Heterocyclic Chemistry Volume 4
A Specialist Periodical Report
Heterocyclic Chemistry Volume 4 A Review of the Liter...
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Heterocyclic Chemistry Volume 4
A Specialist Periodical Report
Heterocyclic Chemistry 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 gridsheets 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 By T. J. Mason
1
1 Reviews General Rings containing Oxygen Rings containing Nitrogen Rings containing Sulphur 1 1
2 Oxirans Preparation Oxidation of Alkenes, using Oxygen or Oxygencontaining Gases Oxidation of Alkenes by Peroxy-acids Oxidation of Alkenes, using Peroxides Synthesis by Halohydrin Cyclizations and Related Reactions Synthesis via Attack of a Carbanion on the Carbonyl Group of Aldehydes and Ketones Synthesis of Chiral Oxirans Synthesis and Reactivities of Aromatic Oxides Miscellaneous Syntheses Spectra and Theoretical Chemistry Reactions Ring-opening Reactions with Electrophiles Cyclization Reactions N ucleophilic Ring-opening Reactions With Oxygen Nucleophiles With Nitrogen Nucleophiles With Sulphur Nucleophiles With Carbanions Reduction and Elimination Reactions Thermal and Photochemical Reactions Reactions with Organometallic Compounds Miscellaneous Reactions
9 11 15 19 21 22 22 23 25 25 28 28 30 33 34 38 39
3 Aziridines Preparation By Direct Insertion
40 40 40
1 3 5 7
Heterocyclic Chemis0
viii
By Cyclization Reactions By Ring-contraction Reactions Synthesis of Chiral Aziridines Spectral and Theoretical Studies Reactions Thermal Reactions Ring-opening to Acyclic Compounds Formation of Other Ring Systems
42 43 43 43 44 44 45 46
4 Azirines Preparation Reactions
47 47 48
5 Thiirans Preparation Reactions The Chemistry of Thiiranium Ions
49 49 50 51
6 Thiirens
51
7 Diaziridines
52
8 Diazirines
53
9 Dioxirans
54
10 Oxaziridines
Chapter 2 Four-Membered Ring Systems By T. V. Lee
54
57
1 Highlights and Reviews
57
2 Systems containing One Nitrogen Atom Azetidines and Azetines Azetidinones
57 57 58
3 Systems containing Two Nitrogen Atoms or One Nitrogen Atom and a Second Heteroatom
63
4 Systems containing Oxygen Oxe tans Dioxetans
65 65 66
5 Systems containing Sulphur
67
6 Miscellaneous Four-Membered Rings
68
Contents
ix
Chapter 3 Five-Membered Ring Systems By G. V. Boyd, S. Gronowitz, 0. Guilloton, and H. Quiniou Part I Thiophens and their Selenium and Tellurium Analogues
71
71
By S. Gronowitz 1 General
71
2 Monocyclic Thiophens Synthesis by Ring-closure Reactions C4 + S Principle C2S + C2 Principle CS 3- C3 Principle Ring-closure of C4S Ring-closure of CzSCz Synthesis from Other Rmgs From Di- and Tetra-hydrothiophens From Other Sulphur Heterocycles From Other Rings Physical Properties of Monocyclic Thiophens Theoretical Calculations Photoelectron and Ultraviolet Spectra Infrared and Raman Spectra Nuclear Magnetic Resonance Mass Spectrometry X-Ray Investigations Miscellaneous Physical Properties Electrophilic Substitution Reactions Electrophilic Ring-closure Reactions Nucleophilic and Radicaloid Substitution Reactions Organometallic Derivatives Lithium Magnesium Mercury, Zinc, and Copper Transition Metals Silicon Photochemistry Cycloaddition Reactions Desulphurization and Hydrogenation of Simple Thiophens Structures and Reactions of Hydroxy-, Mercapto-, and Amino-thiophens Reactivities of Side-Chains Reactions of Thiophen Aldehydes, Ketones, and Carboxylic Acids Reactions of Vinylthiophens and Related Compounds
72 72 72 73 73 74 75 75 75 76 76 77 77 78 78 78 79 79 80 80 83 86 88 88 92 92 92 93 93 95 97 99 101 102 104
Heterocyclic Chemistry
X
Reactions at Benzylic Positions Various Reactions in the Side-Chains of Thiophens Macrocyclic Thiophens Reaction at Sulphur: Thiophen Dioxides Di- and Tetra-hydrothiophens Arylthiophens and Di- and Poly-heterocycles Naturally Occur ring T hio p hens Thiophen Analogues of Steroids Thiophens of Pharmacological Interest Therapy of the Central Nervous System Pharmacodynamic Agents Therapy of Metabolic Diseases Therapy of Infectious Diseases Veterinary and Agricultural Agents Miscellaneous Activities Thiophens of Technical Interest Polymers from Thiophen
104 105 105 106 108 111 113 114 114 114 115 115 116 118 118 119 119
3 Eknzo[ blthiophens and their Benzo-fused Systems Benzo [b] thiophens Synthesis Physical Properties Reactions Benzo [ b ]thiophen S-Oxides Benzo [ c ]thiophens Dibenzothiophens Pharmacologically Active Compounds
120 120 120 12 1 12 1 123 123 124 124
4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Analogues of Anthracene and Phenanthrene Polycyclic Thiophens Thiophen Analogues of Indene Various Carbocycle-fused Systems
125 125 125 127 128
5 Thiophen Fused to Five-Membered Heteroaromatic
Rings Thieno-, Furo-, and Pyrrolo-thiophens Thiophen Fused to Various Five-Membered Rings
129 129 131
6 Thiophen Fused to Six-membered Heteroaromatic Rings Thiophen Analogues of Quinoline Thiophen Analogues of Isoquinoline Pyrimidine-fused Systems Miscellaneous Fused Systems
131 131 132 133 135
7 Selenophens and Tellurophens Monocyclic Selenophens
136 136
Contents
xi Condensed Selenophens Tellurophens
Part I I Systems containing Nitrogen and Sulphur, Selenium, or Tellurium By H. Quiniou and 0.Guilloton
137 138
138
1 Introduction and Reviews
138
2 Isothiazoles Synthesis From Dicyanoacetylene and Sulphur Dioxide (Type A: C-C-C-N + S) From 0-Benzoylpropionamides and Th ionyl Chloride (Type A) From 1,3,2-Oxathiazol-5-ones(Type B; S-N-C + C-C) From 3,3’-Disulphanedipropionyl Chloride and Amine (Type H; S-C-C-C + N) From Aqueous Ammonia and Thioamide Vinylogues (Type H) From Ring-Cleavage of 3 -Azidot h io ph ens From Substituted Enamines and Benzyl Isothiocyanate (Type C-C-N + S-C) Physical Properties Chemical Properties N-Qu at er niz at ion o f Isothiazole s Reactions of 5-Aminoisothiazoles A3-Is0thiazolines Chemical Properties of Isothiazoline-5-thiones A4-1sothiazolines Chemical Properties of Isothiazolin-3-ones Isothiazolidines Physical Properties of Isothiazolidine 1,l -Dioxides
139 139
3 1,2-Benzisothiazolesand their 1,l-Dioxides Synthesis From ortho-Halobenzoyl Compounds, Aqueous Ammonia, and Elemental Sulphur Reactions Reduction 3-Chloro-substitution Photochemistry Synthesis of 1,2-Benzisothiazolin-3-ones and their 1,l-Dioxides From 2-(Methylsulphinyl)benzamides and Thionyl Chloride
139 139 139 140 140 140 141 141 141 141 142 143 143 143 143 143 143
144 144 144 144 144 145 145 145 145
Heterocyclic Chemistry
xii
From Anilines and 2-Chlorothiobenzoyl Chloride From 2-Aminobenzonitriles and SO2 From 2-(Chlorothio)benzoyl Chloride and Substituted Anilines From Thermal Decomposition of N-Substituted 2-(Me th ylt h io)benzamides Physical Properties of 1,2-Benzisothiazolin-3-ones Chemical Properties of 1,2-Benzisothiazolin-3-ones Hydrolysis, Alcoholysis, and Phenolysis Reactions of 1,2-Benzisothiazolin-3-ones with Amines N-Substitution of 1,2-Benzisothiazolin-3-ones 1,2-Benzisothiazoline-3-thione 1,l -Dioxides 1,2-Benzisothiazolidinesand their 1,l -Dioxides
146 146 147 147 148 148 148 148 149 149 149
4 1,2-Benzisoselenazoles 1,2-Benzisoselenazolin-3-ones
150 150
5 2,l -Benzisothiazoles
150
6 Other Condensed Ring Systems incorporating Isothiazole Thieno [2,3c] isothiazoles Isothiazolo [3,4411pyridines Isothiazolo [5,44] pyrimidines 1,2-Dithiolo [4,3c] isothiazoles Naphtho [ 2 , l d ] isothiazole Thieno [3,441isothiazole 1,l-Dioxides
151 15 1 15 1 15 1 152 152 152
7 Thiazoles Synthesis Hantzsch’s Synthesis (Type A; S-C-N From thioureas From thioamides Type B Syntheses (C-C-N C-S) Type C Syntheses (C-C-N-C + S) Type F Syntheses (C-N-C-S + C) Type H Syntheses (S-C C-N-C) Physical Properties Tautomerism of 2-Aminothiazoles Reactions of Thiazoles Reactions of Thiazolium Salts
