Heterocyclic Chemistry

Heterocyclic Chemistry
Volume 4
A Specialist Periodical Report
Volume 4
A Review of the Literature Abstracted

between July 1981 and June 1982
Senior Reporters
H. Suschitzky Department of Chemistry and Applied
Chemistry, University of Salford
0 . Meth-Cohn C.S./.R.,Pretoria, South Africa
Reporters
G . V. Boyd Chelsea College, London
S . D. Carter Queen Elizabeth College, London
G . W. H . Cheeseman Queen Elizabeth College, London
G . P. Ellis UWIST, Cardiff
S. Gronowitz University of Lund, Sweden
0 . Guilloton University of Nantes, France
T. V. Lee Brunel University, Middlesex
J. R. Malpass University of Leicester
T. J. Mason Lanchester Polytechnic, Coventry
H. Quiniou University of Nantes, France
J. M. E. Quirke Florida International University, USA
J. T. Sharp University of Edinburgh
The Royal Society of Chemistry

Burlington House, London W I V OBN
ISBN 0-85 186-833-9
ISSN 0144-8773
Copyright 0 1985
The Royal Society of Chemistry
All Rights Reserved

No part of this book may be reproduced or transmitted in any form
or by any means - graphic, electronic, including photocopying, recording,
taping, or information storage and retrieval systems - without
written permission from The Royal Society of Chemistry
Printed in Great Britain

at the Alden Press, Oxford, London and Northampton
In tr oduc t ion
Volume 4 includes the abstracted literature on heterocyclic chemistry between

July 1981 and June 1982 (i.e. Volumes 95 and 96 of Chemical Abstracts).
The format of previous volumes in respect of chapter arrangement has been
retained, to allow the reader to study readily the progress in an area of
heterocyclic chemistry through all of the four volumes, helped also by a
detailed list of Contents.
Our reviewers have again admirably succeeded in distilling out the salient
features of several thousand references and have presented them in a concise
and readable report. They have also co-operated with skill and patience in a
cost-cutting exercise designed by the RSC editors, and have produced diagrams
by a new method. I t is hoped that these efforts will ensure the economic
survival of the series and eventually bring down the price to a level which will
tempt the individual buyer; the only serious and recurring printing mistake, as
one illustrious heterocyclic chemist remarked, is the price!
Our thanks to all authors for their forbearance in the handling of grid-
sheets and supplying excellent manuscripts, and to the editorial staff of the
Royal Society of Chemistry for smoothing out difficulties.
H. Suschitzky and 0. Meth-Cohn

Contents
Chapter 1 Three-Membered Ring Systems 1

By T. J. Mason
1 Reviews
General
Rings containing Oxygen
Rings containing Nitrogen
Rings containing Sulphur
2 Oxirans 1
Preparation 1
Oxidation of Alkenes, using Oxygen or Oxygen-
containing Gases 1
Oxidation of Alkenes by Peroxy-acids 3
Oxidation of Alkenes, using Peroxides 5
Synthesis by Halohydrin Cyclizations and Related
Reactions 7
Synthesis via Attack of a Carbanion on the
Carbonyl Group of Aldehydes and Ketones 9
Synthesis of Chiral Oxirans 11
Synthesis and Reactivities of Aromatic Oxides 15
Miscellaneous Syntheses 19
Spectra and Theoretical Chemistry 21
Reactions 22
Ring-opening Reactions with Electrophiles 22
Cyclization Reactions 23
N ucleophilic Ring-opening Reactions 25
With Oxygen Nucleophiles 25
With Nitrogen Nucleophiles 28
With Sulphur Nucleophiles 28
With Carbanions 30
Reduction and Elimination Reactions 33
Thermal and Photochemical Reactions 34
Reactions with Organometallic Compounds 38
Miscellaneous Reactions 39
3 Aziridines 40
Preparation 40
By Direct Insertion 40
viii Heterocyclic Chemis0
By Cyclization Reactions 42
By Ring-contraction Reactions 43
Synthesis of Chiral Aziridines 43
Spectral and Theoretical Studies 43
Reactions 44
Thermal Reactions 44
Ring-opening to Acyclic Compounds 45
Formation of Other Ring Systems 46
4 Azirines 47
Preparation 47
Reactions 48
5 Thiirans 49
Preparation 49
Reactions 50
The Chemistry of Thiiranium Ions 51
6 Thiirens 51
7 Diaziridines 52
8 Diazirines 53
9 Dioxirans 54
10 Oxaziridines 54
Chapter 2 Four-Membered Ring Systems 57

By T. V. Lee
1 Highlights and Reviews 57
2 Systems containing One Nitrogen Atom 57
Azetidines and Azetines 57
Azetidinones 58
3 Systems containing Two Nitrogen Atoms or One Nitrogen
Atom and a Second Heteroatom 63
4 Systems containing Oxygen 65
Oxe tans 65
Dioxetans 66
5 Systems containing Sulphur 67
6 Miscellaneous Four-Membered Rings 68
Contents ix
Chapter 3 Five-Membered Ring Systems 71
By G. V. Boyd, S. Gronowitz, 0. Guilloton,
and H. Quiniou
Part I Thiophens and their Selenium and Tellurium
Analogues 71
By S. Gronowitz
1 General 71
2 Monocyclic Thiophens 72
Synthesis by Ring-closure Reactions 72
C4 + S Principle 72
C2S + C2 Principle 73
CS 3- C3 Principle 73
Ring-closure of C4S 74
Ring-closure of CzSCz 75
Synthesis from Other Rmgs 75
From Di- and Tetra-hydrothiophens 75
From Other Sulphur Heterocycles 76
From Other Rings 76
Physical Properties of Monocyclic Thiophens 77
Theoretical Calculations 77
Photoelectron and Ultraviolet Spectra 78
Infrared and Raman Spectra 78
Nuclear Magnetic Resonance 78
Mass Spectrometry 79
X-Ray Investigations 79
Miscellaneous Physical Properties 80
Electrophilic Substitution Reactions 80
Electrophilic Ring-closure Reactions 83
Nucleophilic and Radicaloid Substitution Reactions 86
Organometallic Derivatives 88
Lithium 88
Magnesium 92
Mercury, Zinc, and Copper 92
Transition Metals 92
Silicon 93
Photochemistry 93
Cycloaddition Reactions 95
Desulphurization and Hydrogenation of Simple
Thiophens 97
Structures and Reactions of Hydroxy-, Mercapto-,
and Amino-thiophens 99
Reactivities of Side-Chains 101
Reactions of Thiophen Aldehydes, Ketones, and
Carboxylic Acids 102
Reactions of Vinylthiophens and Related Compounds 104
X Heterocyclic Chemistry
Reactions at Benzylic Positions 104
Various Reactions in the Side-Chains of Thiophens 105
Macrocyclic Thiophens 105
Reaction at Sulphur: Thiophen Dioxides 106
Di- and Tetra-hydrothiophens 108
Arylthiophens and Di- and Poly-heterocycles 111
Naturally Occur ring T hio p hens 113
Thiophen Analogues of Steroids 114
Thiophens of Pharmacological Interest 114
Therapy of the Central Nervous System 114
Pharmacodynamic Agents 115
Therapy of Metabolic Diseases 115
Therapy of Infectious Diseases 116
Veterinary and Agricultural Agents 118
Miscellaneous Activities 118
Thiophens of Technical Interest 119
Polymers from Thiophen 119
3 Eknzo[ blthiophens and their Benzo-fused Systems 120
Benzo [b] thiophens 120
Synthesis 120
Physical Properties 12 1
Reactions 12 1
Benzo [ b ]thiophen S-Oxides 123
Benzo [ c ]thiophens 123
Dibenzothiophens 124
Pharmacologically Active Compounds 124
4 Thiophen Analogues of Polycyclic Aromatic
Hydrocarbons 125
Analogues of Anthracene and Phenanthrene 125
Polycyclic Thiophens 125
Thiophen Analogues of Indene 127
Various Carbocycle-fused Systems 128
5 Thiophen Fused to Five-Membered Heteroaromatic
Rings 129
Thieno-, Furo-, and Pyrrolo-thiophens 129
Thiophen Fused to Various Five-Membered Rings 131
6 Thiophen Fused to Six-membered Heteroaromatic
Rings 131
Thiophen Analogues of Quinoline 131
Thiophen Analogues of Isoquinoline 132
Pyrimidine-fused Systems 133
Miscellaneous Fused Systems 135
7 Selenophens and Tellurophens 136
Monocyclic Selenophens 136
Contents xi
Condensed Selenophens 137
Tellurophens 138
Part I I Systems containing Nitrogen and Sulphur,

Selenium, or Tellurium 138
By H. Quiniou and 0.Guilloton
1 Introduction and Reviews 138
2 Isothiazoles 139
Synthesis 139
From Dicyanoacetylene and Sulphur Dioxide
(Type A: C-C-C-N + S) 139
From 0-Benzoylpropionamides and Th ionyl
Chloride (Type A) 139
From 1,3,2-Oxathiazol-5-ones(Type B;
S-N-C + C-C) 139
From 3,3’-Disulphanedipropionyl Chloride and
Amine (Type H; S-C-C-C + N) 140
From Aqueous Ammonia and Thioamide Vinylogues
(Type H) 140
From Ring-Cleavage of 3 -Azidot h io ph ens 140
From Substituted Enamines and Benzyl
Isothiocyanate (Type C-C-N + S-C) 141
Physical Properties 141
Chemical Properties 141
N-Qu at er niz at ion o f Isothiazole s 141
Reactions of 5-Aminoisothiazoles 142
A3-Is0thiazolines 143
Chemical Properties of Isothiazoline-5-thiones 143
A4-1sothiazolines 143
Chemical Properties of Isothiazolin-3-ones 143
Isothiazolidines 143
Physical Properties of Isothiazolidine 1,l -Dioxides 143
3 1,2-Benzisothiazolesand their 1,l-Dioxides 144
Synthesis 144
From ortho-Halobenzoyl Compounds, Aqueous
Ammonia, and Elemental Sulphur 144
Reactions 144
Reduction 144
3-Chloro-substitution 145
Photochemistry 145
Synthesis of 1,2-Benzisothiazolin-3-ones
and
their 1,l-Dioxides 145
From 2-(Methylsulphinyl)benzamides and Thionyl
Chloride 145
xii Heterocyclic Chemistry
From Anilines and 2-Chlorothiobenzoyl Chloride 146
From 2-Aminobenzonitriles and SO2 146
From 2-(Chlorothio)benzoyl Chloride and Substituted
Anilines 147
From Thermal Decomposition of N-Substituted
2-(Me th ylt h io)benzamides 147
Physical Properties of 1,2-Benzisothiazolin-3-ones 148
Chemical Properties of 1,2-Benzisothiazolin-3-ones 148
Hydrolysis, Alcoholysis, and Phenolysis 148
Reactions of 1,2-Benzisothiazolin-3-ones with Amines 148
N-Substitution of 1,2-Benzisothiazolin-3-ones 149
1,2-Benzisothiazoline-3-thione 1,l -Dioxides 149
1,2-Benzisothiazolidinesand their 1,l -Dioxides 149
4 1,2-Benzisoselenazoles 150
1,2-Benzisoselenazolin-3-ones 150
5 2,l -Benzisothiazoles 150
6 Other Condensed Ring Systems incorporating
Isothiazole 151
Thieno [2,3c] isothiazoles 15 1
Isothiazolo [3,4411pyridines 15 1
Isothiazolo [5,44] pyrimidines 15 1
1,2-Dithiolo [4,3c] isothiazoles 152
Naphtho [ 2 , l d ] isothiazole 152
Thieno [3,441isothiazole 1,l-Dioxides 152
7 Thiazoles 152
Synthesis 152
Hantzsch’s Synthesis (Type A; S-C-N + C-C) 152
From thioureas 152
From thioamides 153
Type B Syntheses (C-C-N +
C-S) 154
Type C Syntheses (C-C-N-C + S) 154
Type F Syntheses (C-N-C-S + C) 154
Type H Syntheses (S-C +
C-N-C) 155
Tautomerism of 2-Aminothiazoles 157
Reactions of Thiazoles 157
Reactions of Thiazolium Salts 158
8 A2-Thiazolines 160
Synthesis 160
Type B Syntheses (C-C-N + C-S) 160
Type J Syntheses (C-S-C-N-C) 16 1
Type K Syntheses (C-C-N-C-S) 16 1
Type E Syntheses (N-C-C-S + C) 162
Reactions 162
Conten ts xiii
Synthesis 165
Type A Syntheses (S-C-N + C-C) 165
Reactions 168
11 Thiazolidines 169
Synthesis 169
Type E Syntheses (N-C-C-S C) + 169
By Hydrolysis of Fused-Ring Compounds 170
Physical Proper ties 170
Chemical Properties 17 1
12 Selenazoles 173
Synthesis and Properties 173
Type A Syntheses (Se-C-N + C-C) 173
13 Benzothiazoles 174
Synthesis 174
From ortho-Aminobenzenethiols (Type A;
S46H4-N + C ) 174
Type B (C6H5-N-C-S) 175
Type E (CGH5-N + C-S) 175
Substitution Reactions on the Thiazole Ring 178
Reactions of 2 -Aminobenzothiazoles 179
Reactions of 2-Mercaptobenzothiazoles 180
Other Reactions of Benzothiazoles 180
Benzo t h iazolines and Benzot h iazolin -2-ones
(and -thiones) 181
Benzothiazolium Salts 18 1
14 Condensed Ring Systems incorporating Thiazole 182
Structure comprising Two Five-Membered Rings ( 5 3 ) 182
Thiazolo [3,241 te t razoles [CN4-C3NS] 182
Thiazolo[2,3-c][ 1,2,4] thiadiazole [C2N2S-C3NS] 182
Thiazolo [2,3-b][ 1,3,4]thiadiazoles [C2N2S-C3NS] 182
Thiazolo-[2,3-c]-, -[3,2-b]-, and -[3,4-b]-[1,2,4]-
triazoles [C2N3-C3NS] 182
Thiazolo[4,5-d]-oxazole, -thiazole, and -selenazole
[C3NX-C3NS] 183
Imidazo-[2,1-b]-and -[5,1-b]-thiazoles
[C3N2-C3NS] 183
Pyrrolo [2,1-b]thiazoles [C4N-C3NS] 184
xiv Heterocyclic Chemistry
Structures comprising One Five-Membered and One
Six-Membered Ring (5,6) 185
Thiazolo [3,241- 1,3,5-triazines [C3NS-C3N3] 185
Thiazolo [3,2471pyridazines [C3NS-C4N2] 185
Thiazolo [3,2-a] pyrimidines [C3NS-C4N2] 185
Thiazolo [5,4-b]pyridines [C3NS-CSN] 186
Structures comprising Two Five-Membered Rings and
One Six-Membered Ring (5,5,6) 186
Benzo [ 1,2d;4,5dfIbis-thiazoles [C3NS-C3NS-C6] 186
Benzo[d]imidazo[2 ,l-blthiazoles
[C3NS-C3N2-C6] 186
Thiazolo [3,44]benzimidazole [C3NS-C3N2-C6] 187
Th iazolo[3',2' :1,2]imidazo [4,5-b]pyrazine
[C3NS-C3N2-C4N2] 187
Pyrrolo [2,1-b]benzothiazole [CSNS-C~N-C~] 187
Structures comprising One Five-Membered Ring and
Two Six-Membered Rings (5,6,6) 187
1,2,4-Triazino[3,4-b]benzothiazole
[C3NS-C3N 3 -C61 187
1,3,5-Triazino [2,1-b] benzothiazole
[C3NS-C3N3-C6] 188
Thiazolo [2,3-b]quinazolines [C3NS-C4N,-C6] 188
Thiazolo [3,2-a]thiapyrano [4,3-d]pyrimidines
[C~NS-C~NZ-C 5x1 189
1,2-0xathiino[5,6-g]benzothiazoles
[C3NS-C4OS-C6] 189
Thiazolo-[2,3-a]- and -[3,4-b]-isoquinolines
[C3NS-CSN-CG] 189
Naphtho [2,3d]thiazole [C3NS-C&6] 190
Other Condensed Systems incorporating Thiazole 190
15 Thiadiazoles and Selenadiazoles 190

1,2,3-Thiadiazoles 190
Synthesis 190
Physical Properties 19 1
1,2,3-Selenadiazoles 19 1
Synthesis 192
Synthesis 194
Condensed 1,3,4-Thiadiazoles 196
Contents xv
Synthesis 196
2,1,3-Benzothiadiazoles and 2,1,3-Benzoselenadiazoles 197
16 Dithiazoles and Diselenazoles 198
1,2,3-Dithiazoles 198
17 Oxathiazoles and Selenathiazoles 200
1,3,2-0xathiazoles 200
1,3,4-Oxathiazoles 200
18 Miscellaneous Ring Systems 201
1,3,2,4-Dithiadiazoles 201
Part I I I Other Five-Membered Ring Systems 20 1

By G. V. Boyd
1 Introduction 201
2 Reviews 202
3 Systems with One Heteroatom and their
Benzo-analogues etc. 203
Furans 203
Formation 203
Reactions 205
Benzo furans 209
Isobenzofurans and 0ther Annelated Furans 212
Pyrrole s 214
Form ation 214
Reactions 2 17
Indoles and Carbazoles 22 1
Formation 22 1
Reactions 223
Isoindoles 227
Other Systems containing One Heteroatom 228
4 Systems containing Two Identical Heteroatoms 229
Dioxoles 229
Dithioles and Related Systems 230
Tetra t hiafulvalenes and Related Compounds 234
Py razoles 236
Formation 236
Reactions 238
Indazoles 240
xvi Heterocyclic Chemistry
Imidazoles 24 1
Formation 24 1
Reactions 242
Benzimidazoles and an Imidazoquinoline 244
5 Systems containing Two Different Heteroatoms 245
Oxathiole s and Selenathioles 245
Isoxazoles 248
Formation 248
Reactions 249
Benzisoxazoles and Other Annelated Isoxazoles 250
Oxazole s 25 1
Formation 25 1
Reactions 253
Benz ox az oles 258
Benzoxaiodoles 260
6 Systems containing Three Identical Heteroatoms 260
1,2,3-Triazoles and Benzotriazoles 260
1,2,4-Triazoles 26 1
Other Systems 264
7 Other Systems containing Three Heteroatoms 264
Oxadiazoles 264
1,2,3-0xadiazoles 264
1,2,4-Oxadiazoles 265
1,2,5-Oxadiazoles 266
1,3,4-0xadiazoles 267
Phosphorus Compounds 268
Miscellaneous 0ther Systems 269
8 Systems containing Four Heteroatoms 270
Tet razoles 270
Other Systems 271
9 Compounds containing Two Fused Five-Membered
Rings (5,5) 272
Hypervalent Sulphur and Selenium Compounds 272
Nitrogen Systems 273
M onoaza-Comp ounds 273
Diaza- and Triaza-Compounds 274
Other Systems 275
10 Compounds containing Fused Five- and Six-Membered
Rings (5,6) 276
Nitrogen Systems 276
Monoaza- and Diaza-Compounds 27 6
Triaza-Compounds 277
Tetra-aza-Compounds and a Penta-aza-Compound 278
Contents xvii
Mixed Oxygen-Nitrogen Systems and a
Diselenoloquinoxaline 279
11 Compounds containing Fused Five- and Seven-Membered
and Fused Five- and Eight-Membered Rings [ (5,7),
(5,5,7), (5,7,7), and (5,5,8)1 282
Chapter 4 Six-Membered Ring Systems 285

B y S. D. Carter, G. W. H. Cheeseman, and
G. P. Ellis
Part I Systems containing Nitrogen 285
By S. D. Carter and G. W. H. Cheeseman
1 Introduction 285
2 Reviews 285
3 Azines and their Hydro-and Benzoderivatives 2 86
Pyridines 286
Synthesis 286
Properties 29 1
Reduced Pyridines 299
Quinoline, Isoquinoline, and their Benzo- and Hydro-
derivatives 302
4 Diazines and their Reduced and Fused Derivatives 3 12
1,2-Diazines 3 12
1,3-Diazines 3 14
1,4-Diazines 322
5 Triazines and Tetrazines 326
6 Fused Systems containing One Five- and One
Six-Membered Ring (5,6) 329
7 Fused Systems containing Two Six-Membered
Rings (6,6) 333
8 Oxazines, Thiazines, and their Fused Derivatives 336
0x azines 336
Thiazines 339
9 Other Oxygen- and Sulphur-containing Systems 34 1
Classified Reference List 344
Part I I Six-Membered Rings containing Oxygen

or Sulphur 345
By G. P. Ellis
1 Reviews 345
xviii He twocyclic Chemistry
2 Heterocycles containing One Oxygen Atom 346
Reduced Pyrans 346
Pyrans 348
Pyrylium Salts 349
Pyran-2 -ones 350
Pyran-3- and -4-ones 355
Chromans 357
Isochromans 361
Chromenes 363
Benzopyrylium Salts 365
Chromanones 366
Chromones 367
F lav ans 370
Flavanones 37 1
Flavones 372
I sofl av one s 373
Dlhydrocoumarins and Dihydroisocoumarins 373
Coumarins 375
Isocoumarins 378
Xanthenes and Xanthones 378
3 Heterocycles containing One Sulphur Atom 380
T hiopyrans 380
Thiochromans and Thiochromenes 38 1
Thiochromanones 382
Thiochromones and Thiocoumarins 382
Thioxanthenes and Thioxanthones 383
4 Heterocycles containing One Oxygen and One
Sulphur Atom 383
Oxa thiins 383
5 Heterocycles containing Two Oxygen Atoms 384
Dioxans 384
6 Heterocycles containing Two Sulphur Atoms 385
1,3-Dithians 385
1,4-Dithians 385
7 Heterocycles containing an Oxygen Atom in each of
Two or More Rings 386
Chapter 5 Seven-Membered Ring Systems 389

By J. T. Sharp
1 Introduction 389
2 Reviews 389
Contents XiX
3 Azepines and Diazepines 389

Azepines 389
Formation 389
Reactions 394
1,2-Diazepines 395
Formation 395
Reactions 397
1,3-Diazepines 399
Formation 399
Reactions 40 1
1,4-Diazepines 40 1
Formation 40 1
Reactions 403
4 Oxepins and Dioxepins 405
Oxepins 405
Formation 405
Reactions 408
D i ox epins 408
5 Thiepins 409
6 Systems containing Two Different Heteroatoms 41 1
Oxazepines 41 1
T hiazepines 413
7 Systems containing Three Heteroatoms 415
Chapter 6 Eight-Membered and Larger Ring Systems 4 19

By J. M. E. Quirke
1 Eight-Membered Rings 419
One Heteroatom 419
Two Heteroatoms 42 1
2 Nine- and Ten-Membered Heterocycles 422
3 Macrocycles Other than Crown Ethers 423
Systems containing Nitrogen as the only Heteroatom 423
Systems containing Sulphur as the only Heteroatom 427
Systems containing Oxygen as the only Heteroatom 427
Syntheses of Macrocyclic Lactones 427
Other Oxygen-containing Derivatives 428
Other Macrocyclic Systems 429
4 Crown Ethers and Related Compounds 429
Synthesis of Crown Ethers 429
Reactions of Crown Ethers 432
Applications of Crown Ethers in Organic Synthesis 434
xx Heterocyclic Chemistry
Synthesis of Cryptands and Other Polycyclic
Systems 43 7
Host-Guest Complexes of Crown Ethers and
Cryptands 439
Chapter 7 Bridged Systems 44 1

By J. R. Malpass
1 General 44 1
2 Physical Methods 44 1
X-Ray and Electron Diffraction 44 1
Nuclear Magnetic Resonance Spectroscopy 443
Miscellaneous Methods 444
3 Nitrogen-containingCompounds 445
Synthesis 445
Cycloadditions 445
0ther Cyclizations 449
Reactions 450
Bridged Azolkanes 453
4 Oxygencontaining Compounds 45 5
Synthesis 45 5
Cycloadditions 45 5
Miscellaneous Other Methods 457
Re actions 458
Bridged Peroxides 460
5 Sulphur-containingCompounds 46 1
6 Silicon- and Germanium-containing Compounds 463
7 Phosphorus-containing Compounds 464
8 Boron-containingCompounds 465
1
Three-Membered Ring Systems
BY T. J. MASON
1 Reviews
General. - Thermally induced ring-enlargement of vinyl three-membered
heterocycles has been reviewed.’
Rings containing Oxygen. - The catalytic epoxidations of alkenes with hydro-
peroxides have been surveyed,2y3as have transition-metal-catalysed stereo-
controlled epoxidations! A major review of oxiran chemistry (956 refer-
ences) has been published as a chapter in Saul Patai’s series on the Chemistry
of Functional Groups (1980).’
Theoretical aspects of the thermal and general chemical reactions of oxi-
rans have been treated by the application of quantum-mechanical methods
to the study of the reactions of the triplet states of isomers.6
Rings containing Nitrogen. - The reactions of aziridines with alkylidene-
phosphoranes and with phosphorus(II1) nucleophiles’ and the reactions of
3 -amino-2H-azirines with NH-acidic compounds have been reviewed.’
Rings containing Sulphur. - The subject of a lecture given in 1980 and pub-
lished in 1981 was some aspects of the chemistry of episulpho~ides.~
2 Oxirans
Preparation. - Oxidation of Alkenes to Oxirans, using Oxygen or Oxygen-
containing Gases. Research into the improvement of the silver catalysts that
are used in the commercial oxidation of ethene has resulted in continued
interest in the doping of the catalyst with alkali-metal salts, particularly
J . Chuche, Bull. SOC.Chim. Belg., 1981, 9 0 , 535.

* J . Sobczak and J . J .Ziolkowski, J. Mol. Catal., 1981, 13, 11.
’ R. A. Sheldon, Aspects Homogeneous Catal., 1981, 4, 3.
D. Hoppe, Nachr. Chem. Tech. Lab., 1982, 30, 281.
M. Bartok and K. L. Lang, in ‘Chemistry of Ethers, Crown Ethers, Hydroxyl Groups,
and their Sulphur Analogues’, ed. S. Patai, Wiley, Chichester, U.K., 1980, Vol. 2,
p. 6 0 9 .
G. R . DeMare, NATO A d v. Study Inst. Ser., Ser. C , 1981, 67 (Comput. Theor. Org.
Chem.), 335.
’ M. Vaultier and R. Carrie, ACS Symp. Ser., 1981, 1 7 1 (Phosphorus Chem.), 51.
H. Heimgartner, Isr. J. Chem., 1981, 21, 151.
G. Maccagnani, Org. Sulfur Chem. Invited Lect. I n t . Syinp., 9 t h, 1980 (publ. 1981),
123.
2 Heterocyclic Chemistly
caesium.1°-12 Spent catalyst may be rejuvenated by treatment with NH3,
MeOH, and CsN03.13
Silver powder with a high surface area has been used to determine the
reactivity of adsorbed oxygen for the epoxidation of perde~terioethene.'~
The results suggest that the alkene oxide is formed only if both surface and
subsurface adsorbed oxygen are present. Two types of adsorbed oxygen were
invoked to explain the results obtained when studying the solid-electrolyte-
aided oxidation of ethene on polycrystalline silver." Solid electrolyte poten-
tiometry (SEP) was used to monitor the chemical potential of the adsorbed
oxygen, the activity of which was not affected by the presence of C02. This
latter appeared to inhibit only the epoxidation reaction. The same group have
also reported that both the selectivity for and the yield of ethylene oxide on
polycrystalline silver may be increased by electrochemical pumping of oxygen
(023.16 The reaction was studied in the solid electrolyte cell C2H4, C2H40,
C 0 2 ,02, AglZr02(Y203)IAg,air, at temperatures around 400 "C and at atmos-
pheric pressure. The cell behaved as a normal epoxidation catalyst under
open-circuit conditions. A study has been made of the bond energies between
adsorbed oxygen and various supported silver catalysts and of their relation-
ship to the activity of such catalysts for epoxidation of ethene." A linear free-
energy relationship between the mean heat of formation of a monolayer of
surface Ago and the catalytic activity was found. Kinetic performance param-
eters have been calculated for a number of supported-silver epoxidation
cata1ysts.l8
Direct oxygenation of alkenes other than ethene and propene is normally
achieved in the liquid phase and in the presence of a catalyst or under U.V.
irradiation. Thus aryl-oxirans (1; n = 1 or 4) were obtained in 37-71% yields
by autoxidation of the corresponding 1-phenyl-cycloalkenes in the presence
of cobalt naphthenate at 50°C."
Unbranched terminal alkenes yield epoxides during autoxidation in the
presence of the soluble catalysts C O Q ~ PrQ3,, TiOQ2, and VOQ2 (Q =
pentane-2,4-dionat0).~' The autoxidation of aromatic vinyl ethers proceeds at
room temperature even in the dark, but irradiation with U.V. light and the use
of a radical generator facilitates the reactions which yield epoxides and
carbonyl compounds in significant quantities?l
lo Mitsubishi Petrochemical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 05 471.

Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 105 750.
I2 Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 108 533.
J. Alfranseder, S . Mayer, S. Rebsdat, J . Riedl, and 1. Schaffelhofer, Ger. Offen.
2 938 245.
l4 C. Backx, J. Moolhuysen, P. Geenen, and R. A. Van Santen, J. Caral., 1981, 72, 364.
I s M. Stoukides and C. G. Vayenas, J. Catal., 1981, 69, 18.
l6 M. Stoukides and C. G. Vayenas, J. Caral., 1981, 7 0 , 137.
A. Auroux and P. C. Gravelle. J. Calorim. Anal. Therm., 1981, 12, 1NT2,-INT2,.
P. Kripylo, L. Moegling, D. Klose, and H. Sueptitz, Chem. Tech. (Leipzig), 1982, 34,
85.
I 9 S . C. Sethi, A. D. Natu, and M. S. Wadia, Heterocycles, 1982, 18 (Spec. Issue), p. 221.
2o U. Barth, H. Friedler, G. Gross, G. Lauterbach, and D. Schnurpfeil, J. Prakr. Chem.,
1981, 323, 887.
21 T. Kanno, M. Hisaoka, H. Sakuragi, and K. Tokumari, Bull. Chem. SOC.Jpn., 1981,
5 4 , 2330.
Three-Membered Ring Systems 3
Photo-epoxidation of alkenes in the presence of benzoins and oxygen has

been shown to proceed via the benzoylperoxy radical (2), which is effectively
trapped by alkene and subsequently yields predominantly trans-epoxides.22
The same intermediate radical (and, as a result, similar reactivities) has been
observed during photo-epoxidation using benzoylformic acid (PhCOCOOH),
but the reactivities of the alkenes were different from those obtained using
p e r o ~ y - a c i d sA
. ~ correction
~ has been published to some previous studies on
the efficiency of benzil-sensitized photo-epoxidation of t r i n ~ r b o r n e n eThe
.~~
new results indicate a lower yield of < 2 moles of epoxide per mole of
diketone that is consumed and thus suggest that a chain mechanism is not
involved for such reactions.
A new reaction system has been reported in which molecular oxygen oxi-
dizes alkenes to epoxides both thermally and photochemically, in the
presence of SO2, under ambient condition^.^' Irradiation of a mixture of pro-
pene and SO2 in acetonitrile at 0 "C caused absorption of 02,to yield propene
oxide as the sole volatile product. A similar reaction occurred at 25 "C in the
dark, in the presence of potassium nitrite.
Direct ozonolysis of the parent vinyl sulphide gives (3) (40%), suggesting
that oxiran intermediates might be involved more generally in the ozonolysis
of vinyl derivatives.26 Ozonolysis of cis- and of trans- 1,2-difluoroethene also
yields epoxides with predominantly retained stere~chemistry.~~
Oxidation of Alkenes to Oxirans by Peroxy-acids. An improved procedure
for epoxidation using aromatic peroxy-acids has been reported .28 After a
normal epoxidation with 3-chloroperoxybenzoic acid (mCPBA) in CH2C12,
activated KF is added to the crude mixture, and this results in the precipi-
tation of both mCPBA and the aromatic acid by-product, leaving an acid-free
reaction mixture for normal work-up. As an alternative, the insoluble
mCPBA-KF complex itself may be used for the epoxidation of alkenes over-
night at room temperature. After filtration and treatment of the CH2C12
solution with more KF (to ensure removal of any residual peroxy-acid),
normal work-up leads to yields in excess of 95% for cyclohexene and styrene
oxides.
22
Y. Sawaki and Y . Ogata, J . A m . Chem. SOC., 1981, 103, 2049.
23 Y. Sawaki and Y. Ogata, J. A m . Chem. SOC.,1981, 103,6455.
24
P. D. Bartlett, A. A. M. Roof, and N. Shimizu, J. A m . Chem. SOC.,1982, 104, 3130.
25 T. Sasaki, J. A m . Chem. SOC.,1981, 103, 3882.
26 L. Morin, D. Barillier, M. P. Strobel, and D. Paquer, Tetrahedron L e t t . , 1981, 2 2 ,
2267.
27 J . W. Agopovich and C. W. Gillies, J . A m . Chem. SOC.,1982, 104, 813.
28 F. Camps, J . Coll, A. Messeguer, and A. M. Pericas, Tetrahedron L e t t . , 1981, 22.
3895.
4
P \
Ph h 0
Ph
- 1 h o\
P Ph ; ]
Fh
@ J$,
Heterocyclic Chemi s t y
(4) (5) CH2 CH2

(6) (7)
The site-selectivity of oxidations by mCPBA is demonstrated in the con-

version of (4; R = Me or Ph) into the corresponding ene epoxide (5).2g The
product is sensitive to acid, so that the conversion is accomplished in a basic
two-phase medium. Normal epoxidation of (6) with mCPBA leads to (7).30
The stereochemistries for such reactions are shown in the predominant for-
mation of the P-epoxide (8) (81%) from the parent alkene, with 12% of the
a - p r ~ d u c t Similar
.~~ epoxidation of the cannabinol (9) leads to a less stereo-
specific isomer distribution of 27.3% and 18.2%.32Remarkable stereoselectiv-
ity has been shown in the epoxidation of the 14,15-unsaturated oestratrienes
( Whereas oxidation of 170-esters and 170-ethers gave 14a ,15a-epoxides
(< 59%),the 170-urethane derivatives displayed a syn-directive effect to yield
140,15P-epoxides (< 87%).
29 R. Y . S. Tan, R . A. Russell, and R. N. Warrender, Aust. J. Chem., 1981, 34,421.

30 H. M. R. Hoffmann and H. Vathke-Ernst, Chem. Ber., 1981, 114, 1182.
31 Meiji Seika Kaisha, Ltd.. Jpn. Kokai Tokkyo Koho 82 0 2 232.
32
I. Yamamoto, S . Narimatsu, K. Watanabe, and H. Yoshimura, Chem. Pharm. Bull.,
1981, 2 9 , 3 3 7 8 .
33 K. Ponsold, G. Schubert, M. Wunderwald, and D. Tresselt, J . Prakt. Chem., 1981,
323, 819.
The rates of epoxidation of cyclododecene with a series of aliphatic
peroxy-acids have been correlated, using the Taft equation.34 The reaction
constant ( p * ) was + 2.0 and the steric constant (6) was found to be essen-
tially zero. A two-parameter correlation has been found for the effect of
basicity and polarity of the solvent on the rate of epoxidation of propene
with peracetic acid.35 Rate constants and activation parameters for the epoxi-
dation of a number of cycloalkenes, including (1 1 ; R = H or COOMe),
(12; R = H, Ph, or 2-furyl), (13), (14), and cyclo-octa-1,5-diene, have been
measured.36 An isokinetic relationship was demonstrated, with the isokinetic
temperature of 3°C. There was only a weak dependence of the rate on the
structure of the alkene.
Alkenes have been epoxidized in high yield, using peroxyformic acid (pre-
pared in situ from formic acid and 85% H202); thus a 90% yield of mono-
epoxide has been prepared from trimethylcy~lodecatriene.~~
Oxidation of Alkenes to Oxirans, using Peroxides. The peroxide (1 5; R =
OOH) is a useful oxidant for a number of alkenes, giving epoxides in good to
moderate yields and generating (15; R = OH).38 The reactivity of this per-
oxide is two orders of magnitude lower than that of peroxyacetic acid but at
least one order of magnitude greater than that of a-peroxy-esters and -nitriles.
Its selectivity relative to the structure of the alkene is similar to that for
peroxyacetic acid.
34 H. J . Schneider, N. Becker, and K. Philippi, Chem. Ber., 1981, 114,1562.

3s V. N. Sarancha, I. A. Opeida, and R. V. Kucher, Dopov. Akad. Nauk Ukr. RSR,
Ser. B , 1981, No. 6,p. 74.
36 A. E. Batog, T. V. Savenko, T. A. Batrak, and R. V. Kucher, Zh. Org. Khim., 1981,
17,2085.
37 G . Kaebisch, R. Truebe, H. Wittmann, S. Raupach, and H. Malitius, Ger. Offen.
3 002 785.
38 A. L. Baumstark and R. S. Pilcher, J. Org. Chem., 1982,47, 1141.
6 Heterocyclic Chemistry
A few years ago, hexafluoroacetone was shown to be an effective catalyst

for the epoxidation of alkenes by H202.39 The reagent is highly toxic, how-
ever, and not commercially available, and so an alternative has been sought.
An efficient alternative catalyst has been found to be hexafluoropropan-
2 - 0 1 , ~but more recently it has been reported that tetrachloroacetone is a use-
ful commercially available alternati~e.~' The reactive species is thought to be
(16; R = OOH), the by-product of epoxidation being the hydrate (16;
R = OH), which is thermally unstable and from which tetrachloroacetone
may be regenerated. The yields are generally good and the selectivity is high,
as illustrated by the formation of (17) (60%) from the epoxidation of
4-vinylcyclohexene with only 4% total yield of other possible mono- and
di-epoxide products.
Two groups have studied the epoxidation of ap-unsaturated ketones with
alkaline H202in methanol; a second-order process. Electron-releasing groups
attached to the &carbon atom in the alkene reduced the rate whereas
electron-attracting groups had the reverse effect !2 In the case of (1 8; R = H
or alkyl), the rate constants in 80%aqueous methanol decreased in the order
H > Me > Pr > ~ e n t y l Spectral
.~~ studies suggested that the origin of this
order of reactivity concerned hindrance to delocalization of charge in the
intermediate.
Base-catalysed epoxidation of norandrostenone ( 19), using H202 in

methanol, produced exclusively the P-epoxide in the A ring.44It was suggested
that the conformations of the A ring were such that the hydroperoxide group
attached at the 5a- or 50-positions could attain an axial confirmation. cis-
Cyclo-octene oxide (20) has been prepared in 60% yield by epoxidation of
39 L. Kim, Br. P. 1 399 639.
40 B. Ganem a n d R. P. Heggs, J. A m . Chem. SOC., 1979, 101, 2484.
41 C. J . Stark, Tetrahedron Lett., 1981, 2 2 , 2089.
42 D. S. R. Rao, Indian J. Chem., Sect. B , 1981, 2 0 , 786.
43 I. G. Tishchenko a n d I. F. Revinski, Vestsi Akad. Navuk B S S R , Ser. Khim. Navuk,
1981, No. 1, p. 90.
44 J. R. Hanson, P. B. Hitchcock, a n d H. J . Wadsworth, J. Chem. Soc., Perkin Trans. I ,
1981, 3025.
cis-cyclo-octene by 30% H 2 0 2 in MeCN at 25-35°C.45 A high yield of
epoxide may be obtained by two-phase epoxidation of alkenes, using
dichloroethane-water with Na2W04 catalyst and a tetra-alkylammonium salt
as the phase-transfer agent.&
One of the most commonly used types of catalyst for epoxidations using
alkyl hydroperoxides is complexes of molybdenum. The yields can be almost
quantitative, as observed when using the n-cyclopentadienyl complex
Cp2MoX2 (X = C1 or Br) with t-butyl hydroperoxide, which gives 98.4% of
diepoxide from the dimer of cyclopentadiene.'" For the epoxidation of
propene by t-butyl hydroperoxide and molybdenum salts of organic acids,
the catalytic activity was little affected by the ligand on the A similar
insensitivity to ligand (and also to valency) was noted in the epoxidation of
cholesteryl acetate with M ~ O ~ ( a c a c MO(CO)~,
)~, and MoC15.49 When cyclo-
hexene was treated wtith t-butyl hydroperoxide and molybdenum porphyrins,
cyclohexene oxide was obtained with up to 85% selectivity at total peroxide
conversion (17-24 hr)." A similar catalyst gave 97% of cis- and 99% of trans-
hex-2-ene oxides from the cis- and trans-alkenes respectively.
A number of different catalysts have been used in the epoxidation of
monoterpenes with t-butyl hydroperoxide and the conditions ~ptimized.'~
While oxidation of a-pinene in the presence of V(acac)3 gave cis-epoxide
(4.4%), campholenic aldehyde was also obtained in the presence of Mo(CO)~.
The n.m.r. line-broadening method was applied to the determination of
the kinetic parameters of the exchange reactions of cumene hydroperoxide,
cumyl alcohol, and cyclohexene in the co-ordination sphere of the complex
H2 [ M o ~ O ~ ( C ~ O ~ ) ~ (4H20
H ~ O* (CH3)2C0.52
* )~] The results revealed that the
first stage of both the decomposition of the hydroperoxide and the epoxi-
dation reaction is the formation of an intermediate compound between a
molybdenum(V) complex and the hydroperoxide.
Synthesis of Oxirans by Halohydrin Cyclizations and Related Reactions. One
of the oldest commercial methods for the production of ethene oxide is the
chlorohydrin route, involving chlorohydration of ethene followed by
dehydrochlorination. An improved procedure for the second stage of this
process has been reported in which a basic ion-exchange resin is used to
45
R. D. Bach and J . W. Knight, Org. Synrh., 1981, 6 0 , 6 3 .
E. Alneri and G. Lana, Ger. Offen. 3 027 349.
47 A. 0. Kolmakov, V. M. Fomin, T. N. Aizenshtadt, and Yu. A. Aleksandrov, Zh.
Obshch. Khim., 1981, 5 1 , 2805.
48 H. R. Hernandez, P. S. Chow, and A. E. Rico, Rev. Ins?. Mex. Pet., 1981, 13, 6 6 .
49 M. Kimura and T. Muto, Chem. Pharm. Bull., 1981, 29, 35.
H. J . Ledon, P. Durbut, and F. Varescon, J. A m . Chem. SOC.,1981, 103, 3601.
51 D. V. Banthrope and S. E. Barrow, Chem. Ind. (London), 1981, 502.
52 A. M. Trzeciak, J . Sobczak, and J . J . Ziolkowski, J. Mol. Catal., 1981, 1 2 , 321.
PCH2CH( OAc)CH2Br
H H
4- M e C6H WCWMe c1
OCOMe
(25)
remove the HCl that is generated during c y c l i ~ a t i o n The

. ~ ~ generation of
styrene oxide (2 1; R = Ph) (85%) from PhCH2ClCH2Cl with 99% purity has
been achieved by simple hydrolysis followed by elimination of HCl from the
intermediate chlorohydrin, using aqueous NaOH.54Other methods for cycliz-
ation include the use of sodium methoxide in methanol to generate (21 ;R =
CloH70CH2) from (22),55 reduction of (23) with sodium borohydride to
yield the cis-epoxide (24),56 or the heating of 0-halogeno-esters with
ammonium or phosphonium salts; e.g. , (25) and Bu4P' Br-, when heated at
180 "C for 2 hours, gave (21 ; R = Me) (95%).57
(27)
Reagents: i, LDA, CH,CII; ii, Bu,N+ F-
Scheme 1
The phosphonate epoxide (28) has been prepared in 58% yield from the
trimethylsilyl ether (26) via fluoride-ion-induced cyclization of the intermedi-
ate (27) (Scheme l).58 The stereochemistry of bromohydrin (31), which
yields the oxiran (33) after sequential reduction and treatment with a base,
has been proved by the use of a novel oxidative bromocarbonation
(Scheme 2).59 Enol (29) of known stereochemistry is converted into the
cyclic bromo-carbonate (32) (79%)upon treatment of the lithium alkoxide of
(29) with dry C02 followed by Brz. Since (32), on treatment with base, gives
T. B. S. Giddey, S. Afr. P. 7 8 0 5 961.

54 Hogyoku C o . Ltd., Jpn. Kokai Tokkyo Koho 81 92 282.
'' Sagami Chemical Research Center, Jpn. Kokai Tokkyo Koho 82 26 6 7 7 .
s6 K. S. Bhat and A. S. Rao, Indian J. Chem., Sect. B , 1981, 20, 355.
57 J . M. Renga and A. H. Emmons, U.S. P. 4 261 906.
M. Sekine, M. Nakajima, and T. Hata, J. Org. Chem., 1981, 46, 4030.
59 M. F. Haslanger and S. Ahmed, J. Org. Chem., 1981, 46,4808.
OH
m
I
A
Scheme 2
(33), and the stereochemistry of (32) follows from that of (29), the structure
of (3 1) is established.
Synthesis of Oxirans via Attack of a Carbanion on the Carbonyl Group of
Aldehydes and Ketones. The dibromo-ketones [34; R = 4-MeC6H4,
4-MeOCsH4, 4-ClCsH4, or 3,4-(MeO)zC6H3] cyclized on dissolving in
MeONa-MeOH, refluxing, and standing for 10 hours at room temperature to
give the compounds (35) (86-95%) by the Darzens mechanism!' A rather
useful, mild, and stereoselective synthesis of a,@-epoxyphenylketones (36;
R' = Me, R2 = PhCH2CH2, Ph, octyl, or 4-CIC6H4; R' = Et, R2 = Ph or
PhCH2CH2)(52-8 1%) involves the reaction of aldehydes R2CH0 with a,a-
dibromo-ketones PhCOCBr2R' in the presence of SnF2.61
Gorc"
Br R
j;r'
Ph CO
Br R COR (36)
(35)
(34)
6o T-Y. Kao and S. Shang, Nan-ching Ta Hsueh Hsueh Pao, Tzu Jan K ' o Hsueh, 1980,
39.
61 S . Shoda and T. Mukaiyama, Chem. L e t t . , 1 9 8 1 , 7 2 3 .
Ph
PhCOCH( B r ) P h "\T/CN
0
(37)
(38)
The use of KCN in the synthesis of oxirans from a-bromo-ketones under

phase-transfer conditions has been investigated.62 Treatment of (37) in
CH2C12with 40% aqueous KCN and aqueous Et3(PhCH2)N' C1- at 20 "C for
4 hours gave (38) (85%) as a 50 : 50 mixture of the cis- and the trans-isomers.
Under homogeneous conditions, using DMF as a solvent, the same mixture
was obtained in 61% yield, but the reaction can be made stereoselective for
the cis-isomer in the presence of solid adsorb ant^.^^ Owing to the insolubility
of KCN, no reaction occurs between (37) and KCN in CH2C12,but when the
same substrate is treated with aqueous KCN that is adsorbed on silica gel
(CH2C12, at 20 OC, for 4 hours), the oxiran (38) (95%) is produced, compris-
ing 88% of the cis-isomer. A similar result is obtained by using benzene as
solvent and alumina as adsorbant. Both silica gel and alumina are thought to
facilitate the reaction by virtue of adsorbing the reacting species onto a sur-
face upon which OH groups are plentiful. The combination of adsorption and
hydrogen-bonding with OH groups on the surface is thought to explain the
stereospecificity. Significantly, both activated carbon and Celite do not pro-
mote the epoxidation, neither material being able to participate via surface
hy drogen-bonding.
The reaction of 1,4-(BrCH2)2C6H4with Me2S gave the sulphonium salt,
which, in aqueous NaOH-C6H6 (containing Bu4N+ Br- as a phase-transfer
catalyst), gave the ylide (39). The ylide reacted in situ with a number of
phenyl-substituted benzaldehydes to give the separable diastereoisomers
(40).64Similar reactions were reported for 1,2- and 1,3-~lides.~'
CH=SMe2
Q CH=SMe2 Ar
62 K. Takahashi, T. Nishizuka, and H. Iida, Synth. Commun., 1981, 11, 757.

63 K. Takahashi, T. Nishizuka, and H. Iida, Tetrahedron L e t t . , 1981, 22, 2389.
64 L. V. Shubina, I. G. Tishchenko, and S. V. Smatser, Dokl. Akad. Nauk B.SSR,
1982, 26, 148.
65 L. V. Shubina, I. G. Tishchenko, and I. I . Medved, Vestsi Akad. Navuk B S S R , Ser.
Khim. Navuk, 1982, No. 1, p. 66.
Three-Membered R ing Systems 11
The sulphonium ylides (42; R4 = R1R2C=CHCH2or R3CH2), derived from

tetrahydrothiophen, have been used for the synthesis of the halogenated vinyl
epoxides [41; R' R2 = Br, C1, or H (however, either R' or R2 must be
halogen); R3 = H, Me, Me2CH, MeCH=CH, H2C=CMe, Me2C=CH, Ph, or
PhCH=CH] (23-87%) by reaction with the appropriate aldehydes.66 The
more complex salt (43), on reaction with HCO(CH2)3COOMe, gave the
( R ,S)-(all-E)-epoxide (44) as a mixture of cis- and trans-is~mers.~'
COOMe
+ -
Ph S e Me CH
(45)
The first examples of reactions of non-stabilized selenium ylides with

enolisable carbonyl compounds have been reported.68 Ylide (45) was gener-
ated in situ from Me,$ePh MeS04 and NaH in the presence of R'COR2 [R' =
Ph, 4-O2NC6H4,Bu, or hexyl; R2 = H, Me, or Et; or R1R2 = (CH2)s] to give
the corresponding oxirans (76-94%).68
Synthesis of Chiral Oxirans. The recently introduced Katsuki-Sharpless
reagent (titanium alkoxide with tartrate) has proved highly effective for the
maiden introduction of chirality into prochiral allylic alcohols. An interesting
development of this procedure has afforded the possibility of kinetic
resolution of racemic allylic alcohols.69 The basis of the method involves the
66 J . P. Beny, J . C. Pommelet, and J . Chuche, Bull. SOC.Chim. Fr., Part 2 , 1981, 369.
67 M. Rosenberger, Eur. Pat. Appl. 36 663.
68 K. Takaki, M. Yasumura, and K. Negoro, Angew Chem., Znt. Ed. Engl., 1981, 20,
671.
69 V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, and K. B. Sharpless,
J. A m . Chem. SOC.,1981, 1 0 3 , 6 2 3 7 .
difference in rates of epoxidation of the enantiomeric alcohols; in the case

of (46)) this difference in rate is 138. Starting with racemic (46), the optical
purity of the remaining unreacted alcohol at 60% conversion is greater than
99.999999%. The method promises to be of great synthetic value. The
epoxy-alcohol products from such reactions are also of synthetic value. It has
been reported that the erythro-threo selectivity is profoundly influenced by
the catalyst used; thus, in the case of racemic (47), the Katsuki-Sharpless
reagent gives 81:19 erythro selectivity whereas in the absence of diethyl
tartrate the ratio swings to 5 :95 in favour of the threo-isomer. In both
cases, the erythro- or threo-epoxy-alcohols possess high enantiomeric purity
(2 92%e.e.).
In a series of papers, the application of titanium alkoxide catalysts to the

synthesis of sugars has been described. Asymmetric epoxidation and kinetic
resolution of (48) afforded (+)-(49) (27%; > 95%e.e.) and (-)-(48) (33%;
72%e.e.).70 The ring-opening reactions of the chiral epoxides that are pro-
duced, for example, from cis- and from trans-(50) provide new routes to
The reagents also find use in the synthesis of pheromones;
e.g., (+)-di~parlure~~and (+)-2,6-dimethylhepta-l,S-dien-3-01 acetate via the
epoxide (52), which was obtained from the dienol (51) by using D-(-)-
70 W. R. Roush and R. J . Brown, J . Org. Chern., 1 9 8 2 , 4 7 , 1371.

71
T. Katsuki, A. W. M. Lee, P. Ma, V. S. Martin, S. Masamune, K. B. Sharpless,
D. Tuddenham, and F. J . Walker, J. Org. Chem., 1982, 47, 1373.
72 P. Ma, V. S. Martin, S. Masamune, K. B. Sharpless, and S . M. Viti, J. Org. Chem.,
1982,47,1378.
73 K. Mori and T. Ebata, Tetrahedron Lett., 1981, 2 2 , 4 2 8 1 .
Fewo):qcJ Me
p
COOMe
tartrate.74 Under the conditions of such epoxidations it is surprising to note

that no decomposition of the iron complex occurred in the formation of (54)
from (53) as part of a total synthesis of an analogue of trichothecene.”
Leucotrienes are substances that are implicated in asthmatic conditions,
and thus their synthesis, or at least the synthesis of their precursors, is of
pharmaceutical interest. Two approaches to the synthesis of (56) have been
published. The first involves the treatment of the threo-hydroxy-ester lactone
( 5 5 ) with K2C03 in methanol,76 while the second uses LDA to convert (57)
into the epoxide (58), which may then be transformed into (56)
(Scheme 3).77
0
H
Me02S0
PhCOO
CHZOTs
H f
I
CH2COOEt
ii
0‘ H
HO ‘
(57) (58)
Reagents i, K,CO,, MeOH; ii, LDA
Scheme 3
74 K. Mori and H. Ueda, Tetrahedron, 1981, 37, 2581.

75 A. J. Pearson and C. W. Ong, J. Am. Chem. SOC.,1981, 103, 6686.
76 N. Cohen, B. 1. Banner, and R. J . Lopresti, Tetrahedron Lett., 1980, 21, 4163.
77 J. Rokach, C-K. Lau, R. Zamboni, and Y . Guindon, Tetrahedron Lett., 1981, 2 2 ,
2763.
(59)
Highly stereoselective epoxidations of acyclic homoallylic alcohols have

been achieved, using the vanadium(v) t-butyl hydroperoxide method .78 A
yield of 90%, with selectivity of > 400 :1, was achieved in the preparation of
(60) from (59), and a detailed model of the transition state was proposed.
The model involves a cyclic transition state (61), for which the required form
is attained by minimizing the steric interactions engendered by the various
substituents. The model successfully predicts the stereochemical outcome of
a range of such epoxidations.
R~CH=CR~COOH
(62)
- I,a, I
COCR’ =C H R ~
(63)
Scheme 4
An efficient process for the synthesis of a,P-epoxy-aldehydes from a,P-

unsaturated acids has been rep~rted.~’ The acid (62) is converted into the
bromo-lactone [64; R’ = a- or P-Me, R2 = Ph or (CH2)5Me; or R’R2 =
(CH2)4 or 2-C,H4(CH2),], via asymmetric bromolactonization of the corres-
ponding acylproline (63; R3 = H or Et). Sequential epoxidation and reductive
cleavage of (64) gives the (2R,3S)-epoxy-aldehydes (65) in good yield, with
e.e. 84-98% (Scheme 4).
The possibility of preparing oxirans via microbial oxidation offers the
prospect of considerable stereoselectivity, owing to the enzymes involved in
such processes. Thus far, however, such conversions have not been a practical
proposition, because of the very low concentrations of alkene that may be
used with the cultures (generally, no more than 1% by volume). A good yield
has been obtained, however, in the microbial transformation of oct-1-ene,
using Pseudomoms oZeovorans.sOThe method employs a two-phase system in
78 E. D. Mihelich, K. Daniels, and D. J . Eickhoff, J. Am. Chem. SOC.,1981, 103, 7690.

79 M . Hayashi, S. Terashima, and K. Koga, Tetrahedron, 1981, 37, 2797.
M. J . DeSmet, B. Witholt, and H . Wynberg, J. Org. Chem., 1981, 46, 3128.
Me a*COOE
H
I
OR
t - Me
?
OS03Me
CH20H -mH.
Me 0
(66) (67) (68)
Scheme 5
which octene is present in sufficient quantities to serve as the second phase.

By this method, 5.6 g (1.4%) of the oxiran, containing 85% of the (R)-isomer,
was obtained from 500 cm3 of octene.
A useful preparation of (+)-(R)-methyloxiran (68) is shown in Scheme 5.81
The overall yield, based on the readily available (+)-@)-ethyl lactate (66;
R = OH), from which (66; R = MeS03) is formed, is 7 1%. The cyclization of
(67) involves distillation of the oxiran as it is produced.
COOEt
COOEt
The epoxysuccinate (2R ,3R)-(70) (94%) is prepared from (2S,3S)-(69)

by treatment with Et3N in CH2C12overnight.82 A number of enantiomerically
pure synthetic building blocks have been prepared from hydroxybutanoic,
malic, and tartaric acids.83 Examples of those with at least two functional
groups are (21; R = CH2CH2Br), (71), and (72; R = H, CH2Ph, CMe20Me,
or Ph).
Synthesis and Reactivities of Aromatic Oxides. The synthesis and absolute

configurations of benzene and naphthalene ( 1S,2S,3S,4S)-diepoxides,
(+)-(73) and (+)-(74), have been reported,84 as have those of the naphtho-
quinone derivative (2S,3R)-(+)-( 75) .85
L. R. Hillis and R. C. Ronald, J. Org. Chem., 1981, 46, 3348.

82 Taisho Pharmaceutical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 110 683.
83 E. Hungerbuehler, D. Seebach, and D. Wasmuth, Helu. Chim-. A c t a , 1981, 64, 1467.
84 K. Koreeda and M . Yoshihara, J. Chem. SOC.,Chem. Commun., 1981, 974.
Y. Harigaya, H. Yamaguchi, and M. Onda, Chem. Pharm. Bull., 1981, 29, 1321.
H@ --H H @\ --H o
@ / /
/
0
; o : o 3-Me00CC6H4
H (74IH O (75)
(73)
The hexahydrophenanthrene 9,lO-oxide (76) has been synthesized,

together with its diastereoisomeric isomer (77).& Both isomers are confor-
mationally rigid and give rise to different diol products under acid hydrolysis;
(76) yields the cis-diol (75%) at a faster rate than (77), which leads to trans-
diol exclusively. This reactivity of (76) has been ascribed to the fact that the
benzilic C-0 bond of the epoxide ring is aligned nearly parallel to the
n-orbitals of the aromatic ring and the epoxide oxygen iscis to the hydrogen
at the adjacent ring junction. For the other isomer the benzilic C-0 is not
aligned and it has the epoxide oxygen trans to the hydrogen at the adjacent
ring junction. Under neutral conditions, (76) gives the rearranged ketone (78)
(85%).
n
(76)
A possible explanation for the difference in carcinogenicity of K - and bay-

region arene oxides has been s~ggested.~' Phenanthrene 9,lO-oxide (79) reacts
with the phosphodiester HOP(O)(OEt), to give 9-phenanthrol (80) whereas
cyclohexene oxide, under the same conditions, gives the phosphotriester (8 1).
If bay-region arene oxides react in the same manner as cyclohexene oxide (to
give potentially carcinogenic diol derivatives) then K-region oxides may well
be detoxified by conversion into phenols, on approaching a molecule of DNA
(or RNA), by the phosphate groups that are present.
'OP( 0 ) ( OEt ) 2
86 J. M. Sayer, H. Yagi, J . V. Silverton, S. L. Friedman, D. L. Whalen, and D. M. Jerina,

J. Am. Chem. SOC.,1982, 1 0 4 , 1 9 7 2 .
87 P. DiRaddo and T. H. Chan, J, Org. Chem., 1 9 8 2 , 4 7 , 1427.
Three-MemberedRing Systems 17
The first examples of syn stereoselective epoxidation of arene dihydro-

diols have been reported with the preparation of (82) and (83) from the
corresponding diols.88 Thus unexpected synepoxidation has been interpreted
as due to the exertion of steric control by the axial benzylic hydroxy-groups,
whereas such control is usually exhibited by equatorial hydroxy-groups.
OH
(84) (85)
The enantiomeric bay-region diol epoxides of benz[a]anthracene (84) and

of chrysene (85) have been synthesized and a rather interesting relationship
between stereochemistry and turnorigenic activity has emerged.89 It appears
that for each of the four metabolically possible bay-region diol epoxides of
both of the above fused systems and for the diol epoxides (86) of
benzo[a]pyrene, those with the (+)-(R ,S)-diol (S,R)-epoxide trans configur-
ation (87) have practically all of the tumorigenic activity. One attractive
explanation for this phenomenon is that the cellular covalent binding site of
these ultimate carcinogens is highly chiral and that only these isomers effec-
tively bind to the site. The benz[c]acridine analogues of (84), i.e. (88), have
been prepared.g0
(87)
H. Lee and R. G. Harvey, Terrahedron Lett., 1981, 2 2 , 1657.
H. Yagi, K. P. Vyas, M. Tanada, D. R. Thakker, and D. M. Jerina, J. Org. Chem.,
1982,47,1110.
R. E. Lehr and S. Kumar, J. Org. Chem., 1981, 46, 3675.
The optically active benz[a]anthracene oxides (89) and (90) have been
synthesi~ed.~' Thermal recemization (at 293-322 K, in CDC13) of the chiral
chrysene 3,4-oxide (91) has been shown to occur via first-order kinetics, with
an activation energy of 25.2 kcal m01-l.'~ The results are consistent with a
reaction mechanism involving an oxepine intermediate (92), as predicted by
theory.
The novel bay-region diol epoxide isomers (93) have proved to be remark-
ably biologically active, despite their relative lack of reactivity towards
hydrolysis (as expected from simple PMO calculations).93 Both diastereo-
isomers prefer the conformation in which the OH groups are quasi-
diequatorial, and these are the most tumorigenic diol epoxides yet tested on
mouse skin.
91 D. R. Boyd, G . S. Fadaginamath, N. D. Sharma, A. F. Drake, S. F. Mason, and D. M.

Jerina, J. Chem. SOC.,Perkin Trans. 1, 1981, 2233.
92 D. R. Boyd, M . G. Burnett, and R. M. E. Greene, J. Chem. SOC.,Chem. Commun.,
1981, 839.
93 J . M. Sayer, H. Yagi, M. Croisy-Delcey, and D. M. Jerina, J . Am. Chem. SOC.,1981,
103,4970.
Three-membered Ring Systems 19
Two bis-imines (94) and (95) have been prepared from the corresponding
diepoxides by reaction with NaN3 and subsequent cyclization of the trans-
azido -alcohols .%
Miscellaneous Syntheses of Oxirans. The vinyl-oxirans (97; R' = Ph or

phenethyl, R2 = H or Me) were prepared by refluxing the benzimidazole
derivatives [96; R3 = CH2CH2(0CH2CH2)20Me]with NaH in THF.95
CR~=CH~
CHR'OH 0
I (97)
R3
Diazomethane reacts with (98) in the presence of Et3N to give a mixture

of (99) and (loo), but, without Et3N, the reaction yields mainly the two
oxirans (101) and (102) (Scheme 6).% Trimethylsilyldiazomethane,
Me3SiCHN2, reacts with aromatic aldehydes RCHO in the presence of Et3N
to give the oxirans (103) and (104), amongst other product^.^'
94 I. Yona and J . Blum, J. Heterocycl. Chem., 1981, 18, 1473.

95 Mitsubishi Chemical Industries Co. Ltd., Jpn. Kokai Tokkyo Koho 81 125 379.
96 H. Meier and A. Binder, Chem.-Ztg., 1981, 105, 149.
97
N. Hashimoto, T. Aoyama, and T. Shioiri, Heterocycles, 1981, 1 5 , 975.
CH2C1
PhCOCOCH2N2 +
(99) @COPh
PhCOCOCl / (100)
dPh~ 1 :
(98)
1 0 COCH2NH2
(101)
+
( 102)
2
Reagents: i, CH,N,, Et,N; ii, CH,N,

Scheme 6
When the valence tautomer of cyclo-octa-1,5-diene (stable below - 20 "C)

is treated with O2 under irradiation from a sodium vapour lamp (a street
lamp), in the presence of tetraphenylporphyrin as sensitizer, the endo-
peroxide (105) can be prepared in 85% yield.98 The endoperoxide serves as
the starting material for three triepoxides (106), (107), and (108) (Scheme 7).
The structures of all three triepoxides have been confirmed by X-ray analysis.
- ii
QV
0 0
-
ii i
Reagents: i, heat, ii, mCPBA; iii, PPh,

Scheme 7
98 W. Adam, 0. Cueto, 0. DeLucchi, K. Peters, E. M. Peters, and H. G . Von Schnering,
J. Am. Chem. SOC.,1981,103, 5822.
CHO
'H
P 0
Flash vacuum thermolysis of (109) at 420 "C and 2 x Torr gave (1 10)
(95%)." The Dewar-furan (1 11; X = 0) has been prepared in six steps from
the corresponding Dewar-thiophen (1 1 1; X = S ) because the direct route via
photolysis of furan proved
Spectra and Theoretical Chemistry of Oxirans.- The use of conformational
analysis, with the aid of torsion-angle notation, permits the interpretation and
prediction of regioselective opening of epoxides."' Values for the molar
refraction, electron polarization, and permanent electron dipole moments for
oxiran and its simple derivatives have been calculated from literature data.lo2
The molar Kerr constants for oxiran and its methyl derivatives in CC14 were
also calculated. The pericyclic reactivities of three-membered heterocycles
have been rationalized, using the relaxation method.lo3
The 13C n.m.r. spectra for (1 12; X = 0, NH, S , or SO) have been recorded
and compared with that for (1 12; X = CH2).lWThe annelation effects of the
three-membered rings were determined. Using 350 MHz 'H n.m.r. and dipole
moments, ( 1 13; R = H) and (1 13; R = OMe) were shown to adopt a boat
conformation, with the 0 of the oxiran ring in a pseudo-axial position.'05
The absolute configuration of alliacolide (1 16) has been established by c.d.
99
A. J. H. Klunder, W. Bos, J . M. M. Verlaak, and B. Zwanenberg, Tetrahedron Lett.,
1981, 22,4553.
100
D.Wirth and D. M. Lemal, J. Am. Chem. SOC.,1982,104,847.
101
E. Toromanoff, Tetrahedron, 1981, 37, 3141.
102
D. Pitea, R. Todeschini, and F. Gatti, J. Chem. SOC., Faraday Trans. 1 , 1981, 77,
1611.
103
0.Henri-Rousseau, P. Pujol, and F. Texier, Bull. SOC.Chim. Fr., Part 2 , 1980,496.
104
M. Christl, H. Leininger, and E. Brunn,J. Org. Chem., 1982,47, 661.
105
J. Huet, Z. Kotkowska-Machnik, and J . Zakrzewski, Org. Magn. Reson., 1981, 16,
236.
22
MeOOCCHZCH2 wewe
(114)
Me Me
0
OH
(115)
Me
Me
HO'
measurements on the degradation products (1 14) and (1 15), both of which

exhibit positive Cotton curves.1o6
The molecular structure of the perfluoro-oxiran (1 17) has been deter-
mined, using gas-phase electron diffracti~n.''~
Reactions of Oxirans. - Ring-opening Reactions with Electrophiles. A ring-
contraction resulted from the treatment of the piperidine (118) with
BF3. OEt,, to yield (1 19) rather than the expected piperidone (12O).lo8The
C-19 group has been shown to have a significant effect on the BF3-catalysed
reactions of SP,6P-~teroids.'~~Thus androstanone (121 ; R = H) reacted with
gaseous BF3 in benzene with loss of the hydroxymethyl group as HCHO and
subsequent dehydration to give the diene (122), but, for (121; R = OAc),
ring-contraction led to ( 1 23). For steroidal Sar,6c~-epoxides,however, an
alternative pathway is possible, involving participation of the C-19 group and
leading to ring-closed products; eg., chloestanol (121 ; R = H) gives (124)
8
with BF3 log or with HC1O4."'
I
COOCH2CC13
( Y C H O
I
COOCH2CC13
ho
I
COOCH2CC13
(118) (119) ( 120)
lo6 A. P. W. Bradshaw, J . R. Hanson, D. N. Kirk, and P. M. Scopes, J. Chem. Soc.,

Perkin Trans. I , 19 8 1, 17 94.
lo' B. Beagley, R. G. Pritchard, and R. E. Banks, J. Fluorine Chem., 1981, 18, 159.
F. H. Hershenson and L. Christensen, Synth. Commun., 1981, 11, 61 5.
l o g H. Mastalerz and P. Morand, J . Chem. SOC.,Perkin Trans. 1 , 1981, 154.
' l o P. Kocovsky and V. Cerny, Collect. Czech, Chem. Commun., 1980, 45, 3190.
The mechanism for the gas-phase reaction of trans-2,3-dideuterioethene

oxide with HBr and HCl has been shown to involve anti ring-opening, with
the formation of erythro-R(CHD)*OH ( R = C1 or Br)."' The reaction of
ethene oxide with HF followed a somewhat different course, affording only
5% of fluorohydrin together with (126) (37%) and oligomers and polymers.
A possible mechanism for this reaction is shown (see Scheme 8) in which two
moles of oxiran react with HF to give intermediate (125), which is open to
polymerization with other oxiran molecules or to ring-expansion, with the
subsequent formation of dioxane (1 26).
T7
I F-
+O
H
+ TJ- [ y7JHIF--[ci>].--<:,
(125)
polymer
Scheme 8
Cyclization Reactions of Oxirans. The search for non-enzymatic cyclizations
of squalene oxide and its analogues continues with the report of the direct
sterol synthesis of (128) (2%) from (127).'12 Although the yield is low, the
procedure involving treatment of (127) in CHzC12 that contains BF3 - OEt2
and ethene carbonate at 0°C for 20 minutes affords four new rings and
seven new asymmetric centres in one laboratory operation. The diepoxide
'I1 G. Bellucci, G. Berti, R . Bianchini, G. Ingrosso, and A. Moroni, J. Chem. SOC.,

Perkin Trans. 2 . 1981, 1336.
112
E. E. Van Tamelen and T. M. Leiden, J. Am. Chem. SOC.,1982, 104, 2061.
24 emistry
Heterocyclic 01
COMe
e M OHO;
(129), on treatment with BF3 * OEt, in CH2C12,gives a mixture of (130) and

(131) (5O%).ll3
,Me
CH=CH2
Other examples of cyclization reactions involving alkenyl groups are the

formation of the pentacyclic ether (133) from the BF3 - OEt2-catalysed
rearrangement of ( 132)'14 and the transannular cyclization of humulene 9,lO-
oxide (134) to (135) (70%)in BF3 * OEt2-acetic anhydride."'
'13 D. Nasipuri and A. K. Samaddar, Indian J. Chem., Sect. B , 1981, 2 0 , 261.
'14 J. W. Blunt, E. J . Ditzel, M. P. Hartshorn, L. H. Sieng, M. H. G . Munro, and W. T.
Robinson, Tetrahedron Lett., 1981, 2 2 , 1923.
'IS H. Shirahama, K. Hayano, Y. Kanemoto, S. Misumi, T. Ohtsuka, N. Hashiba,
A. Furusaki, S . Murata, R. Noyori, and T. Matsumoto, Tetrahedron Lett., 1980,
21,4835.
Me Me
(134) (135)
A remarkably stereoselective intermolecular reaction occurs when trans-

5,6-epoxycis-cyclodecene(1 36) undergoes Friedel-Crafts alkylations with a
number of aromatic compounds (Scheme 9).l16 Four chiral centres are
formed via transannular ring-closure to cation (1 37), which subsequently
undergoes electrophilic substitution; thus, with toluene, (138; Ar =
4-MeC6H4)(64%) was obtained.
Ar
I H
(137)
P HO
Scheme 9
Nucleophilic Ring-opening Reactions of Oxirans. -Reactions with Oxygen

Nucleophiles. Con sider able interest has been shown by Japanese industry in
simple hydrolyses of epoxides to yield glycols. One company has six patents
in this area, concentrating on metal-catalysed hydrations in the presence of
CO,; thus ethylene glycol (95.3% selectivity) was prepared from ethene oxide
-
(loo%), the conversion using catalysts containing Mo or W."' Up to 98%
selectivity for the formation of propane-1,2-diol has been achieved, with 98%
conversion in the hydration of propene oxide using Et4N' I- in the presence
of propene carbonate."' The ene-diol (139) has been prepared from 1,2-
epoxybut-3-ene by hydration, using an alkali-metal iodide and a mineral acid
in the acetone ~olvent.~''
OH
HO
'I6 S. K. Taylor, G. L. Lilley, K, J. Lilley, and P. A. McCoy, J. Org. Chern., 1981, 46,
2709.
'I' Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 9 2 2 2 8 .
'I8 D. K. K. Showa, Jpn. Kokai Tokkyo Koho 81 0 8 336.
'I9 Mitsubishi Petrochemical Co. Ltd., Jpn Kokai Tokkyo Koho 82 0 2 227.
The acid-catalysed hydrolysis reactions of vinyl epoxides (140; n = 1-4)

have been shown to follow an A-1 mechanism, via the intermediate allylic
cations (141).'*' The distributions of products from both (140; n = 1) and
(140; n = 3) were similar, comprising all four possible cis- and trans-1,2- and
-1,4-diols, whereas cyclohexadiene oxide (140; n = 2) gave mainly the trans-
1,2- and -1,4-diols. The reactivity of cyclo-octadiene oxide (140; n = 4) was
some lo3 times less than that of the other epoxides, and it yielded, in
addition to 1,2- and 1,4-diols, the dienol (141) (35%); these results were
attributed to steric effects in the medium-sized ring. A similar anomaly in the
reactivity of cyclo-octane derivatives has been noted in the opening of a,P-
epoxy-silanes.'21 While these reactions normally proceed with nucleophilic
attack at the carbon which is a to silicon, to give (144; R = H, OMe, OH,
OCH2CH=CH2, Br, I, or SCN) (70-92%) from (143; n = 2), the acid-
catalysed methanolysis of (143; n = 4) gave (145) by a transannular reaction.
The previously inaccessible hydroxypyranone (147) has been obtained

from the acid-induced rearrangement of the epoxypyrone (146).'22 The
mechanism involves a retro-Claisen reaction (Scheme 10).
120
A. M. Ross, T. M. Pohl, K. Piazza, M. Thomas, B. Fox, and D. L. Whalen, J. A m .
Chem. SOC.,1 9 8 2 , 1 0 4 , 1 6 5 8 .
A. P. Davis, G. J . Hughes, P. R . Lowndes, C. M. Robbins, E. J . Gwyneth, and G. H.
Witham, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1934.
122 W. J . Ross, A. Todd, B. P. Clarke, S. E. Morgan, and I . E. Baldwin, Tetrahedron
L e t t . , 1981, 2 2 , 2207.
Ph OOE t
(147)
Scheme 10
The furanones (149; R = M e , Et, Pr, Bu, Pi, or Bu') are obtained in
36-59% yields by hydrolysis of the diepoxides (148) in boiling 5% H2S04.'23
Nafion-H sulphonated resin has been found to catalyse both the hydrolysis
and the alcoholysis of cycloalkene oxides to yield (150; n = 1 or 2; R = H,
Me, or PhCH2).124
Me c?i"'"OMe
(148)
oHO
*o
(149)
\ Hoy&)n
RO /'
( 150)
2,6-Di-t -butylphenol reacts with terminal epoxides via 0-or C-alkylation

at the least substituted epoxide carbon atom to give (15 1 ; R = H, Me, Et,
n-octyl, Ph, or CH2Ph) and (152; same R).12' The ratio of C- to 0-alkylation
increases with the complexity of the group R (cyclohexene oxide gives
entirely C-alkylation) and is also increased with the alkali-metal catalyst that
is used, in the order K < Na < Li.
(151) (152) oH
123
124
M. Baumann and W. Hoffmann, Synthesis, 1981, 709.
G . A. Olah, A. P. Fung, and D. Meider, Synthesis, 1981, 280.
125
R . W. Layer, J. Org. Chem., 1981, 46, 5224.
28 Heterocyclic aemistry
ii
1 2
R1R2NH -R R NA1Et2 +
(153) 0 OAlEt2 R1R2; OH
(1541
Reagents: i, Et,Al, ii, H,O
Scheme 11
Reactions with Nitrogen Nucleophiles. Treatment of an epoxide with one of

the diethylaluminium amides [ 153; R' = R2 = Et, CH2Ph, or CH2CH=CH2;
R1R2 = (CH2)4; R' = H, R2 = Pr or Ph] in CH2C12 at room temperature
affords the corresponding 0-amino-alcohol (1 54) in good yield (Scheme
1 1).126
Derivatives of 2-chloro-oxiran have proved to be useful synthons for the
preparation of six-membered heterocycle^.'^^ Treatment of [ 155; R' R2 =
(CH2)4, R3 = HI and of (155; R' = R2 = R3 = Me) with NH3 at - 35 "C
gave (156) (82%) and (157) (80%), respectively. The reactivity of these ox!-
rans may be compared to that of a-chloro-ketones; thus (152; R1 = Pr',
R2 = R3 = H) reacts with Et3N or Me2S to yield (158; R = NEt, C1-) or
( 1 58; R = $Me2 C1-).12'
Reactions with Sulphur Nucleophiles. The addition of Et2AlSPh to the vinyl-

oxiran (159) in benzene at 25 "C for 1 hour gives the (2)-vinyl alcohol (160)
(91%) with about 2% of the (E)-i~orner.'~~
A novel route to the phenoxathiins
12' L. E. Overman and L. A. Flippin, Tetrahedron Lett., 1981, 2 2 , 195.

12' C. Herzig and J . Gasteiger, Chem. Ber., 1981, 114, 2348.
12* J . Gasteiger and C. Herzig, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 868.
129 A. Yashuda, M. Takahashi, and H. Takaya, Tetrahedron Lett., 1981, 2 2 , 2413.
'RL (163)
x3
(161)
'@
SC6C15 - R
R2
/
S C6 C 1
R2
R3
(162)
Scheme 12
(163) via the spiro-oxirans (161; R1 = But, R2 = H, R3 = But or Me;

R' = R2 = Me, R3 = H) has been reported (Scheme 12).130 Initial opening of
the epoxide by pentachlorothiophenoxide anion leads to the intermediate
(162), which undergoes a reverse aldol reaction.
S e Me ph\r..
OH SOMe
The unusual reactivity of selenoboranes towards epoxides gives new selec-

tive routes to P-hydroxy-selenides and ally1 alcohols.131Thus, 1,2-epoxyoctane
with B(SeMe)3 at 0°C for 0.7 h, followed by aqueous NaHC03, gave (164)
(8 1%) whereas the same reaction with styrene oxide gave (165) (63%) as the
major product. For trisubstituted oxirans, however, the products were allylic
alcohols, e.g. (167) (76%) from (166) on treatment with B(SePh)3 at 20°C
for 1.5 h.
130 J . E. Baldwin, P. Cacioli, and J . A. Reiss, Tetrahedron L e t t . , 1980, 21,4971.

13' A. Gravador and A. Krief, Tetrahedron L e t t . , 1981,22, 2491.
Reactions with Carbanions. Although the reaction of the epoxide (1 68) with
Pdo catalyst yields (169),'32 treatment of (168) with Pd(PPh3)4 in the pres-
ence of 1.2 equivalents of malonic ester leads to the single alkylation product
(170) (57%).1s3 This appears to be a general reaction for allylic epoxides, pro-
viding alkylation under neutral conditions with complete regio- and stereo-
specificity. The alkylation proceeds from the same face as the oxygen of the
epoxide, and gives inversion of the ally1 group. Similar reactions have been
reported for 1,4-additions to trans-(171) with a variety of nucleophiles; thus
(172) reacts with (171) in the presence of Pd(PPh3)4 to yield [ 173; R =
(CH2)7Me] (91%) with an E : 2 ratio of 98 : 2.i34
c8H17bw 0
An internal Grignard reaction affords benzocyclobutenol (1 76) (83%)

from the ortho-halogenostyrenes (174; X = Br or I).'35 Lithium exchange
with BuLi in THF at - 78 "C leads to (174; X = Li), which with MgBr2 then
gives (1 76) on warming, presumably via the rearranged intermediate (175).
97 0
M. Susuki, Y . Oda, and R. Noyori, J . Am. Chem. SOC.,1 9 7 9 , 1 0 1 , 1623.

B. M. Trost and G. A. Molander, J. Am. Chem. SOC.,1981, 103, 5969.
134 J . Tsuji, H. Kataoka, and Y. Kobayashi, Terrahedron L e n . , 1981, 22, 2575.
13' E. Akguen, M. B. Glinski, K. L. Dhawan, and T. Durst, J. Org. Chem., 1981, 46,
2730.
4 - R C6 H SO 2v~-j:
4-R1s02Q- R2 H R3
(177) (178)
A simple one-pot synthesis of the bicyclobutanes (178; R1 = H, R2 =

R3 = H or Me; R1 = Me, R2 = H, R3 = Pr') (> 50%) from (177) has been
r e ~ 0 r t e d . lSequential
~~ treatment of (177) in THF at 0 "C with one equiv-
alent each of BuLi, methanesulphonyl chloride, and then BuLi again, to give
(17$), may be accomplished in 10 minutes. Terminal yepoxy-sulphones, on
treatment with two equivalents of MeMgI , give cis-3-phenylsulphonylcyclo-
butanols; thus (179) yields (180).13' This reaction contrasts with that of
(179) with MeLi or with LiNPr:, which gives derivatives of cyclopropyl-
methanol.
Ph
phso> phs+h OH
(179)
The reaction of organomagnesium reagents RMgBr with y ,S -epoxy-ketones,

e.g. (181), affords functionalized tetrahydrofurans (182; R = Et, Ph, or
CH=CH2) (71-75%).138 The ring-opening of the oxiran by the intermediate
alkoxide occurs with inversion of configuration, but, with both organo-
magnesium and organolithium reagents, the cyclization affords a 1 : 1 mixture
of both cis- and trans-tetrahydrofurans (1 82).
+T (181) M:eAT4:
OH (182)
The opening of epoxides, e.g. cyclopentene oxide, with the allylic

Grignard reagent (1 83), in the presence of CuI , affords (1 84) in high ~ie1d.l~'
The allyl-silane (184) may then be converted into the allylic alcohol (185).
The overall process demonstrates the use of (1 83) as a hydroxypropenyl syn-
thon.
MgBr
Me3Siw /
136
Y. Gaoni, Tetrahedron Lett., 1981, 2 2 , 4339.
137
J. M. Decesare, B. Corbel, T. Durst, and J . F. Blount, Can. J. Chem., 1981, 59, 1415.
138
M. Chastrette and G. P. Axiotis, J. Organomet. Chem., 1981, 206, 139.
13' H. Nishiyama, S. Narimatsu, and K. Itoh, Terrahedron Lert., 1981, 2 2 , 5289.
Reactions of alkyl-lithiums with isoprene oxide (1 86) yield p,-y-

disubstituted allylic alcohols of Z c~nfiguration.'~'The proportion of Z -
isomer can be increased by using a base; thus the formation of (187) from
(186) and BunLi is improved fron an isomer yield of 88% in hexane at 0°C
(76% overall yield of allylic alcohols) to an isomer yield of 97% (73% overall)
in the presence of Bu"0Li.
I
,
Enantioselective SN2' reactions of epoxy vinyl sulphones have been
rep~rted.'~'The chiral epoxide (-)-( 188) reacts with MeLi in the presence of
LiC104 in a 1:1 mixture of CH2C12and Et,O at - 78 "C to yield a 95 : 5 mix-
ture of (+)-(189; R' = Me, R2 = H) and (+)-(189; R' = H, R2 = Me) (81%).
Using a mixture of Et3A1 and MeCu, however, the reaction affords solely
(+)-(189; R' = Me, R' = H).
In contrast to their reaction with R'R'CuLi (R' = alkyl, R2 = alkyl or

CN), the reactions of epoxides with the higher order mixed organocuprates
R2Cu(CN)Li2 (R = various alkyl or aryl) give excellent yields of ring-opened
products.'42 The trisubstituted oxiran (190), on reaction with Pr"Cu(CN)Li,
affords only 23% of (191), but with Prn2Cu(CN)Li2 the yield is increased to
86%.
140 M. Tamura and G. Suzukamo, Tetrahedron Lett., 1981, 2 2 , 577.

14' J . C. Saddler and P. L. Fuchs, J. Am. Chem. SOC.,1981, 103, 2112.
14' B. H. Lipshutz, J . Kozlowski, and R. S. Wilhelm, J. Am. Chem. Soc., 1982, 104,
2305.
Three-Mem bered Ring Systems 33
OS iMe OSiMe3
I I
Me
(193)
The enol ethers of substituted 2,3-epoxycyclohexanones, e.g. (192), react

with organocuprates, e.g. MeCu(CN)Li, in a regio- and stereo-specific manner
to yield (in most cases) the 1,4-trans-adducts (193) (95%).'43
Reduction and Elimination Reactions of Oxirans. - The liquid-phase hydro-
genolysis of the spiro-oxirans (194; X = 0, Y = CH2) and (194; X = CH2,
Y = 0) on supported metal catalysts (Pd, Pt,Rh, and Ni) in various solvents
leads to preferential cleavage of the more substituted C-0 bond.'@ For Pd
and Rh catalysts the major products are aldehydes (60 and 80%respectively)
whereas with Pt or Ni the liydrogenoiysis leads mainly to primary alcohols.
Catalytic hydrogenolysis of 3,4-epoxybut-l-ene with cationic rhodium com-
plexes at 30°C under 1 atm of hydrogen gives but-2-enal as the major pro-
duct .14' The hydrogenolysis of methyloxiran on unsupported Pt/C catalysts
leads mainly t o Me2CHOH, and to EtCHO, whereas the aldehyde was pro-
duced if a supported catalyst was used.14 The interpretation of these results
in terms of the role of acidic centres in the isomerization and hydrogenolysis
of oxirans has received some criti~ism.'~'
Epoxides may be reduced t o the less substituted alcohol, using a combi-

nation of NaBH3CN, BF3. OEt2, and THF. The reaction is both regio- and
stereo-~elective;'~~thus 1-methylcyclohexene oxide gives a 97 : 3 ratio of
(195):(196) (overall 87%), with only a trace of trans-(195) being produced.
Stereospecific reduction of epoxybutanoic acid (197) with NaBD4 gave (198)
(52%).149 The reduction of (+)-(R)-(l99) with A1D3 gives a nearly equal mix-
ture of (+)-(S)-(200) and (-)-(S)-(201),150 The inversion that is involved in
143 J. P. Marino and J. C. Jaen, J . A m . Chem. SOC.,1982, 104, 3165.

144 G. Accrombessi, P. Geneste, J. L. Olive, and A. A . Pavia, Bull. SOC.Chim. Fr., Part 2 ,
1981, 19.
14' H. Fujitsu, E. Matsumura, S. Shirahama, K. Takeshita, and I. Mochida, J . Chem. SOC.,
Perkin Trans. I , 1982, 855.
146 M. Bartok, F. Notheisz, and J . T. Kiss, J. Catal., 1981, 6 8 , 249.
14' M. Kraus and H. Davidova, J. Catal., 1981, 68, 252.
14' R. 0. Hutchins, I. M. Taffer, and W. Burgoyne, J. Org. Chem., 1981, 46, 5214.
149 J. R. Mohrig, P. J . Vreede, S. C. Schultz, and C. A. Fierke, J . Org. Chem., 1981 46,
46 5 5.
R. L. Elsenbaumer, H. S. Mosher, J. D. Morrison, and J . E. Tomaszewski, J. Org.
Chem., 1981, 46,4034.
OH Ph
I
D3C+--Ph H H°CDZ*H D
the formation of (201) points to a classical s N 2 attack by A1D3 on the

benzylic site.
Deoxygenation of epoxides to alkenes can be achieved with a number of
reagents, including WCls and BuLi,lS1NbCIS and NaA1H4,lS2and Me3SiCl and
NaI.’” The last combination of reagents has been shown to react stereo-
(95%) from the correspond-
selectively, affording (E)-2,2-dimethylhex-3-ene
ing (E)-epoxide.
Thermal and Photochemical Reactions of Oxirans. - Isotopic labelling has
been used to prove that the thermal rearrangement of phenyloxiran proceeds
via a 1,2-shift of hydrogen, and not phenyl migration (Scheme 13).lS4The
epoxide (202), labelled with 13C at C-2, gives entirely C(2)-labelled phenyl-
ethanol (203) and 3,3-2H2-labelled(202) gives (203) with 2H at both C-1 and
C-2. The method does not, however, distinguish between the transfer of H’
and of H-.
-0
* I
wz’
PhCH- CD2
PhCHD -CDO
Ph
0- / (203)
1 \ + PhCH-CD2
I
(202 1
Scheme 13
Cycloaddition reactions of the carbonyl ylides derived from the thermoly-

sis of (204; n = 1 , 3 , 5 , or 10) led to annelated products (205;n = 1 , 3 , or 5),
but the bridged compound (206) was produced from (204;n = The
stereochemistry of 6n and 877 ring-cyclization reactions of 2-oxaheptatrienyl
M. A. Umbreit and K. B. Sharpless, Org. Synth., 1981, 6 0 , 29.
Is’ M. Sato and K. Oshima, Chem. Lett., 1982, 157.
lS3 R. Caputo, L. Mangoni, 0. Neri, and G. Palumbo, Tetrahedron L e n . , 1981, 22, 3 5 5 1 .
R. M. Roberts and L. W. Elrod, J . Org. Chem., 1981, 46, 3732.
J . Brokatzky and W. Eberback, Tetrahedron Lett., 1980, 2 1 , 4 9 0 9 .
ph-a
Me
MeOOC
\ /
(208)
M Mee‘ O -O
( 209 1
C b
~ The eight-electron cyclization of the con-

dipoles has been ~ t u d i e d . ”,15’
jugated carbonyl ylide (208), generated by thermolysis of (207), gave the
dihydro-oxepin (209). The reaction followed the theoretically expected con-
rotatory process.
The thermal decompositions of the three isomers of (210) all yield mix-
tures of PhCHO, PhOH, C6H6, and furan.lS8It is suggested that two of the
decompositions proceed by similar mechanisms; for trans-(210), via (21 l),
and for the isomer of cis-(210) in which epoxide rings are anti to cyclobutene,
via (212). The first step in the decomposition of the isomer of cis-(210) in
which epoxide rings are syn to cyclobutene is thought to involve the for-
mation of (213).
The first topologically non-planar molecule (2 15) has been produced by
the thermolysis of (214).15’
W. Eberback, E. Haedicke, and U . Trostmann, Tetrahedron Lett., 1981, 22,4953.

lS7 W. Eberback and U. Trostmann, Chem. Ber., 1981, 114, 2979.
158
H. Prinzbach, M. Mass, H. Fritz, and G . McMullen, Tetrahedron L e t t . , 1980, 21,4897.
S . A. Benner, J . E. Maggio, and H. E. Simmons, J. A m . Chem. SOC.,1981, 103, 1581.
Direct (457.9 nm) or photosensitized (by benzophenone) irradiation of

(216) gives rise to the exclusive formation of (217).l6' In contrast to this,
irradiation of the isomer of (216) in which the epoxide oxygen is syn to the
benzene ring yields a mixture of products, of which the major constituent is
(218) (ca 25%). The difference in reactivities of these isomers was explained
in terms of the stereoelectronic effect of the epoxide ring.
Pr
Photolysis of a-epoxy-ketones that are excited in their triplet states leads

to 0-diketones, a-diketones, or fragmentation products.'61 The reaction path-
way depends on the localization of energy for the system; thus (219;
Ar' = Ph, Ar2 = 1-naphthyl), on irradiation at 366 nm, at room temperature,
in MeCN, gave naphthaldehyde (75%)and the a-diketone (220) (8%)whereas
(219; Ar' = 2-naphthyl, Ar2 = Ph), under the same conditions, gave (221)
(66%). The absorption spectra of the ylide intermediates in these reactions
were reported. 0
0 OH
I6O C. C. Liao, H. S. Lin, T. H. Hseu, C. P. Tang, and J . L. Wang, J. Am. Chem. Soc.,
1982,104, 292.
16' P. Hallet, J . Muzart, and J. P. Pete, J. Org. Chem., 1981, 46,4275.
Carbonyl ylides that are derived photochemically from symmetrically sub-

stituted diaryl-oxirans (222; R = Me, Ar = Ph or 2-naphthyl; R = H, Ar =
2-naphthyl) retain their configuration during cycloaddition reactions with
dipolarophiles.'62 Both isomers of (222; R = Me, Ar = Ph) give the same
furan products (223) on irradiation in the presence of maleonitrile. This
result implies that the same ylide (224) is generated from both oxirans.
Adverse interactions of aryl groups would seem to prevent alternative open-
ing of the oxiran ring. The ylides derived from (222; R = Me, Ar = 2-
naphthyl) do not undergo addition reactions whereas those from (222;
R = H, Ar = 2-naphthyl) do; this result may also be explained in terms of
steric effects. Another group has concluded that the regioselectivity in cyclo-
addition reactions of carbonyl ylides is high with electron-rich alkenes but is
low with electron-deficient ones.163
A series of papers on photochemical reactions has reached number 122,

with ten publications concerning the reactions of various vinyl~xirans;'~~for
example, triplet sensitization of (E)-(225) gave (226) and (227) via cleavage
of the C(6)-0 bond.16'
16' J. P. K. Wong, A. A. Fahmi, G. W. Griffin, and N. S. Bhacca, Tetrahedron, 1981, 37,

3345.
163 J. Brokatzky-Geiger and W. Eberbach, Hererocycles, 1981, 16, 1907.
164 N. Bischofberger, G. DeWeck, B. Frei, H. R. Wolf, and 0. Jeger, Helu. Chim. A c t a ,
1981,64, 1766.
16' K. Murato, B. Frei, W. B. Schweizer, H. R. Wolf, and 0. Jeger, Helu. Chim. Acta,
1 9 8 0 , 6 3 , 1856.
clD
PhCH2CO0
-)/y(228) PdLm
Ph CH2 C 1
0 0
li
Ph CH C-P dC l L m
PhCH2!!-ia
Scheme 14
Reactions of Oxirans with Organometallic Compounds. - A general method

for the preparation of halohydrin esters via the reaction of organic halides
with CO (20atm) in the presence of PhPd(PPh3)21 has been described.'66 In
the particular case of benzyl chloride and cyclohexene oxide, (228) (57.5%)
was obtained. A possible mechanism for this reaction is shown in Scheme 14.
Isomerization of a$-epoxy-ketones in the presence of palladium com-
plexes leads to 1,3-diones; thus heating (229) in toluene that contains
Pd(PPh3)4 and (Ph2PCH2)2,at 140°C, for 90 hours gives (230) (94.3%).16'
0
Perilla alcohol (232) (98%) has been prepared by treating 0-pinene epoxide
(231) with HgS04 that is suspended in a water-THF mixture, extracting into
ether, and treating the ethereal extract with dilute H2S04.16'
( 2 3 11
(232)
166 M. Tanaka, M. Koyanagi, and T. Kobayashi, Tetrahedron Lett., 1981,22, 3875.
16' Teijin Ltd., Jpn. Kokai Tokkyo Koho 81 1 5 216.
16* M. Fetizon, J. E. Ecoto, and S. Lazare, Eur. Pat. Appl. 21 952.
Miscellaneous Reactions of Oxirans. - Ethylene carbonate (233; R' = R2 =
H, X = 0) may be prepared by the reaction of ethylene oxide with C02 under
pressure, at 140 OC, in the presence of alkali-metal halide^.'^' The reaction is
catalysed by free anion, which is generated by the use of the complex
between 18-crown-6 and KI.I7O Using complexes of this type, the compounds
(233; X = 0; R' = Me, Ph, or ClCH2; R2 = H or Me) have also been pre-
pared.17' The oxazolidone (233; R' = H, R2 = C1CH2, X = NPr') is prepared
by the reaction of (chloromethy1)oxiran with isopropyl isocyanate in the
presence of ~ i c 1 . I ~ ~
xKo 0
Ph
OY O
(233) (234)
The 1,3-dioxolans (234; R = CH2Cl, Me, or Et) have been prepared under
neutral conditions by the reactions of the corresponding epoxides with benz-
a 1 d e h ~ d e . IThe
~ ~ reactions are catalysed by halide ion and provide a mixture
of cis- and trans-2,4-disubstituted compounds. Using Lewis acid catalysts, the
cis-isomer was preferentially formed whereas catalysis by lithium halides
favoured the trans-isomer.
Thioamides RCSNH2 react with the chloro-oxiran (235) to yield the thia-
zoles (236; X = S, R = Me or Ph) (78%).'74 When (235) reacts with seleno-
urea in CH2C12 at O'C, in the dark, and this is followed by treatment with
Et3N, the selenazole (236; X = Se, R = NH2) (52%) is produced. Cyclization
Of (237; R=4-C1CbH4, 4-NO2C6H4, or 4-MeOC6H4) with the cyclic t h o -
amides (238; X = HC=CHNMe, HC=CHCH=N, or CH2CH2S) provides a
general synthesis of the ring-fused meso-ionic thiazolones (239).17'
169
Nippon Shokubai Kagaku Kogyo Co., Ltd., Jpn. Kokai Tokkyo Koho 8 2 31 682.
170 Nippon Shokubai Kagaku Kogyo Co., Ltd., Jpn Kokai Tokkyo Koho 81 1 2 8 778.
171 K. Naito, H. Koinuma, and H. Hirai, Nippon Kagaku Kaishi, 1982, 290.
17' Seitetsu Kagaku C o . , Ltd., Jpn. Kokai Tokkyo Koho 81 7 3 077.
173 T. Takeda, S. Yasuhara, and S. Watanabe, Yukagaku, 1 9 8 1 , 30,486.
174 J. Gasteiger and C. Herzig, Tetrahedron, 1 9 8 1 , 37, 2607.
17' M. Baudy-Floc 1.1 and A. Robert, Synthesis, 1 9 8 1 , 981.
Thermal uncatalysed insertion of silicon halides into oxirans normally

requires long reaction times and high temperatures. It has been reported,
however, that nucleophilic catalysis renders this reaction of greater synthetic
importance, providing a regioselective route to @protected vicinal halo-
h y d r i n ~ . 'The
~ ~ most effective catalysts appear to be Bun4NC1and Ph3P, the
latter allowing the conversion of phenyl glycidyl ether into (241) (99%) in
CHC13at 0 OC, using (240; X = Cl), after 5 minutes. This should be contrasted
with the uncatalysed reaction, which affords only 23% of product after 24
hours at 25 "C. The conversion of epoxides into protected vicinal halohydrins,
using (240; X = Br or I) in the presence of Et3N, has been incorporated into a
one-pot synthesis of a-bromo- and a-i~do-ketones.'~'The oxidation step is
achieved by adding Jones reagent (Cr03-H2S04) to the first-formed
0-halogenosilyl ether. Overall yields of 58-73% have been achieved (based on
starting epoxide) for (242; R = alkyl, X = Br or I) and cyclic a-halogeno-
ketones. Trialkylsilyl triflate (240; X = OS02CF3) promotes the ring-opening
of oxirans and affords allylic alcohol silyl ethers from tetra-, tri-, and 2,2-
di-substituted oxirans; thus cyclohexene oxide gives (243).'78
3 Aziridines
Preparation. - Direct Insertion. Ethoxycarbonylnitrene (EtOOCN:), gener-
ated by the Et3N-induced a-elimination of 4-N02C6H4S03NHCOOEt,adds
to vinyl chlorides to give aziridines without appreciable contamination by
insertion prod~cts."~The reaction is stereospecific; thus the addition to
(244) gives (245), and the a-chloro-aziridines undergo facile rearrangements
to alkenylamines, e.g. (246).
G. C. An d r e w, T. C. Crawford, and L. G. Contillo, Tetrahedron Lett., 1981, 2 2 ,

3803.
177
J. N. Denis and A. Krief, Tetrahedron Lett., 1981, 2 2 , 1429.
17' S. Murata, M. Suzuki, and R. Noyori, Bull. Chem. SOC.Jpn., 1982, 5 5 , 247.
17' L. Pellacani, F. Persia, and P. A. Tardella, Tetrahedron Lett., 1980, 21, 4967.
COOEt c1
I
pr+pr
c1 Bu H Bu
(244) (245)
On treatment with Pb(OAc)4 in CHC13, the quinazolone derivative (247)

gives (248) stereospecifically, and in good yield, via N-nitrene addition.'" The
stereochemistry of these reactions may be explained in terms of a non-
concerted electrophilic addition of nitrene to the double-bond through a
seven-membered transition state (249). Oxidation, with Pb(OAc), , of
R' ONH2 18' and of RSNH2 lB2 has afforded nitrenes, which add to alkenes to
produce the corresponding aziridines, e.g. (250; R' = Et, Pr", Pr', Bun, Bu',
or Bus; R2 = R3 = R5 = Me, or R2 = R3 = R4 = Me, R5 = H, or R2 = R4 =
Me, R3 = R5 = H, or R2 = R5 = Me, R3 = R4 = H) and [251; R = 2,4-
(N02)2C6H3].Sulphenyl-aziridines, e.g. (252), have been produced by irradi-
ation of N S F in the presence of perfluor~propene.'~~
1
"\-&;:
R N
I
Fw:3
F N
I
SR OR SNSF2
(252)
180
R. S. Atkinson, J . R. Malpass, K. L. Skinner, and K. L. Woodthorpe, J. Chem. SOC.,
Chem. Commun., 1981, 549.
B. V. Ioffe and Yu. P. Artsybasheva, Zh. Org. Khim.,1981, 1 7 , 91 1.
R. S. Atkinson and B. D. Judkins, J. Chem. SOC.,Perkin Trans. I , 1981, 261 5.
lS3 W. Bludssus and R. Mews, Chem. Ber., 1981, 114, 1539.
42 Heterocyclic Ch emistry
Preparation by Cyclization Reactions. A new route to 2-cyano-aziridineshas

been developed, using the reaction of 2-chloro-ketimines with KCN in
methanol.lW Initial nucleophilic attack by cyanide ion on (253; R = Pr', But ,
or cyclohexyl) gives (254), which is followed by cyclization to form (255)
(73-88%). A convenient two-step synthesis of 2-cyano-aziridines has also
been reported in which (256; R = Ph, halogenophenyl, 4-MeC6H4, or
4-MeOC6H4) is cyclized t o (257), using NaOH and the phase-transfer catalyst
PhCH2NEti Cl-.ls5 The compounds (256) were synthesized by the reaction
of the appropriate aromatic amine with CH2CC1(CN), using CU(OAC)~ cata-
lyst.
0
\
iii
J
\ N
X N BHr R
R
(258)
Reagents: i, LiAIH, ;ii, Ph,P, Br, ;iii, RNH, ;iv, BuLi
Scheme 15
An jmproved synthesis of the N-substituted isopropylideneaziridines (258;
R = Pr', But, neopentyl, cyclopropyl, Ph, or 1-adamantyl) is shown in
Scheme 15.lS6
A method for the preparation of 2-bromo-amines, which are precursors for
synthesis of aziridines, has been reported in which DBPA (259) reacts with
styrene or with (E)- or (2)-1-phenylpropene to yield (260; R = H or Me),
which with HCl in benzene give 2-bromo-amine hydrochlorides (261) in
reasonable overall yields.'"
R 0
184
N. DeKimpe, L. Moens, R. Verhe, L. DeBuyck, and N. Schamp, J. Chern. SOC.,Chem.
Commun., 1982, 19.
S. A. Rao, A. Kumar, H. Ila, and H. Junjappa, Synrhesis, 1981, 623.
J . B. P. A. Wijnberg, P. G . Wiering, and H. Steinberg, Synthesis, 1981, 901.
S. Zawadzki and A. Zwierzak, Tetrahedron, 1981, 37, 2 6 7 5 .
F? O Y N R 2
R1 R2 T-7
N
R2 hR1
Preparation by Ring-contraction. The phot ofragment ation of oxazolidines,
e.g. (262; R' = H or Ph, R2 = aryl), provides a new route to aziridines.'"
The reaction proceeds via the elimination of an aldehyde.
The vinyl azides [263; R1 = Me, R2 = Ph; R' = H, R2 = Bun; R' = But,
R2 = H; or R'R2 = (CH,),], on treatment with dimethylsulphoxonium ylide,
give the vinyltriazolines (264) (89-95%).ls9 Flash vacuum pyrolysis of (264)
gave the vinylaziridines (265) (91-94%).
Preparation of Chiral Aziridines. Asymmetric chlorination of the nitrogen
atom of aziridines has been achieved, using Bu'OCl, in the presence of opti-
cally active trifluoromethylcarbinols, as chiral solvating agents.'" Thus (266;
R' = COOEt or Ph, R2 = H) with Bu*OCl in the presence of (+)-(S)-
PhCH(OH)CF3 in CH2C12, at - 60°C, for 3 hours gave chiral (266; R' =
COOEt or Ph, R2 = Cl). Aziridines of opposite chirality were generated by
using (-)-(R)-(C H7)CH(0H)C F 3 .
The aziridinecarboxylic acid (267) has been prepared and resolved, using
PhMeCHNH2.'"
Spectral and Theoretical Studies of Azkidines. Optically active 2-alkyl-

aziridines (268; R' = H or Me, R2 = Me, Prl, or Bu') have been prepared from
their corresponding L-amino-acids and their chiroptical properties recorded.'%
From their 0.r.d. and c.d. spectra it was concluded that a negative Cotton
"' 0. Tsuge, K. Oe, and N . Kawaguchi, Chem. Lett., 1981, 1585.

A. Hassner, B. A. Belinka, M . Haber, and P. Munger, Tetrahedron Lett., 1981, 2 2 ,
1863.
A. Forni, I. Moretti, A. V. Rosyanik, and G. Torre, J . Chem. Soc., Chem. Commun.,
1981, 588.
l p 1 R. G . Kostyanovskii, G. K. Kadorkina, G . V. Shustov, I. I. Chervin, S. S. Nasibov, and
S.V . Var\amov, Izv. Akad. Nauk SSSR, Ser. Khim., 1982, 145.
192 L. Maat and R,W. Wulkan, R e d . Trav. Chim. Pays-Bas, 1981, 100, 204.
effect at 200nm was connected with a cis orientation of the lone pair on
nitrogen with the 2-alkyl substituent. Circular dichroism spectra have also
been reported for benzoylaziridines, allowing configurations to be derived.lg3
The I3C chemical shifts of the unsubstituted carbon in the ring of (268;
R' = H; R2 = H, Me, Et, CONH2, CONHNH2, CH2NH2,CN, or COOMe) and
of 2,2-dimethylaziridine have been correlated with the "N shifts.'% The 15N
shifts were also correlated to Taft inductive and steric constants.
The proton-accepting abilities of cis(269; R' = H, Me, or PhCH,; R2 = H
or NO2) and of trans-(269; R' = H, Me, or PhCH2; R2 = H, Br, or NO2) have
been estimated, using the i.r. spectral shifts that are induced by these aziri-
dines is phenol, 4-bromophenol, and trichloroacetic acid.lg5 The cis-isomers
reacted with all three proton donors but trans-isomers only with CC13COOH.
The absence of complexation for the trans-isomers was attributed to intra-
molecular hydrogen-bonding (when R' is H) and to steric hindrance when
R' is Me or PhCH2.
Two theoretical studies on the structure of aziridine have been published,
one relating to the effect of hyperconjugation on the barriers to the inversion
of nitrogen" and the other to the structures of aziridine-enarnine~."~The
reaction by which (270; R = H, Me, or NH2) are hydrolysed to cis- and to
trans-(27 1) has been subjected to ab initio calculations.198Theoretical predic-
tions have been found to agree with experimental results.
Reactions of Aziridines. - Thermal. Thermolysis of (272; R', R2, R3 = H or
Me) gave (274) and R'CH=CR2R3 (R' and R3 are cis) via the intermediate
(27 3).
(272) (273)
lg3 J . M. J. Tronchet, E. Winter-Mihaly, M. A. M. Massoud,and J. Guist, Helv. Chim. Acta,
1981, 64, 2350.
E. Liepins, I. Kalvins, and P. T. Trapentsier, Khim. Geterotsikl. Soedin., 1981, 1231.
lg5 v. D. Orlov, F. G. Yaremenko, N. V. Lishtvan, and Yu. N. Surov, Khim. Gererotsikl.
Soedin., 1981, 1641.
'91 D. Kost and M. Raban,J. Am. Chem. SOC.,1982,104, 2960.
197 K. Mueller and F. Previdoli, Helv. Chim. Acta, 1981, 64, 2508.
A. M. Sapse, Int. J. Quantum Chem., Quanrum Biol. Symp., 1980, 7, 155.
199 H. G. Zoch, E. Kinzel, and G. Szeimies,Chem. Ber., 1981, 114, 968.
The vinylaziridine (27 5) underwent ring-expansion in refluxing toluene

to give (276).200The mechanism involves a [3,3]-sigmatropic shift.
Ring-opening to Acyclic Compounds. The aziridines (277; R1,R2 = B u t ,
1-adamantyl) undergo selective cleavage with 2-lithio-1,3-dithian to give
the respective compounds (278).201
The A1C13-catalysed addition of 14C-labelled (279; R = Br) to benzene
gives (280) with the label almost exclusively in the position shown.202 The
mechanism proposed for this conversion involves a primary route via the
intermediate (279; R = Ph).
vo
R1
I
R2
RcH23 S02Ph
*
Ph 2CHCH2CH2NHS02Ph
(280 1
(277)
The ring-opening of aziridines by fluorinating agents yields a,P-difluoro-

amines. The stereochemistry of opening can be controlled by the correct
choice of reagent, e.g. anhydrous HF, Olah's reagent, or Et,N.nHF (n = 2,
2.5, or 3).203 Thus (281) with anhydrous HF gives (282) (100%) whereas
(283) (92%) is formed with Olah's reagent.
zoo H. P. Figeys and R. Jammar, Tetrahedron Lett., 1981, 2 2 , 637.

'01 E. R. Talaty, A. R. Clague, J . M. Behrens, M. 0. Agho, D. H. Burger, T. L.
Hendrixson, K. M. Korst, T. T. Khanh, R. A. Kell, and N. Dibaji, Synth. Commun.,
1981, 11,455.
202 W. J . Kensler and S. K. Dheer, J. Org. Chem., 1981,46,4051.
203 G. M. Alvernhe, C. M. Ennakoua, S. M. Lacombe, and A. J . Laurent, J. Org. Chem.,
1981.46,4938.
Electrochemical oxidation of N-acetyl- and N-formyl-aziridine in methanol
at a platinum anode afforded MeCONHCH2CH20Meand HCONHCH2CH2CH-
(OMe)2 respectively; no cyclic products were obtained.2w The polarographic
behaviour of aziridinium salts (284; R = Ph, 4-MeC&, or 3- or 4-BrC6H4) in
water has been reported.205
4-RC6H4S02
(284 1
( 285 1
Formation of Other Ring Systems. A new synthesis of the azetidines (285;

n = 2; R = H, Me, or C1) has been reported, based on methylene insertion
into the aziridine (285; n = 1 ;R = H, Me, or Cl), using Me2S-OcH2.206
Heating the BF3 adducts of the trans-aziridines (286; R' = 4-Br, 4-C1,
4-Me, H, or %No2; R2 = H, 4-Br, or 4-C1) with MeCN gave the BF3 adducts
of the imidazolidines (287) (62-78%).207 With MeONa, (287) isomerized to
the trans-imidazolidines. The same aziridines (286) were found to condense
with acetone in the presence of Et,N to yield the oxazolidines (288)
(55-80%).208 The reaction of (289; R' = OEt, 4-C1C6H4NH,Ph, or Ph2N)
with R2CH(COOEt), (R2 = Ph or Me) afforded (290) via ring-opening and
subsequent cyclization. 209
N y N M e
Me
'04 2. Blum, M. Malmberg, and K. Nyberg, Acra Chem. Scand., Ser. B , 1981, 3 5 , 739.
'05 D. R. Crist, A. P. Borsetti, and M. B. Kass, J. Heterocycl. Chem., 1981, 18, 991.
U. K. Nadir and V. K. Koul, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 4 1 7 .
207 I. G. Tishchenko, 0. N. Bubel, and V. A. Konovalov, Khim. Geterorsikl. Soedin.,
1981, 952.
208
I. G . Tishchenko, 0. N. Bubel, and V. A. Konovalov, Khim. Gererotsikl. Soedin.,
1981, 38.
209
J. Budny and H. Stamm, Arch. Pharm. (Weinheim, Ger.), 1981, 314,657.
H
II Ph
( 2 9 11 02N
4 Azirines
Preparation. - The reaction of (292) with HN3 in 95% acetic acid at room
temperature gave a mixture of cis- and trans(296) in the ratio 40: 60.211
Heating cis(296) to 45-50°C gave the azirine (297). The amidoxime (298;
R' = 2,4,6-C13C6H2NHC0,R2 = H), prepared from the corresponding nitrile,
has been converted into its 0-tosyl derivative (298; R' = same, R2 =
COOMe
3
MeOOC COOMe NOR^
'
R CH
IICNH
( 296)
210 A. Hassner, R. D'Costa, A. T. McPhail, and W. Butler, Tetrahedron L e t t . , 1981, 2 2 ,
3691.
'11 G. L'abbh, J . P. Dekerk, and P. Van Stappen, Bull. SOC.Chim. Belg., 1981, 90, 1073.
4-MeC6H4S02)and treated with base to yield (299) as the sole

This new variant of the Neber rearrangement provides the first synthesis of
unsubstituted amino-azirines and has also been shown to proceed for the
formation of (299; R' = PhS02).
Kinetic studies have suggested that the thermal isomerization of the isox-
azoles (300; R' = Me, R2 = R3 = H, or R' = NH2, R2 =Me, R3 = H) to
(302) involves the azirines (301) as reaction intermediate^.^'^
Reactions of Azirines. - A number of reactions of azirines leading to five- and
six-membered heterocyclic rings are shown in Scheme 16. Compounds (304)
and (305) are formed by addition of MeNCO or R4R5C=C=S (R4, RS = vari-
ous alkyl groups) to the azirine (303; R' = Ph, R2 = Me, R3 = NMe2).2149215
0: +
(308)
H
( 306) (307)
iii, Li,iv, CH,N,; v, Pd(PPh,),
Reagents: i, MeNCO;ii, R4RsC=C=S,
Scheme 16
212 J. A. Hyatt, J. Org. Chem., 1981, 46, 3953.
'I3 J . D. Perez, G. I. Yranzo, and D. A. Wunderlin, J. Org. Chem., 1982, 47, 982.
214 E. Schaurnann, S. Grabley, and G. Adiwidjaja, Liebigs Ann. Chem., 1981, 264.
21s E. Schaumann, S. Grabley, F. F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs
Ann. Chem., 1981, 277.
The reaction of excess lithium in THF with the chloroazirine (303; R' = C1,
R2 = R3 = Ph) gave a mixture containing (306) (10%) and (307)
and the same azirine, with CH2N2, afforded (308) (10-20%) together with
(303; R' = CH2Cl, R2 = R3 = Ph) (45-50%).217 Palladium(0) compounds
catalyse the conversion of 2-allyl-azirines into pyridines and pyrroles; thus
(303; R' = Me, R2 = CH2CH=CH2, R3 = Ph) with Pd(PPh3)4 gives (309)
(18%) together with (3 10) (20%).2'8
The peroxidation of (303; R' = R2 = H, R3 = Ph), using 3-C1C6H4C03H

in chlorobenzene, gave PhCON=CH2, and not an o x a b i c y ~ l o b u t a n e . ~The
'~
aziridiniminium salt (31 1) was formed quantitatively at - 60°C by the
reaction of Ph3C+ BF; with (303; R' = R2 = Me, R3 = NMe2) in CH2C12.220
Using Et4N' CN-, at - 50 O C , the anion attacked the first-formed (31 1) to
yield the aziridine (3 12).
A theoretical approach t o the photochemical ring-opening reactions of
azirines has been published.221
5 Thiirans
Preparation. - The syntheses of silylated thiirans from silyl ketones have been
reported.222 Anhydrous HC1 and then H2S were bubbled through a solution
of (313; X = 0, R' = H or Me) in diethyl ether at - 20°C; subsequent
chromatography under N2 afforded (313; X = S), which, used as the crude
material, was allowed t o react with (4-R2C6H4)2CN2(R2 = H or MeO) t o
yield (3 14) with overall yield 70-90%.
T. C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2905.

217 T, C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2909.
'18 T. Izumi and H. Alper, Organometallics (Washington, D . C . ) , 1982, 1, 322.
219 A. Hassner, B. A. Belinka, and A. S. Steinfield, Heterocycles, 1982, 18, 179.
220
C. Bernard-Henriet, P. Hoet, L. Ghosez, and R. Touillaux, Tetrahedron Lett., 1981,
2 2 , 4 7 1 7.
221 S. Kato and K. Morokuma, Chem. Lett., 1981, 1021.
222
B. F. Bonini, G. Mazzanti, S. Sarti, P. Zanirato, and G. Maccagnani, J. Chem. SOC.,
Chem. Commun., 1981, 822.
The thiazolidine (315; X = S ) has been synthesized and found to be an.
effective sulphur-transfer reagent for the conversion of oxirans into
t h i i r a n ~ .Thus
~ ~ ~ cyclohexene oxide was converted into the corresponding
thiiran quantitatively [and (315; X = S) into (315; X = O)].
The thiiran (318), of interest for the synthesis of radialene, has been pre-
pared from (316; X = 0) by conversion into (316; X = N2HTs) and pyrolysis
of its lithium salt.224The reaction is believed to proceed through the bicyclic
sulphur ylide (3 17).
a;>*
>K-c I
H H
(316 1
+
( 317)
A&
S
(318)
(315)
A 4n-electrocyclization route to (323) is shown in Scheme 17.'" The

initial adduct (321) between (319; NR2 = morpholino, pyrrolidino, or
piperidino) and a -bromoacetophenone (320) yields a transient carbonyl-
thiocarbonyl ylide (322), which undergoes electrocyclization to the thiiran
product (323).
"""&
Ph
~ mJ
(320)
Ph -A2N>d73_ph
Ph
Br- 0
(319)
Ph
-"~h?iPh 0
(322 (323)
Scheme 17
Reactions of Thiirans. - The gas-phase thermolysis of thiiran 1-oxide (324)

has been investigated by field-ionization m.s. at 1043-1404 K.226 The
decomposition of (324) proceeds via extrusion of 0 (to form thiiran) or of
SO (to give ethene) and by rearrangement to 1,2-oxathietan (325). Intermedi-
ate (325) is also involved in the fragmentation of (326). Deuterium labelling
223 R. C. Cambie, G. D. Mayer, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,
224 W. Ando, Y. Haniu, and T. Takata, Tetrahedron Lett., 1981,2 2 , 4815.
225 A. Corsaro, M. Tarantello, and G. Purrello, Tetrahedron Lett., 1981,2 2 , 3 3 0 5 .
226 L. Carlsen and H. Egsgaard, J. Chem. SOC.,Perkin Trans. 2, 1982,279.
7%ree-Membered Ring Sys tems 51
has been used to show that pyrolysis of (324) to ethene in both gas and liquid
phases proceeds with more than 90% retention of ~tereochemistry.2~’The
results suggest that there is a possible contribution from a biradical mechan-
ism in this reaction.
The complex RhCl(PPh3)3 reacts with stilbene episulphoxide in CH2C12to
yield a dimeric complex (327) with sulphur monoxide ligand.228
Ion cyclotron resonance has been used to study the ion chemistry of
~ ’ main reaction of the molecular ion of thiiran
thiiran and a ~ i r i d i n e . ~The
with neutral molecules is transfer of sulphur.
The Chemistry of Thiiranium Ions. - The chemistry of episulphonium ions
and the reactions of alkenes with sulphenyl derivatives have been reviewed.230
Stable thiiranium and thiirenium chlorides have been generated in SO2.231
Kinetic studies for the quantitative generation of (329; R’ = R2 = But,
X = C1) from the ionization of (328) and the equilibrium between (330) and
(331) in SO2 were followed, using n.m.r. spectrometry. Compounds (329;
R1 = But , X = SbC15 or BF4) have been isolated as stable salts at room tem-
per atwe. 232
R1
yR2 I x-
c1 SMe .sc I c1-
6 Thiirens
Photolysis of the argon-matrix-isolated thiadiazole (332) at 265 nm gave the
thiiren (334) via the intermediate (333).233
Electrochemical reduction of (335) at - 1.8 V, followed by methylation,
affords trans-stilbene (40%) and (336) (27%).234Similar reduction of (337)
produces mainly diphenylacetylene (80%) with benzil (10%).
227
W. G. L. Aalbersberg and K. P. C. Vollhardt, Isr. J. Chem., 1981, 21, 145.
228 K. S. Arulsamy, K. K. Pandey, and U . C. Agarwala, Inorg. Chim. Acra, 1981, 54,
L51.
2 2 9 G. Baykut, K. P. Wanczek, and H. Hartmann, Dyn. Mass Spectrom., 1981, 6 , 269.
”O V. A. Smit, N. S. Zefirov, and I. V. Bodrikov, Org. Sulfur Chem., Invited Lecr. Int.
Symp., 9th. 1980, (publ. 1981), 159.
231 V. Lucchini, G . Modena, T. Zaupa, and G. Capozzi, J . Org. Chem., 1982,47, 590.
232 V. Lucchini, G . Modena, G. Valle, and G . Capozzi, J. Org. Chem., 1981, 46,4720.
”’ M. Torres and 0. P. Strausz, Nouv. J. Chim., 1 9 8 0 , 4 , 703.
234 A . J . Fry, K. Ankner, and V. K. Handa, J. Chem. SOC., Chem. Commun., 1981, 120.
Me CO COMe Ph
5
Me
(334)
02
(332) (333) ( 335 1
Ph
yPh
phuso2ph
7 Diaziridines
Photolysis of the tetrazolones (338; R = P i or Me) in MeCN or pentane gave
the corresponding diaziridinone (339).235Photolysis of (340) gave (341) in a
process which is thermally reversible.236
,-y
N- RN-NMe
..,YNRK 0
0
4 - MeC6H4
The guanidines [342; X = Ts, P(O)(OPh),, P(O)(OEt),, or CN] afforded

the diaziridinimines (343) (57-85%) on sequential treatment with Bu’OCl
and But
(342)
(343)
Preparative separations or enrichments of the enantiomers of (344) and

(345) have been achieved by liquid chromatography on triacetylcellulose.238
Almost pure (+)-(344) and (+)-(345) were isolated.
The mass spectra of (346) and related compounds have been reported.239
’” H. Quast and L. Bieber, Chem. Ber., 1981,114,3235.
236 G.Tomaschewski, U. Klein, and G. Geissler, Tetrahedron Lett., 1980,21,4877.
237 G. L’abbk, A. Verbruggen, T. Minami, and S. Toppet, J. Org. Chem., 1981,46,4478.
13’ M. Mintas, A. Mannschreck, and L. Klasinc, Tetrahedron, 1981,37, 867.
239 M. Mintas and K. K. Mayer, Org. MarsSpectrom., 1980, 15, 596.
8 Diazirines
The direct preparation of (347; X = C1 or Br, R = various alkyl or aryl
groups) from the reaction of NaOCl (or NaOBr) with amidines or isoureas in
aqueous DMSO solution was first reported by Graham.240The reaction mech-
anism has been investigated and shown to proceed through initial
N-halogenation; e.g. , (348) from RC(NH)NH2 (R = Pr' or MeO)?41 A sub-
sequent reaction of (348) leads to (347; R = Pr' or MeO, X = C1) via (349)
and the intermediate tight ion-pair (350). The highly explosive (347; R = Ph,
X = C1) has been prepared and used as a source of chl~rophenylcarbene.~~~
Treatment of R2C=NOTs ( R = M e , CF3, COOMe, COOEt, or Ph) with
R'ONH2 (R' = Me, PhCH2, or Et) affords a single-step synthesis of the
diazirines (347; X = R).243
-.
ClN=CRNHCl
N-NC1
/p 1 c1-
R X R LA J
Thermal decomposition of (347; X = C1, R = CF3) produces (trifluoro-

methyl)chlorocarbene, which, in the presence of cyclic dienes, gives ring-
expanded products.244 Thus pyrrole and cyclopentadiene, on treatment with
this diazirine, give (351) (35%) and (352) (23%) respectively. The selectivity
for the reaction of CF3ClC: (generated by this method) with alkenes has been
reported.%' Additions to cis- and to trans-butenes were stereospecific.
(351) (352)
240 W. H. Graham, J. A m . Chem. SOC., 1965,87,4396.
241 R. A. Moss, J . Wlostowska, W. Guo, M. Fedorynski, J . P. Springer, and J . M.
Hirshfield, J. Org. Chem., 1981,46,5048.
242
A. Padwa, M. J . Pulwer, and T. J. Blacklock, Org. Synth., 1981, 60, 53.
243 G. V. Shustov, N. B. Tavakalyan, A. P. Pleshkova, and R. G . Kostyanovskii, Khim.
Geterotsikl. Soedin., 1 98 1, 810.
244
Y. Kobayashi, T. Nakano, H. Iwasaki, and 1. Kumadaki, J. Fluorine Chern., 1981,
18, 533.
2 4 5 R. A. Moss, W. Guo, D. Z. Denney, K. N. Houk, and N. G . Rondam, J. A m . Chem.
SOC.,1981,103, 6164.
Two theoretical treatments of diazirine chemistry have been published,
one dealing with gas-phase photolysis of (347; X = C1, R = Me)246and the
other with the valence-ionization spectra of diazirine (and of dioxiran, cyclo-
propene, and thiiran)."
9 Dioxirans
The evidence for the existence of dioxirans as intermediates in chemical
reactions has been briefly reviewed.248The dioxiran (354) is an intermediate
in the tetraphenylporphyrin-sensitized photo-oxygenation of (353), which is
quantitatively converted into (3 5 5).249
The unimolecular symmetrical ring-cleavage of dioxiran, leading to the
-OCH20.diradical, has been investigated, using ab initio CI calculations.250
0-0
MeCOCH=CHCOOSiMe3
HOK ' O(353)

Me H =1C H C O M e
M e 3 x( C354 (355)
10 Oxaziridines
An improved synthesis of 2-sulphonyloxaziridines has been reported.251Oxi-
dation of (356; R' = Ph, R2 = 3-NO2; R' = Ph, R2 = 4-NO2; R' = Me,
R2 = H; or R1 = PhCH2, R2 = H) by 3-C1C6H4CO3Hin the presence of a
phase-transfer catalyst gives (357) (80-90%). These compounds epoxidize
alkenes in good yield and with retention of stereochemistry; thus trans-
stilbene with (356; R' = Ph, R2 = 4-NO2) gave the trans-stilbene oxide
(95%). 252 H
R'SO~N=CHC~H~R
2
( 356 1
(357)
R2
The photochemical electrocyclic reaction of CH2N=0 to form oxaziridine

has been explored on the basis of the potential-energy surfaces that are
obtained by MIND0/3 CI calculations.253
The reactions of oxaziridines with nucleophilic reagents have been
246 R. Becerra, J . M. Figuera, V. Menendez, A. Tobar, and R. Marinez-Utrilla, An. Quim.,

Ser. A , 1981, 77, 63.
14' W. Von Niessen, W. P. Kraemer, and J . Schirmer, J . Chem. SOC.. Faraday Trans. 2 ,
1981, 77, 1461.
14' W. Adam and R. Curci, Chim. Ind. (Milan), 1981, 6 3 , 20.
14' W. Adam and A. Rodriguez, Tetrahedron Lett., 1981, 2 2 , 3505.
R. Cimiraglia, T. K. Ha, R. Meyer, and H. H. Guenthard, Chem. Phys., 1982, 66, 209.
15' F. A. Davis and 0. D. Stringer, J. Org. Chem., 1982, 47, 1774.
252 F. A. Davis, N. F. Abdul-Malik, S. B. Awad, and M. E. Harakal, Tetrahedron Lett.,
1981, 22, 917.
253 0. Kikuchi, K. Morihashi, and K. Suzuki, Bull. Chem. SOC.Jpn., 1982, 55, 11 33.
Three-Membered Ring Sys terns 55
reviewed.254Attack by amines induces the fragmentation of (358) into (359)

and (360).255The mechanism for this reaction involves the removal of a
proton that is (Y to the nitrogen by base, and not nucleophilic attack at the
nitrogen.
OH
(361)
Iron(I1) sulphate cleaves oxaziridine rings and, in the case of (36 1 ; X = Hz

or 0; R' = But or Ph; R2 = Me, Et, or Ph), it causes a double ring-opening to
yield (362).256
254 Y. Hata, Yuki Gosei Kagaku Kyokaishi, 1981,39, 952.

