 3 .2HgCh and 3TrH.HN0 3 .4AgN0 3 are even more surprising. Mercury(1I)
chloride complexes have been used as aids in the purification of triazoles, but neither their
nature nor the geornetry of their undoubted attachment to N centres is known, and the
sarne applies to the copper salts noted in some of the earliest investigations of triazoles.
The formation and structure of TrzSn are known (nccs44).
Molten 1,2,4-triazole has been tried as a solvent in high temperature chernistry. It is
merely a solvent for some simple salts such as sodium chloride but transition rnetal halides
are complexed in an unknown manner (66CI(L)600). For derivatives of 1-phenyltriazole see
Section 4.12.5.2.4.
Free radical forrnation from triazoles has been little studied. Oxidation of
triazolidinediones to triazolinones may afford a free radical if dehydrogenation is blocked
as in Scheme 35 (74JA333S). The resulting radical is stable in solution and is isolated as its
dimer.
H
N
o 'NCPhMe 2
MeN ----.{
o
N
O 'NCPhMe 2
MeN
o
Scheme 35
4.12.3.2.3 Electrophilic attack at carbon
Nitration of triazole and its C-monoalkyl derivatives fails. Aryltriazoles are nitrated on
the benzene ring but 3-p-nitrophenyltriazole (112) in which the benzene ring is deactivated
affords the N- nitro derivative (113). This rearranges to the C-nitro compound (Scheme
36) through an isotriazole intermediate on kinetic evidence for a first order intramolecular
rearrangernent (ncc37).
Nitration of triazolinones (possibly reacting as 'phenolic' hydroxytriazoles) with fuming
nitric acid affects the heterocyclic ring with sirnultaneous nitration of the benzene ring in
1- and 4-phenyl derivatives. However, 2- or 3-phenyl derivatives of 1,2,4-triazolin-S-one
are nitrated in the benzene ring exclusively (69CB755).
1,2,4- Triazoles
753
H
,/'N 'N HN0 3 -H z S0 4
\\ J '
N Ar
(112) Ar = 4-N0 2 C 6 H 4
NO z
,/'N,
\\IN
N Ar
(113)
H
N
120.C Ar,/' 'N
\\ !.
NJ NOz
Scheme 36
Halogenation proceeds through N- halotriazoles or triazolium derivatives that have been
discussed under Section 4.12.3.'2.4. Also the bromination of N-substituted triazoles by
N- bromosuccinimide in chloroform (7SBSF647) is thought to involve N- bromotriazolium
intermediates. If so, the same applies to halogenations with N- halotriazoles (69ZC32S).
Both 1,2,4 triazole and its 1-benzyl derivative undergo C- hydroxymethylation (55JAI538).
The synthesis of (114) is one of the few examples of a Mannich reaction of azoles (76JMCI057).
Cl
PhCH,Q
Me(N)CH z - N 0
N-N
(114)
Some of the 'complexes' mentioned in Section 4.12.3.2 could include products of C-
chloromercuration (cl. pyrazoles). Although N-unsubstituted triazoles are most likely to
form triazolates on reaction with metalating agents, lithiation of 1-(2-pyridyl)-1,2,4-triazole
(115) indicates the relative reactivities of the triazole and pyridine rings (nAG(E)846) and
provides a method for the formation of bistriazoles (116; Scheme 37). Nitration of 1,4-
dimethyltriazolin-5-one occurs in good yield, but that of the 1,2-dimethyl isomer fails.
Similarly the N- benzoyltriazolium intermediate is formed in the C- benzoylation or diben-
zoylation of 4-phenyl-1,2,4-triazole (66GI084). The reaction occurs on heating the triazole
with benzoyl chloride and does not affect the benzene ring attached to N-4.
R
N
,/' 'N BuLi
J
(115) R = 2-pyridyl
R
N
Li ,/' 'N CuCl z
J --
R R
....N N
N "'-.---/' 'N
'L/f J
(116)
Scheme 37
4.12.3.2.4 Nucleophilic attack at carbon
Exchange of anionic substituents and generation of a transient carbonium ion are con-
sidered here. For some other, mechanistically less well understood reactions, see Section
4.12.3.3 which deals with the reactivity of substituents.
Many triazole derivatives are accessible by exchange of 3- or 5-halo, hydroxy, alkoxy,
aryloxy, alkylthio, arylthio, arnino or cyano groups (67EGP59288, 69BRP1l57256, 70KGS1701,
75BSFI649). A kinetic comparison of haloazole, including halotriazole, reactivities is of
considerable theoretical interest (67JCS(B)641).
The hydrolysis of 3-chloro-4,5-diphenyl-1,2,4-triazole requires the presence of mineral
acid in order to increase the cationic nature of the ring (62MI41200). The same applies to
interhalogen exchanges of halotriazolones (67CB22S0). Thanks to a better leaving group,
bromo compounds are more reactive; 5-bromo-1-methyl-1,2,4-triazole is rnore reactive
than the isomeric 3-bromo-4-methyl compound.
The reaction of 3-iodo-1-methyl-1,2,4-triazole with 2-methylbut-3-yn-2-01 (75IZV690)
has been used to prepare 3-ethynyl-1-methyl-1,2,4-triazole (117; Scheme 38) and the
isomeric 5-ethynyl-1-methyl isomer from the corresponding iodotriazole.
An unusual feature of triazole chemistry is the ready exchange of nitro groups of nitro-
and dinitro-triazoles and nitrotriazolinones (67CB22S0. 70KGS269. 70KGSI701). The reaction
of I-methyl-3,5-dinitro-l,2,4-triazole with hydrazine (70KGS997) exemplifies such reactions
754
1,2,4- Triazoles
Me
(""N,
\\J
N I
HC=CCMe,OH-Cu,CI,
Þ
N N
( N ( N
N-{:=CCMePH N---2'C:=CH
(117)
Scheme 38
in forming 5-hydrazino-l-methyl-3-nitro-l,2,4-triazole but reduction of a nitro group by
the reagent also affords 5-amino-1-methyl-3-nitro-1,2,4-triazole.
Triazolinones are obtained by the alkaline hydrolysis of methyl-sulfinyl or -sulfonyl com-
pounds (118; Scheme 39) (73JMC312). Hydrolysis of alkoxytriazoles to triazolinones
(68AP911) is of practical importance, but the ready conversion of heteroaromatic triazoles
to triazolinones may be complicated by the non-hydrolytic rearrangement of alkoxytriazoles
such as (119) to (120) in Scherne 40 (68JPR168).
Me
N
R("" 'N OW,80'C
\\ ---2' þ
N X
(118) R = 2-furyl; X = SOMe or S02Me
Scheme 39
Me
(""N,
R\\ NH
N--{
o
N
Me( OCH,CH,Cl
N-NH
(119)
CH,CH,CI
N
Me( Y.O
N-NH
(120)
Scheme 40
The nitrosamine (121) and especially diazonium salts (122) prepared from it, as well as
their alkyl and aryl derivatives, are important synthetic intermediates (B-76MI41200, p. 325).
For conditions that decide between nitrosamine function or diazotization see (73JCS(Pl)1357).
At room temperature or in concentrated hydrochloric acid nitrosamines derived from
triazoles are unstable, and their decomposition products include chlorotriazoles
(63LA(665)144); 5-nitrosamino-3-phenyl-1,2,4-triazole affords the 5-bromo compound with
hydrobromic acid at OOC and reacts violently with hydroiodic acid (05LA(343)1). Thermal
arylation with triazole nitrosamines is possible (73JCS(Pl)1357).
H H
N N
R( 'N R( 'N X-
N---2'NHNO N---2'N +
,
(121) (122)
Halotriazoles have been prepared by treatment of (122) and alkyl- or aryl-substituted
derivatives with halogen acids (81HC(37)1, p. 228). The preparation of 3-fluorotriazole required
UV irradiation of (122; X = BF 4 ). Aminotriazolinones and 3,5-diaminotriazole are diazot-
ized and tetrazotized, respectively, to afford 3-halo-1,2,4-triazolinones and 3,5-
dihalotriazoles, respectively (65LA(682)123, 67CB2250).
Treatment of (122) with sodium nitrite affords 3-nitrotriazole (69AJC2251); other
nitrotriazoles and dinitrotriazoles may be prepared by similar techniques (70KGS259,
70KGS26S).
Arylation of triazole by the Gornberg-Bachmann method (72MI41200) has been described.
Direct oxidative thiation (Scheme 41) by heating sulfur with triazoles requires a substituent
on nuclear nitrogen. The preparation of the thione (123) from 4-phenyl-l,2,4-triazole
(66MI41201) is unambiguous, but I-benzyltriazole affords the 5-thione (124) instead of the
3-isomer that would have been expected on steric grounds (70JCS(C)2403).
Ph
N
( 'ìJ
N-N
S..l
------.
Ph
(Ny.S
N-NH
(123)
CH,Ph
N
("" 'N
---2'
S..l
------.
CH,Ph
S"'(N'N
NJ
(124)
Scheme 41
'1,2,4- TrÎazoles
755
Ph
N
1':' N r-
\":0
PhÑh' NMePh
Ph
N
S-pyridine S 'N
) \ J
PhN NMePh
Scheme 42
Thiation has been applied also to triazolium salts (Scheme 42) (70ZN(B)421).
Analogous oxidation and ami nation reactions appear to be unknown.
4.12.3.3 Reactivity of Substituents
4.12.3.3.1 C-Linked suhstituents
The behaviour of alkyl groups situated on the triazole ring is comparable with those of
benzene; thus their oxidation followed by decarboxylation has been much used in synthesis.
Derived functions such as CHzX (X = OH, hal) also behave as expected (ef. 55JA1538), but
acetoxylation (Scheme 43) of 4-hydroxy-3-methyl-1,2,4-triazole (125) with acetic anhydride
to give (126) is remarkable (70JPR610).
OH
N
< )Me
N-N
(125)
OH
N
< )CH 2 0Ac
N-N
(126)
Scheme 43
Quaternization leads to two interesting reactions of C-alkyl-1,2,4-triazoles. The diagnos-
tic value of condensations undergone by a C-Me group situateábetween two substituted
N centres has been mentioned (see Section 4.12.3.2); another example is the determination
of the reactive site of (127) that could yield (128) or (129) on tritylation (Scheme 44).
Quaternization at the N most distant from the tritylated N-1 or N-2 occurs at N-4 to afford
(130) or (131). As the compound obtained does not form a Schiff base, its correct structure
is (130) from which (128) is inferred as structure of the trityltriazole (62JCSS7S).
H CPh 3 CPh 3
N N <N,
<:; Ph,CCl-base ) <jt Me N
or
N Me N Me NJ
(127) (128) (129)
1 Mel 1 Mel
CPh 3 CPh 3
N N
C":-N M CO"
: + : I- e :' + ';N 1-
M N':0 MeN':0
e Me
(130) (131)
Scheme 44
Attempts at dequaternization result in ring cleavage (Scheme 16). Alternatively
(71JCS(B)1648) mesoionic compounds (132) or anhydro bases (133) are formed. These revert
to the triazolium compound on treatment with perchloric acid (Scherne 45).
Ph Ph Ph Ph
.N - N, N N
/'-':- N EtO /.... N R CH /"':- , RCH ' N
\ . + \ _ + i 2 V'. + IN "' \
PhN:0 HCl0 4 PhN':0- Ph N ":0 HCI04 PhNJ
CH 2 R CHR
(132) (133)
Scheme 45
Both C- and N- aryltriazoles may have the aryl group removed by oxidation, preferably
after nitration and reduction to aminoaryl. However, nitration of triazolinone rings may
occur in competition with that of aryl substituents.
756
1,2,4- Triazoles
N-Nitroaryl groups are relatively easy to cleave by basic reagents (71ZC153) but the
formally similar 2-pyridyl compounds resist basic and acidic hydrolysis (72AG(E)846).
Alkenyl- and alkynyl-triazoles have received little attention. By analogy with the
behaviour of other azoles they are expected to polymerize but to be less reactive in addition
reactions than alkenes or alkynes. Although the most promising polymers derived from
triazoles are obtained by different methods (see Section 4.12.5.2.3), some information is
available on potentially polymerizable vinyltriazole (63MI41201). The styryltriazole (134)
could be oxidized to 3-methyl-1-phenyl-1,2,4-triazole, i.e. without affecting either the
triazole or N-phenyl ring, but hydroxylation of the alkene chain failed (S4JCS42S6).
Ph
N
PhCH=CH< 'N
NJ
Me
(134)
In some respects the behaviour of aldehydes and ketones derived from 1,2,4-triazole is
comparable with that of analogous benzene derivatives. One of the rnajor differences is
the dimerization of N-unsubstituted 1,2,4-triazolealdehydes (Scheme 6) (71AJC393)'.
Although both N-substituted and unsubstituted C-acyltriazoles give dinitrophenyl-
hydrazones, only the former can be characterized as oximes; the carbaldehyde oximes resist
hydrolysis. Thiosemicarbazone formation frorn 3-benzoyl-5-phenyl-1,2,4-triazole is excep-
tional. Ready hydrolysis of 3-aroyl-, or 3,5-diaroyl-triazole has been noted (66GI084). Only
one of the two oximes of 3-benzoyl-1-phenyl-1,2,4-triazole undergoes the Beckrnann
rearrangement, but both oximes afford the same amide (135; Scheme 46) (68JCS(C)824). Both
(136) and (137) could be considered for the constitution of the oxime reactive in the
Beckrnann rearrangernent but all evidence favours the former. Failure of (138) to react has
been explained by the low migratory aptitude of the triazolyl group in comparison with that
of the phenyl group.
Ph Ph
(""'N, ..H (""'N,
N' '0 or N
N N . -4
Ph H, )Ph
O-N
(136) (137)
1 PPA
Ph
N
("'" 'N
\\ -1J
N CONHPh
(135)
Scheme 46
Ph
N
< r
N N
--: "-
Ph OH
(138)
1 PPA
no reaction
Preference for dimerization accounts for the failure of N- unsubstituted 1,2,4-triazole-
carbaldehydes to undergo Cannizzaro or benzoin rearrangements (71AJC393) or Döbner
and Perkin reactions (62JCSS7S).
The dimeric hemiaminals are the preferred structure in solution and aldehydes are
favoured in the solid state. In either case one may assume equilibria between major and
minor constituents except for the lack of reducing properties expected in the presence of
free aldehyde in the equilibriurn mixture.
The carboxylic acids of the 1,2,4-triazole series are readily decarboxylated on heating,
but otherwise stable. Esters, amides and hydrazides react normally. Reduction of esters by
lithium aluminum hydride affords triazolylmethanols.
Cyanotriazoles are known (B-76MI41200, p.329). Scheme 47 illustrates some typical uses.
Halogeno-1,2,4-triazoles are reductively dehalogenated with red phosphorus and
hydriodic acid (OSLA(343)1) but, unlike N-halo compounds, not by bisulfite (67ZC184).
Although the halides undergo nucleophilic replacement with greater ease than analogues
in the benzene series, and may be used for the preparation of amines, the kinetics of these
reactions (67JCS(B)641, 73Z0R2535) are of greater interest than their synthetic value. Halo-
genated triazolones react more rapidly still and perrnit the exchange of Br for Cl (67CB2250)
1,2,4- Triazoles
757
H
N,
H0 2 C\\, N
N-1J
CN
H
N
/' 'N
\\ -1J
N CN
H
N
H0 2 C\\, 'N
N-1J
-HCl H CONH 2
N
Me02C\\, 'N
N-{02 Me
Scheme 47
on a ring activated by protonation. Formation of triazolone by reaction with sodium
hydroxide or alkoxytriazole with alkoxides is also possible (B-76MI41200, p. 143).
Reduction of triazolinones with phosphorus sulfide has been one of the early routes to
triazoles (OSJCS62S). Milder reactions may differentiate between conjugation of the ring
double bond with C=O (139) or the lack of it (140) as in Scheme 48 (71BSF3296). The
formation of triazole in the reduction of the triazolinone (140) with lithium aluminum
hydride (71BSF3296) is explicable through the formation of a hydroxytriazoline intermediate.
Me
N,
Me\\, NMe
N--{
o
(139)
LiAIH4
H Me
V N ,
NMe
Me N---{
H 0
Me
N
0::( 'N
HN-1J
Me
(140)
LiA1H4
Me
N
/' 'N
) \\-1J
N Me
Scheme 48
Hydrolysis of alkoxytriazoles affords triazolinones (67CB22S0). Reference has been made
to the sensitivity of triazolinones to hydrolysis and photolysis (see Section 4.12.3.2.1).
Aminotriazoles are comparable to aromatic amines of the benzene series. Their alkylation
and acylation in competition against nuclear nitrogen and functions containing 0 or S has
been mentioned and some reactions of diazo compounds and related nitrosamines have
been considered as examples of nucleophilic attack on a nuclear C atom.
Rearrangement of the mesoionic imines (141) to (142; Scheme 49) is an intramolecular
nucleophilic reaction (74JCS(Pl)627). Both (141) and (142) are accessible through unam-
biguous syntheses.
Me
N E -
Ph ( .... N to ,.1
. + . ----+
':::)
ArN'" ÑPh
(141)
Me
N
Ph..1.-.\N
\". + ,
PhN':.3-
NAr
(142)
Scheme 49
H
N
PhNH\\' 'N
N -1J Ni-H 2
NH 2
H
N
PhNH)' 'N
\\ -1J
N NHCH 2 Ph
Scheme 50
Resistance of the triazole ring to reduction permits reductive condensations as in Scheme
50 (72JMC694).
The hydrazino group may be removed by silver acetate (70KGS997) or by oxidation in the
presence of alkali (7SJCS(Pl)97S).
Some generalized reactions linking triazoles with nitrogen functions of 3- or 5-substituted
triazoles are shown in Scheme 51. The choice between (143) and (144) is governed by the
reaction conditions; temperature and high concentration of acid favours the former, room
temperature and more dilute acid the latter. Coupling of the diazonium compound (or
758
1,2,4- Triazoles
nitrosarnine in acid solution) to azo dyes requires acid conditions; in basic solution the
reaction is inhibited. The use of nitrous acid in these reactions is difficult to generalize: in
addition to reactions leading to (143) or (144), it can also act as oxidant, affording (145).
HOSO Zn-acid
TrN 3 -- TrNHNH, ( TrNHNO
(143)
TrNHNHTr
INH 4 J,S ll '0'
TrN=NTr
(145)
TrNH, HONO /
oT
TrN=NNHTr
MeNO,
TrN 2 --'.) TrN,CH,N0 2
(144) ,
TrN,C 6 H 4 NR,
Scheme 51
Reactions leading to triazene (146) and polydiazoamino-l,2,4-triazole formation are
shown in Scheme 52 (64JOC3449). Both the explosive azides and the safer nitro compounds
may be used to provide leaving groups, e.g. for the preparation of fluorotriazole from
nitrotriazole in liquid hydrofluoric acid at 150 oC (73JOC4353). Similar reactions are available
for nitrotriazolinones. Substituted amines and hydrazines are available for nucleophilic
displacement of nitro groups or by reduction. Although hydrazine can be a useful reducing
agent (70JOC2635) the extent of reduction, or nucleophilic displacernent instead of reduction,
depends on conditions (Scheme 53) (70KGS997).
H
N
H,N( 'N
N-3'NHNO
HO id
H H
N N
H,N( 'N H 2 N( 'N
N-3' N-3'
NH, N+
Ä'
H H
N, /N
H,N( N N )NH 2
N-3' 'L N
N=NNH
(146)
r H h
N
H,N \ 'N H
-3' N
N N==NNH 'N
\-3'
N NH
n ,
Scheme 52
The simplest S-containing derivatives of triazoles are thiones by structure (7lJCS(C)1016,
nCPB2096) but behave as thiols in their most important reactions. Alkylation in cornpetition
against nuclear nitrogen and substituent oxygen has been considered earlier (Section
4.12.3.2.2). Early workers practised the oxidative desulfurization of triazolinethiones to
triazoles. Modern variants include treatment with nitric acid, Raney nickel or hydrogen
peroxide (75LA1264) or photochemical desulfurization (70AJC631). Careful use of the last
mentioned reagent permits the preparation of sulfoxides (65JCS3912); peroxyphthalic acid
affords sulfoxides and sulfones (70JCS(C)2403).
Oxidation of disulfides with halogens may lead to sulfonyl chlorides or the much less
stable bromides which afford sulfonamides. However, replacement of the sulfur function
by halogen or complete desulfurization may also occur. Treatment of the sulfonyl chloride
does not yield the expected esters but is the best way to prepare the sulfonic acids. Electrolytic
oxidation of thiones affords a mixture of sulfonic acids and desulfurized cornpounds. The
action of ozone on disulfides is a feasible but not very convenient reaction leading to sulfonic
acids. Scheme 54 summarizes some of these relationships and the unusual nitration of the
sulfonamide (147) (62BEP619423); for convenience the generalized triazole Tr is shown in
1,2,4- Triazoles
759
PhNHNHz
Me
N
02 N ( 'N NH,NHz
NJ
N0 2 HzO
H2N( N
NJ
NH
AeNHNH z 2
Me
N
N 3 ( 'N
N-.!J
NO z
Me
N
H NNH / 'N AgOAe
2 J
cone. N0 2
În dioxan
Me
N
/ 'N
\\ J
N N0 2
Me ( Me )
HONH/N'N HNO, ON/N'N
\\ J ---.. \\ -1J
N No'T N NO,
Me Me
NON
N" 'ìrN=N-( 'N
02NLN N-1J N02
Scheme 53
HZO Tr-SO-Tr
z.. /
I'croxyphthalic acid
TrSR Tr-S02- Tr
RHal
base
HNO r H z S04
TrS02NHz ) TrS02 NH NO z
(147)
ì NH 3
Clz
TrSH ) TrS02C1 + TrCI + TrH
(148) clý
TrS2Tr
NHzNHz
Scheme 54
(148) as the thiol. Permanganate oxidation of thiones also affords sulfonic acids. Unlike
their benzene analogues, the triazolesulfonic acids are resistant to boiling hydrobromic
acid or heating with alkali. Treatment with hydrazine, however, eliminates the sulfonic acid
function.
760
1,2,4- Triazoles
4.12.3.3.2 N-Linked suhstituents
Rearrangement of acyl and halo groups are the most common reactions of triazoles with
functions on nitrogen. The chemistry of '4-hydroxytriazoles', in effect N-oxides, has been
less extensively studied than that of triazolinones. The N-O bond is cleaved by phosphorus
halides and acidic anhydride but not by oxidation with permanganate or by alkaline
bromination (70JPR610).
The dual nature of 4-aminotriazoles as aromatic amines and unsymmetric hydrazines
gives rise to many interesting reactions (81HC(37)1, p. 161, 483, 607, 611) some of which are
shown in Schemes 55-57. Although nitrous acid normally reacts with both amino and
hydrazino groups, examples of selectivé reactivity are shown in Scheme 58. The nitrosamine
from 4-benzylamino-l,2,4-triazole is cleaved by sodium hydroxide to triazole.
NNO,
N
( )
EtONO,../' N-N
/EIO'
NH,
N
( )
N-N
PhCH,CI
--.-.
ÑN0 2
N
( ....
" + ,:/
PhCH 2 N:':"N
,,!hCH,CI
NH, NH,
N N
( ... s 50:::,/ '-,
:, + . I Cl- ---. \ II
PhCH 2 N:.:.N base PhCH,N-N
Scheme 55
N 8
I N-N
N
EtOO Et
o Ph
AcOH \7
N
NH, ,
N N
r' '-, PhCH=CH, r' '-,
\\ II PbIOAcJ. · \\ II
N-N N-N
h "
.
Ph
/'
NHC
(N) '>:NH
N-N
CICO,Et
.
H
N,
(J
N Ph
Scheme S6
NH,
N
Ph( )Ph
N-N
1 Mel
Ph Ph
KBrO,-acid N /"'=:-N
. I N-N=N-N I
21% N \.::::<N
Ph Ph
1 FSO,Me
NH 2
N
Ph ( " "0,Ph
" + )/
MeÑ:.:.'N
Br,-KOH .
46%
Ph Ph
N 0l'1
I: + :N-N=N-N'..+.:'
MeN'.:0' '\;.:.:-NMe
Ph Ph
Scheme 57
1,2,4- Triazoles
761
NH 2
N
\\ )NHNH 2
N-N
NH 2
N
HONO <'" '" N
----+ \\ II 3
N-N
NH 2
N
\\ 'ì;NHR
N-N
HONO
----+
NH 2 NO
N ./
\\ )N'R
N-N
Scheme 58
Trimethylsilyl-, triethoxysilyl- and trigermyl-triazoles are noted for the intermolecular
exchange of such functions (74JOM(70)347). Reactions of 1-trimethylsilyl-1,2,4-triazole with
acetyl chloride, ethyl chloroform ate or phosgene affords acyltriazoles (60CB2804). Trimethyl-
stannyl compounds (62RTC202) are usually less reactive than the corresponding silicon
derivatives.
4.12.4 SYNTHESIS
4.12.4.1 General Considerations
Difficulties besetting a systematic survey of methods suitable for the preparation of
1,2,4-triazole and derivatives are not merely philosophical but are worthy of notice by
practical organic chemists. In the absence of natural products derived from 1,2,4-triazole
(that is, ignoring products formed through the metabolism of synthetic triazoles in biological
systems), this ring is obtained either by synthesis from acyclic compounds or by transforma-
tion of other cyclic systems. In the former case, analysis of the number and nature of bonds
formed is a convenient, systematic way to approach triazole synthesis but it may be
misleading to the extent of obstructing progress. Synthesis of a 5-membered ring system
symbolized as ABCDE from starting materials A-B and C-D-E suggests the formation
of 2 bonds, say E-A and B-C, from building units containing 2 and 3 eventual ring
centres, ,respectively. Until the mechanism of the reaction is fully understood, it may be
suspected that the first step is the formation of E-A and B-C-D of a comparable
classification status; or that of A and B-C-D-E, the further reaction of which is to be
classified as one of 1-centre and 4-centre fragments. Other possibilities remain, of course.
Since only few syntheses of 1,2,4-triazole have had their mechanisms studied and most of
such studies have been carried out without the benefit of powerful modern methods,
convenience of classification may not be the best guide to the choice of conditions and
most reactive starting materials.
A similar problem may arise when considering the conversion of other cyclic systems
into 1,2,4-triazoles. More serious is the ambivalence that arises when both 1,2,4-triazole
and an isomer with a different ring system are formed from acyclic starting materials. The
equivalence of ring transformation to preparation from an acyclic intermediate is evident
in such cases. Most interconversions of heterocyclic ring systems occur with ring cleavage
and recyclization, hence they are arbitrarily classified as distinct from preparations employing
acyclic materials. Transformations of azoles without distinct bond rupture ar improbable
except by mechanisms with the intermediate formation of strained short-lived bicyclic
systems.
Another problem of classification already encountered in other contexts is the hazy
borderline between 'aromatic' and 'non-aromatic' 1,2,4-triazoles. If the preparations of
triazoles and triazolines are to be discussed in separate sections, preparatively similar
reactions from reactants with the skeleton type N-N-CX-N- will be duplicated with
X = 0 or S and occasionally with X = NHR. The same problem arises in the classification
of reactions consisting of a functional change on the preformed triazole nucleus.
Some of the most useful syntheses of 1,2,4-triazoles have variants which are better
considered together rather than in separate sections of the possible subsets of 5 centres.
Examples to illustrate such reactions are drawn mostly from cases with relatively unreactive
functions that leave the main burden of synthetic strategy on ring synthesis.
In other examples with interest centred on specific functions, principles of ring synthesis
need not be rehearsed and attention is directed to the choice of functions to be carried by
the new-born ring.
In a third group of examples we shall consider the substitution of the preformed ring;
some of this material has been treated in Section 4.12.3 but specific examples of practical
synthetic interest will be given.
762
1,2,4- Triazoles
Still other examples of syntheses for industrial products are reserved for Section 4.12.5.
In the absence of references (81HC(37)1) and (61CRV87) should be cånsulted.
4.12.4.2 Synthesis of Triazole Rings from Acyclic Compounds
4.12.4.2.1 Methods employing hydrazine derivatives
The ease of forming C-N and C=N bonds as compared with the difficulty of N-N
formation practically prescribes the use of hydrazines in the synthesis of 1,2,4-triazoles.
Scheme 59 illustrates synthetic schemes that use one of the following: (a) hydrazine, (b)
an acylhydrazine, (c) amidrazone or (d) acylamidrazone. The dotted lines leave the presence
or absence of a bond open. Thus in (a) possible reactants are (R 5 COX, R 3 COX and NH 3 )
or (R 5 CONH 2 and R 3 COX) or (R 5 COX and H 2 NCOR 3 ) or (R 5 CONHCOR 3 ); X stands
for a suitable leaving group, usually OH, H 2 0.
R 1
HN,
NH 2
/-0 0
(a) R5-C:/' "
... ,.C-R J
N'
R 1
<; HN
R - C=O 'NH
rb ' ) H C 1 -R 3
2 -;:/
o
R'
N
R5-C...... 'NH
II 2
or (b") 0
o
"
C
H 2 N...... 'R 3
--.
R 1
N
R5('" 'N
\\ -.!J
N R 3
(1)
R'
N
R5-C...... 'NH
Ie') " 2 or (e")
NH R 3 COX
R'
HN,
N
R 5COX II
C-R 3
H 2 N......
/
R 1
......N,
R 5_C........ N
1/ ,,
o C-R'
H 2 N......
or (d")
R 1
NH
"-
R 5 -C=0 N
\ /1
HN-C-R J
rd')
Scheme 59
Unless R 1 = Hand R 3 = R 5 , all the syntheses are ambiguous. Cyclization under gentle
conditions avoids the danger of amide-hydrazide interchange (Scheme 60) and the formation
of polycyclic tetrazines that usually accompanies the cyclizing condensations favored by
early authors, e.g. the Pellizzari condensation (ct. b ' or b") of formamide with formylhy-
drazines (1894G22Z) above 200 0 C in poor yields due to difficulties of separation (OSG373).
However, at least one commercial method for the preparation of the parent 1,2,4-triazole
has relied on this method until recently; the product contains a small trace of non-triazole
impurity which on UV irradiation in a triazole matrix produces strong green phosphores-
cence lasting about 20 s.
R m CONH 2 + R n CONHNH 2 R m CONHNH 2 + R n CONH 2
Scheme 60
Although 1,2,4-triazole can be prepared by heating hydrazine with two (preferably more)
equivalents of formamide, the reaction presumably occurs in steps, e.g. as in Scheme 61.
Syntheses corresponding to step 3 are well known, but occur in poor yields or not at all.
Scheme 62 illustrates extensions of these methods proceeding from or through
hydrazidines, amidrazones or acylamidrazones to syntheses of 1,2,4-triazoles with sub-
1,2,4- Triazoles
763
H 2 NNHCHO
H 2 NH 2 + HCONH 2 CONH2
NH HCNHNHCHO
H
". N,
\\ -.!iN
N
Scheme 61
R S CONHNHCOR 3 + R 4 NH 2
R 4
N
RSC(OEth+H2NNHCOR3+RNH2 ) R\\, 'ìJR3
N-N
/NHPh /
RSC /'
NNHCOR 3
Scheme 62
stituents on N-4. Again it is assumed that all such reactions proceed through amidrazone
or acylamidrazone intermediates, also that the formation of these is the rate determining
step in the reactions shown in Schemes 61 and 62. Although this generalization has not
been established, it is supported by the popularity of preparations starting from amidrazones
or acylamidrazones, the success of other syntheses being limited by their suitability for the
formation of these reactive intermediates. Another line of evidence pointing in the same
direction is the elaboration of synthetic methods using starting materials other than ami-
drazones or acylamidrazones for reactions that are best explained by intermediate ami-
drazone formation. Examples of frequently used methods follow.
Synthesis starting from amidrazones (Scheme 59, c'-d") is the most versatile preparation
of the 1,2,4-triazole ring. Application to specific cases is governed by three considerations.
One is the formation of the required amidrazone from a hydrazine with or without
substituents and amide derivatives RC(=NH)X or RC(=NCOR')X where X = halide, OH,
OAlk, SAlk, NHz, etc. With two reactive hydrazinic NH groups, isomeric amidrazones can
be formed but the relative basicities usually predict the correct product. Unsymmetrical
hydrazines YZNNH 2 also form amidrazones but these cannot be cyclized unless Y or Z is
reactive.
Unsubstituted hydrazine can react with an amide derivative (149) to yield the amidrazone
(150) which then either reacts with more (149) or undergoes self-condensation to (151)
which then cyclizes to the triazole (152; Scheme 63) on heating (65JOC3729). Self-condensa-
tion is ambiguous: the formation of (152) may compete against that of dihydrotetrazine
(153) (62CB2546) but basic, rather than the usual neutral or acidic conditions, are required.
Conversion of dihydrotetrazines into triazoles will be considered under Section 4.12.4.3.2.
Tetrazine and triazole formation occur to comparable e'xtents in the reaction of formimino
ether with methylhydrazine (72JOC3504).
A third problem is the ambiguity of cyclizations leading to oxadiazoles or thiadiazoles
as in Scheme 64 where oxadiazole is the minor product (58JOC1912). Conversion of the
amidrazone (154) into the triazole (155; Scheme 65) takes place in basic solution, while
the oxadiazole (156) is obtained in the presence of acid (69JHC965). However, dehydration
of the amidrazone to triazole may take place in polyphosphoric acid.
The formation of alternative heterocycles can be the main reaction with semicarbazides
or thiosemicarbazides which are used extensively in the preparations of triazolinones and
triazolinethiones. Aminoguanidines can give rise to isomeric triazoles. The preferred forma-
tion of thiadiazole (157) from the 1-acylthiosemicarbazide (Scheme 66) is explained by the
protonation of N-4 in strong acid with accompanying loss of nucleophilicity, while in the
presence of base its nucleophilic character is enhanced (73JOC3947) and (158) is obtained.
764
1,2,4- Triazoles
NH NH
R-C.I' H,NNH,) RC.I'
"- "-
X NHNH 2
(150)
( NH2 )
I
HN NH HN N
(R1_;--) R1_;--
(Ir 1
(149)
H
N
R\\ 'N
JR
(152)
N-N
R( R
N-N
H H
(153)
Scheme 63
NHPh Ph 0
/ N ,/ '"
MeSC -. MeS( 'ì;Me + PhNH\\ liMe
NNHCOMe N-N N-N
Scheme 64
,/ , b..e .-?NH H" ,/0",
Ph\\ J -- PhC\ lOAr -. Ph\\ liAr
N HN-NH N-N
(155) (154) (156)
Scheme 65
H
SV N , base
\ IN -- RCONHNHCSNH
HN-1J
R
(158)
strong acid
,
R( SyS
N-NH
(157)
Scheme 66
The formation of oxadiazole (159) or triazole (160) from the thiosemicarbazide (161)
under different conditions of rnethylation in the presence of base (Scherne 67) is less readily
explained (71MI41200). Relative rates of methylation on Sand 0 are involved but the
different ternperatures make a direct comparison irnpossible. The effect of acidity cannot
be neglected as shown in Scherne 68 (63CBI059).
NaOH
Ph
Mel N
) Ph( 'ì;SMe
N-N
(160)
o NH
Ph'/ "'NHPh Me,S04 /
\\ If c 0;. , HSC
N-N 10 o NaOH NNHCOPh
(159)
(161)
Scheme 67
S
PhNH( 'ì;Ph
NHPh ( NH2 ) H<7 N N
S=C/ + PhC?' + CI- :
"NHNH 2 "OEI pH>7 S N'N
PhNJ
Ph
Scheme 68
1,2,4- Triazoles
765
The choice of acylating or cycloacylating agents chosen from RC0 2 H, RCOCl, RC0 2 Alk,
RC(OAlkh, RC(=NH)OEt, etc., usually affects the yield only. The different reactions of
the 4-arylthiosemicarbazide with diethyl carbonate in the presence of methoxide ion
(S9CR(248)1677) and with phosgene in chloroform or chlorobenzene (70LA(73S)lS8) occur in
different solvents and at different acidities (Scherne 69). An unusual cyclization (Scheme
70) utilizes the CCh group as the acid analogue (67JCS33).
S 0
ArNH( Y
N-NH
NHAr
COCl 2 /
c S=C
PhCl or CHCl) "
NHNH 2
Scheme 69
Ph
IEtOl 2 CO t OVN O
McO- \ f
HN-NH
oc N }
I CCIJ
N
H 2 NNH:ONH 2
oc N H
EtOH-H' I N,
I / \\ NH
N N---{
H 0
Scheme 70
Preparation of 3-, 1,5- or 1,3,5-substituted triazoles by reaction of hydrazines with
diacylamines (Einhorn-Brunner reaction) is one of the earliest synthetic methods of triazole
chemistry (OSLA(343)207, 14CB2671) but appreciation of its mechanisrn as involving an ami-
drazone intermediate is of rnore recent origin (S2JCS3418, S4JCS3319). However, early workers
recognized that the mechanism could not be acylation of the hydrazine by diacylarnines
(which are much more reactive acylating agents than 'primary amides) since the reaction
inferred does not occur under the mild conditions of the Einhorn-Brunner reaction but
only at high ternperatures (Pellizzari reaction). The observation that unsymmetrical diacy-
lamines R'CONHCOR" react first at the more electrophilic carbonyl group also supports
the intermediate arnidrazone hypothesis. Thus formylarnides RCONHCHO (R = alkyl, Ph)
afford 1,5-substituted triazoles. If, however, one uses N-acylthioamides instead of diacy-
lamines, acylamidrazone formation will occur on the thione group (60CB663). The use of
semicarbazide in the Einhorn-Brunner reaction results in 3- or 3,5-substituted triazoles
through hydrolysis of the intermediate i-carbamoyl derivative in agreement with the lability
of N-acyl-l,2,4-triazoles. The reactiqn may be extended to N-acylurethanes for the prepar-
ation of triazolin-5-ones. Einhorn-Brunner reactions are illustrated in Scheme 71.
} Rl R'
RSCONHCOR J --. RsCtIN'N --. Rs("'N'N
\ J \\J
HN RJ N R J
R 'NHNH 2
} Rl R 1
N N
RSCSNHCOR3 --. R 3 CO 'N --. R3( 'N
H \ N J N J
R S R S
(R 3 C0 2 H is a stronger acid than R S C0 2 H)
Ph
Et0 2 CNHCOCH J } --. o. (N'N
PhNHNH 2 HN J
Me
R S CONHCOR 3 } --.
H 2 NCONHNH 2
( CONH, ) H
N - N
R S ('" 'N --. R S ('" 'N
\\J \\J
N R3 N R 3
Scheme 71
Replacernent of =0 by Ch or OH by Cl in the diacylamine function -CONHCO or
-CON=C(OH)- also affords triazoles by analogy with the Einhorn-Brunner reaction
(Scheme 72) (66AG(E)960, 76Z0R673).
Many convenient triazole syntheses proceed through amidrazones derived from forrnic
acid. Thus DMF, thionyl chloride and hydrazine react to give the bisarnidrazone (162)
which is then cyclized by transarnination (7SJCS(Pl)12) (Scherne 73).
766
1,2,4- Triazoles
CCI3-C-N=CCCl3 } Ph
Cl z Cl --. CI C("N'N
PhNHNHo 3 \\-1J
" N CCl 3
Scheme 72
ClC-N=CCI } R
Cl 2 Cl --. Cl("N'N
\\-1J
RNHNH z N Cl
Me 2 NCHO } SOCI, MezNCH CHNMe z RNH
-- \\ II ,/......,
H NNH N-N \\ II
z z (162) N-N
Scheme 73
One can use s-triazine (163) as a source of formarnidrazones that react with rnore triazine
(S6JOC1037) or undergo self-condensation in the presence of acid (62CB2S46, 66CB3734). In
the absence of acid the acylic dihydrazone (164) is forrned and can be cyclized to 4-
arninotriazole. Scheme 74 illustrates sorne applications of the triazine rnethod (S7JA2839)
and Scherne 75 the use of trichloro-s-triazine (60AG9S6).
NH'7
N N
)
N
(163)
HzNN=C fH=NNHz ,/ z
HN-NH --. \\ ij
(164) N-N
NH,
/
x=c
"-
NHNH,
( /NHz ) H" HzNCH CHNH 2
H,NH,'HCI) CH ---. \\ II
EtOH..i N N
'NNHz'HCl -
HNH"HCI "'\ H /H'
(" N,
J
R
("N,
J
H
X N'N
HN-1J
X=O,S
H
("N,
or H\\ N
N-1J
X=NH,NR
Scheme 74
Cl
N N
Cl )Cl
N
Me,NCHO
)
(MezNCH=N-CH=NMe z ) Cl-
R
RNHNH, ("N,
- ) \\ N
N-1J
Scheme 7S
Some arnbiguities implied in the acylation and self-condensation of arnidrazones are
obviated by forrning carbonyl derivatives which are then cyclized under oxidative conditions
(Scherne 76). Dehydrogenation with palladiurn (66JMC40S) is thought to proceed with the
forrnation of a triazoline (165) (70JHC100l). An early rnethod, oxidative cyclization of
sernicarbazones (OOJCS224), is still in use but analogous treatment of thiosernicarbazones
results in thiadiazoles. In sorne cases a specific oxidant is not required owing to the
spontaneous oxidation of triazolines (72JOC343). In general, rnercury(II) oxide or silver oxide
in boiling xylene is recornrnended (63CB2996).
The sensitivity of triazolines to oxidation has been used for the unarnbiguous synthesis
of 1,2,4-triazoles (see Section 4.12.4.1) but too few triazolines of sufficient keeping quality
are known to perrnit generalization of structural features required for stability. Thus (165a;
R = pyrazolyl, pyridazolyl, pyrirnidyl, R' = Ph, 2-pyridyl) have been prepared (71JHCI73,
73JHC3S3) while the rnore heavily arylated (165b; R = Ph) could not be isolated even when
atrnospheric oxidation was carefully excluded (69CB31S9); cornpound (165b; R = Me) is
unstable at roorn temperature (Scherne 76) (73BCJ12S0).
1,2,4- TrÎazoles
767
NH ( H ) N
/ 2 Pdß N '
X-C CHPh Ph ( 'N _ Ph\\, /!
NN -1 A
N X X
H X = CH 2 NHC0 2 CH 2 Ph
(165)
X=OH
NH 2
/ KMn04-AcOH
Ph-C + RCHO ,
NNHPh
Ph
N
R'/ 'N
\\ -1
N Ph
H
N
Ph( 'NH
N-i,
o
H
N
R'( Ì/R
HN-N
(165a)
R
N
R( Ì/R
PhN-N
(165b)
Scheme 76
The preparation of 3,5-diaryltriazoles without isolating the interrnediate amidrazones
can be effected by heating an arenenitrile with the arenesulfonate of an arylhydrazine
(S4JCS3461). This method, known as the Potts procedure, may also be extended to the
reactions of arenenitriles with alkyl hydrazide benzenesulfonates, but not to those of
alkenenitriles with arylhydrazine arenesulfonates (61JCSS18). The yield of mixed alkyl-
aryltriazoles obtained by this rnethod (Scherne 77) is depressed by the formation of
diaryltriazole and the amide corresponding to the aryl moiety. Both diaryl- and alkylaryl-
triazoles are obtainable by a modification of this method that reacts free acid hydrazide
and nitrile under pressure and at a sornewhat higher ternperature; even dialkyltriazoles are
prepared this way although in low yields (63CBIOS9). On the other hand, 3,5-dialkyl-1,2,4-
triazoles are obtainable in good yield by the reaction of an alkylnitrile with the zinc chloride
cornplex of hydrazine at 140 oC (76JAP76364SS).
( NH2 )
Ar'-C/ COAr"
/
Ar"CON7 N-NH
Ar'CN
lkCONHNH;
PhSO,
I
: ( NH 2 )
1 Ar'C/ COAlk-+Alk'/ 'N
I / \\//
I NNH N A '
f r
.j.
Ar'CONNH 2
Ar'CONH 2
AlkCONH 2
H
" N,
-) Ar\\ N
N-i.r'
H
N
Ar''/ 'N
\\J
N Ar'
Scheme 77
Of some interesting although rarely used techniques to be rnentioned, the one represented
in Scherne 78 involves an amidrazone interrnediate (72JPRI01). The product is forrnulated
as (167) rather than the rnore plausible 4-0H cornpound (166) (70JPR610).
0-
Me\\, + Ph
N-NH
(167)
NH NOH
Me-C NH,OH, MeC..;/
" "-
NHNHCOPh NHNHCOPh
OH
N
Me\\, Ì/Ph
N-N
(166)
Scheme 78
768
1,2,4- Triazoles
The Chichibabin amidation of azines (168) can be used for the preparation of 3,5-diaryl
triazoles (169) (65CB92S) and could be interpreted to proceed through a bisarnidrazone
interrnediate as shown in Scherne 79. However, the conversion of (168) to (169) by t-butoxide
(76JCS(P1)207) occurs through cleavage of the forrner. Oxidation of sodiurn benzarnidinate
(170) with copper(II) chloride probably gives the sodium derivative, then (169)
(67AG(E)633). Although not widely used, this reaction is one of the few exarnples of N-N
bond forrnation as a preparative strategy for azoles.
ArCH CHAr N. NH 2 ( I I ) N
II II _ Ar : ::r 2 __ Ar)' H 'N
N -N II II \\ J
(168) N--;;-N N Ar
Ph=7(169)
.<:NH ( NNa NNa )
ArC:7 C CI2 , PhC Ph
" ", " /
NHNa "'" NH NH
(170) " '.
."
N-N
Ph( )Ph
HN-NH
Scheme 79
Preparations of amidrazones required for triazole syntheses by the Japp-Klingernann
reaction and sirnilar rnethods involving rnalonic acid or other 1,3-diketo starting rnaterials
are too nurnerous for listing. A curious reaction making use of the chernistry of rnalonic
esters for the synthesis of a triazole is shown in Scherne 80 (70T3069).
NH 2 NH 2
(EtOzChC=CHNHR , RNHCH=NNH z
R = 2-pyridyl '--j ( R ) R
H N N
RNHCH=NN=CHNHR -. ..--...X ÌI -- \\' ÌI
RNH HN - N N-N
Scheme 80
Sorne rnodern triazole syntheses involve arnidrazone interrnediates forrned through rear-
rangernents of isocyanides (75S609), cyanates (73AG447) and isocyanates generated in the
Curtius rearrangernent (69LA(722)29, 69LA(722)3S) are shown in Schernes 81, 82 and 83,
respectively.
NC AeON.
/
ArNHN=C-COzMe
Scheme 81
Ar
("'N,
\\ IN
N COzMe
CHzNO z
/ H 2 0
PhNHNH z + Me3CC=:CNOz - Me3CC -->
'\.
NNHPh
Scheme 82
ArNHN=CPhCONHNH z ArNHN=CPhCON 3 -.
Scheme 83
CNO
/
Me3CC=NNHPh
CHCI3
Ph
O N'N
HNJ
CMej
H
("'N,
Ph \\ NH
N-{
o
4.12.4.2.2 Nitrilimine methods
Huisgen's studies of 1,3-dipolar cycloadditions leading to a great variety of heterocyclic
systerns (61MI41203, SORCRSSO) are applicable to the synthesis of triazoles and derivatives.
Nitrilirnines (171) formed by dehydrohalogenation of C-halobenzylidenephenylhydrazones
(172) react with C N, C=N (as in CNO) to afford triazoles and triazolines in yields of
1,2,4- Triazoles
769
Arc(
Ph
("N,
Ar \\ N
NJ
Ph
PhCCl=NNHPh
(172)
1 Et 3 N
+ -
PhC=N-NPh
(17 ! ') ,o
PhCH=NPh Ph
O N'N
H Ph PhN-1/
>(N'N Ph
Ph N-1/
Ph Ph
Scheme 84
/Ar
N
"--
NCN
PhNCX
x=O; 77%
X=S;86%
Scheme 85
50-75% (Scheme 84). Triazolidine derivatives are obtainable through similar reactions
frorn azornethine irnines, e.g. as shown in Scherne 85.
The versatility of triazole syntheses frorn nitrilirnines is further il1ustr ted in Scherne 86
(6SCB642). Note the simultaneous forrnation of triazole (173) and triazoline (174) frorn the
hypothetical bistriazoline intermediate (175) contrasted with the reaction of the aldoxirne
(176) which permits the stepwise isolation of triazoline (177) or triazole (178).
Ph
N-N
II \ fh
Ph "'W/'\H
I
N H
Ph\\, y,.
N-N Ph
Ph
(175)
^
PhCH=NN=CHPh
+ -
PhC=N-NPh
(171)
RCH=NOH
(176)
H Ph
yN'N
R/\ J
N
HO Ph
(177)
1
Ph
N
Ph" 'N
NJ
Ph
(173 )
Ph
N
Ph( 'N
N-1/
Ph
(174)
Ph
R("N'N
J
(178)
Scheme'86
Examples adduced in Scherne 87 indicate the caution required when a nitrilimine inter-
mediate favours the forrnation of a heterocycle other than triazole. The brorno derivative
(179) of the sernicarbazone (180) is forrnally analogous to (172); the nitrilirnine (181) is
formed even in the presence of such weak bases as sodiurn acetate or water and undergoes
ring closure to the 1,3,4-oxadiazole (182). In anhydrous acetic acid the triazolinone (183;
R = H) is forrned (72JCS(Pl)1918); a similar reaction occurs on treating the N-rnethyl
homologue of (180) with bromine in acetic acid to obtain (183; R = Me).
Another example of ambiguity (Scherne 88) arises out of the addition of phenylisocyanate
in the presence of aluminurn oxide to the nitrilimine (171) that affords a triazolinone (184)
with sorne oxadiazoline (185) as byproduct (64CBI08S), while the addition of phenylcyanate
770
1,2,4- Triazoles
Br 2
H 2 NCONHN=CHAr H 2 NCONHN=CBrAr
(180) ba:( (179)
lA H
NCOÑN=CAr
(181)
0/
Ar( )NH 2
N-N
(182)
R
O N'N
RN-1J
Ar
(183) R=H
Br 2 -AcOH
H 2 NCONMeN=CHAr þ (183) R = Me
Scheme 87
Ph
O N'N + PhN,\,O)Ph
PhN-1J PhN-N
Ph
(184) (185)
PhC=N-ÑPh
(171)
PhN cs 1
'
PhOCN
(186)
Ph
N
Ph\\" J
N OPh
(187)
PhN y S )Ph
PhN - N
(188)
Scheme 88
(186) affords the expected triazole (187). Phenylisothiocyanate reacts with (171) like
phenylisocyanate but in this case thiadiazole (188) is the rnajor product (62LA(658)169).
Further exarnples of triazole preparations by 1,3-cycloadditions will be found under
Section 4.12.4.3.2 which deals with the forrnation of such reactive species frorn heterocyclic
rings other than triazole.
Thanks to the ready availability of nitriles, their reaction with nitrilirnines is a useful
rnethod for the preparation of bistriazoles, e.g. (189) and (190) in Scherne 89.
O i,Et,N PhN.-N,\ -NPh
PhNHN=CIC _ CCl=NNHPh Þ I I
ii, PhCN Phl:::::-N _ N-::::::JPh
(189)
Ph Ph
Et,N N /N"-.,.- ( CF ) -<""N'N
---'---+ \ II 23 \\ II
LN N-3
Ph (190) Ph
PhCCI=NNHPh + NC(CF 2 hCN
Scheme 89
A cornbination of arnidrazone and nitriliurn rnethods (Scherne 90) affords arninotriazole
derivatives (191) in yields of 34-68% or better when hydrochlorides rather than free bases
are isolated (81CI(L)648).
Ar
+ _ /N",
ArNHCPh=NNH 2 + (ChC= NMe 2)CI ---+ P\\ IINMe2
N-N
Scheme 90 (191)
4.12.4.3 Synthesis of Triazole Rings from Other Heterocyclic Systems
Transforrnation of other heterocycles into triazoles implies one or rnore of the following
operations: (i) destruction of rings leaving an intact triazole core behind; (ii) cleavage of
the ring to an acyclic interrnediate which then recyclizes with or without rearrangernent;
1,2,4- Triazoles
771
(iii) destruction of the original ring to form unstable species captured by an added reagent
to form triazole. Conversely, reactions of this nature serve to convert simple triazoles into
those with fused ring systerns or into other heterocyclic rings.
4.12.4.3.1 Destruction of non-triazole rings
Methods of this type are best considered as reactions of the fused ring-systems in question
(see Chapter 4.15). The example illustrated in Scherne 91 is of potential interest in
. pharmacology (75T1363, ct. 74CPB1938). The conversion of the 1-arninoadenosine (192) into
the irnidazolyltriazole (193) amounts to triazole forrnation frorn an amidrazone intermediate
and a formyl group derived frorn the pyrimidine moiety.
H
NH ("'N'N
:ì N \\ -t
HzNN I ') N N
N ,...)
N R N
R
(193)
(192) R = D-l-ribosyl
Scheme 91
Other triazole syntheses by hydrazinolysis, hydrolysis or oxidation of fused ring systems
are briefly treated in (81HC(37)1).
The ring system to be destroyed rnay be constructed as a rneasure of synthetic strategy
as illustrated (Scheme 92) by the preparation of a triazole (194) used to synthesize fused
rings of pharmacological interest. The dihydroquinazoline (195) provides the amidrazone
interrnediate and the aromatic substituent required (75JHC717).
CI O ,COPh
NHCOMe
HO Ph
NHZNH Zþ CI CC I NNHz
JMe
N
(195)
HCOZH þ
CI
YeDPh
N
Me\\, ÌI
N-N
(194)
Scheme 92
4.12.4.3.2 Cleavage and recyc1ization of non-triazole rings
As in Section 4.12.4.2, the two most important acyclic interrnediates considered are (i)
hydrazine derivatives, especially arnidrazones; and (ii) reagents that undergo 1,3-cycloaddi-
tion, especially nitrilimines. Some other or doubtful rnechanisrns are rnentioned for reference
and for comparison when sorne formal similarity rnay overshadow rnechanistic differences.
Scheme 93 sumrnarizes the overall reaction rnuch used for the conversion of 1,3,4-
oxadiazoles (196; X = 0) and thiadiazoles (196; X = S) to triazoles (197) and (198). Inter-
mediates such as (199) and (200) have been isolated in sorne cases and have been reasonably
assumed in others, especially when such amidrazones could be converted either into (197)
or (198) according to the reaction conditions (see also 70KGS991).
R:'(X ÌlR " R"'NH\
N-N
(196)
X=O,S;R', R"=H, Alk, Ar
NHR"'XH
/ /
R'C CR"
\\ II
;)
R'"
HN\ jNHR'"
R'C CR"
\\ II
N-N
(200)
Scheme 93
R'" H
R''(N ÌlR " or R,(N'N
N-N N J
R 1
R"'=H
R"'= Alk, Ar,
OH, NH z
(197)
(198)
772
1,2,4- Triazoles
Examples have been selected partly to illustrate the care needed in the critical assessment
of the plausible Scherne 93 in new situations, and partly to illustrate the general nature of
the reaction for the preparation of triazolines and triazolidines.
Although both ammonia and methylarnine rnay be used to convert the oxadiazole (201)
into the triazoles (202) and (203) in good or excellent yields, respectively (Scherne 94), the
isolated interrnediates (204) and (205) of (Scherne 93) correspond to (199) in the forrner
case and to (200) in the latter (62JOC3240). The conversion of (196; X = 0, R', R" = Ar)
into (198; R', R", R'" = Ar) occurs with considerably inferior yields without isolation of the
amidrazone interrnediate (81HC(37)1, p. 72). The dipentafluoroethyl analogue of (201) reacts
with hydrazine via an interrnediate related to (204) or (205) to give the expected 4-
aminotriazole (66JOC781).
o
FJC( )CF J
N-N
(201)
NHz H
F CC/ COCF F c,/N'N
3 \\ / 3 3 \\ h
N-NH N-g
(204) (202)
H2
NHMe NHMe M N e
/ /
F 3 CC CCF J - FJC\\ //CF J
n N-N
N-N
(205)
(203)
Scheme 94
In general, the action of alkali on aminooxadiazoles (196; X = 0, R' = H, alkyl, aryl;
R" = NH 2 ) affords the acylsemicarbazone intermediate (206) that cyclizes to the triazolinone
(207). Ethanolic alkali reacts by ethanolysis to give (208) which cyclizes to ethoxytriazole
(209; Scherne 95). Recyclization of arninoanilinooxadiazole could afford both of the
triazolinones (210a) and (210b; Scheme 96) but only the latter is obtained (65LA(683)149,
65LA(685)176).
R'CONHNHCONH z
(206)
H
O N'N
HN-{
(207)
1 KOH-EtOH
H
N
R''/ 'N
\\ -1J
N OEt
(209)
R'CONHN=C(OEt)NH z --.
(208)
Scheme 95
H
( /OH /OH ) 0 N
PhNH\\ /fNHPh ---!f--+ Y
N-N '" HN NHPh
"\ (210a)
H
O N'N
Ph N-1J
NHz
Scheme 96 f210b)
Conversions of 2-arnino-5-carboxy-l,3,4-oxadiazole (211) and of the mesoionic acyl-
aminooxadiazole (212) (73KGS1345) into the triazoHnones (213) and (214) are norrnal
(Scherne 97). The latter reaction occurs with deacylation, of course.
An interesting application of the foregoing reactions is the preparation of azotriazoles
(215; Scheme 98) that involves oxidation of the arninoguanidine interrnediate (216) before
cyclization (69JPR213).
O ow
PhNH\\ I/NH z --.
N-N
1,2,4- Triazoles
773
H
,.,..-0 ow 0 N
HzN\\ Ì1CO z H -- 'N
N-N HN-1J
COzH
(213)
Ph
0", .- ow N
PhC '::/NCOPh -- Ph("" 'NH
PhN':.:'N --4.
(212) (214) 0
Scheme 97
R 0
'\\ Ì1NH z
N-N
R=Bu i
PhNHNH 2 , HCI
NH
RCO C-NHNHPh
\ /
HN-NH
(216)
Scheme 98
H
N
KOH, 85 'C PhN,( 'N
z\\ {,
N-.JJ
R
(215)
The transforrnation of oxazolidines (217) to triazolidines (218) (Scherne 99) requires
acidic conditions to cleave the cyclic herniaminal (65RTC408) and obviously does not proceed
through an arnidrazone intermediate.
MeNHNHMe + R'CHO --.
o
R'( )R'
MeN-NMe
(217)
R"NH 2 - AcOH
R"
N
R'( )R'
MeN - NMe
(218)
Scheme 99
The action of diarnines or arninotriazoles on 1,3,4-oxadiazoles (Scherne 100) is a synthetic
route to bistriazoles such as (219) and (220) (68JPR(309)168). Bistriazole (221) formation
combined with alkylation of the resulting triazolinone (ct. Scherne 95) can make use of
glycols instead of rnonohydric alcohols (68KGS372) as in Scherne 101. Related polytriazoles
with arornatic links have also been prepared (81HC(37)1, p. 576).
H
("N,
\\J Et H
N NH, N " N,
INN
N.::::::/ -.!J
Et N
(219)
Et Et
N N H2N(CH2)6NH2
I N-(CHz)6-N I (
N.::::::/ \,;::::oN
Et Et
o
Et( Ì1Et
N-N
(220)
Scheme 100
o 0
HzN( )-(CHz)n-( Ì1NH z
N-N N-N
n = 0, 4, 8
glycol-KOH ".... "- -<""' ÌI
I HOCHzCHzO" / (CHz)n \ I.
N-NH HN-N
(221)
Scheme 101
The rearrangernent of 1,3,4-thiadiazoles to triazoles is sirnilar to that of the oxa analogues,
but the former are less reliable, partly because they require higher ternperatures below
which by-products are favoured. Thus the rearrangement of 2-methylarnino-l,3,4-
thiadiazole (222) to the triazolinethione (223; S,fherne 102) occurs in good yield at 160 0 C
(57CB202), while a sirnilar reaction of (224) to (225) occurs only to the extent of 30% in
boiling rnethanol with the forrnation of an equal amount of (226) (61 YZ1333). However, the
reaction of (224) with hydrazine in methanol gives the 4-amino-5-thione (227) in good yield
in a reaction proceeding through nucleophilic displacement of the halogen and ring opening
to formyl thiocarbohydrazide (62YZ683). The sarne kind of ambiguity besets the reaction of
(228) with aniline (Scherne 103) that leads to a rnixture of triazolethione (229) and
aminoanilinothiadiazole (230) (70IJC391); the latter rearranges to (229) in ethanolic
potassiurn hydroxide (68IJC287).
The effects of unusual leaving groups have to be kept in rnind, such as that of N0 2 shown
in Scherne 104 (61YZ1333).
A brief comparison of rearrangernents of oxadiazoliurn and thiadiazoliurn salts deserves
mention. The sequence of reactions represented in Scherne 105 has been well studied. The
oxodiazolium salt (231) reacts with aniline to afford the acylarnidrazone (232) (71JCS(C)409)
774
1,2,4- Triazoles
S H
( 'ì7 NHMe eNH2,1600Ct S N'N
N-N MeN-.!J
(222)
(223)
NH 2
(NyS (NH 2 NH,
N-NH
(227)
(S)Cl PhCH,NH,-MeOH, hOil(
N-N
(224)
H
S N'N
PhCH N-.!J
2
(225)
Scheme 102
S
( )NHCH 2 Ph
N-N
(226)
H2N(SyS
N-NH \.
(228) H W",S"NHPh
2 \\ II
N-N
(230)
Ph
N S
H 2 N( Y
N-NH
(229)
ì 5 0 '0 KOH-EtOH
Scheme 103
S
R( )NHN0 2
N-N
R = Me3C
CH,Ph
R(NÿS
PhCH'NH 2 ,ð.( N-NH
S
R( )NHCH 2 Ph
N-N
Scheme 104
which on heating with acetic acid cyclizes to the triazolium salt (233) which is also available
by the reaction of (231) with aniline in acetic acid (71JCSfB)1648). A related reaction (Scheme
106) leading to the triazolium salt (234) can be used for the reversible preparation of the
triazoline (235) (70JCS(C)807).
/0" PhNH /- NPh
Ph\\+ II Ph _ PhC'" COPh
PhN-N CI0 4 \ I
PhN-NH
(231)
(232)
Scheme 105
Ph
AcOH. N
--. ( "" N
Ph ( + ',: CI0 4 -
PhN':.3
Ph
(233)
Me
MeNH,-EtOH ( .
t Me: "
" + "
N':':N
Me
Me
Et,:-: ( N
Me
HClO.
N-N
Me
CI0 4 -
(234)
Scheme 106
(235)
These reactions may be cornpared with those of thiazoliurn cornpounds (Scheme 107)
which proceed analogously except when the presence of a good leaving group such as SMe
permits alternatives. The forrnation of the thioacylamidrazone (236) from the thiazolium
1,2,4- Triazoles
775
salt (237) reacting with an amine to give the triazolium salt (238) is reasonably well
established (74Z0R377). Rearrangement of thiadiazolium corn pounds of the types (239) to
triazolium cornpounds by bases depends on the basic strength: aliphatic amines and weaker
aromatic bases may fail to react beyond acyclic interrnediates related to (236) (81HC(37)1,
p. 622). Methylthiothiazolium salts (240) also react differently with bases of different strength
(73IJC753), e.g. as in Scheme 108. The reaction with RNH 2 occurs readily when R:::: Bu,
but only in the presence of excess base for R:::: Ph. Oxadiazolium cornpounds give low
yields of triazolium compounds irrespective of whether aliphatic or aromatic bases are used.
( NHPh J
PhNHNH, Ph
Þ PhC C=S
\ /
N-NH
Me
(236)
S
Ph( )Ph
Ñ::'N
Me
NHPh
N
__ Ph(\)Ph
N':.:.'N
Me
(237)
(238)
Scheme 107
Bu Ph
Ph(N.)S- (BuNH, Ph( ')SMe PhNH, I Ph( )SMe
PhN PhN::N 1- PhN:.:.Ñ 1-
(240)
Scheme 108
S::--... _
Ph(.>:: l
RN::N
(239) R=Me, Ph; X=S-, WPh
Transforrnations of 1,3,4-oxadiazolinones into triazole (81HC(37)1, p. 329) derivatives are
less cornmon than those of 2-aminooxadiazoles. An unusual e1'-ample (Scherne 109) is the
rearrangement of the iminooxazolidinone (241) into the triazolidinedione (242) (75JOC3112).
R
RNyOyO OyNyo
RN-NPh RN-NPh
(241) (242)
Scheme 109
An acylamidrazone (243) is thought to be the intermediate in the rearrangernent of the
arylazo-1,2,4-oxadiazole (244) to the triazole (245) (74JCS(P1)81) notable for the dual role
of catalytic hydrogenation in Scherne 110. The acidic rearrangernent of the 1,2,4-thiadiazole
(246) to (247) (63JCS4558) may proceed through a sirnilar interrnediate. On the other hand,
the thermal or base-induced rearrangernent of the 1,2,4-oxadiazole (248) to (249)
(71JHC137) necessitates N-N bond forrnation and is unlikely to proceed through an
arnidrazone intermediate (Scheme 111). The same applies to N-N bond formation (Scherne
112) in the reaarangement of the 1,2,4-oxadiazolinone (250) to the triazolinone (251)
(74MI41200) while the methyl ester (252) is forrned frorn the aminoimidazolidinetrione (253)
through an acylsernicarbazide intermediate (254) (75JHC771).
Hr Pd
--4
( /NHCHO )
H2N-C
NNHAr
(243)
Ar
("'N,
__ \\ N
N-1I
NH 2
(245)
N
ArN 2 \\
N-O
(244)
Scheme 110
Yet another example of N - N bond formation is presented by an intrarnolecular
reaction of the oxime and imine functions of (255) in the preparation of the triazole (256;
Scheme 113) (74ZC270).
776
1,2,4- Triazoles
H
N II. HCI ( ......N:,..., ......NHPh ) N
H 2 NNH( NHPh H 2 NC "C, -+ H 2 N<:" 'N
N-S \\ SH \\ -.!I
N-NH 2 N NHPh
(246) (247)
(248)
H
<:"N,
\\ -.!IN
N NHAc
(249)
N
Me( rN II. or base
O-N
NHPh
Scheme 111
C0 2 Et
O C /NVO NH,-EtOH
Et 2 \\ I )
N-O
(250)
H
N 0
Et0 2 C( Y
N-NH
(251)
H
O r N
)=0
o N
I
N=CHPh
(253)
H
HCI-MeOH NVO
) Me02CCONHCONHNH2 -+ Me0 2 C( I
(254) N-NH
(252)
Scheme 112
H
......NH, N
ArC COPh AcOH Ar<:" 'N
II --- \\ -.!I
NOH NH N OPh
(255) (256)
Scheme 113
Hydrazinolysis of 1,3-oxazolin-4-ones (257) to afford triazoles with an alcoholic side-chain
(258) (70JCS(C)1515) and extension to iminooxazolidinones (259) to provide (260), an amino
analogue of (258) (74ZC267), is known to proceed through acylarnidrazone analogues
(Scheme 114).
ArbY O
(257)
NH,NH,
-.::.-..+
H
<:"N,
HOCH 2 \\ N
N-.!I
Ar
(258)
HNyNyo
O+Me
Me
(259)
/ NHCOC(OH)Me 2 N H
NH 2 NH, ,
-- H2N-C -+ Me 2 (OH)C\\ N
-"::NNH 2 N-.!I
NH 2
(260)
Scheme 114
Kindred rnethods for the preparation of rnercaptornethyltriazole (261; Scheme 115) from
thiazolidinethiones (262) and (263) are complicated by the reactivity of the thione in the
case of the forrner (71KGS39) but not in that of the latter (81HC(37)1, p. 409). Another example
illustrating the reactivity of the thione and forrnation of triazolinethione through an acylami-
drazone interrnediate (73DOK(211)1369) results in thioacyltriazolinone (264) or the hydrazone
of the phenylacetyl analogue (265; Scheme 116).
A different synthetic strategy for the preparation of triazoles with a carboxylic acid or
related functional sidechain starts from oxazolinones or thiazolinones, i.e. cyclic amides, to
provide the carboxylic function. An ArN; or ArNHN= functional group is attached to
the reactive position to obtain amidrazones with endocyclic arnide and exocyc1ic hydrazide
rnoieties. Note that in the examples, which are not intended to exhaust variations of this
approach, 4-ones as well as 5-ones rnay be used.
1,2,4- Triazoles
777
H
s\ys
(262)
H H
NH,NH, SvN y NyS
, \ N-N I
S S
H,NH,
H
\yo
(263)
Scheme 115
H
NH,NH, S N
, \ 'N
N-1I
H CH 2 SH
(261)
H 2 NN H
II N 0
PhCH C,/ V NH,NH,
2 \\ I (
N-N
H
( 265)
H
S 70
PhCH
MeNHNH,
, PhCH 2 C-C=NCONHNHMe
II I
S SH
Scheme 116
Me
,/N,
-+ PhCH 2 C \\ NH
II N I
S O
(264)
The conversion of 2-phenyl-4-phenylazooxazolin-5-one (266; Ar = Ph) into the ester
(267; Ar = Ph, X = MeO) with methanolic alkali (S7JA19SS) appears to have been observed
before by another worker who, on insufficient analytical data, mistook (267) for the acyclic
intermediate (268), some of which was isolated and identified and then cyclized to (267)
(62JCS575) in an extension of this useful reaction (Scherne 117) (SlHC(37)1, p. 96). The
reaction has been extended to rearrangements of 4-arylazo-2-alkoxy-2-thiazolin-5-ones
(SlHC(37)1, p. 303) which may occur with or without retention of the sulfur.
N N 0 NHCOPh r
ArN Ph --'" ArNHN Ph HX II / Ph'/ ' N
2 I ..-- I XC-C -+ \\
o 0 N-1I
o 0 NNHAr COX
(266) (268) (267)
X=O-, OAlk, SPh, NH 2 , NHAr, NHNH 2
Scheme 117
0= Ph N,y.o
NN-< A
S 0
(269)
ð.
-+
Q
N
O\" 'NPh
HN-{
S
(270)
Scheme 118
The thiazolidinedione (269) rnay be regarded as an acylarnidrazone; its pyrolysis (Scheme
118) affords a triazolidinonethione (270) (74CZ512).
Although these transforrnations or oxazolinones and thiazolinones can be extended to
imidazolones such as (271; Scheme 119), which also proceed through the acylamidrazone
interrnediate (272), the alkaline reagent (0.2% sodiurn hydroxide) rnay cause partial hydroly-
sis of the amide with the formation of acid (273; 2%) or the arnide (274) (69AC(R)434).
PhNHN 1- '-.,M NaOH ( /NHAc ) Me,/ tN
II e ----+ H2NCOC '\ \\-11
N NNHPh N CO -
o 2
(271) (272) (273)
Ph
N,
Me" -1IN
N CONH 2
Scheme 119 (274)
778
1,2,4- Triazoles
The use of 6-membered ring systems as sources of arnidrazones to be converted into
triazoles is relatively rare; the case of 1-arninoadenine (Scherne 91) has already been
mentioned. Transforrnations of 4,6-dihydrazinopyrimidine, hydrazines forrned frorn
haloaminopyridazine (81 HC(37)1, p. 8) and 1 ,2,4-triazines (81HC(37) 1, pp. 409, 424, 488) all involve
amidrazone intermediates cyclized to triazoles with the acyl function derived frorn the
original ring. For instructive examples of preparative links between tetrahydrotetrazine,
forrnazans and 1,2,4-triazoles, see Scheme 120 (81KGS694).
OH
/"-.. N
R Ph R Ph CH20H HO( 'N
HN........çN N........çN RN-1/
Ph Ph Ph
lNaoH
Ph
N
HO( 'N
OHCN-1/
Ph
Ph
N
HO ( 'N
-1/
HOH 2 CN Ph
CH,O
Ph Ph
N N
HO( 'N ('N
HN-1/ --+ -1/
Ph Ph
\
/,....
Ph Ph
PhN-pH HO,--NPh N /N"-.---/N' N
I \ I \ (01 /-\
N /N-CHOH-N /N LN N-1/
"" "" h Ph Y Ph
Ph P
o
Scheme 120
The forrnation of dihydro or tetrahydrotetrazine intermediates in Pellizzari type reactions
carried out at high ternperatures has long been suspected. The conversion of diphenyl-
tetrazine (275) into 3,5-diphenyltriazole (276) by reduction (62LA(654)146) occurs in two
stages (Scherne 121). Formation of the aminotriazole (277) rnay be interpreted as an
intramolecular teacylation of the arnidrazone analogue derived frorn (275) followed by
reductive cleavage of N(4)-NH 2 . The conversion of (275) into (276) with ethanolic alkali
also is consistent with the known lability of N(4)-NH 2 .
( NH ) H
N-N N ' N
Ph( Ph Ph( i;Ph --+ Ph( r
N-N N-N N-3Ph
H H (277) (276)
(275)
Scheme 121
N-N F
H 2 N( NH2 F,/NaF , F 2 ( Y +
N=N N=N N
Scheme 122
Diaminotetrazine is converted by fluorination into polyfluorotriazolines (Scherne 122)
(67USP3326889).
An unusual preparation of triazoles proceeding through an arnidrazone interrnediate
(278; Scherne 123) is the transforrnation of 4,6-diphenyl-1,2,3,5-oxathiadiazine 2,2-dioxide
(279) with hydrazines to 3,5- or 1,3,5-triaryltriazoles (280) (63CB2070) in yields of around
90%.
F F
F 2 N1:=[-NF,
R
Ar' N
RNHNH / A '/ ' N
" Ar'CN=C -. r\\
II" N-3 ,
NSO H NHNH, Ar
3 (280)
(278)
N
Ar'( 'ì
N, .....0
S
O 2
(279) R = H, Ar"
Scheme 123
1,2,4- Triazoles
779
Reference has been rnade to triazole syntheses frorn the use of cyclic amidrazones such
as arninoquinazolines (Scheme 92). Reactions of benzoxazines with hydrazines give related
intermediates (Scherne 124) leading to 4-aryltriazoles (69LA(729)124). Related techniques
include the use of benzoxazinonethiones (281) (72ZC17S) and the acidic rearrangernent of
2,3-benzoxazines (282) (72JHCS81) that afford 5-aryltriazoles (Scherne 125). Reaction of
syrnrnetrical hydrazines with benzoxazinone perchlorate (283) affords 2-aryltriazolium salts
(284) or analogues with an aliphatic side chain (285) when the oxazoliniurn perchlorate
(286) is used as a starting material (81KGS1423) (Scherne 126).
CÓM,
N
R = H, Me
RCONHNH,
.
o
NNHCOR
U",JMe
N
ow
--
yea'H
N
Me( JR
N-N
Scheme 124
H
UoJ:. s
(281)
NH,NH,
)
H
N
S\" N
N OH
H O
eHPh
Ö
(282)
H 3 0+)
Me
Q-i N
N
- N-1I
Ph
CH 2 0H
Scheme 125
NH MeNHNHMe
:)JR 00;'
(283) R = Me, PhCH=CH
Me
' ' ' M
. + ',N e
- N \.:.J CIO-
OH R 4
(284)
o
Me2( JMe
N CIO-
o H 4
(286)
MeNHNHMc
)
Me
N
Me2(OH)C(;' Me
N' 0 CI0 4 -
Me
(285)
Scheme 126
The triazepinethiones (287) (S9JPR(8)298) and (288) (67JCS(C)9S2) both give the same
1-methyl-3-phenyl-1,2,4-triazoline-5-thione (289), the forrner on treatment with base, the
latter with acid (Scherne 127).
HN
s-=Z )Ph
N-N
Me
(287)
Me
N
base S=::'/ 'N
-- \-11
Ph
(289)
H+
--
Ph
N O
s-=Z )Me 2
N-NH
Me
(288)
Scheme 127
4.12.4.3.3 Nitrilimines derived from non-triazole rings
Nitrilimines for the preparation of triazoles are often generated frorn tetrazoles (61MI41203,
62LA(6S3)10S) or frorn 1,3,4-oxadiazoline derivatives, e.g. (290; Scheme 128) (74TL1673),
which thernselves are obtainable by therrnolysis of tetrazoles. As illustrated in Scherne 129
(68CB743, 70JOM(21)427) self condensation of nitrilimines leads to arnbiguity. The rearrange-
ment of (291) to (292) is controversial.
o OMe
<"'" ð. +- .
Ar \\ j"Ph -+ ArC=NNPh .---+ tnazoles
N - NPh
(290)
Scheme 128
780
1,2,4- Triazoles
An interesting application of self-condensation of the interrnediate nitrilirnine already
incorporating the nitrile reagent (67JOC1871) is useful for the preparation of symmetrical
3,5-disubstituted 1,2,4-triazoles such as (293; Scherne 130) but the method illustrated in
Scheme 129 is better for the preparation of unsyrnrnetrical analogues (294).
N
Ph" )./
N-NSiMe3
ð. + -
-+ PhC=NNSiMe 3
NSiMe 3 NSiMe 3
Ph"N'ì!Ph -+ Ph"N'N
/ N-N N-1/
/ Ph
(291) (292)
,o,
SiMe 3
N
PhCH 2 " 'N
N-1/
Ph
H
N
EtOH PhCH <"" 'N
--. 2 \\ -1/
N Ph
(294)
H
/N,
N N
"-1/
N R
,..;:NH
c'"
I'R
NH N
,; N/ 'N
+ RC" -+" -1/
Cl N R
H
N
R<"" 'N
\\ -1/
N R
(293)
Scheme 130
Formation of a nitrilirnine interrnediate rnay be assumed in the synthesis of the
triazolidinedione (295) from the diaziridinone (296; Scheme 131) (76JOC2813).
o
Ä
RN-NR
(296)
PhCONCO
)
COPh
O"'(NyO
RN-NR
(295)
Scheme 131
Photolysis of azirine (297), or thermolysis of the oxazaphosphole (298), affords reactive
azornethines (299) and (300), respectively. These react with azodicarboxylates to give
triazolines (301) and (302) as in Scheme 132 (74HCA1382, 73CB3421). The use of diaziridine
(303) to afford the triazolidinone (304) in Scherne 133 (74JOC3198) may be compared with
the reaction shown in Scherne 131. Therrnal decornposition of the aziridine (305) proceeds
via an ylide (306) which reacts with azodicarboxylate to afford the triazolidine (307) in
very good yield (Scherne 134) (66JOC3924). For sirnilar uses of ylides see (81HC(37)1, p. 516).
N-CO,Et N
N hv + - '- co Et Ph"? "Me
Ph Me 2 -- PhC=NCMe2" ,) (/ 2
Et0 2 CN-NC0 2 Et
(297) (299) (301)
F C (OMeh N-CO,Me
3 P I,
V '-.:\. + - N-CO Me
/\ dO -+ (phC=NC(CF 3 h) ')
F 3 C N- Ph (300)
(298)
N CF
Ph( "f 3
Me0 2 CN-N CF 3
C0 2 Me
(302)
Scheme 132
Et
^
EtN-NEt
(303)
COPh
PhCONCO Et COÑCOPh Et ( NyO
) / -+ /
ÐN " BN-NB
Et (304)
Scheme 133
1,2,4- Triazoles
781
Ph PhMe.d + _
6 - (PhCHNPhCHPh)
Ph Ph (306)
(305)
7J-CO,EI
N-.CO,Et
)
Ph
N
Ph( ìPh
Et0 2 CN-NC0 2 Et
(307)
Scheme 134
Forrnation of the phosphatetrazepinone (308) interrnediate is postulated in accounting
for the mechanisrn of preparing triazoles (309) and (310) from the 'quasi dipole' (311;
Scherne 135) (69AG(E)513).
Ph} ( ArO '( N'::::"'OAr )
'- - ArNCO I \
NNC0 2 Me - N NC0 2 Me--
/ '\ I
Me0 2 C Ph 3 P-NC0 2 Me
(311) (308)
( Ph 3 P::r.: r. N"70Ar ) __ Ph 3 P=N(N"7 0Ar __ H2N( OAr
;/)-N-NC0 2 Me N-NC0 2 Me N-NC0 2 Me
C0 2 Me (309) (310)
Scheme 135
4.12.4.4 Introduction and Modification of Functions on the Triazole Ring
Specific functions in specified positions of the triazole ring are available in three ways:
(i) constituent portions of the ring to be forrned carry the functions; (ii) the preforrned
triazole ring is substituted; and (iii) existing functions are rnodified. These synthetic
approaches are not mutually exclusive. On the contrary, (i) may establish functions on the
ring so as to protect a certain location so that (ii) rnay result in unarnbiguous substitution
whereupon (iii) is used to rernove the protective function. However, rernernber that (iii)
may involve rearrangement, say, frorn N to C.
Examples of all such procedures have been given in Sections 4.12.3,4.12.4.2 and 4.12.4.3;
this section summarizes such information, rnuch of it docurnented in appropriate chapters
of (8IHC(37)1).
4.12.4.4.1 Alkyl and aryl groups
Of about 300 publications dealing with the synthesis of rnono-, di- and tri-alkyl- or
aryl-triazoles, 76% establish the functions by rnethod (i), 18% by (ii) and 6% by (iii); (i)
is broken down further into 63% for arnidrazone rnethods, 3% for 1,3-cycloadditions and
16% for other procedures, rnainly the cleavage of fused ring systems. This rough analysis
will be modified if extended to include current and future references but it may serve as a
heuristic guide for those intending to devise triazole syntheses.
Alkyl- and aryl-triazoliurn compounds are forrned mostly by quaternization of preformed
triazoles, rnore rarely by rearrangernent of oxadiazoles proceeding through acylarnidrazone
interrnediates. An unusual method (Scheme 136) is the addition of the alkoxydiazenium
fluoroborate (312) to the Schiff base (313) to form the triazolium salt (314) through a
rnechanism that rnay involve a triazolidine interrnediate (315) (69CB3176).
( PhCH 2'- + )
N=NOEt
/
Ph
(312)
BF4 - + PhCH=NPh __ ( Ph( NOEt\
(313) PhN-th J
(315)
Ph
N
__ Ph(\'\N
PhN':.:J
Ph
(314)
BF4 -
Scheme 136
Triazolinones and triazolinethiones with alkyl or aryl substituents have been prepared
by the cyclization of appropriate sernicarbazide or thiosernicarbazide derivatives in 84%
of 500 papers; in 14% of such preparations, preforrned triazoles were alkylated or arylated,
782
1,2,4- Triazoles
but the starting rnaterials were prepared rnostly by variations of the amidrazone rnethod.
Also rnost of the alkylations have been carried out on thiones rather than with their oxo
analogues. Similarly, of 200 rnodern syntheses of alkyl- or aryl-arninotriazoles, 90% rnade
use of the cyclization of arninoguanidines or comparable arnidrazones and 10% relied on
1,3-cycloadditions.
Substituted triazolidines have been obtained by Scherne 99, rnany by 1,3-cycloaddition
and rnost of the triazolidinones, thiones and imines by the arnidrazone rnethod. Although
chernical or electrolytic reduction of triazoles leads to ring cleavage rather than the forrnation
of triazolidines, the reduction of triazoliurn salts (316) to triazolidinones or thiones (317;
Scheme 137) is possible (74JCS(P1)633, 74JCS(Pl)642). However, the reduction of triazolinones
(318) and (319) with lithiurn alurninum hydride (Scherne 138) affords the expected
triazolidinone (320) in the forrner case, but paradoxically results in 'oxidation' to the triazole
(321) in the latter (71BSF3296).
Ph Ph
. _w N X
Ph( +)x ---. Ph( Y
MeN:':N MeN-NH
(316) X = 0, S (317)
Scheme 137
H
NOw N 0
Me( Y ---. Me( Y
MeN-NMe MeN-NMe
(318) (320)
H
Now
Me" Y ---.
N-NMe
(319)
( H ) Me
Me(N ìOH -+ (N),N
N-NMe NJ
Me
(321)
Scheme 138
4.12.4.4.2 Halo groups
The application of the arnidrazone rnethod is lirnited. Most of the other published
preparations are equally divided between electrophilic halogenation, nucleophilic displace-
rnent of halogen or nitro groups, and displacernent of diazo or nitrosarnino groups. The
conversion of triazolinones into chlorotriazoles with phosphorus chlorides rnay be regarded
as a nucleophilic displacernent reaction of the hydroxytriazole tautorner, while the prepar-
ation of chlorotriazoles by the action of chlorine on thiones is regarded as oxidative
chlorination.
4.12.4.4.3 Nitrogen functions
Various functions have been reviewed (SlHC(37)1, p. 255): rnost of their preparations rely
on the reactions of arnines, hydrazines, etc., not specific to the chemistry of triazoles,
however a few syntheses proceeding through arnidrazone interrnediates incorporating the
phenylazo or nitrarnino groups have been reported.
When the N-function is part of another heterocyclic systern further substitution, e.g.
alkylation, implies a cornpetition between heterocycles. The preparation and properties of
sorne triazolylpyrazolidine-3,5-diones (322) related to the rnuch used drug butazolidine are
instructive (74AJC2447, 75AJC133, 75AJC421, 76AJC2491). Most of the preparations linking a
triazole ring to further triazoles or other heterocycles rnake use of the cyclization of
arnidrazones.
4.12.4.4.4 Sulfur functions
For synthetic possibilities of sulfur functions see Scherne 54 and Section 4.12.3.3.1.
1,2,4- Triazoles
783
4.12.4.4.5 Carbonyl functions
The two major techniques for the preparation of triazolecarboxylic acids are the arni-
drazone rnethod and transforrnations or replacernents of existing functions. In the forrner
case one can introduce the carboxylic acid through starting rnaterials such as (323). Alterna-
tively, cyclization of other amidrazones can be accornplished with derivatives of oxalic acid,
e.g. by converting the acylarnidrazone (324) into the arnide (325) frorn which the acid rnay
be liberated by hydrolysis. A particularly convenient rnethod for the preparation of carboxy-
lic acids, esters and arnides is the rearrangernent arylazooxazolinones (Scherne 117).
o H R'
R" k 'N----(""N'N
\\J
R'" 0 N Ph
(322) R', R", R'" = H, Alk
NH 2
/
Et02C-C
NNHR
(323)
/NHR"
R'-C
NNHCOCONJ
(324)
R'( yCONJ
N-N
(325)
Conversion of existing functions include the oxidation of aliphatic or aromatic side-chains,
one of the earliest preparative techniques of triazole chernistry. Hydrolysis of cyanides
obtained by displacernent of halo, nitro and diazo groups is of cornparable irnportance.
Reactions of nitrilírnines with ethyl cyanoforrnate have been little used. Given a triazolecar-
boxylic acid or its derivatives, further representatives of this class rnay be obtained by
alkylation, acylation and other nuclear substitutions.
Carbonation of triazole (Scheme 139) under pressure and catalyzed by cadrnium fluoride
(S9BRP816S31) gives rnoderate yields of the rnono- or the di-carboxylic acids (326) and (327)
according to reaction ternperature.
H
("'N,
\ JN
H
K,CO,-CO,-CdF, ( N,
) H0 2 C \ N
J
N C0 2 H
(326)
H
("'N,
+ \\J
N CO 2 H
(327)
Scheme 139
Acyl derivatives other than carboxylic acids and their derivatives rnay be considered in
two categories. One of these, N-acylation, has been discussed earlier (Sectìon 4.12.3.2.2).
If in view of the frequently occurring arnbiguity of such procedures, an unambiguous
synthesis is required, one may proceed as in Scheme 140.
COPh
,&NAc ("'N,
PhC + PhCONHNH 2 __ Me\\ IN
OEt N Ph
Scheme 140
Triazolyl ketones have been synthesized from diacylarnidrazones such as (328), and
through oxidation of benzyltriazole (68JCS(C)824). The rearrangernent of N-acyl- to C-acyl-
triazoles has been rnentioned earlier as well as the reacylation of 1,1-carbonylbis-1,2,4-
triazole.
NHAC
/
Ac-C
,
NNHR
(328)
/Ph
N=C
I "
N NH 2
()
N-N
Ac,O. 25 'C )
( Ph )
/ Ph
N=C N=\ CH=NNHAc
I" I \ N,
,/N......., NH 2 __ ,/N y NH __ ( N
\\ .1/ \\ NJ ph
N-NAc N-NAc (329)
Scheme 141
784
1,2,4- Triazoles
Although 4-formyl triazoles are unstable, a curious method of preparation (Scheme 141)
affords the acyl hydrazone (329) (69JPR646).
The preparation of free 3-carbaldehydes (which must be N-substituted in order to avoid
hemiaminal formation) is best carried out by oxidation of the triazolylrnethanols obtainable
by reduction of the corresponding esters with lithiurn aluminurn hydride. Potassium fer-
ricyanide in amrnonia or lead tetraacetate are suitable oxidants but thermal decornposition
of benzenesuIfonylhydrazides (330) appears best (62JCS575).
R
.......N,
R\\ _l
N CONNHS0 2 Ph
(330)
NH 2
/
R-C
'\.
NNHCOCH(OMeh
(331)
N-Unsubstituted aldehydes are available as derivatives. Acetals are prepared by the
amidrazone methods; other derivatives are obtainable from the hemiarninal, e.g. frorn (331)
(70TL943).
4.12.4.4.6 Metal complexes
For a brief review of metal-triazole complexes see (81HCl37)l, p. 659).
4.12.4.4.7 Triazolidinediones
Triazolidinediones are accessible through the general rnethods illustrated before and
Scheme 142 presents several procedures (see also 80RCR880). Triazolinediones are prepared
by oxidation of the triazolidinediones with lead tetraacetate, t-butyl hypochlorite, N-
bromosuccinimide and the less cornmon oxidant, activated isocyanate (74JOC3506, 73TL2101,
75JCS(p2)132S, 76JHC481).
PhNHCONHNHR
COCI, or CO(OEt),
)
Ph
O NyO
HN-NR
( /NHCONEt2 ) 0 0
O=C _ y
M NNHMe MeN-],;Me
Et 2 NCONCO + MeNHNHMe
NMe2
I
2Me2NNCO _ O N':fO
N- NMe 2
R R
O N':fO O NyO
N-NMe2 MeN-NMe
1 HCI
PhCOÑNMeR; ( \: o ) o yo
/ , HN-NMe
Me R'
Scheme 142
4.12.5 APPLICATIONS
For the greater part of the history of 1,2,4-triazoles only two derivatives were used
extensively: one in small quantities as an analytical reagent and the other on a large scale
for agricultural purposes. The number of triazole derivatives in either of these categories
has increased greatly but only a srnall fraction of approxirnately one thousand patents
covering the preparation and use of triazoles can be treated here.
1,2,4- Triazoles
785
In many applications the use of 1,2,4-triazoles is not specific: the action claimed may be
common to other azoles, or the compound in question may contain not only a triazole ring
but so many other structural features as to make the identification of 'the' active molecular
fragment difficult. In many important instances triazole derivatives are used to control
weeds, fungi, insects and so on. The effectiveness of a given compound varies with the
species, and such variation may be reported in hundreds of papers written by biologists
rather than chemists.
The aim of this short section is to draw attention to such chemical features of 1,2,4-triazoles
that have been recognized to be of practical value and discussed further in Section 4.12.5.1
which deals with analytical and synthetic applications. Uses on a larger scale are treated
in Section 4.12.5.2 and are to be considered merely as examples demonstrating the wide
applicability of 1,2,4-triazoles and to encourage readers with practical interests to search
the vast literature in their special field of technology.
4.12.5.1 Analytical and Synthetic Applications
4.12.5.1.1 Analytical uses
The first 1,2,4-triazole to find practical application was nitron (332; Scheme 143) (05CB856,
05CB861, 05CB4049). Only 0.01 % of nitron nitrate dissolves in dilute hydrochloric acid; the
solubility of the perchlorate is rather less. Nitron has also been used for the determination
of boron, rhenium and tungsten (81HC(37)1, p. 603) but the formation of a mesoionic
non-stoichiometric hydrochloride of nitron (80AJC2237) calls for caution in its use for the
development of new gravimetric procedures. In an elegant modern application (79MI41200),
nitron is linked to polymerized p-chloromethylstyrene for the removal of nitrate from water.
The triazolium chloride (333) is used for the spectrophotometric assay of cobalt (68MI41201),
and the simple thione (334) for that of rhodium and platinum (nMI41201).
Ph
/NHPh CH,O ( N'N
PhN=C" J
NHNHPh N NHPh
\:: CO H Fe03
, or
HONO
Ph
N
( t
N ÑPh
(332)
Scheme 143
Ph
N
,0'--'> N
\ + .
PhNH :3 CI-
(333)
H
S N'N
HNJ
(334)
Azo compounds derived from triazole are coloured ligands for antimony, bismuth and
copper (81HC(37)1, p. 609). Brilliant lakes are forrned with hydroxyphenylazotriazoles
(73AJC1585); the intensity of the colour formed with various metallic ions varies with the
position of the hydroxy group in the phenyl substituent.
Coupling of 3-diazo-1,2,4-triazole to proteins at pH 2.8-6.8 has been shown to affect
tryptophan only, while coupling with histidine and phenols requires the usual basic condi-
tions. This permits a specific determination of tryptophan, sharpened by preparing the
reagent from 3-amino-l,2,4-(5- 14 C)-triazole that permits assay by a scintillation method
(79MI41201).
The reaction of 4-amino-5-hydrazino-1,2,4-triazole-3-thione (38) with aldehydes
(740PP156) has found clinical applications but the wide applicability of the reaction límits
its specific use.
786
1,2,4- Triazoles
4.12.5.1.2 Synthetic uses
Without considering their use as synthons in preparations of fused ring systerns and
compounds with mixed heterocyclic portions, 1,2,4-triazoles find synthetic uses in four
kinds of reaction.
Reference has been made to 1,3,5-tribromotriazole and 1,3-dichlorotriazole which act
as halogenating agents (Section 4.12.3.2.2). Transfer of N-acyl functions to 1,2,4-triazole
has been illustrated in Scheme 28 but N-acyltriazole and especially carbonylditriazole (83)
rnay be used similarly to the analogous imidazole cornpounds (79LA1756) except that the
latter are rnore econornical.
Related to such transacylations is the ability of triazole to accept and transfer acyl groups
so as to rnake it a catalyst for the formation of arnides and esters frorn their constituents.
In particular triazole has been used in the synthesis of peptides. Irnidazole and 1,2,3-triazole
which also possess both weakly acidic and weakly basic groups have similar catalytic action
which, however, is accompanied by racemization not observed when 1,2,4-triazole was
used (65RTC213). It has been found best to catalyze coupling in peptide syntheses such as
Scherne 144 (66LA(691)212). For the use of quinolinesulfonyl-3-nitrotriazolide in nucleotide
synthesis see (80TL4339).
SiMe 3 CO,Bu l
Bu l OCON 3 + ,/N'N _ ,/N'N
"N --.!J --.!J
(335)
NH,
RCH/
'C0 2 H
)
NHCO Bu l
/ '
RCH
"C0 2 H
NH,
/
PhCH20CONHCHR'C02C6H4N02 + R"CH
"-
C0 2 H
H
,....-N,
\\J
N ) PhCH 2 0CONHCHR'CONHCHR"C0 2 H
30'C, 23 h
R'
N
MeNHNHMe+2RCHO+H 2 NR' - R( ÎR
R'=CHR"COX (X=OEt, NH 2 , etc.) MeN-NMe
Scheme 144
! NH,OH
N
RCH:=:CHO
Characterization or N-protection of amino acids by the t-butyloxycarbonyl group can be
carried out either by acyl transfer frorn the triazole (335) prepared as in Scherne 144 or
with t-butyl phenylcarbonate in the presence of triazole (73TL469) in lower yields. Although
1,2,4-triazole acts as a catalyst in the second of these reactions, it has to be present in an
equimolar amount.
The self-condensation of glycine to triglycine at pH 6.7-8.9 is increased 10-20 fold in
the presence of catalysts of which 1,2,4-triazole is one of the best. The reaction is not noted
in basic solutions but the effect is rnaximal at the pH thought to be that of primitive oceans.
The linking of triazole with prebiotic peptide syntheses is speculative and far fetched but
not irrational (81C59).
It has been proposed that triazolidines formed from amino acids (Scheme 144) would
be suitable for the characterization of amino acids and as N-protected starting material for
the synthesis of peptides (64RTC387).
Scherne 145 represents another catalytic property of 1,2,4-triazole. Addition of the
annular NH to the conjugated ketone (336) gives (337), the unstable oxime of which
provides the isoxazole (338) not available by adding hydroxylarnine to (336) in the absence
of triazole (81AG(E)88S).
H
,....-N,
II_l
RCHCH 2 CO-<]
I
,/N,
\ J
(337)
RCH=CHCO-<]
(336)
( R HCH2C(=NOH)-<J )
NH,OH N
-- ,/ 'N --+
"NJ
R\Ll
"_\/
(338)
Scheme 145
1,2,4- Triazoles
787
The cleavage of 4-phenyltriazole by butyllithium in hexane and THF at 0 DC to afford
N-phenylcyanarnide (79TL3129) may have advantages in laboratory scale operations but
appears too expensive for large scale purposes.
Although 1,2,4-triazoline-3,5-dione is unstable even at 0 DC, it can be reacted with dienes
in situ when forrned by the oxidation of urazole (5) with dinitrogen tetroxide (73TL2101).
N-Substituted derivatives are rnore convenient to use.
4.12.5.2 Industrial Uses of Triazoles
4.12.5.2.1 Biological activity
3-Amino-1,2,4-triazole (Amitrole, Arnizol, AT A, Cytrol, ENT 25445, Weedazol) was
the first 1,2,4-triazole to be manufactured on a large scale from aminoguanidine formate
(460S(26)11) for use as a neutral herbicide and defoliant of cotton. Its photo toxic effect and
interference with carbohydrate metabolism (61CRV87, p. 121) are not inconsistent with
biochemical disturbances caused through replacement of histidine with an analogue derived
from triazole rather than imidazole. Inhibition of liver and kidney catalase and impaired
thyroid function in animals and suspected carcinogenetic properties have occasionally
threatened the use of aminotriazole for the protection of edible plants (notably cranberry)
but the ill-effects observed in animals have not been found in humans. On the other hand
aminotriazole has been shown to give some protection to mice against irradiation with
X-rays.
Although sorne derivatives, particularly the furylidene compound, are more effective for
some purposes, none of the more complex triazole derivatives patented as herbicides has
been able to displace aminotriazole.
While aminotriazole in low concentrations rnay promote growth, the bistriazole (339),
prepared from triazole and dichlorodiphenylmethane (72BRP1269619) has the opposite effect.
N--='\ r:::N
I N-CPh 2 -N I
/ \-;:::::J
N N
(339)
4-Butyltriazole is a fungicide but injures seedlings; such damage is avoided if used as
the complex (340) (71SAP7004373). Other fungicides derived from triazole include 0-
phosphorylated triazolinones. Complex triazolylglycol ethers (81EUP21076, 8lGEP2926280)
are claimed to be plant growth regulators and fungicides. Newer herbicides include
triazolidinonethiones with aromatic and lower aliphatic substituents (8lGEP2952685). Com-
pounds of a similar nature are insecticides, acaricides and nematicides (75GEP2407304,
76GEP2554866). Many alkyl and aryl derivatives of mercaptotriazole are active against fungi
and other bacteria (81HC(37)1, p. 251). When the substituent is attached to a cephalo-
sporin (75MI41201) the antibacterial effect is best ascribed to the non-triazole heterocycle
modified by other pharmacologically active groups including the triazole portion. The sarne
applies to the action of (341) against Mycobacterium th. (73FES624) or of carbamates
(342) (80EUP11604) against fungi and animal parasites.
( CS 2 u
Zn ( ÌJ
CS 2 N-N
(340)
(/\H
O/"(J
(341) N SCH 2 CONHNH 2
CHMeCH 2 0Me
,.,.....N....
Me 2 NC0 2 \\ N
NJ
(342)
Ph
O N""N
Me2NCH2CH2N
CHEtPh
(343)
Relatively simple 1,2,4-triazoles display biological activity such as inhibition of
cholinesterase (55MI41200), interference with mitosis (51MI41200) and reversible denaturation
of serum proteins (52MI41200), but the pharmacological significance of 1,2,4-triazoles is
slight in comparison with some other azoles (61CRV87). The simplest thione (334) affords
788
1,2,4- Triazoles
sorne protection of mice against radiation and (343) has anti-inflammatory properties
comparable with the rnuch more economically produced phenylbutazone (64HCA2068). The
greatest prornise of pharmaceuticals derived from triazoles lies in the field of polycyclic
corn pounds outside the scope of this chapter; for virucidal amides see (75GEP2511829).
4.12.5.2.2 Dyes and photographic chemicals
Metalated bisazotriazoles dye fast shades (73JAP7389932); rnany dyes and whitening agents
have been successfully modified by incorporating triazolium salts into their structure
(81HC(37)1, p. 599). Cyanine dyes (59JCS3799) are of irnportance in colour photography. A
cornbination of 1,2,4-triazole and dimethyl sulfide gold(I) chloride can be used to gild glass
(73GEP2245447).
Like the rnore widely used 1,2,3-triazoles, many 1,2,4-triazole derivatives find application
in photography thanks to the adsorption of thiones on silver halides, reactivity with silver
corn pounds or the forrnation of disulfides as potential free radicals. Also S-propargylthiol
(344) stabilizes photographic ernulsions (74GEP2304321).
H
,/N,
\\ IN
N SCH 2 C=CH
(344)
Seleniurn derivatives prepared by the amidrazone rnethod frorn the seleniurn analogue
of thiosemicarbazide are also used for various photographic purposes (81HC(37)1, p. 510).
4.12.5.2.3 Polymers
The preparation of polyrners derived from 1,2,4-triazoles is currently the rnost irnportant
practical application of this heterocyclic systern. Three recent reviews cover the substantial
beginnings of a rapidly expanding field of research (B-72MI41202, 77RCR76, 8IHC(37)1, p.575)
but only the last of them is devoted entirely to 1,2,4-triazoles. As each of the salient points
sumrnarized below is covered by several publications their documentation should be supplied
by reference to these reviews.
Polyrners derived frorn triazoles can be forrned by three fundarnental rnethods. In the
sirnplest way 3,5-disubstituted triazoles are treated with acetylene to obtain 1-vinyl deriva-
tives which are then polyrnerized with free radical catalysts. The resulting polyrners do not
appear to be used on their own but rnixed with other polyrnerized alkenes they facilitate
the dyeing of synthetic fabrics.
A second method is the formation of poly ami des by condensation of dicarboxylic acids
or diisocyanates with diamino corn pounds such as (345), the reaction of which with 2,6-
naphthalenedicarboxylic acid gives heat resistant filrns and fibers.
Ph
H N Oi N ?-O NH
2 l 2
- N-N -
(345)
The rnost-studied method generates the triazole ring in the course of polymerization by
reactions surveyed under Section 4.12.4. Most of the techniques in use convert hydrazides
or arnidrazones into triazoles. Polyhydrazides are thermally cyclized with arnines (Scherne
146). Of particular interest is the reaction of aliphatic or aromatic dicarboxylic acids with
hydrazine that generates polyhydrazides which then react with further hydrazine to polyrners
with repeating units of 4-arninotriazole (Scherne 147). Polyarninotriazoles have been used
to irnprove antistatic, dyeing and laundering properties of polyalkene fibres, also as toners
in electrophotography and to protect metals against corrosion. In addition the free amino
group perrnits the attachrnent of cross-linking groups ànd other functions, e.g. the carboxyl
terrninal of arnino acids leaving the amino terrninal free for anchored peptide syntheses.
Acylation of bisarnidrazones followed by therrnal cyclization of the linear polyrner
(Scherne 148) has provided valuable polyrners of high therrnal stability; benzene and pyridine
1,2,4- Triazoles
789
{CONHNHCOA); NN>'. lt l"
A = (CHz)s
Scheme 146
HOzC-A-COzH
NH 2 NH 2
I
I / Hl l
r _ßAI
A = aliphatic chain, aromatic ring
Scheme 147
HzN NHz
" / CIOCBCOCI
C-A-C )
;f
HzNN NNHz
{ CO HlN"C_A_C/NHz COB }
";f /
NHN N-NH n
LA
A=-, aliphatic chain, aromatic ring A-( B }
L :NH :NH n
Scheme 148
bridges have been used. Polytriazolines formed by using dialdehydes instead of dicarboxylic
acids are unstable.
Of particular interest are the 'ladder' polytriazoles formed from bisamidrazones with di-
and tetra-carboxylic acids or bisbenzoxazinones, e.g. Scherne 149. Such polymers derived
from napththoic acids have a high average molecular weight, high thermal resistance and
good resistance to wear.
o
Oc"" 'CO
HzNN ;fNNH , 99 "::::
C-A-C + I
HlN/ "NH , .-::;
OC, ....CO
o
DMSO
-----+
f B \\ HZ !
NNHC 'I "CO,H N"
c! - C-A
" zHOlC IÍ CONHr/" n
1200 'C
+ cis-isomer
1 O 0 N _A J
N-N - N-N
;f
C" 0 IÍ 0
NH l
1 360'C n
k _tAJ +d,-'wm"
n
Scheme 149
The transformation of polyoxazoles and polytetrazines into polytriazoles are analogous
to transformations treated under Section 4.12.4.3.
Finally, mention should be made of polytriazoles formed by 1,3-addition reactions of
dicyanides with bisnitrilimines conveniently generated frorn bistetrazoles. The polymers
prepared frorn 1,3-dicyanohexafluoropropane were thermally stable but had a low degree
of polymerization.
Detailed tables of 43 polytriazoles will be found in (B-72MI41202).
790
1,2,4- Triazoles
4.12.5.2.4 Other uses
The triazole (346) can be used to stabilize plastics (73JAP7308667). The reaction of tributyl
lead hydroxide and arninotriazole affords (347) which has been recomrnended as an antiwear
cornponent of lubricating oils (68FRP1525268). Diazonium cornpounds detonate, although
they are safer to handle than corn parable derivatives of tetrazole. Polyfluorotriazolines
(67USP3326889) are oxidants; their suitability as bleaching agents, for rocket fuels and
constituents of pyrotechnic cornpositions has been claimed.
Bu' H J
HO O CH CH ---<""N'N
_ 2 2 \\ II
B' N----\"
u S 2 CH 2
(346)
PbBU3
,/N,
\\ _it
N NH
2
(347)
Polyrneric cornplexes of 1-phenyltriazole with transition metal cyanates or thiocyanates
are structurally and stereochernically understood (80MI41200) and an antiferrornagnetic
cornplex of triazole is of potential technical interest (80ZN(A)1387).
4.13
Tetr8zoles
R. N. BUTLER
University College, Galway
4.13.1 INTRODUCTION
4.13.2 STRUCTURE
4.13.2.1 Possible Structures
4.13.2.1.1 Aromatic systems not requiring exocyclic conjugation
4.13.2.1.2 Aromatic systems involving exocyclic conjugation
4.13.2.1.3 Non-aromatic systems
4.13.2.2 Theoretical Methods
4.13.2.2.1 Dipole moments
4.13.2.2.2 Electronic structures and stability
4.13.2.3 Structural Methods
4.13.2.3.1 X-ray diffraction
4.13.2.3.2 IR and UV spectroscopy
4.13.2.3.3 NMR spectroscopy
4.13.2.3.4 ESR spectroscopy
4.13.2.3.5 Mass spectrometry
4.13.2.4 Thermodynamic Aspects
4.13.2.4.1 Intermolecular forces
4.13.2.4.2 Stability and stabilization
4.13.2.5 Tautomerism
4.13.2.5.1 Annular
4.13.2.5.2 Ring-substituent
4.13.3 REACTIVITY AT RING ATOMS: AROMATIC AND NON-AROMATIC
TETRAZOLES
4.13.3.1 General Survey of Reactivity
4.13.3.1.1 Reactions with nucleophiles
4.13.3.1.2 Reactions with electrophiles and electrophilic ring fragmentation
4.13.3.2 Thermal and Photochemical Reactions Involving No Other Species
4.13.3.2.1 Fragmentations involving nitrilimine intermediates
4.13.3.2.2 Fragmentations to azacyclopropanes
4.13.3.2.3 Fragmentations to carbenes and nitrenes
4.13.3.2.4 Rearrangements
4.13.3.3 Electrophilic Substitution
4.13.3.3.1 Basicity
4.13.3.3.2 Electrophilic attack at nitrogen
4.13.3.3.3 Electrophilic attack at carbon and a-exocyclic positions
4.13.3.4 Nucleophilic Substitution
4.13.3.4.1 Acidity
4.13.3.4.2 Nucleophilic substitution at C-5
4.13.3.5 Reactions of Tetrazolate Anions: Alkylation Reactions
4.13.3.5.1 Ring alkylation
4.13.3.5.2 Exocyclic a-alkylation and polyalkylation
4.13.4 REACTIONS OF SUBSTITUENTS
4.13.4.1 General Survey
4.13.4.2 Aldehyde, Carbonyl and Nitrile Substituents
4.13.4.3 Alkoxy and Hydroxy Substituents
4.13.4.4 Amino Substituents
4.13.4.5 Sulfur Substituents
4.13.4.6 Halogen Substituents
4.13.4.7 Alkyl Substituents
4.13.5 SYNTHESIS
4.13.5.1 Ring Synthesis from Non-heterocycles
4.13.5.1.1 Formation of one bond
792
792
792
792
793
794
795
795
795
796
796
797
798
800
801
802
802
803
8C4
804
805
806
806
806
807
808
808
810
810
812
813
813
814
816
816
816
817
817
817
818
819
819
820
821
821
823
823
824
825
825
825
791
792
Tetrazoles
4.13.5.1.2 Formation of two bonds
4.13.5.2 Synthesis from Ring lnterconversions
4.13.5.3 Best Practical Methods
4.13.6 APPLICATIONS
4.13.6.1 Biological and Medicinal Applications
4.13.6.1.1 Analeptic activity (central nervous system)
4.13.6.1.2 Anti-inflammatory activity
4.13.6.1.3 Antimicrobial activity
4.13.6.1.4 Antilipemic activity
4.13.6.1.5 Antiallergic activity
4.13.6.1.6 Other medicinal properties
4.13.6.1.7 Agricultural uses
4.13.6.2 Non-biological Applications
4.13.6.2.1 Explosives and rocket propellants
4.13.6.2.2 Photography
4.13.6.2.3 Miscellaneous applications
t!2t!
832
833
834
834
834
835
835
835
t!36
836
836
837
837
837
837
4.13.1 INTRODUCTION
The first tetrazole derivative (see compound 198) was reported alrnost a century ago
(1885CB1544). Like other higher azoles this class of cornpounds received little attention and
66 years later only 300 tetrazole derivatives were known (47CRV(41)1). By the late forties
the potential of the higher azoles in the fields of explosives, photography and agriculture
had been realized and this led to renewed interest. The subsequent discovery of the
pharrnacological and biochemical properties of tetrazole derivatives has resulted in enor-
rnous developrnent over the past 20 years. Much interesting new chernistry has resulted
frorn this effort. However, in contrast to earlier European textbooks, rnany rnodern
textbooks of heterocyclic chernistry and organic chernistry appear to be unaware of this
class of compounds and the word 'tetrazole' will rarely be found in the index. This is
surprising since as a class the cornpounds are not only the highest azoles but also the
tetrazolic acids are the forrnal nitrogen analogs of the carboxylic acids.
There are three rnajor reviews covering all aspects of the chemistry of tetrazoles as it
stood at the tirne of their writing (47CRV(41)1, B-67MI41300, 77AHC(21)323). Useful reviews of
the chernistry of 2-substituted tetrazoles (76ZC90) and of the rnolecular and metal complexes
forrned by tetrazoles (69CCR(4)463) have been published. Shorter reviews of specific aspects
of tètrazole chernistry include synthesis of tetrazoles frorn arninoguanidines (63AG(E)468),
azidoazornethine-tetrazole isornerisrn (73CI(L)371, 73S123), solvent effects on 1,3-cycloaddi-
tions of azides as a route to tetrazoles (73571) and tetrazolinyl radicals (73AG(E)455).
4.13.2 STRUCTURE
4.13.2.1 Possible Structures
4.13.2.1.1 Aromatic systems not requiring exocyclic conjugation
The tetrazole ring is a 67T-azapyrrole type systern with two tautorneric forrns (1) and (2).
The nurnbering systern of forrn (1) is used to nurnber ring substituents (as against tautorneric
protons) throughout this review. The tetrazole ring is different frorn other azole systerns
insofar as it represents the functional group for a full series of carbazolic acids RCN 4 H,
i.e. full nitrogen analogues of carboxylic acids RC0 2 H. Replacernent of One of the ring
protons leads to three possible types of monosubstituted tetrazoles with substituents at the
1-,2- or 5-positions, respectively. Replacernent of the two ring protons leads to two possible
4
N___N 3
R II
-- __N2
I
H
(1)
--->.
..-
3
N N2
R 11
S__N
N 'H
(2)
Tetrazoles
793
types of disubstituted tetrazoles, namely the 1,5-disubstituted series and the isorneric
2,5-disubstituted derivatives.
A wide range of stable metallic and molecular complexes of tetrazole systems, e.g. (3),
has been described (77AHC(21)323) and many crystal structures have been determined for
these complexes. The tetrazole ring is invariably planar with bond lengths characteristic of
an aromatic system. Tetrazolate anion salts (4) are stable arornatic 67T-systems and they
have been used widely as nucleophiles in synthetic reactions.
PPh 3
I
Rp!'l Pt-H
; I
N"::.-;'N PPh
N 3
(3)
N
R< - ,:1 Na+
j.;-N
(4)
Substituents bearing p-electrons on the tetrazole 5-carbon undergo conjugation with the
tetrazole !'Îng, e.g. 5-aryltetrazoles (5). The interannular conjugation in 5-aryltetrazole
systerns involves a weak resonance electron donation by the tetrazole ring, e.g. (Sa)
(78JCS(P2)1088). Introduction of ortho substituents into the aryl ring or N( 1) substituents on
the tetrazole ring of compounds (5) results in a conforrnational change causing loss of
coplanarity between the rings and reduction or loss of conjugation (81JCS(Pl)390). Conjuga-
tion effects are also present when the aryl ring is bonded to a nitrogen atorn, e.g. compound
(6) (77JPR408). The resonance electron flow is into the tetrazole ring for derivatives contain-
ing strong activating groups such as NH 2 (ct. structure 29). The tetrazole ring itself possesses
a strong electron-withdrawing inductive effect (- I) which surpasses the weak rnesorneric
effect (+ M) and the ring is therefore a deactivating group (79JCS(P2)1670, 790MR(12)631),
(cf. Section 4.13.3.1).
---
\J-\--N
H
(S) Åmax 241 nm
O=< N N
- I
- .Ñ N
H
o- N N
- \ /
N=N
(Sa)
(6) Åmax 236 nm
4.13.2.1.2 Aromatic systems involving exocyclic conjugation
Mesoionic tetrazole systems are well known. In the compound (7), 1,3-dimethyl-5-
iminotetrazole, the exocyc1ic conjugation is to a nitrogen atom (S4JA2894). Conjugation to
oxygen and sulfur atoms is observed in diaryltetrazolium 5-oxides (Sa) and (9a) (71ACS625,
74Z0Rl72S), in the corresponding sulfides (Sb) and in 2,3-diphenyltetrazoliurn-5-thiolate
(9b), also known as dehydrodithizone. The tetrazolyl ylide systern (10) was obtained, along
with other isomers, from the benzylation of 5-dialkylaminotetrazoles (70JOC2074).
Tetrazolium ylides (11) are readily obtained by oxidation of tetrazolylformazans. Oxidation
of substituted forrnazans readily gives 2,3,5-trisubstituted tetrazolium salts (12) when the
N-substituents are not good leaving groups (S3CB8S8). Alkylation of 1,5-disubstituted
tetrazoles may give 1,3,5- and 1,4,5-trisubstituted tetrazolium systems, e.g. (13) and (14)
(72BCJ1471, 7lJOC3807). Fused tetrazolyliurn systerns such as (15) (73TL429S) and (16) (73JHCS,
73JHCS69) are also known and have been found useful in synthesis.
Me Ph
N---N- < :-:--N _ ( NPh N---N
NH=< +1 -X (+::1 X ; + :1 BzR 2 Ñ<()I
""'NMe ?NPh N':'::NPh N--N
N .
(7) (Sa) X=O (9a) X = 0 (10)
(Sb) X=S (9b) X=S
N---N R R
N + N---N N ---N
NR 1 _
ArN-Ñ-<8, Ar , X Ph\-)I 1- P II I-
I \\ N--N N--NR" N--NR N+--N
NVN
Ph R
(11) (12) (13) (14)
4.13.2.1.3 Non-aromatic systems
Non-aromatic (Chapter 4.01) tetrazoles appear to be relatively rare. The 1,2-disubstituted
tetrazoline (18) has been reported as an etherate from the reaction of diazomethane with
hexafluoroazomethane (17) (62DOK(142)3S4). Reduction of 1,4,5-trisubstituted tetrazoliurn
iodides with NaBH 4 gave the il 2 -tetrazolines (19) (73BCJ12S0). These compounds were
stable but upon heating at over 120 0 C compound (19; R 1 = Me) cleaved to rnethyl azide
and N- benzylidenemethylarnine. Fused tetrazoline systems of type (20) have been obtained
from cycloaddition reactions of dehydrodithizone (9b) with substituted alkynes (71CC490,
76JCS(PI )1673). The relative instability of the non-aromatic tetrazole system is also, to some
extent, illustrated by the preferred existence of the iminoazimines (21) in the acylic nitrogen
form (21) rather than the fused tetrazoline forrn (22) (74CC6S9, 73CB1S89, 74CC6S7).
< N N
I . EI 2 0
N--!\!CF,
CF,
794
U '-'::::: + N Br-
...... /
N
Ar
(15)
CFJN=NCF J + CH 2 N 2
(17)
Tetrazoles
R 1
N
N/ "'--s
\\ !(+ \ Cl0 4 -
N-'
R
(16)
EI 2 0 )
(18)
R 1 Ph
N__N PhN- Ñ/N Ph N--N
Ph< II I NJR II I ---7b I )Ph
!\! I N N
N--N 'R N--N
Me S R R
(19) (20)
(21) (22)
Tetrazolines with an exocyclic double bond at the C-5 atom are well known. Systerns of
type (23) are readily obtained from the further alkylation of 1-alkyl-S-arninotetrazoles
(S4JOC439, S7JOC92S). The tetrazolin-5-one structures (24; R 1 = H) and (25; R 1 = H) are the
normal tautomeric structures for 5-hydroxytetrazoles and tetrazole-5-thiols (S8CJC801,
67JOC3S80, S9JA3076). Alkylation of I-substituted tetrazolin-5-ones (24; R 1 = H) gives 1,4-
disubstituted tetrazolinones (24) (S6JA411) and such tetrazolines are also obtained by addition
of organic azides R 1 N 3 to isocyanates RN=C=O, the addition occurring at the N=C bond
(73JOC67S). Although reactions of I-substituted tetrazoline-5-thiones usually occur on sulfur,
hydroxyrnethylation occurred at N-4 giving corn pounds of type (25; R 1 = CH 2 0H)
(64Z0B2S17). Compounds (25; R = Ph, R 1 = R 3 Sn) have also been obtained by treating phenyl
isothiocyanates with triorganotin azides (71AJC64S). Addition of a,ß-unsaturated carbonyl
corn pounds to l-aryltetrazoline-5-thiones in the presence of base gave corn pounds (25;
R 1 = CH 2 CH 2 COX) (76JOC187S). In the absence of base this latter reaction occurred on
sulfur (7SZC146). Low yields of the interesting tetrazolines (26) were obtained on treatrnent
of l-alkyltetrazoline-S-thiones with acetyl chloride (74ZCl6). The first hornoarornatic
tetrazole compound (26a), (6-amino-3-phenyl-l,2,4,5-tetrazine) has recently been reported
from the addition of arnrnonia to 3-phenyl-l,2,4,5-tetrazine. This interesting cornpound
shows a ring-current which causes a strong shielding of the endo-H (8 1.51 p.p.m.) at C-6
since it extends into the shielding region of the hornotetrazole plane (81JOC2138).
R
N--N
HN=< II
N--N
R'
(23)
R 1
N--N
S=< II
N--N
R
(25)
R'
N--N
O=< II
N--N
R
(24)
R
N
=< --NCOMe
S I
N"'"N
1-NH'
Ph(=N/
N-N
H
(26s)
(26) R = n-C J H 7 , n-C 4 H 9
Tetrazoles
795
4.13.2.2 Theoretical Methods
4.13.2.2.1 Dipole moments
In the calculations which have been carried out on the tetrazole system there has generally
been good agreernent between calculated dipole rnoments and rneasured values. The first
such calculation for tetrazole using an SCF-MO 7T-electron method gave /-to 5.22 for
1,2,3,4-tetrazole (27) and /-to 1.63 for 1,2,3,5-tetrazole (28), assurning a regular pentagon
geometry for the ring with sides of 1.32 Å (63JPC721). A large part of the difference in the
mornents was due to the vectorial sum of the (T- bond moments /-tCH and /-tNH. These were
additive in structure (27) but opposing in structure (28). The experimental dipole moment
of tetrazole was 5.11 0 in dioxane (43MI41300) and this suggested that the 1-NH forrn (27)
dominated the annular tautomerism. CNDO-SCF calculations gave a /-to for tetrazole (27)
of 5.23 in good agreernent, but the breakdown of the contributing components was quite
different to those of the SCF-MO approach (67JA683S). The total energy calculated for
form (27) by CNDO-SCF methods was 28.9 kJ mol- 1 higher than that for forrn (28)
suggesting either that the theoretical method was unreliable or that solvation favoured the
1-NH forrn (27) if this is the dominant species. In general, similar energies for both forms
have resulted from many calculations and a slightly lower energy for form (28) has been
suggested by a number of workers (69BSFI097). It seems likely that sol va cion effects are
indeed the dominating factors which favour form (27) in solution. Microwave spectra for
tetrazole in the gas phase gave /-to 2.19 suggesting that form (28) predominated without a
solvent (74JSP(49)423). The dipole moment for N-deuteriotetrazole in the gas phase was
similar, 2.140, while that of C-deuteriotetrazole was 5.300 suggesting that the 1-NH
form of this latter compound was the dominant species.
N--N
H< II
N--N
H
(27)
N
/ N
H I
N--NH
(28)
Measured dipole moments for a series of substituted tetrazoles gave interesting com-
parisons (S6JA4197). The moments for 1-ethyltetrazole (5.46 D) and 2-ethyltetrazole (2.65 D)
were at either side of the mesoionic compound (7) (4.02 D) and the dipole moments could
not be used to identify mesoionic structures. The dipole moments for the 1,5-disubstituted
tetrazole structure were consistently high, >5.3 0, while those of the 2,5-disubstituted
structure were low, < 2.65 D; theoretical calculations support this (6IT237). Recently, dipole
moment measurements were made on 5-(p-tolyl)tetrazole in dioxane (/-to 4.99), its 1-methyl
isomer (/-to 6.03) and its 2-methyl isomer (/-to 2.41) (80JHC1374). These results, when applied
to the annular tautornerisrn of 5-(p-tolyl)tetrazole, suggested 60:1: 10% of the 1-NH forrn
in this medium.
4.13.2.2.2 Electronic structures and stability
The use of ab initio wave functions and full operators gave a calculated value of 5.170
for the dipole rnornent of 1,2,3,4-tetrazole (27) and 2.540 for 1,2,3,5-tetrazole (28)
(74JCS(P2)420). The same approach gave total population figures for the azole series which
indicated that introduction of a nitrogen atom adjacent to a particular ring atom C, N, or
o leads to a consistent drop in the total population by ca. 0.10 electrons. For example, for
N ß azoles total populations varied as follows: C-Nß-C, 7.272; N-Nß-C, 7.178 and
N-Nß-N, 7.061. This is the theoretical basis for a useful NMR chemical shift correlation
for N- alkylazoles discussed below, where isomeric structures containing the units
C-N(Me)-C, N-N(Me)-C and N-N(Me)-N can be easily distinguished by the
chemical shift of the Me group (730C231S).
Application of semiempirical SCF-MO methods involving the Huckel (T/7T approxima-
tion, in which the total energy of the electrons is approximated by assuming additivity of
bond energies and the 7T- energy is calculated by a Pople-type MO-LCAO-SCF treatment,
to the tetrazole system gave calculated resonance energies of 134.6 kJ rnol- 1 and
108.8 kJ rnol- 1 for 1,2,3,4-tetrazole (27) depending on the methods used to estimate the
796
Tetrazoles
various integrals (66JCP(44)759). The resonance energy for the 2H-forrn (28) was estirnated
at 95.66 kJ mol-lor 122.3 kJ mol-I. Calculated heats of combustion for compounds (27)
and (28) were 2673 kJ mol-I and 2698 kJ mol-I, respectively. The measured value is
2710 kJ rnol- 1 . Bond lengths calculated by these SCF-MO methods (66JCP(44)759) are
compared with sorne measured values in Table 1.
Table 1 Calculated and Measured Bond Lengths (Â) of Tetrazoles
Bond Calculated Measured b Measured c Calculated Measured d
(27t (28)"
1-2 1.397 or 1.372 1.34 1.381 1.324 or 1.312 1.34
2-3 1.252 or 1.257 1.29 1.255 1.284 or 1.295 1.29
3-4 1.359 or 1.356 1.33 1.373 1.351 or 1.341 1.32
4-5 1.287 or 1.291 1.30 1.321 1.310 or 1.320 1.35
1-5 1.408 or 1.396 1.30 1.329 1.344 or 1.3 3 7 1.32
a (66JCP(44)759).
h For 1-methyltetrazole in dichlorobis(l-methyltetrazole)zinc(II) (71 IC661).
c For 5-aminotetrazole monohydrate (ó7AX30H).
d For 5-amino-2-methyltetrazole (56AX(9)874).
CNDO /2 calculations of electronic distributions in substituted tetrazoles generally suggest
structures compatible with classical resonance concepts. For example CNDO /2 calculations
on compound (29) showed high negative charges at the 2- and 4-positions as expected for
a resonance hybrid with significant contributions from forms (29a) and (29b) (73T3463). A
linear correlation of Hammett O'-substituent constants with CNDO-calculated charge distri-
butions in a wide range of 5-substituted tetrazoles has been reported (79Z0R844).
N--N
NH 2 < II
N--N
H
(29)
N"'-N
-.. NH 2 =< '" I
N--N-
H
(29a)
N--N
NH 2 =< II
N--N
H
(29b)
4.13.2.3 Structural Methods
4.13.2.3.1 X-ray diffraction
X-ray crystal structures have been reported for a wide range of tetrazoles and these show
the ring to be a planar resonance hybrid. Small differences in bond lengths of the order of
0.02 Å which appear to be present are probably not significant since the standard deviations
are ca. 0.02 Å. The dimensions for 5-bromotetrazole are shown in Figure 1 (a) and the full
dirnensions and literature for 15 other important tetrazole derivatives including those for
the mesoionÎc compound (9b) and for the tetrazole ring in a number of metallic complex
environments rnay be found in (73JCS(P2)2036). In the case of 5-brornotetrazole the ring
proton was not located. The difference in bond lengths at C(5)-N(l) and C(5)-N(4) is
of interest when compared with the similarity in the bond lengths at N(1)-N(2) and
N(3)-N{4). In the tetrazolate anion (Figure 1c), all of the bond lengths are similar as
expected (ó3AXt16)S96). It is of interest to compare the dimensions of the tetrazolate anion
with those of the tetrazolate ring in the ylide 5-(3-chlorobenzyldimethyl-
amrnoniumHetrazolate (Figure 1b) (75JCS(P2)1200).
The rnolecular dimensions of the hydrochloride of mesoionic 5-imino-1,3-dimethyl-
tetrazole (7) are shown in Figure l(d). These suggest a resonance hybrid with major
contributions frorn forms such as (30) and (30a) where the C(5)-N(1) and C(5)-N(4)
bonds retain sorne single bond character and the double bond character is more concentrated
in the N(2)-N(3) and N(3)-N(4) bonds. In the mesoionÎc molecule (9b) the tetrazole ring
and the sulfur atorn form a coplanar arornatic resonance hybrid structure and both phenyl
rings are twisted at 45 0 to this plane with little conjugation between the phenyl and tetrazole
rings (70JA196S). The interring C-N bond length is 1.443 Å which suggests a norrnal C-N
single bond. The structure of the interesting rnolecular complex pentamethylenetetrazole
iodine rnonochloride (31, PMT' ICl) is shown in Figure 2 (67JA6463). In this the tetrazole ring
Tetrazoles
797
Br
N I.345
1.290 104.2 N I
111.4 1.283
106.9 N
105.3 ___
N------1.347
Me
1+
ClC ó H4CH2-N
I
Me
N.__.....} .370
1.309 101.8 N I
115.9 0 1.298
109.7N
1.303 102.9___
N .349
(a)
(b)
H
Me
\
N-.........!:35
110 N
'" I,'"
117 N
104 ___ "'-
N ------ 1.31 Me
(c)
(d)
Figure 1 Bond distances (Å) and angles (0) of the tetrazole ring in: (a) S-Bromotetrazole (73JCS(P2)2036). (b)
S-(3-Chlorobenzyldimethylammonium)tetrazolate (75JCS(P2)1200). (c) Sodium tetrazolate monohydrate (63AX596).
(d) Hydrochloride of 1,3-dimethyl-S-iminotetrazole (55AX211).
N 1.38 1.44
1710 N 129
106 108 1.34
N 1.33
2.34/
,\
I 177"
2.44/./
Cl
N --N........N r
:N J
Cl-V'
(b)
(a)
Figure 2 (a) Average bond distances (Á) and angles (0); and (b) side-view of PMT.lCI
acts as a unidentate ligand with the iodine of ICI bound to N-4 of the tetrazole ring. The
N . . . ICI group is linear and coplanar with the tetrazole ring which is itself planar and the
seven-mernbered ring of PMT is in a chair conformation (Figure 2b). Examples of the
dimensions of other tetrazole derivatives are in Table 1. Two reviews, which discuss the
structures of complexes of tetrazole derivatives, may be consulted for further detailed
inforrnation (77AHC(21)323, 69CCR(4)463).
Me
N--N-
m2=< +1
N",,"NMe
Me
+ N--N
+--+ NH 2 =< +" CI-
N--NMe
(30a)
Q N--N
" lCI
N--N
(31)
(30)
4.13.2.3.2 IR and UV spectroscopy
The tetrazole ring generally shows IR absorption bands in the region 1000-1100 cm- I
and an absorption band between 1095-1120 cm- 1 has been reported in many tetrazole
798
Tetrazoles
derivatives. Other absorptions which have been ascribed to the ring appear at 1000-
1030 em-I and 1045-1085 em-I (65CJC1154). Absorptions at 1265-1298 ern-I, which have
been assigned to the -N-N=N- moiety in higher azole systems such as 1,2,3-triazoles
and thiatriazoles, are also found in many tetrazole derivatives (S-67MI41300). Functional
groups at the 5-position generally show their normal absorptions but 5-SH and 5-0H
groups exhibit thione and ketone bands since they exist in the 1-tetrazolin-5-one forrn.
The exocyclic C=N group of 5-iminotetrazolines, e.g. (23), absorbs at 1640-1670 em-I
and the cyclic C=N of the tetrazole ring generally absorbs at 1590-1600 crn- 1 .
In the UV region the tetrazole ring exhibits only weak end absorption at 200-220 nm.
Most UV spectra of tetrazole derivatives arise frorn the conjugation effects of auxochromic
groups. Tetrazole derivatives containing phenyl and amino substituents show absorptions
in the range 235-255 nm (57MI41300). The UV spectra of sorne tetrazole derivatives illustrate
interesting conjugation effects which are, however, often better probed by NMR spectros-
copy. For example, in the series of phenyltetrazoles (5), (32) and (33), there is extensive
interannular conjugation in compounds (5) and (33) which is reflected in their similar UV
absorptions. Conjugation is much reduced in the 1-methyl isomer (32) due to a steric
conformational change resulting in loss of coplanarity between the rings and the Åmax is
shifted to shorter wavelength. Conjugation effects are also present in N-phenyltetrazoles;
2-phenyltetrazole absorbs at 250 nrn while 1-phenyltetrazole (6), with Åmax 236 nm, shows
reduced conjugation due to ortho proton interactions with the tetrazole 5-CH. The UV
spectra of 1-substituted 5-aminotetrazoles show only end absorption at 218-232 nm for
primary, secondary and tertiary amino groups while 2-substituted 5-arninotetrazoles show
absorptions at ca. 254 nrn. Mesoionic tetrazoles such as compound (7) absorb at 255 nm
and the similarity of this absorption to that of 2-alkyl-5-aminotetrazoles led to some
suggestions of a tautomeric mesoionic structure for these latter compounds. However, this
was not the case and 5-aminotetrazoles exist predominantly in the amino form in solution
(77 AHC(21 )323).
l--
N--N
Me
(32) Åm.. 232 nm
N""'N
I
- N--NMe
(33) Åm.x 240 nm
4.13.2.3.3 NMR spectroscopy
Proton and carbon NMR spectra have been used extensively to distinguish between
isomeric tetrazole systems. A number of different approaches has been developed and the
application of these to tetrazoles represents but one example of their wider use in azole
chernistry. For isorneric tetrazole systems (34) and (35), containing a 5-CH moiety, long
range coupling was observed over four bonds between the 5-CH and the 1-N-Me protons
(J 0.45 Hz) for the structure (34) but not for the structure (35) where there was as-bond
separation between the coupled protons (80M775). This effect was observed in a range of
azoles. In the N-aryltetrazole series the 5-CH proton shift of I-phenyltetrazole (6) (5-CH,
89.00 p.p.m., CDCh, 0.1 moll-I) was considerably more sensitive to solvent effects than
that of the corresponding 2-phenyltetrazole isomer (36) (5-CH, 8 8.63 p.p.rn., CDCh, 0.1
moll-I). This was characteristic of substituted N-aryltetrazoles in general and the greater
solvent-induced shifts at the 5-CH arising from concentration variations or changes of
solvent distinguished the l-aryltetrazoles from their 2-aryltetrazole isorners (77JPR408).
N--N N""'N N""'N
R( II R< I \__ Ph
N--N __NMe
Me
(34) R=H (35) R=H (36)
Tetrazole isomers with rnethyl or alkyl substituents at the 1- and 2-positions can be
readily distinguished by the l H and I3 C chemical shifts of the N-alkyl group. Alkyl groups
bonded to N-1, e.g. (34), are more shielded by ca. 0.15-0.35 p.p.m. in the lH spectra and
by ca. 2-6 p.p.m. in the 13 C spectra relative to their corresponding N-2 isorners, e.g. (35).
Tetrazoles
799
This is part of a larger shielding correlation for N-methyl groups which show increased
shielding for the structural units (A) > (B) > (C) in azole systems. The l-alkyl- and 2-alkyl-
tetrazole structures represent (B) and (C) units respectively. The correlation is due to
electron density effects arising from the electronegativity of the adjacent N atoms (ct.
Section 4.13.2.2) (77CJC1564). Some examples of this correlation for N-methyltetrazole
isomers are gíven in Table 2. Similar correlations are found in proton chernical shifts of
amino groups bonded to the tetrazole ring although there are fewer examples. The shielding
difference between NH protons of 1-N- and 2-N-aminotetrazoles (.M 0.8-1.0 p.p.rn.) is
higher than that for CH protons (69CJC3677, 69TL1537).
Me
I
=C-N-C=
(A)
Me
I
=N-N-C=
(8)
Me
I
=N-N-N=
(C)
Table 2 lH and l3 C NMR Chemical Shifts from TMS for Isomeric N-Methyltetrazoles (34) and (35)
(34) B-unit (35) C-unit
Me shift Me shift
R 1 H (8, p.p.m.) 13C (8, p.p.m.) lH (8, p.p.m.) 13 C (8, p.p.m.) Ref
H 4.27 33.7 4.46 38.8 67JCS(B)516
Me 4.10 33.15 4.30 39-41" 65JOC(30)3472
NH 2 3.82 31.4 4.16 39-41" 77 AHC(21)323
Br 4.13 4.40 67JCS(B)516
CI 4.24 34.11 4.52 39-41" b
Ph 4.16 35.0 4.25 39.4 81JCS(P1)390
4'-MeC 6 H 4 4.16 34.95 4.34 39.7 81JCS(P1)390
4' -ClC 6 H 4 4.20 35.1 4.4 39.7 81JCS(P1)390
2',6' -C1 2 C 6 H 3 3.98 33.7 4.52 39.9 81JCS(P1)390
3' -C S H 4 N 4.20 35.1 4.48 39.8 b
" Overlap of solvent DMSO-d 6 . b Author's unpublished data.
Interesting interannular conjugation effects are evident in the NMR spectra of 5-aryl-
tetrazoles, e.g. (5) and (Sa). This conjugation results in a deshielding shift for H-2' and a
shielding shift for H-3' and H-4' of the phenyl ring so that when conjugation is present, as
for example in compound (37), the difference in chemical shift of the ortho (2'-) and meta
(3'-) aryl protons is as high as 0.6-0.76 p.p.m. In compounds containing an N(l)-substituent,
(38), or a 2' -substituent in the 5-aryl ring the conjugation is inhibited by rotation of the
rings and the shift difference is reduced to 0.1-0.3 p.p.m., this residual difference being
due to tetrazole ring inductive and anisotropic effects on the ortho protons. In carbon
spectra the interannular conjugation causes an upfield shift of ;::: 2.00 p.p.rn. in C-2' of the
aryl ring, e.g. (37), relative to unconjugated systems (38) and there is little difference in
the 3' and 4' carbon shifts. Similar conjugation effects have been observed in N- aryltetrazoles
where N(2)-aryl derivatives show much more conjugation than 1-aryltetrazoles in which
loss of ring coplanarity arises due to a steric interaction between the tetrazole 5-H atom
and the ortho protons of the aryl substituent (81JCS(Pl)390, 74ACS(B)61, 70BSF1345, 70BSF1346,
76T499, 77JPR408).