152 152 152 152 153 154 154 154 155 155 157 157 158
+
+
8 A2-Thiazolines Synthesis Type B Syntheses (C-C-N + C-S) Type J Syntheses (C-S-C-N-C) Type K Syntheses (C-C-N-C-S) Type E Syntheses (N-C-C-S + C) Reactions
+ C-C)
160 160 160 16 1 16 1 162 162
Conten ts
xiii
9 A3-Thiazolines
10 A4-Thiazolines Synthesis Type A Syntheses (S-C-N Type B Syntheses (C-C-N Physical Properties Reactions
164
+ C-C) + C-S)
11 Thiazolidines Synthesis Type B Syntheses (C-C-N + C-S) Type E Syntheses (N-C-C-S C) By Hydrolysis of Fused-Ring Compounds Physical Proper ties Chemical Properties
+
12 Selenazoles Synthesis and Properties Type A Syntheses (Se-C-N
+ C-C)
13 Benzothiazoles Synthesis From ortho-Aminobenzenethiols (Type A; S46H4-N + C ) Type B (C6H5-N-C-S) Type E (CGH5-N + C-S) Physical Properties Chemical Properties Substitution Reactions on the Thiazole Ring Reactions of 2 -Aminobenzothiazoles Reactions of 2-Mercaptobenzothiazoles Other Reactions of Benzothiazoles Benzo t h iazolines and Benzot h iazolin -2-ones (and -thiones) Benzothiazolium Salts
14 Condensed Ring Systems incorporating Thiazole Structure comprising Two Five-Membered Rings ( 5 3 ) Thiazolo [3,241 te t razoles [CN4-C3NS] Thiazolo[2,3-c][ 1,2,4] thiadiazole [C2N2S-C3NS] Thiazolo [2,3-b][ 1,3,4]thiadiazoles [C2N2S-C3NS] Thiazolo-[2,3-c]-, -[3,2-b]-, and -[3,4-b]-[1,2,4]triazoles [C2N3-C3NS] Thiazolo[4,5-d]-oxazole, -thiazole, and -selenazole [C3NX-C3NS] Imidazo-[2,1-b]-and -[5,1-b]-thiazoles [C3N2-C3NS] Pyrrolo [2,1-b]thiazoles [C4N-C3NS]
165 165 165 167 167 168 169 169 169 169 170 170 17 1 173 173 173 174 174 174 175 175 175 178 178 179 180 180 181 18 1 182 182 182 182 182 182 183 183 184
Heterocyclic Chemistry
xiv
Structures comprising One Five-Membered and One Six-Membered Ring (5,6) Thiazolo [3,241- 1,3,5-triazines [C3NS-C3N3] Thiazolo [3,2471pyridazines [C3NS-C4N2] Thiazolo [3,2-a] pyrimidines [C3NS-C4N2] Thiazolo [5,4-b]pyridines [C3NS-CSN] Structures comprising Two Five-Membered Rings and One Six-Membered Ring (5,5,6) Benzo [ 1,2d;4,5dfIbis-thiazoles [C3NS-C3NS-C6] Benzo[d]imidazo[2 ,l-blthiazoles [C3NS-C3N2-C6] Thiazolo [3,44]benzimidazole [C3NS-C3N2-C6] Th iazolo[3',2' :1,2]imidazo [4,5-b]pyrazine [C3NS-C3N2-C4N2] Pyrrolo [2,1-b]benzothiazole [CSNS-C~N-C~] Structures comprising One Five-Membered Ring and Two Six-Membered Rings (5,6,6) 1,2,4-Triazino[3,4-b]benzothiazole [C3NS-C3N 3 -C61 1,3,5-Triazino [2,1-b] benzothiazole [C3NS-C3N3-C6] Thiazolo [2,3-b]quinazolines [C3NS-C4N,-C6] Thiazolo [3,2-a]thiapyrano [4,3-d]pyrimidines [C~NS-C~NZ-C 5x1 1,2-0xathiino[5,6-g]benzothiazoles [C3NS-C4OS-C6] Thiazolo-[2,3-a]- and -[3,4-b]-isoquinolines [C3NS-CSN-CG] Naphtho [2,3d]thiazole [C3NS-C&6] Other Condensed Systems incorporating Thiazole
15 Thiadiazoles and Selenadiazoles 1,2,3-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,2,3-Selenadiazoles 1,2,4-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,3,4-Thiadiazoles Synthesis Physical Properties Chemical Properties Condensed 1,3,4-Thiadiazoles 1,2,5-Thiadiazoles
185 185 185 185 186 186 186 186 187 187 187 187
187 188 188 189 189 189 190 190 190 190 190 19 1 191 19 1 192 192 193 193 194 194 195 195 196 196
Contents
xv Synthesis Physical Properties Chemical Properties 2,1,3-Benzothiadiazoles and 2,1,3-Benzoselenadiazoles
196 197 197 197
16 Dithiazoles and Diselenazoles 1,2,3-Dithiazoles 1,2,4-Dithiazoles 1,4,2-Dithiazoles
198 198 199 200
17 Oxathiazoles and Selenathiazoles 1,3,2-0xathiazoles 1,3,4-Oxathiazoles
200 200 200
18 Miscellaneous Ring Systems 1,3,2,4-Dithiadiazoles
201 201
Part I I I Other Five-Membered Ring Systems By G. V. Boyd
20 1
1 Introduction
201
2 Reviews
202
3 Systems with One Heteroatom and their Benzo-analogues etc. Furans Formation Reactions Benzo furans Isobenzofurans and 0ther Annelated Furans Pyrrole s Form ation Reactions Indoles and Carbazoles Formation Reactions Isoindoles Other Systems containing One Heteroatom
203 203 203 205 209 212 214 214 2 17 22 1 22 1 223 227 228
4 Systems containing Two Identical Heteroatoms Dioxoles Dithioles and Related Systems Tetra t hiafulvalenes and Related Compounds Py razoles Formation Reactions Indazoles
229 229 230 234 236 236 238 240
Heterocyclic Chemistry
xvi
Imidazoles Formation Reactions Benzimidazoles and an Imidazoquinoline
5 Systems containing Two Different Heteroatoms Oxathiole s and Selenathioles Isoxazoles Formation Reactions Benzisoxazoles and Other Annelated Isoxazoles Oxazole s Formation Reactions Benz ox az oles Benzoxaiodoles
24 1 24 1 242 244
245 245 248 248 249 250 25 1 25 1 253 258 260
6 Systems containing Three Identical Heteroatoms 1,2,3-Triazoles and Benzotriazoles 1,2,4-Triazoles Other Systems
260 260 26 1 264
7 Other Systems containing Three Heteroatoms Oxadiazoles 1,2,3-0xadiazoles 1,2,4-Oxadiazoles 1,2,5-Oxadiazoles 1,3,4-0xadiazoles Phosphorus Compounds Miscellaneous 0ther Systems
264 264 264 265 266 267 268 269
8 Systems containing Four Heteroatoms Tet razoles Other Systems
270 270 271
9 Compounds containing Two Fused Five-Membered Rings (5,5) Hypervalent Sulphur and Selenium Compounds Nitrogen Systems M onoaza-Comp ounds Diaza- and Triaza-Compounds Other Systems
272 272 273 273 274 275
10 Compounds containing Fused Five- and Six-Membered Rings (5,6) Nitrogen Systems Monoaza- and Diaza-Compounds Triaza-Compounds Tetra-aza-Compounds and a Penta-aza-Compound
276 276 27 6 277 278
Contents
xvii Mixed Oxygen-Nitrogen Systems and a Diselenoloquinoxaline
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
Chapter 4 Six-Membered Ring Systems B y 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
279
282 285
285
1 Introduction
285
2 Reviews
285
3 Azines and their Hydro-and Benzoderivatives Pyridines Synthesis Properties Reduced Pyridines Quinoline, Isoquinoline, and their Benzo- and Hydroderivatives
2 86 286 286 29 1 299
4 Diazines and their Reduced and Fused Derivatives 1,2-Diazines 1,3-Diazines 1,4-Diazines
3 12 3 12 3 14 322
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 0x azines Thiazines
336 336 339
9 Other Oxygen- and Sulphur-containing Systems Classified Reference List
34 1 344
Part I I Six-Membered Rings containing Oxygen or Sulphur By G. P. Ellis 1 Reviews
302
345 345
He twocyclic Chemistry
xviii
2 Heterocycles containing One Oxygen Atom Reduced Pyrans Pyrans Pyrylium Salts Pyran-2 -ones Pyran-3- and -4-ones Chromans Isochromans Chromenes Benzopyrylium Salts Chromanones Chromones F lav ans Flavanones Flavones I sofl av one s Dlhydrocoumarins and Dihydroisocoumarins Coumarins Isocoumarins Xanthenes and Xanthones
346 346 348 349 350 355 357 361 363 365 366 367 370 37 1 372 373 373 375 378 378
3 Heterocycles containing One Sulphur Atom T hiopyrans Thiochromans and Thiochromenes Thiochromanones Thiochromones and Thiocoumarins Thioxanthenes and Thioxanthones
380 380 38 1 382 382 383
4 Heterocycles containing One Oxygen and One Sulphur Atom Oxa thiins
383 383
5 Heterocycles containing Two Oxygen Atoms Dioxans
384 384
6 Heterocycles containing Two Sulphur Atoms 1,3-Dithians 1,4-Dithians
385 385 385
7 Heterocycles containing an Oxygen Atom in each of Two or More Rings
386
Chapter 5 Seven-Membered Ring Systems By J. T. Sharp
389
1 Introduction
389
2 Reviews
389
Contents
XiX
3 Azepines and Diazepines Azepines Formation Reactions 1,2-Diazepines Formation Reactions 1,3-Diazepines Formation Reactions 1,4-Diazepines Formation Reactions
389 389 389 394 395 395 397 399 399 40 1 40 1 40 1 403
4 Oxepins and Dioxepins Oxepins Formation Reactions D i ox epins
405 405 405 408 408
5 Thiepins
409
6 Systems containing Two Different Heteroatoms Oxazepines T hiazepines
