Heterocyclic Chemistry Volume II Five Membered Heterocycles PDF

Heterocyclic Chemistry II
Heterocyclic Chemistry
R. R. Gupta, M. Kumar, V. Gupta
Volume I: Principles, Three- and Four-Membered Heterocycles
Volumell: Five-MemberedHeterocycles
Volume III: Six-Membered and Higher Heterocycles
Springer-Verlag Berlin Heidelberg GmbH

R. R. Gupta, M. Kumar, V. Gupta
Heterocyclic Chemistry
Volume II:
Five-Membered Heterocycles
With 136 Figures
Springer
Prof. Radha Raman Gupta
Or. Mahendra Kumar
Or. Vandana Gupta
Oepartment ofChemistry
University of Rajasthan
Jaipur-302004 / India
ISBN 978-3-642-08460-7
Library of Congress Cataloging-in-Publication Data

Die Deutsche Bibliothek - Cip-Einheitsaufnahme
Gupta, Radha R.:
Heterocyclic chemistry / R. R. Gupta ; M. Kumar ; V. Gupta.
ISBN 978-3-642-08460-7 ISBN 978-3-662-07757-3 (eBook)

DOI 10.1007/978-3-662-07757-3
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FOREWORD
Today, our world increasingly is conceived of as being molecular. An ever

widening range ofphenomena are described logically in terms ofmolecular
properties and molecular interactions. The majority ofknown molecules
are heterocyclic and heterocycles dominate the fields ofbiochemistry,
medicinal chemistry, dyestuffs, photographic science and are of increasing
importance in many others, including polymers, adhesives, and molecular
engmeenng.
Thus, the importance of heterocyclic chemistry continues to increase
and this three volume work by Drs. R. R. Gupta, Mahendra Kumar and
Vandana Gupta is a welcome addition to the available guides on the
subject. Its scope places it in a useful niche between the single-volume texts
and monographs ofheterocyclic chemistry and the multivolume treatises.
The authors have retained the well tried classical approach but have
succeeded in placing their own individual spin on their arrangement. They
have put together a well selected range from among the most important
ofthe vast array of facts available. This factual material is ordered in a
clear and logical fashion over the three volumes.
The present work should be of great value to students and practitioners
ofheterocyclic chemistry at all levels from the advanced undergraduate
upwards. It will be of particular assistance in presenting a clear and modem
view of the subject to those who use heterocycles in a variety of other
fields and we wish it well.
Alan R. Katritzky
April1998 University ofFlorida
PREFACE
Our aim is to bring out a text-cum-reference book on heterocyclic

chemistry for undergraduate and graduate students, and research workers
who wish to choose heterocyclic chemistry in their research careers. This
will enable them to have a comprehensive knowledge of the syntheses,
properties, reactions and their mechanisms and applications ofheterocyclic
compounds. Efforts have been made to include recent developments in
heterocyclic chemistry and the subject is presented in a simple and lucid
manner, so that those who have some background knowledge of organic
chemistry can understand it well.
For the sake of convenience, subject matter covered in heterocyclic
chemistry has been divided into three volumes:
Volume I : Principles, Three- and Four-Membered Heterocycles
Introduction
Nomenclature ofHeterocycles
Aromatic Heterocycles
Nonaromatic Heterocycles
Heterocyclic Synthesis
Three-Membered Heterocycles
Four-Membered Heterocycles
Volume II : Five-Membered Heterocycles
Introduction
Five-Membered Heterocycles with One Heteroatom
Benzo-Fused Five-Membered Heterocycles with
One Heteroatom
Five-Membered Heterocycles with Two Heteroatoms
Five-Membered Heterocycles with More Than Two
Heteroatoms
Meso-Ionic Heterocycles
VIII
Volume III: Six-Membered and Higher Heterocycles

Introduction
Six-Membered Heterocycles
Seven-Membered Heterocycles
Large Ring Heterocycles
Photochemistry ofHeterocycles
The present Vol. II is a continuation ofVol. I to provide a comprehensive
account ofthe chemistry of five-membered heterocycles to the advanced
students, research workers and industrial as well as medicinal chemists.
It concerns with the syntheses, reactions, properties, structural parameters,
applications, pharmacological/biological significance, etc. for the compounds
with one, two and more heteroatoms and their benzo-fused analogs as well
as mesoionic compounds. The readers mastered the principles for the
syntheses, aromaticity, nonaromaticity, reactions, etc. presented for the
heterocyclic systems in Vol. I can understand well the chemistry of five-
membered heterocycles covered in Vol. II. It will be also useful to those
who are looking for a survey of well-tried fundamental concepts as well
as for information on new developments in the chemistry of five-membered
heterocycles.
We have freely consulted edited scientific works such as Comprehensive
Heterocyclic Chemistry edited by A.R. Katritzky and C.W. Rees,
Advances in Heterocyclic Chemistry edited by A.R. Katritzky and the
Chemistry of Heterocyclic Compounds edited by A. Weissberger and
E.C. Taylor. We are very grateful to editors, authors and publishers of
these works.
We express our thanks to our colleagues and Ph.D. students who
assisted us in proof reading and in several other ways. Our sincere thanks
are also due to Dr. R. Stumpe and Dr. Joe P. Richmond editors at Springer
Verlag for providing valuable suggestions for the preparation ofthe book.
Jaipur, India R.R. Gupta

October, 1998 Mahendra Kumar
Vandana Gupta
Symbols and Abbreviations
a Bond angle distortion or deviation I Coulomb integral (as stated)

A Karplus constant
AIBN I ,2,2'-Azobisisobutyronitrile
~ Resonance integral
Wave number
cone. Concentrated
DE De localization energy
DRE Dewar resonance energy
A Diamagnetic susceptibility exaltation
L'm(8ae) Chemical shift difference
DIBAL Diisobutylaluminium hydride
Dil. Diluted
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
E Bond angle strain I Torsional energy (as stated)
ERE Empirical resonance energy
Eu(fodh Tris-( 6,6, 7, 7 ,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)-
europium
E Extinction coefficient
Conformational free energy
Free energy of activation
Enthalpy difference between conformers
~H Heat of formation (exp.)
HMPAIHMPT Hexamethylphosphoric triamide
HOMO Highest occupied molecular orbital
Ia and le Band intensity in vibrational spectra for axial and equatorial
conformers
X
J Coupling cosntant
!<,; Rate of ring inversion
K, Equilibrium constant of interconvertible conformers
K8 Bond bending force constant
A. Wavelength
LDA Lithium diisopropylarnide
LTA Lead tetraacetate
LUMO Lowest unoccupied molecular orbital
MCPBA m-Chloroperbenzoic acid
NBS N-Bromosuccinirnide
hv Photochemical
nm Nanometer ( 1o-9)
N-PSP N-Phenylselenophthalirnide
pm Picometer (1 o- 12 )
PPA Polyphosphoric acid
R Coupling constants ratio
REPE Resonance energy per n:-electron
\jJ Internal torsional angle
Tc Coalescence temperature
TCNE Tetracyanoethylene
tert Tertiary
TFAA Trifluoroacetic anhydride
TifF Tetrahydrofuran
1HP Tetrahydropyran
e Dihedral angle
TMEDA N,N,N,N-Tetramethylenediamine
Tos I Tosyl p- Toluenesulfonyl
VR Vilsmeier reagent
Dihedral angle deviation
Diamagenetic susceptibility
CONTENTS
Chapter 1. Introduction 1
Chapter 2. Five-Membered Heterocycles with 3

One Heteroatom
Chapter 3. Benzo-Fused Five-Memb~red 181

Heterocycles with One Heteroatom

Two Heteroatoms

More Than Two Heteroatoms
Chapter 6. Meso-Ionic Heterocycles 579
Subject Index 627

CHAPTER 1
INTRODUCTION
Heterocyclic Chemistry is an integral part of organic chemistry and constitutes a

considerable part of the syllabus for undergraduate and graduate students through
out the world. Heterocyclic chemistry deals with heterocyclic compounds which
constitute about sixty-five percent of organic chemistry literature. Heterocyclic
compounds are widely distributed in nature which are essential to life. Genetic
material DNA is also composed of heterocyclic bases-pyrimidines and purines. A
large number of heterocyclic compounds, both synthetic and natural, are
pharmacologically active and are in clinical use. Several heterocyclic compounds
have applications in agriculture as insecticides, fungicides, herbicides, pesticides
etc. They also find applications as sensitizers, developers, antioxidants, copolymers
etc. They are used as vehicles in the synthesis of other organic compounds.
Chlorophyll-photosynthesizing and haemoglobin-oxygen transporting pigments
are also heterocyclic compounds.
Huge amount of research work is generated on various phases of heterocyclic
chemistry and for publication of such research work and review articles, there are
three specialized journals devoted to heterocyclic chemistry:
1. Journal of Heterocyclic Chemistry
2. Heterocycles
3. Heterocyclic Communications
In addition to theses specialized journals, research papers on heterocyclic
chemistry are being published in journals devoted to organic chemistry. There are
three continuing series in heterocyclic chemistry:
1. Advanoes in Heterocyclic Chemistry (edited by A. R. Katritzky, Academic
Press).
2. Chemistry of Heterocyclic Compounds (edited by E. C. Taylor, John Wiley).
3. General Heterocyclic Chemistry (edited by E. C. Taylor, Wiley-Interscience).
2 Heterocyclic Chemistry
In addition to these series, annual reports on "Progress in Heterocyclic

Chemistry" are being published under the sponsorship of International Society of
Heterocyclic Chemistry (edited by H. Suschitzky and E. F. V. Scriven, Pergamon
Press) to highlight new developments in the field of heterocyclic chemistry. A
treatise "Comprehensive Heterocyclic Chemistry" (edited by A. R. Katritzky and
C. W . Rees) has appeared in an eight-volume set in 1984 (Pergamon Press) and
its second edition (edited by A. R.Katritzky and C. W. Rees) has appeared in 1996.
A. R. Katritzky has introduced "Handbook of Heterocyclic Chemistry" (Pergamon
Press, 1985) and a five-volume set on "Physical Methods in Heterocyclic
Chemistry" (Academic Press). One of the authors (R. R. Gupta) as editor has also
introduced a volume on "Physical Methods in Heterocyclic Chemistry" (Wiley-
Interscience, 1984). From time to time several textbooks have appeared:
The Chemistry of Heterocyles (T. Eicher and S. Hauptmann, Thieme, 1995).
Heterocyclic Chemistry (T.L. Gilchrist, Pitman, 1st edn. 1985; 2nd edn. 1992).
Contemporary Heterocyclic Chemistry (George R. Newkome and William
W . Paudler, Wiley-Interscience, 1982).
An Introduction to the Chemistry of Heterocyclic Compounds (R. M . Acheson,
3rd edn., John Wiley, 1976).
Heterocyclic Chemistry (D. W. Young, Longman, 1975).
Heterocyclic Compounds (K. Schofield, Ed., Butterworths, 197 5 ).
Heterocyclic Chemistry (J. A . Joule and G. F. Smith, 2nd edn. Van Nostrand
Reinhold, 1972; J. A. Joule, K. Mills and G. F.Smith, 3rd edn. Chapman & Hall,
1994).
Principles of Modem Heterocyclic Chemistry (L. A. Paquette, Benjamin, 1968).
Heterocyclic Chemistry (A. Albert, 2nd edn. Oxford University Press, 1968).
The Principles of Heterocyclic Chemistry (A. R. Katritzky and J. M. Lagowski,
Academic Press, 1968).
The Structure and Reactions of Heterocyclic Compounds (M. H. Palmer,
E. Arnold, 1967).
The Chemistry ofHeterocyclic Compounds (A . A. Morton, McGraw-Hill, 1946).
We feel the need for a text-cum-reference book in heterocyclic chemistry which
includes new developments in the field and can cater to the need of undergraduate
and graduate students and research workers who have chosen heterocyclic
chemistry, pharmaceutical chemistry and medicinal chemistry etc. in their research
careers. In the present book efforts have been made to include each and every
class of heterocyclic compounds with which students are concerned in their cour-
ses devoted to heterocyclic chemistry. The subject matter has been divided into
sixteen chapters spreading over in three volumes (as mentioned in the preface).
Each chapter except the first (introduction) contains a detailed table of contents.
At the end of each chapter references have been cited, so that readers who are
interested in having more information regarding synthetic pathways, reactions and
their mechanisms, properties, application etc. of heterocyclic compounds may be
able to locate the information they require.
CHAPTER2
FIVE-MEMBERED HETEROCYCLES WITH ONE

HETEROATOM
CONTENTS
GENERAL 8
1.1 Structure and Stability 8
1.2 Aromaticity 9
1.2.1 Aromaticity Order 11
1.3 Reactivity of Five-Membered Heterocycles 11
1.3.1 Comparison with Acyclic Analogs 12
1.3.2 Comparison with Benzene 13
1.3.3 Reactivity Order in Five-Membered Heterocycles 14
1.3.4 Reactivity Comparison with Benzene 16
1.3.5 Effect of Aromaticity on Reactivity 16
1.3.6 Electrophilic Substitution Reactions 18
1.3.6.1 Directing Effect of Ring Heteroatom 20
1.3.6.2 Directing Effects of Substituents 20
in Monosubstituted Heterocycles
1.3.6.3 Directing Effects of Substituents in 25
Disubstituted Heterocycles
1.3.7 Nucleophilic Substitution Reactions 26
1.3.8 Reduction 27
1.3.9 Addition Reactions 27
1.3.10 Cycloaddition Reactions 19
1.3.11 Reactions with Free Radicals 31
1.3.12 Reactions with Electron-Deficient Species 31
2 PYRROLFS 33
2.1 General 33
2.1.1 Extraction 33
2.1.2 Ehrlich Test 34
2.2 Synthesis 34
2.2.1 Cyclization Reactions 34
2.2.1.1 (3 + 2) Cyclization Reactions 34
2.2.1.1.1 Reaction of a-Amino Ketones or 34
a-Amino P-Keto Esters with
P-Diketones or P-Keto Esters (Knorr
Pyrrole Synthesis)
2.2.1.1.2 Reaction of a-Amino Ketones with 36
Alkynes
2.2.1.1.3 Reaction of P-Amino-a,p-unsaturated 37
Esters with Nitroalkenes
2.2.1.1.4 Reaction of a-Diketones with Amines 37
2.2.1.2 (2 + 2 + 1) Cyclization Reactions 38
2.2.1.2.1 Reaction of P-Keto Esters with a-Halo 38
Ketones (Hantzsch Pyrrole Synthesis)
2.2.1.2.2 Reaction of Aldehydes or Ketones 38
with Hydrazine (Piloty-Robinson
Pyrrole Synthesis)
2.2.1.2.3 Reaction of Benzoin with Benzyl 38
Aryl Ketones
2.2.1.2.4 Reaction of Aldehydes with Alkyl 41
Isocyanoacetates
2.2.1.3.1 Reaction of 1,4-Diketones with 41
Ammonia or Ammonia Derivatives
(Paal-Knorr Synthesis)
2.2.1.3.2 Reaction of 1,4-Dienes or Diynes 41
with Amines
2.2.2 Ring Expansion Reactions 43
2.2.3 Extrusion Reactions 43
2.3 Structure 45
2.4 Basicity 46
2.5 Reactions 46
2.5.1 Protonation 46
2.5.2 Proton Exchange 47
2.5.3 Electrophilic Substitution Reactions 49
2.5.3.1 Orientation 50
2.5.3.2 Nitration 50
2.5.3.3 Halogenation 52
2.5.3.3.1 Chlorination 52
2.5.3.3.2 Bromination 52
2.5.3.3.3 Iodination 52
2.5.3.4 Sulfonation 54
Five-Membered Heterocycles with One Heteroatom 5
2.5.3.5 Acylation 55
2.5.3.5.1 Houben-Hoesch Reaction 55
2.5.3.5.2 Gattermann Formylation 56
2.5.3.5.3 Vilsmeier-Haack Reaction 57
2.5.3.5.4 Friedel-Crafts Acylation 58
2.5.3.6 Alkylation 58
2.5.3.7 Hydroxymethylation (Mannich Reaction) W
2.5.3.8 Reactions with Aldehydes and Ketones ro
2.5.3.9 Diazo Coupling 6:t
2.5.4 Reactions on Carbon and Nitrogen Anionic Species 65
2.5.5 Nucleophjlic Substitution Reactions 68
2.5.6 Oxidation (f)
2.5.6.1 Autoxidation (f)
2.5.6.2 Photo-oxidation (f)
2.5.6.3 Oxidation with Chromium Trioxide (f)
2.5.6.4 Oxidation with Hydrogen Peroxide (f)
2.5.7 Reduction 71
2.5.7.1 Catalytic Hydrogenation 71
2.5.7.2 Reduction by Metal-Acid Systems 72
(Chemical Reduction)
2.5.9.1 Reactions with Carbenes 74
2.5.9.2 Reactions with Nitrenes 77
2.5.10.1 (4n + 2n) Reactions 77
2.5.10.1.1 Reactions with DMAD 78
2.5.10.1.2 Reactions with Benzyne 79
2.5.10.1.3 Reaction with Hexafluorobicyclo- 80
[2.2.0]hexa-2,5-diene
2.5.10.2 (27t + 2n) Reactions 80
3 FURANS 82
3.1 General 82
3.2 Synthesis 83
3.2.1 Commercial Method (From Aldopentoses or Ketopentoses) 83
3.2.2 From 1,4-Diketones 83
3.2.3 Cyclization of Alkynes 84
3.2.3.1 Photochemical Cyclization 84
3.2.3.2 From Alkynyl Sulfonium Salts 84
3.2.4 Cyclization ofYlides 85
3.2.4.1 Sulfur Ylides 85
3.2.4.2 Phosphorus Ylides 86
3.2.5 From a-Halocarbonyl Compounds (Feist-Benary Synthesis) 87
3.2.6 Ring Expansion of Small Ring Heterocycles 88
3.2.6.1 Three-Membered Heterocycles 88

3.2.6.2 Four-Membered Heterocycles 89
3.2.7 Transformation of Five-Membered Heterocycles 89
3.2.8 Ring Contraction 5X)
3.3 Structure 91
3.4 Reactions 92
3.4.1 Reactions with Electrophiles 92
3.4.1.1 Reactivity and Orientation Effects 92
3.4.1.2 Directing Effects of Substituents 93
3.4.1.3 Protonation 94
3.4.1.4 Nitration 96
3.4.1.5 Sulfonation 97
3.4.1.6 Halogenation 98
3.4.1.9 Reactions with Aldehydes and Ketones 104
3.4.1.10 Reactions with Diazonium Salts 105
3.4.2 Reactions with Nucleophiles 105
3.4.4 Reactions with Electron-Deficient Species Ill
3.4.6 Photochemical Reactions 118
4 TillOPHENES I21
4.I General I2I
4.1.1 Isolation I22
4.2 Synthesis I22
4.2.1 Intramolecular Cyclization Reactions I22
4.2.1.1 From 4-Aralkylthiocrotononitriles I22
4.2.1.2 From 3-Methylenethiopropenals 123
4.2.2 (4 + I) Cyclization Reactions I24
4.2.2.1 From Hydrocarbons I24
4.2.2.2 From 1,4-Diketones (Paal Synthesis) I25
4.2.3 (3 + 2) Cyclization Reactions I26
4.2.3.1 Reaction of a.,f3-Unsaturated Carbonyl I26
Compounds with Ethyl Mercaptoacetate
4.2.3.2 Reaction of Activated Alkynes with I27
a.-Mercapto Ketones or Esters
4.2.3.3 Reaction of Dimethyl Fumarate with Mercapto Esters 128
4.2.3.4 Reaction of a.-Mercapto Ketones with I29
Activated Methylene Nitriles
(Gewald Synthesis)
4.2.3.5 Reaction of a.-Diketones with Activated I29
Methylene Compounds (Hinsberg Synthesis)
4.2.3.6 Reaction of Alkynes with Mesoionic Heterocycles 13I
4.2.4 (2 + 2 + I) Cyclization Reactions 131
4.3 Structure 132
4.4 Reactions 134

4.4.1.1 Electrophilic Substitutions at Carbon 134
4.4.1.1.1 Orientation 134
4.4.1.1 .2 Directing Effects of Substituents 135
4.4.1.1.2.1 Substituents at Carbon-2 135
4.4.1.1.2.2 Substituents at Carbon-3 136
4.4.1.1.3 Protonation 136
4.4.1.1.4 Nitration 137
4.4.1.1.5 Sulfonation 140
4.4.1.1.6 Halogenation 141
4.4.1.1.6.1 Chlorination 141
4.4.1.1.6.2 Bromination 142
4.4.1.1.6.3 Iodination 144
4.4.1.1.7 Alkylation 144
4.4.1.1.8 Acylation 145
4.4.1.1.9 Reactions with Aldehydes and Ketones 148
4.4.1.1.10 Mercuration 149
4.4.1.1.11 Reactions with Diazonium Salts 150
4.4.1.2 Electrophilic Attack on Sulfur 151
4.4.2 Reactions with Oxidizing Agents 152
4.4.2.1 Formation of Thiophene Sulfoxides and Sulfones 152
4.4.2.2 Oxidative Ring Cleavage 153
4.4.2.3 Oxidation by Metal Ions 153
4.4.3.1 Nucleophilic Attack at Carbon 154
4.4.3.1.1 Nucleophilic Substitutions 154
4.4.3.1.2 Halogen-Metal Exchange 156
4.4.3.2 Nucleophilic Attack at Hydrogen 158
4.4.3.2.1 Lithiation 158
4.4.3.3 Nucleophilic Ring Opening Reactions 159
4.4.4 Reactions with Reducing Agents 160
4.4.4.1 Catalytic Reduction 160
4.4.4.2 Birch Reduction 161
4.4.4.3 Reductive Desulfurization 161
4.4.6.2 Reactions with Nitrenes 165
4.4.7.1 Thermal [4 + 2] Cycloaddition Reactions 165
4.4.7.2 Thermal [2 + 2] Cycloaddition Reactions 167
4.4.7.3 Photocycloaddition Reactions 168
4.4.8 Photosubstitution 170
4.4.9 Photoisomerization 171
REFERENCES 171
1 GENERAL
Five-membered aromatic heterocycles with one heteroatom; pyrrole 2, furan 3 and

thiophene 4, are considered to be derived from cyclopentadienyl anion 1 by
replacing CH group by NH, 0 and S, respectively (scheme-1 ). These five-membered
heterocycles are, therefore, expected to possess characteristics of conjugated
Q +X
-CH- 0 X
H 2:X=NH
1
3:X=O
4:X=S
Scheme-l
dienes and of acyclic amines, ethers and sulfides accordingly. In addition to their
tendency to undergo addition reactions, these heterocycles also have characteristics
associated with aromaticity; (i) electrophilic substitution reactions, (ii) resonance
stabilization and (iii) aromatic sextet involving the lone pair on the heteroatom.
1.1 Structure and Stability 1
Five-membered aromatic heterocycles are planar pentagonal with sp 2-hybridized

atoms. Six n-electrons are distributed over five sp 2-hybridized atoms; each carbon
atom contributes one electron, while the heteroatom contributes two electrons to
the aromatic sextet, which imparts essentially the aromaticity to the heterocyclic
system (Fig. 1) .The structures of these heterocycles, in terms of valence bond
0 X
X= NH, 0 or S
Fig. I. Orbital structure of five-membered heterocycles

description, are considered to be resonance hybrids of the resonating structures

(Fig. 2). However, in the sulfur-containing heterocycle, thiophene, some additional
resonating structures are also possible due to the involvement of d-orbitals of
sulfur in bonding (Fig.3).
0~0~0-~-0~0
X X X X X
(i) (ii) (iii) (iv) (v)
Fig. 2. Resonating structures of five-membered heterocycles with one heteroatom
+..
0 .~
• 0+ . • 0
.~ .~
(vi) (vii) (viii)
Fig. 3. Additional resonating structures of thiophene
The lone pair associated with the heteroatom is involved in the aromatic sextet
and is delocalized over the ring carbons. The stabilization energies of these
heterocycles (87.69 kJ/mol forpyrrole, 66.81 kJ/mol for furan and 121.10 kJ/mol for
thiophene) are approximately half of the value of benzene because only one
uncharged resonating structure contributing to the resonance hybrid is possible
in these heterocycles as compared to two uncharged resonating structures for
benzene. The extra stabilization of thiophene is attributed to the expansion of
valence shell of sulfur by using d-orbitals in hybridization.
1.2 Aromaticity
The aromaticity in these heterocycles is attributed to the delocalization of 7t-

electrons forming an aromatic sextet in which one electron is contributed by each
carbon atom and a pair of electrons is contributed by the heteroatom. The lone
pair of electrons on the heteroatom is considered to have same role as does the
carbon-carbon double bond. The delocalization of n-electrons can be evidenced
by the bond distances. The carbon-carbon single bonds (C-C) and carbon-
heteroatom bond (C-X) acquire partial double bond character (carbon-heteroatom
bond is shorter than that in the corresponding tetrahydro derivative). But the
carbon-heteroatom bond is lengthened and C 2 -X-C 5 bond angle is decreased
with increasing size of the heteroatom (Table I), thus making the molecule to
acquire progressively elongated shape. Moreover, the ratio of C 2-C 3 and
C3-C4 bond lengths is close to unity which is considered as a measure of
aromaticity.
Table 1. Comparison of bond lengths and bond angles in five-membered

heterocycles with one heteroatom
Bond lengths(A) Bond angles( 0 )

Heterocycle C-X Cz-C3 C3-C4 C2-X-C5 X-C2-C3 C2-C3-C4
Pyrrole 1.370 1.382 1.417 109.80 107.70 107.40

Pyrrolidine 1.470 1.540 1.540
Furan 1.362 1.361 1.430 106.50 110.65 111.47
Tetrahydrofuran 1.430 1.540 1.540 106.40 103.70 100.30
Thiophene 1.714 1.370 1.423 92.17 111.47 112.45
Tetrahydrothiophene 1.820 1.540 1.540 93.40 106.10 105.00
Dipole moments in theses heterocycles have also been assumed to be evidence

of the charged resonating structures and hence delocalization of n-electrons. The
magnitude and direction of the dipole moment depend on the resultant of two
structural effects operating in the opposite directions; (i) inductive effect : due to
more electronegative heteroatom on a-bonding electrons and (ii) mesomeric effect :
involving n-electrons (Fig. 4).
Qt Qt
H
or s
direction of dipole due
to electronegative hetero-
atom (inductive effect)
1.57D 1.87D 1.68D
Ot Ot Q-t-
N
H
s
direction of dipole due
to mesomerically electron
release from heteroatom
r r
1.80D 0.52D 0.71 D (mesomeric effect)
t Pyrrole Thiophene Furan

resultant direction of
dipole with magnitude
of dipole moment
t.D = (3.37) (1.35) (0.97)
(t.D = Dsaturated - Daromatic}
Fig. 4. Magnitude and direction of dipole moments
1.2.1 Aromaticity Order
The aromatic character in these 1t-excessive heterocycles depends on the

availability of lone pair of electrons on the heteroatom for cyclic delocalization
which, in tum, depends on the electronegativity of heteroatom. The more
electronegative heteroatom will have stronger attraction for the lone pair of
electrons and will make it less available for cyclic delocalization. The aromaticity
order in these heterocycles depends on the electronegativity of the heteroatom :
0 > N > S and, therefore, the aromaticity follows the order as : thiophene > pyrrole
> furan.
The deshielding and shielding characteristics in NMR spectra of these
heterocycles resulting from the ring current effects have been compared with those
observed in their saturated analogs in order to assess the aromaticity order. The
comparison of chemical shifts of vinylic protons of furan H-2 (8 = 7.29 ppm) and
H-3 (8 = 6.24 ppm) with those for 4,5-dihydrofuran H-2 (8 = 6.31 ppm) and H-3
(8 = 4.95 ppm) indicates the downfield shifting by 8 = 1-1.5 ppm which is attributed
to the presence of aromatic ring current. The similar effect has also been observed
for thiophene; H-2 (8 = 7.18 ppm) and H-3 (8 = 6.00 ppm) and 4,5-tetrahydro-
thiophene; H-2 (8 = 6.17 ppm) and H-3 (8 = 5.63 ppm). The chemical shifts for 13-
protons, apart from pyrrole, show regularity as increasing with decreasing electro-
negativity of the heteroatom. The comparison of chemical shifts observed for the
five-membered heterocycles with that of benzene (8 = 7.29 ppm) indicates the
presence of appreciable aromatic ring currents. However, the ring current effects
depend on the electronegativity of the heteroatom and the ring currents have been
observed to be in the same order as : thiophene > pyrrole > furan.
1.3 Reactivity of Five-Membered Heterocycles 2
Five-membered heterocycles with one heteroatom; pyrrole, furan and thiophene,

are 1t-excessive and are characterized by their ability to undergo electrophilic
substitution reactions on the ring carbons rather than to undergo addition
reactions. The electrophilic attack on the heteroatom is rare in the neutral
heterocycles due to the mesomeric electron release from the heteroatom. The
heteroatom bears partial positive charge and hinders the attack of electrophile,
while the negatively charged carbons facilitate the attack of electrophiles to occur
at the ring carbon atoms (Fig. 5).
o_._._co~w~~9-w~o'+
X E+ X X +.....) X X E
(i) (ii) (iii) E (iv) (v)
Fig. 5. Electrophilic attack on ring carbon atoms

These heterocycles are less reactive towards nucleophiles and are restricted to
undergo deprotonation at the nitrogen or carbon atom. However, the cation formed
by the electrophilic attack on the neutral heterocycle reacts readily with weak
nucleophiles resulting in addition or ring opening reactions. Five-membered
heterocycles undergo Diels-Alder reaction with varying degree of reactivity which
can be correlated with aromaticity.
1.3.1 Comparison with Acyclic Analogs
The reactivity of five-membered heterocycles is compared with that of their acyclic

analogs towards electrophiles to evaluate the effect of heteroatoms in these
heterocycles. The reaction of acyclic analogs, amines, ethers and sulfides, with
electrophile involves electrophilic attack at the heteroatom containing lone pair of
electrons, but in the five-membered heterocycles with one heteroatom the electro-
philic attack occurs at the carbon atoms rather than at the heteroatom (Fig. 6).
R, ,---.....+E
,...x: + (attack of electrophile at heteroatom)
R
9§;):-'E+
X
(attack at carbon atoms)
X = NH,O or S
Fig. 6. Electrophilic attack in acyclic analogs and five-membered heterocycles
The electrophilic substitutions in five-membered heterocycles with one heteroatom,

however, resemble the reactions of enamines, enols and thienols in which
mesomerically electron release from the heteroatom facilitates the electrophilic
attack at the P-carbon rather than at the heteroatom (Fig.7) .
E + E
+ I -H I
X=C-CH2~ X-C=CH
I I
Fig. 7. Electrophilic attack in conjugated acyclic system
1.3.2 Comparison with Benzene
The tendency of five-membered heterocycles with one heteroatom of undergoing

electrophilic substitutions rather than addition reactions inevitably leads to their
comparison with benzene. The aromatic character in these heterocycles is
rationalized by assuming that the lone pair involved in an aromatic sextet does the
same role as does the carbon-carbon double bond in benzene.
The electrophilic substitution in benzene involves two steps; first step involves
attack of electrophile with the formation of cr-complex (with sp3- hybridized carbon
atom) and second step proceeds with the release of proton providing substituted
product (Fig. 8).
Fig. 8. Electrophilic substitution in benzene
Five-membered heterocycles with one heteroatom also undergo electrophilic

substitution reactions at C-2 and C-3 (preferably at C-2) because the transition
states resulting from the attack at these positions (C-2 and C-3) are stabilized
(Fig. 9).
E+
..
I attack at C-2
0
..
X +
E
I
attack at C-3
Fig. 9. Electrophilic substitution in five-membered heterocycles

Since five-membered heterocycles with one heteroatom are n:-excessive with

higher electron density on the carbon atoms and as such their reactivity towards
electrophiles is higher than that of benzene.
1.3.3 Reactivity Order in Five-Membered Heterocycles
The reactivity of five-membered heterocycles towards electrophiles depends on

the electron availability on the ring carbon atoms or mesomerically electron release
from the heteroatom and the greater stabilization of transition state. The order of
reactivity in five-membered heterocycles is : pyrrole > furan >thiophene> benzene
(for comparison). The greater reactivity of pyrrole towards electrophiles is
attributed to the greater electron releasing ability of trivalent nitrogen (when linked
by three bonds) making ring carbon atoms electron rich and to the greater
stabilization of transition states involving positive charge on the tetravalent
nitrogen atom (Fig. 10).
dE
H
N
H
(ii)
Fig. 10. Transition states in pyrrole
Furan is also reactive (although less than pyrrole) towards electrophiles

(preferably at C-2) and the reason is the same as for pyrrole. Since oxygen is more
electronegative than nitrogen and withdraws electrons from the ring carbon atoms,
the positive charge is less readily accommodated by oxygen atom than by nitrogen
atom. The transition state with oxygen atom positively charged resulting from the
electrophilic attack on furan is, therefore, less stable than that of pyrrole (Fig. 11 ).
Thus, furan is less reactive towards electrophiles than pyrrole as phenol is less
reactive than aniline.
OE
H
0
(ii)
Fig. 11. Transition states in furan

Thiophene is less reactive than even furan towards electrophiles. The sulfur
atom is less electronegative than the oxygen atom and therefore withdraws
electrons less readily from the ring carbon atoms. Moreover, +M effect of sulfur
(mesomeric electron release from sulfur) is smaller than that of oxygen because of
not effective overlapping of differently sized p-orbitals of carbon and sulfur than
in carbon and oxygen. The relative reactivity of thiophene and furan can be shown
by the following reaction in which nitration with mild nitrating agent occurs only
in furan nucleus at C-2 (scheme-2).
nitration
~J:J
s c 0 (i) acetyl nitrate
(ii) pyridine
~n
S C 0 N02
II II
0 0
5 6
Scheme-2
The trend of reactivity in these heterocycles can be clearly shown by their

reactions with maleic anhydride. Pyrrole is sufficiently reactive towards electrophiles
and reacts readily as nucleophile with maleic anhydride with the formation of a
substituted product 8 (scheme-3). But furan is less reactive towards electrophiles
Scheme-3
than pyrrole and instead undergoes Diels-Alder reaction as conjugated diene with
maleic anhydride with the formation of cycloaddition product 9 (scheme-4).
+ ..
3
Scheme-4
Thiophene is less reactive towards electrophiles and does not react with maleic
anhydride even as a conjugated diene. Moreover, the relative rates of the reactions
of five-membered heterocycles with trifluoroacetic anhydride also indicate their
reactivity sequence as : pyrrole > furan > thiophene (scheme-S).
0 X
+ (CF 3C0h0
75°C
... Q + CF3COOH
X COCF3
X=NH 530 X 105
X=O 140
X=S
Scheme-S
1.3.4 Reactivity Comparison with Benzene
The electrophilic substitution in thiophene is much easier than in benzene.

Thiophene is brominated 109 times more rapidly than benzene which, in tum, is
10 3-107 times more reactive than pyridine. Thus, benzene is much less reactive
than the five-membered heterocycles towards electrophiles. The reactivity depends
on (i) the stabilization energy and (ii) the stability of transition state. The lower
reactivity of benzene towards electrophiles is attributed partly to the greater
resonance stabilization energy of benzene. The higher energy of the transition
state of benzene than the structurally related transition states of five-membered
heterocycles is also responsible for the lower reactivity of benzene . The stability
order of the transition states has been observed to be as follows (Fig. 12) :
OH
1?\H
~:. x ';: : , > A
l{[';x_H ~y >?.?
N
H
E 0 E ~
H E
Fig. 12. Stability order of transition states
1.3.5 Effect of Aromaticity on Reactivity
The effect of aromaticity on the reactivity can be evidently observed by comparing

the reactions of five-membered heterocycles with those of the acyclic conjugated
systems (>C=C-XI
where X=NH 2 or OH) involving mesomericeffect (+M). Both the
systems (heterocyclic and conjugated acyclic) are with sp2-hybridized carbon
atoms and involve mesomerically electron release from the heteroatom. Acyclic
conjugated systems undergo electrophilic addition reactions because the
mesomerically electron release from the heteroatom facilitates the attack of
electrophile. The intermediate formed by an electrophilic attack in the first step is
then attacked by a nucleophile in the second step with the formation of addition
product (Fig. 13).
Fig. 13. Electrophilic addition in acyclic system
Five-membered aromatic heterocyclic systems with one heteroatom undergo

electrophilic substitution reactions. Furan, being less aromatic, undergoes
substitution as well as addition reactions. In heterocyclic systems, electrophilic
substitution reactions involve the attack of electrophile in the first step with the
formation of cr-complex which subsequently releases a proton in the second step
to provide substituted product (Fig. 14).
fl)?
X
E+ )lr [exH• •+CxH~aH]
X E X E X E
X=NH,O,S (i) (ii) (iii)
Fig. 14. Electrophilic substitution in heterocyclic system
Thus, in both the systems; acyclic and heterocyclic, the first step is the same and
involves an electrophilic attack, but in the second step acyclic conjugated system
instead of losing a proton is attacked by a nucleophile at the positively charged
carbon atom providing addition product.
1.3.6 Electrophilic Substitution Reactions
Five-membered aromatic heterocycles with one heteroatom are n-excessive and are
characterized by their tendency to undergo electrophilic substitution reactions
rather than addition reactions. The reactivity of these heterocycles towards
electrophiles is higher than that of benzene, but comparable with the most reactive
benzene derivatives; aniline, phenol, etc. The higher reactivity of these heterocycles
is attributed to the unsymmetrical charge distribution in resonating structures in
which the ring carbon atoms are with high electron density (Fig. 15).
o- o-
0 N
~W-~-W
N N
o-I!Jo-
N
H H H H
2 (i) (ii) (iii) (iv)
o- o-
0 0
~W-~-W
0 0
~-w~w-- o-I!:Jo-
0 0 0
3 (i) (ii) (iii) (iv)
o- o-
o-r:Jo-
s
4 (i) (ii) (iii) (iv)
Fig. 15. Resonating structures of pyrrole, furan and thiophene
The general mechanism of electrophilic substitution in the five-membered

heterocycles is similar to that in benzene and involves the attack of electrophile in
the first step with the formation of cr-complex, which subsequently loses a
proton in the second step with the formation of substituted product. Five-
membered heterocycles undergo electrophilic substitutions involving electrophilic
attack at the a (C-2 and C-5) and p (C-3 and C-4) positions ofhiglt electron density.
The resonating structures with unlike charges separated (iii and iv) are less stable
and contributing less to the resonance hybrid than those in which unlike charges
are not much separated (i and ii). The electrophilic attack, therefore, occurs
preferably at the a-position (C-2 and C-5) rather than at the P-position (C-3 and
C-4 ). Moreover, the preferential position of electrophilic attack may be rationalized
in terms of resonance stabilization of the intermediates by delocalization of positive
charge (Fig.16).
The intermediate (cr-complex) obtained by electrophilic attack at the a-position
(C-2 and C-5) has three resonating structures, while the intermediate with
electrophilic attack at the P-position (C-3 and C-4) is stabilized by only two
resonating structures (C4=C 5 double bond between C-4 and C-5 remains
mesomerically intact and does not participate in delocalization). The intermediate

with electrophilic attack at the a-position (C-2 and C-5) is more stable (lowest
energy transition state) than that with electrophilic attack at the 13-position (C 3 and
C4 ) and can be represented by the energy profile diagram (Fig. 17).
[ ex.~+cx~cxH]::iU
E
I ..
40~3(13) X E X E X E X E
[dE- dE] OE
5 2 (a)
X
1
-H+ ..
X X X
Fig. 16. Electrophilic substitution in five-membered heterocycles
d-E
H
!od
e_o X
._0
~ --~ E
U.l
._~
X E
Reaction Path~
Fig. 17. Energy profile diagram

1.3.6.1 Directing Effect of Ring Heteroatom
Five-membered aromatic heterocycles with one heteroatom undergo electrophilic

substitutions preferentially at the a-position (C-2 and C-5) rather than at the
13-position (C-3 and C-4) because of greater resonance stabilization of intermediate
(i) leading to the a-substituted product than the intermediate (ii) providing
13-substituted product. However, the ratio of a-substitution to 13-substitution
depends on the directing effect of the ring heteroatom as well as on the reagent
and the reaction conditions.
fi£><H
X E
(i)
The order of a-directing effect of the heteroatom in five-membered aromatic

heterocycles is : furan >> thiophene >> pyrrole. The a-directing influence of the
ring heteroatom in furan (oxygen) is more pronounced than that of the ring
heteroatom (sulfur) in thiophene, while ring nitrogen (in pyrrole) exerts least
powerful a-directing effect among three heterocycles. But because of increased
reactivity of furan compared with thiophene, furan is expected to be less
regioselective than thiophene according to the principle of reactivity and
selectivity. However, the high regioselectivity of furan is attributed to its ability
of complex formation with reagent and greater mesormerically electron releasing
tendency of oxygen than sulfur for the more effective resonance stabilization of
intermediate. The ratio of a- to 13-substitution products is also influenced by the
reaction temperature and the proportion of 13- substitution product increases with
increasing temperature.
1.3.6.2 Directing Effects of Substituents in Monosubstituted

Heterocycles
The preferential a-substitution rather than 13-substitution in these heterocycles

depends on the a-directing effect of the ring heteroatom. But the substituent
present also has its own directing influence on electrophilic substitution in
deciding the position of incoming electrophile. The position to be occupied by an
electrophile, therefore, depends on the balancing effect of the a-directing effect of
the ring heteroatom and the substituent effect depending on the nature and
position of the substituent.
(i) Effect of electron-releasing substituents at C-2
The effect of electron-releasing substituents at C-2 position is similar to that of

ortho-para directing substituents in benzene and tend to direct incoming
electrophile to C-5 position. The ortho-para directing effect of a substituent is
also enhanced by the a-directing effect of the ring heteroatom. In the presence of
weakly electron-releasing substituents (Cl, CH3) at C-2 position, the a-directing
effect is the prevailing effect, but with strongly activating substituents
(OCH 3 , NHCOCH 3) the a -directing effect is more pronounced. The substitution
may occur at C-3 due to the ortho-effect of electron-releasing substituents
(scheme-6).
~ E
+
.. ~ fi
do,
+
X R E X R X R
~ ~
HN03
+
(CH 300h0 02N S CH3
S CH3 S CH3
10 11 12
Scheme-6
(ii) Effect of electron-withdrawing substituents at C-2
The effect of electron-withdrawing substituents is similar to the meta-directing

effect in benzene. The presence of electron-withdrawing substituent at C-2 causes
substitution at C-4 due to directing influence of the substituent. But the directing
effect of substituent competes with the a-directing effect of heteroatom which
causes substitution to occur at C-5. Thus, the substitution depends on both the
prevailing opposite effects and the ratio of the products (C-4 and C-5 substitution)
varies with the relative effectiveness of both the opposing factors (nature of
heteroatom for a-directing effect and substituent effect) (scheme-7). The formation
of 2,5-disubstituted furan is rationalized by the most powerful a -directing effect of
oxygen in furan than that of sulfur and nitrogen in pyrrole and thiophene,
respectively.
(iii) Effect of electron-releasing substituents at C-3
The presence of electron-releasing substituents at C-3 will reinforce the a-directing

effect of ring heteroatom with the substitution at C-2 (scheme-8).
22 Heterocyclic Chemist1y
Q S N02
nitration
02N
~ S N02
13 16
+h
0 2N
Q S N02
nitration
02N
~ S N02 S N02
14 17(15%) 18 (85%)
h
02N
~
N N02
nitration
02N
~ N N02
+
N N02
H H H
15 19 (20%) 20 (80%)
Scheme-7
X = NH, 0, S
G = electron-releasing
group (halogen)
d~ X E
Scheme-S
If the electron-releasing substituent is alkyl, the reactivity of a-positions (C-2

and C-5) does not differ appreciably and in case of the sterically hindered alkyl
group or incoming electrophile, the substitution at C-2 is restricted and occurs at
C-5 (scheme-9).
d
CH3
(i) HCN/HQ
(ii) H 2 0
0
21
C(CH3)J
d 0
acetylation
23
Scheme-9
(iv) Effect of electron-withdr awing substituents at C-3
The effect of electron-withdrawing substituent at C-3 is similar to the meta-

directing effect in benzene and is reinforced by the a-directing effect of ring
heteroatom. Thus, the combined effect of both the effects; meta-directing effect of
the substituent and a-directing effect of the heteroatom, causes substitution to
occur at C-5 most favourably (scheme-10).
X = NH, 0 or S
W =electron-withdrawing group (-CHO)
Scheme-10
The orientation effects of the different substituents with their electronic effects are
represented schematically (Figs. 18-23) :
(i) Substituents with I and + M effects

(a) substituents at C-2
E+~0X- G (-1 and +M effect- halogen)

Fig. 18
due to ortho effect
~
E~ X R (+I effect-alky I group)
a-directing effect
Fig. 19
(b) substituents at C-3
G (-I and +M effects)
o~ X E+
Fig. 20
R (+I effect-alkyl group)
''"ic•lly hindc"d f Q\
alkyl group/electrophile '-------..._ +
E
Fig. 21
(ii) Substituents with -1 and -M effects

(a) substituents at C-2
/ least deactivated position
+rn
E~ X W (-I and -M effects : -N0 2 , -CN, -COR)
most activated by
(C-4 is least deactivated
a-directing
(C-5 is most activated by
effect of heteroatom
a-directing effect of heteroatom)
Fig. 22
(b) substituents at C-3
0
W (-1 and -M effects)
(due to combined effect of
E+ ~ a-directing effect of heteroatom
X and substituent effect)
Fig. 23
1.3.6.3 Directing Effects of Substituents in Disubstituted

Heterocycles
Electrophilic substitution in disubstituted five-membered aromatic heterocycles

with one heteroatom depends on the directing effect of the ring heteroatom as well
as on the nature and position of the substituents already present similarly as for
monosubstituted heterocycles. The positions expected for the electrophilic attack
are indicated in the disubstituted heterocycles (Fig. 24):
r:(
CH3
H3 Ch r:(
CHO
/ X CH3 / X CH3 / X CH3
a-directing effect of a-directing effect of a-directing effect of

heteroatom reinforced heteroatom + ortho- heteroatom + meta-
effect of electron- directing effect of
releasing substituent electron-withdrawing
substituent (a-directing
effect reinforced)
N02 N02 02N
/
r:(
X CH3 /
r:(X Br /
~ X N02
a-directing effect of a-directing effect of combined effect

heteroatom + substituent heteroatom + meta- (a-directing effect
effect (a-directing effect directing effect of of heteroatom +
reinforced) substituent substituent effect)
Fig. 24. Directing effects of substituents in disubstituted heterocycles

Electrophilic substitutions in 2,5-disubstituted heterocycles normally occur at

the ~-position . However, in some cases, specially with furan, electrophilic
substitution occurs with the displacement of a-substituent (carboxyl, acyl or
halogen) ( scheme-11 ).
[ ;;xo2
H3C ~; COOH
]-co~n
H3C 0 N0 2
26
Scheme-11
1.3.7 Nucleophilic Substitution Reactions
Five-membered aromatic heterocycles with one heteroatom are n-excessive and do

not undergo nucleophilic substitution reactions. The unreactivity of n-excessive
heteroaromatic halides towards nucleophiles is comparable with that of aryl
halides. However, heteroaromatic halides substituted with strong electron-
withdrawing substituents undergo nucleophilic substitution reactions under
forcing conditions. The mechanism of nucleophilic substitution in 2-halo-5-
nitrothiophene is presented ( scheme-12).
0 2N
n~S
27
Br
[ u~ /:J<B~
02N S
(i)
Nu 0 2N S
(ii)
Nu 02N
J:;)<Br]
S Nu
(iii)
Ill
-sr
Scheme-12
The relatively high reactivity of 2-halo-5-nitrothiophene compared with the

corresponding pyrrole and furan has been rationalized by the additional
stabilization of intermediate (delocalization of negative charge) by involving
d-orbitals of sulfur (Figs. 25 and 25a) .
O
.. -
H O
.. -
S
H
Nu
0 Nu
Fig. 25 Fig. 25a
1.3.8 Reduction
Five-membered n-excessive heterocycles can be reduced with the possibility of

two dihydro-29 and -30 and one tetrahydro-31 derivatives (scheme-13). The
number of possible isomers increases with increasing degree of substitution
(scheme-14).
0 .. 0
X X
29
+
Q 31
Scheme-13
H, F\ ,H H, F\ .,H
+X
R X
X+
R R
X,x.
X 'R
cis trans
34
H, f\ ,H H, f\ .,H
RXXXR + R X X /.. R
cis trans
35
Scheme-14
1.3.9 Addition Reactions
Five-membered aromatic heterocycles with one heteroatom undergo their

characteristic electrophilic substitution reactions. However, the reaction, specially
of furan, with acetyl nitrate results in the formation of 2,5-addition product 37
( scheme-15). The abnormal behaviour of furan is attributed to the lower aromatic

stabilization energy of furan and is evident by comparing the nitration of pyrrole
and furan with acetyl nitrate. The first step is the same in both the cases and
involves the attack of electrophile (N0 2 +) at C-2 with the formation of a-complexes.
+ AcO H, f \ "H
• A .. A
0 N
H
2
+
-H
+
-H
0 0
3
Scheme-IS
The second step involves deprotonation to form substituted (aromatic) product or

the attack of nucleophile with the formation of addition (nonaromatic) product
depending on the relative activation energy of deprotonation and nucleophilic
addition and also on the aromatic stabilization energy of heterocyclic ring system.
The high stabilization energy of pyrrole and lower activation energy of
deprotonation due to partially developed aromatic character in transition state are
responsible for the deprotonation in the second step to provide substituted
pyrrole 36 (scheme-16), but lower stabilization energy of furan and higher energy
of activation of deprotonation lead furan to undergo nucleophilic addition in the
second step providing 2,5-addition (nonaromatic) product 37.
__.. [0;--
O H~ " H--OA]
AcO ' + , c -AcOH
...
~ N02 ~ N02
Scheme-16
1.3.1 0 Cycloaddition Reactions
Five-membered aromatic heterocycles; pyrrole, furan and thiophene, with varying

degree of aromaticity are considered to be related with conjugated dienes and,
therefore, expected to undergo characteristic reactions of conjugated dienes. Since
aromaticity is inversely related to the dienic characteristics, furan is the least
aromatic (lowest resonance energy although much higher than that of conjugated
diene) amongst three heterocycles and, therefore, undergoes cycloaddition
reactions. Furan reacts as a diene with dienophiles in Diels-Alder (4 + 2)
cycloadditions and pohotochemical (2 + 2) cycloadditions (scheme-17). Pyrrole has
Q:
X= NH or 0 38
39
Scheme-17
more aromatic character than furan and is, therefore, less susceptible towards
characteristic reactions of dienes. However, pyrrole substituted with electron-
withdrawing substituent at nitrogen behaves as a diene and undergoes
cycloaddition reactions with dienophiles (scheme-18).
...
41
Scheme-18
Thiophene is the most aromatic among these aromatic heterocycles and,

therefore, fails to undergo cycloaddition reactions with dienophiles under normal
conditions. However, when thiophene is heated under pressure with maleic
anhydride, cycloadduct 42 is obtained in moderate yield involving (4 + 2)
cycloaddition ( scheme-19). Thiophene sulfoxides and sulfones in which aromatic
0s
4
+
c1: 0
. 0
0
42
Scheme-19
lone pairs are involved in bonding behave as diene and undergo characteristic
reactions of conjugated dienes (scheme-20).
? Pe<'Oidoxid•tion [ 9 + Q ]__._
0 0
43 44
Scheme-20
1.3.11 Reactions with Free Radicals
Five-membered aromatic heterocycles are expected to undergo free radical

substitution reactions similarly as benzenoid systems, but some what modified by
the presence of heteroatoms. Free radical substitution in pyrrole is considered to
provide three possible monosubstituted products, whereas in furan and thiophene
two monosubstituted products are possible (scheme-21). However, these
heterocycles react with free radicals preferentially at the 2-position with varying
degree of reactivity. Thiophene is estimated approximately to be three times more
reactive than benzene towards free radical acylation, while furan is 12 times more
reactive than benzene.
0 N
H
R
.. G- N
H
R
+
0 N
H
+
0 N
I
R
46 47 48
R
0 X
(X= 0, S)
R
. G- X
49
R
+
0 X
50
Scheme-21
1.3.12 Reactions with Electron-Deficient Species
Furan and thiophene undergo addition reactions with carbenes involving C2-C3
bond with the formation of cyclopropane derivatives 51 when treated with diazo
compounds, but pyrrole gives 2-substituted product 52 (scheme-22). However,
pyrrole 53 substituted with electron-withdrawing substituent at the nitrogen atom
also undergoes addition reaction with carbene with the formation of cyclopropane
derivative 54 (scheme-23).
The reaction of pyrrole with dichlorocarbene, generated by the reaction of
chloroform with a base, provides 3-chloropyridine 55 or pyrrole-2-carbaldehyde 56
depending on the reaction conditions (scheme-24).
32 Heterocyclic C hemistry
X
0 + N2CHCOO~H 5 ---i~ zY--cooc 2 H5
X
(X=O, S)
51
0
N
+ N 2CHCOO~H 5 _ _.,.~ ~
N CH 2COOG.2Hs
H H
52
Scheme-22
0
N
+ N 2CHCOO~H 5 ---1~ zY--coo~H 5
N
I I
COOCH3 COOCH3
53 54
Scheme-23
('Y-c1
~CI
- HCI
~~
H
0
CHCI3
+ : CCI2 b
ase
N
H
o~~ oH•~
NH CCI 2 N CHCI2 N CHO
H H
56
Scheme-24
2 PYRROLES3- 5
2.1 General
Pyrrole is an important 1t-excessive aromatic heterocycle because this ring system

is incorporated as a basic structural unit in porphyrins; porphin (haem) and chlorin
(chlorophyll), and corrins (vitamin B 12) . Moreover, the presence of pyrrole ring
system in porphobilinogen 57 (intermediate in biosynthesis of porphyrins and
vitamin B 12), biliverdin and bilirubin (pyrrole-based bile pigments) and pyrrolnitrin
58 (with antibiotic activity) has provided an impetus to the pyrrole chemistry.
HOOC - CH 2 -CH 2
n N
H
57
C~COOH
C~NH2
Cl
N
H
58
Cl
Pyrrole was isolated in pure form from bone oil in 1857 and its structure was
established in 1870, although the characteristic behaviour of pyrrole of imparting
red colour to the pine wood moistened with an acid led to its discovery in 1834
as a substance present in bone oil and coal tar.
2.1.1 Extraction
washed with washed with

Bone oil _ _ _ ___. Bone oil free from Bone oil free from
alkali acidic substances dil. acid
bases
steam KOH
1 fractional
distillation
Pure pyrrole Potassium pyrrole Fraction between

distillation fusion 100-150°C
2.1.2 Ehrlich Test
It is a characteristic test for pyrrole in which the reaction of pyrrole (or alkyl pyrrole
with free 2- or 3-position) with 4-dimethylaminobenzaldehyde in the presence of
hydrochloric acid produces purple colouration due to the formation of cation 59
(scheme-25).
Scheme-25
2.2 Synthesis
2.2.1 Cyclization Reactions
Pyrroles are generally synthesized by the cyclization reactions involving

nucleophilic-electrophilic interactions. The synthetic methods are arranged on the
basis of number of fragments involved in the cyclizations.
2.2.1.1 (3 + 2) Cyclization Reactions
2.2.1.1.1 Reaction of a-Amino Ketones or a-Amino P-Keto Esters with

P-Diketones or P-Keto Esters (Knorr Pyrrole Synthesis)
This is the most widely used method and involves the cyclizative condensation
of a-amino ketones or a-amino-P-keto esters (three atom fragment - with
nucleophilic nitrogen and electrophilic carbonyl carbon) with P-diketones or P-keto
esters (two atom fragment - with electrophilic carbonyl carbon and a nucleophilic
carbon) with the formation of N-C 2 and C3-C 4 bonds (scheme-26).
60 61
R = H, CH3 , COOC 2H 5 ; R 1 = COCH3 , COOC 2H 5
Scheme-26
The reaction is considered to proceed with the formation of enamine intermediate

60a involving attack of nucleophilic amino group of a-amino ketone or a-amino-
P-keto ester 60 on the electrophilic carbonyl carbon of P-diketone or P-keto ester
(N-C 2 bond formation). Subsequent cyclization takes place with the nucleophilic
attack of P-carbon of enamine 60a on the electrophilic carbon of carbonyl group
of a-amino ketone or a-amino-P-keto ester (scheme-27).
H C R1
3 \ I
HO-C-C
H-i~
R ~ CH3
+
-H
61
Scheme-27
The mechanism is generalized as follows (scheme-28) :
H E + '-.. C' H
~0 , _,.. E
""-c--.o ' / H C ~ C cyclization
I .,..C
H, + H I f'\ H-...1 II
.,..c,.~c~' H./'....N_....C,H
H NH2 H"' ~0
I~
E = electron-withdrawing group H
E
0 N
H
isomerization
Scheme-28
2.2.1.1.2 Reaction of a-Amino Ketones with Alkynes
The reaction of a-amino ketones 62 with alkynes 63 proceeds with the

nucleophilic addition of amino group to the electrophilic carbon of alkyne with the
formation of enamine intermediate 64 which on intramolecular cyclization provides
pyrroles 65 involving nucleophilic W-carbon of enamine intermediate)-electrophilic
(carbonyl carbon) interaction with the formation of C3-C4 bond (scheme-29) 6 .
H3CHCOOCH3
... Ho-p-~-H
•
1 COOCH 3
H3c,
R~N>-coocH 3 H-C C
R/ 'N~ 'coocH 3
H
Scheme-29
2.2.1.1.3 Reaction of ~-Amino-a,~-unsaturated Esters with Nitroalkenes
The reaction of ~-amino-a,~-unsaturated esters 66 (three-atom fragment) with

nitroalkenes (two-atom fragment) provides substituted pyrroles 70 involving
(3 + 2) cyclization with the formation of N-C2 and C3-C4 bonds (scheme-30f
,R2
C2H 500C, ....,.CH
c \
11 CH2N02
H3C....-
c
'NHR1
67
Scheme-30
The reaction is considered to proceed with the conjugate addition of enamine

to nitroalkene followed by intramolecular cyclization involving nucleophilic
addition of amino group to the aci-form 68 of nitronate ion. The driving force for
the elimination of nitrogen substituent is provided by the aromatic stability of the
resulting pyrrole 70.
2.2.1.1.4 Reaction of a-Diketones with Amines
Base catalyzed (3 + 2) cyclizative condensation of a-diketones 71 with amines 72

substituted with electron-withdrawing substituents at a,a '- positions results in
the corresponding pyrroles 73 with the formation of C2- C3 and CcC5 bonds
(scheme-31)8.
C6Hs-C-C-C6Hs
II II
0 0
71
+
E-H2C, /CH2-E
N
H
72 73
E =CN, COOC2Hs
Scheme-31
2.2.1.2 (2 + 2 + 1) Cyclization Reactions
2.2.1.2.1 Reaction of ~-Keto Esters with a-Halo Ketones (Hantzsch Pyrrole

Synthesis)
The reaction of ~-diketones or ~-keto esters 74 with a-halo ketones or aldehydes

76 in the presence of ammonia or primary amine affords pyrroles 78 involving
(2 + 2 + 1) cyclization with the formation of N-C 2, C3-C4 and N-C 5 bonds
(scheme-32). The reaction proceeds via stabilized enamine intermediate 75 which
on C-alkylation and N-alkylation by a-halo ketone leads to the formation of
corresponding pyrrole.
However, in this method ~-keto ester 74 can combine directly with a -halo ketone
76 involving nucleophilic attack on the carbonyl carbon of a-halo ketone with the
formation of furan 79 as a byproduct (scheme-33).
2.2.1.2.2 Reaction of Aldehydes or Ketones with Hydrazine (Piloty-Robinson

Pyrrole Synthesis)
The condensation of aliphatic aldehydes or ketones with hydrazine under strongly

acidic conditions affords pyrroles involving (3 + 3) sigmatropic rearrangement and
cyclization (scheme-34). This reaction can also be applied for the preparation of
N-substituted pyrroles by condensing ketones with methylhydrazine or N,N'-
dimethylhydrazine9 .
2.2.1.2.3 Reaction of Benzoin with Benzyl Aryl ketones
The reaction of benzoin 84 with benzyl aryl ketones in the presence of ammonium
acetate results in the formation of polyaryl substituted pyrroles 87 involving
(i)
78
Scheme-32
C2H500C, CzHsOOC,
CHz CH
I ......,.,.___......,~ II
1,......c~ c ..
R 0 R1 ,...... 'oH
74
79
Scheme-33
acid
(RCH2bC=O + H2N-NH2 (RCH2hC=N-N= C(CH2Rb
+ R 80 R
(RCH2hC==O
+
'fH H n~
... H RH2C
,-C,-- --""'C'
N- N
H H
CH2R
81
82
Scheme-34
(2 + 2 + 1) cyclization. The reaction is considered to proceed via an enamine

intermediate 86 of which keto and enol forms are interconvertible and undergo
dehydrative cyclization to provide the corresponding pyrrole 87 (scheme-35) 10.
Ar
Ar"'-.. ,..OH Ar........._ ,-OH /
C CH
CH II II
I + c c
/C.:::. Ar/ 'N""' 'Ar
Ar 0 H
84 85 86a
Ar, /Ar
H
Ar........._ ~0 /
Ar
Ar
Ahr -H 20 c-c \JC CH
v ~~ HO""I
c
II~
c b~t
Ar/H'N""' 'Ar
Ar N Ar Ar/H'N""' 'Ar
H H
H
87 86b
Scheme-35
2.2.1.2.4 Reaction of Aldehydes with Alkyl lsocyanoacetates
The condensation of alkyl isocyanoacetates with aldehydes in 2:1 ratio proceeds

to involve an initial conjugate addition followed by an anionic cyclization with the
formation of C2-C3, C3-C 4 and CcC5 bonds (scheme-36) 11 .
,.NC
RCH=O + CH2
' COO~Hs
89 88
Scheme-36
2.2.1.3 (4 + 1) Cyclization Reactions
2.2.1.3.1 Reaction of 1,4-Diketones with Ammonia or Ammonia Derivatives

(Paal-Knorr Synthesis)
It is the most general method and involves (4 + 1) .:yclizative condensation of 1,4-

diketones (enolizable) with ammonia or its derivatives with the formation ofN-C2
and N-C 5 bonds (scheme-37) 3•12 •13 . The reaction is considered to proceed with the
successive attacks of nucleophilic nitrogen on the carbonyl carbon and finally
followed by dehydration (aromatization) for which driving force is provided by the
stability of the resulting pyrrole.
2.2.1.3.2 Reaction of 1,4-Dienes or Diynes with Amines
Metal ion assisted amination of 1,4-dienes or diynes with primary amines

followed by cyclization provides N-substituted pyrroles (Schemes-38 and 39) 14- 16 .
H2e-eH2
R, I \
benzene
/e e,
acid HO I II R
NHR 1 0
91
t
+
-H20
He-eH2
/e-;.e,
,, '
R ~HR 1 0~
92
93
Scheme-37
eH2=eH-eH=eH2 Cu(0Ac}2
AcOH
Pd/C 0
N
I
R
96
Scheme-38
R
~ N R
11
R
97
Scheme-39
2.2.2 Ring Expansion Reactions
2-Acylaziridines 98 undergo ring expansion reactions to provide pyrroles 99

involving ring-opened dipolar intermediates (scheme-40) 17 .
c;o HC
3 \
/O
c HUCH2 c
-
/0
H3CWC'R1 ~ /.79'1
+./I 9' 1 CH/1"'/C R
HC n/C R ~+ I
N ~ '-· · I N H
I .,. N H I
R I
R R
98
R1
0 N
I
R
99
Scheme-40
Vinylazirines 100 also undergo ring expansion reactions, but two isomeric
pyrroles 103 and 104 are obtained depending on the reaction conditions. Thermal
reaction involves a nitrene intermediate 101, while photochemical reaction
proceeds via a nitrile ylide intermediate 102 (scheme-41) 18 .
2.2.3 Extrusion Reactions
The complex ring systems, formed by (3 + 2) cycloaddition of activated alkynes

substituted with electron-withdrawing substituents, with mesoionic heterocycles
hv HsC6~CH=CH-R
..,.__ \\/
N
102
r{_j N C5Hs
H
104 103 101
Scheme-41
105- 107, undergo extrusion reactions with the cleavage of larger ring leaving the
pyrrole ring system intact (scheme-42) 19•20 .
Co
)!i:, 0
E E
o
___._
+~~J;-
!'.
E-c=c-E
- C02
(E=COOCH3 ) / N
R I
E R R
105
}+'R
102
E E
+
R2 N~R1
I
N
~
r;)5R1 I
R R
106 109
R1 R E E
~JrJ
0 s K N
I
R1
R
107 110
Scheme-42
2.3 Structure
Pyrrole has a planar pentagonal structure with four carbon atoms and nitrogen
atom sp 2-hybridized. Each ring atom forms two sp 2-sp 2 cr-bonds to its neighbouring
ring atoms and one sp 2-s cr-bond to a hydrogen atom. The remaining unhybridized
p -orbitals, one on each ring atom (with one elctron on each carbon and two
electrons on nitrogen), are perpendicular to the plane of cr-bonds and overlap to
form a 7t-molecular system with three bonding orbitals. The six 1t-electrons form
an aromatic sextet which is responsible for the aromaticity and renders stability to
the pyrrole ring (Fig. 26). Pyrrole molecule has C2v symmetry with the following
molecular dimensions (Fig. 27):
Fig. 26. Orbital structure of pyrrole
,-------1.417A
8 1 = 109.8"
H
82 = 107.7" ~----1.077A
'M---<
~----l.382A
83 = 107.4°
~,......_---1.076A
84= 12l.SO H
....._.::._ _ _ _ l.370A
85 = 125.SO ..__ _ _ _ _ 0.996A
Fig. 27. Molecular dimensions of pyrrole
The Ca-N and Cp-C,r bonds are shorter than the normal single bonds, whereas
Ca-Cp bonds are longer than the normal double bonds. The molecular dimensions
of pyrrole reflect cyclic de localization with the involvement oflone pair of electrons
on the nitrogen. Pyrrole is considered to be resonance hybride of the resonating
structures (i-iv) with electron-rich carbons which lead to its classification as a
7t-excessive aromatic heterocycle (Fig. 28).
2 (i) (ii) (iii) (iv)
Fig. 28. Resonating structures of pyrrole
2.4 Basicity
Pyrrole is extremely a weak base because the lone pair of electrons on the nitrogen
atom is involved in the cyclic delocalization and is, therefore, less available for
protonation. Moreover, pyrrole is a weaker base than pyridine and even than
aniline in which lone pair on the nitrogen atom is involved in the resonance and
not essentially contributes to the aromatic sextet. The protonation of pyrrole at
nitrogen or carbon-2 or carbon-3 of the ring reduces its basicity and destroys its
aromaticity (scheme-43). However, C- and N-alkyl substituents enhance the
basicity of pyrrole but the electron-withdrawing substituents on the ring make
pyrrole a weaker base.
+H
+
+H
+ r=\/H
+ ~:t-.A
-H N H
H
Scheme-43
2.5 Reactions
2.5.1 Protonation
The protonation of pyrrole at nitrogen is most rapid than that at C-2 and results
in thermodynamically more stable 2H-pyrrolium cation (than lH-pyrrolium cation),
although carbon-3 is protonated but to a lesser extent. Moreover, the pKa (-3.80)
of its conjugate acid corresponds to the protonation preferentially at carbon-2
rather than at nitrogen atom (scheme-44).
0 N
H
+
f\.,H
~+/<..
N
H
H
Scheme-44
Pyrrole on treatment with mineral acid under carefully controlled conditions

produces a trimer, 2,5-di(2-pyrrolyl)pyrrolidine 112. The formation of trimer is
considered to involve an electrophilic attack of less thermodynamically favoured
but more reactive J3-protonated pyrrole on neutral pyrrole. Although, an alternative
sequence involving electrophilic attack of a-protonated pyrrole on neutral pyrrole
has not been ruled out in which the resulting 2-(2-pyrrolyl)-~ 3 -pyrroline 113
undergoes acid catalized tautomerization to produce 2-(2-pyrrolyl)-~ 2 -pyrroline
111 (scheme-4 5)21 •22 .
The dimerization of 3,4-dirnethylpyrrole 114 in the presence of 6N hydrochloric
acid also proceeds to involve a- protonated species (scheme-46)2 3 . Moreover, the
acid catalyzed intramolecular conversion of 2-acylpyrroles 116 into 3-acylpyrroles
117 also involves protonation preferentially at carbon-2 (scheme-47)24 .
2.5.2 Proton Exchange
The hydrogen atom attached to the pyrrolyl nitrogen (N-H) undergoes very rapid
exchange in either acidic, basic or neutral media, but the exchange of C-H
(hydrogen attached to ring carbon) does not occur at an appreciable rate. The acid
catalyzed H ~ D exchange at the position-1 is 100 times greater than that at
carbon-2 or carbon-3 (scheme-48). The rapid H ~ D exchange at the position-
1 is attributed to the kinetically favoured reaction due to very low activation
energy for the N-H bond breaking and bond forming in comparison to the
activation energy for a C-H bond.
The relative rate of a : J3 H ~ D exchange is generally between 1.0 and 2.0
for pyrrole and 1- alkylpyrroles. In 2- alkylpyrroles H ~ D exchange is kinetically
favoured at the position-3, while the exchange rate is highest at the position-2 for
3-alkylpyrroles (scheme-49).
r::
0
·~
N
·.:
Q)
E
0
...
~
113
Scheme-45
Scheme-46
n?
~-X
N
I
COR
H+
~~:t-.A
f\
N
I
/COR
H
~ !(+)
N
I
H
r-f-coR -H+
~I( )\
rl
N
I
COR
CH3 CH3 CH3 CH3

116 117
Scheme-47
0 N
acidic, basic
or neutral media 0 N
I
H
D
2 118
Scheme-48
ocr ~
~D
tz+A
N R
H
-H
+
n;
N
I
D
R
I D
D
R 119
0
R
R
r=(H +
-H
fS_
N
+ DCI~
~+X
N D N D
H H H
Scheme-49
2.5.3 Electrophilic Substitution Reactions
Pyrrole is a 1t-excessive aromatic heterocycle. The 7t-excessive character of pyrrole

makes it susceptible towards electrophilic substitution reactions rather than
addition reactions. Pyrrole undergoes electrophilic substitution preferentially at
carbon-2 providing thermodynamically stable product, although the substitution at
carbon-3 is also favoured in some kinetically controlled reactions.
The preferential substitution at carbon-2(a) rather than at carbon-3(P) may be
rationalized by higher stability of the transition state (a-complex) resulting from the
electrophilic attack at carbon-2 than that obtained by electrophilic attack at carbon-
3 (Fig. 29). The transition state (a-complex) involved in C-2( a) substitution is,
therefore, stabilized to a greater extent than that involved in C-3 (13) substitution.
Fig. 29. Electrophilic substitution in pyrrole
2.5 .3.1 Orientation
(i) The substituents attached to the nitrogen atom of pyrrole (position-!) do not
have an appreciable effect unless they are bulky or strongly electron-
releasing or electron-withdrawing substituents. The presence of bulky group
exerts steric hindrance and directs electrophilic attack at the position-3. The
proportion of 3-substitution increases with increasing steric effect of the
substituent at the position-! .
(ii) Electron-releasing substituents at carbon-2 of the pyrrole ring facilitate
electrophilic substitution at the position-S (C-5), while the presence of
substituent at carbon-3 causes substitution at the position-2 (C-2).
(iii) Electron-withdrawing substituents at carbon-2 result in electrophilic
substitution at both carbon-4 and carbon-5, but the ratio depends upon the
-M effect of the substituent as the proportion of 4-isomer increases with
effect. The presence of electron-withdrawing substituent at carbon-3 facilitates
the attack of electrophile at carbon-5.
2.5.3.2 Nitration
Because of the sensitivity of the pyrrole ring to oxidation and acid catalyzed
dimerization and polymerization, pyrrole is not nitrated under strong acidic
conditions. The reaction of pyrrole with nitrating mixture (cone. HN0 3 + cone.
H2 S0c suitable for nitration of benzenoid compounds) results in its extensive
decomposition. Pyrrole is nitrated by nitric acid in acetic anhydride at low
temperature with the formation of 2-nitropyrrole 120 as a major product together
with 3-nitropyrrole 121 (scheme-50) 22 .
HN03 + (CH3C0)20
0 N
H
II
+ CH3-C-ON02
1G-20'C
2 120 121
Scheme-50
Nitration of substituted pyrroles by acetyl nitrate [HN03+(CH 3COhOJ also pro-

vides 2- and 3-nitro derivatives but the formation of 3-nitro derivative is favoured
with increasing steric effect of the substituent at the position-! (scheme-51 )22 •25 •
N02
0 N
U+ON N02 N
I I I
R R R
122 123
Scheme-51
Nitration of pyrroles substituted with electron-withdrawing substituents at

carbon-2 generally produces comparable amounts of 4- and 5-nitro derivatives 124
and 125, whereas with electron-releasing substituents at carbon-2, the 3-, 4- and
5-nitropyrroles 126, 127 and 128 in a ratio of 3 : 2 : 5 are obtained
(scheme-52 )22 •26- 28 •
126 127 128
Scheme-52
2.5.3.3 Halogenation
The high reactivity of pyrrole ring system causes it to undergo halogenation at

all the strongly activating positions. The special reagents with mild conditions are,
therefore, required for the halogenation of pyrroles.
2.5.3.3.1 Chlorination
Chlorination of pyrrole with sulfuryl chloride in ether results in polychlorination

providing mono-, di-, tri-, tetra- and finally pentachloro-pyrroles depending on the
quantity of sulfuryl chloride (scheme-53). Chlorination of pyrrole with elemental
chlorine in warm aqueous alkali produces 3,4-dichloromalimide 131 which is
considered to be derived from the solvolysis of pentachloro-2H-pyrrole 130a
(scheme-53) 29 .
l
Cl excess C ACl
0
Chi
so2c;2 USOzClz fl \\ SOzClz -
-----~~ 1 '\
ether
Cl
ether ~
~ (one mole) N Cl Cl ~ Cl Cl N Cl
H
129 130a
~ c\=/'
A .. A
OH
HzO
rH
l
C X fCl
.0
c1
0 N 0 Cl N Cl
H
131 130b
Scheme-53
2.5.3.3.2 Bromination
Bromination ofpyrrole with bromine in acetic acid gives 2,3,4,5-tetrabromopyrrole

132, but pyrrole substituted with electron-withdrawing substituent undergoes
bromination providing monobrominated pyrroles 133 and 134 (scheme-54).
However, with bromine in carbon tetrachloride, 3-bromopyrrole 136 is obtained by
the isomerization of thermodynamically less stable 2-bromopyrrole 135
(scheme-55) 30 .
2.5.3.3.3 Iodination
Iodination of pyrrole with iodine in aqueous potassium iodide provides

tetraiodopyrrole 137 (scheme-56). However, iodination ofpyrrole substituted with
0 N
H
+ Br2
GI 3COOH
-----..
Br
X N
H
132
Br
Br
0.:_ Br, CRjCXXJH ~ + ~
N COO~H 5 Br N COOC 2 H5 N COOC2H5
H H H
133 134
Schene-54
135 136
Scheme-55
electron-withdrawing substituent at the position-2 results in substitution at the

position-4 (scheme-57).
0 N
+ I2 ~
KI
I
):( N I
H H
137
Scheme-56
Q+I2
N
H
COCH3
~
~COCH 3
H
138
Scheme-57
Pyrrole-2-carboxylic acids 139 polysubstituted by electron-withdrawing

substituents undergo iodinative decarboxylation to provide the corresponding
2-iodopyrroles 140 (scheme-58).
KI
Scheme-58
2.5.3.4 Sulfonation
Pyrrole and its N- and C-alkylpyrroles cannot be sulfonated under ordinary

conditions as these are polymerized by concentrated sulfuric acid. These are,
therefore, sulfonated by mild sulfonating agent (pyridine-sulfur trioxide) of low
acidity. The reaction of pyrrole with pyridine-sulfur trioxide complex at 100°C
provides pyrrole-2-sulfonic acid (scheme-59). Pyrroles substituted with electron-
Scheme-59
withdrawing substituents require vigorous reaction conditions (chlorosulfonic

acid, cone. sulfuric acid and oleum). If both the a-positions are blocked, the
sulfonation occurs at the ~-position (scheme-60) 22 .
~
pyridine-S03
R N R l00°C
H
141
Scheme-60
2.5.3.5 Acylation
Acylation of pyrrole produces N-acyl- or C-acylpyrroles depending upon the

reaction conditions. Acylation of pyrrole with acetic anhydride at I 00-150°C
affords 2-acyl- 143 and 2,5-diacyl- 144 pyrroles, but pyrrole with acetic anhydride
in the presence of sodium acetate provides N-acylpyrrole 145 (scheme-61).
0 N
H
-+
0 N
GI3COONa
0 N
H I
COCH3
145
Scheme-61
N-Acylpyrroles 145 can be obtained by the reaction of alkali metal salt of

pyrroles with an acyl halide (scheme-62).
0 N
+ RCOCI 0 N
+ I
M COR
145
Scheme-62
However, the general methods used for C-acylation are :
2.5.3.5.1 Houben-Hoesch Reaction
The reaction of pyrrole with aliphatic nitrile and hydrochloric acid (RCN/HCl) in
the presence of Lewis acid introduces an acyl group at the a-position of pyrrole
nucleus (scheme-63). The reaction proceeds as depicted in (scheme-64). However,
if both the a-positions are occupied, the acylation occurs at the 13-position. The
rate of acylation is decreased, if the electron-withdrawing substituent is present
at the a-position.
0 N
+ RCN + HCI
H
Scheme-63
+ Cl
-
o+R-C= NH_..aH
C= NH
-=!~C
N
=NH~n
N COR
N N 1
H H 1 H R H
R
Scheme-64
2.5.3.5.2 Gattermann Formylation
The reaction of pyrrole with zinc cyanide and hydrochloric acid results in C-
formylation involving attack of imidoformyl electropohile at the position-2(a)
(scheme-65). If both the a-positions are occupied, C-formylation occurs at the
0 Zn(CNh H20
N HCI
~CH=NH
N
~
N CHO
H H H
Zn(CN) 2 + 2HC1 ZnC1 2 +2HCN

ZnC1 2 + HCl WinC1 3
HC=N + H+ZnC1 3
[TNHl
H--C=NH
+ ZnC1 2 + Cl
Scheme-65
But the electron-withdrawing substituent at the a-position inhibits

~-position.
formylation (scheme-66) 22 . C-Formylation is very significant reaction in pyrrole
chemistry because of the use of pyrrole-2-carbaldehyde in porphyrin synthesis.
n OHhCfXJC H
COOC 2H5
2 5
Zn(CNh
HQ
R N R R N R
H H
146 147
R
R
h N
H
COOC2Hs
Zn(CN) 2
HQ
No reaction
Scheme-66
2.5.3.5.3 Vilsmeier-Haack Reaction
It is the most effective method for C-formylation and acylation ofpyrroles in which
pyrrole is treated with phosphorus oxychloride and N,N-dimethylformamide
(DMF + POC13). The reaction proceeds with C-formylation at the position-2
involving immonium ion as an intermediate (scheme-67).
Cl'. (t
CI-P=O
Cl/
0 N
H
Scheme-67
However, the reaction of !-substituted pyrroles with dimethylformamide and

phosphorus oxychloride provides 2-and 3-formylpyrroles and their ratio depends
upon the steric effect of the substitutent present at the position-! . The presence
of bulky group at the position-! causes Vilsmeier-Haack formylation to occur at
the position-3 (scheme-68).
1/"('CHO
0 N
POC13
(CH3hNCHO
z) N
I I
C(CH3)3 C(CH3h
149 150
Scheme-68
2.5.3.5.4 Friedel-Crafts Acylation
Generally, pyrroles are sufficiently reactive and are acylated by acyl chloride
without using Lewis acid because Lewis acid promotes polymerization of pyrrole.
Pyrroles substituted with electron-releasing substituents and the pyrroles which
are susceptible to acid catalyzed polymerization are acylated by acyl chloride in
the presence of pyridine. The addition of pyridine facilitates acylation due to the
formation of very reactive (N-acylpyridinium) electrophile. However, pyrroles
substituted with electron-withdrawing substituents or sterically hindered
substituents at the position-2 are acylated by Friedel-Crafts acylation.
2.5.3.6 Alkylation
Because of high reactivity of the pyrrole ring, Friedel-Crafts alkylation of pyrrole

with alkyl halides and highly reactive allyl- and benzyl halides results in
polyalkylation under milder conditions (scheme-69).Therefore, it is not possible to
obtain monoalkylated product.
The reactivity of pyrroles substituted with electron-withdrawing substituents
towards Friedel-Crafts alkylation is decreased because of co-ordination of
substituent with Friedel-Crafts catalyst. The reaction of ethyl pyrrole-2-carboxylate
with alkene in the presence of Lewis acid results in the formation of 4-isopropyl-
151 and 4,5-diisopropyl- 152 derivatives (scheme-70).
Friedel-Crafts alkylation ofpyrrole Grignard reagent 153 produces 2-alkylpyrrole
via 1-alkylpyrrole involving Hofmann-Martius type rearrangement (scheme-71).
O+CH31~
~ (excess)
Scheme-69
Q N COO~H 5
+
H
Scheme-70
0 N
+CH31
H
Scheme-71
2.5.3.7 Hydroxymethylation (Mannich Reaction)
Pyrrole undergoes Mannich reaction with formaldehyde and primary or secondary

amine in the presence of an acid with the introduction of functionalized alkyl
group at the a-position. However, if both the a-positions (a, a') are substituted,
the substitution then occurs at a free P-position. The reaction is considered to
involve electrophilic attack of iminium electrophile which is produced in situ from
the reaction offormaldehyde with amine in the presence of an acid (scheme-72) 22 .
The product of Mannich reaction (Mannich base) is synthetically useful as it
undergoes a number of transformations providing important compounds.
--
+
- H
0 N
H
Scheme-72
2.5.3.8 Reactions with Aldehydes and Ketones
The reaction of pyrrole with aliphatic aldehydes and ketones in the presence of
an acid gives unstable and highly reactive electrophile, azafulvenium cation 154,
which on subsequent reaction with pyrrole eventually leads to the formation of
polymeric products; cyclic tetramer 155 with acetone, while linear tetramer with
aldehyde. The presence of two methyl groups force pyrrole rings into coplanar
conformation and leads to the formation of a cyclic tetramer in the reaction with
actone (scheme-73). But the reaction of pyrrole (with single free position) with
formaldehyde in the presence of acid medium provides bis(2-pyrrolyl)methane
156 (scheme-74).
(cyclic tetramer)
0 N
H
155
linear tetramer
Scheme-73
Similarly, the reaction ofpyrrole with aromatic aldehyde and acid in the presence
of air results in the formation of cyclic tetramer, tetraphenylporphyrin 157,
involving highly reactive and unstable azafulvenium cation 157a (scheme-75).
CH2=0 _H--l+ •~ l;);RR H -HzO hRR