255 W.H. Rastetter, W. R. Wagner, and M. A. Findeis, J. Org. Chem., 1982,47,419.
256 D. St. C. Black and L. M. Johnstone, Angew. Chem., Inr. Ed. Engl., 1981, 2 0 , 669.
2
Four-Membered Ring Systems
BY T. V. LEE
1 Highlights and Reviews

A review on the synthesis of the carbopenam antibiotics has appeared.’ The
1-azabicyclo[2.1.O]pentane skeleton has been reported this year,415as is the
first readily performed displacement of 4-acetoxyazetidinone with enolate
anion equivalent^.^' Most notable, however, is the preparation and utilization
of a series of 1,2-diazetidinium y l i d e ~ ?which
~ appear to have great potential
in heterocyclic synthesis. The one ‘missing” cyclo-adduct of singlet oxygen
and cycloheptatriene has now been as has the first, highly
unstable, benzodithiet .55
2 Systems containing One Nitrogen Atom

Azetidines and Azetines. - A new synthesis of azetidine, allowing its prepar-
ation on a large scale, has been described.2 The new method involves the
addition of sodium azide t o acrolein and reduction of the addition product to
3-azidopropanol (l), whose reaction with triphenylphosphine, followed by
distillation, gave azetidine in 30% yield.
An improved preparation of 3,3-dimethylazetidine has also been reported,
permitting the rate of formation of the enamine (2) to be ~ t u d i e d . ~
Me
H 2C =CHCHO -NaN3
N 3 ( C H 2 ) 30H 3
Meb
NaBH4
(1)
distil
0
1-Azabicyclo[2.1.01pentanes (3) can be readily prepared by the reaction
of methyl a-bromoacrylate and imine anions as shown in Scheme 1.4 The
elimination of bromide from the anion (4) has been suggested as the pathway
’ T. Kametani, Heterocycles, 1982, 17 (Special Issue), 463.
J. Smuskovicz, M . P. Kane, L. G. Laurian, C. G. Chichester, and T. A. Scahill, J. Org.
Chem., 1981,46, 3562.
H. W. Thompson and J. Swistok, J. Org. Chem., 1981,46,4907.
B. Fouchet. M. Joucla. and J . Hamelin, Terrahedron L e t t . , 1981, 22, 3397.
57
Me
I
PhCH=NCCOOMe
I
Li
+
Me OK7hMe
Ph I
COOMe
Li
(4)
Scheme 1
by which the reaction proceeds. The same skeleton has been described in the
patent literature.'
a-Keto-azetidines (5) are formed by the photolysis of 2-aminocyclo-
hexanones6 and the new, interesting heterocycle (6) has been prepared and
its X-ray structure r e p ~ r t e d . ~
0
Ph
Azetidinones. - This section only includes novel results on the preparation or

reactions of the azetidinone nucleus. The chemistry of p-lactam antibiotics is
not included.
Readily available azetidine-2-carboxylic acid or the corresponding esters
provide the starting point for a new approach to azetidin-2-ones, involving an
oxidative decarboxylation. For example, the reaction of the enamino
0-silylated keten acetal(7) (Scheme 2) with singlet oxygen gives the azetidin-
2-one (8).8 The same authors have applied three of their previous syntheses of
azetidinone to the total synthesis of (+)-3-aminocardicinic acid.g
By a mixture of chemical and enzymatic methods, Japanese workers have
succeeded in preparing (S)- and (R)-4-methoxycarbonylmethylazetidin-2-one
(1 2) and (1 1). As shown in Scheme 3 , treatment of dimethyl P-aminoglutarate
(9) with pig liver esterase gave the half ester (lo), which, upon cyclization,
afforded the (R)-azetidinone ( 1 1). Thus the esterase cleaves the p r o 8 methyl
ester group selectively. Alternatively, protection of the free amino-group in
(9) results in selective cleavage of the pro-R methyl group and eventual
Meija Seika Kaishi Ltd, Jpn. Kokai Tokkyo Koho 81 3 9 0 6 4 (Chern. Abstr., 1981,
9 5 , 11 5 258u).
J . C. Arnold, J . Cossy,and J . P. Pete, Tetrahedron, 1981, 37, 1921.
E. E. Glover, D. J. Pointer, J. B. Wilford, and M . Elder, J. Chern. SOC., Chern.
Cornrnun., 1981,481.
H. H. Wasserman, B. H. Lipshutz, A. W. Tremper, and J . S. Wu, J. Org. Chem., 1981,
46, 2991.
H. H. Wasserman, C. J . Hlasta, A. W. Tremper, and J . S. Wu, J . Org. Chern., 1981, 46,
2999.
Four-Membered Ring Systems 59
r
i,ii
___)
(8)
Reagents: i, lithium di-isopropylamide; ii, Me, Bu'SiCl; iii, singlet oxygen.

Scheme 2
(9)
1
0
iii
PhCH20y
I
H2N H H
I
\j
i,iv H 2y/L'~~I
HOOC COOMe
(12) (S)
Reagents: i, pig liver esterase; ii, Ph,P, PySSPy, MeCN; iii, ClCOOCH,Ph, Et,N; iv, H,,
Pd/C.
Scheme 3
formation of the (S)-azetidinone (1 2)." The condensing agent that was used
in these cyclizations is itself novel," and is potentially very useful.
A Reformatsky type of reaction has been utilized in a novel route to
0-lactams, by allowing carbodi-imides and a-bromo-esters to react in the pres-
ence of zinc metal.12 Cyanuric chloride has been shown to activate the
la
M. Ohno, S. Kobayashi, T. Iimori, Y-F. Wang, and T. Izawa, J. Am. Chem. Suc.,
1981,103,2405.
'l
S. Kobayashi, T. Iimori, T. Izawa, and M. Ohno, J. Am. Chem. SOC.,
1981, 303, 2406.
'' K. Piotrowska and D. Mostowicz, J. Chem. Soc., Chem. Commun., 1981, 41.
stereospecific formation of cis-azetidinones from carboxylic acids and
imines.13 The same transformation can also be achieved by using NN-bis-
(2-0x0-3-oxazolidiny1)phosphorodiamidic ch10ride.l~
Phase-transfer catalysis has become highly useful in the synthesis of
azetidinones. It facilitates the one-pot synthesis of azetidinones from
a-amino-acids and acid chlorides such as (13)." It also promotes the reaction
of P-amino-acids and methanesulphonyl chloride to form azetidinones. l6
The reaction of 0-silylated keten acetals and benzyl N-chloromethyl-
carbamates (14), in the presence of titanium tetrachloride, results in the for-
mation of a-ureidomethylated carboxylates (15), which are readily converted
Me ,OS i M e COOCH2Ph
I
BrCH2CCOC1
I H2,Pd/C
I + N\Me - - ,
Br base
Me
I
Ha C- NCOOCH2Ph COOMe
Me
C1
(14)
into azetidinones." The known reaction of 0-silylated keten acetals and
imines to form azetidin-2-ones has now been extended to allow the prepar-
ation of P-lactams that bear heteroatom-containing substituents.18
As shown in Scheme 4, a new approach to 3-methylene-azetidin-2-ones has
been described. The reaction of the acrylamide (16) with n-butyl-lithium,
followed by the addition of toluene-4-sulphonyl chloride, gives the
azetidinone (17), in 60% yield.lg In the same paper it is reported that lithum
phenylethynolate reacts with imines (in a highly stereoselective manner) to
form azetidinones, in a promising new approach to functionalized azetibin-
ones.
-om
OH OTs
l$3
0
Reagents: i, 2 equiv. of BunLi, THF, at - 7 8 " C ;ii, toluenep-sulphonyl chloride;

iii, 2 5 " C.
Scheme 4
l3
M. S. Manhas, A. K. Bose, and M. S. Khajavi, Synthesis, 1981, 209.
l4
D. R. Shridar, B. Ram, and V. L. Narayana, Synthesis, 1982,63.
T. Okawara, Y. Noguchi, T. Matsuda, and M. Furukawa, Chem. Lett., 1981, 185.
l6
Y. Watanabe and T. Mukaiyama, Chem. Lett., 1981,443.
l7
K. Ikeda, Y. Terao, and M. Sekiya, Chem. Pharm. Bull., 1981, 29, 1747.
la
I. Ojima, S. Inaba, and M. Nagai, Synthesis, 1981, 545.
R. M. Adlington, A. G. M. Barrett, P. Quayle, A. Walker, and M. J . Betts, J. Chem.
SOC.,Chem. Commun., 1981,404.
The patent literature contains a report of the synthesis of an azetidin-2-one
by cyclization of the iron complex (18), which is derived from the iron ester
complex (19)."
CH,Ph
It has been demonstrated that azetidinones are produced, in good yield, by

the oxidative cyclization of fly-unsaturated amidosulphonyl esters as shown in
Scheme 5.21
Reagents: i, Br, , NaHCO, ; ii, Bun, SnH.

Scheme 5
Another new approach involves the photolysis of a 2-pyridone to form the

bicyclic species (20), ozonolysis of which gives an azetidine that bears a sub-
stituent at C-4.22 Workers at the same laboratory have described an improved
preparation of the intermediate ( 2 1),23 which is the key intermediate in their
synthesis of thienamycin. This route has now been modified to make it an
asymmetric synthesis.24
2o
S. V. Ley and E. M. Hebblethwaite, Eur. Pat. Appl. 38661. (Chem. Abstr., 1982, 96,
181 0642).
21
A. J. Biloski, R. D. Wood, and B. Ganem, J . A m . Chem. SOC.,1982, 104,3233.
22
T. Kametani, T. Mochizuki, and T. Honda, Heterocycles, 1982, 19, 89.
'' T. Kametani, T. Nagahara, Y. Suzuki, S. Yokohoma, S-P. Huang, and M . Ihara, Terra-
hedron, 1981, 37, 715.
24
T. Kametani, T. Nagahara, and M. Ihara, Heterocycles, 1981, 16, 767.
62 Heterocyclic Chemistiy
Some interesting spiro P-lactams (22) are obtained from the reaction of
2-imino-2,5-dihydro-1,3,4-thiadiazoles and ketones.25 The products presum-
ably arise via a [27r + 27r] cycloaddition followed by elimination of a mole-
cule of nitrogen.
Me
Me
$yL NPh + Ph /Aph- -#
Me
Me
(22)
3-Chloro-4-methylsulphinylazetidin-2-ones (23) have been shown to form

highly useful 4-alkoxyazetidinones, stereospecifically, when heated in the
presence of an The intermediate (24)has been proposed, in which
the chlorine substituent directs the incoming nucleophile to the P-face.
0
t
XSMe
0
ic
ROH
clQoR
0
The reaction of 4-acetoxyazetidin-2-one with enolate anions is difficult,

but now a high-yield equivalent has been introduced. This involves the
react ion of 0-silylated enolat es and 4-acet oxy- 1-trimet hylsilyloxyaze t idin-2-
one (25) in the presence of trimethylsilyl trifluoromethane~ulphonate.~~
OSiMe
+ &R2
R1
-
Me S i-OT f F
0
~ NSiMe3
~ O R ~
Tertiary carbanions such as (26) also react with 4-acetoxyazetidinone to give

the carbon-substituted 0-lactam (27).28 The reaction proceeds in high yield,
and the product can be oxidized to a sulphoxide and converted into the 4-
alkylidene derivative by elimination of benzenesulphenic acid .28 Full details
of a cyclization reaction of 4-acetoxyazetidin-2-ones have a~peared.~’
’’ I. Yamamoto, I. Abe, M. Nozawa, J . Motoyoshiya, and H. Gotoh, Synthesis, 1981,
81 3 .
26
M. D. Bachi and A. Gross, J. Chem. SOC.,Chem. Commun., 1981, 959.
21
A. G. M. Barrett and P. Quayle, J . Chem. SOC.,Chem. Commun., 1981, 1076.
C . W, Greengrass and D. W. T. Hoople, Tetrahedron Lett., 1981, 2 2 , 1161.
29
T. Kametani, T. Honda, J . Sasaki, H. Terasawa, and K. Fukumoto, J. Chem. SOC.,
Aminolysis of the azetidin-2-one (28) results, via epoxide opening, in

cleavage of the amide bond to form the pyrrolidinone (29).30The addition of
N-lithio-4-vinylazetidin-2-one to vinyl phosphonates allows ready access to
the carbapenam ring-system.”
3 Systems containing Two Nitrogen Atoms or One Nitrogen

Atom and a Second Heteroatom
In the presence of phosgene, the bis-iminodiazetidine (30) undergoes a ring-
opening reaction to give, it is believed, the unstable guanidine derivative (31),
which cyclizes to a triazine upon addition of an aromatic amine.32
Ph Ph
PhN<l>NPh D C0Cl2
-
Ph Ph
1
(30)
0
Ph Ph
PhN /k NPh
PhNH2 clKNYNKcl
NPh NPh 0
Ph N ANANPh-
Ph (31)
30
S. Kano, S. Shibuya, and T. Ebata, J. Heterocycl. Chem., 1981, 18, 1239.
31
B. Venugopalan, A. B. Hamlet, and T. Durst, Tetrahedron Lerr., 1981, 2 2 , 191.
32
R. Richter and M. Ultich,J. Org. Chem., 1981, 46, 3011.
A short series of papers by Taylor and co-workers has highlighted the syn-
thetic utility of 172-diazetidinium ylides, e.g. (32).33-35 For example, its
reaction with dimethyl acetylenedicarboxylate forms a 1 : 1 cyclo-adduct (33)
at ambient temperature; upon warming, this loses carbon monoxide to form
a 2: 1 cyclo-adduct. The intermediacy of the ylide (34) in this process has
been indicated.33
C/ph
+N4 'Ph COOMe
+ MeOOCCSCCOOMe c
COOMe
0 0
(33)
I
'Ph Ph
COOMe COOMe
N COOMe MeOOC COOMe
As one might expect, the addition of carbanions to the ylide (34) results in
addition to the iminium bond. Similarly, this bond is reduced to form the
diazetidinone (3 5 ) , which displays some interesting chemistry, such as ring-
expansion to an oxadiazine upon treatment with acetic anhydride.33 Conver-
sion of the ylide into 3-oxo-1,2-diazetidinium tosylate (36) is achieved by
using toluene-p-sulphonic acid. Treating the tosylate with a 173-dicarbonyl
compound provides a novel route to p y r a ~ o l e s . ~ ~
Pi
Me C- 0- CMe
0 Me
~i~
(35)
-0Ts + 70% MeOH

Me
0
(36) CH2COOMe
It has now been shown that the products of the [2n + 2n] cycloaddition
of ketimines and sulphur oxides are 172-thiazetidin-3-one 1-oxides (37).36
33
E. C. Taylor, R. J. Clemens, H, M. L. Davies, and N. F. Haley, J. A m . Chem. SOC.,
1981, 103, 7659.
34
E. C. Taylor, H. M. L. Davis, R. J. Clemens, H. Yanagisawa, and N. F. Haley, J. A m .
Chem. SOC., 1981, 1 0 3 , 7 6 6 0 .
35
E. C. Taylor, N. F. Haley, and R. J . Clemens, J. A m . Chem. SOC., 1981, 103, 7743.
36
A. Dondoni, P. Giorgianni, A. Battaglia, and G. D. Andreetti, J. Chem. SOC.,Chem.
Commun., 1981, 3 5 0 .
Furthermore, 1,2:thiazetidine 1-oxides are the products from N-sulphinyl-
sulphonamides and dimethylketen N-phenylimine, and not 1,2,4-
thiadiazetidine 1-oxide, as previously r e p ~ r t e d . ~ ’
p-toly 1
*+s-”/
4 Systems containing Oxygen

Oxetans. - A mechanistic investigation of the reaction of methylthiotri-
methylsilane (38) and oxetan, in the presence of a catalytic amount of zinc
chloride, suggests the involvement of an oxonium cation-methylthiozinc
dichloride ion-pair, resulting in the formation of (3-methy1thiopropoxy)-
trimethylsilane (39).38 A dependence of the stereochemistry of the photo-
addition products of aldehydes and alkenes on the concentration of alkene
has been ~bserved.~’ Additional examples of the known photo-addition of
benzophenone to 2,5-dimethylthiophen to form an oxetan have been
reported4’ and the unusual bis(cyanomethy1ene)oxetan (40) has been
described
+ MeSSiMe3
(38)
ZnC12
f (39)
Me
OSiMe3
Me
Me.+fCHCN
0% CHCN
(40)
(41) a ; R 1 = H , R2= Ph
b ; R 1= P h , R 2 = H
The oxetans (41a) and (41b) have been shown to be the products of the
reaction of benzaldehyde and he~amethylDewarbenzene.~~ An efficient one-
pot synthesis of oxetan from 1,3-diols has been developed this year.43
37
G. L’abbt5, A. van Asch, J-P. Dekerk, and T. Minami, Tetrahedron Lett., 1981, 22,
583.
H. A. Firgo and W. P. Weber, J. Organometal. Chem., 1981, 2 2 2 , 2 0 1 .
39
G. Jones, 11, Z. H. Khalil, and X . T. Phan, Tetrahedron Lett., 1 9 8 1 , 2 2 , 3823.
40
C . Rivas, D. Pacheco, F. Vargas, and J . Ascanio, J. Heterocycl. Chern., 1 9 8 1 , 1 8 , 1 0 6 5 ,
41
Yu. M. Skvortsov, A. G. Mal’kina, A. N. Volkov, B. A. Trofimov, and G. A. Kalabin,
USSR P. 8 5 2 870 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 5 5 1 3 ) .
42
M. A. J. Carless and H. S. Trivedi, J. Chem. SOC.,Chern. Cornrnun., 1981, 9 5 0 .
43
P. Picard, D. Leclercq, J-P. Bats, and J . Moulines, Synthesis, 1 9 8 1 , 5 5 0 .
The ylide (42) is formed when carbon dioxide and dimethyl acetylene-
dicarboxylate react in the presence of a trialkyl phosphite (Scheme 6). The
reaction of (42) with an aromatic aldehyde afforded the furan (43).44
COOMe
(42) (43)
Reagents: i, CO,,ii, (RO),P; iii, ArCHO.

Scheme 6
Amongst the few reported reactions of oxetans is their non-stereospecific

conversion into oxazines when treated with nit rile^^^,^ and the reaction of
the @)-lactone (44) with a Grignard reagent as the key step in a novel syn-
thesis of (R,R)-phytol?’
i
Me
(44)
Dioxetans. - The ‘missing’ cyclo-adduct of cycloheptatriene and singlet oxy-

gen, the 1,2-dioxetan (49, has now been isolated at - 30°C. At ambient
temperature it is rapidly converted into benzaldehyde , suggesting that the
benzaldehyde that is produced in the oxygenation of cycloheptatriene with
singlet oxygen is formed via this intermediate?8 The interesting chemilumin-
escent dioxetan (46) has also been ~repared.~’
0-0 Me
(45) (46)
44
D. V. Griffiths and J . C. Tebby, J. Chem. SOC.,Chem. Commun., 1981,607.
45
T. M. Pavel, Zh. Org. Khim., 1982, 18, 178.
46
0. N. Chernysh and S. I. Yakimovich, Zh. Org. Khim., 1982,18,181.
47
T. Fujisawa, T. Sato, T. Kawara, and K. Ohashi, Tetrahedron Lett., 1981, 22, 4823.
48
W. Adam and H. Rebello, Tetrahedron Lett., 1981,22,3049.
49
H. Nakamura and T. Goto, Heterocycles, 1981,15,1119.
Four-MemberedRing Systems 67
5 Systems containing Sulphur
A novel conversion of chalcones into 2,4-diaryl-thietans has been described,
as shown in Scheme 7. The reaction involves a reductive cyclization of the
phosphorodithioate (47) and proceeds in excellent yields. This and the fact
that the staring chalcones are readily available make this a potentially ver-
satile method.”
-
0
PhCHZCHCPh
0
II i
PhCH-CH2!Ph
I
S,
/p
S’ ‘OEt
,OEt -
ii ,iii
S
II
Reagents: i, (EtO),PSH; ii, NaBH,; iii, NaH.
Scheme 7
The thieten 1,l-dioxide (48) has been prepared by cycloaddition of an

enamine and sulphene at O°C.51 Mild thermolysis causes a ready retrocyclo-
addition to occur. Additional stable .P-sultines have been isolated, by the
reaction of the anion of a sulphoxide with a ketone and cyclization of the
resulting P-hydroxy-sulphoxide with sulphuryl ~hloride.’~Treatment of
2-methylthietan (49) with alumina at 150-350 “C results in the formation
of te trahydrothiophen and but -3-enethiol .53
Previously difficult substitution reactions of 1,3-dithietan 1,1,3,3-

tetroxide (50) are now possible. The formation of the silyl derivative (51)
(see Scheme 8), its conversion into the dithieten (52), followed by the
addition of electrophiles forms the substitution product^.'^ The dithieten
(52) can be considered as the first enol ether of a sulphone. The transient
benzothiet (53) has been prepared by the thermolysis of (54), its structure
having been confirmed by i.r. and photoelectron s p e c t r o s ~ o p y . ~ ~
so
Y. Ueno, L. D. S. Yadav, and M. Okawara, Synthesis, 1981,547.
51
L. N. Koikov, P. B. Terent’ev, and N. S. Kulikov, Zh. Org. Khim., 1981,17, 1087.
52
M. D. Gray, D. R. Russell, D. J . H. Smith, T. Durst, and B. Gimbarzevsky, J. Chem.
SOC.,Perkin Trans. 1 , 1981, 1826.
53
A. K. Yus’kovich, T. A. Danilova, and E. A. Viktorova, Khim. Geterotsikl. Soedin.,
1982,184 (Chem. Abstr., 1982,96,162 455m).
”
U. Rheude and W. Sundermeyer, Chem. Ber., 1981,114,3378.
55
H . Breitenstein, R. Schulz, and A. Schweig, J. Org. Chem., 1982,47, 1979.
68 Heterocyclic chemistry
(50) (51) (52)
( R = SiMe3)
Reagents: i, C,H,SO,SiMe,, Et,N; ii, BunLi; iii, D,O.
Scheme 8
(54) (53)
6 Miscellaneous Four-Membered Rings

This year has seen a notable increase in the work being done under this
category. A study of the gas-phase pyrolysis of silacyclobutanes has been
mades6 and the photoreaction of benzosilacyclobutane with aldehydes and
ketones is reported to form 1:l adducts, but not via a o-silaquinone
methide ."
Irradiation of the silyl-substituted alkyne ( 5 9 , as shown in Scheme 9,
results in the formation of the disilacyclobutane (56), indicating the transient
formation of a silicon-carbon doubly bonded intermediate.58 The compound
(56) is uncharacteristically stable to atmospheric oxygen but it does react
with stronger oxidants, such as m-chloroperoxybenzoic acid, to form a
Ph
RC'C-8i-R
I
Ph
- i
R2C=C=SiPh
2-
R2C.792
Ph,2 Si--SiPh2
ii -R2Cy
Ph2Si
fR2
iPh 2
(55) ( H = SiMe3) (56)
(57)
Reagents: i, h v ; ii, rn-chloroperoxybenzoic acid.

Scheme 9
disilacyclopentane (57).58 Furthermore, disilacyclobutanes are the major pro-
ducts that are formed by treating bromotrisilylmethanes, such as (58), with
alkyl-lithi~ms.~~The silaethene (59) was suggested as an intermediate. A
56
N. Auner and J . Grobe, J. Organometal. Chem., 1 9 8 1 , 2 2 2 , 33.
57
R. Okazaki, K-T. Kang, and N. Inamoto, Tetrahedron Lert., 1 9 8 1 , 2 2 , 2 3 5 .
M. Ishikawa, D. Kovar, T. Fuchikama, K. Nishimura, M. Kumada, T. Higuchi, and
S. Miyamoto, J. A m . Chem. Soc., 1981, 103, 2324.
59
N. Wiberg, G. Preiner, and 0. Schieda, Chem. Ber., 1981, 114, 2087.
SiMeg
I
Me2Si-C( SiMe3)2
I I Me2Si=C(SiMe3)2
Br Br (59)
(581 I
SiMeg
(60)
silicon-containing bicyclo[ l.l.O]butane (60) has now been prepared and its
structure confirmed by X-ray analysis.60
Scheme 10 shows the preparation of the first isolable example of a new
heterocyclic ring-system, namely the 3-silaoxetan (6 1).61
Me Me
Ph
Ph2CHC1 -*
(61)
Reagents: i, Mg; ii, Me,SiCl, ;iii, N-bromosuccinimide; iv, H,O.
Scheme 10
A novel preparation of a 4-bromophosphetan (62) has been described; it
proceeds by the reaction of l-bromo-3,3-dimethylbut-l-ene with phenyl-
phosphorous dichloride in the presence of aluminium chloride, and sub-
sequent reduction of the oxide.62
Me
I
Me- CCH=CHBr Me Me
I
Me
+ Me Me
PhPC 1 Me Ph
The short-lived phosphene (63) yields the oxaphosphetan (64) upon

+
[27r 27r] cycloaddition with ap-unsaturated ketones.63 The reaction of
sodium phenylacetylide with tellurium metal forms a 1,3-ditelluretan and not,
as had previously been reported, a 1,3-ditellurole.@
Ph Ph
Ph
I /Ph
O=P=C
'
P
h
CI H = C H R ~
(63)
(64)
6o
G . Fritz, S. Wartanessian, E. Matern, W. Honle, and H. G . von Schnering, 2. Anorg.
Allg. Chem., 1981,475,8 7 .
61
J. V. Swisher, J. Perman, P. D. Weiss, and J . R. Ropchan, J. Organometal. Chem.,
1981, 215,373.
Mazhar-ul-Haque, W. Horne, S. E. Cremer, P. W. Kremer, and P. K. Kafarski, J. Chem.
SOC.,Perkin Trans 2,1981,1138.
63
M. Regitz and H. Eckes, Tetrahedron, 1981, 37, 1039.
64
S.L. Bender, N. F. Haley, and H. R. Luss, Tetrahedron Lett., 1981, 22, 1495.
3
Five-Membered Ring Systems
~~~ ~~~ ~~
BY G. V. BOYD, S. GRONOWITZ, 0. GUILLOTON & H. QUINIOU
PART I: Thiophens and their Selenium and Tellurium Analogues

by S. Gronowitz
1 General
Useful reviews on redox transformations of thiophen derivatives (1 79
references),' on the stereochemistry of carbonyl derivatives of five-membered
heterocycles (257 references): on synthetic approaches to dihydrothiophens
(1 35 reference^),^ and on biosteric thiophens4 have been published. Aspects
of thiophen chemistry have been treated in reviews on the synthesis of
+
heterocycles by thermal [2 21 cycloaddition reactions of acetylenes' and
on aspects and perspectives of organic heterocyclic A review
comparing the chemistry of thieno [2,3-b]- and thieno [3,2-b]-thiophen with
that of benzo [ b ]thiophen and quinoline has been published.8 In Advances in
HeterocycZic Chemistry, the development of benzo [ b ]thiophen from 1968 to
1980' and of selenophen from 1970 to 1980 was presented." Other aspects
of thiophen chemistry are treated in chapters on Dewar Heterocycles," on
Cyclizations under Vilsmeier Conditions,12 on Polyfluoroheteroaromatic
compound^,'^ and on Reactions of Benzyne with Heterocyclic compound^.'^
Several dissertations treating various aspects of thiophen chemistry have
1
L. I. Belen'kii and V. P. Gul'tyai, Khim. Geterotsikl. Soedin., 1981, 723.
2
V. N. Sheinker, A. D. Garnovskii, and 0. A. Osipov, Usp. Khim., 1981, 50, 632.
3
W. G. Blenderman and M. M. JoulliB, Heterocycles, 1982, 19, 11 1.
4
R. Bdhm, Wiss. Z. - Martin-Luther-Univ. Halle- Wittenberg, M a t h . - N a t u r e . Reihe,
1981, 30, 3 .
5
D. N. Reinhoudt, Bull. SOC. Chim. Belg., 1981, 90, 633.
6
W. Schroth, Wiss. Z. - Martin-Luther-Univ.Halle- Wittenberg, Math.-Naturwiss. Reihe,
1981, 30, 97.
I
W. Schroth, Wiss. Z. - Martin-Luther-Univ. Halle- Wittenberg, Math.-Naturwiss. Reihe,
1981, 30, 29.
8
L. H. Klemm, Heterocycles, 1981, 1 5 , 1285.
9
R . M. Scrowston, Adv. Heterocycl. Chem., 1981, 29, 171.
10
A.-B. Hornfeldt, Adv. Heterocycl. Chem., 1981, 30, 127.
11
Y. Kobayashi and I. Kumadaki, Adv. Heterocycl. Chem., 1982, 31, 169.
12
0. Meth-Cohn and B. Tarnowski, Adv. Heterocycl. Chem., 1982, 31,207.
l 3 R. D. Chambers and R. C. Sargent, Adu. Heterocycl. Chem., 1981,28, 1.
l 4 M. R. Bryce and J . M. Vernon, Adv. Heterocycl. Chem., 1981, 28, 183.
I s C. Y. Lai, DiSs. Abstr. Int. B , 1981,42,2376.
l6 W.A. Lindley, Diss. Abstr. Int. B , 1981, 41,4524.
'' R. D. Thompson, Diss. Abstr. Int. B , 1981,42, 1900.
D. Margosian, Diss. Abstr. Int. B., 1981, 41, 4125.
l9 D. L. Singer, Diss. Abstr. Int. B , 1981,42, 1899.
'O V. Lorprayoon, Diss. Abstr. Int. B , 1981,41, 4197.
" D. Dell Mazza, Diss. Abstr. Int. B , 1981,41, 3031.
'' M. A. Khadim, Diss. Abstr. Int. B, 1981,42, 1457.
71
2 Monocyclic Thiophens
+
Synthesis of Thiopens by Ring-closure Reactions. - C4 S Principle. The
reaction of C6 hydrocarbons with hydrogen sulphide on a chromium-
containing catalyst led to thiophen derivative^.^^ A 94% yield of thiophen
has been obtained in the reaction of diacetylene with hydrated sodium
sulphide in KOH-DMS0.24 A number of mono- and di-glycosylthiophens has
been prepared by the reaction of mono- and di-glycosylbutadiynes with
sodium hydrosulphide, in connection with work on the biological activity of
C-glycosyl derivative^.^' The formation of 2,5-diamino-3,4-dicyanothiophen
in the reaction of tetracyanoethane with hydrogen sulphide in the presence of
pyridine has been confirmed.26 It has been shown that the thiophen that is
formed in the reaction of ethyl cyanoacetate with sulphur in the presence of
triethylamine is diethyl 2,5-diaminothiophen-3,4-dicarboxylate, and not
die thy1 2,4-diaminothiophen-3,5-dicarboxylate as previously claimed.*' The
first step in the reaction is most probably oxidative coupling to sym-diethyl
dicyanosuccinate, which then reacts by analogy with tetracyanoethane.
A patent describes the synthesis of the useful penicillin side-chain 3-
thienyhnalonic acid through the reaction of sodium sulphide with (l), which
was prepared by the A1C13-catalysed addition of chloroacetyl chloride to
acetylene followed by condensation with diethyl malonate.28
The reaction of ( 2 ) with alkanesulphenyl chlorides led to a mixture of (3)
and (4). Lower reaction temperatures favoured the formation of (3).29 The
reaction of vinylidene chloride with hydrogen sulphide at 470-550°C gave
15% of 2-chloro- and 16%of 3-chloro-thiophen as the main product^?^'
23 M. A. Ryashentseva, E. P. Belanova, and Kh. M. Minachev, Neftekhimiya, 1982, 22,

231.
l4 M. G. Voronkov, B. A. Trofimov, V. V. Kryuchkov, S. V. Amosova, Yu. M. Skvortsov,
A. N. Volkov, A. G . Mal'kina, and R. Ya. Mushii, Khim. Geterotsikl. Soedin., 1981,
1694.
25 J. M. J . Tronchet and A. P. Bonenfant, Helv. Chim. Acta, 1981, 64, 2322.
26 0. E. Nasakin, V. V. Alekseev, V. K. Promonenkov, I. A. Abramov, and A. Kh.
Bulaj, Zh. Org. Khim., 1981, 17, 1958.
" K. Gewald and A. Martin, J. Prakt. Chem., 1981, 3 2 3 , 843.
28 K. T. Veal and T. J . Grinter, Eur. Pat. Appl. 38 121, 1981.
l9 C. M. Angelov and K. V. Vachkov, Tetrahedron Lett., 1981,22,2517.
isa
M. G. Voronkov, E. N. Deryagina, V. I. Perevalova, and 0. B. Bannikova, Zh. Org
Khim., 1981, 17, 1103.
Five-Membered Rings: Thiophens and their Se and Te analogues 73
+
C2S C2 Principle. The reaction of nitroacetonitrile with a-mercapto-
ketones in the presence of triethylamine yields 4-substituted 2-arnino-3-
nitrothiophens.30 Various aryl- or heterocycle-substituted acetonitriles, such
as p-anisyl-, 2-pyridyl-, or 2-quinolyl-acetonitriles, reacted with esters of
thioglycollic acid in the presence of alkoxides to give 3-substituted 2-arnino-4-
hydroxythiophens, which exist as the 4-keto-ta~torner.~' The reaction of 2,4-
dichlorophenacyl cyanide with mercaptoacetaldehyde in the presence of
triethylamine gave 2-amino-3-(2,6-dichlorobenzoyl)thiophen in 86% yield."
Other examples of the use of the Gewald reaction for the synthesis of 2-
aminothio phen-3-car boxylates , by the modification using the reaction of
ketones with cyanoacetates and sulphur in the presence of base, have been
published. 33 The lithium salts of 2-arylethenethiolates react with alkyl
phenylpropiolates to give alkyl 2,4-diarylth1ophen-3-carboxylates, while the
corresponding potassium salts only give conjugate addition to (5). Minor
amounts of ( 6 ) are in both cases formed as by-products.% The reaction of
ethyl y-chloroacetoacetate with sodium sulphide and ethyl cyanoacetate in
the presence of triethylamine was used for the synthesis of 2-amino-4-
e t hoxy carbonylme t hyl-3-methoxy carb onyl thiophen .34-a
Ph
\ /COOR'
RC=C-S /"="\H R
(5) (6)
CS + C3 Principle. The Fiesselmann reaction between a-formyl arylaceto-

nitriles and methyl thioglycollate has been used for the preparation of methyl
3-amino-4-arylthiophencarboxylates.35 The reaction of (7) with ethyl thiogly-
collate in the presence of potassium carbonate gave (8) in 70% yield.36
(7)
30 Nippon Kayaku Co. Ltd., Jpn. Kokai Tokkyo Koho 81 100 780,1981.
31 Yu. M . Volovenko and F. S. Babichev, USSR P. 767 105, 1980 (Otkrytiya, Izobret.,
Prom. Obraztsy, Tovamye Znaki, 1980, 119).
3 2 D. Binder and P. Stanetty, J. Chem. Res. (s), 1981, 102.
3 3 F. J. Tinney, W. A, Cetenko, J. J . Kerkleski, D. T. Connor, R. J. Sorenson, and D. J .
Herzig, J. Med. Chem., 1981, 24, 878.
34 L. S. Rodionova, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 2071.
.34aNippon Kayaku Co. Ltd., Jpn. Kokai Tokkyo Koho 81 143 245,1981.
3 5 G. Kirsch, D. Cagniant, and P. Cagniant, J. Heterocycl. Chem., 1982, 19, 443.
36 K. Gewald, U. Hain, and E. Schindler, Ger. (East) P. 146 952, 1981.
From (8a) the thiophencarboxylic acids (8b) were prepared by reaction
with thioglycollic acid.36a The reaction of benzylideneaminoacetonitrile with
ethyl thioformate and sodium hydride in THF gave the salt (9) in an (E/Z)
ratio of 8 : 2. The reaction of (9) with methyl chloroacetate gave (lo), which
upon treatment with hydrogen chloride in wet diethyl ether gave methyl 3,4-
diaminothiophen-2-carboxylate,a key intermediate for biotin ~ynthesis.~’A
full study on the formation of compounds of type (1 1) in the reaction of
allenylsilver(1) reagents and carbon disulphide, mentioned in the previous
Report, has appeared. Through reaction with electrophiles, (1 1) was trans-
formed into (1 2).%
c1
Ring-closure of C.S. The reaction of (13) with LDA led to a 2,4-diamino-

thiophen, which according to n.m.r. exists in the imino-form (14).39
Compounds of type (14a), prepared by the condensation of methyl aryl
ketones with phenyl isothiocyanates in the presence of sodium hydroxide
followed by alkylation, gave the aminothiophens (14b) if R2 is COPH or
COMe, without additional catalysis by a base. On the other hand, if R2 is
C02Et or CONH2, the thiazolidones (14c) were obtained; and if R2 is CH2Br,
(1 4d) was the product.39a
Ph Ph
R’CO
H’ c=c
\S/CH2
I
(14c) H
C=C
\,NCH2 (14d)
36aM.Gosh, R. Mukherjee, B. G . Chatterjee, and J. K. Ray, Indian J. Chem, Sect. B ,

1981, 20, 243.
3’ Ph. R o s y , F. G. M. Vogel, W. Hoffmann, J . Paust, and A. Nurrenbach, Tetrahedron
Lett., 1981, 22, 3493.
’* J . Meijer, K. Ruitenberg, H. Westmijze, and P. Vermeer, Synthesis, 1981, 551.
39 M. Yokoyama, M. Kurauchi, and T. Imamoto, Tetrahedron Lett., 1981, 22, 2285.
39aN. Ben Mansour, W.-D. Rudorf, and M. Augustin, 2. Chem. 1981, 21,69.
Ring-closure of C2SC2.Ally1 1,2,2-trichlorovinyl sulphides ( 15) gave a
mixture of (16) and (17) upon heating to 100 - 120°C.40
Synthesis of Thiopens from Other Rings. - From Di- and Tetra-h,ydrothio-

phens. Compound (18) was prepared by the reaction of ethyl a-bromobutyrate
with methyl P-mercaptopropionate followed by base-catalysed cyclization.
Treating the oxime of (18) with hydrogen chloride in ether gave the amino-
thiophen (19a).41 A similar approach was used for the synthesis of (19b).
The starting 3-keto-derivative was prepared by Michael addition of methyl
thioglycollate to methyl crotonate, followed by Dieckmann c y ~ l i z a t i o n . ~ ~
Treatment of (20) with sulphuryl chloride in methylene chloride at 5"C,
followed by treatment with pyridine at room temperature, gave (21).43
Another example of the aromatization of hydrothiophens via chloro-
derivatives is in the preparation of (23) by the reaction of (22) with N -
. ~ ~ catalytic dehydrogenation of
chlorosuccinimide followed by ~ y r i d i n e The
2- and 3-alkyltetrahydrothiophenshas been in~estigated.~'
CN
40 E. Nagashima, K. Suzuki, and M. Sekiya, Tetrahedron Lett., 1981,22, 2587.

41 P. N. Confalone, G. Pizzolato, M. R . Uskokovic, and M . Rouge, US P. 4 317 915,
1982.
41
D. Binder, C. R. Noe, and M. Zahora, Arch. Pharm. (Weinheim, Ger.), 1981, 314,
557.
43 P. W. Raynolds, US P. 4 307 239, 1981.
44
J . B. Press, C. M. Hofmann, G. E. Wiegand, and S. R. Safir, J. Heferocycl. Chem.,
1982,19,391.
45 M. V. Vagabov, Vestn.Mosk. Univ., Ser. 2: Khim., 1982,23,52.
76 Heterocyclic Chemi s m
From Other Sulphur Heterocycles. The diazo-ketone (24), prepared from
2H-thiopyran-3(6H)-one and phenyl azide, yields (25) upon heating, which
apparently is the stable tautomer of 3-hydroxy-4-phenylaminomethylthiophen,
and (26). The structures of both compounds were proven by X-ray crystallo-
graph^.^^ The thermal and photochemical reactions of 1,4-dithiin sulphoxides
(27) have been re-investigated. In acetonitrile as solvent, 2,4-diarylthiophens
(28) and 1,3-dithioles (29) were formed, the proportions depending strongly
on the aryl group. In carbon tetrachloride, on the other hand, only (29)
was formed, except with (27; Ar = p-chlorophenyl), which yielded 68%of (29)
and 32% of (28). Photolysis gave, in addition to (29), (30) and the reduced
thiin,and no 2,4-diarylthiophen was formed.47
From Other Rings. Instead of preparing 5-aryl-2-hydroxythiophens (32) by

allowing 4-aryl-4-oxobutanoic acid to react with P2S5,it is considered better
to prepare first the butenolide (31) by treatment of the acid with acetic
anhydride followed by sodium hydrosulphide. The crude (32) can be trans-
formed into (33) in a one-pot procedure by its reaction with an aromatic
aldehyde and hydrogen chloride.48 A patent describes the synthesis of more
(31) Y = 0 (33)
(32) Y = S
16
K. Skinnemoen and K. Undheirn, Heterocycles, 1981, 16, 929.
47 K. Kobayashi and K. Mutai, Temhedron Lett., 1981, 2 2 , 5201.
4a G. A. Miller, N. D. Heindel, and I . A. Minatelli, J. Heterocycl. Chern., 1981,18,1253.
complex 2,5-dialkylthiophens by the reaction of the corresponding furans
with hydrogen sulphide in the presence of various strong acids.49
The strange metal-organic heterocycle (34), upon treatment with
cerium( IV) salts, gave t etrame thy1 thiophent etracarboxylat e in almost quanti-
tative yield.”
MeOOC
MeOOC P-Me
MeOOC I
Me
Physical Properties of Monocyclic Thiophens. - Theoretical Gzlculations.

Calculations by the CNDO/2, ab initio STO-3G7 and ab initio SCF methods
of the structure and degree of aromatic character in thiophen, furan, and
pyrrole have been carried *52 Enhanced aromaticity of thiophen com-
pared to furan was considered to be primarily due to the delocalization of
C(2)-C(3) m-bonds to the vacant d-orbitals of ~ulphur.’~First electron
affinities, valence ionization potentials, and photoionization cross-sections
of furan, thiophen, selenophen, and tellurophen have been determined .53
Calculations on the C(S) levels in thiophen and other aromatic heterocycles
have been carried out by the SSC-MO The 13C n.m.r. shifts, lowest
singlet-singlet and singlet-triplet transition energies, and dipole moments for
thiophen and its annelated analogues were calculated and compared with
experimental results.55 The two low-lying singlet excited states of fourteen
monophenylated five-membered heterocycles have been studied with respect
to the ordering of their energy levels and the oscillator strengths of the
pertinent transition^.'^ Many theoretical calculations on different aspects of
the electrophilic reactivity of thiophen derivatives have been performed. The
effect of the heteroatom on activity and selectivity in furan, thiophen, and
pyrrole has been estimated by CND0/2 calculations of localization energies:’
by the same method, the effect of the electrophilic agents8 has been calcu-
lated. Calculations have been carried out on 2-methoxy-5-methylthiothiophen,
2,5-bis(methy1thio)thiophen7and all of their possible C-protonated forms, in
49 V. G. Kharchenko, I. A. Markushina and T. I. Gubina, USSR P. 677 330, 1981

(Otkrytiya, Izobret., From. Obraztsy, Tovamye Znaki, 198 1, 242).
E. Lindner, A. Rau, and S. Hoehne, Angew. Chem., 1981,93, 822.
F. R. Cordell and J. E. Boggs, J. Mol. Struct., 1981, 85, 163.
5 2 G . Nhray-Szab6 and M. R. Petenon, J. Mol. Struct., 1981,85, 249.
5 3 V. Galasso, J. Mol. Struct., 1982,86, 231.
5 4 Z. B. Maksic and K. Rupnik, N o w . J. Chim., 1981, 5, 515.
55
Yu. B. Vysotskii, B. P. Zemskii, E. A. Zemskaya, and N. N. Alekseev, Zh. Strukt.
Khim., 1981, 2 2 , 13.
56 A. Mehlhorn, F. Fratev, and V. Monev, Tetrahedron, 1981, 37, 3627.
’’ L. I. Belen’kii and I. A. Abronin, Zh. Org. Khim., 1981, 17, 1129.
” LA. Abronin, L. I. Belen’kii, G . M. Zhidomirov, and Ya. L. Gol’dfarb, Zh. Org.
Khim., 1981, 17, 1134.
order to understand the distribution of isomers in electrophilic substitution
of these compound^.'^ Charge-density-activation-energy correlations have
been performed for the bromination of 2-halogen0thiophens.~A b initio
calculations on the deprotonation at the 2-positions of thiophens have been
carried out.61
Photoelectron and Ultraviolet Spectra. The He-I and He-I1 photoelectron
spectra and the U.V. absorption spectra of styrylthiophen and a-cyano-
styrylthiophen have been interpreted by comparison with the spectra of
related compounds, and with the aid of INDOIS-CI calculations.62 The
photoelectron spectra of sulphur heterocycles absorbed onto a (1 10) surface
of copper have been studied.63964The m.c.d. spectra of thiophen and seleno-
phen have been disc~ssed.~’
Inflared and Raman Spectra. Detailed i.r. and Raman studies of rotational
relaxation of furan and thiophen have been carried as well as of the
modes of vibrational relaxation of thiophen by isotropic Raman
The far4.r. absorption of thiophen in liquid and plastic phases has been
studied.% The i.r. and Raman spectra of 2-chloro- and 2-bromo-thiophen and
of the corresponding selenophens and tellurophens have been a~signed.~’
Calculated rotational and centrifugal distortion constants for thiophen and
tetradeuteriothiophen in the vibrational ground state have been compared
with experimental data.72 Hy drogen-bonding in 0-hydroxy-sulphides of the
thiophen series has been studied by the i.r. technique.73 The i.r. spectrum
of the yttrium salt of thiophen-2-carboxylic acid has been ~tudied.’~
Nuclear Magnetic Resonance. 13C n.m.r. spectra of 39 thiophen and furan
chalcones have been reported,” and analysis of the principle components
s9 Ya. L. Gol’dfarb, I. A. Abronin, M. A. Kalik, and V. K. Zav’yalova, Khim. GeterorsikL

Soedin., 1981, 1035.
60
M. J. Nanjan, V. Kannappan, and R. Ganesan, 2. Phys. Chem. (Frankfurt am Main),
1981, 127, 13.
61
G. Seconi, C. Eaborn, and J . G. Stamper, J. Organomef. Chem., 1981, 204, 153.
S. Millefiori, G. Scarlata, A. Millefiori, and D. Carbone, 2. Phys. Chem (Frankfurt
am Main), 1981, 128, 63.
63
T. M. Thomas, F. A. Grimm, T. A. Carlson, and P. A. Agron,J. Electron Spectrosc,
Relnf. Phenom., 1982,25,159.
6 4 N. V. Richardson and J. C. Campuzano, Vacuum, 1981, 31,449.
6 5 J. W. Waluk, E. Vogel, and J. Michl, J. Org. Chem., 1981, 46, 3306.
66 J. P. Pinan-Lucarre, J. Loisel, and L. Vincent-Geisse, Chem. Phys., 1981, 62, 251.
61
J. P. Pinan-Lucarre and T. Nguyen-Tan, Chem. Phys., 1981, 62, 2 6 5 .
68
J. P. Pinan-Lucarre, J. Loisel, and J. Vincent-Geisse, J. Raman Spectrmc., 1981,
11, 174.
69 W. Schmitz, Nuovo Cimento SOC.Ital. Fis. B , 1981, 63, 386.
lo J. P. Pinan-Lucarre, D. C. Edewaard, and K. D. Moeller, Spectrochim Acta, PartA,
1981, 37, 977.
” G . Paliani and R. Cataliotti, Spectrochim. Acta, Part A , 1981, 37, 707.
I2
F. N. Bolotina, L. N. Gunderova, I. Ya. Zemlyanukhina, A. Kh. Mamleev, V. G.
Marutsenko, N. M. Pozdeev, V. F. Pulin, and I. M. Sverdlov, Zh. Smckt. Khim., 1980,
21, 182.
73
S. N. Rustamova, M. M. Seidov, N. Yu. Ibragimov, and S. M. Aliev, Dokl. Akad.
Nauk Azerb. SSR,1980, 36, 39.
14
M. Singh, B. L. Mathur, and K. S. Gharia, Bull. SOC.Chim. BeZg., 1981, 90, 515.
75
G. Musumarra and F.P. Ballistreri, Org. Magn. Reson., 1980, 14, 384.
Five-MemberedRings: Thiophens and their Se and Te analogues 79
has been used for assignment of the observed chemical shifts.76 The I3C
n.m.r. shifts and direct C-H coupling constants for a number of compounds
of the types (35)77 and (36)78 have been studied, and the effect of substi-
tuents has been discussed. The non-pseudocontact components of the shifts
that are induced by [Yb(fod),] in thiophen-2-carbaldehyde have been
determined and found to be largest at the carbonyl carbon and at the 3- and
5 -carbons.79 Conformational and dynamic processes of a thiophenopara-
cyclophane have been studied by dynamic n.m.r.80 The 'H n.m.r. spectra of
some aminothiophens have been discussed.81 Metal complexes of thiophen-2-
carbaldehyde have been studied by 'H and I3C n.m.r. and by i.r. and U.V.
spectroscopy.82
Mass Spectrometry. The mass spectra of thiophen-2- and -3-~arboxanilides,8~*~~

of thiophenic chalcone of 2,5-diaryl-substituted thiophens,86
of a t e r t h i e n ~ l ,and
~ ~ of some chromium tricarbonyl c o m p l e x e ~ have
~ ~ * all
~~
been studied.
X-Ray Investigations. The crystal structures of 1,1,4,4-tetramethyl-lH,4H-
thieno[3,4-c] thiophen,gO of (37):' of (38),92 of triple-layered [2,2] -
I6
G. Musumarra, S. Wold, and S. Gronowitz, Org. Magn. Reson., 1981, 17, 118.
I1
G. Musumarra and F. P . Ballistreri, Chem. Scr., 1981, 18, 209.
78 F. P. Ballistreri, G. Musumarra, and G. Scarlata, Chem. Scr., 1981, 18, 214.
19
R. J. Abraham, D. J. Chadwick, and F. Sancassan, Tetrahedron Lett., 1981, 22,
2139.
80
T. Olsson, D. Tanner, B. Thulin, 0. Wennerstroem, and T . Liljefors, Tetrahedron,
1981, 37, 3473.
C. Galvez and F. Garcia, J. Heterocycl. Chem., 1981, 18, 851.
82
S. Burman and D. N. Sathyanarayana, J. Inorg. Nucl. Chem., 1981,43, 1189.
83 S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, Phosphorus Sulfur,
1981, 10, 317.
84 S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, J. Heterocycl. Chem.,
1981,18,1011.
A. Arcoria, F. P. Ballistreri, G. Musumarra, and S . Occhipinti, Org. MassSpectrom.,
1981, 16, 54.
86
R. Jimbnez and E. Cortbs, J. Heterocycl. Chem., 1982,19,447.
81
C. D. Gatsonis and P. T. Kosmidis, Pharm. Delt., Epistem. Ekdosis, 1980, 6, 21.
88
V. I. Khvostenko, Yu. S. Nekrasov, I. I. Furlei, N. I. Vasyukova, and G. A. Tolstikov,
J. Organomet. Chem., 1981, 212, 369.
89 M. El-Borai and M. F. Abdel-Megeed, Phosphorus Sulfur, 1980, 9, 165.
90
I. Goldberg, M. Freund, and S . Braverman, J. Cryst. Mol. Struct., 1981, 11, 157.
91
R. H. Hall, H. J. den Hertog, Jr., D. N. Reinhoudt, S. Harkema, G. J . van Hummel,
and J. W. H. M. Uiterwijk, J. Org. Chem., 1982,47, 977.
92
A. Hordvik, K. Junge and I. Pedersen, Acta Chem. Scand., Ser. A , 1981, 35, 607.
80 He terocy cIic Chemistry
paracyclophanes containing thiophen rings,93 and of some other thiophen
derivatives have been
Miscellaneous Physical Properties. The microwave spectrum of 2,3-dihydro-
thiophen shows the molecule to be puckered97 and to have a barrier to
inversion of 328 cm-' . The non-planarity of 2-oxotetrahydrothiophen has
been demonstrated by microwave s p e c t r o ~ c o p y . ~ ~
The saturated vapour pressures of chloro and chlorosilyl derivatives of
thiophen have been determined.99 Liquid vapour isothermal equilibrium for
thiophen with benzenelW and with alcohols"' has been measured. The
formation constants, extinction coefficients, and total absorption intensities
for complexes between thiophens and iodine have been determined. '02
The adsorption of thiophen on montmorillonites'03~104 and on other
catalyst^'^^^'^^ has been investigated. Several papers of an analytical nature
and on the separation of thiophen from benzene have appeared.lo7- '12
Electrophilic Substitution Reactions of Monocyclic Thiophens. - A careful
kinetic investigation of the protodesilylation of substituted trimethylsilyl-
thiophens, either with aqueous HC104 in methanol or aqueous H2S04 in
acetic acid, gave values of log k which, except for the nitro-compounds,
showed excellent linear correlations with the corresponding ortho-, meta-,
or para-substituted trimethylsilylbenzenes. The effect of substituents was
larger in the thiophen than in the benzene ~ e r i e s . " ~ * Mixtures
"~ of 2- and 3-
93 Ya. Kai, J. Watanabe, N. Yasuoka, and N. Kasai, Acta Crystallogr., Sect. B , 1980,
36, 2276.
94
B. Tinant, B. Coene, J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Struct.
Commun., 1981, 10, 259.
95
A. Carpy, D. Hickel, a n d A. Nuhrich, Cryst. Struct. Commun., 1981, 10, 1387.
96 D. Zobel and G. Ruban, Acta Crystallogr., Sect. B , 1981, 37, 1867.
97 J. R. Durig, T. S. Little and Y. S . Li, J. Chem. Phys., 1982, 76, 3849.
9a J. L. Alonso, J. Chem. SOC.,Chem. Commun., 1981, 577.
99 V. E. Ditsent, I. I. Skorokhodov, M. N. Zolotareva, V. I. Savushkina, and B. M.
Tabenko. Zh. Prikl. Khim.. 1981, 54, 1617.
100
M. Diaz Pena,, A. Compostizo, A. Crespo Colin, and I. Escudero, J. Chem. Thermo-
dyn., 1981, 13, 869.
101
0. F. Aguirre, B. R. Inostroza, A. R. Lopez, V. F. Romero, L. J. Triday, and R. E.
Trujillo, Scientia (Valpamiso), 1979, 44, 38.
102
S. H. Etajw, G. B. El-Hefnawey, and N. T. Abdel Ghany, Ann. Chim. (Rome), 1982,
72,95.
103
E. K. Varfolomeeva, L. K. Zgadzai, E. Kh. Ivoilova, R. Sh. Kharitonova, and S. S.
Sunchaleeva, Kolloidn. Zh., 1981, 43, 6 3 3 .
104
E. K. Varfolomeeva, L. K. Zgadzai, E. Kh. Ivoilova, S. S. Sunchaleeva, and R. Sh.
Kharitonova, Kolloidn. Zh., 1981, 43, 962.
105
V. I. Erofeev and I. V. Kalechits, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 5 0 5 .
106
V. I. Erofeevand I. V. Kalechits, Kinet. Katal., 1982, 23,426.
l o 7 L. G. Proskurvakova, V. F. Lisenkov, and L. A. Kogan, Khim. Prom-st., Ser.: Metody
Anal. Kontrolya Kach. Prod. Khim. Prom-st., 1981, 9.
' 0 8 A. A. Miroshnichenko and L. G. Fedosyuk, Koks Khim., 1981, No. 9, p. 26.
lo9 A. A. Miroshnichenko and L. G. Fedosyuk, Koks Khim., 1981, No. 11, p. 28.
' l o A. E. Habboush, S. M. Farroha, and Z. F. Savaya, J. IraqiChem. SOC.,1980, 5, 81.
Ill
L. Ya. Kolyandr, V. G. Titarenko, T. G. Shcherbakova, and S. V. Kulyasova, Koks
Khim., 1981, No. 6, p. 24.
'12 T. D. Zaika, Yu. N. Usenko, and A. A. Motuz, Khim. Tekhnol. (Kiev), 1981, No. 1,
p. 21.
113
G. Seconi, C. Eaborn, and J. Stamper, J. Orgunomet. Chem., 1980, 204, 153.
'I4 G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2, 1981, 931.
perfluoroalkylated thiophens have been obtained upon thermolysis of

perfluoroalkyl iodides in the presence of thiophen. '15
The Nafion-H-catalysed acylation of thiophen gave acylthiophens only in
moderate yields.' l 6 Treatment of thiophen with phenyl isocyanate or phenyl
isothiocyanate in the presence of NC13 in nitromethane gave the N-
phenylamide and the N-phenylthioamide of thiophen-2-carboxylic acid in
high yields."' The reversibility of bromination in the thiophen series is
illustrated by the formation of a mixture of acyl derivatives and tetra-
bromothiophen in the A1C13-catalysed acylation of 2,5-dibromo- and 2,3,5-
tribromo-thiophen.l18 Another example is the formation of (40) by
treatment of (39; X = Br) with PPA. No migration of chlorine occurs during
the ring-closure of (39; X = Cl).'19 A very interesting result was obtained in
the AICl,-catalysed reaction of (41) with benzene, toluene, or ethylbenzene,
which yielded (42) and (43) in 77% and 9% yields, respectively. When half an
equivalent of A1Cl3 was used, approximately equal amounts of (42; Ar = Ph)
and (43; Ar = Ph) were obtained. Treatment of (43; Ar = Ph) with AlC13 in
benzene also yielded (42). The mechanism of this interesting cine-arylation
is not clear.12' In connection with this work, the chlorination of 3-benzyl-4-
phenylthiophen with sulphuryl chloride was undertaken, which gave a
mixture of the 2- and 5-chloro-derivatives.120The cations produced by
treatment of chlorothiophens in HS03F or AICl3-HC1-CH2CI2 systems have
been observed by n.m.r. Protonation occurs exclusively at the a-carbon, both
in 2-chloro- and 2,5-dichloro-thiophen." The basicities of the a- and 0-
positions of thiophen in the gas phase have been studied by ion-cyclotron
resonance. a-Protonation was preferred, which was also the case for pyrrole
and furan, in accordance with NMDO calculations. '22
c1
(41)
*rlgcl
(42)
CH2Ar
(43)
115
A. B. Cowell and C. Tamborski, J. Fluorine Chem., 1981,17,345.
116
H. Konishi, K. Setsugu, T. Okano, and J. Kiji, Bull. Chem. SOC. Jpn., 1982, 55,
957.
1I?
E. Jagodzinska, T. Jagodzinski, and Z. Jablonski, Khim. Geterotsikl. Soedin., 1980,
1287.
118
M. J. del Agua, A. S. Alvarez-Insda, and S. Conde, J. Heterocycl. Chem., 1981, 18,
1345.
119
J. B. Press and N. H. Eudy, J. Heterocycl. Chem., 1981, 18, 1261.
120
T. Sone, H. Kawasaki, S. Nagasawa, N. Takahashi, K. Tate, and K. Sato, Chem.
Lett., 1981, 399.
121
Y. Yokoyama, Y. Yamashita, K. Takahashi, and T. Sone, Chem. Lett., 1981, 813.
122
R. Houriet, H. Schwarz, W. Zummack, J. G. Andrade, and P. von Ragu6 Schleyer,
Nouv. J. Chim., 1981, 5 , 5 0 5 .
82 Heterocyclic Chemi s t y
Hydrogen-deuterium exchange under phase-transfer conditions has been
studied with 2-methyl- and 2-nitro-thiophen. No exchange was observed for
the latter compound.123
The catalytic deuterium exchange of thiophen over y-alumina has been
studied. 124 (Chlorodifluoromethy1thio)thiophen was substituted in the 5-
position, when it reacted with chlorodifluoromethanesulphenyl chloride in
the presence of trifluoromethanesulphonic acid, to yield (44).’” Treatment
of 2,3-bis-(4-fluorophenyl) thiophen with trifluor omethylsulphenyl chloride
and t rifluoroace tic acid gave the 5-t rifluorome t hy lthio-derivat ive .12’ a Several
thiophensulphonyl chlorides have been prepared by the reaction of thiophen
or of 5-bromo-3-chloro-, 4,5-dibromo-, or 4-chloro-5-bromo-thiophen with
chlorosulphonic acid. The sulphonyl chlorides were transformed into amides
and other derivative^.'^^*^^' The Friedel-Crafts reaction between 3-bromo-
thiophen and 2-nitrophenylacetyl chloride gave (45).12’ From 2-t-butylthio-
phen and pivaloyl chloride, 2-t-butyl-5pivaloylthiophen was obtained by the
same rea~ti0n.l~’In connection with work on 2H-, 3H-, and 14C-labelled
suprofen 46, bromination was achieved in the 5-position, using A1C13 as a
swamping catalyst. The ketone (47) was prepared by Friedel-Crafts acylation
of thiophen with 3-bromo-p-toluic carbonyl chloride. 130*131
0
C 1F2CS SCF2C1
lZ3 W. J. Spillane, P. Kavanagh, F. Young, H. J.-M. DOU, and J. Metzger, J. Chem. SOC.,
Perkin D a m . 1 , 1981, 1763.
124
G. Ya. Katsapov, E. N. Osmanov, and K. Kh. Razikov, React. Kinet. Catal. Lett.,
1981, 17, 227.
12’ M. R. C. Gerstenberger, A. Haas, and H. Pauling, Helu. Chim. Acta, 1982, 65,490.
C. Cherkofsky, US P. 4 302 461, 1981.
I26
R. J. Cremlyn, K. H. Goulding, F. J. Swinbourne, and K.-M. Yung, PhosphorusSulfur,
1981, 10, 111.
I27
I. T. Barnish, P. E. Cross, R. P. Dickinson, M. J. Parry, and M. J. Randall, J. Med.
Chem., 1981, 24, 959.
1 2 * J. Guillaume, L. NCdClec, M. Cariou, and A. Allais, Heterocycles, 1981, 1 5 , 1227.
l Z 9 1. Murata, K. Nishino, S. Yano, Y. Kohashi, and K. Yamamoto, Croat. C h e m Acta,
1980, 53, 615.
I 3 O Y. Mori, M. Shibata, K. Toyoshi, S. Baba, M. Horie, Y. Oshika, and K. Ohira, Radio-
isotopes, 1981, 30, 584.
13’ Y. Mori, M. Shibata, K. Toyoshi, S. Baba, M. Horie, Y. Oshika, and K. Ohira, Radio-
isotopes, 1981, 30, 590.
In connection with developments of new syntheses of biotin, 3-acetylamino-
2-methoxycarbonylthiophen was nitrated at - 30°C with H N 0 3 in H2S04 to
give a mixture of the 4-nitro- and 5-nitro-isomers in a 60:40 ratio. The
isomers were easily separated by crystallization from t ~ l u e n e . ~2-Amino-4-
'
ethoxycarbonylmethyl-3-methoxycarbonylthiophenhas been nitrated in the
" nitration of 5-bromo- and of 5-methyl-2-cyclopropylthio-
5 - p o ~ i t i o n . ~The
phen with nitric acid in acetic anhydride has been investigated. With the
bromo-derivative, substitution in the 3-position and ipso-substitution to give
5-nitro-2-cyclopropylthiophenwere observed. In the methyl case, it is
claimed (without proof) that the 3-nitro-derivative is formed, the main
product (44%) being (48).'32 A detailed paper on the nitration of 2,5-
dime thyl- and 2,5-dimethyl-3,4-dibromo-thiophen, reviewed in last year's
Report, has now appeared. 133 2-Formylthiophen, upon nitration with copper
and aluminium nitrates in acetic anhydride, gave the 5-isomer as the diacetate,
while 2-acetylthiophen gave a mixture of the 4- and 5-nitro-isomers. At 70-
90" C, 2-formylthiophen was oxidized to thiophen-2-carboxylic acid. 134 The
nitration of a,P-unsaturated thiophen ketones has been studied under various
conditions, and led to mixtures of ring-nitrated ketones and (49).'34-'36
Me c ! OH
ON02 R <
j CH=i!-COMe
N02
(49)
(48)
Electrophilic Ring-closure Reactions. - In a series of interesting papers,
several thienospirans have been described, prepared by cyclization onto
thiophen. Thus (50) and (5 1) were converted into ( 5 2 ) and (53), respectively,
13'S. S. Mochalov, T. P. Surikova, F. M. Abdel'razek, V. D. Zakharova, and Yu. S.

Shabarov, Khim. Geterotsikl. Soedin., 198 1, 189.
133 H. Suzuki, I. Hidaka, A . Iwasa, T. Mishina, and A. Osuka, Bull, Chem. SOC. Jpn.,
1981, 54, 771.
134 Yu. D. Churkin, L. V. Panfilova, V. D. Lugovoi, and N. V. Boiko, K h i m Geterotsikl.
Soedin., 1981, 913.
13' Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn,
Geterotsikl. Soedin., 1981, 325.
136 Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn.
by treatment with PPA.13' Alternative starting materials were (54),(55), and
(56), which led to (57), (58), and (59), re~pective1y.l~'Six-membered fused
systems (61) could be prepared by treating (60) with PPS or concentrated
phosphoric acid and acetic anhydride. 13' Alternatively, (62), prepared from
The Grinard reagent of 2-(bromopropy1)thiophen and cyclohexanone, gave
(63) upon treatment with 9ooJo sulphuric acid in ether. Treatment with 50%
H2S04 led only to olefm formation.13* When (64) reacted with thiophen
under Friedel-Crafts conditions, it gave (65), which, after Wolff-Kishner
(54)
(57) (58) (59)
13' P. Stanetty, J. Chem. Res. (S), 1981, 99.

138 P. Stanetty, J. Chem Res. (S), 1981, 100.
reduction, was ring-closed to (66) with PPA.’39 Treatment of (67) with PPA
finally gave (68).13’
Electrophilic ring-closure of 2-geranylthiophens (69) has been studied in
great detail. With concentrated H2S04 in nitroethane, at -40°C, it was
possible to obtain (72; R = H) in 80% yield; SnC14 gave also (72), but in
somewhat lower yield. Trifluoroacetic acid in methylene chloride led only to
the formation of (70; R = H) and (71; R = H), in the proportions 4 : 1.
When R = C02H, ring-closure was slowed down, and only (70) and (71)
were obtained, in various proportions. After treating (69; R = C02H) with
SnC14 in methylene chloride for 72 hours at room temperature, a 59% yield
of (72) and (73) was obtained, in the proportions 2: 1 . 1 4 0 Treatment of (74)
(72) (73)
139
P. Stanetty, J. Chem. Res. (S), 1981, 139.
140
A. V. Semenovskii and M. M. Emel’yanov, Izv. A kad. Nauk SSSR, Ser. Khim., 1980,
2578.
86 Heterocyclic Chemi s t v
with conc. H2SO4 in a nitromethane-toluene mixture (1 : 1) at - 40°C led to
a mixture of (75) and (76).141 The Friedel-Crafts cyclizations of lV-(3-
theny1)- and of N-(2-thenyl)-glycine, using 80% H2SO4, gave (77) and (78),
re~pective1y.l~~ The cyclohepta [ b ]-fused systems (79) and (80) were
obtained by treating the appropriate acid chloride with SnC14 in CS2
CQ (77)
0
(79)
Nucleophilic and Radicaloid Substitution Reactions of Monocyclic Thio-

phens. - The rate constants for the reaction of 5-substituted 2-bromo-3-
nitrothiophens, in methanol, with various substituted d i n e s to give 5-
substituted N(3-nitro-2-thienyl)anilines have been measured at various tem-
peratures. It was found that the sensitivity parameters that were obtained
from Hammett and Bronsted correlations were practically independent of the
starting system.'44 The kinetics of piperidino-substitution of methyl 2-
methoxy-3-nitrothiophen-5-carboxylateand 5-acetyl-2-methoxy-3-nitrothio-
phen, in which the methoxy-group is the leaving group, have been investigated
and the mechanism has been discussed.145
Six bis(nitrothieny1) sulphides have been prepared by the reaction of
appropriate bromonitrothiophens and sodium ~ u 1 p h i d e . lA~ large
~ number of
sulphides has also been prepared by nucleophilic substitutions of substituted
thiophenolates with substituted 5-bromothiophen-2-sulphonamidesin
DMF.'27 With less activated halothiophens, copper-promoted nucleophilic
substitution must be used, as in the reaction of 2-chlor0-5-iodothiophen'~~
or of 3-br0mothiophen'~~with substituted thiophenolates, or in the ring-
14' A. V. Semenovskii and M. M. Ernel'yanov, Izv. Akad. Nauk SSSR,Ser. Khim., 1981,
1359.
142
K. Satake, T. Irnai, M. Kirnura, and S. Morosawa, Heterocycles, 1981, 16, 1271.
143
T. Frejd, J. 0. Karlsson, and S. Gronowitz, J. Org. Chem., 1981,46, 3132.
144
G . Consiglio, C. Arnone, D. Spinelli, R. Noto, and V. Frenna, J. Chem. SOC.,Perkin
Trans. 2, 1981, 388.
145
G . Consiglio, C. Arnone, D. Spinelli, and R. Noto, J. Chem. Soc., Perkin Trans. 2,
1981,642.
146
G. Ronsisvalle and G. Blandino, Farmaco, Ed. Sci., 1981, 36, 785.
147
Z. Polivka, J. Holubek, E. Svitek, J. Metygovd, and M. Protiva, Collect. Czech. Chem.
Commun., 1981,46,2222.
14' J. W. H.Watthey and M. Desai, J. Org. Chem., 1982, 47, 1755.
closure of (81) to (82). Higher yields and more reproducible results were
obtained if the formamide of (81) was used in the reaction with K2CO3
and Cu powder in DMF.'28 Furthermore, phenyl ethers have been prepared by
the copper-promoted reaction between 3-bromothiophen, copper bronze,
anhydrous K2C03, and substituted phenols. After refluxing for a week, high
yields were obtained.I4* The reaction of 2,4-di-iodothiophen in the presence
of CuO could be utilized for the preparation of 2-methoxy-4-iodothiophen
and 2,4-dimetho~ythiophen,'~' while Ullmann-type coupling between 2-
iodothiophen and methyl 2-iodobenzoate was used for the preparation of
methyl (2-thieny1)benzoate in low yield. Better yields of the desired product
were obtained by the reaction of the diazonium salt of methyl anthranilate
with t h i ~ p h e n . ' It
~ ~is claimed that the reaction of 3-iodothiophen with
diethyl malonate in quinoline in the presence of CuBr gave 69% yield of
diethyl3-thienylmal0nate.'~'
(2)-Dialkenylcuprates were coupled with 2-iodothiophen in the presence

of ZnBr and catalytic amounts of Pdo complex to give vinylthiophen~.'~~
Palladium-graphte, prepared by the reduction of PdC12 by C8K, has also
been used as a catalyst in the preparation of vinylthiophens from 2-
iodothiophen. l S 3 The palladium-catalysed reaction of 2,4-dibromothiophen
with propargylzinc chloride gave a 70% yield of 4-bromo-2-( 1-propyny1)-
thiophen, containing small amounts of the 2-bromo-4-( 1-propynyl) isomer.
The use of 4-bromo-2-iodothiophen increased the yield to 80% and eliminated
the formation of the by-prod~ct."~l-Methy1-2-(3-thienyl)pyrrolehas been
synthesized in 73% yield by the palladium-catalysed coupling of 3-bromothio-
phen with 1-methyl-2-pyrrolylzinc c h l ~ r i d e . ' ~ ~
Halothiophens
" have been
condensed with terminal acetylenes under carbon monoxide at temperatures
of about 120°C and pressures of 80atm, in the presence of triethylamine
and a Pdn catalyst, to give acetylenic ketones.'54b
I49
Ya. L. Gol'dfarb, M. A. Kalik, and V. K. Zav'yalova, Khim. Geterotsikl. Soedin..,
1981,182.
Is' S. Mataka, T. Ohshima, and M. Tashiro, J. Org. Chem., 1981, 46, 3960.
J . P. M. Houbiers and P. G. Mueris, US P. 4 262 129, 1981.
l S 2 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1981, 2 2 , 3851.
I s 3 D. Savoia, C. Trombini, A. Umani-Ronchi, and G. Verardo, J. Chem. SOC.,Chem.
Commun., 1981, 541.
IS4
J. 0. Karlsson, S. Gronowitz, and T. Frejd, J. Org. Chem., 1982, 47, 374.
154aA. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett.,
1981, 22, 5319.
1s4bT.Kobayashi and M. Tanaka, J. Chem SOC.,Chem Commun., 1981, 333.
The scope of the reactions of 5-nitro-3-thienylethyl chloride and acetate
with the lithium salt of 2-nitropropane to give (83) (cf.this series, Vol. 2, p.
80) has been investigated. The cyano-group was not found to be sufficiently
active, since 4-cyano-2-thienyl-methyl and -ethyl chlorides only gave 0-
alkylated products by an s N 2 mechanism. The SN(AEAE) reaction also
occurred between benzenethiolate and 4-nitro-2-thienylmethyl acetate, and
a moderate yield of 4-nitro-2-thienylmethyl phenyl sulphide was obtained.”’
I
(83) Me2CN02
The mechanism of the reaction of thiophens with a variety of radicals such

as .OH, Cl’, NH,’, and SO2 has been studied in a detailed investigation using
the e.s.r. technique. The radicals that were detected were mainly hydroxy
adducts, but also included 2-thenyl and thenyloxy radicals. Evidence for the
involvement of radical cations was also pre~ented.’’~The rate constants for
the reaction of O(3P) with thiophen were determined by using the discharge
flow-resonance fluorescence technique. l S 7 Homolytic substitution of thiophen
by MeCOcH, and MeCOcHCOMe radicals, generated from acetone and
acetylacetone by using Mnm acetate, led regiospecifically to the 2-thienyl
ketones.’ 58 The reduction of 2-bromo-5-nitrothiophen and of 2-iodo-5-
nitrothiophen in DMF has been studied by polarography, e.s.r. spectroscopy,
and preparative electrolysis. Further reactions of the radical anions to form
nitrothienyl radicals and their dimers were observed and a mechanism was
pr~posed.”~
Organometallic Derivatives of Monocyclic Thiophens - Lithium. Numerous
a-substituted thiophens have been prepared via metallation of thiophens with
organolithium derivatives, Thus 2-thienyl-lithium has been allowed to react
with tetraisopropylthiuram disulphide to give S(2-thienyl) N,N-di-isopropyl-
dithiocarbamate in quantitative yield. ‘60 Through the reaction of 2-thienyl-
lithium with tellurium in THF, the tellurolate was obtained, which was con-
verted into various products.16’ The reaction of 2-thienyl-lithium with 1 , l -
dichloro-2,2-difluoroethene has been developed into a very useful method for
155
P. J . Newcombe and R. K. Norris, Aust. J. Chem., 1981, 34, 1879.
lS6 B. C. Gilbert, R. 0. C. Norman, and P. S. Williams, J. Chem. Soc., Perkin Trans. 2 ,
1981, 207.
151
J. H. Lee and I. N. Tang, J. Chem. Phys., 1981, 7 5 , 137.
Is* R. S. Min, V. S. Aksenov, M. G . Vinogradov, and G. I. Nikishin, Izv. Akad. Nauk
SSSR,Ser. Khim., 1981,2315.
Is’ I. M . Sosonkin, G. N. Stogov, T. K. Ponomareva, A. N. Domarev, A. A. Glushkova,
and G. N. Freidlin, Khim. Geterofsikl. Soedin., 1981, 195.
K. Y. Jen and M. P. Cava, Tetrahedron Lett., 1982,23,2001.
161
L. Engman and M. P. Cava, Organometallics, 1982, 1,470.
the preparation of acetylenic and polyacetylenic derivatives. Thus when (84),
formed in this reaction, reacted with excess butyl-lithium followed by
dichlorodifluoroethene and trimethylsilyl chloride, 2,5-bis(trimethylsilyL
ethyny1)thiophen was produced. Coupling of (85) with cupric acetate in
pyridine gave (86).16' The reaction of 2-thienyl-lithium with geranyl bromide
and with (E,E)-farnesyl bromide was used for the synthesis of (69a)" and
of (7 4) ,14' respectively . Met allation of 2-met h ylthiophen with but yl-lithium,
followed by reaction with vinyl azides, was used for the synthesis of 2-amino-
5-methylthiophen.' 63
The reactions of 2- and of 3-thienyl-lithium with pyridazine are dependent
upon the solvent and the temperature that is used. Thus, using THF as co-
solvent, at low temperatures, the 4-position of pyridazine is attacked, leading
(after hydrolysis and oxidation) t o 4-(2-thienyl)- and 4-(3-thienyl)-pyridazine.
If ether is used as the solvent, at O"C, 3-(2-thienyl)- and 3-(3-thienyl)-
pyridazines were obtained after oxidation. The structures of the initially
formed dihydro-derivatives were studied to some extent.'@ The reaction of
(87) with butyl-lithium followed by formaldehyde gave (88).16' The reaction
of 2-phenylthiophen with butyl-lithium followed by ethyl 2-thienylglyoxylate
was used for the synthesis of (89).lM The directing effect of a 3-phenoxy-
and of a 3-phenylthio-group on metallation with phenyl-lithium has been
investigated. While the 3-phenoxy-group almost exclusively directed lithiation
to the 2-position, a 1 : 1 mixture of 2- and 5-lithiated derivatives was obtained
with 3-(pheny1thio)thiophen. 148 Dilithium derivatives were obtained by
treatment of thiophen-2- and -3-carboxylic acids, which reacted with various
electrophiles to give 5-substituted thiophen-2-carboxylic acids and 2-
substituted thiophen-3-carboxylic acids, re~pectively.'~~ The metallation of
(84) R = H
(85) R = C s C S i M e 3
Ph
R CH=CHCH2NMe2 HO' 'COOE t

(87) R = H
(89)
( 8 8 ) R = CH20H
K. Okuhara, Bull. Chem. SOC.Jpn., 1981, 54, 2045.

163
A. Hassner, P. Munger, and B. A. Belinka, Jr., Tetrahedron Lett., 1982, 23,699.
164 J . Bourguignon, C. BBcue, and G. QuCguiner, J. Chem. Res. ( S ) , 1981, 104.
165
Yoshtomi Pharmaceutical Industries Ltd., Jpn Kokai Tokkyo Koho 8 1 169 685,
1981.
A. T. Jeffries, K. C. Moore, D. M. Ondeyka, A. W. Springsteen, and D. W. H.
MacDowell, J. Org. Chem., 1981, 46, 2885.
D. W. Knight and A. P. Nott, Tetrahedron Lett., 1980, 21, 5 0 5 1 .
3-bromothiophens with LDA followed by trimethylsilyl chloride has been
used for the preparation of 3-bromo-2-(trimethylsilyl)thiophens.'68
The reaction of 3-thienyl-lithium, prepared by halogen-metal exchange
of 3-bromothiophens, has been used for the synthesis of many geminal 3,3-
dithienyl derivatives of pharmacological interest. Thus the reactions with
ethyl 3-bromopropionate, ethyl cyclopropylcarboxylate, and (90) were used
for the synthesis of (91),16' (92),170 and (93),17' respectively. The reaction
of 3-thienyl-lithium with quinoxaline has been used for the preparation of
2,3-di(3-thienyl)quinoxaline. 172
The reaction of 3-thienyl-lithium with trialkylboranes gave 'ate' complexes,
which upon reaction with bromine or iodine yielded the corresponding 3-
alkylthi~phens.'~~ Halogen-metal exchange between acetal-protected 5-
bromothiophen-2-carbaldehyde and butyl-lithium, followed by reaction with
nicotinaldehyde, was used for the synthesis of (94) in connection with the
preparation of inhibitors of thromboxane ~ynthetase."~Halogen-metal
exchange of 3 -bromo-4-phenylthiophen followed by reaction with benzal-
dehyde gave (99.'"'
'CHMe2
CHO
(94) (95)
168
S . Gronowitz, T. Frejd, J. 0. Karlsson, K. Lawitz, P. Pedaja, and K. Pettersson,
Chem. Scr., 1981,18, 192.
J. Engel, A. V. Schlichtegroll, and W. S. Scheldrick, Arzneim.-Forsch., 1982, 32,
475.
170
A. Kleemann, J. Heese, and J . Engel, Arzneim.-Forsch., 1981, 31, 1178.
F. J. Stiefel, US P. 4 310674, 1982.
T. Kauffmann, M. Ghanem, and R. Otter, Chem. Ber., 1982, 115,459.
I. Akimoto, M. Sano, and A. Suzuki, Bull. Chem. SOC.Jpn., 1981, 54, 1587.
174
T. Tanouchi, M. Kawamura, I. Ohyama, I. Kajiwara, Y. Iguchi, T. Okada, T. Miya-
moto, K. Taniguchi, M. Hayashi, K. Iizuka, and M. Nakazawa, J. Med. Chem., 1981,
24, 1149.
The halogen-metal exchange between 4-iodo-2-methoxythiophenand
butyl-lithium, followed by reaction with dimethyl disulphide, carbon dioxide,
or DMF, was used for the synthesis of various 4-substituted 2-methoxythio-
phens.14’ In connection with work on optically active 3-(cyclohexeny1)-
thiophens, substituted 3-thienyl-lithium derivatives were allowed to react
with cyclohexanones and cyclohexenones.175 The reaction of 3,4-
dibromothiophen with two equivalents of butyl-lithium and sulphur, followed
by CS2, was used for the synthesis of (96), an intermediate for the synthesis
of the ‘organic metals’ (97).176
The synthetic usefulness of the ring-opening reaction of 3-thienyl-lithium
derivatives has been further demonstrated. It was found that 2-(trimethylsily1)-
3-thienyl-lithium ring-opens very fast, in contrast to 3-thienyl-lithium
compounds with a free 2 - p o ~ i t i o n This
. ~ ~ ~was utilized for the total synthesis
of some naturally occurring acetylenic thioenol ethers. Thus (98) was trans-
formed by the reaction with butyl-lithium and methyl iodide into (99), which
after desilylation and Pd-catalysed coupling with (2)-methyl 3-bromoacrylate
was converted into (100). Another isomer was obtained through coupling
with (,!?)-methyl 3-bromoa~ry1ate.l~The ring-opening of cyclo [ b ]-fused
systems (10 1) with phenyl-lithium, followed by reactions with electrophiles
such as benzyl chloride or ethyl bromoacetate, led to a regio- and stereo-
specific synthesis of (102).143
(101) n = 1-4 ( 1 0 2 ) n = 1-4

R2= CH2COOH or CH2Ph
175
A. Svensson and R. Hikansson, Chem. Scr., 1981, 18,202.
176 P. Shu, L. Chiang, T. Emge, D. Holt, T. Kistenmacher, M. Lee, J. Stokes, T. Poehler,
A. Bloch, and D. Cowan, J. Chem. SOC.,Chem. Commun., 1981,920.
Mugnesium . Metallation of 2,3,4-trichlorothiophen with ethylmagnesium
bromide and halogen-metal exchange between tetrachlorothiophen and the
same reagent has been achieved, and the resulting Grignard reagents have
been characterized by their reactions with C 0 2 and with trimethylsilyl
~hloride."~The reaction of hexabromo-2,2-bithienyl with magnesium under
entrainment conditions gave the 5,5'-dimagnesium derivative.'% Ethyl 2-
thienylglyoxylate has been prepared by the addition of thiophen-2-
magnesium bromide to diethyl oxalate in THF instead of diethyl ether.'79
Thienyl derivatives of Group IVB elements have been prepared by the
reaction of thiophen-2-magnesium bromide with the corresponding silicon,
germanium, tin, and lead halides. The electron-acceptor properties of these
substituents with the n-electron system of thiophen were investigated by
means of 'H, 13C, "'Si, l19Sn, and ""Pb n.m.r. spectroscopy.lg0 The reaction
of thiophen-2-magnesium bromide with a-chlorocyclohexanone offered a
convenient synthesis of 2-(2-thienyl)cyclohexanone .l 38
Mercury, Zinc, and Copper. The thermal decomposition of 2-thienylmercury
thiocyanate, azide, acetate, and trifluoromethylsulphonate has been investi-
gated. lgl Thienylmercury derivatives have been cross-coupled with primary
and secondary alkyl- and alkenyl-cuprate reagents.lg2 2-Thienylzinc chloride
has been coupled with iodobenzene and vinyl bromide, using Pd ~ata1ysis.l~~
3,4-Dichloro-2-thienylcopper and trichloro-2-thienylcopper have been coupled
with 1,2,A,5-tetrachloro-3-iodobenzene. 184
Damition Metals. A detailed paper on the Pd-assisted alkenylation of

thiophen with various olefins to give mono- or di-alkenylated products has
been p ~ b 1 i s h e d . l The
~ ~ reaction of the thiophenmercury derivatives (103)
with trinorbornenylpalladium chloride and lithium chloride (1 0 : 1 : > 2) in
acetonitrile led to the air-stable Pd complex (104). The saturated analogue
'" M. T. Rahman, J. Indian Chem. SOC.,1981, S8,21.

Yu. V. Shklyaev, Yu. P. Dormidontov, and I. I. Lapkin, Khim. Geterotsfkl. Soedin.,
1981,468.
17' L. M. Weinstock, R. B. Currie, and A. V. Lovell, Synth. Commun., 1981, 11, 943.
l B 0 E. Lukevits, 0. A. Pudova, Yu. Popelis, and N. P. Erchak, Zh. Obshch. Khim., 1981,
51, 115.
C. A. Obafemi, J. Organomet. Chem., 1981, 219, 1.
R. C. Larock and D. R. Leach, Organometallics, 1982, 1, 74.
E.-I. Negishi, F.-T. Luo, R. Frisbee, and H. Matsushita, Heterocycles, 1982, 18, 117.
M. T. Rahman, Monatsh. Chem., 1982,113, 91.
l B 5 Y. Fujiwara, 0. Maruyama, M. Yoshidomi, and A. Taniguchi, J. Org. Chem., 1981,
46, 851.
reacted similarly. Subsequent coupling with alkenylcuprates, followed by
further reactions, gave (109, and desulphurization with Raney nickel led to
bicyclic and tricyclic prostanoic acid analogues such as (1O6).l8(j The cyclo-
metallation of 2(2-thienyl)- and 2-(3-thienyl)-pyridine with Pd", Rh" and 7
Ru" complexes has been in~estigated.'~'The cleavage of (107) with iodine

has been studied.'88
Silicon. The dehy dr ocondensa t ion of met hyldi-(2-thieny1)silane with various

alcohols in the presence of amines has been in~estigated.'~~ The template
effect of thiophen in the photochemical chlorination of (108) with sulphuryl
chloride has also been studied.'"
Photochemistry of Monocyclic Thiophens. - The HCCS radical has been

J 3
identified, by theoretical calculations, as a transient species during the flash

photolysis of thiophen.'" Various physical measurements, such as differential
scanning calorimetry, thermogravimetry, and mass-spectral studies, have been
R. C. Larock, D. R . Leach, and S. M. Bjorge, Tetrahedron Lett., 1982, 2 3 , 7 1 5 .

187
M. Nonoyama and S. Kajita, Transition Met. Chem., 198 1 , 163.
N. E. Kolobova and L. 0. Goncharenko, Izv. Akad. Nauk SSSR, Ser. Khim., 1981,
6,6 7.
189
E. Lukevits and M. Dzintara, Zh. Obshch. Khim., 1981,51, 2043.
I9O R. Breslow and D. Heyer, J. Am. Chem. SOC., 1982, 104,2045.
D. L. Cooper, Chem. Phys. Lett., 1 9 8 1 , 8 1 , 4 7 9 .
carried out on the photo-products that are derived from the photosensitized
cycloaddition reactions between thiophen derivatives and methyl-substituted
maleic anhydrides and maleimide~."~The photoaddition of excited benzo-
phenone to 2,3-dimethyl-, 3,4-dimethyl-, and 2,3,5-trimethyl-thiophenhas
been attempted. Only the 2,3-dimethyl derivative gave a good yield of the
oxetan (109).'93 In a detailed investigation of the photochemistry of 3-aryl-
2-isoxazolines, the 3-(2-thienyl) derivative was also studied. In the presence of
thiophen, cycloaddition products such as (1 10) were formed.'" Photo-
chemical or thermal decomposition of (1 11) gave (1 12), and the structure
(1 12a) was proven by X-ray cry~tallography.~~~ Photolysis of (1 13) gave,
somewhat unexpectedly, (1 14).196 The photocyclization of (1 15) led to the
spiro-annelated product (1 16).19' The photochemical trans-cis isomerization
of (1 17) and of the corresponding selenophen analogue has been examined
( 1 1 0 ) A r = p-NCC6H4 or (111) a ; R = Ph
p- MeOOCC6H4 b ; R = Me
(112) a; R = Ph
b ; R = Me
BraS
19* R. A. Bolivar, E. Cotte, C. Perez, and C. Rivas, Themzochim. Acta, 1981, 45, 125.
193 C. Rivas, D. Pacheco, F. Vargas, and J. Ascanio, J. Heterocycl. Chem., 1981, 18,
1065.
194
T. Kumagai, K. Shimizu, Y. Kawamura, and T. Mukai, Tetrahedron, 1981, 37,3365.
19' C. J. Moody, C. W. Rees, S. C. Tsoi, and D. J. Williams, J. Chem. SOC., Chem.
Commun., 1981,927.
196 S. Jeganathan and M. Srinivasan, Indian J. Chem., Sect. B y 1980, 19, 1028.
19' J.-C. Gramain, Y. Troin, and D. Vallee, J. Chem. SOC., Chem. Commun., 1981, 832.
and quantum yields have been determined.’” Photochemical ring-closure,
in the presence of iodine, of (1 18) gave (1 19),’99 and (121) was obtained
from (12O).*Oo The isomeric triphenyleno [2,1-b] thiophen was obtained from
the 2-thienyl analogue of ( 120).200
Cycloaddition Reactions of Monocyclic Thiophens. - Reviews on sigmatropic

additions and cyclosubstitutions in five-membered heterocyclic compounds
with exocyclic double bonds201 and on syntheses and reactions of hetero-
cycles under high pressures201ahave been published. Interesting work on the
A1C13-catalysed thermal [2 + 21 cycloadditions of but-2-ynedinitrile to
alkylthiophens and further reactions of the adduct have been carried out.
Thus (122b) gave (123a) in 61% yield, together with 4% of 3,4,5,6-tetra-
methylphthalonitrile. The unsymmetrical (122c) gave (123b) and (123c) in
44% and 20% yields, respectively, in addition to 6% of the corresponding
phthalonitrile. Compound (122d) gave 55% of (123d), together with 5.5% of
R1u::
Me
(122) a; R’= R ~ H = (123) a; R1= R2= Me

b ; R1= R2= Me b ; R1= H, R2= But
c ; R1= But, R2= H 2
C ; R1= B u t , R = H
d ; R1= R 2 = (cH2)4 d; R1= R2= (CH2)4
19* M. Reinkhardt, V. G. Mitina, N. S. Pivnenko, and V. F. Lavrushin, Zh. Obshch.

Khim., 1980,5 0 , 2770.
199
R. Pratap, Y. Tominaga, M.L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981,
18,973.
200
201
R. F’ratap, M. L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981,18,1457.
V. N. Drozd and N. S. Zefirov, SulfurRep., 1981,1, 271.
201uK. Matsumoto, T. Uchida, and R M. Acheson, Heterocycles, 1981, 16, 1367.
(124). On the other hand, 2,5-dimethylthiophen reacted differently from
tri- and tetra-alkylthiophens, and gave the 2 : 1 adduct (1 25) in 26% yield.202
Thermal rearrangements of (122a-c) to (126) occur in high yields at 110-
14OoC, while photochemical rearrangement occurs to (1 27) via cleavage of
the C( 1)-S bond; prolonged irradiation of (127c) leads to (128). Mechanistic
suggestions for the rearrangements are given.203 Extrusion of sulphur occurs
when the compounds (126) and (127) are heated to 285°C in solution,
yielding phthalonitriles. From (1 23d), (37) was also obtained." 2-Thienyl-
thiones (129) react with maleic anhydride to yield (1 30), while their reactions
with trinorbornene gave (1 3 l).204Benzyne reacted with various thiophens by
addition to the sulphur and 0-carbon and gave, after loss of acetylene, benzo-
[ b ]thiophens in low (0.5-3.8%) but reproducible yields.205 Evidence for
the formation of 2,3-dehydrothiophen by slow vacuum thermolysis of
thiophen-2,3-dicarboxylicanhydride has been obtained by trapping it with
2,3-dimethylbu tadiene .206*207
H CN
"Y' Me
CN Me Me
Me ( 1 2 6 ) a ; R1= R2= M e
= H
CN
( 1 2 7 ) a ; R1= R2= Me
R2= H
b ; ql= B u t ,
1 2 t
c; R = H , R = BU
202
R. H. Hall, H. J. den Hertog, Jr., and D. N. Reinhoudt, J. Org. Chem., 1982, 47,
967.
203
R. H. Hall, H. J. den Hertog, Jr., and D. N. Reinhoudt, J. Org. Chem., 1982, 47,
972.
'04 H. Ohmura and S. Motoki, Chem. Left., 1981, 2 3 5 .
' 0 5 D. del Mazza and M. G. Reinecke, J. Chem. Soc., Chem. Commun., 1981, 124.
2 0 6 M. G. Reinecke, J . G . Newsom, and K. A. Almqvist, Tetrahedron, 1981, 37,4151.
*07 M. G. Reinecke, J . G. Newsom, and L.-J. Chen, J. Am. Chem. Soc., 1981, 103,
2760.
Carbenoid ring-expansion of thiophen to a 2H-thiopyran has been
observed in the rhodium-catalysed reaction with (132), which gave (133) and
(134).208 Evidence has been presented that the nitrene intermediate (139,
obtained from the corresponding nitro- or azido-derivatives in the usual way,
first gives the aziridine intermediate (136), which then leads to interesting
heteropolycyclic systems such as 3-(2-thienyl)indole derivative^.^'^
Desulphurization and Hydrogenation of Simple Thiophens. - The reduction

of (137) with seven equivalents of lithium in ethylamine at - 20°C gave
(138) in 30-75% yield. The same alcohol was, of course, formed from (137d)
(137) a ; R1= R2= H

b; R1= H, R2= Me
c; R1= Me, R2= H
d; R1= R 2= Me
e; ='R H, R ~ =Et
and (137e), but the (E):(Z)ratios were 9:l and 3:2, respectively. Further-
more, the dihydrothiophens (1 39), prepared via electrochemical reduction of
thiophen-2-carboxylic acids followed by reduction of the methyl ester with
'08 L. Chan and S. A. Matlin, Tetrahedron Lett., 1981, 22, 4025.

'09 P. C. Hayes, G. Jones, C. Keates, 1. Kladko, and P. Radley, J. Chem. Res. (S), 1980,
288.
LiA1H4, gave (138) upon reaction with five equivalents of lithium,21o9211
A modified method for the synthesis of (139) has been described.212Birch
reduction of 2-acylthiophens and of 2-acyl-5-alkylthiophens, followed by
alkylation with alkyl halides, gave 2-acyl-, 2-alkyl-, or 2-acyl-2,5-dialkyl-
thiophens in good yields. Oxidation of these compounds to the 1,l-dioxides
by MCPBA, followed by thermolysis, offers a convenient route to 1,3-
dienyl ketones.213 The Birch reduction of 2-t-butyl-5-pivaloylthiophen to the
corresponding 2,5-dihydrothiophen was a key procedure in the synthesis of
2,6-di-t-butyl-4-methylthiopyrylium salts.'29 Birch reduction of (140) was
used for the synthesis of (141).14' The technical importance of the removal
of thiophens from oil and coal has led to a great number of papers on catalytic
dehydro sulphur ization ? 4-232
'lo A. V. Lozanova, A. M. Moiseenkov, and A. V. Semenovskii, Izv. Akad. NaukSSSR,

Ser. Khim., 1980, 1932.
A. V. Lozanova, A. M. Moiseenkov, and A. V. Semenovskii, Izv. Akad. NaukSSSR,
Ser. Khim., 198 1, 838.
2 1 2 W. G. Blenderman and M. M. Joullid, Synth. Commun., 1981, 11, 881.
'13 K. Kosugi, A. V. Anisimov, H. Yamamoto, R. Yamashiro, K. Shirai, and T. Kuma-
moto, Chem. Lett., 198 1, 1341.
214
P. Pokornf and M. Zdraiil, Collect. Czech. Chem. Commun., 1981,46,2185.
215
J. Devanneaux and J. Maurin, J. Catal., 1981, 69, 202.
216
M.-A. Apecetche, J. Lemaitre, and B. Delmon, Bull. SOC.Chim. Be@, 1981, 90,419.
2 1 7 Yu. I. Yermakov. A. N. Startsev. V. A. Burmistrov, and B. N. Kuznetsov, React.
Kinet. Catal. Lett:, 1980,14, 155..
21 8
M. R. Blake, M. Eyre, R. B. Moyes, and P.B. Wells, Stud. Surf. Sci. Catal., 1981, 7,
591.
219
M. Sugioka and K. Aomura, Hokkaido Daigaku Kogakubu Kenkyu Hokoku, 1980,
79.
220
D. H. Broderick, A. V. Sapre, B. C. Gates, H. Kwart, and G. C. A. Schuit, J. Catal.,
1982, 73, 45.
221
P. Davidova and P. Kovacheva, Neftekhimiya, 1982, 22,93.
222
Yu. I. Ermakov, B. N. Kuznetsov, A. N. Startsev, P. A. Zhdan, A. P. Shepelin, V. I.
Zaikovskii, L. M. Plyasova, and V. A. Burmistrov, J. Mol. Catal., 1981, 11, 205.
223
S. Gultekin, Chim. Acta Turc., 1981, 9, 257.
214
T. W. Matheson and K. C. Pratt, React. Kinet. Cafal. Lett., 1981, 18, 21.
22s
F. E. Massoth and K. S. Chung, Stud. Surf. Sci. Catal., 1981, 7 , 629.
226
A. V. Mashkina, V. N. Yakovleva, N. E. Buyanova, and Z. A. Dovbii, Kinet. Katal.,
1982, 23, 58.
227 Y. Okamoto, H. Tomioka, T. Imanaka, and S . Teranishi, Stud. Surf. Sci. Catal.,
1981, 7, 616.
"* F. Ruette and E. V. Ludena, J. Catal., 1981, 67, 266.
229 I. Rajca, A. Borowski, and A. Marzec, Erdoel Kohle, Erdgas, Petrochem., 1982, 35,
36.
"O R. Ramachandran and F. E. Massoth, Can. J. Chem. Eng., 1982, 60, 17.
231 A. M. Kuliev, F. A. Teimurova, and I. F. Mustafaeva, Khim. Vys. Energ., 1981, 15,
379.
232 M. Sugioka and K. Aomura, Hokkuido Daigaku Kogakubu Kenkyu Hokoku, 1981,
53.
The Structures and Reactions of Hydroxy-,Mercapto-, and Amino-thiophens.-
A convenient synthesis of the 2-aryl-5-hydroxythiophensystem consists of
the reaction of the corresponding butenolides with sodium hydrosulphide-
hydrogen chloride .48 3-Hydroxy-4-anilinomethylthiophenexists in the stable
tautomeric form (25).46 The allyl ether of dimethyl 3-hydroxythiophen-
2,5-dicarboxylate was prepared in DMF by its reaction with sodium hydride
and allyl bromide.233
Thienylthioethanols were obtained in high yields by the reaction of
thiophen-2-thiols with ethylene oxide.234 The reaction of 2,4-dinitro-3-
bromothiophen with sodium dimethylthiocarbamate or sodium t-butyl-
trithiocarbonate yielded (142). Decomposition of (142b) in glacial acetic acid
led to a mixture of (143) and (144) in moderate yield. The reaction of
thiophen-3,4-dithiol with phosgene chloride, followed by nitration, gave
( 145).235 The reaction of thiophen-2-thiol with p-(methylsulphonyl)bromo-
benzene was used for the preparation of 2-thienyl p(me thylsulphony1)phenyl
~u1phide.l~~
A dramatic increase in the number of papers on the synthesis of derivatives
of thiophensulphonic acids can be n 0 t e d , ~ 2 ~ - and ~ ~ is~certainly
* ~ ~ - con-
~ ~ ~
nected with the interest in such compounds with bacterioci-
da1,237,239 -241 or pesticidal activity.lz6*236 The reaction kinetics of substi-
tuted thiophen-2-sulphonyl chlorides and of thiophen-3-sulphonyl chloride
NO2 02N
(142) a; R = NMe2
b ; R = SBut
233
D. Binder, C. R. Noe, and B. C. Rager, Arch. Pharm. (Weinheim, Ger.), 1981, 314,
751.
234
A. V. h i s i m o v , V. S. Babaitsev, and E. A. Viktorova, Vesfn. Mosk. Univ., Ser. 2:
Khim., 1981, 22, 508.
2 3 5 K. Rasheed and J. D. Warkentin, J. Heterocycl. Chem., 1981, 18,1581.
236 R. J. Cremlyn, F. J. Swinbourne, and K.-M. Yung, J. Heterocycl. Chem., 1981,
18,997.
237 C. T. Goralski, US P. 4 264 774, 1981.
238 V. A. Martyushenko and M. M. Kremlev, Vopr. Khim. Khim. Tekhnol., 1980, 60, 3.
239 G. Levitt, Eur. Pat. Appl. 41 404,1981.
240 A. M. El-Naggar, F. S. M. Ahmed, A. M. Abd El-%lam, and T. M. Ibrahim, Egypt. J.
Chem., 1981, 23,273.
241 C. T. Goralski, US P. 4 309 554,1982.
and fluoride with anionic and neutral nucleophiles has been studied in detail,
and the reaction mechanism discussed. Hammett- and Taft-type correlations
were o b s e r ~ e d . ~The
~ ~ catalytic
, ~ ~ ~ effects of silver nitrate and of silver
nitrite on the hydrolysis of substituted thiophen-2-sulphonyl chloride were
also investigated .244
Methyl 3-amino-4-arylthiophen-2-carboxylates have been hydrolysed and
decarboxylated to relatively stable 4-arylaminothiophens. They could also be
diazotized and reduced to methyl 4-arylthiophen-2-carbo~ylates.~~ Catalytic
reduction of 2-amino-3-nitrothiophen to the unstable 2,3-diaminothiophen,
using Raney nickel W2, was achieved; the crude product reacted with biacetyl
to give 2,3-dimethylthieno[2,3-b] p y r a ~ i n e .Several
~ ~ ~ aminothiophens have
been prepared by Curtius-type reactions. Trimethylsilyl azide, containing
trace amounts of potassium azide and 18-crown-6 ethers, is considered to be
a safe and stable substitute for hydrazoic acid for the preparation of acyl
azides from unreactive acid chlorides, and was used for the preparation of
ethyl 4-etho~ythiophen-3-carbamate.~~~ From 2-nitrothiophen-2-carbonyl
azide, t-butyl 5-nitrothiophen-2-carbamate and 2-amino-5-nitrothiophenhave
been prepared.8' 3-Aminothiophen has been prepared from thiophen-3-
carboxylic acid via isopropyl 3-thienylcarbamate. It was demonstrated that
the instability of 3-aminothiophen was due to polymerization via di(3-
thieny1)amine and tri(3-thien~l)amine.~~'
Selective hydrolysis of (146), followed by Curtius reaction, was used for
the preparation of ( 147).233 Some t-butyl 4-methoxy-2-thienylcarbamates
have also been prepared.248 From (147) and analogous methoxy derivatives,
the hydrazine derivatives were prepared by reaction with o-(p-nitrobenzoy1)-
hydroxylamine and sodium hydride in DMF.233* 248 N-Alkylated derivatives
of acylaminothiophencarboxylic acid appear to be of medicinal interest ?49 * 250
242 A. Arcoria, F. P. Ballistreri, G. Musumarra, and G. A. Tomaselli, J. Chem. Soc..

Perkin Trans. 2, 1981,221.
243 F. P. Ballistreri, k Cantone, E. Maccarone, G. A. Tomaselli, and M. Tripolone, J.
Chem. SOC.,Perkin Trans. 2, 1981,438.
244 F. P. Ballistrera and G. A. Tomaselli, J. Heterocycl. Chem., 1981, 18, 1229.
245 D. Binder, C. R. Noe, F. Geissler, and F. Hillebrand, Arch. Pharm. (Weinheim, Ger.),
1981, 314, 564.
246 J. D. Warren and J. B. Press, Synth. Commun., 1980, 10, 107.
141
'S. Rault, M. Cugnon de Servricourt, and M. Robba, Recl. Trav. Chim. Pays-Bas, 1982,
101, 205.
248
D. Binder, B. C. Prager, and C. R. Noe, J. Chem. Res. (S), 1981, 140.
249 B. P. Clark, W. B. Jamieson, W. J. Ross, A. Todd, and J. P. Verge, Br. P. 1598 900,
1981.
H. H. Lautenschlaeger, H. Betzing, J. Winkelmann, M. Probst, and B. Stoll, Ger.
Offen. 3 020 575, 1981.
The reaction of (148) with glycol and hydrogen peroxide gave (149).251
Compound (19b) has been reduced with LiAlH4 to the corresponding alcohol,
which was converted into the aldehyde and bromomethyl and aminomethyl
derivatives that are of pharmaceutical interest.42 A mild method for the
hydrolysis and decarboxylation of various amides of methyl 3-aminothiophen-
2-carboxylates has been developed.252 Thermal decomposition of (1 50) led
to cleavage of the thiophen ring, with extrusion of sulphur and formation of
the isothiazole (15 1).253
H H
(148) R = CN or COOEt (149)
Reactives of Side-Chains of Monocyclic Thiophens. - The rate constants

for the esterification of some 3-, 4-, and 5-substituted thiophen-2-carboxylic
and of some 2- and 4-substituted thiophen-3-carboxylic acids2”
with diazodiphenylmethane in methanol solution have been measured, and
linear correlations gave information about the transmission of substituent
effects. The rates of alkaline hydrolysis of ethyl thiophen-2-carboxylate in
ethanol-water and DMSO-water media have been measured and compared
with those of other heterocyclic esters.256 The kinetics of iodination of 2-
acetylthiophen in methanol-water, using different carboxylate buffers, have
been Basicity constants have been measured for P(2-thienyl)-
acrylamides and compared with those of the corresponding benzene and
furan derivatives .258 The acidity constants of (E)a-phenyl-P-(2 -thieny1)-
acrylic acids and analogous furan-, selenophen-, and pyridine-substituted
compounds have been measured, and have been rationalized by an equation
involving separate contributions of polar, conjugative, and steric effects of
the heterocycles.259
251 H. Wamhoff, G. Hendrikx, and M. Ertas, Liebigs Ann. Chem., 1982,489.
252 I. G. C. Coutts, M. Edwards, and D. J. Richards, Synthesis, 1981,487.
253
C. J. Moody, C. W. Rees, and S. C. Tsoi, J. Chem. SOC.,Chem. Commun., 1981,5 5 0 .
254 R. Noto, S. Buscemi, G. Consiglio, and D. Spinelli, J. He&rucycZ. Chem., 1981, 18,
735.
255 G. Consiglio, D. Spinelli, S. Gronowitz, A-B. Hornfeldt, and R. Noto, Chem. Scr.,
1982,19,46.
256
G. V. Rao, M. Balakrishnan, N. Venkatasubramanian, P. V. Subramanian, and V.
Subramanian, Indian J. Chem, Sect B , 1981,20, 793.
251
N. Satyanarayana, P. R Rao, and E. V. Sundaram, Indian J. Chem., Sect. B , 1981,
20, 733.
”* G. Alberghina, M. E. Amato, S. Fisichella, and S. Occhipinti, Gazz. Chirn. Ztul., 1981,
111,231.
259
E. Maccarone, A. Mamo, G. Perrini, and M. Torre, J. Heterocycl. Chem., 1981,18,735.
102 Heterocyclic Chernistry
Reactions of Thiophen Aldehydes, Ketones, and Carboxylic Acids. - Numer-
ous anils have been prepared from thiophencarbaldehydes wtih aromatic
and heterocyclic amines, and products from their reaction with mercaptoacetic
acid and diazomethane have been d e ~ c r i b e d . ~ ~ p-(Phenylsulphony1)-
'-~~~
benzoic acid, thenylidene hydrazides, and thenylidene hydrazides of p,p'-
diphenylsulphonyldicarboxylic acids have been synthesized; they show
antibacterial activity.266* 267 Thiophen-2-carbaldehyde has been condensed
with 2-methyl-3-nitrochromone in connection with work on 242-thienyl)-
pyrrolo [3,2-b][ 11 benzopyrans,268 and with 2-trimethylsiloxyfuran to give
2-thenylidene-4-b~tenolide.~~' It has been allowed to react with 2-fluoro-3-
pyridyl-lithium to yield the corresponding carbin01.~~'Further interest has
been shown in chalcone-type derivatives that are obtained from thiophen-
~arbaldehydes~~' -273 and in their use in synthesis; e.g., for 2-amino-4-(2-
thieny1)pyridines through the reaction with ma lo no nit rile^.^^^ 5-Nitro-
thiophen-2-carbaldehyde has been condensed with amides of carboxymethane-
sulphonic acid to give (1 52).275 2-Acetylthiophens were condensed with
(153) to give (154).276
Electrochemical hydrodimerization of thiophen-2-carbaldehyde via the
anion radicals led only to a 10% yield of the pinacol; the same amount of
260 M. S. K. Youssef, Croat, C h e m Acta, 1980, 53,453.

"'
262
M. S. K. Youssef, Rev. R o u m Chim., 1981, 26,471.
M. S. K. Youssef and'Kh.M. Hassan, Rev. Roum. Chim., 1981, 26,81.
26 3
W . D. Rudorf and M. Augustin, 2. Chem., 1982, 22, 255.
264 M. S. K. Youssef, J. Chem Technol. Biotechnol., 1981, 31, 363.
265 M. S. K. Youssef, Rev. R o u m C h i m , 1981, 26, 1005.
266 A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28, 159.
267 A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28,229.
268 C. Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981, 234.
269 M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron L e t t , 1981, 22,
4269.
2 70
T. Gungor, F. Marsais, and G. Queguiner, J. Organomef Chem., 1981, 215,139.
271
Yu. D. Churkin and L. V. Panfilova, USSR P. 802 282, 1981 (Otkrytiya, Izobret.,
Prom Obraztsy, Tovamye Znaki, 1981, 86).
2 7 2 N. Geum, F. Ghozland, J. P. Gorrichon, and P. Maroni, Bull. Soc. Pharm. Bordeaux,
1981, 120, 39.
273 E. Degny, S. Z. Zard, R. Pastor, and A. Cambon, Tetrahedron L e a , 1981, 22,2169.
274 N. Latif, N. Mishriky, and N. S. Girgis, Indian J. Chem, Secf B y 1981, 20,147.
275 D. R. Shridhar, C. V. Reddy Sastry, K. B. Lal, A. K. Manvah, G. S. Reddi, K. K.
Bhopale, H. N. Tripathi, R. S. Khokhar, K. Tripathi, and G. S. T. !hi,Indian J.
Chem, Sect. B, 1981, 20,234.
276
A. I. Pavlyuchenko, E. I. Kovshev, and V. V. Titov, K h i m GeterotsikL Soedin., 1981,
85.
(155) was also obtained.277 However, another group found that, by adding
small amounts of LiC104 to the reaction medium, the yield of 1,2-di(2-
thienyl)ethane-l,2-diolcould be increased to 80%.278
Two one-pot procedures for the conversion of thiophencarbaldehydes into
the nitriles consist in treatment with nitroethane and pyridine hydro-
chloride279 or with hydroxylamine hydrochloride and N-methylpyrroli-
done.280 2-Thenoylacetonitrile has been allowed to react with CS2 in the
presence of sodium hydride to give the disodium salt (156), which was
alkylated with various reagents.281
A very convenient method for the synthesis of (1 58) consists in the side-
chain bromination of 2-thienyl ethyl ketone followed by reaction with
sodium methoxide in methanol and with methanesulphonyl chloride in
pyridine, which gave (157) in 88% yield. Treatment of (157) with calcium
carbonate led to 1,2-rearrangement of the thienyl group to give (158).282
Metal complexes of ~yn-thiophen-2-aldoxime,~~~ thiophen-2-carbaldehyde
2-benzothia~olylhydrazone,~~~ and thiophen-2-carbaldehyde thiosemicarba-
have been studied.
The reaction of ethyl thiophen-2-carboxylate with triphenylphosphine-
CC14 gave (1 59), which upon acidic hydrolysis afforded the dichloromethyl
ketone.286 2-Thenoyl chloride reacts with some piperazine derivatives.287
Trimethylsilyldiazomethane has been used as a safe reagent in the Arndt-
Eistert reaction for the transformation of 2-thenoyl chloride into benzyl 2-
thienylacetate .288
Na' -S S- Na+
H
(155) OMe
(157)
Me OE t
(158) (159)
277 V. P. Gul'tyai, L. M. Korotaeva, A. P. Rodionov, and A. M. Moiseenkov, Izv. Akad

NaukSSSR, Ser. Khim., 1981, 1150.
278
V. P. Gul'tyai, L. M. Korotaeva, A. S. Mendkovich, and I. V. Proskurovskaya, Izv.
Akad. NaukSSSR, Ser. Khim., 1981, 834.
2 79
D. Dauzonne, P. Demerseman, and R. Royer, Synthesis, 1981,739.
280 P. Audoye, A. Gaset, and J. P. Gomchon, Chimia, 1982, 36,4.
281 W.-D. Rudorf and M. Augustin, Phosphorus Sulfur, 1981,9,329.
282
G.-I. Tsuchihashi, K. Kitajima, and S. Mitamura, Tefmhedron Lett., 1981, 22,4305.
283 H. B. Singh, D. Singh, R K. Negi, and V. K. Gupta, J. Inorg. Nucl. Chem., 1981,
43, 1915.
284 T . Odashima and H. Ishii, Nippon Kagaku Kaishi, 1982,425.
28s C. G. R. Nair and K. K. Aravindakshan, J. Inst. Chem. (India), 1981, 53, 295.
286 M. Suda and A. Fukushima, Tetrahedron Lett., 1981, 22, 759.
287 G. Drugarin, I. Jianu, P. Geita, and A. Drugarin, Pharmazie, 1981, 36, 709.
T. Aoyama and T. Shioiri, C h e m P h a m Bull., 1981,29, 3249.
104 Heterocyclic Chemisliy
Reactions of Vinylthiophens and Related Compounds.- 2-Aroyl-5-vinyl-
thiophens react with triphenylphosphine, palladium chloride, and carbon
monoxide to give 2-(5-aroyl-2-thienyl)propionic acid.289 Cycloaddition of
sulphene, from methanesulphonyl chloride and triethylamine, to 2(a-
dimethylaminoviny1)thiophen gave (1 60).290 The synthesis of some substi-
tuted 3-(2-thienyl)acryloylamino-acids has been described.291 Some reactions
of ~-chloro-~(2-thienyl)vinylphosphonicacid dichlorides have been ~ t u d i e d . 2 ~ ~
Reactions at Benzylic Positions. - The catalytic oxidation, using a cobalt

bromide catalyst, of 2,5-dimethylthiophen to the d i a l d e h ~ d e ,of~ ~
3-methyl-
~
2-ethylthiophen to 2-acetyl-3-methylthiophen and 1-(3-methyl-2-thienyl)-
ethyl a ~ e t a t e , ~ "of the four isomeric methyl acetothienones to the cor-
responding acetylthiophencarboxylic and of 2-acetoxymethy1thio-
phen to thiophen-2-carboxylic acid296 has been reported. The Wittig
reaction between 2- and 3-thenyltriphenylphosphonium salts and crocetin
dialdehyde has been used for the synthesis of carotenoid analogues with
terminal thiophen rings.297
The Wittig reaction between diethyl 2-thenylphosphonate and 2-acetyl-
naphthalene was the first step in the synthesis of pyreno [ b ]t h i 0 ~ h e n s . l ~ ~
2-Thenyl chloride and 3-thenyl bromide have been allowed to react with
ethylglycine to give N-(2-thenyl)- and N-(3-thenyl)-glycine, and have been
used for an alternative synthesis of tic10pidine.l~~The reactions of 2-thenyl
chloride and of 2,5-dichloro-3-thenyl chloride with the lithium enolate of
ethyl cyclohexanecarboxylate gave (50) and (5 1).13' Similarly, (67) was
obtained from 2-(2-thienyl)ethyl bromide .139 2-Thenyl ally1 ether, upon
treatment with butyl-lithium at - 3OoC, underwent a [2,3] -sigmatropic
rearrangement to give 4-(2-thenyl)but- 1-en-4-01.~~'
Esters of 3,4,5-trichloro-2-hydroxymethylthiophen have been prepared?99
Jpn. Kokai Tokkyo Koho 82 32 279,1982.
291
L. N. Koikov, P. B. Terent'ev, and N. S. Kulikov, Zh. Org. Khim., 1981, 17, 1087.
A. M. El-Naggar, M. N. Aboul-Enein, and A. A. Makhlouf, Glm. Hem. Drus Beograd,
1981,46,545.
2 9 2 G. F. Nazvanova, V. V. Moskva, T. Sh. Sitdikova, and F. A. Kashfarova,Izv. Vyssh.
Ucheb. Zaved. K h i m Khim. Tekhnol., 1982, 25,37.
293 I. Iovel, Yu. Sh. Gol'dberg and M. V. Shimanskaya, USSR P. 883041, 1981
(Otkrytiya, Izobref, R o m Obraztsy, Tovamye Znaki, 1981, 102).
294 M. N. Volkov and 0. k Kazakova, Khim Geterotsikl. Soedin., 1981,758.
295
0.A. Kazakova, M. N. Volkov, and P. A. Konstantinov, Zh. Org. Khim., 1981,
17, 511.
296 T. V. Shchedrinskaya, A. A. Leichenko, and M. N. Volkov, Zh. Org. Khim., 1981,
17,2177.
197
H. R. Brahmana, K. Katsuyama, J. Inanaga, T. Katsuki, and M. Yamaguchi, Tetra-
hedron Lett., 1981, 22, 1695.
298
A. V. Anisimov, L. V. Mozhaeva, and E. A. Viktorova, Zh. Org. Khim., 1981, 17,
1560.
299
S. G. Kon'kova, A. A. Safaryan, and A. N. Akopyan, Arm. Khim Zh., 1981, 34,
790.
Various Reactions in the Side-Chains of Thiophens. - The preparation of
various N-substituted thieno [3,2-fl morphans from 2,5-dimethylthieno [3,2-
fl morphan has been de~cribed.~" Several thiophen isosteres of proto-
berberine alkaloids have been prepared, starting from amides between 3-
thienylacetic acid and substituted 0-phenylethylamine or /3-(3-thienyl)ethyl-
amine, followed by classical cyclization to dihydroisoquinolines, reduction to
the tetrahydro system, and Mannich-type reaction with f~rmaldehyde.~'~
A new mild and convenient method for esterification of a-keto-acids has
been applied to 2-thienylglyoxylic acid.302 A convenient method for the
resolution of &(2-thienyl)alanine has been described.303
Macrocyclic Thiophens. - Novel macrocyclic Schiff-bases (1 6 l), containing
thiophen, have been prepared by the non-template condensation of a,w-
amino-ethers with thiophen-2,5-dicarbaldehyde. Silver complexes were
prepared and crystal structures were determined both for some macrocycles
and for a silver complex.304 In attempts to prepare bridged thia[l7]-
annulenes, (1 62) was prepared through the reaction of 2,5-dichloromethyl-
thiophen with p-carb oxyt oluene-cu-t hiol. Transformation of the carb oxyl
groups of (162) into bromomethyl, followed by reaction with sodium
sulphide, gave (1 63). The Wittig reaction of 3,4-diformyl-2,5-dimethylthiophen
S S
T
6 b
7- AT-,
(161)
(163)
300
J. Bosch, M. Alvarez, and R. Granados, Anal. Quim, 1981, 77,346.
301
S. Jeganathan and M. Srinivasan, Phosphorus Sulfur, 1 981, 11, 12 5.
302 J. M. Domagala, Tetrahedron Lett., 1980, 21,4997.
303 A. W. Lipkowski and G. Fluoret, Pol. J. Chem., 1980, 54,2225.
304 N. A, Bailey, M. M. Eddy, D. E. Fenton, G. Jones, S. Moss, and A. Mukhopadhyay,
J. Chem SOC.,Chem. Commun., 1981,628.
106 Heterocyclic Chemisw
with pent-4-ynyltriphenylphosphoniumylide gave (1 64), which by Glazer
coupling was transformed into (165). It could not be conclusively established
7');
that prototropic rearrangement with potassium t-butoxide in t-butyl alcohol
gave (166).305
~ Melfs]MeJ I
- -
- - (CH =CH)
6
(165) (166)
Reaction at Sulphur: Thiophen Dioxides. - The stable S-ylide (167) was

formed, in 40% yield, in the reaction of 2-isobutenylthiophen with dimethyl
diazomalonate in the presence of rhodium acetate .306 The transient thiophen
1,l -dioxide that is formed on treatment of 3,4-dibromotetrahydrothiophen
1,l-dioxide with base gave mono- and di-adducts such as (168) - (1 72) in the
presence of 1,3-dipoles such as N-a-diphenyl nitrone and mesitonitrile oxide.
The structures of the adducts were partly proven by X-ray cry~tallography.~~'
The reaction of 13C-labelledtransient thiophen 1,l -dioxide with 6-dimethyl-
aminofulvene has been utilized for the preparation of 13C-labelleda ~ u l e n e . ~ ' ~
Rate constants for the reaction of 2,3,4,5-tetrachlorothiophen1,l -dioxide
with para-substituted styrenes have been measured, and MO calculations on
this type of cycloaddition have been carried The reaction of tetra-
chlorothiophen 1,l-dioxide with (172) led to (173), having an iceane
'05 T. M. Brown, W. Carruthers, and M. G. Pellatt, J. Chem. Soc., Perkin Trans. 1 , 1982,
483.
' 0 6 V. M. Shostakovskii, A. E. Vasil'vitskii, V. L. Zlatkina, and 0. M. Nefedov, Izv.
Akad. NaukSSSR, Ser. Khim., 1980,2180.
'07 A. Bened, R. Duran, D. Pioch, P. Geneste, J. P. Declercq, G. Germain, J. Rambaud,
and R. Roques, J. Org. Chem., 1981,46,3502.
308
K.-P. Zeller and S. Berger, 2. Namrforsch., Teil. B y1981, 36, 858.
309 K. Kanematsu, K. Harano, and H. Dantsuji, Heterocycles, 1981, 16, 1145.
skeleton.310 It was found that 2,5-dimethyl-3-chlorothiophen1,l-dioxide
reacted with butyl-lithium via addition to the 4,5-position to give a mixture
of the enynes (174a) and (174b), after ring-opening and loss of sulphur
dioxide. With the corresponding 3-bromo-derivative, a competing halogen-
metal exchange occurs, followed by ring-opening to a vinyl sulphinate, which
was trapped as (1 75) with benzyl br~mide.~"Nitration of 3,4-dimethylthio-
phen 1,l-dioxide with N204in chloroform gave 23% of the 2,5-dinitro-3,4-
dimethylthiophen 1,l-dioxide, which gave (176) when refluxed in ~ y l e n e . ~ " ~
Theoretical calculations on the barrier to inversion in thiophen 1-oxide
have been carried out and compared with results for 1,2,5-thiadiazole 1-
oxides.312 The addition of dichlorocarbene to 2,Sdihydrothiophen 1,l-
dioxides has been used for the synthesis of (177), and further reactions of
this system have been investigated.313 The photocycloaddition of 2,s-
dihydro-3-methylthiophen 1,l-dioxide to citraconic anhydride gave (178),
which was transformed into the corresponding dimethyl ester. Upon heating,
the ester eliminated SOz to give (1 79), which, under the reaction conditions,
underwent Cope rearrangement to the geraniol derivative (180).314 Upon
flMe
R1 1
(174) a; R = M e , R = Bu
2
b ; R1= Bu, R = M e
2 M e f M eSOOCH 2Ph
(175)
02NCH=CH-CH=
I I
Me
(176)
Me
CHN02
(177) (178) 0
Me
(179)
310
D. P. G. Hamon and P. R. Spurr, J. Chem Soc., Chem. Commun., 1982,372.
31 1
J. 0.Karlsson, S. Gronowitz, and A. Hallberg, Actu Chem. Scund., Ser. B, 1982,
36, 341.
'
"
'M
. V. Titova, V. M. Berestovitskaya, and V. V. Perekalin, Metody Sint., Str. Khim.
Prevrushch. Nitrosoedin., 1980, 37.
312
J. S. Amato, S. Karady, R. A. Reamer, H. B. Schlegel, J. P. Springer, and L. M.
Weinstock, J. A m C h e m SOC.,1982, 104,1375.
Y . Gaoni,J. Org. Chem., 1981, 46,4502.
314
J. R. Williams and C. Lin, J. Chem. SOC.,Chem Commun., 1981,752.
treatment of 2,5dihydrothiophen 1-oxide and 2,s-dihydrothiophen 1,l-
dioxide with strong bases, the resulting anions underwent ring-opening to
buta-l,3-dienylsulphenateand buta-l,3-dienylsulphinates,which could be
alk~lated.~"Nitration of 3-methyl-4,5-dihydrothiophen 1,l -dioxide occurred
in the 2-position, while the 3-phenyl analogue reacted in the p a r a - p ~ s i t i o n . ~ ' ~
The reaction of salts of dithiocarbamic acid with 3-substituted 4J-dihydro-
thiophen 1,l-dioxides or 3,4-disubstituted thiophen 1,l-dioxides gave (1 82)
via (181).317 Treatment of (183) with thionyl chloride gave (184), which
underwent cycloaddition with ~yclopentadiene.~'~ The chlorination of cis-
2,s-diphenyltetrahydrothiophen 1,l-dioxide occurred with inversion to give
the trans-2,5-dichloro-2,5-diphenylthiophen 1 , l-dioxide, as proven by X-ray
~rystallography.~'~ Some other aspects of the chemistry and use of dihydro-
and tetrahydro-thiophen 1,l -dioxide320-326 and of sulphilimine and related
derivatives327- 329 have been published.
Di- and Tetra-hydrothiophens.- Direction control in the preparation of the

very useful 3-oxotetrahydrothiophenshas been achieved by using half-thiol
315 R. L. Crumbieand D. D. Ridley, Aust. J. Chem., 1981, 34, 1017.

316 M. V. Titova, V. M. Berestovitskaya, and V. V. Perekalin, Zh. Org. Khim., 1981,
17, 1322.
317
T. E. Bezmenova, G. I. Khaskin, V. I. Slutskii, P. G. Dul'nev, L. N. Zakharov, V. I.
Kulishov, and Yu. T. Struchkov, Khim. Geteroaikl. Soedin., 1981, 907.
318 G. A. Tolstikov, N. N. Novitskaya, and E. E. Shul'ts, Zh. Org. Khim., 1981, 17,
1111.
319
S. E. Lauritzen, C. RQmmhg, and L. SkattebQl, Acta Chem. Scand., Ser. B , 1981,
35, 263.
320 S. M. Lukashov, P. I. Parkhomenko, Yu. N. Usenko, and T. E. Bezmenova, USSR
P. 522 605, 1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981,
2 86).
321 P. I. Parkhomenko, Ukr. Khim. Zh. (Russ. E d ) , 1980,46, 1294.
322 P. G. Dul'nev and T. E. Bezmenova, USSR P. 794012, 1981 (Otkrytiya, Izobret,
Prom. Obmztsy, Tovamye Znaki, 1981, 95).
323
A. Ts. Malkhasyan, E. M. Asatryan, S. M. Mirakyan, and G. T. Martirosyan, USSR
P. 810696, 1981 (Otkrytiya, Izobret, Prom. Obraztsy, Tovamye Znaki, 1981, 92).
324 R. A. Dorofeeva, T. E. Bezmenova, T. N. Arkhipova, and T. I. Piskunova, USSR
P. 787 409,180 (Otkrytiya, Izobret, Prom. Obraztsy, Tovamye Znaki, 1980,96).
32s L. N. Shkaraputa, L. A. Tishchenko, V. T. Sklydr, I. A. Manza, and A. G. Gordienko,
Khim TekhnoL (Kiev), 1981, 32.
326 F. Mauer, I. Hammann, and B. Homeyer, Ger. Offen. 3 003 019, 1981.
327 G. Abe and J. M. Shreeve, J. Chem. Soc., Chem. Commun., 1981,242.
328 T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20, 2432.
329 T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20,2894.
diesters in the Dieckmann c y c l i ~ a t i o n Improved
.~~ methods for the synthesis
of 3-oxo-4-methoxycarb onyl- and 3-oxo-2-met hoxycarbonyl-te t rahy dr othio-
phen, by carrying out the reaction of methyl thioglycollate with methyl
acrylate under different conditions, have been described.331 The condensation
of methyl thioglycollate with cyclohexenone gave (1 SS), and its further
chemistry and stereochemistry were investigated.332 The Tic&-catalysed
photochemical reaction of (186) in methanol gave ( 187).333The carbene that
was generated from (188) by treatment with MeLi gave ( 189).334 Irradiation
of (190) in benzene gave 63%of diphenyl disulphide and 49% of (19 1). Brief
irradiation of (190) in acetonitrile gave, however, (192) as the main
p r ~ d u c t . ~ ~From ~ reactive 1,3-dipole (193), formed in the reaction
' , ~ ~the
between diazomethane and thiobenzophenone, the di- and tetra-hydrothio-
phens (194) - (196) were obtained by reaction with the appropriate
d i p ~ l a r o p h i l e .Evidence
~~~ for the existence of 2,2,5,5-tetramethyl-1-thia-
" >r d ) S
B CHMe
Me Me
(189) OH
(193) ( 194) Ph
(195) X = 0 , N M e , or N P h
Y. Yamada, T. Ishii, M. Kimura, and K. Hosaka, Tetrahedron Lett., 1981, 22, 1353.
331
H.-J. Liu and T. K. Ngooi, Can. J. Chem., 1982, 60,437.
332
P. N. Confalone, E. Baggiolini, B. Hennessy, G. Pizzolato, and M. R. Uskokovik,
J. Org. Chem., 1981, 46,4923.
333 K. Saito, H. Yuki, T. Shimada, and T. Sato, Can. J. Chem., 1981, 59, 1722.
3 3 4 M. S. Baird, J. Chem. Res. (S), 1981, 352.
335 T . Sasaki, K. Hayakawa, and S. Nishida, Tetrahedron Lett., 1980, 21, 3903.
336 T. Sasaki, K. Hayakawa, and S. Nishida, Tetrahedron, 1982, 38, 7 5 .
337 I. Kalwinsch, L. Xingva, J. Gottstein, and R. Huisgen, J. Am. Chem. SOC., 1981,
103, 7032.
cyclopent-3-yne as a reactive intermediate has been presented. It was trapped
as a cyclo-adduct with phenyl azide and 2 , 5 - d i m e t h y l f ~ r a nThe
. ~ ~sulphonium
~
ylide (197) can be isolated, since its [3,2] -sigmatropic rearrangement is
inhibited by steric strain. It reacts in a bimolecular fashion to give butadiene,
2,5-dihydrothiophen, and (198).339 Treatment of (199) with base led to
(200) via a ring-opening reaction.340 Tetrahydrothiophens have been prepared
from dithiotetritols.'' A method for condensing various salicylaldehydes
with y-thiobutyrolactone has been described.342 A detailed investigation, by
i.r. and n.m.r. spectroscopy, of the tautomerism of 2- and 4-ethoxycarbonyl-
thiolate-3-ones has been carried out .M3
Sulphur analogues of prostaglandins that contain di- and tetra-hydrothio-
phen rings, such as the sulphur analogue of A6-PGIIm and (52)- and (5@-6,9-
thiapro~tacycline,~~ have been described. A series of methylated derivatives
of 2-thiobiotin has been synthesized and their i.r. and their 'H and I3C
n.m.r. spectra have been investigated.% Other aspects of di- and tetra-
hydrothiophens are discussed in refs. 347 - 350.
cdyJMe
(199)
338
J. M. Bolster and R. M. Kellogg, J. Am. Chem. SOC., 1981, 103,2868.
339 S. Mageswaran, W. D. Ollis, and I. 0. Sutherland, J. Chem. Soc., Perkin Trans. 1 ,
1981,1953.
340 H. J. Federsel and G. Merenyi, J. Org. Chem., 1981, 46,4724.
341 R. A. Sanchez, Synthesis, 1982,148.
3 4 2 G. A. Miller and N. D. Heindel, J. Org. Chem., 1981, 46,4751.
343 F. DUUS,Tetrahedron, 1981, 37,2633.
344
H. Yokomori, Y. Torisawa, M. Shibasaki, and S. Ikegami, Heterocycles, 1982, 18,
251.
34 5
K. C. Nicolaou, W. E. Barnette, and R. L. Magolda, J. Am. Chem. SOC., 1981, 103
3472.
346 H. Haster and H. Kohn, J. HeterocycL Chem., 1981, 18, 1425.
3 4 7 J. Thiem and H. P. Wessel, Liebigs Ann. Chem., 1982, 607.
348
C. F. Service and A. E. Tipping, J. Fluorine Chem., 1982, 20, 135.
349
J. W. Lown, R. R. Koganty, and A. V. Joshua, J. Or& Chem., 1982, 47, 2027.
3 5 0 W. Kunz, Eur. Pat. Appl. 46 138, 1982.
Arylthiophens and Di- and Poly-heterocycles.- The reaction of (201) with
sulphur gave (202) in 45% yield.351 Treatment of the hydrazone (203) with
PPA at 110°C gave (204), the structure of which was proven by desulphuri-
zation of a degradation product with Raney nickel. From the simple phenyl-
hydrazone of ethyl 2-thienyl glyoxylate, (205) and (206) were obtained in
a 7 : 3 ratio. Authentic (206) was prepared via the Friedel-Crafts reaction of
5(p-nitropheny1)thiophen with oxalyl ester 5-Substituted 2,3-
diarylthi~phens~’~ and 2- [4(3-methyl-:!-thienyl)phenyl] propionic
have been synthesized as anti-inflammatory agents.
The reactions of bithienyls in the presence of molybdenum and tungsten
halides have been in~estigated.~”Some unsaturated bithienyl ketones have
been prepared via condensation of 2-formyl-5‘-methyl-2,2’-bithienyl and 2-
formyl-5’ethyl-2,2’-bithienyl with methyl ketones.356
3,2’: 5‘,3”-Terthiophen and other terthienyls have been prepared by
converting the appropriate t hiophencarbaldehyde into et hynylthiophen,
followed by coupling to dithienylbutadiyne and ring-closure of the middle
ring through reaction with sodium s ~ l p h i d e . ~ ’ ~
(205)
351 V. Ya. Sosnovskikh, Zh. Org. Khim., 1981, 17, 1777.