41 1 41 1 413
7 Systems containing Three Heteroatoms
415
Chapter 6 Eight-Membered and Larger Ring Systems By J. M. E. Quirke
4 19
1 Eight-Membered Rings One Heteroatom Two Heteroatoms
419 419 42 1
2 Nine- and Ten-Membered Heterocycles
422
3 Macrocycles Other than Crown Ethers Systems containing Nitrogen as the only Heteroatom Systems containing Sulphur as the only Heteroatom Systems containing Oxygen as the only Heteroatom Syntheses of Macrocyclic Lactones Other Oxygen-containing Derivatives Other Macrocyclic Systems
423 423 427 427 427 428 429
4 Crown Ethers and Related Compounds Synthesis of Crown Ethers Reactions of Crown Ethers Applications of Crown Ethers in Organic Synthesis
429 429 432 434
Heterocyclic Chemistry
xx
Synthesis of Cryptands and Other Polycyclic Systems Host-Guest Complexes of Crown Ethers and Cryptands
Chapter 7 Bridged Systems By J. R. Malpass
43 7 439 44 1
1 General
44 1
2 Physical Methods X-Ray and Electron Diffraction Nuclear Magnetic Resonance Spectroscopy Miscellaneous Methods
44 1 44 1 443 444
3 Nitrogen-containingCompounds Synthesis Cycloadditions 0ther Cyclizations Reactions Bridged Azolkanes
445 445 445 449 450 453
4 Oxygencontaining Compounds Synthesis Cycloadditions Miscellaneous Other Methods Re actions Bridged Peroxides
45 5 45 5 45 5 457 458 460
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 hydroperoxides have been surveyed,2y3as have transition-metal-catalysed stereocontrolled epoxidations! A major review of oxiran chemistry (956 references) 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 oxirans 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 alkylidenephosphoranes 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 published in 1981 was some aspects of the chemistry of episulpho~ides.~ 2 Oxirans Preparation. - Oxidation of Alkenes to Oxirans, using Oxygen or Oxygencontaining 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. 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.
* J . Sobczak and J . J .
’
’
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-electrolyteaided oxidation of ethene on polycrystalline silver." Solid electrolyte potentiometry (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 atmospheric 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 relationship to the activity of such catalysts for epoxidation of ethene." A linear freeenergy relationship between the mean heat of formation of a monolayer of surface Ago and the catalytic activity was found. Kinetic performance parameters 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
I2
Mitsubishi Petrochemical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 05 471. Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 105 750. 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. 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. l4
2o
21
U. Barth, H. Friedler, G. Gross, G. Lauterbach, and D. Schnurpfeil, J. Prakr. Chem., 1981, 323, 887. 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 oxidizes alkenes to epoxides both thermally and photochemically, in the presence of SO2, under ambient condition^.^' Irradiation of a mixture of propene 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 precipitation 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 overnight 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
23 24
25 26
Y. Sawaki and Y . Ogata, J . A m . Chem. SOC., 1981, 103, 2049. Y. Sawaki and Y. Ogata, J. A m . Chem. SOC.,1981, 103,6455. P. D. Bartlett, A. A. M. Roof, and N. Shimizu, J. A m . Chem. SOC.,1982, 104, 3130. T. Sasaki, J. A m . Chem. SOC.,1981, 103, 3882. L. Morin, D. Barillier, M. P. Strobel, and D. Paquer, Tetrahedron L e t t . , 1981, 2 2 , 2267.
27 28
J . W. Agopovich and C. W. Gillies, J . A m . Chem. SOC.,1982, 104, 813. F. Camps, J . Coll, A. Messeguer, and A. M. Pericas, Tetrahedron L e t t . , 1981, 22. 3895.
J$,
Heterocyclic Chemi s t y
4
Ph P \ h 0
-
Ph (4)
1
P Ph h o\ ; ]
@
Fh (5)
CH2
(6)
CH2 (7)
The site-selectivity of oxidations by mCPBA is demonstrated in the conversion 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 formation 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 stereospecific isomer distribution of 27.3% and 18.2%.32Remarkable stereoselectivity 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%).
H
29
30 31
32
R. Y . S. Tan, R . A. Russell, and R. N. Warrender, Aust. J. Chem., 1981, 34,421. H. M. R. Hoffmann and H. Vathke-Ernst, Chem. Ber., 1981, 114, 1182. Meiji Seika Kaisha, Ltd.. Jpn. Kokai Tokkyo Koho 82 0 2 232. 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.
Three-Membered Ring Systems
5
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 essentially 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 epoxidation 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 (prethus a 90% yield of monopared in situ from formic acid and 85% H202); 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 peroxide 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
3s
36 37
38
H. J . Schneider, N. Becker, and K. Philippi, Chem. Ber., 1981, 114,1562. V. N. Sarancha, I. A. Opeida, and R. V. Kucher, Dopov. Akad. Nauk Ukr. RSR, Ser. B , 1981, No. 6,p. 74. A. E. Batog, T. V. Savenko, T. A. Batrak, and R. V. Kucher, Zh. Org. Khim., 1981, 17,2085. G . Kaebisch, R. Truebe, H. Wittmann, S. Raupach, and H. Malitius, Ger. Offen. 3 002 785. 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, however, and not commercially available, and so an alternative has been sought. An efficient alternative catalyst has been found to be hexafluoropropan2 - 0 1 , ~but more recently it has been reported that tetrachloroacetone is a useful 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. cisCyclo-octene oxide (20) has been prepared in 60% yield by epoxidation of 39 40 41 42 43
44
L. Kim, Br. P. 1 399 639. B. Ganem a n d R. P. Heggs, J. A m . Chem. SOC., 1979, 101, 2484. C. J . Stark, Tetrahedron Lett., 1981, 2 2 , 2089. D. S. R. Rao, Indian J. Chem., Sect. B , 1981, 2 0 , 786. I. G. Tishchenko a n d I. F. Revinski, Vestsi Akad. Navuk B S S R , Ser. Khim. Navuk, 1981, No. 1, p. 90. J. R. Hanson, P. B. Hitchcock, a n d H. J . Wadsworth, J. Chem. Soc., Perkin Trans. I , 1981, 3025.
Three-Membered Ring Systems
7
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 cyclohexene 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 transhex-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 epoxidation 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
47
48 49 51
52
R. D. Bach and J . W. Knight, Org. Synrh., 1981, 6 0 , 6 3 . E. Alneri and G. Lana, Ger. Offen. 3 027 349. A. 0. Kolmakov, V. M. Fomin, T. N. Aizenshtadt, and Yu. A. Aleksandrov, Zh. Obshch. Khim., 1981, 5 1 , 2805. H. R. Hernandez, P. S. Chow, and A. E. Rico, Rev. Ins?. Mex. Pet., 1981, 13, 6 6 . 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. D. V. Banthrope and S. E. Barrow, Chem. Ind. (London), 1981, 502. A. M. Trzeciak, J . Sobczak, and J . J . Ziolkowski, J. Mol. Catal., 1981, 1 2 , 321.
8
Heterocyclic Chemistry PCH2CH( OAc)CH2Br
H
H
WCWMe OCOMe
4- M e C6H
c1
(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 cyclization 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 intermediate (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 54
'' s6 57
59
T. B. S. Giddey, S. Afr. P. 7 8 0 5 961. Hogyoku C o . Ltd., Jpn. Kokai Tokkyo Koho 81 92 282. Sagami Chemical Research Center, Jpn. Kokai Tokkyo Koho 82 26 6 7 7 . K. S. Bhat and A. S. Rao, Indian J. Chem., Sect. B , 1981, 20, 355. 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. M. F. Haslanger and S. Ahmed, J. Org. Chem., 1981, 46,4808.