~+
~+
R N
H CH 2 R N CH 2
I H
~
)i_CH -ti
R R R R
..0-H_ ____JI ) - )R
2 R N
R N N R H
H H
156
Scheme-74
H
+
~ /C6H5
0 N
H
-H 20
c
N
H ' H +
-H
0 N
H
0 N
H
air
157
Scheme-75
The reaction of pyrrole with aromatic aldehyde substituted with electron-

releasing substituent at para-position is facilitated and produces purple red
colouration due to the formation of resonance stabilized azafulvenium cation 159.
This reaction forms the basis of Ehrlich test (scheme-76). Similarly, the electron-
releasing substituent on the pyrrole ring can stabilize the positive charge and,
therefore, promotes the formation of azafulvenium salt.
Scheme-76
The reaction of pyrroles (having single free position) with aldehydes and
ketones in the presence of hydriodic acid and hypophosphoric acid results in an
alkylation at the vacant position involving reduction of the reactive intermediate,
azafulvenium cation 160 (scheme-77).
R R R R
R
)[§ N R~CH2
H H
R R
h ..
160
I
reduction
R N CH3
H
Scheme-77
2.5.3.9 Diazo Coupling
Pyrrole undergoes diazo coupling reactions very readily with benzenediazonium

salts providing 2-aza- 161a or 2,5-bis(aza)- 161b pyrroles depending on the
reaction conditions (scheme-78). The rate of the reaction is faster in an alkaline
0 - N = N - C 6 H5
N
H
161a
CsHs-N=Nn N=N-CsHs
(aqu. C2H 50H) N
+ H
NaOH 161b
Scheme-78
media as it involves pyrrolyl anion and results in the formation of 2,5-bis(aza)-

pyrrole 161b. If both the a-positions are occupied, diazo coupling occurs at the
13-position (scheme-79).
H3C
n N
H
CH 3
+ CsHs-N=N-CI-..-~ H3C
n N
H
N=N-CsHs
CH3
162
Scheme-79
The reaction of bis(2-pyrrolyl)methanes 163 with benzenediazoanium salts

provides 2-arylazapyrroles 164 (scheme-80). The reaction is considered to proceed
with the attack of diazonium cation at carbon-2 of the ring and involves 2-pyrrolyl-
methyl cation 165 with the formation ofpyrrolyl alcohol166 which with diazonium
cation produces second molecule of arylazapyrrole with the elimination of
formaldehyde (scheme-80).
166
Scheme-SO
2.5.4 Reactions on Carbon and Nitrogen Anionic Species
Pyrrole is a weaker base than secondary amine but much more acidic (pKa=l7 .5)
than aliphatic amine or aniline. The hydrogen atom attached to the nitrogen of
pyrrole can be abstracted by a strong base. The pyrrolyl anion is mesomerically
stabilized and exhibits ambident property by which electophile may attack at
nitrogen and at carbon-2 or -3 (scheme-81).
Scheme-81
Pyrrole reacts with alkali metals and forms N-metallated pyrroles. These metal
salts exist as the solvent separated ion-pairs or contact ion-pairs depending on the
size of the metal cation. The havier metals have high covalent character in the
N-metal bond. These characteristics, however, can be modified by the change in

the polarity of the solvent. The position of substitution (on nitrogen or carbon),
therefore, depends upon the nature of the solvent and the size of the metal cation.
2.5.4.1 Alkylation
The alkylation of sodium and potassium salts of pyrrole produces predominantly

N-alkylated products, while magnesium and lithium salts provide mainly the
products of C-alkylation. Moreover, the alkyl halides which promote SN 1 reaction
also facilitate predominantly C-alkylation. Thus, pyrrolylsodium with allyl bromide
in THF produces 1- and 2-allylpyrroles in I : 4 ratio (scheme-82) 22 .
0 + CH2=CH-CH2-X
THF
... O+Q
N
~ N CH2-CH=CH 2
+ CH2-CH=CH2
Na
167 168
Scheme-82
C-Alkylation and /or N-alkylation of pyrrolyl salts can be interpreted in terms of

'hard-soft acid-base' theory. The salts of the harder cations(Li+,Mg+2) undergo
C-alkylation, while the soft cations (such as quaternary ammonium salts) favour
N-alkylation. N-Alkylation, therefore, increases with the larger metallic cation and
with the more solvating power of the solvent.
Generally, the alkylation ofpyrrole occurs preferentially at the position-2 and can
be rationalized by involving a cyclic transition intermediate 169 (scheme-83). The
alkylation with primary alkyl halides in the polar solvents occurs almost exclusively
at the nitrogen atom which is the characteristic reaction of pyrrolyl anion, while
the alkylation with allyl bromide or sec- or tert- alkyl halides facilitating SN 1
reaction, occurs at carbon of the pyrrole ring even in highly polar solvent.
0 N
I
~
RX
~
N R
H
R M--x
169
Scheme-83
2.5.4.2 Acylation
Acylation of the soft alkali metal salts of pyrrole occurs at the position-}
(N-acylation) with the formation ofN-acyl derivatives, but facile thermal rearrange-
ment produces the corresponding C-acyl derivatives. However, under phase-
transfer conditions, N-acylation takes place without undergoing thermal
rearrangement ( scheme-84 )31 •32 .
0~+
----.. 0 .
N
I
CO~H 5
(M = alkali metal)
Scheme-84
The site of acylation is changed with the change in the hardness of the acylating
agent and is attributed to the variation in the ability of the reagent to co-ordinate
with metal ion and consequently its ability to change the hardness of the metal
ion and its association with a pyrrolyl anion. The acylation of pyrrolyl magnesium
bromide by S-ethyl chlorothioformate results in preferentially C-2 acylation due to
its weak co-ordination with magnesium ion. But the addition of tetrame-
thylenediamine (TMEDA), which co-ordinates strongly with the metal ion, causes
reversal in the site of acylation providing exclusively pyrrole-1-thiocarboxylic ester
171 (scheme-85).
Scheme-85
The presence of electron-withdrawing substituents at the position-2 of a pyrrolyl

anion stabilizes the anion with the reduction in association with the metal ion and
hence causes acylation preferentially at the position-!, while the presence of electron
-releasing substituents destabilizes the pyrrolyl anion with the strong association
ofpyrrolyl anion with metal and results in preferentially C-acylation (scheme-86).
RCOCI -----~•~ ~ N COOC 2 H5

I
COR
..
172 173
Q N CH 3
+ RCOCI
RC
~ N CH 3
I II H
MgBr 0
174 175
Scheme-86
2.5.5 Nucleophilic Substitution Reactions
The n-electron excessive character of pyrrole renders it relatively inert towards

nucleophilic substitutions or addition reactions. The nucleophilic substitution
reactions are rare in pyrroles, however occur only if pyrrole is protonated or
substituted with electron-withdrawing substituents.
The reaction of 3,4-dinitropyrrole with sodium methoxide proceeds via the
formation of trans-2,3-dimethoxy-4-nitro-il4 -pyrroline 176 which under acidic
conditions provides 2-methoxy-4-nitropyrrole 177 involving cine-substitution,
while in the presence of a base 3-methoxy-4-nitropyrrole 178 is obtained involving
ipso-substitution (scheme-87) 33 ·34 .
178
Scheme-87
The acid catalyzed nucleophilic substitution in 3-amino-2-(2-aminophenyl)- pyrrole ·

179 involves nucleophilic attack of the phenylamino group on the protonated
aminopyrrolyl with the cyclization to provide pyrrolo[3,2-b]indole 180 (scheme-88) 35 .
Scheme-88
2.5.6 Oxidation
2.5.6.1 Autoxidation
Pyrroles are extremely susceptible to oxidation and provide polymeric products. The
reaction of pyrroles with atmospheric oxygen (triplet oxygen) causes autoxidation
involving radical reaction. The presence of electron-releasing substituents
enhances the susceptibility of pyrroles to oxidation, while the electron-
withdrawing substituents make them relatively inert to oxidation (scheme-89) 36 .
2.5.6.2 Photo-oxidation
Photosensitized oxidation of pyrrole produces 5-hydroxy-113-pyrrolin-2-one 186

via 2,5-peroxide intermediate 185 involving (4 + 2) cycloaddition (scheme-90) 37 .
2.5.6.3 Oxidation with Chromium Trioxide
The oxidation of pyrroles with strong oxidizing agent, chromium trioxide-sulfuric

acid, provides maleimides 188 with the elimination of substituents from 2- and 5-
positions, if present, however the pyrrole ring is preserved (scheme-91) 38 .
2.5.6.4 Oxidation with Hydrogen Peroxide
The oxidation of pyrrole with warm hydrogen peroxide in pyridine over a pH range
of 4-6 produces a tautomeric mixture of pyrrolin-2-ones 189 and 190 (scheme-
92)39-42. The presence of electron-releasing substituents makes pyrroles susceptible
to oxidation by hydrogen peroxide, while the pyrroles with electron-withdrawing
substituents are less susceptible to oxidation.
0 N
Go N
I
I
R R
181
183
~0
N
I
R
182 181
Scheme-89
.
0
N
H
02
hv, sensitizer
0
FA 185
0
o=(J(H
N
H
186
OH
Scheme-90
R R
R
Jj N
Cr03-H2S04
60°C
0~0 N
H H
177 188
Scheme-91
~0
N
0-v;.?~ ~H- 0-oH / 11~9

N (J{OH N OH N ~ ~
H H H ~~O
N
H
190
Scheme-92
2.5. 7 Reduction
2.5.7.1 Catalytic Hydrogenation
Pyrroles can be catalytically hydrogenated at moderate temperature with the

formation of pyrrolidines. The presence of electron-withdrawing substituents at
the a- and ~-positions resists the reduction of the ring, but the substituents are
reduced preferentially (scheme-93). In contrast, the presence of electron-withdrawing
~ ~CH,OH
H2
N COOR catalyst
I I
H H
(a or~)
191 192
Q N CH=CH2
H2
catalyst ~CH,-CH 3
I I
H H
193 194
Scheme-93
substituents on the nitrogen atom facilitates the reduction of the ring because of
increasing dienic character of the pyrrole ring (scheme-94).
0 N
I
Hz
catalyst Q I
0 N
I
COOR COOR CH 3
195 196 197
0 Q Q
6 6
Hz
6
N
catalyst
198 199 200

Scheme-94
2.5. 7.2 Reduction by Metal-Acid Systems (Chemical Reduction)
The reduction of pyrroles by metal-acid systems (Zn/CH 3COOH or HCl) proceeds

via the pyrrolium cations with the formation of the corresponding ~ 3 -pyrroline
201 as a major product alongwith ~ 1 -202 and ~ 2 -203 pyrrolines which are
further reduced to pyrrolidines 204 (scheme-95) 36•38.4 3 .
Zn / HCI nH Zn/l HUH

R
H
N R R
H ',,~ R ----~-~ R
H N R+
cis 201 trans
fT\ Zn / H•
+
H~H f\~H
A+A ~A)<..
R~t:J~R R N R R N R
H H
202
• Zn I H+
R_[)_R
N
H
204
Scheme-95
Pyrrole is a 7t-excessive heterocycle and undergoes free radical substitution

reactions preferentially at the a-position, although the substitution at the
~-position and at the nitrogen atom also occurs in some cases. Pyrrole reacts with
benzyl radicals with the formation of 2-benzylpyrrole 205 (scheme-96). But when
0 N
H
R
0H N
or
0
N
H
0 N
H
205
Scheme-96
treated with triphenylmethyl radicals, pyrrole behaves as a diene and provides an

adduct, 2,5-di(triphenylmethyl)pyrrole 206 (scheme-97).
0 N
HUH
(HsCshC N C(CsHsh
H H
206
Scheme-97
Pyrrole reacts abnormally with tert-butylperoxy radicals providing quasi dimer,

2-(2-pyrrolyl)-.'l 1-pyrroline 207 (scheme-98). However, N-methylpyrrole does not
behave normally with tert-butylperoxy radicals and the reaction proceeds with the
0 N
H
G-0N N
H
207
Scheme-98
abstraction of hydrogen atom from theN-methyl group and results in either radical
dimerization or involves the attack of radical at the position-3 (scheme-99).
[9] 0
<?H2
dllnerization [C:>-CH,]
208
2
L::oCH,-(J
N
I
CH3
209
Scheme-99
N-Methylpyrrole undergoes normal free radical benzoyloxylation with benzoyl

peroxide and provides 2-benzoyloxypyrrole 210 and 2,5-dibenzoyloxypyrrole 211
(scheme-100).
210 211
Scheme-100
2.5.9.1 Reactions with Carbenes
(i) The reaction of pyrrole with dichlorocarbene, generated from chloroform

and strong base, results in the formation of pyrrole-2-carbaldehyde 56
involving electrophilic attack of carbene at the a-position of pyrrole; and
the ring expanded product, 3-chloropyridine 55, involving the insertion of
carbene into the C2-C3 bond of pyrrole (scheme-101). The ratio of the
formylated product to the ring expanded product depends upon the
reaction conditions in which carbene is generated. When carbene is
generated from chloroform with a strong base, equal amounts of both
the products are obtained. But the formation of ring expanded product is
favoured, if carbene is generated under weakly basic or neutral
conditions 22 •43 -46 .
OH
_-Cl_....
~CI
~ J
N
n-....n
55
N CHCI2 N CHO
- H
56a 56
Scheme-101
(ii) The reaction of pyrrole with carbenes, generated by light or copper

catalyzed decomposition of diazo esters or diazo ketones, provides
a-substituted product 212. If both the a-positions are occupied,
13-substituted product 213 is obtained (scheme-102)43 .
0 N
H
+ N2CHCOOC2Hs
hvtOJ
O-N
H
C~COOC 2 H 5
[:CHCOOC 2H5]
212
-D- t
+ N2CHCOOC2Hs Jj__
C~COOC 2 H 5
R N R R N R
H H
213
Scheme-102
The reaction of N-methylpyrrole with ethoxycarbonylcarbene proceeds via a

cyclic intermediate 214 with the formation of predominantly 2-substituted product
215 (scheme-103) 47 . But the reaction of 1-methoxycarbonylpyrrole 217 with
0
:rnc~H 5
+ teu(I)Br ~
N
I N 2 CH~H 5
CH:3
~
O--cH 2 COOC;_Hs
I
CH:3
215
Scheme-103
ethoxycarbonylcarbene produces addition products; 2-azabicyclo[3.1.0]hex-3-

ene 218 and 2-azatricyclo[ 4.1.0.03•5]heptane 219 derivatives in preference to the
substitution products due to higher dienic character induced in the pyrrole ring
by an electron-withdrawing substituent (scheme-104) 48 -50 .
0+ t
:rnc~H 5
Cu(I)Br
N
I N 2CHCOOc;H 5
COOCH3
217
c,H,ooc ~'cHc~:ooc 2 H 5
H N H
I
COOCH3
219
Scheme-104
2.5.9.2 Reactions with Nitrenes
The reaction of pyrrole with ethoxycarbonylnitrene, generated by the copper-

catalyzed thermal decomposition of ethyl azidoformate, produces 2-amino-1-
ethoxycarbonylpyrrole 222 (scheme-105). The reaction proceeds with the insertion
of nitrene into the C2-C 3 bond giving 2,3-adduct 220 which rearranges to 2,5-
cycloadduct 221. The cleavage of diazacyclobutane ring in 2,5-cycloadduct leads
to the formation 2-amino-1-ethoxycarbonylpyrrole 222.
f");:COOC,Hs
H
N H
I
H
2,3-adduct
220
~ rearrangerrent
H
N
1)--NH, ~Ncooc,H,
I
COOC2Hs 2,5-adduct
222 221
Scheme-105
2.5.10 Cycloaddition Reactions
n-Excessive aromatic character of pyrrole causes it to undergo electrophilic

substitution reactions. Pyrrole is less susceptible to cycloaddtion reactions as the
dienic character is inversely related to the degree of aromaticity. However, if
pyrrole is substituted at the nitrogen atom by an electron-withdrawing substituent,
the aromaticity of pyrrole is reduced and exhibits enhanced dienic character
compared with pyrrole itself.
2.5.10.1 (41t + 21t) Reactions
Pyrroles undergo two types of reactions with n-deficient alkenes and alkynes
(dienophiles) (scheme-1 06).
(i) Michael-type addition in which dienophile acts as an electrophile with the

substitution at the a-position of the pyrrole ring.
(ii) Diels-Alder type cycloaddtion.
~
N
/E
/C=C,
H
0
/ I E
R
+ E-c=c-E trans
~
FA
N
I N-R
~E-
R
E-C C-E
E = electron-withdrawing group E
Scheme-106
2.5.10.1.1 Reactions with DMAD
The reaction of pyrrole with dimethyl acetylenedicarboxylate (DMAD) in the

presence of a proton donor results in the formation of Michael-type addition
product 223 involving electrophilic attack at the a-position of the pyrrole ring
(scheme-107). However, the reaction ofN-methylpyrrole with dimethyl acetylene-
,COOCH3
0 N
+
c
Ill
c
___.. ~
N
/COOCH3
C=C, +
~
N C=C,
/H
H 'coocH3 H I H H I COOCH3
COOCH3 COOCH 3
trans 223 cis
Scheme-107
dicarboxylate (DMAD) under aprotic conditions involves (4 + 2) cycloaddition of

DMAD across the 2,5-positions of pyrrole ring with the formation of an adduct,
azanorbomadiene 224, which reacts with a second molecue of DMAD providing
dihydroindole 225 (scheme- I 08) 51 -53 .
,COOCH 3
C.,..COOCH 3 H3C-N---C,
Ill _..
C-COOCH3
c 'coocH COOCH3
3
CH 3 COOCH3
I
224
~._---J
GOOCH 3 ....
OOCH
CH300C COOCH 3 3
225
Scheme-108
Pyrroles substituted with electron-withdrawing substituents at the nitrogen also

undergo ( 4 + 2) cycloaddition reactions with DMAD across the 2,5-positions of
the pyrrole ring providing azanorbomadiene 226. The azanorbomadienes with
bulky or electron-withdrawing substituents do not react further with the second
molecule of DMAD but retro-Diels-Alder extrusion of acetylene leads to 3,4-
disubstituted pyrroles 227 (scheme-109).
0
GOOCH 3 N- GOOCH 3 CH300C GOOCH 3
0~ 1r +
c,
__..l::rCOOCH3
'I !J - HC=CH
-~ N
GOOCH 3 GOOCH 3 boocH 3
COOCH3
226 227
Scheme-109
2.5.10.1.2 Reactions with Benzyne
The reaction of pyrrole with benzyne proceeds with the a-substitution in the
pyrrole ring involving Michael-type condensation and provides 2-phenylpyrrole
228 rather than the cycloaddition product (scheme-110). But N-alkylpyrroles and
pyrroles (with electron-withdrawing substituents at nitrogen)with benzyne afford
azanorbomadienes 229 involving (4 + 2) cycloaddition (scheme-111) 54 .
0 N
H
+
[10] Q----0
H
228
&Br
Mgt THF
~
I
Scheme-110
.,...R
N
0 N
I
+
IQ ..
R
R = alky~ COOR 229
Scheme-111
2.5.10.1.3 Reaction with Hexafluorobicyclo[2.2.0)hexa-2,5-diene
The reaction ofpyrrole with hexafluorobicyclo[2.2.0]hexa-2,5-diene 230, however,

produces monoadduct 231 and diadduct 232 involving Diels-Alder type
cycloaddition (scheme-112)55 .
2.5.10.2 (27t + 2n) Reactions
Pyrroles participate in photochemical (2 + 2) cycloaddition reactions. The irradiation

of pyrrole with DMAD in the presence of triplest sensitizer produces the
ring expanded product, azepine 234, via 233 involving (2 + 2) cycloaddition
(scheme-113 )56 .
However, the photochemical reaction of N-substituted pyrroles with aliphatic
aldehydes and ketones results in the regiospecific formation of 3-(1-hydroxyalkyl)-
pyrroles 236 via oxetane intermediate 235 involving (2 + 2) cycloaddition reaction
(scheme-114)56 .
F F F
0 N
+ )¢(~
H F F F F
231
I
F F
232
Scheme-112
/COOCH3
0 N
H
C
+ Ill
c
hv
..
'-coOCH3
233 234
Scheme-113
Scheme-114
3 FURANS57- 59
3.1 General
The history of furan started with the first furan derivative, furan-2-carboxylic acid
or 2-furoic acid, which was obtained by Scheele in 1780 by the dry distillation of
mucic acid. In 1860 the structure offuran-2-carboxylic acid was correlated with that
of the product obtained by the oxidation of furan-2-carbaldehyde or furfural with
silver oxide. Furan-2-carbaldehyde was obtained by the oxidation of sucrose using
manganese dioxide and sulfuric acid. Furan was first isolated in 1870 from pine
wood and also obtained by heating barium salt of furan-2-carboxylic acid. Furan
was given the name tetrahydrophenol in view of containing four carbon atoms with
one oxygen atom and its resemblance to phenols in the reactions.
The commercial importance of furan is specially due to its role as a precursor
of the very widely used solvent tetrahydrofuran (THF). Furan is manufactured by
the gas-phase decarbonylation of furan-2-carbaldehyde (furfural) which, in tum, is
obtained by the action of acid on vegetable wastes.
Furan is numbered as shown and exists into two partially reduced forms which
are systematically named as 2,3-dihydrofuran 237 and 2,5-dihydrofuran 238.
a•Oa
P' p
However, .1 (delta) can be used to indicate the position of double bond. The
saturated or completely reduced from is named as 2,3,4,5-tetrahydrofuran (THF)
239.
0 0
0 0 Q
2,3-Dihydrofuran 2,5-Dihydrofuran 2,3,4,5-Tetrahydrofuran
(.1 2-dihydrofuran) ( .1 3-dihydrofuran)
237 238 239

3.2 Synthesis
3.2.1 Commercial Method (From Aldopentoses or Ketopentoses)
Acid catalyzed consecutive dehydrations of aldoses or ketoses 240 result in

the formation of a-ketoaldehydes 242 via 1,2-enediol 241. The resulting
a-ketoaldehyde 242 undergoes acid catalyzed cyclization involving carbon-
oxygen bond formation to provide furfural which on steam distillation at 400°C in
the presence of oxide catalyst gives the corresponding furan (scheme-115).
HOHC-CHOH HOHC-CH
I I
+ I II
H
HC CHOH HC C-OH
/ \ I I \ I
R OHcHO R OHcHO
240 241a
HC=CH/1.. HOHC-CH2
I ~I I ' I
• HC \ C=O HC
I
C=O
R
I \. · I
g
CHO R
I \ I
OHcHO
I~
242 241b
,,
HC-CH
c
\\
c
R/ 'o,... 'CHO
distil
R
D 0
Scheme-115
3.2.2 From 1,4-Diketones
Acid catalyzed intramolecular dehydrative cyclization of 1,4-diketones provides

furans. The reaction is known as Paal-Knorr synthesis and proceeds with the
intramolecular addition of enolic -OH of one carbonyl group to the other carbonyl
group (scheme-116). Although sulfuric acid is normally used, the other reagents
such as zinc chloride, acetic anhydride, phosphorus pentaoxide and phosphoric
acid are also used to cause cyclization and dehydration of 1,4-diketones. This
reaction is limited only to the easily available 1,4-diketones which are not sterically
hindered. However, numerous alternative methods involving 1,4-diketones directly
or indirectly have also been used to synthesize furans in excellent yields 60-63 .
\ I \ I
- -- / c,r........... c
HC-CH C-CH
I \ I; '
/c,, ;p-........ ;.z . . . . ._
0 0 6" 0~
H
Scheme-116
3.2.3 Cyclization of Alkynes
3.2.3.1 Photochemical Cyclization
Photochemical reaction of alkynic ketones in alcohol proceeds via 1 : 1adduct

formation with the abstraction of a-hydrogen atom from alcohol by the excited
carbonyl oxygen and produces furans involving dehydrative cyclization
(scheme-117) 64 .
J:\ . . . _H__0_ H5Cs

2
~
~-10:_ H
HO.'\. 0
17\. J R
H5C5
(0
...,..,.1--- /~ ~
\
r:oH
C=C
1
bHR
H5Cs 0 R
~ H H
Scheme-117
3.2.3.2 From Alkynyl Sulfonium Salts
The reaction of alkynyl bromide with dimethyl sulfide in acetonitrile results in

alkynyl sulfonium salts 243 which with B-diketones provide furans 245 via an
intermediate 244 ( scheme-118)65 .
+ -
HC=C-CH 2S(CH 3h Br
c
2 5 f
H oHI prototropic
rearrangerrent
() + -
H2C=C=CHS(CH 3h Br
243
+
CH 3COCH 2COCH 3
244
245
Scheme-118
3.2.4 Cyclization ofYiides
3.2.4.1 Sulfur Ylides
The reaction of alkyne dicarboxylates with sulfur ylides proceeds with the addition
of carbanion centre of the ylide to the electron-deficient centre of ester giving an
intermediate betain 246 which cyclizes to provide furan 247 with the elimination
of dimethyl sulfide. However, the intermediate betain 246 may undergo 1 3, -acyl
migration with the formation of rearranged ylide 248 which on cyclization provides
isomeric furan 249 with the loss of dimethyl sulfide (scheme-119)66 .
The reaction of sulfur ylides with 13-diketones or 13-keto esters also produces
furans 250 (scheme-120) 67 . The reaction proceeds with 0-phenacylation of 13-
diketone or 13-keto ester and involves cyclization followed by dehydration
(scheme-120). But the reaction ofphenacyl halide with 13-diketone or 13-keto ester
provides isomeric furan 251 involving C-phenacylation (scheme-121).
249 248
Scheme-119
- +
C6H 5COCHS(CH 3h
+
or
C~COCH 2 COOC 2 H 5
~ cyclization
HsCt(oc:H 3
3
HOt(
HsC6 COCH3
0 CH3
250
Scheme-120
3.2.4.2 Phosphorus Ylides
Phosphorus ylides can also be conveniently used for the synthesis of furans. The
reaction of sodium salt of a-hydroxy ketone 252 with 13-ethoxyvinyltriphenyl-
phosphonium salt 253 gives phosphorus ylide 254 which undergoes intramolecular
Wittig reaction providing dihydrofuran 225 and subsequently furan 256 with the
loss of ethanol (scheme-122)68 .
C6H5COCH20
+
CH3COCH2COCH3
n
COCH3
CsHs 0 CH 3
251
Scheme-121
..
252 253 254
h
HsCs R
~---C-2H-5 0_H_ _ H C
s 6 0 OC2Hs
256 255
Scheme-122
3.2.5 From a-Halocarbonyl Compounds (Feist-Benary Synthesis)
The reaction of a-halo aldehydes or ketones with P-keto esters in the presence of
a base, sodium hydroxide or pyridine, results in the corresponding furans 259
involving aldol-type condensation (scheme-123).
base
+-Cl
h
C2H 5 00C, ,oH C2H 5 00C, /OH C2H 500C CH 3
c- c- CH3 c- c- CH3
H3C
It
?-.J
,...c,+/CH2
\ ____..
-H+
H3C
It \
,...C, /C'H
0 H
-H,o H3C 0
H 259
258
Scheme-123
3.2.6 Ring Expansion of Small Ring Heterocycles
3.2.6.1 Three-Membered Heterocycles
Alkynic oxiranes 260 undergo ring-expansion reaction under the influence of

sulfuric acid and mercury (II) sulfate and produce furans via alkynic diols 261 . But
in the presence of sulfuric acid alone, alkynic diols 261 are obtained as the major
products (scheme-124 )69 .
1R
HC::C-C-CH 2 H2S04 1
R R
0\\
t
'o' ----1~ HC =c-c,-CH20H _____.. I ~
HgS0 4
OH 0
260 IH2S04 -
R=a&yl~--------------~
261
Scheme-124
3.2.6.2 Four-Membered Heterocycles
The reaction of oxetanes 262 with boron trifluoride in diethyl ether results in the
formation of the ring expanded products, tetrahydrofurans 265, via a carbocation
intermediate 263 (scheme-125f0 •
262
Scheme-125
3.2. 7 Transformation of Five-Membered Heterocycles
Oxazoles 266 undergo (4 + 2) Diels-Alder cycloaddition reaction with alkynic

dienophiles (DMAD) with the formation of cycloaddition products 267 which
subsequently provide the corresponding furans 268 via retro-Diels-Alder reaction
with the loss of nitrile. In this transformation C-3 and C-4 of the resulting furan
are provided by the alkynic moiety (scheme-126) 71 - 73 .
R=COOCH 3
RHR ~-RICN
R2 ~0~R3
268
Scheme-126
3.2.8 Ring Contraction
Oxidative ring contraction of pyrylium salts 269 with aqueous hydrogen peroxide
and perchloric acid provides 2-acylfurans 272 (scheme-127) 74 . The reaction
proceeds with the formation of hydroperoxide intermediate 270 which undergoes
an acid catalyzed degradation through an open-chain oxo cation 271 .
rt .._
.
269 270 271
CH3
___.J
H3C 0 COCH3
272
Scheme-127
Base catalyzed ring contraction of 1,2-dioxins 273 also affords furans 275 via
an intermediate, 2-hydroxy-2,5-dihydrofuran 274 (scheme-128) 75 .7 6 .
275
Scheme-128
3.3 Structure
Furan has planar pentagonal structure in which four carbon atoms and oxygen
atom are in sp 2-hybridized state. The sp 2 -hybridized orbitals overlap with each
other and with s-orbitals of hydrogen to form carbon-carbon,carbon-oxygen and
carbon-hydrogen bonds. Two lone pairs of electrons on oxygen are in different
orbitals; one lone pair of electrons is in sp 2-hybridized orbital, while other is in
n-orbital. Four n-orbitals of four carbon atoms (each containing one electron) and
n-orbital of oxygen atom (with lone pair) are parallel to each other and are
perpendicular to the plane of the ring. The lateral overlapping of n-orbitals
produces a n-molecular orbital containing six n-electrons (Fig.30).
H
'c-ag/"/
oO
O QH lone ~air in
___.,.
p-orb1tal
0 , 'Q/ 0C)._~ second Ione pair. .m

H-C,
8'H sp2-orbital
Fig. 30. Molecular orbital structure of furan
The bonding in furan is similar to that in pyrrole, but the difference is that the
hydrogen atom attached to the nitrogen in pyrrole is replaced by the sp 2 -orbital
of oxygen containing lone pair of electrons which does not participate in the
aromatic sextet. Thus, furan is a planar conjugated heterocyclic system with
de localized six n-electrons and has following molecular dimensions (Fig. 31) :
Bond lengths (A) Bond angles (C)
O-C2 = 1.362 C2-0-C5 106.50
502
4 3
C2-C3 = 1.361 O-C2-C3 110.65
C3-C4 = 1.430 C2-C3-C4 = 106.07
C2-H 1.075
p O-C2-H 115.98
C3-H = 1.077 C2-C3-H 127.83
Fig. 31. Structural parameters of furan
Furan is considered to be the resonance hybrid of the following resonating

structures in which the lone pair on the oxygen atom is delocalized around the ring
(Fig.32). The positively charged trivalent oxygen makes the dipolar structures less
0~-0 0-~
0 0 0
(i) (ii) (iii) (iv) (v)
Fig. 32. Resonating structures of furan
stable because of high electronegativity of oxygen and, therefore, contributing

less to the resonance hybrid of furan. But classical (non-polar) structure contributs
significantly as reflected by the C-C bond lengths in furan.
3.4 Reactions
3.4.1 Reactions with Electrophiles
3.4.1.1 Reactivity and Orientation Effects
Furan is n-excessive heterocycle and exhibits greater reactivity towards electrophilic

substitutions. As far as the comparison of reactivity is concerned, furan lies
between pyrrole and thiophene i.e. less reactive than pyrrole, but more reactive
than thiophene. The lower reactivity of furan than pyrrole is because the oxygen
atom accommodates positive charge less readily than the nitrogen atom, while
the higher reactivity of furan than thiophene can be attributed to the smaller
orientation effect (+M effect) of sulfur than that of oxygen.
Furan undergoes electrophilic substitution preferentially at the C-2 and C-5

positions (a-substitution) and these positions are comparatively 6x 10 11 times more
reactive than a benzene position. If these positions (C-2 and C-5) are occupied, the
substitution takes place at the C-3 and C-4 positions (~-substitution) and these
positions are also even more reactive than a position of benzene. The preferential
electrophilic substitution at the C-2 and C-5 positions (a-substitution) is attributed
to the resonance stabilization of the transition state resulting from the attack of
electrophile at the a-position and the powerful orientational effect of the ring
oxygen (Fig. 33).
[Q~+cxH~ dH]-L u
/ 0 E 0 E 0 E 0 E
Q· t""
(i) (ii) (iii) (a-sbstitution)
[~E- d.E]
E
0
+
-H ...
0
(i) (ii) (~-s bs titution)
Fig. 33. Electrophilic substitution in furan
3.4.1.2 Directing Effects of Substituents
Although the a-positions of furan are more reactive than the ~-positions towards
electrophilic substitutions, the ratio of a-substitution to ~-substitution (a : ~)
depends upon the balancing effect of the ring oxygen and the substituent
(position as well as nature). The presence of substituents with +I or -1 (+M) effect
at the position-2 of furan causes substitution to occur at the position-S, while the
substituents exhibiting -1 ( -M) effect deactivate C-5 position due to the mesomeric
effect. But this effect is usually overpowered by the powerful orientational effect
of the ring oxygen and directs the substitution to occur at the C-5 position
(scheme-129). However, the -M effect of the substituent (carbonyl group) is
enhanced in the presence of a Lewis acid with the deactivation of C-5 position
and the substitution takes place at the C-4 position, although this effect competes
with the orientational effect of the ring oxygen.
HN0 3
Scheme-129
The substituents with +I effect at the C-3 position activate the C-2 position by
the electronic effect and direct substitution to C-2 position. However, the steric
effect of the substituent at C-3 causes substitution to occur at the C-5 position
with the formation of a mixture of 2- and 5- substitution. The substituents with
-I ( -M) effect at the C-3 position reinforce the directing effect (orientational) of
the ring oxygen and facilitate the electrophilic substitution at the C-5 position.
The position of electrophilic attack in the disubstituted furans depends upon
the directive effect of the substituents and the orientational effect of the ring
oxygen. Electrophilic substitutions in 2,5-disubstituted furans usually occur at the
13-position which is adjacent to the electron-releasing group. However, in some
cases the a-substitution is strong and the ipso-substitution takes place with the
expulsion of carboxyl, acyl or halogen group (scheme-130).
Scheme-130
3.4.1.3 Protonation
Protonation of furan generates reactive electrophilic intermediate which

participates in polymerization and the ring opening reactions. Furans substituted
with electron-withdrawing substituents are stable towards acid, but furans
substituted with electron-releasing substituents usually undergo polymerization
with mineral acids due to facile protonation at the position-2 (scheme-131).
Furan is readily hydrolyzed under very mild acidic conditions. The reaction is
considered to proceed via protonated intermediate involving protonation at the
C-2 position rather than at the oxygen atom and results in the formation of a
ring-opened product, succindialdehyde (scheme-132). However, furans with
methanolic hydrochloric acid also undergo ring opening reactions involving
13-protonation (scheme-133) 77 .
The reaction of 2,5-dimethylfuran with perchloric acid in aqueous DMSO,
contrary to furan and 2-methylfuran leading to polymerization, also proceeds with
13-protonation providing acetonylacetone ( scheme-134 ).
Acid catalyzed hydrogen-deuterium exchange reaction of 2-methylfuran
proceeds with the H ~ D exchange at the C-5 position involving an
electrophilic addition-substitution mechanism (A-SE 2) (scheme-135) 78 .
H +
H
0
279 278
H,cJJ!
+
H
polymer
280
Scheme-131
0 0 [V:]
~ [~H]
unstable
Scheme-132
+
-H
Scheme-133
H 3C J[J2CH
0 3
Scheme-134
D+ __......
Scheme-135
3.4.1.4 Nitration
Furan is nitrated with mild nitrating agent, acetyl nitrate, at low temperature. The
reaction proceeds by an addition-elimination mechanism involving an intermediate,
2,5-addition product 282 ( scheme-136) . In certain cases, the intermediate 2,5-
addition product 282 may be isolated, if a base (pyridine) is not used to eliminate
acetic acid (scheme-13 7) 79 .
0 0
[HN0 3 +Ac 20)
-IO"Cto -20"C
[ll:XH ]
O N0 2
warm or
base (pyridine)
-AcOH
H, ! \ ... H
A_A
_JAcO-
AcO 0 N0 2
282
Scheme-136
111 fum HN03

~CHO
283
Scheme-137
3.4.1.5 Sulfonation
Furan is sulfonated with the complex of sulfur trioxide with pyridine or

dioxane and provides 2-sulfonic or 2,5-disulfonic acid depending on the reaction
conditions (scheme-138)80 . However, furan substituted with an electron-withdrawing
0 0
C5H 5N-S0 3
Ha u 0 S~H
Scheme-138
substituent at the position-2 can be sulfonated by oleum with the formation of

5-sulfonic acid derivative (scheme-139).
C\
0 COOH
Scheme-139
3.4.1.6 Halogenation
Since furan reacts vigorously with bromine and chlorine at room temperature with
the formation of polybromo- and polychloro-furans, respectively, the milder
conditions are required for the formation ofmonobromo- and monochloro-furans.
Bromination of furan with dioxane-dibromide (Br 2 + dioxane) at -5 °C gives
2-bromofuran (scheme-140).
0 0
dioxane + Br2
-s•c Q 0 Br
Scheme-140
The reaction of furan with bromine in carbon disulfide at -50°C produces

2,5-dibromo-2,5-dihydrofuran 285 which on warming provides 2-bromofuran.
The reaction is considered to proceed by an addition-elimination mechanism
(scheme-141 ) 81 . But the bromination of fur an in methanol at -1 0°C in the presence
0 0
+ Br2
cs2
--..
-50"C
[ex.0
H]---.-BraH____..war m
Br H 0 Br -HBr
(cis+ trans)
G 0 Br
285
Scheme-141
of a base provides 2,5-dimethoxy-2 ,5-dihydrofuran 287 involving an attack of

nucleophile on the cations 286a and 286b rather than an elimination of a proton
(scheme-142).
0 0
[CXH 0 Br
286a
Scheme-142
Bromination of furan substituted with an electron-withdrawing substituent at

the position-2 generally provides 5-bromo derivative involving an electrophilic
substitution mechanism (scheme-143 ). But bromination with bromine in the
u 0 CHO
+ Br2
S, quinol
CICH2-CH2CI Br ~ 0 CHO
u
288
Br~coOCH 3
CICH2-CH2CI
+ Br2
0 COOCH3
289
Scheme-143
presence of aluminium chloride affords 5-bromo- and 4,5-dibromo-derivatives

(scheme-144). However, in the presence of a solvent, Br-:::::::=::. Cl exchange also
occurs at the position-S (scheme-145).
G h
Br
+ Br2 Al03 ~ +
0 GOOCH 3 Br 0 GOOCH 3 Br 0 COOCH 3
289 290
Scheme-144
Q 0 COOCH3
+ Br2 _____
A1Cl
3 _.,._
CICH2-CH2CI
Br +
B~~COOCH: CI~COOCH,+ h
290 291
Cl 0
292
COOCH 3
Scheme-145
Chlorination of furan with chlorine in the presence of dichloromethane at -40°C

provides 2-chlorofuran as a major product (scheme-146). If the electron-
withdrawing group is present at the position-2, only 5-chloro derivative is
obtained (scheme-147).
Cl
+~+hCl 0 Cl Cl 0 Cl
(29%) (7%)
Scheme-146
Cl ~ 0 COOCH 3
293
Scheme-147
3.4.1.7 Alkylation
Furan does not undergo Friedel-Crafts alkylation. The catalysts required in

Friedel-Crafts alkylation affect polymerization because of the acid sensitivity of
furan. The alkylation is affected by alkenes at the position-2 in the presence of mild
catalysts (phosphoric acid or boron trifluoride) (scheme-148).
0 0
+
~CH-CH, I
294 R
Scheme-148
The reaction of furan with isobutene and phosphoric acid on Kieselguhr results
in a mixture of 2- and 3-alkylated (tert-butylation) furans 295 and 296 and their
proportions depend on the temperature (scheme-149)82 • However, furans substituted
0 0
+
H3C,
H3C
H3P04
/C=CH2----i~
~
0
+
C(CH3b
295
Scheme-149
with electron-withdrawing substituents at the position-2 undergo Friedel-Crafts

alkylation at room temperature providing a mixture of alkylfurans (scheme-150) 83 .
297 298
+
(CH 3)2HC)---{CH(CH3)2
(CH 3)2HC
)(_~
0 CHO
299
(CH 3hHC
n 0
300
(CH3hHCh
COCH 3
+
301
z_~
0 COCH 3
cs2 +
AlCI 3 (CH3hHCh
room tempt.
)(_~
(CH 3hHC 0 COCH 3
302
Scheme-150
3.4.1.8 Acylation
The acylation of furan with acid anhydrides in the presence of mild catalysts such
as phosphoric acid or boron trifluoride etherate results in exclusively 2-acylfuran
(scheme-151). The acylation of furans can be performed also with acetyl p-toluene
sulfonate or Ac 20-SnC1 4 , although trifluoroacetic anhydride does not require any
catalyst 84 .
0 0
O-cocH 3
Scheme-151
The acylation of 3-methylfuran with acid anhydride and phosphoric acid gives
2- and 5-acyl derivatives in 2 : 1 ratio (scheme-152) 85 . If both the a-positions are
occupied, acylation takes place at the P-position (scheme-153).
0
CH3 CH3
0
+ (CH,CO),O
G+ 0
305
COCH3
Scheme-152
COCH 3
H3C
;6_ 0 CH 3
307
Scheme-153
The acylation of furans, containing ester group at the position-2, with acid
anhydride and boron trifluoride etherate affords 5-acyl derivative 308, while with
acid anhydride-tin(IV) chloride the acylation occurs at both the C-4 and C-5
positions. The acylation at the position-4 is probably because of co-ordination of
the catalyst to the carbonyl oxygen of an acid anhydride (scheme-154)83•86•87 .
C\+
0 COOCH3
(RC0)20
R-C~COOCH,
~ 308
R-C
~~
0 GOOCH
0 3
II 308
R-C +
tA0
309
COOCH 3
Scheme-154
3.4.1.9 Reactions with Aldehydes and Ketones
The acid catalyzed reaction of furan with aldehydes produces a mixture of

oligomers involving reactive electrophile 313 (scheme-155), but the reaction of
2-methylfuran affords 317 (scheme-156).
0
R
+ ' C=O
/ f.')-cHOH
0 H 0 I
R
0
oligomers
0
(+)=CHR
0
...
313
Scheme-155
The reaction of furan with protonated ketones results in the formation of a cyclic
tetramer 318 analogous to that obtained from pyrrole. The yield of the cyclic
tetramer is improved with the change in pH by adding lithium perchlorate 88
(scheme-156).
Scheme-156
318
3.4.1.10 Reactions with Diazonium Salts
Furan undergoes phenylation rather than diazo coupling on reaction with

benzenediazonium salts (scheme-157). Moreover, the reaction of furan with 2,4-
dinitrobenzenediazonium salt in the presence of acetic acid results in the formation
0 0
NaOH
Scheme-157
of pyrrole derivative 322 involving either electrophilic substitution or cycloaddition

(scheme-158). But under the same conditions, 2,5-dimethylfuran undergoes diazo
coupling with 2,4-dinitrobenzenediazonium salt with the formation of azo compound
323 (scheme-159).
3.4.2 Reactions with Nucleophiles
Nucleophilic substitutions in furans are concerned mainly with the halofurans. The
reactivity of halofurans towards nucleophilic substitutions is some what greater
than that of the corresponding aryl halides. The greater reactivity of the halofurans
is attributed to the higher electron deficiency on the carbon atoms by the electron
attracting tendency of oxygen. However, this effect is opposed by the directive
effect of oxygen and the repulsion of nucleophile by p-electrons on the oxygen
atom. Although 2-halofurans do not react with sodium methoxide at 100°C, the
reaction with piperidine is approximately 10 times faster than the corresponding
aryl halides. The reactivity of 2-halofurans is, however, decreased towards
nucleophilic substitutions when methyl group is present at the position-3 or -5
(scheme-160).
(electrophilic
b . . )
su st1tut10n
1
H20 OI3COOH
( cycloaddition) 319
~
~H~O- ~O
H 0 N=N _ N0 O~NO, qNO,
2
-
HO N 0
N02 N02
321 322
Scheme-158
Scheme-159
Scheme-160
The nucleophilic substitution reactions involving substitution of the halogen

atom from the position-3 are rare, but 3-methoxyfuran is obtained by the reaction
of 3-iodofuran with methanolic sodium methoxide in the presence of copper (II)
oxide (scheme-161 ).
0
I
CuO
+
0
Scheme-161
The presence of an electron-withdrawing group (nitro, carboxy or carboalkoxy)

facilitates nucleophilic substitutions (scheme-162). These reactions proceed either
Br
~ 0 COOCH 3 CH30
~ 0 GOOCH 3
326 327
Br~N0 2 (C2HshNH
(C 2 H5 hN
~ 0 N0 2
328 329
Br~CHO ~
Nai
CH 3COOH I 0 CHO
330 331
Scheme-162
by an addition-elimination mechanism or possibly by an electron-transfer

mechanism involving readical anion 333 (scheme-163) 89 •90 .
addition-elimination Nu_ F\ -
+ :Nu
Brx_,_0 Ac::: 0
.~ 332 H
' electron- +-B;
n
' transfer
L--------~
333
Nu O CHO
334
Scheme-163
The reaction of substituted 2-acylfurans with ammonia or ammonia derivatives,

however, results in the formation of a ring expanded product 338 rather than a
substituted product (scheme-164)91 .
R
n\ NH Rn
I
0
\
COR'
__3_.,.,._ +
H3N 0
_...R
C,O
I
335 336
£XOH _j
337
R N R'
338
Scheme-164
Furan reacts with free radicals involving preferential attack at the position-2 and
the resulting intermediate either loses a hydrogen radical to produce 2-substituted
furan or reacts further with the radical to produce 2,5-disubstituted-2,5-dihydrofuran.
Thus, furan undergoes free radical substitution as well as free radical addition
depending on the generation of the free radicals (scheme-165).
...
Q+
R
RH
-H
0 R
0+ 0
R ~ f[[XR
0 H
(substitution)
R
... R>CXR
H 0 H
(addition)
Scheme-165
The reaction of furan with aryl radicals, generated by the decomposition of

N-nitrosoacetanilides or from the diazonium salts under aprotic conditions,
provides exclusively 2- arylfuran, but with dibenzoyl peroxide cis- and trans-
2,5-addition products 340a and 340b are obtained. The formation of the addition
products is attributed to the relatively greater stability of an intermediate 339
(scheme-166)92 - 94 .
Hf:J>····
......·
.
0
:
+ 0 0
0 I
~c,
0:-- CsHs
339
H>CXH ~
C6 H5C0 2 0 0 2CC 6 H5
trans cis
340
Scheme-166
The reaction of 2-methylfuran with methyl radicals, generated from diacetyl

peroxide, gives 2,5-dimethylfuran involving free radical substitution at the
position-S, but 2,5-dimethylfuran is hardly attacked by the methyl radicals
(scheme-167)95 .
No reaction
Scheme-167
However, the reaction of 2,5-dimethylfuran with dibenzoyl peroxide involves

the attack of radical at the methyl group rather than attacking the furan ring
(scheme-168).
0 0
II II
C6 H5C-O-O-C-C 6 H5
H3C
JC\) 0 CH2-0-C-C6Hs
341
Scheme-168
Furan reacts anomalously with aromatic thiyl radicals, generated from the
reaction of thiol with Fen ton's reagent, with the formation of normal 2-substituted
furan 343 alongwith anomalously 2,3-disubstituted furan 345 (scheme-169)96 .
ArS ff:J<H -H Q
y
~
:; 0 Ar S SAr
dAr
343
+342
f!D<~fYSAr_A_~_H-1..,~
0
344
SAr 0 -H
[0::~,]- S
345
SAr
Scheme-169
Furan undergoes addition reaction with carbene, generated from diazomethane in

the presence of copper bromide, and leads to cyclopropanation with the insertion
of carbene into the C2-C3 bond (scheme-170) 97 .
0 0
+
CuBr
Scheme-170
The reaction of furan with carbene, generated by ultraviolet radiation of a

solution of ethyl diazoacetate, also produces cyclopropane derivative 347
which, however, on brief heating at 160°C is rearranged to the ring-opened
aldehyde 348 ( scheme-171 )98 .
hv ~CHCOOC2Hs
0
347
H H
.. d I
~cooc2H 5 16a'C
H 0 H H
348
Scheme-171
Similarly, the reaction of furan with ethoxycarbonylnitrene also proceeds with

the initial insertion of nitrene into the C2-C3 bond with the formation of aziridine
349 which on subsequent ring opening and cyclization provides pyrrolinone 351
(scheme-172)99 .
350
~0
N
or
I
COOC2H5
351
Scheme-172
3.4.5 Cycloaddition Reactions
Furan, inspite of being n-excessive heterocycle, behaves as a diene and undergoes

(4 + 2) cycloaddition reactions with dienophiles with the formation of
thermodynamically more stable exo-products than the kinetically favoured endo-
products. The reaction of furan with maleic anhydride in acetonitrile at 40°C
provides initially endo-adduct 352, which is coverted to exo-adduct 353 by retro-
addition followed by readdition in an alternative orientation. The exo-adduct is 8.0
kJ/mol more stable than the endo-adduct (scheme-173) 100 .
Q:
0
H
0 0
+
4(J'C
.. + 0
0
0
352 (endo) 353 (exo)
Scheme-173
Similarly, the reaction of furan with male imide at room temperature results in the
formation of endo-adduct 354 which on heating at 90°C rearranges to exo-adduct
355 (scheme-174).
90"C
t0
Q + <:H _2_soc.. . _., o+£(~ _0
0
0
~;r
0
354 (endo) 355 (exo)
Scheme-174
The ethylenic dienophiles substituted with only one electron-withdrawing

substituent (acrylonitrile and methylacrylate) react very slowly with furan at room
temperature providing moderate yields of both endo- 356 and exo- 357 adducts
(scheme-175). The reaction is greatly accelerated either by the addition of Lewis
0 0 kr+~ CN CN
356 (endo) 357 (exo)
Scheme-175
acid (zinc iodide) which increases the electrophilicity of the dienophile or by using
high pressure and the adducts are obtained in improved yields 101 .
The reaction of furan with cyclopropene at room temperature proceeds with
the formation of 1 : 1mixture of exo- 358 and en do- 359 adducts ( scheme-17 6) 102 .
But with halocyclopropenes only the endo-adducts are obtained which
undergo electrocyclic ring opening with the stereospecific 1,2-halogen migration
(scheme-1 77) 103 •
H 0
)>
0
0 b ~
25°C
+ +
0
H
358 (endo) 359 (exo)
Scheme-176
0
CI)><CI 80"C
+
18 hrs .
0 F
Cl
F Cl
Cl F
360 361
O Cl
~F Cl
362
Scheme-177
Furan undergoes cycloaddition reaction with vinylene carbonate also and

provides a separable mixture of endo- 363 and exo- 364 adducts of different dipole
moments (scheme-178) 104 .
(>=o-~o+
0 o~0
~o o-lo
363 ( endo) 364 ( exo )
Scheme-178
Furans react readily with alkynic dienophiles under mild conditions providing
oxanorbornadienes 365 and 365a in excellent yields (scheme-179).
ether
~COOCH3
COOCH3
365
0 0 ~CF3
CF 3
365a
Scheme-179
The reaction of furan with dimethyl acetylenedicarboxylate (DMAD) is

temperature dependent. The initially formed adduct 365 acts as a dienophile and
reacts further with furan to give the diadducts 366 and 367 at 25°C, while 368 and
369 at higher temperature (scheme-180) 105 .
Furan fails to react with ethyl propiolate at room temperature, but at 130°C
provides unusual product 371. The product 371 is probably formed by ( 4 + 2)
cycloaddition of an intermediate adduct 370 with the second molecule of ethyl
propiolate (scheme-181) 106 . 2,5-Dimethylfuran, however, reacts readily with ethyl
propiolate with the formation of a monoadduct 372 which undergoes (4 + 2)
cycloaddition with the second molecule of 2,5-dimethylfuran affording diadducts
373 and 374 (scheme-182).
Furans substituted with electron-withdrawing substituents at the position-2
exhibit reduced reactivity, while the electron-withdrawing substituents a.t the -3 or
3- and 4-positions do not effect dienic character of the ring appreciably. The
reaction of furan-2-carbaldehyde with DMAD gives thermally unstable adduct
375, but furan diester reacts very readily with DMAD providing the stable adduct
376 (scheme-183).
0 0
25°C
~_g0(endo • exo)
+ CH 300C COOCH3
0 366
0 +
~COOCH,
=\)
0
COOCH3 (endo • endo)

365
CH300C COOCH3
+high tempt. 367
0 0
£
CH300C
CH300C + CH300C
0
HH
368 369
Scheme-180
0
130"C
~COOC,H,
370
~ cH=c-cooc2Hs
371
Scheme-181
374
Scheme-182
~
, 0 _>.-CHO
40hrs
~GOOCH,
+ COOCH3
CH 3ooc-c=c-c oocH (thermally unstable)
375
ROOCHCO OR
(_) -~
80'C
ROOC~COOCH3
0 ROOC COOCH3
+ 376
cH 3ooc-c=c-c oocH3
Scheme-183
Furans substituted with varying substituents undergo cycloaddition reactions

readily with benzynes.The cycloaddition of an unsymmetrical benzyne with furan
is however, not considerably effected and the ratio of the products remains almost
the same (scheme-184) 107.
0
0
CH 3
R= CH 3, (CH 3 hC, COOCH 3
378
Scheme-184
The reaction of furans with cyclopropanones also provides (4 + 2) cycloaddition

products 380 with the participation of cyclopropanones as oxallyl zwitterions 379
(scheme-185) 108 .
0 0
379 380
Scheme-185
3.4.6 Photochemical Reactions
Furans undergo photochemical (2 + 2) cycloaddition reactions when irradiated

with carbonyl compounds (such as aliphatic aldehydes and ketones, a,[3-
unsaturated aldehydes, diketones and aromatic and heteroaromatic aldehydes and
ketones) to provide oxetanes (scheme-186) 109 .
The photochemically sensitized (2 + 2) cycloaddition of 2-acylfuran with
2,3-dimethyl-2-butene produces two products 384 and 385 in which product 384
is obtained by the addition of 2,3-dimethyl-2-butene to the furan ring, while 385
is produced by (2 + 2) addition of an alkene to the carbonyl group (scheme-187)94
c);tH
H C2Hs
0 0
+ C2H 5CHO
hv
0 H
381
c);tc H
H C6 H5
hv 6 5
+ (C 6 H5 )2CO
0 H
382
~~H
+
~ 0 CHO
hv
0
383
':0
0
0
\
Scheme-186
~H, CH3
CH 3
0 C-CH3
II
H3C, /CH 3 0
~/CH 3 +
c
II hv 384
o c~::-..
-..:0
/c, +
H3C CH3 ~ CH3CH
I I
3
0 C-C-CH3
I I
O-C-CH3
\
385 CH3
Scheme-187
Furan undergoes photochemical (4 + 4) cycloaddition with benzene with the

formation of 2,5: 1',4'-adduct 386 as a major product alongwith other three minor
products 387, 388 and 389. The major product 386 is unreactive towards
nucleophiles, but undergoes thermal Cope rearrangement to provide 390
(scheme-188) 110•
0+0 0 ~
hv
15<fC
k cr:o
386
+
387
+
Cope
rearrangem:nt ~ 60-7ooc
H H
H~
® H 0
aso
0 388
H H
+
390
389
Scheme-188
The photo-oxygenation of furan with singlet oxygen at low temperature gives

a bicyclic peroxide 391 which with methanol forms hydroperoxide 392 involving
nucleophilic attack at an a-position (scheme-189) 111 •112 .
0 0
Hf:J<H
CH30 0 0-0H
392
Scheme-189
The irradiation of alkylfurans with an excess of propylamine results in

photochemical transformation with the formation of N-propylpyrroles 393
(scheme-190). Moreover, in some cases, the bond reorganization is also possible
alongwith photochemical transformation ( scheme-191) 113 .
Scheme-190
CH 3
hv
07
CH2-CH 2-CH 3
394
Scheme-191
4 THIOPHENES 114- 116
4.1 General
Thiophene made its debut in the chemical literature with its discovery by Victor
Meyer in 1882 as contaminant of coal tar benzene (commercial benzene). The
discovery of thiophene was based on the fact that the indophenine test (blue
colour with isatin and concentrated sulfuric acid), given by commercial benzene,
depended on the presence of thiophene. But the pure benzene obtained by
decarboxylation of benzoic acid did not give indophenine test.
Thiophene is a 7t-excessive aromatic heterocycle and is uniquely aromatic among
the five-membered heterocycles. The presence of sulfur atom in thiophene has
consequence particularly on the aromaticity which in turn considerably influences
the properties and reactions of thiophene. The aromatic character of thiophene is
retained even when it is substituted and fused with another aromatic ring.
Thiophene ring system exists into two partially reduced forms; 2,3-dihydro-
thiophene 395 and 2,5-dihydrothiophene 396, but only one tetrahydrothiophene
(thiophane) 397 is possible.
0s 0s Q
2,3-Dihydrothiophene 2,5-Dihydrothiophene 2,3,4,5-Tertrahydrothiophene
(t. 2-dihydrothiophene) ( t, 3-dihydrothiophene)
395 396 397
Thiophene ring system is present as an importnat component in the synthetic

pharmaceuticals and dyes. Biotin (vitamin H) containing tetrahydrothiophene is
the most important naturally occuring thiophene derivative. Bioisosteric relationship
of thiophene with benzene has led to the synthesis of various biologically active
drugs with the replacement of benzene rings by thiophene rings.
4.1.1 Isolation
Thiophene occurs in the benzene fraction of coal tar. The boiling point of
thiophene (84 °C) is very close to that of benzene (80°C) and, therefore, it is very
difficult to separate them by the fractional distillation. However, thiophene because
of its greater reactivity forms thiophene-2-sulfonic acid with cold concentrated
sulfuric acid, while benzene remains unaffected. Thiophene-2-sulfonic acid is
soluble in water and, therefore, separated out with water from the water insoluble
benzene. Thiophene can also be separated by refluxing the mixture with aqueous
mercuric acetate. Thiophene is mercurated readily even in cold, while benzene
does not. Thiophene may be regenerated by distilling mercurated derivative of
thiophene with hydrochloric acid.
4.2 Synthesis
4.2.1 Intramolecular Cyclization Reactions
4.2 .1.1 From 4-Aralkylthiocrotononitriles
Intramolecular cyclization of cis-4-aralkylthiocrotononitriles 398 in the presence of

hydrochloric acid in dry ether provides 2-aminothiophene 402 with the formation
of C-S bond ( scheme-192) 117 . The reaction is considered to proceed via
Ha
(dry ether)
R= -CH2-C6H5
HC=CH
,.C6H5 I \
-CH H2C........_ /C~NH
'c6H5
s
401
Scheme-192
an intramolecular attack of the protonated nitrile on the sulfide sulfur with the
formation of a cyclic sulfonium ion intermediate 400 which is attacked by a
chloride ion to provide 2-aminothiophene 402 with the removal of aralkyl chloride.
The mechanism is supported by the fact that trans-aralkylcrotononitriles fail to
undergo intramolecular cyclization to provide 2-aminothiophene.
4.2.1.2 From 3-Methylenethiopropenals
The reaction of 3-chloropropenals (a,~-unsaturated aldehydes with ~-chloro

group) with sodium sulfide and halomethylene derivative or with mercaptomethylene
derivative leads to the formation of 3-methylenethiopropenals 404 which undergo
an intramolecular cyclization in the presence of a base to provide thiophenes 405
involving carbanion addition to the carbonyl group 118 (Perkin condensation) with
the formation of C2-C3 (~-to sulfur atom) bond. 3-Chloropropenals 403 are
obtained by the reaction of ketones with DMF and phosphorus oxychloride
(Vilsmeier-Haack reaction) (scheme-193 ).
R2. . . ._ ,...CHO
POCI 3 c
II
DMF 1 ,...C, ,...CH 2E
R S
Rl & R2 =alkyl or aryl groups

E= N0 2, CN, COR, COOR
405
Scheme-193
4.2.2 (4 + 1) Cyclization Reactions
(4 + 1) Cyclization reactions involve the condensation of four-carbon unit with a

suitable sulfurizing agent and are grouped into two classes :
(i) the reactions in which four-carbon unit is from hydrocarbons and the
sulfurizing agent includes elemental sulfur or hydrogen sulfide.
(ii) the reactions involving 1,4-dicarbonyl compounds as four-carbon unit and
phosphorus sulfides or hydrogen sulfide as sulfurizing agents.
4.2.2.1 From Hydrocarbons
The cyclization of hydrocarbons such as butanes, butenes, or butadienes with

sulfur at high temperature (500-600°C) provides thiophenes (scheme-194).
+ 4S 500-600'C .,. 0s
Cl
500'C
0 s
500'C
Scheme-194
However, alkenes and alkadienes substituted with aryl groups are cyclized
readily with sulfur at comparatively lower temperature to provide thiophenes in
excellent yields ( scheme-195).
The reaction of 2,3-di(tert-butyl)-1 ,3-butadiene 406 with sulfur dichloride
provides structurally interesting 3,4-di (tert-butyl) thiophene 407 (scheme-196) 119 .
/CH3
CH-CH
s
/f \
C6H5 -CH CH3
77%
HsC6-H2C CH 3
s
250'C
HsC6
h S C6H5
80"/o
Scheme-195
Scheme-196
4.2.2.2 From 1,4-Diketones (Paal Synthesis)
This is the most widely used method and involves the reaction of 1,4-diketones
with phosphours pentasulfide (P 2 S5 ). The reaction is considered to involve the
steps as in (scheme-197).
The reaction of keto acids or diacids (salts) with phosphorus pentasulfide
results in the formation of thiophenes in poor yield, but with phosphorus trisulfide
thiophenes are obtained in much improved yields (scheme-198).
Thiophenes are prepared in excellent yields on laboratory scale from appropriately
substituted succinic acid salts by heating with phosphorus trisulfide (scheme-199).
H'\.
(~C-CH 2
~~r'
c c
I\\ 11\_R'
R S 0~
408
+ HI
HC-CH
II I_....R'
c c
R,...... 's . . . . '\
OH
409
Scheme-197
CH 3 - CO- CH 2 - CH 2COONa
Scheme-198
-+
0s
CH 2COONa
I -+
CH 2COONa
Scheme-199
4.2.3 (3 + 2) Cyclization Reactions
4.2.3.1 Reaction of u,I3-Unsaturated Carbonyl Compounds with

Ethyl Mercaptoacetate
The reaction of a,f3-unsaturated carbonyl compounds, substituted with [3-chloro-

group and consisting a three-atoms unit 411, with ethyl mercaptoacetate, involved
as two-atoms unit, in the presence of a base provides thiophenes 413
(scheme-200) 120 . The reaction proceeds by nucleophilic attack of the thiolate anion
at the [3-carbon followed by an internal Claisen-type condensation with the
formation of C-S and C-C bonds (scheme-20 1).
R2 R3
R1.Jr.:>.--COOC2Hs
413
Scheme-200
0 0
II 3 II
R2-..... C/C- R [HSCH CNV' H] (C H ) N ~
'c. . . C-R3
II~~~~--, +-H+ 2 ....,....,'-'2
s
5
II
srn CNV' H -Ha
2 3
c
R1 Gt
/ c~Cl +
2 ....,....,'-'2 5
1
R .....- 's-CH2-COOC 2H5
412a
411
R2......_ /OH
rr--?-R3
1 ,......C, ,......CH .......____
R s 'cooc2Hs
+-H 0 2
412b
Scheme-201
4.2.3.2 Reaction of Activated Alkynes with a.-Mercapto Ketones or

Esters
The condensation of activated alkynes with a-mercapto ketones or esters involves

Michael-type nucleophilic addition of the thiolate anion to an alkyne and
cyclization of the resulting carbanion 415 to provide thiophenes 417 (scheme-202).
H, /COOC2H5
c
II
/c,
C2H500C S-y~
COCH3
414
Scheme-202
4.2.3.3 Reaction of Dimethyl Fumarate with Mercapto Esters
The reaction of dimethyl fumarate, constructing a two-atoms unit, with mercapto

ester as a three-atoms unit in the presence of a base involves (3 + 2) cyclization
providing tetrahydrothiophene 418 which on treatment with hydroxylamine
followed by the reduction and aromatization affords the corresponding thiophene
420 (scheme-203) 121 .
419
Scheme-203
4.2.3.4 Reaction of a.-Mercapto Ketones with Activated Methylene

Nitrites (Gewald Synthesis)
The condensation of a-mercapto Ketones (three-atoms unit) with activated

methylene nitriles (two carbon-atoms unit) in the presence of a base (pyridine or
triethylamine) leads to the formation of 2-aminothiophenes 424 involving
following steps (scheme-204) 12 2:
base
DMF(5<J'q
421
424 423 422
Scheme-204
4.2.3.5 Reaction of a.-Diketones with Activated Methylene

Compounds (Hinsberg Synthesis)
It involves the condensation of a-diketones with dirnethylene sulfides containing

methylene groups activated by the electron-withdrawing groups (-COR, -COOR,
-CN as in his-keto sulfides, thiodiacetates and thiodiacetonitriles) in the presence
of alcoholic sodium ethoxide to provide thiophenes 428 involving Aldol-type
condensation (scheme-205) 123 • However, with thiodiacetonitrile the products vary
with the substituents on a-diketones. When the substituents are alkyl or phenyl,
5-cyanothiophene-2-carboxamides 432 are obtained, but with alkoxy group
3-hydroxy-2,5-dicyanothiophenes 437 are produced (scheme-206) 124 .
R1-c-c-R2 HO, ~0
~~ ~ C2H 50Na
R
1_....C-C--R2
I
+ CH CH2
ROOC -H2C, _....CH2-COOR ROOC/ "- / \
s S COOR
R 1 and R2 = H, OH, OR, alkyl or aryl 425
R1 R2
Ho-4---f-oH
H/(_)<H
R~R 2 ROOC S COOR
~-)\ 427tL__ _
ROOC s COOR... -2H20 I 426
428
Scheme-205
Scheme-206
4.2.3.6 Reaction of Alkynes with Mesoionic Heterocycles
The reaction of alkynes, substituted with electron-withdrawing substituents, with

meso-ionic heterocycles such as 1,3-dithiolium-4-olates 438 and 1,3-thiazolium-4-
olates 439 leads to the formation of thiophenes 442 via the intermediates 440 and
441 involving (3 + 2) cyclization (scheme-207) 125 •126 .
Scheme-207
4.2.4 (2 + 2 + 1) Cyclization Reactions
The reaction of alkenes with sulfur is very old method for the synthesis of
thiophenes. The reaction of stilbene with sulfur produces tetraphenylthio-
phene 443 (scheme-208). The alkenes with lower molecular weights also provide
s .
Scheme-208
thiophenes when heated with sulfur (scheme-209). Thionyl chloride has also been
CH300C
G- s COOCH3
444
2 C~=CH-COOCH3
s +
CH300C -O- S COOCH3
445
Scheme-209
used as a sulfurizing agent and its reaction with propiophenone or butyrophenone

provides the corresponding thiophene 446 (scheme-210) 127.
HsC~~:sHs
446
Scheme-210
4.3 Structure
Thiophene is a planar molecule with sp2 -hybridized ring atoms. Six rc- electrons
of the thiophene ring involved in an aromatic sextet are contributed by four
rc-electrons from the four carbon atoms (one electron from each carbon atom)
and two electrons by the sulfur atom. The second lone pair on the sulfur atom
occupies sp 2 -hybridized orbital in the plane of cr-bond (Fig.34).
second ione pair in

sp2-hybrid orbital
Q~-p-atomic orbital
s ~--- sp2-hybridized
'- sp2-hybridized
atomic orbital
Fig. 34. Molecular orbital structure of thiophene
The bond equivalence is not attained in thiophene as is evident from the

following molecular dimensions (Fig. 35) 128 :
Bond lengths (A) Bond angles ( 0

)
d
C2-S 1.714 H C2-S-C5 92.17
C2-C3 1.370 S-C2-C3 111.47
C3-C4 1.423 Cz-CJ-C4 112.45
C2-H 1078 s H C2-C3-H 123.28
C3-H 1.081
s
Fig. 35. Molecular dimensions in thiophene
Thiophene is uniquely 1t-excessive aromatic heterocycle and has the highest

resonance stabilization energy among the five-membered heterocycles. The
resonance stabilization of thiophene is attributed to the expansion of valence
shell by using d-orbitals in hybridization. In the resonating structures (i-v), the
sulfur atom uses p-orbitals and acts as an electron donor, while the resonating
structures (vi-x) involve d-orbital participation and in these structures sulfur acts
as an electron acceptor.
0s ~
Ds ~
W-~
s 0s ~
-0
s
(i) (ii)
+ ...... ......
(iii) (iv) (v)
0s ~
0+
s
(\ii)
~
0s ds +0 s
(\i) (\iii) (ix) (x)
Fig. 36. Resonating structures involving p- and d-orbitals

4.4 Reactions
Electrophilic substitution reactions in thiophene occur predominantly at the carbon

atoms and the substitution at the sulfur atom is relatively rare.
4.4.1.1 Electrophilic Substitutions at Carbon
Thiophene is the least reactive towards electrophiles among the five-membered

aromatic heterocycles with the reactivity order : pyrrole > furan > thiophene. But
thiophene is more reactive than benzene by 103-105 factor. The reactivity of
thiophene is considerably influenced by the substituents as trifluoroacetylation of
2-methylthiophene is faster than that of thiophene. The steric effects in the
substitution reactions are comparatively smaller in magnitude in thiophene than in
benzene because of the larger external bond angle in thiophene than that in
benzene 129 .
Electrophilic substitution reactions in thiophene proceed by a mechanism similar
to that in benzene and involves the attack of electrophile in the first step with the
formation of a a-complex (rate determining step). But the mercuration of thiophene
probably differs from the general mechanism and involves the co-ordination of
mercury with sulfur.
4.4.1.1.1 Orientation
Thiophene undergoes electrophilic substitution reactions slowly and selectively at

an a-position to sulfur rather than at the 13-position. The preferential electrophilic
attack at an a-position in thiophene can be explained on the basis of stability of
the transition state. The transition state resulting from the electrophilic attack at
an a-position is stabilized over the transition state of 13-electrophilic attack (three
resonating structures for a-attack and two resonating structures for 13-attack). The
stability of transition state 447 of a-electrophilic attack is attributed to an allylic
stabilization and the electron donation from the sulfur atom, while in the transition
state 448 the electron-releasing effect of sulfur is the only stabilizing factor
(Fig. 37). Thus, the combination of allylic stabilization and the electron-releasing
effect of sulfur favours electrophilic attack at an a-position.
The a : 13 reactivity ratio depends on the nature of electrophiles and the reaction
temperature. The milder electrophiles and low temperature favour higher a : 13
reactivity ratio. The a-directing effect of sulfur in thiophene is smaller than that
of oxygen in furan because of smaller +M effect of sulfur than oxygen due to less
overlapping of differently sized orbitals of carbon and sulfur.
trl-E
l(_i;)
s
448
Fig. 37. Electrophilic substitution in thiophene
4.4.1.1.2 Directing Effects of Substituents
The sulfur heteroatom in thiophene tends to direct the incoming electrophile to

the a-position rather than to the B-position and the a : B ratio depends on the
nature of the electrophile. The substituents present on the ring also have directing
effects and the position of electrophilic attack, therefore, fmally depends on the
balancing effect of both the effects; directing effect and substituent effect.
4.4.1.1.2.1 Substituents at Carbon-2
(i) The presence ofsubstituents (-R, -X, -OR, -NH 2, -NHR) with +I effect or
-1 (+M) effect at carbon-2 directs the electrophilic attack to the unsubstituted
a-position (C-5) rather than to the B-position because these substituents
are capable of stabilizing the adjacent positive charge by resonance or
inductive effect (Fig. 38).
H, h H, F\ H, F\
F: __..A~~~ A~X ~ A-tA
E S RES RES R
+
~_J
-H
E S R
Fig. 38. Directing effect of substituents at C-2

(ii) However, the substituents with -I and -M effects (-N0 2 , -CN, -COR)
destabilize the adjacent positive charge and cause the electrophilic
substitution at the a-position (C-5), but very slowly due to the balancing
effect of a-directing or activating effect of the sulfur atom and the electron-
withdrawing effect of the substituent. The substitution also occurs at the
position-4 because of being the least deactivated position.
4.4.1.1.2.2 Substituents at Carbon-3
(i) The substituents with +I effect and -I (+M) effect (-R, -X, -OR, -NH 2 ,
-NHR), which are capable of stabilizing the adjacent positive charge
involving allylic carbonium ion, direct the electrophile to the adjacent
position (C-2) (Fig. 39). But the substituents with considerable steric effect
direct substitution to C-5.
d QE OE
R R R
E ~+ ~ ~+
S H S H S H
Fig. 39. Directing effect of substituents at C-3
(ii) However, the electron-withdrawing substituents with -I and -M effects

(-N0 2 , -CN, -COR, -COOR) at C-3 cause electrophilic substitution at
C-5 because both the effects are operating in the same direction.
4.4.1.1.3 Protonation
Thiophene is very stable to aqueous mineral acids, but not to the strong acids.
Thiophene undergoes protonation exclusively at the position-2 with the formation
of thiophenium ion 449 when treated with fluorosulfonic acid (scheme-211) 130 .
R
D S R
Ji!'XH
S H
449
Scheme-211
The thiophenium ions are generally unstable and polymerized at moderate

temperatures. However, the reaction of thiophenes with hydrochloric acid and
aluminium chloride results in the formation of stable a-protonated thiophenium
ions 450 (scheme-212) 131 •
R1
n S R2
R 1 & R2 = H, CH3
+ HCI+AICI3 ~
Scheme-212
The reaction of thiophene with 100% phosphoric acid gives a trimer 453
involving a-protonated thiophenium ion (scheme-213).
c.%~
'/H ~ ~
~+ +
~s -H s
H ~ ~ H ~
H S H S
451 452
40 IH+
Scheme-213
Hydrogen= deuterium exchange in thiophene is faster at an a-position than

at the f3-position. The rate of hydrogen deuterium exchange is affected with the
position of methyl group present on the thiophene ring and follows the order :
3 > 5 > 4.
4.4.1.1.4 Nitration
Thiophene undergoes nitration predominantly at an a-position with the formation

of 2-nitrothiophene, when treated with mild nitrating agent, acetyl nitrate [mixture
of fuming nitric acid and acetic anhydride], at 10°C. Although small amount of
3-nitrothiophene is also obtained (scheme-214), the a-selectivity in nitration
decreases with the strong nitrating agents (scheme-215).
l<J'C
u S
95%
N02
+
5%
Scheme-214
u
N0 2
0s + HN03
S N02
+ 0s
85% 15%
Scheme-215
The nitration of thiophenes substituted with electron-releasing substituents

(with +I effect) at C-2 provides 3-nitro- and 5-nitrothiophenes (scheme-216). But
when the substituent is with considerable steric hindrance, the nitration occurs
exclusively at C-5 (scheme-217 ).
Q S R
+ HN03 _H.....;2;;_s_o..;...4__..
R = alkyl group 70%
Scheme-216
02N
fi S C(CH3b
454
Scheme-217
Thiophenes substituted with electron-releasing substituents ( +M effect) involve

nitration at the a- and 13-positions (scheme-218), but in halothiophenes nitration
takes place exclusively at C-5 (a-position) (scheme-219).
Q S OR
+ HN03
02N
~ S
455 (80%)
OR
+
rf:: 456 (20%)
Scheme-218
Q S X
X=halogen 457
Scheme-219
Thiophenes with electron-withdrawing substituents at C-2 undergo nitration at

the C-4 and C-5 positions providing 4-nitro- and 5-nitro derivatives (scheme-220).
Q S
+ HN03
COOH
458 (75%) 459(25%)
Scheme-220
However, thiophenes substituted with strong electron-withdrawing substituents

at C-2 involve ipso-substitution during nitration with nitrating mixture of concen-
trated nitric and sulfuric acids (scheme-221 ). The ipso-substitution proceeds via
less stable ipso-intermediate, thus providing small amount of the ipso-substituted
product (scheme-222) 132•
460 461
02N +
~ S N02
462
Scheme-221
462
Scheme-222
4.4.1.1.5 Sulfonation
Thiophene is sulfonated readily with 95% sulfuric acid at room temperature with
the formation of thiophene-2-sulfonic acid (70%), and higher yield (90%) is
obtained by the sulfonation with pyridine-sulfur trioxide complex ( scheme-223 ). But

the sulfonation of 2-halothiophenes with 95% sulfuric acid occurs exclusively at
an a-position (C-5) (scheme-224).
0s + H 2S04
3~0"C
(95%)
Scheme-223
Q S X
+ H2S04
X=Cl, Br, I
Scheme-224
The reaction of thiophene with chlorosulfonic acid affords thiophene-2-sulfonyl

chloride 467 in low yield (scheme-225).
0s rna 3
Scheme-225
4.4.1.1.6 Halogenation
Thiophene undergoes halogenation preferentially at an a-position.
4.4.1.1.6.1 Chlorination
Thiophene reacts so rapidly with chlorine even at -30°C that a mixture of

chlorinated thiophenes, containing mainly 2-chloro- and 2,5-dichloro-thiophenes
with small amounts of tri- and tetrachloro-thiophenes and chlorine-addition
products, is obtained involving both substitution as well as addition reactions. It
is, therefore, difficult to obtain monochlorothiophene. However, monochlorothio-
phene is obtained when thiophene reacts with one mole of chlorine (scheme-226).
But chlorination with an excess of chlorine in the presence of iodine as catalyst
yields hexachlorothiophene (scheme-227).
0 +CI2_-30"___..c. ~ + ~ + n Cl
n
S S Cl Cl S Cl Cl S Cl
Cl Cl CI~CI
ruldition pmduot< + +
Cl S Cl l(s)-__CI
Scheme-226
c1-ha
Cl Cl
0s + Cl 2 (excess)
12 catalyst
prolonged reaction Cl S Cl
Scheme-227
4.4.1.1.6.2 Bromination
Bromination of thiophene by molecular bromine in acetic acid-ether mixture

or in carbon tetrachloride results in the formation of 2-bromothiophene. The
reaction of thiophene with N-bromosuccinimide also provides 2-bromothiophene
(scheme-228). But bromination of thiophene in the presence of a base yields
mainly 2,5-dibromothiophene (scheme-229).
CH3CCX:)H
+ Br2
0s
ether I CC1 4
~Br
0
+ ~N-Br
0
Scheme-228
0s base Br~Br 468
Scheme-229
3-Bromothiophene 470 is, however, obtained by the selective a -debromination

of2,3,5-tribromothiophene 469 resulting from 2-bromothiophene (scheme-230) 133 .
BrJ) Br
0--sr }[)__
J:J-
s Br s Br
BrJ:).__Br
Br
0--sr ~ •NH,I Br s Br
469 Br
Zn dust
... 0 s
470
Scheme-230
The bromination of 2-acetylthiophene in the presence of sodium acetate or

acetic acid results in nuclear bromination in place of side chain bromination
(scheme-231 ) 134 .
~
' 8/-cocH 3
Scheme-231
4.4.1.1.6.3 Iodination
Iodination of thiophene with iodine in the presence of mercury (II) oxide gives
mainly 2-iodothiophene (70%) (scheme-232). The acid catalyzed reaction of
thiophene with iodine and iodic acid also produces 2-iodothiophene, but in better
yield (75%). The iodination of thiophene has also been effected by iodine in the
presence of silver trifluoromethane sulfonate at 0°C 135 .
0s HgO
. ~
S I
+
1~1
Scheme-232
4.4.1.1. 7 Alkylation
Alkylation of thiophene under Friedel-Crafts conditions results in polyalkylation

and polymerization probably because of the successive protonation and
electrophilic substitutions. However, alkylation of thiophene with alkenes in the
presence of phosphoric acid or boron trifluoride gives a mixture of a-and 13-isomers
(scheme-233). The poor a-selectivity is due to the indiscriminate attack of highly
Scheme-233
reactive carbonium ion at the a- and 13-positions during alkylation. The a-

selectivity is not effected in the alkylation of thiophenes if substituted with either
methyl-, tert-butyl-, or thiomethyl- at the position-2 (scheme-234) 136 . But electron-
~
S R
+ (CH3hCH-CI
(CH3hCH ~ S R
R = CH 3 , (CH 3 hC, SCH 3
Scheme-234
withdrawing substituents at the position-2 have considerable effect and favour

alkylation predominantly at the position-4 because of the swamping catalyst effect
(scheme-235) 137 .
Q
(CH3hCH
excess
Al03 S COCH3
+ WO/o
Q/R
s c
+
= ,,
Al\111110
1\ 1%
Cl Cl
(swamping catalyst effect)

472
Scheme-235
4.4.1.1.8 Acylation
Thiophene is polymerized when treated with acetyl chloride in the presence of

aluminium chloride, but undergoes acylation exclusively at an a-position (a : ~ =
200 : 1) when acylated by acid anhydrides in the presence of phosphoric acid or
by acid chlorides in the presence of stannic chloride (scheme-236). The reactivity
of a-position in thiophene is much higher than that of the ~-position towards
acylations and therefore leads to the a-substitution selectively.
0s
Scheme-236
Thiophenes substituted with electron-releasing substituents such as methyl-,

tert-butyl- or thiomethyl- at the position-2 undergo acylation exclusively at the
position-5 (a-substitution) (scheme-237). The presence of phenyl group at the
position-3 activates already activated a-position and also to the adjacent
Scheme-237
~-position tosome extent and both a- and ~-substituted products are formed
(scheme-238). But the acylation of2-acylthiophenes in the presence of Lewis acid
occurs at the position-4 probably because of co-ordination of Lewis acid with
oxygen of an acyl group (scheme-239).
+
COCH3 s
473 (70%) 474 (30%)
Scheme-238
0
II
CH3-C
G-
S COCH3
+ (excess) ~
S COCH 3
Scheme-239
Thiophene undergoes Vilsmeier formylation at an a-position when treated with