3 5 2 R. Fusco and F. Sannicol6, J. Org. Chem., 1982, 47, 1691.
3s3 S. C. Cherkofsky, Eur. Pat. Appl. 24 042, 1981.
3 54
T. Kodama, M. Nakabayashi, I. Watanabe, H. Hirano, N. Abe. K. Tanaka, and H. Arai,
US P. 4 230 719,1980.
3 5 5 M. G. Voronkov, V. Z. Annenkova, N. I. Andreeva, V. M. Annenkova, and K. A.
Abzaeva, Izv. Sib. Otd. Akad. NaukSSSR, Ser. Khim. Nauk, 1981, No. 3 , p. 147.
356 Yu. D. Churkin, L. V. Panfilova, E. L. Boreko, M. M. Timofeew, and V. I. Votyakov,
Khim-Farm. Zh., 1982, 16, 167.
3 5 7 J.-P. Beny, S. N. Dhawan, J. Kagan, and S. Sundlass, J. Org. Chem., 1982,47, 2201.
The Vilsmeier formylation of 2- and 3(2-pyrrolyl)thiophen occurs in the
free a-pyrrolic position. If this position is blocked, as in 2- and 3(5-
methoxycarbonylpyrrolyl)thiophen,formylation occurs both in the 5 -position
of the thiophen ring and the 3-position of the pyrrole ring, and in the 2-
position of the thiophen ring and the 3-position of the pyrrole ring,
respectively .358 Starting from 2-(1-pyrrolyl)thiophen-3-carboxylic acid the
corresponding azide gave (207) upon Curtius rearrangement. From the 3-
amino-derivative, (208) was prepared in several steps.359 Similar work has also
been carried out with 3 4 1-pyrrolyl)thiophen-2-carboxylic acid, which also
smoothly underwent Vilsmeier formylation in the 2-position of the pyrrole
ring.360 Compounds (209), prepared through the reaction of a-acetylenic
ketones with p-mercaptoethylamine in the presence of base, gave (210) and
(2 1 1), respectively, upon reaction with hydrazine and h y d r ~ x y l a m i n e . ~ ~ ~
Electrophilic nitration of thienylpyridazines has been studied in
By the addition of 2- and 3-thienyl-lithium to quinoxaline, mono- and di-
thienyl-substituted quinoxalines have been preparedl” and their lithiation
and self-addition further investigated.362 From 1,s -diketones containing
thienyl and fury1 substituents, pyrylium and thiopyrylium salts such as (2 12)
have been prepared.363 13C N.m.r. spectra of compounds related to (212)
have been i n ~ e s t i g a t e d .1,5-Diketones
~~ were also used for the synthesis of
Ph 0
I
S-C=CH-C
II
NH-C=CH -C
I
Ph 0
II
Ph
( 2 1 2 ) X = 0 or S
358
J.-P. Boukou-Poba, M. Farnier, and R. Guilard, Can. J. Chem., 1981,59,2962.
359 S. Rault, M. Cugnon de SBvricourt, N.-H.Dung, and M. Robba, J. HeterocycL Chem.,
1981, 18,739.
360
Y. Effi, M. Cugnon de S h i c o u r t , S. Rault, and M. Robba, Heterocycles, 1981, 16,
1519.
36 1
T. E. Glotova, A. S. Nakhmanovish, G. G. Skvortsova, T. N. Komarova, I. D. Kalikh-
man, and M. G. Voronkov, Zh. Org. Khim., 1981, 17,749.
362 T. Kauffmann and R. Otter, Chem. Ber., 1982, 115, 1825.
363 V. G. Kharchenko, E. V. Burov, and V. A. Sedavkina, Khim. Geterotsikl. Soedin.,
1981, 1604.
364 k R. Katritzky, J. M. Lloyd, and R. C. Patel, Chem. Scr., 1981, 18,256.
2-(2-thienyl)hydroquinolines and related compounds.365 Several 2 -amino-3-
cyano-4,6-di(thienyl) -substit ut ed pyridines and 3-cyan04 ,6-di(thieny1)-
substituted pyridin-2-ones have been prepared by allowing the appropriate
propenones to react with malononitrile and ethyl cyanoacetate , respec-
t i ~ e l y Some
. ~ ~ ~2(2-thienyl)chromones have been prepared from hydroxy-
acet ophenones and t hio phen-2 -carbaldehyde through oxidative cy clization ?7
Several 5 ‘(t hienyl) -substituted 3-methyl-4-pyr azolylcarb oxylic acid derivatives
have been prepared by closure of the pyrazolyl ring, by the reaction of 2-
aroyl-3-methylaminobut-2-enoic acid esters with h y d r a ~ i n e Starting
. ~ ~ ~ from
(213), (214) was prepared by condensation with CS2, followed by alkylation
with ethyl bromoacetate and methyl iodide and then r i n g - c l ~ s u r e .Electro-
~~~
philic substitution reactions of 1-methyl-2-5-[S’-methyl-2‘-(2-thienyl)] -
benzimidazoles have been studied.370 Ethyl p-alkylphenylthiophen-2-
carboxylates and some related thienylpyridines have been prepared and
their liquid-crystalline properties studied.37’
The mass spectra of some formyl derivatives of 2(2‘-thienyl)indole have
been elucidated.372 The electroreduction of 4-(2-thienyl)quinoxaline has
been further in~estigated.~’~ The preparation of 2,5-bis(benzoxazolyl)-
thiophens from thiophen-2,5-dicarboxylic acid has been patented .374- 375
X = NH, N M e , 0 , or S
(214)
Naturally Occurring Thiophens. - A review on the formation of heterocyclic

compounds, including thiophen derivatives, by enzymic and non-enzymic
browning in relation to food flavour has been Some thiophens
have been found as trace constituents in the essential oil from Thymus
capitatus.377 From steam-distilled hop oils, 3-(4-methylpent-3-enyl)thiophen
365 T. V. Zabolotnova, V. A. Kaminskii, and M. N. Tilichenko, Khim. Geterotsikl.

Soedin., 1981,471.
366 N. Latif, F. M. Asaad, and N. S. Girgis, Indian J. Chem., Sect. B , 1981,20,463.
36 7
D. P. Sarbaggya, K. Rangachari, k K. D. Mazurndar, and K D. Banerji, J. Indian
Chem SOC.,1981,58,196.
368 P. Plath and W. Rohr, Synthesis, 1982,318.
36 9
M. Augustin and W. Dolling, 2. Chem., 1981, 21,216.
370 M. M. El’chaninov, A. M. Simonov, V. P. Kosenko, and L. Ya. Oleinikova, Khim.
371
L. A. Karamysheva, E. I. Kovshev, A. I. Paviuchenko, K. V. Roitman, V. V. Titov,
S. I. Torgova, and M. F. Grebenkin,Mol. Crysf. Liq. Cryst., 1981,67,241.
372 B. S. Holla and S. Y. h b e k a r , J. Indian Chem. SOC.,1981, 58,400.
313 T. P. Devi, C. Kalidas, and C. S. Venkatachalam, Bull. Chem SOC.Jpn., 1982, 5 5 ,
286.
3 7 4 W. Schreiber, Eur. Pat. Appl. 31 296, 1981.
375 S. Kell, W. Kipping, B. Noll, W. Rauner, H. Weinelt, H. Krausse, and R. Fischer,
Ger. (East) P. 147 667,1981.
376 G. Vernin and J. Metzger, Bull. SOC.Chim. Belg., 1981,90, 553.
377
V. P. Papageorgiou and N. Argyriadou, Phytochemistry, 1981, 20,2295.
114 He terocycZic Chemistry
has been isolated.378 The new naturally occurring thiophens (21 5) and (216)
have been isolated from Pterocaulon virgatum. 379 Using H-labelled thiophens,
the biosynthesis of terthienyl and other naturally occurring thiophens in
Tagetes patula was studied.380 The identification and analyses of thiophens
from oil and coal have been d e s ~ r i b e d . ~ ~ ' - ~ ~ ~
Thiophen Analogues of Steroids. - A 6a-substituted optically pure steroid

with thiophen as the A ring has been prepared via asymmetric induction.
The absolute configurations of the precursors and of the cyclized products
were determined by c.d.384
Thiophens of Pharmacological Interest. - There has been an almost explosive
development in the number of papers and patents in this field, and the space
that is available allows only a very brief summary. However, most references
will be included, for the benefit of those interested in this field.
Therapy of the Central Nervous System. Many new tricyclic neuroleptic
thiophens have been prepared,14'* 38s -388 such as (2 17)38s and (2 18).386
Numerous diazepine analogues have been prepared as t ranquillizers ,389 -396
378
J. A. Elvidge, S. P. Jones, and T. L. Peppard, J. Chem. SOC., Perkin Trans. 1 , 1982,
1089.
3 79
F. Bohlmann, W.-R. Abraham, R. M. King, and H. Robinson, Phytochemistry, 1981,
20,825.
380
R. Jente, G.A. Olatunji, and F. Bosold, Phytochemistry, 1981, 20,2169.
381
D. Bodzek, K. Bularz, M. Sobkowiak, and G. Alexander, Koks, Smola, Gaz., 1981,
26, 101.
382
N. K. Lyapina, M. A. Parfenova, V. S. Nikitina, A. A. Vol'tsov, and L. A. Mel'nikova,
Khim. TekhnoL Topl Masel, 1982,27.
383
A. Attar and F. Dupuis, Adv. Chem. Ser., 1981, 192,239.
384
A.. k Macco and H. M. Buck, J. Org. Chem., 1981, 46,2655.
385
E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 896, 1981.
386
V. Figala, R. Riedel, G. Rainer, and K. Klemm, Eur. Pat. Appl. 39 519, 1981.
387 E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 895,-1981.
388 E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 898, 1981.
389 Jpn. Kokai Tokkyo Koho 80 143 977,1980.
390 T. Masuko, Jpn. Kokai Tokkyo Koho 80 143 990,1980.
391
J. K. Chakrabarti and D. E. Tupper, Br. P. 1577 743,1980.
392 T. Masuko, Jpn. Kokai Tokkyo Koho 80 143 988,1980.
393 F. Hunziker, R. Fischer, P. Kipfer, J. Schmutz, H. R. Buerki, E. Eichenberger, and
T. G. White, Eur. J. Med. Chem. - Chim. Ther., 1981, 16, 391.
394 K H. Weber, A. Bauer, P. Danneberg, and F. J. Kuhn, US P. 4 263 310, 1981.
395 M. Velasco, F. Velasco, C. Cepeda, R. Romo, and M. A. Perez-Toledo, Neurophama-
cology, 1981, 20,461.
396 W. Sinenberg and 0. Spohn, Ger. Offen. 2 940 737, 1981.
and 2-phenylamino-2-imidazolinesas analgesic^;^'^ some thienopyridino-

pyrazines showed potentiation of p e n t ~ b a r b i t a l . 399
~~~'
Pharmacodynamic Agents. Compounds that are active as adrenergic receptor
blockers and antiarhythmics, such as piperidine derivatives of 3-hydroxy-
thiophen-2-carboxylic acid,400 have been prepared 8
0
'
- Basic dithienyl
derivatives have been prepared as vasodilator^^^-^^^ and thienylpropanol-
amine acids as hypotensive agents.'13 Thenoylphenoxyacetic a ~ i d s ~ ~ ~
and other types of thiophen derivative have attracted continued
Therapy of Metabolic Diseases. Many very varied thiophen derivatives, such

as 2- [4-(2-thenoyl)phenyl] propionic 2,6-di-t-butyl-4-thenoyl-
phenols?23 4H-5,6-dihydro cy clopent a [ b] t hiophen-4-carb oxy lic acid ,424 and
391
H. Staehle, H. Koeppe, W. Kummer, W. Kobinger, and K. Stockhaus, Ger. Offen.
2 951 601,1981.
3 9 8 D. Frehel and J. P. Maffrand, Fr. Demande 2 457 869, 1980.
399
R. Boigegrain and J. P. Maffrand, Fr. Demande 2 463 145, 1981.
400
F. F. Frickel, G. von Philipsborn, C. D. Mueller, and D. Lenke, Ger. Offen. 2 950 064,
1981.
4 0 1 H. Tucker, J. Me& Chem., 1981, 24,1364.
402
S. Carboni, A. da Settimo, P.L. Ferrarini, G. Primofiore, 0. Livi, V. Menichetti, M.
del Tacca, E. Martinotti, C. Bernardini, and A. Bertelli, Eur. J. Med Chem. -Chim.
Ther., 1982, 17, 159.
403 G. Bobowski and J. M. Gottlieb, J. Heterocycl. Chem., 1982, 19,21.
404 W. L. Matier and W. E. Kreighbaum, U S P. 4 321 398, 1982.
40 5 R. I. Mrongovius, P. Ghosh, A. G. Bolt, and B. Temai, Arzneim.-Fomch., 1981, 31,
1718.
406
J. Buendia and L. Taliani, Fr. Demande 2 646 952, 1981.
407 Belg. P. 886471,1981.
408
S. Kubo, K. Morikawa, M. Yamazaki, I. Matsubara, and H. Kato, Nippon Yukurigaku
Zasshi, 1981, 78, 571.
409 F. J. Stiefel, US P. 4275 198, 1981.
410 R. Andreoli Rovat and X. Cirera Dotti, Span. P. 493 741, 1981.
4 1 1 L. M. Brenner, US P. 4 282 227, 1981.
4 1 2 Jpn. Kokai Tokkyo Koho 81 61 373,1981.
413
A. W. Oxford, J. Bradshaw, and I. H. Coates, Eur. Pat. Appl. 21 840, 1981.
4 1 4 W. Liebenow and K. Mannhardt, Ger. Offen. 2 923 345,1980.
4 1 5 W. Liebenow and K. Mannhardt, Ger. Offen. 2 942 643,1981.
416 W. Liebenow and K. Mannhardt, Arch. Pharm (Weinheim, Ger.), 1981, 314,409.
417 G. Thuillier, J. Laforest, B. J. M. Cariou, P. A. R. Bessin, J. S. Bonnet, and J. E.
Thuillier, US P. 4 255 585, 1981.
418 E. J. Cragoe, Jr. and W. F. Hoffman, US P. 4 237 130, 1980.
419
W. F. Hoffman, O.W. Woltersdorf, Jr., F. C. Novello, E. J. Cragoe, Jr., J. P. Springer,
L. S. Watson, and G. M. Fanelli, Jr., J. Med. Chem., 1981,24, 865.
420 A. Nuhrich, C. Lablanche, G. Devaux, A. Carpy, P. Dufour, C. Nguyen-Ba, and J.
Roquebert, Eur. J. Med Chem. -Chim. Ther., 1981, 16,551.
4 2 1 Jpn. Kokai Tokkyo Koho 81 99471,1981.
4 2 3 Austrian P. 361 467, 1981.
414
J. Barbara Adroher, J. M. Carulla Oliver, S. Julia Arechaga, J. A. Oliva Granell, and
J. A. Poch Gabarro, Span. P. 487 841, 1980.
many others, have been investigated as anti-inflammatory 13' *425-431
Many analogues of prostaglandin that contain thiophen rings have been
re pa red.‘'^^-^^^ Thiophens with antihistaminic activity have been investi-
gated?37--441 The popular antihistamine methapyrilene has been shown to
be a potent hepato~arcinogen.4~~ Hypolipidemic thiophensw3--446. and
inhibitors of the aggregation of platelets have been d e s ~ r i b e d . ~ ~ , ~ ~
Antidiabetic thiophencarboxylic acidsw9 and s~lphonylureas~~" have been
prepared.
Therapy of Infectious Diseases. In connection with side-chains of 0-lactams,
several patents on the synthesis and purification of 2-thienylacetic acid~51-455
425 L. A. Koskenniska and R. A. Saxlund, Eur. Pat. Appl. 29 740, 1981.

426 A. E. Sloboda, J. W. Hanifin, and D. N. Ridge, Austrian P. 363930, 1981.
427 A. C. Goudie, R. W. Ward, and H. E. Rosenberg, Eur. Pat. Appl. 35 853, 1980.
428
W. Opitz, M. Schwiertz, S. Raddatz, and P. R. Imberge, Arzneim.-Forsch., 1981,
31,402.
429 B. Lacaze, Fr. Demande 2 461 496, 1981.
431 R. Boigegrain and J. P. Maffrand, Fr. Demande 2 478 640, 1981.
432
W. Bartmann, G. Beck, 3. Knolle, and R. H. Rupp, Tetrahedron Lett., 1982, 23,
2947.
433 G. Beck, U. Lerch, B. Schoelkens, and R. H. Rupp, Ger. Offen. 2 946 116, 1981.
434 E. W. Collington, P. Hallett, C. J. Wallis, and J. Bradshaw, Eur. Pat. Appl. 32 432,
1981.
435 T. Tamura, N. Inukai, H. Iwamoto, I. Yanagisawa, Y. Ishii, T. Takagi, K. Tomioka,
and M. Murakami, YamunouchiSeiyuku Kenkyu Hokoku, 1980,4,16.
438 Jpn. Kokai Tokkyo Koho 81 118080,1981.
4 3 9 D. B. Judd, J. Bradshaw, J. W. Clitherow, B. J. Price, J. W. M. Mackimon, R. Hayes,
and L. Carey, Eur. Pat. Appl. 27744, 1981.
440 Jpn. Kokai Tokkyo Koho 80 167 275, 1980.
4 4 1 H. H. Lautenschlaeger, H. Betzing, J. Winkelmann, and M. Probst, Ger. Offen.
2 946 810,1981.
442 R. Ziegler, B. Ho, and N. Castagnoli, Jr., J. Med. Chem., 1981, 24, 1133.
443 Y. Kawamatsu, T. Sohda, and Y. Imai, Eur. J. Med Chem. - Chim. Ther., 1981,
16, 355.
4 4 5 R. A. Parker, Eur. Pat. Appl. 46 595, 1982.
446 J. Courregelongue and J. P. Maffrand, Fr. Demande 2 464 953, 1981.
448 I. Imada, H. Sugihara and M. Kawada, Eur. Pat. Appl. 26 000,1981.
449 G. F. Holland, US P. 4 282 246, 1981.
4 5 0 V. Hitzel, R. Weyer, K. Geisen, and G. Regitz, Eur. Pat. Appl. 31 088,1981.
4 5 1 B. P. Fabrichnyi, F. M. Stoyanovich, Yu. B. Vol'kenshtein, S. Z. Taits, Ya.L.
Gol'dfarb, A. S. Mezentsev, M. A. Panina, I. B. Karmanova, and V. A. Koval'skaya,
USSR P. 677 331, 1981 (Ofkrytiyu, Izobref., From. Obrazfsy, Tovurnye Znuki,
1981, 270).
452 B. P. Fabrichnyi, S. Z. Taits, Yu. B. Vol'kenshtein, I. F. Shalavina, I. B. Karmanova,
V. A. Koval'skaya, F. M. Stoyanovich, E. P. Zakharov, Ya. L. Gol'dfarb, e f ul., USSR
P. 599 508, 1981 (Ofkrytiyu, Izobret., Prom. Obrazfsy, Tovamye Znuki, 1981,
270).
453 J. C. Vallejos and Y. Christidis, Fr. Demande 2 470 127, 1981.
454 M. Foa and L. Cassar, US P. 4 287 352,1981.
45s
3-t hie nylmalonic acid ,456 45 and a! -amino-2-t hieny lacet ic a cid458 have
appeared, New penicillins and cephalosporins with thiophen in the side-chain
have been prepared .459-463 Derivatives of clavulanic acid that include
thiophen rings4@ and azeto [ 1 , 2 a ] thieno [3,2-c] ~ y r i d i n e ~ ~also ’ show
antibacterial activity. N i t r o t h i o p h e n ~ ~ with
~ ~ - ~antibacterial
~~ and anti-
parasitic activity, thiophencarbaldehyde thiosemicarbazones with anti-
tubercular and many other structures with antibacterial
activity have been s ~ r e e n e d ? ~ l - ~A’ ~large number of patents treat thieno-
pyrimidone and related compounds as antifungal 484 and some
other thiophen derivatives with a n t i f ~ n g a l ~ ~ ’and -~~~ antimolluscal
456 P. C. Harris and J. A. Wilcox, Eur. Pat. Appl. 21 645, 1981.

457 S. H Malik, C. E. Windus, and D. E. Clark, Ew. Pat. Appl. 21 644,1981.
458 B . P. Fabrichnyi, I. F. Shalavina, and Ya. L. Gol’dfarb, USSR P. 771 100, 1980
(Otkrytiya, Izobret., &om. Obraztsy, Tovamye Znaki, 1980, 138).
4 5 4 P. Feyen and W. Schrock, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 808.
460 C. Palomo-Nicolau and A. L. Palomo-Coll, An. Quim., Ser. C, 1981, 7 7 , 87.
46 1
P. Mazzeo and F. Segnalini, Farmaco, Ed. Sci., 1981, 36,916.
462 J. Colome and C. Ferrer, Belg. P. 886 715, 1981.
4 6 3 J. E. Dolfini, USSR P. 812 184, 1981 (Otkrytiya, Izobref, Prom. Obraztsy, Tovarnye
Znaki, 1981,227).
464
P. M. Denerley, Eur. Pat. Appl. 25 287, 1981.
466 P. Gavral, M. C. Rigothier, J. C. Gantier, R. C. Coumes, J. P. Gorrichon, and A.
Gaset, Eur. J. Med. Chem. -Chim, Ther., 1981, 16,151.
4 6 7 A. Gaset, R. C. Goumes, J. P. Gorrichon, L. Albertini, J. P. Calmon, and G. Michel,
Fr. Demande 2 484 784, 1981.
468 H. Dolman and J. Kuipers, Eur. Pat. Appl. 31 173, 1981.
469 Yu. D. Churkin, E. A. Rudzit, L. V. Panfilova, and D. A. Kulikova, USSR P. 770 045,
1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981,313).
470 Yu. D. Churkin, E. A. Rudzit, L. V. Panfilova, and D. A. Kulikova, USSR P. 770 044,
1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981,313).
4 7 2 K. A. M. Walter, US P. 4 272 545, 1981.
4 7 3 B. M. Kirichenko, A. V. Vladzimirskaya, and P. M. Steblyuk, Farm. Zh. (Kiev),
1981,61.
474 M . S . K. Youssef, S. R. El-Ezbawy, and A. A. Abdel-Wahab, Acta Pharm. Jugosl.,
1981,31,67.
4 7 5 D. R. Shridhar, C. V. Reddy Sastry, B. Lal, G. S . Raddi, K.K. Bhopale, R. S. Khokar,
and K. Tripathi, Indian J. Chem., Sect. B, 1980,19, 1065.
477
T. Kametani, K. Kigasawa, M. Hiiragi, K. Wakisaka, S. Haga, H. Sugi, K. Tanigawa,
Y. Suzuki, K. Fukawa, 0. Irino, S. Saita, and S . Yamabe, Heterocycles, 1981, 16,
1205.
479 Jpn. Kokai‘Tokkyo Koho 81 59 778,1981.
481 Jpn. Kokai Tokkyo Koho S i 22 789,1981.
482 I. A. Kharizomenova, A. N. Grinev, N. V. Samsonova, E. K. Panisheva, N. V. Kaplina,
I. S. Nikolaeva, T. V. Pushkina, and G. N. Pershin, Khim-Farm. Zh., 1981,15,40.
484 A. R. Burrell, J. M. Cox, N. F. Elmore, J. H. E. Marsden, and M. C. Shephard, S. Afr.
P. 80 00 822,1981.
487
H. Boeshagen, K. H. Buechel, W. Draber, 1. Haller, and M. Plempel, Ger. Offen.
3 017 881, 1981.
118 Heterocyclic Chemis fry
propertiesM8 have been prepared. A thiopheneylnonatetraene has been

patented as an antiturnour agent.489
Veterinary and Agricultural Agents. Thiophency clopropanecarboxylic
acid4903491 and derivatives of 3,4-dihydro~ythiophen~~~
have been patented
as pesticides. Compounds such as (2 19)493 and (220)p94 and others,495-497
have also been suggested as pesticides.
Miscellaneous Activities. Great interest in the synthesis of biotin and inter-

mediates for biotin can be noted.37:498-501Other biological aspects of
thiophen derivatives have been treated.502-5'0
488 G. Madulo-Leblond, P. Gayral, J. Guillaumel, J.-M. Clavel, P. Demerseman, and R.

Royer, Eur. J. Med. Chem. -Chim. Ther., 1981, 16,267.
489 M. J. Klaus and B. A. Pawson, US P. 4 256 878, 1981.
492 K. Sato, M. Miyahara, T. Hibi, T. Wada, S. Nagai, Y. Hirota, T. Yorie, and H. Sugiura,
Eur. Pat. Appl. 32 748, 1981.
493 G. Levitt, Eur. Pat. Appl. 30 142, 1981.
4 9 5 Jpn. Kokai Tokkyo KohoSl 167 679,1981.
496 M. T. Clark, Br. P. 1 574429, 1980.
498 E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, Eur. Pat. Appl. 19 788, 1980.
499 E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, US P. 4 247 704, 1981.
P. A. R o s y and F. Vogel, Ger. Offen. 3 018 109, 1981.
E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, US P. 4245 104,1981.
A. W.-J. Chow, R. J. Gyurik, and R. C. Parish, Eur. Pat. Appl. 24 842, 1981.
G. H. Phillipps, C. Williamson, I. P. Steeples, B. MacDonald Bain, and R. A. Borella,
Eur. Pat. Appl. 44 705, 1982.
E. Haddock and W. J. Hopwood, Br. Pat. Appl.. 2 078 212, 1982.
M. Bayssat, F. Sautel, J. C. Depin, and A. Betbeder-Matibet, USSR P. 795472,
1981 (Otkrytiya, Izobref, Prom Obraztsy, Tovumye ZnaM, 1981,229).
G. Grimmer, J. Jacob, and K. W. Naujack, Z. Anal. Chem., 1981, 306,347.
M. h i and T. F. Slater, IRCSMed Sci;Libr. Compend., 1981, 9,25.
508
R. Muneyuki, T. Mitsugi, and E. Kondo, Chem. Ind. (London), 1981,159.
509 K. J. Brown, G. W. Tannock, R. B. Elliott, and D. R. Lines, Microbial. Immund.,
1980, 24, 603.
'lo P. Staben, A. S. Bhargava, C. Schobel, F. Siegmund, and P. Gunzel, Arzneim.-Forsch.,
1981,31-2,1735.
Thiophens of Technical Interest. - Many patents cover the synthesis of azo-
dyes from aminothiophens such as (22 1),510 (222),'" and others.34a*512-515
Several patents describe solid-state lithium batteries with the iodine-thiophen
charge-transfer complex .'16-'19
Polymers from Thiophen. - By the use of sodium t-butoxide, 5-methyl-

thiophen-2-carbaldehyde has been polycondensed in DMF to give poly-
(thiophen-2,5-diyl)~inylene.~*~ From 4,4' -azodibenzaldehyde and bifunctional
Wittig reagents from 2 ,5-dichloromethylthiophen, conjugated polymers with
azobenzene units were prepared.521 Polymeric azomethines with azobenzene
units have been prepared from 4,4-di-iminoazobenzene and 2,s -diformylthio-
hen.'^^ The metathesis reaction has been applied to unsaturated polymers
that contain thiophen A patent describes the preparation of linear
polythiophen-2,s - y l e n e ~ ) , ' ~and
~ the electrical conductivity of their arsenic
pentafluoride complexes has been measured ,525 Electrophysical properties of
polymeric films that have been prepared from thiophens in a glow discharge
have been
'I1 R. R. Giles and M. A. Weaver, US P. 4 301 068, 1981.

'Iz D. Mullen, Br. Pat. Appl. 2 0 7 8 7 1 3 , 1982.
513 D. Mullen, Rr. Pat. Appl. 2 041 961,1980.
'I4 Jpn. Kokai Tokkyo Koho 81 120 764,1981.
S. Saito, S. Kashihara, and G. Takeshima, GS News Tech. Rep., 1981, 40, 8 2 .
"'Jpn. Kokai Tokkyo Koho 82 13 670,1982.
519
L. P. Klemann, G. H. Newman, E. L. Stogryn, T. A. Whitney, and D. Farcasiu, US
P. 4 293 623,1981.
s20 G. Kossmehl and k Yaridjanian, Makromol. Chem., 1981, 182,3419.
5 2 1 G. Kossmehl and J. Wallis, Makromol. Chem., 1982, 183, 331.
5 2 2 G. Kossmehl and J. Wallis, Makromol. Chem., 1982, 183, 347.
523
K. Hummel and 0. A. Wedam,MakromoZ. Chem., 1981,182, 3041.
s 2 5 G. Kossmehl and G. Chatzitheodorou, Makromol. Chem., Rapid Commun., 1981,
2, 551.
526
T. A. Starostina, V. L. Materikin, A. B. Gil'man, V. M. Vozzhennikov, and L. F.
Rybakova, Vysokomol. Soedin., Ser. B , 1982, 24,269.
3 Benzo[ 6J thiophens and their Benzo-fused Systems
Benzo[6 J thiophens. - Synthesis. The Michael addition of chalcone to (223)
gave (224). The sulphone corresponding to (223) can also be used for the
synthesis of benzo [bJ thiophens: using (225) gave (226) in 63% yield.527
Compound (227), easily available by treatment of (228) with base, yields (229)
upon reaction with ethyl bromoacetate or phenacyl bromide.528 Methyl 4,7-
dihydro-4,7-dioxobenzo [ b ]thiophen-2 -carboxylate has been synthesized by
the reaction of methyl mercaptoacetate with activated 1 , 4 - b e n ~ o q u i n o n e s . ~ ~ ~
Sub st it ut ed 3-benzylideneb enzo [b ] t hio phen-2 -ones have been prepared .530
Irradiation of methyl 2-phenylthioacetoacetate in benzene-methanol gave
methyl 3-methylbenzo[ b ]thiophen-2-carboxylate in 66% yield. Other aryl
derivatives reacted similarly.531Dimethyl benzo [ b ]thiophen-2,3-dicarboxylate
was formed in the thermal reaction of 3-morpholinosydnone with dimethyl
acetylenedicarboxylate (DMAD) .532 The Stobbe condensation between p -
tolyl 2-thienyl ketone and dimethyl succinate, followed by cyclization, was
used for the synthesis of benzo [ b ]t h i o p h e n ~ .3-Bromothiochroman-4-one
~~~
and its S-oxide underwent ring-contraction on heating to give mixtures of
products, including t h i ~ i n d i g o .535
~ ~ Dehydrogenation
* of 2,3-dihydrobenzo-
[bJ thiophens over different types of catalysts has been used for the synthesis
of benzo [ b ]t h i ~ p h e n s . ~ ~ Irradiation
~-~~* of 1,2-benzisothiazole in the
CN
(228) ( 229) R = COOEt or COPh
521
k M. van Leusen and J . W. Terpstra, Tetrahedron Lett., 1981, 22, 5097.
528
K. Gewald and H. Schafer, 2. Chem., 1981, 21, 183.
52Y
V. M. Ruiz, R Tapia, J. Valderrama, and J. C. Vega, J. Heterocycl Chem., 1981,
18, 1161.
530
C. Camoutsis, P. Catsoulacos, G. Salem, A. Terzis, and S. E. Filippakis, J. Heterocycl
Chem., 1981, 18,1405.
531
T . Sasaki, K. Hayakawa, and H. Ban, Tetrahedron, 1982, 38, 85.
532
H. Gotthardt and F. Reiter, Chem. Ber., 1981, 114, 2450.
533
H. H. Moussa and S. Abdel-Meguid, J. Heterocycl. Chem., 1981, 18, 1519.
534
N. E. MacKenzie and R. H. Thomson, J. Chem SOC.,Perkin Trans. 1 , 1 9 8 2 , 395.
53 5
P. J. Cox, N. E. MacKenzie, and R. H. Thomson, Tetrahedron Lett., 1981, 22,2221.
5 36
T . Yu. Filippova, Kh. M. Minachev, Ya. I. Isakov, M. V. Vagabov, and E. A. Kara-
khanov, Vestn. Mosk. Univ., Ser. 2: Khim., 1981, 22, 5 1 1 .
531
M. V. Vagabov, E. A. Viktorova, B. I. Liogon'kii, R Z. Aleksanyan, S. K. Dzhamalov,
and E. A. Karakhanov, Neftekhimiya, 1980, 20, 887.
538
M. V. Vagabov, Neftekhimiya, 1981, 21, 619.
presence of DMAD gave dimethyl 7-cyanobenzo [b] thiophen-2,3-
dicarboxylate in addition to mixtures of cis- and trans-substituted phenylthio-
alkene~.’~~’ Some benzo [b] thiepins have been ring-contracted to benzo [b]-
t h i ~ p h e n s . ’Prop-2-enyl
~~~ 2,3,4,5 -tetrafluorophenyl sulphide underwent a
Claisen rearrangement in N, N-diethylaniline to give 4,5,6,7-tetrafluoro-2,3-
dihydro-2-methylbenzo [b] t h i ~ p h e n .The ~ ~ ~reaction of 2-methylthiophen
with tetrafluoroethylene at 650°C gave (230), in addition to (231).540
(230) ( 231)
Physical Properties of Benzo[b] thiophens. The aromatic electronic delocali-

zation in benzo [b] thiophen has been calc~lated.’~~ The m.c.d. spectra of
benzo [b] thiophen and dibenzothiophen have been analy~ed.’~*Chemical
thermodynamic properties of benzo [b] thiophen and other condensed
systems have been determined.543 The crystal structures of 5 -nitroso-4-
(phenylethyl)benzo[b] t h i ~ p h e n , ’1,2,3,5-tetramethylbenzo[b]
~~ thiophenium
t e t r a f l ~ o r o b o r a t e ,and
~ ~ ~a spiro-benzo[b]thieno [2,1-b] have been
determined.
Reactions of Benzo[b] thiophens. Photochemical cycloaddition of 2,3-
dichlorobenzo[b] thiophen with vinyl bromide under benzophenone-sensitized
conditions gave a mixture of isomers of (232) in the presence of free-radical
inhibitor^.'^^ The products from the photocyclization of DMAD with
substituted benzo [b] thiophens are (233) or (234), depending upon the
538aM.Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 525.

538bA.Chatterjea, B. Sen, and S. K. Chatterjee, J. Chem. SOC.,Perkin Trans. 1, 1981,
1707.
539 G. M. Brooke and D. I. Wallis, J. C h e m Soc., Perkin Trans. 1 , 1981, 1659.
540 A. M. Maksimov, V. E. Platonov, G. G. Yakobson, 0. M. Yakhlakova, R. A. Bekker,
B. L. Dyatkin, and I. L. Knunyants, Izv. Sib. Otd. A k ad Nauk SSSR, Ser. Khim.
Nauk, 1981, No. 6, p. 128.
5 4 1 A. Mehlhorn and J. Fabian, Croat. Chem. Acta, 1981, 54,427.
542 N. Igarashi, A. Tajiri, and M. Hatano, Bull. C h e m SOC.Jpn., 1981, 54, 1511.
543 S. E. Stein and B. D. Barton, Thermochim. Acta, 1981, 44, 265.
544
K. Rou t and F. M. Miao, Acta Crystallogr., Sect. B , 1982, 38, 685.
5 4 5 R. M. Acheson, R. J. hince, G. hocter, J . D. Wallis, and D. J. Watkin, J. Chem. SOC.,
Perkin Trans. 2, 1981, 266.
546 P. J . Cox and R. A. Howie, Acta Crystallogr., Sect. B, 1982, 38,657.
5 4 7 D. C. Neckers and F. L. Wagenaar, J. Org. Chem., 1981,46,3939.
irradiating wa ~ e l e n g t h . ’ The
~ ~ photo chemical react ions of 2 -aryl-, 3-aryl-,
and 2,3-diaryl-benzo [b] thiophens in neutral solution in the presence of
primary and teritary amines have been investigated; they led only to a minor
extent to cyclization but gave, in most cases, adducts and d i m e r ~ . ’ ~ ~
In the presence of moist A1C13, aromatic compounds such as benzene,
toluene, anisole, phenetole, diphenyl ether, and methylthiobenzene added
across the 2,3-double bond of benzo[b]thiophens to give a mixture of 2-
and 3-(para-substituted aryl)-2,3-dihydrobenzo [ b ]thiophens. It has been
suggested that benzo [ b ]thiophen is protonated by moist AlCl,, and that the
resulting carbo-cation reacts with a second aromatic compound, which with
benzene or chlorobenzene as solvent is the benzo [bJ thiophen itself.5501551
With anisole the formation of a ring-opened product, (E)-4-methoxy-2’-
methylthiostilbene, was also observed, and is believed to occur via the S -
methylated benzo [b] t h i ~ p h e n . ’ ~The
~ addition reactions of benzene and
toluene have also been investigated with acetoxy- and hydroxy-benzo [ b ] -
thiophens. Normal Fries-rearranged products were found for the 4- and 7-
OAc derivatives, which sometimes react further to produce their dihydro-
derivatives. Alternatively, benzene can add across the double bond to give
the 2- (for 6-OAc) or 3-phenyl-2,3-dihydrobenzo [ b ]thiophens (for 7-
OAC).”~Isomerization of 2- and 3-methylbenzo [b]thiophen on aluminosili-
cate catalysts at 300-5OO0C has been inve~tigated.’~~ Ally1 2-benzothienyl
sulphide underwent a [3,3] -sigmatropic rearrangement to give 3-allylbenzo-
[b] thiophen-2-thiol, which ring-closed to a mixture of 2-methyl-2,3-dihydro-
benzothieno [2,3-b] thiophen, 2-methylbenzothieno [2,3-b] thiophen, and
benzot hieno [2,3-b] dihydro t h i ~ p y r a n . ” ~3-Benzo [b ] t hienyl-lithium reacted
with quinoxaline to give 2-benzo- and 2,3-dibenzo-[b] thieny1quinoxaline.ln
6-Fluorobenzo [ b ]thiophen-2(3H)-one has been prepared via diazotization of
sodium (2-amino-4-fluoropheny1)acetate followed by reaction with sodium
sulphide and ring-clo~ure.’~’ The reaction of 3-amino-2-ethoxycarbonyl-
benzo [b] thiophen with 2,s -dimethoxytetrahydrofurangave 3(1 -pyrrolyl)-
2-ethoxycarbonylbenzo [ b ]thiophen, which through Curtius reaction was
548 S. R. Ditto, P. D. Davis, and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 521.

549 A. Buquet, A. Couture, A. Lablache-Combier, and A. Pollet, Tetrahedron, 1981, 37,
75.
P. D. Clark, K. Clarke, D. F. Ewing, R. M. Scrowston, and F. Kerrigan, J. Chem.
Res. (S), 1981, 307.
P. D. Clark, D. F. Ewing, F. Kerrigan, and R. M. Scrowston, J. Chem. SOC.,Perkin
Trans. I , 1982, 615.
552 P. D. Clark, L. K. k Rahman and R. M. Scrowston, J. Chem SOC.,Perkin Trans. I ,
1982, 815.
553 M. V. Vagabov, Neftekhimiya, 1981, 21,658.
554
k V. Anisimov, V. S. Babaitsev, S. Ya. Grobovenko, T. k Danilova, and E. A.
Vik orova, Khim. GeterotsikL Soedin., 1981, 615.
555 K. iindeldr, M. Ryska, J. Holubek, E. Svdtek, J. Metys‘ovd, J. Protiva, and M. Protiva,
Collect. Czech. Chem Commun., 1981, 46, 118.
transformed into (235).556 The reaction of the 6-halogeno-2H,3H-benzo-

[ b ]thiophen-2,3-diones with alkoxides in the presence of crown ether gave
radicals whose e.s.r. spectra indicated that the radical anions of the starting
product d i m e r i ~ e .The
~ ~ condensation
~ of 3-methyl-4-phenylcyclobut -3-ene-
1,2-dione with benzo [b] thiophen-2-carbaldehyde gave the corresponding
alkenyl derivative.558 The reaction of 3-bromobenzo [ b ]thiophen with
sodium thiosalicylate, followed by ring-closure,gave (236).559
Benzo[b] thiophen S-Oxides.- Mild methods for the oxidation of 2,3-

dihydrobenzo [ b ]thiophens to the sulphoxide have been d e v e l ~ p e d561 .~~~~
The photochemical reactions of various 2- and 3-substituted benzo [b1-
~ ~ ~ 3-chlorobenzo [ b ]-
thiophen 1-oxides led to different p h o t o d i m e r ~ .From
thiophen-2 -carboxylic acid 1,l -dioxide, 1,3-0xazinones of biological interest
were obtained through cyclization reactions with cyanamides and carbodi-
i m i d e ~ Secondary
.~~~ amines add to 2-phenylbenzo [b] thiophen 1,l -dioxide
to give 3-amino-substituted 2,3-dihydro-2-phenylbenzo [ b ]thiophen 1,l-
Benzo[c ] thiophens. - Compound (237), obtained by isomerization of 1-

methoxycarbonyl-2,3-benzodithianin methanolic sodium hydroxide at O"C,
gives the benzo [c] thiophen (238) upon heating to r e f l ~ x The
. ~ ~reaction
~ of
o-methylbenzyl alcohol with CS2 at about 500°C in the presence of catalyst
yielded up to 80% of dihydrobenzo [c] t h i ~ p h e n . ~ ~ ~
MeOOC SH
556 M. Cugnon de Sikicourt, H. EL-Khashef, S. Rault, and M. Robba, Synthesis, 1981,

710.
5 5 7 k Alberti, F. Ciminale, G . F. Pedulli, L. Testaferri, and M. Tiecco, J. Org. Chem.,
1981, 46, 751.
5 5 8 W. R e d and M. Vogl, Chem Ber., 1982, 115,403.
5 5 9 K. Grlitzer and D. Holscher, Arch. Pharm. (Weinheim, Ger.), 1982, 315, 193.
sf,' Y. Watanabe, T. Numata, and S. Oae, Synthesis, 1981, 204.
5 6 1 S. Oae, Y. Watanabe, and K. Fujimori, Tetrahedron Lett., 1982, 23, 1189.
5 6 2 M. ElFaghi El Amoudi, P. Geneste, and J.-L. Olivd, J. Org. Chem., 1981, 46,4258.
5 6 3 W. X e d , G:Oremek, and R. Pauli, Arch. Pharm (Weinheim, Ger.), 1982, 315, 324.
564
F. Sauter, U. Jordis, P. Stanetty, G. Huttner, and L. Otruba, Arch. Pharm. (Weinheim,
Ger.), 1981, 314, 567.
5 6 5 G. Cignarella, A. Nuvole, and M. M. Curzu, Gazn Chim. Ital., 1981, 111, 333.
566 F. Azizian and J. S. Pizey, J. Chem. Tech. Biotechnol., 1981, 31, 163.
Dibenzo thiophens. - The hydrode sulphur izat ion of dib enzot hi0phen by
supported noble metal catalysts has been in~estigated.'~~ Several polyamides
have been prepared by condensing dibenzothiophen-2,8diamine with
aromatic diacyl dichlorides or dibenzothiophen-2,8 -dicarboxylic acid
chlorides with aromatic diamines. The corresponding dibenzothiophen
sulphones were also Oxazoline-protected dibenzothiophen-l-
carboxylic acid was metallated in the 2-position, and via reaction with
ethylene oxide and further reaction was converted into (239), which was
studied as a dopamine antagonist.569 Metallation of 4,4'difluorodiphenyl
sulphone, followed by reaction with trimethylchlorosilane, gave trimethyl-
silyl derivatives, which were ring-closed to 2,8-difluorobenzo [b] thiophen 5 5 -
dioxide and reduced to the corresponding d i b e n z o t h i ~ p h e n .The
~ ~ ~nitro-
group of 2-nitrodibenzo [b] thiophen 5,5-dioxide could be selectively reduced
electrochemically.s71 The [7 J -, [9] -, [ 111 -, [ 131-,and [ 151- heterohelicenes
with alternant thiophen and benzene rings have been synthesized by photo-
cyclization of precursor olefins and diolefins, and their n.m.r. spectra were
investigated.572 Acylation, Mannich reaction, Vilsmeier formylation , and
diazo coupling of (240) have been found to occur predominantly in the
pyrrolic 0-position, except for acylation , which occurred at the nitrogen, and
formylation, which also gave some a - i ~ o m e r . ~ ~ ~
R
(239) (240)
Pharmacologically Active Compounds. - 2-Aryl-3-alkoxybenzo[bJ thiophens

have been shown to possess hypolipidemic activity.574 Alkyl and poly-
halophenyl esters of benzo [b] thiophen-3-carbamic acid show antibacterial
and antifungal activities.575 Benzo [b] thiophen-3-sulphonamides show
herbicidal Derivatives of 2-cyano-3-hydroxybenzo [b J thiophen
show sympatholytic
567 E. Dhainaut, H. Charcosset, C. Gachet, and L. de Mourgues, A p p L Catal., 1982,
2, 75.
568
P. R. Srhivasan, V. Mahadevan, and M. Srinivasan, Makromol. Chem., 1981, 182,
1937.
5 6 9 C. R. Ellefson and K. A. ho da n, J. Med Chem., 1981, 24, 1107.
570 M. C. Brirlon, M. M. de Bertorello, and H. E. Bertorello, An. Asoc. Quim. Argent.,

1981, 69,247.
5 7 1 L. H. Klemm and Q. N. Porter, J. Org. Chern., 1981, 46,2184.
572 K-I. Yamada, S. Ogashiwa, H. Tanaka, H. Nakagawa, and H. Kawazura, Chem. Lett.,
1981, 343.
5 73
L. A. Kintsurashvili, T. E. Khoshtariya, L. N. Kurkovskaya, and N. N. Suvorov,
Khim Geterotsikl. Soedin, 1981, 211.
i:: F. Sauter, Fr. Demande 2 447 914, 1980.
A. Shafiee, M. Vossoghi, J . Wossooghi, and S. Yazdani, J. Pham. Sci., 1981, 7 0 , 5 6 6 .
5 7 6 G. Levitt, Eur. Pat. Appl. 45 196, 1982.
577
R. R. Royer, L. J. A. Rene, and M. E. M. Aurousseau, Eur. Pat. Appl. 20 266, 1980.
4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons
Analogues of Anthracene and Phenanthrene. - Keto-enol tautomerism in a
naphtho- and several anthra-thiophen systems [such as (241) G (242)J has
been studied. The system (241) +(242) was obtained via the Friedel-Crafts
reaction of thiophen with naphthalene-2,3-dicarboxylic anhydride .followed
by ring-closure. A [c] -fused system was similarly obtained by starting from
2,5 -dimethylthiophen. The other [b] -fused system was prepared from 2-
bromo-3-chloronaphthalene, which was converted into the aldehyde, allowed
to react with 2-thienyl-lithium,and then reduced. The chloro-substituent was
then transformed into a carboxy-group and the system was r i n g - c l o ~ e d . ~ ~ ~
Aromatic hydrocarbons add across the 1,2-bond of naphtho [2,1-b] thiophen
in the presence of AlC& to give 1-aryl-l,2-dihydro-derivativesat room
temperature. At higher temperatures, 2-arylnaphtho [2,1 -b]thiophens are
obtained. Treatment of the 1-aryl-2,3-dihydrothiophens with DDQ yields 1 -
arylnaphtho [2,1-b] t h i ~ p h e n s . ~ ’Naphtho
~ [ 1,2-b]thiophens react similarly,
although, in addition to 2-aryl-2,3-dihydro-derivatives, 2,3-dihydronaphtho-
[ 12-b]thiophen was formed.580 Naphtho [ 1,8-bc]thiophen-2-one reacted
with dimethyl sulphate to give (243) .581 Treatment of 8 -benzoylmercapto-2-
naphthol with polyphosphoric acid gave (244) in 63% yield. Treatment of
(245) with sodium hydroxide in DMF gave (246) in 82% yield.582
(244) 0
(245)
Polycyclic Thiopens. - In connection with the renewed interest in such

compounds as constituents in coal and their potential mutagenic and/or
carcinogenic properties, many such compounds have been synthesized by
578
W. A. Lindley and D. W. H. MacDowell, J. Org. Chem., 1982, 47,705.
579 P. D. Clark and D. M. McKinnon, Can. J. Chem., 1981, 59,227.
P. D. Clark and D. M. McKinnon, Can. J. Chem., 1981, 5 9 , 1297.
Yu. I. Rozhinskii and V. L. Plakidin, Zh. Org. Khim., 1981, 17, 1783.
R. Neidlein and G. Schafer, Chem.-Ztg., 1981, 105, 89.
Castle and co-workers. Thus from (1 19) the pyrenothiophen (247) was
prepared by side-chain bromination and further tran~f0rmation.l~~ The last
missing pyrenothiophen (248) was prepared from 4-bromopyrene by halogen-
metal exchange and reaction with 2,2,2' 2'-tetraethoxydiethyl disulphide,
followed - by closure of the thiophen ring.199 Triphenaleno [2,3-b]thiophen
(249) was obtained through the reaction of lithiated oxazoline-protected
thiophen-3-carboxylic acid with phenanthrene-9-carbaldehyde,followed by
ring-closure. The synthesis of the [ 1,241 -isomer (12 1) and the corresponding
[2,1-b] -isomer has already been mentioned.200 Using similar synthetic
strategy as mentioned above, (250) was prepared via the Wittig reaction of
2-acetylbenzo [b] thiophen and benzyltriphenylphosphonium salt, followed
by photochemical ring-closure and side-chain modification of the methyl
group. The starting reaction for the synthesis of (251) was metallation of
oxazoline-protected benzoic acid with benzo [bj thio~hen-2-carbaldehyde.~~~
All isomers of the parent anthra [b] thiophens and benzo [b] thiophens have
been prepared. Some of them were obtained by cycloaddition reactions
between 2- or 3-vinylthiophens and 1,4-naphthoq~inone.~~ Benzo [ b ]-
phenanthreno [ d ]thiophens such as (252) were prepared in a straightfonvard
way by the Wittig reaction between benzo [b] thiophen-2-carbaldehyde and
diethy 1 2 -naphthy lmet hylpho sphonat e and photochemical ring -closure.585
Starting from phenanthrene-9-thiol, a thiophen ring was elaborated in the
(247)
s83 R. D. Thompson, M. Iwao, M. L. Lee, and R. N. Castle, J. HeterocycL Chem., 1981,

18,981.
5.34
Y. Tominaga, M. L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981, 18,967.
R. hatap, M. L. Lee, and R. N. Castle, J. HeterocycL Chem., 1982, 19,219.
synthesis of (253). In addition, benzo [ 1,2-b] phenaleno [4,3-bc]thiophen
has been ~ynthesized.’~~ Phenaleno [ 1,9-bc]thiophen (254) was prepared,
starting from 1 -methylnaphtho [2,1 -b]t h i ~ p h e n . ~ ~ ’
The reaction of malonyl chloride with 2-phenylbenzo [ b ]thiophen led to
a mixture of (255) and (256) and their t a u t o m e r ~ .The ~ ~ ~synthesis and
reactions of some new thiapseudophenalenone derivatives have been
inve~tigated.~~’
(256)
Thiophen Analogues of Indene. - Detailed papers on the reaction of diazo-

indenothiophens with DMAD and methyl propiolate have now been
p~blished.’’~This investigation has been extended to the reaction with
mono- and di-benzoylacetylene, which gave similar products, such as (257).
However, the benzo-fused indene gave (258) as the main p r o d ~ c t . ’ By
~
5 86
588
HN-
(257)
N
7’I
\ 1
\
/
R. Pratap, R N. Castle and M. L. Lee, J. HeterocycL Chem., 1982, 19,439.

”’ Y. Tominaga, M. L. Lee, and R. N. Castle, J. Heterocycl. Chem., 1981, 18,977.
R. Neidlein and G. Schafer, Chem.-Ztg., 1981, 105, 91.
589 R. Neidlein and E. A. Varella, Chem. Chron., 1980, 9 , 79.
590 S. Mataka, T. Ohshima, and M. Tashiro, J. Heterocycl. Chem., 1982, 19,65.
treatment of the thienylglycollic acids with A1Cl3 in benzene, indenes could
be prepared. Thus from (259), (260) was obtained in 79% yield and could
be hydrolysed and dicarboxylated to the parent indene.166
Various Carbocycle-fused Systems. - Azuleno [2,1-b]thiophens have been

prepared from ethyl 2 -chloro-3-formylazulene-l -carboxylate and ethyl
merca~toacetate.~~' The reaction of (261) with sulphur in quinoline gave
(262).592 It is claimed that, in the cation of (263), the charge is largely
localized on the carbon atom that is flanked by the two thiophen rings.593
An unusual cleavage of a carbon-carbon double bond has been observed in
the reaction of (264) with ethanedithiol and toluene-p-sulphonic acid, giving
(265) in 40% yield. The structure was proven by X-ray c r y ~ t a l l o g r a p h y . ~ ~
Ph
+
Me Me
591
K. Yamane, K. Fujimori, and T. Takeuchi, Bull. Chem. SOC.Jpn., 1981, 54,2537.
592
Yu. N. Porshnev, T. N. Ivanova, L. V. Efimova, E. M. Tereschenko, M. I. Cherkashin,
and K. M. Dyumaev, Zh. Org. Khim., 1982, 18,150.
5 9 3 T. M. Brown and W. Carruthers, J. Chem SOC.,Perkin Trans. 1 , 1981, 2904.
594 B. Hanquet, M. El Borai, R. Guilard, and Y. Dusausoy, Tetrahedron Lett., 1982,
23, 2859.
5 Thiophen Fused to Five-Membered Heteroaromatic Rings

Thieno-, Furo-, and Pyrrolo-thiophens.- Partial rate factors for the detritiation
of thieno [2,3-b] thiophen and thieno [3,2-b] thiophen that were specifically
labelled with tritium in each position have been measured, along with that for
thiophen in either pure trifluoroacetic acid or a mixture of acetic acid and
trifluoroacetic acid. Annelation of thiophen by thiophen produced a
comparable change in reactivities of the CY- and P-positions, in contrast to
annelation by benzene, where the reactivity of the (?-position is markedly
increased relative to that of the ~ y - p o s i t i o n . ~ ~ ~
The formation of thienothiophens in connection with attempts to prepare
tetrathiafulvalenes has been described in three detailed papers. Attempts to
deprotonate (266; X = H) led to (267), together with the trithiones (268)
and other products. The mechanisms were discussed. Treatment of (268;
R’ = R2 = Ph) or (268; R’ = Ph, R2 = Me) with triethylphosphine in boiling
xylene gave the corresponding compound (267). Treatment of (269) with
P4S10 also gave (267) together with (268).596 The reductive coupling of (266;
X = C1) with zinc of TiC13, which led to the desired 1,1’,2,2’-tetrathiafulvalenes,
also gave (268) as a 4,5-Disubstituted 1,2-dithiole-3-thiones
reacted with 2,3-diphenylcyclopropenethioneto give thieno [3,2-b] thiophen.
Using the 4,5-diphenyl-l,2-dithiole-3-thione gave (270) as a by-product. The
reaction of the 1,2-dithiole-3-thiones with cyclopropenones gave thieno [3,2-
b] fur an^.^^^ 2,7-Diaminobenzo [b] thieno [3,2-b] benzothiophen has been
prepared by reduction of 4,4’-diamino-2,2’-stilbenodisulphonyl chloride in
55% HI and subsequent treatment of the product with a dehydrogenating
agent .599
J
+S
- €tt--DFt; l s a
R1 ‘d’
X I I
S ‘R s
R2 R2
( 2 6 6 ) X = H or C 1 r) (267) (268)
R1 R1= R2= P h ; R1= R2= (CH=CH)2;
2
’
R1 R1= Ph, R2= H; R1= H, R = P h ;
(269) or R1= P h , R2= M e
Ph
Ph
595 W. J. Archer and R. Taylor, J. Chem. Soc., Perkin Trans. 2 , 1982, 295.
596 H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1729.
597
H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1928.
598
H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1982, 315.
599 S. Yu. Zherdeva, A. Ya. Zheltov, and B. I. Stepanov, Izv. Vyssh. Uchebn. Zaved.,
K h i m K h i m Tekhnol., 1981, 24,246.
The Fischer indole synthesis has been very difficult to carry out in the
thiophen series. However, the reaction of (271) with cyclohexanone gave
(272) in good yield.248 Attempts to apply the Fischer reaction to (273),
which was prepared from (147), led to (274). Compound (275), of interest
as a 0-blocker, was instead obtained starting from (272).233 Heating 2- and 3-
(w-azido)vinylthiophen, prepared via bromoacetylthiophen and azidoacetyl-
thiophen, followed by reduction and dehydration, gave thieno[2,3-b] - and
thieno [3,2-b] -pyrrole.600 Thermolysis of (276) gave diethyl thieno[3,2-b] -
pyrrole-5,6-dicarboxylate in 76% yield.253
The reaction of (277) with methyl chloroacetate followed by ring-closure
gave (278), which could be hydrolysed and decarboxylated to the parent
+
compound.6o' A review on [3 13 - and [4 + 11-cycloadditions of
isocyanides to dipoles and to nitroalkenes mentions work from a French
-om-7- MeOOC "M2

I
COOBut
(273) (274)
H
(275)
MeHNHC CHNHMe
M e I O OI C w ) COOMe
S
Me Me
6oo G. Kumar, K. Rajagopalan, S. Swaminathan, and K. K. Balasubramanian, Indian J.

Chem., Sect. B , 1981, 2 0 , 2 7 1 .
601
E. A. Panfdova, I. Ya. Kvitko, A. D. Kuptsov, and k V. El'tsov, Zh. Om. Khim.,
1981, 17,1564.
thesis, describing the formation of (280) from butyl isocyanide and (279).602
9-Aza-azuleno [2,1-b] thiophen has been prepared from 2-chloro-3-formyl-l-
aza-azulene by annelating the thiophen ring by the Fiesselmann reaction.603
OH
rJyc:l2rfN)
H
(279)
(280)
I
COOMe
CONHBu
Thiophen Fused to Various Five-Membered Rings. The reaction of ethyl

L
3-cyano-5,S-diethoxy-2-oxopentanoatewith P4Sl0 gave thieno[2,3-c]-

isothiazole-3-carboxylic acid, and not, as previously claimed, thieno [3,4-
d] isothiazole-4-carboxylic acid. The parent compound was obtained by
decarboxylation, and also by deamination of thieno [2,3c] isotkiazol-3-
amine.604 Alkylation of the product of the reaction between sodium 3-
iminobutyronitrile and CS2 gave (281), which upon oxidation with iodine
gave (282), which could be ring-closed to (283). This compound was
deaminated, hydrolysed, and decarboxylated to yield 3-methylthieno [3,2-
d] isothiazole, which underwent bromination and nitration in the 5-
p~sition.~’’ Lithiation of 3-methylthieno[3,26] isothiazole and its S-bromo-
derivative led to ring-opening of the isothiazole ring, giving 3-acetyl-2-
(buty1thio)thiophen and 3-acetyl-2-(butylthio)thiophen-5-carboxylic acid,
respecti~ely.~”~ 3-Aminothieno[3,4-d] isothiazole 1,l -dioxides have been
prepared by heating thieno [3,4-d] isothiazol-3(2H)-one 1,l-dioxide with the
hydrochlorides of primary and secondary aliphatic amines, phosphorus
pentoxide, and N,N-dimethylcyclohexylamineat 240”C.606 4,6-Diphenyl-
thieno[3,4c] [ 1,231oxadiazole reacted with trinorbornene to give four stereo-
isomeric 1 :2 ad duct^.^'^
,&
CN
Me SCH2COOEt SCH2COOEt COOEt

NH2 s-
(2811 (282) (283)
6 Thiophen Fused to Six-Membered Heteroaromatic Rings
Thiophen Analogues of Quinoline. - Pyrolysis of 3-(2-thienyl)propenal 0-
methyloxime at 650°C in a silica tube gave a 33% yield of thieno[3,2-b]-
pyridine.‘08 New methods for the synthesis of 3-cyanopyridine-2-thiones
602 A. Foucaud, Bull. SOC.Chim. Belg., 1981, 90,545.

‘03 K. Yamane, K. Fujimori, and T. Takeuchi, Chem. Lett., 1981, 293.
604 F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 385.
605
F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 393.
606 K. G. Jensen and E. B. Pedersen, 2. Naturforsch., Teil. B, 1981, 36, 1640.
607
0.Tsuge, T. Takata, and M. Noguchi, Heterocycles, 1981, 16, 789.
608 C. L. Hickson and H. McNab, Synthesis, 1981,464.
facilitated the preparation of thieno [2,3-b]pyridines and pyrido [2’,3;2,3] -
thieno[4,561 pyrimidine^.^" 2-Chloroquinoline-3-carbaldehyde reacts with
methyl thioglycollate to give (284); (285) was obtained in a similar way from
2-chloro-6-bromo-3-formylthieno[2,3-b] pyridine.610 Refluxing vinyl quino-
linethiones with sodium hydrogen selenide in ethanol gave 2,3-dihydrothieno-
[2,3-b]quinolines.611 Dimethoxybenzo [b] thieno [2,3-b] quinoline has been
synthesized .530 The mass spectra of thieno-pyridines6’’ and thieno [2,341-
quinoline61 have been analysed. The spectral and magnetic properties of
complexes of divalent transition metals with thieno [2,3-b] thiophen have
been investigated.614 Detailed investigations of the photolysis of thieno [2,3-
b] pyridine N-imides have been carried out: (286; X = H) gave (287; X = H),
while (286; X = C02Et, Ac, or COPh) gave a mixture of (287) and (288).
Similar results were obtained with derivatives of thieno [3,2-b] ~ y r i d i n e . ~ ~ ’
-N- X
( 286 1
Thiophen Analogues of Isoquinoline. - A catalytic dehydrogenation of

4,5,6,74etrahydrothieno [3,2c] pyridine to thieno [3,2c] pyridine over a
chromium catalyst has been patented.616 Oxazolones (289), easily obtained
( 289)
‘09 k A. Krauze, Z. A. Bomika, A. M. Shestopalov, L. A. Rodinovskaya, Yu. E. Pelcher,

G. Ya. Dubur, Yu. A. Sharanin, and V. K. Promonenkov, Khim. Geterotsikl. Soedin.,
1981, 377.
610
0. Meth-Cohn, B. Narine, B. Tarnowski, R. Hayes, A. Keyzad, S. Rhouati, and A.
Robinson, J. Chem SOC.,Perkin Trans. I , 1981, 2509.
6 1 1 I. K. Raja, Curr. Sci., 1981, 5 0 , 364.
6 1 2 L. H. Klemm, J. Shabtai, J . Michaud, and J. N. Louris, J. Heterocycl. Chem., 1981,
18, 1383.
613
N. Soundararajan, R. Palaniappan, V. T. Ramakrishnan, T. K. Thiruvengadam, K.
Kanakarajan, K. Natarajan, and P. Shanmugam, Org. Mars Spectrom., 1980, 15,
651.
‘14 0.Piovesana, L. Sestili, and C. Troni, J. Inorg. Nucl. Chem., 1981, 43,2321.
615 T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 1981, 29, 3173.
616 Belg. P. 886470.
from thiophen-2-carbaldehyde and N-aroylglycine, gave 4-arylthieno [3,2-
c] pyridine-6-carboxylic acid by an intramolecular Friedel-Crafts reaction.617
4-Arylthieno [2,3-c] pyridines and 7-arylthieno [3,2-c] pyridines have been
prepared by heating 2-(2-thenylamino)- 1-aryl-ethanols or -propanoh and 2-
, (3-thenylamino)l -aryl-ethanols or -propanols in PPA.618 Starting from 3-
1 chloroisonico tinonitrile, 3 -amino-2-et hoxy carbonyl- and 3-amino-:! -phenyl-

thieno [2,3-c]pyridines were obtained by nucleophilic substitution with
sodium thioglycollate or toluene-a-thiolate followed by ring-clo~ure.~'~
Benzo [b] thieno[2,3-c] pyrylium perchlorates were obtained in high yields in
the acylation of benzo [ b ]thiophen-3-ylacetone with aliphatic acid anhydrides
in the presence of 70% perchloric acid. Treatment of the products with
ammonia converts them into benzo [b]thieno [2,3-c]pyridines in high
yields.620 Irradiation of thieno [2,3-c] pyridine N-imides gave the novel
diazepine-fused systems (290) and (29 1) together with (292). Analogous
products were obtained from the thieno [3,2-c] -fused systems. The reaction
of (290; X = C 0 2 E t ) with acetic acid-ethanol led to (293), which upon
reaction with hydrogen chloride ring-closed to (294). The [3,2-c] -fused
system similarly gave 4-ethoxycarbonylthieno[3,2-c] pyrrole.62'
Pyrimidine-fused Systems. - Owing to their pharmaceutical interest, many

new thienopyrimidine derivatives are still being synthesized. The reaction of
2-amino-3-cyanothiophenswith carbonyl sulphide has been used for the
preparation of thieno [2,3-d] -2-thio-o~opyrimidine.~~~ The reaction of 2,5 -
diamino-3,4-diethoxycarbonylthiophen with phenyl isocyanate in the presence
617
N. F. Eweiss and A. A. Hosni, J. Univ. Kuwait, S c i , 1981, 8, 195.
618
J.-P. Maffrand, R. Boigegrain, J. Courregelongue, G. Ferrand, and D. Frehel, J.
Heterocycl. Chem., 1981, 18, 727.
619
J. L. LaMattha and R. L. Taylor, J. Org. Chern., 1981, 46,4179.
620
V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Gererotsikl. Soedin.,
1981,1351.
621
T . Tsuchiya, H. Sawanishi, M. Enkaku, and T. Hirai, Chem. Pharrn. Bull., 1981,
29, 1539.
622
M. A. Hernandez, F.-L.Chung, R. A. Earl, and L. B. Townsend, J. 0%.Chem., 1981,
46, 3941.
of triethylamine gave (295), and with triethyl orthoformate, 3,6-dihydro-
thieno [2,3-d :5,4-b'] dipyrimidine-4,5-dione was ~ b t a i n e d . ~ '
A series of compounds of the type (296) has been prepared from 2-amino-
3-ethoxycarbonylthiophens followed by reaction with 6-chloropyridine-3 -
carboxylic acid or its ester, and the carboxylic function of (296) has been
further modified. The compound showed anti-allergic activity.33 A double
ring-closure of (297), obtained from (19b), gave (298), of interest as an
anti~oagulant.~'Condensation of 2-amino-3-ethoxycarbonylthiophens with
a-thiocyanoacetophenone gave (299);623 by its reaction with formamide, 4-
oxo-(3H)-thieno [2,3-d] pyrimidines, and with benzyl isothiocyanate, 2-
mercapto-3-benzyl-4-oxothieno[2,3-d]pyrimidines, were obtained.624 N-
Arylthieno [2,3-d] pyrimidin-4-amines have been prepared by heating 2-
acylaminothiophen-3-carbonitriles with a mixture of phosphorus pentoxide,
arylamine hydrochloride, and NN-dimethylcyclohexylamine.625Similarly,
thieno [2,3-d] pyrimidin-4(3H)-ones were prepared from ethyl or methyl 2-
acylaminothiophen-3-carboxylate, using the same reagent .626 They have also
been prepared from the same starting materials via the thieno-o~azines.~~' The
reaction of 2-amino-3-et hoxy carb onylthiophens with y-halocr ot ononitrile s
0 0 0
H H
COOMe
623
H. K. Gakhar, S. Bharadwaj, A. Jain, and P. Baveja, J. Indian Chern. SOC., 1981,
58, 1017.
624 V. J. Ram, H. K. Pandey, and A. J. Vlietinck, J. Heterocycl. Chern., 1981, 18, 1277.
625 K. E. Nielsen and E. B. Pedersen, Chem. Scr., 1981, 18,245.
626 K. E. Nielsen and E. B. Pedersen, Chern. Scr., 1981, 18, 135.
627 M. J. Kulshreshtha, S. m a t t , M. Pardasani, and N. M. Khanna, J. Indian Chern. SOC.,
1981, 58, 982.
gave (300).628Photochemical ringclosure of (301) gave (302).629 Syntheses

and reactions of 2-chloro-3,4-dihydrothieno-pyrimidinesand -quinazo-
lines6309631and of 2-substituted 4-chlorothieno[2,3-d] have
been studied. Cyclodehydration of 2-carboxymethylmercaptothieno[2,3-d]-
pyrimidin-4(3H)-ones, leading to derivatives of thiazolo [3,2-a] thieno [2,3-
d] pyrimidine, has been investigated.633
R2
Miscellaneous Fused Systems. - An elegant synthesis of thieno [2,3-d] -

pyridazine in 40% yield consists of heating thiophen-2-carbaldehyde azine
with A1C13-triethylamine at 170-200°C.634 2,3-Dimethylthieno[3,4-b] -
pyrazine has been prepared from 2,4-diamin0thiophen.~~'A derivative of the
unusual thienopterine (303; R = OH) that was isolated from human urine in
1940, namely (303; R = H), has been synthesized from 2-amino-3,s-dicyano-
6-chloropyrazine in nine steps. First a thiophen ring is fused by reaction with
1-metcaptopropan-2-oneand then ring-closed to an amino-ketone intermediate,
followed by conversion of the amino-group into a methylthio-group via the
bromo-derivative, and finally annelation of the pyrimidine ring.635 Double
react ion of N-aroylt hioace t amide with a-halogeno carb oxy lic esters gave
(303) bH
628 M. S%se and S. Johne, J. Prakt. Chem., 1981, 3 2 3 , 647.

629 T. Itoh, H. Ogwa, K. A. Watanabe, and N. Kawahara, Chem. Pharm. Bull., 1981,
29, 1039.
630 H. Yamaguchi and F. Ishikawa, J. Heterocycl. Chem., 1981, 18,67.
"' H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 30,28.
632 H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 3 0 , 326.
633 P. €3 Talukdar, S. K. Sengupta, and A. K. Datta, Indian J. Chem., Sect. B y 1981,
20, 538.
634 S . K. Robev, Tetrahedron Lett., 1981, 2 2 , 345.
635 E. C. Taylor and L. A. Reiter, J. Org. Chem., 1982, 47, 528.
intermediates of the type (304), which spontaneously underwent double
cyclization to (305).636 Treatment of 2-acylamino-3-ethoxycarbonylthiophens
with t riphenylphosphine-hexachlor oet hane- t riet hylamine gave thieno-fuse d
6H- 1,3-0xazin-6-ones.637 The react ion of 2 -aminothi ophen-3-carboxamide s
with SOClz, SClz, or SzCl2 gave thieno-fused 1,2,6-thiadia~ines.~~~ Benzo-
thienothiazines have been obtained by diazotization of 2-aminobenzo [ b ]-
thiophen-3-carboxylate, followed by the reaction with SO2 to give the
sulphon 1 chloride, which was amidated with ethyl glycinate and ring-
closed.6 Y
Thieno [2,3-~]coumarins have been re pa red.^^'? 641 Reactions of 5-
phenylthieno [3,2-b] pyran-7-one, 2-phenylbenzo [b] thieno [3,2-b] pyran-4-
one, and the corresponding thiones with sodium ethylate, guanidines,
hydrazines, and enamines have been investigated.a2 Pyridino [3,2-b] thieno-
[3,4-c] [ 1,4] diazepines that have potential CNS activity have been prepared
from (23)."4
NH
1
P.
COOR~
7 Selenophens and Tellurophens

Monocyclic Selenophens. - Heating divinyl selenide to 380-45OoC gave a
50% yield of ~ e l e n o p h e n . The
~ ~ reaction of sym-tetracyanoethane with
hydrogen selenide in DMF-pyridine gave 92% of 2,5-diamino-3,4-dicyano-
selenophen.26 The reaction of lithium phenylethynylselenolate with methyl
phenylpropiolate gave, under certain conditions, methyl 2,4-diphenyl-
~elenophen-3-carboxylate.~ Halogen-metal exchange of 3,4-dibromoseleno-
phen with butyl-lithium at - 7OoC, followed by reaction with dimethyl
disulphide, gave 3-bromo-4-(methylthio)selenophen, which upon renewed
halogen-metal exchange and reaction with DMF gave 4-(me thy1thio)-
~elenophen-3-carbaldehyde.~~' The electrochemical reduction of selenophen-
636 P. I(rey and H. Dehne, 2. Chem., 1981, 21, 31.

637 D. Achakzi, M. Ertas, R. Appel, and H. Wamhoff, Chem. Ber., 1981, 114, 3188.
638 W. Offermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim, Ger.), 1981,
314, 168.
639 R. F'fiiter, Eur. Pat. Appl. 2 1 058, 1981.
640 G. k Miller and N. D. Heindell, Synthesis, 1981, 894.
64L M. Trkovnik, R. Djudiic, I. Tabakovic, and M. Kules, Org. Prep. Proced. I n t . , 1982,
14, 21.
642
P. Netchitailo, B. Decroix, and J. Morel, J. Heterocycl. Chem., 1982, 19, 327.
643
M. G. Voronkov, B. A. Trofimov, E. N. Deryagina, E. N. Sukhomazova, N. K.
Gusarova, V. A. Potapov, and S. V. Amosova, Zh. Org. Khim., 1982, 18,223.
644 M. L. Petrov, V. Z. Laishev, and A. A. Petrov, Zh. Org.Khim., 1981, 17,667.
6 4 5 A. Konar and V. Litvinov, Chem. Scr., 1982, 19,176.
2-carboxylic acid gave a mixture of three dimeric acids, in contrast to the

behaviour of the corresponding furan- and thiophen-carboxylic acids, which
give the 2,5-dihydro-deri~atives.@~ Poly(selenien-2,5-ylene)has been prepared
by converting 2,5-dibromoselenophen into the Grignard reagent and poly-
merization with Ni” salt^.^'
Condensed Selenophens. - The reaction of lithium phenylacetylide with the
complex butyl-lithium-potassium t-butoxide gave the ortho-metallated
phenylacetylide, which reacted with selenium to give benzo [b] selenophen.a8
The reaction of benzo [b J selenophen with a-hydroxy-N-benzyloxycarbonyl-
glycine in the presence of sulphuric acid gave, after further modification,
benzo [b] ~elenienylglycine;~~ in the text this was claimed to be the 2-isomer,
based on n.m.r. data, but in the experimental part and in Chemical Abstracts
~ 77Se n.m.r. spectra of 79 mono- or di-
it is given as the 3 - i s 0 m e r . ~The
substituted benzo[b] s e l e n ~ p h e n s , ~as
’ ~ well as the 77Se and 13C n.m.r.
spectra of thienoisoselenazoles, selenoloisothiazoles, selenoloisoselenazoles,
and thienoisothia~oles,~~~ have been published. The synthesis and reactions
of new selenapseudophenalenones have been in~estigated.~’~
The reaction of 2-methyl-3-benzoylfuran with NN-diethylseleno propion-
amide gave 1 -phenylselenolo [ 3,441 furan. The thiophen analogue was
obtained similarly, using thioacetamide. Applying the same reaction to
phenyl 3-methylindol-2-yl ketone gave 3-phenylselenolo [3,4-b] indole and 3-
phenylthieno [3,4-b]ind01e.~’~Selenolo [3,4-b]thiophen, the last hitherto
unknown ‘classical’ selenolothiophen, has been best synthesized via quaterni-
zation of 4-(methylthio)selenophen-3-carbaldehyde with bromoacetate
followed by cyclization and decarboxylation. It could also be obtained from
methyl 4,5-bis(chloromethyl)thiophen-2-carboxylate by its reaction with
sodium hydrogen selenide and aromatization of the ring. The ‘H, I3C, and
77Se n.m.r. spectra were analysed. Similar to its sulphur analogue, but in
contrast to the selenium analogue, i.e, selenolo [3,4-b] selenophen, selenolo-
[3,4-b] thiophen was unstable and polymerized easily.@’ Vilsmeier
formylation of selenolo [2,3-c] thiophen gave a mixture of the 4- and 6-formyl
derivatives in a 3 :2 ratio. Metallation with butyl-lithium followed by reaction
with DMF gave a ring-opened product, 4-($?-butylselenoethenyl)thiophen-3-
carbaldehyde, together with the 4- and 6-carbaldehydes in a ratio of 1 :4.654
646 V. P. Gultyai, T. G. Konstantinova, A. M. Moiseenkov, V. P. Litvinov, and A. Konar,

Chem. Scr., 1982, 19,95.
647 M. D. Bezoari, P. Kovacic, S. Gronowitz, and A.-B. Hornfeldt, J. Polym. Sci., Polym.
Lett. Ed., 1981, 19, 347.
648
H. Hommes, H. D. Verkruijsse, and L. Brandsma, J. Chem. SOC., Chem. Commun.,
1981, 366.
6 4 9 T. Sadeh, M. A. Davis, R. Gil, and U. Zoller, J. Heterocycl. Chem., 1981, 18, 1605.
650
M. Baiwir, G. Llabrbs, L. Christiaens, and J.-L. Piette, Org. Magn. Reson., 1981,
16, 14.
651
N. V. Onyamboko, M. Renson, S. Chapelle and P. Granger, Org.Magn. Reson., 1982,
19, 74.
6 5 2 R. Neidlein and E. A. Varella, Chem. Chron., 1980, 9, 91.
6s3 A. Shafiee and S. Sattari, J. Heterocycl. Chem., 1982, 19, 227.
6 5 4 S. Gronowitz, A. Konar, and V. P. Litvinov, Izv. Akud. Nauk SSSR, Ser, Khim.,
1981,1363.
Substituent effects in 2-substituted selenolo [3,2-b] selenophens have been
studied by ‘H, 13C, and 77Se n.m.r. spectroscopy; good linear correlations
between these shifts and those of thieno [3,2-b] thiophens were ~bserved.~”
The ‘H, 13C, and 77Se n.m.r spectra of some selenolo[3,2c] thiophens have
also been CND0/2 calculations have been carried out on
selenophen and on [2,3-b] -, [3,2-b] -,and [3,4-b] -fused ~elenophens.~’~
Tellurophens.- In the reaction of sodium 2-phenylethynyltellurolate with
DMAD, dimethyl 4-phenyltellurophen-2,3-dicarboxylate was formed in low
yield.658 Di-2-tellurienyl ketone was prepared by allowing tellurophen to
react with butyl-lithium and C02.6592,5-Dihydrotellurophen 1,l -dichlorides
were obtained through the reaction of butadiene, isoprene, or 2,3-dimethyl-
butadiene with tellurium tetrachloride in acetonitrile. They were easily
reduced to the corresponding 2,5-dihydrotellurophens with aqueous sodium
sulphide.660 Reactions of benzotelluracyclopentane di-iodide have been
investigated.661
PART 11: Systems containing Nitrogen and Sulphur, Selenium, or Tellurium

by H. Quiniou and 0.Guilloton
1 Introduction and Reviews

A review describes the pharmacological properties of 1,2-benzisothiazoles.’
In connection with thiazoles, we find several reviews or papers: thiazoles in
food aromas;2 patellamides, which are antineoplastic cyclic peptides, from
the marine tunicate Lissoclinum pateZZa, which contain an unusual fused
oxazoline-thiazole unit;3 and polythiazole-containing peptide antibiotic^.^
An interesting total synthesis of the aglycon of bleomycin A2 should also be
mentioned.
655 S. Gronowitz, A. Konar, and A.-B. Hornfeldt, Chem. Scr., 1982, 19, 5.
656 S. Gronowitz, A. Konar, I. A. Abronin, and V. P. Litvinov, Izv. Akad. Nauk SSSR,
Ser. Khim., 1981, 1285.
I. A. Abronin, A. Z. Djumanazarova, V. P. Litvinov, and A. Konar, Chem. Scr., 1982,
19, 75.
658 V. Z. Laishev, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 2064.
659 W. Lohner and K. Praefcke, J. Organomet. Chem., 1981, 208,43.
660 J. Bergman and L. Engman, J. Am. Chem. Soc., 1981, 103,2715.
661 T. N. Srivastava, P. C. Srivastava, and R. Kumar, J. Indian Chem. SOC.,1982, 59, 186.
’ A. De, Prog. Med. Chem., 1981,18,117 (Chem. Abstr., 1982,96,154817).

* G. Vernin, Riv. Ital. EPPOS, 1981, 6 3 , 190 (Chem. Abstr., 1981, 95,132 706).
C. M. Ireland, A. R. Durso, Jr., R. A. Newman, and M. P. Hacker, J. Org. Chem.,
1982,47,1807.
L. B. Sokolov, L. E. Alekseeva, and E. B. Ratsino, Antibiotiki (Moscow), 1981, 27,
299 (Chem. Abstr., 1982, 96,187 131).
T. Takita, Y. Umezawa, S. Saito, H. Morishima, H. Umezawa, Y. Muraoka, M.
Suzuki, M. Otsuka, S. Kobayashi, and M. Ohno, Tetrahedron Lett., 1981, 22,671.
Five-Membered Rings: Systems containing N and S, Se, or Te 139
0the r ring systems reviewed include 3 -acyl-1,3- thiazolidine-2 -thione
(monitored aminolysis),6 benzothiazoles in the aquatic environment ,' and
1,2,5-thiadiazole and its selenium analogues.8
Selenium and tellurium compounds that include nitrogen are also described
in proceedings published in 1981.9
2 Isothiazoles
Synthesis. - From Dicyanoacetylene and Sulphur Dioxide (Type A; C-C-C-
N + S)." Dicyanoacetylene (NCCGCCN) reacts with SOz and HBr t o give
35% of 5-cyano-3,4-dibromoisothiazole (l)."
Synthesis of Isothiazoles from P-Benzoylpropionamidesand Thionyl Chloride
(Type A ) . N-Phenyl-0-benzoylpropionamide ( 2 ) and SOCl2 give 5 -benzoyl-2-
phenylisothiaaolin-3-one (3)."
0
II
NcfiBr
Br
PhCO(CH2)2CONHPh
(2) oQc'hp
(1) (3)
Synthesis of Isothiazoles from I ,3,2-0xathiazol-5-ones (Type B; S-N-C +

C-C). The thermal reaction of meso-ionic 1,3,2-oxathiazol-5-one [4; R = 2,3,4-
(Me0)3C6H2] with dimethyl acetylenedicarboxylate (DMAD) at 80°C with
0
'r
C02 evolution gives 80% of isothiazole (5; R the same) (Scheme 1).12
+
%
' Me00CCECCOOMe
MeOOC COOMe
(4) (5)
Scheme 1
Y. Nagao and E. Fujita, Heterocycles, 1982,17, 537.

B. Brownlee, J. H. Carey, and M. E. Fox, Sci. Sere-Can.,Inland Waters Dir., 1981,
126 (Chem. Abstr., 1982,96,204953).
W. S l i m and A. Thomas, Wiad. Chem., 1981, 35, 373 (Chem. Abstr., 1982, 96,
52 194).
D. Cagniant and G. Kirsch, Proc. 3rd Int. Symp. Org. Selenium Tellurium Compd.,
Metz, France, 1979.
l o Yu. L. Zborovskii, I. V, Smirnov-Zamkov, and V. I. Staninets, Zh. Org. Khim. 1982,
18,675 (Chem. Abstr., 1982,96,217750).
l 1 R. J. S. Beer and D. Wright, Tetrahedron, 1981, 37, 3867.
l 2 H. Gottmardt, F. Reiter, and C. Krumer, Liebigs Ann. Chem., 1981, 1025.
* For definitions of the types A, B, etc. for isothiazoles, see p. 110 of Volume 1 of this
series.
Visible-light-induced fragmentation of ( 5 ) gives a nitrile sulphide intermediate
RCSN-S-, which decays unimolecularly to give S and RCN, or whch can be
partially trapped with DMAD to form the isomeric isothiazole (6).
Synthesis of Isothiazoles from 3,3'-DisulphunedipropionylChloride and
+
Amine (Type H; S-C-C-C N ) . 3,3'-Disulphanedipropionylchloride, (SCH2 --
CH,COC1)2, reacts with 2,6-MezC6H3NHzto give (SCH2CHzCONHC6H3Me2-
2,6)*.13 This latter compound is treated with S02C12 t o give 4-isothiazolin-
"/o
3-one (7). The oxidation of (7) with 3-C1C6H4CO3Hgives the corresponding
1,l -dioxide (8).
MeOOC -
RyN'ycOOMe a,' "/o
' cs'k
Me
O2
Me
0 0
(6)
(7) (8)
Synthesis of Isothiazolesfrom Aqueous Ammonia and Thioamide Vinylogues
(Type H). Aqueous ammonia transaminates the thioamide vinyl~gues.'~ In
addition, the 3-amino-1-arylpropenethiones, in the presence of elemental
sulphur, undergo ring-closure to give 65-95% of 5-arylisothiazoles (9)
(Scheme 2).
S
II
ArCCH=CHNH2 =
SH
I
ArC=CHCH=NH - sx
Synthesis of Isothiazoles by Ring-Cleavage of 3-Azidothiophens. 3-Azido-

thiophen-2-carbaldehyde is condensed with N3CH2C02Et to give (10; R =
H).lS Thermal decomposition of (10; R = H) in toluene gives cleavage of the
thiophen ring and extrusion of acetylene to yield 19% of isothiazole (1 1)
together with 17% of the cyclization product (12). The thermolysis of the
azide (10; R = C02Et) gives (13).
CH=CRCOOE t
[R = HI NC
\[R = COOEt] (11) (12)
(13)
l3 Meiji Seika Kaisha Ltd., Jpn. P. 81 118 073,1981 (Chem. Abstr., 1982, 96,35 235).
l4 H. Quiniou, Phosphorus Sulfur,198 1, 10, 1 .
C. J . Moody, C. W. Rees, and S. C. Tsoi, J. Chem. SOC.,Chem. Commun., 1981, 550.
Five-Membered Rings: Systems containing Nand S, Se, or Te 141
Synthesis of Isothiazoles porn Substituted Enamines and Benzyl Isothio-

+
cyanate (Type C-C-N S-C). h i d e vinylogues (14; R' = PhCO, 4-C1-
C6H4C0, 4-MeOC6H4C0,or 4-MeC,H4CO; R2 = SMe or NHEt; R3 = Ph or
Et), when treated with PhCONCS, give the intermediates (15), then
pyrimidinethiones (1 6) and isothiazoles ( 17).16 The structure of the isothia-
zoles is further confirmed by subjecting the intermediates (1 5 ) to oxidation
by bromine, which also gives isothiazoles (Scheme 3). Similarly, the nitro-
enamine (14; R' = NO2) gives the intermediate R3NHCR2=C(N02)-
CSNHCOPh, then the isothiazole (17; R' = NO2), but no pyrimidinethiones.
R1CH=CR2NHR3 S
(14)
+
SCNCOPh
N
,COPh
:' 6 R3P h
I1
R1
\C"S'H
II ,COPh
N
RwC\NH
I
R3
(15)
(17)
Scheme 3
Physical Properties of Isothiazoles. - The i.r. and U.V. spectra of 3 3 -

bis(methy1thio)isothiazoles (18; R = H, CN, NH2 etc.) have been studied."
(18)
Chemical Properties. - N-Quaternization of Isothiazoles. 3-Chloroisothiazole
is quaternized by FS03Me; the salt is then treated with MeNH2 and passed
through an ion-exchanger (Cl-) to give (19; R' = R2 = Me; Z = C1).18 Other
16
V. Aggarwal, H. Ila, and H. Junjappa, Synthesis, 1982, 65.
17
G. Mille, J. C. Poite, M. Guliano, and J. Chouteau, Spectrosc. Lett., 1981, 14, 271.
18
J. Rokach, C. S. Rooney, and J . E. Cragoe, Jr., U.S.P. 4 2 9 2 4 3 0 , 1981 (Chem.
A h * . , l 9 8 2 , 9 6 , 3 5 2 3 6 ) a n d 4 2 6 7 3 4 1 , 1 9 8 1 (Chem. Absstr., 1981,95,132864).
salts (19; R1 = H, alkyl, Ph, or PhCH2; R2 = alkyl, Ph, or PhCH,; Z = halide,
sulphonate, nitrate, phosphate, or various carboxylates) can also be prepared.
3-Methoxyisothiazole is quaternized as above .l Other 3-alkoxy-2-alkyliso-
thiazolium salts and their derivatives (20; R' = alkyl, or alkenyl; R2 =
alkoxy, PhCH20, OCKMe, CH2=CHCH20,or CH2=CMeCH20; R3 = H, C1,
or Br; R4 = H or C1; X = counter ion), are similarly prepared, as are 3-
haloisothiazolium salts (21; R1 = alkyl or alkenyl; R2 = C1 or Br; R3 = H,
Me, Et, C02Me, C02Et, C1, Br, NO2, or cyano; R4 = H, Me, Et, C1, Br, cyano,
C02Me, or C02Et; X = anion).20
(20) (21)
Reactions of 5-Aminoisothiazoles. 5-Amino-3-methylisothiazole (22) gives
1 : 1 adducts with nitriles RCN [R = (un)substituted Ph] or EtOCMe=NH
to give the thiadiazoles [23; R = (un)substituted Ph or Me] .21 5-Amino-3-
methylisothiazole-4-carboxylic acid (24), in benzene that contains pyridine,
reacts with C1CH2COC1 and then with HNR2 to give 5-dialkylamino-
acylamino-3-methyl-4-carboxylic acid derivatives (25; R = Me or Et; n = 1
or 2).22
5-Amino-3-alkylisothiazolium hydrochlorides (26; R' = H or Me) are
diazotized and coupled with substituted or annelated anilines to give the free
bases, which are quaternized to yield the salts [27; R' = Me, Et, CH2CH20H,
CH2CH(OMe)Me,. or CH2CH=CH2; R2, R3 = H or Me; R4 = Me or Et; R5 =
H, Me, Et, Pr, Pr', CH2CH20H, or CH2=CHCH2 ; R6 = H, Me, Et, Pr, or Pr';
R4R6 in combination with an amino-ring can form an annelated morpholine
residue; X = anion] .23
( 2 2 ) R1= .H (23)
( 2 4 ) R1= COOH
(26) (27)
l9 J. A. Vhgilio, M. Manowitz, and E. Heilwell, U.S.P. 4262127, 1981 (Chern. Abstr.,
1981,95,62 181).
J. A. Virgilio, M. Manowitz, and E. Heilwell, U.S.P. 4281 136, 1981 (Chern. Abstr.,
1981,95,203 937).
" K. Akiba, A. Noda, K. Ohkata, T. Akiyama, Y. Murata, and Y. Yamamoto, Hefero-
cycles, 1981, 15, 1155.
'' Z. Machon, M. Mordawski, and M. Wilimowski, Pol. P. 104 802,1979 (Chern. A bstr.,
1981,95,80 942).
23 B. Gertisser, Ger. Offen. 3 029 746,1981 (Chern. Abstr., 1981,9S,26 600).
Five-Membered Rings: Systems containing N and S,Se, or Te 143
A?-Isothiazolines.- Chemical Properties of Isothiazoline-5-thiones. By treat-
ment with (EtO),P in benzene, isothiazoline-5-thiones (28) are desulphurized
to bis(isothiazoly1idene) (29; R1,R2,R3 = Me, H, Ph; But, H, Ph; Ph, H, Ph;
or 4-HOC6H4, H, Ph).24
(29)
A4-1sothiazolines.- Chemical Properties of Isothiazolin-3-ones. Examples
of additions to carbon-carbon double-bonds have been given. Thus 2-octyl-4-
isothiazolin-3-one 1,l-dioxide (30; R = octyl) is treated with diethyl
dithiophosphate to give 4- or 5-(diethyldithiophosphoryl)-2-octylisothiazo-
lidin-3-one 1,l -dioxide (3 1; R = octyl)?' -- - Chloro-5-methyl-4-phenyl-2-
isothiazolin-3-one with Me2NCS2Na gives substitution products (32). Other
derivatives (33), with R3 = CN or polymethyleneimino, were described.26
5-Benzoyl-2-phenylisothiazolin-3-one (34) with (MeC02)2CH2 in MeOH that
contains NaOMe, at room temperature, gives the pyrrolinone ( 3 9 , which
gives the pyronomaleimide (36) on refluxing in ~ y l e n e . ~ '
(\& O2
0
88t$ cf~$
Et2PS
0
0
Me
0
R3fs\c
R2
0
(30) (31) (32) (33)
0 0
PhCO[aO p h ceM;; ~ pho@ ~ ~ NPh
(34) Ph 0
(35) (36)
Isothiazolidines. - Physical Roperties of Isothiazolidine 1,I -Dioxides. Proton

n.m.r. (60, 90, and 250MHz) spectra have been reported for isothiazolidine
1,l-dioxides (sultams) (37; R' = H or Me, R2 = H or substituent) and com-
24
RENR2(37)
P. D. Clark and D. M. McKinnon., J. Heferocycl. Chem., 1981, 18,437.
2s G. A. Miller and E. D. Weiler, U.S.P. 4302240, 1981 (Chem. Absfr., 1982, 96,
162 930).
26
27
R. B. Petigara, Eur. Pdt. Appl. 31 705,1981 (Chem. Abstr., 1981,95, 187 235).
R. J. S. Beer and D. Wright, Teimhedron, 1981, 37,3867.
pared with those of propane-l,3-~ultone.~~ The paramagnetic shift that is
induced by the NH group is smaller than that induced by 0. Low-temperature
n.m.r. shows coupling effects with the NH proton.
3 1 ,ZEknzisothiazolesand their 1,l-Dioxides
Synthesis. - From ortho-Halobenzoyl Compounds, Aqueous Ammonia, and
Elemental Sulphur. Treating a mixture of 2,5-C1(N02)C6H3CHO and sulphur
in DMF at 70°C with 25% aqueous NH3 gives 95% of 5-nitro-1,2-benziso-
thiazole (38) (Scheme 4).29 Other compounds (39; R' = H, aliphatic, cyclo-
aliphatic, optionally annelated aromatic, halo, alkoxy, NO2, or NR2 ;R2-= H,
aliphatic, cyclo-aliphatic, arylaliphatic, or aromatic; R3 = H, aromatic or
heterocyclic) are similarly prepared by he ter ocyclization.
Scheme 4
Reactions of 1,2-Benzisothiazoles.- Reduction. Thiophenol reduced com-
pounds (41), (42), and (43) to o-mercaptophenylformamidines [40; R' = H,
Me, Et, or 4-C1C6H4;R2 = H, Me, or Et; R3 = H, Me, Et, or Ph; R4 = H, 4-C1
or 6-C1; or R1R2 = (CH,),, R3 = Me, R4 = HI with good yields.30
R3N=C-NR1R2
\
NR'
,S +,R3
28 K. H. Albert, H. Duerr, S. H. Dos, and J. P. Zahra, Org. Mugn. Reson., 1980, 14,
209.
29 H. Hagen, J . Markert, and H. Ziegler, Ger. Offen 3018108, 1981 (Chem. Absstr.,
1982, 9 6 , 6 8 980).
30 H. Boeshagen and W. Geiger, Liebigs Ann. Chem., 1982,14.
3-Chloro-substitution. 3-Chloro-l,2-benzisothiazole 1,l-dioxide with 3-
(hydroxymethy1)pyridine in toluene/Et3N gives (44).31Other ethers or
thioethers(45; Z = 0 or S ; R = R1,CH2R2 [R' = (un)substitutedimidazolyl,
thiazolinyl, etc.; R2 = (un)substituted furyl, imidazolyl, etc.] } are similarly
prepared.
Photochemistry. The photochemical reaction of benzisothiazoles (46; R = H)

with DMAD gives a mixture of [48;2 (30%), E (50%)] and the substituted
benzo thiophen (47) (Scheme 5). 32 5-Chlorobenzisothiazole be haves similarly.
A mechanism involving initial cleavage of the thiazole ring to a diradical has
0sLi
R\
MeOOCC%COOMe
hv
~
MeOOCC =CHCOOMe
I
CN
CN
(46) (47) R
(48)
Scheme 5
been proposed. Irradiation (300 nm) or 3-phenyl-l,2-benzisothiazole (49;
R' = R2 = H) in EtOCH=CH2 for 90-150h under N2 gives 80% of 2,3-
dihydro-l,4-benzothiazepine(50).32* 33 The structure of the latter compound
was determined by X-ray analysis. The same reaction has been described for
photocycloaddition of other benzisothiazoles (49; R' =Me, R2 = H ; R' =
H, R2 = C1) and alkenes. The reaction is regio- and stereo-specific.
Ph
Synthesis of 1,2-Benzisothiazolin-3-onesand their 1,l-Dioxides. - From 2-

(Methy1sulphinyl)benzamides and Thionyl chloride. The reaction of 2-
(methylsulphiny1)benzamides with thionyl chloride, a novel and convenient
31 T. Nihon and S. Noyaku, Jpn. P. 81 133 287,1981 (Chem. Abstr., 1982, 96, 759).
32 M. Sindler-Kulyk and D. C. Neckers, Tetmhedron Lett., 1981, 22, 525 and 529.
33 M. Sindler-Kulyk, D.C. Neckers, and J. R. Blount, Tetrahedron, 1981, 37, 3377.
(51 ; R = Et,
method for preparing 2-substituted 1,2-benzisothiazolin-3-ones
Pr, But, C6Hll, PhCH2, Ph, or 4-MeC6H4), has been described (Scheme
6).%
?
0 C1- Me
S-Me
CNHR
-[-HCl]
0
II
0 0
Scheme 6
Synthesis from Anilines and 2-Chlorothiobenzoyl Chloride. 2,4-(02N)zC& -

NH2, when treated with 2-C1C6H4CSC1 and oxidized with H 2 0 2 , gives
(52).35
( 5 2 ) R = 2,4-(N02)2C6H3
Synthesis of 1,2-BenzisothiazoEin-3-one I ,I -Dioxides from 2-Aminobenzo-

nitriles and SO2. 2,6-o2N(Meo)C6H3CN is reduced and the 2,6-
NH2(MeO)C6H3CN is treated with NaNOz followed by SO2 to give 3-amino-
4-methoxy-l,2-benzisothiazole1,l-dioxide, which underwent demethylation
followed by hydrolysis to give (53).36
bP’e
\
OH
34 Y. Uchida and S. Kozuka, J. Chem. SOC., Chem. Commun., 1981, 510.

35 Jpn. P. 81 6 5 882 (Chem. Abstr., 1982,96,20089).
36 G. Trummlitz, W. Eberlein, W. Engel, and G. Schmidt, Ger. Offen. 3 01 5 113, 1981
(Chem. Abstr., 1982,96,104 222).
Synthesis of 1,2-Benzisothiazolin-3-0ne 1,I -Dioxides from 2-(Ch1orothio)-
benzoyl Chloride and Substituted Anilines. 2-(C1S)C6H4COCl with 2,4-
(02N)zC6H3NH2 gives a benzisothiazolinone derivative (54), which is
oxidized by H z 0 2 to give [55; R = 2,4-(02N)2C6H3].37 By this method (or
other methods), ( 5 5 ; R = fluoro-, nitro-, trifluoromethyl-, cyano-, alkoxy-
carbonylalkanoyl-, carboxy-, carbamoyl-, acylamino-, alkylsulphonyl-, N,N-
dialkylsulphamoyl-, trifluoromethoxy-, trifluoromethylthio-, trifluoromethyl-
sulphonyl-, or trifluoromethylsulphinyl-phenyl) are also prepared.
Synthesis of 1,2-Benzisothiazolin-3-onesfrom Thermal Decomposition of

N-Substituted 2-(Methylthio)benzarnides. The compounds 2-MeSC6H4CON-
(But)OCOR (R = Ph or 4-MeC6H4) are prepared by acylating ButNHOCOR
with 2-MeSC6H4COC1in the presence of pyridine.% Compound (56; R = Me,
4-MeC6H4, or 4-C1C6H4) is prepared by treating 2-MeSC6H4CON(OH)But
with RCOCl. Thermal decomposition of (56), at 200°C in o-dichlorobenzene,
gives (57) as the initial product of the thermolysis. Subsequent decomposition
gives the isothiazolinone (58), RC02H, 2-MeSC6H4CONHBut, RC02Me,
RCONHBU~, and (59) (Scheme 7).
It
OCOR - SCH20COR
C'
II
'But
0 0
(59) + other products
Scheme 7
37 H. Jones, R. L. Clark, and M. Zimmerman, U. S. P. 4 276 298, 1981 (Chem. Abstr.,

1981,95, 203 929).
38 Y. Uchida, Y. Kobayashi, and S. Kozuka, Bull. Chem. SOC.Jpn., 1981,54,1781.
Physical Properties of 1,2-Benzisothiazolin-3-ones. - The infrared spectra
of N-substituted isobenzothiazolinone 1,l -dioxides have been measured
and characteristic frequencies for the S-N stretching vibration disc~ssed.3~
The medium bands at 819-870cm-1 are assigned to the S-N stretching.
Chemical Properties of 1,2-BenzisothiazoIin-3-ones. - Hydrolysis,Alcoholysis,
and Phenolysis. Hydrolysis of N-nitro-imides (60) generally involves N-N02

bond cleavage, which is catalysed by the HN03 that is formed in the reaction;
in the absence of acid catalysis, (60) is hydrolysed with N-S02 bond
cleavage.40 Alcoholysis occurs at the N-CO bond. The effect of solvent on the
alcoholysis has been studied. N-Carbamoylsaccharins are split between the
N and the CO of the carbamoyl with phenols. Thus 3-(Me02CNH)C6H40H
reacts with (61 ; R = Ph) and Et3N, in acetone at 4OoC,to give (62).
Reactions of 1,2-Benzisothiazolin-3-ones
with Amines. - N-(Phenylsulphonyl)
saccharin (63) with RNH2 (R = Ph, PhCH2, or Bu), in solvents, at room
temperature, affords the ringopened adducts (64):l When heated at its
melting point, (64; R = Ph) gives 93% of (65 ; R = Ph). With N-unsubstituted
saccharins and primary and secondary aliphatic amine hydrochlorides, at
240°C, in the presence of P205 and NN-dimethylcyclohexylamine,there is
a single dehydration between the carbonyl and the amino-group to give
(65)?2
39 Y. Abe, T. Horii, T. Oka,S. Kawamura, and T. Nakabhayashi, Annu. Rep. Radiat.

Cent. Osaka Prefect., 1980, 21,67 (Chem. Abstr., 1982, 96,68 159).
40
I. K. Koslova, 0. A. Luk'yanov, and V. A. Tartakovskii, Izv. Akad. Nauk SSSR. Ser.
Khim., 1981,2556 (Chem. Abstr., 1982, 96, 67902).
41 Y. Imai, H. Okunoyama, K. Hirata, and M. Ueda, Nippon Kagaku Kaishi, 1982, 111
(Chem. A bstr., 1982, 96,104 134).
42 K. G. Jensen and E. B. Pedersen, 2. Naturforsch., TeiZ. B , 1981, 36, 1640 (Chem.
Abstr., 1982, 96, 122 677).
N-Substitution of 1,2-Benzisothiazolin-3-ones.- Saccharin K salt, when
stirred with BuOCHC1CH2CC13 in 1 : 10 H20/Me2C0, at room temperature,
gives the trichloropropane derivative (66).43
1 ,l -Dioxides. - The sodium salt of 1,2-benziso-

1,2-Benzisothiazoline-3-thione
thiazoline-3-thione 1,l-dioxide (67), when treated with RX (R = PhCH2,
On
PhCH2CH2, PhCH=CHCH2, CH2zCHCH2, CHGCCH2, NCCH2, or Me;X = C1,

Br, or I) gives 80-93% of ( 6 Q 4 From the latter, the corresponding thiols
RSH are produced with piperidine in almost quantitative yield. Compound (68)
is claimed as being an odourless crystalline equivalent of thiols.
1,2-Benzisothiazolidinesand their 1,l-Dioxides. - 2-MeC6H4S02C1, when

brominated to 2-BrCH2C6H4SO2C1 and then treated with NH40H, gives
(69; R' , R 2 , R3 = H). This compound reacts with C1SCCl2CHCl2 t o give
(70; R1 = SCC12CHC12, R2 = H)?' Infrared data indicate that (69; R',
R2 = Ph; R3 = NH2) exists in equilibrium with (70); (69) was stabilized when
R' = But or
?-IP
43 Jpn. P. 81 43 265,1981 (Chem. Abstr., 1981,95,97587).

44 K. Inomata, H. Yamada, and H. Kotake, Chem. Lett., 1981, 1457.
4s D. C. K. Chan, U.S.P. 4 253 865,1981 (Chern. Abstr., 1981,95,80935).
46 R. Valters, D. Balode, R. Kampare, and S. Valtere, Khim. Geterotsikl. Soedin., 1981,
1209 (Chern. Abstr., 1981,95,203048).
4 1,2-Benzisoselenazoles
- p-Toluidine, when treated with 2-ClSe-
1,2-Benzisoselenazolin-3-ones.
C6H4COC1, gives 90% of (71; R' , R 2 , R3 = H, R4 = 4-Me, n = O).47 Other
benzisoselenazolinones (R1, R2 = H, halogen, alkyl, alkoxy, OH, CF3, or
NO2; R'R' =R3R4 = OCHZO; R3, R4 = H, halogen, alkyl, alkoxy, OH,
CF3, NO2, dialkylamino, cyano, C02H, or alkoxycarbonyl; n = 0-4) were
also described.
5 2,l-Benzisothiazoles
2,l -Benzisothiazol-3-ylaceticacid and its methyl and ethyl esters, e.g. (72;
R = CH2C02Me), have been prepared.48 Rates of rearrangement of benziso-
thiazolyl benzoate (73) to benzoxazinone (74) were determined spectro-
photometrically at 25 "C. The curves are characteristic of an autocatalytic
reaction. Adding sulphur produces a 1000-fold acceleration in the rate.
Derivatives of 3-amino-2,l-benzisothiazoles were described, as well as their

coupling to give azo-dyes (75); R' represents an aniline, 1,2,3,4-tetrahydro-
quinoline, or benzoylmorpholine coupler that contains an N-sulphoalkyl
group and a variously substituted benzene ring4' 2,l -Benzisothiazolium salts
react with several stabilized carbanions to give products that are derived by
attack at the carbon atom of the heterocyclic ring5' Thus the benzisothia-
Q""\(
-
R2
N= NR'
mMj+
zolium iodide (76) reacts with Na+-CH(C02Et), to give the benzisothiazo-
line derivative (77).
\
Uj
(76)
1-
\
(77)
C( COOE t )
(75)
47 A. Welter, L. Christiaens, and Wutz-Peitz, Eur. Pat. Appl. 44453, 1982 (Chem.
Abstr., 1982,96,199699).
48 M. Davis and K. C. Tonkin, Aust. J. Chern., 1981, 34, 755.
4 9 M. A. Weaver, C. A. Coats, Jr., and J. C. Fleischer, U.S.P. 4265 812, 1981 (Chern.
Abstr., 1981, 95,26606).
D. M. McKinnon, K. A. Duncan, and L. M. Millar, Can. J. Chem., 1982,60,440.
6 Other Condensed Ring Systems incorporating Isothiazole

Thieno[ 2 , 3 4 isothiazoles. - The reaction of (78) with Na in liquid NH3 and
then H 2 0 gives 5-methoxythieno [2,3-c] isothiazole (79).”
‘CH( OE t )
(78) (79)
Isothiazolo[3,4-bJ pyridines - Diazotization of 3-amino-5-cyanoisothiazolo-

[3,444 pyridines (80) and coupling with m-diethylaminoace tanilide gives
the corresponding azo-compounds (8 1).52- Other similar compounds are also
de~cribed.’~
( 8 0 ) R = NH2
(81) R = N = N A r
Isothiazolo[ 5,441 pyrimidines. - 5-Formy1-6-mercaptouraci1, when treated

with NH20H, gives isothiazolo [5,4d] pyrimidine (82).54 This compound is
also prepared by heating the oxime (83) with NaSH.
Me
Me
5’ Ya. L. Gol’dfarb, M. A. Kalik, and V. K. Zav’yalova, Izv. Akad. Nauk SSSR, Ser,
Khim., 1981, 2771.
52 B. R. Fishwick, and T. S. B. Sayer, Eur. Pat. Appl. 26596, 1981 (Chem. Abstr.,
1981, 95, 82 388).
53 P. Gregory and T. S. B. Sayer, Br. P. 2 0 7 4 598, 1981 (Chem. Abstr., 1982, 96,
164 132).
54 K. Hirota, T. Asao, T. Fujioka, and S. Senda, Nippon Kagaku Kaishi, 1981, 721
(Chem. Abstr., 1981, 95,150 597).
1,2-Dithiolo[4,3c]isothiazoles. - 3-Aroylamino-6-mercapto- 1,2-dithiolo [4,3-
c] isothiazoles (84) are obtained, in good yields, by treating NCCSzM (M =
alkali metal or te tra-alkylammonium) with RCOCl.55
s- s
(84)
Naphtho[ 2,141 isothiazole. - The compound (85) is prepared by the reaction

of 1-halo-2-(dihalomethyl)naphthaleneor 1-halo-2-formylnaphthalene with
S and NH3, at elevated temperature and pressure, in the presence of an
“hieno[ 3,441 isothiazole 1,l -Dioxides: - 3-Aminothieno [3,4d] isothiazole

1,l-dioxides (86; R = Pr, Me2CHCH2, or EtCHMe) are prepared from thieno-
[3,4-&Iisothiazolin-3-one 1,l-dioxide and hydrochlorides of primary and
secondary aliphatic amines with P 2 0 5 and NN-dimethylcyclohexylamineat
240°C.42
7 Thiazoles
Synthesis. - Hantzsch ’s Synthesis (Type A; S-C-N + C-C). * From thioureas.
Starting from thioureas, the following compounds have been obtained: 2-
amino-4-(4-benzyloxyphenyl) thiazoles,” 2 -(2 -amino-5-hydroxythiazol-4-y1)-
1 -(4-chloro-3-methylpheny1)e thanone,58 2-benzylidenehydrazino-4-( 1,5-di-
me thyl-2-phenyl-3-pyrazolon-4-y1)-5-e t hylthiazoles, 59 2 -amino-4- [2 -(4-ace ta-
” H. u. Kibbel, u. Ohnmacht, and J. Teller, Ger. (East) P. 148341, 1981 (Chem.
Abstr., 1982,96,20 092).
56 H. Adolphi, H. Fleig, and H. Hagen, Br. P. 1 579424,1980 (Chem. Abstr., 1981, 95,
37 120).
’’ Y. Kawamatsu, T. Sohda, and Y. Imai, Eur. Pat. Appl. 27957,1981 (Chem. Absstr.,
1981,95,132 863).
M. El-Kadi, M. A. El-Hashash, and M. A. Sayed, Rev. Roum. Chim., 1981, 26,1161.
5 9 H. Amal, 0. Ates, and A. Salman, Dogu, Ser. C, 1980, 4, 13 (Chem. Abstr., 1982,
96,52 232).
* For definitions of the types A, By efc., for thiazoles, thiazolines, and thiazolidines,
see p. 1 1 9 of Volume 1 of this series
midophenylsulphonylamido)ethyl] thiaz~les,'~ 2-(2-aminothiazol-4-y1)-2-
hydroxyiminoacetic acids and substituted derivatives which are useful as
intermediates in the manufacture of antibiotic oxime derivatives of 7-amino-
thiazolylacetamidocephalosporanic acids:' substituted 2-amino-4-phenyl-
thiazole s,6, substituted 4-aryl- or 4-(2 -furyl)-2-(substi tu ted pheny1amino)-
thiazole s,63 niridazole ,64 4-substi tu t ed 2 -aminothiazole -5-carboxylic acids,65
NN-dimethylJV"'(4-phenylthiazol-2 -yl)thioureas ,66 2-amino-5-isopro yl thia-
zolyl-4-carboxylic ester and 4-isopropylthiazolyl-5-carboxylicester!7 242-
aminothiazo1-4-y1)-2-(syn)-methoxyiminoaceticester,68 substituted 2-anilino-
4-fluoroaryI-thia~oles,~~ 4-substituted 2-aminothia~oles,~~ and 2-amino-4-
aryl-thia~oles.'~5-Acyl-2-aminothiazoles are also prepared by cleavage of
the S-S bond of disulphidocarbamidines, H,NC(=NH)SSC(=NH)NH,, and
react ion with &diket ones.
Synthesis from thioamides. Compounds prepared using thioamides include 4-
(4-chlorophenyl)-2-[4-(hydroxy or acyl)phenyl] thiazol-5-ylacetic a ~ i d s , ' 2-
~
(hydroxyphenyl)thiazole-4-carboxylic acids and derivatives,% and substituted
From HC( S)NH2 and XCH2CO(CH2)30COMe(X =
2,4,5-triarylthiazole~.~~
halo) are formed 5-(2-hydroxyethyl)-4-methylthiazoleas the major product
and 4-(3-hydroxypropyl)thiazole as a by-pr~duct.'~Also noted are 2,4-
6o 0. V. Isakova, A. M. Sipyagin, and V. G. Kartzev, Zh. Org. Khim., 1981, 17, 1522
(Chem. Abstr., 1982,96,6507).
61 J. Martel, J. Tessier, and P. Girault, Fr. Demande 2475 043, 1981 (Chem. Abstr.,
1982, 96,6477); Br. P. 1 580 623,1980 (Chem. Abstr., 1981, 95,150 643).
62 Y. Kawamatsu, T. Sohda, and Y. Irnai, Eur. J. Med. Chem.-Chim. Ther., 1981, 16,
355.
63 B. G. Khadse, S. R. Lokhande, and D. G. Kulkarni, Indian J. Chem., Sect. B , 1981,
20,683 (Chem. Abstr., 1981,95,187 140).
64 D. G. Deng and S . X . Lu, Yao Hsueh Hsueh Puo, 1981, 16,14 (Chem. Abstr., 1981,
95, 132 756).
65 R. K. Howe and L. F. Lee, Eur. Pat. Appl. 27108, 1981 (Chem. Abstr., 1981, 95,
115 528).
66 R. Yoda, Y.Yamarnoto, and Y. Murakami, Kyoritsu Yakka Daigaku Kenkyu Kenkyu
Nenpo, 1980,25,37 (Chem. Abstr., 1981, 95,115 369).
6 7 A. Barton, S . P. Breukelrnan, P. T. Kaye, G. D. Meakins, and D. J. Morgan, J. Chem.
Soc., Perkin Trans. 1 , 1982 , 159.
6 8 A. Huwiler and L. Tenud, Eur. Pat. Appl. 45005, 1982 (Chem. Abstr., 1982, 96,
217 829).
69 R. B. Pathak, B. Jahan, and S . C. Bakel, Bokin Bobai, 1981, 9 , 477 (Chem. Abstr.,
1982, 96, 20 018).
70 M. S. Shingare and D. B. Ingle, Marathwada Univ. J, Sci., Sect. A , 1980, 19, 5 (Chem.
Abstr., 1982, 96,181 188).
71 R. C. Joshi and K. A. Thakar, Marathwada Univ. J. ScL, Sect. A , 1980, 19,95 (Chem.
Abstr., 1982,96,181 189).
72
A. Kreutzberger and H. Schimmelpfennig, Arch. Phurm. (Weinheim, Ger.), 1981, 314,
385 (Chem. Abstr., 1981,95, 80 800).
73 J. F. Cavalla and R. A. Franklin, Eur. Pat. Appl. 37 710, 1981 (Chem. Abstr., 1982,
96, 52 295).
'4 E. Draeger and H. Luebbers, Ger. Offen. 3002989, 1981 (Chem. Abstr., 1981,
95, 169 175).
75 K. Matsumoto and K. H. P. Peck, Eur. Pat. Appl. 37 274,1981 (Chem. Abstr., 1982,
96,122 780).
76 T. M. Filippova, A. R. Bekker, T. I. Ozorova, V. M. Belova, V. G. Mairanovskii, and
A. M. Yurkevich, Khim. Farm. Zh., 1982, 16, 201 (Chem. Abstr., 1982, 96,
199 570).
diaryl-5-~yanothiazoles,~~ 1-(thiazol-2-yl)pyrazolidin-3-ones and derivatives:'

and 4-alkoxyaryl-, 4-bromoalkylaryl-, and 4-alkenylaryl-thia~oles.~
Type B Syntheses of Thiazoles (C-C-N +
C-S). Enamino-esters CF3C-
(NH2)=CHC02Et, with ClCOSCl, are converted into 2-chloro-4-trifluoro-
methylthiazole-5-carboxylic esters and derivatives.80 Thioketens and 3-
dimethylamino-2H-azirines give 2-substituted 4-(NN-dimethylcarbamoyl)-5-
(NN-dimet hylamino) t hiazoles .'
Type C Syntheses of Thiazoles (C-C-N-C +
S). N-(Cyanomethy1)imines
R1COCH(CN)N=CR20Et (R1 = EtO, R2 = Me; R' = NH2, R2 = Me or Ph),
when treated with H2S, give thiazoles (87) and imidazoles (88).82 Of the
same type, the substituted 2-azabutadiene Me2NCH=C(C02Me)N=C(SMe)2,
with H2S , gives 2 -methylt hio t hiazole-4-carboxylic acid methy1 ester (89) .83
Treatment of the imine Me2C=NMe at 400-5OO0C with SOz and a Zr02/
CaOlNaOH catalyst gives 4-methylthia~ole.~
H
(87) (88) (89)

Type F Syntheses of Thiazoles (C-N-C-S + C). Substituted N-thiocarba-
molyformamidines R2CSN=CR"Me2 react with ally1 bromide to give an
azavinamidinium salt, which, upon treatment with a base, gives an ethylidene-
A2-thiazoline (R1 = R2 = Me2N; R1 = H, R2 = morpholino). This last com-
pound, upon heating or treatment with toluene-p-sulphonic acid, undergoes
allylic rearrangement to the thiazole (90) with migration of the NN-dimethyl-
amino-group (Scheme 8) .8s 2,4-Disubstit u t ed 5-benzoyldianilinothiazoles are
NMe
I
Scheme 8
77 A. Corsaro, M. Tarantello, and G. P. Purrello, Tetrahedron Lett., 1981,22,3305.
78 A. M. Richter and E. Fanghaenel, Ger. (East) P. 150 203, 1981 (Chem. Abst., 1982,
96,52 303).
79 T. Hara and J. C. Sheehan, Heterocycles, 1981,16, 1295.
R. K. Hoowe and L F. Lee, U.S.P. 4251 261, 1981 (Chem. Absfr., 1981, 95,
62 179).
E. Schaumann, S. Grabley, F. F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs Ann.
Chem., 1981,277.
8 2 A. K. Sen and A. K. Mukhopadhyay, Indian. J. Chem., Sect. B , 1981, 20,275 (Chem.
Abstr., 1981, 95,97673).
8 3 R. Gompper and U. Heinemann, Angew. Chem., 1981,93,297.
84 S. J. Amato, S. Karady, and L. M. Weinstock, U. S. P. 4 282 364, 1981 (Chem.
Abstr., 1981,95,203936).
R. Gompper and J. Schelble, Synthesis, 1981,647.
also described, using an analogous The thioamide vinylogues also
react with bromoacetone to give 5-a~etyl-2-phenylthiazole.~'
+
Type H Syntheses of Thiazoles (S-C C-AX'). Base-induced cycloadditions
of tosylmethyl isocyanide (4-MeC6H4S02CH2NC) and an isothiocyanate
RNCS (R = alkyl, allyl, PhCO, aryl, etc.) have been investigated. Depending
on the reaction conditions, thiazoles (91) and/or imidazoles (92) are
obtained. A high-yield ring-transformation of (91) to (92) occurs in THF/
BuLi."
sl MeaHlyNl
R
MeaR;y N N
O2 O2
(91) (92)
Physical Properties of Thiazoles. - The mass spectra of the thiazoles [93;

R' = Ph, R2 = H, R1R2 = (CH& or (CH2)4, R3 = H; R' = CICH2 , R2 = H,
R3 = H or F] and thiazolinone (94) show a major decomposition mechanism
involving elimination of PhCN.89 The spectrum of (94) showed a fragment
ion (m/z = 90) corresponding to cleavage of an azomethine bond and no loss
of PhCN. The U.V. spectra of 2,4-diphenylthiazoles with the 4-phenyl group
substituted by a Schiffs base or benzylamine were also recorded.g0 A more
important interaction between the two moieties of the Schiff's bases was
observed in the case of thiazolyl derivatives. The ionization constants of the
hydrazones (95; R' = H, R2 =Me; R1 = R2 =Me; R' = Ph, R2 =Me) and
R2 c"~N-N=cYJ
86 K. N. Rajasekharan and A. Sulekha, Indian J. Chem., Sect. B , 1981,20, 549 (Chem.
Abstr., 1981,95, 187 134).
'' M. A. Riahi and J . P. Radhrte, C. R . Hebd. Seances Acad. Sci., Ser. 2, 1981, 293,
671.
88 S. I? J. M. Van Nispen, J. H. Bregman, D. G. Van Engen, A. M. Van Leusen, and H.
Saikachi, Red. Trav. Chim. Pays-Bas, 1982, 101,28.
8 9 A. A. Tsurkan, V. M. Adanin, and A. M. Zyakum, Farm. Zh. (Kiev), 1981, 1, 66
(Chem. Abstr., 1981, 9 5 , 60 767).
90
V. Farcasan and A. Donea, Stud. Univ. Babes-Bolyai, Ser. Chem., 1980, 25, 76.
(96) were determined spectros~opically.~~ Both series of esters (97) and (98)
show carbonyl doublets in the i.r. spectrum that are caused by rotational
isomerism; the more intense absorptions of the 4-carboxylates are at lower
wavenumbers whereas those of the 5-carboxylates are at the higher wave-
n ~ m b e r . ~ In
' both series, the stronger bands arise from the more stable
forms; for the 4-carboxylates, these are the carbonyl 0,s-syn-s-trans-rotamers.
The 'H n.m.r. spectral assignments of thiazole amides [99; n = 1-3; R =
H, MeCONH(CHz), (rn = 2 or 4), Me, or NH2] related to bleomycin A2 have
been described.% The polythiazole-containing antibiotics thiocillins I, 11, and
I11 were compared with micrococcin P1 by analysis of acid hydrolysates of
the native and the reduced antibiotics as well as by means of 'H and 13C
n.m.r. s p e c t r o s ~ o p y The
. ~ ~ structures of these three compounds were assigned
on the basis of the proposed structure of micrococcin P I . The absolute
configuration of myxothiazole, an antifungal antibiotic from a gliding
bacterium, has been determined by X-ray analysis of its degradation products
(loo)." Compound (100) was obtained from myxothiazole by ozonolysis
followed by reduction with NaBH4 (MeOH, at - 70°C) and chromatography
on silica gel. Extensive analyses of spectral data and results of acid hydrolyses
led to the assignment of a cyclic peptide structure to dolastatin 3 (from
Dolabella auri~ularia).~~
+ CH2)$HC
Me2S( oj-jsyRcl-
II
(99)
91 J. Lukasiewicz, D. hfisiuna, S. Bilinski, and L. Bielac; Chem. Anal. (Warsaw), 1981,

26, 207.
92
J. M. Riordan and T. T. Sakai, J. Heterocycl. Chem., 1981, 1 8 , 1 2 1 3 .
93 J. Shoji, T. Kato, Y. Yoshimura, and K. Tori, J. Antibiot., 1981, 34, 1126.
94 W. Trowitzch, G. Hoefle, and W. S. Sheldrick, Tetrahedron Lett., 1981,22,3829.
9s
G. R. Pettit, Y. Kamano, P. Rown, D. Gust, M. Inoue, and C. L. Herald, J. Am.
Chem. SOC.,1982, 104,905.
Five-Membered Rings: Systems containing N a n d S, Se, or Te 157
Tautomerism of 2-Aminothiazoles. - The imino-form (1 01) predominates
only when the SOzAr group is bonded to the exocyclic nitrogen atom.96
In all other cases the amino-form (102) is prevalent. The 13C and ‘Hn.m.r.,
i.r., and U.V. spectra of 4- or 5-substituted 4-thiazolin-2-ones and their N-
or O-Me derivatives were studied.97 The i.r. and ‘Hn.m.r. spectra show that
the parent compounds exist entirely or predominantly in the 2-0x0-form in
solution. In contrast, U.V. and 13C n.m.r. spectroscopy did not clearly
distinguish between the 2-0x0- and 2-hydroxy-structures. The kinetics and
mechanism of spontaneous acid-, base-, and metal-ion-induced hydrolyses of
N-salicylidene-2-aminothiazolewere also de~cribed.’~Studies on the poly-
morphism of sulphathiazole and its crystallographic behaviour under pressure
have also been rep0rted.9~
[syNR3R
R1LyNso2Ar
R2 NH
R1
R2
Reactions of Thiazoles. - 2-Bromothiazole is silylated to give compounds

which undergo ipso-substitution with ketens to give, after hydrolysis, two 2-
acylthiazoles .loo 4,5-Disubstituted 2-chloro thiazoles are obtained by diazo-
tization of the corresponding thiazoles and then ~hlorination.~’
In the limited space available we have only mentioned references
concerning the reactions of 4-substituted thia~oles,~’ *lol*lo2 5-substituted
t hiazoles, lo3* ‘04 2-aminothiazoles, ”’-’
21 and, finally, miscellaneous re-
action^,^'^'^^ leaving out many patents.
’‘ L. Forlani, Gazz. Chim. Ifal., 1981, 111, 159.