9
Three-Membered Ring Systems
OH
m
I
A
H
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,adibromo-ketones PhCOCBr2R' in the presence of SnF2.61
Gorc" Br
R
j;r' Ph CO
R
Br (34)
6o 61
COR
(36)
(35)
T-Y. Kao and S. Shang, Nan-ching Ta Hsueh Hsueh Pao, Tzu Jan K ' o Hsueh, 1980, 39. S . Shoda and T. Mukaiyama, Chem. L e t t . , 1 9 8 1 , 7 2 3 .
10
Heterocyclic Chemistry Ph
PhCOCH( B r ) P h (37)
"\T/CN 0
(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, comprising 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 surface 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 promote 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
62
63 64
Ar
K. Takahashi, T. Nishizuka, and H. Iida, Synth. Commun., 1981, 11, 757. K. Takahashi, T. Nishizuka, and H. Iida, Tetrahedron L e t t . , 1981, 22, 2389. 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.
11
Three-Membered R ing Systems
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 generated 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 67
68
69
J . P. Beny, J . C. Pommelet, and J . Chuche, Bull. SOC.Chim. Fr., Part 2 , 1981, 369. M. Rosenberger, Eur. Pat. Appl. 36 663. K. Takaki, M. Yasumura, and K. Negoro, Angew Chem., Znt. Ed. Engl., 1981, 20, 671. 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 .
Heterocyclic Chemistry
12
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 produced, 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 71
W. R. Roush and R. J . Brown, J . Org. Chern., 1 9 8 2 , 4 7 , 1371. T. Katsuki, A. W. M. Lee, P. Ma, V. S. Martin, S. Masamune, 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.,
73
K. Mori and T. Ebata, Tetrahedron Lett., 1981, 2 2 , 4 2 8 1 .
1982,47,1378.
K. B. Sharpless,
Three-Membered Ring Systems
p
Fewo):qcJ Me
13
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
H CHZOTs
f
I CH2COOEt ii 0‘
H
HO ‘ (57)
(58)
Reagents i, K,CO,, MeOH; ii, LDA
Scheme 3 74 75 76
77
K. Mori and H. Ueda, Tetrahedron, 1981, 37, 2581.
A. J. Pearson and C. W. Ong, J. Am. Chem. SOC.,1981, 103, 6686. N. Cohen, B. 1. Banner, and R. J . Lopresti, Tetrahedron Lett., 1980, 21, 4163. J. Rokach, C-K. Lau, R. Zamboni, and Y . Guindon, Tetrahedron Lett., 1981, 2 2 , 2763.
14
Heterocyclic Chemistry
(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.
- I,a,
R~CH=CR~COOH (62)
I
COCR’ =C H R ~ (63)
Scheme 4 An efficient process for the synthesis of a,P-epoxy-aldehydes from a,Punsaturated 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 corresponding 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
79
E. D. Mihelich, K. Daniels, and D. J . Eickhoff, J. Am. Chem. SOC.,1981, 103, 7690. 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.
15
Three-Membered Ring Systems H I
Me a*COOE
t
OR (66)
-
? CH20H
OS03Me (67)
-m H.
Me
Me
0
(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 naphthoquinone derivative (2S,3R)-(+)-( 75) .85
82
83 84
L. R. Hillis and R. C. Ronald, J. Org. Chem., 1981, 46, 3348. Taisho Pharmaceutical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 110 683. E. Hungerbuehler, D. Seebach, and D. Wasmuth, Helu. Chim-. A c t a , 1981, 64, 1467. 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.
Heterocyclic Chemistry
16
H@
--H
H @\
/
o @
--H
/
/
;
o
:
H
(74IH
o
0
3-Me00CC6H4 O (75)
(73)
The hexahydrophenanthrene 9,lO-oxide (76) has been synthesized, together with its diastereoisomeric isomer (77).& Both isomers are conformationally 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 transdiol 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 bayregion 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
87
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 . 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 dihydrodiols 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 configuration (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 effectively 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.
18
Heterocyclic Chemistry
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 remarkably biologically active, despite their relative lack of reactivity towards hydrolysis (as expected from simple PMO calculations).93 Both diastereoisomers prefer the conformation in which the OH groups are quasidiequatorial, and these are the most tumorigenic diol epoxides yet tested on mouse skin. 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. 91
19
Three-membered Ring Systems
Two bis-imines (94) and (95) have been prepared from the corresponding diepoxides by reaction with NaN3 and subsequent cyclization of the transazido -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
I
R3
0 (97)
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 95 96 97
I. Yona and J . Blum, J. Heterocycl. Chem., 1981, 18, 1473. Mitsubishi Chemical Industries Co. Ltd., Jpn. Kokai Tokkyo Koho 81 125 379. H. Meier and A. Binder, Chem.-Ztg., 1981, 105, 149. N. Hashimoto, T. Aoyama, and T. Shioiri, Heterocycles, 1981, 1 5 , 975.
Heterocyclic Chemistry
20
CH2C1 PhCOCOCH2N2
PhCOCOCl (98)
/
+
@COPh
(99)
(100)
1 dPh~ 1 : +
0
COCH2NH2
2
( 102)
(101)
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 endoperoxide (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.
21
Three-Membered Ring Systems CHO
'H
P 0
Torr gave (1 10) Flash vacuum thermolysis of (109) at 420 "C and 2 x (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
100
101 102
103 104
105
A. J. H. Klunder, W. Bos, J . M. M. Verlaak, and B. Zwanenberg, Tetrahedron Lett., 1981, 22,4553. D.Wirth and D. M. Lemal, J. Am. Chem. SOC.,1982,104,847. E. Toromanoff, Tetrahedron, 1981, 37, 3141. D. Pitea, R. Todeschini, and F. Gatti, J. Chem. SOC., Faraday Trans. 1 , 1981, 77, 1611. 0.Henri-Rousseau, P. Pujol, and F. Texier, Bull. SOC.Chim. Fr., Part 2 , 1980,496. M. Christl, H. Leininger, and E. Brunn,J. Org. Chem., 1982,47, 661. J. Huet, Z. Kotkowska-Machnik, and J . Zakrzewski, Org. Magn. Reson., 1981, 16, 236.
wewe
22
Heterocyclic Chemistry
MeOOCCHZCH2
Me
Me
(114)
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 determined, using gas-phase electron diffracti~n.''~
Reactions of Oxirans. - Ring-opening Reactions with Electrophiles. A ringcontraction 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) with BF3 log or with HC1O4."'
8 I
COOCH2CC13 (118)
( Y C H O
I
COOCH2CC13 (119)
ho I
COOCH2CC13 ( 120)
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. lo6
23
Three-Membered Ring Systems
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 +O I F-
+
TJ-
[ y7JHIF--[ci>].--<:,
H (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 112
G. Bellucci, G. Berti, R . Bianchini, G. Ingrosso, and A. Moroni, J. Chem. SOC., Perkin Trans. 2 . 1981, 1336. E. E. Van Tamelen and T. M. Leiden, J. Am. Chem. SOC.,1982, 104, 2061.
24
Heterocyclic 01 emistry
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,lOoxide (134) to (135) (70%)in BF3 * OEt2-acetic anhydride."' '13
'14
'IS
D. Nasipuri and A. K. Samaddar, Indian J. Chem., Sect. B , 1981, 2 0 , 261. 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. 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.
Three-Membered Ring Systems
25
Me
Me
(135)
(134)
A remarkably stereoselective intermolecular reaction occurs when trans5,6-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
P HO
(137)
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 1,2epoxybut-3-ene by hydration, using an alkali-metal iodide and a mineral acid in the acetone ~olvent.~''
-
HO
'I6 'I' 'I8
'I9
OH
S. K. Taylor, G. L. Lilley, K, J. Lilley, and P. A. McCoy, J. Org. Chern., 1981, 46, 2709. Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 9 2 2 2 8 . D. K. K. Showa, Jpn. Kokai Tokkyo Koho 81 0 8 336. Mitsubishi Petrochemical Co. Ltd., Jpn Kokai Tokkyo Koho 82 0 2 227.
26
Heterocyclic Chemistry
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 trans1,2- 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,Pepoxy-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 acidcatalysed 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
122
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. W. J . Ross, A. Todd, B. P. Clarke, S. E. Morgan, and I . E. Baldwin, Tetrahedron L e t t . , 1981, 2 2 , 2207.
27
Three-Membered Ring Systems
OOE t
Ph (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
Hoy&)n
\
RO /'
(149)
( 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) 123 124
125
(152)
oH
M. Baumann and W. Hoffmann, Synthesis, 1981, 709. G . A. Olah, A. P. Fung, and D. Meider, Synthesis, 1981, 280. R . W. Layer, J. Org. Chem., 1981, 46, 5224.
28
Heterocyclic aemistry
R1R2NH -R
ii
1 2 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 vinyloxiran (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'
12' 12* 129
L. E. Overman and L. A. Flippin, Tetrahedron Lett., 1981, 2 2 , 195. C. Herzig and J . Gasteiger, Chem. Ber., 1981, 114, 2348. J . Gasteiger and C. Herzig, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 868. A. Yashuda, M. Takahashi, and H. Takaya, Tetrahedron Lett., 1981, 2 2 , 2413.