N,N-dimethylformamide (DMF) in the presence of phosphorus oxychloride
(scheme-240). However, 2-methoxythiophene on Vilsmeier formylation leads to
the formation of a-substituted product 475 predominantly with the small amount
of ~-substituted product 476 (scheme-241). In 3-phenylthiophene Vilsmeier
formylation occurs preferentially at an a-position, but phenyl group activates the
adjacent ~-position also and results in formylation at the ~-position affording
small amount of the ~-substituted product 478 (scheme-242).
/fl.. HOH
~ 5 /'-cHO
Scheme-240
OHC
,JQ_ S OCH3
475
(rmjor product)
POCI 3
+ CHO
tj__
S OCH3
476
(minor product)
Scheme-241
OHC
formylation +
s
477 478
Scheme-242
4.4.1.1.9 Reactions with Aldehydes and Ketones
(i) Acid catalyzed condensation of thiophene with benzaldehyde results in the

formation of binuclear product 479, but with acetone in the ratio 2 : 1 and
3 : 1 gives the products 480 and 481, respectively. However, with
formaldehyde polymeric product 482 is obtained (scheme-243).
(ii) The reaction of thiophene with isatine in the presence of sulfuric acid gives
deep blue colouration due to the formation ofindophenine 484 (indophenine
test) (scheme-244).
0+ ob)
I 0 N #
cone. H2S04
s
H
483a
484
t
483b
Scheme-244
(iii) Thiophene undergoes chloromethylation when treated with formaldehyde

and hydrochloric acid with the formation of 2-chloromethylthiophene 485
or 2,5-bis( chloromethyl)thiophene 486 depending on the reaction conditions
(scheme-245).
~
HCHO(excess) o~ HCHO
HQ HQ
CIH2C s CH2CI (3Q-40"C) s (a'C)
486
Scheme-245
(iv) The reaction of thiophene with formaldehyde and ammonium chloride leads
to the formation of2-aminomethylthiophene (scheme-246). N,N-Dimethyl-
aminomethylation of thiophene is effected by using N,N-dimethyl (methylene)
ammonium chloride.
0s
HCHO
+ (excess)
Scheme-246
4.4.1.1.10 Mercuration
Thiophene reacts very easily with mercury(II) acetate ( 105 times faster than
benzene) resulting in acetoxymercuration of all the free nuclear positions (scheme-
247). Thiophenes deactivated by electron-withdrawing substituents also undergo
mercuration at the free nuclear positions providing the products like 488 and 489.
Scheme-247
H 3C-~-OHghHgOCOCH 3
C2H~OC _i(s~COOC 2 H 5
488
The reaction of thiophene with mercury(II) chloride, however, results in chloro-

mercuration with the formation of thiophene-2-mercury chloride or thiophene-2,5-
dimercury chloride (scheme-248).
~HgCI CH~N' 0s (room tempt.)
Scheme-248
4.4.1.1.11 Reactions with Diazonium Salts
Thiophene is not sufficiently reactive to diazo coupling and undergoes arylation

rather than coupling reaction when treated with diazonium salts under alkaline
conditions and produces 2-aryl- or 2,5-diarylthiophene probably by the mechanism
depicted in (scheme-249). However, 2-methyl-, 2-tert-butyl-, 2-phenyl- and 2,4-
490
~ -N2
N0 2 . -H
+
N02
0 2N 0 2N
492 491
Scheme-249
dimethyl-thiophenes with diazonium salts under acidic conditions result in the

formation of coupled products involving normal coupling at the position-2
(scheme-250).
R1 = CH3
R1 = C(CH3)3
R1 = CsH 5
R1 = CH3
Scheme-250
4.4.1.2 Electrophilic Attack on Sulfur
Thiophene undergoes S-alkylation when reacts with strong (hard) alkylating

agents such as trimethyloxonium tetrafluoroborate [(CH3h0+BF 4-] and alkyl
fluorosulfonates (ROS0 2F) containing non-nucleophilic counterions (BF4- or
PF 6- ) because with nucleophilic counterions ( n the S-alkylthiophenium cations
produced result in a reversal of the initialS-alkylation (scheme-251).
0s + -
+ (CH3)JOBF4 ~ (J
s I
-
BF4
NaPF6
(J
s
I
-
PF6
CH3 CH3
494 495
Scheme-251
.. .. . PFs
-
Fig. 40. Resonating structures of S-alkylthiophenium cation

Alkyl thiophenium salts, although involve participation of the lone pair on sulfur
in an aromatic sextet, exhibit reduced aromaticity. The reduced aromaticity is
attributed to the less effective overlapping of the lone pair on sulfur atom with the
ring n-electrons because of sulfur being sp3-hybridized and the alkyl group not
being coplanar with the thiophene ring 138 .
4.4.2 Reactions with Oxidizing Agents
4.4.2.1 Formation of Thiophene Sulfoxides and Sulfones
Oxidation of thiophene with m-chloroperbenzoic acid yields unstable thiophene

sulfoxide 496 and thiophene sulfone 497 but both react immediately and finally
provide Diels-Alder adduct 498 (scheme-252).
R
D S
MCP~A [
R
)[)]-+-~-+- I
S
II
R
q
S
~
R
R =HorCH 3 0 0 0 R
\. 496 + 497) 498
y.---:..::....:.--
Scheme-252
However, oxidation of thiophenes, containing sterically hindered group, with

one equivalent of m-chloroperbenzoic acid produces the corresponding sulfoxides
499, but with three equivalents of m-chloroperbenzoic acid the sufones 500 are
obtained 139 . Thiophene sulfones behave as dienes and undergo Diels-Alder
reaction with dienophiles providing Diels-Alder adducts 501 (scheme-253).
R
_)()_ S R
MCPBA
(one equiv.) R
_)()_S R
II
0
~499 0
I MCPBA ..
_)()_ 0 0 0
(three equiv.) R S R I 0
~~
0 0
R 0
500 501
Scheme-253
4.4.2.2 Oxidative Ring Cleavage
Oxidation of 2,5-dimethylthiophene with photogenerated singlet oxygen 2) eo

results in the ring cleavage with the formation of trans-diketone 504 and cis-
sulfene 505 via a cyclic peroxide intermediate 502 by 1,4-addition of singlet
oxygen with thiophene (scheme-254) 140 •
hv (520nm)
(methylene blue)
502
...
H3C
/q~cH,
s-o
0
/----~~~~ c/f\c,
'6 IH3 CH 3
II
0
504 503 505
Scheme-254
4.4.2.3 Oxidation by Metal Ions
The reaction of thiophene with potassium tetrafluorocobaltate leads to the

fluorination of thiophene involving an initial oxidation of thiophene to the cation-
radical 506 by the metal ion and subsequent quenching by atomic fluorine
(scheme-255) 141 .
(i) co+ 3
Fy:=:xF .....,..I--F2_F'IJA (ii)KCOF4
F S F F S F
511 510
Scheme-255
4.4.3.1 Nucleophilic Attack at Carbon
4.4.3.1.1 Nucleophilic Substitutions
Halothiophenes are relatively inert to the nucleophilic substitutions, but their

reactivity is greater than the aryl halides. Thiophenes conjugatively substituted
with electron-withdrawing substituents are much more reactive to the nucleophilic
substitutions than the corresponding benzenoid compounds. The greater reactivity
in thiophenes is attributed to the increased stability of the intrermediate than
that in benzenoid compounds due to the ability of sulfur to stabilize the carbanion
(Fig. 41).
(iv)
Fig. 41. Nucleophilic substitution mechanism

However, in some cases nucleophilic substitutions do not follow the normal

course of substitution (introduction of nucleophile on the carbon bearing leaving
group), but involve cine-substitution (introduction of nucleophile on the carbon
adjacent to the carbon bearing leaving group). The reaction of 2- bromothiophene
with sodium amide in liquid ammonia produces 3-bromothiophene, but with
potassium amide in liquid ammonia 3-aminothiophene is obtained (scheme-256).
Br
NaNH 2
NH3 (liquid) d s
Scheme-256
The cine-substitution neither involves an addition-elimination mechanism nor

an elimination-addition mechanism, but involves a series of steps leading to the
bromine migration (rearrangement) with NaNH/NH 3 and to an amination with
KNH 2/NH 3 (Schemes-257 and 258) 142 .
~
c( 0-
Br
ff1.. NaNH2
(}__ S Br +
~ ---"' NH3
S Br Ss fu
T
S Br (liquid)
0 Br \., Br
s
NH,
(§_+ ~
S S Br
Scheme-257
Nucleophilic substitution of halogen in unactivated halothiophenes is difficult

and is effected under the forcing conditions using copper salts as catalysts
(scheme-259) 143 .
~
Br
Gs
KNHz
NH3
Br (liquid)
~
S
-
Br
S Br
d S
+
Br
0-
s
0- ~NH3
d
NH2
()_
NH2
NH2
MI, s~
s s S Br
Scheme-258
H3C
~
S Br
OJCN
pyridine H3C
~
S CN
Br OCH3
d s
OJO,KI
CH30H,il
d s
~
S Br
OJSBu"
quinoline ~SBun
Scheme-259
4.4.3.1.2 Halogen-Metal Exchange
Bromine -== lithium exchange occurs very rapidly when bromothiophenes react
with n-butyllithium in ether at -70°C (scheme-260). Since bromine~ lithium
exchange decreases steric overcrowding, the percentage of 2-lithio derivative 514
d
COOH
0
Br
-7fJ'C
+ n-Buli ~
s s
Scheme-260
in relation to the 5-lithio derivative 515 in 3-alkyl-2,5-dibromothiophene 513

increases with increasing the steric effect of an alkyl substituent (scheme-261).
R R R
n{
Br.-( 8 )-Br
+ n-Buli ~ Br.-(rl)-u + Li .-(s)-Br
rl
8
513 514 515
R =CH3 190/o 81%
= CzHs 23% 77%
= CHz-CH2 -CH3 28% 72%
= CHz-CH2-CH2-CH3 57% 43%
=Br 100%
Scheme-261
Fluoro- and chlorothiophenes are relatively inert and thus effectively used for
the selective exchange (scheme-262).
Br
~
s Cl
+n-BuU
516 518
Scheme-262
The reactivity of a-bromine

-== lithium exchange reaction isand,higher than that of P-bromine in bromine
therefore, a-boromine ·is more labile than
P-bromine (scheme-263).
Br Br Br
b-_
s Br
+ n-BuU - Q__ S Li
ro,~ ~
H3cf S COOH
519 520 521

Scheme-263
The reaction of 2,3-dibromothiophene 522 with n-butyllithium involves stepwise

bromine ~ lithium exchange because of the reactivity difference of a- and
~-bromine atoms (scheme-264).
o_+
Br
0-Li
Br
0-Li
Li
n-BuLi
n-BuLi
S Br
522 523 524
COOH
(j__
S COOH
... COz
+
H 30
525
Scheme-264
4.4.3.2 Nucleophilic Attack at Hydrogen
4.4.3.2.1 Lithiation
The reaction of thiophene with n-butyllithium in ether results in a -lithiation

exclusively due to the higher acidity of a-position. However, the orientation of
lithiation in thiophenes depends on the nature and the position of the substituent
already present on the ring 144 :
(i) The presence of substituent at the position-2 effects the lithiation
exclusively at the position-S irrespective of the nature of the substituent
(scheme-265).
n
'(s/--R
+ n-BuLi ~ n
u/Z..s/--R )0_
HOOC S R
Scheme-265
(ii) The presence of the substituent at the position-3 with ortho-directing

effect causes lithiation predominantly at the position-2 irrespective of its
steric effect (scheme-266). If the substituent at C-3 does not exhibit ortho-
d
OR OR
s
+ n-Buli .. 0--u
Scheme-266
directing effect, lithiation occurs at C-2 and C-5 and the ratio of the
products depends on the steric effect of the substitutents (predominantly
at C-5 if substituent is bulky) (scheme-267).
u-0
R R
d s
+ n-Buli +
Scheme-267
(iii) In 3,4- or 2,5-disubstituted thiophenes, lithiation occurs at ortho- to the

substituent exhibiting stronger directing effect (scheme-268).
tfu
R OR R OR
0 s
+ n-Buli .
526 527
Scheme-268
4.4.3.3 Nucleophilic Ring Opening Reactions
Nucleophiles can also affect the cleavage of the thiophene ring. The reaction of
nitro thiophene with secondary amine produces disulfide 530 involving nucleophilic
attack of amine at the position-S, followed by the ring cleavage and oxidative
dimerization (scheme-269) 145· 146.
~ dimerization
Scheme-269
The reaction of thiophene with Grignard reagents in the presence of bis

(triphenylphosphine)nickel dichloride also results in the ring opening with the
formation of ring-opened products 531 (scheme-270) 147.
H5C5- CH = CH- CH =CH- C5H5

531
Scheme-270
4.4.4 Reactios with Reducing Agents
4.4.4.1 Catalytic Reduction
Because of the catalyst-poisoning nature of sulfur in thiophene, catalytic reduction

occurs with the excess of catalyst with the formation of thiophane
( tetrahydrothiophene) (scheme-271 ).
0s Pd/C
Q
Scheme-271
4.4.4.2 Birch Reduction
The reduction of thiophene with lithium-ammonia or sodium-ammonia in the

presence of methanol produces 2,3-dihydro- and 2,5-dihydro-thiophenes as the
major products. However, 2,5-dihydrothiophene undergoes desulfurization with
the cleavage of ring providing 2-butene (scheme-272).
0s 0s + 0s
-S
~
Scheme-272
4.4.4.3 Reductive Desulfurization
Thiophenes are reductively desulfurized by Raney nickel in methanol or ethanol

at 60-70°C involving the cleavage of C-S bonds and the hydrogenation of C=C
double bonds with the formation of four-carbon unit containing substituents at
their predetermined positions (scheme-273) 148 . The reductive desulfurization can
be used to prepare a number of acylic compounds which are difficult to prepare
by other methods.
Scheme-273
Thiophene undergoes free radical substitutions preferably at the position-2

because the transition state (allylic free radical) resulting from free radical attack
at the position-2 is more stabilized than the transition state resulting from the
attack at the position-3 (Fig. 42)149-151 .
I attac:atC-2. n ..... Q
S X S
.....,.._Q
X S X
0
S
_x____....
. _ _ _ I
attack at C-3
r. ~ Z+;)
I( s)
C_
X X
Fig. 42. Free radical substitution in thiophene

o: s
Phenylation of thiophene by phenyl radicals generated by Gomberg reaction

provides 2-phenylthiophene and 3-phenylthiophene in the ratio 90 : 5
(scheme-274). But phenylation by phenyl radicals, obtained from phenyl-
azotriphenylmethane, is however less selective and produces 2-phenylthiophene
and 3-phenylthiophene in 72 : 28 ratio (scheme-275).
0s ... G- S C6Hs
+
(major)
Scheme-274
0s
Scheme-275
The reaction of thiophene with benzoyl peroxide radical affords 2,2'-bithienyl

534 with small amount of 2-benzoyloxythiophene 535 involving addition-
dimerization-elimination sequence rather than the phenylation (scheme-276) 149 .
0s +C H
6
coo___.. rt:X...H
5 S O-C-CsHs ____..
-H Gs OCOCsHs
II
532 0 535
~ dUremation
G--() HH
s 534
+
s~ [ H5C6-~-:>CJ--n S S
J
:COC 6 Hs
2C6H5COOH 0 533
Scheme-276
However, the substituents on the thiophene ring effect the orientation of

phenylation:
(i) The presence of ortho-directing substituents at the position-2 causes
phenylation at both C-3 and C-5 positions because of both the existing
competing effects : a-directing effect of the sulfur atom and ortho-directing
effect of the substituent. The phenylation at the position-3 predominates
with the electron-withdrawing substituents, while phenylation occurs
predominately at the position-S with the electron-releasing substituents
(scheme-277) 151 •
ri
CsHs
HsCs ~
S R
+
S R
536 537
(tmjor product) (minor product)
(minor product) (tmjor product)
Scheme-277
(ii) The presence of subsituents at the position-3 effects phenylation

predominantly at the position-2 because of the reinforcing effect of both the
effects (scheme-278).
d
R
+ C6Hs
__.. ();
R
+
HsC6
J:JR S
S C6Hs
s
538 539
R=CH 3 (major product) (minor product)
R= N0 2 (major product) (minor product)
Scheme-278
Thiophene undergoes cycloaddition reactions with carbenes with the formation of

cyclopropane derivatives involving the addition of carbene to C2-C 3 bond of
thiophene. Copper bromide catalyzed reaction of thiophene with diazomethane
produces thiabicyclo[3 .l.O]hex-3-ene 540 (scheme-279) 152 •
0s CuBr
Scheme-279
Similarly, photochemical reaction of thiophene with diazoacetic acid ester

(ethoxycarbonylcarbene) also produces cyclopropane derivative 541 (scheme-
280)153.
0s + N2CHCOOC 2H5
hv
Scheme-280
4.4.6.2 Reactions with Nitrenes
The reaction of thiophene with ethoxycarbonylnitrene results in the formation of

N-ethoxycarbonylpyrrole. The reaction is considered to involve the attack of
nitrene at C-2 and the ring opening to thiocarbonyl intermediate 543 followed by
cyclization and extrusion of sulfur (scheme-281 ) 154 .
hv c_x;;
s0 NCOO~H 5
542
•
;:£? - H~~-CO~H,
COOC2Hs 543
544
Scheme-281
4.4. 7 Cycloaddition Reactions
Thiophene exhibits least dienic character because of being the most aromatic
among the five-membered heterocycles; pyrrole, furan and thiophene. Thiophene
therefore fails to undergo cycloaddition reactions with common alkynes and other
dienophiles under the normal conditions. However, thiophene can be induced to
undergo cycloadditions:
(i) if reacts with highly reactive alkynes and other dienophiles,
(ii) if the reactivity of thiophene is increased by the substituents and
(iii) if the reaction is carried out at high pressure.
4.4. 7.1 Thermal [4 + 2] Cycloaddition Reactions
The reaction of thiophene with maleic anhydride at 100°C and high pressure ( 15
kbar) results in the formation of exo-cycloadduct 42 involving (4 + 2)
cycloaddition 155 •156 . But the reaction of 2,5-dimethoxythiophene with maleic
anhydride produces his-adduct 547 because of the activity of thiophene ring. The
reaction proceeds with the initial addition of maleic anhydride followed by the
extrusion of sulfur providing a diene 546 which then adds to the second molecule
of maleic anhydride (scheme-282) 157 .
~0
0
42
(exo-adduct)
0
545
t
:~
-S
0
c~:
CH30 H 0
547 546
Scheme-282
Thiophene reacts with activated alkynes with the formation of benzene

derivatives 549 involving (4 + 2) cycloaddition and the extrusion of sulfur from
the resulting unstable cycloadduct 548 (scheme-283) 158 •159 .
s
E-c=c-c -----~~ tJ~A ~ex~
: : : : -. . E
E
E=CN,COOR E
548 549
Scheme-283
The reaction of thiophene with tetrafluorobenzyne gives cycloadduct 550 which

loses sulfur to provide tetrafluoronaphthalene 551 (scheme-284) 160 . However, the
0+1¢cF
F s F
F
-S
~ F~
S F F
F F F F
550 551
Scheme-284
reaction of thiophene with benzyne has been reported to yield naphthalene in low
yield (33%) (scheme-285) 16 1.
-S
• (X)
Scheme-285
4.4.7.2 Thermal [2 + 2] Cycloaddition Reactions
Tetramethylthiophene undergoes (2 + 2) cycloaddition reaction with dicyano-

acetylene in the presence of aluminium chloride providing cycloadduct 553
(scheme-286) 162•163 •
Scheme-286
Thiophenes 554 substituted with an amino group at the position-3 exhibit

enaminic activity at the position-2 and undergo (2 + 2) cycloaddition with activated
alkynes in non-polar solvents whereas in polar solvents electrophilic substitution
takes place at the position-2 (scheme-287) 164- 166 .
0
o s
+ E-c=c-E-- rf;E S H E
non-polar
solvent
C,H6, 3<J'C 1
554
555
0
rn 3 oH~ polar solvent
+0 - & S E
~CH...._ 556
S C E
~
H I
QE
E
u-E
560 559
0 N
~E s
561
u 558
E
557
Scheme-287
4.4. 7.3 Photocycloaddition Reactions
Photochemical reactions of 2,3-dimethyl- and 2,5-dimethyl-thiophenes with

benzophenone or similarly related carbonyl compounds result in the formation of
oxetanes 562 involving (2 + 2) cycloaddition (scheme-288) 167- 169 .
hv
~CeHs
H3C S CH3
562
Scheme-288
2-Methyl- and 3-methyl-thiophenes also undergo photosensitized (2 + 2)

cycloadditions with 2,3-dirnethylmaleic anhydride, but the cycloadduct differs with
the position of methyl group. In 2-methylthiophene the addition occurs on
CcC5 (unsubstituted) bond and with 3-methylthiophene addition takes place on
C2 -C 3 bond (substituted) (scheme-289) 170 .
mCOOH
0 H CH 3
H3C~
H3C JO S
+
H3C
I o
hv
C6H 5COC6H5
H3C S H
COOH
CH3
0
563
0 CH3 CH3
0+
CH 3
H3c~
H3C
I o
hv
C6H 5COC6H5 ~H CH 3
s S H COOH
0
564
Scheme-289
Photochemical rea~tion of 2-acetylthiophene with alkenes (2,3-dimethylbutene)

leads to the formation of major product 565 involving (4 + 2) cycloaddition but
the minor products 566 and 567 are obtained by (2 + 2) cycloadditioin
(scheme-290) 171 .
Thiophene and 2,5- dimethyl thiophene undergo photochemically induced (4 + 2)
cycloaddition with acetylenedicarboxylate with the formation of phthalic ester
(scheme-291 ) 172 . The reaction is considered to involve the triplet state of
thiophene and proceeds via a biradical 568.
..
S H CH3
hv
CH3
CH C H3
3 ~ CH3
0
565
(major product)
+
CH3
/11
"-o~CH3
H3C
9+CH3 +
CH 3
<#~::
C CH 3
H3C,... ~0
567 566
(minor product) (minor product)
Scheme-290
S CH 3 568
~coo:_J
CH3 COOR
570 569
Scheme-291
4.4.8 Photosubstitution
Thiohene undergoes photosubstitut ion at the position-2 rather than

photocycloaddition when irradiated in the presence of 3,4-dichloromaleimide 571
and leads to the formation of 2-substituted product 572 (scheme-292) 173 .
Five-Membered Heterocycles with One Heteroatom I7I
0s +
hv
0
572
Scheme-292
4.4.9 Photoisomerization
However, when 2-phenylthiophene is irradiated 3-phenylthiophene is obtained as

a result of photochemical isomerization. The reaction is considered to involve most
probably cyclopropene-3-thiocarbaldehyde 573 as an intermidiate (scheme-293) 174 •
hv.,. .
573
Scheme-293
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166. D. N.Reinhoudt, G. Okay, W. P. Trompenaars, S. Harkema, D. M. W.Van
den Ham and G. J. Van Hummel, Tetrahedron Lett. 1529 (1979).
167. C. Rivas, M. Velez and 0. Crescente, Chern. Commun. 1474 (1970).
168. C. Rivas and R. A. Bolivar, J. Heterocyc/. Chern. 10, 967 (1973).
169. C. Rivas, D. Pacheco, F. Vargas and J. Ascanio, J. Heterocycl. Chern. 18,
1065(1981).
170. T. Nakano, C. Rivas, C. Perez and K. Tori, J. Chern. Soc. Perkin Trans. 1,
2322(1973).
171. T. S. Cantrell, J. Org. Chern. 39, 2242 (1974).
172. H. J. Kuhn and K. Gollnick, Chern. Ber. 106, 674 (1973).
173. H. Warnhoffand H. J. Hupe, Tetrahedron Lett. 125 (1978).

174. K. Jug and H. -P. Schluff, J. Org. Chern. 56, 129 (1991).
CHAPTER3
BENZO-FUSED FIVE-MEMBERED
HETEROCYCLES WITH ONE HETEROATOM
CONTENTS
GENERAL 187
l.l Reactivity 188
l.2 Orientation 188
l.3 Dibenzoheterocycles 189
2 BENZOPYRROLES 190
2.1 Indoles 191
2.l.l General 191
2.1.2 Synthesis 194
2.1.2.1 Reaction of o-Nitrotoluene with Diethyl 194
Oxalate (Reissert Indole Synthesis)
2.1.2.2 From o-N itropheny lnitroethy lene 195
( o,ro- Dinitrostyrene)
2.1.2.3 Palladium Catalyzed Cyclization 196
2.1.2.4 Madelung Indole Synthesis 196
2.1.2.5 Isonitrile Cyclization 197
2.1.2.6 Bischler Indole Synthesis 198
2.1.2.7 Fischer Indole Synthesis 199
2.1.2.8 Gassman Indole Synthesis 203
2.1.2.9 Nenitzescu Indole Synthesis 203
2.1.2.10 From Pyrroles 206
2.1.2.11 FromAzirines 207
2.1.3 Structure 208
2.1.4 Reactions 208
2.1.4.1 Reactions with Electrophiles 2(1)

2.1.4.1.1.1 Reaction with Proton Acids 210
2.1.4.1.1.2 Basicity 211
2.1.4.1.1.3 H-::::::=::: D Exchange 211
2.1.4.1.1.4 DirnerizationandTrimerization 212
2.1.4.1.2 Nitration 212
2.1.4.1.3 Nitrosation 215
2.1.4.1.4.2 Brornination 218
2.1.4.1.4.3 Iodination 218
2.1.4.1.6 Acylation 221
2.1.4.1.6.1 Friedel-Crafts Acylation 221
2.1.4.1.6.2 Vilsmeier-Haack Formylation 222
2.1.4.1.8 Reactions with Aldehydes and 224
Ketones
2.1.4.1.8.1 Ehrlich Test 224
2.1.4.1.8.2 With Aromatic 225
Aldehydes and Ketones
2.1.4.1.8.3 With Aliphatic 225
Aldehydes and Ketones
2.1.4.1.8.4 With a , ~-Unsaturated 227
Ketones
2.1.4.1.9 Mannich Reaction 227
2.1.4.2 Reactions on Carbon and Nitrogen Anionic Species 228
2.1.4.2.2 Acylation 231
2.1.4.3 Reactions with Nucleophiles 232
2.1.4.4 Oxidation 233
2.1.4.5 Reduction 234
2.1.4.6 Reactions with Electron-Deficient Species 237
2.1.4.7 Reactions with Free Radicals 238
2.1.4.8 Cycloaddition Reactions 239
2.2 Isoindoles (Benzo[ c]pyrroles) 240
2.2.1 General 240
2.2.2 Synthesis 242
2.2.2.1 Cyclization Reactions 242
2.2.2.1.1 Froma-Bromo-o-toluicAcid 242
2.2.2. 1.2 FromN-Cyanomethyl-N-methyl-o- 243
chlorobenzylamine
Benzo-Fused Five-Membered Heterocycles with One Heteroatom 183
2.2.2.1.3 From 1,4-Diketones 243

2.2.2.2 Extrusion Reaction 243
2.2.2.3 Ring Transformation Reactions 244
2.2.2.3.1 FromPhtha1imidines 244
2.2.2.3.2 Fromlsoindolines 245
2.2.2.3.3 FromPyrroles 247
2.2.3 Reactions 247
2.2.3.1 Reactions with Electrophiles 247
2.2.3.l.l Protonation 248
2.2.3.1.3 Acylation 249
2.2.3.1.5 Formy1ation 250
(Ehrlich Test)
2.3 Indolizines (Pyrrocolines) 254
2.3.1 General 254
2.3.2 Synthesis 255
2.3.2.1 Reaction ofPyridines with a-Halocarbonyl 255
Compounds (Tschitschibabin Reaction)
2.3.2.2 Reaction of Pyridine with Alkynic Compounds 257
2.3.2.3 Reaction of2-Pyridyllithium with 258
2-Chloromethyloxirane
2.3.2.4 1,3-DipolarCycloadditionReactions 258
2.3.3 Structure 259
2.3.4 Reactions 260
2.3.4.1 .1 Protonation 261
2.3.4.1.2 Nitration 262
2.3.4.1.5 Acylation 264
2.4 Carbazoles (Dibenzopyrroles) 267
2.4.1 General 267
2.4.2 Synthesis 268
2.4.2.1 From Cyclohexanone Phenylhydrazones 268

(Borsche Synthesis or Modified Fischer Indole
Synthesis)
2.4.2.2 Reaction of Anilines with a-Halocyclohexanones 268
2.4.2.3 From Diarylamines 269
2.4.2.3.1 Oxidative Cyclization 269
2.4.2.3.2 Photochemical Cyclization 270
2.4.2.4 Reductive Cyclization of o-Nitrobiphenyls 271
2.4.2.5 Fromo-Azidobiphenyls 271
2.4.2.6 From 1-Arylbenzotriazoles 272
(Graebe-Ullmann Synthesis)
2.4.2.7 Nenitzescu Reaction 272
2.4.2.8 Annelation of Indoles 272
2.4.3 Structure 273
2.4.4 Reactions 274
2.4.4.1.2 Nitration 275
2.4.4.1.4 Chlorination 276
2.4.4.1.7 Acylation 277
3 BENZOFURANS 279
3.1 General 279
3.2 Benzo[ b ]furans 282
3.2.1 Synthesis 282
3.2.1 .1 Intramolecular Cyclization ofa-Substituted 282
Phenols
3.2.1.2 Cyclodehydration of a-Aryloxyketones 283
3.2.1.3 Reaction of o-Acylphenols with 284
a-Halo Ketones and Esters
3.2.1.4 Reaction of o-Acylphenols with 285
Dimethylsulfoxonium Methylide
3.2.1.5 Fromp-Benzoquinones 286
3.2.1.6 Ring Contraction (From Coumarins) 287
3.2.2 Structure 287
3.2.3 Reactions 288
3.2.3.1.1 Reactivity and Orientation 288
3.2.3.1.2 Directing Effects of Substituents 289

3.2.3.1.4 Nitration 289
3.2.3.1.7 Acylation 293
3.2.3.1.9 Reaction with Diazonium Salts 295
3.2.3.7 Photochemical Reactions 300
3.2.3. 7.I Photodimerization 300
3.2.3.7.2 Photosensitized Cycloaddition 301
3.2.3.7.3 Photooxygenation 301
3.3 Benzo [c] furans 302
3.3.1 General 302
3.3.2 Synthesis 302
3.3.2.1 Retro-Diels-Alder Reaction 302
3.3.2.2 Reductive Cyclization of o-Dibenzoylbenzenes 303
3.3.2.3 Reaction ofDibenzoylacetylene with Dienes 303
3.3.2.4 From Benzophenones 304
3.3.3 Reactions 305
3.3.3.2.1 Photodimerization 307
3.3.3.2.2 Photocycloaddition 307
3.3.3.2.2.1 With Cycloheptatriene 307
3.3.3.2.2.2 WithCyclohexadiene 308
3.3.3.2.3 Photooxygenation 308
3.4 Dibenzofurans 309
3.4.1 General 309
3.4.2 Synthesis 310
3.4.2.1 From2,2'- Dihydroxybiphenyls 310
3.4.2.2 FromDiphenyl Ethers 310
3.4.2.3 Fromo-Arninodiphenyl Ethers 311
(PschorrType Cyclization)
3.4.2.4 Wittig Reaction 312
3.4.3 Reactions 312
3.4.3.1Reactions with Electrophiles 312

3.4.3.1.2 Nitration 314
3.4.3.1.3 Formylation 316
3.4.3.2 Metallation (Lithiation) 316
4 BENZOTIIIOPHENES 320
4.1 General 320
4.2 Benzo[b ]thiophenes 321
4.2.1 General 321
4.2.2 Synthesis 322
4.2.2.1 Oxidative Cyclization ofMercaptocinnamic Acids 322
4.2.2.2 Reaction ofCinnamic Acid with Thionyl Chloride 323
4.2.2.3 Dehydrative Cyclization 323
4.2.2.3.1 From Arylthioacetaldehyde Acetals 323
4.2.2.3.2 From Arylthio Methyl Ketones 324
4.2.2.4 Reaction ofMercaptoaldehyde or Acid with 324
a-Halo Acids or Ketones
4.2.2.5 From Benzenethiols (Thiophenols) 325
4.2.2.6 From Thiophene-2,3-dicarboxylic Anhydride 326
4.2.3 Reactions 327
4.2.3.1.1 Electrophilic Attack at Carbon 327
4.2.3.1.1.1 Orientation 327
4.2.3.1.1.2 Directing Effects of 328
Substituents
4.2.3.1.1.3 Nitration 328
4.2.3.1.1.4 Halogenation 328
4.2.3.1.1.5 Sulfonation 329
4.2.3.1.1.6 Alkylation 330
4.2.3.1.1.7 Acylation 331
4.2.3.1.1.8 DiazoCoupling 331
4.2.3.1.2 Electrophilic Attack at Sulfur 332
4.2.3.2 Reactions with Oxidizing Agents 333
4.2.3.2.1 Formationofl-Oxidesand 1,1-Dioxides 333
4.2.3.2.2 Oxidative Ring Opening 334
4.2.3.3.1 Metallation 334
4.2.3.3.2 Ring Opening by Nucleophiles 335
4.2.3.3.3 Addition ofNucleophiles 335
4.2.3.4 Reactions with Reducing Agents 335

4.2.3.6.1 Thermal (2 + 2) Cycloaddition Reactions 337
4.2.3.6.2 Photochemical (2 + 2) Cycloaddition 337
Reactions
4.2.3.7 Photosubstitution 338
4.3 Benzo[c ]thiophenes 339
4.3.1 General 339
4.3.2 Synthesis 339
4.3.2.1 From 1,4-Diketones 339
4.3.2.2 From o-Bis (chloromethyl) benzene 340
4.3.2.3 Ring Contraction of 1,2-Dithiins 341
4.3.2.4 Annelation of Thiophenes 341
4.3.3 Reactions 341
4.3.3.2 Oxidative Ring Opening Reactions 342
4.4 Dibenzothiophenes 343
4.4.1 General 343
4.4.2 Synthesis 344
4.4.2.1 Oxidative Cyclization ofDiphenyl Sulfides 344
4.4.2.2 Reductive Cyclization ofDiphenyl Sulfoxide 344
4.4.2.3 FromBiphenyls 344
4.4.2.4 From Diphenyl sulfones 345
4.4.2.5 From2-Allylbenzo[ b ]thiophenes 345
4.4.3 Reactions 346
REFERENCES 347
1 GENERAL
The fusion of a benzene ring with five-membered aromatic heterocycles (n:-

excessive pyrrole, furan and thiophene) results in benzo[a], benzo[b] and benzo[c]
fused heterocycles depending on the annelation of the benzene ring on to the 'face
a' (1,2-bond), 'face b' (2,3-bond) and 'face c' (3,4-bond), respectively.
'CO '(X), 'CC

4 3
6~ X # 2
6~ X 6 ~ :::::,._ ;
5 4 3 7 1 7 1
1: X = N lndolizine 2: X= NH Indole 5: X= NH Isoindole

3: X= 0 Benzo[b]furan 6: X = 0 Benzo[ c]furan
4: X= S Benzo[b]thiophene 7: X= S Benzo[c]thiophene
Benzo[a] heterocycle Benzo[ b] heterocycles Benzo[c] heterocycles
Benzo[ b] heterocycles are stable, but benzo[ c] heterocycles are stable only at
low temperature. The resonance energies of the benzo[c] heterocycles are
substantially lower than those for the benzo[b] heterocycles. Thus, the fusion of
a benzene ring to 3,4-bond (face c) results in relatively less stable bicyclic
heterocycles than those resulting from the 2,3-bond fusion (face b). The
aromaticity sequence in benzo[b] heterocycles is similar to that in five-membered
heterocycles : benzo[ b]thiophene> benzo[b]pyrrole > benzo[ b ]furan, but somewhat
different aromaticity sequence is observed in benzo[ c] heterocycles : isoindole >
benzo[c]thiophene > benzo[c]furan.
1.1 Reactivity
These bicyclic heterocycles differ in their chemical properties from the basic
heterocyclic systems. These heterocycles involve electrophilic attack in the
heterocyclic ring, but the presence of electron-withdrawing substituents on the
heterocyclic ring or the electron-releasing substituents on the benzene ring
facilitates the electrophilic substitution in the benzene ring. Benzene annelation to
the 'face b' of furan or thiophene ring decreases reactivity towards electrophilic
substitution reactions and it is much more pronounced in case of furan.
1.2 Orientation
The directing effect of the heteroatom in benzo[ b] heterocycles is expected to

favour ~-substitution over a-substitution in the heterocyclic ring on the basis of
the stability of cr-complex (Fig. 1). But in fact benzo[b]pyrrole (indole) and
benzo[b ]thiophene undergo P-substitution, while benzo[ b ]furan involves mainly

a-substitution, thus reflecting strong a-directing effect of the oxygen atom.
H E
~ L ~(X;x: .1- ~
P-substitution a-substitution
(more stable) (less stable)
Fig. 1. Orientation effect of heteroatom in benzo[b] heterocycles
1.3 Dibenzoheterocycles
The fusion of two benzene rings, one each on 2,3- and 4,5-bonds of the five-
membered heterocycles (pyrrole, furan and thiophene) results in dibenzo-
heterocycles; dibenzopyrrole (carbazole) 8, dibenzofuran 9 and dibenzothiophene
10, respectively.
,():-0, 70:))3 ,CO),

6 5 4 3 9 1 2 9 1
a N9 1 6 0 4 6 s 4
H 5 5
Carbazole Dibenzofuran Dibenzothiophene
8 9 10
The annelation affects the bond distances of the central heterocyclic system
with an appreciable increase in the carbon-heteroatom bond. The C6-C6• bond
distance is shorter than the interannular bond of biphenyl and the central
heterocyclic ring, therefore, retains diminished aromaticity. These heterocycles are
slightly bow-shaped and exhibit small dihedral angles between the planes of the
five- and six-membered rings (Table-1 ).
190 Heterocy clic Chemistry
Table 1. Comparison of bond lengths of dibenzoheterocycles with parent

heterocycles
0 X Q)J X
Parent heterocycles Dibenzoheterocycles

X C-X(A) C-X (A) C6-C 6.(A) dihedral angle (0 )
NH 1.383 1.414 1.477 1.0

0 1.362 1.404 1.481 1.12
s 1.714 1.740 1.441 0.5-1.2
These heterocycles behave as diphenylamine, diphenyl ether and diphenyl

sulfide in their reactions and the electrophilic substitution occurs at the para-
position to the heteroatom.
(para to heteroatom)~ :;:;;- -..;::: /(para to heteroatom)
Q)J X
S: X = NH
9 : X=O
10: X=S
2 BENZOPYRROLES
Benzopyrroles are constructed by the fusion of a benzene ring with a pyrrole ring
in different ways and include following heterocycles:
Indole(trivial name): fusion of the benzene ring to the 'face b' (2 ,3-bond) or
a ,p-positions of the pyrrole ring.
4 3 IUPACname Other names
5~2 1H-benzo[b]pyrrole a,l3-benzopyrrole

1-azaindene
6~N/ 1-benzazole
7 H
1
Isoindole (trivial name): benzene ring fused to 'face c' (3,4-bond) of the pyrrole
ring.
~3 2
5cc4 IUPACname Other name
NH 1H-isoindole
6 :::::::,... ::::::,....... 2H-benzo[c ]pyrrole
7 1
lndolizine (trivial name): benzene ring fused to 'face a' ( 1,2-bond) of the
pyrrole ring.
;: : ;- 1
7(08 IUPAC name Other name
2 pyrrolo[ 1,2-a]pyridine pyrrocoline
6:::::::,... N j
4 3
5
Carbazole (trivial name): fusion of benzene rings to 2,3- and 4,5-bonds of the
pyrrole ring.
,Q-0,
6
8
5
gN
4
1
3
IUPACname
Dibenzopyrrole
2.1 Indoles 1- 7
2.1.1 General
Indole is the most common member of the benzopyrrole class. The chemistry of
indole has been and continues to be an attractive field of heterocyclic chemistry
because of the presence of indole structural unit in many of the natural products
of varying important physiological activity. Some naturally occuring indoles with
their applications are given as follows :
Indole-3-acetic acid plant growth regulating hormone
CO' N
CH2COOH
Serotonine 5-hydroxy derivative vasoconstrictor

of tryptamine and is
obtained from tryptophan
amino acid by hydroxylation
and decarboxylation
Reserpine isolated from tranquillizing and

Rauwolfia serpentine antihypertensive
species effects
~ _;=(CH3
0- C \.____{ OCH 3
OCH 3 OCH3
Vincristine isolated from used in the

(dirneric indole) Catharanthus roseus treatment of
leukemia because
it arrests mitosis
by an interaction
with the protein
tubulin
Ergotamine extracted from used as vasocons-

Clavicepus trictor for treatment
...::0
R-c" (grain parasite) of migrain headache
Indigo obtained from indican vat dye

13-glucoside of indoxyl
which occurs in plants
The synthetic derivatives of indole also exhibit diversified biological activity

relating to antiinflammation and antihypertension(CNS) as follows :
Indomethacin antiinflammatory agent used in the

treatment of
osteoarthritis
Oxypertine tranquillizer used in the

treatment of
mental illness
Indoramine antihypertensive drug used as an

antihypertension
agent
Iprindole neurotransmitters
N
I /CH3
CH 2- CH 2- CH 2- N
'cH 3
Pindolol antihypertensive ~-blocking

activity agent
2.1.2 Synthesis
2.1.2.1 Reaction of o-Nitrotoluene with Diethyl Oxalate (Reissert

Indole Synthesis)
The reaction of o-nitrotoluene 11 with diethyl oxalate in the presence of a base

(Claisen condensation) gives o-nitrophenylpyruvate 13 which on reductive
cyclization followed by dehydration leads to the formation of indole-2-carboxylate
15 via o-aminophenylpyruvate 14. The 2-ethoxycarbonyl substituent in
indole may be removed, if required, by hydrolysis and thermal decarboxylation
(scheme- I )8·9 .
11
X- OC ,, CH
N,
C-COOH
hydrolysis
H ~!J.
16 -CO~ 15
X~
-v--N/ H
17
Scheme-l
2.1.2.2 From o-Nitrophenylnitroethylene (o,w-Dinitrostyrene)
The reductive cyclization of o-nitrophenylnitroethylene (o, ((}-dinitrostyrene) 18,

prepared by the reaction of o-nitrobenzaldehyde with nitromethane, followed by
subsequent aromatization with the elimination of ammonia results in the formation
of indole involving N-C 2 bond formation (scheme-2) 10- 12 .
However, the reductive cyclization of aldehyde 22 resulting from the
hydroformylation of nitrostyrene 21 provides 3-methylindole (skatole) 24
(scheme-3) 13 .
(X CHO
+
N02
~
~N/
H
2 20 19
Scheme-2
CH3
(JC C'~H 2 _c_o_IH_2_1Rh_-_c~ ~CHO

N0 2 U N o2
reductive
cyclization
21 22
..
24
Scheme-3
2 .1. 2.3 Palladium Catalyzed Cyclization
The reaction of o-allylaniline 25 with palladium(II) chloride in acetonitrile involves

palladium ion catalyzed nucleophilic cyclization and proceeds with the formation
of organopalladium intermediate 26 which on subsequent reaction with triethylamine
provides 2-methylindole 27 (scheme-4) 14 .
2.1.2.4 Madelung Indole Synthesis
It involves intramolecular cyclization ofN-acyl-o-aminotoluenes (N-acyl-o-toluidines

or toluamides) 28 with a strong base, sodamide or tert-butoxide, at high
temperature. However, the strong bases, n-butyllithium and LDA, cause the
reaction to occur relatively at lower temperature (20°C) (scheme-S). The reaction
is considered to proceed with the deprotonation of methyl group and the
nucleophilic addition to the amide carbon. This reaction is used to synthesize
2-alkyl- and 3-arylindoles.
(XCH~
~CH_JCH2
.. r ,.CI
NH2 Pd
t 'CI
H Cl
/
-Pd02 N CH2-Pd
+ H "c1
-H
27a 26
isomerization
~CH3
~N;-
H
Scheme-4
(X CH3 NaNH 2
c'fp 2sO"c
N,..... 'R
H
28
20"C +n-BuLi
31 32
Scheme-S
2.1.2.5 Isonitrile Cyclization
The reaction of o-tolyl isocyanide 33 with lithium dialkylamide at -78°C proceeds

via lithiation of the methyl group affording lithiated intermediate 34 which (i) on
cyclization at room temperature provides lithiated indole 35 and finally indole on
hydrolysis, (ii) if treated with alkyl halide and subsequently with additional LDA,
the methyl group is alkylated before cyclization affording 3-alkylindole 36 and
(iii) with acyl halide in the presence of cupric oxide produces 3-acylindole 37
(scheme-6) 15 .
(XCH, (XCH,LI R'
00
+
-78°C (i) R'X
+ LiNR2
N=c +
N::C
(ii) LiNR 2 N
H
33 34 36
7
co
COR
N
H
....
HOH
01 N
Li
(X) N
H
2 35 37
Scheme-6
2.1.2.6 Bischler Indole Synthesis
The reaction of a-hydroxy- or a-halo ketones with arylamine in the presence of

an acid provides indoles 42 involving (i) N-alkylation, (ii) electrophilic intramolecular
cyclization and (iii) aromatization (scheme-7). If the substituents R 1 and R 2 are
different, the scrambling of the substituents (migration of the substituents) occurs
+~ 2
~~. ~c"'R
~~-CH
N
H ' R1
39
....
+
-H
42 40
Scheme-7
under vigorous conditions (excess of aniline and acid catalyst) with the formation
of an isomeric product 45 involving ortho-shift (scheme-8) 16.
O ,bH
o~c"'R
ortho-shift
N ' H R1
38
o$R' H
45
+
H
Scheme-S
2.1.2.7 Fischer Indole Synthesis
It is the most widely used method for the synthesis of indoles and involves an
acid catalyzed cyclization of the arylhydrazones of appropriate aldehydes and
ketones with the elimination of ammonia ( scheme-9) 17-20 . The most commonly used
acid catalysts affecting cyclization are; zinc chloride, boron trifluoride and
polyphosphoric acid. However, the choice of the catalyst depends on the structure
of arylhydrazone .
R2 R2
O
I 1 I 1
HC, ,R + OHC~ ,....R
"y -::::::;::::H~ j~y ,H
NH ¥IN
(i) N~ N "+ ' H
46 H H
(iV) 47 48 (ii)
o='c"
2
...-------. 2 R2 R H
....,___ (J(C, /-- aC,c. .-

+~ I R H " ... H R1 H\ / R1
-H -NH3
I , "' R1
I ~c
NH2
2 "'
R ~ N,c'NH (iii)
" '
2 ~ \~NH-;- ~
NH +
N
+
R1 H H 2 H
N 51 50 49
H
42
Scheme-9
The mechanism of Fischer indole synthesis 1s considered to involve the

following steps :
(i) hydrazone-enehydrazine tautomerism,
(ii) Claisen-type rearrangement [(3,3) sigmatropic rearrangement] involving
cleavage of N-N bond and formation of C-C bond,
(iii) cyclization involving nucleophilic attack on imine carbon with the formation
of N-C 2 bond and
(iv) aromatization with the elimination of ammonia.
The structure of indole so formed depends on the direction of formation and
cyclization of the enehydrazine tautomer. The cyclization tends to proceed in the
direction of forming more highly substituted enehydrazine. Thus, the arylhydrazone
of unsymmetrical ketone produces predominantly the indole derived from shifting
of hydrgoen atom (prototropic shift) to the more highly substituted enehydrazine
(scheme-10) . However, the preferred direction of cyclization varies with the acid
catalyst as high acidity and temperature favour cyclization to the less substituted
position 21 .
(XI q,
/ R
Q
HC~ /
C-CH 3 H+
I C-CH 3
NH ____.. ~ I
N~ N
H H
(highly substituted) (preferred direction)
of cyclization
53 55
or
[aIH2C~:,
~
I"CH2
N,NH
J
H
(not favoured) (not formed)
54
Scheme-10
When the degree of substitution is equivalent, usually the mixture of both

possible cyclization products is obtained as illustrated by the generalized
Scheme-11 .
A
c
Q
D I
CH
' C.;::./,
"
C B
or 1
N. . NH
H
Scheme-11
Limitation : Indole itself cannot be prepared directly as this reaction fails with
acetaldehyde hydrazone. Indole is prepared indirectly by the Fischer reaction from
phenylhydrazone of pyruvic acid involving cyclization and decarboxylation
a
(scheme-12).
H3C, ,......COOH +
C
II
H
_. ~COOH ~~
N
..,..N ~N/ -C02 ~N/
H H H
56 57 2
Scheme-12
Extension : Jaap-Klingemann reaction is an excellent method for synthesizing

arylhydrazones which are not obtained directly. It involves the coupling of
diazonium salts with P-diketones (p-keto acids and P-ketoesters) or with enamines
in the presence of a base (scheme-13) . However, when the carbon atom at which
coupling occurs does not contain hydrogen atom, the prototropic shift is not
possible and the reaction proceeds with the cleavage of C-C bond providing
ary !hydrazone 62 ( scheme-14 ) 22 .
0 0
II II
+ CH3-C-CH2-C- OR
OH
H0
I II
CH 3-C=CH-C-OR
0 0
II II
CH3-C-1f-C-O R
N-NH
6 59 58
Scheme-13
Co o
6
+ cH3
N:N I I /;
CH3-C=C-C-O R
,---111-o
N\D
0 CH 0
II I 3 II CH 3COONa
+ CH 3 -C-CH-C-OR
CfC
~~ ~ /)
CH 3 0
QO I
_CH 3
OHI
0 CH3 0
II I /;
~
I ~ .....,.._-_o_H_CH -C-C-COOR ......,.....__
3 1~1
CH3-c-c,-C-O R
C-C-OR
M-~9 H,O HO ~-o ~-o

CH3COOH
62 61 60
Scheme-14
2.1.2.8 Gassman Indole Synthesis
The reaction of aniline with tert-butyl hypochlorite gives N-chloroaniline 63 which

on treatment with ~-ketosulfide produces azasulfonium salt 64. The sulfonium salt
64 with a weak base is deprotonated and generates sulfur ylide 65 which
undergoes intramolecular rearrangement known as Sommelet-Hauser reaction
[(3 ,2) sigmatropic rearrangement] with the cleavage ofN-S bond and the formation
of C-C bond providing a-amino ketone 67. The cyclization of the resulting
a-amino ketone affords 3-methylthioindole 68 but the methylthio-group can be
easily removed by the reaction with Raney nickel leading to the formation of 27
(scheme-15 )23 .
~NHCI
v
-7ffC
CH 3SCH2COCH3
-7ffC
63
~~--;/CH3
V 'CH 2 COCH3
64
rearrangement
Ch
NH
~
aromatization
CH-COCH 3 .::;;::::=:------"--
OC~ '
CH-C-CH
H I I II 3
SCI-!:3 CH3S 0~
66 67 cyclization -HzO
(JC}cH 3
Raney Ni
~C-CH3
H
SCI-!:3
27 68
Scheme-15
2.1.2.9 Nenitzescu Indole Synthesis
The reaction of p-benzoquinone with ~-aminocrotonates results in the formation

of 5-hydroxyindoles 75. The reaction is considered to proceed with an enamine
addition to a , ~-unsaturated ketone, followed by cyclization involving oxidative-
reductive transformations (scheme-16) .
72
COOC2Hs
I
HO'O=c
''c-CH
I
~
3
N
.. [H]
H
75
Scheme-16
However, in unsymmetrically substituted p-benzoquinones, the directing effects

of the substituents depend on the electronic and steric effects and can be
generalized as follows :
(i) the presence of electron-releasing group (D = OH, OR) at the position-2 of

p -benzoquinone deactivates C-3 but directs the attack of nucleophile
preferably to C-5 due to more electrophilic character of the carbonyl
carbon-1 .
electron-releasing group
~ 0
D~
deactivated fo' /
nucleophilic attack
0 ~ pccfcrrcd position fm
nucleophilic attack
(ii) the electron- withdrawing group (W = CF3 , COOR) at the position-2 causes
nucleophilic attack at carbon-3.
electron-withdrawing group
~ 0
P'cfcrrcd position fo' _ _ . :

nucleophilic attack
'¢0
(iii) the small group with moderate electron-releasing effect (M = CH3 , Cl,
Br, I) directs the nucleophile either to C-5 or C-6 giving a mixture of indoles.
M'Qf
0
I I preferred positions for
'
__..... nucleophilic attack
(iv) the sterically hindered group at the position-2 causes nucleophilic attack at
C-5. The steric effects are superimposed on the electronic effects.
sterically hindered group
~ 0
st>-.......__
0
pcoferred po,ition fo'
nucleophilic attack
2.1.2.10 From Pyrroles
The reaction of 2- or 3-vinylpyrroles 76 with n-electron deficient alkenes and

alkynes leads to the formation of the corresponding tetrahydro- 77 and dihydro-
78 indoles involving (4 + 2) cycloaddition reaction. The resulting tetrahydro- and
dihydro-indoles can be easily aromatized to indoles 81 and 82, respectively
(scheme-17)24 •25 .
NC-CH=CH-CN
76
ROOC -c= C-COOR
81
ROO~COOR ROO~COOR ROOC~OOR
[ _')=!- ___..... [ _)-! _ ___.. ~.J

N N N
I I I
CH3 CH3 CH 3
n ~ ~
Scheme-17
2.1.2.11 From Azirines
2H-Azirines are thermally transformed to indoles involving nitrene formation

with the cleavage of carbon-nitrogen bond (scheme-18) 26 •27 . Thermally initiated
H c
5 6
~ -~-l~
N
83
..
84
co 2 H
Scheme-18
reactions, however, can be effected even at room temperature in the presence of

transition metal catalyst. The reaction of 2H-azirines 88 with palladium complex at
room temperature proceeds via complexation of azirine with palladium complex 89
with the formation of indoles 90 (scheme-19)2 8 .
~CH, H
..
90
Scheme-19
2.1.3 Structure
Indole is a planar molecule with sp 2 -hybridized atoms (carbon atoms and nitrogen
atom). The sp 2 - hybrid orbitals of the carbon and nitrogen atoms overlap axially
with each other and with s orbitals of the hydrogen atoms forming C-C, C-N,
C-H and N-H cr-bonds. The unhybridized p-orbitals on the carbon and nitrogen
atoms (perpendicular to the plane of cr-bonds) overlap laterally forming a
n-molecular orbital with 1On-electrons (two electrons are contributed by nitrogen
atom and eight electrons by carbon atoms) (Fig. 2). Indole is considered to be
Fig. 2. Molecular orbital structure of indole
resonance hybrid of the following resonating structures (Fig. 3). Thus, indole is
an aromatic heterocycle as it is cyclic planar with delocalized 1On electrons.
(i) (ii) (iii) (iv) (v)
Fig. 3. Resonating structures of indole
2.1.4 Reactions
Indole is constructed by the fusion of a benzene ring to the n-excessive pyrrole

ring. The reactivity of indole is thereofore expected to be similar to that of pyrrole.
But the fusion of a benzene ring to the ·~-face' of a pyrrole ring deactivates the
position-2 of the resulting indole towards electrophilic attack (reverse of pyrrole ).
Although in resonating structure (v) the position-2 is negatively charged (electron

rich centre), the benzenoid character of the benzene ring is disturbed and does not
contribute significantly to the resonance hybrid. The effect of the fusion of a
benzene ring to the ·~-face' of a pyrrole ring is therefore to change the position
of the greatest electron density of pyrrole from the position-2 to position-3.
2.1.4.1 Reactions with Electrophiles
The rr-electron excessive character of indole makes it extremely susceptible to

undergo electrophilic substitution reactions. The electrophilic substitution at the
position-3 (~-substitution) is preferred over the substitution at the position-2
(a-substitution). The preferential ~-substitution over a-substitution in the pyrrole
ring of indole is rationalized by the comparable stabilities of the a-complexes
(transition states) resulting from the electrophilic attack at the positions -2 and
-3 (Fig. 4).
j
~-substitution
... ~:-~E
(at position-3)
V--tfH
00 +E+
V--~Y
H
-[c:E;x:-
(ii)
N
H
""- a-substitution ~H
(at position-2) ~·~AE
H
(i) (ii)
[
ccx:- .o::x:-o:;x:
+
H
(~
H
(iv)
~
H
(iii)
Fig. 4. Electrophilic substitution in indole
The cr-complex resulting from the electrophilic attack at the position-3 is

contributed by the resonating stmctures involving effective stabilization due to
the involvement of lone pair on nitrogen without dismption of the benzenoid
structure. But, in contrast, the cr-complex resulting from the electrophilic attack at
the position-2 (a-substitution) involves resonating structures with the charge

distribution over the benzene ring disrupting the benzenoid structure. Thus, the
stabilizing influence of nitrogen on a-complex (transition state) is more effective
if resonating structure is with benzenoid structure W-substitution) than that in
which benzenoid structure is not retained (a-substitution).
However, if position-3 is already substituted, the electrophilic substitution in
indole occurs at the position-2 initially with the formation of 3,3-disubstituted 3H-
indole which then rearranges to 2,3-disubstituted indole. The presence of electron-
withdrawing substituents at the position-!, -2 or -3 of the pyrrole ring deactivates
the pyrrole ring of indole towards electrophilic attack and the substitution occurs
in the benzene ring in the positional reactivity order : 6 > 4 > 5 > 7. The electron-
releasing substituents on the benzene ring exert normal directional influence on the
electrophilic substitution29 .
2.1.4.1.1.1 Reaction with Proton Acids
Protonation of indole in a dilute acid produces stable 3H-indolium cation 91, but
in strong acidic conditions the protonation can also occur at the positions-! and
-2 with the formation of lH-indolium- 92 and 2H-indolium- 93 cations.
w:
H H
cQ H
(Q H H H
3H-Indolium lH-Indolium 2H-Indolium

cation cation cation
91 92 93
The thermodynamic stability of 3H-indolium cation 91 over lH-indolium cation

92 and 2H-indolium cation 93 is attributed to its resonance stabilization with the
retention of benzenoid character of the benzene ring and the de localization of the
positive charge over nitrogen and carbon-2. lH-Indolium cation 92 resulting from
the protonation at nitrogen, although retains the benzenoid structure, involves
localization of positive charge on nitrogen causing instability to the cation. The
instability of 2H-indolium cation 93 is due to the disruption of benzenoid structure
and the localization of positive charge on nitrogen.
2.1.4.1.1.2 Basicity
Indoles are very weak bases. The pKa values for indoles are: indole (-3.6),
1-methylindole (-2.3), 2-methylindole (-0.3) and 3-methylindole (-4.6). Thus, it is
evident that the methyl groups at the positions-! and -2 enhance basicity by 1000
times. But the methyl group at the position-3 exerts unusual effect and decreases
basicity by approximately 1.0 pKa. The enhanced basicity of 2-methylindole is
attributed to the stabilization of 2-methyl-3H-indolium cation 94 due to electron-
releasing effect of the methyl group at the position-2, while the lower basicity of
3-methylindole than indole is because of its stabilization in unprotonated form due
to the hyperconjugative stabilizing effect exerted by the methyl group at the
position-3. Moreover, the greater hyperconjugative stabilization of 2-methyl-3H-
indolium cation 94 due to two hydrogen atoms at the position-3 than that of
3-methyl-3H-indolium cation 95 involving only one hydrogen at the position-3 is
also considered the cause of stronger base strength of 2-methylindole.
H H
~-cH3
V-;:~
H
2-Methyl-3H-indolium 3-Methyl-3H-indolium 3-Methylindole
cation cation
94 95 24
2.1.4.1.1.3 H ~ D Exchange
The exchange of hydrogen attached to nitrogen in indole is most rapid when

treated with weakly acidic D20 (deuterium oxide). The exchange of hydrogen at
carbon does not occur at an appreciable rate (pH=7). The ratio of exchange rates
is; 300: 1 (N-H: C3-H). The higher exchange rate ofN-H than C3-H is attributed
to the lower activation energy of N-H bond breaking than that of C-H bond
breaking, thus making N-H exchange more favourable than that at carbon-3
(C-H exchange). However, with increasing acidity (low pH), the exchange of
hydrogen at carbon-3 is very much faster than at other carbon atom (scheme-20) 30 .
Although N-H exchange is most rapid in the acid solution also, the concentration
is very low and the equilibrium is shifted to the side of unprotonated indole.
(X) (X) 00
020
D2S04
(pH= 7) low pH
N N N
H I I
co ~
2 96 D 97 D
D
N
H
98
Scheme-20
2.1.4.1.1.4 Dimerization and Trimerization
Indole undergoes acid-catalyzed dimerization and produces dimer, 2-(3-indolyl)

indoline 100. The dimerization proceeds via 3H-indolium cation 91 which acts as
an electrophile and attacks the second molecule of indole providing dimer 100. The
protonation of dimer 100 produces an electrophilic species 101 which with another
molecule of indole provides a trimer 103 (scheme-21) 31 .
2.1.4.1.2 Nitration
Because of the acid sensitivity of indole nucleus, the products of nitration of

indoles with different nitrating agents depend upon the reaction conditions. The
nitration of indole in strongly acidic conditions with normal nitrating agents (cone.
HN0 3 + cone. H2 S0 4 ) results in the formation of polymeric products. But the
nitration of indole with benzoyl nitrate in acetonitrile or with ethyl nitrate in the
presence of sodium ethoxide at low temperature provides 3-nitroindole 104
(scheme-22) 32 .
However, 2-methylindole 27 because of its increased acid stability due to the
presence of methyl group at the position-2 requires vigorous conditions for the
nitration. The nitration of 2-methylindole with concetrated nitric acid in the
presence of concetrated sulfuric acid at 0°C affords 2-methyl-5-nitroindole via
2-methyl-3H-indolium cation 94 rather than substitution at C-3 because the
protonation of position-3 deactivates indole for further electrophilic attack and
substitution occurs at C-5 (similarly as m-nitration of aniline involving nitration of
cation). However, with concetrated nitric acid alone or with nitric acid-acetic acid
at 50°C, the nitration occurs at the positions-3 and -6 with the formation of
3,6-dinitro derivative via 2-methyl-3-nitroindole 107. If the reaction temperature is
raised to 90°C, 3,4,6-trinitro derivative 109 is obtained (scheme-23).
~
Hv-.':y H H
~--!t~ ~ ~
v-.':;r
H
~rf
H
2 91
OGf H ...
+
H
H
H
dimer
100
101
trimer
102 103
Scheme-21
cr5'
0
(Q
II
C6 H5 -C-ON0 2
CH 3CN (low tempt.)
N N
H or -+ H
C2H 50N0 2 (C 2HsONa) 104
Scheme-22
Scheme-23
The presence of electron-withdrawing substituent at the position-3 deactivates

the heterocyclic ring and directs the attack of nitronium ion on the benzene ring
(scheme-24). However, the presence of methyl group at position-2, in addition to
the acyl group at the position-3, facilitates the substitution of acyl group by nitro
group (ipso- substitution) involving nitro-deacylation by enhancing the reactivity
of position-3 towards electrophilic attack of nitronium ion due to its electron-
releasing effect (scheme-25) 32 .
COCH3 MOCH3
~
v
HN0 3 or
N') HNO rCH 3COOH lJ_N'/
H H
110 112
Scheme-24
M
~Nr
2
CH,
H
107
Scheme-25
2.1.4.1.3 Nitrosation
The reaction of indole with nitrous acid proceeds rapidly via 3-nitroso-3H-indolium
intermediate 115 with the formation of a complex mixture containing dimeric
products 120 and 122 alongwith 3-nitrosoindole 116, which exists in equilibrium
with its stable tautomeric form 3-oximino-3H-indole 117. If indole is treated with
amyl nitrite and sodium ethoxide, the nitrosation results in 3-oximino-3H-indole 117
exclusively (scheme-26) 32 .
N
122 120 H
Scheme-26
The nitrosation of 2-methylindole 27 with sodium nitrite in the presence of

acetic acid occurs at the position-3 with the formation of only 3-oximino-2-
methylindole 124, stable tautomeric form of 3-nitroso-2-methylindole 123. If
3-methylindole is nitrosated, N-nitroso-3-methylindole 125 is obtained (scheme-
27)32. The formation of N-nitroso derivative substantiate the kinetic studies on
2-methylindole that C-nitrosation proceeds via N-nitrosation 33 .3 4 .
N-OH
~
~:/
CH3
124
Chlorination of indole with sulfuryl chloride affords 3-chloroindole 126. But with
an excess of sulfuryl chloride 3-chloroindole so produced reacts further with
sulfuryl chloride and provides 2,3-dichloroindole 128 via 3,3-dichloro-3H-indole
127 (scheme-28) 35 . 3-Chloroindole 126 is stable at high pH, but under acidic
conditions it is hydrolyzed to oxindole 132. (scheme-29) 36 .
Cl
(X) N
S0 2CI 2
00 N
S0 2CI 2
(excess)
[cQCI]
H H
2 126
Cl
(r}-cl N ~';:
128 H 127 H
Scheme-28
[ Cl H ]
Cl Cl H
~ cQ
+ +
Cit~:
H 30 H 20 -H
.
N
H H
127 129
H H
(JC}o-= (0-oH
N :::::::,... N
-HO
~H N OH
H H H
132 131 130
Scheme-29
The chlorination of indole with sodium hypochlorite, however, proceeds to

involve N-chloroindole 133 which subsequently rearranges to 3-chloroindole 126
(scheme-30) 37· 38 . If methyl group is present at the position-2, 3-chloro-2-
methylindole 134 produced reacts with an excess of sodium hypochlorite and
results in 3,3-dichloro-2-methyl-3H-indole 136 via the rearrangement of 1,3-
dichloro-2-methylindole 135 (scheme-31 )37 .
Cl
(X)
2
N
H
NaOCl
(X)
133
N
Cl
I
rearrangement
00 126
N
H
Scheme-30
cQ-cH, cQ-cH, c:Q;cH,

Cl Cl
NaOCI NaOCI
N N N
H I
Cl
134 135 136
Scheme-31
Bromination of indole occurs at the position-3 with the formation of 3-bromoindole

137. If the position-3 of indole is already substituted, the bromination takes place
at the position-2 (scheme-32) 39 .
co
Br
N
H
Brz!dioxane
or
BrziDMF
ex) N
H
or
2 pyridinium bromide perbrornide 137
cxS' N
H
Br 2
ether oSBr N
H
24 138
Scheme-32
Bromination of 3-methylindole 24 with N-bromosuccinimide in the presence of

acetic acid gives 2-bromo-3-methylindole 138 which further reacts with an excess
ofN-bromosuccinimide with the formation of2,6-dibromo-3-methylindole 139. If
reaction is carried out in aqueous or alcoholic media, 5-bromo-3-methyloxindole
140 is produced (scheme-33) 36.4°. Thus, the reactions not only depend on the
directive influence of the substituent already present, but also upon the reaction
conditions. If the position-3 is occupied by an electron-withdrawing substituent,
the heterocyclic ring is deactivated for the electrophilic attack and the bromination
occurs in the benzene ring (scheme-34) 41 .
2.1.4.1.4.3 Iodination
The reaction of indole with iodine in the presence of chloroform at low temperature
produces 1:1 charge-transfer complex 143 which collapses to 3-iodoindole
144 (scheme-35). If the position-3 is occupied, iodination takes place at the
position-2 .
~Br--~3Br
V-1H V-N/
H
138
I
NBS (excess)
~3 Br
BrN - N /
H
139
140
Scheme-33
~NCOOC2Hs __N_B_S_o_r_B~rz~~
V-Nf CH COOH
3
H
141 142
Scheme-34
[011,]
I
(X) N
H
ljCHC1 3
or
Iz!DMF
~
ex) N
H
1:1 complex
143 144
Scheme-35
Indole, because of its acid sensitivity, is sulfonated with pyridine-sulfur trioxide

complex and provides indole-3-sulfonic acid 14542 instead of indole-2-sulfonic acid
as erroneously reported earlier in the literature (scheme-36) 43 .
0
()) N
H
N
I -
so3
~
(Pyridine-SO 3)
o5'H N
H
2 145
Scheme-36
If the position-3 is already occupied, the sulfonation occurs at the position-2 via
an initial reversible sulfonation at the position-3 (scheme-37).
24 146 147
Scheme-37
2.1.4.1.6 Acylation
2.1.4.1.6.1 Friedei-Crafts Acylation
Indoles substituted with electron-withdrawing substituents undergo Friedel-Crafts

acylation. However, indole with acetic anhydride in the presence of acetic acid
produces !-acetyl- 148 and 1,3-diacetyl- 149 indoles. But with acetic anhydride in
the presence of sodium acetate, the reaction proceeds via an anion 150 with the
formation of 1-acetylindole exclusively (scheme-38).
cr5CH
00
3
(X) N
H
(CH3CO)p
CH3COOH N
I
+
N
I
COCH3 COCH3
2 148 149
00 2
N
H
(CH3CO)p
CH3COONa [CQ] 150

(CH3CO)p
(X) N
I
148 COCH3
Scheme-38
The reaction of indole with acetic anhydride in the presence of vinyl acetate or
perchloric acid produces 3-acetylindole 110. If indole is treated with acetic
anhydride in the presence of magnesium perchlorate, 2-acetylindole 151 is
obtained (scheme-39)41 . If the position-3 of indole is already substituted, acylation
~CH3
~
~N/
H
CH2=CHCOOCH3
or perchloric acid
V-NJ H
2 110
~ ~COCH3
~N/ magnesmm ~N/
H perchlorate
2 151 H
Scheme-39
occurs at the position-2 involving rearrangement of initially formed 3-acetyl-3-

substituted indolium ion 152 (scheme-40). However, if both the positions in
24
Scheme-40
heterocyclic ring of indole are substituted by the methyl groups, the acylation with
acetic anhydride in the presence of anhydrous aluminium chloride takes place on
the benzene ring ( scheme-41 )41 .
~
V-N/ CH,
3
H
154 155
Scheme-41
2.1.4.1.6.2 Vilsmeier-Haack Formylation
Indole undergoes Vilsmeier-Haack formylation with the formation of3-formylindole

159 when treated with N,N-dimethylformamide (DMF) in the presence of
phosphorus oxychloride. The reaction is considered to involve the attack of
immonium chloride electrophile at the position-3 and proceeds as in (scheme-42).
However, indoles substituted even with electron-withdrawing substituents at
the position-2 undergo formylation at the position-3 under Vilsmeier-Haack
conditions (scheme-43). If position-3 is substituted with an electron-withdrawing
substituent, the formylation at the position-2 is difficult. The presence of an
electron-releasing substituent at the position-3, however, facilitates formylation at
the position-2 (scheme-44) 41 .
~
v-·N/ H
159 158 157
Scheme-42
CHO
0)- N
H
COOC 2 H5
DMF/P003
25°C 0)- N
H
COOC 2 H 5
160 161
Scheme-43
cxS' N
24 H
DMF/P003
cOCHO 162 H
N
Scheme-44
2.1.4.1.7 Alkylation
The reaction of indole with an excess of methyl iodide in the presence of DMF
at 80-90°C produces 3-methylindole 24. But at an elevated temperature (> I 00°C)
further methylation proceeds via 3,3-dimethyl-3H-indolium ion 163 with the
formation of 2,3-dimethylindole 154 which on methylation finally leads to the
formation of I ,2,3,3-tetramethyl-3H-indolium iodide 165 (scheme-45).
, ..........,
~j
excess
~ GI 3I
~N/ 8~90"C >IOO"C

H H
2 24 163
~CH~H,- --- ~ CH,--. ~1H

~;{/ ~N/ ~N)\CH 3 -H
I - H H
CH3 I
165 154 164
Scheme-45
2.1.4.1.8.1 Ehrlich Test
The acid catalyzed reaction of p-N,N-dimethylaminobenzaldehyde with indoles

unsubstituted at the position-3 (free reactive position) produces purple-red
colouration which is attributed to the formation of coloured salt 168
( scheme-46) 29.44·45 . If the position-3 is substituted, the reaction takes place at the
position-2 but very slowly. The sensitivity of the reaction (Ehrlich test) depends
upon the substituents on the heterocyclic ring. The electron-withdrawing
substituents retard the reaction, while electron-releasing substituents enhance the
rate of the reaction by stabilizing the resulting cation 168.
168
Scheme-46
2.1.4.1.8.2 With Aromatic Aldehydes and Ketones
The reaction of indole with aromatic aldehydes or ketones in the presence of

hydrochloric acid also produces similar type of coloured cation as with p-N,N-
dimethylaminobenzaldehyde. The resulting cation 170 is stabilized if the aromatic
aldehydes or ketones bear electron-releasing substituents otherwise subsequently
reacts with a second molecule of indole providing colourless bisindolylmethane
172 which can be oxidized to a coloured cation 173 (scheme-47).
2.1.4.1.8.3 With Aliphatic Aldehydes and Ketones
The reaction of indole with aliphatic aldehydes is similar to that with aromatic
aldehydes and produces the corresponding unstable cation 175 which
subsequently with a second molecule of indole produces bisindolylmethane 176
(scheme-48). But with aliphatic ketone, 3-vinylindole derivative 178 is formed
(scheme-49).
oicto H H
_[o_J..
172 173
Scheme-47
OH H
'
H+~ cC) ~H20
/
H C,
~ + HCHO
~N/
H H
2 174 175
(X)
oo>:o
H2
I
N
H
H H
176
Scheme-48
~+
v-N/ H
2
178
Scheme-49
2.1.4.1.8.4 With a,~-Unsaturated Ketones
The reaction of indole with a,~-unsaturated ketone involves Michael type addition
at the position-3 of indole providing a,~-alkylated product 179 (scheme-50).
~
v-N/ H
2 179
Scheme-50
2.1.4.1.9 Mannich Reaction
The reaction of indole with formaldehyde and N ,N-dimethylamine in the presence

of a weak acid results in aminomethylation with the formation of 3-N,N-
dimethylaminomethylindole (gramine) 181. The reaction involves ~-attack of an
elctrophile immonium ion, generated by the reaction of formaldehyde with N,N-
dimethylamine, and proceeds as depicted in (scheme-51 )36 . When the position-3
is occupied, the aminomethylation occurs at the position-! rather than at the
position-2, thus indicating the low reactivity of the position-2 (scheme-52) 46 .
(CH 3 )2N~H2 1\J~H • (CH3)2NH-CH 20:.J

-H 20
+ +
[(CH3)2N-CH2 ..,.,.~'---l•~(CH3)2N=CH2)
Scheme-51
HCHO/(CH3)zNH
CH3COOH
24
Scheme-52
2.1.4.2 Reactions on Carbon and Nitrogen Anionic Species
The pKa value for N-H dissociation of indole (20.95) is comparable with that of
pyrrole (23 .05) 47 . Like pyrrole, indole undergoes deprotonation when treated with
sodamide, potassium hydroxide, n-butyllithium or Grignard reagents with the
formation ofN-indolyl salts. The resulting salts exist as contact ion pairs or solvent
separated ion pairs (with alkali metals) or with high N-metal covalent character
(heavier metals). These characteristics of the salts control the reactions of
N-indolyl anion. The N-indolyl anion 150a produced by the abstraction of
hydrogen atom by a base is stabilized by resonance (scheme-53). Because of the
ambident nature of an indolyl anion the attack of an electrophile occurs at the
nitrogen atom or at the carbon atom depending on the nature of the metal ion,
attacking reagent, solvent and temperature.
00 2
N
H
base
[CX> 150a
.. .. 00] 150b
Scheme-53
The site of alkylation in the indolyle salts is generalized on the basis of the ' hard-
soft acid-base' concept. The salts of the soft cations (Na+, K +) which exist as
solvent separated ion pairs or contact ion pairs produce predominantly N-alkylated
products, whereas the salts of the harder cations (Mg+2) lead to substitution
preferentially at carbon-3 (scheme-54 )48 .
(X) N
H
KOH
DMSO 00 N+
K
RX
(R = C6H5CH 2) (X) N
I
R
cQH'-b:'
2 183 184
\7
(X) N
H
C2H5MgBr
ether (X) N
I
HOH
0
N
H
MgBr
2 185 186
Scheme-54
The alkylating agents such as allyl halides which are capable of producing
electrophile very readily favour C-alkylation (scheme-55) 36 . If the position-3 is
Scheme-55
substituted, 3-substituted 1-allylindole 191 and 3,3-disubstituted-3H-indole 192

are obtained (scheme-56) 49 .
190 191 192
Scheme-56
N-Alkylindoles are selectively lithiated at the position-2 when treated with

n-butyllithium (scheme-57).
~COOH
~N/
I
CH 3
(i) C0 2
~
~+ n-Buli ~ ~N/- Li
+ (ii)HzO 195
~N/ ~ ~(CH 3 )zS04

I
CH 3 CH3 f
193
194 ~ CH3
~N/
I
196 CH3
Scheme-57
The alkylation of indole at higher temperature and pressure favours substitution

at carbon-3 . The presence of electron-withdrawing substituents at the a- or ~
position of indole increases its acidity and the mild conditions are required for the
alkylation.
2.1.4.2.2 Acylation
Similarly as in alkylation, the acylation of the indolyl salts with soft cations
produces N-acylated products which thermally rearrange readily to the
corresponding C-acylated products (scheme-58)
COR
(Q N+
~RCOO
~V-N/
I
rearrangement ~
l::J-_N'J
H
Na
COR
187 193 37
Scheme-58
The acylation ofindolylmagnesium halides with acylating reagents is complicating

as compared to the alkylation reactions and the formation of the products depends
upon the nature (stronger) ofacylating regents. The acylation ofindolylmagnesium
halide with acyl chlorides produces 3-acyl- 110 and 1,3-diacyl- 149 indoles, while
with ethylchloroformate acylation occurs at the position- ! providing ethyl indole-
1-carboxylate 194 alongwith ethyl indole-3-carboxylate 141 and indole-! ,3-
dicarboxylic ester 195 (scheme 59) 50 . The change in the site of acylation depends
cx5CH 3
+ o:SCH,
I....._ _ _ _ac_y_l_at_io_n_ _ _ t
H
___,J
I
COCH3
149
110
141 195
Scheme-59
upon the ability of changing nature of the metal ion and its association with an
indolyl anion. However, the presence of electron-withdrawing substituents on an
indolyl anion stabilizes the anion and reduces its association with the metal cation
which causes acylation to occur preferentially at the nitrogen atom. But with
electron-releasing substituents C-acylation is preferred36 .
2.1.4.3 Reactions with Nucleophiles
n-Electron excessive character of indole makes it relatively inert towards

nucleophilic attack. However, indoles substituted with electron-withdrawing
substituents at the nitrogen atom undergo nucleophilic substitution reactions.
Suitably substituted 2-acyl-1-benzenesulfonylindoles 196 undergo intramolecular
nucleophilic substitution at C-3 in the presence of a base with the elimination
of benzenesulfonyl group providing indolyl ethers 198 which on base
catalyzed reaction yield quinones 201 related to the anticancer alkaloid ellipticine
(scheme-60)51 -53
~~
V-~Ac~N
II
197 °
•
OCH3
cx5z1b H ~";::>
198
oxidation
0 0
200 201
Scheme-60
2.1.4.4 Oxidation
lndoles are comparatively less susceptible than pyrrole towards oxidation and
produce monomeric, dimeric and trimeric oxidation products. The presence of
electron-releasing substituents enhances the susceptibility of indoles towards
oxidation, while indoles with electron-withdrawing substituents are relatively inert.
Indole is oxidized by air with the formation of indolin-3-one (indoxyl) 203 via
3-hydroperoxy-3H-indole 202. The radical 204 formed by the abstraction of
hydrogen atom from the position-2 of indolin-3-one 203 is stabilized and can
dimerize to produce indigo 206 or can react further with the formation of 207 and
208. The formation of 207 and 208 can be rationalized in terms of nucleophilic
attack by non-oxidized indoles upon the oxidized intermediate at the position-2
(scheme-61 )2 9 .
CO- N
H
.
H
~0
~-H
207 N Vl-N)-
H H
204
dimerizatio/
further
0 H
~n N
205
206
~
~N/
H
-H N
H trimer
208
Scheme-61
The base catalyzed autoxidation of indoles leads to the cleavage of C 2-C 3 bond
with the formation of 2-acylaminophenyl ketones 211 via dioxetane derivatve 210
involving the attack of electrophilic oxygen at the position-3 followed by the
nucleophilic attack of the peroxide anion at the position-2 (scheme 62) .
CJ&cH, -b-~-:-~e•~
H
CH
154 209 I 3 210
~C=O /
v-N-COCH3
H
211
Scheme-62
Oxidation of indoles with ozone also results in the cleavage of C 2-C 3 bond with
the fomation of 2-acylaminophenyl ketones 211 (scheme-63) 54 .
CH 3
~ CH 3 3 I
VlN/ . ~C=O
v-N-COCH
H H 3
154 211
Scheme-63
Oxidation of indoles with hydrogen peroxide under weakly acidic conditions

produces indigo 206 and 2,2-di(3-indolyl)indolin-3-one 208. These products are
considered to be obtained via the initial formation of indolin-3-one 203.
2.1.4.5 Reduction
Indoles are generally selectively reduced either in the six-membered ring or in the
five-membered ring with different reducing agents.
(i) Indole can be catalytically hydrogenated to indoline 212 (selectively five-

membered ring leaving six-membered ring intact), when indole in ethanol
is passed over Raney nickel at high temperature and high pressure
(scheme-64). However, ruthenium catayzes the hydrogenation of indole to
octahydroindole. The catalytic reduction of indole at room temperature and
atmospheric pressure in the presence of an acid also provides indo line 212
via 3H-indolium salt.
~
~N/
H
Raney Ni
C2H50H
(100°C & 85 atm.)
(X) N
H
2 212
Scheme-64
(ii) Indoles are easily reduced to indolines by zinc- phosphoric acid or tin-
hydrochloric acid via 3H-indolium cation (scheme-65) 29·55·56 .
o=J
H H
(X) N
Zn-H3P0 4
or
.. (X) N
Sn- HO
H H H
2 212
Scheme-65
(iii) N-Unsubstituted indoles are reduced in the six-membered ring providing