3' 2' N
4' 1' <-
N--NMe
o-< 'N
"
- i\í'"N
Me
(37)
(38)
A correlation of the aryl proton chemical shifts of a wide range of substituted 5-
aryltetrazoles with a number of substituent parameters has confirmed the strong electron-
withdrawing inductive effect of the tetrazole ring (790MR(12)631). NMR conformational
studies of acetyl groups directly bonded to tetrazole ring nitrogen atoms have also been
reported (76TL533, 73CR(C)(277) 1163). Nitrogen-14 NMR studies of tetrazole systems have
been carried out (77AHC(21)323) and, in general, the signal of the singly bound nitrogen was
sharper and higher upfield than that of the doubly bound nitrogens. The spectrum of
800
Tetrazoles
trirnethylenetetrazole showed four separate 14 N signals for the four ring nitrogen atoms.
The 14 N shifts generally correlated with calculated 7T- charge densities and they probably
can be used to distinguish (B) and (C) structural units also. For example, the compounds
(34) and (35) gave 14N_Me shifts from internal nitrornethane of + 150 p.p.rn. and
+103 p.p.m., respectively (73MI41300). The pure quadrupole resonance spectrum of 14N in
tetrazole and in the other parent azoles has been measured and correlated with electron
densities. While three of the four expected resonances for imidazole and five of six expected
resonances for 1,2,4-triazole were observed, only two resonances were observed for tetrazole
which was piezoelectric and difficult to work with (68MI41300).
Electron densities control the proton shifts in tetrazoles and this is well illustrated by the
5-CH shifts of 89.5 p.p.m. for the neutral molecule in D 2 0, 88.73 p.p.m. for the anion
in 2M NaOD and 89.95 p.p.m. for the cation in trifluoroacetic acid (67JCS(B)516). The
higher shielding observed in the proton NMR spectra of tetrazolate anions in general is
due to increased electron densities rather than altered ring currents or anisotropic effects
(73JCS(P2)568). This is not the case for the 13C shift of the tetrazole 5-carbon which appears
to be controlled more by orbital screening effects than by electron density. Thus the C-5
shifts of tetrazolate anions are generally deshielded by various amounts, rather than shielded
relative to the parent tetrazole. For example, the C-5 shifts from TMS of 5-amino-, 5-methyl-
and 5-phenyl-tetrazole were 156.6, 156.9 and 155.6 p.p.m., respectively in aqueous
(CD 3 hSO, and the shifts for the corresponding anions were 164.1, 160.2 and 160.35 p.p.m.
(77MI41300). Protonation sites of a number of tetrazoles have been established by cornparing
the I H NMR spectra of tetrazolium salts with those of tetrazoles measured in acidic solutions.
For 1-aryl- and 2-aryl-tetrazoles protonation occurred exclusively at the N(4)-position
(77T1399). The applications of NMR spectra to tautomerism in tetrazoles is discussed in
Section 4.13.2.5.
4.13.2.3.4 ESR spectroscopy
Electron spin resonance spectroscopy has been applied to tetrazole systems in the study
of tetrazolinyl radicals (40) which are obtained by oxidation of formazans (39), by reduction
of tetrazolium salts (41) or by disproportionations of mixtures of both (73AG(E)455, 66JOC442).
The tetrazolinyl radicals are stabilized when R 1 and R 2 are strong resonance electron-
withdrawing groups. The ESR spectra show a nine-line splitting characteristic of spin density
on two pairs of equivalent 14 N atoms confirming the cyclic tetrazolinyl structùre as against
an alternative acyclic structure (42) which would have appreciable spin density on one pair
of nitrogen atoms only. The g values for the tetrazolinyl radicals are ca. 2.0037 and the
spin density at N(2)-N(3) [a(N z . 3 ) 6.1-8.6 G] is generally larger than that at N(l)-N(4)
[a(N 1 .4) 5.4-5.8 G]. The cyclic structure was confirmed with radicals of type (43) where
hyperfine splitting due to the four ring nitrogens only was observed. Spin density on the
exocyclic azo group in an acyclic structure would give a splitting pattern due to three pairs
of equivalent 14N atoms for this radical and this was not observed. Most of these radicals
have been detected in solution as interrnediates between cornpounds (39) and (41) but the
radical (44) has been isolated as green-black needles which decompose at 126-127 oc. Its
ESR spectrum in benzene consists of nine groups: a(N 1 .4) 5.6; a(N z . 3 ) 6.1, a(H o ) 1.0 and
a(H m ) 0.5 G. The radical was monomeric in the solid state and the rnagnetisrn of the solid
suggested a free radical content of 94% (69AG(E)520).
R 1
N--NH/ -H. <--NR 1 +e f-- NR I
R-{ -- R I +--- R i7 +1
::;::.N ......NRZ N::;::.NR z
N "2
R
(39) (40) (41)
R' R 1 R 1
N--N( N / N""N/
-< ""'N
R-< R . R-{
-. -.
N N N
II 1\ I.
N N" N
" 0 "R z
W R Z
(42)
Tetrazoles
801
N--NPh
PhN=N< tl
r-r- NPh
(43)
/N--NC6H N02-P
Me3C I
r-r-NC6H N02-P'
(44)
4.13.2.3.5 Mass spectrometry
Mass spectral fragmentation patterns can be used to distinguish between the 1,5-di-
substituted tetrazole structure (45) and the isomeric 2,5-disubstituted structure (46)
(690MS(2)433, 680C2855). The former compounds gave molecular ions while the latter gave
unusual (M + 1) ions with no molecular ion. Compounds of type (46) fragmented by two
main pathways. Process (a) involved loss of N 2 giving the fragment [M - N z ] which was
followed by loss of a hydrogen to give an even-electron fragment [M - HN z ]. The fragment
[M - N z ] also ejected CHzN' giving a strong [M - Nz-CHzN] ion. The cleavage (b) involved
loss of the elernents RCN z ', probably in a nurnber of steps, giving the ion [Me - N z +].
N--N
R< "
N
(45)
.... :::,.N
R-\";;f<-b
....'X--::- N -a
N Me'
(46)
The fragmentation pattern for structure (45) was more complicated. The main processes
are outlined in Figure 3. In this case loss of N z (cleavage g) made only a minor (5%)
contribution. The most intense ion was [M - HN z ] arising from process (c) and this fragrnent
subsequently lost HCN. A composite of these two steps also occurred when CH z N 3 was
lost (process f). The fragmentation (e) gave a strong MeN z + ion with loss of RCN z '. The
loss of N 3 , (process d), like the loss of N z , was only of minor significance. However, important
fragmentative loss of N z has been observed with a number of 1,5-disubstituted tetrazoles
containing substituents such as COzMe and aryl groups at both the 1- and 5-positions.
Hammett correlations of the intensity of the [M+ - N z ] ion with electronic substituent effects
have been reported (77Z0R2218, 67JA5958). The nature of the substituents, as well as the,
ring substitution pattern, clearly plays an important role in influencing the preferred
fragmentation pathways.
c
:
CHAH/
e \ I '
-..-.... N N
R-L',)<':'/k
. 'N ".
,'Wi
, I
/ I
I
d
/
f g
I
H+CH2 ;
(I :
.N--'N
R-{'-.JII
N.P.I:'!
I ......
Figure 3 Main mass spectral fragmentations of 5-substituted I-methyltelrazoles
Among individual tetrazole molecules which have displayed interesting mass spectra are
5-aminotetrazole and I-phenyl-5-phenoxytetrazole. The forrner showed seven metastable
ions and two main fragrnentation pathways (i) NH 2 -CN 4 H..... HN 3 ..... HN z , and (ii)
NHz-CN 4 H --+ CH 3 N 3 -+ HN z , HzN z , CHzN (70JHC1223). A 1,3 0 N phenyl migration
was detected in 1-phenyl-5-phenoxytetrazole when this compound lost a CO molecule
without loss of either ôf the phenyl rings (69CCll10). Mass spectral fragmentation patterns
for 5-aryltetrazoles and 5-heteroaryltetrazoles have also been described. The main frag-
mentations of the tetrazole rnoiety were (a) loss of N z followed by HCN giving an aryl-
nitrenium ion Ar-Nt, and (b) loss of HN 3 giving the species Ar-CNt (77ZC65). Complex
mass spectra, arising from five different fragmentation pathways, have been reported for
802
Tetrazoles
substituted l-aryl-tetrazole-5-thiones (73MI41301). Mass spectral fragmentations of aryl
tetrazolines of type (23-25; R = Ph) involved loss of the Ph-N=C=X moiety where X is
the exocyclic atom at the 5-position (75JHCI031). Mass spectral fragrnentations of N(l)-
and N(2)- aryltetrazoles began by elirnination of N z followed by HCN but different isotopic
abundances allowed a distinction between the isomers to be rnade (760MS(11)167).
4.13.2.4 Thermodynamic Aspects
4.13.2.4.1 Intermolecular forces
(i) Melting and boiling points
There has been relatively little study of the thermodynarnic features of the tetrazole
series and there is a paucity of quantitative data on details of associative characteristics.
Since there are three doubly bound pyridine-type nitrogen atorns in the ring which can
serve as proton acceptors, the availability of active hydrogens to provide intermolecular
hydrogen bonding is an irnportant factor influencing the melting and boiling points. Simple
5-substituted tetrazoles are generally white solids. Replacement of the ring NH hydrogen
of a 5-substituted tetrazole by a small substituent usually causes a large decrease in the
melting point if the 5-substituent has no NH or OH bonds (series 1-5 and 7; Table 3). The
sarne pattern is not observed when the 5-substituent has NH or OH bonds (series 6, 9, 10;
Table 3) since association by hydrogen bonding is still possible in the crystal.
"- /
N-H..............c::::N
/
Intermolecular hydrogen bond
Table 3 Melting and Boiling Points of Some Tetrazoles
N--N N--N N""'N
R( II R( 1\ R< I
N......N N......N ......NR'
H R'
Se rie s
no. R M.p. (OC) R R' M.p./b.p. (oe) R R' M.p. jb. p. (OC) Ref.
1 H 156 H Me 39 H Me 147 (atm) 47CRV(41)1
2 H 156 H Et 164 (30 mm) H Et 71 (35 mm) 47CRV(41)1
3 Me 148 Me Me 73-74 Me Me 57 (13 mm) 65JOC3472
4 Br 148 Br Me 72-74 b Br Me 59-61 (4 mm) 56JA411
5 Ph 213 Ph Me 103 Ph Me 51 5lJA4470
6 NHz 203 NHz Me 226 NHz Me 105 56JA411
7 NMez 239" H NEtz 56 {O.02 mm)C
8 NH z 203 H NH z 142 (0.7 mm) H NH z 89-91 (O.3 mm) 69CJC3677
9 BzNH 181 NHz Bz 190 NH z Bz 86 7lJCS{C)703
10 HOd 260 HOd Me 124 HOd Me 137 56JA411
a (66ACS2795). b (71CJCZ139). C(65LA(688)93). d Tetrazolone form.
Introduction of substituents with NH or OH bonds at C-5 generally raises the melting
point (compare the parent compound for series 1,6,9, 10; Table 3) as might be expected
for extra hydrogen bonding. However, since the introduction of an NMez group at C-5
produces a higher melting point than an NH z group (parent cornpound series 7; Table 3)
the rise in the melting point may not be due entirely to hydrogen bonding. Effects such as
the overall polar character of the molecule and molecular packing in the crystalline state
probably also exert important influences on melting and boiling points. The sharp contrast
between the effect of an amino substituent at the 5-position and at the N(l)- and N(2)-
positions (series 7 and 8; Table 3) suggests that the high melting points associated with the
ring NH moiety may arise from an especially cornpact association of the rings in the solid
state. In molecules where hydrogen bonding is not possible, for exarnple the 1,5- and
2,5-disubstituted series (Table 3) the more polar 1,5-disubstituted forrn (high dipole
Tetrazoles
803
moment) usually has a higher melting point or boiling point than the corresponding
2,5-disubstituted isomer (lower dipole mornent). However such trends are precarious and
there is at present no detailed information on the interrnolecular forces betWeen tetrazole
molecules.
(ii) Solubility
There appears to be no quantitative solubility data available for the tetrazole series.
However, a useful qualitative table of solubilities has been drawn up (47CRV(41)1). Insofar
as the 5-substituted tetrazoles, RCN 4 H, are the nitrogen analogues of the carboxylic acids,
RCOzH, solubilities cornparable to those of the carboxylic acid series might be expected
if due allowance is made for the fact that the tetrazole molecules are solids whereas the
lower carboxylic acids are liquids. In general this expectation is fulfilled and the lower
tetrazoles are highly soluble in water and probably completely rniscible with it. For this
reason simple tetrazoles such as 5-methyltetrazole, 5-chlorotetrazole, etc. cannot be easily
crystallized from water and are best purified by recrystallizations from solvents such as
ethyl acetate or benzene-pentane. Aromatic tetrazoles and tetrazoles where the ring NH
proton has been replaced are much less soluble in water and generally are easily crystallized
frorn aqueous alcohol. However small tetrazole molecules where the ring NH has been
replaced by a srnall group which does not greatly disrupt the water structure are often quite
soluble in water. The structures of the solutions of the N- unsubstituted tetrazole series are
probably related to those of the corresponding carboxylic acid species. Studies of the
concentration and temperature dependence of the NH proton resonance of 5-methyl-
tetrazole in liquid SOz have suggested the presence of one or more types of dimeric
hydrogen-bonded species which cornpare with the well-known dimers of acetic acid
(65JOC3472). Whether or not tetrazole molecules might form larger aggregates of trimers,
tetramers, etc., as do some of the lower azole molecules, has not been reported.
Me H. N
,f'-N/ '.N -:::: \
N f I I N
'N-::::N.........-N--J'
t1 Me
5-MethyltetrazoIe climer
(iii) Chromatography
Many tetrazole derivatives are solids which often decornpose when heated above their
melting points. Possibly for this reason there appears to be relatively little application of
gaseous and liquid chromatographic techniques in the tetrazole field. However isomeric
tetrazoles can generally be effectively separated by column chromatography using columns
of alumina or silica gel. Paper and thin-layer chromatography have also been effectively
applied to tetrazole analogs of sorne carboxylic acids and Rr values comparable to those of
the carboxylic acids have been reported (70MI41300). Thin-layer chromatography has also
been applied to tetrazoliurn salts and their formazan reduction products (69MI41300).
4.13.2.4.2 Stability and stabilization
(i) Thermochemistry and aromaticity
The measured heat of formation of tetrazole has been reported as 28.1 eV (2710 kJ mol-I)
which compares with a calculated value of 27.7-:1:.0.2 eV (66JCP(44)759). Resonance energies
ranging from 0.992 to 1.396 eV have been calculated for the tautomers of tetrazole. Similar
resonance energy values have been quoted for pyrazole and the triazoles and somewhat
lower values of 0.773-0.994 e V for imidazole. The heats of formation of pyrazole (39.4 e V),
imidazole (39.8 eV) and 1,2,4-triazole (34.4 eV) are sornewhat higher than for tetrazole
(66JCP(44)759). These values suggest that the tetrazole ring is a normal aromatic system but
probably slightly less stable than the lower azoles. Ionization potentials of 9.53-9.64 eV
and 9.37-9.58 eV have been calculated for 1,2,3,5- and 1,2,3,4-tetrazole, respectively.
These values, which represent the orbital energy, with opposite sign, of the highest occupied
molecular orbital, are reasonably close to the values of 9.24 eV for benzene and 9.3-9.4 eV
for triazoles and they differ somewhat from the values of 8.90 eV for pyrrole and 8.99 eV
for imidazole (67MI4130l).
804
Tetrazoles
4.13.2.5 Tautomerism
4.13.2.5.1 Annular
The main methods by which the annular tautomerism (1) (2) has been studied are
NMR spectroscopy, dipole moment measurements and theoretical calculations. The latter
two approaches (Section 4.13.2.2) indicate similar energies for both forms and suggest that
the predominance of the 1,2,3,4-tetrazole form (1), observed in solutions, may be due to
a solvation effect. In the gas phase the 1,2,3,5-tetrazole form (2) appears to be the preferred
form (77 AHc(21)323{-
The proton and 3C NMR spectra of tetrazole, when compared with those of N(1)- and
N(2)-alkyl isomers, agree with the dipole moment results and suggest that form (1) is the
preferred form in solution. In the proton NMR spectrum of tetrazole measured in
deuteroacetone at -90 oC, separate C(5)-H signals were observed, along with other signals
attributed to slow reversible addition of acetone to the tetrazole nitrogen, and assigned to
the tautomers (1) (85%) and (2) (15%) by comparison with N-methyl derivatives (69TL495).
In the 13C NMR spectrum of tetrazole in DMF the C-5 chemical shift was 143.9 p.p.m.,
similar to that of 1-methyltetrazole (144.9 p.p.m.) and different from that of 2-methyl-
tetrazole (153.5 p.p.m.). Similar results were obtained in dioxane, water, DMSO and
acetone, the C-5 chemical shift apparently showing little or no solvent sensitivity (74JOC357).
However, this insensitivity to solvent may be a feature of the parent molecule. With a large
substituent at the 5-position, e.g. compound (47), where the two rings are twisted
orthogonally, 13C spectra indicated 91 % of the more polar 1,2,3,4-tetrazole form (47) in
DMSO solution (10 DMSO 49) but only 68% of this 1-NH form in dioxane-d 6 (10 dioxane
2.2). A similar pattern of 13C NMR results was obtained with 5-(2'-methylphenyl)tetrazole
(48) where the form (48a) was indicated to the extent of 86% in DMSO and 73% in
dioxane (S4UP41300). Carbon-13 spectra for 5-(4'-methylphenyl)tetrazole and its N(1)- and
N(2)-methyl isomers measured in DMSO-H 2 0 (83: 17 v/v) gave a 1-NH: 2-NH tautomeric
ratio of 88: 12, while dipole mornent measurements in dioxane gave a value of 60: 40 for
the same ratio (SOJHC1373). From calculated ionization constants for 1H- and 2H-tetrazoles
it has been predicted that electron withdrawing substituents at C-5 should orient the
tautomerism to the 2-NH form (69JCS(B)1240).
'2'CI N
4! f I' -..
5'- 6' N......N
CI
(47)
/i'\J-"I
N......N
Me
--.
NO--N
Ar< -- I
V N
(48a)
(48b)
Recently the influence of some substituents at the 5-position on the tautomerism has
been measured by using the C-5 chemical shift of the N(1)- and N(2)-methyl isomers as
models for the C-5 chemical shift of the 1-H and 2-H tautomers, respectively. Using these
models it is expected that the C-5 chemical shift of the parent 5-substituted tetrazole,
representing an equilibrium mixture of both tautomers, should always fall between the
extremity limits of each of the N- methyl isomers which represent the individual tautomers.
This was found to be the case for all examples studied except for tetrazole itself containing
a proton at the C-5 atom. In DMSO-water (4: 1 v/v) the 1-NH:2-NH tautomer per cent
ratios were found to be 93: 7, 55: 45, 48: 52 and 84: 14 for 5-amino, 5-methyl-, 5-chloro-
and 5-phenyl-tetrazole, respectively (77MI41300). The influence of substituents in the phenyl
ring of substituted 5-phenyltetrazoles is shown in Table 4 (S1JCS(P1)390). In general, electron-
withdrawing substituents oriented the tautomerism towards the 2-NH form. Ortho-
substituents in the 5-phenyl ring, however, caused out-of-plane rotation of the rings and
the 1- NH form was strongly dominant in such cases, e.g. (47). Quantitative linear correlations
of log K T with the Hammett (J values of the para substituents, and also with log Ka of the
tetrazolic acids have been noted (S4UP41300).
Comparisons of the 13C_1H coupling constant of the C(5)-H bond of tetrazole with
those of N(1)- and N(2)-substituted tetrazoles also indicates the Rreference for the 1-NH
tautomer of tetrazole in solution. Thus in DMSO the value of J( 3C-H) for tetrazole was
216 Hz while that of 1-phenyltetrazole was 216 Hz and that of 2-phenyltetrazole 211 Hz.
Tetrazoles
805
Table 4 13C Chemical Shifts and Tautomerism of Substituted 5-Phenyltetrazoles in DMSO
13C Chemical shift (p.p.m.t
5-Phenyl Parent I-NH form
substituent compound I-NMe form 2-NMe form (%) K T Ref
H 155.6 154.2 164.25 86 6.14 78JCS(P2)1087
4'-Me 155.3 154.1 164.3 88 7.33 78JCS(P2) 1087
2'-Me 155.35 153.85 164.6 86 6.14 8lJCS(P1)390
4' -NO z 155.8 152.7 162.5 68 2.12 78JCS(P2)1087
2'-NO z 153.9 151.95 160.7 78 3.54 78JCS(P2)1087
4'-CI 154.9 153.1 163.3 82 2.03 84UP41300
2'-Cl 153.45 152.6 162.4 91 10.1 8lJCS(P1)390
2',6'-Cl z 151.4 150.6 159.9 91 10.1 8lJCS(P1)390
a TMS as internal standard. b K T =[1-NH]j[2-NH].
In acetone solution the J( l3 C-H) for tetrazole was 217.5 Hz and that of I-methyl- and
2-methyl-tetrazole 218.1 and 213.5 Hz, respectively (76T499. 76JCS(P2)736). The 14N NMR
shifts (from internal nitromethane) of tetrazole (106 p.p.m. in acetone) and its N(l)-methyl
isomer (NMe, 150 p.p.m., CHCh) and N(2)-methyl isomer (NMe, 101 p.p.m., CCI 4 ) do
not appear to agree with the other results and they have led to suggestions that tetrazole
may exist in the 1,2,3,5 form (2) in solvents such as acetone (72T637). However, the factors
involved in nitrogen chemical shifts are more complicated and less reliable than proton and
carbon chemical shifts for studies of tautomerism.
4.13.2.5.2 Ring-substituent
Tetrazole-tetrazoline tautomerism of type (49) (50) is readily observed when the
exocyclic atom X is a or S. This was established by IR spectroscopy over 20 years ago and
the tetrazoline form (50) was found to be the dominant form (B-67MI41300). More recently
l3C NMR spectral data, e.g. (50) and (50a), have confirmed the IR data (75ZC402). The
148.7 148.3 CO Ph
N-'N \ -'N '\ N-'N
HX< II xd.( II od.( II
N N N N N N
R R CH1Ph
(49) (50) X = 0 (50a)
C-5 chemical shifts of compounds (51), (52) and (53) illustrate the thione structure of
1-substituted tetrazole-5-thiols in DMSO solution (Scheme 1) (77JOC3725, 76JOC1875). When
the exocyclic atom X in (49) is an NR' moiety, this type of tautomerism does not occur to
any appreciable extent in solution and the aminotetrazole form is preferred (77AHC(21)323).
However, if the R' substituent on the amino group allows for special stabilization via an
intramolecular hydrogen bond, the tetrazoline form may again dominate, e.g. structure (54)
versus (55). This effect has been detected via the intramolecular hydrogen bond of structures
such as (55). This causes a large reduction in the upfield movement of the NH signal on
dilution with non-polar solvents such as CCl 4 which results from cleavage of intermolecular
hydrogen bonds for structures (54). Such dilution has little effect on intramolecular hydrogen
bonds, as in structure (55) (69JCS(B)680).
(51)
155.1 N-'N
Mes II
N N
Ph
(52)
R
163.2-164.7 N-'N
S II
N..-N
Ph
(53)
N-'N
HS< II
N N
Ph
H
163.8 N-.
S
N N
Ph
Scheme 1
The possibility of an aminotetrazole-iminotetrazoline tautomerism in the solid state has
proved problematic (77AHC(21)323). IR spectra of sorne substituted 5-aminotetrazoles seem
to possess an exocyclic imino absorption and laser-Raman spectra of two forms of hydrated
806
Tetrazoles
H" N-'N
N< II
Me H/ N......N
"S=O.... Me
/
Me
O--H
Me--( -'N
N =< II
N--N
Me
(54)
(55)
5-aminotetrazole have been interpreted in terms of both an amino form and an imino form
which are interconvertible in the solid state (72MI41300).
4.13.3 REACTIVITY AT RING ATOMS: AROMATIC AND
NON-AROMATIC TETRAZOLES
4.13.3.1 General Survey of Reactivity
4.13.3.1.1 Reactions with nuc/eophi/es
Singly bound pyrrole-type nitrogen atoms have an electron-donating activating influence
in azole rings while doubly bound pyridine-type nitrogens exert an electron-withdrawing
deactivating influence. The tetrazole ring with three doubly-bound pyridine-type nitrogens
is a deactivated electron-deficient system. Hammett substituent constants for the tetrazole
ring are Urn 0.64 and Up 0.57 which make the ring comparable with deactivating groups
such as CF 3 and S02Me. The field (F) and reSOnance (R) contributions to the Hammett
u-values, in accordance with the Swain and Lupton equation u = IF + rR, were F 1.17 and
R -0.03 corresponding to a strong electron-withdrawing inductive effect comparable to
that of a nitro group and a weak electron-donating resonance effect (79JCS(P2)1670,
78JCS(P2)1087).
Because of the deactivated 7T-deficient nature of the ring, nucleophilic attack can readily
occur on tetrazoles. Nucleophilic replacement of halogens at the C-5 position has been
widely used for the synthesis of disubstituted tetrazoies, e.g. (56). Kinetic studies of the
reaction between 5-bromo-l-methyltetrazole and the 2-methyl isomer with piperidine have
shown the I-methyl compound to be considerably more reactive. Comparison of these
kinetics with similar reactions for a series of azoles has suggested that two to three
deactivating doubly bound nitrogens (-N=) are required to overcome the electron release
frorn one pyrrole-type nitrogen atom in these systems (67JCS(B)641).
N-'N
ArOH + CI< II
N--N
Ph
K 2 CO,
N-'N
I Aro< II
N--N
Ph
(56)
acetone
Base-induced deuterium-protium exchange at the C-5 atom of N-substituted tetrazoles
occurs readily via carbanionic type intermediates, e.g. (57). The reaction for I-substituted
tetrazoles had a Hammett p-value of + 1.3 in piperidine-MeOD-DMF (69TL3377). In the
acidic pH range 3-5, ylide type species (58; R 1 = H) are also considered to be involved in
the exchange arising from initial protonation at N-l or N-2 followed by D+ abstraction.
MeN N
\ /
N=N
(57)
RN NR 1
\ +/
N=N
(58)
The rate of deuterium-protium exchange for I-methyltetrazole was lO s times faster than
that of 2-rnethyltetrazole in agreement with a general trend that ring protons a to singly
bound nitrogens exchange much more rapidly than those located ß to such nitrogens
(nJA5759). Treatment of I-methyltetrazole with n-butylIithium at -60 oC in THF gave the
carbanionic tetrazolyl derivative (59) which was stable below -50 o C. The corresponding
I-phenyl derivative (60) was stable below -70 o C. On warming above these temperatures
the tetrazolylIithiums decomposed to the corresponding substituted lithium cyanamides
Tetrazoles
807
(61) and nitrogen. These carbanionic tetrazoles underwent normal Grignard type reactions
at the C-5 atom (Scheme 2) (70CJC2139, 77AHC(21)323).
N.......N
X< /I
N--N
Me
X = Br, I
N....... N
X . // 50'C
LI\ /I -- RNCN +N 2
N--N I
R Li(61)
(59) R = Me PhCOR
(60) R=Ph OH
I N-N
Ph-C< II
I N--N
R Me
i,S 1 ii, H+
N.......N
S=< II
N......N
Me
Scheme 2
The most common nucleophilic type reactions at the tetrazole nitrogens arise from the
acidity of the ring N-H bond. Tetrazole, with acidic pKa 4.89 in water, is the nitrogen
analogue of formic acid (pK a 3.75) while 5-methyltetrazole (pK a 5.56) similarly relates to
acetic acid (pKa 4.75) (B-67M141300) and in general the 5-substituted tetrazoles represent
the nitrogen analogues of the carboxylic acids. These tetrazolic acids form stable anions
when treated with bases and the tetrazolate anions are ambident in character and thus
when used as nucleophiles may give rise to 1- or 2-substituted tetrazoles (Scheme 3).
Reactions of this type are used widely for the synthesis of 1,5- and 2,S-disubstituted
tetrazoles.
RCN 4 H
NaOH
---
N.......N N.......N
R<() Na+ R< "
N......N N......N
Me
I
N N
R/ I
\......NMe
Scheme 3
4.13.3.1.2 Reactions with electrophiles and electrophilic ring fragmentations
There are few reports of electrophilic substitutions at tetrazole carbon and then only
when the ring N-H bond has already been substituted. Treatment of N-phenyltetrazoles
with bromine or mercury(II) acetate results in substitution at the tetrazole C-5, but nitration
of N-phenyltetrazoles occurs on the phenyl ring (B-67MI41300). Electrophilic attack occurs
readily on the tetrazole ring nitrogens. The N(2)-position is generally the preferred site for
attack but substitution at the N-1 site also occurs most notably when the S-substituent is
a strongly activating group such as alkoxy or amino. Attack at the N-2 site facilitates a
subsequent ready loss of N 2 with ring fragmentation (Scheme 4). This reaction, and also
the thermal decomposition of 2,5-disubstituted tetrazoles (62), is now a standard method
for generating nitrilimines (63; Scheme 4) (77AHC(21)323). A total ring fragmentation,
N.......N
R< /I
N--N
H
E+
---
-H+
N-'NE
R< I
N,;:::-N
+-
----+ RC=N-NE
-N 2
(63)
(62)
Scheme 4
involving loss of 2 molecules of N 2 , is observed in some electrophilic reactions of tetrazoles,
particularly when the 5-substituent contains a labile hydrogen atom, e.g. as in Scheme 5.
808
Tetrazoles
In these reactions the electrophiles are often halogens and a mechanism involving exocyclic
halogenation and loss of a hydrogen halide rnolecule generating a tetraazafulvene intermedi-
ate (64) is considered to be involved (Scheme 5) (77AHC(21)323, 'cf. 82TL121).
RHX<-- [ RBrX(--I ] [ RX =< N"", ] -2N,. RX= CBr 2 or X=CR
N N N N N
H H N
(64) X=N X=CR 1
Scheme 5
4.13.3.2 Thermal and Photochemical Reactions Involving No Other Species
4.13.3.2.1 Fragmentations involving nitri/imine intermediates
Thermal fragmentation of 2,5-disubstituted tetrazoles results in loss of N 2 and generation
of a reactive nitrilimine intermediate (67). The Hammett p-values for the N-phenyl and
C- phenyl rings of diaryltetrazoles (65) were + 1.16 and -0.23, respectively, suggesting an
unsymmetrical transition state of type (66) (68T3787). Subsequent additions of the
nitrilimines to unsaturated bonds such as alkenes, imines, alkynes and nitriles give an added
importance to the parent tetrazoles as synthetic precursors (Scheme 6). Among the rnost
;--NC 6 H 4 Y
XC6H4\ I
N""N
(65)
[ Arl l
ô-/
Ar-{--i
N""N 8 +
(66)
l-N,
N-- NA 1
Ar< ' r
x y
[ArC=:Ñ-ÑAr 1 ]
(67)
=y N.RtCH=NOH(-H,O)
N-NAr 1
Ar )R 1
N
Scheme 6
N--N ro - N
1/ Ph f
Ph\ I
N N
r\-!-- Me
"=( N N
O
hv
Me
U O )
[ O N-N)Rl
OzN Ñ-O J
I
o
Scheme 7
interesting synthetic applications of this reaction are cases where a cyclization site exists in
one of the tetrazole substituents thereby allowing an intramolecular cyclization of the
nitrilimine. Some recent useful applications are shown in Scheme 7 (78JOC1664, 78ZC214).
NO o- N/N""7
2 ,
- N R
NO z
--+
(X N
Ç? I N
02 N N
02 CR
Tetrazoles
809
The original reaction was developed using acyl groups as substituents on the tetrazole
2-position and is now widely referred to as the Huisgen reaction (Scheme 8) for synthesizing
substituted oxadiazoles, thiadiazoles and 1,2,4-triazoles, e.g. (70) (65CB2966). The final step
involves a heteroelectrocyclization in the nitrilimines (69) (80AG(E)947). The entire reaction
may be carried out in situ or the compounds (68) may be isolated in some cases. For
example, when the 5-substituent R was an aryloxy group, compounds of type (68; X = 0)
were low melting solids (77AHC(21)323).
N---NH
R.# I
VN
x
II
RICCI
R 1
N-"NAx
R( I
N N
(68)
-N z +-
-- RC=N-NCR 1
II
X
(69)
I
N-N
R( )R 1
X
+
..- RC=N-N=CR 1
"-- -
(70) X=O,S,N
Scheme 8
Photolysis of 2,5-diphenyltetrazole in benzene solution gave 2,4,5-triphenyl-l,2,3-
triazole (72) as the main product (28%) and benzil osazone (3%; Scheme 9) (71JOC1589).
A nitrilimine intermediate (71) seems a likely precursor to these products. Recently,
diphenylnitrilimine, showing IR and UV absorptions at 2228 em -1 and 377 nm, respectively,
has been directly detected in the photolysis of 2,5-diphenyltetrazole at 77 K in an ether-
pentane-ethanol glass (80JA2093). On warming to 160-175 K the nitrilimine dimerized to
1,2-diphenylazo-1,2-diphenylethylene (73) (80C(34)504). Comparable triazole and dimeric
products have also been reported from the photolysis of 2-methyl-5-phenyltetrazole
(69JOC4118). Flash thermolysis of 2,5-diaryltetrazoles at 400-500 oC gave 96-100% yields
of 3-arylindazoles such as (74) in a reaction also involving nitrilimine intermediates
(78JOC2037). Photolysis of 5-substituted tetrazoles in THF resulted in loss of N z and the
formation of 3,6-disubstituted 1,2-dihydro-1,2,4,5-tetrazines (75) in a reaction considered
to involve dimerization of the N-unsubstituted nitrilimine species. Minor yields of 3,5-
disubstituted 1,2,4-triazoles were also formed by further photolysis of the tetrazine products
(75) (70T2619). The mechanism is supported by lSN labelling experiments which indicated
that ring-transposition with N-atom scrambling did not occur during photolysis and that
nitrogen expulsion occurred from positions 3 and 4 (nCC781). Reactions involving the
alternative iminonitrene species, PhC(N)=NH, did not give tetrazine-type products
(70JHC71).
;---NPh
Ph\ I
N"""N
1400-S00 'c
Ph
7" I N
/
H
(74)
hv
-..
[PhC=Ñ-ÑPh]
(71)
/60 K, glass
\:. PhH
Ph N=NPh
PhXN=NPh
(73)
N
PhC: NPh
Ph N
(72)
+
(PhC=NNHPhh
Scheme 9
I
N-"NH
R.# I
4\ -- N
N'-'"""
3
N-N
[RC=NNW] __ R JI R
-N z \ I
N-N
H H
(75)
810
Tetrazoles
4.13.3.2.2 Fragmentations to azacyclopropanes
Elimination of N 2 from 1,4-disubstituted tetrazole derivatives (76) leads to substituted
diaziridine compounds of type (77) and a number of synthetic applications of this general
reaction have been developed recently. Photolysis of il 2 -tetrazolines such as (78) in
dichloromethane gave a ready elimination of nitrogen and 60-70% yields of 1,2,3-trisub-
stituted diaziridines of type (79) (74CLl8S). Most 1,4-disubstituted tetrazolines (80) contain
R Me
X N-'N X NR N-' N NM
>( " ><ï Ph< " Ph<'ï e +Nz
Y N--N y' NR N--N ÑMe
R Me
(76) (77) (78) (79)
an exocyclic double bond at C-S. Fragmentations of such systems give heterocyclic analogues
of methylenecyclopropanes (Scheme 10) (80AG(E)276). These fragmentations were more
readily achieved by photolytic rather than thermal means since the tetrazole derivatives
tend to be thermally stable. With tetrazoline-5-thiones sulfur was extruded as well as N 2
giving carbodiimides and the three-membered rings were not formed. Tetrazolines contain-
ing an exocyclic alkylidene moiety gave iminoaziridines (81) rather than methylene-
diaziridines (7SAG(EJ428). Mechanistic insight into these reactions was obtained when the
triplet diradical (83) was directly detected by its ESR spectrum on photolysis of the
tetrazoline (82) in a butyronitrile matrix at -195 oc (78JA1306). The radical (83) is a nitrogen
analogue of trimethylmethane. The synthetic applications of these and related fragmentation
reactions for the synthesis of heterocyclic analogues of methylenecyclopropanes have
recently been thoroughly reviewed (80AG(E)276).
X
NR RN^NR 0
RllN x = CHR ' x=o )\
( \ / + N z
hv N=N hv RN-NR
(81) (80)
X=NR'/
/hv
\'X=S
hv '\.
NR 1
)\
RN-NR
RN=C=NR+S+N 2
Scheme 10
NMe
^
MeN NMe
\ /
N=N
(82)
hv
-195'C
NMe
Me ^ Me
(83)
4.13.3.2.3 Fragmentations to carhenes and nitrenes
Photolysis of S-substituted tetrazolate anions results in loss of two molecules of N 2 and
generation of a carbene which gives normal insertion reactions (Scheme 11) (71TL4489).
The reaction involved an initial excitation of the anion to a long-lived triplet state. This
lost a nitrogen molecule giving a fragment which abstracted a proton from the medium
generating a diazoalkane intermediate which was photolyzed to the carbene (Scheme 11).
The initial triplet state could be quenched by treatment with suitable acceptors and it rnay
be used as a photosensitizer (69TL4863). Rearrangements characteristic of diazoalkane species
were observed with substrates such as S-cyclopropyltetrazolate (84) from which the main
product was the cyclobutyl methyl ether (86). Attempts to generate dicarbenes by photolysis
of di(tetrazol-5-yl)benzenes resulted only in consecutive reactions each involving a mono-
carbene pathway (77 AHC(21 1323).
Tetrazoles
811
RCN 4 - RCN 4 -* -No) [R-ë=N-Nr RCHN z
IhV
f"O'
RCH:
A*+RCN 4 -
R=Ph
MCoy
RCHzOMe
tcJOhcxanc
RCH 2 Q
Scheme 11
N-N
':xi<
(84)
Gas-phase pyrolysis of 5-aryltetrazoles and fused tetrazoloazines has been used as a
convenient route to aryIcarbenes and nitrenes. The ease of synthesis of labelled tetrazole
derivatives has given rise to interesting studies of the behaviour of some of these reactive
intermediates, e.g. Scheme 12. When 2-pyridyltetrazole (87), carrying a 13 C label at the
tetrazole 5-carbon, was pyrolyzed at 400 oC the carbene (88) was formed. This rearranged
to the nitrene (89) which dimerized to compound (90) carrying the label exclusively in the
ortho-positions. Thus when no ring contraction was observed, no scrambling of the label
occurred. At higher temperatures, 670 o C, the ring-contracted product (94) was observed.
This showed the expected label distribution for prior isomerizations to 1H- benzazirine (92)
and iminocyclohexadienylidenes (91) and (93) which therefore appear to play an essential
role in ring contractions of arylnitrenes (76JA1258).
hv
---+
H'
[>CHN 2
MeOH
--.
hv
Ì'--. D OMe
VCH20Me +
(85) 28 %
(86) 72%
CA N <l 0 0*
.& I --. I h * +-- )
N N......NH N CH: N
(87) (88) f
['ONH '- .q. .Q-J 670'C Q.
--,. -
NH NH :N:
(93) (92) (91) (89)
1 1 400 'C
*
()--êN
*
O N=N O
(94)
(90)
Scheme 12
UV photolysis of 1,5-disubstituted tetrazoles also results in elimination of nitrogen and
gives reactions which appear to involve the iminonitrene intermediates (95; Scheme 13).
Thus photolysis of 1,5-diphenyltetrazole and 5-phenoxy-1-phenyltetrazole gave compounds
(96) and (97), respectively, as major products. Some other products also arose from further
photolysis of these primary products and with 5-aryloxy-1-phenyltetrazoles a minor com-
petitive pathway involved a homolysis of the aryl-oxygen bond and gave rise to some
biphenyls when benzene was the solvent. Photolysis of dimethyl tetrazole-1,S-dicarboxylate
(98) gave the oxadiazole (100) while thermolysis gave the oxadiazolone (101). Both reactions
812
Tetrazoles
involved the nitrene intermediate (99) and it has been suggested that a singlet nitrene,
favouring insertion, was involved in the thermal reaction while the photoreaction involved
a longer-lived triplet nitrene (71JAI534, 77AHC(21)323, 73JCS(P1)469). Flash vacuum pyrolysis
of 2-methyl-5-phenyltetrazole at 550 0 C and 10- 4 Torr gave Ph-CH=N-N=CH 2 and
Ph-N=C=N-Me and this latter compound was also obtained from pyrolysis of I-methyl-
5-phenyltetrazole (SOCCS02). N-Arylbenzimidoyl nitrenes which cyc1ize on to the ortho-
position have been invoked to explain the interesting series of products observed on
thermolysis and photolysis of 5-phenyl-1-(2,6-dimethoxyphenyl)tetrazoles (Scheme 14)
(76CC414). Therrnolysis reactions of sorne 5-aminotetrazole derivatives are discussed in
Section 4.13.4.4.
N--N No (XN)R
R( II hv R-{
-- --+
N--N N N
Ph I H
Ph \96) R=Ph
(95) (97) R = OPh
N-'N
MC0 2 C( II
N--N
COzMe
(98)
hv
--
or.l
No
Me0 2 C-{ Jl
NOMe
(99)
N-. O
Meo 2 C( I
N:?OMe
(100)
N 0
Meo 2 c( r
N..... O
Me
(101)
Scheme 13
N'N
Ph( "
N.....N
R 6 R
I
R 1
R = OMe
-.
R R R N
A (X N f'ì(" " Ph
R 1 IN=C=NPh + I )Ph +
R R 1 R
Scheme 14
4.13.3.2.4 Rearrangements
One of the best-known thermal rearrangernents of tetrazoles is that of substituted
5-aminotetrazoles (103). In general 5-alkyl-1-arylaminotetrazoles (103) rearrange to 1-
alkyl-5-arylaminotetrazoles (105) when heated (Scheme 15). The reaction is an equilibrium
and both forrns are usually present in the melt. The reaction is first order in tetrazole and
electron-withdrawing substituents in the aryl ring favour the arylamino form (105). There
was a linear correlation between log K and Hammett (J'- values of substituents. The re-
arrangement involves ring opening to a reactive, bent imidoylazide (104) which has the
required cis-orientation of the azido group and the imino lone pair for ring-closure but is
sufficiently long-lived for rotation of the C(5)-N(4) bond and an amino-imino proton
tautomeric change. In this situation competitive 67T- heteroelectrocyclization occurs prefer-
entially on the imino nitrogen with highest electron density (S4JASS, S3JOC1269). Thermal
rearrangement of l-aryltetrazole-5-thiones to 5-arylamino-1,2,3,4-thiatriazoles, a sulfur
analogue of Scheme 15, has also been observed (67JOC3SS0). The cyclization of imidoyl
azides is discussed in Section 4.13.5.
Displacement of chloride from 5-chloro-1-phenyltetrazole can be used to synthesize
5-alloxyl-l-phenyltetrazoles (106). These readily undergo Claisen-type 3,3-sigmatropic
rearrangements when heated giving the products (108) with inversion. It has been suggested
that ground state contributions from polar forms such as (107) may facilitate the rearrange-
Tetrazoles
813
Ar
N'N 180"C
RNH\ " ( )
N--N
(103) R = alkyl
t
[ RNH_C=N:,Ar
çp'
N ".
N.
N/
R
N'N
ArNH\ "
N--N
(105)
r
R--;N=CNHAr j
. I
.. N
:N, I;
N
(104)
Scheme 15
ment (67JOC2956). A comparable 1,3-sigmatropic-type rearrangement of 5-alkoxy-1-aryl-
tetrazoles (109) occurred when these compounds were heated in the presence of NaI
(74JHC491). An interesting 1,4-sigmatropic-type migration has recently been reported with
1-alkoxy-5-phenyltetrazoles (111) on heating at 190-200 o C. The rearranged 3-alkyl-
tetrazole 1-oxides (112) were formed in yields of 30-53% (78TL399). The mesoionic 2,3-
diphenyltetrazolium 5-oxide and 5-sulfide (113) underwent a thermal rearrangement to the
corresponding 1,3-diphenyl derivatives (114) when heated at 150 oC as 2% w /w dispersions
in acid-washed sand. The rearrangement was confirmed by X-ray crystallography of the
products (76CC343).
N'N
RCH=CHCHO< "
I N--N
R' Ph
(106)
+-+
N-'N
RCH=CHCH-Õ=( "
I N--N
R' Ph
(107)
>100"C
--
RCHCH=CHR '
N'N
o=( "
N--N
Ph
(108)
R
N-'N N-'N N-'N N
< -'NMe
RO< " o=( " Ph< " --+ Ph 1
N--N N--N N--N w=:N
Ar Ar OMe I
0-
(109) (110) (111) (112)
_ -< :-:-;NPh
X : + :1
;'::NPh
150"C - -< NPh
--X :+:1
;'::N
Ph
(114) X=O,S
(113) X=O,S
4.13.3.3 Electrophilic Substitution
4.13.3.3.1 Basicity
The tetrazole ring is a weak base on which protonation occurs preferentially at N-4. A
basic pKa value of -3.0 has been quoted for tetrazole in aqueous H 2 S0 4 , Because of the
weak protophilic properties of a series of 1,5-disubstituted tetrazoles it was not possible
to measure basicity constants for these compounds in water. However, in formic acid pK b
values of ca. 2 were obtained for a range of tetrazoles and there was little difference between
individual compounds because of the levelling effects of the solvent. The pK b values in
formic acid correspond to basic pKa values of ca. +4.6 which are not comparable to those
obtained in aqueous sulfuric acid (77AHC(21)323). Recently a useful linear relationship
between the acidity and basicity constants of a range of 5-substituted tetrazoles has been
reported: pK a =0.78 pK BW +6.37 (81KGS599). Tetrazoles are also weak 7T-donors and
they form charge-transfer complexes with 7T-acids such as tetracyanoethyIene and
814
Tetrazoles
I ,3.5-trinitrobenzene (66JPC3688). The cornpound 1,5-pentamethylenetetrazole (PMT) was
a strong electron-donor towards Lewis acids although it showed no basic properties in
water. While complexes of type PMT'h and PMT.lBr were observed in solution, the
complex PMT.ICI was a stable solid. Its structure is described in Figure 2 (Section 4.13.2.3).
4.13.3.3.2 Electroplrilic attack at nitrogen
Electrophiles such as acyl halides and irnidoyl halides attack the 5-substituted tetrazole
ring at the N(2)-position giving the Huisgen reaction outlined in Scheme 8 (60CB2885,
61CB1555). Further exarnples of sirnilar electrophilic reactions are in Scherne 16. Cyanogen
brornide reacted with 5-aryloxytetrazoles to give the 2-cyanotetrazoles (116). Unstable
2-tosyltetrazoles (118) were obtained when 5-dirnethylarninotetrazole was treated with
p- toluenesulfonyl chloride at 10 oC in pyridine. At norrnal ternperatures in pyridine the
products of the reaction were cornpounds (120) derived frorn (118). Mild warrning of
cornpounds (118) in water gave the arnides (119) by solvent addition to the expected
nitrilirnine interrnediate (77AHC(21)323). In the reaction of benzoyl chloride with 5-phenyl-
tetrazole containing a 15N label at the N(l)- and N(4)-positions to give 3,5-diphenyl-l,3,4-
oxadiazole (123), half of the label was present in the oxadiazole product confirrning N 2 loss
frorn the 1,2(3,4) positions of the tetrazole ring and suggesting interrnediates of type (121)
and (122) (61JOC2372).
N--N
ArO( 'II
N--N
H
(115)
BrCN
--
Et,N
N N
ArO\. I
N--NCN
(116)
N--N
Me2N( II
N--N
H
(117)
CISOzAr
N""N
Me 2 N\. I
N--NS0 2 Ar
(118)
o
II
Me2NCNHNHS02Ar
(119)
1 pyridine
Mc,NC=NNHS0 2 Ar Cl-
- I
N
o
(120)
Scheme 16
*
N""'N
Ph\. I 0
Ñ--N, II
C-Ph
*+
Ph-C=N-N
N:N
--- C-Ph
-d
*
N-N
Ph( )Ph
o
(121)
(122)
(123)
The preferred site for electrophilic attack is, however, apparently quite sensitive to the
nature of the 5-substituent and strongly activating groups rnay orient the attack to the N-1
site. Thus attack by cyanogen brornide and rnethanesulfonyl chloride on 5-rnethoxy- and
5-ethoxy-tetrazoles occurred at the I-position causing ring opening to irnidoyl azides, e.g.
ROC(N 3 )=N-S0 2 Me, which were obtained in high yields (80JHC187). Arylsulfonyl-
tetrazoles obtained on treatrnent of tetrazole with arylsulfonyl chlorides, for use as condens-
ing agents in nucleoside synthesis, have been described as 1-arylsulfonyltetrazoles, although
the structural question as to why they did not open to azides as might be expected was not
discussed (76CJC670). Other electrophiles which attack the 5-substituted tetrazole ring at
the N-2 position are isocyanates and diketene. However, when the 5-substituent is an NH 2
group, the electrophilic substitution with these electrophiles also changes preferentially to
the N(1)-position. Treatrnent of 5-arninotetrazole with isocyanates gave the 1-(N-alkylcar-
boxarnido)tetrazoles (125) and with chlorosulfonyl isocyanate as electrophile the attack at
Tetrazoles
815
N-1 was accornpanied by ring opening and cyclization on to the 5-amino group giving
S-azido-2H-1,2,4,6-thiatriazin-3( 4H)-one 1,I-dioxide (127; Scheme 17) (80JOC1662). On
treatment of 5-aryltetrazoles with diketene a norrnal N(2)-attack occurred giving rise to
oxadiazoles by a Huisgen-type reaction. The reaction of 5-arninotetrazole with diketene,
however, gave cornpound (150; Scherne 22) in quantitative yield probably via N(I)-attack
followed by cyc1ization of the 5-amino group (76CPB2549). On treatment of tetrazole with
vinyl ethers CH 2 =CHOR, a 2-NH addition reaction occurred giving 2-alkoxyethyltetrazoles
(128) (80Z0R1313). Treatment of S-substituted tetrazoles with benzonitrile oxide gave a
rnixture of the N(l)-substituted cornpound (129) and its N(2) isorner. Therrnolysis of
cornpounds (129) provided a new route to 1 ,2,4-oxadiazoles (130) (81BSB193). An interesting
electrophilic degradation of the tetrazole ring of 3-(tetrazol-5-yl)chrornones (cl. structure
251) with Vilsmeier reagents RCONR z and POCh to a carbonyl hydrazidine group
(-CONHN=C(R)NR z ) has also been reported (74TL1187).
RNJlyO
N--'N
H 2 N< "
N--N
N--'N
NH 2 < "
N--N
H
RN=C=O
(124)
2NCO
N 3
HN N
O N/ 02
H
(127)
(125)
o H
^ N--'N
NHz NH-<"
N--N
(126)
---%::
Scheme 17
( ' CHMe(ORJ
N:::'N
(128)
PhC=NOH
I
N--'N
R< "
N--N
(129)
ð
---+
R('1 Ph
O--N
(130)
Quaternization of 5-substituted 2-aryltetrazoles occurred at the N(4)-position but further
alkylation of N(l)-aryl 5-substituted derivatives occurred at both the N(2)- and N(3)-
positions. An unusual conversion of 1-alkyl-5-aryltetrazoles (131) into the corresponding
2-alkyl isomers (133) occurred on heating with an alkyl iodide. The reaction has been
explained in terrns of a quaternization at the 3-position giving a 1,3-dialkyl-5-phenyl-
tetrazoliurn iodide (132) which elirninated a rnolecule of alkyl iodide to give the
therrnodynamically more stable isorner (nzC261, 7IJOC3807). An interesting intrarnolecular
electrophilic attack occurred at the tetrazo(e N(l )-position in the azacarbo cations (133a)
which are forrned by solvolysis of the corresponding hydrazonyl halides (67JCS(C)239). Ring
cleavage to an azide occurred when the tetrazole ring was unsubstituted and a fused
s-triazolotetrazole (133b) resulted when the tetrazole ring NH was substituted by an alkyl
group.
R R
N .N N--'N N"'N
Ph< II RI Ph\ +1/ 1- RI Ph\ ---I
N-N N--NR N--NR
(131) (132) (133)
N-N
Ar(
N NMe
\ /
N=N
(133b)
R=Me
-H'
+
ArC=NNH
. ); R
:N, .ýN
N
(133a)
R=H
-H'
N-NH
Ar( )N 3
N
(133c)
816
Tetrazoles
4.13.3.3.3 Electrophilic attack at carbon and a-exocyclic positions
There have been few reports of electrophilic substitutions on the tetrazole C(5)-H site
of N- substituted tetrazoles, the only cases apparently being brornination and acetoxymercur-
ation (Section 4.13.3.1.1(ii)). When the C-5 atom bears an active a-site (CH or NH),
interesting ring degradations are encountered which appear to involve preferred electrophilic
attack at the a-exocyclic position (Scherne 18). The presence of a labile H on the ring
nitrogen atoms and a potential leaving group at the 5-exocyclic a-position, arising frorn
the electrophilic attack, allows for loss of a srnall rnolecule and generation of a tetraazaful-
vene interrnediate lScherne 5). This fragrnents with loss of two rnolecules of N z and generates
a carbene species which leads to the products (Scherne 18) (77 AHc(21)323, 76AG!E)113).
N__N
RR'CH( 11
N......N
H
N N Br
-, B /
RNH( II RN=C
N......N 'Br
H
1 Br,
R = ArCH=N /
IBr,
OACI40r'o'
RCBr=CBrR'
Br
/
ArC=NN=C
I ,
Br Br
Scheme 18
+ -
RN=C:
4.13.3.4 Nucleophilic Substitution
4.13.3.4.1 Acidity
The tetrazole ring l-CN 4 H, the tetrazolic acid group), represents the forrnal nitrogen
analogue of the carboxylic acid group, -COzH (58MI41300. 56MI41300). In general substituted
5-aryltetrazoles are somewhat stronger acids than the cornparable benzoic acids (Table 5).
This increased acidity has been ascribed to enhanced resonance stabilization of the aryl-
tetrazolate anion and to a greater solvation of the tetrazolate anion as compared to the
carboxylate anion (79JCS(P2)1670). Introduction of electron-withdrawing groups into the
5-phenyl ring increases the acidity of the aryItetrazolic acids and electron donating sub-
stituents have the reverse effect of decreasing acidity, in general agreernent with substituent
effects in benzoic acids. The well-known acid-strengthening effect of ortho-substituents in
benzoic acids, however, does not apply in the aryltetrazolic acid series (Table 5) and
ortho- substituted 5-phenyltetrazoles are not generally stronger acids than the corresponding
para- substituted cornpounds as is the case for substituted benzoic acids. Changes of inter-
annular conjugation effects in ortho-substituted 5-aryltetrazoles arising frorn loss of ring
coplanarity are likely to contribute to these differences (79JCS(P2)1670, 78JCS(P2)1087).
Table 5 Comparative Acidities of 5-Aryltetrazolic Acids lXC 6 H 4 CN 4 H) and
Benzoic Acids (XC 6 H 4 CO z H) in 50% Ethanol-Water (79JCSCP2)1670>
Substituent X
Tetrazolic acid Ka x 10 5
Benzoic acid Ka x 10 5
H
p-Me
o-Me
p- MeO
m-Br
p-Br
o-Br
p-Cl
o-Cl
p-NO z
0- N0 2
1.05
0.67
0.61
0.56
4.13
2.06
2.09
3.23
1.99
20.2
9.42
0.178
0.115
0.085
0.603
0.447
2.95
Tetrazoles
817
The influence of substituents directly bonded to C-5 on the acidity of the tetrazole ring
follows the expected trend of electron-withdrawing groups enhancing the acidity. For the
series of 5-substituents NH z , Me, H, Cl, CF 3 , the pKa values in water were 5.93, 5.56,
4.89, 2.07 and 1.14, respectively. Many tetrazole analogues of amino acids have been
synthesized and found to exhibit pKa values in close agreement with those of the correspond-
ing amino acids. Incorporation of these tetrazole arnino acid analogues into peptides has
also been achieved. These nitrogen analogues of the amino acids exist in the zwitterionic
form similar to their carboxylic acid counterparts (77AHC(21)323, B-67MI41300) (cf. Section
4.13.6).
4.13.3.4.2 Nucleophilic substitution at C-5
Because of the deactivated nature of the tetrazole ring, leaving groups On the 5-carbon
atom are readily displaced by nucleophiles (Scheme 19). The most cornmon usage of this
reaction has been with halogens as leaving groups and alcohols or phenols as nucleophiles,
e.g. compound (56) (77AHC(21)323). The reaction may also be used to obtain substituted
5-hydrazino- and 5-amino-tetrazoles when hydrazines and arnines are used as nucleophiles.
Kinetic studies of this reaction with piperidine as nucleophile and base-induced protium-
deuterium exchange at C-5 have been discussed in Section 4.13.3.1. Nucleophilic solvolysis
type reactions at c-s are readily observed on heating 1,4-disubstituted 5-imino- and
5-thioxo-tetrazoles in aqueous solutions when the exocyclic nitrogen and sulfur atoms are
replaced by an oxygen atom giving 1,4-disubstituted tetrazolones (77AHC(21)323)
N-N
PhNHNH( '"
N---N
Ph
PhNHNH z
(
R=Ph
R
N
Br<
N
MeO
...---R = Me
,tJ--NMe
MeO\, I
N""'N
R=Me
HO
H
N
=< --NMe
o I
N.,;;:N
Scheme 19
4.13.3.5 Reactions of Tetrazolate Anions: Alkylation Reactions
4.13.3.5.1 Ring alkylation
The most common tetrazole anion is the tetrazolate species (134a-c). This is an arnbident
system in which reactions can occur at the 1- or 2-positions and also at the a -exocyclic
site at C-5 if the a -atom is suitable, e.g. (134c). Anionic character at the tetrazole ring
carbon has also been observed, for example in the reaction of N-substituted tetrazoles
with alkyllithium cornpounds, and this is discussed in Section 4.13.3.1 (Scheme 2).
N_'N N--Ñ N--N
R( " -. R( I R("
Ñ N N.,;;:N N.......N
H
(134a) (134b)
(134c) R = SH, NHz, OH
The most important reactions of tetrazolate anions are alkylations in which the anion is
used as a nucleophile in substitution reactions mainly with alkyl halides and sulfates. Many
such reactions have been reported and a variety of conditions and reagents have been
employed. The products are rnixtures of N(l)- and N(2)-alkyl isorners, the relative propor-
tions of which depend upon the conditions of the alkylation and the influence of the
5-substituent. In general, electron-donating substituents at C-5 tend to favor slight1y
alkylation at the N(l)-site while electron withdrawing substituents favor N(2)-alkylation.
The position of alkylation was also influenced by the steric requirernents of the alkylating
agent and was found to be insensitive to electronic effects of para-substituents on benzyl
818
Tetrazoles
halide alkylating agents. This suggests an SN2 type process where the electronic effects of
substituents on the alkyl halide often tend to cancel (77 AHC(21)323, B-67MI41300}.
In the series of substituted 5-phenyltetrazoles (135) electron-withdrawing substituents
had a rnuch larger effect than electron-donating groups. The isorner distribution of the
products was linearly related to the Harnrnett u value of 4' -substituents but required exalted
u-values for strong resonance-electron withdrawing groups such as N0 2 , and norrnal
u-values for strong resonance electron donating groups such as MeO. For exarnple, the
ratio of (137): (136) for 4'-N0 2 , -H and -Me groups was 6.15, 2.2 and 2.05, respectively.
Substituents at the 2'- and 6' -positions caused out-of-plane rotation of the rings and,
interestingly, oriented the alkylation toward the N(1)-position and not away from it as
might be expected for steric reasons (81JCR(S)174}. Linear Harnmett relationships were also
found for the alkylation of substituted 5-phenyltetrazoles with dirnethylsulfate in
acetonitrile. The product orientation was influenced as well by the nature of the cation and
the temperature. For the alkylation of potassium 5-phenyltetrazolate with dimethylsulfate
in acetonitrile the ratio of (137): (136) was 4.72 at 10 oC and 1.86 at 35 0 C (81Z0R146,
79Z0R839}. The net charges on the N(l)- and N(2)-sites of sorne tetrazolate anions have
been estirnated by MINDOj3 calculations. For exarnple, the net atornic charges for the
5-methyltetrazolate anion were -0.3027 at N-l and -0.1577 at N-2. The N(I)-position
should therefore be rnore nucleophilic. The general and sornetirnes regioselective preference
for reactions to occur at the N(2)-site has been ascribed to stt;ric hindrance of the
N( I )-position by the 5-substituent (80JA2968}. The large product differences observed for
alkylation of 5-(p-substituted phenyl)tetrazolate anions, where steric effects are constant,
however, also indicate an irnportant electronic influence. The observed quantitative trends
suggest that the balance of arnbident reactivity may reflect a harder Coulornbic-controlled
reaction at N-l in competition with a softer orbital-controlled reaction at N-2 (81JCR(S)174}.
01 " y 2' N
II \'\ l' n N EtOH-H,O (J : 1)
.' '/ '\ J I + Mel . - )
- N --N
" 6 ' +
. Na
y
A r--
c;-\N--N
Me
y
6-< N"""N
+ ::.. I
- N--NMe
(135) (136) (137)
The quantitative substituent trends which have been established for substituted 5-phenyl-
tetrazoles are also qualitatively evident for substituents directly bonded to the 5-carbon
(Table 6). However, direct cornparisons under identical reaction conditions are rare and
the data in Table 6 are not strictly corn parable because of the variety of conditions of
rnedium and temperature. Selective N(l)-alkylation has been obtained by blocking off the
2-position with a tri-n -butylstannyl group, when treatment of the 2,5-disubstituted deriva-
tives with normal alkylating agents such as Mel and Me2S04 gave up to 90% N (l)-alkylation
and the BU3Sn blocking group at N-2 was removed during the reaction (73BCJ2176}. Organic
media or neutral alkylations with reagents such as diazomethane tend to favor ring-alkylation
of tetrazoles at the N(2)-position. Examples for methylation with diazornethane and sorne
recent t-butylations of 5-substituted tetrazoles are in Table 6.
4.13.3.5.2 Exocyclic a-alkylation and polyalkylation
Mono-alkylation of the exocyclic ex -position at C-5 is generally not favored for 5-arnino-
and 5-oxo-tetrazoles and, if encountered at all, it usually occurs in 10%. Benzylation of
5-arninotetrazole occurred at the exocyclic 5-amino position to the extent of about 6-10%
for a series of p-substituted benzyl chlorides and the main reaction was at the ring N-atorns.
Benzylation of 5-dialkylaminotetrazoles was sornewhat exceptional when exocyclic quater-
nization occurred, giving a 29% yield of the ylide (10) as well as the ring-alkylated isomers.
Dialkylation of ring-alkylated tetrazoles rnay occur on an exocyclic 5-arnino group and for
example basic rnethylation of cornpounds (138) and their 2-rnethyl isomers occurred
exclusively at the exocyclic amino group (66JOC3182}. However, rnethylation of 5-amino 2-
methyltetrazole (139) and its 1-rnethyl isomer occurred on N-4 giving the mesoionic
compound (7) and 5-irnino-1,4-dirnethyltetrazoline, respectively. When 5-hydroxytetrazole
(tetrazolinone) was treated with diazomethane, a rnixture of 5-rnethoxy l- and -2-rnethyl-
tetrazoles and dimethylated tetrazolines was formed. Further rnethylation of 1-rnethyl-
Tetrazoles 819
Table 6 AIkyIations of TetrazoIes
Alkylating Main product Ratio
5-Substituent agent (%) N(2)-R :N(1)-R Ref
(i) Anions
NH l Me l S04 55 1: 3 54JA923
ArCH=NNH Mel 60 1:6 66JOC3182
NO l Mel 57 3:1 54JA923
Me Mel 0":1 65JOC3472
CF 3 Mel 6: 1 62JOC3248
Me EtOlCCHlBr 49 1:2 69CJC813
CF 3 EtOzCCHzBr 76 1 :0" 69CJC813
CF 3 n-C g H 17 Br 71 18:1 62JOC2085
MeOCH l EtOzCCHlBr 47 1 : 1.24 72ACS541
MeOCHlCH l Me l S04 47 1: 1.1 61MI41300
H EtOlCCHzBr 55 1:2 69CJC813
H CHz=CHCHzBr 37 1 : 1.25 59JOC1565
H Me3SiCI 70 0":1 63CB2750
CI EtOlCCHlBr 63 7:1 69CJC813
EtOlC PhCHlBr 34 1.7: 1 75CB887
pyridin-3-yI MeI 30 1 :0" 67JMC149
RzNCHlCH z EtI 43 4:3 70JMC777
(ii) Neutral molecules
NH z CHzN z 50 1 : 1.06 56JA411
Me CHlN l 47 5:1 65JOC3472
Br CHlN l 68 5:1 56JA411
NH z t- BuOH, CuCI, 58 1.4: 1 76JHC391
RNCNR b
MeS t-BuOH, CuC!, 59 4: 1 76JHC391
RNCNR b
CI t-BuOH, CuCI, 30 1.4: 1 76JHC391
RNCNR b
" Isomer either not delected or not reported. b R = cyclohexyl.
tetrazolin-5-one occurred at N-4 (80%), exocyclic oxygen (10%) and N-3 (1%)
(77 AHC(21)323, B-67MI41300).
N__N
ArCH=NNH( II
N..-N
Me
N N
NH z < I
N..-NMe
OH N
I --N
RCHCHzS< II
N..-N
Ph
(138)
(139)
(140)
Polyalkylation of N-substituted 5-thioxotetrazoles generally occurs on the exocyclic
sulfur atom (cf. however, Section 4.13.2.3). Treatment of l-phenyltetrazoline-5-thione with
Me! or CH 2 N 2 gave 5-methyl-l-phenylthiotetrazole and a similar reaction with substituted
epoxides gave products of type (140) (77ZC60). The mesoionic compound dehydrodithizone
(9b) was also alkylated preferentially on exocyclic sulfur to give 5-alkyl-2,3-
diphenylthiotetrazoliurn salts (77AHC(21)323).
4.13.4 REACTIONS OF SUBSTITUENTS
4.13.4.1 General Survey
Substituents on the tetrazole ring generally behave normally and show their expected
characteristic reactions. The electron-withdrawing character of the ring may influence the
relative reactivity of substituent groups at the 5-carbon atom when they appear in N(1)-
or N(2)-substituted tetrazole rings. The N(l)-substituted ring (high dipole moment) is more
electron withdrawing than the N(2)-substituted isorner (low dipole moment) and substituents
which are electron deficient in character are therefore generally more reactive towards
nucleophiles in N(l)-substituted tetrazoles. However, these trends are not yet well estab-
lished in the literature although they are clearly visible with sorne of the substituent groups
(Figure 4).
820
Tetrazoles
-
N
ó ß--- N
x--Z 1\
J W- N
../ /
Nu R
ó+ N N
x I
/ N..-N'R
Nu
more reactive
Figure 4 Reactivity of electron deficient a-substituents to nucleophiles
4.13.4.2 Aldehyde, Carbonyl and Nitrile Substituents
Tetrazoles with an aldehyde group at the S-position have recently been prepared as
outlined in Scherne 20. The 1-substituted tetrazole-S-carbaldehydes (141) were more
reactive than the corresponding 2-substituted isorners. They formed hydrates such as (142)
and herniacetal dirners (143). The aldehyde groups showed the range of norrnal aldehyde
reactions for both 1- and 2-substituted tetrazole-S-carbaldehydes. On treatment of the
1-substituted aldehydes with base deforrnylation occurred giving the parent 1-substituted
tetrazole. In particular the I-substituted tetrazole-S-carbaldehydes were considerably rnore
reactive towards nucleophilic reagents than the 2-substituted isomers. The parent N-
unsubstituted tetrazole-S-carbaldehyde has been prepared by cycloaddition of hydrazoic
acid with (EtOhCHCN in pyridine followed by hydrolysis to the aldehyde. In the solid
state this exists in the interesting dimeric structure (141a) (75CB887, 77CZ403}.
N..-N
\I )CH,Cl
N.......N -
R
R = alkyl, aryl
pyridine
N--N D "
\I ;>-CH 2 -N+ '\
N.......N -
R
O.
Me2NC6H4NO-p N I --N l -o ' M
Þ I / CH=N " e2
N.......N .-
Y R
N--N
\I )
N.......N
R
ow N--N
\I )CHO
N.......N
R
(141)
/R=H
N--N OH
II )CH/
N.......N "OH
R
(142)
OH
N N
1/ -N -- \
N I N
\ N...... I;
N OH N
(141a)
II
N--N N-N
\I }-CHOCH -< \I
N.......N I I w-- N
R OH OH R
(143)
Scheme 20
Carbonyl substituents at the C(S)-position are readily introduced by oxidizing secondary
alcoholic groups or rnethylene moieties, e.g. ArCH 2 , located at the 5-position. These
carbonyl groups generally behave normally, particularly when they are of the aroyl, ArCO,
type. For exarnple, oxidative degradation gives rise to S-carboxytetrazoles, Grignard addi-
tions give the expected tertiary alcohols and halogenation reactions give the expected
ex -halocarbonyl compounds. However, 5-acetyltetrazoles undergo sorne unexpected reac-
tions. Thus treatrnent of 5-acetyl-l-phenyltetrazole with NaOI gave a deacetylation to
S-iodo-1-phenyltetrazole and treatrnent with KCN or arnines gave a degradation to 1-
phenyltetrazole (B-67MI4130t}.
A nitrile group at the tetrazole 5-position also exhibits normal reactions. It is readily
hydrolyzed to the amide and carboxylic acid groups and on treatment with H 2 S it is converted
into a thioarnide function. Addition of hydroxylamine to a nitrile substituent at the tetrazole
C-5 gives an amidoxime substituent, -C(NH 2 )=NOH, at the 5-position (76ZC90}. Treat-
rnent of S-cyano-2-phenyltetrazole with MeMgI followed by AcCI gave S-acetyl-2-phenyl-
tetrazole but ring degradation to AcN(Ph)CN occurred in the cornparable reaction with
S-cyano-1-phenyltetrazole (81CZ194}.
Tetrazoles
821
4.13.4.3 Alkoxy and Hydroxy Substituents
Reductive cleavage of 5-aryloxy-1-phenyltetrazoles (144) has proved to. be an effective
method for removing hydroxy groups frorn phenols which is all the more useful because
of the ease with which phenols can be converted into 5-aryloxytetrazoles. The tetrazole
C(5)-0 bond is apparently stronger than the phenol C-O bond hence giving rise to the
elusive aryl-oxygen cleavage. The reaction has been widely used with a variety of phenol
types. The strength of the tetrazole C(5)-O bond is also illustrated by the ready cleavage
of 5-alkoxytetrazoles on the alkyl-oxygen bond when heated in hydrochloric acid under
conditions mi1der than those required for norrnal Zeisel type cleavages of arylalkyl ethers
(66JA4271, 77AHC(21)323, B-67MI41300).
N--N
---+ ArO< I'
N.....N
Ph
(144 )
Acylation reactions of l-aryltetrazol-5-ones generally occur on the N(4)-position, but
acylation of the exocyclic oxygen atom occurred in up to 50% yield when the acylating
agent was 2-methylpropanoyl chloride (73ZC429). Fragmentation and rearrangement reac-
tions of 5-alkoxytetrazoles are discussed in Section 4.13.3.2 and alkylations of these systems
in Section 4.13.3.5.
N__N
ArOH + Cl< II
N.....N
Ph
Pd/C
H
N--N
ArH + O=< 'I
N.....N
Ph
4.13.4.4 Amino Substituents
Amino substituents on the tetrazole ring, whether located on the ring nitrogens or at the
5-carbon atom, generally behave normally giving the reactions expected for primary amines
(77AHC(21)323). Thus 1-aminotetrazole (145) gives normal nucleophilic addition-elimination
type reactions with electrophilic reagents such as aldehydes, sulfonyl halides and isocyanates
(Scheme 21). The reaction with acyl halides involves acetylation of the ring N(4)-position
as well as the amino group and gives rise to the substituted 1,3,4-oxadiazoles (146; Scheme
21) (66CB850). Heating of 5-aminotetrazole (147) with acid chlorides and anhydrides also
results in ring fragmentation to oxadiazoles. When this reaction was terminated early to
avoid oxadiazole formation, acylation of the 5-amino group occurred giving 5-
acylamidotetrazoles as products. The ring fragmentation in this reaction may involve a
second acylation at the N(2)-position of the ring as in the Huisgen reaction but the possibility
of a thermal fragmentation of the initial 5-acylamidotetrazole to an irnino nitrene has also
been postulated (76CPB2549). Treatment of 5-aminotetrazole with ethoxycarbonyl or benzoyl
isothiocyanate in pyridine gave the 5-amidotetrazoles (148; Scheme 21). The reaction
involved an addition at the 5-amino group followed by elimination of HSCN (73CB2925).
PhNHCONHN N
\ /
N=N
P
N--N
< II ArCH=O
N.....N
NH
2 COCl
(145)
1 ArS02 C1
ArCH=NN N
\ /
N=N
o
" N--N
RCNH < II
N.....N
H
(148)
o
RCONH( )R
N-N
RCOC!
ì RCONCS
N--N
NH 2 < II
N.....N
H
(147)
ArSO NHN N
2 \ I
N=N
(146)
Scheme 21
5-Aminotetrazole undergoes a number of useful condensation reactions with some
difunctional electrophilic reagents (Scheme 22). Cyclization with 2-alkyl-3-ethoxyacroleins
822
Tetrazoles
gave tetrazolo[1,5-a]pyrirnidines (149) in which the azido-tetrazole isomerism has been
directly detected (80AGE924). The reaction with diketene gave 7-methyltetrazolo[1,5-a]-
pyrimidin-5-one (150) (76CPB2549). Treatment of 5-aminotetrazole with methyl acrylate
gave cornpound (151; Scherne 22) arising frorn addition at the 1-NH site. Heating of
compound (151) resulted in a secondary cyclization to the 5-amino group giving the
tetrahydrotetrazolopyrirnidinone (152). Similar cyclization reactions were observed on
treatment of 5-arninotetrazole with acetylenedicarboxylic esters (ncBI03).
H
O NyNN
N il
-N
N-N
NH 1 < II
N--N
H
CO,R
N......N
II )NH 1
N.......N
CH 1 CH 2 C0 1 R
(151)
"
Ry?' ! 2CLO
O OEt EtOH.H,O L o
(152)
R C N......
A IN
N N
(149)
Me
NH
o N N
\ /
N=N
(150)
Scheme 22
Diazotization of 5-aminotetrazole with sodium nitrite in aqueous hydrochloric acid gives
the explosive diazonium salt (102). This diazoniurn compound is readily reduced to tetrazol-
5-ylhydrazine and it also undergoes dediazoniation reactions. Diazotization of ring N-
substituted 5-arninotetrazoles with sodium nitrite in 10% hydrochloric acid gave stable
prirnary nitrosamines of type (153). These nitrosarnines were readily reduced to hydrazines
and, when heated in aromatic hydrocarbon solvents, they displayed Gornberg-Bachmann
type homolysis reactions giving 5-aryltetrazoles. When 5-aminotetrazoles are diazotized in
a very dilute acidic medium, for exarnple pentyl nitrite in acetic acid, the products are often
triazenes of type (154) (75CRV241). Nitration of ring-substituted 5-arninotetrazoles occurs
on the exocyclic arnino group giving 5-nitroarninotetrazoles and this also occurs when the
5-arnino group is a secondary arnine. On treatment with oxidizing agents such as KMn04
and Ca{OClh, 5-arninotetrazoles undergo an oxidative dimerization to azotetrazoles, e.g.
(155) (B-67MI41300).
N......N
II )NHNO
N.......N
R
(153)
N......N
II )N=NOH
N.......N
R
MeN...... N N--NMe
I )N=NNH< I
N:::::'N N""N
(154)
R
N.-N
'I) >NH 1
N-N
CalDcn,
R R
N.-N N--N
II >N=N\ II
N-..N N......N
(155)
Therrnolysis of 5-aminotetrazole above 200 0 C gave hydrazoic acid (HN 3 ), hydrazonium
azide (HsNs), cyanamide and a polyrner (CH 3 N 3 )n and the reaction was sensitive to the
mediurn used (nCI(L)294). Thermal decornposition of explosive tetrazole-5-diazonium salts
(102) has been used to generate carbon in the atomic state (74JA 7830).
H
N__N
CI-N:=N\ II
N......N
(102)
[ N l
,,2
C
ð. N/ 'N
-
3N 2 +
Tetrazoles
823
4.13.4.5 Sulfur Substituents
Alkylation reactions of 1-substituted tetrazoline-5-thiones occur on the exocyclic sulfur
atom but acylation reactions may occur on the sulfur and also the ring nitrogens, usually
at N-4. However, acylation of I-substituted tetrazoline-5-thiones also occurs to some extent
at N-2 and low yields of rare 1,2-disubstituted tetrazolines of type (26) have been reported.
S- versus N-alkylation of the tetrazoline-5-thione system is comrnented on in Sections
4.13.2.1 and 4.13.3.5.
Disulfides (156) and (157) may be obtained by mild oxidation of tetrazoline-5-thiones
or by treatment with aryl halosulfides. Oxidation of the tetrazoline-5-thione group with
strong oxidizing agents such as KMn04 converts it into a sulfonic acid group, S03H
(77 AHC(21)323, B-67MI41300). Treatment of di(tetrazol-5-yl) disulfides (156) with diazoalkanes
gives the interesting rearranged compounds (158) as the rnajor products along with minor
yields of the S -alkylated compounds (159) (78CB566). Oxidative desulfurization of 1-
substituted tetrazole-5-thiones may be used to obtain 1-aryltetrazoles. Protection of the
5-thione function has also been achieved by treatment with hydroxybenzyl halides which
alkylate the sulfur atom and can subsequently be readily removed (77 AHC(21)323, 78JOC1197).
N_N N_N N N
" )SH H 2 0 2 ) II )SSAr c CISAr HSJ' "
N N N-.N \__N
R R R
(156) Ar = 1-substituted tetrazoI-5-yI
(157)
(156)
R'CHN 2 )
S R
^ N N
RN N-CH-S -< " +
\ /, N --N
N=N R 1
(158)
R R
N_N N N
)-SCHS-< "
......N l N--N
(159)
The 5-thiotetrazole system undergoes a number of interesting induced rearrangements
in which the tetrazole moiety migrates away from the sulfur atom. These include the
acid-promoted Smiles rearrangement (160 162; Scheme 23) which involves a migration
of the tetrazole ring from sulfur to nitrogen (76JOC3395). Migration of the tetrazole ring
from sulfur to oxygen was observed on alkylation of the compounds (161) with methyl
iodide and potassium carbonate in acetone when the products were the tetrazolyl ethers
(163; Scheme 23) (B-76MI41300). Recently the compound 1-phenyltetrazoline-5-thione has
been found to be a useful agent for inducing acylations and rnacrocyclic lactonizations. The
compound was first treated with t- butyl isocyanide which by insertion into the 5-SH bond
gave a thioformirnidate group, -SCH=NCMe3, at the tetrazole 5-position. Treatment of
this product with w-hydroxyalkanoic acids gave a thiocarboxylate group -SC(O)ROH, at
the tetrazole 5-position which was in equilibrium with the rearranged thione form containing
the w-hydroxyalkanoyl group HORCO at the tetrazole N-l position. Such compounds
were highly active acylating agents and the labile acyl moiety underwent lactonization with
the w-hydroxy group giving high yields of 16-, 17-, 18- and 20-membered lactones
(81AG(E)771).
N N
(X O-< 1/
I N--N
MeO SMe R
Mel
YH
R 1 .. N N H+
X S-<" --
N--N
R
(160) X=N; Y=NH; R1=H
(161) X=CH;Y=O;R 1 =OH
N N
ri'Y NH -< 1/
t ,\, __N
N S
H
(
K 2 C0 3 (for 161)
(163)
(162)
Scheme 23
4.13.4.6 Halogen Substituents
The essential reaction of halogen substituents at the tetrazole carbon atom is that of
nucleophilic displacement. This readily occurs because of thé 7T-deficient deactivated nature
824
Tetrazoles
of the ring. The use of the reaction in synthesis with nitrogen and oxygen nucleophiles and
the results of kinetic and mechanistic studies have already been discussed and illustrated
in Sections 4.13.3.1 and 4.13.3.4.2.
4.13.4.7 Alkyl Substituents
Alkyl groups on the tetrazole ring might be expected to show a significant degree of CH
lability due to the electron-withdrawing effect of the ring. This is observed to a certain
extent but in general the alkyl groups are not highly labile and, for example, reactions such
as condensations with benzaldehyde are not observed. Treatment of N-aryltetrazoles
containing a 5-alkyl substituent with phenyllithium or phenylsodium gives 5-(a -metallo-
alkyl)tetrazole derivatives (165) which undergo normal substitution reactions (Scheme 24).
The tetrazole 5-CH 2 moiety of 5-benzyltetrazoles may be oxidized to a carbonyl group
under controlled conditions to give 5-benzoyltetrazoles. Halogen atoms on a tetrazole
5-a -alkyl substituent undergo normal nucleophilic substitution reactions (e.g. Schemes 20
and 24) (75ZCI02, 76ZC90). Recently, an interesting rearrangement of the bis(l-aryltetrazol-
5-yl)dichloromethanes (166) to the 1,2,3-triazole compounds (167) has been reported on
heating the former with powdered copper in toluene (80Z0R2623). The electron-withdrawing
power of the tetrazole ring allowed for the formation of stable ylides of type (169). When
the tetrazole N-phenyl substituent was at the N(2)-position, the ylides were less stable due
to the reduced electron-withdrawing effect of the ring. The compounds (169) underwent
characteristic ylide substitution and addition reactions (Scheme 25) (76JCS(D)909).
L' COzH N
11 N--N I--N
RCH< II RCH--< \I
N--N N--N
Ar Ar
N--N
RCH 2 < II
N--N
Ar
(164)
PhLi
(165)
for R = CI 1 NH,Ph
1 R NCH2CH2C1
N--N
PhNHCH z < II
N--N
Ar
R'2NCHzCHz N
r --N
RCH--{ II
N--N
^r
Scheme 24
Ar CI Ar
N_N I N__N
II )-c--<- II
N-"N I N--N
(166)
å,Cu
toluene
Ar NAr
N_N
II N
N__ _
(167)
o x- Na2CO,
N--N
RCH-< \I
N--N
Ph
(168) R= H
o
N__N
Rë-< II
N--N
Ph
(169) R= H
""-CS 2
Me
o
N__N
C-< II
(MeShC N--N
Ph
;/ N C O j
í169) R = alkyl
(169) R = CONHPh
(170)
Scheme 25
Tetrazoles
825
4.13.5 SYNTHESIS
4.13.5.1 Ring Synthesis from Non-heterocycles
4.13.5.1.1 Formation of one bond
(i) Generation and cyclization of imidoyl azides: azidoazomethine-tetrazole isomerism
Molecules with an azide group bonded to a doubly bound carbon may exist in the acyclic
or cyclic forms (171) and (172). When X is an oxygen atom, the molecule exists in the
acyclic form (171) and when X is a sulfur atom, the cyclic form predominates. When X is
an N-R' moiety, an equilibrium of both forms may be present or either forrn may
RC =x x..... N
I == R 1/
N 3 N--N
(171) (172)
predominate. Thus the synthesis and cyclization of imidoyl azides (174; Scheme 26) from
imidoyl derivatives (173) containing a suitable leaving group is a principal route to 1-
substituted and 1,5-disubstituted tetrazoles (175) (77 AHC(21)323).
x
I N -
R!C=NR 2
-x-
(173)
R 2
R!-C=N:
I '
N + '\
)
W
(174 )
Scheme 26
N.....N
----+ R 1< /I
N--N
R 2
, (175)
The cyclization of imidoyl azides (174) usually occurs spontaneously. In the cyclization
the formation of the activated complex entails a movement of the imino lone-pair toward
the terminal azido nitrogen at the same time as a lone pair is being formed on the central
azido nitrogen at the expense of the azido terminal 7T-bond. The transition state resembles
the reactant azide and the geometrical changes to the tetrazole ring structure occur late on
the reaction profile (76JA16SS). The cyclization is an example of a 1,5-heteroelectrocyclization
operating in conformation with the principle of conservation of orbital symmetry and the
imidoyl azide tetrazole system is a nitrogen analogue of the hypothetical pentadienyl
anion-cyclopentenyl anion system (SOAG(E)947).
There are two main structural constraints on the cyclization. One of these is a stereoelec-
tronic effect which arises from the required cis orientation of the imino lone pair and the
azido group, The other arises from the electronic effects of substituents on the imino moiety.
Imidoyl azides in which the azido group and the imino lone pair are in a trans arrangement
do not cyc1ize without prior inversion in accordance with the requirements of the transition
state, e.g. compounds (176)-(178). In the compounds (178), interestingly, the azido form
is stabilized by an intramolecular hydrogen bond. These azides are readily converted into
tetrazoles by treatments which bring about the required geometrical isomerizations of the
imino moiety. For example, heating of the azides (176) with acyl chlorides gives a cyclization
to 1-(acyl)hydroxy-5-substituted tetrazole derivatives and heating or changing the pH of
the medium for the azides (177) and (178) gives ready cyclizations to the corresponding
tetrazoles (77 AHC(21)323, SOJOC4302, SOJCS(P2)S3S).
RC=N'
I "'-
N 3 OH
Ar!
"'- .,
C=N
/ "'-
N 3 N=CHAr 2
Ph
t o\H
H ;'
-N
N 3 'Et
h ç O .
-N'
,
N 3 Et
(176)
(177)
(178)
Electron-withdrawing substituents around the imino moiety favor the azido form while
electron-donating substituents enhance ring closure and favor the tetrazole form. Thus
compounds such as (179)-(181) exist as azides due to the deactivation of the imino group
(Scheme 27) and when the CF 3 group of compound (180) was replaced by an Me group,
826
Tetrazoles
the rnolecule existed as a tetrazole (69LA(725)29). Competitive cyclizations are possible in
the addition reactions of carbodiimides with azides or hydrazoic acid. The favored tetrazole
is that arising from cyclization of the intermediate imidoyl azide on to the nitrogen with
the stronger electron-donating substituent, e.g. (183). When one of the irnino nitrogen
atoms contains a strong deactivating group such as S02, e.g. compound (182), cyclization
does not occur to this nitrogen and the products are compounds of type (184; Scheme 27).
+
NH z
/
R-C SbCl 6
"
N 3
CF 3 C=NR
I
N 3
RSOzN=CR 1
I
N 3
(179)
(180) R = ß-naphthol
(181)
R'
N--N
I HN 3 1 '
RSOzN=C=NR ----. RSOzNHC= -R --+ RSOzNH 1\
/ N--N
(182) (183) (184)
Scheme 27
Among the environmental constraints on the cyclization of imidoyl azides are temperature
and the solvent system. Higher temperatures inhibit the cyclization and favor cleavage of
the tetrazole ring which is an endothermic process (73S123). The solvent system used for
the synthesis of imidoyl azides, and therefore also for their cyclization, may have a large
effect on the efficiency of the process. Traditional aqueous or alcoholic rnedia rnay give rise
to cornpetitive solvolysis of the imidoyl substrate (Scheme 28) and reactions in such rnedia
often involve long reaction times and tedious separations in the work-up. The use of dipolar
aprotic solvents avoids many of these difficulties and these solvents also activate the azide
anion through lack of hydroxylic solvation. Such rnedia are therefore favored for tetrazole
synthesis (76JOC1073). Acidic media in which the imidoyl azide might be protonated, e.g.
CF 3 C0 2 H, also inhibit tetrazole formation while basic media, where the electron density
on the imino moiety may be increased, e.g. through anion formation, tend to favor the
cyclization process.
NR 1
I' NaN, I'
R-C R-C
"- HoO "-
Cl N 3
NR 1 NR 1
I'
+R-C
"-
OH
1
1
R 1
N--N
R\ II +
N--N
o
\I
RCNHR 1
Scheme 28
Another important route to the imidoyl azide system is by diazotization of amidrazones
(185) via the hydrazine form (186; Scheme 29). The resultant imidoyl azides (187) generally
cyclize immediately to substituted tetrazoles (188) and a variety of such systems has been
RCNHR I
II
NNH z
(185)
R 1
HNO N--N
-" RC=NR 1 RC=NR 1 --+ R/ II
I I
NHNH z N 3 N"-''i
(186) (187) (188) R = alkyl, aryl
Scheme 29
prepared by this reaction. If the substituent R in compounds (187) is an alkylamino group
and Ria hydrogen atom, the resulting azide (189) may cyclize by path (a) or (b) (Scheme
30). Cyclization occurs to the imino nitrogen of highest electron density and path (a) is
favored.
Tetrazoles
827
R t
N--N
H 2 N\ "
N--N
H
H N--N
? R1-N-C=NH R1NH\ II
3}b N--N
(189) R t =Me, 11%
R 1 = Me, 65%
Scheme 30
The literature abounds in examples of 5-substituted tetrazoles, 1-substituted tetrazoles
and 1,5-disubstituted tetrazoles prepared via imidoyl azide intermediates and the reviews
mentioned in Section 4.13.1 may be consulted for further examples of these. When the
imidoyl azide moiety is part of another heterocyclic ring, the cyclization gives rise to fused
tetrazolo heterocycles and in many such systems both forms are observed in equilibrium
(77AHC(21)323). Systems of this type are discussed in Chapters 4.15, 4.36 and 4.37.
(ii) Cyclization of formazan and tetrazene derivatives
Acyclic units, other than irnidoyl azides which contain a potential tetrazole ring, are the
formazan, -N=N-C=N-NH-, and tetrazene, -C-NH-N=N-NH-, systems. Cyc-
lizations of derivatives of these rnay provide routes to substituted tetrazoles. Oxidation of
formazans (190) readily gives tetrazolium salts (191) in high yields (Scheme 31). If one of
the formazan N-substituents is a good leaving group, e.g. R 1 in compounds (190), the
cyclization may result in a cleavage of this group thereby giving rise to 2,5-disubstituted
tetrazoles (192; Scheme 31) (76ZC90). Syntheses of 2,5-disubstituted tetrazoles by this
method rnay also be achieved without isolation of the formazan interrnediates and, for
example, treatment of aldehyde toluene-p-sulfonylhydrazones with aromatic diazonium salts
in NaOH-EtOH or pyridine gives compounds (192) directly in up to 78 % yields (76BCJ1920).
Oxidation of tetrazolylformazans (193), obtained from the coupling of diazonium salts with
tetrazol-5-ylhydrazones, gives interesting tetrazoliurn ylides of type (194) (74KGS268,
73KGS1570). Oxidation of dithizone, [S-C(N=NPh)=N-NHPh]2 readily gives mesoionic
N""N
Ar/ I
\__NAr 1
(192)
R 1 = -SO,Ph; -C\NH,) = NH
.
ArC=NNHRl
I 1
N=NAr
'0'
---.
/N""NR t
Ar +1 I
N--NAr
(191)
(190)
Scheme 31
N--N
/I >N=NC=NNHAr
N......N I
H Ph
(193)
K 3 FctCN)6
N_N
'8LÑ-NAr
Þ N--T// \
N N
Ph
(194)
2,3-diphenyl-2H-tetrazoliurn-5-thiolate (9b) (61JA5023, 70JA1965). Treatment of 2-
diazoacetophenone (195) with potassiurn t-butoxide in t-butyl alcohol gave 5-benzoyl-Z-
phenacyltetrazole (196) as well as benzoic acid and 2-phenacyltetrazole from cleavage of
compound (196). The reaction has been explained in terms of an initial attack by base on
the terminal N of the diazo moiety followed by addition of the resulting species to an
PhCOCHN 2
KOCMe3
o
" l--NCH 2 COPh
PhC\ I
N""'N
(196)
(195)
\0 I
\I 0
Ph-C-C-N=N-OCMeJ
/
"Ñ-CH 2 COPh
(197)
Scheme 32
828
Tetrazoles
unchanged rnolecule of starting material ultirnately giving the interrnediate (197) which
cyclizes to compound (196; Scherne 32) (69CJC3997). Diazotization of substituted hydrazidines
leads to good yields of 2,S-disubstituted tetrazoles (198) and it was this reaction which led
to the first tetrazole derivative compound (198; R = CN, Ar = Ph) (1885CB1544). This was
subsequently converted into tetrazole by oxidative degradations.
RC= NNHAr
I
:"-:Hz
N"- N
HONO / --
þ R I
N--NAr
(198)
Treatrnent of acylhydrazines with diazonium salts gives rise to tetrazenes (199) which
can be readily dehydrated with base to give 1,S-disubstituted tetrazoles (Scheme 33). The
reaction is also effective with 1,2-diacylhydrazines since one of the acyl groups is cleaved
during the dehydrative cyclization, which may be conveniently carried out in situ without
isolation of the tetrazene. This reaction can be useful for the synthesis of l-aryltetrazoles
using 1,2-diforrnylhydrazine as substrate (B-67MI41300). Mesoionic tetrazolium S-oxides
(8a) are obtained on treatment of bislalkylsulfonyl)methanes with diazoniurn salts. Hydra-
zOnes of type (200) are also obtained frorn these reactions and the tetrazenes
(201) derived from these are considered to be precursors to the tetrazoles (Scheme 34)
(74Z0Rl725). Treatment of arene- and heteroarene-diazoniurn salts with diazomethane is
a related reaction which has been used to obtain 1-aryltetrazoles, e.g. compound (202).
The quantity of diazomethane used in this reaction is irnportant and if excess is available
rnethylation of the products may occur (70CB3284).
o 0
II II NaOH
RCNHNH 2 +Cl-NI Ar RCNHNHN=NAr ---+
(199)
N--N
R< II
N--N
Ar
Scheme 33
ArN, . ArN 2 '
IRS0 2 }zCH 2 ....-. (RS0 2 }zC=NNHAr ---.
(200)
(RS0 2 hC=NNAr
I
N
II
NAr
N
H 2 0 8 --NAr
Þ .O + I
-2RSO,H N--N
Ar
(201)
(8a)
Scheme 34
NQN2 + Cl-
N
H
CH,N,
--
n
N N^N N
H \ I
N=N
(202)
4.13.5.1.2 Formation of two bonds
(i) Addition of azide ion to nitrites, nitrWurn ions and isonitrites
The addition of the azide anion to nitriles is the rnost widely used route to S-substituted
tetrazoles (203). This reaction can prove highly sensitive to the nature of the cation M+
and the type of solvent used. It is also sensitive to the nature of the substituent R of the
nitrile and it works best when R contains electron-withdrawing groups. In hydroxylic or
alcoholic solvents the reaction usually requires a few days at reflux temperatures and the
yields may be rnedium or poor. The best conditions tend to be in dipolar aprotic solvents
such as DMF, using ammonium azide as the source of azide ion. The work-up procedures
RC=N + M+N3-
i, Ù. solvent
ìi. acid
N__N
R< II
N--N
H
(203)
Tetrazoles
829
involve the freeing of the anionic tetrazolate salt by acid treatment. The overall reaction
involves addition of hydra zoic acid (HN 3 ) but the use of azide ion and subsequent acid
treatment is more convenient than generating solutions of hydrazoic acid (77AHC(21)323,
73S71).
A wide range of 5-substituted tetrazoles has been prepared using this reaction (Scheme
35). The vinyltetrazoles (204) were readily obtained when Al(N 3 h was the source of azide
ion but the reaction failed when either NH 4 N 3 , UN 3 or NaN 3 was used. Treatment of
tetracyanoethylene with sodium azide at -20 o C in DMF gave the compound (205) and a
series of substituted 5-vinyltetrazoles (206) has also been reported. 5-Aryltetrazoles (207)
and heteroaryltetrazoles are readily prepared by this reaction either in dipolar aprotic
solvents or in solvents such as mixtures of butanol and acetic acid. Best results are obtained
when the aryl groups contain electron-withdrawing substituents. Trifluorornethyltetrazole
(209) was obtained in 75% yield at room temperature on treatment of trifluoroacetonitrile
with NaN 3 in acetonitrile as solvent, thereby illustrating the extent to which electron-
withdrawing groups enhance the nucleophilic azide attack (77 AHC(21)323, 73S71, B-67MI41300).
R 2
I
R 1 -C-CN4H
I
NH 2
(208)
RI D CN4H
(207)
!
N--N
F3 C < /I
N--N
/ (2:)
het-Ar-CN 4 H
.- RC=N +M+N 3 - ---+- R t OCN 4 H; R 1 SCN 4 H
.r/
x Y
"- /
C=C
/ "-
CN CN 4 H
(205) X=Y=CN
(206)
!
R P=NCN4H
CH 2 =CR 1 CN 4 H
(204)
Scheme 35
Treatment of nitrilium salts (210) with azide ion allows for the synthesis of a range of
1,5-disubstituted tetrazoles (211) (nJOc343). The scope of this reaction has been expanded
by the generation of nitrilium ions in solution from reactions of carbocations with nitriles.
In the presence of azide ion (Scheme 36) such reactions give rise to 1,5-disubstituted
tetrazole products. The reaction has been applied to carbocations generated by solvolysis
of leaving groups (Scherne 36; X = ArS03) and by addition of eleètrophiles to alkenes in
the presence of a nitrile solvent. For example the reaction of styrene with Br2 and AgCI0 4
in acetonitrile containing azide ion gives the tetrazole (213; Scheme 36) arising from trapping
of the bromoniurn-styrene species by the nitrile followed by addition of azide ion (7IACRIO).
+
R 1 C=NR 2 BF 4 -
NaN,
N--N
Þ R 1 < II
N--N
R 2
(210)
(211)
MeC=N + N,- jN--N
RX -4 R+ IIX- MeC=NR -- Me< II
N--N
R
(212)
(213) R = PhCHCHzBr
Scheme 36
Other useful tetrazole syntheses involving nitrilium ions include Beckmann reaction of
oximes in the presence of azide ion (83JCR(S)18) and the reaction between ketones and 2 mol
of hydrazoic acid in acidic rnedia, the Schmidt reaction (Scheme 37). For example, treatrnent
830
Tetrazoles
of acetophenone with 2 rnol of hydrazoic acid in sulfuric acid gives mainly 5-rnethyl-l-
phenyltetrazole (Scheme 37). When 1 mol of HN 3 is used in the Schmidt reaction, the
products are amides due to attack of water on the nitrilium intermediate. The reaction has
been used with steroidal ketones in recent years to synthesize compounds containing a
tetrazole ring fused to a steroid systern, e.g. compounds of type (214) (76JCSlPl)1210,
77 AHC(21)323).
-
o OH OH
\I H+ \I HN I
PhCMe --. PhCMe Ph-C-Me
I +
HN-N=N
i- H2o
..... - 2
MeC=NPh -- Ph,C-Me
"II
H2ý - N N=N
MeCONHPh N__N N__N
Me< II + Ph< II
N--N N--N
Ph Me
<5%
Scheme 37
SF 3 ) N __Nf\ \
CHC1 3 II '>--f'
N--J
(214)
The reaction of isocyanides with hydrazoic acid has long been one of the main routes to
I-substituted tetrazoles (Scherne 38). The reaction tends to be sluggish requiring long
periods of time but it is sensitive to acid catalysis and reaction times have been cut from
days to hours by simply adding one drop of acid to the mixture (69TLS081). The acid catalyzed
reaction involves the protonated isocyanide (215) which is attacked by azide ion. When
isocyanides are treated with azide ion in the presence of Mannich type reagents or enamines,
1,5-disubstituted tetrazoles are obtained with the enamine moiety bonded to the tetrazole
C-5 (Scherne 39). Thus treatment of isocyanides with formaldehyde and hydra zoic acid in
piperidine gives compounds of type (216). This reaction, which is known as the U gi reaction,
involves the addition of a Mannich type carbocation and azide ion to the isocyanide
(77 AHC(21)323, B-67MI41300).
00\ +2HN J
N--N
RN=ë + HN3 ---+- < II
1 H+ w- N
+ l
RN =C'H N 3 R
(215)
Scheme 38
RN=C + HCHO + NaN)
HNJ
H+
C N--N
. N-CH2 II
N--N
R
[RN=C +
lW
/
CNCH 2 0H 1 + NaN)]
(216)
Scheme 39
Tetrazoles
831
(ii) Cycloaddition of azides to -C -N and -C=N - systems
Cycloaddition of covalent azides with nitriles may lead to 1,5-disubstituted or 2,5-
disubstituted tetrazoles (Scheme 40) (69CRV359). When the nitrile contains electron-with-
drawing substituents such as perfluoroalkyl groups, the 1,5-disubstituted tetrazoles (217)
are readily formed. This reaction was not successful unless such strong electron-withdrawing
groups were present on the nitrile (621OC2085). When the azide was trimethylsilyl azide,
the alternative type of cycloaddition occurred with normal nitriles and gave the 2,5-
disubstituted tetrazoles (218) (68CB743, 66CB2512). Recently the 5-aryloxy-1-benzyl-
tetrazoles (219) have been reported to be forrned in high yields from the reaction of cyanic
esters, ArOCN, with benzyl azide under high pressure in nitromethane at 105 oC (Scheme
40) (80IZV2668). Cycloaddition of alkyl azides with nitrilium salts yields tetrazolium salts
such as compounds (220) (76TL1485).
N--N
R 1 N 3 + RC=N ---. R< II
N--N
/ (2 ) R=perfluoroalkyl
N--NR ' N__N
R< I ArO< II
w=-N Ì\ÍN
(218) R 1 = SiMe3 CH 2 Ph
(219)
Scheme 40
R ' N 3 + MeN=CCHR 2 ,FS0 3 - -+
R 1
N__N
R 2 ('H<+ II X-
N--N
Me
(220)
The reactions of covalent azides with the isocyanate system are summarized in Scheme
41. Addition of organic azides and azide ion to isocyanates occurs at the -N=C- bond
and gives l,4-disubstituted tetrazolin-5-ones (221; Scheme 41). The reaction of organic
azides with isothiocyanates is a complicated reaction giving a mixture of five different
products of which the tetrazoles (223) are minor constituents and the rernaining compounds
are sulfur heterocycles. Organometallic azides, and also azide ion, add to the -N=C-
RI -BZ x=s
R 2 =Ar
Bz
N--N
S=< II
N--N
Ar
Á s (22:
N--N
R1N3 + RZN=(,= X x=o þ o=( il
j 2 ;N
X - CMe R = R,Sn. R =Ph
: 2 (221)
R = H x=s
SnR 3
N--N
Y N S=< II
I J --N N--N
MezC{ II Ph
N--N
R Z
(226) Y = H
(226a) Y = NHz
Scheme 41
R
N__N
ArSOzN=< "
S......N
(224)
XO' ! R'. ,,",0,
SiMe3
I N__N
RN-< II
N--N
R Z
(223) :512.5%
(222)
832
Tetrazoles
bond of isothiocyanates to give tetrazoline-5-thiones such as compounds (222; S'cherne 41)
(73JOC675, 77JOC1l59, 74JA3973, 59JA3076). When the isothiocyanate contains a sulfonyl
rnoiety bonded to the N atom, the addition of organic azides occur on the C=S bond
giving thiatriazoles (224; Scheme 41) (see also Chapter 4.28). Trimethylsilyl azide adds to
carbodiirnides to give the substituted 5-(trimethylsilylarnino)tetrazoles (225) which could
be readily desilylated. Heating or aryl isocyanates with 2 rnol of trirnethylsilyl azide without
a solvent gave high yields of the tetrazolones (221; R 1 = H). This reaction appeared to
involve Initial addition of the silyl azide to the C=O bond giving an imidoyl azide,
Ar-N=C(N 3 )-OSiMe3, which cyclized and desilylated rapidly. No tetrazoles were
encountered in the reactions of trimethylsilyl azides with isothiocyanates and the products
were thiatriazoles and cyanamides encountered in low yields (SOJOC5130). Treatment of
keteneirnines with hydrazoic acid in ethereal solution, frorn which atmospheric oxygen was
excluded, gave a mixture of the tetrazoles (226) and (226a). The latter cornpounds arose
frorn addition of HN 3 to the C=C bond as well as the C=N bond and subsequent
fragmentation of the spiro 1,2,3-triazole adduct. In the presence of air compounds (226;
Y = 02H) were also formed and for R 2 = p-MeC 6 H 4 , the yields of cornpounds (226), (226a)
and (226; Y =02H) were 57, 26 and 16%, respectively (7SJOC3042).
When aldehyde hydrazones are heated with aryl azides in basic solution, 2,5-disubstituted
tetrazoles (227) are forrned along with a primary arnine derived from the azide (Scheme
42). The reaction works best when the aryl azide contains strong electron-withdrawing
groups, e.g. 2,4- (N0 2 hC 6 H 3 N 3 , and a mechanism involving a [3 + 2] cycloaddition of the
hydrazone anion with the azide followed by tautomerism and loss of ArNH- (Scheme 42)
has been proposed (6SJHC565, SOMI41300, 6ST37S7).
R 1 CH=NNHR 2
base
[ ;N-"'NR2 J
RICH I ---
'N:JNÑAr
N-"'NR 2
R 1 < I + ArNW
N:::::'N
(227) = 15% R 1 = C0 2 H, Ar, fur-2-yl,
indol-3-yl; R 2 = CONH 2 , CH 2 C0 2 Et, Ar
Scheme 42
4.13.5.2 Synthesis from Ring Interconversions
Interconversions of lower azole ring systems into substituted tetrazole rings have been
used to a limited extent to prepare tetrazole derivatives. The reactions usually involve basic
conditions with substrates which often have a labile proton. Exarnples of the rnain types
of ring interconversions which yield tetrazole derivatives are shown in Scherne 43. Heating
5-arylarninothiatriazoles with base gives tetrazoline-5-thiones (229) in a reaction involving
a competitive degradation to isothiocyanate and azide ion. When the aryl group of the
substrate (228) is replaced by an alkyl group, only the ring degradation is observed on
heating with base (B-67MI41300). The rnesoionic 1,2,3,4-oxatriazolium compounds (230) also
rearrange to a mesoionic tetrazole system, 1 ,3-diaryltetrazoliurn 5-oxides (8a), on treatrnent
with base (71ACS(25)625). Treatment of the 3-diazoamino-5-methylisoxazoles (231) with
base gives tetrazole derivatives of type (232) in an example of a general heterocyclic
rearrangement (64T461, 77 AHC(21)323). Rearrangements of 1,2,3-triazole systems containing
oxy and unsaturated nitrogen substituents at the 4- and 5-positions, e.g. compounds (233),
S-"'N
ArNH\ II
N--N
H
NaOH =< N-... N
----+ S \I
N--N
Ar
(229)
O-"'N
PhÑ(3 1
__NPh
base
----+
_ /;\NPh
O\ I
N--N
Ph
(8a)
M
ArNHN=N )
N-- O
NH,
N=N
Ar , )CH,COMe
N -
(232)
(230)
Ot ;
PhCON N
(233)
NaGEt
N N
H 0 2C\ I
N--NPh
(228)
(231)
(234)
Scheme 43
Tetrazoles
833
result in the formation of 2,5-disubstituted tetrazoles (Scheme 43) (B-67MI41300). Sorne
tetrazole derivatives have also been obtained by cleavage of oxazoline and oxazolidine
systems by treatment with sodium azide under acidic conditions (77AHC(21)323). These
reactions usually involve imidoyl azide type intermediates and are not strictly ring intercon-
versions but rather another method of generating imidoyl azides for tetrazole synthesis.
Addition of HN 3 to azirines to give azidoaziridines (235) has recently been reported. These
compounds, when heated to 80 o C, gave isomerizations to the tetrazoles (236) as well as
decornposition to nitriles, ArCN (77CB2939).
N 3
Ar--*yNH
C0 2 Et
(235)
4.13.5.3 Best Practical Methods
I!.
--
N--N
Ar( "
N--N
CH 2 C0 2 Et
(236)
One of the most important tetrazole derivatives for synthetic purposes is 5-aminotetrazole.
This is commercially available and can be easily synthesized from the reaction of cyanamide
with hydrazoic acid or by diazotization of arninoguanidine (Scheme 44) (B-67MI41300).
Diazotization of 5-aminotetrazole gives a reactive (and explosive) diazonium salt which can
be treated in situ to give tetrazole itself and normal dediazoniation reactions can be used
to prepare a range of 5-substituted tetrazoles (Scherne 44) (B-67MI41301, 77AHC(21)323).
Tetrazole can also be readily obtained in yields of 95% by hydrolysis of ethyI5-tetrazolecar-
boxylate with KOH followed by acidification with HCI0 4 (76ZC53). Treatment of nitriles
with azide ion is the best route to 5-substituted tetrazoles (237) and optimum conditions
are usually achieved by heating in DMF. The length of the heating period is determined
by the reactivity of the nitrile. A number of work-up procedures may be ernployed depending
upon the solubility of the tetrazole product (73S71). The most convenient route to 1,5-
disubstituted tetrazoles (238) involves displacement of imidoyl leaving groups (usually
halide) by azide ion. Imidoyl halides of type (238) are readily available from the dehydration
of ami des with PCl s and, without purification, they can be dissolved in DMF and the
resulting solution added slowly to a DMF solution of sodium azide (Scheme 45). After
appropriate stirring, the 1,5':disubstituted tetrazole can usually be precipitated by careful
addition of water (73S71).
jÍ'N__N HNO
H 2 N\ "
N--N
H
lHNO,
N--N
Ñ 2 ( "
N--N
H
NH 2 C=N
N--N
( "
N--N
H
H 3 PO,
--
HI
N--N
O=< "
N--N
H
RC=N + NaN.!
NH
II
NH 2 NHCNH 2
SnCl,
HCI
N--N
Þ NH 2 NH( "
N--N
H
,\x
N--N
x( II
N--N
H
X= CI, Br
Scheme 44
NH 4 0
DMF
N--N
R( "
N--N
H
(237)
834
Tetrazoles
o
/I
R 1 C-NHR 2
C!
pC! I
R1C= R2
NaN,
----
DMF
N__!\:
R'< 'I!
:,\--N
R'
(238)
(239)
Scheme 45
Direct alkylation of 5-substituted tetrazoles is often the best rnethod of obtaining sirnple
2,5-disubstituted tetrazoles. The 1,5-isorners, which are forrned as cornpetitive side products,
are usually separated with ease by fractional crystallization or better by colurnn chrornatogra-
phy on alurnina or silica gel which gives excellent separations of rnost tetrazole isorners
(81JCR(S) 174). Another convenient synthesis of 2,5-disubstituted tetrazoles (241) is the
forrnazan rnethod (Scherne 31). By coupling aldehyde arylsulfonylhydrazones (240) with
diazoniurn salts in basic solutions, compounds (241) rnay be obtained directly in yields of
up to 78% (76BCJ1920).
RCH=NNHS0 2 Ar + Ar'N/Cl-
(240)
l'aOI1
EtOH, 5 'C
:'\ N
R/ I
\__NAr '
(241)
For rnany special tetrazole derivatives there is often not a choice of routes and in general
the best synthetic routes are those already outlined in Sections 4.13.5.1.1 and 4.13.5.1.2.
4.13.6 APPLICATIONS
4.13.6.1 Biological and Medicinal Applications
There is now a large nurnber of separate tetrazole corn pounds reported specifically for
potential biological activity. A table of biologically active tetrazole types which provides a
base for a literature search has been drawn up (77 AHC(21)323). A recent review of the
rnedicinal applications of tetrazoles lists over 300 references (80MI41301). Biological activity
in tetrazoles is encountered due to the spëcial rnetabolisrn of the disubstituted tetrazole
systern and also because in 5-substituted tetrazole cornpounds the tetrazole ring is isosteric
with a carboxylic acid group and of cornparable acidity. Hence for all biologically active
rnolecules possessing a carboxylic acid group (C0 2 H) there is a theoretical nitrogen analogue
possessing a tetrazolic acid group (CN 4 H) and since the tetrazole rnoiety appears to be the
rnetabolically rnore stable of the two a considerable exploration of these rnolecules is
ongoing.
Tetrazole analogues of arnino acids have pKa values agreeing closely with those of the
corresponding arnino acids. A range of peptides with a tetrazole group incorporated has
been synthesized. For exarnple the tetrapeptide (242) was prepared and found to show
activity for stirnulating gastric acid secretion which was cornparahle to that of the norrnal
peptide (243). IR spectra of these aminotetrazolic acids suggested that they exist io the
zwitterionic forrn as do the carboxylic analogues (S9JOCl643, 69JCS(C)809, 7IT2317, 71T1783,
77 AHc(2l)323).
CH 2 X
I
z- Trp-Met-NH -CH -CO- Phe-NH 2
(242) X = CN 4 H
(243) X = C0 2 H
4.13.6.1.1 Analeptic activity (central nervous system)
In general 1,5-dialkyltetrazoles, in which the N(1)-substituent has four to six carbons,
show activity on the central nervous systern. When the 1- and 5-positions are bridged by
a rnethylene chain, the activity is rnaxirnized. Pentarnethylene tetrazole (244), which is
probably the rnost irnportant biologically active tetrazole, is a standard drug in this area
Tetrazoles
835
and is known as leptazol (and previously as metrazol). It is used as a stimulant for the
central nervous system and to counteract the effects of overdosage of barbiturates. It is
more effective when administered parenterally than orally due to a slow absorption from
the stomach after oral dosage. Its main metabolites are 6- and 8-hydroxypentalenetetrazoles,
the main elimination pathway of the drug being through biotransformation in the liver
(SOMI41301, 76JPSI03S, 74ZPC(355)1274). A number of other 1,5-disubstituted tetrazoles includ-
ing 1-alkyl-5-(alkoxy- or substituted-amino) and l-(alkoxy- or substituted-amino)-5-alkyl
systems and the derivatives (245) have displayed sedative activity on the central nervous
system (SOMI41301).
(244)
RJ ( N N......N
2 1 )-(CH z )" -< I
R N NíN
R' R4
(245)
O N
---- ,
N__J N
4.13.6.1.2 Anti-inflammatory activity
Anti-inflarnrnatory activity is shown by both N -substituted and N- unsubstituted
tetrazoles. The tetrazolylalkanoic acids (246) and the ortho-substituted 5-phenyltetrazoles
(247) represent examples of both classes. Some indole systerns with a 5-alkyltetrazole group
at the indole 3-position e.g. (248), also show antiinflarnmatory activity (SOMI41301,
77AHC(21)323). A series of substituted 2-(tetrazol-5-yl)benzoxazoles which showed
antiinflammatory activity were used in sunburn preventing and shaving preparations
(73GEP231423S).
(246)
N--N
Q1 V"
Ii N--N
H
NH
Ó
CF.,
(247)
(Q XCN l-I
I
::::::,...
R
(248) X = CH z , S(CHz)m OCH z
/N--N(CHz)zCOzH
Ar\ I
N N
4.13.6.1.3 Antimicrobial activity
A range of cephalosporin derivatives containing N-substituted tetrazole rings has been
prepared and found to display antibacterial activity (80MI41301). In such cornpounds the
tetrazole rnoiety is a substituent group on the underlying biologically active substrate.
However, some rnore sirnple tetrazole derivatives such as l-(p-substituted phenyl)tetrazoles
have also shown bactericidal properties (77USP4036S49). Sorne sirnple 5-arylarninotetrazoles
have been found to inhibit the growth of measles virus (70SAP6S04307).
4.13.6.1.4 Antilipernic activity
Nicotinic acid exhibits hypocholesteremic effects due to its lipolysis inhibitory activity.
The nitrogen analogue of nicotinic acid, corn pound (249), was a weaker in vitro lipolysis
inhibitor but it depressed free fatty acid levels in dogs with a longer retention time than
nicotinic acid. N-Methyl derivatives of cornpound (249) were inactive and in this case the
tetrazole group was paralleling the carboxylic acid group but with a longer retention tirne
due to its greater rnetabolic stability (67JMC149). The preferred tautorneric structure of
cornpound (249) in vitro was the I-NH forrn (S2JCR(S)122). Corn pound (250) represents
another exarnple of an active antilipernic tetrazole rnolecule which has progressed to clinical
tests (6SMI41301). The compound (249; R = CH 2 0CONHMe) has been claimed useful for
treating thrornbosis (72JAP(K)7242770).
836
Tetrazoles
N--N
01 7 II
I N --N
R ,,;:
N H
(249) R = H
CI N
o- SCH2-\=
H
(250)
4.13.6.1.5 Antiallergic activity
Derivatives of the chrornone systern (251) containing carboxy groups at C-2 exhibit
antiallergic properties and are used in the treatrnent of bronchial asthrna. Such activity was
also found in chrornone systerns bearing an N-unsubstituted tetrazole group at C-2, C-6 and
C-8. Chrornones with COzH groups at C-3 are inactive because of decreased acidity due
to intrarnolecular hydrogen bonding between the carboxylic acid group and the 4-carbonyl
oxygen. Such an effect was not present when the 3-C0 2 H group was replaced by a CN 4 H
group and 3-(tetrazol-5-yl)chrornones were about 2.5 tirnes as active as when the tetrazole
group was at the chrornone 2-position. The acidity of the tetrazole ring was essential for
the activity and N -rnethyltetrazol-5-ylchrornones were inactive (80MI41301). A large nurnber
of substituted chrornone derivatives with tetrazole groups located at C-2 and C-3 have
been prepared as potential antiallergic agents (77AHC(21)323).
ro o.
6?-" 3
I i
7 2
8 0
I
(251)
4.13.6.1.6 Other medicinal properties
Many other tetrazole systerns have been explored for biological activity. Areas where
significant activity has been encountered include antihypotensive activity, horrnonal activity
in tetrazole derivatives of potent non-steroidal oestrogens, bronchodilating effects, anti-
cholinergic agents, diuretic agents and radioprotective agents (80MI41301. 77AHC(2J)323).
4.13.6.1.7 Agricultural uses
Tetrazole compounds of type (246) containing aryl or heteroaryl substituents at C-5 and
alkanoic acid derivatives at N-2 are effective agents for regulating plant growth. For example
esters of compound (246; Ar = p-CIC 6 H 4 ) at application levels of 1000 p.p.rn. caused an
average shoot-length decrease in apple and plurn trees of 100 and 86%, respectively. A
range of tetrazole rnolecules of this type has been found useful as inhibitors of top growth
for vegetables, fruit trees, cereals and canes (73GEP2310049, 75USP3865570, 77AHC(21)323).
Application of 5-arninotetrazole to the soil at planting tirne has caused ternporary albinisrn
in sorne plants and reduction of tetrazoliurn salts to red colored forrnazans has been used
to detect the activity of reducing enzyrnes in seeds (B-67MI41300). In contrast to the
growth-inhibiting tetrazoles, growth acceleration for roots of plants has been claimed for
1-(1H -tetrazole)acetic acid (252) (71JAP(K)7135742).
N--N
< II
N--N
CH 2 C0 2 H
(252)
Tetrazoles
837
4.13.6.2 Non-biological Applications
4.13.6.2.1 Explosives and rocket propellants
Certain types of tetrazole derivatives are explosive and rnay be used as rocket propellants.
Substituted 5-cyanovinyltetrazoles (205) and their salts and polyrners have been clairned
as propellants (67USP3338915). Metallic salts of tetrazole derivatives such as cadrniurn
tetrazolyl azide, copper nitrotetrazole and lead azotetrazole can be used in prirners. Addition
of 5-aminotetrazole to nitrocellulose propellant powders rendered them flashless without
loss of propellant potential (B-67MI41301). The silver salt of 5-azidotetrazole was hypersensi-
tive to mechanical stimuli and highly explosive (71MI41300). Cornplexes of alurninum hydride
with 1,5- and 2,5-disubstituted tetrazoles (AIH 3 -tetrazole), prepared at low ternperatures in
ether, are also explosive (68USP3396170). Cornplexes of 5-nitrarnino- and 5-hydrazino-
tetrazole with Ni 2 + and Cu 2 + were explosive on heating over copper foil but Fe 2 + complexes
did not explode (79BAP21). Nitrotetrazoles are potential prirnary explosives and studies of the
deflagration to detonation transition for l-rnethyl- and 2-rnethyl-5-nitrotetrazoles are
reported and compared with PbN 3 (76MI41300).
4.13.6.2.2 Photography
Several types of tetrazole derivatives have proved useful in photography. Stabilization
of silver halide emulsions against fogging is displayed by substituted 5-rnercaptotetrazole
derivatives either as thione forms, such as 1-phenyltetrazoline-5-thione, or as 5-S-
substituted derivatives. Compound (253) is used as a cornponent of AgBr ernulsions in
color filrns where its function is to liberate an inhibitor against over-developrnent.
Bistetrazoles, separated by an alkylene chain with 2-5 carbon atorns, e.g.
HN 4 C-(CH 2 )n -CN 4 H, are also photographic antifoggants. In general, tetrazole derivatives
have been used as additives to improve the developrnent process and the presence of
N -substituted tetrazolinethione cornpounds increases the size of the silver particles and
reduces fogging when they are present in rnonolayer or multilayer silver halide filrns.
Tetrazolium salts can be used to produce colored irnages arising from their conversion into
forrnazans by reducing agents generated by exposure of iron(III) salts to light (70FRP1596860,
72GEP2060196, 69BEP722025, 79GEP2909190, B-67MI41300).
OC 16 HjJ N
COCH2S-< --
W. N
SOjH Ph
(253)
4.13.6.2.3 Miscellaneous applications
The cornplexing ability of a nurnber of substituted tetrazoline-5-thiones has rendered
these cornpounds useful for gravirnetric deterrninations of transition rnetals. Ions such as
Cu 2 +, Cu+, Ag +, Au+, Hg+ and Cd2+ can be detected in the 0.5-50 mg range by precipitation
(77 AHC(21)323).
Ditetrazoles of type (254), obtained from the reaction of potassiurn 5-phenyltetrazolate
with 1,2-dibromoethane, have proved useful for curing unsaturated elastomers in a cross-
linking process that involved thermal elirnination of N 2 frorn the ditetrazole to forrn
dinitrilirnine 1,3-dipoles (72MI41301).
(254)
o
ArS0 2 N^NBU
\ I
N=N
(255)
{j __N N-- N
" I; I
I N (CH2)6 V(CF2)j n
(256)
N N N N
Ar{ I I \ Ar
.- N - C H CH -N /
N 2 2 .....N
838
Tetrazoles
Polyrner cross-linking has also been achieved with l-arylsulfonyl-4-butyltetrazolin-5-ones
(255) and with bistetrazolyl-rn -phenylene rnolecules of this type (72GEP2226525). Tetrazole
polyrners of type (256) were prepared from therrnal reactions of diazides with dinitriles.
They are constituted as flexible fibers and have been clairned for use as therrnally stable
propellant binders and as plastics (68USP3386968).
4.14
Pentazoles
I. UGI
Technische Universität, München
4.14.1 INTRODUCTION
4.14.2 STRUCTURE
4.14.2.1 The First 15 N Experiment
4.14.2.2 Experimentum Cruds
4.14.2.3 Mechanistic Alternatives
4.14.3 REACTIVITY
4.14.3.1 Structure Dependence
4.14.3.2 Crystalline Arylpentazoles
4.14.3.3 Miscellaneous
4.14.3.4 Perspectives
839
839
839
841
841
843
843
843
844
845
4.14.1 INTRODUCTION
Most of the basic types of heteroarornatic compounds were discovered in the second half
of the last century, the classical age of organic chemistry (B-16MI41400). In the azole series,
their stability towards electrophiles and oxidants was observed to increase with the number
of nitrogen atorns in the heterocyclic ring, from pyrrole to tetrazole, for reaSOns which are
nowadays quite well understood (B-68MI41400). Thus, it has been a challenge to prepare
pentazole (1), the last member of the azole series. (Whether or not pentazole is a heterocycle
is debatable. All its ring atoms are of the same kind, and thus pentazole rnay be called a
homo cyclic system. On the other hand, within organic molecules, nitrogen is a 'heteroatom',
and pentazole is a ring of heteroatorns, which makes it a heterocycle.)
/N""N
HN I
'N""N
(1)
Until the second half of this century none of these efforts was successful (lOCB2904,
15CB410, 15CB1614, 57èB414, 57JA1249, 03CB2056) although some pentazole derivatives had
been produced unknowingly whenever an arenediazonium ion was reacted with azide to
form an aryl azide (1893CB86). Hantzsch (03CB2056) felt intuitively that pentazoles are forrned
by the latter reaction,,, and he tried to obtain arylpentazoles frorn arenediazoniurn com-
pounds. Since the pentazoles are short-lived under ordinary conditions, there was little
chance of discovering a pentazole by the experimental methods of classical organic chernistry
(64AHC(3)373).
4.14.2 STRUCTURE
4.14.2.1 The First 15 N Experiments
The first experimental evidence for the existence of a pentazole derivative came frorn
Clusius and Hürzeler (54HCA789) in Zürich. They studied the forrnation of phenyl azide
and nitrogen from benzenediazonium ion and azide by 15N-labelling techniques, and they
839
H40
Pentazoles
found that this reaction does not follow the general pattern of the Gries-Sandrneyer type
reactions (S3AG1SS). In a typical experirnent the aforementioned authors S4HCA789) diazot-
ized unlabelled aniline (with a natural 15 N abundance of 0.37%) with I N-labelled nitrite
(with 2.57% 15 N ), and they. reacted the resulting ß -labelled benzenediazoniurn ion (63JA12Z)
with un labelled azide. The 15 N content at the various sites of the products is given (percentage
in brackets) in Scherne 1.
PhNH 2 "NO, Þ PhN:=N N; Þ PhN=N=N + N:=N
t t ttt ttttt
;::. ;::. ;::. ;::. ;::. ;::. :g :g
'" '" '" '" '" '"
s c::ì <2 <j <2 <2 c:i <2 <2 <2
Scheme 1
Frorn the results of this and other 15N-labelling experiments Clusius and Hürzeler
(S4HCA789) concluded that the considered reaction cannot proceed by a uniform reaction
mechanisrn, and it rnust involve some competing, parallel reactions. They surnmarized their
results by Scherne 2. In this scherne the outcorne of the 15N-labelling experiments was
represented in terrns of three 'cornponents'.
PhN=N=N+N:=N <2%
+ _1' c d e a b
PhN:=N + N =N =N--.PhN=N =N + N:=N -85%
a h c d e a bed e
PhN=N=N+N:=N -lS%
a d h e
Scheme 2
In retrospect, it is easy to see why this representation was unfortunate. It was bound to
rnislead the investigators because both its first and second components correspond
in their labelling patterns to distinct mechanistic types of reactions, narnely the classical
Gries-Sandrneyer type and a reaction via benzenediazoazide (3; Scherne 3). Thus, Clusius
and Hürzeler (B-68MI41400) were led to assume that the third pattern of labellings rnust also
represent the 15 N -l abe lling pattern of a distinct reaction rnechanism. Therefore, in their
1954 paper (S4HCA789), these investigators excluded explicitly the intermediacy of phenyl-
pentazole (2) in the reaction of the benzenediazonium ion and azide, since a reaction via
(2) cannot be correlated with anyone of the patterns in Scherne 2. The third labelling
pattern would have corresponded to decomposition of (2) via (2a), while decornposition
via (2b) would have been 'forbidden'. Since this is not cornpatible with the structural
syrnrnetry of (2), the latter interpretation cannot be valid.
b b
. N_ N_
t. -Ne a/ -Ne
PhN ----+- PhN .-.+.
a, __Nd ,>:' _Nd
N 'N
c c
(2a)
(2b)
+ - /
PhN:=N+N=N=N
/N"'N
PhN I
, __N
N
(2) (30%)
/
PhN=N=N+N:=N
PhN=NN=N=N
(3) (70%)
Scheme 3
At the tirne when the above paper (54HCA789) appeared Huisgen and Ugi (S6AG70S) had
decided to approach the classical pentazole problern with rnodern rnethods. They studied
the reaction between o-quinone diazides and alurninum azide (S4ZN(B)49S, S4ZN(B)496).
in THF at low ternperatures by kinetic and gas volumetric rnethods. There was sorne
evidence for the formation of two distinct isorneric adducts from the above reactants. The
rnajor one decomposed with extrernely rapid evolution of nitrogen, while the decornposition
of the rninor isomer took place in a first-order reaction that could be followed quite
conveniently (S9TH41400). It was conjectured that these isorneric adducts might be a
diazoazide and a pentazole. Accordingly, we were prepared to see Scheme 3 as an alternative
interpretation of the 15N-experirnents by Clusius and Hürzeler (54HCA789).
Pentazoles
841
4.14.2.2 Experimentum Crucis
A kinetic investigation of the forrnation of phenyl azide and nitrogen frorn ben-
zenediazonium chloride and lithium azide in rnethanol at 0 oC revealed the forrnatÎon of
two distinct interrnediates (56AG705, 57CB2914, 59TH41400). The ratio of their relative arnounts
was approximately Q = k/ k O = 1: 2 (Schemes 3 and 4). Both of these interrnediates decorn-
posed by first-order reactions to form phenyl azide and nitrogen. At 0 oC the major inter-
mediate decomposes extrernely rapidly, while the minor one reacts at a rate which can
be conveniently followed by gas volumetric techniques. Below -25 oC the 'fast reaction'
still proceeds quite rapidly, whereas, on its tirne scale, the 'slow reaction' seems to cease
(59TH41400). Thus, it was apparent that under suitable conditions it would be possible to
study the two rnechanistic pathways separately by 15 N labelling rnethods. An experimentum
crucis was planned accordingly, and a collaboration between Zürich and Munich was
arranged for a joint execution of this experirnent (56AG753). Lithium azide and [ß_ 15 N]_
benzenediazonium chloride were combined at -25 oC in methoxyethanol. The 'first' nitrogen
evolved (see Scheme 4) was collected, and subsequently the reaction rnixture was warmed
up to 0-10 oc. Then a 'second' portion of nitrogen was produced (see Scheme 4), and taken
as a separate sarnple (k >>k'). After that, a solution of sodiurn hydroxide and sodium arsenite
in aqueous methoxyethanol was added. The phenyl azide was reductively cleaved into
aniline and nitrogen (5SCB2330), the 'third' nitrogen sample. The 15 N content of the three
sarnples was deterrnined by Clusius and Vecchi (56AG753) by an analysis of the rotational
fine structure of the electronic spectra. The present MS methods were not then available.
A similar experiment was carried out with p-ethoxybenzenediazonium chloride.
* k *
ArN=N-N=N=N ___ ArN=N=N+N=N
'first nitrogen'
.. * /:'
ArN=N+N3"
*
N_
/ -N k'
PhN I ___ ArN=N=N+N=N
\ -N , d . ,
N- secon mtrogen
Scheme 4
The results of both experirnents were fully in accord with Scheme 4. I!?- this scherne k
and k' are the rates of decomposition of (4) and (5) (see Scherne 5), and k and k O are the
hypothetical formation rates of (4) and (5), based on their relative arnounts Q.
4.14.2.3 Mechanistic Alternatives
The existing evidence is insufficient to decide whether the forrnation and decomposition
of the arylpentazoles (5) and the arenediazoazides (4) take place independently by sorne
[2 + 3] cycloaddition leading to (5; Scherne 5), or whether the arylpentazoles (5) are forrned
frorn the arenediazoazides (4) by 1,5-electrocyclization, as has been suggested by Huisgen
(Scheme 6) (SOAG(E)947, SOAG979). .
ArN=NN=N=N
.. _ /' (4)
ArN=N+N=N=N " ArN 3 +N z
'\. /N"'N /'
ArN I
\ __N
N
(5)
Scheme 5
ArN=N+N=N=Ñ -. ArN=NN=N=N -. ArN 3 +N z
(4)
1
/
/N"'N
ArN I
, __N
N
(5)
Scheme 6
842
Pentazoles
Neither of the two schernes can be cornpletely ruled out. lSN-Labelling experirnents,
conventional kinetic rneasurernents, or theoretical reasoning and MO calculations (61CB273)
do not lead to a clear-cut decision. Therefore, a 'two-phase experirnent' was designed in
order to obtain further evidence (63T1801). In 80% aqueous methanol (phase I) at -30 o C,
benzenediazoniurn chloride and lithiurn azide react to form benzenediazoazide (3) and
phenylpentazole (2) in the proportion of Or = 2.03:f: 0.05, and benzenediazoazide decorn-
poses at a rate of k r = 5.7 x 10- 3 s -1. The same reaction was carried out in the presence of
a second phase (phase II: carbon tetrachloride + n -hexane, 22 + 78 wt. %; approxirnately of
the sarne density as phase I, favoring intirnate contact of the liquid phases), with rapid
stirring. Although no rneasurable change in the ratio of benzenediazoazide to phenylpen-
tazole was observed (OI+/I = 1.96:f: 0.05), a considerably slower rate of benzenediazoazide
decornposition (kI+/I = 2.3 X 10- 3 S-I) was found. Frorn the fact that in the two-phase systern
the decornposition of benzenediazoazide is slower than in phase I alone, one can conclude
that in the two-phase systern, the benzenediazoazide formed in phase I rnigrates, in a
significant arnount, to phase II where it decomposes. A relevant difference between the
two rnechanisrns under discussion is that, whereas in the mechanisrn of Scherne 5 the
observed ratio 0 is independent of k (0 = k/ k O ; Scherne 4), in the alternative reaction
mechanism 0 is a function of k (0 = k/ k4...S)' As has been shown above, we have 0, "'" O'+/I
and k, > k'+11 which indicates that 0 is independent of k3. In combination with the fact
that in one-phase systerns the value of 0 depends upon the solvent (see Table 1), the
results of the 'two-phase experirnent' suggest an independent formation and decornposition
of benzenediazoazide and phenylpentazole according to Schemes 3-5.
Table 1 The Influence of Solvent upon the Ratio Q
at -30 oC
Solvent (wt. % ) Q
Methanol/water (SO + 50) 1.84
Methanol/water (75 + 25) 2.00
Methanol 2.45
Melhanol/THF (50 + 50) 2.77
Methanol/n-butanol (50+50) 2.92
Methanol/ n -butanol (10 + 90) 3.16
It could be objected that benzenediazoazide could exist in two isorneric forrns (e.g. cis
and trans forrns), one of which would very rapidly be transformed (Scheme 7) into phenyl-
pentazole, while the other isorner would decompose independently, and that the ratio in
which these isorneric forrns of benzenediazoazide are generated corresponds to the observed
ratio O. Yet such different chemical behavior of the stereoisomers of benzenediazoazide
has been shown to be improbable by Roberts (61CB273), who calculated the 'flexibility' of
the benzenediazoazide rnolecule. However, these MO calculations were of the sirnple HMO
type (61CB273), and their results ought to be taken cum grano salis. Thus the outcome of
the 'two-phase experirnent' yields some pertinent inforrnation, but it does not really
discriminate between the rnechanistic alternatives.
N
/Ý'
N
N_N/Ý'
ArN/Ý'
--- ArN 3 + N z
/
ArN; +N:ï
h N
ArN Y "N
II
N
II
N
Scheme 7
If one assurnes a sufficiently low relative interconversion rate for the stereoisornerÎC
diazoazides, Scherne 7, a variation of Scheme 5, becomes an attractive rnechanistic interpre-
tation based on the 'two-phase experiment' (64AHC(3)373, 63T1801).
IN"'N
+_____ ArN I
, -::oN
N
/'
i
4.14.3 REACTIVITY
Pentazoles
843
4.14.3.1 Structural Dependence
The relative tendency of formation, Q, and the rate of decornposition, k, of the
arylpentazoles in methanol at OOC (see Scherne 4) show a marked structure dependence
(see Table 2) (58CB531). The rate data for the rn- and p-substituted phenylpentazoles follow
a Hammett relationship (B-40MI41400, 53CRV(53)191) with p = + 1.01. The o-substituted
phenylpentazoles are not readily forrned and they decompose particularly fast.
Table 2 The Relative Yields and Rales of Decomposition of the
Arylpentazoles (MeOH, OOC).
Substituent on aryl group
4-NO z
4- Me 2 NH +
3-NO z
3-CI
4-CI
H
3-Me
3-HO
4-Me
4-HO
4-EtO
4-Me z N
4-0-
2-NO z
2-CI
2-Me
2,4,6- Me 3
Q k'x 10 4 (S-I)
6.1 59
51
4.6 36
3.3 23
3.5 12.1
3.2 8.4
2.6 7.6
2.0 7.1
1.9 5.6
1.9 3.2
1.9 3.0
1.2 1.7
0.9
24 92
8 86
3.4 31
13 23
4.14.3.2 Crystalline AryIpentazoles
The data in Table 2 provide some guidance as to which of the arylpentazoles have a
good chance of being isolatable, namely those listed in Table 3 (58CB2324). The main
problem in the preparation and purification of arylpentazoles is to find conditions under
which they do not decompose, but can be separated frorn the contarninating aryl azides
and inorganic compounds. The best system found for the isolation of the arylpentazoles
was the two-phase combination of aqueous methanol and petroleum ether at -40 to -20 oc.