Three-Membered Ring Systems
x3
29
'RL
(163)
(161) SC6C15
'@
R
S C6 C 1
/ R2
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
OH
ph\r.. SOMe
The unusual reactivity of selenoboranes towards epoxides gives new selective 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 13'
J . E. Baldwin, P. Cacioli, and J . A. Reiss, Tetrahedron L e t t . , 1980, 21,4971. A. Gravador and A. Krief, Tetrahedron L e t t . , 1981,22, 2491.
30
Heterocyclic Chemistry
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 presence 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, providing alkylation under neutral conditions with complete regio- and stereospecificity. 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
134
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. 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.
31
Three-Membered Ring Systems
4 - R C6 H SO
2v~-j: 4-R1s02QR2 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 equivalent 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-phenylsulphonylcyclobutanols; thus (179) yields (180).13' This reaction contrasts with that of (179) with MeLi or with LiNPr:, which gives derivatives of cyclopropylmethanol. Ph
phso>
phs+h
(179)
OH
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 organomagnesium and organolithium reagents, the cyclization affords a 1 : 1 mixture of both cis- and trans-tetrahydrofurans (1 82).
M:eAT4:
+T (181)
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 synthon. Me3Siw
136
137 138
13'
/
MgBr
Y. Gaoni, Tetrahedron Lett., 1981, 2 2 , 4339. J. M. Decesare, B. Corbel, T. Durst, and J . F. Blount, Can. J. Chem., 1981, 59, 1415. M. Chastrette and G. P. Axiotis, J. Organomet. Chem., 1981, 206, 139. H. Nishiyama, S. Narimatsu, and K. Itoh, Terrahedron Lert., 1981, 2 2 , 5289.
32
Heterocyclic Chemistry
Reactions of alkyl-lithiums with isoprene oxide (1 86) yield p,-ydisubstituted 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 mixture 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
14' 14'
M. Tamura and G. Suzukamo, Tetrahedron Lett., 1981, 2 2 , 577. J . C. Saddler and P. L. Fuchs, J. Am. Chem. SOC.,1981, 103, 2112. B. H. Lipshutz, J . Kozlowski, and R. S. Wilhelm, J. Am. Chem. Soc., 1982, 104, 2305.
33
Three-Mem bered Ring Systems OS iMe
I
OSiMe3
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 hydrogenolysis 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 complexes at 30°C under 1 atm of hydrogen gives but-2-enal as the major product .14' The hydrogenolysis of methyloxiran on unsupported Pt/C catalysts leads mainly t o Me2CHOH, and to EtCHO, whereas the aldehyde was produced 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 combination 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 mixture of (+)-(S)-(200) and (-)-(S)-(201),150 The inversion that is involved in 143 144
J. P. Marino and J. C. Jaen, J . A m . Chem. SOC.,1982, 104, 3165. G. Accrombessi, P. Geneste, J. L. Olive, and A. A . Pavia, Bull. SOC.Chim. Fr., Part 2 , 1981, 19.
14' 146
14' 14' 149
H. Fujitsu, E. Matsumura, S. Shirahama, K. Takeshita, and I. Mochida, J . Chem. SOC., Perkin Trans. I , 1982, 855. M. Bartok, F. Notheisz, and J . T. Kiss, J. Catal., 1981, 6 8 , 249. M. Kraus and H. Davidova, J. Catal., 1981, 68, 252. R. 0. Hutchins, I. M. Taffer, and W. Burgoyne, J. Org. Chem., 1981, 46, 5214. 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.
34
Heterocyclic Chemistry
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 stereoselectively, affording (E)-2,2-dimethylhex-3-ene (95%) from the corresponding (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 phenylethanol (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-.
wz’
* PhCH-
-0
I
CD2 PhCHD
Ph
1 (202 1
\
+ PhCH-CD2 I
0-
/
-CDO
(203)
Scheme 13 Cycloaddition reactions of the carbonyl ylides derived from the thermolysis 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 Is’ lS3
M. A. Umbreit and K. B. Sharpless, Org. Synth., 1981, 6 0 , 29. M. Sato and K. Oshima, Chem. Lett., 1982, 157. 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 .
35
Three-Membered Ring Systems
ph-a Me
\ /
M
MeOOC
(208)
Mee‘
O
-O
C
b
( 209 1
dipoles has been ~ t u d i e d . ”,15’ ~ The eight-electron cyclization of the conjugated carbonyl ylide (208), generated by thermolysis of (207), gave the dihydro-oxepin (209). The reaction followed the theoretically expected conrotatory process. The thermal decompositions of the three isomers of (210) all yield mixtures 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 formation of (213). The first topologically non-planar molecule (2 15) has been produced by the thermolysis of (214).15’
lS7 158
W. Eberback, E. Haedicke, and U . Trostmann, Tetrahedron Lett., 1981, 22,4953. W. Eberback and U. Trostmann, Chem. Ber., 1981, 114, 2979. 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.
Heterocyclic Chemistry
36
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 pathway 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.,
16'
P. Hallet, J . Muzart, and J. P. Pete, J. Org. Chem., 1981, 46,4275.
1982,104, 292.
Three-Membered Ring Systems
37
Carbonyl ylides that are derived photochemically from symmetrically substituted 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 opening of the oxiran ring. The ylides derived from (222; R = Me, Ar = 2naphthyl) 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 cycloaddition 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'
164
J. P. K. Wong, A. A. Fahmi, G. W. Griffin, and N. S. Bhacca, Tetrahedron, 1981, 37, 3345. J. Brokatzky-Geiger and W. Eberbach, Hererocycles, 1981, 16, 1907. N. Bischofberger, G. DeWeck, B. Frei, H. R. Wolf, and 0. Jeger, Helu. Chim. A c t a ,
16'
K. Murato, B. Frei, W. B. Schweizer, H. R. Wolf, and 0. Jeger, Helu. Chim. Acta,
16' 163
1981,64, 1766. 1 9 8 0 , 6 3 , 1856.
Heterocyclic Chemistry
38
clD -)/y
PhCH2CO0
Ph CH2 C 1
(228)
PdLm
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 complexes 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 11 166
16' 16*
(232) M. Tanaka, M. Koyanagi, and T. Kobayashi, Tetrahedron Lett., 1981,22, 3875. Teijin Ltd., Jpn. Kokai Tokkyo Koho 81 1 5 216. M. Fetizon, J. E. Ecoto, and S. Lazare, Eur. Pat. Appl. 21 952.
Three-Membered Ring Systems
39
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 prepared.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
(233)
O Ph Y O
(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 benza 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 thiazoles (236; X = S, R = Me or Ph) (78%).'74 When (235) reacts with selenourea 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. 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. 170
40
Heterocyclic Chemistry
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 haloh 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-halogenoketones. Trialkylsilyl triflate (240; X = OS02CF3) promotes the ring-opening of oxirans and affords allylic alcohol silyl ethers from tetra-, tri-, and 2,2di-substituted oxirans; thus cyclohexene oxide gives (243).'78
3 Aziridines Preparation. - Direct Insertion. Ethoxycarbonylnitrene (EtOOCN:), generated 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).
177
17' 17'
G. C. An d r e w, T. C. Crawford, and L. G. Contillo, Tetrahedron Lett., 1981, 2 2 , 3803. J. N. Denis and A. Krief, Tetrahedron Lett., 1981, 2 2 , 1429. S. Murata, M. Suzuki, and R. Noyori, Bull. Chem. SOC.Jpn., 1982, 5 5 , 247. L. Pellacani, F. Persia, and P. A. Tardella, Tetrahedron Lett., 1980, 21, 4967.
41
Three-Membered Ring Systems c1
COOEt
I
pr+pr
c1 (244)
Bu
Bu
H (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 nonconcerted 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 irradiation of N S F in the presence of perfluor~propene.'~~
"\-&;: R
1
SR
N
I
OR
Fw:3 F
N
I
SNSF2 (252)
180
lS3
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. 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)~ catalyst. 0
J
iii
\
\
X
N
BHr
R
N 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
184
0
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 .
43
Three-MemberedRing Systems
F? R1
R2
O Y N R 2
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 optically 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-alkylaziridines (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.
Heterocyclic Chemistry
44
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 aziridines 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 intramolecular 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 predictions 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) lg3
(273)
J . M. J. Tronchet, E. Winter-Mihaly, M. A. M. Massoud,and J. Guist, Helv. Chim. Acta, 1981, 64, 2350.
lg5 '91 197
199
E. Liepins, I. Kalvins, and P. T. Trapentsier, Khim. Geterotsikl. Soedin., 1981, 1231. v. D. Orlov, F. G. Yaremenko, N. V. Lishtvan, and Yu. N. Surov, Khim. Gererotsikl. Soedin., 1981, 1641. D. Kost and M. Raban,J. Am. Chem. SOC.,1982,104, 2960. K. Mueller and F. Previdoli, Helv. Chim. Acta, 1981, 64, 2508. A. M. Sapse, Int. J. Quantum Chem., Quanrum Biol. Symp., 1980, 7, 155. H. G. Zoch, E. Kinzel, and G. Szeimies,Chem. Ber., 1981, 114, 968.