4,7-dihydroindoles 213 and finally 4,5,6,7-hydroindols 214, when treated
with lithium or sodium in liquid ammonia in the presence of methanol (Birch
reduction) (scheme-66). N-Substituted indoles are also similarly reduced to
!-substituted 4, 7-dihydroindoles.
~
[():?] (X)
Ii- NH 3 Ii- NH 3
CHPH
~N/ (excess)
H H
2 213 214
Scheme-66
The reduction of 5-methoxy-1-methylindole 215 with lithium-ammonia (liquid)

in the absence of alcohol produces very slowly 5-methoxy-1-methyl-2,3-
dihydroindole 216, whereas in the presence of alcohol 4,7-dihydroindole 217 is
obtained (scheme-67).
217
Scheme-67
(iv) Because of the n-excessive character, indoles are not reduced by hydride-
transfer reagents (lithium aluminium hydride, sodium borohydride and
diborane). N-Unsubstituted indoles can also be reduced to indolines with
diborane under basic conditions involving protonation at the position-3
(scheme-68). 63 The reduction of indoles can be effected in excellent yields
01
-
(X) N
H
B2H6
• (X) N
I
CH 30
N
I
/s, ,..-B~
H H H I OCH3
2 218 H
219
(X) . ~H ..
f)
CH30-H
212
N
H
~-)
/I'\.-··-.
CH30 H \..!:!)
220
Scheme-68
by sodium cyanoborohydride in the presence of acetic acid or by

trimethylamine-diborane I pyridine-diborane in the presence of acid medium
with the formation of indolines (scheme-69) 57-62 .
~ ~:H
V-N/ H
or
(CH 3) 3N-B 2HJCH3COOH
V-Nf'.H
H
C5H5N-B 2HJCH 3COOH
2 212
Scheme-69
2.1.4.6 Reactions with Electron-Deficient Species
Indole undergoes Reimer-Tiemann reaction when treated with dichlorocarbene,

generated from chloroform and strong base, with the formation of a mixture of
indole-3-carbaldehyde 159 and ring expanded product, 3-chloroquinoline 224. The
ratio of the products depends on the mode of generation of carbene. Approximately
equal amounts of the products are obtained with strong base, but under weakly
basic conditions the ring expanded product is favoured. The formation of the
products has been rationalized by two reaction pathways (scheme-70).
H CCI2
~~~
V-N) V-/
150 221
t
00
CHO H CHCI2
~(JQ
CHC13
N
H
base
V-Nl-.-
H
~ I ~
N
2
159 ~CI 222
c"/ c1
~'c1.,~
V-N/' -HCl
I~
~t_._)
N
223 H 224
Scheme 70
The reaction pathway leading to indole-3-carbaldehyde 159 involves

electrophilic attack of dichlorocarbene upon an indolyl anion 150, whereas the
second reaction pathway involves insertion of carbene into C 2-C 3 bond of indole
and proceeds via cyclopropyl intermediate 223 .
The reaction of indoles with carbenes, generated from copper or light catalyzed
decomposition of diazo esters and diazo ketones, produces the corresponding
3-indolyl esters and ketones without the formation of ring expanded product
(scheme-71 )29 .
~
V-N/
H
2 225
Scheme-71
2.1.4. 7 Reactions with Free Radicals
The reaction of indole with benzyl radical, generated by thermal decomposition

of tert-butylperoxide in toluene, produces a mixture of benzylated indoles
involving benzylation at the carbon and nitrogen atoms in the five membered ring
(scheme-72) 64
~
V-N/
H
2 227
229
Scheme-72
When N-methylindole reacts with benzoylperoxy radical, free radical attack

occurs at the position-3 with the formation of 3-benzoyloxy-1-methylindole 230.
If the position-3 is already substituted, the radical substitution takes place at the
o5c
position-2 (scheme-73) 65 .
0 6 5
II • H
C6H 5 C-O
I
CH 3
_c_6_H_s_g_-_o_· ~230 ~NH,- OCOCsH5

(C 6 H5C00) 2 ~N/
I
CH 3
231 232
Scheme-73
2.1.4.8 Cycloaddition Reactions
Indoles do not participate in Diels-Alder cycloaddition reactions, but undergo

Michael addition reaction with rr-deficient alkenes and alkynes involving attack at
the position-3 of the indole nucleus. The reaction of indole with dimethyl acetylene
dicarboxylate (DMAD) gives 3-vinylindole 233 which with second molecule of
DMAD provides (4 + 2) cycloaddition product 234 involving exocyclic double
bond (scheme- 74 )66 •67 .
~ + E-c=c-E
~N/ (E = COOCH 3)
H
2
E
aromatization
E
235 234
Scheme-74
However, indole with 1,2,4,5-tetrazines provides indolepyridazines via (4 + 2)

cycloaddition followed by extrusion of nitrogen and aromatization (scheme-75) 68 .
E E
N~N
(X) N
H
+ II
NIN
I
arornatiazation
-N2
N
E H E
2 236 237
Scheme-75
Photocyclization of 1-methylindole with DMAD proceeds to involve (2 + 2)

cycloaddition providing cycloadduct 238 which is thermally transformed into
benzazepine 239 (scheme-76) 69 •70 .
hv E
E-c=c-E
(E=COOCH)
2
~E/
U .. FEN
I
CH 3
239
Scheme-76
2.2 Isoindoles (Benzo[c]pyrroles) 56
2.2.1 General
Isoindole is an isoelectronic with indole i.e. 1On-electron system, and retains

appreciable aromatic character with substantial resonance energy (48 .6 kJ/mol) as
the bond lengths in isoindole differ from those in the polyenes71 . Isoindole Sexists
in two tautomeric forms; 2H-isoindole (isoindole) Sa and lH-isoindole (isoindolenine)
Sb, and the energy difference between two tautomers is 33.0 kJ/mol.
5cc4
~ NH
6 ~ ~ 2
cc CGN
7 1
s
NH
~
H H
2H-Isoindole IH-Isoindole
(isoindole) ( isoindolenine)
Sa 5b
The isoindole tautomeric form is favoured over the corresponding isoindolenine

form (with low resonance energy, although with conjugated benzenoid system).
However, the substituents and the solvents affect the tautomeric nature of the
compound. The presence of an aryl group at carbon- ! results in increasing
proportion of isoindolenine. Although two isoindolenine structures Sb(i) and
Ar
~H
~N V-fN
H H H
Sb(i) Sb(ii)
Sb(ii) are possible, the structure Sb(i) in which C=N is conjugated with both the
aromatic rings is favoured. The electron-releasing substituents present on the
pyrrolic ring also stabilize the isoindolenine tautomeric form Sb 72 . The nature of
the solvent also affects the position of equilibrium. The isoindolenine tautomeric
form Sb predominates in hydroxylic solvents because of the hydrogen bonding
with imine nitrogen, whereas isoindole form Sa is favoured in the solvents capable
of donating lone pair through the hydrogen bonding with pyrrolic NH.
2H-Isoindole S is considered to be contributed by the following resonating
structures in which the lone pair on nitrogen is involved in the I01t-electron system
(Fig. 5):
~~H_+ ~- ...~&+
NH~ ~I:+-
~
NH~
~ ........ ~
NH= () ( )NH
8-
H H
(i) (ii) (iii)
Fig. 5. Resonating structures of isoindole
However, isoindole is kinetically unstable but the presence of electron-

withdrawing substituents at the positions-! and -3 increases its stability. The
sterically protecting groups at the positions- I and -3 also stabilize the isoindoles.
2.2.2 Synthesis
2.2.2.1 Cyclization Reactions
2.2.2.1.1 From a-Bromo-o-toluic Acid
The synthesis of isoindoles from a-bromo-o-toluic acid 240 involves the

following sequence of the reactions with the formaton ofN-C bond (scheme-77) 73 .
(I COOH
+HN
CH 2 Br
~
I #
__..
CXCOOH 0
~
I CH 2 -N
~
I ~
0 #
240 Ar 241 242
CX c~o
I
o t 0
CH,-N reaohon (J__

Fried~l-Crafts~COCI
~
0
CH,-N~
cQI~
244 O Ar "':,..
NHNH
2 2 .,. N 243 0
~
H H
5b
Scheme-77
2.2.2.1.2 From N-Cyanomethyl-N-methyl-o-chlorobenzylamine
The reaction ofN-cyanomethyl-N-methyl-o-chlorobenzylamine 245 with potassium

amide in the presence of liquid ammonia proceeds to involve intramolecular
nucleophilic addition of carbanion to aryne and subsequent aromotization with the
elimination of HCN. The cyano group stabilizes the carbanion and facilitates
aromatization (scheme-78)14 .
~C~~,..CH3 KNHz ('VC~~-CH3

~CI CH2CN
LiquidNH3 V~6H-CN
CCN-CH,
245
aromatization
~------
-HCN
0:
t) 246
c~,N-CH
2
CH
3
I
248 247 CN
Scheme-78
2.2.2.1.3 From 1,4-Diketones
The reductive amination of o-dibenzoylbenzene provides 1,3-diphenyl-2-

methylisoindo1e 249 involving (4 + 1) cyclization with the formation ofN-C 1 and
N-C3 bonds (scheme-79) 75 •76 •
C6Hs
HCOOH N-CH 3
or ~
NaBH 4
C6Hs
249
Scheme-79
2.2.2.2 Extrusion Reaction
Pyrolysis of benzo-7-azabicyclo[2.2.1]heptanes 251, obtained by cycloaddition of

pyrrole with benzyne followed by reduction, produces isoindoles involving retro-
Diels-Alder reaction with the extrusion of ethylene (scheme-80) 72 .
Scheme-SO
2.2.2.3 Ring Transformation Reactions
2.2.2.3.1 From Phthalimidines
The reductive alkylation or arylation of N-substituted phthalimidines 253 with

alkyl- or aryllithium leads to the formation of isoindoles involving nucleophilic
addition to the carbonyl group with the elimination of water (scheme-81 )77 .
o R 6u+
CCN-R R'Li- (J(;N-R cCN-R

R' OH
253 254 255

I-H20
~
cc
lOO'C LiAlli4 f R'
CCN-R
+ -
(i) (CH3)PBF4
N-R (ii) base
:::::::,....
252 256
Scheme-81
The reduction of phthalimidines, unsubstituted at C-1 or C-3, with lithium

aluminium hydride also produces isoindoles 252. However, with trialkoxonium
salts in the presence of a base 1-alkoxyisoindoles 257 are obtained (scheme-81)
2.2.2.3.2 From Isoindolines
(i) The vapour-phase pyrolysis of N-methoxycarbonyloxyisoindoline 258 at

reduced pressure yields isoindole 5 which is trapped at low temperature
(scheme-82) 78 .
CO).
H H
~ 500"C
NT<?-CT?CH3 -C02 •
cc~
I N ~ cc~
::::::,..... NH
\! \.J -CHpH ~ ~
258 5
Scheme-82
(ii) The oxidation of N-substituted isoindolines 259 to N-oxide followed by

reaction with acetic anhydride in the presence of triethylamine at low
temperature provides the corresponding N-substituted isoindoles. This
method has been used for N-alkyl- and N-aryl-isoindoles (scheme-83) 79 .
Scheme-83
(iii) The reaction of isoindolinium salts 263 with phenyllithium at low

temperature also results in the formation of insoindole 248 involving
elimination reaction (scheme-84).
Scheme-84
However, with 2-benzyl-2-methylisoindolium salt 264, the other competitive

reactions also occur at high temperature (scheme-85) 80 .
200"C
266
Scheme-85
(iv) N-Substituted indolines 267 with good leaving substituents undergo

elimination reaction in the presence of a base with the formation of
isoindoles ( scheme-86) 81 -83 .
(CN-Tos
267
base
CGN H H
cc ::::::,.....
5
NH
Scheme-86
2.2.2.3.3 From Pyrroles
The reaction of 2,5-disubstituted pyrroles 268 with 1,4-diketones in the presence

of an acid results in annelation of the pyrrole ring with the formation of isoindoles.
The reaction is considered to be an electrophilic aromatic substitution and
proceeds under the influence of an acid (scheme-87) 84 .
HC,C=O
3 (\ ~H, H,Cj:;CH,
/~~ ai3COOH HC
21 -2H20
H2C NH NH
I + ::::::,..... ll<J'C H2C
H2C, ~1) H + CH
. . . c=o 3
H3C lj CH 3 H3C OH
268 269
~3 ::::::,.....
NH
H3C CH 3
270
Scheme-87
2.2.3 Reactions
Isoindoles react very readily with electrophiles at the most reactive positions-! and
-3 which correspond to the a-position in pyrrole (Fig. 6).
Fig. 6. Schematic representation of electrophilic substitution in isoindole
Isoindole is a stronger base than pyrrole and indole. The protonation in isoindole
occurs at the positions-! and -3. lsoindoles substituted with phenyl groups at the
positions-! and -3 are also protonated at the position-! or -3.
The acid catalyzed H ~ D exchange at the position-! does not occur but
under basic and neutral conditions the H ~ D exchange occurs at the position-2 56 .
N-Methylisoindole 248 undergoes acid catalyzed polymerization involving
electrophilic intermediate 271 generated by protonation at the position-! or -3
(scheme-88).
248
Polymer ..._ ..__ ~--------
H H
271
Scheme-88
Because of the susceptibility of isoindoles towards oxidation, the reaction of

1-phenylisoindole 272 with sodium nitrite in the presence of acetic acid results in
oxidative dimerization with the formation of dimer 273 (scheme-89) 56 .
272
Scheme-89
2.2.3.1.3 Acylation
Isoindoles undergo acylation very readily even under mild conditions when
treated with acetic anhydride in the presence of pyridine at room temperature
(scheme-90). However, the presence of electron-withdrawing group (-COOC 2H 5)
at the position-! deactivates the ring towards acylation.
(CH3CO)p
pyridine
274
Scheme-90
lsoindoles are alkylated at the position-! or -3 under Mannich reaction conditions.

However, electron-withdrawing substituents at the position-! restrict isoindole
to undergo Mannich reaction ( scheme-91 )56 .
1\
CH2-N\.__/O
NH
:::::-
CsHs
275
Scheme-91
2.2.3.1.5 Formylation
Isoindoles undergo Vilsmeier-Haack formylation under mild reaction conditions at

the position- I or -3 providing formyl derivatives of isoindoles 278 (scheme-92).
+ -
rrJ:=N(CH,),CI
DMF/POC13
NH + (CH 3)2N=CHCI
:::::-
~·
CH2CsHs CH2CsH 5
276
«
CHO 277
OH
NH ...
:::::-
CH2CsHs
278
Scheme-92
2.2.3.1.6 Reactions with Aldehydes and Ketones (Ehrlich Test)
The reaction of isoindole with aromatic aldehydes or ketones in the presence of

an acid produces purple red colour due to the formation of azafulvenium salt 280
which is subsequently changed into blue coloured bis(l-isoindolyl)methane 282
(scheme-93) 56 .
OH
I
H+ oc;+
.f'CH-Ar
+
H CHAr
NH + ArCHO ~ I~
/NH -HzO
//
~ ~~
~NH
~
C H CsHs 280 CsHs

272 6 5 279 CA7~
NH
~
CsHs
Ar Ar
I I
CHyo~
H HN L~Hc:~
~ #
~'"l~
CsHs CsHs C6 H5 CsH 5
282 281
Scheme-93
2.2.3.2 Oxidation
Isoindoles are highly susceptible towards aerial oxidation. The presence of

electron-releasing substituents enhances their sensitivity towards oxidations,
while the electron-withdrawing substituents make them relatively inert to oxidation.
lsoindoles without substituents at the position-2 undergo autoxidation in air with
the initial formation of hydroperoxide 283 (scheme-94)56 .
Scheme-94
Morever, isoindoles with substituents at the position-2 on autoxidation in air in

the presence of THF provide phthalimide derivatives 288 via endo-peroxide
intermediate 286 (scheme-95) 85 .
~:~CH 3 THF
~
~~-
CH 3 CH3 CH3 CH 3
285 286
0
~N-CH 3 ,.
0
288
Scheme-95
2.2.3.3 Reduction
Isoindoles are catalytically hydrogenated to isoindolines at moderate temperature

and pressure (scheme-96). However, the presence of electron-withdrawing
substituent at the position- I or -3 restricts the hydrogenation of pyrrolic ring and
CX(NH Raney Ni
Pt orPd
CH 3
289 290
Scheme-96
the six-membered ring is reduced with the formation of 4,5,6,7-tetrahydroiso-

indoles 292 (scheme-97) 56 . But the electron-withdrawing or aryl group at the
nitrogen atom (position-2) increases dienic character of the heterocyclic ring and
facilitates the reduction of pyrrolic ring.
Raney Ni
292
Scheme-97
Isoindoles exhibit diene-type characteristics and undergo (4 + 2) cycloaddition

reactions with dienophiles with the formation of cycloadducts (scheme-98).
0 0
+
Go 0
cc
0 0
293
NH
~
0 0
+
GNH .. NH
0 0
294
Scheme-98
(4 + 2) Cycloaddition of 2-methylisoindole 248 with benzyne produces a

cycloadduct 295 which on further reaction with benzyne gives
dihydrobenzo[a]carbazole 296, but with dichlorocarbene, generated under phase-
transfer conditions, is deaminated and yields anthracene (scheme-99) 86 •87 . Similarly,
isoindoles undergo (4 + 2) cycloaddition reaction with DMAD also and leads to
the formation of 1 : 2 adduct 298. The initially formed cycloadduct 297 may be
isolated, if isoindole is substituted at the 1,3,4 and 7-positions (scheme-100) 56 .
296
Scheme-99
cc 248
N-CH3 + E-C=C-E _____..
(E = COOCH3)
E E
Scheme-100
2.3 Indolizines (Pyrrocolines) 88•89
2.3.1 General
Indolizine is an aromatic heterocycle with 101t de localized electrons. It is an

isoelectronic with indole and isoindole and is consisting of five-membered and
six-membered rings with a nitrogen atom at a ring junction. The bridgehead
nitrogen atom influences the characteristics of both the rings and renders
indolizine to exhibit the characteristics of pyrrole and pyridine rings.
7
(0
6 ~
~ .~.
8
N
4
//
3
2 (Pyrrolo [1,2-aJ pyridine)
2.3.2 Synthesis
2.3.2.1 Reaction of Pyridines with a-Halocarbonyl Compounds

(Tschichibabin Reaction)
It is the most versatile method and involves the condensation of pyridine,

substituted with an activated methylene substituent at carbon-2, with
a-halocarbonyl compound followed by an intramolecular cyclization with base
(scheme-101) 90 . However, this reaction fails in the synthesis ofindolizines without
302 301
Scheme-lot
substituents on the pyrrole ring. The reaction with a-bromo ester instead of
a-bromo ketone results in the formation of 2-hydroxyindolizines (scheme-! 02) 91 .
Parent indolizine is prepared by the reaction of ethyl 2-pyridylacetate with ethyl
bromopyruvate with the formation of quaternary salt which is cyclized in the
presence of a base. Subsequent hydrolysis and thermolysis lead to the formation
of indolizine (scheme-! 03 )92 .
Scheme-102
ac o-
cyclization ~ base
H coor-H 9oO~Hs
' / "Z s CH 0 ..._
-H+ I ' /OH ~ I l.. II_../
~ ~ N .... CH,C,COO~H 5 ~ N, /C\
f
3V_8__H_3o_+l_t\---t~
rvvv-. + 2 + CH 2 COO~Hs
~O::Hs
~~J -C0 2
309 1
Scheme-103
2.3.2.2 Reaction of Pyridine with Alkynic Compounds
The reaction of pyridine with dimethyl acetylenedicarboxylate in methanol results

in the formation of indolizines 314 and 315 with the sequence of following steps
(scheme-104). The reaction proceeds to involve nucleophilic addition with the
0 N
+ CH3ooc-c=c-coocH3 ....... al
~ ~--c'
\
C-COOCH3
COOCH3
310
H COOCH3
~
~Nx
COOCH3
aromatization
314
+
CH 300C
313
CH- COOCH 3
I
OCH3
cr>:::CH,
CH30-CH-COOCH3
315
Scheme-104
formation of zwitterion 310 which on protonation followed by Michael type

addition of methoxide ion results in zwitterion 311. The zwitterion 311 with a
second molecule of dimethyl acetylenedicarboxylate gives zwitterion 312 which on
cyclization and subsequent aromatization produces 314 and 315 (scheme-104)93 .
2.3.3.3 Reaction of 2-Pyridyllithium with 2-Chloromethyloxirane
The reaction of 2-pyridyllithium 316 with 2-chloromethyloxirane 317 results in

the formation of 2-hydroxy-2,3-dihydro-IH-indolizinium chloride 318 which on
treatment with sodium hydroxide yields indolizine (scheme-105) 94 .
Qn-Buli [(lJ +..---v-r-C_H2C_.I c i } O H
eo
N Br
316 317 H H Cl-
318
I
;} ... NaOH
1
Scheme-lOS
2.3.2.4 1,3-Dipolar Cycloaddition Reactions
Pyridinium ylides undergo I ,3-dipolar cycloaddition reactions with dipolarophiles

(containing C=C functional group) with the formation of indolizines 322
(scheme- I 06)95 •96 .
Scheme-106
However, with ethylenes (functionalized alkenes), dihydroindolizines 324 are

obtained as intermediates which on treatment with dehydrogenating agents
produce indolizines 325 (scheme-107) 97 .
Q,_/coocH, ~~:
c +CH 3-CH=CHCOOCH3 __.. ~-N-/'H
H
CH 300C H
(),~/GOOCH, MCH, 324
,. Pb(CH3C00)4 1
c ~N-( CH3
H
323 COOCH3
325
Scheme-107
2.3.3 Structure
Indolizine shows considerable bond alternation with the following bond lengths
(Fig. 7). Indolizine is represented by the resonating stuctures (Fig. 8) :
1.409A
1.357 A---,t l~ r-==1.410A
. . - - 1 .372A
1.406A-_..~N~
rY\ 1.423A
1.389A
1.369A----'·
1.384A----'-
tt 1.386A
Fig. 7. Structural parameters of indolizine
Although n-electrons are delocalized over both the rings, the resonating
structures (v) (vi) and (vii) are not very important and the resonance stabilization
of indolizine is mainly due to the five-membered pyrrolic ring (iv). The resonance
hybrid is contributed mainly by (i), (ii), (iii) and (iv), although the resonating
structure (ii) is comparatively less contributing than (iii) because of the greater
charge separation.
(i) (ii) (iv)
t
Hm"::::
~ J N
H
-.. . . . . I Q=)- ~n.:>"::::,

+
N
H
J ~ N::--.
+
H
(v) (\4) (\ii)
Fig. 8. Resonating structures of indolizine
The comparison of resonance energies of indole (0.047 p), isoindole (0.029 p) and
indolizine (0.027 p) indicates the order of resonance stabilization as : indole >
isoindole > indolizine. Thus, it can be inferred that the resonance stabilization is
affected with the change in the position of the nitrogen atom98 .
2.3.4 Reactions
Indolizines are rr-excessive heterocycles as pyrroles, indoles and isoindoles. The

rr-excessive character of indolizines renders them to undergo electrophilic
substitution reactions readily rather than nucleophilic substitution reactions. Since
indolizines are isomeric and isoelectronic with indoles and isoindoles, the chemical
reactions of indolizines are similar to those of indoles and isoindoles. But
indolizines differ in cycloaddition reactions by involving entire rr-electron system
with the formation of cyclazines.
Because of the greater electron density at the positions-3 and -1 as shown by the
resonating structures of indolizine, the electrophilic substitution occurs at the
positions-3 and -1. The molecular orbital treatment has shown the order of electron
density in indolizine as : 3 > I > > 5. The attack of electrophile, therefore, takes
place preferentially at the position-3 followed by at position- I.
m la
..
CP lb
The electrophilic substitution occuring preferentially at the position-3 is

rationalized by comparing the resonance stabilization of the intermediates
(Wheland intermediates) resulting from the electrophilic attack at the positions-3
and -1.
~E
CQ H E
(attack at position-3)
. .. ~~-~
(attack at position- I)
In N-bridged heterocycles, according to the thumb rule, the conjugation of

double bond via carbon atom is favoured over the cojugation via nitrogen
atom. Thus, the indolizinium intermediate involving electrophilic attack at the
position-3 is more resonance stabilized than that involving attack at the
position-!. If position-3 is already substituted, substitution occurs at the
position-!. The experimental evidences also support that the electrophilic
substitutions in indolizines occur at the position-3 or at the position-! or
simultaneously at the positions-3 and -1 .
Indolizine is a weak base with pKa = + 3.9, but stronger than indole. The basicity
of indolizine is increased with the introduction of methyl group, but unexpectedly
low basicity of 3-methylindolizine is due to the change in the site of protonation.
Indolizine is protonated exclusively at the position-3 because of the formation of
most stabilized cation (scheme- I 08).
~
~N--1'
Scheme-108
However, in 3-substituted indolizines the protonation occurs at both 1- and 3-

positions providing a mixture of 1- and 3-protonated salts. But 3,5-disubstituted
indolizine is protonated only at the position-3 because the protonation at position-
3 reduces overcrowding.
2.3.4.1.2 Nitration
Indolizines are nitrated very readily at the position-3 or -1 depending upon the
reaction conditions. Nitration of2-methylindolizine 326 with a mixture of nitric acid
and sulfuric acid occurs at the position-! with the formation of 2-methyl-1-
nitroindolizine 327 (scheme-109). But when 2-methylindolizine 326 is treated with
326 327
Scheme-109
nitric acid in the presence of acetic anhydride at -70°C, nitration takes place at the
position-3 with the formation of 2-methyl-3-nitroindolizine 328 (scheme-11 0) 99 .
326
Scheme-110
N itrosation of indolizines occurs at the position-3 or -1 by the reaction with nitrous

acid or N-nitrosodiphenylamine. The reaction of 2-methylindolizine with nitrous
acid results in nitrosation at the position-3 with the formation of 2-methyl-3-
nitrosoindolizine (scheme-111) 100 .
~ CH
~N-r 3
N=O
326 329
Scheme-111
lndolizines undergo Mannich reaction with the aminoalkylation at the position-3

or, if position-3 is substituted, at the position-1 (scheme-112). The Mannich bases
of indolizines produce indolizine derivatives of CNS depressant activity 88 •89 .
co 3
cq 331 COCH3
c q - C H , _c_H_2_0_/_(C_H_3_h_N_H_,.
333 COC 6 Hs
-
(i)CN
(ii) OH
Scheme-112
2.3.4.1.5 Acylation
Indolizines are acylated at the position-3 or at the position-! (less easily) using
acid chlorides and acid anhydrides . The acylation ofindolizine with acetic anhyride
in the presence of acetic acid at 140°C occurs at the position-3 with the formation
of3-acylindolizine 331 (scheme-113).
co 1
j
(CH3CO)z0
CH3COOH
140"C 0? 331
j
COCH3
Scheme-113
Indolizines also undergo Vilsmeier-Haack formylation at the position-3 or at the

position- !, if position-3 is substituted. Vilsmeier-Haack formylation of indolizine
leads to the formation of indolizine-3-carbaldehyde exclusively ( scheme-114 ).
(i) DMF/POC13
(ii) HzO
~
~N-r
CHO
1 337
Scheme-114
Indolizine is highly fluorescent and gives coloured salts when treated with
aldehydes and ketones in the presence of an acid (Ehrlich test) (scheme-115).
2.3.4.2 Oxidation
Indolizines are air and light sensitive and oxidized with the cleavage of five-
membered ring providing picolinic acid derivatives 341 (scheme-116).
..
1 H
~bo ~- H_zO_ ~r~)

~~--1'339 ""'- N(CH,), ~~J338 VN(CH,),
Scheme-115
C 'o ¢
COOH
COOH
HzOz
OCH3 • +
340 341
Scheme-116
2.3.4.3 Reduction
Indolizine ring system is hydrogenated preferentially in the six-membered ring with

palladium catalyst in neutral solution, but in the presence of an acid five-
membered ring is reduced via indolizinium cation 343 (scheme-117).
[~:]
~ Hz, Pd/C ~ Hz, Pd/C
~N_J' CH3COOCzHs ~N_J' HBr
342 1
.
343
~~ - '
~~-lsr-
344
Scheme-117
The reduction of indolizine with sodium in ethanol or liquid ammonia results in

a mixture of 5,6, 7 ,8-tetrahydro- 342 and 5,6-dihydroindolizines 345 ( scheme-118).
Na
+
C2H 50H
or
liquid NH 3 342 345
Scheme-118
Indolizines undergo cycloaddition reactions with dienophiles with the formation of

cyclazines involving entire rc-electron system. The reaction of indolizine with
dimethyl acetylenedicarboxylate (DMAD) in the presence of dehydrogenating
catalyst results in the formation of [2.2.3]cyclazine 347 (scheme-119) 101 .
1
+
cH 3ooc-c=c-cooc H3
347
Scheme-119
Cyclazines are planar cyclic conjugated molecules with delocalized rc-electrons

and are named by indicating the numbers of atoms in the rings between the points
of attachment to nitrogen. These are numbered as follows :
'XX'
2 3
5
71 # 5
6 8
[2.2.3]Cyclazine [3.3 .3]Cyclazine
348 349
2.4 Carbazoles (Dibenzopyrroles) 102
2.4.1 General
Carbazole 8 is a dibenzopyrrole or benzo[b]indole and is analogous to anthracene.

It is numbered in a manner similar to anthracene. Carbazole was first discovered
in 1872 and isolated from the crude anthracene fraction of coal-tar. Its derivatives
also occur as plant alkaloids e.g. ellipticine exhibiting significant antitumor
activity 103 . Some of the carbazole derivatives are used as dyestuffs. N-
N
H
Ellipticine nucleus
Vinylcarbazole which is a photo-conductive has been of particular significance

because of its use as a monomer for commercially important polymer (plastic) with
photoconducting properties.
2.4.2 Synthesis
2.4.2.1 From Cyclohexanone Phenylhydrazones (Borsche Synthesis

or Modified Fischer Indole Synthesis)
It is the modified Fischer indole synthesis and involves the use of cyclohexanone
phenylhydrazones 350 as the starting materials which are obtained by the reaction
of phenylhydrazines with cyclohexanone. The acid-catalyzed cyclization of
cyclohexanone phenylhydrazones results in the formation of tetrahydrocarbazoles
354 which are easily aromatized to carbazoles by heating with sulfur or palladium
(scheme-120). The reaction is considered to proceed via electrophilic substitution
or rather a [3,3] sigmatropic shift in which weak N-N bond is broken and C-C bond
is formed with the retention of nitrogen atom attached to the benzene ring in
hydrazones (scheme-120).
Q-D N
H
354 352
I
8
Scheme-120
2.4.2.2 Reaction of Anilines with a-Halocyclohexanones
The reaction of anilines with a-halocyclohexanones yields tetrahydrocarbazoles

via an a-anilinoketone intermediate 355 involving electrophilic cyclization
(scheme- 121 ) 104 .
354 357 356
Scheme-121
The presence of electron-releasing substituents in the ring (aniline) favours the

electrophilic cyclization. If nitrogen is substituted with an electron-releasing group,
different product is formed (scheme-122) 105 .
~
~NHR
N
I
R
359
Scheme-122
2.4.2.3 From Diarylamines
2.4.2.3.1 Oxidative Cyclization
Oxidative cyclization of diarylamines 360 with palladium acetate in the presence

of acetic acid at 110°C results in the formation of carbazoles 361 (scheme-123) 106 .
QD N
I
R
CH3COOH
llO"C
QSJ N
I
R
360 361
Scheme-123
This method has been used in the synthesis of ellipticine, the plant alkaloid, with
antitumor activity (scheme-124) 107 .
CH3
Q N
H
Pd(OCOCH3h
CH3COOH
CH3
362 363
Scheme-124
2.4.2.3.2 Photochemical Cyclization
Photochemical dehydrogenative cyclization of diary1amines leads to the formation

of carbazoles. The reaction is considered to proceed via oxygen sensitive
intermediate 364 (scheme-125) 108•109 •
QD N
R
I
#
hv
an
-
HH
N
R
I
-2H
Q-D N
I
R
360 364 361
Scheme-125
2.4.2.4 Reductive Cyclization of o-Nitrobiphen yls
The reductive cyclization of o-nitrobiphenyls 365 with triethtylphosphite or

tris(methylsilyl)phosphite provides carbazoles. The reaction proceeds to involve
nitrene intermediate 369 and the nitrogen atom is inserted into the aromatic ring
at the ortho-position with the formation of C-N bond (scheme-126) 110•111 . This
method has been used to synthesize alkaloids containing carbazole ring system. 113
8 369 368
Scheme-126
2.4.2.5 From o-Azidobiphenyls
Photolysis or pyrolysis of o-azidobiphenyls 370 also leads to the formation of

carbazoles via nitrene intermediate with the elimination of nitrogen (scheme-127) 112 •
370 369 8
Scheme-127
2.4.2.6 From 1-Arylbenzotriazoles (Graebe-Ullmann Synthesis)
1-Arylbenzotriazole 373, obtained by diazotization of 2-aminodiphenylamine, on

thermolysis or photolysis yields carbazole with the extrusion of nitrogen involving
an intermediate 374 which is recyclized at the ortho-positions of the benzene rings
(scheme-128).
(XNH 2 HN02 ((
+
N=N
cyctm.tion
(X\ N'
6
NH NH
6371
6 372 373
Q-0 recyclization ~·
~N.
N
,)-yH
u
H
8
374
Scheme-128
2.4.2. 7 Nenitzescu Reaction
The reaction of p-benzoquinone with aromatic amines contammg electron-

withdrawing substituents at para-position results in the formation of carbazoles
with the formation ofC-C and C-N bonds (scheme-129) 114 •
2.4.2.8 Annelation of lndoles
The reaction of indoles with 1,4-diketones in the presence of an acid provides

the corresponding carbazoles involving electrophilic substitution followed by
cyclization and dehydration (scheme-130) 115 •116 •
b:-0
HO N02
N
H
378 377
t I
Scheme-129
~ + R-C-CH -CH -C-R

~N/ II 2 2 II
H 0 0
R
2 379
Scheme-130
2.4.3 Structure
The molecule of carbazole is slightly bow-shaped with the small dihedral angle of
1° between the planes of the five-membered and benzenoid rings. The molecular
dimensions for carbazole obtained from X-ray diffraction studies are presented
(Fig. 9).
The comparison of bond lengths and bond angles of carbazole with those of
pyrrole indicates that the internal bond angles of pyrrole are not changed with the
fusion of benzene rings, but the bond lengths, particularly C-N bond, are
increased. The bond (C 11 -C 12 ) is shorter than the interannular bond of biphenyl,
thus indicating that pyrrole ring retains, although diminished, aromaticity with the
fusion of benzene rings.
Bond lengths (A) Bond angles (0 )
Cl-C2 1.372 C-N-C 108.3

C2-C3 1.393 N-C 10-C 11 109.7
C3-C4
C 1-C 10
c 1-N
1.392
1.403
1.393
7 trQ
8 13 N 10
Hg
1
2
C10-C 1-C2
Cl-C2-C3
C2-C3-C4
115.6
123.9
120.1
cll-cl2 1.477 C3-CcC 11 117.9
C 10-C 11 1.408 CcC 11 -C 10 120.6
N-H 1.020 Cll-CJO-Cl 121.9
Fig. 9. Structural parameters of carbazole
2.4.4 Reactions
2 .4.4.1 Reactions with Electrophiles
Pyrrole ring is 7t-excessive and therefore more susceptible towards electrophilic

attack than the fused benzene ring in indole. But in carbazole in which both the
sides of pyrrole ring are fused with benzene rings, the central pyrrole ring does
not contain any reactive carbon centre as in indole. The electrophilic substitution
in carbazole, therefore, occurs at the benzene rings. Carbazole behaves as
diphenylamine in its substitution reactions and the electrophilic attack occurs
predominantly at the positions-3 and -6 i.e. para to the nitrogen and to a lesser
extent at the positions- I and -8. However, there are certain evidences that in some
cases the initial electrophilic attack occurs at the position-9.
Carbazole is a weaker base (pKa = -6.0) than its acylic analogue diphenylamine
because of the involvement of the lone pair on nitrogen of the central pyrrole ring
in cyclic delocalization, thus indicating the aromatic character of the central pyrrole
ring. However, the protonation occurs at the pyrrolic nitrogen (scheme-131 ).
QSJ N
Q:D N
H H.I '
H
380
Scheme-131
2.4.4.1.2 Nitration
Carbazole is nitrated with nitric acid or with ethyl nitrate with the formation of
3-nitro- 381 and 3,6-dinitro- 382 carbazoles alongwith I ,3,6,8-tetranitrocarbazole
383 (scheme-132).
Q-D
N02
N
H
+ HN03(C2H,;ON02)
Q-0 N
H
8 381
'9::Q
02N N02 02N + N02
+
Q-0 N
02N H N02 H
383 382
Scheme-132
Nitrosation of carbazole with sodium mtnte in acetic acid yields initially

9-nitrosocarbazole 384 which on treatment with nitric acid is converted into
3-nitrocarbazole 381 and 3,6-dinitrocarbazole 382 (scheme-133).
382
Scheme-133
2.4.4.1.4 Chlorination
Chlorination of carbazole with sulfuryl chloride gives 3-chloro- 385 and 3,6-
dichloro- 386 carbazoles (scheme-134).
Q-0 Q-0
Cl
Q-D _s_oa_
Cl Cl
2_ +
N N N
H H H
8 385 386
Scheme-134
2.4.4.1.5 Brornination
Bromination of carbazole with bromine in carbon disulfide or with NBS results in

a mixture of 3-bromo- 387, 3,6-dibromo- 388, 1,3,6-tribromo- 389 and 1,3,6,8-
tetrabromo- 390 carbazoles (scheme-135).
Q-0 +Q-0
Br Br Br
Q-D N N N
H H H
387 388
Brt:;iJ:l'
8
Br'QQ........ , Br
~ /; ~ # +
N
H Br
Br ~ Br
389 390
Scheme-135
Carbazole is sulfonated with sulfuric acid providing carbazole-3-sulfonic acid 391

as the major product, although di- and tri-sulfonic acids are also obtained in low
yields (scheme-136).
QO Q-0
S03H H03S S03H
Q-O-H2_so~· +
N N N
H H H
8 391 392
Scheme-136
2.4.4.1.7 Acylation
Acylation of carbazole with acetic anhydride in the presence of boron trifluoride-

ether produces N-acyl derivative 393. Further acylation requires vigorous
conditions and affected only using aluminium chloride as a catalyst with the
formation of 2,9-diacylcarbazole 394 which on base catalyzed hydrolysis gives
2-acylcarbazole 395 (scheme-137) 117. Thus, acylation of the five-membered ring
occurs more readily than the six-membered ring with the formation of
N-acylcarbazole. Acylation of carbazole under Vilsmeier-Haack conditions has
been reported to provide both 3- and 9-acyl derivatives (scheme-138) 118•119•
S03 H
Q-0 N
H
A~O/BF r-ether
NI
.-1
H 3 c'c~o
!
8
393
acylation A!0 3
OH
Q-O-cocH 3 Q-O-cocH 3
N NI
H
H 3 c'c~o
395 394
Scheme-137
CHO
Q-0 N
Q-V +Q-0
N N
H
H CHO
8 396 396a
Scheme-138
2.4.4.2 Oxidation
Five-membered heterocyclic rings are comparatively more readily oxidized than the
six-membered benzenoid rings. The presence of electron-releasing substituents on
the six-membered rings facilitates the oxidation of carbazole. The oxidation
reactions appear to have some ambiguity, however carbazole undergoes oxidative
dimerization providing probably 9,9'-bicarbazyl397 with the possible formation of
1,3'- 398 and 1,9'- 399 bicarbazyls.
Q-0 N
au
I
N
397 398 399
2.4.4.3 Reduction
Catalytic hydrogenation of carbazole over Raney nickel at 200°C and high pressure
results in the formation of 1,2,3,4-tetrahydro- 400 and 1,2,3,4,5,6,7,8-octahydro-
401 carbazoles leaving pyrrole ring intact as an aromatic ring (scheme-139).
Q-0 N
Raney Ni
Hz Q-0 N
+ Q-0 N
H 200"C& H H
high pressure
400 401
Scheme-139
Carbazole is weakly acidic with pKa = 19.90. However, if carbazole is treated with
a strong base, the nitrogen bound proton is abstracted with the formation of
N-carbazyl anion 402 which can be alkylated when treated with alkyl halides and
acylated with acyl halides (scheme-140). Carbazole is vinylated at the nitrogen
atom by acetylene in the presence of sodium hydroxide with the formation of
N-viny Icarbazole 405 (scheme-140).
Q-0 strong base

NaNH2
Q-0
~h
- . ; ~ #
RCH2CI Q-0--..;;
~h ~ #
N (Liquid NH 3) ~ N
H or I
NaOH 402 CH2R
II
Q-0
403
N
~~O:O
N
I I
CH=CH2 COR
405 404
Scheme-140
3 BENZOFURANS
3.1 General
Benzofurans exist into two isomeric structures depending on the position of fusion
of furan ring with the benzene ring :
Benzo[b]furan 3 the fusion of a benzene ring to 2,3-positions or face 'b' of the
furan ring.
Benzo[c]furan 6 the fusion of a benzene ring to 3,4-positions or face 'c' of the
furan ring.
Dibenzofuran 9 the fusion of two benzene rings at the 2,3- and 4,5-positions
(on both the sides) of the fur an ring.
9 1 2
5~
,'QS)'
4 3 (p)
5 ~2(a)
6V-J 7 1
6~9
7 1 6 0 4
5
3 6 9
Benzofuran ring system is incorporated in the reduced or modified form into

many natural products and synthetic pharmaceuticals of varying biological and
pharmacological activities. Some benzofuran derivatives with their activities are as
follows:
Aflatoxins carcinogenic and toxic 120
Trimethylpsoralen and its derivatives photoreactive cross linking reagents

for nucleic acids 121
Furocoumarins for treatment of psoriasis (associated

(Methoxalen) with over production of DNA) and
other dermal disease 122
0
Usnic acid inhibition effect on myco-

becterium tuberculosis
5-Cinnamoylbenzofurans hypertensive, vasodilating and spasmolytic
2-Aminomethyl-2,3-dihydrobenzofurans antidepressants and

hypertensives
5-Acyl-2,3-dihydrobenzofuran- diuretic and antitussives

2-carboxylic acids
R-C'(Q-
0
II
~ I COOH
:::::::,. . 0
5-Benzofuranyl carbamates insecticidals
0
II H
OR-C-N~
~c!
Ruscodibenzofuran 123
CH3
OH
3.2 Benzo[b]furans 124- 128
Benzo[b]furan, commonly known as benzofuran, was first prepared from coumarin

and thus earlier named as coumarone. Benzo[b]furan was later isolated by
distillation of bituminous coal which is also a source of methyl- and hydroxy-
benzofurans.
3.2.1 Synthesis
3.2.1.1 Intramolecular Cyclization of o-Substituted Phenols
The intramolecular cyclization of a-substituted (with saturated or unsaturated alkyl

groups - CH=C=CH2 , -CH2-CH=CH2, - CH=C(X)-Ar, -C-=CR, -CH2CHO, -CH2COR)
phenols 406a, 406b and 406c leads to the formation of benzo[b]furans under
variable reaction conditions involving nucleophilic attack of the phenolic oxygen
at an internal carbon with the formation C2-0 bond (scheme-141).
a:H -CH=CH
co
406a 407a
2 2
cxc~,CHO PPA
03.
•
OH OH 0
Rc=ceu cxc=c-R
406b 3
~1
OH OH
base
• (JQ-R 0
406c 407b
Scheme-141
3.2.1.2 Cyclodehydration of a-Aryloxyketones
a-Aryloxyketones undergo cyclodehydration (similar to Bischler indole synthesis)

when treated with a dehydrating agent (H 2 S04 , ZnCl 2 , POCl3 , KOH or PPA) and
provide benzo[b]furans via cationic intermediate, generated by protonation of
carbonyl group, with the formation ofC-C bond (y- to oxygen) (scheme-142)J29.
+ R
~
O~C_R
Q (X HO~C_R
H+ -H20
~
I I
O,..CH 2
•
~
I
O
I
,..CH 2
•
V-C?
408
Scheme-142
However, in some cases the rearrangement (migration of group from the

position-3 to position-2) results with the change in the conditions of
cyclodehydration (scheme-143) 130.
C6 Hs
r-
CI~
v-cr
PPA -CH
3
CI UO~C-C6HS
~
I I
,..CH
410
CH 3
~ a~-
O 'CH 3
v-cr
409
C.Hs
411
Scheme-143
Benzo[b ]furans unsubstituted at the positions-2 and -3 are obtained by

cyclodehydration of acetals in the presence of PPA (scheme-144).
00
+
H
PPA
0
412 3
Scheme-144
3.2.1.3 Reaction of o-Acylphenols with a-Halo Ketones and Esters
The reaction of o-acylphenols with a-halo ketones or esters followed by

intramolecular aldolization and subsequent dehydration results in the formation of
benzo[b]furans. The reaction proceeds with the addition of carbanion to the
carbonyl carbon with the formation ofC2-C3 bond (schemes-145 and 146) 131 .
ex+
II
C-R
OH
HOH
cyclization
414 R
. ~R'
~;-
415
Scheme-145
OC
~
CHO
OH
+ CICH2COCH3
KOH ~CHO
~ OCH COCH 3 2
416
cyclization
~COCH3
~r
418
Scheme-146
3.2.1.4 Reaction of o-Acylphenols with Dimethylsulfoxonium

Methylide
The reaction of a-acylphenols with dimethylsulphoxonium methylide results in the

formation of benzo[b]furans involving initial nucleophilic addition of sulfur ylide
to the carbonyl group followed by nucleophilic attack of the phenolic oxygen at
the internal carbon with the formation of C-C and C-0 bonds (scheme-147) 132 .
Ot ;;~ ,_R
c
OH
+
R
~
V-c? 408
-H 20
420
Scheme-147
3.2.1.5 From p-Benzoquinones
The reaction of a-ketocarbanions with p-benzoquinones containing at least one

unoccupied position provides benzo[b]furans involving (3 + 2) cyclization
(scheme-148). The reaction proceeds with the initial nucleophilic attack of
carbanion on p-benzoquinone with the formation of C-C bond and followed by
nucleophilic attack of the phenolic oxygen at the carbonyl carbon with the C-0
bond formation (scheme-148).
H,:~o
+ _ ,..COCH3
+ Na CH,
COCH3
CH3
421
428 429
Scheme-148
3.2.1.6 Ring Contraction (From Coumarins)
It is a convenient laboratory synthesis and proceeds with the bromination of

coumarin 430. The resulting dibromocoumarin 431 on alkaline degradation gives
coumarilic acid 433 which is decarboxylated to benzo[ b]furan (scheme-I49).
Br
~~~BrKOH [ ~Br]
v-..-o.Ao
430
UoSo -H,o 431
~(coo
432
~ distil. ~COOH ... -Br 1
~cf --C0 2 ~r
3 433
Scheme-149
3.2.2 Structure
The molecular orbital structure of benzo[b ]furan is similar to that of furan.

However, the additional structural feature in benzo[ b)furan is that I 0 n-electrons
are distributed over the cyclic system instead of six n-electrons as in furan.
Benzo[b]furan is considered to be resonance hybrid of the following resonating
structures (Fig. I 0) :
():) .......... 0) .......... ():) ~- ():)c1

0
+
0
+
#
+
(i) (ii) (iii) (i'1
t t
()) .......... (X>-~()::)~-():)
0 0
+
- ::::,....,0
+
~ ::::,....,0
+
('1 (\i) (\ii) (\iii)
Fig. 10. Resonating structures of benzo[ b]furan

3.2.3 Reactions
Benzo[b]furans are highly aromatic and exhibit characteristic properties relating to

the aromaticity.
3.2.3.1.1 Reactivity and Orientation
The fusion of a benzene ring to the face 'b' of the furan ring decreases reactivity
towards electrophiles. Benzo[b]furan is expected to undergo electrophilic
subsitution at P-position as in indole, but instead electrophilic substitution occurs
at the a-position because of the most powerful a-directing effect of the oxygen
ring atom. The transition state (3H-cation) resulting from the electrophilic attack
at the P-position is less stable than that resulting from the attack at the a-position
because the ring oxygen being highly electronegative accommodates positive
charge less readily than the ring carbon, thus providing insufficient stabilization
to the 3H-cation (Fig. 11) Moreover, the preferential a-substitution over
00
E
E+
attack at P-position [~E] ~
-H
+
(t)
(less stable)
(Q-E
0
3
.. [CO<]
+
Iattack at a-position
E+ ~
-H
0
(more stable)
Fig. 11. Schematic representation of electrophilic substitution in benzo[b]furan
P-substitution in benzo[b]furan can be rationalized on the basis of its behaviour

as a conjugated diene. The high electronegativity of the ring oxygen inhibits, upto
certain extent, the interaction of the lone pair on the oxygen atom with two double
bonds to form an aromatic system and thus makes benzo[b]furan to react to a
considerable extent as a conjugated diene (styrene) in which the electrophile is
expected to add at the terminal position i.e. C-2 and favours a-substitution
(similarly as in butadiene) (Fig. 12).
+
E
.. +
CH 2 -CH-CH=CH 2 (not stabilized)
I
E
Fig. 12. Electrophilic substitution in conjugated diene
3.2.3.1 .2 Directing Effects of Substituents
The presence of electron-releasing substituents at the position-2 directs the

incoming electrophile to the position-3, while the electron-releasing substituent at
the position-3 causes electrophilic substitution to occur at the position-2. The
electron-withdrawing substituent at the position-2 deactivates the five-membered
furan ring towards electrophilic substitution and causes substitution in the
benzene ring at the position-S and in some cases at the position-7 also. The
presence of electron-releasing substituents in the benzene ring activates the
benzene ring and results in substitution at ortho or para to the substituent.
However, the electron-withdrawing substituents in the benzene ring deactivate it
and cause substitution in the furan ring at the position-2.
Benzo[b]furans are acid sensitive and undergo polymerization in the presence of
a strong acid, but with electron-withdrawing substituents at the position-2 are
stable towards acids. 2-Methylbenzo[b]furan is protonated at the position-3 with
pKa = -13.3 (scheme-150).
+
H
407 434
Scheme-150
3.2.3.1.4 Nitration
Nitration of benzo[ b]furan with nitric acid in acetic acid produces 2-nitrobenzo[b]
furan 435 (Scheme-151 ), but nitration of 2-phenylbenzo[b]furan 436 gives 3-nitro-
2-phenyl- 437 and 6-nitro-2-phenyl- 438 benzo[b]furans (scheme-152).
+
IH
~+
o=)<NO,
~ JtJH
CH 3COOH ]
[
v-J
~
435
Scheme-151
436 437
+
~CsHs
02N~r
438
Scheme-152
However, nitration of 2-bromobenzo[b]furan 439 with nitric acid and sodium

nitrite proceeds by an addition-elimination mechanism with the formation of
2-nitrobenzo[b]furan 435 (scheme-153).
0:)--sr HNO, +
NaNOz
439 440
0:)--No,~
435
Scheme-153
Benzo[b]furan is polymerized by sulfuric acid, but sulfonated with sulfur trioxide-

pyridine complex at the position-3 with the formation ofbenzo[b]furan-3-sulfonic
acid 441 (in contrast to other electrophilic substitutions in benzo[b]furan)
(scheme-154).
~
V-c!
3 441
Scheme-154
However, benzo[b]furan-2-sulfonic 444 acid is obtained by the oxidation of

benzo[b]furan-2-sulfinic acid 443 which in turn is obtained by the reaction of
2-lithiobenzo[b]furan 442 with sulfur dioxide (scheme-155).
(X)--sr + n-Buli -- ~Li

V-r
l
439 442
HOH S0 2
Oxidation
(t}so,H
444 443
Scheme-155
The reaction of benzo[ b ]furan with halogens proceeds by an addition-elimination

mechanism with the formation of 2- and 3-halogenated benzo[b]furans.
Bromination of benzo[ b]furan proceeds to involve the attack of electrophile in the

first step at the position-2 with the formation of a-complex 445 which undergoes
one of the following steps depending on the reaction conditions (scheme-156) :
Bt
(X)
I
0
roH
11
H
(X) 0
+ Br2 ----...
0 Br
lli-
(-4<Y'C) H
3 442 446(trans)
~'~~
Br-
-HBr
(X)-sr 0
439
Br
()j 0
~
base
447
Scheme-156
(i) the attack of bromide ion at C-3 to give 2,3-trans addition product 446,
(ii) the attack of bromide ion at the bromine atom with the formation of
benzo[b]furan and
(iii) the attack of bromide ion at C2-H to provide 2-bromobenzo[b]furan 439.
However, the addition product 446 on heating with a base produces 3-

bromobenzo[b]furan 447.
Chlorination ofbenzo[b]furan in ether or carbon tetrachloride at 0-25°C produces

a mixture of cis- and trans-2,3-dichloro-2,3-dihydrobenzo[b]furans 448 which on
treatment with a base leads to the formation of 3-chlorobenzo[b] furan 449 and on
heating at 100°C in the presence of acetic acid provides 2-chloro derivative 450
(scheme-157) 133 .
ether ~c~H
~cl'c1
448 (cis +trans)
~-CI ..rn,(X)()HII c,H,oN•. ~

~r 100'C C2H50H V-c?
450 449
Scheme-157
3.2.3.1.7 Acylation
Benzo[b]furan undergoes Vilsmeier- Haack reaction to provide benzo[ b]furan-2-

carbaldehyde 451 (scheme-158) 134 .
~ DMF
~CHO
~~ POC13 ~r
3 451
Scheme-158
Benzo[b]furan is acylated at the position-2 by acid anhydrides in the presence

of phosphoric acid or tin chloride as a catalyst. If position-2 is substituted with
an alkyl group, acylation with acid chlorides in the presence of tin chloride occurs
at the position-3 (scheme-159) 134 .
~ + (RC0)20 ~COR
V-J V-c!
3 452
COR 1
(Q-R+ R 1ax::I ~R
l0L-T
407 453
Scheme-159
Alkylation ofbenzo[b]furan with tert-butyl chloride in the presence of zinc chloride

as catalyst results in a mixture of 2- and 3-substituted benzo[ b ]furans 454 and
455 in 1 : 2 ratio (scheme-160).
(CH3)JC
~C(CH3)3
V-c!
+~
l0L-cl
3 454 455
Scheme-160
Benzo[ b ]furan is chloromethylated at the position-2 when treated with

formaldehyde and hydrochloric acid in the presence of zinc chloride, but 2-methyl-
and 2-phenyl-benzo[ b ]furans are chloromethylated at the position-3 (scheme-161 ).
~ + HaiO+HCl
~~
(X)--R + HCHO+HCI
407 457
(R = CH 3 , C6 H5 )
Scheme-161
3.2.3.1.9 Reaction with Diazonium Salts
Benzo[ b ]furan is arylated at the position-3, if reacts with 2,4-dinitrobenzene

diazonium sulfate in aqueous acetic acid (scheme-162) 135 .
458
Scheme-162
Nucleophiles attack benzo[b)furan at the position-2. The reaction ofbenzo[b]furan

with ethanolic hydroxide under the drastic conditions proceeds with the cleavage
of furanoid ring and provides 461 and 462 involving Cannizzaro reaction of the
resulting aldehyde intermediate 460 (scheme-163).
Benzo[ b ]furan is lithia ted at the position-2 via deprotonation with the formation
of 2-lithiobenzo[b]furan 442 when treated with n-butyllithium in ether at -10°C
(scheme-164) 136 . However, 2-lithiobenzo[b)furan is also obtained by the reaction
of 2-bromobenzo[b]furan with n-butyllithium involving bromine-:::::::=:: lithium
exchange (scheme-165).
OH ~CH=CHOH
V-oH
459
461 Cannizzaro
+ reaction
460
462
Scheme-163
(JQ 0
n-Buli
ether
-lffC
[CQ- Lt] (X}-u or
0
442
Scheme-164
(X}-sr 0
n-Buli
(X}-u 0
439 442
Scheme-165
3-lithiobenzo[b]furan 463, obtained by bromine~ lithium exchange from

3-bromobenzo[b]furan 447, is thermally unstable and is cleaved to 2-ethynylphenol
464. But at -ll5°C, 3-lithiobenzo[b ]furan is stable and carboxylated to benzo[b ]-
furan-3-carboxylic acid 465 (scheme-166) 137 .
Br Li
~
~;___.....
n-Buli ~ ring cleavage
(X c=cH
u~ 15 to -60"C -
Oli
+
0)
463 464
COOH
-ll5°C
(i) C0 2 .. 0
(ii) HOH
465
Scheme-166
3.2.3.3 Oxidation
Benzo[ b]furan is susceptible towards oxidation and is oxidized in the furanoid ring.
Oxidation of benzo[b]furan with permanganate and chromic acid results in
2-hydroxybenzoic acid. If position-3 is substituted with a methyl group,
2-hydroxyacetophenone is obtained (scheme-167).
CXGOOH
00
KMn04
H 2 S0 4
0 OH
00 CX:o
R R
K 2Cr 20 7
H 2 S0 4
0
(KMn0 4 /H 2 S0 4 )
OH
(R=CH 3 , C6H 5)
Scheme-167
Ozonolysis of benzo[b]furan produces a mixture of 2-hydroxybenzaldehyde and

2-hydroxybenzoic acid (scheme-168).
00 0
CH0 3
~CHO +
V-oH
Scheme-168
~COOH
V-oH
3.2.3.4 Reduction
Benzo[b]furan is easily reduced by hydrogen over palladium or sodium-

alcohol in the furanoid ring with the formation of 2,3-dihydrobenzo[b]furan 466
(scheme-169). But the reduction with Raney nickel at higher temperature causes
reduction of both the benzenoid and furanoid rings (scheme-170).
(X) 0
+ Hz
Pd/C
100'C
or
(Na-c;H50H)
co 466
0
Scheme-169
(X) ())
Raney Ni
+ 4H 2
high tempt.
0
467
Scheme-170
However, reduction of benzo[b]furan with excess sodium in liquid ammonia

followed by quenching with ammonium chloride or methyl alcohol results in the
cleavage of furanoid ring and produces 2-ethylphenol. Similarly, 2-methybenzo-
[b]furan gives 2-propylphenol (scheme-171).
(XCH2 -CH 3
()) 0~
Na/NH 3
OH
Na/NH 3 (XCH,-CH,-CH,
(X}:-cH,
0~ OH
407
Scheme-171
The reaction of benzo[b]furan with dichlorocarbene in hexane gives an unstable

addition product 468 which rearranges to benzopyran 469. The resulting
benzopyran on treatment with water is dimerized to chromenyl ether 470
(scheme-172).
(X) 0
hexane
cx::CX:o 470
~CI
~OACI
469
Scheme-172
Copper-promoted reaction of benzo[b]furan with ethyldiazoacetate results in a

mixture of expected cyclopropanes 471 and 472 (scheme-173) 138 .
H
~COOC 2 H 5
~/'H
471 (major)
+
H
~,,,,cooc 2 H 5
~/'H
472 (minor)
Scheme-173
Benzo[b]furan does not undergo cycloaddition reactions because of its enhanced

aromaticity. However, 2-vinylbenzo[ b ]furans undergo (4 + 2) cycloadditions
involving exocyclic double bond (scheme-174).
NC CN
\ I
+ C=C __..
I \
NC CN
473 (TCNE)
+
0
::o
CH-CO
II
CH-CO
475
Scheme-174
3.2.3. 7 Photochemical Reactions
3.2.3.7.1 Photodimerization
Benzo[ b ]furan undergoes photodimerization providing low yields of syn- and anti-
dimers, when irradiated in benzene with acetophenone sensitized irradiations
(scheme-175) 139 .
OQ 0
H H
477 (anti)
Scheme-175
3.2.3. 7.2 Photosensitized Cycloaddition
Benzo[b]furan undergoes photosensitized (2 + 2) cycloaddition with DMAD

providing a mixture of cycloadducts 478, 479, 480 and 481 depending on the
irradiation wave lengths (scheme-176) 140 .
~COOCH3~H
~nD + I I
O H COOCH~ 0 COOCH3
4 78 4 79 COOCH3
CH300C COOCH3 0c:=P+

COOCH3
+ I I
~ 0
481 H 480 COOCH3
Scheme-176
3.2.3.7.3 Photooxygenation
Benzo[b]furan and 2-methylbenzo[b]furan do not undergo photooxygenation. But

2,3-dimethylbenzo[b]furan 482 is susceptible towards photooxygenation and gives
an unstable peroxide 483 at -78°C which at higher temperature rearranges to
2-acetoxyacetophenone 484 (scheme-177).
~
v;-
3
CH, photosensitzer
~;0
~cf'cH3
482 483 rearrangement 2f1'C
(XI COC.....
HI-3_ _....
~ OCOCH3
484
Scheme-177
3.3 Benzo[c]furans 141 - 143
3.3.1 General
The fusion of a benzene ring to the 3,4-positions of furan ring results in less stable
and highly reactive benzo[c ]furan or isobenzofuran. Benzo[ c ]furan remained
unknown untill 1971 , although its 1,3-diphenyl derivative was recognized and
synthesized in 1905.
5 ~02
6~
7 1
6
Benzo[c ]furan is stabilized by steric protection of the substituents at the

positions- ! and -3. Benzo[c]furans with alkyl or alkoxy substituents at the
position- I are unstable, but 1 ,3-diarylbenzo[ c]furans are stable and are used for
trapping unsaturated compounds. The presence of electron-withdrawing
substituents on the furanoid ring stabilizes the benzo[c]furan ring system.
3.3.2 Synthesis
3.3.2.1 Retro-Diels-Aider Reaction
This is the most common method for the synthesis ofbenzo[c]furan and involves
(4 + 2) cycloaddition offuran with benzyne with the formation of naphthalene oxide
485 which on reduction followed by pyrolysis produces benzo[c]furan involving
retro-Diels-Alder reaction (scheme-178) 144 .
Scheme-178
If naphthalene oxide 485 is treated with 3,6-di(2'-pyridyl)-1 ,2,4,5-tetrazine 487,

the resulting cycloadduct 488 produces benzo[c]furan at 110°C via retro-Diels-
Alder reaction (scheme-179) 145 .
_1_10"--ic~ CCa
6
Py
+
488 ~Py
Py
~ ....
N
N
489
Scheme-179
3.3.2.2 Reductive Cyclization of o-Dibenzoylbenzenes
The reductive cyclization of o-dibenzoylbenzenes with zinc dust in acetic acid

results in the formation of 1,3-diphenylbenzo[c]furans 490. The reductive
cyclization can also be affected by potassium or sodium borohydride, triphenyl
phosphite and metals (sodium, lithium, potassium) (scheme-180).
Scheme-180
3.3.2.3 Reaction of Dibenzoylacetylene with Dienes
The reaction of dibenzoylacetylene with acyclic dienes produces 1,2-diaroyl-

cyclohexadienes 491 which undergo cyclization when treated with p-toluene-
sulfonic acid to provide benzo[c]furans 491a (scheme-181) 146 .
HC
'l-CHR
CsHs
I
c . . . c~o
¢c?•Hs C.::::.
_. ~Hs
y<>~
t. ~
I + Ill ::::::,._
0
HC~ c,c'l-o
"CHR
I
R CsHs R C6 H5
CsHs
491 491a
Scheme-181
3.3.2.4 From Benzophenones
Electron-withdrawing substituents stabilize the benzo[c]furan system to such an

extent that 1-cyano-3-phenylbenzo[c]furan 494 is crystalline solid and is obtained
from benzophenone (scheme-182) 147• The base catalyzed hydrolysis of the
resulting benzo[c ]furan 494 gives carboxylic acid derivative 495, while catalytic
hydrogenation leads to the formation of 1,3-dihydrobenzo[c]furan derivative 496.
--o¢o
CN
HCN
OH
!
494 c 6 H5
catalytic
reduction
~0
~·
COOH
-
OH
cx}:H'
CsHs
496
Scheme-182
3.3.3 Reactions
Benzo[c]furan is the least aromatic among the benzo[c]fused five-membered

heterocycles as its resonance energy is substantially lower than that of its
benzo[b ]isomer.
Moreover, the benzene ring in benzo[c]furan does not have Kekule structure and
therefore considered as the heterocyclic analogue of cyclopentadiene.
Benzo[c]furans are highly reactive as dienes and undergo cycloaddition reactions
across the most reactive positions-! and -3 corresponding to the a-positions in
furan. The high reactivity ofbenzo[c]furans in cycloaddition reactions is attributed
to the regeneration of the benzenoid ring.
Benzo[c]furans behave as highly reactive dienes and undergo (4 + 2) cycloaddition

reactions with dienophiles. Benzo[c]furan reacts at 0°C with maleic anhydride,
N-phenylmaleimide and methyl vinyl ketone providing endo : exo (3 : 1) mixture
of cycloadducts. (scheme-183).
cc
0
0 +
::::::.....
0
497
0
. N-C6 H5
mr-COCH,
498
.. ~
0
499
Scheme-183
1,3-Diarylbenzo[c]furans are stable and undergo (4 + 2) cycloaddition reactions

with some unstable unsaturated compounds at the positions-! and -3 of the
furanoid ring (scheme-184). However, with cycloheptatriene, (4 + 6) and (4 + 2)
cycloadducts are obtained (scheme-185).
IQ 010
o:;:s
+
#
500
::::::,......
C6H5
490
+
c-c~
Ill CH-.1 we~
II CH2
c._c~ C-./
501
Scheme-184
0
490
Scheme-185
3.3.3.2 Photochemical Reactions
3.3.3.2.1 Photodimerization
1 ,3-Diphenylbenzo[c]furan 490 undergoes photodimerization with the formation of

photodimer 504 of unknown stereochemistry when irradiated in benzene with
acetophenone sensitized irradiation (scheme-186).
hv
C6H5COCH3
(sensitizer)
504
Scheme-186
3.3.3.2.2 Photocycloaddition
3.3.3.2.2.1 With Cycloheptatriene
1,3-Dipheny1benzo[c]furan undergoes photosensitized (4 + 4) and (4 + 6) cycloa-

dditions with cycloheptatriene providing (4 + 4) and (4 + 6) cycloadducts 505 and
506, respectively (scheme-187). (4 + 4) Cycloadducts are considered to be
(4 +4)
0 C6Hs
505 (endo + exo)
C6Hs
C6Hs
506 ( endo + exo)
Scheme-187
formed in a concerted manner via an exciplex intermediate in a n-n* singlet state.

The [4 + 6] cycloadducts are probably formed in a stepwise manner from an excited
n-n* triplet of I,3-diphenylbenzo[c]furan.
3.3.3.2.2.2 With Cyclohexadiene
Photochemical (4 + 2) cycloaddition of I ,3-diphenylbenzo[ c ]furan with

cyclohexadiene produces cycloadduct 507 ( exo and endo) (scheme-188).
+
0 ~
hv
C6H5
507 (endo + exo)
Scheme-188
3.3 .3 .2 .3 Photooxygenation
1,3-Diphenylbenzo[c]furan undergoes photooxygenation in ether at -50°C with

the formation of peroxide 508 which on reduction with potassium iodide in acetic
acid gives I ,2-dibenzoylbenzene, but with methyl alcohol hydroperoxide 509 is
obtained (scheme-I89).
cq~H
H5C6 OCH3
509
Scheme-189
3.3.3.3 Oxidation
Oxidation of I ,3-diphenylbenzo[c]furan with chromic acid or permanganate results

in the formation of I ,2-dibenzoylbenzene (scheme-I90).
Oxidation
490
Scheme-190
3.3.3.4 Reduction
Catalytic reduction of I,3-diphenylbenzo[c]furan in the presence of lithium,

sodium or potassium results in cis-I ,3-diphenyl-I ,3-dihydrobenzo[c ]furan 511
(scheme-I9I ) 148 .
er:;:5 oq:5
:::::,......
+2e-
(Ii orNa)
rn 3oH
CG~
C5H5 C6Hs HsC6 H
490 510 511
Scheme-191
3.4 Dibenzofurans 126•127•149
3.4.1 General
The fusion of benzene rings to both the sides (2,3-bond ' face b' and 4,5-bond 'face
d ') of the furan ring results in dibenzofuran and is numbered as :
Dibenzofuran is an aromatic molecule and is comparable with phenanthrene in

its electronic structure. The annelation of furan, however, does not appreciably
affects the aromaticity, although C-0 and C-C (interannular) bond lengths are
considerably lengthened (C-O bond is 1.404A as compared to 1.36A in furan). The
internal bond angles do not change appreciably. With the following structural
parameters, dibenzofuran exhibits bow-shaped structure with small dihedral angle
(l.l2°)(Fig. 13):
CI-C2 1.389 C--0-C 104.1

C2-C3 1.393 0-CII-CIO 112.3
C3-C4 1.388 CII-C6-C7 116.7
C-0 1.404 0 C6-C7-Cs 120.9
5
CIO-CI2 1.393 9 C7-Cs-C9 121.9
C8-C9-C 10 117.9
Fig. 13. Structural parameters of dibenzofuran
3.4.2 Synthesis
3.4.2.1 From 2,2'-Dihydroxybiphenyls
It is the classical method for the synthesis of dibenzofurans and involves an acid
catalyzed dehydration of 2,2'-dihydroxybiphenyls 512 or their methyl ethers
(scheme-192) 150 .
3.4.2.2 From Diphenyl Ethers
Photochemical cyclization of diphenyl ethers in the presence of iodine results in

the formaltion of dibenzofurans (scheme-193).
~H~H
Q-(f~ ~.~+'!--/ ~v;_,)-_(
HO OR \j HO OR ~ OR
512 513 ~ 514
(R=H,CH3)
~H
O:D ~
+
-H
0
-ROH
~r\~"
o &,OHR
9 515
Scheme-192
Scheme-193
Oxidative cyclization of diphenyl ethers with palladium acetate in acetic acid also
provides dibenzofurans.
3.4.2.3 From o-Aminodiphenyl Ethers (Pschorr Type Cyclization)
a-Aminodiphenyl ethers are also used to synthesize dibenzofurans involving

Pschorr type cyclization in which o-arninodiphenyl ethers 518 are diazotized to
convert them into diazonium salts 519 which on treatment with copper (II) salt
undergo cyclization with the evolution of nitrogen (scheme-194) 15 1.
ND~ ~ 0:0-o:::::
+ ;,.,N
(XN:OHI~~(XI
~
0
# ~ ~ 0
# -N
2
\.
0
,I
518 519 9
Scheme-194
3.4.2.4 Wittig Reaction
The reaction of 6-methoxy-4-methylbenzo[b]furan-2-carbaldehyde 520 with methoxy-

methylenephosphorane gives 6-methoxy-2-(p-methoxyvinyl)-4-methylbenzo[ b] furan
521 which undergoes (4 + 2) cycloaddition with dimethyl acetylenedicarbox-
ylate (DMAD) involving exocyclic double bond to provide dibenzofuran 522
(scheme-195) 152 .
522
Scheme-195
3.4.3 Reactions
Dibenzofuran is considered to behave similarly as 2,2'-linked diphenyl ether and

the substitution occurs at the reactive positions, ortho- and preferably para- to
the ring oxygen. However, the reactivity of these positions towards electrophi1ic
substitution is comparatively reduced than in diphenyl ether because of the
involvement of the lone pair on the ring oxygen in the aromaticity of the five-
membered ring. The reactive positions in dibenzofuran are shown by the
resonating structures (Fig. 14). The position-2 (para- to oxygen) is more reactive
than the position-4 (ortho- to oxygen) in electrophilic substitution reactions. The
reduced reactivity of the position-4 is attributed to the strain in the five-membered
ring produced in the transition state of substitution. The electrophilic substitutions,
therefore, occur preferably at the position-2. Further substitution takes place at the
position-8 with the formation of 2,8-disubstituted derivative.
Fig. 14. Resonating structure of dibenzofuran
Bromination of dibenzofuran with bromine in carbon disulfide occurs at the

position-2. If position-2 is substituted with hydroxyl group, bromination takes
place at the position-1. But, if hydroxyl group is at the position-3, bromination
occurs at the position-2 (scheme-196).
Br
Q-0 0
Br 2
CSz
QSj 0
9 523 Br
OH OH
QSj 0
Br 2
CSz
0
03:5-oH
524 527 Br
~OH
Br 2
CSz
0 0
525 528
Scheme-196
The presence of an acetylamino group at the position-2 directs the bromination

at the position-3, while an acetylamino group at C-3 causes bromination to occur
at the position-2 (scheme-197). If position-4 is substituted with a m ethoxy or
hydroxyl group, the bromination takes place at the position-! (scheme-198).
OcO--sr
NHCOCH3 NHCOCH3
OS) 0 0
529 531 Br
Q-V-NHCOCH3
0
532
Scheme-197
Br
Br 2
Scheme-198
3.4.3.1.2 Nitration
Nitration of dibenzofuran with nitric acid in acetic anhydride is anomalous and

occurs at the position-3 with the formation of 3-nitrodibenzofuran 535. Further
nitration takes place at the position-S with the formation of 3,8-dinitro derivative
536. If dibenzofuran is nitrated with ethyl nitrate and aluminium chloride m
nitromethane, the nitration occurs at the position-2 (scheme-199).
QD 0
537 536
Scheme-199
The presence of an acetylamino group at the position-2 causes nitration to occur

at the position-3 . If acetylamino group is present at the position-3 , nitration takes
place at the position-2 (scheme-200).
NHCOCH3 NHCOCH3
529 538
QD 0 NHCOCH3
(:~hO NHCOCH3
530 539
Scheme-200
Nitration of 4-acetylamino- and 4-hydroxydibenzofurans with nitric acid in

accetic anhydride at ooc introduces nitro- group at the position-3, but nitration
with nitric acid in acetic acid at 60°C results in 1-nitro derivative 542 (scheme-201 ).
NHCOCH3 NHCOCH3
540 541
NHCOCH 3
542
Scheme-201
3.4.3.1.3 Fonnylation
Dibenzofuran does not undergo formylation under Vilsmeier-Haack conditions but

formylated at the position-2 when treated with hydrogen cyanide and hydrochloric
acid in the presence of aluminium chloride (Gattermann formylation) (scheme-202).
CHO
QSJ 0
HCN-HCI
OS) 0
9 453
\ DMF
'------'1..... No reaction
POC1 3
Scheme-202
Ifposition-2 is substituted with a methoxy group, Vilsmeier-Haack formylation

takes place at the position-3 (scheme-203).
OCH3
~OCH, ___DM__F~
\_(0_)-J POC13
QS5--cHO
0
544 545
Scheme-203
Dibenzofuran is sulfonated at the position-2 with the formation of 2-sulfonic acid

546 when treated with chlorosulfonic acid. Further sulfonation occurs at the
position-8 and results in 2,8-disulfonic acid 547 (scheme-204).
3.4.3.2 Metallation (Lithiation)
Dibenzofuran is lithiated with the deprotonation at the position-4 when treated

with n-butyllithium (scheme-205). 4-Bromodibenzofuran 549 is lithiated by
n-butyllithium with bromine -:::::::=::::. lithium exchange with the formation of
9 546 547
I t
Scheme-204
Q)J 0
n-BuLi
Scheme-205
4-lithiodibenzofuran 548 which provides following dibenzofuran derivatives

(scheme-206):
549
NHzOCH3
-l<J'C
553
Scheme-206
(i) carboxylic acids - by the reaction with carbon dioxide.