” S. P. Cornwell, P. T. Kaye, A. G. Kent, and G. D. Meakins, J. Chem. SOC., Perkin
Trans. I , 1981, 2340.
98 A. C . Dash, B. Dash, and S. Praharaj, J. Chem. SOC.,Dalton Trans., 1981, 2063.
9 9 H. Kala, H. Moldenhauer, R. Giese, G. Kedvessy, B. Selmeczi, and K. Pintye-Hodi,
Pharmazie, 1981, 36, 833.
loo A. Medici, P. Pedrini, and A. Dondoni, J. Chem. SOC.,Chem. Commun., 1981, 655.
l o ’ Fr. Demande 2 447 380, 1980 (Chem. Abstr., 1981,95, 80 994).
lo2 Neth. Appl. 81 00 539,1981 (Chem. Abstr., 1982,96, 52 078).
l o 3 R. C. Grabiak, R. K. Howe, and D. E. Schafer, Eur. Pat. Appl. 44 201, 1982 (Chem.
Abstr., 1982, 96, 162 687).
I. Simiti, A. Muresan, and M. Coman, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 744
(Chem. Absfr., 1982, 96,52 197).
105
F. Kai, H. Takeshita, S. Sukimoto, and K. Tamaoku, J. Inorg. Nucl. Chem., 1981,
43, 3013; I. Liepa, E. Gudriniece, and V. Barkane, Latv. PSR Zinat. Akad. Vestis,
Kim. Ser., 1981, 4,477 (Chem. Abstr., 1982, 96,21 268).
l o 6 A. Gursoy and D. Gokcek, Doga, Ser. C, 1981, 5 , 27 (Chem. Absa., 1982, 96,
52 221).
Io7 I. M. Bazavova, R. G. Dubenko, and P. S. Pel’kis, Zh. Org. Khim., 1981, 17, 191
(Chem. Abstr., 1981, 95,7129).
lo’ A. Medici, P. Pedrini, C. Venturoli, and A. Dondoni, J. Org. Chem., 1981,46,2790.
Io9 R . B. Pathak and S. C. Bahel, Bokin Bobai, 1981, 9, 125 (Chem. Abstr., 1981, 95,
24 899).
I10
S. M. M. Zaidi, R . K. Satsangi, P. Nasir, R. Agarwal, and S. S. Tiwari, Pharmazie,
1980, 35,755 (Chem. Abstr., 1981, 95,24 966).
Reactions of Thiazolium Salts. - Base-induced attack of thiazolium salts and
rearrangement of subsequent 2-hydroxy-A4-thiazoline was studied by U.V.
kinetic spectroscopy (two consecutive irreversible steps).123 The first step was
the nucleophilic attack of OH- on C-2 of (103; R = H or Me), affording the
thiazoline (104), with measured third-order rate constants. The second step
was the nucleophilic cyclization of the thiolate (105) to form the thietans
(106) (Scheme 9).
The mechanism of H-D exchange of H-2 in the thiazolium ions (107) was
studied by 'H n.m.r. A tetrahedral intermediate, formed by addition of a
nucleophile, is proposed. The effects of solvents and size of the nucleophile
on the reaction were studied.'24 However, elsewhere it is claimed that the
kinetic data demonstrate that the exchange of H at the 2-position of
thiazolium ions cannot occur through a tetrahedral intermediate.12'
L. Forlani, P. de Maria, E. Foresti, and G. hadella, J. Org. Chem., 1981, 46, 3178
112
M. H. Bahar and B. K. Sabata, Indian J. Chem., Sect. B , 1981, 20,328.
S. H. Yang and I. C. Tsai, Kao Teng Hsueh Hsiao Hua Hsueh Pao, 1981, 2 , 188
(Chem. Abstr., 1981, 95,132 726).
114
A. F. Youssef, H. H. Farag, N. M. Omar, M. A. Abdel Kader, and H. H. Awad, Egypt.
J. Pham. Sci., 1978 (publ. 1980), 19,247 (Chem. Abstr., 1981,95,80 796).
115
S . P. Srivastava, J. S. Upadhyaya, and M. P. Sharma, Indian J. Chem., Sect. B , 1981,
20, 631; J. S. Upadhyaya and P. K. Srivastava, J. Indian Chem. SOC., 1981, 58,
789.
R. Jain, S. Tyagi, and S. Agarwal, J. Indian Chem. SOC.,1981, 58, 1112.
'I' Z. Ma, B. Si, and L. Huang, Yaoxue Xuebao, 1981, 16, 793 (Chem. Abstr., 1982,
96,122 691); Yaoxue Tongbao, 1981, 16,57 (Chem. Abstr., 1982,96,35 162).
M. A. El-Maghraby and A. Abou El Ela Hassan, Indian J. Chem., Sect. B , 1981,
20, 256.
119
/ I. T. Depeshko, V. I. Treskach, P. A. Bezuglyi, V. P. Chernykh, L. M. Voronina, and
V. 0. Chubenko, Farm. Zh. (Kiev), 1981, 2, 38 (Chem. Abstr., 1981, 95,108536).
120
P. N. Bhargava, S. Prakash, and R. Lakhan; Indian J. Chem., Sect. B , 1981, 20,
927.
I21
B. G. Yasnitskii, V. A. Oridoroga, T. V. Medvedeva, and E. B. Dol'berg, Khim.-
Farm. Zh., 1982, 16, 205 (Chem. Abstr., 1982, 96, 180 546).
122
M. H. Bahar and B. K. Sabata, Indian J. Chem., Sect. B , 1981, 20, 870.
1 2 3 H. J. Federsel and G. Merenyi, J. Org. Chem., 1981, 46, 4724.
124
K. Karimian, I. Ganjian, and M. Askari, Tetrahedron Lett., 1981, 22, 581; K.
Karimian, F. Mohtarami, and M. Askari, J. Chem. SOC.,Perkin Trans. 2, 1981,
1538.
P . Haake, Tetrahedron Lett., 1981, 22, 2939.
r\
C1- ---
( CH2 i
Me NMeCOR M eI N M e C O R
Scheme 9
Thiazolium bromide (1 08) reacts with keten thioacetals (MeS)2C=C(CN)2,

etc., in the presence of NaH or Et3N, to afford iminothiazolines [109; Z =
(NC)2C, Me02CC(CN), or tosylimino] Treating (109) with NaOMe results
in cyclization to give imidazo[2,1-b] thiazoles [ 110; R' = C02Me, R2 = CH-
(CN), or CH2CN; R' = H, R2 = tosylamino] .
CyNCSMe NCH2COOMe
The following have also been described: cationic azo-dyes (1 1l), prepared
by diazo-coupling and quaterni~ation,'~'and the effects of alkali128 and of
126
K. Kurata, H. Awaya, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Yakugaku
Zasshi, 1981, 101, 991 (Chem. Abstr., 1982, 96, 104 144).
1 2 7 P. Gregory and D. Thorp, Br. Pat. Appl. 2070050, 1981 (C'hem. Abstr., 1982, 96,
201 252).
'21 R. F. W.Hoprnann and G. P. Brugnoni,Angew. Chem., 1981, 93, 1005.
160 He terocycIic Chemistry
alkali that is released from glass containers12' on vitamin B1 (thiamin). We
also note the claim of an improved procedure for the synthesis of derivatives
of 2-a1kyldihydrothiamin ketones : treating the (pyrimidinylme thy1)thiazolium
salt (1 12; R = Me, Et,,!IP Ph, or CH2CHMeCH2CH2CH=CMe2)with KOPr'
in P h H gives 78-95% of substituted hexahydrofuro[2,3-d] thiazole (1 13).'30
The synthesis and characterization of thiaminium tribromocadmium(I1) and
thiaminium tri-iodocadmium(I1) complexes (1 14; X = Br or I)131 and the
luminescence spectra of some thiamin derivatives have also been r e ~ 0 r t e d . l ~ ~
X-
8 A2-Thiazolines
Synthesis. - Type B Syntheses (C-C-N +
C-S). Thiazolines [ 1 15 ;R' = Ph,
naphthyl, or biphenyl; R2,R3 = C1-4 alkyl or R2R3= (CH2), (n = 5-8)] have
been prepared. Thus Me2C(NH2)CxH, when treated with CS2, gave (115;
H2cxT
R' = H, R2 = R3 = Me), which with l-chloro-2,6-dinitro-4-trifluoromethyl-
R2 N SR1
129 N. N. Rahman and Q. N. Masuda, Dacca Univ. Stud. Part B , 1981, 29, 4 1 (Chem.
Abstr., 1982, 96, 168621).
130 K. Karimian, M. Askari, M. Farahani, and N. Sachinvala, Synthesis, 1981,48.
1 3 ' A. Adeyemo, A. Shamin, and T. Williams, J. Chem. SOC.Pak., 1981, 3 , 99 (Chem.
Abstr., 1981, 95,231 060).
1 3 ' G. A. Gachko, L. N. Kivach, S. A. Maskevich, A. A. Maskevich, and Yu. M. Ostrovskii,
Dokl. Akad. Nauk B. SSR,1981, 25,852 (Chem. Abstr., 1981, 95,202 806).
benzene gave [ 1 1 5 ; R1 = 2,6,4-(o2N),(F3C)C6H3, R2 = R3 = Me] .133 The
complex NaS2CCN.3DMF and NH2CH2CH2C1gave the thiazoline (1 16).lM
S
I1
/SyCNH2
(116)
Type J Syntheses of A2 -Thiazolines (C-S-C-N-C). The thiazolines (1 17)

are prepared by cyclization of NCN=C(SMe)NHR with (Me2CH)2NLi (THF,
at - 3OoC, for 20 min, under nitr~gen).'~'The reaction of Me2NCR'=NCR2
(R' = R2 = Me2N; R' = H, R2 = morpholino) with BrCH2CH=CH2 gives an
(117)
azavinamidinium salt Me2NCR1 =fi

-1CR2(SCH2CH=CH2) Br-, which, upon
treatment with NaNH2/NH3 or KOBut, gives the ethylidenethiazolines ( 1 18);
the latter, upon heating or treatment with 4-MeC6H4SO3H, rearrange through
N-allylic displacement t o the thiazoles (1 19) (Scheme
Type K Syntheses of A2-Thiazolines (C-C-N-C-S). Reactions of the

diastereoisomers ClCHPhCHMeNCS with MeONa, Et2NH, or PhNH2 gave
stereospecifically cis- and trans-(l20; R = MeO, PhNH, or Et2N).136 Com-
pound (120) reacts with NaSH, yielding cis- and trans-(121), which are
converted with (Me0)2S02 into (120; R = MeS). Configurations were
determined from the nuclear Overhauser effect.
NH
Me Me
(120) (121)
133 E. I. Aoyagi, U. S. P. 4272 306,1981 (Chern. Abstr., 1981,95,97786).
1 3 4 H.U. Kibbel, M. Kuecken, E. Peters, and H. Weber, J. Prakt. Chem., 1981, 323,41.
1 3 5 M. Yokoyama, M. Kurauchi, and T. Imamoto, Tetrahedron Lett., 1981, 22,2285.
136
L. Kniezo, P. Kristian, M, Budesinsky, and K. Havrilova, Collect. Czech. Chem.
Commun., 1981, 46,71 7.
Type E Syntheses of A2-Thiazolines (N-C-C-S +
C). PhC02H reacts with
NH2(CH2)2SH in the presence of Ph3P, CC14, and tertiary bases to give 45%
of A2-thiazoline (1 22).13' In addition, we mention the synthesis of the nitro-
sothiazoline (123).138
(S7.(T
fSIPh N N
Reactions of A2-Thiazolines.- The photolysis of Me2S2 in cyclopropane that

contains the thiazoline (124) gives only the radical (125), by selective
abstraction of hydrogen by MeS' radical, whereas H is abstracted from both
the 4- and the 5-position in the reaction of (124) with the ButO' radical. The
e.s.r. spectrum of (124) with ButO' has been re~0rted.I~' Mercapto-
ethylamine salts HSCH2CHR'NH2-HX (R' , X = H, C1; H, Br; or Me, C1) are
prepared by hydrolysis of aminothiazolines (126; R2 = H or alkyl) with HX
(for example, 25% HC1, for 72h).I4' Analogous results are obtained by
proceeding in two steps: alkaline hydrolysis, giving HSCH2CHR1NHCONHR2,
and then acid h y d r ~ l y s i s . ' ~In~ the hydrolysis of thiazolinium tetrafluoro-
borates (127), the same scission of the C-S bond is observed under thermo-
dynamic control (KOH, H20, at 45"C), whereas under kinetic control
(NaOH, 15-crown-5, PrCN, Ac20, at - 78" C), preferential cleavage of the
C-N bond is 0 b ~ e r v e d . l ~ ~
The ability of 2-aminothiazoline (128) to complex metal ions has been
investigated: 2-aminothazoline does not form powerful coupling ligands
with Ca, Mg, Mn, Ni, Cu, or Zn ions.143 The amino-group is the sole electron-
donor that is involved in the complexing of 2-aminothiazoline. 2-Hydrazino-
A2-thiazoline has been condensed with diethyl oxalate and oxamic acid
esters.14 The reaction of 2-hydrazinothiazoline with diethyl oxalate gives
13' H. Vorbrueggen and K. KrolikieWicz, Tetrahedron Lett., 1981, 22,4471.

13* J. Oiry, J. Martinez, J. L. Imbach, and F. Winternitz, Eur. J. Med. Chern.-Chirn.
Ther., 1981, 16, 539.
1 3 9 L. Grossi, L. Linazzi, and G. Placucci, Tetrahedron Lett., 1981, 22,251.
140 Jpn. P. 82 0 9 758,1982 (Chem. Abstr., 1982, 96, 217 230).
14' Jpn. P. 82 1 1 960,1982 (Chern. Abstr., 1982, 96,217232).
1 4 2 L. Khouri and M. K. ploustian, J. Org. Chem., 1981, 46,5052.
143
2. X. Huang, P. M. May, and D. R. Williams, Eur. J. Cancer Clin. Oncol., 1981, 17,
1151 ; Z. X. Huang, P. M. May, D. R. Williams, and M. Gosalvez, Inorg. Chim. Acta,
1981, 56,41.
144 K. H. Ongania,Chem. Ber., 1981, 114, 1200.
the thiazolotriazinedione (129) as the only product, whereas with RNHCO-
C0,Et (R = H or Ph), the hydrazides (130) are obtained. Compound (130;
R = H) is cyclized to (131) with NaOEt, whereas (130; R = Ph) gives the
thiazolotriazole (13 1; R' = CONHPh); (I 3 1; R' = H) is obtained by treating
(129) with NaOH. The thiazolines (132) react with appropriate alkenes by
1,3-dipolar cycloaddition to give, for example, the cyclo-adduct (133; R' =
Me, R2 = COMe, R3 = Me).'45 Compound (133; R' = OEt, R2 = C02Et,
R3 = H), on treatment with aqueous AgN03 followed by reduction with
NaBH4, gives the pyrrolidine (134; R' = H).
As regards the syntheses and reactions of A2-thiazolin-4-ones (and
-thiones), we have only noted references 100 and 146-155.
14' G. A. Kraus and J. 0. Nagy, Tetrahedron Lett., 1981, 22,2727.

146 M. A. E. Khalifa, E. M. Zayed, A. A. A. Elbanany, and G. H. Tammam, Chem. Ind.
(London), 1981, 35.
'41 P. Kutschy, M. Dzurilla, P. Kristian, and K. Kutschyova, Collect. Czech. Chem.
Commun., 1981, 46,436.
14' S. M. Ramsh, Y. G. Basova, A. I. Ginak, N. A. Smorygo, and A. A. Rodin, Khim.
Geterotsikl. Soedin., 1982, 30 (Chem. Abstr., 1982, 96, 142 747).
149
Yu. G. Basova, S. M. Ramsh, and A. I. Ginak, Khim. Geterotsikl. Soedin., 1981,
1046 (Chem. Abstr., 1982, 96, 68 880).
150
M. T. Omar and M. A. Kasem, J. Heterocycl. Chem., 1981, 18, 1413.
M. R. H. Elmoghayar, M. K. A. Ibraheim, A. H. H. Elghandour, and M. H. Elnagdi,
Synthesis, 1981,635.
1 5 * M. Muehlstaedt and R. Widera, J. Prakt. Chem., 1981, 323,451.
R. Pacura and E. Tarasavicius, Farm. Zh. (Kiev), 1981, 6, 62 (Chem. Abstr., 1982,
96, 100 783).
154
G. L.'abb&, G. Vermeulen, S. Toppet, G. S. D. King, J. Aerts, and L. Sengier, J.
15' G.Gattow and W. Eul, 2.Anorg. Allg. Chem., 1981, 483, 121.
9 A3-Thiazolines
(135; R' , R2 = H or Me) are
2-(Alky1thio)alkyl-4,5-dialkyl-A3-thiazolines
prepared by the iminolysis of MeSCHR2CH2CH0 followed by cyclo-
condensation with MeCOCH(SH)CH2R3.156
Me
(135)
MeC(NH2)=C(N=NR2)C02R' (R1 = Me, Et, or But; R2 = Ph or 2,4,6-Me3 -

CgH2), prepared either from MeC(NH2)=CHCO2R' and R2N,' C1- or from
MeCOC(=NNHR2)C02R' and NH3, react with the dithians (1 36) to give the
A3-thiazolines (137).lS7 Compounds (137) are acylated at S with (R4CO)20
(R4 = Me or Ph), with ring cleavage, to give (Z)-PhNHN=C(C02R1)CMe=
NCH=CHSCOR4. ClCH2CH0 is condensed with NH3, Me2C0, and NaHS in
aqueous Me2C0 at 0-10°C to produce the A3-thiazoline (138), which is
treated with HCN to give the thiazolidine (139); the latter is hydrolysed by
aqueous HC1 to yield racemic c y ~ t e i n e . ' ~ ~
n
COOR
The cyclopropyl azide (140) is smoothly decomposed at 70°C to give a

nitrene that can interact not only with the three-membered ring but also with
the double bond, leading to the A3-thiazoline (141) and the thiazolidine
Me Me
N
H-C Me
a (140) (141)
D. A. Whithycombe, B. D. Mookherjee, C. J. Mussinan, M. H. Vock,and C. Giacino,

U.S.P. 4 2 5 5 583, 1981 (Chern. Abstr., 1981, 95, 7268).
15' J. Gasteiger and U. Strauss, Chem. Ber., 1981, 114, 2336.
J . Martins, H. Offermanns, and P. Scherberich, Angew. Chern., 1981, 93, 680.
(1 42).lS9 The 5-(arylmethylene)-2-piperidino(or morpholino)-2,4-diphenyl-
A3-thiazolines (144; R = p-C1C6H4, X = 0 or CH2; R = Ph, X = 0) are
obtained by a Grignard reaction of the A2-thiazolin-4-one (143) with
PhBr .
2,2,4-Trimethyl-A3-thiazoline is oximated with NaN02 in HOAc and the
oxime is treated with MeNCO to give (145).161 Treatment of 2-amino-A2-
thiazolin-4-one gives the sodium enolate (146). 149
10 A4-Thiazolines
Synthesis. - Type A (S-C-N +
C-C). 1-Acetyl-4-phenylthiosemicarbazide
is condensed with chloroacetone and w-bromacetophenone to give derivatives
of A4-thiazolines (147) and (148; R = Me or Ph).'62 Hydrolysis of (147) with
boiling 15% HCl yields (149). Compounds (147; R = Me) and (1 48; R = Me),
when boiled with 10% NaOH, give (150), but when R = Ph they are stable
under these conditions.
A4-Thiazolines (1 5 1; R' , R2 = H, halogen, alkyl, cycloalkyl, thienyl,

pyridyl, or variously substituted aromatic; R3 = variously substituted Ph)
have been prepared.'63 Thus NCCHzCSNHz is treated with BrCHzCOBut to
R. Jorritsma, H. Steinberg, and T. J. De Boer, R e d . Trav. Chim. Pays-Bas, 1984, 100,

307.
16' M.T.Omar, M. M . Habashi, M . E. Shabaan, and M . A. Kasem, Synthesis, 1981,318.
16' C. Luethy and P. Winternitz, Eur. Pat. Appl., 39 520, 1981 ((Chem. Abstr., 1982,96,
104 226).
16' S. Bilinski and B. Marcewicz-Rojewska, Ann. Univ. Mariae Curie-Sklodowska, Sect.
D,1979, 34,383 (Chem. Abstr., 1981,95,24898).
163 Neth. A D ~80. 01 920,1980 (Ctern. Abstr., 1981,95,169174).
166 Heterocyclic Chemis@
give 4-t-butyl-2-cyanomethylthiazole, which was treated with 2,6-Cl(F)-
C6H3COCl to yield [ 151; R1 = But, R2 = H, R3 = 2,6-Cl(F)C6H3]. The
thiazoles (152; R = Ph or p-anisyl) and the A"-thiazolines (153; R' = Ph,
R2 = Et or allyl; R1 = p-anisyl, R2 = Et) were prepared by cyclo-condensation
of a-bromopropyl antipyryl ketone with thiosemicarbazones R2NHC(S)-
NHN=CHR' or by the reaction of R2NHC(S)NHNH2 with R'CHO and
subsequent cyclo-condensat ion with a-bromoprop yl antipyryl ketone. 59
A4-Thiazolines (154; with a wide variety of substituents) have been pre-
pared.'@ Thus cyclo-condensation of 4,3-Cl(Me2NS02)C6H3COcH2Br with
PhNHCSNHMe gives a thiazolidinol which on dehydration with acid yields
(154; R' = C1, R2 = R7 = R8 = Me, R3-R6 = H).
The reactions of monoprotic thioureas with ethyl chloroacetate, bromo-
malonate, and bromocyanoacetate have been ~tudied.'~' Thus p-R1C6H4-
NHCSNHR2 (R1 = Me or H, R2 = Et) with MeCOCHClC0,Et gave Et2NH-
HCI, p-R1 C6H4NCS, @-R1C6H4NH)2CS, the A4-thiazoline (155), and the
oxathiole (156; R' = Me or H). PhNHCSNR2 (R = Me or Et) with BrCH-
(C02Et), gave R2NH.HBr, PhNCS, the thiazolinone (1 57), and (PhNH)2CS.
Me
(153)
02SNR7R8
(154)
0 LYNPh NPh
164 H. J. Lang, B. Sewing, and E. Granzer, Ger. Offen. 2 9 2 6 7 7 1 , 1981 (Chem. Abstr.,
1 9 8 1 , 95, 2 5 048).
'" H. Singh, A. S. Ahuja, and N. Malhotra, J. Chem. Soc., Perkin Trans. 1, 1 9 8 2 , 6 5 3 .
Five-Membered Rings: Systems containing N a n d S, Se, or Te 167
Type B Syntheses of A4-Thiazolines (C-C-N +

C-S). CF3C(NH2)=CHC02Et
was heated with ClCOSCl in benzene to yield the A4-thiazolin-2-one (1 58)."
Compound (158) and POC13 in DMF were refluxed to give the thiazole (159).
We also find the cyclo-condensation of MeC(NH,)=CHCN with ClCOSCl,
giving 5-cyano-4-methyl-A4-thiazolin-2-one.'66
The A4 -thiazolines (161 ; R1, R2 = alkyl; X = 0, S, or NH) were prepared
by the reaction of (160; R3 = H, halogen, or alkoxy) with 2-H2NC6H4XH.I6'
Thus (160; R' = R2 = Et, R3 = H) was refluxed with O - ( H ~ N ) & ~ in
H ~EtOH
to give (161; R' = R2 = Et, X = NH).
(160) 8 (161)
Physical Properties of A4-Thiazolines. - The thiazolinylidene structure of

(1 62; R1 = H, R2 = Me) has been proved by u.v., and pK1/pK2 values were
determined.'@ The 13C and 'H n.m.r., i.r., and U.V.spectra of 4- or 5-substi-
tuted A4-thiazolin-2-ones (163) and their N- or O-methyl derivatives (164)
have been studied. The i.r. and 'H n.m.r. spectra show that the parent com-
pounds exist entirely or predominantly in the 2-0x0-form in solution. In
contrast, U.V. and I 3 C n.m.r. do not clearly distinguish between the possible
2-0x0-and 2-hydroxy-struct~res.~~~ The barriers t o rotation of the RCH2
groups in the A4-thiazolines (165; R1 = Me, Et, or Pr', R2 = Me or But;
R2 Me3C
R2 ('Y' N
'CH~R~
(165)
H. Foenter and V. Mues, Ger. Offen. 3025303, 1982 (Chem. Abstr., 1982, 96,
142 842).
K. Peseke and C. Vogel, Ger. (East) P. 143775, 1980 (Chem. Abstr., 1981, 95,
62 178).
J. Lukasiewicz, D. Misiuna, S. B i l h k i , and L. Bielak, Chem. Anal. (Warsaw), 1981,
26,207.
169 S. P. Cornwell, P. T. Kaye, A. G. Kent, and G. D. Meakins, J. Chem. Soc., Perkin
Trans. I , 1981,2340.
R1 = 4-MeOC6H4,. R2 = Bu? and the methylthiothiazolinium ions (166;
R = Me, Et, or Pr') were studied by 'H dynamic n.m.r. and molecular orbital
calculations."O The barrier to rotation for the But compounds was indepen-
dent of R, but was caused by strain in the ground state.
'N
Me3C
(166)
Reactions of A4-Thiazolines. - By thermal rearrangement with loss of H2S,

the imino-A4-thiazolines (167) give 7-substituted 3-phenyl-1H-imidazo [ 1,2-
a ] benzimidazoles (168; R = H, Me, MeO, EtO, Br, or HO)."l 4-Aminothia-
zoline-2-thiones (1 69; X = S) were successively treated with Me2S04 and
H2NNH2*H20to give the corresponding hydrazones (169; R1 = Ph, R2 =
Ph02C, CN, or morpholinocarbonyl; R' =Me, R2 = CN; Rf = H2C=CHCH2,
R2 = CONH,; X = NNH2).ln The rearrangement of 4-aminothiazolin-2-
ylidenemalononitriles [169; R' = Ph, Me, H2C=CHCH2, or PhCH2 ; R2 =
H2 NCO or Et02C; X = C(CN)2 ] yields the 2,4-diaminothiophen derivatives
(170). The 4-aminothiazolin-2-ylidenecyanamides (169; R' = Ph or CH2=
CHCH2, R2 = H2NC0 or Et02C, X = NCN) react to form the substituted 2,4-
diaminothiazoles (1 71). The reaction of the thiazolinylacetates (1 72; R =
C02Et or CN) with Me2S04 and then CH2(CN)2 gives the diaminopyrrolo-
thiazoles (173).
CN H2N NCH2COOEt H2N COOE t
170
C. Roussel, B. Blaive, R. Gallo, J. Metzger, and J. Sandstroem, Org. Magn. Reson.,
1980, 14, 166.
R. P. Soni,Aust. J. Chem., 1981, 34, 1557.
"* K. Gewald, U. Hain, and P. Hartung, Monatsh. Chem., 1981, 112, 1393 (Chem.
Abstr., 1982, 96, 217 746); K. Gewald, M. Kleinert, and U. Hain, Ger. (East) P.
151 628,1981 (Chem. Abstr., 1982,96,181 275).
The reactions of K2(MX4) (M = Pd or Pt, X = Cl or Br) with the thiazoline
(174) and its deuteriated derivatives were studied in aqueous solution at pH 1
and 5.5.'73 Complexes ML2X2=2XH and ML2Xz [L = (174)] were isolated
and characterized by elemental analysis, pH titration, and i.r. and 'H and 13C
n.m.r. spectra. The ligands are protonated primarily at N-1 of the pyrimidine
moiety, whereas the site of metallation is either N-3 or the S atom of the
thiazoline ring. With CuI', Ag', Mn", Fe"', and Pd" ions the A4-thiazolines
(1 75 ; R = Me, Ph, or 3-or 4-pyridyl) form complexes." Cu" ions form 1 :2
metal-ligand complexes with (174) and a 1 : 1 metal-ligand complex with
(1 75 ; R = 4-pyridyl). The proton-donating and -accepting and association
constants for the A4-thiazolin-2-one and the oxazolidine-2-thione were
determined by i.r. spectroscopy in CC14.17' The proton-donating and
-accepting constants are claimed to be useful for selecting pairs of compounds
forming hetero-dimers of greater stability than the corresponding homo-
dimers. The use of 3-methyl-2-(2,4-dimethylphenylimino)-A4-thiazoline as
copolymer has also been m e n t i ~ n e d . ' ~ ~
m]aMe
HO cyN-N Me NH
1 1 Thiazolidines
Synthesis. - Type B Syntheses (C-C-N + C-S). 2-Arylaminothiazolidines
are prepared from R2NHCH2CH2C1and R'NCS (Et3N, CHC13).17'
Type E Syntheses of Thiazolidines (N-C-C-S + C). The nucleophilic dis-
placement by SH- of OS03H from H2NCR3R4CR'R20S03H followed by
cyclo-condensation with ketones gave 84% of thiazolidines (1 76 ; R1-R4 = H,
R5 = Me, R6 = Et).l% On the other hand, (176) was hydrolysed with 35%
HC1 to give HSCR'R2CR3R4NH2.HC1 in good yield. The calcium salt of
cysteineglucuronic acid is obtained by using D-glucuronic acid, L-cysteine
173 N. Hadjiliadis and J. Markopoulos, J. Chem. SOC.,Dalton Trans., 1981,1635.

174 D. Misiuna and S. Bilinski, Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 1979,
35,143 (Chem. Abstr., 1982, 96,134 799).
175
E. Gentric, J. Lauransan, C. Roussel, and J. Metzger, Nouv. J. Chim., 1980, 4, 743.
176 C. D'Hondt, D. bhrnann, and E. Neuenschwander, Eur. Pat. Appl. 25413, 1981
(Chem. Abstr., 1981, 95,110 182).
17' 0. Ekhner and W. Stendel, Rorn. P. 66 113,1979 (Chem. Abstr., 1981,95,25050).
178 Y. Osawa, M. Itoh, and S. Uchikuga, Ger. Offen. 3025461, 1981 (Chem. Abstr.,
1981, 95,6489).
hydrochloride, and CaC03 .'"
(s)-Me2C(SH)CH(NHi)C02R1 C1- (R' = Me
or Et) with 5,2-R2(HO)C6H3CH0(R2 = H, C1, or NO2) in EtOH-NaOAc gave
the corresponding thiazolidines (177; R3 = a-HJ3-H; R4 = H), which with
ClCH2COCl yield the corresponding compound (1 77; same substituents,
with R4 = COCH2C1).'80 This last compound was cyclized by NaH in HMPT
to give derivatives of 2,3-dihydro-l1bH-[3,2-d] [ 1,4] benzoxazepin-5(6H)-
one.
Me
NR
(177)
Synthesis of Thiazolidines by Hydrolysis of Fused-Ring Compounds. With
PC15 at 60" C, the methyl 6-phthalimidopenicillinate gives the a-methyl
6-phthalimidopenicilloate ester ( 178).18'
COOMe
I
,L
NH
MeOOC
(178)
Physical Properties of Thiazolidines. - The crystallographic data, bond

lengths, and bond angles were determined for 4-ethyl-4-methyl-5-methylene-
2-p-tolyliminothiazolidine (1 79). In the crystal, (1 79) is associated as a
centrosymmetric dimer .lB2 The direct-current and differential-pulse polaro-
graphic behaviours of benzylpenicilloic acid (180) have been discussed. The
differential-pulse peak current is linearly related to concentration in the range
1-20 x mol i-'.i83
,CH 2NHCOCH 2Ph
Me
Et HOOC
Jpn. P. 81 150075,1981 (Chem. Abstr., 1982,96,218222).

180 I. Torrini, M. P. Paradisi, and A. Romeo, J. Heterocycl. Chem., 1981, 18,1451.
"' M. Kowcevik, J . J. Herak, and B. Gaspert, Croat. Chem. Acta, 1981, 54, 367 (Chem.
Abstr., 1982, 96, 181 029).
I82
A. A. Espenbetov, A. I. Yanovskii, Yu. T. Struchkov, L. A. Tsoi, and S. T.
Cholpankulova, Khim. Geterotsikl. Soedin., 1981, 1617 (Chem. Abstr., 1982, 96,
122 681).
U. Forsman and A. Karlsson, Anal. Chim. Acta, 1981, 128, 135 (Chem. Abstr., 1981,
95,121 186).
Chemical Properties of Thiazolidines. - The me tal-complexing properties of
L-thiazolidine-4-carboxylic acid and of 2-amino-A2-thiazoline hydrochloride
with Mg2+, Ca2', Ni2+, Mn2+, Cu2+, and Zn2+ have been in~estigated.'~~
Thiazolidine-4-carboxylic acid (1 8 1) was successively converted into 4-
C02Me, 4-CH20H, 4-CH2Br, 4-NH2, and 4-NHCOR The
zinc sulphide complex with thiazolidine-4-carboxylic sodium salt derivatives
(1 82) was also de~cribed.'~' Other derivatives of N-acylthiazolidine-4-
carboxylic acids have also been prepared.'&- lg2 (2RS)-Methylthiazolidine-
(4R)-carboxylic acid is claimed to be a latent cysteine.'" Acylation of the
N-exo-position of 2-iminothiazolidines'" and of 2-spirothia~olidines~~~
has been described. Thermolysis of quaternary salts of 2-arylaminothiazo-
lidines (1 83) and of 2-alkylimino-A2-thiazolines
(184) led to (185) and (186),
respectively.'% H2NCH2CH2S03Hwas prepared by oxidative (H202) ring-
(183) (184) (185) ( 186 1
cleavage of thiazolidine derivatives (187);197 R1R2C(SH)CH(NH2)P(0)(OH)X

(R1 = alkyl; R2 = H or alkyl; X = H, OH, alkyl, or aryl) were prepared by
hydrolytic ring-cleavage of (188).lg8 The electroreduction of the disulphide
gives the corresponding thiol (1 89).lg9 Other N-acylated 2-arylthiazolidines
have also been described.200
lB4 Jpn. P. 80 81 869,1980 (Chem. Abstr., 1981,95,97781).
Jpn. P. 80 167 280,1980 (Chem. Abstr., 1981,95,43090).
186
M. Oya, J . Iwao, and T. Iso, PCT Int. Appl. 81 02 893, 1981 (Chem. Abstr., 1982,
96,123 303).
Jpn. P. 81 79 687,1981 (Chem. Abstr., 1981,95,204362).
Jpn. P. 81 83419,1981 (Chem. Abstr., 1981,95,181 197).
T. Ohashi, K. Shimazaki, K. Kan, H. Kondo, and K. Watanabe, Fr. Demande
2471 975,1981 (Chem. Abstr., 1982,96,7080).
I 9 O E. W. Petrillo and M. A. Ondetti, Fr. Demande 2473 517, 1981 (Chem. Abstr.,
1982,96,7079).
19' Jpn. P. 81 95 179,1981 (Chem. Abstr., 1982,96,35232).
19' Jpn. P. 81 92 279,1981 (Chem. Abstr., 1982,96,6718).
193
H. T. Nagasawa, D. J . D. Goon, R. T. Zera, and D. L. Yuzon, J. Med. Chem., 1982,
25,489.
1 9 4 Jpn. P. 81 133278,1981 (Chem. Abstr., 1982, 96,104223).
1 9 ' Belg. P. 884 875,1981 (Chem. A bstr., 1981, 95,80936).
19' L. A. Tsoi, S. T. Cholpankulova, G. K. Ryskieva, and A. D. Salimbaeva, Khim.
Geterotsikl. Soedin., 1981,917 (Chem. Abstr., 1981, 95,187 137).
19' Jpn. P. 82 26 654,1982 (Chem. Abstr., 1982,96,199089).
19' K. J. M. Andrews, Eur. Pat. Appl. 33 919,1981 (Chem. Abstr., 1982,96,52 498).
1 9 9 Jpn. P. 81 90991,1981 (Chem. Abstr., 1981,95,194476).
Jpn. P. 81 87 573,1981 (Chem. Abstr., 1981,95,187240).
We have noted the following references concerning thiazolidin-2-ones

(and -2-thiones and - s e l o n e ~ ) , ' ~ ~ thiazolidin-4-0nes,'~~1
*~~'-~~ 165 *207-228
201
N. E. Plevachuk, B. S. Zimenkovskii, I. I. Gal'kevich, and P. M. Steblyuk, Farm. Zh.
(Kiev), 1981,4,40 (Chem. Abstr., 1981,95,160 062).
'02 J. F. h c h e r , G. Bourgery, P. Dostert, C. Douzon, P. Guerret, A. Lacour, and M.
Langlok, Fr. Demande 2 458 547,1981 (Chem. Abstr., 1981,95,132 868).
'03 C. H. Li, Y. H. Yieh, Y. Lin, Y. J. Lu, A. H. Chi, and C. Y. Hsing, Tetrahedron Lett.,
1981, 22,3467.
204 Y. Nagao, T. Miyasaka, K. Seno, M. Yagi, and E. Fujita, Chem. Lett., 1981,463.
205 F. A. Devillanova and G. Verani, Tetrahedron, 1981, 37, 1803.
206
M. V. Andreocci, M. Bossa, F. A. Devillanova, C. Furlani, G. Mattogno, G. Verani,
and R. Zanoni, J. Mol, Struct., 1981, 71,227.
'07 S. Y. Solov'eva, S. M. Ramsh, and A. I. Ginak, Khim. Geterotsikl. Soedin., 1981,
477 (Chem. Abstr., 1981, 95,80 900).
'08 A. M. Osman, M. A. Abbady, and F. M. Atta, Indian J. Chem., Sect. B , 1981, 20,
524 (Chem. Abstr., 1981,95,114964).
209 S . S. Meher, S. Naik, R. K. Behera, and A. Nayak, J. Indian Chem. SOC., 1981, 58,
274 (Chem. Abstr., 1981, 95, 80 817).
210 I. V. Smolanka, N. P. Mano, and T. A. Krasnitskaya, Khim. Geterotsikl. Soedin.,
1981,627 (Chem. Abstr., 1981, 95,203 812).
"I T. N. Rao, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 174
(Chem. Abstr., 1982, 96,68 886).
'12 K. Peseke, N. C. Castanedo, and I. Bohn, Ger. (East) P. 147356, 1981 (Chem.
Abstr., 1981, 95, 203 938).
B. V. Tkachuk and N. M. Turkevich, Farm. Zh. (Kiev), 1981, 1, 24 (Chem. Abstr.,
1981, 95,43 370).
H. Aoyama, S. Suzuki, T. Hasegawa, and 0. Yoshimori, J. Chem. SOC.,Perkin Trans.
I , 1982, 247.
R. Lakhan, Agric. Biol. Chem., 1982, 46, 557 (Chem. Abstr., 1982, 96, 157 185).
M. J. Korohoda, Pol. J. Chem., 1981, 55,359 (Chem. Abstr., 1982, 96,20030).
N. T. Dang, D. T. Nguyen, T. T. Tran, and H. T. Cao, Tap Chi Hoa HOC, 1981, 19,
14 (Chem. Abstr., 1982, 96, 52 237).
'18 M. A. Kaldrikyan and A. V. Khekoyan, Khim. Geterotsikl. Soedin., 1981,41 (Chem.
Abstr., 1981, 95,150 520).
'19 N. Ben Mansour, W. D. Rudorf, and M. Augustin, 2. Chem., 1981, 21, 69 (Chem.
Abstr., 1981, 95,62 071).
220 R. Soliman, Pharmazie, 1981, 36,91 (Chem. Abstr., 1981, 95,62 100).
221 A. J. Cowper, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 111
(Chem. Abstr., 1982, 96,20 01 7).
222 R. M. Di h r d o and M. G. Bock, Synthesis, 1981,825.
K. A. Agaev and M. M. Turkevich, Farm. Zh. (Kiev), 1981, 2 , 43 (Chem. Abstr.,
1981, 95,121 044).
2'4 Yu. G. Basova, S. M. Ramsh, and A. I. Ginak, Zh. Org. Khim., 1981, 17,663.
2 2 5 S. M. Ramsh, A. I. Ginak, Yu. G. Basova, and L. P. Shamina, Zh. Org. Khim, 1981,
17, 846 and 851 (Chem. Abstr., 1981, 95,96462 and 96463); Yu. G. Basova, S. M.
Ramsh, and A. 1. Ginak, ibid., 1981, 17, 986 (Chem. Abstr., 1981, 95, 114 365).
2 2 6 A. J. Cowper, R. R. Astik, and K. A. Thaker, J. Inst, Chem. (India), 1981, 53,224
(Chem. Abstr., 1982, 96, 122 679); B. N. Singh, PhosphorusSulfur, 1981, 11,357.
2 2 7 N. B. Mansour, W. D. Rudorf, and M. Augustin, 2 . Chem., 1981, 21, 284 (Chem.
Abstr., 1982,96, 35 149).
228
L. D. Dave, S. K. Thampy, and S. K. Thulasidas, J. Indian Chem SOC.,1981, 58,
1003 (Chem. Abstr., 1981,95,214 331).
Five-Membered Rings: Systems containing Nand S,Se, or Te 173
and thiazolidine-
thiazolidine-2,4-diones and 2-thioxothiazolidin-4-0nes,~~'-~~~
2,5-dione~.~~~
12 Selenazoles
Synthesis and Properties. - Type A Syntheses (SE-C-N + C-C). The (+)-p-
(2-amin0-1,3-selenazol-4-yl)alanine (1 90) has been obtained, starting from
H2NC(Se)NH2 and C1CH2COCH2C1.244R1NHCSeNHNHCOR2 (R' = Et or
Ph; R2 = Me, Ph, or 2- or 3-pyridyl) were prepared from R'NCSe and
R2CONHNH2 by refluxing in EtOH.245 These selenosemicarbazides (R' =
Et) react with ClCH2COMe to yield (191), whereas if R' is a phenyl group
the A4-selenazolines (1 92) are formed.
H 2NCHCH2 Me
I
COOH
( 190)
229 B. Buchmanand D. N. Hamilton, J. Agric. FoodChem., 1981, 29,1285.

230
S . Satsumabayashi and J. Nakayama, Nippon Shika Daigaku Kiyo, Ippan Kyoiku-
kei, 1981, 10,155 (Chem. Abstr., 1 9 8 1 , 9 5 , 8 0 797).
231 H. Singh, P. Singh, and K. Deep, Chem. Ind. (London), 1981, 252.
232 E. F. Granin, E. D. Sych, V. V. Vyalykh, L. T. Gorb, E. K. Mikitendo, and L. P.
Charuiskaya, Fiziol. Akt. Veshchestva, 1980, 12, 60 (Chem. Abstr., 1981, 95,
19 525).
233 R. D. Khachikyan, S. M. Atashyan, and S. G. Agbalyan, Arm. Khim. Zh., 1981, 34,
775 (Chem. Abstr., 1982, 9 6 , 6 8 899).
2 34
M. Valentiny, A. Martvon, and P. Kovac, Collect. Czech. Chem. Commun., 1981,
46, 2197.
235
H. K. Gakhar, P. Baveja, and N. Kumar, Indian J. Chem., Sect. B , 1982, 21, 64
(Chem. Abstr., 1 9 8 2 , 9 6 , 2 1 7 811).
236
M. S. Fadeeva, T. I. Filaeva, and 0. Ya. Sdobnova, Deposited Document, 1980,
VINITI 2987 (Chem. Abstr., 1982, 96, 34 365); M. S. Fadeeva, R. S. Lebedev, T. I.
Filaeva, and 0. Ya. Sdobnova, Deposited Document, 1980, VINITI 3380 (Chem.
Abstr., 1982, 96,34 366).
13' V. Machacek, V. Sterba, and H. Zahradnickova, Collect. Czech. Chem. Commun.,
1981,46,3097.
238 A. A. Artamonov, L. I. Timoshenko, G. M. Musienko, and L. P. Klimok, Khim.
Geterotsikl. Soedin., 1981,1127 (Chem. Abstr., 1981, 95,203 880).
2 3 9 M. T. Omar and F. A. Sherif, Synthesis, 1981, 742.
240 G. Buchbauer and M. Kern, Arch. Pharm. (Weinheim, Ger.), 1980, 313,1043 (Chem.
Abstr., 1981, 95,25 275).
241 E. K. Mikitenko and N. N. Romanov, Khim. Geterosikl. Soedin., 1981, 199 (Chem.
Abstr., 1981, 95, 7130).
2 4 2 M. T. Omar and F. A. Sherif, Indian J. Chem., Sect. B , 1981, 20, 849 (Chem. Abstr.,
1982, 96, 162 578).
243
F. J. Vinick and S. Jung, J. Org. Chem., 1982, 47, 2199.
244 R. N. Hanson and M. A. Davis, J. Heterocycl. Chem., 1981, 18,205.
2 4 5 B. Marcewicz-Rojewska and S. Bilinski, Acta Pol. Phurm., 1980, 37, 159 (Chem.
Absrr., 1981, 95, 7160).
The treatment of oxazolium salts (193; R' = R3 = Ph, R2 = Me; R1-3 =
Ph; R' =p-BrC6&, R2 = R3 = Ph; R' =p-tolyl, R2 = Me, R3 = Ph; R' =p-
MeOC6H4, R2 = R3 = Ph; R' = a-furyl, R2 = R3 = Ph; X = tosyloxy or
C104) with HSe- gives R3COCH2NR2C(Se)R', which when treated with
HC104 gave selenazolium salts (194).246 Treatment of (194; R'-3 = Ph;
R' = p-tolyl, R2 = Me, R3 = Ph) with MeONa gave the A4-selenazolines
(195).
R","Y":-
R
'2
No major differences in the mass-spectral behaviour between the sulphur-

and selenium-containing compounds have been o b s e r ~ e d The
. ~ ~predominant
form in the tautomerism of A2-thiazolin-4-ones/thiazolidin-4-ones depends in
part on the 5 - s u b s t i t ~ e n t . Thus
~ the condensation of 2-amino-A2-
selenazolin-4-ones (196) with RCHO (R = Ph, 4-C1C6H4, 2,4-C12C6H3, or
4-02Nc&) gave the benzylideneselenazolnones (1 97), whereas the
condensation with RCHO [R = 4-MeOC6H4, 2,4-(MeO)2C6H3, or 3,4-
(Me0)2C6H3] gave the tautomeric iminoselenazolidin-4-ones (1 98). This last
structure is also claimed for the imino-N-acylated compounds.249 Sulpho-
0 Rcyse7(mz
alkylations of selenazoles were also rnenti~ned.~"
1SeYNHz 0
Rcxz
0
13 Benzothiazoles
Synthesis. - From ortho-Aminobenzenethiols ( o p e A ; S - C a 4 - N + C). *
The cyclization between RNC and o-NH2C6H4SH gives a 2-substituted
benzothiaz~le.~~'
~
246 0. P. Shvaika and V. F. Lipnitzkii, Zh. Obshch. Khim., 1981, 51, 1842 (Chem.
Absfr., 1982, 96,20035).
24 1
G . N. Jham, R. N. Hanson, R. W. Giese, and P. Vouros, J. Heferocycl. Chem., 1981,
18, 1335.
248
I. B. Levshin, A. A. Tsurkan, and K. A. V'yunov, Zh. Org. Khim., 1981, 17, 865
(Chem. A bsfr., 1981,95,132 761).
249 I. B. Levshin, A. A. Tsurkan, E. A. Rudzit, and G. N. Neshchadim, Khim.-Farm. Zh.,
1981, 15, 27 (Chem. Absfr., 1981, 95, 80 838).
2 50
H. Kampfer, D. Wendisch, M. Hase, and M. Glass, Eur. Pat. Appl. 34 279, 1981
(Chem. Abstr., 1982, 96, 51 812).
251 I. F. Szabo, I. Farkas, L. Somsak, and R. Bognar, A c f a Chim. Acad. Sci. Hung., 1981,
106,61 (Chem. Abstr., 1981, 95,62 576).
* For definitions of the types A, B, etc. for benzothiazoles, see p. 133 of Volume 1 of
this series.
Type B Syntheses of Benzothiazoles (C6H5-N-C-S). Following a known
method, arylthioureas were oxidized to give substituted 2-aminobenzo-
t h i a ~ o l e sand ~ [(2-thioxoimidazolidin)-3-yl] b e n z ~ t h i a z o l eby
~ ~2- ~ ~bromine,
~
and substituted 2-aminobenzothiazoles- by SOC12254 or Br2 (Cl,) and
H ~ S ,255
O ~
Type E Syntheses (C6H5-N + C-S). Treatment of substituted anilines with
NH4SCN gives substituted 2 - a m i n o t h i a ~ o l e sand ~ ~ ~there are also references
concerning the synthesis of b e n z o t h i a ~ o l e s . ~ ~ ' - ~ ~
Physical Properties of Benzothiazoles. - The electronic spectra of some
benzothiazole derivatives have been m e a ~ u r e d . ~The~ ~ -luminescence
~~~
spectra of some benzothiazole derivatives269 and of the benzothiazoline-2-
thiones2" were also described. The new picosecond laser photolysis system
has also been used and gives well-resolved absorption ~pectra.~"The 13C and
252 I. Ueda, M. Matsuo, S. Satoh, and T. Watanabe, Eur. Pat. Appl. 22 317, 1981 (Chem.
Abstr., 1981, 95,7266).
2 5 3 R. J. S. Beer, H. Singh, D. Wright, and L. Kr. Hansen, Tetrahedron, 1981, 37, 2485.
2s4 M. Richter, M. Augustin, W. Kochmann, M. Pallas, W. Schnelle, H. J. Hartmann,
M. Sieler, and K. Goetzschel, Ger. (East) P. 147 540, 1981 (Chem. Abstr., 1981,
95,169171).
2 5 5 Jpn. P. 82 09 774,1982 (Chem. Abstr., 1982,96,217832).
2 5 6 A. J. Lin and S. Kasina, J. Heterocycl. Chem., 1981, 18, 759; W. Eberlein, G.
Trummlitz, W. Engel, G. Schmidt, G. Engelhardt, and R. Zimmerman, Ger. Offen.
3017976,1981 (Chem. Abstr., 1982, 96,68983).
257
Z.-H. Zhu, %-I. Wang, and J.-D. Wang, Hau-Tung Hua Kung Hsueh Yuan Hsueh Pao,
1981 , No. 1, p. 33 (Chem. Abstr., 1981,95,170 975).
2 58
S. K. Dubey, R. Rastogi, and S. Sharma,Monatsh. Chem., 1981, 112,1387.
2 5 9 G. Rabilloud and B. Sillion, J. Chem. Res. (S), 1981 , 264.
260
R. E. Brown, V. St. Georgiev, and B. Loev, U.S. P. 4 298 742, 1981 (Chem. Abstr.,
1982, 96,68972).
261 K. T. Potts, A. J. Elliot, G. R. Titus, D. Al-Hilal, P. F. Lindley, G. V. Boyd, and T.
Norris, J. Chem. SOC.,Perkin Trans. 1,1981,2692.
2 6 2 L. Benati and P. C. Montevecchi, J. Org. Chem., 1981,46,4570.
26 3
J. J. Nestor, G. H.Jones, and B. H. Vickery, Eur. Pat. Appl. 42 753, 1981 (Chem.
Abstr., 1982, 96,163 214).
264 G. P. Dhareshwar, P. N. Chhaya, and B. D. Hosangadi, Indian J. Chern., Sect. B y
1980, 19,831 (Chem. Abstr., 1981, 95,6745).
2 6 5 D. Shatapathy and P. K . Misra, Indian J. Chem., Sect. B y 1981,20,84 (Chem. Abstr.,
1981, 95,23682).
166 N. N. Romanov, Ukr. Khim. Zh. (Russ. Ed.), 1981, 47, 1280 (Chem. Abstr., 1982,
96, 124 505).
267 E. A. Chaika, G. I. Matyushecheva, and L. M. Yagupol'skii, Zh. Org. Khim., 1982,
18, 186 (Chem. Abstr., 1982, 96,201 246).
2 6 8 A. M. Osman and M. S. K. Youssef, Spectrochim. Acta, Part A , 1981,37, 811.
269
Z. Salamon and A. Skibinski, Dyes Pigm., 1981, 2, 239 (Chem. Abstr., 1981, 95,
1 17 044).
2 7 0 M. S. Fadeeva, R. S. Lebedev, T. I. Filaeva, and 0. Ya. Sdobnova, Deposited
Document, 1980,VINITI 3380 (Chem. Abstr., 1982,96,34366).
2 7 1 T. Nakayama, S. Tai, K. Hamanoue, and H. Teranishi, Mem. Fac. Ind. Arts, Kyoto
Techn. Univ. Sci. Technol., 1980,29,46 (Chem. Abstr., 1981,95,131 926).
15N n.m.r. spectra of (199) and (200) were measured.2n The largest difference
between the (E)- and (2)-isomers was shown by the 13C-1sN coupling con-
stants ( J ) between C-1 of the Ph ring and N-1 of the triazene chain. For
[199; ( E ) / ( Z ) ] (, J ) is 0 and 7.7 Hz, respectively; for [200; ( E ) / ( Z ) ] (. J ) is
16.0 and 9.9 Hz, respectively. The 'H n.m.r. spectra of p(benzothiazol-2-
y1azo)-NN-dimethylanilines with the substituent R at the 6-position of the
benzothiazole system were measured and correlated with the Hammett 0-
constants for R = H, Me, MeO, EtO, H2N, C1, Br, and 02N.273 The substi-
tuent effect was primarily of resonance through the .rr-electron system. Other
'H and 13C n.m.r. spectra of acrylic a m i n o - e ~ t e r sand~ ~ of
~ cyanine dyes,275
respectively, including the benzothiazole system, have also been mentioned.
The mass spectra of derivatives of 2-phenylaminobenzothiazole and of
its isomers have been recorded.276 The mass spectrum of (201) was used t o
determine the ratio of oxime t o nitroso-tautomers as 83.9: 16.1.277 An
intense molecular ion and interesting fragmentations are observed in both the
positive- and negative-ion mass spectra of nitro-derivatives of 2-aminobenzo-
thiazole (loss of HNCO and H 2 0 re~pectively),~~' A NOz group at position
4 has a pronounced effect on the fragmentation. The separation by thin-
layer chromatography of some 1-(benzothiazol-2-yl)-3-methyl-4-aryl-
hydrazonopyrazolin-5-one derivatives has been studied [benzo-fused ring
substituted at C-6 (R1); aryl substituted at C-2 (R2), C-3 (R3), C-4 (R4);
R' = H, C1, or OMe; R2 = H, C1, Me, or OMe; R3 = H or Me; R4 = H, C1, Me,
"' E. Fanghaenel, S. Simova, and R. Radeglia, J. Prakt. Chem., 1981,323,239 (Chem.

Abstr., 1981, 95,79 681).
273 D. Simov, V. Koleva, A. Penchev, and B. Gulubov, God. Sofii. Univ. Khim. Fak.,
1980,71,81 (Chem. Abstr., 1981,95,5940).
2 7 4 E. H. M. Ibrahim, M. 0. Abdel Rahman, and I. M. Abdellah, Egypt. J. Chem., 1979,
22,265 (Chem. Abstr., 1981,95,41675).
2 7 5 C . Reichardt and U. Rust, 2. Naturfomch., Teil. B , 1982, 37,236.
276 Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh.
Org. Khim., 1981,17,614(Chem. Abstr., 1981,95,23703).
2 7 7 N. A. Klyuev, 1. S. Shpileva, L. I. Medvedeva, G. N. Lipunova, and N . P. Bednyagina,
Khim. Geterotsikl. Soedin., 1981,1506 (Chem. Abstr., 1982, 9 6 , 51 648).
278 S. Claude, R. Tabacchi, L. DUC,and J. F. Marrel, Helv. Chim. Actu, 1981,64,1545.
NO2, or OEt] .279 The best results were obtained with a 40: 15 hexane-
ethyl acetate mixture. The pK, values were determined for the acid-base
equilibrium of N-(2-benzothiazolyl)succinamic acid (202) by potentiometric
titration in 60% aqueous dioxan and 50% ethanol.280
H
N 0 COOH
(202)
The protonation of triazenic systems that are bonded at C-2 with 6-

substituted 3-methylbenzothiazolines occurs on N-1 of the triazene moiety
to form (203).281 The rate constants k,(H) and k,(D) were determined for
H-D and D-H exchange at C-2 in the benzothiazoles (204; R = H, 6-N02,
543, 5- or 6-Me, 6-NH2, or 6-NME2).282The plots of log k,(H) and log k,(D)
against the am + ap values of the substituents, according to the Hammett-
Jaffe equations, are slightly curved. The primary hydrogen is0 tope effect
+
k,(H)/k,(D) against the am ap values of the substituents is a more pro-
+
nounced curve, showing a maximum near the a m a, value of -0.3. The
authors conclude that the use of the primary hydrogen isotope effect in the
prediction of reaction mechanisms seems unreliable. The kinetics of solvo-
lysis of 2-trimethylsilylbenzothiazole in MeOH, alone or containing NaOMe,
and in MeOH/H20 (5 :2) that contains HC104 have been determined; they
show first-order rate constants at 25°C.283 The mechanism of solvolysis is
discussed in relation to the rate isotope effects in MeOD, and the effects of
base and of acid on the rate of solvolysis.
The distribution of products of the thermal dissociation of benzothiazole-
cyanines (205; n = 1-5, R = Et, X = I) that was observed by gas chromato-
H
279 V. K. Mahesh, M. Maheshwari, and V. Kumar, Fresenius 2. Anal. Chem., 1981,

309,404 (Chem. Abstr., 1982,96,144 438).,
V. P. Chernykh, V. I. Makurina, V. I. Kabachnyi, and P. A. Bezuglyi, Zh. Fiz. Khim.,
1981,55,1893 (Chem. Abstr., 1981,95,203080).
281 E. Fanghaenel and J. Hohlfeld, J. B a k f . Chem., 1981, 323, 245 (Chem. Abstr.,
1981,95,79443).
0.Attanasi, P. Battistoni, and G. Fan, Phosphorus Sulfur,1981, 10,271.
283 G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2,1981,1051.
graphy and mass spectrometry is consistent with atomic charges, bond
orders, bond dipole moments, and reactivity indexes that were obtained by
M.O. calculations of the ground state by the PPP method.284 The thermolysis
of (205; R = Me, Et, Pr, or Bu; X = C1, Br, or I) and of the anhydro-base
(206) gives the same volatile products, but ..in different proportions (ethane,
ethylene, 2-methylben~othiazole).~~~ The thermolysis data have been
explained in terms of a fragmentation scheme that is consistent with the
molecular diagrams of electron densities and bond orders that have been
calculated for (205; R = Et) and (206) in the PPP approximation.
The flash photolysis of benzothiazolino-spirochromenes (207; R1 = Me,
CH2Ph, Ph, OMe, SMe, etc.; R2 = Me, Et, or P f ; R3 = H, SMe, NO2, or OMe;
R4 = OMe, H, CH20Me, CH20CH2CH20CH2CH2Me, or CH2SEt) was
studied.286 The electron-donating substituents decrease the extent of photo-
lysis. Hammett correlations involving inductive, resonance, and steric
parameters were established for three compounds; the steric effect is the most
important; polar solvents decrease the extent of photolysis. The kinetics of
N-methy la tion of substi tu t ed 2-(2-furany1)benz ot hiazoles have be en de -
termined spectrophotometrically at 80°C.287 The electron-donating methyl
group accelerates the reaction, whereas the halogens have the opposite effect.
Chemical Properties of Benzothiazoles. - Substitution Reactions on the

Thiazole Ring. 2-Chlorobenzothiazoles are obtained by substitution of
2-NaS(K)-benzothiazoles by C12288 or by reaction of S0C12 with 2-NH2NH-
b e n z o t h i a z ~ l e s .2-Chlorobenzothiazoles
~~~ are etherified to benzothiazol-2-yl
ethers,290 also obtained by displacement of the 2-methylsulphonyl group by
2 84
V. G. Khesin, M. A. Alperovich, P. I. Abramenko, R. D. Raikhina, and T. D.
Medvedeva, Khim. Geterotsikl. Soedin., 1982, 188 (Chem. Abstr., 1982, 96,
219 261).
285
V. G. Khesin, M. A. Alperovich, and P. I. Abramenko, Khim. Geterotsikl. Soedin.,
1981,1626 (Chem. Abstr., 1982,96,164115).
286
D. Gaude, R. Gautron, R. Guglielmetti, and J. C. Duffy, Bull. SOC.Chim. Fr., Part 2,
1981,14.
287
L. Fiser-Jakic and K. Jackopcic, Croat, Chem. Acta, 1981, 54, 245 (Chem. Abstr.,
1981,95,219491).
288
H. Knorr, R. Handte, L. Willms, and T. Tammer, Eur. Pat. Appl. 43 573, 1982
(Chem. Abstr., 1982,96, 142 845).
289
T. Papenfuhs, Ger. Offen. 3 023 227,1982 (Chem. Abstr., 1982,96,104229).
290
S. Kuyama, M. Aya, and J. Saito, Eur. Pat. Appl. 37 524,1981 (Chem. Abstr., 1982,
96, 52 298); 37 525, 1981 (Chem. Abstr., 1982, 96, 52 296); 37 526, 1981 (Chem.
Abstr., 1982, 96, 52 297); 37 527, 1981 (Chem. Abstr., 1982, 96, 68978); 37 938,
1981 (Chem. Abstr., 1982, 96, 68984); Jpn. P. 81 29535, 1981 (Chem. Abstr.,
1981, 95, 62459); 81 79683, 1981 (Chem. Abstr., 1981, 95, 203934); V. Mues
and W. Behrenz, Ew. Pat. Appl. 44008,1982 (Chem. Abstr., 1982,96,199672).
phenols.2g1 The substitution (or addition-elimination) of the 2-amino-group
of the 2-aminobenzothiazole by itself gives 2,2'-iminobis(benzothiazo1e)
compounds [208; R (alike or different) = H, alkyl, halogen, alkoxy, CN, or
NO,; n = 1-31 .292
H
Reactions of 2-Aminobenzothiazo2es. (Un)substituted 2-aminobenzothiazoles

are diazotized to give dyes293*2" and 2-halo-derivatives. HC1 gives luciferin
and its analogues (209; R1 = OH; R2 = H or OH)?" condensed with CS2
(DMF , H, 0, KOH), these give 2-aminobenz othiazol yldithiocarbama tes ,
which are oxidized to the dimers (210; R = C1, Br, Me, or AcNH).~'~Iso-
cyanates give substituted derivatives of benzothiazolylurea (2 11; R1 =
R1
H H
(211)
291 L. Willms, R. Handte, and H. Mildenberger, Eur. Pat. Appl. 44497, 1982 (Chem.
Abstr., 1982,96,199676).
2 9 2 T. Paoenfuhs, Ger. Offen. 2 947489,1981 (Chem. Abstr., 1981,95,97 784).
2 9 3 K. Nishida, T. Tamura, Y. Ando, T. Morirnoto, T. Katoh,and H. Iwamoto,Arn. Dyest.
Rep., 1981, 70,17 (Chem. Abstr., 1981,95,170 969).
294 A. K. Panigrahi, B. K. Panigrahi, P. Mishra, and R. N. Mohanty, J. Inst. Chem.
(India), 1981,53, 79 (Chem. Abstr., 1981, 95,188622).
2 9 5 H. G. Batz and K. Wulff, Ger. Offen. 2929115, 1981 (Chem. Abstr., 1981, 95,
196 172).
296 A. Gvozdjakova, T. Goegh, and Z. Odlerova, Czech. P. 192 444,1981 (Chem. A bstr.,
-1982,96,122782).
CONHC6H4R3; R3 = H, o- or p-C1; R2 = H, OEt, or OMe);297 3-ClC6H4-

COCH2Br, for example, gives 2-(3-~hlorophenyl)imidazo [2,1 -b]benzothiazole
(2 12).298 Reactions of 2-hydrazinobenzothiazoles with p y r ~ v a l d e h y d e ~ ~ ~
and with 2-substituted pentane-2,4-diones have also been r e p ~ r t e d . ~ ~
Reactions of 2-Mercaptobenzothiuzoles. The (un)subs tituted 2-mercapt o-

benzothiazoles react with an amine and O2 in the presence of H 2 0 and
cobalt phthalocyanine to give high yields of sulphenamide (2 13):" they also
react with morpholine in the presence of NaOC1.302 These sulphenamides
could be the first step in the conversion into disulphides (214).303 The 2-
mercaptobenzothiazoles are substituted in alkaline solution with halo-
corn pound^.^^*^^^
Other Reactions of Benzothiuzoles. The regio- and stereo-specific photo-

cycloaddition reaction (4h, under Nz, high- ressure Hg arc) or 2-phenyl-
benzothiazole with R1RC2=CR3R4 (R1= Rg = R4 = H, R3 = OEt; R' =
R4 = H, R2 = R3 = Me; R1 = R3 = Me, R2 = R4 = H) gives the benzo-
thiazepines (219,306 the structure of which was assigned by acidic ring-
297 M. K. Lee, B. C. Seoh, Y. G. Chung, K. J. Min, and H. Y. Kang, Yongnam Taehakkyo
Nonmunjip Chayon Kwahak Pyon, 1980, 14, 231 (Chem. Abstr., 1982, 96,
142 745).
298 K. Murase, T. Mase, and K. Tomioka, Ger. Offen. 3030982, 1981 (Chem. Abstr.,
1982, 96,6724).
2 9 9 C. L. R. Pinto and E. K. Libergott, In$ INT, 1981, 14,12 (Chem. Abstr., 1981,9 5 ,
90443).
300 S. N. Sawhney, R. K. Tomer, 0. Prakash, I. Prakash, and S . P. Singh, Indian J. Chem.,
Sect. 8,1981,20,314 (Chem. Abstr., 1981, 95,62069).
3 0 1 A. S . Cobb and D. J. Williams, Eur. Pat. Appl. 29718, 1981 (Chem. Abstr., 1981,
95, 150 644); H.Zengel and M. Bergfeld, Ger. Offen, 2 944 225 (Chem. Abstr., 1981,
95,26410).
' 0 2 A. M. Herzog, G. Aivanese, and M. F. B. Mavro, Rom. P. 68 398, 1979 (Chem.
Abstr., 1981, 95, 25 049); P. Klucovsky, J. Masek, V. Sudek, L. Jozsa, and J. Kollar,
Czech. P. 184 052,1980 (Chem. A bsfr., 1981, 95,25046).
303
A. N. Lazovenko, V. A. Ignatov, V. E. Maizlish, and V. F. Borodkin, Izu. Vyssh.
Uchebn. Zaved., Khim. Khim. Tekhnol., 1981, 24, 685 (Chem. Abstr., 1981, 9 5 ,
219 547).
304
E. Sidoova and Z. Odlerova, Czech. P. 189212, 1981 (Chem. Abstr., 1982, 96,
162 686).
305
T. Doll, E. Schacht, H. E. Radunz, and E. Schulze, Ger. Offen, 2 950 095, 1981
(Chem. Abstr., 1981,95,132865).
306
M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981,22,2081.
cleavage followed by recyclization. The thermal cyclization of 2-(o-fluoro-
benzamido)benzothiazole gives 5H-benzothiazolo [3,2421 quinazolin-5-ones
(216; R = H, C1, OMe, or OEt).307
Benzothiazolines and Benzothiazolin-2-ones (and -thiones). The syntheses
of substituted spiro-2-benzothiazolines308 and 2-methoxycarbonyl-2-
phenacyl-1 ,3-benzothiazolines30g have been described. By treatment in
boiling DMSO, benzothiazolines yield 1,4-benzothiazines, in some cases
together with b e n z o t h i a z ~ l e s .Most
~ ~ ~ of the work related to benzothiazolin-
2-ones (and -thiones) concerns N-alkylation and the modification of the N-
alkylated chains.3119312
Benzothiazolium Salts. The benzothiazolium N-phenacylide adds to the
endocyclic double bond of methylenecyclopropenes that have no acyl group
in the 4-position to give stable [3 + 21 cyclo-adducts (217).313 This is
claimed to be the first example of the formation of stable [3 21 cyclo- +
adducts in the reaction of 1,3-dipoles with methylenecyclopropenes. Other
cycloadditions of benzothiazolium N-phenacylide with olefinic dipolar ophiles
from the same team are also mentioned. Various reactions of other benzo-
thiazolium salts have also been d e ~ c r i b e d . ~ ' ~ - ~ l ~
Ft l
I "2
307 D. H. Kim, J. Heferocycl. Chem., 1981, 18, 801.

308 F. Sauter, P. Stanetty, and A. Blaschke, J. Chem. Res. (S),1981, 4, 98; G. Liso, G.
Trapani, A. Reho, and A. Latrofa, Tetrahedron Lett., 1981, 22,1641.
309 Yu. S. Andreichikov, S. P. Tendryakova, Ya. A. Nalimova, E. L. Pidemskii, and T. B.
Karpova, U.S.S.R. P. 625 392,1981 (Chem. Abstr., 1981,95, 150 646).
3 1 0 G. Liso, G. Trapani, A. Latrofa, and P. Marchini, J. Heterocycl. Chem., 1981, 18,
279.
Y. Hamari and K. K. Kogyo, Jpn. P. 81 20 581, 1981 (Chem. Abstr., 1981, 95,
4 3 171) Jpn. P. 81 127 365,1981 (Chern. A h t r . , 1 9 8 2 , 9 6 , 8 5 583).
3 1 2 J. P. Chupp, Fr. Demande 2479221,1981 (Chern. Abstr., 1982,96,181272).
3 1 3 0 . Tsuge, H. Shimoharada, and M. Noguchi, Chem. Lett., l981,1493;Heterocycles,
1981, 1 5 , 807.
314 N. N. Romanov, K. V. Fedotov, and 0. I. Tolmachev, Dopov. Akad. Nauk Ukr.
RSR, Ser. B: Geol., Khim. Biol. Nauki, 1980, 11, 59 (Chem. Abstr., 1981, 95,
7191).
3 1 s 0. Tsuge, M. Tanaka, H. Shimoharada, and M. Noguchi, Heterocycles, 1981, 16,
1705.
316 H. Balli, H. Gruener, R. Maul, and H. Schepp, Helv. Chim. A c t a , 1981, 64,648.
317
R. R. Schmidt and H. Hensen, Chem. Ber., 1981, 114, 1723.
14 Condensed Ring Systems incorporating Thiazole

Structures comprising Two Five-Membered Rings ( 5 3 ) . - Thiazolof 3,2-d] -
tetrazoles [CN4-CflS]. 1-Aryl-5-mercaptotetrazoles react with 4-XCsH4 -
COCH2Br. The resulting derivatives are cyclized to 1,5-diaryl-lH-thiazolo[3,2-
d] tetrazol-4-ium perchlorates (2 18).318
R1
R2 (YN'iN- N c10;
Thiazolor2, 3-cJ/1,2,4] thiadiazole /C2N2S-CflSJ. The molecular and crystal

structure of 5,6-dihydrothiazole [2,3-c] [ 1,3,4] thiadiazol-3-one (219) has
been determined by X-ray c r y ~ t a l l o g r a p h y . ~ ~ ~
Thiazo10/2,3- bJ [1,3,4/ t hiadiazoles [C2N2S-CflS]. 2 -Amino-5-ally1thi ot hia-

diazole is acylated with RCOCl to give amides, which undergo cyclization
with NaOH to yield 5-methyl-[ 1,3J thiazolo [2,3-b] [ 1,3,4] thiadiazol-4-ylium-
2-amidates (220).320 These amidates are alkylated, giving thiazolothiazolium
salts.
Thiazolo-f 2,3-c] -, -f3,2-b] -, and -(3,4-b/ -f1,2,4] triazoles [C2N3-CflS].

The hydrazo-derivative (221) was cyclized with NaOEt to the dihydro-
thiazolotriazole (222; R = CONHPh).'* Compound (222; R = H) was also
obtained by opening and re-cyclizing (223) with NaOH. Refluxing [224;
csy$o
(221)
0
318
M. A. Eldawy, I. Chaaban, and A. S. Mehanna, Egypt. J . Pharm. Sci., 1978, 19, 185.
319 A. F. Cameron, I. R. Cameron, and F. D. Duncanson, J. Chem. SOC.,Perkin Trans. 2 ,
1981, 789.
320 G. Jaeger and H. Heitzer, Synthesis, 1981, 704.
R = Ph or R1C6H4 (R' = 243, 4-C1, 2-Me, 4-MeO)I in NaOMe-MeOH gave
the thiazolotriazoles (225).321 2-Substituted 5,6-dihydrothiazolotriazol-
5-ones were also described.322 Thiazolotriazole-5-thiones(226; R' = Ph,
R2 = Ph or Me) and (226; R' = Me, R2 = Ph or Me) have been obtained by
heating equimolecular quantities of 5-substituted 3-amino-4-oxothiazolidine-
2-thiones with PhC(=NR2)C1.323
R1 R2
H C Z CCH S
HN-N Me N-N N-N
Thiazolo[4,5-dJ-oxazole,-thiazole, and -selenazole (C3 NX-C3NSJ. The

cycloaddition of ethyl 3-p-anisyl-5-bromo-4-oxothiazolidin-2-ylidenecyano-
acetate with KOCN gives the 2,3,4,5-tetrahydrothiazolo[4,5-d] oxazol-2-one
derivative (227; X = O).324 The sulphur and selenium analogues can be
obtained, starting from KSCN and KSeCN, respectively.
COOEt
Imidazo-/2,l-b]- and -/S,l-bJ -thiazoles [ C a 2- C a S J . Derivatives of

imidazo [2,1 -b]thiazole are obtained by intramolecular Michael addition,
followed by elimination of methanethiol, to yield [228; R' = C02Me, R2 =
CH(CN)2 or CH2CN; R' = H, R2 = tosylamino] .126 Intramolecular cycli-
zation of 3-aminoethyl-2-iminothiazolines gives 2,3,5,6-tetrahydroimidazo-
321 V. P. Upadhyaya and V. R. Srinivasan, Indian J. Chem., Sect. B y1981,20, 161.

322 G. Mazzone, F. Bonina, R . R. Arrigo, and G. Blandino, Farmaco, Ed. Sci., 1981,
36, 181 (Chem. Abstr., 1981,95,6695).
323
E. K. Mikitenko and N. N. Romanov, Khim. Geferofsikl.Soedin., 1981, 564 (Chem.
Abstr., 1981,95, 80 834).
324 K. Peseke and N. C. Castanedo, Ger. (East) P. 147361, 1981 (Chem. Absfr., 1981,
95,203 939).
[2,1-b] thiazoles (229; R = Ph, 02NC6H4, H2NC6H4, or MeC6H4),325and

of substituted 2-imino-3-(2-hydroxyethyl)thiazolidine gives [229; R = 2-
(3-methylbenzofuranyl)] .326 The thiazole ring is often built in the second
step. Imidazolidinethiones and cu-brorno-ketone~,~~' imidazolidinethiones and
2-chlorohydroxamoyl chloride ,328 and imidazole thiol and ethyl bromo-
acetate329 condense, giving imidazothiazole derivatives. Sometimes the
thiazole ring is built in the first step, e.g. condensation of 2-aminothiazole
with phenacyl bromides.330 The crystal and molecular structures of a 2,3,5,6-
tetrahydroimidazo [2 ,1411 thiazole derivative and of a 2,3-dihydroimidazo-
thiazol-6(5H)-one have been described.319 Aminomethylation (with HCHO
and piperidine or morpholine), bromination, and nitrosation of (228; R1 =
H, R2 = 2-furanyl) and its derivatives were studied.331 Derivatives of the ring-
system (230; R = Ph, 4-MeC6H4, 4-ClCsH4, 4-02NC6H4, or 2- or 3-MeC6H4)
were also described.332 'Levamisole' (2,3,5,6-tetrahydro-6-phenylimidazo-
[2,1-b] thiazole) remains the object of considerable interest (close to 60
references).
Pyrrol0[2,1-b/ thiazoles [CJJ-C&S/. The pyrrolothiazoles (23 1 ; R = H or

Et02C) were synthesized from the cycloaddition reaction of imidazothiazole
with PhCOC-CCOPh followed by elimination of a nitrile group from the
cyclo-adduct .333
COP h
325 M. E. Menim, U.S.S.R. P. 847 915,1981 (Chem. Abstr., 1982,96,6727).

326 S . Nielek and T. Lesiak, Chem. Ber., 1982, 115, 1247.
327
T. Hara, Y. Kayama, and H. Fukushima, J. Heterocycl. Chem., 1981,18, 1089.
328 D. F. Bushey and T. D. J. D'Silva, Eur. Pat. Appl 43263, 1982 (Chem. Abstr.,
1982,96,199666).
329 A. Ali and R. K. Saksena, J. Indian Chem. SOC.,1981,58,1117.
S. N. Sawhney, D. R. Kodali, G. S. Dhindsa, and S. P. Singh, Indian J. Chem., Sect.
B y1982, 21,134.
331
N. Saldabols, L. L. Zeligman, S. Hillers, and J. Popelis, Org. Soedin. Sery, 1980,
2,220 (Chem. Abstr., 1982,96,122692).
332 A. F. A. Shalaby, M. A. Abdel Aziz, and S. S. M. Boghdadi, 2.Naturforsch., Teil. By
1981,36, 501 (Chem. Abstr., 1981,95,97 667).
333 N. Abe, T. Nishiwaki, T. Omori, and E. Harada, Bull. Chem SOC. Jpn., 1982, 55,
200.
Structures comprising One Five-Membered and One Six-Membered Ring
(5, 6). - Thiazolo/3,2-a/-l,3,5-triazines (C,NS-C, N3]. Dihydro-3,4-2H-
thiazolotriazinones (232; R' = R2 = H, R3 = Me, Ph, etc.) were prepared
by Mannich reactions of 2-imino-4-thiazolidin-4-ones with CH20 and
R3NH2.207 Thiazolo [3,2-a] triazine-2,4-diones (and 2-thioxo-4-ones) (233 ;
X = 0 or S; R1 = H, Me, or halo; R2 = cyclohexyl, Ph, MeC6H4, or
02NC6H4) have been obtained by treating a 2-thiazolylurea derivative with
C1C02CC1~.334
(232) (233 0
ThiazoZo[3,2-b]pyridazines (C3 NS-C4Nz/. Treatment of thiazolo [3,2-b]-

pyridazin-4-ium perchlorates (234; R' , R2 = H, Ph, or Me) with NzH4 affords
the 1,4-bis-(2-vinylpyridazin-3-ylidene)tetrazenes(235) and several other
products, depending upon the reaction time, temperature, and substituent .335
Thiazolo[3,2-a]pyrimidines [C3NS-C4N2J. Ethyl 4-chloroacet oacetate

condenses with 4-amino-6-hydroxypyrimidine-2-thiol to yield ethyl 7-ami1-10-
2,3-dihydro-3-hydroxy-5(H)-oxothiazolo [3,2a] pyrimidine-3-ace tate (236)
(X-ray), and not ethyl 3-hydroxy-5-amino-7-oxothiazolino [3,2a] pyrimidine-
3-acetate, as previously reported by the authors.336 The cyclization of substi-
334 N. Matsui, K. Maeda, M. Kaeriyama, Y. Yasuda, A. Nakata, and M. Mizuno, Belg. P

889 390,1981 (Chem. Abstr., 1982,96,142898).
335 K. Satoh and T. Miyasaka, Chem. Lett., 1981,1153.
3 36
E. Campaigne, K. Folting, J. C. Huffman, and T. P. Selby, J. Heterocycl. Chem.,
1981, 18,5 7 5 .
tuted (2-pyrimidiny1thio)acetic acids in the presence of AcaO gives meso-
ionic thiazolo [3,2a] pyrimidine derivatives (237).314 Several bicyclic fused
compounds of thiazolium salts and perhydropyrimidine, (238) and (239),
have been synthesized from halo-ketones and cyclic t h i ~ u r e a s . ~ ~6,7-
’
Dihydro-5,7-dioxo-8-(2,3,5-tri-0-acetyl-40)-Dribofuranosyl)thiazolopyrimidi-
nium hydroxide inner salts have been described and claimed as the first
examples of class 11 meso-ionic xanthine n ~ c l e o s i d e s . ~ ~ ~
Thiazolo/S,4-b/pyridines [CJ?S-C,N/. 2-(Ary1hydrazino)- and 2-

(ary1amino)-thiazolopyridines (240) were prepared by condensing 2-chloro-
3-isothiocyanatopyridine with phenylhydrazines or anilines in EtOH .339
(240)
Structures comprising Two Five-Membered Rings and One Six-Membered

Ring (5,5,6). - Benzo[lY2-d; 4,5-d’/ -bis-thiazoles (CflSCflS-C, 3. The
condensation of 2,3,5,6-tetramethylthiazolo[4,5-f] benzothiazolium diper-
chlorate with orthoesters RC(OEt), (R = H, Me, Et, or Ph) or with 1,1,3,3-
tetramethoxypropane gives polymeric cyanines (241) and (242; X = CHCH=
CHCH=CH), r e ~ p e c t i v e l y . ~ ~
( 241) (242)
Benzo[d/ imidazo/2,1-b/ thiazoles [CflSCJ?, -CJ Cyclization of [ ( 5 -

substituted 2-benzimidazolyl)thio] acetic acids by heating in Dowtherm A or
337 G. B. Foscolos, G. Tsatsas, and E. Costakis, Chem. Chron., 1980, 9 , 239 (Chem.
Abstr., 1981,95,169054).
338
R. A, Glennon, E. Schubert, and R. G. Bass, Tetrahedron Lett., 1981,22,2753.
3 3 9 B. G . Khadse, S. R. Lokhande, P. P. Chaudary, M. B. Bhide, and S. Ghooi, Bull.
Haffkine Inst., 1980,8,21 (Chem. Abstr., 1982, 96,35 153).
340 G. Kossmehl and P. Bocionek, Mukromol. Chem., 1981, 182,3427 and 3445 (Chem.
Absk., 1982,96,105786 and 105 787).
Ac20/pyridine gave (243; R = NO2, OMe, Me, C1, or C02Me) and (244) in
a 1 : 1 ratio in all casesM1 The separation of (243) and (244) was successfully
carried out and their structures (the direction of cyclization) were suggested
on the basis of n.m.r. spectra.
Thiazolo/3,4-a]benzimidazole [C3NS€f12 -C6j. 1,3-Diphenylthiazolo [3,4-

a ] benzimidazole (245), containing quadrivalent S, reacts as a thiocarbonyl
ylide dipole with fulvene and tropone systems.342
Ph
Thiazolo[3',2' ; 1,2Jirnidazo[4,5,-bJpyrazine [C3NS€3N2€4N2 J. Cyclo-

condensation of chloropyrazine with urea gives imidazopyrazinol, which is
treated with P4Sl0 to give imidaz~pyrazinethiol.~~ Treating this thiol with
BrCH2CH2Br gives 2,3-dichloro-7,8-dihydrothiazolo [3',2': 1,2] imidazo [4,5-
b ]pyrazine (246).
Pyrrolo(2,l -bJ benzothiazole [CflS-C&C, J. This homologue of (23 1)

is obtained by following a similar method.333
Structures comprising One Five-Membered Ring and Two Six-Membered
Rings (5,6,6). - 1,2,4-Triazinol[3,4-b]benzothiazole [C3NS-C3N3-C6J. In
concentrated HCl, refluxing triazinobenzothiazol-3-one (247) with 4-
(247)
341 K. Tanaka, M. Ino, and Y. Murakami, Chem. Pharm. Bull., 1981, 29, 1876 (Chem.
Abstr., 1981, 95, 220 004).
342 0. Tsuge, H. Shiraishi, and M. Noguchi, Chem. Lett., 1 9 8 1 , 2 13.
343 Y . C. Tong, J. Heterocycl. Chem., 1981, 18, 751.
R'C6H4COR2 (R' = H, NO2, Me, or MeO; R2 = H or Me) gave (248; R3 =
H), whereas (248; R3 = Me) was obtained in the presence of MeOH.344
1,3,5-Triazino[2,l-bJ benzothiazole [cfls-cfl3-c6]. MeCON(CH2 C1)2

reacts with 2-benzothiazolamine to give (249);"' 'H and 13C n.m.r. data are
given.
f-JSYN> N
#NAc
Thiazol0[2,3-b] quinazolines (CflS-Cfl2 -C6J. The cycloaddition reaction

of alkali-metal salts of 2-mercapto-4(3H)-quinazolinones with 3-benzoyl-3-
bromopropionic acids and esters gives acids (250) and lactones (25 1).346
344 M. D. Kazanis and P. E. Macheras, Chem. Chron., 1980, 9, 201 (Chem. Abstr.,
1981,95, 115475).
345 H.Boehme and J . P. Denis, Arch. Pharm. (Weinheim, Ger.), 1982, 315,227.
346
G.Rovnyak, V. Shu, and J. Schwartz, J. Heterocycl. Chern., 1981, 18,327.
Thiazol0[3,2-a] thiapyrano[4,3-d] pyrimidines f C3NS-C4N2-C5XJ. Tricyclic
thiazolo [3,2-a]thiapyrano [4,3-d]pyrimidines and related analogues (252 ;
X = S, SO2, 0, NMe, NAc, or CH2) are prepared by the cycloaddition
reaction of dibenzylidene ketones with 2-aminothiazoline .346
1,2-Oxathino[.5,6-gJ benzothiazoles f C f l s - ~ ~ O The

~ ~polar
~ ] .1,4-addition
of CH2 =SOz to benzothiazolones gives oxathiino-benzothia~oles.~’
Thiazolo-/2,3-a] - and -/3,4-b] -isoquinolines ( C ~ ~ S - C S N - CThe
~ ] .fusion of
2,3,5,6-tetrahydrothiazoloisoquinoliniumperchlorate (253) gives the vinyl
sulphide (254).348 Thiazoloisoquinolinium salts (255; R1 = C1, alkylthio, or
PhCH2S; X = Cl, I, HS04, BF4, or FS03) react with heteroarylamines to give
(25 6).349
H C =CH- S
(253) ( 254)
347
L. Mosti, G. Menozzi, and P. Schenone, J. Heferocycl. Chem., 1981, 18, 1069.
348 H. Singhand S. C. Malhotra, Synfh. Commun., 1981, 11, 635.
349
D. Farge, A. Jossin, G. Ponsinet, and D. Reisdorf, Eur. Pat. Appl. 30 198, 1981
(Chem. Abstr., 1982,96,6715).
Naphtho[2,3-d] thiazole [C&%c6 -C6]. The 2,3 -dihydro-2-thioxonaphtho-
[2,3-d] thiazole-4,9-dione (257) is prepared by cyclo-condensation of 2-amino-
3-chloronaphthoquinone with Na2S and CS2.350
Other Condensed Systems incorporating Thiazole. - Dihydro- and tetrahydro-

cyclopropa [d] thiazole derivative^,^" cyclenothiazoles,352 hexahydrocyclo-
octa[d] thiazolo [3,2-a] pyrimidines,353 2-amino-10,ll -dihydrophenanthro-
[ 1 , 2 - d ] t h i a ~ o l e 2-aza-l,3-dimethyl-6-oxa-7,7-diphenyl-4-thiabicyclo[3.2.0]-
,~~~
he~t-2-ene,~” and 4-substituted 2-amino-7-oxochromeno[6,5-d] thiazoles and
4,6,7-trisubstituted 2-amino-9-oxochromeno[4,3-d] thiazoles have also been
mentioned.3s6
15 Thiadiazoles and Selenadiazoles

1,2,3-Thiadiazoles. - Synthesis. @-Unsaturated p-tosylhy drazones PhCH=
CHCR’=NNHTs (R’ = H, Ts = p-MeC6H4SO2) were treated with SOCl2,
SC12, or S2C12 to give 40, 18, and 27% of (258; R1 = H); when R1 = Me,
55 and 18% of (259; R2 = PhCH=CH) were obtained from SC12 or S2C12.357
Saturated substituted hydrazones R’ CH2C(CH2R2)=NNHR3 (R’ = H,
alkenyl, etc.; R2 = alkyl, C02Et, C1, S02Ph, Ph, or substituted phenyl; R3 =
CONH2, S02C6H4Me-4, or C02Et) cyclize with SOCl2 to give (260) and
(261).358 The regioselectivity was discussed in terms of the Z/E equilibrium
350 T. Nakamori, Y. %to, and T. Kasai, Nippon Kagaku Kaishi, 1982, 98 (Chem. Abstr.,
1982, 96, 104 156).
P. B. Hitchcock, R. W. McCabe, D. W. Young, and G. M. Davies, J. Chem. SOC.,
Chem. Commun., 1981,608.
352 H. Eilingsfeld, P. Neumann, G. Seybold, D. Lenke, and L. Friedrich, Eur. Pat. Appl.
44443,1982 (Chem. Abstr., 1982,96,199 675).
353 M. I. Ali, A. El-F. G. Abou, and N. M. Youssef, J. Chem. Eng. Data, 1981, 26, 214
(Chem. Abstr., 1981, 9 5 , 7197).
3 5 4 S. Kumar and K. S. Sharma, Indian J. Chem., Sect. B , 1981, 20, 380.
3 5 5 T. Nakano and A. Martin, Org. Mass. Spectrom., 1981, 16, 5 5 .
3 5 6 J. R. Merchant, G. Martyres, and M. S . Venkatesh, Indian J. Chem., Sect. B, 1981,
20,493.
357 F. Bellesia, R. Grandi, U. M. Pagnoni, and R. Trave, Gazz. Chim. Ital., 1981, 111,
289.
0. Zimmer and H. Meier, Chem. Ber., 1981, 114, 2938.
ratio of the starting compound; hydrogens of CH2 are more reactive than
those of CH3. Glycosyl isothiocyanates R'NCS react with R2CHN2 (R2 =
H or C02Et) to give the corresponding 5-glycosylaminothiadiazoles .359 The
reactions of cis-3-(2-furyl)propenoyl isocyanate with PhCH2NH2, piperidine,
and CH2N2 gave the corresponding cis thiourea and derivatives of thiadia-
zo1e .360
Physical Properties of 1,2,3-ThiadiazoZes. Lanthanide-induced shifts have
been used for elucidation of the structure of thermally generated monoxides
of l72,3-thiadiazo1es (lH and l3C). A calculation has been developed for the
evaluation of lanthanide-induced shifts according to the McConnell-
Robertson equation.=l The 0' ind 0 : parameters of triazoles were also
determined by 19F n.m.r. spectroscopy.x2
Chemical properties of 1,2,3-ThiadiazoZes. The pyrolysis of 4- and 5-methyl-
1,2,3-thiadiazoles gives methylthioketen, MeCH=C=S.363 The photolysis of
argon-matrix-isolated 4-acetyl-5-methylthiadiazole at 265 nm gives the thiiren
(262) via ring-closure of the carbene (263) that is formed in the s-trans-s-cis-
c o n f o r r n a t i ~ n The
. ~ ~ alkylation of the thiadiazoles (264; R1 = NH or C02Et,
R2 = H) and (264; R1 = H or Ph, R2 = NHCOR3) gives the corresponding
compounds (265) and (266), r e s p e c t i ~ e l y . ~The ~ meso-ionic compounds
(265) and (266), when treated with HC1, give the corresponding 4- and 5 -
amino-salts.
A,,
Me
R~COR
NMe
R
1,2,3-!3elenadiazoles. - The substituted hydrazones R' CH2C(CH2R2)=

NNHR3 (R1 = H, alkenyl, etc.; R2 = alkyl, C02Et, C1, S02Ph, Ph, or substi-
tuted Ph; R3 = CONH2, S02C6H4Me-4, or C02Et) cyclize with H2Se03
359 H. Ogura, H. Takahashi, and 0. Sato, Chem. Pharm. Bull., 1981, 29, 1843 (Chem.
Abstr., 1981, 95, 187 574).
360
P. Kutschy, P. Kristian, M. Dandarova, and J. Kovac, Collect. Czech. Chem.
Commun., 1981,46,1160.
3 6 1 U. Pluecken and H. Meier, 2. Nahtrforsch., Teil. B, 1981, 36, 1305.
362 J. Elguero, C. Estopa, and D. Ilavsky, J. Chem. Res. (S), 1981, 364.
363 B. Back, H. Svanholt, and A. Holm, Acta Chem. Scand., Ser. A , 1980, 34, 625.
3 6 4 M. Torres and 0. P. Strausz, N o w . J. Chim.,1980, 4, 703.
3 6 5 K. Masuda, J. Adachi, H. Morita, and K. Nomura, Chem. Pharm. Bull., 1981, 29,
1743 (Chem. Abstr., 1981, 95, 115405); K. Masuda, J. Adachi, H. Nate, H.
Takahata, and K. Nomura, J. Chem SOC.,Perkin Trans. 1 , 1981, 1591.
to give (267) and (268).358 Some 'H and 13C n.m.r. spectra of thirty seven
1,2,3-~elenadiazoleshave been recorded.366 Coupling constants ('H-'H,
13C-lH, 77Se-'H, and 77Se-'3C) were discussed. The treatment of 4-phenyl-
selenadiazole with KOH in dioxan gives the 2-phenylethynylselenolate,
PhC-CSe- K+.367 Other 4-substituted compounds are similarly treated and
then alkylated to give RC-C-SeR', as opposed to PhNCS giving the N-(5-
substituted 1,3-thiaselenol-2-ylidene)phenylamines (269; R = Ph, p-tolyl,
p-anisyl, p-C1C6H4,or But) when treated in this manner.368
1,2,4-Thiadiazoles.- Synthesis. Benzoyl isothiocyanate (PhCONCS) and the

aryl-ureas H2NCONHC6H4R (R = H, 2-Me, 3-Me, 2-Me0, 3-Me0, 3-C1, or
4-C1), give PhCONHC(S)CONHC6H4R. These thiobiurets are cyclo-dehydro-
genated by H2C)/HCl to the thiadiazoles (270).369 With alkyl or aryl +
isothiocyanates. N 3 -unsubstituted amidrazone ylides HN-cR -NrNMe3

give N3-thiocarbamoylamidrazone ylides, thermolysis of which gives the 3-
alkyl(or aryl)-5-alkyl(or aryl)amino-l,2,4-thiadiazoles(27 1; R' = Ph or Me;
R2 = Ph, 2-naphthyl, Me, Et, alkyl, or c y c l ~ h e x y l ) . ~ N'-Substituted
~~
thioureas R2NC(S)NH2, when treated with (EtOS),, give thiadiazoles (272;
R = Et, Pr, Bu, Ph, NR!,, or m ~ r p h o l i n o ) . ~The
~ ' oxidation of mixtures of
thiourea and 1-aryl-3-(2-pyridyl)thioureas also gives t h i a d i a ~ o l e s . ~The
~
bis(p-methoxyphenyl) selenoxide is claimed to function as a mild oxidizing
agent for the synthesis of 1,2,4-thiadiazoles from thioureas or t h i ~ a m i d e s . ~ ~ ~
366
H. Meier, J. Zountsas, and 0.Zimmer, 2.Naturforsch., Teil. B, 1981, 36,1017.
367 Y. V. Zachinyaev and D. S. Orlov, Khim. Promst., Ser. Reakt. Osobo Chist.
Veshchestva, 1980,6,51 (Chem. Abstr., 1981,95,42 552).
368
V. 2. Laishev, M. L. Petrov, and A. A. Petrov, Otkrytiya, Izobret., Prom. Obraztsy,
Tovarnye Snaki, 1981, 32, 114 (Chem. Abstr., 1982, 96, 34 860); ibid,, 1981, 40,
89 (Chem. Abstr., 1982,96,85 563).
369 M. N. Basyouni, A. M. A. El-Khamry, M. M. Habashy, M. E. Shaban, and M. M. El-
Adly, Synthesis, 1981,232.
370 R. F. Smith and T. P. Feltz, J. Heterocycl. Chem., 1981, 18,201.
371 H. Kagami, T. Hanzawa, N. Suzuki, S. Yamaguchi, M. Saito, and S. Matoki, Bull.
Chem. SOC.Jpn., 1980,53, 3658.
372 P. V. Indukumariand C. P. Joshua, Indian J. Chem., Sect. B , 1981,2 0 , 651.
3 13
F. Ogura, H. Yamaguchi, T. Otsubo, and H. Tanaka, Bull. Chem. SOC.Jpn., 1982,
55, 641.
5-Amino-3-methylisothiazole and nitriles RCN give thiadiazoles [273 ; R =
(un)substituted Ph or EtOCMe=NH] .21
Physical Properties of 1,2,4-Thiadiazoles. The X-ray determination of the

1 : 1 adduct between 'Hector's Base' (274; R = H) and methyl isocyanate
shows that it forms without a heterocyclic rearrangement; the compound is
a 5 -(N-methylthiocarbamoylimino)4-phenyl-3-phenylamino-4H-1,2,4-thia-
diazoline [274; R = MeNHC(S)] .374
Chemical Properties of 1,2,4-Thiadiazoles. A "N n.m.r. study indicates that

the acylation of (275; R = H) by ClCH,COCl or ClC02Ph involves attack at
N-2 of the ring and subsequent rearrangement to (275; R = COCH2Cl or
C02Ph).375 The acylation of (275; R = H) by MeNCO to give (275; R =
CONHMe) involves attack at the NH2 group. The 5-iminiothiadiazoline salts
(276) react with R'CCl=NR2 to give the tetra-azathiapentalenes (277; R' =
2
R~N- S- NR
MesK lJNHR
N
s\N
N -
R2 = Ph, e t ~ . ) In
. ~the
~ ~presence of base, (276) decomposes into R2NH-
CR'=NCN. With diphenylketen, (276; R1 = p-MeOC6H4, R2 = Me) gives
(278) as a primary product at room ternperature.ls4 Compound (278)
rearranges to (279) when it is heated in a polar solvent; the structure of
(279) was confirmed by X-ray analysis and shown to be a zwitterion.
374 A. F. Cuthbertson and C. Glidewell, Acra Crysrallogr., Sect. B , 1981, 37,141.9.

375 A. Reiss, W. Walek, and S. Dietzel, J. Prakr. Chem., 1981, 3 2 3 , 279.
376 G. L'abb6 and G. Vermeulen, Bull. SOC.Chim. Belg., 1981, 90, 89.
(278) (279)
1,3,4-Thiadiazoles. - Synthesis. 1,3,4-Thiadiazoles are obtained by cyclo-

dehydration or by oxidation of 1-acy1-377-379or 1-thioacyl-thiosemicarba-
~ i d e s . ~ ~Thioacylated
' diaminoguanidines R' CSNHNH-C(=NH)-NH-N=
CR2R3 (R' = Ph, R2 = R3 = Me, etc.) are also cyclized by mineral acids,
leading to hydrazone-thiadiazole derivatives (280) by elimination of NH3 or
to thiadiazoles by elimination of NzH4.381 The cyclo-condensation reaction
of H2NNHCSNHR' (R' = H, alkyl, or Ph) with MSC(S)OR2 (M =alkali
H
(280) (281)
metal, R2 = alkyl) by refluxing in water gives the 2-mercaptothiadiazoles
(281).382 Amination of (282) by RNH2 (R = H or Ph) gives (283) (Scheme
11y3
N-N
JSYS Me I] SCH2CONHR
0 N\N=C( SMe)Me
(283)
(282)
1 t [-MeSH]
-
RNH2 0
N- N II
0 s
II It
RNHCCH2SCNHN=C(SMe)Me
II p 5 C N H R
M e l C \ S M e HS'
Scheme 11
The pyrazole-hydrazide (284) has been cyclized by P2S5 to give the 5-
pyrazolylthiadiazole (285).3&1 The thiadiazinone (286) undergoes thermal
377 D. L. Booth and R. M. Rodebaugh, U.S. P. 4283 543, 1981 (Chem. Abstr., 1981,
95, 187269).
378 M. J. Lavanish, U.S. P. 4 269 983,1981 (Chem. Abstr., 1981,95,62229).
379 S. Singh, L. D. S. Yadav, and H. Singh, Indian J. Chem., Sect. B , 1981, 2 0 , 518.
380
P. V. I. Indukumari, C. P. Joshua, and V. P. Rajan, Indian J. Chem., Sect. B , 1981,
2 0 , 384.
F. Kurzer and J. L. Secker, Tetrahedron, 1981, 37, 1429.
382 E. F. Rothgery, U.S. P. 4 252 962,1981 (Chem. Abstr., 1981,95,7295).
383 E. K. Mikitenko, N. N. Romanov, and I. S. Shpileva, K h i m Geterofsikl. Soedin.,
1981, 339 (Chem. Abstr., 1981,95,24940).
384 J. C . Lancelot, D. Maume, and M. Robba, J. Heferocycl. Chem., 1981, 18, 1319.
fragmentation at 550°C and 0.08Torr, giving PhCN, MezNCN, and the
thiadiazole (287).385
H : :
’N
Me2N (
N
‘7’
/ Ph
Me2N f ‘>Ph
-N N
HNCOMe N‘ (287)
Physical Properties of 1,3,4-Thiadiazoles. Ultraviolet spectra of some 2-

benzylideneamino-5 -phenyl-1,3,4-thiadiazoles have been reported.386 The
H n.m.r. spectral properties and conformational preferences of some open-
chain and cyclic aromatic sulphides that contain 1,3,4-thiadiazole
spectroscopic data of metal (Mn, Fe, Co, Ni, Cu, or Zn) chelates of N-(5-
phenyl-l,3,4-thiadiazol-2-yl)dithiocarbamic conductometric and i.r.
and Raman determinations on thirteen complexes of Zn, Cd, or Hg with 2-
methyl-5-mercapto-l,3,4-thiadiazole,389 and thermogravimetry of some
noble- and common-metal chelates of 5-amho-l,3,4-thiadiazole-2-thi01~~~
were also described, as well as the mass-spectral fragmentation of 2-phenyl-
1,3,4-thiadiazolin-5-0ne.~~~
Chemical Properties of 1,3,4-Thiadiazoles. Thermal decomposition of cis-
(288) proceeds at 50°C to give (E,E)-ButC=NN=CHBut, but decomposition
of trans-(288) proceeds only at 145’ C, giving (E)-ButHC=NNHCOBut and
SO, which disproportionates to S and Several reactions of substituted
2-mercaptothiazoles with chloroacetamides~93chlorodiaminotriazines,3~ and
ethyl bromoacetate-hydrazine-substituted ben~aldehydes,~” and of 2,5-
385
A. E. Baydar, G. V. Boyd, and P. F. Lindley, J. Chem. Soc., Chem. Commun.,
1981,1003.
386
M. R. Mahmoud, R. Abdel Hamide, and F. Abdel Goad, 2. Phys. Chem. (Leipzig),
1981,262, 551 (Chem. Abstr., 1981,95,79479).
387
F. Bottino and S. Papalardo, Org. Mugn. Reson., 1981, 16,l.
388
H. Singh, L. D. S. Yadav, and S. B. S. Mishra, J. Inorg. Nucl. Chem., 1981, 43,
1701.
389
A. C. Fabretti, G. C. Franchini, G. Peyronel, and M . Beller, Spectrochim. Actu,
Part A , 1981, 37, 5 8 7 .
390
K. N. Johri and B. S. Arora, Thermochim. Acta, 1982, 54,237.
391
G. Bouchoux, Y. Hoppilliard, M . Golfier, and M. G. Guilleriez, Org. Mass.Spectrom.,
1981, 16,29.
392
H. Quast and F. Kees, Chem. Ber., 1981, 114,802.
393
A. K. Ramrakhyani, R. S. Shukla, and P. Kumar, J. Indian Chem. Soc., 1981, 5 8 ,
307.
394
A. J. Cowper, G . S. Trivedi, R. R. Astik, and K. A. Thaker, J. Inst. Chem (India),
1981, 53,92,141.
395
A. K. S. Gupta and K. Hajela, J. Indian Chem Soc., 1981,58, 690.
dimercaptothiadiazole with MoC1, to give the disulphide (289),396 have
been described. Substituted 2-aminothiazoles undergo cycloaddition reactions
with (C02H), 397 and R02CC-CC02R (R = H or a l k ~ l ) . ~ ’ ~
HN -N
Condensed 1,3,4-Thiadiazoles. The preparation of 7-0~0-7H-1,3,4-thiadia-

zolo [3,24] pyrimidine-5-carboxylic compounds has been mentioned above. 1-
(Acylamino)-l,2,3,4-tetrahydropyrimidine-2-thionesreact with H2S04 to
give 7H-1,3,4-thiadiazolo[3,2-a] pyrimidine-6-methanesulphonic acids.399
Cyclo-condensation of derivatives of 1-aminopyrimidine-2-thione with
RC02H gives 2,7-disubstituted 5H-1,3,4-thiadiazolo[3,2.a] pyrimidin-5-
ones.4oo From 1-amino-4,6-diphenylpyridine-2-thione and Ph3P, the resulting
iminophosphorane was treated with C 0 2 t o give the thiadiazolopyridinium-
olate (290).401 The synthesis of 5-methyl-[ 1,3] thiazolo [2,3-b] [ 1,3,4] -
thiadiazol-4-ylium-2-amidates (29 1) has also been described.320
Ph
(290)
1,2,5-Thiadiazoles.- Synthesis, The 1,2,5-thiadiazole ring system and its

selenium analogue have been reviewed (over 1 17 reference^).^^ 3,4-Diethoxy-
and 3,4-bis(methylthio)-l,2,5-thiadiazole 1-oxides have been prepared,
starting from diethyl di-imino-oxalate and dimethyl di-iminodithio-oxalate,
respectively. Alkylthio- and alkoxy-groups are further substituted by amines
(292; R’ = R2 = OEt,-SMe, or pyrrolidino; R’ = morpholino, R2 = OEt,
SMe, or NHCH2Ph).402 The amino-3-morpholino-4-thiadiazole oxide is
converted into ring-N-substituted compounds by allowing it to react with
396 M. B. Ferrari, G . G. Fava, and C. Pelizzi, Inorg. Chim.Acta, 1981, 55, 167.
397 H. Paul and G . Huschert, Z. Chem., 1981,21, 185.
398 S. Herrling, U.S. P. 4281 120,1981 (Chem. Abstr., 1981,95,187294).
399 D. Heydenhauss, G. Jaenecke, and B. Feuerstein, 2. Chem., 1981,21, 31.
400 T. Tsuji and K. Takenaka, Bull. Chem. SOC.Jpn, 1982,5 5 , 637.
40’ P. Molina, M. Alajarin, A. Arques, and R. Benzal, J. Chem. SOC., Perkin Trans. 1 ,
1982,351.
402 S. Karady, J. S. Arnato, D. Dortmund, and L. M. Weinstock, Heterocycles, 1981,
16, 1561.
Five-MemberedRings: Systems containing Nand S, Se, or Te 197
0
II
NOs\
R211 fiRl
(292)
PhNCO or CH2=CHC02Me?03 The reaction of N4S4 with various aryl and
alkyl benzyl ketones, oxindole, benzyl a-pyridyl ketone, or a-phenacyl-
S
' N N'
Ph
pyridine affords the corresponding 1,2,5-thiadiazole (293).404 Other

derivatives of 1,2,5-thiazole 1-oxide and 1,l-dioxide have been described,
being potent histamine H2-recept or antagonists.'"
Physical Properties of I ,2,5-Thiadiazoles. An inversion barrier was
theoretically and experimentally investigated for 1,2,5-thiadiazole 1-oxides
(pyramidal, SO struct~re).'"~ The crystal and molecular structures of
sulfame t role have been determined .406
Chemical Properties of lY2,5-Thiadiazoles. Lithiation and carbonylation of
one methyl of 3,4-dimethyl-1,2,5-thiadiazolewere described, followed by
subsequent transformation into alcohol, mesylate, and vinyl derivative^.‘"^
The reaction of 2,5-dicyclohexyl-l,2,5-thiadiazole-3,4-dione with RC6H4-
S02N3 gave the compounds (294; R = 4 M e 0 or 3-02N).408
NS02C6H4R
c6Hll\N/ I'\N/
S C 6H 11
2,1,3-Benzothiadiazolesand 2,1,3-Benzoselenadiazoles.- Biologically active

substances among benzo-2,1,3-thiadiazole derivatives have been reviewed,
with 83 references.- The synthesis of 4-bromobenz0-2,1,3-thiadiazole-7-
4u3 S. Karady, J. S. Amato, D. Dortmund, R. A. Reamer, and L. M. Weinstock, Hetero-

cycles, 1981, 16, 1565.
404 A. A. Algieri, G. M. Luke, R. T. Standridge, M. Brown, R. A. Partyka, and R. R.
Crenshaw, J. Med. Chem., 1982,25, 210.
40 5
J. S. Amato, S. Karady, R. A. Reamer, H. B. Schlegel, J . P. Springer, and L. M .
Weinstock, J. Am. Chem. SOC., 1982, 104,1375.
406 C. H. Koo, Y. J. Chung, H. S. Shin, and J. S . Suh, Bull. Korean Chem. Soc., 1982,
3, 9 (Chem. Abstr., 1982, 96,208 771).
407 D. L. Boger and C. E. Brotherton, J. Heterocycl. Chem., 1981, 18, 1247.
408 R. Neidlein and W. Lehr, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 650.
409 I. A. Belen'kaya and G. P. Krokhina, Deposited Document, 1980, VINITI 3843-
80 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 8 851).
sulphonamide was de~cribed.~"K2PdC14 reacts with (295) to give PdLC12
[L = (295), where X = Se, R = 4- or 5-CH2CHNH2C02H or X = S, R = 4-
CH2CHNH2C02H] and PdL2C12 [L = (295), where X = S, R = 5 -
CH2CHNH2C02H].411 The complexes were characterized by i.r., u.v., and 'H
n.m.r. spectra. The ground- and excited-state configurations of the electrons
of 4-substituted benzothiadiazoles (295; X = S; R = H, NH2, or OH) were
calculated; the .rr-lo-bonds, total energies, and heats of atomization of (295),
their protonated forms, and their tautomers were tabulated. The hydroxy-
and amino-tautomers are more stable than the 0x0- and imino-tautomers,
respectively. Compounds (295) are protonated on N-1 ?12 The linear
dichroism and m.c.d. spectra of 2,1,3-benzothiadiazole and 2,1,3-benzo-
selenadiazole were measured and c.d. spectra reported for the 0-cyclodextrin
compound with the heterocycle.413 The kinetics of formation and equi-
librium data have been reported for the Meisenheimer complexes of the
benzothia- and benzoselena-diazoles (295; X = S, or Se; R = 4-NO2) with
MeO- in MeOH/DMS0.414
16 Dithiazoles and Diselenazoles

1,2,3-DithiazoIes. - Amide or carbamate vinylogues H2NCR'=CR2COR3
[R' = R2 = R3 = Me; R'R2 = (CH2)4, R3 = EtO; or R' = Ph, R2 = R3 =
Me] react with S2C12,giving (296).415 With R2 = H in MeOH that contains
Et3N, it undergoes methoxylation in the 5-position of the 5 H-l,2,3-dithiazole
ring (296; R2 = OMe). N-Thiosulphinylamines are otherwise claimed as
4'0 M. A. Kaldrikyan and L. A. Grigoryan, Khim. Gererotsikl. Soedin., 1981, 7 (Chem.

Abstr., 1981, 95, 150 551).
411 S. A. D'yachenko, M. I. Bureneva, M. P. Papirnik, V. G. Pain, N. V. Ostashkova, and
A. I. Stetsenko, Zh. Obshch. Khim., 1981, 51, 1912.
412 V. V. Davydov, B. E. Zaitsev, V. G . Sheban, and A. K. Molodkin, Deposited Docu-
ment, 1980, VINITI 2583-80, 75-83.
413
H. Yamaguchi, A. Uchida, F. Yoneda, and H. Baumann, J. Chem. SOC., Furuduy
Tram. 2, 1981, 947.
414 C. Deicha and F. Terrier, J. Chem. Res. ( S ) , 1981, 312.
415 R. Okazaki, K. Inoue, and N. Inamoto, Heterocycles, 1981, 15, 803.
intermediates?l6 1,2,3-Dithiazolium salts and stabilized 1,2,3-dithiazolyl
radicals of the type (297) are also obtained by treating enamines with S2C12
or S2Br2,or with 33S8 and C12 or Br2, re~pectively.~"
1,2,4-Dithiazoles.- The luminescence spectra of (298) have been discussed

in terms of intramolecular charge-transfer from the thione group to the ring.
Vibrational frequencies were obtained from the luminescence spectra:36
the structures and energies of mass-spectral fragments that were derived from
S-amino-l,2,4-dithiazoline-3-thione were also in~estigated.~~' The reaction of
the o-quinonoid 1,2,4-dithiazolidine derivative (299) with (H2NCH2)2
gave 2-HOC6H4CSNH2 and (300; X = NH), whereas the reaction of (299)
with HOCH2CH2NH2 gave 2-HOC6H4C(=NH)NH(CH2)20H, which, upon
heating, cyclized to (300; X = 0). Heating (299) in triethylene glycol at
180" C gives (301), which is an intermediate in the above reactions.419 Treating
the dithiazolium salt (302) with C1Rh(PPh3)3 gives [303 ;M = RhC12(PPh3)2].
HNs
L
:
A H
(298) dTb
(299)
x-
( 301)
The reaction of Pt(PPh,), with (302) is solvent-dependent: in CHC13, [303;

M = Pt(PPh3),] is formed, whereas in C6H6 the product is [303; M = PtCl-
(PPh3)] ?20
416 R. Okazaki, K. Inoue, and N. Inamoto, Bull. Chem. SOC.Jpn., 1981,54,3541.

417 R. Mayer, G . Domschke, S. Bleisch, and A. Bartl, 2. Chem., 1981,21, 324.
418 J. R. Bews and C. Glidewell, Theo. Chem., 1982,3, 377.
419 G.Wagner, D. Briel, and S. Lektner, 2. Chem., 1981,21, 261.
4 20
A. W. Gal, J. W. Gosselink, and F. A. Vollenbroek, Inorg. Chim. Actu, 1980, 32,
235.
174,2-Dithiazoles. - Dithiazolidin-3-ones and -thiones (304; X = 0 or S;

R = Ph, 0 - , m-, or p-tolyl, or 0 - , rn-, or p-C1C6H4) are prepared by treating
PhN=CClSCl with RNHCOSH.NEt, and RNHCS,H.NEt,, respectively.
Treating (304; X = 0 or S) with PhCH2NH2 gives (304; X = NCH2Ph)!21
17 Oxathiazolesand Selenathiazoles
l73,2-0xathiazoles. - Meso-ionic oxathiazolones [305 ; R = 2,4-Me2C6H3,
2,4,5-Me3C6H2, or 2,3,4-(Me0)3C6H2] are prepared by the reaction of
DL-HSCHRC0,H with EtONO. Compound [305; R = 2,3 ,4-(Me0),C6H2]
reacts with DMAD at 80°C, with evolution of C02, to give the isothiazole
(306). Photochemical decomposition of (305; R = 2,4,5-Me3C6H2) in the
presence of DMAD gives (307).12
1,3,4-0xathiazoles. - Nitrile sulphides, formed by the thermal decarboxy-

lation of oxathiazolones (308; R2R3 = 0),undergo 1,3-dipolar cycloaddition
N- S
421 R. T. Jadhav, N. M. Nimdeokar, and M. G . Paranjpe, Indian J. Chem, Sect. B , 1980,

19, 970.
Five-Membered Rings: Other systems 201
with activated carbonyl compounds: C13CCH0, (C13C)2C0, and PhCOCF3
give trisubstituted oxathiazoles (308). The structures of (308; R' = Ph,
R2 = H, R3 = CC1,; R1 = 4-MeOC6H4,R2 = Ph, R3 = CF3) were determined
by X-ray crystallogra hic analysis. The oxathiazole ring is planar, with a
localized C=N bond.42P
18 Miscellaneous Ring Systems

1,3,2,4-Dithiadiazoles. - The reaction of S4N4 with Br2 in CS2 yields CS3N2-
Br2 and the 5-(bromosulphenyl)-1,3,2,4-dithiadiazolium tribromide (309)
(X-ray analysis).423
N- S
PART 111: Other Five-Membered Ring Systems by G. V. Boyd
1 Introduction
This Part deals with the remaining heterocylic compounds that contain five-
membered rings. Monocyclic systems, their benzo-analogues, other annelated
heterocycles, and compounds with two or more linked five-membered rings
are reviewed first. There follows a survey of those bi- and poly-cyclic systems
in which a five-membered ring of the previous type is fused t o a heterocycle
containing five, six, seven, or eight atoms. The order in each section is
generally that of increasing saturation, so that the fully conjugated 'aromatic'
compounds are mentioned first, dihydro- and 0x0-derivatives follow, and
completely hydrogenated compounds are discussed last. For some ring
systems, e.g. furans, pyrroles, and indoles, it was found convenient t o survey
methods of synthesis and reactions in separate sub-sections.
As in previous years, the Reporter had t o be severely selective: only about
430 of the nearly 1000 relevant articles are reviewed briefly. However, as in
last year's Report, references to other papers are listed at the end of each
sub-section, and in order to assist the reader, these are accompanied by
appropriate references to Chemical Abstracts.
422 A. M. Damas, R. 0. Gould, M. M. Harding, R. M. Paton, J . F. ROSS,and J. Crosby,

J. Chem. SOC,,Perkin Trans. I , 1981,2991.
423 G. Wolmerschaeuser, C. JSrueger, and Y. M. Tsay, Chem. Ber., 1982, 115, 1126.
2 Reviews
There are general reviews on heterocyclic syntheses by cycloaddition
reactions of isocyanates' and on the use of heterocyclic cations in preparative
organic chemistry.2 More specific topics are 5-hydroxymethylfuran-2-carb-
aldehyde ,3 isobenzofurans and related ortho-quinonoid systems,4 the
conversion of 2H-cyclohepta [ b ]furan-2-one (1) into derivatives of azulene,'
the synthesis of indoles from o-alkylphenyl isocyanides,6 and abnormal
Fischer indolization reactions of o-methoxyphenylhydra~ones.~ Two reviews
on isoindoles have and a lecture on highly conducting charge-
transfer complexes that are based on heterocyclic selenium and tellurium
donors has been reprinted." Recent advances in the chemistry of imidazole"
and in the use of nitro-imidazoles as radiosensitizers12 have been summarized.
There have been reviews on benzimidazole N-oxides13 and on dihydrobenzi-
midazoles, benzimidazolones, benzimidazolethiones, and related com-
p o u n d ~ .Other
~ ~ topics are synthetic applications of 1,3-dithiolium and 1,3-
oxathiolium salts" and of isoxazoles, l6 the chemistry of benzisoxazoles,'7
2-amino-oxazoles,18 5-oxazolones (2)," furoxans, benzofuroxans, and
related systems,20921 the synthesis of five-membered meso-ionic com-
and t e t r a ~ o l e s . ~ ~
A. Foucaud, Bull. SOC.Chem. Belg., 1981,90, 545.

' K. Akiba, Kagaku (Kyo to ) , 1981,36,850 (Chem. Abstr., 1982,96,19 253).
A. Faury, A. Gaset, and J . P. Gorrichon, Inf. Chim., 1981, 2 14,203 (Chem. Abstr.,
1981,95, 150 278).
U. E. Wiersum, Aldrichimica Acta, 1981, 14,53.
K. Takase and M. Yasunami, Yuki Gosei Kagaku Kyokaishi, 1981, 39,1172 (Chem.
Abstr., 1982,96,217 283).
Y. Ito, Kagaku no Ryoiki, 1982, 36, 91 (Chem. Abstr., 1982,96, 199 436).
' H. Ishii,Acc. Chem. Res., 1981, 14,275.
R. Bonnett and S. A. North, Adv. Heterocycl. Chem., 1981,29, 341.
F. S. Babichev, V. A. Kovtunenko, and A. K. Tyltin, Usp. Khim., 1981,5 0 , 2073.
l o E. M. Engler, Proc. Int. Symp. Org. Selenium Tellurium Compd., 3rd, 1979,357.
11
M. R. Grimmett, Adv. Heterocycl. Chem., 1980, 2 7 , 241.
'' H.Monney, J . Parrick, and R. G. Wallace, Pharmacol. Ther., 1981, 14, 197.
l 3 D. M. Smith, Chem. Heterocycl. Compd., 1981,40,287.
l4 D. M. Smith, Chem. Heterocycl. Compd., 1981,40, 333.
l 5 K. Hirai, H. Sugimoto, and T. Ishiba, Yuki Gosei Kagaku, 1981, 39, 192 (Chem.
Abstr., 1981,95,42942).
l6 A. A. Akhrem, F. A. Lakhvich, and V. A. Khripach, Khim. Geterotsikl. Soedin.,
1981,1155.
'' R. K. Smalley, Adw. Heterocycl. Chem., 1981, 29, 1.
l 8 L. Peshakova, V. Kalcheva, and D. Simov, Khim. Geteerotsikl. Soedin., 1981, 101 1.
l 9 A. K. Mukerjee and P. Kumar,.Heterocycles, 1981, 16, 1995.
'O A. J. Boulton, Bull. SOC. Chim. Belg., 1981, 90,645.
'' A. Gasco and A. J. Boulton, Adw. Heterocycl. Chem., 1981,29,251.
'' V. G. Yashunskii and V. V. Ogorodnikova, Khim. Geferofsikl.Soedin., 1981,291.
23 G. I. Koldobaskii, V. A. Ostrovskii, and V. S. Poplavskii, Khim. Geterotsikl. Soedin.,
1981, 1299.
3 Systems with One Heteroatom and their Benzo-analogues etc.
Furans. - Formation. Treatment of the epoxy-ketones (3; R1,R2, R3 =
alkyl) with toluene-p-sulphonic acid yields furans (4).24Phenacyl bromide
undergoes electrochemical reduction to give 2,4-diphenylf~ran.~’Tetra-t-
butylfuran has been obtained by reductive desulphurization of compound
(5).26 Photolysis of the (2)-diazo-ester N2CHCHT(CN)C02Et yields 3-
cyan0-2-ethoxyfuran.~~ The stabilized ylide PhCH2NMe2-cHCOAr (Ar = 4-
biphenylyl) reacts with dimethyl acetylenedicarboxylate to form the ester
(6) with loss of benzyldimethylamine.28 The thermal isomerization of 1,l-
diacetylcyclopropane to the dihydrofuran (7) has been rep~rted.~’The
photo-addition of tetramethylethylene to the acetylenic ketone MeCXCOMe
results in compound (8).30 The methylenedihydrofuran (9) is formed from
acetylacetone and the chloride H C E C C M ~ ~ C ~ . ~ ~
(3)
(4)
L
(7)
(9)
Carbonylation of a mixture of ethylene, ethanol, and diphenylacetylene in
the presence of rhodium carbonyl gives the butenolide Another
formation of a butenolide, that of compound (12), is by flash vacuum
pyrolysis of diphenylmethyl propiolate, Ph2CHO2C=CH. It has been
suggested that the ester isomerizes to the methylene-carbene (1 l), which
yields the product by intramolecular insertion.33 Ozonization of tetraphenyl-
H :C=CH
\
Et 0
Ph
(10) (11) (12)
24 R.A. Cormier and M. D. Francis, Synth. Commun., 1981, 11, 365.

25
F.Barba, M. D. Velasco, and A. Guirado, Synthesis, 1981,625.
26 A.Krebs, E. Franken, and S. Muller, Tetrahedron Lett., 1981,22, 1675.
27 C.Guiborel, R. Danion-Bougot, D. Danion, and R. Carrie, Tetrahedron Lett., 1981,
22,441.
28 R. W. Jemison, S. Mageswaran, W. D. Ollis, I. 0. Sutherland, and Y. Thebtaranonth,
J. Chem. SOC.,Perkin Trans. 1 , 1981,1154.
2 9 N. S. Zefirov, S. I. Kozhushkov, and T. S. Kuznetsova, Khirn. Geterotsikl. Soedin.,
1981,1285.
30 S . Hussain and W. C. Agosta, Tetrahedron, 1981,37, 3301.
31 R. Chenevert, J . Page, R. Plante, and D. Beaucage, Synthesis, 1982,7 5 .
32 (a) P. Hong, T. Mise, and H. Yamazaki, Chern. Lett., 1981,989;( b ) ibid., p, 993.
33 R. F. C. Brown, F. W. Eastwood, N. Chaichit, B. M. Gatehouse, J . M. Pfeiffer, and D.
Woodroffe, Aust. J. Chem., 1981,34, 1467.
cyclopentadienone results in a mixture of the diketone PhCOCHPhCOPh
and the butenolide (13).% Bullatenone (14) has been prepared from the
acetylenic glycol HOCHPhCGCCMe20H by acetylation, followed by
oxidation with silver per~hlorate.~’ A general method for the synthesis of 4-
ylidenebutenolides (1 6) is the tin(1V)-chloride-catalysed reaction of an
aldehyde or ketone R’ R’CO with 2-trimethylsilyloxyfuran and subsequent
dehydration of the resulting alcohol (1 5).36 Treatment of mesitoylacrylic
acid with acetic anhydride in the presence of a copper(1) salt yields the cis-
bifuranylidenedione (17; Ar = 2,4,6-Me3C6H2) and the trans-isomer, which
crystallize in a blue-black self-charge-transfer form and a scarlet non-charge-
transfer form, re~pectively.~’
* ‘ O0 W ’ 0’
Addition of dichloroketen to cyclohexenyl phenyl sulphoxide yields the

cis-lactone (18).38 The methylbutanolide (19) is formed by the reaction of
but-3-en-1-01 with carbon monoxide in the presence of palladium(I1) chloride,
copper( 11) chloride, and triphenylphosphine .39 Palladium( 0)-phosphine
complexes catalyse the carboxylation of isopropylidenecyclopropane to give
the furanone (20).40
no
H2cTto
34 P. S. Bailey and T. M. Ferrell, J. Org. Chem., 1981, 46, 5028.
3s H. Saimoto, T. Hiyama, and H. Nozaki, J. A m . Chem. SOC.,1981, 103,4975.
36 M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron Lett., 1981, 22,
4269.
37 M. J . Begley, L. Crombie, G. L. Griffiths, R. C. F. Jones, and M. Rahrnani, J. Chem.
SOC.,Chem. Commun., 1981,823.
38 J. P. Marino and M. Neisser, J. A m . Chem. SOC., 1981, 103, 7687.
39 J. R. Norton, Prepr. Div. Pet. Chem., A m . Chem. SOC.,1980, 2 5 , 368.
40 Y. Inoue, T. Hibi, M. Sakate, Y. Kamashima, and H. Hashimoto, Nippon Kagaku
Kaishi, 1982, 276 (Chem. Abstr., 1982, 96, 217 611).
Reactions of Furans. Pyrolysis of the ester (21) yields a mixture of the cyclo-
butanone (22) and the dimeric compound (23)!l The lactone (25) is
produced when octahydrodibenzofuran (24) is oxidized with m-chloro-
peroxybenzoic acid .42
A mixture of 2-t-butylfuran and 2J-di-t-butylfuran is obtained by the

action of t-butyl chloride on furan in the presence of mesitylenemolybdenum
tri~arbonyl.4~ The intermediate in the nitration of furan-2-aldehyde in acetic
anhydride has been identified as compound (26).* Treatment of 5-bromo-2-
furoic acid with sulphur tetrafluoride in hydrogen fluoride yields the
dihydrofuran (27).45 Bromo-furans are converted into aryl-furans by cross-
coupling with aryl Grignard reagents in the presence of nickel(I1jphosphine
c ~ m p l e x e s .2-Furoic
~~ acid is lithiated at position 5 , 3-furoic acid at C-2!7
2-Methylfuran yields the 5-methylthio-derivative by lithiation and subsequent
treatment with dimethyl disulphide.'@8 The corresponding phenylthio-
compound (28) has been converted into a series of 4-substituted 2-methyl-
furans (29; R = alkyl, Me3Si, C02H, or RCHOH) by the sequence: bromi-
nation, lithiation, treatment with the appropriate electrophile, and, finally,
desulphurization with Raney nickel!' 2-Lithiofuran reacts with copper( 11)
41 W. S. Trahanovsky, T. J. Cassady, and T. L. Woods, J. Am. Chem. SOC.,1981, 103,

6691.
42 S. B. Gingerich, W. H. Campbell, C. E. Bricca, P. W. Jennings, and C. F. Campana,
J. Org. Chem., 1981, 46, 2589.
43 D. J . Milner, J. Organomet. Chem., 1981, 217, 199.
44 A. Gaset and J . P. Gorichon, Org. Mugn. Reson., 1981, 16, 239.
4 5 V. V. Lyalin, R. V. Grigorash, L. A. Alekseeva, and L. M. Yagupolskii, Zh. Org.
Khim., 1981, 17, 1774.
46 L. N. Pridgen and S. S. Jones, J. 0%.Chem., 1982,47,1590.
4 7 D. W. Knight and A. P. Nott, J. Chem. SOC.,Perkin Trans. I , 1981, 1125.
48 C. H. Eugster, M. Balmer, R. Frewo, and J. H. Bieri, Helv. Chim. Actu, 1981, 64,
2636.
49 S. M. Nolan and T. Cohen, J. 0%.Chem., 1981,46,2473.
chloride to give 2,2'-bifuran (30); lithiation of the latter, followed by the
action of copper chloride, yields the quaterfuran (3 l)."
Two unusual cycloaddition reactions of furans are the addition of maleic

anhydride to the thioketone (32) to give compound (33)51 and the formation
of the intramolecular Diels-Alder adduct (35) from the ester (34).52
Sensitized photo-oxygenation of 2-methoxymethylfuran at - 60°C yields
the peroxide (36), which isomerizes to the aldehyde-ester OCHCH=CHC02-
Ph
Ph
(33)
CH20Me at - 10"C.53 The corresponding photo-adduct (37) of methyl 2,5-

dimethyl-3-furoate rearranges to the diepoxide (38) on heating.54 The pale
0
" T. Kauffmann, H. Lexy, and R. Kriegesmann, Chem. Ber., 1981, 114,3667.

51 H.Ohmura and S. Motoki, Chem. Lett., 1981,2 3 5 .
5 2 H. Kotsuki, A. Kawamura, M. Ochi, and T. Tokoroyama, Chem. Lett., 1981,917.
" B. L. Feringa and R. J. Butselaar, Tetrahedron Lett., 1981, 2 2 , 1447.
54 (a) M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Chem. SOC.,Chem. Cornmun.,
1981, 720;( b ) M. L. Graziano and R. Scarpati, J. Chem. SOC.,Perkin Trans. I , 1981,
1811.
yellow fulgide (39) is suitable for chemical actinometry in near-ultraviolet
and visible regions, being reversibly transformed into the deep red dihydro-
benzofuran (40).55
Me = M e m o
Me Me
0 Me Me 0
Me
(39) (40)
The azides (41; R = H, Pr’, or But) decompose at room temperature to

nitrogen and the cyano-compounds NCCH=CHCOCOR at different rates, the
t-butyl derivative being the least stable. This is attributed to the instability
of the intermediate nitrene (42), whose planarity is impeded by the bulky
Thermolysis of the azide (43) yields a mixture of the benzindolizine
(44) and its 4,5-dihydro-derivative.”
(41)
R *’
(43)
COOMe
The synthesis of the diatropic [ 141annuleno [c]furan (45) has been

described .58
II 7I
But But
” H. G. Heller and J . R. Langan, J. Chem. SOC.,Perkin Trans, 2, 1 9 8 1 , 341.