45
Three-Membered Ring Systems
H
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 *
Ph 2CHCH2CH2NHS02Ph
S02Ph
(280 1
(277)
The ring-opening of aziridines by fluorinating agents yields a,P-difluoroamines. 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 '01
202
203
H. P. Figeys and R. Jammar, Tetrahedron Lett., 1981, 2 2 , 637. 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. W. J . Kensler and S. K. Dheer, J. Org. Chem., 1981,46,4051. G. M. Alvernhe, C. M. Ennakoua, S. M. Lacombe, and A. J . Laurent, J. Org. Chem., 1981.46,4938.
46
Heterocyclic Chemistry
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 '05 207
2. Blum, M. Malmberg, and K. Nyberg, Acra Chem. Scand., Ser. B , 1981, 3 5 , 739. 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 . 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.,
209
J. Budny and H. Stamm, Arch. Pharm. (Weinheim, Ger.), 1981, 314,657.
1981, 38.
Three-Membered Ring Systems
II
H ( 2 9 11
47
Ph
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
'
R CH
NOR^ IICNH
( 296) 210
A. Hassner, R. D'Costa, A. T. McPhail, and W. Butler, Tetrahedron L e t t . , 1981, 2 2 ,
'11
3691. G. L'abbh, J . P. Dekerk, and P. Van Stappen, Bull. SOC.Chim. Belg., 1981, 90, 1073.
Heterocyclic Chemistry
48
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 isoxazoles (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 = various alkyl groups) to the azirine (303; R' = Ph, R2 = Me, R3 = NMe2).2149215
0: +
(308) H ( 306)
(307)
Reagents: i, MeNCO;ii, R4RsC=C=S, iii, Li,iv, CH,N,; v, Pd(PPh,),
Scheme 16 212
'I3 214 21s
J. A. Hyatt, J. Org. Chem., 1981, 46, 3953. J . D. Perez, G. I. Yranzo, and D. A. Wunderlin, J. Org. Chem., 1982, 47, 982. E. Schaurnann, S. Grabley, and G. Adiwidjaja, Liebigs Ann. Chem., 1981, 264. E. Schaumann, S. Grabley, F. F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs Ann. Chem., 1981, 277.
Three-Membered Ring Systems
49
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%.
217
'18 219 220
T. C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2905. T, C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2909. T. Izumi and H. Alper, Organometallics (Washington, D . C . ) , 1982, 1, 322. A. Hassner, B. A. Belinka, and A. S. Steinfield, Heterocycles, 1982, 18, 179. C. Bernard-Henriet, P. Hoet, L. Ghosez, and R. Touillaux, Tetrahedron Lett., 1981, 2 2 , 4 7 1 7.
221 222
S. Kato and K. Morokuma, Chem. Lett., 1981, 1021. B. F. Bonini, G. Mazzanti, S. Sarti, P. Zanirato, and G. Maccagnani, J. Chem. SOC., Chem. Commun., 1981, 822.
Heterocyclic Chemistry
50
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 prepared 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
A&
I
H
S
+
H
(316 1
(318)
( 317)
(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 carbonylthiocarbonyl ylide (322), which undergoes electrocyclization to the thiiran product (323).
"""& ~
Ph
mJ
Ph
-A2N>d73_ph Ph
Br-
(320)
0
(319)
-"~h?iPh
Ph
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). Intermediate (325) is also involved in the fragmentation of (326). Deuterium labelling 223 224 225 226
R. C. Cambie, G. D. Mayer, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC., Perkin Trans. I , 1981, 52. W. Ando, Y. Haniu, and T. Takata, Tetrahedron Lett., 1981,2 2 , 4815. A. Corsaro, M. Tarantello, and G. Purrello, Tetrahedron Lett., 1981,2 2 , 3 3 0 5 . L. Carlsen and H. Egsgaard, J. Chem. SOC.,Perkin Trans. 2, 1982,279.
51
7%ree-Membered Ring Sys tems
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 mechanism 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 thiiran and a ~ i r i d i n e . ~The ~ ’ main reaction of the molecular ion of thiiran 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 temper atwe. 232
yR2
R1
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. 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. 228
”’
52
Heterocyclic Chemistry Me CO
COMe
Ph
5
Me
02
(334) (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. 236 237
G.Tomaschewski, U. Klein, and G. Geissler, Tetrahedron Lett., 1980,21,4877. 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.
Three-MemberedRing Systems
53
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 mechanism has been investigated and shown to proceed through initial N-halogenation; e.g. , (348) from RC(NH)NH2 (R = Pr' or MeO)?41 A subsequent 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
/p 1
N-NC1
-.
R
ClN=CRNHCl
LA J
R
X
c1-
Thermal decomposition of (347; X = C1, R = CF3) produces (trifluoromethyl)chlorocarbene, which, in the presence of cyclic dienes, gives ringexpanded 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)
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. 240
Heterocyclic Chemistry
54
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, cyclopropene, 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 Me HOK ' O(353)
M e 3 x( C354 H =1C H C O M e
(355)
10 Oxaziridines An improved synthesis of 2-sulphonyloxaziridines has been reported.251Oxidation 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 transstilbene 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
14' 14'
14' 15' 252
253
R. Becerra, J . M. Figuera, V. Menendez, A. Tobar, and R. Marinez-Utrilla, An. Quim., Ser. A , 1981, 77, 63. W. Von Niessen, W. P. Kraemer, and J . Schirmer, J . Chem. SOC.. Faraday Trans. 2 , 1981, 77, 1461. W. Adam and R. Curci, Chim. Ind. (Milan), 1981, 6 3 , 20. 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. F. A. Davis and 0. D. Stringer, J. Org. Chem., 1982, 47, 1774. F. A. Davis, N. F. Abdul-Malik, S. B. Awad, and M. E. Harakal, Tetrahedron Lett., 1981, 22, 917. 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. D. St. C. Black and L. M. Johnstone, Angew. Chem., Inr. Ed. Engl., 1981, 2 0 , 669.
256
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 preparation 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
NaBH4
3 distil
(1)
Meb
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
Heterocyclic Chemistry
58 Me
I
PhCH=NCCOOMe
I Li
+
Me
OK7hMe COOMe
Ph
I
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-aminocyclohexanones6 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 azetidin2-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
iii
0
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 presence of zinc metal.12 Cyanuric chloride has been shown to activate the la 'l
''
M. Ohno, S. Kobayashi, T. Iimori, Y-F. Wang, and T. Izawa, J. Am. Chem. Suc., 1981,103,2405. 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.
60
Heterocyclic Chemistry
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-chloromethylcarbamates (14), in the presence of titanium tetrachloride, results in the formation of a-ureidomethylated carboxylates (15), which are readily converted Me
,OS i M e
I BrCH2CCOC1
COOCH2Ph
I
+
I
Br
N\Me
H2,Pd/C -
-
,
base
Me
I
Ha C- NCOOCH2Ph
Me
COOMe
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 preparation 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 azetibinones. OH
l$3
0
-om OTs
Reagents: i, 2 equiv. of BunLi, THF, at - 7 8 " C ;ii, toluenep-sulphonyl chloride;
iii, 2 5 " C.
Scheme 4 l3
l4 l6 l7 la
M. S. Manhas, A. K. Bose, and M. S. Khajavi, Synthesis, 1981, 209. 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. Y. Watanabe and T. Mukaiyama, Chem. Lett., 1981,443. K. Ikeda, Y. Terao, and M. Sekiya, Chem. Pharm. Bull., 1981, 29, 1747. 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.
Four-Membered Ring Systems
61
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 substituent 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
21 22
'' 24
S. V. Ley and E. M. Hebblethwaite, Eur. Pat. Appl. 38661. (Chem. Abstr., 1982, 96, 181 0642). A. J. Biloski, R. D. Wood, and B. Ganem, J . A m . Chem. SOC.,1982, 104,3233. 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, Terrahedron, 1981, 37, 715. 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 presumably arise via a [27r + 27r] cycloaddition followed by elimination of a molecule of nitrogen.
Me
$yL
+ Ph
NPh
/Aph-
-#
Me
M e
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 ROH
ic
clQoR 0
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-2one (25) in the presence of trimethylsilyl trifluoromethane~ulphonate.~~ OSiMe
+
Me S i-OT f
&R2
R1
F
~ NSiMe3 ~ O
R
0
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 4alkylidene derivative by elimination of benzenesulphenic acid .28 Full details of a cyclization reaction of 4-acetoxyazetidin-2-ones have a~peared.~’
’’ 26 21
29
I. Yamamoto, I. Abe, M. Nozawa, J . Motoyoshiya, and H. Gotoh, Synthesis, 1981, 81 3 . M. D. Bachi and A. Gross, J. Chem. SOC.,Chem. Commun., 1981, 959. 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. T. Kametani, T. Honda, J . Sasaki, H. Terasawa, and K. Fukumoto, J. Chem. SOC., Perkin Trans. I , 1981, 1884.