Compound
Table 3 Crystalline Arylpentazoles
Decomposition point (oC)
Yield (%)
Phenylpentazole
p- Tolylpentazole
p -Chlorophenylpentazole
p- Methoxyphenylpentazole
p - Ethoxyphenylpentazole
p -Dimethylaminophenylpentazole
27
32
21
38
42
52
-5 to 3
2-5
8-10
13-15
26-29
50-54
After the forrnation of an arylpentazole from an arenediazonium chloride and sodiurn
azide, the accompanying aryl azide is soluble in the petroleum ether, and the sodium
chloride stays in the aqueous methanol, whereas generally the arylpentazole is not soluble
in anyone of the two solvent phases (56AG705, 57CB2914, 58CB2324). The pentazole can be
collected by filtration. Note that the crystalline arylpentazoles tend to explode violently at
temperatures above their decomposition points (see Table 3); they should be handled with
great care, in small amounts and at low temperatures.
With the isolation of the crystalline arylpentazoles some experirnents become possible
whicb require pure pentazole derivatives. Thus, crystalline 15 N -labelled p- ethoxyphenylpen-
tazole was used to determine its molecular weight and to confirm its chernical structure
according to Scheme 8 (59CBI864). Recently, Wallis and Dunitry (83CC910) have determined
the structure of p-dimethylaminophenylpentazole by X-ray crystallography.
844
Pentazoles
100%
15
O N
I ""N
EtO Ij , N,__N
- N
50% 50%
0 " 15 15 '
----+ EtO 'I _ '\ N=N=N + N=N
Na,sncoH'41
50%
EtO O NH2 + 15 =N
Scheme 8
The UV spectra of the (p-substituted phenyl)pentazoles indicate that, as a substituent
of a benzenoid systern, the pentazolyl group is capable of strongly interacting with electron-
rich substituents on the phenyl group, in analogy to the nitro group. When this study took
place, PE spectra were not available; it would be interesting to study the PE spectra of the
arylpentazoles. According to kinetic studies with pure phenylpentazole, the solvent has a
strong influence on its rate of decornposition (58CB2324); a solvent of low polarity enhances
the rate of decornposition (see Table 4).
Table 4 The Decomposition of Phenylpentazole in Various Solvents
Sa/vent
k'X10 4 (s-l)
n-Hexane
Carbon tetrachloride
n-Butanol
Toluene
THF
Methanol
Chloroform
Acetone
Acetonilrile
Formic acid
Carbon tetrachloride/acetonitrile (20)
Carbon tetrachloride/acetonitrile (40)
Carbon tetrachloride/acetonitrile (60)
Carbon tetrachloride/acetonitrile (80)
Melhanol/water (50)
Acelic acid/water (25)
45.2
34.0
16.9
12.4
10.4
9.8
8.9
7.7
4.1
2.3
15.1
11.2
8.0
7.1
5.7
5.8
4.14.3.3 Miscellaneous
In view of the enthalpies and activation energies of the decornposition of arylpentazoles,
the activation energy of the reverse process (100-120 kJ rnol- 1 ), narnely the formation of
arylpentazoles frorn aryl azides and nitrogen, should not be high enough to prohibit this
reaction. In order to determine whether or not the decornposition of arylpentazoles is
reversible, a [ß- 1s N]-p-ethoxyphenyl azide filrn on charcoal was exposed to unlabelled
nitrogen (45-50 0 C, 380 atrn., 100 h), but no exchange of IS N occurred (59TH41400). This
excludes the possibility of reversible forrnation of an arylpentazole under the given condi-
tions. Kinetic evidence as well as Is N -l abe lling studies of the reaction between diazomethane
and hydrazoic acid indicate that the forrnation of rnethyl azide proceeds neither via
rnethanediazoazide nor via rnethylpentazole, but according to Scheme 9 (58HCA1823).
CH 2 =N=N + HN=N=N -. MeN=N=N + N::=N
ab ede abede
Scheme 9
It seerns worthwhile to investigate whether or not the arylpentazoles forrn transition
rnetal complexes, for example of type (7). These could be converted into pentazole cornplexes
(8) without destruction of the pentazole systern. Unsubstituted pentazole (1) would be
expected to be a strong acid with a highly 'arornatic' anion (6) which could possibly forrn
ferrocene analogs such as MJI(Nsh, where Mil represents a divalent metal ion. Unfortunately,
it has not been possible to investigate the properties of unsubstituted pentazoles, since neither
Pentazoles
845
oxidative degradation of the carbocyclic rnoiety, nor reductive cleavage of the N-C bond
converted arylpentazoles into pentazole. Ozonization of p-dirnethylarninophenylpentazole
in rnethylene chloride at approxirnately -60 oC caused decornposition of both the substituted
benzene and the pentazole ring (S9TH41401, 61AGl72). Attempted cleavage of the N -C bond
of phenylpentazole by reduction with sodium in liquid arnrnonia led to destruction of the
pentazole ring (61AGl72); aniline and nitrogen were forrned, presurnably via a 2,3-dihydrQ
intermediate (see Scheme 11). A relevant analogy would seern to be the reductive degradation
of the tetrazole ring (40JA2002). An ab initio LCAO-SCF-MO cornparison of (1) and (6) has
been carried out recently (83CJC143S).
Ar
N/N<N N
--+ N(J'N
\\ I II \ ï I
Nï N N"'-N
I
M M
I I
Ln Lm
(7) (8)
Scheme 10
N
/ .:::oN
N - 1
'æ N
(6)
O NH 2 +2N 2 -- O N :: -I- 0 +(6)
Scheme 11
4.14.3.4 Perspectives
Active experimental research in pentazole chernistry ceased about 20 years ago, not
because all the problems in this field had been solved, but mainly because no new inves-
tigators have entered the field. Probably too few are cognizant of the unsolved problems
of pentazole chemistry. The present author left the field because he was distracted from it
by the many new challenging problems of which he becarne aware when he was confronted
with isocyanide chemistry (56AG705, 57CB2914, 62AG(E)8, 62AG9, B-71MI414QO, B-75MI41400).
This arose from an attempt to prepare sorne aryl isocyanides as starting materials for
aryltetrazoles. Their UV spectra were of interest for cornparison with those of the corre-
sponding pentazoles (56AG70S, 57CB2914). The lack of preparative routes to pure isocyanides
was the first step on the way to the realization that isocyanide chernistry was still terra
incognita, with many areas waiting to be explored (62AG9, 62AG(E)8, B-71MI41400, B-75MI41400,
B-81MI41400).
4.15
Triazoles and Tetrazoles with Fused
Six-membered Rings
s. w. SCHNELLER
University of South Florida
4.15.1 INTRODUCTION
4.15.2 STRUCTURE
4.15.2.1 [1,2,4 lTriazalapyridines
4.15.2.2 [1,2,3lTriazalapyridines
4.15.2.3 [1,2,4lTriazalapyridazínes and [1,2,3lTriazalapyridazine
4.15.2.4 [1,2,4 ]Triazalapyrimidines
4.15.2.5 [1,2,3 lTriazalapyrimidines
4.15.2.6 [1,2,4lTriazalapyrazínes and [1,2,3]Triazalapyrazínes
4.15.2.7 [1,2,4]Triazalatriazínes
4.15.2.8 Tetrazalapyridines and Related Systems
4.15.2.8.1 Tetrazala[1,5-a]pyridine
4.15.2.8.2 Tetrazala[1,5-b]pyridazíne
4.15.2.8.3 Tetrazala[1,5-a]pyrimidine and tetrazala[1,5-c]pyrimidine
4.15.2.8.4 Tetrazala[1,5-a]pyrazine
4.15.2.8.5 Tetrazala[1,5-b][1,2,4]triazíne and tetrazala[5,1-f1[1,2,4]triazíne
4.15.3 REACTIVITY
4.15.3.1 [1,2,4]Triazalapyridines and their Fused Benza Derivatives
4.15.3.1.1 [1,2,4lTriazala[4,3-a]pyridine
4.15.3.1.2 [1,2,4]Triazala[1,5-a]pyridine
4.15.3.1.3 [1,2,4]Triazalaquinalines and [1,2,4]triazalaisaquinalines
4.15.3.2 [1,2,3]Triazalapyridines and their Fused Benza Derivatives
4.15.3.2.1 [1, 2, 3lTriazala[1,5-a]pyridine
4.15.3.2.2 [1,2,3lTriazala[4,5-b]pyridine and [1,2,3]triazala[4,5-c]pyridine
4.15.3.2.3 [1, 2, 3]Triazala[1, 5-a]quinaline
4.15.3.2.4 [1,2,3 lTriazala[5,1-a]isaquinaline
4.15.3.3 [1,2,4lTriazalapyridazines and their Fused Benza Derivatives
4.15.3.3.1 [1,2,4 lTriazala[ 4,3 -b ]pyridazíne
4.15.3.3.2 [1,2,4 lTriazala[3,4-a]phthalazíne
4.15.3.3.3 [1,2,4lTriazala[1,5-b]pyridazine
4.15.3.4 [1,2,3 ]Triazala[4,5-d]pyridazine
4.15.3.5 [1,2,4]Triazalapyrimidines and their Fused Benza Derivatives
4.15.3.5.1 [1 ,2,4]Triazala[ 4,3-a]pyrimidine and [1 ,2,4]triazala[ 4,3-c]pyrimidine
4.15.3.5.2 [1,2,4lTriazala[1,5-a]pyrimidine
4.15.3.5.3 [1,2,4 lTriazala[1,5-c]pyrimidine
4.15.3.5.4 [1,2,4lTriazala[4,3-c]quinazaline and [1,2,4]triazala[1,5-c]quinazaline
4.15.3.5.5 [1,2,4 lTriazala[1 ,5-a]quinazaline
4.15.3.5.6 [1,2,4lTriazaliJ[5,1-b]quinazaline
4.15.3.6 [1,2,3lTriazalapyrimidines and their Fused Benza Derivatives
4.15.3.6.1 [1,2,3 lTriazala[1,5-a]pyrimidine
4.15.3.6.2 [1,2,3 lTriazala[1,5-c]pyrimidine
4.15.3.6.3 [1,2,3 lTriazala[4,5-d]pyrimidine
4.15.3.6.4 [1,2,3 lTriazala[1 ,5-a]quinazaline
4.15.3.7 Triazalapyrazínes and their Fused Benza Derivatives
4.15.3.7.1 [1,2,4lTriazala[4,3-a]pyrazíne
4.15.3.7.2 [1,2,4lTriazala[1,5-a]pyrazine
4.15.3.7.3 [1,2,3lTriazala[1,5-a]pyrazíne
4.15.3.7.4 [1,2,3lTriazala[4,5-b]pyrazine
4.15.3.7.5 [1,2,4lTriazala[4,3-a]quinaxaline
4.15.3.8 [1,2,4]Triazalatriazínes
4.15.3.8.1 [1,2,4 lTriazala[1 ,2,4 ]triazínes
4.15.3.8.2 [1,2,4]Triazala[1,3,5]triazines
847
849
853
853
856
858
858
858
859
859
859
860
860
860
860
861
861
861
861
864
865
866
866
867
868
868
868
868
870
871
871
872
872
872
873
873
873
874
874
874
875
875
876
876
876
877
877
878
878
878
878
878
848
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.3.9 Tetraza/apyridines and their Fused Benza Derivatives
4.15.3.9.1 Tetraza/a[1,5-aJpyridine
4.15.3.9.2 Tetraza/a[1,5-b]isaquina/ine
4.15.3.9.3 Tetraza/a[1,5-a]quina/ine
4.15.3.9.4 Tetraza/a[5,I-a]isaquina/ine
4.15.3.10 Tetraza/a[1 ,5-b ]pyridazine
4.15.3.11 Tetraza/apyrimidines and their Fused Benza Derivatives
4.15.3.11.1 Tetraza/a[1,5-aJpyrimidine
4.15.3.11.2 Tetraza/a[1,5-c]pyrimidine
4.15.3.11.3 Tetraza/a[J,5-a]quinaza/ine
4.15.3.11.4 Tetraza/a[1,5-c]quinaza/ine
4.15.3.12 Tetraza/a[1,5-a]pyrazine and Tetraza/a[1,5-a]quinaxa/ine
4.15.3.12.1 Tetraza/a[1,5-a]pyrazine
4.15.3.12.2 Tetraza/a[1,5-a]quinaxa/ine
4.15.4 SYNTHESIS
4.15.4.1 [l,2,4]Triaza/apyridines and their Fused Benza Derivatives
4.15.4.1.1 [1,2,4]Triaza/a[4,3-aJpyridine
4.15.4.1.2 [1,2,4 ]Triaza/a[1,5 -a]pyridine
4.15.4.1.3 [1,2,4]Triaza/aquina/ines and [1,2,4]triaza/aisaquina/ines
4.15.4.2 [1,2,3]Triaza/apyridines and their Fused Bènza Derivatives
4.15.4.2.1 [1,2,3 ]Triaza/a[1,5-aJpyridine
4.15.4.2.2 [1,2,3 ]Triaza/a[4,5-b]pyridine and [1,2,3 ]triaza/a[4,5-cJpyridine
4.15.4.2.3 [1.2,3]Triaza/a[1,5-alquina/ine and [1,2,3]triaza/a[5,1-a]isoquina/ine
4.15.4.3 [1,2,4]Triaza/apyridazines and their Fused Benza Derivatives
4.15.4.3.1 [1 ,2,4]Triaza/a[ 4,3-b]pyridazine
4.15.4.3.2 [1,2,4 ]Triaza/a[1,5-b]pyridazine
4.15.4.4 [1,2,3 ]Triaza/a[4,5-d]pyridazine
4.15.4.5 {I,2,4]Triaza/opyrimidines and their Fused Benza Derivatives
4.15.4.5.1 [1,2,4]Triaza/a[4,3-a]pyrimidine
4.15.4.5.2 [1,2,4]Triaza/a[1,5-a]pyrimidine
4.15.4.5.3 [1,2,4]Triaza/a[4,3-cJpyrimidine
4.15.4.5.4 [1,2,4 ]Triaza/a{1 ,5-c]pyrimidine
4.15.4.5.5 [1,2,4 ]Triaza/a[4,3-clquinaza/ine and [1,2,4 ]triaza/a[1,5-c]quinaza/ine
4.15.4.5.6 [1,2,4 ]Triaza/a[1,5-aJquinaza/ine
4.15.4.5.7 [1,2,4 ]Triaza/a[5, 1-b lquinaza/ine
4.15.4.5.8 [1,2,4]Triaza/a[4,3-a]quinaza/ine
4.15.4.6 [1,2,3]Triaza/apyrimidines and their Fused Benza Derivatives
4.15.4.6.1 [1,2,3]Triaza/a[1,5-a]pyrimidine
4.15.4.6.2 [1,2,3 ]Triaza/a[1,5-c]pyrimidine
4.15.4.6.3 [1,2,3]Triaza/a[4,5-dJpyrimidine
4.15.4.6.4 [J,2,3]Triaza/a[1,5-aJquinaza/ine
4.15.4.6.5 [1,2,3]Triaza/o[1,5-clquinaza/ine
4.15.4.7 Triaza/apyrazines and their Fused Benza Derivatives
4.15.4.7.1 [1,2,4 ]Triaza/a[4,3-a]pyrazine
4.15.4.7.2 [1,2,4TTriaza/o[1,5-a]pyrazine
4.15.4.7.3 [1,2,3]Triazo/a[1,5-a]pyrazine
4.15.4.7.4 [1,2,3]Triaza/o[4,5-b]pyrazine
4.15.4.7.5 [1,2,4 ]Triaza/a[4,3-aJquinaxa/ine
4.15.4.7.6 [J,2,3]Triaza/o[1,5-aJquinaxa/ine
4.15.4.8 [1,2,4]Triaza/atriazines
4.15.4.8.1 [1,2,4 ]Triaza/o[ 4,3 -b][1 ,2,4 ]triazine
4.15.4.8.2 [1,2,4 ]Triaza/o[3,4-c][I,2,4]triazine
4.15.4.8.3 [J,2,4]Triaza/a[5,I-c][1,2,4]triazine
4.15.4.8.4 [1 ,2,4]Triaza/a[4,3-d][I,2,4]triazine
4.15.4.8.5 [1,2,4]Triazo/a[3,4-f][1,2,4]triazine
4.15.4.8.6 [1, 2,4]Triaza/a[1,5-b][1,2,4]triazine
4.15.4.8.7 [1,2,4 ]Triaza/o[J,5-d][1,2,4]triazine
4.15.4.8.8 [1, 2,4]Triaza/o[4,3-a][I,3,5]triazine
4.15.4.8.9 [1,2,4 ]Triaza/a[1,5 -a][I,3,5]triazine
4.15.4.9 Tetraza/apyridines and their Fused Benza Derivatives
4.15.4.9.1 Tetraza/a[1,5 -a ]pyridine
4.15.4.9.2 Tetraz%[1,5-b ]isaquinaline
4.15.4.9.3 Tetraz%[1,5-a]quino/ine
4.15.4.9.4 Tetrazo/a[5,I-a]isaquina/ine
4.15.4.10 Tetraza/a[l,5-b]pyridazines and their Fused Benza Derivatives
4.15.4.11 Tetraza/apyrimidines and their Fused Benza Derivatives
4.15.4.1/./ Tetraza/a[1,5-a]pyrimidine
4.15.4.11.2 Tetraza/a[1,5-c]pyrimidine
4.15.4.11.3 Tetraza/a[1,5-a]quinaza/ine
4.15.4.11.4 Tetraza/a[1,5-c]quinaza/ine
4.15.4.12 Tetraza/a[1,5-a]pyrazine and Tetraza/a[1,5-a]quinaxa/ine
4.15.4.13 Tetrazo/atriazines
879
879
879
879
879
880
880
880
881
881
881
881
881
882
882
882
882
884
886
887
887
887
888
888
888
889
890
890
890
890
891
891
892
893
893
893
894
894
894
894
895
895
895
895
896
897
897
898
898
898
898
899
899
899
899
900
900
900
900
901
901
901
902
902
902
902
902
902
902
903
903
903
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.4.13.1 Tetrazala[1,5-b][1,2,4 ]triazine
4.15.4.13.2 Tetrazala[5,1-c][1,2,4 ]triazine
4.15.4.13.3 Tetrazala[1,5-d][1,2,4 ]triazine
4.15.4.13.4 Tetrazala[5,1-f][1,2,4]triazine
4.15.5 APPLICATIONS
849
903
903
903
903
903
4.15.1 INTRODUCflON
In planning a chapter such as this whose breadth is large and whose space is restricted,
a decision had to be made as to which 'six-mernbered rings are the most important upon
their fusion to triazoles and tetrazoles. Based on an analysis of those ring systems attracting
the greatest attention in the literature, this chapter will focus on triazoles and tetrazoles
fused to pyridines (1,2,8-10 and 46), pyridazines (13-15 and 50), pyrirnidines (18-21,
26-28, 53 and 54), pyrazines (31-34 and 57) and triazines (37-45, 59-62). Both 1,2,4-
and 1,2,3-triazoles are considered and, in rnost cases, the two fused rings have one nitrogen
atom in common. The only exceptions to this are generally those cases where a fused
1,2,3-triazole represents part of an 8-azapurine, a series that has no bridgehead nitrogen.
[1,2,4 ]Triazolopyridines
a "" \
2N
::::,...NV
(1)
[1,2,4 ]Triazolo[ 4,3 -a ]pyridine
o:r ""NN
N-J'
I
(3)
[1,2,4]Triazolo[ 4,3-a ]quinoline
a ""
N 4 )
::::,... -N
(2)
[1,2,4 ]Triazolo[ 1 ,5 -a ]pyridine
N\
N-J'N
(4)
[1,2,4]Triazolo[ 4,3-b ]isoquinoline
C(r
I N
"" \
::::,... N-J'N
(5)
[1,2,4 ]Triazolo[3,4-a ]isoquinoline
N
rC)
(6)
[1,2,4]Triazolo[1,S-b ]isoquinoline
l(x
I N
::::,... ;)
(7)
[1 ,2,4]Triazolo[ 5, 1-a ]isoq uinoline
[1,2,3 ]Triazolopyridines
\N
4)l_ I
N N
H
(9)
[1,2,3 ]Triazolo[ 4,5 -b ]pyridine
(8)
[1,2,3 ]Triazolo[1, S-a ]pyridine
{):)
aN-ll
(11)
[1,2,3]Triazolo[ 1 ,5 -a ]quinoline
H
(t \
N S I II N
::,.... N
(10)
[1,2,3 ]Triazolo[ 4,5 -c ]pyridine
1.-9
::::,... ::r,t
(12)
[1,2,3]Triazolo[S, 1-a ]ìsoquìnoline
850
Triazoles and Tetrazoles with Fused Six-membered Rings
\
N N--.J'N
(13)
r 1,2,4 ]Triazolo[ 4,3-b ]pyridazine
Triazolopyridazines
N) - >
(14)
[1,2,4]Triazolo[I,5-b ]pyridazine
N\
"..-N--.J'N
N
(16)
[1,2,4 ]Triazolo[ 4,3-b ]cinnoline
N N
r'BY1
N
(18)
[1.2,4]Triazolo[ 4,3-a ]pyrimidine
('y \
NO N 4 31/
-N
(21)
[1,2,4 ]Triazolo[ 1,5 -c ]pyrimidine
:r N
I }
N::--, N
(15)
[1,2,3 ]Triazolo[ 4,5 -d]pyridazine
"":::
--9 N
;..- \
::--, ..-N--.J'N
N
(17)
[1,2,4 ]Triazolo[3 ,4-a ]phthalazine
[1,2,4 ]Triazolopyrimidines
\
I, ,- 2N
N NtJ'
(19)
[1,2,4 ]Triazolo[ 4,3 -c ]pyrimidine
Çy "":::
--9 N
,.... \
N
N N--.J'
(22)
[1,2,4 ]Triazolo[ 4,3 -c ]quinazoline
Qy "":::
--9 N
;..- >
N N_J
(24)
[I,2,4]Triazolo[I,5-c ]quinazoline
N
G 4
I 2N
::::,... BN_N"
(26)
[1,2,3 ]Triazolo[ 1,5 -a ]pyrimidine
N N
r 4 'Y3\
N_N'/
(20)
[1 ,2,4]Triazolo[ 1,5 -a ]pyrimidine
& NYN;
""::: N-N
I
--9
(23)
[1 ,2,4]Triazolo[ 1,5-a ]quinazoline
NyN>
N-N
(25)
[1,2,4 ]Triazolo[ 5, 1-b ]quinazoline
[ l,2,3]Triazolopyrimidines
I' 1- 2'N
N N t
(27)
[l,2,3]Triazolo[I,5-c ]pyrimidine
I N )N
Q N-N'
(29)
[1,2,3 ]Triazolo[I,5-a ]quinazoline
:J: N
N I N
'
N N
H
(28)
[1 ,2,3]Triazolo[ 4,5-d]pyrimidine
N
N N_N'
(30)
[1,2,3]Triazolo[1,5-c ]quinazoline
Triazoles and Tetrazoles with Fused Six-membered Rings
Nry \
N0N
(31)
[1,2,4]Triazolo[ 4,3-a ]pyrazine
rN x \
I ,/N
N N
(34)
[1,2,3]TriazoJo[ 4,5-b ]pyrazine
N N
rSY'iN
5 /NV
N
(37)
[1,2,4]TriazoJo[ 4,3-b ][1,2,4]triazine
N
r 7 )
A ;.N
Nt 4 N
\ 2 I
N='
(40)
[1,2,4 ]Triazolo[3,4-Hl ,2,4 ]triazine
F N
3 \
N' 4N
l:7J
N
(43)
[1,2,4 ]Triazolo[ 1 ,5-d][ 1 ,2,4 ]triazine
TriazoJopyrazines
Nry '\
N r
(32)
[1,2,4]Triazolo[I,S-a ]pyrazine
N N\
O N-....lN
,"::
#
(35)
[1 ,2,4]TriazoJo[ 4,3-a ]quinoxaline
Triazolotriazines
F N
2 \
N4 IN
(71
N/
(38)
[1 ,2,4]Triazolo[3,4-c ][1 ,2,4 ]triazine
N N
( s 'r: I '\
'5 N 31/
"N/ -N
(41)
[1 ,2,4]Triazolo[I,5-b ][1,2,4]triazine
N N
(' YI2N
N NV
(44)
[1,2,4]Triazolo[ 4,3-a ][1 ,3,5]lriazine
Tetrazolopyridines
,
N t
(46)
Tetrazolo[1,5-a ]pyridine
N\
N_J'N
(47)
Tetrazolo[I,5-b ]isoquinoline
& ;..-oN,
;,N
1 : N -N
(48)
Tetrazolo[ 1,5 -a ]quinoline
U -- 'N
N 4 II
N/ -N
(50)
Tetrazolo[I,5-b ]pyridazine
Telrazolopyridazines
ü::X -::?' __N,
;,N
::::,... '" /N-N
N
(51)
Telrazolo[I,5-b ]cinnoline
851
N
7 '-. iN
N 4 3//
::::,... -N
(33)
[1,2,3 ]Triazolo[I,5 -a ]pyrazine
N
O N IIN
""" -N
'#
(36)
[1,2,3 ]Triazolo[ 1,5 -a ]quinoxaline
N
12
NYN)
N
(39)
[1,2,4 ]Triazolo[ 4,3 -d][ 1 ,2,4 ]triazine
N:=\
I I \
N 3N
( SY
I 4 N
5",
N
(42)
[1,2,4]Triazolo[5, l-c ][1,2,4]triazine
N N
(' 'yl,\
N N 4 31/
-N
(45)
[1,2,4 ]Triazolo[ 1,5 -a][ 1,3,5]triazine
C(r "::
# N
;..-0 \
::::,... N _ J'N
(49)
Tetrazolo[ 5, I-a ]isoquinoline
1# N
;..-0 ,
;,N
:::"'N/N_N
(52)
Telrazolo[5, I-a ]phthalazine
852
Triazoles and Tetrazoles with Fused Six-membered Rings
Tetrazolopyrimidines
N N
C 4Y3 'N
N -rl
(53)
Tetrazolo[1 ,5-a ]pyrimidine
& N Y N
0.--'
;,N
":::: N_N 7
'#
(55)
Tetrazolo[ 1,5 -a ]quinazoline
rY 'N
N 6 N 4 J/;
-N
(54)
Tetrazolo[1 ,5-c ]pyrimidine
Qy "::::
# N
.-- \
N
N, N il
-N
(56)
Tetrazolo[I,5-c ]quinazoline
Tetrazolopyrazines
N \
N t
(57)
Tetrazolo[1 ,5-a ]pyrazine
N N\
6' I ;,N
":::: N_N 7
1#
(58)
Tetrazolo[ 1,5 -a ]quinoxaline
Tetrazolo[ 1 ,2,4 ]triazines
N N
f'B Y "
"N tN
(59)
Tetrazolo[ 1,5-b ][1,2,4 ]triazine
N=N
I 3 \
N' 4N
t)
(61)
Tetrazolo[ 1,5 -d][ 1,2,4 ]triazine
N=N
I 3 \
N4 IN
(7;[
N
(60)
Tetrazolo[ 5, l-c ][ 1 ,2,4 ]triazine
N
r 7 Ì!
A 5N
N 9' 4N"
3 I
N=N
(62)
Tetrazolo[5, I-f][1 ,2,4]triazine
Only representative monofused benzene systerns of pyridine, e.g. quinoline (3, 11 and
48) and isoquinoline (4-7, 12, 47 and 49), pyridazine, e.g. cinnoline (16 and 51)
and phthalazine (17 and 52), pyrirnidine, e.g. quinazoline (22-25, 29-30 and 55-56), and
pyrazine, e.g. quinoxaline (35, 36 and 58) are presented with no effort directed towards
the polybenzo derivatives or any benzo derivatives of the triazines. These latter cornpounds
seern to be of less significance than those described and have been eliminated from a
detailed discussion for the sake of brevity.
Other simple bicyclic ring systerns known but not covered here include [1,2,4]triazolo[1,2-
a ]pyridazine (64Z0B390), [1,2,3]triazolo[1,5-b ]pyridazine (63) (67 AJC713), [1,2,4]tria-
zolo[l ,2-a ][1 ,2,4 ]triazine (64) (75CJC355), [1 ,2,3]triazolo[1 ,5-b ][1,2,4 ]triazine (65)
(ó3CB 1827), [1 ,2,3]triazolo[5, l-c ][1,2,4]triazine (66) (72TL4719), [1,2,3]triazolo[ 4,5-d]-
[1,2,3]triazine (as 2,8-diazapurines) (67) (66JMC733,72JMCI82), [1,2,4]triazolo[ 4,3-b]-
[1,2,4,S]tetrazine (68) (71CHE665), tetrazolo[I,5-b ][1,2,4,S]tetrazine (69) (71CHE668),
[1 ,2,3]triazolo[5, 1-d][1 ,2,3,5]tetrazine (70) (79TL4253), [1,2,4]triazolo[3,4-c ][1,4 ]oxazine
(71) (68CBI979), [1,2,3]triazolo[S,1-c][1,4]oxazine (72) (80Z0R730), [1,2,3]triazolo[4,S-
d][ 1,3]oxazine (73) (70CC858), tetrazolo[S, 1-b ][1 ,3]oxazine (74) (75TL695),
[1,2,4 ]triazolo[ 5, I-b ][ 1,3 ]thiazine (75) (80JCS(Pl) 1352), [1,2,4 ]triazolo[3 ,4-b ][ 1,3 ]thiazine
Triazoles and Tetrazoles with Fused Six-membered Rings
853
(76) (79H(12)1171), [1,2,4]triazolo[3,4-c ][1,2,4 ]thiadiazine (77) (74BSF1395), [1,2,4 ]tria-
zo10[3 ,4-b ][ 1,3,4 ]thiadiazine (78) (78IJC(B)481) ap.d [1,2,4 ]triazolo[ 5, l-c ][1 ,2,4,6 ]thia-
triazine (79) (77JCR(S)238).
Miscellaneous Examples of Fused Triazoles and Tetrazoles
N::::N
05 0 R 1 Ph
Bz --I( N Me
Ph ß_: N Ph(" NPh ( R 2 ( 'iN
;,N
N N--{ Me N-N
N Ph 0 N N
(63) (64) (65) (66)
0
H :XN:N N NyN, ...NyN R 1
...N
N'" --, N " :;;--
Ph ...N.JN Ar N...N_ l I N
N N R 2 N y N_N'1
N H N
0
(67) (68) (69) (70)
0 o]ctJ:
O N, oÄy: (yN\N
NH N_JN Me2Nl I I;N
N--{ N I;
N N -N
S R
(71) (72) (73) (74)
R 2 H
Ç syN\ C SyN'N 02S.....N. ,(N\ (SyN\ 02 ......NyN\ Pr;
R 1 N_! N-{ N-1 RI N Nìt MeNyN- t
o 0
(75) (76) (77) (78) (79)
In the following presentation, structures (1)-(62) will be used, as is custornary, to represent
the parent heterocycle of the derivative under discussion. It should also be noted that the
structures are all drawn (with several exceptions) using [1,2,4]triazolo[4,3-a]pyridine (1)
as the prototype. Thus, the focus of visual orientation will be a bridgehead nitrogen in the
lower center part of the ring system. This had been done not out of disrespect for the
recognized molecular orientations but in an effort to &Împlify the relationships of these
diverse systerns to one another.
4.15.2 STRUCTURE
4.15.2.1 [l,2,4]Triazolopyridines
The proton NMR spectral data for (1) and (2) are shown in Table 1. It can be seen that
H-3 of (1) is at a lower field relative to the H-2 of (2) and this observation is very useful
in distinguishing [4,3-a] systerns frorn their [1,5-a] isomers. As a consequence of this, only
the H-3 or H-2 protons for (4)-(7) are recorded in Table 5. It is interesting to note that
there is an H(3)-H(8) coupling (1 Hz) in (1) (66JOC3522). The 14 N NMR and UV spectral
data for (1) and (2) are given in Tables 3 and 4, respectively. The mass spectral fragmentations
of (1) and (2) (71OMS(5)1) indicated both systerns undergo loss of hydrogen cyanide (or
various nit riles for the substituted derivatives) frorn their rnolecular ions to give a three-
mernbered ion that is cornmon to both systerns. Extensive molecular orbital calcula-
tions have produced bond orders, electron densities, etc. for systerns (1) and (2)
(68MI41500, 66JOC265, 72JPR515, 70CB3817) and these are in agreernent with the chernical
properties described later.
Similar spectral and rnolecular orbital data are available for the fused compounds (3)
(nJOC4410, 76AJC815, 80AJC499), (5) (66JHC158, 70CB3817, 70IJC894, 71CB3925, 7lRTC1225,
nJOc441o) and (7) (71CB3925, 71CB3965, 71RTC1225).
Melting points for this series of cornpounds ar given in Table 6.
00
VI
.j:>.
Table 1 I H NMR Spectral Data for Selected Fused Triazoles and Tetrazoles
IH chemical shifts (8, p.p.m.)
Compound H-l H-2 H-3 H-4 H-5 H-6 H-7 H-8 Solvent 1 (Hz) Ref is'
N
<::>
-
(1) 8.86 8.21 6.88 7.28 7.79 CDCI 3 15.6 = 6.7, 1 5 . 7 = 1.2,15.8 = 1.2, 66JOC3522
'"
h.7 = 6.7, 1 6 . 8 = 1.2,17.8 = 9.0, $:)
h.8 = 1.0 ::!
$::)..
(2) 8.35 8.62 7.04 7.52 7.82 CDCI 3 15.6 = 6.6, 15.7 = 1.3.1 5 . 8 = 1.2, 66JOC3522
1 6 . 7 = 6.6, 1 6 . 8 = 1.2, h.B = 8.8
(8) 8.05 8.70 7.00 7.20 7.70 CDCI 3 11.5 = 0.8, 17.8 = 9.0, h.8 = 1.25, 78HCA1755
1 5 . 8 = 1.0,1 6 . 7 = 6.5, 15.7 = 1.0, N
<::>
1 5 . 6 =7.0 -
(14) 8.38 8.44 7.42 8.08 CDCI 3 16.7 = 4.2, 17.8 = 8.9, 16.8 = 1.8 73TL1677 '"
(18) 9.26 9.00 7.13 8.73 (CD 3 hSO 77 AJC2515 .
...
(19) 9.40 9.47 7.97 7.77 (CD 3 hSO 17.8 = 6.0, 1 5 . 8 = 1.0 78AJC2505
(20) 8.52 8.87 7.17 8.95 CDCI 3 1 5 . 6 = 4.8, 15.7 = 1.0, h.7 = 6.9 73TL1677
(21) 8.67 9.80 8.30 7.90 (CD 3 hSO h.8=6,1 5 .8= 1 78AJC2505 '"
(27) 8.18 9.68 8.05 7.72 CDCI 3 h.8 = 6.7,1 5 . 8 = 1.6,11.5 = 0.6 78JHC1041 $::)..
(28) 9.68 10.33 CF 3 CO z H 69CJCl129 V)
(32) 8.50 8.58 8.19 9.37 CDCI 3 1 5 . 6 = 4.5, 15.8 = 1.5 73TL1677 .
,
(33) 8.30 9.30 8.60 8.00 9.30 CDCI 3 11.5 = 1.0,1 5 . 8 = 1.3,15.6 = 5.0 78HCA1755
(34) (I-benzyl) 8.75 8.65 CDCI 3 15.6 = 1.0 72JOC4124
(37) 9.13 8.61 8.45 CDCI 3 1 6 . 7 = 1.5 77JOC1018
(38) (6-Me) 8.78 8.43 CD0 3 77JOC1Q18
....
(41) (6-Me) 8.59 8.67 CDCI 3 77JOC1018
$::)..
(42) 7.83 6.16 6.94 CDCI 3 1 6 . 7 = 2.4 77JOC1018 :;z;,
(46) 8.91 7.38 7.74 8.11 CDCI 3 7IT5121 S.
(53) 9.30 7.76 9.85 (CD 3 hSO 65JOC826 OQ
(57) 8.83 8.36 9.64 CDCI 3 1 5 . 8 = 1.6,1 6 . 8 = 0.5, 1 5 . 6 = 4.7 66JHC435 '"
13 C Chemical Shifts (p.p.m.)
Compound C-2 C-3 C-5 C-6 C-7 C-8 C-8a Miscellaneous Solvent Ref.
(13) 139.04 146.57 121.20 124.61 143.31 (CD 3 hSO 76JHC1057
(14) 152.50 144.55 123.04 125.92 144.05 (CD 3 hSO 76JHC1057
(20)-7 -one (as anion) 152.50 154.10 97.20 160.10 158.30 (C-3a) (CD 3 hSO 74JOC3226
(23) (5-NH z -2-Me) 161.30 158.70 125.60 124.70 134.10 114.50 (C-9) (CD 3 hSO 80HCA1
135.30 (C-9a)
154.00 (C-3a)
(28)-7-NH z (as anion) 155.80 158.90 124.00 (C-7a) (CD 3 hSO 74JOC3226
154.20 (C-3a)
(31) see discussion
(32) see discussion
E'
N
<::>
-
'"
$:)
::!
â
'"
.
...
;::;-
'"
V)
.
:;z;,
S.
OQ
'"
Table 2 l3C NMR Spectral Data for Selected Fused Triazoles and Tetrazoles
00
l.J1
l.J1
856
Triazoles and Tetrazoles with Fused Six-membered Rings
Table 3 14 N NMR Spectral Data for Selected Fused Triazoles and Tetrazoles
Compound
14N Chemical Shifts a (p.p.m.)
2 3 4
Solvent
Ref.
76JMR(2l)185
76JMR(2l) 185
76JMR(2l)185
76JMR(2!)185
N-!
(1)
(2)
(8)
(46)
+60.1:f:4.2
+ 150.0:f: 1.0
+1l8.1:f:9.0
+185.5:f:0.2
+140.7:f:0.3
+1l9.9:f:0.2
+ 129.2:f: 0.2
+94.1:f:2.2
+40.9:f: 3.2 -30.6:f: 3.9
+70.5:f: 11.2 +10.0:f: 2.4
+61.8:f: 1.2
· Relative to nitromethane.
Et2 0
Et20
Et2 0
Et 2 0/Me 2 CO
Table 4 UV Spectral Maxima (nm) for Selected Fused Triazoles and Tetrazoles
Compound Solvent A (log ê or e) Ref.
(1) Cyc10hexane 306 (3.34),274 (3.67),213 (4.38) 68MI41500
(2) (2-Me) Cyc10hexane 294 (3.20),273 (3.57), 217.5 (4.58) 68MI41500
(8) Cyc10hexane 299 (3.36h 270 (3.33),214 (4.35) 68MI41500
(14) EtOH 277 (3.57), 208 (4.56) 75JHCI07
(18) H 2 0, pH 5 293 (3.35), 266 (3.24),256 (3.23) 77AJC2515
(19) H 2 O 258 (3.77), 249 (3.79) 78AJC2505
(20) H 2 0, pH 4 272 (3.59) 77AJC2515
(21) Dioxane 256 (3.78),254 (3.71) 78AJC2505
(22) MeOH 240 (4.60) 70JOC3448
(24) MeOH 240 (4.39) 70JOC3448
(27) Heptane 340 (2.65),323 (3.08), 309 (3.21), 78JHCI041
301 (3.21), 294 (3.20),266 (3.75)
(28) H 2 O 263 (3.87) 66JCS(B)427
(31) EtOH 299 (3.57), 206 (4.46) 64JOC2542
(32) EtOH 280 (3.75),207 (4.60) 75JHC107
(33) EtOH 283 (4935), 274 (4860) 78HCA1755
(35) MeOH 284 (3.95) 68JHC485
(46) EtOH 293 (3.16),265 (3.62) 68MI41500
(57) H 2 O 270 (4500),203 (12000) 66JHC435
Compound
Chemical shift (8, p.p.m.)
Solvent
Table 5 I H NMR Chemical Shifts for the Triazole Proton in Selected Benzo Derivatives
(4) perchlorate
(5)
(6)
(7)
(11)
(12)
(17)
(22)
(24)
(CD 3 hSO
(CD 3 hSO
CDCb
(CD 3 hSO
CDCb
CDCb
CDCl 3
CDCb
CDCb
8.95
9.38
8.58
8.64
8.04
8.30
9.00
9.50
8.60
Ref.
78JHC463
71RTC1225
77H(6)949
71RTC1225
72JOC2022
72JOC2022
69JOC3221
70JOC3448
70JOC3448
4.15.2.2 [1,2,3 ] Triazolopyridines
Molecules containing a fused 1,2,3-triazole ring, as in (8), (11), (12), (26), (27), (33) and
(36), frequently display a diazo characteristic in their chemical reactivity that leads to
homolytic and heterolytic ring fission. This is a result of an equilibrium that can exist
between the closed and open forms (A) and (B) analogous to the ring-chain tautomerism
exhibited by fused tetrazoles. Sorne studies have been undertaken (71JCS(C)2156) to evaluate
the role that this equilibrium plays in the physical and chemical properties of fused
1,2,3- triazoles.
N:=:N N:=N
( J (Ny>
(A) (8)
$:)
N
Table 6 Melting Points (oC) for Selected Fused Triazoles and Tetrazoles <::>
'"
Ring system M.p. Ref. Ring system M.p. Ref. Ring system M.p. Ref. $:)
::!
(1) (hydrate) 36 57JCS4510 (21) 117-119 78AJC2505 (45) (5-NH z ) >320 dee. 80JHC1121
(2) 102 66JOC260 (22) 213-214 70JOC3448 (46) 158-160 71T5121 â
(4) 227-228 78JHC463 (24) 109-110 70JOC3448 (47) 122 76JHC881 N
(5) 130-132 71RTC1225 (27) 130-131 78JHCI041 (48) 155-156 76JOCI073 <::>
(6) 160-161 77H(6)949 (28) 174-175 66JCS(B)427 (49) 138-140 79JHC1567
'"
(7) 95-96.5 71RTC1225 (31) 194-195 62JOC3243 (50) 108-111 63CPB348 ;ê.
(8) 34 75JHC481 (32) 127 73TL1677 (51) (6,7,8,9- ) 142-143 71BSF3043 ...
(10) 245 (dee.) 71JHC47 (33) 126-126.5 78HCA1755 (52) (6-oxo) 287 67CBI073 ;::;-
(11) 81.5-82 72JOC2022 (34) (I-CH z Ph) 91.5 72JOC4124 (53) 121-123 57JAP570777
(12) 110-111 72JOC2022 (35) 234 60JA4044 (54) 77-79 65JOC829 '"
(13) 156-158 76JHC639 (37) 165-166 77JOCI018 (55) (5-NHNH z ) 242-243 63Z0B2475
(14) 157-158 75JHCI07 (38) (6-Me) 137-138 77JOCI018 (56) (5-Me) Í80 80H(14)1759 V)
::(.
(15) 308-309 70CPB1685 (41) (6-Me) 146-148 77JOCI018 (57) 90.8-91 66JHC435 I
(17) 184-185 69JOC3221 (42) 176-177 77JOCI018
(18) 216-219 77AJC2515
(19) 165-167 78AJC2505
(20) 140-141 73TL1677
S.
()Q
'"
00
VI
-J
858
Triazoles and Tetrazoles with Fused Six-membered Rings
The proton and nitrogen NMR and UV spectral data for (8) are given in Tables 1,3 and
4 and a mass spectral analysis of (9) and (10) has been reported in the literature (74CS(6J222).
The triazole proton NMR spectral peaks for (11) and (12) are given in Table 5 and the
melting points for this series of compounds are presented in Table 6.
4.15.2.3 [l,2,4]Triazolopyridazines and [l,2,3]Triazolopyridazine
Little proton NMR spectral information is available on neutral compounds of this series
(B-73NMR288, B-73NMR302). However, there are data available on the 5-oxides of (13) and
on its N -methyl derivatives (69JHC559). In fact, this latter study had been quite revealing
in determining the site of methylation in various [4,3-b] fused compounds. On the other
hand, considerable proton NMR spectral data for the (14) series have been reported and
the chemical shifts for (14) itself are given in Table 1. The 13C NMR spectral data for both
(13) and (14) are in Table 2 and more can be found in the literature (76JHCI057) for various
derivatives. In the mass spectral fragmentation (70JHC639) of [1,2,4 ]triazolo[ 4,3-
b ]pyridazines, the molecular ion is the most abundant ion. Beyond this, however, the rnajor
fragments are not consistent from one derivative to the next and depend on the substituents
present on the ring. Electron density calculations have been performed on (13) and some
of its derivatives and these results confirm those found chemically upon methylation (see
reactivity section) (69JHC559). The crystal structures of (13) and (14) have been deterrnined
and indicate that these molecules are planar with the N(5)-C(6) and C(7)-C(8) bonds of
(13) being considerably alkenic and those same two bonds of (14) being aromatic (78AXl136).
This interpretation is supported by the reactivity found for these compounds. The UV and
melting point data for the ring systerns of this series are given in Tables 4 and 6 with the
triazolo proton NMR absorption for (17) given in Table 5. The proton NMR spectral data
for derivatives of (15) have also been described (B-73NMR288, B-73NMR302).
4.15.2.4 [1,2,4]Triazolopyrimidines
The proton NMR spectral data for (18)-(21) are given in Table 1 and extensive analysis
of this data for (20) has been used to evaluate its reactivities and electronic structure
(64CPB204,72JPR515) which correlate well with its charge distributions calculated by the
sirnple MO methods. Another report has appeared which correlates the calculated electronic
spectra with the electronic structure of derivatives of (18) and (20) (72T5779). Vysotskii
and Zemskii (80KGS984) have used a quantum chemical interpretation to analyze the
Dimroth-like rearrangements in (18)-(21) and Guerret, Jacquier and Maury (71JHC643)
have compared the electron densities of a number of polyazaindolizines as a means of
rationalizing the mechanisms of these rearrangernents in different systerns.
The 13C NMR spectral data for representatives of the (20) and (23) series are given in
Table 2 and the UV absorption maxima for (18)-(22) and (24) are presented in Table 4.
The UV data have been very useful in distinguishing [1,2,4 ]triazolo[ 4,3-a ]pyrirnidines frorn
their [1,5-a] isomers (68T2839). An X-ray structural analysis has been carried out
on 2-amino-7-methyl-5-(1-propyl)-[1,2,4]triazolo[1,5-c]pyrimidine (63JCS5642) and this
showed the two heterocyclic rings to be almost planar with the two planes inclined at an
angle of 6 0 to each other. The bond lengths were reported to be considerably less than
normal single bond lengths and they appeared more as conjugated double bonds and single
bonds.
The melting point data for the ring systems of this series are given in Table 6 and the
proton NMR chemical shift assignments for the triazole protons in (22) and (24) are given
in Table 5.
4.15.2.5 [1,2,3]Triazolopyrimidines
The diazo character of fused triazoles that was described in Section 4.15.2.2 is also of
structural significance for this series of compounds (74JCS(Pl)2030) and is discussed in Section
4.15.3.6.1. The NMR and UV spectral data and melting points for representatives of this
series are given in Tables 1, 2, 4 and 6. The mass spectral fragmentations for (27) have
Triazoles and Tetrazoles with Fused Six-membered Rings
859
been reported with the molecular ion showing only a 47% relative intensity while the ion
with rn/e 65 was the most intense (7SJHCI041). Molecular orbital calculations have been
conducted on (28) and found to correlate well with its observed properties
(690Cl129,69CR(D)(26S)295S).
4.15.2.6 [1,2,4 ]Triazolopyrazines and [1,2,3 ]Triazolopyrazines
The proton NMR and UV spectral data and melting points for representatives of this
series are given in Tables 1, 4 and 6. The DC NMR spectral data for (31) and (32) are
worthy of special note since they afford a useful method for distinguishing between the
isomers (SOJCS(Pl)506). The chemical shift for C-2 in the 13 C NMR spectrum of (32) was
greater than the C-3 for the corresponding (31). This is also true for derivatives of these
two ring systems. The l H NMR data can also be used for structural diagnosis since the
relative positions of the signals due to H-2 and H-3 in (32) and (31), respectively, were
reported (sOJCS(Pl)506) to be the reverse of those observed for the corresponding carbon
atoms in the 13 C spectra. This was assumed (sOJCS(P1)506) to be due to shielding by lone
pairs of electrons on the nearby basic nitrogen atoms which would be the greatest for (32).
The mass spectral fragmentations for representatives of the (31) (71OMS(5)663), (32)
(71OMS(5)663), (33) (7SHCA1755) and (36) (7SHCA1755) ring systems have been described.
Compound (31) showed decomposition from its molecular ion by loss of nitrogen while its
3-alkyl derivatives lost the corresponding alkyl cyanide from the triazole nucleus. The
3-amino compounds expelled cyanamide from the molecular ion whereas a phenyl sub-
stituent produced a 1,2-phenyl migration. In the case of the parent (32), hydrogen cyanide
was lost from the molecular ion and alkyl cyanides were eliminated from the molecular
ions of the 2-alkyl derivatives.
Quantum chemical calculations have been performed on (31) and (32) to enlighten their
propensity to undergo Dimroth-like rearrangements (SOKGS9S4). These calculations show
satisfactory correlations with what actually occurs.
4.15.2.7 [1,2,4 ] Triazolotriazines
Most of the structural data for this series of compounds is on substituted, often poly-
substituted, derivatives and is of little value to a chapter such as this. Some NMR
spectral data and melting point values for sorne simple representatives of the triazolotriazines
are shown in Tables 1 and 6. Further NMR spectral data in the 1,2,4-triazine class are reported
for the [4,3-b] (77JOC101S), [3,4-c] (77JOC101S), [4,3-d] (69BSF3670, SIT4353), [3,4-f]
(79JHC555), [1,5-b] (77JOC101S), [5, l-c] (76JCS(P1)1492) and [1,5-d] (69BSF3670) systems
and in the 1,3,5-triazine class they are available for the [4,3-a] (70T3357) and [1,5-a]
(74JOC2143) derivatives. Many of these same references contain mass spectral and UV data
on various substituted compounds of this series and there is a report (70T3357) on the
calculated electron densities for the [1,2,4 ]triazolo[ 4,3-a ][1 ,3,5]triazines.
4.15.2.8 Tetrazolopyridines and Related Systems
Tetrazoles fused to six-membered nitrogen heterocycles wherein the two rings share a
nitrogen are known to exist in equilibrium with the azido tautomer (C) (D) (73S123).
The nucleophilicity of the common nitrogen that is part of the six-membered ring in the
equilibrium is responsible for determining whether the tetrazolo or azido forms predominate
in the equilibrium. If the atom is poorly nucleophilic, then the azido form is preferred, for
example 1,3,5-triazines exist entirely in the azido tautomer (73S123); if it is highly nucleophilic
(as in pyridine versus the diazines), then the fused tetrazole predominates. From this, it is
not surprising that electron-withdrawing groups on the azine favor the azido form while
U;N 0: 3
(C) (D)
860
Triazoles and Tetrazoles with Fused Six-membered Rings
electron-donating groups encourage tetrazolo fusion. Protonation of the heterocycle leads
to the azido tautorner. Other factors which influence the isornerization are solvent polarity
(polar solvents shift the equilibrium toward the tetrazole and less polar solvents shift it
toward the azido form) and temperature (raising the temperature encourages azido forrna-
tion at the expense of tetrazole) (735123). This latter parameter supports the fact that the
tetrazolo to azido shift is endothermic.
4.15.2.8.1 Tetrazolo[1,5-a]pyridine
Tetrazolo[1,5-a]pyridines generally exist in the tetrazolo form. As exceptions, the 6-nitro
derivative exists as an equilibrium mixture of both forms whereas the 5-chloro compound
prefers the azido tautorner (735123, 71T5121, 70T4969). The l H and 14 N NMR and UV spectral
data and melting point for (46) are given in Tables 1, 3, 4 and 6, and molecular orbital
generated data (6SMI41500) and photoelectron spectral data (SOJHC6S9) on (46) are also
available. Spectral measurements on (48) and (49) are described elsewhere
(76HCA259, 76AJC799, SOAJC499) while their melting points and that of (47) are reported in
Table 6.
4.15.2.8.2 Tetrazolo[1,5-h ]pyridazine
Compound (50) and its derivatives generally exist only in the tetrazolo form even in
trifluoroacetic acid (73S123). Electron-withdrawing groups destabilize the tetrazolo tautorner
as evidenced by the preference for 3-azidopyridazine 1-oxide (63CPB34S) and 3-azido-6-
nitropyridazine 1-oxide (70JOC247S,70T4969).
The mass spectral fragmentation pattern for (50) (70JHC639) and its X-ray crystal structure
(7SAXI136) have been reported. The most abundant species in the mass spectrum of (50)
is the [M - 56] ion which corresponds to the loss of four nitrogens. The X-ray picture of
(50) indicates it is a planar molecule with a great deal of alkenic character associated with
the double bonds of the pyridazine ring.
4.15.2.8.3 TetrazoloI1,5-a]pyrimidine and tetrazololl,5-c]pyrirnidine
The parent [1,5-a] system has been reported to prefer the tetrazolo tautorner in the solid
state and an equilibrium rnixture of azido and tetrazolo in solution, with the azido form
being exclusively present in chloroform. In comparing (53) and (54) the tetrazolo tautorner
seems rnore stable in the former case (73S 123). The [1,5 -a ]pyrimidines with electron -donating
groups at C-5 (and C-7) showed no tendency to tautomerize to azides whereas those with
electron-withdrawing groups at C-5 (and C-7) favored the azido form (70T4969,735123).
Tetrazolo[1,5-c ]pyrimidines can also exist in equilibrium with 4-azidopyrimidines
although, in the solid state, the parent cornpound (54) is predorninantly in the tetrazolo
form (735123). The effect of substituents on this equilibriurn can be correlated with that
reported in the [1,5-a] system, that is, the azido tautomer is preferred when electron-
withdrawing groups are in positions 5 and 7 of the tetrazolo[1 ,5-c ]pyrimidine and electron-
donating groups at C-8 favor the tetrazole product (70T4969,735123).
Tetrazolo[1,5-a ]quinazolines exist almost entirely as tetrazoles whereas the [1,5-c ]quin-
azolines are in equilibrium with the azido tautomer (73S123).
Other structural data for cornpounds of this class are in Tables 1 and 6 and can be found
throughout the literature cited in Sections 4.15.3.11 and 4.15.4.11.
4.15.2.8.4 Tetrazolo[1,5-a]pyrazine
In the solid state (57) and its derivatives prefer the tetrazolo form whereas in solution
an equilibrium exists (73S123). As in the other systerns described here, the substituent on
the pyrazine ring can greatly influence the position of the tetrazolo-azido equilibrium
(SlMI41500).
Tables 1,4 and 6 have additional data for (57).
Triazoles and Tetrazoles with Fused Six-membered Rings
861
4.15.2.8.5 Tetrazolo[1,5-b][1,2,4]triazine and tetrazolo[5,1-f][1,2,4]triazine
Compounds derived from (59) exist exclusively in the tetrazolo tautomers and are planar
and aromatic upon NMR spectral analysis (76JOC2860). In the [5,1-f] series the azido form
predominates in the solid state and will remain in this tautomer for two months. However,
once placed in solution, the azido tautomer shifts exclusively over to the tetrazolo tautomer.
This process, which has an activation energy of 85.7 kJ mol-I, is encouraged by the presence
of a 6-amino group (79JHCSSS).
4.15.3 REACTIVITY
4.15.3.1 [1,2,4]Triazolopyridines and their Fused Benzo Derivatives
4.15.3.1.1 [1,2,4]Triazolo[4,3-a]pyridine
In order to determine the relative stability of [1,2,4 ]triazolo[ 4,3-a ]pyridines in contrast
to other bridgehead nitrogen heterocycles (namely, indolizines) oxidation of (1) with
potassium permanganate at room temperature yielded l,2,4-triazole-3-carboxylic acid (80)
(66JOC26S). Since pyrazolo[l,5-a ]pyridine was similarly oxidized to pyrazole-3-carboxylic
acid, it has been suggested (66JOC26S) that the additional nitrogen atoms in the five-
membered rings (relative to indolizine) confer greater stability on that portion of the bicyclic
system.
The greater stability of the triazole rings was further evidenced by the rearrangement of
(1) to the isorneric [1,2,4]triazolo[1,5-a ]pyridine (2) in warm sodium hydroxide solution
(66JOC26S). Similarly, 3-methyl- and 3-amino-[1,2,4 ]triazolo[ 4,3-a ]pyridine underwent
rearrangement to 2-methyl- and 2-amino-[1,2,4]triazolo[I,5-a]pyridine (81 and 82) as
shown in Scheme 1. Deamination of (82) via its diazonium salt and hypophosphorus acid
produced (2). Treatment of the diazonium salt with cuprous chloride yielded 2-chloro-
[1,2,4]triazolo[1,5-a]pyridine, the same product obtained from the basic treatment of
3-chloro-[l,2,4]triazolo[ 4,3-a ]pyridine. The 3-methylthio-[ 4,3-a] system was rearranged
to the 2-methylthio-[1,5-a] product but the 3-mercapto- and 3-hydroxy-[4,3-a] corn-
pounds decomposed, without rearrangement, under the appropriate basic conditions. It is
interesting to note that 3-amino-[1,2,4]triazolo[ 4,3-a ]pyridine underwent rearrangement
and not hydrolysis in this process, contrary to what might have been predicted if amino-imino
tautomerism had been operative. The rearrangement of these derivatives could not be
effected with sodium ethoxide or dilute acid (66JOC26S).
o: ---N
N_)R
(2) R=H
(81) R=Me
(82) R = NH 2
-OH o: ---N, KMn04 H0 2 Cr-:::- N ,
( _ N -- I NH
R - H, Me, NH 2 N---f R = H N=::::/
R
(80)
Scheme 1
The rearrangement involves (66JOC26S,71JHC643) attack of the hydroxide ion at the C-5
position of the [l,2,4]triazolo[4,3-a]pyridine nucleus to give intermediate (83) which,
subsequently, undergoes ring closure at the triazole N-l which is more nucleophilic than
N-4 in the 1,2,4-triazole anion (Scheme 2). This rearrangement, and a variety of others
like it (vide infra), is related to the Dimroth rearrangement (70JHCI019) and was expected
to go more readily with the appearance of an electron-withdrawing group on the pyridine
and to be less likely to occur with an electron-donating group on this ring. To test this
o: N (E N
--- \ "-"\
N--. :-:N
N---f N:::.J
R R
OH
Ç CHO N
P ., \ -+ 0: --- \R
- ; N N_ /
N:d' N
R
(83)
Scheme 2
862
Triazoles and Tetrazoles with Fused Six-membered Rings
hypothesis, 8-nitro-[1,2,4]triazolo[4,3-a]pyridine (84) was prepared and reduced catalyti-
cally to the 8-amino derivative (85) (70JHCI019). Compound (84); upon treatrnent with
10% sodium hydroxide solution for 30 minutes, or fusion or gently warrning in formic acid
for 1 hour or at room ternperature for a longer period of time, became 8-nitro-
[1,2,4]triazolo[1,5-a]pyridine (86). On the other hand, (85) required treatrnent with 10%
sodium hydroxide solution for 48 hours to rearrange to (87) while formic acid produced
only the 8-forrnamido derivative. No isomerization of (85) occurred upon heating.
;YN\
N-J'N
R
N>
N--N
(86) R=N0 2
(87) R = NH 2
(84) R = N0 2
(85) R = NH 2
As a result of this observation, reacting 2-hydrazino-3-nitropyridine with aliphatic acids
(a typical route to [1,2,4 ]triazolo[ 4,3-a ]pyridines, see later) led directly to various 8-nitro-
[1,2,4]triazolo[1,5-a]pyridines. As an aside, this provides a very useful way into the
8-substituted [1,5-a] series since the 8-nitro group of (86) is readily reduced to the 8-arnino
derivative which, in turn, is susceptible to the usual diazoniurn conversions (70JHCI019). It
can be assurned that this could also be applied to other 8-nitro derivatives.
The above mechanistic interpretation was supported by investigating the preparation of
6-nitro-[l,2,4]triazolo[4,3-a]pyridines (88a) wherein the electron-withdrawing group is
adjacent to the C-5 site of the nucleophilic attack that initiates rearrangernent. In this case
only the [1,5-a] product (88b) was detectable upon ring closure of 2-hydrazino-5-
nitropyridine with carboxylic acids or ortho esters. Further proof of this facile rearrangement
process was the production of 2-methyl-8-nitro[1,2,4]triazolo[1,5-a]pyridine upon nitration
of 3-methyl-[1 ,2,4 ]triazolo[ 4,3-a ]pyridine using potassium nitrate-concentrated sulfuric
acid at 120 oC for 10 hours (70JHCI019).
N'N N>
02N N-J' 02N N__:
(88a) (88b)
The rearrangement also occurs when 2-hydrazino-5-nitropyridine is treated with
cyanogen brornide and carbon disulfide to result in 2-amino-6-nitro-[1,2,4]triazolo[1,5-
a ]pyridine and 6-nitro-[1,2,4 ]triazolo[1,5-a ]pyridine-2-thiol, respectively (70JHCI019). The
rearrangement has also been used (76JOC3124) for the synthesis of nucleosides of the [1,5 -a]
system.
This isornerization has also been reported to occur in other fused 1 ,2,4-triazoles (7lJHC643)
and the results from these studies support the ring opening/ring closing Dirnroth type
process for this occurrence (see Table 7). The extreme ease of rearrangement in the
pyrimidine and 1,2,4-triazine systems can be attributed to the increase in electron deficiency
at the C-5 center as a result of the additional nitrogen or two in the pyridine ring. This
rearrangement is driven by the greater stability of the [1,5-a] systern, a fact that has been
substantiated by CNDO calculations (7lJHC643). Further application of this process will be
made as the reactivities of the other ring systems are described.
Brornination of [1,2,4]triazolo[4,3-a]pyridine in methanol gave the 3-bromo derivative
(89), the same product obtained from the Sandmeyer reaction on 3-amino-
[1,2,4]triazolo[4,3-a]pyridine (66JOC265). Blockage of the 3-position of (1) gave no nuclear
Table 7 General Survey of Dimroth-type Rearrangements in the Fused Triazoles
Starting compound
Product
(1)
(18)
(19)
(31)
(38)
(39)
(2)
(20)
(21)
(32)
(42)
(43)
Ref.
70JHCI019,66JOC265
59JOC787, 60JCS1829, 66CB2237
63JCS5642, 65JCS3357
68JHC485, 66JCS2038, 70CC1524
69BSF2492
69BSF3670
Triazoles and Tetrazoles with Fused Six-membered Rings
863
bromination. The bromine in (89) would not form a Grignard reagent and could not be
displaced by nucleophiles.
f ."r.N\ N\
N--fN N--fN
Sf
(89) (90)
The ring system (1) did not undergo any other electrophilic substitution reactions (nitra-
tion, sulfonation, Friedel-Crafts, Vilsmeier formylation), was inert to sodamide, could not
be metalated with butyllithium and could not be readily oxidized with hydrogen peroxide
to an N-oxide (66JOC26S). Compound (1) could not be reduced at atmospheric pressure by
hydrogen but at 3 atm using a palladium-charcoal catalyst the 5,6,7,8-tetrahydro derivative
(90) was obtained (7S01291).
As with the [1,5-a] analog mentioned above, 3-amino-[1,2,4]triazolo[4,3-a]pyridine
underwent typical diazonium reactions. It could be acylated and transformed into Schiff
bases. The 3-amino group had little influence as an electron-donating group for stimulating
electrophilic substitution of the fused triazole nucleus (66JOC26S).
3-Hydroxy-[1,2,4]triazolo[4,3-a]pyridine (91) was reluctant to react with the common
hydroxylic chlorinating agents, giving at best, the 3-chloro compound in only 15% yield
with phosphorus oxychloride-dimethylaniline. Methylation of (91) produced 2-methyl-
[1,2,4]triazolo[4,3-a]pyrid-3-one (92) whereas methylation of the 3-thiol (93) resulted in
methyl [1,2,4]triazolo[ 4,3-a ]pyrid'-3-yl sulfide (94), a molecule also resi tant to nucleophilic
substitution (66JOC26S). Potassium ferricyanide oxidation of (93) resulted in the correspond-
ing disulfide.
rr N \
N--fN
SR
(93) R = H
(94) R=Me
Except for 3-amino-[1,2,4]triazolo[4,3-a]pyridine (95), protonation and quaternization
of (1) and its derivatives occurred primarily at N-1 (96) (68JHC29). In some cases the
N(2)-methyl isomer was obtained and it underwent thermal rearrangement to the N-1
analog (68JHC29). Molecular orbital calculations confirm this by showing N-1 to be the more
basic site. In the case of (95), N-2 is the most basic site as a consequence of the amidine
system present and reaction occurs there (66JOC26S, 65JCS2778). 1-Methyl-[1,2,4]triazolo[ 4,3-
a ]pyridinium iodide (97) can be reduced with sodium borohydride to the unstable (98)
(66JOC26S). N-Amination of (1) with O-p-tolyisulfonylhydroxylamine gives the N-1
ammonium salt (99) (76JCS(P1)367).
R R
a ;.--! < Q I'\
N I N
:::::,.., N--f :::::,.., --f
(96)
Q: ;.--N\
:::::,.., N--fN
R
(100) R = C0 2 H
(101) R = CONH 2
The 3-methyl group of 3-methyl-[1,2,4]triazolo[4,3-a]pyridine was inert to metalation
and could not be condensed with benzaldehyde (66JOC26S). Attempts to make the 3-
carboxylic acid (100) by hydrolysis of the 3-carboxamide (101) led instead to (1) by an
apparent decarboxylation of the intermediate (100) (66JOC2S1).
In addition to those 6- and 8-substituted [4,3-a] systems mentioned previously in the
Dimroth rearrangement discussion, a variety of 5-substituted derivatives has been described
(78JHC439) from ring closure of 6-chloro-2-hydrazinopyridine (see synthesis section). A
useful material obtained from this investigation was 5-chloro-[1,2,4]triazolo[4,3-a]pyridine
(102) which was susceptible to nucleophilic substitution by strong nucleophiles (sodium
rrI'\
N--fN
OH
(91)
a ;.--N\
NMe
:::::,.., N--(
(92) 0
Q: ;.--N\
"'" N---JN
NH 2
(95)
Me
N\
N--fN
NH 2
rr 'N
N--f
(98)
(99)
a ;.--N\
+NR
"'" N---J
NH 2
(97)
864
Triazoles and Tetrazoles with Fused Six-membered Rings
ethoxide 103 and potassium thioethoxide 104) but not weak ones (hydroxide, water,
ammonia). On the other hand, oxidation of (104) with rn-chloroperbenzoic acid to (105)
produced a more labile C-5 substituent which upon reaction with potassium hydroxide
solution produced (106) (shown in its predominant keto form) which was ribosylated to
(107) (78UP41500). Compound (106) could not be prepared from ring closure of 2-
hydrazinopyridin-6-01, and (105) was found to be inert towards ammonia. There was little
steric interference to substitution at C-5 of (102) by a peri C 3 substituent since (108)
underwent reaction with thioethoxide to produce (109). Compound (109), however, could
not be oxidized to the sulfone analogous to (105), apparently due to steric incompatability
for the new oxygen atoms at C-5.
N\
N--þ N
R
çr N
o
(106)
o
a N N
..;::; I
N
HOH,cd
HO OH
(107)
(102) R=Cl
(103) R = OEt
(104) R = SEt
(105) R '" S02Et
N\
N---þ N
R Bu'
(108) R = Cl
(109) R = SEt
Reaction of [1,2,4]triazolo[4,3-a]pyridine (1) with tetracyanoethylene in methanol has
been reported to give (110) (81IJC(B)10). With dimethyl acetylenedicarboxylate in boiling
benzene or toluene, the ring-fused system (1) gave three products, the cyano-
pyridopyrimidinone (111; 20%), the pyridylpyrazole derivative (111a; 20%), and the
1 : 2 adduct (112; 1 %) of the initial bicyclic system. In methanol solution (111) was formed
exclusively in 70% yield (82CC1280, 81IJC(B)lO). The formation of these three products rnay
be rationalized in terms of an initial Michael addition to DMAD of the triazolopyridine
(1) via its two nucleophilic centers C-3 and N-1 and a subsequent series of rearrangements.
N\
N-JN
C(OMehCH(CNh
NÌ1C02Me
N-}CN
o
(111)
(110)
Me02C C0 2 Me
,..N
N
H
(111a)
N\ N
N f 2 N-N
N--( /C0 2 Me NyN )R2
Me0 2 C" -LC0 2 Me
Me0 2 C R 1 R 1
(112) (113)
Definitive evidence for the alkenic nature of the pyridine dienic unit arose when several
[1,2,4 ]triazolo[ 4,3-a ]pyridines were found to undergo photodimerization (77T1247). The
products from this process resulted from dimerization between the 5,6-double bond in one
molecule with the 7,8-double bond in another to give (113).
4.15.3.1.2 [1,2,4]Triazolo[1,5-a]pyridine
Beyond those reactions mentioned briefly in the previous section, for example reduction
of (86) to (87), little is known about the reactivity of [1,2,4]triazolo[1 ,5-a ]pyridine (2). It
cannot be brominated or nitrated and is stable to acid, base and reducing agents. It shows
similar triazole ring stability to (1) by its oxidation with potassium perrnanganate to (80)
(66JOC260). Most of the reactivity data on this ring system deals with 2-rnethyl-
[1,2,4]triazolo[1,5-a]pyridine (114). For example, nitration of (114) with potassium nitrate
in concentrated sulfuric acid gave (115) and (116). Catalytic reduction of these two com-
pounds produced (117) and (118) both of which were susceptible to the Sandmeyer
procedure resulting in the bromo derivatives (119) and (120) (66CPB523). Amination of the
Triazoles and Tetrazoles with Fused Six-membered Rings
865
[1,5-a] system with O-p-tolylsulfonylhydroxylamine gave the N-1 amino derivative
(76JCS(Pl)367).
R (114) R=H
cr ,...-N,\ (115) R = N0 2
./Me (117) R = NH 2
N-N (119) R=Br
cr -- N (116) R = N0 2
\Me (118) R=NH 2
R N.....N'/ (120) R=Br
4.15.3.1.3 [1,2,4]Triazoloquinolines and [1,2,4]triazoloisoquinolines
In this series of compounds (5) and its derivatives have been the most extensively studied.
The parent compound is stable towards mineral acid but in the presence of 4.5N potassium
hydroxide solution [1,2,4]triazolo[5,1-a]isoquinoline (7) was obtained. The mechanism for
this conversion is similar to that for isomerization of [1,2,4 ]triazolo[ 4,3-a ]pyridines
described earlier and is given in Scheme 3 (71RTC1225). Oxidation of both (5) and (7) with
potassium permanganate give 3-(2-carboxyphenyl)-[1,2,4 ]triazole (121) (71CB3925).
CCr rJ CCr ""::
I 7'" __N, -+ , -+ 7'" __N
N--f'N cHb rJ;jN N.....)
(5) (7)
Scheme 3
Ç& ""::
# K,
C0 2 H -- NH
N::::::/
(121)
Treatment of (5) with bromine in methanol or acetic acid or with N- bromosuccinimide
gave the 3-bromo derivative (122) which with red phosphorus/hydriodic acid was reductively
dehalogenated back to (5). Chlo'rination of (5) with sodium hypochlorite yielded (123).
Both (122) and (123) could also be obtained from (124) and phosphorus tribromide and
phosphorus oxychloride, respectively. In contrast to the [4,3-a]pyridine series, the 3-bromo
substituent of (122) could be displaced by nitrogen nucleophiles (66JHC158). Subjecting (5)
to nitration (nitric add/concentrated sulfuric acid) resulted in 7-nitro-[1,2,4]triazolo[3,4-
a ]isoquinoline (125) (70IJC894, 75CB3762). On the other hand, resembling the [4,3-
a]pyridines, (5) was i.nert to Vilsmeier formylation, N-oxide formation, and sodamide
addition (70IJC894).
CCr ""::
# N
-- ,
N--f'N
X
(122) X = Br
(123) X = CI
(124) X=OH
(126) X = NH 2
(127) X = OPh
(133) X=OMe
(134) X=SH
(135) X = SMe (125)
The 3-amino derivative (126) could not be easily synthesized by the customary method
of reacting 1-hydrazinoisoquinoline with cyanogen bromide but reaction of (127) with
ammonium acetate in a sealed tube did form (126) as did ring closure of 1-
hydrazinoisoquinoline with S-methylisothiourea (71CB3947). It was possible to perform the
standard diazonium reactions with (126) (70IJC894).
Cò: ""::
(128) R = Li
# N (129) R=I
N (130) R = C0 2 Li
; (131) R=CH(OH)Me
R (132) R = C0 2 Me
Additional C-3 derivatives of (5) have arisen from the C-3 lithio derivative (128)
(obtainable from (122) and butyllithium). For example, (128) reacts with iodine to give
Cò: ""::
02 N # N
-- ,
N
N--f'
866
Triazoles and Tetrazoles with Fused Six-membered Rings
(129), with carbon dioxide to produce (130) and with acetaldehyde to result in the
hydroxyethyl compound (131) (71CB3940). Reaction of compound (130) with diazomethane
provides a route to the methyl ester (132) (71CB3940). Also, the C-3 proton of (5) can be
exchanged for deuterium in acid and basic solution (70CB3817).
Methylation of (5) produced (7SCB3762) the N-l and N-2 isomeric methyl derivatives
while methylation of (124), known to exist in the lactam tautomer (66JHClS8) under a
variety of conditions, yielded the N(2)-methyl product (71CB39SS). The 3-0-methyl isorner
of this latter product (133) was available via the reaction of (123) with sodium rnethoxide.
Refluxing (124) with phosphorus pentasulfide in xylene resulted in (134) which could not
be dethiated with Raney nickel. However, dilute nitric acid followed by aqueous sodium
hydroxide solution did transform (134) into (5). Methylation of (134) yielded (135)
(66JHClS8) whereas methylation of (126) produced the N-2 product (136) (71CB3947).
CCr ":::
N
-- \
NMe
N--{
NH
( 136)
The fact that the C(5)-C(6) bond.of (5) possesses a great deal of alkenic character has
been confirmed by HMO calculations and the ease with which halogenations, hydrogenations
and oxidations occur at this center (71CB392S). In addition, (5) undergoes photodimerization
via a [2 + 2] cyc1oaddition similar to that described earlier for obtaining (113) (77T1263).
Cornpound (3) also demonstrated a dimerization ability (77T1263).
[1,2,4]Triazolo[4,3-b]isoquinoline (4) is very unstable and, consequently, very little has
been done with this ring system. On the other hand, the isomeric o-quinoid system
[1,2,4]triazolo[1,5-b]isoquinoline (6) seems slightly more stable due to the contributing
resonance structures (137) but its chernical reactivity remains to be explored (77H(6)949). Its
2-methyl derivative does undergo a Diels-Alder reaction with maleirnide derivatives
(77H(6)949) that involve the C-5jC-10 positions (see 137 for numbering).
10 -
oa N oa N
I )R..- I R
...:::t:;i'N ...:::t'J'N>
5 -
(137)
An interesting result occurred when [1,2,4]triazolo[5,1-a]isoquinoline (7) was treated
with butyllithiurn. Instead of obtaining the 2-lithio derivative as would have been expected
by comparison with (5), the 5-lithio product (138) was isolated (71CB396S). Bromination of
(138) gave (139) and reaction with acetaldehyde formed (140) and carbon dioxide yielded
(141). Permitting (138) to warm from -70 to 20 0 C resulted in 1-cyanarninoisoquinoline,
via a sequence of steps requiring initial isomerization of (138) to the 2-lithio compound.
As with (5), the C(5)-C(6) bond of (7) displayed typical alkenic properties (71CB396S).
CO:
I ú _')
N,
R
(138) R = Li
(139) R = Br
(140) R = CH(OH)Me
(141) R = C0 2 H
4.15.3.2 [1,2,3]Triazolopyridines and their Fused Benzo Derivatives
4.15.3.2.1 [1,2,3 ITriazolo[1,5-a lpyridine
Cornpound (8), under Vilsmeier formylation and nitration (nitric acid-acetic anhydride)
conditions, proceeded as might have been expected for electrophilic substitution reactions
to give the l-substituted products (142) and (143). Reduction of (143) gave predominantly
the imidazopyridine (144) with a small amount of the tetrahydro derivative (145)
(81JCS(Pl)78). Heating (8) in 0 2 0 led to the 1-deutero derivative (78HCA17SS) via deuter-
ation-deprotonation or via the tautomeric 2-(diazornethyl)pyridine tautorner of (8).
Triazoles and Tetrazoles with Fused Six-membered Rings
867
N_!\t
(C o :=:-- ßN
-.:Y N
::::::,.,1
(144)
N:2
N !/
-N
(142) R = CHO
(143) R = NO z
On the other hand, reaction of (8) with bromine, chlorine or mercury(II) acetate led to
the ring-opened products (146)-(148). This result was rationalized (SlJCS(Pl)7S) as involving
loss of nitrogen from either (149) or (150; Scheme 4) (SlJCS(Pl)7S). If the electrophile (E)
is an electron-withdrawing group (CHO, N0 2 ), (149) will be longer-lived and deprotonation
competes successfully with the loss of nitrogen. If E is only weakly stabilizing to the
diazonium intermediate (150), nucleophilic attack with loss of nitrogen is preferred. A
similar explanation has been put forward (SlJCS(Pl)78) for the formation of (144) upon
reduction of (143).
(145)
(Q ;.. d;:
(149)
iT Tl
E
-H+ (G c;;;--
( ) N
N_I4'
H H E H E
N2 # N; NU
-N,
(150) (146) E = Nu = Sr
(147) E=Nu=CI
(148) E = HgOAc, Nu = OAc
Scheme 4
Irradiation (À > 200 nm) of (8) matrix-isolated in argon gives l-aza-l,2,4,6-cyclohep-
tatetraene (151) (7SJA2S2,79RTC334) via, first, 2-diazomethylpyridine and, then, triplet
2-pyridylmethylene (152). Continued irradiation leads to triplet phenylnitrene (7SJA6245),
the same product obtained from the irradiation of phenyl azide. Thermolysis of (8) has
given the same results (72TL2239, 74T1301, 75JA7467). The existence of (152) in the photolysis
of (8) has been substantiated by the reported isolation of (153)-(155) on irradiation in
methanol (69JHC503).
CN
(151)
firëH
N
(152)
O IR
::::::,., N
(153) R = Me
(154) R = CHzOMe
(155) R = CHzCHzOH
4.15.3.2.2 [1,2,3 }Triazolo[ 4,S-b]pyridine and [1,2,3 ]triazolo[ 4,S-c}pyridine
There is very little that can be said about the reactivity of these ring systems since most
of the desired derivatives are available by diazotization of an appropriate diaminopyridine
(see synthesis section) and reactivity of the bicycle is not necessary to make the various
compounds. In any event, alkylation of both (9) and (10) yields all possible N-l, N-2 and
N-3 isomeric products (71RTCllS1, l,i5IJCS4, 76JOC1449) and a chI oro substituent in either
system is readily displaced by nucleophiles (73JOCI095,76JOC1449). A rearrangement has
also been reported to occur in this series when 4,6-diamino-lH-[1,2,3]triazolo[4,5-
c ]pyridine (156) was treated with 12% ethanolic ammonia in a bomb at 150 oc and found
to give 85% conversion to 5,7-diamino-3H-[1,2,3]triazolo[4,5-b]pyridine (157) after 120
hours. This rearrangement was believed to involve diazopyridine intermediates such as
(158) and (159) and indicated that (157) was thermodynamically more stable than (156)
(73JOCI095). No conversion of (157) into (156) was observed up to 175 oc.
868
Triazoles and Tetrazoles with Fused Six-membered Rings
N (t N1I 1 2 N (( NH I 2 N"N N O N II 2 Ñ?N a N I/ 2 Ñ?N
H 2 N :::::,.., N I I
H 2 N '>-.N N H1N:::::,.., NH H1N '>-.N NH
H H
(156) (157) (158) (159)
Another interesting rearrangement in this series occurred (76JOC3784) when (160) was
treated with sodium hydrogen sulfide in butanol and found to give the expected (161) and
the [1,2,3]thiadiazolo[4,5-c]pyridine (162). Furthermore, heating (161) gave (162) whereas
heating (162) in the presence of potassium carbonate gave (161).
CI S
(X I N"N Lx "
H N '>-. I H N I N IN
2 N N 2 N N
H H H
(160) (161) (162)
Pyrolysis of (9) and (10) at 500 oC gave 2-cyanopyrrole and 3-cyanopyrrole, respectively,
which were interconvertible at 800 oC (70T3965).
NH 2
f\!.çyN,
H2N S N
4.15.3.2.3 [1,2,3 ]Triazolo[1,5-a ]quinoline
Compared to many other fused 1,2,3-triazoles described herein, (11) is remarkably stable
as evidenced by its inertness to irradiation and to heat (72JOC2022). This stabilization was
rationalized as the consequence of extensive 'T1'- electron de localization in the tricyclic system.
4.15.3.2.4 [1,2,3]Triazolo[ 5,1-a ]isoquinoline
In contrast to (8), compound (12) is reasonably stable (75CB3794), undergoing hydrogena-
tion and oxidation at the C(5)-C(6) double bond to give (163) and (164), respectively.
Also, (12) undergoes base-promoted deuterium exchange at C-5 (75CB3794).
I
:::N
(163)
":::
::;::;--
C0 2 H NH
N - I
-N
(164)
4.15.3.3 [l,2,4]Triazolopyridazines and their Fused Benzo Derivatives
4.15.3.3.1 [1,2,4 ]Triazolo[ 4,3-b ]pyridazine
[1,2,4 ]Triazolo[ 4,3-b ]pyridazines are very reluctant to undergo electrophilic substitution
reactions (74MI41501) but they do undergo hydrogen-deuterium exchange under acid- and
base-catalyzed conditions. Under acid only H-3 was exchanged but with base the exchange
reaction followed the order of H-3>H-8>H-7>H-6. The mechanism for the acid-
catalyzed exchange involves (165) as the initial produ t; (165) then rearranges to (166) via
an H-3 deprotonation step (74MI41501). In the base process, H-3 is removed to form the
C-3 anion which is then deuterated (74MI41501).
D
N'N o: ---N,
_ /N.J '>-. /N.JN
N + N D
(165) (166)
As structure (165) indicates, N-1 is the most basic center in (13). This was further
supported (69JHC559) upon methylation of (13) to give exclusively (167). However, it is
Triazoles and Tetrazoles with Fused Six-membered Rings
869
interesting to note that methylation of 3-methyl- (168), 8-methyl- (169), ami 3,8-dimethyl-
[1,2,4)triazolo[4,3-b)pyridazines (170) gave mixtures of N-l and N-2 quaternized products
(171) and (172) in the ratios of 2:1,1:2 and 1:4, respectively. From these results and
MO calculations, it was concluded (69JHC559) that the 8-methyl group exerts a steric effect
at N-l and the 3-methyl group demonstrates an electronic effect by increasing the electron
density at N-2. In the 3,8-dimethyl case, where both the steric and electronic effects favor
methylation at N-2, a 4: 1 ratio in favor of N-2 methylation was observed.
U e
I '
::,.., ....NJ N I -
N +
R 1
a -..-I;'!, (168) R 1 =H,R 2 =Me
zN (169) R 1 =Me,R 2 =H
....N-{ (170) R 1 =R 2 =Me
cx e
I \
o....NJN I-
ON + Me
(171)
o: N\
NMe
,/ N:::::/
N " Me 1-
(172)
(167)
Under the reaction conditions employed, these quaternizations were irreversible and the
products were stable except to heat upon which they lost the N-methyl group (69JHC559).
However, upon heating these derivatives in a sealed tube, rearrangements occurred
(69JHC559). Heating (173) at 255 oC for 45 minutes give a mixture (65: 35) of (173) and
(174). On the other hand, heating (174) at 215 oC for 25 minutes afforded the same products
in a 33: 67 ratio of (173) to (174). This thermal equilibrium is shown in Scheme 5.
Me Me
N,
/ JN
(173)
Me
2SS'C a: N,
( ,Þ NMe
21S C N:::-- /
N'/ + "'"
(174)
Scheme 5
Free radical chlorination of the [1,2,4 ]triazolo[ 4,3-b )pyridazine' ring system follows a
stepwise introduction of the chlorine atoms in the following order of positions: 3> 8 > 7 > 6.
This eventually leads to the perchloro derivatives (74MI41501). .
Oxidation of [1,2,4]triazolo[4,3-b]pyridazines with selenium dioxide has produced the
3-oxo derivatives (175) (76JHC639), compounds also available by ring closure from 3-
chloropyridazines and semicarbazide (71JHC415). Catalytic hydrogenation (75G1291) of (13)
produces the 7,8-dihydro derivative (176) whereas a similar hydrogenation of the 6-chloro
derivative of (13) gave (13) and (176). On the other hand, reduction of (13) with sodium
borohydride (76JHC835) gives the 5,6,7,8-tetrahydro derivative (177). This reduction pro-
ceeded through (176).
R 1
N'NH Q: N, ("y:::N,
RZ N/N N/NJN N/NJN
o H
(175) (176) (177)
Hydrazinolysis of (13) produced a 3-(2'-pyrazolin-3'-yl)-[1,2,4]triazole (178) (nJHcl171).
The mechanism for this process is given in Scheme 6 which indicates that the addition of
hydrazine occurs at the N(5)-C(6) bond of (13) and this is followed by bond cleavage.
Hydrazinolysis of (167) resulted in the tricyclic product (179) via an intramolecular cycliz-
ation (74MI41501). Ring opening of another quaternized derivative of (13) occurred when
N, [ N, N, J
N....NJN -+ HzNHN N/NJN -+ ìlN
(13) H H I 2
HzN
/
N, N,
\. N-ßN'- \...NH N--.fN
... NHz NHz
(178)
Scheme 6
870
Triazoles and Tetrazoles with Fused Six-membered Rings
(174) was found to produce (180) and (181) when reacted with base (74MI41501). This rin&
opening involved breakage of the C(3)-N(4) linkage of (174).
Me
N-N
NJ O Me I NHN(Me)CHO O Me I NHNHt\1e
N_N N ::,... /N ::,... /N
H H N N
(179) (180) (181)
Oxidation of the [4,3-b ]pyridazine ring system with potassium permanganate occurs by
cleavage of the C(7)-C(8) bond. Thus, 3-phenyl-[1,2,4]triazolo[4,3-b]pyridazine was
oxidized to 3-phenyl-l,2,4-triazole-5-carboxylic acid (74MI41501).
[1,2,4 ]Triazolo[ 4,3-b ]pyridazine undergoes a number of [3 + 2] photocycloadditions with
cyclic and open chain alkenes; the products result from the addition of the alkene to
positions 1 and 8 of (13) with concurrent opening of the pyridazine ring (77JHC41l) at
N-4/N-5 as illustrated in Scheme 7. The mechanisrn for this reaction involves the radical
addition of the alkene to the excited triazolopyridazine at its C-8 position. This is believed
to be followed by a sequence of steps that include homolytic cleavage of the N(4)-N(5)
bond, formation of a nitrene at the former N-S center with concornitant ring closure by
the side-chain alkyl radical (from the alkene addition) onto the former N -1 atom, and either
retention (for molecules like 183) or loss (for molecules like 182) of hydrogen cyanide
(73JHC801).
HZ ,CN
VNì-==::N + N N
o N, J N, J
(182) N (183) N
N,
_ -/ JN
N
(13)
CH l CH 2 CN
O N) +O N)
'N 'N
Scheme 7
Cornpound (13) has also been shown to undergo photoalkylation at its C-7 and C-8
positions when irradiated in the presence of an alcohol (74JOC793, 80JOC2320). These reactions
proceed through the alkylated 7,8-dihydro derivatives (184) and (185) which, upon heating,
undergo dehydrogenation-hydrogenolysis to (186) and (187). This is illustrated in Scherne
8. In sorne cases (74JOC793) the unsubstituted 7,8-dihydro derivative (188) is also obtained.
The other product in this case was the aldehyde corresponding to the alcoholic side chain
arising from some type of retro-aldol process involving (184) and (185).
RCHOH
RCH_OH a N \
N
hv '" N //
N / --.:/
(184)
1
N\
../ -ßN
N
(13)
RIHO)CH U N ,
+ N
'" / N--ß
N
(185)
1
Q: N\
"'N/N-ßN
(188)
a RCHl N
::7 "'\
'" /N-ßN
N
(186)
Scheme 8
RCH2 N\N
../N--ß
N
(187)
4.15.3.3.2 [1,2,4 ]Triazolo[3,4-a]phthalazine
Compound (17) can be brorninated at its 3-position with N- brornosuccinirnide or brornine
and the resulting bromo compound (189) is susceptible to nucleophilic substitution
Triazoles and Tetrazoles with Fused Six-membered Rings
871
(69JOC3221). Nitration of 6-methyl-[1,2,4]triazolo[3,4-a]phthalazine in fuming nitric acid-
concentrated sulfuric acid produced the 8-nitro cornpound (190). On the other hand,
attempted nitration of (17) with copper nitrate-acetic anhydride gave only the 3-acetyl
compound. The Vilsmeier formylation failed on (17) (69JOC3221); however, deuterium
exchange occurred at C-3. The 3-carbaldehyde (see synthesis section) underwent the benzoin
condensation and was oxidized to the 3-carboxylic acid.
tù
I N
-- \
N"N--ßN
H
(189) (190) (191) (192)
Methylation of (17) with methyl iodide in boiling methanol gave N-2 methylation whereas
room temperature methylation gave the N-l isomer. Reduction of (17) with lithium
aluminum hydride or sodium borohydride gave the 5,6-dihydro derivative (191) (69JOC3221)
while catalytic hydrogenation of the 6-chloro derivative of (17) produced (192) (7SG1291),
the same product isolated from treating (17) with alcoholic potassium hydroxide (69JOC3221).
Compound (17) was stable towards hot mineral acids (69JOC3221).
tù
I N
-- \
'" "N --ßN
N Br
02N 2x
N
-- \
Me '" "N--ßN
N
Qy
I
:;:::N ,
NC NH
N
4.15.3.3.3 [1,2,4 ]Triazolo[1,5-b ]pyridazine
As with (13), compound (14) is very reluctant to undergo electrophilic substitution
reactions (74MI41S01) and, besides its [3 + 2] photocycloaddition with cyclohexene (73JHC801)
and hydrazinolysis (74JOC2143) as with (13) (see Schemes 7 and 6, respectively), very little
has been done with the unsubstituted ring system (14) (74MI41S0J). On the other hand, a
great deal is known about 6-chloro-[1,2,4]triazolo[1 ,5-b ]pyridazine (193). Its chlorine has
been replaced by a large number of nucleophiles to give (194). The 6-azido compound has
been prepared by nitrosation of the 6-hydrazino system and from the tetrazolo[1,5-
b ]pyridazine (195) by formation of the triazole ring and tetrazolo-azido isomerization
(74JOC2143). Methylation of the 6-oxo compound (194c) afforded the 6-methoxy (194e)
and N(5)-methyl compounds. Chlorination of (193) gave 6,7,8-trichloro[1,2,4]triazolo[1,5-
b ]pyridazine (74JOC2143). Hydrogenation of (193) over palladium formed the tetrahydro
material (196) (74JOC2143). A similar set of reactions has been carried out on 6-chloro-
[1,2,4]triazolo[1,5-b ]pyridazine 3-oxide (76JHC487).
(193) X = Cl
(194a) X = NH z
(194b) X = NHNH z
(194c) X=OH
(194d) X = SH
(194e) X = OMe
(195)
er N
-->
N"N'
H
(196)
a N
-- >
x "'N/N-t-f
CX N,
;,N
HON=HCHN "'N"N'Ní'
Oxidation of 2-phenyl-[1,2,4 ]triazolo[1,5-b ]pyridazine with potassium permanganate
yielded 3-phenyI-1,2,4-triazole-5-carboxylic acid (74MI41S01).
4.15.3.4 [1,2,3]Triazolo[ 4,S-d]pyridazine
As mentioned in the synthesis section, most derivatives of this ring systèm can be prepared
by the diazotization of a variety of 4,5-diaminopyridazines and reactions on (15) and its
derivatives for additional representatives are not necessary. In any case, 4-methylthio-
[1,2,3 ]triazolo[ 4,5-d]pyridazine (197) has proven to be a versatile intermediate due to its
reactions with nucleophiles (amines, hydrazine, ammonia) (69JHC93) that replace the 4-
methylthio group. Since the synthesis of (197) involves reactions of substituted
[1,2,3]triazolo[ 4,5-d]pyridazines, it is described here in Scheme 9 rather than in the
synthesis section. There is another report that demonstrates that the 4-methoxyl group
may be more versatile than the methylthio group in the nucleophilic substitution reactions
in this series (70CPB168S). Similar substitution reactions have been documented for the
isomeric [1,2,3]triazolo[4,5-c ]pyridazines (64JHC247, 67JHCS5S).
872
Triazoles and Tetrazoles with Fused Six-membered Rings
:) 0 )= 0 N )= s N SMe
HN I NH2 HN I '" HN I " N :X 1 N
I -- I N-- I N-- I N
N"" NH 2 N"" N N N/ N N/
H H H
(197)
Scheme 9
4.15.3.5 [1,2,4]Triazolopyrimidines and their Fused Benzo Derivatives
4.15.3.5.1 [1,2,4 ]Triazolo[ 4,3-a ]pyrirnidine and [1,2,4 ]triazolo[4,3-c]pyrirnidine
The most significant reactions of ring systems (18) and (19) are the Dimroth-like rear-
rangements into their [1,5-a] and [1,5-c] isomers, respectively. These transformations are
discussed in Sections 4.15.4.5.1 and 4.15.4.5.3.
4.15.3.5.2 [1,2,4 ]Triazolo[1,5-a]pyrirnidine
Electrophilic substitution occurs in (20) at C-6 (61CPB808) which is also the site of
acid-catalyzed deuterium exchange (68JOCI087); in contrast base-catalyzed deuterium
exchange occurs at C-7 (68JOCI087). Methylation and protonation of (20) take place at
N-3 to give (198a) and (198b); hydrolysis of (198a) formed 3-arnino-4-methyl-l,2,4-triazole
(199) (68JHC691). Treatment of (20) with phenyllithium gave the 7-phenyl- (200) and
5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidines (201). This was believed to be the result of a
greater delocalization of the electrons into the 5-membered ring due to resonance con-
tributors (202) and (203) to the ground state which rendered the pyridine ring electron
deficient at C-5 and C-7 (72JHC1157).
N
C'r)
x-
(198a) R = Me
(198b) R=H
Me
N
H 2 N( i;
N-N
N N
R 2 C Y >
::::,... N N
R 1
(199)
(200) R' = Ph, R 2 = H
(201) R 1 = H, R 2 = Ph
N - N
C yN> +-+ C yN
::::,... N ::::,...
(202) (203)
A number of 5- and 7-monosubstituted and 5,7-disubstituted [1,2,4]triazolo[1,5-
a]pyrirnidines have resulted from reactions on the 5,7-dihydroxy, -aminohydroxy and
-hydroxymercapto derivatives. The hydroxy derivatives were amenable to chlorination
which was followed by a variety of nucleophilic substitution reactions or hydrogenolyses.
The mercapto groups were susceptible to alkylation and subsequent nucleophilic substitution
(6ICPB801,63CPB845).
Substituted [1,2,4]triazolo[1,5-a]pyrimidine I-oxides appear to be vulnerable to heat-
prornoted valence tautomerism into isomericN-oxides via a nitrosoimine as the interconver-
sion shown in Scherne 10 illustrates (74CC486).
0-
\ Ar
+N=\
I
N N N N N N
Me C Y >Ar Me c y ')-Ar Me C I
::::,... N Ñ . ::::,... N NO ó N
Me I Me Me
0_
Scheme 10
Triazoles and Tetrazoles with Fused Six-membered Rings
873
4.1S.3.5.3 [1,2,4 ]Triazolo[1,S-c ]pyrirnidine
Under certain hydrolytic conditions [1,2,4]triazolo[1,5-c ]pyrimidines undergo ring fission
to produce the same amides (204) as shown later in the ring opening-ring closure isomeriz-
ation of the [4,3-c] series into the [1,5-c] series (see Scheme 11). There is no indication
of (204) closing to form the thermodynamically less stable [4,3-c] system and, in some
cases, it ring closes back to the initial [1,5-c] system (7SAJC2S0S). There was, however, an
exception to this when 5-methyIthio-[1,2,4]triazolo[I,5-c ]pyrimidine (205) was treated with
hydrazine; the rearranged product (206) was obtained rather than the expected [1,5-c]
isomer (207) (79KGS262).
N>
N N_r:
NH
NH 2
(204) (205) (206) (207)
A variety of 2-substituted [1,2,4]triazolo[I,5-c ]pyrimidines were obtained when
2-bromo derivative (Scheme 11) was treated with nucleophiles (65JCS33S7).
H(Y H )
OCR N-N
N>
N N-N
SMe
N'N
N N-.ß
NHNH 2
the
R 1 (]NHNH 2 CICOzEt) R 1 (]NHNHC0 2 Et RI N>=O
N N N N N N_N
R 2 R 2 R 2 H
1 A/solvent 7 1 POBr,
RI N\ RI
I I NH I I' )Br
N N____/ N N-N
R 2 . 1> R 2
Scheme 11
4.15.3.S.4 [1,2,4]Triazolo[ 4,3-c ]quinazoline and [1,2,4]triazolo[1,S-c]quina;oline
The most significanÚeactions of (22) and its derivatives are the Dimroth-like rearrange-
ments to the [1,5-c] isomers discussed in the synthesis section. The [1,5-c] compounds do
not rearrange into the [4,3-c] derivatives.
Treatment of (22) with hot aqueous sodium hydroxide gave 3-(2-aminophenyl)-I,2,4-
triazole (208). Evidence that this latter reaction involved an initial attack of hydroxide ion
at the 5-position arose from the isolation of 3-(2-benzamidophenyl)-1,2,4-triazole (209)
upon the action of hot base on 5-phenyl-[1,2,4]triazolo[4,3-c]quinazoline (210).
Apparently, under these rearrangement conditions, hydrolysis of the intermediate amide,
for example (209), is faster than ring closure to the [1,5-c] isomer. Similar ring opening
reactions were observed with the [1,5-c] series, a system which also underwent typical
alkenic addition reactions at the C(5)-N(6) double bond (70JOC344S).
Qy
1# N
RHN 'N
HN....j'
(208) R=H
(209) R = COPh
Qy ":::
# N
=-- \
N
N N--f'
Ph
(210 )
4.15.3.S.S [1,2,4]Triazolo[1,S-a]quinazoline
An example of the work done on this ring system is in the ease with which the 5-chloro
derivative (211) underwent nucleophilic substitution (SOHCA1). Compound (211) was pre-
pared from the corresponding 5-oxo substance and oxalyl chloride (SOHCA1).
874
Triazoles and Tetrazoles with Fused Six-membered Rings
(Ç lr NYN )
-...:::::: N'-N
I
(211)
4.15.3.5.6 [1,2,4]Triazolo[5,1-b ]quinazoline
Apparently, the o-quinoid arrangement in (25) has precluded it from a systematic
reactivity study. This is substantiated by the preparation of the 9-oxo derivative (212) which
prefers to exist in the keto tautomer shown rather than the enolic one (213) which would
involve the less stable 0- quinoid structure (79JCS(P2)1708).
üÇ l Y'N> C( r NyN )
N-N N-N
OH
o
(212) (213)
4.15.3.6 [l,2,3]Triazolopyrimidines and their Fused Benzo Derivatives
4.15.3.6.1 [1,2,3 ]Triazolo[1,5-a ]pyrimidine
Using 5,7 -dimethyl-[1,2,3]triazolo[1,5-a ]pyrimidine (214), N- bromosuccinimide in
chloroform yielded not the expected 3-bromo product (215), but 2-(a,a-dibromomethyl)-
4,6-dimethylpyrimidine (216) and, in lesser amounts, 4,6-dimethylpyrimidine-2-carbal-
dehyde diethyl acetal (217) (76JOC385). The latter product was due to ethanolysis of (216)
by the trace amounts of ethanol in the solvent since, following its removal, (216) was the
only product. Use of N-chlorosuccinimide and iodine monochloride proceeded in the same
way giving rise to (218) and (219), respectively. The mechanism for these transformations
is illustrated in Scheme 12 and is postulated to involve a 'diazonium cation' (76JOC385).
N
Me C 'r"'N
N-J
Me
(214)
N Br
Me C N
N-J
Me
(215)
N
Me C Ì1CHXY
N
Me
(216) X = Y = Br
(218) X = Y = Cl
(219) X=I. Y=Cl
N
Me C Ì1CHlOElh
N
Me
(217)
N
Me C N
N-J
Me
F
X H
X. Me c N0 + Me c N Ì1CHXY
N N -N 2 N
Me Me
X = Br, Cl, I
Y = Br, Cl
N -
Me C ìI"N+
N III
Me N
Scheme 12
A similar mechanism has been proposed for the ring opening of the 3-phenyl derivative
of (214) in acetic acid to give the acetoxybenzylpyrimidine compound (220; Scheme 13).
In this reaction, the proton of the acetic acid adds to the diazonium intermediate and this
is followed by acetate displacement of the nitrogen (71JCS(C)2156). It is interesting to note
that the 3-amide (221) did not ring open in acetic acid apparently due to stabilization of
the diazo zwitterionic species in equilibrium with (221) (see Scheme 12).
Triazoles and Tetrazoles with Fused Six-membered Rings
M C N CONH2 N CONH 2
c r::o-- Me c
N II W
N-...r-1 N "'
Me Me N
(221)
[ N Ph ] N
Ph C 'i""N -+ Ph C ìfH(OAC)Ph
N-...r-1 N
Me Me
(223) (224)
N Ph N
Me C N Me C ìfH(OAC)Ph
N-...r-1 N
Me Me
(220)
Ph
H: 2 N,-::::::'\ PhCOCH 2 COMe
I'N )
HN-...J AcOH
(222)
875
Scheme 13
Condensation of benzoylacetone with (222) in acetic acid did not form (223) but rather
(224). Compound (223) is most certainly formed in this process since a customary method
for preparing the [1,2,3]triazolo[1,5-a ]pyrimidine molecule was used; however, upon forma-
tion, (223) rearranged to (224) under the acetic acid conditions (Scheme 13) (71JCS(C)2156).
4.15.3.6.2 [1,2,3 jTriaz%[1,5-c ]pyrimidine
Since trifluoroacetic acid was known to favor the open chain tautomer in the
azidoazinejtetrazoloazine isomerization (see the tetrazole portion of this section), it was
felt that traces of trifluoroacetic acid would shift the equilibrium in favor of (225) over
(27). However, addition of trifluoroacetic acid to a wet DMSO or chloroform solution of
(27) gave the covalent hydrate (226) which was suggested to be in equilibrium with the
open form (227; Scheme 14) (78JHCI041).
+
I I'N I II 'N
N N-...J N N \_
(27)
(225)
HCOHNHC=CH,-::::::'\
I I 'N , NH
HN)(N-"'Ñ N N
HO H
(226) (227)
Scheme 14
4.15.3.6.3 [1,2,3]Triaz%[4,5-d]pyrimidine
Methylation of the parent system (28) with dimethyl sulfate gave the 1-,2- and 3-methyl
isomers in a ratio of 1.5: 1: 1.1 (69JCS(C)1084). 3-Substituted derivatives of (28) underwent
reaction with Grignard reagents to form the 7-alkyl-6,7-dihydro derivatives (228) which
were transformed into the unsaturated analogs (229) upon oxidation with potassium fer-
ricyanide (79CPB3176). The most acidic proton in 3-substituted (28) is at C-7 (79CPB2431).
These systems also undergo covalent hydration (66JCS(B)427, 66JCS(B)438) to give the 6,7-
dihydro-7 -hydroxy product. At room temperature in dilute acid or base [1,2,3 ]triazolo[ 4,5-
d]pyrimidines are hydrolyzed to 4-amino-1,2,3-triazole-5-carbaldehydes (230)
(77JCS(Pl)1819). The mechanism advanced (77JCS(Pl)1819) for this is given in Scheme 15
showing that hydration occurred at C-5.
H R 2
HN><Y- 'N
__Jl /
N 1
(228)
:x R2 N
N I "N
/
N N
R 1
(229)
N J .. R HN :C .. R OHC C .. R OHC C .!)(R
: :N -+ ::N -+ ::N -+ ::N
N "ï / OHCHN "' / OHCHN ... I H 2 N \,:{
(230)
Scheme 15
876
Triazoles and Tetrazoles with Fused Six-membered Rings
[1,2,3 ]Triazolo[ 4,5 -d]pyrirnidines are also susceptible to ring opening by active methylene
compounds wherein the initial reaction takes place at C-7 (79CPB2861), analogous to the
Grignard process described previously. For example, reaction of the parent cornpound with
malononitrile gave (231) which, upon treatment with alkali, ring closed to the
triazolopyridine (232; Scheme 16). Similar triazolopyridines (233)-(235) were obtained
from (28) and cyanoacetamide, pentane-2,4-dione and ethyl acetoacetate (73JCS(Pl)1620).
Aliphatic and cyclic ketones also have been used in this reaction with (28) (79CPB2861).
NrN N ---. (CNhC=HCrN"N ---. NC 'N
.. )l.N 1 HlNHC=Nl!....N 1 HlN N)l.N
N H H H
(28) (231) (232)
(233) R 1 = NH 2 , R 2 = CONH l
(234) R t = Me, R 2 = COMe
(235) R 1 = Me, R 2 = C0 2 Et
Scheme 16
Pyrolysis of (28) did not give a cyanoimidazole as would have been expected based on
the pyrolysis of [1,2,3]triazolo[ 4,5-b ]pyridine which gave 2-cyanopyrrole (70T396S). Instead,
(28) produced hydrogen cyanide and ammonia.
Further reactivity studies can be found in the many pyrimido-substituted
[1,2,3]triazolo[4,5-d]pyrimidines (as 8-azapurines) which undergo various transformations
(for example, nucleophilic substitution of chlorine substitutents, diazotization of amino
groups, etc.) to produce potentially biologically useful molecules (6IJOC4433,72JMC879). In
addition hydrogenation occurs to form the 6,7-dihydro derivatives (66JCS{B)427).
R2 N N
Rl ..J-- I
N N
H
4.15.3.6.4 [1,2,3 ]Triazolo[I,5-a]quinazoline
The investigations (66JCS(C)2290) On the reactivity of this ring system have centered around
5-oxo-3-phenyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]quinazoline (see Scheme 17) whose pre-
paration is given in Section 4.15.4.6.4. The latter two reactions in Scheme 17 resemble
those discussed previously for [1 ,2,3]triazolo[1 ,5-a ]pyrimidines and depicted in Scheme 12.
N Ph Me Ph
M (Ç O r N (5 0 N N
N_ It + N It
I N '-':::-N
# '#
H
(5 0 NìfH(OAC)Ph
'-'::: N
I
#
Mel
K,CO,
(5 0 N
N I;
-N
I
AcOH
H
á o NìfHClPh
N
'#
AcCI
---+
AcOH
Scheme 17
4.15.3.7 Triazolopyrazines and Their Fused Benzo Derivatives
4.15.3.7.1 [1,2,4]Triazolo[4,3-a]pyrazine
As will be described in the synthesis section, [1,2,4]triazolo[4,3-a]pyrazines can be
induced to rearrange to their [1,5-a] isomers in basic or acidic solution (7IJHC643). On the
Triazoles and Tetrazoles with Fused Six-membered Rings
other hand, the nucleus is very stable to oxidation by hot potassium permanganate (68JHC48S)
but gives the 7-oxide (236) upon treatment with peracetic acid (80JCS(Pl)S06). Reaction of
(236) with acetic anhydride gave (237) and with phenyl isocyanate it gave (238).
o
HN N\
N--.fN
Õ'Ñ N\
N--.fN
(236)
(237)
X N
N \
N--.fN
(238) X = NHPh
(241) X = OMe
(243) X = NH 2 (3-Ph)
877
N N\
N--.fN
X
(239) X = Br
(240) X = OMe
(242) X = SPh
OMe
N N\
N-J'N
Ph
(244)
Bromination of (31) yielded the 5-bromo derivative (239) (77JOC4197). Reaction of (239)
with sodium methoxide yielded the 5- and 8-methoxy compounds (240) and (241)
(77JOC4197). The latter product arose by the tele substitution pathway involving attack by
the methoxide ion at C-8. Inexplicably, sodium thiophenoxide produced only the C-5
product (242). If a large group is present at C-3, the C-8 substitution product is the only
one obtained with no indication of the C-5 isomer (77JOC4197). Treatment of 5-chloro-3-
phenyl-[1,2,4]triazolo[4,3-a]pyrazine with ammonia resulted in (243) which could also be
obtained from the 8-methoxy-3-phenyl compound (244). Attack by the nucleophile at C-8
in all of these cases is promoted by the electron-withdrawing capabilities of N-7 (77JOC4197).
With this in mind, it is not surprising that 8-chloro-[1,2,4]triazolo[4,3-a]pyrazines are
susceptible to C-8 substitution by many nucleophiles (78JHC987).
The 3-amino substituent of various [1,2,4]triazolo[4,3-a]pyrazines can be acylated
(69JCS(C)1S93) but it is inert towards normal diazotization procedures (68JHC48S). The
3-hydroxy compound could not be chlorinated with phosphorus oxychloride and in the
IR spectrum it appeared to exist in both the keto and enol forms (68JHC48S).
Both the [4,3-a] and [1,5-a] compounds are susceptible to hydrazinolysis and form
triazole products. This ring cleavage proceeds via attack of the hydrazine at the electron
deficient C-5 or C-8 positions of the bicyclic starting compound (76H(4)943).
4.15.3.7.2 [1,2,4jTriazolo[1,5-ajpyrazine
Bromination of the parent system (32) resulted in the 5-bromo derivative which with a
variety of nucleophiles at elevated temperatures could be converted into other 5-substituted
[1,2,4]triazolo[1,5-a]pyrazines (245). At room temperature, tele substitution occurred and
the C-8 products (247) were obtained (74TL4S39). Base-catalyzed deuterium exchange occurs
at C-5 of (32) and treatment with hot, 50% aqueous sodium hydroxide formed 3-
aminomethyl-1,2,4-triazole (246) and glycolic acid as a result of base attack at C-5.
X
N N>
N_J
N
H 2 NH 2 C( >
HN_j
N N>
N_J
X
(245) X = SH, SPh, OEt, NHNH 2 (246) (247) X = NHNH 2 , NHOH, NH 2
Oxidation of (32) with peracetic acid or rn-chloroperbenzoic acid gave the 7-oxide (248).
Compound (248) was converted into (249) with phosphorus oxychloride and the chlorine
atom of (249) replaced by hydrazine to give (250) (80JCS(Pl)S06).
X N
N >
N_
O,+ N
N I=-- \
N_ (I
(248)
(249) X = CI
(250) X = NHNH 2
o 0
N N
N_
o
(251)
4.15.3.7.3 [1,2,3jTriazolo[1,5-ajpyrazine
Heating [1,2,3]triazolo[1,5-a]pyrazine (33) in deuterium oxide caused three protons to
be exchanged and for (251) to result. NMR evidence indicated that H-5 was the first one
exchanged followed by H-l and then H-8 (78HCA17SS).
878
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.3.7.4 [1,2,3 /Triaz 010[4, 5-b /pyrazine
1- Benzyl-5,6-dimethyl[ 1 ,2,3 ]triazolo[ 4,5-b ]pyrazine was inert towards aqueous hydro-
chloric acid, aqueous base or hydrazine hydrate (nJOc4124) and the benzyl group resisted
removal when the ring system was treated with sodium in liquid ammonia or hydrogen.
These examples indicate that the ring system represented by (34) is very stable (nJOC4124).
4.15.3.7.5 [1,2,41Triazolo[4,3-a]quinoxaline
As mentioned in Section 4.15.4.7.5, this ring system does not rearrange to the [1,5-a]
isomers but is oxidized to 4-ones with potassium permanganate (70KGS851) even if a methyl
group is present at the 4-position prior to oxidation.
4.15.3.8 (1,2,4]Triazolotriazines
4.15.3.8.1 [1,2,41Triazolo[I,2,4]triazines
In addition to the rearrangements discussed later in the synthesis section (for example
[3,4-c ].....[5, l-c] and [4,3-d] ..... [l,5-d]) there are several other reactivity features of these
triazolotriazines that are worthy of note. For exarnple, [1,2,4 ]triazolo[ 4,3-b ][ 1 ,2,4 ]triazines
are stable to heat, boiling acetic acid and pyridine and upon nitration (if the 3-position
is unsubstituted) give the 3-keto products as shown by (252) (76JCS(Pl)1492). The [4,3-b]
corn pounds react with Grignard reagents to produce 7-substituted derivatives (77JOCI018)
and if the [4,3-b] and [5,I-c] systems possess a triazole amino group, they are susceptible to
diazonium reactions which are often used as a route to the unsubstituted derivative
(7óJCS(PI )1492).
N==,,\
HO I N
( N N J: N
Ph /" 10-- 'NH Ph I
Ph N/N'ì\' Ph N/NH
(252) 0 (253)
[1,2,4 ]Triazolo[5, 1-c][ 1 ,2,4 ]triazines are stable to acids, bases and heat (76JCS(Pl) 1492)
and do not undergo rearrangement. Interestingly, when 6,7-diphenyl[I,2,4]triazolo[5,I-c]-
[1,2,4]triazine was warmed in 1N hydrochloric acid, a covalent hydrate (253) was obtained.
Alcohols also added in a similar covalent fashion (76JCS(P1)1492).
4.15.3.8.2 [1,2,4/Triazolo[I,3,5/triazines
The hydrolytic reactions of the rnethoxy derivatives (254) and (255) were used in a
structure proof (70T3357) and show the interesting reactivity in this series. This is shown in
Scheme 18.
Mt:O(NyN'N
N N--.f
Ph
(254)
N
cone HCI H 2 NCOHN'-;:::- ,
. Þ I N
HN-Þ'
Ph
N N
(Y'N
N N /; H 2 0
-...y
OMe Ph
(255)
H
(( NyN'N
N y N-.ß
Ph
o
Scheme 18
In the [1,5-a][1,3,5] system it should be mentioned that 5-azaadenine could not be
diazotized to 5-azahypoxanthine (65JA 1980). Methylation of this latter compound produced
the 6-methyl derivative (65JA1980) shown in Scheme 19.
(N yN ) ---4 (NyN)
HNyN N MeNyN N
o 0
Scheme 19
Triazoles and Tetrazoles with Fused Six-membered Rings
879
4.15.3.9 Tetrazolopyridines and their Fused Benzo Derivatives
4.15.3.9.1 Tetrazolo[1,5-a]pyridine
Nitration of (46) gave (256) and bromination yielded (257) (71T5121). The presence of
the azido tautomeric form in this series has been determined, for example, by reaction of
(46) with dimethyl acetylenedicarboxylate to give (258) (71T5121), by cycloadditions with
enamines (65TL1965) and by therrnolysis to form, primarily, 2-cyanopyrrole (76JA1259). The
last product was proposed to have come from 2-pyridylnitrene which, in turn, arose from
loss of nitrogen from the azido tautomer (70T4969, SOJA6159). Methylation of (46) produced
(259) (75JCS(Pl)1232) while reaction of it and its derivatives with triphenylphosphine formed
the iminophosphoranes (260) (71T5359).
(256) X = N0 2
(257) X = Bf
N/N"'N
(j( \d
N R R
(258) R = C0 2 Me
Me
a N
I \
- t
x-
R ' 0 1 N=PPh3
R2 N
N\
x N- l
(259)
(260)
4.15.3.9.2 Tetrazolo[1,5-b ]isoquinoline
Bromination of (47) led to 3-azido-4-bromoisoquinoline (261). On the other hand,
trifluoroacetic acid caused only the tetrazolo tautomer (262) to exist in the equilibriurn of
(47) with its azido partner. This is due to elimination of the unfavored 0- quinoid structure
(47) from the tautorneric equilibrium and formation of the more stable naphthalenic
structure (262) which, consequently, is preferred over the azido form (SlJOCS43). To extend
this equilibrium study further, NMR investigations on substituted derivatives of (47) indi-
cated that electron-releasing groups on the isoquinoline favor the tetrazolo tautorner whereas
electron-attracting substituents favor the azido tautomer. Furthermore, the tetrazole was
found to be preferred in OM SO solution relative to chloroforrn solution (S1JOCS43).
Br H
00 1 '-':::::N3 m-N\N
,,'iN - t
(261) (262)
4.15.3.9.3 Tetrazolo[1,5-a]quinoline
Pyrolysis of (48) gave (263) and (264), the same products observed from pyrolysis of
(49) (SOJA6159). Both of these processes were believed to involve the common intermediate
(265) which arose from the corresponding 2-quinolylnitrene or l-isoquinolylnitrene. These
latter rnaterials resulted from the loss of nitrogen from the azido tautomers of (48) and
(49) (SOJA6159).
(263)
CN
m
N/
H
(264)
U..;::-l
N
(265)
0 1 CH1CN
CN
4.15.3.9.4 Tetrazolo[ 5,1-a]isoquinoline
The C(5)-C(6) center of (49) shows typical alkenic character by undergoing hydrogena-
tion and oxidation at that site. Deuteration and metal exchange occur at C-5 and the metal
introduced in this way can be replaced by a number of electrophilic groups (for example
C0 2 H). Chlorine atoms at C-5 or C-6 can be replaced by nucleophiles and a C-6 chlorine
atorn is rernovable by an elimination-addition sequence. Nitration of (49) takes place at
C-7 (75CB37S0).
880
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.3.10 Tetrazolo[1,5-b ]pyridazine
Tetrazolo[I,5-b ]pyridazine (50) does not undergo electrophilic substitution even under
the most drastic conditions (74MI41501) whereas methylation, protonation and oxidation
lead to monocyclic products (Scheme 20) due to a shift of the tetrazolo-azido equilibrium
upon creating an electron-deficient pyridazine ring (see Section 4.15.2.8) (74MI41501).
Unlike [1,2,4 ]triazolo[ 4,3-b ]pyridazines, (50) did not undergo photolytically-promoted
cycloaddition with alkenes (in particular, cyclohexene) (73JHC801); however, irradiation of
(50) and its alkyl derivatives did give 3-cyanocyclopropenes and, in trace arnounts, 3-
cyanopyrazoles (ncclo59, 73CPB2517). Also, in contrast to [1,2,4]triazolo[ 4,3-b ]pyridazines,
(50) was not susceptible to photoalkylation with methanol (74JOC793).
Me! N3
N"N
Me [-
H,O, 0 1 N3
PPA ::""Ñ"N
I
0_
Q: o--N\
I. N
"'N"N_N '
(50)
H, S0 4
W IN3
::,...+ N
N"
H HSO;
Scheme 20
Derivatives of (50) are reluctant to undergo hydrogen-deuterium exchange under neutral
or acid conditions but with the 6-chloro derivative, base-catalyzed exchange occurs with
concurrent substitution by DO-(71M837}. Catalytic hydrogenation of (50) produces the
5,6,7,8-tetrahydro product (75G1291), the same product obtained from sodium borohydride
reduction (76JHC835).
A number of reactions of 6-azidotetrazolo[1,5-b ]pyridazine (63CPB348) have been repor-
ted and include (i) reduction to (266), (ii) substitution by alkoxide and hydroxide to (267)
and (268), (Îii) reaction with secondary amines (76JOC3152) to form (269) and (270) in a
thermal process involving irnines and (iv) interaction with ethyl acrylate to give the 1: 2
adduct (271) (74MI41501). Since 6-azidotetrazolo[I,5-b]pyridazine can also, potentially,
form a second fused tetrazole, the equilibrium between 7 -methyl- and 8-methyl-6-
azidotetrazolo[I,5-b]pyridazine (Scheme 21) has been studied {74MI41501}.
N\
X N"N_;N
(266) X = NH z
(267) X=OR
(268) X = OH
(269) X=NHR
(270) X=N=C(R z )NRR 1
Q: N\
H N
a N CH 2 HN", "N_- (f
N.... N N
C0 2 Et
Et0 2 C
(271)
N Me
Me Q: ..... \ Q: N\
N N
N 3 "'N"N_N" N 3 "'N"N_N"
Scheme 21
No reactions analogous to 2-pyridylnitrene (see Section 4.15.3.9.1) could be observed
for (50) decomposing to 2-pyridazinylnitrene (74MI41501).
4.15.3.11 Tetrazolopyrimidines and their Fused Benzo Derivatives
4.15.3.11.1 Tetrazolo[1,5-a]pyrimidine
Treatment of (53) with 1N sodium hydroxide gives the ring opened sodiurn salt of (272)
which, upon acidification, regenerates tetrazolo[1,5-a ]pyrimidine (65JOC826). The gas-phase
Triazoles and Tetrazoles with Fused Six-membered Rings
881
thermolysis of (53) and its derivatives has been reported to yield aminopyrirnidines by
hydrogen abstraction and l-cyanopyrazoles via ring contraction (70T4915, 71T361). These
reactions proceeded via the nitrene (273) which arose from the loss of nitrogen from the
azido tautomer of the corresponding tetrazolo[1,5-a]pyrimidine. Derivatives of (53) have
also displayed cyc1oaddition reactions typical of azides (73S123).
ÌíN N
N-N 1
OH H
(272)
N
( )N:
N
(273)
4.15.3.11.2 Tetrazolo[1,5-c]pyrimidine
In contrast to the [1,5-a] system, this series readily combined with water to form the
covalent hydrate (274) (65JOC829) which arose as a result of the positive character of C-5
caused by the electron-attracting tetrazole ring. None of the azido tautomer (275) could
be detected. Catalytic hydrogenation of (274) produced (276). Thermolysis of (54) and its
derivatives produced 1-cyanoimidazoles by a ring contraction similar to that described in
Section 4.15.3.11.1 (70T4915, nHcA2633).
N'N
HNXN_N'I
HO H
(274)
r "tJ
HNXN
HO H
(275)
("yN'N
HN,,-/N_N'I
OH
(276)
4.15.3.11.3 Tetrazolo[1,5-a]quinazoline
RefIuxing 5-azidotetrazolo[1,5-a]quinazoline in 6N hydrochloric acid produced quinazo-
line-2,4-dione (63Z0B2475) via nucleophilic displacement of the '2'- and 4-azido groups by
water followed by keto-enol tautomerism.
4.15.3.11.4 Tetrazolo[1,5-c]quinazoline
Similar to tetrazolo[I,5-c ]pyrimidine, (56) underwent rapid hydration to form (277).
Upon heating, this hydrate underwent ring opening to 5-(2-aminophenyl)tetrazole (278)
(67KGSI096).
Qy
N
:;.; ,
N
HNXN_r-f
HO H
(277)
N
H 2 N 0-- 'N
HN II
-N
(278)
4.15.3.12 Tetrazolo[1,5-a ]pyrazine and Tetrazolo[1,5-a ]quinoxaline
4.15.3.12.1 Tetrazolo[1,5-a]pyrazine
The parent ring system (57) undergoes de uteri urn exchange at C-5 (78HCA1755) and
thermolysis in organic solvents to produce 1-cyanoimidazoles (see Section 4.15.3.11.2) via
ring contraction of a pyrazinylnitrene, the intermediate arising from loss of nitrogen from
the azido tautomer of (57) (70T4915, nHCA565, 72HCA2633). l-Cyanobenzimidazoles arise
from tetrazolo[1,5-a]quinoxalines (nHcA2633). Further evidence of the azido form came
from refluxing 5,6-diphenyltetrazolo[1,5-a]pyrazine with acetic anhydride to produce an
882
Triazoles and Tetrazoles with Fused Six-membered Rings
acetylated imidazole, and from treating the diphenyl compound with dirnethyl acety-
lenedicarboxylate to form pyrazinylpyrazole (71JOC446). It is interesting to note that
treatment of 5-aminotetrazolo[1,5-a ]pyrazine with acetic anhydride led to 2-acetamido-6-
azidopyrazine (i.e. retention of the azido group) being isolated as the product (80JHCll).
This indicated that the 2-acetamido substituent stabilized the azido functionality and
prevented it from losing nitrogen for further transformations or reverting to the tetrazolo
tautomer.
4.15.3.12.2 Tetrazolo[1,5-ajquinoxaline
In addition to the thermolysis mentioned in the previous section, compounds of this
series are readily oxidized to the 4-ones which, in turn, can be alkylated at N-5 (70KGS851).
4.15.4 SYNTHESIS
4.15.4.1 [l,2,4]Triazolopyridines and their Fused Benzo Derivatives
4.15.4.1.1 [1,2,4]Triazolo[4,3-a]pyridine
The preparation of [1,2,4]triazolo[4,3-a]pyridines, as with many of the compounds of
this chapter, can occur by two routes: ring closure of an appropriate heterocyclic hydrazine
(here, a hydrazinopyridine) with an acidic type cyclodehydrating agent which also supplies
the carbon of the triazole rnoiety (Scherne 22), and construction of the pyridine portion of
the fused ring system onto a preformed 1,2,4-triazole nucleus. The latter method introduces
the possibility of isomer formation depending on the particular nitrogen of the 1,2,4-triazole
nucleus to which cyclization occurs and is of little synthetic utility. On the other hand, ring
closure of 2-hydrazinopyridines (279) has been used extensively (66JOC251,66CB2593) for
preparing [1,2,4]triazolo[ 4,3-a ]pyridines.
-0 1 NHNH2 Ù \
R 1 -. R! 2N
:::::,... N :::::,... NV
R 2
(279)
Scheme 22
A wide variety of substituted 2-hydrazinopyridines can be used in this procedure to
produce a number of pyrido-substituted [1,2,4]triazolo[4,3-a]pyridines. The required 2-
hydrazinopyridines are available (66JOC251) from the reaction of hydrazine with the
appropriate 2-bromopyridines which are in turn obtainable by diazotization of the corre-
sponding 2-aminopyridines.
[1,2,4 ]Triazolo[ 4,3-a ]pyridine (1), and its 3-alkyl derivatives, are available from 2-
hydrazinopyridines and the appropriate carboxylic acids, anhydrides or esters (66JOC251).
A selection of the [1,2,4]triazolo[4,3-a]pyridines prepared in this way is given in Table 8.
In some cases (78JHC439) it was best to isolate the intermediate hydrazide and carry out a
subsequent cyclodehydration with, for example, phosphorus oxychloride, to realize the
desired product. There seems to be some steric influence on the ring closures as reflected
in the considerably depressed yields obtained for the 3,5-disubstituted derivatives
(66JOC251,78JHC439).
The use of ortho esters as the ring closing agent with (279) is less efficient, giving yields
reduced by 20%, which is in contrast to the synthesis of [1,2,4]triazolo[4,3-a]pyrazines
(vide infra) where the ortho ester is the best cyc1ization agent. This facile ring closure with
2-hydrazinopyrazines is suggested (66JOC251) to be due to difference in the basic strengths
of the heterocyclic nitrogen atoms (pyridine, pKa = 5.2; pyrazine, pKa = ca. 0.6) since the
ring closure probably involves nucleophilic attack of the heterocyclic ring nitrogen on an
intermediate carbocation of the hydrazide side-chain.
The 3-aryl-[1,2,4]triazolo[4,3-a]pyridines are best prepared by heating the
hydrazinopyridine with an equimolar arnount of the appropriate acid or ester or, in the
Triazoles and Tetrazoles with Fused Six rnernbered Rings
883
Table 8 Examples of 3-Alkyl- and 3-Aryl-[1,2,4]triazolo[4,3-a]pyridines Prepared from
2- Hydrazinopyridines and Carboxylic Acids, Anhydrides, Esters or
Ortho Esters (66JOC251, 78JHC439, 70JHC703, 70JHC1019)
Ù -- \
R 1 2N
N
R 2
R 1 R 2 R 1 R 2 R 1 R 2
H H 7-Me Et 5-CI H
SoMe H 8-Me Et S-Cl Me
6-Me H S,7- Me 2 Et S-Cl Et
7-Me H H 2-Styryl S-Cl Bu'
8-Me H H 2-Thienyl S-Cl CH 2 Cl
5,7- Me 2 H H 2-Furyl 5-Ph,7-CF 3 H
SoMe Me H 2-Pyridyl S-Me,7-CF 3 H
6-Me Me H 2- Thienylvinyl 8-N0 2 H
7-Me Me S-Me Ph 8-N0 2 Me
S,7- Me 2 Me 6-Me Ph
H Pr 7-Me Ph
H Et 8-Me Ph
5-Me Et 5,7- Me 2 Ph
6-Me Et
case of solid aromatic acids (e.g. benzoic), fusing the two reagents together. Some of the
derivatives made in this way are illustrated in Table 8.
The use of dicarboxylic acids or their derivatives in this procedure gave di(3-
[1,2,4]triazolo[4,3-a]pyridyl)alkanes (280) either directly or following thermal or phos-
phorus oxychloride promoted ring closure of the intermediate hydrazides. Oxalic acid gave
only the [1,2,4]triazolo[4,3-a]pyridine-3-carboxylic acid (100) whereas ethyl oxamate gave
the corresponding 3-carboxamide (101) rather than the alternative six-membered ring
product (281). Haloacetic acids failed when utilized as ring closing agents for preparing the
3-halomethyl compounds (66JOC2S1).
(100) R = OH
(101) R = NH2
Fusion of (279) with urea or ethyl allophanate or reaction with excess ethyl chloroformate
yielded the 3-hydroxy derivatives (91). Urea seems to be the reagent of choice (66JOC2S1)
and involves a semicarbazide intermediate. The spectral data for these compounds indicate
that they exist predominantly as the keto tautomer (282).
R LCYN'N (91) X = 0 R LL'yNNH (282) X = 0
N-J (93) X=S - N....j (283) x=s
XH (95) X=NH 'k
(280)
N'N
NyOH
o
(281)
N,
N-JN
COR
N, IN
N-Z N
(CH 2 )n
Carbon disulfide, thiophosgene or potassium trithiocarbonate effectively produced the
3-thiols (93) when reacted with (279), with carbon disulfide being the most efficient reagent.
With this latter reagent, an intermediate dithiocarbamic acid was formed initially which
subsequently underwent ring closure with loss of hydrogen sulfide. Thiourea, in contrast
to urea, failed to produce a thiol, resulting instead in 2-aminopyridine thiocyanate which
arose from the decomposition of (279; R 1 = H) to 2-aminopyridine on prolonged heating.
The 3-thiols exist predominantly as the 3-thione tautomer (283).
The 3-amino-[1,2,4]triazolo[4,3-a]pyridines (95) have been prepared by the reaction of
(279) with cyanogen bromide (66JOC2S1). It was necessary to neutralize the product from
this reaction with sodium acetate in order to obtain the free base. This synthesis proceeds
via an intermediate cyanohydrazine. Cyanogen chloride has been used in preparing 3-
amino-[l ,2,4 ]triazolo[ 4,3-c ]pyrimidines or 2-amino-[ 1 ,2,4 ]triazolo[ 1,5 -c ]pyrimidines (vide
infra), depending on the reaction conditions (63JCSS642).
884
Triazoles and Tetrazoles with Fused Six-membered Rings
[1,2,4 ]Triazolo[ 4,3 a ]pyridines possessing pyrido substitution other than alkyl have been
only briefly studied (78JHC439, 70JHC703). This is due to the inaccessibility of the appropriate
2-hydrazinopyridines. A number of 5-chloro-[1,2,4]triazolo[4,3-a]pyridines have been
prepared from ring closure of 6-chloro-2-hydrazinopyridine and these are given in Table 8.
A variety of 3-substituted 8-nitro-[1,2,4]triazolo[ 4,3-a ]pyridines (70JHCI019) have been
prepared via a number of the aforementioned ring closure methods with 2-hydrazino-3-
nitropyridine. These products readily undergo rearrangernent to the isomeric [1,5-a] series
as described elsewhere in this chapter. Reduction of the 8-nitro substituent of several of
these derivatives resulted in the corresponding 8-amino products that offer the potential
starting point for other 3,8-disubstituted systems of this type.
Other less widely used methods of ring closing 2-hydrazinopyridines to [1,2,4]triazolo[ 4,3-
a ]pyridines use thioimino ethers (76JOC3124,79MI41500) to produce 3-alkyl derivatives
(Scherne 23) and 1,3,4-oxadiazoles (Scherne 23) (69JPR71) to form 3-hydrazino derivatives.
An oxidative ring closure of pyrid-2-yl arylhydrazones is reported (65IJC162) to give the
3-aryl corn pounds. The 2-alkyl- or -aryl-1,2,4-triazoliurn salts in the [4,3-a ]pyridine,
[3,4-a ]isoquinoline and [4,3-a ]quinoline systems have been reported to arise frorn the
reaction of pyridine, isoquinoline and quinoline, respectively, with diazeniurn fluoroborates
as shown in Scheme 24 (69CB3159).
O (! N
-;?' ,NHNH 2 NH -;?' =--- \
I + II -+ N
::::,... N RCSCH 2 Ph ::::,... N--J'
R
0 1 NHNH2 + )t \ -+ N\N
::::,... N H 2 N....... O /R N--J'
NHNHCOR
Scheme 23
R 1 BF.- o: N
-;?' " + -;?' =--- \
I + N=N -+ NR I
o R 2Ct:í'2 "OEt ::::,... N-t
Scheme 24
4.15.4.1.2 [1,2,4 ]Triazolo[1,5-a ]pyridine
As with the [4,3-a] series, any synthesis involving ring closure onto a preformed 1,2,4-
triazole to fuse the pyridine ring has not been practical but a number of methods have
been developed beginning with substituted pyridines. For example, oxidative cyclization of
N- (2- pyridyl)alkyl- or -aryl-amidines (284) (66JOC260) has been accomplished using lead
tetraacetate in refluxing benzene to give the cornpounds listed in Scheme 25 (66JOC260).
However, since this rnethod was limited in its ability to produce 2-unsubstituted derivatives,
an alternative route was developed (66JOC260,66CPB506) by treating 2-aminopyridines with
hydroxylamine-O-sulfonic acid to produce the 1,2-diaminopyridinium salts (285) which
could be converted into their free bases (286) by ion exchange on an Arnberlite IRA-400
resin. Ring closure of either of these two products with carboxylic acids or their chlorides
produced the derivatives presented in Scherne 26 (66JOC260, 66CPB506). Some of these sarne
[1,2,4]triazolo[1,5-a]pyridines could also be produced by the 1,3-dipolar cycloaddition
reactions of nitriles to the N-iminopyridine (287; Scherne 27) (66CPB506). This method is
of limited utility since no reports of substituted N-iminopyridines undergoing this reaction
-Û NHCR2 Ù =---N
R 1 I 1\ -+ R I }R2
::::,... N NH ::::,... N-N
(284)
R 1 H H 4-Me 4-Me 4-Me 5-Me 5-Me 6-Me 6-Me 7-Me 7-Me 5,7-Me2 5,7-Me2
R 2 Et Ph Me
Ph
Et
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Scheme 25
Triazoles and Tetrazoles with Fused Six-membered Rings
885
-Ú NH -o NH D NH Ù o--N
R 1 I 2 --. R 1 1 2 1- --. R 1 --. R 1 >R z
N +NNH z NNHz N.....J
(285) (286)
R 1 H 4-Me 5-Me 6-Me 7-Me H H H
R 2 H H H H H Me Ph 4-Pyridyl
Scheme 26
a -OH a R'CN UN>
::::,.. NNHz '- __ Rz
+ + NH N.....N
(287)
Scheme 27
have appeared and it can be assumed that such groups would have a drastically variable
effect on the dipolar cyc1oaddition.
[1,2,4]Triazolo[1,5-a]pyridines have also been produced by the isomerization of
[1,2,4]triazolo[ 4,3-a ]pyridines. This procedure has been described previously in the reac-
tivity section for the [4,3-a] series.
Rather than forrning the N(3)-N(4) bond by oxidative means (Scheme 25) (66JOC260),
a recent report (74JOC2143) described a cyc1odehydration process to form the same bond.
In this regard, a 2-aminopyridine was reacted with N,N -dimethylformamide dimethyl acetal
to give the corresponding N,N-dimethylaminomethylene derivative (288). Displacement
of the dimethylamino group with hydroxylamine gave the hydroxyiminomethylenearnino
derivative (290) or (289). Cyc1odehydration of (290) with polyphosphoric acid resulted in
the 2-unsubstituted triazolopyridine (291). The scope of this rnethod remains to be deter-
mined. Rather than this stepwise procedure it has been found (8IJOC3123) more convenient
to treat the N,N-dimethylformamidines (292) with hydroxylarnine-O-sulfonic acid in
methanol/pyridine to produce [1,2,4]triazolo[1,5-a]pyridines. This procedure could also
be used on the formimidates (293). The bicyclic compounds prepared by this route are
given in Scheme 29.
0 , NHz -+ 0 , N=CHNMez --. 0 1 N=CHNHOH 0 1 NHC=NOH --. N\
R1::::,.. N R 1 ::::,.. N Rl N Rl N Rl N.....1
(288) (289) (290) (291)
Scheme 28
Rl N=CHRZ-+ R N>
N - N""'N
(292) R2=NMe2 R 1 =H,6-Me,7-Me,8-Me
(293) R 2 = OEt
Scheme 29
[1,2,4]Triazolo[1,5-a]pyridine l-oxides (294) (79H(12)1l57) have been synthesized by
treating 1-amino-2-chloropyridinium rnesylate (295) with hydroxylarnine to form (296).
Reaction of (296) with carboxylic acids gave the N-oxides (294; Scheme 30). The unsub-
stituted compound (294; R = H) was rnost conveniently obtained by treating (296) with
N,N-dimethylformamide dimethyl acetal.