(ii) phenols - if treated with molecular oxygen in the presence of Grignard
reagent,
(iii) amines - if reacts with 0-methylhydroxylamine and
(iv) sulfinic acids - by treating with sulfur dioxide.
The reaction of dibenzofuran with sodium hydroxide results in the cleavage of the
furanoid ring with the formation of 2,2'-dihydroxybiphenyl (scheme-207) .
0:0 0
NaOH
q-p HO OH
9 512
Scheme-207
However, 2-bromo- and 2-iodo-dibenzofurans provide 2-aminodibenzofuran 555

when heated with NaNH 2 or aqueous ammonia in the presence of copper(!)
bromide (scheme-208).
X NH 2
QSj 0 Cu CDBr
QSj 0
523: X =Br ~ 555
524: X= I
Scheme-208
Fluorodibenzofurans 556 also undergo nucleophilic substitution reactions with

the substitution at the position-3 (scheme-209)
F F
NaOCH 3
F OCH3
F F
556 557
Scheme-209
3.4.3.4 Reduction
Catalytic hydrogenation of dibenzofuran over platinum gives 1,2,3,4-tetrahydro-

dibenzofuran 558, while over sodium or rubidium at high temperature results in the
cleavage of furanoid ring with the formation of phenylcyclohexane as a major
product and biphenyl as a minor product. The reduction of dibenzofuran with
Raney nickel in methanol results in trans-2-phenylcyclohexanol (scheme-210).
Q0 0
Pt
O:D 0
9 558
Q0 0
9
oo+o -o 800/o 10%
Q0 0
Raney Ni
00 HO
Scheme-210
Birch reduction of dibenzofuran with sodium dissolved in liquid ammonia leads

to the formation of 1,4-dihydrodibenzofuran (scheme-211).
Q0 0
Na
Liqu.NH 3 QD 0
9 549
Scheme-211
4 BENZOTHIOPHENES
4.1 General
The fusion of benzene ring(s) to the thiophene ring results in benzo[b]thiophene

4, benzo[c]thiophene 7 and dibenzothiophene 10 which comprise the class of
benzothiophenes.
~
V-s/
4 7
O:SJ s
10
Benzo[ b ]thiophenes and their condensation with other chromophoric systems

form an interesting class of thioindigo 560 -thioindigoid 561 dyes . Because of
0 0
560 561
the bioisosteric relationship of benzo[ b ]thiophene with indole, benzo[ b ]thiophenes

have been shown to exhibit similar biological activities.
~2COOH
exhibits plant growth promoting
activity similar to indole acetic acid
~sl
562
effective antagonist
of tryptophan
563
4.2 Benzo[h]thiophenes 153- 156
4.2.1 General
The fusion of a benzene ring to the 2,3-positions or face 'b' of the thiophene ring
results in benzo[b ]thiophene. Benzo[b ]thiophene is a heterocyclic analogue of
naphthalene and named as thionaphthalene or thianaphthalene. Benzo[b]thiophene
ring system is numbered as follows :
5~2
s~s/
7 1
4
Benzo[b]thiophene is low-melting solid (m.p. 32°C, dipole moment 0.62D) and

can be represented by the following resonating structures (Fig. 15) :
(i) (ii) (iii) (il)
-co-co o:t
t - ~
(\iii)
01
(\) (\i)
(\ii)
Fig.15. Resonating structures of benzo[b]thiophene
The resonating structures involving destruction of the benzenoid 6n-electron

system contribute less to the resonance hybrid.
4.2.2 Synthesis
4.2.2.1 Oxidative Cyclization of Mercaptocinnamic Acids
Oxidative cyclization of o-mercaptocinnamic acid in the presence of an alkaline

solution of potassium ferricyanide leads to the formation of benzo[ b ]thiophene
with the loss of carbon dioxide involving sulfenium ion as an intermediate 565
(scheme-212).
CX CH=CH-COO-H--~-~
SH
564
~
~~
4 566
Scheme-212
Moreover, oxidative cyclization of a-mercaptocinnamic acid with iodine-ethanol/

dioxane/nitrobenzene or with chlorine-carbon tetrachloride also produces
benzo[b]thiophene. The reaction is considered to involve sulfenium ion
intermediate 569 and proceeds with the attack on centre of high electron density
(C=C bond of aromatic ring) with the formation ofC-S bond (Scheme-213) 157 .
,.COOH CH -
CH=C x2 () ~ _....COOH -X
()
,SH • I c 'sx ~
oo-
-HX ~
(X 2 = 12 I Cl 2) 568
567
COOH~
+cp-+
~ COOH~
Q;1~
I~
COOH
s ~ s : : :,. ~~
570 H
569
I -co2 • ~
~s/
4
Scheme-213
4.2.2.2 Reaction of Cinnamic Acid with Thionyl Chloride
The reaction of cinnarnic acid with thionyl chloride in the presence of pyridine
provides benzo[b]thiophene-2-carbonyl chloride 574. The cyclization is facilitated,
if electron-releasing substituent is presesnt at para-position to the site of ring
closure, while retarded with an electron-withdrawing substituent (scheme-214) 158 .
v v
H ....... CI
RO~CH=9H S00 2 R O y y c ... C .... COCI
COOH pyridine
SOCI
-S0 2,-HC1
I
f
571
RO~~~H
P
CIJ' .... S00 2 -S0 2, -HCI
COCI • -C1
-HCI -H ~ S
RO~C~~~CI
RO'C0-573
Cl H 0?~'~ I'COCI
~
I s' COCI 572
574
Scheme-214
4.2.2.3 Dehydrative Cyclization
4.2.2.3.1 From Arylthioaceta1dehyde Acetals
This is the most widely used method for the synthesis of benzo[ b]thiophenes and
involves dehydrative cyclization of arylthioacetaldehyde acetals in the presence of
polyphosphoric acid or other acid catalyst (scheme-215). The acetals are obtained
~ + CICH2 CH(OR) 2
~SH
~ PPA
~s/
4
Scheme-215
by the reaction of arylthiols with chloroacetaldehyde dialkyl acetal in the presence

of sodium ethoxide.
Cyclization of ortho- and para-substituted acetals provides 7- and 5-substituted
benzo[b]thiophenes respectively, while meta- substituted acetal leads to the
formation of a mixture of 4- and 6-substituted benzo[b]thiophenes and the ratio
depends on the nature of the substitution and the method of cyclization.
4.2.2.3.2 From Arylthio Methyl Ketones
The dehydrative cyclization of arylthio methyl ketones in the presence of

polyphosphoric acid or other acid catalysts, such as cone H2 S04 , HF, AlCl3 , ZnCl2
or P20 5 also results in benzo[b]thiophenes. The reaction proceeds to involve
electrophilic attack on the aromatic ring with an elimination of water molecule
( scheme-216) 153 . The reaction is enhanced if an electron-releasing substituent is
present at the position para- to the site of ring closure.
0:5' ~
576 577 578
-H20
R
579
Scheme-216
4.2.2.4 Reaction of Mercaptoaldehyde or Acid with a-Halo Acids

or Ketones
The condensation of a-mercaptobenzaldehyde 580 with chloroacetic acid in

the presence of a base affords benzo[b]thiophene (scheme-217). Similarly,
a-mercaptobenzoic acid (thiosalicylic acid) 581 with choroacetone in the presence
of a base results in 2-acetyl-3-hydroxybenzo[b]thiophene 582 in excellent yield
(scheme-217).
e CHO
SH
+ CIC~COOH
NaOH
C2H 50H
~COOH
V-s/
00 .
580 570
Ll I
s
Q 4
OH
~
COOH
NaOH
+ CIC~COCH3 COCH3
SH
~s/
581 582
Scheme-217
4.2.2.5 From Benzenethiols (Thiophenols)
The reaction of thiophenol with chloroacetic acid followed by acid catalyzed

cyclization and reduction with zinc in acetic acid leads to the formation of
benzo[b]thiophene (scheme-218).
~ + CIC~COOH
~SH
co s
Zn
Scheme-218
4
The reaction of benzenethiols (thiophenols), however, with alkynes particularly

with dimethyl acetylenedicarboxylate (DMAD) in ethyl acetate or acetic acid also
provides benzo[b]thiophenes 587 (scheme-219) 159 . The rate of the reaction is
enhanced, if benzenethiol is substituted with an electron-releasing substituent at
the para- position, but with electron-withdrawing substituent vinyl sulfide 588 is
obtained as a major product.
Ro I +
c....... GOOCH 3
Ill
c,
CH3~H;
Ra/"'-/COO CH3
-:::r
~
I-;;;
c
II
_,.c,
l
or
~ SH
S COOCH 3
COOCH3 CH 3COOH
l
585
(R =electron-withdrawing (R =electron-releasing
group) group)
COOCH3 ~H ,COOCH3
R'QH
I
COOCH3 R m -
1 ~ ,.-H
Ra~
-9'
C~
-..:::c-coocH3
-9' I -9'
::::.... SrCOOCH3 ::::.... S COOCH3 ::::.... - S/
588 587 586
Scheme-219
4.2.2.6 From Thiophene-2,3-dic arboxylic Anhydride
Flash vacuum thermolysis of thiophene-2,3-dicarboxylic anhydride 589 in the

presence of thiophene as a trapping agent leads to the formation of benzo[b]
thiophene with the extrusion of sulfur involving (4 + 2) cycloaddition of an initially
formed thiophyne intermediate 590 with thiophene (scheme-220) 160 .
<X)
0
[?J) Q
50CY'C
a FVf
co on
589
s
.. -S
4 591
Scheme-220
4.2.3 Reactions
4.2.3.1.1 Electrophilic Attack at Carbon
The fusion of a benzene ring to the face 'b' of the thiophene ring decreases the
reactivity and thus causes benzo[b ]thiophene to exhibit lower reactivity than
thiophene in electrophilic substitution reactions.
4.2.3.1.1.1 Orientation
Benzo[b]thiophene is expected to undergo electrophilic substitution reactions

preferentially at the 13-position in the five-membered ring similarly as in indole. Of
course, in contrast to thiophene, benzo[ b ]thiophene undergoes electrophilic
substitution reactions in the thiophene ring, although at both the positions-a and
-13, but preferentially at the 13-position. The reactivity ratio (13 : a) depends upon
the nature of the electrophile and the reaction temperature. The percentage of
a-substitution increases with temperature.The preferential attack of electrophile at
the 13-position can be rationalized by comparing the stability of the transition states
resulting from the electrophilic attack at the 13- and a-positions (Fig. 16).
~--E-+--~~s
~ sl
~ ---~w .. H E
c)jE
attack at 13-position
(JQ
I
S (more stable)
.__ _E_+_ _ -11•~ ~H ..,.,.1---11•~ ~H

attack at a-position ~sj'\.E ~Sj'\.E
(less contributing)
H E Ill
~ more stable than ~H ~H
~+I ~SAE ~s/'\.E
(less stable)
Fig. 16. Schematic representation of electrophilic substitution in benzo[ b]thiophene

The fusion of benzene ring to the thiophene ring decreases the reactivity of the
a-position and increases the reactivity of the ~-position in electrophilic substitution
reactions. Thus, the rate of ~-substitution increases with large depression in the
a-substitution. Although in benzo[ b ]thiophene all the positions are more reactive
than in benzene, the order of reactivity of the different positions is as follows:
order of reactivity = 3 > 2 > 6 > 5 > 4 > 7
4.2.3.1.1.2 Directing Effects of Substituents
The generalization of preferential electrophilic substitution in benzo[ b]thiophene,

however, seems invalid if the five-membered thiophene ring is substituted with
deactivating substituents or if the six-membered benzene ring is substituted with
activating substituents. In both the conditions the substitution occurs in the
benzene ring rather than in the five-membered thiophene ring. The presence of
activating groups at the position-3 or -2 directs the electrophilic attack at the
position-2 or -3, respectively. If an electron-withdrawing or deactivating substituent
is present in the five-membered ring, electrophilic substitution occurs in the six-
membered ring. Moreover, an electron-releasing or activating substituent in the
benzene ring causes substitution to occur at the ortho- or para- position in the
same ring 153 .
4.2.3.1.1.3 Nitration
Nitration of benzo[b]thiophene with concentrated nitric acid in the presence of

acetic acid results in a mixture of 3-nitro- 592 and 2-nitro- 593 benzo[b ]thiophenes
in 5 : 1 ratio (scheme-221) 153 . If acetyl group is present at the position-3, the
co -rn-~_co _o. . ; 3;_H- - ~ o5'

4 592
+
593
Scheme-221
thiophene ring is deactivated and the substitution occurs in the benzene ring with
the formation of a mixture of 4-, 5-, 6- and 7-nitrobenzo[b]thiophenes.
4.2.3.1.1.4 Halogenation
Chlorinationlbromination of benzo[b ]thiophene with chlorine/bromine in acetic

acid under controlled conditions provides predominantly 3-chloro/bromo
benzo[b]thiophene (scheme-222). If benzo[b]thiophene is treated with chlorine in

the presence of one mole of iodine, 2, 2, 3, 3, 4, 5, 6, 7-octachloro-2,3-
dihydrobenzo[b]thiophene 595 is obtained. (scheme-222) 161 .
00
X
I ...
X 2 (Cl2 I Br2)
co
CH,CXXJH
594 a: X= Cl
b: X= Br
Cl
Cl
Cl
4 \ Cl2
I2 (1 mole)
...
Cl Cl
Cl
595
Scheme-222
Iodination of benzo[b]thiophene with iodine in the presence of mercuric oxide

produces 3-iodobenzo[b]thiophene (scheme-223).
~ ~
V-sl HgO ~sl
Scheme-223
4.2.3.1.1.5 Sulfonation
Benzo[b]thiophene is sulfonated with pyridine-sulfur trioxide with the formation

of benzo[b]thiophene-3-sulfonic acid 597 as the major product alongwith benzo-
[b]thiophene-2-sulfonic acid 598 as the minor product (scheme-224).
S03H
~ pyridine-S03
~ + ~so3H
~s7 ~s/
~~
597 598
Scheme-224
If position-2 or -3 is substituted with a methyl group, sulfonation or chlorosul-

fonation occurs at the free position in the five-membered ring (scheme-225).
599 601
CH 3
~3
~- S0 CI or(S0 H)
V--sl or
pyridine-S03 V--sl 2 3
600 602
Scheme-225
4.2.3.1.1.6 Alkylation
Alkylation of benzo[b]thiophene with alkenes or alkanols in the presence of an

acid provides a mixture of2- and 3-alkylbenzo[b]thiophenes (scheme-226).
~+ CH3-CH=C~ ~ ~ CH(CH3h
~s/ ~sr
cx5(CH ,), +603
604
Scheme-226
Benzo[b]thiophene undergoes chloromethylation at the positio-3 with the

formation of predominating 3-chloromethylbenzo[ b]thiophene 605 when treated
with formaldehyde and hydrochloric acid (scheme-227).
00 4
+ HCHO
HO
605
Scheme-227
4.2.3.1.1.7 Acylation
Benzo[b ]thiophene undergoes Friedel-Crafts acylations in the presence of Lewis

acid catalyst (AlC1 3, BF3, SnC14 , H2S04) providing 3-acylbenzo[b]thiophene 606 as
the major product (scheme-228).
COR
~
(() +
4
RCOCI
V-sl 606
Scheme-228
However, benzo[b]thiophenes with carbonyl group containing side chain at the

position-3 undergo intramolecular acylation at the position-2. If position-2 is
occupied, the cyclization occurs at the position-S (scheme-229). In benzo-
607
0
II
~:H,-C-0 PPA
Scheme-229
[b ]thiophenes containing side chain at the position-2, intramolecular cyclization

occurs either at the position-3 or -5 depending on the length of the side chain.
4.2.3.1.1.8 Diazo Coupling
2- And 3-methylbenzo[b]thiophenes undergo diazo coupling with 2,4-dinitro-

benzenediazonium salts at the position-3 and -2, respectively with the formation
of azo dyes 611 and 612 (scheme-230).
Scheme-230
4.2.3.1.2 Electrophilic Attack at Sulfur
Benzo[b ]thiophenes undergo S-alkylation with strong alkylating reagents containing

non-nucleophilic counterions (Cl04-, PF6- and BF4-). The resulting S-alkylated
product may react with nucleophilic counterion (1- ), if present, and causes reversal
of the initial alkylation (dealkylation) (scheme-231) 162 .
OQs
[err~]
amon
Ag00 4
(r)+CH3I exchange
s Cl04- I
- CH 3
4 CH3 CI04
613 (unstable) 614 (unstable)
dealkylation ~
-CH3I '0-s/
4
(if non-nucleophilic anion is absent)
Scheme-231
Benzo[b ]thiophenes substituted with an alkyl group of suitable length undergo

intramolecular S-alkylation when treated with silver hexafluorophosphate in the
presence of dichloromethane (scheme-232) 163 .
616
Scheme-232
S-Alkylated benzo[b]thiophenes exhibit reduced aromatlcity because sp3 -

hybridized sulfur causes less effective overlapping of the lone pair on sulfur with
the ring n-system.
4.2.3.2 Reactions with Oxidizing Agents
4.2.3.2.1 Formation ofl-Oxides and 1,1-Dioxides
Oxidation of benzo[b]thiophene with m-chloroperbenzoic acid or hydrogen

peroxide leads to the formation ofbenzo[b]thiophene 1,1-dioxide (sulphone) 617
which reacts as a vinyl sulphone and undergoes (4 + 2) cycloaddition with
cyclopentadiene and also self Diels- Alder cycloaddition under the forcing
conditions (scheme-233) 153.
~
~s/
MCPBA
000
s
~ oj)
~I
~ s
~~ ~~
0 0 0 0
4 617 ~ 618
~V;s:
~"a
H
620 619
Scheme-233
Oxidation of benzo[b]thiophene with tert-butyl hypochlorite, however, gives

a mixture of benzo[b]thiophene !-oxides involving chlorination as well
(Scheme-234) 164 .
co s
(CH3hCOO
(0-cl
s II
+ d}H S Cl
II
co
4 621 0 622 0
+ Cl +
ex) s
+
s
II
594 623 °
Scheme-234
4.2.3.2.2 Oxidative Ring Opening
Ozonolysis of benzo[b]thiophene in dichloromethane at low temperature results

in the cleavage of five-membered thiophene ring with the formation of aldehydes
624 and 625 (scheme-235) 165 .
co
0
aD+ OD
II
CHO CHO c-s
03
CH 2Cl2
s s-s
-78°C SH CHO
4 624 625
Scheme-235
4.2.3.3.1 Metallation
Benzo[ b ]thiophene is lithia ted readily at the position-2 by treating with

n-butyllithium with the formation of2-lithiobenzo[b]thiophene which can be used
to obtain 2-substituted derivatives ( scheme-236). But 2-methoxybenzo[ b]thiophene
has been reported to undergo lithiation at the position-3.
(Qs n-BuLi
627
Scheme-236
4.2.3.3.2 Ring Opening by Nucleophiles
The reaction of benzo[b]thiophene with Grignard reagent in the presence of

bis(triphenylphosphine)nickel dichloride as catalyst proceeds with the cleavage of
five-membered thiophene ring involving replacement of C-S bonds by C-C bonds
(scheme-237) 166 .
CO s
+CH 3MgBr
Scheme-237
4.2.3.3.3 Addition ofNucleophiles
The reaction of benzo[ b ]thiophene with cyclic secondary amines proceeds with
the addition of amine across the C2-C3 bond of benzo[ b]thiophene providing
addition product 629 (scheme-238) 167 .
4.2.3.4 Reactions with Reducing Agents
Benzo[ b]thiophene is reduced to 2,3-dihydrobenzo[b]thiophene 630 by sodium in

alcohol. But the reduction with sodium-ammonia results in the cleavage of
heterocyclic ring with the formation of 2-ethylbenzenethiol 631 (scheme-239).
H
~/H
V-sA NJ
628
~~H
V-l>\ NJ
629
Scheme-238
0)s Na
C2H 50H 0)s
630
CXCH -CH,
(Qs Na-NH 3 2
SH
631
Scheme-239
The reaction of benzo[ b]thiophene with ethyldiazoacetate proceeds with the

addition of carbene across the C2-C 3 and CcC 5 bonds providing 632 and 633
(scheme-240) 153 •
~
V-s/
Scheme-240
Benzo[b]thiophenes undergo thermal and photochemical cycloaddition reactions

across the C2-C3 bond 168 .
4.2.3.6.1 Thermal (2 + 2) Cycloaddition Reactions
Benzo[b ]thiophenes substituted with electron-withdrawing substituents at the

heterocyclic ring undergo (2 + 2) cycloaddition with electron-rich alkynes
(scheme-241).
~R
E
~ + R-c=c-R
lJ-sr
E =electron-withdrawing substituent
R =electron-releasing substituent
Scheme-241
4.2.3.6.2 Photochemical (2 + 2) Cycloaddition Reactions
Benzo[b]thiophene undergoes photochemical (2 + 2) cycloadditions with halo-

genated alkenes when irradiated in the presence of acetophenone or benzophenone
as sensitizer (scheme-242).
~S + CIHC=CHCI
~~/ (cis or trans )
hv
sensitizer
~~I
633a (cis + trans)
Scheme-242
Photochemical (2 + 2) cycloaddition of benzo[b]thiophene with dimethyl

acetylenedicarboxylate (DMAD) results in the formation of cycloaddition products
634 and 635 depending on the irradiation wave length (scheme-243) 140 •170 .
COOCH3
•~ ~S COOCH 3
,______h_v______
I
300nm lJ-sY
CO
634
hv! COOCH3
+
S ~GOOCH,
CH 300C-C~C-COO:H, rearran~COOCH,
3~nm ~ ~s!'COOCH 3
635
Scheme-243
4.2.3.7 Photosubstitution
Photoexcitation ofbenzo[b]thiophene in the presence of dibromomaleic anhydride

results in both photosubstitution as well as photocycloaddition providing the
products 636 and 637. The photosubstitution is favoured with increasing
temperature and the polarity of the solvent (scheme-244) 171 .
Br:q
0
636
(cycloaddition product)
S Br I +
0
o 0
s 637
(substituted product)
Scheme-244
4.3 Benzo[c]thiophenes 172
4.3.1 General
The fusion of benzene ring to the 3,4-positions or face 'c' of the thiophene ring
results in less stable benzo[c]thiophene which is, however, stabilized if substituted
with sterically protecting substituents particularly at C-1 and C-3. Benzo[c]thiophene
is also named as isobenzothiophene and the ring system is numbered as follows :
Benzo[c]thiophene is appreciably aromatic (RE = 184 kJ/mol) but less than its
benzo[b] analogue (RE = 222kJ/mol). Benzo[c]thiophene is considered to be
contributed by the following resonating structures (Fig. 17) :
(i) (iii)
Fig. 17. Resonating structures of benzo[c]thiophene
The dipolar resonating structures are higher energy resonance contributors, but
aromaticity of the benzene ring provides stabilization to thiocarbonyl-ylide like
resonance structures (ii) and (iii).
4.3.2 Synthesis
4.3.2.1 From 1,4-Diketones
The treatment of 1,4-diketone, obtained by the reaction of 1,3-butadiene with

dibenzoylacetylene and existing in bis-enol orientation, with sulfurizing agent,
phosphorus pentasulfide, results in benzo[c]thiophene (scheme-245) 146•173 .
491a 491b
CsHs 1
~s~
~CH
638 6 5
Scheme-245
4.3.2.2 From o-Bis(chloromethyl)benzene
The reaction of o-bis( chloromethyl)benzene with sodium sulfide yields 1,3-dihy-

drobenzo(c)thiophene (2-thiahydrindane) 639 which is converted into its 2-S-oxide
640. The dehydration of 2-S-oxide 640 with alumina leads to the formation of
benzo[c ]thiophene ( scheme-246) 174 .
~s
~
7
Scheme-246
The dehydration of 2-S-oxide 640 with acetic anhydride proceeding via

Pummerer rearrangement also produces benzo[c ]thiophene 7 with the subsequent
loss of acetic acid 175 • The vapour phase catalytic reduction of 1,3-dihydrobenzo
[c]thiophene ( thiahydrindane) 639 over palladium-carbon also affords benzo[c]-
thiophene (scheme-246) 176 .
4.3.2.3 Ring contraction of 1,2-Dithiins
4,5-Benzo-1 ,2 dithiins 642 substituted with electron-withdrawing substituents at

the 3- or I and 6-positions are rearranged to benzo[c ]thiophenes when treated with
a base at elevated temperature. The reaction proceeds through an anionic
rearrangement with the elimination of hydrogen sulfide (scheme-247) 177 .
E = electron-withdrawing
substituent (-COOCH3 )
Scheme-247
4.3.2.4 Annelation of Thiophenes
The reaction of 2,5-dimethylthiophene with acetonylacetone in the presence of

hydrogen fluoride results in annelation of thiophene with the formation of 1,3,4,7-
tetramethylbenzo[c]thiophene 646 (scheme-248).
4.3.3 Reactions
Although benzo(c]thiophene is appreciably aromatic, it is highly reactive and, in

contrast to benzo[b]thiophene, exhibits diene-type characteristics. Benzo[c ]-
thiophene undergoes (4 + 2) cycloaddition reactions with dienophiles across the
HF H3C~CH 3
-2Hz; H3CnCH3
s
646
Scheme-248
most reactive positions C-1 and C-3 adjacent to the sulfur atom and corresponding
to the a-positions in monocyclic thiophene (scheme-249). However, benzo[c]-
thiophene is comparatively less reactive than benzo[c]furan in cycloaddition
reactions.
o¥o
~
.. ~0
0
(X>
647
:::::::-
oo=>-Ph
0
I ~
..
o¥o I
Ph
648
0
Scheme-249
4.3.3.2 Oxidative Ring Opening Reactions
The reaction of 1,3-diarylbenzo[c]thiophenes with photogenerated singlet oxygen

results in ring opening with the formation of 1,2-diaroylbenzenes involving
cycloadduct intermediate 649 (scheme-250).
Scheme-250
4.4 Dibenzothiophenes
4.4.1 General
The heterocycle resulting from the fusion of two benzene rings (one on each side-
at 2,3- and 4,5-positions) to thiophene is known as dibenzothiophene. The
dibenzothiophene ring system is numbered as follows :
,QS),
9 1 2
6 s 4
5
The fusion of benzene rings to the thiophene ring does not change appreciably
the internal bond angles of the central thiophene ring. However, C-S bond is
considerably increased (C-S = 1.740A) as compared to C-S bond in thiophene
(C-S = 1.714A) and with this elongation the aromaticity of the central ring is still
retained although in modified form (somewhat reduced). Dibenzothiophene
acquires bow-shaped configuration with 0.4-1.2° dihedral angle.
Dibenzothiophene S-oxide 650 exhibits antiaromatic character with the
lengthening of carbon-sulfur bond as sulfur atom is sp3-hybridized (pyramidal)
and oxygen atom being 59° out of plane.
0::0 0
s
I
650
4.4.2 Synthesis
4.4.2.1 Oxidative Cyclization of Diphenyl Sulfides
Oxidative cyclization of diphenyl sulfides with iodine in the presence of ethylene

glycol results in the formation of dibenzothiophenes (scheme-251) 178 .
QO s
ethylene glycol
~
QD s
10
Scheme-251
Photochemically initiated cyclization of diphenyl sulfides in the presence of

oxidizing agents such as iodine or oxygen also leads to the formation of
dibenzothiophenes 179 .
4.4.2.2 Reductive Cyclization of Diphenyl Sulfoxide
The reductive cyclization of diphenyl sulfoxide with sodamide in the presence of

toluene proceeds through the electronic shift with the formation of dibenzothi-
ophene (scheme-252).
~7~0 NaNH 2 ~ Wi:)H~

~ 8 ~c6Hsrn3 ~~~~~If\.& ~
+ s s
c;-b Q
I ~I
~OH
651 652 653
Q-0 s
10
Scheme-252
4.4.2.3 From Biphenyls
The reaction of biphenyls with sulfur in the presence of aluminium chloride

catalyst produces dibenzothiophenes.
OO+s 0:0 s
10
Scheme-253
4.4.2.4 From Diphenyl Sulfones
Lithiation of diphenyl sulfone 654 with n-butyllithium followed by oxidation of

the resulting dilithiodiphenyl sulfone 655 with copper(II) chloride gives
dibenzothiophene S,S-dioxide (sulfone) 656 which on reduction with lithium
aluminium hydride produces dibenzothiophene 10 (scheme-254).
Qs_{)n-Buu
if'"\)
654 655 656
0:0 s
10
...
Scheme-254
4.4.2.5 From 2-AIIylbenzo[b]thiophenes
The reaction of 2-allylbenzo[b]thiophenes 657 with dichloromethyl methyl ether

and tin(IV) chloride at low temperature results in cyclization providing the
corresponding dibenzothiophenes (scheme-255) 180 .
~ J:'
V- ~"'-cH28
Cl2CHOCH3
Sn04 0:0
-50 to -70"C s
657 10
Scheme-255
4.4.3 Reactions
Dibenzothiophene behaves as diphenyl sulfide in substitution reactions and the

electrophilic substitutions occur predominantly at the position para- to the sulfur
atom i.e. positions-2 and -8. The order of reactivity of the different positions in
dibenzothiophene towards electrophiles is : 2 = 8 > 4 > 3 >> 1 as is evident from
the contributing resonance structures (Fig. 18) 181 :
~
7~-J-J3~ V+)-J'
6 s 4
f>r--r\
s
Q:D s -
5
(il) QiD
(i)
0r-f\+
~
- s. . )-J
~·-~ ~+)-J
s
(v) (iv)
Fig. 18. Resonating structures of dibenzothiophene
Thus electrophilic substitutions; nitration, bromination, acylation and

formylation, occur predominantly at the position-2.
Dibenzothiophene is lithiated usually at the position-4 with n-butyllithium in ether

in the presence of tetrahydrofuran at low temperature with the formation of
4-lithiodibenzothiophene 658 (scheme-256).
Q-0 s
n-BuLi I ether
THF, Cf'C
QS) s Li
10 658
Scheme-256
4.4.3.3 Oxidation
Oxidation of dibenzothiophene with chlorine and water or by controlled oxidation

with hydrogen peroxide affords dibenzothiophene S-oxide (scheme-257).
QO
s
Q2/H20
or
H202
QO
s
(controlled) II
0
10
650
Scheme-257
However, oxidation with 30% hydrogen peroxide in acetic acid at 80°C

produces dibenzothiophene S,S-dioxide, which on reduction with lithium
aluminium hydride provides dibenzothiophene (scheme-258).
QO ~s~
QO
s
0 0
10 656 10
Scheme-258
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CHAPTER4
FIVE-MEMBERED HETEROCYCLES WITH TWO

HETEROATOMS
CONTENTS
GENERAL 363
1.1 Structures 364
1.2 Basicity 365
1.3 Structure versus Chemical Reactivity (Consequences of 367
Additional Nitrogen Atom)
1.3.1.1 Electrophilic Attack at Carbon 367
1.3.1.1.1 Orientation 367
1.3.1.1.1.1 1,3-Azoles 368
1.3 .1.1.1.2 1,2-Azoles 369
1.3.1.2 Electrophilic Attack at Nitrogen-3 370
1.3.2.1 Nucleophilic Attack at Carbon 371
1.3.2.2 Nucleophilic Attack at Hydrogen (Deprotonation) 372
2 1,3-AZOLES 374
2.1 lmidazoles 375
2.1.1 General 375
2.1.2 Synthesis 377
2.1.2.1 Reaction of a-Hydroxy- or a-Halo Ketones 377
with Amidines
2.1.2.2 Reaction of a-Amino Ketones with Cyanates, 378
Thiocyanates or Isothiocyanates
(Marckwald Synthesis)
2.1.2.3 Reaction of a-Diketones, a-Hydroxy-, a-Halo- 378

or a-Amino Ketones with Formamide
(Formamide Synthesis)
2.1.2.4 Reaction of Oxamide with Phosphorus Oxychloride 379
(Wallach Synthesis)
2.1.2.5 Reaction of Arylaldoximes with Propiolate Ester 380
2.1.2.6 Reaction of 1,2-Diaminoalkanes with 380
Carboxylic Acids and Aldehydes or Ketones
2.1.2.7 Ring Trasformation (From Oxazoles) 381
2.1.2.8 Ring Contraction (From Pyrazines) 381
2.1.3 Structure 382
2.1.3.1 Hydrogen Bonding 383
2.1.3.2 Tautomerism 383
2.1.4 Reactions 384
2.1.4.1 Reactivity 384
2.1.4.2.1 Electrophilic Attack at Nirtogen 385
2.1.4.2.1.1 Protonation (Basicity) 385
2.1.4.2.1.2 N-Alkylation 386
2.1.4.2.1.3 N-Acylation 387
2.1.4.2.2.1 Orientation 388
2.1.4.2.2.2 Nitration 389
2.1.4.2.2.5 Acylation 391
2.1.4.2.2.6 Diazo Coupling 392
2.1.4.2.2.7 Reactions with Aldehydes 393
and Ketones
2.1.4.2.2.8 Oxidation 394
2.1.4.3.1 Nucleophilic Attack at Carbon 394
2.1.4.3.2 Nucleophilic Attack at 396
Hydrogen (Deprotonation)
2.1.4.3.2.1 Deprotonation of NH (Acidity) 396
2.1.4.3.2.2 Deprotonation of Carbon-2 396
2.1.4.3.2.2.1 H ~ D 397
Exchange
2.1.4.3.2.2.2 Metallation 397
2.1.4.3.2.2.3 C-Acylation via 398
Deprotonation
2.1.4.5 Reactions with Dienophiles 399
2.1.4.6 Photochemical Cycloaddition Reactions 399
Five-Membered Heterocycles with Two Heteroatoms 359
2.2 Oxazoles 401

2.2.1 General 401
2.2.2 Synthesis 402
2.2.2.1 Cyclodehydration of a-Acylamino Ketones 402
(Robinson-Gabriel Synthesis)
2.2.2.2 Reaction of a-Halo Ketones with Primary 402
Amides (Bliimlein-Lewy Synthesis)
2.2.2.3 Reaction of a-Hydroxyamino Ketones 402
with Aldehydes
2.2.2.4 Reaction of Tosylmethyl Isocyanide 403
with Aldehydes
2.2.2.5 Reaction of a-Metallated lsocyanides with 403
Acid Derivatives
2.2.2.6 Ring Transformations 404
2.2.2.6.1 From C-Acylaziridines 404
2.2.2.6.2 From lsoxazoles (Isomerization) 405
2.2.3 Structure 405
2.2.4 Reactions 406
2.2.4.2.1 Electrophilic Attack at Nitrogen 407
2.2.4.2.1.1 Protonation (Basicity) 407
2.2.4.2.1.2 N-Alkylation 407
2.2.4.2.2.2 Mercuration 409
2.2.4.2.2.3 Vilsmeier-Haack Formylation 409
2.2.4.3.2 Nucleophilic Attack at Hydrogen 411
2.2.4.3.2.1 Metallation 411
2.2.4.3.2.2 H ~ D Exchange 412
2.2.4.4 Thermal Reactions (Cornforth Rearrangement) 413
2.2.4.7 Photooxygenation 415
2.3 Thiazoles 416
2.3.1 General 416
2.3.2 Synthesis 417
2.3.2.1 Synthesis of Thiazoles 417
2.3.2.1.1 Reaction of a-halo Ketones with 417
Thioamides (Hantzsch's Synthesis)
2.3.2.1.2 Reaction of a-Acylamino Ketones with 418
Phosphorus Pentasulfide
(Gabriel Synthesis)
2.3.2.1.3 From a-Aminonitriles 418

(Cook-Heilbom's Synthesis)
2.3.2.1.4 From a-Thiocyano Ketones 419
(Tchemiac's Synthesis)
2.3.2.1.5 Reaction of a-Mercapto Ketones 419
or a-Mercapto Acids with Nitriles
2.3.2.2 Synthesis of Benzothiazoles 421
2.3.2.2.1 Synthesis from o-Aminothiophenols 421
(2-Aminobenzenethiols)
2.3.2.2.1.1 Reaction with Aldehydes 421
2.3.2.2.1.2 Reaction with 1,2-Diketones 421
2.3.2.2.1.3 Reaction with Acids and 422
Acid Derivatives
2.3.2.2.2 From Arylthioureas (Hugershoffs Method) 422
2.3.3 Structure 422
2.3.4 Reactions 423
2.3.4.1.1.1 Basicity 424
2.3.4.1.1.2 N-Alkylation (Reaction 424
with Alkyl Halides)
2.3 .4.1.2.1 Nitration 425
2.3.4.1.2.4 Alkylation 427
2.3.4.1.2.6 Diazo Coupling 427
2.3.4.2 Condensation Reactions 428
2.3.4.4 Desulfurization 430
2.3.4.5.1.1 Amination 430
2.3.4.5.1.2 Ring Cleavage 431
2.3.4.5.1.3 Displacement of Halide 431
2.3.4.5.1.4 Metal-Halogen Exchange 432
432
-==
2.3.4.5.2.1 Metallation
2.3.4.5.2.2 H D Exchange 433
2.3.4.6 Photochemical Rearrangements 434
3 1,2-AZOLES 435
3.1 Pyrazoles 435
3.1.1 General 435
3.1.2 Synthesis 436

3.1.2.1.1 Reaction of 13-Diketones with Hydrazines 436
3.1.2.1.2 Reaction of a,I3-Unsaturated Carbonyl 437
Compounds with Hydrazines
3.1.2.2 1,3-Dipolar Cycloadditions 439
3.1.3 Structure 440
3.1.3.1 Hydrogen bonding 441
3.1.3.2 Tautomerism 441
3.1.4 Reactions 442
3.1.4.2 Electrophilic Attack at Nitrogen 443
3.1.4.2.1 Basicity 443
3.1.4.2.2 Acidity 443
3.1.4.2.3 N-Alkylation 443
3.1.4.2.4 N-Acylation 443
3.1.4.2.5 Michael Addition 445
3.1.4.3 Electrophilic Attack at Carbon 445
3.1.4.3.1 Reactivity and Orientation 445
3.1.4.3.2 Nitration 447
3.1.4.3.5 Mercuration 449
3.1.4.3.6 Diazo Coupling 450
3.1 .4.6.2.1 Metallation 452
3.1.4.6.2.2 Ring Cleavage via 452
Deprotonation
3.1.4.9 Photochemical Transformation 454
3.2 Isoxazoles 455
3.2.1 General 455
3.2.2 Synthesis 458
3.2.2.1 Reaction of 13-Diketones with Hydroxylamine 458
3.2.2.2 Reaction ofNitrile N-Oxides 459
with Alkenes and Alkynes
3.2.3 Reactions 460
3.2.3.2.1 Electrophlic Attack at Nitrogen 461
3.2.3.2.1.1 Basicity 461
3.2.3.2.1.2 N-Alkylation 461

3.2.3.2.2.1 H -:::::;::::: D Exchange 462
3.2.3.2.2.2 Nitration 463
3.2.3.2.2.5 Chloromethylation and 466
Hydroxymethylation
3.2.3.4.1 Nucleophilic Displacement 468
3.2.3.4.2 Ring Cleavage via C-Deprotonation 468
3.2.3.4.3 Reductive Ring Cleavage 471
3.2.3.5 Condensation Reactions 471
3.2.3.6 Rearrangement 472
3.2.3.7 Photochemical and Thermal Reactions 472
3.3 Isothiazoles 473
3.3.1 General 473
3.3.2 Synthesis 474
3.3.2.1 Oxidative Cyclization ofy-lminothiols 474
3.3.2.2 Ring Transformation 475
3.3.2.3 From Alkenes 476
3.3.2.4 From a, ~-Unsaturated Carbonyl Compounds 476
3.3.3 Structure 477
3.3.4 Reactions 478
3.3.4.1.1 Nitration 478
3.3.4.1.3 N-Alkylation 479
3.3.4.2 Side Chain Reactivity 480
3.3.4.2.1 Reaction with Aromatic Aldehydes 480
3.3.4.2.2 Decarboxylation 480
3.3.4.3.2 Ring Transformation 481
3.3.4.3.3 Lithiation 482
3.3.4.3.4 Ring Cleavage 482
3.3.4.4 Photochemical Transformation 482
REFERENCES 483
1 GENERAL
Five-membered heterocycles with two heteroatoms may be considered to be

derived from pyrrole, furan and thiophene by the replacement of -CH= group by
sp 2-hybridized azomethine nitrogen (pyridine-type nitrogen) at the position-2 (a)
(+)-N=
0
at position-2
(-)-CH=
X
(X=NH, O, S)
(+)-N=
at position-3
[) X
or -3 (!3). These heterocycles are termed as azoles and depending on the position
of azomethine nitrogen (-N=) are classified as :
(i) 1,2-Azoles : If azomethine nitrogen (-N=) is substituted at the position-2.
4 3 4 3 4 3
sCN sCN
0/2 sCN
S....-2
N~2
H 1 1
Pyrazole Isoxazole Isothiazole
1 2 3
(ii) 1,3-Azoles When insertion of azomethine nitrogen (-N=) IS at the

position-3 .
3 3
4 3
4 N 4 N
s[)2 s()2 s()2
N1 0 s1
H 1
Imidazole Oxazole Thiazole
4 5 6
1.1 Structures
The molecular orbital structures of azoles are similar to those of five-membered

aromatic heterocycles with one heteroatom. In azoles each atom is sp 2-hybridized
and the n:-molecular orbital is consisting of the Pz obritals of the ring atoms. The
aromatic sextet of six delocalized n:-electrons is contributed by one electron from
each carbon atom and one from the azomethine nitrogen (pyridine-type nitrogen),
while two electrons are donated from the heteroatom similarly as in pyrrole, furan
and thiophene.
The azomethine nitrogen ( -N=) has its lone pair of electrons in sp 2 -hybridized
orbital which is in the plane of the ring, i.e. orthogonal to the plane of n:-molecular
orbital. The lone pair on azomethine nitrogen, therefore, does not participate in the
aromatic sextet but makes azoles to behave as bases (available for protonation) and
to exhibit certain degree of nucleophilic character (Fig. I).
'------lone pair (not involved

I ' 3-Azoles in aromatic sextet) I,2-Azoles
Fig. 1. Molecular orbital structures of azoles
The azoles are aromatic because of the cyclic delocalization of six n:-electrons
and are considered to be contributed by the following resonating structures
(Fig. 2):
1,2-Azoles :
0 ...... 0
X
N Z+~N
X
...... -~+~N
F\ ..._..1\_.._..n
X
~+,N ~+
X X
.... N
(i) (ii) (iii) (iv) (v)
1,3-Azoles :
![) X
[.)~ -
X
c.)X
N
C)-~t)
X X
(i) (ii) (iii) (il) (\)
Fig. 2. Resonating structures of 1,2- and 1,3-azoles
These resonating structures are not equivalent in their contribution to the

resonance hybrid. In 1,2-azoles the resonating structure (v) is relatively more
stabilized than the others because of a- C=N and a- C=X+ groups. 1,2-Azoles,
therefore, involve electrophilic attack perferably at the position-4. Similarly, in 1,3-
azoles, the resonating structures (iii) and (v) are more stabilized by a- C=N and
a- C=X+ groups, respectively and thus contributing more to the resonance hybrid.
The electrophilic attack in 1,3-azoles, therefore, occurs preferentially at the
position-4 or-5.
1.2 Basicity
The presence of additional pyridine-type nitrogen (azomethine nitrogen) with lone

pair of electrons has considerable effect on the basicity in azoles. The lone pair
of electrons on the pryidine-type nitrogen is not involved in maintaining
aromaticity but it is available for the protonation. Thus the pyridine-type nitrogen
(-N=) makes azoles more basic than the five-membered aromatic heterocycles with
one heteroatom. However, the basicity of pyridine-type (azomethine) nitrogen is
effected by the interaction with second heteroatom (X) in azoles and, therefore,
depends upon the nature and the relative position of the second heteroatom (X)
as is evident from the pKa values of azoles (Fig.3).
The second heteroatom (X), other than pyridine-type nitrogen, possesses two
mutually opposite effects: (i) mesomerically electron-releasing effect ofheteroatom
(base-strengthening effect) (ii) inductively electron-withdrawal effect (base-
weakening effect).
(i) When both the heteroatoms are nitrogen and are present at the 1- and 3-
positions (imidazole), the mesomeric effect (base-strengthening effect) is
strong and predominates over the inductive effect. Thus imidazole is a
stronger base than pyridine (pKa = 5.2). But the inductive effect (base-
weakening effect) predominates when heteroatom is oxygen (powerful
inductive electron-withdrawal) or sulfur and thus reduces basicity of
oxazole and thiazole (Fig. 4).
0+N
NH 0+ 0
..,..NH 0+
s
_...NH
H
+
pKa 2.52
+
-2.97
+
-0.51
c-JH
N
r>H 0
r>Hs
H
pKa 7.00 0.80 2.53
Fig. 3. pKa values of azoles
UNH
... '(+.)
X
(ii)
inductive electron- mesomeric electron-

withdrawal destabilizes cation release stabilizes cation
Fig. 4. Inductive and mesomeric effects in 1 ,3-azoles
(ii) When both the heteroatoms are nitrogen and present at the 1- and
2-positions, the inductive effect (base-weakening effect) predominates over
the base-strengthening effect and thus the basicity is reduced. Moreover,
the base-weakening effect increases with oxygen and sulfur and causes
further reduction in the basicity (Fig. 5).
0)NH
X
+ .. CNH X
(i) (ii)
inductive electron- mesomeric electron-
withdrawal destabilizes cation release stabilizes cation
(strong base-weakening (weak base-strengthening
effect) effect)
Fig. 5. Inductive and mesomeric effects in 1,2-azoles

1.3 Structure versus Chemical Reactivity

(Consequences of Additional Nitrogen Atom)
Since the azoles are considered to be derived from the five-membered aromatic
heterocycles with one heteroatom by replacing -CH= group by pyridine-type
(azomethine) nitrogen at the position-2 or -3, the chemistry of azoles therefore
shows similarities with that of the five-membered aromatic heterocycles with one
heteroatom and of pyridine.
1.3.1.1 Electrophilic Attack at Carbon
The introduction of pyridine-type nitrogen into five-membered n-excessive

heterocycles causes withdrawal of electrons from the ring carbon atoms, thus
making azoles less susceptible towards electrophilic attack. The azoles are,
therefore, markedly less reactive than the five-membered heterocycles; pyrrole,
furan and thiophene, due to the presence of electronegative pyridine-type
nitrogen. The reactivity order in 1,2-azo1es is found to be as depicted in (Fig. 6) :
> 0s N >
Fig. 6. Reactivity order in 1,2-azoles
Similarly, in 1,3-azoles the reactivity order is as follows (Fig. 7) :
f) N
> ()s > () 0
H
Fig. 7. Reactivity order in 1,3-azoles
1.3.1.1.1 Orientation
The directing effect of the additional nitrogen (pyridine type-electronegative) will

be similar to that of an electron-withdrawing group i.e. meta-directing effect in
benzene. But in azoles second heteroatom; pyrrol-type nitrogen, furan-type oxygen
and thiophene-type sulfur, releases electrons mesomerically to the a-position and
exhibits effect similar to that of the electron-releasing group i.e. ortho-effect in

benzene. The combination of both the effects decides the position of electrophilic
attack in the azole ring.
1.3.1.1.1.1 1,3-Azoles
The combination of both the effects, due to pyridine-type nitrogen (m-directing

effect) and singly bonded second heteroatom (-NH-, -0- and -S-) with ortho-
effects, leads to the attack of electrophile mainly at the position-5 (tautomerism in
imidazole makes 4- and 5-positions equivalent). Moreover, the preferential position
of electrophilic attack in terms of pyridine-~-reactivity and pyrrole, furan,
thiophene-a-reactivity is represented schematically (Fig. 8) :
weakly activated by~

electron-releasing effect
3
of X (-NH-, -0- and -S-) si( ) 2

rN ....--- deactivated by inductive
effect of pyridine-type
nitrogen
strongly activated by ~ ~ ~ ~ost s~~ngly deac:ivated
electron-releasing effect Y pyndme-type mtrogen
of X (a- to -X- or~- to-N=) (a- to-N=)
Fig. 8. Schematic representation of electrophilic attack in 1,3-azoles
The preferential electrophilic attack at the position-5 in 1,3-azoles can be

rationalized by the relative stabilities of the transition states resulting from the
attack of electrophile at the positions-2, -4 and -5 (Fig. 9). The transition state
~r> -L [ H:r> ~ HX) ~ H>C;]

X EX EX
+
EX
attack at C-5
Fig. 9. Electrophilic attack at C-2, C-4 and C-5 in 1,3-azoles

resulting from the electrophilic attack at position-2 is stabilized by three resonating

structures, but involve highly unfavoured resonating structure with positively
charged sextet N-3. Therefore, in 1,3-azoles the attack of electrophile occurs
preferentially at the position-5.
1.3.1.1.1.2 1,2-Azoles
The resultant effect of both the electronic effects existing in 1,2-azoles directs the
attack of electrophile at the position-4. It is also evident from the schematic
representation in 1,2-azoles (Fig. I 0). Moreover, the preferential electrophilic attack
activated by electron-release '\.. a- to pyridine-type

from X as in pyrrole, furan "' / nitrogen and deactivated
and ~h~ophene (pyridine f3- o~ by electron-withdrawal
N
t x"
reactivity) by -N=
l_._- - - - - deactivated due to pyridine

type nitrogen as y- to -N=
Fig. 10. Schematic representation of electrophilic attack in 1,2-azoles
at the position-4 in 1 2, -azoles is supported by relative stabilities of the

intermediates resulting from the attack of electrophile at the positions-3, -4 and
-5 (Fig.11 ).
0?---L [~E-~1
X
attack at C-3
~eN [:sd)-E~Nl
X
~CN-L [EH~N - EH£';N+-EH£:N]

attack at C-4
X X X X
attack at C-5 (unfavoured)
Fig. 11. Electrophilic attact at C-3, C-4 and C-5 in 1,2-azoles

The resonating structures of the intermediates resulting from the electrophilic

attack at the positions-3 and -5 involve unfavoured structures with positively
charged sextet nitrogen. The position-4 is the preferred site of electrophilic attack
in 1,2-azoles. 1,2-Azoles are relatively much less reactive than 1 ,3-azoles in
electrophilic substitutions due to the predominantly existing inductive (electron-
withdrawing) effect in 1,2-azoles. Moreover, 1,2-azoles do not usually undergo
electrophilic substitution reactions under the acidic conditions because of
increasing further the electron-withdrawing effect of the azomethine nitrogen
(pyridine-type) on protonation.
However, 1 3, -azoles exhibit low reactivity in acid media than in neutral meida,
because in acid media the electrophile will have to attack electron-deficient species.
The position of electrophilic attack in the azolium cation is deduced on the basis
of greater stabilization (involving greater charge separation) of the intermediate.
(Fig. 12). Since the intermediate (i) has greater charge separation than in the
intermediate (ii), the attack of electrophile will occur preferentially at C-5 rather than
at C-4 in 1,3-azoles in acidic conditions ( azolium ions).
attack at C-5
[rr--c;]
X X
H
EtNH
I.....------~-~
E+
+ +~
\
attack at C-4 X
(ii)
Fig. 12. Electrophilic attack in 1,3-azolium cation
1.3.1.2 Electrophilic Attack at Nitrogen-3
The electrophilic attack at azomethine nitrogen (pyridine-type) depends upon (i)

the electron density on the pyridine-type notrogen and (ii) the substituents
present on the azole ring. The nature and position of the heteroatom other than
azomethine (pyridine-type) nitrogen determine the electron density on the
pyridine-type nitrogen. The interaction of pyridine-type nitrogen with pyrrole-type
nitrogen, oxygen or sulfur has considerable influence due to the presence of two
opposite electronic effects; (i) mesomeric effect and (ii) inductive effect. The
balancing effect of both these effects determines the electron density at pyridine-
type nitrogen. The inductive effect is stronger when two nitrogen atoms are in 1,2-
positions or the second heteroatom is oxygen or sulfur and thus lowers the
electron density on nitrogen. While with two nitrogen atoms in 1,3-position, the
mesomeric effect is stronger and makes position-3 with higher electron density.
The electron density on pyridine-type nitrogen (-N=) is also effected by the

substituents on the azole ring. The inductively electron-withdrawing substituents
(N0 2 , CHO, COR) at a- to pyridine-type (azomethine) nitrogen decrease electron
density and makes the attack of electrophile difficult at N-3. But the presence of
mesomerically electron-releasing substituents (-NH 2 , -OR) at a- or y- to the
azomethine nitrogen (-N=) increases the electron density and facilitates the attack
of electrophilic at N-3 . The fusion of benzene ring to the azole ring and the
substituents with weak electronic effects do not effect appreciably.

1.3.2.1 Nucleophilic Attack at Carbon
The inductively electron-withdrawal effect of both the heteroatoms in azoles

causes nucleophilic attack to occur readily under the mild conditions than those
required for nucleophilic attack in pyridine. Moreover, azolium rings in which the
electron-withdrawal effect is increased with the protonation of pyridine-type
nitrogen (N-3) react with nucleophiles more rapidly than the neutral azole rings .
In 1,3-azoles the position-2 is electron deficient and the attack of nucleophile
occurs at carbon-2, but in 1,2-azoles the positions-3 and -5 are electron deficient
R
+I
~l
/[)JNu
X
tyNu
X=NH,Oand S
and are, therefore, the sites of nucleophilic attack. The presence of electron-
withdrawing substituents on the azole ring facilitates the attack of nucleophiles,
while eleceton-releasing substituents hinder the nucleophilic reactions.
Displacement of Halide : Haloazoles undergo nucleophilic substitution reactions.

The nucleophilic displacement of halide is facilitated if the transition state is
mesomerically stabilized, thus depending on the position (orientation) of the ring
heteroatoms and halogen atom. 1,3-Azoles undergo nucleophilic substitution
reactions favourably with the replacement of halide ion by nucleophile if halogen
atom is substituted at the position-2.
![~X Cl
X=NH,OandS
1,2-Azoles undergo nucleophilic substitutions if occupied with halogen at the

positions-3 and /or -5. Ifboth the positions-3 and -5 in 1,2-azoles are occupied with
halogen atoms and the position-4 is occupied with electron-withdrawing substituent,
the halogen atom at position-S is preferentially replaced by nucleophile because
of the formation of mesomerically stabilized transition state.
EH(CI)
~
(CI))(_X_,N
)( ,.'N
(CI) X
1.3.2.2 Nucleophilic Attack at Hydrogen (Deprotonation)
The azoles and especially azolium ions are deprotonated with the abstraction of
proton by a base providing anion which is stabilized and can accept deuteron from
the solvent with the H ~ D exchange. In 1,3-azoles, C-2 (position-2) is
deprotonated in the presence of a base as the resulting anion is stabilized by (i)
sp 2-hybridization (increased s-character stabilizes anion) and (ii) flankening of
electron-withdrawing heteroatoms (HC=N is more acidic than HC=CH) (scheme-!).
H
_![)__
X H
:B
. ()_
X
(deprotonation at C-2)
Scheme-l
However, under strongly basic conditions, both C-2 and C-5 are deprotonated
with the abstraction of protons by a base from the positions-2 and -5 (scheme-2).
H
_![)__
X H
:s ...
H
_1[)-X
+
_()__
X H
(deprotonation at C-2) (deprotonation at C-5)
Scheme-2
1,3-Azolium cations (quaternary salts) are deprotonated very readily with the
abstraction of proton by a base from C-2 because of the increased electron attra-
cting tendancy ofpyridinium-type (-N=) nitrogen. The anion of 1,3-azolium cation
is stabilized and can be deuterated resulting in H-:::::::=::: D exchange (scheme-3).
R
/
:B f/N
-BH tz.+)-
x
Scheme-3
The relative rates of H ~ D exchange at C-2 in 1,3-azolium ions are :
R R R
(J (Js (J
/ / /
> >
0 N
H
105.5 103.5 1
The fastest H ~ D exchange in oxazolium cation is attributed to the enhanced

acidity of C2-H due to the presence of highly electronegative oxygen atom.
1,2-Azoles (pyrazole and isothiazole) undergo deprotonation at C-5 under basic
conditions, but isoxazole is deprotonated at C-3 with the cleavage of the ring
(scheme-4).
R H
n{
H_l( ,'N
X
H
:B
... -0 x"
(Pyrazole and Isothiazole)
R-Zf: 0~
:B
...
Oxazole
Scheme-4
1,2-Azolium cations (pyrazolium and isothiazolium quaternary salts) are

deprotonated at C-5 but require mild basic conditions similarly as C-2 deprotonation
in 1,3-azolium cations (scheme-S). But isoxazolium salt is deprotonated at C-3 under
Scheme-S
mild basic conditions and the resulting unstable anion undergoes ring opening
reaction with the formation of unstable a-ketoketimine which reacts readily with
acids and produces activated esters which are used in the peptide synthesis
(scheme-6).
a-ketoketimine
~ rn,cooH
/COOCH3 /COOCH3
Hf = q isomerization
"
HC-C
\\
H3 C .....-C~ NHR H C .....-C, N-R
~0 3 OH
Scheme-6
2 1,3-AZOLES
1,3-Azoles include imidazole, oxazole and thiazole and are considered to be derived
from pyrrole, furan and thiophene, respectively with the replacement of -CH=
group by azomethine (pyridine-type) nitrogen from the position-3.
2.1 Imidazoles 1- 4
2.1.1 General
Imidazole is a five-membered heterocyclic system with three carbon atoms and two
nitrogen atoms at the positions-! and -3. It is also named as 1,3-diazole. The
nitrogen atom at position-! bears a hydrogen atom and is regarded as pyrrole-type
nitrogen. The second nitrogen atom at position-3 is similar to that in pyridine and
is regarded as pyridine-type nitrogen.
, . - - - pyridine-type nitrogen
411~
5~ )2
N1
H ~ pyrrole-type nitrogen
4
Imidazole 4 exists in three partially reduced forms 7, 8 and 9 and designated as

follows depending on the position of double bond. The completely reduced form
of imidazole is known as irnidazolidine 10.
C) C) (N C)
N N)
H H H H
2-Irnidazoline 3-Irnidazoline 4-Irnidazoline Irnidazolidine
7 8 9 10
The fusion of a benzene ring to the 4,5-positions of an imidazole ring results in

benzimidazole 11 and is numbered as follows :
Imidazole nucleus is present in a number of important naturally occurring

products, as amino acid e.g. histidine 12 (involved in the biochemical reactions of
living systems) and purine 13 (forming bases of nucleic acid). The reduced form
H N
t-r-1
N-'Y NH 2
Histidine Adenosine-base
12 13
of the imidazole ring is also present in naturally occurring biotin (vitamin H) 14.
HNANH
t)_(CH,)4COOH
s
Biotin (Vitamin H)
14
Moreover, imidazole nucleus is also present in the pharmacologically important

drugs, some of which with their activities are given as below :
Azomycin
antibiotic
(2-Nitroimidazole)
Matronidazole anticancer
[ 1-(2-Hydorxyethyl)-2- (radiosensitizer in
methyl-5-nitroimidazole] radiotherapy)
Clotrimazole anticancer
2.1.2 Synthesis
2.1.2.1 Reaction of a -Hydroxy- or a-Halo Ketones with Amidines
The reaction of a-hydroxy- or a-halo ketones with amidines (R=CH 3 , C6H 5) results
in imidazoles with the formation of I ,5- and 3,4-bonds (scheme-7) 5 .
1~
R, ~0
c
I
c
+
H2N
I;
\
C-R ..
R2 ""'H'OH HN
(R = H,CH 3,C6H 5)
20 R1 R2
(==(
N~ ,.....NH
c
I
R
21
Scheme-7
If a -hydroxy- or a-halo ketones are treated with formadine (R = H), a mixture of

imidazoles 21 and oxazoles 23 is obtained. The ratio of the products depends on
a-hydroxy ketones; with aliphatic a-hydroxy ketones (acyloins) imidazoles are

produced preferentially, but with aromatic a-hydroxy ketones (benzoins), oxazoles
are predominantly obtained.
2.1.2.2 Reaction of a-Amino Ketones with Cyanates, Thiocyanates

or Isothiocyanates (Marckwald Synthesis)
The reaction of a-amino ketones with cyanates, thiocyanates or isothiocyanates

produces 3H-imidazoline-2-thiones (2-mercaptoimidazoles) 26 which can be
converted readily to the corresponding imidazoles by oxidation or dehydrogenation
(scheme-8). If a-amino ketones are treated with cyanamide in place of thiocyanate
or isothiocyanate, 2-aminoimidazoles are obtained2 .
24 25
R1 R~ R~ +-H20
'Ite-N\\ Rendy Ni
e-N
11 11 isomerization
e-NH
11 1
R2-e, /eH R2-e, /e, R2-e, /e~
N N SH N S
H H H
27 26b 26a
Scheme-8
2.1.2.3 Reaction of a-Diketones, a-Hydroxy-, a-Halo- or a-Amino

Ketones with Formamide (Formamide Synthesis)
The forrnamide synthesis is an extension of the earliest synthetic method which

involved the reaction of glyoxal, formaldehyde and ammonia (scheme-9). The
H, .:;:::.0
e
I
,.....e~
+ + o=e\
I
H
()N
H 0 H H
4
Scheme-9
modified synthesis involves the reaction of a-diketones, a-hydroxy-, a-halo- or

a-amino ketones with formamide . The reaction is considered to proceed as
depicted in (scheme-10) 6 .
R\, _.....OH R\, _.....OH

HCONH2 C
I'NHCHO
HCONH2 c
I 'NHCHO
c
R2 ........ H'X c
or {j R2 ,......H'NHCHO
1
R........._ ~o 28 29
c~
c
I (X= OH, halogen, NH 2) ~-H 2 0
R2 ....-H'X
R1 N R1. . . . ._ _.....NHCHO
R2
)C> N
-HCOOH c
II
c
R2 ....- 'NHCHO
31 30
Scheme-10
2.1.2.4 Reaction of Oxamide with Phosphorus Oxychloride (Wallach

Synthesis)
The reaction ofN,N'-disubstituted oxamide with phosphorus oxychloride produces

chlorine-containing intermediate 33 which on reduction with hydriodic acid affords
!-substituted imidazole 34 ( scheme-11) 1.
CONHCH3
Cl,
c~
~N-CH3
I + POC13 ---1•~ [ I ~
CONHCH3 C:-...
Cl "" "'N- CH3
32a
Cl
J[) N +
-H
I
CH3
34
Scheme-11
2.1.2.5 Reaction of Arylaldoximes with Propiolate Ester
The reaction of arylaldoximes with propiolate ester proceeds to involve cyclization

of amidine intermediate 36, obtained from Claisen rearrangement of the adduct
35, and provides imidazole-4-carboxylate 37 with the formation of 3,4-bond
(scheme-12) 2 .
0 0
NOH CH N,... ' HN ......V'CH
It Ill _ // ~~ I~ II
C6Hs-C + C ~ C6H5 Cl CH - . . C H -C /fCH
\ 1 I -....---- 6 5 .;:::.N
NH 2 COOR NH 2 COOR H 'cooR
35a
H OH
37 36
Scheme-12
2.1.2.6 Reaction of 1,2-Diaminoalkanes with Carboxylic Acids and

Aldehydes or Ketones
When 1,2-diaminoalkanes are treated with carboxylic acids and aldehydes or

ketones at high temperature in the presence of dehydrogenating agent (Pt/Al 20 3),
2-alkylimidazoles are obtained (scheme-13).
0
400"C 'cH-N,, -HzO -):-NH
+
~
I
C-R .. I
CH
C-R
I
.. )>_
HO / ' OH h R
NH2 Pt/A~0 3 / N
): ~
38
r NH
39
N
)-_R
40
Scheme-13
2.1.2. 7 Ring Transformation (From Oxazoles)
Oxazoles undergo ring transformation when treated with ammonia, formamide,

hydrazine or amine in the presence of a Bronsted acid. The reaction is considered
to proceed as follows (scheme-14 )5 :
Scheme-14
2.1.2.8 Ring Contraction (From Pyrazines)
2-Chloropyrazine 47 undergoes ring contraction to imidazole if treated with

potassium amide in liquid ammonia. The reaction proceeds to involve the following
mechanisrn(scherne-15) 3 :
47
f) N
...-HCN
H
4 50
Scheme-15
2.1.3 Structure
Imidazole is a planar molecule with the following structural parameters (Fig. 13) :
Bond lengths (A) Bond angles e>
N 1-C2 1.349 UN C2-N 1-C5 107.20
Cz-N3
N3-C4
1.326
1.378
~ ..N ) NI-C2-N3
Cz-N3-C4
111.30
105.40
1.358 H 109.8
CcCs N3-CcCs
C 5-N 1 1.369 CcC5-N 1 106.30
Fig. 13. Structural parameters in imidazole
The structure of imidazole is with the combined structural features of both pyrrole
and pyridine. The aromatic sextet is contributed by one electron each from three
carbon atoms and the pyridine-type nitrogen but two electrons are contributed by
the pyrrole-type nitrogen. Imidazole is an aromatic heterocycle with resonance
energy of 59 kJ/mol and is considered to be resonance hybrid of the following
resonating structures (Fig. 14). The dipolar resonating structures indicate
- -
[)
N
(:) ~[)+
N N
H H H
(i)
- c.)
(i~
N
N
(~
H
(\i)
Fig. 14. Resonating structures of imidazole
the amphoteric nature of imidazole. The resonating structure (iv) contributes much
more to the resonance hybrid as the negative charge is more stabilized on the
nitrogen than on the carbon. The resonating structure (v) is also important as the
positive charge on C-2 is stabilized by the negative charge on the nitrogen-3 with
the reduction in electron availability at the position-2 due to the electron-
withdrawing effect of both the nitrogen atoms.
2.1.3.1 Hydrogen Bonding
The boiling point of imidazole (b.p. 256°C} is relatively higher as compared to

boiling points of other five-membered heterocyclic systems. The higher boiling
point of imidazole is attributed probably to the intermolecular hydrogen bonding
of the type N-H-···N (Fig. 15). But the hydrogen bonding is not possible if the
position- I of imidazole is substituted. N-Substituted imidazoles, therefore, have
much lower boiling points ( 1-methylimidazole; b.p. 198°C).
---H-N
F\
V
N---H-N
I
v
\
N---H-N
I
v
\
N---- [)
N
I
CH 3
(b.p. 19SOC)
Fig. 15. Hydrogen bonding in imidazole
2.1.3.2 Tautomerism
Imidazole exists into two identical tautomers with the rapid exchange of proton
between two annular nitrogens (-NH- and =N-) (Fig. 16). But asymmetrical
[) N
//NH
~)
N
(identical)
Fig. 16. Tautomerism in imidazole
imidazole exists in two distinct tautomeric forms which cannot be separated as the
interconversion occurs readily with the rapid proton transfer, although two
tautomers may exist predominantly in one form (Fig. 17). Thus with the existing
tautomerism in asymmetrical imidazoles, the numbering becomes complicated. In
such compounds the position of atom to which substituent is attached is indicated
by two numbers to avoid confusion. This tautomerism is not possible with
N-substituted imidazoles.
== H3C
~>-----.. 4(5)-Methylimidazole
N
H
4-Methylimidazole 5-Methylimidazole
Fig. 17. Tautomerism in asymmetrical imidazole
2.1.4 Reactions
2.1.4.1 Reactivity
Imidazole is considered to exhibit properties of pyrrole as well as of pyridine

because of the presence of pyrrole-type and pyridine-type nitrogens in the
imidazole ring system (Fig. 18). The reactivity of imidazole can be inferred from the
pyrrole-P and
pyridine-a
r~: •
basic
pyrrole-a and ----.~ i(_ / -.--- pyrrole-a and pyridine-a
pyridine-P N acidic
H
Fig. 18
structural specificity of the imidazole nucleus relating to the pyrrole-type nitrogen

and pyridine-type nitrogen and from the resonating structures contributing
maximum to the imidazole nucleus (refers to Fig. 14) :
(i) electrophilic attack occurs at N-3 (pyridine-type) but not at N-1 (pyrrole-
type) because the lone pair on pyrrole-type nitrogen is involved in the
aromatic sextet.
(ii) the attack of electrophile also occurs at the annular carbon atoms (C-4 and
C-5).
(iii) the attack of nucleophile takes place at C-2 or N-1.
(iv) amphoteric nature of imidazole.
Imidazolium ion, involving quatemization of pyridine-type nitrogen, loses its

basic character and becomes less susceptible towards electrophilic substitutions,
but the nucleophilic substitution at C-2 is facilitated. Thus the electrophilic substit-
utions in acid medium involve imidazolium ion and therefore occur with difficulty.
2.1.4.2.1 Electrophilic Attack at Nirtogen
Imidazole contains two nitrogen atoms; pyrrole-type nitrogen and pyridine-type

nitrogen, but the attack of electrophile occurs at pyridine-type nirtogen containing
lone pair in the plane of the ring (orthogonal to the plane of n-molecular orbital)
because the attack of electrophilic at pyrrole-type nitrogen disrupts the aromaticity
with the use oflone pair involved in aromatic sextet (Fig. 19). If the attacking elect-
rophile is a proton, there will be simply a tautomeric interconversion (scheme-16).
r>
E
I
+ //N
N
+E zN)
I
H
Fig. 19. Electrophilic attack in imidazole
r):N
+H
+
-- - rr
+tH
-H
+
gNH
zN)
I ~)-
H H
Scheme-16
2.1.4.2.1.1 Protonation (Basicity)
Imidazole is the most basic (pKa = 7 .0) among I ,3-azoles; oxazole (pKa = 0.8) and
thiazole (pKa = 2.5), and forms salts with acids. Imidazole is a stronger base even
than pyridine (pKa = 5.2). The abnormally high basicity of imidazole is attributed
to the relatively low electronegativity of nitrogen and the symmetrical structure of
the imidazolium cation which is resonance stabilized (scheme-17). Thus with this
property imidazole at physiological pH (7.4) exists in both the forms; free base and
imidazolium cation, and causes histidine (unit of protein containing imidazole) to
act as a proton acceptor or a proton donor depending upon the enviomrnent.
+/
H /
H
H
+ l[r{)~ . . . . . . [)
N N
H H
pka=7.0
Scheme-17
2.1.4.2.1.2 N-Alkylation
Imidazoles substituted at N-1 are alkylated readily at N-3 with the formation of
quaternary salts (scheme-18). But the alkylation of imidazole (with free-NH group)
+ 1 CH3 1 CH3 1 CH3
() N
() N
~ [ ) - (?;
N N X
I I I I
CH3 CH3 CH3 CH3
51 52 a 52b 52
Scheme-18
produces protonated N-alkylimidazole which can be deprotonated by a base

(imidazole) to provide N-alkylimidazole ( scheme-19).
r> N
H
CHrX
53b 53
()
4 53 a
N
I
CH 3
51
Scheme-19
2.1.4.2.1.3 N-Acylation
Imidazoles with free NH group can be N-acylated by the reaction with acid chloride
(2 : 1 ratio) in an inert solvent at room temperature with the formation of N-
acylimidazoles 55 via N-3 acylimidazolium cation 54 (scheme-20).
COR
() ()
I
0. +
II -H
+R-e-x~ ~
N N
H
4 54 a 54b 55
Scheme-20
The reactivity of N-acylimidazoles is comparable with that of acyl halides and

acid anhydrides and are used as 'acyl transfer' reagents in certain biological
processes. These are easily hydrolyzed in water (pH = 7.0) at 25°C as the amide
stabilization is much less effective through the nitrogen lone pair because of its
involvement in an aromatic sextet.
Imidazole is an excellent nucleophile and catalyzes hydrolysis of ester or acid
derivatives (scheme-21 ).
~D
c-o
N:----. ---- +//bR'
( ) ~ -OR'
( ) +R-C-OR'
N
H
(II
0
--- N
H
1~ -H+
COR
. ()
/
RCOOH +
N
Scheme-21
The reactions at the carbon atoms in imidazole ring are expected to be similar to
those in aromatic heterocycle which is less reactive than pyrrole and more reactive
than pyridine towards electrophiles. Since the carbon atoms are less susceptible
to electrophilic attack than the pyridine-type nitrogenin imidazole, the electrophilic
substitutions resulting in C-substitution are, therefore, considered to proceed via
an initial N-substitution involving an addition-elimination mechanism.
However, the reactivity of imidazole towards electrophiles varies with the
reaction conditions. The reactions under acidic conditions involve imidazolium
cation which exhibits deactivating effect towards electrophilic attack and therefore
the attack of electrophile occurs with difficulty. But the attack of eletrophile is
facilitated if the reaction involves an imidazole anion or neutral imidazole.
2.1.4.2.2.1 Orientation
In imidazole ring system the attack of electrophile occurs preferentially at C-5

which is the most activated position for the electrophilic attack as predicted in
terms of the pyrrole-a-reactivity and pyridine-(3-reactivity (Fig. 20). However, the
tautomerism in imidazole makes C-4 and C-5 positions equivalent. The preferential
attack of electrophile at C-5 (or C-4 being tautomerically equivalent) in imidazole
pyridine-a
deactivated [ \ 4 3
pyrrole-P __..UN
pyridine-(3 ~ 5~ )\ 2 ~ pyridine-a ]
activated
[
_) ~1 \_ deactivated
Pyrrole-a
pyrrole-a
Fig. 20. Orientation effect of nitrogen atoms in imidazole
can be explained in terms of the relative stabilities of the a-complexes

(intermediates) resulting from the electrophilic attack at the positions-2, -4 and
-5 (Fig. 21 ). The electrophilic substitution at the position-2 is unfavourable because
the intermediate resulting from the electrophilic attack at the position-2 involves
highly unfavoured and less contributing resonating structure (i) with positive
charge at N-3.
atC-2 rl(_ N\/H~+ eNX ..... ~+x

/--E
FN
N
H
E N
H
E
~ H H
(i) (ii) (iii) ~
(less contributing)
N H
atCA Et-) -EHtJ EHt )

(highly unfavoured) \/
/--E
[)
N
t H
N N N N
H H H H
(i)
(ii)
Fig. 21. Electrophilic attack at different positions in imidazole
Imidazole is nitrated with a mixture of concentrated nitric and sulfuric acids at

160°C with the formation of 4-nitroimidazole. The reaction proceeds to involve the
attack of electrophile (nitronium ion) at the position-4 of the imidazolium cation
(imidazole conjugate acid) (scheme-22).
Scheme-22
When imidazole is treated with 50-60% oleum (H 2SOcS0 3) at 160°C, the

sulfonation occurs at the position-4 involving the attack of electrophile on the
imidazolium cation (scheme-23).
H0 S'rN
f)
3
H2S04+S03
~ )\
N 16<J'C N
H H
57
Scheme-23
Imidazole is brominated very readily by bromine in aqueous solution or organic

solvent with the bromination at the available vacant nuclear positions providing
2,4,5-tribromoimidazole (scheme-24). In contrast to the resistance of nitration or
Br\-N
f) N
Br_J(N)\_Br
H H
Scheme-24
sulfonation at position-2, the bromination at position-2 in imidazole is an

interesting feature of this reaction. The reason of entering bromine at the
position-2 can be explained by the bromination of 1,4,5-trimethylimidazole 59 with
bromine in carbon disulphide involving an addition-elimination mechanism with
the formation of 2-bromo derivative 60 (scheme-25).
The reaction proceeds via an initial N-bromination followed by nucleophilic
attack of bromide ion at C-2 and subsequent elimination of hydrogen bromide.
Thus nucleophilic attack of bromide ion at C-2 facilitates the bromination in
imidazole at the position-2 (scheme-25). Moreover, such a hypothesis is supported
by the reaction of imidazole with cyanogen bromide in which 2-bromoimidazole 61
is obtained with the elimination of hydrogen cyanide (scheme-26).
Scheme-25
![)N
BICN
![)_N Br
H H
61
Scheme-26
Imidazole is iodinated only under alkaline conditions and produces 2,4,5-

triiodoimidazole 62 involving an imidazolyl anion as the reactive species. The
reaction proceeds to involve the attack of molecular iodine at the position-4 of
imidazolyl anion ( scheme-27).
2.1.4.2.2.5 Acylation
Imidazole does not undergo Friedel-Crafts reactions as it is markedly deactivated

in the presence of Lewis acids. However, !-substituted imidazoles undergo
C-acylation or C-aroylation when treated with acyl- or aroyl halide in the presence
of triethylamine ( scheme-28) 2 . The reaction mechanism is proposed to involve an
initial N-acylation or N-aroylation followed by C-2 deprotonation of imidazolium
cation and intramolecular rearrangement. The presence of electron-withdrawing

substituent at C-4 of the imidazole ring does not allow the reaction to occur
because it restricts an initial N-acylation.
,)-)__-[It)
N I N
H -
62
Scheme-27
COR 1 COR 1 COR 1
() /~- ()-= f:)___ -

+I I I
N ArCOCl N H N H
c~H N _
co:J
I I I I 0
R R R R
N
~Q
N- 7 f:{
1
(C2HshN
(~
N COR
~fJYc'R1~()-
N N
-
HO
I I I
R R R
Scheme-28
N-Unsubstituted imidazoles substituted with activating substituents (electron-

releasing) undergo diazo coupling readily in alkaline medium preferentially at the
position-2 (scheme-29). The reaction preceeds to involve the coupling of
diazonium ion with an anion of N-unsubstituted imidazole at the position-2. The
presence of electron-releasing substituents on the imidazole ring facilitates diazo
coupling, while the electron-withdrawing substituents deactivate the imidazole ring

towards electrophilic attack of the diazonium ion to a greater or lesser extent.
N-Substituted imidazoles fail to undergo diazo coupling as the involvement of an
imidazole anion is not possible in the reaction.
()
R
+
Ar-N=N
pH 7-11
N
H
Scheme-29
2.1.4.2.2. 7 Reactions with Aldehydes and Ketones
N-Unsubstituted imidazoles undergo hydroxymethylation at the position-4

(or C-5) when treated with formaldehyde in the presence of DMSO (scheme-30).
()
N
HCHO
DMSO
H
Scheme-30
However, with N-substituted imidazole hydroxymethylation occurs at the

positon-2 (Scheme-31 ). The reaction preceeds with the electrophilic attack initially
intramolecular
rearrangement
()_H_CH~~
N
.. (I ,2-rnigration)
I
CH3
51
Scheme-31
at the positon-3 (N-hydroxymethylation) followed by C-2 deprotonation and

intramolecular rearrangement ( 1,2-rnigration).
2.1.4.2.2.8 Oxidation
Imidazole ring is resistant to oxidation, but it is degraded by hydrogen peroxide

and perbenzoic acid (scheme-32).
CONH2
I
[J/
CONH2
N
H ""'~ C6 H5 -C-O-OH
II
'---------~--~ NH3 + NH2CONH 2
Scheme-32
Photosensitized oxidation of imidazole with singlet oxygen produces irnidazolidone

68 via a cyclic peroxide 67a (scheme-33).
67a 67b 68
Scheme-33
2.1.4.3.1 Nucleophilic Attack at Carbon
Imidazoles undergo nucleophilic substitution reactions very readily with the

nucleophilic attack at the position-2, if substituted with electron-withdrawing
substituents or quaternized. However, the position of electron-withdrawing
substituent can modify the site of nucleophilic attack.
2-Haloimidazoles undergo nucleophilic substitution reactions with the replacement

of halogen by nucleophiles. The halogen atoms at the 4- and 5- positions of
imidazoles are normally unreactive but activated by the a- or y- electron-
withdrawing substituent (scheme-34). However, in some cases nucleophilic attack
results in the cleavage of the ring (scheme-35).
N
[)_ Br + RNH2 .. fN
N)-NHR
I I
CH3 CH3
HsC6 69
HsC"):-N 70
H5C6
):)_
N Br
+ HN8 HC¥~)-_N8
5 6
I
CH3 CH3
72
02N 71
):)
02N
Cl N
+ KCN ... NC
)[) N
I I
CH3 CH 3
73 74
Scheme-34
COC5H5 /COC5H5
[)
+I
C6H5COCI [)~ OH ~N
(/ H
N
H OH
N
I
N~H
I
COC5H5 COC5H5
75 76
NHCOCsH 5 HC/NHCOCsH5
/
HC OH
II II
HC HC, ,...CHO
'NHCOCsH 5 N
78 77
'
COC5H 5
Scheme-35
2.1.4.3.2 Nucleophilic Attack at Hydrogen (Deprotonation)
2.1.4.3.2.1 Deprotonation ofNH (Acidity)
Imidazole is a very weak acid (pKa = 14.90), but stronger than pyrrole (pKa = 17.5).
The acidic character of imidazole is attributed to the enhanced de localization in the
symmetric imidazolyl anion resulting from the deprotonation of NH by a strong
base (scheme-36).
f)
N
H
(i) (ii)
resonating structures of imidazolyl anion
Scheme-36
2.1.4.3.2.2 Deprotonation ofCarbon-2
Hydrogen atom attached to C-2 of imidazole, and particularly imidazolium ion, is

acidic and can be abstracted as a proton by a base with the generation of
imidazolium ylide 79. The mechanism involves initially N-3 protonation followed
by C2 -H deprotonation (scheme-37). The characteristic of imidazole ring with
H H H
f)_
I
[)_
+I /
~ == f~;_
N H N H N ~
H H H -
OCH3
f~-N
__jI
H
H
79
Scheme-37
which C2-H is deprotonated by a base forming imidazolium ylide 79 causes

imidazoles to undergo reactions at C-2 as depicted in (schemes-38 and 39) .
2.1.4.3.2.2.1 H ~ D Exchange
Base-catalyzed H ~ D exchange in imidazole is fast at the position-2, while very

slow at the positions-4 and -5. However, the rate of exchange falls off at the
position-! because of the formation of unreactive anion. 1,3-Dimethylimidazolium
cation 80 is deuterated at the position-2 via the ylide intermediate 81 (scheme-38).
+1 CH3 +1 CH3
r>- N
I
H
r)-
N
I
CH3 X CH3
80 81
Scheme-38
2.1.4.3.2.2.2 Metallation
N-Substituted imidazoles· are lithiated preferentially at the position-2 with the

deprotonation of C2-H when treated with n-butyllithium and results in 2-
lithioimidazoles 83 which can be used to synthesize a number of imidazole
derivatives (scheme-39).
R'X
... r>-R.
N
I
I
R
r>-
84
N H
+ n-Buli ~r)- N
li+
COz
H 20
... rN
N~COOH
I I I
R R R
85
I DMF
... rN
N~CHO
I
R
86
Scheme-39
2.1.4.3.2.2.3 C-Acylation via Deprotonation
N-Substituted imidazoles can be acylated at the position-2 when treated with acid
chloride in the presence of triethylamine. The reaction proceeds to involve an
initial N-acylation followed by deprotonation of C 2-H and 1,2-shift of the acyl
group (scheme-40).
+/COC 6 H5 f\coc 6 H5
t:)N
+ C6 H5COCI ~ t:Yl.
N H
(C2HshN
-HO
f:)-
N
I I I
R R R
f:~ .. (1,2-shift) 1
N COC 6 H5
I
R
Scheme-40
The reaction of imidazole with chloroform at 550°C results in the formation of

5-chloropyrimidine 90 as the major product. However, with 2-methylimidazole,
4-chloropyrimidine 91 and 2-chloropyrazine 92 are also obtained (scheme-41). The
formation of these products can be explained if reaction is considered to proceed
with the insertion of carbene into either C-C or C-N bond.
Cl
fA N
N
R
+ CHCI3 550"C..
CIL
~
Jr +,A ~NxCI
l J+ ( I
H N N R N R
90 91 92
R=H
9 0
R= CH 3
11 8
Scheme-41
2.1.4.5 Reactions with Dienophiles
The reaction of imidazole with DMAD results in N-alkylation with the formation
of 93 instead of providing a cycloaddition product (scheme-42).
CH3CN ()
N
I
c~
CH 3 00C"' "'CH- COOCH 3
93
Scheme-42
However, I ,2-dimethylimidazole with DMAD affords a cycloaddition product 95

involving nucleophilic addition to dienophile (DMAD) with the initial formation of
N-3 quaternary salt 94 which is subsequently cyclized by nucleophilic addition at
C-2 (scheme-43) 7•8 .
E E
\ I
(r;_c:,
C=C
E-c=c-E
(E = COOCH 3)
I
CH 3
E E
\ I 94
C=C
...
I \
N C-E
( ~c'~E E-c=c-E
N CH3
I
CH 3
95
Scheme-43
2.1.4.6 Photochemical Cycloaddition Reactions
Photochemical reaction of imidazoles, substituted with electron-releasing

substituents at 1- and/or 2- positions, with acetone leads to the formation of
a-hydroxyalkylimidazoles 98. The reaction is considered to involve the attack of
excited carbonyl oxygen at C-5 rather than at C-4 because C-5 is more reactive and
the radical intermediate at C-5 is more stable than that at C-4. The reaction
proceeds as depicted in (scheme-44).
Scheme-44
However, benzophenone reacts differently with 1,2-dimethylimidazole and the

reaction proceeds with the addition of benzophenone at 2-methyl group
(scheme-45). But this reaction is very sensitive to the substituents as with
1-acetylimidazole addition of benzophenone occurs across the CrC 5 bond with
the formation of oxetane ring (scheme-46).
(N (N OH
(C 6 H 5)zCO )\_ I_....C 6H5
N)\_CH3 N CH2-c,
I hv I C6H5
benzene
CH 3 CH 3
99
Scheme-45
H5C5 H
() N
(C 6H5) 2CO
hv
HsCs~)
H N
I
I benzene
COCH3 COCH3
100
Scheme-46
2.2 Oxazoles 9- 14
2.2.1 General
Oxazole is considered to be derived from furan by the replacement of -CH=

(methine group) from the position-3 by the azomethine nitrogen (-N=). Oxazole ring
system is numbered as follows :
The chemistry of oxazoles began in 1876 with the synthesis of 2-methyloxazole,

although parent oxazole 5 was synthesized in 1947 and 1962. The interest in the
chemistry of oxazole was developed during the world war when penicillin was
considered to contain the oxazole ring system, but the discovery of oxazoles as
dienes in Diels-Alder reaction and in 1,3-dipolar cycloaddition reactions of meso-
ionic heterocycles gave impetus to the development of oxazole chemistry. 2,5-
Diaryloxazoles are used as fluorescent whitening agents because of their
scintillating properties.
The fusion of benzene ring to the 4,5-positions of the oxazole ring results in
benzoxazole 101 and numbered as follows :
Two partially saturated oxazoles with different position of double bond are
possible and are named as; 4,5-dihydro- 102 and 2,5-dihydro- 103 oxazoles. Fully
saturated oxazole is named as oxazolidine 104.
C) 0
102
()103 104
2.2.2 Synthesis
2.2.2.1 Cyclodehydration of a-Acylamino Ketones (Robinson-

Gabriel Synthesis)
It involves cyclodehydration of a-acylamino ketones in the presence of dehy-

drating agents such as H 2 S04 , PC15 , POC1 3 and SOC12 However, polyphosphoric
acid, phosgene or anhydrous hydrogen fluoride have also recently been used to
facilitate the cyclization. The reaction proceeds via an intermediate 106 with the
formation of C5-0 bond and demonstrated by 18 0 labelling that the oxygen atom
of the oxazole ring is derived from that of the acyl group (scheme-47) 15 •
H RC-N~
I J~J
c c
R.....- \\ c:;:-tt '
0 0 R
105
108
Scheme-47
2.2.2.2 Reaction of a-Halo Ketones with Primary Amides (Bliimlein-

Lewy Synthesis)
The condensation of a-halo ketones with primary amides leads to the formation
of oxazoles. This method is suitable for the oxazoles containing one or more aryl
groups (scheme-48). However, with the use of formamide (R=H), 2-unsubstituted
oxazoles are obtained. This method can also be extended to synthesize
2-aminooxazoles involving the use of urea and its derivatives or cyanamide 16 .
2.2.2.3 Reaction of a-Hydroxyamino Ketones with Aldehydes
The reaction of a-hydroxyamino ketones 112 with aldehydes in the presence of

sulfuric acid and acetic anhydride provides oxazoles in which C-2 atom comes form
aldehyde (scheme-49).
2\"
+ .. R, 'lo +
('14.C
H'- -1
NH2
II
---;c, ,.....c,
R1 0 R +
R2 109 -H
)----~ cyclization
R1,.....l(O~R
111
Scheme-48
115 114
Scheme-49
2.2.2.4 Reaction of Tosylmethyl Isocyanide with Aldehydes
The reaction of tosylmethyl isocyanide with aldehydes in the presence of

potassium carbonate results in the formation of 5-alkyl or 5-aryl-oxazoles 119 with
the elimination of toluene-p-sulfinic acid involving dihydrooxazole intermediate
118. The reaction proceeds with the nucleophilic addition of tosylmethyl isocy-
anide to aldehyde followed by cyclization and facile aromatization (scheme-50) 17 .
2.2.2.5 Reaction of a-Metallated lsocyanides with Acid Derivatives
The reaction of a-metallated isocyanide 120, obtained by treating isocyanides with

n-butyllithium or potassium tert-butoxide, with carboxylic acid derivatives; acyl
chlorides, esters or arnides, affords oxazoles 122. The reaction preceeds via
keto isocyanide intermediate 121 as depicted in (scheme-51).
+
-H - + -
Tos -CH 2-NC---.Tos -CH-N=c
TosiJ..~
£)
C-N
-TosH H ~/ \\
; c , ,....cH
R 0 R 0
119 118
Scheme-50
1 ~0 R
\ +
n-Buli + -
R -c......
X
HC-N ,,,
RCH2NC • RCH-N=c
-
I
1/c,, c
li+ -X R 0
120 121
R
',,C-N) R\
C-N
+ J~
R1-c,
• d' ~'c
0 R1/ \·~
OH
122
Scheme-51
2.2.2.6 Ring Transformations
2.2.2.6.1 From C-Acylaziridines
C-Acylaziridines 123 undergo thermal rearrangement at 220°C and provide

oxazoles 126 via azomethine ylides 124 involving 1 5, -dipolar cyclization
(scheme-52) 12 .
22CfC
-(CH3)3CH
Scheme-52
2.2.2.6.2 From Isoxazoles (Isomerization)
Isoxazoles are isomerized to oxazoles on flash vaccum pyrolysis (scheme-53).
kJc 6 H5
Ll
.. c . . . ~
H ~CaHs
or
H
~NII
/\.)
CoJc,CaHs
N ,......c~
HsCs ~N H
5 6
c~
0 HsCs
127 128 129
HsCa
_(N •o~C6H5
130
Scheme-53
2.2.3 Structure
The oxazole ring is planar with considerable bond fixation as indicated by the bond
lengths in oxazole (with appreciable difference in C2- N and CcN bonds). Oxazole
although possesses a sextet of n-electrons but the complete delocalization is
restricted due to the presence of electronegative oxygen atom and upto some
extent the nitrogen atom. The aromaticity order has been observed to be similar
as in the five-membered heterocycles with one heteroatom : thiophene > pyrrole

> furan. Oxazole is the least aromatic among the 1,3-azoles and exhibits diene-type
character.
Oxazole molecule is considered as the resonance hybrid of the following
resonating structures (the predominance of inductively electron-withdrawing effect
Bond lengths (A) Bond angles ( 0 )
C2-0 1.357 C2-0-Cs 103.9

~-N
CcN
CcCs
1.293
1.395
1.353
() 0
O-C2-N
C2-N- C4
N-CcC5
115.0
103.9
109.7
Cs-0 1.370 CcC5-0 108.1
Fig. 22. Structural parameters in oxazole
of the electronegative oxygen over its mesomerically electron-releasing effect,

however, restricts the complete delocalization upto some extent) (Fig. 23).
Molecular orbital methods have predicated C-4 being with highest net charge,
while C-2 with lowest net charge.
() 0
C)~-C)
0 0
(i) (iii) (i~
Fig. 23. Resonating structures of oxazole
2.2.4 Reactions
2.2.4.1 Reactivity
Oxazole contains pyridine-type nitrogen at the position-3 and furan-type oxygen

at the position-1. Oxazole is, therefore, considered as the hybrid of both the
heterocyclic systems and exhibits characteristic properties associated with (i)
pyridine- type nitrogen; protonation, N-alkylation and the reactivity of halogen
atom at the position-2 and (ii) furan-type oxygen; diene-type characteristics due
to bond localization.
2.2.4.2.1 Electrophilic Attack at Nitrogen
2.2.4.2.1.1 Protonation (Basicity)
Oxazole (colourless liquid, b.p. = 69-70°C) is very weak base with pKa = 0.8 ± 0.2
as it forms unstable salts (hydrochlorides and picrates). The weakly basic nature
of oxazole is attributed to the balancing effect of the two structural effects
operating in the opposite directions due to the presence of electronegative oxygen
atom (Fig. 24) : (i) strong inductively electron-withdrawing effect (base-weakening
effect) and (ii) weak mesomerically electron-releasing effect.
..
inductive effect mesomeric effect
(strong) (weak)
Fig. 24. Structural effects in oxazole
Oxazoles form quaternary salts, N-alkyloxazolium salts 131, with alkylating agents.
In alkyloxazolium salts 131, the acidic hydrogen at C-2 can undergo H ~ D
exchange easily via the heterocyclic ylides 132 generated as the intermediates
during the process.
J)_
R1 R R1 R
R2
Ji 0
131
H X R2 0
132
quaternary salt ylide
The oxazole ring does not undergo electrophilic substitutions easily unless the
oxazole ring is substituted with electron-releasing substituents. The reduced
reactivity of the oxazole ring towards electrophiles is attributed to its electron
deficiency caused by effective inductively electron-withdrawal effect of both the
electronegative heteroatoms. The coupled electron-withdrawal effect of both the
heteroatoms; oxygen and nitrogen, affects position-2 most strongly. However, the
positions-4 and -5 are also affected by the electron-withdrawal effect of nitrogen
and oxygen respectively, but the mesomerically electron-releasing effect of oxygen
makes position-4 comparatively electron rich and therefore susceptible to
electrophilic attack. The order of susceptibility of the carbon atoms of the oxazole
ring towards electrophilic attack is as : C-4 > C-5 > C-2. Molecular orbital
approximations have also predicted the higher electron density in oxazole ring at
C-4 than at C-5 and lowest at C-2 and supported the theoretical predictions
(Fig. 25).
deactivated by
nitro~en
most strongly
and
deactivated
activated by
oxygen
deactivated by
predominating
inductive
effect of oxygen
and
activated by mesomeric
effect of oxygen
Fig. 25. Effects of heteroatoms in oxazole ring
Electrophilic substitutions carried out under acidic conditions (nitration,

sulfonation and chlorosulfonation) do not occur in the oxazole ring because of the
involvement of highly electron-deficient oxazolium cation.
Bromination of 2-methyl-4-phenyloxazole 133 with bromine or NBS takes place at

the position-S providing 5-bromo derivative 134. If position-S is already
substituted, bromination occurs at the position-4 (scheme-54).
HsC6
tNOACH3
Br2
or
NBS
HsC6
Br
)[NO~CH3
133 134
Br
HsC6
)[_~
0 CH 3
Br 2
HsC6
)[_~ 0 CH 3
135 136
Scheme-54
2.2.4.2.2.2 Mercuration
Mercuration of oxazole with mercury (II) acetate in acetic acid occurs at C-4 or
C-5 depending upon the available unsubstituted position. If both the positions-
4 and -5 are substituted, mercuration occurs at the position-2 (scheme-55).
HsC6
+ Hg
.,OCOCH3
CHjCXJOH J:~
'ococH3 H5 C6 0 HgOCOCH 3
138
Scheme-55
2.2.4.2.2.3 Vilsmeier-Haack Formylation
Vilsmeier-Haack formylation of 5-methyl-2-phenyloxazole 139 with dimethyl

formamide (DMF) and phosphorus oxychloride occurs at the position-4
(scheme-56).
OHC
H3C
)[_~
0 C5H5
DMF
POC13 H3C
)[_~ 0 C5H5
139 140
Scheme-56
The oxazole ring is electron-deficient with lowest electron density at the position-
2. The attack of nucleophiles, therefore, occurs readily at the position-2 (C-2),
however electron-withdrawing substituent at C-4 facilitates nucleophilic attack on
the oxazole ring.
Oxazoles when treated with ammonia or formarnide at 200°C involve the attack
of nucleophile at the position-2 and transformed into imidazoles via the cleavage
of the oxazole ring (scheme-57).
Scheme-57
The presence of electron-withdrawing substituents facilitates the attack of

nucleophiles with the cleavage of the oxazole ring (scheme-58).
t \\'
OHC OHC H H
OHC+N~
0/
N/ OH
..~tfJ.
X __..
.. 0 \
H
OH
OHC+N,,
HC
,, I
CH ____,. HC
,, I;
CH
\,_..) 0 OH 0 0
146 147 148 149
Scheme-58
The halogen atoms attached to the carbon atoms of the oxazole ring can be
replaced by nucleophiles with the following reactivity order:
C2-halogen >> Cchalogen > C5-halogen.
Thus, the halogen atom attached at C-2 of the oxazole ring is easily replaced by
nucleophiles (scheme-59). The reactivity of halogen atom at C-2 is considerably
enhanced by quatemization.
ex 0
150
Cl
+RNH2 .. cX-3O
151
NHR
-a .. (
N
o~NHR
152
Scheme-59
2.2.4.3.2 Nucleophilic Attack at Hydrogen
Oxazole with unsubstituted 2-position can be deprotonated preferentially at the

position-2 by a strong base.
Oxazoles with unsubstituted 2-position are lithiated preferentially at C-2 because

of the acidity of hydrogen atom at C-2. The resulting 2-lithiooxazoles 154 are
unstable and remain in equilibrium with the open chain isocyanides 155
(scheme-60) 18 .
()
R R R + -
t~
)j-N=c
+ n-Buli __..
HC,
0 C\j L1 Oli
153 154 155
Scheme-60
The hydrogen atom at C-5 is less acidic, but the acidity is enhanced if C-4 is
substituted with an electron-withdrawing substitutent and the lithiation occurs at
C-5 even when the position-2 is unsubstituted (scheme-61) 19 .
()
ROOC
+ n-Buli
0
156 157
Scheme-61
2.2.4.3.2.2 H ~ D Exchange
The hydrogen at C-2 in oxazole is more acidic than that at C-5 and therefore
H ~ D exchange occurs preferentially at C-2 (scheme-62).
R R
H
)[~ 0 H
t~ 0 D
153 158 159
Scheme-62
The effect is enhanced in oxazolium ions because of the stability of ylide

intermediate 161 involved in the exchange process (scheme-63).
R R R
[~§: .......... C)-

+/ / /
![)_ 0 H
CH30D
0
- (~-
0
160 161 R
+/
![)_0 D
162
Scheme-63
2.2.4.4 Thermal Reactions (Cornforth Rearrangement)
Oxazole and its simple alkyl-and aryl derivatives are thermally stable upto 400°C.
But oxazoles containing a carbonyl substituent (aldehyde, ester, amide or acyl
chloride etc.) at the position-4 are rearranged on heating at 90-l20°C to isomeric
oxazoles in which the carbonyl substituent becomes a part of the oxazole ring. The
reaction is called as the Cornforth rearrangement and is considered to proceed via
a 1,5-diploar intermediate 164 (Scheme-64) 20 .
~0
R-C
~'r~/
R2 ~R1
163 164 165
R 1 = alkyl or aryl
R2 = OH, OR, or Cl
Scheme-64
Oxazoles undergo photochemical isomerization when irradiated in ethanol or in

benzene giving a mixture of photoisomers. The reaction proceeds to involve the
ring contraction-ring expansion mechanism and the electrocyclic mechanism
(scheme-65) 21 .
----
168 169 170
Scheme-65
Oxazoles exhibit diene-type characteristics and undergo Diels-Alder reaction with

alkenic and alkynic dienophiles involving interaction of the highly occupied
molecular orbital of the oxazole and the lowest unoccupied orbital of the
dienophile. The presence of electron-releasing substituents on the oxazole ring
facilitates the reactions with dienophiles (scheme-66).
R 1HC=CHR 1
•
I
RO
)[N0)
R
R1
R
172
R1
171
\ R2 c=cR 2
•
R2 R2
173
Scheme-66
The cycloadducts resulting from the cycloaddition of oxazoles with alkenic

dienophiles in certain cases can be isolated and characterized, but acid or base
catalyzed cleavage of the ether bridge in primary cycloadducts leads to pyridine
derivatives ( scheme-67). However, the reaction of oxazoles with alkynic dienophiles
}[>--R 1 r<o-
R 0
+
RO 0 ~ 0
174
HO-b
R
R~ ~
HOVR
N -HCN
!J ..
H
NC NC
153 177 178 179
Scheme-67
proceeds in different way and leads to the formation of furans with the elimination
of cyanide in the retro-Diels-Alder reaction (scheme-68) 9 •
E-c=c-E ___....
RO:&( R-C:ON
(E=COOCH 3)
E 180 E
Scheme-68
2.2.4. 7 Photooxygenation
Oxazoles react with singlet oxygen with the formation of a bicyclic adduct 183
involving addition of oxygen across the C-2 and C-5 positions. The bicyclic adduct
183 formed is subsequently decomposed in two ways depending on the solvent
(scheme-69t
ether /0,
R2-c=N + R1-C C-R 3
I~
II II
e
0 0
184
R2 I )oR2
)!:_o).-_
N -N
O~R1
02
R3 R1___..R3
o-o
182 183
I alcohol ..,
185 186
Scheme-69
2.3 Thiazoles 22 - 25
2.3.1 General
Thiazole ring system containing sulfur and nitrogen heteroatoms at the positions-
! and -3, respectively is involved in many of the natural products. The most
important naturally occuring thiazole derivative is thiamine (vitamin B 1) 187 which
contains both pyrimidine and thiazole ring systems. Penicillins 188 are also
important naturally occuring products and contain reduced thiazole ring system
(thiazolidine).
HOO<;.
H.+~~o
H3C/~c-);:-\' If H
H3C s H NHCOR
187 188
Thiamine (vitamin B 1) penicillin G (R = CH 2C6H 5)
Moreover, a number of thiazole derivatives exhibit pharmacological activities.