’‘ P. J. Newcornbe and R. K. Norris, Tetrahedron Lett., 1 9 8 1 , 2 2 , 6 9 9 .
5 7 K. Yakushijin, T. Tsuruta, and H. Furukawa, Chem. Pharm. Bull., 1 9 8 2 , 30, 140.
H. Ebe, T. Nakagawa, M. Iyoda, and M. Nakagawa, Tetrahedron Lett., 1 9 8 1 , 2 2 ,
4441 .
208 Heterocyclic Chem istry
- ~ ~reaction^^'-'^ of furans should be
Other papers on the f ~ r r n a t i o n ’ ~and
noted.
59 R. Dams, M. Malinowski, I. Westdorp, and H. J. Geise, J. Org. Chem., 1981, 46,
2407 (Chem. Abstr., 1981, 95,693).
6o J. A. Donnelly, P. J. Macken, and S. O’Brien, Isr. J. Chem., 1981, 21, 185 (Chem.
Abstr., 1982,96, 52 102).
61 R. Antonioletti, M. D’Auria, G. Piancatelli, and A. Scettri, J. Chem. SOC., Perkin
Trans. 1,1981,2398 (Chem. Abstr., 1981, 95,203654).
6 2 M. G. Vinogradov, V. I. Dolinko, and G. I. Nikishin, Izw. Akad. Nuuk SSSR, Ser.
Khim., 1981, 700 (Chem. Abstr., 1981, 95, 24673).
6 3 D. W. Knight and A. P. Knott, J. Chem. Soc., Perkin Trans. 1 , 1982, 623 (Chem.
Abstr., 1982, 96, 217 547).
64 0. E. Nasakin, V. V. Alekseev, V. K. Promonenkov, A. Kh. Bulai, and S. Yu.
Silvestrova, Khim. Geterotsikl. Soedin., 1981, 744 (Chem. Abstr., 1981, 95,
150 302).
65 M. G. Vinogradov, M. S. Pogosyan, A. Ya. Shteinshneider, and G. I. Nikishin, Izw.
Akud. NaukSSSR, Ser. Khim., 1981,2077 (Chem. Abstr., 1982,96,52 099).
66 J. Benaim and A. L’Honor6, J. Organomet. Chem.,q980, 202, C53 (Chem. Abstr.,
1981,95, 60 862).
67 A. Gomez-Sanchez, B. M. Stiefel, R. Fernandez-Fernandez, C. Pascual, and J.
Bellanato, J. Chem. SOC., Perkin Trans. I , 1982, 441 (Chem. Abstr., 1982, 96,
199 457).
M. Larcheveque, C. Legueut, A. Debal, and J. Y. Lallemand, Tetrahedron Lett.,
1981, 22, 1595 (Chem. Abstr., 1981, 95,96 983).
6 9 Yu. M. Skvortsov, A. G. Malkina, B. A. Trofimov, A. N. Volkov, and V. M. Bzhezo-
vskii, Zh. Org. Khim., 1981, 17, 884 (Chem. Abstr., 1981, 95, 150295).
70 P. J. Babidge and R. A. Massy-Westdropp, Aust. J. Chem., 1981, 34, 1745 (Chem.
Abstr., 1981, 95, 219 925).
71 H. Suzuki, H. Yashima, T. Hirose, M. Takahashi, Y. Morooka, and T. Ikawa, Tetra-
hedron Lett., 1980, 21,4927 (Chem. Abstr., 1981, 95,6931).
72 S. D. Rychnovsky and P. M. Bartlett, J. A m . Chem. SOC., 1981, 103, 3963 (Chem.
Abstr., 1981, 95,150 294).
73 S. Gelin and B. Chantegrel, J. Heterocycl. Chem., 1981, 18, 663 (Chem. Abstr.,
1981, 95, 132 583).
74 T. Shono, H. Hamaguchi, I. Nishiguchi, M. Sasaki, T. Miyamoto, M. Miyamoto,and
S. Fujita, Chem. Lett., 1981, 1217 (Chem. Abstr., 1981, 95, 219749).
75 Y. Nakada, T. Hata, C. Tamura, T. Iwoka, M. Kondo, and J. Ide, Tetruhedron Lett.,
1981, 22,473 (Chem. Abstr., 1981,95, 6696).
76 G. I. Nikitin, V. G. Glukhovtsev, Yu. V. Ilin, and A. V. Ignatenko, Izw. Akud. Nauk
SSSR,Ser. Khim., 1982,447 (Chem. Abstr., 1982,96,199465).
77 J. ApSimon, V. S. Srinivasan, M. R. L’Abb6, and R. Seguin, Heterocycles, 1981, 15,
1079 (Chem. Abstr., 1981,95,23 754).
78 T. Shono, Y. Matsumura, K. Tsubata, and J. Takata, Chem. Lett., 1981, 1121 (Chem.
Abstr., 1981, 95, 186 969).
7 9 K. Ohno and M. Machida, Tetrahedron Lett., 1981, 22, 4487 (Chem. Abstr., 1982,
96, 122 540).
K. Yakushijin, M. Kozuka, T. Morishita, and H. Furukawa, Chem. Phurm. Bull.,
1981, 29,2420 (Chem. Abstr., 1982, 96,19903).
A. Murai, K. Takahashi, H. Taketsuru, and T. Masamune, J. Chem. SOC., Chem.
Commun., 1981,221 (Chem. Abstr., 1981,95, 1 1 5 163).
82 H. Kotsuki and H. Nishizawa, Heterocycles, 1981, 16, 1287 (Chem. Abstr., 1981,
95, 219 923).
83 S. Takano, Y. Oshima, F. Ito, and K. Ogasawara, Yukuguku Zusshi, 1980, 100, 1194
(Chem. Abstr., 1981, 95, 24 871).
84 H. Hart and S. Shamouilian, J. Org. Chem., 1981, 46, 4874 (Chem. Abstr., 1981,
95, 203 613).
85
R. H. Hall, S. Harkema, H. J. Den Hertog, G. J. Van Hpmmel, and D. N. Reinhoudt,
J. R. Neth. Chem. SOC.,1981, 100, 312 (Chem. Abstr., 1982, 96, 6498).
86 H. K. Hall, Jr., P. Nogues, J. W. Rhoades, R. C. Sentman, and M. Detar, J. Org.
Chem., 1982,47,1451 (Chem. Abstr., 1982,96, 142 593).
8 7 L. Fisera, J. Kovac, J. Lesko, and V. Smahovsky, Chem. Zvesti, 1981, 35,93 (Chem.
Abstr., 1981, 95,42 788).
Benzofurans. - Treatment of a mixture of o-dichlorobenzene and cyclo-
hexanone with sodamide and sodium t-but oxide yields tetrahydrobenzofuran
by the aryne mechanism outlined in Scheme 1.% The formation of the
Scheme 1
diarylfuran (48) by photolysis of the vinyl bromide (46) proceeds via the
vinyl cation (47).” 2-Phenylbenzofuran (50) is obtained by oxidation of the
adduct (49) of phenylsulphene, PhHC=S02, to t r ~ p o n e . ’ Pentafluorophenyl
~
oc.-(49)
Ph
(46)
,so2
A. P. Cowling, J . Mann, and A. A. Usmani, J. Chem. Soc.. Perkin Trans. 1 , 1981,

2116 (Chem. Abstr., 1981,95,150297).
” N. A. Vaidya, W. J . Nizon, Jr., A. A. Fatmi, and C. de W. Blanton, Jr., J. Org. Chem.,
1982,47,2483 (Chem. Abstr., 1982, 96,217 615).
90 P. D. Williams and E. LeGoff, J. Org. Chem., 1981, 46, 4143 (Chem. Abstr., 1981,
95,168 609).
y1 K. Hirai, H. Suzuki, H. Kashiwagi, Y. Moro-oka, and T. Ikawa, Chem. Lett., 1982, 23
(Chem. Abstr., 1982, 96,122170).
92 N. Yoneda, A. Suzuki, and Y. Takahashi, Chem. Let?., 1981, 767 (Chem. Abstr.,
1981,95,96 977).
93 R. Martinez-Utrilla and M. A. Miranda, Tetrahedron, 1981, 37, 21 1 1 (Chem. A bsrr.,
1981,95, 150 300).
94 J. P. Bachelet and P. Caubere, J. Org. Chem., 1982,47,234.
9 5 T. Suzuki, T. Kitamura, T. Sonoda, S. Kobayashi, and H. Taniguchi, J. Org. Chem.,
1981,46,5324.
96 B. D. Deanand W. E. Truce, J. Org.Chem., 1981,46, 3575.
propargyl ether, C6F50CH2CrCH,is converted into the benzofuran (52) on
heating, by way of the Claisen rearrangement product (5 l).” The preparation
of 14C-labelled 1,2,7,8- and 2,3,7,8-tetrachlorodibenzofuranshas been
de~cribed.’~Free-radical cyclization of the o-allyloxy-diazonium salt (53),
induced by tributylstannane, yields 2,3-dihydro-3-methylbpzofuran (54).”
The thioether (55) is formed by the action of the salt MeS(SMe)2 SbC1, on
o-allylphenol. loo
F
CH=C=CH2
(51)
- F \ m
Me F
F
(52)
Me
Irradiation Of the ester (56) in methanol leads to the rearranged phthalide

(57).”’ The oxonium salt (59) is produced by the action of aluminium
chloride on the ester chloride (58).lo2
Me0
OMe
(56)
@ -Me
COOMe c1 a1c14-
c1
0
(58) (59)
97 ( a ) G. M. Brooke and D. I. Wallis, J. Chem. Soc., Perkin Trans. I , 1981, 1417;( b )

G. M. Brooke, ibid., 1982, 107.
9 8 A. P. Gray, W. J . McClellan, and V. M. Dipinto, J . Labelled Compd. Radiopharm.,
1981,18, 507.
99 A. L. J. Beckwith and G. F. Meijs, J. Chem. SOC.,Chem. Commun., 1981,136.
loo G. Capozzi, V. Lucchini, F. Marcuzzi, and G. Modena, J. Chem. SOC.,Perkin Trans.
101
1, 1981,3106.
102 M. E. Jung and R. B. Blum, J. Chem. SOC., Chem. Commun., 1981,962.
M. V. Rao, S. H. E. Ashry, and M. V. Bhatt, Tetmhedron Lett., 1981,22, 145.
3-Amino-2-nitrobenzofuran (60) undergoes an astonishing transformation
in acetic acid, giving the diazo-compound (6 1).'03 The benzofuranone (62)
is converted into the cyclohexadienone ( 6 3 ) on treatment with methyl iodide
and sodium methoxide.lW Flash vacuum pyrolysis of methylenephthalide
(64) results in the rearranged indanedione (65); the isomer (66), on the other
hand, eliminates carbon monoxide to give ben~0furan.l'~Pummerer's ketone
103
P. Demerseman, S. Risse, and R. Royer, J. Heterocycl. Chem., 1981, 18, 695.
lo4 J . K. Makrandi and S. K. Grover, J. Chin. Chem. SOC.(Taipei), 1981,28,65 (Chem.
Absfr., 1981, 95, 80 609).
'05 R. Bloch and P. Orvane, Tetrahedron Lett., 1981, 22, 3597.
(67) is converted into a mixture of the azide (68) and the ring-expanded
product (69) by the action of hydrazoic acid.lo6
For other work on benzofurans, see references 107-1 12.
Me
i f T a e M
MeaT- 0 \ 0
Me
Isobenzofurans and other Anneiated Furans. - 1-Methoxyisobenzofuran (72 ;

R =Me) is formed when the acetal (70) is heated in toluene that contains
a trace of acetic acid."3 The acetoxy-analogue (72; R = Ac) has been
generated by the action of 3,6-di-2'-pyridyl-l,2,4,5-tetrazine
on the adduct
q Me0 OMe
C. W. Bird, Y. P. S. Chauhan, and D. R. Turton, Tetrahedron, 1981,3 7 , 1277.

lo' P. Bravo and C. Ticozzi, Heterocycles, 1981, 16, 713 (Chem. Absfr., 1981, 95,
114 324).
108
P. Marshall, B. Mooney, R. Prager, and A. D. Ward, Synthesis, 1981, 197 (Chem.
Abstr., 1981,95,132 595).
l o 9 K. Kurosawa and Y. Morita, Bull. Chern. SOC. Jpn., 1981, 54,635 (Chem. Abstr.,
1981, 95, 6934).
110
L. Fisera, M. Dandarova, J. Kovac, P. Mesko, and A. Krutosikova, Collect. Czech.
Chem. Comrnun., 1981,46,2421 (Chem. Abstr., 1982, 96,68873).
E. W. Warnhoff and F. W. Yerhoff, Heterocycles, 1981, 15, 777 (Chem. Abstr.,
1981, 95,24 678).
'12 A. M. Andrievskii, A. N. Poplavskii, and K. M. Dyumaev, Zh. Vses. Khim. 0-ua, 1981,
26,101 (Chem. Abstr., 1981,95,61 886).
M. A. Makhlouf and B. Rickborn, J. 0rg. Chem., 1981,46,2734.
PY DP
Scheme 2
(71) of benzyne to 2-acetoxyfuran (Scheme 2).li4 Treatment of compound
(73) with methyl vinyl ketone in acetic acid yields the isobenzofuran adduct
(74) as a 3 : 2 mixture of endo- and exo-i~omers.'~~ 1-Methylisobenzofuran
adds to the quinone acetal (75) to yield solely the endo-adduct (76).l16 The
isoindene (77) is oxidized by air to a mixture of acetone and 1,3-diphenyliso-
benzofuran (78).'17 The stable endo-peroxide (79) is produced by the action
Me0
9 0
OMe
Me
Me0
0
OMe
Ph
Ph
( 7 7 ) X = CMe2 (79)
But
(75) (76) (78) X = 0
R. A. Russell, D. E. Marsden, M. Sterns, and R. N. Warrener, Aust. J . Chem., 1981,

3 4 , 1223.
B. A. Keay, D. K. W. Lee, and R. Rodrigo, Tetrahedron Lett., 1980, 21, 3 6 6 3 .
R. N. Warrener, B. C. Hammer, and R. A. Russell, J. Chem. Soc., Chem. Commun.,
1981,942.
'" E. Johansson and J. Skramstad, J. Org. Chem., 1981, 46, 3752.
214 Heterocyclic Chem istr),
The isobenzofuran (78)
of singlet oxygen on 1,3-di-t-b~tylisobenzofuran.~~~
undergoes a [4n + 4n] cycloaddition to the o-quinone-di-imine (80) to give
compound (81).'19
COPh Ph
COPh
(80) (81)
A modified mechanism for the formation of the cycloheptafuranone (83)

by pyrolysis of phenyl propiolate (82) has been proposed.12* The action of
copper(1) phenylacetylide on the azulene ester (84) leads to the azuleno [2,1-
b ] furan (85).121
Pyrroles. - Formation. A general synthesis of pyrroles is exemplified by the

reaction of the nitro-olefin (86) with the enamine (87) to yield the ester
Pyrroles (89; R' =Me, Ph, MeO, or MeS; R2 =COPh, CN, or
C02Me; R3 = Me or Ph) are formed fromN-(tosylmethy1)imines TosCH2N=C-
(0Me)R' and electron-deficient ole fins R2CH=CHR3 in a base-catalysed 1,3-
anionic cycloaddition, followed by elimination of toluene-p-sulphonic acid
I. Saito, A. Nakata, and T. Matsuura, Tetrahedron Lett., 1981, 22, 1695.

W. Friedrichsen, M. Roehe, and T. Debaerdemaeker, 2. Naturforsch., Teil. B, 1981,
36, 632.
R. F. C. Brown and F. W. Eastwood, J. Org. Chem., 1981,46,4588.
''I T. Morita, T. Nakadate, and K. Takase, Heterocycles, 1981, 15, 835.
''' H. Meyer, Liebigs Ann. Chem., 1981, 1534.
Five-Membered Rings: Other systems 2 15
and methan01.l~~ The cyclopropane (90) forms 1-t-butyl-3-methylpyrroleby
a carbene -+carbene rearrangement .124 Palladium(I1) chloride catalyses the
conversion of the amino-alcohol PhCzCH(OH)CH2NH2 into 2-phenyl-
pyrrole12’ and the reaction of buta-1,3-diene with ethylamine to give 1-
ethyl pyrr ole ?26 1,3,4-Triphenyl-1,2-diazabu t a-1,3-diene (PhN=N CHPh=CHPh)
and acetylacetone form the pyrrole (91) under the influence of copper(I1)
~hloride;’~’the 0-chloroazoalkene Me02CN=NCH=CHC1similarly reacts with
acetylacetone to yield (92).12* Heating N-formylsarcosine with the acetylene
Br
MeJCNBJ NHPh
M
AcQcHAc2
e
NHCOOMe
PhC=CS02CF3 results in the pyrrole (94) via a munchnone cyclo-adduct

(93), shown in Scheme 3 .12’ Tciphenyl-vinylphosphonium bromide reacts
with the sodium salt Na+ PhC(CN)NPhCOPh to form 1,2,5-triphenyl-
HOOC
OHC
N‘
Me Me Me Me
Scheme 3
pyrrole.” The antibiotic pyrrolomycin B has been shown to have the

structure (95).131
c1 c1
H OH
123 H. A. Houwing and A. M. Van Leusen, J. Heterocycl. Chem., 1981, 18,1127.

124 J. Arct and L. Skatteboel, Tetrahedron Lett., 1982, 23, 113.
12’ K. Utimoto, H. Miwa, and H. Nozaki, Tetruhedron Lett., 1981, 22,4277.
126 J . E. Baeckvall and J . E. Nystroem, J. Chem. SOC.,Chem. Commun., 1981, 59.
12’ 0. Attanasi, P. Bonifazi, E. Foresti, and G. hadella, J. Org. Chem., 1982, 47, 684.
12* T. L. Gilchrist, B. Wrton, and J . A. Stevens, Tetrahedron Lett., 1981, 22, 1059.
H. C. Berkand J . E. Franz, Synth. Commun., 1981, 11, 267.
J. V. Cooney and W. E. McEwen, J. Org. Chem., 1981,46,2570.
131 M. Kaneda, S. Nakamura, N. Ezaki, and Y. Iitaka, J. Antibiot., 1981, 34, 1366.
The isopropylidenepyrroline (96) is produced by the action of phosphorus
pentoxide on the oxime Me2C=CHCH2CH2CMe=NOH.'32 Reductiomycin, a
new antibiotic, is the pyrroline (97).'33
Me OH
(96) H
(97)
+
Treatment of the quaternary ammonium salt PhC=CCH2NMe2CH2C0Ph
Br- with sodium hydroxide gives, inter alia, the betaine (98)." Controlled-
potential electrolysis of y-nitro-ketones on a mercury cathode yields 1 -
pyrroline 1-oxides, pyrrolines, or pyrrolidines, according to conditions; thus
the oxide (99) is obtained from the compound 02NCMe2CHPhCH2COPh.'35
The pyrrolinone (101) results from autoxidation of the furan derivative
(1 OO).'36 Irradiation of the amide (1 02) leads to the pyrrolidinone (103) by an
unprecedented [ 1,6] shift of hydr~gen.'~'
Me2
COPh
M:L)Ph
Me
I
0-
-pJ-==x
phoI
( 100)
I
,,
Ph
HO
E
0
(98) ( E = COOEt) (101)

(99)
132 R. E. Gawley, E. J. Termine, and K. D. Onan, J. Chem. SOC., Chem. Commun.,

1981,568.
133 K. Shimizu and G. Tamura, J. Antibiot., 1981, 34, 654.
134 S. Mageswaran, W. D. Ollis, D. A. Southam, I. 0. Sutherland, and Y. Thebtaranonth,
J. Chem. SOC.,Perkin Trans. 1 , 1981, 1969.
135 M. Cariou, R. Hazard, M. Jubault, and A. Tallec, Tetrahedron Lett., 1981, 2 2 ,
3961.
136 K. Yakushijin, M. Kozuka, and H. Furukawa, Chem. Pharm. Bull., 1980, 2 8 , 2178.
'" H. Aoyama, Y. Inoue, and Y. Omote, J. Org.Chem., 1 9 8 1 , 4 6 , 1965.
Five-MemberedRings: Other systems 217
Reactions of @moles. 1,3-Di-t-butylpyrrole forms the first stable protonated
pyrrole, the salt (104).'38 Electrophilic substitution of pyrrole with Me$+
or Me2FC+ in the gas phase occurs mainly at the fl-p~sition,'~'as does
nitration and Friedel-Crafts acylation of 1-phenylsulph~nylpyrrole.~~~
Pyrrole-2,5-dialdehyde has been prepared by Vilsrneier-Haack formylation of
the ester (1 0 9 , followed by hydr01ysis.l~~A similar method has been used to
convert the di-acetal (1 06) into pyrrole-2,3 ,S-tri~arbaldehyde.'~~
N-Benzoyl-
pyrrole reacts with benzene in the presence of palladium(I1) acetate to yield a
mixture of 1 -benzoyl-2,5-diphenylpyrrole:, the bipyrrolyl (107), and com-
pound (108).'43 Treating lithiated N-methylpyrrole with nickel(I1) chloride
results in the polypyrrolyls (109; n = 0-4).'44 2-Aryl-1-methylpyrroles are
obtained by cross-coupling of 1-methylp:yrrol-2-ylmagnesiurn bromide with
aryl halides in the presence of palladium( 0)-phosphine complexes.'4s
Bu Ir
N-Chloropyrrole, prepared from pyrrole and aqueous sodium hypo-

chlorite, rearranges in methanol to a mixture of 2- and 3-chloropyrroles; 2,5-
dichloropyrrole is also formed.'46 Anodic (oxidation of 1,2,5-trimethylpyrrole
in the presence of cyanide ions yields the pyrroline (110) as the primary
Me
(110)
138
R. Gassner, E. Krumbholz, and F. W. Steuber, Liebigs Ann. Chem., 1981, 789.
139
M. Speranza, J. Chem. SOC.,Chem. Commun., 1981,1177.
140
(a) R. X . Xu, H. J . Anderson, N. J . Gogan, C. E. Loader, and R. McDonald, Tetra-
hedron Lett., 1981, 2 2 , 4899; ( b ) J. Rokach, P. Hamel, M. Kakushima, and G . M.
Smith, ibid., p. 4901.
141
R. Miller and K. Olsson, Acta Chem. Scand., Ser. B, 1981, 35, 303.
142
C. E. Loader, G. H. Barnett, and H. J . Anderson, Can. J. Chem., 1982, 60, 383.
143
T. Itahara, J. Chem. SOC.,Chem. Commun., 1981, 254.
144
T. Kauffmann and H. Lexy, Chem. Ber., 1981, 114,3674.
145
A. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett.,
1981, 2 2 , 5319.
146
M. De Rosa, J. Org. Chem., 1982, 47, 1008.
218 Heterocyclic Chernistv
product, which in hot methanol forms mainly 2-cyanomethyl-l,5-dimethyl-
pyrr01e.l~' It has been shown by deuterium labelling and n.m.r. spectroscopy
that the conversion of the alcohol (1 1 1) into the chloride (1 13) occurs by
randomization of the carbon atoms of the side-chain via the cyclopropane
intermediate (1 12).148
The pyrrole (1 14) reacts with dimethyl acetylenedicarboxylate to form

the pyrazole (1 16) in a complex process involving an intermediate pyrazoline
(1 1 5).149 Nitrosation of the hydroxypyrrole (1 17) results in the ring-
expanded product (1 18).lS0
Me 1I ,1
NMe
I M e -
E
E 17:- :uE
Me Me
(115) (116)
(114)
( E = COOMe)
Whereas the reaction of 1 -methyl-2-vinylpyrrole with dimethyl acetylenedi-

carboxylate at 80°C affords mainly the rearranged Diels-Alder product
14' L. Eberson, Acta Chem. Scand., Ser. B , 1980,34,747.

14* K. M. Smith, Z. Martynenko, and H. D. Tabba, Tetrahedron Lett., 1981,2 2 , 1291.
A. G . Schultz and R. Ravichandran, Tetrahedron Lett., 1981, 2 2 , 1771.
T. Momose, T. Tanaka, T. Yokota, N. Nagamoto, H. Kobayashi, and S. Takano,
Heterocycles, 1981, 15, 843.
(119), the Michael adducts, cis- and trans-(120), are produced at room
temperature.lS1 Treatment of the pyrrole (121) with the acetylenic ester
yields the phthalate (123), the bridge of the intermediate cyclo-adduct (122)
being extruded as dimethylamin~nitrene.~~~ The 2H-pyrrole (124) functions
as a dienophile towards cyclopentadiene but as a diene towards trans-
piperylene; with cyclohexa- 1,3-diene, both types of adduct are formed.lS3
Me
Me
Me
The pyrrolidinone (125) reacts with formic acid to yield the bicyclic
ester (127) by way of a [3,3] sigmatropic rearrangement of the cation (126),
followed by electrocyclization and addition of formic acid (Scheme 4).'%
Scheme 4
15' R. A. Jones and J. Sepulveda Arques, Tetrahedron, 1981,37,1597.
15' A. G. Schultz, M. Shen, and R. Ravichandran, Tetrahedron Lett., 1981,22, 1767.
153 B. K. Rammash, C. M. Gladstone, and J. C. Wong, J. Org. Chern., 1981,46,3036.
P. M. M. Nossin and W. N. Speckamp, Tetrahedron Lett., 1981,2 2 , 3289.
The product of the action of phosphorus pentachloride on pyrrolidinone is
(128), contrary to a previous report.lS5 The ylide (129) undergoes a [2,3]
shift to compound (130) under the influence of sodium hydride.lS6
-
c1
c
1eJ
.-
J 1,1 2
r
r2
(128) EHE ’ ‘CHZ/C\COPh
( 129)
( E = COOMe)
EHC
I
‘CH<
(130)
C
‘COPh
Several other articles on the f o r r n a t i ~ n ~ ~ and

’ - ~ ~reactions
~ 169-186 of
pyrroles have appeared.
l’’ S. L. Smith, W. J. Layton, M. Govindan, and H. W. Pinnck, J. Org. Chem., 1981,

46,4076.
l S 6 R. Gompper and B. Kohl, Angew. Chem., Inr. Ed. Engl., 1982,21, 198.
0. E. Nasakin, V. V. Alekseev, V. K. Romonenkov, Yu. P. Belo, A. Kh. Bulai, and
S. Yu. Silvestrova, Khim. Geterotsikl. Soedin., 1981, 407 (Chem. Abstr., 1981,
95,80624).
L. Grehn and U. Ragnarsson, J. Org. Chem., 1981, 46, 3492 (Chem. Abstr., 1981,
95,2195).
J. 0.Madsen, M. Meldal, S. Mortensen, and B. Olsson, Acta Chem. Scand, Ser. B ,
1981, 35, 77 (Chem. Absfr., 1981,95, 1 1 5 190).
1 6 0 A. Ts. Malkhasyan, E. M. Nazaryan, Zh. L. Dzhandzhulyan, S. M. Mirakyan, and G.
T. Martirosyan, Ann. Khim. Zh., 1981, 34, 612 (Chem. Abstr., 1981,95,186992).
16’ K. Achiwa and M. Sekiya, Chem. Lett., 1981, 1213 (Chem. Abstr., 1981, 95,
219 935).
162 Y. Izawa, K. Yokoi, and H. Tomioka, Chem. Lett., 1981, 1473 (Chem. Abstr., 1981,
95, 219 539).
163 E. J. Browne, B. W. Skelton, and A. H. White, Ausf. J. Chem., 1981, 34, 897 (Chem.
Abstr., 1981,95, 168 901).
164 J. Barluenga, F. hlacios, S. Fustero, and V. Gotor, Synthesis, 1981, 200 (Chem.
Abstr., 1981,95,6957).
H. von Dobeneck, E. Brunner, H. Bunke, G. Metzner, R. Schmidt, E. Weil, and J.
Sonnenbichler, LiebigsAnn. Chem., 1981,410 (Chem. Abstr., 1981,95,61 900).
166 G. Kinast, Liebigs Ann. Chem., 1981, 1561 (Chem. Abstr., 1981,95, 203 672).
K. W. Blake, I. Gillies, and R. C. Denney, J. Chem. SOC., Perkin Trans. I , 1981,700
(Chem. Abstr., 1981,95,24 696).
J. Bosch and M. Rubiralta, J. HeterocycL Chem., 1981, 18, 485 (Chem. Abstr.,
1981,95, 80 633).
169 J. A. De Groot, G. M. Gorter-La Roy, J. A Van Koeveringe, and J. Lugtenborg,
O v a Prep. Proced. Inf., 1981, 13, 97 (Chem. Abstr., 1981,95,42 805).
170 J. P. Boukou-Poba, M. Farnier, and R. Guilard, Can. J. Chem., 1981, 59, 2962
(Chem. Abstr., 1981,95,203669).
17’ M. R C. Gerstenberger, A. Haas, and F. Liebig, J. Fluorine Chem., 1982, 19, 461
(Chem. Abstr., 1982,96, 162 471).
172 K. C. Nicolaou, D. A. Qaremon, and D. P. Papahatjis, Tetruhedron Lett., 1981, 2 2 ,
4647 (Chem. Abstr., 1982,96, 142 609).
173 C. E. Loader and H. J. Anderson, Can. J. Chem., 1981, 59, 2673 (Chem Abstr.,
1982,96, 19 901).
174 J. M. Brittain, R. A. Jones, J. S. Arques, and T. A. Saliente, Synrh. Commun., 1982,
12, 231 (Chem. Abstr., 1982,96,217 628).
17’ D. P. Schumacher and S. S. Hall, J. Org. Chem., 1981, 46, 5066 (Chem. Abstr.,
1981, 95,203 673).
176 S. Petruso, L. Lamartina, 0. Migliara, and V. Spiro, J. Chem. SOC.,Perkin Trans. I ,
1981,2642 (Chem. Abstr., 1981,95, 203 667).
177 J. S e r a , G. Naray-Szabo, K. Simon, K. Daroczi-Csuka, I. Szilagi, and L. Parkanyi,
Tetrahedron, 1981, 37, 1565 (Chem. Abstr., 1981,95, 150 588).
Indoles and Carbazoles. - Formation. 2-Arylindoles (132) are formed by
intramolecular Wittig reaction of the phosphonium salts (1 3 1).'87 The
hydroxamic acids PhN(OH)COCH2COR (R = alkyl or aryl) cyclize in boiling
toluene to mixtures of indoles (133) and 3-isoxazolones (1 34).188Irradiation
of a solution of o-iodoaniline and the potassium enolate of acetone affords 2-
methylind~le.'~'The enamino-ketone (1 35) cyclizes photochemically to 1,2-
dimethylindole (1 36) with elimination of acetaldehyde." The styrene
derivative (1 37), obtained by the action of Meerwein's acetal, Me,NCH(OMe),,
on o-nitrotoluene, yields 1-hydroxyindole on treatment with zinc."'
Azidobenzocyclobutanes (1 38; R = Me, Ph, or CH,Ph) are converted into
indoles (133) by the action of concentrated sulphuric acid.'92
Br-
(131)
I Me
Me (137)
(136)
178 J. C Grarnain, L. Ouazzani-Chahdi, and Y. Troin, Tetrahedron Lett., 1981, 22,

3185 (Chem. Abstr., 1982,96, 19 899).
179 R. Gompper and B. Kohl, Angew. Chem., Int. Ed. Engl., 1982, 21, 198 (Chem.
Abstr., 1982,96, 181 090).
J. F. W. Keana and S. A. Boyd, J. Labelled Compd. Radiopharm., 1981, 18, 403
(Chem. Abstr., 1981,95,97494).
M. W. Tse-Tang, B. J. Gaffney, and R E. Kelly, Heterocycles, 1981, 15, 965 (Chem.
Abstr., 1981 , 95,42 152).
la' K. Tabei, H. Ito, and T. Takada, Heterocycles, 1981, 16, 795 (Chem. Abstr., 1981,
95, 61 904).
183
T. Sano. Y. Horiguchi, and Y. Tsuda, Heterocycles, 1981, 16, 359 (Chem. Abstr.,
1981,95,42 156).
184
J. M. Rib0 and A. Valles, J. Chem. SOC.,Chem. Commun., 1981,205 (Chem. Abstr.,
1981,95, 61 094).
G. Dannhardt and R. Obergrusberger, Arch. Pharm. (Weinheim, Ger.), 1981, 314,
81 1 (Chem. Abstr., 1982,96,19 900).
186
J. M. Brittain, R. A. Jones, R. 0. Jones, and T. J. King, J. Chem. SOC.,Perkin Tmns.
I , 1981,2656 (Chem. Abstr., 1981,95,219 999).
187
(a) M. Le Corre, A. Hercouet, and H. Le Baron, J. Chem. SOC., Chem. Commun.,
1981, 14; ( b ) ACS Symp. Ser., 1981, 171, (Phosphorus Chem.), p. 153 (Chem.
Abstr., 1982,96, 52 128).
189
K. Mohri, Y. Oikawa, K. Hirao, and 0. Yonernitsu, Heterocycles, 1982, 19, 515.
R. Beugelrnans and G. Roussi, Tetrahedron, 1981,37, Suppl. 1, p. 393.
I9O 0. Watson, E. T. Kennedy, and D. R. Dillin, Tex. J. Sci., 1980, 32, 357 (Chem.
Abstr., 1981, 95,42 812).
1 9 ' M. Somei and T. Shoda, Heterocycles, 1981, 16, 1523.
19' G. Adam, J. Andrieux, and M. Plat, Tetrahedron Lett., 1981, 22, 3181.
Treatment of P-nitrostyrene with acetyl chloride and iron( 111) chloride
gives 3-chloroindolin-2-one (1 39).Ig3 The nitrone (140) forms the rearranged
cyclo-adduct shown with dimethyl acetylenedicarboxylate .Iw The bridged
benzindolinone (142) results from the action of butyl-lithium on the anilide
(141).lg5
MeOOC COOMe
Ph
6
c1
m
o
QQR N3
The main product of the reaction of the biphenyl derivative (143) with
triethyl phosphite is 9-ethyl-4,5-dimethylcarbazole(1 44).Ig6 Treatment of
the diamine (145) with phosphoric acid yields a mixture of carbazole and 2-
t-butyl~arbazole.~~' Di-lithiation of the o-bromoaniline derivative (1 46),
followed by addition of 2-chlorocyclohexanone, affords the hexahydro-
carbazole ( 147).lg8
Et
(144)
HO
(145) (146) (147)

193
J. Guillaumel, P. Demerseman, J. M. Clavel, and R. Royer, J. HeterocycL Chem.,
1980, 17, 1531.
194 J. A. Damavandy and R. A. Y. Jones, J. Chem. Soc., Perkin Trans 1 , 1981,712.
19' W. J. Houlihan, Y. Uike, and V. A. Parrino, J. Org. Chem., 1981,46,4515.
196
Y. Tsunashima and M. Kuroki, J. HeterocycL Chem., 1981, 18, 315.
l g 7 M. Tashiro, Y. Fukuda, and T. Yamato, Heterocycles, 1981, 16, 771.
l g 8 P. A. Wender and A. W, White, Tetrahedron Lett., 1981, 22, 1475.
Reactions of Indoles. 2-Arylindoles react with tosyl azide under phase-
transfer conditions to give 3-diazo-compounds (1 48).’99The phenylazoindole
(149; R = N2Ph) is converted into the nitroindole (149; R = NO2) by ipso-
nitration.2m Indoles are oxidized by thallium( 111) nitrate to mixtures of
oxindoles and isatins.201 Sensitized photo-oxygenation of the indole (1 50)
yields the hydroperoxide (1 5 l), which forms compound (1 52) on treatment
with methanolic potassium borohydride.m2 Vilsmeier-Haack formylation of
1,2,3-trimethylindole affords mainly the aldehyde (1 53).203 The free-radical
reaction of the indoles (154; R = CH,OH, C1, or SMe) with the nitroxide
ButN(OCPh)O* leads to a mixture of the indolone (155) and the dimeric
compound (1 56).204 A mixture of 1,3-dichloro-2-methylindoleand the
Me
(149)
Me OOH Me OH
Me m\ P h -> o\r..- 6:
Me \ HOH2C \ N
(153)
199 A. Gonzales and C. Galvez, Synthesis, 1981,741.

2oo M. Colonna, L. Greci, and M. Poloni, J. Chem. SOC., Perkin Trans. 2, 1981,6 2 8 .
201 T. Ohnuma, H. Kasuya, Y. Kimura, and Y. Ban, Heterocycles, 1982, 17 (Spec. Issue),
p. 377.
202 C. Amsterdamsky and J. Rigaudy, Tetrahedron Lett., 1981,22, 1403.
203 C. Bastianelli, A. Cipiciani, S. Clementi, and G. Giulietti, J. Heterocycl. Chem., 1981,
18, 1 2 7 5 .
204 C. Berti, M. Colonna, L. Greci, L. Marchetti, and M. J. Perkins, J. Chem. SOC., Chem.
Commun., 1981,694.
3H-indole (157) results from the action of sodium hypochlorite on 2-
methylind~le.~~' Hydroxyl radicals, produced from titanium( 111) chloride
and hydrogen peroxide, react with indole to yield the trimer (158).206
Homolytic ipso-substitution of the indoles (159; R = CH20H, Ac, or CHO)
by benzoate radicals leads to the ester (159; R = 02CPh)?07
The iodonium salt (160) reacts with ammonium chloride to yield a

mixture of 3-chloroindole and, surprisingly, 2-chloroindole .*08 Treatment of
1-hydroxy-2-phenylindole with benzoyl chloride yields either 1-benzoyloxy-
or 3-benzoyloxy-2-phenylindole, depending on conditions to' the combined
action of benzoyl chloride and quinoline 1-oxide on the aforementioned
hydroxyindole leads to compound (1 6 1).2'o 1-Chloroisatin ( 1 62) oxidizes
benzyl alcohol photochemically to benzaldehyde.211 1-Methylisatin reacts
with two equivalents of benzylidenetriphenylphosphorane to yield the spiro-
compound (163).212
& H
c1
02CPh
(161)
205
M. D. Rosa, L. Carbognani, and A. Febres, J. Org. Chem., 1981,46,2054.
206 T. Kaneko, M. Matsuo, and Y. Iitaka, Chem. Pharm. Bull., 1981,29, 3499.
207 M. Colonna, L. Greci, and M. Poloni, Tetrahedron Lett., 1981, 22, 1143.
208 (a) V. A. Budylin, M. S. Ermolenko, F. A. Chugtai, and A. N. Kost, Khim Getero-
tsikL Soedin., 1981, 1494;( b ) V. A. Budylin, M. S.'Ermolenko, F. A. Chugtai, P. A.
Sharbatyan, and A. N. Kost, Ibid., p. 1503.
209 T. Nagayoshi, S. Saeki, and M. Hamana, Chem. Pharm Bull., 1981, 29, 1920.
210 T. Nagayoshi, S. Saeki, and M. Hamana, Chem Pharm. Bull., 1981,29,.1827.
211 C. Berti and L. Greci, Synth. Commun., 1981, 1 1 , 681.
212 M. K. Eberle, G. G. Kahle, and M. J. Shapiro, J. Org. Chem., 1982,47,2210.
The purple charge-transfer complex of indole with tetracyanoethylene
decomposes in neutral or basic media to the 3-substituted indole (164),
whereas under acidic conditions the 2-(tricyanoviny1)-isomer is formed.213
The cyclo-adducts of 1-benzyl-3-vinylindole to tetracyanoethylene and maleic
anhydride are the cyclobutane (165) and the tetrahydrocarbazole (1 66),
respectively.214 The reaction of 9-methyl-l,2,3,4-tetrahydrocarbazole (1 67)
with dimethyl acetylenedicarboxylate in aqueous acetic acid yields a mixture
of the bridged compounds (168) and (169).215 The photo-adduct (170)
of methyl acrylate to 1-benzoylindole rearranges to the benzazepine (1 7 1)
in hot xylene.216
I H
H CH,Ph (166)
HQOOH
x0): Me
-
Me
COPh
COOMe
(170)
__c
a (169)
COPh
/
COOMe
(171)
D. S. Johnston, Photochem. Photobiol., 1982, 35, 127.

'I4 J. D. Lambert and Q. N. Porter, Aust. J. Chem., 1981, 34, 1483.
'Is R. M. Acheson, M. C. K. Choi, and R. M. Letcher, J. Chem. SOC.,Perkin Trans. I,
1981,3141.
216 M. Ikeda, K. Ohno, M. Takahashi, T. Uno, Y. Tamura, and M. Kido, J. Chem. SOC.,
Perkin Trans. 1 , 1982,741.
The azabenzofulvene (1 72) unexpectedly forms compound (1 73) by the
~ ~ ~mechanism of the decomposition of the
action of a ~ e t y l a c e t o n e .The
hydroperoxides (174) to yield mixtures of the 3H-indoles (175) and the
ketones (176) has been elucidated.218 The action of hydrochloric acid on the
indolines (177; R1,R2 = Me, Et, PhCH2, or Ph) results in dehydration and
rearrangement to the indoles (178), the order of migratory aptitude being
PhCH2 > Ph > alkyL219
' N
Me OOH
Ar - ~
' N
Me
A
OH
I + ocoM
\
- NHCOAr
H H
Attention is drawn to other articles on the formation220-226 and re-

a c t i o n ~ of
~ ~indoles.
~ - ~ ~ ~
21 7
D. I. Bishop, I. K. ALKhawaja, and J. k Joule, J. Chem. Reg (S), 1981, 361.
218
F. McCapra and P. V. Long, Tetrahedron Lett., 1981, 22, 3009.
21 9
C. Berti, L. Greci, and M. Poloni, J. Chem. SOC., Perkin Trans. I , 1981, 1610.
220
R. J. Olsen and 0. W. Cummings, J. Heterocycl. Chem., 1981, 18, 439. (Chem.
Absfr., 1981, 95, 6 1 916).
221
H. Galons, J. F. Girardeau, C. C. Farnoux, and M. Miocque, J. Heferocycl. Chem.,
1981, 18, 561 (Chern Absfr., 1981, 95, 168014).
222
W. J. Houlihan, V. A. Parrino, and Y. Uike, J. Org. Chem., 1981, 46, 4511 (Chem.
Abstr., 1981, 95, 219 936).
223
Y. Tamura, J. Uenishi, H. Maeda, H.-D. Choi, and H. Ishibashi, Synthesis, 1981,
534 (Chem Abstr., 1981, 95, 150 331).
224
U. Kucklander and H. Toberich, Chem. Ber., 1981, 114, 2238 (Chem Absfr., 1981,
9 5 , 1 15 188).
225
I. Erden and D. Kaufmann, Tetrahedron Lett., 1981, 22, 215 (Chem Absfr., 1981,
9 5 , 6 1 712).
226
K. H. Grellmann, W. Kuhnle, H. Weller, and T. Wolff, J. A m Chern Soc., 1981,
103,6889 (Chem. Absfr., 1981,95,202 921).
227
G . W. Gribble and S. W. Wright, Heterocycles, 1982, 19, 229 (Chem Absfr., 1982,
96, 162482).
Isoindoles. - The stable isoindole (179) is produced by the action of organic
peracids on the 1,3-dihydro-derivati~e.~ The isoindole (180) forms the
Michael adduct (1 8 1) with dimethyl acetylenedicarb~xylate.~~~ Treatment of
228 Y. Kikugawa, Synthesis, 1981,460 (Chem. Abstr., 1981,95,80 644).

229
L. S. Hegedus, P. M. Winton, and S. Varaprath, J. Org. Chem., 1981, 46, 2215
(Chem Abstr., 1981,95,6963).
230 M. Terashima and M. Fujioka, Heterocycles, 1982, 19, 91 (Chem. Abstr., 1982,
96, 104024).
2 3 1 K. L. Erickson, M. R. Brennan, and P. A. Namnum, Synth. Commun., 1981, 11,
253 (Chem. Abstr., 1981,95,42 813).
232 Y. Murakami and H. Ishii, Chem. Pharm. Bull., 1981, 29, 711 (Chem. Abstr., 1981,
95,23 786).
233 A. Shafiee and S. Sattari, Synthesis, 1981,389 (Chem Abstr., 1981,95,80 640).
234 J. Bergman and B. Sjoeberg, Heterocycles, 1982, 19, 301 (Chem. Abstr., 1982, 96,
181 096).
235 J. Bergman, H. Goonewardena, and B. Sjoeberg, Heterocycles, 1982, 19,297 (Chem.
Abstr., 1982,96, 181 201).
236 A. Kubo and K. Uchino, Heterocycles, 1981, 16, 1441 (Chem Abstr., 1981, 95,
168912).
237 M. Abdelkader and H. K. Hall, Jr., J. Org. Chem., 1982, 47, 292 (Chem Abstr.,
1982,96,52 123).
238 E. Badger, S. Di Cataldo, A D. Kahle, J. Nadelson, and M. J. Shapiro, J. Heterocycl.
Chem., 1981, 18,623 (Chem. Abstr., 1981,95,97506).
239 G. Bobowski, J. HeterocycZ. Chem., 1981, 18, 1179 (Chem. Abstr., 1982, 96,
68 857).
240 G. Kalaus, J. Galambos, M. Kajtar-Peredy, L. Radics, L. Szabo, and C. Szantay,
Heterocycles, 1981, 15, 1109 (Chem Abstr., 1981,95,62 032).
241 T. Noriya and N. Yoneda, Chem. Pharm. Bull., 1982, 30, 158 (Chem. Abstr., 1982,
96, 162 481).
242 T. V. Stupnikova, T. V. Nuzhnaya, T. A. Zaritovskaya, and S. N. Baranov, Dopov.
Akad. Nauk Ukr. RSR, Ser. B: GeoL, K h i m BioL Nauk, 1981, 50 (Chem Abstr.,
1981,95,203821).
243 M. Fukui, Y. Yamada, A. Asakura, and T. Oishi, Heterocycles, 1981, 15,415 (Chem
Abstr., 1981,95,42 807).
244 P. P. Righetti, A Gamba, G. Tacconi, and G. Desimoni, Tetrahedron, 1981, 37,
1779 (Chem. Abstr., 1981,95, 169 023).
245 Y. Kikugawa and M. Kawase, Chem. Lett., 1981, 445 (Chem Abstr., 1981, 95,
42 815).
246 M. Zander, Chem. Ber., 1981, 114,2665 (Chem. Abstr., 1981,95,115 197).
247 C. Berti and L. Greci, J. Org. Chem., 1981, 46, 3060 (Chem Abstr., 1981, 95,
41 810).
248 G. Use and R. Kreher, Chem.-Ztg., 1982, 106, 143.
249 S . S. Simons, Jr., H. L. Amrnon, R. Doherty, and D. F. Johnson, J. Oq. Chem.,
1981,46,4739.
a mixture of N-methylisoindole and the chloride (182) yields the Diels-
Alder adduct (183) of a bicyclo[ 1.2.01 butene derivative.2m Intramolecular
cycloaddition of the amide MeCH=CHCH=CHCON=C(NMe2)CMe=CH2
results in the tetrahydroisoindolone (1 84).251
c1 Me
I N
Me
(184)
For other papers on isoindoles, see references 252-258.

Other Systems containing One Heteroatom. - The stannole (185) is trans-
formed by the action of iodine trichloride into the 6n-iodolium cation (186),
which has been isolated as a stable iodide, tetraphenylborate, and hexachloro-
stannate .259
l S oH. G. Zoch, A. D. Schluter, and G. Szeimies, Tetrahedron Lett., 1981, 2 2 , 3839.

251
R. Prewo, J. H. Bieri, U. Widmer, and H. Heimgartner, Helv. Chim. Acta, 1981,
64, 1515.
252 G. W. Gribble and C. S. LeHoullier, Tetrahedron Lett., 1981, 2 2 , 9 0 3 (Chem Abstr.,
1981, 95, 61 911).
253 S. Atmaram, k R. Forrester, M. Gill, and R. H. Thomson, J. Chem. Soc., Perkin
Tmns I , 1981, 1721 (Chem. Abstr., 1981, 9 5 , 9 6 527).
254 F. G. Kathawala,. H. F. Schuster, and M. J. Shapiro, Tetrahedron Lett., 1981, 2 2 ,
3703 (Chem Abstr., 1982,96, 52 120).
255 L. Hoesch and B. Koeppel, Helv. Chim Acta, 1981, 64, 864 (Chem. Abstr., 1981,
9 5 , 9 7 504).
C. Leuenberger, L. Hoesch, and A. S. Dreiding, Helv. Chim. Acta, 1981, 64, 1219
(Chem Abstr., 1981, 9 5 , 7 9 698).
257 L. Hoesch, Helv, Chim Acta, 1981, 64, 890 (Chem. Abstr., 1981, 95, 80 628).
258 P. Sanna, F. Savelli, and G. Cignarella, J. HeterocycL Chem., 1981, 18, 475 (Chem
Abstr., 1981, 95, 132 601).
259 V. R. Sandel, G. R. Buske, S. G. Maroldo, D. K. Bates, D. Whitman, and G. Sypniew-
ski, J. Org. Chem., 1981, 46, 4069.
4 Systems containing Two Identical Heteroatoms
Dioxoles. - A series of 1,2-dioxolans (187; R' , R2, R3 = Me or Ph) has been
prepared by the action of lead(1V) acetate on the peroxides PhR'CHCH2-
CR2R302H.260Treatment of the ester Me2CHCH2CHC102CMewith anti-
mony pentachloride affords the 1,3-dioxolanium salt (188) by way of a retro-
pinacoline rearrangement.261 Methyl a-diazoacetoacetate, MeCOCN2C02Me,
reacts with aldehydes RCHO (R = Pr", Pr', or Ph) in the presence of the salt
[(CF,CO),CH] 2Cu to yield the 1,3-dioxoles ( 189).262 The monophenyl
ether of p-dihydroxybenzene is converted into the spiro-benzo-l,3-dioxole
(190) under the influence of 'active' manganese d i o ~ i d e . 2t-Butylcyanoketen
~~
and t-butyl isocyanide form the 1,3-dioxole derivative (191) by an unusual
addition reaction.2H
R3 Me
1 R 2 Et\O
I
Ph Me
SbC1,-
Irradiation of the dioxolenone (192) in an argon matrix at 8 K yields

carbon monoxide, carbon dioxide, and a transient intermediate regarded as
dichloroketen.26s Lithium aluminium deuteride reduces the dioxolan (1 93)
to the alcohol (194) in 98% enantiomeric excess.266
260 H. Kropf and H. Von Wallis, Synthesis, 1981,237.

"' G. N. Dorofeenko, S. V. Borodaev, and S. M. Lukyanov, Zh. O g . Khim., 1981, 17,
2233.
"' M. E.Alonso and A. W. Chitty, Tetrahedron Lett., 1981,2 2 , 4181.
263 I. G. C. mu tts , M. R. Hamblin, and S. E. Webby, J. Chem. SOC., Perkin Trans. I ,
1981,493.
264 H. W. Moore and C C. Yu, J. Org. Chem., 1981,46,4935.
2 6 5 M. Torres, J. Ribo, A. Clement, and 0. P. Strausz, Nouv. J. Chim., 1981, 5 , 351.
W. J. Richter, J. Org. Chem., 1981,46, 5119.
Other articles on dioxoles have a ~ p e a r e d . ~ ~ ~ - ~ ~ l
Dithioles and Related Systems. - Base-catalysed condensation of the 1,2-
dithiolium salt (1 95) with ethylidenemalononitrile yields the dithiole ( 196).272
The action of potassium borohydride on the enamine (197) results in the
rearranged thiopyranthione (199), presumably via compound (1 98).2n
Deprotonation of the bisulphate (200) or heating the tosylhydrazone (201)
produces the thienothiophen (202).274 It has been reported275 that the
dihydrodithiolone (203) is desulphurized by hexae thylphosphoric triamide
to yield the thietanone (204). 1,2-Dithiole-3-thiones (205; X = S; R', R2 =
H, Me, or Ph) are oxidized to the corresponding S-oxides (205; X = SO) by
rn-chloroperoxybenzoic the latter yield stable 0-methyldithiolium
salts on treatment with triethyloxonium f l u ~ r o b o r a t e . ~ ~ ~
'Ph
(202 1
267 T. Takeda, S. Yasuhara, and S. Watanabe, Nippon Kagaku Kaishi, 1981, 466 ( C h e m
Abstr., 1981, 95, 62 040).
268 C. Meister and H. D. Scharf, Synthesis, 1981,733 ( C h e m Abstr., 1981, 95, 219 922).
269 V. V. Mezheritskii, L. G. Minyaeva, L. V. Mezheritskaya, A. L Pikus, and G. N.
Dorofenko, Zh. O q . Khim., 1981, 17,2225 (Chem. Abstr., 1982, 96, 68865).
270 C. M. Dicken and P. DeShong, J. Org. Chem., 1982, 47, 2047 (Chem Abstr., 1982,
96, 199 565).
271 V. I. Boev, Zh. Org. Khim., 1981, 17, 1340 (Chem. Abstr., 1981, 95, 203800).
2 7 2 J, M. Catel and Y. Mollier, Bull. SOC. Chim. Fr., Part 2, 1981, 113.
273 M. Barreau and C. Cotrel, Tetrahedron Lett., 1981, 22, 4507.
274 H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1729.
2 7 5 M. G. Linkova, 0. V. Kuldisheva, and I. L, Knunyants, Izv. Akad. Nauk SSSR, Ser.
Khim., 1981, 1633.
276 H. Behringer and E. Meinetsberger, Phosphorus Sulfur, 1981, 12, 1 1 5.
2 7 7 M. A. Perez and G. Kresze, Liebigs Ann. Chem., 1981, 1510.
278 M. A. Perez and G. Kresze, Liebigs Ann. Chem., 1981, 1505.
Perfluorobut-2-ene reacts with potassium fluoride and sulphur to give the
1,3-dithiole (206).279 The preparation of the stable dithiole derivative (207)
has been described.2m Electrophiles attack the benzylidenedithiole (208;
R = H) at C-6 to yield compounds (208; R = Br, NO, or N2Ph).281
l,k
MeOOC
2' F5 But Me0OC<-,
(206)
C2F5
- Ph
(207) (208)
The allylsulphonium salt (209) is recommended as a synthetic equivalent
of the unstable ally1 trifluorome thanesulphonate.282 Treatment of methyl
diazoacetate with an excess of thiobenzophenone yields a mixt+llr_e_of the
dithioles (2 10) and (2 11) by way of the thiocarbonyl ylide Ph2C=S-CHC02-
Me.283 The resistivities and magnetic susceptibilities of the radical-anion salts
(212; R1,R2= H, Me, or Ph; n = 1 or 2) have been measured.284 The meso-
ionic 1,3-dithiolium 4-oxide (2 13) forms the intramolecular cyclo-adduct
(2 14).285
gkg~~
Ph
L.+LOOEt
I
CH2CH =CH2
(2091
Ph
(210)
COOMeM e i < T A P .
(211)
h
NC
rA
R1
R2 ;Me
(212)
- NC
219
D. J . Burton and Y. Inouye, Chern. Lett., 1982,201.
280 K. Takahashi, K. Takase, and Y. Noda, Chern. Lett., 1981,805.
281 M. V. Iakshmikantham and M. P. Cava, J. 0%.Chem., 1981, 46, 3246.
282 E. Vedejs and J. Eustache, J. Org.Chem., 1981, 46, 3353.
I. Kalwinsch and R Huisgen, Tetrahedron Lett., 1981,22, 3941.
284 F. Kato and T. Tanaka, Bull Chem SOC.Jpn., 1981,54, 1237.
285 H. H. Gotthardt and M. Otmar, Liebigs Ann. Chem., 1981,347.
The bicyclic dithiolan (215; R = H) yields a stabilized lithium salt, which
reacts with a range of electrophiles to yield the derivatives (2 15 ;R = D, Me,
allyl, Me& etc.).286Treatment of the ethanedithiol derivative (2 16) with
butyl-lithium generates the salt -S2CSCH2CH2SCSi 2Li+.287 Free-radical
addition of 1,3-dithiolan to hex-1-ene to yield 2-n-hexyl-l,3-dithiolan occurs
under the influence of t-butyl hydroperoxide.288 2-Ethoxy-1,3-dithiolan
reacts with a variety of ketones R'R2C0 under the influence of mercury(I1)
chloride to give the dithiolans (217; R', R2 = Me, Pr, or Ar).289
1,3-Benzodithiolium perchlorate (218; R = H, X = C104) is highly

explosive.290 Its 2-methylthio-derivative (218; R = MeS) condenses with 1 -
ethylaminonaphthalene to give the stable quinone-methide imine (2 19):"
Lithium trialkyl(alkyny1)borates Li' R13BC-CR2 (R', R2 = n-C5HI1 or
n-C,H13) react stereoselectively with the salt (218; R = H, X = BF4) to
produce vinylboranes (220) in high cis :trans ratios, which on hydrolysis and
286 R. Okazaki, M. Ooka, T. Akiyama, and N. Inamoto, Heterocycles, 1982, 18 (Spec.

Issue), p. 241.
"'S. Tanimoto, T. Oida, K. Hatanaka, and T. Sugimoto, Tetrahedron Lett., 1981,
2 2 , 655.
288 N. A, Batyrbaev, V. V. Zorin, S. S. Zlotsklia, and D. L. Rakhmankulov, Zh. Org.
Khim., 1981, 17, 1934.
289
(a) S. Jo, S. Tanimoto, T. Oida, and M. Okano, BuZL Chem SOC.Jpn., 1981, 54,
1434;( b ) ibid., p. 3237.
290 k Pelter, Tetrahedron Lett., 1981,22, i (Chem Abstr., 1981,95,97 643).
291 J. Nakayama, N. Matsumaru, and M. Hoshino, J. Chem Soc., Chem Commun.,
1981, 565.
FiveMembered Rings: Other systems 233
deprotec t ion yield olp-unsat ura t ed aldehydes stereospecifically .292 The first
isolable o-thioquinone methide, compound (222$, has been obtained by
irradiating a mixture of cyclohexene and the naphthodithiolethione (22 1).293
5-Methyl-1,3-benzodithioliumperchlorate (218; R = H, X = C10,; 5-Me)
condenses with 2-hydroxy-l,6-methano[ 101annulene to yield the stable
quinone methide (223).294
@\
S
S
I
Methyl phenylpro iolate reacts with the selenolate PhC-CSe- K' to give
the diselenole (224)!g5 The action of trifluoroacetic acid on the tellurium
analogue PhC-CTe- Na' results in a mixture of (E)- and (2)-ditellurafulvenes
(225).296 The bis(ditel1uro)tetracene (226) has been prepared by treatment
of the corresponding tetrachlorotetracene with sodium telluride.*"
Te- Te
1 I
Te- Te
z9' k Pelter, P. Rupani, and P. Stewart, J. Chem Soc., Chem. Commun., 1981, 164.
293 R Okazaki, K. Sunagawa, M. Kotera, K. T. Kang, and N. Inamoto, Bull. Chem SOC.
Jpn., 1982, 55, 243.
294 R. Neidlein and H. Zeiner, Angew. Chem., Int. Ed, Engl., 1981, 2 0 , 1032.
295 M. L. Petrov, V. Z. Laishev, and A. k Petrov, Zh. Org. Khim., 1981, 17, 667.
296 M. V. Lakshmikantham, M. P. Cava, M. Albeck, L. Engman, F. Wudl, and E. Aharon-
Shalom, J. Chem. Soc., Chem. Commun., 1981, 829.
297 D. J. Sandman, J. C. Stark, and B. M. Foxman, Organometallics (Washington, D.C.),
1982, 1,739 (Chem. Abstr., 1982, 96, 181 218).
For other work on dithioles, see references 298-307.
Tetrathiafulvalenes and Related Compounds. - Thermolysis of the 1,1',2,2'-
tetrathiafulvalenes (227; R' ,R2= H, Me, or Ph) furnishes thienothiophens
(22 8).308 Dimethy1 acetylene dicarb oxylate reacts with carbon diselenide at
5000 atmospheres to yield the tetraselenafulvalene (229).=' The synthesis of
symmetrically substituted tetrathiafulvalenes with long alkyl chains, e.g.
compound (230; R = C17H35), by standard methods has been de~cribed.~"
R1 R1
( 2 2 9 ) E = COOMe
(230 )
The bis-dithiolan (23 l), obtained from ethane-l,2-dithiol and 2,5-dihydro-
2,5-dimethoxyfuran, forms a 1 : 1 ion-radical salt with tetracyanotetrafluoro-
(231)
298 T. P. Vasileva, V. M. Bystrova, M. G. finkova, 0. V. Kildisheva, and I. L. Knunyants,
Izv. Akad NaukSSSR, Ser. Khim., 1981,1850 (Chem. Abstr., 1981,95,219867).
299 K. Gewald and H. Shaefer, J. Prakt. Chem., 1981, 323, 135 (Chem. Abstr., 1981,
95,80 778).
300 M. L. Petrov, V. A. Bobylev, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 1772
(Chem Abstr., 1981,95,186275).
301 I. M. Gella, V. N. Vakula, and V. D. Orlov, K h i m GeterotsikL Soedin., 1981, 1245
(Chem. Abstr., 1981,95,220001).
302 F. k Carey, 0. D. Dailey, Jr., and T. E. Fromuth, Phosphorus Sulfur, 1981, 10,
163 (Chem Abstr., 1981,95,203798).
303 K. Hatanaka, S. Tanimoto, P. Sugimoto, and M. Okano, Tetrahedron Lett., 1981,
2 2 , 3243 (Chem. Abstr., 1982,96, 19 617).
304 F. A. Carey and 0. D. Dailey, Jr., Phosphoms Sulfur, 1981, 10, 169 (Chem. Abstr.,
1982,96,35 143).
305 V. N. Elokhina, A. S. Nakhmanovich, R V. Karnaukhova, I. D. Kalikhman, and M.
G. Voronkov, Khim. GeterotsikL Soedin., 1981, 329 (Chem. Abstr., 1981, 95,
42 963).
306 I. Degani, R. Fochi, and V. Regondi, Tetrahedron Lett., 1981, 22, 1821 (Chem
Abstr., 1981,95, 114967).
jo7K . Fuji, M. Ueda, K. Sumi, and E. Fujita, Synth. Commun., 1981, 11, 209 (Chem
Abstr., 1981,95,62 039).
jo8H .Behringer and E. Meinetsberger, Liebips Ann. Chem., 1981,1928.
309 (a) Y. Okamoto and P. S . Wojciechowski, J. Chem. Soc., Chem Commun., 1981,
669; ( b ) J. E. Rice, P. S. Wojciechowski, and Y. Okamoto, Heterocycles, 1982, 18
(Spec. Issue), p. 191.
J. Kreicberga, D. Bite, V. A. Kampars, R. Kampare, and 0. Neilands, Zh. Oq. Khim.,
1981, 17, 1055.
quinodime thane .311 ‘Elect rocryst allizat ion’ of a mixture of tetra thiafulvalene
(X), tetraethylammonium bromide, and tetraethylammonium iodide gives
the mixed halide adducts XBr0.2310.46 and XBr0.4710.24.312 The tetracyclic
compound (233) is produced by the action of triethyl phosphite on the dione
(232).313 Treatment of tetracyanotetrathiafulvalene (230; R = CN) with salts
of 4-methylbenzene-l,2-dithioleresults in a mixture of the benzodithiin
(234) and the salts of (235).314 The phosphorane (236) reacts with carbon
disulphide to give, inter alia, dibenzotetrathiafulvalene (237).315 The
divinylogous tetrathiafulvalene (238) has been prepared.316
311 D. J. Sandman, G. D. Zoski, W. k Burke, G. P. Hamill, G. P. Ceasar, and A. D.

Baker, J. Chem SOC.,Chem. Commun., 1981,829.
312 P. A. C. Gane, P. Kathirgamanathan, and D. R. Rosseinsky, J. Chem. SOC.,Chem.
Commun., 198 1,378.
313
E. M. Engler, N. Martinez-Rivera, and R. R. Schumaker, Org. Coat. PZust. Chem.,
1979,41, 52 (Chem. Abstr., 1 9 8 1 , 9 5 , 6 1 153).
314 E. M. Engler, V. V. Patel, and R. R. Schumaker, Tetrahedron Lett., 1981, 2 2 , 2035.
315 J. Nakayama, S. Maruyama, and M. Hoshino, BUZZ. Chern. SOC.Jpn., 1981, 54, 2845.
316 R. Neidlein and H. Zeiner, Arch. Pharm. (Weinheim, Ger.), 1982, 315, 90.
Deselenation of compound (239) with triethyl phosphite yields the syn-
tetraselenafulvalene (240), together with the anti-i~omer.~"A five-step
synthesis of the tetratellurafulvalene (241) has been d e ~ c r i b e d . ~ ' ~
Pyrazoles. - Formation. A mixture of the pyrazoles (242) and (243) is

produced by thermolysis of the azines PhCH=CHCH=NN=CMeCH=CHAr?"
The reaction of diazodibenzoylmethane with 1-diethylaminopropyne,
Ph
CH= CHCH 2Ph CMe=CHCH2Ax
Et2NC-CMe, yields the rearranged adduct (244), together with the 1 : 2

adduc t (245). 320 Dimethy1 1,2,4,5- te t razine -3,6-dicarb oxyla te and benzyl
E t 2N Me Et 2N p iBz
BZ N" Me "N
I
( B z = PhCO) Me
(245
317 E. Fanghanel, G. Schukat, and J. Schutzendubel, 2.Chem., 1981,2 1,447.

318 F. Wudl and E. Aharon-Shalom, J. Am. Chem. SOC.,1982, 104, 1154.
319 E, E. Schweizer and S. N. HiTwe, J. Org. Chem., 1982,47, 1652.
320
R. Huisgen, M. P. B. Verderol, A. Gieren, and V. Lamm, Angew. Chem., Int. Ed.
Engl., 1981,2 0 , 694.
isocyanide form the pyrazole (246) in a [4 + 11 cycloaddition reaction.321

The action of hydrazine on the allenic nitrile MeEtC=C=CHCN leads t o the
aminopyrazole (247).322
PhHC=N rLCOOMe
MeOOC
’N
H H
(246) (247 1
The azo-compound (248) rearranges thermally t o the pyrazole (249).323

The 1-pyrazoline (250) is formed from the thioketen S-oxide ButPfC=C=SO
and 2 - d i a ~ o p r o p a n e .The
~ ~ ~ally1 chloride H2C=C(COPh)CH2C1 reacts with
1,l -dimethylhydrazine to yield the pyrazolidine derivative (25 l).325
Numerous betaines (252; R’ ,R2,R3 = H or Me) have been prepared by the
action of aromatic aldehydes on the appropriate p y r a z ~ l i d i n o n e s .Treat-
~~~
ment of diethyl acetylmalonate with 1,l -dimethylhydrazine affords the
amine-imide (253) .327
EtOOC
0 N’
Me2
CHAr
(253)
Antipyrine (254; R = H) reacts with fluorine-18 in acetic acid under

nitrogen to yield the fluoro-derivative (254; R = F) in a radiochemical yield
0 ’N
Ph
(254 1
321 P. Imming, R. Mohr, E. Muller, W. Overheu, and G. Seitz, Angew. Chem., Int, Ed.
Engl., 1 9 8 2 , 21, 284.
322 Z. T. Fomum, S. R. Landor, P. D. Landor, and G. W. P. Mpango, J. Chem. SOC.,
323 P. S. Engel, and D. B. Gerth, J. A m . Chem. SOC.,1981, 103, 7689.
324 E. Schaumann, H. Behr, G. Adiwidjaja, A. Tangerman, B. H. M. Lammerink, and
B. Zwanenburg, Tetrahedron, 1981, 37, 217.
325 R. Gompper and B. Kohl, Angew. Chem., Int. Ed. Engl., 1 9 8 2 , 2 1, 199.
326 G. Geissler, K. Angermuller, I. Behning, S. Fuerneisen, W. Fust, M. Hippius, B.
Muller, G . Schauer, H. Slezak, and G . Tomaschewski, 2. Chem., 1981, 2 1 , 3 5 6 .
321
M . Poje and N. Bregant, Tetrahedron Lett., 1980, 21, 5 0 5 9 .
of 13.7771.~~~ The synthesis of iodo[ 'lC] antipyrine for positron emission
tomography has been reported.329 Treatment of the phenylhydrazone Me2C=
CHCH2CH2CHMeCH2CH=NNHPhwith sulphuric acid and acetic acid results
in an intramolecular [3' + 21 cationic cycloaddition to yield the octahydro-
indazole (2 5 5). 330
Reactions of Pyrazoles. N-Nitropyrazoles nitrate aromatic compounds under

Lewis acid conditions.331 Pyrazole as a nucleophile undergoes two successive
cine-substitutions with 1,4-dinitropyrazole, yielding the terpyrazolyl
(256).332Irradiation of the deuterium-labelled cyanopyrazole (257) affords
a mixture of the isomeric imidazoles shown in Scheme 5.333
Scheme 5
The diazidopyrazolinone (258) is converted into the triazolecarboxylic

acid (259) under the influence of sodium h y d r ~ x i d e A
. ~ mixture
~ of [1,3]
328 C. Y. Shiue and A. P. Wolf, J. Labelled Compd. Radiopharm., 1 9 8 1 , 18, 1059.

329
J . A. Campbell, R. D. Finn, T. E. Boothe, B. Djerinouni, M. D. Ginsberg, A. H.
Lockwood, A. J . Gilson, and H. J . Ache, J. Nucl. Med., 1 9 8 1 , 22, 538 (Chem. Abstr.,
1981, 95, 132 796).
330 B. Fouchet, M. Joucla, and J . Mamelin, Tetrahedron Lett., 1981, 2 2 , 1 3 3 3 .
331
G. A. Olah, S. C. Narang, and A. P. Fung, J. Org. Chem., 1 9 8 1 , 4 6 , 2 7 0 6 .
332 R. P. M. Berbee and C. L. Habraken, J. Heterocycl. Chem., 1 9 8 1 , 18, 559.
333 J. A. Barltrop, A. C. Day, A. G. Mack, A. Shahrisa, and S. Wakamatsu, J. Chem.
Soc., Chem. Commun., 1 9 8 1 , 6 0 4 .
334 G. Weber, G. Mann, H. Wilde, and S. Hauptmann, 2. Chem., 1980, 2 0 , 4 3 7 .
rearrangement products (261) and (262) is produced by irradiation of the
pyrazolinone (260),335 while the tetramethyl analogue (263) undergoes
rearrangement and r i n g - ~ p e n i n g . ~ ~ ~
The diazopyrazole (264) reacts with electron-rich olefins to yield

rearranged cyclo-adducts; thus Me2C=CHNEt2 affords compound (265).337
The 1,3-dipolar cyclo-adduct (266), formed from 9-diazofluorene and
dimethyl acetylenedicarboxylate, readily loses nitrogen; the resulting spiro-
cyclopropene (267) rearranges to the cyclopentafluorene (268) on
Me Me
"Yke
P h p " a . P h p " "
9-v
(2//N
N6 4 ) NEt2
(265)
-
E
N E
( E = COOMe) E'
(268)
335 G. Singh, D. Singh, and R. N. Ram, Tetrahedron Lett., 1 9 8 1 , 2 2 , 2 2 1 3 .
336 H. Cardy and E. Poquet, Tetrahedron, 1981, 37, 2279.
337 A. Padwa and T. Kumagai, Tetrahedron Lett., 1981, 22, 1199.
heating3% A [2,3] sigmatropic shift in the ammonium imide (269) leads
to the tetrahydropyridine (270).339 The hydroperoxide (27 1) oxidizes
tertiary amines to amine oxides, and sulphides to sulphoxides.MO
Me
OOH
Bi
(271)
(270)
Other papers on the formation341-344 and reaction^^^-^'^ of pyrazoles

have appeared.
Indazoles. - The photochemical amination of nitro-indazoles has been
reported; thus 1 -methyl-4-nitroindazole yields the 3-amino-derivative
(272).352 10-Diazoanthrone adds 4-methylbenzyne to form a mixture of the
N02
Me
338
W. Burgert, M. Grosse, and D. Rewicki, Chem. Eer., 1982, 115, 309.
339 K. Burger, 0. Dengler, and D. Hubl, J. Fluorine Chem., 1982, 19, 589.
340 A. L. Baumstark and D. R. Crisope, Tetrahedron Lett., 1981, 22,4591.
341 M. Bin Mohamed and J. Parrick, Org. Prep. Proced. Int., 1981, 13, 371 (Chem.
Abstr., 1982,96,6645).
342 H. Schaefer and K. Gewald, J. Prukt. Chem., 1981, 323, 332 (Chem. Abstr., 1981,
95, 115 376).
343 K. Oida, Bull. Chem. SOC.Jpn., 1981,54, 1429 (Chem. Abstr., 1981,95,87661).
344 S. Kitane, T. Kabula, J. Vebrel, and B. Laude, Tetruhedron Lett., 1981, 22, 1217
(Chem. Abstr., 1981,95, 187 142).
345 S. Sugiura, S. Ohno, and M. Hori, Yukuguku Zusshi, 1981, 101,27 (Chem. Abstr.,
1981,95,62064).
346 M. V. Gorelik, S. P. Titova, and V. I. Rybinov, Zh. Org. Khim., 1981, 17, 1124
(Chem. Abstr., 1981,95,132741).
3 4 7 G. Adembri, A. Camparini, F. Ponticelli, and P. Tedeschi, J. Heterocycl. Chem.,
1981, 18,957(Chem. Abstr., 1982,96,6644).
348 K. Burger, F. Hein, 0. Dengler, and J. Elguero, J. Fluorine Chem., 1982, 19, 437
(Chem. Abstr., 1982,96,181 191).
349 D. Zeigan, E. Kleinpeter, H. Wilde, and G. Mann, J. Prukt. Chem., 1981, 323, 188
(Chem. Abstr., 1981,95,79442).
350 P. L. Anelli and P. D. Croce, Guzz. Chim. Itul., 1981, 111, 269 (Chem. Abstr., 1982,
96, 52 224).
351 L. L. Rodina, N. V. Barmenkova, and I. K. Korobitsyna, Zh. Org. Khim., 1981,
17,1899 (Chem. Abstr., 1982,96,35155).
3 5 2 P. Bouchet, R. Lazaro, M. Benchidmi, and J. Elguero, Tetrahedron, 1980, 36, 3523.
3H-indazoles (273) and (274); thermolysis of either yields both the 3- and 4-
methyl derivatives of the phenol (276) by way of the spiro-intermediate
(275).353 The benz[cd] indazolone (278) is formed when the azide (277)
is heated or p h o t o l y ~ e d . ~ ~
0 0
II OH
( 2 7 3 ) 3-Me 3 4
Me
( 2 7 4 ) 4-Me
(276)
Imidazples. - +Formation. Treatment of the dipiperidinium salt

C5HIoN=CHCH=NC5H,o 2Br- with N-arylbenzamidines affords mixtures of
the imidazolines (279) and (280).355Compound (281) is one of the products
of the complex photolysis of the imine PhCOCPh=NCHzPh.356 The oxime

PhC(CH2NHAr)=NOH (Ar = p-MeC,H,) condenses with phenylglyoxal to
353
K. Hirakawa, Y. Minami, and S. Hayashi, J. Chem. Soc., Perkin Trans. I , 1982, 577.
3 54
P. C. Montevecchi and P. Spagnolo, J. Org. Chem., 1982,47, 1996.
355 M. L. Mahati, R. Stradi, and E. Rivera, J. Heterocycl. Chem., 1981, 18, 921.
356 G. Prasad, B. P. Giri, and K. N. Mehrotra, J. Org. Chem., 1982, 47, 2 3 5 3 .
yield the irnidazoline N-oxide (282).357 Further studies by Butler on the
formation of imidazolones from ureas have appeared; thus urea and 1,2-
diaminoethane form imidazolidin-2-one (284) via the isocyanate (283).358
The Schiff base PhCH=NCHPh2 dimerizes to the imidazolidine (285) on
irradiation .359
N
II
rLo :x,..::
H CH2Ph
Reactions of Imidazoles. Thermolysis of 1-triphenylmethylimidazoleresults

in migration of the imidazolyl group to yield compound (286).360 Sensitized
photo-oxygenation of 4,5-diphenylimidazole in methanol affords a mixture
of the imidazolinone (287) and the imidazolidinone (288).361 The imidazole
(289; R = H) undergoes lithiation at C-5; subsequent treatment with diphenyl
disulphide gives the di(pheny1thio)-derivative (289 ; R = PhS).362 Co-
pyrolysis of 2,4-dime thylimidazole and chloroform results in a complex
mixture, containing imidazole and methyl-, dimethyl-, and chloromethyl-
~ ~ ~confusion about the structures of N-
pyrimidines and - p y r a ~ i n e s .The
methyl derivatives of iodo-nitro-imidazoles has been cleared up: the supposed
l-methyl-2,5-di-iodoimidazole is actually the 4,5-di-iodo-compound; it yields
4-iodo-1-methyl-5-nitroimidazole on nitration.= The reaction of the bromo-
Ph H
phk--,o
Me0 R o N S P h
357 H. Gnichtel and B. Moeller, Chem. Ber., 1981,114,3176.

”* A. R. Butler and I. Hussain, J. Chem. SOC.,Perkin Trans. 2, 1981,21 7.
3 5 9 B. P. Giri and K. N. Mehrotra, Indian J. Chem., Sect. B , 1981,2 0 , 806.
360 I. Saji, K. Tamoto, H. Yamazaki, and H.Agui, Heterocycles, 1981, 15, 943.
361 H. H. Wasserman, M. S. Wolff, K. Stiller, I. Saito, and J. E. Pickett, Tetrahedron,
Suppl., 1981,191.
B. Iddon and B. L. Lim, J. Chem. SOC.,Chem. Commun., 1981,1095.
363 M. A. Khan, J. Pharm. (Lahore), 1980,2 , 81 (Chem. Abstr., 1981,95,132 753).
364 J. P. Dickens, R. L. Dyer, B. J. Hamill, T. A. Harrow, R. H. Bible, Jr., P. M. Finnegan,
K. Henrick, and P. G. Owston, J. Org. Chem., 1981,46, 1781.
cyclohexadienone (290; R = Br) with imidazole affords the substitution
product (290; R = imidazol-1-yl), together with the two phenols (291 ;
R = imidazol-1-yl) and (29 1; R = But) and 2,6-di-t-butyl-l,4-benzo-
q ~ i n o n e .The
~~~diazafulvene (293) is obtained by the action of benzyl-
magnesium iodide on the 4H-imidazole (292).366
0
Photo-substitution of benzene by the imidazolinone (294; R = Cl) yields

the diphenyl compound (294; R = Ph).367 NN'-Diacetylimidazolin-2-one
gives the Diels-Alder adduct (295) with cyclopentadiene, and the photo-
adduct (296) with ethylene.368*369Treatment of NN'-dimethylimidazoline-2-
thione with bromine and toluene-p-sulphonamide leads to the thione-S-
imide (297).370 The thione-thiol tautomerism of the nitroxides (298)+(299)
has been studied by e.s.r. spectro~copy.~~'
Et
(294)
365 G. Fukata, T. Itoh, and M. Tashiro, Heterocycles, 1 9 8 1 , 16, 549.

366 R. Gompper, M. Junius, and H. U. Wagner, Tetrahedron Lett., 1981, 22, 2973.
367 H. Wamhoff, W. Kleimann, G. Kunz, and C. H. Theis, Angew. Chem., Int. Ed. Engl.,
1 9 8 1 , 20, 612.
368 R. A. Whitney, Tetrahedron Lett., 1 9 8 1 , 22, 2 0 6 3 .
369 K. H. Scholz, J. Him,H. G. Heine, and W. Hartmann, Liebigs Ann. Chem., 1 9 8 1 ,
248.
370 A. Koide, T. Saito, M. Kawasaki, and S. Motoki, Synthesis, 1 9 8 1 , 4 8 6 .
3 7 1 R . Darcy, J. Chem. SOC.,Perkin Trans. 2 , 1 9 8 1 , 1 0 8 9 .
Attention is drawn to other papers on the f ~ r m a t i o n ~ ~and
- ~ ’re-
~
actions380-389of imidazoles.
Benzimidazoles and an Imidazoquinoline. - Aryl sulphimides p-RC6H4NSMe2
(R = C1, Br, or NO2) react with nitrile oxides ArCNO to yield mixtures of
benzimidazole N-oxides (300) and 1,2,4-benzoxadiazines (301).390 The
betaine (302) results from the action of Chloramine T on benzimidazoline-2-
t h i ~ n e N-Phenylcarbimide
.~~~ dichloride, PhN=CC12, reacts with the amidine
I
0-
( 300)
372 A. C. Veronese, G. Cavicchioni, G. Servadio, and G. Vechiati, J. Heterocycl. Chem.,

1980, 17,1723 (Chem. Abstr., 1981,95,7142).
373 A. R. Butler and I. Hussain,J. Chem. SOC.,Perkin Trans. 2, 1981, 310 (Chem. Abstr.,
1981, 9 5 , 6 2 072).
374 G. M. Devasia and P. M. Shafi, Indian J. Chem., Sect. B , 1981, 20, 657 (Chem.
Abstr., 1981, 95, 220 009).
3 7 5 J. R. Pfister, W. Kurz, a n d T. T. Harrison, J. Heterocycl. Chem., 1981, 18, 831
(Chem. Abstr., 1981,95,132 755).
376 G. Neef, U. Eder, a nd G. Sauer, J. Org. Chem., 1981, 46, 2824 (Chem. Abstr., 1981,
95,42 992).
377 J. Moskal, J. Bronowski, and A. Rogowski, Monatsh. Chem., 1981, 1 1 2 , 1405 (Chem.
Abstr., 1982, 96, 84 852).
378 P. Reynaud, J. D. Brion, and C. Davrinche, J. Heterocycl. Chem., 1980, 17, 1789
(Chem. Abstr., 1982,96, 20 026).
3 7 9 W. Wendelin, W. Kern, I. Zmoelnig, and H. W. Schramm, Monatsh. Chem., 1981,
112, 1091 (Chem. Abstr., 1981, 95, 220008).
380 C. Kashima, M. Shimizu, a n d T. Tajima, Heterocycles, 1981, 15, 961 (Chem. Abstr.,
1981, 95,42 989).
381
P. Goldman and J . D. Wuest, J. A m . Chem. SOC.,1981, 103, 6224 (Chem. Abstr.,
1981,95,132 752).
382 R. Pellicciari, M. Curini, N. Spagnoli, a n d P. Ceccherelli, Synthesis, 1981, 629 (Chem.
Abstr., 1981, 95, 187 147).
383 R. F. Pratt and K. K. Kraus, Tetrahedron Lett., 1981, 22, 2431 (Chem. Abstr., 1981,
95, 169 114).
384 M. W. Anderson, R. C. F. Jones, and J. Saunder, Tetrahedron Lett., 1981, 22, 261
(Chem. Abstr., 1981, 95, 7145).
3 8 5 H. Gnichtel and M. Ekier, Liebigs Ann. Chem., 1981, 312 (Chem. Abstr., 1981, 95,
71 50).
386 G. I. Shchukin, I. A. Grigorev, and C. B. Volodarskii, Izv. Akad. Nauk SSSR Ser.
Khim., 1981,1581 (Chem. Abstr., 1981,95, 187 150).
387 M. Yokoyama, K. Hosi, a n d T. Inamoto, Synthesis, 1981, 908 (Chem. Abstr., 1982,
96, 51 786).
3 8 8 V. T. Balzaretti, A. R. Suarez, a n d 0. R. Orio, A n . Asoc. Quim. Argent., 1980,
68, 163 (Chem. Abstr., 1981, 95, 23 775).
jsp J. Hocker and H. Giesecke, Org. Synth., 1981, 60, 49 (Chem. Abstr., 1982, 96,
51 932).
S. Shiraishi, T. Shigemoto, S. Katsuta, a n d S. Ogawa, Nippon Kagaku Kaishi, 198 1,
989 (Chem. Abstr., 1981,95, 169 144).
391 R. J. S. Beer, A. Naylor, a n d D. Wright, Acta Chem. Scand., Ser. A , 1981, 35, 25,
PhN(OH)CH=NBut to yield the benzimidazolidinone (303).392The cyclo-
butenedione derivative (305) is formed from o-phenylenediamine and the
is0 thiocyanate (304). 393
scNao
t
CH= NBu
Ph 0
A potent mutagen, isolated from broiled sardines, has been identified as

the imidazo [4,5-f] quinoline (306).3"
N-
Il N H 2
5 Systems containing Two Different Heteroatoms

Oxathioles and Selenathioles. - The formation of 1,2-0xathiolan (308) by
pyrolysis of the phthalimido-derivative (307) has been reported.395 The
0
3 92
H. G. Schrecker and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 289.
393 w. fied and H. Dietschmann, Liebigs Ann. Chem., 1981, 1003.
394 H. Kasai, 2. Yamaizumi, S. Nishimura, K. Wakabayashi, M. Nagao, T. Sugimura,
N. E. Spingarn, J. H. Weisburger, S. Yokoyama, and T. Miyazawa, J. Chem. Soc.,
Perkin Trans. 1 , 1981, 2290.
395 A. P. Davis and G. H. Whitham, J. Chem. Soc., Chem. Commun., 1981,741.
dynamic equilibrium of the sulphurans (309)-\310) (R = C02H, CO,Et,
or Ac) has been i n ~ e s t i g a t e d . ~A
’ ~ mixture of cis- and trans-persulphurans
gD
(312) is produced by the action of bromine trifluoride on the spiro-sulphuran
(3 1 11.397
But
Me t t
Bu Bu
Me \
HOMe C
(309)
F3C CF3
&LF
F7P
0
F3C- CF3
(312)
The 1,3-0xathioles (3 13) and (3 15) equilibrate by way of the thiocarbonyl

ylide (314).398 The action of potassium t-butoxide on the chloromethyl
COPh
(313) (314)
396 W. Y. Lam and J. C. Martin, J. Org. Chem., 1981,46,4468.

397 R. S. Michalakand J . C. Martin, J . Am. Chem. SOC., 1982, 104,1683.
398 K. Oka, A. Dobashi, and S. Hara, J. A m . Chem. Soc., 1981, 103,2757.
compound (3 16) leads to the rearranged oxathiole (3 1 ' 3 , which undergoes

an acid-catalysed ring-opening to give acetonyl vinyl sulphide, MeCOCH2-
SCH=CH2.399 Treatment of dimedone with the sulphur di-imide PhS02N=
0
C1H2C K.. Me - H 3 c c A Me : : h y , . , . h T e Me
(316 1 (317) (318)
S=NS02Ph affords the spiro-oxathiole (3 18).4"0 A general synthesis of 1,3-

oxathiole-2-imines is exemplified in Scheme 6.401
MeCHC 1 S (i) NaOMe [-HC1]
(ii) heat [-MeOH] * M

Mee a , A N C O P h
MeACNO I + II
Me0"hHCOPh
Scheme 6
The 1,3-benzoxathiole (3 19) is lithiated at position 7.402 Pyrolysis of the

benzoxathiolone (320) at 780°C yielded cyclopentadienethione (32 l),
whose photoelectron spectrum was r e ~ o r d e d . ~ @ ~
Successive treatment of the selenide (322) with 1,l '-carbonyldi-imidazole

and t-butyl hydroperoxide affords the benzoxaselenolone (323).w4*405
399 J . Mattay and H. D. Scharf, Tetrahedron Lett., 1982, 23,47.

400 E. S. Levchenko, S. N. Gaidamaka, V. N. Kalinin, and L. V. Budnik, Zh. Org. Khim.,
1981,17,990.
401 M. Kulka, Can. J. Chem., 1981,59, 1557.
402 A. M. Bernard, S. Cabiddu, P. P. Piras, and F. Sotgiu, J. Heterocycl. Chem., 1981,
18,639.
403 R . Schulz and A. Schweig, Angew. Chem., Int. Ed. Engl., 1981,20, 571.
404
W. Nakanishi, S. Murata, Y. Ikeda, T. Sugawara, Y. Kawada, and H. Iwamura, Tetru-
hedron Lett., 1981, 22,4241.
405 W.Nakanishi, Y. Ikeda, and H. Iwamura, J. Org. Chem., 1982,47,2275.
Isoxazoles. - Formation. The combined action of copper(I1) nitrate and
acetic anhydride on 1,2-diphenylcyclopropaneleads to a mixture of 3 3 -
diphenylisoxazole and its 4-nitro-derivati~e.~~ Dimethyl azidomaleate
affords the azirine (324) on heating, whereas the azidofumaric ester yields
the isoxazole (325).407 5 -Amino-4-ethy1thio-3-methylisoxazole (326) is
produced from the acrylonitrile derivative MeCBr=C(SEt)CN and hydroxyl-
amine .408
(324) ( 325)
( E = COOMe) (326)
The action of hydroxylamine on the dibromo-ketone (327) unexpectedly

resulted in the isoxazoline (328).409 The spiro-isoxazoline (330) is formed
by anodic oxidation of the phenolic oxime (329).410 Three novel reactioy
leading to isoxazolines have been reported: the nitrone PhCH=CHCPh=N-
(CH2SMe)-O- undergoes 1,5-dipolar cyclization and elimination on heating,
to yield compound (33 1),4ii silylation of secondary nitro-alkanes gives
silyl-nitronates, which, in the presence of triethylamine, undergo 1,3-cyclo-
addition to olefins; thus sequential treatment of Me2CHN02 with trimethyl-
406 L. D. Sychkova, 0. L. Kalinkina, and Yu. D. Shabarov, Zh. Org. Khim., 1981, 17,
1435.
407 G. L’Abbb, J . P. Dekerk, and P. Van Stappen, Bull. SOC. Chim. Belg., 1981, 90,
1073.
408 F. Pochat, Tetrahedron Lett., 1980,21, 3755.
409 C. J. Rao, K. M. Reddy, and A. Murthy, Indian J. Chem., Sect. B , 1981,20,282.
410 H.Noda, M. Niwa, and S. Yamamura, Tetrahedron Lett., 1981,22, 3247.
411 Ngan Sim Ooi and D. A. Wilson, J. Chem. Res. ( S ) , 1980,394.
silyl chloride, triethylamine, and methyl propiolate yields the isoxazoline
(332) via the nitrone Me2C=N(OSiMe3)--0-,412and acetylation of the sodium
salt of nitroetpane, followed by elimination of acetic acid, affords the nitrile
oxide MeC-N+-, which adds dimethyl fumarate to form compound
(333).413 The keten-imine PhCOCPh=C=NPh reacts with N-phenylhydroxyl-
amine to yield the isoxazole-imine (334), which spontaneously rearranges to
the oxazole-imine (335) by way of an intermediate a ~ i r i d i n e . ~ ~ ~
7 6 : : Meooc77,M MeOOC.
( 333) (334) (335)
Reactions of Isoxazoles. The kinetics of the isoxazole -+ azirine rearrange-

ment (336) (337) and those of the isoxazole oxazole transformation
-+ -+
(338) +. (339) have been determined:l’ Palladium(I1) chloride-triphenyl-

phosphine catalyses the cross-coupling of 4-iodo-3,5-dimethylisoxazole with
styrene to yield the trans- compound (340).416 3,5-Dimethylisoxazole can be
lithiated in two stages, first at the 5-methyl group and then at the 3-methyl
Isoxazoles add hypochlorous acid to form 4-chloro-2,3-dihydro-
5-hydroxyisoxazoles.418
412 S. K. Mukerji and K. B. G. Torssell, Acta Chern. Scand., Ser. B , 1981, 35, 643.
413 K. Harada, E. Kaji, and S. Zen, Chem. Pharm. Bull., 1980,28, 3296.
414 F. DeSarlo, A. Guarna, P. Mascagni, R. Carrie, and P. Guenot, J. Chem. SOC.,Perkin
Trans. I , 1981,1367.
415 J . D. Perez, R. G. De Diaz, and G. I. Yranzo, J. Org. Chem., 1981,46, 3505.
416 H. Yamanaka, M. Shiraiwa, E. Yamamoto, and T. Sakamoto, Chem. Pharrn. Bull.,
1981,29, 3543.
417 D. J. Brunelle, Tetrahedron Lett., 1981,22, 3699.
418 S. D. Skolov, V. F. Rudchenko, K. F. Turchin, A. P. Pleshkova, A. B. Zolotoi, 0. A.
Dyachenko, L. 0. Atovmyan, and R. G. Kostyanovskii, Dokl. Akad. Nauk SSSR,
1981,258,906.
Photolysis of the isoxazoline (341) gave a mixture of the isomeric
oxazoline (342), the imine PhC(=NH)CH2CH0, and ben~onitrile.~”The
isoxazolines (343; R1 = alkyl, R2 = H or CH20H, R3 = H or OH, R4 =Me
or CH,OH) yield predominantly the 0-amino-alcohols (344) on reduction
with lithium aluminium h ~ d r i d e . ~ Isoxazolinones
~’ (345; R’ , R2 = alkyl,
Ph, or C02Et) are hydroxylated at C-4 by m-chloroperoxybenzoic acid.421
The dimer (346) of C-benzyl-N-methylnitrone is slowly converted into 1-
methyl-3,4-diphenylpyrrole(347) at room temperature.422
R4
Me
( 344) (345) bH (346) (347)
Other articles on the and reaction^^^'-^^^ of isoxazoles

should be noted.
Benzisoxazoles and Other Annelated Isoxazoles. - The sodium-me thoxide-
induced cyclization of the nitro-ketone (348) furnishes 3-phenyl-2,l-
benzisoxazole (349)429 5-Chloro-2,l-benzisoxazole
adds dimethyl acetylenedi-
carboxylate to give the Diels-Alder product (350), while the parent com-
419 T. Kumagai, K. Shimizu, Y. Kawamura, and T. Mukai, Tetrahedron, 1981, 37, 3365.
420 V. Jaeger, W. Schwab, and V. Buss, Angew. Chem., Int. Ed. Engl.. 1981, 20, 601.
421 C. Baldoli, E. M. Beccalli, E. Licandro, and A. Marchesini, Guzz. Chim. Itul., 1981,
111, 347.
422 F. DeSarlo, A. Brandi, and P. Mascagni, Synthesis, 1981, 561.
423 R. F. Cunico, J. Organomet. Chem., 1981, 212, C51 (Chem. Abstr., 1981, 95,
96 645).
424 B. J. Wakefield and D. J. Wright, J. Chem. Res.(S), 1981, 129 (Chem. Abstr., 1981,
95, 1 1 4 994).
425 H. Yamanaka, M. Shiraiwa, T. Sakamoto, and S. Konno, Chem. Pharm. Bull., 1981,
29, 3548 (Chem. Abstr., 1982, 96, 122 673).
426 Z. W. Wicks, Jr. and P. P. Patel, J. Org. Chem., 1981, 4 6 , 4 0 6 8 (Chem. Abstr., 1981,
95, 132 722).
427 V. F. Rudchenko, V. G. Shtamburg, and R. G. Kostyanovskii, Izv. Akad. Nauk SSSR,
Ser. Khim., 1981, 1183 (Chem. Abstr., 1981, 95, 132 719).
428 V. F. Rudchenko, V. G . Shtamburg, A. P. Heshkova, and R. G . Kostyanovskii, Izv.
Akad. NaukSSSR, Ser. Khim., 1981,2549 (Chem. Abstr., 1 9 8 2 , 9 6 , 8 5 4 5 5 ) .
429 M. Jawdosiuk, I. Kmiotek-Skarzynska, and E. Czarnecka, Pol. J. Chem., 1981, 55,
379.
pound does not rea~t.4~'The dipyridinium salt (351) has been de~cribed.4~'
Thermolysis of the anthraisoxazolone (3 52) in isopropylbenzene yields the
insertion product (3 53).432
0-
\ 'I NH
0 0 0 Me2CPh
+
2 C 5H5 NH
(351 1
For other papers, see references 4 3 3 4 3 5 .

Oxazoles. - Formation. Oxazole-carboxylic esters (354) are obtained from
ethyl isocyanoacetate and carboxylic acids RC02H in the presence of
diphenyl phosphorazidate, (PhO),P(0)N3 ?36 A general synthesis of oxazoles
(355; R' ,R2,R3 = alkyl or Ph) is by treatment of oximes R2C(=NOH)CH2R3
with acid chlorides R' COCl!37 Treatment of tosylmethylimines TosCH2N=
CR' R2 (R1 = alkyl or Ph; R2 = C1, MeO, or MeS) with aromatic aldehydes
yields 2,5-disubstituted oxazoles (356);438 the analogous reaction of the
carb odi-imide TosCH2N=C=NCPh3 affords the tritylamino-deriva tive (3 56 ;
R' = Ph3CNH).439 The oxazolium salt (357) is formed by the combined
action of acetic anhydride and perchloric acid on the amide HOCHPh-
CONH2.440 -
c104
(354) (355) ( 356) ( 357 1

430
R. C. Boruah, J . S. Sandhu, and G. Thyagarajan, J. Heterocycl. Chem., 1981, 18,
1081.
431 R. Neidlein and S. Thorn, Arch. Pharm. (Weinheim, Ger.), 1 9 8 2 , 315, 353.
432 L. M. Gornostaev, A. P. Eskin, and E. D. Korniets, Zh. Org. Chem., 1 9 8 1 , 17, 2344.
433 Y. Inukai, Y. Oono, T. Sonoda, and H. Kobayashi, Bull. Chem. SOC. Jpn., 1981,
54, 3447 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 8 8 7 5 ) .
434 R. FUSCO, S. Maiorana, P. Del Buttera, E. Licandro, and A. Alemagna, Chim. Ind.
(Milan), 1981, 6 3 , 4 0 1 (Chem. Abstr., 1982, 96, 6631).
435A. S. Yavorskii and A. A. Mazurov, Khim. Prom-St., Ser.: Reakt. Osobo Chist.
Veshchestva, 1980, 53 (Chem. Abstr., 1981, 95, 80 383).
436 ( a ) Y. Hamada and T. Shiori, Tetrahedron Lett., 1982, 23, 2 3 5 ; ( b ) Y. Hamada, S .
Morita, and T. Shiori, Heterocycles, 1982, 17, (Spec. Issue), p. 321.
437 G. S. Reddy and M. V. Bhatt, Indian J. Chem., Sect. B , 1981, 2 0 , 322.
438 H. A. Houwing, J . Wildeman, and A. M. Van Leusen, J. Heterocycl. Chem., 1981,
18, 11 33.
439 A. M. Van Leusen, H. J. Jeuring, J . Wildeman, and S. P. J. M. Van Nispen, J. Org.
Chem., 1 9 8 1 , 4 6 , 2 0 6 9 .
440 Yu. I. Ryabukhin, V. D. Karpenko, and G. N. Dorofeenko, Zh. Org. Khim., 1982,
18, 230.
The reaction of the oxiran (358; Ar =p-N02C6H4) with methyl thio-
cyanate results in the oxazoline (359).#l Treatment of the isocyanide
CNCH2C 0 2Et with me thoxyace taldehyde affords the trans-oxazoline (3 60),
which is cleaved by bases to yield mainly the (a-N-formylenamine (361).442
The perbromide (362) is produced by the action of bromine on N-
benzoylpropargylamine .443
PhC
8-.,o/#A EtOOC
PhC'
A II r y J SMe
The N-t-butoxycarbonylamino-acid anhydride [ButOCONH(CHzPh)-

COI2O cyclizes to the oxazolone (363) in the presence of triethylamine.w
2-Phenyl-5H-oxazo1-4-ones (364; R' , R2 = H or Me) are produced by the
acid-catalysed ring-closure of NN-dimethylbenzamido-amidesPhCONHCR' -
R2CONMez.445 Condensation of trimethyl orthoformate with glycollic amide
gives the oxazolidin-4-one (365).446 A new synthesis of a meso-ionic
oxazolium 4-oxide, compound (366), is by the action of triethyl phosphite
on the diacylamide PhCOCONPhCOPh.447-The acetylimine AcN=CMe02C-
COC1, obtained by treating diacetylamine with oxalyl chloride, cyclizes to
the oxazolidinedione (367) on heatingM8
441 I. G. Tishchenko, 0. N . Bubel, and 0. H. Grinkevich, Dokl. Akad. Nuuk B . SSR,

1981, 25, 543.
442 I. Hoppe and U. Schollkopf, Synthesis, 1982, 129.
443 G. Capozzi, C. Caristi, M. Gattusa, and G. Stagno D'Alcontres, Tetrahedron Lett.,
1981, 22, 3325.
444 N. C. Benoiton and F. M. F. Chen, J. Chem. SOC.,Chem. Commun., 1981, 1225.
4 4 5 D. Obrecht and H. Heimgartner, Chimiu, 1982, 36, 78.
446 D. Y. Kim, S. I. Hong, N. S. Choi, and J. S. Shim, Pollimo, 1981, 5, 467 (Chem.
Abstr., 1982,96, 199 563).
44 1
M. J. Haddadin, A. M. Kattan, and J . P. Freeman, J. Org. Chem., 1982,4 7 , 723.
448 R. Richter and G . H. Temme., J. Org. Chem., 1981, 46, 2015.
The base-catalysed addition of acetone to trans-aziridines (368) affords

oxazolidines (369).@’ The complex reaction of 2-aminoethanol with nitrous
acid results in the nitroso-compound (370).450
Reactions of Oxazoles. 2-, 4-, and 5-Nitro-oxazoles can be prepared by the

action of dinitrogen tetroxide on the corresponding iodo-cornpo~nds?~~
Whereas oxazoles are metallated at C-5, the acid (371) undergoes lithiation
at the methyl s u b s t i t ~ e n t ?The
~ ~ reaction of 2,4-dimethyloxazole with ethyl
propiolate yields a mixture of the furans (373) and (374); these are formed
by extrusion of acetonitrile from intermediate Diels-Alder adducts such as
(3 72) .453
( 372 (373) (374)
The dihydro-oxazolium salt (375) gives the ring-expanded product (376)

on treatment with sodium mal~nonitrile.~’~ The oxazoline (377), prepared
by the action of trimethyl phosphate on the imine F3CC(=CF2)N=CC1Ph,
rearranges to the oxazole (378) in the presence of caesium flu0ride.4’~ 3-
449 I. G. Tishchenko, 0. N. Bubel, and V. A. Konovalov, Khim. Geterotsikl. Soedin.,

1981, 38.
450 J. E. Saavedra, J. Org. Chem., 1981, 46, 2610.
451 W. J. Hammar and M. A. Rustad, J. Heterocycl. Chem., 1981, 18, 885.
452 A. I. Meyers and J. P. Lawson, Tetrahedron Lett., 1981, 22, 3163.
453 (a) T. Jaworski and T. Mizerski, Pol. J. Chem., 1981, 55, 317; ( b ) T. Jaworski, T.
Mizerski, and K. Mazur, ibid., p. 321; ( c ) T. Jaworski and T. Mizerski, ibid., p. 4 7 ;
( d ) H. Koenig, F. Graf, and V. Weberndoerfer, Liebigs Ann. Chem., 1981, 668.
454 M. Lheme, P. Le Perchec, J. Garapon, and B. Sillion, Tetrahedron Lett., 1982, 2 3 ,
73.
455 K. Burger and H. Goth, J. Fluorine Chem., 1981, 17, 585.
Methyl-1-phenylisoquinoline (380) is obtained when the oxazoline (379)
is heated with phosphorus pentoxide ?56 An efficient synthesis of alkylated
and dialkylated acetic acids consists in the alkylation of 4,s-dihydro-
oxazoline bound to polystyrene, followed by hydr0lysis.4~' The asymmetric
synthesis of a series of a-alkylphenylacetic acids CnH2n+1CHPhC02H (n =
1-5) from the chiral oxazoline (381) has been de~cribed.4'~Another example
of the use of oxazolines for asymmetric synthesis is the preparation of the
optically active binaphthyl (383) from 1-lithionaphthalene and compound
[382; R = (-)-menthy1].459 The stereoselective formation of threo-aldol
products (385; R2 = Et, Pr, n-pentyl, etc.) from the chiral boron compound
(384; R' = bornyl) and aldehydes R2CH0 has been reported;- the reaction
of the lithium enolate of the optically active oxazolidinone (386) with alkyl
bromides or aldehydes likewise proceeds with high kinetic diastereo-
selectivity .461
Me
Me
456 T. Kopczynski and S. Goszczynski, Pol. J. Chem., 1981, 5 5 , 393.

457 A. R. Colwell, L. R. Duckwall, R. Brooks, and S. P. McManus, J. Org. Chem., 1981,
46, 3097.
458 S . Shibata, H. Matsushita, H. Kaneko, M. Noguchi, M. Saburi, and S. Yoshikawa,
Chem. Lett., 1981,217.
459 J . M. Wilson and D. J. Cram, J. A m . Chem. SOC.,1982, 104,881.
460 A. I. Meyers and Y. Yamomoto, J. A m . Chem. SOC., 1981, 103,4278.
461 (a) D. A. Evans, M. D. Ennis, and D. J. Mathre, J. A m . Chem. SOC.,1982, 104,1737;
( b ) D. A. Evans, J. Bartroli, and T. L. Shih, ibid., 1981, 103, 2127.
Photo-oxygenation of the oxazoles (387; n = 2 or 3) gives transient cyclo-

adducts (388), which are transformed into the lactones (389);462 a similar
reaction with the alcohol (390) yields the triacylamide (39 l), which cyclizes
to the macrocyclic lactone (392) under the influence of toluene-p-sulphonic
Me
Me cj [ CH2] *COOH M e F $ 0-0
[ C H 2 ]
,COOH HOO
Thermolysis of the oxazolidinone (393) yields a mixture of methyl

isocyanate and the ketol PhCOCMe20H?64 The 3H-indole (395) is obtained
when the methyleneoxazolidinone (394) is heated with zinc ~hloride.4~’
Me Me
(393) ( 394) (395)
A new reagent for activating carboxylic acids for amide formation is the
phosphonate (39QM6 The azomethine imine (397), obtained from diphenyl-
keten and diethyl azodicarboxylate, forms the 1,3-cyclo-adduct (398) with
COOE t
Ph
Ph OEt
462 H. H. Wasserman, J . E. Pickett, and F. S. Vinnick, Heterocycles, 1981, 15, 1069.

463 H. H. Wasserman, R. J . Gambale, and M. J. hlwer, Tetrahedron Lett., 1981, 2 2 ,
1737.
464 N. Saito, K. Hatakeda, S. Ito, T. Asano, and T. Toda, Heterocycles, 1981, 1 5 , 905.
465 H. Laas, A. Nissen, and A. Niirrenbach, Synthesis, 1981,958.
466 T. Kunieda, Y . Abe, T. Higuchi, and M. Hirobe, Tetrahedron Lett., 1981, 2 2 , 1257.
25 6 Heterocyclic Chemistry
phenyl isocyanate.467 The &unsaturated ketone MeCOCH2CH=CMe2 is
obtained by the combined action of tin(I1) chloride and citric acid on the
2H-oxazolone (399).468 The latter undergoes a photochemical sigmatropic
rearrangement to compound (400), which in turn isomerizes to the oxazolone
(401) on heating.&' The thermal conversion of the cyclopropenyloxazolone
(402) into the pyridine (404) proceeds by way of the nitrile ylide (403).470
CH,CH=CMe,
Me
Ph
A general synthesis of cyanoethyl ketones, in which a-amino-acids function

as nucleophilic acyl equivalents, is outlined in Scheme 7.471
ii
RCH-NH2 -*
I
COOH
( R = alkyl; A r = 2,4,6-Me3C6H2)
/
iii
J
CH CH CN
R c N H
RCOCHzCHzCN 1
COOH
0
A Ar
Reagents: i, ArCOC1; ii, H,C=CHCN; iii, HO-; iv, Pb(OAc),
Scheme 7
467 E. Fahr, E. Buttner, K. H. Keil, J . Markert, F. Scheckenbach, R. Tiedemann, and J .
Fontaine, Liebigs Ann. Chem., 1981, 1433.
46 0
U . Niewohner and W. Steglich, Angew. Chem., Int. Ed. Engl., 1981, 20, 395.
469 A. Padwa, M. Akiba, L. A. Cohen, and J . G. MacDonald, Tetrahedron Lett., 1 9 8 1 ,
2 2 , 2435.
470
A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. A m . Chem.
Soc., 1982, 104, 286.
411
H. Wegmann and W. Steglich, Chem. Ber., 1981, 1 1 4 , 2 5 8 0 .
The azlactone (405; Ar = p-C1C6H4) reacts abnormally with p-xylene,
yielding the ketone (406)!n Several unusual reactions of the munchnone
(407) have been described: it gives the adduct (408) with tetrachloroe-
benzoquinone pn with 6-phenylfulvene it forms the pyrrole (409) with
elimination of carbon dioxide and dehydrogenation, together with the
'di-adduct' (4 10);474 and with tetrachlorocyclopropene the pyridone (412),
which results from the cyclo-adduct (41 l), is produced.475
"1-1
MeN
Ph
CHPh
Ph
c1 Ph
c1 Ph
412 M. A. El-Hashash, A. A. Mify, A. M. Kaddah, and S. S. El-Kady, Synthesis, 1981,

798.
473 W. Friedrichsen, I. Schwarz, B. Epe, and K. F. Hesse, 2.Naturforsch., Teil. B , 1981,
36, 622.
474 (a) W. Friedrichsen and W. D. Schroer, Liebigs Ann. Chem., 1 9 8 1 , 4 7 6 ; ( b ) T.
Debaerdemaeker, W. D. Schroer, and W. Friedrichsen, ibid., p. 502.
475 M. L. Deem, Org. Prep. Proced. Int., 1 9 8 1 , 1 3 , 4 1 4 .
For other papers on the formation and reactions of oxazoles, see
references 476-478 and 479-482, respectively.
Benzoxazoles. - Both 0-and m-halogenobenzanilides (41 3) are converted into
the amidines (415) by potassium amide in liquid ammonia; these are formed
by aryne cyclization to 2-phenylbenzoxazole (41 4) and subsequent aminoly-
S ~ S The
. ~ conversion
~ of acetophenone oxime into 2-methylbenzoxazole by
the action of phosphorus oxychloride involves a Beckmann rearrangement .484
Pyrolysis of aryl azidoformates, Ar02CN3, gives benzoxazol-2-0nes!~~ The
azide (416) is converted into the benzoxazole (417) on heating?86 The
Q-0
1-
NHCOPh NHCOPh
NH
m \ P h - o N \ y\’ OH Ph
\ \ ‘ 0
Hal
(413)
416
C. F. Hoyng, M. G. McKenna, and D. L. Walters, Synthesis, 1982, 191. (Chem.
Abstr., 1982,96,162 577).
417
G. Cavicchioni, P. Scrirnin, A. C. Veronese, and F. D’Angeli, J . Chem. Soc., Chem.
Commun., 1981,416 (Chem. Abstr., 1981,95, 115 356).
418
F. U. Luebke, T. P. Kosulina, and V. S. Kulnevich, Khim. Geterotsikl. Soedin., 1981,
894 (Chem. Absrr., 1981,95,203 809).
479
A. R. Katritzky and A. Zia, J. Chem. Soc., Perkin Trans. 1 , 1982,131 (Chem. Abstr.,
1982,96,181 196).
480
K. J. Edgar and C. K. Bradsher, J. Org. Chem., 1982,47, 1585 (Chem. Abstr., 1982,
96, 142 740).
481
L. N. Pridgen and L. B. Killrner, J. Org. Chem., 1981,46, 5402 (Chem. Abstr., 1982,
96,6634).
482
0. Tsuge, K. Oe, and N. Kawaguchi, Chem. Lett., 1981, 1585 (Chem. Abstr., 1982,
96,8 5 347).
483
484
M. 1. El-Sheikh, A. Marks, and E. R. Biehl, J. Org. Chem., 1981,46,3256.
S. Fujita, K. Koyama, and Y. Inagaki, Synthesis, 1982,68.
485
0. Meth-Cohn and S. Rhouati, J. Chem. Soc.. Chem. Commun., 1981,241.
4a6
A. Tanaka and T. Usui, Heterocycles, 1981, 16,963.
cyclohexadiene derivative (418) eliminates methanol to yield a mixture of
the rearranged azepine (4 19) and the dihydrobenzoxazole (420).487 Oxidative
cyclization of the diamide (421) by thallium(II1) trifluoroacetate affords the
benzoxazole (422);488 the phenols (423; R = Ph, Ac, or CN) are transformed
into compounds (424) by anodic oxidation in a~etonitrile.~~’ The benzoxa-
zole (426) is formed by the action of benzonitrile oxide on the sulphimide
(425) .490
NHAc NHA c
(423)
The complex reaction of dimethyl acetylenedicarboxylate with 2-methyl-

benzoxazole in ethanol yields, inter alziz, the benzoxazoloazepine (427):’l
Both the S-and the N-acyl derivatives of benzoxazole-2-thione are effective
acylating agents for amines and alcohols.492
E E
( 4 2 7 ) E = COOMe
487 H. H. Eckhardt, D. Hege, W. Massa, H. Perst, and R. Schmidt, Angew. Chem., Int.
Ed. Engl., 1981, 2 0 , 699.
488 K. S . Y. Lau and D. I. Basiulis, Tetrahedron Lett., 1981, 22, 1 175.
489 E. L. Dreher, J . Bracht, M. El-Mobayed, P. Hutter, W. Winter, and A. Rieker, Chem.
Ber., 1982, 115, 288.
490 T. Shiraishi, Chem. Lett., 1981, 843.
491 N. Kawahara, M. Katsuyama, D. Itoh, and H. Ogura, Heterocycles, 1981, 16, 235.
492
M. Ueda, K. Seki, and Y. Imar, Synthesis, 1981,991.
Benzoxaiodoles. - N.m.r. spectroscopy shows that diphenyliodonium-2-
carboxylate exists in the cyclic form (428).493 The stable periodonium salt
(430) has been prepared from the benzoxaiodole (429).494
(428)
CF..
0 Y C F 3
CF3
-
I CF3S03
c1
(429) (430)
6 Systems containing Three Identical Heteroatoms

1,2,3-Triazoles and Benzotriazoles. - The alkenediazonium salt (43 1 ; Ar =
p-N02C6H4) is converted into the triazoles (432; R = H or alkyl) by the
action of ami11es.4~~Anodic oxidation of the oxime phenylhydrazone of
benzil, HON=CPhCPh=NNHPh, gives the N-oxide (433).496 The alkenyl-
triazolines (434; R1,R2 = H or alkyl) afford the aziridines (435) on flash
vacuum pyrolysis.497 Photolysis of the 4-alkylaminotriazoles (436; R = alkyl)
yields 2-alkylpyrroles rather than the expected 3-alkylpyrr0les.4~~The
(.431) Ph
(433)
N* ,NCH=CH2
N
R' RI
(434 1 (435)
4y3 D. Del Mazza, M. G. Reinecke, and W. B. Smith, Org. Magn. Reson., 1980, 14,540.
494 (a) D. B. Dess and J. C. Martin, J. Am. Chem. SOC.,1982, 104,902;( b ) T. T.Nguyen,
R. L. h e y , and J . C. Martin, J. Org. Chem., 1982,47, 1024.
495
R. W. Saalfrank and E. Ackermann, Chem. Ber., 1981, 114,3456.
496 N. Henning, T. Dassler, and W. Jugelt, 2.Chem., 1982,22, 25.
497 A. Hassner, B. A. Belinka, Jr., M. Haber, and P. Munger, Tetrahedron Lett., 1981,
22, 1863.
498 M. M. Ito, Y. Nomura, Y. Takeuchi, and S. Tomoda, Chem. Lett., 1981, 1519.
spiro-triazolines (437), prepared from aryl azides and 9-methylenefluorene,

afford 9-arylaminophenanthrenes (438) on heating.499 1-Chlorobenzotriazole
does not oxidize diphenylmethanol to benzophenone, but instead forms
com poun d (43 9).
Sl
p 3-
d N=N
(437)
NA r
\
(438)
/ NHAr p!
PhCCIZ
(4391
H
Other work on 1,2,3-triazoles has appeared.501-so3

1,2,4-Triazoles.- Benzonitrile oxide and benzaldehyde N-methylhydrazone
yield the oxime PhCH=NNMeCPh=NOH, which undergoes acid-catalysed
cyclization to the triazole (440).’@’ The azo-compound PhN=NCHMeNH2
undergoes a complex reaction, on heating, to yield compound (441).’05
The ammonium imide (442) is obtained from NN-dimethylhydrazine and a-
chlorobenzylidenecarbamoyl chloride, PhCCl=NCOCl;506 a similar betaine,
compound (443), is produced by the action of cobalt(II1) fluoride on the
hydrazine Me2NN(SiMe3)2.s07 Thiocarbonyl-1 ,l’-di-(1,2,4-triazolyl) (444;
R = triazol-1 -yl) reacts with methylene-NN-dimethylhydrazoneto give the
substitution product (444; R = CH=NNMe2).’”
Me
(4401
Me2 s//c\R
(443) (444)
499 K. Hirakawa and Y. Tanabiki, J. Org. Chem., 1982,47,280.

500 A. Rangadurai, V. S. Srinivasan, V. Thiagarajan, and N. Venkatasubramanian, Indian
J . Chem., Sect. B , 1981,2 0 , 898.
501 F. Lubbe, K. P. Grosz, W. Hillebrand, and W. Sucrow, Tetrahedron Lett., 1981, 22,
227 (Chern. Abstr., 1981,95,61 647).
502 M. Begtrup and J. Holm, J. Chem. SOC.,Perkin Trans. 1 , 1981, 503 (Chem. Abstr.,
1981, 95,7162).
A. E. Siegrist, Helv. Chim. Acta, 1981,64,662 (Chem. Abstr., 1981,95, 132 759).
504 F. Risitano, G. Grassi, and F. Foti, J. Chem. Res. (S)., 1981, 65.
505 P. Metra and J . Hamelin, Can. J. Chem., 1982,6 0 , 285.
’06 M. Takahashi, K. Takiguchi, and S. Imaizumi, Synthesis, 1982, 155.
V. Zuern, W. Schwarz, W. Rozdzinski, and A. Schmidt, 2. Naturforsch., Teil. B ,
1982,37, 81.
C. Larsen and D. N. Harpp, J . Org. Chem., 1981,46, 2465.
The combined action of ethyl propiolate and triethylamine on the salt
(445) results in the ester (447), which arises from the intermediate cyclo-
adduct (446).'09 The triazolones (448) decompose thermally to nitrogen,
carbon monoxide, and the imines ArN=CMe2.510 The stable betaine (450)
is produced by the reaction of 4-phenyl-l,2,4-triazoline-3,5-dione (449)
with diazodeoxybenzoin, PhCN,COPh,S1l whereas diazoacetophenone is
reported512 to yield an oligomer (451).
Br- I COPh
CH2COPh
(445 1
Some unusual, cycloaddition reactions of the triazolidinedione (449) have

been described. These include the formation of the strained compound (453)
from the trans,cis-nonadiene (452)'13 and that of the anomalous adducts
(452) 0Ao: Ph
(453)
509
M. Petrovanu, C. Luchian, G. Surpateanu, and V. Barboiu, Tetrahedron, 1981, 37,
2805,2811.
(a) L. M. Cabelkova-Taguchi and J. Warkentin, Can. J. Chem., 1981, 59, 1 0 6 ; ( b )
ibid., p. 3087.
511 W. Bethauser, M. Regitz, and W. Theis, Tetrahedron Lett., 1 9 8 1 , 22, 2535.
512 I. K. Korobitsyna, L. L. Rodina, and A. V. Lorkina, Zh. 0%. Khirn., 1 9 8 1 , 17,
2021.
'13 P. G. Gassmanand R. C. Hoye, J. Am. Chem. SOC., 1981, 1 0 3 , 2 4 9 8 .
(455; n = 6,7, or 8) from the distorted cyclohexa-l,4-dienes (454).’14 The
reaction of (449) with the bicyclo [ 1.1 .O] butane (456) yields the rearranged
adduct (457);’*’ compound (458) likewise affords a rearranged product,
compound (459).’16 Prolonged heating of the triazolinedione with the nor-
+
bornene (460) gives the [2n 2771 cyclo-adduct (461).517 Hydrazinolysis
of the urazole (462) affords the azo-compound (463).’18
(454 (455)
Me 0
Me 0
(456
(457
514
P. G. Gassman and R. C. Hoye, J. A m . Chem. SOC., 1981, 103,2496.
515 R. L. Amey and B. E. Smart, J. Org. Chem., 1981,46,4090.
516 W.Adam, 0. De Lucchi, and D. Scheutzow, J. Org. Chern., 1981,46,4130.
517 W.Adam and 0. De Lucchi, Tetrahedron Lett., 1981,22,929.
”’ W.Adam, L. A. Arias, and 0. De Lucchi, Synthesis, 1981,543.
Several other papers on 1,2,4-triazoles should be noted.519-521
Other Systems. - Th,e trithiolan (464) has been prepared from the phos-
phonium betaine Ph3PCMe2CS; and rhenium( I) pentacarbonyl bromide ."*
Treatment of sodium phenylethynyl telluride with hydrogen chloride gives
the 1,2,4-tritellurolan(465).523
S A2 T X h
kS!efTe
CMe , CHPh
7 Other Systems containing Three Heteroatoms

Oxadiazoles. - 1,2,3-OxadiazoZes. Irradiation of the sydnone (466) affords
the betaine N-oxide (467) in low yield;524 the reaction with dimethyl
acetylenedicarboxylate gives a mixture of the pyrrole (468) and the
oxazinone (469); both originate from the intermediate cyclo-adduct
'19 W. Ried and H. E. Erle, Chem. Ber., 1982, 115, 475 (Chem. Abstr., 1982, 96,
142 613).
"O G. Grassi, F. Risitano, and F. Foti, J. Chem. Res. ( S ) , 1981, 56 (Chem. Abstr., 1981,
9 5 , 2 4 896).
521 W. Adam and 0. De Lucchi, Tetrahedron Lett., 1981, 22, 3501 (Chem. Abstr., 1982,
96, 68 91 8).
s22 U. Kunze, R. Merkel, and W. Winter, Angew. Chem., Int. Ed. Engl., 1982, 2 1 , 2 9 1 .
523 M. V. Lakshmikantham, M. P. Cam, M. Albeck, L. Engman, P. Carroll, J . Bergman,

and F. Wudl, Tetrahedron Lett., 1981, 22, 4199.
524 H. Gotthardt and F. Reiter, Chem. Ber., 1981, 114, 1737.
Electrolysis of 3-phenylsydnone in the presence of tetra-

ethylammonium tosylate at a platinum anode results in formation of the 4-
t 0syloxy -deriva t ive .526 3-Pheny lsy dnone reacts with cyclo-octa t etraene t o
yield mainly compound (470).527
1,2,4-Oxadiazoles. Mesitonitrile oxide adds NN-dicyanomethylamine, MeN-

(CN),, to yield the oxadiazole (471; Ar = 2,4,6-Me3C6H2).528The action of
hydroxylamine on the cyanoimino-ether ArCH,C(OEt)=NCN (Ar = 2,6-
C12C6H3) unexpectedly leads to the 3-amino-oxadiazole (472).529 3-Azido-
5-phenyl-l,2,4-oxadiazole(473) reacts with dimethylformamide to form
the imine (474);530 flash vacuum pyrolysis of the azide affords benzoyl
I
CN (472)
(473) (474)
(471)
cyanide via the tetrazole ( 4 7 9 , which undergoes fission of the nitrogen-

oxygen bond.531 The hydrazino-oxadiazole (476) is converted, on heating,
into a mixture of the Dimroth rearrangement product (477; R = NH,), the
oxadiazolinone (477; R = H), and the triazine (478).532 The oxadiazolidin-
;’r””\
ph(o,N,fN - Ph
- -
[-2N2]
Ph
‘c’
II
0
NC Ph,
C
II
0
,CN
(4743) (477) (478)

525 H. Gotthardt and F. Reiter, Chem. Ber., 1981, 114, 2450.
526 H.-J. Tien, T. Nonaka, and M.-Y.Yeh, J. Chin. Chem. SOC. (Taipei), 1981, 28, 161
(Chem. Abstr., 1981, 95, 169 089).
527 A. Padwa and R. Lim, Tetrahedron Lett., 1982, 23, 11.
528 P. H. Benders, D. N. Reinhoudt, and D. M. W. Van den Ham, R e d : J. R. Neth.
Chem. SOC., 1981, 100,330.
529 M. J. Dimsdale, J. Heterocycl. Chem., 1981, 18, 37.
P. Choi, C. W. Rees, and E. H. Smith, Tetrahedron Lett., 1982, 23, 125.
531 P. Choi, C. W. Rees, and E. H. Smith, Tetruhedron Lett., 1982, 23, 121.
532 G. Adembri, A. Camparini, F. Ponticelli, and P. Tedeschi, J. Chem. SOC., Perkin
Trans. I , 1981, 1703.
0
( 479 1
- 0
HN---f-
(4801
Ph
one (480) is one of the products of the reaction of compound (479) with
phenylmagnesium bromide.533 The hydrazone (48 1) is converted into the
indazole (482), as outlined in Scheme 8.534
Ph
-
PhCON
__t Ph<?+N
0- N
/ \Me /\ Me
Ph Ph Me
(481)
J H
NCOPh
N
’
Me
Scheme 8
1,2,5-0xadiazoles. Benzaldehyde oxime reacts with nitrogen tetroxide to

yield the furoxan (483), contrary to a previous report.535 The furoxans
(484; R = Ar or PhCH2) rearrange to the oximino-isoxazolines (485), thus
Ph IImr “111 Lo-

N L O O N+
Me -VNoH N\O
533 F. M. A. Abdel-Megeid, M. A. Salama, F. M. Moti, and N. M. Yousif, Egypt. J. Chem.,

1979, 22, 53 (Chem. Abstr., 1 9 8 2 , 9 6 , 162 608).
534 N. Vivona, G . Macaluso, G. Cusmano, and V. Frenna, J. Chem. SOC.,Perkin Trans. I ,
1982, 165.
535 N. Suzuki, S . Wakatsuki, and H. Izawa, Heterocycles, 1981, 16, 1195.
confirming Angeli’s original assignment .536 The di-sulphone (486) is a
source of the nitrile oxide (487), which can be trapped by styrene as the
1,3-dipolar cyclo-adduct (488).537Caro’s acid oxidizes the benzofuroxan
(489) to 1,2,4-trinitroben~ene.’~~
Ph0,Sl-I :02Ph
- Ph02SC
111, - Ph02S
Ph
02Nei
ATkre\ \ + N’
I
0-
0
Me
Me
( 489 1
1,3,4-0xadiazoles.The- oradiazoline (490) decomposes in solution to yield

the carbonyl ylide Me2C-O=CMeOMe as the initial product .539 Flash vacuum
pyrolysis of the N-butenyloxadiazolinone (49 1) affords a mixture containing
the dienes (492) and (493). These are forme’d via a nitrile imine and a diazo-
compound as the key intermediates (see Scheme 9).%’
N- Ph CN2
[-co 1 I
PhC H - C w
Me
/
Ph \ Me
(491)
PhC :
.j,
Me
(493)
Scheme 9
536
A. J . Boulton, D. E. Coe, and P. G . Tsounga, Gazz. Chim. Ital., 1981, 111, 167.
537 R. A. Whitney and E. S. Nicholas, Tetrahedron Left., 1981, 2 2 , 3371.
538 ( a ) J. H. Boyer and C. Huang, Heterocycles, 1 9 8 2 , 1 9 , 2 8 5 ; ( b ) J. Chem. SOC.,Chem.
Commun., 1981, 365.
539 M. Ekkhaziand J . Warkentin, J. A m . Chem. SOC.,1981, 103, 2 4 7 3 .
540 A. Padwa, T. Caruso, S. Nahm, and A. Rodriguez, J. A m . Chem. SOC.,1 9 8 2 , 104,
2865.
Other article^^^^-"^ on oxadiazoles should be noted.
Phosphorus Compounds. - The synthesis of the chiral phosphate (494) has
been described.554 The silyl ether cis-Me3SiOCMe=CMeOSiMe3 reacts with
MeOP(0)F3 to yield the dioxaphospholen (495).555 Treatment of the
tetramer (496) with boron trifluoride affords the di-co-ordinated phosphorus
compound (497).556 The imines (499) are obtained when the 1,2,3-diaza-
phospholine (498) is heated with aryl a ~ i d e s . ” The
~ oxazaphosph$ne (500)
decomposes to trimethyl phosphate and the nitrile ylide (CF3)2C-NECPh.558
‘.
Ph Ph
I
-I-
o\p/O
Me-Me
OXp/O
1 :o O
‘Me 0 ‘OSiMe3
(494 1 (4951 (496)
p l y ! P h
Ph
Ph
ArN Ph OMe
(498) (499 ) (500 1
541 G. Ronsisvalle, F. Guerrera, and M. A. Siracusa, Tetrahedron, 1981, 37, 1415 (Chem.
Abstr.. 1981. 95. 115 363).
542
G. Zinner, H. G. Schecker, and W. Heuer, Arch. Pharm. (Weinheim, Ger.), 1 9 8 1 ,
314, 1006 (Chem. Abstr., 1 9 8 2 , 96, 122 696).
543
H. G. Schecker and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 2 6 8
(Chem. Abstr., 1981, 95, 2 4 933).
544
M. Neitzel and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1 9 8 1 , 314, 10 (Chem.
Abstr., 1981, 9 5 , 2 4 9 2 7 ) .
54 5
G. Zinner, M. Menzel, R. Sunderdiek, and E. Fischer, Arch. Pharm. (Weinheim, Ger.),
1981, 3 1 4 , 2 9 4 (Chem. Abstr., 1981, 95, 132 757).
546
S . S . Jones, D. B. Staiger, and D. F. Chodosh, J. Urg. Chem., 1 9 8 2 , 47, 1969 (Chem.
Abstr., 1 9 8 2 , 9 6 , 181 212).
547
V. Frenna, N. Vivona, A. Corrao, G. Consiglio, and D. Spinelli, J. Chem. Res. ( S ) ,
1981, 308 (Chem. Abstr., 1 9 8 2 , 9 6 , 103 375).
54 8
V. Frenna, N. Vivona, D. Spinelli, and G. Consiglio, J. Heterocycl. Chem., 1981, 18,
7 2 3 (Chem. Abstr., 1981, 9 5 , 1 8 6 380).
549
R. Calvino, A. Gasco, A. Serafino, and D. Viterbo, J. Chem. SOC., Perkin Trans. 2 ,
1981, 1 2 4 0 (Chem. Abstr., 1981, 9 5 , 2 0 3 6 8 1 ) .
550
N. N. Makhova, I. V. Ovchinnikov, B. N. Khasanov, and L. I. Khmelnitskii, Izv. Akad.
Nauk SSSR, Ser. Khim., 1 9 8 2 , 6 4 6 (Chem. Abstr., 1 9 8 2 , 9 6 , 199 600).
551
J. A. Usta, M. J. Haddadin, C. H. Issidorides, and A. A. Jarrar, J. Heterocycl. Chem.,
1981, 18, 655 (Chem. Abstr., 1981, 95, 169 132).
5 52
M. J . Strauss, A. DeFusco, and F. Terrier, Tetrahedron Lett., 1981, 22, 1945 (Chem.
Abstr., 1981, 95, 1 5 0 545).
5 53
R. Socher, C. Csongar, I. Mueller, and G. Tomaschewski, Z. Chem., 1981, 21, 1 8 2
(Chem. Abstr., 1 9 8 1 , 9 5 , 132 763).
5 54
P. M. Cullis and G. Lowe, J. Chem. SOC.,Perkin Trans. I , 1981, 231 7 .
555
R. Schwarz and I. Ugi, Angew. Chem., Int. Ed. Engl., 1 9 8 1 , 20, 7 8 9 .
5 56
C. Malavaud, L. Lopez, T. N’G. M’Pondo, M. T. Boisdon, Y. Charbonnel, a n d J.
Barrans, A . C. S. Symp. Ser., 1981, 171, (Phosphorus Chem.), p. 4 1 3 .
557
G. Baccolini, P. E. Todesco, and G. Bartoli, Phosphorus Sulfur, 1981, 10, 387.
558
( a ) K. Burger, H. Goth, K. Einhellig, and A. Gieren, Z. Naturforsch., Teil. B , 1981,
36, 3 4 5 ; ( b ) K. Burger, S. Tremmel, W. D. Roth, and H. Goth, J. Heterocycl. Chem.,
1981, 1 8 , 2 4 7 .
A reversible migration of the phenyl group from phosphorus to iron has been
observed for the system (501) =+(502).559
For other papers on phosphorus systems, see references 560-568.