0-
I
e CI NOH
::::,.. NHz -+ NNHz -+ N.....)R
-OMs
(295)
(296)
(294)
Scheme 30
A number of substituted [1,2,4 ]triazolo[1,5-a ]pyridine 3-oxides (297) have been obtained
from the reaction between 2-pyridylsulfimides (289) and nitrile oxides (Scherne 31)
(76JCS(Pl)2166).
886
Triazoles and Tetrazoles with Fused Six-membered Rings
RI
O ,Ñ-SMe 2
N
R 3
R'CN-å
þ
R 1
N
N_ìR2
R 3 1+
O.
(297)
(298)
Scheme 31
4.15.4.1.3 [1,2,4]Triazoloquinolines and [1,2,4]triazoloisoquinolines
[1,2,4 ]Triazolo[ 4,3-a ]quinolines can be prepared by the ring closure of 2-hydrazinoquino-
lines with carboxylic acids (74MI41502) or by oxidative cyclization of quinol-2-ylhydrazones
of arornatic and heterocyclic aldehydes (65IJC162). [1,2,4]Triazolo[3,4-a]isoquinolines can
also be prepared in similar ways from 1-hydrazinoisoquinoline (66JHC158, 71RTC1225,
6SIJC162,67IJC403).
To obtain the [1,2,4]triazolo[ 4,3-b ]isoquinoline series it was not possible to displace the
halogen atorn of 3-chloroisoquinoline with hydrazine. However, 3-hydrazinoisoquinoline
2-oxide could be prepared from the corresponding 3-chloro 2-oxide, and it could be
selectively reduced by titanium trichloride to 3-hydrazinoisoquinoline, a relatively unstable
cornpound (78JHC463). This hydrazino derivative was unresponsive to the usual carboxylic
acid type ring closures generally used to rnake fused [4,3-x] systerns. The desired products
(299) could be obtained by cyclodehydration of the rnonoacylhydrazino compounds (300)
with polyphosphoric acid. These derivatives (299) were, however, unstable and had to be
characterized as their perchlorate salts (301; Scherne 32) (78JHC463) to eliminate the
0- quinoid structure.
(0 1 NHNH2-+ (0 1 NHNHCOR-+ N'N
hN hN N--f
R
(300) (299) R = H, Me
H
Cû 7'" , N,
N--fN
+ R
ClO.-
(301)
Scheme 32
Another o-quinoid linear system (6) has been synthesized by first reacting 3-
formamidoisoquinoline with O-mesitylenesulfonylhydroxylamine to give (302). Heating
(302) in polyphosphoric acid resulted in [1,2,4]triazolo[1,5-b ]isoquinoline (Scherne 33)
(77H(6)949).
(0 1 NHCHO -+ mNHCHO -+ N\
h N NH2 N_rf
.0Mes
(302)
Scheme 33
(6)
[1,2,4]Triazolo[5,1-a]isoquinoline (7) is available by the previously described method of
reacting the N' ,N' -dimethylformarnidine derivative of l-arninoisoquinoline with hydroxyl-
arnine-O-sulfonic acid followed by ring closure (81JOC3123). 2-Substituted derivatives of
(7) can be obtained by the oxidative cyclization (lead tetraacetate) of N-(l-
isoquinolyl)amidines as shown in Scherne 34 (71CB3965).
'ò RC Có C(x
: I NH , A<Ó,' : INH R : N R
N N NH N_Î
Scheme 34
Triazoles and Tetrazoles with Fused Six-membered Rings
887
4.15.4.2 [1,2,3]Triazolopyridines and their Fused Benzo Derivatives
4.15.4.2.1 [1,2,3 ]Triazolo[1,5-a]pyridine
The older rnethod of preparing [1,2,3]triazolo[1,5-a ]pyridines by oxidation of the
hydrazones of 2-pyridyl aldehydes and ketones (S7JA678,S7JCS4S06) with silver oxide,
potassiurn ferricyanide, etc. has given way to a cleaner oxidant, namely nickel peroxide,
which gives the 1,2,3-ring systern in greater than 90% yield (Scherne 35) (76SC69). Other
synthetic approaches include the treatment of picoline-2-carbaldehyde p- toluenesulfonylhy-
drazone with base (64CB3493), the treatment of pyrid-2-yl ketones with p-toluenesulfonyl
azide (Scherne 36) (66CB2918) and cyclodehydration of the amine salts of picoline-2-
carbaldehyde and pyrid-2-yl ketone oximes with polyphosphoric acid (7SJHC481). The
starting materials for this last procedure (303; Scheme 37) are available from the correspond-
ing oximes (304) and O-mesitylenesulfonylhydroxylamine, a typical reagent for synthesizing
heterocyclic N-arnines. [1,2,3]Triazolo[1,5-a]quinolines (11) can also be made in this way
from quinol-2-yl oxirnes (7SJHC481).
crl N N'-PO CC ) N ] (t) ::o---R
I 11- N
N NH 2 (-'Hz) N'.N N_J
Scheme 35
0 , CH2COR
N
i. base
ii, TosN 3 Þ
COR ]
+
N W
(r) ===---COR
- N
N_J
Scheme 36
R R R
O IC=NOH _ O ,C=NOH _ N
N NH2 -J
-OMes
(304) (303)
Scheme 37
In a much poorer yield, compound (8) was the product from the thermal decomposition
of 5-(2-pyridyl)tetrazole (305) at 400 OCj10- 3 Torr (78HCA17SS). Cornpound (305) was
prepared by treating pyridine-2-carbonitrile with hydrazoic acid. [1,2,3]Triazolo[1,5-
a ]pyridines are also the products from the treatment of 1-arninoquinolizinium salts (306a)
with nitrous acid in a process proceeding via (306b) (69TL1S49).
a- Nt
,
N
(305)
(306a)
+
R
C;OH
(306b) 2
co l N 2
#R
4.15.4.2.2 [1,2,3 ]Triazol?[ 4,S-h ]pyridine and [1,2,3 ]triazolo[ 4,S-c ]pyridine
Compounds (9) and (10) have been most extensively studied as 1-deaza-8-azapurines
and 3-deaza-8-azapurines, respectively, and have been almost exclusively prepared
by diazotization of 2,3-diarninopyridines (for 9 and its derivatives) (67CB1646,
71RTC1l81,73JOCI09S) and 3,4-diaminopyridines (for 10 and its derivatives) (Scheme 38)
(6SJMC296, 73JOCI09S). A rather interesting synthetic entry into the [4,5-b] series was repor-
ted (70JOC1l31) to involve the reaction of sodium azide with 5-nitropyridin-2(lH)-one to
give [1,2,3]triazolo[ 4,5-b ]pyridin-5(4H)-one after the loss of nitrous acid (Scherne 39).
Pyrido[ 4,3-e ][1,2,4 ]triazines have been shown to undergo basic rearrangernent to
[1,2,3]triazolo[4,5-c]pyridines as illustrated in Scheme 40 (7IJHC47).
888
Triazoles and Tetrazoles with Fused Six-membered Rings
X NH2 -+
y )NH2
N
X û N
I \'N
Y N I
N H
Scheme 38
b y tr y H
X ""::: NH X ""::: N
I 2 I '\
N # NH 2 -+ N # ;N
H
Ú N02 -+ ÛN N
o NON N
H H
Scheme 39
N CONH 2
(X I 'ìNH2 -+ N'N
N Ñ<,N N J'
1
0_
Scheme 40
[1,2,3]Triazolo[ 4,5-d]pyrimidines (8-azapurines) possessing 5-arnino, 5-oxo or 5-thioxo
groups undergo ring opening with a variety of active methylene compounds to give 1,2,3-
triazoles of the type (307) and (308). Hydrolytic ring closure of these materials provides
entry into [1,2,3]triazolo[ 4,5-b ]pyridines with substituents at positions 5 and 6 (309)
(73JCS(P1)1620). 8-Azapurine itself reacted with dimedone, ethyl acetoacetate and pentane-
2,4-dione to give (310), (311) and (312), respectively, without any indication of the triazole
intermediate resembling (307) and (308) (73JCS(Pl)1620).
N/ J CH=c(CN)R N J CH=C(CN)R
'N NHC(=NH)NH 2 'N NHCNH 2
H H JI,
,
(X N
R
H 2 N I N /N
N H
(307) R = CN, C0 2 Et, CONH 2
(308) X = S, 0; R = C0 2 Et, CN
(309) R = CN, CONH 2
o
r;
Me2 ,JL IN
N N
H
(310)
ROC 'N
Me .J-- I
N N
H
(311) R = OEt
(312) R=Me
4.15.4.2.3 [1,2,3 ]Triazolo[1,5-a]quinoline and [1,2,3 ]triazolo[5,1-a]isoquinoline
In addition to the rnethod mentioned earlier for preparing (11) and its derivatives from
quinol-2-yl oxirnes (75JHC481), reaction of quinaldine with benzenesulfonyl azide gave (11)
via ring-chain tautornerism of 2-diazomethylquinoline (72JOC2022). Perforrning the same
reaction on I-methylisoquinoline gave the isomeric [1,2,3]triazolo[5,1-a]isoquinoline (12).
This latter ring systern and sorne of its derivatives have also been prepared by the oxidation
of isoquinolin-1-yl ketone hydrazones or by the reaction of isoquinolin-l-yl ketones with
tosylhydrazine (75CB3794).
4.15.4.3 [l,2,4]Triazolopyridazines and their Fused Benzo Derivatives
4.15.4.3.1 [1,2,4/[Triazolo[4,3-b]pyridazine
The rnost fruitful and general route to (13) and its derivatives seems to be via oxidative
ring closure (using bromine or lead tetraacetate) of the alkylidene or arylidene derivatives
of the corresponding 3-hydrazinopyridazine (Scheme 41) (66T2073). Alternatively, therrnal
Triazoles and Tetrazoles with Fused Six-membered Rings
889
ring closure of the hydrazides obtained frorn 3-hydrazinopyridazines and acid chlorides
may be utilized (66T2073). The ortho ester and carboxylic acid and anhydride ring closures
widely ernployed to prepare other fused triazoles do not seem to be as useful
(69M671, 81JHC1523) in the pyridazine series probably owing to the decreased nucleophilicity
of N-2 of the six-mernbered ring. Thioimino ethers have also been used in this series as
triazole ring-closing reagents (8IJHC893). 4-Amino-1,2,4-triazole upon reaction with ß- keto
acetals provides a route to this series starting from the triazole moiety, a rarely useçl.
approach in preparing fused triazoles (Scheme 42) (79JCS(Pl)3085).
0 1 NHN=CHR a ;.--N'N
..-N ....N-ß
N N R
Scheme 41
Me
MeCOCH 2 CH(OM e I2 a ;.--N, a =-N,
Þ N+ N
Me ....N-ß ....N-ß
N N
Scheme 42
The versatile 5-oxides of this series can be synthesized via ring closure of an appropriate
3-hydrazinopyridazine l-oxide (68JHC513) or, in much lower yield, by direct oxidation of
the bicyclic heterocycle (70JOC2478).
[1,2,4 ]Triazolo[3,4-a ]phthalazine (17) and its derivatives are best synthesized frorn an
appropriate 1-hydrazinophthalazine and ortho esters (3-alkyl), carbon disulfide (3-
mercapto), urea (3-hydroxy) and cyanogen bromide (3-amino) (69JOC3221). The 3-chloro
derivative was prepared by oxidative cWorination of the 3-rnercapto compound or by
treatment of (17) with sodium hypochlorite solution. Acid hydrolysis of the bis secondary
amine derived frorn the 3-dichlorornethyl derivative of (17) and rnorpholine yielded the
3-carbaldehyde (69JOC3221).
6,7,8,9- Tetrahydro-[1,2,4 ]triazolo[ 4,3-b ]cinnolines have been prepared from 3-
hydrazino-5,6,7,8-tetrahydrocinnolines and the reagents just described for (17)
(71BSF3043), and also by condensing 2-hydroxymethylenecyclohexanone with 4-arnino-
1,2,4-triazole (79JCS(Pl)3085).
N
I" 'N
H 2 NN-ß
4.15.4.3.2 {1,2,4]Triazolo[1,5-h ]pyridazine
Of the routes developed to (14) and its derivatives two have emerged as the rnost useful.
In the first case (74JOC2143), by analogy to a preparation of (2), various 3. aminopyridazines
are first converted into their N,N-dimethylaminornethylene derivative's (313) with N,N-
dimethylformamide dimethyl acetal. These latter derivatives with hydroxylamine become
the hydroxyiminomethylenearnino compounds (314). Cyclization of (314) with polyphos-
phoric acid then gives the desired [1,2,4]triazolo[1,5-b ]pyridazines. Included arnong these
products are several possessing a 6-chloro substituent that perrnits easy access to a number
of other derivatives by nucleophilic substitution (see reactivity section). Oxidative cyclization
(76JHC487) of (314b; R = Cl) gave the versatile 3-oxide (315) which could be converted
into (14).
0 1 N=CHNMe2
R ....N
N
(313)
0 1 N=CHNHOH
R N
N....
(314a)
0 1 NHCH=NOH
R N
N....
(314b)
a N
CI ....:)
N \
0_
(315) (316)
The other rnethod to (14) and a large number of its derivatives (75JHCI07) involves
N- amination of 3-arninopyridazines with 0- mesitylenesulfonylhydroxylarnine to form the
N- aminodiaziniurn salts (316). These salts can then be cyclized to the [1,5-b] system with
NH2
R :NNH 2
N -OMes
890
Triazoles ,and Tetrazoles with Fused Six-membered Rings
forrnic acid, acetic anhydride or benzoyl chloride depending on the C-2 s bstituent (H, Me
or Ph) desired.
The 2-phenyl derivatives have been prepared (72TL4179) by oxidative ring closure of the
arnidines (317) which are, in turn, available from 3-aminopyridazines and benzonitrile
(Scherne 43).
0 1 NH2 -+
R "N
N
0 1 NHCPh
II -+
R "N NH
N
(317)
a N
;.-- )Ph
R N N_N
Scheme 43
4.15.4.4 [1,2,3 ]Triazolo[ 4,5-d]pyridazine
This ring systern, often viewed as 2,8-diaza-3-deazapurine, and some of its derivatives
have been prepared by diazotization of the appropriate 4,5-diarninopyridazine
(69JHC93,70CPB168S) as Scheme 44 represents for the formation of (15) itself. There are
no other practical syntheses for this series of corn pounds. A similar approach has been
used for preparing the isorneric [1,2,3]triazolo[ 4,5-c ]pyridazines with the 7 -chloro derivative
being a useful cornpound (67JHCSSS).
0 :7 I NH 2 HN0 2 ) t;Jr N
N NHz N N'
(15) H
Scheme 44
4.15.4.5 [1,2,4]Triazolopyrimidines and their Fused Benzo Derivatives
4.15.4.5.1 [1,2,4]Triazolo[ 4,3-a]pyrimidine
Due to the rapid rearrangement of the [4,3-a] series into the [1,5-a] series (see Section
4.15.4.5.2) uncontaminated [1,2,4 ]triazolo[ 4,3-a ]pyrimidines are difficult to prepare. The
only useful methods available (Scherne 45) seern to be treatrnent of an appropriate 2-
hydrazinopyrimidine with a low boiling ortho ester (for 3-H, 3-Me, 3-Et and 3-Pr) or
oxidative ring closure of an arylidene derivative of 2-hydrazinopyrimidine to forrn the 3-aryl
corn pounds (77 AJC2S1S).
N N N N
R C y N R C )NHN=CHAr Rf )NHNH z
::::,.., N-..j' ::::,.., N N
Ar
Scheme 45
N N
R'C\OEt)3 C \
) R I N
::::,.., N-J
R 1
4.15.4.5.2 [1,2,4]Triazolo[1,5-a ]pyrimidine
The Dimroth-like rearrangement of [1,2,4]triazolo[ 4,3-a]pyrimidines in acid or alkali
has been extensively used as a synthetic route to the isorneric [1,5-a] series (see Table 7).
Thus, ring closure of a 2-hydrazinopyrirnidine will initially give a [4,3-a] product which
quickly rearranges to the [1,5-a] isomer, the material isolated frorn the reaction. The
rearrangernent does not occur under neutral conditions and proceeds with ring opening at
N(4)-C(5) to give (318) in a rnanner similar to that described for [1,2,4]triazolo[4,3-
a ]pyridine (Scherne 2). The rates for isornerization are pH dependent, increasing at pH
10-12.5 for alkali rearrangement or when the pH nears the pKa of the [4,3-a ] rnaterial
(pH 1.5-2.5) for acidic rearrangernent (77AJC2S1S). The rearrangernent was slowed by a
3-alkyl group due to electron donation retarding nucleophilic attack at C-5 and raising the
pKa. As suspected, electron-withdrawing groups at C-3 increased the rate of rearrangement
Triazoles and Tetrazoles with Fused Six-membered Rings
891
(77AJC2S1S). A 5-methyl substituent retarded the rearrangement greatly, a result due to
steric hindrance by the methyl group to nucleophilic attack at C-5 prior to N(4)-C(5)
bond fission (77AJC2S1S).
Ny.
I:' - ,N
:::::... N'V
OH
(318) (intermediate in alkali isomerization)
HN-N
/ \\ + MeCOCHzCOMe
HzN<.::::- /NHz
N
Several other rnethods have been put forward for preparing [1,2,4]triazolo[1,5-
a ]pyrirnidines: the reaction of 1,3-dicarbonyl compounds with 3-arnino-1,2,4-triazoles
(79JCS(Pl)308S, 67JCS(C)S03, 61CPB801) (see Scheme 46 which relates this method with the
rearrangernent method) (66CB2237), dehydrative cyclization of oxirnes with polyphosphoric
acid (Scheme 47) (74JOC2143) and ring closure of 1,2-diarninopyrirnidiniurn mesitylenesul-
fonates with carboxylic acids, anhydrides or acid chlorides (Scherne 47) (7SJHCI07). Of
these, the last route is preferable since the other two require somewhat more synthetically
inaccessible starting rnaterials. They do, however, make available rnany significant pyrirnido-
substituted derivatives (61CPB801).
N N
Me c \
I NHz
:::::... N-N
Me
N N N
Me C " 'N Me C )NHNH z
:::::... N-J N
Me NHz Me
Scheme 46
N N N N N
R C " jRI R ( )NH z R ( )NH z -. R ( )NHCH=NOH
:::::... N-N :::::... NHz N N
R R -OMes R R
Scheme 47
N N
R C Y'j
:::::... N-N
R
Reaction of the pyrirnidin-2-ylsulfimides (319) with aromatic nitrile oxides is reported
to give the 3-oxides of the [1,5-a] system (320) (76JCS(Pl)2166).
N
R ( )N=SMe z
N
R
(319)
N N
R C Y'\
N +I/Ar
:::::... -N
R I
0_
(320)
4.15.4.5.3 [1,2,4]Triazolo[ 4,3-c ]pyrimidine
[1,2,4 ]Triazolo[ 4,3-c ]pyrimidines, like their isomeric [4,3-a] compounds, are difficult to
prepare without contamination by the corresponding [1,5-c] analogs (76S833, 63JCSS642). As
with (18), ortho ester cyc1ization of 4-hydrazinopyrimidines (78AJC2S0S) was the most
satisfactory route since the resulting [4,3-c], [1,5-c] and ethoxyalkylidene (321) derivatives
could be separated without much difficulty. Heating of the alkylidene (321) in a vacuum
also provided a rneans to (19) and its derivatives (78AJC2S0S).
R 3 R
RZrnNHN=COEt
N. ::./N
R 1
(321)
(ìNHCH=NOR
N ::./N
(322) R = H
(323) R = Ac
4.15.4.5.4 [1,2,4]Triazolo[1,5-c]pyrimidine
Two routes are available for preparing this ring systern: (i) treatment of 4-
arninopyrimidines with N,N-dimethylformarnide dimethyl acetal and hydroxylamine to give
892
Triazoles and Tetrazoles with Fused Six-membered Rings
(322) followed by acetylation to (323) and warming (765833) and Oi) the Dirnroth-type
rearrangernent of the [4,3-c] series (78AJC2S0S).
In contrast to the smooth Dimroth-type transformation in the [4,3-a] --. [1,S-a] systerns,
the [4,3-c] --. [1,5-c] conversions were complicated by the stabilities of the interrnediates
(324), which are often isolable. These interrnediates were always the terrninating point in
any atternpted rearrangernent of the [4,3-c] derivatives in aqueous buffer (pH 1-13). The
fact that complete rearrangement of the [4,3-a] series to the [1,5-a] series occurred in
aqueous buffer, whereas the [4,3-c] did not cornpletely rearrange, has been explained by
the nature of the respective fission products: the intermediate from the [4,3-a] corn pounds
(325) is a reactive hydroxymethylene corn pound whereas the interrnediate frorn initial ring
opening of the [4,3-c] derivatives (324) is a relatively unreactive arnide (78AJC2S0S).
(NyN\
HN-ßN
OH
(324) (compare with 204) (325)
A 5-rnethyl group on [1,2,4 ]triazolo[ 4,3-c ]pyrimidines retards the rearrangernent as a
result of reducing the electron density at C-5 and sterically crowding this site towards
nucleophilic approach. A C(8)-methyl group had a similar retarding effect due only to a
rnesomeric effect. On the other hand, a C(7)-methyl substituent had no effect on the rate.
These results, together with the isolation of the amide intermediate (324), indicate ring
opening occurs at the N(4)-C(5) center in the [4,3-c] series.
In contrast to aqueous buffer, formic acid and glacial acetic acid caused the triazolo[4,3-
c ]pyrimidines to rearrange completely to their [1,5-c] counterparts. This rnerely seerns to
be a catalytic effect operative on intermediate (324).
rYN'N
RCONH HN-ß
4.15.4.5.5 [1,2,4 ]Triazolo[ 4,3-c ]quinazoline and [1,2,4]triazolo[1,5-c ]quinazoline
Ring systern (22) and its derivatives are best synthesized by treating 4-hydrazinoquinazo-
lines with ortho est rs in the presence of potassium carbonate (70JOC3448). Ornission of the
carbonate always resulted in a mixture of the [4,3-c] (22) and [1,5-c] (24) ring systerns,
apparently due to rearrangernent of the [4,3-c] into the [1 ,5-c] by the traces of the
appropriate acid in the ortho ester. This assumption was verified by treating 4-
hydrazinoquinazolines with carboxylic acids and by warrning the [4,3-c] systems with a
carboxylic acid to give, in both cases, [1,2,4]triazolo[1,5-c ]quinazolines (Scherne 48)
(70JOC3448). This rearrangernent, which is also prornoted by heat, is the preferred route
to the [1,5-c] series (24).
R'OOEtJ,
Qy
# N
1\
6 N
N N-ß
R' R'
(22)
1 R'CO,H
o
NHNH2
N N
R 1
R'CO,H
Qy
# N
0--- lR2
N N_
RI
(24)
Scheme 48
The [4,3-c] --. [1,5-c] isomerization is not unlike that described previously in this chapter
for the [4,3-a ]pyridines and [4,3-a]- and [4,3-c]- pyrirnidines in that covalent hydration
occurs at the C(5)-N(6) double bond of (22) with initial nucleophilic attack at C-5. This
is followed by ring opening to an amide, resembling (324) from the [4,3-c ]pyrirnidine
Triazoles and Tetrazoles with Fused Six-membered Rings
893
systern, which subsequently undergoes ring closure at N-1 of the 1,2,4-triazole nucleus to
give (24). The therrnal isomerization rnay follow a different pathway involving a zwitterion
(70JOC344S).
An alternative, more limited, route to (24) and its derivatives involves the 2-amino
compound (326) which results from the reaction of aminoguanidine and the [3, l]benzoxazine
(327; Scherne 49) (6SCB2106). Diazotization of (326) and then hypophosphorus acid pro-
duces 2-substituted derivatives of (24) (70JOC344S).
R' H,NNHC,.NH)NH,
,ÇR
N
(327)
M
N
N N;.-" JNHz
""'N
R
(326)
Scheme 49
4.15.4.5.6 [l,2,4]Triazolo[l,5-a]quinazoline
The synthetic studies of this ring systern have been rather limited and the recent reaction
of 2-hydrazinobenzoic acid with N- cyanoimidates (Scheme 50) seems to offer the best route
to (23) and its derivatives. The 5-oxo products are susceptible to rnany useful transformations
as described in Section 4.15.3.5.5 (SOHCAl).
0 1 NHNHz R"
+ C=NCN--+
COzH EtO/
H
o N'-y;;::::N
I JR
'<:::::: N.....N
1#
Scheme 50
4.15.4.5.7 [l,2,4]Triazolo[5,1-b]quinazoline
This ring system, in its 6,7,8,9-tetrahydro form, has been prepared (79JCS(Pl)30SS) by the
reaction of 2-hydroxymethylenecyclohexanone with 3-arnino-1,2,4-triazoles (Scherne 51).
In the fully arornatic form, compound (25) and its [3,4-b] isomer are apparently not
particularly stable due to the o-quinoid nature of the structure.
(yO + HzN(N ÌìR --+ ("'yNtN JR + [l,S-a]ísomer
CHOH HN-N N
Scheme 51
4.15.4.5.8 [l,2,4]Triazolo[ 4,3-a]quinazoline
Very little is available on [1,2,4]triazolo[4,3-a]quinazolines but some representatives of
this ring systern have been prepared (for exarnple 329) (64Z0B174S) and the ring systern
has pharrnaceutical usefulness (79MI41S01).
& NyN'N
N-f
,'.::::
#
(328)
R
O NyN'N
N-f
'.::::
1#
(329)
894
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.4.6 [1,2,3)Triazolopyrimidines and thcir Fuscd Bcnzo Dcrivativcs
4.15.4.6.1 [1,2,3 ]Triazolo[1,5-a ]pyrirnidine
Condensation of arnino-l,2,3-triazoles with ß-dicarbonyl cornpounds is an efficient route
to substituted [1,2,3 ]triazolo[ 1 ,5-a ]pyrirnidines (71JCS(C)2156). Scherne 52 illustrates this
with pentane-2-4-dione. Care rnust be exercised in this condensation as the products
readily undergo ring opening with loss of nitrogen to forrn pyrirnidines (see 330) as described
in rnore detail in the reactivity section. Benzoylacetone and dibenzoylrnethane required
acetic acid to prornote their reaction with the arninotriazole and, as a consequence, only
the pyrirnidines analogous to (330) were obtained (71JCS(C)2156) with no triazolopyrirnidine
detected. Reaction of the arninotriazole with diethyl rnalonate or ethyl benzoyl acetate did
not lead to the bicyclic heterocycle. Condensation of 5-arnino-4-phenyl-1H-l,2,3- triazole
with ethyl acetoacetate gave (331) (73JCS(Pl)943).
R 1
HlN
I 'N + MeCOCHlCOMe
HN_
N R 1
_Me ( N
::::,... N_N"
Me
Scheme 52
(330)
Ph
Me ç N
N I,
-N
o
(331)
N
Rl ( )CHRR l
::::,... N
R 3
4.15.4.6.2 [1,2,3]Triazolo[1,5-c]pyrirnidine
Little is known about this series of cornpounds but the parent structure (27) has been
synthesized via the oxidative ring closure of pyrirnidine-4-carbaldehyde hydrazone (Scherne
53) (78JHCI041).
CH(OMeJz CH=NNHl Pb,OAcl.
N N il,N,H. N N
N
N N_N"
(27)
Scheme 53
4.15.4.6.3 [1,2,3 ]Triazolo[ 4,5-d]pyrirnidine
This ring systern is of prirnary interest as 8-azapurine, derivatives of which could serve
as purine antagonists in viruses and cancer. As such, they offer sorne biological prornise in
that they are not incorporated into rnarnrnalian DNA, a fact that dirninishes the risk of
rnutagenesis. The usual rnethod of preparing [1,2,3]triazolo[ 4,5-d]pyrirnidines (61JOC4433)
is to treat a 4,5-diarninopyrirnidine with nitrous acid (Scherne 54). This is very versatile for
synthesizing pyrirnido derivatives of the (28) ring systern since 2- and 6-rnonosubstituted
or 2,6-disubstituted 4,5-diarninopyrirnidines will give the corresponding bicyclic ring systern
substituted at positions 5, 7 or both. Corn pounds of this series can also be synthesized by
ring closure of a 4,5-disubstituted 1,2,3-triazole (Scherne 55) (81JCS(Pl)2344).
Scheme 54
o
HlNOcfN'N HClOEtI, þ N I N'N
MeHNl:.... I HCl l..Jl I
N N N
H Me H
Scheme 55
:) Cl Cl N
N NH l NaNO, N
H NI I NHR AcOH Þ H Nl,. I ,N
1 '-::::::: 1 N N
N R
Triazoles and Tetrazoles with Fused Six-membered Rings
Many 8-azapurine analogs of the naturally occurring purines have been prepared by
these rnethods and some examples include 8-azaadenosine (332) (70JHC21S), 8-azaguanine
(333) (61MI41S00) and 8-azatheophylline (334) (74MI41500).
:JC NHl N
N I ''N
'
N N
HOH,cd
HO OH
(332)
:r o N
HN
H NI I ,N
2 "::::N N
H
(333 )
895
o
MeN:XN
O N N
Me H
(334)
A rather interesting approach to this ring systern involves, for exarnple, treatrnent of
4,6-diaminopyrirnidine with 2-azido-3-ethylbenzothiazolium tetrafluoroborate to give 8-
azaadenine. This is illustrated in Scherne 56 (78HCAI08) and rnay have general application.
NH 1 N
Nr
_J-- /
N N
H
N J NHl o= s
I ! + I )N 3 -
'-':::,. NH 1 N
N Et
BF -
Scheme 56
4.15.4.6.4 [1,2,3ITriazolo{1,5-alquinazoline
A representative of this ring system (narnely, 5-oxo-3-phenyl-4,S-
dihydro[1,2,3]triazolo[1,5-a]quinazoline (335)) has been prepared by the reaction between
o-azidobenzoic acid and phenylacetonitrile in the presence of sodium rnethoxide
(66JCS(C)2290). This is illustrated in Scherne 57.
[ H N("N ] 0= 0 N
CO,H CO:H: h " H N P: N
N 7" "':: 'N
o 3 + PhCH1CN - a - I ð
(335)
(j
P Y);N
N 'N'
Ph
(336)
W "':: N::o-N'NH Yn l
ð -.../
I N I CHN 1
N N -N 2 N N
Ph Ph
(337)
Scheme 57
4.15.4.6.5 [1,2,3ITriazolo[1,5-c IquinazoUne
S-Phenyl [1,2,3]triazolo[I,5-c]quinazoline (336) has been prepared by heating 5-(2-
phenyl-4-quinazolinyl)tetrazole (337) in rnesitylene at 160 0 C as shown in Scherne 57
(78HCA1755).
4.15.4.7 Triazolopyrazines and their Fused Benzo Derivatives
4.15.4.7.1 [1,2,4 ITriazolo{ 4,3-a lpyrazine
The rnost efficient rnethod of preparation of (31) and its alkyl derivatives was reported
(62JOC3243) to be via ring closure of 2-hydrazinopyrazines with ortho esters (Scherne 58).
896
Triazoles and Tetrazoles with Fused Six-membered Rings
Now that the rneans for fusing triazoles to pyridine and the three diazines have been
presented, it can be concluded that the ease of ring closure of the corresponding hydrazines
is dependent on the pKa of the nitrogen of the six-rnernbered ring onto which closure takes
place. Thus, the order of reactivity with ortho esters as cyclizing agents is pyrazine>
pyrirnidine > pyridazine > pyridine (62JOC3243). The procedures ernployed in the other
triazole ring fusions (such as the carboxylic acids or anhydrides or phosphorus oxychloride
cyclodehydrations on the hydrazides) failed in the pyrazine series.
R R
N
NHNH2 R 2 C10EtI, Þ N
N\N
Rl
N Rl
N
R1 R1 R 2
R 1 = H, Me, Ph in various combinations; R 2 = H, Me, Et
Scheme 58
Treatrnent of 2-hydrazinopyrazines with carbon disulfide in chloroform or cyanogen
chloride produced the 3-thiol and 3-amino derivatives (338) and (339), respectively, while
fusion with urea or reaction with phosgene gave the 3-hydroxy derivatives (340)
(68JHC485, 66JCS(C)2038, 69JCS(C)1593). The carbon disulfide ring closure has not always been
successful in the pyrazine series (62JOC3243,66JCS(C)2038) so the pyrazino substituents rnay
play an electronic role in this conversion. A nurnber of 3,8-disubstituted [1,2,4 ]triazolo[ 4,3-
a ]pyrazines have been prepared by ring closure (using ortho esters or thioirnino ethers) of
3-chloro-2-hydrazinopyrazines (78JHC987, 79JOCI028, 79MI41500). Included arnong these
derivatives is the nucleoside (341).
(338) X = SH
(339) X = NH 2
(340) X = OH
NH 2
N
N\
N ßN
HOH,cd
HO OH
(341)
N
N\
N
N
R X
4.15.4.7.2 [1,2,4 ]Triazolo[1,5-a]pyrazine
The two rnost useful routes to (32) and sorne of its derivatives are (i) the ring closure of
the N-arninodiaziniurn salt (342) with carboxylic acids, anhydrides or acid chlorides as
previously rnentioned for the pyridazines and pyrimidines (75JHCI07) and (ii) the cyclodehy-
dration of the hydroxyirninornethylenearnino cornpound (343) with polyphosphoric acid as
reported herein for the pyridine, pyridazine and pyrirnidine analogs (74JOC2143). These two
rnethods are shown in Scherne 59.
N
NH2
NH2
(342)
N
N>R
N
NHCH=NOH
N-N
N
(343)
Scheme 59
2-Phenyl-[ 1 ,2,4 ]triazolo[ 1 ,5-a ]pyrazines have been prepared by the oxidative ring closure
of N(2)-pyrazinylbenzarnidines (344) as shown in Scherne 60. The benzarnidines were
synthesized frorn 2-arninopyrazines and benzonitrile, a reaction that failed with aliphatic
nitriles (64JOC2542).
N
NHC(=NH)Ph
R
N
(344)
Scheme 60
As in the other systerns discussed up to this point, the [4,3-a ]pyrazine series is susceptible
to the Dimroth-like rearrangernent into the [1,5-a] corn pounds (68JHC485,66JCS(C)2038).
N
I NH2 Pi)CN
R -t 1/ ---'-----+
N
N
PblOAcI 4 Þ R N 10- JPh
N-N
Triazoles and Tetrazoles with Fused Six-membered Rings
897
For exarnple, when 5,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine was refluxed with 10%
sodium hydroxide solution for 60 hours, a 20% yield of the isorner.ic 5,8-dimethyl-
[1,2,4]triazolo[1,5-a]pyrazine was obtained. No rearrangement occurred in acid or under
the influence of heat (68JHC48S). The poor yield obtained in this isomerization rnay be due
to two factors: (i) electronic deactivation and steric crowding caused by the 5-rnethyl group
and/or (ii) the great 7T-electron density associated with C-5 (as determined by HMO
calculations) for [1,2,4 ]triazolo[ 4,3-a ]pyrazines in general (68JHC48S).
On the other hand, the 3-amino derivatives rearrange under the influence of heat or hot
aqueous hydrochloric acid, sodium carbonate or sodiurn hydroxide. For example, reaction
of (345) with acid gave the rearranged product wherein the amino group had been hydrolyzed
to the hydroxy cornpound (346; Scheme 61). That this hydrolysis took place after isorneriz-
ation was proven by the inability of the corresponding 3-hydroxytriazolo[ 4,3-a ]pyrazine
to undergo this rearrangernent (66JCS(C)2038). The 3-arnino derivative unsubstituted in the
pyrazine ring was too susceptible to hydrolytic breakdown to ptoduce any product recogniz-
able as having arisen via a rearrangement route.
N N\ N N >
'- 1- N ---+ '- 1- OH
R N R N_r:
R NH 2 R
(345) R = Me or Ph (346)
Scheme 61
6,8-Dibromo[1,2,4]triazolo[1,5-a ]pyrazine 3-oxide (347), as a representative N-oxide
in the [1,5-a] series, was obtained by the oxidative cyclization of (348) (76JHC487).
Br
N NHCH=NOH
Br N
(348)
Br N
N >
Brl N-N
\+
0-
(347)
Scheme 62
A [1,2,4]triazolo[1,5-a]pyrazine analog of guanine has been prepared by cyclization of
a 1,5-disubstituted triazole (77JHC697).
4.15.4.7.3 (1,2,3 ]Triazolo{l,5-a ]pyrazine
Compound (33) has been prepared in 20% yield by the therrnolysis of 5-(2-
pyrazinyl)tetrazole as shown in Scherne 63 (78HCA17SS).
N=N
N CN HN 3 ) N N/NH N CH=N2 ----,-+ N N
N N -N 2 N N_Ñ
(33)
Scheme 63
4.15.4.7.4 {1,2,3 ]Triazolo{4,5-h]pyrazine
A variety of 1-benzyl-[1,2,3 ]triazolo[ 4,5-b ]pyrazines has been prepared by the condensa-
tion between cx-dicarbonyl cornpounds and 4,5-diamino-l-benzyl-l,2,3-triazole (Scheme
64) (72JOC4124). 2-Phenyl derivatives have been synthesized in a similar way using 4,5-
diamino-2-phenyl-1,2,3-triazole (Scherne 64) (78JOC341).
CH 2 Ph N CH 2 Ph
H 2 N ( N'N RCOCOR Rf' X N'N
H N // R l ij
2 N N N
N
H 2 N l \
NPh
H 2 N '"-N
Scheme 64
N N
RCOCOR 1 R ( ): \
) NPh
R 1 '" '"- /
N N
898
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.4.7.5 (1,Z,4]Triazolo[ 4,3-a ]quinoxaUne
Cyclization of 2-hydrazinoquinoxalines occurs very readily with carboxylic acids and
esters and ortho esters. This is in contrast to the pyrazines which could only be cyclized
with ortho esters (60JA4044,68JHC48S). Pyrolysis of the hydrazones derived from 2-
hydrazinoquinoxalipe have led to various corn pounds of this series (60JA4044).
The I-hydroxy, -mercapto and -arnino derivatives were prepared, as in the pyrazine series,
by ring closure of the hydrazine with urea, carbon disulfide and cyanogen brornide, respec-
tively (68JHC48S). The I-aryl corn pounds arose via phosphorus oxychloride cyclodehydration
of the corresponding ring opened aroylhydrazines (68JHC48S). As rnight be expected, the
[4,3-a]quinoxalines did not rearrange to the [1,5-a] isorners. The 5-oxides in the [4,3-
a ]quinoxalines were prepared by ring closure of the appropriate 2-hydrazinoquinoxaline
4-oxide (78JOC412S).
4.15.4.7.6 [1,Z,3]Triazolo[1,5-a]quinoxaline
There are two syntheses of this ring reported (67 JA2633, 78JOC412S). The first involved
the reductive cyclization of the 1-(2-nitrophenyl)-1H-1,2,3-triazole (349) to (350), whereas
the other route gave a variety of 5-oxides (351) by the sodiurn methoxide ring closure of
the tosylhydrazones (352). These two routes are shown in Scherne 65.
C0 2 Me OMe CO M
Me0 2 C/'N N ' 2 e
\ II Bu,P ,- 'N
oN-N Û N_,j
(349) (350)
-0 R
'N "f(=NNHTS)R 1
N __
U
(352)
-o'N N
N'-J
U
(351)
Scheme 65
4.15.4.8 [1,2,4]Triazolotriazincs
4.15.4.8.1 [1,Z,4]Triazolo[ 4,3-h ]{1,2,4]triazine
The [1,2,4]triazolo[4,3-b][1,2,4]triazines have been prepared, primarily (i) from the
known (68CB2747) 7-oxo-[1,2,4]triazolo[4,3-b][1,2,4]triazines by the sequence of steps
shown in Scherne 66, (ii) via the condensation of 3,4-diarnino-1,2,4-triazoles with cx-
dicarbonyl reagents (Scheme 66) (64CB2179) and (Hi) by the ring closure of 3-hydrazino-
1,2,4-triazines with carboxylic acids and ortho esters (Scherne 66) (77JOCI018). The latter
cyclization to the [4,3-b] product rather than the [3,4- c] ìsomer was explained by the
enhanced nucleophilicity of N-2 as corn pared to N-4 (77JOCI018, 81JHC13S3). Ring closure
of 3-hydrazino-5,6-diphenyl-1,2,4-triazine with cyanogen brornide produced 3-amino-6,7-
diphenyl-[ 1,2,4 ]triazolo[ 4,3-b ][1 ,2,4 ]triazine with no evidence for the [3,4-c] isorner
(76JCS(Pl)1492), in agreement with the increased nucleophilicity at N-2. If N-2 was blocked,
ring closure occurred at N-4 to give the [3,4-c] products (64CB218S).
H H
o N y N S N N N N
X --, X , MeS ( ,
N-- I N-- 'N
R 1 ....N--.j' R! ....N--.j' R I ....N--.j'
N R N R N R
N N
H 2 NHN ( , HgO
- I N
RI:::". ....N--.j'
N R
N N
r y,
R 1 ,...N --.j' N
N R
N l ( N N 1 N Ìl
H2N 'N R'COCOR 2 ) R ,"'" 'N .RC0 2 Hor R ( I NHNH 2
H NN /I R 2 N 1/ ROOE!), R 2::::". N
2 R N.... R N....
Scheme 66
In studying the N-2 versus N-4 closure competition further, an investigation (7SBSF8S7)
of the effect of the substituent R on the ring closure of 3-hydrazino-5-hydroxy-1 ,2,4-triazines
(353) showed that when R was electron-donating and carboxylic acids were used as the
Triazoles and Tetrazoles with Fused Six-membered Rings
899
cyclizing agents, [1,2,4]triazolo[4,3-b][1,2,4]triazines were the products. However, if R
were electron-attracting, acids and ortho esters gave [1,2,4 ]triazolo[3,4-c ][1 ,2,4 ]triazines
(38). Beginning with 3-hydrazino-5,5,6-trimethyl[1,2,4 ]triazine, dihydro derivatives of both
the [4,3-b] and [3,4-c] series have been obtained (79JHC427).
R
F
R tr( NyN
Rt N
N-:::'
(354)
N
HOr Ì1NHNH 2
R
/N
N
(353)
R
jI
Rtr(NyN
R2
N
N-:::'
(355)
4.15.4.8.2 [1,2,4]Triazolo[3,4-c ][1,2,4 ]triazine
Of the two methods just described for preparing the [3,4-c] system the one which
employed the electron-attracting groups on (353) was the only remotely useful one but it
was limited since it also produced some of the [1,2,4]triazolo[5,1-c][1,2,4]triazines (42)
by a Dimroth related process (75BSF857). In an effort to circumvent this rearrangement
problem, 3-hydrazino-1,2,4-triazole was condensed with a-dicarbonyl compounds under
controlled conditions and found to give the derivatives represented by (354). However, if
the temperature or reacting time were not carefully controlled, only the rearranged [5,1-c]
derivative (355) was obtained (77JOCI018). The conversion of the [3,4-c] isomer (354) into
the [5,1-c] isorner (355) could also be accomplished with aqueous sodium hydroxide.
4.15.4.8.3 [1,2,4 ]Triazolo[ 5,l-c ]{1,2,4 ]triazine
In addition to the Dimroth rearrangement of [1,2,4]triazolo[3,4-c][1,2,4]triazines dis-
cussed in the last section, derivatives of (42) would probably be accessible by the general
application of a special case which involved the reaction of 1-acetonyl-5-chloro-1,2,4-
triazole (356) with hydrazine to produce the dihydro compound (357). Lead tetraacetate
oxidation of (357) formed (358) (77JOCI018).
N
I N
MeCOCH 2 N-J'
CI
(356)
IN,
NyN
MeC /NH
N
(357)
f,
r(NyN
Me
N-;:::-N
(358)
Treatment of 3-arnino-5 -hydrazino-1 ,2,4-triazole with benzil produced 2-arnino-6,7-
diphenyl-[1 ,2,4 ]triazolo[5, 1-c][ 1,2,4 ]triazine via either direct forrnation involving cycliz-
ation on the triazole N -lor attack at N -4 of the triazole to yield the [3,4-c] compound
which rearranged to the [5,1-c] isorner (76JCS(Pl)1492). Ring closure of 3,4-diamino-1,2,4-
triazines with carboxylic acids is also a route to various [1,2,4]triazolo[5,1-c][1,2,4]triazines
(64CB2173).
4.15.4.8.4 [1,2,4]Triazolo[ 4,3-d][1,2,4]triazine
This series of compounds is prepared by ring closure of the appropriate 4-hydrazino-1,2,4-
triazines with carboxylic acids, carbon disulfide, cyanogen bromide, etc. to give the 3-
unsubstituted or 3-substituted (alkyl, thiol, amino) derivatives (67CB3467, 81JHC1353).
4.15.4.8.5 [1,2,4]Triazolo[3,4-f][1,2,4]triazine
As with the [4,3-d] series of the previous section, derivatives of (40) are available by
ring closure of various 6-hydrazino-1,2,4-triazines (74JPR667, 79JHC555). There is also a
report whereby these compounds have been prepared from 1,2,4-triazoles (70JPR669).
900
Triazoles and Tetrazoles with Fused Six-membered Rings
4.15.4.8.6 [1,2,4]Triazolo[1,5-b ]{1,2,4]triazine
These cornpounds have been prepared in two ways frorn 3-arnino-l,2,4-triazines. In the
first case, the arninotriazine is converted into the arnidine (359) with N,N-dirnethylfor-
rnarnide or -acetarnide acetal. Reaction of the arnidine with hydroxylarnine produces the
amidoxime (360) and cyclization with phosphorus oxychloride forms the desired bicyclic
product (361) (77JOCI01S). Also, the desired ring systern can be synthesized by treating
3-arnino-1,2,4-triazines with acetonitrile in the presence of alurninurn chloride to afford
the acetarnidines (362) which, in one case (R J = R 2 = Me), can be transforrned into
the [1,5-b] product with lead tetraacetate (77JOCI01S). These two routes are shown in
Scherne 67.
R 2 ( N) NH 2
Rl N
N....
N R N R
R 2 ( )N=CNMe2 ---4 R 2 ( )NHC=NOH
Rl::::... N R l::::... N
N.... N....
(359) (360)
1
N R N
R2 ( )N=CNH2 ---4 R2 ( yN\R
Rl::::... N Rl'>-. N 1/
N.... N.... -N
(362) R = Me (361)
Scheme 67
4.15.4.8.7 [1,2,4]Triazolo[1,5-d][1,2,4]triazine
Ring closure of 5(3 )-alkyl-3(5)-carboxyhydrazino-1,2,4-triazole with triethyl orthofor-
rnate has produced the [1,5-d] product along with the [4,3-d] (Scherne 68) (SlT4353).
There has also been a reported rearrangernent of the [4,3-d] systern to the [1,5-d] isorner
with warrn forrnic acid (69BSF3670).
R
Fli
HNVN
CONHNH 2
---4
R
FN\
N X N
) +
o N....N
H
Scheme 68
R
J'I,
N X N
)
o N....N
H
4.15.4.8.8 [1,2,4 ]Triazolo[ 4,3-aJ[1,3,5]triazine
Ring closure of syrnrnetrically 4,6-disubstituted (or, of course, unsubstituted) 2-hydrazino-
1,3,5-triazines via oxidation of the alkylidene or arylidene derivatives has been shown to
give the ring systern represented by (44) with no structural ambiguity (70T3357). With
rnonosubstituted and diversely substituted 2-hydrazino-l,3,5-triazines cyclization of the
alkylidene or arylidene derivatives gives both possible products with electronic and steric
factors controlling which product will predorninate (70T3357). This ring system can also be
prepared frorn 1,2,4-triazoles (53JOC1610).
4.15.4.8.9 [1,2,4 ]Triazolo[1,5-aJ[1,3,5]triazine
In addition to the rearrangement of the [4,3-a] systerns into the [1,5-a] analogs in a
Dirnroth process (70T3357), several rnethods have been ernployed for this series of corn-
pounds, often viewed as 5-azapurines. In one case, the 5,7-dirnorpholino derivative (363)
was synthesized by treating the oxirne derivative (364) with polyphosphoric acid (74JOC2143).
This rnethod has been used extensively for fused triazoles and is described in many sections
of this chapter for other ring systems.
Triazoles and Tetrazoles with Fused Six-membered Rings
901
Two purine analogs (narnely, 5-azaadenine 365 and 5-azahypoxanthine 366) of this series
have been prepared (65JA1980). The routes to these two cornpounds are shown in Scherne
69. The most efficient route to 5-azaadenine is via the reaction of 3-amino-1,2,4-triazole
with ethyl N- cyanoformimidate (80JHC1121).
N Ìl N N
Rr- I NHCH=NOH -. R( Y >
N N N N_N
R R
(364) (363) R = morpholino
N N l N N ]
(' NHCH=NP'" '-., calei"?,) r- '-.,
\\ I \ II cyanamIde \ II
N-NH HN-N HNCN N-N
H
H 2 N(N)
HN-N
l CN
HOEI
(NyN\
N N_J
NH 2
-.
N
H 2 N( Ì1
HN-N
i, KOCN )
ii, H+
N
H 2 N( )
H 2 NOCN-N
(365)
N N
IEtO),CH) (y >
HNyN_N
o
(366)
Scheme 69
4.15.4.9 Tetrazolopyridines and their Fused Benzo Derivatives
4.15.4.9.1 Tetrazolo[1,5-a]pyridine
Tetrazolo[1,5-a ]pyridines have been prepared frorn either the corresponding halopyridine
and sodiurn azide in the presence of acid with spontaneous electrocyclic ring closure, or by
nitrosation of the appropriate 2-hydrazinopyridines (7lT5121, 76JOC1073) as shown in Scherne
70. The reaction of 2-nitroaminopyridines with hydrazine under the influence of Raney
nickel (72JHC461) and 2-aminopyridines with p-toluenesulfonyl azide (79JHC1567) are two
other useful routes to tetrazolo[1,5-a]pyridines.
Ú ;..--N, X=NHNH, -û 1 X X=CI -(X N,
R N I + R ---R N
::::::,... N_J NaN0 2 , H ::::::,... N NaN, ::::::,... N_l'f'
Scheme 70
4.15.4.9.2 Tetrazolo[l,5-h]isoquinoline
Attempts at preparing 3-azidoisoquinoline frorn the 3-chloro precursor were unsuccessful
due to the inertness of the chloro substituent. However, if 3-chloroisoquinoline was first
converted into its N-oxide, its susceptibility to nucleophilic substitution was enhanced.
Thus, reaction of the N-oxide with hydrazine gave the 3-hydrazine N-oxide which, upon
nitrosation and deoxygenation, gave the desired 3-azidoisoquinoline (367). This material
was rather stable, with electrocyclization to (47) taking place only upon crystallization
(Scheme 71) (76JHC881, 81JOC843).
CO "'::::N3 CC N,
I .-l N
::::::,... ó N ::::::,...::::::,... N_J
(367) (47)
Scheme 71
Diazotization of 2,3-diarninoisoquinoliniurn tosylate is another route to derivatives of
(47) (81JOC843).
902
Triazoles and T.øtrazoles with Fused Six-membered Rings
4.15.4.9.3 Tetrazolo[1,5-a]quinoline
The ring system can be prepared in the usual way by treating a 2-chloroquinoline with
arnmoniurn azide (76JOCI073) to give the 2-azido derivative which cyclizes to the fused
tetrazole. Therrnolysis of o-azidocinnamonitriles has also given tetrazolo[1,5-a]quinolines
(SOJOC4767) via a cycloaddition of the azido group to the neighboring nitrile.
Cornparison of the NMR spectra of the isomeric systems (48) and (49) with that of (47)
indicates that (47) exists in an equilibrium with its open azido forrn whereas (48) and (49)
are almost exclusively present as the tetrazolo valence tautorner (76JHCSSl). This equilibriurn
for (47) is solvent dependent (76JHCSSl), it is influenced by the substituents present on the
rnolecule (SIJOCS43), and it rnay be an atternpt by the molecule to counteract the instability
introduced by ring closure to the o-quinoid structure (47).
4.15.4.9.4 Tetrazolo[5,1-a]isoquinoline
Diazotization of 1-hydrazinoisoquinolines (67IJC403) and reaction of p-toluenesulfonyl
azide with l-aminoisoquinoline (79JHC1579) are two methods that have been described for
preparing tetrazolo[5, 1-a ]isoquinolines.
4.15.4.10 Tetrazolo[1,5-b ]pyridazines and their Fused Benzo Derivatives
A large variety of derivatives of ring systems (50)-(52) has been prepared by the standard
rnethods of reacting 3-chloropyridazines with azide anion (63CPB34S,7IJOC446) or 3-
hydrazinopyridazines (63CPB34S, 65JHC67, 7IJOC446), 3-hydrazinocinnolines (71BSF3043) and
I-hydrazinophthalazines (67CBI073) with nitrous acid. It is interesting to note that treatrnent
of 3-chlorocinnolines with sodiurn azide did not give the corresponding tetrazole (7 1 BSF3043).
4.15.4.11 Tetrazolopyrimidines and their Fused Benzo Derivatives
4.15.4.11.1 Tetrazolo[1,5-a]pyrirnidine
The parent ring systern (53) was prepared by diazotization of 2-hydrazinopyrirnidine
(57JAP570777). Alkyl derivatives of (53) have been synthesized by the condensation of
ß-dícarbonyl cornpounds with 5-aminotetrazole (79JCS(Pl)30S5). For exarnple, treatrnent of
5 -arninotetrazole with pentane- 2,4-dione gave 5,7 -dirnethyltetrazolo[ 1,5 -a ]pyrirnidine
(Scherne 72) (65JOCS26).
N N N
H N'-:::::- , Me c ,
2 I N + MeCOCH 2 COMe ---+ I N
HN_r4' N_N'/
Me
Scheme 72
4.15.4.11.2 Tetrazolo[1,5-c]pyrimidine
Many representatives of this ring systern have been prepared by treating the appropriate
4-chloropyrimidine with sodium azide (65JOCS29). It is interesting to note that atternpts to
synthesize 8-arnino derivatives of (54) by diazotization of 5-arnino-4-hydrazinopyrimidines
yielded [1,2,3]triazolo[4,5-d]pyrirnidines instead (65JOCS29).
4.15.4.11.3 Tetrazolo[1,5-a]quinazoline
Reaction of 2-chloroquinazoline with sodiurn azide gave derivatives of (55) (63Z0B2475)
whereas the condensation between 2-hydroxymethylenecyclohexanone and 5-
aminotetrazole forrned 5,6,7 ,8-tetrahydrotetrazolo[1,5-a ]quinazoline (79JCS(P1)30S5).
Triazoles and Tetrazoles with Fused Six-membered Rings
903
4.15.4.11.4 Tetrazolo[l,5-c]quinazoline
Nitrosation of 4-hydrazinoquinazolines has been reported as the route to the [l,5-c]
system (80H(14)1759).
4.15.4.12 Tetrazolo[1,5-a ]pyrazinc and Tetrazolo[1,5-a ]quinoxaline
As in the other fused tetrazoles, the pyrazines have been prepared frorn diazotization of
a 2-hydrazinopyrazine (71JOC446) or via azide substitution on a 2-halopyrazine
(66JHC435,80JHCll). Likewise, the quinoxalines can be synthesized by the diazotization of
2-hydrazinoquinoxalines or the azide-halide displacement (78ZC92).
4.15.4.13 Tetrazolotriazines
4.15.4.13.1 Tetrazolo[l,5-h][l,2,4]triazine
Representatives of this ring system have been prepared by treating various 3-hydrazino-
1,2,4-triazines with nitrous acid (76JOC2860). X-ray analysis has verified these products to
be the [1,5-b][1,2,4] system rather than the isorneric [5,1-c][1,2,4] system which could
have also resulted frorn the 3-hydrazino starting material (76JOC2860).
4.15.4.13.2 Tetrazolo[5,l-c][l,2,4]triazine
In view of the discussion in the last section which implied that 3-azido-1,2,4-triazines
are very short-lived and indicated that they cyclize exclusively at N-2 to give the [1,5-b]
isomer, the only means into the [5,1-c] series is by blocking the N-2 position and treating
the resulting 3-hydrazino-l,2,4-triazine with nitrous acid. This has been done (64CB2185)
and, by design, led only to derivatives with an N-8 substituent (Scheme 73).
N=N
I \
O r N 0 N.ó N
ì NHNH2 HNO x: I
Me" ....NMe --4 Me "" INMe
N N....
Scheme 73
4.15.4.13.3 Tetrazolo[l,5-d][l,2,4]triazine
Substituted derivatives of this ring system have been synthesized by treating an appropriate
4-hydrazino-l,2,4-triazine with nitrous acid (67CB3467).
4.15.4.13.4 Tetrazolo[5,1-f][l,2,4]triazine
Reaction of 3-arnino-6-hydrazino-1,2,4-triazin-5(2H)-one (368) with nitrous acid has
produced (369) as a representative of this class of compounds (79JHC555).
o NON
Y 'ì NH2 HN0 2 Þ X 'ìNH2
H2NHN ....NH ".... /NH
N N" N
\ I
N=N
(368) (369)
Scheme 74
4.15.5 APPLICATIONS
These are summarized in Table 9.
904
Triazoles and Tetrazoles with Fused Six-membered Rings
Parent compound
Table 9 Miscellaneous Applications of Various Fused Triazoles
[1,2,4 ]Triazolo[ 4,3-a ]pyridine
[1,2,4 ]Triazolo[3,4-a ]isoquinoline
[1,2,3]Triazolo[ 1,5-a ]pyridine
[1,2,3 ]Triazolo[ 4,5-b ]pyridine
[I,2,3]Triazolo[ 4,5-b ]quinoline
[1,2,4]Triazolo[ 4,3-b ]pyridazine
[1,2,4 ]Triazolo[3,4-a ]phthalazine
[1,2,4 ]Triazolo[I,5-a ]pyrimidine
[I,2,3]Triazolo[ 4,5-d]pyrimidine
[1,2,4 ]Triazolo[ 4,3 -a ]pyrazine
[I,2,4]Triazolo[ 4,3-a ]quinoxaline
Applications
Photography
Cardiovascular
Antiinflammatory
Organic synthon
Pesticide
Antiallergic
Vasodilating, hypotensive
Cardiovascular, photography
Anxiolytic
C- Terminal peptide sequencing
Hydralazine metabolism
Budralazine metabolism
Photography
Herbicidal
Emelie
Seedling growth
Enzyme probe
Bronchodilator
Rice growth control
Ref.
71MI41500
67NEP6614979
73FRP2135297
80TL4529
75HCA1521
80JCR(S)308
61FRP1248409
81JMC592
78DIS(B)(39)233
74JMC381,75JMCI031,
79CPB2820
77CPB830
80MI41500
80MIP41500
78GEP2805483
77MI41500
69B2412
69JCS(C)1593
77USP4008322
908
References
VOLUME 5 REFERENCES
186ILA(l18)151 A. Strecker; Liebigs Ann. Chern., 1861,118, 151. 552, 596
1875LA(l75)243 L. Medicus; Liebigs Ann. Chern., 1875, 175,243. 502
1882CB253 E. Fischer; Ber., 1882, 15, 253. 558
1882LA(215)265 E. Fischer; Liebigs Ann. Chern., 1882,215,265. 593
1882LA(215)316 E. Fischer; Liebigs Ann. Chern., 1882,215,316. 534, 540
1882M(3)796 J. Horbaczewski; Monatsh. Chern., 1882,3,796. 568
1883 LA(221 )336 E. Fischer and L. Reese; Liebigs Ann. Chern., 1883,221,336. 540, 552
1885CB 1544 J. A. B1adin; Ber., 1885, 18, 1544. 735, 792, 828
I 886ZPC( 10)258 J. Kossell; Hoppe-Seyler's Z. Physiol. Chern., 1886, 10,258. 552
1887CB1176 T. Zincke and A. T. Lawson; Ber., 1887,20, 1176. 722
1887M(8)201 J. Horbaczewski; Monatsh. Chern., 1887,8,201. 568
1888CBI149 L. Claisen and O. Lowman; Ber., 1888,21, 1149. 121
1888CB2751 H. von Pechmann; Ber., 1888,21,2751. 670
1889C B2929 E. Buchner; Ber., 1889,22,2929. 142
I 889LA(250)294 G. Hofmann; Liebigs Ann. Chern., 1889,250,294. 118
1889LA(251 )235 R. Behrend and O. Roosen; Liebigs Ann. Chern., 1889,251, 235. 582
1890CB225 G. Bruhns; Ber., 1890,23,225. 540
1892CB225 A. Andreocci; Ber, 1892,25,225. 738
1 892ZPC( 16)329 M. Kruger; Hoppe-Seyler's Z. Physiol. Chern., 1892,16,329. 552
1 893<:'B86 E. Noelting and O. Michel; Ber., 1893,26,86. 839
1893CBI719
1893CB2385
I 894G222
1895CB2480
I 895MI40900
1897 AP(23 5)469
1897CB559
1897CBI846
1897CB2220
1897 C B2226
1 897CB223 I
I 897CB2400
1897C B2584
1898CB2550
1898CB2619
1898C B3270
1898CB3272
1898ZPC(24)364
1899CB68
1899CB435
1899C B2721
00CB58
00CB644
00CBI371
00CB3035
00JCS(77)224
0lCB258
0lCB637
0lCBI165
0lCBI170
02CB2563
02GEPI42468
03CB2056
04JPR(69)509
05CB856
05CB861
05CB4049
05G373
05JCS(87)625
05LA(343)1
05 LA(343)207
06AP(244)I I
06CB227
06CBI831
07 AP(245)312
07CB3752
07ZPC(51)425
08CBI76
09CB659
09LA(364) 183
IOCB2904
IOCB3553
12JBC(II)67
I3JBC( 14)299
References
R. von Rothenburg; Ber., 1893,26, 1719.
E. Bamberger and P. de Gruyter; Her., 1893,26,2385.
G. Pellizzari; Gazz. Chirn. Ital., 1894, 24, 222.
E. Fischer; Ber., 1895,28, 2480.
M. Gomberg; Am. J. Chern., 1895,17,403.
H. van der Slooten; Arch. Ph arm. (Weinheirn, Ger.), 1897,235,469.
E. Fischer; Ber., 1897,30, 559.
E. Fischer; Ber., 1897,30, 1846.
E. Fischer; Ber., 1897,30,2220.
E. Fischer; Her., 1897,30, 2226.
E. Fischer; Ber., 1897, 30, 2231.
E. Fischer; Ber., 1897,30,2400.
H. Brunner and H. Leins; Ber., 1897,30,2584.
E. Fischer; Ber., 1898, 31, 2550.
E. Fischer; Ber., 1898,31,2619.
E. Fischer; Her., 1898, 31, 3270.
E. Fischer; Her., 1898,31,3272.
M. Kruger and G. Salamon; Hoppe-Seyler's Z. Physiol. Chern., 1898,24,364.
T. B. Baillie and J. Tafel; Ber., 1899,32,68.
E. Fischer; Ber., 1899,32,435.
E. Fischer and F. Ach; Ber., 1899,32,2721.
A. Hantzsch and o. Silberrad; Ber, 1900,33,58.
H. von Pechmann and W. Bauer; Ber., 1900,33,644.
W. Traube; Ber., 1900,33, 1371.
W. Traube; Ber., 1900,33,3035.
G. Young and E. Witham; J. Chern. Soc., 1900,77,224.
J. Tafel: Her., 1901,34,258.
F. Kunckell; Ber., 1901,34,637.
J. Tafel and B. Ach; Her., 1901,34, 1165.
J. Tafel and B. Ach; Ber., 190 I, 34, 1170.
E. Fischer and H. Tullner; Her., 1902,35,2563.
Boehringer; Ger. Pat. 142468 (1902).
A. Hantzsch; Ber., 1903,36, 2056.
R. Stolle and L. Gutmann; J. Prakt. Chern., 1904,69,509.
M. Busch; Ber., 1905,38,856
M. Busch; Ber., 1905,38,861.
M. Busch and G. Mehrtens; Ber., 1905,38,4049.
G. Pellizzari and A. Soldi; Gazz. Chirn. Ital., 1905,35,373
G. Young; J. Chern. Soc., 1905,87,625.
W. Manchot and R. Noll; Liebigs Ann. Chern., 1905, 343, I.
A. Einhorn, E. Bischkopf, C. Ladisch, T. Mauermayer, G. Schupps, E. Sprängerts
and B. Szelinski; Liebigs Ann. Chern., 343, 207.
W. Traube; Arch. Pharrn. (Weinheirn, Ger.), 1906,244, II.
W. Traube and W. Nithack; Ber., 1906,39,227.
G. Dedichen; Ber., 1906, 39, 1831.
E. Schmidt and W. Schwabe; Arch. Ph arm. (Weinheirn, Ger.), 1907,245,312.
J. Tafel and J. Dodt; Ber., 1907,40,3752.
R. Burian; Hoppe-Seyler's Z. Physiol. Chern., 1907,51,425.
R. Majima; Ber., 1908,41, 176.
H. von Pechmann and W. Bauer; Ber., 1909,42,659.
O. Dimroth; Liebigs Ann. Chern., 1909,364, 183.
O. Dimroth and G. DeMontmollin; Ber., 1910,43,2904.
H. Biltz; Ber., 1910,43,3553.
c. O. Johns; 1. Bioi. Chern., 1912,11,67.
c. O. Johns and A. G. Hogan; J. Bioi. Chern., 1913, 14,299.
909
142
736
762
557
550, 551
529
534
534
562
562
532
557
551
529
557
601
562, 60 I
598
541
502, 534
534
752
701
571
571
766
541
119
541
541
582
577
839
116
785
785
785
762
757
754, 756
765
558, 559
576
742
529
541
538
647
701
696
839
540
596
578
910
13JBC(14)381
13JBC(l5)515
13JCS1391
13MI41000
14(,B1671
14CB3163
14JBC(l7)1
14LA(406)22
ISCB410
15CB1614
16G308
16JB(,(25)607
B-16M141400
17LA(413)155
20CB2327
20MI41000
21('B1676
21 CB2191
21CB2201
11G71
21 LA(423)200
21l.A( 423 )242
2IZPC(117)23
12GEP338926
22 LA( 426 )306
13LA(432)266
23MI41000
24CBI381
24(' B2092
24HCA713
25CB393
2SCB 1704
15LA(441)203
25LA(441)215
26CBI360
26CB 1742
26(' B2048
26CB2921
46('B1926
27CBII<)
27CB766
27LA(454) 164
27LA(459)39
18CBI140
28CB 1409
28J PR(l18) 198
30CB2876
30G644
30G866
30JPR( 125)498
31CB752
3IMI40<)O()
31J PR(l34)31 0
32LA(498)1
References
c. O. Johns and E. J. Baumann; J. Bioi. Chern., 1913,14,381.
C. O. Johns and E. J. Baumann; J. Bioi. Chern.. 1913,15,515.
G. T. Morgan and F. M. G. Micklethwait: J. Chern. Soc., 1913, 103, 1391.
J. Wellisch; Biochem. Z, 1913, 49. 173.
K. Brunner: Ber., 1914,47,2671.
M. Bachstez; Ber., 1914,47,3163.
C. O. Johns; J. Bioi. Chern., 1914, 17, I.
H. Biltz and F. Damm; Liebigs Ann. Chern., 1914,406,21.
J. Lifschitz; Ber., 1915, 48, 410.
T. Curti us, A. Darapsky and E. Müller; Ber., 1915,48, 1614.
E. Oliveri-Mandala; Gazz. Chim. Ital., 1916.46,308.
P. A. Levene and J. K. Senior: J. Bioi. Chern., 1916,25,607.
E. Hjelt; 'Geschichte der Organischen Chemie', Vieweg u. Sohn, Braunschweig.
1916.
H, Biltz and K. Strufe; Liebigs Ann. Chern., 1917,413, 155.
H. Biltz and F. Max: Ber., 1920,53,2327.
S. Frankel and K. Zeimer; Biochem. Z, 1920, 1l0, 234.
H. Biltz and L. Herrmann; Ber., 1921,54, 1676.
M. P. Schmidt and A. Hagenböcker; Ber., 1921,548,2191.
M. P. Schmidt and A. Hagenböcker; Ber., 1921, 548, 2201.
G. G. Cusmano; Gazz. Chim. Ital., 1921,51,71.
H. Biltz and K. Strufe: Liebigs Ann. Chern., 1921,423,100.
H. Biltz and K. Strufe; Liebigs Ann. Chern., 1921,423,242.
J. Herzig; Hoppe-Seyler's Z Physiol Chern., 1921, 117, 23.
Kalle & Co., Ger. Pat. 338926 (1922) (Chern. Ahstr., 1922, 16, 2869).
H. Biltz and R. Bulow; Liebigs Ann. Chern., 1922,426, 306.
560, 578
579
699
623,641
765
113
534
540
839
839
690
577
839
540
535
641
534
722
722
722
533, 558
582
535
722
535
W. Traube, F. Schottlander, C. Goslich, R. Peter, F. A. Meyer, H. Schluter, W.
Steinbach and K. Bredow; Liebigs Ann. Chern., 1923,432, 266. 550, 574, 577
E. Sucharda; Rocz. Chern., 1923,3,236 (Chern. Abstr., 1925,19,72). 613
F. Reindel: Ber., 1924,57, 1381,
A. E. Tschitschibabin; Ber., 1924,57,1092.
J. Sarasin and E. Wegmann; Helv. Chim. Acta.. 1914,7,713.
F. Reindel and H. Rauch; Ber., 1925,58,393.
A. E. Tschitschibabin; Ber., 1925, 58, 1704.
A. Prüsse; Liebigs Ann. Chern., 1925,441,203.
R. Behrend; Liebigs Ann. Chern., 1925,441,215.
L. Schmid and B. Bangler; Ber., 1926.59, 1360.
R. StoI1é; Ber., 1926,59,1742.
A. E. Tschitschibabin; Ber., 1926,59,1048.
F. Reindel and H. Rauch; Ber., 1926,59,2921.
F. Reindel and A. von Putzer-Reybegg; Ber., 1926,59,2926.
A. Vilsmeier and A. Haack; Ber., 1927,60, 119.
A. E. Tschitschibabin and A. V. Kirsanow; Ber., 1927,608, 766.
K. Fries: Liebigs Ann. Chern., 1927,454. 164.
O. Dimroth and W. Michaelis; Liebigs Ann. Chern., 1927,459,39.
G. Wittig, F. Bangert and H. Kleiner: Ber., 1928,618, 1140.
H. Biltz and H. Rakett; Ber., 1928,61, 1409.
H. Biltz and A. Beck; J. Prakt. Chern., 1928. 118, 198.
H. Biltz and H. Pardon; Ber., 1930,63,2876.
G. B. Crippa, G. Bellani and A. Merubini; Gazz. Chim. Ital., 1930,60,644.
M. Gaiotti, G. Barro and L. Saito; Gazz. Chim. Ital., 1930,60,866.
T. Curti us and W. Klavehn; 1. Prakt. Chern., 1930, 125,498.
H. Biltz and J. Sauer; Ber., 1931,64,752. .
P. A. W. Self and W. R. Rankin; Quart. 1. Pharmacal., 1931,4,346.
H. Biltz and H. Pardon; J. Prakt. Chern., 1932, 134, 310.
O. Diels, K. Alder, H. Winckler and E. Petersen; Liebigs Ann. Chern., 1932,
498,1.
612
612,613
587
611
631
582
568
632
707
610,611,631
613
612
573
635
721
712,713
719
540, 588, 589
533
558
722
707
709
560
533
535
633
33JCS662
34JA700
34JCSI639
34JIC867
34LA(511)168
35GI52
35JCS955
35LA(515)185
35MI40900
36MI40900
36MI40901
37CB2309
38CB718
38CB2347
39JA351
39YZ97
39YZI85
40CBI62
40JA2002
40MI41200
B-40MI41400
400S(20) 16
400S(20)73
41 RTC453
42CBI338
42CBI936
42JCS232
42MI41100
43JCS383
43MI41100
43MI41200
43MI41300
43RTC580
448J(38)309
44JAI805
44JBC(153)203
45HCA850
45JCS556
45JCS75I
46JAI799
46JCS852
460S(26) II
46USP2509084
47CRV(41)1
47JCS943
48JAI240
48JA3109
48JA3429
48JA3669
48JCS967
References
J. M. Gulland and T. F. MacCrae; J. Chern. Soc., 1933,662.
S. M. E. Englert and S. M. McElvain; J. Am. Chern. Soc., 1934,56,700.
J.M. Gulland, E. R. Holiday and T. F. MacCrae; J. Chern. Soc., 1934, 1639.
P. C. Mitter and N. Chatterjee; J. Indian Chern. Soc., 1934, 11,867 (Chern. Abstr,
1935, 29, 2953).
O. Diels and J. Reese; Liebigs Ann. Chern., 1934,511, 168.
M. Milone; Gazz. Chirn. Ital., 1935,65, 152.
E. Bergmann and H. Heimhold; J. Chern. Soc., 1935,955.
K. Alder and G. Stein; Liebigs Ann. Chern., 1935,515, 185.
G. 8argioni; Boll. Chirn-Farrn., 1935,64,869 (Chern. Abstr., 1936,30,2320).
G. Hunter; Nature (London), 1936,37,405.
G. Hunter; Biochern. z., 1936,30, 1183.
R. Weidenhagen and H. Wegner; Ber., 1937,70,2309.
H. Bredereck and G. Richter; Ber., 1938,71,718.
R. Weidenhagen and U. Weeden; Ber., 1938, 71B, 2347.
J. R. Spies and T. H. Harris, Jr.: J. Am. Chern. Soc., 1939,61,351.
E. Ochiai and M. Karii; Yakugaku Zasshi, 1939,59,97 (Chern. Abstr., 1939,33,
3791).
E. Ochiai and M. Sibata; Yakugaku Zasshi, 1939,59, 185 (Chern. Abstr., 1939,
3 8 -
K. W. F. Kohlrausch and R. Seka; Ber., 1940,73, 162.
R. O. Roblin, Jr., J. H. Williams, P. S. Winnek and J. P. English; J. Am. Chern.
Soc., 1940, 62, 2002.
W. Hückel, N. Datow and E. Simmersbach; Z. Phys. Chern., 1940, A186, 129.
L. P. Hammett; 'Physical Organic Chemistry', McGraw-Hill, New York, 1940.
R. E. Damschroder and W. D. Peterson; Org. Synth., 1940,20, 16.
H. D. Porter and W. D. Peterson; Org. Synth., 1940, 20, 73.
H. J. Backer and G. L. Wiggerink; RecI. Trav. Chirn. Pays-Bas, 1941,60,453.
H. Specker and H. Gawrosch; Ber., 1942,75, 1338.
R. Weidenhagen, G. Train, H. Wegner and L. Nordstrom; Ber., 1942,75, 1936.
W. E. Allesbrook, J. M. Gulland and L. F. Story; J. Chern. Soc., 1942,232.
E. G. Taylor; Can. J. Res., 1942, 20B, 161 (Chern. Abstr., 1942,36,6398).
J. Baddiley, B. Lythgoe, D. McNeill and A. R. Todd; J. Chern. Soc., 1943,383.
K. A. Jensen and A. Friediger; Kgl. Danske Videnskab. Se/skab, Mat.-fys. Medd.,
1943,20, I (Chern. Abstr., 1945,39,2068).
K. A. Jensen and A. Friediger; Kg/. Danske Videnskab. Se/skab Mat.-fys. Medd.,
1943, 20, I (Chern. Abstr., 1945, 39, 2068).
K. A. Jensen and A. Friediger; Kg/. Danske Videnskab. Se/skab. Mat.-fys. Medd.,
1943, 20, I (Chern. Abstr., 1944, 38, 3629).
H. J. Backer and H. 80S; RecI. Trav. Chirn. Pays-Bas, 1943,62,580.
A. Neuberger; Biochern. J., 1944,38,309.
C. F. H. Allen, J. Van Allan and C. V. Wilson; J. Am. Chern. Soc., 1944,66,1805.
A. A. Plentl and R. Schoenheimer; J. Bio]. Chern., 1944, 153,203.
P. Ruggli and F. Buchmeier; He/v. Chirn. Acta, 1945,28,850.
G. A. Howard, B. Lythgoe and A. R. Todd; J. Chern. Soc., 1945,556.
F. G. Mann and J. W. G. Porter; J. Chern. Soc., 1945,751.
911
533
341
536
664
142
12
558
703,711
564
552
552
92
592
639
552
647
649
686
845
739
843
422
288
126
684
639
589
690
572
681
743
795
120
623,641
631
596
86
573
548, 552, 588, 598
R. F. Coles and C. F. Hamilton; J. Am. Chern. Soc., 1946,68, 1779. 707
G. W. Kenner and A. R. Todd; J. Chern. Soc., 1946,852. 573
C. F. H. Allen and A. Bell; Org. Synth., 1946,26, II. 787
W. E. Decker; U.S. Pat. 2 509084 (1946) (Chern. Abstr., 1950,44,8366). 592
F. R. Benson; Chern. Rev., 1947,41, I. 792,802,803
F. E. King and T. J. King; J. Chern. Soc., 1947,943. 578
L. F. Cavalieri, V. E. Blair and G. B. Brown; J. Am. Chern. Soc., 1948,70, 1240.
A. Bendich, J. F. Tinker and G. B. Brown; J. Am. Chern. Soc., 1948,70,3109.
D. Heyl, S. A. Harris and K. Folkers; J. Am. Chern. Soc., 1948,70,3429.
D. Hey!, E. Luz, S. A. Harris and K. Folkers; J. Am. Chern. Soc., 1948,70,3669.
J. Davoli, B. Lythgoe and A. R. Todd; J. Chern. Soc., 1948,967.
577,
582, 596
552, 560
641
641
536
912
48JCSI157
48JCS1389
48JCS 1685
48JCSI960
48JOC815
480S(28)87
48RTC29
48YZI91
48Z0B2116
48Z0B2129
49JAI436
49JAI885
49JA2297
49JA3973
49JA3994
49JAP49177355
49JCS786
49JCS I 071
49JCS2329
49JCS2490
49JCS3001
490S(29)54
49RTCIOl3
49USP248 1953
49YZ496
50BSB573
50CB201
50CRV(46)I
50HCAI183
50JA2587
50JBC( 185)423
50JBC( 185)435
50J Be( 185)439
50JCS 1884
50JCS 1888
50LA(566)58
51AG511
51AX81
5lJAI207
51JA1650
5lJAI864
5lJA4360
51JA4470
5lJ A4609
5lJA5235
5lJBe( 189)401
51 JBC(l93)425
5lJCS2411
51MI40100
51 MI40101
51 M 140400
51MI41200
51MI41201
510S(31)43
51YZ760
52B1(51)133
52CB390
52('BI012
52DOK(87)783
References
W. Wilson; J. Chern. Soc., 1948, 1157.
V. Petrow and J. Saper; J. Chern. Soc., 1948, 1389.
J. Davoli, B. Lythgoe and A. R. Todd; J. Chern. Soc., 1948, 1685
J. W. Cornforth and H. T. Huang; J. Chern. Soc., 1948, 1960.
J. L. Riebsomer; J. Org. Chern., 1948, 13,815.
H. D. Porter and A. Weissberger; Org. Synth., 1948,28, 87.
F. Kogl, G. M. van der Want and C. A. Salemink; Reel. Trav. Chim. Pays-Bas,
1948,67,29. 618,619,635,640
J. Haginwa; Yakugaku Zasshi, 1948,68, 191 (Chern. Abstr., 1953,47,8074). 118
A. M. Khaletski and M. S. Eshmann; Zh. Obshch. Khim., 1948, 18, 2116. 557
E. S. Golovchinskaya; Zh. Obshch. Khim., 1948,18,2129. 549,550,593
571
635,636
536
119, 156
699, 707
288
J. C. Sheehan and C. A. Robinson; J. Am. Chern. Soc., 1949,71, 1436. 728
J. R. Vaughan, Jr., J. Krapcho and J. P. English; J. Am. Chern. Soc., 1949,71,1885. 617,
618,635,636
699
552, 589
290
564
140
R. A. Henry and W. M. Dehn; J. Am. Chern. Soc., 1949,71,2297.
L. F. Cavalieri, J. E. Tinker and G. B. Brown; J. Am. Chern. Soc., 1949,71,3973.
R. G. Jones; J. Am. Chern. Soc., 1949,71,3994.
T. Shioi; Jpn. Pat. 49 177355 (1949) (Chern. Abstr., 1951,45,7590).
W. Batty and B. C. L. Weedon; J. Chern. Soc., 1949, 786.
A. H. Cook, A. C. Davis, I. M. Heilbron and G. H. Thomas; J. Chern. Soc., 1949,
1071.
A. H. Cook and E. Smith; J. Chern. Soc., 1949,2329.
K. J. M. Andrews, N. Anand, A. R. Todd and A. Topham; J. Chern. Soc., 1949,
2490.
A. H. Cook and E. Smith; J. Chern. Soc., 1949, 3001.
E. F. M. Stephenson; Org. Synth., 1949,29, 54.
C. A. Salem ink and G. M. van der Want; Reel. Trav. Chim. Pays-Bas, 1949,68,
1013. 618,619,621,635,640
G. Schwarz; U.S. Pat. 2481953 (1949) (Chern. Abstr., 1950,44,5737). 612
T. Takahashi and J. Shibasaki; Yakugaku Zasshi, 1949, 69, 496 (Chern. Abstr.,
1950,44,4474).
589
588, 590
558, 560
577, 590
288
631
A. DeCat and A. van Dormael; Bull. Soc. Chim. Belg., 1950,59,573. 647
H. Bredereck, H.-G. von Schuh and A. Martini; Chern. Ber., 1950,83,201. 533
F. R. Benson and W. L. Savell; Chern. Rev., 1950,46, I. 670,705, 708, 722
H. Stenyl, A. Staub, C. Simon and W. Baumann; Helv. Chim. Acta, 1950,33,
1183. 322
L. F. Cavalieri and A. Bendich; J. A,m. Chern. Soc., 1950,72,2587. 576
A. Bendich, S. S. Furst and G. B. Brown; J. Bioi. Chern., 1950, 185,423. 593
A. Bendich, W. D. Geren and G. B. Brown; J. Bioi. Chern., 1950,185,435. 593
E. Shaw; J. BioI. Chern., 1950, 185, 439. 583, 568, 586, 588
A. H. Cook and G. H. Thomas; J. Chern. Soc., 1950, 1884. 588,589
A. H. Cook and G. H. Thomas; J. Chern. Soc., 1950, 1888. 590
K. Alder and W. Trimborn; Liebigs Ann. Chern., 1950,566, 58. 720
T. Wieland and L. Bauer; Angew Chern., 1951, 63, 511.
W. Cochran; Acta Crysta/logr., 1951,4,81.
J. C. Sheehan and C. A. Robinson; J. Am. Chern. Soc., 1951, 73, 1207.
J. Davoli and B. A. Lowy; J. Am. Chern. Soc., 1951,73, 1650.
L. C. King and R. J. Hlavacek; J. Am. Chern. Soc., 1951,73, 1864.
J. E. Fagel, Jr. and G. W. Ewing; J. Am. Chern. Soc., 1951,73,4360.
R. A. Henry; 1. Am. Chern. Soc., 1951,73,4470.
R. Abrams and L. Clark; J. Am. Chern. Soc., 1951,73,4609.
G. B. Elion, E. Burgi and G. H. Hitchings; J. Am. Chern. Soc., 1951,73,5235.
D. W. Woolley and E. Shaw; J. Bioi. Chern., 1951, 189,401.
R. A. Alberty, R. M. Smith and R. M. Bock; J. Bioi. Chern., 1951, 193,425.
N. Campbell and E. B. McCall; J. Chern. Soc., 1951,2411.
C. C. J. Roothaan; Rev. Mod. Phys., 1951,23,69.
G. G. Hall; Proc. R. Soc. London, Ser. A, 1951,205,541.
L. E. Orgel, T. L. Cottrell, W. Dick and L. E. Sutton; Trans. Faraday Soc., 1951,
47, 113.
W. D. Jackson and J. B. polya; Aust. J. Sci., 1951, 13, 149.
L. E. Orgel, T. L. Cottrell, W. Dick and L. E. Sutton; Trans. Faraday Soc., 1951,
47,113.
R. H. Wiley and P. E. Hexner; Org. Synrh., 1951,31,43.
T. Matsukawa and S. Ban; Yakugaku Zasshi, 1951,71,760.
E. A. Johnson; Biochem. J., 1952,51, 133.
F. Bohlmann; Chern. Ber., 1952,85,390.
F. Korte; Chern. Ber., 1952,85,1012.
M. A. Prokof'ev, E. G. Antonovich and Y. P. Shvachkin; Dokl. Akad. Nauk
SSSR, 1952,87, 783 (Chern. Abstr., 1954,48, 169).
600
508
728
552
120
690
802
572
572, 575
652
525
631
7
7
172
787
742
288
647
524
68
618,635
647
52HCAI67
52JA350
52JA411
52JA3242
52JA4897
52JA4917
52JA4960
52JCS3418
52JCS3448
52JCS4410
52JCS4735
B-52MI40900
52MI41200
52Z0B2220
52Z0B2225
53AGI55
53AX369
53 BJ(54)646
53CB88
53CB96
53CB333
53CB858
53CR(236)2519
53CRV(53)191
53HC(6-1)
53HCAI324
53JAI14
53JA263
53JA746
53JA5753
53JBC(204)847
53JBC(204)1019
53JOC 1269
53JOCI610
B-53MI40900
53MI40901
53MI40902
54CB57
54CI(L) 1458
54CRV41
54HCA789
54JA88
54JA667
54JA923
54JA2894
54JA4470
54JA4933
54JA5087
54JA5633
54JA6073
54JCSI41
54JCS 1850
54JCS2060
54JCS270 I
54JCS3319
54JCS3461
54JCS4256
54JCS4508
54JGUI045
54JOC439
54LA(590)232
54MI40900
References
F. Moulin; He/v. Chirn. Acta, 1952,35, 167.
E. Schipper and A. R. Day; J. Am. Chern. Soc., 1952,74,350.
G. B. Elion, E. Burgi and G. H. Hitchings; J. Am. Chern. Soc., 1952,74,41 I.
H. R. Snyder, F. Verbanac and D. B. Bright; J. Am. Chern. Soc., 1952,74,3242.
E. A. Falco, G. B. Elion, E. Burgi and G. H. Hitchings; 1. Am. Chern. Soc., 1952,
74, 4897.
F. R. Benson, L. W. Hartzel and W. L. Savell; J. Am. Chern. Soc., 1952,74,4917.
W. A. Reckhow and D. S. Tarbell; J. Am. Chern. Soc., 1952,74,4960.
M. R. Atkinson and J. B. Polya; J. Chern. Soc., 1952,3418.
F. L. Rose; J. Chern. Soc., 1952, 3448.
G. R. Ramage and G. Trappe; J. Chern. Soc., 1952,4410.
W. R. Bamford and T. S. Stevens, 1. Chern. Soc., 1952,4735.
H. C. Urey; 'The Planets', Yale University Press, 1952.
P. Dunn, E. A. Parkes and J. B. Polya; Aust. J. Exp. BioI. Med. Sci., 1952,30,437.
E. S. Golovchinskaya and E. S. Chaman; Zh. Obshch. Khirn., 1952,22,2220.
E. S. Golovchinskaya and E. S. Chaman; Zh. Obshch. Khirn., 1952,22,2225.
E. Pfeil; Angew. Chern., 1953,65, 155.
P. J. Wheatley; Acta Crystallogr., 1953,6,369.
A. Albert; Biochern. J., 1953,54,646.
H. Bredereck and G. Theilig; Chern. Ber., 1953,86, 88.
H. Bredereck and G. Theilig; Chern. Ber., 1953,86,96.
H. Bredereck, I. Hennig, W. Pfleiderer and G. Weber; Chern. Ber., 1953,86,333.
R. Kuhn and W. Münzing; Chern. Ber., 1953,86,858.
M. Polonovski, M. Pesson and R. Zelnik; C.R. Hebd. Seances Acad. Sci., 1953,
236,2519.
H. H. Jaffe; Chern. Rev., 1953,53, 191.
K. Hofmann; Chern. Heterocyc/. Cornpd., 1953,6-1.
K. Clusius and M. Vecchi; He/v. Chirn. Acta., 1953,36, 1324.
J. H. Speer and A. L. Raymond; J. Am. Chern. Soc., 1953,75, 114.
R. K. Robins, K. J. Dille, C. H. Willits and B. E. Christensen; J. Am. Chern.
Sac., 1953, 75, 263.
I. A. Kaye, C. L. Parris and W. J. Burlant; J. Am. Chern. Soc., 1953,75,746.
A. R. P. Paterson and S. H. Zbarsky; J. Am. Chern. Soc., 1953,75, 5753.
R. O. Hurst, A. M. Marko and G. C. Butler; 1. Bio/. Chern., 1953,204,847.
G. B. Brown and V. S. Weliky; J. Bio/. Chern., 1953,204, 1019.
W. L. Garbrecht and R. M. Herbst; J. Org. Chern., 1953,18, 1269.
D. W. Kaiser, G. A. Peters and V. P. Wystrach; J. Org. Chern., 1953,18, 1610.
A. I. Oparin; 'Origin of Life', Dover Publications, New York, 1953.
E. S. Golovchinskaya and I. Sbornik; Statei Obshch. Khirn. Akad. Nauk SSSR,
1953, 1, 702.
S. L. Miller; Science, 1953,117,528.
913
708
645
572
69
575, 591
699
635
765
338
648
706
569
787
549
550
840
354
525
156
156
574
793
567
843
385
577
573
593
631
586
525
529, 603
812
900
569
593
569
J. Goerde1er; Chern. Ber., 1954,87,57.
G. F. Duffin, J. D. Kendall and H. R. J. Waddington; Chern. Ind. (London),
1954, 1458. 745,748
J. H. Boyer and F. C. Canter; Chern. Rev., 1954,54,41. 710
K. C1usius and H. Hürzeler; He/v. Chirn. Acta, 1954,37,789. 839,840
R. A. Henry, W. G. Finnegan and E. Lieber; J. Am. Chern. Soc., 1954,76,88. 812
L. W. Hartzel and F. R. Benson; J. Am. Chern. Soc., 1954,76,667. 684,685,728
R. A. Henry and W. G. Finnegan; J. Am. Chern. Soc., 1954,76,923. 819
R. A. Henry, W. G. Finnegan and E. Lieber; J. Am. Chern. Soc., 1954,76,2894. 793
C. Djerassi and G. R. Pettit; J. Am. Chern. Soc., 1954,76,4470. 631
R. H. Wiley, N. R. Smith, D. M. Johnson and J. Moffat; J. Am. Chern. Soc.,
1954, 76, 4933. 685, 700
K. L. Dille and B. E. Christensen; J. Am. Chern. Soc., 1954,76,5087. 596
A. G. Beaman; J. Am. Chern. Soc., 1954,76, 5633. 557, 558, 559, 562, 563, 572, 597
A. Bendich, P. J. Russell, Jr. and J. J. Fox; J. Am. Chern. Soc., 1954,76,6073. 524, 592
M. R. Atkinson and J. B. Polya; J. Chern. Soc., 1954, 141. 746
G. D. Buckley; J. Chern. Soc., 1954, 1850. 717
A. Albert and D. J. Brown; J. Chern. Soc., 1954,2060. 523,524,525,571,
572, 575, 579, 593, 596
347
746, 765
767
739, 756
I. M. Bassett and R. D. Brown; J. Chern. Soc., 1954, 2701.
M. R. Atkinson and J. B. Polya; J. Chern. Soc., 1954,3319.
K. T. Potts; J. Chern. Soc., 1954, 3461.
M. R. Atkinson, E. A. Parkes and J. B. Po1ya; J. Chern. Soc., 1954,4256.
M. R. Atkinson, A. A. Komzak, E. A. Parkes and J. B. Polya; J. Chern. Soc.,
1954, 4508.
M. A. Prokof'ev and Y. P. Shvachkin; J. Gen. Chern. USSR (Eng/. Transl.), 1954,
1045 (Chern. Abstr., 1955,49,9661).
R. M. Herbst and D. F. Percival; 1. Org. Chern., 1954, 19,439.
D. Jerchel, M. Kracht and K. Krucher; Liebigs Ann. Chern., 1954,590,232.
D. J. Brown; J. Appl. Chern., 1954,358.
23
739
647
794
576
571
914
54MI40901
54MI40902
54MI40903
54MI40904
54MI41100
54MI41101
54ZN(B)495
54ZN(B)496
55AJCI00
55AX211
55CB I 093
55CBII17
55CB1306
55CB 1932
55CR(241)1049
55FES235
55FES616
55FES733
55JAI53R
55JA1703
55JA2351
55JA2569
55JA2572
55JA5105
55JA5922
55JA6204
55JA6532
55JCS896
55JCS2834
55JGU939
55LA(593)207
55 M 140900
55MI41000
55MI41100
55MI41200
55Z0B1366
56AC( R)275
56AG705
56AG753
56AP453
56AX874
56BSF888
56CB 1940
56CR(243)380
56CR(243)2090
56G797
56HCA986
56JAI59
56JA217
56JA242
56JA41I
56JA784
56JA1375
56JAI618
56JAI928
56JA2418
56JA2858
56JA3508
56JA3511
56JA4130
References
N. Urabe and K. Yasukochi; J. Electrochern. Soc. Jpn., 1954,22,469
N. Urabe and K. Yasukochi; J. Electrochern. Soc. Jpn., 1954,22,525.
M. Ishidate, M. Sekiya and I. Kurita; J. Ph arm. Soc. Jpn., 1954,74,420.
I. Lasnitzki, R. E. F. Matthews and J. D. Smith; Nature (London), 1954, 173,346.
K. L. Cheng; Anal. Chern., 1954,26, 1038.
G. H. N. Towers and D. C. Mortimer; Nature (London), 1954, 174, 1189.
E. Wiberg and H. Michaud; Z. Naturforsch., Teil B, 1954,9,495.
E. Wiberg and H. Michaud; Z. Natuiforsch., Teil B, 1954, 9, 496.
R. D. Brown; Aust. J. Chern., 1955,8, 100.
J. H. Bryden; Acta Crystallogr., 1955,8,211.
K. Schilling, F. Krohnke and B. Kickhofen; Chern. Ber., 1955,88, 1093.
F. Krohnke, B. Kickhofen and C. Thoma; Chern. Ber., 1955,88, 1117.
H. Bredereck and A. Edenhofer; Chern. Ber., 1955,88, 1306.
H. Priewe and A. Poljak; Chern. Ber., 1955,88, 1932.
P. Grammaticakis; C. R. Hebd. Seances Acad. Sci., 1955,241, 1049.
M. L. Stein and L. D'Antoni; Farmaco Ed. Sci., 1955, 10, 235.
G. B. Crippa and A. Crippa; Farrnaco Ed. Sci., 1955, 10,616 (Chern. Abstr., 1956,
50, 1840).
G. Serchi, L. Sancio and G. Buchi; Farrnaco Ed. Sci., 1955,10,733.
R. G. Jones and C. Ainsworth; J. Am. Chern. Soc., 1955,77, 1538.
R. H. Wiley and J. Moffat; J. Am. Chern. Soc., 1955,77, 1703.
S. L. Miller; J. Am. Chern. Soc., 1955,77, 235\.
C. H. Willits, J. C. Decius, K. L. Dille and B. E. Christensen; J. Am. Chern. Soc.,
1955, 77, 2569.
R. H. Wiley, N. R. Smith, D. M. Johnson and J. Moffat; J. Am. Chern. Soc.,
1955, 77, 2572.
R. H. Wiley, K. H. Hussung and J. Moffat; J. Am. Chern. Soc., 1955,77,5105.
F. Schaefer; J. Am. Chern. Soc., 1955,77,5922.
R. F. Wilson and L. E. Wilson; J. Am. Chern. Soc., 1955,77,6204.
C. S. Rondestvedt, Jr. and P. K. Chang; J. Am. Chern. Soc., 1955,77,6532.
P. R. Brook and G. R. Ramage; J. Chern. Soc., 1955,896.
J. D. Bower and G. R. Ramage; J. Chern. Soc., 1955,2834.
M. A. Prokof'ev and Y. P. Shvachkin; J. Gen. Chern. USSR (Engl. Transl.), 1955,
25,939 (Chern. Abstr., 1956.50,3458).
R. Hüttel and G. Wetzel; Liebigs Ann. Chern., 1955,593,207.
B. G. Bolyrev and R. G. Matrika; J. Appl. Chern. USSR, 195528,399.
R. Fusco and S. Rossi; Rend. 1st. Lomb. Sci. Lett., Cl. Sci. Mat. Nat., 1955,88,
194 (Chern. Abstr., 1956,50,10743).
L. Cambi, L. Canonica and C. Sironi; Atti Accad. Nazi. Lincei, Rend., CI. Sci.
Fis. Mat. Nat., 1955, 18,583 (Chern. Abstr., 1956,50,3940).
J. B. Polya; Nature (London), 1955,176, 1175.
N. K. Kochetkov; Zh. Obshch. Khirn., 1955,25, 1366.
541
541
580
604
731
722
840
840
346, 347, 348
797
610,611,632
631,632
580
554
739
728
645
537
753, 755
698
569
518
748
690, 700
657
731
685
648
614
647
698, 699
598
653
731
787
716
N. Gagnoli and A. Ricci; Ann. Chirn. (Rome), 1956,46,275. 138
R. Huisgen and I. Ugi; Angew. Chern., 1956,68,705. 840,841,843,845
I. Ugi, R. Huisgen, K. C1usius and M. Vecchi; Angew. Chern., 1956,68,753. 841
G. Ehrart and I. Hennig; Arch. Pharrn. (Weinheirn, Ger.), 1956,289,453 549,550,
551, 574, 593
796
567
27
J. H. Bryden; Acta Crystallogr., 1956,9,874.
R. Zelnick, M. Pes son and M. Po1onovski; Bull. Soc. Chirn. Fr., 1956,888.
W. Otting; Chern. Ber., 1956,89, 1940.
A. Pullman, B. Pullman and G. Berthier; c.R. Hebd. Seances Acad. Sci., 1956,
243, 380. 505
N. P. Buu-Hoi and N. D. Xuong; C. R. Hebd. Seances Acad. Sci., 1956,243,2090. 647
D. Da1 Monte, A. Mangini and R. passerini; Gazz. Chirn. Ital., 1956,86,797. 197
P. Schmidt and J. Druey; Helv. Chirn. Acta, 1956,39,986. 329
R. G. Jones; J. Am. Chern. Soc., 1956,78, 159. 652
G. B. Elion, W. H. Lange and G. H. Hitchings; J. Am. Chern. Soc., 1956,78,217. 560
F. L. Muehlmann and A. R. Day; J. Am. Chern. Soc., 1956,78,242. 645
K. Hattori, E. Lieber and J. P. Horwitz; J. Am. Chern. Soc.. 1956.78,41 \. 794,802,819
R. K. Robins; J. Am. Chern. Soc., 1956,78,784. 323,329
C. O. Miller, F. Skoog, F. S. Okumura, M. H. yon Saltza and F. M. Strong; J.
Am. Chern. Soc., 1956,78, 1375.
A. F. McKay and W. G. Hatton; J. Am. Chern. Soc., 1956,78, 1618.
J. A. Montgomery: J. Am. Chern. Soc., 1956,78, 1928.
R. K. Robins, F. W. Furcht, A. D. Grauer and J. W. Jones; J. Am. Chern. Soc.,
1956,78,2418. 323,324
G. B. Elion, W. H. Lange and G. H. Hitchings; J. Am. Chern. Soc., 1956,78,2858. 572
G. B. Elion and G. H. Hitchings; J. Am. Chern. Soc., 1956,78,3508 557,563,597,598
L. B. Mackay and G. H. Hitchings; J. Am. Chern. Soc., 1956,78,351 \. 550,551,593
D. G. Markees and G. W. Kidder; J. Am. Chern. Soc., 1956, 78, 4130. 619,635
602
647
573, 597
56JA4197
56J A5832
56JA5857
56JCSI045
56JCS3975
56JCS4288
56JOCI90
56JOC599
56JOCI037
56JOCI276
56LA(598)186
56M679
56MI40900
56MI41100
B-56MI41300
57 AqR)362
57 AqR)366
57AG732
57 AP20
57BSBI36
57CB202
57CB382
57CB414
57CB698
57CB2914
57CPB240
57G597
57JA490
57JA670
57JA678
57JAI249
57JAI518
57JAI955
57JA2185
57JA2839
57JA5276
57JA6401
57JA6407
57JA642I
57JAP570777
57JCS442
57 JCS682
57JCSI556
57JCS2356
57JCS2521
57JCS4506
57 JCS45 I 0
57JOC568
57JOC654
57JOC925
57JOC954
57JOC959
57JPC261
57MI40100
57MI40101
B-57MI40400
B-57MI40700
B-57MI40800
B-57MI40900
B-57MI41100
57MI41300
F. Cacace and R. Masironi; Ann. Chirn (Rome), 1957,47,362. 551
F. Cacace and R. Masironi; Ann. Chirn. (Rome), 1957,47,366. 551
J. Jennen; Angew. Chern., 1957,69,732. 232
A. Dornow and O. Hahm1!nn; Arch. Ph arm. (Weinheirn, Ger.), 1957,290,20. 618,636
R. H. Martin and Z. Tarasiejska; Bull. Soc. Chirn. Belg., 1957,66, 136. 642,645
J. Goerdeler and J. Galinke; Chern. Ber., 1957,90,202. 773
R. Gompper; Chern. Ber., 1957,90, 382. 713
R. Criegee and A. Rimmelin; Chern. Ber., 1957,90,414. 839
G. Huber; Chern. Ber., 1957,80,698. 596
R. Huisgen and I. Ugi; Chern. Ber., 1957,90,2914. 841,843,845
M. Ishidate and H. Yuki; Chern. Ph arm. Bull., 1957,5,240. 579
S. Checchi and M. Ridi; Gazz. Chirn. Ital., 1957,87, 597. 334
R. K. Robins and H. H. Un; J. Am. Chern. Soc., 1957,79,490. 564
B. S. Gorton and W. Shive; J. Am. Chern. Soc., 1957,79,670. 635
J. H. Boyer, R. Borgers and L. T. Wolford; J. Am. Chern. Soc., 1957,79,678. 887
J. P. Horwitz and Y. A. Grakauskas; J. Am. Chern. Soc., 1957,79, 1249. 839
O. YogI and E. C. Taylor; J. Am. Chern. Soc., 1957,79, 1518. 569,580
G. W. Sawdey; J. Am. Chern. Soc., 1957,79, 1955. 777
J. A. Montgomery and L. B. Holum; J. Am. Chern. Soc., 1957,79, 2185. 564, 593
C. Grundmann and A. Kreutzberger; J. Am. Chern. Soc., 1957,79,2839. 766
A. F. McKay, G. Y. Paris and M. E. Kreling; J. Am. Chern. Soc., 1957,79,5276. 139
R. N. Prasad and R. K. Robins; J. Am. Chern. Soc., 1957,79, 6401. 564, 584, 590
R. K. Robins; J. Am. Chern. Soc., 1957,79,6407. 313
H. Graboyes and A. R. Day; J. Am. Chern. Soc., 1957,79,6421. 618,619,635,636
K. Shirakawa; Jpn. Pat. 570777 (1957) (Chern. Abstr., 1958,52,4699). 857,902
J. W. Clark-Lewis and M. J. Thompson; J. Chern. Soc., 1957,442. 636
D. J. Brown and S. F. Mason; J. Chern. Soc., 1957,682. 524,525
A. Lawson and C. E. Searle; J. Chern. Soc., 1957, 1556. 113
E. G. Brain and I. L. Finar; J. Chern. Soc., 1957,2356. 93
M. J. S. Dewar and P. M. Maitlis; J. Chern. Soc., 1957,2521 7
J. D. Bower and G. R. Ramage; J. Chern. Soc., 1957,4506. 887
J. D. Bower; J. Chern. Soc., 1957,4510. 307,334,857
M. W. Bullock, J. J. Hand and E. L. R. Stokstad; J. argo Chern., 1957,22,568. 552
E. Lieber, T. S. Chao and C. N. R. Rao; J. argo Chern., 1957,22,654. 713
D. F. Percival and R. M. Herbst; J. argo Chern., 1957,22,925. 794
B. R. Baker, K. Hewson, H. J. Thomas and J. A. Johnson, Jr.; J. arg. Chern.,
1957,22,954.
B. R. Baker and K. Hewson; J. argo Chern., 1957,22,959.
M. M. Williams, W. S. McEwan and R. A. Henry; J. Phys. Chern., 1957,61,261.
H. A. Staab, W. Otting and A. Ueberle; Z. Elektrochern., 1957,61, 1000.
D. F. Othmer, P. W. Maurer, C. J. Molinary and R. C. Kowalski; Ind. Eng.
Chern., 1957,49, 125.
T. L. Jacobs; in 'Heterocyclic Compounds', ed. R. C. Elderfield; Wiley, New
York, 1957, vol. 5, p. 57.
E. S. Schipper and A. R. Day; in 'Heterocyclic Compounds', ed. R. C. Elderfield;
Wiley, New York, 1957, vol. 5, p. 194.
E. S. Schipper and A. R. Day; in 'Heterocyclic Compounds', ed. R. C. Elderfield;
Wiley, New York, 1957, vol. 5, p. 194. 469,476,490
'Ciba Foundation Symposium on the Chemistry and Biology of Purines', ed. G.
E. W. Wolstenholme and C. M. O'Connor; Churchill, London, 1957.
References
M. H. Kaufman, F. M. Ernsberger and W. S. McEwan; J. Am. Chern. Soc., 1956,
78,4197.
J. R. E. Hoover and A. R. Day; J. Am. Chern. Soc., 1956,78,5832.
F. F. Blicke and R. L. Schaaf; 1 Am. Chern. Soc., 1956,78,5857.
Y. Oakes, R. Pascoe and H. N. Rydon; 1 Chern. Soc., 1956, 1045.
D. B. Ishay; 1. Chern. Soc., 1956,3975.
R. D. Brown and M. L. Heffernan; J. Chern. Soc., 1956,4288.
R. H. Wiley, K. F. Hussung and J. Moffat; J. argo Chern., 1956,21, 190.
L. Goldman, J. W. Marsico and A. L. Gazzola; J. argo Chern., 1956,21,599.
C. Grundmann and R. Rätz; J. argo Chern., 1956,21, 1037.
M. M. Baizer, J. R. Clark, M. Dub. and A. Loter; J. arg. Chern., 1956,21, 1276.
R. Huttel, O. Schafer and G. Welzel; Liebigs Ann. Chern., 1956,598, 186.
K. Schlogel and H. Woidich; Monatsh. Chern., 1956,87,679.
R. M. Bock, N.-S. Ling, S. A. Morell and S. H. Lipton; Arch. Biochern. Biophys.,
1956, 62, 253.
R. F. Wilson and L. E. Wilson; Anal. Chern., 1956,28,93.
R. M. Herbst; 'Essays in Biochemistry', ed. S. Groff; Wiley, New York, 1956,
p. 141.
E. H. Hoggarth; in 'Chemistry of Carbon Compounds', ed. E. H. Rodd; Elsevier,
Amsterdam, 1957, p. 439.
E. Lieber, C. N. R. Rao and C. N. PilIai; Curro Sci., 1957,26, 167.
915
795
713
578
637
529
349
708
573
766
552
89
649
525
731
816
629
552
742
27,29
29
168
424
501,511,
524, 556
670
798
916
570S(37)26
57QR15
57T( I )75
57Z0B1276
57Z0BI712
58AG571
58AP368
58AX83
58AX453
58CB531
58CB1841
58CB2324
58CB2330
58CJC801
58CJC1441
58CPB443
58G463
58G977
58GI035
58HCAI052
58HCAI823
58JA404
58JA421
58JA599
58JAI669
58JA2751
58JA2755
58JA2759
58JA3738
58JA3899
58JA3932
58JA4979
58JA5744
58JA6083
58JA6265
58JA6671
58JBC(230)717
58JCS2821
58JCS2973
58JCS3259
58JCS406-J
58JCS4107
58JOC 125
58JOC191
58JOCI051
58JOC 1534
58JOCI912
58JOC1916
58JOC20 I 0
58LA(614)1
58LA(614)4
58LA(615)42
58M557
58M562
58M588
58M597
58MI40200
58Ml40900
58Ml40901
58Ml40902
F. Cramer and K. Randerath; Angew. Chern., 1958,70,571.
A. Dornow, O. Hahmann and E. H. Rohe; Arch. Pharrn. (Weinheirn, Ger.), 1958,
291. 368.
D. J. Sutor; Acta Crystallogr., 1958,11,83.
D. J. Sutor; Acta Crystallogr., 1958, 11,453.
I. Ugi and R. Huisgen; Chern. Ber., 1958,91,531.
A. Dornow and K. Rombusch; Chern. Ber., 1958,91, 1841.
I. Ugi, H. Perlinger and L. Behringer; Chern. Ber., 1958,91,2324.
I. Ugi, H. Perlinger and L. Behringer; Chern. Ber., 1958,91, 2330.
E. Lieber, C. N. R. Rao, C. N. Pillai, J. Ramachandran and R. D. Hites; Can.
J. Chern., 1958,36,801.
E. Lieber, C. N. R. Rao, T. S. Chao and H. Rubinstein; Can. J. Chern., 1958,
36, 1441.
T. Takahashi, F. Yoneda and S. Yoshimura; Chern. Ph arm. Bull., 1958,6,443.
S. Cusmano and M. Ruccia; Gazz. Chirn. Ita!., 1958,88,463.
D. Dal Monk, A. Mangini, R. Pawerini and C. Zanli; Gazz. Chirn. Ital., 1958,
88, 977.
D. Dal Monte, A. Mangini and F. Montanardi; Gazz. Chirn. Ita!., 1958,88, 1035.
P. Schmidt, K. Eichenberger and J. Druey; Helv. Chirn. Acta, 1958,41, 1052.
K. Clusius and F. Endtinger; Helv. Chirn. Acta, 1958, 41, 1823.
J. A. Montgomery and L. B. Holum; J. Am. Chern. Soc., 1958,80,404.
E. C. Taylor, J. W. Barton and T. S. Osdene; J. Am. Chern. Soc., 1958,80,421.
L. A. Carpino; J. Am. Chern. Soc., 1958,80,599.
J. J. Fox, I. Wempen, A. Hampton and I. L. Doerr; J. Am. Chern. Soc., 1958,80,
1669.
H. C. Koppel and R. K. Robins; J. Am. Chern. Soc., 1958,80,2751.
M. A. Stevens, D. I. Magrath, H. W. Smith and G. B. Brown; J. Am. Chern. Soc..
1958, 80, 2755. 539, 554, 555
M. A. Stevens and G. B. Brown; J. Am. Chern. Soc., 1958,80,2759. 595
H. J. Schaeffer and H. J. Thomas; J. Am. Chern. Soc., 1958,80,3738. 558
E. Shaw, J. Am. Chern. Soc., 1958,80,3899. 583,584
A. Giner-Sorolla and A. Bendich; J. Am. Chern. Soc., 1958,80,3932. 524,550,551,
553, 556, 564
512
524, 574, 587
629,652
H. C. Brown and Y. Okamoto; J. Am. Chern. Soc., 1958,80,4979.
A. Giner-Sorolla and A. Bendich; J. Am. Chern. Soc., 1958,80,5744.
J. A. Carbon; J. Am. Chern. Soc., 1958,80,6083.
T. P. Johnston, L. B. Holum and J. A. Montgomery; J. Am. Chern. Soc., 1958,
80, 6265. 560
R. K. Robins; J. Am. Chern. Soc., 1958,80,6671. 562, 563, 593
M. Adler, B. Weissmann and A. B. Gutman; J. Bio!' Chern., 1958,230,717. 600
J. Clark and G. R. Ramage; J. Chern. Soc., 1958,2821. 648
B. M. Lynch, R. K. Robins and C. C. Cheng; J. Chern. Soc., 1958,2973. 306,309
I. L. Finar and R. J. Hurlock; J. Chern. Soc., 1958,3259. 331
R. Hull; J. Chern. Soc., 1958,4069. 549
C. L. Leese and G. M. Timmis; J. Chern. Soc., 1958,4107. 572
G. B. Brown and V. S. Weliky; J. Org. Chern., 1958,23, 125. 562
C. C. Cheng and R. K. Robins; J. Org. Chen!., 1958,23,191. 319
J. H. Boyer, C. H. Mack, N. Goebel and L. R. Morgan, Jr.; J. Org. Chern., 1958,
23,1051.
R. N. Castle and W. S. Seese; J. Org. Chern., 1958,23, 1534.
R. M. Herbst and J. E. Klingbeil; J. Org. Chern., 1958,23, 1912.
E. Leiber, C. N. R. Rao, T. S. Chao and J. Ramachandran; J. Org. Chern., 1958,
23, 1916.
D. S. Acker and J. E. Castle; J. Org. Chern., 1958,23,2010.
W. Kirmse and L Horner; Liebigs Ann. Chern., 1958, 614, 1.
W. Kirmse and L. Horner; Liebigs Ann. Chern., 1958,614,4.
W. Pfleiderer and K.-H. Schündehütte; Liebigs Ann. Chern., 1958,615,42.
K. Hohenlohe-Oehringen; Monatsh. Chern., 1958,89,557.
K. Hohenlohe-Oehringen; Monatsh. Chern., 1958,89,562.
K. Hohenlohe-Oehringen; Monatsh. Chern., 1958,89,588.
K. Hohenlohe-Oehringen; Monatsh. Chern., 1958,89,597.
A. K. Majumdar and M. M. Chakrabartty; Anal. Chirn. Acta, 1958,19,372.
E. S. Golovchinskaya; Zh. Prik!. Khirn., 1958,31,918.
E. S. Golovchinskaya, V. M. Fedosova and A. A. Cherkasova; Zh. Prikl. Khirn.,
1958, 31, 1241.
J. W. Littlefield and D. B. Dunn; Nature (London), 1958, 181,254.
References
E. Lieber, T. S. Chao and C. N. R. Rao; Org. Synrh., 1957,37,26.
W. Baker and W. D. Ollis; Q. Rev., Chern. Soc., 1957,11, 15.
R. H. Martin and J. Mathieu; Tetrahedron, 1957, 1,75.
T. V. Protopopova and A. P. Sko1dinov; Zh. Obshch. Khirn., 1957,27, 1276.
G. A. Garkusha; Zh. Obshch. Khirn., 1957,27, 1712.
713
736, 743
648
290
563
539
618,636
508
508
843
710
843, 844
841
794
685
635
404
684, 685
684
310
844
597
314, 329
78
557
598
709
652
763
690
572
714
159
338
707
707
707
707
51
548
548
600
58MI41300
58N492
59ACS888
59AG524
59AG753
59AJC543
59BBA(36)343
59BRP816531
59CB566
59CB1500
59CB 1864
59CB2902
59CPB602
59CR(248) 1677
59CR(248) 1832
59GI654
59HC(13)432
59HCA349
59JAI93
59JAI898
59JA2442
59JA2452
59JA2515
59JA3039
59JA3076
59JA3789
59JA5997
59JA6329
59JAP5910468
59JCS2893
59JCS3061
59JCS3157
59JCS3799
59JCS4040
59JOC134
59JOC320
59JOC562
59JOC787
59JOCI455
59JOCI565
59JOCI643
59JOCI813
59JOC2019
59JPR(8)298
59M402
59MI40100
59MI40200
B-59MI40400
59MI40900
59MI40901
590S(39)27
59TH4 1 400
59TH41401
59TL9
60AC(R)125
60AG708
60AG956
60AJC49
C. Pedersen; Acta Chern. Scand., 1959, 13, 888.
H. Bredereck, H. Herlinger and I. Graudums; Angew. Chern., 1959,71,524.
H. Bredereck, R. Gompper, H. G. V. Schüh and W. Theilig; Angew. Chern., 1959,
71, 753.
R. D. Brown and M. L. Heffernan; Aust. 1 Chern., 1959,12,543.
B. Pullman and A. Pullman; Biochirn. Biophys. Acta, 1959,36,343.
Henkel and Cie G.m.b.H., Br. Pat. 816'531 (1959) (Chern. Abstr., 1960,54,1552).
H. Bredereck, G. Kupsch and H. Wieland; Chern. Ber., 1959,92,566.
J. Donat and E. Carstens; Chern. Ber., 1959,92, 1500.
I. Ugi, H. Perlinger and L. Behringer; Chern. Ber., 1959,92, 1864.
W. Ried and E. Torinus; Chern. Ber., 1959,92,2902.
T. Takahashi, F. Yoneda and R. Oishi; Chern. Pharrn. Bull., 1959,7,602.
M. Pesson, G. Polmanss and S. Dupin; C. R. Hebd. Seances Acad. Sci., 1959,
248, 1677.
N. P. Buu-Hoi and N. D. Xuong; C. R. Hebd. Seances Acad. Sci., 1959,248,1832.
M. Rucda and D. Spinelli; Gazz. Chirn. Ital., 1959,89, 1654.
E. M. Smolin and L. Rapoport; Chern. Heterocycl. Cornpd., 1959,13,432.
P. Schmidt, K. Eichenberger, M. Wilhelm and J. Druey; Helv. Chirn. Acta, 1959,
42, 349. 329
R. N. Prasad, C. W. Noell and R. K. Robins; J. Am. Chern. Soc., 1959,81, 193. 574,593
G. B. Elion, I. Goodman, W. Lange and G. H. Hitchings; 1 Am. Chern. Soc.,
1959,81,1898
E. C. Taylor, O. Vogi and C. Cheng; J. Am. Chern. Soc., 1959,81,2442.
E. C. Taylor and K. S. Hartke; 1 Am. Chern. Soc., 1959,81,2452.
A. Giner-Sorolla, I. Zimmerman and A. Bendich; J. Am. Chern. Soc., 1959,81,
2515. . 524, 548, 549, 550, 593
T. L. Loo, M. E. Michael, A. J. Garceau and J. C. Reid; J. Am. Chern. Soc., 1959,
81, 3039. 557
J. P. Horwitz, B. E. Fisher and A.J. Tomasewski; J. Am. Chern. Soc., 1959,81,3076. 794, 832
S. R. Breshears, S. S. Wang, S. G. Bechtolt and B. E. Christensen; 1 Am. Chern.
Soc., 1959,81,3789.
C. W. Noell and R. K. Robins; J. Am. Chern. Soc., 1959,81,5997.
S. S. Chissick, M. J. S. Dewar and P. M. Maitlis; J. Am. Chern. Soc., 1959,81,6329.
S. Yamada and T. Mizoguchi; Jpn. Pat. 59 10468 (1959) (Chern. Abstr., 1960,
54, 18 555).
J. Baddiley, J. G. Buchanan, F. E. Hardy and J. Stewart; J. Chern. Soc., 1959,2893.
A. Adams and R. Slack; 1 Chern. Soc., 1959,3061.
D. Harrison and A. C. B. Smith; J. Chern. Soc., 1959,3157.
G. F. Duffin, J. D. Kendall and H. R. J. Waddington; J. Chern. Soc., 1959,3799.
References
E. Lieber and E. Oftedahl; Trans. Illinois State Acad. Sci., 1958,51,41 (Chern.
Abstr., 1962,56,4151). .
K. Winterfeld and H. Schuler; Naturwissenschaften, 1958,45,492.
G. Shaw and D. N. Butler; J. Chern. Soc., 1959,4040.
E. Lieber, C. N. R. Rao and T. U. Rajkumar; J. Org. Chern., 1959,24, 134.
C. W. Noell and R. K. Robins; J. Org. Chern., 1959,24,320.
J. H. Burckhalter and D. R. Dill; 1 Org. Chern., 1959,24,562.
C. F. H. Allen, H. R. Beilfuss, D. M. Burness, G. A. Reynolds, J. F. Tinker and
J. A. Van Allan; 1 Org. Chern., 1959,24,787.
M. Israel and A. R. Day; J. Org. Chern., 1959,24, 1455.
W. G. Finnegan and R. A. Henry; J. Org. Chern., 1959,24, 1565.
J. M. McManus and R. M. Herbst; 1 Org. Chern., 1959,24, 1643.
H. Zimmer and J. B. Mettalia; J. Org. Chern., 1959,24, 1813.
E. C. Taylor, C. C. Cheng and O. Vogl; J. Org. Chern., 1959,24,2019.
G. Losse and W. Farr; J. Prakt. Chern., 1959,8,298.
F. Asinger, M. Thiel and R. Sowada; Monatsh. Chern., 1959,90,402.
T. Balaban; Stud. Cercet. Chirn., 1959,7,257.
R. Schindler, H. Will and L. Holleck; Z. Elektrochern., 1959,63, 596.
A. Albert; 'Heterocyclic Chemistry', Ath[one Press, London, 1959.
J. M. Buchanan and S. C. Hartman; Adv. Enzyrnol., 1959,21, 199.
S. C. Hartman and J. M. Buchanan; Annu. Rev. Biochern., 1959,28,365.
C. Ainsworth; Org. Synth., 1959,39,27.
I. Ugi; Habilitation Thesis, University of Munich, 1959.
H. Perlinger; Doctoral Thesis, University of Munich, 1959.
E. C. Taylor and C. Cheng; Tetrahedron Lelt., 1959,9.
917
816
635
708, 709
563
485
347
505
783
574
537
843
576
635
765
647
719
608
564
560, 569
318,322
541
557
668
721
583
86
617,636
747,748,
788
584, 585
7[3
535, 563
529
862
617,618,619,635,636
819
834
552
584
779
425
30,33
73
168
504
504
288
840, 841, 844
845
568
M. Melandri, G. Vittorina and A. Buttini; Ann. Chirn. (Rome), 1960,50, 125
(Chern. Abstr., 1960,55,27 306).
H. Bredereck, O. Christmann, I. Graudums and W. Koser; Angew. Chern., [960,
72, 708.
H. Gold; Angew. Chern., 1960,72,956.
R. D. Brown and M. L. Heffernan; Aust. J. Chern., 1960, 13,49.
636
562
766
172,173
918
60AP203
60AX946
60BBA(45)49
60BBR(2)207
60BBR(3 )596
60BJ(76)621
60CB663
60CBII06
60CBI206
60CB2001
60CB2353
60CB2804
60CB2810
60CB2885
60CPB539
60CPB999
60G413
60G83 I
60JA222
60J A463
60JAI148
60JAI469
60JA2587
60JA2633
60J A2li41
60JA2654
60JA3144
60JA3147
60JA3189
60JA3773
60JA4044
60J A4592
60JA5007
60JA5148
60JCSII13
60JCS1352
60JCS 1363
60JCSI829
60JCS2536
60JCS4347
60JCS4705
60JOC 148
60JOOl3
60JOC395
60JOC46I
60JO('[573
60JOC2108
60LA(638)136
60MI40900
60MI41000
60RTC836
60Z0B327
60Z0BI878
60ZO B2427
60Z0B3332
60ZOB3339
60Z0B3628
61 AC'(R) 1409
61AGI5
61 AG63
6IAGI72
61 AP404
References
K. Winterfeld and H. Schuller; Arch. Pharm. (Weinheim, Ger.), 1960,293,203.
H. W. W. Ehrlich; Acta Crystallogr., 1960, 13,946.
F. Bergmann, H. Ungar and A. Kalmus; Biochem. Biophys Acta, 1960,45,49.
J. Oro; Biochem. Biophys. Res. Commun., 1960,2,207.
L. Slechta; Biochem. Biophys. Res. Commun., 1960,3,596.
A. Albert and E. P. Serjeant; Biochem. J., 1960, 76, 621.
J. Goerdeler and H. Horstmann; Chern. Ber., 1960,93,663.
A. Domow and M. Siebrecht; Chern. Ber., 1960,93, 1106.
H. Bredereck. O. Christmann and W. Koser: Chern. Ber., 1960, 93, 1206.
A. Dornow and J. Helberg; Chern. Ber., 1960,93,2001.
W. Kirmse: Chern. Ber., 1960,93,2353.
L. Birkofer, P. Richter and T. Ritter; Chern. Ber., 1960,93,2804.
L. Birkhofer, H. P. Kuhlthau and A. Ritter; Chern. Ber., 1960,93,2810.
R. Huisgen, J. Sauer and M. Seidel; Chern. Ber., 1960,93,2885.
T. Takahashi, K. Kanematsu, R. Oh-ishi and T. Mizutani; Chern. Pharm. Bull.,
1960, 8, 539.
T. Itai and S. Suzuki; Chern. Pharm. Bull., 1960,8,999.
P. Griinanger, D. Vita Finzi and E. Fabbri; Gazz. Chim. ltal., 1960,90,413.
M. Ruccia, G. Natale and S. Cusmano; Gazz. Chim. Ital., 1960,90,831.
C. D. Jardetzky and O. Jardetzky; J. Am. Chern. Soc., 1960,82,222.
J. A. Montgomery and K. Hewson; J. Am. Chern. Soc., 1960,82,463.
M. A. Stevens, H. W. Smith and G. B. Brown; J. Am. Chern. Soc., 1960.82,1148.
S. C. Bell and W. T. Caldwell; J. Am. Chern. Soc., 1960,82, 1469.
L. F. Cavalieri and A. Bendich; J. Am. Chern. Soc., 1960,72,2587.
G. D. Daves, Jr., C. W. Noell, R. K. Robins, H. C. Koppel and A. G. Beaman:
J. Am. Chern. Soc., 1960,82,2633. 557,572,574
R. M. Izatt, J. H. Rytting, L. D. Hansen and J. J. Christensen; J. Am. Chern.
Soc., 1960,88,2641.
R. K. Robins; J. Am. Chern. Soc., 1960,82,2654.
E. Richter, J. E. Loeffler and E. C. Taylor: J. Am. Chern. Soc., 1960,82,3144.
525
560
568,
584, 587
E. C. Taylor and P. K. Loeffler; J. Am. Chern. Soc., 1960,82,3147. 323,585
M. A. Stevens. H. W. Smith and G. B. Brown;.I. Am. Chern. Soc., 1960,82,3189. 629,652
J. W. Jones and R. K. Robins; J. Am. Chern. Soc., 1960,82,3773. 538,551,553
D.-I. Shiho and S. Tagami; J. Am. Chern. Soc., 1960,82,4044. 898
J. A. Montgomery and C. Temple, Jr.: .I. Am. Chern. Soc., 1960,82,4592. 595
D. W. Moore and A. G. Whittaker: J. Am. Chern. Soc., 1960,82,5007. 678
N. J. Leonard and W. K. Musker; J. Am. Chern. Soc., 1960,82,5148. 137
J. H. Lister and G. M. Timmis; J. Chern. Soc., 1960, I I 13. 580
A. Grimison, J. H. Ridd and B. V. Smith; J. Chern. Soc., 1960, 1352. 389
J. H. Ridd and B. V. Smith; J. Chern. Soc., 1960, 1363. 389
L. A. Williams; .I. Chern. Soc., 1960, 1829. 862
M. A. McGee, G. T. Newbold, J. Redpath and F. S. Spring: J. Chern. Soc., 1960,
2536.
G. M. Blackburn and A. W. Johnson; J. Chern. Soc., 1960,4347.
A. Albert; J. Chern. Soc., 1960,4705.
E. C. Taylor and C. C. Cheng; J. Org. Chern., 1960,25, 148.
H. Rapoport and H. H. Chen; J. Org. Chern., 1960,25,313.
J. A. Montgomery and C. Temple, Jr.; J. Org. Chern., 1960,25,395.
H. W. Heine and H. S. Bender; J. Org. Chern., 1960,25,461.
R. W. Balsiger and J. A. Montgomery; J. Org. Chern., 1960,25, 1573.
M. E. Freed and A. R. Day; J. Org. Chern., 1960, 25, 2108.
H. Gehlen and G. Blankenstein; Liebigs Ann. Chern., 1960,638, 136.
L. Slechta; Biochem. Pharmacal., 1960, 5, 96.
S. K. Chatterjee, M. M. Dhar, N. Anand and M. L. Dhar: J. Sri. Ind. Res., Sect.
e. 1960, 19, 35.
B. G. Van den Bos; Red. Trav. Chim. Pays-Bas, 1960,79,836.
G. Va. Urestskaya, E. I. Rybkina and G. P. Men'shikov; Zh. Obshch. Khim.,
1960,30,327.
E. S. Chaman, A. A. Cherkasova and E. S. Golovchinskaya; Zh. Obshch. Khim.,
1960, 30, 1878.
B. P. Lugovkin: Zh. Obshch. Khim., 1960,30,2427.
E. S. Golovchinskaya, I. M. Ovcharova and A. A. Cherkasova; Zhur. Obshch.
Khim., 1960, 30, 3332.
I. M. Ovcharova and E. S. Golovchinskaya; Zh. Obshch. Khim., 1960,30,3339.
E. S. Golovchinskaya and E. S. Chaman; Zh. Obshch. Khim., 1960,30,3628.
A. M. Bellini; Ann. Chim. (Rome), 1961,51,1409 (Chern. Ahstr.. 1962,56,15509).
P. Schmidt, K. Eichenberger and M. Wilhelm; Angew. Chern.. 1961,73,15.
H. Bredereck, F. Effenberger and G. Rainer; Angew. Chern.,. 1961, 73, 63.
I. Ugi: Angew. Chern., 1961,73,172.
K. Winterfeld and G. B. Singh; Arch. Pharm. (Weinheim, Ger.), 1961,294,404.
635
177,179
577
569
603
523
765
332
531
696, 713
45
749,761
576, 577
814
616
652
714
441
523
552, 553
555
647
539
318
578
550
596
707
573, 574, 592
155
562
635
736
603
615,635
750
557
549
549
548
540
593
625,
626,645
329
568
845
614
61CB273
61CB1555
61 CB2503
61CI(L)292
61CJC2516
61CPB801
61CPB808
61 CR(253)687
61CRV87
61 FRP 1248409
61G849
61G933
61 HC(15-1)460
6IHC(15-1)481
6IHC(15-1)643
61HC(15-2)764
6IHC(15-2)774
61HC(15-2)801
61HC(15-2)802
61 HC(15-2)835
61HC(15-2)903
6IHC(15-2)906
6IHC(15-2)916
6IJA248
6IJA630
6IJA1113
6IJA2022
6IJA2574
61JA2708
6IJA2934
6IJA4038
6IJA5023
6IJCS504
6IJCS518
6IJCS2589
6IJCS4468
6IJCS4845
6IJCS5048
6IJOC45I
6IJOC526
6IJOCI660
6IJOCI861
6IJOCI914
61JOC2372
6IJOC2396
6IJOC2715
6IJOC3386
6IJOC3401
6IJOC3446
6IJOC3714
6IJOC3837
6IJOC4433
6IJOC4480
6IJOC496I
6IJOC4967
61 LA(641)94
61 LA(647) I 16
6ILA(647)155
61 LA(647)161
61 LA( 648)72
61 LA(649) I 14
61 LA(649) 131
61MI40400
61 MI40900
References
919
J. D. Roberts; Chern. Ber., 1961,94,273. 842
R. Huisgen, H. J. Sturm and M. Seidel; Chern. Ber., 1961,94, 1555. 814
R. Huisgen, J. Sauer and M. Seidel; Chern. Ber., 1961,94,2503. 146
F. Eloy, R. Lenaers and C. Moussebois; Chern. Ind. (London), 1961,292. 62,7[
R. A. Abramovitch and K. A. H. Adams; Can. J. Chern., 1961,39,2516. 335
Y. Makisumi; Chern. Pharrn. Bull., [961,9,801. 872,891
Y. Makisumi; Chern. Pharrn. Bull., 1961,9,808. 872
C. Nofre, A. Lefler and A. Cier, C.R. Hebd. Seances Acad. Sci., 1961,253,687. 543
K. T. Potts; Chern. Rev., [961,61,87. 735,739,746,762,787
Laboratoire Roger Bellon, Fr. Pat. [ 248409 (1961) (Chern. Abstr., 1962,56,10160). 904
R. Fusco, G. Bianchetti and D. Pocar; Gazz. Chirn. Ital., 1961,91, 849. 704,714
R. Fusco, G. Bianchetti and D. Pocar; Gazz. Chirn. Ita/., 1961,91,933. 714
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, 15(1),460. 608,614,631
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, IS (1),481. 612
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, 15 (1),643. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 196[, IS (2),764. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, 15(2),774. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, IS (2), 80 I. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, IS (2), 802. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, IS (2), 835. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961,15(2),903. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, IS (2),906. 608
W. L. Mosby; Chern. Heterocycl. Cornpd., 1961, 15(2),916. 608,659
E. C. Taylor and J. A. Zoltewicz; J. Arn. Chern. Soc., 196[,83,248. 323
J. A. Montgomery and C. Temple, Jr.; J. Arn. Chern. Soc., 1961,83,630. 529
G. A. Usbeck, J. W. Jones and R. K. Robins; J. Arn. Chern. Soc., 1961,83,1113. 553
R. Mechoulam, F. Sondheimer, A. Melera and F. A. Kincl; J. Arn. Chern. Soc.,
1961, 83, 2022.
R. K. Robins, E. F. Godefroi, E. C. Taylor, L. R. Lewis and A. Jackson; 1 Arn.
Chern. Soc., 1961,83,2574.
S. S. Chissick, M. J. S. Dewar and P. M. Maitlis; J. Arn. Chern. Soc., [961,83,2708.
E. Klingsberg; J. Arn. Chern. Soc., 196[,83,2934.
A. G. Beaman and R. K. Robins; J. Arn. Chern. Soc., [961,83,4038.
J. Ogilvie and A. Corwin; J. Arn. Chern. Soc., 1961,83,5023.
C. L. Angell; 1 Chern. Soc., 1961, 504.
D. R. Liljegren and K. T. Potts; J. Chern. Soc., [961,518.
J. A. Davoli and K. A. Kerridge; J. Chern. Soc., [961,2589.
F. Bergmann and M. Tamari; J. Chern. Soc., [961,4468.
R. N. Nay[or, G. Shaw, D. V. Wilson and D. N. Butler; J. Chern. Soc., 1961,4845.
J. Clark and J. H. Lister; J. Chern. Soc., 196[,5048.
M. Hauser, E. Peters and H. Tieckelmann; J. Org. Chern., 1961,26,451.
J. J. Fox and D. van Praag; J. Org. Chern., 196[,26,526.
F. Bergmann and A. Kalmus; J. Org. Chern., 196[,26, 1660.
F. F. Blicke and C.-M. Lee; J. Org. Chern., 196[,26, 1861.
H. G. Mautner; J. Org. Chern., [961,26, 1914.
R. M. Herbst; J. Org. Chern., 1961,26,2372.
Y. F. Shealy, R. F. Struck, L. B. Ho[um and J. A. Montgomery; J. Org. Chern.,
1961,26,2396.
E. C. Taylor, G. A. Berchtold, N. A. Geockner and F. G. Stroehmann; 1 Org.
Chern., 1961,26,2715.
R. W. Balsiger, A. L. Filkes, T. P. Johnston and J. A. Montgomery; 1 Org. Chern.,
1961,26,3386.
I. L. Doerr, I. Wempen, D. A. Clarke and J. J. Fox; J. Org. Chern., 1961,26,3401.
R. W. Balsiger, A. L. Filkes, T. P. Johnston and J. A. Montgomery; 1 Org. Chern.,
1961,26,3446.
S. S. Joshi and I. R. Gambhir; 1 Org. Chern., [961,26,37[4.
L. R. Lewis, F. H. Schneider and R. K. Robins; 1 Org. Chern., 1961,26,3837.
Y. F. Shealy, R. F. Struck, J. D. Clayton and J. A. Montgomery; J. Org. Chern.,
1961,26,4433.
E. Schipper and E. Chinery; J. Org. Chern., [961,26,4480.
E. C. Taylor, J. W. Barton and W. W. paudler; 1 Org. Chern., 1961,26,4961.
E. C. Taylor and A. L. Borror; J. Org. Chern., 1961,26,4967.
S. Hünig and K. H. Oette; Liebigs Ann. Chern., 196[,641,94.
W. Ried and E.-U. Köcher; Liebigs Ann. Chern., 1961,647, 116.
W. Pfleiderer and G. Nubel; Liebigs Ann. Chern., 1961,647, 155.
W. Pfleiderer; Liebigs Ann. Chern., 1961,647, 161.
H. A. Staab and W. Benz; Liebigs Ann. Chern., 1961,648,72.
H. Ballweg; Liebigs Ann. Chern., 1961,649, [14.
H. Lettre and C. Woenckhaus; Liebigs Ann. Chern., 1961,649, 131.
H. Zimmermann and H. Geisenfelder; Z. Elektrochern., [961,65,368.
J. Oró and A. P. Kimball; Arch. Biochern. Biophys., 1961,94,2[7.
650
530
668
91
557, 596
827
518
767
329
575, 576
585, 595,
652
573
313
573
557
666
574
814
652
130
577, 578
560,56[,
564
564, 566
65
530
876, 894
422
576
328
748
316,332
524
524, 533
698
550, 563
548, 551
208
569
920
B-61MI41100
B-61M141101
B-61MI41200
B-61MI41201
61MI41202
61 MI41203
61 MI41300
6IM[41500
61RTC545
61RTC1348
61 T(l2)51
61T( (4)237
61 YZI333
61Z0B2645
61Z0B3406
62ACS155
62ACS1800
62AG9
62AG(E)8
62AXI179
62B558
62BEP619423
62CB403
62CB414
62CB937
62CB956
62CBI275
62CBI812
62CB2546
62CPB620
62CPBI075
6200 K(l42)3 54
62G I 040
62HC(16)1
62HC A37
62HCA1620
62HC A2383
62HCA2441
62JA62
62JA993
62JA 1412
62JAI914
62JA2005
62JA2148
62JA2453
62JA3008
62JCS575
62JCS 1863
62JCS2083
62JCS2927
62JCS2937
62JGU1876
62JMCI5
62JMCI067
62JOC195
62JOC567
62JOC973
62JOC986
J. H. Boyer; in 'Heterocyclic Compounds', ed. R. E. Eldertield; Wiley, New
York, 1961, vol. 7, p. 384. 670,695,698,705,708,721,722
A. Streitwieser; 'Mo[ecular Orbital Theory for Organic Chemists', Wiley, New
York, 1961, p. 33.