~
Four-Membered Ring Systems
63
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 ringopening reaction to give, it is believed, the unstable guanidine derivative (31), which cyclizes to a triazine upon addition of an aromatic amine.32 Ph PhNNPh
Ph D C0Cl2
Ph
Ph
(30)
0
PhN
Ph
/k
NPh PhNH2
Ph N ANANPhPh
30 31
32
1
Ph
clKNYNKcl NPh
NPh
0
(31)
S. Kano, S. Shibuya, and T. Ebata, J. Heterocycl. Chem., 1981, 18, 1239. B. Venugopalan, A. B. Hamlet, and T. Durst, Tetrahedron Lerr., 1981, 2 2 , 191. R. Richter and M. Ultich,J. Org. Chem., 1981, 46, 3011.
Heterocyclic Chemistry
64
A short series of papers by Taylor and co-workers has highlighted the synthetic 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
COOMe
COOMe
COOMe
N
Ph
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 ringexpansion to an oxadiazine upon treatment with acetic anhydride.33 Conversion 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
Me
0
~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 34
35
36
E. C. Taylor, R. J. Clemens, H, M. L. Davies, and N. F. Haley, J. A m . Chem. SOC., 1981, 103, 7659. 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 . E. C. Taylor, N. F. Haley, and R. J . Clemens, J. A m . Chem. SOC., 1981, 103, 7743. A. Dondoni, P. Giorgianni, A. Battaglia, and G. D. Andreetti, J. Chem. SOC.,Chem. Commun., 1981, 3 5 0 .
Four-Membered Ring Systems
65
Furthermore, 1,2:thiazetidine 1-oxides are the products from N-sulphinylsulphonamides and dimethylketen N-phenylimine, and not 1,2,4thiadiazetidine 1-oxide, as previously r e p ~ r t e d . ~ ’
*+s-”/
p-toly 1
4 Systems containing Oxygen Oxetans. - A mechanistic investigation of the reaction of methylthiotrimethylsilane (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 photoaddition 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 ZnC12 +
MeSSiMe3
f
Me OSiMe3
(38)
(39) Me Me.+fCHCN 0%
(40)
CHCN
(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 onepot synthesis of oxetan from 1,3-diols has been developed this year.43 37
39 40 41
42
43
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 . G. Jones, 11, Z. H. Khalil, and X . T. Phan, Tetrahedron Lett., 1 9 8 1 , 2 2 , 3823. C . Rivas, D. Pacheco, F. Vargas, and J . Ascanio, J. Heterocycl. Chern., 1 9 8 1 , 1 8 , 1 0 6 5 , 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 ) . M. A. J. Carless and H. S. Trivedi, J. Chem. SOC.,Chern. Cornrnun., 1981, 9 5 0 . P. Picard, D. Leclercq, J-P. Bats, and J . Moulines, Synthesis, 1 9 8 1 , 5 5 0 .
Heterocyclic Chemistry
66
The ylide (42) is formed when carbon dioxide and dimethyl acetylenedicarboxylate react in the presence of a trialkyl phosphite (Scheme 6). The reaction of (42) with an aromatic aldehyde afforded the furan (43).44
COOMe
(43)
(42)
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 synthesis of (R,R)-phytol?’
i
Me
(44)
Dioxetans. - The ‘missing’ cyclo-adduct of cycloheptatriene and singlet oxygen, 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 chemiluminescent dioxetan (46) has also been ~repared.~’
0-0
(45)
44
45
46 47 48 49
Me
(46)
D. V. Griffiths and J . C. Tebby, J. Chem. SOC.,Chem. Commun., 1981,607. T. M. Pavel, Zh. Org. Khim., 1982, 18, 178. 0. N. Chernysh and S. I. Yakimovich, Zh. Org. Khim., 1982,18,181. T. Fujisawa, T. Sato, T. Kawara, and K. Ohashi, Tetrahedron Lett., 1981, 22, 4823. W. Adam and H. Rebello, Tetrahedron Lett., 1981,22,3049. 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 versatile method.” 0
II
PhCHZCHCPh
-
0
PhCH-CH2!Ph
i
I
ii ,iii
,OEt
S, /p
S’ ‘OEt
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 retrocycloaddition 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 1,1,3,3tetroxide (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 51 52
53
” 55
Y. Ueno, L. D. S. Yadav, and M. Okawara, Synthesis, 1981,547.
L. N. Koikov, P. B. Terent’ev, and N. S. Kulikov, Zh. Org. Khim., 1981,17, 1087. M. D. Gray, D. R. Russell, D. J . H. Smith, T. Durst, and B. Gimbarzevsky, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1826.
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. H . Breitenstein, R. Schulz, and A. Schweig, J. Org. Chem., 1982,47, 1979.
Heterocyclic chemistry
68
(50)
(52)
(51)
( 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
(55)
-
R2C.792
i
ii -R2Cy
fR2
R2C=C=SiPh 2-
Ph,2 Si--SiPh2
( H = SiMe3)
(56)
Ph2Si
iPh 2 (57)
Reagents: i, h v ; ii, rn-chloroperoxybenzoic acid.
Scheme 9 disilacyclopentane (57).58 Furthermore, disilacyclobutanes are the major products that are formed by treating bromotrisilylmethanes, such as (58), with alkyl-lithi~ms.~~ The silaethene (59) was suggested as an intermediate. A 56 57
59
N. Auner and J . Grobe, J. Organometal. Chem., 1 9 8 1 , 2 2 2 , 33. 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. N. Wiberg, G. Preiner, and 0. Schieda, Chem. Ber., 1981, 114, 2087.
69
Four-Membered Ring Systems SiMeg
I
Me2Si-C(
SiMe3)2
I
I
Br
Br
Me2Si=C(SiMe3)2 (59)
I
(581
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 phenylphosphorous dichloride in the presence of aluminium chloride, and subsequent reduction of the oxide.62 Me
I I Me
Me- CCH=CHBr
Me
Me
Me
+
Me Me
PhPC 1
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 I /Ph O=P=C ' P h (63) 6o
61
63 64
Ph
CI H = C H R ~ (64)
G . Fritz, S. Wartanessian, E. Matern, W. Honle, and H. G . von Schnering, 2. Anorg. Allg. Chem., 1981,475,8 7 . 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. M. Regitz and H. Eckes, Tetrahedron, 1981, 37, 1039. 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
2 3
4
L. I. Belen'kii and V. P. Gul'tyai, Khim. Geterotsikl. Soedin., 1981, 723. V. N. Sheinker, A. D. Garnovskii, and 0. A. Osipov, Usp. Khim., 1981, 50, 632. W. G. Blenderman and M. M. JoulliB, Heterocycles, 1982, 19, 11 1.
R. Bdhm, Wiss. Z.
- Martin-Luther-Univ. Halle- Wittenberg, M a t h . - N a t u r e . Reihe,
1981, 30, 3 . 5
6
D. N. Reinhoudt, Bull. SOC. Chim. Belg., 1981, 90, 633. W. Schroth, Wiss. Z. - Martin-Luther-Univ.Halle- Wittenberg, Math.-Naturwiss. Reihe,
I
W. Schroth, Wiss. Z. - Martin-Luther-Univ. Halle- Wittenberg, Math.-Naturwiss. Reihe,
1981, 30, 97. 1981, 30, 29.
8
L. H. Klemm, Heterocycles, 1981, 1 5 , 1285. 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. 9
71
72
Heterocyclic Chemistry
2 Monocyclic Thiophens Synthesis of Thiopens by Ring-closure Reactions. - C4 S Principle. The reaction of C6 hydrocarbons with hydrogen sulphide on a chromiumcontaining 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 3thienyhnalonic 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.
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. 25
Five-Membered Rings: Thiophens and their Se and Te analogues
73
+
C2S C2 Principle. The reaction of nitroacetonitrile with a-mercaptoketones in the presence of triethylamine yields 4-substituted 2-arnino-3nitrothiophens.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-4hydroxythiophens, which exist as the 4-keto-ta~torner.~' The reaction of 2,4dichlorophenacyl 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 2aminothio 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-4e t hoxy carbonylme t hyl-3-methoxy carb onyl thiophen .34-a Ph
\
RC=C-S
/COOR'
/"="\H (5)
R (6)
CS + C3 Principle. The Fiesselmann reaction between a-formyl arylacetonitriles and methyl thioglycollate has been used for the preparation of methyl 3-amino-4-arylthiophencarboxylates.35 The reaction of (7) with ethyl thioglycollate in the presence of potassium carbonate gave (8) in 70% yield.36
(7)
Nippon Kayaku Co. Ltd., Jpn. Kokai Tokkyo Koho 81 100 780,1981. 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. 30 31
Heterocyclic Chemistry
74
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 3,4diaminothiophen-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 transformed into (1 2).% c1
Ring-closure of C.S. The reaction of (13) with LDA led to a 2,4-diaminothiophen, 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
’
c=c
H
I \S/CH2
C=C
(14c)
H
\,NCH2
(14d)
36aM.Gosh, R. Mukherjee, B. G . Chatterjee, and J. K. Ray, Indian J. Chem, Sect. B , 1981, 20, 243.