Miscellaneous other Systems containing Three Heteroatoms. - Catechol is
converted into the 1,3,2-benzodioxathiolan(503) by the action of EtNSF2.s69
The cyclic iminodiacyl peroxide (504) is obtained from the imino-compound
MeN(COC1)2 and hydrogen p e r ~ x i d e . ' ~The hydroxamic acid HOCPh2-
CONHOH reacts with carbonyldi-imidazole to yield the dioxazolone (505):'l
The i.r. and Raman spectra of 1,3-dimethyl-l,3-diaza-2-boracyclopentanes
(506; R = C1, Br, or NMe2) have been reported.572 The zwitterionic salt
559
P. Vierling, J. G. Riess, and A. Grand, J. A m . Chem. SOC.,1981, 103,2466.
560 N. Ayed, F. Mathis, and B. Baccar, C. R . Hebd. Seances Acad. Sci., Ser. 2, 1981,
292, 187 (Chem. Abstr., 1981,95,186 195).
561 I. V. Konovalova, L. A. Burnaeva, N. K. Novikova, 0. S. Kedrova, and A. N. Pudovik,
Zh. Obshch. Khim., 1981, 51,995 (Chem. Abstr., 1981,95, 114 754).
562
M. Yu. Antipin, Yu. T. Struchkov, Yu. V. Balitskii, and Yu. G. Gololobov, Zh.
Strukt. Khim., 1981,22,98 (Chem. Abstr., 1982,96,6703).
563 M. M. Sidky, M. F. Zayed, A. A. El-Kateb, and I. T. Hennawy, Phosphorus Sulfur,
1981,9,343 (Chem. Abstr., 1981,95,62086).
564 K. Burger, H. Goth, and E. Burgis, 2. Naturforsch., Teil. B , 1981, 36, 353 (Chem.
Abstr., 1981,95,80 826).
5 6 5 L. I. Nesterova and Yu. G. Gololobov, Zh. Obshch. Khim., 1981, 51, 1663 (Chem.
Abstr., 1981,95, 187 167).
C. R. Hall, T. D. Inch, and N. E. Williams, J. Chem. SOC.,Perkin Trans. I , 1982,639
(Chem. Abstr., 1982,96,181 207).
5 6 7 C. R. Hall and T. D. Inch, J. Chem. SOC.,Perkin Trans. I , 1981,2368(Chem. Abstr.,
1981,95, 149 795).
568 M. R. Marre, J. F. Brazier, R. Wolf, and A. Klaebe, Phosphorus Sulfur, 1981, 11, 87
(Chem. Abstr., 1982,96,5 8 0 0 ) .
569 M. Mohammadi and J . M. Shreeve, J. Fluorine Chem., 1981, 18, 357.
570 H. Hagemann, Angew. Chem., Int. Ed. Engl., 1981,20, 784.
571 D. Geffken, Liebigs Ann. Chem., 1982,21 1.
5 7 2 G. Davidson and S. Phillips, J. MoZ. Struct., 1981,72, 99.
(507) is formed by the action of B4HI0 on NNN‘N’-tetramethyl-o-phenylene-
diarnir~e.’~Proton, l l B , and ”N n.m.r. spectroscopy has revealed that the
boronate (508) exists in equilibrium with the spiro-compound (509).574
Me2 B3H8
(507 1 (508)
Other articles on these systems have appeared.575-580
8 Systems containing Four Heteroatoms

Tetrazoles. - The high-pressure reaction of phenyl azide with dicyanogen
yields 5-cyano-1-phenyltetrazole (5 1O).581 The (trinitromethy1)tetrazole
(511) has been prepared by the action of trimethylsilyl azide on cyano-
trinitr~methane.’~~5-Aryltetrazoles (51 2) are transformed into the oxadia-
zoles (5 13) by reaction with aroyl isothiocyanates Ar2CONCS.583 The
573 P. C. Keller, Inorg. Chem., 1982,21, 445.

574 T. Burgemeister, R. Grobe-Einsler, R. Grotstollen, A. Mannschreck, and G. Wulff,
Chem. Ber., 1981, 114,3402.
575 N. V. Vasilev, A. F. Kolomiets, and Z. Sokolskii, Zh. Vses. Khim. 0 - va , 1981,26,
350 (Chem. Abstr., 1981,95, 132 772).
576 K. Nandi and J. Goerdeler, Chem. Ber., 1981, 114, 1972 (Chem. Abstr., 1981, 95,
42 968).
577 J. L. Kice and S.-T. Liao, J. Org. Chem., 1981, 46, 2691 (Chem. Abstr., 1981, 95,
24 435).
578 W. Weber and K. Niedenzu, J. Organomet. Chem., 1981, 2 0 5 , 147 (Chem. Abstr.,
1981,95,62 078).
579
R. Goetze, H. Noth, H. Pommerening, D. Sedlak, and B. Wrackmeyer, Chem. Ber.,
1981, 114,1884 (Chem. Abstr., 1981,95,60836).
W. Weber and K. Niedenzu, Synth. React. Inorg. Metal-Org. Chem., 1981, 11, 211
(Chem. Abstr., 1981,95,43054).
( a) M. M. Krayushkin, A. M. Beskopylny, S. G. Zlotin, G. A. Stashina, and V. M.
Zhulin, Dokl. Akad. Nauk S S S R , 1981, 259, 370; ( b ) M. M. Krayushkin, V. N.
Yarovenko, 0. A. Lukyanov, and V. M. Zhulin, Izv. Akad. Nauk SSSR, Ser. Khim.,
1981,2764.
582
V. Grakauskas and A. H. Alber, J. Heterocycl. Chem., 1981, 18, 1477.
583 M. Uher, J . Foltin, F. Povazanec, and J. Kovac, Collect. Czech. Chem. Commun.,
1981,46,1492.
thermal conversion of the oxime (5 14) into the oxadiazole (516) proceeds via
the valence tautomer (5 15).’% The naphthoxytetrazole (5 17), obtained from
1-naphthol and 5-chloro-1-phenyltetrazole, is reduced to naphthalene by the
action of hydrazine in the presence of palladium.585 The tetrazolinone (5 18;
X = 0)affords the diaziridinone (5 19) on photolysis, while the corresponding
thione (518; X = S) decomposes to nitrogen, sulphur, and NN‘-dimethyl-
carbodi-imide .586 Dehydrodithizone (520) adds benzyne to yield the azimine
(521); with diphenylcyclopropenethione,the adduct (522) is formed.587
Ph
(514)
N=N
I I
MeNKNMex
Several other reports on tetrazoles have a ~ p e a r e d . ’ ~ ~ - ’ ~ ~

Other Systems. - The meso-ionic oxatriazolium oxides (523) are formed by
the action of sodium acetate on the hydrazones A~NHN=CBTNO~.’~~ The
NAr
(523)
-0
584 J . Plenkiewicz and T. Zdrojewski, Bull. SOC.Chim. Belg., 1981,90, 193.

585 I. D. Entwistle, B. J . Hussey, and R. A. W. Johnstone, Tetrahedron Lett., 1980,
21,4747.
586 H. Quast and L. Bieber, Chem. Ber., 1981, 114,3253.
”’ K. T. Potts, A. J . Elliott, G. R. Titus, D. At-Hilal, P. F. Lindley, G. V. Boyd,and T.
Norris, J. Chem. SOC.,Perkin Trans. I , 1981,2692.
R. N. Butler, V. C. Garvin, and T. M. McEvoy, J. Chem. Res. ( S ) , 1981,174 (Chem.
Abstr., 1981,95,114 552).
’” L. I. Vereshchagin, A. V. Maksikova, L. G. Tikhonova, S. R. Buzilova, and G. V.
Sakovich, Khim. Geterotsikl. Soedin., 1981, 688 (Chem. Abstr., 1981,95, 1 1 5 398).
D. Moderhack, Z . Naturforsch., Teil. B, 1981, 36, 656 (Chem. Abstr., 1981, 95,
114 332).
s91 D. Moderhack, Chem.-Ztg., 1981, 105,194 (Chem. Abstr., 1981,95,132 767).
s92 V. P. Shchipanov and N. A. Klyuev, Khim. Geterotsikl. Soedin., 1981, 694 (Chem.
Abstr., 1981,95,132 762).
272 Heterocyclic Chemi s t y
amidrazone hydrochloride MeC(NI-i2)=NNHMe.HCl reacts with phosphorus
pentachloride to yield the triazaphosphole (524), which forms the dimer
(525). 594
C 1 N, N
,
c12
I I
9 Compounds containing Two Fused Five-Membered Rings ( 5 3 )

Hypervalent Sulphur and Selenium Compounds. - Treatment of the amino-
thiatriazole (526) with benzoyl chloride yields the dioxathiadiazapentalene
(527) with loss of nitrogen; N-phenylbenzimidoyl chloride, PhCCl=NPh,
affords the nitrogen analogue (528).595 The oxadiselenazapentalene (529 ;
X = Se) undergoes selenium-oxygen exchange on treatment with mercury(I1)
acetate to give 3,4-dimethyl-l ,6-dioxa-6ah4-selena-2-azapentalene(529 ;
X = O).596Compound (530) forms the rearranged adduct (531) with phenyl
isothiocyanate .597
593 M. N. Martynova, M. S. Pevzner, N. A. Smorygo, and N. M. Serebryakova, Khim.

594 (a) A. Schmidpeter, H. Tautz, and F. Schreiber, 2. Anorg. Allg. Chem., 1981, 475,
211; ( b ) H. Tautz and A. Schmidpeter, Chem. Ber., 1981, 114, 825.
595 G. L'abbi and G. Vermeulen, Bull. SOC. Chim. Belg., 1981, 90, 89.
596 D. H. Reid, R. Walker, and R. G. Webster, J. Chem. SOC., Perkin Trans. I , 1981,
1596.
59' R. J. S. Beer, H. Singh, D. Wright, and L. K. Hansen, Tetrahedron, 1981, 37, 2485.
Nitrogen Systems. - Monoaza-Compounds. Gas-phase pyrolysis of the

condensation product (532) of pyrrole-2-aldehyde with Meldrum's acid gives
pyrrolizin-3-one (533).598 The acid chloride (535) is produced by the action
of phosphorus pentachloride on the pyrrole derivative (534).'" Treatment of
the enamine (536) with dimethyl acetylenedicarboxylate in methanol yields,
inter alia, the diester (5376).@' A'(')-Dehydropyrrolizidine undergoes dimeri-
zation to yield mainly compound (538).601 The pyrroloindoloquinone (540)
is produced by irradiation of the benzoquinone derivative (539).602
H
(534) (535)
H -
N /
Ph
(537) E = COOMe
0
E
(539) ( E = COOEt) (5401
59a H. McNab, J. Org. Chem., 1981, 46, 2809.

599 R. Neidlein and G. Jeromin, Chem. Ber., 1982, 115, 706.
6oo W. Verboom, G. W. Visser, W. P. Trompenaars, D. N. Reinhoudt, S. Harkema, and
G. J. Van Hummel, Tetrahedron, 1981, 37,3525.
601 K. Sumoto, S. Fujii, 0. Yamashita, T. Somehara, and S. Miyano, J. Heterocycl.
Chern., 1981, 18,413.
602 M. Akiba, S. Ikuta, and T. Takada, Heterocycles, 1981, 16, 1579.
Dzizza- and Triaza-Compounds. The photochemical rearrangement of the
anti-‘bimane’ (541) to the fused oxazinone (542) has been r e p ~ r t e d . ~ ~
4-Ary1-3,S-dihydroxypyrazoles (543) condense with acetylacetone to afford
the novel ‘paraionic’ 8~-betaines(544).604 The isomerization (545) -+(546)
has been observed.@” The urazole (547) adds the thioketen NCPhC=C=S
to form the heterocycle (548).606 Dye-sensitized photo-oxygenation of the
pyrazolo [ 1,24z]benzotriazole (549) yields mainly the epoxide (550).‘07
OH :I
0
I
Me
(543) (544)
(542 1
&,: N\N
(545)
( E = COOMe)
(547)
A mo
603 H. Kanety, H. Dodiuk, and E. M. Kosower, J. Org. Chem., 1982, 47,207.

‘04 G. Zvilichovsky and M. David, J. Org.Chem., 1982,47,295.
R. J . Sundberg and B. C. Pearce, J. Org. Chem., 1982, 47, 725.
606 L. Capuano, F. Braun, J. Lorenz, R. Zander, and J . Bender, Liebigs Ann. Chem.,
1981, 1361.
607 A. Albini, G. F. Bettinetti, G. Minoli, and G. Vasconi, J . Chem. SOC., Chem.
Commun., 1981, 1089.
Other work on aza-compounds will be found in references 608-6 16.
Other Systems. - Treatment of the spiro-compound (55 1) with lead(1V)
acetate results in insertion of oxygen, with the formation of the stable
diacyl ortho-ester (552).617 The furazan (553) reacts with nitrosobenzene to
yield the betaine (554).618
For other papers, see references 6 19-622.
608 S. Miyano, 0. Yamashita, S. Fujii, T. SOmehara, K. Sumoto, F. Satoh, and T. Masuda,

Heterocycles, 1981, 16, 755 (Chem. Abstr., 1981,95,61 903).
609 K. Maruyama and Y. Kubo, J. Org. Chem., 1981, 46, 3612 (Chem. Abstr., 1981,
95,96 552).
610 M. E. K. Cartoon and G. W. H. Cheeseman, J. Orgunomet. Chem., 1981, 212, 1
(Chem. Abstr., 1981,95,80 631).
611 E. M. Kosower, D. Faust, M. Ben-Shoshan, and I. Goldberg, J. Org. Chem., 1982,47,
214 (Chem. Abstr., 1982, 96,35 156).
P. Merot, C. Gadreau, and A, Foucaud, Tetrahedron, 1981, 37, 2595 (Chem. Abstr.,
1982,96, 34 997).
613 F. S. Babichev, Yu. L. Briks, and N. N. Romanov, Ukr. Khim. Zh. (Russ. Ed.), 1981,
47, 735 (Chem. Abstr., 1981,95,115407).
614 A. Albini, G. F. Bettinetti, and G. Minoli, J. Chem. SOC.,Perkin Trans. I , 1981, 1821
(Chem. Abstr., 1981,95, 1 1 5 457).
H. A. Elfahdam, K. U. Sadek, G. E. H. Elgemei, and M. H. Elnagdi, Chem. Lett.,
1982,119(Chem. Abstr., 1982,96,162583).
616 V, A. Chuiguk and Yu. A. Fedorov, Khim. Geterotsikl. Soedin., 1981, 991 (Chem.
Abstr., 1981, 95,169090).
617 S. Mohr, Angew. Chem., Int. Ed. Engl., 1981,20, 689.
6 1 8 I. V. Tselinskii, S. F. Melnikova, and S. N. Vergizov, Zh. Org. Khim., 1981, 17,
1123.
619 V. Sudarsanam, K. Nagarajan, K. R. Rao, and S. J. Shenoy, Tetrahedron L e f t . , 1980,
21,4757 (Chem. Abstr., 1981,95,24902).
620 T. P. Kofman and M. S. Pevzner, Khim. Geterofsikl. Soedin., 1981, 1403 (Chem.
Abstr., 1982, 96,52 238).
621 R. P. Soni, J. Prukt. Chem., 1981, 323, 516 (Chem. Abstr., 1981,95,150536).
622 L. Bihats and P. Hencsei, Mugy. Kem. Foly., 1981, 8 7 , 137 (Chem. Abstr., 1981,
95, 169 078).
10 Compounds containing Fused Five- and Six-Membered
Rings (5,6)
Nitrogen Systems. - Monoaza- and Diaza-Compounds. Indolizine ( 5 5 5 )
dimerizes to 3,3’-bi-indolizine on heating with palladium in ~ y l e n e . 6The
~~
reaction of 2-methylindolizine with tropone yields a mixture of compound
(5 56) and its 3 ’,4‘ -dihydr o-der ivative .624
3
(555)
2-Aminopyridine condenses with 2,3-epoxybutanal to give the azaindo-

lizine (557).625 The coupling product of the piperidino-enamine C5HI0-
NCH=CHC02Et with benzenediazonium fluoroborate affords compound
(558) on treatment with triethylamine; the reader is referred to the original
paper626 for an explanation of this interesting reaction. The action of p -
bromoacetylpyridine on 2-aminopyridine N-oxide leads to the hydroxyaza-
indolizine (559) .627 1-Aminobenzimidazole condenses with acetophenone in
the presence of zinc chloride to afford the pyrido [ 1,2-a] benzimidazole
( 5 60) .628 The cy clization product of die thy1 di(o -nitrobenzy1)malona te has
structure (561), contrary to a previous report.629 The action of bromine on
07 CHMeOH O J C O O E t
(558)
Q=*:
(557) (559 1
Ph 0-
623 A. Kakehi, S. Ito, A. Hamaguchi, and T. Okano, Bull. Chem. SOC. Jpn., 1981, 54,
2833.
624 Y. Yamashita, D. Suzuki, and M. Masumura, Heterocycles, 1981, 16, 1697.
625 W. C. Lumma, Jr., and J. P. Springer, J. Org. Chem., 1981, 46, 3735.
626 C. B. Kanner and U. K. Pandit, Tetrahedron, 1981, 37, 3519.
627 L. W. Deady and M. S. Stanborough, Aust, J. Chem., 1981, 34, 1295.
628 V. V. Kuzmenko, V. N. Komissarov, and A. M. Simonov, Khim. Geterotsikl. Soedin.,
1981,1497.
629 K. Gorlitzer and J. Weber, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 850.
the perchlorate (562) yields the azetopyridinium salt (563), as shown by X -

ray crystallography.6m
Ph
Q\
=1 N V " H 2
c104
-
- QNTp \
c104
-
-- B r
Ph
(562) (563)
Triaza-Compounds. 2-(E thoxymethy1eneamino)pyridine is converted into

the triazolopyridine (564) by the action of hydroxylamine-0-sulphonic
a ~ i d . 6 ~ Anodic
' oxidation of the hydrazone Ar'NHN=CHAr2 (Ar' = p-
NO2C6H4, Ar2 =p-MeC6H4) in the presence of pyridine and tetraethyl-
ammonium perchlorate affords the salt (565).632 Oxidative cyclization of the
pyridylhydrazone PyCH=NNHPy (Py = 2-pyridyl) by means of mercury( 11)
acetate yields compound (566).633 2,4,6-Triphenylpyrylium fluoroborate
reacts with amidrazones ArC(NH2)=NNH2 in the presence of triethylamine
to give the pyrazolopyrimidines (567).634 The tricyclic compound (568) is
(564 1 PY Ar
(565) (566 ) (567)
0 (568)
H
obtained by the reaction of 2-aminobenzimidazole with diphenylcyclo-
p r ~ p e n o n e . ~ Compound
~' (569), an analogue of isoindole, undergoes ring-
expansion to the pyridazinoquinoxaline (570) on treatment with sodium
EN-NHE
OH
E. E. Glover, D. J. Pointer, J. B. Wilford, and M. Elder, J. Chem. SOC., Chem.

Commun., 1981,481.
Y.-I. Lin and S. A. Lang, Jr., J. Org.Chem., 1981,46,3123.
632 1. Tabakovic and S. Crljenak, Heterocycles, 1981, 16, 699.
633 R. N. Butler and S. M. Johnston, J. Chem. Soc., Chem. Commun., 1981, 376.
634 A. R. Katritzky and. A. T. Thomas, Heterocycles, 1982, 18, (Spec. Issue), p. 21.
T. Eicher and G. Franke, Liebigs Ann. Chem., 1981, 1337.
278 Heterocyclic Chemistiy
Several interesting transformations of pyrazolo [ 1,541 -
pyrimidines have been described. The diester (571) reacts with phenol with
cleavage of the pyrimidine ring to yield the cyclohexadienone derivative
(572).637 Treatment of the cyclopropa-compound (573) with ethanol leads
to the pyrazolo-azepine (574),638 while N-methylaniline gives, inter alia, the
pyrrole (575) and the pyridone (576).639
E COOE t
CN H CN CN
bNqm
(571) (572) (573)
( E = COOEt)
Drn CN PhMeN /
(575
(574) H CN AC (576)
Tetra-aza-Compounds and a Penta-aza-Compound. The 4H-imidazole (577)

reacts with formamidine to yield the rearranged product (578).@' The
betaine (579) is reporteda' to isomerize to compound (580) when irradiated.
Thermolysis of the tetrazoloquinoxalines (581 ; X = 0 or NPh) results in the
heterocycles (5 82).642
0- 0
(5771
NH2 (578) (579) (580)
R. Kreher and G. Use, Tetrahedron Lett., 1 9 8 1 , 2 2 , 4 0 4 5 .

"'T. Kurihara and K. Nasu, Chem. Pharm. Bull., 1 9 8 1 , 29, 2520.
T. Kurihara, T. Tani, K. Nasu, M. Inoue, and T. Ishida, Chem. Pharm. Bull., 1981,
29, 3214.
639 T. Kurihara, T. Tani, and K. Nasu, Chem. Pharm. Bull., 1981, 29, 1548.
640 R. S. Hosmane, V. Bakthavachalam, and N. J . Leonard, J. A m . Chem. SOC., 1982,
104, 235.
64 1
H. J . Timpe, R. Burggraf, and U. Lammel, J. Prakt. Chem., 1 9 8 1 , 323, 6 2 7 .
642 E. Lippmann and E. Tober, 2. Chem., 1981, 21, 7 1 .
For other work, see references 643-668.
Mixed Oxygen-Nitrogen Systems and a Diselenoloquinoxaline. - The 0-
methyloxime (583) cyclizes thermally to the furopyridine (584) by way of
643
S. Tanaka and A. Terada, Heterocycles, 1981, 16, 717 (Chem. Abstr., 1981, 95,
1 1 5 248).
644
A. R. Katritzky, N. E. Grazeskowiak, and J. Alvarez-Builla, J. Chem. Soc., Perkin
Trans. I , 1981,1180 (Chem. Abstr., 1981, 95,115212).
645
J. Mirek and A. Haas, J. Fluorine Chem., 1981, 19, 67 (Chem. Abstr., 1982, 96,
35 01 1).
646
Y. Yamashita, D. Suzuki, and M. Masamura, Heterocycles, 1981, 16, 1499 (Chem.
Abstr., 1981,95,203710).
641
A. Arques, H. Hernandez, P. Molina, and M. J. Vilaplana, Synthesis, 1981, 916
(Chem. Abstr., 1982, 96,35 159).
648
Y. Kobayashi, I. Kumadaki, and E. Kobayashi, Heterocycles, 1981, 15,1223 (Chem.
Abstr., 1981,95,7148).
649
R. R. Astikand K. A. Thaker, J. Indian Chem. SOC., 1981, 58, 1013 (Chem. Abstr.,
1982,96,52 227).
6 50
I. Jirkovsky and R. Baudy, Synthesis, 1981,481 (Chem. Abstr., 1981,95,132 81 2).
651
S. Mataka, K. Takahashi, and M. Tashiro, J. Heterocycl. Chem., 1981, 18, 1073
(Chem. Abstr., 1982,96, 52 223).
652
H.Meyer, Liebigs Ann. Chem., 1981, 1523 (Chem. Abstr., 1982,96,35 161).
653
V. A. Azimov, N. N. Bychikhina, and L. N. Yakhontov, Khim. Geterotsikl. Soedin.,
1981, 1283 (Chem. Abstr., 1981,95,219982).
6 54
E. W. Collington, D. Middlemiss, T. A. Panchal, and D. R. Wilson, Tetrahedron Lett.,
1981, 2 2 , 3675 (Chem. Abstr., 1982,96,35 167).
655
H. Gnichtel and B. Moeller, Liebigs Ann. Chem., 1981, 1751 (Chem. Abstr., 1982,
96,20023).
6 56
S. Veeraraghavan and F. D. Popp, J. Heterocycl. Chem., 1981, 18, 905 (Chem.
Abstr., 1981, 95.219 983).
651
S. Veeraraghavan and F. D. Popp, J. Heterocycl. Chem., 1981, 18, 775 (Chem.
Abstr., 1981,95,150 594).
658
K. Matoba, K. Itoh, K. Kondo, T. Yamazaki, and M. Nagata, Chem. Pharm. Bull.,
1981,29, 2442 (Chem. Abstr., 1982,96,6687).
659
K. Takeda, K. Shudo, T. Okamoto, and T. Kosuge, Chem. Pharm. Bull., 1981, 29,
1282 (Chem. Abstr., 1981,95,97 634).
660
0. Neilands, D. Rikule, B. Adamsone, V. Kampars, and G. Pukitis, Latv. P.S.R.
Zinat. Akad. Vestis, Kim. Ser., 1980,663 (Chem. Abstr., 1981,95,6990).
66 1
C.-S. Lee, T. Ohta, K. Shudo, and T. Okamoto, HeterocycZes, 1981, 16, 1081 (Chem.
Abstr., 1981,95,203 786).
66 2
M. H. Elnagdi and H. Wamhoff, Chem. Lett., 1981, 419 (Chem. Abstr., 1981, 95,
24 975).
663
E. P. Papadopoulos, J. Heterocycl. Chem., 1981, 18, 515 (Chem. Abstr., 1981,95,
97 71 8).
664
G. U. Baig and M. F. G. Stevens, J. Chem. SOC.,Perkin Trans. I , 1981,1424 (Chem.
Abstr., 1981,95,97 740).
66 5
G. Ege and K. Gilber, J. Heterocycl. Chem., 1981, 18, 695 (Chem. Abstr., 1981,
95,169140).
666
H. J. Timpe, S. Missal, R. Manzoor, and E. Affi, J. Prakt. Chem., 1981, 323, 459
(Chem. Abstr., 1981,95,131 861).
667
J. K. Horton and M. F. G. Stevens, J. Chem. SOC., Perkin Trans. I , 1981, 1433
(Chem. Abstr., 1981, 95,97666).
668
A. A. Konstantinchenko, P. I. Lyashenko, and A. F. Pozharskii, Khim. Geterotsikl.
Soedin., 1981, 1114 (Chem. Abstr., 1981,95,220014).
an iminyl The pyridinium salt (585) is converted into compound
(586) by the action of nickel-aluminium alloy in alkaline solution.6m
Heating the Schiff‘s base (587) gives a mixture of stereoisomeric products
(589), whch are formed by an intramolecular cycloaddition reaction of the
dipolar tautomer (588)?” The kinetics and regiochemistry of the addition
of various olefins to the oxazoloisoquinolinium salts (590) (obtained from
Reissert compounds) to yield pyrroles (59 1) have been The
(588)
(E = COOMe)
Ar
R1 0
669 C. L. Hickson and H. McNab, Synthesis, 1981,464.

670 G . Fukata, T. Itoh, and M. Tashiro, Chem. Lett., 1981,1345.
0. Tsuge, K. Ueno, and I. Ueda, Heterocycles, 1981, 16, 1503.
6 I2
W. E. McEwen, M. A. Hernandez, C.-F.Ling, E. Marmugi, R. M. Padronaggio, C. M.
Zepp, 111, and J . J . Lubinkowski, J. Org. Chem., 1981,46,1656.
urea (592) cyclizes to the betaine (593) under the influence of triphenyl-
~ ~ furan analogue (594) of isatoic
phosphine and carbon t e t r a ~ h l o r i d e . The
anhydride, unlike the latter, is attacked by oxygen and nitrogen nucleophiles
solely at the amide carbonyl group.674 A photochemical isoxazole -+ oxazole
rearrangement, (595) + (596), has been observed for the isoxazolo[4,5c] -
pyridine system.675 The oxadiazinobenzimidazole (597) is cleaved to 2-
(dimethoxymethy1)benzimidazole and benzamide on photolysis in
methanol .676
0
Ph Ph H
(592 (593) ( 594
(595
The novel fused diselenole (599) has been prepared by treatment of the
quinoline-derivative (598) with sodium hydrogen ~ e l e n i d e . ~ ~ ~
6 13
P. Molina, M. Alajarin, A. Arques, and R. Benzal, J. Chem. SOC., Perkin Trans. 1 ,
1982, 351.
6 14
J. B. Press, N. H. Eudy, and T. 0. Olagbemiro, J. Org. Chem., 1981, 46, 3853.
615
G. Adembri, A. Camparini, D. Donati, F. Ponticelli, and P. Tedeschi, Tetrahedron
Lett., 1981, 2 2 , 2 1 2 1 .
676 B. R. Rao, G. Mohiuddin, and K. Ahmed, Indian J. Chem., Sect. B , 1 9 8 1 , 2 0 , 1 5 8 .
671
T. K. Raja, J. Indian Chem. SOC., 1981, 5 8 , 1 7 4
Several other reports on mixed systems have been p ~ b l i s h e d . 6 ~ ~ - ~ ~
11 Compounds containing Fused Five- and Seven-Membered

and Fused Five- and Eight-Membered Rings [(5,7), (5,5,7),
(5,7,7), and (5,5,8)1
The azepino-indole (600; E = C02Me) is produced by thermolysis of methyl
2-azidodiphenylmethane-4'-carboxylate,N3C6H,CH2C6H4C02Me.685 Treat-
ment of the pyrrolo-azepine (60 1) with benzoylmethylenetriphenyl-
phosphorane, PhCOCH=PPh3, yields the bridged compound (602) by
successive Michael addition and intramolecular Wittig reaction.686 The
imidazo-azepine (604) is formed from (603) by ring-expansion with diazo-
methane.687 Addition of dimethyl acetylenedicarboxylate to the cyclo-
E t OOC Ph
EtOOC
(603) (604)
678 N. Desideri, F. Manna, and M. L. Stein, J. Heterocycl. Chem., 1981, 18, 1085 (Chem.
Abstr., 1982,96, 52 201).
6 7 9 G. Haas, J. L. Stanton, and T. Winkler, J. Heterocycl. Chem., 1981, 18, 619 (Chern.
Abstr., 1981, 9 5 , 9 7 721).
'*' D. H. Kim, J. Heterocycl. Chem., 1981, 18, 1389 (Chem. Abstr., 1982,96,217741).
F. L. Merchan, Synthesis, 1981, 965 (Chem. Abstr., 1982, 96, 122 710).
J . M. Paris, J . M. Couquelet, and M. M. Payard, Tetrahedron Lett., 1981, 22, 1591
(Chem. Abstr., 1981, 9 5 , 9 7 657).
683 S. F. Vasilevskii, V. A. Gerasimov, and M. S . Shvartsberg, Izv. Akad. Nauk SSSR,
Ser. Khim., 1981, 902 (Chem. Abstr., 1981, 95, 97658).
684 S. K. Kotovskaya, G. A. Mokrushina, 1,Ya. Potovskii, and M. V. Polyakova, Khim.
Geterotsikl. Soedin., 1981, 654 (Chem. Abstr., 1981, 95, 114439).
6 8 5 R. N. Carde, P. C. Hayes, G. Jones, and C. J. Cliff, J. Chem. SOC.,Perkin Trans. I ,
1981, 1132.
W. Flitsch and E. R. F. Gesing, Chem. Ber., 1981, 114, 3146.
687 T. Kurihara, T. Tani, and K. Nasu, Heterocycles, 1981, 16, 1677.
heptapyrrole (605) yields compound (606).688 The acetylenic ester reacts
with 3-methyl-2-phenylindolizine[cf. ( 5 5 5 ) ] t o yield the fused azocine
(607), whose structure was established by X-ray ~rystallography.~~’
CN
CN
/ Me Ph
For other articles on these systems, see references 690-701.
N. Abe and T. Nishiwaki, Bull. Chem. SOC.Jpn., 1981, 54, 1277.

689 C. M. Gupta, R. K. Rizvi, S. Kumar, N. h a n d , M. R. N. Murthy, and K. Venkatesan,
Indian J. Chem., Sect. B , 1981, 20, 735.
690 U. Wolf, Z. Nuturforsch., Teil. B , 1981, 36, 383 (Chem. Abstr., 1981, 95, 7155).
691 A. Hallberg and A. R. Martin, J. Heterocycl. Chem., 1981, 18, 1255 (Chem. Abstr.,
1982, 96, 19 939).
6 9 2 S. Nakatsuka, H. Miyazaki, and T. Goto, Chem. Lett., 1981, 407 (Chem. Abstr.,
1981, 95, 7110).
6 9 3 A. M. Vega, M. T. Martinez, J. A. Palop, J. M. Mateo, and E. Fernandez-Alvarez,
J. Heterocycl. Chem., 1981, 18, 889 (Chem. Abstr., 1982, 96, 104 201).
694 M. Chabannet and S. Gelin, J. Chem. Res. ( S ) , 1982, 20 (Chem. Abstr., 1982, 96,
199 647).
6 9 5 J. W. Dick, W. K. Gibbon, D. Leaver, and J. E. Roff, J. Chem. SOC.,Perkin Trans. I ,
1981, 3150 (Chem. Abstr., 1982,96, 122 597).
696 S. Ito, T. Ohizumi, a n d T. Maeda, J. Org. Chem., 1982, 47, 369 (Chem. Abstr.,
1982, 96, 35 138).
697
M. G. Beal, W. R. Ashcroft, M. M. Cooper, and J. A. Joule, J. Chem. SOC.,Perkin
Trans. I , 1982, 435 (Chem. Abstr., 1982, 96, 199 642).
6 9 8 Atta-ur-Rahman a nd N. Waheed, J. Chem. SOC. Pak., 1981, 3 , 167 (Chem. Abstr.,
1982,96, 122 664).
6 9 9 J. E. Johansen, B. D. Christie, and H. Rapoport, J. Org. Chem., 1981, 46, 4914
(Chem. Abstr., 1981, 95, 203 791).
looD. Tourwe, E. De Cock, a n d G. Van Binst, J. Org. Chern., 1981, 46, 5321 (Chem.
Abstr., 1981, 95, 219 689).
70’ G. Rihs, H. Fuhrer, and A. Marxer, Helv. Chim. Acta, 1981, 64, 769 (Chem. Abstr.,
1981, 95, 97 656).
Six-Membered Ring Systems
BY S. D. CARTER, G.W. H. CHEESEMAN,AND G.P. ELLIS
PART I: Systems containing Nitrogen by S. D.Carter and G. W. H. Cheeseman
1 Introduction
The format of the previous year has been retained. The reader's attention is
drawn to the terminal classified reference list. This has been compiled from
references which it has not been possible t o include in the text.
2 Reviews
In the past year, reviews on l,8-naphthyridines7' perimidines,2 polyazaphen-
a n t h r e n e ~ ,3-azabicyclo[3.3.l]nonanes~
~ and 1,2- and 2,l-benzothiazines'
have appeared. Reviews on specialist aspects of pyridine chemistry are
devoted to the reactions of newly available pyridines; a,a'-disubstituted
pyridines,' the reactions of pyridines with nucleophiles,8the electrochemistry
of 1,l'-disubstituted 4,4'-bipyridinium ions (the viologens such as paraquat):
dihydropyridines," and 4-aryl-dihydropyridines (a new class of calcium
antagonists)." Reviews have been published on the cyclization of oximes and
amides to quinolines and isoquinolines,12 quinoline- and isoquinoline-
diones,13 benzo[a]- and benzo[c]-quinolizinium ions,14 azachrysene prepar-
ation," quinazolines with plant-growth-regulating and biocidal activities,16
quinazolines in pharmaceutical research," isotopic hydrogen exchange in
W. Czuba, Wiad. Chem., 1980,34,593 (Chem. Abstr., 1981,95,24860).
' A. F. Pozharskii and V. V . Dal'nikovskaya, Russ. Chem. Rev. (Engl. Transl.), 1981,
50, 816.
W.Sliwa and H . Zamarlik, Wiad. Chem., 1980, 34, 631 (Chem. Abstr., 1981, 95,
24 859). -b
R . Jeyaraman and S. Avila, Chem. R e v . , 1981,81,149.
D. E. Kulha,Adv. Hererocycl. Chem., 1981,28,73.
H. Beschke, Aldrichimica Acra, 1981,14, 13.
L. N. Yakhontov and D. M. Krasnokutskaya, Rum. Chem. Rev. (Engl. Transl.), 1981,
50, 565.
A. N. Kost, S. P. Gromov, and R. S. Sagitullin, Tetrahedron, 1981,37,3423.
C. L. Bird and A. T. Kuhn, Chem. SOC.R e v . , 1981,10,49.
l o D. M. Stout and A. I. Meyers, Chem. Rev.,1982,82,223.
F. BOssert, H. Meyer, and E. Wehinger, Angew. Chem., Int. Ed. Engl., 1981,20, 762.
S. Goszcznski, T. Kopezynski, and M. Lozynski, Chem. Inz. Chem., 1980, 15, 57
(Chem. Abstr., 1981,95,97463).
l 3 J. Mlochowski and J. Piatkowska, Wiad. Chem., 1981, 35, 25 (Chem. Abstr., 1981,
95,150 297).
l4 S.-U.-D. Saraf, Heterocycles, 1981, 16,803.
l 5 M. J. Hearn and S. L. Swanson, J. Hererocycl. Chem., 1981,18,207.
l6 M. Susse and S. Johne, 2. Chem., 1981,21,431.
17
S . Johne, Pharmazie, 1981,36,583.
285
purines," aza- and deaza-analogues of purine n u c l e o ~ i d e s , and ~ ~ adenine
analogues used as dimensional probes of enzyme-coenzyme binding sites.20
Reviews dealing with various aspects of synthesis have covered high-pressure
reactions,21 the use of transition metals,22enamide photocyclizations (leading
mostly t o fused p y r i d i n e ~ ) and, ~ ~ the utility of more specific synthons such as
vinylacetylenes and d i a c e t y l e n e ~ ?malononitrile
~ derivatives," and isatoic
anhydrides.26 Reactivity aspects are reviewed in articles on the photo-
chemistry of nitrogen-containing hetero~ycles,2~phase-transfer
, ~ ~ the reactions of benzyne3' and of carbenes and nitrenes31
h e t e r o - a r y n e ~and
with heterocyclic compounds. In addition, reviews on heteroaromatic
N-imines and N-amino-azonium salts,32 "N-labelled compounds ,33 and barriers
t o inversion of N-methyl groups in six-membered rings34 are now available.
3 Azines and their Hydro- and Benzoderivatives

Pyridines. -Synthesis. A key step in a synthesis of optically active nicotine
derivatives is the hydrogen-bromide-induced cyclization of the nitrile (1) t o
the bromopyridine (2).3'
OH
I
EtO
Me
Is J . R. Jonesand S. E. Taylor, Chem. SOC.Rev., 1981, 10, 329.

l9 T. D. Miniker and M. N. Preobrazhenskaya, Chem. Heterocycl. Compd. (Engl. Trunsl.),
1981,17,97.
2o N. J. Leonard, Acc. Chem. Res., 1982, 15, 128.
21 K. Matsumoto, T. Uchida, and R. M. AchesokHeterocycles, 1981, 16, 1367.
22
( a ) J . L. Davidson and P. N. Preston, Adv. Heterocycl. Chem., 1982, 30, 319;
( b ) L. S. Hegedus, J. Orgunomet. Chem., 1981, 207, 185.
23 I. Ninomiya and T. Naito, Heterocycles, 1981, 15, 1433.
24 I. A . Maretina, A . E. Tsil'ko, and Yu. A. Zaichenko, Russ. Chem. Rev. (Engl.
Trunsl.), 1981, 5 0 , 657.
2 5 F. Freeman, Synthesis, 1981, 925.
26 ( a ) G. M. Coppola, Synthesis, 1980, 505; ( b ) T. Kappe and W. Stadlbauer, Adv.
2' S. T. Reid, Adv. Heterocycl. Chem., 1982, 30,239.
2 8 R . Gallo, H. J.-M. DOU,and P. Hassanaly, Bull. SOC.Chim. Belg., 1981, 90, 849.
2 9 M. G. Reinecke, Tetrahedron, 1982, 38,428.
30 M. R. Bryce and J . M. Vernon, A d v . Heterocycl. Chem., 1981, 28, 183.
3 1 C. Wentrup, Adv. Heterocycl. Chem., 1981, 28,232.
32 Y. Tamura and M . Ikeda, A d v . Heterocycl. Chem., 1981, 29,71.
33 W. Freyer, 2. Chem., 1981, 21,47.
34 A . R. Katritzky, R. C. Patel, and F. G. Riddell, Angew. Chem., Int. Ed. Engl., 1981,
20, 521.
35 C. G. Chavdarian, E. B. Sanders, and R . L. Bassfield, J . Org. Chem., 1982, 47, 1069.
Six-Membered Rings: Systems containing nitrogen 287
A further example of a one-bond-forming pyridine synthesis is provided by
the intramolecular cyclization of 0-alkyl-oximes such as (3) under conditions
of flash vacuum pyrolysis. Cyclization occurs as a result of the generation of
conjugated iminyl radicals (4) (Scheme l).36
(3) (4) (x = 0 or S)
Scheme 1
Di- and tri-acylated imines, formed by the reaction of aldehydo- or keto-

esters with aza-Wittig reagents [Ph3P=NCOR], are moderately active dieno-
philes. Cycloaddition occurs with a good degree of regiospecificity, as illus-
trated by the example shown in Scheme 2.37
MegSiO
x+ IOMe
N
COOBut
benzene
ref lux
Scheme 2
15 h o u r s
[ 84%]
The sigma-complexes of cyclobutadienes and aluminium halides react with

activated nitriles (e.g. Et0,CCN) to yield substituted pyridines. The sigma-
complexes are themselves formed by aluminium-bromide-promoted cyclo-
dimerization of alkynes (Scheme 3).38In an extension of this work, Dewar-
H
Ill
R
-
Reagents: i, AlBr,, CH,Cl,; ii, EtOOCCN
Scheme 3
pyridones have been prepared in a one-pot synthesis from alkynes, aluminium
halides, and isocyanates (Scheme 4).39
It is of interest that the reaction of alkynes with isocyanates in the
presence of bis(cyc10-octa-l,5 -diene)nickel(O) and tricyclohexylphosphme
36 C. L. Hicken and H. M . McNab, Synthesis, 1981,464.

37 M. E. Jung, K. Shishido, L. Light, and L. Davis, Tetrahedron L e t t . , 1981, 22,*4607.
H. Hogeveen, R. F. Kingman, and D. M . Kok, J. Org. Chem., 1982,47,989.
39 H.Hogeveen and D. M. Kok, J. Org. Chem., 1982,47,997.
1;
Me
Me
+ MeNCO --
A1C13
Me
185x1
Scheme 4
gives the isomeric 2-pyrid0nes.~A further application of alkynes to pyridine
synthesis involves the cycloaddition of alkynes to a,w-cyano-alkynes, using
dicarbonyl(cyclopentadieny1)cobalt as catalyst (Scheme 5).41
Scheme 5
A number of syntheses of pyridines and of reduced pyridine rings have
been based on reactions in which azabutadienes participate, Thus 3,4-
dihydropyridones are formed by reactions of 1-azabutadienes with the
ih+
lithium enolates of substituted acetates (Scheme 6).42
Ph
EtOOCU i,ii
NMe
Me
Reagents: i, room temperature for 20 hours; ii, H,O [ 78761
Scheme 6
Pyridones have also been prepared by Eels-Alder addition of 2-azabuta-
dienes with alkynes as shown in Scheme 7.43
Symmetrical 3,5-disubstituted pyridines (7) result from the reaction of
two moles of enamine and one of N-methylene-t-butylamine (5) (Scheme 8).
Under mild conditions, the intermediate aza-dienes (6) can be isolated, thus
offering the further possibility of obtaining unsymmetrically 3 ,5-disubstituted
pyridines by this route.@
40 H. Hoberg and B. W.Oster, Synthesis, 1982,324.
41 D. J . Brien, A. Naiman, and K. P. C. Vollhardt, J. Chem. SOC., Chem. Commun.,
1982,133.
42 M. Komatsu, S. Yamamoto, Y. Ohshiro, and T. Agawa, Tetrahedron L e t t . , 1981,22,
3769.
43 F. Sainte, B. Serckz-Poncin, A.-M. Hesbain-Frisque, and L. Ghosez, J. A m . Chem.
SOC.,1982,104,1428.
44 M. Komatsu, H. Ohgishi, S. Takamatsu, Y. Oshiro, and T. Agawa, Angew. Chem., Int.
Ed. Engl., 1982, 21,213.
BufMe2SiOy ~ 0 \9 COOMe
ii,iii
/’ COOMe
HNKR 0 0s iMe2Bu
R
Reagents: i, CF,S020SiMe2But, Et,N; ii, MeOOCCSCOOMe; iii, HCI

Scheme 7
;lUt (7)
Reagents: i, TsOH, PhH, at 200°C; ii, R’CH=CHNRZ,
(6)
Scheme 8
The use of 1,2,4-triazine in pyridine synthesis has been reported pre-
viouslyp5 it has now been shown that pyridines can be formed by addition of
triazines t o pyrrolidine enamines that are generated in the reaction medium
(Scheme 9).“
1
Me /
Reagents: i, pyrrolidine, CHCl,, 4A molecular sieve
Scheme 9
The formation of pyridines by Diels-Alder addition of dienes and imines
has been further e ~ p l o i t e d . ~ ’
There have been several reports of the use of cyano-acetamides as C-C-N
synthons in pyridone synthesis.& The C-C-C component that is required for
the formation of a six-membered ring may be either an arb-unsaturated
carbonyl compound or a dicarbonyl compound. Alternatively, pyridones have
been formed by base-promoted cyclocondensation of cyano-acetamides with
a-keto-ketene S,N-acetals (Scheme 1O).49
45 S. D. Carter and G. W. H. Cheeseman, in ‘Heterocyclic Chemistry’ Vol. 3 , ed.
H. Suschitzky and 0. Meth-Cohn (Specialist Periodical Reports), The Royal Society
of Chemistry, London, 1 9 8 2 , Chapter 4 .
46 D. L. Boger, J. S. Panek, and M. M. Meier, J. Org. Chem., 1982, 4 7 , 895.
47
S. M. Weinreb, F. Z. Baska, S. Hibino, N. A. Khatri, D. Kim, W. E. Pye, and T.-T. Wu,
J. A m . Chem. SOC., 1 9 8 2 , 1 0 4 , 5 3 6 .
48
J . L. Soto, C. Seoane, and A. M. Mansilla, Org. Prep. Proced. Int., 1 9 8 1 , 13, 331;
A. A. Krauze, Z. A. Bomika, A. M. Shestopalov, L. A. Rodinovskaya, Yu. 8. Pelcher,
G. Ya. Dabur, Yu. A. Sharanin, and V. K. Promonenkov, Khim. Geterotsikl, Soedin.,
1 9 8 1 , 377; V. S. Hawalder and S. V. Sunthankar, Indian J. Chem., Sect. B , 1980, 19,
151.
49 V. Agganval, G. Singh, H. Ila, and H. Junjappa, Synthesis, 1982, 214.
290 Heterocyclic Chemis try
R1
RfsMe +
qCN
d C \ 0
I
R5
Scheme 10
NaOPr
HOPI-’ RYxcN
R1
i
R5
0
It has also been found that the reaction of a-keto-ketene dithioacetals (8)
with the carbanions derived from methyl ketones (9) gives unsaturated 1,5-
dicarbonyl compounds (10). The latter compounds can be ring-closed to
pyridines (1 1) by treatment with ammonium acetate.”
S Me
R1
ap-Unsaturated nitriles such as benzylidenemalononitrile have been used as

three-carbon synthons in pyridine synthesis; ring formation involves initial
Michael addition to the activated double-bond (Scheme 1 1).51
ArCH=C(CNI2 + NCCH2CONHNH2 - i
NcQ
2N
NH2
Reagents: i, piperidine, methanol
Scheme 1 1
Certain aryl-dihydropyridines [e.g. (12)], prepared by conventional
Hantzsch synthesis, have been found to be highly effective calcium antagon-
ists and are used to reduce blood pressure and in the treatment of angina
pect oris .s2
Pyridme derivatives have also been prepared by ring-transformation
reactions. For example, 3-alkoxy-pyridine N-oxides (1 4) result from the acid-
catalysed rearrangement of 1,2-0xazines (1 3).s3
K. T. Potts, M. J. Cipullo, P. Ralli, and G. Theodoridis, J . A m . Chem. Soc., 1981,
103, 3584.
51
J. L. Soto, C. Seoane, P. Zamorano, and F. J . Cuadrado, Synthesis, 1981, 5 2 9 ;
S . Kambe, K. Saito, A. Sakurai, and H. Midorikawa, ibid., p. 531; K. Saito, S. Kambe,
A. Sakurai, and H. Midorikawa, ibid., p. 2 11.
52 F. Bossert, H. Meyer, and E. Wehinger, Angew. Chem., Int. Ed. Engl., 1981, 20, 762.
53 T. L. Gilchrist, G. M. Iskander, and A. K. Yagoub, J. Chem. Soc., Chern. Commun.,
1981,696.
MeoocorMe
Six-Membered Rings: Systems containing nitrogen
R:pNco
Me
H
H
C6H4N02-0
R1O
’0
(13)
H+
R40H ~
i
0-
29 1
Fused pyridines (16) are formed as the major products on flash vacuum
pyrolysis of 0-phenethylsulphonyl azides (1 5). Yields ranging from 41 to 70%
are reported for this complex ring-transformation pro~ess.’~
(15) (16)
x = H , Me, C 1 , or OMe
Pyridines are formed on thermolysis of cycloprop-2-enyloxazolines.

Evidence has been obtained for the intermediacy of azabenzvalenes in these
transformations (see, for example, Scheme 12).”
Ph
Dh
Scheme 12
Properties of Pyridines. Additional carbon-1 3 n . m ~ . , ’nitrogen-1

~ 5 n.rn.~.,’~
U.V. and p h o t ~ e l e c t r o n , and
~ ~ fluorescence spectra” have been reported.
Spin-spin coupling constants in azines have been calculated and compared
54
R. A. Abramovitch, W. D. Holcomb, and S. Wake, J. A m . Chem. Soc., 1981, 103,
1525.
55
A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. A m . Chem.
SOC.,1982, 104,286.
S6
R. Mommisse, E. Freyne, E. Esmans, J . Lepoivre, and F. Alderweireldt, Hetero-
cycles, 1981, 16, 1893.
57
H. J. Jakobsen, P.-Y. Yang, and W. S. Brey, Org. Magn. Reson., 1981, 17, 290.
C. Dreier, J. Becher, E. G. Frandsen,and L. Henriksen, Tetrahedron, 1981, 37,2663.
59
G. Koitz, W. Fabian, H.-W. Schmidt,and H. Junek, Monatsh. Chem., 1981, 112,973.
H
II
0
(17)
with the experimentally determined values for H-H, C-H, N-H, C-C, and
C-N spin-spin coupling constants.60 No evidence could be found that the
2-pyridyl cation (1 8), generated by thermolysis of the thiatriazolopyridine
oxide (17), has any aryne-like properties. For example, with furan, no cyclo-
addition was observed; instead the product of normal electrophilic substi-
tution, i.e. 2-(2-pyridyl)furan, was formed in 30% yield.61
Pyridine rings that are constrained in a biphenylene system show increased
reactivity to aqueous sodium hydroxide. Thus the reaction of 1,8-diazabi-
phenylene (19) with 2.5M sodium hydroxide at 150 "C gives the pyridyl-
pyridone (20) in 96% yield.62
The reaction of pyridine with LDA in HMPA at 0 "C affords mainly 4,4'-
bipyridine. Under these conditions, LDA reacts as a one-electron donor, and
dimerization occurs via a radical-anion ir~termediate.~~ It had been found pre-
viously that, in THF, 2,2'-bipyridine is formed. The reaction of dioxanyl or
cyclohexyl radicals with 2- and 3-substituted pyridines (21 ; R = CN, COMe,
or C02Me) gives a single product, derived from substitution at the 5- and 6-

position, respectively. With 4-substituted pyridines, substitution occurs pre-
ferentially at the 3 - p o ~ i t i o n The
. ~ free-radical carbamoylation of 3-acyl-
pyridines has been used in a general preparation of 2,Sdisubstituted pyridines
(Scheme 13).6s
Outstanding stereochemical problems associated with the biosynthesis of
nicotine have been resolved by 2H n.m.r. measurements.66 An unexpected
6o S. A. T. Long and J . D. Memory, J. Magn. Reson., 1981,44,355.

61 J. F. Bunnett and P. Singh, J . Org. Chem., 1981,46,4567.
6 2 J. A. H. MacBride and P. M . Wright, Tetrahedron L e t t , , 1982,23, 1109.
" G. R. Newkome and D. C. Hager, J, Org. Chem., 1982,47,599.
6 4 D. Chianelli, L. Testaferri, M. Tiecco, and M . Tingoli, Tetrahedron, 1982, 38, 657.
6 5 E. Langhals, H. Langhals, and C. Ruchardt, Liebigs Ann. Chem., 1982,930.
66 I. D.Wigle, L. J . J . Mestichelli, and I. D. Spenser, J. Chem. SOC., Chem. Commun.,
1982,662.
ocoR/ocoRocH
R1R2V-C
II
ii a
HOOC '
293
0
Reagents: i, HCONR'R', ButOOH, FeSO,; ii, N,H,, KOH
Scheme 13
reaction occurs when the 3-acetyl-2-pyridone (22) is heated under reflux with
phosphoryl chloride. This results in the formation of the 3-ethynyl-2-
chloropyridine (23) in 33% yield.67
Pyridines (and quinolines) bearing a trimethylstannyl (SnMe3) substituent
at the 2-, 3-, or 4-position undergo iododemetallation to give the correspond-
ing iodo-derivatives upon treatment with iodine. The trimethylstannyl com-
pounds are themselves prepared by the reaction of the corresponding chloro-
or bromo-derivat ives with t rimethylst annylsodium8! The selective 3 -debro-
mination of 3 ,5-dibromo-4-hydroxy-2-pyridone has been rep0rted.6~ The
reaction of 3 -chloro-4-cyanopyridne with methanolic sodium me thoxide
gives the imino-ether (24) whereas treatment with sodium methoxide in DMF
COMe O C E C H
hl e Me '
gives 4cyan0-3-methoxypyridine.~~ A general method for the formylation of

heterocyclic amines, including 2- and 4-aminopyridinesY involves heating
with trisformamidomethane [HC(NHCH0)3] at 165-1 70 O C . ? l A detailed
study of the reaction of 2-aminopyridine with phenacyl bromides has indi-
cated that the first step is alkylation on the ring nitrogen.72
Amongst the recently reported uses of allenes in heterocyclic synthesis is
the formation of 44minopyridopyrimidines (25) from cyano-allenes and
2-aminopyridines (Scheme 14).73
67 T. Kato, M. Sato,and A. Wagai, J. Heterocycl. Chem., 1981, 1 8 , 603.

68 Y. Yamamoto and A. Yanagi, Heterocycles, 1 9 8 1 , 1 6 , 1161.
69 M. J . Robins, C. Kaneko, and M. Kaneko, Can. J . Chem., 1981, 59, 3356.
70 J. L. LaMattina and R. L. Taylor, J. Org. Chem., 1981, 4 6 , 4179.
71 B. Stanovnik, J . Zmitek, and M. Tigler, Heterocycles, 1981, 1 6 , 2173.
72 E. S. Hand and W. W. Paudler, Tetrahedron, 1 9 8 2 , 3 2 , 4 9 .
73 Z . T. Fomum, J . T. Mbafor, P. D. Landor, and S. R . Landor, Tetrahedron Lett.,
1981, 22,4127.
-
RYR2
bN
+
NC VYR2 NH
The sequential addition of two Grignard reagents to 2-(N-methyl-N-

formy1)aminopyridine (26) provides a high-yielding synthesis of unsym-
metrical secondary alcohols (Scheme 15). The success of the method is attri-
butable to the stability of the chelated intermediate (27).74
Reagents: R’MgX, THF, at 0 ° C ; ii, R’MgX, THF, reflux; iii, H,O+

Scheme 15
3-Pivaloylamino-5-methoxypyridinehas been selectively acylated and
alkylated in the 4-position by successive reaction with n-butyl-lithium and an
electrophile. The activating effect of a N-pivaloylamino- (NHCOBU~)or a
methoxy-group alone failed to give ortho-lithiati~n.~’ A new general route to
nitroso-substituted heterocycles, particularly useful when direct nitrosation
is inapplicable, as in the case of pyridine, is illustrated in Scheme 16.
i,ii iii
Reagents: i, N-chlorosuccinimide, Me’s; ii, NaOMe, iii, rn-chloroperoxybenzoic acid

Scheme 16
The nitroso-derivatives are useful intermediates and may be oxidized
(03 in CH2C12 or NaOCl) to the corresponding nitro-compounds or used as
dienophiles .76
74 D. L. Cominsand W. Dernell, Tetrahedron Lett., 1981, 2 2 , 1085.
75 Y. Tamura, M . Fujita, L.-C. Chen, M . Inoue, and Y. Kita, J. Org. Chem., 1981, 46,
3564.
76 E. C. Taylor, C.-P. Tseng, and J . B. Rampa1,J. Org. Chem., 1982,47, 552.
A b initio calculations on hydroxypyridine-pyridone gas-phase equilibria
have been carried out; the split-valence basis that was used, together with
full optimization of geometry, is said to give considerably greater accuracy
than previously achieved .77 An improved synthesis of 2-amino-3-alkoxy-
pyridines by phase-transfer-catalysed alkylation of 2-amino-3-hydroxy-
pyridines has been reported.78 -Irradiation of 4-methyl-2( 1H)-pyridone (28)
gives the bicyclic lactam (29), which has been transformed into an isomeric
mixture of 0-lactams (30) (Scheme 17).79
Reagents: i, hv (310nm); ii, O,, MeOH, at - 78 OC;iii, NaBH,

Scheme 17
An analogous photo-isomer of N-benzyloxycarbonylmethyl-2(1H)-

pyridone has been prepared and various transformations of its cyclobutene
ring have been explored.80 The photodimerization of N-methyl-2(1H)-
pyridone in water gives exclusively the products of [4 + 41 addition; the
yields of trans-anti- (3 l), trans-syn-, cis-anti-, and cis-syndimers were 5 1 ,
0.6, 11.2, and 6.8%, respectively. In non-aqueous solvents (ethanol or
benzene), only anti-dimers were formed." The thermal cycloaddition of
dimethyl acetylenedicarboxylate to 2( 1H)-pyridones also occurs across
positions 3 and 6. Reaction is favoured where steric buttressing of the methyl
groups in the starting pyridone occurs; for example, the cyclo-adduct (32) is
,COOhIe
Me
(31 1
trans-anti
(trans w.r.t. d o u b l e bonds;

anti w.r.t. amido functions)
77 M. J. Scanlan, I. H. Hillier, and R. H. Davies, J . Chem. SOC., Chem. Commun., 1982,

685.
78
J . A. Bristol, I. Gross, and R. G. Lovey, Synthesis, 1981, 971.
79 J . Brennan, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 8 8 0 .
W. J . Begley, G. Lowe, A. K. Cheetham, and J . M . Newsam, J. Chem. SOC.,Perkin
Trans. I , 1 9 8 1 , 2 6 2 0 .
Y. Nakamura, T. Kato, and Y . Morita, J. Chem. SOC.,Perkin Trans. I , 1982, 1187.
formed in 71% yield. No reaction occurred with simple olefins.82 [2 21 +
Cyclo-adducts, e.g. (33), have been isolated from irradiation of 2(1H)-
pyridones with halo-alkene~.~~
-
H
+ C12C=CH2
0 0
Me Me H
The pyridone (34) has been advocated for the protection of the amino-
group in primary amines and amino-acids (Scheme 1 8).84
0 0
(34)
Reagents: i, RNH,, C,H,N, at room temperature;ii, PrNH, or PhNH,, C,H,N, H,O, at
room temperature
Scheme 18
2-Lithio-3-ethoxypyridine, obtained by the reaction of 3-ethoxypyridine
with n-butyl-lithium and TMEDA in THF at - 40 'C, reacts with a wide range
of electrophiles to give 2,3-disubstituted pyridine~.~'Esters (R' COOR2) are
obtained by the reaction of S-2-pyridylthioates (2-C5H4N-S-COR') with
lithium dialkyl-cuprates (R22CuLi) under oxygen.86 The reaction of these
substrates in a nitrogen atmosphere is known to produce ketones (R' COR2).
Pyridinium salts, e.g. ( 3 9 , have been de-ethoxycarbonylated by reaction
Ph Ph Ph
B ~ ~ N H ~
_____c
Ph
Me Ph Ph
(35)
82 G. P. Gisby, S. E. Royall, and P. G. Sammes, J. Chem. SOC.,Perkin Trans. I , 1982,
169.
83 K. Somekawa, R. Imai, R. Furukido, and S. Komamoto, Bull. Chem. SOC.Jpn., 1981,
54,1112.
84'
E. Matsumura, M. Arigu, Y. Tohda, and T. Kawashima, Tetrahedron Lett., 1981, 22,
757.
85 F, Marsais, G . LeNard, and G. Queguiner, Synthesis, 1982,235.
86 S. Kim, J. I . Lee, and B. Y . Chang, J . Chem. SOC.,Chem. Commun., 1981, 1231.
with t-butylamine; however, with methylamine, a N-methylpyridinium salt is
f ~ r m e d . ~ The
’ synthetic potential of N-alkyl- (and substituted alkyl-)-
pyridinium salts continues to be exploited.88 Thus alkenes,88a aromatic
arylmethyl cyanides,sab arylmethyl and various
heterocycles88c have been prepared via these intermediates. Two papers
report the use of N-ethoxycarbonylpyridinium chloride in the preparation of
4-alkyl-pyridines.*’ The more direct approach is outlined in Scheme 19.
R
COOE t COOE t
( R = Bun, PhCH2CH2, o r P h )
Reagents: i, RCu . BF,, THF; ii, 0,
Scheme 19
The ring-opening sequences illustrated in Schemes 20-22 have interesting
synthetic PO t en t ial .90-92
(x-(4-Pyridyl) esters and a-(4-pyridyl)nit riles have been prepared by the
regiospecific attack of the lithium derivatives of esters and nitriles on N-(2,6-
dimethyl-4-oxopyridin-1-yl)pyridiniumsalts .93
R1 R1 R1
i ii
___t
NH
I I 1
R2 R2 R2
Reagents: i, BunLi, THF, at - 78 to 0°C; ii, H,O

Scheme 20
81
A. R. Katritzky, R. Awartani, and R. C. Patel, J. Org. Chem., 1982,47, 498;A. R.
Katritzky, A. Prout, B. J. Agha, and M. Alajarin-Ceron, Synthesis, 1981,959.
(a) A. R. Katritzky and A. M. El Mowafy, J. Chem. SOC.,Chem. Commun., 1981,96;
( b ) P. M. Fresneda, M. J. Lidon, P. Molina, and M. J. Vilaplana, Synthesis, 1981,71 1 ;
(c) A. R. Katritzky, R. L. Lanathorne, R. C. Patel, and G. Lhommet, Tetrahedron,
1981,37,2383.
89
K. Akiba, H.Matsuoka, and M. Wada, Tetrahedron Lett., 1981, 2 2 , 4093;K. Akiba,
Y. Iseki, and M. Wada, ibid., 1982, 23, 429.
90 A. R. Katritzky, D. Winwood, and N. E. Grzeskowiak, Tetrahedron, 1982,38, 1169.
D. Reinehr and T. Winkler, Angew. Chem., Znt. Ed. Engl., 1981,2 0 , 881.
92
A. N. Kost, R. S. Sagitullin, and A. A. Fadda, Org. Prep. Proced. Int., 1981, 13,203.
93 M. P. Sammes, C. M. Lee, and A. R. Katritzky, J. Chem. SOC.,Perkin Trans. I , 1981,
2476.
ii ,iii
H2N- CHO
SR
PhCHOCOP h
Reagents: i, PhCOC1, PhCHO; ii, OH-; iii, Me,CHNH,, PhH, at 0 ° C
Scheme 21
W R 2
\ \ NHR~
R1
Scheme 22
New ways continue to be reported of carrying out familiar transformations
of pyridine N-oxides. Thus a number of pyridine N-oxides have been deoxy-
genated in acetonitrile with trimethylsilyl chloride-sodium iodide and zinc.
The method is not so high-yielding when electron-withdrawing substituents
are pre~ent.’~ The complexes that are formed by pyridine N-oxides and anti-
mony pentachloride lose hydrogen chloride on heating; subsequent hydrolysis
yields 2( 1H)-pyridones (Scheme 23).95
R R R
0- I -
OSbC15
~ o s b c 1 4
Scheme 23
-&
H2°
H 0
Phosphoryl chloride and triethylamine appears to be the reagent combi-

nation of choice for the conversion of 2-methylpyridine 1-oxide into
2-chl0romethylpyridine.~~ The mechanism of the acylamination and amino-
arylation of the side-chain of 2- and 4-methylpyridine l-oxides (Scheme 24)
QMe - n
0
I- I
CH
2 -
L T h ‘Ph
O Y N P h
Ph
Reagents: i, PhClC=NPh, strong base NCOPh

H
Scheme 24
94
T. Morita, K. Kuroda, Y. Okamoto, and H. Sakurai, Chem. Lett., 1981,921.
95 J . Yamamoto, M. Imagawa, S. Yamauchi, 0. Nakazawa, M . Umezu, and T. Matsuura,
Tetrahedron, 1981, 37, 1871.
% M. L. Ash and R. G. Pews, J . Heterocycl. Chem., 1981, 18, 939.
Six-Mem bered Rings: Systems containing nitrogen 299
has been shown to be mostly free-radical. This followed from the observation
of C.I.D.N.P. signals and the isolation of radical-coupling by-products.”
Vacuum pyrolysis (800 *C,0.1 mmHg) of 2-benzylpyridine 1-oxide yields
a tricyclic product (36),98 and 4-dimethylaminopyridine 1-oxide (DMAP
(36)
1-oxide) has been shown to be an efficient oxidizing agent for the conversion
of alkyl halides into aldehydes or ketones (Scheme 25).99
Scheme 25
A number of N-arylthio-pyridinium salts, e.g. (37), have been prepared; it
is of interest that they undergo nucleophilic attack on sulphur and not on the
pyridine ring (Scheme 26).’0°
KCN
c 1-
I N02
SC6H4N02-p
(37) Scheme 26
The tetrafluoroborate from (37) serves as a source of 4-nitrophenyl-

sulphenium ion (p-NO2C6H4S’), which can attack anisole to give a para-
substituted product.
Reduced Pyridines. - Recent calculations (ab initio and semi-empirica:) on
the relative stabilities of the five dihydropyridines give results which vary
markedly according to the method used, with the two enaminic isomers (1,2-
and 1,4-dihydro) predicted to be either more or less stable than the three
imino forms! lo’
97
R. A. Abramovitch, D. A. Abramovitch, and P. Tomasik, J . Chem. SOC.,Chem. Com-
mun., 1 9 8 1 , 5 6 1 .
98 A. Ohsawa, T. Kawaguchi, and H . Igeta, Chem. Lett., 1981, 1 7 3 7 .
99
S . Mukaiyama, J . Inanaga, and M. Yamaguchi, Bull. Chem. SOC.Jpn., 1 9 8 1 , 5 4 , 2 2 2 1 .
loo R. A. Abramovitch, A. L. Miller, and J . Pilski, J. Chem. SOC.,
Chern. Commun., 1 9 8 1 ,
703.
101
S. Bohm and J . Kuthan, Collect. Czech. Chem. Commun., 1 9 8 1 , 4 6 , 2 0 6 8 .
i.ii
'- -l
OMe
COOMe
(39)
Reagents: i, RM, THF; ii, ClCOOMe [ e .e . 82-94%1

Scheme 27
1,4-Dihydropyridines (39) for use as chiral hydride-ion-transfer agents have
been prepared from the chiral 3-pyridyloxazoline (38) (Scheme 27); chemical
yields are good, as are the enantiomeric excesses (e.e.).'02
Addition of n-butyl-lithium to 2-fluoropyridine occurs at - 40 " C , and
hydrolysis of the resulting reaction mixture yields 2-butyl-6-fluoro-2 ,5-
dihydropyridine. At lower temperatures (- 60 "C), 2-fluoropyridine under-
goes competitive 3-lithiation. 2,5-Dihydropyridines in general have poor
stability, and must be stored in the cold and under nitrogen.lo3 Piperidine N-
imides and N-oxides undergo some interesting transformations on heating in
refluxing xylene or toluene.lm The ring-expanded product (41) is obtained
from the imide (40), the oxazepine (43) is the sole product from the methyl-
piperidine N-oxide (42), and with the benzyl analogue (44) a mixture of ring-
expanded product (45) and benzyloxypiperidine (46) is obtained.
Ac
( 4 0 ) X = N A c , R = Me (43) R = M e (46)
(41)
( 4 2 ) X = 0, R = M e ( 4 5 ) R = CH2Ph
( 4 4 ) X = 0 , R = CH2Ph
Ruthenium(@-catalysed reactions of diamines or amino-alcohols have been

used to prepare piperidines .lo' A simple synthesis of ~-piperidine-:!-carboxylic
acid (48) from L-lysine (47) has also been reported (Scheme 28).'06
lo' A. I. Meyers, N. R. Natale, D. G. Wettlaufer, S. Rafii, and J . Clardy, Tetrahedron
Lett., 1981, 22,5123.
lo' F. Marsais, P. Granger, and G. Qukguiner, J. Org. Chem., 1981, 46, 4494.
I04
T. Tsuchiya and H. Sashida, ( a ) Chem. Pharm. Bull., 1981, 29, 1887; (b) ffetet-0-
cycles, 1980, 14, 1925.
lo' B.-T. Khai, C. Concilio, and G. Porzi, J . Org. Chem., 1981,46, 1757; S . I. Murahashi,
K. Kondo, and T. Hakata, Tetrahedron Lett., 1982, 23,229.
lo6 L. Kisfaludy and F. Korenczki, Synthesis, 1982, 163.
H2N-(
H2N
CH )
hz,L-
i
Q'\cooH
Reagents: i, Na,[ Fe(CN),(NO) 1, at pH 9.5
Scheme 28
Cyanation of methoxypiperidines and related compounds has been carried

out with trimethylsilyl cyanide (Scheme 29).'07 A novel approach t o the syn-
(x = CH2, 0 , o r NAc)
Reagents: i, Me,SiCN, SnC1,
Scheme 29
thesis of quinuclidine involves the use of a piperidine N-oxide as starting

material (Scheme 30).'08
Me
COOMe
Reagents: i, TFAA, CH,Cl,, at 0°C; ii, KCN, at pH 4
Scheme 30
Bicyclic products (50) and (51) have been obtained from the protected
piperidinone (49) by intramolecular Michael addition (Scheme 3 1).'09
Improved methods for preparing 1-aryl4-piperidones have been
reported."' Formation of a piperidine N-oxide was shown to take place with
lo' V. Asher, B. Becu, M . J . 0. Anteunis, and R. Callens, Tetrahedron L e t t . , 1981, 22,

141.
108
M . Lounasmaa and A. Koskinen, Tetrahedron L e t t . , 1982, 2 3 , 349.
T. Imanishi, N. Yagi, H. Shin, and M. Hanaoka, Tetrahedron L e t t . , 1981, 2 2 , 4001.
'lo E. C. Taylor and J . S. Skotnicki, Synthesis, 1981, 606.
( 4 9 ) R = carbobenzoxy (50)
Scheme 3 1
a high degree 95%) of stereoselectivity; thus oxidation (H202, acetone, at

25 " C ) of a series of 4-t-butyl-N-alkyl-piperidinesgave the axial l-oxides."'
Bicyclic amidines such as (52) and (53) undergo a-chlorination when treated
with carbon tetrachloride in the dark, under nitrogen, at room temperature
(Scheme 32). They also undergo hydrogen-deuterium exchange at the
a-posit ion in deut erio chloro fo rm .'
m-rx,
R R
+ CHC13
(52) R = H
( 5 3 ) R = Me
Scheme 32
Quinoline, Isoquinoline, and their Benzo- and Hydro-derivatives. - Relatively

few syntheses of quinolines are based on 2,3-disubstituted pyridines; a recent
addition t o their number is illustrated in Scheme 33. The essential steps are
Michael addition, intramolecular acylation, and aromatization via loss of
toluene-p-sulphenic acid."3
0
II
+ phc\ Ph
- i
[72%1
Reagents: i, KOBU', DME, at 2 0 ° C for 24 hours
Scheme 33
'I1 Y. Shvo and E. D. Kaufman, J . Org. Chem., 1981,46,2148.

'I2 S . Lofas and P. Ahllberg, J. Chem. SOC.,Chem. Commun., 1981,998.
A. M. van Leusen and J . W. Terpstra, Tetrahedron Lett., 1981,2 2 , 5097.
__c __c
\ Pr
H
Reagents: i, [PdCl,(MeCN),], CuCl,, LiC1, THF, 125°C

Scheme 34
Aniline that is ortho-substituted with a hexa-2,5-dienyl side-chain under-

goes catalytic, palladium-assisted cyclization to 2-propylquinoline (Scheme
34);Il4 this is only one of a series of ring-closure reactions involving palladium-
promoted nucleophlic attack on an alkene. A tetrahydroquinoline (55) is
or
produced by the action of trifluoroacetic acid on the hydroxylamine (54).
This method has also been used to prepare 1,4-benzo~azines."~
HN Me Me
I H
HO
(55)
(54)
Intramolecular Diels-Alder addition is the key step in a new synthesis of

fused tetrahydroquinolines (Scheme 35).'16 Starting materials are prepared
from the appropriately substituted o-amino-NNdimethylbenzylamines. 2,4-
+
NMe
N- SiMe3 'N
I
CH= CH
Reagents: i, CsF, MeCN, reflux

Scheme 35
Diphenyl-2-methyl-l,2-dihydroquinolines(56) have been prepared from

lithium anilides and phenylacetylene (Scheme 36)."'
The conversion of acetanilides into 2-dialkylamino-quinolines has been
carried out by a high-temperature (250°C) reaction with a mixture of NN-
'I4 L. S. Hegedus, P. M . Winton, and S. Varaprath, J . Org. Chem., 1981,46,2215.
'Is M. Kawase and Y. Kikagawa, Chem. Pharm. Bull., 1981,29, 1615.
Y. Ito, S. Miyata, M . Nakatsuka, and T. Saegusa, J . A m . Chem. SOC.,1980,103, 5250.
A. Arduini, F. Bigi, G. Casiraghi, and G. Casnati, Synthesis, 1981 ,975.
304 Heterocyclic Chemist?y
8\ NHLi
i -iii c
ap Ph
H Me
(56)
Reagents: i, SnCl,, toluene, reflux; ii, PhC=CH (2 equivalents), reflux; iii, H,O
Scheme 36
dialkyl-formamide, dialkylamine, and phosphorus pentoxide (Scheme 37)

(see also p. 305).'18
" O O \ , l i r , 0
- i
EtO /
m N E t 2
H
Reagents: i, HCONEt,, HNEt,, P,O,, at 250°C
Scheme 37
5-Hydroxycarbostyril (59) has been obtained by dehydrogenation of the
product (58) that is obtained from allowing 3-amino-2-cyclohexenone (57)
to react with acrylic acid (Scheme 38). The enaminone ( 5 7 ) is readily pre-
pared from cyclohexane-l,3-dione and ammonia."'
NH2
i* &-pm H
\
H
0
(57)
(58) (59)
Reagents: i, H,C=CHCO,H, at 140°C; ii, Pd/C, at 190°C
Scheme 38
' ~ ~ of "N n.m.r. data

Compilations of I3C n.m.r. data for 4 - q ~ i n o l o n e sand
for decahydroquinolines121have appeared.
N-Carboalkoxy-l,2-dihydroquinolines have been prepared by the method
illustrated in Scheme 39.'22
'18 B. W. Hansen and E. B. Pedersen, Liebigs Ann. Chem., 1981, 1485.
'19 T.Shono, Y . Matsumura,and S, Kashimura, J. Org. Chem., 1981,46, 3719.
12' A. R. Katritzky, J . Ellison, J . Frank, P. Rakdczy, L. Radics, and G. Gks-Baitz, Org.
Magn. Reson., 1981, 16,2 8 0 .
12' F. W. Vierhapper, G. T. Furst, R . L. Lichter, S. N. Y . Fanso-Free, and E. L. Eliel, J .
A m . Chem. SOC.,1981,103,5629.
122
D. E. Minter and P. L. Stotter, J. Org. Chem., 1981,46,3965.
Six-Mernbered Rings: Systems containing nitrogen 305
COOMe
[88%l
Reagents: i, BH, THF, THF, at - 78 "C; ii, NaH,Al(OCH,CH,OMe),, PhH, THF, at
- 78 "C;iii, MeO,CCl, at 0 ° C
Scheme 39
2-, 3-, and 4-Methylquinolines are simply converted into the corresponding
l-formyl-1,2,3,4-tetrahydroquinolinesby heating them with triethyl-
ammonium formate at 160 "C until the evolution of carbon dioxide ceases.123
1,l-Dialkoxy-l,2-dihydrocyclobuta[b]quinolines(61) have been obtained
in good yields, starting from 2-methylquinoline, the key intermediate being
the spiro-compound (60), which is derived by reaction with dichloro-
carbene. Hydrolysis of the cyclobuta[b]quinolines yields 2-methylquinoline-
3-carboxylic esters (62).'24
Selective reduction (LiAlH4, THF, at - 70 "C) of 3,4-dicarbomethoxy-

quinoline at low temperatures unexpectedly affords 3-formyl4-carbometh-
o ~ y q u i n o l i n e . '2-
~ ~and 4-Substituted aminoquinolines have been obtained by
heating quinolones with a mixture of amine hydrochloride, phosphorus
pentoxide, and NN-dimethylaniline at 250 0C.126 In a related reaction,
4-amino-2-quinolones have been prepared from 4-hydroxy-2-quinolones by
heating at 250-300 "C with benzylammonium chloride. Under these con-
ditions, debenzylation occurs, so the expected benzylamino-compounds were
not is01ated.l~~Photolysis of quinolyl and isoquinolyl azides in the presence
of methoxide ions provides a convenient route to the corresponding methoxy-
substituted bicyclic azepines and benzodiazepines. Illustrative of these poss-
ibilities is the conversion of 5-azidoquinoline (63) into the pyridoazepine (64)
(Scheme 40).12*
123
M. Ferles and 0. Kocihn, Collect. Czech. Chem. Commun., 198 1 , 46, 15 18.
124 Y. Hamada, M. Sugiura, and M. Hirota, Tetrahedron L e t t . , 1981, 22, 2893.
12s
A. Godard and G. Qukguiner, Tetrahedron L e t t . , 1981, 22, 4813.
126
E. B. Pedersen and D. Carlsen, Chem. Scr., 1981, 18, 240.
127 W. Stadlbauer and T. Kappe, Synthesis, 1981, 833.
F. Hollywood, Z. U . Khan, E. F. V. Scriven, R. K. Smalley, H . Suschitzky, D. R.
Thomas, and R. Hull, J . Chem. Soc., Perkin Trans. 1 , 1982, 431.
OMe
- i
(63)
Reagents: i, hv, NaOMe, MeOH, dioxan
Scheme 40
In the route to 4-alkyl-quinolines (65) that is outlined in Scheme 41, the

starting materials are obtained by sequential reactions of quinoline with ethyl
chloroformate and a trialkyl ph~sphate.'~'(see also p. 310)
Quinoline N-oxide is converted into 2-cyanoquinoline, in 57% yield, by
treatment with diethyl phosphorocyanidat e, (Et0)2P(0)CN ; isoquinoline
Reagents: i, Bu*Li, THF, at - 78 "C; ii, R'X, at room temperature, iii, NaI, HMPA
a t 160-180°C
Scheme 41
N-oxide similarly yields lcyanoisoquinoline, in 8 1% ~ie1d.l~'Tetrahydro-

quinoline is activated to deprotonation at the 2-position by conversion into
the formamidine derivative (66). Subsequent reaction of the anion with elec-
trophiles leads to 2-substituted derivatives (see also p. 31 1) (Scheme 42).131
8\3 - i-iii - 80\

iv-vi
(66) LJ H
E
Reagents: i, HCOOEt; ii, Et,O+ BF; ; iii, ButNH,; iv, ButLi, THF; v, electrophile;
vi, hydrolysis
Scheme 42
12' K. Akiba, T. Kasai, and M. Wada, Tetrahedron Le t t . , 1 9 8 2 , 2 3 , 1709.

130
S. Harusawa, Y. Hamada, and T. Shioira, Heterocycles, 1 9 8 1 , 1 5 , 981.
13' A. I. Meyers and S. Hellring, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 5 119.
The vast majority of syntheses of isoquinoline are based on benzenoid
intermediates. It is therefore noteworthy that a key step in a recent synthesis
of ellipticine involves the construction of a benzene ring onto a pyridine by an
intramolecular Diels-Alder addition (Scheme 43).'j2
Me
H H Me
Me
H Me
Scheme 43
A recent paper on the Pictet-Gams synthesis of isoquinolines (Scheme 44)

describes the use of oxazoline intermediates for an improved method of pre-
paring the starting materials.' j3 ortho-Halogena t ed N-alkyl-N-acyl-
benzylamines (67) can be cyclized to dihydroisoquinolones (68) by their
reaction with KNHz in liquid ammonia or with LiNPr', in THF under thermal
OH
\
R2 R2
Scheme 44
or photolytic conditions. When R' = R2 = OMe, under aryne-generating con-

ditions, amination products predominate, so the use of excess KNH2 in liquid
ammonia is contra-indicated.134
Dihydroisoquinolones (70) are also produced by the photo-induced cycliz-
ation of N-alkyl-N-(chloroacety1)benzylamines (69). The yield is best when R
is t-b~ty1.l~'
132
S. Kano, E. Sugino, S. Shibuya, and S . Hibino, J. Org. Chem., 1981,46,2979.
133 J. R. Falck, S. Manna, and C. Mioskowski, J . Org. Chem., 1981,46, 3742.
134
S. V. Kessar, P. Singh, R . Chawla, and P. Kumar, J . Chem. SOC., Chem. Comrnun.,
1981,1074.
13' T. Hamamada, Y. Okuno, M. Ohmori, T. Nishi, and 0. Yonemitsu, Chem. Pharm.
Bull., 1981, 29, 128.
R2
R3
I
( 6 7 ) X = C1 or B r
NMe
R1w
R2 \
(68)
R3
c1
The Pictet-Spengler reactions between epinephrine (noradrenalin) and

formaldehyde and acetaldehyde have been investigated. The products from
the reaction with acetaldehyde (Scheme 45) may be responsible for some of
the physiological effects of ethan01.l~~
HO
H O W N M e = * H \
HO O G N M e + "@NMe \
HO
Me Me'
Scheme 45
Treatment of the dilithio-derivative of N,2-dimethylbenzamide (7 1) with
NN-dimethylcarboxamides (RCONMe2) yields N-methyl-l(2H)-isoquinolones
(73). The intermediate (72; R = H) is isolated when NN-dimethylformamide
is used.'37
d N H M e b\ e R d\ N /M R e
' Me OH
13' H. A. Bates, J . Org. Chem., 1 9 8 1 , 4 6 , 4 9 3 1 .

137 R. S. Mali, B. K. Kulkami, and K. Shankaran, Synthesis, 1982, 329.
0 0
+ R2CH=CR3
0-
I
- dR
hv
\ R3
R2
R’= H or alkyl
R1= R2= H , R3= Me
X = Br or I
90&1
Scheme 46
Isocarbostyrils [ 1(2H)-isoquinolones] are obtained by the SRN1 reactions

of o-halo-benzamides with ketone enolates (Scheme 46).138
Friedel-Crafts reactions between arylacetyl chlorides and Schiff bases have
been used to synthesize a range of l-aryl-3-oxo-l,2,3,4-tetrahydroisoquinolines
(Scheme 47); the modified procedure that was used appears t o be advan-
tageous in certain cases.13’
Scheme 47 ir
Another synthesis of isoquinolines in which two ring bonds are formed

involves the reaction of benzyl halides (74) with the sodium salt of N -
(t osy1amino)acet a1deh y de dimet h yl acet a1. Treatmen t of the intermediate
(75) with hydrochloric acid results both in ring-closure and aromatization
(Scheme 48).I4O
OMe
(74) (75)
Scheme 48
’”
139
R . Beugelmans and M. Bois-Choussy, Synthesis, 1981, 729.
A. P. Venkov and N . M. Mollov, Synthesis, 1982, 2 1 6 .
D. L. Boger, C. E. Brotherton, and M. D. Kelley, Tetrahedron, 1 9 8 1 , 37, 3977.
Phosphonate analogues of Reissert compounds (76) have been prepared
and converted into 1-alkyl-isoquinolines (Scheme 49).14' Treatment of a num-
ber of N-methylisocarbostyrils with mercuric acetate gave rise to 4-mercuri-
ated derivatives, which underwent insertion reactions with methyl acrylate
and with styrenes in the presence of palladium chloride (Heck reaction).142
CH2R
(76) ( R = a l k y l or a r y l )
Reagents: i, BuLi, THF, at - 70°C; ii, RCHO; iii, HC1
Scheme 49
In an extension of earlier work on pyridones and quinolones, the photo-
initiated addition of alkenes to the isoquinolone (77) has been carried out; a
subsequent reaction of the adduct with a Lewis acid gave the corresponding
cyclobutene (Scheme
R R
OMe
\ Me
0 0 0
(77)
Reagents: i, RCH=CH,, hv, MeOH; ii, BF,.Et,O
Scheme 50
Irradiation of the isoquinoline imide (78) in methanol that contains
potassium hydroxide gives the diazepine (79), but no diazepine is formed in
the absence of potassium hydroxide.'44
K. Y. Akiba, Y. Negishi, K. Kurumaya, N. Ueyama, and N. Inamoto, Tetrahedron

Lett., 1981,22,4977.
14' S. F. Dyke and M. J . McCartney, Tetruhedron, 1981, 37,431.
143 T. Naito and C. Kaneko, Tetrahedron Lett., 1981, 22,2671.
144 M. Enkaku, J . Kunta, and T. Tsuchiya, Heterocycles, 1981,16, 1923.
The reduction of imines such as 3,4-dihydroisoquinolines with chiral
sodium triacyloxyborohydrides [NaB(Oa~yl)~Hl has been effected in optical
yields of up to 7 l%.14' Two new methods for the preparation of 1-substituted
tetrahydroisoquinolines have been reported. These both involve directed 1-
lithation and subsequent reaction with electrophiles. The directing groups on
nitrogen are CH=N-R'& and P(0)(NMe2)2 (see above)14' respectively, both of
which are readily removable.
The reaction of 2-fluoro-5-nitrobenzaldehyde with a wide variety of aryl-
amines gives mixtures of the corresponding 2-arylamino-5-nitrobenzaldehydes
and the related anils. Both aldehydes and anils underwent acid-catalysed
cyclization to the corresponding 2-nitroacridines (80).'48 The acridine N -
oxide (81) was obtained as the major product by the reaction of
o-fluorobenzyl cyanide with p-chloronitrobenzene in met hanolic potassium
hydroxide.'41
The acridinedione (82) smoothly reduces benzyl alcohols and arylalkenes
in methylene chloride at room temperature in the presence of an equi-
m""'
molecular amount of trifluoroacetic acid.'50
fJJ+Jc1 tJyJ
0
R
7 H
Regiospecific ring-closure of the 2-aminobiphenyl (83) to the phenanthri-

dine (84) is achieved by sequential reaction with butyl-lithium and NN-
dimethylformamide. Conventional ring-closure procedures result in ring-
closure at the alternative o r t h o - p ~ s i t i o n . Potent
'~~ analgesic properties have
OMe OMe
(83) (84)
K. Yamada, M. Takeda, and T. Iwakuma, Tetrahedron L e t t . , 1981,22,3869.
146 A. I. Meyers, S. Hellring, and W. T. Hoeve, Tetrahedron L e t t . , 1981,22, 5115.
14' D. Seebach and M. Yoshifuji, Helv. Chim. Acta, 1981, 64, 643.
14' J. Rosevear and J . F. K. Wiltshire, Aust. J. Chem., 1981,34,839.
149
Z. Vejdglek, M. Rajher, A. DlabaE, M . Ryska, J . Holubek, E. Svhtek, and M. Protiva,
Collect. Czech. Chem. Commun., 1980,45,3593.
S . Singh, S.Chhina, V . K. Sharma, and S. S . Sachdev, J . Chem. SOC., Chem. Com-
mun., 1982,453.
Is' N. S. Narasimhan, P. S. Chandrachood, and N. R. Shete, Tetrahedron, 1981,37, 825.
been reported for the complex phenanthridine derivative (85); apparently this
does not bind to the opiate recept~r.''~Benzacridines have been synthesized
from the oxime of 1-tetralone as shown in Scheme 51lS3 and dihydro-
dihydroxybenzacridines have been synthesized as possible carcinogenic meta-
bolites of benzo[a]- and benzo[~]-acridines.''~
Ar
Reagents: i, LiNPi, ;ii, o-NH,C,H,COAr
Scheme 51
4 Diazines and their Reduced and Fused Derivatives

1,2-Diazines. - Pyridazin-4-ones (87; R = Ph or OMe) are obtained when
a-0x0-hydrazones (86; R = Ph or OH) are refluxed in dimethylformamide
dimethyl acetal;"' we reported last year on the formation of pyridazin-3-
ones from similar hydrazones?'
The photorearrangement of chlorinated pyridazines to pyrazines has been
further investigated. Radical-stabilizing substituents at C-4 and/or C-5 of the
pyridazine appear to be essential for the reaction to proceed; thus (88) gives
(89) but 3,6-dichloropyridazine is inert under the same c~nditions.''~As a
result of further experiments, the suggestion that the thermal rearrangement
of' certain perfluoroalkyl-pyridazines can be thermally sensitized has been
discarded in favour of a mechanism involving radical-initiated valence iso-
merization .l"
lS2 M. R . Johnson and G. M . Milne, J . Heterocycl. Chem., 1980,17, 1817.

lS3 D. J. Park, T. D. Fulmer, and C. F. Beam, J. Heterocycl. Chem., 1981, 18, 649.
l S 4 M. Schaefer-Ridder and U. Engelhardt, J. Org. Chem., 1981, 46,2895.
l S 5 S. Plescia, G . Daidone, J. Fabra, and V. Spiro, J. Heterocycl. Chem., 1981, 18, 3 3 3 .
M. A. Fox, D. M . Lemal, D. W. Johnson, and J. R. Hohman, J . Org. Chem., 1982,47,
398.
l S 7 R. D. Chambers, W. K. R. Musgrave, and C. R . Sargent, J. Chem. SOC., Perkin
Trans. I , 1981, 1071.
Coupling of terminal acetylenes with 3-chloropyridazines has been per-
formed, using the Pd"-Cu'-Et2NH system, giving 3-(alkyny1)pyridazines in
yields of up to 78%; phenylacetylene gives (90) with 3-chloropyridazine
1-oxide but only gives tars with the isomeric 2-0xide.l'~ 3-(Alkyny1)cinnolines
have been similarly prepared from 3-iodo- and 3-bromo-cinnolines, and
attempts to couple alkenes have been reported; it is not unusual, in this type
of reaction, to obtain small amounts of homo-coupling products ( i e . biaryls),
but an excellent yield of 3,3'-bicinnolinyl (81%) was obtained from 3-bromo-
cinnoline and styrene .l 59
The pyridine (91) is known to possess potent and long-lasting anti-
Ph
I
0-
(90)
secretory activity; in the course of studies on anti-ulcer drugs, a range of
pyridazine analogues has been prepared (Scheme 52) and some of them, while
retaining marked anti-ulcer activity, have much lower acute toxicities than
(9 1).I6O Ar Ar
0"-
R 'N/N
-
[ 4 3- 8 9%1 [46-92%]
Reagents: i, NaNH,, AICH,CN, PhH; ii, H,S, C,H,N, Et,N
Scheme 52
A number of publications have appeared on the alkylation of heterocycles
under phase-transfer conditions (see also pp. 295, 3 18, and 331); these
reactions appear t o proceed in high yield and with great selectivity. Alky-
lation of pyridazin-3-ones with primary and secondary alkyl bromides gives
high yields of 2-N-alkyl derivatives; electron-deficient ole fins may also be
used as the alkylating agents, thus acrylonitrile affords the cyanoethyl deriv-
ative (92).I6l
F0
1
Ph
NC
(92)
A. Ohsawa, Y. Abe, and H. Igeta, Chem. Pharm. Bull., 1980, 28, 3488.
lS9 D. E. Ames and D. Bull, Tetrahedron, 1982, 38, 383.
160 T.Yamada, Y. Nobuhara, H. Shimamaru, K. Yoshihara, A. Yamaguchi, and M . Ohki,
Chem. Pharm. Bull., 1981, 29, 3433.
16' T. Yamada and M. Ohki, Synthesis, 1981, 631.
Attempts to prepare cinnoline-3,4-dicarboxylic acid (94) from 3,4-
dime thylcinnoline apparently foundered on the relative inertness of the
3-methyl group; the hitherto unknown diacid was eventually formed by acid
hydrolysis of the dinitrile (93), itself prepared as shown in Scheme 53.'62
c1 X
(93) X = CN
( 9 4 ) X = COOH
Reagents: i, NaO,SC,H,Me-p, DMF, at 0 ° C ; ii, KCN, DMF, at 5-10°C
Scheme 53
Reduction of 5- and 8-nitrocinnolines with zinc amalgam in aqueous acetic

acid gives the corresponding 4- and 7-amino-indoles; these conditions have
previously been used to effect ring-contraction of 4-alkyl- and 4-aryl-
~ i n n o l i n e s . ' Treatment
~~ of the perhydropyridazine (95) with hot concen-
trated sulphuric acid results in nearly quantitative rearrangement to the
pyrazole (96).'64
1,3-Diazines. - Heating 1-benzylpyrazoles with sodamide gives the corres-
ponding 1,2dihydr0-2-phenylpyrimidines.~~~ Fair yields of 4-(dimethylamino)-
pyrimidines (98) are obtained when the 2-azapentamethinium salts (97) are
treated with ammonium acetate. 166
N-Aryl-amidines condense with ethyl propiolates to- give pyrimidin-3H-
~ ~ yields of 2-
4-ones (99), none of the 1H-isomers being r e ~ 0 r t e d . lGood
0 Me
NMe2 R -
c104
(97) (98)
D. E. Ames and D. Bull, Tetrahedron, 1981, 37, 2489.

S. Somei, S. Inoue, S. Tokutake, F. Yamada, and C. Kaneko, Chem. Pharm. Bull.,
1981, 2 9 , 7 2 6 .
M. Lora-Tamayo, P. Navarro, D. Romero, and J . L. Soto, A n . Quim., 1981, 77, 296.
B. A. Tertovand Y. G. Bogachev, Khim. Geterotsikl. Soedin., 1981, 119.
R. Gompper and U. Heinemann, Angew. Chem., Int, Ed. Engl., 1981, 20, 297.
K. A. Gupta, A. K. Saxena, and P. C. Jain, Synthesis, 1981, 905.
Me
Me
amino-3,4-dihydropyrimidines, e.g. (1 00), are obtained by the condensation

of guanidines with enones in t-butyl alcohol at room temperature.168
Stirring p-acyl-enamines (10 1) with primary amines in formalin gives fair
quantities of tetrahydropyrimidines (102) (Scheme 54).'69
(102) [40-62%]
Reagents: i, RZNH2,40% formalin, at room temperature
Scheme 54
The [Ni(acac)2 1-catalysed reaction of 1,3-dicarbonyl compounds
(MeCOCH2COR) with cyanogen gives the highly substituted pyrimidines
(103); in the three cases reported (R = Me, Ph, and OEt), the yields range
CONH
RCO
Me COMe
I
m2
(103)
from 22 to 100%.'70In another synthesis involving nitriles, trifluoroaceto-

nitrile condenses with enamines to give the 2,4-bistrifluoromethylpyrimidines
(104) (Scheme 55).I7l
(104)
Scheme 55
168 Y. H. Kim, C. M. Yoon, and N . J . Lin, Hererocycles, 1981, 16, 49.
H. Mohrle and H. W. Reinhardt, Arch. Pharm. (Weinheim, G e r . ), 1981, 314, 767.
170 B. Corain, M. Basato, and H.-F. Klein, Angew. Chem., Inr. Ed. Engl., 1981, 20, 972.
"' K. Burger, F. Hein, U . Wassmuth, and H. Krist, Synthesis, 1981,904.
Pyrimidines have been formed in a ‘one-pot’ procedure by heating
0-dicarbonyls with aldehydes and ammonium acetate (Scheme 56); yields are
not very good but the simplicity of the procedure is some recommen-
dation.’72
R2
I R2
[ 12-47?,]
Reagents: i, NH,OAc, DMSO, HOAc, 0,, at 80-90°C
Scheme 56
Two publications have appeared on the use of 13C n.m.r. to determine the
site of protonation (or protonation ratios) in pyrimidines. Three-bond coupl-
ing, e.g. 3 decreases markedly across quaternized nitrogen, as shown
with the two methylated derivatives (105) and (106).’73
I 1-
1,le I-
(105) (106)
3
3Jc -H = 5.8 Hz Jc -H = 1 3 . 4 Hz
2 6 2 6
Trimethylsulphoxonium ylide dsplaces the chloro-group in 2-chloro-4,6-
dimethylpyrimidine to give the ylide (107); acylation of this product, fol-
lowed by reduction with Raney nickel, gives the 2-acylmethyl derivatives
(108) (Scheme 57). Similar sequences have been performed starting from 4-
chloropyrimidines, 4-chloroquinazoline, 2-chloro-5,6-diphenylpyrazine,and
3-chloro-6-phenylpyridazine; yields are generally good, but the initial step
Me \N
rj -Me
C1
i Me c,L!Me-
fails with less reactive substrates such as ch10ropyridines.l’~
Me
0
(107)
-
Me ‘
Me
(108)
CH~COR
Reagents: i, Me,$(O)CH,, THF, reflux; ii, RCOX; iii, Raney nickel

Scheme 57
172
A. L. Weis and V. Rosenbach, Tetrahedron Lett., 1981, 22, 1453.
173 ( a ) D. V . Griffiths and S. P. Swetnam, J . Chem. SOC., Chem. Commun., 1 9 8 1 , 1 2 2 4 ;
( b ) J . Riand, C. Coupry, and M.-T.Chenon, J. Chem. SOC.,Perkin Trans. 2, 1 9 8 1 , 7 8 3 .
174 H. Yamanaka, S. Konno, T. Sakamoto, S. Niitsuma, and S. Noji, Chem. Pharm. Bull.,
1981. 29.2837.
Further investigations into the palladium(I1)-catalysed cross-coupling of
ole fins with i o d o p y r i m i d i n e ~ ' ~have
~ ~ been published. As previously
reported,'75b 2-iodo-4,6-dimethylpyrimidine and its 4-iodo-2,6-dimethyl
isomer do not couple with ethyl acrylate if a reagent mixture of P ~ ( O A C ) ~ ,
Ph3P, and Et3N is used; however, omission of the triphenylphosphine permits
the coupling to proceed in reasonable velds. Palladium black can also be used
as the ~ a t a 1 y s t . l ~ ~
Conversion of 2- and 4-chloropyrimidines to the corresponding nitriles has
been achieved via quaternary salts as shown in Scheme 58; yields are generally
R R R
OCl- CA+ - i
Reagents: i, Me,N, PhH; ii, Et,N+ CN-, CH,CI,

N M e 3 C1-
ii
Scheme 58
good, 2- and 4-chloroquinazolines behave similarly, and 2-chloroquinoxalines

can be directly converted into the nitrile by their reaction with tetraethyl-
ammonium cyanide.'77 4,5'-Bipyrimidines, e.g. (1 09), are obtained when 5-
bromopyrimidines are treated with b ~ t y l - l i t h i u m . Attempts
'~~ at direct con-
version of the chloropyrimidine (1 10; X = C1) into the amine (1 10; X = NHJ
(required in the course of studies on the synthesis of bleomycin) gave only
very low yields; a nearly quantitative transformation was achieved by forming
the azide (1 10; X = N3) followed by h ~ d r 0 g e n a t i o n . l ~ ~
Heating 5-nitropyrimidine with amidines [RC(=NH)NH2] in refluxing
ethanol gives 2-substituted pyrimidines (1 11) and/or pyridines (1 12), depend-
ing on the nature of R; thus benzamidine gives exclusively (1 11; R = Ph)
(84%) whereas phenylacetamidine gives the pyridine (1 12; R = Ph) (67%).180
Treatment of 5-nitropyrimidin-2-one with acetone and acid gives the adduct
(1 13), which, o n treatment with a base, is converted into p-nitrophenol;'81
the transformation of 5-nitropyrimidine into p-nitrophenol by treatment with
ketones and base has previously been reported.17sb
175
(a) S. D. Carter and G . W. H. Cheeseman, in 'Heterocyclic Chemistry', ed.
H. Suschitzky and 0. Meth-Cohn, (Specialist Periodical Reports), The Royal Society
of Chemistry, London, 1 9 8 1 , Vol. 2 , Chapter 4 ; ( b ) R. K. Smalley, ibid., Vol. 1 , 1 9 8 0 .
176 T. Sakamoto, H. Arakida, K. Edo, and H. Yamanaka, Heterocycles, 1981, 16, 965.
177
K. Hermann and G. Simchen, Liebigs Ann. Chem., 1 9 8 1 , 333.
178
A. Kowalewski, L. Strekowski, M. Szajda, K. Walenciak, and D. J . Brown, Austr. J .
Chem., 1 9 8 1 , 3 4 , 2 6 2 9 .
179 W. K. Hagmann, F. Z. Basha, M. Hashimoto, R. B. Frye, S. Kojo, and S. M . Hecht, J .
Org. Chem., 1981, 46, 1413.
P. Barczynski and H. C. van der Plas, J. Org. Chem., 1 9 8 2 , 4 7 , 1 0 7 7 .
J. J. Fox, T.-L. Su, L. M. Stempel, and K. A. Watanabe, J . Org. Chem., 1982, 4 7 ,
1081.
Me2N
' R (3N02 H2N

RQNo2
HN-N02 0
Pyrimidine N-oxides are formed when pyrimidine-2-thiones are heated

with ethanolic hydroxylamine; in cor\,trast, the corresponding 2-ones give
isoxazoles (Scheme 59).182
0 -
[X = 01
R3
t
' NAX -
R1
N [x=S]
R3 fJ
+
'
I
0-
NHR'
[ 66-80%]
[ 28-80%]
Scheme 59
Weak Lewis acids, such as trimethylsilyl triflate, are reported to be more
efficient catalysts than stannic chloride for the synthesis of nucleosides from
silylated bases.ls3 Several publications have appeared on the alkylation of
pyrimidinones. Uracil and quinazolinediones give high yields of NN-dialky-
lated products upon treatment with an excess of an alkylating agent (RX or
R2S04) under phase-transfer condition^.'^^ Uracils have also beenN-alkylated,
using methyl iodide in glyme, in the presence of KF and alumina.185 Treat-
ment of uridine with dimethyl sulphate at pH > 12 gives a mixture of 0- and
N-methylated products, but exclusive N-alkylation occurs (87%) in the
presence of boric acid."'
Treatment of uracils with iodine monochloride gives the corresponding
5-iodouracils; 5-chlorouracils can be prepared with iodobenzene di~hloride.*~'
"' C. Kashima, A. Katoh, Y. Yokota, and Y . Omote, Chem. Pharm. Bull., 1981, 29,
2516.
183
H. Vorbruggen, K. Krolikiewicz, and B. Bennua, Chem. Ber., 1981, 114, 1234.
M. Hedayatullah, J. Heterocycl. Chem., 1981, 18, 339.
lB5 J . Yamawaki, T. Ando, and T. Hanafusa, Chem. Lett., 198 1, 1143.
Y . Hisanaga, T. Tanabe, K. Yamauchi, and M. Kinoshita, Bull, Chem. SOC. Jpn.,
1981, 54,1569.
187
M. J . Robins, P. T. Barr, and J . Gizicwicz, Can. J. Chem., 1982, 60, 554.
0
HO OH
(114)
Pyrimidine nucleosides have been chlorinated at the 5-position with m-chloro-
peroxybenzoic acid in DMA-HCl; thus uridine gives khlorouridine (1 14) in
90% yield and 8-chloropurines have been similarly prepared.'88
5-Methylhydantoins (1 16) are obtained when the acetoxyuracils (1 15) are
treated with dilute sodium hydroxide (Scheme 60).18'
0 0 0
Me
Scheme 60
Stabilized Wittig reagents g. Ph3PCHCONH2, eact with 5-hydrox -

uracils to give good to excellent yields of 5-substitution products; noteworthy
is the simple preparation of 5-~arbamoymethyluridine, a minor component of
transfer RNA, depicted in Scheme 61, previous routes to this type of com-
pound being less satisfactory."
0 0 0
R R R
( R = B -D-ribofuranosyl) 99%
Reagents: i, Br,, H,O; ii, C,H,N, H,O; iii, Ph,P=CHCONH,, dioxan, reflux
Scheme 61
E. K. Ryu and M. MacCoss,J. Org. Chem., 1 9 8 1 , 4 6 , 2 8 1 9 .
189 B. A. Otter, I. M . Sasson, and R. P. Gagnier, J . 0%.Chem., 1982, 47, 508.
K. Hirota, M. Suematsu, Y. Kuwabara, T. Asao, and S. Senda, J . Chem. SOC., Chem.
Commun., 1 9 8 1 , 6 2 3 .
Pyrimidinethiones have been converted into their oxygen analogues by the
action of halogens in basic media;’” the reverse operation has been accom-
plished for certain nucleosides in a two-step process, as outlined in Scheme 62
0 S
- ii
R R R
[ 77%] [ 85%]
(R = 6-D-triacetoxyribofuranosyl)
Reagents: i, p-C1C,H40POCl,, 172,4-triazole,C,H,N; ii, NaSH, H,O, acetone
Scheme 62
for t r i a c e t o ~ y u r i d i n e . ’2-Thiouridines
~~ (1 17) have been desulphurized, using
an azo-compound, PhCON=NCOPh, in mildly alkaline aqueous tetrahydro-
furan (Scheme 63); the generality of this reaction is limited in that the iso-
meric 4-thiouridine (1 18) merely gives a quantitative yield of d i ~ u l p h i d e . ’ ~ ~
X 0
R’ R1
[ 47-7591
(117) X = 0 , Y = S
(118) X = S , Y = 0
( R1= $-D-rihofuranOsy~ acetonide)

Scheme 63
Treatment of the cyanamide (119) with hot aqueous acid gives the
quinazolin-2-one (1 20) (98%).lW Variable (23-75%) yields of quinazolin-4-
ones (121) have been obtained from anthranilic acid and ketenimines
R2C=C=NAr.19’
19’ H. Singh, P. Singh, and N . Malhotra, J. Chem. SOC.,Perkin Trans. I , 1981, 2647.
19’ W. L. Sung, J . Chem. SOC.,Chem. Commun., 1982, 522.
193 0. Mitsunobu, N. Ito, S . 4 . Saito, T. Ogihara, H. Tamaoki, H. Nagusawa, H . Suzuki,
and J . Kimura, Tetrahedron L e t t . , 1982, 2 3 , 517.
194 J. Synth. Methods, 1981,7,75 814W.
J . Sv6tlik and A. Martvdn, Collect. Czech. Chem. Commun., 1981,46,428.
Six-Membered Rings: Systems containing nitrogen 32 1
Ph 0
Quinazolin-4-ones are also formed by heating o-nitrobenzanilides with

benzylamine (Scheme 64).'96
Reagents: i, PhCH,NH,, Ph,O, reflux

Scheme 64
Heating the o-(azidomethy1)imines (1 22) in the presence of fluoroboric
acid affords the dihydroquinazolines (1 23); the reaction appears t o be insensi-
tive t o the nature of the aryl group.'" The ylide (125) does not give the
expected cinnoline (124) upon heating in toluene; instead the quinazolin-4-
one (126) is isolated, in 86% yield. An as yet unidentified intermediate, iso-

meric with the starting material, can be isolated after short periods of heating
and separately converted into the quinazoline (1 26) (Scheme 65).198
0
I
COOMe
(125)
Scheme 65
'91 C. V. C. Rao, K. K. Reddy, and N. V. S. Rao, Indian J. Chem., Sect. B , 1 9 8 1 , 1 9 , 6 5 5 .

19' R. Kreher and U. Bergmann, Heterocycles, 1 9 8 1 , 16, 1693.
19' A. Alemagna, P. Del Buttero, E. Licandro, and S. Maiorana, J. Chem. SOC.,Chem.
Commun., 1 9 8 1 , 8 9 4 .
1,4-Diazines. - Like phenylglyoxal, 2-furylglyoxal condenses with amino-
acetamide to give a 5-arylpyrazin-2-one (1 27) (28%); chlorination of this
material, followed by phase-transfer-catalysed oxidation of the fury1 group,
affords the carboxylic acid (1 28) (Scheme 66).199
(127) (128)
Reagents: i, POCl,, reflux; ii, KMnO,, H,O, PhH, (C,H,,),N.HCI
Scheme 66
Much interest is at present centred on piperazine-2,5-diones, with particu-
lar emphasis on synthetic approaches to the antibiotic bicyclomycin (1 29),
which is active against Gram-negative bacteria. Stirring a-halo-carboxamides
with an ion-exchange resin in a two-phase system (CH2Cl2/SO%aq. NaOH)

gives good yields of the symmetrical diones (130).200 Far more general is the
R'
lg9 N. Sat0 and S. Arai, J. Heterocycl. Chem., 1982, 19, 407.

T. Okawara, Y. Noguchi, T. Matsuda, and M. F. Furukawa, Chem. Lett., 1981, 1 8 5 .
Six-Memb ered Rings: Systems containing nitrogen 323
B 0c-P r o- Phe - OMe ____t
H H
Reagents; i, 4M-HC1; ii, N-methylmorpholine, HOAc , bu tan-2-01, reflux
Scheme 67
route from N-protected dipeptide esters exemplified in Scheme 67; a wide

variety of optically pure cyclic dipeptides has been obtained in this way, and
yields are generally excellent ,201
The substituted acrylic acid (131) has been converted into the [4.2.2]
system (132) in fairly good overall yield (Scheme 68); particularly note-
ii-iv
LOCOOEt
0
v,vi
[65%)
-
CH 2B r
CH2
(132)
Reagents: i, PrNH,, PrNC, EtOCOOCH,CHO, MeOH, at 50°C; ii, 0,;iii, Me,S;
ivy DBU;v, NaOH; vi, C,H,N - HBr,
Scheme 68
worthy is the first step, a four-component reaction?02 In an alternative
approach, the readily available formylpiperazinedione (1 33) was converted
into the diol (134) (7 steps; 43%), which, upon treatment with acid,
afforded the bicyclic system (1 35); the bridgehead hydroxyl function was
then introduced by silylation, lithiation, and treatment with a peroxymolyb-
denum complex, giving (1 36) (30%) (Scheme 69).203
201 K. Suzuki, Y. Sasaki, N. Endo, and Y. Mihara, Chem. Pharm. Bull,, 1981, 29, 233.
'02 T. Fukuyama, B. D. Robins, and R. A. Sachleben, Tetrahedron Lett., 1981, 2 2 , 4155.
'03 R. M . Williams, Tetrahedron Lert., 1981, 2 2 , 2341.
0 0
0 0
(133) (134) (135) X = R = H

(136) X = OH, R = SiMe2But
Scheme 69
Both of the above routes lead to a bicyclic system with a substituted
methyl group at position 1, and further elaboration would be required if the
triosyl side-chain of bicyclomycin was desired. By starting with the l-unsubsti-
tuted bicycle (1 37), (&)-NN',O-trimethylbicyclomycin (140) has been pre-
pared (with other stereoisomers) by an aldol reaction at the bridgehead
position with the aldehyde (1 38) followed by hydrolysis of the acetonide
(139) (Scheme 70). Some degree of stereocontrol is observed in this reaction
(2)-( 137) 'b--

(f)-( 138)
Roil
RO
(?)-(139) R = a c e t o n i d e
(+)-(140) R = H
Scheme 70
in that the four pairs of enantiomeric acetonides that are formed are found in
a ratio of 9 :3 :3 :1, with the major product (1 39) possessing the natural rela-
tive stereochemistry.2"
The tetrakis(triphenylphosphine)palladium(O)-catalysed dechlorination of
a variety of chloropyrazines with sodium formate generally gives excellent
yields fo5 the same catalyst has been used to promote cyanodechlorination
with KCN in DMF.206
Good yields of quinoxaline mono-N-oxides (1 42) are obtained by treat-
ment of the enaminones (141) with a base; the compounds (141) are them-
204 S . 4 . Nakatsuka, K. Yoshida, and T. Goto, Tetrahedron Lett., 1981,22,4973.

205 Y.Akita and A. Ohta, Heterocycles, 1981, 16, 1325.
206 Y. Akita, Y. Shimazaki, and A. Ohta, Synthesis, 1981,974.
Six-Memb ered Rings :Systems containing nitrogen 325
selves readily obtained from cyclohexane-l,3-diones and o-nitroanilines
(Scheme 7 1).'07 2,3-Dihydroxy-l,4dioxan has been proposed as a useful,
stable equivalent of non-aqueous glyoxal; it condenses with o-phenylene-
COOH
diamine in ethanol to give an excellent yield of quinoxaline.2083,3-Dialkyl-

1,2,3,4-tetrahydroquinoxalin-2-ones (1 43) are formed when o-phenylene-
diamine is treated with ketones, chloroform, and strong base under phase-
transfer conditions (Scheme 72);'09 piperazinones have previously been
obtained in similar fashion.
(143)
Reagnets: i, CHCl,, 50% aq. NaOH, CH,Cl,, BzEt,NCl, at 1 0 ° C
Scheme 72
Quinoxaline-thiones (1 44) have been prepared by heating 1,2-diamino-

benzene with a-halo-ketones (RCOCH,X), sulphur, and triethylamine in
dimet hyl sulphoxide .'lo
Bis-deoxygenation of 2,3-disubstituted quinoxaline di-N-oxides has been
performed under very mild conditions with a variety of reagents. such as hex-
achlorodisilane or trifluoroacetic anhydride plus sodium iodide .211
3',4,9,9'-Tetrahydrofuro[2,3-b]quinoxalines, e.g. (145), are obtained in
quite good yields when 0-dicarbonyl compounds react with N-alkyl-
quinoxalinium iodides in the presence of amine bases; the structure of one of
these products was demonstrated by X-ray
207 S. Miyano, N. Abe, K. Takeda, and K.Sumoto, Synthesis, 1981,60.

208 M. C. Venuti, Synthesis, 1982,61.
2 0 9 J. T. Lai, Synthesis, 1982,71.
210 J. Synth. Methods, 1981, 7 , 76408W.
211 F. R. Homaidan and C. H. Issidorides, Heterocycles, 1981,16, 41 1.
2 1 2 V. N. Charushin, 0. N. Chupakhin, and A.I. Rezvukhin, Heterocycles, 1981, 16, 195.
uNx alJ-Jc
H I I
H Me
H
N S
Me
Treatment of 2-chloroquinoxaline with the potassium enolate of 3,3-

dimethylbutan-2ane in liquid ammonia (for 15 minutes, in the dark) gives a
mixture of the substitution product (146) (70%) and the furoquinoxaline
(147) (15%); the former is not converted into the latter by potassamide in
liquid ammonia. The formation of (146) is said t o represent the first example
of a thermal SRNlreaction in the quinoxaline series; addition of one equiv-
alent of di-t-butyl nitroxide (DBNO) totally supresses the production of
(146), the furoquinoxaline (147) (43%) being the only product that can be
isolated. Contrastingly, 4-choroquinazoline undergoes straightforward substi-

tution, uninhibited by the addition of DBN0.213
The octahydrophenazine (149) has been obtained (82%) by the action of
ammonia on the chloro-oxiran (148) followed by aerial oxidation; other
pyrazines can be similarly obtained.214
5 Triazines and Tetrazines
The first reported synthesis of 1,2,3-triazine involves the oxidation of
1-aminopyrazole with nickel peroxide?'' other oxidants, such as lead tetra-
acetate, are ineffective, although they can be used to prepare substituted
1,2,3-triazines.
The generality of the synthesis of 1,3,5-triazines from N-cyano-amidines
and amide chlorides that was reported last year4' has been further developed;
this route allows the preparation of s-triazines with a wide variety of substi-
oo
21 3
(148)
c1
(149)
OEt
(150)
D. R. Carver, J . S. Hubbard, and J . F. Wolfe, J . Org. Chem., 1982,47, 1036.
214 C. Herzig and J . Gasteiger, Chem. Bec., 1981, 114,2348.
21 5
A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, J . Chem. SOC.,Chem. Commun., 1981,
1174.
0 0
[ 58-95%]
Reagents: i, sym-triazine, HOAc, Ac,O, BF, *Et,O, reflux
Scheme73
tuents, a typical example being (1 s-Triazine can be a useful one-carbon

synthon; its use in the synthesis of isoflavones is depicted in Scheme 73.217
Investigations continue into the synthetic uses of cyanuric chloride :18 par-
ticularly noteworthy is the 'one-pot' synthesis of 6-lactams that is shown in
Scheme 74; the stereochemistry of the product is exclusively cis.218c
6OOE t COOE t
[ 58x1
Reagents: i, cyanuric chloride, Et,N, CH,Cl,
Scheme 74
1,2,3,5-Tetrazinones (1 52) are formed when the guanidine derivatives

(151) are treated with phosgene (Scheme 75); small amounts of the dipolar
triazolinones (153) can also be isolated; on heating, these are converted into
Reagents: i, ArN,+ BF; ;ii, COCl,, C,H, N (153)
Scheme 75
the tetrazinones (1 52).219 Phosgene has also been used to prepare the hitherto
unknown dihydrotetrazine-dione (1 55) from the carbono-hydrazide (1 54);
oxidation to the aromatic derivative (156) can be performed with alkaline
'16 R. L. N. Harris, Aust. J. Chem., 1981, 34, 623;Synthesis, 1981, 907.
"' H. C. Jha, F. Zilliken, and E. Breitmaier, Angew. Chem., Int. Ed. Engl., 1981, 20,
102.
"'( a ) R. J . Lahoti and D. R. Wagle, Indian J. Chem., Sect. B , 1981, 20, 852; ( b ) ibid.,
1981, 2 0 , 1007; ( c ) M. S. Manhas, A. K. Bose, and M. S. Khajavi, Synthesis, 1981,
209.
'I9 A. E. Baydar, G . V. Boyd, P. F. Lindley, and A. Walton, J . Chem. Soc., Chem. Com-
mun., 1982,225.
OH
BzN NBz i,ii HN iii,iv N f i N

I I NH2 - I I - I I1
NH2
(154) HNYNH""IfN
0 0
(155) ( 156)
Reagents: i, COC1,; ii, H,, Pd; iii, NaOH, H,O,; iv, H,O+
Scheme 76
hydrogen peroxide (Scheme 76), and some other chemistry of this system is
described.220
A series of 3-alkyl- or 3-ary1-6-amjr10-1,2,4,5-tetrazines
has been made by
addition of amines to 3-substituted tehrazines followed by oxidation, in situ,
of the dihydro-adducts with permanganate (Scheme 77).221 Cycloaddition
m2 NHR~
N&
'
I
N v
It
N
- R*NH2
"1wN -
-N
IJ
[OI N
I
N
A
v
N
II
N
R1 R1 R1
Scheme 77
reactions of tetrazines continue to be\ investigated. Silyl-acetylenes
(RCzCSiMe3) give pyridazines (1 58) when heated with the tetrazine (157) in
1,2-dibrornoethane; enolizable ynones (e.g. MeCOC-'CSiMe3) give mixtures of
products, cycloaddition occurring either across the triple bond [giving acyl-
pyridazines, e.g. (1 58; R = COMe)] or across the enol double bond [giving
(after loss of water) alkynylpyridazines, e.g. (1 59)]?22 In similar fashion, the
COOMe COOMe COOMe
(157) (158) (159)
acetamidines (1 6 1 ; R = Pri or But) react with the diphenyltetrazine (1 60) to

give the pyridazines (1 6 2 ) (Scheme 78)223 rather than triazines, as are
obtained when benzamidine reacts with tetrazines; some considerable degree
of regioselectivity can be exhibited in this latter reaction, as is exemplified in
220 F. A. Neugebauer and H. Fischer, Liebigs Ann. Chern., 1982, 387.