J. H. Boyer; in 'Heterocyclic Compounds', ed. R. C. E1derfield; Wiley, New
York, 1961, vol. 7, p. 425.
J. H. Boyer; in 'Heterocyclic Compounds', ed. R. C. Elderfield; Wiley, New
York, 1961, vol. 7, p. 460.
H. Zimmermann; J. Elektrochem., 1961,65,368.
R. Huisgen; Proc. Chern. Soc., [961,357.
W. G. Finnegan and S. R. Smith; J. Chromatogr., 1961,5,461.
K. Anzai and S. Suzuki; 1 Antibiot., Ser. A, 1961, 14,253.
C. A. Sa[emink; Recl. Trav. Chim. Pays-Bas, 1961,80,545.
H. N. Bojarska-Dah1ig; Recl. Trav. Chim. Pays-Bas, 1961,80, 1348.
A. J. Boulton and A. R. Katritzky; Tetrahedron, 1961, 12,51.
A. J. Owen; Tetrahedron, 1961, 14,237.
H. Saikachi and M. Kanaoka; Yakugaku Zasshi, 1961,81, 1333 (Chern. Abstr.,
1962, 56, 7304).
E. S. Chaman and E. S. Go1ovchinskaya; Zh. Obshch. Khim., 1961,31,2645.
B. P. Lugovkin; Zh. Obshch. Khim., 1961,31,3406.
References
S. Gronowitz and P. Moses; Acta Chern. Scand., 1962, 16, 155.
T. Kindt-Larsen and C. Pedersen; Acta Chern. Scand., 1962, 16. 1800.
I. Ugi; Angew. Chern., 1962,74,9.
I. Ugi; Angew. Chern., Int. Ed. Engl., 1962, 1,8.
R. F. Bryan and K.-1. Tomita; Acta Crystallogr., 1962,15, 1179.
B. C. Pal; Biochemistry, 1962, I, 558.
C. Holstead; Belg. Pat. 619423 (1962) (Chern. Abstr., 1963,59, (2826).
H. Bredereck, E. Siegel and B. Fohlisch; Chern. Ber., 1962, 95, 403.
H. Bredereck and B. Fohlisch; Chern. Ber., 1962,95,414.
S. Hünig and K. Hübner; Chern. Ber., 1962,95,937.
H. Bredereck, F. Effenberger and E. H. Schweizer; Chern. Ber., 1962,95,956.
H. A. Staab, M. Lueking and F. H. Duerr; Chern. Ber., 1962,95, 1275.
H. Bredereck, O. Christmann, W. Koser, P. Schellenberg and R. Nast; Chern.
Ber., 1962, 95, 1812.
H. Behringer and H. J. Fischer; Chern. Ber., 1962,95,2546.
Y. Makisumi; Chern. Pharm. Bull., 1962,10,620.
M. [kehara, A. Yamazaki and T. Fujieda; Chern. Pharm. Bull., 1962, 10, 1075.
V. A. Ginsburg, A. Ya. Yakubovich, A. S. Filatov, G. E. Zelenin, S. P. Makarov,
V. A. Shpanskii, G. P. Kotel'nikova, L. F. Sergienko and L. L. Martynova;
Dok/. Akad. Nauk. SSSR, 1962,142,354 (Chern. Abstr., 1962,57,45(8).
R. Fusco, G. Bianchetti, D. Pocar and R. Ugo; Gazz. Chim. Ita/., 1962,92, 1040.
D. J. Brown; Chern. HeterOcycI. Compd., 1962, 16, I.
J. Büchi, W. Vetsch and P. Fabiani; Helv. Chim. Acta, 1962,45,37.
P. Schmidt, K. Eichenberger and M. Wilhelm; Helv. Chim. Acta, 1962,45,1620.
E. Jucker and E. Rissi; Helv. Chim. Acta, 1962,45, 2383.
H. U. Daeniker and J. Druey; Helv. Chim. Acta, 1962,45,2441.
C. D. Jardetsky; 1 Am. Chern. Soc., 1962,84,62.
H. W. Heine and D. A. Tomalia; J. Am. Chern. Soc., 1962,84,993.
D. L. Smith and P. J. Elving; J. Am. Chern. Soc., 1962,84, 1412.
J. W. Jones and R. K. Robins; J. Am. Chern. Soc., 1962,84, 1914.
672
735
738
742
768, 779
819
895
618.619,635
713
30
795
773
550
549
138
695,718
845
845
508
530, 552
758
549
549. 550
157
582
749
533
763, 766
307, 331
561
794
704,714
570
328
328
645
718
512
718
540
531, 532, 533,
535, 552
519
530. 552
163
560
755, 756, 777. 784
535, 557
719
208
583
K. Biemann and J. A. McCloskey; J. Am. Chern. Soc., 1962,84,2005.
N. J. Leonard and J. A. Deyrup; 1 Am. Chern. Soc., 1962,84,2148.
R. A. Carboni and J. E. Castle; J. Am. Chern. Soc., 1962,84,2453.
L. B. Townsend and R. K. Robins; J. Am. Chern. Soc., 1962,84,3008.
E. J. Browne and J. B. Polya; J. Chern. Soc., 1962,575.
K. R. H. Wooldridge and R. Slack; J. Chern. Soc., 1962, 1863.
A. J. Boulton and A. R. Katritzky; J. Chern. Soc., 1962,2083.
A. F. Bedford, P. B. Edmonson and C. T. Mortimer; 1 Chern. Soc., 1962,2927.
G. Shaw and D. V. Wilson; 1 Chern. Soc., 1962,2937.
I. I. Grandberg and G. V. Klyuchko; 1 Gen. Chern. USSR (Engl. Transl.), 1962,
32, 1876.
J. A. Montgomery, K. Hewson and C. Temple, Jr.; J. Med. Chern., 1962,5, 15.
A. G. Beaman and R. K. Robins; J. Med. Chern., 1962,5, 1067.
J. A. Montgomery, R. W. Balsiger, A. L. Filkes and T. P. Johnston; J. Org. Chern.,
1962,27,195.
M. A. Stevens, A. Giner-Sorolla, H. W. Smith and G. B. Brown; J. Org. Chern..
1962, 27, 567. 539. 548, 555. 595
T. P. Johnston, A. L. Filkes and J. A. Montgomery; J. Org. Chern., 1962, 27.
973.
A. J. Beaman, J. F. Gerster and R. K. Robins; J. Org. Chern., 1962,27,986.
272
529
562, 573
566
531,564
559, 578.
598
62JOC990
62JOC 1309
62JOCI671
62JOC2085
62JOC2150
62JOC2163
62JOC2209
62JOC2478
62JOC2500
62JOC263I
62JOC2943
62JOC3240
62JOC3243
62JOC3248
62JOC3545
62JOC4080
62JOC4300
62JOC4633
62JPC359
62JPR(288)199
62LA(653)105
62LA(654)146
62LA(657)156
62LA(658)169
62M632
B-62MI40900
62MI40901
62MI40902
62MI40903
62MI40904
62MI40905
62MI41200
620S(42)69
62PNA(48) 1300
62RTC202
62T539
62T985
62TL387
62YZ683
62ZC 153
62Z0B447
62Z0B452
6220B1655
6220B2015
63ACS2575
63AF878
63AG604
63AG742
63AGIIOI
63AG(E)468
63AG(E)565
63AG(E)633
63AHC(2)245
63AHC(2)365
63AX596
63AX907
63AXI157
63BBA(72)62
63BSFIOOO
63BSF2742
63CB802
63CBI059
63CB 1827
L. B. Townsend and R. K. Robins; J. Org. Chern., 1962,27,990.
J. P. Freeman; J. Org. Chern., 1962,27, 1309.
C. Temple, Jr., R. L. McKee and J. A. Montgomery; J. Org. Chern., 1962,27, 1671.
W. R. Carpenter; J. Org. Chern., 1962,27,2085.
Y. F. Shealy, C. A. Krauth and J. A. Montgomery; 1. Org. Chern., 1962,27,2150.
R. C. De Selms; J. Org. Chern., 1962,27,2163.
D. G. Farnum and P. Yates; J. Org. Chern., 1962,27,2209.
G. B. Elion; 1. Org. Chern., 1962,27,2478.
P. H. Laursen and B. E. Christensen; J. Org. Chern., 1962,27,2500.
K. T. Potts and T. H. Crawford; J. Org. Chern., 1962,27,2631.
H. W. Heine and A. C. Brooker; J. Org. Chern., 1962,27,2943.
H. C. Brown and M. T. Cheng; J. Org. Chern., 1962,27,3240.
P. J. Nelson and K. T. Potts; J. Org. Chern., 1962,27,3243.
W. P. Norris; J. Org. Chern., 1962,27,3248.
S. Cohen, E. Thorn and A. Bendich; J. Org. Chern., 1962,27,3545.
J. A. Montgomery, A. L. Fikes and T. P. Johnston; J. Org. Chern., 1962,27,4080.
D. Y. Curtin, R. J. Crawford and D. K. Wedegaertner; J. Org. Chern., 1962,27,
4300.
C. W. Bills, S. E. Gebura, J. S. Meek and O. J. Sweeting; 1. Org. Chern., 1962,
27,4633.
R. M. Izatt and J. J. Christensen; J. Phys. Chern., 1962,66,359.
W. Knobloch and H. Kuehne; J. Prakt. Chern., 1962,288, 199.
R. Huisgen, R. Grashey, M. Seidel, G. Wallbillich, H. Knupfer and R. Schmidt;
Liebigs Ann. Chern., 1962,653, 105.
R. Huisgen, J. Sauer and M. Seidel; Liebigs Ann. Chern., 1962,654, 146.
U. Schmidt; Liebigs Ann. Chern., 1962,657, 156.
R. Huisgen, R. Grashey, M. Seidel, H. Knupfer and R. Schmidt; Liebigs Ann.
Chern., 1962,658, 169,
G. Spiteller and M. Spiteller-Friedmann; Monatsh. Chern., 1962,93,632.
K. Biemann; 'Mass Spectrometry', McGraw Hill, New York, 1962.
J. Altman and D. Ben-Ishai; Bull. Res. Council Isr., 1962, ttA, 4.
M. Ya. Fel'dman; Biochern. USSR, 1962,27,378.
C. E. Liau, K. Yamashita and M. Matsui; Agric. Bioi. Chern. Jpn., 1962,26,624.
A. G. Beaman and R. K. Robins; J. Appl. Chern., 1962, 12,432.
J. Oró and A. P. Kimball; Arch. Biochern. Biophys., 1962,96,293.
S. Naqui and V. R. Srinivasan; J. Sci. Ind. Res., 1962, 21B, 195 (Chern. Abstr.,
1962,57, 12473).
R. Huisgen and K. Bast; Org. Synth., 1962,42,69.
R. M. Kliss and C. N. Matthews; Proc. Natl. A cad. Sci. USA, 1962,48, 1300.
J. G. A. Luijten, M. J. Janssen and G. J. M. Van der Kerk; RecI. Trav. Chirn.
Pays-Bas, 1962,81,202. 761
E. J. Browne and J. B. Polya; Tetrahedron, 1962, 18, 539. 738
H. Hamano and H. F. Hameka; Tetrahedron, 1962, 18,985. 172,346,347,348
R. Huisgen, R. Grashey and R. Krischke; Tetrahedron Lell., 1962,387. 339
H. Saikachi and M. Kanaoka; Yakugaku Zasshi, 1962,82, 683 (Chern. Abstr.,
1963,58,4543).
H. Beyer and A. Hetzheim; Z. Chern., 1962,2, 153.
G. I. Chipen and V. Ya. Grinshtein; Zh. Obshch. Khirn., 1962,32,447.
B. P. Lugovkin; Zh. Obshch. Khirn., 1962,32,452.
V. M. Berezovskii and A. M. Yurkevich; Zh. Obshch. Khirn., 1962,32, 1655.
E. S. Chaman and E. S. Golovchinskaya; Zh. Obshch. Khirn., 1962,32,2015.
References
921
559, 594
188
591
819,831
652
635
686
529, 532, 560, 572
652
740, 749
155
772
895, 896
819
548
648
A. Hordvik; Acta Chern. Scand., 1963,17,2575.
D. L. Aldous and R. N. Castle; Arzneirn.-Forsch., 1963, 13,878.
R. Huisgen; Angew. Chern., 1963,75,604.
R. Huisgen; Angew. Chern., 1963,75,742.
K. Winterfeld and H. Franzke; Angew. Chern., 1963,75, 1101.
F. Kurzer; Angew. Chern., Int. Ed. Engl., 1963,2,468.
R. Huisgen; Angew. Chern., Int. Ed. Engl., 1963,2,565.
R. Huisgen; Angew. Chern., Int. Ed. Engl., 1963,2,633.
R. Gompper; Adv. HeterocycI. Chern., 1963,2,245.
N. K. Kochetkov and S. D. Soko1ov; Adv. Heterocycl. Chern., 1963,2,365.
G. J. palenik; Acta Crystallogr., 1963,16,596.
K. Hoogsteen; Acta Crystallogr., 1963, 16,907.
R. H. Stanford, Jr.; Acta Crystallogr., 1963, 16, 1157.
A. J. Guarino, M. L. Ibershof and R. Swain; Biochirn. Biophys. Acta, 1963,72,62.
M. Maziere, N. P. Buu-Hoi and N. D. Xuong; Bull. Soc. Chirn. Fr., 1963, 1000.
J. Renault, C. Fauran and F. Pellerin; Bull. Soc. Chirn. Fr., 1963,39,2742.
R. Fusco, G. Bianchetti, D. Pocar and R. Ugo; Chern. Ber., 1963,96,802.
H. Weidinger and J. Kranz; Chern. Ber., 1963,96, 1059.
R. Pfleger, E. Garthe and K. Rauer; Chern. Ber., 1963, 96, 1827.
707
589
525
622
779
778
336
770
519
519
576
551
580
597
569
753
288
569
773
662
751
549
572
548, 549,
593
9
652
702
702, 712
635
792
143,702
143,702,712
100
58, 59, 88,
90, 104, 106
796, 797
509
9
603
647
334
714
764, 767
852
922
63CB2070
63CB2750
63CB2851
63CB2996
63CI(L)953
63CJC274
63CJCï 807
63CJC2380
63CPB265
63CPB348
63CPB845
63G90
63G1196
63IJC30
63JAI22
63J A2026
63JA2967
63JA3719
63JCS42
63JCS 1276
63JC S 1666
63JCS2032
63JCS4558
63JCS5556
63JCS5642
63JGU525
63JGU2519
63JMC289
63JMC471
63JOC543
63JOC945
63JOC981
63JOC99I
63JOC 1305
63JOC1336
63JOCI379
63J OC 1662
63JOC1837
63JOC2087
63J00310
63JOC2560
63JOC2677
63JOC3041
63JOC3329
63JPC72I
63LA(663)108
63LA(663) I 13
63LA(665)144
B-63MI40400
B-63MI40600
63 M 140900
63MI40901
B-63MI40902
63MI40903
63MI40904
63MI40905
63MI41000
63MI41001
B-63MI41 100
778
819
720
766
563
699
562, 563,
578, 579
B. M. Lynch; Can. J. Chern., 1963,41,2380. 699
Y. Mizuno, M. Ikehara, T. Itoh and K. Saito; Chern. Pharrn. Bull., 1963, II, 265. 615
T. Itai and S. Kamiya; Chern. Pharm. Bull., 1963, 11, 348 857, 860, 880, 902
Y. Makisumi; Chern. Pharm. Bull., 1963, 11,845. 872
R. Scarpati, D. Sica and A. Lionetti; Gazz. Chirn. Ita/., 1963,93,90. 714
G. Palazzo and G. Corsi; Gazz. Chirn. Ita/., 1963,93, 1196. 91
P. C. Jain, S. K. Chatterjee and N. Anand; Indian J. Chern., 1963, 1,30. 615
J. M. Insole and E. S. Lewis; J. Arn. Chern. Soc., 1963,85, 122. 840
N. J. Leonard and R. A. Laursen; J. Arn. Chern. Soc., 1963,85,2026. 512
P. Yates and D. G. Farnum; J. Arn. Chern. Soc., 1963,85,2967. 721
N. J. Leonard and T. Fujii; 1 Arn. Chern. Soc., 1963,85,3719. 525,530
P. J. Bunyan and J. I. G. Cadogan; J. Chern. Soc., 1963,42. 335
D. J. Brown and J. S. Harper; J. Chern. Soc., 1963, 1276. 578,695
O. Meth-Cohn, R. K. Smalley and H. Suschitzky; J. Chern. Soc., 1963, 1666. 641
D. Buttimore, D. H. Jones, R. Slack and K. R. H. Wooldridge; 1 Chern. Soc.,
1963, 2032.
L. E. A. Godfrey and F. Kurzer; J. Chern. Soc., 1963,4558.
N. K. Roberts; J. Chern. Soc., 1963,5556.
G. W. Miller and F. L. Rose; 1 Chern. Soc., 1963,5642
A. N. Kost, G. K. Faizova and I. I. Grandberg; J. Gen. Chern.
Transl.), 1963, 33, 525
I. I. Grandberg, S. V. Tabak, G. K. Faizova and A. N. Kost; J. Gen. Chern. USSR
(Engl. Trans/.), 1963,33,2519.
E. Dyer, J. M. Reitz and R. E. Farris, Jr.; J. Med. Chern., 1963,6,289.
W. A. Bowles, F. H. Schneider, L. R. Lewis and R. K. Robins; J. Med. Chern.,
1963, 6, 471. 530, 536, 562
K. T. Potts; J. Org. Chern., 1963,28,543. 745,751
J. F. Gerster, J. W. Jones and R. K. Robins; J. Org. Chern., 1963,28,945. 562, 598
J. R. Piper and T. P. Johnson; J. Org. Chern., 1963,28,981. 139
N. Shachat and J. J. Bagnell, Jr.; J. Org. Chern., 1963,28,991. 140
T. P. Johnston and A. Gallagher; J. Org. Chern., 1963,28, 1305. 517
G. DeStevens, A. Halamandaris, M. Bernier and H. M. Blatter; J. Org. Chern.,
1963,28, 1336. 324
S. Cohen, E. Thorn and A. Bendich; J. Org. Chern., 1962,28, 1379. 549
E. Y. Sutcliffe and R. K. Robins; 1 Org. Chern., 1963,28, 1662. 529,530,538,561,595
Y. Mizuno, M. Ikehara, T. Itoh and K. Saito; J. Org. Chern., 1963,28, 1837. 615,635
T. C. Myers and L. Zeleznick; J. Org. Chern., 1963, 25, 2087. 531, 552
A. J. Beaman and R. K. Robins; J. Org. Chern., 1963,28,2310. 529,540,563
R. M. Cresswell and G. B. Brown; J. Org. Chern., 1963,28,2560. 561,590
M. H. Krackov and B. E. Christensen; J. Org. Chern., 1963,28,2677. 577
R. K. Robins, J. K. Horner, C. V. Greco, C. W. Noell and C. G. Beames, Jr.;
J.Org. Chern., 1963,28,3041.
Y. Mizuno, M. Ikehara, K. A. Watanabe, S. Suzaki and T. Itoh; J. Org. Chern.,
1963,28,3329.
J. B. Lounsbury; J. Phys. Chern., 1963,67,721.
T. Pyl, S. Melde and H. Beyer; Liebigs Ann. Chern., 1963,663, 108.
T. Pyl, F. Waschk and H. Beyer; Liebigs Ann. Chern., 1963,663, 113.
H. Gehlen and J. Dost; Liebigs Ann. Chern., 1963,665, 144.
A. L. McClellan; 'Tables of Experimental Dipole Moments', Freeman, San
Francisco, 1963.
B. Pullman and A. Pullman; 'Quantum Biochemistry', Interscience, New York,
1963.
D. S. Letham; Life Sciences, 1963,2,569.
A. Veillard and B. Pullman: J. Theor. Bioi., 1963,4,37.
J. G. Flaks and L. N. Lukens; in 'Methods in Enzymology', ed. S. P. Colowick
and N. O. Kaplan; Academic, New York, 1963, vol. 6, p. 52.
R. K. Robins; Biochern. Prep., 1963, 10, 145.
F. Bergmann and M. Kleiner; Isr. J. Chern., 1963, 1,477.
C. U. Lowe, M. W. Rees and R. Markham; Nature (London) 1963, 199,219.
B. Stanovnik and M. Tisler; Croat. Chern. Acta, 1963,35, 167.
T. Kurihara and T. Chiba; Tohoku Yakka Daigaku Kenkyu Nenpo, 1963, 10,65.
References
H. Weidinger and J. Kranz; Chern. Ber., 1963,96,2070.
L. Birkofer, A. Ritter and P. Richter; Chern. Ber., 1963,96,2750.
G. Wittig and B. Reichel; Chern. Ber., 1963, 96, 2851.
A. Spassov, E. Go1ovinsky and G. Russev; Chern. Ber., 1963,96,2996.
J. B. Lloyd; Chern. Ind. (London), 1963,953.
B. M. Lynch and T. L. Chan; Can. J. Chern., 1963,41,274.
A. F. Lewis, A. G. Beaman and R. K. Robins; Can. J. Chern., 1963,41, 1807,
105
775
680
858, 862, 883, 891
USSR (Engl.
A. L. McClellan; 'Tables of Experimental Dipole Moments', Freeman, San
Francisco, 1963.
207
207
550, 551
619,641
616
795
647
116
754
176,282
347
601
505
504
598
535
569
635
616,
635
677
63MI41200
63MI41201
63 N224
63PMH(l)1
63PMH(l)98
63PMH(l)I77
63PMH(I)189
63PMH(2)1
63PMH(2)161
63PNA(49)737
63T1801
63TLl499
63YZ373
63Z0BI650
63Z0B2475
63Z0B2942
63Z0B3205
63Z0B3342
64AqR)735
64AGI44
64AG(E)138
64AG(E)693
64AHq3)1
64AHq3)263
64AHq3)373
64AJCI128
64AXI26
64B494
64B880
64CB934
64CBI085
64CBI225
64CB2173
64CB2179
64CB2185
64CB3349
64CB3476
64CB3493
64CC230
64CC23I
64CJC43
64CPB204
64CPB639
64CPB866
64CPB1351
64CRVI29
64D1S2690
64Hq20) I
64HCA838
64HCA942
64HCA2068
64JAI242
64JA2025
64JA2213
64JA2948
G. 1. Chipen and V. Ya. Grinshtein; Latvija PSR Zinatnu Akad. Vestis Kirn. Ser.,
1962,255 (Chern. Abslr., 1963,59, 12789).
H. Hopff and M. Lippay; J. Makrorno/. Chern., 1963,66, 157.
H. Leltre, H. Ballweg, H. Maurer and D. Rehberger; Naturwissenschaften, 1963,
50, 224. 563, 564, 593
A. Albert; Phys. Methods Heterocycl. Chern., 1963,1, I. 50
A. Albert; Phys. Methods Heterocycl. Chern., 1963, 1,98. 690
W. Pfleiderer; Phys. Methods Heterocycl. Chern., 1963, 1, 177. 31,32,207
S. Walker; Phys. Methods Heterocycl. Chern., 1963, 1, 189. 176
S. F. Mason; Phys. Methods Heterocycl. Chern., 2, I. 197
A. R. Katritzky and A. P. Ambler; Phys. Methods Heterocy/. Chern., 1963,2,161. 24,26,
27,199,200
C. Ponnamperuma, R. M. Lemmon, R. Mariner and M. Calvin; Proc. Natl. Acad.
Sci. USA, 1963,49,737.
1. Ugi; Tetrahedron, 1963, 19, 180 I.
S. Matsuura and T. Goto; Tetrahedron Leu., 1963, 1499.
A. Takamizawa and S. Hayashi; Yakugaku Zasshi, 1963,83,373.
E. S. Golovchinskaya, D. A. Koiganova, L. A. Nikolaeva and E. S. Chaman;
Zh. Obshch. Khirn., 1963,33, 1650.
1. N. Goncharova and 1. Y. Postovskii; Zh. Obshch. Khirn., 1963,33,2475.
References
B. P. Lugovkin; Zh. Obshch. Khirn., 1963,33,2942.
B. P. Lugovkin; Zh. Obshch. Khirn., 1963,33,3205.
E. S. Chaman and E. S. Golovchinskaya; Zh. Obshch. Khirn., 1963,33,3342.
U. Croalto and A. Fava; Ann. Chirn. (Rorne), 1964,54,735 (Chern. Abstr., 1965,
62, 11197).
F. G. Willey; Angew. Chern., 1964,76, 144.
F. G. Willey; Angew. Chern., Int. Ed. Eng/., 1964,3, 138.
A. J. Boulton, P. B. Ghosh and A. R. Katritzky; Angew. Chern., Inc. Ed. Eng/.,
1964,3, 693.
G. F. Duffin; Adv. Heterocycl. Chern., 1964,3, I.
K. A. Jensen and C. Pedersen; Adv. Heterocycl. Chern., 1964,3,263.
1. Ugi; Adv. Heterocycl. Chern., 1964,3,373.
P. J. Black, M. L. Heffernan, L. M. Jackman, Q. N. Porter and G. R. Underwood;
Aust. 1. Chern., 1964, 17, 1128.
H. M. Sobell and K.-1. Tomita; Acta Crystallogr., 1964,17, 126.
A. D. Broom, L. B. Townsend, J. W. Jones and R. K. Robins; Biochernistry, 1964,
3,494.
G. B. Brown, G. Levin and S. Murphy; Biochernistry, 1964,3,880.
L. Birkofer, A. Ritter and H.-P. Kuhlthau; Chern. Ber., 1964,97,934.
R. Huisgen, R. Grashey, H. Knupfer, R. Kunz and M. Seidel; Chern. Ber., 1964,
97, 1085.
D. Pocar, G. Bianchetti and P. D. Croce; Chern. Ber., 1964,97, 1225.
A. Dornow, H. Mensel and P. Marx; Chern. Ber., 1964,97,2173.
A. Dornow, W. Abele and H. Menzel; Chern. Ber., 1964,97,2179.
A. Dornow, H. Menzel and P. Marx; Chern. Ber., 1964,97,2185.
A. Dornow and W. Abele; Chern. Ber., 1964,97,3349.
R. Neidlein; Chern. Ber., 1964,97, 3476.
H. Reimli ér; Chern. Ber., 1964,97,3493.
D. S. Letham, J. S. Shannon and 1. R. C. McDonald; Chern. Cornrnun., 1964,230.
G. Sh w and D. V. Wilson; Chern. Cornrnun., 1964,231.
C. N, R. Rao and R. Venkataraghavan; Can. J. Chern., 1964,42,43.
Y. Makisumi,)i. Watanabe and K. Tori; Chern. Pharrn. Bull., 1964,12,204.
M. Ikehara,,Ji. Uno and F. Ishikawa; Chern. Pharrn. Bull., 1964,40,639.
Y. Mizun9, T. Itoh and K. Saito; Chern. Pharrn. Bull., 1964,12,866.
F. Yoneda, T. Ohtaka and Y. Nitta; Chern. Pharrn. Bull., 1964, 12, 1351.
F. H. C. Stewart; Chern. Rev., 1964,64, 129.
J. M. Gill; Ph.D. Dissertation, Indiana University, 1963 (Diss. Abstr., 1964,24,
2690).
R. H. Wiley and P. Wiley; Chern. Heterocycl. Cornpd., 1964,20, I.
923
748
756
569
842
511,513
216
550, 588
857, 881,
902
549
549
548, 550,
564
685
697
697
86
52,77, 80
62,102
839, 842
307
510
530, 552
554, 555
533, 535
769
721
899
800
898
340
717
721, 887
519,601
601
685
858
556
620
628,650
701
14
206,228, 232, 239,
252,273,277
59
13,23
C. Moussebois and F. Eloy; He/v. Chirn. Acta, 1964,47,838.
C. Moussebois and J. F. M. Oth; He/v. Chirn. Acta, 1964,47,942.
Ph. Gold-Aubert, D. Melkonian, and L. Toribio; He/v. Chirn. Acta, 1964,47,
2068.
R. E. Holmes and R. K. Robins; J. Arn. Chern. Soc., 1964,86, 1242.
P. A. S. Smith, L. O. Krbechek and W. Resemann; J. Arn. Chern. Soc., 1964,86,
2025.
M. E. Munk and Y. K. Kim; 1. Arn. Chern. Soc., 1964,86,2213.
R. Shapiro; J. Arn. Chern. Soc., 1964,86,2948.
788
540
697
714
551
924
64J A4506
64JA472I
64JA5320
64JCS446
64JCS792
64JCS4226
64JHC34
64JHC42
64JHCI15
64JHC 163
64JHC 182
64JHC247
64JMClO
64JOC942
64JOC1715
64JOC I 720
64JOC1988
64J0C2542
64JOC26 I I
64JOC3209
64JOC3403
64JOC3449
64J00707
64J00733
64JPS962
64LA(673)78
64LA(678)95
64M242
64M140100
B-64M 140400
64M140600
B-64MI40800
64M140900
64M 14090 I
64M141000
64M141001
64M141100
B-64MI41101
B-64M141102
64N 137
64RT087
64T46 I
64TLl477
64TL2999
64USP3128274
642C 454
6420B390
6420B1137
64Z0B 1745
6420 B 2472
6420B2517
6420B3254
References
F. D. Marsh and M. E. Hermes; J. Am. Chern. Soc., 1964,86,4506. 726
E. C. Taylor and E. E. Garcia; J. Am. Chern. Soc., 1964,86,4721. 512,554,555
L. B. Townsend, R. K. Robins, R. N. Loeppky and N. J. Leonard; J. Am. Chern.
Soc., 1946, 86, 5320.
M. P. L. Caton, D. H. Jones, R. Slack and K. R. H. Wooldridge; J. Chern. Soc.,
1964, 446.
S. Lewin; J. Chern. Soc., 1964,792.
W. L. F. Armarego; J. Chern. Soc., 1964,4226.
C. W. Noell and R. K. Robins; J. Heterocyel. Chern., 1964, 1,34.
T. Kuraishi and R. N. Castle; J. Heterocyel. Chern., 1964, 1,42.
J. A. Montgomery and H. J. Thomas; J. Heterocyel. Chern., 1964, I, 115.
E. Campaigne and F. Haaf; 1. Heterocyel. Chern., 1964, I, 163.
M. Maim and R. N. Castle; J. Heterocyel. Chern., 1964, I, 182.
G. A. Gerhardt and R. N. Castle; J. Heterocyel. Chern., 1964, 1,247.
E. Dyer and H. S. Bender; J. Med. Chern., 1964,7, 10.
W. J. Fanshawe, V. J. Bauer and S. R. Safir; J. Org. Chern., 1964,29,942.
E. Campaigne and M. C. Wani; 1. Org. Chern., 1964,29,1715.
C. G. Overberger and H. A. Friedman; J. Org. Chern., 1964,29, 1720.
J. Bullock and O. Jardetzky; J. Org. Chern., 1964,29, 1988.
G. M. Badger, P. J. Nelson and K. T. Potts; J. Org. Chern., 1964,29,2542.
Y. Mizuno, T. Itoh and K. Saito; J. Org. Chern., 1964,29,2611.
A. Giner-Sorolla, E. Thorn and A. Bendich; J. Org. Chern., 1964,29,3209.
552
23
551
307,309,610,614
648
651
530, 552
119
629,652
871
559
281
663
663
511
856, 896
619,620
539, 549,
556, 559, 563
635
758
D. L. Garmaise and J. Komlossy; J. Org. Chern., 1964,29,3403.
M. Hauser; J. Org. Chern., 1964,29,3449.
E. F. Godefroi, C. A. Van der Eycken and C. Van der Westeringh; J. Org. Chern.,
1964,29,3707.
G. A. Reynolds; J. Org. Chern., 1964,29,3733.
T. G. Alexander and M. Maientha1; J. Pharm. Sci., 1964, 53, 962.
W. Pfleiderer and F. Sagi; Liebigs Ann. Chern., 1964,673, 78.
W. Ried and H. Mengler; Liebigs Ann. Chern., 1964,678,95.
G. R. Revankar and S. Siddappa; Monatsh. Chern., 1964,95,242.
G. Pouzard, L. Pujol, J. Roggero and E. J. Vincent; J. Chim. Phys. Phys. Chim.
BioI., 1964,613.
R. Huisgen, R. Grashey and J. Sauer; in 'The Chemistry of Alkenes', ed. S.
Patai; Wiley-lnterscience, 1964, part 1, p. 739.
G. Geisler, J. Fruwert and A. Kuennecke; Z. Phys. Chern., 1964,41,49 (Chern.
Abstr., 1964, 61, 6892).
H. Bredereck, R. Gompper, H. G. V. Schüh and G. Theilig; in 'Newer Methods
of Preparative Organic Chemistry', ed. W. Foerst; Academic, New York, 1964,
vol. 3, p. 241.
S. Cohen and A. Vincze; Isr.1. Chern., 1964,2, 1.
N. B. Smirnova and J. Ya. postovskii; Zh. Vses. Khim. Obshch. D. I. Mendeleeva,
1964,9,711 (Chern. Abstr., 1964,62,9130).
B. Mariani and R. Sgarbi; Chim. Ind. (Milan), 1964,46,630 (Chern. Abstr., 1964,
61, 12117).
2. Talik and B. Brekiesz; Rocz. Chern., 1964,38,887 (Chern. Abstr., 1965,62,5271).
J. H. Boyer, R. Moriarty, B. de B. Darwent and P. A. S. Smith; Chern. Eng.
News, 1964, 42, 6.
R. Huisgen, R. Grashey and J. Sauer; in 'The Chemistry of A1kenes', ed. S. Patai,
Interscience, New York, 1964, pp. 835 If.
'Kirk-Othmer Encyclopedia of Chemical Technology', Wiley-lnterscience, New
York, 2nd edn., 1964, p. 737.
H. Goldner, G. Dietz and E. Carstens; Naturwissenschaften, 1964,51, 137.
J. Strating, W. E. Weening and B. Zwanenburg; Reel. Trav. Chim. Pays-Bas,
1964,83,387.
H. Kano and E. Yamazaki; Tetrahedron, 1964,20,461.
W. D. Crow and N. J. Leonard; Tetrahedron Leu., 1964,23, 1477.
H. Tiefenthaler, W. Dörsche1n, H. Göth and H. Schmid; Tetrahedron Leu., 1964,
2999.
G. H. Hitchings, G. B. Elion and L. E. Mackay; U.S. Pat. 3 128274 (1964) (Chern.
Abstr., 1964,60, 14523).
H. Goldner, G. Dietz and E. Carstens; Z. Chern., 1964,4,454.
Y. S. Shabarov, A. P. Smirnova and R. Y. Levina; Zh. Obshch. Khim., 1964,34,
390 (Chern. Abstr., 1964,60, 12005).
L. A. Niko1aeva and E. S. Golovchinskaya; Zh. Obshch. Khim., 1964,34, 1137.
N. N. Vereshchagina and I. Y. postovskii; Zh. Obshch. Khim., 1964,34, 1745
(Chern. Abstr., 1964,61,8307).
1. M. Ovcharova and E. S. Golovchinskaya; Zh. Obshch. Khim., 1964,34,2472.
1. Ya. Postovskii and V. L. Nirenburg; Zh. Obshch. Khim., 1964,34,2517 (Chern.
Abstr.. 1964,61, 14664).
1. M. Ovcharova and E. S. Golovchinskaya; Zh. Obshch. Khim., 1964,34,3254.
661
723
512
533
711
635
17
169
362
485
548
564
630
621
708
7\0
730
580
786
832
27
\61
550
580, 597
852
540, 550
893
557
794
564
65ACS2434
65AFI0
65AG414
65AG(E)417
65AHC(4)75
65AHC(4)107
65AHC(5)119
65AJC379
65AXIli
65AX573
65B650
65BSF769
65BSF2617
65CB334
65CB642
65CB928
65CBI138
65CB1153
65CB2715
65CB2966
65CB2985
65CB3025
65CB3142
65CB3992
65CB4014
65CC596
65CHE165
65CHE375
65CHE531
65CJC1154
65CPB142
65CPB1207
65CR(261)1872
65FES634
65G33
65G 1220
65IJC84
651JC138
65IJC162
65JA306
65JA749
65JA1772
65JA1976
65JA1980
65JA2225
65JA3023
65JA3752
65JA3768
65JA4976
65JAP6522265
65JCS623
65JCS2778
65JCS3017
65JCS3312
65JCS3357
65JCS3456
65JCS3770
65JCS3912
65JCS5590
References
925
B. Bak, C. H. Christensen, T. S. Hansen, E. J. Pedersen and J. T. Nielsen; Acta
Chern. Scand., 1965, 19, 2434. 58
K. W. Merz and P. H. Stahl; Arzneirn.-Forsch., 1965,15, 10. 578
L. Birkofer and A. Ritter; Angew. Chern., 1965,77,414. 698,708
L. Birkofer and A. Ritter; Angew. Chern., Int. Ed. Engl., 1965,4,417. 698,708
R. Filler; Adv. Heterocycl. Chern., 1965,4,75. 66, 69, 89,90
R. Slack and K. R. H. Wooldridge; Adv. Heterocycl. Chern., 1965,4, 107. 104, 135
F. Kurzer; Adv. Heterocycl. Chern., 1965,5, 119. 95,96,97, 105, 130, 135, 140
G. M. Badger and R. P. Rao; Aust. J. Chern., 1965,18,379. 336
D. G. Watson, D. J. Sutor and P. Tollin; Acta Crystallogr., 1965, 19, 111. 509
D. G. Watson, R. M. Sweet and R. E. Marsh; Acta Crystallogr., 1965,19,573. 502,505,
507, 508, 509
I. J. Borowitz, S. M. Bloom, J. Rothschild and D. B. Sprinson; Biochernistry,
1965,4, 650. 582
J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1965,769. 254
J. Filippi and J. Givern; Bull. Soc. Chirn. Fr., 1965,2617. 552
R. R. Schmidt; Chern. Ber., 1965,98,334. 157
R. Huisgen, R. Grashey, E. Aufderhaar and R. Kunz; Chern. Ber., 1965,98,642. 745,769
A. Spassov and S. Robev; Chern. Ber., 1965,98,928. 768
R. Huisgen, L. Möbius and G. Szeimies; Chern. Ber., 1965,98, 1138. 704,712
R. Huisgen and G. Szeimies; Chern. Ber., 1965,98, 1153. 17,679,703,711,712
G. Bianchetti, D. Pocar, P. Dalla Croce and A. Vigevani; Chern. Ber., 1965,98,
2715.
R. Huisgen, C. Axen and H. Seidl; Chern. Ber., 1965,98,2966.
R. Huisgen and H. Blaschke; Chern. Ber., 1965,98,2985.
C. F. Kröger, L. Hummel, M. Mutscher and H. Beyer; Chern. Ber., 1965,98,3025.
W. Ried and M. Schön; Chern. Ber., 1965,98,3142.
R. Huisgen, L. Möbius, G. Müller, H. Stangl, G. Szeimies and J. M. Vernon;
Chern. Ber., 1965,98,3992. 703,711,720
R. Huisgen, R. Knorr, L. Möbius and G. Szeimies; Chern. Ber., 1965,98,4014. 685,708,
709
724
A. C. Oehlschlager, R. Tillman and L. H. Zalkow; Chern. Cornrnun., 1965,596.
Z. I. Miroshnichenko and M. A. Alperovich; Chern. Heterocyc1. Cornpd. (Eng!.
Trans!.), 1965, 1, 165.
B. V. Ioffe and D. D. Tsitovich; Chern. Heterocyc1. Cornpd. (Engl. Trans!.), 1965,
1,375.
B. K. Martsokha and A. M. Simonov; Chern. Heterocycl. Cornpd. (Eng!. Transl.),
1965,1,531.
M. Tremblay; Can. J. Chern., 1965,43,1154.
A. Takamizawa and Y. Hamashima; Chern. Pharrn. Bull., 1965, 13, 142.
A. Takamizawa and Y. Hamashima; Chern. Pharrn. Bull., 1965,13, 1207.
A. LeBerre, M. Donnoy and J. Godin; c.R. Hebd. Seances Acad. Sci., 1965,261,
1872.
T. Vitali, F. Mossini and G. Bertaccini; Farrnaco Ed. Sci., 1965,20,634 (Chern.
Abstr., 1966,64,9710).
G. F. Bettinetti and L. Capretti; Gazz. Chirn. Ital, 1965,85,33.
D. Pocar, G. Bianchetti and P. Dalla Croce; Gazz. Chirn. Ital., 1965,95, 1220.
P. C. Jain, S. K. Chatterjee and N. Anand; Indian J. Chern., 1965,3,84.
S. K. Chatterjee, P. C. Jain and N. Anand; Indian J. Chern., 1965,3, 138.
S. Naqui and V. R. Srinivasan; Indian 1. Chern., 1965,3, 162.
P. Scheiner, J. H. Schomaker, S. Deming, W. J. Libbey and G. P. Nowack; 1.
Arn. Chern. Soc., 1965,87,306.
A. L. Logothetis; 1. Arn. Chern. Soc., 1965,87,749.
R. E. Holmes and R. K. Robins; 1. Arn. Chern. Sac., 1965,87, 1772.
E. C. Taylor and R. W. Morrison, Jr.; J. Arn. Chern. Sac., 1965,87, 1976.
E. C. Taylor and R. W. Hendess; J. Arn. Chern. Soc., 1965,87, 1980.
R. J. Pugmire, D. M. Grant, R. K. Robins and G. W. Rhodes; J. Arn. Chern.
Sac., 1965, 87, 2225.
R. J. Crawford, R. J. Dummel and A. Mishra; 1. Arn. Chern. Soc., 1965,87,3023.
J. F. Gerster and R. K. Robins; J. Arn. Chern. Soc., 1965,87,3752.
R. J. Crawford and A. Mishra; J. Arn. Chern. Soc., 1965,87,3768.
J. P. Ferris and L. E. Orgel; J. Arn. Chern. Soc., 1965,87,4976.
Jpn. Pat. 65 22265 (1965) (Chern. Abstr., 1966,64,3566).
S. Matsuura and T. Goto; J. Chern. Soc., 1965,623.
W. L. F. Armarego; J. Chern. Soc., 1965,2778.
G. B. Barlin and N. B. Chapman; 1. Chern. Sac., 1965,3017.
L. A. Summers, P. F. H. Freeman and D. J. Shields; J. Chern. Soc., 1965,3312.
G. W. Miller and F. L. Rose; J. Chern. Soc., 1965,3357.
L. A. Cort; J. Chern. Soc., 1965,3456.
D. J. Brown and N. W. Jacobsen; J. Chern. Soc., 1965,3770.
F. Kurzer and K. Douraghi-Zadeh; J. Chern. Sac., 1965,3912.
D. D. Perrin; J. Chern. Soc., 1965,5590.
704
152, 809
709
746
723
116
216
246
798
310
313
341
641
748
704,714
867
635,640
884, 886
703,711
725
564
580
878, 901
510,514
188,256
558
254
584
628
511,593
863,614,627,642,648,650
524, 561
719
862, 873
663
523
758
385
926
65JCS5958
651HC53
651HC67
65JHCI96
65JHC247
651HC253
65JHC287
651HC291
65JHC331
651HC410
651HC453
65JMC296
65JMC667
65JMC708
65JOCI99
65JOC408
65JOC638
65JOC732
65JOC826
65JOC829
65JOCIII0
65JOC 1114
65JOCI916
65JOC2403
65JOC2857
65JOC3235
65JOC3346
65JOC3472
65JOC3597
65JOC3601
65JOC3729
65JOC4066
65JOC4081
65JOC4085
65JOC4205
65JOU95
65JPR(30)96
65 LA( 682) 123
65LA(683) 149
65LA(685)176
65LA(686)134
65LA(688)93
65LA(688)205
65M741
65MI40100
65MI40800
65 M 140900
B-65M140901
B-65MI40902
65MI40903
65MI40904
65MI40905
65M[40906
65 M 140907
65MI40908
65MI41100
86
613,631
902
621,640
629,
652
T. Ichikawa, T. Kato and T. Takenishi; J. Heterocycl. Chern., [965,2,253. 583
L. M. Werbel and M. L. Zamora; J. Heterocycl. Chern., 1965,2,287. 628,643,650,653
N. J. Leonard, K. L Carraway and J. P. Helgeson; J. Heterocycl. Chern., 1965,
2, 291.
C. K. Bradsher, E. F. Litzinger, Jr. and M. F. Zinn; J. Heterocycl. Chern., 1965,
2, 33 1.
W. W. Paudler and D. E. Dunham; J. Heterocycl. Chern., 1965,2,410.
H. F. Ridley, R. G. W. Spickett and G. M. Timmis; J. Heterocycl. Chern., 1965,
2,453.
M. M. Vohra, S. N. Pradhan, P. C. Jain, S. K. Chatterjee and N. Anand; J. Med.
Chern., 1965,8,296. 635,636,640,887
A. Giner-Sorolla and A. Bendich: J. Med. Chern., [965,8, 667. 563
J. A. Montgomery and K. Hewson; J. Med. Chern., 1965, 8, 708. 618,619,621,622,
635,636,640
V. Papesch and R. M. Dodson; J. Org. Chern., 1965,30,199. 310,324,338,342
R. M. Cresswell, H. K. Maurer, T. Strauss and G. B. Brown; J. Org. Chern.,
1965,30,408. 554
J. J. Looker; J. Org. Chern., 1965,30, 638. 709
E. Campaigne and F. Haaf; J. Org. Chern., 1965,30,732. 119
C. Temple, Jr. and J. A. Montgomery; J. Org. Chern., 1965,30,826. 854,880,902
C. Temple, Jr., R. L McKee and J. A. Montgomery, J. Org. Chern., 1965,30,829. 857,881,
902
J. W. Marsico and L. Goldman; J. Org. Chern., 1965,30,3597.
C. Temple, Jr., C. L. KussnerandJ. A. Montgomery; J. Org. Chern., 1965,30,3601.
H. C. Brown and C. R. Wetzel; J. Org. Chern., 1965,30,3729.
Y. Mizuno, N. Ikekawa, T. ltoh and K. Saito: 1 Org. Chern., 1965,30,4066.
W. W. Paudler and H. L. Blewitt; J. Org. Chern., 1965,30,4081.
J. P. Paolini and R. K. Robins; 1 Org. Chern., 1965,30,4085.
A. C. Oehlschlager and L. H. Zalkow; J. Org. Chern., 1965, 30, 4205.
V. F. Lavrushin, V. D. Bezuglyi, G. G. Belous and V. G. Tishchenko; 1 Org.
Chern. USSR (Eng!. Trans!.), 1965, 1,95.
W. König, M. Coenen, W. Lorenz, F. Bahr and A. Bassi; J. Prakt. Chern., 1965,
30,96. 719
H. Gehlen and J. Schmidt; Liebigs Ann. Chern., 1965,682, 123. 745,754
H. Gehlen and W. Schade: Liebigs Ann. Chern., 1965,683, 149. 772
H. Gehlen and K. Moeckel; Liebigs Ann. Chern., 1965,685, 176. 772
F. Lingens and H. Schneider-Bernlöhr; Liebigs Ann. Chern., 1965,686, 134. 142
H. Bredereck, B. Föhlisch and K. Walz; Liebigs Ann. Chern., 1965,688,93. 802
H. Gold; Liebigs Ann. Chern., 1965,688,205. 678,698,708
F. Asinger, W. Schafer and A. V. Grenacher; Monatsh. Chern., 1965,96,741. 649
F. Eloy; Fortschr. Chern. Forsch., 1965,4,807. 31
M. R. Grimmett; Rev. Pure Appl. Chern., 1965, 15, 101. 485
G. P. Hager, J. C. Krantz, J. C. Harman and R. M. Burgison; J. Arn. Pharrn.
Assoc., 1965, 43, 152.
C. Ponnamperuma; 'The Origins of Prebiological Systems and their Molecular
Matrices', Academic, London, 1965, p. 221.
K. W. Merz and P. H. Stahle; 'Behrage Zur Biochemie und Physiologie von
Naturstoffen', Fischer-Verlag, Jena, 1965, p. 285.
J. Iball and H. R. Wilson; Proc. R. Soc. London, Ser. A, 1965,288,418.
G. B. Brown, K. Suguira and R. M. Cresswell; Cancer Res., 1965,25,986.
H. Berthod and A. Pullman; J. Chirn. Phys., Phys. Chirn. Bio!., 1965,62,942.
Z. Neiman and F. Bergman; Isr. J. Chern., 1965,3, 161.
Y. Fujimoto and N. Ono; Pharrn. Soc. Jpn., 1965,81,3671.
G. Shaw; New Scientist, 1965,25,788.
G. Bianchetti, P. Dalla Croce, D. Pocar and G. Gallo; Rend. Inst. Lornb. Sci.
Lett., 1965, 99A, 296.
References
A. J. Boulton, A. C. Gripper Gray and A. R. Katritzky; J. Chern. Soc., 1965, 5958.
J. P. Paolini and R. K. Robins; J. Heterocycl. Chern., 1965,2,53.
W. D. Guither, D. G. Clark and R. N. Castle; 1 Heterocycl. Chern., 1965,2,67.
R. J. Rousseau and R. K. Robins; J. Heterocycl. Chern., 1965,2, 196.
J. A. Gerhardt, D. L. Aldous and R. N. Castle; J. Heterocycl. Chern., 1965,2,247.
W. C. Coburn, M. C. Thorpe, J. A. Montgomery and K. Hewson; J. Org. Chern.,
1965,30, 1110.
W. C. Coburn, Jr., M. C. Thorpe, J. A. Montgomery and K. Hewson: J. Org.
Chern., 1965,30, 1114.
S.-C. J. Fu, E. Chinoporos and H. Terzian: J. Org. Chern., 1965,30, 1916.
J. G. Lombardino; J. Org. Chern., 1965,30,2403.
B. R. Baker and P. M. Tanna; 1 Org. Chern., 1965,30,2857.
J. A. Montgomery and H. J. Thomas; J. Org. Chern., 1965,30,3235.
M. Charton; J. Org. Chern., 1965,30,3346.
J. H. Markgraf, W. T. Bachmann and D. P. Hollis; J. Org. Chern., 1965,30,3472.
530
610,631
306
575
511,512
512
117
612
529
530, 552, 594
364
799, 802,
803, 819
531
564
763
615,619
611
611,613
724
254
575
569
559
508, 520
555
505
559, 560
580
601
704, 714
65MI41200
65P933
65PC40100
65PNA(54) 1052
65RCR237
65RTC213
65RTC408
65T3209
65T3435
65TLl965
65TL2039
65TL2059
65YZI58
65ZC304
65ZC381
66AqR)190
66ACS57
66ACS754
66ACSI555
66ACS1907
66ACS2795
66AF541
66AG392
66AG(E)308
66AG(E)699
66AG(E)960
66AHq6)1
66AHq6)45
66AHq6)347
66AHq7)39
66AH q7) 183
66AHq7)301
66AP441
66AX397
66B756
66B2082
66B3007
66B3057
66BSF61O
66BSF619
66BSF775
66BSF2075
66BSF2529
66BSF2832
66BSF2990
66BSF3041
66BSF3524
66BSF3727
66BSF3744
66BSF3934
66CB317
66CB475
66CB618
66CB850
66CB944
66CB1618
G. Palazzo and L. Baiocchi; Ann. Chern., (Rome), 1966,56, 190.
J. Sandström and I. Wennerbeck; Acta Chern. Scand., 1966,20,57.
A. Hordvik; Acta Chern. Scand., 1966,20,754.
M. Begtrup and C. Pedersen; Acta Chern. Scand., 1966,20, 1555.
A. Hordvik and J. Sletten; Acta Chern. Scand., 1966,20, 1907.
K. A. Jensen, A. Holm and S. Rachlín; Acta Chern. Scand., 1966, 20, 2795.
A. Zimmer and R. W. Atchley; Arznheirn.-Forsch., 1966, 16,541.
H. G. Zachau, D. Dutting and H. Feldman; Angew. Chern., 1966,78,392.
E. C. Taylor, S. Vromen, R. V. Ravindranathan and A. McKillop; Angew. Chern.,
Int. Ed. Engl., 1966,5,308.
A. Wagner, C. W. Schellhammer and S. Petersen; Angew. Chern., Int. Ed. Engl.,
1966, 5, 699.
H. G. Schmelzer, E. Degener and H. Holtschmidt; Angew. Chern., Int. Ed. Engl.,
1966,5,960. 765
J. H. Lister; Adv. Heterocycl. Chern., 1966,6, I. 501
R. E. Lyle and P. S. Anderson; Adv. Heterocycl. Chern., 1966,6,45. 415
A. N. Kost and I. I. Grandberg; Adv. Heterocycl. Chern., 1966,6,347. 47,54,58,
60,65,69,74,79,88,90,100,105,106, 168, 171,
207,222, 238, 241, 254, 260, 266, 268, 272, 273, 276, 277
H. Prinzbach and E. Futterer; Adv. Heterocycl. Chern., 1966,7, 39. 64,67, 89,
97, 103, 114
60, 80, 95
30
750
508
619,
621,622
565
531,552
References
H. Deuschl; Ber. Bunsenges. Phys. Chern., 1965,69,550.
P. M. Dunnill and L. Fowden; Phytochemistry, 1965,4,933.
J. A. Elvidge; personal communication to R. Slack and K. R. H. Wooldridge;
Adv. Heterocycl. Chern., 1965,4, 114.
C. O. Miller; Proc. Nat. Acad. Sci. USA, 1965,54, 1052.
A. I. Busev, V. K. Akimov and S. I. Gusev; Russ. Chern. Rev. (Engl. Trans!.),
1965,34, 237.
H. C. Beyerman, W. Maassen van den Brink, F. Weygand, A. Prox, W. König,
L. Schmidhammer and E. Nintz; Recl. Trav. Chirn. Pays-Bas, 1965,84,213.
B. Zwanenburg, W. Weening and J. Strating; Recl. Trav. Chirn. Pays-Bas, 1965,
84, 408.
D. S. Jones, G. W. Kenner, J. Preston and R. C. Sheppard; Tetrahedron, 1965,
21, 3209.
R. Ottinger, G. Boulvin, J. Reisse and G. Chiurdoglu; Tetrahedron, 1965,21,3435.
R. Fusco, S. Rossi and S. Miaorana; Tetrahedron Lell., 1965, 1965.
G. Bianchetti, P. Dalla Croce and D. Pocar; Tetrahedron lell., [965,2039.
B. Shimizu and M. Miyaki; Tetrahedron Lell., 1965, 2059.
A. Takamizawa, S. Hayashi and H. Sato; Yakugaku Zasshi, 1965,85, 158.
J. Schmidt and H. Gehlen; Z. Chern., 1965,5,304.
C. F. Kröger and W. Freiberg; Z. Chern., 1965,5,381.
A. Hetzheim and K. Mockel; Adv. Heterocycl. Chern., 1966,7, 183.
G. Spiteller; Adv. Heterocycl. Chern., 1966,7,301.
G. Zinner, R. Moll and B. Boehlke; Arch. Pharrn., 1966,299,441.
H. Ringertz; Acta Crystallogr., 1966,20,397.
R. J. Rousseau, L. B. Townsend and R. K. Robins; Biochemistry, 1966,5,756.
G. B. Chheda and R. H. Hall; Biochemistry, 1966,5,2082.
M. D. Litwack and B. Weissman; Biochemistry, 1966,5,3007.
A. Giner-Sorolla, S. O'Bryant, J. H. Burchenal and A. Bendich; Biochemistry,
1966,5,3057.
J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1966,610.
J. Eiguero, G. Guiraud and R. Jacquier; Bull. Soc. Chirn. Fr., 1966,619.
J. Elguero, G. Guiraud, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1966,
775.
J. Eiguero, A. Fruchier and R. Jacquier; Bull. Soc. Chirn. Fr., 1966,2075.
L. Petit and P. Touratier; Bull. Soc. Chirn. Fr., 1966,2529.
J. E[guero and R. Jacquier; Bull. Soc. Chirn. Fr., 1966,2832.
J. Elguero, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1966,2990.
J. Eiguero, A. Fruchier and R. Jacquier; Bull. Soc. Chirn. Fr., 1966, 3041.
E. J. Vincent, R. Phan-Tan-Luu, J. Metzger and J. M. Surzur; Bull. Soc. Chirn.
Fr., 1966,3524 (Chern. Abstr., 1967,66,64912).
J. E1guero, R. Jacquier and H. C. N. Tieu Duc; Bull. Soc. Chirn. Fr., 1966,3727.
J. E1guero, R. Jacquier and H. C. N. Tien Duc; Bull. Soc. Chirn. Fr., 1966,3744.
J. Seyden-Penne, L. T. Minh and P. Chabrier; Bull. Soc. Chirn. Fr., [966,3934.
D. Martin and A. Weise; Chern. Ber., 1966,99,317.
R. Huisgen, G. Szeimies and L. Möbius; Chern. Ber., [966,99,475.
H. Gnichtel and H. J. Schönherr; Chern. Ber., 1966,99,618.
I. Hagedorn and H.-D. Winkelmann; Chern. Ber., 1966,99,850.
H. Bredereck, P. Schellenberg, R. Nast, H. Heise and O. Christmann; Chern.
Ber., 1966, 99, 944.
J. Goerde1er and G. Gnad; Chern. Ber., 1966,99, 1618.
927
738
303
33
601
169,300
786
773
643
512
879
714
530, 552
216
742
742
748
739
9
701
9
802
548
601
319,329
169
556
199,255
231
231
186
647
231
264
212
15, 17
231
198
559
686
703, 705, 711
274
821
532
695
928
66CB2237
66CB2512
66CB2593
66CB2918
66CB2955
66CB3734
66CC352
66CHEI34
66CHE413
66CI(L)600
66CPB506
66CPB523
66DOK( 170)354
66FES811
66G I 084
66GEPI208303
66HC(21-1)67
66HC A272
66IJCI46
66IJC403
66JAI074
66JA2077
66JA2614
66JA3829
66JA3963
66JA4271
66JA4759
66JAP6610114
66JBC(241)1091
66JCP(44)759
66JCS(B)285
66JCS(B)427
66JCS(B)433
66JCS(B)438
66JCS(C)10
66JCS(C)80
66JCS(C)921
66JCS(C) I 127
66JCS(C)2038
66JCS(C)2290
66JHC27
66JHCl58
66JHC241
66JHC435
66JMC29
66JMC38
66JMCI05
66JMCI60
66JMC354
66JMC373
66JMC405
66JMC493
66JMC545
66JMC733
66JMC868
66JOC59
66JOC251
66JOC260
A. Kreutzberger; Chern. Ber., 1966,99,2237. 862,891
L. Birkofer and P. Wegner; Chern. Ber., 1966,99,2512. 698,710,831
T. Kauffmann, K. Vogt, S. Barck and J. Schulz; Chern. Ber., 1966,99,2593. 882
M. Regitz; Chern. Ber., 1966,99,2918. 887
H. A. Staab and G. Malek; Chern. Ber., 1966,99,2955. 749
A. Spassov, E. Golovinsky and C. Demirov; Chern. Ber., 1966,99,3734. 766
J. E. Baldwin, J. A. Kapecki, M. G. Newton and I. C. Paul; Chern. Comrnun.,
1966, 352.
R. G. Glushkov and O. Y. Magidson; Chern. Heterocycl. Cornpd. (Engl. Transl.),
1966, 2, 134 (Chern. Abstr., 1966, 65, 5460).
V. I. Minkin, S. F. Pozharskii and Yu. A. Ostroumov; Chern. Heterocycl. Cornpd.
(Engl. Trans/.), 1966,2,413. 172,173,177
A. J. Easleal and M. G. Ruthven; Chern. Ind. (London), 1966,600. 752
T. Okamoto, M. Hirobe, Y. Tarnai and E. Yabe; Chern. Pharrn. Bull., 1966, 14,506. 884
T. Okamoto, M. Hirobe and E. Yabe; Chern. Pharrn. Bull., 1966, 14,523. 864
R. A. Stukan, V. I. Gol'danskii, E. F. Makarov, B. V. Borshagovskii, N. S.
Kochetkova, M. I. Rybinskaya and A. N. Nesmeyanov; Dok/. Akad. Nauk
SSSR, 1966, 170,354.
G. Palamidessi and F. Luini; Farmaco Ed. Scl., 1966,21,811 (Chern. Abstr., 1967,
66, 37886).
R. Fusco, F. D'Alo and A. Masserini; Gazz. Chlrn. Ital., 1966,96, 1084.
F. Huebenett and H. Heinze; Ger. Pat. I 208303 (1966) (Chern. Abstr., 1966, 64,
8190).
D. S. Breslow and H. Skolnik; Chern. Heterocycl. Cornpd., 1966,21-1,67.
J. Büchi, P. Fabiani, H. U. Frey, A. Hofstetter and A. Schomo; Helv. Chirn.
Acta, 1966,49,272-
B. D. Mehrotra, P. C. Jain and N. Anand; Indian J. Chern., 1966,4, 146.
P. C. Jain, S. K. Chatterjee and N. Anand; Indian 1 Chern., 1966,4,403.
J. P. Ferris and L. E. Orgel; J. Am. Chern. Soc., 1966,88, 1074.
J. A. Happe and M. Morales; J. Am. Chern. Soc., 1966,88, '2077.
R. H. Hall, M. J. Robins, L. Stasiuk and R. Thedford; 1 Am. Chern. Soc., 1966,
88,2614.
J. P. Ferris and L. E. Orgel; J. Am. Chern. Soc., 1966,88,3829.
R. J. Crawford and A. Mishra; J. Am. Chern. Soc., 1966,88,3963.
W. J. Musliner and J. W. Gates, Jr.; J. Am. Chern. Soc., 1966,88,4271.
P. Scheiner; J. Am. Chern. Soc., 1966,88,4759.
T. Saito, I. Kumashiro and T. Takenishi; Jpn. Pat. 66 10 144 (1966) (Chern. Abstr.,
1966, 65, 13 737).
J. R. Fiorini, H. H. Bird and P. H. Bell; J. BioI. Chern., 1966,241, 1091.
M. J. S. Dewar and G. J. Gleicher; J. Chern. Phys., 1966,44,759.
G. B. Barlin; J. Chern. Soc. (B), 1966,285.
A. Albert; J. Chern. Soc. (B), 1966,427.
J. W. Bunting and D. D. Perrin; J. Chern. Soc. (B), 1966,433.
A. Albert; J. Chern. Soc. (B), 1966,438.
F. Bergmann, Z. Neiman and M. Kleiner; J. Chern. Soc. (C), 1966, 10.
R. K. Smalley; 1 Chern. Soc. (C), 1966,80.
G. Shaw, B. M. Smallwood and D. V. Wilson; J. Chern. Soc. (C), 1966,921.
M. W. Partridge and M. F. G. Stevens; J. Chern. Soc. (C), 1966, 1127.
S. E. Mallett and F. L. Rose; 1 Chern. Soc. (C), 1966, '2038.
G. Tennant; J. Chern. Soc. (C), 1966,2290.
C. K. Bradsher and D. F. Lohr, Jr.; J. Heterocycl. Chern., 1966,3,27.
G. S. Sidhu, S. Naqui and D. S. Iyengar; J. Heterocycl. Chern., 1966,3, 158.
References
703
661
690,731
645
753. 756
57
127
295
617,619
615,617,635
570
516
601
569, 584
255
821
711,724
569
603
671, 796, 803
620,621,622,640
856, 875, 876
513
875
558, 576, 577
641
595, 601
307, 330
896, 897
876, 895
121
853, 865,
866, 886
L. B. Townsend and R. K. Robins; J. Heterocycl. Chern., 1966,3,241. 511
H. Rutner and P. E. Spoerri; J. Heterocycl. Chern., 1966,3,435. 854,856,857,903
L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli, A. Gamba, A. Olivi
and W. Murmann; J. Med. Chern., 1966,9,29. 647
G. Palazzo, G. Corsi, L. Baiocchi and B. Silvestrini; J. Med. Chern.. 1966,9,38. 294
J. A. Montgomery and K. Hewson; J. Med. Chern., 1966,9, 105. 619,621,622,640
A. J. Dietz, Jr. and R. M. Burgison; J. Med. Chern., 1966,9, 160. 577
J. A. Montgomery and K. Hewson; J. Med. Chern., 1966,9,354. 615,618,636
A. G. Beaman, W. Tautz, R. Duschinsky and E. Grunberg; J. Med. Chern., 1966,
9.373.
H. A. Burch and W. O. Smith; J. Med. Chern., 1966,9,405.
M. J. Komet; J. Med. Chern., 1966,9,493.
A. H. M. Raeymaekers, F. T. N. Allewijn, J. Vandenberk, P. J. A. Demoen, T.
T. T. Van Offenwert and P. A. J. Janssen; J. Med. Chern., 1966,9,545. 139
Y. F. Shealy and C. A. O'Dell; J. Med. Chern., 1966,9,733. 701,852
M. P. Mertes and N. R. Patel; J. Med. Chern., 1966,9,868. 645
P. E. Fanta and E. N. Walsh; J. Org. Chern., 1966,31,59. 155
K. T. Potts and H. R. Burton; J. Org. Chern., 1966, 31, 251. 863, 882, 883
K. T. Potts, H. R. Burton and J. Bhattacharyya; J. Org. Chern., 1966,31,260. 134,864,
884. 885
551
766
297
66JOC265
66JOC342
66JOC442
66JOC781
66JOC806
66JOC809
66JOC935
66JOC966
66JOC 1295
66JOC1413
66JOC1417
66JOC1587
66JOCI890
66JOC2202
66JOC2210
66JOC2380
66JOC2685
66JOC2867
66J OC3182
66JOC3258
66JOC3522
66JOC3914
66JOC3924
66JOC4239
66JPC3688
66JPR(305)54
66JPR(305) 199
66KGS143
66LA(691)142
66LA(691)212
66LA(692)134
66LA(693)233
66LA(695)77
66LA(698)145
66LA(698)174
66LA(699)112
66LA(699)127
66LA(699)145
B-66MI40900
66MI40901
66MI40902
66MI40903 ,
66MI40904
66MI40905
66MI41200
66MI41201
66NKK71
66PNA(56)52
66PNA(56)60
66RCR9
66RCR122
66RCRI22
66RTC429
66RTCI195
66RTCI254
66T835
E. C. Taylor and A. Abul-Husn; J. Org. Chern., 1966,31,342.
O. W. Maender and G. A. Russell; J. Org. Chern., 1966,31,442.
H. C. Brown, H. J. Gisler, Jr. and M. T. Cheng; J. Org. Chern., 1966,31,781.
E. F. Godefroi, C. A. M. Van der Eycken and P. A. J. Janssen; J. Org. Chern.,
1966,31, 806.
W. W. Paudler and J. E. Kuder; J. Org. Chern., 1966,31,809.
C. Temple, Jr., W. C. Coburn, M. C. Thorpe and J. A. Montgomery; J. Org.
Chern., 1966,31,935.
J. C. Parham, J. Fissekis and G. B. Brown; J. Org. Chern., 1966,31,966.
W. W. Paudler and H. L. Blewitt; J. Org. Chern., 1966,31, 1295.
H. J. Thomas and J. A. Montgomery; J. Org. Chern., 1966,31, 1413.
C. Temple, Jr. and J. A. Montgomery; 1. Org. Chern., 1966,31,1417.
G. R. Harvey; J. Org. Chern., 1966,31, 1587.
R. D. Elliott, C. Temple, Jr. and J. A. Montgomery; J. Org. Chern., 1966,31,1890.
J. A. Montgomery, K. Hewson, S. J. Clayton and H. J. Thomas; J. Org. Chern.,
1966,31,2202. 511,531,532
C. Temple, Jr., C. L. Kussner andJ. A. Montgomery; J. Org. Chern., 1966,31,2210. 511, 564
F. B. Stocker, M. W. Fordice, J. K. Larson and J. H. Thorstenson; J. Org. Chern.,
1966, 31, 2380.
N. Nagasawa, I. Kumashiro and T. Takenishi; J. Org. Chern., 1966,31,2685.
L. A. Carpino, P. H. Terry and S. D. Thatte; J. Org. Chern., 1966,31,2867.
R. N. Butler and F. L. Scott; J. Org. Chern., 1966,31,3182.
J. F. Gerster and R. K. Robins; 1. Org. Chern., 1966,31,3258.
K. T. Potts, H. R. Burton, T. H. Crawford and S. W. Thomas; J. Org. Chern.,
1966, 31, 3522.
T. Sasaki and K. Minamoto; J. Org. Chern., 1966,31,3914.
H. W. Heine, R. Peavy and A. J. Durbetaki; J. Org. Chern., 1966,31,3924.
A. Giner-Sorolla and A. Bendich; J. Org. Chern., 1966,31,4239.
T. C. Wehman and A. I. Popov; J. Phys. Chern., 1966,70,3688.
W. König, M. Coenen, F. Bahr, B. May and A. Bassi; J. Prakt. Chern., 1966,305,
54.
G. Rembarz, B. Kirchhoff and G. Dangowski; J. Prakt. Chern., 1966,305, 199.
L. M. Sitkina and A. M. Simonov; Khirn. Geterotsikl. Soedin., 1966, 143 (Chern.
Abstr., 1966, 65, 88 955).
H. Goldner, G. Dietz and E. Carstens; Liebigs Ann. Chern., 1966,691, 142.
Th. Weiland and W. Kahle; Liebigs Ann. Chern., 1966,691,212.
H. Goldner, G. Dietz and E. Carstens; Liebigs Ann. Chern., 1966,692, 134.
H. Goldner, G. Dietz and E. Carstens; Liebigs Ann. Chern., 1966,693,233.
W. Walter, J. Voss and J. Curts, Liebigs Ann. Chern., 1966,695,77.
H. Goldner, G. Dietz and E. Carstens; Liebigs Ann. Chern., 1966,698, 145.
R. Feinauer and W. Seeliger; Liebigs Ann. Chern., 1966, 698, 174.
T. Pyl and W. Baufeld; Liebigs Ann. Chern., 1966,699, 112.
T. Pyl and W. Baufeld; Liebigs Ann. Chern., 1966,699, 127.
H. Goldner, G. Dietz and E. Carstens; Liebigs Ann. Chern., 1966,699, 145.
J. A. Stock; in 'Experimental Chemotherapy', Academic, London, 1966, vol.4.
A. Giner-Sorolla; Galenica Acta, 1966, 19,97.
J. J. Fox, K. A. Watanabe and A. Bloch; Prog. Nucleic Acid Res. Mol. Bioi., 1966,
5, 251.
Y. Fujimoto and N. Ono; J. Pharrn. Soc. Jpn., 1966,86,364.
J. S. Shannon and D. S. Letham; N.Z. J. Sci., 1966,9, 833.
A. Vincze and S. Cohen; Isr. J. Chern., 1966,4,23.
H. G. O. Becker, H. Boettcher, T. Roethling and H. J. Timpe; Wiss. Z. Tech.
Hochsch. Chern. Leuna-Merseburg, 1966,8,22 (Chern. Abstr., 1966,64,9596).
I. Ya. Postovskii and I. L. Shegal; Khirn. Geterotsikl. Soedin. Akad. Nauk Law.
SSR, 1966,443 (Chern. Abstr., 1966,65,16960).
A. Tatematsu, T. Goto and S. Matsuura; Nippon Kagaku Zasshi, 1966,87,71.
D. Klambt, G. Thies and F. Skoog; Proc. Nat. Acad. Sci. USA, 1966,56,52.
J. P. Helgeson and N. J. Leonard; Proc. Nat. A cad. Sci. USA, 1966,56,60.
Yu. A. Naumov and I. I. Grandberg; Russ. Chern. Rev. (Engl. Transl.), 1966,35,
9.
A. F. Pozharskii, A. D. Garnovskii and A. M. Simonov; Russ. Chern. Rev. (Engl.
Transl.), 1966,35, 122. 346,351,356,367,389,392,405,410,413
A. F. Pozharskii, A. D. Garnovskii and A. M. Simonov; Russ. Chern. Rev. (Engl.
Transl.), 1966,35,122. 467,469,470,472,480,481,490,491
B. G. Van den Bos, A. Schipperheyn and F. W. Deursen; Reel. Trav. Chirn.
Pays-Bas, 1966,85,429.
C. L. Habraken, E. C. Westra, G. H. Bomhoff and R. A. Heytink; Recl. Trav.
Chirn. Pays-Bas, 1966, 85, 1195.
G. E. Trout and P. R. Levy; Recl. Trav. Chirn. Pays-Bas, 1966,85, 1254.
W. Adam and A. Grimison; Tetrahedron, 1966,22,835.
References
K. T. Potts, H. R. Burton and S. K. Roy; J. Org. Chern., 1966,31,265.
929
853, 861, 862,
863
322
800
772
661
627
511,565
595
610
552
511,566,579
716
636
641
532, 534
250, 327
818,819
552, 562
853, 854
719
780
549
814
719
704
390
555, 580,
581,596
786
591
554, 555, 596
560
580, 596
155
627
627
596
604
556, 564
603
593
519
529
748
754
519
601
601
169,255
751
260
588
347
930
66T2073
66T2[ 19
66T2453
66T246 I
66T(S7)213
66TL2627
66TL3445
66TL4043
66TL4387
66TL5369
66TL6043
66Z0B816
66ZPC(51)297
67 ACS633
67 AG786
67AG98t
67AG(E)258
67 AG(E)261
67AG(E)633
67AHC(8)1
67 AHC(8)143
67 AHC(8)277
67AJC713
67AJCI779
67AJC[991
67APIOOO
67AX135
67AX308
67BSF289
67BSFI833
67BSF2619
67BSF2630
67BSF2998
67BSF3502
67BSF3516
67BSF4716
67C226
67CB71
67CBI073
67CBI646
67CB2064
67CB2250
67CB2280
67CB2494
67CB2577
67CB3418
67CB3467
67CB3485
67CB3736
67CC488
67CC918
67CCI01 t
67CCC2155
67CJC697
67CJC953
67CJCI727
67CPB909
67CPB[066
67CR(C){265)1507
67EGP59288
67FES82[
References
A. Pollak and M. Tis1er; Tetrahedron, 1966,22,2073.
R. A. Olofson, J. M. Landesburg, R. O. Berry, D. Leaver, W. A. H. Robertson
and D. M. McKinnon; Tetrahedron, 1966,22, 2[ 19.
P. K. Kadaba; Tetrahedron, 1966,22, 2453.
P. Bouchet, J. Eiguero and R. Jacqukr; Tetrahedron, ,1966, 22, 2461.
A. A. Gordon, A. R. Katritzky and F. D. Popp; Tetrahedron, 1966,22, Suppl. 7,
213.
B. M. Lynch and H. J. M. Dou; Tetrahedron Lett., 1966, 2627.
Y. Kishi, T. Goto, S. Inoue, S. Sugiura and H. Kishimoto; Tetrahedron Lett.,
1966, 3445.
C. H. Krauch, J. Kuhls and H.-J. Piek; Tetrahedron Leu., 1966,4043.
R. M. Carman, D. J. Brecknell and H. C. Deeth; Tetrahedron Lett., 1966,4387.
H. H. Takimoto and G. C. Denault; Tetrahedron Lett., 1966,5369.
S. Maiorana, D. Pocar and P. D. Croce; Tetrahedron Lett., 1966, 6043.
E. Ebed, E. S. Chaman and E. S. Go1ovchinskaya; Zh. Obshch. Khirn., 1966,36,
816.
H. Schmid and P. Krenmayr; Hoppe-Seyler's Z. Physiol. Chern., 1966,51,297.
M. M. Begtrup and C. Pedersen; Acta Chern. Scand., [967. 21, 633.
M. Regitz; Angew. Chern., 1967,79,786.
H. Dorn and A. Zubek; Angew. Chern., 1967,6,981.
W. Pfleiderer and F. E. Kempter; Angew. Chern., Int. Ed. Engl., [967,6,258.
A. Messmer and A. Gelléri; Angew. Chern., Int. Ed. Engl., 1967,6,261.
Th. Kauffmann, J. Albrecht, D. Berger and J. Legler; Angew. Chern., Int. Ed.
Engl., 1967,6,633.
J. M. Tedder; Adv. Heterocycl. Chern., 1967,8, I.
B. S. Thyagarajan; Adv. Heterocycl. Chern., 1967,8, 143.
K.-H. Wunsch and A. J. Boulton; Adv. Heterocycl. Chern., 1967,8,277.
888,889
23
717
185,207
739, 740
183
643
160
697, 705
744
715
550
51 [
706
670
272
580
[34
768
96, 44[
102
64,71,74,
85,91,93, [08
N. A. Evans, R. B. Johns and K. R. Markham; Aust. J. Chern., [967,20,713. 852
G. W. Evans and B. Milligan; Aust. J. Chern., [967,20, 1779. 743
F. H. C. Stewart; Aust. J. Chern., 1967,20, 1991. [37
R. Brandes and H. J. Roth; Arch Pharrn. (Weinheirn, Ger.), 1967,300,1000. 552
C. W. Reimann, A. D. Mighell and F. A. Mauer; Acta Crystallogr., 1967,23, 135. 227
K. C. Britts and I. L. Karle; Acta Crystallogr., 1967,22,308. 796
L. Bardou, J. E1guero and R. Jacquier; Bull. Soc. Chirn. Fr., 1967,289. 23[
H. Lumbroso, C. Pigenet, R. Nasie1ski-Hinskens and R. Promel; Bull. Soc. Chirn.
Fr., 1967, 1833. 522
J. Eiguero, A. Fruchier and R. Jacquier; Bull. Soc. Chirn. Fr., 1967,2619. [99,224,232
R. Jacquier, M. L. Roumestant and P. Viallefont; Bull. Soc. Chirn. Fr., 1967,
2630.
J. Eiguero, E. Gonzales and R. Jacquier; Bull. Soc. Chirn. Fr., [967,2998.
P. Bouchet, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1967,3502.
741
678, 679
185,199,
200,207
J. L. Aubagnac, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1967,3516. 188,199
P. Bouchet, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., [967,4716. 255
K. Biemann and P. V. Fennessey; Chirnia, 1967,21,226. 519
R. Huisgen and V. Weberndörfer; Chern. Ber., 1967,100,71. 721
W. Köhler, M. Bubner and G. Ulbricht; Chern. Ber., 1967, 100, 1073. 857,902
H. Sieper; Chern. Ber., 1967, 100, 1646. 887
J. Goerdeler and R. Sappelt; Chern. Ber., 1967, 100,2064. 667
C. F. Kröger and R. Miethchen; Chern. Ber., 100, 2250. 752,753, 754, 756, 757
H. Bredereck, F. Effenberger and H. G. Osterlin; Chern. Ber., [967, 100,2280. 575,576
R. Huisgen, G. Szeimies and L. Möbius; Chern. Ber., 1967, 100,2494. 708
A. Dornow and K. Dehmer; Chern. Ber., 1967,100,2577. 272
A. Hetzheim, O. Peters and H. Beyer; Chern. Ber., 1967,100,3418 492
T. Sasaki and K. Minamoto; Chern. Ber., 1967, 100,3467. 899,903
L. Birkofer and P. Wegner; Chern. Ber., 1967, 100,3485. 679,698,699
D. Martin and A. Weise; Chern. Ber., 1967, 100, 3736. 157
S. N. Ege; Chern. Cornrnun., [967,488. 220,22[
P. D. Callaghan and M. S. Gibson; Chern. Cornrnun., [967,918. 704
F. McCapra and Y. C. Chang; Chern. Cornrnun., 1967, IO[ I. 642
F. M. Stojanovic and Z. Arnold; Collect. Czech. Chern. Cornrnun., 1967,32,2[55. 706
E. B. Dennler and A. R. Frasca; Can. J. Chern., 1967,45,697. 276
J. W. Lown and J. C. N. Ma; Can. J. Chern., 1967,45,953. 663
J. H. Looker and J. W. Carpenter; Can. J. Chern., 1967,45, 1727. 706
M. Saneyoshi and G. Chihara; Chern. Pharrn. Bull., [967, 15,909. 559
B. Shimizu and M. Miyaki; Chern. Pharrn. Bull., 1967, IS, 1066. 552
J. Eiguero and R. Wolf; c.R. Hebd. Seances Acad. Sci., Ser. C, 1967,265, 1507. 236
H. G. O. Becker, V. Eisenschmidt and K. Wehner; Ger. (East) Pat. 59288 (1967)
(Chern. Abstr., 1969, 70, 28 922).
T. Vitali, F. Mossini and G. Bertaccini; Farrnaco Ed. Sci., 1967,22, 82[ (Chern.
Abstr., 1968, 68, 87 234).
753
641
67GI09
67G289
67G304
67GI411
67HC(22)1
67HCA2244
67IJC403
67JA81
67JA2618
67JA2633
67JA2719
67JA4760
67JA5958
67JA5959
67JA5977
67JA6463
67JA6835
67JCS(B)410
67 JCS(B)516
67JCS(B)583
67JCS(B)64I
67JCS(B)954
67 JCS(C)33
67JCS(C)239
67JCS(C)503
67 JCS(C)952
67 JCS(C) 1254
67JCS(C)2005
67JHC66
67JHC301
67JHC555
67JMCI04
67JMCI09
67JMCI30
67JMCI49
67JOCI151
67JOCI825
67JOCI871
67 JOC2022
67JOC2245
67JOC2252
67 JOC2430
67JOC2823
67JOC2956
67JOC3032
67JOC3258
67 JOC3580
67JOC3856
67JPC2375
67 JPR(308)82
67KGSI096
67 LA(707) 147
67LA(71O)118
67MI40400
67MI40401
67MI40402
B-67MI40900
67MI40901
P. Ferruti, D. Pocar and G. Bianchetti; Gazz. Chirn. Ital., 1967,97, 109.
G. Bianchetti, P. D. Croce, D. Po car and A. Vigevani; Gazz. Chirn. Ital., 1967,
97, 289.
G. Bianchetti, D. Po car, P. D. Croce and R. Stradi; Gazz. Chirn. Ital., 1967,97,
304.
G. Gaudiano, C. Ticozzi, A. Umani-Ronchi and P. Bravo; Gazz. Chirn. Ital.,
1967,97, 1411. 718
L. C. Behr, R. Fusco and C. H. Jarboe; Chern. Heterocycl. Cornpd., 1967,22, 1. 168,
171,199, 206,222,229,230,233,238,239,242,253,254,255,256,258,
259,260,261,262,265,266,268,273,274,275,277,281,282,286
H. Tiefenthaler, W. Dörscheln, H. Göth and H. Schmid; Helv. Chirn. Acta, 1967,
50,2244. 46,161,219,220,221
M. D. Nair and S. R. Mehta; Indian J. Chern., 1967,5,403. 888,902
J. E. Anderson and J. M. Lehn; J. Am. Chern. Soc., 1967, 89, 81. 189
R. A. Carboni, J. C. Kauer, J. E. Castle and H. E. Simmons; J. Am. Chern. Soc.,
1967,89,2618.
J. C. Kauer and R. A. Carboni; J. Am. Chern. Soc., 1967,89,2633.
J. M. Rice and G:O. Dudek; J. Am. Chern. Soc., 1967,89,2719.
M. E. Hermes and F. D. Marsh; J. Am. Chern. Soc., 1967,89,4760.
R. M. Moriarty,J. M. Kleigman and C. Shovlin; J. Am. Chern. Soc., 1967,89,5958.
R. M. Moriarty,J. M. Kleigman and C. Shovlin; J. Am. Chern. Soc., 1967,89,5959.
W. E. Thiessen and H. Hope; 1. Am. Chern. Soc., 1967,89,5977.
N. C. Baenziger, A. D. Nelson, A. Tulinsky, J. H. Bloor and A. I. Popov; J. Am.
Chern. Soc., 1967,89,6463. 796
J. E. Bloor and D. L. Breen; J. Am. Chern. Soc., 1967,89,6835. 19,795
T. C. Chou, H. H. Un and R. Varma; J. Chern. Soc. (B), 1967,410. 522
G. B. Barlin and T. J. Batterham; J. Chern. Soc. (B), 1967,516. 678,741,742,799,800
D. J. Blythin and E. S. Waight; J. Chern. Soc. (B), 1967,583. 204
G. B. Barlin; J. Chern. Soc., (B), 1967,641. 739,753,756,806
G. B. Barlin; J. Chern. Soc. (B), 1967,954. 524,561
B. C. Ennis, G. Holan and E. L. Samuel; J. Chern. Soc. (C), 1967,33. 765
R. N. Butler and F. L. Scott; J. Chern. Soc. (C), 1967,239. 815
R. G. W. Spickett and S. H. B. Wright; J. Chern. Soc. (C), 1967,503. 891
G. J. Durant; J. Chern. Soc. (C), 1967,952. 779
F. Bergman, M. Rashi, M. Kleiner and R. Knafo; J. Chern. Soc. (C), 1967, 1254. 576
A. J. Boulton, A. R. Katritzky and A. Majid Hamid; J. Chern. Soc. (C), 1967,2005. 720
C. K. Bradsher and M. F. Zinn; J. Heterocycl. Chern., 1967, 4, 66. 117
P. K. Kadaba and N. F. Fannin; J. Heterocycl. Chern., 1967,4,301. 717
H. Murakami and R. N. Castle; J. Heterocycl. Chern., 1967,4,555. 628,651,871,890
C. P. Bryant and R. E. Harmon; J. Med. Chern., 1967, 10, 104. 536
S. C. J. Fu, B. J. Hargis, E. Chinoporos and S. Malkiel; J. Med. Chern., 1967,
10,109.
E. J. Reist, D. F. Calkins and L. Goodman; J. Med. Chern., 1967,10, 130.
G. F. Holland and J. N. Pereira; J. Med. Chern., 1967, 10, 149.
J. C. Parham, J. Fissekis and G. B. Brown; J. Org. Chern., 1967,32,1151.
A. Yamazaki, I. Kumashiro and T. Takenishi; J. Org. Chern., 1967,32, 1825.
H. C. Brown and R. J. Kassal; J. Org. Chern., 1967,32, 1871.
P. Scheiner; J. Org. Chern., 1967,32,2022.
K. T. Potts, S. K. Roy and D. P. Jones; J. Org. Chern., 1967,32,2245.
I. Bhatnagar and M. V. George; J. Org. Chern., 1967,32,2252.
W. W. Paudler and J. E. Kuder; J. Org. Chern., 1967,32,2430.
L. M. Weinstock, P. Davis, B. Handelsman and R. TuB; J. Org. Chern., 1967,
32, 2823.
J. K. Elwood and J. W. Gates, Jr.; J. Org. Chern., 1967,32,2956.
A. Yamazaki, I. Kumashiro and T. Takenishi; J. Org. Chern., 1967,32,3032.
A. Yamazaki, I. Kumashiro and T. Takenishi; J. Org. Chern., 1967,32,3258.
J. C. Kauer and W. A. Sheppard; J. Org. Chern., 1967,32,3580.
Y. Rahamim, J. Sharvit, A. Mandelbaum and M. Sprecher; J. Org. Chern., 1967,
32, 3856.
A. D. Mighell and C. W. Reimann; J. Phys. Chern., 1967,71,2375.
G. Hauptmann and K. Hirschberg; J. Prakt. Chern., 1967,308,82.
N. N. Vereshchagina, I. Y. Postovskii and S. L. Mertsalov; Khirn. Geterotsikl.
Soedin., 1967, 1096. 881
H. Hoberg; Liebigs Ann. Chern., 1967,707,147. 698,717
M. Regitz and A. Liedhegener; Liebigs Ann. Chern., 1967,710,118. 695
R. D. Brown and B. A. W. Coller; Theor. Chirn. Acta, 1967,7,259. 172,176,177
W. Adam and A. Grimison; Theor. Chirn. Acta, 1967,7,342. 172,177,183
J. L. Aubagnac, P. Bouchet, J. Elguero, R. Jacquier and C. Marzin; J. Chirn.
Phys. Phys. Chirn. Bioi., 1967,64, 1649.
R. K. Robins; in 'Heterocyclic Compounds', ed. R. C. Elderfield; Wiley, New
York, 1967.
R. A. Sanchez, J. P. Ferris and L. E. Orgel; J. Mol. BioI., 1967,30,223.
References
931
700,714
714
704,714
163,723
898
519
692, 709
159,801
159
12
575
539
819,835
595
590
780
714,724
743, 748
707
614
127
813
590
558, 584,
587,588
794,812
519
179
717
188
501
569
932
67MI40902
67MI4[000
67MI41001
67MI41100
B-67MI4[ 101
B-67MI41200
B-67MI41300
67MI41301
67MIP41000
67NEP6614979
67PNA(57)75I
67PNA(58)I279
67RTCI249
67T239
67T387
67T479
67T1297
67T25 13
67T2739
67T2855
67TLl3I7
67TL2029
67TL2I09
67TL3295
67TL4261
67TL4379
67TL5315
67USP3326889
67USP3338915
67USP3341549
67ZCI84
67Z0R968
67Z0RI540
68ACS 1655
68AG329
68AG(E)321
68AHC(9) [07
68AHC(9)165
68AP911
68B372 1
68BBR(33)436
68BRP[ 112128
68BSF707
68BSF3866
68BSF4222
68BSF4403
68BSF5009
68RSF5019
68CB536
68CB611
68CB743
68CB829
68CB[979
68CB2[06
R. H. Hall, L. Csonka, H. David and B. McLennan; Science, [967,156,69.
V. G. Granik and R. G. Glushkov; Khirn.-Farrn. Zh., 1967, I, 16 (Chern. Abstr.,
1968, 68, 68 955).
S. Takase, T. Demura and K. Tabata; Kogyo Kagaku Zasshi, [967, 70, 1826
(Chern. Abstr., 1968, 68, 114498).
H. Krieger and M. Sodervall; Suornen Kern., [967,408,294 (Chern. Abstr., 1968,
68,77841).
B. P. Stark and A. J. Duke; in 'Extrusion Reactions', Pergamon Press, Oxford,
[967, pp. 135,327. 670,704,724
A. R. Katritzky and J. M. Lagowski; 'The Principles of Heterocyclic Chemistry',
Academic, New York, 1968.
F. R. Benson; 'Heterocyclic Compounds', ed. R. C. Elderfie[d; Wiley, New York,
1967, vol. 8, p. I. 792,798,805,807,8[7,818,819,820,821,822,823,828,829,
830, 832, 833, 836, 837
803
W. Woznicki and B. Zurawski; Acta Phys. Polonica, 1967,31,95.
V. G. Granik and R. G. Glushkov; USSR Pat. [96876 (1967) (Chern. Abstr.,
1968, 68, 95 859).
J. R. Geigy A. G., Neth. Pat. 66 14979 (1967) (Chern. Abstr., 1968,68,69003).
U. L. RajBhandary, S. H. Chang, A. Stuart, R. D. Fau[kner, R. M. Hoskinson
and H. G. Khorana; Proc. Nat. Acad. Sci. USA, 1967,57,751.
C. Alexander, Jr. and W. Gordy; Proc. Natl. Acad. Sci. USA, 1967,58, 1279.
P. Cohen-Fernandes and C. L. Habraken; RecI. Trav. Chirn. Pays-Bas, [967,86,
1249. 199
R. Mechoulam and A. Hirshfeld; Tetrahedron, 1967,23,239. 649,650
B. Stanovnik and M. Tisler; Tetrahedron, 1967,23,387. 628,650
D. S. Letham, J. S. Shannon and I. R. C. McDona[d; Tetrahedron, 1967,23,479. 60[
K. L. Nagpal and M. M. Dhar; Tetrahedron, 1967,23, 1297. 648
W. Adam, A. Grimison and G. Rodríguez; Tetrahedron, 1967,23,2513. 172,183,190,347
B. Stanovnik and M. Tisler; Tetrahedron, 1967,23,2739. 628,650
G. Yagil; Tetrahedron, 1967,23,2855. 225
K. Koshimizu, T. Kusaki, T. Mitsui and S. Matsubara; Tetrahedron Left., 1967,
1317.
M. E. C. Biffin, D. J. Brown and Q. N. Porter; Tetrahedron Left., 1967,2029.
W. Freiberg, C. F. Kröger and R. Radeglia; Tetrahedron Left., 1967,2109.
S. Hauptmann, H. Wilde and K. Moser; Tetrahedron Left., 1967,3295.
H. Kato, S. Sato and M. Ohta; Tetrahedron Left., 1967,4261.
W. D. Crow and C. Wentrup; Tetrahedron Left., 1967,4379.
P. Beak, J. L. Miesel and W. R. Messer; Tetrahedron Left., [967,5315.
H. A. Brown; U.S. Pat. 3326889 (1967) (Chern. Abstr., 1967,67,64407).
M. Brown; U.S. Pat. 3338915 (1967) (Chern. Abstr., 1968,68,87299).
U.S. Pat. 3341549 (1967) (Chern. Abstr., 1968,68, [05195).
R. Miethchen and C. F. Kröger; Z. Chern., 1967,7, 184.
G. S. Akimova, V. N. Chistokletov and A. A. Petrov; Zh. Org. Khirn., 1967,3,
968 (Chern. Abstr., 1967, 67, 100 071).
R. A. Khmel'nitskii, A. P. Krasnoshchek, A. A. Polyakova and I. I. Grandberg;
Zh. Org. Khirn., 1967,3, [540.
References
60[
624,643
635
725
735
624,643
904
605
520
60[
272
741
134, 706
47, 743
687, 726
220
778, 790
837
661
752, 756
710
202,204
LA. Carlsson and J. Sandström; Acta Chern. Scand., 1968,22, 1655. 177
R. Huisgen; Angew. Chern., 1968,80,329. 702
R. Huisgen; Angew. Chern., Int. Ed. Engl., 1968,7,321. 702
L. M. Weinstock and P. I. Pollak; Adv. HeterocycI. Chern., 1968,9, 107. 44,58,61,75,
86,92,95,97, 105, 127
J. Sandstrom; Adv. HeterocycI. Chern., 1968,9, 165. 59,92,93,94,95,97, 105
H. Gehlen and K. H. Uteg; Arch. Pharrn. (Weinheirn, Ger.), 1968,301,911. 754
F. E. Hruska, C. L Bell, T. A. Victor and S. S. Dany[uk; Biochemistry, 1968,7,
3721.
C. E. Bugg, U. T. Thewalt and R. E. Marsh; Biochern. Biophys. Res. Cornrnun.,
1968,33,436.
Br. Pat. 1112128 (1968) (Chern. Abstr., 1968,69,77 258).
J. E[guero, E. Gonzalez and R. Jacquier; Bul/. Soc. Chirn. Fr., 1968,707.
J. Elguero, R. Jacquier and D. Tizané; Bull. Soc. Chirn. Fr., 1968,3866.
M. Dormoy, J. Godin and A. LeBerre; Bull. Soc. Chirn. Fr., 1968,44,4222.
J. Eiguero, A. Fruchier and R. GiI; Bull. Soc. Chirn. Fr., 1968,4403.
J. Elguero, E. Gonzalez and R. Jacquier; Bul/. Soc. Chirn. Fr., 1968, 5009.
J. Eiguero, G. Guiraud, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1968,
5019.
R. Huisgen, H. Gotthardt and R. Grashey; Chern. Ber., 1968, 101,536.
A. Giner-Sorolla; Chern. Ber., 1968,101,611.
E. Ettenhuber and K. Rühlman; Chern. Ber., 1968, 101, 743.
R. Huisgen, R. Grashey and H. Gotthardt; Chern. Ber., 1968, 101,829.
J. Körösi and P. Berencsi; Chern. Ber., 1968,101, 1979.
W. Ried and J. Valentin; Chern. Ber., 1968, 101,2106.
5[ I
509
120
198, 223,
224, 231
188,250
341
189
195,223
23 [,232
717
548, 549, 593
779, 831
260
852
893
68CB2747
68CB3265
68CB3734
68CC200
68CC727
68CC977
68CCI002
68CCI026
68CCI337
68CHE322
68CJC2855
68CPB2011
68CPB2172
68CR(C)(267) 1461
68DOK(l81)1397
68FRPI525268
68G681
68G949
68IJC287
68IJC616
68JA988
68JAI884
68JAI923
68JA2131
68JA266I
68JA2970
68JA2979
68JA3543
68JA4232
68JA6588
68JCS(C)344
68JCS(C)824
68JCS(C)1268
68JCS(C) 1329
68JCS(C)1516
68JCS(C)1731
68JCS(C)1937
68JCS(C)2510
68JHCI3
68JHC29
68JHC35
68JHCI99
68JHC351
68JHC407
68JHC485
68JHC513
68JHC565
68JHC679
68JHC691
68JHC699
68JHC863
68JMC52
68JMC981
68JMCI164
68JOC530
68JOC642
172,173,174,175,198,199
M. Regitz, W. Anschütz and A. Liedhegener; Chern. Ber., 1968,101,3734. 712
Z. Neiman; Chern. Cornrnun., 1968,200. 540
P. R. Briggs, W. L. Parker and T. W. Shannon; Chern. Cornrnun., 1968,727. 741
T. S. Cantrell and W. S. Haller; Chern. Cornrnun., 1968,977. 694
Z. Neiman and F. Bergmann; Chern. Cornrnun., 1968, 1002. 512
D. W. Crow and C. Wentrup; Chern. Cornrnun., 1968, 1026. 687,726
B. M. Lynch; Chern. Cornrnun., 1968, 1337. 672
R. G. Glushkov and A. R. Todd; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1968,
4,322 (Chern. Abstr., 1968,69, 106668).
R. R. Fraser and K. E. Haque; Can. J. Chern., 1968,46,2855.
Y. Mizuno, S. Tazawa and K. Kageura; Chern. Pharrn. Bull., 1968,16,2011.
A. Yamazaki, I. Kumashiro, T. Takenishi and M. Ikehara; Chern. Ph arm. Bull.,
1968, 16, 2172.
B. Pullman, H. Berthod, E. D. Bergmann, F. Bergmann, Z. Neiman and H.
Weiler-Feilchenfeld; c.R. Hebd. Seances Acad. Sci., Ser. C, 1968,267, 1461.
A. N. Nesmeyanov, M. 1. Rybinskaya, N. S. Kochetkova, V. N. Babin and G.
B. Shul'pin; Dokl. Akad. Nauk SSSR, 1968,181,1397 (Chern. Abstr., 1968,69,
113 021).
W. L. Perilstein and H. A. Beatty; Fr. Pat. 1525268 (1968) (Chern. Abstr., 1969,
71, 30 588).
R. Scarpati, M. L. Grazioni and R. A. Nicolaus; Gazz. Chirn. Ital., 1968,98,681.
D. Pocar, S. Maiorana and P. D. Croce; Gazz. Chirn. Ital., 1968,98,949.
Y. R. Rao; Indian J. Chern., 1968,6,287.
P. C. Jain and N. Anand; Indian J. Chern., 1968,6,616.
P. Scheiner; J. Am. Chern. Soc., 1968,90,988.
G. A. OJah and A. M. White; J. Am. Chern. Soc., 1968,90, 1884.
E. M. Burgess, R. Carithers and L. McCullagh; J. Am. Chern. SQc., 1968,90,1923.
R. F. Bleiholder and H. Shechter; 1. Am. Chern. Soc., 1968, 90, 213 1.
R. J. Roussea, R. K. Robins and L. B. Townsend; 1. Am. Chern. Soc., 1968,90,
2661.
F. P. Boer, J. Flynn, E. T. Kaiser, O. R. Zaborsky, D. A. Tomalia, A. E. Young
and Y. C. Tong, J. Am. Chern. Soc., 1968, 90, 2970.
H. Linschitz and J. S. Connolly; J. Am. Chern. Soc., 1968,90,2979.
F. J. Weigert and J. D. Roberts; J. Am. Chern. Soc., 1968,90,3543.
R. J. Pugmire and D. M. Grant; J. Am. Chern. Soc., 1968,90,4232.
L. D. Hansen, B. D. West, E. J. Baca and C. L. Blank; J. Am. Chern. Soc., 1968,
90, 6588.
A. Albert and K. Tratt; J. Chern. Soc. (C), 1968,344.
E. J. Browne and J. B. Polya; J. Chern. Soc. (C), 824.
D. E. Burton, A. J. Lambie, D. W. J. Lane, G. T. Newbold and A. Percival; J.
Chern. Soc. (C), 1968, 1268.
H. EI Khadem, H. A. R. Mansour and M. H. Meshreki; J. Chern. Soc. (C), 1968,
1329. 685, 711
G. Shaw, B. M. Smallwood and D. V. Wilson; J. Chern. Soc. (C), 1968, 1516. 595
D. M. G. Martin and C. B. Reese; J. Chern. Soc. (C), 1968, 1731. 566
E. B. Mullock and H. Suschitzky; J. Chern. Soc. (C), 1968, 1937. 259
G. Dallas, J. W. Lown and J. C. N. Ma; 1. Chern. Soc. (C), 1968,2510. 663
N. R. Patel, W. M. Rich and R. N. Castle; J. Heterocycl. Chern., 1968,5, 13. 629,652
W. W. Paudler and R. J. Brumbaugh; J. Heterocycl. Chern., 1968,5,29. 863
J. G. Lombardino; J. Heterocycl. Chern., 1968,5,35. 628
M. D. Coburn and T. E. Jackson; J. Heterocycl. Chern., 1968,5, 199. 747
A. Kovacic, B. Stanovnik and M. Tisler; J. Heterocycl. Chern., 1968,5,351. 628
C. Wijnberger and C. L. Habraken; J. Heterocycl. Chern., 1968,5,407. 242
K. T. Potts and S. W. Schneller; J. Heterocycl. Chern., 1968,5,485. 856,862,877,896,
897, 898
889
832
577
872
References
T. Sasaki, K. Minamoto and S. Fukuda; Chern. Ber., 1968,101,2747.
H L. Finar; J. Chern. Soc. (B), 1968,725.
A. Pollak, B. Stanovnik and M. Tisler; J. Heterocycl. Chern., 1968,5,513.
J. E. Baldwin and S. Y. Hong; J. Heterocycl. Chern., 1968,5,565.
J. Altman and D. Ben-Ishai; J. Heterocycl. Chern., 1968,5,679.
W. W. Paudler and L. S. Helmick; 1. Heterocycl. Chern., 1968,5,691.
G. García,Muñoz, J. Iglesias, M. Lora- Tamayo and R. Mandroñero; J. Heterocycl.
Chern., 1968, 5, 699.
E. P. Lira; J. Heterocycl. Chern., 1968,5,803.
A. Giner-Sorolla, C. Nanos, J. H. Burchenal, M. Dollinger and A. Bendich; 1.
Med. Chern., 1968, II, 52.
V. J. Bauer, H. P. Dalalian, W. J. Fanshawe, S. R. Safir, E. C. Tocus and C. R.
Boshart; J. Med. Chern., 1968, II, 981.
W. B. Wright, Jr. and H. J. Brabander; J. Med. Chern., 1968, II, 1164.
C. Temple, Jr., B. H. Smith, Jr. and J. A. Montgomery; J. Org. Chern., 1968,33,
530.
Y. Yamada, I. Kumashiro and T. Takenishi; J. Org. Chern., 1968,33,642.
933
898
665
801
619,621
584, 588
521
691,731
790
714
704,715
773
615,619
711,724
33
692, 694
711
587
9
545
672,680,741
14
690
696
756, 783
722
723
531
556, 564
291,292
128
577
570
934
68JOC I 087
68J OC 1097
68JOC 1145
68JOC 1350
68JOCI638
68JOC2062
68JOC2291
68JOC2543
68JOC2606
68JOC2828
68JOC2954
68JOC2956
68JOC3766
68J0C3941
68JOU692
68JPR(309)168
6RJSP(26)139
68KGS372
68KGS953
6RKGS954
6RLA(711)46
68LA(711)65
68LA(713)149
68LA(716)11
68M2157
B-68M140900
R-68M140901
68MI40902
68MI40903
68MI40905
68MI40906
68MI40907
68MI40908
68MI41100
B-68M141101
68MI41200
68MI41201
68MI41300
68MI41301
B-68M141400
68MI41500
68N299
680S( 48)8
680S(48)113
68PNA(60)450
68RTC II
68T239
68T349
68TI875
68T2623
68T2757
68T2839
68T3787
68T4217
68TL23I
68TL325
68TL789
68TL3277
References
W. W. Paudler and L. S. Helmick; J. Org. Chern., 1968,33, 1087.
H. W. Heine, A. B. Smith, III and J. D. Bower; 1. Org. Chern., 1968,33, 1097.
P. A. S. Smith and J. G. Wirth; J. Org. Chern., 1968,33, 1145.
L. D. Spicer, M. W. Bullock, M. Garber, W. Groth, J. J. Hand, D. W. Long, J.
L. Sawyer and R. S. Wayne; J. Org. Chern.. 1968,33, 1350.
W. W. Paudler and H. G. Shin; J. Org. Chern., 1968,33, 1638.
V. Boekelheide and N. A. Fedoruk; 1. Org. Chern., 1968,33,2062.
R. Huisgen; J. Org. Chern., 1968,33, 2291.
F. M. Hershenson, L. Bauer and K. F. King; J. Org. Chern., 1968,33,2543.
J. A. Settepani and J. B. Stokes; J. Org. Chern., 1968,33,2606.
R. J. Rousseau and L. B. Townsend; J. Org. Chern., 1968,33,2828.
J. H. Hall: J. Org. Chern., 1968,33,2954.
L. T. Creagh and P. Truitt; J. Org. Chern., 1968,33,2956.
K. T. Potts, U. P. Singh and J. Bhattacharyya; J. Org. Chern., 1968,33,3766.
611,872
154
727
139
612
339
143
645
281
590
722
741
307,311,
338
139
254
754, 773
W. J. Houlihan and W. J. Theuer; J. Org. Chern., 1968,33,3941.
A. V. EI'tsov and N. M. Omar; 1. Org. Chern. USSR (Engl. Transl.), 1968,4,692.
H. Gehlen and J. Stein; J. Prakt. Chern., 1968,309, 168.
R. E. Rondeau, H. M. Rosenberg and D. J. Dunbar; J. Mol. Spectrosc., 1968,26,
139.
M. S. Skorobogatova, N. P. Zolotareva and Y. A. Levin; Khirn. Geterotsikl.
Soedin., 1968,372.
R. M. Bystrova and Y. M. Yutilov; Khirn. Geterotsikl. Soedin., 1968,953 (Chern.
Abstr., 1969,70,96718).
Y. M. Yutilov and R. M. Bystrova; Khirn. Geterotsikl. Soedin., 1968,954 (Chern.
Abstr., 1969,70,96717).
G. Wittig and H. L. Dorsch; Liebigs Ann. Chern., 1968,711,46.
G. Wittig and J. Meske-Schüller; Liebigs Ann. Chern., 1968,711,65.
W. Ried and R. Giesse; Liebigs Ann. Chem, 1968,713, 149.
E. Müller and H. Meier; Liebigs Ann. Chern., 1968,716, II.
T. Kappe, E. Lender and E. Ziegler; Monatsh. Chern., 1968,99,2157.
A. Albert; 'Heterocyclic Chemistry', Athlone Press, University of London, 1968.
'Synthetic Procedures in Nucleic Acid Chemistry', ed. W. W. Zorbach and R.
P. Tipson; Wiley-Interscience, New York, 1968, vol. I. 501,504,536,562,592,
593, 594, 595, 597
SOl
501,590
522
601
680
773
617
616,618
697, 706
697, 706
272
691
253,272
521
R. Shapiro; Prog. Nucleic Acid. Res. Mol. Bioi., 1968,8,73.
G. B. Brown; Prog. Nucleic Acid. Res. Mol. Bioi., 1968,8,209.
H. Weiler-Feilchenfeld and E. D. Bergmann; [sr. J. Chern., 1968,6,823.
R. H. Hall and B. I. S. Srivastava; Life Sciences, 1968,7,7.
A. Pullman, E. Kochanski, M. Gilbert and A. Denis; Theor. Chirn. Acta, 1968,
10, 231.
F. Jordan and B. Pullman; Theor. Chirn. Acta, 1968,9.242.
H. Lund; Discuss. Faraday Soc., 1968,45, 193.
D. J. Brown; in 'Mechanisms of Molecular Migrations', ed. B. S. Thyagarajan;
Wiley-Interscience, New York, 1968, vol. I, p. 209.
J. T. Daycock, G. P. Jones, J. R. N. Evans and J. M. Thomas; Nature (London),
1968, 218, 672.
C. Calzolari and L. Favretto; Analyst, 1968, 93, 494.
L. Guibé and E. A. C. Lucken; Mol. Phys., 1968,14,73.
D. T. Nash, L. Gross, W. Haw and K. Agre; J. Clin. Pharmacal., 1968,8,377.
L. A. Paquette; 'Principles of Modern Heterocyclic Chemistry', Benjamin, New
York, 1968. 839,840
V. Galasso, G. De Alti and A. Bigotto; 71Jeor. Chirn. Acta, 1968,9,222. 853,856,860
C. Franzke, H. Griehl, S. Grunert and E. Hollstein; Naturwissenschaften, 1968,
55, 299.
H. Dorn and A. Zubek; Org. Synth., 1968,48,8.
J. I. G. Cadogan and R. K. Mackie; Org. Synth., 1968,48, 113.
J. J. Lichter and W. Gordy; Proc. Natl. Acad. Sci. USA, 1968,60,450.
H. C. Beyerman, L. Maat, A. Sinnema and A. Van Veen; Recl. Trav. Chirn.
Pays-Bas, 1968,87, II.
J. Kobe, B. Stanovnik and M. Tisler; Tetrahedron, 1968,24,239.
P. Scheiner; Tetrahedron, 1968,24,349.
S. O. Lawesson, E. Schroll, J. H. Bowie and R. G. Cooks; Tetrahedron, 1968,
24, 1875. 359
A. Pollak, B. Stanovnik and M. Tisler; Tetrahedron, 1968,24,2623. 628
P. Scheiner; Tetrahedron, 1968,24, 2757. 704,705,710,724
A. H. Beckett, R. G. W. Spickett and S. H. B. Wright; Tetrahedron, 1968,24,2839. 858
S.-Y. Hong and J. E. Baldwin; Tetrahedron, 1968,24,3787. 808,832
R. Buyle and H. G. Viehe; Tetrahedron, 1968,24,4217. 132
N. E. Alexandrou and E. D. Micromastoras; Tetrahedron Leu., 1968,231. 686
J. Sauer and K. K. Mayer; Tetrahedron Leu., 1968,325. 160
B. Loev and M. M. Goodman; Tetrahedron Leu., 1968,789. 653
H. H. Wassermann, K. Stiller and M. B. Floyd; Tetrahedron Leu., 1968,3277. 376
505
505
689
695
739
785
800
835
600
288
288
520
635
628
710
68TL3727
68TL3805
68TL3873
68TL4811
68TL5707
68USP3386968
68USP3394143
68USP3396170
68ZC458
68Z0R689
69AqR)434
69ACSI091
69ACS2733
69AG1l5
69AG(E)132
69AG(E)513
69AG(E)520
69AHql0)1
69AJC2251
69AX(B)135
69AX(B)595
69AX(B)1330
69AX(B) 1338
69AX(B)1608
69AX(B)2355
69B2412
69BCJ750
69 BCJ3099
69BEP722025
69BRP1157256
69BSB147
69BSF1097
69BSF1687
69BSF2061
69BSF2064
69 BSF2492
69BSF3292
69BSF3300
69BSF3302
69BSF3306
69BSF3316
69BSF3670
69BSF4075
69BSF4466
69BSF4469
69BSF4474
69CI09
69C303
69CB269
69CB417
69CB755
69CB2216
69CB3000
69CB3159
69CB3176
69CC381
69CC458
69CC500
69CC818
69CC905
69CCl110
References
J. D. Vaughan and M. O'Donnell; Tetrahedron Lett., 1968,3727.
C. E. Olsen and C. Pedersen; Tetrahedron Lett., 1968,3805.
T. Goto, S. Inoue and S. Sugiura; Tetrahedron Lett., 1968,3873.
M. Israel, L. C. Jones and E. J. Modest; Tetrahedron Lett., 1968,4811.
A. Morimoto, K. Noda, T. Watanabe and H. Takasugi; Tetrahedron Lett., 1968,
5707.
W. R. Carpenter; U.S. Pat. 3386968 (1968) (Chern. Abstr., 1968,69,28106).
M. Wolf; U.S. Pat. 3394143 (1968) (Chern. Abstr., 1968,69,77265).
N. R. Fetter and B. K. Bartocha; U.S. Pat. 3 396170 (1968) (Chern. Abstr., 1968,
69, 87 170).
S. Hoffmann and E. Mühle; Z. Chern., 1968,8,458.
A. P. Krasnoshchek, R. A. Khmel'nitskii, A. A. Polyak ova and 1. 1. Grandberg;
Zh. Org. Khirn., 1968,4,689.
M. Ruccia and N. Vivona; Ann. Chirn. (Rome), 1969,59,434.
M. Begtrup and C. Pedersen; Acta Chern. Scand., 1969,23, 1091.
M. Begtrup and P. A. Kristensen; Acta Chern. Scand., 1969,23,2733.
935
671,742
712
624,642,643
637
302
838
746
837
233
204
777
712
700,
701,727
721
721
781
800
75, 76, 85, 86, 108
741, 754
738
A. Albert; Angew. Chern., 1969,81, 115.
A. Albert; Angew. Chern., Int. Ed. Engl., 1969,8, 132.
E. Brunn and R. Huisgen; Angew. Chern., Int. Ed. Eng/., 1969,8,513.
F. A. Neugebauer; Angew. Chern., Int. Ed. Eng/., 1969,8,520.
A. J. Boulton and P. B. Ghosh; Adv. Heterocyc/. Chern., 1969,10, 1.
E. J. Browne; Aust. l. Chern., 1969,22,2251.
P. Goldstein, J. Ladell and G. Abowitz; Acta Crystallogr., Part B, 1969,25, 135.
A. D. Mighell, C. W. Reimann and A. Santoro; Acta Crystallogr., Part B, 1969,
25, 595. 227
E. Sletten, J. Sletten and L. H. Jensen; Acta. Crystallogr., Part B, 1969,25,1330. 509
G. M. Brown; Acta Crystallogr., Part B, 1969,25, 1338. 509
J. Sletten and L. H. Jensen; Acta Crystallogr., Part B, 1969,25, 1608. 508,509
D. L. Smith and E. K. Barrett; Acta Crystallogr., Part B, 1969,25,2355. 209
R. Wolfenden, J. Kaufman and J. B. Macon; Biochemistry, 1969,8,2412. 904
H. Kawashima and 1. Kumashiro; Bull. Chern. Soc. lpn., 1969,42,750.539,554,555,596
H. Mizuno, T. Fujiwara and K. Tomita; Bull. Chern. Soc. lpn., 1969,42,3099. 508,509
J. F. Willems and F. C. Heugebaert; Be/g. Pat. 722025 (1969) (Chern. Abstr.,
1970,72,66949).
H. Becker and K. Wehner; Br. Pat. 1 157256 (1969) (Chern. Abstr., 1969, 71,
81 375). 753
G. L'abbé, P. Ykman and G. Smets; Bull. Soc. Chirn. Be/g., 1969,78, 147. 704
M. Roche and L. Pujol; Bull. Soc. Chirn. Fr., 1969, 1097. 171,172,173,176,
179,187,795,671,672
J. Elguero, R. Jacquier and D. Tizané; Bull. Soc. Chirn. Fr., 1969, 1687. 187
G. Coispeau, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,2061. 272
J. Eiguero, A. Fruchier and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,2064. 230,233
J. Daunis, R. Jacquier and P. Viallefont; Bull. Soc. Chirn. Fr., 1969,2492. 862
J. L. Aubagnac, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,3292. 189
J. L. Aubagnac, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,3300. 284
J. L. Aubagnac, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,3302. 254
J. L. Aubagnac, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,3306. 186,207
J. L. Aubagnac, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,3316. 188,189,
199,202
J. Daunis, R. Jacquier and P. Vaillefont; Bull. Soc. Chirn. Fr., 1969,3670. 859, 862,900
J. Elguero, E. Gonzalez, J. L. Imbach and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,
4075.
C. Dittli, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,4466.
C. Dittli, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,4469.
C. Dittli, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1969,4474.
J. P. Dubois and H. Labhart; Chirnia, 1969,23, 109.
A. Hetzheim and H. Pusch; Chirnia, 1969,23,303 (Chern. Abstr., 1969,71,101 827).
R. R. Schmidt and D. Schwille; Chern. Ber., 1969, 102, 269.
M. Regitz and H. Scherer; Chern. Ber., 1969, 102,417.
C. F. Kröger, R. Miethchen, H. Frank, M. Siemer and S. Pilz; Chern. Ber., 1969,
102, 755.
M. Regitz and W. Anschütz; Chern. Ber., 1969,102,2216.
R. Walentowski and H.-W. Wanzlick; Chern. Ber., 1969, 102,3000.
T. Eicher, S. Hünig, H. Hansen and P. Nikolaus; Chern. Ber., 1969,102,3159.
T. Eicher, S. Hünig and P. Nikolaus; Chern. Ber., 1969,102,3176.
J. Kiburis and J. H. Lister; Chern. Cornrnun., 1969,381.
J. A. Montgomery and H. J. Thomas; Chern. Cornrnun. 1969,458.
A. Albert; Chern. Cornrnun., 1969,500.
G. C. Barrett, A. R. Khokhar and J. R. Chapman; Chern. Cornrnun., 1969,818.
D. Elad and 1. Rosenthal; Chern. Cornrnun., 1969,905.
F. L. Bach, J. Karliner and G. E. Van Lear; Chern. Cornrnun., 1969, 1110.
837
425
243
243
243
160,221
630,655
157
695
752
712
540, 664
766, 884
781
563, 598
652
721
113, 138
545
80!
936
69CCR(4)463
69CHE805
69CJC813
69C JC 1129
69CJC3677
69CJC3997
69CPBI128
69CPBI924
69CPB2209
69CR(C)(268) 1798
69CR(C)(269)570
69C R( D)(268)2958
69CRV345
69CRV359
69FRPI578366
69GI131
691ZVI44
691ZV655
69JA711
69JA796
69JA3676
69JA5625
69JBC(244)2498
69JBC(244)4072
69JCP(51)1862
69JCS( B)270
69JCS(B)307
69JCS(B)680
69JCS(B)1240
69JCS(C)152
69JCS(C)809
69JCS(C)1056
69JCS(q1065
69JCS(q1084
69JCSIQll17
69JCS(Q1474
69JCS(C)l478
69JCS(C)1593
69JCS(C)2251
69JCSIC)2379
69JCSIQ2497
69JCS( C )2624
69JHC93
69JHí.199
69JHC503
69JHC545
69JHC559
69JHC947
69JHC965
69JMC43
69JMC717
69JMC945
6QJMCI124
69JOC36
69JOC747
69JOC973
69JOC978
69JOC98I
6QJOC 1025
69JOCI141
69JOC 1170
69JOCI396
69JOCI746
R. Raap; Can. J. Chern., 1969,47,3677.
P. Yates, R. G. F. Giles and D. G. Farnum; Can. J. Chern., 1969,47,3997.
A. Yamazaki, J. Kumashiro and T. Takenishi; Chern. Pharrn. Bull., 1969, 17,1128.
A. Takamizawa and K. Hirai; Chern. Pharrn. Bull., 1969, 17, 1924.
J. Adachi; Chern. Pharrn. Bull., 1969, 17,2209.
Kha Yang Thang and J.-L. Olivier; CR. Hebd. Seances Acad. Sci., Ser. C, 1969,
268, 1798.
P. Bouchet, J. Eiguero, R. Jacquier and F. Forissier; CR. Hebd. Seances Acad.
Sci., Ser. C 1969,269, 570
B. Pullman and H. Berthod; CR. Hebd. Seances Acad. Sci., Ser. D, 1969,268,2958.
G. L'abbé; Chern. Rev. 1969,69,345.
G. L'abbé; Chern. Rev., 1969,69,359.
E. J. Cragoe, Jr. and J. H. Jones; Fr. Pat. 1578366 (1969) (Chern. Abslr.. 1970,
72,1115(4).
R. Stradi and D. Pocar; Gazz. Chirn. Ital., 1969,99,1131.
J. N. Vorazhtsov and K. A. Barkhash; Izv. Akad. Nauk SSSR, Ser. Khirn., 1969,144.
E. A. Arutyunyan, V. J. Gunar, E. P. Gracheva and S. I. Zav'yalov; Izv. Akad.
Nauk SSSR, Ser. Khirn., 1969,655.
J. L. Brewbaker and H. Hart; J. Am. Chern. Soc., 1969,91,711.
M.1. S. Dewar and T. Morita; J. Am. Chern. Soc., 1969,91,796.
J. E. McMurry; J. Am. Chern. Soc., 1969,91,3676.
P. O. P. Ts'O, N. S. Kondo, R. K. Robins and A. D. Broom; J. Am. Chern. Soc.,
1969, 91, 5625.
G. Stohrer and G. B. Brown; J. Bio/. Chern., 1969,244,2498.
A. Myles and G. B. Brown; J. BioI. Chern., 1969,244,4072.
H. H. Chen and L. B. Clark; J. Chern. Phys., 1969,51, 1862.
D. J. Brown and P. B. Ghosh; 1. Chern. Soc. (B), 1969,270.
E. Borello, A. Zecchina and E. Guglielminotti; J. Chern. Soc. (B), 1969,307.
R. N. Butler; J. Chern. Soc. (B), 1969,680.
M. Charton; J. Chern. Soc. (B), 1969, 1240.
A. Albert; J. Chern. Soc. (C), 1969, 152.
J. S. Morley; J. Chern. Soc. (C), 1969,809.
E. J. Browne and J. B. Polya; 1. Chern. Soc. (C), 1969, 1056.
A. Co Day and R. N. Inwood; J. Chern. Soc. (C), 1969, 1065.
A. Albert, W. Pfleiderer and D. Thacker; J. Chern. Soc. (C), 1969, 1084.
G. C. Barrett and A. R. Khokhar; J. Chern. Soc. (C). 1969, 1117.
C. W. Rees and R. C. Storr; J. Chern. Soc. (C), 1969, 1474.
C. W. Rees and R. C. Storr; J. Chern. Soc. (C), 1969, 1478.
J. Maguire, D. Paton and F. L. Rose; J. Chern. Soc. (C), 1969, 1593.
R. L. Jones and C. W. Rees; 1. Chern. Soc. (C), 1969, 2251.
A. Albert; 1. Chern. Soc. (C), 1969,2379.
I. L. Finar.and B. J. Millard; J. Chern. Soc. (C), 1969,2497.
S. N. Ege; J. Chern. Soc. (C), 1969,2624.
S. F. Martin and R. N. Castle; J. Helerocycl. Chern., 1969, 6, 93.
J. A. White and R. C. Anderson; J. Helerocycl. Chern., 1969,6, 199.
J. H. Boyer and R. Selvarajan; J. Heterocycl. Chern., 1969,6,503.
C. Wijnberger and C. L. Habraken; 1. Helerocycl. Chern., 1969,6,545.
M. Japelj, B. Stanovnik and M. Tisler; J. Heterocycl. Chern., 1969,6,559.
J. B. Wright; J. Heterocycl. Chern., 1969,6,947.
P. M. Hergenrother; J. Helerocycl. Chern., 1969,6,965.
J. Nematollahi and J. R. Nulu; J. Med. Chern., 1969,12,43.
A. Giner-Sorolla; 1. Med. Chern., 1969, 12,717.
V. J. Bauer, W. J. Fanshawe, G. E. Wiegand and S. R. Safir; 1. Med. Chern.,
1969, 12,945.
R. P. Williams, V. J. Bauer and S. R. Safir; J. Med. Chern., 1969,12, 1124.
L. Field and R. B. Barber; J. Org. Chern., 1969, 34, 36.
C. N. Eaton and G. H. Denny, Jr.; J. Org. Chern., 1969,34,747.
E. Dyer, R. E. Farris, Jr., C. E. Minnier and M. Tokizawa; J. Org. Chern., 1969,
34,973. 521,559
U. Wölcke and G. B. Brown; J. Org. Chern., 1969,34,978. 539,554,555,595
U. Wölcke, W. Pfleiderer, T. Delia and G. B. Brown; 1. Org. Chern., 1969.34,981. 555
A. D. Broom and R. K. Robins; J. Org. Chen/., 1969,34, 1025. 522,595
C. Arnold, Jr. and D. N. Thatcher; J. Org. Chern., 1969,34, 1141. 709
E. C. Taylor, Y. Maki and A. McKillop; J. Org. Chern., 1969,34, 1170. 529
J. A. Montgomery and K. Hewson; J. Org. Chern., 1969,34, 1396. 552
P. K. Freeman and R. C. Johnson; J. Org. Chern., 1969,34, 1746. 706
References
A. J. Popov; Coord. Chern. Rev., 1969,4,463.
B. V. loffe, V. S. Stopskii and N. B. Burmanova; Chern. Heterocycl. Cornpd. (Eng/.
Trans/.), 1969,5,805.
R. Raap and J. Howard; Can. J. Chern., 1969,47,813.
B. M. Lynch, A. J. Robertson and J. G. K. Webb; Can. J. Chern., 1969,47,1139.
792, 797
285
819
206.854.
859
799, 802
828
584
114
75
308
240
859
670, 705
831
626,646
714
720
557
275
208, 742
726
526
554
539
517
33
685
805
364, 804
695, 696
834
739, 740
188
875
138
727
727
877, 896,904
745
690,721
204
218,255
629,871,890
70
867
201
858, 868, 869
201,317
763
652
554, 556
291
291
137
597
69JOC2129
69JOC2153
69JOC2157
69JOC2720
69JOC3221
69JOC4118
69JOU1480
69JOU1790
69JPR71
69JPR213
69JPR646
69JPRI058
69KGS159
69KGS1114
69LA(722)29
69LA(722)38
69LA(725)29
69LA(729)73
69LA(729) 124
69M671
69MI250
69M1438
69MI40300
69MI40301
69MI40400
B-69MI40401
B-69MI40900
69MI40901
69MI40902
69M140903
69MI40904
69MI40906
69MI40907
69MI41000
69MI41001
69MI41002
69MI41003
69MI41100
B-69MI41101
69MI41200
69MI41300
690MR(I)249
690MR(I)431
690MS(2)433
690MS(2)729
690MS(2)739
69RRC763
69RRC1263
69RTC1263
69S17
69T3053
69T3287
References
937
C. K. Bradsher, R. D. Brandau, J. E. Boliek and T. L. Hough; J. Org. Chern.,
1969,34,2129. 632
I. Scheinfeld, J. C. Parham, S. Murphy and G. B. Brown; J. Org. qern., 1969,
34,2153. 596
A. Giner-Sorolla, C. Gryte, A. Bendich and G. B. Brown; J. Org. Chern., 1969,
34,2157. 554, 555, 595, 596
P. Aeberli and W. J. Houlihan; J. Org. Chern., 1969,34,2720. 315
K. T. Potts and C. Lovelette; J. Org. Chern., 1969,34,3221. 856, 871, 889
R. R. Fraser, G. Gurudata and K. E. Haque; J. Org. Chern., 1969,34,4118. 720,809
N. M. Omar and A. V. El'tsov; J. Org. Chern. USSR (Engl. Trans!.), 1969,5,1480. 254,
256
F. I. Luknitskii, D. O. Taube and B. A. Vovsi; J. Org. Chern. USSR (Engl. Transl.),
1969,5,1790 (Chern. Abstr., 1970,72,21671).
H. Gehlen and R. N. Neumann; J. Prakt. Chern., 1969,311,71.
H. Gehlen and R. Neumann; J. Prakt. Chern., 1969,311,213
H. G. O. Becker, J. Witthauer, N. Sauder and G. West; J. Prakt. Chern., 1969,
311, 646.
W. Hampel; J. Prakt. Chern., 1969,311, 1058.
G. I. Chipen and R. P. Bokaldere; Khirn. Geterotsik!. Soedin., 1969, 159.
V. Ya. Grinshtein and V. Ya. Strazdin; Khirn. Geterotsikl. Soedin., 1969, 1114.
H. NeunhoefIer, M. Neunhoeffer and W. Litzius; Liebigs Ann. Chern., 1969,722,
29.
H. NeunhoefIer; Liebigs Ann. Chern., 1969,722,38.
E. Zbiral and J. Ströh; Liebigs Ann. Chern., 1969,725,29.
I. Betula; Liebigs Ann. Chern., 1969,729,73.
W. Ried and B. Peters; Liebigs Ann. Chern., 1969,729, 124.
M. Japelj, B. Stanovnik and M. TiSler; Monatsh. Chern., 1969,100,671.
H. Junek and I. Wrtilek; Monatsh. Chern., 1969, 100, 1250.
E. Zbiral and J. Stroh; Monatsh. Chern., 1969,100, 1438.
K. M. Pazdro; Rocz. Chern., 1969,43, 1089.
G. C. Barrett and A. R. Khokhar; J. Chrornatogr., 1969,39,47.
M. N. Aboul-Enein, Y. M. Abou-Zeid and S. M. EI-Difrawy; Pharrn. Acta Helv.,
1969,44, 570.
M. J. S. Dewar; 'The Molecular Orbital Theory of Organic Chemistry', McGraw-
Hill, New York, 1969, pp. 378-382.
F. Yoneda, K. Ogiwara, M. Kanahori and S. Nikigashi; 'Proceedings of the 4th
International Symposium on the Chemistry and Biology of Pteridines', 1969,
145.
J. M. Andre, M. C. Andre, D. Hahn, D. Klint and E. Clemenli; Hung. Phys.
Acta, 1969,27,493.
M. Sundaralingam; Biopolyrners, 1969,7,82.
P. Tollin and A. R. I. Munns; Nature (London), 1969,222, 1170.
J. P. Ferris, J. E. Kuder and A. W. Catalano; Science, 1969,166,765.
B. Mely and A. Pullman; Theor. Chirn. Acta, 1969,13,278.
C. Giessner-Prettre and A. Pullman; Theor. Chirn. Acta, 1969, 13,265.
G. Hornyak, K. Lempert and K. Zauer; Acta Chirn. (Budapest), 1969,61, 181
(Chern. Abstr., 1969,71,70570). 628,653,655
S. Ostroversnik, B. Stanovnik and M. Tisler; Croat. Chern. Acta, 1969,41, 135
(Chern. Abstr., 1971, 72, 12684).
V. I. Schvedov, L. B. Altukhova, L. A. Chernyshkova and A. N. Grinev; Khirn.-
Farm. Zh., 1969,3, 15 (Chern. Abstr., 1970,72,66899).
A. Nawojski; Rocz. Chern., 1969,43, 573 (Chern. Abstr., 1969,70, 115142).
G. Berthier, L. Praud and J. Serre; Quantum Aspects Heterocyel. Cornpd. Chern.
Biochern., Proc. Int. Syrnp. 1969, 1970,2,40.
A. G. Cook; in 'Enamines, Structure, and Reactions', ed. A. G. Cook; Dekker,
New York, 1969, p. 211.
R. B. Dickinson and N. W. Jacobsen; Anal. Chern., 1969,41, 1324.
J. H. Tyrer, M. J. Eadie and W. H. Hooper; J. Chrornatogr., 1969,39,312.
J. Eiguero, C. Marzin and D. Tizané; Org. Magn. Reson., 1969, 1,249.
T. J. Batterham and C. Bigum; Org. Magn. Reson., 1969,1,431.
D. M. Forkey and W. R. Carpenter; Org. Mass Spectrorn., 1969,2,433.
S. W. Tam; Org. Mass Spectrorn., 1969, 2, 729.
B. K. Simons, R. K. M. R. Kallury and J. H. Bowie; Org. Mass Spectrorn., 1969,
2,739.
C. Chiriac, L. Stoicescu-Crivetz and I. Zugravescu; Rev. Rourn. Chirn., 1969, 14,
763.
C. Chiriac, L. Stoicescu-Crivetz and I. Zugravescu; Rev. Rourn. Chirn., 1969,14,
1263.
K. B. De Roos and C. A. Salemink; Reel. Trav. Chirn. Pays-Bas, 1969,88, 1263.
D. Seebach; Synthesis, 1969, 17.
P. K. Kadaba; Tetrahedron, 1969,25,3053.
P. Beak and W. Messer; Tetrahedron, 1969,25,3287.
660
884
772
784
272
746
751
768
768
826
540, 541
779
889
333
717
126
138
295
173
592
505, 506
523
509
570
505, 506
505
650
643
617
672
714
742
803
189,190
290
801
204
204
260
231,300
635, 636
717
717
160,377
938
69T3287
69T3453
69T4265
69T5421
69TL63
69TL27I
69TL289
69TL495
69TL495
69TL785
69TLl537
69TLl549
69TL2589
69TL2595
69TL3377
69TL4863
69TL5081
69USP3461123
69YZ1657
69ZC27
69ZC241
69ZC300
69ZC325
69Z0R153
70ACS2137
70ACS3248
70AG81
70AG(E)54
70AG(E)67
70AHC(lI)1
70AHC(l2)103
70AHC(l2)213
70AJC63I
70AX(B)380
70AX(B)521
70AX(B)1880
70B3701
70BC J849
70BCJ2535
70BCJ3344
70BC 33344
70BCJ3909
70BSF231
70BSF273
70BSF1121
70BSF1129
70BSFI345
70BSFI346
70BSFI571
70BSFI576
70BSF1936
70BSF1974
70BSF2717
70BSF3147
70BSF3466.
70BSF4119
70C 134
References
P. Beak and W. Messer; Tetrahedron, 1969,25,3287.
R. Buy1e and H. G. Viehe; Tetrahedron, 1969,25,3453.
J. Nyitrai and K. Lempert; Tetrahedron, 1969,25,4265.
G. L'abbé, P. Ykman and G. Smets; Tetrahedron, 1969,25,5421.
G. L'abbé and H. J. Bestmann; Tetrahedron Leu., 1969,63.
J. Reisch and A. Fitzek; Tetrahedron Leu., 1969, 271.
M. Sprinzl, J. Farkas and F. Sorm; Tetrahedron Leu., 1969,289.
M. L. Roumestant, P. Viallefont, J. Elguero and R. Jacquier; Tetrahedron Leu.,
1969,495.
M. L. Roumestant, P. Viallefont, J. Eiguero and R. Jacquier; Tetrahedron Leu.,
1969, 495.
U. WöJcke, N. J. M. Birdsall and G. B. Brown; Tetrahedron Leu., 1969,785.
B. M. Lynch; Tetrahedron Leu., 1969, 1537.
L S. Davies and G. Jones; Tetrahedron Leu.. 1969, 1549.
R. Huisgen, K. von Fraunberg and H. J. Sturm; Tetrahedron Leu., 1969,2589.
R. Huisgen and K. V. Fraunberg; Tetrahedron Leu., 1969,2595.
A. C. Rochat and R. A. Olofson; Tetrahedron Leu., 1969,3377.
P. Scheiner; Tetrahedron Leu., 1969,4863.
D. H. Zimmerman and R. A. Olofson; Tetrahedron Leu., 1969,5081.
J. H. Jones and E. J. Cragoe, Jr.; U.S. Pat. 3461123 (1969) (Chern. Abstr., 1969,
71, 101 883).
Y. Kishi, S. Sugiura, S. Inoue and T. Goto: Yakugaku Zasshi, 1969, 89, 1657
(Chern. Abstr., 1970, 72, 90406).
G. Jarnecke, V. Buchholtz and K. Teubner; Z. Chern., 1969,9,27.
M. Wahren; Z. Chern., 1969,9,241.
R. Miethchen, H.-U. Seipt and C. F. Kröger; Z. Chern., 1969,9,300.
H. G. O. Becker, V. Eisenschmidt, M. Buhig, K. Jahnisch, N. Klein, W. Kowalski,
R. Misse1witz, R. Müller, P. Reimann, C. Roth, W.-D. Sauter, W. Schössler
and B. Thorein; Z. Chern., 1969,9,325.
B. K. Strelets and L. S. Efros; Zh. Org. Khirn., 1969, 5, 153 (Chern. Abstr., 1969,
70, 86 889).
221
132
422
704, 716
716
218
272
740, 804
679
555
799
887
709
46
806
810
830
646
643
664
695
752
752, 753
21
P. Groth; Acta Chern. Scand., 1970,24,2137.
F. K. Larsen, M. S. Lehmann, I. Søtofte and S. E. Rasmussen: Acta Chern.
Scand., 1970, 24, 3248. 173, 179
S. Petersen and H. Heitzer; Angew. Chern., 1970,82,81. 701
G. Zumach and E. Kuhle; Angew. Chern., Int. Ed. Engl., 1970,9,54. 130
S. Petersen and H. Heitzer; Angew. Chern., Int. Ed. Engl., 1970,9,67. 701
S. T. Reid; Adv. Heterocycl. Chern., 1970,11, I. 45,46,78,79,81, 108
M. R. Grimmett; Adv. Heterocycl. Chern., 1970, 12, 103. 51,54,59,60,72,
78, 86,92, 104, 106, 126, 346, 351, 353, 355, 358, 362, 364, 384,
385,388,391,400,403,404,412,419,420,425,430,443,462,464,
467,468,469,473,476,480,481,483,484,485,487,491,493
H. Lund; Adv. Heterocycl. Chern., 1970, 12,213. 73
A. J. -Blackman; Aust. l. Chern., 1970,23,631. 744,758
J. L. Galigné and J. Falgueirettes; Acta Crystallogr., Part B, 1970,26,380. 178
C. W. Reimann, A. Santoro and A. D. Mighell; Acta Crystallogr., Part B, 1970,
26, 521.