Some of them with their activity are as :
Sulfathiazole antibiotic
2-(4-Chlowphenyl) HOOC -CH,t>-o~ antiinflammatory

thiazol-4-ylacetic acid S ~ I
~ Cl
Thiabendazol
[2-( 4-Thiazolyl)benzirnidazole]
CX N>-rJ
N
anthelrninitic
and fungicide
H S
Niridazole schistosomicidal
[1-(5-Nitro-2-thiazolyl)-
2-imidazolidinone]
Because of the high thermal stability of the thiazole nucleus, the polymers
incorporating thiazole ring system have also been synthesized.
2.3.2 Synthesis
2.3.2.1 Synthesis of Thiazoles
2.3.2.1.1 Reaction of a-Halo Ketones with Thioamides (Hantzsch's Synthesis)
This is the most general method for the synthesis of thiazoles and involves the
cyclizative condensation of a-halo ketones with thioamides. The reaction proceeds
with the nucleophilic attack of sulfur atom of thioamide on the a-carbon atom of
a-halo ketone with the formation of a-thio ketone 189 which on transprotonation
and subsequent dehydration produces the corresponding thiazole (scheme-70).
R2
',,e-N,,
R1,......C, /C-R
s
191
Scheme-70
This method can be used to synthesize a number of thiazoles with the structural
modifications in the a-halo ketones and thioamides. Thiazole itself is obtained by
the condensation of chloroacetaldehyde with thioforrnamide (scheme-71 ). However,
2-aminothiazoles are synthesized by treating a-halo ketones with thiourea.
H, ~0
I
H2C,
c
Cl
+
c
s~ 'H
NH 2
I () s
6
Scheme-71
2.3.2.1.2 Reaction of a-Acylamino Ketones with Phosphorus Pentasulfide

(Gabriel Synthesis)
This method is similar to that of thiophene from 1,4-diketones and is used to

synthesize alkyl-, aryl- or alkoxy-thiazoles substituted at the 2- or 5- or 2,5-
positions involving treatment of a-acylamino ketones 192 with stoichiometric
amount of phosphorus pentasulfide (scheme-72).
R2
\
HC-NH
I \
R1 _.....
c\\ II '
c 3
17ff'C
0 0 R
192
R2
. :C-NH~ '~
c/I c
J'
(/R
R1,.... \H 3
195 194 193b
Scheme-72
2.3.2.1.3 From a-Aminonitriles (Cook- Heilborn's Synthesis)
The reaction of a-aminonitriles 196 with dithioacids or esters, carbon disulfide,

carbon oxysulfide and isothiocyanates under mild conditions results in the
formation of 5-aminothiazoles (scheme-73).
R1-yH-NH: HS'c-R2 _-_H..;.2s...._... [R'-~~H-~~'R' R'j~\, 2

]
C~N f/ N S UfNHSH R
196 197a 197b
R 1 = C 6H 5 , COOC2H 5
R 2 = H, CH 2 C6H 5
R1
+ S=C=S
',,C-N\\
H2N . . . c,s,....c . . . . R2
198
+ O=C=S
+ S=C=NR 2 ____...
201 202
Scheme-73
2.3.2.1.4 From a-Thiocyano Ketones (Tcherniac's Synthesis)
The acidic hydrolysis of a-thiocyano ketones or treatment with arnines or sulfur

compounds leads to the formation of 2-substituted thiazoles (scheme-74).
2.3.2.1.5 Reaction of a-Mercapto Ketones or a-Mercapto Acids with Nitriles
The reaction of a-mercapto ketones or acids with nitriles results in cyclization with
the formation of C-N and C-S bonds to provide thiazoles (scheme-75). If
a-mercapto ketones are condensed with cyanamide (R2=NH2), 2-aminothiazoles are
obtained.
tN
R, ~0 R, -:;::.0 R
c
I
H2C, ,.....C
s
/;;
N H+
H 20
C
H2t,
NH2
s
A 0
H+
-H 20
. s)-OH
203 204 205
t:l
0 R
II
CH3-C-SH CH3COOH
+
(R = C6H 5) S SH
206
tN
R
R, ~0 R, -:;::.0
c N
+ R1NH2____..
c NH .:1
...
I I;; I II
H2C, ,.....c H C C
2 's.....- 'NHR 1
HO
s)-NHR 1
s
(R = CH 3 ) (R 1 = CH 3) 207 208
Scheme-74
R\, ~0
C NH
I II
H2C, ,.....C, 2
S R
209 210
dry HCI
alcohol
214
Scheme-75
2.3.2.2 Synthesis of Benzothiazoles
2.3.2.2.1 Synthesis from o-Aminothiophenols (2-Aminobenzenethiols)
2-Aminobenzenethiols are oxygen sensitive and therefore used as acid salts,

alkaline salts, zinc salts or disulfides which generate free 2-aminobenzenthiols
under reducing conditions. 2-Aminobenzenethioles are appreciably reactive and
react with a number of compounds to produce benzothiazoles (schemes-76-78).
2.3.2.2.1.1 Reaction with Aldehydes
R-
(X
~
NH2
+
H or
-
OH
+
SH
217
(X N erN
I , /R
H
~ _ 2H ...- 1 eye 1izatlon
·
1
R- rR ....,_R- C
S S ~ 'H
221 220
Scheme-76
2.3.2.2.1.2 Reaction with 1,2-Diketones
R- cr NH2
SH
+
217
~N ICHJCOOH
R-~- S.,__C6 H5 ....,__j
223
Scheme-77
2.3.2.2.1.3 Reaction with Acids and Acid Derivatives
R-
(X NH2
+ ~c
Z
I
o::;.- ' 1
~ R- 0~
I ~c~---=o
~
~
'/
••
R1
SH R SH()
217 Z=OHORClNH 224 cyclization
' ' ' 2
R__eyN}-R' • -H,O R 0-~xR'

~s ~sOH
226 225
Scheme-78
2.3.2.2.2 From Arylthioureas (Hugershofrs Method)
R-a H
S
n
N, ... NHAr o=N
(i)Br2 / CHC13or(C04,CS2 ,S2C12)R-
(ii)S0 2,NaOHorKOH ~ S
}-NHAr I
Scheme-79
2.3.3 Structure
Thiazole is considered to be derived from thiophene by the replacement of -CH=

group by the pyridine-type (azomethine) nitrogen at the position-3 . Thiazole is
expected to be structurally related with thiophene and pyridine but geometrically
the structure of thiazole is very close to the average of the structures of thiophene
and 1,3,4-thiadiazole. Thiazole molecule is planar with the following structural
parameters (Fig. 26) :
Bond lengths (A) Bond angles e)
C2-S 1.724 4 3 C2-S-C5 89.3°
C2- N
CcN
Cc C5
1.304
1.372
1.367
J[),
s
S-C2-N
C2-N-C4
N- Cc C5
115.2
110.1
115.8
C5- S 1.713 C4-Cs- S 109.6
Fig. 26. Structural parameters in thiazole

The C2-N bond is shorter than the CrN bond, thus having more p-character.
The structure of thiazole is considered as the resonance hybrid of the following
resonating structures. However, some additional resonating structures are also
possible with the involvement of d-orbitals of sulfur (Fig. 27).
C)
s
-C:)~C>
s s
(i) (ii) (iii) (i~ / (~
C)-
s
(\i)
Fig. 27. Resonating structures of thiazole
The 1t-bond orders calculated by molecular orbital methods have indicated

thiazole molecule to be aromatic with some dienic character. The ring current for
thiazole is in accordance with its aromatic character.
Localization energies have predicted decreasing order of the electrophilic
reactivities as : 5 > 2 > 4 and the nucleophilic reactivities follow the order : 2 >
5 > 4. Three hydrogen atoms in thiazole are predicted to have the order of acidity
as: H-2 >> H-5 > H-4.
2.3.4 Reactions
Thiazole is a 7t-excessive heterocycle and it contains thiophene type sulfur atom

at the position- I and pyridine-type nitrogen atom at the position-3. Thiazole is
therfore expected to have similarities with both pyridine and thiophene in its
chemical reactions.
The ring nitrogen atom in both thiazole and pyridine is sp 2-hybridized and the
lone pair is localized in sp 2-hybrid orbital in the plane of the ring. However, the
lone pair on nitrogen in thiazole is less reactive than that in pyridine because of
the enhanced aromaticity in the pyridine ring and the effective stabilization of the
positive charge on the nitrogen atom in pyridine than that in thiazole during the
reaction at nitrogen. This effect accounts for the lower basicity and the lower
rate ofN-alkylation for thiazole (Fig. 28).
+0 0+
I I I I
N N
0 (i)
~
~I
(ii)
~
(J
(iii)
~
#
(i~
+/ / /
()
+ /
![) ~ ![)+ ~
c.N) ~
s s s s
(i) (ii) (iii) (i~
Fig. 28
Thiazole is a weaker base (pKa = 2.5) than pyridine (pKa = 5.2). The basicity of
thiazole is enhanced with the alkyl substituent at the carbon atoms due to their
+I effect which decreases in the order as : C-2 > C-4 > C-5 (pKa = 3.43, 3.15 and
3.12 for 2-methyl-, 4-methyl- and 5-methyl derivatives, respectively). The presence
of electron-releasing substituent ( +M) at C-2 increases basicity considerably, while
the electron-withdrawing substituent at C-5 causes decrease in its basicity.
2.3.4.1.1.2 N-Aikylation (Reaction with Alkyl halides)
Thiazoles undergo N-alkylation with alkyl halides with the formation ofthiazolium
salts. The resulting thiazolium cation is stabilized by resonance and the positive
charge resides most predominantly on the sulfur atom (scheme-80).
![)
s
RX ~ + [cf-- cJR]
s s
X
Scheme-80
The presence of alkyl substituents at the positions-2 and -4, ortho to the
nitrogen atom, inductively accelerates the reaction but sterically retards the
reaction. Because of the dissymetric structure of the thiazole ring, the steric effect
of the alkyl substituent at C-4 is greater than that when it is at C-2 b ecause the
bond angle R-C 2-N (123.6°) is greater than the bond angle R- CcN (119.4°).
Five-Membered Heterocycles with Two Heteroatoms 42S
Although thiazole ring is 7t-excessive, the presence of pyridine-type nitrogen

deactivates thiazole ring towards electrophilic attack. The reactivity of thiazole ring
is further lowered in electrophilic substitutions proceeding under acidic conditions
(nitration, sulfonation and Friedel-Crafts reaction) because of the involvement of
protonated thiazole. However, thiazoles undergo electrophilic substitutions readily
if the thiazole ring is substituted with electron-releasing substituents (-OH and
-NH 2). The attack of electrophiles occurs preferentially at the position-S of the
thiazole ring, but if it is already occupied the electrophilic attack takes place at the
position-4.
Thiazole is much less reactive and does not undergo nitration with nitrating
reagents even under forcing conditions. However, 4-methylthiazole is nitrated at
the position-S under relatively mild conditions. If position-S is occupied, the
nitration takes place at the position-4, but the reactivity of position-S in thiazole
ring is two to three times greater than that of position-4 ( scheme-81 ).
H,):N
tJ
H3C
HNOrH 2 S0 4-S0 3
s 160"C o2N s)
229 230
£N HNO rH 2 S0 4-S0 3
o,)cN
H3C S) 160"C H3C S)
231 232
Scheme-81
Sulfonation of thiazole occurs at the position-S under forcing conditions by the

reaction with olum at 2S0°C in the presence of mercury (II) sulfate (scheme-82).
However, 2-aminothiazole is sulfonated at low temperature with the formation of
sulfamic acid 235 which on heating rearranges to 2-aminothiazole-S-sulfonic acid
236 (scheme-83).
()s
6
Scheme-82
(~
S N~
H 2 S04
OOC
( N
\\ ~
s/' NHS0.3H-~H0 3 S
.
JCN\\
S./"-. N~
234 235 236
Scheme-83
Thiazole does not react with bromine or chlorine in an inert solvent, but
2-methylthiazole undergoes brornination at the position-S giving S-bromo derivative.
If the position-S is occupied, the bromination does not occur.However, the
presence of electron-releasing substituent at the position-2 facilitates bromination
at the position-S even under mild conditions (scheme-84).
(N Br 2
JCN
s)\CH3 CHQ3 / ~ Br sACH3
237 238
Br 2
JCN
H3C s~CH3 No reaction
239
(N Br 2
JCN
s~NH2 CH 3COOH Br S~NH2
240 241
Scheme-84
2.3.4.1.2.4 Alkylation
Thiazoles activated by the substituents substituted at the positions-2 and -4

undergo alkylation at the position-S when treated with tert-butyl alcohol in the
presence of sulfuric acid (scheme-8S).
Scheme-85
Thiazole is mercurated at the positions-2,4 and S in the order : C-S > C-4 > C-2,
providing 2,4,S-tris(acetoxymercury)thiazole 245 on treatment with mercury acetate
in the presence of aqueous acetic acid (scheme-86).
0
II
CH3COHg
ffN CH COOH 0 )r-N 0

--3 ---1~
l(_ _)
s
+ Hg(OCOCH3h
II
CH3COHg ~ s~
- ·' HgOCCH
II 3
245
Scheme-86
2-Aminothiazole undergoes diazo coupling with diazonium salts with the substitution
of diazo group at the position-S (scheme-87).
Scheme-87
2.3.4.2 Condensation Reactioos
The position-2 in thiazole is electron-deficient and the substituents at the position-

2 exhibit enhanced reactivity than the substituents at the positions-4 and -5.
Although the position-4 is also a to the nitrogen atom but due to bond fixation
it is little influenced even on quatemization. Thus 2-methylthiazoles are appreciably
reactive and undergo condensation reactions with aldehydes (scheme-88).
t:l +OcHo
H3C
ZnC1 2
160"C
S CH3
247
Scheme-88
2-Aminothiazoles also undergo condensation reactions with aromatic aldehydes

under mild conditions (scheme-89). This reaction is used to synthesize a number
of biheterocycles 250 (scheme-90).
~\
(S/-NH2 + OcHo
234
Scheme-89
CH3-C-CH=CH-CI
II
.. ~r-~1::
-l)
0 S N
250
Scheme-90
2.3.4.3 Oxidation
Thiazole ring is relatively resistant to oxidation, but the thiazoles substituted with
activating groups are oxidized to their N-oxides 251 by hydrogen peroxide or
peracetic acid (scheme-91 ).
Scheme-91
Trisubstituted thiazoles 252 undergo photosensitized oxygenation with the

formation of ring cleaved products depending on the sensitizer and the solvent
used (scheme-92).
CHCl 3 I methylene
blue
C6H5
\
/
COC 6H
5
'I C=N\ /
C5H5
C6H5-C-C-C 6H5 CH N ...-s C
II II 6 5 'c...... 'coc 6 H5 'c 11
0 0 C H, ~
sII 6 5 0
0
+
255 254
Scheme-92
2.3.4.4 Desulfurization
Thiazoles undergo desulfurization when treated with Raney nickel, but the
products formation depends upon the reaction conditions (scheme-93).
R2 hydrolysis R2
neutral ' C=N
I I
' C=O
R)-N 1 I
conditions CH 3 CH2R CH 3
Z8 AR1 257 +
R 1CH 2NH 2
256~ R2
alkaline
' C-N
II II
Ni / H 2 R2-CH-NH
I I
conditions /CH ,.c, CH 3 CHR 1
HS R1 OH I
OH
258 259
R1 CHO + R2-CH-NH2 •
I
CH 3
Scheme-93
In thiazole ring, the position-2 is with lowest 7t-electron density (position-2

electron-dificient, position-4 almost neutral and position-S slightly electron-rich)
and is, therefore, most susceptible for the nucleophilic attack. However, the
reaction of nucleophiles with thiazoles require either activation of the thiazole ring
or the strong nucleophiles. The quatemization of the ring nitrogen considerably
enchances the reactivity of the thiazole ring towards nucleophilic attack at C-2
making H-2 acidic.
2.3.4.5.1.1 Amination
Thiazoles can be aminated at the position-2 by treating with sodium amide at 150°C
with the transfer of hydride ion (analogous to Tschichibabin reaction in pyridine)
(scheme-94).
150"C
Scheme-94
2.3.4.5.1.2 Ring Cleavage
Thiazoles are resistant to attack by hydroxide ion, but thiazolium cations (salts) are
susceptible towards attack of hydroxide ion under mild conditions and results in
the cleavage of the ring (scheme-95).
260 261 262 263
Scheme-95
2.3.4.5.1.3 Displacement of Halide
Thiazoles with halogen atom at the position-2 undergo nucleophilic substitution

reactions with the replacement of halogen atom by nucleophiles (scheme-96).
Moreover, 4-halo- and 5-halothiazoles also undergo nucleophilic substitution
reactions. The reactivity of halothiazoles varies with the position of halogen atom
and the nature of the reagent used:
(i) with methoxide ion in methanol 5-halo- > 2-halo- > 4-halo-
reactivity follows the order
(ii) with thiophenoxide in methanol 2-halo- > 4-halo- > 5-halo-
reactivity follows the order
264
f/N
Q--cl + RNHz
's~NHR
266 267
Scheme-96
2.3.4.5.1.4 Metal-Halogen Exchange
2-Halothiazoles undergo halogen~ metal exchange when treated with

n-butyllithium and Grignard reagents (scheme-97).
n-Buli
(~
s~u
(')__ /
~
S Br'\ 268
C2H5MgBr
~
(N
s~MgBr
269
Scheme-97
Thiazoles are deprotonated preferentially at C-2 by a strong base. Thus thiazole

is metallated with the abstraction of acidic hydrogen at C-2 when treated with n-
butyllithium or ethyl magnesium bromide (scheme-98).
() s
+ n-Buli
ether
-6(J'C
![~
s~Li
6 268
() + C 2H 5MgBr
ether
C1'C-25°C
(Ns~MgBr
s
269
Scheme-98
2.3.4.5.2.2 H ~ D Exchange
(i) Neutral thiazoles
Thiazoles undergo deuterodeprotonation (H ~ D exchange) when treated with

CH 3 0Na in CH 3 0D, but the hydrogen to be exchanged depends on the pH. At low
pH (<II) only hydrogen at C-2 is exchanged, while at higher pH (12 to 14) both
C-2 and C-5 hydrogen atoms are exchanged at a similar rate (scheme-99) 26 .
0
)[)
s
Scheme-99
(ii) Thiazolium cations (Quaternary salts)
In thiazolium salts, H ~ D exchange occurs readily at C-2 because the stabilized

ylide 270 is easily formed by the base induced abstraction of enhanced acidic
hydrogen at C-2. The resulting ylide 270 accepts deuterium from the solvent with
the deuteration of thiazolium salt (scheme- I 00) 25 .
R
+/
![~ + OH~
S H
260 270a 270b
Scheme-100
The ease of the formation of 2-ylide restults from the combined effect of the
following factors:
(i) The highs-character of the C-H a-bond, (ii) the electron-withdrawing effect
of the positively charged nitrogen and (iii) stabilization of the ylide
involving d-cr overlapping of the electron pair of the anion with an empty
d-orbital of sulfur.
2.3.4.6 Photochemical Rearrangements
Alkyl- and aryl- thiazoles undergo photochemically induced rearrangements with

the formation of isomeric thiazoles and isothiazoles. The formation ofthiazoles and
isothiazoles can be rationalized by the free-radical mechanism involving ring
contraction and ring expansion (scheme-1 01 )27 •
Scheme-101
3 1,2 AZOLES
3.1 Pyrazoles 28 - 33
3.1.1 General
Pyrazole is a n-excessive heterocycle and contains two nitrogen atoms; pyrrole-

type and pyridine-type, at the positions- I and -2. Benzo-fused pyrazole is known
as benzopyrazole 276 or more commonly indazole with the numbering as shown
in the structures 1 and 276. Pyrazole exists in three partially reduced forms 277,
278, and 279 with the different positions of double bond.
4 3
5~~
~ I N1/~
6
7 H
276
l-or il 1-Pyrazoline 2-or il2-Pyrazoline 3-or il 3-Pyrazoline

227 278 289
Pyrazole ring is incorporated into many of the commercially available

pharmaceuticals, agrochernicals and dyestuffs. Some important pyrazole derivatives
with their activity are listed as :
Difenamizole analgesic,
0 antiinflammatory
II and antipyratic
[R= -NH-C-N(CH3h l
Difenzoquat herbicide
3-Pyrazo1in-5-ones analgesic, antipyratic

and antiinflammatory
(i) antipyrine; R = H
(ii) propyphenazone; R = -CH(CH3h
(iii) ampyrone; R = -NH 2
(iv) isopyrine; R= -NH-CH(CH3) 2
0, 0-Diethyl- agrochemicals
0-(3-methyl-5-pyrazolyl)
phosphate and
phosphorothioate
3.1.2 Synthesis
3.1.2.1 (3 + 2) Cyclization Reactions28•29.34
Pyrazo1es are synthesized by the condensation of 1,3-difunctionalized compounds

with hydrazine or its derivatives involving (3 + 2) cyclization.
3.1.2.1.1 Reaction of ~-Diketones with Hydrazines
This is the most widely used method and involves the reaction of ~-diketones with
hydrazine or monosubstituted hydrazine in the presence of an acid (scheme-102).
The reaction proceeds via the formation of hydrazone 280 which on subsequent
cyclization and dehydration produces the corresponding pyrazole 282. However,
this method suffers from the disadvantage as with unsymmetrical ~-diketones
generally a mixture of isomeric pyrazoles is formed (scheme-1 03).
Scheme-102
283 284
Scheme-103
3.1.2.1.2 Reaction of a,I3-Unsaturated Carbonyl Compounds with Hydrazines
The reaction of a,l3-ethylenic carbonyl compounds, substituted with a readily

replaceable substituent at a- or 13-position, with hydrazines results in the formation
of expected pyrazoles (scheme-104).
However, with a,l3-acetylenic carbonyl compounds a mixture of two isomers is
obtained due to two competing reaction processes; (i) the first reaction proceeding
via the intermediacy of hydrazone, followed by cyclization and dehydration, while
(ii) the second process involves Michael type adddition, followed by dehydrative
cyclization (scheme-105). The preferred reaction path, however, depends on the
nature of the molecule undergoing reaction and effected also by the solvent and
temperature.
Cl Cl
I I
C5H5- C- C= CH- C5H5 C6H5-C-C=C H-C6H5
II II
0 N-NHC6H 5
+ 285
H2N-NHC5H5
H5C6 ·-HCItl
' ,,C-CH
N,
N
I
\\
/c . . . . c6 H5 [ C6H5-~,. ~-C6HJ
N-C6H5
H
C5H5
287 286
Scheme-104
290 291
n-(C6H5
HCJ( ,'N ,....__

3 N
I
CH 3
293
Scheme-lOS
3.1.2.2 1,3-Dipolar Cycloadditions
(i) 1,3-Dipolar cycloaddition of diazoalkanes with functionalized alkynes

results in the formation ofpyrazoles (scheme-106). The reaction proceeds
through a transition state involving energetically most favourable
interaction of 4n-electrons of 1,3-dipole [diazoalkane-with electrophilic
and nucleophilic centres-ambivalent] with 2n-electrons of dipolarophile
(methylpropiolate) (HOMO of diazoalkane- LUMO of dipolarophile).
COOCH3
N~N·.C/COOCH3]
+~~
I
[ \ ,,
CH H2C- -CH
294
t
N ...... cl
COOCH3
It
N II
H~c-CH
296 295
Scheme-106
(ii) The reaction of norbornadiene with diazoacetate in the presence of either

Fe(C0)5 or Co2 (CO)g produces 1,3-dipolar cycloaddition adduct 297
which undergoes cycloreversion under the reaction conditions providing
pyrazole 298 (scheme-107)35 .
[~~,Hsj
oaJO:,Hs _0 '- ~N
N
297
I
N
H
298
Scheme-107
(iii) 1,3-Dipolar cycloaddition reactions of sydnones (meso-ionic heterocycles,

1,2,3-oxadiazolium-5-olates) with alkynic dipolarophiles result in the
formation of pyrazoles with the evolution of carbon dioxide (scheme-
108)36,37_
-
o)t~
R2 _i( +-:.- N ...,....
N
11
R
(i)
COOCH3
R'~N ....,.___
N -C02
11
R
301
Scheme-108
3.1.3 Structure
The structural parameters in pyrazole are summarized (Fig. 29) :

N 1-N2 1.349 C 5-N 1-N2 113.1
N2-C3 1.331 4 3 NI-N2-C3 104.1
C3-C4
CcCs
1.416
1.373
sf:N
N; 2
N2-C3-C4
C3-CcCs
111.9
104.5
H
C 5-N 1 1.359 CcC5-N 1 104.1
NI-H 0.998
Fig. 29. Structural parameters in pyrazole

The N-H bond is displaced from the bisector of ring angle by nearly 5° towards
second nitrogen atom. The structural parameters in pyrazole indicate sufficient
bond delocalization and hence aromaticity.The resonance energy of pyrazole has
been found to be 123 kJ/mol and thus suggesting pyrazole to be more aromatic
than imidazole, although both pyrazole and imidazole are of comparable stability.
Pyrazole is a colourless solid with m.p. 69-70°C. The boiling point of pyrazole
( 186-188°C} is much higher than that of its N-alkyl derivatives (N-methylpyrazole,
b.p. = l27°C}. The higher boiling point of pyrazole is attributed to the
intermolecular hydrogen bonding. But with the replacement of hydrogen by methyl
group, the boiling point is decreased due to the absence of intermolecular
association. However, the introduction of alkyl group at the carbon increases
boiling point. The intermolecular association in pyrazole may be linear or cyclic
(dimer and trimer) (Fig. 30).
linear association
cyclic association
(dimer)
cyclic association
(trimer)
Fig. 30. Hydrogen bonding in pyrazole
3.1.3.2 Tautomerism
Pyrazole exists in two identical tautomeric forms with the movement of proton
between two annular nitrogen atoms. Thus two nitrogen atoms are indistinguishable
(Fig. 31a). But asymmetrically substituted pyrazole exists in two non-separable
tautomers due to the rapid interconversion of tautomers, although one tautomeric
form predominates over the other (Fig. 31 b). Therefore, 3-substituted pyrazole is
identical with 5-substituted pyrazole. The numbering in such compounds is
cmplicated and the atoms are identified by two numbers. IfR=CH 3, the compound
is named as 3 (5) methylpyrazole.
r;NH
N
Fig. 31a. Tautomerism in pyrazole
R R
0 N
H
OH N R
~N
N
H
Fig. 31b. Tautomerism in substituted pyrazole
3.1.4 Reactions
3.1.4.1 Reactivity
Pyrazole exhibits characteristic reactions of pyrrole and pyridine because of

containing pyrrole-type and pyridine-type nitrogen atoms at the positions- I and
-2. Pyridine-type nitrogen is susceptible to electrophilic attack but it is less
nucleophilic than the pyridine nitrogen atom. The hydrogen atom attached to the
nitrogen atom (N-1) in pyrazole is more acidic than the pyrrolic N-H in pyrrole and
can be easily removed by nucleophiles.
The electrophilic attack in pyrazole, in contrast to pyrrole at C-2 (a-attack),
occurs preferentially at C-4. The attack ofnucleophiles takes place at C-3, but with
strong nucleophiles the abstraction of proton leads to the ring opening. Two types
of ions are involved in the proton transfer in pyrazole; (i) pyrazolium cation 302
and (ii) pyrazole anion 303 (scheme-109).
~. __!{__ 0+
l(_ ,.."N. - - l(_ ..:NH
N N
I H
H
~~
~:-::.~r
\:/NH
H
pyrazole anion pyrazolium cation
303 302
Scheme-109
3.1.4.2 Electrophilic Attack at Nitrogen
3.1.4.2.1 Basicity38.J9
Pyrazole is a weaker base (pKa = 2 5. 2) than imidazole. The mesomerically electron-

releasing effect of the pyrrole-type nitrogen although increases the electron
density on nitrogen and facilitates the reactions with electrophilic reagents, but
inducitvely electron-withdrawing effect of the adjacent nitrogen at the position-2
makes lone pair less available for protonation. In pyrazole, the inductive effect
predominates over the mesomeric effect and thus causes pyrazole to be less basic
than imidazole. Moreover, relatively lower basicity is attributed to the extra
destabilization of n-bonding after protonation. The destabilization of n-bonding
for pyrazole is greater than for imidazole because the lone pair on pyrrole-
type nitrogen (position- I) in pyrazole does not contribute appreciably to the
delocalization of the positive charge appearing at the pyridine-type nitrogen at
position-2 after protonation. The presence of methyl group at the position- I, which
is base-strengthening in imidazole, causes base-weakening effect in pyrazole due
to steric hindrance.
3.1.4.2.2 l\cidity
Pyrazole is a very weak acid with pKa = 14.21 (for proton loss), but more acidic
than pyrrole. Thus the acidity of the five-membered ring system increases with the
introduction of pyridine-type nitrogen (-N=). However, with the introduction of
electron-withdrawing groups (-I and -M effect) the acidity increases considerably
(3,5-dinitropyrazole; pKa = 3 14).
.
3.1.4.2.3 N-Mkylation
Pyrazoles with free -NH group are readily alkylated by methyl iodide or dimethyl
sulfate with the formation of N-alkylpyrazoles. In unsymmetrical pyrazoles, the
position taken by the entering alkyl group depends upon the nature of the
alkylating agent and the experimental conditions. Generally, N-alkylation occurs at
the less hindered position. But if the substituent is with lone pair of electrons, the
nucleophilicity of the adjacent nitrogen is enhanced due to electrostatic field and
affects the composition ofthe mixture (scheme-110) 40 •41 . However, pyrazoles with
substituent on nitrogen form quaternary salts when alkylated with alkyl halides.
3.1.4.2.4 N-l\cylation
Pyrazoles with free N-H group undergo acylation when treated with acetyl chloride
(alone or in the presence of pyridine) or acetic anhydride. In unsymmetrical
pyrazoles, although acylation occurs at both the nitrogens, the product of N-
acylation at less hindered nitrogen is predominantly obtained because of the
transformation of the less stable isomer 311 into more stable isomer 310 in the
reaction medium (scheme-Ill).
ON
R
+ (CH,),SO,
N
H
304
a: R = CH3 305 (35%) 306 (65%)

b: R = C6H 5 (25%) (75%)
R
H,CJ()N H
DMF
K1
307
a: R = C09"C2H5
+
309
Scheme-110
~-.0
R
0 N
H
I
COR'
310
(major product)
1~ R
~ (minor product)
~N"~ 'COR'
311
Scheme-111
3.1.4.2.5 Michael Addition
N-Unsubstituted pyrazoles undergo Michael addition with activated alkenes and

alkynes. However, with activated alkynes two successive additions occur if the
intermediate alkene obtained during the reaction is reactive enough (scheme-112).
But with methyl ethynyl ketone two successive additions occur at the same carbon
atom (scheme-113 )42 .
CH3 CH3
H c)( )
3
~
N
+ E-c=c-E __....... H
(E=COOCH) 3
c.JZr-(
N
)
H 3 I
)[j
282 cH 3 _.....C~ _.. . E
CH E C,
3 312 H
HC ..,N
3 N, /N CH
HC-CH N 3
I \
E E
313
Scheme-112
eN N
I
eN N
I
+ . . . . c~ _.......H CH- CH2COCH 3
v
H C I
CH=C-COCH3 \ N-N
COCH3
314
Scheme-113
3.1.4.3 Electrophilic Attack at Carbon
3.1.4.3.1 Reactivity and Orientation
The reactivity of pyrazole is similar to that of benzene and reacts readily with
electrophiles, but the presence of pyridine-type nitrogen ( -N=) in pyrazole makes
it less reactive than pyrrole. Pyrazolium cation is deactivated towards electrophiles,
but pyrazole anion reacts almost as readily as phenols.
Multiply bonded nitrogen (pyridine-type) deactivates the positions-3 and -5

which correspond a-and y-positions (electron-deficient) of pyridine, while
position-4 is activated towards electrophiles due to electron-release from the
pyrrole-type nitrogen. The electrophilic substitution in pyrazole, therefore, occurs
at the position-4 as shown below (Fig. 32) :
position of electrophilic attack

r----
nt ,.,:N.._
pyridine [ activated by
-P- electron release ~ deactivated position
position from pyrrole-type • (pyridine-a-position)
mtrogen '(_
deactivated position/ ~/
(pyridine-y-position)
Fig. 32
Moreover, the preferential attack of electrophile at the position-4 in pyrazole is

evidenced also from the relative stability of the intermediates resulting from the
electrophilic attack at the positions-3, -4 and -5 (Fig. 33). The resonating structures
for the attack at C-3 and C-5 involve highly unfavourable positively charged sextet
nitrogen (azomethine or pyridine-type) but such unfavourable resonating structure
with positively charged sextet nitrogen is not involved for electrophilic attack at
C-4. The attack of electrophile, therefore, preferentially occurs at the position-4.
ON __E_+_---i~
N (attack at C-3)
H
ON t EHi"nf:voumble) E~
N (attack at C-4) + N,...N ~ ~~;N
H H H
ON __E_+_--t~ HE;oN ~EH>(;N+~>CN

N (attack at C-5) N N E N
H H H H
(unfavourable)
Fig. 33
3.1.4.3.2 Nitration
Nitration of pyrazole with nitrating mixture of concentrated nitric and sulfuric acids
occurs at the position-4 (scheme-114). If pyrazole is nitrated with concentrated
+
N02
315
Scheme-114
nitric acid in acetic anhydride, the nitration occurs at the position- I (at nitrogen)
providing 1-nitropyrazole 316 which is converted into 4-nitropyrazole 315 when
treated with concentrated sulfuric acid (scheme-115). The reaction proceeds with
-+
(CH 3COONCh)
eN N
I
H 2S0 4 ~+
l(_ ..:NH
N
I
N02 N02
316 317
o,NCNH .
N
H
315
Scheme-115
the transfer of nitro group through a cation 317 because 1-nitropyrazole 316 has
been an efficient nitrating agent for the aromatic hydrocarbons. The positions
of nitration in substituted pyrazoles with different nitrating agents are shown in
(Fig. 34). Ifpyrazole is substituted with phenyl group at the position- I, it competes
with pyrazole ring and nitration occurs at para-position (scheme-116).
Fig. 34. Nitration at different position with different nitrating agents
02N 0 2N
ON ON ON ON
6 ¢ ¢
HN0 3 N HN0 3 HN0 3
¢rN0
N N N
H2S04 H2S0 4 H2S0 4
(20"C) 2
(lO"C) (lOO"C)
I
N02 N02 N0 2
318 319 320 321
Scheme-116
Pyrazoles undergo sulfonation only under vigorous reaction conditions with the
introduction of sulfonic acid group at the position-4 (scheme-117).
RD
(H 2S04 + S03 )
20%oleum
prolonged
N heating
H 1:R=H
282: R = CH 3
Scheme-117
Halogenation of pyrazoles usually occurs at the position-4. Pyrazoles can be

chlorinated by chlorinating reagents such as chlorine water, chlorine in carbon
tetrachloride, hypochlorous acid, chlorine in acetic acid and sulfuryl chloride in
chloroform. Pyrazoles are brominated by bromine in chloroform and bromine in
acetic acid (scheme-118).
Scheme-118
3.1.4.3.5 Mercuration
Pyrazoles are chloromercurated at the position-4 by the reaction with mercury (II)
chloride providing 325. Mercuration occurs at the position-4, if 1-phenylpyrazole
326 is treated with mercury acetate (scheme-119). The reaction with 3- or
5-phenylpyrazole also results in the introduction of acetoxymercury group at the
position-4.
+ HgC12
..,.......ococH3
+ Hg
'ococH3
Scheme-119
3.1.4.3.6 Diazo Coupling
Generally pyrazoles do not undergo diazo coupling with diazonium salts. If the
activating group is present at the position-3 or 5, the diazo coupling occurs easily
at the position-4 (scheme-120).
+
--C-IaH~s-:,N:tN
X
-
H
329
Scheme-120
3.1.4.4 Oxidation
Pyrazole ring is generally stable to oxidation, however with peroxide transformed

into its 2-oxide (scheme-121 ).
ON
N
H202
CH 3COOH
0+-N
/N-O
I I
R R
330
Scheme-121
The oxidation of pyrazoles with alkaline KMn0 4 causes alkyl side chain to
transform into carboxylic group (scheme-122).
OCH, n-(COOH
!( )~
N N
H H
304a 331
Scheme-122
3.1.4.5 Reduction
The reduction of pyrazoles with sodium and alcohol or by catalytic hydrogenation

over palladium results in 2-pyrazolines (scheme-123).
eN
N H
Na/C 2H50H
or
H2/Pd
eN
N H
278
Scheme-123
Halopyrazoles are unreactive, but the electron-withdrawing substituent attached

at a- to the halogen atom makes reactive towards nucleophilic substitutions
(scheme-124).
+ RNH2 ~:ON
H ~
333
Scheme-124
The irradiation of pyrazoles with nucleophilic reagents results in nucleophilic

photosubstitution with the replacement of hydrogen atom by nucleophile from the
position-4 (scheme-125). Ifposition-4 is already occupied, the hydrogen atom is
substituted from the position-S (scheme-126)43 •44 .
R1
0 N
I
-
CN
hv
R
334
Scheme-125
4S2 Heterocyclic Chemistry
h
02N CH3
-
CN
hv
N
I
R
336
R = p-N0 2-C6H4
Scheme-126
N-Substituted pyrazoles are lithiated at the position-S when treated with n-

butyllithium. If position-S is occupied, the lithiation occurs at the N-alkyl group
(scheme-127).
n-Buli
u£}N I
CH 3
339
n-Buli ~
CH30~N,...·N
I
CH2Li
341
Scheme-127
3.1.4.6.2.2 Ring Cleavage via Deprotonation
Pyrazole ring unsubstituted at the position-3 is cleaved by a strong base

(NaNH 2 ) via deprotonation at C-3 (scheme-128) 31 .
0 N
I
n?
i(_ 't.N
N
I
R R
Scheme-128
The reaction of pyrazoles with dichlorocarbene in neutral conditions results in ring

expansion providing 5-chloropyridazines 344. However, under basic conditions
the reaction proceeds with the attack of dichlorocarbene at the position-4 with the
formation of 4-dichloromethylpyrazoles 345 which on treatment with sodium
ethoxide provide ring expanded 6-ethoxymethylpyridazines 346 (scheme-129)3 1.4 5.
346 344
Scheme-129
Pyrazole is expected theoretically to react as azadiene or 1,3-dipole of azomethine

imine and undergoes cycloaddition reactions with dienophiles or dipolarophiles
(Fig. 35).
azadiene
... . ... . +(';N-
N
H
azomethine-
imine type
Fig. 35
Moreover, pyrazole may be considerd as an alkene or imine and undergoes

cycloaddition with dienes or 1,3-dipoles (Fig. 36).
alkene part ~o~ ~ imine part

...-N
N
H
Fig. 36
However, the reactions are theoretically possible but are not practically feasible
and the reactions involving cycloadditions are not known for pyrazoles. Pyrazoles
undergo cycloaddition with DMAD involving side chain (scheme-130).
CH2=CH
ON N
I
+ E-c=c-E
(E =COOCH3)
R
347
Scheme-130
3.1.4.9 Photochemical Transformation
Pyrazoles are photochemically transformed into imidazoles involving the exchange

of positions N-2 and C-3 of pyrazole with the positions C-2 and N-3 of imidazole.
The photochemical reaction proceeds with the cleavage of the weakest N-N
bond, followed by cyclization of the resulting diradical intermediate 350 to azirine
351 and then rearranges to imidazole (scheme-131 ).
R4VNR"~ N
I1
R
349
353 352
Scheme-131
3.2 Isoxazoles 47 - 50
3.2.1 General
lsoxazole is a five-membered n-excessive heterocycle with oxygen (furan-type) and

nitrogen (pyridine-type) at the positions- I and -2, but differs from oxazole by the
presence of N-0 bond. The partially reduced form of isoxazole (dihydroisoxazole
or isoxazoline) exists in three isomeric forms; 354, 355, and 356, depending on
the position of double bond. The position of double bond may be represented by
prefix ~ (delta) with superscript. The completely reduced form of isoxazole is
known as 2,3,4,5-tetrahydroisoxazole (isoxazolidine) 357.
4 3
so~N2
o,... ~ pyridine-type nitrogen
1 ~ furan-type oxygen
eN
0
4,5-Dihydro-
eN 0
2,5-Dihydro-
eN o"'
2,3-Dihydro-
eN 0
2,3,4,5-Tetrahydro-
isoxazole isoxazole isoxazole isoxazole
2-lsoxazoline 3-Isoxazoline 4-Isoxazoline Isoxazolidine
(11 2-isoxazoline) (113- isoxazoline) (114 -isoxazoline)
354 355 356 357
The fusion of benzene ring to 4,5- and 3,4-positions of the isoxazole ring system
results in 1,2-benzisoxazole (or indoxazene) 358 and 2, 1-benzisoxazole ( anthranil)
359, respectively. These ring systems51 •52 are numbered as shown in the
structures 358 and 359.
4 3
5~N
6~0 2
7
'.():')~
7 1
358 359
Isoxazoles exhibit a number of interesting medicinal and agricultural activity.

Some of the important isoxazoles with their activity are presented:
Sulfonarnides
H2N-o-SO,NH
~CH3
(i) Sulfamethoxazole antibacterial
NO' -K
CH3 CH 3
H2 so 2NH ~-;~
- 0
(ii) Sulfisoxazole antibacterial
Semisynthetic penicillins
c::p--J<
(i) Oxacillin (X= Y =H) CONH
(ii) Cloxacillin (X= H, Y = Cl)
(iii) Dicloxacillin (X= Y = Cl)
(iv) Floxacillin (X= F, Y = Cl) COOH
Isoxicam
W 02
OH
CH3
CONH~
t{,_ - )>- CH
antiinflammatory
'o 3
Acivicin CIHH antitumor
t·r,o)-?H-COOH
NH2
Isoxazole carboxylic acids R COX hypoglycemics,
t~
and derivatives antidiabetics
X=OH,NHR' antiinflammatory
0 and analgesics
Isoxazolyl ureas herbicide
3-Hydroxy-5-methylisoxazoles soil fungicides
1,2-Benzisoxazoles pesticides and
insecticides
Isoxazole is a colourless liquid (b.p. = 95°C; D.M. = 2.75 ± 0.010 in benzene and
3.1 ± 0.030 in dioxane) with strong pyridine like odour. The boiling point of
isoxazole is although lower than that of pyrazole and imidazole but higher than that
of oxazole and furan. The higher boiling point of isoxazole is attributed to the
greater intermolecular association in isoxazole molecules involving pyridine-type
nitrogen and hydrogen at C-3 (Fig. 37).
Fig. 37. Hydrogen bonding in isoxazole

Isoxazole is considered an aromatic heterocycle as it exhibits electrophilic

substitution reactions and the NMR chemical shifts for the ring protons are
consistent with those of an aromatic system. The ring heteroatoms, however,
modify appreciably the aromatic character of isoxazole. Isoxazole is considered to
be resonance hybrid of the following resonating structures (Fig. 38) :
(i) (ii) (iii) (iv) (v)
Fig. 38. Resonating structures of isoxazole
3.2.2 Synthesis
3.2.2.1 Reaction of ~-Diketones with Hydroxylamine
This is the most general and widely used method which involves condensation-
cyclization (3 + 2 cyclization) of P-diketones with hydroxylamine in the presence
of an acid. The reaction proceeds via the monoxime intermediate 360 which
subsequently on cyclizative-dehydration leads to the formation of isoxazoles 363
(scheme-132)49 .
R-COCH2COR
+
NH20H
J:!N . ., .__
R
R o"' -H20
363
Scheme-132
The symmetrical P-diketones provide 3,5-disubstituted isoxazoles, but

unsymmetrical P-diketone with hydroxylamine provides a mixture of isomeric
isoxazoles (scheme-133). The ratio of the products depends upon the acid
concentration and the direction of enolization (Fig. 39).
n
R1 R2
R1COCH2COR 2
R'J:i
+
H
+ +
NH 20H R1 O.,...N
0
364 365
Scheme-133
Fig. 39. Enolization in ~-diketones
This reaction has been extended to involve the reaction of hydroxylamine

hydrochloride with C-C-C system of varying functional groups (scheme-134).
(i) R-CO-CH=CH-X + NH 20H.HCI -..~N

R 0....-
n n
(X = halogen, OCH3 , N(CH 3) 2 )
366 COOR R
(ii) R-CO-CH2-CO-COOR + NH20H.HCI---.. +

R:J(- .,...'N /(~)~
0 ROOC 0
367 368
(major) (minor)
"')
(ill R 0 DNH2
-c=c-c=N + NH 2 H.HCI -..
R .,...N
0
369
Scheme-134
3.2.2.2 Reaction of Nitrile N-Oxides with Alkenes and Alkynes
The reaction of nitrile oxides, generated in situ by treating chloroximes with a base
(triethylamine), with alkenes and alkynes results in isoxazoles via 1,3-dipolar
cycloaddition (scheme-135) 49 .
Cl R-C=N-0
(! -
I base
R-C=NOH • +cH=c-v ~
-HO
t (Y =COR, COOH, COOR) ~
y_c:
+ -
R-C=N-0
+
CHrGI=CH-X
0
/l _.,..., H
370
L[H~CH~ -HX
H3C
t( /'N
R
X 0 0
371 372
Scheme-135
3.2.3 Reactions
3.2.3.1 Reactivity
Isoxazole contains furan-type oxygen and pyridine-type nitrogen at the

positions-! and -2, it is therefore considered to exhibit characteristic reactions of
furan and pyridine. But isoxazole undergoes electrophilic substitutions more
readily than pyridine and less readily than furan because of combined effect of
both the structural effects in isoxazole; (i) the electron-withdrawing effect of the
pyridine-type nitrogen and (ii) the electron-releasing effect of the furan-type
oxygen. As position-4 in isoxazole is with high electron density, electrophilic
substitution, therefore, occurs at the position-4. The electron-releasing substituents
at the positions-3 and I or -5 exert activating effect, while the electron-withdrawing
substituents at C-3 and I or C-5 exert deactivating effect on the isoxazole nucleus
at the position-4 . The substituent at the position-S exerts activating or deactivating
effect on the position-4 more strongly than the effect exerted by the substituent
if present at the position-3 .
3.2.3.2.1 Electrophlic Attack at Nitrogen
Isoxazole is a weak base with pK3 = -2.97 because of the base-weakening effect
of the furan-type oxygen. Moreover, the presence of methyl group(s) at the
position-3 and/or position-S causes further base-weakening effect due to steric
hindrance which is comparatively greater if methyl group is present at the
position-3 rather than at the position-S (3-methylisoxazole, S-methylisoxazole and
3,S-dimethylisoxazole correspond to pK3 values of 1.62, 2.0 I and 1.61, respectively).
Isoxazole, although least basic among the azoles, undergoes N-alkylation when
treated with alkyl iodides or sulfates with the formation of quaternary azolium salts.
However, the isoxazolium salts with bulky N-substituents are obtained by treating
isoxazoles with an alcohol in the presence ofperchloric acid (scheme-136).
70%HC104
375
Scheme-136
Both the heteroatoms influence the electrophilic substitutions in isoxazole ring.

The electron-withdrawing nature of the pyridine-type nitrogen retards the attack
of electrophile, but the electron-releasing effect of the furan-type oxygen atom
facilitates electrophilic attack in isoxazole nucleus (Fig. 40). The preferential attack
of electr-ophile at the position-4 in isoxazole ring can be rationalized by the relative
stability of the intermediates resulting from the attack at the positions-3,-4 and
-S (Fig. 41 ). The intermediates resulting from the electrophilic attack at C-3 and
C-S involve unfavourable resonating structures with positively charged nitrogen
contammg sextet of electrons. However, the resonating structures for the

intermediate resulting from the attack of electrophile at C-4 do not involve such
unfavourable resonating structure. Thus electrophilic substitutions in isoxazoles
occur at the position-4, but isoxazoles fail to undergo electrophilic substitutions
if position-4 is occupied.
activated by mesomerically - - - . 4
electron-releasing effect
of oxygen ~
5
~ ~
N
0 ...- 2
0
3 ...,. deactivated by electron-
withdrawal by pyridine-
type nitrogen
(pyridine-!3-position) ~ 1 (pyridine-a-position)
deactivated by (i) mesomerically electron-withdrawal by nitrogen
(pyridine-y-position)
(ii) inductively electron-withdrawal by oxygen
Fig. 40
c:+0 ...
(attack at C-3)
E+
• [dE~ 0 ...
unfavourable
• d-E]
(ii)
(i)
~0N + E+ ____.. [E=tN ... ... E~N]

F\]
0 ...
~oca~ackatc:4> [ H._ h (i) H>CJ <H~'

.,...N +E--.. E~_ ..... N ........ E ~N+.._.. At~N
o o o' E o
(attack at C-5) unfavourable
(i) (ii) (iii)
Fig. 41. Electrophilic attack at different positions in isoxazole
3.2.3.2.2.1 H ~ D Exchange
Isoxazole undergoes H ~ D exchange reaction in D 2S04 at the position-4

(scheme-137). The presence of methyl group at the positions-3 and -5 activates the
isoxazole nucleus with the enhancement of H ~ D exchange reaction rate. The
activating effect of the methyl group, if present at the position-5, is relatively

greater than that present at the position-3. The activating effect in 3,5-dimethyl-
isoxazole is the sum of the effects exerted by both the methyl groups present at
the positions-3 and -5 separately.
Scheme-137
lsoxazole is nitrated at the position-4 by the nitrating mixture of concentrated

nitric and sulfuric acids under controlled conditions (35-40°C) (scheme-138).
02N
eN
0
HN0 3
H 2S0 4
'()
0
2 (35-41J'q
376
Scheme-138
Nitration of 5-methylisoxazole 377 with nitrating mixture at 60-70°C

porduces 5-methyl-4-nitroisoxazole 378 involving following reaction mechanism
(scheme-139):
...,_
+
-H
Scheme-139
However, nitration of 3-methyl-5-phenylisoxazole 379 with nitrating mixture

occurs at the para-position of the phenyl ring . But nitration with acetyl nitrate
takes place at the para-position of the phenyl ring as well as at the position-4 of
the isoxazole ring ( scheme-140).
379 AyO
381
Scheme-140
Isoxazole ring is resistant to sulfonation, however sulfonated with oleum under

drastic conditions with the introduction of sulfonic acid group at the position-4
(scheme-141). But 5-phenylisoxazole 383 is sulfonated by chlorosulfonic acid with
the sulfonation of only phenyl ring at the meta- and para- positions (scheme-142).
Scheme-141
383 384
Scheme-142
Isoxazoles undergo halogenation with chlorine or bromine at the position-4 with
the formation of the corresponding 4-chloro- 386 or 4-bromo- 387 isoxazoles
(scheme-143).
H,c'i:}cH,
388
Scheme-143
If the phenyl ring is present at the 3- and/or 5-position, halogenation takes place
at the position-4 of the isoxazole ring (scheme-144). Isoxazo1es are iodinated with
iodine in the presence of concentrated nitric acid (scheme-145).
Cl
Scheme-144
conc.HN0 3
Scheme-145
3.2.3.2.2.5 Chloromethylation and Hydroxymethylation
The reaction of isoxazoles with formaldehyde and hydrochloric acid in the

presence of zinc chloride results in chloromethylation at the position-4
(scheme-146).
::})cH 3
390
Scheme-146
Similarly, the treatment with formaldehyde in the presence of sulfuric acid causes
hydroxymethylation at the position-4 of the isoxazole ring (scheme-147).
~:})CH3
391
Scheme-147
Isoxazoles are mercurated in the position-4 when treated with mercury acetate
(scheme-148).
d.? 383
/
N
Scheme-148
3.2.3.3 Oxidation
Isoxazoles are stable towards oxidizing agents, but unsaturated side chains and
the oxygenated functional groups are oxidized to their corresponding acids
(scheme-149).
rlCH=CH2 KMn04
H,C-OCOOH
H3c...Z0 /'N
393 394
CH20CH3
~N CH3COOzH
H,C-OCOOH
H3C 0/
395 396
Scheme-149
The stability of different heterocycles can be compared by using oxidation

reactions, which indicate isoxazole ring to be more stable than the furan ring while
less stable than the pyrazole ring (scheme-150).
t:P0
CCOOH
0
zr:N
397 398
COOH
N
H
0 N
H
399 331
Scheme-150
3.2.3.4.1 Nucleophilic Displacemen t
Since isoxazole is with highest electron density at the position-4, it is therefore

the preferred site for the electrophilic attack. The isoxazoles substituted with
halogen atom at the position-4 will be less susceptible to nucleophilic substitution
(SN2) reactions. However, the halogen atom at the position-S can be replaced if
position-4 is substituted with the suitable activating substituent ( scheme-151 )48 .
NC CH 3
RNH2
R-W-t~
H 0
401
Scheme-151
The halogen atoms at the 3- and 5-positions can be replaced by nucleophiles

if activated by ring quaternization ( scheme-152) .
rl~l
I(
0
/'N._CH
- 3
+ RS . n:R
I(· /'N._CH
0 - 3
Cl Cl
402 403
Scheme-152
3.2.3.4.2 Ring Cleavage via C-Deprotona tion
The reaction of 3-unsubstituted isoxazoles with a base (hydroxide or ethoxide ions)

proceeds with the nucleophilic attack at C3-H and leads to the ring opened
product (3-ketonitrile 405 with the cleavage of the N-0 bond (scheme-153).
Quaternization of the nitrogen atom increases the reactivity of the isoxazole ring
towards nucleophiles . The 3-unsubstituted isoxazolium salts 406 react rapidly
even with a weak base with the cleavage of N- 0 bond and provide unstable
N-substituted ketoketimines 408 which converts carboxylic acids into acylating
agents ( scheme-154)49 .
8-
, H--OH
IIi\
H3C~ 0•.'N
8-
404
CH3-C-CH2CN
II
0
405
Scheme-153
H
n-<~.
c~ _,\N--R ·B
3 0
406
HC-C-NHR
/J ,,
c 0
/ \ c
H3C o-1 ~0
R'
410 409
Scheme-154
If isoxazoles are substituted at the position-3, but unsubstituted at the

position-S, the ring cleavage proceeds differently and the reaction courses depend
upon the nature of the substituents (scheme-155). If position-3 is substituted with
a group that can be eliminated as an anion (such as cl- and eN-), the reaction
proceeds without the cleavage of C3-C4 bond of the isoxazole ring with the
elimination of substituent at C-3 as an anion (scheme-156).
When 3-acylisoxazoles 416 are treated with a base, the reaction proceeds via the
initial attack of a base at the carbonyl carbon to provide a carboxylate salt and a
(3-ketonitrile 417 (scheme-157).
412
Scheme-155
c=N
HC~
/ + a-
IC2Hs0~
C=O
415
Scheme-156
Scheme-157
3.2.3.4.3 Reductive Ring Cleavage
Isoxazole ring is easily cleaved under reducing conditions. The catalytic

hydrogenation of isoxazoles results in ring opening with the formation of
enarninones 419 which under mild conditions are hydrolyzed to 1,3-diketones 420
and reduced to arninoketones 421 . Enarninones 419 can be transformed into a
number of heterocycles 422 (scheme-158)49 .
The reduction of isoxazoles with lithium aluminium hydride produces arninoketones
involving cleavage ofN-0 bond (scheme-158).
R'
~~+
R-t0'~
Raney Ni •
90%
R-C-CH=C-R'
II I
0 NH2
421 420
Scheme-158
3.2.3.5 Condensation Reactions
The methyl group at the position-S will be more reactive than the methyl group
at the position-3, if position-4 is substituted with an electron-withdrawing group.
Thus, 5-methyl group with enhanced reactivity is easily condensed with aromatic
aldehydes in the presence of diethylamine, but 3-methyl group remains intact
(scheme-159).
o,\,(:
H3C..J(_O....'~ ArCHO
423
Scheme-159
3.2.3.6 Rearrangement
Isoxazoles (also other heterocycles with N-0 bond), substituted with suitable side
chains of three atoms (hydrazone, oximine and imidine) at carbon a- to the
pyridine-type nitrogen, undergo special type of thermal and base catalyzed
rearrangement, known as Boulton-Katritzky rearrangement, by following generalized
mechanism ( scheme-160) 53 :
Scheme-160
3.2.3.7 Photochemical and Thermal Reactions
Isoxazoles are photochemically or thermally transformed into oxazoles via 2H-

azirine intermediate 428 (scheme-161) 49 .
Hvor~
2,5-0xazole
429
Scheme-161
3.3 lsothiazoles 54 - 57
3.3.1 General
The chemistry of isothiazole began in 1956 with its first synthesis, although its
derivative saccharin 430, non-carbohydrate sweetening agent, was prepared in
1879. Isothiazole is numbered as shown in structure 3.
4 3
5o~N
s ... 2
Benzene ring is fused to the isothiazole ring in two ways providing possibly
two isomers of benzisothiazole 58 depending on the positions of attachment;
1,2-benzisothiazole or benz[d)isothiazole 431 and 2,1-benzisothiazole or benz[c]-
isothiazole 432 and are systematically numbered as :
Saccharin is the most important synthetic isothiazole derivative and is used as

non-nutritive sweetner. Isothiazole ring is incorporated into biologically active
compounds of the medicinal and industrial applications. Some of the isothiazole
derivatives are listed with their activity.
0
C2Hs
I sedative, hypnotic
(i) N-CH-CONH2 and anticonvulsant
~
s,,
0 0
0N
CH3
(ll) H,c-N~
~-ss/r
hypoglycaomic •ctivity
CH3
1 \ C6Hsn-(
(iii) H3c- N N- 6H-( _)~ appetite suppressant activity
\__/ s/
0
II
Ar-NH-C CH 3
(iv) 0
II
Jd~
I N
antiinflammatory
C6Hs-C-~ S/
CH 3
(v) H,N-Q-so,NH-0 ""tib•cteri.U •ctivity
(vi) herbicidal activity
3.3.2 Synthesis
3.3.2.1 Oxidative Cyclization of y-Iminothiols
This is the most widely used method for the synthesis of isothiazoles and involves
oxidative cyclization of y-iminothiols 433b (or their tautomers 13-iminio thiones
433a) with halogens or hydrogen peroxide resulting in isothiazoles with the
formation of N-S bond ( scheme-162)55•59 . The cyclization occurs by nucleophilic
--
R' /CH2 R R', ~CH, , R R'' //CH
~ '-.. ,R
---
'c "c"' c c x2 c c
II II I II I II
s NH SH NH [12]
X~sV:NH
433a 433b
434
R = alkyl, OR, SR, OH
R' = NH 2 , H, Ar +-x
R'
. R H
t:<Ns
-H+
R' . . . . cqc,c-R
\ + ,,
S-N
V'H
436
435
Scheme-162
substitutionm on the sulfur atom via 434. This synthetic method can be extended
to obtain benzisothiazoles (scheme-163 )58 .
12
~N
~s/
437 3
~
~N/s
438 3a
Scheme-163
3.3.2.2 Ring Transformation
lsoxazoles can be transformed into the corresponding isothiazoles by an initial

catalytic hydrogenation with the cleavage ofN-0 bond followed by sulfurization
to the thioamide 441 and oxidative cyclization with chloranil (scheme-164 )55 ·60 .
[ ;:<~,]
R' S
441
R
R'~
[0]
chloranil
s
442
Scheme-164
3.3.2.3 From Alkenes
Isothiazoles can be prepared by passing a mixture of an alkene, sulfur dioxide and

ammonia over an oxide catalyst at an elevated temperature (scheme-165).
Scheme-165
Propene and isobutene afford isothiazole and 4-methylisothiazole respectively,

but !-butene and 2-butene produce a mixture of 3- and 5-methylisothiazoles
because of isomerization.
3.3.2.4 From a,(3-Unsaturated Carbonyl Compounds
The reaction of a,(3-unsaturated aldehydes or ketones, substituted with

thiosulfonate at (3-position, with ammonia or amines at low temperature results in
the formation ofisothiazoles involving (4 + 1) cyclization (scheme-166).
0
0
II
CH=CH-C-R -3<Y'C
I - + + NH3
s-so3 Na s
443
Scheme-166
3.3.3 Structure
lsothiazole (yellow liquid, b.p. 113°C) is a planar heterocycle with six 7t-delocalized
electrons and behaves as a stable aromatic molecule. The degree of the bond
fixation in isothiazole is very small as is evident from the comparison of the bond
lengths of the isothiazole derivatives61 with the standard values of the single and
double bonds (Fig. 42).
Standard bond lengths (A) Bond lengths (A)
C-C 1.537 S-N 1.661
C=C
S-N
1.335
1.735 H')JOH C-N
C3-C4
1.316
1.397
C-N 1.413 1.380
CH 3 -S02 s N CcCs
C=N 1.290 C-S 1.715
C- S 1.812
C=S 1.554
Fig. 42. Structural parameters in isothiazole derivatives
Isothiazole is the most aromatic among 1,2-azoles and follows the order as :
isothiazole > pyrazole > isoxazole. Isothiazole is considered to be the resonance
hybrid of the resonating structures in which the carbon atoms and the nitrogen
atom bear negative charge, while the sulfur atom bears small positive charge
(Fig. 43).
~-CN
s
CN~CN-
s s
(i) (ii) (iii) (i~ (~
Fig. 43. Resonating structures of isothiazole
The resonating structure (iv) is stabilized by a C=N and a C=s+ and, therefore,
contributing considerably to the resonance hybrid. Moreover, the charge density
approximation has also indicated C-4 with highest electron density, while C-3 with
lowest electron density. The position-4 in isothiazole is, therefore, 104 times more
reactive towards electrophiles than expected on the basis of n-electron density.
3.3.4 Reactions
Isothiazole is the least reactive towards electrophiles among 1,2-azoles with the
reactivity order as : pyrazole > isoxazole > isothiazole, similarly as in five-membered
heterocycles with one heteroatom: pyrrole > furan > thiophene. The electrophilic
substitution in isothiazole occurs at the position-4 because of the higher stability
of the transition state resulting from the electrophilic attack at C-4 than those
resulting from the attack of electrophile at C-3 and C-5 (Fig. 44). The resonating
structures for the transition states due to electrophilic attack at C-3 and C-5 involve
very unfavourable structures with positively charged azomethine nitrogen.
attack at C-3
[ dE~,..,
s,...
(unfavourable)
attack at C-4
'-a-t a_c_~_+a_t ~
-C---15 [ >QN ~~-S-,...N~>0-~-'lN]
(unfavourable)
Fig. 44. Electrohilic attack at different positions in isothiazole
3.3.4.1.1 Nitration
Isothiazole is nitrated under vigorous conditions at the position-4 using nitrating

mixture of sulfuric and nitric acids at 230°C (scheme-167).
445
Scheme-167
Isothiazole is sulfonated at the position-4 when treated with oleum (cone. H2 S04
+ S03) at 150°C (scheme-168).
Scheme-168
3.3.4.1.3 N-Aikylation
Isothiazole ring nitrogen is readily alkylated by diazomethane, dimethyl sulfate or

alkyl halides, ifposition-3 or -5 in the isothiazole ring is substituted with a hydroxyl
group which can be tautomerized to the ring NH structure (scheme-169). Although
amino group at the position-3 or -5 in the isothiazole ring may be considered to
have similar involvement in tautomerism, aminoisothiazole exists predominantly as
amino tautomer and undergoes diazotization.
OH 0]
Q=QH 0-cH,
0
[
CH 30H
447a 447b 448
Scheme-169
3.3.4.2 Side Chain Reactivity
3.3.4.2.1 Reaction with Aromatic Aldehydes
5-Methylisothiazole is condensed with an aromatic aldehyde due to enhanced

reactivity of the methyl group (scheme-170).
Scheme-170
3.3.4.2.2 Decarboxylation
Isothiazoles substituted with carboxylic groups at the ring carbon atoms

decarboxylate most readily with the removal of a carboxylic group that is adjacent
to the ring heteroatom ( scheme-171).
/c)
HOOC
mesitylene
reflux, 2 hrs. s
452
Scheme-171
The relative reactivities of the halogen atoms towards nucleophilic substitutions

depend on their positions in the isothiazole ring . Because of being the position-
4 with high electron density (most preferred site for electrophilic substitution), the
halogen atom at the position-4 would be less susceptible towards nucleophilic
substitutions. Halogen atoms at the positions-3 and -5 in the isothiazole ring are
reactive in nucleophilic substitutions, if position-4 is substituted with an electron-
withdrawing substituent. But halogen atom at the position-3 is less reactive than
the halogen atom at the position-S ( scheme-172) 55 .
:J:>CI_NH_3.•~.
453
Scheme-172
3.3.4.3.2 Ring Transformation
The reaction of quaternary isothiazolium salts 456 with phenylhydrazine results

in pyrazole 457 (scheme-173).
456
Scheme-173
However, the treatment of isothiazolium salt 458 with reactive methylene

compounds leads to the formation of thiophene derivative 459 involving cleavage
of the N-S bond (scheme-174).
458 459
Scheme-174
3.3.4.3.3 Lithiation
Isothiazoles are lithiated at the position-S by the reaction with n-butyllithium and
provide 5-lithioisothiazoles which react with a wide ranging reagents to introduce
functional groups at the 5-position of the isothiazole ring (scheme-175).
R R
'CN
s
460
+ n-Buli
Scheme-175
3.3.4.3.4 Ring Cleavage
Isothiazoles are stable to nucleophillic attack of hydroxide ions, but isothiazolium

salts involve the attack of hydroxide ions at the ring carbon providing ring opened
product 466 via 465 with the cleavage of the N-S bond (scheme-176).
Scheme-176
3.3.4.4 Photochemical Transformation
Isothiazoles are photochemically transformed into thiazoles via an intermediate 467

(scheme- 177). The equilibrium is set up between isothiazole and thiazole55 •64 .
tJ
R R
0 s
hv
..........----
s
443 467
Scheme-177
3.3.4.5 Oxidation
Trisubstituted isothiazoles are oxidised by peracids to their 1-oxidies 468 which

are further oxidized to 1, 1-dioxides 469. But oxidation of isothiazoles, unsubstituted
at the position-3, with hydrogen peroxide in acetic acid at 80°C provide 1,2-thiazol-
3(2H)-one-1, 1-dioxides 470 (scheme-178)65 .
R R R R R R
R
):j
s
N
[0]
Peracids
R
):j
s
N
[0]
R
):j N
II 0-;:::::.S.:::::-0
0
468 469
R 0
Rb
R
R b s
N
H202
CH3COOH
800C 0-;:::::.S.:::::-0
470
Scheme-178
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CHAPTERS
FIVE-MEMBERED HETEROCYCLES WITH MORE

THAN TWO HETEROATOMS
CONTENTS
GENERAL 491
1.1 Effects of Additional Nitrogen Atoms 492
2 TRIAZOLES AND TETRAZOLES 492
2.1 1,2,3-Triazoles 492
2.1.1 General 492
2.1.2 Synthesis 493
2.1.2.1 Oxidative Cyclization ofbis-Hydrazones of 493
a-Diketones
2.1.2.2 Cycloaddition of Azides with Alkynes 494
2.1.3 Reactions 495
2.1.3.1 Amphoteric Nature 495
2.1.3.2 Electrophilic Substitutions 496
2.1.3.2.2 Acylation 498
2.1.3.3 Thermal and Photochemical Reactions 499
2.1.3.4 Dimroth Rearrangement 501
2.1.3.5 Ring Cleavage Reactions 502
2.2 l 2, ,4-Triazoles 503
2.2.1 General 503
2.2.2 Synthesis 504
2.2.2.1 From Hydrazine Derivatives 504
2.2.2.2 From Nitrilimines 505
2.2.3 Structure 506
2.2.4 Reactions 506

2.2.4.1 · Acidity-Basicity 506
2.2.4.2.1 Reactions with Electrophiles 508
2.2.4.2.1.1 Electrophilic Attack at 508
Nitrogen
2.2.4.2.1.2 Quatemization 509
2.2.4.2.1.3 Electrophilic Attack at Carbon 509
2.2.4.2.2 Reactions with Nucleophiles 510
2.2.4.2.3 Reactions with Electron-Deficient Species 511
2.2.4.2.3.1 Reactions with Nitrenes 511
2.2.4.2.3.2 Reactions with Carbenes 511
2.2.4.2.4 Oxidation 512
2.2.4.2.5 Thermal and Photochemical Reactions 512
2.3 Tetrazoles 513
2.3.1 General 513
2.3.2 Synthesis 513
2.3.2.1 From Imidoyl Chlorides 513
2.3.2.2 From Amidrazones 515
2.3.2.3 From Nitriles 516
2.3.2.4 From Nitrilium Salts 516
2.3.2.5 From Isonitriles 517
2.3.3 Structure 517
2.3.3.1 Hydrogen Bonding 518
2.3.4 Reactions 519
2.3.4.2.1.1 Acidity 520
2.3.4.2.1.2 H ~ D Exchange 521
2.3.4.2.1.3 Metallation 521
2.3.4.2.2 Nucleophilic Attack at C-5 522
(Nucleophilic Substitutions)
2.3.4.3.1 Reactions Involving 522
Nitrilimine Intermediates
2.3.4.3.2 Reactions Involving Carbene Intermediates 524
2.3.4.3.3 Reactions involving Nitrene Intermediates 524
2.3.4.4 Rearrangements 525
3 OXADIAZOLES 525
3.1 1 2,3-0xadiazoles
, 526
3.2 1,2,4-0xadiazoles 527
3.2.1 General 527
3.2.2 Synthesis 528
3.2.2.1 Cyclization Reactions (From Amidoximes) 528
Five-Membered Heterocycles with More Than Two Heteroatoms 489
3.2.2.2 I ,3-Dipolar Cycloadditions 528

3.2.3 Structure 529
3.2.4 Reactions 529
3.2.4.1 Electrophilic Substitution Reactions 529
3.2.4.2 Nucleophilic Substitution Reactions 530
3.2.4.3 Reactions of Substituents 530
3.2.4.5 Ring Cleavage via C-Deprotonation 532
3.3 1 2, ,5-0xadiazoles 533
3.3.1 General 533
3.3.2 Synthesis 534
3.3.2.1 Furazans 534
3.3.2.1.1 Dehydration of a-Dioximes 534
3.3.2.1.2 Ring Transformations 534
3.3.2.2 Furoxans 535
3.3.2.2.1 Oxidation of a-Dioximes 535
3.3.2.2.2 Dehydration of a-Nitro Ketone Oximes 536
3.3.3 Structure 536
3.3.4 Reactions 537
3.3.4.3 Ring Cleavage via C-Deprotonation 538
3.4 1,3,4-0xadiazoles 540
3.4.1 General 540
3.4.2 Synthesis 541
3.4.2.1 From Diacylhydrazines 541
3.4.2.2 Ring Transformation 541
3.4.3 Structure 542
3.4.4 Reactions 543
3.4.4.2.1 Nucleophilic Substitution Reactions 544
3.4.4.2.2 Nucleophilic Attack with Ring Cleavage 545
4 TillADIAZOLES 547
4.1 1 ,2,3-Thiadiazoles 547
4.1.1 General 547
4.1.2 Synthesis 547
4.1.2.1 Pachmann and Nold Synthesis 547
4.1.2.2 Hurd-Mori's Classical Synthesis 548
(From Hydrazones)
4.I.3 Structure 549

4.I.4 Reactions 549
4.I.4.2 Reactions with Nucleophiles 550
4.1.4.2.3 Nucleophilic Attack at Sulfur 55I
4.1.4.3 Oxidation 55I
4.I .4.4.I Thermal Reactions 552
4.1.4.4.2 Photochemical Reactions 552
4.1.4.4.3 Rearrangements 553
4.2 I ,2,4-Thiadiazoles 553
4.2.1 General 553
4.2.2 Synthesis 554
4.2.2.1 Oxidative Cyclization ofThioacylamidines 554
4.2.2.2 From Amidines 554
4.2.2.3 Heterocyclic Ring Transformations 555
(Oxazole and Oxadiazole Rearrangements)
4.2.3 Structure 557
4.2.4 Reactions 557
4.2.4.3.1 Nucleophilic Substitution Reactions 559
4.2.4.3.2 Ring Cleavage 560
4.2.4.3.2.1 Nucleophilic Attack at 560
Carbon
4.2.4.3.2.2 Nucleophilic Attack at 560
Sulfur
4.2.4.4 Reduction 56I
4.3 I ,2,5-Thiadiazoles 56 I
4.3.I General 561
4.3.2 Synthesis 562
4.3.2.1 From o-Diamines [(4 +I) Cyclization] 562
4.3.3 Structure 563
4.3.4 Reactions 563
4.3.4.1 Stability 563
4.4 I,3,4-Thiadiazoles 566
4.4.I General 566
4.4.2 Synthesis 567
4.4.2.1 From Thiosemicarbazides 567

4.4.2.2 From Dimethylformamide 568
4.4.2.3 From Hydrazine 568
4.4.3 Structure 569
4.4.4 Reactions 569
(Quaternization)
570
=
4.4.4.3.1 H D Exchange 570
4.4.4.3.3 Amination 571
4.4.4.4 Reactions Involving Ring Formation 572
REFERENCES 573
1 GENERAL
Five-membered heterocycles with more than two heteroatoms are considered to be

derived from pyrrole, furan and thiophene by the replacement of methine groups
(-CH=) by pyridine-type nitrogen (-N=) atoms from the different positions and are
z,
named as (Fig. 1) 1 :
N-N
with two !(~,...N ~
,...N N, ,...N I( )\
-N=atoms X X X X
0
1,2,3- 1,2,4- 1,2,5- 1,3,4-
(-)-CH= X= NH (Triazoles); X = 0 (Oxadiazoles); X = S (Thiadiazoles)
X ( +)--N = N-N
II ''
ff ~\ X = NH (Tetrazoles)
with three '- ,...N N, ,...N X=O(Oxatriazoles)
X X X= S (Thiatriazoles)
-N=atoms 1,2,3,5-
1,2,3,4-
Fig. 1. Heterocycles with more than two heteroatoms