"' A. Counotte-Potman and H. C. van der Plas, J. Heterocycl. Chem., 1981, 19, 123.
222 L. Birkofer and E. Hansel, Chern. Ber., 1981, 114, 3154.
223 H. P. Figeys, A. Mathy, and A. Dralants,Synth. Comrnun., 1981, 11, 655.
Six-Membered Rings :System s containing nitrogen 329
R = 2-pyridyl [7.5%1
F. = methyl [ oq1
Scheme 79
Scheme 79.224The site selectivity that is exhibited in the reactions of the

usaturated hydrazones (1 63) with the tetrazine (1 57) is markedly influenced
by the substituent on the hydrazine (Scheme 80).225
R = methyl [ 75%]
R = phenyl [ 17x1
Scheme 80
6 Fused Systems containing One Five- and One Six-Membered

Ring (596)
The oxadiazolopyrimidine 1-oxide (164) is attacked by nucleophiles at
position 7 of the pyrimidine ring and not, as expected, in the oxadiazolo-ring.
Oxidation of the covalent adduct (1 6 5 ) , obtained by addition of water, with
lead tetra-acetate and then with manganese dioxide yields the dinitro-
pyrimidinone (1 66) (Scheme 8 1).226
224
H. P. Figeys and A. Mathy, Tetrahedron L e t t . , 1981, 22, 1393.
225
G. Seitz and W. Overheu, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 3 7 6 .
226 G. Tennant and C. W. Yacomeni, J. Chem. SOC.,Chem. Commun., 1982, 6 0 .
(164) (165)
Reagents: i, H,O; ii, Pb(OAc),; iii, MnO,
Scheme 81
A remarkable synthesis of pyrazolopyrimidines (1 69) involves the reaction
of the azines (167) with nitriles; the intermediate 1 : 2 molecular adducts
(168) can be isolated, and they readily cyclize on treatment with acid
(Scheme 82).227
R1 R1
H R1
Me
Me
(167)
1
R = Me, P h , o r p-C1C6H4
R2= Ph o r p-MeC6H4 (168) (169)
[ 50-65$]
Reagents: i, LiNPI,, THF, at - 78"C, R'CN; ii, lM-H,SO,, at room temperature
Scheme 82
The pyrimidinones (1 70), formed from 0-aminocrotonamide and N-acyl-
glycinates, cyclize o n treatment with polyphosphoric acid, initially t o
imidazo[ lY5-a]pyrimidines(1 7 1); at higher temperatures, imidazopyridines
(1 72) are formed (Scheme 83).228
0 0
R
M
e
Reagents: i, PPA, at 100-110°C; ii, PPA, at 180-190°C
Scheme 83
The reaction of diaminomaieonitrjle with N-methylacet onit rilium trifluoro-
methanesulphonate [Me-CGN-Me S03CF3], followed by a treatment with
sodium carbonate, yields the imidazole (173). The latter compound is readily
227
J . Barluenga, L. Muiiiz, and V. Gotor, J. Chem. SOC.,Chem. Commun., 1982, 454.
N. Katagiri, A. Koshihara, S. Atsuumi, and T. Kato, J. Urg. Chem., 1982, 47, 167.
Six-Membered Rings: Systems containing nitrogen 33 1
Me Me
CN
CN
(173) (174)
cyclized; thus reaction with acid anhydrides furnishes 6-cyano-purines

(1 74).229
An attempt to prepare 5-methyladenine (176) from the imidazole (175)
and formamidine resulted in the formation of the imidazotriazine (177)
(Scheme 84).230
Me
N
H2N NH2
(175) (176)
(177)
Reagents: i, H,NCH=NH,+ MeCO,-, NaOEt, HOEt, at 20°C
Scheme 84
A product (1 80), of unexpected structure, was also obtained by treatment
of the Michael adduct (179) of the amino-pyrimidone (178) and ethyl
propiolate with acid.231
Methylation of purines (and related systems) bearing NH, OH, or SH
groups with NN-dimethylformamide dimethylacet a1 gives the corresponding
N-, 0-, and S-methyl derivatives. With purine itself, 45% of the 7-methyl- and
30% of the 9-methyl-derivative is formed.232Alkylation of unionized adenine
results mainly in alkylation at N-3, whereas alkylation of the anion yields pre-
dominantly N-9-substituted adenine.233 Methylation of adenine under phase-
transfer conditions gives a nearly quantitative yield of 9 - m e t h ~ l a d e n i n e . ~ ~ ~
Alkylation of N-substituted adenines occurs preferentially at N-1, but
acylation of the amino-group causes alkylation to occur at N-7.235
Hydrolysis of the quaternary salt (1 S l ) , obtained from adenine and phenyl
chloroformate, yields isoguanine (182) as a result of a ring-opening, ring-
closure sequence.236
229 B. L. Booth and M. F. Proenca, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 7 8 8 .
230 R. S. Hosmane, V. Bakthavachalam, and N. J. Leonard, J . Am. Chem. SOC., 1982,
104,235.
231 F. Yoneda and R. Koga, Heterocycles, 1981, 16, 2137.
232 B. Stanovnik, M. TiBler, A. Hribar, G. B. Barlin, and D. J . Brown, Aust. J. Chem.,
1981,34,1729.
233 M. Rasmussen and J. A. Hope, Aust. J . Chem., 1982, 3 5 , 535.
234 M. Hedayatullah, J . Heterocycl. Chem., 1982, 19, 249.
235 Y. Maki, M. Suzuki, K. Kameyama, M. Kawai, M . Suzuki, and M. Sako, Heterocycles,
1981,15,895.
236 R. F. Pratt and K. K. Kraus, Tetrahedron Lett., 1981, 2 2 , 2 4 3 1 .
x%HF xk;)
0 0
0
Me
AJ
0-). hie
NH
I
CH=CHC02Et
0
Me
CH 2NHA r
(178) (180)
(179)
0
C1- I H
COOPh
(181)
6-Amino- and 6-alkylamino-9-alkyl-purines are deaminated on treatment
with sodium in liquid ammonia, and similar treatment of (methy1thio)purines
results in S - d e m e t h y l a t i ~ n .6-Mercapto-purines
~~~ have been obtained from
6-amino-purines by reaction with hydrogen sulphide in aqueous formic acid
under pressure.238 The reaction between adenine and benzenediazonium ions
under basic aqueous conditions yields N-6-substituted t r i a ~ i n e s ; ~under
~ ' the
same conditions, guanine furnishes products from azo-coupling at position
8 .240 Bazotization of 2-aminopurine nucleosides under non-aqueous con-
ditions has been utilized to introduce fluorine, chlorine, and bromine into
the 2-position .241
The reaction of dimethyl acetylenedicarboxylate with the thiazolo-
pyrimidine 1-oxide (1 83) resulted in the formation of the pyrimidothiazine
(1 84). The latter compound underwent thermal ring-contraction t o the
pyrrolopyrimidine (1 85) (Scheme 85).242
( Z = COOMe)
Reagents: i, MeO,CC=CCO,Me; ii, MeOH, reflux
Scheme 85
1 37
2 38
N. J. Kos and H. C. van der Plas, J. Org. Chem., 1981,46,5000.
J. Synth. Methods, 1981,7,77892W.
239 A. Chin, M.-H. Hung,and L. M. Stock, J. Org. Chem., 1981,46,2203.
240 M.-H. Hung and L. M. Stock, J. Org. Chem., 1982,47,448.
241 M. J. Robins and B. U z n h s k i , Can. J . Chem., 1981,59,2608.
241
K. Senga, M. Ichiba, H. Kanazawa, and S. Nishigaki, J. Chem. SOC.,Chem. Commun.,
1981,278.
0 0
0'A - 5 N 0 2
Me
Me
i M
0 AN
e
Me
N
OH
bR
(186) [42-52%1
Reagents: i, ArCHO, piperidine, DMF, reflux
Scheme 86
Pyrrolopyrimidines were also formed by the base-promoted reaction of the
5-nitro-6-methylpyrimidinedione(1 86) with aromatic aldehydes (Scheme
86).243
7 Fused Systems containing Two Six-Membered Rings (6,6)

Treatment of 6-amino-5-arylazo-uracils (1 87) with either urea or NN'-
carbonyldi-imidazole gave pyrimidotriazines (1 88). The latter compounds
were hydrolysed with alkali to triazinecarboxylic acids (1 89) (6-azauracil-S-
carboxylic acids) (Scheme 87).244'
0 NA r 0
0 0
Me Me H
(187) (188) (189)
Reagents: i, urea, at 220-240°C for 2 hours; ii, NaOH, EtOH, H,O

Scheme 87
Pyrimidinopyrimidines (1 92) are obtained by ring-expansion of the pyra-
zolopyrimidine N-oxides (1 91 ), these being readily prepared from bromo-
methyl-nitrouracil (190) (Scheme 88).245
0
NCH2R -oMAk)R
ii
HN
0
Me Me Me
( 190) (191) (192)
Reagents: i, RCH,NH,; ii, NaOEt, EtOH

Scheme 88
243 F. Yoneda, M. Motokura, and M. Otagiri, Chem. Lett., 1981, 1273.
244 F. Yoneda and M. Higuchi, J. Heterocycl. Chem., 1980, 17, 1365.
245
K. Hirota, Y. Yamada, T. Asao, and S. Senda, J. Chem. Soc., Perkin Trans. 1 , 1982,
277.
334 He terocy c lie Chemis try
Two modes of cyclization have been observed when the 6-(1’-alkylhydra-
zino)isocytosines (1 93) are treated with a-keto-acids (R2CH2COC02H) in
refluxing water. Pyruvic acid yields a pyrimidopyridazine (194; R2 = H)
whereas arylpyruvic acids tend to give pyrrolopyrimidines (1 95) via Fischer-
type ring-closure.2a
H ~ \N
N *<4 (193)
N(R~)NH,
3,3-Dimethoxy-2-pyrrolidinopropene
H2N
H (N y
(194)
N’y
R1
H2N
H
i
%
(196) has been shown to be a useful

N
(195)
R1
synthon for the synthesis of formylpterins and related compounds. Thus

treatment of (196) with nitrosyl chloride, followed by hydrolysis, yields 1,l-
dime thoxy-3-oximino-2-propanone (1 97), which on treatment with amino-
malononitrile gives a pyrazine (198) that is suitable for elaboration to a
formylpterin (Scheme 89).247 Two nine-step syntheses, from pyrazine inter-
mediates, of deoxyurothione (199) have been announced. A practical syn-
thesis of the urinary thienopterin urothione (200) still remains a synthetic
challenge .248
( 196) (197) (198)

Reagents: i, NOCl, THF; ii, H,O; iii, H,NCH(CN),, TsOH
Scheme 89
(6RS)-5-Formyl-6-methyl-5,6,7,8-tetrahydropterin has been prepared
from the parent pterin by formylation with formic acid and acetic
anhydride.249 In solution, it exists in two rotameric forms, as do other 5-acyl
derivatives. The absolute configuration of natural 5,6,7,8-tetrahydrobiopterin
(201) at C-6 is R .250
The reaction of bromoacetic acid, NN-dimethylformamide, and phos-
phoryl chloride yields a triformylmethane derivative, which was condensed (in
water) with 2,4-diaminopyrimidin-6( 1H)-one to give the pyridopyrimidine-6-
carbaldehyde (202). The latter compound was used as an intermediate for the
synthesis of 5 -deazapt erin .251
246 V. L. Styles and R . W. Morrison, J. Org. Chem., 1982, 47, 585.

247
E. C. Taylor and D. J. Dumas, J. Org. Chem., 1981,46, 1394.
2 48
E. C. Taylor and L. A. Reiter, J. Org. Chem., 1982, 47, 528.
249
A. N. Ganguly, 1. H. Bieri, and M. Viscontini, f f e l v . Chim. A c t a , 1981, 64, 367.
*” W. L. F. Armarego, P. Waring, and B. Paal, Aust. J. Chern., 1982, 35, 785.
2s1 C. Temple, R. D. Elliott, and J . A. Montgomery, J . Org. Chern., 1982, 47, 761.
0 0
H2N G HNY?
HN3(Nxxe
c "
(199) R = H
YOH
CH~R
H2N
H
( 2 0 1 ) R = (1'~,2's)-cH--CHMe
I I
( 2 0 0 ) R = OH OH OH
a
The 5-deazaflavin (203), in combination with flavin mononucleotide

(FMN), provides an efficient catalytic system for the aerobic oxidation of
benzylamines to benzaldehydes (Scheme 90).252 Alternatively, an auto-
Et
P h C H 2NH
PhCH=NH
X q&---(Eo (203)
Et
0
0
PhCHO
Scheme 90
recycling system for the reduction of carbonyl compounds to alcohols is
derived by combination of the 5-deazaflavin (204) and formic acid
(Scheme 91). No reduction of benzaldehyde by formic acid alone could be
detected under the reaction conditions.253A further auto-recycling system for
the oxidation of alcohols under neutral conditions involves the participation
of pyridodipyrimidines (Scheme 92).254
252
S. Shinkai, H. Kuroda, 0. Manabe, and F. Yoneda, J. Chem. SOC.,
Chem. Commun.,
1981, 391.
253 F. Yoneda, K. Kuroda, and M. Kamishimoto, J. Chem. SOC.,Chern. Cornmun., 1981,
1160.
254
F. Yoneda, H. Yamato, and M. Ono, J. A m . Chem. SOC.,1981, 103, 5943.
HCOOH
Me H
q z oA a x o
Me
(204)
0
x
P h CH OH
Scheme 91
PhCHO
0 0
H R2 H
R R4 CHOH
Scheme 92
8 Oxazines, Thiazines, and their Fused Derivatives

Oxazines. - The action of nitrous acid on the enones (205) gives mixtures of
oximes (206) and 4-0~0-~,6-dihydro-1,2-4H-oxazines (207); the former can
be converted into the latter by brief heating, whereas heating for a longer
period results in ring-contraction (Scheme 9?).”’
COR
Me Me Me
I
Reagents: i, NaNO,, HOAc; ii, xylene, reflux
Scheme 93
255 C. Deshayes and S. Gelin, Tetrahedron L e t t . , 1981, 2 2 , 2 5 5 7 .

Irradiatim of the 1,2-oxazines (208) affords a variety of products, depend-
ing on the groups at position 6. The 6-unsubstituted material (208; R = H)
gives the hydroxy-pyrroline (209) (1 00%) whereas the diphenyl analogue
(208; R = Ph) gives the oxime (210) (80%);the different products that are
RQ
R-
N
(208)
" HO DPh
formed reflect the relative ease of fission of C-0 and N - 0 bonds.256Depend-
ing on the base used, 3-methyl4,5-dihydro-1,2-6H-oxazine can be selectively
alkylated either at the exocyclic methyl group or in the ring; the ring-
alkylated products have been used as starting materials in the synthesis of
vinyl ketones (Scheme 94), and yields can be excellent.257
R
&-i,ii
0
Reagents: i, LiNBu'Pi, at - 65 "C; ii, RX; iii, LiNMe,, at - 95 "C; iv, Et,O+ BF;,
CH,Cl,, at room temperature; v, Me,N, at - 65 "C; vi, SiO,, H,O
Scheme 94
Good yields of 5-oxo-1,3-oxazines (212) have been obtained by treatment
of the diazo-ketones (211) with strong The reaction of N-alkyl-
cyanamides (RNHCN) with diketen gives oxazin-4-ones (2 13), which may be
transformed into uracils (214) by refluxing in acetic acid.259
When forming anthraniloyl derivatives (21 6) from isatoic anhydride (21 5)

and nucleophiles, competitive attack at the other carbonyl group [giving the
acids (217)] can be a problem; the use of 4-dimethylaminopyridine as a
catalyst suppresses the latter route in those cases that have been studied.260
256 H. Saiki and T. Mukai, Chem. L e t t . , 1981, 1561.
257
R. Lidor and S. Shatzmiller, J. A m . Chem. SOC.,1981, 103, 5916.
258
V. G. Kartser and A. M. Sipyagin, Chem. Heterocycl. Compd., (Engl. Transl.), 1980,
16, 1000.
259
T. Kato, Chem. Pharm. Bull., 1981, 29,862.
260 M. C. Venuti, Synthesis, 1 9 8 2 , 267.
The furan analogue of isatoic anhydride (2 18) reacts with alcohols and amines
(NuH) to give exclusively the acids (219), no amine (220) ever being
detected .26
0 0 0
NH, NHCONu
H
(215)
Successive treatment of salicylic acids with ethyl chloroformate, sodium

azide, and triphenylphosphine gives quite good overall yields of 1,3-benzo-
xazinones (221); the intermediate imidophosphoranes (222) can be iso-
lated.2623,l-Benzoxazines (223) are formed by the action of phosgeniminium
0
OCOOE t
salts (Cl2C=hR1R2 X-) upon methyl anthranilate.263Cinnamoylbenzoic acids

(224) are reported to give styrylbenzoxazines (225) upon reaction with
sodium azide and sulphuric
Heating the azo-compound (226; X = OH) with thionyl chloride gives an
excellent yield of the 1,4-benzoxazine (227); the authors suggest that the
reaction proceeds via the acid chloride (226; X = Cl), with the transfer of
chlorine being intramolecular in nature.265
261 J . B. Press, N. H. Eudy, and T. 0. Olagbemiro, J. Org. Chem., 1981, 46, 3853.
"' H. B. Stegman, F. Stocker, and G. Wax, Synthesis, 1981, 816.
263 I. Bitter, L. Szocs, and L. Toke, Acra Chim. Acad. Sci. Hung., 1981, 107, 5 7 .
164 J. Synth. Methods, 1982, 8 , 7 5 327X.
265 M. Byers, A. R. Forrester, I. L. John, and R . H . Thomson, J . Chem. SOC., Perkin
Trans. 1 , 1981, 1092.
*
/o /
0
0
\ Ar
HN /o /
339
TMe
N
II I
Me
Me
m
Me
“l
Me
NMe
RF4
Thiazines. - Butadipes react with N-sulphinyldimethylammonium tetra-

fluoroborate (Me,N=S=O BFi) to give lY2-thazines,e.g. (228).266Thermoly-
sis of the azides (229; R = Me or Ph) affords the cyclic sulphimides (230) in
excellent these materials can be converted into the isomeric thia-
zines (232) by a thermally induced [1,4] shift of the group on sulphur.267b
Irradiation gives the ring-contracted thienopyrroles (233), it being suggested
that these arise via the formation of (231) followed by successive [1,5]
shifts of RS and H (Scheme 95).267a
a S ’
- i
COOEt
G
S
R
/ COOEt
- ii
S
COOE t
SR
( 232) (233)
Reagents: i, toluene, reflux; ii, h v (350 nm), MeCN; iii, PhBr, reflux
Scheme 95
166 G. Kresze and M. Rossert, Liebigs Ann. Chem., 1 9 8 1 , 5 8 .
267
( a ) C. J. Moody, C. W. Rees, S. C. Tsoi, and D. J. Williams, J . Chem. SOC., Chem.
Cornrnun., 1 9 8 1 , 9 2 7 ; (b) R . D. Grant, C. J . Moody, C. W. Rees, and S. C. Tsoi, ibid.,
1982,884.
The oxazinium salts (234) react with hydrogen sulphide to give the corres-
ponding thiazinium salts (235), which can be converted into thiazinones
(236) (59-73%) by treatment with sodium carbonate.268 Similar thiazinones
have also been prepared from thioacyl isocyanates and olefins or acetylenes;
the regioselectivity of these cycloadditions is demonstrated by the formation
of (237) from ethyl vinyl ether and thiobenzoyl isocyanate.269Good yields of
2-iminothiazines (238) are obtained by heating 1-azabutadienes
(R’ N=CH-CR2=CHPh) with isothiocyanates (R3NCS) in benzene.270
0 0
-
c104
( 236) (237)
(234) X = 0
(235) X = S
A novel and hgh-yielding rearrangement is observed upon irradiation of

the 2-alkylidene-1,3-thiazine (239) (Scheme 96); the reaction is promoted by
the addition of acetone, and the authors suggest that a type of di-n-methane
rearrangement may be inv~lved.~”
COOEt
COOEt
( 239 1 Scheme 96
Good yields of thiamorpholine SS-dioxides are obtained by treatment of
oxathian SS-dioxide with a variety of nitrogen nucleophiles (Scheme 97);
some chemistry of these thiamorpholines is described.272 The isocepham
R
Reagents: i, RNH,, OH-, EtOH, reflux
Scheme 97
268 Y. Yamamoto, Y. Azuma, and S. Ohnishi, Heterocycles, 1981, 15, 851.
269 J. Goerdeler, M.-L. Tiedt,and K. Nandi, Chem. Ber., 1981, 114, 2713.
270 Y. Ohshiro, T. Hirao, N. Yamada, and T. Agawa, Synthesis, 1981,896.
271 H. B, Hitchcock, R. W. McCabe, D. W. Young, and G . M . Davies, J. Chem. Soc.,
Chem, Commun., 1981,608.
212
F. Asinger, M. Kaussen, I. Gold-Martin, and A. Saus, Monatsh. Chem., 1981, 112,
643.
0 0-Mes 0
It H
P h CH C -N
i
)2
E to06
Reagents: i, S,, KOBU', THF

Scheme 98
(241) is formed in 80% yield cy the reaction of the phosphonate (240) with
sulphur and potassium t-butoxide (Scheme 98); a similar reaction has also
been used to form a 3 - t h i a - a n a l o g ~ e . ~ ~ ~
Trifluoroacetic-anhydride-inducedcyclodehydration of the sulphoxides
(242) leads to the cyclic ylides (243) (Scheme 99); one of these compounds
Me Me
Reagents: i, TFAA, CH,Cl,

Scheme 99
has been independently synthesized by methylation (using NaH and MeI) of
the 1,4-thiazine (244), only the product of S-alkylation being reported.274
9 Other Oxygen- and Sulphurcontaining Systems

Heating the azides (245) in refluxing toluene results in the formation of the
corresponding benzo[ 1,4,2]dithiazines (246);275a these latter compounds
react with dime t hyl acet ylenedicarboxyla t e (DMAD) to give benzo dit hiins
(247) (Scheme
273 G . H. Hakimelahi and A. Ugolini, Tetrahedron Lett., 1982, 2 3 , 9 1 3 .
274
T. L. Gilchrist and G. M. Iskander, J . Chem. SOC.,Perkin Trans. I , 1982, 8 3 1 .
275
( a ) J. Nakayama, M. Ochiai, K. Kawada, and M. Hoshino, J. Chem. SOC.,Perkin
Trans. I , 1981, 618; ( b ) J. Nakayama, J . Fukushima, R . Hashimoto, and M. Hoshino,
J . Chem. SOC., Chem. Commun., 1982, 612.
- a>R
DSXR -a) COOMe
i
N3 COOMe
(245) ( 246) (247)

Reagents: i, toluene, reflux; ii, MeOOCCXCOOMe, o-C&C,H,, reflux
Scheme 100
The fused oxadiazine (249) is formed, in excellent yield, by heating the
nitroso-compound (248) in light p e t r ~ l e u m . ~ ' ~
N NHCOOEt N'
"\N IIQ,B0
Ar Ar
Phenylazostilbene (250) cyclo-adds regiospecifically to fluorenethione,

giving a 1,3,4-thiadiazine (25 1); the opposite regioselectivity is exhibited with
fluorenylidenesulphene, a 1,2,3-thiadiazine (252) being the major product
(Scheme 10l).277 The previously unreported 1,3,4-thiadiazin-6-ones, e.g. (254),
Ph
Ph Y N \ N p h
H [57%] [91%1 H
Ph R2 Ph
( 250) ( 251)
(252)
( R2= f luorenylidene)
Scheme 101
have been prepared by cyclodehydration of the thiosemicarbazones, e.g. (253),

with dicyclohexylcarbodi-imide, and some of the chemistry of this system has
been investigated. Flash vacuum pyrolysis (at 550 ' C , at 0.08 mmHg) gave
Me 2N A sCmH Me2N
(254)
276 P. Giori, D. Mazzotta, G. Vertuani, M. Guarneri, D. Pancaldi, and A. Brunelli, Far-

muco, Ed. Sci., 1981, 36, 1019.
277
B. F. Bonini, G. Maccagnani, G . Mazzanti, G. Rosini, and E. Foresti, J. Chern. Soc.,
Perkin Trans. I , 1 9 8 1 , 2 3 2 2 .
benzonitrile, NN-dimethylcyanamide, and the thadiazole (255), there being
no evidence for any formation of d i a ~ e t e . ~ ~ ~
Two publications have recently appearecj ,on the formation of six-
membered heterocycles from nitrilimines (PhN-NXR) and suitably hetero-
substituted olefins; thus the selenate (256) gives a selenadiazine (257)279aand
the phosphonite (258) affords a phosphadiazine (259)?79b
Ph Ph
Me2N
( 256)
Se "'3
Me2N Se
( 257 1
COOE t "'"a (258)
P( OEt ) [J
N\N
E t oHP*o 'gHqN02-P
( 259 1
A new, hgh-yielding route to 173-didehydro-2,1,3-benzothiadiazin4-one

(260) consists of treating anthranilamide with thionyl chloride or sulphur
dichloride; ketones react with this cyclic ylide to give quinazolines,
e.g. (261).280
0
0
H Me
The previously unreported azapenem system has been prepared, albeit

with loss of stereochemical integrity, by desulphurization of the azacephem
(263), itself prepared from the monocyclic 0-lactam (262) (Scheme 102).281
COOR ( 263)
R = p-nitrobenzyl
(262)
Ar = 2-benzothiazolyl
Reagents: i, AgOAc, PhH, reflux; ii, PPh,, MeCN, at room temperature
Scheme 102
278 A. E. Baydar, G. V. Boyd, and P. F. Lindley, J. Chem. SOC.,Chem. Commun., 1981,
1003.
279 ( a ) V . A. Bobylev, M. L. Petrov, V. N. Chistokletov, and A. A. Petrov, J. Org. Chem.
USSR (Engl. Transl), 1982, 18, 200. ( b ) A. Yu. Platonov, I. G. Trostyanskaya,
M. A. Kazankova, and V. N. Chistokletov, Zh. Obshch. Khim., 1982, 5 2 , 268; via
J. Synth. Methods, 1982,8 , 7 5 653X.
280
K. Eger,Arch. Pharm. (Weinheim, Ger.), 1981,314, 176.
281 G. Johnson and B. C. Ross,J. Chem. SOC.,Chem. Commun., 1981,1269.
344 He terocycZic Chemistry
The thioketen dimers (264) have been converted into dithiadiazines (265)
by treatment with methanolic sodium azide followed by concentrated hydro-
Roocx
RmcxcN
chloric acid.282
S S S I I
" COOR
NCCO
'OR NC
Classified Reference List

Pyridines. - W. Bornatsch, H. Reel, and K. H. Schundehutte, Chem. Ber., 1 9 8 1 , 1 1 4 , 9 3 7 .
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E. Schmitz and S. Schramm, J. Prakt. Chem., 1 9 8 2 , 3 2 4 , 8 2 .
C. Seoane, J. L. Soto, P. Zamorano, and M. Quinteiro, J. Heterocycl. Chem., 1981, 1 8 ,
309.
F. Maiolo, L. Testaferri, M. Tiecco, and M. Tingoli, Tetrahedron L e t t . , 1981, 22, 2 0 2 3 .
A. R. Katritzky, A. Chemprapai, R. C. Patel, and A. Tarraga-Tomas, J. Org. Chem.,
1982,47,492.
J. P. Kutney, L. Kaczmarek, D. Mostowkz, and B. R. Worth, Can. J. Chem., 1982, 6 0 ,
323.
R. F. Francis, H. M. Howell, and D. T. Fetzer, J. Org. Chem., 1 9 8 1 , 4 6 , 2 2 1 3 .
E. Gossinger,Monatsh. Chem., 1981, 1 1 2 , 1 0 1 7 .
M. V . Denisko, G. V. Parel, and M. N. Tilichenko, Chem. Heterocycl. Compd. (English
Transl.), 1 9 8 1 , 1 7 , 5 8 0 .
Quinolines, Isoquinolines, and their Benzo- and Hydro-derivatives. - Y. Watanabe,
Y. Tsuji, and Y. Ohsugi, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 2 6 6 7 .
Y.Watanabe, S. C. Schim, and T.-A. Mitsudo, Bull. Chem. SOC. Jpn., 1981, 54, 3460.
J. Ackroyd and F. Scheinmann, J . Chem. Res. ( S ) , 1 9 8 2 , 89.
0. Meth-Cohn, B. Narine, and B. Tarnowski, J. Chem. Soc., Perkin Trans. I , 1981, 1520.
E. 0. Sidorov, A. I. Matern, and 0. N. Chupakhin, J. Org. Chem. USSR (Engl. Transl.),
1 9 8 1 , 1 7 , 357.
S. Konno, M. Shiraiwa,and H. Yamanaka, Chem. Pharm. Bull., 1 9 8 1 , 2 9 , 3 5 5 4 .
D. S . Dime and S. McLean, J. Org. Chem., 1 9 8 1 , 4 6 , 4 9 9 9 .
R. C. Schnur and H. R. Howard, Tetrahedron L e t t . , 1981, 2 2 , 2 8 4 3 .
T. Shono, M . Sasaki, K. Nagami, and H.Hamaguchi, Tetrahedron L e t t . , 1982, 23, 9 7 .
M. J. Tanga and E. J. Reist, J . Org, Chem., 1 9 8 2 , 4 7 , 1365.
H. J. W. van der Haak and H. C. van der Plas, J. Org. Chem., 1 9 8 2 , 4 7 , 1673.
1,2-Diazines. - M . F. Ahern, A. Leopold, J. R. Beadle, and G. W. Gokel, J. A m . Chem.
SOC.,1 9 8 2 , 1 0 4 , 5 4 8 .
J. B. Bunting, V. S.-F. Chew, and S. Sindhuatmadja, Can. J. Chem., 1981, 59, 3195.
1,3-Diazines. - T. Momose, T. Tanaka, T. Yokota, N. Nagamoto, H. Kobayashi, and
S . Takano, Heterocycles, 1981, 15, 8 4 3 .
H. J. Bestmann and R. W. Saalfrank, Chem. Ber., 1981, 1 1 4 , 2 6 6 1 .
B. Stanovnik, M. Tigler, N. Trckk, and B. VerEek, Vestn. Slov. Kem. Dms., 1981, 28,
45.
I. Saito, H. Sugujama, N. Furukawa, and T. Matsuura, Tetrahedron L e t t . , 1 9 8 1 , 22,
3265.
282 K. Peseke, 2. Chem., 1981, 21, 1 0 2 ,
Six-Membered Rings: Systems containing oxygen or sulphur 345
A. M. Lamazoucre and J. Sotiropoulos, Tetrahedron, 1 9 8 1 , 3 7 , 2 4 5 1 .
K. Hirota, Y. Kitade, and S. Senda, Tetrahedron Lett., 1981, 22, 2409.
I. I. Naumenko, M. A. Mikhaleva, and V. P . Manaev, Chem. Heterocycl. Compd. (Engl.
Transl.), 1 9 8 1 , 1 7 , 7 1 0 .
G. Dietz and F. Bahr, Pharmazie, 1980, 3 5 , 7 5 1 .
1,4-Diazines. - H. Gnichtel, B. Schnitt, and G. Schlunk, Chem. Ber., 1 9 8 1 , 114, 2536.
J . D. M. Herscheid, J. H. Colstee, and H. C. T. Ottenheijm, J. Org. Chem., 1 9 8 1 , 4 6 ,
3346.
K. Keyns, E. Behse, and W. Francke, Chem. Ber., 1 9 8 1 , 1 1 4 , 2 4 0 .
H. Wamhoff and W. Kleimann, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 7 4 3 .
A. G. Anastassiou, H. S . Kasmai, and M. R. Saadein, Angew. Chem., Int. Ed. Engl., 1981,
20, 115.
Triazines and Tetrazines. - T. C. Gallagher and R. C. Storr, Tetrahedron Let t ., 1 9 8 1 , 22,
2909.
F. Pochat, Tetrahedron Lett., 1 9 8 1 , 22, 3595.
Y. Nakayama, Y. Sanemitsu, M. Mizutani, and H. Yoshioka, J. Heterocyl. Chem., 1981,
18,631.
Fused Systems containing One Five- and One Six- or Two Six-Membered Rings. - R. C.
Moschel, W, R. Hudgins, and A. Dipple, Tetrahedron Lett ., 1981, 2 2 , 2 4 2 7 .
J. Armand, K. Chekir, P. Ple, G. Qukguiner, and M. P. Simonnin, J. Org. Chem., 1 9 8 1 ,
46,4754.
Oxazines, Thiazines, and their Fused Derivatives. - M. Yoko'yama, M. Nakamura,
H. Ohteki, T. Imamoto, and K. Yamaguchi, J. Org. Chem., 1 9 8 2 , 4 7 , 1090.
G. Just, Y. S . Tsantrizos, and A. Ugolini, Can. J. Chem., 1981, 5 9 , 2 9 8 1 .
G. Schneider, L. Hackler, and P. Sohhr, Tetrahedron Lett., 1981, 2 2 , 341.
C.-P. Maschmeier, H. Tanneberg, and H. Matschiner, 2. Chem., 1 9 8 1 , 21, 2 1 9 .
M. Yokoyama, M. Nakamura, T. Imamoto, and K. I. Yamaguchi, J. Chem. SOC., Chem.
Commun., 1 9 8 1 , 5 6 0 .
-
Other Oxygen- and Sulphur-containing Systems. M. Christl, U. Lanzendorfer, and
S . Freud, Angew. Chem., Int. Ed. Engl., 1981, 20, 6 7 4 .
L. Bruchk, L. Garanti, and G. Zecchi, J. Chem. Soc., Perkin Trans. I , 1 9 8 1 , 2 2 4 5 .
PART 11: Six-Membered Rings containing Oxygen or Sulphur by G. P. Ellis
1 Reviews
The synthesis of tocopherol and related compounds has been reviewed.' The
conformations of coumarins which have anticoagulant action on blood have
been studied crystallographlcally.2 A valuable review of the occurrence and
distribution of the 462 flavonoids that had been found in plants up to the
time of its writing was published3 in 1981. The use of 4-phenyl-l,3-dioxan as
an intermediate in the synthesis of fragrant compounds has been surveyed?
Chlorinated dibenzodioxins are important compounds, and the first part of
a timely review of the thermal formation of these compounds has appeared.'
All chemists who are active in the benzopyrone field will be saddened to
know of the death of Professor K. Venkataraman; his life and work is sum-
marized in an appreciation.6
R. Odo, Kagaku ( K y o t o ) , 1981, 36, 127 (Chem. Abstr., 1 9 8 1 , 9 5 , 6 1 620).
I. Csoeregh, Chem. Commun. Univ. Stockholm, 1 9 8 1 , No. 7 , p. 1 (Chem. Abstr.,
1 9 8 2 , 9 6 , 198 666).
E. Wollenweber and V. H. Dietz, Phytochemistry, 1 9 8 1 , 2 0 , 8 6 9 .
L. Cerveny, A. Marhod, and V. Ruzicka, Chem.-Ztg., 1981, 1 0 5 , 2 5 1 .
G. G. Choudhry and 0. Hutzinger, Toxicol. Environ. Chem., 1982, 5 , 1 (Chem.
Abstr., 1982, 96, 1 8 0 2 5 6 ) .
A. V. R. Rao, Indian J. Chem., Sect. B , 1 9 8 1 , 2 0 , No. 7 , i.
2 Heterocycles containing One Oxygen Atom
Reduced Pyrans. - Antibiotic compounds of this type' continue to receive
attention. Methyl pseudomonate C (1) has been converted, in several steps,
into methyl pseudomonate A (2) by a process which is an improvement on
the original work.' The diol group of (1) was protected as its benzylidene
acetal while the double bond was epoxidized. Deprotection and hydrogen-
olysis gave (2), which was hydrolysed to the acid.g A newly developed Diels-
HOCHCHCH=CHCH~'
MI e I 9 O H
A, '
--CHZCPC'
COO( CHz ) *COOMe
M
e OH
(2)
Alder reaction, catalysed by dimethylaluminium chloride, has been employed
in a new total synthesis of pseudomonic acids A and C from hexa-1,s-diene."
In a further study of the ionophore antibiotic lasalocid" (3), it has been
subjected to Mannich and Baeyer-Villiger reactions. The former took an
unusual course in that the carboxyl was replaced by an aminomethyl group.12
The natural ionophore X-14547A (4) has been synthesized from two separ-
ately prepared segments ( 5 ) and (6) of the m ~ l e c u l e . l4
'~~
The conformation of 17epi-deoxysalinomycin (a close relative of the anti-
biotic) has a definite form in solution but it cannot exist as a head-to-tail
hydrogen-bonded structure. The relevance of these deductions to its biologi-
cal role has been disc~ssed.'~ One of the constituents of the secretion of the
bee Andrena wilkella is the bis-spiropyran (7), and this has been synthesized
from ethyl (+)-(S)-3-hydroxybutenoate, obtained from the reduction of
ethyl acetoacetate by yeast .I6
G. P. Ellis, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0. Meth-Cohn,

(Specialist Periodical Reports) The Royal Society o f Chemistry, London, 1980,
Vol. 1, p. 331.
a A. P. Kozikowski, R. J. Schmiesing, and K. L. Sorgi, J. A m . Chem. SOC., 1980, 102,
6577.
A. P. Kozikowski, R. J . Schmiesing, and K. L. Sorgi, Tetrahedron Lett., 1981, 22,
2059.
B. B. Snider and G. B. Phillips, J. A m . Chem. SOC., 1982, 104, 11 13.
I' G. P. Ellis, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0. Meth-Cohn,
(Specialist Periodical Reports) The Royal Society of Chemistry, London, 198 1 ,
Vol. 2 , p. 284.
l2 D. L. Coffen and D. A. Katonak, Helv. Chim. Actu, 1 9 8 1 , 6 4 , 1 6 4 5 .
l 3 K. C. Nicolaou, D. P. Papahatjis, D. A. Claremon, and R. E. Dolle, J. Am. C h e n
SOC.,1981,103,6967.
l4 K. C. Nicolaou, D. A. Claremon, D. P. Papahatjis, and R. L. Magolda, J. Am. Chem.
SOC.,1981,103, 6969.
l5 M. J. 0. Anteunis and N. A. Rodios, Bull. SOC. Chim. Be&., 1981,90,471.
K. Mori and K. Tanida, Tetrahedron, 1981, 37, 3221.
Me
OH 0 Et OH
H'
(3) Me
COOH COOMe
I
Mlru:H=CEt
1 COEt
MeCH
Me
,-. (4)
Me
The use of ' H n.m.r. and chemical reactions in the determination of

stereochemical assignments for reduced cyclopropapyrans (8) has been
extended to the 7-phenyl derivative, which was synthesized from 5,6-dihydro-
2H-pyran and a,a-dichlorotoluene. Reduction of the chloro-compound (8)
with LAlH4 gave the endo-isomer (9), which was isomerized to the exo-form
(1 0) by t-butoxide." Dichlorocarbene adds on to 5,6-dihydro-4-methyl-2H-
pyran to give the cyclopropa[c]pyran (1 1) and to 5,6-dihydro4-methylene-
2H-pyran to form the spiran (12) in high yields."
H Ph
(13 1 (12)
17
D. H. Corbin, G . D. Hobbs, and J . D. Woodyard, J. HeterocycL Chem., 1981, 18,
643.
18
A. A. Gevorkyan, N. M . Khizantsyan, P. I. Kazaryan, and G . A. Panosyan, Khim.
Geterotsikl. Soedin., 1981, 167 (Chem. Abstr., 1981, 9 5 , 6986).
Tetrahydropyran-2-carboxylic acids are decarboxylated by concentrated

sulphuric acid and the resulting carbonium ions, such as (14), are relatively
stable; this was demonstrated by ‘H n.m.r. spectroscopy. Cineolic acid (15),
which was known to produce the lactone (1 7), also yielded the oxonium ion
(1 6 ) , which was convertible into the lactone.”
Pyrans. - Highly fluorinated 2H-pyrans have been synthesized by low-

temperature condensation of the perfluoralkene (18) with an alkyl aryl
ketone (1 9; R = CN, COCF3, or COCF2CF3).202,4,6-Triarylpyrylium salts
are converted, in good yield, into 2-alkoxy-2,4,6-triaryl-2H-pyrans or
2-amino-2,4,5-triaryl-2H-pyranson treatment with sodium alkoxides or
secondary amines, respectively.’l Several methods of converting pyranones

and pyrylium salts into pyridine derivatives are known.22 Recently, several
2-amino-4H-pyrans, e.g. (20), have been converted into 2-pyridones or their
dihydro-derivatives by mild treatment with nitrosylsulphuric acid or sulphuric
acid, respectively.”
phoo- -
H H
(r..
ONOS03H
NC / CN NC
Ph I I NH2
Ph [87%] CN
(20)
l9 H. A. Bates, J. Am. Chem. SOC.,1982,104,2490.

2o T. Kitazume, K. Chino, and N. Ishikawa, J. Fluorine C h e m , 1981,18,213.
21 G. W. Fischer, T. Zimmermann, and M. Weissenfels, 2. Chem., 1981, 21, 260, 282.
22 C. Seoane, J. L. Soto, P. Zamorano, and M. Quinteko, J. Heterocycl. C h e m , 1981,
18, 309.
Sir-Memb ered Rings: Systems confaining nitrogen 349
Pyrylium Salts. - New uses for known and novel pyrylium salts continue to
emerge. New routes to pyrylium salts consist of acylation of the 1,s-diene
(21) in the presence of perchloric acid23 and the reaction of 3-chloro-2-
methylprop-1-ene with aluminium chloride and perchloric acid to give the
useful 4-chlo ro met hyl-2,6 -dimet h ylp yr ylium perchlorat e .24
A 2,4,6-trimethylpyrylium salt which is safer to store than the perchlor-
ate is the sulphonic acid salt (22), which has been synthesized from isobutene
and acetic anhydride.25 Pyrylium salts that carry acid or ester groups are
becoming more common; one of these has been synthesized in two steps, in
good yields, from a keto-acid and a ketone [23; R' = Ar or R'R2 =
(cH2)41.26
+
HC104
H2C=CMe( CH2) 2CMe=CH2 + Ac20 ___)
(21)
Me -+
COOH
I
PhCCH=CHCOOH + R1CCH2R2
II II
0 0 0 0
+ COOH
MeoMe
(23)
CH 2COOH
1 -
Me so3
(22)
The less reactive pyrylium salts added on tributylphosphine (but not tri-
phenylphosphine) to give a phosphonium salt (24), which, on heating with di-
isopropylethylamine, gave the bi-4H-pyran (25) in high yield. When the
tertiary amine (with or without a catalytic amount of tributylphosphine) was
Ar Ar
0PBr3 Ar
(25)
Ar
'.OAr (26)
23 V. I. Dulenko and V. M. Golyak, Khim. Geterotsikl. Soedin., 1981, 844 (Chem.
Abstr., 1 9 8 1 , 95, 150 339).
l4 V . I. Dulenko, N. N. Alekseev, and V . M . Golyak, Khim. Prom-st., Sec. Reakt.-Osobo
Chist. Veshchestva, 1 981, 7 9 (Chem. Abstr., 1982, 96, 68751).
25 A. Dinculescu and A. T. Balaban, Org. Prep. Proced. In?., 1982, 14, 39.
26 N. V . Kholodova, Yu. P. Andreichikov, and G. N. Dorofeenko, K h i m Geterotsikl.
Soedin., 1 9 8 1 , 162 (Chem. Abstr., 1 9 8 1 , 9 5 , 6 9 7 0 ) .
used, reduction to the 4H-pyran (26) occurred.27 Addition of alkoxide to
2,4,6-triphenylpyrylium salt may occur at C-2 or C 4 or at both positions. A
kinetic study of this reaction, and the effect of changing the 4-substituent,
has suggested that the reaction may be controlled more by distribution of
electron charge than by orbital characteristics.28
Further extensions of the use of pyrylium salts as synthons have
for example, their reaction with h~drazines.~'The xanthylium
salt (27; A = 0) reacted with amines under very mild conditions and in good
yield and it has been used to synthesize sulphones, sulphides, and ethers in
the presence of phase-transfer catalysts; for example, 2-hexyloxynaphthalene
was obtained in 70% yield by heating the acridinium salt (27; A = NC6HI3)
with sodium 2-naphthoxide and Bu4N' BFi.31 A phase-transfer catalyst has
also been used to promote the addition of active-methylene compounds to
2,4,6-triphenylpyrylium perchlorate; the product (28) was converted into a
highly substituted benzoate ester (28a).32 Ester-containing pyrylium salts,
e.g. (291, have been converted into ~ y r i d i n eand
~ ~ pyridiniumM analogues,
which are useful synthons.
K p h O : O O E CMeOH
t [86%];r Ph G
Ac20 ' O Et
C O OAc
+ /
\ A / Ph
-
/ BF4 \ (28) (28a)
P h o COOEt cA04: Ph 0+
COOE t PhNH2
[95%1
~ Ph 0+Ph
COOE t
-
Ph Ph Ph BF4
(29)
Pyran-2-ones.- Following earlier syntheses of the xanthyrones that contain

enolizable side-chains, a number of pyran-2-ones, containing non-enolizable
substituents, have been synthesized; for example, from the pyran-2-one (30)
and cyanoacetate (31), the xanthyrone (32) was obtained and its behaviour
with magnesium methoxide was e ~ a m i n e d . ~Bis(pyran-2-ones)
' such as (33)
27 G . A. Reynolds and C. H. Chen, J. Heterocycl. Chem., 1981, 18, 1235.
l8 G. Doddi, G. Illuminati, N. Insam, and F. Stegel, J. Om.C h e m , 1982,47,960.
29 G. P. Ellis, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0. MethCohn,
(Specialist Periodical Reports), The Royal Society of Chemistry, London, 1982,
Vol. 3, p. 295.
30 A. R. Katritzky, P. Ballesteros, and A. T. Tomas, J. Chem. SOC.,Perkin Trans. 1 ,
1981, 1495.
31 A. R. Katritzky, A. Saba, and R. C. Patel, J. Chem. SOC..Perkin Trans I , 1981, 1492.
32 G. N. Dorofeenko, A. V. Koblik, and K. F. Suzdalev, Zh. Org. K h i m , 1981,17, 1050.
33 A. R. Katritzky, A. Chermprapai, R. C. Patel, and A. T. Tomas, J. Om.Chem., 1982,
47,492.
34 A. R. Katritzky, P. Awartani, and R. C. Patel, J. Org. Chem., 1982,47,498.
35 S . R. Baker, L. Crombie, and R. V . Dove, J. Chem. Soc.. Perkin Tmns. I , 1981, 165.
Six-Membered Rings: Systems containing oxygen or sulphur 35 1
have been synthesized with and without a 14C label in the bridge.36 Using a
previously discovered process in which the reactants are melted together, fur-
ther variations in the structures of xanthyrones have been developed, includ-
ing unsymmetrical bis(pyran-2-ones), e.g. ( 3 9 , whose reactions were
studied?' The enolic structure of diethyl glaucophanic enol (34) has been
confirmed by X-ray analysis.38 When some xanthyrones, e.g. (35), were
treated with activated manganese dioxide, dehydrodimerization occurred, and
the structure of the product was confirmed by X-ray ~rystallography.~'
CN
I
MeOOC / Ac
+ MeOCH=yCOOMe
CN
- t4eOOC
'C
Me
(33) R1= Me, R2= Ac
1 2
(34) R = R = Ac
(35) R 1 = Me, R ~ =COOMe
The electron-rich character of keten acetals (36) means that they undergo
cycloaddition with ketens; with judicious choice of reactants, this results in
the formation of dihydropyran-2-ones, e.g. (37), which are hydrolysed to the
dioxoderivative (38)."O 0-Keto-esters are cyclized by their reaction with 3-
hydroxy-aldehydes and titanium(l\r) chloride to form 5,6-dihydropyran-2-
ones?l Aroylarylacetylenes condense with either ethyl cyanoacetate or aceto-
acetate in the presence of a base to form 4,6-diarylpyran-2-ones (39).4*
(Et0)2C=CHCCHC1Me lLg,.CHIC Me H+ C l
Me H C v
+
0
(36)
II
C 1 2CHCOC1
Et3N
____t
EtO OEt
c1
- 0
c1
(37) (38)
36 S. R. Baker and L. Crombie, J. Chem Soc., Perkin Trans. 1,1981,172.

'' S . R. Baker and L. Crombie, J. Chem. SOC.,Perkin Trans 1,1981, 178.
'* S. R. Baker, M. J . Begley, and L. Crombie, J. Chem. Soc., Perkin Trans. 1, 1981, 182.
39 S. R. Baker, M. J . Begley, and L. Crombie, J. Chem. Soc., Perkin Tram. I , 1981, 190.
40 W. T. Brady and R. D. Watts, J. Org. Chem., 1981,46, 4047.
41 G. Falsone and B. Spur, Liebllps Ann. Chem., 1981,565.
42
F. A. Fouli and M. N. Basyouni, Acta Chim Acad. Sci Hung.,1981, 106,297.
CN
PhC=CCOAr +
I
CH2COOEt
( A r = 4-H-, 4-Me0-, or
/ CN
Ph
4-C1-C6H4 ) (39)
H\C/Me
11 + MeCH(COC1)2
E tOOCCH2C /C\Ml?, (41)
(40)
(43) (44)
A total synthesis of the antibacterial pyranone nectriapyrone (42) has

been achieved from ethyl trans-4-methyl-3-oxohex-4-enoate (40) and methyl-
malonyl dichloride (41) in four steps.43 The marine antibiotic (?)-malyngolide
(43)@ has been synthesized from ethyl 2-oxocyclopentane-2-carboxylate45
and subsequently by an improved route through the cyclopentanone (44).&
Shorter and more convenient syntheses have been described for the stereo-
chemically important (*)-Prelog-Qerassi lactonic acid (47). One depends on
the intramolecular hydroboration of the diene (45) to give, after oxidation,
the lactone (46).47 In another synthesis, 2-methylpent-4-enal is converted into
the lactone (47) in eight steps, including stereoselective hydroboration-
oxidation of the diene (48) to give the desired isomer as the major product?8
A third synthesis utilizes the reaction of but-2-enyltributyltin with the
aldehyde (49), and gives the pyran-2-one (50) stereoselectively; this, on ozon-
olysis, is converted into the lactonic acid (47) in 85% yield.49
Fomannosin (53), isolated from a wood-rotting fungus, has been syn-
thesized in eleven steps from the cyclopentene (51) and the triester (52).”
Synthesis has been achieved from the dione (54) of an enzyme inhibitor
called compactin ( 5 5 ) , which has potential as a regulator of cholesterol bio-
43 H. N . Abramson and H. C. Wormser, J. HeterocycL C h e m , 1981,18,363.

44 Ref. 29,p. 296.
45 K. Matsuo, T. Kinuta, and K. Tanaka, Chem Pharm. BulL, 1981,29,3047.
K. Matsuo and K. Tanaka, Chem. Pharm. Bull., 1981,18,3070.
4’ W.C.Still and K. R . Shaw, Tetrahedron Lett., 1981,22,3725.
D.J. Morgans, Tetrahedron Lett., 1981, 22, 3721.
49 K. Muruyama, Y. Ishihara, and Y. Yamamoto, Tetrahedron Lett., 1981, 22, 4235.
50 M. F. Semmelhack and S. Tomoda, J. Am. Chem. SOC.,1981, 103,2427.
-
Me Me.. /H
H
But Me2S i O C H 2/c\c'--
But M e 2S iOCH 2/c *CH
I H\
I O' H
MeCH
\CH2CMe=CH2 M/ rMe
,c'cH2CHCH20H
(45)
We.
1 H
7
H o Mo e / c0 y y
(47)
; e
But Me 2S iOCH
Txo
Me0
(46)
Me
ButMe2SiO(CH ) CMe
211
H2C=CHCH2CHCH
I
Me
(48)
CH=CH2
1
MeOOC CHO MeHC
Bu SnCH ,CH=CHMe
~
(47)
(49)
Me3Si0
"2'=r'O< <I 'J
+ COOEt - 4
COOMe COOEt h0ch2

/
(.5 2 ),
(53)
HO
~ynthesis.’~ An ingenious application of the diene-like properties of pyran-2-
ones has been applied to the synthesis of antitumour anthra~yclines.’~ The
bicyclic pyran-2-one (56), through its reaction with juglone (57), has given
the tetracycle (58), which is an analogue of anthra~ycline.’~
0 0
(57) (58)
Carbon-1 3 n.m.r. spectroscopy has been employed to distinguish between

a large number of tetronic acid derivatives and 5,6-dihydro-4-methoxypyran-
2-ones. Some earlier assignments need to be reconsidered in view of these
data.54 Assignment of 13C n.m.r. signals has been made for the pyrone (59),
which is a metabolite of Aspergillus melleus; the assignments were used in a
study of the biosynthetic pathway of the pyrone and related compound^.'^
Amongst the reactions of pyran-2-ones which have received attention are
the Friedel-Crafts acylation of 6-methoxy-4-methylpyran-2-one to give the
5-acetyl derivative (60) and its conversion into the phthalate ester (61) on
reaction with dimethyl butynedioate. The diester (61) was then converted
into anthraq~inones.’~ 5,6-Dihydropyran-2-ones, e.g. (63 ; R = H), have been
photochemically brominated at C-3 in high yields, but, when the nitrile
(63;R = CN) was similarly treated, the bromomethyl derivative (62) was
Me kd)
aoM : & o oCOOMe
‘OOMe
HO /
0 Me Me
Me
(60) (61)
(59)
N. Y. Wang, C. T. HSU,and C. J. Sih, J. A m . C h e m Soc., 1981,103,6538.

52 For a review, see I. R. Brown, Prog, Med. C h e m , 1978, 15, 165.
53 M. E. Jung, M. Node, R. W. F’fluger, M. A. Lyster, and I . A. Lowe, J. Ow. Chem.,
1982,47, 1152.
54 A. Pelter and M. T. Ayoub, J. C h e m SOC., Perkin Trans. 1,1981, 1 173.
J . S. E.Holker and T. J. Simpson, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1397.
56 M. E. Jung and R. W. Brown, Tetrahedron Lett., 1981,22,3 3 5 5 .
~ b t a i n e d . ' ~5,6-Dihydro-4-methoxypyran-2-ones
underwent hydrazinolysis
to give high yields of the 2-hydroxypyrazoles (64), but phenylhydrazine
failed to react.58 The products from the reaction of primary and secondary
Meu
amines with 5,6-dihydro-4-hydroxypyran-2-ones (65) are not 2-amino-
derivatives, as originally believed, but 4-aminopyran-2-ones, e.g. (66)."'
H
[ "!I
HOCHPhCH2
I
(64)
MeD /
OH
(65)
PhNH2, MeOH
[76%1
NHPh
(66)
Pyran-3- and -4-ones.- Little work has been reported on the synthesis of
3-hydroxy-4H-pyran-4-ones, whch should be good precursors of 5,6-
-Me
MeuMe
dihydropyran-3(4H)-ones. In an improved method, 3-methyleneheptane-2,6-
dione (67) has been converted, in three steps, into the 3-one (68), which on
"'m)<,
treatment with SeOz gave 2,6-dimethyl-3-hydroxypyran-4-one
(CH20H) 0
(69):'
NaBH4
[%%I
Me 0
HZC (67) H2C H2C
/
[56%] HC (OMe)
0
(69)
Pyrylium salts are readily convertible into benzenoid compounds, but a

similar conversion of pyran-4-ones is less well established. 3,5-Diacetylpyran-
4-one (70), on heating with piperidine or morpholine, yielded the phenol
(7 1). Analogous conversions were described.61 Stegobinone (72; 2S,3R ,7RS),
'' G. Falsone and B. Spur, LiebigsAnn. C h e m , 1982,191.

58 M. T. Ayub, M. Y. Shandala, G. M. G. Bashi, and A. Pelter, J. Chem SOC., Perkin
Trans. 1, 1981, 697.
59 B. Nedjar-Kolli, M. Hamdi, J . Perie, and V. Herault, J. HeterocycL C h e m , 1982, 19,
543.
6o K. Sato, S. Inoue, T. Tanami, and M. Ohasi, J. Chem. SOC., Perkin Trans. 1 , 1981,
1015.
61 F. Eiden, E. G . Teupe, and H. P. Leister, Arch. Pharm. (Weinheim, Ger.), 1981, 314,
347.
::Q:: +
OH
0
(71)
CHMeCE t
II
Me"
0
which is the pheromone of the drugstore beetle, has received considerable

attention recentlyf2' it and its (2R ,3SY7RS)-isomerhave been synthesized
from (2 R ,3S)- and (3R , ~ S ) - A C O ( C H M ~ ) ~ C Oand ~ H the diketone
(EtC0)2CHMe.62b
In strong acids (e.g. FS03H-SbF5), 2,6-dimethylpyran-4-one is doubly
protonated at the exocyclic oxygen atom, according to evidence obtained
from n.m.r. s p e c t r o ~ c o p yA
. ~variety
~ of products have been identified when
pyran-4-ones are irradiated; it has been shown that the furan (74) is a second-
ary rather than a primary product of the photolysis of 2,3,6-trimethylpyran-
4-one. Cyclopentenones [such as (73)] are formed first and are converted
into the ketone (74) via acyclic species." Oxidation of the pyranone (75;
R = Me or Ph) with chloroperoxybenzoic acid gave the epoxide (76), which,
on treatment with acid, giave the otherwise inaccessible 5-hydroxypyran-4-
ones ( ~ 1 . ~ ~
Me
.. Me
(73) (74)
RC
COOEt
- oQ
RCO
CmE - :H 0)
"
0 0 0 0
(75) (76) (77)
62 (a) Ref. 7 , p. 336; ref. 11, p. 289; ( b ) K. Mori, T. Ebata, and M. Sakakibara, Tetra-
hedron, 1981,37,709.
63 V. Gold and T. Mah, J. Chem. Soc., Perkin Trans. 2, 1981,812.
6 4 J. W.Pavlik, T. E. Snead, and J . R. Tata,J. Heterocycl. Chem., 1981,18,1481.
65
W.J. Ross, A. Todd, B. P. Clark, S. E. Morgan, and J. R . Baldwin, Tetrahedron Lett.,
1981,22,2207.
Chromans. - 2,4-Diethoxychromans (78) (mainly cis) represent a new type

of chroman and have been prepared in high yield from a phenol (but not a
deactivated phenol) and malonaldehyde bis(diethy1 acetal) in the presence
of SnCl,; they are converted into the benzopyrylium salts (79), in excellent
yield, by treatment with perchloric acid.66 A Wittig-Horner reaction of the
chiral phosphoryl (S)-sulphoxide (81) and the ketone (80) gave the chiral
sulphoxide (82), which was cyclized by aqueous alkali to a mixture which
contained 22% diastereoisomeric excess of (2S)-chroman (R)-sulphoxide.
This was converted, in three steps, into the aldehyde (83), which is a useful
synthon for a-to~opherol.~'
OEt
HC104
/ (78)
Me8..'.
AcO \
mM (CH2)3COMe
+
( MeO) 2P=0
Ar8-CH2
I
0-
I _qC
Me
Ho \
CH2SAr
Me Me
(81) (82)
(80) I
( A r = 4-MeC6H4) t
Me
(83)
Condensation of several dihydroxybenzoic acids with 2-methylbut-3-en-
2-01 gives 2,2-dimethylchromans. For example, 2,3-dihydroxybenzoic acid,
the alcohol, and boron trifluoride etherate, at room temperature, yielded a
mixture of three chromans (84)-(86).68 The product that is formed in high
66 F. Bigi, G. Casiraghi, G. Casnati, and G . Sartori, J. HeterocycL Chern., 1981, 18,

1325.
67 J. A.Akkerman, H. De Koning, and H. 0. Huisman, Heterocycles, 1981,15,797.
68 M. Marta, G. B. M. Bettolo, F. Delle Monache, and A. Lupi, Farmaco, Ed. S c i , 1981,
36, 794 (Chern. Abstr., 1981,95, 219 947).
R'
1 2
(84) R = R = H
1 2
( 8 5 ) R = CH2CH=CMe2, R = H
( 8 6 ) R1= H , R2= CH 2CH=CMe2
yield by heating 2-naphthol, acetaldehyde, and hydrochloric acid has been

identified as the benzochroman (87), but 2-naphthol, acetaldehyde diethyl
acetal, and mineral acid reacted at 20 "C to form the xanthene (88).69
3,5-Xylenol has been converted into the spiran (89), in good yield, by
hydroxymethylation and oxidation, the quinine methide (90) being an
Me
(89)
intermediate .70 Several naturally occurring spirochromans of the trichothecene

type have anti-cancer activity. A new approach to a precursor called
calonectrin (9 l ) , via the methylenepyran (93), is efficient, stereoselective,
and potentially applicable to the synthesis of related compound^.^' The
related verrucarol (92) has been synthesized from the bicyclic ketone (94) in
seventeen steps,72 and verrucarin J (95) and roridin H (96) are amongst com-
pounds isolated from Myrotheciurn vermcaria. 73 New syntheses of the
'' J . A. Van Allan, D. D. Giannini, and T. H. Whitesides, J. Om. Chem., 1982,47, 820.
70
P. Cacioli, M. F. Mackay, and J . H. Reiss, Tetrahedron Lett., 1980, 21,4973.
'' G. A. Kraus, B. Roth, K. Frazier, and M. Shimagaki, J. Am. Chem Soc., 1982, 104,
1114.
R. H. Schlessinger and R. A. Nugent, J. Am. Chem. SOC.,1982,104, 1116.
B. B. Jarvis, G. P. Stahly, G. Pavanasasivan, J. 0. Midioso, T. De Sfiva, E. P. Mazzola,
and R. F. Geoghegan, J. Org. Chem., 1982,47, 1117.
H H
Me
BuTMe2Si0
1 2 3
(91) R = R = OAc, R = H (93)
1 3
(92) R = R = OH, R2= H
(95) R = -CH=C(CH2)20C-
I II
Me 0
Me Me
OH
Me Me Me Me
2
(97) R1= H , R = M e (99)
(98) R1= M e , R2= H
dihydroedulans I and 11, (97) and (98), from the alcohol (99) have been
described.74
Hexahydrochromans and their cyclopentane homologues have been syn-
thesized by reductive cyclization of enamines, e.g. (1 00), followed by
h y d r o l y s i ~ .A~ ~revised structure (101) (confirmed by X-ray crystallography)
has been postulated for the product of oxidation of 2,2,5,7,8-pentamethyl-
chroman-641 with potassium superoxide and oxygen.76
The precocenes are important compounds in the chemistry of insects; in
an effort to predict the biological activity of these and related compounds, a
study has been made of the kinetics and the products of hydrolysis of 3,4-
dihydroprecocene I 3,4-epoxide (1 02) in aqueous solvent^.^' The stretching
74 H. Etoh, K. Ina, and M. Iguchi, Agric, Biol. Chem., 1980,44,2871 (Chem. Abstr.,
1981,95,24716).
75 S. Carlsson and S. 0. Lawesson, Tetrahedron, 1980,36, 3585.
76 S. Matsumoto, M. Matsuo, and Y. Iitaka, Tetrahedron Lett., 1981,22,3649.
77 A. F. Hamnett, A. Pottridge, G . E. Pratt, R. C. Jennings, and K. M. Scott, Pestic. S c i ,
1981,12,245.
Mew
0 Rmr:
Me
CH2
(104)
Me
Me
Ho \
Me
(105) R = H
(106) R = CHO
frequencies of several 4-alkyl- and 4-alkylthio-chroman-4-01~have been used

t o deduce the conformations of the molecules.78 From a study of the quinone
methide (103) and related spiro-compounds, it has been shown that regio-
selective dimerization of tocopherol is not explained by bond fixation and
Mills-Nixon effects. The methide (103) has been shown to be more readily
formed than its isomer (1 04). A Vilsmeier-Haack reaction on the chromanol
(105) failed to produce the aldehyde (106).79
When 3-iodo-2,2,7-trimethylchroman-5-ol (107) is passed through a
column of alumina-potassium hydroxide, the spiro-dienone (1 08) is formed.
This reaction may have a biosynthetic relevance to halo-chromans.80 7-
78
K. Hanaya, S. Onodera, Y. Ikegami, H. Kudo, and K. Shimaya,J. Chem. SOC.,Perkin
Trans. 2 , 1981,944.
'' F. M . Dean, D. A. Matkin, and M. 0. A. Orabi, J. Chem. SOC.,Perkin Trans. 1 , 1981,
1437.
RI. F. C. Brown, B. R . Matthews, and I. D. Rae, Tetrahedron Lett., 1981,22,2915.
Hydroxychromans, such as (1 09), undergo Pechinann cyclization to give the

angular, i.e. (1 lo), rather than the linear benzodipyrans.81
Isochromans. - The antibiotic (*)-nanaomycin A (1 11) has been synthesized
by two routes from 2-bromo-8-methoxy-1,4-naphthoquinone.82 Readily
accesssible indanones have been converted into isochromans, which have been
elaborated into 9-demethoxyeleutherin (1 12) and 9-deoxynanaomycin A
methyl ester (1 13).83 Some pharmacological interest has appeared in 1-(piper-
'CH2COOMe
azinoalky1)isochromans (1 1S), which were synthesized from a phenethyl

alcohol [e.g. (1 14)], ethyl acetoacetate, and boron trifluoride, followed by
reaction with the piperazine.w
A. S. Majumdar and R. N. Usgaonkar, Cuw. Sci., 1982, 5 1 , 94 (Chem. Abstr., 1982,

96, 199 554).
82 T. Kometani, Y. Takeuchi, and E. Yoshii, J. Chem. SOC., Perkin Trans. I , 1981,
1197.
83 T. Kometani and E. Yoshii, J. Chem. SOC.,Perkin Trans I , 1981, 1191.
84 J . B. McCall, R. B. McCall, R. E. Ten Brink, B. V . Kamdar, S. J. Humphrey, V . H.
Sethy, D. W. Harris, and C. Daenzer, J. Med. Chem., 1982,25, 7 5 .
I ii-iv
The lability of the substituent in lethoxyisochroman (1 16) towards

n ~ c l e o p h i l e scontinues
~~ to be studied; with benzylamine, (+)-l-benzylamino-
isochroman (1 17) was formed, but, when this was heated at a higher tempera-
ture, it rearranged into 4-benzylisoquinoline (1 18) via the ring-opened inter-
mediates.% Replacing the amine by an arylamine gave the l-aminoisochroman
(1 19; R = NHAr) or l-(4-aminoaryl)isochroman (1 19; R = 4-NH2C6H4),or a
mixture of both. Reactions with amides and sulphonamides have also been
studied.87
85Ref. 29, p. 298.

86M . Yamato, T. Ishikawa, and T. Kobayashi, Chem P h a m Bull., 1981,29, 7 2 0 .
" M. Yamato, T. Ishikawa, and S. Yamada, Chem. Pharm. Bull., 1982, 30,843.
Chromenes. - Continuing interest in the precocenes is shown by the synthesis,
in good yield, of both I (120; R = H) and I1 (120; R = MeO), respectively,
from the corresponding chromanone by reduction and dehydration,88 and of
precocene I1 (1 20; R = MeO) from methoxyquinol and 2-methylbut-3-en-2-01
(1 21) in two steps.89 The 2,2-ditritiomethyl homologues of both compounds
(1 20) have been synthesized from the appropriate o-hydroxyacetophenone
and 1,3-ditritioa~etone.~'The anti-juvenile hormone activity of several
analogues of precocene has been related to their I3C n.m.r. spectra."
(120) a ; R = H
b ; R = Me0
-0
MeoooH
Ho \ + I
H2C=CHCMez
OH
( 1 2 11
z:zCH=CMe2
Meom Ho \
(120b)
/
When salicylaldehyde is heated with a 2-nitrovinylamine (1 22), 2-amino-

3-nitro-2H-chromenes (1 23) are formed.92 A number of cannabichromene-type
compounds have been synthesized, in moderate yields, by condensing citral
with the 2-lithio-derivative of a 3-methoxyanisole (1 24; R = H or alkyl).'j
(124)
S. A. Banerji and N. C. Goomer, Indian J. Chem., Sect. B , 1981, 2 0 , 144.
M. Uchiyama and I. C. Overeem, R e d . , J. R . Nerh. Chem. SOC.,1981,100, 408.
A. Banerji and N. C. Goomer, J. Labelled Compd. Radiopharm., 1981, 18, 1737
(Chem. Abstr., 1982,96, 199 470).
91 A. P. Ottridge, R. C . Jennings, and G. T. Brooks, Dev. Endocrinol. (Amsterdam),
1 9 8 1 , l S (Juv. Hormone Biochem.), p. 381 (Chem. Abstr., 1982,96, 181 0 5 0 ) .
92 L. Rene and R. Royer, Eur. J. Med. Chem., 1982, 17, 89 (Chem. Abstr., 1982,
96, 162 492).
93 M. de la Torre, F. Garcia, and R. Cruz, J. Heterocycl. Chem., 1981, 18, 125 1.
Ho
H \ O: : : W
/ / /
0 (126) R = H
(125) (127) R = M e
(129)
The structure of haemofluorone B, isolated from a plant, was postulated
(from spectral data) to be either (125) or (126).w995A synthesis of the tri-
methyl ether (127), via the phenalenone (128), has now been achieved, and
this was identical with the trimethyl ether of haemofluorone B.96
Contrary to an earlier report, DDQ dehydrogenates chromans which lack
hydroxyl groups, and the yields are sufficiently encouraging for this to be
considered as a method of synthesis of various chr~menes.~’ The 4-halogen
atom of 3,4-dichlorochromans is the more reactive, and may be preferentially
hydrolysed to the alcohol, which, on oxidation, gives the 3-halogeno-
chromanone. When the latter is boiled with zinc and acetic acid, it is con-
verted into the bischromene (129).98 The 6-lithiochromene (130) is a useful
intermediate in the synthesis of the alkaloid acronycine (131) and related
0
OMe
0
(130)
(131)
94 R. G . Cooke and 1. J . Dagley,Aust. J. Chem., 1979, 32, 1841.

95 A. L. Chaffee, R . G. Cooke, I. J . Dagley, P. Perlmutter, and R. L. Thomas, Aust.
J. Chem., 1981, 34, 587.
% G. I. Feutrill and M. L. Whitelaw, Aust. J. Chem., 1981,34, 1523.
97 V. K.Ahluwalia and R. S. Jolly, Synthesis, 1982,74.
98 J . D. Hepworth, T. K. Jones, and R. Livingstone, Tetrahedron, 1981, 37,2613.
compounds .99 Another base-catalysed annelation of chromenes yields a 2-
pyridone (1 32), together with the coumarin (1 33) as a by-product.'00
(132) R = NH
(133) R = 0
Benzopyrylium Salts. - Dichloromethoxybutane has been used in the cycliz-

ation of the benzyl phenyl ketone (134) to give (after addition of perchloric
acid) the pyrylium salt (135). The latter reacted normally with methylamine
to form the isoquinolinium salt (1 36)."' A complex series of transformations
has been suggested to account for the formation of the pyrylium salt (1 38)
by the reaction of the chromone (137) with malononitrile-acetic
anhydride.lm
Me0
: r ~ ~
~ ~ 2
Me0 \ : !h
-
(134)
(135) c lo4
TIoMe
(136)
Ar =
HOOCCHB \ OMe
+
Reagents: i, C H 2 ( C N 1 2 , Ac 0; ii, H C 1 , H C l O
2 4
The azide ion added on to 2-benzopyrylium salts to give the azidopyran,

e.g. (139); on thermolysis, these gave a mixture of products in various propor-
tions, depending on the substituents in the salt.'03
99 J . H. Adams, P. M. Brown, P. Gupta, M. S, Khan, and J . R . Lewis, Tetrahedron,

1981, 37,209.
loo C. N. O'Callaghan, J. Chem. SOC.,Perkin Trans. I , 1981,2273.
l o r I. V . Shcherbakova, G. N. Dorofeenko, and E. V. Kuznetsov, Khim. Geterotsikl.
Soedin., 1981, 313 (Chem. Abstr., 1981, 95, 80 653).
lo2 M. Mazzei, A. Ermili, E. Sottofattori, and G. Roma, J. Heterocycl. Chem., 1981, 18,
863.
J.-P. Le ROUX,P.-L. Desbene, and J. C. Cherton, J. Heterocycl. Chem., 1981, 18,847.
Ph
- -
Ph
13OoC r 25%1
+
c lo4
- (139)
0s
\
[ 8%1
/
Chromanones. - One of the recently discovered minor constituents of hashish

is a 5-hydroxychromanone called cannabichromanone (140), which was first
identified by g.1.c.-m.s. The suggested structure has been confirmed by a syn-
thesis of the compound from 2,2-dimethyl-5-hydroxy-7-pentylchromanone
and methyl vinyl ether, a process which also produced varying amounts of the
spiran (141), depending on the conditions. The chromanone (140) has no
effect on the nervous system@
.' '
The acyl azide (142; R = CON3) has been photolysed in the presence of
several aromatic compounds, e.g. benzene, anisole, or aniline. The nitrenes
that were produced were in the triplet state, and yielded 3-substituted
dihydronaphtho[2,1-b]pyrans (142; R = CONHPh, CONHC6H40Me, or
CONHNHPh respectively). Coumarins behaved similarly.105 Spectral examin-
ation has shown that the equilibrium between the butanedione and the cyclic
hemiacetal structure (143; R = H, Me, or MeO) lies entirely on the latter's
104
L. Chiodini, M. Di Ciommo, and L. Merlini, Heterocycles, 1981,16, 1899.
M. A. Elkasaby and N. A. Noureldin,Indian J. Chern., Sect. B , 1980,19, 1080.
side. '06 The stereochemist ry of a number of 3-met hyl-2-hy dr oxy chr omanones
'
has been studied, using H n.m.r. spectroscopy, at different temperatures and
in various media.'"
Chromanones are known t o condense at C-3 with aldehydes under the
influence of a variety of condensing agents.'08 In the presence of orthophos-
phoric acid, the 3-benzylidene derivative was obtained, but condensation in
piperidine gave the benzylchromone .log The chromanone (144) has been
cyclized under Dieckmann conditions t o give (after further treatment) the 6-
oxatetracycline derivative (145; R' = CSPh, R2 = H). A further three steps
were necessary t o produce the 6-oxa analogue of tetracycline (145; R' = Me,
R2 = OH)."'
Chromones. - A novel intramolecular Wittig reaction between a carbonate
ester (146) and a phosphorus ylide has yielded a 2-phenoxychromone (147)
NHCSPh NM~R'
OH
CONH
OH
0 g o 0
in moderate yield'" and the reaction has been applied to the synthesis of
several chromones related to demethoxycapillarisin (1 48).'12 Thermal cycliz-
ation of the keto-ylides (149) produced the chromone (150), which on
hydrolysis was converted into 3 -acetyl-4-h ydr oxycoumarin.' l3 An improved
synthesis of 2-acetylchromone from chromone-2-carbonyl chloride has been
described. l4'
Synthetic methods leading to chromone-3-carboxylic acids are not very
numerous, and so a recent base-catalysed cyclization of 2-fluorobenzoyl
'06 E. Morera and G . Ortar, Tetrahedron Lett., 1 9 8 1 , 22, 1273.

lo' J . Borbely, V. Szabo, and P. Sohar, Tetrahedron, 1 9 8 1 , 3 7 , 2 3 0 7 .
I. M. Lockhart, in 'Chromenes, Chromanones and Chromones', ed. G . P. Ellis, Wiley,
New York, 1 9 7 7 , p. 2 7 6 .
109
A. Levai, 2. Dinya, I . B. Schag, G . Toth, and A. Szollosy, Phamazie, 1 9 8 1 , 36, 4 6 5
(Chem. Abstr., 198 1 , 9 5 , 1 6 8 9 2 2 ) .
'lo R. Kirchlechner, Tetrahedron Lett., 1 9 8 1 , 22, 1497.
'" H.Takano and M . Hashimoto, J. Chem. SOC.,Chem. Commurz., 1 9 8 1 , 2 8 2 .
'12 H.Takano, M. Hashimoto, Y. Koma, H. Horiai, and H. Kikuchi, J. Chem. SOC.,
Chenz. Commun., 1 9 8 1 , 4 7 4 .
'I3 P. Babin, J . Donogues, and M. Petraud, Tetrahedron, 1 9 8 1 , 37, 1131.
'14 P. S. Bevan, G. P. Ellis, and H. K. Wilson, J. Chem. SOC.,Perkin Trans. I , 1 9 8 1 , 2 5 5 2 .
(148) (149) (150)
chloride with a 3-0x0-ester t o this type of acid is welc~me."~Many

chromones have been synthesized in the hope that they would possess bio-
logical activity. An Italian team has described a group of 2-cyclopropyl-
chromone-6-carboxylic acids (151; R', R2 = alkyl or alkoxy) which are many
times more potent than cromoglycic acid in animal tests.'16
Chromones are usually reduced by sodium borohydride to the chroman-
4-01s, but when sodium bis(methoxyethoxy)aluminium dihydride was used,
the main product from 2,3-dimethylchromone was the 2H-chromene.'"
Irradiation of 2-styrylchromones in air led t o cyclization and the formation
of the benzo[a]xanthones (1 52).l18 The versatility of 3-nitrochromone as a
synthon continues t o be demonstrated, for instance, as a source of non-

chromone heterocycles through its reactions with nucleophiles in a Michael
reaction.'lg Reduction t o the amine and condensation with various unsatu-
rated compounds, for example dimethyl acetylenedicarboxylate and diethyl
ethoxymethylenemalonate, have led to new tricyclic compounds.12' Reduc-
tion of 3-nitro-2-styrylchromone with triethyl phosphite resulted in cycliz-
ation to the pyranopyrrole (1 53).121 A variety of substituents, when attached
at C-2, may be displaced by a nucleophile. The sulphinyl and sulphonyl
groups have been used in this way in the reparation of a number of 2-amino-,
2-alkoxy-, and 2-pheno~y-chromones.~~' An attempt t o convert di(cyano-
methyl) chromone-2 $-dicarboxylate into the ditetrazolylmethyl ester regio-
selectively gave a single monotetrazole monocarboxamide, which was shown
to be the 2-carboxamide (154).l14
'15 G. M. Coppola and R. W. Dodsworth,Synthesis, 1981, 523.
'16 G. Doria, C. Romeo, A. Forgione, P. Sberze, M. Tibolla, M. L. Corno, and G . Cadelli,
Eur. J. Med. Chem., 1981, 16, 367.
11' H. Yamaoka, T. Hakucho, and K. Akiba, Heterocycles, 1981,15, 1159.
I. Yokoe, K. Higuchi, Y. Shirataki, and M. Komatsu, Chem. Pharm. Bull., 1981, 29,
2670.
'19 G. Haas, J. L. Stanton, and T. Winkler,J. Heterocycl. Chem., 1981,18, 619.
120 D. T. Connor, P. A. Young, and M. von Strandtmann, J. Heterocycl. C h e m , 1981,
18, 697.
lZ1 C . Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981,234.
122 J. R. Bantick and J. L. Suschitzky, J. Heterocycl. Chem., 1981, 18,679.
m-ph
Six-Membered Rings: Systems containing oxygen or sulphur
0
i -”- o - i ~ c o N H 2
N\
n
369
The side-chain of the antibiotic hedamycin contains two epoxy-groups,

whose oxygen atoms have been shown by X-ray analysis t o lie above one
another; a similar stereochemistry was detected in the diepoxide from the
simpler chromone (155).123 The 13C n.m.r. spectra of a wide selection of
chromones (and some flavones) have been interpreted and used to dis-
tinguish between positional isomers.124
The acid chlorides of several chromone-2-carboxylic acids have been used
in the Freidel-Crafts reaction to prepare 2-aroyl-chromones which were
pharmacologically active.’26 Decarboxylation of a heterocyclic acid is often
a facile reaction but removal of an aldehyde group is unusual. Chromone-3-
carboxaldehyde (1 56) has been decarbonylated by heating with piperidine t o
give the acrylophenone (157), which cyclized again, with loss of piperidine
and one carbon atom.I2’
o;> I
0
I CHO
piperidine,
[77%]
co
(157)
The ready availability of the 3-aldehyde (1 56) has resulted in its chemistry
being widely studied.128Under azlactone-forming conditions, it was converted
into the oxazolones (1 58), which on acid hydrolysis gave the conjugated acid
(1 59) - a convenient intermediate.12’ Condensation with indane-1,3-dione,
thiohydantoin, hydroxylamine, and various hydrazines gave the expected
A. Fredenhagen, W. Ritter, U. Sequin, and M . Zehnder, Chimia, 1981, 36, 334

(Chem. Abstr., 1982,96,51 502).
lZ4 U. Sequin, Helv. Chim. Acta, 1981,64, 2654.
125 G . P. Ellis and J . M. Williams, J. Chern. SOC.,Perkin Trans. I , 1981,2557.
’% M. Payard, P. Tronche, J . Bastide, P. Bastide, and G . Chavernac, Eur. J. Med. Chern.,
1981, 16,453.
G. K. Ghosh and S. Khan, Synthesis, 1981,719.
12’ Ref. 1 1 , p . 301;ref.29,p. 301.
lZ9 W. D. Jones, J. Chem. SOC.,Perkin Trans. 1 , 1981, 344.
37 0 Heterocyclic Chemktry
W ANu
0QJ 0
CH -
R
0
(159)
CH=CCOOH
I
OH
(158)
derivative^.'^' Reaction with o-phenylenediamine has given a product that

was formulated as a tetra-aza[ 14lannulene (1 60), which forms complexes
with Ni, Cu, and Zn.13' With active methylene groups and enamines, the
pyran ring of (1 56) may or may not survive.132
Chromones that carry an electron-withdrawing group (e.g. CHO or CN) at
C-3 react with diazoalkanes t o give the 2-alkyl homologues in good yields.
Diazomethane reacts with chromone-2-carboxaldehyde t o form a mixture
of the ketone (161) and the oxiran (162).'33
Flavans. - New tannins have been synthesized by stereoselective condensation
of flavan-3,4-diols with resorcinols, and their stereochemistry has been corre-
lated, using circular d i ~ h r o i s m , but
' ~ ~ the general rule thus demonstrated had
exceptions among some 2,3cis-3,4cis-diastereoisomers, e.g. (1 63), which
130 V. K. Polyakov, R. G. Shevtsova, and S. V. Tsukerman, Ukr. Khim. Zh. (Russ. Edn.),
1981,47,85 (Chem. Abstr., 1981,95,97512).
I. Sigg, G. Haas, and T. Winkler, Helv. Chim. Actu, 1982, 65,275.
G. Haas, J . L. Stanton, A. von Sprecher, and P. Wenk, J. Heterocycl. Chem., 1981,
18, 607.
133 F. M. Dean and R. S. Johnson, J. Chem. SOC.,Perkin Trans. I , 1981,224.
134 J. I . Botha, D. A. Young, D. Ferreira, and D. G . ROUX,J. Chem. Soc., Perkin
Trans. I , 1981,1213.
were produced photochemically .I3’ The chemical shifts of various hydrogen

atoms of catechins have been determined by bromination and debromination.
During this work, an acid-catalysed migration of bromine from C-6 to C-8 of
(+)-catechin tetramethyl ether (1 64) was d e m 0 n ~ t r a t e d . l ~ ~
(164)
Several [4,6]- and [4,8]-biflavanoids have been synthesized from flavan-

3,4-diols and flavan-3-01s in aqueous acid at ambient temperature - conditions
which simulate one step in the biosynthesis of some natural tannin^.'^' Flavan
and several dihalogenoflavans have been found t o be potent anti-rhinovirus
agents; 4’,6-dichloroflavan was the most interesting compound.’%
Flavanones.- A simple method of synthesizing 5,3’-dihydroxy-4’-methoxy-
flavanone (1 65) has been described.I3’ 3-Nitroflavanones have been synthe-
sized by heating 2’-hydroxy-2-nitroacetophenone,benzaldehyde, and
(165)
ammonium acetate. Bromination of the product followed by heating in

pyridine gave the nitroflavone (1 66).I4O Cyclization of (E)- and (Z)-chalcones
(167) 0
135 J. H. van der Westhuizen, D. Ferreira, and D. G . ROUX, J. Chem. SOC., Perkin
Trans. 1,1981,1220.
13‘ H. K. L. Hundt and D. G . ROUX,J. Chem. SOC.,Perkin Trans. 1, 1981, 1227.
13’ J . J . Botha, D. Ferreira, and D. G . ROUX,J. Chem. SOC., Perkin Trans. 1 , 1981, 1235.
D. J . Bauer, J. W. T. Selway, J . F. Batchelor, M . Tisdale, I. C. Caldwell, and D. A.
Young,Nuture (London), 1981,292, 369.
V. H. Deshpande and A. D. Patel, Indian J. Chem., Sect. B , 1981, 2 0 , 917.
140 C. Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981,236.
to 3-bromoflavanones (167) has been shown by spectrometry to be about 20
times faster from the (Z)-i~omer.'~~
Flavones. - A new approach to 3-substituted flavones from flavon-3-01s(1 68;
Ar = 4-MeC6H4) has been developed by successive oxidation, Wittig reaction,
reduction, or conjugate addition to give, for instance, the cyano-ester
(1 69).'42 4',7-Dimethoxy-3',5,6-trihydroxyflavonehas been synthesized and
a new natural flavone, called nuchensein, has thus been shown not to have
this structure.143
3.
CHCN
0
When toluene-p-sulphonic acid is used as the condensin agent, o-hydroxy-

dibenzoylmethanes give high yields of methoxyflavones." Carbon-13 n.m.r.
spectra of several 3-hydroxyflavones have been determined and compared
with those of a u r o n o l ~ ;from
~ ~ a study of the 13C n.m.r. spectra of naturally
occuring flavones and flavanones, changes in the spectral assignments of
diosmetin and luteolin have been suggested.'& Lanthanide shift reagents are
useful in the determination of structure of many compounds and have been
applied successfully to polymethoxylated fla~0nes.l~'
New products have been isolated from the photolysis of 3-flavonols in
methanol; for example, 3-arylphthalides (172) were minor products and were
derived from the diketones (1 70). Some flavanols also gave small amounts of
the keto-ester (171), but photolysis was inhibited in the presence of some
metal ions,'48 e.g. Cu2', Ni2+, Fe3+, Co2+,and Be2+.
14' S. K. David, L. Main, and K. Bold, J. Chem. Soc., Perkin Trans. 2 , 1981,1367.
14* M. A. Smith, L. E. Klebanoff, C. T. Morrow, and B. B. Sandel, J. Org. Chem., 1982,
47, 1702.
143 V. K. Sharma, S. K. Garg, and S. R. Gupta, Indian J. Chern., Sect. B , 1981,20,991.
144 P. K.Jain, J . K. Makrandi, and S. K. Grover, Curr. Sci., 1981,50,857.
14' A. Pelter, R. S. Ward, R. Haensel, and F. Khaliefi, J. Chern. Soc., Perkin Trans. I ,
1981,3182.
146 B. Mendez, A. C. Rojas, A. Bahsas, R. Jaimes, and J . Triana, Acta Cient. Venez.,
1980,31,394 (Chem. Abstr., 1981,95,149 388).
1
4
' P. Joseph-Nathan and D. Abramo-Bruno, Phytochemistry, 1981,20,313.
I. Yokoe, K. Higuchi, Y. Shiratoki, and M. Komatsu, Chem. Pharm BuZL, 1981,29,
894.
Isoflavones. - An interesting condensation of a benzyl cyanide with a salicylic
ester (1 73) in boiling pyridine containing t-butoxide has given 2-aminoiso-
flavones (174).14' Robustigenin (1 76), which occurs in Dewis rubusta, has
been synthesized from the deoxybenzoin (175).150 An earlier report that iso-
flavone may be synthesized via an enamine has been disputed and the pro-
cedure shown t o yield 2 -morpholino-2H-isoflavene.' s'
Combined g.1.c. and m.s. has been shown t o provide a reliable method of
distinguishing between seven naturally occurring isoflavones, as their tri-
methylsilyl ethers. Retention indices and the relative abundances of several
ions enable the monitoring of selected ions to identify the isoflavones in sub-
microgram q ~ a n t i t i e s . ' Isoflavones
~~ have been reduced to the isoflavanones
in THF-toluene at - 65 "C with Bul2A1H (DIBAL).lS3
Dihydrocoumarins and Dihydroisocoumarins. - The potential of thallium
compounds in organic synthesis continues to be developed in a variety of
reactions. One of these was the synthesis of dihydrocoumarins by oxidative
cyclization of 3-arylpropionic acids, e.g. (1 77), by thallium(1D) trifluoro-
acetate-trifluoracetic acid (TTFA). The coumarin was accompanied by
methyl 3-(2-hydroxyphenyl)propionate (178), which was formed by ring-
(177)
14' Yu. M. Volovenko, V. A. Litenko, and A. D. Kapustyan, Dopov. Akad. Nauk Ukr.
RSR, Ser. B ; GeoL, Khim., BioL Nauki, 1981,No. 7 , p. 40 ( C h e m Abstr., 1981,95,
168 924).
150 M. Nakayama, S. Ohira, and T. Matsai, Bull. Chem. SOC.Jpn., 1981, 5 3 , 831.
F. M. Dean and R. S. Varma, Tetrahedron Lett., 1981,22,2113.
lS2 M. D. Woodward, Phytochemistry, 1981,20,532.
S . Antus, A. Gottsegen, and M. Nogradi, Synthesis, 198 1 , 574.
opening of the coumarin. Reaction conditions and the substitution pattern on
the phenyl ring of (177) gave rise t o variations in the relative proportions of
products.154 Several dihydroisocoumarins, e.g. (1 79), have been synthesized
from benzenoid compounds via indan-1-one by a route which enables
deuterium t o be incorporated at specific positions. This is relevant t o the bio-
synthesis of the antibiotic citrinin (1 8O).ls5
*eM HrQ
Me \
Me Me
Me Me
Me Me
Conversion of pyrans into pyridines is well established, but an example of

the converse reaction was recently described in which the benzylisoquinoline
(181; R = 6,7-dimethoxy) was treated with cyanogen bromide to give the iso-
chroman (1 82)? Oxidation of alpinigenine (183), which is present in several
species of poppies, gave the isochromanone (1 84).15'
HOOC f
A il
154 E. C. Taylor, J . G. Andrade, G. J. H. Rall, I. J. Turchi, K. Steliou, G . E. Jagdmann,

and A. McKillop, J. Am. Chem. SOC.,1981, 103, 6856.
l S 5 J. Barber and J. Staunton, J. Chem. SOC.,Perkin Trans. 1, 1981,1685.
lS6 S. Prior and W. Wiegrebe,Arch. Pharm. (Weinheim, Ger.), 1981, 3 1 4 , 5 7 7 .
"' D. Lavie, H. Berger-Joseph, T. Yehezkel, H. E. Gottlieb, and E. C. Levy, J. Chem.
SOC.,Perkin Trans. 1 , 1981, 1019.
The spirodihydroisocoumarins (1 85) and (186) show promise in prevent-
ing the release of histamine from mast cells, and a number of variations on
these structures have been made in order to study the relationship between
structure and activity.'''
Q (185)
NCHZPh
73 (186)
N
CH2Ph
Coumarins. - There is interest in the synthesis of 3-substituted cownarins:

cyclization of substituted salicylaldehydes with cyanoacetamide, followed by
treatment with phosphoryl chloride in DMF, has given coumarin-3-
carbon it rile^.^^^ High yields of 3-phenylcoumarins were obtained when ortho-
hydroxy-aldehydes or -ketones were treated with phenylacetyl chloride-
potassium carbonate.16' When cyclohexane-1,3-diones (1 87) were condensed
with triethyl orthoformate and either urea and thiourea and the initial
product (188) was allowed to condense with nitriles, the 3-carboxamide
(189) was obtained in good yield.16' The antibacterial activity of some
sulphones has prompted the synthesis of 3-arylsulphonyl-coumarins by
oxidation of sulphides.162
( 187) (188) ( 189)
Phenols are convenient substrates for the synthesis of coumarins, but the
uncertainty and limited applicability of the Pechmann reaction is a disadvant-
age. The effect of substituents on the mode of cyclization has been investi-
gated and 13C n.m.r. spectroscopy has been used t o correlate ortho-proximity
effects with those in benzenoid corn pound^.'^^ Some phenols do not react
under Pechmann conditions but do so when the keto-ester is replaced by tri-
ethyl orthoacrylate (190).'@
158
M. Yamoto, K. Hashigaki, A. Tsutsumi, and K. Tasaka, Chern. Pharrn. BUZZ., 1981,
29, 3494.
159 P. Czerney and H. Hartmann, J. Prakt. Chern., 1981,323,691.
P. P. Rao and G. Srimannarayana, Synthesis, 1981,887.
lbl I. Trummer, E. Ziegler, and 0. S. Wolfbeis, Synthesis, 1981,225.
lb2 J . R. Merchant and P. J. Shah, J. Heterocycl. Chem., 1981,18,441.
A. G . Osborne, Tetrahedron, 1981,37,2021.
164 J . A. Panetta and H. Rapoport, J. Org. Chem., 1 9 8 2 , 4 7 , 9 4 6 .
37 6
ooH + H2C=CHC(OEt)3
(190)
- 3 steps
( 191) OH
4-Hydroxycoumarin is an important intermediate for many reactions, and

a recent one-step synthesis is of interest. 2-Acetoxybenzoyl chloride (19 1)
was condensed with diethyl malonate in the presence of magnesium hydroxide
to give the ~oumarin.'~'
Photolysis of coumarin-3-carbonylazides gives nitrenes in the triplet state,
and these have been trapped by hydrocarbons and by aniline.'66 Prenyl ethers
of 3-hydroxycoumarins undergo an abnormal Claisen rearrangement and give
the 4-allylic compound (193), but, in the presence of an 8-methoxy-group,
the side-chain is further rearranged as in (192).'67
wo\ / OH
I CH2CH=CMe2
MeCHC=CH
I (193)
(192) Me
Coumarins are known to react with amines t o give variow.products, for

example 2,3-dihydrobenzofurans. 3-Bromocoumarin has been shown to give
the benzofuran (194) on heating with piperidine but coumarin itself gave
2'-hydroxycinnamic acid amides.la The behaviour of coumarin-3-carboxylic
acid with amines depends on the ratio of reactants and the t e m p e r a t ~ r e . ' ~ ~
When 8-acetyl-7-hydroxy-4-methylcoumarin was subjected to a Mannich
reaction, the benzodipyran (195) was formed in 80% ~ie1d.l~'Several other
tricyclic products have been prepared from coumarins; for example, the
16' A. K. Das Gupta, R. M. Chatterjee, and K. R. Dass, Indian J. Chem., Sect. B , 1981,
20, 511.
"'M. A. Elkasaby and N. A. Noureldin, Indian J. Chem., Sect. B , 1980,19, 1080.
R. R. Shah and K. N. Trivedi, Indian J. Chem., Sect. B , 1981, 20,210.
I. E. El-Kholy, M. M. Mishriky, and H. M. Feid-Allah, J. HeterocycL C h e m , 1981,
18, 105.
169 A. A. Avetisyan, E. V. Vanyan, Zh. G. Boyadzhyan, and M. T. Dangyan, A r m Khim.
Zh., 1981, 34,876 (Chem. Abstr., 1982, 96, 35 022).
'O S. D. Samant and R. A. Kulkarni, Indian J. C h e m , Sect. B , 1981, 20,246.
oopo)/pe
\
go
..J I I
\
/ (196) 0
(194)
(195)
benzopyrano[2,3]pyrazines (1 96) (wrongly called ‘benzopyranopyrimidines’

in the paper) were obtained by cyclizing 4-chloro-3-nitrocoumarin with an
a-amino-acid.’ 71
A third ring was fused to 3-hydroxycoumarin by its reaction with benzyl-
ideneacetone t o give the ketone (197), which cyclized to the pyranobenzo-
pyran (1 98) under acetylation conditions.172 Treatment of 3-amino-7-
fJ&
hydroxycoumarin with bromoacetone and cyclization of the product has
given psoralen derivatives such as (199).ln In a new example of the addition
q H o A C 2 O *
P hCHCH 2A c OAc Me
Ph
(197) Me (199)
(198)
of alkenes to the 3,4-double bond, cyclobuta[c]coumarins (200; R = H or Me)
and (201) have been obtained.174 A pentacyclic heterocycle (202) was formed
when 4-hydroxycournarin was warmed with 4’-hydroxyflavylium chloride
in dilute acid.’75
”’ Z. Stunk, M. Trkovnik, M. Laban, and R. Jankovic, J. HeterocycL Chern., 1981,18,

511.
V. K. Ahluwalia, K. Mukherjee, and N. Rani, Heterocycles, 1981,16, 1353.
173 C. Antonello, S. M. Magno, 0. Gia, 0. Baessato, and M. Palumbo, Farmaco, Ed. Sci.,
1981,36, 565.
174 T. Naito, N. Nakayama, and C. Kaneko, C h e m Lett., 1981,423.
17’ L. Jurd, J. HeterocycL Chern., 1981,18,429.
Reduction of coumarins to the dihydro-derivatives has frequently been
achieved, but a more efficient procedure has emerged from a new study of
this conversion. The most effective method was catalytic reduction in ethanol
at 150 "C and under a high pressure (1 500 psi) of hydrogen of give mostly the
2-hydroxy-3-phenylbutanoate, which was readily cyclized with PPA to the
dihydro~oumarin.'~~ Hydroboration of 3-arylcoumarins, followed by oxi-
dation, gave isoflavanones; the latter have been dehydrogenated (with DDQ)
to isoflavones.'" A reaction of wide potential value is the selective hydrolysis
by zinc and methanol of phenolic acetates in the presence of aliphatic acetate
groups. ' 7 8
Isocoumarins. - Indanones such as (203), as their enol esters, have been ozon-
olysed to give the dihydroisocoumarin-3-01, which yielded the isocoumarin
(204) when heated with toluenep-sulphonic acid.1793-Arylisocoumarins have
been synthesized, in good yield, by heating homophthalic acids with aroyl
chlorides.18' Phthalaldehydic esters (205) react with N-acylglycines to give
isocoumarin-3-carboxylic acids, e.g. (206).18'
Xanthenes and Xanthones. - A new approach t o the synthesis of tetracyclic

xanthones that are related t o bikaverin has employed a photo-Fries rearrange-
ment of the ester (207) to (208). Demethylation and oxidation of the latter
gave the spiran (209), which was thermolysed t o the xanthone (210).'82 The
methylenebisquinol (21 1) has been cyclodehydrated to a xanthene by phos-
phoryl ~ h l 0 r i d e . l ~ ~
114
F. D. Mills,J. Heterocycl. Chem., 1980,17, 1597.
1I1
B. S. Kirkiacharian, J. D. Brion, M. Gomis, and P. Reynaud, Heterocycles, 1980, 14,
1929.
118
A. G. Gonzalez, Z . D. Jorge, H. L. Dorta, and F. R. Luis, Tetruhedron Lett., 1981,
22,335.
179
R. H. Carter, M. J. Garson, R. A. Hill,J. Staunton, and D. C. Sunter, J. Chem. SOC.,
Perkin Trans. I , 1981,471.
180
K. Nozawa, M. Yamada, Y. Tsuda, and K. Kawai, Chem. Pharm. Bull., 1981, 29,
249 1.
181
J . N. Chatterjea, K. R. R. P. Singh, and C. Bhakta, Natl. Acad. Sci Lett. (India),
1 9 8 1 , 4 , 8 3 (Chem. Abstr., 1982,96, 122 582).
182
J. R. Lewis and J . G . Paul, J. Chem. Soc., Perkin Trans. I , 1981,770.
183
H. Obara, J. Onodera, T. Shibata, and K. Shibayama, Bull. Chem. SOC.J p n , 1981,
54, 1261.
OMe
The Willgerodt reaction has been applied to 2-propionylxanthone t o give

xanthon-2-ylpropionic acid.'@ A new type of functional group, the
a-chlorothiosulphenyl function, has been produced at the 9-position by the
reaction of sulphur dichloride with xanthione (21 2). The new compound
(214), which has five adjacent electrophilic sites, may be in equilibrium with
the ionic form (2 13), which is formed from xanthione and sulphur dichloride-
tin(1V) chloride .lS5
H. Marona, Pol. J. Chem., 1980, 54, 2059 (Chem. Abstr., 1981,95, 24 727).
I. W.J . Still, G . W. Kutney, and D. McLean, J. Ow. Chem., 1982,47, 555.
3 Heterocycles containing One Sulphur Atom
Thiopyrans. - A convenient synthesis of 2-phenylthiopyran-4-one (21 7) has
been developed from methyl styryl ketone and ethyl formate. The enolate
(21 5) that was formed was acetylated and immediately treated with triethyl-
amine and hydrogen sulphide to give the dihydrothiopyran4one (21 6).'%
When the sulphides (218; R' = H or Me, R2 = Me or H) were heated, a mix-
ture of the thiopyran (219) and a dihydrothiophen (220) was formed, but not
all vinyl sulphides react in this way.18'
phv
PhCH=CHCCH=CHO-
II
0
(215)
*c201 [ 7 7 % ]
8
PhCH=CHCCH=CHOAc - H S ,[59%1
Et N - phQ
0 0
+ ..ac
ClH2C
R1 c1
The 3,s-dicarboxylate (223) has been synthesized from the diester (221)
by oxidation of the tetrahydrothiopyran (222).18' Sulphur analogues of
thromboxane A2 compounds have been ~ynthesized.'~' The alkenedienyne
(224) underwent a double cyclization on treatment with trifluoroacetic
acid.lg0 An interesting conversion of a pyran-2-thione into a thiopyran-2-one,
in low yield, has been achieved by heating."'
I
But
But
I
(B~~S),CHCH=CC=CC=CHCH(OM~)~ -
c i s + trans
Bu L S Bu
(224)
lS6 C. H. Chen, J . 3 . Doney, and G. A. Reynolds, J. Org. Chern., 1981,46,4604.
187
E. Nagashima, K. Suzuki, and M. Sekiya, Tetrahedron Lett., 1981,22,2587.
C . H. Chen, G . A. Reynolds, and B. C. Cossar, J. Org. Chern., 1981,46,2752.
S . Kosuga, N . Hamanaka, and M. Hayashi, Tetrahedron Lett., 1981,22, 1345.
190 Y. Aso, M. Iyoda, S. Fujisawa, S. Yamaguchi, and M. Nakagawa, Tetrahedron Lett.,
1981, 22, 3061.
19' A. Roedig and K. Fleischmann, Chern. Ber., 1981, 114,292 1.
6-Chloro-3-thiabicyclo[3.1.01hexane 3,3-dioxides, e.g. (225) and (226)
[synthesized in good yield from sulpholene and dichlorocarbene], are useful
intermediates; for example, the cyclopropane ring is opened by hydrochloric
acid or butyl-lithium. lg2
Reduction of 4-thianone oximes (227; R = alkyl or aryl) with LiAlH4 gave
a mixture of epimeric amines, which were separated chromatographically.
Their conformations were confirmed by independent stereospecific syn-
thesis.lg3 The use of mass spectrometry in the identification of various iso-
mers and analogues of trans-2,5-dimethyltetrahydropyran-4-one has been dis-
cussed.'94
'R Cl
(225) R = C1, R = H
2
SwNoH
(226) R1= H , R = Me
Thiochromans and Thiochromenes. - Cyclization of 0-(pheny1mercapto)-

propyl phenyl ketones (228) with perchloric acid gave a mixture of products,
the pyrylium salt (229) and the thiochroman (230; R' = Me or Ph, R2 = Ph
or Me) pred~minating.'~'An improved procedure has been developed for the
synthesis of 1-thiaphenalene(232) from the acid chloride (23 1).'%
acl SCHzcoc1
lg2 Y. Gaoni, J. Org. Chem., 1981,46,4502.

lg3 P. K. Subramanian, K. Ramalingam, N. Satyamurthy, and K. D. Berlin, J. Org.
Chem., 1981,46,4376.
lg4 A. V. Serbin, P. I. Zakharov, Yu. I. Blokhin, and B. V . Unkovskii, Khim. Geterotsikl.
Soedin.,1981,619 (Chem. Abstr., 1981,95,131 792).
l g 5 R. S . Devdhar, V. N. Gogte, and B. D. Tilak, Indian J. Chem., Sect. B , 1980, 19,
1014.
lg6 L. Y. Chiang and J . Meinwald, J . Org. Chem., 1981,46,4060.
Thiochromanones.- In addition to the expected product of 0-benzoylation,
heating thiochroman-4-one (233) with benzoic anhydride-perchloric acid in
carbon tetrachloride gave the dichloride (234).'"
Many thiocresols underwent the Pechmann reaction with ethyl 2-
oxocyclohexanecarboxylate to give the tricyclic compound (235; R = H or
Me), which was oxidized by hydrogen peroxide to the sulphone.lg8 N -
Tosylsulphimides (236), prepared from thiochromanones and chloramine-T,
have been converted into the 1,2-benzothiazepin-5-0nes (238), in high yield,
by silica gel.lg9 The sulphinium salt (237) also undergoes ring-expansion, but
this competes with ring-cleavage to give a mixture of products.200
Irradiation of thiochromanone, like several pyrans, has led t o a mixture
of several stereoisomers that contain a cyclobutane ring?"
( 235) ( 2 3 6 ) R = NTs
( 2 3 7 ) R = C(COOMe)2
Thiochromones and Thiocoumarins. - Thiochromone is converted into a mix-
ture of stereoisomers on irradiation in benzenoid solvents, and the difference
between its behaviour and that of the sulphone has been ascribed mainly to
the differing natures of the lowest excited state of each compound.201Thio-
chromones are not reduced by sodium borohydride alone, but the 4H-
thiochromene is the main product in the presence of cerium(@) chloride."'
Reduced 3-aryl-thiocoumarins have been synthesized from cyclohexane-
1,3-diones and 172-dithiolium iodides (239) via the thioxo-compound
(240) .2m
(239) ( 240)
19' I. W. J . Still and S. B. Abhyankar, Can. J . Chem., 1982,47,373.
198 K. M. Bakre and J . R. Merchant,Zndian J. Chem., Sect. B , 1981,20, 346.
199 Y.Tamura, Y . Takebe, S. M. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and
M. Kise, J. Chem. SOC.,Perkin Trans. I , 1981,1037.
2oo Y. Tamura, Y. Takebe, C. Mukai, and M. Ikeda,HeterocycZes, 1981,15,875.
201
I. W.J . Still and T. S. Leong, Tetrahedron Lett., 1981, 22, 1183.
202 M. Mosaddak, J . M. Catel, R . Pinel, and Y. Mollier, Bull. SOC. Chim. Fr., Part 2,
1981,125.
Thioxanthenes and Thioxanthones. - Several possible metabolites of the
neuroleptic chlorprothixene (241) have been synthesized; for example, the
geometric isomers of 3-, 4-, 6-, and 7-hydroxy- and -methoxy-derivati~es.~~~
Lucanthrone (242; R' = R2 = H) is known t o have anti-tumour properties,
and acts through an unidentified active metabolite. To explore the possibility
that this may be a hydroxyl or amino derivative, a number of such com-
pounds (242; R1 or R2 = OH or NH2) have been s y n t h e ~ i z e d . X-ray
~~*~~~
analysis showed that the sulphilimine (243) exists in a boat form, with the
S-substituent in an axial and the 9-methyl in an equatorial position?06
4 Heterocycles containing One Oxygen and One Sulphur Atom
Oxathiins. - The sulphones (244) have been cyclized, in moderate yields, to
the oxathiins (244a) by acetic anhydride-P0C13?" Tropone in mineral acid
adds on 2-mercaptoethanol to give a mixture of the 1,4-oxathiins (245).20s
Bicyclic lactones such as (246a) have been synthesized from the oxathiinone
\ a
WR1
(246b; thp = tetrahydropyranyl)?09
WCl \
CH(CH212NMe2
-
0
/
HN( CH2I2NEt2
\
Ik'
-
NTs
Me
(241) ( 242 (243)
( ArCOOCH2) 2S02
( 244)
-
O2
(244a)
(246a) (246b)
203 K. Sindelar, J . Jilek, J . Koerbl, F. Jancik, E. Svatek, J . Metysova, and M. Protiva,
Collect. Czech. Chem. Commun., 1980,45, 3166.
204
S . Archer, K. J . Miller, R. Rej, C. Periana, and L. Fricker, J. Med. Chem., 1982, 2 5 ,
220.
'05 S. Archer and R. Rej, J . Med. Chem., 1982, 25, 328.
'06 Y. Tamura, C. Mukai, M . Ikeda, and M. Kido, Chem. Lett., 1981,619.
'07 V. Baliah, K. Ganapathy, and S. Ananthapadmanabhan, Indian J. Chem., Sect. B ,
1981,20,334.
M. Cavazza, G. Morganti, A. Guerriero, and P. Francesco, J. Chem. Soc., Perkin
Trans. I , 1981,1868.
'09 E. Vedejs, D. M. Gapinski, and J . P. Hagen, J. Org. Chem., 1981,46, 5451.
5 Heterocycles containing Two Oxygen Atoms
Dioxans. - The cis- and the trans-isomer of 2-methyl-3-phenylbenzodioxan
have been synthesized by aluminium-chloride-catalysed cyclization of threo-
and eryth ro - 1-phenyl-2-(2-hydroxyphenoxy)propanols, for example the
threo-isomer (247).210 A highly substituted dioxan (248) has been synthe-
sized by treatment of 2-ethoxypent-1-en-3-01 with a catalytic amount of
toluene-p-sulphonic acid at 20 'C, but the dihydrodioxin (249) was formed,
in 70% yield, when the reactants were heated?"
Crown ethers that contain benzodioxin grouping have been syn-

thesized from the diols (250; R1,R2 = H, alkyl, or aryl) and di-(2-chloroethyl)
ether?12 The valuable pharmacological properties of a compound that was
prepared from the reaction of 2,3-dihydrobenzodioxin-2-carboxylic acid with
ethylenediamine have been known for 20 years, and the drug was believed to
be the imidazoline (251), but recent work has shown it t o be the dioxole
(253). The dioxan (25 1) has now been synthesized from catechol and chloro-
a~rylonitrile.2~~An improved synthesis of the adrenergic blocking agent (252)
and its enantiomer from 2-hydroxymethylbenzodioxan has been reported?14
A study of the formation of dibenzo-1,4-dioxins from 2-bromophenoxides
suggests that a Smiles rearrangement
HN/\
bH
The 1,3-dioxans (254; R = alkyl) and (255; R = H or Pr') have been
shown by 'H and '3C n.m.r. spectroscopy to have chair forms and equa-
torial s u b ~ t i t u e n t s .Dioxan
~ ~ ~ is cleaved by treatment with trimethylsilyl
'lo G. Proietti, S. Corsano, and E. Castagnino, J. Heterocycl. Chem., 1981,18,415.

'I1 N. A. Keiko, T. N. Musorina, I. D. Kalikhman, and M. G. Voronkov, Izu. Akad.
Nauk, SSSR,Ser. Khim., 1980,2534 (Chem Abstr., 1981,95,24942).
'12 G. Coudert, G. Guillaumet, and M. Leonard, Tetrahedron Lett., 1981,22,4703.
213 C . B. Chapleo and P. L. Myers, Tetrahedron Lett., 1981,22,4839.
'14 A. K. Willard, R. L. Smith, and E. J. Cragoe, J. Org. Chem., 1981,46,3846.
'14' C. A. Ramsden, J . Chem. SOC.,Perkin Trans. 1,1981,2456.
'15 L. F. Lapuka, E. A. Kantor, R. S. Musaviror, and D. L. Rakhmankulov, Zh. Obshch.
Khim., 1981,51,934 (Chem. Abstr., 1981,95,96847).
iodide at 40°C, the main products being (Me3Si)20, (CH21)2, and
(Me3SiOCH2)2?I6 When 2,3-dihydro-l,4dioxin (256) was treated with ethyl
diazoacetate and the product was hydrolysed, treated with sodium azide, and
subjected to a Curtius rearrangement, the urea (257) was ~btained.~"
6 Heterocycles containing Two Sulphur Atoms

1,3-Dithians.- 1,3-Dithienium fluoroborate (258) effects regiospecific alky-
lation of 0-silylated enolates of carbonyl compounds to produce 1,3-
dicarbonyl derivatives, e.g. (259)?18 A wider variety of substituents in 1,3-
dithians is obtainable by allowing aromatic aldehydes t o react with the sul-
phone (260)?19
lY3-Dithianssuch as (261) are synthesized from 3(trimethylsilyl)propynal
and propylene-l,3-dithiol, and are versatile intermediates?20
CH2[-iCH2COOEt] + ArCHO
0 2
E tOOC
( 260) Ar (261)
1,4-Dithians.- A new synthesis of thianthrene and its symmetrically substi-

tuted derivatives has been described in which a lY2,3-benzothiadiazole(262)
is heated in benzene that contains di-t-butyl peroxide.221 1-(3-Chloroethyl-
216
M. G. Voronkov, V. G. Komarov, A. I. Albanov, I. M. Korotaeva, and E. I. Dubin-
skaya, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1391 (Chem. Abstr., 1981, 95,
133 006).
217 H. Jendralla and W. Pflaumbaum, Chem. Ber., 1982,115,229.
I. Paterson and L. G. Price, Tetrahedron Lett., 1981,2 2 , 2829,2833.
219 V. Balhh, S. Prema, C. B. Jawaharsingh, K. N. Chockalingam, and R. Jeyaraman,
Synthesis, 1981,995.
220 N. H. Andersen, A. D. Denfiston, and D. A. McCree, J. Org. Chem., 1982,47,1145.
P. C. Montevecchi and A. Tundo, J . Org. Chem., 1981,46,4998.
thio)alk-1-ynes (263) have been cyclized, by their reaction with dilithium

disulphide, to the 1,4-dithiin (264).222
A new type of sulphoxide rearrangement in the thermolysis of 1,4-dithiin
sulphoxides at 7OoC has produced the 1,3-dithiole (265) and the thiophen.
Photolysis in methanol gave similar r e ~ u l t s . 2 ~ ~
7 Heterocycles containing an Oxygen Atom m each of Two or

More Rings
A cytotoxic polyether, called okadaic acid, has been isolated from two
marine sponges. Its structure is similar to that of another cytotoxic spnge
ingredient, acanthifolicin, except that it lacks a thioepoxy-group. BI 9225
Several rotenone-like compounds which contain two or three fused pyran
rings have been synthesized?26 (-)-Sarracenin (266), a naturally occurring
iridoid, has been synthesized from (+_)-methyllactate:27 as also has (*)-
R. S. Sukhai, R. DeJong, H. D. Verkruizsse, and L. Brandsma, R e d . , J. R. Neth.

Chem. SOC.,1981,100, 368.
223 K. Kobayashi and K. Mutai, Tetrahedron L e f t . , 1981,22, 5201.
K. Tachibana, P. J . Scheuer, Y. Tsukitani, H. Kikuchi, D. Van Engen, J . Clardy,
Y. Gopichand, and F. J. Schmitz, J. Am. Chem. SOC.,1981,103,2469.
225 F. J . Schmitz, R. S. Prasad, Y. Gopichand, M. B. Hossain, and D. van der Helm,
J. A m . Chem. SOC.,1981,103,2467.
N. P. Peet and S . Sunder, J. Heterocycl. Chem., 1981, 18, 1123.
221
S. W. Baldwin and M . T. Crimmins, J. A m . Chem. SOC.,1982,104,1132.
semburin (267), a volatile natural oil, from 5,6-dihydropyran-2-one and
diethyl malonate?28
The structures and absolute configurations of acetoxyeriobrucinol methyl
ether (268; R = OAc) and of eriobrucinol methyl ether (268; R = H) have
been studied by X-ray ~rystallography.2~’ Similar studies have been made on
the halogenoacetates of (-)-bruceol (269; R = OCOCH2X) and (k)-
deoxybruceol(269; R = H).230
0
228 Y. Ohfune, K. Takaki, H. Kameoka, and T. Sakai, Chem. Lett., 1982,209.

229 E. L. Ghisalberti, P. R. Jefferies, C. L. Raston, B. W. Skelton, A. H.White, and
G. K. Worth, J. Chem. SOC.,Perkin Trans. 2,1981,576.
230 E. L. Ghisalberti, P. R. Jefferies, C. L. Raston, B. W. Skelton, A. D. Stuart, and
A. H.White, J. Chem. SOC.,Perkin Trans. 2 , 1981, 583.
5
Seven-Membered Ring Systems
BY J. T. SHARP
1 Introduction
There has been a slight decrease in the total number of papers and patents
this year, due in particular to a slackening in the flood of patents concerned
with benzo[ 1,4]diazepines and related systems that are of potential pharma-
cological value. However, interest in 1,2- and 1,3-diazepines and in oxepin
chemistry continues to increase and there has been a welcome upswing in the
number of papers concerned with systems containing three heteroatoms,
although this is still an area with much unexplored territory.
2 Reviews
General reviews on carbenes and nitrenes in heterocyclic chemistry' and on
the synthesis of saturated heterocycles2 have been published this year, and
also specific reviews on 1,2-dia~epines,~1,2-ben~odiazepines,~ thiepins,'
dithiepins; and aza-a~ulenes.~
3 Azepines and Diazepines

Azepines. - Formation. The thermal and photolytic decomposition of aryl
azides provides important routes to azepines via inter- and intra-molecular
reactions of the derived nitrene with aromatic rings. New work has been
reported on several aspects of this chemistry.
In the first study on the decomposition of phenyl azide in the presence of
electrophilic reagents it has been shown that both thermal and photochemical
reactions lead to the azepinone (2) and to disubstituted arenes such as (4).8
The azepinone is thought to be formed by the addition of acetic acid to the
didehydroazepine intermediate (1) and subsequent acetolysis, and the disub-
stituted arenes are formed from the nitrenium ion (3).
C. Wentrup, Adv. Heterocycl. Chem., 1981, 2 8 , 2 3 1 .

W. J . Ross, Gen. Synth. Methods., 1981, 4, 279.
V. Snieckus and J . Streith, Acc. Chem. Res., 1981, 14, 348.
T. Tsuchiya, Yuki Gosei Kagaku Kyokaishi, 1981, 39, 99.
I. Murata and K. Nakasuji, Top. Curr. Chem., 1981, 97, 33.
R. S. Sukhai, R. DeJong, H. D. Verkruijsse, and L. Brandsma, Recl.: J. R . Neth.
Chem. Soc., 1981,100, 368.
M. Kimura, Yuki Gosei Kagaku Kyokaishi, 1981, 39, 690.
H. Takeuchi and K. Koyama, J. Chem. Soc., Chem. Commun., 1981, 202; J. Chem.
SOC.,Perkin Trans. I , 1982, 1269.
3 89
The didehydroazepine (1 ) or benzazirine intermediates that are generated

by the photolysis of phenyl azide have also been intercepted by the 'naked'
anions that are produced from various potassium salts when they are used in
the presence of crown ether^.^ Potassium acetate and hydroxide both gave
the azepinone (2) while potassium halides gave only the o-halo-anilines.
E
H Ts
(5)
In the intermolecular reaction of the nitrene that is derived from tosyl

azide with benzene, little of the N-tosylazepine ( 5 ) is obtained at normal
pressures, but the yield is markedly increased when the reaction takes place
under a high pressure of nitrogen; for example, t o 48% at CQ 90atm.l' In a
similar reaction with dimethyl terephthalate, it is suggested that the reaction
involves an initial [1,3] cycloaddition of the azide to the aromatic ring to
give ( 6 ) , rather than a nitrene reaction.
The vinylaziridine (8) reacts with various alkynes and alkenes t o give,
respectively, the dihydro- and tetrahydro-azepines (7) and (9). These reactions
R. Colman, E. F. V. Scriven, H. Suschitzky, and (the late) D. R. Thomas, Chem. Ind.
(London), 1981,249.
lo N. R. Ayyangar, R . B. Bambal, and A. G. Lugade, J. Chem. SOC.,Chem. Commun.,
1981,790;Heterocycles, 1982, 18,77.
Seven-Membered Ring Systems 39 1
probably involve intermediates of the type (10). In cases where X is an easily

enolized group (NOz or keto C=O), the reaction takes an alternative path t o
give, for example, the enamine (1 l)." R
RxoMe
XN
H
-
.y:
H+
XN
6 R
Me
\
/
R OR Me
RQR
0
The amino-substituted benzenium ion (13; X = Ts), prepared by the elimi-

nation of methanol from (1 2), rearranged t o give the 1H-azepine (14) in 72%
yield. Similar reactants with X = R'CO gave only the bicyclic oxazolines (15),
but these, on heating, rearranged t o give the azepines (14).12
N-Phenyl-2-vinylaziridines and their heterocyclic analogues, e.g. (16), are
known to rearrange to give benzo- or hetero-fused azepines, e.g. (18). A
(16) (17) (18)
( a ) A. Hassner, R . d'costa, A. T. McPhail, and W. Butler, Tetrahedron L e t t . , 1981,

2 2 , 3691; ( b ) A. Hssner and W. Chau, ibid., 1982, 23, 1989.
l2 H. Eckhardt, D. Hege, W. Massa, H. Perst, and R . Schmidt, Angew. Chem. Int. Ed.
Engl., 1981, 2 0 , 699.
kinetic study has now shown that the effects of substituents on the rate of
this reaction parallel those in benzenic 0-Claisen rearrangements, and the
reaction is therefore best described as a 3,3-sigmatropic rearrangement . I 3 The
full report on thermal transformation of dihydro-3H-cyclobut[b]indolesto
1H-1-benzazepines (see last year's Report) has now appeared.14
A convenient new route to 2-benzazepines ( 2 1) involves the synthesis of
the acetylenic benzophenone (20) via the palladiumcatalysed coupling of
(1 9) with propargylphthalimide followed by hydration of the alkyne and
spontaneous ring-closure."
R
m
The amino-alcohol ( 2 2 ) , on treatment with base, undergoes ringopening
and re-cyclization to give the 2-benzazepinone (23).16
R \
m N H
CH2Ph
OH
e - R
R \
m 2 P -h
NMe
R \
CH2Ph
The keto-amide ( 2 5 ; R = OMe), on treatment with PPA, gives only the

oxazole (24), but it can be converted into the 3-benzazepine (26) via reduc-
tion (by borohydride) to the alcohol followed by cyclization with PPA.17
Ph Ph
The 0-hydroxyethylamine (28) precursors for the 3-benzazepine system

(29) can conveniently be prepared by the reduction of 2-oxazolines (27) with
diborane.I8
13
H. P. Figeys and R. Jammar, Tetrahedron Lett., 1981, 2 2 , 637.
l4 M. Ikeda, K. Ohno, M. Takahashi, T. Uno, Y. Tamura, and M . Kido, J. Chem. SOC.,
Perkin Trans. 1 , 1982, 741.
E. J. Trybulski, E. Reeder, J. F. Blount, A. Walser, and R. I. Fryer, J. Org. Chern.,
1982,47,2441.
l6 J. Hknin, J . Likforman, and J . Gardent, Bull. SOC.Chim. Fr., Part 2 , 1981,458.
'' D. Berney and K. Schuh, Helv. Chim. Actu, 1981, 64, 373.
L. N. Pridgen, L. B. Killmer, and R. L. Webb, J. Org. Chem., 1982,47, 1985.
Seven-Membered Ring Systems 393
Intramolecular insertion of a nitrene into aromatic rings is a versatile route

to fused azepine systems; recent examples include (30),” (3 1),20 (32),21 and a
dimer of (33).22
H
The benzofuro-annelated azabicyclo[ 3.2.01heptenone (34) undergoes both

thermal and acid-catalysed ring-expansion. The former gives (36) directly
while acid catalysis gives firstly (35), which is isomerized to (36) by treat-
ment with base.23
+)eo - &OR
0
& 0
- R
‘ 0 R
R H
(34) (35) (36)
l9 R . N. Carde, P. C. Hayes, G. Jones, and C. J . Cliff, J. Chem. SOC.,Perkin Trans. 1 ,

1981,1132.
2o 0. Meth-Cohn and S. Rhouati, J. Chem. SOC.,Chem. Commun., 1981, 241.
R. A. Abramovitch, S. B. Hendi, and A. 0. Kress, J. Chem. SOC., Chem. Commun.,
1981.1087.
12
0 . Meth-Cohn and S. Rhouati, J. Chem. SOC.,Chem. Commun., 1980, 1161.
*’ H-D. Becker and K. Gustafsson, J. Org. Chem., 1981,46,4077.
A new class of indenobenzazepine alkaloids has been produced by the

transformation of spirobenzylisoquinolines: a reaction which probably
parallels a biogenetic pathway.24 8,14-Cycloberbine has been converted into
the benzindanoazepine system.25
The dihydropyrrolo[ 1,2a]azepinone (38), prepared via the reaction of the

anion of 2-formylpyrrole with but-3-en-2-one,has been dehydrogenated with
DDQ to give (37) and also converted into (39), the first unsubstituted
pyrroloazepine, by reduction (using a borohydride) and acid-catalysed
dehydration.26
c1- Me 2N
(41)
4(Dimethylamino)-5-aza-azulene (4 l), as blood-red crystals, has been

obtained by the reaction of (40) with amrn~nia.~’
Reactions of Azepines. The first N-unsubstituted lfi-azepine (43) has been
prepared by the reduction of the N-tosyl derivative (42); it is stabilized by
hydrogen-bonding to the adjacent carbonyl group.28
R-CC=O R-C=O
(42) (Ts = tosyl) (43)
The compound that is formed by the reaction of the salt (44) with
aqueous base has now been shown to be ( 4 9 , and not (46), as previously
reported .29
24 G . Blasko, S. F. Hussain, A. J. Freyer, and M. Shamma, Tetrahedron Let t ., 1981, 22,

3127 (see also pp. 3131,3135,3139,and 3143).
25
M. Hanaoka, M. Inoue, K. Nagami, Y. Shimada, and S. Yasuda, Heterocycles, 1982,
19, 313.
26 G. Jones and P. M. Radley, J. Chem. Soc., Perkin Trans. 1 , 1982, 1123.
27 K. Hafner and H-P.Krimmer, Angew, Chem,, Inr. Ed. Engl., 1980, 19, 199.
28 N. R. Ayyangar, A. K. Purohit, and B. D. Tilak, J. Chem. SOC., Chem. Commun.,
1981,399.
29 G . Jones and P. Rafferty, J. Org. Chem., 1982,47,2792.
Sev en-Membered Ring Systems 395
0 Br
(44) (45) (46)
o-Chloranil reacts with 1-ethoxycarbonyl-1H-azepinet o give the [6 + 41

adduct (47) as the major product. This is the first example of an adduct of
this type with chloranil, and it is suggested that its formation may be
favoured by polar attraction (48).30
6- 6+
c14 6- 6+
(47) ( E = COOEt) (48)
The reactions of l-alkoxycarbonyl-1H-azepineswith singlet oxygen had

previously been reported to give only a [4 + 21 adduct, but in a re-
investigation it has now been shown that the [6 + 21 adduct (49) is produced
in ca 30%yield.31 Its chemistry was also studied.
H H
I I
MeN- ( CH ) 4C=CPh
I
HNAc
Unlike the N-imides of five- and six-membered cyclic amines, the azepine
derivative (50) does not undergo ring-expansion but instead a facile elimi-
nation to give (51), probably because only the larger ring is able to achieve
the required transition state for the elimination reaction.32
3H-3-Benzazepin-2-ones can be alkylated in the l-position in good yield,
using sodium hydride and alkyl halides.33
1,a-Diazepines.- Formation. A range of 2-substituted 3,4-dihydro-1,2-
diazepines, e.g. (52), has been prepared by the reaction of cuP;uS -unsaturated
ketones with a variety of monosubstituted hydrazines.%
30 K. Saito, S. Iida, and T. Mukai, Heterocycles, 1982, 19, 1197.

31
T. Kumagai, A. Tokida, K. Kidoura, 0. Geshimoto, and T. Mukai, Tetrahedron Lett.,
1982,23,873.
32 S. Wawzonek and J. M. Shradel, J, Org. Chem., 1981, 46,2410.
33 K. Orito and T. Matsuzaki, Tetrahedron, 1980, 36,1017.
34 P. N. Anderson, C. B. Argo, and J . T. Sharp, J. Chern. SOC., Perkin Trans. I , 1981,
2761.
I
MeC=O
Me
I
HC=C-CH=CH2
- RNHNH2 Me (J-.
-N
Me
(52)
A mechanistic study on the 1,7-electrocyclization of the diazo-compound

(53), which gives both of the diazepine isomers (55) and ( 5 6 ) , has been
carried out. Competition between cyclization at the deuteriated and non-
deuteriated sites showed a kinetic isotope effect of ca 4.5, which is consistent
with the operation of a fast pre-equilibrium between the diazo-compound
and the intermediates (54a, b) followed by a competing sigmatropic
migration of ‘H or 2H.35
(54b) (56)
Much work has been done on the photochemical ring-expansion of pyri-

dine N-imides to 1,2-diazepines, but it has previously not proved possible to
extend this reaction to the formation of 2,3-benzodiazepines (58) from iso-
quinoline N-imides (57). Now, however, it has been shown that this reaction
can be effected in 30-50% yield if it is done in the presence of base.36 Full
reports have now been published on the photolysis of thieno-, furo-, and
pyrr~lo-[b]-~’and - [ ~ ] - p y r i d i n eN-imides.
~~ These reactions give both 1,2-
and 1,3-diazepines fused to the heteroaromatic rings (see these Reports,
Volumes 2 and 3).
35
T. K. Miller, J . T. Sharp. G . J. Thomas, and I. Thompson, Tetrahedron Lett., 1981,
22, 1537.
36 M. Enkaku, J . Kurita, and T. Tsuchiya, Heterocycles, 1981, 1 6 , 1 9 2 3 .
” T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 1981, 29, 3173.
38 T. Tsuchiya, H. Sawanishi, M. Enkaku, and T. Hirai, Chem. Pharm. Bull., 1981, 29,
1539.
Seven -Membered Ring Systems 397
R1
(57)
The N-nitrene (59; n = 2) undergoes a formal intramolecular insertion

with a C-H bond in the electron-rich aryl ring to give the fused 1,2-
benzodiazepine system (60) in moderate yield. This reaction shows a marked
preference for a seven-membered transition state, as no parallel reaction was
observed for (59;n = l).39
R1
0
(59)
The diazepinoindole system (62) has been synthesized, in high yield, by

the reaction of the aminimide (61) with base.40The full report on the thermal
ring-expansion of 4- and 6-vinyl-1,2,5,6-tetrahydropyridine and 2-vinylpiperi-
dine N-imides has now a ~ p e a r e d . ~ '
Me
H
TsO-
(62)
(61)
Reactions of I,2-Diazepines. The type of reaction which takes place between

2,3-benzodiazepines (63) and acylating reagents seems to be strongly depen-
dent both on the substitution pattern of the diazepine and the nature of the
acylating reagent. In cases where R' and R2 are H or Me, the reaction with
c,:*
acetic anhydride gives the 3-acetyl derivative (64).j6 However, a similar
c,:
\
R1 -N
(63)
Ac20 ;
. \
R1
(64)
-
39 R. S. Atkinson, J . R. Malpass, and K. L. Woodthorpe, J. Chern. Soc., Chern. Corn-
mum, 1 9 8 1 , 1 6 0 .
40 Y . Tamura, I. Morita, H. Tsubouchi, H . Ikeda, and M. Ikeda, Heterocycles, 1982,
17, 163.
4* T. Tsuchiya and M. Sashida, Chern. Pharrn. Bull., 1981 , 29, 1887.
OAc XR
(66) (67) X = 0 or S
acylation of the 4-phenyl derivative (65) takes place at N-2 to give the
unstable species (66), which readily reacts with 0 or S nucleophiles to give
(67).42 The reaction with acyl or sulphonyl halides, however, can take two
further paths, either ring-contraction to give the isoquinoline N-imide hydro-
chloride (69) or via dimerization of the short-lived dehydrochlorinated
species (68).42
dimer
(65) - RCOCl
c-R
c1- II
0 \
3H-1,2-Diazepines (70) react with di-iron nonacarbonyl to give a complex

of the type (71), containing the tetrahedral Fe2N2 system. Complexation
much reduces the activation energy for inversion of the diazepine ring and
destroys the strong activating effect of the azo-group on the rate of 1,5-
sigmatropic hydrogen migration^.^^
R1 R1
MeCy
42 D. P. Munro and J. T. Sharp, Tetrahedron Lett., 1982, 2 3 , 345.
43 C. B. Argo and J. T. Sharp, Tetrahedron Lett., 1981, 2 2 , 3 5 3 .
NR
The conformations of some mono- and di-acyl derivatives of more highly

substituted 2,3-benzodiazepines (72; R’ = Ac or COEt; R2 = H, Ac, or COEt)
have been studied by n.m.r.44
rG
Ac
Ph
hv OH-
___t Ph Ph ___)
Ph Ar
(73) (74)
A conversion between the lH-1,2-diazepine (73) and the 4H-1,2-diazepine

(75) has been effected by photoisomerization, to give (74), followed by alka-
line dea~ylation.~’
1,3-Diazepines.- Formation. The full papers have now been published on the
thermal isomerization of lH-l,2-diazepines (76) t o the fully unsaturated 1H-
1,3-diazepine system (79).46-48Further work has confirmed the dependence
of this reaction path o n the presence of electron-donating substituents (either
R’ or R2)which favour cleavage of the N-N bond in the intermediate (77),
rather than cleavage of the C-N bond, which leads to the pyridinium N-imide.
In a similar way, the photochemical reactions of quinoline N-imides (80) that
have electron-donating substituents in the 6- or 8-positions passed through
intermediates analogous t o (77) and (78) to give 3H-1,3-benzodiazepines(8 l),
and 1-methylisoquinoline N-imides likewise gave 1H-lY3-benzodiazepines
c.
(82):’
R2
R1
-N
W
(77) (79)
( E = COOEt) (78)
44 P. Sohar, V. Z. Mekesfalvi, A. Neszmelyi, T. Lang, and J . Korosi, Kem. Kozl., 1980,

54,290 (Chem. Abstr., 1981,95,203162).
45 W.Abraham, K. Buck, and D. Kreysig, Z.Chem., 1982,22,57.
46 J. Kurita, M. Kojima, and T. Tsuchiya, Heterocycles, 1981, 16, 137.
47
J. Kurita, H. Kojima, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 1981, 29,
3688.
48 J. Kurita, H. Kojima, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 1981, 29,
3696.
49 T. Tsuchiya, S. Okajima, M. Enkaku, and J . Kurita, J . Chem. Soc., Chem. Commun.,
1981,211.
(80) (81) (82)

A series of 4,5-dihydro-4-phenyl-3H-1,3-benzodiazepines (83) has been
synthesized by the reaction of diamines (84; R' = H, R2 = alkyl or cyclo-
alkyl) with a variety of ortho-esters. The 1H analogues (85) were also pre-
pared from (84;R' = Me, R2 = MeCO or PhCO) by dehydration, using phos-
phorus pentachloride or thionyl ~ h l o r i d e . ~ ~ ~ ~ '
[R1= M e ]
Ph
Ph
(83) (84) (85)
The imidazo[ 1,2a][ 1,3]diazepine (87) has been prepared, by the hydro-
genolytic ring-expansion of (86), and further converted into the fully unsatu-
rated system (88).52
E E
H H
(87) (88)
(86)
( E = COOEt)
The reaction of urea with the chloro-ester (90), giving (91), provides a
new route t o 1,3-diazepines; however, NN'-dimethylurea did not show a
parallel reaction, and gave only the imidazolone (89).53
-
dCHZCME MeNHNHMe
II
0
C1CH2CCH2COOEt NH2m2 *
MeNK9;Me0
(90)
0
(89) (91)
50 H. M. Geyer, L. L. Martin, C. A. Cricklow, F. W. Dekow, D. B. Ellis, H. Kruse, L. L.
Setescak, and M. Worm. J. Med. Chem., 1982, 2 5 , 340.
51 L. L. Martin, L. L. Setescak, M. Worm, C. A. Cricklow, H. M . Geyer, and J . C. Wilker,
J. Med. Chem., 1982, 2 5 , 346.
52
T. Kurihari, T. Tani, and K. Nasu, Heterocycles, 1981, 16, 1677.
53 R. J. Breckenridge and C. J . Suckling,J. Chern. Res. (S), 1982, 166.
Seven-Mernbered Ring Systems 40 1
R blkNH R
(93)
( R = CF3)
H
R R
(94)
H
In some work which parallels earlier studies in oxepin chemistry, the

compound (93), which is a valence-bond isomer of the 1,3-diazepine system,
has been prepared by the isomerization of (92). Both thermal and photo-
chemical decomposition of (93) gave another valence-bond isomer (94).54
Reactions of 1,3-Diazepines. The 1,3-diazepine system (96) was found t o be
very susceptible to decomposition by water, acids, silica gel, and alumina, and
could only be isolated via chromatography on Sephadex. Hydrolysis at ca
5 0 ° C gave (95) and photolysis gave (97):’ The hydrolysis, photolysis, and
reduction by borohydride of the thieno-fused analogues (98) and (99) were
Mex=)E
also investigated.37y38
NCHO
H
(95) (97)
E
(99)
(E = C O O E t )
1,4-Diazepines.- Formation. The reaction between 1,2-diamines and con-

jugated enones, known to give 1,4-diazepines (100) and a variety of other
products, has been studied in greater depth by 13C n.m.r. spectroscopy. The
product compositions for a variety of enones are reported, and it was con-
firmed that, in the absence of solvent, the diazepine may be formed as the
54 Y . Kobayashi, T. Nakano, M . Nakajima, and I. Kumadaki, Tetrahedron Lett., 1981,

22,1113,1369.
H Me
Ph
NMe Ph
H
sole or the main product. However, the diazepines are easily transformed
into macrocyclic products during post-reaction work-up procedures that
involve diethyl ether.” NN-Dimethylethylenediamine (101) reacts regio-
specifically with ap-disubstituted vinamidinium salts, e.g. (1 02); the more
reactive secondary amino-group attacks exclusively at the more reactive, less
hindered site to give the more stable diazepinium salt (103).56 2-Phos-
phoniovinamidinium salts have been similarly allowed to react with o-phenyl-
enediamine to give (104).”
u l yH p h -3
c104
~ ~- q‘5 3
c1 \
Me 0
H Ac
i
c1 \
NAC
0
(105) 0
(104) (106)
Reagents: i, Pd(0Ac)2, CO
A new synthesis of diazepam has been achieved, via the palladium-

catalysed carbonylation of (105) to give (106), which was further converted
into diazepam by a known route.”
The bis-imidazolin-4-one derivatives (1 07), prepared by the reaction of

a-halo-acetanilides with hexamine, were hydrolysed to give (1 08), which were
converted into the diazepinones (109) by reaction with base. The authors
55
D. Lloyd, W. Scheibelein, and K. Hideg, J. Chern. Res. ( S ) , 1981,62.
56 D. Lloyd, C. A. McCann, and D. R. Marshall, J. Chern. Res. (S),1981,356.
57
R. Gomppet, E. Kujath, and H-U. Wagner, Angew. Chem., Int. Ed. Engl., 1982, 21,
543.
M. Ishikura, M. Mori, T. Ikeda, M. Terashima, and Y. Ban, J. Org. Chern., 1982, 47,
2456;Heterocycles, 1982,19, 19l;ibid.,1981, 16, 1491.
Seven -Memb ered Ring Sy stern s 403
recommend this as the best route to 1-unsubstituted 1,4-benzodiazepin-2-

ones."
The new imidazo[2,1-c][ 1,4]benzodiazepine (1 11) has been synthesized by
reduction of the nitro-aldehyde (1
RC=~-c
/OEt
\\+
NH2
BF~- -
i
H
CR
(112)
Reagents : i, o-phenylenediamine
The 2-amino-4-phenyl-3H-1,5-benzodiazepines (1 13) can be produced con-
HCCOOMe
II
C
a;%-
the imidates (1 12), using HMPA as the solvent .61
a;>
veniently, in a one-pot process, by the reaction of o-phenylenediamine with
H
0
II
HCCOOMe H
CH2COOMe
(114) (115)
MeOOC
f-"
(116)
The mode of reaction of allenes with 1,2-diamines seems to be strongly

dependent on the substituents on the allene. Allenic nitriles give imidazoles
via double Michael addition but the 1,3-diester (1 14), on reaction with 0-
phenylenediamine, gave only the 1,5-benzodiazepine (1 16). The enamine
intermediate (1 15) apparently strongly favours a 7-exo-trig cyclization over
the competing 5-exo-trig alternative.62
Reactions of 1,4-Diazepines. 6-Aryldihydrodiazepinium salts, e.g. ( 1 17),
readily undergo electrophilic substitution at the para-position of the arene
ring to give, for example, (118). This position, rather surprisingly at first
59 M . Hannaun, M . h i & , D. Kolbah, N. Blahrid, and F. Kajfef, J. Heterocycl. Chem.,
1981.18.963.
6o G. Stefancich, M. Artico, S. Massa, and F. Corelli, Synthesis, 1981, 321.
61 P. Unangst, J. Heterocycl. Chem., 1981, 18,1257.
62 J. Ackroyd and F. Scheinmann, J. Chem. SOC., Chem. Commun., 1981, 339; J.
Chem. Res. ( S ) , 1982,89.
H H H
sight, is activated by the electron-rich diazepinium cation. In accord with this,

the reaction is inhibited by ortho-groups which prevent coplanarity of the
rings .63
The protiodebromination of the diazepinium salt (1 19) by its reaction

with triphenylphosphine is thought to occur via nucleophilic attack on
bromine, to generate the onium anion (120), which subsequently abstracts a
proton from the solvent to give (1 2 1). The formulation of the intermediate as
(120), with the carbanionic electron pair orthogonal to the diazepinium
n-system, would preserve the delocalization energy of the vinamidinium
n-system (ca 80 kJ mol-'); however, MNDO calculations indicate that the
alternative formulation (122), having an allenic n-system (LC-C-C = 150"),
is preferred.64965
In a new procedure, several 3-substituted diazepam derivatives (124) have

been prepared, in moderate to good yields, by allowing metallated diazepams
(123) to react with alkyl iodides, carbonyl compounds, or esters. Two equiv-
alents of lithium di-isopropylamide (LDA) were required to produce an equi-
librium concentration of (123) that was sufficiently high for synthetic use.%
63 D. Lloyd, K. S. Tucker, and D. R. Marshall, J. Chem. SOC., Perkin Trans. I , 1981,
726.
64 D. Lloyd, R. K. Mackie, G. Richardson, and D. R . Marshall, Angew. Chem., Int. Ed.
Engl., 1981,2 0 , 190.
A. F. Cuthbertson, C. Glidewell, and D. Lloyd, J. Chem. Res. ( S ) , 1982,80.
66 B. E. Reitter, Y. P. Sachdeva, and J . A. Wolfe, J. Org. Chem., 1981,46,3945.
A similar base-induced alkylation of the chiral benzodiazepine (1 25) gave sub-

stituted derivatives ( 1 27) of predominantly (3R) configuration, as expected
for quasi-equatorial attack on the P conformer of ( 126).67
Further work has been reported on the electrochemical reduction of 2,3-
dihydro- lY4-diazepiniumsalt s.68
Conformations and barriers to inversion in NN'-dialkylperhydro-l,4-
diazepine-2,3-dione and its mono- and di-thio-analogues have been studied by
' H n.m.r. and by molecular-mechanics calculations. The results indicate a
twist-boat conformation and also that the dominant part of the inversion
barrier is steric rather than electrostatic in origin.69The influence of tempera-
ture and substituents on the conformation of the 5-phenyl-l,5benzodiazepin-
1-one system has been studied by lanthanide-shift-assisted H n.m.r. spec-
tro~copy.~'Some I3C n.m.r. assignments for diazepam, fluazepam, and
clonazepam have been re-assigned, and assignments for nitrazepam are
''
r e p ~ r t e d . ~The
' N chemical shifts of various lY4-benzodiazepineshave also
been reported.72 The mass-spectrometric fragmentation pathways of a large
number of lY5-benzodiazepineshave been determined.73974
4 Oxepins and Dioxepins
Oxepins. - Fonnation. The tetrahydro-oxepin derivatives (1 29) and (1 30),
notable as the first heterocyclic trans-cycloheptenes," have been synthesized
via decomposition of the diazonium ion (128). They rearranged slowly to the
cis-isomers at room temperature but could readily be trapped as Diels-Alder
adducts with 2,3-dimethylbuta-1y3-diene.75
The full paper on the thermal isomerization of (32)-butadienyl-oxirans,
e.g. (1 3 l), leading to dihydro-oxepins and 2,3-dihydro-3-vinylfurans
(see last
67 E. Decorte, R. Toso, A. Sega, V. Sfinjib, Z. RuZik-ToroZ, B. Kojib-Prodid, N. Bresciani-
Pahor, G. Nardin, and L, Randaccio, Helw. Chim. Acta, 1981,64, 1145.
68 D. Lloyd, C. A. Vincent, and D. J . Walton, J. Chem. SOC.,Perkin Trans. 2 , 1982,801.
6 9 R. Isaksson and T. Liljefors, J. Chem. SOC.,Perkin Trans. 2 , 1981,1344.
7 0 M. Aversa, C. Giannetto, G. Romeo, P. Ficarra, and M . G. Vigorita, Org. Magn.
Reson., 1981,15, 394,
71 A. Patra, A. K. Mukhopadhyay, A. K. Mitra, and A. K. Acharyya, Org. Magn. Reson.,
1981,15,99.
7 2 B. Unterhalt, Arch. Pharm. (Weinheim, Ger.), 1981,314,7 3 3 .
73 M. E. Maza, M. Galindez, R. Martinez, and E. Cortles, J. Heterocycl. Chem., 1982, 19,
107.
74
M. del R. Arellano, R . Martinez, and E. Cortks, J. Heterocycl. Chem., 1982, 19, 321.
7 5 H. Jendrall, Chem. Ber., 1982, 115,220.
* A thiadiazepine that contains a trans azo-group was reported last year.

406 Heterocyclic Chem istly
Me
-MeOH
+
year's Report), has now appeared.76 Further work has shown that the 8n-
electron cyclization leading from (132) to (133) takes place in the expected
conrotatory fashion. The structure of a Diels-Alder adduct of (133) was
determined by X-ray analysis.77
The cis-divinyloxirans (134; R = H or Ph) also undergo thermal isomeriz-

ation to dihydro-oxepins (1 35) under mild conditions. The analogous trans-
isomers require a much higher temperature, and in addition they give 2-vinyl-
2,3-dihydrofurans,e.g. (136).78
Ph Ph
76 W. Eberbach and U. Trostmann, Chern. Ber., 1981,114,2979.

77 W. Eberbach, E. Hadicke, and U. Trostmann, Tetrahedron Lett., 1981, 22,4953.
78 J-P. Beny, J-C. Pommelet, and J . Chuche, Bull. SOC.Chim. Fr., Part 2, 1981, 377.
G
R20 R1 Me
R2d
Me
The application of the new method of 1,2-carbonyl transposition in oxe-

pins [e.g. (1 37) to (1 38)] that was mentioned in last year's Report to the syn-
thesis of a key intermediate [139; R' = - (CH2)3CH(Me)CH20THP] in the
route to zoapatanol has now been reported."
The full report on the synthesis of the hexano-bridged oxepin (140) has
now appeared" and further work has been reported on its oxidative cleavage
to give cyclodecenes and cyclodecadienes, and on some addition reactions."
The structure of the dehydration product of 2,6-di-t-butyl-4-phenyl-l-
(p-tolyl)cyclohexa-2,5-diene-1,4-diol, previously postulated as a fully unsatu-
rated oxepin, has now been confirmed by X-ray analysis.82
(141)
reagents: i, B u L i , at -1OOOC; ii, 25OC
The Parham cycloalkylation has been extended to provide a general route

to oxygen heterocycles; thus the reaction of (141) with butyl-lithium at
- 100°C, followed by warming to 25 O C , gives the 1-benzoxepin (142)in
> 70% yield.83
Several l-haloalkyl-1,3,4,5-tetrahydro-2-benzoxepins, e.g. (144)' have been
synthesized via the electrophilic cyclization of mixed acetals, e.g. (143)?
CH ,,B r
L d
(143) (144)
79 V. V. Kane and D. L. Doyle, Tetrahedron Lett., 1981, 2 2 , 3027.

8o W. Tochtermann and P. Rosner, Chem. Ber., 1981, 114, 3725.
" P. Rosner, C. Wolff, and W. Tochtermann, Chem. Ber., 1982, 115, 1162.
A. Rieker, S. Berger, D. Mootz, M. Steffen, and W. Wunderlich, Chem. Ber., 1982,
1 1 5 , 385.
83 C. K. Bradsher and D. C. Reames, J. Or%. Chem., 1981,46, 1384.
84 R. E. TenBrink and J. M. McCal1,J. Heterocycl. Chem., 1981, 18, 821.
Ph
(145)
Reactions of Oxepins. The 2-benzoxepin-3-one (145) was synthesized in a

six-step route from 2-aminobenzophenone. Its pyrolysis at 640 O C , at
0.07 mmHg, gave 2-benzoylstyrene (146) in 96% yield; this is a reaction path
similar to that observed earlier in the pyrolysis of analogous monocyclic lac-
tones."
QCHOZ
H
- Hm -2
RHN--
The oxepin epoxide (148) is readily isomerized to (147) under protic con-
ditions, but the epoxide ring can be opened by amine nucleophiles, e.g. to
give (1 49), without significant ring-contraction.=
RCO 0 0 H O
Me
OR
* H
(151)
The sensitized photolysis of (150) proceeded only via a 1,5-acyl shift to
give (1 5 l), which subsequently underwent isomerization of the double bond
to give the more stable isomer (152). This result, in accord with earlier work
on phenyl migration, confirms that [ 1,5] shifts are characteristic in the triplet
excited state of this system.''
Dioxepins. - Two new routes to 1,2-dioxepins have been published; in the
first, the oxidation of the hydroperoxide (153) gives (154) in rather low
85 R. F. C. Brown, F. W. Eastwood, N. Chaichit, B. M . Gatehouse, J . M. Pfeiffer, and

D. Woodroffe, Aust. J. Chem., 1981, 34, 1467.
86 W. H. Rastetter, T. Chancellor, and T. J . Richard, J. Org. Chem., 1982,47, 1509.
'' N. Hoshi and H. Uda, J. Chem. SOC.,Chem. Commun., 1981, 1163.
Seven-Mernbered Ring Systems 409
R-C
H
I/(CH
I
Ph
1
H00-C'3
YH3
I
- Pb(OAcI4
R
CH3 Ph
(10-1 4%) yield,88 while the 3,7-methano-bridged system (1 56) was produced
in ca 70% yield by the reaction of the 1,2-diazepine (1 55) with 90% hydrogen
peroxide at - 78 0C.89
H2°2 ~
Me Me
(155) (156)
Further work on the acid-catalysed rearrangement of 4,5-dihydro-l,3-

dioxepins (1 57) to tetrahydrofuran-3-carbaldehydes(158) and (1 59) has
shown that the reaction is stereoselective and favours the (2)-isomer (158)
under kinetically controlled conditions (ca 8 : 1 at - 78 O C , for the example
shown). At higher temperatures, these isomerize to the more stable (E)-
isomers.g0
Several conformational studies on 1,3-91-93and on 1,4-dioxepinsM have
been reported.
-
H+
OHC
;I
5 Thiepins
In a continuation of recent work on the preparation of stabilized thiepins,
Murata has followed the preparation of (160) with the simpler system (161).
The enhanced stability of (160) was attributed principally to the effect of the
bulk of the t-butyl groups, which disfavours ring-closure to the thianorcara-
H. Kropf and H. van Wallis, Synthesis, 1981, 633.
89 R. M. Wilson and J. W. Rekers, US P. 4 2 9 1 0 5 1 (Chem. Abstr., 1981, 95, 204014).
H. Frauenrath, J. Runsink, and H-D. Scharf, Chem. Ber., 1982, 115, 2728.
91 I, Yavari, Org. Magn. Reson., 1980, 14, 511.
92 G. L. Kamalov, V. E. Kuz'min, V. N. Sharygin, and G . M . Verkhivker, Teor. Eksp.
Khim., 1 9 8 1 , 1 7 , 1 0 9 (Chem. Abstr., 1981,95,6349).
93 R. St-Amour and M . St-Jacques, Can. J. Chem., 1981, 59,2283.
94 D. Menard and M. St-Jacques, Can. J. Chem., 1981, 5 9 , 1160.
( 1 6 0 ) R1= M e , R2= COOEt
( 1 6 1 ) R1= R2= H
diene tautomer, together with a possible contribution by the ester group act-
ing to diminish the anti-aromaticity in the system. Interestingly, however, the
simpler system (161) is the more stable, having a half-life of ca 195 h at
130 "C compared to ca 7 h for (160).95
The 2-methylenethiepin l-oxide (1 64) has been prepared by the thermoly-
sis of (162). A P-elimination produces the sulphenic acid (163), which
cyclizes to give ( 164).96
R
I
R-CrC
But-
\
(CH2>4
/
s\\o
- R-CEC
H\
) \ p 2 ) ,
0-0
- H'cT3 //s
0
(164)
(162) (163)
In a new, general route to cyclic P-oxosulphonium salts, the 3-0x0-
thiepinium perchlorate (166) was prepared by adding the phenylthio-diazo-
ketone (1 65) to perchloric acid in chloroform?'
0
HC10,
ph-6
A high-yielding synthesis of thiepan has been achieved by allowing 1,6-
c lo,
dibromohexane to react with sodium sulphide under concentrated and

heterogeneous condition^.^^
Sulphonium methanides, e.g. (167), which are prepared by the reaction of
thiachroman-4-ones with dimethyl diazomalonate, rearranged in the presence
of base to give 1-benzothiepins, e.g. ( 169).99This reaction parallels the recent
conversion of sulphonylimines into 1,2-benzothiazepines (e.g., see ref. 104).
95 K. Yamamoto, S. Yamazaki, Y. Kohashi, I. Murata, Y. Kai, N. Kanehisa, K. Miki, and
N. Kasai, Tetrahedron Lett,, 1982, 2 3 , 3195.
96 R. Bell, P. D. Cottam, J. Davies, and D. N. Jones, J. Chem. Soc., Perkin Trans. 1 ,
1981,2106.
97 W. T. Flowers, A. M . Freitas, G. Holt, and S. C. Purkiss, J. Chem. SOC.,Perkin Trans.
I , 1981, 1119.
98 A. Singh, A. Mehrotra, and S. L. Regen, Synth. Commun., 1981, 11,409.
99 Y. Tamura, Y. Takebe, C. Mukai, and M . Ikeda, Heterocycles, 1981, 15, 875; J.
Chem. Soc., Perkin Trans. 1 , 1981,2978.
I
E2k- E 2C-
Straightforward syntheses of lenthionine (1,2,3,4,6-pentathiepan)and

1,2,4,6-tetrathiepan from bis-chloromethyl disulphide have been achieved@
.' '
Studies on the crystal structure and conformational analysis of 1,4-
dithiepan"' and on the dynamic behaviour of the l-methyl-l-benzo-
thiepinium system have been reported.lo2
6 Systems containing Two Different Heteroatoms

Oxazepines. - In an unusual reaction, the N-hydroxyphthalimido-ether (1 70)
rearranges (under basic conditions) to give the 1,2-oxazepine derivative (171)
in moderate yield, together with ( 172).lo3
0
OH
0
(170)
A range of 1,3-oxazepines that are fused to 0-lactam rings has been pre-
pared by a free-radical annelation technique. The reaction of (173) with tri-
butyltin hydride generated (1 74), which cyclized predominantly via endo-
addition when R' is H to give, for example, (175) (47%); however, in cases
where R' is a radical-stabilizing group, e.g. C02R or Ph, the alternative ex0
mode was the dominant path, to give, for example, (176) (68%).'04 Similar
cyclizations and substituent effects were observed for analogous acetylenic
substrates . O5
loo I. W. J. Still and G. W. Kutney, Tetrahedron L e t t . , 1981, 22, 1939.

''I W. N. Setzer, G. S. Wilson, and R . S . Glass, Tetrahedron, 1981, 37, 2735.
Io2 H. Hofmann and F. Dickert, 2. Naturforsch., Teil B , 1981, 36, 974.
N. Amlaiky, G. Leclerc, and A. Carpy, J. Org. Chem., 1982, 47, 517.
Io4 M. D. Bachi and C. Hoornaert, Terrahedron Letr., 1981, 22,2689,2693.
M. D. Bachi and C. Hoornaert, Tetrahedron L e t r . , 1982, 23,2505.
Following earlier work on the conversion of azidopyrans and azido-

chromenes into 1,3-oxazepines and 1,3-benzoxazepines, respectively, it has
now been shown that the pyrolysis of 1-azidoisochromenes (177) gives 3,l-
benzoxazepines (1 78) in moderate yield.lW
The course that is taken in reactions of 1,3-oxazolium salts (179) with

stabilized carbanions is strongly dependent on the nature of the substitu-
ents on the carbanion; in some cases, attack at the 2-position leads to 1,4-
oxazepines, e.g. (180).'O'
CN
The unsubstituted pyrrolo[ 1,2-a][4,l]benzoxazepine system (1 83) has

been prepared from (182) by heating or by treatment with phosphorus
pentoxide. The 6-0x0-derivative (1 84) was also prepared from (18 l), by
selective reduction of the aldehyde and cyclization .lo*
I-P. LeRoux, P-L.Desbene, and J-C. Cherton, J. Heterocycl. Chem., 1981, 18, 847.
lo' M. Dreme, P. LePerchec, J. Garapon, and B. Sillion, Tetrahedron Lett., 1 9 8 2 , 2 3 , 7 3 .
108 S. Massa, F. Corelli, and G . Stefancich, J. Heterocycl. Chem., 1981, 829.
Thiazepines. - The full report has now appeared on the preparation of 1,2-
benzothiazepines by the rearrangement of thiochroman-4-one N -
tosyIsulphimides'Og [cf.the preparation of 1-benzothiepins (1 69)].
Irradiation of 3-arylbenzisothiazoles (185) in the presence of alkenes gives

174-benzothiazepines, e.g. (187), in high yield. Several mechanisms are poss-
ible, but it seems likely that the primary process is formation of the biradical
(1 86)."0y"' In a formally similar reaction, 2-phenylbenzothiazole (188) gave
1,s-benzothiazepines (1 89); however, the unsubstituted system was photo-
st able.' l 2
Io9 Y. Tamura, Y. Takebe, S. M. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and

M. Kise, J. Chem. SOC.,Perkin Trans. 1 , 1981 , 1037.
'Io M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 529.
'I1 M . Sindler-Kulyk, D. C. Neckers, and J . R. Blount , Tetrahedron, 1981 , 37, 3377.
'I2 M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 208 1.
R1 R1 R1 R1
The thiyl radicals (1 9 1) react via addition to both ends of the double bond
and also by a rather unusual reaction, involving allylic abstraction, to give the
thiazolidine (190). The proportions of the products were found to be very
sensitive to the experimental condition^."^
The 0-lactam (192) was transformed into the 1,4-benzothiazepine (193) in

quantitative yield by the action of either mild or strong base^."^
RN:cl>.
H
0
H
!
H "COOH kOOH
(194) (195)
( R = L-a-amino-6-adipyl)
Ph
I
Two groups have synthesized the thiazepinone (1 94) and its sulphoxide to
test them as possible intermediates in the biosynthesis of isopenicillin N
(195).1i53116However, neither (194) nor its sulphoxide behaved as substrates
in a cell-free synthetase system from Cephalosporium acremonium. '15
The thiazepinone (196) undergoes an interesting photorearrangement in
which ring-contraction is accompanied by a 1,2-shift of chlorine."'
M. Kaafarani, M. P. Crozet, and J-M. Suzur, Bull. SOC.Chim. Fr., Part 2 , 1981,449.
'14 L. Fodor, I. Szabo, G . Bernath, L. Phrkhnyi, and P. Sohhr, Tetrahedron Lett., 1981,
2 2 , 5077.
'I5 G . Bahadur, J . E. Baldwin, T. Wan, M. Jung, E. P. Abraham, J. A. Huddleston, and
R. L. White, J. Chem. Soc., Chem. Commun., 1981, 1146.
S. Wolfe, R. J. Bowers, S. K. Hasan, and P. M. Kazmaier, Can. J. Chem., 1981, 59,
406.
117
H. Wamhoff and W. Kleimann, J . Chem. Soc., Chem. Commun., 1981,743.
7 Systems containing Three Heteroatoms
(Ary1azo)anils that have a free ortho-position, e.g. (197; R = H), are known
to cyclize to give benzotriazines; however, it has now been shown that, when
R is methyl, the reaction takes a different path to give the 1,3,4-benzo-
triazepine (199) in high yield, probably via (198)."'
1 L
Ph
(198)
( E = COOMe)
The lH-1,2,4-triazepine (200) has been prepared, in > 90% yield, by the
reaction between diphenylnitrilimine and tetrachlorocyclopropene.119
c1 c1 c1
-c1 n
(200)
A recent report on the synthesis of 1,3,4-benzotriazepin-S-ones

(202), via
the reaction of o-aminobenzoylhydrazine with isothocyanates and sub-
sequent treatment with DCCD, has now been shown to be in error. An
unequivocal alternative synthesis has shown that the products are the
oxadiazoles (2O1).l2O
NN
- 0 0
II
a c - NH2
2 Jt)
\
&oJmR*zl
m2
(201)
The 1,3,4-benzoxadiazepine salt (204) has been simply prepared by treat-

ment of the hydrazone (203) with perchloric acid in acetic anhydride.l2'
The 1,3,4-thiadiazepinethione(205) has been isolated as purple needles
from the reaction of dehydrodithizone with diphenylcyclopropenethione.122
R. Fusco and F. Sannicolo, Tetrahedron Letr., 1982, 23, 1829.
M. L. Deem, Synthesis, 1981, 322.
120 S. Sunder, N. P. Peet, and R. J. Barbuch, J. Hererocycl. Chem., 1981, 18, 1601.
V. I. Fomenko and A. I. Fomenko, Izv. Vyssh. Uchebn. Zaved., Khim. Khim.
Tekhnol., 1981, 24,1469 (Chem. Abstr., 1982,96, 199 645).
''' K. T. Potts, A. J. Elliot, G . R . Titus, D. Al-Hilal, P. E. Lindley, G. V. Boyd, and
T. Norris, J. Chem. Soc., Perkin Trans. I , 1981, 2692.
PhN X N P h
I; \I
“\.As
+ +
Ph
S
S-
The ‘4,7-lactams’, e.g. (206) and (207), which are easily functionalized via
metallation at the position (Y to the carbonyl, are important precursors in the
synthesis of pen ern^.'^^ The preparation of chiral (206) from 6-amino-
penicillanic acid and of chiral (207) from 4-acetoxyazetidinone have been
described .12‘-
The iodomethyl sulphide (208), obtained from a penicillin precursor, has

been converted into 3,1,6-oxathiazepine azetidinone (209) by treatment with
base and into the 1,3,6-dithiazepine (210) by the reaction of its mesyl ester
with hydrogen sulphide and trieth~1amine.l~’
S-CH21
E Me
E Me
(209) (210)
(208) 2
(E = COOR )
123 H. R. Pfaendler, in ‘Recent Advances in the Chemistry of @-LactamAntibiotics’, ed.

G. I. Gregory, Royal Society of Chemistry Special Publication No. 38, 1981, p. 368.
124 A. Crugnola, A. Longo, F. Casabuona, and P. Lombardi, Tetrahedron Lett., 1981, 2 2 ,
4141,4145
12’ D. 0. Spry, Tetrahedron Lett., 1981, 2 2 , 3695.
Ph
3
OH o-soz
The addition of sulphene to N-benzylidene-2-hydroxyanilines,e.g. (2 1 l ) ,

gives an unstable adduct (212), which rearranges to give the 1,2,5-benzoxa-
thiazepine (2 13).'26
Thioacyl isocyanates react with 2-bromoethanol to give urethanes (2 15),

which generally react with base to give oxazolidinones (214); however, when
R is t-butyl, the 1,5,3-oxathiazepinone (216) is obtained in 60% yield.127
M. Rai and B. Kaur, J. Chem. SOC.,Chem. Commun.,1981,971,

127 K. Nandi and J . Goerdeler, Chem. Ber., 1981, 114, 1972.
Eight-Membered and Larger Ring Systems
BY J. M. E. QUIRKE
1 Eigh &MemberedRings
One Heteroatom. - Azocine derivatives have been synthesized by a variety of
ring-opening reactions. The /?-lactam carboxylic acid (1) rearranges in H2S04
to form the azocine (2).l
The reaction between the tricyclic oxaziridine (3) and iron(I1) sulphate
opens up an efficient route to a variety of eight- and nine-membered oxo-
lactams, e.g. (4).2 There have been several reports of ring-expansions with
- ~ the tetrahydropyridine ( 5 ) reacts with methyl acetylene-
a l k y n e ~ . ~Thus
carboxylate to give (6). The reaction is thought to occur via the cyclobutene
intermediate .3
0
Me
7QCHPh( Y MOe N H 2
Me Me
01,.
Me
(4) (5)
H. W. Janssen, S. Mohr, and A. Mondon, Chem. Ber., 1981, 114,2158.

D. St C. Black and L. M. Johnstone, Angew. Chem.. I n r . Ed. Engl., 1981, 20, 670.
R. M. Acheson and G. Paglietti, J. Chem. Res. ( S ) , 1981, 306.
H. Takahata, A. Tomiguchi, and T. Yamazaki, Heterocycles, 1981, 16, 1569.
’ N. Kawahara, T. Nakajima, T. Itoh, and H. Ogura, Hererocycles, 1981, 16,729.
419
The first eight-membered cyclic ketenimine (7) was synthesized as a mix-

ture of two diastereoisomers, which interconvert through inversion.6 Tetra-
and hexa-hydroazocin-2(1H)-ones that bear a halogen substituent at position
3 undergo dehydrohalogenation rather than substitution reactions. This has
been attributed to conformational effects.' The azocine anion (8) underwent
thermal ring-closure to give the bicyclic anion (9). The ease of rearrangement
of (8) shows that it lacks the stability associated wi,ih aromatic systems.'
1
The first synthesis of 6H-dibenzo[b,f oxocin (10) was accomplished via
the intramolecular Wittig reaction of (1 1).
- 4nl
0
i
( H2C=CHCH2)
II
0
Reagents: i, BH,Cl. Me,S, CHC1,OMe (12)
Scheme 1
A facile one-pot synthesis of 1-thiacyclo-octan-5-one1-oxide (1 2) has been

reported (Scheme l)." The sulphoxide (1 3) reacts with butyl-lithium to form
the bicyclic product (14)." This is a novel nucleophilic addition to an inacti-
vated double bond, 0
'
Me +* @
Me ( 1 3 ) Me Me H
(14)
J . Fhl, K. Schink, and W. Kosbahn, Chem. L e t t . , 1981, 527.
D. D. Ridley and G. W. Simpson, Aust. J. Chem., 1981, 34, 569.
A. G. Anastassiou, H. S. Kasmai, and D. Hauger, J. Chem. Soc., Chem. Commun.,
1981,647.
B. Begasse and M. LeCorre, Synthesis, 1981, 197.
l o M. E. Garst and J. N. Bonfiglio,Synth. Commun., 1 9 8 1 , 1 1 , 2 3 1 .
V. Cere, C. Paolucci, S. Pollicino, E. Sandri, and A. Fava, J. Chem. SOC., Chem.
Commun., 1981,764.
Eight-Membered and Larger Ring Systems 42 1
Two Heteroatoms. - The reaction between the dianils (15) and 1,4-
dichlorobutane provides a convenient route to the substituted 1,4-diazocines
( 16).12 Similarly, (1 7 ) reacts readily with 1,3-diarylbenzo[c]furansto give the
cyclo-adduct (1 8), which undergoes thermal rearrangement to the 2H-
benzimidazole (1 9).13 The new 1,5-benzodiazocine ring system (20) was pre-
pared by cyclization of (21), on heating with S0Cl2 in t01uene.l~Magnetic
circular dichroism studies' on 1,4-dihydro-1,4-diazocine and the 1,4-dimethyl-
and 1,4-di(methoxycarbonyl)-derivativesprovide further evidence of the loss
of aromatic character in 1,4-diazocines with electron-attracting substituents.
COMe
(19) (20) (21)
3,7-Dimethyl-3,7-diazabicyclo[3.3.1 Inonane was analysed by photo-

electron spectroscopy and it was shown to occur in the chair-chair confor-
mation. MNDO calculations on the compound indicate that, in the chair-
chair conformation, the N-N interaction is mainly through space.16 Proton
affinities and ionization energies were determined, by photoelectron spectros-
copy, for a series of six bicyclic amines and diamine~.'~The radical cation of
(22) was very long-lived, and is presumed to be stabilized by three-electron
a-bonding interactions.
n
l2 G . Singh and K. N. Mehrotra, Hererocycles, 1981, 16, 1341.
l3 W. Friedrichsen, M . Roehe, and T. Debaerdemaeker, 2. Nururforsch., Teil. B , 1981,
36,632.
l4 E. Aiello, G . Dattolo, G. Cirrincione, A. M. Almerico, and I. D'Asdia, J. Heterocycl.
Chem., 1981,18,1153.
Is J . W. Waluk, E. Vogel, and J . Michl, J. Org. Chem., 1981, 46, 3306.
l6 P. Livant, K. A. Roberts, M. D. Eggers, and S. D. Worley, Terruhedron, 1981, 37,
1853.
I' R . W. Alder, R. J . Arrowsmith, A. Casson, R. B. Sessions, E. Heilbronner, B. Kovac,
H. Huber, and M. Taagepera, J. Am. Chem. SOC.,1981,103,6137.
A new heterocyclic system (23) has been synthesized from ring-cleavage of

the dioxepin (24), followed by isomerization of the 7,8-dihydrodioxocin
derivative and Diels-Alder cyclization of the product with 2,3-dimethylbuta-
1,3-diene.'* A novel fluorinated benzo-heterocycle (25) was synthesized from
salicylic acid and perfluor0-2-methylpent-l-ene.'~
1,5Dithiacyclo-octane and its 1-oxide derivative are very easily oxidized
and reduced, respectively.20 These compounds are useful models for bio-
chemical proton- and electron-transfer reactions. The speed of the reactions
is attributed to intramolecular catalysis by the transannular thioether group.
Nuclear magnetic resonance and mass spectrometric studies on the novel
ring system (26) indicate that there is intramolecular co-ordination between
the phosphorus and tin atoms.21
The reaction between the bicyclic ozonide (27) and hydrogen peroxide
yields the [5.3.1] bicyclic structure (28), which was investigated by X-ray
crystallography. The eight-membered ring was shown to occur in the boat-
chair conforma tion .22
2 Nine- and Ten-Membered Heterocycles

The piperidine (29) undergoes a thermal [2,3] sigmatropic rearrangement to
give (30).23 Bicyclic amidines are partially hydrolysed by aqueous KOH to
give the corresponding ring-enlarged lactam ?4
A new method for the synthesis of medium-ring lactones from cyclic
sulphide precursors has been reported.25 The thiolo-lactone (3 1) rearranges
'*H. Jendralla,Chem. Ber., 1982, 115,201.

l9 N. Ishikawa, T. Kitazume, K. Chino, and E. -S. Mustafa, J. Fluorine Chem., 1981, 18,
447.
'O , I . T. Doi and W. K. Musker, J. Am. Chem. SOC.,1981,103, 1159.
21 A. Tzschach and W. Uhlig, Z. Anorg. Allg. Chem., 1981, 475,251.
'' K. I, McCullough, M. D. Walkinshaw, and M. Nojima, J. Chem. Res. (S), 1981, 369.
23 T. Tsuchiya and H. Sashida, Chem. Pharm. Bull., 1981,29, 1887.
24
C. Heidelberger, A. Guggisberg, E. Stephanou, and M. Hesse, Helv. Chim. A c t a , 1981,
64,399.
25 E. Vedejs and D. W. Powell, J. Am. Chem. SOC.,1982,104,2046.
Eight-Membered and Larger Ring Systems 423
Me' 'NCOOEt
N-N
via an S to 0 acyl-transfer process, on treatment with camphorsulphonic acid,

to form (32). The reaction has been successfully effected with a variety of
hydroxyalkyl thiolo-lactones.
A four-carbon cyclo-enlargement of the cyclic thioketal(33) by a [4 -t 21
cycloaddition with dichloroketen yields the 1,4-dithia-derivative (34).26 This
is a potentially valuable route to many multifunctional dithia-macrocyclic
systems.
MeP HS
Me 5(33)
Me
Treatment of Br(CH2),Br with Na2S under heterogeneous conditions

yields the appropriate thia~ycloalkane.~'Similarly, the oxidative cyclization
(34)
of the dithiol HS(CH2)mX(CH2)nSH (X = 0, C H 2 , or S ) with iodine yields

the corresponding medium-ring disulphide .28 A general synthesis of medium-
ring and macrocyclic disulphides and a variety of dithia-crown ethers has been
devised, using caesium dithiolates as starting materials [reaction (l)].29
-S( c h a i n a ) S -
Cs+ CS+
+ Br(chain b)Br -DM?? FS>
(chain a)
b) (chain (1)
3 Macrocycles Other than Crown Ethers

Systems containing Nitrogen as the only Heteroatom. - The aza[ 18lannulene
(35) has been synthesized by photolysis of (36) at - 80 0C.30a Aza[l4]-
annulenes have been prepared by the same route.30b An efficient route to
16
ai
6. Rosini, G. G. Spineti, E. Foresti, and G. Pradella, J. Org. Chem., 1981, 46,2228.
A. Singh, A.Mehrotra, and S. L. Regen, Synth. Commun., 1981, 11,409.
'* M. H. Goodrow and W. K. Musker, Synthesis, 1981,457.
'' J. Buter and R. M. Kellogg, J. 0%.Chem., 1981,46,4481.
'* (a) W.Gilb and G. Schroder, Chem. Ber., 1982, 115, 240; ( b ) H. Rottele and
G. Shroder ibid., p. 248.
n
macrocyclic lactams bearing three nitrogen atoms was reported in a synthesis

of celacinnine alkaloids. The triamino-ester (37) reacted with tris(dimethy1-
amino)borane to give (38), which readily cyclized to the desired l a ~ t a m . ~ ~
Covalent silicon templates have proved valuable in the synthesis of macro-
cyclic amides. Thus, treatment of the 1,3,2-diazasilolidines (39) with
ClOC(CH2)n COC1, or with other activated derivatives of carboxylic acids,
gave the amide (40).32
COOE t
n
RN, ,NR
(37)
u
N’ “H
(38)
OEt
Si
(39)
Me2
Macrocyclic polyamines are assuming a role of increasing importance as

models for biological systems Fifteen- to eighteen-membered macrocycles
that bear four to six amine moieties form stable 1 : 1 complexes with
inorganic phosphates, AMP, ADP, and ATP,33 and the macrocicles play a
valuable role in the study of the binding of phosphate in vivo. The com-
31 H. Yamamoto and K. Maruoka, J. Am. Chem. SOC.,1981,103,6133.

” E. Schwartz and A. Shanzer, J. Chem. SOC.,Chem. Commun., 1981,634.
33 E. Kimura, M. Kodama, and T. Yatsunami,J. Am. Chem. SOC., 1982,104,3182.
(41)
pounds also form ternary complexes with Mg2+- and Ca2+-nucleotide com-
plexes. Some polyamino-macrocycles have the intriguing property of com-
plexing with two transition-metal atoms, and have unique structure and
chemical and physical properties. The binucleating macrocycle (41) forms a
monohydroxy-bridged dicopper(I1) complex which seems to be stable from
pH 6 to pH 1 1. Spectroscopic studies on the compound gave circumstantial
evidence for the presence of a similar bridged copper system in oxyhaemo-
cyanin .34 The spherically shaped 32-membered ring (42) binds strongly with
cyclohexane, whilst methylcyclohexane and benzene are not so well
retained?'
A general route to tri- and hem-aza-macrocycles has been reported, using

monotosylated ethylenediamine with N-tosyla~iridine.~~ The product was
treated with benzoyl chloride, and was converted into the disodium salt. The
cyclization was effected by reaction with bisulphonate esters. Hexa-aza-
macrocycles have also been prepared by condensing disulphonamide salts of
the tritosylated diethylenetriamine with disulphonate esters.37
There have been further developments in the study of 'octopus' cyclo-
phanes as models for enzymes, schematically shown in (43). Thus (44) incor-
porates not only uncharged hydrophobic, spin-labelled, and fluorescent
probes, but also anionic compounds, including bulky dyes. It may selectively
catalyse the hydrolysis of p-nitrophenyl carboxylates that bear long alkyl
chains. The tricyclic lactam (45) exists in solution as slowly ring-inverting
34 P. K. Coughlin and S. J . Lippard, J. Am. Chem. SOC.,1981, 103, 3228.
3s F. Vdgtle and W. M. Muller, Angew. Chem., Int. Ed. Engl., 1982, 21, 147.
( a ) A. E. Martin, T. M . Ford, and J. E. Bulkowski, J. Org. Chem., 1982, 47, 412;
(b) A. E. Martin and J. E. Bulkowski, ibid., p. 41 5 .
'
3 Y. Murakami, A. Nakano, K. Akiyoshi, and K. Fukuya, J. Chem. SOC., Perkin
Trans. I , 1981,2800.
426 Heterocyclic Chem is try
0
o y &\ f l
(43)
X = bound s u b s t r a t e
0
+
( 4 4 ) R = e. g. , ( CH2)10NMe3 I-
(45) R 1=. M e , R2= CH2Ph
enantiomeric helical conformations, which undergo spontaneous resolution

when crystallized, as the 1: 1 adduct, from toluene.38
The phosphonium fluoride (46) is the first example of a phosphonium salt
that contains an ionic fluoride?' The compound has considerable potential as
a fluorinating reagent
38 S. J . Edge, W. D. Ollis, J . S. Stephanatou, and J . F. Stoddart, Tetrahedron Let t .,

1981,22,2229.
39 J . E. Richman and R. B. Flay, J. A m . Chem. SOC., 1981, 103, 5265.
Systems containing Sulphur as the only Heteroatom. - A variety of sulphur-
containing cyclophanes were synthesized by the dilution principle, using an
improved apparatus.w The equipment will prove valuable in the preparation
of many macrocyclic systems. The iron-catalysed reaction between bis-(2,4-
dimethoxyphenyl) sulphide and S2C12 gave four macrocyclic systems, includ-
ing (47).41 The formation of (47) occurs by the unusual electrophilic cleavage
of C-arvl-S bonds.
Systems containing Oxygen as the only Heteroatom. - Syntheses of Macro-

cyclic Lactones. Macrolides have been synthesized, in good to excellent
yields, from w-hydroxyalkanoic acids by tri-phase catalysis, using a 1% poly-
styrene gel; the reaction occurs via the mesylate?2 In another approach, to
avoid highdilution cyclizations, w-hydroxyalkanoic acids were treated with
toluene-p-sulphonic acid in a micro-emulstion of water, propan-2-01, and
toluene to give the lactone. This is the first example of the use of micro-
emulsions as a medium for chemical ~ynthesis.4~ The reaction of caesium
carbonate with an w-haloalkanoic acid in dimet hylformamide provides an
efficient route to macrocyclic lactones. The reaction proceeds via a S N 2
mechanism, and the efficiency of the caesium has been attributed, in part, to
its large size and the resultant low ratio of charge to surface area.@
Activated carboxyl moieties have also been used to effect cyclizations.
1-Phenyl-2-tetrazoline-5-thione undergoes reaction with t -butyl isocyanide to
give a mixture of the corresponding thioformimidate and formamidine, which
react in turn with the carboxylic acid to form (48) and (49). Such com-
pounds are very powerful acylating agents, and readily cyclize to give the
lactone?’ 2(w-Hydroxyalkyl)-4,5-diphenyloxazoles can be considered as
masked activated carboxyl groups. Photo-oxidation of such oxazoles prob-
ably occurs via the unstable 2,5-endoperoxide derivative, which undergoes
rearrangement through an imino-anhydride to yield the triamide (SO), which
undergoes selective intramolecular nucleophilic attack at the acyl carbonyl
40
S. Karbach, W. Lohr, and F. Vogtle, J. Chem. Res. ( S ) , 1981,314.
41 F. Bottino and S. Pappalardo, J. Chem. SOC.,Perkin Trans. 1 , 1981,718.
42 S. L. Regen and Y . Kimura, J. A m . Chem. SOC., 1982,104,2064.
43 A. Gonzalez and S. L. Holt, J. Org. Chem., 1981,46,2594.
44 W.H.Kruizinga and R. M. Kellogg, J. A m . Chem. SOC.,1981, 103,5183.
45 U. Schmidt and M. Dietsche, Angew. Chem., Inr. Ed. Engl., 1981,2 0 , 771.
that is derived from the 2-position of the oxazole.46 The method has been
successfully used in the synthesis of derivatives of crown ethers.
Lactones have also been synthesized from the rearrangement of cyclic
compounds. Thus (5 1 ) undergoes base-catalysed isomerization and reduction
to form the phenylsulphonyl lactone. The sulphone group is reductively
cleaved with sodium amalgam and Na2HP04 to form the lactone?’
A novel series of lactones was synthesized by condensation of propiolac-
tones to form the macrocyclic lactones (52), using the cyclic tin-oxygen
compound (53) as a template.48
OH
0
n 0
I
R2Sn
I
SnR2
I
0 0
I
!302Ph W
(51) ( 5 3 ) R = C4H9
Other Oxygen-containing Derivatives. Acetone and furan condense in an

acidic medium to form (54):’ The yield is increased by the addition of metal
salts, e.g. LiC104. The increase has been attributed to acidity (pH) effects
rather than to effects of metal ion templates. This is the first demonstration
of the importance of the effects of pH in metal-assisted cyclizations. Com-
pound (54) is cleaved by m-chloroperoxybenzoic acid to form the novel
~ ~ endoperoxide (56)
octaketone ( 5 5 ) , with a cis-enedione c o n f i g u r a t i ~ n .The
is converted into a bis-epoxide on treatment with catalytic amounts of
cobalt(@ 5 ,10,15,20-tetraphenylporphine at - 10 ‘C, and the epoxide
rearranges to ( 5 7 ) at 20 O C . ’ ~
(a) H. H. Wasserman, R. J . Gambale, and M. J. Pulwer, Tetrahedron, 1981, 37, 4059;

( b ) H. H. Wasserman, R. J. Gambale, and M. J . Pulwer, Tetrahedron Let t ., 1981, 2 2 ,
1737.
47
V . Bhat and R. C. Cookson, J. Chem. SOC.,Chem. Commun., 1981,1123.
48 A. Shanzer, J. Libman, and F. Frolow, J. A m . Chem Soc., 1981, 103,7339.
49 M. Healy and A. J . Rest, J. Chem. Soc.. Chem. Commun., 1981, 149.
I. Erden, P. Golitz, R. Nlder, and A. de Meijere, Angew. Chem., Int. Ed. Engl., 1981,
20, 583.
P. D. Williams and E. LeGoff, J. Ow. Chem., 1981,46,4143.
Me Me
Me Me
Me Me
(54) (55)
(56) (57)
Other Macrocyclic Systems. The first synthesis of crown arsanes (58), which
are air-stable, and which should prove useful in chelating transition metals,
~ novel fourteen-membered rings (59) are of interest
has been r e p ~ r t e d . ’The
because of their potential in chelating metals.53
(58) I-, = 1, 2 , or 4
(59) x = 0, S, NMe, or PPh
4 Crown Ethers and Related Compounds

There have been two books published on the crown including a
two-volume work by Patai.
Synthesis of Crown Ethers. - The fundamental approach to the syntheses
(cyclization by nucleophilic substitution of the separate halves of the ring)
remains unchanged. The metal-catalysed cyclization of (60) to form benzo-
52 J. Ennen and T. Kauffmann, Angew. Chem., In?.Ed. Engl., 1981, 2 0 , 118.
53 E. P. Kyba, R. E. Davis, C. W. Hudson, A. M. John, S. B. Brown, M. J . McPhaul,
L-K.Liu, and A. C. Glover, J. A m . Chem. SOC., 1981 , 103, 3868.
’* ‘The Chemistry of Ethers, Crown Ethers, Hydroxyl Groups and their Sulphur
Analogues’, ed. S. Patai, Wiley, Chichester, 1980, Vols. 1 and 2.
55 6 Topics in Current Chemistry’, Springer Verlag, New York, 1981, Vol. 9 8 .
430 Heterocyclic Chemis try
0
a: :D R&2
O( CH2)3COOEt
O( CH2) 3COOEt
0
(60) (61) R1= R 3 = H ,
R2= R 4 = COOE t
2 4
or R'= R 3= COOEt, R = R = H
18-crown4 has been studied, and the catalytic effects of both alkali-metal
and alkaline-earth cations in methanol have been mea~ured.'~The observed
acceleration ranged from 13.2 for Cs' to 540 for Sr2+. The differences in
catalytic effect were attributed to a combination of the proximity of the
reactive ends of (60) and the extent of interaction between the cation and
the oxide anion. Similar template effects were observed in the condensation
of diethyl malonate and ethylene glycol to give 1,4,8,1 l-tetraoxacyclotetra-
de~ane-5,7,12,14-tetraone.~~
The crown ethers (61) have been synthesized by a novel Dieckmann con-
densation of the diester (62) under high d i l ~ t i o n . ' The
~ ester and ketone
groups are readily removed.
A number of intriguing crown ethers have been prepared by conventional
routes, including a derivative of 18-crown-6 that bears a trans double bonds9
and the first 'crowned' redox system (63).60 The hydroxylated crown ethers
(64) are prepared by condensation of epichlorohydrin with diphenols.6' The
hydroxyl substituent plays a valuable role in binding crown ethers to poly-
mers and in linking crown ethers together; e.g., (66) was formed by conden-
sation of the hydroxymethyl crown ether (65) with substituted malonic
esters.62 A direct approach to 0x0-crown ethers has been devised [reaction
56 G. Ercolani, L. Mandolini, and B. Masci, J. A m . Chem. SOC.,1981, 1 0 3 , 2 7 8 0 .

57 B. Thulin and F. Vogtle, J. Chem. Res. ( S ) , 1981, 256.
58
J . H. P. Tyman, J . Grundy, and G. R. Brown, J. Chem. SOC., Perkin Trans. I , 1981,
336.
59 A. Merz, M . Eichner, and R . Tomahogh, Tetrahedron Lett., 1981, 22, 1319.
'* K. Sugihara, H. Kamiya, M . Yamaguchi, T. Kaneda, and S. Misumi, Tetrahedron
Lett., 1981, 22, 1619.
61
G. S. Heo, R . A. Bartsch, L. L. Schlobohm, and J. G. Lee, J. Org. Chem., 1981, 46,
3574.
62 I. Ikeda, T. Katayama, M. Okahara, and T. Shono, Tetrahedron Lett., 1981, 22, 3615.
Eight-Membered and Larger Ring Systems 43 1
ixJ-
( 6 4 ) X = e.g., (CH2CH2)20 or (CH2)3
0 Et 0
n /+0-"-s,"-**
(2)].63The replacement of ethereal oxygen atoms by carbonyls is important

in developing synthetic ionophores. Monoaza-crown ethers may be readily
synthesized from ClCH2(CH20CH2)nCH2CI and HO(CH2)2NH(CH2)20H in
the presence of ButONa.@
HO( CH20CH2) CH20H

Y
+ (2)
N2CHCO( CH2)xCOCHN2
4(Jo
0
CH2)
Efficient methods for the isolation and purification of crown ethers by

complexing with alkaline-earth salts6'' or with non-ionic compounds65b have
been reported. These methods allow the purification of 18-crown-6 without
the need for potentially hazardous distillations. Barium methanedisulphonate
is the best salt, and nitromethane the best non-ionic reagent, for purification
of 18-crown-6.
63 S. Kulkowit and M . A. McKervey, J. Chem. SOC.,Chem. Commun., 1981,616.
64 H . Maeda, Y. Nakatsuji, and M. Okahara, J. Chem. SOC., Chem. Commun., 1981,471.
65
( a ) F. de Jong, D. N. Reinhoudt, A. van Zon, G. J . Torny, and E. M. van de
Vondervoort, Recl. Trav. Chim. Pays-Bas, 1981, 100,449; ( b ) A. van Zon, F. de Jong,
D. N. Reinhoudt, G . J. Torny and Y. Onwezen, ibid., p. 4 5 3 .
Reactions of Crown Ethers. - Irradiation of the unsaturated crown ether (67)

in benzene, containing catalytic amounts of iodine, and with oxygen bubbling
through the solution, gave (68) in 5040% yield.66 There were no products
arising from intramolecular [ 2 + 21 cyclization of the two alkene moieties in
n
(68)
(69)
the crown. The macrocyclic lactone (69) was formed from the reaction of
2,5-furo-18-crown-6 with singlet oxygen via the intermediate 0zonide.6~The
mode of opening of the furan is in marked contrast to that of 2,s-dimethyl-
furan, which forms a hydroperoxide under similar conditions. 3,4-
Diaminobenzo-15-crown-5 reacts with EtOCH=CCHMe,CHO to form (70),
66 M. Eichner and A. Merz, Tetrahedron Lett., 1981, 22,1315.

61
B. L. Ferringa, Tetrahedron Lett., 1981, 22, 1443.
Eigh t-Mem bered and Larger Ring Systems 433
y (71) R = H ; n = 1
( 7 2 ) R = Me3C; n = 2
which acts as a double ionophore, with the ability to bind Ni" (or Co') and
Na' (or K') ions.68
There have been a series of publications on photoresponsive crown ethers
by Shinkai and co-workers. These compounds, e.g. (71), exhibit photo-
induced cis-trans isomerism. In the cis form, the crowns are eclipsed, whilst
in the trans form they are well separated. For this reason, the compounds
have been called 'butterfly' ethers. Their large geometrical change, and the
good reversibility of that change, make such compounds good candidates to
act as photoantennae. The presence of two t-butyl groups in the 2- and 2'-
positions (72)69 reduces the sizes of the cavities of the crowns, probably due
to steric repulsion of the alkyl groups. Isomerization to the cis form occurs
on irradiating with U.V. light, and the concentration of the cis-isomer of (72)
is enhanced by the presence of caesium ions, which can bind to both crown
rings.
In a similar way, crown ethers bearing a photoresponsive anionic cap have
been synthesized. The cis form (73) extracts sodium and calcium ions more
efficiently than the trans form. This increase has been attributed to aaintra-
NO,
(73) R = (CH2l3CH3
R. Kruse and E. Breitmaier, Chem. Ber., 1981, 114,832.

69
S. Shinkai, T. Ogawa, Y. Kusano, 0. Manabe, K. Kikukawa, T. Goto, and T. Matsuda,
J. Am. Chem. SOC.,1982,104,1960.
434 Heterocyclic Chem is try
molecular complex between both the phenoxide anion, and the crown, with
the metal ion. Calcium ions may be transported across a liquid membrane
by using this crown, under a countercurrent of proton fluxes and irradiation
by U.V. light.70
The crown ether (74) has been used to determine the mode of cis to trans
isomerization of derivatives of azobenzene. The process occurs via an inver-
sion mechanism rather than a rotation mechanism, as was shown by the small
effect of pressure on the course of the reaction.71 The azo system (75) also
photaisomerizes by inversion; in this case, steric factors exclude the possibil-
ity of a rotation mechanism.n
Applications of Crown Ethers in Organic Synthesis. - The first selective CH-

insertion of aryl-halocarbenes has been reported.73 The free carbene, gener-
ated in situ from PhCHC12, ButO- K', and 18-crown-6, reacts with (76) to
give (77). Aryl diazo-cyanides are readily formed from the diazonium tetra-
fluoroborates with KCN and 18-crown-6. The cyanides undergo [2 + 41
M M
ee & k
(76) R = H
(77) R = PhCHCl
70
S. Shinkai, T. Minami, Y. Kusano, and 0. Manabe, J, A m . Chem. SOC., 1982, 104,
1967.
" T. Asano, T. Okada, S. Shinkai, K. Shigematsu, Y. Kusano, and 0. Manabe, J. A m .
Chem. SOC.,,1981,103,5161.
72
H. Rauz and E. Luddecke, J. A m . Chem. SOC.,1982,104, 1616.
73 K. Steinbeck and J. Klein, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 7 7 3 .
Eigh t-Mem bered and Larger Ring Systems 43 5
cycloadditions with 1,3- d i e n e ~ Dicyclohexyl-18-crown-6
.~~ plays a valuable
role in reductions of alkyl fluorides by dissolving metals.75 The reaction is
particularly efficient when it is effected in toluene and when Na-K alloy is
used. Nearly quantitative yields of trans-alkenes have been produced from the
Wadsworth-Emmons modification of the Wittig reaction when the phosphon-
ate anion is generated from 15-crown-5 and sodium hydride at 0-25 0C.76
This route enables the preparation of heterocyclic stilbene analogues which
were produced in low yields by previous methods. The superoxide radical
anion has been chemically generated from potassium superoxide, using
dicyclo hexyl-18-crown-6 .77
0
(79) (80)
Anions from the Schiffs base (78) can be C- or N-alkylated with ethyl
iodide or diethyl sulphate. The ratio of the products depends both on the
solvent and on the presence of 18-cr0wn-6.~~ In non-polar solvents, the crown
ether increases the solubility of the base, and C-alkylation is the major path-
way. In dipolar aprotic solvents, the 18-crown-6 breaks up ion pairs by sol-
vation of the Na' cation, and favours N-alkylation. A nerylsulphonamide,
formed from (79), undergoes regiospecific reductive desulphonylation to give
nerol which implies that (79) is an effective synthon for cisoid iso-
prenoids. Chiral complexes of crown ethers, e.g, (Ell), catalyse the Michael
addition reaction of P-keto-esters and methyl vinyl ketone to give adducts in
high optical yields."
74
M. F. Ahern, A. Leopold, J . R. Beadle, and G . W. Gokel, J, A m . Chem. Soc., 1982,
104, 548.
75
T. Ohsawa, T. Takagaki, A. Haneda, and T. Oishi, Tetrahedron Letr., 1981, 22, 2583.
76
R. Baker and R. J . Sims, Synthesis, 1981, 117.
77
G. W. Ruddock, J . A. Raleigh, and C. L. Greenstock, Biochem. Biophys. Res. Com-
mun., 1981,102, 554.
78
S . Akabori, M. Ohtomi, K. Shimada, and A. Takemura, Bull. Chem. SOC.Jpn., 1981,
54,1273.
79
A. M . Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Angew. Chem., In?. Ed.
Engl., 1981, 20, 1057.
80
D. J . Cram and G . D. Y. Sogah, J. Chem. SOC.,Chem. Commun., 1981, 6 2 5 .
The formation of macrolides from w-alkoxy-thioester derivatives of crown

ethers (82) and ButO- K+ has been studied. The role of the crown ether is to
provide stabilization of the transition state for the attack of the alkoxide ion
on the carbonyl group of the thioester by placing the carbonyl oxygen
adjacent to the complexed K+ ion.81
Immobilized derivatives of 18-crown-6 are efficient catalysts for the
preparation of cyanoalkanes from the bromo-derivatives.82
The bicyclic crown ether (83) shows allosteric effects.83 Thus the rate of
binding of the second Hg"(CN), to the molecule is ten times faster than the
rate of binding of the first Hg''(CN), group. The study suggests that, for
systems with less flexible subunits, allosteric effects may be even more
marked.
(83)
W. H. Rastetter and D. P. Phillion, J. Org. Chem., 1981,46,3209.
A.van Zon, F. de Jong, and Y. Onwezen, R e d . Trav. Chim. Pays-Bas,1981, 100,
429.
J. Rebek, Jr., R. V . Wattley, T. Costello, R. Gadwood, and L. Marshall, Angew.
Chem., Int. Ed. Engl., 1981,20,605.
( 8 5 ) R = 4-MeC6H4S02
Synthesis of Cryptands and Other Polycyclic Systems. - A general strategy

for the synthesis of spherical macrotricyclic ligands has been devised by Lehn
and co-workers.w In a sequence of unambiguous steps, the macrocyclic,
macrobicyclic, and macrotricyclic ligands are formed. The rings are pro-
duced by coupling one component, bearing two terminal acid chloride groups,
to a component that contains two amine moieties. The spherical cryptand
(84) has been formed in this way.85 Similar techniques have been used to pre-
pare a new class of compounds - bridged cylindrical macrotetracycles. Thus
(85) was condensed with the dichloride of naphthalene-2,6-dicarboxylicacid
to give a tricyclic compound. Removal of the protecting group and a third
condensation produced the tetracyclic species (86). Other cylindrical hosts,
composed of crown ether rings fused by an ethylene unit, have been prepared
by the high-dilution cyclization of the diol ditosylate (87).86
( 8 6 ) R = -Ch2
84 E. Graf and J.-M. Lehn, Helv. Chim. Acm, 1981, 64, 1040.
F. Kotzyba-Hilbert, J.-M. Lehn, and K. Saigo, J. Am. Chem. SOC., 1981, 103, 4266.
'' D. M. Walba, R. M. Richards, S. P. Shenvood, and R. C. Haltiwanger, J. A m . Chem.
SOC.,1981, 103,621 3.
An improved route to [l.l.l]cryptand has been reported in which the

lithium complex of [ 1.1 Idiazacoronand was condensed with diethylene glycol
bis(methanesu1phonate). The reaction occurs through a template effect,
owing to intramolecular NH hydrogen-b~nding.~'Hydroxymethyl[2.2.2.]-
cryptand has been synthesized by conventional methods. The compound may
be bound onto a polymer support (88).88This system allows the cryptand to
be used as a phase-transfer catalyst without the problem of recovering the
compound at the end of the reaction. Similarly, bifunctional benzo-cryptands
have been prepared by well-documented routes. These compounds not only
bind metal ions but can act as spin-labels or tracers by covalently bonding to
Meooc
host molecules through the aromatic ring."
CH20CH2-18-crown-6
ICH2CH20 \
An elegant synthesis of D3 bis(cyclotriveratryleny1) by condensation of

(89) and (90) has been described. The chiral D3 symmetry of (91) arises from
the spatial arrangement of the six equivalent achiral aromatic residues.%
HO Me0 OH
OMe OH
(90)
(91)
87
R. Annunziata, F. Montanari, S. Quici, and M. T. Vitali, J. Chem. SOC., Chem. Com-
mun., 1981,777.
F. Montanari and P. Tundo,,J. Org. Chem., 1982, 47, 1298.
89 0. A. Gansow, A. R. Kausar, and K. B. Trippett, J. Heterocycl. Chem., 1981, 18,297.
90 J . Gabard and A. Collet, J. Chem. SOC.,Chem. Commun., 1981, 11 37.
Host-Guest Complexes of Crown Ethers and Cryptands. - The complexation
of primary alkylammonium salts by macrocyclic multidentate compounds has
been reviewed?’
The binding constants of 1S-crown-5 and 18-crown-6 with Na’ in a wide
range of methanol-water mixtures have been published.= The first proven
‘neutral-component complexes’ of crown hosts which contain water that is
bound exclusively in the centre of the cavity have been rep0rted.9~The crown
ether (92) forms a dihydrate, which has been investigated by X-ray crystal-
lography. One water molecule lies below the plane of the ring, and forms
hydrogen-bonds with 0-1 (92). Polymer-bound benzo-18-crown-6 that is
complexed with KCl undergoes quantitative release of the bound salt on heat-
ing to 60°C.94 This phenomenon is likely to be of value in the study of the
effect of temperature on phase-transfer catalysis by polymeric crown ethers.
0
Crown ethers with a flexible side-chain extending from the macrocycle, to

which are attached electron-donor groups, are called ‘lariat ethers’. Initial
reports on the enhanced binding of sodium by the lariat ether (93)”‘ relative
to that by 15-crown-5 in CH2C12/H20systems are in marked contrast to the
diminished binding of (94) in methanol.95b Nitrogen lariat ethers (95) have
also been p r e ~ a r e d . 9The
~ ~ binding data indicate that the expected corre-
lation between the size of the ring and the cation that is bound is of less sig-
nificance than in other systems. The binding constants reflect the total num-
ber of oxygen atoms present both in the ring and in the side-chain. The
nitrogen seems to play an insignificant role as a donor ligand.
91 S. L. Baxter and J . S. Bradshaw, J. Hererocycl. Chem., 1981, 18,233.

92 D. M . Dishong and G . W. Gokel, J. Org. Chem., 1 9 8 2 , 4 7 , 1 4 7 .
93
G . R. Newkome, H. C. R. Taylor, F. R . Fronczek, T. J . DeLord, and D. K. Kohli, J.
Am. Chem. SOC.,1 9 8 1 , 1 0 3 , 7 3 7 6 .
94 A. Warshawsky and N. Kahana, J. Am. Chem. SOC.,1982,104,2663.
95
( a ) G. W. Gokel, D. M . Dishong, and C. J . Diamond, J. Chem. SOC., Chem. Commun.,
1980, 1053; ( b ) D. M . Dishong, C. J . Diamond, and G. W. Gokel, Tetrahedron Lett.,
1981, 22, 1663; (c) R. A. Schultz, D. M . Dishong, and G . W. Gokel, J. Am. Chem.
SOC.,1982, 104,625.
(93) R = CH20(CH2)20(CH2)3Me, X = 0
(94) R = CH20H, X = 0
(95) R = H , X = N(CH2CH20)nMe
The binding of cationic platinum complexes, e.g. [ P t ( b p ~ ) ( N H ~2+,

) ~ lto
dibenzo-30-crown-10 involves the expected N-H - * - 0 hydrogen-bonds from
the cis NH3 ligands on Pt"; also, the benzene rings enter into charge-transfer
interactions with the aromatic ring of the bipyridyl (bpy) ligands?6 These
effects are observed in both the solid state and in solution in acetonitrile.
The tetracyclic crown ether (84) forms by far the most stable and most
sele+ctiveNH4+ complex known?' The cation is bound by a tetrahedral array
of N-H - - - N hydrogen-bonds to the four nitrogen sites and by twelve electro-
static interactions with the oxygen atoms of the ligand. The [1.1.1] cryptand
binds one or two protons, either outside or inside its intramolecular cavity.
The rates of transfer of protons into and out of the cavity are very slow, and
the internally monoprotonated species cannot be deprotonated unless the
cryptand is destroyed?8 The general-acid-catalysed dissociation of
Ca[2.2 .212+ and Li[2.1.2]+ has been investigated." The catalysis of dissoci-
ation of Ca[2.2.2I2' by a general acid is due to a rate-determining proton-
transfer step. The acid-catalysed dissociation of Li[2.1.1]+ shows very small
isotope effects, and the reaction is indicative of a very unsymmetrical
transition state for the proton-transfer step, followed by competitive dissoci-
ation of Li+ from Li[2.2.2]H2+, and then by deprotonation.
Cryptands have been used for the separation of isotopes; 40Ca and @Ca
have been separated, using [2.2.1] and [2.2.2], the lighter isotope being
enriched in the organic phase.lW Similarly, preliminary results on the separ-
ation of 22Naand 24Na, using [2.2.1], are promising."'
96 H. M . Colquhoun, J . F. Stoddart, D. J. Williams, J . B. Wolstenholme, and R. Zarzycki,

Angew. Chem., Inr. Ed. Engl., 1981, 20,1051.
97
E. Graf, J.-P. Kintzinger, J.-M. Lehn, and J . LeMoigne, J. Am. Chem. SOC., 1982,
104,1672.
'* P. B. Smith, J. L. Dye, J. Cheney, and J.-M. Lehn, J. Am. Chem. Soc., 1981, 103,
6044.
99 B. G. Cox, W. Jedral, P. Firman, and H. Schneider, J. Chem. SOC., Perkin Trans. 2,
1981,1486.
loo K. G. Heumann and H. P. Schiefer, Z . Naturforsch., Teil. B, 1981, 36, 566.
101
A. Knocheland R. D. Wilken, J. Am. Chem. Soc., 1981, 103, 5707.
7
Bridged Systems
BY J. R . MALPASS
1 General
Reviews on saturated bicyclic peroxides ('the prostaglandin connection')' and
on 3-azabicyclo[3.3 .l]nonanes2 have appeared. A wide range of bridged
heterocycles, formed by cycloaddition reactions, will be found in reviews on
the chemistry of the isoindoles? reactions of benzyne with heterocyclic com-
pounds: Diels-Alder reactions of hetero-substituted 1,3-dienes,' heterarynes,6
and six-membered meso-ionic heterocycle^.^ Many examples of the synthetic
usefulness of bridged boranes can be found in Pelter's Tilden Lecture" and in
a review by Browngb on asymmetric synthesis using chiral organoborane
reagents.
2 Physical Methods
X-Ray and Electron Diffraction. - An exceptionally long C-1-C-2 bond
(1.657a) is found in the caged compound (1)' and the pattern of bond
lengths of the naphthalene moieties in the bridged binaphthyl (2) is
unusual;" bond angles in (3) are appreciably distorted." X-Ray studies of
(4)12 and (5)13 have led to the correction of earlier structural assignments.
Work on the nitrone dimer (6) has been followed up by an X-ray s t r ~ c t u r e ' ~
and the structure of the dimethyl ester of (7) (a dimer of an intermediate in
the Weiss glyoxal reaction) has been defined." A by-product (8) in the treat-
' W. Adam and A. J . Bloodworth, Top. Curr.Chem., 1 9 8 1 , 9 7 , 1 2 1 .
' R . Jeyaraman and S. A d a , Chem. Rev., 1 9 8 1 , 8 1 , 1 4 9 .
R. Bonnett and S. A. North, Adv. Heterocycl. Chem., 1 9 8 1 , 2 9 , 3 4 1 .
M. R. Bryce and J. M. Vernon, Adv. Heterocycl. Chem., 1981, 2 8 , 1 8 3 .
M. Petrzilka and J. I. Grayson, Synthesis, 1 9 8 1 , 753.
M. G. Reinecke, Tetrahedron, 1 9 8 2 , 3 8 , 4 2 7 .
' W. Friedrichsen, T. Kappe, and A. Bottcher, Heterocycles, 1 9 8 2 , 19, 1 0 8 3 .
( a ) A. Pelter, Chem. SOC. Rev., 1 9 8 2 , 11, 191; (b) H . C. Brown, P. K. Jadhav, and
A. K. Mandal, Tetrahedron, 1 9 8 1 , 37, 3547.
K. Harano, T. Ban, M. Yasuda, E. Osawa, and K. Kanematsu, J. Am. Chem. SOC.,
1981,103,2310.
lo J. D. Kopp, I. Bernal, M. M. Harris, and P. K. Patel, J. Chem. Soc., Perkin Trans. 2 ,
1981, 1621.
A. A. Espenbetov, A. I. Yanovski, Yu. T. Struchkov, L.A. Simonyan, and N . P.
Garnbaryan, Izv. Akad. Nauk SSSR,Ser. Khim., 1 9 8 2 , 6 0 7 .
l2 S. N. Whittleton, P. Seiler, a n d J. Dunitz, Helv. Chim. Act a, 1 9 8 1 , 64, 2 6 1 4 .
13
M. J. Begley, J . P. Benner, and G. B. Gill, J . Chem. Soc., Perkin Trans. I , 1981, 11 12.
14
T. Ota, S. Masuda, H. Tanaka, and M. Kido, Bull. Chem. SOC.Jpn., 1 9 8 2 , 5 5 , 171.
15
S . H. Bertz, W. 0. Adams, and J. V. Silverton, J. Org.Chem., 1 9 8 1 , 4 6 , 2 8 2 9 .
44 1
COOE t
0 F3C
COOE t HO
(3)
(4)
HooJ&cooH
0
(7) ( 8 ) P = 2-pyridyl ( 9 ) X = COOEt
ment of 2-lithiopyridine with 2,2'-bipyridine is the result of anionic [6 41 +

cycloaddition,16 and X-ray data have been used in the assignment of structure
(9) to the product of treatment of 2-dichloromethyl-3,5-bisethoxycarbonyl-
4-methylpyrrole with aqueous base." X-Ray and n.m.r. studies have been
reported for 3-oxa-7-azabicyclo[3.3.l]nonan-9-one (which has a chair/chair
conformation),'8a for (10) (chair/boat),'8b for an unsymmetrically N -
substituted 3,7-diazabicyclo [3.3.1] nonane disastereois~rner,~~ and for the
novel bicyclic ketal (ll), which has a chair conformation of the six-
membered ring.?' Participation by the transannular OH group during the
oxidation of 5-hydroxy-1-thiacyclo-octaneby iodine is evident from the
isolation and X-ray analysis of the salt (1 2),2l and the hydroxycyclobutanone
16
G. R. Newkome, D. C. Hager, and F. R. Fronczek, J. Chem. SOC.,Chem. Commun.,
1981,858.
17
J. M. Brittain, R. A. Jones, and T. J. King,J. Chem. SOC.,Perkin Trans. 1,1981,2656.
(a) P. Arjunan, K. D. Berlin, C. L. Barnes, and D. Van der Helm, J. Org. Chem., 1981,
46, 3196; (b) N. S. Pantaleo, D. Van der Helm, K. Ramarajam, B. R. Bailey, and
K. D. Berlin, ibid., p. 4199,
U. Horlein, T. Schroder, and L. Born,Liebigs Ann. Chem., 1981,1699.
D. M.Walba, R. C. Haltiwanger, M. D. Wand, a n d M. C. Wilkes, Tetrahedron, 1981,
3 7 , 1663.
A. S. Hirschon, J. D. Beller, M. M. Olmstead, J. T. Doi, and W. K. Musker, Tetru-
hedron L e t t . , 1981,2 2 , 1195.
Bridged Systems 443
(1 3) has been shown to exist as a remarkable 1 : 1 mixture with the tautomer

(14) in a single crystal.22 A gas-phase electron-diffraction study of 3-
silabicyclo[3.2.l]octane has been reported.23
Br Br
(13) (14)
Nuclear Magnetic Resonance Spectroscopy.- A study of protonation-induced

shifts in the 13C n.m.r. spectra of cyclic amines includes work with the
l-azabicyclo[2.2.2]octane system.% Measurements of lanthanide-induced
shifts in bicyclic lactams that are linked to diphenyl ethers have been
reported2’ and caution is advised concerning the use of LSR shifts in assign-
ment of configuration at C-7 in (lS).26 Long-range ‘H-”F coupling in the
compounds (1 6) has been r e - i n t e r ~ r e t e d .Conformational
~~ studies using
n.m.r. spectroscopy include work on Treib’s hemiacetal (17),”8 a range of
isomeric derivatives of cocaine:’ and 5-phenyl-l-azabicyclo[3.3 .l]nonan-
2-onee3’ A barrier of 9.0kcal mol-’ t o inversion at nitrogen for the bicyclic
n
0B; (16) R1,R2

R1
= alkyl, H
R3= H o r R3R3 = b o n d (17)
OH
22
R. C. Glen, P. Murray-Rust, F. G. Riddell, R. F. Newton, a n d P. B. Kay, J. Chem.
Soc., Chem. Commun., 1982,25.
23 Q . Shen, R. L. Hilderbrandt, C. S. Blankenship, a n d S. E. Cremer, J. Organornet.
Chem., 1981,214,155.
24 M. Perhsamy, Heterocycles, 1982, 18,127.
25
P. H.Mazzochi, H. L. Ammon, L. Liu, E. Colicelli, P. Ravi, and E. Burrows, J . Org.
Chern., 1981, 46,4530.
26 B. P. Mundy, G. W. Dirks, R. M. Larter, A. C. Craig, K. P. Lipkowitz, and J. Carter, J.
Org. Chem., 198 1,46,4005.
27 G. W. Gribble and W. J. Kelly, Tetrahedron L e t t . , 1981,22, 2475.
D.W.Anderson and G. L. Buchanan, Tetrahedron, 1981,37,977.
29
F. 1. Carroll, M. L. Coleman, a n d A. H. Lewin, J. OR. Chem., 1982,47,13.
30
G. L. Buchanan, J. Chem. Soc., Chem. Commun., 1981,814 ( c f . ref. 23 in last year’s
Re port ).
hydrazine (1 8) indicates that the positive nitrogen exerts only weak electron-
withdrawal from N-2.3’ Carbon-13 and proton n.m.r. spectra confirm that
(19) is a delocalized 14n aromatic system32 and allow study of (20), which is
the preferred conformation of the monoprotonated form of a bridged
annu~enone.~~
Miscellaneous Methods. - Photoelectron spectra of (21) demonstrate that
there is significant interaction between the lone pair on nitrogen and the car-
bony1 group at position 5.% Investigations of ionization energies and proton
affinities in bicyclic amines and diamines have formed the basis for a full
discussion of through-space and through-bond interactions in systems, e.g.
(22), of different ring sizes; it is proposed, for example, that (22a; n = 4) is
inwardly pyramidalized at nitrogen and that (outside) protonation causes a
large increase in strain energy.35 The binding of protons by the cryptand (23)
has been studied and five mono- and di-protonated forms have been identi-
fied:6a an attractive and efficient synthesis of (23) and derivatives has
appeared?6b Ultraviolet and photoelectron spectra of [Fe(C0)3] complexes
of (24) have been discussed.37 The phosphorus atom in (25) has been shown
P O 7
E t OOC-N
( n = 2, 3 , or 4 )
( 2 2 a ) X = CH (23)
(22b) X = N
31
S. F. Nelsen and P. M. Gannett, J. A m . Chem. SOC., 1 9 8 1 , 1 0 3 , 3300.
32 R. J . Hunadi and G. K. Helmkamp, J. Org. Chem., 1 9 8 1 , 4 6 , 2 8 8 0 .
33
H. Ogawa, N. Kariya, T. Imoto, H. Kato, and Y. Taniguchi, Croat. Chem. Acta, 1981,
5 3 , 637.
34 F. Carnovale, T. H. Gran, J . B. Peel, and A. B. Holmes, J. Chern. SOC.,Perkin Trans. 2 ,
1981,991.
35 R. W. Alder, R. J . Arrowsmith, A. Casson, R. B. Sessions, E. Heilbronner, B. Kovac,
H. Huber, and M . Taagepera, J . Am. Chem. SOC., 1 9 8 1 , 103, 6 1 3 7 . [See also Tetm-
hedron Lett., 1 9 8 2 , 2 3 , 4 1 8 1 for synthesis of (22b)l.
36 (a) P. B. Smith, J . L. Dye, J . Cheney, and J . M. Lehn, J. Am. Chem. SOC.,1 9 8 1 , 1 0 3 ,
6 0 4 4 ; ( b ) R. Annunziata, F. Montanari, S. Quici, and M. T. Vitali, J. Chem. SOC.,
Chem. Commun., 1 9 8 1 , 7 7 7 .
37 G. Granozzi, A. Ajo, T. Boschi, and R . Roulet, J. Organomet. Chem., 1 9 8 1 , 224, 147.
Bridged Systems 445
(by e.s.r.) to be trigonal-bipyramidal and the nitrogen ligands interconvert by

a Berry pseudorotation mechanism in the solid state?8
Interesting applications of physical methods will also be encountered in
many of the following references.
3 Nitrogen-containing Compounds
Synthesis. - Cycloadditions. The azadiene (26) behaves as a dienophile with
cyclopentadiene but as a diene with acyclic 1,3-dienes and with cyclohexa-
1,3-dienes in cycloaddition reaction^.^' The double bond of Dewar-thiophen
(27a) is protected as the pyrrole adduct (28a) in a stepwise conversion into
(28b) and hence into Dewar-furan (27b)."O A rearrangement intrudes during
the addition of dimethyl acetylenedicarboxylate (DMAD) t o 1-(NN-dimethyl-
amino)-2,5-dimethylpyrrole, giving the pyrazole (29) as the ultimate pro-
duct .41 Dienophiles such as N-phenylmaleimide add t o N-t-butyl-5-nitroiso-
~ ~N-t-butylbenzisoindole?2b ka[3.1. llpropellanes, e.g. (3 l ) , are
i n d 0 1 e ~and
formed from N-methylisoindoles when they react with chlorobicyclobutanes,
e.g. (30), in the presence of base43 and the addition of DMAD to 2,l-
benzisoxazoles occurs straightforwardly.44
H
N
Z 2
(X = CF3) X
(26) (27a) Y = S (28a) Y = S (29) z = COOM~
(27b) Y = 0 (28b) Y = 0
J . H. H. Hamerlinck, P. H. H. Hermkens, P. Schipper, and H. M. Buck, J. Chem. SOC.,

'~3
Chem. Commun., 1981,358.
39 B. K. Rammash, C. M. Gladstone, and J . L. Wong, J. Org. Chem., 1981, 46,3036.
40 D. Wirth and D. M . Lemal, J. Am. Chem. SOC.,1982,104,847.
41 A. G. Schultz and R. Ravichandran, Tetrahedron Lett., 1981, 22,1771.
42
(a) G. Use and R. Kreher, Chem. Zrg., 1982, 106, 143; ( b ) R. Kreher and G . Use,
Heterocycles, 1982, 19, 637.
43 H. G. Zoch, A. D. Schluter, and G. Szeimies, Tetrahedron Lett., 1981,22, 3835.
44 R. C. Boruah, J. S. Sandhu, and G. Thyagarajan, J. Heterocycl. Chem., 1981, 18,
1081.
+ 3;- ( X = rnorpholino)
xONo
Scheme 1
‘Catalytic’ Diels-Alder addition of enamines (generated in situ) with 1,2,4-

triazines leads to pyridine derivative^^^ and the addition of enamines (or enol
ethers) to 5-nitro-1,3-diazines is regio~elective~~
(Scheme 1). Tetrazines react
with trimethylsilylalkynes47a and also with 3,3-dimethylcyclopropene,form-
ing mono- and bis-adducts, e.g. (32).“7b In contrast, the addition of isocyanides
to tetrazines gives transient [4+ 13 adducts, e.g. (33); these lose nitrogen,
forming diazacyclopentadienonimines, which finally tautomerize to the
pyrazoles (34).48The primary adduct (36)from the reaction of benzvalene
with (35) breaks down, with rearrangement, t o yield the tetracyclic diketone
(37):’ Intramolecular cycloaddition of alkenyl-substituted isoquinolinium
salts produces bridged iminium salts. e.g. (38).” Stereochemical studies of the
N/cH2ph
R-
( R = COOMe)
(33) (34)
‘* D. L. Boger, J . S. Panek, and M. M. Meier, J. Org. Chem., 1982,47,895.

V. N. Charushin and H. C. Van der Plas, Tetrahedron L e t t . , 1982,23,3965.
‘’ ( a ) L. Birkofer and E. Hansel, Chem. Ber., 1981,114, 3154;( b ) F-X.Huber, J . Sauer,
W. S . McDonald, and H . Noth, Chem. Ber., 1982,115,444.
48
P. Imming, R. Mohr, E. Miiller, W. Overheu, and G. Seitz, Angew. Chem., Int. Ed.
Engl., 1982,21, 284.
49
M. Christl, U. Lanzendorfer, and S. Freund, Angew. Chem., Int. Ed. Engl., 1981,2 0 ,
674.
G.P. Gisby, P. G. Sammes, and R. A. Watt, J . Chem. SOC.,Perkin Trans. 1 , 1982,249.
Bridged Sys terns 447
Ph
I I
N0-
Ph
H
(35) (37)
cycloaddition to 2-pyridones of N-phenylmaleimideS1 and of DMADS2 are

noted; a cycloaddition of pyridone to methyl acrylate forms the first step in
an eight-step synthesis of (*)-epi-ib~gamine.’~ Diels-Alder addition of phenyl
vinyl sulphone t o N-carboethoxy-2-alkyl-l,2-dihydropyridinesis stereo-
~elective.’~1,4-Adducts are found, together with 1,2-adducts, in the photo-
addition of chloroethylenes to 2-pyridones.”
A detailed classification of two-electron cyclo-addends includes N-phenyl-
triazolinedione (PTAD).56 Enantiomerically pure unsaturated [4.4.2]pro-
pellanes have been isolated by means of Diels-Alder addition of (-)-endo-
bornyltriazolinedione followed by separation of the resulting diastereoisomeric
urazoles and re-formation of the propellanes.” The product (39) of 1,7-
dipolar cyclization of a conjugated carbonyl ylide has been intercepted by
addition of PTAD across the diene moiety,58 as has the dimer of cyclo-octa-
1,5-dien-3-yne [yielding the adduct (40)].59 Similar [4 + 21 additions of
PTAD have been reported with a variety of substituted cyclopentadienes,6’
(38)
(39)
(40)
51
( a ) V. S. Pilipenko and N. P. Shusherina, Zh. Org. Khim., 1981, 2122; ( b ) N. P.
Shusherina, V. S. Pilipenko, 0. K. Kireeva, B. I. Geller, and A. U. Stepanyants, ibid.,
1980,2390.
51
(a) G . P. Grisby, S. E. Royall, and P. G. Sammes, J. Chem. SOC., Perkin Trans. I ,
1982, 169;( b ) K.Matsumoto, Y. Ikemi, S. Nakamura, T. Uchida, and R. M. Acheson,
Heterocycles, 1982,19,499.
53 H. Tomisawa, H. Hongo, H. Kato, K. Sato, and R. Fujita, Heterocycles, 1981, 16,
1947; see also T.Imanishi, N. Yagi, H. Shin, and M. Hanoaka, Tetrahedron Lett.,
1981, 22, 4001 for a different approach.
54
G. R. b o w , J. T. Carey, K. C. Cannon, and K J. H e w , Tetrahedron L e t t . , 1982,23,
2527.
55 K. Somekawa, R. Imai, R. Furukido, and S. Kumamoto, Bull. Chem. SOC.Jpn., 1981,
54,1112.
56 L. T. Scott, I. Erden, W. R. Brunsvold, T. H. Schultz, K. N. Houk, and M. N. Paddon-
Row, J. Am. Chem. SOC.,1982, 104, 3659.
W.D. Klobucar, L. A. Paquette, and J. F. Blount, J. Org. Chem., 1982,46,4021.
’* W. Ebenbach, E. Hadicke, and U. Trostmann, Tetrahedron L e t t . , 1981,22, 4953.
5 9 H. Meier, T. Echter, and 0. Zimmer, Angew. Chem., Int. Ed. Engl., 1981,20, 865.
6 o T. Dabaerdemaeker, W. D. Schroer, and W. Friedrichsen, Liebigs Ann. Chem., 1981,
502.
Ph A
OMe
OO
<,” N-N
R (44)
(43)
cyclohexadienes,61 and bicyclononatrienes, cyclo-octatriene epoxide, and

cyclo-octatrienone,62 and with steroid d i e n e ~ A
. ~full
~ account of the prepar-
+
ation and trapping of (41) with ITAD (as the [8 21 adduct (42)) has
appeared;@ endo- and exo-adducts have been isolated in the reaction of N -
methyltriazolinedione (MTAD) with 11-cyano-1$-methano[ 1O]ann~lene.~’
The balance between homocycloaddition [giving (43)] and ene-reaction
pathways in the reactions of PTAD and MTAD with bicyclo[3.2.l]octa-
2,6-diene (and derivatives) has been fully investigated by The for-
mation of the anomalous product (45) from (44) is apparently the result of
distortion of the 1,4-diene.6’ PTAD adds to (46) (and also to the exo-isomer)
to give both unrearranged 1,2-addition products and skeletally rearranged pro-
ducts6* Addition of triazolinediones across the central bond of bicyclo-
butanes gives (47) together with an ene a d d ~ c t . ~The
’ primary products of
the addition of MTAD to fulvenes rearrange and dimerize, yielding (48).m
1
( 4 7 ) R = Me or Ph
0 R 2 = Me, CN, COYH2,
(45)
or COOEt
61 (a) M. Christ1 and M. Lechner, Chem. Ber., 1982,115, 1; (b) W. Bethauser, M. Regitz,
and W. Theis, Tetrahedron Lett., 1981,22,2535.
6 2 W. Adam, 0. Cueto, and 0. de Lucchi, Chem. Ber., 1982,115,1170.
63 D. S. Morris, D. H. Williams, and A. F. Norrk, J. Chem. SOC.,Chem. Commun., 1981,
424; N. A. Bogoslovski, G. E. Litvinova, I. A. Titova, G. I. Samokhvalov, V. G.
Mairanovskii, V. M. Gurevich, and T. M. Filippova, Zh. Org. Khim., 1981,17,1909.
64 T. L. Gilchrist, C. W. Rees, and D. Tuddenham, J. Chem. SOC.,Perkin Trans. I , 1981,
3214.
65
P. Ashkenazi, M. Kaftory, D. Arad, Y.Apeloig, and D. Ginsburg, Helv. Chim. Acta,
1981,64,579.
66 W. Adam and 0. de Lucchi, Tetrahedron Lett., 1981, 22, 3501; W. Adam, 0.de
Lucchi, and D. Scheutzow, J. Org. Chem., 1981,46, 4130;W.Adam, 0.de Lucchi,
K. Peters, E-M. Peters and H. G. von Schnering, J. Am. Chem. SOC.,1982,104,161.
“ P. G. Gassman and R. C. Hoye, J. Am. Chem. SOC.,1981,103,2496.
6 8 I. Erden, Chem. Lett., 1981,263.
6 9 R. L. Amey and B. E. Smart, J. Org. Chem., 1981,46,4090.
70
H.Olsen,Angew. Chem., Int. Ed. Engl., 1982,21, 383.
Bridged Systems 449
Me
(48) R = Me or Ph
Synthesis by Other Cyclizations. The epimeric amines (49) have been made
by means of a novel sN2 reaction of the corresponding 2-bromo-6-amino-
cyclohexanone d e r i ~ a t i v e .Double
~~ Michael addition of (+)-a-methylbenzyl-
amine t o cyclo-octa-2,7-dienone derivatives forms the basis of a synthesis of
the enantiomeric forms of adaline (50).n Intramolecular Friedel-Crafts alkyl-
ation has been used in the synthesis of derivatives of the 2,6-methanobenz-
azepine ,m 2,6-methan0-3-benzazocine,~~~ 2,6-rnethan0-3-benzazonine,~~ and
2,s -methano-3-benzazocine and 1,4-ethano-2-benzazepine skeletons.74c
pyoH
Cl
R H
H ( 5 0 ) R = n-pentyl
(49)
A simple synthesis of 1-aza-adamantan-4-one has been de~cribed.~’7-

Chloro-l,7-dia~a-’~ and 1-aza-7-oxa-bicyclo[2.2.1] heptane~’~ have been pre-
pared in good yield. Both 1,4- and 1,5-nitrogen-bridged products result from
treatment of cyclo-octa-l,3-diene with HzNCN and N-bromosuccinimide,78
and iterated cycloaddition of nitrones to cyclic dienes gives a wide range of
azabicyclic diols, including the [3]manxine-6,9-diol (5 l), the conformational
71 R. F. Parcell and J. P. Sanchez, J. Org. Chem., 1981,46,5228.

72 R. K. Hill and L. A. Renbaum, Tetrahedron, 1982, 38, 1959.
73 L. Stella, B. Raynier, and J . M. Surzur, Tetrahedron, 1981, 37,2843.
74 ( a ) R. T. Parfitt, P. H. Redfern, D. Carr, B. Iddon, and H. Suschitzky, Eur. J. Med.
Chem. - Chim. Ther., 1981, 16, 421; ( b ) G.R. Proctor and F. J . Smith, J. Chem.
Soc., Perkin Trans. I , 1981, 1754;(c) R. Achini, Helv. Chim. Ac ta , 1981,64,2203.
75 R. M. Black,Synthesis, 198 1,829.
76 G. V. Shustov, N. B. Tavakalyan, and R. B. Kostyanovskii, Izv. Akad. Nauk SSSR,
Ser. Khim., 1981, 1677.
77 H. H. Lau and U. Schollkopf, Liebigs Ann. Chem., 1981,1378.
78 G . Haufe and E. Kleinpeter, Tetrahedron Lett., 1982,23,3555.
1
( 5 2 a ) R = H , R2= C1
( 5 2 b ) R1R2= bond (53)
equilibrium of which was studied by n.m.r. ~pectrometry.'~ Arylamines add

in a 1,4-manner to cyclo-octa-1,3-diene under the influence of HgO.*'
Dehydrogenation of (52a) affords the di-isocyanate dimer (52b),8l and routes
to (53) (and other heterocyclic analogues),82 to (54),83 and to [2.3.3]cycla-
zinesWare noted.
Reactions of Nitrogen-containing Compounds. - Irradiation of cyclic nitro-
compounds in base (i.e. as the nitronate anion) leads to ring-expansion [e.g.
(55)+(56)],85 the benzenesul honyl-amine (57) is formed by means of a
photochemical rearrangement! and photolysis of 1-azido-adamantane in
aqueous NaCN, in the presence of a phase-transfer catalyst, gives (58).87 A
re-examination of bridgehead versus methylene migration in the Beckmann
rearrangement of derivatives of (59) shows that both pathways occur, but
that the preference can vary markedly with conditions.88
79
J. T. Bailey, I. Berger, R. Friary, and M. S. Puar, J. Om. Chem., 1982,47, 857.
80
J. Barluenga, J . Perez-Prieto, and G. Asensio, J. Chem. SOC.,Chem. Commun., 1982,
1181.
R. Richter, B. Tucker, and H. Ulrich, J. Otg. Chern., 1981, 46, 5 2 2 6 .
82 J. M. MeUor, A. P. No t t , R. N. Pathirana, and J. H. A. Stibbard, Synthesis, 1982, 325.
83 A. R. Butler, I. Hussain, and K. M. Peet,J. Chem. SOC.,Perkin Trans 2 , 1981, 320.
84
J. W. Dick, W. K. Gibson, D. Leaver, and J. E. Roff, J. Chem. SOC., Perkin Trans. 1 ,
1981,3150.
85
K. Yamada, T. Kanekiyo, S. Tanaka, K. Naruchi, and M. Yamamoto, J. Am. Chem.
SOC.,1981,103,7003.
86 K. Umano, J. Koura, and H. Inoue, Bull. Chem. SOC.Jpn., 1981, 54,2827.
87
T. Sasaki, S. Eguchi, and T. Okano, J. Org. Chem., 1 9 8 1 , 4 6 , 4 4 7 4 .
G . R. Krow and S. Szcepanski, J. Org. Chem., 1 9 8 2 , 4 7 , 1 1 5 3 .
Bridged Systems 45 1
hv
H ( 5 7 ) R = COOMe o r CN
Me
QCN
(58) (59) ( 6 0 ) n , rn = 1, 2
The heterolysis of P-halo-amines (60) has been examined as a function of

ring sizesg and studies with P-halo-aza-adamantanes have been reported.g0
Silver-ion-assisted heterolysis of the two diastereoisomeric N-chloroamine
invertomers (61a) and (61 b) proceeds by completely different pathways
(Scheme 2); the rate of reaction of (61b) varies with substitution in the
ben~o-ring.~' Treatment of the hydroxy-amine (62) with tosyl chloride gives
the rearranged tosylate (63) together with the oxygen-insertion products (64)
and (65).%
H
N
A; /OH
Ag+ Y O H
Scheme 2
a9
J . W. Bastable, A. J . Cooper, I. R. Dunkin, J . D. Hobson, and W. D. Riddell, J. Chem.
SOC., Perkin Trans I , 1 9 8 1 , 1 3 3 9 ; J . W. Bastable, I. R. Dunkin, and J . D. Hobson,
ibid., p. 1 3 4 6 .
90 J . G . Henkel and W. C. Faith,J. Org. Chem., 1 9 8 1 , 4 6 , 4 9 5 3 .
91
M. L. Durrant and J . R. Malpass, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 1 0 2 8 .
92
A. Heesing and W. Herdering, Tetrahedron Lett., 1 9 8 1 , 2 2 , 4 6 7 5 .
The azabicyclo[2.2.1] heptadiene derivative (66)plays a key role in the total

synthesis of the fungal metabolite (67),93 and the lactam (68) is a useful pre-
cursor to carbocyclic ribonucleosides." Diels-Alder adducts from various
cyclic hexa-l,3-dienes and nitroso-compounds have seen use as precursors of
polyhydro~y-amines.~~ Adducts from cyclopentadienes and nitroso-alkenes
(69a) rearrange easily to aziridino-oxirans (70)96and a variety of pathways
for thermal decomposition has been reported for (69b).9' Thermal decompo-
sition of bicyclic oxazines is a useful source of nitrosyl cyanideg8" and.of
transient C-nitrosocarbonyl compounds~8beach of which cyclo-adds to
simple and complex dienes. Relatively easy, non-concerted retrocycloaddition
in caged systems, for example (71), has been investigated.w The size of the
bicyclic framework in ylides (72) controls the proportions of [3,3]- and [1,2]-
rearrangement .'O0 Kinetic and thermodynamic aspects of the formation of
tropinone oxides have been investigated"' and the lithium-tetrahydro-
aluminate-induced ring-contraction of the tropinone derivative (73), giving
(74), has been observed.lm A series of papers covers the synthesis and
reactions of a variety of azapropellanes with nitroso-aromati~s,'~~~ singlet
oxygen,loJb and triazolinedione~.'~~~ The intermediacy of substituted deriva-
(69a) R = a l k e n y l
(69b) R = b e n z y l (70) R = alkenyl
93 T. Fukuyama and Y. M. Yung, Tetrahedron Lett., 1981, 22,3759.

94 R. C. Cermak and R. Vince, Tetrahedron Lett., 1981, 22,2331.
9s G. Kresze and W. Dittel, Liebigs Ann. Chem., 1981, 610, and earlier papers in this
series.
% E. Francotte, R. Merenyi, B. Vandebulcke-Coyette, and H. G. Viehe, Helv. Chim.
Acta, 1981, 64, 1208.
97 D. Ranganathan, S. Ranganathan, and C. B. Rao, Tetrahedron, 1981, 37,637.
98 (a) P. Horsewood, G. W. Kirby, R. P. Sharma, and J. G. Sweeney, J. Chem. SOC.,
Perkin Trans. I , 1981,1802; (b) G. W. Kirby and J. G. Sweeney, ibid., p. 3250.
99 W. D. Klobucar, R. L. Burson, and L. A. Paquette,J. Org. Chem., 1981,46,2680.
l o o W. D. Ollis, 1.0. Sutherland, and Y. Thebtaranonth, J. Chern. SOC., Perkin Trans. I ,
1981,1963.
lo' Y.Shvo and E. D. Kaufman,J, Org. Chem., 1 9 8 2 , 4 7 , 2 1 9 0 .
'02 S. Sarel and E. Dykman, Heterocycles, 1981, 15,719.
103
( a ) R. Ashkenazi, R. Gleiter, W. von Philipsborn, P. Bigler, and D. Ginsburg, Tetru-
hedron, 1981, 37, 127; (b)I. Landheer and D. Ginsburg, ibid., pp. 133, 143;
(c) M. Peled and D. Ginsburg, ibid., pp. 151, 161.
Bridged Systems 453
&GNPh
\
heat
c
0
li;J"Ph
0
Me Me
(72) n = 1 or 2 0
m = O o r l (74)
x = O o r l (73) R = I o r H
tives of azabenzvalene (75) has been invoked in the rearrangement of cyclo-

propenyl-azirines to pyridines.'("'
Bridged Azoalkanes. - The formation of (76) from bicyclobutane has been
rep~rted,~"' together with studies of its thermolysis in solution, its gas-phase
pyrolysis,'056 and its p h o t o l y ~ i s The
.~~~synthesis
~ of azoalkanes from the
corresponding urazoles by hydrazinolysis (rather than the usual oxidative
hydrolysis methods) takes place in good yield [e.g.,70% for (77a)J.lo6 The
resolution and determination of the absolute configuration of an optically
active 4,5-diazatwist-4-ene (79), derived from (78), has been achieved.lo7
(76) (77a) R = H
(77b) RR = CMeZ
104
A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. Am. Chem.
SOC.,1982,104,286.
lo5 (a) M. H. Chang and D. A. Dougherty, J. Org. Chem., 1981, 46, 4092; ( b ) J. Am.
: Chem. SOC.,1982, 104, 1131; (c) ibid., p. 2333.

W. Adam, L. A. Arias, and 0. de Lucchi,Synthesis, 1981,543.
R. Askani, H. Eichenauer, and J . Kohler, Chem. Ber., 1982, 115,748.
454 Heterocyclic Chernisty
(78) ( R = COOPh) (79)
Picosecond fluorescence spectroscopy has allowed direct observation of a

hydrocarbon singlet 1,3-diradical from (77b),"& and detailed descriptions of
studies on the decomposition of (77b) have been published in full.'08b Flash
vacuum pyrolysis of (80)'09' and of (81)'09b and further details of the
thermal and photochemical decomposition of (82)109c have been described.
n
( 8 0 ) RR = 0
(81) R = H ( 8 2 ) RR = H 2 , CH2CH2, or C P h 2 (83) n = 1 o r 2
Bicyclic azo-compounds have been converted into the corresponding con-

gested hydrazines, for example (83); the relative thermodynamic stability and
kinetics of decomposition of the derived radical cations have been compared
with data from less congested analogues.'" The reaction of (77a) with
phthalimidonitrene gives the azimine (84)l" and the conversions of (85) +
(86) and of (87) -+(88) have been reported."*
( 8 5 ) R 1 , IE2= M e , Ph (86)
108
( a ) D. F. Kelley, P. M. Rentzepis, M. R. Mazur, and J. A. Berson, J. A m . Chem. SOC.,
1982, 104, 3764; (b) M. Rule, J. A. Mondo, and J. A. Berson, ibid., p. 2209; M. G.
Lazzara, J. J. Harrison, M. Rule, E. F. Hilinski, and J. A. Berson, ibid., p. 2233, plus
accompanying papers.
109
( a ) W. Adam, N. Carballeira, and 0. de Lucchi, J. A m . Chem. SOC.,1981,103,6406;
( b ) W. Adam, 0. de LUCCM,and K. Hill, ibid., 1982, 104, 2934; (c) W. Adam and
0. de Lucchi, J. Org. Chem., 1981,46,4133.
110
S . F. Nelson and W. P. Parmelee, J. Org. Chem., 1981, 46, 3453.
111
C. Leuenberger, L. Hoesch, and A. S. Dreiding, Helv. Chim. Actu, 1981, 64, 1219.
112
(u)H.Olsen and J . F . M. Oth, Angew. Chem., I n f . Ed. Engl., 1981, 2 0 , 83;
(b) H. Olsen, ibid., p. 984.
4 Oxygen-containingCompounds
Synthesis. - Cycbadditiuns. A 'bis-heteroannelation' approach to (*)-
ligularone (90) from (89) has been r e ~ 0 r t e d . l 'Other
~ intramolecular cyclo-
additions include the conversions of (91) into (92)114 and the intramolecular
addition to the benzyne (93)' which is the key to the synthesis of (*)-
mansonone (94).' l5
This section is dominated by cycloadditions involving furans and isobenzo-
furans. The new dienophile ethyl (diethoxyphosphiny1)propynoate is highly
cc1d2 c;B
l\ Ic1
c1
c1
'13 P. A. Jacobi and D. G. Walker,J. Am. Chem. SOC.,1981,103,4611.

'14 M. E. Jung and L. A. Light, J. Org. Chem., 1 9 8 2 , 4 7 , 1 0 8 4 .
'" W. M . Best and D. Wege, Tetrahedron Lett., 1981, 22,4877.
R
R
O G
II II Ph
( 9 5 a ) XR = -COC-
( 9 5 h ) R = CN ( 9 6 ) R = II or CH
3
(97)
X = 0 or "Me2
reactive and regiospecific ,l l6a ethynedicarbonyl dichloride' l6 and but ynedi-

nitrile116c give mono- and/or bis-adducts [for example ( 9 5 ) ] , and bis-benzyne
adducts (96) have been transformed into phenanthrenes.''6d Work continues
on the addition of furan to ally1 trichloroallylium ions,"7b and
~ x o a l l y l s . " ~Additions
~~~ t o furan and substituted furans involving cyclo-
propenes,'18 ethyl cyan~formate,"~substituted acrylonitriles,'20 and maleic
anhydride12' are noted. Photochemical reactions of benzenes with furans have
been examined,'22 and the cage compounds (97)123(from 2,s-dimethylfuran
and a-nitrosostyrene) and (98)'24 (from furan and 1,2,3,6-tetrahydrobenzo-
cyclobutene-3,6-diones) are the result of multi-step pathways. The preference
for exo-addition of furan to (99)125and the observed endo stereoselectivity
in the addition of maleic anhydride and DMAD to (100) have been dis-
cussed.' 26
0 (100)
(98) (99)
'16 ( a ) R. G. Hall and S. Trippett, Tetrahedron Lett., 1982, 2 3 , 2603; (b) G. Maim and
W. A. Jung, Chem. Ber., 1982, 115, 804; (c) R. H. Hall, S. Harkema, H. D. Hartog,
G. J. Van Hummel, and D. N. Reinhoudt, R e d . : J. R. Neth. Chem. Soc., 1981,100,
312; ( d ) H. Hart and S. Shamouilian, J. Org. Chem., 1981,46,4874.
"' ( a ) R. Henning and H. M. R. Hoffmann, Tetrahedron Lett., 1982, 2 3 , 2305;
(b) B. Fohlisch, W. Gottstein, R. Heiter, and I. Wanner, J. Chem. Res.(S), 1981,246;
(c) B. Fohlisch, R. Herter, E. Wolf, J. J. Stezowski, and E. Eckle, Chem. Ber., 1982,
115, 355; (a) A. P. Cowling, J. Mann, and A. A. Usmani, J. Chem. Soc., Perkin
Trans. I , 1981,2116.
J. M . Birchall, K. Burger, R. N. Haszeldine, and S. N. Nona, J. Chem. SOC.,Perkin
Trans. I , 1981,2080.
A. W. McCulloch, A. G. McInnes, and D. G. Smith, Can. J. Chem., 1981,59,1395.
120 H. Kotsuki and H. Nishizawa, Heterocycles, 1981, 16, 1287.
''I ( a ) S. T. Akhmedov, N. S. Sadykhov, R. S. Akhmedova, and N. S. Zefirov, Khim.
Geterotsikl. Soedin., 1981, 1593; ( b ) D. Gravel, R. Deziel, F. Brisse, and L. Hechler,
Can. J. Chem., 1981,59,2997.
l a Z T. S. Cantrell, J. Org. Chem., 1981,46,2674.
123 D. Mackay and K. N. Watson, J. Chem. SOC.,Chem. Commun., 1982,777.
lZ4 M. Oda and Y . Kanao, Chem. Lett., 1981, 1547.
125
P. D. Bartlett, G. L. Combs, A-X.T. Le, W. H. Watson, J. Galloy, and M. Kimura,
J. A m . Chem. SOC.,1982,104, 3131.
J-P. Hagenburgh, P. Vogel, A. A. Pinkerton, and D. Schwarzenbach, Helu. Chim.
Acta, 1981, 64, 1818.
Bridged Systems 457
Cycloaddition of diphenylisobenzofurans to (10 1),12' to sulphenes,'28 to