J. Berthou, J. E1guero and C. Rérat; Acta Crystallogr., Part B, 1970,26, 1880.
D. F. Babcock and R. O. Morris; Biochemistry, 1970,9,3701.
I. Hori, K. Saito and H. Midorikawa; Bull. Chern. Soc. lpn., 1970,43,849.
9
227
178,179
601
272,316,
320, 331
Y. Iwakura and K. Kurita; Bull. Chern. Soc. lpn., 1970,43, 2535. 135
M. Kamiya; Bull. Chern. Soc. lpn., 1970, 43, 3344. 175, 198,346,347,348,349
M. Kamiya; Bull. Chern. Soc. lpn., 1970,43,3344. 742
Y. Ohtsuka; Bull. Chern. Soc. lpn., 1970,43,3909. 591
J. Elguero, R. Gélin, S. Gélin and G. Tarrago; Bull. Soc. Chirn. Fr., 1970,231. 231
M. Roche and L. Pujol; Bull. Soc. Chirn. Fr., 1970,273. 172,177,672
J. Elguero, R. Jacquier and D. Tizané; Bull. Soc. Chirn. Fr., 1970, 1121. 250
J. Elguero, R. Jacquier and D. Tizané; Bull. Soc. Chirn. Fr., 1970, 1129. 188,199,207
J. Elguero, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1970, 1345. 183,799
J. Elguero, R. Jacquier and S. Mondon; Bull. Soc. Chirn. Fr., 1970, 1346. 183,231,799
J. L. Barascut, J. Elguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1970, 1571. 216
J. Elguero, R. Jacquier and S. Mondon: Bull. Soc. Chirn. Fr., 1970, 1576. 216
J. Elguero, R. Jacquier and D. Tizané; Bull. Soc. Chirn. Fr., 1970, 1936. 254
J. Eiguero, R. Jacquier, V. Pellegrin and V. Tabacik; Bull. Soc. Chirn. Fr., 1970,
1974. 253,267,289
G. Coispeau and J. Elguero; Bull. Soc. Chirn. Fr., 1970,2717. 169,277,278
J. P. Chapelle, J. Eiguero, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1970,
3147. 188,216,285
J. E1guero and C. Marzin; Bull. Soc. Chirn. Fr., 1970,3466 188
J. Elguero, R. Jacquier and C. Marzin; Bull. Soc. Chirn. Fr., 1970,4119. 276
A. R. Katritzky; Chirnia, 1970,24, 134. 36,37,38
70CB272
70CB788
70CBI908
70CBI918
70CB I 949
70CBI954
70CB3252
70CB3284
70CB3289
70CB3533
70CB3811
70CB3817
70CC56
70CC286
70CC289
70CC858
70CCI068
70CC 1089
70CCI524
70CHEI94
70CHE628
70CHE744
70CHEI183
70CHEI321
70CHEI339
70CHEI515
70CHEI568
70CJC1371
70CJCI716
70CJC2006
70CJC2139
70CPB964
70CPBI526
70CPBI685
70CR(C)(270) 1688
70CR(C)(271)958
70FRPI596860
70GlIO
70GII06
70GEPI957711
70GEP2009134
70HCA648
70ICI597
70IJC391
70IJC894
70IZV420
70JAI965
70JA2929
70JA4079
70JA4088
A. Hetzheim and H. Beyer; Chern. Ber., 1970, 103, 272.
H. König and R. Geiger; Chern. Ber. 1970, 103, 788.
F. P. Woerner and H. Reimlinger; Chern. Ber., 1970, 103, 1908.
H. Reimlinger, J. J. M. Vandewalle, G. S. D. King, W. R. F. Lingier and R.
Merenyi; Chern. Ber., 1970,103, 1918.
H. Reimlinger, A. Noels and J. Jadot; Chern. Ber., 1970,103, 1949.
H. Reimlinger, A. Noels, J. Jadot and A. van Overstraeten; Chern. Ber., 1970,
103, 1954.
H. Reimlinger, M. A. Peiren and R. A. Mereyi; Chern. Ber., 1970,103,3252.
H. Reimlinger and R. Merényi; Chern. Ber., 1970, 103, 3284.
G. Häfelinger; Chern. Ber., 1970, 103,3289.
A. Hetzheim, H. Pusch and H. Beyer; Chern. Ber., 1970, 103, 3533.
A. J. Hubert and H. Reimlinger; Chern. Ber., 1970,103,3811.
H. Reimlinger, W. R. F. Lingier and R. Merényi; Chern. Ber., 1970, 103,3817.
G. B. Ansell, D. M. Forkey and D. W. Moore; Chern. Cornrnun., 1970,56.
A. D. Baker, D. Betteridge, N. R. Kemp and R. E. Kirby; Chern. Cornrnun., 1970,
286.
W. R. Dolbier; Chern. Cornrnun., 1970,289.
A. Albert; Chern. Cornrnun., 1970,858.
F. Yoneda, K. Ogiwara, M. Kanahori and S. Nishigaki; Chern. Cornrnun., 1970,
1068.
M. Ohashi, K. Tsujimoto and T. Yonezawa; Chern. Cornrnun., 1970, 1089.
F. L. Rose, G. J. Stacey', P. J. Taylor and T. W. Thompson; Chern. Cornrnun.,
1970, 1524.
A. F. Pozharskii, L. M. Sitkina, A. M. Simonov and T. N. Chegolya; Chern.
Heterocyc1. Cornpd. (Engl. Trans!.), 1970,6, 194.
Yu. P. Andreichikov and A. M. Simonov; Chern. Heterocyc1. Cornpd. (Engl.
Transl.), 1970,6,628.
B. L. Moldaver and M. E. Aronzon; Chern. Heterocyc1. Cornpd. (Engl. Trans!.),
1970,744.
A. F. Pozharskii, É. A. Zvezdina, Yu. P. Andreichikov, A. M. Simonov, V. A.
Anismova, and S. F. Popova; Chern. Heterocyc1. Cornpd. (Engl. Trans!.), 1970,
6,1183.
B. V. Ioffe and N. L. Zelenina; Chern. Heterocyc1. Cornpd. (Eng!. Trans!.), 170,
1321.
B. A. Tertov and P. P. Onishchenko; Chern. Heterocycl. Cornpd. (Engl. Transl.),
1970,6, 1339.
P. I. Abramenko and V. G. Zhiryakov; Chern. Heterocycl. Cornpd. (Eng!. Transl.),
1970,6, 1515.
B. E. Zaitsev, N. A. Andronova, R. B. Zhurin and L. B. Preobrazhenskaya;
Chern. Heterocycl. Cornpd. (Eng!. Transl.), 1970, 1568.
R. G. Micetich and C. G. Chin; Can. J. Chern., 1970,48, 1371.
S. Jerumanis and A. Martel; Can. J. Chern., 1970,48, 1716.
R. G. Micetich; Can. J. Chern., 1970,48,2006.
R. Raap; Can. J. Chern., 1970,49,2139.
M. Ogata, H. Matsumoto, S. Takahashi and H. Kano; Chern. Pharrn. Bul!., 1970,
18, 964.
A. Nakamura and S. Kamiya; Chern. Pharrn. Bull., 1970,18, 1526.
M. Yanai, T. Kinoshita, S. Takeda, M. Mori, H. Sadaki and H. Watanabe; Chern.
Pharrn. Bull., 1970, 18, 1685. 629,652,871,890
E. J. Vincent, R. Phan-Tan-Luu, J. Roggero and J. Metzger; C. R. Hebd. Seances
Acad. Sci, Ser. C, 1970,270, 1688.
F. Texier and R. Carrié; C. R. Hebd. Seances Acad. Sci., Ser. C, 1970,271,958.
Agfa-Gevaert A.-G., Fr. Pat. 1596860(1970) (Chern. Abstr., 1971,75,5907).
L. PentimaIli and V. Passalacqua; Gazz. Chirn. Ita!., 1970,100,110 (Chern. Abstr.,
1970,72, 121492).
L. PentimaIli and G. Milani; Gazz. Chirn. Ital., 1970, 100, 1106 (Chern. Abstr.,
1971,74,125609).
E. J. J. Grabowski, E. W. Tristram and R. J. Tull; Ger. Pat. 1957711 (1970)
(Chern. Abstr., 1970,73,66621).
I. Pintér, A. Messmer, F. Ordogh and L. Pallos; Ger. Pat. 2 009 134 (l970)(Chern.
Abstr., 1970,73,98955).
J. M. J. Tronchet and F. Perret; Helv. Chirn. Acta, 1970,53,648.
R. M. Churchill, K. Gold and C. E. Maw; Inorg. Chern., 1970,9, 1597.
M. V. Konher; Indian J. Chern., 1970,8,391.
D. S. Iyengar, S. Husain and G. S. Sidhu; Indian J. Chern., 1970,8,894.
E. P. Girtcheui, Z. S. Volkova, V. I. Gunar, E. Arutyuuyan and S: I. Zavyalov;
Izv. Akad. Nauk SSSR, Ser. Khirn., 1970,420.
Y. Kushi and Q. Fernando; J. Am. Chern. Soc., 1970,92, 1965.
N. Bodor, M. J. S. Dewar and A. J. Harget; J. Am. Chern. Soc., 1970,92,2929.
A. J. Jones, D. M. Grant, M. W. Winkley and R. K. Robins; J. Am. Chern. Soc.,
1970,92,4079.
F. E. Hruska, A. A. Grey and I. C. P. Smith; J. Am. Chern. Soc., 1970,92,4088.
References
939
662
722, 728
709,711
152
234,240
233,269
272, 331
828
173,179
653
692
853, 866
367
204
252
852
581
694
862
384,448
430
199
440
281
245
JI6
200
69
545
66
807
380
341
20
726
837
627
627
646
732
303
227
773
853, 865
560
796, 827
742
514
523
940
70JA4751
70JA5118
70JA6218
70JA744[
70JA7617
70JAP7039709
70JCS(B)596
70JCS(B)1692
70JCS(C)63
70JCS(C)85
70JCS(C)230
70JCS(C)807
70JCS(C)1313
70JCS(C) 1397
70JCS(C)1515
70JCS(C)[540
70JCS(C)1842
70JCS(C)2206
70J CS( C )2298
70JCS(C)2403
70JHC25
70JHC71
70JHC75
70JHCI17
70JHC2 [ I
70JHC215
70JHC227
70JHC247
70JHC355
70JHC36[
70JHC439
70JHC639
70JHC703
70JHC715
70JHC79 [
70JHC821
70JHC863
70JHC895
70JHC923
70JHC96[
70JHC991
70JHC [001
70JHCIOl9
70JHCI029
70JHC[[13
70JHCI149
70JHCI223
70JHC 1237
70JHC[269
70JHCI329
70JHCI391
70JHCI435
70JMC77
70JMCI64
70JMC777
70JOCI131
70JOC 1138
70JOC[ 146
70JOCI965
70JOC2074
References
B. Evans and R. Wolfenden; J. Am. Chern. Soc., 1970,92,4751.
S. Trofimenko; J. Am. Chern. Soc., 1970,92,5118.
A. B. Evnin, D. R. Arnold, L. A. Karnischky and E. Strom; J. Am. Chern. Soc.,
1970,92,6218.
C. E. Bugg and U. Thewalt; J. Am. Chern. Soc., 1970,92,7441.
K. Nakanishi, N. Furutachi, M. Funamizu, D. Grunberger and 1. B. Weinstein;
J. Am. Chern. Soc., 1970,92,7617.
K. Shirakawa, O. Aki, Y. Nakagawa and K. Otsu; Jpn. Pat. 7039709 (1970)
(Chern. Abstr., 1971,75,5954).
H. Weiler-Feilchenfe[d and Z. Neiman; J. Chern. Soc. (B), 1970,596.
R. E. Burton and 1. L. Finar; J. Chern. Soc. (B), [970, 1692.
545,601
230
188
509
605
560
522
171,172,173,
174,175,176,177,742
134
747
695
774
272
115
776
626,644
194
531,564
336
754, 758
J. K. Landquist; J. Chern. Soc. (C), 1970,63.
M. A. Khan and J. B. Polya; J. Chern. Soc. (C), 1970,85.
A. Albert; J. Chern. Soc. (C), 1970,230.
G. V. Boyd and M. D. Harms; J. Chern. Soc. (C), 1970,807.
J. H. Lister, D. S. Manners and G. M. Timmis; J. Chern. Soc. (C), 1970, 1313.
G. V. Boyd and S. R. Dando; J. Chern. Soc. (C), 1970, 1397.
E. J. Browne, E. E. Nunn and J. B. Polya; J. Chern. Soc. (C), [970, 1515.
A. Albert and K. Ohta; J. Chern. Soc. (C), 1970, 1540.
J. Feeney. G. A. Newman and P. J. S. Pauwels; J. Chern. Soc. (C), 1970, 1842.
G. Shaw and B. M. Smallwood; J. Chern. Soc. (C), 1970,2206.
S. M. Mackenzie and M. F. G. Stevens; J. Chern. Soc. (C), 1970,2298.
A. J. Blackman and J. B. Polya; J. Chern. Soc. (C), 2403.
M. A. Kira, M. N. Aboul-Enein and M. 1. Korkor; J. Heterocycl. Chern., 1970,
7,25.
J. H. Boyer and P. J. A. Frints; J. Heterocycl. Chern., 1970,7,71.
A. Giner-Sorolla; J. Heterocycl. Chern., 1970,7,75.
G. R. Revankar and L. B. Townsend; J. Heterocycl. Chern., 1970,7, [17.
V. Sunjic, T. Fajdiga and M. Japelj; J. Heterocycl. Chern., 1970,7,211.
J. A. Montgomery, H. J. Thomas and S. J. Clayton; J. Heterocycl. Chern., 1970,
7,215.
N. B[aievié, F. Kajfd and V. Sunjié; 1. Heterocycl. Chern., 1970,7,227.
M. A. Khan and B. M. Lynch; J. Heterocycl. Chern., 1970,7,247.
H. J. Beim and A. R. Day; 1. Heterocycl. Chern., 1970,7,355.
G. L'abbé and A. Hassner; J. Heterocycl. Chern., 1970,7,361.
R. E. Harmon, V. L. Rizzo and S. K. Gupta; J. Heterocycl. Chern., [970,7,439.
V. Pirc, B. Stanovnik, M. Tis[er, J. Marsel and W. W. Paudler; J. Heterocycl.
Chern., 1970,7,639.
S. Portnoy; J. Heterocycl. Chern., 1970,7,703.
C. L. Schmidt and L. B. Townsend; 1. Heterocycl. Chern., 1970,7,715.
1. Perillo and S. Lamden; J. Heterocycl. Chern., 1970,7,791.
T. Kametani, K. Sota and M. Shio; J. Heterocycl. Chern., 1970,7,821.
R. A. Long, J. F. Gerster and L. B. Townsend; J. Heterocycl. Chern., 1970,7,863.
W. H. De Camp and J. M. Stewart; J. Heterocycl. Chern., 1970,7, 895.
K. R. Henery-Logan and E. A. Keiter; J. Heterocycl. Chern., 1970,7,923.
J. E. Oliver and J. B. Stokes; J. Heterocycl. Chern., [970,7,961.
L. D. Hansen, E. J. Baca and P. Scheiner: J. Heterocycl. Chern., 1970,7,991.
F. H. Case; J. Heterocycl. Chern., 1970,7, 1001.
K. T. Potts and C. R. Surapaneni; J. Heterocycl. Chern., 1970,7, 1019.
M. Israel, S. K. Tinter, D. H. Trites and E. J. Modest; J. Heterocycl. Chern., 1970,
7, 1029.
R. Pater; J. Heterocycl. Chern., [970,7, 1[13.
M. D. Coburn, E. D. Loughran and L. C. Smith; J. Heterocycl. Chern., 1970,7,
1149.
L. E. Brady; J. Heterocycl. Chern. 1970,7, 1223.
M. A. Khan and B. M. Lynch: J. Heterocycl. Chern., 1970,7, 1237.
G. Alonso, M. T. Garda-López, G. Garda-Muñoz, R. Madroñero and M. Rico;
J. Heterocycl. Chern., 1970,7, 1269.
G. R. Revankar and L. B. Towshend; J. Heterocycl. Chern., 1970,7, 1329.
M. D. Coburn and P. N. Neuman; J. Heterocycl. Chern., 1970,7, 1391.
G. Alonso, G. García-Muñoz and R. Madroñero; J. Heterocycl. Chern., 1970,7,
1435.
M. P. Mertes and A. J. Lin: J. Med. Chern., 1970, 13, 77.
H. R. Snyder, Jr. and L. E. Benjamin; J. Med. Chern., 1970, 13, 164.
L. Huff and R. A. Henry; J. Med. Chem., 1970, 13,777.
H. U. Blank, 1. Wempen and J. J. Fox; J. Org. Chern., 1970, 35, 1131.
B. Stanovnik, M. Tisler, M. Ceglar and V. Bah; J. Org. Chern., 1970,35, 1138.
E. C. Wu and J. D. Vaughan; J. Org. Chern., [970,35, 1146.
K. T. Potts and R. Armbruster; J. Org. Chern., 1970,35, 1965.
L. Huff, D. M. Forkey, D. W. Moore and R. A. Henry; J. Org. Chern., 1970,35,
2074.
126, 277
809
556
289
749
895
364
272, 331
635
685,713
358, 445
858, 860
883, 884
627
463
750
323, 324
179,181
281
443, 700
742
766
861, 862, 883,
884
592
731
750
801
230, 231
700
289
368
289
645
666
8[9
887
650
290
131
793
70JOC2215
70JOC2246
70JOC2478
70JOC2635
70JOC3097
70JOC3444
70JOC3448
70JOC345I
70JOC3768
70JOC398I
70JOM(21)427
70JPR610
70JPR669
70KGS248
70KGS259
70KGS265
70KGS269
70KGS558
70KGS851
70KGS991
70KGS997
70KGSI146
70KGSI621
70KGSI701
70LA(734)56
70LA(734)70
70LA(734) 173
70LA(735) 158
70LA(742)85
70M724
B-70MI40100
70MI40400
B-70MI4040 I
B-70MI40402
B-70MI40403
B-70MI40500
B-70MI40900
70MI40901
B-70MI40902
70MI40903
70MI40904
70MI40905
70MI41000
70MI41001
70MI41100
B-70MI41101
References
941
P. A. S. Smith, G. J. W. Breen, M. K. Hajek and D. V. C. Awang; J. Org. Chern.,
1970,35,2215. 98,697,707
R. A. Olofson and R. V. Kendall; J. Org. Chern., 1970,35,2246. 232,746,747
A. Pollak, B. Stanovnik and M. Tisler; J. Org. Chern., 1970, 35, 2478. 628, 860, 889
J. T. Witkowski and R. K. Robins; J. Org. Chern., 1970,35,2635. 758
A. B. Evnin, A. Lam and J. Blyskal; J. Org. Chern., 1970,35,3097. 426
R. E. Harmon, F. Stanley, Jr., S. K. Gupta and J. Johnson; J. Org. Chern., 1970,
35, 3444.
K. T. Potts and E. G. Brugel; J. Org. Chern., 1970,35,3448.
K. T. Potts and S. Husain; J. Org. Chern., 1970,35,3451.
S. P. McManus, J. T. Carroll and C. U. Pittman, Jr.; 1. Org. Chern., 1970,35,3768.
T. Kuneida and B. Witkop; J. Org. Chern., 1970,35,3981.
S. S. Washburne and W. R. Peterson, Jr.; J. Organornet. Chern., 1970,21,427.
H. G. O. Becker, G. Goermar and H. J. Timpe; J. Prakt. Chern., 1970,312,610.
692, 712
857, 873, 892, 893
701
141
530
779
755, 760,
767
H. G. O. Becker, D. Beyer, G. Israel, R. Muller, W. Riediger and H. J. Timpe;
J. Prakt. Chern., 1970,312,669.
V. Va. Grinshtein, A. A. Strazdin' and A. K. Grinvalde; Khirn. Geterotsikl. Soedin.,
1970,248.
L. I. Bagal, M. S. Pevzner, A. N. Frolov and N. I. Sheludyakova; Khirn.
Geterotsikl. Soedin., 1970,259.
L. I. Bagal, M. S. Pevzner, N. I. Sheludyakova and V. M. Kerusov; Khirn.
Geterotsikl. Soedin.," 1970, 265.
L. I. Bagal, M. S. Pevzner and V. Va. Samarenko; Khirn. Geterotsikl. Soedin.,
1970,269.
L. I. Bagal and M. S. Pevzner; Khirn. Geterotsikl. Soedin., 1970,558.
N. G. Koshel', E. G. Kovalev and I. Y. Postovskii; Khim. Geterotsikl. Soedin.,
1970,6,851.
O. P. Shvaika, V. V. Artemov and S. N. Baranov; Khirn. Geterotsikl. Soedin.,
1970,991.
L.1. Bagal, M. S. Pevzner, A. P. Egorov and V. Va. Samarenko; Khirn. Geterotsikl.
Soedin, 1970,997. 753,757,758
Y. M. Yutilov and R. M. Bystrova; Khirn. Geterotsikl. Soedin., 1970, 1146 (Chern.
Abstr., 1971,74,53655).
A. D. Grabenko, L. N. Kulaeva and P. S. Pelkis; Khirn. Geterotsikl. Soedin.,
1970, 1621 (Chern. Abstr, 1971,74,76359).
L. I. Bagal, M. S. Pevzner, V. Ya. Samarenko and A. P. Egorov; Khirn. Geterorsikl.
Soedin., 1970, 170 I.
B. Eistert and E. Endres; Liebigs Ann. Chern., 1970, 734, 56.
M. Regitz and G. Himbert; Liebigs Ann. Chern., 1970,734,70.
F. Boberg and R. Schardt, Liebigs Ann. Chern., 1970,734, 173.
K. Sasse; Liebigs Ann. Chern., 1970,735, 158.
A. Schoeberl and K. H. Magosch; Liebigs Ann. Chern., 1970,742,85.
J. Kobe, B. Stanovnik and M. Tisler; Monatsh. Chern., 1970, 101, 724.
J. A. Pople and D. L. Beveridge; 'Approximate Molecular Orbital Theory',
McGraw-Hili, New York, 1970, pp. 57-84.
M. A. Khan; Rec. Chern. Prog., 1970,31,43.
G. Berthier, L. Praud and J. Serre; in 'Quantum Aspects of Heterocyclic Com-
pounds in Chemistry and Biochemistry', ed. E. D. Bergmann and B. Pullman;
Israel Academy of Science, Jerusalem, 1970, p. 40. 172,177,183,190
P. A. S. Smith; in 'Nitrenes', ed. W. Lwowsld; Wiley-Interscience, New York,
1970, p. 144.
'The Chemistry of Synthetic Dyes and Pigments', ed. H. A. Lubs; American
Chemical Society, Washington, 1970.
R. J. Suhadolnik; 'Nucleoside Antibiotics', Wiley-Interscience, New York, 1970,
p.354.
R. J. Suhadolnik; 'Nucleoside Antiobiotics', Wiley- Interscience, New York, 1970.
899
739
754
746, 754
753
742, 746
878, 882
771
618
118
753
706,721
703
281
765
664
631
7
231
263
298,290
343
504,601,
602, 603
522
S. Arnott; Prog. Biophys. Mol. BioI., 1970,21,265.
H. Weiler-Feilchenfeld and Z. Neiman; in 'Quantum Aspects of Heterocyclic
Compounds in Chemistry and Biochemistry', ed. E. D. Bergman and B.
Pullman; Academic, New York, 1970, p. 308.
B. M. Pyatin. V. G. Granik and R. G. Glushov; Khirn.-Farrn. Zh., 1970,4,22
(Chern. Abstr., 1971,74, 112016).
J. A. Miller; Cancer Res., 1970,30,559.
G. Stohrer and G. B. Brown; Science, 1970,167, 1622.
H. O. Hankovszky and K. Hideg; Acta Chirn. (Budapest), 1970,63,447 (Chern.
Abstr., 1970,72, 100597).
L. Del Corona, G. Massaroli and G. Signorelli; Boll. Chirn. Farm., 1970, 109,
665 (Chern. Abstr., 1971,75, 20297).
K. Fukui; Fortschr. Chern. Forsch., 1970,15, I.
P. Scheiner; in 'Selective Organic Transformations', ed. B. S. Thyagarajan;
Wiley-Interscience, New York, 1970, vol. I, p. 327. 670,704,724
521
566
526
539
663
636
711
942
B-70M141102
70MI41300
700MS(3) 1 549
700MS(4)203
70PAC(24)495
70PNA(65)27
70SAP6804307
70TI393
70T2497
70T26 I 9
70T3069
70T3357
70T3965
70T4339
70T49 I 5
70T4969
70TH40400
70TL943
70TLl013
70TLl411
70TL 1879
70TL2823
70TL3099
70TL378I
70TL385I
70TL4215
70TL46I I
70TL5083
70TL5225
70UP40400
70USP3541093
70USP3549633
70YZ423
70YZ441
70YZ707
70ZC220
70ZC224
70ZC338
70ZN(B)421
70Z0R908
71ACRIO
71ACRI7
71 ACS249
71ACS625
71ACS2087
71AFI532
7IAG(E)743
7IAG(E)810
7IAHC(l3)77
71AJC393
71AJC645
71AJCI229
71 AJC 2405
71API21
71AP763
71 AX( B)573
7IAX(B)986
7IAX(B)1227
7IAX(B)1859
71BC1I85
71 BCJ858
71 B1(I25)841
References
J. P. Anselme; in 'The Chemistry of the Carbon-Nitrogen Double Bond', ed. S.
Patai; Wiley-Interscience, New York, 1970, p. 299. 717
Z. Grzonka; 1. ChromalOgr., 1970,51,310. 803
J. van Thuijl, K. J. Klebe and J. J. van Houte; Org. Mass Spectrom., 1970,3, 1549. 202
M. Ohashi, K. Tsujimoto, A. Yoshino and T. Yonezawa; Org. Mass Spectrom.,
1970,4,203. 687,688
H. Labhart, W. Heinzelmann and J. P. Dubois; Pure Appl. Chern., 1970,24,495. 160
A. J. Jones, M. W. Winkley, D. M. Grant and R. K. Robins; Proc. Natl. Acad.
Sci. USA, 1970,65,27. 515
W. B. Scanlon and W. L. Garbrecht; S. Afr. Pat. 6804 307 (1970) (Chern. Abstr.,
1970,73,56100). 835
G. Desimoni and G. Minoli; Tetrahedron, 1970,26, 1393. 706
A. W. K. Chan, W. D. Crow and I. Gosney; Tetrahedron, 1970,26,2497. 23
P. Scheiner and J. F. Dinda, Jr.; Tetrahedron, 1970,26,2619. 809
C. M. Gupta, A. P. Bhaduri and N. M. Khanna; Tetrahedron, 1970,26,3069. 768
J. Kobe, B. Stanovnik and M. Tisler; Tetrahedron, 1970,26,3357. 859,878,900
C. Wentrup and W. D. Crow; Tetrahedron, 1970,26,3965. 868,876
T. Aratani, Y. Nakanisi and H. Nozaki; Tetrahedron, 1970,26,4339. 724
C. Wentrup and W. D. Crow; Tetrahedron, 1970,26,4915. 881
C. Wentrup; Tetrahedron, 1970,26,4969. 860, 879
M. Roche; Ph.D. Thesis, University of Marseille, 1970. 198
E. J. Browne; Tetrahedron Lett., 1970,943. 93,784
R. P. Panzica and L. B. Townsend; Tetrahedron Lett., 1970, 1013. 646
J. Reiter, P. Sohar and L. Toldy; Tetrahedron Lett., 1970, 1411. 647
C. Belzecki and J. Trojnar; Tetrahedron Lett., 1970, 1879. 662
M. Regitz and G. Himbert; Tetrahedron Lett., 1970,2823. 692,703,712
J. Elguero, R. Jacquier and C. Marzin; Tetrahedron Lett., 1970,3099. 256
J. Goerdeler and K. Bruning; Tetrahedron Lett., 1970, 3781. 129
K. Sakai and J. P. Anselme; Tetrahedron Lett., 1970,3851. 744
M. A. Kira, Z. M. Nofal and K. Z. Gadalla; Tetrahedron Lett., 1970,4215. 126,277
M. Bobek, 1. Farkas and F. Sorm; Tetrahedron Lett., 1970,4611. 272
R. Grashey, M. Baumann and R. Hamprecht; Tetrahedron Lett., 1970,5083. 127
P. Ykman, G. L'abbé and G. Smets; Tetrahedron Lett., 1970,5225. 679,717
J. Eiguero, A. Fruchíer and R. GiI; unpublished results, 1970. 188,189
R. J. Tull and P. I. Pollak; U.S. Pat. 3541093 (1970) (Chern. Abstr., 1971,74,
141 878). 645
E. J. J. Grabowski, E. W. Tristram and R. J. Tull; U.S. Pat. 3549633 (1970)
(Chern. Abstr., 1971,74,53847). 646
S. Sugiura, S. Inoue and T. Goto; Yakugaku Zasshi, 1970,90,423 (Chern. Abstr.,
1970, 73, 45 459). 642
S. Sugiura, H. Kakoi, S. Inoue and T. Goto; Yakugaku Zasshi, 1970, 90, 441
(Chern. Abstr., 1970, 73, 45 462). 643
S. Sugiura, S. Inoue and T. Goto; Yakugaku Zasshi, 1970,90,707 (Chern. Abstr.,
1970, 73, 98 904). 643
R. Miethchen, A. H. Albrecht and E. Rachow; Z. Chern., 1970, 10,220. 699
G. Stríckmann and G. Barnikow; Z. Chern., 1970, 10, 224. 253
H. Lettau; Z. Chern., 1970,10,338. 367
R. Walentowski and H. W. Wanzlich; Z. Naturforsch., Teil B, 1970,25,421. 755
B. V. Ioffe, YU. P. Artsibasheva and L. M. Levina; Zh. Org. Khim., 1970,6,908. 281
A. Hassner; Acc. Chern. Res., 1971,4, 10. 829
S. Trofimenko; Acc. Chern. Res. 1971,4,17. 169
M. Begtrup; Acta Chern. Scand., 1971,25,249. 672,700
C. Christophersen and S. Treppendahl; Acta Chern. Scand., 1971,25,625. 793,832
M. Begtrup and K. V. Poulsen; Acta Chern. Scand., 1971,25,2087. 52,672.698
T. Wagner-Jauregg; Arzneim.-Forsch., 1969,19,1532. 343
T. Kauffmann; Angew. Chern., Int. Ed. Engl., 1971, 10,743. 168,258,268
K.-H. Magosch and R. Feinauer; Angew Chern., Int. Ed. Engl., 1971, 10,810. 148
B. Pullman and A. Pullman; Adv. Heterocycl. Chern., 1971,13,77. 501,506,521
E. J. Browne; Aust. J. Chern., 1971,24,393. 736,756
P. Dunn and D. Oldfield; AUst. J. Chern., 1971,24,645. 794
S. Beveridge and R. L. N. Harris; Aust. J. Chern., 1971,24, 1229. 135
R. K. Buckley, M. Davis and K. S. L. Srivastava; Aust. J. Chern., 1971,24,2405. 95
F. Eiden and G. Evers; Arch. Pharm. (Weinheim, Ger.), 1971,304,121 (Chern.
Abstr., 1971,75,5833). 316
R. Weidlein and H. Krull; Arch. Pharm. (Weinheim, Ger.) 1971,304,763. 127
E. Thorn and A. T. Christensen; Acta Crystallogr., Part B, 1971,27,573. 179
M. N. Sabesan and K. Venkatesan; Acta Crystallogr., Part B, 1971,27,986. 179
W. H. De Camp and J. M. Stewart; Acta Crystallogr., Part B, 1971,27, 1227. 178
C. A. Kosky, P. Ganis and G. Avitabile; Acta Crystallogr., Part B, 1971,27,1859. 227
T. Sasaki, T. Yoshioka and Y. Suzuki; Bull. Chern. Soc. Jpn., 1971,44, 185. 719
T. Sasaki, K. Kanematsu and M. Uchide; Bull. Chern. Soc. Jpn., 1971,44,858. 340
P. F. Swann and P. M. Magee; Biochem. J., 1971,125,841. 531
71 BRPI232758
71BRPI238105
71 BRPI248146
71BSF679
71BSFl031
71 BSFI040
7IBSFI925
71BSF3043
71BSF3296
71BSF3642
71BSF4021
71CBI562
71CB2053
71CB3062
71CB3146
71CB3510
71 CB3925
71CB3940
71CB3947
71CB3955
71CB3965
71CC394
71CC490
71CC532
71CC537
71CC873
71CC889
71CCI022
71CCI519
71CHEI32
71CHE665
71CHE668
71CHE746
71CHE752
71CHE809
71CHEI036
71CHE1l56
71CHEI163
71CHEI534
71CJCI792
71CJC2139
71CJC3119
71CPBI611
71CPBI731
71 G569
71GEPI950076
71GEP2129855
R. J. Tull and P. I. Pollak; Br. Pat. 1232758 (1971) (Chern. Abstr., 1971,75,49
134). 646
R. J. Tull and P. I. Pollak; Br. Pat. 1238105 (1971) (Chern. Abstr., 1971,75,88
639). 626,646
R. J. Tull and P. I. Pollak; Br. Pat. 1248146 (1971) (Chern. Abstr., 1971,75, 140
887). 626,646
A. Lablache-Combier and M. A. Remy; Bull. Soc. Chirn. Fr., 1971,679. 169
P. Guerret, J.-L. Imbach, R. Jacquier, P. Martin and G. Maury; Bull. Soc. Chirn.
Fr., 1971, 1031. 649
R. Jacquier, J.-M. Lacombe and G. Maury; Bull. Soc. Chirn. Fr., 1971, 1040. 354
J. Eiguero; Bull. Soc. Chirn. Fr., 1971, 1925. 220,255,276
J. Daunis, M. Guerret-Rigail and R. Jacquier; Bull. Soc. Chirn. Fr., 1971,3043. 857, 889,
902
J. Daunis, Y. Guindo, R. Jacquier and P. Viallefont; Bull. Soc. Chirn. Fr., 1971,
3296. 741,744, 757, 782
F. Texier and R. Carrié; Bull. Soc. Chirn. Fr., 1971,3642. 703
J. Roggero and M. Audibert; Bull. Soc. Chirn. Fr., 1971,4021. 130
E. Brunn, E. Funke, H. Gotthardt and R. Huisgen; Chern. Ber., 1971,104,1562. 473,489
W. Broser and U. Bollert; Chern. Ber., 1971,104,2053. 281
L. Birkofer and M. Franz; Chern. Ber., 1971,104,3062. 184
H. R. Kricheldorf; Chern. Ber., 1971,104,3146. 138
H. Wamhoff and P. Sohár; Chern. Ber., 1971,104,3510. 704,715,721
H. Reimlinger, J.-M. Gilles, G. Anthoine, J. J. M. Vandewalle, W. R. F. Lingier,
E. de Ruiter, R. Merényi and A. Hubert; Chern. Ber., 1971, 104,3925. 853,865,866
H. Reimlinger, W. R. F. Lingier and J. J. M. Vandewalle; Chern. Ber., 1971,104,
3940.
H. Reimlinger, W. R. F. Lingier, J. J. M. Vandewalle and R. Merényi; Chern.
Ber., 1971, 104,3947.
H. Reimlinger, J. J. M. Vandewalle, W. R. F. Lingier and F. Billiau; Chern. Ber.,
1971, 104,3955.
H. Reimlinger, W. R. F. Lingier, J. J. M. Vandewalle and R. Merényi; Chern.
Ber., 1971, 104,3965. - 853, 866, 886
J. A. Elvidge, J. R. Jones and C. O'Brien; Chern. Cornrnun., 1971,394. 526
P. Rajagopalan and P. Penev; Chern. Cornrnun., 1971,490. 794
C. W. Rees and A. A. Sale; Chern. Cornrnun., 1971,532. 723
P. J. Fagan and M. J. Nye; Chern. Cornrnun., 1971,537. 327
K. Bolton, R. D. Brown, F. R. Burden and A. Mishra; Chern. Cornrnun., 1971,873. 738
W. F. Cooper, N. C. Kenny, J. W. Edmonds, A. Nagel, F. Wud1 and P. Coppens;
Chern. Cornrnun., 1971,889.
G. Kan, M. T. Thomas and V. Snieckus; Chern. Cornrnun., 1971, 1022.
T. L. Gilchrist, G. E. Gymer and C. W. Rees; Chern. Cornrnun., 1971, 1519.
A. M. Simonov and I. I. Popov; Chern. Heterocyc/. Cornpd. (Eng/. Trans/.), 1971,
7,132.
I. Y. Postovskii and V. A. Ershov; Chern. Heterocyc/. Cornpd. (Eng. Trans/.), 1971,
7,665.
V. A. Ershov and I. Y. Postovskii; Chern. Heterocyc/. Cornpd. (Eng!. Trans/.),
1971,7,668.
Yu. Va. Usaevich, I. Kh. Fel'dman and E. I. Boksiner; Chern. Heterocyc/. Cornpd.
(Eng/. Trans/.), 1971,7, 749.
A. F. Pozharskii, I. S. Kashparov, Yu. P. Andreichikov, A. I. Buryak, A. A.
Konstantinchenko and A. M. Simonov; Chern. Heterocyc/. Cornpd. (Eng/.
Trans/.), 1971,7,752.
A. D. Gamovskii, Yu. V. Kolodyazhnyi, O. A. Osipov, V. I. Minkin, S. A. Giller,
I. B. Mazheika and I. I. Grandberg; Chern. Heterocyc/. Cornpd. (Eng/. Trans/.),
1971,7,809.
A. F. Pozharskii, V. V. Kuz'menko and A. M. Simonov; Chern. Heterocyc/. Cornpd.
(Eng!. Trans/.), 1971,7, 1036.
A. F. Pozharskii, É. A. Zvezdina, I. S. Kashparov, Yu. P. Andreichikov, V. M.
Mar'yanovskii and A. M. Simonov; Chern. Heterocycl. Cornpd. (Eng/. Trans/.),
1971,7, 1156.
B. A. Tertov, A. V. Koblik and N. I. Avdyunina; Chern. Heterocycl. Cornpd.
(Eng/. Trans!.), 1971,7, 1163.
A. P. Sineokov and V. S. Kutyreva; Chern. Heterocyc/. Cornpd. (Eng!. Trans/.),
1971,7, 1534.
R. Raap; Can. J. Chern., 1971,49,1792.
R. Raap; Can. J. Chern., 1971,49,2139
J. W. Lown and K. Matsumoto; Can. J. Chern., 1971,49,3119.
T. Fujii and T. Itaya; Chern. Pharrn. Bull., 1971,19, 1611.
T. Fujii, T. Sato and T. Itaya; Chern. Pharrn. Bull., 1971, 19, 1731.
A. C. Veronese, C. DiBello, F. Filira and F. D'Angeli; Gazz. Chirn. Ita/., 1971,
101,569 (Chern. Abstr., 1972,76,3810).
E. Scheiffele; Ger. Pat. 1950076 (1971) (Chern. Abstr., 1971,75,36 102).
GAF Corporation, Ger. Pat. 2 129855 (1971) (Chern. Abslr., 1972,76, 128833).
References
943
866
865, 866
866
9
161
692
438
852
852
424, 443
368
351
410
442
448
139
69, 698
802
341
539
554
658
340
730
944
71GEP2129863
71GEP2 I 29864
71 HC(24-2) 1
711C661
711C2594
7lJA1534
7lJAI880
7lJA1887
7lJA3056
7lJA6129
7lJA7045
7lJAP7133956
7lJAP7133957
7lJAP(K)7135742
7lJCS(B)415
7lJCS(B)1648
7I1CS(B)2299
7I1CS(B)2350
7I1CS(B)2365
7I1CS(C)409
7I1CS(C)675
7lJCS(C)679
7lJCS(C)703
7I1CS(C)706
7lJCS(C)1016
7I1CS(C)1193
7I1CS(C)1482
7I1CS(C)1501
7I1CS(C)1610
7lJCS(C)1615
7I1CS(C)2147
7lJCS(C)2156
7lJCS(C)2748
7I1CS(C)3910
711HC25
7lJHC37
7lJHC47
711HC137
711HCI73
711HC311
7lJHC379
711HC415
7lJHC557
711HC571
711HC643
71JHC657
711HC707
7lJHC773
711HC785
7lJHC835
7lJHC1035
711MC997
7110CI0
7110C222
7110C446
7IJOC 1589
7IJOCI846
7IJOC2635
7IJOC3084
7110C3087
71100211
References
GAF Corporation, Ger. Pat. 2 129863 (1971) (Chern. Abstr., 1972,76, 128832). 730
GAF Corporation, Ger. Pat. 2 129864 (1971) (Chern. Abstr., 1972, 76, 99674). 731
J. H. Lister; Chern. Heterocycl. Compd., 1971,24(2), 1. 501,517,518,533,
538,540, 548, 551, 558
796
227
812
514
J. Adamson and E. E. Glover; J. Chern. Soc. (C), 1971,2748.
M. F. Lappert and J. S. Poland; J. Chern. Soc. (C), 1971,3910.
D. G. Farnum, A. T. Au and K. Rasheed; J. Heterocycl. Chern., 1971,8,25.
W. W. Paudler, D. J. Pokorny and J. J. Good; J. Heterocycl. Chern., 1971,8,37.
A. Lewis and R. G. Shepherd; 1. Heterocycl. Chern., 1971,8,47.
hM. Ruccia, N. Vivona and G. Cusmano; J. Heterocycl. Chern., 1971,8, 137.
F. H. Case; J. Heterocycl. Chern., 1971,8, 173.
J. van Thuijl, K. J. Klebe and J. J. van Houte; J. Heterocycl. Chern., 1971,8,311.
G. H. Milne and L. B. Townsend; J. Heterocycl. Chern., 1971,8,379.
P. Francavilla and F. Lauria; J. Heterocycl. Chern., 1971,8,415.
J. P. Chupp; J. Heterocycl, Chern., 1971,8,557.
S. N. Lewis, G. A. Miller, M. Hausman and E. C. Szamborski; J. Heterocycl.
Chern., 1971, 8, 571. 15
P. Guerret, R. Jacquier and G. Maury; J. Heterocycl. Chern., 1971,8,643. 627,643,648,
858, 861, 862, 876
23
246
741
342
116
273
291,292
128
117
709, 882,
902, 903
160, 809
131
N. C. -Baenziger and R. J. Schultz; Inorg. Chern., 1971,10,661.
J. Reedijk, B. A. Stork-Blaise and G. C. Verschoor; Inorg. Chern., 1971,10,2594.
R. M. Moriarty and P. Serridge; 1. Am. Chern. Soc., 1971,93, 1534.
R. J. Pugmire and D. M. Grant; J. Am. Chern. Soc., 1971,93, 1880.
R. J. Pugmire, M. J. Robins, D. M. Grant and R. K. Robins; J. Am. Chern. Soc.,
1971,93, 1887.
N. J. Leonard, A. J. Play tis, F. Skoog and R. Y. Schmitz; J. Am. Chern. Soc.,
1971,93,3056.
E. E. van Tamelen and T. H. Whitesides; J. Am. Chern. Soc., 1971,93,6129.
P. Haake, L. P. Bausher and J. P. McNeal; J. Am. Chern. Soc., 1971,93, 7045.
S. Kawano, S. Zoga, H. Watanabe and T. Sato; Jpn. Pat. 7133956 (1971) (Chern.
Absrr., 1976, 76, 3902).
S. Kawano, S. Zoga, H. Watanabe and T. Sato; Jpn. Pat. 7133957 (1971) (Chern.
Abstr., 1971, 75, 151 835).
T. Kamitani, S. Tsubouchi and N. Yamamoto; Jpn. Kokai 7135 742 (1971)(Chem.
Abstr., 1972, 76, 14550).
G. Casalone and A. Mugnoli; J. Chern. Soc. (B), 1971,415.
G. V. Boyd and A. J. H. Summers; J. Chern. Soc. (B), 1971, 1648.
P. Dembeck, A. Ricci, G. Seconi and P. Vivarelli; J. Chern. Soc. (B), 1971,2299.
S. O. Chua, M. J. Cook and A. R. Katritzky; J. Chern. Soc. (B), 1971,2350.
A. G. Burton, P. P. Forsythe, C. D. Johnson and A. R. Katritzky; J. Chern. Soc.
(B), 1971,2365.
G. V. Boyd and A. J. H. Summers; J. Chern. Soc. (C), 1971,409.
J. Clark and T. Ramsden; J. Chern. Soc. (C), 1971,675.
J. Clark and T. Ramsden; J. Chern. Soc. (C), 1971,679.
F. L. Scott and 1. C. Tobin; J. Chern. Soc. (C), 1971,703.
D. R. Sutherland and G. Tennant; 1. Chern. Soc. (C), 1971,706.
A. J. Blackman and J. B. Polya; J. Chern. Soc. (C), 1971, 1016.
A. J. Boulton, I. J. Fletcher and A. R. Katritzky; 1. Chern. Soc. (C), 1971, 1193.
G. Barker and G. P. Ellis; J. Chern. Soc. (C), 1971, 1482.
N. J. Cusack, G. Shaw and G. J. Litchfield; 1. Chern. Soc. (C), 1971, 1501.
B. G. Hildick and G. Shaw; J. Chern. Soc. (C), 1971, 1610.
D. J. Dunwell and D. Evans; J. Chern. Soc. (C), 1971, 1615.
T. Sasaki and K. Kanematsu; J. Chern. Soc. (C), 1971,2147.
D. R. Sutherland and G. Tennant; J. Chern. Soc. (C), 1971,2156.
G. A. Miller and M. Hausman; J. Heterocycl. Chern., 1971,8,657.
O. Tsuge and H. Samura; J. Heterocycl. Chern., 1971,8,707.
K. T. Potts, R. Armbruster and E. Houghton; J. Heterocycl. Chern., 1971,8,773.
B. Stanovnik and M. Tisler; J. Heterocycl. Chern., 1971,8,785.
I. Lalezari and A. Shafiee; J. Heterocycl. Chern., 1971,8, 835.
E. Ajello; J. Heterocycl. Chern., 1971, 8, 1035.
H. V. Secor and J. F. De Bardeleben; J. Med. Chern., 1971, 14,997.
K. T. Potts and S. Husain; J. Org. Chern., 1971,36, 10.
R. W. Franck and S. J. M. Gilligan; J. Org. Chern., 1971,36,222.
T. Sasaki, K. Kanematsu and M. Murata; J. Org. Chern., 1971,36,446.
c. S. Angadiyavar and M. V. George; J. Org. Chern., 1971,36, 1589.
K. T. Potts and R. Armbruster; 1. Org. Chern., 1971,36, 1846.
N. J. M. Birdsall, T. C. Lee, T. J. Delia and J. C. Parshaw; J. Org. Chern., 1971,
36, 2635.
P. Cohen-Fernandes and C. L. Habraken; J. Org. Chern., 1971,36,3084.
M. Fraser; J. Org. Chern., 1971,36,3087.
E. C. Taylor, G. P. Beardsley and Y. Maki; 1. Org. Chern., 1971,36,3211.
306
601
220
92
645
645
836
9
755, 774
443
369
223,238
773
648
647,648
802
679,696
740, 758
87
136
59
316,343
655
184,282
856, 874,
875, 894, 713
643
717
327
611,613
887
775
766
202,290
563
869
466
539
235,259,270
309
591
7IJOC3368
7IJOC3594
7IJOC3807
7 IJOM(27) I 85
7IJPR722
7IJPR882
7IJPRI148
7IJPS74
7IJST(9)32 I
7IJST(9)465
71KGS39
71KGS275
71KGS279
71KGS428
71KGS471
7 I KGS700
71KGS867
7ILA(743)50
7 I LA(750)39
71M837
B-7 I M 140200
71MI40400
71MI40401
71MI40500
B-71MI40900
B-71MI40901
B-71MI40902
71 MI40903
7IMI40904
71MI40905
71MI40906
71MI40907
71MI40908
71MI41100
71MI41 !OI
71MI41102
B-71 MI41 103
B-71MI41104
71MI41200
71MI41300
B-71MI41400
71MI41500
B-7IMS
7IOMR(3)595
710MS(5)1
710MS(5)427
710MS(5)663
7IOMS(5)IIOI
7IPMH(3)1
7IPMH(3)67
71 PMH(3)77
7IPMH(3)103
References
945
K. T. Potts and S. Hussain; J. Org. Chern., 1971,36,3368.
H. Steinmaus, I. Rosenthal and D. EIad; J. Org. Chern., 1971,36,3594.
T. Isida, S. Kozima, K. Nabika and K. Sisido; J. Org. Chern., 1971,36,3807.
D. H. O'Brien and C. P. Hrung; J. Organornet. Chern., 1971,27, 185.
K. Fabian and H. Hartmann; J. Prakt. Chern., 1971,313,722.
S. Hauptmann, H. Wilde and K. Moser; J. Prakt. Chern., 1971,313,882.
G. Bamikow and J. Boedeker; J. Prakt. Chern., 1971,313, 1148.
J. P. LaRocca, C. A. Gibson and B. B. Thompson; J. Pharrn. Sci., 1971,60,74.
O. Martensson; J. Mol. Struct., 1971,9,321.
G. L. Blackman, R. D. Brown, F. R. Burden and A. Mishra; J. Mol. Struct., 1971,
9,465.
O. P. Shvaika, V. N. Artemov and S. N. Baranov; Khirn. Geterotsikl. Soedin.,
1971,39.
M. S. Pevzner, E. Ya. Fedorova, I. N. Shokhor and L. I. Bagal; Khirn. Geterotsikl.
Soedin., 1971,275.
A. V. Kazymov, L. P. Schelkina and N. G. Kabirova; Khirn. Geterotsikl. Soedin.,
1971,279 (Chern. Abstr., 1971,75,35878).
Y. M. Yutilov and I. A. Svertilova; Khirn. Geterotsikl. Soedin., 1971,428 (Chern.
Abstr., 1972,76, 3755).
M. O. Lozinskii, A. F. Shivanyuk and P. S. Pe1kis; Khirn. Geterotsikl. Soedin.,
1971,471 (Chern. Abstr., 1972,76,25184). 129,131,138
L. A. Vlasova and I. Ya. postovskii; Khirn. Geterotsikl. Soedin., 1971, 700. 747
A. D. Garnovski, Y. V. Kolodyahnyi, O. A. Osipov, V. I. Minkin, S. A. Hiller,
I. B. Mazheika and I. I. Grandberg; Khirn. Geterotsikl. Soedin., 1971,867.
K. D. Hesse; Liebigs Ann. Chern., 1971,743,50.
H. Dorn and D. Arndt; Liebigs Ann. Chern., 1971,750,39.
V. Pirc, B. Stanovnik and M. Tisler; Monatsh. Chern., 1971,102,837.
A. R. Katritzky and J. M. Lagowski; 'Chemistry of the Heterocyclic N-Oxides',
Academic, New York, 1971, p. 51.
D. N. Kravtsov, L. A. Fedorov, A. S. Peregudov and A. A. Nesmeyanov; Proc.
Acad. Sci. USSR (Engl. Transl.), 1971, 196, 18.
E. Kochanski, J. M. Lehn and B. Levy; Theor. Chirn. Acta, 1971,22, Ill.
H. Dahn and J. P. Fumeaux; Bull. Soc. Vaudoise Sci. Natur., 1970,70, 313 (Chern.
Abstr., 1971,75, 140791).
F. C. Sleward and A. D. Krikorian; 'Plants, Chemicals and Growth', 1971,
Academic, New York.
R. H. Hall; 'The Modified Nucleosides in Nucleic Acids', 1971, Columbia
University Press, New York. 560,561,562,604
A. R. Katritzky and J. M. Lagowski; 'Chemistry of the Heterocyclic N-Oxides',
Academic, London, 1971. 501,554,562
Z. Neiman; Isr. J. Chern., 1971,9, 119. 541,543
L. A. Gutorov, L. A. Nikolaeva and E. S. Golovchinskaya, Khirn.-Farrn. Zh.,
1971,5, 17 (Chern. Abstr., 1972,76, 126935).
J. Filip and L. Bohacek; Radioisotopy, 1971,12,949.
K. Nakanishi, S. H. Blobstein, M. Funamizu, N. Furutachi, G. van Lear, D.
Grunberger, K. Lanks and I. B. Weinstein; Nature (London), 1971,234, 107.
N. C. Yang, L. S. GoreIic and B. Kim; Photochern. Photobiol., 1971, 13,275.
J. Schmidt and D. C. Borg; Radiation Res., 1971,46,36.
J. M. Stewart, R. L. Clarke and P. E. Pike; J. Chern. Eng. Data, 1971, 16, 98
(Chern. Abstr., 1971,74,76377).
L. Y. Ezerskya and N. A. Petrusha; Onkologiya, 1971,2,45.
N. A. Petrusha; Onkologiya, 1971,2,10.
D. Philips; in 'Photochemistry', Chemical Society, London, 1971, vol. 2, p. 795.
T. Sheradsky; in 'The Chemistry of the Azido Group', Wiley, New York, 1971,
p.331. . 670,705, 708, 710
I. Simiti and D. Ghiran; Farrnacia (Bucharest), 1971, 19, 199 (Chern. Abstr.,
1971,75,76692).
A. J. Barratt, L. R. Bates, J. M. Jenkins and J. R. White; U.S. NTIS. AD. Rep.,
1971, No. 752370 (Chern. Abstr., 1973,78,124508).
I. Ugi; 'Isonitrile Chemistry', Academic, New York, 1971.
G. Fischer; Wiss. Z. Tech. Hochsch. Chern. 'Carl Schlorlernrner' Leuna-Merseburg,
1971, 13, 71 (Chern. Abstr., 1971,75,48939).
Q. N. Porter and J. Baldas; 'Mass Spectrometry of Heterocyclic Compounds',
Wiley, New York, 1971.
R. M. Claramunt, J. EIguero and R. Jacquier; Org. Magn. Reson., 1971,3,595.
K. T. Potts, E. Brugel and U. P. Singh; Org. Mass Spectrorn., 1971,5, l.
F. Compernolle and M. Dekeirel; Org. Mass Spectrorn., 1971,5,427.
K. T. Potts and E. Brugel; Org. Mass Spectrorn., '1971,5,663.
J. van Thuijl, K. J. Klebe and J. J. van Houte; Org. Mass Spectrorn., 1971,5, 1101.
A. Albert; Phys. Methods Heterocycl. Chern., 1971,3, I.
W. L. F. Armarego; Phys. Methods Heterocycl. Chern., 1971,3,67.
W. L. F. Armarego; Phys. Methods Heterocycl. Chern., 1971,3,77.
W. L. F. Armarego; Phys. Methods Heterocycl. Chern., 1971,3, 103.
372, 402, 438
545
793,815
213
119
134,706
136
647
12
290
776
742
617
618,621
176,177
284
236
880
55
236
195
337
601
563
563
605
545
520
717
729
729
731
764
837
845
904
30, 202
182
853
686
859
202
50,51
21,23, 197,198,199
684
684
946
71 PM H(3)297
7IPMH(4)21
7IPMH(4)55
7IPMH(4)121
71 PMH(4)265
71RTC594
71RTC654
71RTCI166
71RTCI181
71 RTCI225
71SAP7004373
71TI23
71T133
71T361
71 T845
71TI783
711'2317
711'2415
71 T2453
71T4117
71T5121
71T5359
71T5623
71T5873
71TH40400
71TL633
71TLl441
71TLl591
71 TLl993
71TL2725
71TL4243
71 TL4489
71 USP3565892
71ZCI53
71ZCI79
71ZC421
72AC(R) I I
72ACRIO
72ACS21
72ACS541
72ACS1243
72AG1187
72AG(E)846
72AG(E) I 102
72AHC(l4)1
72AHC(l4)43
72AJC335
72AX(B)79I
72AX(B)1982
72AX(B)3316
72B1235
72BBR(46)125
72BBR(46)597
72BCJl47 I
References
Va. L. Gol'dfarb, V. I. Yakerson, V. A. Ferapontov, S. Z. Taits and F. M.
Stoyanovich; Phys. Methods Heterocycl. Chern., 1971,3,297. 32,207
E. A. C. Lucken; Phys. Methods Heterocycl. Chern., 1971,4,21. 195
J. H. Ridd; Phys. Methods Heterocycl. Chern., 1971,4,55. 70,241
R. F. M. White and H. Williams; Phys. Methods Heterocycl. Chern., 1971,4,121. 13, 14,
15, 18,678
A. R. Katritzky and P. J. Taylor; Phys. Methods Heterocycl. Chern., 1971,4,265. 24,
25, 199, 20 I, 202, 739
D. A. de Bie, H. C. van der Plas and G. Guertsen; Recl. Trav. Chirn. Pays-Bas,
1971,90,594.
K. B. De Roos and C. A. Salemink; Recl. Trav. Chirn. Pays-Bas, 1971,90,654.
411
615,
618
K. B. De Roos and C. A. Salemink; Recl. Trav. Chirn. Pays-Bas, 1971,90, 1166. 618
K. B. De Roos and C. A. Salemink; Recl. Trav. Chirn. Pays-Bas, 1971,90, 1181. 867,887
C. Hoogzand; Recl. Trav. Chirn. Pays-Bas, 1971,90, 1225. 853,856,865,886
H. O. Bayer, R. S. Cook and W. C. Yon Meyer; S. Afr. Pat. 7004373 (1971)
(Chern. Abstr., 1972, 76, 113 224).
J. Eiguero, R. Jacquier and D. Tizané; Tetrahedron, 1971,27, 123.
J. Eiguero, R. Jacquier and D. Tizane; Tetrahedron, 1971,27, 133.
C. Wentrup and W. D. Crow; Tetrahedron, 1971,27,361.
G. L'abbé, P. Ykman and G. Smets; Tetrahedron, 1971,27,845.
Z. Grzonka and B. Liberek; Tetrahedron, 1971,27, 1783.
Z. Grzonka, E. Rekowska and B. Liberek; Tetrahedron, 1971, 27, 2317 (see also
other papers of the series).
T. Fujii, T. Itaya, C. C. Wu and F. Tanaka; Tetrahedron, 1971,27,2415.
J. P. Albrand, A. Cogne, D. Gagnaire and J. B. Robert; Tetrahedron, 1971,27,
2453.
R. Neidlein and H. Reuter; Tetrahedron, 1971,27,4117.
T. Sasaki, K. Kanematsu and M. Murata; Tetrahedron, 1971,27,5121.
787
189,211
18
881
704,716
834
834
554
354, 355
130
709, 854, 857,
860, 879, 901
T. Sasaki, K. Kanematsu and M. Murata; Tetrahedron, 1971,27,5359. 879
P. Ykman, G. L'abbé and G. Smets; Tetrahedron, 1971,27,5623. 679,704,709,716
H. Wamhoff, H. W. Dürbeck and P. Sohár; Tetrahedron, 1971,27,5873. 712
S. Mignonac-Mondon; Ph. D. Thesis, University of Montpellier, 1971. 216
C. S. Angadiyavar, K. B. Sukumaran and M. V. George; Tetrahedron Left., 1971,
633.
E. Abushanab; Tetrahedron Left., 1971, 1441.
J. Farkas and Z. Flegelova; Tetrahedron Left., 1971, 1591.
N. K. Kochetkov, V. W. Shibaev and A. A. Kost; Tetrahedron Lect., 1971, 1993.
H. Kasai, M. Goto, S. Takemura, T. Goto and S. Matsuura; Tetrahedron Left.,
1971,2725.
D. Kobelt, E. Paulus and G. Lohaus; Tetrahedron Lect., 1971,45,4243.
P. Scheiner; Tetrahedron Left., 1971,4489.
U.S. Pat. 3565892 (1971) (Chern. Abstr., 1971,75,36041).
G. Henning and F. Wolff; Z. Chern., 1971,11, 153.
J. Sieler, H. Wilde and S. Hauptmann; Z. Chern., 1971, 11, 179.
H. Hartmann; Z. Chern., 1971, 11,421.
727
644
276
648
605
9
810
661
756
134, 706
140
G. Werber, F. Buccheri and M. L. Marino; Ann. Chirn. (Rome), 1972, 62, II
(Chern. Abstr., 1972,77,48004). 136
J. L. Kurz; Acc. Chern. Res., 1972,5, 10. 601
L. O. Carlsson; Acta Chern. Scand., 1972, 26, 21. 209
A. K. Sorensen and N. A. Klitgaard; Acta Chern. Scand., 1972,26,541. 819
M. Begtrup; Acta Chern. Scand., 1972,26, 1243. 695
D. Seebach and D. Enders; Angew. Chern., 1972,84, 1187. 717
T. Kauffman, J. Legler, E. Ludorff and H. Fischer; Angew. Chern., Int. Ed. Engl.,
1972, 11,846. 753, 756
D. Seebach and D. Enders; Angew. Chern., Int. Ed. Engl., 1972, 11, 1102. 717
K. R. H. Wooldridge; Adv. Heterocycl. Chern., 1972,14, 1. 47,58,61,63,65,69,
75, 88, 91, 93, 97, 98, 100, 104, 106, 108, 135
M. Davis; Adv. Heterocycl. Chern., 1972, 14,43. 47, 85,94,97
A. J. Blackman and J. H. Bowie; Aust. l. Chern., 1972,25,335. 741
J. Lapasset and J. Falgueriettes; Acta Crysta/logr., Part B, 1972, 28, 791. 178
T. F. Lai and R. E. Marsh; Acta Crystallogr., Part B, 1972,28, 1982. 509
J. Lapasset, A. Escande and J. Falgueirettes; Acta Crystallogr., Part B, 1972,28,
3316. 178
M. Tomasz, J. Olson and C. M. Mercado; Biochemistry, 1972, 11, 1235. 527
H. Berthod and B. Pullman; Biochern. Biophys. Res. Cornrnun., 1972,46, 125. 522
J. R. Barrio, J. A. Secrisl, III and N. J. Leonard; Biochern. Biophys. Res. Cornrnun.,
1972,46,597. 610,648
T. Isida, S. Kozima, S.-I. Fujimori and K. Sisido; Bull. Chern. Soc. lpn., 1972,
45, 1471. 793
72BRP1269619
72BSB295
72BSF248I
72BSF2807
72BSF3503
72CB103
72CB188
72CB196
72CB388
72CB794
72CB1497
72CB1759
72CB2963
72CB2975
72CC37
72CC126
72CC 199
72CC544
72CC709
72CC78 I
72CC827
72CC1059
72CHE57
72CHE445
72CHE742
72CHEII31
72CHE1142
72CHE1280
72CHE1533
72CI(L)294
72CJC3186
72CJC3472
72CPB69
72CPB605
72CPB623
72CPB958
72CPB2096
72CR(C)(274)1192
72CR(C)(274)2192
72CRV497
72CSC253
72E1198
72G23
72G491
72GEP2032088
72GEP2032172
72GEP2060196
72GEP2226525
72HCA565
72HCA919
72HCA2633
P. Guerret, R. Jacquier and G. Maury; Bull. Soc. Chirn. Fr., 1972,3503.
H. Reimlinger, M. A. Peiren and R. Merényi; Chern. Ber., 1972,105, 103.
H. Gotthardt; Chern. Ber., 1972, 105, 188.
H. Gotthardt; Chern. Ber., 1972, 105, 196.
E. Kranz, J. Kurz and W. Donner; Chern. Ber., 1972, 105,388.
H. Reimlinger, M. A. Peiren and R. Merenyi; Chern. Ber., 1972,105,794.
W. Pfleiderer, tyt. Shanshal and K. Eistetter; Chern. Ber., 1972, 105, 1497.
L. Birkofer and M. Franz; Chern. Ber., 1972, 105, 1759.
G. Himbert and M. Regitz; Chern. Ber., 1972, 105, 2963.
G. Himbert and M. Regitz; Chern. Ber., 1972, 105,2975.
C. L. Habraken and P. Cohen-Fernandes; J. Chern. Soc., Chern. Cornrnun., 1972,
37.
J. P. Ferris and F. R. Antonucci; 1. Chern. Soc., Chern. Cornrnun., 1972, 126.
F. Texier, R. Carrie and J. Jaz; 1. Chern. Soc., Chern. Cornrnun., 1972, 199.
P. G. Harrison; 1. Chern. Soc., Chern. Cornrnun., 1972,544.
J. Castells, M. A. Merino and M. Moreno-Mañas; J. Chern. Soc., Chern. Cornrnun.,
1972,709.
P. Scheiner and W. M. Litchman; 1. Chern. Soc., Chern. Cornrnun., 1972,781.
A. A. Reid, J. T. Sharp and S. J. Murray; 1. Chern. Soc., Chern. Cornrnun., 1972,
827.
T. Tsuchiya, H. Arai and H. Igeta; J. Chern. Soc., Chern. Cornrnun., 1972, 1059.
Yu. N. Portnoy, G. A. Go1ubeva and A. N. Kost; Chern. Heterocyc1. Cornpd.
(Eng/. Trans/.), 1972,8, 57.
M. A. Lapitskaya, A. D. Garnovskii, G. A. Golubeva, Yu. V. Kolodyazhnyi, S. A.
Alieva and A. N. Kost; Chern. Heterocycl. Cornpd. (Eng/. Trans/.), 1972,8,445.
P. M. Kochergin, M. A. Klykov and I. S. Mikhailova; Chern. Heterocyc1. Cornpd.
(Eng/. Trans/.), 1972,8,742.
A. F. Pozharskii, V. V. Kuz'menko, Yu. V. Kolodyazhnyi and A. M. Simonov;
Chern. Heterocyc1. Cornpd. (Eng/. Trans/.), 1972,8, 1131.
O. N. Poplin and V. G. Tishchenko; Chern. Heterocyc1. Cornpd. (Eng/. Transl.),
1972,8, 1142.
M. M. Medvedeva, A. F. Pozharskii and A. M. Simonov; Chern. Heterocyc1.
Cornpd. (Eng/. Trans/.), 1972,8, 1280.
S. N. Kolodyazhnaya, A. M. Simonov and I. G. Uryukina; Chern. Heterocyc1.
Cornpd. (Eng/. Trans/.), 1972,8, 1533. 353,429,439
H. Reimlinger; Chern. Ind. (London), 1972,294. 822
D. M. Findlay, M. L. Roy and S. McLean; Can. J. Chern., 1972,50,3186. 720
R. S. Glass, J. S. Blount, D. Butler, A. Perrotta and E. P. Oliveto; Can. J. Chern.,
1972,50,3472.
A. Nakamura and S. Kamiya; Chern. Pharrn. Bull., 1972,20,69.
Y. Maki and E. C. Taylor; Chern. Pharrn. Bull., 1972, 20, 605.
H. Yamada and T. O. Kamato; Chern. Pharrn. Bull., 1972,20,623.
T. Fujii, T. Itaya and S. Moro; Chern. Pharrn. Bull., 1972,20,958.
S. Kubota and M. Uda; Chern. Pharrn. Bull., 1972,20,2096.
J. L. Aubagnac, J. Eiguero, B. Rérat, C. Rérat and Y. Uesu; c.R. Hebd. Seances
Acad. Sci., Ser. C, 1972,274, 1192.
G. Barnathan, T. H. Dinh, A. Ko1b and J. Igo1en; c.R. Hebd. Seances Acad. Sci.,
Ser. C, 1972,274,2192.
S. Trofimenko; Chern. Rev., 1972,72,497.
B. Bovio and S. Locchi; Cryst. Stmct. Cornrnun., 1972, 1, 253.
G. Magnusson, J. A. Nyberg, N. O. Bodin and E. Hansson; Experientia, 1972,
28,1198.
G. D. Andreetti, G. Bocelli, L. Cavalca and P. Sgarabolto; Gazz. Chirn. Ital.,
1972, 102, 23.
G. Desimoni, A. Gamba, P. P. Righetti and G. Tacconi; Gazz. Chirn. Ita/., 1972,
102, 491.
ClBA-Geigy AG, Ger. Pat. 2032088 (1972) (Chern. Abstr., 1972,76, 128835).
Bayer AG, Ger. Pat. 2032172 (1972) (Chern. Abstr., 1972,76, 128834).
H. Maeder, R. Otto, P. Marx and W. Puesche1; Ger. Pat. 2 060196 (1972) (Chern.
Abstr., 1973, 78, 22 517).
G. J. Smets and J. M. Vandensavel; Ger. Pat. 2226525 (1972) (Chern. Abstr.,
1973, 78, 58984).
C. Wentrup; He/v. Chirn. Acta, 1972,55, 565.
B. Jackson, M. Märky, H.-J. Hansen and H. Schmid; He/v. Chirn. Acta, 1972,
55,919.
C. Wentrup, C. Thétaz and R. G1eiter; He/v. Chirn. Acta, 1972,55, 2633.
References
E. Regel, K. H. Buechel, R. R. Schmidt and L. Eue; Br. Pat. 1269619 (1972)
(Chern. Abstr., 1972,77,5477).
C. Draguet and M. Renson; Bull. Soc. Chirn. Be/g., 1972,81,295.
P. Guerret, R. Jacquier and G. Maury; Bull. Soc. Chirn. Fr., 1972,2481.
J. E1guero, R. Jacquier and S. Mignonac-Mondon; Bull. Soc. Chirn. Fr., 1972,2807.
947
745, 787
154
628
12,
261, 262
647
822
150
150
306, 312, 342
142
574
184,267
692
692
752
274
154
752
212
809
268
880
257
178
447
346,410
468
407
351
314
134
568
554
740, 758
179
585
169,225,226,235,236
178
302
9
208
730
730
837
838
881
154
881
948
72JA1199
72JA2460
72JA2530
72JA5759
72JA6337
72JAP(K)7225190
72JAP(K)7242770
72JCS(PI)46I
72JCS(PI )619
72JCS( P [)769
72JCS( P [)783
72JCS( P [ )909
72JCS(PI)914
72JCS( P I )997
72JCS(PI)1519
72JCS(PI)1918
72JCS( P [ )2567
72JCS( P2)68
72JCS(P2)585
72JCS( P2)632
72JCS( P2) I 077
72JCS(P2) [420
72JCS(P2)1654
72JCS( P2 )22 [ 8
72JHC41
72JHC87
72JHC99
72JHC235
72JHC363
72JHC46 I
72JHC465
72JHC581
72JHC623
72JHC7[7
72JHC939
72JHC95I
72JHC[ 157
72JHC[ 171
72JHC[ 195
72JHC1373
72JHC1385
72JMC[82
72JMC694
72JMC841
72JMC879
72JOC343
72JOC1454
72JOC[464
721OC[867
7210C [871
72JOC2022
72J00049
72JOC2158
72JOC2259
72J00351
72J 00 I 06
References
B. Singh, A. Zweig and J. B. Gallivan; J. Am. Chern. Soc., 1972,94, 1199.
J. D. Vaughan and W. A. Smith; J. Am. Chern. Soc., 1972,94,2460.
R. L. Tolman, C. W. Smith and R. K. Robins; J. Am. Chern. Soc., 1972,94,2530.
H. Kohn, S. J. Benkovic and R. A. Olofson; J. Am. Chern. Soc., 1972,94,5759.
C. W. Gillies and R. L. Kuczkowski; J. Am. Chern. Soc., 1972,94,6337.
T. Irikura, K. Kasuga, T. Hashizume, M. Ohashi, M. Yuge and M. Yamada;
(Kyorin Pharmaceutical Co. Ltd.), Jpn. Kokai 72 25190 (1972) (Chern. Abstr.,
1973, 78, 4251).
K. Sugiura, R. Ushijima and K. Shimizu; Jpn. Kokai 72 42770 (1972) (Chern.
Abstr., 1973, 78, 72 158).
A. Albert; 1 Chern. Soc., Perkin Trans. 1, 1972,461.
D. Pocar, R. Stradi and L. M. Rossi; J. Chern. Soc., Perkin Trans. 1, 1972,619.
D. Pocar, R. Stradi and L. M. Rossi; J. Chern. Soc., Perkin Trans. 1, [972,769.
T. Sasaki, K. Kanematsu and K. Hayakawa; J. Chern. Soc., Perkin Trans. I, 1972,
783.
G. V. Boyd and P. H. Wright; J. Chern. Soc., Perkin Trans. 1, 1972,909.
G. V. Boyd and P. H. Wright; J. Chern. Soc., Perkin Trans. 1, 1972,914.
G. Bianchetti, R. Stradi and D. Pocar; J. Chern. Soc., Perkin Trans. 1, 1972,997.
R. N. Butler, P. O'Sullivan and F. L. Scott; J. Chern. Soc., Perkin Trans. I, [972,
1519 and earlier references listed therein.
F. L. Scott, T. M. Lambe and R. N. Butler; J. Chern. Soc., Perkin Trans. 1, 1972,
1918.
V. Caló, F. Cimina[e, L. Lopez, F. Naso and P. E. Todesco; J. Chern. Soc., Perkin
Trans. 1, 1972,2567.
S. Bradbury, C. W. Rees and R. C. Storr; J. Chern. Soc., Perkin Trans. 2,1972,68.
Z. Neiman; J. Chern. Soc., Perkin Trans. 2, 1972,585.
M. W. Austin; J. Chern. Soc., Perkin Trans. 2, 1972,632.
P. J. Taylor; 1 Chern. Soc., Perkin Trans. 2, 1972, 1077.
F. Pietra and F. De[ Cima; 1 Chern. Soc., Perkin Trans. 2, [972, 1420.
M. R. Grimmett, S. R. Hartshorn, K. Schofield and J. B. Weston; J. Chern. Soc.,
Perkin Trans. 2, 1972, 1654.
G. G. Aloisi, E. Bordignon and A. Signor; 1 Chern. Soc., Perkin Trans. 2, 1972,
2218.
B. T. Gillis and R. A. Izydore; J. Heterocycl. Chern., 1972,9,41.
R. Selvarajan and J. H. Boyer; J. Heterocycl. Chern., 1972,9,87.
T. Hirata, L.-M. Twanmoh, H. B. Wood, Jr., A. Goldin and J. S. Driscoll; J.
Heterocycl. Chern. 1972, 9, 99.
H. Höhn, T. Denzel and W. Janssen; 1 Heterocycl. Chern., [972,9,235.
J. T. Edward and I. Lantos; J. Heterocycl. Chern., [972,9,363.
J. P. Paolini; J. Heterocycl. Chern., 1972,9,461.
T. Itoh, S. Kitano and Y. Mizuno; J. Heterocycl. Chern., [972, 9, 465.
G. Pifferi and P. Consonni; J. Heterocycl. Chern., 1972, 9, 581.
R. P. Panzica and L. B. Townsend; J. Heterocycl. Chern., [972,9,623.
M. T. García-Lopez, G. García-Muñoz and R. Madroñero; 1 Heterocycl. Chern.,
1972,9,717.
C. L. Habraken, C. I. M. Beenakker and J. Brussee; J. Heterocycl. Chern., 1972,
9, 939. 199,224,225
V. Sprio and S. Plescia; J. Heterocycl. Chern., 1972,9,951. 320,332
W. W. paud[er, C. I. P. Chao and L. S. Helmick; J. Heterocycl. Chern., 1972,9,
1157. 615,630,653,872
A. Bezeg, B. Stanovnik, B. Sket and M. Tisler; J. Heterocycl. Chern., [972,9, 1171. 869
F. A. Lehmkuhl, J. T. Witkowski and R. K. Robins; J. Heterocycl. Chern., 1972,
9,1195.
P. B. M. W. M. Timmermans, A. P. Uijttewaal and C. L. Habraken; J. Heterocycl.
Chern., [972,9, 1373. 182,260,261
D. L. Trepanier and P. E. Krieger; J. Heterocycl. Chern., 1972,9, 1385. 666
J. A. Montgomery and H. J. Thomas; J. Med. Chern., 1972, 15, 182. 652,852
B. B[ank, D. M. Nichols and P. D. Vaidya; J. Med. Chern., [972,15,694. 757
M. Kawana, G. A. Ivanovics, R. J. Rousseau and R. K. Robins; J. Med. Chern.,
1972, 15, 841.
W. Hutzenlaub, R. L. To[man and R. K. Robins; J. Med. Chern., 1972,15,879.
L. A. Lee, R. Evans and J. W. Wheeler; J. Org. Chern., [972,37,343.
K. B. Wagener, S. R. Turner and G. B. Butler; J. Org. Chern., 1972,37, 1454.
H. A[per and E. C. H. Keung; 1 Org. Chern., 1972,37, 1464.
A. A. Watson and G. B. Brown; J. Org. Chern., 1972,37, 1867.
G. Zvilichovsky and G. B. Brown; J. Org. Chern., 1972,37, 1871.
R. A. Abramovitch and T. Takaya; J. Org. Chern., 1972,37,2022.
K. T. Potts and S. Husain; J. Org. Chern., 1972,37,2049.
J. N. Wells, O. R. Tarwater and P. E. Manni; J. Org. Chern., 1972,37,2158.
161
241
712
806
[2
635
835
695
714
714
328
[ [3
1 [3
714
134
769
399
208
521
259
92
232
238,268
636
328
693
751
272, 322
367
901
6[5
779
652
703
700
T. J. Curphey and K. J. Prasad; 1. Org. Chern., 1972,37,2259.
K. Sakai and J. P. Anse1me; J. Org. Chern., 1972,37,2351.
T. Sasaki, K. Kanematsu and A. Kakehi; J. Org. Chern., 1972,37,3106.
652
876
766, 829
750
663
590, 596
596
856, 868, 888
701
425,
426,467
748
274
153, 339
72JOC3213
72JOC3504
72JOC3965
72JOC3985
72JOC4045
72JOC4124
72JOC4136
72JOC4401
72JOC4410
72JOC4464
72JOM(39) 179
72JOM(44)117
72JPC3362
72JPRI01
72JPR515
72JPR923
72KGS691
72LA(757)9
72LA(759) 107
72LA(764) 112
72 M 140300
72 M 140400
72MI40600
B-72MI40900
B-72MI40901
B-72MI40902
72MI40903
72MI41000
72MI41200
72MI41201
72MI41202
72MI41300
72MI41301
72MIP41000
720MR(4)247
720MS(6)1139
72PAC(30)135
72PAC(30) 145
72PMH(5)1
72RTC650
72RTC850
72S259
72S618
72T21
72T637
72T3845
72T3987
72T5207
72T5779
72TL439
72TL2235
72TL2239
References
949
P. Ykman, G. Mathys, G. L'abbé and G. Smets; J. Org. Chern., 1972,37,3213.
H. Kohn and R. A. Olofson; J. Org. Chern., 1972,37,3504.
S. Hammerum and P. Volkoff; J. Org. Chern., 1972,37,3965.
C. G. Tindall, Jr., R. K. Robins and R. L. Tolman; J. Org. Chern., 1972,37,3985.
J. Buter, S. Wassenaar and R. M. Kellogg; J. Org. Chern., 1972,37,4045.
C. A. Lovelette and L. Long, Jr.; 1. Org. Chern., 1972,37,4124.
R. W. Begland and D. R. Hartter; J. Org. Chern., 1972,37,4136.
R. A. Wohl and D. F. Headley; J. Org. Chern., 1972,37,4401.
K. T. Potts, J. Bhattacharyya, S. L. Smith, A. M. Ihrig and C. A. Girard; J. Org.
Chern., 1972,37,4410.
E. C. Taylor and F. Yoneda; J. Org. Chern., 1972,37,4464.
S. S. Eaton, G. R. Eaton and R. H. Holm; J. Organornet. Chern., 1972,39, 179.
S. Kozima, T. Itano, N. Mihara, K. Sisido and T. Isida; J. Organornet. Chern.,
1972,44,117.
J. Hennessy and A. C. Testa; J. Phys. Chern., 1972,76,3362.
H. G. O. Becker, H. Goermar, H. Haufe and H. J. Timpe; J. Prakt. Chern., 1972,
314, 101.
E. Kleinpeter, R. Borsdorf, G. Fischer and H.-J. Hofmann; J. Prakt. Chern., 1972,
314,515.
H. G. O. Becker and R. Ebisch; J. Prakt. Chern., 1972,314,923.
N. O. Saldabol and J. Popelis; Khirn. Geterotsikl. Soedin., 1972, 691 (Chern.
Abstr., 1972,77, 126503).
K. Burger, J. Fehn and A. Gieren; Liebigs Ann. Chern., 1972,757,9.
M. Haake, H. Fode and B. Eichenauer; Liebigs Ann. Chern., 1972,759, 107.
M. Brugger and F. Korte; Liebigs Ann. Chern., 1972, 764, 112.
1. Z. Siemion, W. Steglich and L. Wilschowitz; Rocz. Chern., 1972,46, 21.
F. A. Cotton and D. J. Ciappenelli; Symh. React. lnorg. Meta/-Org. Chern., 1972,
2, 197.
C. G. Begg and M. R. Grimmett; J. ChrornaLOgr., 1972,73,238.
G. C. Levy and G. L. Nelson; 'Carbon-13 NMR for Organic Chemists', Wiley-
Interscience, New York, 1972.
J. B. Stothers; 'Carbon-13 NMR Spectroscopy', in 'Organic Chemistry', ed. A.
T. Blomquist and H. Wasserman; Academic, New York, 1972. 510,554,555
A. Pullman and B. Pullman; in 'Jerusalem Symposium on Quantum Chemistry
and Biochemistry', Israel Academy of Sciences and Humanities, 1972, vol. 4,
p. I. 501,505,507,508,510,511,512,
513,519,522,523,555,556
J. Igolen, K. H. Dinh, A. Kolb and C. Perreur; J. Med. Chirn. Ther., 1972,7,207. 585
B. Bobranski and J. Stankiewicz; Diss. Pharrn. Pharrnacol., 1972,24,301. 637
M. A. Khan and J. B. Polya; Rev. Latinoarner. Quirn., 1972,3,119 (Chern. Abstr.,
1973,78,72019).
A. V. Radushev and E. N. Prokhorenko; Zh. Anal. Khirn., 1972,27,2209 (Chern.
Abstr., 1973,78,66590).
R. J. Cotter and M. Matzner; 'Ring-forming Polymerizations Part Rl, Heterocyc-
lic Rings', Academic, New York, 1972.
J. H. Nelson and F. G. Baglin; Spectrosc. Lell., 1972,5,101 (Chern. Abstr., 1972,
77, 47707).
N. V. Schwartz; J. Appl. Polyrn. Sci., 1972,16,2715 (Chern. Abstr., 1973,78,17288).
Y. M. Yutilov and L. 1. Kovaleva; USSR Pat. 332 089 (1972) (Chern. Abstr., 1972,
77, 114408).
R. Stradi, D. Pocar and G. Bianchetti; Org. Magn. Reson., 1972,4,247.
A. Maquestiau, Y. Van Haverbeke and R. Flammang; Org. Magn. Spectrorn.,
1972,6, 1139. 741
J. E. Guillet; Pure Appl. Chern., 1972,30, 135. 731
H. J. Heller and H. R. Blattmann; Pure Appl. Chern., 1972,30, 145. 731
P. J. Wheatley; Phys. Methods Heterocycl. Chern., 1972,5, I. 9,178,179,501,507,517
J. E. Schelling and C. A. Salemink; Recl. Trav. Chirn. Pays-Bas, 1972,91,650. 618,
619,635
496
727
601
337
716
763
204
553
147
854,878,897
127,472
156
853
581
213
682,710
433
767
853,858
751
611
717
131
654
113
213
362
510
754
785
788, 789
806
837
622
714
P. J. Lont and H. C. van der Plas; Recl. Trav. Chirn. Pays-Bas, 1972,91,850.
M. Cinquini and S. Colonna; Synthesis, 1972,259.
J. Corse and J. Kuhnle; Synthesis, 1972,618.
Y. Tamura, N. Tsujimoto, Y. Sumida and M. Ikeda; Tetrahedron, 1972,28,21.
M. Witanowski, L. Stefaniek, H. Januszewski, Z. Grabowski and G. A. Webb;
Tetrahedron, 1972,28,637. 672,684,741,805
P. Bravo, G. Gaudiano, P. P. Ponti and C. Ticozzi; Tetrahedron, 1972,28,3845. 164
K. B. Sukumaran, C. S. Angadiyavar and M. V. George; Tetrahedron, 1972,28,
3987.
F. Khuong-Huu, J. P. Le Forestier and R. Goutarel; Tetrahedron, 1972,28,5207.
C. Glier, F. Dietz, M. Scholz and G. Fischer; Tetrahedron, 1972,28, 5779.
E. Zbiral and E. Hugl; Tetrahedron Lell., 1972,439.
W. D. Crow, A. R. Lea and M. N. Paddon-Row; Tetrahedron Lell., 1972,2235.
W. D. Crow, M. N. Paddon-Rowand D. S. Sutherland; Tetrahedron Lell., 1972,
2239.
702
647
858
648
222
867
950
72TL3637
72TL4179
72TL4719
72ZC 130
72ZCI75
73ACS66I
73ACS1509
73ACSI845
73ACS 1987
73ACS2051
73ACS2757
73ACS3101
73AG447
73AG(E)240
73AG(E)405
73AG(E)455
73AG(E)591
73AG(E)806
73AJC 1585
73AJC2435
73AJC2683
73API55
73AP209
73AP561
73AP697
73AP730
73AP801
73AX(B)714
73AX(B)1974
73 B 188
73BCJ506
73BCJ667
73BCJl250
73 BC Jl836
73BCJ2176
73BCJ2215
73BCJ2600
73BSF288
73BSF1849
73BSF2676
73BSF2996
73BSF3159
73BSF3401
73BSF3442
73CB288
73CB745
73CB1589
73CB2070
73CB2415
73CB2925
73CB3092
73CB3203
73CB3391
73CB3421
73CC7
73CC402
73CC917
73CHE88
I. Søtofte; Acta Chern. Scand., 1973,27,661. 178
M. Y. Ali, J. Dale and K. Titlestad; Acta Chern. Scand., 1973,27, 1509. 643
T. La Cour and S. E. Rasmussen; Acta Chern. Scand., 1973,27,1845. 178,179
C. E. Olsen; Acta Chern. Scand., 1973,27, 1987. 714
M. Begtrup; Acta Chern. Scand., 1973,27,2051. 266
H. Rasmussen and E. Sletten; Acta Chern. Scand., 1973,27,2757. 509
M. Begtrup; Acta Chern. Scand., 1973,27,3101. 190,191,192,354
C. Derycke, V. Jaeger, M. van Meersche and H. G. Viehe; .4ngew. Chern., 1973,
85,447.
M. Franck-Neumann and C. Buchecker; Angell'. Chern., Int. Ed. Engl., 1973, 12,
240.
F. Hervens and H. G. Viehe; Angell'. Chern., Int. Ed. Engl., 1973,12,405.
F. A. Neugebauer; Angell'. Chern., Int. Ed. Engl., 1973,12,455.
W. Saenger; Angel\'. Chern., Int. Ed. Engl., 1973,12,591.
H. G. Viehe and Z. Janousek; Angel\'. Chern., Tnt. Ed. Engl., 1973, 12,806.
J. B. Po1ya and M. Woodruff; Aust. l. Chern., 1973,26, 1585.
C. G. Begg, M. R. Grimmett and P. D. Wethey; Aust. l. Chern., 1973,26,2435.
D. J. Gale and J. F. K. Wilshire; Aust. l. Chern., 1973,26,2683.
J. Reisch and W. F. Ossenkop; Arch. Pharrn. (Weinheirn, Ger.), 1973,306, 155.
H. Moehrle and S. Mayer; Arch. Pharrn. (Weinheirn, Ger.), 1973,306,209.
A. Kreutzberger and R. Schucker; Arch. Pharrn. (Weinheirn, Ger.), 1973,306,561.
A. Kreutzberger and R. Schucker; Arch. Pharrn. (Weinheirn, Ger.), 1973,306,697.
A. Kreutzberger and R. Schucker; Arch. Pharrn. (Weinheirn, Ger.), 1973,306,730.
A. Kreutzberger and R. Schucker; Arch. Pharrn. (Weinheirn, Ger.), 1973,306,801.
T. P. Singh and M. Vijayan; Acta Crystallogr., Part B, 1973,29,714.
T. J. Kistenmacher; Acta Crystallogr., Part B, 1973,29, 1974.
S. H. Blobstein, D. Grunberger, I. B. Weinstein and K. Nakanishi; Biochemistry,
1973, 12, 188.
Y. Ohtsuka; Bull. Chern. Soc. lpn., 1973,46,506.
Y. Hayasi, H. Nakamura and H. Nozaki; Bull. Chern. Soc. lpn., 1973,46,667.
T. Isida, T. Akiyama, N. Mihara, S. Kozima and K. Sisido; Bull. Chern. Soc.
lpn., 1973,46, 1250. 741,766,794
F. Yoneda, M. Higuchi, T. Matsumura and K. Senga; Bull. Chern. Soc. lpn.,
1973,46, 1836.
T. Isida, T. Akiyama. K. Nabika, K. Sisido and S. Kozima; Bull. Chern. Soc.
lpn., 1973,46,2176.
I. Arai; Bull. Chern. Soc. lpn., 1973,46,2215.
T. Nagai, Y. Fukushima, T. Kuroda, H. Shimizu, S. Sekiguchi and K. Matsui;
Bull. Chern. Soc. lpn., 1973, 46, 2600.
J. L. Aubagnac, 1. E1guero and J. L. Gilles; Bull. Soc. Chirn. Fr., 1973,288.
J. L. Barascut, R. M. Claramunt and J. Eiguero; Bull. Soc. Chirn. Fr. 1973, 1849.
C. Chapuis, A. Gauvreau, A. Klaebe, J. J. Périé and J. Roussel; Bull. Soc. Chirn.
Fr., 1973,2676.
C. Malavaud, M.-T. Boisden and J. Barrans; Bull. Soc. Chirn. Fr., 1973,11,2996.
P. Bouchet and C. Coquelet; Bull. Soc. Chirn. Fr., 1973,3159.
J. Eiguero and C. Marzin; Bull. Soc. Chirn. Fr., 1973,3401.
R. Mertz, D. Van Assche, J. P. Fleury and M. Regitz; Bull. Soc. Chirn. Fr., 1973,
3442.
A. Gieren; Chern. Ber., 1973, 106,288.
W. Sucrow, M. Slopianka and C. Mentzel; Chern. Ber., 1973,106,745.
F. A. Neugebauer and H. Fischer; Chern. Ber., 1973, 106, 1589.
J. Reisch and W. F. Ossenkop; Chern. Ber., 1973, 106,2070.
P. Schneiders, J. Heinze and H. Baumgarte1; Chern. Ber., 1973,106,2415.
H. J. Schrepfer, L. Capuano and H.-L. Schmidt; Chern. Ber., 1973, 106,2925.
A. Engelmann and W. Kirmse; Chern. Ber., 1973, 106,3092.
W. Hutzenlaub, H. Yamamato, G. B. Barlin and W. Pl1eiderer; Chern. Ber., 1973.
106, 3203.
A. Haas and V. Plass; Chern. Ber., 1973,106,3391.
K. Burger and K. Einhellig; Chern. Ber., 1973,106,3421.
E. E. Schweizer, C. S. Zim, C. L. Labaw and W. P. Murray; l. Chern. Soc., Chern.
Cornrnun., 1973,7.
M. J. Nye, M. J. O'Hare and W. P. Tang; l. Chern. Soc., Chern. Cornrnun., 1973,
402.
T. Fujii, T. Itaya, K. Mohri and T. Saito; l. Chern. Soc., Chern. Cornrnun., 1973.
917.
A. D. Garnovskii, A. M. Simonov and V. I. Minkin; Chern. Heterocycl. Cornpd.
(Engl. Transl.), 1973, 9, 88.
References
J. L. Huppatz; Tetrahedron Leu., 1972,3637.
M. Zupan, B. Stanovnik and M. Tisler; Tetrahedron Lett., 1972, 4179.
H. Mackie and G. Tennant; Tetrahedron Leu., 1972,4719.
G. Barnikov and H. Ebeling; Z Chern., 1972, 12, 130.
G. Wagner and S. Leistner; Z Chern., 1972, 12, 175.
268
890
852
135
779
768, 785
318
277
792, 800
523
128
768
377, 378
246
218
633
656
657
657
656
178
509
605
591
154
580
818
744
443
243
747
354
17
286
278
713
179
281
794
219
113
821
28!
592
130
780
277
201
586
347.349
73CHE465
73CHElO74
73CHEI173
73CHEI175
73CI(L)371
73CJCI741
73CJC2315
73CJC3765
73CPB692
73CPB 1342
73CPBI470
73CPBI676
73CPB2026
73CPB2146
73CPB2517
73CR(C)(277) 1153
73CR(C)(277) I 163
73CRV93
73CSC469
73CSC473
73DOK(21 [)1369
73FES624
73 FRP2135297
73GEP2133998
73GEP2210633
73GEP2245447
73GEP23I 0049
73GEP2314238
73HC(27)801
73HC(27)807
73HC(27)818
73IC508
73IJC747
73IJC753
73JA27
73JA324
73JA4452
73JA7174
73JA8452
73JAP7308667
73JAP7389932
73JCS(PI)I64
73JCS(PI)170
73JCS(PI)221
73JCS(PI)319
73JCS(PI)469
73JCS(PI)545
73JCS(PI)555
73JCS(PI)705
73JCS(PI)943
73JCS(PI)1209
73JCS(PI)1357
References
S. S. Novikov, L. I. Khmel'nitskii, O. V. Lebedev, V. V. Sevastyanova and L. V.
Epishina; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1973,9,465.
I. N. Somin, N. I. Shapranova and S. G. Kuznetsov; Chern. Heterocycl. Cornpd.
(Engl. Transl.), 1973,9, 1074.
V. I. Ofitserov, Z. V. Pushkareva, V. S. Mokrushin and K. V. Ag[itskaya; Chern.
Heterocycl. Cornpd. (Engl. Transl.), 1973,9, 1173.
L. B. Volodarskii; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1973,9, [175.
R. N. Butler; Chern. Ind. (London), 1973,371.
A. Taurins and V. T. Khouw; Can. J. Chern., 1973,51,1741.
R. N. Butler; Can. J. Chern., 1973,51,2315.
J. Rokach, Y. Girard and J. G. Atkinson; Can. J. Chern., 1973,51,3765.
A. Yamazaki, T. Furukawa, M. Akiyama, M. Okutsu, I. Kumashiro, and M.
Ikehara; Chern. Pharrn. Bull., 1973,21,692.
S. Kubota and M. Uda; Chern. Pharrn. Bull., 1973,21, 1342.
M. Kamiya and Y. Akahori; Chern. Pharrn. Bull., 1973,21, 1470.
T. Fujii, C. C. Wu, T. Itaya, S. Moro and T. Saito; Chern. Pharrn. Bull., 1973,
21, 1676.
H. Ogura, K. Kubo, Y. Watanabe and T. Itoh; Chern. Pharrn. Bull., 1973,21,2026.
S. Suzue, M. Hirobe and T. Okamoto; Chern. Pharrn. Bull., 1973,21,2146.
T. Tsuchiya, H. Arai and H. Igeta; Chern. Pharrn. Bull., 1973,21,2517.
M. Ferrey, A. Robert and A. Foucaud; c.R. Hebd. Seances Acad. Sci., Ser. C,
1973,277, 1153. .
M. M. L. Pappalardo, J. Eiguero and C. Marzin; C.R.Hebd. Seances Acad. Sci.,
Ser. C, 1973,277, 1163 (Chern. Abstr., 1974,80,70186).
R. N. Butler, F. L. Scott and T. A. F. O'Mahony; Chern. Rev., 1973,73,93.
F. Bechtel, J. Gaultier and C. Hauw; Cryst. Struct. Cornrnun., 1973,3,469.
F. Bechtel, J. Gaultier and C. Hauw; Cryst. Struct. Cornrnun., 1973,3,473.
V. N. Artemov, S. N. Baranov, N. A. Kovach ahd O. P. Shvaika; Dok/. Akad.
Nauk SSSR, 1973,211, 1369.
A. Gasco, V. Mortarini and E. Reynaud; Farrnaco Ed. Sci., 1973,28,624.
C. J. Cavallito and A. P. Gray; Fr. Pat. 2 [35297 (1973) (Chern. Abstr., [973,79,
96989).
Ger. Pat. 2133998 (1973) (Chern. Abstr., 1973,78,97690).
H. Meyer, F. Bossert, W. Vater and K. Stoepel; Ger. Pat. 2 210633 (1973) (Chern.
Abstr., 1973,79, 146519).
W. J. Chambers; Ger. Pat. 2245447 (1973) (Chern. Abstr., 1973,79,5460).
E. F. George and W. D. Riddell; Ger. Pat. 2310049 (1973) (Chern. Abstr., 1974,
80, 23 539).
H. Moeller and C. Gloxhuber; Ger. Pat. 2314238 (1973) (Chern. Abstr., 1975,
82, 4263).
M. Tisler and B. Stanovnik; Chern. Heterocycl. Cornpd., 1973,27,801.
M. Tisler and B. Stanovnik; Chern. Heterocycl. Cornpd., 1973,27, 807.
M. Tisler and B. Stanovnik; Chern. Heterocycl. Cornpd., 1973,27, 818.
L. J. Guggenberger, C. T. Prewitt, P. Meakin, S. Trofimenko and J. P. Jesson;
Inorg. Chern., 1973, 12, 508.
J. Mohan, V. K. Chadha and H. K. Pujari; Indian J. Chern., 1973,11,747.
P. B. Talukdar, S. K. Sengupta and A. K. Datta; Indian J. Chern., 1973,11,753.
P. H. Kasai and D. McLeod; J. Am. Chern. Soc., 1973,95, 27.
H. Saitô, Y. Tanaka and S. Nagata; J. Am. Chern. Soc., 1973,95,324.
G. A. Rogers and T. C. Bruice; J. Am. Chern. Soc., 1973,95,4452.
C. R. Frihart and N. J. Leonard; J. Am. Chern. Soc., 1973,95,7174.
W. E. McEwen, P. E. Stott and C. M. Zepp; J. Am. Chern. Soc., 1973,95,8452.
M. Minagawa and M. Akutsu; Jpn. Pat. 7308667 (1973) (Chern. Abstr., 1973,
79, 19662).
T. Nakajo, S. Maeda and T. Kurahashi; Jpn. Pat. 73 89932 (1973) (Chern. Abstr.,
1974,81, 65 182).
F. T. Boyle and R. A. Y. Jones; J. Chern. Soc., Perkin Trans. I, 1973, 164.
F. T. Boyle and R. A. Y. Jones; J. Chern. Soc., Perkin Trans. I, 1973, 170.
C. W. Rees and M. Yelland; J. Chern. Soc., Perkin Trans. I, 1973,221.
H. E. Foster and J. Hurst; 1. Chern. Soc., Perkin Trans. I, 1973,319.
P. D. Dobbs and P. D. Magnus; J. Chern. Soc., Perkin Trans. 1, 1973,469.
C. W. Rees and A. A. Sale; J. Chern. Soc., Perkin Trans. I, 1973,545.
T. L. Gilchrist, G. E. Gymer and C. W. Rees; J. Chern. Soc., Perkin Trans. 1,
973, 5525.
R. Fielden, O. Meth-Cohn and H. Suschitzky; J. Chern. Soc., Perkin Trans. I,
1973,705.
D. R. Sutherland, G. Tennant and R. J. S. Vevers; J. Chern. Soc., Perkin Trans. 1,
1973,943.
T. Hirata, H. B. Wood, Jr. and J. S. Driscoll; J. Chern. Soc., Perkin Trans. 1,
1973, 1209.
R. N. Butler, T. M. Lambe, J. C. Tobin and F. L. Scott; J. Chern. Soc., Perkin
Trans. 1, 1973, 1357.
951
395
436
652,667
455, 474
792
136
182, 183,795
450
588
740
521
554, 555
248
338
880
129
799
253,254
178,181,
200
178
776
787
904
647
634
788
836
835
608,628
608
608
227
663
775
206
741
660
537
76
790
788
269
269
253, 326
332
812
719
692, 706
380, 409
894
751
754
952
73JCS(PI)1588
73JCS(PI)1620
73JCS(PI)1625
73JCS(PI)1634
73JCS(PI)1794
73JCS(PI )1903
73JCS(PI)2089
73JCS(PI)237[
73JCS( P 1)2506
73JCS(PI)2580
73JCS(PI )2595
73JCS(PI)2644
73JCS(PI)2901
73JCS(P2)1
73JCS(P2)4
73JCS(P2)9
73JCS(P2)568
73JCS( P2)936
73JCS(P2)137[
73JCS(P2)1675
73JCS(P2)1889
73JCS(P2)2036
73JCS( P2)2 [38
73JHC5
73JHC201
73JHC267
73JHC353
73JHC363
73JHC417
73JHC419
73JHC431
73JHC569
73JHC755
73JHC801
73JHC82 [
73JHC849
73JHC885
73JHCI021
73JHCI055
73JMC292
73JMC3[2
73JMC537
73JMC643
73JMC1272
73JMCI296
73JMR(l0)130
73JMR(l2)225
73JOC613
73JOC675
73JOC806
73JOC825
73JOC844
73JOC[095
D. W. Dunwell and D. Evans; J. Chern. Soc., Perkin Trans. I, 1973, 1588.
A. Albert and W. Pendergast; J. Chern. Soc., Perkin Trans. I, 19073, [620.
A. A[bert and W. Pendergast; J. Chern. Soc., Perkin Trans. I, 1973, 1625.
A. Albert; J. Chern. Soc., Perkin Trans. I, 1973, 1634.
A. Albert and W. Pendergast; J. Chern. Soc., Perkin Trans. I, 1973, 1794.
S. M. Hecht and D. Werner; J. Chern. Soc., Perkin Trans. I, 1973, 1903.
T. Sasaki, K. Kanematsu, A. Kakehi and G. I. Ito: J. Chern. Soc., Perkin Trans.
I, 1973, 2089.
G. A. Jaffari and A. J. Nunn; J. Chern. Soc., Perkin Trans. I, 1973,2371.
K. Yamauchi and M. Kinoshita; J. Chern. Soc., Perkin Trans. I, 1973,2506.
Y. Tamura, Y. Mild, Y. Sumida and M. Ikeda; J. Chern. Soc., Perkin Trans. I,
1973, 2580.
E. E. Glover, K. D. Vaughan and D. C. Bishop; J. Chern. Soc., Perkin Trans. I,
1973, 2595. 635
R. R. Atkins, S. E. J. Glue and I. T. Kay; J. Chern. Soc., Perkin Trans. 1,1973,2644. 132
H. E. Foster and J. Hurst; J. Chern. Soc., Perkin Trans. 1,1973,2901. 310,311,315,
339
742
742
742
K. T. Potts, R. Dugas and C. R. Surapareni; J. Helerocycl. Chern., 1973, 10,821.
R. Roe, Jr., J. S. Paul and P. O'B. Montgomery, Jr.; J. Helerocycl. Chern., 1973,
10, 849.
A. H. Albert, R. K. Robins and D. E. O'Brien; J. Helerocycl. Chern., 1973, 10,885.
R. P. Rao, R. K. Robins and D. E. O'Brien; J. Helerocycl. Chern., 1973,10,1021.
J. W. A. M. Janssen, C. G. Kruse, H. J. Koeners and C. L. Habraken; J. Helerocycl.
Chern., 1973,10, 1055. 198,224,225
C. Temple, Jr., B. H. Smith, R. D. Elliott and J. A. Montgomery; J. Med. Chern.,
1973, 16, 292.
E. B. Âkerblom and D. E. S. Campbell; J. Med. Chern., [973, 16,312.
J. H. Jones, W. J. Holtz and E. J. Cragoe, Jr.; J. Med. Chern., 1973,16,537.
R. A. Sharma, M. Bobek, F. E. Cole and A. Bloch; J. Med. Chern., 1973,16,643.
G. J. Durant, J. M. Loynes and S. H. B. Wright; J. Med. Chern., 1973,16, 1272.
H. Berner, H. Reinshagen and M. A. Koch; J. Med. Chern., 1973,16, 1296.
J. P. Jacobsen, O. Snerling, E. J. Pedersen, J. T. Nielsen and K. Schaumburg;
J. Magn. Reson., 1973, 10, 130. 196,197,290
M. C. Thorpe and W. C. Coburn, Jr.: J. Magn. Reson., [973, 12,225. 354
C. Temple, Jr., B. H. Smith, Jr. and J. A. Montgomery: J. Org. Chern., 1973,38,
613.
J.-M. Vandensavel, G. Smets and G. L'abbé; J. Org. Chern., 1973,38,675.
E. C. Taylor and R. C. Portnoy; J. Org. Chern., 1973,38,806.
A. S. Katner; J. Org. Chern., 1973,38, 825.
R. M. Kellogg; J. Org. Chern., 1973,38,844.
C. Temple, Jr., B. H. Smith, Jr. and J. A. Montgomery; J. Org. Chern., [973,38,
1095.
References
R. C. Seccombe and C. H. L. Kennard; J. Chern. Soc., Perkin Trans. 2, 1973, I.
R. C. Seccombe and C. H. L. Kennard; 1. Chern. Soc., Perkin Trans. 2, 1973,4.
R. C. Seccombe and C. H. L. Kennard; J. Chern. Soc., Perkin Trans. 2, 1973,9.
S. Bradamante, G. Pagani and A. Marchesini; J. Chern. Soc., Perkin Trans. 2,
1973, 568.
H. Ferres, M. S. Hamdam and W. R. Jackson; J. Chern. Soc., Perkin Trans. 2,
1973, 936.
B. Fernandez, I. Perillo and S. Lamden; J. Chern. Soc., Perkin Trans. 2, 1973, 1371.
S. Clementi, P. P. Forsythe, C. D. Johnson and A. R. Katritzky; J. Chern. Soc.,
Perkin Trans. 2, 1973, 1675.
J. A. Elvidge, J. R. Jones, C. O'Brien, E. A. Evans and H. C. Sheppard; J. Chern.
Soc., Perkin Trans. 2, 1973, 1889.
G. B. Ansell; J. Chern. Soc., Perkin Trans. 2, 1973, 2036.
J. A. Elvidge, J. R. Jones, C. O'Brien, E. A. Evans and H. C. Sheppard; J. Chern.
Soc., Perkin Trans. 2, 1973, 2138.
H. Alper and R. W. Stout; J. Helerocycl. Chern., 1973, 10, 5.
M. Israel and L. C. Jones; J. Helerocycl. Chern., 1973, 10,201.
R. Weber and M. Renson; J. Helerocycl. Chern., 1973, 10,267.
F. H. Case; J. Helerocycl. Chern., 1973, 10, 353.
L. M. Werbel, A. Curry, E. F. Elslager and C. Hess; J. Helerocycl. Chern., 1973,
10, 363.
B. Rayner, C. Tapiero and J.-L. Imbach; J. Helerocycl. Chern., 1973,10,417.
L. B. Townsend, D. W. Miles, S. J. Manning and H. Eyring; J. Helerocycl. Chern.,
1973, 10,419.
M.-T. Chenon, R. J. Pugmire, D. M. Grant, R. P. Panzica and L. B. Townsend;
J. Helerocycl. Chern., 1973,10,431.
H. Alper and R. W. Stout; J. Helerocycl. Chern., 1973,10,569.
R. Jacquier, H. Lopez and G. Maury; J. Helerocycl. Chern., 1973,10,755.
J. S. Bradshaw, B. Stanovnik and M. Tis[er; J. Helerocycl. Chern., 1973, 10,801.
439
876,888
721
721
639
272, 329
153
230
229
337
800
278
425
239
526, 527
796, 797
526
793
6[6,637
21
766
637
652,513
523
308
793
613
870,
871,880
339
526
272
647
636
754
646
626,
645
614
622,640
636
794, 832
118
3[8
147
867,887
73JOCI437
73JOC 1769
73JOC2049
73JOC2708
73JOC2821
73JOC2887
73JOC289I
73JOC3087
73JOC3420
73JOC3495
73JOC3762
73JOC3947
73JOC3995
73JOC4324
73JOC4353
73JOC4379
73JPCI629
73JPR497
73JPR539
73JPS839
73JPSIOII
73KGS64
73KGSI38
73KGSI38
73KGS570
73KGS707
73KGSI345
73KGSI570
73KGSI686
73LAI03
73LA278
73LA380
73LA578
73LA636
B-73M140100
73MI40400
B-73M140401
B-73M140402
B-73 MI40403
73MI40700
B-73M140701
B-73M140800
B-73M140801
B-73M140900
B-73M140901
B-73M140902
73MI41100
73MI41 IOI
References
953
J. E. Oliver and P. E. Sonnet; J. Org. Chern., 1973,38, 1437.
K. T. Potts and A. J. Elliott; J. Org. Chern., 1973,38, 1769.
E. Abushanab, A. P. Bindra, L. Goodman and H. Peterson, Jr.; J. Org. Chern.,
1973,38, 2049.
J. Tanaka and S. I. Miller; J. Org. Chern., 1973,38,2708.
J. E. McMurry and A. P. Coppolino; J. Org. Chern., 1973,38,2821.
M. Kawazu, T. Kanno, S. Yamamura, T. Mizoguchi and S. Saito; J. Org. Chern.,
1973,38, 2887.
N. Takamura, N. Taga, T. Kanno and M. Kawazu; J. Org. Chern., 1973,38,2891.
K. T. Potts and J. Kane; J. Org. Chern., 1973,38,3087.
J. Salomon and D. Elad; J. Org. Chern., 1973,38,3420.
H. J. J. Loozen and E. F. Godefroi; J. Org. Chern., 1973,38,3495.
D. S. Noyce and G. T. Stowe; 1. Org. Chern., 1973,38,3762.
R. A. Coburn, B. Bhooshan and R. A. Glennon; J. Org. Chern., 1973,38,3947.
R. Y. Ning, P. B. Madan and L. H. Sternbach; J. Org. Chern., 1973,38,3995.
Y. Tamura, K. Sumoto, H. Matsushima, H. Taniguchi and M. Ikeda; J. Org.
Chern., 1973,38,4324.
S. R. Naik, J. T. Witkowski and R. K. Robins; J. Org. Chern., 1973,38,4353.
J. V. Hay, D. E. Portlock and J. F. Wolfe; J. Org. Chern., 1973,38,4379.
A. Samuni and P. Neta; J. Phys. Chern., 1973,77, 1629.
H. Hartmann, H. Schäfer and K. Gewald; J. Prakt. Chern., 1973,315,497.
K. Gewald, M. Hentschel and R. Heikel; J. Prakt. Chern., 1973,315,539.
A. Shafiee, I. Lalezari, S. Yazdany and R. Pournorouz; J. Pharrn. Sci., 1973,62,
839.
J. R. Nulu and J. Nematollahi; J. Pharrn. Sci., 1973,62, 1011.
P. B. Terent'ev, S. M. Vinogradova, A. N. Kost and A. G. Strukovski; Khirn.
Geterotsikl. Soedin., 1973,64.
B. A. Tertov and P. P. Onishchenko; Khirn. Geterotsikl. Soedin., 1973, 138.
Y. M. Yutilov and I. A. Svertilova; Khirn. Geterotsikl. Soedin., 1973, 138 (Chern.
Abstr., 1973,78,97547).
R. M. Bystrova and Y. M. YutiIov; Khirn. Geterotsikl. Soedin., 1973,570 (Chern.
Abstr., 1973, 79, 3 I 98 I).
V. V. Mel'nikov, V. V. Stolpakova, M. S. Pevzner and B. V. Gidaspov; Khirn.
Geterotsikl. Soedin., 1973,707.
A. Ya. Lazaris, S. M. Shmuilovich and A. N. Egorochkin; Khirn. Geterotsikl.
Soedin., 1973, 1345.
V. P. Shchipanov, K. L. Krashina and A. A. Skachilova; Khirn. Geterotsikl.
Soedin., 1973, 1570 (Chern. Abstr., 1974,80,59898).
T. N. Pliev, R. M. Bystrova and Y. M. YutiIov; Khirn. Geterotsikl. Soedin., 1973,
1686 (Chern. Abstr., 1974,80,82803).
H. J. Willen brock, H. Wamhoff and F. Korte; Liebigs Ann. Chern., 1973, 103.
E. Hugl, G. Schulz and E. Zbiral; Liebigs Ann. Chern., 1973,278.
K. Dimroth and K. Severin; Liebigs Ann. Chern., 1973,380.
U. Heep; Liebigs Ann. Chern., 1973, 578.
W. Walter and M. Radke; Liebigs Ann. Chern., 1973,636.
M. Witanowski, L. Stefaniak and H. Januszewski; in 'Nitrogen NMR', ed. M.
Witanowski and G. A. Webb; Plenum, New York, 1973, p. 163. 20
F. Török, A. Hegedüs and P. Pulay; Theor. Chirn. Acta, 1973,32,145. 173,176,177,181
M. Witanowski and G. A. Webb; 'Nitrogen NMR', Plenum Press, New York,
1973, 163.
H. C. van der Plas; 'Ring Transformations of Heterocycles', Academic Press,
New York, 1973, vols. I and II.
A. J. Boulton: in 'Aromalic and Heteroaromatic Chemistry', The Chemical
Society, London, 1973, vol. I, p. 156.
I. Butula; Croat. Chern. Acta, 1973,45,297 (Chern. Abstr., 1973,79,92 099).
F. G. Riddell; in 'Aliphatic, Alicyclic, and Saturated Heterocyclic Chemistry',
The Chemical Society, London, 1973, vol. I, part 3, p. 31. 425,426,444
M. R. Grimmett; in 'MTP International Review of Science, Organic Chemistry,
Series I', ed. K. Schofield; Butterworths, London, 1973, vol. 4, p. 55. 458,459,472
H. C. van der Plas; in 'Ring Transformations of Heterocycles', Academic, New
York, 1973, vol. 2.
J. Brooks and G. Shaw; 'Origin and Development of Living Systems', Academic,
London, 1973.
'Physicochemical Properties of Nucleic Acids', ed. J. Duchesne; Academic,
London, 1973, vol. I. 501, 506, 520, 523
'Synthetic Procedures in Nucleic Acid Chemistry', ed. W. W. Zorbach and R.
S. Tipson; Wiley-Interscience, 1973, vol. 2. 501,504,510,511,512,514,
516,517,518,524
Yu. L. Frolov, V. B. Mantisivoda, V. B. Modonov, S. N. Elovskii, E. S. Domnina
and G. G. Skvortsova; Teor. Eksp. Khirn., 1973,9,238 (Chern. Abstr., 1973,
79,41757).
P. Mauret, J. P. Fayet, M. Fabre, J. Elguero and M. del C. Pardo; J. Chirn. Phys.
Phys. Chirn. Bioi., 1973,70, 1483 (Chern. Abstr., 1974,80,59218).
474
116
625,644
700, 709
726
604
604
131
545
437,489
395
763
335
166
758
430, 448
206
140
136
116
652
204,205
243
620
616
740
772
827
616
647
648
353
716
698, 699
195
286
286
419
493
519,567
672
677
954
73MI41102
B-73MI41103
73MI41300
73MI41301
73NKK996
B-73NMR
730MR(5)453
730MS(7)57
730MS(7)271
730MS(7)1165
730MS(7)1267
730PPI05
73P2445
73PC41100
73S71
73S123
73S300
73TlOI
73Tl95
73T435
73T44 I
73Tll35
73TI413
73TI833
73Tl983
73T2173
73T327 I
73T3285
73T3463
73T3469
73T4045
73T4049
73TH40400
73TL469
73TL891
73TLl137
73TLl417
73TLl677
73TL2101
73TL378I
73TL4295
73TL4619
73TL5075
73UKZ277
73UKZ350
73UK.Z703
73ZC 176
73ZC429
73Z0BI683
73Z0R2006
73Z0R2535
74ACS(B)61
74ACS(B)425
309, 326
308,319
185
656
252
164
205,361,
688, 689
Y. Tanaka, S. R. Velen and S. I. Miller; Tetrahedron, 1973,29,3271. 699
Y. Tanaka and S. I. Miller; Tetrahedron, 1973,29,3285. 700
M. A. Schroeder, R. C. Makino and W. M. Tolles; Tetrahedron, 1973,29,3463. 672, 796
M. A. Schroeder and R. C. Makino; Tetrahedron, 1973,29,3469. 172,175,672
M. K. Eberle, G. G. Kahle and S. M. Talati; Tetrahedron, 1973,29,4045. 256
M. K. Eberle and G. G. Kahle; Tetrahedron, 1973,29,4049. 257
E. Henry; Ph.D. Thesis, University of Montpellier, 1973. 201
G. Bram; Tetrahedron Lett., 1973,469. 786
P. Bouchet, C. Coquelet, J. Elguero and R. Jacquier; Tetrahedron Lett., 1973,891. 219
H. Taguchi; Tetrahedron Lett., 1973, 1137. 692
T. Yamazaki and H. Schechter; Tetrahedron Lett., 1973, 1417. 318
S. Polanc, B. Vercek, B. Stanovnik and M. TEHer; Tetrahedron Lett., 1973, 1677. 854
J. E. Herweh and R. M. Fantazier; Tetrahedron Lett., 1973,2101. 784,787
R. Baumes, J. Elguero, R. Jacquier and G. Tarrago; Tetrahedron Lett., 1973,3781. 249
A. Gelléri and A. Messner; Tetrahedron Lett., 1973,4295. 793
I. A. Korbukh, F. F. Blanco and M. N. Preobrazhenskaja; Tetrahedron Lett.,
1973,4619.
K. Maeda, T. Hosokawa, S. Murahashi and I. Moritani; Tetrahedron Lett., 1973,
5075.
N. S. Miroshnichenko, 0.1. Shkrebtii and A. V. Stetsenko; Ukr. Khirn. Zh. (Russ.
Ed.), 1973,39,277 (Chern. Abstr., 1973,79, 19020).
N. S. Miroshnichenko, I. G. Ryabokon and A. V. Stetsenko; Ukr. Khirn. Zh.
(Russ. Ed.), 1973,39,350 (Chern. Abstr., 1973,79,32233).
A. V. Stetsenko and N. S. Miroshnichenko; Ukr. Khim. Zh. (Russ. Ed.), 1973,
39,703 (Chem. Abstr., 1973,79, 105515).
H. Kunzek and G. Bamckow; Z Chem., 1973, 13, 176.
E. Lipmann, R. Widera and E. Kleinpeler; Z Chern., 1973,13,429 (Chem. Abstr.,
1974, 80, 82 829).
A. N. Pudovik, N. G. Khusainova and Z. A. Nasyballina; Zh. Obshch. Khim.,
1973,43, 1683.
I. I. Afonina and F. Y. Perveev; Zh. Org. Khim., 1973,9, 2006 (Chern. Abstr.,
1974,80,27171).
N. N. Mel'nikova, M. S. Pevzner, N. M. Malysheva and L. I. Bagal; Zh. Org.
Khirn., 1973,9, 2535.
References
V. P. Chernetskii, N. A. Petrusha and J. V. Alekseeva; Fiziol. Aktiv. Veshchestra,
1973,5, 121.
M. Witanowski and G. A. Webbs; 'Nitrogen NMR', Plenum Press, London, 1973.
M. Witanowski, L. Stefaniak, H. Januszewski and J. Eiguero; J. Chim. Phys.
Phys. Chim. Bioi., 1973,70,697.
E. Lipmann, H. Löster and A. Antonowa; J. Signal AM2, 1973,2,209 (Chern.
Abstr., 1975,82, 30496).
K. Takahashi, K. Mitsuhashi and T. Zaima; Nippon Kagaku Kaishi, 1973,996
(Chem. Abstr., 1973, 79, 31 986). 435
T. J. Batterham; 'NMR Spectra of Simple Heterocycles', Wiley, New York, 1973. 13, 15,
182. 183, 184, 185, 186, 187, 188, 189, 190,510,678,858
R. Danion-Bougot and R. Carrié; Org. Magn. Reson., 1973,5,453. 185
A. J. Blackman and J. H. Bowie; Org. Mass Spectrorn., 1973,7,57. 741
A. Maquestiau, Y. Van Haverbeke, R. Flammang, and J. Eiguero; Org. Mass
Spectrom., 1973,7,271.
J. van Thuijl, K. J. Klebe and J. J. van Houte; Org. Mass Spectrom., 1973,7,1165.
A. Maquestiau, Y. Van Haverbeke, R. Flammang, M. C. Pardo and J. Eiguero;
Org. Mass Spectrom., 1973,7, 1267.
T. Caronna and L. Filini; Org. Prep. Proced. Int., 1973, 105.
D. S. Letham; Phytochemistry, 1973, 12,2445.
K. M. Kern, S. M. Masson, Y. K. Kim and M. E. Munk; personal communication,
1973.
P. K. Kadaba; Synthesis, 1973,71.
M. TiSler; Synthesis, 1973, 123.
F. Yoneda and T. Nagamatsu; Synthesis, 1973,300.
M. K. Saxena, M. N. Gudi and M. V. George; Tetrahedron, 1973,29, 101.
P. Ykman, G. L'abbé and G. Smets; Tetrahedron, 1973,29, 195.
J. P. Marquet, J. D. Bourzat, J. Andre-Louisfert and E. Bisagni; Tetrahedron,
1973,29,435.
J. D. Bourzat, J. P. Marquet, A. Civier and E. Bisagni; Tetrahedron, 1973,29,441.
J. P. Deleux, G. Leroy and J. Weiler; Tetrahedron, 1973,29, 1135.
A. Kreutzberger and R. Schucker; Tetrahedron, 1973, 29, 1413.
L. Schrader; Tetrahedron, 1973,29, 1833.
O. Tsuge, K. Sakai and M. Tashiro; Tetrahedron, 1973,29, 1983.
S. Cradock, R. H. Findlay and M. H. Palmer; Tetrahedron, 1973,29,2173.
703
717,792,829,833
792, 826, 859, 860, 881
337
248
717
729
684
800
802
686
202
688
247
601
289
136
636
640
640
135
821
716
634
756
M. Begtrup: Acta Chern. Scand., Ser. B, 1974,28,61.
C. E. Olsen; Acta Chem. Scand., Ser. B, 1974,28,425.
194, 355, 674, 799
703
74AG(E)47
74AG(E)79
74AG(E)627
74AHC(16)1
74AHC(16)33
74AHC(16)123
74AHC(17)99
74AHC(17)213
74AHC(17)255
74AJC2041
74AJC2267
74AJC2331
74AJC2343
74AJC2447
74API77
74AP211
74AP444
74AP504
74AX(B)166
74AX(B)273
74AX(B)557
74AX(B)590
74AX(B)1490
74AX(B) 1528
74AX(B)2009
74AX(B)2246
74AX(B)2500
74AX(B)2505
74BBA(361)231
74BCJ785
74BSF673
74BSF768
74BSF1395
74BSF1453
74BSF2547
74CB715
74CB1318
74CB2127
74CB2284
74CB3454
74CC339
74CC486
74CC551
74CC657
74CC659
74CC702
74CC941
74CC957
74CHE358
74CHE376
74CHE471
74CHE813
74CHE992
74CHE1215
References
955
J. B. Hendrickson; Angew. Chern., Int. Ed. Engl., 1974, 13,47.
T. van Vyve and H. G. Viehe; Angew. Chern., Int. Ed. Eng!., 1974,13,79.
T. Kauffmann; Angew. Chern., Int. Ed. Engl., 1974, 13,627.
J. A. Elvidge, J. R. Jones, C. O'Brien, E. A. Evans and H. C. Sheppard; Adv.
Heterocycl. Chern., 1974, 16, 1. 69, 70, 245
T. L. Gilchrist and G. E. Gymer; Adv. Heterocycl. Chern., 1974, 16, 33. 46, 53, 54, 55,
58,69,92,94,97, 105, 106, 108, 109,670,695,705,708
F. Minisci and O. Porta; Adv. Heterocycl. Chern., 1974, 16, [23. 73,419
R. Lakhan and B. Temai; Adv. Heterocycl. Chern., 1974,17,99. 55,57,58,59,60,
62,63,65,'66,69,70,74,76,88,91,92,93,97, 106;107
H.-J. Timpe; Adv. Heterocycl. Chern., 1974, 17,213. 72, 109
M. J. Cook, A. R. KatrÏtzky and P. Linda; Adv. Heterocycl. Chern. 1974,17,255. 32,33,
208
281
254
400
241
751,782
331
219
330
750
508
J. F. K. Wilshire; Aust. 1 Chern., 1974,27,2041.
N. A. Evans, D. E. Rivett and J. F. K. Wilshire; Aust. J. Chern., 1974,27, 2267.
B. E. Boulton and B. A. W. Coller; Aust. J. Chern., 1974,27,2331.
B. E. Boulton and B. A. W. Coller; Aust. J. Chern., 1974,27,2343.
M. Woodruff and J. B. Po1ya; Aust. J. Chern., 1974,27, 2447.
T. Denzel; Arch. Pharrn. (Weinheirn, Ger.), 1974, 307, 177.
J. Reisch and A. Fitzek; Arch. Pharrn. (Weinheim, Ger.), 1974,307,211.
H. H Otto; Arch. Pharrn. (Weinheirn, Ger.), 1974,307,444.
K. Sunderdiek and G. Zinner; Arch. Pharrn. (Weinheirn, Ger.), 1974,307, 504.
T. J. Kistenmacher and T. Shigematsu; Acta Crystallogr., Part B, 1974,30, 166.
L. Fanfani, A. Nunzi, P. F. Zanazzi and A. R. Zanzari; Acta Crystallogr., Part
B, 1974,30, 273.
T. P. Singh and M. Vijayan; Acta Crystallogr., Part B, 1974,30, 557.
J. Toussaint, O. Dideberg and L. Dupont; Acta Crystallogr., Part B, 1974,30,590.
A. Escande, J. L. Galingné and J. LaPasset; Acta Crystallogr., Part B, 1974,30,
1490.
T. J. Kistenmacher and T. Shigematsu; Acta Crystallogr., Part B, 1974,30,1528.
A. Escande and J. Lapasset; Acta Crystallogr., Part B, 1974,30,2009.
C. Brassy, A. Renard, J. Delettré and J. P. Momon; Acta Crystallogr., Part B,
1974,30,2246.
C. Brassy, J. P. Momon, J. De1ettré and J. Lepicard; Acta Crystallogr., Part B,
1974,30,2500.
R. L. Harlow and S. H. Simonsen; Acta Crystallogr., Part B, 1974,30,2505.
S. D. Rose; Biochirn. Biophys. Acta, 1974,361,231.
T. Kitazume and N. Ishikawa; Bull. Chern. Soc. Jpn., 1974,47,785.
A. Darchen and D. Peltier; Bull. Soc. Chirn. Fr., 1974,673.
P. Corbon, G. Barbey, A. Dupre and C. Caullet; Bull. Soc. Chirn. Fr., 1974,768.
A. Étienne, A. Le Berre and J.-P. Giorgetti; Bull. Soc. Chirn. Fr., 1974, 1395.
P. Guerret, R. Jacquier, H. Lopez and G. Maury; Bull. Soc. Chirn. Fr., 1974, 1453.
R. Baumes, R. Jacquier and G. Tarrago; Bull. Soc. Chirn. Fr., 1974,2547.
W. Winter and E. Mül1er; Chern. Ber., 1974, 107,715.
W. Sucrow, C. Mentzel and M. Siopianka; Chern. Ber., 1974,107, 1318.
W. Winter and E. Muller; Chern. Ber., 1974, 107, 2127.
H. R. Rackwilz and K. H. Scheit; Chern. Ber., 1974, 107,2284.
C. Reichard and E. U. Würthwein; Chern. Ber., 1974, 107,3454.
G. V. Boyd, T. Norris and P. F. Lindley; J. Chern. Soc., Chern. Cornrnun., 1974,
339.
T. L. Gilchrist, C. J. Harris, C. J. Moody and C. W. Rees; J. Chern. Soc., Chern.
Cornrnun., 1974,486.
F. Yoneda, S. Matsumoto and M. Higuchi; J. Chern. Soc., Chern. Cornrnun., 1974,
551.
J. J. Barr, R. C. Storr and J. Rimmer; J. Chern. Soc., Chern. Cornrnun., 1974,657.
M. J. Rance, C. W. Rees, P. Spagnolo and R. C. Storr; J. Chern. Soc., Chern.
Cornrnun., 1974,659. 794
M. Begtrup; J. Chern. Soc., Chern. Cornrnun., 1974,702. 197,680,681
C. W. Rees, R. W. Stephenson and R. C. Storr; J. Chern. Soc., Chern. Cornrnun.,
1974, 941.
S. Mansy and R. Tobias; J. Chern. Soc., Chern. Cornrnun., 1974,957.
I. I. Popov, A. M. Simonov, V. 1. Mikhailov and N. A. Sil'vanovich; Chern.
Heterocycl. Cornpd. (Engl. Trans!.), 1974, 10,358.
V. I. Ofitserov, Z. V. Pushkareva, V. S. Mokrushin and T. V. Rapakova; Chern.
Heterocycl. Cornpd. (Eng!. Transl.), 1974, 10, 376.
V. S. Troitskaya, N. D. Konevskaya, V. G. Vinokurov and V. 1. Tyulin; Chern.
Heterocycl. Cornpd. (Eng!. Transl.), 1974,10,471.
Z. I. Moska1enko and G. P. Shumelyak; Chern. Heterocycl. Cornpd. (Engl. Trans!.),
1974, 10, 813.
B. E. Mandrichenko, I. A. Mazur and P. M. Kochergin; Chern. Heterocycl. Cornpd.
(Engl. Transl.), 1974, 10,992.
V. S. Troitskaya, Yu. D. Timoshenkova, Yu. A. Pentin and V. I. Tyulin; Chern.
Heterocycl. Cornpd. (Engl. Transl.), 1974,10, 1215.
282
126, 277
282
179
178
179
675
508
179
227
227
178
627
471
472
254
853
630,653
248
709
189
229
597
281
178
872
581
794
307,339
527
437
629
199,290
116
647
199
956
74CHEl217
74CHEl225
74CHEI491
74CHE1492
74CI(L)38
74CJC833
74CJC2296
74CJC3474
74CJC398I
74CLl85
74C L409
74CL95I
74CPB70
74CPB207
74CPB214
74CPBI269
74CPBI938
74CPB2142
74CPB2466
74CR(C)(278)359
74CR(C)(279)717
74CRV279
74CS(6)222
74CSC713
74CZ512
74GEP230432I
74GEP23 14488
74GEP25 13864
74H(2)473
74HCA750
74HCA873
74HCAI259
74HCAI382
74JAI465
74JAI957
74JA2010
74JA2014
74JA248I
74JA3335
74JA3708
74JA3973
74JA4276
74JA4962
74JA5894
74JA7797
74JA7830
74JAP7420175
74JAP74 I 26679
74JCP(7[)415
74JCS(PI)81
74JCS(PI )297
74JCS(PI)349
74JCS(PI)627
74JCS(PI)633
References
G. G. Skvortsova, N. D. Abramova and B. V. Trzhtsinskaya; Chern. Heterocycl.
Cornpd. (Engl. Transl.), [974,10,1217. 444,446,450
B. I. Khristich, G. M. Sudorova and A. M. Simonov; Chern. Heterocycl. Cornpd.
(Engl. Transl.), 1974,10, 1225.
I. I. Popov and A. M. Simonov; Chern. Heterocycl. Cornpd. (Engl. Transl.), [974,
10, 1491.
M. V. Povstyanoi, P. M. Kochergin, E. V. Logachev, E. A. Yakubovskii, A. V.
Akimov and V. V. Androsov; Chern. Heterocycl. Cornpd. (Eng/. Transl.), 1974,
10, 1492.
K. Akagane and G. G. Allan; Chern. Ind. (London), 1974,38.
R. E. Wasylishen, J. B. Rowbotham and T. Schaefer; Can. J. Chern., 1974,52,833.
J. W. ApSimon, J. Elguero, A. Fruchier, D. Mathieu and R. Phan Tan Luu; Can.
J. Chern., 1974,52, 2296.
A. R. Bassindale and A. G. Brook; Can. J. Chern., 1974,52,3474.
S. Fischer, L. K. Peterson and J. F. Nixon; Can. J. Chern., 1974.52,3981.
T. Akiyama, T. Kitamura; T. Isida and M. Kawanisi; Chern. Lell., 1974, 185.
H. Iwasaki; Chern. Lell., 1974,409.
J. H. Lee, A. Matsumoto, M. Yoshida and O. Simamura; Chern. Lett., 1974,951.
I. Adachi, R. Miyazaki and H. Kano; Chern. Pharrn. Bull., 1974,22,70.
K. Arakawa, T. Miyasaka and H. Ochi; Chern. Pharrn. Bull., 1974,22,207.
K. Arakawa, T. Miyasaka and H. Ochi; Chern. Pharrn. Bull., [974,22,214.
Y. Maki, M. Suzuki, K. Izuta and S. Iwai; Chern. Pharm. Bull., 1974,22, [269.
G. T. Huang, T. Okamoto, M. Maeda and Y. Kawazoe; Chern. Pharrn. Bull.
1974,22, 1938.
A. Nakemura and S. Kamiya; Chern. Pharrn. Bull., 1974,22,2142.
T. Fujii, S. Kawakatsu and T. Itaya; Chern. Pharrn. Bull., 1974,22,2466.
F. Abjean; c.R. Hebd. Seances Acad. Sci., Ser. C, 1974,278,359.
R. Faure, J.-R. Uinas, E. J. Vincent and J.-L. Larice; C. R. Hebd. Seances Acad.
Sci., Ser. C, 1974,279,717. 20
P. N. Preston; Chern. Rev., 1974,74,279. 390,408,409,412,420,429,432,445,353,356,
358,359,361,458,460,469,470,472,490,493,495
O. Thorstad and K. Undheim; Chern. Scr., 1974,6,222. 858
P. Domiano and A. Musati; Cryst. Struct. Cornrnun., 1974,3,713. 178
R. Neidlein and H. G. Hege; Chern.-Ztg., 1974,98,512. 777
K. Lohmer, A. yon Koenig and A. Mueller; Ger. Pat. 2304321 (1974) (Chern.
Abstr., 1974,81,144229).
H. Staehle, H. Koeppe, W. Kummer and W. Hoefke; Ger. Pat. 2314488 (1974)
(Chern. Abstr., 1974, 82, 4317).
Ger. Pat. 2513 864 (1974) (Chern. Abstr., 1974,84,5005).
T. Nishiwaki; Heterocycles, [974,2,473.
F. Troxler, H. P. Weber, A. Jaunin and H. R. Loosli; Helv. Chirn. Acta, 1974,
57,750.
C. B. Chapleo and A. S. Dreiding; He/v. Chirn. Acta, 1974,57, 873.
C. B. Chapleo and A. S. Dreiding; Helv. Chirn. Acta, 1974,57, 1259.
P. Gilgen, H. Heimgartner and H. Schmid; Helv. Chirn. Acta, 1974,57, 1382.
G. E. Wilson, Jr. and T. J. Bazzone; J. Am. Chern. Soc., 1974,96, 1465.
Y. Akasaki and A. Ohno; 1 Am. Chern. Soc., 1974, %, 1957.
J. P. Ferris and F. R. Antonucci; J. Am. Chern. Soc., 1974,96,2010.
J. P. Ferris and F. R. Antonucci; J. Am. Chern. Soc., 1974,96,2014.
G. A. Rogers and T. C. Bruice; J. Am. Chern. Soc., 1974,96,2481.
P. L. Gravel and W. H. Pirkle; J. Am. Chern. Soc., 1974,96,3335.
G. E. Palmer, J. R. Bolton and D. R. Arnold; J. Am. Chern. Soc., 1974,96,3708.
G. L'abbé, E. Van Loock, R. Albert, S. Toppet, G. Verhe[st and G. Smets; J.
Am. Chern. Soc., 1974,96,3973.
K. T. Potts and D. McKeough; J. Am. Chern. Soc., 1974,96,4276.
R. B. Meyer, Jr., D. A. Shuman and R. K. Robins; J. Am. Chern. Soc., 1974,96,
4962. 587, 589, 590
N. J. Leonard and C. R. Frihart; J. Am. Chern. Soc., 1974,96, 5894. 537
A. M. Feinberg, K. Nakanishi, J. Barciszewski, A. J. Rafalski, H. Augustyniak
and M. Wiewiórowski; J. Am. Chern. Soc., 1974,96,7797.
S. Kammula and P. B. Shevlin; J. Am. Chern. Soc., 1974,96,7830.
A. Kotone, J. Fujita and M. Hoda; Jpn. Pat. 7420175 (1974) (Chern. Abstr., 1974,
81, 105517).
A. Kotone, M. Hoda and T. Fujita; Jpn. Pat. 74126679 (1974) (Chern. Abstr.,
1975, 82, 170962).
A. Lautié and A. Novak; J. Chern. Phys., 1974,71,415.
J. A. Maddison, P. W. Seale, E. P. Tiley and W. K. Warburton; J. Chern. Soc.,
Perkin Trans. J, 1974,81. 775
D. J. Le Count and A. T. Greer; J. Chern. Soc., Perkin Trans. J, 1974,297. 281,654
D. J. Brown and R. K. Lynn; J. Chern. Soc., Perkin Trans. I, 1974,349. 577, 596, 636
A. R. McCarthy, W. D. Ollis and C. A. Ramsden; J. Chern. Soc., Perkin Trans.
I, 1974, 627.