1.1 Effects of Additional Nitrogen Atoms2-s
(i) Basicity : The base strength generally decreases with increasing the
number of nitrogen atoms because of inductively electron-withdrawing
effect of the pyridine-type nitrogen atoms ( diazines are weaker bases than
pyridine). The additional nitrogen atoms in these heterocycles, therefore,
have base-weakening effect as a result of which these systems are with
lower basicity
(ii) Acidity : The acidity of the ring system increases with the number of
nitrogen atoms as tetrazoles are more acidic than triazoles. Triazoles are
comparable with phenol in acid strength, while 1H-tetrazole behaves as an
acid (acetic acid). The positions of nitrogen atoms (orientation) do not
affect considerably the acid strength as 1,2,3-triazole is slightly more acidic
than 1 ,2,4-triazole. But the effect of orientation on acidity is much less than
the effect of the total number of nitrogen atoms.
(iii) The tendency of the ring system towards electrophilic attack falls off with
the introduction of additional pyridine-type nitrogen atoms. Triazoles,
oxadiazoles and thiadiazoles are, therefore, resistant towards electrophilic
attack and undergo electrophilic substitutions only if powerful electron-
releasing substituents are present.
(iv) The introduction of pyridine-type nitrogen atoms in the ring system affects
the ease of quaternization. The quaternization of triazoles, oxadiazoles
thiadiazoles and tetrazoles requires stronger reagents and reaction conditions.
2 TRIAZOLES AND TETRAZOLES
2.1 1 ,2,3-Triazoles 6- 9
2.1.1 General
I ,2,3-Triazole 1 is a planar five-membered heterocyclic system with two carbon and

three nitrogen atoms (one pyrrole-type and two pyridine-type) in the 1-,2- and 3-
positions. It was also named as v-triazole (v for vicinal) to distinguish it from
s-triazole (s for symmetrical). 1,2,3-Triazole exists in two tautomeric forms ; lH- and
2H-froms, in which 1H-form was initially considered more stable than the 2H-form,
but spectral studies have confirmed the predominance of symmetrical2H-form. The
destabilization of 1H-form is considered to be due to repulsive forces between the
nonbonding electron pairs on the nitrogen atoms at positions-2 and -3 (Fig. 2).
1H-form 2H-form
1H-1 ,2,3-Triazole 2H-1 ,2,3-Triazole (2, 1,3-triazole or osotriazole or 1,2, 5-triazo le)
Fig. 2. Tautomeric forms of 1,2,3-triazole
The fusion of a benzene ring with both the forms of I ,2,3-triazole results in
benzotriazoles which are named and numbered as shown in structures 2 and 3.
Benzotriazole also exists in two tautomeric forms, but 1H-form predominates over
the 2H-form (Fig. 3).
5(X1 N,,N
4 3 4 3
5u::;---N,NH
~ /2 ~ ~ /2
6 1N 6 1N
7 H 7
2 3
1H-form 2H-form
1H-Benzo[d][l,2,3-triazole] 2H-Benzo[d][ 1,2,3-triazole]
( 1,2,3-Benzotriazole) (2, 1,3-Benzotriazole)
Fig. 3. Tautomeric forms of benzotriazole
1 ,2,3-Triazoles find their applications in medicines as sedatives, antiinflammatory,

analgesics etc. and in agriculture as herbicides, fungicides and antibacterial agents.
The industrial applications of 1,2,3-triazoles include their uses as fluorescent
whiteners, light stabilizers and optical brightners.
2.1.2 Synthesis
2.1.2.1 Oxidative Cyclization of bis-Hydrazones of a-Diketones
Bis-hydrazones of a-diketones 4 undergo oxidative cyclization when treated with

mercury acetate or manganese dioxide to provide 1-amino-1 ,2,3-triazoles 5
involving N 1-N 2 bond formation (scheme-1) 10•11 .
Scheme-l
However, with unsymmetrical his-hydrazone 6, both possible 1,2,3-triazoles; 7

and 8, are obtained (scheme-2) 12 .
-
OH
6 7 8
Scheme-2
2.1.2.2 Cycloaddition of Azides with Alkynes
This is the most versatile route to synthesize 1H- 1,2,3-triazoles and involves
thermal 1 ,3-dipolar cycloaddition of a wide variety of organic azides to alkynes
with the formation of C5-N 1 and CcN3 bonds (scheme-3) 6•9 •13 . However, the
HsC6
110"C
ff-~ + If~
18 hrs. L( ,N HsC6
A N,N
N
I I
(R = alkyl, vinyl, aryl, acyl, R R
arenesulfonyl) 9 10
(major product) (minor product)
Scheme-3
cycloaddition of trimethylsilyl azide to alkynes at higher temperature produces

N -trimethylsilyl-1 ,2,3-triazoles. The silyl group can be easily removed to obtain 1H-
1,2,3-triazoles in good yields (scheme-4) 14 .
150-17fJ'C
R'ff-~
6-20hrs. R~ _..N
N
I
Si(CH3)J
11
Scheme-4
The parent compound 1,2,3-triazole 1 is obtained by the direct addition of hyd-

razoic acid to alkynes substituted with an electron-withdrawing group (scheme-5).
HC::C-COOH + HN3
~~~
~ 'Z._ _..N
N
H
1
Scheme-5
2.1.3 Reactions
2.1.3.1 Amphoteric Nature
1,2,3-Triazole is a weak base but it can also behave as a weak acid with comparable
strength to phenol (scheme-6). The presence of methyl group at the position- I
does not affect base strength considerably as 1-methyl-1 ,2,3-triazole exhibits
basicity comparable to 1,2,3 triazole. But with methyl group at the position-2,
basicity is decreased. 2-Methyl-1 ,2,3-triazole is therefore a much weaker base. The
base-weakening effect of methyl group in 2-methyl-1,2,3-triazole can be explained
by the formation ofpyrazolium-type cation 13, while very weak base strengthening
effect of the methyl group in 1-methyl-1 ,2,3-triazole is atributed to the formation
ofimidazolium-type cation 12 (Fig. 4).
+ +
+H ~~~ H
~
l( /N ---;-
-H N -H
pKa = 1.2 H pKa = 9.4
(ii) (i) (i) (ii)
~
F~
~ _,N
N
(iii)
Scheme-6
+
//~,H //NH ~\
(+N
i(_ _,N ~ tz..+~~ ' CH3
N N N/
I I H
CH3 CH3
a b a b
imidazolium-type cations pyrazolium-type cations
12 13
Fig. 4.
2.1.3.2 Electrophilic Substitutions
1 ,2,3-Triazole undergoes electrophilic substitution at a ring carbon or at a ring

nitrogen as three-hydrogen atoms are available (two-hydrogen atoms on ring
carbons and one-hydrogen atom on nitrogen) for the electrophilic replacement
(Fig. 5). Moreover, in unsymmetricall ,2,3-triazole, N-H is present at three different
- /"):N
......,....H
twoC H~ V \\
+ H _,N
N
One N-H H
Fig. 5. Three replaceable hydrogens

positions due to tautomerism and therefore three different N-substitutions are

possible with the formation of three possible isomers (Fig. 6). But in symmetrical
~
[,...N ~~~H
(!..,_ .~N
N N
H
Fig. 6. Three N-H positions
1,2,3-triazole two N-H positions result in two different N-substitutions with the
formation of two isomeric N-substituted derivatives (Fig. 7).
~ I \ I \
N, ,...N N~ ,...NH HN, ~N
N N N
H
I I
identical
Fig. 7. Two N-H positions
1 ,2,3-Triazoles undergo N-alkylation with a variety of alkylating agents. The ratio

of isomers depends upon the nature of alkylating agents and the reaction
conditions. Methylation of 1,2,3-triazole with diazomethane occurs preferentially at
N-2 with the formation of 2-methyl-2H-1,2,3-triazole 14. But methylation with
methyl iodide in the presence of silver salt takes place preferentially at the
position-! (scheme-7).
CH 2N2 ;:N
f ~,H /,..._......:;......;:....-t.,.~ N . . . ~-CH 3 (at position-2)
N,...N "-.
~
CH 3I [N \\
H silver salt ,... N (at position-!)
N
I
CH3
Scheme-7
The steric effects of the substituents also affect the formation of products.
Methylation of 4-phenyl-lH-1,2,3-triazole 16 with dimethyl sulfate occurs at
N-1 and N-2 to provide 1-methyl- 17 and 2-methyl- 18 isomers in 62% and 38%
yields, respectively, but sterically hindered 1-methyl-5-phenyl derivative 19 is not
formed (scheme-S).
16
Scheme-S
2.1.3.2.2 Acylation
Acylation of 1,2,3-triazoles with acyl halides or acid anhydrides occurs initially at

the position-!, but in some cases acyl group may migrate from the position-! to
the position-2 when 1-acyl derivative is heated above l20°C or treated with a base
(scheme-9).
~~~ >120'C
l!..._ ,_N
N
I
COCH3
20 21 22
Scheme-9
Bromination of 1,2,3-triazole with bromine occurs at the positions-4 and -5 with the
formation of 4,5-dibromo-1 ,2,3-triazole 23, but with an excess of sodium hypobromite
in acetic acid 1,4,5-tribromo-1 ,2,3-triazole 24 is formed (scheme-10). The high
Br\-~
+ Br
2
sr-ZN,..N
[,..N
~ H
N 23
H
Br\-~,
+ NaOBr
sr-ZN,..N
I
Br
24
Scheme-10
reactivity of 1,2,3-triazole towards bromination is due to the pyrrole-type nitrogen

because bromination of 2-methyl-1 ,2,3-triazole 25 occurs comparatively very
slowly. However, the presence of iron filings as catalyst facilitates bromination to
occur readily at the positions-4 and -5 with the formaion of 2-methyl-4,5-dibromo-
1,2,3-triazole 26 (scheme-11 ).
Br Br
Fe H
N, ,..N
Br 2 N
I
CH 3
26
Scheme-l!
2.1.3.3 Thermal and Photochemical Reactions
1,2,3-Triazoles are stable towards oxidation and reduction, but undergo thermal and
photochemical reactions under forcing conditions with the extrusion of nitrogen.
The reactions proceed with the involvement of an intermediate in any one of the
three mesomeric forms: (i) iminocarbene, (ii) zwitterion or (iii) diradical, depending
on the nature of substituents and the reaction conditions (scheme-12) 12•15 .
R2
R2 R2 R2
R1NR--;-- RJN• ---- ,l

r~ ~
...
/ hv
R3..- N, /N -Nz
N 3 R N
11 R1 1
R (i) (ii) (iii) R
(iminocarbene) (zwitterion) (diradical)
Scheme-12
(i) Vapour phase pyrolysis of unsymmetrically substituted I ,2,3-triazoles 27

and 28 proceeds via iminocarbene intermediates 29a and 29b with the
formation of IH-azirine derivative 30 which rearranges to two isomeric 2H-
azirines 31 and 32 (scheme-13).
29a
400-SOO'C t
Scheme-13
(ii) Pyrolysis of 4,5-diphenyl-1 ,2,3-triazole 33 also proceeds via iminocarbene

intermediate 34 with the extrusion of nitrogen to provide 2,3,5,6-
tetraphenylpyrazine 35 (scheme-14) 16 .
[HsC.~ ]---=C.XNXC.Hs
HsC6
)[ ,,
N 290"C
HsC6 /N -Nz
N HsC6 ~ HsC6 N CsHs
H
33 34 35
Scheme-14
(iii) Irradiation of 1-phenylbenzo-1 ,2,3-triazole 36 produces carbazole 38 via a

diradical intermediate 37 with the elimination of nitrogen (scheme-15).
38
Scheme-15
2.1.3.4 Dimroth Rearrangement 17
5-Amino-1 ,2,3-triazoles 39 undergo Dirnroth rearrangement 17 in which ring nitrogen

and its attached substituent is exchanged with an imino group at an a -position.
The rearrangement proceeds to involve ring opening by cleavage of the N-N bond
and subsequent cyclization via diazoimine intermediates 40 and 41 (scheme-16).
~ ~ ~ ~
~ ___ t : N rearrangement Q~ N ___ )[ ~
Jr'. N - - \\ + /""1. \\ + ---- I N
R1HN N/ R1HN ~ N RHN ~ -, N RHN N/
I N N I
R I 11 R1
R R
39 40 41 42
Scheme-16
The position of the equilibrium is influenced by the nature of the substituents and
also by the solvent basicity (pH of the solvent). The presence of electron-attract-
ing and large groups favours the tautomeric form in which these groups are on the
exocyclic nitrogen, while the alkyl groups prefer to be on cyclic nitrogen (scheme-
17). More basic solvent shifts the equilibrium to the more acidic NH-triazole.
44
Scheme-17
2.1.3.5 Ring Cleavage Reactions
Amino-, azido- and diazomethyl-1 ,2,3-triazoles undergo ring cleavage reactions

with the evolution of nitrogen at elevated temperatures involving concerted
processes (scheme-18) 18 .
HsCs HsCs
f) D fri~
N=N-Nl6:'.,N
>SO"C
N=C
~=~
N
-N2 N~
I I
CaHs CaHs
45 46
..
48
Scheme-18
2.2 1,2,4-Triazoles 5, 19- 21
2.2.1 General
1,2,4-Triazoles are cyclic hydrazidines with hydrogen atom (or substituent) on

either hydrazide nitrogen 49 or on amide nitrogen 50. Parent 1,2,4-triazole (lH-
form) is in tautomeric equilibrium with 1,3,4-triazole (4H-form). The interconversion
4 3 4 3
N-N
5"-.
~~~N s/( )2
N...-2
N1
H H
1
lH-1 ,2,4-Triazole 4H-1 ,2,4-Triazole ( lH-1 ,3,4-triazole)
49 50
of two tautomeric forms occurs rapidly and their separation is difficult, however,
1,2,4-triazole tautomer is preferred over 1,3,4-triazole tautomer (less symmetricallH-
form is favoured over symmetrical4H-form) (scheme-19).
4 1
N 3 HN~2
II~ s ~ ~N (1 ,2,4 > 1,3,4)
5 "'-. ,..N
N 2 N...-3
H 4
1
1,2,4-Triazole 1,3 ,4-Triazole
Scheme-19
N-Unsubstituted 1,2,4-triazoles exist in two tautomeric forms (if substituents R3

and R 5 are different) with the predominance of lH- or 2H- form depending on the
conditions (scheme-20).
2H-form
Scheme-20
2.2.2 Synthesis
2.2.2.1 From Hydrazine Derivatives
Synthesis of 1,2,4-triazoles involves the use of (i) hydrazine, (ii) acylhydrazine, (iii)
amidrazone or (iv) acylamidrazone and represented schematically in (scheme-21).
(i) Hydrazine-
0 0 I
II II
R2 ,
c 'N, c 'R3 +
RNHNH 2 ~
H
(ii) Acylhydrazine - 1 [ R1
R /
0 HN/ HN,
II , 0 N
+ NH __.. II II
3/c, c c
R NH2
1
c
0~ 'R2
R3,; 'N,
H
'R2l
Scheme-21
Einhorn-Brunn er Reaction
This reaction involves the condensation of diacylamines 51 with monosubstituted

hydrazines in the presence of a weak acid and proceeds via an amidrazone
intermediate 52 (scheme-22) . lfN-acy1thioamide 54 is used instead of diacylamines,
the acylamidrazone formation occurs on the thione group (scheme-23).
Scheme-22
54
53
Scheme-23
2.2.2.2 From Nitrilimines
1,3-Dipolar cycloadditions ofnitrilimines 56, obtained by dehydrohalogenation of

C-halobenzylidenephenylhydrazones 55, with nitriles leads to the formation of
1,2,4-triazoles (scheme-24).
+ -
CsH 5 -C=N-NHC 6 H5 C6 H5 -C=N-N-C 6 H5
I
Cl 56
55
Scheme-24
2.2.3 Structure
1,2,4-Triazole has a planar structure with the following structural parameters 22 :
Bond lengths (A) Bond angles (D)
NI-Nz 1.359 4 Cs-NI-Nz 110.2

Nz-CJ 1.323 N 3 NI-Nz-CJ 102.1
C3-N4 1.359 5
I(~
,..N Nz-C3-N4 114.6
NcCs 1.324 N 2 CJ-NcCs 103.0
NI-Cs 1.331 H NcCs-NI 110.1
NI-H 1.030
C3-H 0.930
C5-H 0.930
Fig. 8. Structural parameters of 1,2,4-triazole
1,2,4,Triazole is aromatic and its resonance energy has been estimated to be

205.9 kJ/mol which is comparable with that of pyrazole. The calculated energy
difference between two tautomers of 1,2,4-triazole also supports the preference of
lH-tautomer over the 4H-tautomer23 .
2.2.4 Reactions
2.2.4.1 Acidity-Basicity
1,2,4-Triazole is slightly less acidic (pKa = 10.04 for proton loss), but more basic
(pKa = 2.45 for proton addition) than 1,2,3-triazole. The basicity of 1,2,4-triazole is
attributed to the mesomeric stabilization of the imidazolium type cation 57 formed
on protonation. Moreover, the maximum separation of protonated nitro gens (N 1
and N 4 rather than N 1 and N2 ) makes the cation most stable (scheme-25).
57(ii)
Scheme-25
2.2.4.2 Reactivity
1,2,4-Triazole is considered to be derived from benzene by replacement of

-CH=CH- by -NH- and the replacement of two -CH= by two -N= atoms (Fig. 9) :
0
(-)-CH=CH- ;(+)-NH- p~
'-... ,...N
(-)-CH= ;(+)-N= N
(-)-CH= ;(+)-N= H
Fig. 9.
The replacement of -CH=CH- in benzene by -NH- enhances the electron density

and hence makes 1,2,4-triazole susceptible towards electrophilic attack as
compared to benzene. But the replacement of two -CH= by two -N= atoms causes
the resulting 1,2,4-triazole to be nearly unreactive towards electrophiles. Therefore,
1,2,4-triazoles fail to undergo nitration, sulfonation and N-oxidation. However,
1,2,4-triazole anion undergoes alkylation and acylation very readily.
I ,2,4-Triazoles undergo nucleophilic substitutions, if substituted with electron-
withdrawing substituents. The reactivity of 1,2,4-triazole ring towards nucleophiles
is enhanced in 1,2,4-triazolium cations and meso ionic 1,2,4-triazoles.
2.2.4.2.1 Reactions with Electrophiles
2.2.4.2.1.1 Electrophilic Attack at Nitrogen
Alkylation of N-unsubstituted 1,2,4-triazoles generally occurs at N-1 rather than at

N-4. If there is choice of alkylation between N-1 and N-2 due to the nature of subst-
ituents at the positions-3 and -5, the alkylation occurs at both the positions (N-1
and N-2) with the formation of both N-alkylated products in a ratio depending on
the alkylating agent (scheme-26). However, alkylation of3-halo-l ,2,4-triazoles with
dimethyl sulfate in the absence of a base occurs at N-1, N-2 and N-4 (scheme-27) 24 .
R1 R1 R1
R
2
J-iN
,..N
GI 3I-NaOH
or
rn2N2
R
,Ji N
+
R2
N=\
A N,..N-CH3
H I
CH3
59 60 61
Scheme-26
Cl Cl Cl
z---(
H3C Cl
t~
N=( 'N---(
(GI 3hS04
,..N + ~ ,..N-CH 3 + ,..N ~
N N N N
H I
CH3
62 63 64 65
Scheme-27
If trimethylsilyl group is present at N-1, the alkylation occurs selectively at

N-2 with the removal oftrimethylsilyl group (scheme-28) 25 .
N\
~ ,..N-R + Si(CH3)3X
N
67
Scheme-28
2.2.4.2.1.2 Quaternization
1 2, ,4-Triazoles substituted with alkyl, aryl or acyl substituents on N-1 or N-4

undergo quatemization when treated with powerful quatemizing reagents,
trialkyloxonium tetrafluoroborates. The quatemization occurs on the nitrogen atom
furthest away from the substituted nitrogen (maximum distance between
substituents on annular nitrogen atoms). Thus 1,2,4-triazole substituted on N-1 is
quatemized on N -4 and vice-versa. !-Substituted and 4-substituted 1,2,4-triazoles
are, therefore, quatemized at N-4 and N-1 positions, respectively (scheme-29) 26 .
Diquaternization is also possible with an excess of trimethyloxonium
tetrafl uoro borate.
H3C, +
~~~ ~~~
"- ,....N "- ,....N
N N
I I
CH3 CH3
68 69 70
Scheme-29
2.2.4.2.1.3 Electrophilic Attack at Carbon
1,2,4-Triazole and its C-monoalkyl derivatives fail to undergo nitration. If 1,2,4-

triazole is substituted with an aryl group on carbon, nitration occurs on the
benzene ring. But in 3-p-nitrophenyl-1 ,2,4-triazole 71 in which benzene ring is
deactivated by the nitro group, the nitration results in C-nitro derivative 73 via N-
nitro derivative 72 (scheme-30) 27 .
t-P-N0
N
2 z--r0-N0
N
2
I
H N02
71 72
12<J'C
rearrangement
73
Scheme-30
Halogenation of 1,2,4-triazole is considered to proceed via N-halo-1 ,2,4-triazole

74 with the formation of3-halo-1 ,2,4-triazole 62 (scheme-31).
[Z( l
Cl
z~,..N
N
H
a2
-Ha
.. rearrangement
t\ N
H
49 74 62
Scheme-31
2.2.4.2.2 Reactions with Nucleophiles
1 ,2,4-Triazoles substituted with halo-group at the position-3 or-5 undergo

nucleophilic substitution reactions (scheme-32). The ease of nucleophilic
~~ + RNH2
~~
CI,)(N,..N H2N)(N,..N
I I
CH 3 CH 3
75 76
Scheme-32
displacement is increased with the quatemization of nitrogen or by the presence

of an additional electron-withdrawing substituent on the other ring carbon atom.
R
'+
N~
CIJ(N,..N
I
CH3
77
2.2.4.2.3 Reactions with Electron-Deficient Species
2.2.4.2.3.1 Reactions with Nitrenes
The reaction of 1-alk:yl-1 ,2,4-triazoles 78 with nitrenes, generated by irradiation

of azides, results in the formation of N-irnines 79 (scheme-33) 28 .
N-COCH3
I
hv N~
~+_,N
N
I
R
79
Scheme-33
2.2.4.2.3.2 Reactions with Carbenes
The reaction of 1,2,4-triazoles 80 with dichlorocarbene does not proceed with the
ring expansion as in pyrazole and imidazole, but results in the formation of bis-or
tris-1 ,2,4-triazoles (scheme-34)29 .
R R
R
_;---<
N
.,N
:ca2
A
N~
/N
CH
H R N
3
R=ai3
80 81
CsH5~
z~,..N
(C6H 5hC0 2 N~ I -...;;:::N
(C2Hs))N
l: N-C-N
:::::-..1I '--
J
N N CsH5 N
H
82
Scheme-34
2.2.4.2.4 Oxidation
1,2,4-Triazole ring is resistant to oxidation, but N-aminotriazoles 83 undergo

oxidative fragmentation via a nitrene intermediate 84 when treated with lead
tetraacetate. The formation of nitrene intermediate from N-aminotriazoles causes
destabilization of the triazole ring scheme-35) 30 .
R R
R~
/~--(
N
I
.,....N R;) -N I
2
NH 2 N:
83 84
Scheme-35
2.2.4.2.5 Thermal and Photochemical Reactions
1,2,4-Triazole ring is thermally stable, howevermesoionic 1,2,4-triazolium-3-olates

85 undergo photochemical fragmentations as shown in (scheme-36) 31 .
C6 H5 -N=N-C 6 H5
N~o
I( N_....N-c 6 Hs
I
C6Hs
87
86
Scheme-36
2.3 Tetrazoles32- 34
2.3.1 General
Tetrazole is six n-electron heteroaromatic system and contains three pyridine-type

and one pyrrole-type nitrogen atoms. Tertrazole exists in two tautomeric forms;
1,2,3,4-tetrazole {lH-form) 89 and 1,2,3,5-tetrazole (2H-form) 90, with the
predominance of 1,2,3,4-tetrazole {lH-form) (Fig. 10). The numbering in the tetrazole
ring system is adopted as in lH-form.
4 3 3 2
N-N N=N
5
I( \\N 4~ ,..~H
N,..2 N 1
H1 5
1,2,3,4-Tetrazole 1,2,3,5-Tetrazole
(lH-form) (2H-form)
89 90
Fig. 10. Tautomeric forms of tetrazole
Tetrazole ring represents tetrazolic acid functional group (CN4 H) of carbazolic

acids (RCN4 H). Tetrazoles are, therefore, considered nitrogen analogues of
carboxylic acids (RCOOH) with comparable acidity. The tetrazole ring exhibits
strong electron-withdrawing inductive effect (-1 effect) which is more effective
than its weak mesomeric effect (+M effect). The tetrazole ring, therefore, behaves
as a deactivating group and the flow of the electrons is towards the ring if
substituted with strong activating group 35 •
Tetrazoles exhibit potential biological activity because of being tetrazole ring
isosteric with carboxylic acid group and metabolically more stable than the
carboxylic acid group. The replacement of carboxylic acid group in the biologically
active compounds by the tetrazole ring, therefore, produces possibly more
effective tetrazole derivatives. Tetrazole analogues of amino acids, aminotetrazolic
acids, with comparable biological activity have been synthesized and exist similarly
in the zwitterionic form 32 .
2.3.2 Synthesis
2.3.2.1 From Imidoyl Chlorides
The reaction of imidoyl chlorides 91 with azides (sodium azide or hydrazoic acid)
in the presence of DMF produces imidoyl azides 92 which undergo 1,5-
heteroelectrocyclization to provide 1,5-disubstituted tetrazoles 94. The cyclization

of imidoyl azides occurs via an activated complex 93 with the movement of
imino lone pair towards azido terminal nitrogen and at the same time the shifting
of rc-electrons of azido terminal rc-bond to the central azido nitrogen as a lone pair
(scheme-37)32 .
..
93
Scheme-37
The cyclization of the imidoyl azides depends on the following factors :

(i) Stereoelectronic effect : cis-Orientation of the imino lone-pair and azido
group is required for the cyclization of imidoyl azide. The trans-orientation
does not favour cyclization without prior inversion. If intramolecular
hydrogen bonding stabilizes the imidoyl azide, the tetrazole formation
occurs only if the treatment of reagent brings about the required
geometrical isomerization of the imino group (scheme-38).
Scheme-38
(ii) Electronic effects : The presence of electron-withdrawing substituents

around the imino group does not favour the cyclization, but electron-
releasing substituents facilitate cyclization.
(iii) Solvent effect : The acidic media inhibits cyclization due to the protonation
of imidoyl azide, while basic media favours tetrazole formation because of
the increased electron density on the imino moiety.
(iv) Temperature : Higher temperature restricts the cyclization of imidoyl azide,
but favours instead tetrazole ring cleavage.
2.3.2.2 From Amidrazones
The reaction of amidrazones 95 via the hydrazine form 96 with nitrous acid
( diazotization) results in irnidoyl azides which undergo cyclization immediately with
the formation of I ,5-disubstituted tetrazoles 94 (scheme-39).
R1-C-NHR 2 R1-C=NR 2
II I
N-NH2 NHNH2
95 96
...
93
Scheme-39
If R 1 substituent is an aminoalkyl and R 2 is a hydrogen atom in imidoyl azide

92, the cyclization involving imino nitrogen of highest electron density is
favoured (scheme-40).
H
R 1-N-C=NH
.....J I ·,· .,
! +~N /
(favoured) N"'- N , / (not favoured)
pt path ~--" nnd path
Scheme-40
2.3.2.3 From Nitrites
It is the most widely used method and involves reaction of nitriles with sodium
azide in the presence of dipolar aprotic solvent (DMF) to provide 5-substituted
tetrazoles (scheme-41) . The reaction is sensitive to the nature of the solvent as in
hydroxylic or alcoholic solvents the product is formed in poor yield, while optimum
yield of the product is obtained with dipolar aprotic solvents.
(i)DMF,~ N-N
R-C=N + NaN 3 II ''
(ii) HCl R~ _,N
N
H
Scheme-41
2.3.2.4 From Nitrilium Salts
The reaction of nitrilium salts with sodium azide also leads to the formation of 1,5-
disubstituted tetrazoles (scheme-42) 37 .
+ 2 -
[R-C=NR ]BF4 +
Scheme-42
This reaction has been extended to the nitrilium ions generated in solution by
the reaction of nitriles with carbocations in the presence of sodium azide
(scheme-43) 38 .
NaN 3
Scheme-43
2.3.2.5 From Isonitriles
The acid catalyzed reaction of isonitriles with hydrazoic acid affords !-substituted
tetrazoles. The reaction proceeds to involve protonated isonitrile followed by the
attack of azide ion (scheme-44).
+
N-N
(R-N=cH) II ,..N
'-., ''
N
I
R
Scheme-44
However, the reaction of isonitriles with azide in the presence of Mannich type
reagent (formaldehyde + piperidine) results in the formation of 1,5-disubstituted
tetrazoles 98. The reaction is known as Ugi reaction and proceeds with the
addition of Mannich type carbocation moiety at C-5 (scheme-45) 32 .
HCHO+ C N H __{..
Scheme-45
2.3.3 Structure
Tetrazole molecule is planar with the following structural parameters (Fig. 11) :
Bond lengths (A) Bond angles e>

Nl-N2 1.347 Cs-Nl-N2 105.3
4 3
N2-N3 1.283 N-N Nl-N2-N3 106.9
N3-N4 1.345 s
\\
I( ,...N N2-N3-N4 112.2
NcCs 1.290 N 2 NJ-NcCs 104.2
H1
Nl-Cs 1.351 NcCs-Nl 111.4
Fig. 11. Structural parameters of 1,2,3,4-tetrazole
Tetrazole is aromatic because it contains six delocalized n-electrons. Dipole

moment of tetrazole (l!o = 5.11D in dioxane) has also suggested to exist it
predominantly in the lH-form (calcd 1-lo = 5.22D) rather than in the 2H-form (calcd
~-t 0 =l.63D).
N-Unsubstituted tetrazoles exhibit intermolecular hydrogen bonding because of

the presence of three pyridine-type nitrogens (-N=) in the ring as proton acceptors
and the availability of the active hydrogen at the position- I. The intermolecular
hydrogen bonding in tetrazoles influence their melting and boiling points (Fig. 12).
" NI
I
HI
I
N=\
.......... I \ I
N-H- -N NH--N
/ ~N..... ~
Fig. 12. Hydrogen bonding in N-unsubstituted tetrazoles
The replacement of hydrogen attached to the nitrogen at the position- I by a

small substituent causes large decrease in the melting point due to the absence
of intermolecular hydrogen bonding (tetrazole; m.p. = 156°C and 1-methyltetrazole;
m.p. = 39°C).
The introduction of substituents with N-H or 0-H bonds at C- 5 generally raises
melting points due to extra intermolecular hydrogen bonding (5-amino-1,2,3,4-
tetrazole; m.p. =203°C)
2.3.4 Reactions
Tetrazole ring contains both types of nitrogen atoms; one pyrrole-type and three
pyridine-type . The pyrrole-type nitrogen exerts electron-releasing effect and thus
activating effect, while pyridine-type nitrogens exert electron-withdrawing effect
and thus deactivating effect which makes the tetrazole ring n-electron deficient.
The n-electron deficiency in tetrazole ring causes it to undergo reactions with
nucleophiles readily. Electrophilic attack in the tetrazole ring generally occurs on
the nitrogens and results in the ring fragmentation with the loss of nitrogen
(dediazoniation).
Tetrazole ring undergoes electrophilic substitutions with the attack of electrophiles

preferentially at N-2 which facilitates fragmentation of the ring providing nitrili-
mines 99 with the loss of nitrogen (N 2) (scheme-46) 32 • This type of mechanism
E + {'. -
/
R-C=N-N-E
N-N~ + N-N~
~+
E II '
II ,...N
''
R~ + • R~~N
N -H N R-C=N-N-E
H
99
Scheme-46
can be evidenced by the reaction of 5-phenyltetrazole 100 with benzoyl chloride.

The reaction proceeds with the electrophilic attack at N-2 to provide 2,5-diphenyl-
1,3,4-oxadiazole 103 involving intramolecular cyclization of nitrilirnine intermediate
102 (scheme-47) 39 .
N-N
~ ,,N + C6 H5COCI
HsCs N. . .
H
100
N-N
HsCs_f(
0 )-c6 H5 ....,....___
103
Scheme-47
If position-S is substituted with strongly activating substituent (alkoxy or

amino), the preferred site of electrophilic attack is changed and occurs at N-1 . The
reaction of 5-alkoxytetrazoles 104 with methanesulfonyl chloride involves
electrophilic attack at N-1 and proceeds with the cleavage of the ring (N-N bond)
to provide imidoyl azides 106 (scheme-48) 40 .
N-N N-N
r.
I! '' II ''
RO~H,....N + RO--"....N . . . ~
N I
S02CH3
R = CH3, C2Hs
105
104 RO, + _
C-N=N=N
II
N,
S02CH 3
106
Scheme-48
2.3.4.2.1.1 Acidity
The tetrazole ring ( -CN 4 H, tetrazolic acid group) is considered as the nitrogen
analogue of the carboxylic acid group (-COOH). In general, 5-substituted tetrazoles
represent nitrogen analogues of the carboxylic acids and are called as the tetrazolic
acids. But 5-phenyltetrazole is relatively more acidic than benzoic acid because of
the enhanced resonance stabilization and greater solvation of the tetrazolate anion
than the carboxylate anion. The nature of the substituents at C-5 influences the
acidity of the tetrazole ring. The acidity of the tetrazole ring is increased with the
substitution of electron-withdrawing substituents at C-5, while electron-releasing
substituents cause decrease in acidity. 5-Substituted tetrazoles (tetrazolic acids)
form stable tetrazolate anions when treated with bases. The tetrazolate anions
exhibit ambident character and therefore can react at N-1 or N-2. The alkylation of
the tetrazolate anion with alkyl halides produces !-alkyl- or 2-alkyltetrazole
depending on the reaction conditions and the nature of the substituent at C-5
(scheme-49).
N-N OH N-N N-N N-N

II ''
R~ ,..N • R~
II ,..N
'' R_l( N1-~ ~ I
R~ ,..N
N
''
N N
H
(i) (ii) (iii)
N=N
~ N;:::N
I(-\\
R~ .... ~- R~....j,N
N N
QI31/
(iv) ; 107
N-N
II
R~ ,..N
''
N
I
CH3 109
108
Scheme-49
2.3.4.2.1.2 H ~DExchange
N-Substituted tetrazoles undergo base-induced H ~ D exchange readily at

C-5 via a carbanionic type intermediate 110. The rate ofH ~ D exchange is 105
times faster in 1-methyltetrazole 110 than in 2-methyltetrazole 111 and attributed
to the greater reactivity of the a-position as compared to P·position to the pyrrole-
type nitrogen32 .
N-N
II ,..N
-"'- ''
N
I
CH3
110 111
The reaction of substituted tetrazoles with n-butyllithium in the presence of THF

at -60°C results in C-lithiation at the position-S with the formation of 5-lithio
derivatives 112 which undergo ring cleavage at higher temperature providing the
corresponding lithium cyanamides 113 with the loss of nitrogen (scheme-50) 32 .
N-0
THF ~II '' 5CJ'C
n-8uLi ~ ,..N R-N-C=N
-6CJ'C I
Li ~~ Li
R
112 113
Scheme-50
2.3.4.2.2 Nucleophilic Attack at C-5 (Nucleophilic Substitutions)
Because of the n-deficient deactivated nature of the tetrazole ring, 5-halotetrazoles

undergo nucleophilic substitutions with the replacement of halogen atom from the
position-S. The kinetic studies have shown 1,5-disubstituted tetrazoles (5-bromo-
1-methyltetrazole 112) to undergo nucleophilic substitution reactions more readily
than 2,5-disubstituted tetrazoles (5-bromo-2-methyltetrazole 115) probably because
of greater stabilization of the intermediate 113 resulting from the
1,5-disubstituted tetrazoles as compared to that 116 resulting from 2,5-disubstituted
tetrazoles (scheme-51) 32 .
r;N - N-N
'''?~ Nu,)~ ~1
~N-N
-II '' Nu, 11 -Br II ''
8 r ~ N,..N 8r ~ ,..N f)~ ,..N ~A ,..N
N 8r N Nu N
I I I I
CH3 CH3 CH3 CH3
112 (i) (ii) 114
N=N
8
r
A~ . . ~ 'cH3 [
Nu N=N,
,..))(_ ,..N-..CH
~~
8;
8r c~ 3
115 116 117
Scheme-51
2.3.4.3.1 Reactions Involving Nitrilimine Intermediates
(i) 2,5-Disubstituted tetrazoles 118 undergo thermal fragmentation with the

extrusion of nitrogen (N 2) and the formation of a reactive nitrilimine
intermediate 119 which can undergo 1,3-cycloaddition with alkenes, imines,

alkynes and nitriles (scheme-52). If intramolecular cyclization is possible
+ .. -
t
R2 -C=N-N-R 1
-Nz..
2 + - 1
R -C=N-N-R
119
'
/c=c, / I
Scheme-52
with the involvement of substituent in nitrilimine intermediate 122, five-

membered heterocycles 123 with three heteroatoms (oxadiazoles,
thiadiazoles and triazoles) are obtained involving 1,5-heteroelectrocyclization
and the reaction is referred to as the Huisgen reaction (scheme-53)41 •42 •
N=N -N2 1 + .. .()

fJ(\ ~ R -C=N-N-C-R
R 1~ ,....N........_ _
N c-o ~II
I
+
R'-crR
121 R 0
+
1_}(
N-N
)- ...
R O R
123 122
Scheme-53
(ii) Photochemical fragmentation of 5-substituted tetrazoles in THF also

proceeds to involve a nitrilimine intermediate 124 with the extrusion of
nitrogen (N2) and leads to the formation of tetrazine derivative 125
involving dimerization of the nitrilimine intermediate (scheme-54).
N-N
hv + - dllnerization
[R-C=N-NH] _ _ _...,._ R--< }-R
124 N-N
H H
125
Scheme-54
2.3.4.3.2 Reactions Involving Carbene Intermediates
Photochemical fragmentation of 5-substituted tetrazolate anions 107 involves

photochemical excitation of the tetrazolate anion with the extrusion of two
molecules of nitrogen and generation of carbene intermediate which undergoes
insertion reactions (scheme-55).
N-N
f (···.. \
hv +
R~:::..~ N ____..... [R-C=N-.~]
N
107 ~ H+ (from medium)
hv
RCHN2
Scheme-55
2.3.4.3.3 Reactions involving Nitrene Intermediates
1,5-Disubstituted tetrazoles 126 are photolyzed with the loss of nitrogen molecule
and the reaction proceeds to involve an iminonitrene intermediate 127 (scheme-56).
hv
~
128
Scheme-56
2.3.4.4 Rearrangements
Substituted 5-aminotetrazoles undergo thermal rearrangements with the existance

of both the forms 129 and 132 in equilibrium. The rearrangement proceeds via a
reactive imidoylazide intermediate 130 involving rotation of the C5-N 4 bond and
an amino-imino proton tautomeric change (scheme-57). The 6n-heteroelectro-
cyclization occurs preferentially on the imino nitrogen with higher electron density.
180"C
t
R2 -N=C-NHR 1
. :. \
:N, ~N
N
130 131
Scheme-57
3 OXADIAZOLES
Oxadiazoles are considered to be derived from furan by the replacement of two

methine (-CH=) groups by two pyridine-type nitrogens (-N=). There are four
isomeric types of oxadiazoles depending on the positions of the nitrogen atoms
in the oxadiazole ring and are numbered as shown in (Fig. 13).
4 3 4 3 4 3
4~3 N-N
~~~\ f(
N~ II \\
s~ __...N
0
5
0/2
N N N
s 'o...-2
sf( )2
2 0
1 1 1 1
1,2,3-0xadiazole 1,2,4-0xadiazole 1,2,5-0xadiazole 1,3,4-0xadiazole
Fig. 13. Isomeric oxadiazoles

The replacement of two -CH= groups in furan by two pyridine-type nitrogens

(-N=) reduces aromaticity of the resulting oxadiazole ring to such an extent that
the oxadiazole ring exhibits character of the conjugated diene. The electrophilic
substitutions in oxadiazole ring are extremely difficult at the carbon atoms because
of relatively low electron density on the carbon atoms due to electron-withdrawal
effect of the pyridine-type nitrogen atoms. However, the attack of electrophiles
occurs at the nitrogens, if oxadiazole ring is substituted with an electron-releasing
group. Oxadiazole ring is generally resistant to the nucleophilic attack. Halo-
substituted oxadiazoles, however, undergo nucleophilic substitutions with the
replacement of halogen atom by nucleophiles. Oxadiazoles undergo nucleophilic
substitutions similarly as occurring at an aliphatic sp 2-carbon atom, but not as
aromatic nucleophilic substitutions.
3.1 1,2,3-0xadiazoles
1,2,3-0xadiazoles are not known as these exist entirely in the diazo ketone tauto-
meric form 134 (Fig. 14). 1,2,3-0xadiazoles occur only in the form of mesoionic
oc )(
Fig. 14. Diazoketone form of 1,2,3-oxadiazole
heterocycles known as sydnones. Sydnones are represented by mesoionic form

and are considered to be contributed by resonating structures (Fig. 15).
R R R R
J]j.N
/ +/ +/ +/
-
0
;\
.. N
-
0 1:~',...N 1:''
~0
- N
,...N ~0
rN'- ,...N
0/ 0 0 0
135 (i) (ii) (iii)
Fig. 15. Resonating structures of sydnones

The higher dipole moments of the sydnones, generally greater than 6D and
comparable with that of 4-Nitro-N,N-dimethylaniline 136 (6.87D), also support
strongly polar character of the sydnones.
3.2 1,2,4-0xadiazoles 43 ·44
3.2.1 General
I ,2,4-0xadiazoles find their uses as anaesthetics, analgesics, antispasmodics,

antitussives, anthelmintics and antiinflammatory. Some of the 1,2,4-oxadiazoles
with their activity are as follows :
Oxalmine, Bredon, anaesthetic,

Perebron antiinflammatory
X= -NH(CH 2)2N(C 2Hs)2 Irrigor anaesthetic
X= -CH 2N(C 2H 5h anaesthetic,
analgesic
anaesthetic,
antiinflammatory .
anaesthetic,
antispasmodic,
antiinflammatory
3.2.2 Synthesis
3.2.2.1 Cyclization Reactions (From Amidoximes)
The reaction of amidoximes 142 with an anhydride results in dehydrative

cyclization providing 1,2,4-oxadiazoles 145 (scheme-58) 45 . The reaction proceeds
to involve 0-acylation in the first step and followed by dehydrative cyclization in
0 R1
II
R-C
\
+
H2N-c ,,
I
/0 N
R-c I
II HO
0 142
HN-('_j
~[RH~O/N
-HzO
144b
Scheme-58
the second step to afford the corresponding 1,2,4-oxadiazoles in which C-5 carbon
is furnished by an anhydride. However, acid chlorides, ketones, esters and amides
can also be used to furnish C-5 carbon in 1,2,4-oxadiazoles (scheme-59) 46 .
0
II 160-180"C
R-C-NH2
10 min.
Scheme-59
3.2.2.2 1,3-Dipolar Cycloadditions
1,3-Dipolar cycloaddition of nitrile oxides (4n-electron-three atom system) to

nitriles (2n-electron system-dipolarophile) leads to the formation of 1,2,4-
oxadiazoles 146 (scheme-60).
146
Scheme-60
3.2.3 Structure
1,2,4-0xadiazole ring is planar with high degree of diene character (little aromatic)
as both C-N bond lengths reflect conjugated double bond character. 1,2,4-
0xadiazole ring system is therefore conisdered to be a conjugated system rather
than an aromatic system. The structural parameters in 1,2,4-oxadiazole are
summarized as (Fig. 16) :

Ot-Nz 1.418 O-N2-C3 103.2
4 3
Nz-C3
C3-N4
1.303
1.380 5 rz~
o. . . N2
Nz-C3-N4
C3-NcCs
114.2
102.8
NcCs 1.287 1 NcC5-0 113.8
0 1-C5 1.332 N 2-0-C5 106.1
Fig. 16. Structural parameters in 1,2,4-oxadiazole
3.2.4 Reactions
3.2.4.1 Electrophilic Substitution Reactions
1,2,4-0xadiazole ring is less susceptible towards electrophilic attack. If 1,2,4-

oxadiazole ring is substituted with an aromatic ring at C-3 or C-5, the oxadiazole
ring behaves as an electron-withdrawing group and directs the incoming
electrophile to the meta-position (scheme-61 ).
HN03 +H2S04
Scheme-61
3.2.4.2 Nucleophilic Substitution Reactions
1,2,4-0xadiazoles undergo nucleophilic substitutions with the replacement of a

halogen atom from C-5 involving nucleophilic addition-elimination mechanism
(scheme-62).
[1);(-;(']
CH3 CH3
Cl
:1(-i
,.N
OH
• -
-0
• HOJ(O,.N
~-{
0 HO 0
149 150
Q CH3
.. J(-i
CH3
RNHz
• CIJ-i
V ,.N -0 RN ,.N
RN 0 H 0
H 151
Scheme-62
3.2.4.3 Reactions of Substituents
The methyl group at C-5 of the 1,2,4-oxadiazole ring is more reactive than that at
C-3. The greater reactivity of the methyl group at C-5 is attributed to the greater
stabilization of anion 153 resulting from 1,2,4-oxadiazole 152 with methyl group at
C-5 than 155 obtained from 3-methyl-1,2,4-oxadiazole 154 (scheme-63).
z-i0
CH3
,.N
=s ..
[
t>~ ..(cH,
. z-N-{CH,]
0
,.N
154 155a 155b
Scheme-63
The greater reactivity of the methyl group at C-5 can be explained by the
reactions depicted in (scheme-64).
Scheme-64
3.2.4.4 Reduction
(i) The reduction of 1,2,4-oxadiazole with diborane in the presence of

tetrahydrofuran leads to the formation of d 2-oxadiazoline 161 (scheme-65)47 .
THF
Scheme-65
(ii) Neutral catalytic reduction of 1,2,4-oxadiazole with platinum oxide, Raney

nickel or palladium-carbon occurs with the cleavage of N-0 bond
(scheme-66)43 .
Pd/C
160
Scheme-66
(iii) Reduction with lithium aluminium hydride, in contrast, proceeds with the
cleavage of C-0 bond to provide amidoximes 163 (scheme-67) 43 .
NOH
R 1 -c~
161
' NHCH2R2
163
Scheme-67
3.2.4.5 Ring Cleavage via C-Deprotonation
1,2,4-0xadiazole ring is readily cleaved via C-deprotonation in alkaline solution

with the formation of corresponding cyanamide 164 (scheme-68).
Jt-{
R
0
H
,..N
-
OH
-H
+
[
. ~~-P] ----...
R;J( ,..N
{9
H
R-C-N-c=N
II
0
164
Scheme-68
Photolysis of 1,2,4-oxadiazoles involves cleavage of N-0 bond with the formation

of 165 in which extra hydrogens are taken from the solvent (scheme-69).
0
II
N-C-R2
hv
R 1 -c~
ether
' NH2
165
Scheme-69
3.2.4. 7 Rearrangements
1,2,4-0xadiazoles 166 containing a suitable side chain at an a-position to the

pyridine-type nitrogen undergo base catalyzed or thermal rearrangement which is
generalized by (scheme-70).
,.N
base or Ll HC" \ - A
b II
- N,
,,
,....B
c
~ R'
R-C,... \...__/
... II fl i
0 N, ,.,..N
N
I1
R
167
Scheme-70
3.3 1 ,2,5-0xadiazoles 48- 50
3.3.1 General
1,2,5-0xadiazole 168 and its N-oxide, 1,2,5-oxadiazole 2-oxide 169, are known by
their trivial names; furazan and furoxan, respectively and are numbered as follows :
4 3 4 3
~ ~+-
N, ,....N N, ,..N-O
5 0 2 5 0 2
168 169
The fusion of a benzene ring with furazan 168 and furoxan 169 at the
3,4-positions leads to benzofurazan 170 and benzofuroxan 171, respectively.
Benzofurazan is also named as 3,4-benzo-1 ,2,5-oxadiazole or 2, l ,3-benzoxadiazole
and benzofuroxan is named as 3,4-benzo-1 ,2,5-oxadiazole 2-oxide or 2,1 ,3-benzo-
xadiazole 1-oxide.
170 171
I ,2,5-0xadiazole ring system is incorporated into many compounds with wide

spectrum of biological activity. 1,2,5-0xadiazoles have found their uses as plant
growth regulators, pesticides, herbicides, rhodenticides, anticancer agents, anti-
convulsants and muscle relaxants. The presence of nitro- and N-oxide groups in
1,2,5-oxadiazoles makes them effective against cancer.
3.3.2 Synthesis
3.3.2.1 Furazans
3.3.2.1.1 Dehydration of a-Dioximes
This is the most widely used method and involves dehydration of suitably
substituted a-dioximes 173 which are obtained by oximation of 1,2-diones 172 or
nitrosation-oximation of ketones (scheme-71). However, the reaction conditions
vary with the nature of the substituents.
n
R1 R1 R1 R2
' C=O
I
'c=NOH
I
-H 20
/
C=O /C=NOH N, ,.....N
0
R2 172 R2 173 174
(i) RONO, base

(ii)NHzOH
t
Scheme-71
3.3.2.1.2 Ring Transformations
1,2,4-0xadiazoles 175 containing an oxime side chain at the position-3 undergo a

special type of heterocyclic rearrangement involving side chain when heated in
hydrochloric acid and provide 3-acylamino-1 ,2,5-oxadiazoles 176 (scheme-72) 51 .
+
H
175 176
Scheme-72
Isoxazoles 177 also undergo this type of rearrangement providing 1 ,2,5-

oxadiazoles 178 (scheme-73)0
+
H
177 178
Scheme-73
3.3.2.2 Furoxans
3.3.2.2.1 Oxidation of a-Dioximes
Oxidative cyclization of a-dioximes with oxidizing agents such as potassium

ferricyanide, lead tetraacetate, N-iodosuccinimide, alkaline hypohalites and cerium
(IV) ion leads to the formation of furoxans 179 (scheme-74) 0 Electrochemical
oxidation of a-dioximes is also possible 52 0
R2 1
R1 ' R
' C=NOH
I
oxidative p-(+ -
cyclization "-...
N-O
/C=NOH o""
R2
173 179
Scheme-74
3.3.2.2.2 Dehydration of a-Nitro Ketone Oximes
Dehydrative cyclization of a-nitro ketone oximes 181 with sulfuric acid or

phosphoric acid at 110-l20°C results in furoxans 182. a-Nitro ketone oximes are
obtained by thermal isomerization of nitro-nitroso adducts 180 which in tum are
prepared by treatment of alkenes with dinitrogen trioxide (scheme-75). However,
sulfur trioxide and chlorosulfonic acid in DMF are used as effective dehydrating
agents for the preparation of furoxans which are thermally sensitive to the ring
cleavage.
R-CH-NO R-C=NOH
I ____.. I
R-CH-N02 R-CH-N02
180 181
R)::~o .. -H 20
R ~
Q
182
Scheme-75
3.3.3 Structure
1,2,5-0xadiazole ring is planar and symmetrical with following structural parameters

(Fig. 17) :
Bond lengths (A) Bond angles e)

O-N 2 1.38 N2-0-N5 110.4
4 3
N2-C3 1.30 ~ O-N2-C3 105.8
N N
C3-C4 1.42 s'o,..2 N2-C3-C4 109.0
1.30 1 109.0
CcNs CJ-CcNs
O-N5 1.38 CcN5-0 105.0

The C=N bond length (C 3-N 2 and CcN 5) (1.30A) is intermediate between that
of formaldoxime ( 1.27 A) and pyridine ( 1.34A) and suggests high degree of diene
character in I ,2,5-oxadiazole. However, comparison with cyclopentadiene indicates
small degree of aromatic character in I ,2,5-oxadiazole ring. The C3-C4 bond
acquires double bond character. The bond lengths, therefore, reflect n-electron
delocalization with small degree of aromatic character in I ,2,5-oxadiazole.
In I,2,5-oxadiazole 2-oxide (furoxan), the exocyclic oxygen at N-2 causes
distortion in the ring from planarity. However, C3-C4 bond acquires double bond
character and suggests n-electron delocalization as in I,2,5-oxadiazole. The 0 1-N 2
bond (I.42-I.46A) is longer than N2-0 (exocyclic) bond (1.18-1.25A).
3.3.4 Reactions
I ,2,5-0xadiazoles exhibit very low reactivity towards electrophiles as benzo-fused

I ,2,5-oxadiazoles undergo electrophilic substitutions in the benzene ring and 1,2,5-
oxadiazole ring remains intact. The quatemization of the ring nitrogen is also
difficult, but occurs only if the ring is substituted with an electron-releasing
substituent. The reaction of amino-1 ,2,5-oxadiazoles 183 with 2-chloro-I-acylalkenes
in the presence of perchloric acid results in quatemization of the ring nitrogen with
the formation of oxadiazolopyrimidinium salts 184 (scheme-76) 53 .
0 CH3
II I
CH 3-C-CH =C-CI
183
Scheme-76
In spite of the low n-electron density on the carbon atoms, I,2,5 -oxadiazole ring
is generally resistant to nucleophilic attack. However, benzo-fused I ,2,5-oxadiazoles
185 substituted with halogen atom undergo nucleophilic substitutions with the
replacement of a halogen atom by nucleophiles involving 'normal' and 'cine'-
substitutions (scheme-77). The relative amounts of the normal 186 and cine 187
products depend on the polarity of the solvent and on steric effects. The presence
of electron-withdrawing substituent facilitates nucleophilic attack.
:Nu
185
Scheme-77
3.3.4.3 Ring Cleavage via C-Deprotonation
The hydrogen atoms in 1,2,5-oxadiazole can be abstracted as protons by a strong

base with the cleavage of the ring providing a-oximinoacetonitrile 188 (scheme-78).
base
N=C-CH=N -0
188
Scheme-78
Similarly, monosubstituted 1,2,5-oxadiazoles 189, irrespective of the nature of

the substituent, undergo ring opening reactions in the presence of a strong base
with the formation of oximes 190 of a-ketonitriles. The reaction proceeds to
involve C-deprotonation of 1,2,5-oxadiazole ring (scheme-79).
base
190
189
Scheme-79
3.3.4.4 Rearrangements
I ,2,5-0xadiazoles 191 substituted at position-3 with side chains such as

hydrazone, oxime and amidine are thermally transformed into new heterocyclic
systems containing hydroximino substituent. The transformation is generalized as
depicted in (scheme-80) 51 .
R X
K~l
N
'vu· N
X=Y-Z (C =N-N, C=N-0, N=C-N)

ZH
R1
R
I I R1
R C
n~,N ..-:c"---.1
~~ II \\
N .. N NH2 OH N, _....N
'VCi N
H
191 192
Scheme-SO
I ,2,5-0xadiazoles undergo thermal and photochemical reactions with the cleavage

of0 1-N 2 and C 3-C4 bonds providing nitriles and nitrile oxides (scheme-8I).
R I R
)-~\( 200"C
N...... ,,
, N R-C=N +
hv
0 '
Scheme-81
I ,2,5-0xadiazole 2-oxides are thermally or photochemically isomerized into I ,2,5-

oxadiazole 5-oxides 194 via a dinitroso intermediate 193. But at high temperature
(>200°C), furoxan (1 ,2,5-oxadiazole N-oxide) ring is cleaved at the O-N2 and C3-C4
bonds to provide two nitrile oxide fragments (scheme-82). If furoxan ring is

substituted with bulky groups or the ring is strained, the process of the ring
cleavage becomes easier and requires low temperature (scheme-82).
[:>=( l
R2 R1
It \\
-+H
O-N, ,....N
0
0 0
194
2 + - 1 + -
R -C=N-0 + R -c=N-0
Scheme-82
3.4 1,3,4-0xadiazoles54 - 56
3.4.1 General
1,3,4-0xadiazole 195 is a thermally stable aromatic heterocycle and exists in two

partially reduced forms ; 2,3-dihydro-1 ,3,4-oxadiazole (~2 -1 ,3,4-oxadiazoline) 196
and 2,5-dihydro-1,3,4-oxadiazole (~ 3 -1 , 3,4-oxadiazoline) 197 depending on the
position of the double bond. The completely reduced from of 1 3, ,4-oxadiazole is
designated as 2,3,4,5-tetrahydro-1 ,3,4-oxadiazole ( 1,3,4-oxadiazolidine) 198.
N-NH
I()
0
195 196 197 198
1,3,4-0xadiazoles find their medicinal applications and are used as analgesics,

antipyretics, diuretics, antiinflammatory, hypnotics and sedatives. 1,3,4-0xadiazoles
have also been used as herbicides, fungicides, bactericides and insecticides. 13,4-
,
0xadiazole ring is incorporated to synthesize heat resistant polymers because of
thermal stability of 1,3,4-oxadiazole ring. 1 ,3, 4-0xadiazoles are also used as
dyestuffs, fluorescent whiteners and scintillators.
3.4.2 Synthesis
3.4.2.1 From Diacylbydrazines
Thermal or acid catalyzed intramolecular cyclization of diacylhydrazines 199

results in 2,5-disubstituted 1,3,4-oxadiazoles 200 (scheme-83). The reaction is
considered to involve nucleophilic attack of carbonyl oxygen of an amide group
at the carbon of the second amide group with the formation of C2-0 bond. It can
also be used to synthesize monosubstituted 1,3,4-oxadiazoles.
+ N-N
il orH
R1_,}(0 )-R2
200
Scheme-83
4.3.2.2 Ring Transformation
Thermal fragmentation of 5-substituted tetrazoles 100 with the extrusion of

nitrogen results in the generation ofnitrilimine intermediate 201 which undergoes
1,3-dipolar cycloaddition with isocyanates to provide 1,3,4-oxadiazoles 203
(scheme-84).
N-NH
II '
R-"'. ...: N
N"'
+
I R-C=N-NH ..
-
. +
R-c=N-NHI
-
N-N
R-Z )-NHR 1
•
[R-g:;NR'l
0
203 202
Scheme-84
However, 2-acyltetrazoles 204 on thermal fragmentation extrude nitrogen with

the formation of nitrilimines 205 which undergo heteroelectrocyclization directly
with the formation of 2,5-disubstituted 1,3,4-oxadiazoles 206 (scheme-85). The
reaction is widely referred to as the Huisgen reaction.
+ i)
R1-C=N-N-C-R2
~~
N-N
+
t __.. II
R1~o/--R2
\\
R'-~-R' 206
205
Scheme-85
3.4.3 Structure
1,3,4-0xadiazole ring is symmetrical and planar with the following structural

parameters (Fig. 18) :

N3-N4 1.399 C2-0-Cs 102.0
4 3
C2-N3 1.297 N-N ~-N 113.4
NcCs 1.297 51( )2 C2-N3-N4 105.6
O-C2 1.348 0 N3-NcC5 105.6
1
0-Cs 1.348 O-C5-C4 113.4
1,3,4-0xadiazole is an aromatic, molecule with resonance energy 167.4 kJ/mol.

The bond lengths in I 3, ,4-oxadiazole reflect n-electron delocalization. However, the
C=N bond lengths are very close to that in acyclic compounds ( 1.27A) and
therefore indicate some dienic character in I ,3,4-oxadiazole.
2-Hydroxy-, 2-mercapto- and 2-amino-1 ,3,4-oxadiazoles exist in equilibrium with

the tautomeric oxadiazolines (Fig. 19).
N-N
R_l(o)._XH
X= 0, S, NH
Fig. 19. Tautomeric equilibrium
3.4.4 Reactions
1,3,4-0xadiazole contains pyridine-type nitrogen atoms at the positions-3 and -4

which cause electron-withdrawal from the carbon atoms at the positions-2 and -5.
1 ,3,4-0xadiazoles, therefore, have low electron density on the carbon atoms and
relatively higher electron density on the nitrogen atoms. The reactions of 1,3,4-
oxadiazoles involve (i) attack of electrophiles at the nitrogen atom and (ii) attack
of nucleophiles at the carbon atoms.
Because of very low 1t-electron density on the carbon atoms, the attack of
electrophiles preferentially occurs at nitrogen. Alkylation of 1,3,4-oxadiazoles 206
occurs at the position-3 with the formation of 1,3,4-oxadiazolium salts 207
(scheme-86).
R
+ /
N-N N-N
H5C6 _./( 0 )-CH3
+ RX ____..
HsCs
_!( O)- CH3 x
206 207
Scheme-86
However, the alkylation of 2-alkoxy-1 ,3,4-oxadiazoles 208 with alkyl halides

produces labile oxadiazolium salts 209 which undergo 0 -dealkylation to provide
4-alkyloxadiazolin-5-ones 210 (scheme-87) 57 .
N-N
HsC6.,)( 0 )-0CH 3 + RX
208
210
Scheme-87
The carbon atoms in I ,3,4-oxadiazole ring are relatively with low rc-electron density
and therefore attack of nucleophiles occurs at the carbon atoms. The reaction
proceeds either with nucleophilic substitution or with ring cleavage as represented
(scheme-88).
R
)-~
O X
+ Nu ~ R_i( )(J ]
[ N-V 0 Nu
211
N-N
RJ(~x + Nu ~
211
..
0 + N-N
II /X H
R-C-NH-N=C, ~:-\'<X
R 0 Nu
214 Nu 213
Scheme-88
3.4.4.2.1 Nucleophilic SubstitutionReactions
1,3,4-0xadiazoles substituted with chloro- or sulfonyl group at the postion-2

undergo nucleophilic substitution reactions. The reaction of 2-chloro-1 ,3,4-
oxadiazoles 211 (X=Cl) with nucleophiles such as amines, thiourea or azide ion
proceeds with the substitution of chloro group by nucleophile and results in the
corresponding 2-substituted 1,3,4-oxadiazoles 212 (scheme-89).
-a .. N-N
R,)( 0)-. NHR 1

211 212
Scheme-89
3.4.4.2.2 Nucleophilic Attack with Ring Cleavage
The reactions of alkyl-or aryl-1 ,3,4-oxadiazoles 215 with nucleophiles involve the
cleavage of 1,3,4-oxadiazole ring with the formation ofhydrazine derivatives 216
which may recyclize to provide 1,2,4-triazoles 217 (scheme-90).
~N-N
+ RNH 2
1:1( )- 2
R -G R 216
• - H 20
215 N-N
R 1 = R2 = H, alkyl, aryl
R1_1( N )-R2
R
217
Scheme-90
Alkyl- and aryl-1,3,4-oxadiazoles undergo acid or base catalyzed ring opening

reactions in aqueous solution with the formation of diacylhydrazines ( scheme-91 ).
This reaction is the reverse of the intramolecular cyclization of diacylhydrazines
(scheme-83) for the synthesis of 1,3,4-oxadiazoles.
+
H orOH
Scheme-91
(i) 1,3,4-0xadiazole is thermally stable and the stability of the ring is increased
with the substitution of the aryl groups. However, 1,3,4-oxadiazolin-5-ones
218 undergo thermal and photochemical ring opening reactions with the
loss of carbon dioxide to provide nitrilimines 219 (scheme-92).
R1-C=N-N-R2
11 I hv
t
R-c=i:J-N-R
1 2
218 219
Scheme-92
(ii) Photochemical irradiation of 2,5-diphenyl-1 ,3,4-oxadiazole 220 with

benzo[b]thiophene 221 leads to the formation of oxadiazepine 223 as a
major product. But irradiation of2,5-diphenyl-1 ,3,4-oxadiazole and benzo[b]-
thiophene with benzophenone as a sensitizer results in (2 + 2) cycloadduct
224 (scheme-93) 58 .
fI
220 222
t
221
hv C6H 5COC6 H 5
H C6 H 5
~---t--r 0
)--csHs
N-N
H
224 223
Scheme-93
4 THIADIAZOLES
Thiadiazoles are considered to be derived from thiophene by replacing two -CH=

(methine) groups by pyridine-type nitrogens (-N=) and include four isomeric
members depending on the relative positions of the nitrogen atoms. Thiadiazoles
are named as shown in (Fig. 20) :
N-N
(. .~. N ~~~ ~
N, ..... N I()
' . ..... N
s s s s
1,2,3-Thiadiazole I ,2,4-Thiadiazole 1,2,5-Thiadiazole I ,3,4-Thiadiazole
Fig. 20. Isomeric thiadiazoles
4.1 1 2 3-Thiadiazoles59- 61
' '
4.1.1 General
I ,2,3-Thiadiazole 225 is a neutral five-membered aromatic heterocycle with three

contiguous heteroatoms and is numbered as shown in structure 225.
I ,2,3-Thiadiazoles have been found to possess antibacterial, insecticidal and

herbicidal activity. The analogues of 1,2,3-thiadiazole-4-carboxylic acid exhibit
sedative and hypnotic activity comparable to benzodiazepines.
4.1.2 Synthesis
4.1.2.1 Pechmann and Nold Synthesis
This method involves dipolar cycloaddition of diazomethane to phenyl isothio

cyanate to provide I ,2,3-thiadiazoles 227 (scheme-94). It has some limitations as
H2C-N]
+ [ 7~s. .'~
C6Hs
J[ N,,
226
H~ s""N
~
CH
6 5 227
Scheme-94
methyl isothiocyanate does not react with diazomethane at room temperature but
at higher temperature I ,2,3-thiadiazole 228 produced reacts further with the second
molecule of diazomethane and provides 1,2,3-triazole 229 involving Dimroth
rearrangement (scheme-95).
J[ ~
CH3S N,...N
I
CH3
229
Scheme-95
4.1.2.2 Hurd-Mori's Classical Synthesis (From Hydrazones)
This is the most widely used method for the synthesis of 1,2,3-thiadiazoles and
involves cyclocondensation of a-methylene hydrazones 230, (derived from a-
methylene ketones) with thionyl chloride (scheme-96) 62 . The cyclization occurs
R1-C-CH R2 + RNHNH2-.
II 2
0
R 1 & R2 =alkyl or aryl
Scheme-96
predominantly at the more reactive methylene site rather than at the methyl site
(if R 1=CH 3). However, sulfur dichloride (SC1 2) has also been used in place of
thionyl chloride to obtain I ,2,3-thiadiazoles in improved yield63 .
4.1.3 Structure
1,2,3-Thiadiazole is a planar molecule with the following structural parameters

(Fig. 21):

S-N2 1.692 N2-S-C5 92.9
N2-N3 1.290 4 ~ N2-N3-C4 114.0
( \\
N3-C4 1.366 5 ,...N S-N2-N3 111.2
s 2
CcCs 1.369 1 N3-CcC5 114.2
S-C5 1.689 CcC5-S 107.8
Fig. 21. Structural parameters in 1,2,3-thiadiazoles
The bond lenghts in 1,2,3-thiadiazole indicate considerable n-electron

delocalization in 1,2,3-thiadiazole. The interesting structural features exhibited by
1,2,3-thiadiazole molecule include the nearly equal bond lengths of S-N 2 and S-
C5 bonds and very short N 2-N 3 bond.
4.1.4 Reactions
1,2,3-Thiadiazole is a n-excessive heterocycle in which the nitrogen atoms

particularly N-3 are comparatively with higher electron density and the carbon
atoms are with lower electron density. The attack of electrophiles at carbon is very
rare and therefore occurs at the nitrogen atoms. The attack of nucleophiles occurs
at the carbon atoms and results in either nucleophilic substitution or ring cleavage.
The reaction of 1,2,3-thiadiazoles with dimethyl sulfate results inN-alkylation with

the formation of a mixture of quaternary salts 233 and 234 (scheme-97). However,
in some cases, alkylation occurs exclusively at the position-3 64 ·65 .
.
Scheme-97
The halogen atom in 1,2,3-thiadiazoles at the position-S is reactive and can be

replaced by nucleophiles. The reaction of 5-chloro-1 ,2,3-thiadiazole 235 with
sodium methoxide proceeds with the replacement of chlorine substituent
(scheme-98)66 .
R
)[
~ -+
CHpNa
Cl S,....N
235
Scheme-98
4.1.4.2.2 Ring Cleavage via C-Deprotonation
The C 5-H in 1,2,3-thiadiazole is reactive and can be abstracted as a proton by a

base. Deprotonation of 1,2,3-thiadiazole ring occurs at C-5 under strongly basic
conditions and leads to the ring cleavage with the extrusion of nitrogen
(scheme-99). However, 1,2,3-thiadiazoles substituted at C-5 can be deprotonated at
C-4 and the resulting anion 239 can be alkylated (scheme-100).
_H2_o •lR S
s
)=cHR
237
Scheme-99
H
)[
~ H3)[c ~
base
R ,...N R ,...N
s s
238 239 240
Scheme-100
4.1.4.2.3 Nucleophilic Attack at Sulfur
If 1,2,3-thiadiazole is substituted at both the carbons (C-4 and C-5), the reaction
with n-butyllithium followed by methyl iodide proceeds with the initial attack of
nucleophile at sulfur and results in the fragmentation of the ring with the evolution
of nitrogen (scheme-! 01 ).
R-c=c-R
R)-~ (i) Buli +
N2
R~-,...N
s +
BuSCH 3 + Lii
241
Scheme-101
4.1.4.3 Oxidation
Oxidation of 1,2,3-thiadiazole with one equivalent ofperacid occurs at N-3 with the
formation of 1,2,3-thiadiazole 3-oxide 242, but with three equivalent of peracid
1,2,3-thiadiazole trioxide 243 is produced involving oxidation of N-3 and of the
sulfur atom (scheme-102) 67 .
0
II
CH3-C-O-OH
(three equiv.)
241
Scheme-102
Thermal and photochemical reactions are considered to proceed via diradical

intermediates with the extrusion of nitrogen.
4.1.4.4.1 Thermal Reactions
Thermal decomposition of 1,2,3-thiadiazoles leads to the formation of thioketenes

via a diradical intermediate 245 (scheme-103).
900K
-Nz
Scheme-103
4.1.4.4.2 Photochemical Reactions
Photolysis of 1,2,3-thiadiazole produces thiirene 246 which can be trapped by an

alkyne to provide thiophene 247 (scheme-104) 68 .
!/~
'~/N
hv \ j _F_3_c_-_c_c_-_c_F_3_.
s -Nz s
225 246
Scheme-104
However, irradiation of 1,2,3-thiadiazole in an argon matrix at 8K gives thiirene

which upon further irradiation affords thioketene (scheme- I 05) 69 •70 .
!/~
<(
225
s
/N
hv
argon, 8K [Y]246
hv
CH2=c=s
Scheme-lOS
4.1.4.4.3 Rearrangements
1,2,3-Thiadiazole 3-oxides 242 are isomerized into I ,2,3-thiadiazole 2-oxides 248

when photochemically irradiated (scheme-! 06).
hv 'F-~+
Zs /N--0
248
Scheme-106
4.2 1,2,4-Thiadiazoles 59 ·71 - 74
4.2.1 General
I ,2,4-Thiadiazole 249 is a sulfur and nitrogen containing 7t-excessive aromatic

heterocycle and is numbered as shown in structure 249. The partially reduced
4 3
~~~
5'-.
/N
s 2
1
249
1,2,4-thiadiazoles are known as dihydro-1,2,4-thiadiazoles (thiadiazolines) and are

named according to the position of the double bond. The fully reduced ring
system of I ,2,4-thiadiazole is referred to as 2,3,4,5-tetrahydro-1 ,2,4-thiadiazole
(thiadiazolidine) 253.
HN~ N\ N\ HN\
( /N ( /NH I( s/
NH ( /NH
s s s
Ll2-1,2,4- Ll 3-1,2,4- Ll4-1,2,4- 1,2,4-
Thiadiazoline Thiadiazoline Thiadiazoline Thiadiazolidine
(4,5-dihydro-) (2,5-dihydro-) (2,3-dihydro-) (2,3,4,5-tetrahydro-)
250 251 252 253
1,2,4-Thiadiazoles have been used mainly as fungicides 254, 255 and 256 under
a viariety of names such as Terrazole, Pansoil, Truban, Aaterra etc. 1,2,4-
Thiadiazoles also find their uses as herbicides, insecticides and bactericides.
4.2.2 Synthesis
4.2.2.1 Oxidative Cyclization of Thioacylamidines
Oxidative cyclization of thioacylamidines 257 with oxidizing agents such as

bromine, iodine, nitric acid, acidic hydrogen peroxide and arylsulfonyl halides in
the presence of pyridine leads to the formation of 1,2,4-thiadiazoles 258
(scheme-1 07) 71 .
R1
\
C-NH
I/ \ oxidative
HN .;.:C-R2
sr cyclization
257
Scheme-107
4.2.2.2 From Amidines
The reaction of amidines with sodium hypochlorite followed by potassium

thiocyanate results in 5-amino-1 ,2,4-thiadiazoles 260 (scheme-1 08f 1• However,
259 260
Scheme-108
parent 1,2,4-thiadiazole is obtained by the following course of reactions