2-phenyl-3-spirocyclopropylazirines ,12' and to o-benzoq~inonedi-imines~~~
have been reported. The _preparation and trapping of l - r n e t h ~ x y - 'and
~~~
l-benzyl-isobenzofuran131b have been described and a high degree of regio-
and stereo-specificity is observed in the reactions of a range of 1-substituted
isobenzofurans with quinone acetals, for example in the formation of
(102). l3lC
Synthesis by Miscellaneous Other Methods. An s N 2 reaction with inversion
at the cyclpropyl carbon in (103) has been demonstrated u n a m b i g u ~ u s l y . ~ ~ ~
The tosylates (104) could not be isolated but cyclized spontaneously to

(105).'33 Two approaches have been described to the oxabicyclo-octene
moiety (1 06) that is present in certain antibiotics'% and nucleophilic addition
of the hydroxyl function to the C=C bond in systems such as (107) has been
ascribed to the relief of strain in the ground state.13' An intramolecular
Michael addition converts (1 08) into (1 09).136
127
D. Dopp, U. Langer, and H. Libera, Chem. Ber., 1982, 115, 346.
E. Block and M. Aslam, Tetrahedron Lett., 1982,23,4203.
129 0. Tsuge, T. Ohnishi, and H. Watanabe, Heterocycles, 1981, 16,2085.
W. Friedrichson, M. Roehe, and T. Debaerdemaeker, 2. Naturfursch., Teil. B , 1981,
36, 632.
13' ( a ) M. A. Makhlouf and B. Rickborn, J. Org. Chem., 1981,46,2734; ( b ) J. G. Smith,
S. S. Welankiwar, N. G. Chu, E. H. Lai, and S . J. Sondheimer, ibid., p. 4658; ( c ) R. N.
Warrener, B. C. Hammer, and R. A. Russell, J. Chem. SOC., Chem. Commun., 1981,
942; R. A. Russell, D. E. Marsden, M. Sterns, and R. N. Warrener, Aust. J. Chem.,
1981, 34, 1223.
132
L. A. M. Turkenburg, W. H. de Wolf, F. Bickelhaupt, C. H. Stam, and M. Konijn, J.
Am. Chem. SOC.,1982,104,3471.
133 C. A. Grob, B. Giinther, and A. Waldner, He2v. Chim. Acta, 1981, 64,2709.
134 M. Sudani, Y. Takeuchi, E. Yoshii, and T. Kometani, Tetrahedron Lett., 1981, 22,
425 3.
135 G. M. R. Tombo, R. A. Pfund, and C. Canter, Helv. Chim. Actu, 1981,64,813.
'36 A. Nishinaga, K. Nakamura, and T. Matsuura,J. Org. Chem., 1982, 47, 1431.
(104) ( R R = 0 or R = H ) (105)
0 0
Descriptions of a variety of routes to a-multistriatin (1 10) and related

compounds have been ~ub1ished.l~'Two reported syntheses of sarracenin
(1 11) are based on a photo-annelation strategy.'38 Caged multicyclic ethers
inlcude the sugar (1 12), having a twist-brendane structure,139 pentacyclic
diethers based on heterodiamantanes,lm and the ether (1 13).14' Derivatives of
the 9-oxabicycloC3.3.l]nonane skeleton have been made.142
HO
Po
kOOMe (112)
Reactions of Oxygen-containingCompounds.- Studies of the bridged oxepin

(1 14) show no evidence for the presence of the oxonorcaradiene t a ~ t o m e r ; ' ~ ~ '
oxidative cleavage of (1 14) yields (1 15).1436 The addition of new dienophiles
13' (a) J. P. Marino and H. Abe, J. Org. Chem., 1981,46, 5379; ( b ) R. W. Hoffmann and
W. Helbig, Chem. Ber., 1981, 114, 2802; (c) D. E. Plaumann, B. J. Fitzsimmons,
B. M. Ritchie, and B. Fraser-Reid, J. Org. Chem., 1982,47, 941; see also accompany-
ing papers for synthesis of exo-brevicomin and frontalin.
13* S. W. Baldwin and M. T. Crimmins, J. A m . Chem. SOC.,1982, 104, 1132.
lJ9 P. Koll, H-G. John,and J. Kopf, LiebigsAnn. Chem., 1982,626.
I4O W. Ammann and C. Ganter, Helv. Chim. Actu, 1 9 8 1 , 6 4 , 9 9 6 .
14' K. Hirao, Y. Kajikawa, and 0. Yonemitsu, Heterocycles, 1982, 17, 631.
14' ( a ) J. Kagan, D. A. Agdeppa, A. I. Chang, S-A. Chen, M. A. Harmata, B. Melnick,
G. Patel, C. Poorker, S. P. Singh, W. H. Watson, J. S. Chen, V. Zabel, and A. N. Y.
Moore, J. Org. Chem., 1981, 46, 2916; (b) A. Toshimitsu, T. Aoai, S. Uemura, and
M. Okano, ibid., p. 302 1.
143 (a) P. Rosner, C. Wolff, and W. Tochtermann, Chem. Ber., 1982, 115, 1162;
( b ) W. Tochtermann and P. Rosner, ibid., 1981, 114, 3725.
Bridged Systems 459
\ /
R2
(116) R 1 , R2= H , OMe
(114) X = COOEt (115)
to (24) is illustrated in the formation of (1 16);lWa investigations with halo-

geno- and methoxy-derivatives of (24) have been carried out.'44b The forma-
tion of benzene rings from 1,4-oxygen-bridged systems is illustrated by the
conversion of (1 17) into (1 18)14' and by the aromatization of (1 19), using
- LiAlH
TiCl
toluene-p-sulphonic acid in acetic anhydride.'& There is apparently little

relief of strain during the hydrolysis of the bicyclic ortho-ester (120), so that
the rate of initial ring-opening differs little from that for acyclic or mono-
cyclic m0de1s.l~' Rearrangement of the oxahomoadamantane (121a) in acid
produces (122), but no skeletal rearrangement occurs in the case of (121b).lM
'*OH
R
(120) R = H or Ph
(119)
The intriguing thermoneutral diotropic transfer of hydro en (1 23) f (1 24)

9!1
occurs 30 times faster than the retro-Diels-Alder reaction.
144 (a) J. Tamariz and P. Vogel, Helv. Chim. A ct a, 1981, 64, 188; ( b ) C. Mahaim and
P. Vogel, ibid., 1982,65,866.
Y.D. Xing and N. Z. Huang, J, OR. Chem., 1982,47,140.
146 J. G. Smith and N. G. Chu, J. 0%.Chem., 1981,46,4083.
14' R. A. Burt, Y. Chiang, H. K. Hall, Jr., and A. J . Kresge, J. A m . Chem. SOC., 1982,
104,3687.
148
H.Duddeck, V. Wiskamp, and D. Rosebaum, J. Org. Chem., 1981,46,5332.
149
J. P. Hagenbuch, B. Stampfli, and P. Vogel, J. A m . Chem. SOC.,1981, 103,3934.
dH
(121a) R = Me
(121b) R = H
- H+
& OH
o$X
Brid ed Peroxides. - Discussions of the mechanism 0f,lSoa and solvent effects

in,'' 4 the reaction of singlet oxygen with conjugated dienes include examples
of bicyclic peroxides. The photo-oxygenation of 1,4-disubstituted naph-
thalenes is thought to proceed partly via '02and partly via the 0;.radical
anion.lSoc A hitherto unknown 1,4-adduct from singlet oxygen and cyclo-
octatetraene (125) has been is~lated'~'' and the isomeric adduct (126) has
been converted into oxygen-functionalized derivatives [such as the triepoxide
(1 27)? Photo-ox genation of 7-substituted cycloheptatrienes's2D and
substituted furans's2'9c extends earlier work on the parent systems. Photo-
sensitized oxygenation of (128) gives (129) or (130), depending on con-
d i t i o n ~addition
; ~ ~ ~ to a 1,4-diazepine gives the bicyclic peroxide (131).lM
(126)
150 (a) B. M. Monroe, J. Am. Chem. SOC., 1981, 103, 7253; (b) M. Matsumoto and
K. Kuroda, Synth. Commun., 1981, 11, 987; (c) J. Santamaria, Tetrahedron Lett.,
1981,22,45 11.
( a ) W. Adam and G. Hug, Tetrahedron Lett., 1982, 23, 3155; (b) W. Adam,
0. Cueto, 0. de Lucchi, K. Peters, E. M. Peters, and H. G. von Schnering, J. Am.
Chem. SOC.,1981, 103, 5822.
( a ) T. Asao and M. Yagihara, Heterocycles, 1981, 15, 985; (b) M. L. Graziano, M. R.
Iesce, B. Carli, and R. Scarpati, J. Heterocycl. Chem., 1981, 18, 1105; (c) B. L.
Feringa and R. J. Butselaar, Tetrahedron Lett., 1981, 22, 1447.
l S 3 W. Ando, H.Miyazaki, K. Ueno, H. Nakanishi, T. Sakurai, and K. Kabayashi, J. Am.
Chem. SOC., 1981, 103, 4949; H-S. Ryang and C. S. Foote, ibid., p. 4951. See also
H-S.Ryang and C . S. Foote, Tetrahedron Lett., 1982, 23, 2551 for a study of acid-
catalysed decomposition of (129).
lS4 V. T. Ramakrishnan and J. H. Boyer, Heterocycles, 1981, 16, 1345.
Studies on endoperoxide analogues of prostaglandins and

the paths that are followed on decomposition of bicyclic peroxides such as
(1 32) in the presence of p a l l a d i ~ m ( 0 ) ' and
~ ~ ~r ~ t h e n i u m ( I I ) ' ~have
~ ~ been
investigated, as has the breakdown of (133) in the presence of PPh3.15' The
thermal decomposition of (134) leads t o (135) when R1 = R2 = Me but gives
a mono-oxiran derivative with other bridgehead sub~tituents.'~~ Loss of COz
constitutes the major pathway in the thermal decom osition of (136)'" and
the detailed mechanisms of the photodissociation'6ga and thermal. dissoci-
ation160b of endoperoxides that are derived from aromatic compounds have
been investigated.
(CH2In
COOMe
R R > b o
( 1 3 2 ) RR = b o n d , n = 2
";:>lk:
R1 0'
( 1 3 4 ) R1. R2= Me, Ph

Me$ T j M e
(133) R = H, n = 1 (135)
R3= H o r COOMe
Ph
I
5 Sulphur-containing Compounds
ortho-Quinonoid compounds undergo [4 + 41 addition with meso-ionic
heterocycles; an adduct (1 37) from a 1,3-thiazolium-4-olate is shown.16' The
lS5 A. J. Bloodworth and H. J. Eggelte, J. Chem. SOC., Perkin Trans. 1 , 1981, 3272, and
references therein.
( a ) M. Suzuki, Y. Oda, and R. Noyori, Tetrahedron Lett., 1981, 2 2 , 4413; (b) M.
Suzuki, R. Noyori, and N. Hamanaka,J. Am. Chem. SOC.,1982,104,2024.
15' E. L. Clennan and P. C. Heah,J. Org. Chem., 1981,46,4107.
158
M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Chem. SOC.,Chem. Commun., 1981,
720 (cf. ref. 146a in last year's Report).
l S 9 J. P. Smith, A. K. Schrock, and G. B. Schuster, J. A m . Chem. SOC.,1982,104, 1041.
(a) S-Y.Hou, C. G. Dupuy, M. J. McAuliffe, D. A. Hrovat, and K. B. Eisenthal, J.
Am. Chem. SOC.,1981, 103, 6982; (b) N. J. Turro, M-F. Chow, and J. Rigaudy, ibid.,
p. 7218.
16' W. Freidrichsen, W. D. Schroer, I. Schwartz, and A. Boettcher, 2. Naturforsch. TeiZ.
B , 1981, 36, 609.
462 Heterocyclic Chernis try
Ar
I 0
Ar K
(138) ( 1391
(137 1
(R1, R2 = a l k y l , a r y l )
NNPh Ph
(140) (141) (142)
(R = alkyl)
primary products (1 38) from the reaction of maleic anhydride with enamine-
thiones rearrange to the bicyclic system (139).162 Treatment of (140) with
alkali produces (1 4 l), which equilibrates with the triazinecarboxylate
(142).163 A total synthesis of gliotoxin (143) and related compounds has
been describedlM and work with bridged thia[ 17lannulenes is r e ~ 0 r d e d . l ~ ~
The bicyclic sulphonium salt (144) is attacked by soft nucleophiles at C-6 and
by hard nucleophiles at C-1 Some intriguing thermal and photochemical
transformations of (145) have been shown to proceed via vinylketen inter-
mediate~.~~'
0
X X
(144) X = O A c
(143) 1
( 1 4 5 a ) R = H , €IOAc
2=
( 1 4 5 b ) R1R2= 0
16' G. Adiwadjaja, T. Roll, and W. Walter, Tetrahedron L e t t . , 1981, 22, 3175.

J . Gasteiger, U. Strauss, and U . Schubert, Angew. Chem., Int. Ed. Engl., 1981, 20,
867.
164 T. Fukuyama, S-I.Nakatsuka, and Y . Kishi, Tetrahedron, 1981, 37,2045.
165 T. M. Brown, W. Carruthers, and M . G. Pellatt, J. Chem. SOC.,Perkin Trans. 1 , 1982,
483.
I. Lundt and B. Skelbaek-Pederson,Acta Chem. Scand., Ser. B , 1981, 35, 637.
16' T. Miyashi, N. Suto, T. Yamaki, and T. Mukai, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 4 4 2 1 .
Bridged Systems 463
Me, ,Me Me ye
'5i-0
X
' x
2 (147) ( X = COOMe) Ph
( 1 4 6 ) R1, R = H , C1,
o r Me (148)
6 Silicon- and Germanium-containing Compounds

2-Silabicyclo [2.2.1] heptanes (146) constitute a new class of bicyclic bridged
silanes.168 The thermal and photolytic decomposition of (1 47) has been
shown to give (148) via a radical mechanism,169contradicting an earlier study.
Pyrolysis of (149) gives ~ilaethenes.'~'Upon photolysis, (1 50a) interconverts
with the product of di-n-methane rearrangement (1 Sob), although the irrever-
sible formation of tetramethyldisilene (which can be trapped by reactive
dienes) is rapid at room temperature.171J1na The closely related example
(151a) yields (1S1b).'72b
-CF3
(150a) X = Si-Si bond (150b)
( 1 4 9 ) X = H , D , or C1
(151a) X = 0 , SiMe2, (151b)
CH2, etc.
1,l-Dimethylgermole has been prepared for the first time, and trapped as
the maleic anhydride a d d ~ c t dimethylgermylene,
;~~~ generated thermally
from (152), behaves as a singlet species in its additions to conjugated
dienes. 174 Me
Ge2
(152)
168
S. E. Cremer and C. Blankenship, J . Org. Chem., 1982,47, 1626.
169
T. J . Barton, W. F. Goure, J . L. Witiak, and W. D. Wulff,J. Organomet. Ch e w. , 1982,
225, 87.
170
G. Maier, G. Mihm, and H. P. Reisenauer, Angew. Chem., Int. Ed. Engl., 1981, 20,
597.
171
J . D. Rich, T. J . Drahnak, R. West, and J . Michl, J. Organornet. Chem., 1981,212, C1.
172
Y. Nakadaira, T. Otsuka, and H. Sakurai, Tetrahedron Let t ., 1981, 22 ( a ) p. 2417;
( b ) p. 242 1.
1 73
A. Laporterie, G. Manuel, J . Dubac, P. Mazerolles, and H. Iloughmane, J. Organomet.
Chern., 1981,210, C33.
114
M. Schriewer and W. P. Neumann, Angew. Chem., Int. Ed. Engl., 1981,20, 1019.
II
0
Me
7 Phosphorus-containing Compounds
The conformational limitations that are imposed upon phosphorus in bicyclic
systems are illustrated by the surprising conversion of (153) into (154), in
which attack occurs at the methyl rather than benzylic carbon, owing to the
inability of the benzylic group to become apical in the trigonal-bipyramidal
intermediate.17'
Me
Adducts, e.g. (1 5 9 , are formed when 1-phenylphospholes are heated with

dienophiles such as diphenylethyne; they are the result of preferential trap-
ping of the 2-phenylphosphole t a ~ t 0 m e r . l ~Interception
~ of the 1,4-
diphosphabenzene (157) [formed from the 1,4-diphosphabarrelene (1 56)]
gives a range of bicyclic adducts, including (1 58).'" Pyrones give short-lived
cyclo-adducts (1 59) with P~CZP.'~'Tervalent phospholes have been trapped
with dien~philes'~' and syntheses of (160)180a and (161)'sob have been
recorded.
17' L, D. Quinn and S. C. Spence, Tetrahedron Lett., 1982,23,2529.
F. Mathey, F. Mercier, C. Charrier, J . Fischer, and A. Mitschler, J. A m. Chem. SOC.,
1981,103,4595.
177 Y. Kobayashi, S. Fujino, and I. Kumadaki, J. A m . Chem. SOC.,1981, 103,2465.
178
G. Markl, G. Y. Jin, and E. Silbereisen, Angew. Chem., Int. Ed. Engl., 1982,21, 3 7 0 .
179 F. Mathey and F. Mercier, Tetrahedron Lett., 1981, 2 2 , 319.
(a) Y. Kashman and A. Rudi, Tetrahedron L e t t . , 1981, 2 2 , 2695; ( b ) Mazhar-ul-
Haque, W. Horne, S. E. Cremer, and J . T. Most, J. Chem. SOC.,Perkin Trans. 2 , 1981,
1000.
Bridged Systems 465
I \
Ph Ph
(160) Z = 0 or "We2 (161)
( + endo-isomer)
8 Boron-containing Compounds
1-Bora-adamantane (1 62)"la forms 1 : 1 complexes with carbonyl com-
pounds; these complexes rearrange on heating to give (163), usually as the
corresponding dimer.18'* The reaction of (162) with N-chloro-amines yields
(1 64).181b
c1
9-Borabicyclo[3.3.l]nonane (9-BBN) has found use in the selective hydro-

boration of alkenes in the presence of other reducible functional groups182
and its reaction with alkynylstannates has been studied.'83 cuStanny1- and
a-silyl-substituted crotyl-9-BBN show promise as reagents for the stereo-
regulated synthesis of acyclic systems.'@ A series of papers covers the
question of olefin-alkyl exchange in B-alkyl-9-BBN'~,'~~~ the kinetics of
reduction of substituted benzaldehydes with 9-BBN,'= and the kinetics and
mechanism of hydroboration of alkynes with 9-BBN dimers.lac Selective
dehalogenation of tertiary alkyl, benzyl, and ally1 halides in the presence of
secondary or primary alkyl or aryl halides is possible with (165).'86 The
"' (a) B. M . Mikhailov and T. K. Baryshnikova, J. Organomet. Chem., 1981, 219, 295;
(b) B. M. Mikhailov, T. K. Baryshnikova, and A. S. Shashkov, ibid., p. 301 ; (c) B. M.
Mikhailov, E. A. Shagova, and M . Y. Etinger, ibid., 1981, 220, 1.
182
H. C. Brown and J . C. Chen, J. Ow. Chem., 1981,46, 3978.
183
B. Wrackmeyer and C. Bihlmayer, J. Chem. SOC.,Chem. Commun., 1981,1093.
la4 Y. Yarnarnoto, H. Yatagai, and K. Maruyarna, J. A m . Chem. SOC.,1981, 103, 3229.
( a ) M . M . Midland, J . E. Petre, S. A. Zderic, and A. Kazubski, J. A m . Chem. SOC.,
1982, 104, 528; (b) M . M . Midland and S. A. Zderic, ibid., p. 525; (c) K. K. Wang,
C. G. Scouten, and H. C. Brown, ibid., p. 531.
H.Toi, Y. Yamamoto, A. Sonoda, and S. I. Murahashi, Tetrahedron, 1981, 37,2261.
lithium salt of 9-BBN catalyses the reduction of esters by LiBH,; B-methoxy-

9-BBN also permits the rapid and efficient reduction of esters by LiBH4 in the
presence of other reducible groups such as chloro and nitro.lB7
18' H. C. Brown and S. Narasimhan, J. Org. Chem., 1982,47, 1604.

Heterocyclic Chemistry - Vol4

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Heterocyclic Chemistry - Vol4

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A Review of the Literature Abstracted

The Royal Society of Chemistry

All Rights Reserved

Printed in Great Britain

Volume 4 includes the abstracted literature on heterocyclic chemistry between

H. Suschitzky and 0. Meth-Cohn

Chapter 1 Three-Membered Ring Systems 1

Chapter 2 Four-Membered Ring Systems 57

Part I I Systems containing Nitrogen and Sulphur,

15 Thiadiazoles and Selenadiazoles 190

Part I I I Other Five-Membered Ring Systems 20 1

Chapter 4 Six-Membered Ring Systems 285

Part I I Six-Membered Rings containing Oxygen

Chapter 5 Seven-Membered Ring Systems 389

3 Azepines and Diazepines 389

Chapter 6 Eight-Membered and Larger Ring Systems 4 19

Chapter 7 Bridged Systems 44 1

J . Chuche, Bull. SOC.Chim. Belg., 1981, 9 0 , 535.

lo Mitsubishi Petrochemical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 05 471.

Photo-epoxidation of alkenes in the presence of benzoins and oxygen has

(4) (5) CH2 CH2

The site-selectivity of oxidations by mCPBA is demonstrated in the con-

29 R. Y . S. Tan, R . A. Russell, and R. N. Warrender, Aust. J. Chem., 1981, 34,421.

34 H. J . Schneider, N. Becker, and K. Philippi, Chem. Ber., 1981, 114,1562.

A few years ago, hexafluoroacetone was shown to be an effective catalyst

Base-catalysed epoxidation of norandrostenone ( 19), using H202 in

remove the HCl that is generated during c y c l i ~ a t i o n The

T. B. S. Giddey, S. Afr. P. 7 8 0 5 961.

The use of KCN in the synthesis of oxirans from a-bromo-ketones under

62 K. Takahashi, T. Nishizuka, and H. Iida, Synth. Commun., 1981, 11, 757.

The sulphonium ylides (42; R4 = R1R2C=CHCH2or R3CH2), derived from

The first examples of reactions of non-stabilized selenium ylides with

difference in rates of epoxidation of the enantiomeric alcohols; in the case

In a series of papers, the application of titanium alkoxide catalysts to the

70 W. R. Roush and R. J . Brown, J . Org. Chern., 1 9 8 2 , 4 7 , 1371.

tartrate.74 Under the conditions of such epoxidations it is surprising to note

74 K. Mori and H. Ueda, Tetrahedron, 1981, 37, 2581.

Highly stereoselective epoxidations of acyclic homoallylic alcohols have

An efficient process for the synthesis of a,P-epoxy-aldehydes from a,P-

78 E. D. Mihelich, K. Daniels, and D. J . Eickhoff, J. Am. Chem. SOC.,1981, 103, 7690.

(66) (67) (68)

which octene is present in sufficient quantities to serve as the second phase.

The epoxysuccinate (2R ,3R)-(70) (94%) is prepared from (2S,3S)-(69)

Synthesis and Reactivities of Aromatic Oxides. The synthesis and absolute

L. R. Hillis and R. C. Ronald, J. Org. Chem., 1981, 46, 3348.

The hexahydrophenanthrene 9,lO-oxide (76) has been synthesized,

A possible explanation for the difference in carcinogenicity of K - and bay-

86 J. M. Sayer, H. Yagi, J . V. Silverton, S. L. Friedman, D. L. Whalen, and D. M. Jerina,

The first examples of syn stereoselective epoxidation of arene dihydro-

The enantiomeric bay-region diol epoxides of benz[a]anthracene (84) and

91 D. R. Boyd, G . S. Fadaginamath, N. D. Sharma, A. F. Drake, S. F. Mason, and D. M.

Miscellaneous Syntheses of Oxirans. The vinyl-oxirans (97; R' = Ph or

Diazomethane reacts with (98) in the presence of Et3N to give a mixture

94 I. Yona and J . Blum, J. Heterocycl. Chem., 1981, 18, 1473.

Reagents: i, CH,N,, Et,N; ii, CH,N,

When the valence tautomer of cyclo-octa-1,5-diene (stable below - 20 "C)

Reagents: i, heat, ii, mCPBA; iii, PPh,

measurements on the degradation products (1 14) and (1 15), both of which

(118) (119) ( 120)

lo6 A. P. W. Bradshaw, J . R. Hanson, D. N. Kirk, and P. M. Scopes, J. Chem. Soc.,

The mechanism for the gas-phase reaction of trans-2,3-dideuterioethene