W. D. Ollis and C. A. Ramsden; J. Chern. Soc., Perkin Trans. I, [974,633.
438
437
654
483
13
189
254
455
810
508
163
68
232,264
232,264
338
77[
314
554
248
788
658
647
202
633
308
318
780
18
446
221,436
22[
660
752
251
832
116
605
822
746
746
518
757
782
74JCS(PI)642
74JCS(PI)903
74JCS(PI)1028
74JCS(PI)1284
74JCS(PI)1422
74JCS(PI)1871
74JCS(PI)1970
74JCS(PI)2030
7 4J CS(P I )2229
74JCS(P2) 174
74JCS(P2)382
74JCS(P2)389
74JCS(P2)420
74JCS(P2)420
74JCS(P2)420
7 4J CS(P2)449
74JCS(P2) I 298
74JHC39
74JHC77
74JHC135
74JHCI99
74JHC223
74JHC233
74JHC327
74JHC423
74JHC49I
74JHC615
74JHC623
74JHC641
74JHC645
74JHC69I
74JHC873
74JHC885
74JHC92 I
74JHC991
74JHCIOI I
74JHCI013
74JHCI093
74JMC381
74JMC645
74JMC846
74JMR(15)98
74JOC63
74JOC95
74JOC357
74JOC793
74JOC957
74JOC962
74JOCI007
74JOCI047
References
957
W. D. Ollis and C. A. Ramsden; J. Chern. Soc., Perkin Trans. J, 1974,642.
G. P. Ellis and R. T. Jones; J. Chern. Soc., Perkin Trans. J, 1974,903.
G. V. Boyd and T. Norris; J. Chern. Soc., Perkin Trans. 1, 1974, 1028.
J. L. Wong and D. S. Fuchs; J. Chern. Soc., Perkin Trans. 1, 1974, 1284.
R. W. Baldock, P. Hudson, A. R. Katritzky and F. Soti; J. Chern. Soc., Perkin
Trans. 1, 1974, 1422.
T. Nishiwaki, F. Fujiyama and E. Minamisono; J. Chern. Soc., Perkin Trans. 1,
1974, 1871.
R. G. R. Bacon and S. D. Hamilton; J. Chern. Soc., Perkin Trans. 1, 1974, 1970.
A. Albert; J. Chern. Soc., Perkin Trans. 1, 1974,2030.
M. Rabat, F. Bergmann and 1. Tamir; J. Chern. Soc., Perkin Trans. J, 1974,2229.
J. A. Elvidge, J. R. Jones, C. O'Brien, E. A. Evans and H. C. Sheppard; 1. Chern.
Soc., Perkin Trans. 2, 1974, 174.
A. G. Burton, M. Dereli, A. R. Katritzky and H. O. Tarhan; J. Chern. Soc., Perkin
Trans. 2, 1974,382.
A. G. Burton, A. R. Katritzky, M. Konya and H. O. Tarhan; J. Chern. Soc., Perkin
Trans. 2, 1974,389.
M. H. Palmer, R. H. Findlay and A. J. Gaskell; J. Chern. Soc., Perkin Trans. 2,
1974,420. 176,177,346
M. H. Palmer, R. H. Findlay and A. J. Gaskell; J. Chern. Soc., Perkin Trans. 2,
1974,420.
M. H. Palmer, R. H. Findlay and A. J. Gaskell; 1. Chern. Soc., Perkin Trans. 2,
1974, 420. 672, 673
P. Bouchet, C. Coquelet and J. Eiguero; J. Chern. Soc., Perkin Trans. 2,1974,449. 201,268
E. N. Maslen, J. R. Cannon, A. H. White and A. C. Willis; J. Chern. Soc., Perkin
Trans. 2, 1974, 1298.
D. M. Halverson and R. N. Castle; J. Heterocycl. Chern., 1974,11,39.
W. A. Nasutavicus and J. Love; J. Heterocycl. Chern., 1974, 11,77.
J. J. Bergman and B. M. Lynch; J. Heterocycl. Chern., 1974,11, 135.
J. Kobe, R. K. Robins and D. E. O'Brien; J. Heterocycl. Chern., 1974,11, 199.
B. M. Lynch and B. P.-L. Lem; J. Heterocycl. Chern., 1974, 11,223.
R. J. Rousseau, J. A. May, Jr., R. K. Robins and L. B. Townsend; J. Heterocycl.
Chern., 1974, 11, 233.
1. Lalezari and Y. Levy; J. Heterocycl. Chern., 1974,11,327.
E. Alcalde, J. de Mendoza, J. M. Garcia-Marquina, C. Almera and J. Eiguero;
J. Heterocycl. Chern., 1974,11,423.
A. Vollmar and A. Hassner; J. Heterocycl. Chern., 1974,11,491.
K. Hayes; J. Heterocycl. Chern., 1974, 11,615.
S. Plescia, S. Petruso and V. Sprio; J. Heterocycl. Chern., 1974,11,623.
P. W. K. Woo, H. W. Dion, S. M. Lange, L. F. Dahl and L. J. Durham; J.
Heterocycl. Chern., 1974, 11,641.
T. C. Thurber, R. J. Pugmire and L. B. Townsend; J. Heterocycl. Chern., 1974,
11,645. 682,683,719
T. Novinson, K. Senga, J. Kobe, R. K. Robins, D. E. O'Brien and A. A. Albert;
J. Heterocycl. Chern., 1974, 11,691.
T. Novinson, D. E. O'Brien and R. K. Robins; J. Heterocycl. Chern., 1974,11,873.
A. Walser, T. Aynn and R. 1. Fryer; 1. Heterocycl. Chern., 1974,11,885.
E. Alcalde, J. de Mendoza and J. Eiguero; J. Heterocycl. Chern., 1974, 11,921.
J. Kobe, D. E. O'Brien, R. K. Robins and T. Novinson; J. Heterocycl. Chern.,
1974,11,991.
M. Davis, L. W. Deady and E. Homfeld; J. Heterocycl. Chern., 1974, 11, lOll.
J. Arriau, O. Chalvet, A. Dargelos and G. Maury; J. Heterocycl. Chern., 1974,
11, 1013.
D. L. Nagel and N. H. Cromwell; J. Heterocycl. Chern., 1974,11, 1093.
S. B. Zak, T. G. Gilleran, J. Karliner and G. Lukas; J. Med. Chern., 1974, 17,381.
T. Novinson, R. Hanson, M. K. Dimmitt, L. N. Simon, R. K. Robins and D. E.
O'Brien; 1. Med. Chern., 1974, 17,645.
K. Okumura, K. Matsumoto, M. Fukamizu, H. Yasuo, Y. Taguchi, Y. Sugihara,
1. Inou, M. Seto, Y. Sato, N. Takamura, T. Kanno, M. Kawazu, T. Mizoguchi,
S. Saito, K. Takashima and S. Takeyama; J. Med. Chern., 1974,17,846.
M. C. Thorpe, W. C. Coburn, Jr. and J. A. Montgomery; J. Magn. Reson., 1974,
15,98. 510,514
J. K. Crandall and W. W. Conover; 1. Org. Chern., 1974,39,63. 725
A. Bhattacharya and A. G. Hortmann; J. Org. Chern., 1974,39,95. 114
J. Eiguero, C. Marzin and J. D. Roberts; J. Org. Chern., 1974,39,357. 18,191,192,
211, 354, 355, 680, 742, 804
J. S. Bradshaw, M. Tisler and B. Stanovnik; J. Org. Chern., 1974,39, 793. 870,880
M. Komatsu, Y. Ohshiro, K. Yasuda, S. Ichijima and T. Agawa; J. Org. Chern.,
1974,39,957.
R. K. Howe and J. E. Franz; 1. Org. Chern., 1974,39,962.
R. C. Gearhart, R. H. Wood, R. C. Thorstenson and J. A. Moore; 1. Org. Chern.,
1974,39, 1007.
P. A. S. Smith and E. M. Bruckmann; 1. Org. Chern., 1974,39, 1047.
782
353, 470
262
558
74
221
431
858
534
526
238
238
795
178,212
628
559
194
312,320
306,31 I
621,641
653
272, 333
813
456
320
601
325
649
288
184, 202
325
185
627
286
904
312
604
18
14
179
727
958
74JOCI233
74JOCI802
74JOCI833
74JOCI909
74J00023
74JOC2143
74J00301
74J00663
74JOOl98
74J00226
74J00438
74J00506
74J00608
74JOC3651
74J00739
74J00763
74J00788
74JOM(65)C51
74JOM(70)347
74JOU 1542
74JPRI47
74JPR667
74JPR705
74JSP(49)423
74JST(22)40 I
74KGS268
74KGS851
74KGS854
74LAI132
74LAI399
74M38
74M427
74M834
74MI40100
74MI40400
74MI40401
74MI40402
74MI40403
74MI40404
74MI40405
74MI40406
B-74M140407
B-74M140408
B-74M140700
B-74M140900
B-74M140901
74MI40902
74MI40903
74MI40904
References
G. J. de Voghel, T. L. Eggerichs, Z. Janousek and H. G. Viehe: J. Org. Chern.,
1974,39, 1233.
R. A. Abramovitch and R. B. Rogers; J. Org. Chern., 1974,39, 1802.
D. Fortuna, B. Stanovnik and M. TEner: J. Org. Chern., 1974,39, 1833.
J. J. Wilcznyski and H. W. Johnson: J. Org. Chern., 1974,39, 1909.
L. B. Townsend, R. A. Long, J. P. McGraw, D. W. Miles, R. K. Robins and H.
Eyring; J. Org. Chern., 1974,39,2023.
S. Polanc, B. Vercek, B. Sek, B. Stanovnik and M. TEner; J. Org. Chern., 1974,
39,2143. 859,871,885,889,891,896,900
D. S. Noyce, G. T. Stowe and W. Wong; J. Org. Chern., 1974,39,2301. 430.448
J. P. Freeman and E. Janiga; J. Org. Chern., 1974,39,2663. 269
M. Komatsu, N. Nishikaze, M. Sakamoto, Y. Ohshiro and T. Agawa; J. Org.
Chern., 1974,39,3198.
P. Dea, G. R. Revankar, R. L. Tolman, R. K. Robins and M. P. Schweizer: J.
Org. Chern., 1974,39,3226.
D. F. Wiener and N. J. Leonard; J. Org. Chern., 1974,39,3438.
J. H. Wikel and C. J. Paget, J. Org. Chern., 1974,39,3506.
F. Wudl, M. L. Kaplan, E. J. Hufnagel and E. W. Southwick, Jr.; J. Org. Chern.,
1974,39,3608.
G. A. Ivanovics, R. J. Rousseau, M. Kawana, P. C. Srivastava and R. K. Rohins:
J. Org. Chern., 1974,39,3651.
G. J. Siuta, R. W. Franck and R. J. Kempton; J. Org. Chern., 1974,39,3739.
V. Nair and K. H. Kim; J. Org. Chern., 1974,39,3763.
M. P. Servé; J. Org. Chern., 1974,39,3788.
N. F. Borkett and M. J. Bruce: J. Organorner. Chern., 1974,65, C51.
V. N. Torocheshnikov, N. M. Sergeyev, N. A. Viktorov, G. S. Goldin, V. G.
Poddubny and A. N. Koltsova: J. Organorner. Chern., 1974,70,347.
N. I. Kudryashova, L. B. Piotrovskii, V. A. Naumev, N. B. Brovtsyna and N. B.
Khromov-Borisov: J. Org. Chern. USSR (Engl. Transl.), 1974, 10, 1542.
M. I. Ali, M. A. Abou-State and A. F. Ibrahim: J. Prakr. Chern., 1974,316, 147.
L. HeiniscÞ.; J. Prakr. Chern., 1974,316,667.
F. Ritschl and H. Dorn: J. Prakr. Chern., 1974,316,705.
W. D. Krugh and L. P. Gold: J. Mol. Speerrose., 1974,49,423.
L. Nygaard, D. Christen, J. T. Nielsen, E. J. Pedersen, O. Snerling, E. V.:.t.:rgaard
and G. O. SØrensen; J. Mol. Srruer., 1974,22,401. 173,181,290
V. P. Shchipanov and G. F. Grigor'eva; Khirn. Geterorsikl. Soedin., 1974, 268
(Chern. Abstr., 1974,80,133352).
M. M. Tsitsika, S. M. Khripak and J. V. Smolanka: Khirn. Geterorsikl. Soedin.,
1974, 851.
Y. M. Yutilov and J. A. Svertilova; Khirn. Gererotsikl. Soedin., 1974,854 (Chern.
Absrr., 1974,81, 120536).
H. Dürr, W. Schmidt and R. Sergio: Liebigs Ann. Chern., 1974, 1132.
H. Ertel and G. Heubach; Liebigs Ann. Chern., 1974, 1399.
F. Asinger, W. Leuchtenberger and V. Gerber: Monarsh. Chern., 1974, 105,38.
J. Schantl: Monatsh. Chern., 1974,105,427.
A. Furlan, M. Furlan, B. Stanovnik and M. Tisler: Monatsh. Chern., 1974, 105,834.
W. A. Lathan, L. A. Curtiss, W. J. Hehre, J. B. Lisle and J. A. Pople: Prog. Phys.
Org. Chern., 1974,11, 175.
J. L. Barascut, C. Tamby and J. L. Imbach; J. Carbohydr., Nucleosides, Nucleo-
tides, 1974, 1,77.
J. Elguero and A. Fruchier; An. Quírn., 1974,70, 141.
B. L. Kam and J. L. Imbach: J. Carbohydr., Nucleosides, Nucleorides, 1974,1,287.
Y. Ferré, E. J. Vincent, H. Larivé and J. Metzger: J. Chirn. Phys. Phys. Chirn.
Bioi., 1974,71,329.
J. A. Korbukh, M. N. Preobrazhenskaya and O. N. Judina; J. Carbohydr.,
Nucleosides, Nucleotides, 1974,1,363.
V. S. Troitskaya, YU. D. Timoshenkova, V. G. Vinokurov and V. I. Tyulin; Vesrn.
Mosk. Univ., Khirn., 1974,677. 199,200
E. Alcalde, J. M. Garía-Marquina and J. de Mendoza: An. Quírn., 1974,70,959. 263.266
Yu. P. Kitaev and B. I. Buzykin; 'Hydrazones', Academy of Sciences of the
USSR, Moscow, 1974.
A. J. Myers; 'Heterocycles in Organic Synthesis', Wiley-Interscience, New York,
1974.
F. G. Riddell; in 'Saturated Heterocyclic Chemistry', The Chemical Society,
London, 1974, vol. 2, p. 237.
A. Bloch; in 'Drug Design', ed. E. J. Ariens: Academic, New York, 1974, vol. 4,
p.286.
F. Bergmann, D. Lichtenberg, U. Reichman and Z. Neiman: 'Jerusalem Sym-
posium of Quantum Chemistry and Biochemistry,' Israel Academy of Science,
1974, vol. 6, p. 397. 501,560,561
M. Ikehara and Y. Ogiso; J. Carbohydr. Nucleosides, Nucleorides, 1974, 1,401. 560
N. V. Zheltovskii and V. J. Danilov; Biofizika, 1974, 19, 784. 517
J. Salomon and D. Elad; Photoehern. Phorobiol., 1974, 19,21. 545
281
636
272
269
328
780
855
595
784
15
629,652
724
153
694
213
213,761
458
663
899
182
12,795
827
746, 750
620,622
251
662
656
745
628
7
288,289
188,189
289
199
289
168
250
427
603
74MI41100
B-74MI41101
74MI41200
74MI41500
74MI41501
74MI41502
740MR(6)272
740MS(8)347
740PPI56
74PMH(6)1
74PMH(6)53
74PMH(6)95
74PMH(6)199
74RCRI089
74RTC3
74RTCI60
74RTC317
74S30
74S32
74S41
74S198
74S815
74T445
74Tl301
74T2677
74T2903
74T394 I
74TH40100
74TLI29
74TL253
74TL269
74TLI 187
74TLI609
74TLI673
74TLI987
74TL2163
74TL2643
74TL2695
74TL3893
74TL442I
74TL4539
74UKZ99
74ZCI6
74ZC267
74ZC270
74Z0R377
74Z0RI725
74Z0RI787
74Z0R2467
74ZPC(355)1274
75ACR361
75ACS(A)647
75ACS(B)1089
75AGI
75AG(E)15
75AG(E)86
75AG(E)428
P. Mauret, J. P. Fayet, M. Fabre, J. Eiguero and J. De Mendoza; J. Chirn. Phys.
Phys. Chirn. BioI., 1974,71, 115 (Chern. Abstr., 1974,80, 132537).
C. W. Rees and R. C. Storr; Lect. Heterocycl. Chern., 1974,2,71.
R. Un; Chirn. Acta Turc., 1974, 2, I (Chern. Abstr., 1975, 82, 57623).
C. J. Coulson, R. E. Ford, E. Lunt, S. Marshall, D. L. Pain, J. H. Rogers and
K. R. H. Woodridge; Eur. 1. Med. Chern., 1974,9,313.
B. Stanovnik; Lectures Heterocycl. Chern., 1974,2, S-27.
T. Bany, A. Maliszewska-Guz and B. Modzelewska-Banachiewicz;
1974,48, 1445.
J. Eiguero, A. Fruchier and M. C. Pardo; argo Magn. Reson., 1974,6,272.
L. Birkofer, M. Franz and G. Schmidtberg; argo Mass Spectrorn., 1974,8,347.
R. G. Dickinson and N. W. Jacobsen; Org. Prep. Proced. Int., 1974,6, 156.
E. Heilbronner, J. P. Maier and E. Haselbach; Phys. Methods Heterocycl. Chern.,
1974, 6, I. 30
J. Sheridan; Phys. Methods Heterocycl. Chern., 1974,6,53. 8,171,181,676
B. C. Gilbert and M. Trenwith; Phys. Methods Heterocycl. Chern., 1974,6,95. 177,206
K. Pihlaja and E. Taskinen; Phys. Methods Heterocyc/. Chern., 1974,6, 199. 32
E. S. Golovchinskaya; Russ. Chern. Rev. (Engl. Trans!.), 1974,43, 1089. 556
R. De Bode and C. A. Salemink; Recl. Trav. Chirn. Pays-Bas, 1974,93,3. 642
J. E. Schelling and C. A. Salemink; RecI. Trav. Chirn. Pays-Bas, 1974,93,160. 619,636
S. Hoff and A. P. Blok; Recl. Trav. Chirn. Pays-Bas, 1974,93,317. 718
W. Schãfer, H. W. Moore and A. Aguado; Synthesis, 1974,30. 137
J. R. Williams and G. M. Sarkisian; Synthesis, 1974,32. 126
A. M. M. E. Omar; Synthesis, 1974,41. 458
H. Lind and H. Kristinsson; Synthesis, 1974, 198. 707
E. Duranti and C. Balsamini; Synthesis, 1974,815. 454
K. B. Sukumaran, S. Satish and M. V. George; Tetrahedron, 1974,30,445. 134
C. Wentrup; Tetrahedron, 1974,30, 1301. 867
M. Maeda, K. Nushi and Y. Kawazoe; Tetrahedron, 1974,30,2677. 543,546
A. Escande, J. Lapasset, R. Faure, E. J. Vincent and J. Eiguero; Tetrahedron,
1974,30,2903; erratum 1975,31,2. 175,176,177,179,180,198
E. Breitmaier and W. Voelter; Tetrahedron, 1974,30,3941. 515
D. Norbury; Ph.D. Thesis, University of Wales, 1974. 12
J.-L. Imbach, J. L. Barascut, B. L. Kam and C. Tapiero; Tetrahedron Lelt., 1974,
129.
M. H. Palmer and R. H. Findlay; Tetrahedron Lelt., 1974,253.
R. Fusco, L. Garanti and G. Zecchi; Tetrahedron Lelt., 1974,269.
A. Nohara; Tetrahedron Lelt., 1974, 1187.
J. Vilarrasa, E. Meléndez and J. Elguero; Tetrahedron Lelt., 1974, 1609.
G. Scherowsky and H. Franke; Tetrahedron Lelt., 1974, 1673.
A. Gieren, F. Pertlik and S. Sommer; Tetrahedron Lelt., 1974, 1987.
D. N. Reinhoudt and C. G. Kouwenhoven; Tetrahedron Lett., 1974,2163.
K. K. Balasubramanaian and B. Venugopalan; Tetrahedron Lelt., 1974,2643.
D. S. Kemp, M. Trangle and K. Trangle; Tetrahedron Lelt., 1974,2695.
S. Minami, Y. Kimura, T. Miyamoto and J. Matsumoto; Tetrahedron Lett., 1974,
3893.
T. Yamazaki, G. Baum and H. Shechter; Tetrahedron Lelt., 1974,4421.
B. Vercek, B. Stanovnik and M. TEHer; Tetrahedron Lelt., 1974,4539.
M. V. Povstyanoi and P. M. Kochergin; Ukr. Khirn. Zh. (Russ. Ed.), 1974,40,
99 (Chern. Abstr., 1974, 80, 82902).
E. Lipmann, D. Reifegerste and E. Kleinpeter; Z. Chern., 1974, 14, 16 (Chern.
Abstr., 1974, 81, 25615).
S. Leistner, G. Wagner and H. Richter; Z. Chern., 1974, 14, 267.
R. Schmidt, G. Westphal and B. Froehlich; Z. Chern., 1974, 14, 270.
O. P. Shvaika and V. I. Fomenko; Zh. Org. Khirn., 1974,10,377.
V. M. Neplynev and P. S. Pel'kis; Zh. argo Chirn., 1974, 10,1725 (Chern. Abstr.,
1974,81, 136059).
I. A. Korbukh, O. N. Judina and M. N. Preobrazhenskaya; Zh. Org. Khirn., 1974,
10, 1787.
A. V. El'tsov, V. P. Martynova, E. R. Zakhs and L. P. Shustova; Zh. argo Khirn.,
1974,10,2467 (Chern. Abstr., 1975,82,57613).
H. W. Vohland, P. E. Schulze, W. Koransky, G. Schulz and B. Acksteiner;
Hoppe-Seyler's Z. Physiol. Chern., 1974, 355, 1274 (Chern. Abstr., 1975,
82,92 876).
References
959
677
670
775
895
868,869,870,871,880
Rocz. Chern.,
K. N. Houk; Acc. Chern. Res., 1975,8,361.
K. Nielsen; Acta Chern. Scand., Ser. A, 1975,29,647.
J. M. Bakke and K. A. Skjervold; Acta Chern. Scand., Ser. B, 1975,29, 1089.
D. Seebach and D. Enders; Angew. Chern., 1975,87, I.
D. Seebach and D. Enders; Angew. Chern., Int. Ed. Engl., 1975, 14, 15.
C. Reichardt and K. Halbritter; Angew. Chern., Int. Ed. Engl., 1975,14,86.
H. Quast and L. Bieber; Angew. Chern., Int. Ed. Engl., 1975, 14,428.
886
187
204
785
513
677
317
815
225
779
278
720
444, 446
728
342
212
877
654
794
776
775
775
793, 828
289
611,612
835
711
674
274
717
717
281
810
960
75AG( E)560
75AG(E)646
75AG(E)647
75AG(E)665
75AG( E)775
75AJC133
75AJC421
75AJCI583
75AJCI861
75ANY(255)177
75ANY(255)292
75APO(l1)267
75AX(B)211
75AX(B)548
75AX(B)2119
75AX(B)2862
75131490
75BCJI484
75BSB499
75BSRI189
75BSF647
75BSF857
75BSF1649
75BSFI675
75CB372
75CB887
75CB3762
75CB3780
75CB3794
75CC125
75CC 128
75CC 146
75CC319
75CC964
75CCC 1199
75CHE81
75CHEI23
75CHE343
75CHE371
75CHE461
75CHE718
75CH E751
75CHE995
75CHEI416
75CI(L)278
75CJCI19
75CJC355
75CJC2944
75CL499
75CPB452
References
W. Sucrow, M. Slopianka and V. Bardakos; Angew. Chern., Int. Ed. Eng/., 1975,
14, 560.
H. Dürr and B. Weiss; Angew. Chern., Int. Ed. Eng/., 1975, 14,646.
H. Dürr and H. Schmitz; Angew. Chern., Int. Ed. Eng/., 1975, 14,647.
A. Dorlars, C. W. Schellhammer and J. Schroeder; Angew. Chern., Int. Ed. Eng/.,
1975, 14, 665.
G. L'abbe; Angew. Chern., Int. Ed. Eng/., 1975, 14,775.
M. Woodruff and J. B. Polya; Aust. J. Chern., 1975,28, 133.
M. Woodruff and J. B. Polya; Aust. J. Chern., 1975,28,421.
M. Woodruff and J. B. Polya; Aust. 1. Chern., 1975,28, 1583.
L. W. Deady, R. G. McLoughlin and M. R. Grimmett; Aust. J. Chern., 1975,28,
1861.
J.-L. Imbach; Ann. N. Y. Acad. Sci., 1975,255,177.
J. A. Montgomery, R. D. Elliott and H. J. Thomas; Ann. N. Y. Acad. Sci., 1975,
255, 292. 608,652
M. Liler; Adv. Phys. Org. Chern., 1975, 11,267. 202,255,256
T. J. Kistenmacher and T. Shigematsu; Acta. Crystallogr., Part B, 1975,31, 211. 509, 513
L. Dupont, 1. Toussaint, O. Dideberg, J. M. Braham and A. F. Noels; Acta
Crystallogr., Part B, 1975,31,548.
J. Delettré, R. Bally and J. P. Momon; Acta CrystalIogr., Part B, 1975,31,2119.
G. S. Mandel and R. E. Marsh; Acta. CrystalIogr., Part B, 1975,31,2862.
L. F. Christensen, R. B. Meyer, Jr., 1. P. Miller, L. N. Simon and R. K. Robins;
Biochemistry, 1975, 14, 1490.
F. Yoneda and T. Nagamatsu; Bull. Chern. Soc. Jpn., 1975,48, 1484.
J. Eiguero, C. Marzin and M. E. Peek; Bull. Soc. Chirn. Be/g., 1975,84,499.
J. Eiguero, R. Faure, J. P. Ga1y and E. J. Vincent; Bull. Soc. Chirn. Be/g., 1975,
84,1189.
A. Bernardini, P. Viallefont, J. Daunis, M. L. Roumestant and A. B. Soulami;
BulI. Soc. Chirn. Fr., 1975,647. 746,752,753
J. Daunis and M. Follett; BulI. Soc. Chirn. Fr., 1975,857. 898,899
J. L. Barascut, P. Viallefont and J. Daunis; Bull. Soc. Chirn. Fr., 1975, 1649. 753
P. Mauret, J. P. Faye! and M. Fabre; BulI. Soc. Chirn. Fr., 1975, 1675. 176,177,677
C. Metzger and J. Kurz; Chern. Ber., 1975, 108,372. 661
D. Moderhack; Chern. Ber., 1975, 108,887. 819,820
H. Reimlinger, J. J. M. Vandewalle, R. Merényi and W. R. F. Lingier; Chern.
Ber., 1975, 108,3762.
H. Reimlinger, W. R. F. Lingier and J. J. M. Vandewalle; Chern. Ber., 1975, 108,
3780.
H. Reimlinger, W. R. F. Lingier and R. Merényi; Chern. Ber., 1975,108,3794.
1. L. Wong and J. H. Keck, Jr.; J. Chern. Soc., Chern. Cornrnun., 1975, 125.
J. Dingwall and J. T. Sharp; J. Chern. Soc., Chern. Cornrnun., 1975, 128.
F. Yoneda, S. Matsumoto and M. Higuchi; 1. Chern. Soc., Chern. Cornrnun., 1975,
146.
c.-Y. Shiue and S. H. Chu; J. Chern. Soc., Chern. Cornrnun., 1975,319.
C. C. Duke, A. J. Liepa, J. K. MacLeod, D. S. Letham and C. W. Parker; J.
Chern. Soc., Chern. Cornrnun., 1975,964.
A. Martvoìí, S. Stankovský and J. SvetIík; Collect. Czech. Chern. Cornrnun., 1975,
40,1199.
G. K. Rogul'chenko, I. A. Mazur and P. M. Kochergin; Chern. Heterocycl. Cornpd.
(Eng/. Trans/.), 1975, 11, 81.
I. I. Popov, A. M. Simonov and A. A. Zubenko; Chern. Heterocycl. Cornpd. (Engl.
Trans/.), 1975, 11, 123.
B. A. Tertov and A. S. Morkovnik; Chern. Heterocycl. Cornpd. (Eng/. Trans/.),
1975, 11,343.
M. V. Povstyanoi, P. M. Kochergin, E. V. Logachev and E. A. Yakubovskii;
Chern. Heterocycl. Cornpd. (Eng/. Trans/.), 1975, 11,371.
I. I. Popov, P. V. Tkachenko and A. M. Simonov; Chern. Heterocycl. Cornpd.
(Engl. Trans/.), 1975,11,461.
P. V. Schatnev, M. S. Shvartsberg and I. Va. Bernshtein; Chern. Heterocycl.
Cornpd. (Eng/. Trans/.), 1975, 11,718.
M. V. Povstyanoi, M. A. K1ykov, N. M. Gorban' and P. M. Kochergin; Chern.
Heterocycl. Cornpd. (Eng/. Trans/.), 1975, 11,751.
Z. V. Pushkareva, V. I. Ofitserov, V. S. Mokrushin and K. V. Aglitskaya; Chern.
Heterocycl. Cornpd. (Eng/. Transl.), 1975,11,995.
N. D. Abramova, G. G. Skvortsova, B. V. Trzhtsinskaya and M. V. Sigalov;
Chern. Heterocycl. Cornpd. (Eng/. Trans/.), 1975, 11, 1416.
G. L'abbe, G. Mathys and S. Toppet; Chern. Ind. (London), 1975,278.
B. M. Lynch, M. A. Khan, S. C. Sharma and H. C. Teo; Can. J. Chern., 1975,
53, 119. 306,307,311
D. H. Hunter and R. P. Steiner; Can. J. Chern., 1975,53,355. 852
D. F. Rendle, A. Storr and J. Trotter; Can. J. Chern., 1975,53,2944. 237
M. Hamaguchi and T. Ibata; Chern. Leu., 1975,499. 162
T. Kato and S. Masuda; Chern. Pharrn. BulI., 1975,23.452. 337
281
251
251
299
163
281,751,782
782
225
210
513
179
178
510
546
161. 337
184
214
865,866
879
868,888
527
250
581
581
585
717
648
438
447
654
450
438
656
652,667
450
718
75CPB759
75CPB955
75CPB2401
75CPB2643
75CPB2678
75CR(C)685
75CRV241
75DIS(B)(36)1712
75DOK(224)847
75E996
75EGPIII074
75FESI97
75FES650
75GI291
75GEP2407304
75GEP2407305
75GEP2511829
75H(3)217
75HCA688
75HCA1521
75HCA2192
75IJC468
75IJC668
75IZV690
75IZV2766
75JAI238
75JAI285
75JA2369
75JA3351
75JA4627
75JA4636
75JA4990
75JA6008
75JA6197
75JA7467
75JAP7504074
75JCS(D)176
75JCS(D)718
75JCS(D)749
75JCS(PI)1
75JCS(PI)12
75JCS(PI)41
75JCS(PI) 125
75JCS(PI)275
75JCS(PI)386
75JCS(PI)406
References
961
R. Marumoto, Y. Yoshioka, O. Miyashita, S. Shima, K.-I. Imai, K. Kawazoe
and M. Honjo; Chem. Ph arm. Bull., 1975,23,759.
S. Kubota and M. Uda; Chem. Ph arm. Bull., 1975,23,955.
M. Seikiya and J. Suzuki; Chem. Pharm. Bull., 1975,23,2401.
T. Itaya, T. Saito, K. Kawakatsu and T. Fujii; Chem. Pharm. Bull., 1975,23,2643.
A. Nagel and H. C. van der Plas; Chem. Pharm. Bull., 1975,23,2678.
C. Simionescu, T. Liandru, C. Gorea and V. Gordoza; c.R. Hebd. Seances Acad.
Sci., Ser. C, 1975,685.
R. N. Butler; Chem. Rev., 1975,75, 241.
J. C. B. Komin; Diss. Abstr. Int. B, 1975,36, 1712.
S. B. Bulgarevich, O. A. Osipov, V. S. Bolotnikov, T. V. Lifintseva, V. N. Sheinker
and A. D. Garnovskii; Dokl. Akad. Nauk SSSR, 1975,224,847 (Chem. Abstr.,
1976, 84, 43 053).
Z. Neiman; Experientia, 1975,31,996.
S. Hauptmann, R. Ludwig and E. Tenor; Ger. (East) Pat. 111074 (1975) (Chem.
Abstr., 1976,84,31078). 746
G. Palazzo and G. Picconi; Farmaco Ed. Sci., 1975,30, 197. 614,635
A. Omodei-Sale and E. Toja; Farmaco Ed. Sci., 1975,30,650. 644
M. Kac, F. Kovac, B. Stanovnik and M. Tisler; Gazz. Chim. Ital., 1975,105,1291. 863,
869,871,880
H. Hoffmann, I. Hammann, B. Homeyer and W. Stendel; Ger. Pat.
2407304 (1975) (Chem. Abstr., 1976,84,4965).
Bayer AG, Ger. Pat. 2407305 (1975) (Chem. Abstr., 1975,83,206290).
J. T. Witkowski and R. K. Robins; Ger. Pat. 2511829 (1975) (Chem. Abstr.,
1976, 84, 4966).
K. Hirai and T. Ishiba; Heterocycles, 1975,3,217.
A. J. Bates, I. J. Galpin, A. Hallett, D. Hudson, G. W. Kenner, R. Ramage and
R. C. Sheppard; Helv. Chim. Acta, 1975,58,688.
K. Rüfenacht; Helv. Chim. Acta, 1975,58, 1521.
A. Edenhofer; Helv. Chim. Acta., 1975,58,2192.
S. Sharma, R. N. Iyer and N. Anand; Indian J. Chem., 1975,13,468.
S. P. Gupta and P. Singh; Indian J. Chem., 1975, 13,668.
S. F. Vasilevskii, A. N. Sinyakov, M. S. Shvartsberg and I. L. Kotlyareveskii;
Izv. Akad. Nauk SSSR, Ser. Khim., 1975,690.
N. K. Kochetkova, A. N. Kost, V. W. Shibaev, R. S. Sagitullin, A. A. Kost and
Y. V. Zavy'alov; Izv. Akad. Nauk SSSR, Ser. Khim., 1975,2766 (Chem. Abstr.,
1976,84, 105526).
E. J. Schantz, V. E. Ghazarossian, H. K. Schnoes, F. M. Strong, J. P. Springer,
J. O. Pezzanite and J. Clardy; 1. Am. Chem. Soc., 1975,97, 1238.
R. C. Bingham, M. J. S. Dewar and D. H. Lo; J. Am. Chem. Soc., 1975,97,1285,
1294, 1302, 1307.
M. Dreyfus, G. Dodin, O. Bensaude and J. E. Dubois; J. Am. Chem. Soc., 1975,
97, 2369.
L. G. Marzilli, L. A. Epps, T. Sorrell and T. J. Kistenmacher; J. Am. Chem. Soc.,
1975, 97, 3351.
M.-T. Chenon, R. J. Pugmire, D. M. Grant, R. P. Panzica and L. B. Townsend;
J. Am. Chem. Soc., 1975,97,4627.
M. T. Chenon, R. J. Pugmire, D. M. Grant, R. P. Panzica and L. B. Townsend;
J. Am. Chem. Soc., 1975,97,4636.
N. J. Leonard and T. R. Henderson; J. Am. Chem. Soc., 1975,97,4990.
J. Bordner, W. E. Thiessen, H. A. Bates and H. Rapoport; J. Am. Chem. Soc.,
1975,97,6008.
A. Holm, N. HaITit and N. H. Toubro; J. Am. Chem. Soc., 1975,97,6197.
C. Mayor and C. Wentrup; J. Am. Chem. Soc., 1975,97, 7467.
A. Kotone, M. Hoda and T. Fujita; Jpn. Pat. 7504074 (1975) (Chem. Abstr.,
1975,83,114414).
D. F. Rendle, A. Storr and J. Trotter; J. Chem. Soc., Dalton Trans., 1975, 176.
D. J. Patmore, D. F. Rendle, A. Storr and J. Trotter; J. Chem. Soc., Dalton Trans.,
1975,718.
K. R. Breakell, D. J. Patmore and A. Storr; J. Chem. Soc., Dalton Trans., 1975,
749.
T. L. Gilchrist, G. E. Gymer and C. W. Rees; J. Chem. Soc., Perkin Trans. I,
1975, I. 686, 692, 693, 698
T. L. Gilchrist, C. W. Rees and C. Thomas; J. Chem. Soc., Perkin Trans. l, 1975,
12.
B. M. Adger, M. Keating, C. W. Rees and R. C. Storr; J. Chem. Soc., Perkin
Trans. 1, 1975,41.
J. A. May, Jr. and L. B. Townsend; J. Chem. Soc., Perkin Trans. 1, 1975, 125.
I. J. Ferguson and K. Schofield; J. Chem. Soc., Perkin Trans. 1, 1975,275.
N. W. Alcock, B. T. Golding, D. R. Hall, U. Horn and W. P. Watson; J. Chem.
Soc., Perkin Trans. 1, 1975,386.
Y. Tamura, Y. Sumida, Y. Miki and M. Ikeda; J. Chem. Soc., Perkin Trans. 1,
1975,406.
590, 664
740, 741
569
554
592
569
822
703
672
521
787
732
788
lIS
728
904
140, 466
645
505
753
648
604
7
514
531
514
514
570,515
604
ISO
867
748
227
227
236
765
269
619,621
455, 456
633
339
962
75JCS(PI)798
75JCS(PI )975
75JCS(PI)1232
75JCS(PI)1695
75JCS(PI )2240
75JCS(P2)928
75JCS(P2)1200
75JCS(P2)1325
75JCS(P2)1600
75JCS(P2)1609
75JCS(P2)1624
75JCS(P2)1632
75JCS(P2)1695
75JCS(P2)1791
75JHCI07
75JHCI19
75JHCI43
75JHCI71
75JHC207
75JHC21 I
75JHC225
75JHC279
75JHC379
75JHC471
75JHC4!!1
75JHC493
75JHC505
75JHC517
75JHC523
75JHC597
75JHC675
75JHC717
75JHC77 I
75JHC861
75JHC883
75JHCI031
75JHCI039
75JHCI045
75JHC 1127
75JHCI137
75JHCl191
75JHCl199
75JHCl233
75JMC460
75JMCI031
75JOC252
75JOC356
75JOC363
75JOC385
75JOC431
G. Cooper and W. J. Irwin; J. Chern. Soc., Perkin Trans. 1, 1975,798.
R. G. Dickinson and N. W. Jacobsen; J. Chern. Soc., Perkin Trans. 1, 1975,975.
S. Anderson, E. E. Glover and K. D. Vaughan; J. Chern. Soc., Perkin Trans. 1,
1975, 1232.
M. H. Palmer, R. H. Findlay, S. M. F. Kennedy and P. S. Mcintyre; J. Chern.
Soc., Perkin Trans. 1, 1975, 1695. 175,186,230
W. Pendergast; J. Chern. Soc., Perkin Trans. 1, 1975, 2240. 541
H. J. C. Yeh, K. L. Kirk, L. A. Cohen and J. S. Cohen; J. Chern. Soc., Perkin
Trans. 2, 1975,928.
G. B. Ansell; J. Chern. Soc., Perkin Trans. 2, 1975, 1200.
M. E. Burrage, R. C. Cookson, S. S. Gupte and I. D. R. Stevens; J. Chern. Soc.,
Perkin Trans. 2, 1975, 1325.
A. R. Katritzky, B. Terem, E. V. Scriven, S. Clementi and H. O. Tarhan; J. Chern.
Soc., Perkin Trans. 2, 1975, 1600.
M. Dereli, A. R. Katritzky and H. O. Tarhan; J. Chern. Soc., Perkin Trans. 2,
1975, 1609.
A. R. Katritzky, S. Clementi and H. O. Tarhan; J. Chern. Soc., Perkin Trans. 2,
1975, 1624.
A. R. Katritzky, H. O. Tarhan and B. Terem; J. Chern. Soc., Perkin Trans. 2,
1975, 1632.
M. H. Palmer, R. H. Findlay, S. M. F. Kennedy and P. S. Mcintyre; J. Chern.
Soc., Pekin Trans. 2, 1975, 1695.
D. E. McGreer, I. M. E. Masters and M. T. H. Liu; J. Chern. Soc., Perkin Trans.
2, 1975, 1791.
Y. Tamura, J.-H. Kim and M. Ikeda; J. Heterocycl. Chern., 1975,12, 107.
References
Y. Tamura, Y. Miki and M. Ikeda; J. Heterocyc/. Chern., 1975, 12, 119.
P. K. Kadaba; J. Heterocyc/. Chern., 1975, 12, 143.
A. D. Broom and G. H. Milne; J. Heterocyc/. Chern., 1975,12, 171.
E. Abushanab, A. P. Bindra and L. Goodman; J. Heterocyc/. Chern., 1975, 12,207.
E. Abushanab, A. P. Bindra, D.-Y. Lee and L. Goodman; J. Heterocyc/. Chern.,
1975,12,211.
Y. Tamura, H. Hayashi, Y. Nishimura and M. Ikeda; J. Heterocyc/. Chern., 1975,
12, 225.
E. Gonzalez, R. Sarlin and J. E1guero; J. Heterocyc/. Chern., 1975,12,279.
O. Fuentes and W. W. Paud1er; J. Heterocyc/. Chern., 1975,12,379.
T. Nishimura, K. Nakano, S. Shibamoto and K. Kitajima; J. Heterocyc/. Chern.,
1975, 12, 471.
Y. Tamura, J.-H. Kim, Y. Miki, H. Hayashi and M. Ikeda; J. Heterocyc/. Chern.,
1975, 12, 481.
C. Y. Shiue and S. H. Chu; J. Heterocyc/. Chern., 1975,12,493.
F. Texier and J. Bourgois; J. Heterocycl. Chern., 1975, 12, 505.
J. D. Ratajczyk and L. R. Swett; J. Heterocycl. Chern., 1975,12,517.
M. Winn; 1. Heterocycl. Chern., 1975, 12, 523.
D. M. Mulvey and H. Jones; J. Heterocycl. Chern., 1975, 12,597.
A. Shafiee and I. La1ezari; J. Heterocycl. Chern., 1975,12,675.
A. Walser, T. Flynn and R. I. Fryer; J. Heterocyc/. Chern., 1975,12,717.
T. J. Schwan and R. L. White, Jr.; J. Heterocyc/. Chern., 1975, 12,771.
M. F. DePompei and W. W. Paudler; J. Heterocycl. Chern., 1975, 12,861.
R. C. Anderson and Y. Y. Hsiao; J. Heterocyc/. Chern., 1975,12,883.
N. W. Rokke, J. J. Worman and W. S. Wadsworth; J. Heterocyc/. Chern., 1975,
12, 1031.
H. J. J. Loozen, B. J. van der Beek, E. F. Godefroi and H. M. Buck; 1. Heterocycl.
Chern., 1975,12, 1039.
T. P. Seden and R. W. Turner; J. Heterocycl. Chern., 1975, 12, 1045.
Y. C. Tong; 1. Heterocyc/. Chern., 1975,12, 1127.
L. R. Swett, J. D. Ratajczyk, C. W. Nordeen and G. H. Aynilian; J. Heterocyc/.
Chern., 1975,12, 1137.
N. P. Peet and S. Sunder; J. Heterocyc/. Chern., 1975,12, 1191.
P. L. Southwick and B. Dhawan; J. Heterocyc/. Chern., 1975,12, 1199.
A. T. Nielsen; J. Heterocyc/. Chern., 1975, 12, 1233.
T. Novinson, J. P. Miller, M. Scholten, R. K. Robins, L. N. Simon, D. E. O'Brien
and R. B. Meyer; J. Med. Chern., 1975, 18,460.
H. Zimmer, R. Glaser, J. Kokosa, D. A. Garteiz, E. V. Hess and A. Litwin; J.
ed. Chern., 1975,18, 1031.
A. A. Macco, E. F. Godefroi and J. J. M. Drouen; J. argo Chern., 1975.40,252.
N. J. Leonard, A. G. Morrice and M. A. Sprecker; J. Org. Chern., 1975,40,356.
A. G. Morrice, M. A. Sprecker and N. J. Leonard; J. argo Chern., 1975,40,363.
K. Yamauchi, M. Hayashi and M. Kinoshita; J. Org. Chern., 1975,40,385.
A. Holm, K. Schaumburg, N. Dahlberg, C. Christophersen and J. P. Snyder; J.
argo Chern., 1975, 40, 431.
662
757
879
447
796, 797
749, 784
238
238
238,239
238
673
255
856, 889,
891,896
339
717
526
625,
644
644
283
272
614,615
358, 422
887,888
597
715
272, 313, 326, 332
332
446
142
771
775
624,643
135
802
641
530
645
343
136
272
281
313,331
904
431,660
567
567
530
53
751OC746
751OC810
751OC915
751OC1348
75JOCI815
751OC2042
751OC2045
751OC2562
751OC2600
751OC2604
75JOC2916
75JOC2920
751OC3112
75JOC3296
751OC3373
751OC3376
751OC3379
751OC3708
751OM(88)115
751OU902
751OUI130
75KGS690
75KGS844
75KGSIOOO
75KGSI389
75LA449
75LA470
75LAI264
75LAI465
75LAI934
75M417
75MI059
75MI461
75MI40400
75MI40401
75MI40402
75MI40403
B-75MI40404
B-75MI40800
B-75MI40900
75MI40901
75MI40902
75MI40903
75MI41000
75MI41001
75MI41002
75MI41100
K. Bechgaard, D. O. Cowan, A. N. Bloch and L. Henriksen; 1. argo Chem., 1975,
40, 746.
R. J. De Pasquale, C. D. Padgett and R. W. Rosser; J. argo Chem., 1975,40,810.
J. W. A. M. Janssen, P. Cohen-Fernandes and R. Louw; J. Org. Chem., 1975,
40,915.
V. Nair and K. H. Kim; J. argo Chem., 1975,40, 1348.
S. M. Hecht, D. Werner, D. D. Traficante, M. Sundaralingam, P. Prusiner, T.
Ito and T. Sakurai; J. argo Chem., 1975,40,1815. 192,211,281
J. K. Crandall, W. W. Conover and J. B. Komin; J. argo Chem., 1975,40,2042. 703
J. K. Crandall, L. C. Crawley and J. B. Komin; J. argo Chem., 1975,40, 2045. 703,715
J. H. M. Hill, T. R. Fogg and H. Guttmann; J. Org. Chem., 1975,40,2562. 634
K. T. Potts and J. Kane; 1. Org. Chem., 1975,40,2600. 131
M. H. Elnagdi, M. H. R. Elmoghayar, E. A. A. Hafez and H. H. Alnima; J. Org.
Chem., 1975, 40, 2604.
E. S. Hand and W. W. Paudler; J. argo Chem., 1975,40,2916.
P. C. Srivastava, G. A. Ivanovics, R. J. Rousseau and R. K. Robins; J. argo Chem.,
1975,40,2920.
C. J. Wilkerson and F. D. Greene; J. argo Chem., 1975, 40, 3112.
J. Pitha; J. Org. Chem., 1975,40,3296.
E. Abushanab, A. P. Bindra, D.-Y. Lee and L. Goodman; J. Org. Chem., 1975,
40, 3373.
E. Abushanab, D.-Y. Lee and L. Goodman; J. Org. Chem., 1975,40,3376.
E. Abushanab, A. P. Bindra and L. Goodman; 1. Org. Chem., 1975,40,3379.
D. G. Bartholomew, P. Dea, R. K. Robins and G. R. Revankar; J. argo Chem.,
1975,40,3708.
P. G. Moniotte, A. J. Hubert and P. Teyssie; 1. Organomet. Chem., 1975,88, liS.
V. I. Ofitserov, V. S. Mokrushin and I. A. Korbukh; J. Org. Chem. USSR (EngI.
TransI.), 1975, 11,902.
I. I. Popov, A. M. Simonov and A. A. Zubenko; J. Org. Chem. USSR (EngI.
Transl.), 1975, 11, 1130.
A. S. Elina and I. S. Musatova; Khim. Geterotsikl. Soedin., 1975, 690 (Chem.
Abstr., 1975, 83, 114336).
S. M. Khripak, M. M. Tsitsika and I. V. Smolanka; Khim. Geterotsikl. Soedin.,
1975,844.
S. M. Khripak, M. M. Tsitsika and I. V. Smolanka; Khim. Geterotsikl. Soedin.,
1975, 1000.
Y. M. Yutilov and L. I. Kovaleva; Khim. Geterotsikl. Soedin., 1975, 1389 (Chem.
Abstr., 1976,84,43936).
K. Tortschanoff, H. Kisch and O. E. Polansky; Liebigs Ann. Chem., 1975,449.
C. Reichard and K. Halbritter; Liebigs Ann. Chem., 1975,470.
H. Behringer and R. Ramert; Liebigs Ann. Chem., 1975, 1264.
C. Rufer, K. Schwarz and E. Winterfeldt; Liebigs Ann. Chem., 1975, 1465.
C. Ivancsics and E. Zbiral; Liebigs Ann. Chem., 1975, 1934.
C. Ivancsics and E. Zbiral; Monatsh. Chem., 1975,106,417.
H. Berner and H. Reinshagen; Monatsh. Chem., 1975, 106, 1059.
F. Asinger, A. Saus, E. Fichtner and W. Leuchtenberger; Monatsh. Chem., 1975,
106, 1461.
R. Paredes and W. R. Dolbier; Rev. Latinoamer. Quím, 1975,6,29.
F. D. Höppner, H. J. Hofmann and C. Weiss; J. Signalaufzeichnungsmaterialien,
1975, 1, 75.
A. Garcia-Tapia, V. Gómez-Parra, R. Madroñero, L. Nebrada and S. Vega; An.
Real. A cad. Ciencias Exact. Fis. Nat., 1975, 421.
J. Vilarrasa, C. Galvez and M. Calafell; An. Quím. 1975,71,631.
S. Sternhell; in 'Dynamic Nuclear Magnetic Resonance Spectroscopy', ed. L.
M. Jackman and F. A. Cotton; Academic Press, New York, 1975, p. 185.
A. E. A. Porter; in 'Saturated Heterocyclic Chemistry', The Chemical Society,
London, 1975, vol. 3, p. 197. 458,459,464,466
G. A. Le Page; in 'Antineoplastic and Immunosuppressive Agents, Part II', ed.
A. C. Sartorelli and D. G. Johns; Springer-Verlag, Berlin, 1975, p.426.
F. Yoneda; Kagaku No Kyoiki, 1975,29,482.
L. L. Bennett, Jr. and D. L. Hill; Mol. Pharmacol., 1975, 11, 803.
T. Urushibara, Y. Furuichi, C. Nishimura and K. Miura; FEBS Left., 1975,49,
385.
J. A. May, Jr. and L. B. Townsend; J. Carbohydr., Nucleosides, Nucleotides, 1975,
2, 271.
S. Kitano, A. Nomura, Y. Mizuno, T. Okamoto and Y. Isogai; J. Carbohydr.,
Nucleosides, Nucleotides, 1975,2,299.
A. S. Elina, I. S. Musatova, M. A. Muratov and M. D. Mashkovskii; Khim.-Farm.
Zh., 1975, 9, 10 (Chem. Abstr., 1975, 82, 170 839).
K. Tsujimoto, M. Ohashi and T. Yonezawa; Hukusokan Kagaku Toronkai Koen
Yoshishu, 1975,8,4 (Chem. Abstr., 1976,84, 163670).
References
963
liS
709
206
153
140
611
660
775
505, 528
625
625
625,
626,644
627,648
162
629
437
626
746,748
748
619
255
184,281
758
437
647,648
648
619,635
422
252
210
269,272
184
209
504
SOl
603
600
619
618,621
626
694
964
B-75M141101
75M[41200
75M[41201
B-75M[41400
75M[P464584
750MR(7)455
750MS558
75P2512
75P2539
75PNA318
75RTCI53
75S20
75S162
75S609
75S645
75S675
75S703
75S798
75Tl171
75TI363
75TI461
75TI463
75Tl783
751'2914
75TL33
75TL695
75TLl219
75TL2807
75TL4085
75 US P3865570
75ZCI02
75ZCI46
75ZC402
75ZC'482
75ZN(B)6:'2
75Z0BI821
76AC'H(89)265
76AG I 31
76AG724
76AG(E)113
76AG(E)123
76AG(E)378
76AHC(19)1
76AHC( (9)3
76AHC(20)65
76AHC(20)145
76AHC(SI)1
76AHC'(S I )32
76AHC'(S I )266
References
J. L. Neumeyer; in 'Principles of Medicinal Chemistry', ed. W. O. Foye; Lea
and Febiger, Philadelphia, 1975, p. 774.
G. Wagner, B. Dietzsch and U. Krake; Pharrnazie, 1975,30,694 (Chern. Abstr.,
1976,84,90504).
R. M. De Marinis, J. R. E. Hoover, G. L. Dunn, P. Actor, J. V. Uri and J. A.
Welsbach; J. Antibiot., 1975,28,463.
'Peptides 1974', ed. Y. Wolman; Wiley, New York, 1975, p.74.
L. P. Makhno, T. G. Ermakova, E. S. Damnina, L. A. Tatarova, G. G. Skvortsova
and V. A. Lopyrev: USSR Pat. 464 584 (1975)(Chern. Abstr., 1975,83, 1(4416).
L. Marchetti, L. Pentimalli, P. Lazzerelte, L. Schenetti and F. Taddei; Org. Magn.
Reson., 1975, 7, 455.
A. Maquestiau, Y. Van Haverbeke, R. Flammang, M. C. Pardo and J. Eiguero;
Org. Mass Spectrorn., 1975, 10,558.
T. A. LaRue and J. J. Child; Phytochemistry, 1975, 14,2512.
T. Sugiyama, E. Kitamura, S. Kubokawa, S. Kobayashi, T. Hashizume and S.
Matsubara; Phytochernistry, [975, 14,2539.
C. M. Wei and B. Moss; Proc. Natl. Acad. Sci. USA, 1975,72,318.
J. E. Schelling and C. A. Salemink; Reel. Trav. Chirn. Pays-Bas, 1975,94, 153.
T. Nishiwaki; Synthesis, 1975,20.
S. Kasina and J. Nematollahi; Synthesis, 1975, 162.
K. Matsumoto, M. Suzuki, M. Tomie, N. Yoneda and M. Miyoshi; Synthesis,
1975,609.
K. Grohe; Synthesis, 1975,645.
R. Lantzsch and D. Ar1t; Synthesis, 1975,675.
F. Seng and K. Ley; Synthesis, 1975,703.
S. M. S. Chauhan and H. Junjappa; Synthesis, 1975,798.
K. S. Balachandran, 1. Hiryakkanavar and M. V. George; Tetrahedron, 1975,31,
1171.
G. F. Huang, M. Maeda, T. Okamoto and Y. Kawazoe; Tetrahedron, 1975,31,
1363.
A. N. Nesmeyanov, E. B. Zavelovich, V. N. Babin, N. S. Kochetkova and E. 1.
Fedin; Tetrahedron, 1975,31, 1461.
A. N. Nesmeyanov, E. B. Zavelovich, V. N. Babin, N. S. Kochetkova and E. I.
Fedin; Tetrahedron, 1975,31, 1463.
A. Holm, L. Carlsen, S.-O. Lawesson and H. Kolind-Andersen; Tetrahedron,
1975,31,1783.
A. Kolb, C. Gouyette, T. H. Dinh and J. Igolen; Tetrahedron, 1975,31,2914.
R. R. Schmid and H. Huth; Tetrahedron Left., 1975, 33.
A. Krantz and B. Hoppe; Tetrahedron Left., 1975,695.
B. :::astro, J. R. Dormoy, B. Evin and C. Selve; Tetrahedron Left., 1975, 1219.
B. Green and D.-W. Lin; Tetrahedron Left., 1975,2807.
J. EIguero, G. Uouquet and C. Marzin; Tetrahedron Left., 1975,4085.
E. F. George and W. D. Riddell; U.S. Pat. 3 865 570 (1975) (Chern. Abstr., 1975,
83, 54601).
E. Lippmann, A. Könnecke and G. Beyer; Z. Chern., 1975,15,102 (Chern. Abstr.,
1975,83,28159).
E. Lippmann and D. Reifegerste; Z. Chern., 1975, 15, 146.
A. Könnecke, E. Lippmann and E. Kleinpeter; Z. Chern., 1975, 15,402 (Chern.
Abottr., 1976,84,73399).
E. Bulka and W. D. Pfeiffer; Z. Chern., 1975, 15,482.
K. Burger, H. Schickaneder and A. Meffert; Z. Natuiforsch., Teil B, 1975,30,622.
S. B. Bulgarevich, V. S. Bolotnikov, V. N. Sheinker, O. A. Osipov and A. D.
Garnovskii; Zh. Obshch. Khirn., 1975,45, 1821 (Chern. Abstr., 1975,83,178013).
G. Szilágyi and H. Wamhoff; Acta Chirn. Acad. Sci. Hung., 1976,89,265.
A. Padwa; Angew. Chern., 1976,88, 131.
H. Vorbrugger and K. Krolikiewicz; Angew. Chern., 1976,88,724.
G. Höfle and B. Lange; Angew. Chern., Int. Ed. Engl., 1976, 15, 113.
A. Padwa; Angew. Chern., Int. Ed. Engl., 1976,15, 123.
U. Felcht and M. Regitz; Angew. Chern., Int. Ed. Engl., 1976, 15,378.
W. D. Ollis and C. A. Ramsden; Adv. Heterocycl. Chern., 1976,19, I.
732
746
787
845
748
627
203
303
619
600
615,619
491
435
768
334
667
435, 492
281
707
771
213
192
55
585
287
852
728
714
365
836
824
794
805
666
275
672
697
708
559
816
148, 708
271
2,45,47,76,
171,201,286
743
13, 68, 88, 89, 105
44,84
W. D. Ollis and C. A. Ramsden; Adv. Heterocycl. Chern., 1976, 19,3.
L. B. Clapp; Adv. Heterocycl. Chern., 1976,20,65.
A. Holm; Adv. Heterocycl. Chern., 1976,20, 145.
J. Elguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. !, 1976, I. 15,35,36,37,38,169,170,177,182,185,199,200,
201,210,213,215,222,223,224,265,737,741,742,743
J. Eiguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. !, 1976,32.
J. EIguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. !, 1976,266.
677
366
76AHC(SI)280
76AHC(SI)281
76AHC(SI)295
76AHC(SI)296
76AHC(SI)502
76AJC799
76AJC815
76AJC89I
76AJCI039
76AJC249 I
76AX(B)714
76AX(B)853
76AX(B)2216
76AX(B)2314
76B898
76BCJl43
76BCJl920
76BCJl980
76BCJ3607
76BSB545
76BSB697
76BSB795
76BSFI84
76BSFI92
76BSFI95
76BSF476
76BSF869
76BSFI861
76BSFI983
76BSF2025
76CBI625
76CBI638
76CBI898
76CB2596
76CC23
76CC48
76CCI55
76CC250
76CC326
76CC343
76CC414
76CC658
76CC685
76CCCI551
76CHE304
76CHE433
References
965
J. Elguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. I, 1976,280. 364,365,366.367
J. Eiguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. I, 1976,281. 677,691
J. Eiguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. I, 1976,295. 691
J. Eiguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. 1, 1976,296. 35,36,691
J. Eiguero, C. Marzin, A. R. Katritzky and P. Linda; Adv. Heterocycl. Chern.,
Suppl. I, 1976,502. 501, 502, 509,520
M. L. Heffernan and G. M. Irvine; Aust. l. Chern., 1976,29,799. 860
M. Heffernan and G. M. Irvine; Aust. l. Chern., 1976,29,815. 853
K. Bhushan and J. H. Lister; Aust. l. Chern., 1976,29,891. 537,543
A. L. Cossey, R. L. N. Harris, J. L. Huppatz and J. N. Phillips; Aust. l. Chern.,
1976,29, 1039. 632
M. Woodruff and J. B. Polya; Aust. l. Chern., 1976,29,2491. 782
J. Meunier-Piret, P. Piret, J. P. Putzeys and M. van Meerssche; Acta Crytallogr.,
Part B, 1976,32,714. 675
P. Prusiner, M. Sundaralingam, T. Ito and T. Sakurai; Acta Crystallogr., Part B,
1976,32,853. 178
L. Dupont, O. Dideberg, J. M. Braham and A. F. Noels; Acta Crystallogr., Part
B, 1976,32,2216. 179
R. L. Harlow and S. H. Simonsen; Acta Crystallogr., Part B, 1976,32,2314. 179
H. Kasai, M. Goto, K. Ikeda, M. Zama, Y. Mizuno, S. Takemura, S. Matsuura,
T. Sugimoto and T. Goto; Biochemistry, 1976, 15, 898. 605
K. Fukushima, A. Kobayashi, T. Miyamoto and Y. Sasaki; Bull. Chern. Soc. lpn.,
1976,49, 143. 227
S. Ito, Y. Tanaka, A. Kakehi and K. Kondo; Bull. Chern. Soc. lpn., 1976,49, 1920. 827, 834
H. Ochi, T. Miyasaka, K. Kanada and K. Arakawa; Bull. Chern. Soc. lpn., 1976,
49, 1980. 309, 311, 338
T. Fuchigami and K. Odo; Bull. Chern. Soc. lpn., 1976,49,3607. 137
A. A. Ouyahia, G. Leroy, J. Weiler and R. Touillaux; Bull. Soc. Chirn. Belg.,
1976,85,545. 185,189
A. Maquestiau, Y. Van Haverbeke. J. C. Vanovervelt and R. Postiaux; Bull. Soc.
Chirn. Belg., 1976,85,697. 209
A. Maquestiau, Y. Van Haverbeke, M. Williame and M. Begtrup; Bull. Soc.
Chirn. Belg., 1976,85,795. 687
P. Bouchet, C. Coquelet, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1976,
IK 220
P. Bouchet, C. Coquelet, J. Eiguero and R. Jacquier; Bull. Soc. Chirn. Fr., 1976,
In 3W
P. Bouchet and C. Coquelet; Bull. Soc. Chirn. Fr., 1976, 195. 220
A. Le Berre and C. Porte; Bull. Soc. Chirn. Fr., 1976,476. 281
J. L. Aubagnac, D. Bourgeon and R. Jacquier; Bull. Soc. Chirn. Fr., 1976,869. 204
H. J. M. Dou and J. Metzger; Bull. Soc. Chirn. Fr., 1976, 1861. 387
J. L. Barascut, B. Kam and J. L. Imbach; Bull. Soc. Chirn. Fr., 1976, 1983. 289
J. Bourgois, F. Tonnard and F. Texier; Bull. Soc. Chirn. Fr., 1976,2025. 716
K. H. Buechel and H. Erdmann; Chern. Ber., 1976, 109, 1625. 398
K. H. Buechel and H. Erdmann; Chern. Ber., 1976,109, 1638. 423
V. Bardakos and W. Sucrow; Chern. Ber., 1976, 109, 1898. 261
P. Luger, C. Tuchscherer, M. Grosse and D. Rewicki; Chern. Ber., 1976, 109,2596. 252
M. Baudy and A. Robert; l. Chern. Soc., Chern. Cornrnun., 1976,23. 129
J. C. Cass, A. R. Katritzky, R. L. Harlow and S. H. Simonsen; l. Chern. Soc.,
Chern. Cornrnun., 1976,48. 391
K. Senga, H. Kanazawa and S. Nishigaki; l. Chern. Soc., Chern. Cornrnun., 1976,
155. 581
T. Tuschiya, J. Kurita and K. Ogawa; l. Chern. Soc., Chern. Cornrnun., 1976,250. 287
L. H. Dao and D. Mackay; l. Chern. Soc., Chern. Cornrnun., 1976,326. 750
P. N. Preston, K. K. Tiwari, K. Turnbull and T. J. King; l. Chern. Soc., Chern.
Cornrnun., 1976,343. 813
T. L. Gilchrist, C. J. Moody and C. W. Rees; l. Chern. Soc., Chern. Cornrnun.,
1976,414. 812
F. Yoneda, T. Nagamura and M. Kawamura; l. Chern. Soc., Chern. Cornrnun.,
1976,658. 656
K. Tsutsumi, I. Takagishi, H. Shizuka and K. Matsui; l. Chern. Soc., Chern.
Cornrnun., 1976, 685. 253, 254
M. Uher, A. Rybár, A. Martvon and J. Lesko; Collect. Czech. Chern. Cornrnun.,
1976,41, 1551. 718
A. F. Pozharskii, V. V. Kuz'menko, I. S. Kashparov, Z. I. Sokolov and M. M.
Medvedeva; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1976,12,304. 412
B. V. Trzhtsinskaya, L. F. Teterina, V. K. Voronov and G. G. Skvortsova; Chern.
Heterocycl. Cornpd. (Engl. Transl.), 1976, 12,433. 444
966
76CHE437
76CHE465
76CHE696
76CHE917
76CHE924
76CHEI278
76CHEI280
76CJC343
76CJC617
76CJC670
76CJCI329
76CJCI752
76CPB804
76CPB1331
76CPBl336
76CPBI561
76CPB1870
76CPB2267
76CPB2274
76CPB2549
76CRV187
76FES209
76FES797
76GEP2429195
76GEP2539461
76GEP2554866
76H(4)749
76H(4)943
76H(4)1115
76H(4)1503
76H(4)1655
76H(5)127
76H(5)285
76HCA259
76HCAI203
76HCA1512
76HCA2362
761C2788
761C2794
761JC(B)55I
76JA711
76JAI258
76JAl259
76JA1492
76JAI685
76JA3737
76JA3987
76JA5414
76JA7401
76JA7408
76JAP7636455
I. I. Popov, Yu. G. Bogachcv, P. V. Tkachenko, A. M. Simonov and B. A. Tertov,
Chern. Heterocycl. Compd. (Eng/. Trans/.), 1976,12,437.
V. S. Mokrushin, V. I. Ofitserov, T. V. Rapakova, A. G. Tsaur and Z. V. Push-
kareva; Chern. Heterocycl. Compd. (Eng!. Trans!.), 1976.12,465.
A. F. Vlasenko, B. E. Mandrichenko, G. K. Rogul'chenko, R. S. Sinyak, I. A.
Mazur and P. M. Kochergin; Chern. Heterocycl. Compd. (Eng/. Trans/.), 1976,
12, 696.
V. P. Piskov, V. P. Kasperovich and L. M. Yakoleva; Chern. Heterocycl. Compd.
(Eng/. Trans/.), 1976,12,917.
V. I. Ofitserov, Z. S. Mokrushin, Z. V. Pushkareva and N. V. Nikiforova; Chern.
Heterocyc/. Compd. (Eng!. Trans/.), 1976,12,924.
G. G. Skvortsova, B. V. Trzhtsinskaya, L. F. Teterina and V. K. Voronov; Chern.
Heterocycl. Compd. (Eng/. Trans/.), 1976,12, 1278.
V. S. Kobrin and L. B. Volodarskii; Chern. Heterocycl. Compd. (Eng!. Trans!.),
1976, 12, 1280. 369,415,423,455
R. T. Baker, S. J. Rettig, A. Storr and J. Trotter; Can. 1. Chern., 1976,54,343. 227
R. E. Wasylishen and M. R. Graham; Can. J. Chern., 1976,54,617. 354
J. Stawinski, T. Hozumi and S. A. Narang; Can. J. Chern., 1976, 54, 670. 814
J. Eiguero, A. Fruchier and M. C. Pardo; Can. J. Chern., 1976,54, 1329. 194,260,290
C. Sabaté-Alduy and J. Bastide; Can. J. Chern., 1976, 54, 1752. 215
Y. Tanaka and M. Sano; Chern. Pharm. Bull., 1976,24,804. 301
M. Sekiya, J. Suzuki and Y. Tcrao; Chern. Pharm. Bull., 1976,24,1331. 568,569
S. Kubota and M. Uda; Chern. Pharm. Bull., 1976,24, 1336. 748
N. Yamaji, Y. Yuasa and M. Kato; Chern. Pharm. Bull., 1976,24, 1561. 589
T. Kametani, Y. Kigawa, T. Takahashi, H. Nemoto and K. Fukimoto; Chern.
Pharm. Bull., 1976, 24, 1870.
H. Koga, M. Hirobe and T. Okamoto; Chern. Pharm. Bull., 1976,24,2267.
K. Kaji and M. Kawase; Chern. Pharm. Bull., 1976,24.2274.
T. Kato, T. Chiba and M. Daneshtalab; Chern. Pharm. Bull., 1976,24,2549.
References
c. W. Spangler; Chern. Rev., 1976,76, 187.
E. Abignente, F. Arena, P. De Caprariis and L. Parente; Farmaco Ed. Sci., 1976,
31,209 (Chern. Abstr., 1976,84,164684).
O. Uri, P. L. Ferrarini and I. Tonetti; Farmaco Ed. SCi., 1976,31,797.
H. Eilingsfeld and R. Niess; Ger. Pat. 2429195 (1976) (Chern. Abstr., 1976,84,
135 649).
CIBA-Geigy AG, Ger. Pat. 2539461 (1976) (Chern. Abstr., 1976,85, 110 108).
T. Shigematsu, M. Tomida, T. Shibahara, M. Nakazawa and T. Munakata; Ger.
Pat. 2 554 866, 1976 (Chern. Abstr., 1976, 85, 117 969).
F. Yoneda and T. Nagamatsu; Heterocycles, 1976,4,749.
B. Vercek, B. Stanovnik and M. TiS1er; Heterocycles, 1976,4,943.
M. TiSler and B. Stanovnik; Heterocycles, 1976,4, 1115.
F. Yoneda, M. Kawamura, T. Nagamatsu, K. Kuretani, A. Hoshi and M. Iigo;
Heterocycles, 1976,4, 1503.
M. Rueda, N. Vivona and G. Cusmano; Heterocycles, 1976,4, 1655.
G. G. Habermehl and W. Ecsy; Heterocycles, 1976,5, 127.
T. Itoh and Y. Mizuno; Heterocycles, 1976,5,285.
C. Thétaz, F. W. Wehrli and C. Wentrup; He/v. Chim. Acta, 1976,59,259.
H. P. Haerter, H. Lichti, U. Stauss and O. SChindler; He/v. Chim. Acta, 1976,
59, 1203.
W. Heinzelmann, M. Märky and P. Gilgen; He/v. Chim. Acta, 1976,59, 1512.
W. Heinzelmann, M. Märky and P. Gilgen; He/v. Chim. Acta, 1976, 59, 2362.
L. D. Brown and J. A. Ibers; Inorg. Chern., 1976,15,2788.
L. D. Brown and J. A. Ibers; Inorg. Chern., 1976,15,2794.
A. Sharma and G. B. Behera; Indian J. Chern., Sect. B, 1976,14,551.
C. Meali, C. S. Arcus, J. L. Wilkinson, T. J. Marks and J. A. Ibers; J. Am. Chern.
Soc., 1976, 98, 711.
C. Thétaz and C. Wentrup; J. Am. Chern. Soc., 1976,98, 1258 (see also p. 1260
and earlier papers of the series).
R. Harder and C. Wentrup; J. Am. Chern. Soc., 1976,98, 1259.
P. D. Cook, R. J. Rousseau, A. M. Mian, P. Dea, R. B. Meyer, Jr. and R. K.
Robins; J. Am. Chern. Soc., 1976,98, 1492.
L. A. Burke, J. Eiguero, G. Leroy and M. Sana; J. Am. Chern. Soc., 1976,98, 1685.
K.-C. Chang and E. Grunwald; J. Am. Chern. Soc., 1976,98,3737.
N. J. Leonard, M. A. Sprecker and A. G. Morrice; J. Am. Chern. Soc., 1976,98,
3987.
Y. Shimizu, L. J. Buckley, M. Alam, Y. Oshima, W. E. Fa\1on, H. Kasai, I. Miura,
V. P. Gu\1o and K. Nakanishi; J. Am. Chern. Soc., 1976,98,5414.
A. H.-J. Wang, J. R. Barrio and I. C. Paul; J. Am. Chern. Soc., 1976,98,7401.
J. R. Barrio, P. D. Sattsangi, B. A. Gruber, L. G. Dammann and N. J. Leonard;
1. Am. Chern. Soc., 1976,98,7408.
T. Misawa, Y. Shimizu and Y. Nakacho; Jpn. Pat. 7636455 (1976) (Chem. Abstr.,
1976,85, 123928).
407,410
629
647,648
354, 358
445, 666
446
340
234
655
815,821,
822
249
614
728
135
730
787
592
624,643,877
272
656
249
641
615
860
647
489
272
675
675
631
227
811
879
642
825
363
567
604
610
610,627
767
76JAP(K)768 I 826
76JCS(D)455
76JCS(D)909
76JCS(PI)75
76JCS(PI)207
76JCS(PI)367
76JCS(PI)545
76JCS(PI)1210
76JCS(PI)1492
76JCS(PI)1547
76JCS(PI)1673
76JCS(PI)I722
76JCS(PI)1991
76JCS(PI)2166
76JCS(P2)315
76JCS(P2)736
76JCS(P2) 1089
76JCS(P2)1176
76JHCI55
76JHC205
76JHC257
76JHC301
76JHC391
76JHC395
76JHC455
76JHC48I
76JHC487
76JHC509
76JHC545
76JHC601
76JHC639
76JHC673
76JHC793
76JHC807
76JHC835
76JHC88I
76JHC899
76JHCI057
76JHC1153
76JHC 1305
76J\C833
76JMC229
76JMC262
76JMC512
76JMC517
76JMC778
76JMC814
76JMC839
F. Yoneda and T. Nagamatsu; J. Chern. Soc., Perkin Trans. 1, 1976, 1547.
G. V. Boyd, T. Norris and P. F. Lindley; J. Chern. Soc., Perkin Trans. J, 1976, 1673.
S. Anderson, E. E. Glover and K. D. Vaughan; J. Chern. Soc., Perkin Trans. J,
1976, 1722.
D. G. Doughty, E. E. Glover and K. D. Vaughan; J. Chern. Soc., Perkin Trans.
J, 1976, 1991.
T. L. Gilchrist, C. J. Harris, D. G. Hawkins, C. J. Moody and C. W. Rees; J.
Chern. Soc. Perkin Trans. J, 1976,2166. 166, 885,891
A. S. Afridi, A. R. Katritzky and C. A. Ramsden; 1. Chern. Soc., Perkin Trans.
2, 1976,315. 286
M. Begtrup; J. Chern. Soc., Perkin Trans. 2, 1976,736. 191,192,681,805
R. B. Moodie, K. Schofield and J. B. Weston; J. Chern. Soc., Perkin Trans. 2,
1976, 1089.
R. J. Badger and G. B. Barlin; J. Chern. Soc., Perkin Trans. 2, 1976, 1176.
R. R. Crenshaw, G. M. Luke and D. F. Whitehead; J. Heterocycl. Chern., 1976,
13, 155.
M. L. Graziano and R. Scarpati; J. HeterocycI. Chern., 1976, 13,205.
F. G. Baddar, F. H. AI-Hajjar and N. R. EI-Rayyes; J. Heterocycl. Chern., 1976,
13, 257.
A. Shafiee; J. Heterocycl. Chern., 1976, 13,301.
R. A. Henry; J. HeterocycI. Chern., 1976,13,391.
S. Plescia, E. Aiello, G. Daidone and V. Sprio; J. Heterocycl. Chern., 1976,13,395.
H. AI-Jallo, M. Shandala, F. AI-Hajjar and N. AI-Jabour; J. Heterocycl. Chern.,
1976,13,455.
E. E. Knaus, F. M. Pasutto, C. S. Giam and E. A. Swinyard; J. Heterocycl. Chern.,
1976, 13, 481.
K. Babic, S. Molan, S. Polanc, B. Stanovnik, J. Stres-Bratos, M. TiSler and B.
Vercek; J. Heterocycl. Chern., 1976,13,487. 871,889,897
M. P. Servé, P. G. Seybold, W. A. Feld and M. A. Chao; J. HeterocycI. Chern.,
1976, 13, 509.
R. W. Hamilton; J. HeterocycI. Chern., 1976,13,545.
G. C. Wright; J. Heterocycl. Chern., 1976,13,601.
M. Iwao and T. Kuraishi; J. Heterocycl. Chern., 1976,13,639.
V. V. Kane, H. Werblood and S. D. Levine; J. Heterocycl. Chern., 1976,13,673.
G. Garcia-Munoz, R. Madronero, C. Ochoa, M. Stud and W. Pfleiderer; J.
Heterocycl. Chern., 1976, 13, 793. 665,666
B. T. Keen, D. K. Krass and W. W. paudler; 1. HeterocycI. Chern., 1976, 13,807. 653
P. K. Kadaba, B. Stanovnik and M. TiSler; J. HeterocycI. Chern., 1976, 13, 835. 869,880
G. Hajós and A. Messmer; J. Heterocycl. Chern., 1976,13,881. 857,901,902
J. Prime, B. Stanovnik and M. Tisler; J. HeterocycI. Chern., 1976,13,899. 273
R. J. Pugmire, J. C. Smith, D. M. Grant, B. Stanovnik and M. Tisler; J. Heterocycl.
Chern., 1976, 13, 1057.
P. K. Kadaba; J. Heterocycl. Chern., 1976, 13, 1153.
S. Y. K. Tam, J. S. Hwang, F. G. De las Heras, R. S. Klein and J. J. Fox; J.
Heterocycl. Chern., 1976, 13, 1305.
V. V. Nadkarny, R. S. Rao and D. S. Fernandes; J. Indian Chern. Soc., 1976,53,
833.
M. M. Hashem, K. D. Berlin, R. W. Chesnut and N. N. Durham; J. Med. Chern.,
1976, 19, 229.
R. R. Crenshaw, G. M. Luke and P. Siminoff; J. Med. Chern., 1976,19,262.
T. Novinson, B. Bhooshan, T. Okabe, G. R. Revankar, R. K. Robins, K. Senga
and H. R. Wilson; J. Med. Chern., 1976,19,512.
T. Novinson, T. Okabe, R. K. Robins and T. R. Matthews; J. Med. Chern., 1976,
19,517.
G. Corsi, G. Palazzo, C. Germani, P. S. Barcellona and B. Silvestrini; J. Med.
Chern., 1976, 19,778.
D. G. Bartholomew, J. H. Huffman, T. R. Matthews, R. K. Robins and G. R.
Revankar; J. Med. Chern., 1976, 19, 814.
W. D. Kingsbury, R. J. Gyurik, V. J. Theodorides, R. C. Parish and G. Gallagher;
J. Med. Chern., 1976, 19,839.
References
Mitsui Toatsu Chemicals, Inc., Jpn. Kokai 76 81826 (1976) (Chern. Abstr., 1976,
85, 110109).
L. Menabue and G. C. Pellacani; J. Chern. Soc., Dalton Trans., 1976,455.
A. R. Katritzky and D. Moderhack; J. Chern. Soc., Dalton Trans., 1976,909.
G. Cooper and W. J. Irwin; J. Chern. Soc., Perkin Trans. 1, 1976,75.
J. T. A. Boyle, M. F. Grundon and M. D. Scott; J. Chern. Soc., Perkin Trans. J,
1976,207.
E. E. Glover and K. T. Rowbottom; J. Chern. Soc., Perkin Trans. 1, 1976,367.
G. Cooper and W. J. Irwin; J. Chern. Soc., Perkin Trans. 1, 1976,545.
H. Singh, K. K. Bhutani and L. R. Gupta; J. Chern. Soc., Perkin Trans. J, 1976,
1210.
E. J. Gray and M. F. G. Stevens; J. Chern. Soc., Perkin Trans. 1, 1976, 1492.
967
730
137
824
161,450
768
863,865
54, 450
830
859, 878,
898,899
581
794
615
648
396
561
322
714
281
117
819
272
281
784
672
294
622,640
869
749
855,858
726
272
728
294
322
647
655,656
293
627
232,233
968
76JMCI057
76JMC 1352
76JMR(21)185
76JOC I 87
76JOC385
76JOC568
76J0C730
76JOC I 073
761OC1244
76JOCI449
76JOC [758
76JOCI875
76JOC I 889
76JOC2120
76JOC2303
761OC28 13
761OC2860
76JOC2874
76JOO I 24
76JOC3152
76100395
76JOC3549
76JOC3775
76JOC378[
761OC3784
76JOC4033
76JOM([21)285
76JOU929
76JPSI038
76KGSI252
76KGS 1277
76KGSI396
76LA745
76MI71
76MI307
76M 1413
76MI40100
B-76M140200
R-76MI4020[
76M 140300
76MI40400
76M 14040 I
B-7óM140402
76MI40403
B-76M140404
B- 76M 140500
References
M. Gall, J. B. Hester, Jr., A. D. Rudzik and R. A. Lahti; J. Med. Chern., 1976,
19, 1057. 753
P. K. Adhikary, S. K. Das and B. A. Hess, Jr.; J. Med. Chern., 1976, 19, 1352. 6[2,614
M. Witanowski, L. Stefaniak, S. Szymanski, Z. Grabowski and G. A. Webb; J.
Magn. Reson., 1976,21, 185.
K. T. Potts, D. R. Choudhury and T. R. Westby; J. Org. Chern., 1976,41, 187.
T. Novinson, P. Dea and T. Okabe; 1. Org. Chern., 1976,41,385.
B. N. Ho[mes and N. J. Leonard; J. Org. Chern., 1976,41,568.
H. K. Spencer, M. P. Cava, F. G. Yamagishi and A. F. Garito; 1. Org. Chern.,
1976,41,730. [62
P. K. Kadaba; J. Org. Chern., 1976,41, 1073. 826,857,901,902
S. Barcza, M. K. Eberle, N. Engstrom and G. G. Kahle; J. Org. Chern., 1976,
41,1244.
J. A. May, Jr. and L. B. Townsend; J. Org. Chern., 1976,41, 1449.
J. W. A. M. Janssen, C. L. Habraken and R. Louw; J. Org. Chern., 1976,41, 1758.
G. L'abbé, G. Vermeulen, J. Flémal and S. Toppet; J. Org. Chern., 1976,41, [875.
D. W. Wiley, O. W. Webster and E. P. Blanchard; J. Org. Chern., 1976,41, 1889.
G. Baum and H. Shechter; J. Org. Chern., 1976,41,2120.
S. M. Hecht, B. L. Adams and J. W. Kozarich; J. Org. Chern., 1976,41,2303.
C. A. Renner and F. D. Greene; J. Org. Chern., 1976,41,2813.
M. M. Goodman, J. L. Atwood, R. Carlin, W. Hunter and W. W. Paudler; J.
Org. Chern., 1976,41,2860.
J. E. Baldwin, O. W. Lever and N. R. Tzodikov; J. Org. Chern., 1976,41,2874. 188,250
T. Huynh-Dinh, J. Igolen, J.-P. Marquet, E. Bisagni and J.-M. Lhoste; J. Org.
Chern., 1976,41,3[24.
S. Po[anc, B. Stanovnik and M. TiSler; 1. Org. Chern., 1976, 41, 3 I 52.
H. W. Altland; 1. Org. Chern., 1976,41,3395.
E. S. Hand and W. W. paudler; J. Org. Chern., 1976,41,3549.
M. K. Eber[e and L. Brzechffa; J. Org. Chern., 1976,41,3775.
M. H. Elnagdi, M. R. H. EI-Moghayar, D. H. Fleita, E. A. A. Hafez and S. M.
Fahmy; J. Org. Chern., [976,41,3781.
C. Temp[e, Jr., B. H. Smith, C. L. Kussner and J. A. Montgomery; 1. Org. Chern.,
1976, 41, 3784.
M. Clagett, A. Gooch, P. Graham, N. Ho[y, B. Mains and J. Strunk; J. Org.
Chern., 1976,41,4033.
W. R. Peterson, Jr., B. Arkles and S. S. Washburne; J. Organomet. Chern., 1976,
121, 285.
M. O. Lozinskii and V. S. Dmitrukha; 1. Org. Chern. USSR (Engl. Transl.), [976,
12,929 (Chern. Abstr., 1976,85,21284).
H. W. Jun; J. Pharm. Sci., [976,67, 1038.
Y. M. Yutilov and I. A. Svertilova; Khim. Geterotsikl. Soedin., [976, [252 (Chern.
Abstr., 1977,86, 55343).
Y. M. Yutilov and I. A. Svertilova; Khim. Geterotsikl. Soedin., 1976, 1277 (Chern.
Abstr., 1978,88,22739).
N. O. Saldabol and S. A. Hillers; Khim. Geterotsikl. Soedin., 1976, [396 (Chern.
Abstr., 1977,86, 106468).
H. Vorbruggen and K. Krolikiewicz; Liebigs Ann. Chern., 1976,745.
G. Ziguener, W. B. Lintschinger, A. Fuchsgruber and K. Kollmann; Monatsh.
Chern., 1976,107,171.
H. Schindlbauer and W. Kwiecinski; Monatsh. Chern., 1976, 107, [307.
K. Gewa[d and G. Heinhold; Monatsh. Chern., 1976, 107, 1413.
O. L. Stiefvater; Chern. Phys., 1976, 13, 73.
K. Schofield, M. R. Grimmett and B. R. T. Keene; 'The Azoles', Cambridge
University Press, London, 1976, p. 60.
K. Schofield, M. R. Grimmett and B. R. T. Keene; The Azoles', Cambridge
University Press, London, 1976, p. 28 I.
G. Werber, F. Buccheri, N. Vivona and M. Gentile; Chim. Ind. (Milan), 1976,
58, 382.
K. Tsurumi, A. Abe, H. Fujimura, H. Asai, M. Nagasaka and H. Mikaye; Folia
Pharmacol. Jpn., 1976,72,41.
G. Alonso, C. Díez, G. García-Muñoz, F. G. de las Heras and P. Navarro; J.
Carbohydr., Nucleosides, Nucleotides, 1976,3, 157.
K. Schofield, M. R. Grimmett and B. T. R. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976. [68, [71,
182, 184, [86, [97, 199,206,222,224,225,228,229,230,
232,233,234,237.238,239,240,241,242,243,245,246,
247,260,261,262,263,264,265,266,267,268,269,270,278
J. EIguero and C. Marzin; Adv. Org. Chern., 1976,9 (1),533. 169,255,256,299
'The Merck Index', ed. M. Windholz; Merck & Co., Rahway, New Jersey, 9th
edn., 1976. 234,291,292,293,294,295,296,297,298,299,300,301
J. E[guero, C. Marzin, A. R. Katritzky and P. Linda; 'The Tautomerism of
Heterocycles', Academic, New York, 1976, p. 531.
856
[49
874
537
257
867
270
794, 805
539
252
54[
780
86[,903
880
823
614
257
272
868
164
720
647
835
618
636
631
557
649
429
466
[2
50
50
[36
294
289
309
B-76MI40600
76MI40700
B-76MI40701
B-76M140800
76MI40900
B-76MI40901
76MI40902
76MI40903
76MI40904
76MI40905
76MI40906
76MI40907
76MI41000
76MI41001
76MI41002
76MI41100
76MI41101
76MI41102
B-76MI41103
B-76MI41104
B-76MI41200
76MI41300
76NKK782
760MSI67
B-76PH123
B-76PH403
76RTC67
76RTC74
76RTCI27
76S52
76S189
76S261
76S268
76S349
76S482
76S489
76S798
76S833
76SC5
76SC69
76T337
76T493
76T499
K. Schofield, M. R. Grimmett and B. R. T. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976. 346,348,
350, 353, 356, 360, 367, 372
C. A. Matuszak and A. J. Matuszak; J. Chem. Educ., 1976,53,280. 384,392
K. Schofield, M. R. Grimmett and B. R. T. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976. 382,384,
389,93,396,397,398,400,401,403,404,405,406,411, 413, 415,
417,433,435,436,437,438,441,443,444,445,447,448,450, 453, 454
K. Schofield, M. K Grimmett and B. R. T. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976.
R. J. H. Davies, Annu. Rep., 1976, 73B, 375.
'Photochemistry and Photobiology of the Nucleic Acids', ed. S. Y. Wang;
Academic, London, [976, vols. I and 2.
G. Barnathan, T. H. Dinh, A. Kolb and J. Igolen; J. Med. Chim. Ther., 1976, 11,
67.
F. M. Scabel, Jr., M. W. Trader and W. R. Laster, Jr.; Proc. Am. Cancer Res.,
1976, 17, Abstr. 181.
M. Okutsu and A. Yamazaki; Nucleic Acids Res., [976,3,231.
P. M. Schwartz, C. Shipman, Jr. and J. C. Drach; Antimicrob. Agents, Chemother.,
1976, 10, 64.
G. A. LePage, L. S. Worth and A. P. Kimbal; Cancer Res., 1976,36, 1481.
C. E. Case and T. H.. A-Yeung; Cancer Res., 1976,36, 1486.
C. Tapiero, J.-L. Imbach, R. P. Panzica and L. B. Townsend; J. Carbohydr.,
Nucleosides, Nucleotides, 1976,3, 191.
A. S. Elina, I. S. Musatova, N. A. Novitskaya, M. A. Muratov and M. D. Mashkov-
skii; Khim.-Farm. Zh., 1976,10,35 (Chem. Abstr., 1976,86, 106524).
N. K. Kochetkov, V. N. Shibaev, A. A. Kost, A. P. Razjivin and A. Y. Borisov;
Nucleic Acids Res., 1976,3, 1341.
D. Spinelli, A. Corrao, V. Frenna, M. Rucci a, N. Vi nova and G. Cusmano;
Chem. Ind. (Milan), 1976,58,383.
S. Toppet, G. Wouters and G. Smets; J. Polym. Sci. Polym. Leu., 1976,14,389.
Y. Ueda; Chemotherapy (Tokyo), 1976,24, 1661.
K. Schofield, M. R. Grimmett and B. R. T. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976,
p.159.
I. Fleming; 'Frontier Orbitals and Organie Chemical Reactions', Wiley-Inter-
science, London, 1976, p. 154.
K. Schofield, M. R. Grimmett and B. R. T. Keene; 'Heteroaromatic Nitrogen
Compounds: The Azoles', Cambridge University Press, Cambridge, 1976. 735,739,
740,742,743,746,750,751,754,756,757
C. M. Tarver, T. C. Goodale, R. Shaw and M. Cowperthwaite; Off. Nav. Res.
(Tech. Rep.) ACR (US), 1976, ACR-221, Proc. Symp. Int. Detonation 6th, 231
(Chem. Abstr., 1980,92,8480).
N. Matsumura, Y. Otsuji and E. Imoto; Nippon Kagaku Kaishi, 1976,782 (Chem.
Abstr., 1976,85,32929).
A. Könnecke and E. Lippmann; Org. Mass Spectrom., 1976, 11, 167.
A. Lablache-Combier; in 'Photochemistry of Heterocyclic Compounds', ed. O.
Buchardt; Wiley-Interscience, New York, 1976, p. 123.
O. Buchardt; 'Photochemistry of Heterocyclic Compounds', Wiley-Interscience,
New York, 1976, p. 403.
D. N. Reinhoudt and C. G. Kouwenhoven; Recl. Trav. Chim. Pays-Bas, 1976,
95,67.
A. Rykowski and H. C. van der P1as; Recl. Trav. Chim. Pays-Bas, 1976,
95,74.
C. Kroon, A. M. van den Brink, E. J. Vlietstra and C. A. Salemink; Reel. Trav.
Chim. Pays-Bas, 1976,95, 127.
G. Ege and P. Arnold; Synthesis, 1976,52.
K. K. Balasubramanian and R. Nagarajan; Synthesis, 1976, 189.
M. Ferrey, A. Robert and A. Foucaud; Synthesis, 1976,261.
N. Goetz and B. Zeeh; Synthesis, 1976,268.
T. Wagner-Jauregg; Synthesis, 1976,349.
N. E. Alexandrou and S. Adamopoulos; Synthesis, 1976,482.
M. Narita and C. U. Pittman, Jr.; Synthesis, 1976,489.
F. De Ange1is, A. Gambacorta and R. Nicoletti; Synthesis, 1976, 798.
B. Jenko, B. Stanovnik and M. Tisler; Synthesis, 1976,833.
C. F. Beam, R. M. Sandifer, R. S. Foote and C. R. Hauser; Synth. Commun.,
1976,6, 5.
S. Mineo, S. Kawamura and K. Nakagawa; Synth. Commun., 1976,6,69.
M. Araki, M. Maeda and Y. Kawazoe; Tetrahedron, 1976,32,337.
B. Koren, F. Kovac, A. Petrie, B. Stanovnik and M. Tisler; Tetrahedron, 1976,
32, 493.
A. Könnecke, E. Lippmann and E. Kleinpeter; Tetrahedron, [976,32,499.
References
969
489
504
520
558, 585
603
585
603
603
603
652
626
626,648
720
681
729
670, 692
711
823, 837
136
802
218
704, 724
720
653
636
28[
141
129
137
282,283
706
114,126
246
891,892
125, 277
887
543
272
799, 805
970
76T619
76TI 555
76T1909
76T2165
76T242I
76TL45
76TL 79
76TLl99
76TL571
76TLlI99
76TLl485
76TL3313
76TL3483
76TL3695
76TL3807
76TL4175
76TL4333
76USP3939161
76USP3948885
76USP3968103
76ZCI6
76ZC53
76ZC90
76ZC I 02
76ZC280
76ZC337
76ZC398
76Z0R673
77ACR403
77 AF82
77AG(E)323
77AHC(21)2
77AHC(21)175
77 AHC(21 )207
77AHC(21)323
77AJC421
77 AJC2005
77 AJC2515
77AX(B)253
77AX(B)413
77BBA(491 )253
77BCJ953
77BCJ2375
77 BCJ2505
77 BCJ2689
77BSB281
77B5B949
77BSB961
77BSF171
77BSF1163
77CB373
77CB2939
References
M. Schneider and H. Strohäcker; Tetrahedron, 1976,32,619.
K. van der Meer and J. J. C. Mulder; Tetrahedron, 1976,32, 1555.
G. De Luca, C. Panattoni and G. Renzi; Tetrahedron, 1976,32, 1909.
R. M. Kellogg; Tetrahedron, 1976,32,2165.
G. Domány, J. Nyitrai and K. Lempert; Tetrahedron, 1976,32,2421.
A. Dhainaut, J. L. Montero, B. Rayner, C. Tapiero and J. L. Imbach; Tetrahedron
Leu., 1976, 45.
M. M. Htay and O. Meth-Cohn; Tetrahedron Leu., 1976,79.
S. A. Khan and K. M. Sivanandaiah; Tetrahedron Leu., 1976, 199.
G. M. Devasia; Tetrahedron Lett., 1976, 571.
Y. Maki, M. Suzuki and K. Ozeki; Tetrahedron Leu., 1976, 1199.
H. Quast and L. Bieber; Tetrahedron Leu., 1976, 1485.
G. Assef, J. Kister, J. Metzger, R. Faure and E. J. Vincent; Tetrahedron Leu.,
1976, 3313.
J. E. Abola, D. J. Abraham and L. B. Townsend; Tetrahedron LeU., 1976,3483.
K. Ishikawa, Kin- Ya Akiba and N. Inamoto; Tetrahedron Leu., 1976,3695.
H. Abe, M. Uchiyama, Y. Tanaka and H. Saito; Tetrahedron Leu., 1976,3807.
M. Rull and J. Vilarrasa; Tetrahedron LeU., 1976,4175.
A. R. Katritzky, M. Michalska, R. L. Harlow and S. H. Simonsen; Tetrahedron
Leu., 1976,4333.
J. D. Ratajczyk, R. G. Stein and L. R. Swett; U.S. Pat. 3939161 (1976) (Chern.
Abstr., 1976,84,164835).
ICN Pharmaceuticals, Inc., U.S. Pat. 3948885 (1976) (Chern. Abstr., 1976,85,
6010).
ICN Pharmaceuticals, Inc., U.S. Pat. 3968103 (1976) (Chern. Abstr., 1976,85,
94 660).
K. Peseke; Z. Chern., 1976, 16, 16.
A. Könnecke and E. Lippmann; Z. Chern., 1976, 16, 53 (Chern. Abstr., 1976,85,
21225).
E. Lippmann and A. Könnecke; Z. Chern., 1976,16,90.
H. Dehne and M. Süsse; Z. Chern., 1976, 16, 102.
S. Hauptmann and H. Wilde; Z. Chern., 1976, 16,280.
M. Pulst and M. Weissenfels; Z. Chern., 1976, 16,337.
M. Augustin and W. Dölling, Z. Chern., 1976, 16, 398.
B. S. Drach, V. A. Kovalev and A. V. Kirsanov; Zh. Org. Khirn., 1976, 12,673.
255
206
271
146
376
585
390
728
376, 479
541
831
20, 355
509
69
605
371
474
323
729
729
132
833
792, 820, 824, 827
717
689
133
132
765
J. A. McCloskey and S. Nishimura; Ace. Chern. Res., 1977, 10,403.
E. Winkelmann, W. Raether, H. Hartung and W. H. Wagner; Arzneirn.-Forsch.,
1977,27,82.
M. Franck-Neumann and J. J. Lohmann; Angew. Chern., Int. Ed. Eng/., 1977,
16, 323. 251
R. N. Butler; Adv. Heterocycl. Chern., 1977,22,72. 263
R. Filler and Y. S. Rao; Adv. Heterocycl. Chern., 1977,21, 175. 64,78
Y. Takeuchi and F. Furusaki; Adv. Heterocycl. Chern., 1977,21,207. 80
R. N. Butler; Adv. Heterocycl. Chern., 1977,21,323. 46,51,53,54,69,70,73,
92,94,95, 102, 105, 106, 109, 792, 793, 797, 798, 799, 804,
805,807,808,809,810,812,813,814,816,817,818,819,821,
823, 825, 827, 829, 830, 832, 833, 834, 835, 836, 837
M. Woodruff and J. B. Polya; Aust. l. Chern., 30, 421. 740
B. K. M. Chan, N. H. Chang and M. R. Grimmett; Aust. 1. Chern., 1977,30,2005. 449
D. J. Brown and T. Nagamatsu; Aust. l. Chern., 1977,30,2515. 854,856,890,891
T. J. Kistenmacher and M. Rossi; Acta Crystallogr., Part B, 1977,33,253. 509
J. P. Declercq, G. Germain, M. Van Meerssche, A. Bettencourt, Z. Janousek and
H. G. Viehe; Acta Crystallogr., Part B, 1977,33,413.
K. W. Ehler, E. Girard and L. E. Orgel; Biochirn. Biophys. Acta, 1977,491,253.
M. Takahashi, H. Tan, K. Fukushima and H. Yamazaki; Bull. Chern. Soc. lpn.,
1977, SO, 953.
M. Kinoshita and Y. Suzuki; Bull. Chern. Soc. lpn., 1977,50,2375.
Y. Ogata, K. Tagaki and E. Hayashi; Bull. Chern. Soc. lpn., 1977,50,2505.
O. Makabe, H. Suzuki and S. Umezawa; Bull. Chern. Soc. lpn., 1977, SO, 2689.
A. Maquestiau, Y. Van Haverbeke, R. Flammang and C. de Meyer; Bull. Soc.
Chirn. Be/g., 1977,86,281.
A. Maquestiau, Y. Van Haverbeke and J. C. Vanovervelt; Bull. Soc. Chirn. Be/g.,
1977,86,949.
A. Maquestiau, Y. Van Haverbeke and J. C. Vanovervelt; Bull. Soc. Chirn. Be/g.,
1977, 86, 961.
P. Bouchet, C. Coquelet and J. Elguero; Bull. Soc. Chim. Fr., 1977. 171.
R. Lazaro, D. Mathiew, R. Fhao Tan Luu and J. Elguero; Bull. Soc. Chirn. Fr.,
1977, 1163.
G. Grenner and H.-L. Schmidt; Chern. Ber., 1977, 110,373.
G. Szeimies and K. Mannhardt; Chern. Ber., 1977, 110, 2939.
504
613
178
649
133
640
697
729
203
215
265
169,182.
263,267
121,278
510
833
77CC505
77CC556
77CC843
77CHE210
77CHEllIO
77CHE1160
77CJC1564
77CPB830
77CPBI147
77CPB1923
77CPB3087
77CR(C)(284)509
77CZ403
77DO K(234)343
77G91
77GEP2700012
77H(6)383
77H(6)727
77H(6)929
77H(6)945
77H(6)949
77H(6)1627
77H(8)109
77H(8)433
77HC(30-1)1
77HC(30-2) I 17
77HC(30)179
77HCA521
77HCA3035
77IJC(B)629
77JA633
77JA714
77JA2740
77JA2818
77JA3934
77JA5096
77JA7257
77JA7806
77JCR(M)2813
77JCR(S)140
77 JCR(S)238
77JCS(PI)78
77JCS(PI)470
77 JCS(PI)672
77JCS(PI)765
77 JCS(PI)939
77JCS(PI)1819
77JCS(PI)2096
77 JCS(P2)724
77 JCS(P2) I 024
77 JCS(P2) 1779
P. Shu, A. N. Bloch, T. F. Carruthers and D. O. Cowan; J. Chern. Soc., Chern.
Cornrnun., 1977,505.
S. Senda, K. Hirota, T. Asao and Y. Yamada; J. Chern. Soc., Chern. Cornrnun.,
1977, 556.
H. Dürr, S. Fröhlich, B. Schley and H. Weisgerber; J. Chern. Soc., Chern.
Cornrnun., 1977,843.
V. V. Dovlatyan, K. A. Eliazyan and L. G. Agadzhanyan; Chern. Heterocycl.
Cornpd. (Engl. Transl.), 1977,13,210.
M. A. Iradyan, A. G. Torosyan, R. G. Mirzoyan and A. A. Aroyan; Chern.
Heterocycl. Cornpd. (Engl. Transl.), 1977, 13, 1110.
M. I. Knyazhanskii, P. V. Gilyanovskii and O. A. Osipov; Chern. Heterocycl.
Cornpd. (Engl. Transl.), 1977,13, 1160. 357,381,382
R. N. Butler, T. M. McEvoy, F. L. Scott and J. C. Tobin; Can. J. Chern., 1977,
55, 1564.
R. Moroi, K. Ono, T. Saito, T. Akimoto and M. Sano; Chern. Pharrn. Bull., 1977,
25, 830.
Y. Yamazaki, R. Moroi and M. Sano; Chern. Pharrn. Bull., 1977,25, 1147.
T. Koyama, T. Hirota, C. Bashou, T. Nanba, S. Ohmori and M. Yamoto; Chern.
Pharrn. Bull., 1977,25, 1923.
Y. Okamoto and T. Veda; Chern. Pharrn. Bull., 1977,25,3087.
J. Bourgois and F. Texier; C. R. Hebd. Seances Acad. Sci., Ser. C, 1977,284,509.
D. Moderhack; Chern.-Ztg., 1977, 101,403 (Chern. Abstr., 1978,88,37706).
N. K. Kochetkov, V. N. Shibaev, A. A. Kost, A. P. Razzhivin and S. V. Ermolin;
Dok/. Akad. Nauk SSSR, 1977,234,343 (Chern. Abstr., 1977,87, 102261).
G. Desimoni, P. Righetti, G. Tacconi and A. Vigliani; Gazz. Chirn. Ital., 1977,
107, 91.
G. Arcari, L. Bernardi, G. Falconi, F. Luini, G. Palamidessi and U. Scarponi;
Ger. Pat. 2700012 (1977) (Chern. Abstr., 1977,87,201535).
J. H. Lister; Heterocycles, 1977,6,383.
M. A. Khan and A. E. Guarconi; Heterocycles, 1977,6,727.
D. T. Hurst and J. A. Saldanha; Heterocycles, 1977,6,929.
K. Senga, J. Sato and S. Nishigaki; Heterocycles, 1977,6,945.
Y. Tamura, M. Iwaisaki, Y. Miki and M. Ikeda; Heterocycles, 1977,6,949.
References
971
liS
335
251
657
433
799
904
179
568
431
724
820
648
250
623
534
340
627
337
856,
866,886
SOl
166
615
120,267
267,608,612,613,614
267
666
318
T. Fujii, T. Itaya and T. Saito; Heterocycles, 1977,6, 1627.
Y. Tomimatsu, K. Satoh and M. Sakamoto; Heterocycles, 1977,8, 109.
T. Itoh, J. Inaba and Y. Mizuno; Heterocycles, 1977,8,433.
J. A. Paolini; Chern. Heterocycl. Cornpd., 1977,30-1, 1.
H. L. Blewitt; Chern. Heterocycl. Cornpd., 1977,30-2,117.
G. Maury; Chern. Heterocycl. Cornpd., 1977,30, 179.
A. Edenhofer and W. Meister; Helv. Chirn. Acta, 1977,60, 521.
H. Meier and H. Heimgartner; Helv. Chirn. Acta, 1977,60,3035.
K. Nagarajan, V. P. Arya, S. J. Shenoy, R. K. Shah, A. N. Goud and G. A. Bhat;
lndian J. Chern., Sect. B, 1977, 15,629.
W. L. Magee and H. Shechter; J. Arn. Chern. Soc., 1977,99,633.
V. Markowski, G. R. Sullivan and J. D. Roberts; J. Arn. Chern. Soc., 1977,99,714.
T. C. Clarke, L. A. Wendling and R. G. Bergman; J. Arn. Chern. Sac., 1977,99,
2740.
H. Tanino, T. Nakata, T. Kaneko and Y. Kishi; J. Arn. Chern. Soc., 1977,99,2818.
L. B. Clark; J. Arn. Chern. Soc., 1977,99,3934.
M. F. Zady and J. L. Wong; J. Arn. Chern. Soc., 1977,99,5096.
G. Dodin, M. Dreyfuss, O. Bensaude and J.-E. Dubois; J. Arn. Chern. Soc., 1977,
99, 7257.
D. Poppinger, L. Radom and J. A. Pople; J. Arn. Chern. Soc., 1977,99,7806.
D. Bartholomew and I. T. Kay; J. Chern. Res. (M), 1977,2813.
D. Clérin, B. Meyer and J. P. Fleury; J. Chern. Res. (S), 1977, 140.
D. Bartholomew and I. T. Kay; J. Chern. Res. (S), 1977,238.
D. G. Doughty, E. E. Glover and K. D. Vaughan; J. Chern. Soc., Perkin Trans.
1, 1977,78.
D. W. S. Latham, O. Meth-Cohn, H. Suschitzky and J. A. L. Herbert; J. Chern.
Soc., Perkin Trans. I, 1977,470.
I. J. Ferguson, K. Schofield, J. W. Barnett and M. R. Grimmett; J. Chern. Soc.,
Perkin Trans. I, 1977,672.
F. Yoneda, T. Nagamatsu, T. Nagamura and K. Senga; J. Chern. Soc., Perkin
Trans. I, 1977,765.
M. Bonadeo, C. De Micheli and R. Gandolfi; J. Chern. Soc., Perkin Trans. I,
1977,939.
A. Albert and C. J. Lin; J. Chern. Soc., Perkin Trans. I, 1977, 1819.
J. Grimshaw and D. Mannus; J. Chern. Soc., Perkin Trans. 1, 1977,2096.
M. J. S. Dewar and I. J. Turchi; J. Chern. Soc., Perkin Trans. 2,1977,724.
G. E. Hawkes, E. W. Randall, J. Eiguero and C. Marzin; J. Chern. Soc., Perkin
Trans. 2, 1977, 1024. 194,195,196,290
N. A. Rodios and N. E. Alexandrou; J. Chern. Soc., Perkin Trans. 2, 1977,1779. 678
641
251
510,516
255,256
604
517
543, 544
310
7
132
286
132, 853
627
492
234, 456
336
268
721,875
220
7
972
77JH07
77JHC59
771HC65
77JHCI55
77JHCI95
77JHC227
77JHC375
77JHC387
77JHC411
77JHC439
77JHC511
771HC517
77JHC607
77JHC647
77JHC697
77JHC813
77JHC889
77JHC993
771HCI013
77JHCI163
77JHCI171
77JHCI175
77JHC 1321
771MC386
771MC664
771MC847
771MCI189
771MR(28)217
771MR(28)227
7710C542
7710C592
7710C659
7710C847
7710<:941
771OCIOl8
7710CI159
7710Cl 555
7710C1633
7710CI639
771OC2893
7710C3132
77100377
7710C3725
7710C4197
771OM(127)273
7710M(l32)69
7710U1817
7710U1872
771PR65
References
P. Bravo and G. Gaviraghi; J. HeterocycI. Chern., 1977,14,37.
M. K. Eberle and P. Schirm; J. Heterocycl. Chern., 1977,.14, 59.
S. A. Lang, E. M. Lovell and E. Cohen; J. Heterocycl. Chern., 1977, 14,65.
M. H. Elnagdi, E. M. Kandeel, E. M. Zayed and Z. E. Kandil; J. HeterocycL
Chern., 1977,14, 155.
1. A. Montgomery, A. T. Shortnacy and S. D. Clayton; J. Heterocycl. Chern., 1977,
14,195. 619,620,621
M. H. Elnagdi, M. R. H. Elmoghayar, E. M. Kandeel and M. K. A. Ibrahim; J.
Heterocycl. Chern., 1977, 14,227.
A. S. Shawali; J. HeterocycI. Chern., 1977,14,375.
S. E. Ealick, D. van der Helm, K. Ramalingam, G. X. Thyvelikakath and K. D.
Barlin; 1. HeterocycI. Chern., 1977,14,387.
1. S. Bradshaw, 1. E. Tueller, S. L. Baxter, G. E. Maas and 1. T. Carlock; J.
Heterocycl. Chern., 1977, 14,41 I.
1. P. Hénichart, R. Houssin, B. Lablanche, F. Baert and L. Devos; J. Heterocycl.
Chern., 1977, 14,439.
K. Okada, 1. A. Kelley and 1. S. Driscoll; J. Heterocycl. Chern., 1977, 14,51 I.
R. 1. Sundberg; J. HeterocycI. Chern., 1977,14,517.
D. C. H. Bigg and S. R. Purvis; 1. Heterocycl. Chern., 1977, 14,607.
T. C. Thurber and L. B. Townsend; J. Heterocycl. Chern., 1977, 14,647.
M. V. Pickering, M. T. Campbell, 1. T. Witkowski and R. K. Robins; J. Heterocycl.
Chern., 1977, 14,697. 897
T. Denzel and H. Hoehn; J. Heterocycl. Chern., 1977, 14,813. 618,635,636
1. J. Baldwin, P. K. Lumma, G. S. Ponticello, F. C. Novello and 1. M. Sprague;
J. Heterocycl. Chern., 1977, 14,889.
M. Iwao and T. Kuraishi; J. Heterocycl. Chern., 1977,14,993.
1. P. Affane-Nguema, 1. P. Lavergne and P. Viallefont; J. Heterocycl. Chern.,
1977, 14, 1013.
N. W. Gilman, B. C. Holland and R.1. Fryer; J. Heterocycl. Chern., 1977, 14, 1163.
N. W. Gilman and R. I. Fryer; J. Heterocycl. Chern., 1977,14, 1171.
T. Kametani, K. Kigasawa, M. Hiiragi, K. Wakisaka, O. Kusama, H. Sugi and
K. Kawasaki; J. Heterocycl. Chern., 1977, 14, 1175.
V. I. Cohen and S. Pourabass; J. Heterocycl. Chern., 1977,14, 1321.
W. E. Kirkpatrick, T. Okabe, I. W. Hillyard, R. K. Robins, A. T. Dren and T.
Novinson; J. Med. Chern., 1977,20,386.
K. Ramalingam, L. F. Wong, K. D. Berlin, R. A. Brown, R. Fischer, 1. Blunk
and N. N. Durham; J. Med. Chern., 1977,20,664.
K. Ramalingam, G. X. Thyvelikakath, K. D. Berlin, R. W. Chesnut, R. A. Brown,
N. N. Durham, S. E. Ealick and D. van der Helm; J. Med. Chern., 1977,20,847.
1.1. Baldwin, P. K. Lumma, F. C. Novello, G. S. Ponticello, 1. M. Sprague and
D. E. Duggan; J. Med. Chern., 1977,20, 1189.
M. Witanowski, L. Stefaniak, S. Szymanski and H. lanuszewski; J. Magn. Reson.,
1977,28,217.
P. R. Srinivasan and R. L. Lichter; J. Magn. Reson., 1977,28,227.
A. V. Zeiger and M. M. loullié; J. Org. Chern., 1977,42,542.
A. D. Dawson and D. Swern; J. Org. Chern., 1977,42,592.
M. T. Chenon, C. Coupry, D. M. Grant and R. 1. Pugmire; J. Org. Chern., 1977,
42,659. 191,211,213
N. Murai, M. Komatsu, T. Yagii, H. Nishihara, Y. Ohshiro and T. Agawa; J.
Org. Chern., 1977,42,847.
H. Kohn, M. 1. Cravey, 1. H. Arceneaux, R. L. Cravey and M. R. Willcott, III;
J. Org. Chern., 1977,42,941.
1. Daunis, H. Lopez and G. Maury; J. Org. Chern., 1977,42, 1018.
165
654
178,180
272
330
272, 326
178
870
739
139
448
358
719
446,447
635
272
273
273
273
353, 359
316
294
294
635
195
195
454
727
466
443
854, 859, 878,
898,899,900
832
17
129
129
270
G. L'abbé, G. Verhelst and S. Toppet; J. Org. Chern., 1977,42, 1159.
R. D. Srivastava and I. M. Brinn; J. Org. Chern., 1977,42, 1555.
K. T. Potts, S. 1. Chen, 1. Kane and 1. L. Marshall; J. Org. Chern., 1977,42,1633.
K. T. Potts and S. 1. Chen; J. Org. Chern., 1977,42, 1639.
C. L. Habraken and E. K. Poels; J. Org. Chern., 1977,42,2893.
B. Coxon, A. 1. Fatiadi, L. T. Sniegoski, H. S. Hertz and R. Schaffer; J. Org.
Chern., 1977, 42, 3132.
E. S. Hand, W. W. Paudler and S. Zachow; J. Org. Chern., 1977,42,3377.
1. Bartels-Keith, M. Burgess and 1. Stevenson; 1. Org. Chern., 1977,42,3725.
1. Bradaè, Z. Furek, D. laneziè, S. Molan, I. Smerkolj, B. Stanovnik, M. TiSler
and B. Verèek; 1. Org. Chern., 1977,42,4197. 624,643,877
T. Hitomi and S. Kozima; J. Organornet. Chern., 1977, 127,273. 682,683
R. Gassend, 1. C. Maire and 1. C. Pommier; J. Organornet. Chern., 1977, 132,69. 213
M. V. Gorelik and T. Kh. Gladysheva; 1. Org. Chern. USSR (EngL Trans/.), 1977,
13, 1817.
V. N. Sheinker, L. G. Tishchenko, A. D. Garnovskii and A. M. Simonov; 1. Org.
Chern. USSR (Eng/. Trans/.), 1977,13, 1872.
1. Faust; J. Prakt. Chern., 1977,319,65.
661
612
19,805
423
393
136
77JPR408
77JPR895
77JPR911
77JSP(65)313
77KGS411
77KGS556
77KGS933
77LAI06
77LA956
77LA1183
B-77MI40100
77MI40400
77MI40401
B-77MI40402
B-77MI40600
B-77MI40700
B-77MI40800
B-77MI40900
B-77MI40901
77MI40902
77MI40903
77MI40904
77MI41000
77MI41001
77MI41100
77MI41101
B-77MI41102
77MI41300
77MI41500
770MR(9)1
770MR(9)235
770MR(9)716
77RCR76
77RCR374
77RRC471
77S804
B-77SH(1)
77T45
771751
77T803
77T1247
77T1253
77T1263
77T1399
77T2069
77T2677
77TLl 031
References
973
A. Könnecke, S. Behrendt and E. Lippmann; J. Prakt. Chern.,
(see also other papers in the series).
W. Freyer and G. Tomaschewski; J. Prakt. Chern., 1977,319, 895.
W. Freyer; J. Prakt. Chern., 1977,319,911.
G. L. Blackman, R. D. Brown, F. R. Burden and W. Garland; J. Mol. Spectrosc.,
1977,65,313.
G. A. Mokrushina, I. Y. Postovskii and S. K. Kotovskaya; Khirn. Geterotsikl.
Soedin., 1977,411 (Chern. Abstr., 1978,87,53170).
N. O. Saldabol and J. Popelis; Khirn. Geterotsikl. Soedin., 1977, 556 (Chern.
Abstr., 1977,87,68240).
Y. M. Yutilov and A. G. Ignatenko; Khirn. Geterotsikl. Soedin., 1977,993 (Chern.
Abstr., 1977,87, 167943).
S. W. Park and W. Ried; Liebigs Ann. Chern., 1977, 106.
W. Kliegel and G. H. Frankenstein; Liebigs Ann. Chern., 1977,956.
R. Meyer, U. Schöllkopf and P. Böhme; liebigs Ann. Chern., 1977, 1183.
1977, 319, 408
793, 798, 799
209
209
677
617,636
612
621
445
427
358, 426,
477
K. F. Freed; in 'Modem Theorelical Chemistry. Semiempirical Methods of
Electronic Structure Calculation. Part A: Techniques', ed. G. A. Segal; Plenum,
New York, 1977, pp. 201-253.
K. L. Clay, W. D. Watkings and R. C. Murphy; Drug Metab. Dispos., 1977,5, 149.
F. H. Deis, G. W. Lin and D. Lester; Alcohol Aldehyde Metab. Syst., 1977,3,399.
w. M. Jones and U. H. Brinker; in 'Peri cyclic Reactions', ed. A. P. Marchand
and R. E. Lehr; Academic Press, New York, 1977, vol. 1, p. 110.
A. E. A. Porter; in 'Saturated Heterocyclic Chemistry', The Chemical Society,
London, 1977, vol. 4, p. 188.
D. A. Wilson; in 'Salurated Heterocyclic Chemislry', The Chemical Society,
London, 1977, vol. 5, p. 186.
D. A. Wilson; in 'Saturated Heterocyclic Chemistry', The Chemical Society,
London, 1977, vol. 5, p. 186.
'Cyclic 3'5'-Nucleotides: Mechanism of Action', ed. H. Cramer and J. Schultz;
Wiley-Interscience, London, 1977.
T. J. Kistenmacher and L. G. Marzilli; 'Jerusalem Symposium of Quantum
Chemistry and Biochemistry', Israel Academy of Science, 1977, vol. 9, p. 7.
P. S. Song; Annu. Rep. Prog. Chern., 1977,748,35.
R. P. Agarval, T. Spector and R. E. Parks, Jr.; Biochern. Pharrnacol., 1977,26,359.
R. Boone and B. Moss; Virology, 1977,79,67.
N. O. Saldabol, J. Popelis, L. N. Alekseeva, A. K. Yalynskaya and N. D. Mos-
kaleva; Khirn.-Farm. Zh., 1977, ll, 64 (Chern. Abstr., 1977,87,84898).
D. Y. Mukhametova, N. A. Akmanova, A. Y. Svetkin and Y. V. Svetkin; Izv.
Vyssh. Uchebn. Zaved., Khirn. Khirn. Tekhnol., 1977, 20, 187 (Chern. Abstr.,
1977,87,23159).
V. Messori, L. Baldi and G. Bianchetli; Chirn. Ind. (Milan), 1977,59,438.
N. A. Petrusha, V. P. Chernetskii and Z. O. Rengevich; Onkologiya, 1977,8,9.
K. H. Büchel; 'Pllanzenschutz und Schädlingsbekämpfung', Thieme, Stutt-
gart, 1977.
R. N. Butler and T. M. McEvoy; Proc. R. Irish A cad. (RIC Centenary Issue),
1977,778,359.
K. Maekawa and R. Takeya; J. Fac. Agric., Kyushi Univ., 1977,21,99 (Chern.
Abstr., 1977,87, 17148).
U. Berg, S. Karlsson and J. Sandström; Org. Magn. Reson., 1977,9, 1.
A. Fruchier, E. Alcalde and J. Eiguero; Org. Magn. Reson., 1977,9,235.
P. Bouchet, A. Fruchier, G. Joncheray and J. Eiguero; Org. Magn. Reson., 1977,
9,716.
A. L. Rusanov, S. N. Leont'eva and Ts. G. Iremashvi1i; Russ. Chern. Rev. (Engl.
Transl.) 1977,46,76.
A. N. Volkov and A. N. Nikol'skaya; Russ. Chern. Rev. (Engl. Transl.)' 1977,46,
374.
J. P. Fayet, M. C. Vertut, P. Mauret, R. M. Claramunt and J. Eiguero; Rev.
Rourn. Chirn., 1977,22,471.
K. H. Mayer, D. Lauerer and H. Heitzer; Synthesis, 1977, 804.
w. L. F. Armarego; 'Stereochemistry of Heterocyclic Compounds', Wiley, New
York, 1977, part 1. 353,354,702
B. Chantegrel, D. Hartmann and S. Gelin; Tetrahedron, 1977,33,45. 272
C. Dietrich-Buchecker and M. Franck-Neumann; Tetrahedron, 1977,33,751. 251
M. Jeliñska and J. Sobkowski; Tetrahedron, 1977,33,803. 527
K. T. Potts, E. G. Brugel and W. C. Dunlap; Tetrahedron, 1977,33, 1247. 162,864
K. T. Potts, W. C. Dunlap and E. G. Brugel; Tetrahedron, 1977,33, 1253. 162
K. T. Potts, W. C. Dunlap nd F. S. Apple; Tetrahedron, 1977,33, 1263. 866
A. Könnecke, E. Lippmann and E. Kleinpeter; Tetrahedron, 1977,33, 1399. 800
P. Freche, A. Gorgues and E. Levas; Tetrahedron, 1977,33,2069. 276
E. Lüddecke, H. Rau, H. Dürr and H. Schmitz; Tetrahedron, 1977,33,2677. 251
D. S. Kemp and J. Reczek; Tetrahedron Leu., 1977, 1031. 728
7
301
301
251,265
368
427
468
504
501
517
601,603
601
611
632
732
729
731
800, 804
904
209
186,194
190,194
788
169
177
269
974
77TL2685
77TL3453
77TL4627
77UP41100
77USP4008322
77USP4036849
77USP4039531
77ZC60
77ZC65
77ZC26 I
77ZC262
77ZN(B)307
77ZN(B)430
77Z0R2218
nzo R2626
78ACS(B)683
78AG63
78AG(E)67
78AG(E)455
78AHC(22)71
78AHC(22)72
78AHC(22)184
78AHC(23)171
78AHC(23)263
78AHC(23)265
78AJC 179
78AJC2505
78AJC2675
78AX(B)293
78AX(B)1136
78AX(B)2229
78BAP291
78BCJ251
78BCJ563
78BRPI528801
78BRPI531752
78BSBI89
78BSI"(2)485
78BSF(2)602
78CB566
78CB2258
78CB2813
78CC447
78CC453
78CC485
78CC652
78CC857
78CCC3103
78CHE73
P. Koisaker, P. O. Ellingsen and G. Woeien; Acta Chern. Scand., Ser. B, 1978,
32, 683.
H. Kunz; Angew. Chern., 1978,90,63.
H. Kunz; Angew. Chern., Int. Ed. Eng/., 1978,17,67.
E. Schaumann, J. Ehlers and U. Behrens; Angew. Chern., Int. Ed. Engl., 1978,
17, 455.
J. A. Zoltewicz and L. W. Deady; Adv. Heterocyc/. Chern., 1978,22,71.
J. A. Zoltewicz and L. W. Deady; Adv. Heterocycl. Chern., 1978,22, 72.
J. Eiguero, R. M. Claramunt and A. J. H. Summers; Adv. Heterocycl. Chern.,
1978, 22, 184. 246, 263, 267
I. J. Fletcher and A. E. Siegrist; Adv. Heterocycl. Chern., 1978, 23, 171. 92
R. M. Acheson and N. F. Elmore; Adv. Heterocycl. Chern., 1978,23,263. 151,233,248
R. M. Acheson and N. F. Elmore; Adv. Heterocycyl. Chern., 1978,23,265. 419,420
C. G. Freeman, J. V. Turner and A. D. Ward; Aust. l. Chern., 1978,31, 179. 647
D. J. Brown and T. Nagamatsu; Aust. l. Chern., 1978,31,2505. 854,856,873,891,892
E. R. Cole, G. Crank and E. Lye; Aust. l. Chern., 1978,31,2675. 381
I. Leban, B. Stanovnik and M. TiSIer; Acta Crystallogr., Part B, 1978,34,293. 179,181
L. Golic, I. Leban, B. Stanovnik and M. Tisler; Acta Crystallogr., Part B, 1978,
34,1136.
V. Langer, K. Huml and L. Lessinger; Acta Crystallogr., Part B, 1978,34,2229.
L. Stefaniak; Bull. Acad. Pol. Sci., Ser. Sci. Chirn., 1978,26,291.
A. Kakehi, S. Ito, Y. Konno and T. Maeda; Bull. Chern. Soc. lpn., 1978,51,251.
S. Shiraishi, T. Shigemoto and S. Ogawa; Bull. Chern. Soc. lpn., 1978,51,563.
B. Parton and F. L. Rose; (lCI Ltd.), Br. Pat. 1528801 (1978) (Chern. Ahstr.,
1979,91, (24859).
B. Parton and F. L. Rose; (lCI Ltd.), Br. Pat. 1531752 (1978) (Chern. Abstr.,
1979,90,205761).
J. P. Fayet, M. C. Vertut, P. Mauret, R. M. CIaramunt, J. Eiguero and E. Alcalde;
Bull. Soc. Chirn. Be/g., 1978,87,189. 177,178
J. Bourgois, M. Bourgois and F. Texier; Bull. Soc. Chirn. Fr., Part 2. 1978,485. 703,710,
714,717,725
281
823
318
632
155
References
S. Inoue, H. Kakoi, M. Murata, T. Goto and O. Shimomura; Tetrahedron Left.,
1977, 2685.
H.-M. Wolff and K. Hartke; Tetrahedron Left.. 1977,3453.
L. Åsbrink, C. Fridh and E. Lindholm; Tetrahedron Left., 1977,52,4627.
H. Wamhoff; unpublished results.
B. A. Dreikorn and T. D. Tibault; U.S. Pat. 4008322 (1977) (Chern. Abstr., 1977,
86, 166387).
W. V. Curran, A. S. Tomcufcik and A. S. Ross; U.S. Pat. 4036849 (1977) (Chern.
Ahstr., 1977, 87, 117876).
Hoechst Aktiengesellschaft, U.S. Pat. 4039531 (1977) (Chern. Abstr., 1977,87,
186088).
E. Lippmann, D. Reifegerste and E. Kleinpeter; Z. Chern., 1977, 17,60 (Chern.
Abstr., 1977,87,5875).
A. Antonowa, R. Herzschuh and S. Hauptmann; Z. Chern., 1977,17,65.
A. Könnecke and E. Lippmann; Z. Chern., 1977, 17,261.
G. Kempter, W. Ehrlichmann and R. Thomann; Z. Chern., 1977, 17,262.
M. H. Elnagdi, E. M. Kandeel and M. R. H. Elmoghayar; Z Naturforsch., Teil
B, 1977,32,307.
M. H. Elnagdi, E. M. Zayed, E. M. Kandeel and S. M. Fahmy; Z Naturforsch.,
Teil B, 1977,32,430.
N. A. Klyuev, E. N. Istratov, R. A. Khmel'nitskii, V. A. Zyranov, V. L. Rusinov
and I. Va. Postovskii; Zh. Org. Khirn., 1977,13,2218 (Chern. Ahstr., 1978,88,
50091).
N. O. Saldabol and O. E. Lando; Zh. Org. Khirn., 1977,13,2626 (Chern. Abstr.,
1978,88, 136573).
A. Le Berre and C. Porte; Bull. Soc. Chirn. Fr., Part 2, 1978, 602.
W. Tochtermann, H. Gustmann and C. Wolff; Chern. Ber., 1978,111,566.
H. Dürr and H. Schmitz; Chern. Ber., 1978, 111,2258.
H. Wamhoff and L. Lichtenthäler; Chern. Ber., 1978, 111, 2813.
A. Robert and A. Le Marechal; l. Chern. Soc., Chern. Cornrnun., 1978,447.
V. M. Colburn, B. Iddon, H. Suschitzky and P. T. Gallagher; l. Chern. Soc.,
Chern. Cornrnun., 1978, 453.
K. T. Suzuki, H. Yamada and M. Hirobe; l. Chern. Soc., Chern. Cornrnun., 1978,
485.
A. R. Butler, C. Glidewell and D. C. Liles; 1. Chern. Soc., Chern. Cornrnun., 1978,
652.
G. J. Gainsford and A. D. Woolhouse; 1. Chern. Soc., Chern., Cornrnun., 1978.857.
A. Holý; Collect. Czech. Chern. Cornrnun., 1978,43,3103.
P. V. Tkachenko, A. M. Simonov and I. I. Popov; Chern. Heterocycl. Carnpd.
(Eng/. Trans/.), 1978, 14, 73.
624
466
517
696
904
835
730
819
801
815
616
320
321
801
611
708
728
728
9
49,51,52,386
229
858,860
509
14,19
337
166
614
614
164
516
9
376
604
438
78CHEI123
78CHE1366
78CLl 093
78CPBI929
78CPB2905
78CPB2924
78CPB3154
78CPB3240
78CR(C)(287)439
78CS(l3) 157
78CZ361
78DIS(B)(39)233
78FESI4
78FES543
78FES799
78GEP2804909
78GEP2805483
78GEP2806199
78H(9)757
78H(9)1207
78H(9)1437
78 H(l 0)241
78H(l1)121
78H(l1 )293
78HC(33)118
78HC(33)882
78HC(33)885
78HCAI08
78HCAI29
78HCA234
78HCA618
78HCA1477
78HCAI755
78ICI990
78IC3026
78IJC(B)48I
78IJC(B)53I
78IJC(B)1015
78IJC(B)I 030
78JA282
78JAI275
78JA1306
78JA2767
78JA3674
78JA4617
78JA5122
78JA5701
78JA6245
78JA6538
78JAP(K)7898932
78JBC(253) 171 0
717
854,856,859,866,
877,881,887,895,897
J. Reedijk, J. C. Jensen, H. van Koningsveld and C. G. Kralingen; Inorg. Chern.,
1978,17, 1990.
L. D. Brown, J. A. Ibers and A. R. Siedle; Inorg. Chern., 1978,17,3026.
S. Bala, R. P. Gupta, M. L. Sachdeva, A. Singh and H. K. Pujari; Indian J.
Chern., Sect. B, 1978, 16, 481.
P. K. Dubey and C. V. Ratnam; Indian J. Chern., Sect. B, 1978,16,531.
Y. Khandelwal and P. C. Jain; Indian J. Chern., Sect. B, 1978,16, 1015.
B. K. Pattanayak, D. N. Rout and G. N. Mahapatra; Indian J. Chern., Sect. B,
1978, 16, 1030.
O. L. Chapman and J.-P. LeRoux; J. Arn. Chern. Soc., 1978,100,282.
C. Guimon, G. Pfister-Guillouzo and M. Begtrup; J. Arn. Chern. Soc., 1978,100,
1275.
H. Quast, L. Bieber and W. C. Danen; J. Arn. Chern. Soc., 1978,100, 1306.
G. M. Brown, J. E. Sutton and H. Taube; J. Arn. Chern. Soc., 1978, 100, 2767.
D. Poppinger and L. Radom; J. Arn. Chern. Soc., 1978,100,3674.
H. Yamada, M. Hirobe, K. Higashiyama, H. Takahashi and K. T. Suzuki; J.
Arn. Chern. Soc., 1978,100,4617.
M. J. Mirbach, K. C. Liu, M. F. Mirbach, W. R. Cherry, N. J. Turro and P. S.
Engel; J. Arn. Chern. Soc., 1978,100,5122.
M. D. Gordon, P. V. Alston and A. R. Rossi; J. Arn. Chern. Soc., 1978, 100,5701.
O. L. Chapman, R. S. Sheridan and J.-P. LeRoux; J. Arn. Chern. Soc., 1978,100,
6245.
E. M. Burgess and M. C. Pulcrano; J. Arn. Chern. Soc., 1978,100,6538.
Hitachi Chemical Co., Jpn. Kokai Tokkyo Koho 7898932 (1978) (Chern. Abstr.,
1979, 90, 38930).
S. Muthukhishnan, B. Moss, J. A. Cooper and E. S. Maxwell; J. Bioi. Chern.,
1978,253, 1710.
References
N. A. Klyuev, N. M. Przhevalskii, I. I. Grandberg and A. A. Perov; Chern.
Heterocycl. Cornpd. (Eng!. Trans!.), 1978,14, 1123.
Yu. S. Tsizin and S. A. Chernyak; Chern. Heterocycl. Cornpd. (Engl. Transl.),
1978, 14, 1366.
K. Matsumoto and T. Uchida; Chern. LeU., 1978, 1093.
T. Fujii, T. Itaya, T. Saito and M. Kawanishi; Chern. Pharrn. Bull., 1978,26,1929.
F. Yoneda, M. Higuchi, K. Mori, K. Senga, Y. Kanamori, K. Shimizu and S.
Nishigaki; Chern. Pharrn. Bull., 1979,26,2905.
K. Takeda, K. Shudo, T. Okamoto and T. Kosuge; Chern. Pharrn. Bull., 1978,
26, 2924.
F. Yoneda, M. Noguchi, M. Noda and Y. Nitta; Chern. Pharrn. Bull., 1978,26,
3154.
K. Senga, Y. Kanamori and S. Nishigaki; Chern. Pharrn. Bull., 1978,26,3240.
J. Eiguero and M. Espada; c.R. Hebd. Seances Acad. Sci., Ser. C, 1978,287,439.
S. Gronowitz and S. Liljefors; Chern. Scr., 1978, 13, 157.
C. Bak, K. Praefike and L. Henriksen; Chern.-Ztg., 1978, 102,361.
C. S. Alleyne; Diss. Abstr. Int. B, [978,39,233.
G. Auzzi, L. Cecchi, A. Costanzo, L. P. Vettori and F. Bruni; Farrnaco Ed. Sci.,
1978,33, 14.
P. L. Ferrarini and O. Livi; Farrnaco Ed. Sci., 1978,33,543.
G. Auzzi, L. Cecchi, A. Costanzo, L. P. Vettori and F. Bruni; Farrnaco Ed. Sci.,
1978,33,799.
R. W. Clarke and A. W. Oxford; Ger. Pat. 2 804909 (1978) (Chern. Abstr., 1978,
91, 57044).
G. E. Davies and D. M. Foulkes; Ger. Pat. 2 805 483 (1978) (Chern. Abstr., 1979,
90, 67478).
Ger. Pat. 2806199 (1978) (Chern. Abstr., 1978,89, 180052).
C. B. Kanner and U. K. Pandit; Heterocycles, 1978,9,757.
K. Isomura, Y. Hirose, H. Shuyama, S. Abe, G. Ayabe and H. Taniguchi;
Heterocycles, 1978, 9, 1207.
K. Senga, Y. Kanamori and S. Nishigaki; Heterocycles, 1978,9, 1437.
I. Hayakawa, K. Yamazaki, R. Dohmori and N. Koga; Heterocycles, 1978,10,241.
K. L. Williamson and J. D. Roberts; Heterocycles, 1978, 11, 121.
T. Miyashi, Y. Nishizawa and T. Mukai; Heterocycles, 1978, 11,293.
H. Neunhoeffer; Chern. Heterocycl. Cornpd., 1978,33, 118.
H. Neunhoeffer; Chern. Heterocycl. Cornpd., 1978,33,882.
H. Neunhoeffer; Chern. Heterocycl. Cornpd., 1978,33,885.
H. Balli and L. Felder; Helv. Chirn. Acta, 1978,61, 108.
J. P. Pauchard and A. E. Siegrist; Helv. Chirn. Acta, 1978,61, 129.
W. Heinzelmann; Helv. Chirn. Acta, 1978,61,234.
W. Heinzelmann; Helv. Chirn. Acta, 1978,61,618.
M. Maerky, H. Meier, A. Wunderli, H. Heimgartner, H. Schmid and H. J. Hansen;
Helv. Chirn. Acta, 1978,61, 1477.
C. Wentrup; Helv. Chirn. Acta, 1978,61, 1755.
975
204
430
285
586
576
614
656
576
269
268
119
904
310
728
334
651
904
647
633
163
576
618,
639
20
267
608
608
608
241, 895
632
221
221
227
676
853
635
645
119
867
205, 689
810
386
7
515
199,255
282
867
444
722
601
976
78JCR(S)298
78JCR(S)366
78JCR(S)407
78JCS(P1)881
78JCS( PI )909
78JCS(PI)1381
78JCS(P2)19
78JCS( P2)99
78JCS(P2)865
78JCS(P2)1087
78JHC I
78JHC64
78JHC81
78JHC[19
78JHC127
78JHCI85
78JHC221
78JHC319
78JHC'353
78JHC439
78JHC463
78JHC'625
78JHC807
78JHC'813
78JHC'839
78JHC'937
78JHC'987
78JHC1021
78JHCI041
78JHC' I 043
78JHC1149
78JHC' I 159
78JHC' 1 175
78JHCI227
78JHC 1287
78JHCI349
78JHCI447
78JHC1451
78JHCI543
78Jl C'264
78JMC112
78JMC'883
78JMC'965
78JMC'1073
78JMCI212
78JM R(29)45
78JOC289
781OC341
78JOC658
78JOC808
78JOC 1197
7810C 1233
78JOC 1664
78JOC2037
M. Winnewisser, J. Vogt and H. Albrëcht; J. Chern. Res. (S), 1978,298.
D. Johnston, J. Machin and D. M. Smith; 1. Chern. Res. (S), 1978,366.
H. Singh and C. S. Gandi; J. Chern. Res. (S), 1978,407.
R. N. Butler, A. B. Hanahoe and W. B. King; J. Chern. Soc., Perkin Trans. I,
1978,881.