(scheme-1 09). But the reaction of amidines with trichloromethylsulfenyl chloride in
/NH 2 NaOCl
H-C~ + HCNS
NH
(i) HiRaney Ni
~~~ (ii) CH30H/(C2H 5) 3N
"-. /N
s
249 262
Scheme-109
the presence of a base produces 5-chloro-1 ,2,4-thiadiazoles 264 and with

dicholoromethylsulfenyl chloride 3-substituted 1,2,4-thiadiazoles 265 are obtained
(scheme-11 0)71 .
/NHz pyridine
R- C~ + C12XCSC1
NH (X=H,Cl) -HCl
R
\...- N cyclization
II \\ ~•_ ___,
N, /-x -ma
s
264: X= Cl
265: X=H
Scheme-110
4.2.2.3 Heterocyclic Ring Transformations (Oxazole and

Oxadiazole Rearrangements)
Thermal rearrangements of thioureas 267, 270 and 273, resulting by treating

5-alkyl-3-amino-1 ,2,4 oxadiazoles 266, 5-alkyl-3-aminoisoxazoles 269 and 4-alkyl-3-
amino-1 ,2,5-oxadiazoles 270 with phenylisothiocyanate, proceed through a common

mechanism involving cleavage of the N-0 bond to provide 1,2,4-thiadiazoles 268,
271 and 274, respectively (scheme-Ill).
NH 2
/~-1
R~ ,....N
+
0
266
H H
I
Jj
I~
NH2 N ' N
'c .... 'cH
R 0 N
_ _
+C6Hs-N-C-S~
~0
(II
S
6 s
270
269
R NH 2
H+
N, ,....N
0
272
Scheme-111
4.2.3 Structure
1,2,4-Thiadiazole is a planar molecule with the following structural parameters

(Fig. 22):

S-N2 1.649 C5-S-N 92.8
4 3
N2-C3 1.317 S-N2-C3 107.1
C3-N4 1.366 5 rz~,...N N2-C3-N4 120.1
s 2
NcCs 1.313 1 C3-NcC5 107.7
C5-S 1.707 NcC5-S 112.3
Fig. 22. Structural parameters in 1,2,4-thiadiazole
4.2.4 Reactions
4.2.4.1 Reactivity
1,2,4-Thiadiazole is sensitive to acid and alkali. 1,2,4-Thiadiazole is easily oxidized

by 30% hydrogen peroxide and is reductively cleaved readily by reducing agents.
However, the substituents at the positions-3 and -5 of 1,2,4-thiadiazole ring exert
stabilizing influence and stabilize the ring towards acid, alkali, oxidizing and
reducing agents.
The presence of two pyridine-type nitrogen atoms which exhibit inductively
electron-withdrawing effect make the ring carbons least reactive towards
electrophiles. However, quatemization occurs with the attack of electrophiles at the
nitrogen atoms, if the ring is activated by electron-releasing substituents. 1,2,4-
Thiadiazole ring is reactive towards nucleophiles and the attack of nucleophiles
generally results in nucleophilic substitution or ring cleavage.
1,2,4-Thiadiazoles substituted with an electron-releasing substituent (-NH 2) at the

position-5 are alkylated by alkyl halides initially at N-4 with the formation of N-
4-alkyl derivatives which on warning with ethanol undergo Dirnroth rearrangement
to provide 5-alkylamino-1,2,4-thiadiazoles 281 (scheme-112). But with phenacyl
bromide the initially formed N-4 derivative 282 undergoes cyclization with the
CH 3I __..
Scheme-112
formation of fused imidazolothiadiazoles 283 (Scheme-113? 1. However, the

reaction of I ,2,4-thiadiazole with trirnethyloxoniurn tetrafluoroborate [(CH 3)p+ BF4-]
results in diquatemary salt (scheme-114) 76 •
Br
I-H20
~-HBr
Scheme-113
J/~
"-. ,.....N
+
s
249
Scheme-114
4.2.4.3.1 Nucleophilic Substitution Reactions
The position-S in 1,2,4-thiadiazole is more reactive towards nucleophilic attack

because of being relatively with lower electron density as compared to the
position-3. The halogen atom at the position-S can be replaced by nucleophiles
involving addition-elimination mechanism ( scheme-115).
~N--(
R
,-_
Cl~ . . . ~,/ :Nu~ c1, 1
[
n
'\?
N_!_;R
,
f\ ]-a
~ci~/~\7 ___.~ \~
---IR N--IR
',_,
s , As.....
Nu /'-;::,Nu s,.....
S,.....N Nu
285 286 287
Scheme-115
The nucleophilic substitution in 5-chloro-1 ,2,4-thiadiazoles 285 is faster than in

six-membered heteroaromatics. The higher reactivity towads nucleophilic
substitutions is attributed to the greater stabilization of the intermediate 286
(additionally by inductive effect of sulfur).
The halogen atom at position-3 of 1,2,4-thiadiazoles exhibits inertness and is
much more difficult to replace by nucleophiles because de localization of negative
charge on both the nitrogen atoms is not possible. However, it can be replaced
only under drastic conditions (scheme-116).
Scheme-116
4.2.4.3.2 Ring Cleavage
4.2.4.3.2.1 Nucleophilic Attack at Carbon
The presence of substituents at the positions-3 and -5 in 1,2,4-thiadiazoles exert

stabilizing influence, however the reactions leading to ring cleavage occur with the
attack of nucleophiles at C-5 (scheme-117).
c;_-i NH2
N
0H.,. HN\(
H2N~ \
NH2
-S .. II
H
H2N, .,. N, .,. NH2
c c
II
H2N S/
H\3 tj"~ NH 0
290 291 292

Scheme-117
4.2.4.3.2.2 Nucleophilic Attack at Sulfur
Soft nucleophiles attack at the sulfur atom of 1,2,4-thiadiazoles with the cleavage
ofthe ring (scheme-118).
CsHs
H C _/(
~--(N-CH3
5 6 s
I
CN
293 294
Scheme-118
1,2,4-Thiadiazole when treated with a weak base (K2C0 3) in D 20 is deuterated at

the position-S with the formation of monodeutero 1,2,4-thiadiazole 295
( scheme-119)77 .
,~\\ ,~\\
H~ /N D~ /N
s s
249 295
Scheme-119
4.2.4.4 Reduction
1,2,4-Thiadiazoles are catalytically reduced with the cleavage of nitrogen-sulfur

bond (scheme-120).
Zn-HQ
Scheme-120
4.3 1,2,5-Thiadiazoles 61 ·78- 80
4.3.1 General
1,2,5-Thiadiazole is an aromatic heterocycle and is numbered as shown in its

structure 298. 1 ,2,5-Thiadiazole does not exist in the reduced forms as the reduced
systems are much less stable and are readily hydrolytically desulfurized to the
open chain compounds with N-C-C-N structural skeleton.
4~3
II \\
N N
s 's . . . 2
1
298
1 ,2,5-Thiadiazoles find pharmaceutical, agricultural and industrial applications.

The pharmaceuticals incorporating 1,2,5-thiadiazole ring system are used as
antibiotics, histamine H 2-receptor antagonists and P-adrenergic blocking agents
(Timolol). Timolol 299 (hemimaleate salt) is used as an active chemotherapeutic
agent in Blocadren and Timoptic. Blocadren is used for the treatment of high blood
pressure and Timoptic is used as eye drops in the treatment of eye disease
glaucoma. 1 ,2,5-Thiadiazoles are also used as herbicides, fungicides, bactericides,
insecticides and plant growth regulators. 1,2,5- Thiadiazole ring system is also
involved into a number of polymers with desirable chemical and thermal stability.
4.3.2 Synthesis
4.3.2.1 From o-Diamines [(4 + 1) Cyclization]
This is the most widely used and versatile method and involves the reaction of
o-diamines (acyclic N-C-C- N system with N-C groups sp, sp2 or sp 3 hybridized)
with sulfur monochloride or sulfur dichloride to provide appropriately substituted
1,2,5-thiadiazoles (scheme-121 ) 78•81 - 84.
n
R R R
\
HC-CH
I I + sa 2 N, _...N
NH2 NH2 s
300 301
NC CN
HN~
c
I
_...CN
+ sa 2 ~
H
N, ,....N
HN..,
~c,
CN s
302 303
R,
HC-Cv
I
NH2 NH2
I
ho
+ sa 2 ..
R
n
N, _...N
s
OH
304 305
Scheme-121
4.3.3 Structure
1,2,5-Thiadiazole is a planar heterocycle with C2v symmetry. The structural

parameters for 1,2,5-thiadiazole are as (Fig. 23) :
Bond lengths (A) Bond angles (0)

S-N = 1.631 4~3 N-S-N 99.6
~ ~ S-N-C 106.4
C=N = 1.328 N N
s 's,.2
C-C = 1.420 N-C-C 113.8
Fig. 23. Structural parameters in 1,2,5-thiadiazole
The structural parameters indicate that the carbon-carbon bond length is nearly
the same as C3-C4 in thiophene ( 1 4. 23A). It is longer than that in benzene ( 1 3. 97A),
while shorter than the carbon-carbon single bond in cyclopentadiene (1.46A).
Thus, carbon-carbon bond (C3-C4 ) in 1,2,5-thiadiazole exhibits double bond
character. The C-N bond length (1.328A) in 1,2,5-thiadiazole is intermediate
between that of pyridine and oxadiazole and, therefore, reflects to acquire partial
single bond character also. Similarly, the S-N bond length in 1,2,5-thiadiazole
indicates the presence of double bond character. The bond lengths in 1,2,5-
thiadiazole predict n-electron delocalization and hence the aromaticity in the ring.
4.3.4 Reactions
4.3.4.1 Stability
1,2,5-Thiadiazole is a weak base with pKa = 11 .90. 1,2,5-Thiadiazole ring system is

generally stable to mineral acids, but slightly sensitive to bases. 1,2,5-Thiadiazole
is thermally stable, but 3,4-diphenyl-1 ,2,5-thiadiazole 1, !-dioxide 306 is decomposed
into benzonitrile and sulfur dioxide when heated at 250°C (scheme-122) 78 .
H5Cs C6 H5
H
N, ,.N
25<J'C
~s~
0 0
306
Scheme-122
1,2,5-Thiadiazole ring system is with very low electron density at the nitrogen and
sulfur heteroatoms and is therefore relatively inert towards electrophilic attack.
However, electrophilic substitutions can occur only if 1,2,5-thiadiazole ring is
substituted with electron-releasing substituents (-NH 2 or -CH 3 ) 78 ·79 .
1,2,5-Thiadiazole ring is susceptible towards nucleophiles with the attack either at

carbon, sulfur or a ring proton.
(i) The attack of nucleophile at carbon results in nucleophilic substitution with
the formation of a substituted product (Fig. 23).
R Cl
K~u
N, .,....N
(attack at carbon)
s
Fig. 23. Nucleophilic attack at carbon
(ii) The attack of nucleophile at sulphur leads to the formation of rearranged

product or causes ring cleavage (Fig. 24).
(attack at sulfur)
Fig. 24. Nucleophilic attack at sulfur
(iii) The attack of nucleophile at a ring hydrogen proceeds with the abstraction
of a proton providing ring cleaved product or involves proton exchange
(Fig. 25).
~H Cl
_l ~n
tJ/
.Nu N N (attack at ring hydrogen)
Fig. 25. Nucleophilic attack at hydrogen

The reaction of 1,2,5-thiadiazoles with organometallics (n-butyllithium or

Grignard reagents) involves the attack ofnucleophile usually at the ring sulfur, but
the attack at the ring carbon also occurs providing a different product
(scheme-123)85 .
HsCs C H
\..._._/ 6 5
1/ ~
N N-M
\
S-R
308
Scheme-123
The reaction of quaternary compound 309 with ammonia (nitrogen nucleophile)

in acetonitrile proceeds to involve attack at sulfur or carbon (path A or B) with
the formation of rearranged product 313 (scheme-124)83 .
OR
rl+
N, ..;,N, + NH3
PathB rl+
N, ..;,N
NH2
S \; CH3
309
path A~
rlNCH3
[~;-cHl
NHCH3
~OR
N
..
... rl ..
N, ,....N
N, NH2
s ..
\
s-NH2 s <:;:'~
NH2
133
310 312
Scheme-124
But the reaction of quaternary compound 314 with carbon nucleophile (CN)
involves the attack at sulfur followed by ring cleavage and subsequent cyclization
to provide ring expanded product 316 (scheme-125) 86 .
3
n-{3
rN-CH,
N-CH N-CH
N,\_NHCH3 .
s-c=N N,SANH
314 315
lJ 316
Scheme-125
4.4 1,3,4-Thiadiazoles 61 •87- 90
4.4.1 General
1 ,3,4-Thiadiazole is a sulfur-containing aromatic heterocycle with nitrogen atoms

at the 3-and 4-positions and is numbered as shown in its structure 317.
4 3
N-N
s/( )2
s
1
317
1,3,4-Thiadiazole exists in two partially reduced (dihydro-) forms , 318 and 319
and named as 1,3,4-thiadiazolines depending on the position of the double
bond. The completely reduced (tetrahydro-)1,3,4-thiadiazole is known as 1,3,4-
thiadiazolidine 320.
N-NH
I()
s
~ 2 -I ,3,4-Thiadiazoline ~ 3 -I ,3,4-Thiadiazoline I ,3,4-Thiadiazolidine
(2,3-dihydro-) (2,5-dihydro-) (2,3,4,5-tetrahydro-)
318 319 320
1,3,4-Thiadiazoles exhibit varying biological activity and are, therefore, fmd their
uses in the fields of pharmaceuticals (acetazolamide 321 as diuretic and 2-amino-
1,3,4-thiadiazole 322 as antitumor agent in dogs) and agrochemicals (methidathion
323 as an insecticide and 324 as herbicide).
N-N
I(S)-NH2
s 322
II
(CH 30)2PSH2C,
N-N N-N
(CH 3)JC.J(S)- NHCHJ 0~ 5 )-0CH3

323 324
4.4.2 Synthesis
4.4.2.1 From Thiosemicarbazides
This is the most common method to synthesize 5-substituted 2-amino-1,3,4-

thiadiazoles and involves acylation of thiosemicarbazide 325 followed by
dehydrative cyclization using sulfuric acid, polyphosphoric acid, phosphorus
halides or more recently methane sulfonic acid (scheme-126)91 • However, 2-amino-
s HN-NH
II (R 1C0h0 I \
R-NH-C-NH-NH2 /c c
RHN ''s 0
/f ' 1
R
325 326
!
RHN S
3 4
N-N
Ji()z
1
R 1 -H20
[
RHN HS
/
II
c\ N-NI c'
\\
OH R
1
l
327
Scheme-126
1,3,4-thiadiazole is obtained by heating thiosemicarbazide with a mixture of formic

acid and hydrochloric acid (scheme-127) 92 .
N-N
HCOOH/ HO
I(S)-NH2
322
Scheme-127
4.4.2.2 From Dimethylformamide
The reaction ofN,N-dimethylformamide with thionyl chloride produces formamidoyl

chloride 328 which on treatment with N,N-diformylhydrazine and with sodium
ethoxide gives a free base 329. The free base 329 obtained undergoes cyclization
in the presence of hydrogen sulfide with the formation of parent 1,3,4-thiadiazole
317 (scheme-128).
Cl H H
+ I _ (i) OHC -N-N-CHO
(CH3hN-CHO + SOCI 2 -_-::8~0~:-~(CH3hN=CH a
328 N-N (ii) C2H5 0Na
N-N H2S It ,,
!() HC CH
I I
s (CH 3hN N(CH 3h
317 329
Scheme-128
4.4.2.3 From Hydrazine
This is the one pot-synthesis of2,5-dialkyl-1,3,4-thiadiazoles 331 and involves the

reaction of hydrazine with aldehyde and elemental sulfur. The reaction proceeds
via an intermediate 330 which is subsequently cyclized to 331 with the evolution
of hydrogen sulfide involving the formation of C-S bond (scheme-129).
N-N
+ It \\
R-cI c-R
I
SH SH
330
Scheme-129
4.4.3 Structure
1,3,4-Thiadiazole is a planar molecule with C2v symmetry and the structural

parameters are summarized as (Fig. 26) :
Bond lengths (A) Bond angles (0)

C-N = 1.302 N-N C-S-C 86.4
c-s = 1.72I Z)
s
S--C-N 1I4.6
N-N = 1.37I C-N-N 112.2
Fig. 26. Structural parameters in I,3,4-thiadiazole
The C- N bond length in 1,3,4-thiadiazole is very close to that in thiazole and

the C-S bond length is nearly similar to that in thiophene. The N-N bond in 1,3,4-
thiadiazole also acquires some double bond character. The bond lengths in 1,3,4-
thiadiazole reflect that the single bonds acquire double bond character while
double bonds acquire some single bond character and therefore suggest larger
de localization of 7t-electrons in 1,3,4-thiadiazole than in I ,3,4-oxadiazole. But 1,3,4-
thiadiazole exhibits lower aromaticity than that in 1,2,5-thiadiazole.
4.4.4 Reactions
4.4.4.1 Reactivity
I ,3,4-Thiadiazole ring is 7t-electron deficient because of the presence of two

pyridine-type nitrogen atoms and hence does not react readily with electrophiles
at nitrogen or at carbon. If the ring is substituted with the electron-releasing
substituent, the attack of electrophile occurs at nitrogen with quatemization. I,3,4-
Thiadiazole ring is susceptible towards nucleophiles and the attack of nucleophile
occurs with the nucleophilic displacement or ring cleavage. The reactions
involving ring formation between two nitrogens (ring nitrogen and amino group
nitrogen) are common, if 1,3,4-thiadiazole ring is substituted with an amino group
at the position-2.
4.4.4.2.1 Electrophilic Attack at Nitrogen (Quaternization)
The attack of electrophiles in I,3,4-thiadiazole ring occurs at both ring nitrogen

atoms. The reaction of I ,3,4-thiadiazoles with methyl iodide results in quaternization
at N-3 and N-4 and the ratio of the products depends upon the substituents
present at the positions-2 and -5 (scheme-130) 93 •
+ /CH3 H3C, +
N-N N-N N-N
CH31 ~ II \\ +
R2.J( )-R1 + R2~ /'--R1 R2.J( )-R1
s s s
332 R 1=H; R2=CH 3 334 (55%) 335 (45%)
333 R 1=C 2H5; R 2=CH 3 336(43.5%) 337 (56.4%)
Scheme-130
1,3,4-Thiadiazole does not undergo electrophilic substitutions at the ring carbon

atoms because of the low electron density due to the presence of electron-
withdrawing nitrogen atoms at the positions-3 and -4.
4.4.4.3.1 H ~ D Exchange
l ,3,4-Thiadiazoles undergo base induced H ~ D exchange at the position a - to

the sulfur when treated with D 20 under strongly basic conditions (scheme-131 ).
base/~0
Scheme-131
4.4.4.3.2 Ring Cleavage via C-Deprotonation
1,3,4-Thiadiazoles unsubstituted at least at one a-position undergo ring opening

reaction via C-deprotonation when treated with a strong base (scheme-132).
R
Sf-p
l1 H
. +
338
Scheme-132
4.4.4.3.3 Amination
The reaction of 1,3,4-thiadiazoles (containing one free a-position) with hydroxyl-

amine in the presence of a base results in nuclear amination via an imine inter-
l
mediate 341 with the formation of2-amino-1,3,4-thiadiazoles 342 (scheme-133) 90 .
N-N
R)(s~H
base
.. [ N-NH
R_j(sXHNHOH
.
-H20
N-NH
R,J(sANH
338 340 N-N 341
+
NH20H R_l(S)-NH2
... I
342
Scheme-133
Halo-1 ,3,4-thiadiazoles 343 undergo nucleophilic substitution reactions readily

with the replacement of halogen atom (a-to ring sulfur) by nucleophiles. The
replacement of halogen atom in 1,3,4-thiadiazole nucleus is easier because of the
presence of electronegative nitrogen atoms which inductively attract electrons
from the ring carbon atoms and make them with low electron density (scheme-134 ).
N-N
R.J(s)-O~H 5
344
.. R.J(
N-N
S~ NHQ;H 5
343 345
+ .
343
Scheme-134
4.4.4.4 Reactions Involving Ring Formation
In 2-amino-1 ,3,4-thiadiazoles, the presence of nitrogen atom at the position-3

facilitates ring formation involving nitrogen of an amino group. The reaction of 2-
amino-1 ,3,4-thiadiazole with ~-diketones results in the formation of bicyclic
compounds. The reaction, however, depends on the nature of the B-diketones.
The reaction of 2-amino-1 ,3,4-thiadiazole 322 with ethylacetoacetate produces a
mixture of 347 and 348, but 347 is converted into 348 (bicyclic compound) on
heating (scheme-135). However, the reaction with pentane-2,4-dione results in 4,6-
N-N
I()- +
S NH2
322
Scheme-135
dimethyl-2-thiocyanopyrimidine 350 via a bicyclic intermediate 349 (scheme-136).
0 0
N-N II II
II \\ + CH3-C-CH2-C-CH3__. .
~S/'NH2
322
Scheme-136
The reaction of 2-amino-1,3,4-thiadiazole 322 with diethyl malonate proceeds

initially with the formation of an ester 351 which is then cyclized to bicyclic
compound 352 on heating (scheme-137).
N-N N-N 0
II ) -
"-s NH2
+
I( )-NHCOCH 2g-OC2Hs
s
322 351
Scheme-137
The reaction of 2-amino-1 ,3,4-thiadiazole 322 with haloaldehydes and haloketones

also provides bicyclic compounds, imidazo[2,1-b][1,3,4]thiadiazo les 353
incorporating both the nitrogens in the ring (scheme-138)94 .
N-N
II \\ + [
R-CH-C=O
I I ~R-C=C-OH1
I I
N-N~I
~II)=. R
"- 8 /'NH2 Cl R Cl R "'- -N
s
322 353
Scheme-138
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CHAPTER6
MESO-IONIC HETEROCYCLES
CONTENTS
I GENERAL 581
2 CLASSIFICATION 583
3 CHEMISlRYOFMESO-IONICHETEROCYCLES 584
3.1 Chemistry of Meso-Ionic Heterocycles of Type-A 584
3.1.1 1,3-0xazolium-4-olates 585
3.1.1.1 Synthesis 585
3.1.1.1.1 From a-Diazoimides (Diazo Ketones) 585
3.1.1.1.2 Fromlrnides 585
3.1.1.2 Reactions 585
3.1.2 1,3-0xazolium-5-olates (Miinchnones) 587
3.1.2.1.1 From N-Acylamino Acids 587
3.1.2.2.1 Cycloaddition Reactions 588
3.1.2.2.1.1 Reactions with Alkenes 588
and Related Compounds
3.1.2.2.1.2 Reactions with Alkynes 592
3.1.2.2.1.3 Reactions with Carbonyl 593
Compounds
3.1.2.2.1.4 Reaction with Carbon Disulfide 594
3.1.2.2.1.5 Reactions with lsothiocyanates 594
and Isocyanates
3.1.2.2.2 Reactions with Nucleophiles 595
3.1.2.2.3 Reactions with Small Ring Heterocycles 5%

3.1.2.2.4 Photochemical Reactions 5%
3.1.3 1,3-0xathioliwn-4-olates 597
3.1.4 1, 3-0xathiolium-5-olates 598
3.1.5 1 3, -Diazoliwn-4-olates 600
3.1.5.1.1 From Amino Amides 600
3.1.5.1.2 From Amidines 600
3.1.5.1.3 From 1,3-0xazoliwn-5-olates 601
3.1.6 1,3-Diazoliwn-4-aminides 601
3.1.7 1,3-Dithioliwn-4-olates 604
3.1.7.1.1 From Dithioglycolic Acids 604
3.1.7.1.2 From Dithiobenzoic Acids 605
3.1.7.2.1 Cycloaddition with Alkynes 606
3.1.7.2.2 Cycloaddition with Alkenes 606
3.1.7.2.3 Cycloaddition with Compounds 607
Containing Carbon-Heteroatom
Double Bonds
3.1.7.2.4 Photochemical Cycloaddition 607
3.1.8 1 ,2,3 -0xadiazolium-5-olates (Sydnones) 609
3.1.8.1.1 From N-Nitroso-a-amino Acids 609
3.1.8.2.1 Cycloadditions with Alkynes 610
3.1.8.2.2 Cycloadditions with Alkenes 611
3.1.8.2.3 Photochemical Reactions 612
3.2 Chemistry of Meso-Ionic Heterocycles of Type-B 614
3.2.1 1,2-Diazoliwn-4-aminides 614
3.2.1.2.1 Thermal Isomerization 615
Meso-Ionic Heterocycles 581
3.2.1.2.2 Reaction with DMAD 616

3.2.2 1,2-Dithiolium-4-olates 616
3.2.2.1.1 From Propane- 1,3-dione Esters 616
3.2.2.1.2 From 1,3-Diarylpropane-1,2,3-triones 617
3.2.2.1.3 From 1,1,3,3-Tetrabromo-1,3- 617
diary lpropan-2-ones
3.2.2.2.1 Desulfurization 618
3.2.2.2.2 Reactions with Ammonia and Its 618
Derivatives
3.2.2.2.3 Thermal Reactions 620
3.2.3 1,2,3,4-Tetrazolium-5-thiolates 620
3.2.3.1.1 From Dithizone 620
3.2.3.1.2 From Diphenylthiocarbazide 621
3.2.3.2.2 Thermal Rearrangement 621
3.2.3.2.3 Cycloaddition Reactions 622
3.2.3.2.4 Reactions involving Dehydrodithizone 623
as Acyclic Valence Tautomer
REFERENCES 624
1 GENERAL
The term meso-ionic (mesomeric+ ionic) was first introduced by Baker and Ollis 1•2
in 1949 to describe the structure of N-phenylsydnone 1 as a resonance hybrid of
the dipolar resonating structures (i-iii) (Fig. 1).
+ .,N,
- + .,N, .,N, + C N"G)N,
H5C6 -N 0 HsC6-N" 0 HsC 6-N '0 Hs 6- + 0
c=c = ,c-c
..,._ \ I \ I - \ I
,c-c,,
'' I
,c=c ~
H 0 H
\
0 H" 'o H 0
(i) (ii) (iii) - 1
Fig. 1. Resonating structures of N-phenylsydnone

According to the original definition, the term meso-ionic was defined as :

"a five- or six-membered heterocycle which cannot be represented satisfactorily by
any one covalent or polar structure and possesses a sextet of electrons in
association with the atoms comprising heterocyclic ring". But the term meso-ionic
has been restricted to the five-membered heterocycles and the definition of meso-
ionic heterocycle has been modified as :
"A five-membered heterocycle which cannot be represented satisfactorily by
any one covalent or polar structure and possesses a sextet of electrons in
association with the five atoms comprising the ring"3 .
The meso-ionic heterocycles can be represented by a general formula where a,
b, c, d, e and fare atoms or groups of atoms derived from carbon or heteroatoms.
The heterocyclic ring bears a fractional positive charge which is balanced by a
corresponding partial negative charge located on a exocylic atom or group of
atoms covalently attached to the ring through a carbon atom (Fig. 2)4 .
Fig. 2. Representation of meso-ionic heterocycles
Meso-ionic heterocycles can be regarded as internal salts in which a functional

group attached to the heterocyclic ring can sustain a negative charge as in case
of 1,3-diazolium-4-olates 2. But 4-ethoxydiazonium salt 3, which is not meso-ionic,
is an external salt in which a positive charge on the nitrogen atom is balanced by
negative iodide counterion.
The five-membered heterocycles in which an exocyclic heteroatom is attached

covalently to the heterocyclic ring through a cyclic heteroatom (not through a
carbon atom) are known as betains. Betains include N-Oxides, N-imides etc. and
are represented as :
cr:>o-
-
~+ ~ +~
N, .... N- 0- 0- .-N N
o 'o. .
1
CH3 2a 3a
2 CLASSIFICATION
Meso-ionic heterocycles can be divided into two general classes; type-A and
type-B, depending upon the contribution of electrons by the ring atoms to
the n-electron system of the ring.
(i) Type-A: Meso-ionic heterocycles in which each of two non-adjacent atoms
of the five-membered ring contributes two electrons to the n-electron
system are referred to as type-A and represented as in (Fig. 3) :
b-a
!G)\
c.. . ._ ,....e-7
d
5
Fig. 3. Representation of type-A meso-ionic heterocycles; a and c each
contribute 2-electrons, while each of b, d, e and f contribute !-
electron to the n-electron system
(ii) Type-B : Meso-ionic heterocycles in which each of two adjacent atoms of

the five-membered ring contributes two electrons to the n-electron system
are known as type-B and represented as in (Fig. 4) :
2 1
b-a
I \1
~,d,....e,f1
1
6
Fig. 4. Representation of type-B meso-ionic heterocycles; b and c each
contribute 2n-electrons, while each of a, d, e and f contribute
In-electron
The two general types of meso-ionic heterocycles exhibit quite distinct chemical
properties :
Type-A meso-ionic heterocycles participate in 1,3-dipolar cycloaddition reactions
as these heterocycles are regarded as being derived by the union of 1,3-dipoles
8 and heterocumulenes 9 (scheme-!).
~b ~a
+C....._ + e
d .:::::.f
8 9
Scheme-l
The important chemical property oftype-B meso-ionic heterocycles is their facile

ring opening to provide acyclic valence tautomers 10 (scheme-2).
b=a
\
e=f
I
c=d
10
Scheme-2
3 CHEMISTRY OF MESO-IONIC
HETEROCYCLES3- 5
3.1 Chemistry of Meso-Ionic Heterocycles of Type-A
With the general structural formula 4, 5 for type-A meso-ionic heterocycles, if a,

b, c, d, e and fare suitably substituted carbon and heteroatoms (nitrogen, oxygen
and sulfur), there are 144 structural possibilities, but nearly seventy meso-ionic
heterocycles of type-A have been reported. The syntheses and reactions of some
important meso-ionic heterocycles of type-A are being presented.
3.1.1 1,3-0xazolium-4-olates
1,3-0xazolium-4-olates are represented by the following general structure 11 .
3.1.1.1 Synthesis
3.1.1.1.1 From a-Diazoimides (Diazo Ketones)
The thermal cyclization of a-diazoimides or diazo ketones 12 in the presence of

copper(II) acetylacetonate as catalyst provides 1,3-oxazolium-4-olates 11 . The
reaction proceeds to involve a carbene intermediate 13 with the evolution of
nitrogen (scheme-3) 6•7 .
;ro
R1 R2 R1 R2
Jfo
R1 R2
)"-N/ Cu (acac)z )"-N/
o o )=o -----..
N-
2 3
~
-N2 :c
R ' R3 R3
12 13 11
Scheme-3
3.1.1.1.2 From Imides
The reaction of imides 14 with triethyl phosphite also affords 1,3-oxazolium-4-

olates 11 and the reaction mechanism is depicted in (scheme-4) 8 .
3.1.1.2 Reactions
1,3-0xazolium-4-olates behave as carbonyl ylides and undergo 1,3-dipolar

cycloaddition reactions with alkenes and carbonyl compounds providing bicyclic
adducts (scheme-5) 9.
16
Scheme-4
Jfo
R1 R2
R3
11
+ RCH=CHR
(R =COOCH3)
17 0
Ar
+ ArCHO
0
18
Scheme-S
However, with alkynes (DMAD), the initially formed bicyclic adduct 19

undergoes retro Diels-Alder reaction with the extrusion of isocyanate to provide
the corresponding furan 20 (scheme-6).
R,
c
+ Ill
,...c
R
R R
R' )j__0
R' -R-~-CO---'
...,..,..___
20
Scheme-6
3.1.2 1,3-0xazolium-5-olates (Miinchnones)
1,3-0xazolium-5-olates are isomeric with 1,3-oxazolium-4-olates 11 and are also

known as munchnones. These are represented by the general structure 21.
R1
fr:.o
R2 -N~Q
R3
21
3.1.2.1 Synthesis
3.1.2.1.1 From N-Acylamino Acids
1,3-0xazolium-5-olates 21 are synthesized by cyclodehydration of N-acylamino

acids 22 with acetic anhydride at low temperature (scheme-7).
R1
)=o
R2 -N
3 >--cooH
R
22
Scheme-7
3.1.2.2 Reactions
3.1.2.2.1 Cycloaddition Reactions
I,3-0xazolium-5-olates 21 undergo I,3-dipolar cycloaddition reactions with a

number of dipolarophiles.
R1
R1 R1
~0 \'-)r-:0 )+o
--
R'-N~Q ·~-
/N ~ 0
~
,N~ 0
R3 R2 R2
R3 R3
21 (i) (ii)
3.1.2.2.1.1 Reactions with Alkenes and Related Compounds
I ,3-Dipolar cycloadditions of I ,3-oxazolium-5-oiates to aikenes and other related

compounds containing double bond result in the formation of bicyclic adducts 23
which on heating extrude carbon dioxide readily with the formation of final
products via I,3-dipole 24 (scheme-8) 9 .
The cycloaddition of I,3-oxazolium-5-olates with styrene affords 2-pyrrolines
(2 ,3-dihydropyrrole) 27 involving mechanism as depicted in (scheme-9). However,
1,3-oxazolium-5-olates with alkenic dipolarophiles containing suitable leaving
groups afford pyrroles 30 and 32 (scheme-I0) 9 .
R2
\
R1
N R1
fr.o
R2 -N~Q
R3
+ X=Y
(dipolarophile)
.. :iff
R3 0
RI =R3 23 -C02
22
final product depending tautomerization [ x-v ]
on the nature of
dipolarophile RA.A:--R
1 3
24
Scheme-S
R1 R2....._
(r.o
..
~
R'-N~Q + Ph-CH=CH2
0
R3 H
RI =R3 H R3 0
22 25
~ -ro,
Ph
RhR
1
N
12
3
tautomerization
~nH
R1 +
N
- R3
R 12
R
27 26
Scheme-9
R1
R'-Nro
(r..o
+ CICH =CHN02 .,.
R3
R 1 =R 3
+
CICH=CHCN
-HO
32
Scheme-10
5(411)-0xazolones 33 are in tautomeric equilibrium with 1,3-oxazolium-5-olates 34

(R 2=H) which can explain the formation of 1-pyrrolines 36 (scheme-11) 9 .
R1
)r-o
N0 R3
0
EHC=CHE -----...
(E=COOCH 3)
R 1 =R 3
33
E E
RhR
1
N
36
3
t tautomerization
Scheme-11
However, cycloaddition of 1,3-oxazo1ium-5-o1ates with cyclopropenes and

cyclobutenes results in the ring expanded products 39 (scheme-12) 10•
R2
R1 /
)r.o N 1
R2 -N~Q
R3
+
o( CN
... ~0
NC R3 0
NCDCN .. Nw
21 37
.. 1-m2
R1
;J 7
N R3
R1 R3
N
12
R 12
R
39 38
Scheme-12
The intramolecular cycloaddition of 1,3-oxazolium-5-olates 40 with alkenes

results in a mixture ofregioisomers 41 and 42. The regioselectivity depends upon
the substituents on the meso-ionic ring as with R 1=CH3 and R 3 =C 6H 5 two products
41 and 42 are obtained, but with R 1=R3=CH3 only one product 41 is obtained
(scheme-13) 11 .
42
Scheme-13
However, in some cases, the cycloaddition proceeds to involve valence-

tautomeric form (acylaminoketene form) 43 ofl ,3-oxazolium-5-olates (scheme-14) 12.
45
Scheme-14
3.1.2.2.1.2 Reactions with Alkynes
1,3-Dipo1ar cycloaddition of 1,3-oxazolium-5-olates with alkynes results in the

formation of pyrroles with the elimination of carbon dioxide (scheme-15). The rate
of cycloaddition is increased, if alkyne is activated by the electron-withdrawing
substituents.
Scheme-15
However, in some cases, the meso-ionic species is generated in situ in the

presence of a dipolarophile. Cyclodehydration ofN-acylamino acids 48 with acetic
anhydride in the presence of alkynic dipolarophiles proceeds with the formation
of 1,3-oxazolium-5-olates in situ providing the corresponding pyrrole derivatives
49 (scheme-16) 9 .
Scheme-16
3.1.2.2.1.3 Reactions with Carbonyl Compounds
Cycloaddition of 1,3-oxazolium-5-olates with carbonyl compounds proceeds with

the formation ofbicyclic adducts 50 which with the loss of carbon dioxide followed
by the cleavage of the ring provide enamines 51 (scheme-17)9 .
Scheme-17
3.1.2.2.1.4 Reaction with Carbon Disulfide
The reaction of 1,3-oxazolium-5-olates with carbon disulfide yields 1,3-thiazolium-

5-thiolates 53 with the elimination of carbon dioxide from the bicyclic adducts 52
(scheme-18) 13 •14 .
R2
I
+ s=c=s ----..
0
~~R3 S
52
....,...,__ _...J, -C02
Scheme-18
3.1.2.2.1.5 Reactions with Isothiocyanates and lsocyanates
Cycloaddition of 1,3-oxazo1ium-5-olates with phenyl isothiocyanate results in new

meso-ionic species, 1,3-diazolium-5-thiolates 55 involving an initially formed
bicyclic adduct 54 (scheme-19) 9 .
R2 R1
R,)G£s ..
N -C02
I
CsHs
55
Scheme-19
However, with isocyanates stable bicyclic cycloadduct 56 is obtained

(scheme-20) 15 .
+ R-N=C=O
Scheme-20
3.1.2.2.2 Reactions with Nucleophiles
1,3-0xazolium-5-olates react very readily with nucleophiles; water, alcohol and

amine, providing the products 57, 58 and 59, respectively (scheme-21) 16 .
R1
\
.. R2 -N
I
\
C=O
CH-COOH
I
R3 57
R1
..
\
C=O
2 I
+ ROH R -N 0
\ //
CH-C'
I 'OR
R3 58
R1
.
\
C=O
2 I
+ RNH 2 R -N 0
\ //
CH-C'
I 'NHR
R3 59
Scheme-21
3.1.2.2.3 Reactions with Small Ring Heterocycles
The reaction of 1,3-oxazolium-5-olates with 2,2-dirnethyl-3-dimethylaminoazirine 60

affords oxazoline derivatives 61 (scheme-22) 17 •18 .
Rl = R3 = C6Hs
R 2 = CH 3
Scheme-22
The irradiation of 4-unsubstituted 1,3-oxazolium-5-olates 62 in chloroform-ethanol

yields ester 64 involving intermediacy of the valence-tautomer ketene 63
(scheme-23) 19.
63 64
Scheme-23
However, photo-oxidation of 1,3-oxazolium-5-olates 65a results in dibenzamides

66. The reaction is considered to proceed with the formation of an intermediate
endo-peroxide 65 (scheme-24) 20 .
R1 R2
'
'(r.o N R1
R'-N~o hv 0~~-
R3 RJ 0
65a
65
Rl = R3 = C6Hs
R 2 = CH 3
Scheme-24
3.1.3 1,3-0xathiolium-4-olates
1,3-0xathiolium-4-o1ates are represented by the structure type 67.
3.1.3.1 Synthesis
1,3-0xathiolium-4-olates are unstable and are generated in situ by cyclodehydration

of the acids 68 using acetic anhydride or dicyclohexylcarbodiimide (scheme-25).
R1
cf"c=s (ai3CD)zO
\
CH-COOH
/
R2 68
(R 1=NR 2 or SRgroup)
Scheme-25
Although the 1,3-oxathiolium-4-olates are not isolable, however they can be

isolated as 1,3-oxathiolium perchlorates by treating acid 68 with acetic anhydride
and perchloric acid (scheme-26? 1•22 .
perchloric acid
Scheme-26
3.1.3.2 Reactions
1,3-0xathiolium- 4-olates undergo 1,3-cycloaddition reactions with alkynic

dipolarophiles to afford furans 70 via the formation of bicyclic adduct 69
(scheme-27).
+ E-c=c-E ~ ~~
- - - - l..
(E=COOCH 3)
E R2 0
)j
69
R
1
__s...J
R ....,..11---eo
2
70
Scheme-27
3.1.4 1,3-0xathiolium-5-olates
1,3-0xathiolium-5-olates are represented by the general structure 71.

3.1.4.1 Synthesis
Cyclodehydration of aroylthioglycolic acids 72 in the presence of trifluoroacetic

anhydride yields 1,3-oxathiolium-5-olates (scheme-28) 23•24 .
TFAA
72
Scheme-28
3.1.4.2 Reactions
1,3-0xathiolium-5-olates undergo 1,3-dipolar cycloaddition reactions with alkynic

dipolarophiles providing thiophene derivatives 74 with the loss of carbon dioxide
from the initially formed unstable cycloadducts 73 (scheme-29) 24·25 .
Scheme-29
3.1.5 1,3-Diazolium-4-olates
1,3-Diazolium-4-olates are imidazole-related meso-ionic heterocycles and are

represented by the structure 75.
3.1.5.1 Synthesis
3.1.5.1.1 From Amino Ami des
The general method to synthesize 1,3-diazolium-4-olates involves the reaction of

amino amides 76 with triethyl orthoformate or with N-phenylbenzimidoyl chloride
(scheme-30).
C6 H5C=N-C6 H5
I
Cl
(C6Hs=R4)
Scheme-30
3.1.5.1.2 From Amidines
Base catalyzed condensation ofN, N'-disubstituted amidines 77 with a-bromoacyl

chloride results in good yields of 1,3-diazolium-4-olates (scheme-31 )26 .
.
Scheme-31
3.1.5.1.3 From 1,3-0xazolium-5-olates
The reaction of 1,3-oxazolium-5-olates 21 with phenyl isocyanate proceeds to

involve 1,3-cycloaddition reaction with an initial formation of a cycloadduct 78
which provides the corresponding 1,3-diazo1ium-4-olate 79 with the loss of carbon
dioxide (scheme-32) 27 .
21 78
Rl =R3 =C6Hs
R2=CH3
Scheme-32
3.1.5.2 Reactions
1,3-Diazolium-4-olates undergo 1,3-cycloaddition reactions with alkenic and alkynic

dipolarophiles. 1,3-Cycloaddition with alkynes (DMAD) proceeds with the
formation of thermally unstable bicyclic intermediates 80 which are converted to
pyrroles 81. But with alkenes (dimethyl fumarate), bicyclic imide 83 is obtained
from the initially formed hi cyclic intermediate 82 with the elimination of methanol
(scheme-33) 27 .
3.1.6 1,3-Diazolium-4-aminides
1,3-Diazolium-4-aminides are represented by the general structure 84 in which the

negative charge is present on the exocyclic nitrogen.
E E
RhR
2
N
13
4
R
81
82 83
Scheme-33
3.1.6.1 Synthesis
1,3-Diazolium-4-aminides are prepared by the reaction of nitriles with benzoyl

chloride followed by the treatment with sodium bicarbonate. The reaction proceeds
to involve intermediacy of the stable aminoimidazolium salt 86 (scheme-34f8 .
\
HC-CN
\ 4
R
Rl = R2= C6Hs
R3 = CH3
R4 = H
Scheme-34
3.1.6.2 Reactions
I ,3-Diazolium-4-aminides behave as I ,3-dipoies and undergo I ,3-cycloaddition

reactions with alkynic dipolarophiles. Thus, cycloaddition of 1,3-diazolium-4-
aminide with dimethyl acetylenedicarboxylate results in pyrrole derivative 88
involving bicyclic adduct 87 as an intermidate (scheme-35) 28 . Similarly, the reaction
with diethyl azodicarboxylate affords a stable bicyclic adduct 89 (scheme-35).
87
E
~ E
R)j__R
4
N
2
13
R
89 88
Scheme-35
3.1. 7 1,3-Dithiolium-4-olates
1,3-Dithiolium-4-olates are represented by the general structure 90 which is

considered as the resonance hybrid of the resonating structures (i-v) (Fig. 5).
·?-
R1
sya
R1 R1
{=s+
..
~6 R2
-- s #
R2
6
...
R2
90 (i) (ii)
R1
+ R1 R1 ~
.. ..
S0
f=s
R2
0
.. . S0
ps
R2
0
·~
s -
R2
0
(~ (i~ (iii)
Fig. 5. Resonating structures of 1,3-dithiolium-4-olates
3.1.7.1 Synthesis
3.1.7.1.1 From Dithioglycolic Acids
1 3, -Dithiolium-4-olates 90 are prepared by cyclodehydration of dithioglycolic acids

91 with acetic anhydride-triethylamine at 0°-10°C (scheme-36). However,
(CH 3CO)z0- (C 2H 5hN

-H20
91
Scheme-36
the product obtained by cyclodehydration of thiobenzoylthioglycolic acid 92

(R 1=C6H5, R2=H) with boron trifluoride etherate and acetic anhydride has been
reported to be an intramolecular cycloadduct 93 (scheme-37) 5 .
HsC6
)=s BF3 - (C 2H 5)z0
s
>--COOH (CH3C0h0
-H 20
H
92 93
Scheme-37
3.1.7.1.2 From Dithiobenzoic Acids
I ,3-Dithiolium-4-olates 90 are also prepared by the reaction of dithiobenzoic acids

with a-haloacyl halides (scheme-38) 5 .
s 0
1
R-C
II
+
2
R -CH-C-X
II
...
\
SH
I
X
Scheme-38
3.1.7.2 Reactions
I ,3-Dithiolium-4-olates are very reactive I ,3-dipoles because of containing I ,3-

dipoiar system of a cyclic thiocarbonyl ylide (iv) and hence undergo I ,3-dipolar
cycloaddition reactions with alkenic and alkynic dipolarophiles. The cycloadditions
of unsymmetrical alkenes and alkynes are regioselective and have been explained
in terms of the frontier molecular perturbation theory 29 .
3.1.7.2.1 Cycloaddition with Alkynes
Cycloaddition of 1,3-dithiolium-4-olates 90 with alkynes results in the formation of

nonisolable adducts of type 94 which undergo retro-Diels-Alder type reaction
providing thiophene derivatives 95 with the elimination of carbon oxysulfide
(scheme-39).
90 (i)
R R
R
,)j__ S
2
R -COS
95
Scheme-39
3.1.7.2.2 Cycloaddition with Alkenes
Cycloaddition of 1,3-dithiolium-4-olates, however, with alkenes leads to the

formation of bicyclic addition products 96 without the elimination of carbon
oxysulfide (scheme-40) 29 .
R1
~0 .
~
R R
\ I
+ C=C\ R S
I
R R
R2 R R2
0
90 96
Scheme-40
1,3-Dithiolium-4-olates 90 also combine with cyclic alkenes with the formation

of isolable cycloadducts 97 (scheme-41) 30 .
R1 s
~0 +
R)> .
R2 R
R H
90 97
Scheme-41
3.1. 7.2.3 Cycloaddition with Compounds Containing Carbon-Heteroatom

Double Bonds
1,3-Dithiolium-4-olates also undergo 1,3-dipolar cycloaddition reactions with the

compounds containing carbon-heteroatom double bonds involving (3 + 2)
cycloaddition. Thus, the reaction of 1,3-dithiolium-4-olates 90 with formaldehyde,
prepared in situ by depolymerization of paraformaldehyde, results in regiospecific
formation of2-oxa-6,7-dithiobicyclo[2.2.l]heptanones 98 (scheme-42) 31 .
+ rJ~o
0~
H H
98
Scheme-42
3.1. 7.2.4 Photochemical Cycloaddition
Irradiation of 1,3-dithiolium-4-olate (R 1=R2) in the presence of oxygen and Rose

Bengal in benzene-methanol solution at 10°C produces cycloadduct of type 100
which on fragmentation results in the formation of methyl phenylglyoxylate 101
and dibenzoyl disulfide 102 (scheme-43) 32 .
Rose Bengal
(R 1 = R 2 = C 6H 5)
102
R2 -C-C-OCH
II II 3
0 0
101
Scheme-43
However, photolysis of 1,3-dithiolium-4-olate (R 1=R 2=C 6H5) in benzene solution

affords 1,4-dithiin 104 and diphenylacetylene. The reaction is considered to
involve a bicyclic photointermediate 103 (scheme-44) 33 .
R1
~6
hv
benzene
R2
R 1 = R 2 = C 6H 5
104
Scheme-44
3.1.8 1,2,3-0xadiazolium-5-olates (Sydnones)2•34•35
1,2,3-0xadiazolium-5-olates are commonly known as sydnones because these were

first time prepared by Earl and Mackney in 1935 at the University of Sydney in
Australia. These are represented by the general structure 105 which is considered
as a resonance hybrid of the following resonating structures (Fig. 6) :
105
(i) (ii) (iii) (iv)
Fig. 6. Resonating structures of 1,2,3-oxadiazolium-5-olates (sydnones)
3.1.8.1 Synthesis
3.1.8.1.1 From N-Nitroso-a-amino Acids
1,2,3-0xadiazolium-5-o1ates (sydnones) 105 are prepared by cyclodehydration of

N-nitroso-a-amino acids 106 using trifluoroacetic anhydride (TFAA) as a
dehydrating agent. The synthetic method involves the reaction steps as depicted
in (scheme-45). However, this method fails when R 1=H because the resulting 1,2,3-
oxadiazolium-5-o1ate is immediately tautomerized to 5-hydroxyoxadiazole derivative
108 (scheme-45).
3.1.8.2 Reactions
1,2,3-0xadiazolium-5-olates undergo 1,3-dipolar cycloaddition reactions with alkynic

and alkenic dipolarophiles.
Scheme-45
3.1.8.2.1 Cycloadditions with Alkynes
Thermal cycloaddition of 1,2,3-oxadiazolium-5-olates with alkynes (DMAD) proceeds

with the formation of adducts 109 which eliminate carbon dioxide to afford
pyrazoles 110 (scheme-46). The photochemical cycloaddition of 1,2,3-
E
109
+ 110
E-c=c-E
111 t
-C02
Scheme-46
oxadiazolium-5-olates with alkynes also produces pyrazoles, but by a different

mechanism involving loss of carbon dioxide in the first step followed by addition
to the dipolar intermediate in the second step providing isomeric pyrazoles 111
(scheme-46).
Thermal cycloaddition of 1,2,3-oxadiazolium-5-olates with benzyne affords
benzo[c ]pyrazoles 112 (scheme-4 7) 29 .
Scheme-47
3.1.8.2.2 Cycloadditions with Alkenes
1,2,3-0xadiazolium-5-olates with alkenes, however, yield unstable 1 : 1 adducts 113

which on cycloreversion provide pyrazolines 115 via a dipolar intermediate 114
with the elimination of carbon dioxide (scheme-48) 16 .
+-COz
... R1 :~1R
R2
114
Scheme-48
However, intramolecular 1,3-dipolar cycloaddition of 1,2,3-oxadiazolium-5-

olate (R 1 = 2'-allylphenyl and R2 = C6 H5 ) 116 results in the formation of bridged
adduct 117 (scheme-49)36•37 . But cycloaddition of 1,2,3-oxadiazolium-5-olate
A
N~
I'
Jti
intramolecular CH2
cyclization
0 CsH5
116 117
Scheme-49
(R 1 = C6 H 5 , R2 =H) 118 with isoprene leads to the formation of cadged product

119 alongwith 3-isopropenyl-1-phenylpyrazole (scheme-50) 38 .
N-O
+
R 1 -~~Q
R2
118
119
Scheme-50
(i) Photolysis of I ,2,3-oxadiazolium-5-olates 105 in the absence of external

dipolarophiles usually results in either 1,2,3-triazoles 125 and I or 1,3,4-
oxadiazol-2-ones 126 as the major products involving nitrilimine as an
intermediate 122 (scheme-51)39.4°.
R1
~// v
R1
N-O hv
. ...
' N--N
R1 -~~6 R2
0
-C02
R2 R2
0
105 120 121
124 125
Scheme-51
(ii) The irradiation ofl,2, 3-oxadiazolium-5-olate (R 1=R2=C 6H 5 ) in the presence

of cyclopentadiene affords 2-pyrazoline 127 and 2-vinylpyridine 128
(scheme-52).
R1
w
I H
R1 -~~Q
N-O
+0 -----..
hv
N
\
+0 N CH=CH2
R2 R2 H 128
(RI =R2=C6Hs) 127
Scheme-52
However, irradiation in the presence of carbon disulfide results in the formation

of adducts 129 and 130 (scheme-53).
Scheme-53
3.2 Chemistry of Meso-Ionic Heterocycles of type-B
Meso-ionic heterocycles of type-B are represented by the general structural type

6, 7 in which a, b, c, d, e and f represent groupings derived from the carbon and
heteroatoms (N, 0 and S). The grouping b and c each contribute two-electrons to
the 11-electron system, while a, d, e and f each contribute one-electron. With this
structural type there are 84 possibilities, however nearly fifteen meso-ionic
heterocycles of type-B have so far been discovered. The chemistry of some
important meso-ionic heterocycles of type-B is being presented.
3.2.1 1,2-Diazolium-4-aminides
1,2-Diazolium-4-aminides are represented by the general structural type 131.
R''rG)\R'
R1....-N~NR4
Rs
131
3.2.1.1 Synthesis
The mesylation of 4-amino-1 ,3,5-trimethylpyrazole 132 followed by methylation

with methyl fluorosulfonate and subsequent treatment with perchloric acid
produces a salt 134 which on deprotonation with aqueous alkali provides 1,2-
diazo lium-4-arninide 131 (scheme-54 )41 •
H,C,N-(CH, H3C~N~CH 3
mesylation
~y-NH, ----~
a-I 3S020
N~
NHS02CH3
CH3 CH3
132 133 (i) CH30S0 2F
~HCIO,
H,:~~~:so,cH, KOH
-H
+
H3: ~~~H~HS02CH 3
3
CH3 CH3 00 4
131 134
Scheme-54
3.2.1.2 Reactions
3.2.1.2.1 Thermal Isomerization
1 2, -Diazolium-4-arninides undergo thermal isomerization when heated in benzonitrile

with the formation of isomeric pyrazoles 135 (scheme-55) 41 •
H3C, CH 3
H3C~tfNso,CH3
CH3
131
Scheme-55
3.2.1.2.2 Reaction with DMAD
The reaction of I ,2-diazolium-4-aminide 131 with dimethyl acetylenedicarboxylate

(DMAD) in the presence of acetonitrile results in the formation of 136
(scheme-56)41 .
H,:~~~::o2c~,
CH3
131
Scheme-56
3.2.2 1,2-Ditbiolium-4-olates
1,2-Dithiolium-4-olates are represented by the general structure 137.
3.2.2.1 Synthesis
3.2.2.1.1 From Propane-1,3-dione Esters
The reaction of propane-1,3-dione esters 138 with hydrogen sulfide or

tetraphosphorus decasulfide followed by treatment with perchloric acid yields salts
139 which on deprotonation by pyridine provide 1,2-dithiolium-4-olates 137
(scheme-57) 42 . This method has been used to prepare alkyl, thioalkyl and aryl
derivatives.
R1
I
O=C
\ (i) H 2 S
CHOCOCH3
I (ii)HC104
o=c
\ 2
R
138 (R 1 =R 2)
139
Scheme-57
3.2.2.1.2 From 1,3-Diarylpropane-1,2,3-triones
The reaction of 1,3-diarylpropane-1,2,3-triones 140 with hydrogen sulfide-

hydrogen chloride in ethanol-chloroform yields 141 which on treatment with
triethylamine, pyridine or aqueous sodium bicarbonate afford 3,5-diaryl-1,2-
dithiolium-4-olates 137 (scheme-58) 43 .44 .
o=c\
o=c
I
c=o
\R2
I
R1
H2S
HCl
+'S~:11R2
~
OH
(CzHshN
d~
R2
0
R1
140 (R 1 =R 2 =aryl) 141 137
Scheme-58
3.2 .2.1.3 From 1,1 ,3,3-Tetrabromo-1 ,3-diarylpropan-2-ones
3,5-Diaryl-1, 2-dithiolium-4-olates can also be prepared by the reaction of I, 1,3,3-

tetrabromo-1 ,3-diarylpropan-2-ones with potassium ethyl xanthate and subsequently
with perchloric acid (scheme-59) 43 •44 .
Br Br
R1-t-c-t-R2 (i)KSC(S)OC 2H5
~r ~ ~r (ii) HC104
142 (R 1 =R 2 =aryl)
Scheme-59
3.2.2.2 Reactions
3.2.2.2.1 Desulfurization
Desulfurization of 3,5-diphenyl-1 ,2-dithiolium-4-olate 137 with Raney nickel

followed by oxidation with manganese dioxide leads to the formation of dibenzyl
ketone 143 (scheme-60).
R1
lfo R2
(i) Raney Ni
(ii) Mn02
137 143
(R 1 = R 2 = C 6 H 5 )
Scheme-60
3.2.2.2.2 Reactions with Ammonia and Its Derivatives
The reaction of3,5-diphenyl-1,2-dithiolium-4-olate 137 with methanolic ammonia

yields 3,5-diphenyl-4-hydroxyisothiazole 144 (scheme-61) 45 . But the reaction with
hydrazine results in 3,5-diphenyl-4-hydroxypyrazole 145 (scheme-62).
R1
£~ 6
R2
+ NH3
137
(R l = R 2 = C 6Hs)
Scheme-61
HN--(R'
~y--aH
R2
145
Scheme-62
However, the reaction of 3,5-diphenyl-1,2-dithiolium-4-o late 137 with phenyl-

hydrazine proceeds with the cleavage of the ring providing an open chain product
146 (scheme-63 )43 •44 .
R1
~~0 R2
+ C5HsNHNH2
137 (R 1 = R 2 = C 6H 5) 146
Scheme-63
The reaction of 3,5-diphenyl-1 ,2-dithiolium-4-olate 137 with boiling aniline yields

blue benzothiazine 150. The reaction proceeds to involve indenylamine 149 as an
intermediate with the following steps (scheme-64)5 :
s=<:H,
lfo
C6Hs
sy=o
C6Hs C6Hs
137 147
~-S
Scheme-64
3.2.2.2.3 Thermal Reactions
3,5-Diaryl-1,2-Dithiolium-4-olates are thermally stable. However, when 3,5-diphenyl-

1,2-dithiolium-4-olate 137 is heated at 275°C, tetraphenyl-p-benzoquinone 151 is
obtained with the extrusion of sulfur (scheme-65) 44 .
~Hs
£~6
C5Hs
137
Scheme-65
3.2.3 1,2,3,4-Tetrazolium-5-thiolates
I ,2,3,4-Tetrazolium-5-thiolates are represented by the structure 152. 2,3-Diphenyl-

1 ,2,3,4-tetrazolium-5-thiolate is the most widely investigated meso-ionic heterocycle
of this system and is commonly known as dehydrodithizone (R 1 = R2 = C6H5).
3.2.3.1 Synthesis
3.2.3.1.1 From Dithizone
2,3-Diphenyl-1 ,2,3,4-Tetrazolium-5-thiolate 152 is prepared by oxidation of

dithizone 153 with manganese dioxide or with isoamyl nitrate (scheme-66) 46 .
C6H 5 -NH-NH
oxidation
'c=s
I
C6Hs-N=N
153
Scheme-66
3.2.3.1.2 From Diphenylthiocarbazide
The reaction of diphenylthiocarbazide 154 with diethoxy disulfide also affords

dehydrodithizone 152 (scheme-67) 47 .
H5C5
C6H5-NH-NH
\
c=s ' N-N
C6H 5-NH-NH
/ ... '0\ -
/N, /'-s
H5C5 N
154 152
Scheme-67
3.2.3.2 Reactions
The reaction of dehydrodithizone 152 with chloroacetic acid results in alkylation

at the exocyclic sulfur with the formation oftetrazolium chloride 155 (scheme-68).
H5C6
' N-N
OCH2COOH
Hc
5 6
'0'
,.....N,
N
~s
152
Scheme-68
3.2.3.2.2 Thermal Rearrangement
Dehydrodithizone is thermally rearranged to the isomeric type-A, I ,2,3,4-tetra-

zolium-5-thiolate 156 (scheme-69).
H5C5 /C6H5
' N-N N-N
'0\
H5c 6,.....N, N ~s
'0\
/'-s
H5C6,.....N, N
152 156
Scheme-69
3.2.3.2.3 Cycloaddition Reactions
Dehydrodithizone 152 undergoes a special type of 1,3-dipolar cycloaddition

reactions with dipolarophiles; dimethyl acetylenedicarboxylate, tetracyanoethylene
and ethoxycarbonylrnethylene triphenylphosphorane involving dipolar intermediates
157, 158 and 159 with the formation of 160, 161 and 162, respectively
(scheme-70)49 .
H5C5
' N-N
cH3ooc-c=c-coocH3 + I \\
H5c 6 . . . . N~ /'---..s
N
H5C5 -(--coocH3
' N-N
COOCH3
'G)\
H5C,.....N'
6 N
/-s HC
5 6"
157
N-N
152
\
CN CN I \\
I I HC..-N, N ~ S
._____.., 5 6
c=c
I I
CN CN CH300C )={_GOOCH 3
160
H5C5
' N-N
I \\
H c . . . . N, N ~ S
H-eN
5 6
CN CN CN
161
H5C5
' N-N
+I \\
H5 c 6 . . . . N~N /'---..s
I
_ (P(C5H5b
COOC2H5
159
Scheme-70
3.2.3.2.4 Reactions involving Dehydrodithizone as Acyclic Valence Tautomer
Dehydrodithizone is involved as its acyclic valence tautomer 163 in the following

reactions (Scheme-71 ) 3•48 •50•5 1•
HsC6
' N-N
H c ..,~SV)-s
5 6 N
152
167
co-NR,
168
Scheme-71
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36. H. Meier, H. Heimgartner and H. Schmid, Helv. Chim . Acta 60, I 087 ( 1977).
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38. A. Haneda, T. Imagawa and S. Kawanisi, Bull. Chern . Soc. Japan 49, 748
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39. M. Marky, H. Meier, A. Wunderli, H. Heimgartner, H. Schmid and H. J
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SUBJECT INDEX
Aaterra, 554 Aromaticity, 9-11

Acetazolamide, 567 effect on reactivity, 16, 17
Acidity, 396, 443,492, 506, 520 Aromaticity order, 11, 4 77
Acivicin, 457 Autoxidation, 69, 70
Acylamidrazone, 504 1-Azaindene, 191
Acylations, 55-58, 66-68, 102, 103, Azanorbomadienes, 78, 79
145-147,221-223,231,232,249,264, 2H-Azirines, 207
277, 293,294, 331,387,391,392,443, Azoles:
498 basicity, 365, 366
Acylaziridines, 404 orientation, 367-369
2-Acyl-1-benzenesulfonylindoles, 1,2-azoles, 369, 370
232 1,3-azoles, 368, 369
N-Acylimidazoles, 387 reactions, 367-374
acyl transfer reagents, 387 reactivity, 367
Acyloins, 378 structure, 364
Addition-elimination mechanism, 96, 1,2-Azoles, 363-374,435-483
98, 107,108, 155,390 aromatiaty order, 477
Addition reactions, 27-29 basicity, 365, 366
Aflatoxines, 280 reactivity order, 367-478
Alkylations, 58, 66, 100-102, 144, 145, resonating structures, 364
224,229, 230,249,263,294,330,386, 1,3-Azols, 363-435
424,427,443, 461,479,497,498,508, basicity, 365-366
543, 549,621 reactivity order, 367
Alkyl fluorosulfonates, 151 resonating structures, 365
Amidines, 377, 554, 555 1,3-Azoliumcations, 371-373
Amidrazones, 504,515 Azomethine nitrogen, 363-365, 367, 370,
Amination, 571 371,401
2-Aminobenzenethiols, 421, 422 Azomycin, 376
Aminotetrazolic acids, 513
o-Aminothiophenols, 421,422 Basicity, 211, 261 , 365, 366, 385,407,
Amphoteric nature, 495 424, 443,461,492,506
Annelation, 247, 272,310, 341 Betains, 582
Anthranil, 456 Benzazepine, 240
1-Benzazo1e, 191 Benzofurazan,533

Benzimidazole, 375 Benzofuroxan, 533
Benzisothiazoles, 473 Benzo[a] heterocycle, 187, 188
1,2-Benzisothiazole, 473 Benzo[b] heterocycles, 187-189
2, 1-Benzisothiazole, 473 Benzo[c] heterocycles, 187, 188
Benz[c ]isothiazole, 4 73 3,4-Benzo-1 ,2,5-oxadiazole, 533
Benz[d)isothiazole, 473 3,4-Benzo-1 ,2,5-oxadiazole 2-oxide, 533
Benzo-7 -azabicyclo[2.2.1 ]heptanes, 243 2,1,3-Benzoxadiazole 1-oxide, 533
Benzodiazepines, 54 7 2,1,3-Benzoxadiazole 2-oxide, 533
1,2-Benzisoxazole, 456 Benzopyrazole, 435
2, 1-Benzisoxzole, 456 Benzo[c]pyrazoles, 611
Benzofurans, 279-319 Benzopyrroles, 190-279
Benzo[b]furans, 279,282-301 a,~-Benzopyrrole, 191
orientation, 288 1H-Benzo[b]pyrrole, 191
reactions, 288-301 Benzo[c]pyrroles, 240-254
acylation, 293, 294 Benzothiazine, 619
alkylation, 294, 295 Benzo[b]thiophenes, 188,321-338
cycloaddition reactions, 300 orientation, 327, 328
halogenation, 291-294 resonating structures, 321
nitration, 289, 290 reactions, 327-338
oxidation, 297 acylation, 321
photochemical reactions, alkylation, 330
300,301 S-alkylation, 332, 333
protonation, 289 cycloaddition reactions, 337, 338
reduction, 298 diazo coupling, 331
sulfonation, 291 halogenation, 328-329
with diazonium salts, 295 nitration, 328
with electrophiles, 288-295 oxidation, 333, 334
with electron-deficient photosubstitution, 338
species, 299 reduction, 335, 336
with nucleophiles, 295-297 sulfonation, 329, 330
reactivity, 288 with electrophiles, 327-333
syntheses, 282-287 with electron-deficient
structure, 287 species, 336
Benzo[c]furans, 279,302-309 with nucleophi1es, 334, 335
reactions, 305-309 syntheses, 322-326
cycloaddition reactions, Benzo[b]thiophene 1-oxide, 333,334
305,306 Benzo[b)thiophene 1,1-dioxide, 333
oxidation, 309 Benzo[c]thiophenes, 188,339-343
photochemical reactions, reactions, 341-343
307,308 cycloaddition reactions, 341, 34 2
reduction, 309 resonating structures, 339
syntheses, 302-304 syntheses, 339-341
Subject Index 629
Benzothiazoles, 421 4-Chloropyrimidine, 398

syntheses, 421, 422 5-Chloropyrimidine,398
Benzotriazoles, 493 Cinnamoylbenzofurans, 281
Benzoxazole, 401 Cine-substitution, 155, 537
Bioisosteric relationship, 122 Claisen condensation, 126, 194
Biotin( vitamin H), 122,376 Claisen rearrangement, 200, 380
Birch reduction, 161, 235, 319 Clotrimazole, 377
Bischler indole synthesis, 198, 283 Cloxacillin, 456
Bisindolylmethanes, 225 Condensation reactions, 428, 471
Bliimlein-Lewy synthesis, 402 Cook-Heilbom's synthesis, 418
Borsche synthesis, 268 Cope rearrangement, 119
Brominations,52,98-100, 142,143,218, Cornforth rearrangement, 413
276,292,293,313,314,328,329,390, Corrins, 33
391,449,465,498,499 Coumarilic acid, 287
Bronsted acid, 381 Coumarins, 287
Boulton-Katritzky rearrangement, 472 Coumarone, 282
Cyclazines, 260, 266
Cadged compound, 612 Cyclization reactions, 34-43, 243, 528
Cannizzaro reaction, 295 (2 + 2 + 1)cyclization reactions,
Carbazoles, 189, 191,267-279 38-41, 131,132
reactions, 274-279 (3 + 2)cyclization reactions,
acylation, 277 34-38,126-131,436-438,458
bromination, 276 (4 + 1)cyclization reactions,
chlorination, 276 41-43,124-126,562
nitration, 27 5 Cycloaddition reactions, 29, 30,77-81,
nitrosation, 275 112-118,165-170,253,254,300,337,
oxidation, 278 341, 342, 414, 453, 454, 605-608,
protonation, 274 609--612
reduction, 278 (2 + 2)cycloaddition reactions,
sulfonation, 276, 277 80,167,168,240
with electrophiles, 274-278 (4 + 2)cycloaddition reactions,
with nucleophiles, 279 77-80,165-167,239,240,253,
structure, 273, 274 254,306,333,341,342
syntheses, 268-272 Cycloreversion, 439
Carbazolic acids, 513
Catalytic hydrogenation, 71, 72 Dediazoniation, 519
Catalytic reduction, 160 Dehydrodithizone, 623
Chemical reduction, 72 Desulfurization, 161, 430, 618
Chlorinations, 52, 100, 141, 142, 216, Diazo coupling, 64, 65, 105, 106, 150,
217,293,328,329 151,331,332,392,393,427,450
Chloromethylation, 466 a-Diazoimides, 585
2-Chloropyrazine, 381,398 Diazo ketones, 585
5-Chloropyridazines, 453 1,2-Diazolium-4-aminides, 614-616
reactions, 615,616 Dimethyl acetylenedicarboxylate

thermal isomerization, 615 (DMAD), 78, 79, 89, 90, 115,239,
with DMAD, 616 240, 253,254,266, 312,325,326,
synthesis, 614, 615 338,399,454,590,592,616
1,3-Diazolium-4-aminides, 601-603 Dimerization, 212, 213
reactions, 603 Dimethylaminomethylindole, 227
synthesis, 602, 603 2,2-Dimethyl-3-dimethylamino-azirine,
1,3-Diazolium-4-olates, 582,600,601 596
recations, 601, 602 Dimethylesulfoxonium methylide, 285
synthesis, 600, 601 4,6-Dimethyl-2-thiocyanopyrimidine,
1,3-Diazolium-5-thiolates, 594 572
Dibenzofurans, 189, 190,279,309-319 Dirnroth rearrangement, 501, 548, 557,
reactions, 312-319 558
bromination, 313,314 a-Dioximes, 535
forrnylation, 316 1,2-Dioxins, 90
lithiation, 316-318 1,5-Dipolar cyclization, 404
nitration, 314,315 1,3-Dipolar cycloaddition reactions,
258,401,439,459,460,494,505,506,
reduction, 319
528, 529, 541, 584, 585, 586, 588, 598,
sulfonation, 316, 31 7
599, 607,609,610,622
with electrophiles, 312-316
Dipole moments, 10
with nucleophiles, 318
3,6-Di(2'-pyridyl)-1 ,2,4,5-tetrazine, 303
structure, 31 0
Diquatemary salts, 558
syntheses, 31 0- 312
Directing effects, 20-26, 93, 94, 135,
Dibenzoheterocycles, 189, 190
136, 158,159, 163
Dibenzopyrroles, 267-279
effect of heteroatom, 20, 134
Dibenzothiophenes, 189, 190,343-347
effect of substituents, 20-26, 93, 94,
reactions, 346, 347
135, 136, 289, 328
oxidation, 34 7
1,2-Dithiins, 341
with electrophiles, 346
1,4-Dithiin, 608
with nucleophiles, 346 1,2-Dithiolium-4-olates, 616-620
syntheses, 344, 345 reactions, 618-620
Dibenzothiophene-S-oxide, 343,347 syntheses, 616, 617
Dibenzothiophene-S, S-dioxide, 347 1,3-Dithiolium-4-olates, 604-608
Dicyclohexylcarbodiimide, 597 reactions, 605-608
Dicloxacillin, 456 cycloaddition reactions, 606- 608
Diels-Alder reactions, 29, 112, 152,239, resonating structures, 604
333,401,414 syntheses, 604, 605
Difenamizole, 435 Dithizone, 620
Difenzoquat, 436
Dihydrobenzo[a]carbazole, 253 Ehrlich test, 34, 63, 224, 250, 264, 265
Dihydroindole, 78 Einhorn- Brunner reaction, 504
2,2-Di(3-indolyl)indolin-3-one, 234 Electrocyclic mechanism, 413
Subject Index 631
Electronic effects, 514 structure, 91, 92

Electrophilic substitutions, 18-26, 49- syntheses, 83-91
65,92-105,134-151,496-499,529, Furazans, 533
537,564,570 Furocoumarins, 280
Electron-transfer mechanism, 107 Furoxans,533,535,536
Elimination reaction, 245
Ellipticine, 232, 270 Gabriel synthesis, 418
Ergotamine, 193 Gassmann indole synthesis, 203
6-Ethoxymethylpyridazines, 453 Gattermann formylation, 56, 57, 316
Extrusion reactions, 43, 44, 243, 244 Gewald synthesis, 129
Gomberg reactions, 162
Feist-Benary synthesis, 87, 88 Graebe-Ullmann synthesis, 272
Fischer indole synthesis, 199-202 Gramine, 227
Fischer reaction, 201 Halogenations, 52-54, 98-100, 141-144,
Floxacillin, 456 216-220,291-293,328,329,390,391
Fluorination, 15 3 426, 429,465
Formamide synthesis, 378 2-Haloimidazoles, 395
Formylation, 316 Halopyrazoles, 451
Furans : 5-Halotetrazoles, 522
aromaticity, 9-11 Hantzsch pyrrole synthesis, 3 8
dipole moment, 10 Hantzsch' s synthesis, 417
directing effects of substituents, Heterocumulenes, 584
93,94 Heteroelectrocyclization, 514, 523, 525,
orientation effects, 92, 93 542
reactions, 92-121 Hexafluorobicyclo[2.2.0]hexa-2,5-diene,
acylation, 102, 103 80
alkylation, 100-102 Hinsberg synthesis, 129, 130
cycloaddition reactions, 112-118 Histidine, 376, 385
halogenation, 98-100 Hofmann-Martius rearrangement,
nitration, 96, 97 58,59
photochemical reactions, Houben-Hoesch reaction, 55, 56
118-121 Hugershoffs method, 422
protonation, 94-96 Huisgen reaction, 523, 542
sulfonation, 97-98 Hurd-Mori's synthesis, 548
with aldehydes and ketones, Hydroformylation, 195
104, 105 Hydrogen bonding, 383,441,457, 518
with diazonium salts, 105 Hydroxymethylation, 60,393,394,466
with electron-deficient species, Hydrazone-enehydrazone tautomerism,
111,112 200
with free redicals, 108-111 lrnidazoles, 375-400
with nucleophiles, 105-108 acidity, 396
reactivity, 11, 12, 92, 93 basicity, 385, 386
orientation, 388, 389 with aldehydes and ketones,

reactions, 384-400 224-227
acylation, 391,392 with electom-deficient species,
N-acylation, 387 237-238
N-alkylation, 386 with free radicals, 238-239
cycloaddition reactions, 399,400 with nucleophiles, 232
diazo coupling, 392, 393 structure, 208
halogenation, 390, 391 syntheses, 194-207
nitration, 389 1H-Indolium cation, 210
oxidation, 394 2H-Indolium cation, 210
sulfonation, 390 3H-Indolium cation, 210
with dienophiles, 399 2-(3-Indolyl)indoline, 212, 213
with electron-deficient Indolepyridazines, 240
species, 399 Indolizines, 254-267
with electrophiles, 385-394 reactions, 260-267
with nucleophiles, 394-398 acylation, 264
reactivity, 384, 385 alkylation, 263
structure, 382 cycloaddition reactions, 266, 267
hydrogen bonding, 383 nitration, 262
tautomerism, 383, 384 nitrosation, 262, 263
syntheses, 377-381 oxidation, 264, 265
Imidazolidine, 375 protonation, 261, 262
Imidazolium ion, 385, 386, 396 reduction, 265, 266
Irnidazolium ylide, 396 with aldehydes and ketones,
Irnidazolothiadiazoles, 558 264,265
Irnidazo[2, 1-b]thiadiazoles, 573 with electrophiles, 260-265
Indazole, 435 structure, 259, 260
Indigo, 193, 233 syntheses, 255-259
Indole-3-acetic acid, 192 Indomethacine, 193
Indoles, 191-240 Indophenine test, 121, 148
basicity, 211 Indorarnine, 194
reactions, 208-240 Indoxazene, 456
acylations, 221, 222, 231 Intramolecular nucleophilic substitution,
alkylation, 224, 229 232
cycloaddition reactions, 239, 240 Iodinations, 52-54, 144,218
halogenation, 216-220 Iprindole, 194
nitration, 212-214 Ipsa-substitutions, 68, 214
nitrosation, 215, 216 Isobenzofuran, 302
oxidation, 233, 234 Isobenzothiophene, 339
protonation, 210 1H-Isoindole, 241
reduction, 234-237 2H- Isoindole, 241
sulfonation, 220 Isoindolenine, 241
with electrophiles, 209-222 Isoindoles, 240-254
Subject Index 633
reactions, 247-254 hydroxymethylation, 466

acylation, 249 mercuration, 446
alkylation, 249, 250 nitration, 463, 464
cycloaddition reactions, 253, 254 oxidation, 467
nitrosation, 249 rearrangements, 4 72
oxidation, 251, 252 sulfonation, 464, 465
protonation, 248 with nucleophiles, 468-470
reduction, 252, 253 reactivity, 460
with aldehydes and ketones, resonating structures, 458
250,251 syntheses, 458-460
with electrophiles, 24 7-251 Isoxicam, 456
resonating structures, 242
stability, 241 , 242 Jaap-Klingemann reaction, 20 I, 202
syntheses, 242-247
tautomeric forms , 241 a-Ketoketimine, 374
Isomerization, 405, 476, 615 Knorr pyrrole synthesis, 34-36
Isonitrile cyclization, 197, 198
Isothiazoles, 434, 473-483 Lithiation, 158-159,316,317,334,335,
reactions, 478-483 411,412,432,433, 452,482
N-alkylation, 479
decarboxylation, 480 Madelung indole synthesis, 196, 197
Jithiation, 482 Mannich base, 60, 263
nitration, 478-479 Mannich reaction, 60, 227, 228
nucleophilic substitutions, Mannich reagent, 517
480,481 Marckwald synthesis, 3 78
photochemical transformation, Matellation, 316, 317,334,333-335,412,
482,483 432,433,452,521,522
ring cleavage, 482 Matronidazole, 376
ring transformation, 475, 476, Mercuration, 149,150,409,427, 449,466
481 Meso-ionic heterocycles, 401,440, 526,
sulfonation, 479 581--626
with aldehydes, 480 chemsitry of,
structure, 4 77 type-A; meso-ionic heterocycles,
syntheses, 474-476 584--614
Isoxazoles, 405,455-472, 476, 535 type-B; meso-ionic heterocycles,
basicity, 461 614--623
hydrogen bonding, 457 classification, 583
reactions, 460 type-A; meso-ionic heterocycles,
N-alkylation, 461 583,614
chloromethylation, 466 type-B; meso-ionic heterocycles,
condensation reactions, 4 71 583, 584,614- 623
with electrophiles, 461-466 definition, 582
halogenation, 465, 466 structural representation, 582
Methidethion, 567 structure, 536, 537

Methoxalen, 280 syntheses, 534-536
2-Methyl-3H-indolium cation, 211 1,3,4-0xadiazoles, 540-546
3-Methyl-3H-indolium cation, 211 reactions, 543-546
Michael addition, 78, 239, 445 ring cleavage, 545
Modified Fischer indole synthesis, 268 thermal and photochemical
Munchones,587-597 reactions, 546
with electrophiles, 543, 544
Nenitzescu indole synthesis, 203-206 with nucleophiles, 544, 545
Nenitzescu reaction, 272, 273 structure, 542
Niridazole, 417 syntheses, 541, 542
Nitrations, 50, 51, 96, 97, 137-140,212- 1,2,5-0xadiazole 2-oxides, 533, 536, 540
215,262,289,290,314,315,328,389, 1,2,5-0xadiazole 5-oxide, 539
425,447,448,463,464,478,479 1,2,3-0xadiazolium-5-olates, 609-614
N itrilium salts, 516 reactions, 609-614
Nitrosations, 215, 216, 249, 262, 275 cycloaddition reactions, 610-612
Nucleophilic substitutions, 26, 27, 68, photochemical reactions,
69,105-108,154,155,510,522,530, 612-614
537,538,544,545,550,559,564,571 synthesis, 609-610
1,3,4-0xadiazolium salts, 543
Octahydroindole, 235 2-0xa-6,7-dithiabicyclo [2.2.1 ]-
Osotriazole, 493 heptanones, 607
Oxacillin, 456 Oxanorbornadienes, 115
Oxadiazepine, 546 1,3-0xathiolium-4-olates, 597, 598
Oxadiazoles, 491, 525-546 reactions, 598
1,2,3-0xadiazoles, 525, 526 syntheses, 597, 598
1,2,4-0xadiazoles, 527-533 1,3-0xathiolium-5-olates, 598, 599
reactions, 529-533 reactions, 599
electrophilic substitutions, 529 synthesis, 599
nucleophilic substitutions, 530 Oxazoles, 99,367,401-415
photochemial reactions, 532 basicity, 407
reduction, 531, 532 reactivity, 406
ring cleavage, 532 reactions, 406-415
structure, 529 N-alkylation, 407
syntheses, 528 bromination, 408, 409
1,2,5-0xadiazoles, 533-540 cycloaddition reactions, 414, 415
reactions, 537-540 formylation, 409
rearrangements, 539 mercuration, 401
ring cleavage, 538, 539 photochemical reactions, 409
thermal and photochemical photooxygenation, 413
reactions, 539 protonation, 407
with electrophiles, 537 thermal reactions, 413
with nucleophiles, 537, 538 with electrophiles, 407-409
Subject Index 635
with nucleophiles, 410-412 Photocycloaddition reactions, 168-170,

structure, 405, 406 307,308,337,338,399,400,546,607,
syntheses, 402-405 608
Oxazole-oxadiazole rearrangements, Photodimerization,300,307
555,556 Photoisomerization, 171
1,3-0xazolium-4-olates, 585-587 Photo-oxidation, 69, 70, 596, 597
reactions, 585-587 Photooxygenation, 309
syntheses, 585 Photosubstitutions, I70, 17I, 338
1,3-0xazolium-5-olates, 587-597 Phthelimidines, 244
reactions, 588-597 Piloty-Robinson pyrrole synthesis,
cycloaddition reactions, 588-595 38,39
photochemical reactions, Pindolol, 194
596,597 Porphobilinogen, 33
with nucleophiles, 595 Porphyrins, 33
with small ring heterocycles, 596 Pyrazines, 381
syntheses, 587, 588 Pyrazoles, 435-455
5(4H)-Oxazolones, 590 acidity, 443
Oxetanes, 89,400 basicity, 443
Oxidations, 67-71, 152, 153,233,234, reactivity, 442,445, 446
251,252,264,265,297,309,347,394, reactions, 442-455
429,467,483,512,551 N-acylation, 443-444
Oxidative cyclization, 269,270,322,474, N-alkylations, 443,444
475,493, 494,535,554 cycloaddition reactions, 453,454
Oxidative dimerization, 159, 160 diazo coupling, 450
Oxindole, 216, 217 halogenation, 449
Oxiranes, 89 mercuration, 449
Oxypertine, 193 Michael addition, 445
nitration, 447,448
Paal-Knorr synthesis, 4I, 42 oxidation, 450
Paal synthesis, I25, 126 photochemical transformation,
454,455
Pachmann and Nold synthesis, 547, 548
reduction, 451
Penicillin, 40 I, 416, 456
sulfonation, 448
Pensoil, 554
with electron-deficient species,
Phenylation, I 05, 162-I64
453
Phosphorus ylides, 86, 87
Photochemical cyclizaions, 84, 240, 270
with nucleophiles, 451-453
Photochemical reactions, 1I8-121 ,300,
structure, 440, 441
301,30-308,413,461,512,522-524,
hydrogen bonding, 441
532,539,546,596,597,6I2-614
tautomerism, 441, 442
Photochemical rearrengements, 434
syntheses, 426-440
Photochemical transformations,
Pyridine-[3-reactivity, 388
454,455,482,483
Pyrylium salts, 90
Pyrrocollines, 254-267 Ring contraction, 90, 91 , 287,341 , 381 ,

Pyrrole-a-reactivity, 388 434
Pyrroles, 33-81 Ring contraction-ring expansion
basicity, 46 mechanism, 413, 434
reactions, 46-81 Ring expansion reactions, 43 , 44
acylation, 55-58 Ring transformation reactions,
alkylation, 58, 59 244-247,381 , 404,455,476, 481 , 534,
cycloaddition reactions, 77-81 535,541,542
diazo coupling, 64, 65 Robinson-Gabriel synthesis, 402
electrophilic substitutions, 49-68 Ruscodibenzofuran, 282
halogenation, 52-54
hydroxymethylation, 60 Saccharin, 473
nitration, 50, 51
Semi-synthetic penicillins, 456
nucleophilic substitutions, 68-69
Serotonine, 192
oxidation, 69-71
[3,2] Sigmatropic rearrangement, 203
reduction, 71, 72
[3,3] Sigmatropic rearrangement,
sulfonation, 54
200,268
with aldehydes and ketones,
60-63 Skatole, 195
with elctron-deficient species, Sommelet-Hauser reaction, 203
74-77 Stereoelectronic effect, 514
with free radicals, 73, 74 Sulfamethoxazole, 456
structure, 45, 46 Sulfathiazole, 416
syntheses, 34-44 Sulfisoxazole, 456
Pyrrolo[3,2-b]indole, 68 Sulfonamides, 456
Purines, 376 Sulfonations, 54, 97, 98, 140, 141 , 220,
276,277,291,316,317, 329,330, 390,
Quatemization, 509, 569, 570 425,426,448,464,479
Sulfur ylides, 85, 86
Reactivity, 11-17, 92, 93, 188, 288, 384, Swamping catalyst effect, 145
385,406, 442, 445,446, 460,507, 557 Sydnones, 440,526,609-614
Reactivity order, 14-16, 367, 441,478
Rearrangements, 472, 525,533, 553, 555, Tautomerism, 383, 384,441,442
556 Tchemiac's synthesis, 418
Reductions, 71, 72, 160, 161,234-237, Terrazole, 554
252, 253,265,266,278,298,309,319, Tetrafluorobenzyne, 166
335,336,451,531,532, 561 Tetrahydrofuran(THF}, 82
Reductive cleavage, 471 Tetrahydrothiophene( thiophane ), 122
Reductive desulfurization, 161
Tetraphenylporphyrin, 61
Reimer-Tiemann reaction, 237
2,3,5,6-Tetraphenylpyrazine, 501
Reissert indole synthesis, 194, 195
Tetrazoles, 491 , 492, 513-525
Reserpine, 192
acidity, 520, 521
Retro-Diels-Alder reactions, 79, 243,
302,303, 415, 587,606 reactions, 519-525
rearrangements, 525
Subject Index 637
thermal and photochemical with electrophiles, 564

reactions, 522-524 with nucleophiles, 564-566
with electrophiles, 519, 520 stability, 563
with nucleophiles, 520-522 structure, 563
structure, 517, 518 synthesis, 562
syntheses, 513-517 1,3,4-Thiadiazoles, 566-573
tautomeric forms, 513 reactions, 569-573
1,2,3,4-tetrazole(1H-form), 513 ring formation reactions, 572, 573
1 ,2,3,5-tetrazole(2H-form), 513 with electrophiles, 569, 570
Tetrazolate anion, 520, 521 with nucleophiles, 570, 571
Tetrazolic acid, 520 reactivity, 569
1 ,2,3,4-Tetrazolium-5-thiolates, 620 structure, 569
reactions, 621-623 syntheses, 567, 568
syntheses, 620, 621 1,2,3-Thiadiazole trioxide, 551
Thermal[2 + 2]cycloaddition reactions, 1,2,3-Thiadiazole 3-oxides, 551
167,337 Thiamine( vitamin B 1) , 416
Thermal[4 + 2]cycloaddition reactions, Thianaphthalene, 321
165-167 Thiazoles, 416-434
Thermal reactions, 413, 472, 499, 500, basicity, 424
512, 522, 523, 539,540,546, 620 reactions, 423-434
Thermal rearrangements, 413, 621 alkylation, 424, 427
Thiabendazole, 416 condensation reactions, 428
Thiabicyclo[3 .1.0]hex-3-ene, 164 desulfurization, 430
Thiadiazoles, 491, 547-573 diazo coupling, 427
1,2,3-Thiadiazoles, 547-553 halogenation, 426
reactions, 549-533 mercuration, 427
photochemical reactions, 552 nitration, 425
rearrangements, 553 oxidation, 429
thermal reactions, 552 photochemical rearrangement,
with electrophiles, 549, 550 434
with nucleophiles, 550, 551 sulfonation, 425, 426
structure, 549 with electrophiles, 423-427
syntheses, 547-549 with nucleophiles, 430-434
1,2,4-Thiadiazoles, 553-561 structure, 422, 423
reactions, 557-561 syntheses, 417-422
reduction, 561 Thiazolidine, 416
with electrophiles, 557-559 Thiazolium cations, 431, 433, 434
with nucleophiles, 559, 560 1,3-Thiazolium-5-thiolates, 594
reactivity, 557 Thiirene, 552
structure, 557 Thioacylarnidines 554
syntheses, 554-556 Thiobenzoylthioglycolic acid, 605
1,2,5-Thiadiazoles, 561-566 Thioketene, 552
reactions, 563-566 Thionaphthalene, 3 21
Thiophenes, 121-171 rearrangement, 501, 502

orientation, 134 thermal and photochemical
reactions, 134-171 reactions, 499, 501
acylation, 145-147 syntheses, 493-495
alkylation, 144, 145 tautomeric forms ;
cycloaddition reactions, 165-170 1H-1 ,2,3-triazole, 492, 493
halogenation, 141-144 2H-1 ,2,3-triazole, 492, 493
nitration, 137-140 2,1,3-triazole, 493
oxidation, 152, 153 1,2,4-Triazoles, 503-512
oxidative ring cleavage, 153 acidity-basicity, 506, 507
photocycloaddition reactions, 506-512
reactions, 168-170 oxidation, 512
Photosubstitution, 170, 171 thermal and photochemical
Photoisomerization, 171 reactions, 512
protonation, 136, 13 7 with electrophiles, 508-510
reduction, 158, 159 with electron-deficient species,
sulfonation, 140, 141 511
thermal cycloaddition reactions with nucleophiles, 51 0
165-168 reactivity, 507
with aldehydes and ketones, structure, 506
148, 149 syntheses, 504-506
with diazonium salts, 150, 151 tautomeric forms, 503
with electron-deficient species, 1,2,3-Triazolium-3-olates, 512
164,165 Trimerization, 212, 213
with electrophiles, 134-152 2,4,5-Tris(acetoxymercury)thiazole, 427
with free radicals, 161-164 Truban, 554
with nucleophiles, 154-160 Tschichibabin reaction, 255, 430
structure, 132, 133
syntheses, 122-132 Ugi reaction, 517
Thiophene sulfones, 152 Usnic acid, 281
Thiophene sulfoxides, 152
Thiophenols, 325 Vapour-phase pyrolysis, 245
Thumb rule, 261 Vincristine, 192
Tirnolol, 561 Vilsmeier-Haack reaction,
Triazoles, 492-512 57,146,147,222,223,250,264, 293,
1 ,2,3-Triazoles, 492-502 316, 409
amphoteric nature, 495, 496
reactions, 495-503 Wallach synthesis, 379
acylation, 498 Wittig reaction, 86, 312
alkylation, 497,498
bromination, 498, 499
electrophilic substitutions,
496-499
Topics in Current Chemistry
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Heterocyclic
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able overview of the different aspects discussed
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Heterocyclic Chemistry II

R. R. Gupta, M. Kumar, V. Gupta

Volume I: Principles, Three- and Four-Membered Heterocycles

Volume III: Six-Membered and Higher Heterocycles

Springer-Verlag Berlin Heidelberg GmbH

With 136 Figures

Library of Congress Cataloging-in-Publication Data

ISBN 978-3-642-08460-7 ISBN 978-3-662-07757-3 (eBook)

© Springer-Verlag Berlin Heidelberg 1999

Typesetting: Camera-ready by authors

Today, our world increasingly is conceived of as being molecular. An ever

Our aim is to bring out a text-cum-reference book on heterocyclic

Volume III: Six-Membered and Higher Heterocycles

Jaipur, India R.R. Gupta

a Bond angle distortion or deviation I Coulomb integral (as stated)

Chapter 2. Five-Membered Heterocycles with 3

Chapter 3. Benzo-Fused Five-Memb~red 181

Chapter 4. Five-Membered Heterocycles with 357

Chapter 5. Five-Membered Heterocycles with 487

Chapter 6. Meso-Ionic Heterocycles 579

Subject Index 627

Heterocyclic Chemistry is an integral part of organic chemistry and constitutes a

In addition to these series, annual reports on "Progress in Heterocyclic

FIVE-MEMBERED HETEROCYCLES WITH ONE

3.2.6.1 Three-Membered Heterocycles 88

4.4 Reactions 134

Five-membered aromatic heterocycles with one heteroatom; pyrrole 2, furan 3 and

1.1 Structure and Stability 1

Five-membered aromatic heterocycles are planar pentagonal with sp 2-hybridized

Fig. I. Orbital structure of five-membered heterocycles

description, are considered to be resonance hybrids of the resonating structures

Fig. 2. Resonating structures of five-membered heterocycles with one heteroatom

The aromaticity in these heterocycles is attributed to the delocalization of 7t-

Table 1. Comparison of bond lengths and bond angles in five-membered

Bond lengths(A) Bond angles( 0 )

Pyrrole 1.370 1.382 1.417 109.80 107.70 107.40

Dipole moments in theses heterocycles have also been assumed to be evidence

t Pyrrole Thiophene Furan

1.2.1 Aromaticity Order

The aromatic character in these 1t-excessive heterocycles depends on the

1.3 Reactivity of Five-Membered Heterocycles 2

Five-membered heterocycles with one heteroatom; pyrrole, furan and thiophene,

Fig. 5. Electrophilic attack on ring carbon atoms

1.3.1 Comparison with Acyclic Analogs

The reactivity of five-membered heterocycles is compared with that of their acyclic

Fig. 6. Electrophilic attack in acyclic analogs and five-membered heterocycles

The electrophilic substitutions in five-membered heterocycles with one heteroatom,

1.3.2 Comparison with Benzene

The tendency of five-membered heterocycles with one heteroatom of undergoing

Fig. 8. Electrophilic substitution in benzene

Five-membered heterocycles with one heteroatom also undergo electrophilic

Fig. 9. Electrophilic substitution in five-membered heterocycles

Since five-membered heterocycles with one heteroatom are n:-excessive with

1.3.3 Reactivity Order in Five-Membered Heterocycles

The reactivity of five-membered heterocycles towards electrophiles depends on

Fig. 10. Transition states in pyrrole

Furan is also reactive (although less than pyrrole) towards electrophiles

Fig. 11. Transition states in furan

The trend of reactivity in these heterocycles can be clearly shown by their

1.3.4 Reactivity Comparison with Benzene

The electrophilic substitution in thiophene is much easier than in benzene.

1.3.5 Effect of Aromaticity on Reactivity

The effect of aromaticity on the reactivity can be evidently observed by comparing