M. J. Sasse and R. C. Storr; J. Chern. Soc., Perkin Trans. I, 1978,909.
G. Mackenzie and G. Shaw; J. Chern. Soc., Perkin Trans. I, 1978, 1381.
D. Spinelli, V. Frenna, A. Corrao and N. Vivona; J. Chern. Soc., Perkin Trans.
2, 1978, 19.
M. Begtrup, R. M. Claramunt and J. Eiguero; J. Chern. Soc., Perkin Trans. 2.
1978,99. 191,194,2[2,681
D. J. Evans, H. F. Thimm and B. A. W. Coller; J. Chern. Soc., Perkin Trans. 2,
[978, 865. 346, 347, 348, 349, 400, 428
R. N. Butler and T. M. McEvoy; J. Chern. Soc., Perkin Trans. 2, 1978, [087. 793.805,
806,816
652
References
694
360
[38
706
727
439
720
P. D. Cook, P. Dea and R. K. Robins; J. Heterocyc/. Chern., 1978, 15, I.
K. Senga, M. Ichiba, H. Kanazawa, S. Nishigaki, M. Higuchi and F. Yoneda:
J. Heterocycl. Chern., 1978, 15,64.
L. Grehn; J. Heterocycl. Chern., 1978, 15,81.
A. F. Kluge; J. Heterocycl. Chern., 1978,15, 119.
M. P. Servé, P. G. Seybold and H. P. Covault; J. Heterocycl. Chern., 1978,15,127.
J. Delettré, R. Bally, J. P. Momon, E. Alcalde, J. de Mendoza, R. Faure, E. J.
Vincent and J. Eiguero; J. Heterocyc/. Chern., 1978, 15, [85. 178,272.281
C. Ochoa and M. Stud; J. Heterocyc/. Chern., 1978, 15, 22 [. 666
S. W. Schneller and R. D. Moore: 1. Heterocyc/. Chern., [978, 15, 319. 272
A. Yamazaki and M. Okutsu; J. Heterocycl. Chern., 1978, 15,353. 504
S. W. Schneller and D. G. Bartho[omew; J. Heterocycl. Chern., 1978, 15,439. 863,882,
883,884
856,886
380
736
272
615,
618,6[9
617,
6[8,639
S. W. Schneller and J. L. May; 1. Heterocycl. Chern., 1978, 15,987. 877,896
C. V. Magatti and F.J. Villani: J. Heterocyc/. Chem., [978, 15, 1021. 634
G. Maury, J.-P. Paugam and R. Paugam; J. Heterocyc/. Chern., 1978,15, 1041. 854,856,
859,875,894
A. W. McGee, M. P. Servé and P. G. Seybold; J. Heterocyc/. Chern., [978, 15, [043. 672,673
D. E. Kuhla and H. A. Watson, Jr.; J. Heterocycl. Chern., 1978, 15, 1[49. 631
M. Robba, J. C. Lancelot, D. Maume and A. Rabaron; J. Heterocyc/. Chern.,
1978,15, 1159. 273
M. Kocevar, B. Stanovnik and M. Tisler; J. Heterocyc/. Chern., 1978, 15, 1175. 315,320
F. Fabra, C. Gálvez, A. González, P. Viladoms and J. Vilarrasa; J. Heterocycl.
Chern., 1978,15, 1227.
S. Plescia, G. Daidone, V. Sprio, E. Aiello, G. Datto[o and G. Cirrincione: J.
Heterocyc/. Chern., 1978, 15, 1287.
S. Romani and W. Kloetzer; J. Heterocyc/. Chern., 1978, 15, 1349.
F. Fabra, J. Vilarrasa and J. Coli; J. HeterocycI. Chern., 1978, 15, 1447.
T. Suzuki, N. Katou and K. Mitsuhashi; J. Heterocyc/. Chern., 1978,15, 1451.
P. Bourgeois, 1. Lucrece and J. Donoguès; J. Heterocycl. Chern., 1978,15, 1543.
B. K. Pattanayak, D. N. Rout and G. N. Mahapatra; J. lndian Chern. Soc., [978,
45, 264.
R. D. Elliott and J. A. Montgomery: 1. Med. Chern., 1978,21, 112.
S.-H. Kim, D. G. Bartholomew, L. B. Allen, R. K. Robins, G. R. Revankar and
P. Dea; J. Med. Chern., 1978,21,883.
R. L. Clark, A. A. Pessolano, T.- Y. Shen, D. P. Jacobus, H. Jones, V. J. Lotti and
L. M. Flataker; J. Med. Chern., 1978,21,965.
W. S. Di Menna, C. Piantadosi and R. G. Lamb; 1. Med. Chern., 1978,21, 1073.
P. D. Cook, L. B. Allen, D. G. Streeter, J. H. Huffman, R. W. Sidwell and R. K.
Robins; J. Med. Chern., 1978,21, 1212.
P. Büchner, W. Maurer and H. Rüterjans: J. Magn. Reson., 1978,29,45.
P. D. Cook and R. K. Robins; J. Org. Chern., 1978,43,289.
N. Sato and J. Adachi; J. Org. Chern., 1978,43, 341.
E. S. Hand and W. W. Paudler; J. Org. Chern., 1978,43,658.
W. H. Pirkle and P. L. Gravel; J. Org. Chern., 1978,43,808.
L. D. Taylor, J. M. Grasshoff and M. Pluhar; J. Org. Chern., 1978,43, 1197.
N. F. Haley; 1. Org. Chern., 1978,43, 1233.
A. Pãdwa, S. Nahun and E. Sato; J. Org. Chern., 1978,43, 1664.
C. Wentrup, A. Damerius and W. Reichen; J. Org. Chern., [978,43, 2037.
G. Hajós and A. Messmer; J. Heterocyc/. Chern., 1978, 15,463.
P. Bouchet, G. Joncheray, R. Jacquier and J. Eiguero; 1. Heterocyc/. Chern., 1978,
15, 625.
M. Uda and S. Kubota; J. Heterocycl. Chern., 1978, 15,807.
S. Gelin and D. Hartmann; J. Heterocycl. Chern., [978, 15,813.
B. L. Cline, R. P. Panzica and L. B. Townsend; 1. Heterocycl. Chern., 1978, 15,839.
A. Bernardini, P. Viallefont and R. Zniber; J. Heterocyc/. Chern., 1978, 15,937.
576
135
648
673
364
273
719
263
652
233
[ 19
6[7,618
63[,658
616,636
604
642
510,5[6
642
897
61 I, 632
206
823
260
317,808
147,809
78JOC2289
78JOC2487
78JOC2587
78JOC2665
78JOC2900
78JOC3042
78JOC3370
78JOC3565
78JOC3570
78JOC3732
78JOC3736
78JOC4125
78JOC4381
78JOC4774
78JOC4784
78JOC4853
78JPR508
78JPR521
78JST(43)33
78JST( 43)203
78KGS258
78KGS723
78KGSI525
78LAI476
78LAI491
78LAI916
78M337
78M379
78MI40400
78MI40401
78MI40402
78MI40403
B- 78MI40404
B-78MI40405
B-78MI40500
78MI40600
B-78MI40900
B- 78MI40901
B- 78MI40902
B-78MI40903
B- 78MI40905
78MI40906
78MI40907
B-78MI40908
78MI40909
78MI40910
78MI41000
78MI41001
78MI41002
78MI41003
A. G. Hortmann, J.-Y. Koo and c.-c. Yu; J. Org. Chern., 1978,43,2289.
J. Font, M. Torres, H. E. Gunning and O. P. Strausz; 1. Org. Chern., 1978,43,2487.
J. H. Keck, Jr., R. A. Simpson and J. L. Wong; J. Org. Chern., 1978,43,2587.
S. Gelin, R. Gelin and D. Hartmann; J. Org. Chern., 1978,43,2665.
E. S. Hand and W. W. Paudler; J. Org. Chern., 1978,43,2900.
G. L'abbé, J.-P. Dekerk, A. Verbruggen, S. Toppet, J. P. Declercq, G. Germain
and M. Van Meerssche; J. Org. Chern., 1978,43,3042.
Y. Tamaru, T. Harada and Z. Yoshida; J. Org. Chern., 1978,43,3370.
T, Takeuchi, H. J. C. Yeh, K. L. Kirk and L. A. Cohen; J. Org. Chern., 1978,43,
3565.
Y. Takeuchi, K. L. Kirk and L. A. Cohen; J. Org. Chern., 1978,43,3570.
M. Baudy, A. Robert and A. Foucaud; J. Org. Chern., 1978,43,3732.
R. K. Howe, T. A. Gruner, L. G. Carter, L. L. Black and J. E. Franz; J. Org.
Chern., 1978,43,3736. 147
B. W. Cue, Jr., L. J. Czuba and J. P. Dirlam; J. Org. Chern., 1978,43,4125. 898
K. L. Kirk; J. Org. Chern., 1978,43,4381. 398,401,414,448
E. J. Prisbe, J. P. H. Verheyden and J. G. Moffatt; J. Org. Chern., 1978,43,4774. 658
E. J. Prisbe, J. P. H. Verheyden and J. G. Moffatt; J. Org. Chern., 1978,43,4784. 658
N. Ranganathan and W. S. Brinigar; J. Org. Chern., 1978,43,4853. 455
W. Freyer; J. Prakt. Chern., 1978,320, 508. 209
W. Freyer; J. Prakt. Chern., 1978,320,521. 199
M. H. Palmer and S. M. F. Kennedy; J. Mol. Struct., 1978,43,33. 7,205
M. H. Palmer and S. M. F. Kennedy; J. Mol. Struct., 1978,43,203. 176,177,205
N. O. Saldabol and O. E. Lando; Khirn. Geterotsikl. Soedin., 1978,258 (Chern.
Abstr., 1978,88, 190733).
K. Galankiewicz; Khirn. Geterotsikl. Soedin., 1978, 723.
I. N. Azerbaev, I. A. Poplavskaya, R. G. Kurmangalieva and S. F. Khalilova;
Khirn. Geterotsikl. Soedin., 1978, 1525 (Chern. Abstr., 1979,90,87319).
H. Meyer, F. Bossert and H. Horstmann; Liebigs Ann. Chern., 1978, 1476.
H. Meyer and J. Kurz; Liebigs Ann. Chern., 1978, 1491.
N. Engel and W. Steglich; Liebigs Ann. Chern., 1978, 1916.
F. Wille and W. Schwab; Monatsh. Chern., 1978,109,337.
G. Ciurdaru, Z. Moldovan and I. Oprean; Monatsh. Chern., 1978,109,379.
V. Tabacik and S. Sportouch; J. Raman Spectrosc., 1978,7,61.
U. Wrzeciono and W. Nieweglowska; Pharrnazie, 1978,33,377.
J. Elguero, E. Gonzalez and R. Sarlin; An. Quírn., 1978,74,527.
H. J. M. Dou, J. Elguero, M. Espada and P. Hassanaly; An. Quírn., 1978,74, 1137.
J. Bastide and O. Henri-Rousseau; in 'The Chemistry of the Carbon-Carbon
Triple Bond', ed. S. Palai; Wiley-Interscience, 1978, part 2, p. 447.
D. S. Wulfman, G. Linstrumelle and C. F. Cooper; in 'The Chemistry of
Diazonium and Diazo Groups', ed. S. Patai; Wiley-Interscience, 1978, part 2,
p. 821.
J. G. T. Moffatt, H. P. Albrecht, G. H. Jones, D. B. Repke, G. Frummlitz, H.
Ohrui and C. M. Gupta; in 'Chemistry and Biology of Nucleosides and
Nucleotides', ed. R. Harmon; Academic, New York, 1978, p. 359.
C. Guimon, G. Plì.ster-Guillouzo, G. Salmona and E. J. Vincent; J. Chirn. Phys.
Phys. Chirn. BioI., 1978,75,859.
G. H. Hitchings; 'Handbook of Experimental Pharmacology', Springer, Berlin,
1978.
'Nucleic Acid Chemistry', ed. L. B. Townsend and R. S. Tipson; Wiley-Inter-
science, New York, 1978, part 1. 504, 553, 592, 595, 597
P. Buchner, F. Blomberg and H. Ruterjans; in 'NMR Spectroscopy in Molecular
Biology', 'Jerusalem Symposium of Quantum Chemislry and Biochemistry',
ed. B. Pullman; Reidl, Amsterdam, 1978.
'Nucleic Acid Chemistry', ed. L. B. Townsend and R. S. Tipson; Wiley-Inter-
science, New York, 1978, part 2. 504, 573, 592, 594, 595, 597, 598
'Advances in Cyclic Nucleotide Research', ed. W. J. George and L. J. Ignarro;
Raven Press, New York, 1978, vol. 9.
S. A. Benezra and P. R. B. Foss; Anal. Profiles Drug Subst., 1978,7, 343.
T. Sato and R. Noyori; Kagaku (Kyoto), 1978,33,494.
'Chemistry and Biology of Nucleosides and Nucleotides', ed. R. E. Harmon, R.
K. Robins and L. B. Townsend; Academic, New York, 1978.
H. J. Schaeffer, L. Beauchamp, P. de Miranda, G. B. Elion, D. J. Bauer and P.
Collins; Nature (London), 1978,272, 583.
K. Kimura, T. Sugryama and T. Hashizume; Nucleic Acids Res., 1978, Spec. Pub.
No.5, S339.
H. Foks and M. Janowiec; Acta Pol. Pharrn., 1978,35,281.
P. A. Bartlett, J. T. Hunt, J. L. Adams and J. C. E. Gehret; Bioorg. Chern., 1978,
7,421.
H. G. Lenvartz, M. Hepp and W. Schunack; Eur. J. Med. Chern. - Chirn. Ther.,
1978, 13, 229.
J .-c. Teulade, G. Grassy, J .-P. Girard, J .-P. Chapat and M. Simeon de Buochberg;
Eur. J. Med. Chern. - Chirn. Ther., 1978, 13, 27 I.
References
977
423
14
51!
192
613,631
832
276
352
407
129
631
504
631
634
634
114,462
201,281
359
199,200
266
258
183, 230
282
282
334
361
501
510,513
504
501,516
504
504
603
601
636
667
649
612
978
78MI41004
78MI41005
78MI41006
78MI41007
78MI41008
78MI41009
78MI41010
7RMI41011
78MI41100
78MI41101
78MI41102
78MI41103
B-78MI41104
78MI41105
780MR(l1)27
780MR( 11)234
780MR(l1)385
780MR( 11)578
780MR(lI)617
780MS319
780MS518
780MS571
780MS575
78P2075
78RTC35
78RTC293
78S633
78S675
78S694
78Tll39
78Tll75
78T2229
78T2259
78TH40400
78TL399
78TLl009
78TLl447
78TL2579
78TL4039
78TL4503
78TL458I
78TL5007
78UP41500
78YZ631
78ZC92
7RZC214
78ZN(B)1033
78Z0B705
79ACS(A)687
79ACS(A)693
79ACS(A)697
79ACS(B)483
Y. M. Yutilov and A. G. Ignatenko; Deposited Doc., 1978, VINITi, 3830-78
(Chern. Abstr., 1980, 92, 198 320).
Y. M. Yutilov and I. A. Svertilova; Deposited Doc., 1978, VINITI, 1193-78 (Chern.
Abstr., 1979,91,175261).
Y. M. Yutilov and A.G. Ignatenko; Deposited Doc., 1978, VINITI, 3831-78
(Chern. Abstr., 1980,92, (98321). 621
B. L. Cline, R. P. Panzica and L. B. Townsend; Nucleic Acid Chern., 1978, 1,129. 617,636
J. Biernat, J. Ciesiolka, P. Gornicki, R. W. Adamiak, W. J. Krzyzosiak and M.
Wiewiorowski; Nucleic Acids Res., 1978,5,789.
P. Fernandez-Resa, P. Goya and M. Stud; Nucleic Acids Res., Spec. Publ., 1978,
4,61.
A. A. Kost and S. V. Ermolin; Nucleic Acids Res., Spec. Publ., 1978,4, 197.
J. Biernat, J. Ciesolka, P. Gornicki, W.J. Krzyzosiak and M. Wiewiorowski;
Nucleic Acids Res., Spec. Publ., 1978,4,203.
O. V. Voischcheva and G. V. Shatalov; Izv. Vyssh. Uchebn. Zaved., Khirn. Khirn.
Tekhnol., 1978,21, 1437 (Chern. Abstr., 1979,90, 120782).
R. Boehm; Pharrnazie, 1978,33,83.
A. Contreras, R. M. Sanchez-Perez and G. Alonso; Cancer Chernother. Phar-
rnacol., 1978, I, 243.
R. J. Fass and R. B. Prior; Curro Therap. Res., 1978,24,352.
A. Albert; in 'Nucleic Acid Chemistry', ed. L. B. Townsend and R. S. Tipson;
Wiley, New York, 1978, p. 97.
N. Matsuo and H. Chikako; Transition Met. Chern., 1978,3,366.
K. A. K. Ebraheem, G. A. Webb and M. Witanowski; Org. Magn. Reson., 1978,
11,27.
J. R. Fayet, M. C. Vertut, A. Fruchier, E. M. Tjiou and J. Eiguero; Org. Magn.
Reson., 1978, II, 234. 190, 192, 194
L. Stefaniak; Org. Magn. Reson., 1978, 11,385. 195
S. Toppet, G. Wonters and G. Smets; Org. Magn. Reson., 1978, 11,578. 682
R. Faure, J. Eiguero, E. J. Vincent and R. Lazaro; Org. Magn. Reson., 1978, II,
617.
B. Gioia, L. Citerio and R. Stradi; Org. Mass Spectrorn., 1978, 13, 319.
A. Maquestiau, Y. Van Haverbeke, R. Flammang, A. Menu and C. Wentrup;
Org. Mass Spectrorn., 1978,13,518.
J. L. Aubagnac, P. Campion and P. Guenot; Org. Mass Spectrorn., 1978, 13, 571.
A. Atmani and J.-L. Aubagnac; Org. Mass Spectrorn., 1978, 13,575.
T. W. Baumann, E. Dupont Looser and H. Wanner; Phytochemistry, 1978, 17,
2075.
C. Oldenhof and J. Cornelisse; Recl. Trav. Chirn. Pays-Bas, 1978,97,35.
A. Noordam, L. Maat and H. C. Beyerman; Recl. Trav. Chirn. Pays-Bas, 1978,
97, 293.
L. Baiocchi, G. Corsi and G. Palazzo; Synthesis, 1978,633.
J. A. M. Bastiaansen and E. F. Godefroi; Synthesis, 1978,675
P. K. Kadaba; Synthesis, 1978,694.
T. Avignon, L. Bouscasse and J. Eiguero; Tetrahedron, 1978,34, 1139.
E. Gonzalez, R. Sarlin and J. Eiguero; Tetrahedron, 1978,34,1175.
F. Roelants and A. Bruylants; Tetrahedron, 1978,34, 2229.
O. Bensaude, M. Chevrier and J. E. Dubois; Tetrahedron, 1978,34,2259.
R. Sarlin: Ph. D. Thesis, University of Perpignan, 1978.
J. Plenkiewicz; Tetrahedron Lelt., 1978, 399.
G. Lucente, F. Pinnen and G. Zanotti; Tetrahedron Lett., 1978, 1009.
K. Ienaga and W. Pfleiderer; Tetrahedron Lelt., 1978, 1447.
S. Nakatsuka, T. Ohgi and T. Goto; Tetrahedron Lelt., 1978,2579.
H. Yamada, M. Hirobe, K. Hiyashiyama, H. Takahashi and K. T. Suzuki;
Tetrahedron Lett., 1978, 4039.
G. Le Fèvre and J. Hamelin; Tetrahedron Lett., 1978,4503.
M. J. Haddadin, A. A. Hawi and M. Z. Nazer; Tetrahedron Lett., 1978,4581.
T. Fujii, T. Saito and M. Kawahishi; Tetrahedron Lett., 1978,5007.
S. W. Schneller and D. G. Bartholomew; unpublished result.
K. Kurata, H. Awaya, Y. Tominaga, Y. Matsuda and G. Kobayashi; l'akugaku
Zasshi, 1978, 9S, 631 (Chern. Abstr., 1979,90,22892).
A. Koennecke and E. Lippmann; Z. Chern., 1978, IS, 92.
A. Könnecke, P. Lepom and E. Lippmann; Z. Chern., 1978, IS, 214.
M. Konieczny and G. Sosnowsky; Z. Naturforsch., Teil B, 1978,33,1033 (Chern.
Abstr., 1979,90, 103895).
E. V. Komissarova, N. N. Belyaev and M. D. Stadnichuk; Zh. Obshch. Khirn.,
1978, 4S, 705 (Chern. Abstr., 1978, 88, 190702).
References
I. Søtofte and K. Nielsen; Acta Chern. Scand., Ser. A, 1979,33,687.
K. Nielsen, L. Schepper and I. Søtofte; Acta Chern. Scand., Ser. A, 1979,33,693.
K. Nielsen and I. Søtofte; Acta Chern. Scand., Ser. A, 1979,33,697.
B. R. Tolf, J. Piechaczek, R. Dahlbom, H. Theorell, A. Akeson and G. Lundquist;
Acta Chern. Scand., Ser. B, 1979,33,483.
618
620,62?
648
666
648
648
677
698
728
729
726
691
195
190
360
203
687
202, 359
600
243,247
649
169,275,282
402
703
190,199,210
326
725
211,212.217
272
813
643
590
565, 602
568, 605
256
376
493, 586
864
632
903
808
392, 454
709
674
674
674
291
79AF511
79AG259
79AG(E)239
79AG(E)721
79AHC(24)215
79AHC(25)1
79AHC(25)83
79AHC(25)147
79AHC(25)205
79AJC387
79AJCI727
79AJC2203
79AJC2713
79AJC2771
79AJC2787
79API07
79AP61O
79AX(B)I77
79AX(B)1468
79AX(B)2256
79BAP21
79BAP249
79BEP871985
79BSB289
79BSF(2)529
79BSF(2)633
79CB445
79CBI057
79CB 1529
79CBI635
79CBI712
79CBI719
79CB2829
79CC135
79CC523
79CC568
79CC627
79CHE115
79CHE218
79CHE467
79CHE544
79CHE685
79CHE939
79CHEI237
79CHEI255
79CJC139
79CJC360
79CJC813
79CJC904
References
979
Y. Ykeda, N. Takano, H. Matsushita, Y. Shiraki, T. Koide, R. Nagashima, Y.
Fujimura, M. Shindo, S. Suziki and T. Iwasaki; Arzneirn.-Forsch., 1979,29,511.
D. Seebach; Angew. Chern., 1979,91, 259.
D. Seebach; Angew. Chern., Int. Ed. Eng/., 1979, 18, 239.
G. Bianchi, C. De Micheli and R. Gandolfi; Angew. Chern., Int. Ed. Eng/., 1979,
18, 721. 276,282,283
J. H. Lister; Adv. Heterocyc/. Chern., 1979,24,215. 501
J. W. Bunting; Adv. Heterocyc/. Chern., 1979,25, I. 62,63
G. R. Newkome and A. Nayak; Adv. Heterocyc/. Chern., 1979,25,83. 58,60,61
B. J. Wakefield and D. J. Wright; Adv. Heterocyc/. Chern., 1979,25, 147. 46,51,58,69,
71, 74, 84, 91, 93
60, 110,419
534
P. Hanson; Adv. Heterocyc/. Chern., 1979,25,205.
J. H. Lister; Aust. J. Chern., 1979,32,387.
K. C. Chang, M. R. Grimmett, D. D. Ward and R. T. Weavers; AUst. J. Chern.,
1979,32, 1727.
M. R. Grimmett, K. H. R. Lim and R. T. Weavers; AUst. J. Chern., 1979,32,2203.
D. J. Brown, G. W. Grigg, Y. Iwai, K. N. McAndrew, T. Nagamatsu and R. Van
Heeswyck; Aust. J. Chern., 1979,32,2713.
J. H. Lister, Aust. J. Chern., 1979,32,2771.
P. M. Pojer; Aust. 1. Chern., 1979,32,2787.
H. J. Sattler, H. G. Lennartz and W. Schunack; Arch. Pharrn. (Weinheirn, Ger.),
1979,312, 107.
A. Kreutzberger and K. Burgwitz; Arch. Pharrn. (Weinheirn, Ger.), 1979,312,610.
R. H. P. Francisco, Y. P. Mascarenhas and J. R. Lechat; Acta Crystaffogr., Part
B, 1979,35,177.
R. H. P. Francisco, J. R. Lechat and Y. P. Mascarenhas; Acta Crystaffogr., Part
B, 1979,35, 1468.
L. Golic, 1. Leban, B. Stanovnik and M. Tisler; Acta Crystaffogr., Part B, 1979,
35, 2256.
N. S. V. Subba Rao, M. C. Ganorkar, B. K. M. Murali and C. P. Ramaswamy;
Buff. Acad. Pol. Sci., Ser. Sci. Chirn., 1979,27,21 (Chern. Abstr., 1980,92,25 160).
D. Maciejewska and L. Skulski; Buff. Acad. Pol. Sci., Ser. Sci. Chirn., 1979,27,249.
G. Arcari, L. Bernardi, G. Falconi and U. Scarponi; Be/g. Pat. 871985 (1979)
(Chern. Abstr., 1979,91,39486).
A. Sayarh, M. Gelize-Duvigneau, J. Arriau and A. Maquestiau; Bu/l. Soc. Chirn.
Be/g., 1979,88,289.
J.-C. Teulade, R. Escale, G. Grassy, J.-P. Girard and J.-P. Chapat; Buff. Soc.
Chirn. Fr., Part 2, 1979,529.
M. S. Ouali, M. Vaultier and R. Carrié; Buff. Soc. Chirn. Fr., Part 2, 1979,633.
H. Hansen, S. Hünig and K. Kishi; Chern. Ber., 1979, 112, 445.
R. Appel and L. Willms; Chern. Ber., 1979, 112, 1057.
R. Gompper and K. Schönafinger; Chern. Ber., 1979, 112, 1529.
H. Gotthardt and F. Reiter; Chern. Ber., 1979,112, 1635.
W. Sucrow, F. Lübbe and A. Fehlauer; Chern. Ber., 1979,112,1712.
W. Sucrow, D. Rau, A. Fehlauer and J. Pickardt; Chern. Ber., 1979,112,1719.
L. Birkofer and K. Richtzenhain; Chern. Ber., 1979, 112, 2829.
T. Saito and T. Fujii; J. Chern. Soc., Chern. Cornrnun., 1979, 135.
J. P. Dickens, R. L. Dyer, B. J. Hamill and T. A. Harrow; J. Chern. Soc., Chern.
Cornrnun., 1979, 523.
R. Huisgen and H. U. Reissig; J. Chern. Soc., Chern. Cornrnun., 1979,568.
T. L. Gilchrist, C. W. Rees and J. A. R. Rodrigues; J. Chern. Soc., Chern. Cornrnun.,
1979,627.
A. S. Morkovnik and O. Yu. Okhlobystin; Chern. Heterocyc/. Cornpd. (Eng/.
Transl.), 1979, 15, 115.
V. N. Doron'kin, A. F. Pozharskii and 1. S. Kashparov; Chern. Heterocyc/. Cornpd.,
(Engl. Trans/.), 1979,15,218.
V. P. Semenov, A. N. Studenikov and A. A. Potekhin; Chern. Heterocyc/. Cornpd.
(Eng/. Trans/.), 1979, 15,467.
1. Ya. Kvitko, R. V. Khozeeva and A. V. El'tsov; Chern. Heterocyc/. Cornpd.
(Engl. Trans/.), 1979,15,544.
V. A. Bakulev, V. S. Mokrushin, V.1. Ofitserov, Z. V. Pushkareva and A. N.
Grishakov; Chern. Heterocyc/. Cornpd. (Eng/. Transl.), 1979, 15,685.
A. F. Pozharskii; Chern. Heterocyc/. Cornpd. (Eng/. Transl.), 1979, 15,939.
M. A. Klykov, M. V. Povstyanoi and P. M. Kochergin; Chern. Heterocyc/. Cornpd.
(Engl. Transl.), 1979, 15, 1237.
V. P. Kruglenko and M. V. Povstyanoi; Chern. Heterocyc/. Cornpd. (Eng/. Trans/.),
1979, 15, 1255.
K. R. Breakell, S. J. Rettig, A. Storr and J. Trotter; Can. J. Chern., 1979,57, 139.
M. Mukai, T. Miura, M. Nanbu, T. Yoneda and Y. Shindo; Can. 1. Chern., 1979,
57, 360.
J. Kister, G. Assef, G. Mille and J. Metzger; Can. J. Chern., 1979,57,813.
P. J. Fagan, E. E. Neidert, M. J. Nye, M. J. O'Hare and W. P. Tang; Can. J.
Chern., 1979,57,904.
293
717
717
237,266
389
636
537
727
486
272
227
227
12
837
371
623
367
612
705
707
728
711
717
275
179
709
586
396
250
273
254
411
460,463
372
629
347, 349
656
653
227
256
446
265
980
79CJC 1186
79CJC3034
79CPBI83
79CPBI153
79CPBI207
79CPB2116
79CPB243I
79C PB2518
79CPB2820
79CPB2861
79CPB3176
79CRV447
79FES417
79FES478
79FES751
79FES898
79GEP2815956
79GEP2909190
79H(l2)186
79H(\ 2)657
79H(l2) 1157
79H(l2)1171
79HC(34-1)5
79HC(34-1)67
79HC(34-1)73
79HC(34-1 )76
79HC(34-1)230
79HC(34-1)388
79HC(34-2)9
79HC(34-2)26
79HC(34-2)385
79HC(34-2)421
79HC(34-2)430
79HC(35)365
79HC(35)370
79HC(35)376
79HCA497
79[('658
79\JC(B)428
79/ZV1618
79J A545
79JA1303
79JAI564
79JA3647
79JA3976
79JA3982
79J A4899
79JA5558
79JCR(M)2921
79JCR(S)374
79JCS( D) 1646
79JCS(D) 1867
79JCS(PI)15
79JCS(PI )333
79JCS(PI)1120
W. J. Leigh and D. R Arnold; Can. J. Chern., 1979,57, 1186.
S. C. Sharma and B. M. Lynch; Can. J. Chern., 1979,57,3034.
A. Matsuda, Y. Nomoto and T. Ueda; Chern. Pharrn. Bull., 1979,27, 183.
H. Takahashi, N. Nimura, N. Obata, H. Sakai and H. Ogura; Chern. Pharrn.
Bull., 1979,27,1153.
K. Kubo, N. Ito, Y. /somura, I. Sozu, H. Homma and M. Murakami; Chern.
Ph arm. Bull., 1979,27, 1207.
M. Sakamoto, K. Miyazawa, K. Kuwabara and Y. Tomimatsu; Chern. Ph arm.
Bull., 1979,27,2116.
T. Higashino, T. Katori and E. Hayashi; Chern. Pharrn. Bull., 1979, 27, 2431.
M. Saneyoshi and E. Satoh; Chern. Ph arm. Bull., 1979, 27, 2518.
A. Noda, K. Matsuyama, S.-H. Yen, K. Sogabe, Y. Aso, S. Iguchi and H. Noda;
Chern. Pharrn. Bull., 1979,27, 2820.
T. Higashino, T. Katori and E. Hayashi; Chern. Pharrn. Bull., 1979, 27, 2861.
T. Higashino, T. Katori, S. Yoshida and E. Hayashi; Chern. Ph arm. Bull., 1979,
27,3176.
M. V. George and V. Bhat; Chern. Rev., 1979,79,447.
E. Abignente, F. Arena, M. Carola, P. De Caprariis, A. P. Caputi, F. Rossi, L.
Giordano, C. Vacca, E. Lampa and E. Marmo; Farrnaco Ed. Sci., 1979,34,
417 (Chern. Abstr., 1979,91,39390).
G. Auzzi, L. Cecchi, A. Costanzo, L. Pecori Vettori, F. Bruni, R. Pirisino and
G. B. Gottoli; Farrnaco Ed. Sci., 1979,34,478.
G. Auzzi, L. Cecchi, A. Costanzo, L. Pecori Vettori and F. Bruni; Farrnaco Ed.
Sci., 1979, 34, 751.
G. Auzzi, L. Cecchi, A. Costanzo, L. Pecorivettori and F. Bruni; Farrnaco Ed.
Sci., 1979,34, 898.
Bayer AG, Ger. Pat. 2 815 956 (1979) (Chern. Abstr., 1980, 92, 94406).
K. Okauchi, T. Koitabashi and N. Fujimori; Ger. Pat. 2909190 (1979) (Chern.
Abstr., 1980, 92, 172 437).
K. Takahashi and K. Mitsuhashi; Heterocycles, 1979, 12, 186.
C. Kashima, S. Shirai and Y. Yamamoto; Heterocycles, 1979, 12,657.
A. Tomazie, M. TiSler and B. Stanovnik; Heterocycles, 1979,12,1157.
L. G. Payne, M. T. Wu and A. A. Patchett; Heterocycles, 1979, 12, 1171.
J. V. Metzger, E.-J. Vincent, J. Chouteau and Gi. Mille; Chern. Heterocycl. Cornpd.,
1979, 34-1, 5.
J. V. Metzger; Chern. Heterocycl. Cornpd., 34-1, 67.
J. V. Metzger; Chern. Heterocycl. Cornpd., 1979,34-1,73.
J. V. Metzger; Chern. Heterocycl. Cornpd., 1979,34-1, 76.
G. Vernin; Chern. Heterocycl. Cornpd., 1979,34-1, 230.
J. V. Metzger; Chern. Heterocycl. Com pd., 1979,34-1,388.
R. Barone, M. Chanon and R. Gallo; Chern. Heterocycl. Cornpd., 1979,34-2,9.
J. V. Metzger; Chern. Heterocycl. Cornp. 1979,34-2,26.
J. V. Metzger; Chern. Heterocycl. Cornpd., 1979,34-2,385.
J. V. Metzger; Chern. Heterocycl. Cornpd., 1979,34-2,421.
J. V. Metzger; Chern. Heterocycl. Cornpd., 1979,34-2,430.
G. W. H. Cheeseman and R F. Cookson; Chern. Heterocycl. Cornpd., 1979,35,365.
G. W. H. Cheeseman and R F. Cookson; Chern. Heterocycl. Cornpd., 1979,35,370.
G. W. H. Cheeseman and R F. Cookson; Chern. Heterocycl. Cornpd., 1979,35,376.
E.-P. Krebs and E. Bondi; Helv. Chirn. Acta, 1979,62,497.
G. Minghetti, G. Banditelli and F. Bonati; Inorg. Chern., 1979, 18,658.
P. K. Dubey and C. V. Ratnam; Indian J. Chern., Sect. B, 1979,18,428.
O. A. Luk'yanov, A. A. Onishchenko, V. S. Kosygin and V. A. Tartakovskii; Izv.
Akad. Nauk SSSR, Ser. Khirn., 1979, 1618 (Chern. Abstr., 1979,91,175263). 646
W. M. Litchman; J. Am. Chern. Soc., 1979, 101, 545. 190,191,192,213
S. F. Dyer and P. B. Shevlin; J. Am. Chern. Soc., 1979, 101, 1303. 96
J. R Barrio, F.-T. Liu, G. E. Keyser, P. vanDerLijn and N. J. Leonard; J. Am.
Chern. Soc., 1979,101, 1564.
R. Huisgen, H. U. Reissig and H. Huber; 1 Am. Chern. Soc., 1979, 101,3647.
M. Murai, M. Torres and O. P. Strausz; 1 Am. Chern. Soc., 1979,101,3976.
S. M. Hecht, K. M. Rupprecht and P. M. Jacobs; J. Am. Chern. oc., 1979,101,3982.
M. J. S. Dewar and W. Thiel; J. Am. Chern. Soc., 1977,99,4899,4907.
M. J. S. Dewar and G. P. Ford; J. Am. Chern. Soc., 1979, 101,5558.
J. L. Avril, J. Mayrargue and M. Miocque; J. Chern. Res. (M), 1979,2921.
P. Dapporto and F. Mani; J. Chern. Res. (S), 1979, 374.
A. Murphy, B. J. Hathaway and T. J. King; J. Chern. Soc., Dalton Trans., 1979,
1646.
F. Valach, J. Kohout, M. Dunaj-Jureo, M. Hvastijová and J. Gazo; J. Chern.
Soc., Dalton Trans., 1979, 1867.
S. I. Miller, R-R. Lii and Y. Tanaka; J. Chern. Soc., Perkin Trans. I, 1979, 15.
D. G. Neilson, K. M. Watson and T. J. R Weakley; 1 Chern. Soc., Perkin Trans.
1, 1979, 333.
R. W. Clarke, S. C. Garside, L. H. C. Lunts, D. Hartley, R Hornby and A. W.
Oxford; J. Chern. Soc., Perkin Trans. I, 1979, 1120.
References
182,192,249
272
561
637
632
632
875
560
904
876
875
254
631
331
313
272
719
837
389, 435
281
885
853
58,89
14
14
19
120
19
97
15
15
27
27
608
608
608
468
226
619,635
567
283
44
485
7
7
281
227
227
227
687
659
630, 657
79JCS(PI)1239
79JCS(PI)1833
79JCS(PI )2289
79JCS(PI)2786
79JCS(PI)3085
79JCS(PI)3107
79JCS(P2)653
79JCS(P2) 1327
79JCS(P2) 1670
79JCS(P2) 1708
79JGUI251
79JGU1877
79JHC53
79JHCI57
79JHCI87
79JHC277
79JHC305
79JHC415
79JHC427
79JHC555
79JHC571
79JHC585
79JHC607
79JHC685
79JHC689
79JHC773
79JHC871
79JHC983
79JHCI005
79JHC 1063
79JHCll05
79JHCI153
79JHCI499
79JHCI567
79JHCI579
79JMC237
79JMC356
79JMC496
79JMC807
79JMC944
79JMC958
79JMCI030
79JOC218
79JOC622
79JOCI028
79JOCI450
79JOCI717
79JOC I 740
T. Brown, K. Kadir, G. Mackenzie and G. Shaw; J. Chern. Soc., Perkin Trans.
1, 1979, 3107. 438, 584, 590
H. Fujiwara, A. K. Bose, M. S. Manhas and J. M. van der Veen; J. Chern. Soc.,
Perkin Trans. 2, 1979,653.
J. P. Riley, F. Heatley, I. H. Hillier, P. Murray-Rust and J. Murray-Rust; J. Chern.
Soc., Perkin Trans. 2, 1979, 1327.
J. Kaczmarek, H. Smagowski and Z. Grzonka; J. Chern. Soc., Perkin Trans. 2,
1979, 1670. 793,806,816
R. A. Bowie, P. N. Edwards, S. Nicholson, P. J. Taylor and D. A. Thomson; J.
Chern. Soc., Perkin Trans. 2, 1979, 1708.
L. N. Nikolenko, N. S. Tolmacheva and L. D. Shustov; J. Gen. Chern. USSR
(Engl. Trans!.), 1979,49, 1251.
Yu. M. Kargin, V. Z. Latypova, R. Kh. Fassakhov, A. I. Arkhipov, T. A. Eneikina
and G. P. Sharnin; J. Gen. Chern. USSR (Engl. Transl.), 1979,49, 1877.
A. Rabaron, J. C. Lancelot, D. Maume and M. Robba; J. Heterocycl. Chern.,
1979, 16, 53.
J. A. Montgomery, S. D. Clayton and A. T. Shortnacy; J. Heterocycl. Chern.,
1979,16, 157.
L. W. Deady and M. S. Stanborough; J. Heterocycl. Chern., 1979,16, 187.
R. Paul and J. Menschik; J. Heterocycl. Chern., 1979,16,277.
A. Nagel, H. C. van der Plas, G. Geurtsen and A. van der Kuilen; J. Heterocyc!.
Chern., 1979, 16, 305.
A. F. Janzen, G. N. Lypka and R. E. Wasylishen; J. Heterocycl. Chern., 1979, 16,
415. 454
J. Daunis, L. Djouai-Hifdi and'H. Lopez; J. Heterocycl. Chern., 1979,16,427. 899
C. A. Lovelette; J. Heterocycl. Chern., 1979, 16, 555. 859,861,899,903
N. A. Rodios and N. E. Alexandrou; J. Heterocycl. Chern., 1979,16,571. 678
H. T. Cory, K. Yamaizumi, D. L. Smith, D. R. Knowles, A. D. Broom and J. A.
McCloskey; J. Heterocycl. Chern., 1979,16,585.
P. C. Joshi, S. S. Parmar and V. K. Rastogi; J. Heterocycl. Chern., 1979, 16,607.
S. Olivella and J. Vilarrasa; J. Heterocycl. Chern., 1979, 16,685.
M. Iwao and T. Kuraishi; J. Heterocycl. Chern., 1979, 16,689.
Y. Van Haverbeke, A. Maquestiau and J. J. V. Eynde; J. Heterocycl. Chern., 1979,
16, 773. 272, 332
R. K. Sehgal and K. C. Agrawal; 1. Heterocycl. Chérn., 1979,16,871. 404,437,661
G. Holzmann, B. Krieg, H. Lautenschläger and P. Konieczny; J. Heterocycl.
Chern., 1979, 16,983.
R. Cerri, A. Boido and F. Sparatore; J. Helerocycl. Chern., 1979,16, 1005.
P. C. Srivastava and R. K. Robins; J. fleterocycl. Chern., 1979, 16, 1063.
O. Migliara, S. Petruso and V. Sprio; J. Heterocycl. Chern., 1979, 16, 1105.
J. S. Amato, V. J. Grenda, T. M. H. Liu and E. J. Grabowski; J. Heterocycl.
Chern., 1979, 16, 1153.
R. K. Sehgal and K. C. Agrawal; 1. Helerocycl. Chern., 1979, 16, 1499.
B. Stanovnik, M. Tisler, D. Gabrijelcic, M. Kunaver and J. Zmitek; J. Helerocycl.
Chern., 1979,16, 1567.
E. Barni and P. Savarino; J. Heterocycl. Chern., 1979, 16, 1579.
J. Rokach, P. Hamel, N. R. Hunter, G. Reader, C. S. Rooney, P. S. Anderson,
E. J. Cragoe, Jr. and L. R. Mandel; J. Med. Chern., 1979,22,237.
R. W. Fries, D. P. Bohlken and B. V. Plapp; J. Med. Chern., 1979,22,356.
F. G. de las Heras, R. Alonso and G. Alonso; J. Med. Chern., 1979,22,496.
M. T. García-López, R. Herranz and G. Alonso; J. Med. Chern., 1979,22,807.
R. B. Meyer, Jr. and E. B. Skibo; J. Med. Chern., 1979,22,944.
M. S. Poonian, W. W. McComas and M. J. Kramer; J. Med. Chern., 1979,22,958.
C. Li, M. H. Lee and A. C. Sartorelli; J. Med. Chern., 1979,22, 1030.
B. B. Snider, R. S. E. Conn and S. Sealfon; J. Org. Chern., 1979,41,218.
K. T. Potts, S. K. Datta and J. L. Marshall; J. Org. Chern., 1979,44,622.
T. Huynh-Dinh, R. S. Sarfati, C. Gouyette, J. Igolen, E. Bisagni, J.-M. Lhoste
and A. Civier; J. Org. Chern., 1979,44, 1028. 896
M. F. Zady and J. L. Wong; J. Org. Chern., 1979,44, 1450. 513,543,544
W. A. Sheppard, G. W. Gukel, O. W. Webster, K. Betterton and J. W. Timberlake;
J. Org. Chern., 1979,44,1717.
B. Golankiewicz, J. B. Holtwick, B. N. Holmes, E. N. Duesler and N. J. Leonard;
J. Org. Chern., 1979,44,1740.
References
A. Davidson, I. E. P. Murray, P. N. Preston and T. J. King; J. Chern. Soc., Perkin
Trans. 1, 1979, 1239.
E. E. Glover, L. W. Peck and D. G. Doughty; J. Chern. Soc., Perkin Trans. 1,
1979, 1833.
S. R. Landor, P. D. Landor, Z. T. Fomum and G. W. B. Mpango; J. Chern. Soc.,
Perkin Trans. 1, 1979,2289.
R. E. Busby, J. Parrick, S. M. H. Rizvi and J. G. Shaw; J. Chern. Soc., Perkin
Trans. 1, 1979, 2786.
J. S. Bajwa and P. J. Sykes; J. Chern. Soc., Perkin Trans. 1, 1979,3085.
981
419
615
354,471
246
889,891,
893,902
351
630
874
408,413
419
273
553, 603
631
630, 654
637
519
466
371
635
361,466
459
642
651
396
441
857,901
902
663, 665
291
729
289
666
642
139
284
164, 335
436
659
982
7910C 1765
79JOC2513
79JOC2902
79JOC2957
79JOOl40
791OC3803
79JOC3835
791OC3858
791OC4046
791OC4156
791OC4240
79JOC4532
791OC4R71
79JPR88I
79JPS377
79KGS262
79KGS643
79KGS805
79LAI33
79LA1444
79LAI456
79LAI602
79LAI756
79LA1872
79MI40100
B- 79MI40300
79 M 140400
79MI40401
79MI40402
79 M 140403
79 M 140404
79MI40405
79 M 140406
79MI40407
79MI40408
79MI40409
79MI40410
79MI40411
79MI40412
79MI40413
B- 79MI40414
B-79M140415
B-79M140416
B.79M140900
B-79M140901
B-79M140902
79MI40903
79MI40904
B-79M140905
283
513,515,
542
K. T. Potts and S. Kanemasa; J. Org. Chern., 1979,44,3803. 138, 150,633
J. B. Holtwick, B. Golankiewicz, B. N. Holmes and N. J. Leonard; J. Org. Chern.,
1979, 44, 3835.
E. P. Papadopoulos; J. Org. Chern., 1979,44,3858.
B.-S. Huang and J. C. Parham, J. Org. Chern., 1979,44,4046.
P. Cohen-Fernandes, C. Erkelens, C. G. M. van Eendenburg, J. J. Verhoeven
and C. L. Habraken; J. Org. Chern., 1979,44,4156.
Y. Takeuchi, K. L. Kirk and L. A. Cohen; J. Org. Chern., 1979,44,4240.
R. F. Shuman, W. E. Shearin and R. J. Tull; J. Org. Chern., 1979,44,4532.
Y. Ohtsuka, E. Tohma, S. Kojima and N. Tomita; 1. Org. Chern., 1979,44,4871.
H. Dorn and R. Ozegowski; J. Prakt. Chern., 1979,321,881.
M. J. Kornet and R. J. Garret; J. Pharm. Sci., 1979,68,377.
N. V. Volkova, V. N. Konyukhov, T. G. Koksharova, L. N. Dianova and Z. V.
Pushkareva; Khirn. Geterotsikl. Soedin., 1979, 262 (Chern. Abstr., 1979, 90,
204017).
Y. L. Gol'dfarb, F. M. Stoyanovich, M. A. Marakatkina and G. I. Gorushkina;
Khirn. Geterotsikl. Soedin., 1979,634 (Chern. Abstr., 1979,91,91557).
V. M. Dziomko and B. K. Berestevich; Khirn. Geterotsikl. Soedin., 1979,805.
K. Burger and F. Hein; Liebigs Ann. Chern., 1979, 133.
U. Schöllkopf, P. H. Porsch and H. H. Lau; Liebigs Ann. Chern., 1979, 1444.
E. V. Dehmlow and K. Frake; Liebigs Ann. Chern., 1979, 1456.
U. Schöllkopf and K. Hantke; Liebigs Ann. Chern., 1979, 1602.
W. Walter and M. Radke; Liebigs Ann. Chern., 1979, 1756.
K. I1uaga and W. Pfleiderer; Liebigs Ann. Chern., 1979, 11, 1872.
M. Baudet and M. Gelbcke; Anal. Letr., 1979,12,641.
C. A. Ramsden; in 'Comprehensive Organic Chemistry', ed. D. H. R. Barton
and W. D. Ollis; Pergamon Press, Oxford, 1979, vol. 4, p. 1207.
J. C. Berger and L. C. Iorio; Annu. Rep. Med. Chern., 1979, 14, 27.
R. D. Mackenzie; Annu. Rep. Med. Chern. 1979, 14,74.
C. Chavis, F. Grodenic and J. L. Imbach; Eur. J. Med. Chern., 1979, 14, 123.
I. A. Krol, V. M. Agre, V. K. Trunov, N. V. Rannev, O. V. Ivanov and V. M.
Dziomko; Koord. Khirn., 1979,5, 126.
J. Skladzinski and M. Beskid; Mater. Med. Pol. (Engl. Ed.), 1979, 11,355.
A. C. Grosscurt, R. van Hes and K. Wellinga; J. Agric. Food Chern., 1979,
27, 406.
W. Pett, H. Geissler, G. Dube and D. Zeigan; J. Signalaufzeìchnungsrnaterialien,
1979,6,447. 299
R. M. Claramunt, J. Elguero, C. Marzin and J. Seita; An. Quírn., 1979,75,701. 182,
184,190,191
J. Eiguero, M. Espada, D. Mathieu and R. Phan Tan Luu; An. Quírn., 1979,75,
729.
R. Barone, P. Camps and J. Eiguero; An. Quírn., 1979,75,736.
J. Elguero and M. Espada; An. Quírn., 1979,75,771.
A. Fruchier and J. Eiguero; Spectrosc. Leu., 1979,809.
V. Agre, I. A. Krol, V. K. Trunov, V. M. Dziomko and O. V. Ivanov; Koord.
Khirn., 1979,5,1406.
I. A. Krol, V. M. Agre, V. K. Trunov and O. I. Ivanov; Koord. Khirn., 1979,5, 1569.
F. H. Deis and D. Lester; in 'Biochemical Pharmacology of Ethanol', ed.
E. Majchrowicz and E. P. Noble; Plenum, New York, 1979, vol. 2, p. 203.
M. R. Grimmett; in 'Comprehensive Organic Chemistry', ed. D. H. R. Barton
and W. D. Ollis; Pergamon Press, Oxford, 1979, vol. 4, p. 357.
C. Hansch and A. Leo; 'Substituent Constants for Correlation Analysis in
Chemistry and Biology', Wiley-Interscience, New York, 1979.
G. C. Levy and R. L. Lichter; 'NMR Spectra', Wiley-Interscience, New York,
1979.
'Nucleoside Analogs', ed. R. T. Walker, E. De Clercq and F. Eckstein; NATO
Advanced Study Series, Plenum, New York, 1979.
'The Chemistry of Nucleosides and Nucleotides', ed. R. K. Robins and L. B.
Townsend; Plenum, New York, 1979, vol. I.
G. Shaw; Annu. Rep. Prog. Chern. (B), 1979,448.
M. Kaneko and B. Shimizu; Yuki Gosei Kagaku Kyokaishì, 1979,37,40.
E. Lunt; in 'Comprehensive Organic Chemistry', ed. D. H. R. Barton and W.
D. Ollis; Pergamon, Oxford, 1979, vol. 4, p.493.
References
I. I. Schuster, C. Dyllick-Brenzinger and J. D. Roberts, 1. Org..Chern., 1979,44,
1765.
M. S. Puar, G. C. Rovnyak, A. I. Cohen, B. Toeplitz and J. Z. Gougoutas; J.
Org. Chern., 1979,44,2513.
H. Kimoto and L. A. Cohen; 1. Org. Chern., 1979,44,2902.
V. Bhat, V. M. Dixit, B. G. Ugarker, A. M. Trozzolo and M. V. George; J. Org.
Chern., 1979,44,2957.
N. J. Kos, H. C. van den Plas and B. van Veldhuizen; J. Org. Chern., 1979,44,3140.
195,196
189
432
659
428,445
666
270
397
461
644
272
297
873
631
263
283
462
246
462
391,452,786
566
20
127
292, 293
294
192
227
302
298
230
276
191
194
227
227
291
168
207,268
510
504
504
504
504
501
79MI40906
B-79MI40907
79MI40908
79MI41000
79MI41001
79MI41100
79MI41101
79MI41 102
B-79M141103
B-79MI41104
B-79MI41105
79MI41200
79MI41201
79MI41500
79MI41501
79MIP41100
79MIP41101
79MIP41102
790MR(12)95
790MR(12)205
790MR(12)362
790MR(12)476
790MR(12)579
790MR(12)587
790MR(12)63I
790MSI14
790MSI17
790MS577
79P819
79RCR289
79RTC258
79RTC334
79S66
79S194
79S308
79S470
79S687
79S979
79SA(A)1055
79T389
79T511
79T663
79T1331
79TL53
References
983
F. A. Savin, Ya. V. Morozov, A. V. Borodavkin, V. O. Chekhov, E. I. Budowsky
and N. A. Simukova; Int. J. Quantum Chern., 1979, 16,825.
'Advances in Cyclic Nucleotide Research', ed. G. Brooker, P. Greengard and
G. A. Robison; Raven Press, New York, 1979, vol. 10.
M. Shimizaki, S. Kondo, K. Maeda, M. Ohno and N. Umezawa; J. Antiobiotics,
1979,32, 537.
A. Czarnocka-Janowicz, J. Sawlewicz, J. Jakubowski and M. Janowiec; Acta Pal.
Pharrn., 1979,36,529 (Chern. Abstr., 1981,94,65548).
Y. M. Yutilov, O. G. Eilazyan and A. G. Ignatenko; Deposited Doc., VINITI,
1979, 129-79 (Chern. Abstr., 1980,92,215340).
G. Manecke and C. S. Ruehl; Makrornol. Chern., 1979,180, 103.
T. Higashino, E. Hayashi and T. Katori; Fukosokan, Kagaku Toronkai Koen
Yoshishu, 12th, 1979,171 (Chern. Abstr., 1980,93,95227).
P. G. Fox, G. Lewis and P. J. Boden; Corrosion Sci., 1979, 19,457 (Chern. Abstr.,
1980, 92, 30906).
G. C. Levy and R. L. Lichter; 'Nitrogen-15 NMR Spectroscopy', Wiley-Inter-
science, New York, 1979.
E. Zbiral; in 'Organophosphorus Reagents in Organic Synthesis', ed. J. J. G.
Cadogan; Academic Press, London, 1979, p. 256.
M. R. Grimmett; in 'Comprehensive Organic Chemistry', ed. D. H. R. Barton
and W. D. Ollis; Pergamon Press, Oxford, 1979, vol. 4, p. 357.
Sh. J. Chiou; Dept. Chern. Kansas State Univ. Report, 1979, W80-05462 (Chern.
Abstr., 1981,94,48103).
M. C. De Traglia, J. S. Brand and A. M. Tometsko; Anal. Biochern., 1979,99,464.
G. Doukhan, T. Hunyh-Dinh, E. Bisagni, J.-c. Chermann and J. Igolen; Eur. J.
Med. Chern., 1979,14,375.
A. Hagen, B. Froemmel, H. Kuechmstedt, J. Wunderlich, K. Kottke and E.
Goeres; Pharrnazie, 1979,34,330.
Hoechst Aktiengesellschaft, Can. Pat. 1057760 (1979) (Chern. Abstr., 1979,91,
159 046).
Consejo Superior de Investigaciones Cientificas, Span. Pat. 460 433 (1979) (Chern.
Abstr., 1979,91, 193585).
Consejo Superior de Investigaciones Cientificas, Span. Pat. 475 496 (1979) (Chern.
Abstr., 1979, 91, 107984).
E. Gründemann, D. Martin and A. Wenzel; Org. Magn. Reson., 1979,12,95.
P. Sohár, O. Fehér and E. Tihanyi; Org. Magn. Reson., 1979,12,205.
F. A. L. Anet and J. Yavari; Org. Magn. Reson., 1979, 12, 362.
T. Axenrod, C. M. Watnick and M. J. Wielder; Org. Magn. Reson., 1979, 12,476.
R. Faure, J. Llinares, E. J. Vincent and J. Elguero; Org. Magn. Reson., 1979,12,
579.
E. Gonzalez, R. Faure, E. J. Vincent, M. Espada and J. Elguero; Org. Magn.
Reson., 1979,12,587. 191,192,211
J. Ciarkowski, J. Kaczmarek and Z. Grzonka; Org. Magn. Reson., 1979, 12,631. 793,799
A. Maquestiau, Y. Van Haverbeke, N. Vanovervelt, R. Flammang and J. Elguero;
Org. Mass Spectrorn., 1979, 14, 114.
A. Maquestiau, Y. Van Haverbeke, R. Flammang, H. Mispreuve and J. Elguero;
Org. Mass Spectrorn., 1979,14,117.
W. C. M. M. Luitjen and J. van Thuijl; Org. Mass Spectrarn., 1979,14,577.
C. C. Duke, D. S. Letham, C. W. Parker, J. K. MacLeod and R. E. Simmons;
Phytochemistry, 1979,18,819.
S. D. Sokolov; Russ. Chern. Rev. (Engl. Trans!.), 1979,48,289.
506
504
601
620,622
620
731
721
730
684
716
670, 698
785
785
884,896
893
730
728
728
354
192
355
197,290
195
203
203
202
601
169,171,222,
245,248
A. M. van Leusen, F. J. Schaart and D. M. van Leusen; Reel. Trav. Chirn.
Pays-Bas, 1979,98, 258.
O. L. Chapman, R. S. Sheridan and J.-P. LeRoux; Reel. Trav. Chirn. Pays-Bas,
1979,98,334.
V. I. Cohen; Synthesis, 1979,66.
B. Stanovnik, M. Tisler, M. Kocevar, B. Koren, M. BeSter and V. Kermavner;
Synthesis, 1979, 194.
M. A. Ardakani, R. K. Smalley and R. H. Smith; Synthesis, 1979,308.
K. Masuda, Y. Arai and M. Itoh; Synthesis, 1979,470.
S. Mataka, K. Takahashi and M. Tashiro; Synthesis, 1979,687.
V. Bertini, F. Lucchesini and A. DeMunno; Synthesis, 1979,979.
V. Tabacik, V. Pellegrin and H. H. Günthard; Spectrochirn. Acta, Part A, 1979,
35, 1055. 199,200,290
K. Burger, H. Schickaneder, F. Hein and J. Elguero; Tetrahedron, 1979,35,389. 188,
189
357
527
243,
266,419
444
468
867
118
263
274
718
117
127
F. A. Devillanova and G. Verani; Tetrahedron, 1979, 35, 511.
M. Jelinska, J. Szydiowski and J. Sobkowski; Tetrahedron, 1979,35,663.
P. Bouchet, G. Joncheray, R. Jacquier and J. Elguero; Tetrahedron, 1979,35, 1331.
K. Nagarajan, M. D. Nair and J. A. Desai; Tetrahedron Lett., 1979,53.
984
79TL279
79TLl281
79TLl567
79TLl725
79TL2385
79TL2621
79TL2991
79TL3 129
79TL3159
79TL3179
79TL4253
79TL4709
79USP4141899
79YZ699
79ZC446
79ZN(B)1473
79Z0R839
79Z0R844
79Z0R2534
80ACH(l05)12T
80AG319
80AG979
80AG(E)130
80AG(E)276
80AG(E)310
80AG(E)924
80AG(E)947
80AHC(27)31
80AHC(27)151
80AHC(27)241
80AJC499
80AJC949
80AJCI365
80AJC 1763
80AJC2237
80AJC2447
80AX(B) I 59
80AX(B)1466
80B3773
80BCJ96I
80BCJl638
80BSB51
80C504
80CBI884
80CB2043
80CB2823
80CB2852
80CB3910
80CC82
D. H. R. Barton, C. J. R. Hedgecock, E. Lederer and B. Motherwell; Tetrahedron
Letc., 1979, 279. 537
J. Rokach, P. Hamel, Y. Girard and G. Reader; Tetrahedron Letc., 1979, 1281. 664
G. Ege and K. Gilbert; Tetrahedron Letc., 1979, 1567. 134, 166,263
D. Cooper and S. Trippett; Tetrahedron Letc., 1979, 1725. 728
N. Công-Danh, J.-P. Beaucourt and L. Pichat; Tetrahedron Letc., 1979,2385. 537,593
W. Bihlmaier, R. Huisgen, H. U. Reissig and S. Voss; Tetrahedron Letc.,
1979, 2621.
F. Pochat; Tetrahedron Letc., 1979,2991.
R. A. Olofson and J. P. Pepe: Tetrahedron Lett., 1979,3129.
N. Công-Danh, J.-P. Beaucourt and L. Pichat; Tetrahedron Letc., 1979,3159.
F. Fabra, E. Fos and J. Vilarrasa; Tetrahedron Letc., 1979, 3179.
G. Ege and K. Gilbert; Tetrahedron Letc., 1979,4253.
L. J. Mathias and D. Burkett; Tetrahedron Letc., 1979,4709.
G. Arcari, L. Bernardi, G. Falconi, F. Luini, G. Palamidessi and U. Scarponi;
U.S. Pat. 4 141 899 (1979).
S. Nagai, N. Oda and I. Ito; Yakugaku Zasshi, 1979,99,699.
J. Wrubel and R. Mayer; Z. Chern., 1979, 19,446.
W. H. Guendel; Z Naturforsch., Teil B, 1979,34, 1473.
I. Yu. Shirobokov, V. A. Ostrovskii and G. I. Koldobskii; Zh. Org. Khirn., 1979,
15,839 (Chern. Abstr., 1979,91, 19384).
V. A. Ostrovskii, N. S. Panina, G. I. Koldobskii, B. V. Gidaspov and I. Yu.
Shirobokov; Zh. Org. Khirn., 1979,15,844 (Chern. Abstr., 1979,91,19679).
N. O. Saldabol, E. Liepins, J. Pope lis, R. Gavars, L. Baumane and I. Birgele;
Zh. Org. Khirn., 1979, 15, 2534 (Chern. Abstr., 1980, 93, 26 339).
A. Simay, K. Takács, K. Horváth and P. Dvortsák; Acta Chirn. Acad. Sci. Hung.,
1980,105, 127.
A. Albert and A. Dunand; Angew. Chern., 1980,92,319.
R. Huisgen; Angew. Chern., 1980,92,979.
D. Günther and D. Bosse; Angew. Chern., Int. Ed. Eng/., 1980, 19, 130.
G. L'abbé: Angew. Chern., Int. Ed. Engl., 1980, 19,276.
A. Albert and A. Dunand; Angew. Chern., Int. Ed. Eng/., 1980, 19,310.
W. E. Hull, M. Künstlinger and E. Breitmaier; Angew. Chern., Int. Ed. Engl.,
1980, 19,924. 822
R. Huisgen; Angew. Chern., Int. Ed. Engl., 1980,19,947. 275,809,825,841
P. Hanson; Adv. Heterocycl. Chern., 1980,27,31. 73,103
N. Lozach and M. Stavaux; Adv. Heterocycl. Chern., 1980,27,151. 63,64,65,66,
67,68,70,71,76,90, 103, 105, 114
M. R. Grimmett; Adv. Heterocycl. Chern., 1980,27,241. 53,54,62,70,71,
73, 77, 89, 96, 98, 108, 109, 114,346, 348, 350, 351, 355, 358, 359
360,361,365,367,371,378,379,384,386,387,390,391,392
393,396,397,400,401,402,404,407,412,413,414,417,419
421,422,425,431,432,436,439,440,445,450,453,454,455
446,461,462,464,465,466,467,468,473,474,475,477,478
480,481,485,486,487,488,489,490,491,493,494,496,497
A. J. Jones, P. Hanisch, M. L. Heffernan and G. M. Irvine; Aust. l. Chern., 1980,
33,499.
N. F. Borkett, M. I. Bruce and J. D. Walsh; Aust. l. Chern., 1980,33,949.
L. K. Dalton, S. Demerac and B. C. Elmes; Aust. l. Chern., 1980,33, 1365.
C. W. Fong; Aust. l. Chern., 1980,33, 1763.
J. R. Cannon, C. L. Raston and A. H. White; Aust. l. Chern., 1980,33,2337.
G. J. Gainsford and A. D. Woolhouse; AUst. l. Chern., 1980,33,2447.
A. M. G. Dias Rodrigues, Y. P. Mascarenhas and M. M. Rodrigues; Acta
Crystallogr., Part B, 1980,36, 159.
F. Iwasaki; Acta Crystallogr., Part B, 1980,36, 1466.
A. B. Kremer, W. A. Gibby, C. J. Gubler, R. F. Helfand, A. F. Kluge and H. Z.
Sable; Biochemistry, 1980, 19,3773.
M. Onishi, K. Hiraki, M. Shironita, Y. Yamaguchi and S. Nakagawa; Bull. Chern.
Soc. lpn., 1980,53,961.
T. Keumi, H. Saga and H. Kitajima; Bull. Chern. Soc. lpn., 1980,53, 1638.
A. Maquestiau, Y. Van Haverbeke and J. J. Vanden Eynde; Bull. Soc. Chirn.
Be/g., 1980, 89, 51.
H. Meier, W. Heinzelmann and H. Heimgartner; Chirnia, 1980,34,504 (Chern.
Abstr., 1981,94,155988).
W. Hartmann, K.-H. Scholz and H.-G. Heine; Chern. Ber., 1980, 113, 1884.
F. Sella and D. Hasselmann; Chern. Ber., 1980, 113,2043.
A. Schönberg, E. Singer and P. Eckert; Chern. Ber., 1980, 113,2823.
E. Öhler and E. Zbiral; Chern. Ber., 1980, 113,2852.
A. Steigel and R. Fey; Chern. Ber., 1980, It3, 3910.
K. Nakanishi, H. Komura, I. Miura and H. Kasal; 1. Chern. Soc., Chern. Cornrnun.,
1980, 82.
References
283
192,281
787
538
182,263
852
387
623
234,270
719
636
818
796
612
241
727
841
473
810
727
853,860
235
281
210,268
785
707
227
9
648
235
452
272
809
77
605
471
165
194
526, 538
80CC237
80CC339
80CC444
80CC502
80CC866
80CC866
80CC940
80CC1263
80CCC2417
80CHE1
80CHE66
80CHE169
80CHE180
80CHE418
80CHE443
80CHE628
80CHE936
80CHEl160
80CHE1190
80CJC1080
80CJC1091
80CJC1880
80CJC2624
80CL299
80CPB150
80CPB157
80CPB487
80CPB932
.80CS(15)102
80CS( 15) 193
80CSC1121
80CSC1127
80EUP11604
80EUP13914
80GEP2834879
80GEP2848670
80GEP2852067
80G E P2922591
80GEP2952685
80H(14)97
80H(14)1279
80H(14) 1313
80H(14)1725
80H(14) 1759
80H(14)1963
80HC(39) 1
80HCAI
80lC 170
80lZV2668
285
169,241, 253,256,261,
262,264, 277, 281
G. P. Tolmakov, Yu. M. Udachin, N. S. Paralakha, L. K. Denisov, A. M. Lantsov
and I. I. Grandberg; Chern. Heterocycl. Cornpd. (Eng!. Trans!.), 1980, 16,66.
N. Yu. Deeva and A. N. Kost; Chern. Heterocycl. Cornpd. (Eng!. Trans!.), 1980,
16, 1969.
K. V. Mityurina, V. G. Kharchenko and L. V. Cherkesova; Chern. Heterocycl.
Cornpd. (Eng!. Trans!.), 1980, 16, 180.
R. Paegle, I. Lulie, V. Krisane, I. Mazeika, E. Liepins and M. Lidaks; Chern.
Heterocycl. Cornpd. (Eng!. Trans!.), 1980, 16,418.
M. Tis1er and B. Stanovnik; Chern. Heterocycl. Cornpd. (Eng!. Trans!.), 1980, 16,
443.
V. A. Samsonov and L. B. Vo1odarskii; Chern. Heterocycl. Cornpd. (Eng!. Trans!.),
1980, 16,628.
L. A. Sviridova, G. A. Go1ubeva, A. V. Dovgilevich and A. N. Kost; Chern.
Heterocycl. Cornpd. (Eng!. Trans!.), 1980,16,936.
V. M. Dziomko, B. K. Berestevich, A. V. Kessenikh, R. S. Kuzanyan and L. V.
Shmelev; Chern. Heterocycl. Cornpd. (Eng!. Trans!.), 1980, 16, 1160.
V. V. Dovlatayan, V. A. Pivazyan, K. A. Eliazyan and R. G. Mirzoyan; Chern.
Heterocycl. Cornpd. (Eng!. Trans!.), 1980,16, 1190.
K. S. Chong, S. J. Rettig, A. Storr and J. Trotter; Can. J. Chern., 1980,58, 1080.
K. S. Chong, S. J. Rettig, A. Storr and J. Trotter; Can. J. Chern., 1980,58, 1091.
J. Grimshaw and A. P. DeSilva; Can. J. Chern., 1980,58, 1880.
J. G. Buchanan, A. Stobie and R. H. Wightman; Can. J. Chern., 1980,58,2624.
S. Inoue, K. Okada, H. Tanino and H. Kakoi; Chern. Lelt., 1980,299.
A. Yamane, A. Matsuda and T. Ueda; Chern. Pharrn. Bull., 1980,28, 150.
A. Yamane, H. Inoue and T. Ueda; Chern. Pharrn. Bull., 1980,28, 157.
S. Sugai and K. Tomila; Chern. Pharrn. Bull., 1980,28,487.
K. Kayasuga-Mikado, T. Hashimoto, T. Negishi, K. Negishi and H. Hayatsu;
Chern. Ph arm. Bull., 1980,28,932.
S. Liljefors and S. Gronowitz; Chern. Scr., 1980, IS, 102.
R. Faure, G. M. Assef, E. J. Vincent, N. de Kimpe, R. Verhe, L. de Bruyck and
N. Schamp; Chern. Scr., 1980,15, 193. 19,355,368
M. Sikirica and I. Vickovié; Cryst. Struct. Cornrnun., 1980,9,1121. 178,214
M. Sikirica and I. Vickovié; Cryst. Struct. Cornrnun., 1980,9, 1127. 178
L. Gsell, P. Ackermann and R. Wehrli; Eur. Pat. 11604 (1980) (Chern. Abstr.,
1981,94,65691).
W. C. Lumma; Eur. Pat. App!. 13 914 (1980) (Chern. Abstr., 1981,94,84167).
Schering AG, Ger. Pat. 2834879 (1980) (Chern. Abstr., 1980,93,71758).
Bayer AG, Ger. Pat. 2 848 670 (1980) (Chern. Abstr., 1980, 93, 96810).
Schering AG, Ger. Pat. 2 852 067 (1980) (Chern. Abstr., 1980, 93, 204664).
W. K. Aders, D. Mangold, J. Wahl and G. Rotermund; Ger. Pat. 2 922 591 (Chern.
Abstr., 1981,94, 139804).
S. D. Ziman; Ger. Pat. 2952685 (1980) (Chern. Abstr., 1981,94,84129).
M. Ogata, H. Matsumoto, S. Kida and S. Shimizu; Heterocycles, 1980, 14,97.
S. K. Talapatra, P. Chaudhuri and B. Talapatra; Heterocycles, 1980,14, 1279.
S. Witek, A. Bie1awska and J. Bielawski; Heterocycles, 1980, 14,1313.
R. Kreher and U. Bergmann; Heterocycles, 1980,14, 1725.
R. Chaurasia and S. K. Sharma; Heterocycles, 1980, 14, 1759.
A. Ohta, T. Watanabe, J. Nishiyama, K. Uehara and R. Hirate; Heterocycles,
1980,14, 1963. 393,453,495
K. T. Finley; Chern. Heterocycl. Cornpd., 1980,39, 1. 670,705,708
R. Heckendorn and T. Winkler; He!v. Chirn. Acta, 1980,63, 1. 855,873,893
J. C. Jansen, H. van Konigsveld, J. A. C. van Ooijen and J. Reedijk; lnorg.
Chern., 1980, 19, 170.
M. M. Krayushkin, A. M. Beskopyl'nyi, S. G. Zlotin, O. A. Luk'yanov and V.
M. Zhulin; lzv. Akad. Nauk SSSR., Ser. Khirn., 1980,2668 (Chern. Abstr., 1981,
94, 103 260).
References
J. G. Buchanan, A. R. Edgar, R. J. Hutchison, A. Stobie and R. H. Wightman;
J. Chern. Soc., Chern. Cornrnun., 1980,237.
R. S. Norton, R. P. Gregson and R. J. Quinn; J. Chern. Soc., Chern. Cornrnun.,
1980,339.
T. Tsuchiya, J. Kurita and H. Kojima; J. Chern. Soc., Chern. Cornrnun., 1980,444.
S. Fischer and C. Wentrup; J. Chern. Soc., Chern. Cornrnun., 1980,502.
F. Wud1 and D. Nalewajek; J. Chern. Soc., Chern. Cornrnun., 1980,866.
L.-Y. Chiang, T. O. Poehler, A. N. Bloch and D. O. Cowan; J. Chern. Soc., Chern.
Cornrnun., 1980,866.
C. Bernard and L. Ghosez; J. Chern. Soc., Chern. Cornrnun., 1980,940.
S. N. Ege, E. J. Gess, A. Thomas, P. Umrigar, G. W. Griffin, P. K. Das, A. M.
Trozzolo and T. M. Leslie; J. Chern. Soc., Chern. Cornrnun., 1980, 1263.
V. Hanus, M. Hrazdira and O. Exner; Collect. Czech. Chern. Cornrnun., 1980,45,
2417.
H. Dorn; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1980, 16, 1.
985
234
515
268
812
115
115
694, 715
252
199
257
253
649
169, 263
423,474
254
241
657
227
227
268, 322
262,
270, 328
643
561
559
15
648
238,260
787
643
732
730
718
288
787
452
707
427
473
857,903
227
831
986
80J A525
80JA770
80JAI513
80JA2093
80JA2968
80JA3971
80JA4627
80JA6159
80JA7335
80JCR(M)0514
80JCR(S)308
80JCS(P1)244
80JCS(PI)354
80JCS(PI)481
80JCS(PI )506
80JCS(PI)574
80JCS(PI)938
80JCS(PI)959
80JCS(PI)1139
80JCS(PI)1352
80JCSIPI)1427
80JCS(PI )2009
80JCS(PI)2310
80JCS(PI)2608
80JCS(PI)2728
80JCS(PI)2755
80JCS(P2)535
80JCS(P2)553
80JCS(P2) 1350
SOJHCII
80JHC97
80JHCI13
80JHC137
80JHCI87
80JHC337
80JHC381
80JHC393
80JHC46I
80JHC555
80JHC607
80JHC689
80JHC825
80JHC833
80JHC877
80JH C905
80JHCII15
80JHCI121
80JHCI127
80JHCI309
D. M. Cheng, L. S. Kan, P. O. P. Ts'o, C. Giessner-Prettre and B. Pullman; J.
Am. Chern. Soc., 1980, 102, 525.
P. D. Sattsangi, J. R. Barrio and N. J. Leonard; J. Am. Chern. Soc., 1980, 102,770.
N. Niccolai, H. K. Schnoes and W. A. Gibbons;J. Am. Chern. Soc., 1980, 102,1513.
N. H. Toubro and A. Holm; J. Am. Chern. Soc., 1980, 102,2093.
N. E. Takach, E. M. Holt, N. W. Alcock, R. A. Henry and J. H. Nelson; J. Am.
Chern. Soc., 1980, 102,2968. 818
K. T. Potts, S. Kanemasa and G. Zvilichovsky; J. Am. Chern. Soc., 1980, 102,3971. 133,230
J. Un, C. Yu, S. Peng, I. Akiyama, K. U, L. K. Lee and P. R. LeBreton; J. Am.
Chern. Soc., 1980, 102,4627.
C. Wentrup and H.-W. Winter; J. Am. Chern. Soc., 1980, 102,6159.
R. S. Rogers and H. Rapoport; J. Am. Chern. Soc., 1980, 102,7335.
J. de Mendoza, M. L. Castellanos, J. P. Fayet, M. C. Vertut and J. Elguero; J.
Chern. Res. (M), 1980,0514. 191,234,269
D. R. Buckle; J. Chern. Res. (S), 1980,308. 904
E. Cawgill and N. G. Clark; J. Chern. Soc., Perkin Trans. 1, 1980,244. 462
A. R. Katritzky, M. Michalska, R. L. Harlow and S. H. Simonsen; 1. Chern. Soc.,
Perkin Trans. 1, 1980, 354.
J. S. Bajwa and P. J. Sykes; J. Chern. Soc., Perkin Trans. 1, 1980,481.
C. R. Hardy and J. Parrick; 1. Chern. Soc., Perkin Trans. 1, 1980,506.
J. Motoyoshiya, M. Nishijima, I. Yamamoto, H. Gotoh, Y. Katsube, Y. Oshiro
and T. Agawa; J. Chern. Soc., Perkin Trans. 1, 1980, 574.
R. J. J. Dorgan, J. Parrick and C. R. Hardy; J. Chern. Soc., Perkin Trans. 1, 1980,
938.
E. E. Glover and L. W. Peck; J. Chern. Soc., Perkin Trans. 1, 1980,959.
I. Charles, D. W. S. Latham, D. Hartley, A. W. Oxford and D. I. C. Scopes;
J. Chern. Soc., Perkin Trans. 1, 1980, 1139.
J. P. Clayton, P. J. O'Hanlon and T. J. King; J. Chern. Soc., Perkin Trans. 1,
1980, 1352.
R. E. Busby, M. A. Khan, J. Parrick, C. J. G. Shaw and M. Iqbal; 1. Chern. Soc.,
Perkin Trans. 1, 1980, 1427.
A. Albert; J. Chern. Soc., Perkin Trans. 1, 1980,2009.
T. Brown, G. Shaw and G. J. Durant; J. Chern. Soc., Perkin Trans. 1, 1980,2310.
D. Griffiths, R. Hull and T. P. Seden; J. Chern. Soc., Perkin Trans. 1, 1980,2608.
K. Kadir, G. Shaw and D. Wright; J. Chern. Soc., Perkin Trans. 1, 1980,2728.
Y. Kobayashi, K. Yamamoto, T. Asai, M. Nakano and I. Kumadaki; 1. Chern.
Soc., Perkin Trans. 1, 1980,2755.
A. F. Hegarty, K. Brady and M. Mullane; J. Chern. Soc., Perkin Trans. 2, 1980,
535.
D. B. Bigley, C. L. Fetter and M. J. Clarke; J. Chern. Soc., Perkin Trans. 2,1980,
553.
U. Berg, R. Gallo, G. Klatte and J. Metzger; J. Chern. Soc., Perkin Trans. 2,1980,
1350.
J. T. Shaw, C. E. Brotherton, R. W. Moon, M. D. Winland, M. D. Anderson and
K. S. Kyler; J. HeterocycL Chern., 1980, 17, 11.
L. Citerio, E. Rivera, M. L. Saccarello, R. Stradi and B. Gioia; J. Heterocycl.
Chern., 1980,17,97.
M. T. García-López, R. Herranz and G. Alonso; J. HeterocycI. Chern., 1980, 17,
113.
G. Tarrago, A. Ramdani, J. Elguero and M. Espada; J. Heterocyc/. Chern., 1980,
17, 137. 53, 183,229
O. Subba Rao and W. Lwowski; J. Heterocyc/. Chern., 1980, 17, 187. 814
R. A. Glennon, M. E. Rogers and M. K. EI-Said; J. Heterocyc/. Chern., 1980,17,
337.
Y. C. Tong; J. Heterocycl. Chern., 1980, 17,381.
H. J. M. Dou, M. Ludwikow, P. Hassanaly, J. Kister and J. Metzger; J. Heterocycl.
Chern., 1980, 17,393.
D. L. Kern, P. D. Cook and J. C. French; J. Heterocycl. Chern., 1980,17,461.
J. Bourdais and A. M. M. E. Omar; J. Heterocycl. Chern., 1980, 17,555.
T. J. Kress and S. M. Constantino; J. Heterocycl. Chern., 1980,17,607.
B. Kovac, L. Klasinc, B. Stanovnik and M. Tisler; J. Heterocycl. Chern., 1980,
17,689.
W. A. Feld and M. P. Servé; J. Heterocycl. Chern., 1980, 17, 825.
A. S. Shawali and C. Párkányi; J. Heterocycl. Chern., 1980, 17,833.
A. S. Shawali, M. Sami, S. M. Sherif and C. Parkanyi; J. Heterocyc/. Chern., 1980,
17, 877.
B. Cross, R. L. Arotin and C. F. Ruopp; J. Heterocycl. Chern., 1980,17,905.
W. A. Feld, P. G. Seybold and M. P. Servé; J. Heterocycl. Chern., 1980,17, 1115.
I. Lalezari and S. Nabahi; J. Heterocycl. Chern., 1980,17, 1121.
C. Tsoleridis, J. Stephanidou-Stephanatou and N. E. Alexandrou; J. Heterocycl.
Chern., 1980, 17, 1127.
W. A. Feld, R. Paessun and M. P. Servé; J. Heterocycl. Chern., 1980, 17, 1309.
References
510,515
564
604
809
517
879
604
632
272
859,877
20
272
614
630, 657
852
418
727
414, 467
462
552, 585,
586
538
825
31
229
882,903
481
288
647
627
663
602
635
115
860
694
282,284
631
269
732
857,901
682, 683
694
80JHCI373
80JHCI505
8QJHCI527
80JHCI723
80JHCI757
80JHCI777
80JHCI789
80JMC357
80JMC657
80JMCI188
80JOC76
80JOCI653
80JOCI662
80JOC2320
80JOC2373
80JOC2474
80JOC3172
8010C3738
80JOC3750
80JOC3969
80JOC4038
80JOC4302
80JOC4767
80JOC5105
80JOC5130
80JOM(l88)141
80JPR711
80KGSI21
80KGS528
80KGS984
80KGSI414
80LA542
80LAI455
80M775
80MI40100
80MI40101
80MI40400
80MI40401
80MI40402
80MI40403
80MI40404
80MI40405
B-80MI40406
B-80MI40407
B-80MI40408
80MI40900
B-80MI40901
80MI40902
B-80MI40903
N. J. Curtis and R. S. Brown; J. Org. Chern., 1980,45,4038.
E. P. Ahem, K. J. Dignam and A. F. Hegarty; J. Org. Chern., 1980,45,4302.
L. Garanti and G. Zecchi; J. Org. Chern., 1980,45,4767.
L. A. Paquette and R. F. Doehner; J. Org. Chern., 1980,45,5105.
O. Tsuge, S. Vrano and K. Oe; J. Org. Chern., 1980,45,5130.
J. P. Gasparini, R. Gassend, J. C. Maire and J. Elguero; J. Organornet. Chern.,
1980, 188, 141.
G. Tacconi, A. Gamba Invemizzi, P. P. Righetti and G. Desimoni; J. Prakt.
Chern., 1980, 322, 711.
Y. M. Yutilov, A. G. Ignatenko and O. G. Eilazyan; Khirn. Geterotsikl. Soedin.,
1980, 121 (Chern. Abstr., 1980,92,215357).
V. A. Anisimova, N.1. Avdyunina, A. F. Pozharskii, A. M. Simonov and L. N.
Talanova; Khirn. Geterotsikl. Soedin., 1980, 528 (Chern. Abstr., 1980,93, 149
290).
Y. B. Vysotskii and B. P. Zemskii; Khirn. Geterotsikl. Soedin., 1980,984.
Zh. N. Fidler, E. F. Shibanova, P. V. Makerov, I. D. Kalikhman, A. M. Shulunova,
G. 1. Sarapulova, L. V. Klyba, V. Yu. Vitkovskii, N. N. Chipanina, V. A.
Lopyrev and M. G. Voronkov; Khirn. Geterotsikl. Soedin., 1980, 1414.
S. Linke, J. Kurz, D. Lipinski and W. Gau; Liebigs Ann. Chern., 1980,542.
W. Schörkhuber and E. Zbiral; Liebigs Ann. Chern., 1980, 1455.
J. Elguero, A. Fruchier and A. Könnecke; Monatsh. Chern., 1980, Ill, 775.
P. Ruoff, J. Almlö and S. Saeboe; Chern. Phys. Leu., 1980,72,489.
J. B. Collins and A. J. Streitwieser, Jr.; Cornput. Chern., 1980,1,81.
J. C. Berger and L. C. Iorio; Annu. Rep. Med. Chern., 1980, 15,26.
R. H. P. Francisco, J. R. Lechat, A. C. Massabni, C. B. Melios and M. Molina;
J. Coord. Chern., 1980, 10, 149. 179,227
F. Bonati; Chirn. Ind. (Rorna), 1980,62,323. 169,225,236
J. Terheijden, W. L. Driessen and W. L. Groeneveld; Transition Met. Chern.,
1980, 5, 346.
V. Wrzeciono and E. Linkowska, Pharrnazie, 1980, 35, 593.
T. Inaba, M. Lucassen and W. Kalov; Life Sci., 1980,26, 1977.
'Burger's Medicinal Chemistry', Wiley, New York, 4th edn., 1980.
226
270
301
291,292,293,295,
296, 30 I, 302, 303
L. S. Goodman and A. Gilman, 'The Pharmacological Basis of Therapeutics',
Macmillan, New York, 1980.
P. E. Cassidy; 'Thermally Stable Polymers', Dekker, New York, 1980.
J. B. Lambert, J. F. Marwood, L. P. Davies and K. M. Taylor; Life Sci., 1980,
26, 1069.
G. Shaw; in 'Rodd's Chemistry of Carbon Compounds', ed. S. Coffey; Elsevier,
1980, vol. IV(L), p. I.
G. Shaw; Annu. Rep. Prog. Chern. (B), 1980,299.
G. P. Ellis and R. K. Smalley; in 'Heterocyclic Chemistry', Royal Society of
Chemistry, London, 1980, p. 308.
References
H. Lumbroso, J. Curé and R. N. Butler; J. Heterocycl. Chern., 1980,17, 1373.
A. Kreutzberger and J. Stralmann; J. Heterocycl. Chern., 1980, 17, 1505.
S. Sunder and N. P. Peet; J. Heterocycl. Chern., 1980, 17, 1527.
A. C. Veron ese, G. Cavicchioni, G. Servadio and G. Vecchiati; J. Heterocycl.
Chern., 1980, 17, 1723.
R. W. Middleton and D. G. Wibberley; J. Heterocycl. Chern., 1980,17, 1757.
T. Nakano, W. Rodriguez, S. Z. de Roche, J. M. Larrauri, C. Rivas and C. Pérez;
J. Heterocycl. Chern., 1980,17, 1777.
P. Reynaud, J. D. Brion, C. Davrinche and P.-C. Dao; J. Heterocycl. Chern.,
1980, 17, 1789.
J. R. Piper, A. G. Laseter and J. A. Montgomery; 1. Med. Chern., 1980,23,357.
M. T. García-López, M. J. Domínguez, R. Herranz, R. M. Sánchez, A. Contreras
and G. Alonso; J. Med. Chern., 1980,23,657.
D. L. Temple, Jr., J. P. Yevich,J. D. Catt, D. Owens,C. Hanning, R. R.Covington,
R.J. Seidehamel and K. W. Dungan; J. Med. Chern., 1980,23,1188.
J. F. Hansen, Y. 1. Kim, L. J. Griswold, G. W. Hoelle, D. L. Taylor and D. E.
Vietti; J. Org. Chern., 1980,45,76.
A. J. Boulton, T. Kan-Woon, S. N. Balasubrahmayam, 1. M. Malick and A. S.
Radhakrishna; J. Org. Chern., 1980,45, 1653.
G. H. Denny, E. J. Cragoe, Jr, C. S. Rooney, J. P. Springer, J. M. Hirshfield and
J. A. McCauley; J. Org. Chern., 1980,45, 1662.
D. H. Bown and J. S. Bradshaw; J. Org. Chern., 1980,45,2320.
M. F. Zady and J. L. Wong; J. Org. Chern., 1980,45,2373.
K. T. Potts, R. Ehlinger and S. Kanemasa; J. Org. Chern., 1980,45,2474.
W. C. Guida and D. J. Malhre; J. Org. Chern., 1980,45,3172.
E. S. Hand and W. W. Paudler; J. Org. Chern., 1980,45,3738.
Y. Lin, S. A. Lang, Jr. and S. R. Petty; J. Org. Chern., 1980,45,3750.
V. Nair and S. G. Richardson; J. Org. Chern., 1980,45,3969.
987
795, 804
728
281
475
617,620,
.635, 636
421
471
531
289
647
270
288
815
870
545
133, 151,663
230, 387
611
14
511,514,553,
593, 594, 598
388, 416
825
902
737
832
232
330
623
612
858,859
740
633
716
186, 798
9
7
292,293
295
300,301
601
501,504
504
501
988
BOMI40904
80MI40905
80M 140906
80MI40907
80MI41000
80MI41100
80MI41101
B-80M141102
B-80M141103
80MI41200
80MI41300
B-80M141301
80MI41500
80MIP41100
80MIP41500
800MR(l3)197
800MR( 13)274
800MR(l4)129
800MSI44
800MSI72
800MS533
800PP234
80P2239
80RCR28
80RCR880
80RTC20
80RTC267
80S842
80T! 079
80T2359
80T2505
80T3523
80TH40 1 00
80TH40400
80TL567
80TLI417
80TL2195
80TL3203
80TL3723
80TL4339
80TL4387
80TL4529
80TL473I
80ZCI67
80ZC263
80ZC413
80ZC437
80ZN(A)1387
80Z0B875
S. Yananaka and T. Utagawa; Hakko to Kogyo, 1980,38,920.
F. A. Fuhrman, G. J. Fuhrman, Y. H. Kim, L. A. Pavelka and H. J. Mosher;
Science, 1980,207, 193.
P. G. Mezey, J. J. Ladik and M. Barry; Theor. Chirn. Acta, 1980,54,251.
M. Rufalska and G. Wenska; Wiad. Chern., 1980,34,9.
M. V. Povstyanoi, V. P. Kruglenko and M. A. Klykov; Fizio/. Akt. Veshchestva,
1980, 12,56 (Chern. Abstr., 1980,95,43047).
U. Saha, A. Das, S. Chakraborty, M. Gosh and D. K. Roy; J. Inst. Chern. (India),
1980,52, 196 (Chern. Abstr., 1981,94, 139681).
L. Birkofer and O. Stuhl; Top. Curro Chern., 1980,88,33.
H. Suschitzky and O. Meth-Cohn; 'Heterocyclic Chemistry', The Royal Society
of Chemistry, London, 1980, vol. I, p. 220.
H. Wamhoff; in 'Lectures in Heterocyclic Chemistry', ed. R. N. Castle and S.
W. Schneller; Heterocorporation, Orem/Utah, 1980, vol. V, p. S-61.
C. B. Donker, J. G. Haasnoot and W. L. Groeneveld; Transition Met. Chern.,
1980, 5, 368.
Nguyen Dinh Trieu, Ha Thi Diep, Luong Thu Huong and Le Thi Thanh Vinh;
Tap Chi Hoa Hoc, 1980, 18,22 (Chern. Abstr., 1981,94, 121415).
H. Singh, A. S. Chawla, V. K. Kapoor, D. Paul and R. K. Malhotra; 'Progress
in Medicinal Chemistry', ed. G. P. Ellis and G. B. West; Eisevier/North-
Holland, Biomedical Press, 1980, vol. 17, p. 151. 834,835,836
D. J. Cash and A. N. Ferguson; J. Photographr. Sci., 1980,28, 121. 904
Hoechst Aktiengesellschaft, Swiss Pat. 615 164 (1980) (Chern. Abstr., 1980,93,
73 786).
ICI Ltd., Isr. Pat. 51 570 (1980) (Chern. Abstr., 1981,94, 11549).
T. Axenrod, P. Mangiaracina, C. M. Watnick, M. J. Wieder and S. Bulusu; Org.
Magn. Reson., 1980,13, 197. 196,197,290
L. Stefanik, M. Witanowski and G. A. Webb; Org. Magn. Reson., 1980, 13, 274. 20
G. C. Levy, T. Pekh and P. R. Srinivasan; Org. Magn. Reson., 1980, 14,129. 211
A. Maquestiau, Y. Van Haverbeke, H. Mispreuve, R. Flammang, J. A. Harris,
\. Howe and J. H. Beynon; Org. Mass Spectrorn., 1980, 15, 144.
I. Simiti, H. Demian, A. M. N. Palibroda and N. Palibroda; Org. Mass Spectrorn.,
1980, 15, 172.
A. Atmani, J. L. Aubagnac and V. Pellegrin; Org. Mass Spectrorn., 1980,15,533.
J. Lee, A. Guthrie and M. M. Joullie: Org. Prep. Proced. Int.. 1980, 12, 234.
S. Matsubara; Phytochemistry, 1980, 19,2239.
V. G. Yashunskii and L. E. Kholodov; Russ. Chern. Rev. (Engl. Trans/.), 1980,
49,28.
V. A. Galishev, U. N. Chistoklevtov and A. A. Petrov: Russ. Chern. Rev. (Eng/.
Trans/.), 1980,49,880.
M. J. Wanner, E. M. van Wijk, G. J. Koomen and U. K. Pandit: RecI. Trav.
Chirn. Pay-Bas, 1980,99,20.
N. J. Kos, H. C. van der PI as and A. van Veldhuizen; Recl. Trav. Chirn. Pays-Bas,
1980, 99, 267.
S. Mataka, K. Takahashi, M. Tashiro and Y. Tsuda: Synthesis, 1980,842.
K. Kiec-Kononowicz, A. Zejc, M. Mikolajczyk, A. Zatorski, J. Karolak-
Wojciechowska and M. W. Wieczorek; Tetrahedron, 1980,36, 1079.
P. Caluwe; Tetrahedron, 1980,36,2359.
J. Bergman, L. Renström and B. Sjöberg; Tetrahedron, 1980,36,2505.
P. Bouchet, R. Lazaro, M. Benchidmi and J. Elguero; Tetrahedron, 1980,36,3523.
J. Llinares; Ph.D. Thesis, University of Marseilles, 1980.
J. Llinares; Ph. D. Thesis, University of Marseille, 1980.
R. J. Quinn, R. P. Gregson, A. F. Cook and R. T. Bartlett; Tetrahedron Left.,
1980, 21, 567.
P. Schiess and H. Stalder; Tetrahedron Left., 1980, 1417.
P. Blatcher and D. Middlemiss; Tetrahedron Left., 1974,21,2195.
T. Ogita, N. Otake, Y. Miyazaki, H. Yonehara, R. D. MacFarlane and C. J.
McNeal: Tetrahedron Left., 1980,21,3203.
S. P. J. M. van Nispen, C. Mensink and A. M. van Leusen: Tetrahedron Left.,
1980, 3723.
J. Engels; Tetrahedron Left., 1980,21,4339.
H. J. Chaves das Neves and M. S. S. Pais: Tetrahedron Left., 1980,21,4387.
G. Jones and D. R. Sliskovic; Tetrahedron Left., 1980,4529.
K. K. Balasubramanian, G. V. Bindumadhavan, M. R. Udupa and B. Krebs:
Tetrahedron Left., 1980,21,4731.
B. V. loffe: Z. Chern., 1980,20, 167.
H. Matschiner and H. Tanneberg; Z. Chern., 1980,20,263.
R. Evers, E. Fischer and M. Pulkenat: Z. Chern., 1980,20,413.
G. Weber, G. Mann, H. Wilde and S. Hauptmann; Z. Chern., 1980,20,437.
D. W. Engelfriet, W. L. Groeneveld and G. M. Nap; Z. Naturforsch., Tei! A,
1980,35, 1387.
V. D. Sheludyakov, S. V. Sheludyakova, M. G. Kutnetsova, N. N. Silkina and
V. F. Mironov: Zh. Obschch. Khirn., 1980,50,875.
References
504
601,602
512
504
653
709, 729
699
670
704,712
790
832
730
904
203
741
203
620
602
19
768, 784
566
542
117
663
272
414
245, 266
20
195
602
249
615
602
477
786
602
904
657
255
419
126
720
790
236,271
80Z0R730
80Z0RI313
80Z0R2185
80Z0R2623
8IACS(A)733
8 I ACS(A)739
8 I ACS(A)747
8IACS(A)767
81AF2096
81AG118
8IAG(E)113
81 AG(E)296
81AG(E)771
81AG(E)885
8IAHC(28)1
81 AHC(28)231
81AHC(28)232
81AHC(28)309
8IAHC(29)71
81AHC(29)141
81AJC691
81AJC1361
81AP532
81AX(A)C-63
81 AX(B) 1584
81 BCJ217
81 BCJ1579
81 BCJ2779
81BCJ3221
81BSB193
81 BSB645
81C59
81CBI546
81CBI624
81CB2450
81CB2649
81CB3165
81CB3456
81 CC604
81CC1089
81CC1095
81CC1207
81CHE375
81CHE622
81CHE838
81 CI(L)648
81 CJC2556
81CL331
81CLl519
81CPB426
81CPB597
81CPB1870
I. Søtofte and K. Nielsen; Acta Chern. Scand., Ser. A, 1981,35,733.
I. Søtofte and K. Nielsen; Acta Chern. Scand., Ser. A, 1981,35,739.
I. Søtofte and K. Nielsen; Acta Chern. Scand., Ser. A., 1981,35,747.
U. Anthony, G. Borch, P. Klaeboe, K. Lerstrup and P. H. Nielsen; Acta Chern.
Scand., Ser. A., 1981,35,767.
K. Credner, M. Tauscher, L. Jozic and G. Brenner; Arzneirn.-Forsch., 1981,31,
209 I
D. Danian, B. Arnold and M. Regitz; Angew. Chern., 1981,93, 118. 716
D. Danion, B. Arnold and M. Regitz; Angew. Chern., Int. Ed. Engl., 1981,20,113. 165,716
R. Gompper and U. Heinemann; Angew. Chern., Int. Ed. Engl., 1981,20,296. 468
U. Schmidt and M. Dietsche; Angew. Chern., Int. Ed. Engl., 1981,20,771. 823
C. N. Rentzea; Angew. Chern., Int. Ed. Engl., 1981,20,885. 786
R. D. Chambers and C. R. Sargent; Adv. Heterocycl. Chern., 1981,28, I. 282
C. Wentrup; Adv. Heterocycl. Chern., 1981,28,231. 44,45,87,91,96,
98, 107, 108, 109, 110
246,263,287
163
55
158,719
731
651
References
L. I. Vereshchagin, L. G. Tikhonova, A. V. Maksihova, E. S. Serebryakova, A.
G. Proidakov and T. M. Filippova; Zh. Org. Khirn., 1980,16,730.
A. M. Belousov, G. A. Gareev, Yu. M. Belousov, N. A. Cherkashina and l. G.
Kaufman; Zh. Org. Khirn., 1980, 16, 1313 (Chern. Abstr., 1980, 93, 239321).
YU. A. Sharanin; Zh. Org. Khirn., 1980, 16,2185.
A. F. Shivanyuk, M. O. Lozinskii; Zh. Org. Khirn., 1980,16,2623 (Chern. Abstr.,
1981,94,156837).
C. Wentrup; Adv. Heterocycl. Chern., 1981,28,232.
C. Wentrup; Adv. Heterocycl. Chern., 1981,28,309.
Y. Tamura and M. Ikeda; Adv. Heterocycl. Chern., 1981,29,71.
M. Rueda, N. Vivona and D. Spinelli; Adv. HeterocycI. Chern., 1981,29, 141.
N. A. Evans; Aust. l. Chern., 1981,34,691.
G. B. Barlin, Aust. l. Chern., 1981,34, 1361.
K. A. Kovar, W. Rohlfes and H. Auterhof; Arch. Pharrn. (Weinheirn, Ger.), 1981,
314, 532.
M. R. Taylor and J. A. Westphalen; Acta Crystallogr., Part A, 1981,37, C-63.
B. M. Craven and P. Bend; Acta Crystallogr., Part B, 1981,37, 1584.
T. Shimizu, Y. Hayashi, K. Yamada, T. Nishio and K. Teramura; Bull. Chern.
Soc. lpn, 1981,54,217.
T. Keumi, T. Yamamoto, H. Saga and H. Kitajima; Bull. Chern. Soc. lpn., 1981,
54, 1579.
Y. Nomura, Y. Takeuchi, S. Tomoda and M. M. Ita; Bull. Chern. Soc. lpn., 1981,
54, 2779.
S. R. F. Kagaruki, T. Kitazume and N. Ishikawa; Bull. Chern. Soc. lpn., 1981,
54, 3221.
J. Plenkiewicz and T. Zdrojewski; Bull. Soc. Chirn. Belg., 1981,90, 193 (Chern.
Abstr., 1981, 95, 62089).
A. J. Boulton; Bull. Soc. Chirn. Belg., 1981,90,645.
J. Rabinowitz and A. Hampaï; Chirnia, 1981,35,59.
E. V. Dehmlow and Naser-ud-Din; Chern. Ber., 1981,114, 1546.
E. Cuny, F. W. Lichtenthaler and U. Jahn; Chern. Ber., 1980,114, 1624.
H. Gotthardt and F. Reiter; Chern. Ber., 1981, 114,2450.
R. Appel and E. Hiester; Chern. Ber., 1981, 114,2649.
W. Schörkhuber and E. Zbiral; Chern. Ber., 1981, 114, 3165.
R. W. Saa1frank and E. Ackermann; Chern. Ber., 1981, 114,3456.
J. A. Barltrop, A. C. Day, A. G. Mack, A. Shahrisa and S. Wakamatsu; l. Chern.
Soc., Chern. Cornrnun., 1981,604.
A. Albini, G. F. Bettinetti, G. Minoli and G. Vasconi; l. Chern. Soc., Chern.
Cornrnun., 1981, 1089.
B. Iddon and B. L. Lim; l. Chern. Soc., Chern. Cornrnun., 1981, 1095.
J. E1guero, A. Fruchier and V. Pellegrin; l. Chern. Soc., Chern. Cornrnun., 1981,
1207.
R. E. Valter, E. A. Baumanis, L. K. Stradynya and E. E. Liepin'sh; Chern.
Heterocycl. Cornpd. (Engl. Transl.), 1981, 17,375.
M. V. Povstyanoi, M. A. Klykov and N. A. Klyuev; Chern. Heterocycl. Cornpd.
(Engl. Transl.), 1981, 17,622.
V. V. Dov1atyan, V. A. Pivazyan, K. A. Eliazyan, R. G. Mirzoyan and S. M.
Saakyan; Chern. Heterocycl. Cornpd. (Engl. Transl.), 1981, 17, 838.
J. S. Davidson and K. Karunaratne; Chern. Ind. (London), 1981,648.
M. O. Chang and R. J. Crawford; Can. l. Chern., 1981,59,2556.
A. Albini, G. F. Bettinetti and G. MinoH; Chern. Leu., 1981, 331.
M. M. Ito, Y. Nomura, Y. Takeuchi and S. Tomoda; Chern. Leu., 1981, 1519.
M. Sugiura, K. Kato, T. Adachi, Y. Ita, K. Hirano and S. Sawaki; Chern. Pharrn.
Bull., 1981,29,426.
K. Fukukawa, T. Ueda and T. Hirano; Chern. Pharrn. Bull., 1981,29,597.
K. Omura, R. Marumoto and Y. Furukawa; Chern. Pharrn. Bull., 1981,29,1870.
989
852
815
119
824
675
676, 677
676
201
194,237
509
508
342
451
725
214
815
269
303, 786
711
273
286
728
716
717
489
723
416
181,191
215
656
657
770
255
246
726
598
602, 603
590, 664
990
81CPB2403
81CPB3214
81CPB3760
81CZI94
81EUP21076
81EUP31302
81FES315
81FESI019
81FESI037
81GEP2926280
81GEP2936951
81 H(I 5)265
81 H( I 5)943
81 H(l6)909
81HC(37)1
81 HC(37)289
81HCA662
81 HCA769
811C1519
81 Iel 545
81ICI553
8IIJC(B)10
81JA6977
8IJA7660
8IJA7743
8IJAP8161384
8IJAP(K)81108882
8IJAP(K)81122884
8IJCR(S)174
8IJCR(S)364
8lJCS(P1)78
8IJCS(PI )360
8lJCS(PI)390
8lJCS(PI)403
8IJCS(P1)503
8IJCS(PI)697
8IJCS(PI)1424
8IJCS(PI)1891
8IJCS(PI)2344
8IJCS(P1)2374
8IJCS(PI)2387
8IJCS(PI)2499
8IJCS(PI)2991
81 JeS( P 1 )2997
8IJCS(P2)310
8lJCS( P2)317
8lJCS(P2)403
References
M. Ishino, T. Sakaguchi, I. Morimoto and T. Okitsu; Chern. Ph arm. Bull., 1981,
29, 2403.
T. Kurihara, T. Tani, K. Nasu, M. Inoue and T. Ishida: Chern. Pharm. Bull.,
1981,29,3214.
K. Hirota, Y. Kitade, K. Shimada and S. Senda; Chern. Pharm. Bull., 1981,29,
3760.
D. Moderhack; Chem.-Ztg., 1981,105, 194 (Chern. Abstr., 1981,95, 132767).
B. Zeeh, E. Buschmann and J. Jung; Eur. Pat. 21076 (1981) (Chern. Abstr., 1981,
94, 151896).
CIBA-Geigy AG, Eur. Pat. Appl. 31 302 (1981) (Chern. Abstr., 1981,95, 187267).
G. A. Bistochi, G. De Meo, M. Pedini, A. Ricci, H. Brouilhet, S. Bucherie, M.
Rabaud and P. Jacquignon; Farmaco Ed. Sci., 1981,36,315.
P. Giori, D. Mazzotta, G. Vertuani, M. Guarneri, D. Pancaldi and A. Brunelli:
Farmaco Ed. Sci., 1981,36, 1019.
G. Picciola, F. Ravenna, G. Carenini, P. Gentili and M. Riva; Farmaco Ed. Sci.,
1981,36, 1037.
B. Zeeh, N. Goetz, E. Ammermann and E. H. Pommer: Ger. Pat. 2926280,
(1981) (Chern. Abstr., 1981,94, 192 348). 787
Schering AG, Ger. Pat. 293695 I (1981) (Chern. Abstr., 1982, 96, 52 509). 732
T. Kurihara, T. Tani and K. Nasu; Heterocycles, 1981, 15,265. 285
I. Saji, K. Tamoto, H. Yamazaki and H. Agui; Heterocycles, 1981, 15,943. 377
T. Fujii, T. Saito and I. Inoue: Heterocycles, 1981, 16,909. 586
C. Temple, Jr.; Chern. Heterocycl. Compd., 1981,37, I. 734,735,743,
747,748,749,750,751,754,760,762,771,772,773,775,776, 777, 778, 780,
781, 782, 784, 785, 787, 788
58
730
179
227
514
178
286
820
787
731
293
242
293
C. Temple, Jr.; Chern. Heterocycl. Compd., 1981,37,289.
A. E. Siegrist: Helv. Chim. Acta, 1981,64,662.
G. Rihs, H. Fuhrer and A. Marxer; Helv. Chim. Acta, 1981.64,769.
W. C. Deese, D. A. Johnson and A. W. Cordes: Inorg. Chern., 1981,20, 1519.
G. E. Bushnell, K. R. Dixon, D. T. Eadie and S. R. Stobart; Inorg. Chern., 1981,
20, 1545.
C. W. Eigenbrot and K. N. Raymond: Inorg. Chern., 1981,20, 1553.
P. S. Ram, P. S. N. Reddy and V. R. Srinivasan: Indian J. Chern., Sect. B, 1980,
20,10.
C. F. Wichmann, W. P. Niemczura, H. K. Schoes, S. Hall, P. B. Reichardt and
S. D. Darling; J. Am. Chern. Soc., 1981,103,6977.
E. C. Taylor, H. M. L. Davies, R. J. Clemens, H. Yanagisawa and N. F. Haley;
J. Am. Chern. Soc., 1981,103,7660.
E. C. Taylor, N. F. Haley and R. J. Clemens: J. Am. Chern. Soc., 1981,103,7743.
Jpn. Pat. 8161384 (1981) (Chern. Abstr., 1981,95, 115576).
Nippon Kasei Kogyo K. K., Jpn. Kokai Tokkyo Koko 81 108882 (1981) (Chern.
Abstr., 1982, 96, 56 298).
Tatsuta Electric Wire and Cable Co., Ltd., Jpn. Kokai Tokkyo Koko 81 122884
(1981) (Chern. Abstr.. 1982,96,56656).
R. N. Butler, V. C. Garvin and T. M. McEvoy; J. Chern. Res. (S), 1981, 174.
J. Elguero, C. Estopá and D. Ilavský; J. Chern. Res. (S), 1981,364.
G. Jones, D. R. Sliskovic, B. Foster, J. Rogers, A. K. Smith, M. Y. Wong and
A. C. Yarham; J. Chern. Soc., Perkin Trans. 1,1981,78.
S. H. Askari, S. F. Moss and D. R. Taylor: J. Chern. Soc., Perkin Trans. I, 1981,
360.
R. N. Butler and V. C. Garvin; J. Chern. Soc., Perkin Trans. 1,1981,390.
227
227
864
604
281
148
665
730
730
818,834
107,268
866,867
17
793, 799, 804,
805
459
701
J. de Mendoza, C. Millan and P. Rull; J. Chern. Soc., Perkin Trans. 1,1981,403.
M. Begtrup and J. Holm; J. Chern. Soc., Perkin Trans. I. 1981,503.
M. T. Ayoub, M. Y. Shandala, G. M. G. Bashi and A. Pelter; J. Chern. Soc..
Perkin Trans. I, 1981,697.
G. U. Baig and M. F. G. Stevens: J. Chern. Soc., Perkin Trans. I, 1981, 1424.
J. BarIuenga, J. F. López-Ortiz, M. Tomás and V. Gotor; J. Chern. Soc., Perkin
Trans. I, 1981, 1891.
A. Albert; J. Chern. Soc., Perkin Trans. I, 1981,2344.
J. G. Buchanan, A. Stobie and R. H. Wightman; J. Chern. Soc., Perkin Trans. I,
1981, 2374. 303, 325
G. A. Bhat and L. B. Townsend; J. Chern. Soc., Perkin Trans. I, 1981,2387. 310,313,
315, 325, 343
M. Yokoyama, K. Motozawa, E. Kawamura and T. Imamoto; J. Chern. Soc.,
Perkin Trans. I, 1981,2499.
A. M. Damas, R. O. Gould, M. M. Harding, R. M. Paton, J. F. Ross and J.
Crosby; J. Chern. Soc., Perkin Trans. 1, 1981. 2991.
Z. T. Fomum, S. R. Landor, P. D. Landor and G. W. P. Mpango: J. Chern. Soc.,
Perkin Trans. I, 1981,2997.
A. R. Butler and I. Hussain: J. Chern. Soc., Perkin Trans. 2, 1981,310.
A. R. Butler and I. Hussain: J. Chem Soc., Perkin Trans. 2, 1981,317.
B. Eliasson and U. Edlund; 1. Chern. Soc., Perkin Trans. 2, 1981; 403.
194
656
274
894
428
9
281
355, 482
354,355,471
190
8IJCS(P2)414
8IJHC9
8IJHC117
8IJHC163
8IJHC271
8IJHC333
8IJHC559
81JHC723
8IJHC893
8IJHC921
8IJHC957
8IJHC1073
8IJHC1149
8IJHC1189
8IJHC1319
8IJHC1353
8IJHC1523
81JMC592
8IJMC610
8IJMC735
81JMC830
8IJMC947
8IJMCI521
8IJOC608
8IJOC679
8IJOC843
8IJOC856
8IJOC1781
8IJOC1800
8IJOC2138
8IJOC2203
8IJOC2467
8IJOC2490
8IJOC2706
8IJOC2819
8IJOC2824
81JOC2872
8IJOC3026
8IJOC3123
8IJOC3681
8IJOC4065
8IJOC4717
81JOM(205)147
8IJOM(205)247
8IJOM(208)309
8IJOM(215)131
8IJOM(215)157
8IJOM(215)349
8IJPR188
81JPR279
8IJPS425
81KGS403
81 KGS599
References
Y. Kondo, T. Yamada and'S. Kusabayashi; J. Chern. Soc., Perkin Trans. 2,1981,
414.
M. A. Khan and A. A. A. Pinto; J. Heterocycl. Chern., 1981,18,9.
J. C. Sircar, T. Capiris and S. J. Kesten; J. Heterocycl. Chern., 1981,18,117.
T. Kurihara, K. Nasu, F. Ishimori and T. Tani; J. Heterocycl. Chern., 1981,18,163.
O. Migliara and V. Sprio; J. Heterocycl. Chern., 1981, 18,271.
S. Plescia, G. Daidone, J. Fabra and V. Sprio; J. Heterocycl. Chern., 1981,18,333.
R. P. M. Berbee and C. L. Habraken; J. Heterocycl. Chern., 1981,18,559.
V. Frenna, N. Vivona, D. Spinelli and G. Consiglio; J. Heterocycl. Chern., 1981,
18, 723.
M. Legraverend, E. Bisagni and J.-M. Lhoste; J. Heterocycl. Chern., 1981, 18, 893.
M. L. Malnati, R. Stradi and E. Rivera; J. Heterocycl. Chern., 1981, 18,921.
G. Adembri, A. Camparini, F. Ponticelli and P. Tedeschi; J. Heterocycl. Chern.,
1981, 18,957.
S. Mataka, K. Takahashi and M. Tashiro; J. Heterocycl. Chern., 1981,18,1073.
P. L. Anderson, J. P. Hasak, A. D. Kahle, N. A. Paolella and M. J. Shapiro; J.
Heterocycl. Chern., 1981, 18, 1149.
S. 01ivella and J. Vi1arrasa; J. Heterocycl. Chern., 1981, 18, 1189.
991
444
183,228,238
342
272, 320
321
340
270
720
889
354, 361
269
320
308
171,172,173,176,
177,208
273
898,899
889
J. C. Lancelot, D. Maume and M. Robba; J. Heterocycl. Chern., 1981, 18, 1319.
T. Sasaki and E. Ito; J. Heterocycl. Chern., 1981, 18, 1353.
R. D. Thompson and R. N. Castle; J. Heterocycl. Chern., 1981, 18, 1523.
J. D. Albright, D. B. Moran, W. B. Wright, Jr., J. B. Collins, B. Beer, A. S. Lippa
and E. N. Greenblatt; J. Med. Chern., 1981,24,592.
K. Senga, T. Novinson, H. R. Wilson and R. K. Robins; J. Med. Chern., 1981,
24,610.
J. C. Sircar, T. Capiris, S. J. Kesten and D. J. Herzig; J. Med. Chern., 1981,24,
735.
J. G. Lombardino and l. G. Otterness; J. Med. Chern., 1981,24,830.
R. T. Bartlett, A. F. Cook, M. J. Holman, W. W. McComas, E. F. Nowaswait,
M. S. Poonian, J. A. Baird-Lambert, B. A. Baldo and J. F. Marwood; J. Med.
Chern., 1981,24,947.
J. R. Shroff, V. Bandurco, R. Desai, S. Kobrin and P. Cervoni; J. Med. Chern.,
1981,24, 1521. 233
C. Gönczi, Z. Swistun and H. C. van der P1as; J. Org. Chern., 1981,46,608. 476
C. D. Bedford, E. M. Bruckmann and P. A. S. Smith; J. Org. Chern., 1981,46,679. 727
A. Messmer and G. Hajós; J. Org. Chern., 1981, 46, 843. 879,900,902
K. M. Baines, T. W. Rourke and K. Vaughan; J. Org. Chern., 1981,46,856. 696,707
J. P. Dickens, R. L. Dyer, B. J. Hamill, T. A. Harrow, R. H. Bible, Jr., P. M.
Finnegan, K. Henrick and P. G. Owston; J. Org. Chern., 1981,46,1781.
T. Sasaki, S. Eguchi, M. Yamaguchi and T. Esaki; J. Org. Chern., 1981,46,1800.
A. Counotte-Potman, H. C. van der P1as and B. van Veldhuizen; J. Org. Chern.,
1981,46,2138.
A. Chin, M. H. Hung and L. M. Stock; J. Org. Chern., 1981,46,2203.
S.-F. Chen and R. P. Panzica; J. Org. Chern., 1981,46,2467.
S. Knapp, B. H. Toby, M. Sebastian, K. Krogh-Jespersen and J. A. Potenza; J.
Org. Chern., 1981,46,2490.
G. A. 0lah, S. C. Narang and A. P. Fung; J. Org. Chern., 1981,46,2706.
E. K. Ryu and M. MacCoss; J. Org. Chern., 1981,46,2819.
G. Neef, U. Eder and G. Sauer; 1. Org. Chern., 1981,46,2824.
D. Roux; J. Org. Chern., 1981,46,2872.
A. Nudelman, T. E. Haran and Z. Shakked; 1. Org. Chern., 1981, 46, 3026.
Y.-i. Lin and S.. A. Lang, Jr.; J. Org. Chern., 1981, 46, 3123.
J. B. Holtwick and N.J. Leonard; J. Org. Chern., 1981,46,3681.
K. T. Potts, R. D. Cody and R. J. Dennis; J. Org. Chern., 1981,46,4065.
C. Rav-Acha and L. A. Cohen; J. Org. Chern., 1981,46,4717.
W. Weber and K. Niedenzu; J. Organornet. Chern., 1981,205, 147.
R. Usón, L. A. Oro, M. A. Ciriano, M. T. Pinillos, A. Tiripicchio and M.
Tiripicchio-Camellini; J. Organornet. Chern., 1981,205,247.
J. P. Gasparini, R. Gassend, J. C. Maire and J. Elguero; J. Organornet. Chern.,
1981,208,309.
H. C. Clark and M. A. Mesubi; J. Organornet. Chern., 1981,215, 131.
D. Boyer, R. Gassend, J. C. Maire and J. E1guero; J. Organornet. Chern., 1981,
215, 157.
D. Boyer, R. Gassend, J. C. Maire and J. E1guero; J. Organornet. Chern., 1981,
215, 349.
D. Zeigan, E. Kleinpeter, H. Wilde and G. Mann; J. Prakt. Chern., 1981,323,188.
A. Preiss, W. Walek and F. Dietzel; J. Prakt. Chern., 1981,323,279.
Z. Neiman and F. R. Quinn; J. Pharrn. Sci., 1981,70,425.
K. V. Mityurina, V. G. Kharchenko and L. V. Cherkesova; Khirn. Geterotsikl.
Soedin., 1981,403 (Chern. Abstr., 1981,95,24909).
V. A. Ostrovskii, G. l. Koldobskii, N. P. Shirokova and V. S. Poplavaskii; Khirn.
Geterotsikl. Soedin., 1981,599 (Chern. Abstr., 1981,95,42119).
904
331
342
342
664
396,401
711
794
546
52
257
270
540
471
463
665
885,886
59
128
431,438
235
227
271
235
213,236
232,271
214
19
524
321
873
992
81 KGS694
81KGS1423
81KGSI554
81LA7
81 LA2309
81MI05
81M245
81M675
81 M875
81MI40100
81MI40400
81MI40401
81MI40402
81 M 140403
81MI40404
81MI40405
81 MI40406
B-81M140407
81MI40900
81MI41100
81MI41101
B-81M141400
81 MI41500
81MIP41100
810MR(l5)219
810MS377
810PP371
81 RCR336
81S563
81S727
81S925
811'987
811'991
81T1453
811'3423
81T4353
8IT(S9)191
81TL227
81 TLlI99
81TLl863
81 TL2063
81TL2431
81 TL2973
81UKZI099
81 UP40400
81UP40600
81UP40700
81ZC187
8IZN(A)34
8IZN(A)1246
References
V. P. Shchipanov and N. A. Klyuev; Khirn. Geterotsik!. Soedin., 1981,694.
Yu.1. Ribukhim, L. N. Faleeva and G. N. Dorofeenko; Khirn. Geterotsikl. Soedin.,
1981, 1423.
V. L. Rusinov, I. Y. Postovskii, A. Y. Petrov, E. O. Sidorov and Y. A. A7ev;
Khirn. Geterotsik!. Soedin., 1981, 1554.
R. W. Saa1frank and E. Ackermann; Liebigs Ann. Chern., 1981,7.
R. R. Schmidt, W. Guilliard and D. Heermann; Liebigs Ann. Chern., 1981,2309.
W. Freyer and R. Radeglia; Monatsh. Chern., 1981,112, 105.
M. H. E1nagdi, E. M. Zayed, M. A. Khalifa and S. A. Ghoz1an; Monatsh. Chern.,
1981, 112, 245.
M. A. Khan and A. e. e. Freitas; Monatsh. Chern., 1981, 112,675.
O. S. Wolfbeis; Monatsh. Chern., 1981,112,875.
G. A. Webb, M. Witanowski and L. Stefaniak; Annu. Rep. NMR Spectrosc., 1981,
118.
Y. Imai, T. Nakajima and M. Ueda; J. Polyrn. Sci., Polyrn. Chern. Ed., 1981, 19.
2161.
K. Simon, K. Horváth, D. Korbonits and L Párkányí, J. Cryst. Mol. Struct., 1981,
II, 33.
J. Arriau and J. E1guero; An. Quírn., Ser. C, 1981,77, 105.
e. L. Chatterjee and A. Saran; Int. J. Quanturn. Chern., 1981,8 (Suppl.), 129.
D. M. Bailey and L. W. Chakrin; Annu. Rep. Med. Chern. 1981,16,213.
V. Pellegrin, A. Fruchier and J. Eiguero; J. Labelled Cornpd. Radiopharrn., 1981,
18, 999.
R. Aruga; J. Inorg. Nuc/. Chern., 1981,43,2459.
M. T. García.López and F. G. de 1as Heras; in 'Medicinal Chemistry Advances',
ed. F. G. de las Heras and S. Vega; Pergamon Press, Oxford, 1981, p. 69.
J. R. Jones and S. E. Taylor; Chern. Soc. Rev., 1981,10,329.
R. Böhm and e. Karow; Pharrnazie, 1981,36,243.
G. R. Revankar, V. C. Solan, R. K. Robins and J. T. Witkowski; Nucleic Acids
Syrnp. Ser., 1981,9,65 (Chern. Abstr., 1982,96,35682).
I. Ugi, D. Marquarding and R. Urban; in 'Chemistry and Biochemistry of Amino
Acids, Peptides and Proteins', ed. B. Weinstein; Dekker, New York, 1981, vol.
6, p. 245.
B. Stanovnik, M. TiSler, N. Trcek and B. Vercek; Vestn. Slov. Kern. Drus., 1981,
28,45 (Chern. Abstr., 1981,95,7220).
Sandoz AG, Braz. Pat. 8101239 (1981) (Chern. Abstr., 1982,96,69006).
V. V. Lopyrev, L. I. Larina, T. I. Vaku1'skaya, M. F. Larin, O. B. Nefedova, E.
F. Shibanova and M. G. Voronkov; Org. Magn. Reson., 1981,15,219.
U. e. Pande, H. Egsgaard, E. Larsen and M. Begtrup; Org. Mass Spectrorn.,
1981, 16,377.
M. Bin Mohamed and J. Parrick; Org. Prep. Proced. Int., 1981, 13,371.
V. N. Sheinker, A. D., Garnovskii and O. A. Osipov; Russ. Chern. Rev. (Eng!.
Trans!.), 1981,50,632.
J. Barluenga, N. Gómez, F. Palacios and V. Gotor; Synthesis, 1981,563.
P. G. Baraldi, M. Guarneri, F. Moroder and D. Simoni; Synthesis, 1981,727.
F. Freeman; Synthesis, 1981,925.
A. Ramdani and G. Tarrago; Tetrahedron, 1981,37,987.
A. Ramdani and G. Tarrago, Tetrahedron, 1981,37,991.
S. Rajappa; Tetrahedron, 1981,37, 1453.
A. N. Kost, S. P. Gromov and R. S. Sagitullin; Tetrahedron, 1981,37,3423.
M. Legraverend, J. M. Lhoste and E. Bisagni; Tetrahedron, 1981,37,4353.
H. H. Wasserman, M. S. Wolff, K. Stiller, I. Saito and J. E. Pickett; Tetrahedron,
1981,37, Suppl. 9, 191.
F. Lübbe, K..P. Grosz, W. Hillebrand and W. Sucrow; Tetrahedron Letl., 1981,
227.
A. Padwa and T. Kumagai; Tetrahedron Letl., 1981, 1199.
A. Hassner, B. A. Belinka, Jr., M. Haber and P. Munger; Tetrahedron Letl., 1981,
22, 1863.
R. A. Whitney; Tetrahedron Letl., 1981,2063.
R. F. Pratt and K. K. Kraus; Tetrahedron Letl., 1981, 2431.
R. Gompper, M. Junius and H. U. Wagner; Tetrahedron Letl., 1981,2973.
V. I. Simonenko, I. V. Pyatnitskii and G. K. Nizkaya; Ukr. Khirn. Zh. (Russ.
Ed.), 1980,46, 1099 (Chern. Abstr., 1981,94,53670).
P. Camps, J. Elguero, e. Estopá, R. Faure, A. Fruchier, D. lIavaský, e. Marzin
and J. de Mendoza; unpublished results. 185,190,191,192
W. Robinson and M. R. Grimmett; unpublished work in preparation. 351
W. Robinson and M. R. Grimmett; unpublished work in preparation. 393
D. Zeigan, G. Engelhardt and E. Uhlemann; Z. Chern., 1981,21, 187. 194
M. H. Palmer, I. Simpson and R. H. Findley; Z. Naturforsch., Teil A, 1981,36,
34.
M. H. Palmer, I. Simpson and J. R. Wheeler; Z. Naturforsch., Teil A, 1981,36,
1246. 671, 688, 689
741,778
779
272
717
289
228
320
266
281
20
291,300
179,227
215,282
210
297
291
226
288
501,527
728
729
845
860
732
353
204
290
209, 737
476
323
316
260,261
228
715
312
859,901
406
707
263
718
426, 443
409
415
731
195
81Z0R146
82ACS(B) I 01
82AG139
82AHC(30)239
82CC86
82CC450
82CC1280
82CJC97
82H(19)179
82H(19) 1223
82JA235
82JA1698
82JA3209
82JCR(S)6
82JCR(S)122
82JCS(Pl)165
82JCS(Pl)473
82JCS(Pl)627
82JCS(Pl)759
82JHC1141
82JHC1215
82JMC96
82JMC626
82JMC1168
82JOC81
82JOC167
82JOC214
82JOC295
82JOC536
82JOC2221
82JOC4256
82JOC4323
82JOC5132
82JST(78) 1
82JST(89) 147
82KGS705
82MI40400
82MI40401
82MI40402
82MI41000
82MI41001
820MR(18)0
820MR(18)159
820MR(19)27
820MR(19)225
82P863
82PC40200
82PC40400
82PNA4487
82S844
B. R. Tolf, R. Dahlbom, H. Theorell and A. Akeson; Acta Chern. Scand., Ser.
B, 1982,36, 101.
M. V. Prostenik and I. Butula; Angew. Chern., 1982,94, 139.
S. T. Reid; Adv. Heterocycl. Chern., 1982,30,239.
H. Nakanishi, A. Yabe and K. Honda; J. Chern. Soc., Chern. Cornrnun., 1982,86.
D. H. R. Barton, G. Lukacs and D. Wagle; J. Chern. Soc., Chern. Cornrnun., 1982,
450.
D. G. Heath and C. W. Rees; J. Chern. Soc., Chern. Cornrnun., 1982, 1280.
J. Zukerman-Schpector, E. E. Castellano, A. C. Massabni and A. D. Pinto; Can.
1. Chern., 1982,60,97.
K. Tanaka, S. Maeno and K. Mitsuhashi; Heterocycles, 1982, 19, 179.
S. Takano, Y. Imamura and K. Ogasawara; Heterocycles, 1982, 19, 1223.
R. S. Hosmane, V. Bakthavachalam and N. J. Leonard; J. Am. Chern. Soc., 1982,
104, 235.
P. S. Engel, L. R. Soltero, S. A. Baughman, C. J. Nalepa, P. A. Cahill and R. B.
Weisman; J. Am. Chern. Soc., 1982, 104, 1698.
R. Taylor and O. Kennard; J. Am. Chern. Soc., 1982, 104,3209.
G. Ferguson, B. Kaitner, F. J. Lalor and G. Roberts; J. Chern. Res. (S), 1982,6.
R. N. Butler and V. C. Garvin; J. Chern. Res. (S), 1982, 122.
N. Vivona, G. Macaluso and V. Frenna; J. Chern. Soc., Perkin Trans. I, 1982, 165.
M. Yogo, K. Hirota and S. Senda; J. Chern. Soc., Perkin Trans. I, 1982,473.
D. R. Buckle and C. J. M. Rockell; J. Chern. Soc., Perkin Trans. I, 1982,627.
D. Korbonits, I. Kanzel-Szvoboda and K. Horváth; J. Chern. Soc., Perkin Trans.
I, 1982,759.
S. Juliá, P. Sala, J. M. del Mazo, M. Sancho, C. Ochoa, J. Elguero, J. P. Fayet
and M. C. Vertut; J. Heterocycl. Chern., 1982, 19, 1141.
J. W. Ellis, E. A. Keiter, R. L. Keiter, T. L. Pi and R. A. Uptmor; J. Heterocycl.
Chern., 1982, 19, 1215.
J. A. Montgomery, S. J. Clayton and P. K. Chiang; J. Med. Chern., 1982,25,96.
J. A. Montgomery, S. J. Clayton, H. J. Thomas, W. M. Shannon, G. Arnett, A. J.
Bodner, I.-K. Kim, G. L. Cantoni and P. K. Chiang; J. Med. Chern., 1982,25,
626.
J. C. Emmett, G. J. Durant, C. R. Ganellin, A. M. Roe and J. L. Turner; J. Med.
Chern., 1982,25, 1168.
A. Citterio, F. Minisci and E. Vismara; 1. Org. Chern., 1982,47,81.
N. Katagiri, A. Koshihara, S. Atsuumi and T. Kato; J. Org. Chern., 1982,47,167.
E. M. Kosower, D. Faust, M. Ben-Shoshan and I. Goldberg; J. Org. Chern., 1982,
47, 214. 250
G. Zvilichovski and M. David; J. Org. Chern., 1982,47,295. 215,230,281
J. Elguero, C. Ochoa, M. Stud, C. Esteban-Calderon, M. Martínez-Ripoll, J. P.
Fayet and M. C. Vertut; J. Org. Chern., 1982,47,536.
J. D. Pérez and G. I. Yranzo; J. Org. Chern., 1982,47,2221.
E. Sato, Y. Kanoaka and A. Padwa; J. Org. Chern., 1982,47,4256.
K. Takada, T. Kan-Woon and A. J. Boulton; J. Org. Chern., 1982,47,4323.
D. S. Wofford, D. M. Forkey and J. G. Russell; J. Org. Chern., 1982,47,5132.
R. Taylor and O. Kennard; J. Mol. Struct., 1982,78, I.
M. Sana, G. Leroy, G. Dive and M. T. Nguyen; J. Mol. Struct., 1982,89, 147.
Y. M. Yutilov and I. A. Svertilova; Khirn. Geterotsikl. Soedin., 1982,705 (Chern.
Abstr., 1982,97, 109950).
H. Biere, E. Schröder, H. Ahrens, J. F. Kapp and I. Bottcher; Eur. J. Med. Chern.,
1982, 17, 27.
K. Burger, F. Hein, O. Dengler and J. Elguero; J. Fluorine Chern., 1982, 19,437.
F. Massa, M. Hanack and L. R. Subramanian; J. Fluorine Chern., 1982, 19,601.
J. A. Montgomery; Med. Res. Rev., 1982,2,271.
T. Itoh, T. Sugawara and Y. Mizuno; Nucleosides, Nucleotides, 1982,1, 179.
References
V. A. Ostrovskii, I. Yu. Shirobokov and G. I. Koldobskii; Zh. Org. Khirn., 1981,
17, 146 (Chern. Abstr., 1981,95,23988).
993
818
291
728
46
208
276
864
178,210
284
284,302
659
255
501, 527
227
835
288
286
712
288
230
281
620
640
623
278
639
229
219
148
216
193
501, 527
283
623
291
283
282
608, 652
615,616,
617,618
A. Fruchier, V. Pellegrin, R. Schimpf and J. Elguero; Org. Magn. Reson., 1982,
18, 10. 196,197
G. Aranda, M. Dessolin, M. Gollier and M.-G. Guillerez; Org. Magn. Reson.,
1982, 18, 159. 19
L. D. Colebrook and M. A. Khadim; Org. Magn. Reson., 1982,19,27. 355
P. Cohen-Fernandes, C. Erkelens and C. L. Habraken; Org. Magn. Reson., 1982,
19, 225. 234
E. G. Brown, K. A. M. Flayeh and J. R. Gallon; Phytochemistry, 1982,21,863. 303
R. Taft; personal communication. 49
B. Abarca, J. Quilez and J. Sepúlveda; personal communication. 249
G. A. Olah, S. C. Narang, J. A. Olah and K. Lammertsma; ProC. Nall. Acad.
Sci. USA; 1982,79,4487. 270-
R. Ketari and A. Foucaud; Synthesis, 1982,844. 270
994
82T2193
82TLl21
82TL321
82UP40400
82UP40401
82UP40402
82UP40403
82USP43 15008
82ZC56
83AP588
83AP608
83BSF(2)5
83CBI520
83CC910
83CCI144
83CJCI435
83H(20) 1713
83H(20)1717
83HCAI537
83JA309
83JCR(S)18
83JCS(PI )2273
83JCS(P2)1111
83JOC3
83MI40300
83MI40400
830MS52
83PC40100
83UP40100
83UP40200
83UP40400
84MI41000
84UP41300
References
A. de la Hoz, E. Díez-Barra, M. C. Pardo, J. P. Declercq, G. Germain, M. Van
Meerssche and J. E1guero; Tetrahedron, 1983,39,2193.
P. Choi, C. W. Rees and E. H. Smith; Tetrahedron Lell., 1982, 121.
M. Alam, Y. Oshima and Y. Shimizu; Tetrahedron Lell., 1982,23,321.
J. Eiguero, A. Fruchier, A. de la Hoz, and M. C. Pardo; unpublished results.
A. Fruchier, V. Pellegrin, R. M. Claramunt and J. Eiguero; Org. Magn. Reson.,
accepted for publication.
A. Fruchier, B. Lupo and G. Tarrago, Can. J. Chern., accepted for publication.
A. M. Cuadra, P. Navarro and J. Eiguero; unpublished results.
Bayer A. G., U.S. Pat. 4315 008
M. Schulz, L. Mogel, N. X. Dung and R. Radeglia; Z. em., 1982,22,56.
H. Biere, I. Böttcher and J. F. Kapp; Arch. Pharrn. (Wìenheirn, Ger.), 1983,316,
588.
H. Biere, I. Böttcher and J. F. Kapp; Arch. Pharrn. (Weinheirn, Ger.), 1983,316,
608.
R. M. Claramunt, H. Hemández, J. El-guero and S. Juliá; Bull. Soc. Chirn. Fr.,
Part 2, 1983, 5.
W. Sucrow and G. Bredthaver; Chern. Ber., 1983, 116, 1520.
J. D. Wallis and J. D. Dunitz; J. Chern. Soc., Chern. Cornrnun., 1983,910.
X. Coqueret, F. Bourelle-Wargnier, J. Chuche and L. Taupet; J. Chern. Soc.,
Chern. Cornrnun., 1983, 1144.
Minh-Tho Nguyen, M. Sana, G. Leroy and J. Eiguero; Can. J. Chern., 1983,61,
1435.
R. Faure, E. J. Vincent and J. Eiguera; Heterocycles, 1983,20, 1713.
J. Catalán, P. Pérez and J. Eiguero; Heterocycles, 1983,20,1717.
B. C. Chen, W. von Philipsbom and K. Nagarajan; Helv. Chirn. Acta, 1983,66,
1537.
R. H. Nobes, W. J. Bouma and L. Radom; J. Am. Chern. Soc., 1983, 105,309.
R. N. Butler and D. A. O'Donoghue; J. Chern. Res. (S), 1982, 18.
J. Barluenga, M. Tomás, J. F. López-Ortiz and V. Gotor; J. Chern. Soc., Perkin
Trans. I, 1983, 2273.
S. N. Ege, W. M. Butler, A. Bergers, B. S. Biesman, J. E. Boerma, V. I. Corondan,
K. D. Locke, S. Meshinchi, S. H. Panas and T. D. Spitzer; J. Chern. Soc.,
Perkin Trans. 2, 1983, 1111.
R. Balicki, R. S. Hosmane and N. J. Leonard; J. Org. Chern., 1983,48,3.
K. T. Potts; in '1,3-Dipolar Cycloadditions', ed. A. Padwa; Wiley-Interscience,
New York, 1983, Chap. 8.
A. Katrib, N. R. EI-Rayyes and F. M. AI-Kharafi; J. Electron Spectrosc. Related
Phenorn., 1983,31,317.
E. Larsen, H. Egsgaard, U. C. Pande and M. Begtrup; Org. Mass Spectrorn.,
1983, 18, 52.
G. Morton; personal communication.
M. J. Sammes and A. R. Katritzky; unpublished results, 1983.
M. J. Sammes and A. R. Katritzky; Adv. Heterocycl. Chern., 1983, in press.
J. Catalán and J. Eiguero; J. Chern. Soc., Perkin Trans. 2, accepted for publication.
N.J. Leonard; CRC Crit. Rev. Biochern., 1984, 15, 125.
R. N. Butler, V. C. Garvin, H. Lumbroso and Ch. Liégois; J. Chern. Soc., Perkin
Trans. 2, 1984, in press.
248
808
604
192
196,290
240
242
282,297
234
291
291
230
275
843
281
845
192,211
175
193
7
829
274
255
659
140, 150
205
204
15
16, 19
77, 78
175,224
608,648
804, 805