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. 3’
’*
Five-Membered Rings: Thiophens and their Se and Te analogues
75
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,ydrothiophens. 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 aminothiophen (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 chloroderivatives is in the preparation of (23) by the reaction of (22) with N chlorosuccinimide followed by ~ y r i d i n e The . ~ ~ catalytic dehydrogenation of 2- and 3-alkyltetrahydrothiophenshas been in~estigated.~' CN
40
41
E. Nagashima, K. Suzuki, and M. Sekiya, Tetrahedron Lett., 1981,22, 2587. P. N. Confalone, G. Pizzolato, M. R . Uskokovic, and M . Rouge, US P. 4 317 915, 1982.
41
43 44
45
D. Binder, C. R. Noe, and M. Zahora, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 557. P. W. Raynolds, US P. 4 307 239, 1981. J . B. Press, C. M. Hofmann, G. E. Wiegand, and S. R. Safir, J. Heferocycl. Chem., 1982,19,391. M. V. Vagabov, Vestn.Mosk. Univ., Ser. 2: Khim., 1982,23,52.
Heterocyclic Chemi s m
76
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 crystallograph^.^^ 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 transformed 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 (32) Y = S
16 47
4a
(33)
K. Skinnemoen and K. Undheirn, Heterocycles, 1981, 16, 929. K. Kobayashi and K. Mutai, Temhedron Lett., 1981, 2 2 , 5201. G. A. Miller, N. D. Heindel, and I . A. Minatelli, J. Heterocycl. Chern., 1981,18,1253.
Five-Membered Rings: Thiophens and their Se and Te analogues
77
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 quantitative yield.” MeOOC P-Me
MeOOC
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 compared 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 calculated. Calculations have been carried out on 2-methoxy-5-methylthiothiophen, 2,5-bis(methy1thio)thiophen7and all of their possible C-protonated forms, in 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.
49
’’
78
Heterocyclic Chemistry
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-cyanostyrylthiophen 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 selenophen 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 60
Ya. L. Gol’dfarb, I. A. Abronin, M. A. Kalik, and V. K. Zav’yalova, Khim. GeterorsikL Soedin., 1981, 1035. 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, 69 lo
11, 174. W. Schmitz, Nuovo Cimento SOC.Ital. Fis. B , 1981, 63, 386. J. P. Pinan-Lucarre, D. C. Edewaard, and K. D. Moeller, Spectrochim Acta, PartA, 1981, 37, 977.
” I2
G . Paliani and R. Cataliotti, Spectrochim. Acta, Part A , 1981, 37, 707. 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,
73
S. N. Rustamova, M. M. Seidov, N. Yu. Ibragimov, and S. M. Aliev, Dokl. Akad.
21, 182. 14 75
Nauk Azerb. SSR,1980, 36, 39. M. Singh, B. L. Mathur, and K. S. Gharia, Bull. SOC.Chim. BeZg., 1981, 90, 515. 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 substituents 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 thiophenoparacyclophane 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-2carbaldehyde 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,4Hthieno[3,4-c] thiophen,gO of (37):' of (38),92 of triple-layered [2,2] -
I6 I1 78
19
G. Musumarra, S. Wold, and S. Gronowitz, Org. Magn. Reson., 1981, 17, 118. G. Musumarra and F. P . Ballistreri, Chem. Scr., 1981, 18, 209.
F. P. Ballistreri, G. Musumarra, and G. Scarlata, Chem. Scr., 1981, 18, 214. R. J. Abraham, D. J. Chadwick, and F. Sancassan, Tetrahedron Lett., 1981, 22, 2139.
80
83
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. S. Burman and D. N. Sathyanarayana, J. Inorg. Nucl. Chem., 1981,43, 1189. S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, Phosphorus Sulfur,
84
S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, J. Heterocycl. Chem.,
82
1981, 10, 317. 1981,18,1011.
A. Arcoria, F. P. Ballistreri, G. Musumarra, and S . Occhipinti, Org. MassSpectrom., 1981, 16, 54. 86 81
R. Jimbnez and E. Cortbs, J. Heterocycl. Chem., 1982,19,447. 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.
He terocy cIic Chemistry
80
paracyclophanes containing thiophen rings,93 and of some other thiophen derivatives have been Miscellaneous Physical Properties. The microwave spectrum of 2,3-dihydrothiophen 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 trimethylsilylthiophens, 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 393
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. Thermodyn., 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 . 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, 104
113
'I4
p. 21. G. Seconi, C. Eaborn, and J. Stamper, J. Orgunomet. Chem., 1980, 204, 153. G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2, 1981, 931.
Five-Membered Rings: Thiophens and their Se and Te analogues
81
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 Nphenylamide 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 tetrabromothiophen in the A1C13-catalysed acylation of 2,5-dibromo- and 2,3,5tribromo-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-4phenylthiophen 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 0positions 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
*rlgcl CH2Ar
c1 (41) 115
116
(42)
(43)
A. B. Cowell and C. Tamborski, J. Fluorine Chem., 1981,17,345. 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,
118
M. J. del Agua, A. S. Alvarez-Insda, and S. Conde, J. Heterocycl. Chem., 1981, 18,
119
J. B. Press and N. H. Eudy, J. Heterocycl. Chem., 1981, 18, 1261. T. Sone, H. Kawasaki, S. Nagasawa, N. Takahashi, K. Tate, and K. Sato, Chem. Lett., 1981, 399. Y. Yokoyama, Y. Yamashita, K. Takahashi, and T. Sone, Chem. Lett., 1981, 813. R. Houriet, H. Schwarz, W. Zummack, J. G. Andrade, and P. von Ragu6 Schleyer, Nouv. J. Chim., 1981, 5 , 5 0 5 .
1287. 1345. 120
121 122
Heterocyclic Chemi s t y
82
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 5position, 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-bromothiophen and 2-nitrophenylacetyl chloride gave (45).12’ From 2-t-butylthiophen 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
lZ3 124
SCF2C1
W. J. Spillane, P. Kavanagh, F. Young, H. J.-M. DOU, and J. Metzger, J. Chem. SOC., Perkin D a m . 1 , 1981, 1763. G. Ya. Katsapov, E. N. Osmanov, and K. Kh. Razikov, React. Kinet. Catal. Lett.,
1981, 17, 227. 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, Radioisotopes, 1981, 30, 584. 13’ Y. Mori, M. Shibata, K. Toyoshi, S. Baba, M. Horie, Y. Oshika, and K. Ohira, Radioisotopes, 1981, 30, 590. 12’
Five-Membered Rings: Thiophens and their Se and Te analogues
83
In connection with developments of new syntheses of biotin, 3-acetylamino2-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 5 - p o ~ i t i o n . ~The " nitration of 5-bromo- and of 5-methyl-2-cyclopropylthiophen 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 2,5dime 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 7090" 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 M e
c ! ON02
R
< j
CH=i!-COMe N02
OH (48)
(49)
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
13' 136
Yu. D. Churkin, L. V. Panfilova, V. D. Lugovoi, and N. V. Boiko, K h i m Geterotsikl. Soedin., 1981, 913. Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn, Geterotsikl. Soedin., 1981, 325. Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn. Geterotsikl. Soedin., 1981, 753.
Heterocyclic Chemistry
84
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) 0
13' 138
P. Stanetty, J. Chem. Res. (S), 1981, 99. P. Stanetty, J. Chem Res. (S), 1981, 100.
(59)
Five-Membered Rings: Thiophens and their Se and Te analogues
85
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)
139 140
(73)
P. Stanetty, J. Chem. Res. (S), 1981, 139. A. V. Semenovskii and M. M. Emel’yanov, Izv. A kad. Nauk SSSR, Ser. Khim., 1980, 2578.
Heterocyclic Chemi s t v
86
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-(3theny1)- 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
0
CQ 0
(77)
(79)
Nucleophilic and Radicaloid Substitution Reactions of Monocyclic Thiophens. - The rate constants for the reaction of 5-substituted 2-bromo-3nitrothiophens, in methanol, with various substituted d i n e s to give 5substituted N(3-nitro-2-thienyl)anilines have been measured at various temperatures. 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 2methoxy-3-nitrothiophen-5-carboxylateand 5-acetyl-2-methoxy-3-nitrothiophen, 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 ring14'
A. V. Semenovskii and M. M. Ernel'yanov, Izv. Akad. Nauk SSSR,Ser. Khim.,
1981,
1359. 142 143 144
145
K. Satake, T. Irnai, M. Kirnura, and S. Morosawa, Heterocycles, 1981, 16, 1271. T. Frejd, J. 0. Karlsson, and S. Gronowitz, J. Org. Chem., 1981,46, 3132. G . Consiglio, C. Arnone, D. Spinelli, R. Noto, and V. Frenna, J. Chem. SOC.,Perkin Trans. 2, 1981, 388. G . Consiglio, C. Arnone, D. Spinelli, and R. Noto, J. Chem. Soc., Perkin Trans. 2, 1981,642.
146 147
14'
G. Ronsisvalle and G. Blandino, Farmaco, Ed. Sci., 1981, 36, 785. Z. Polivka, J. Holubek, E. Svitek, J. Metygovd, and M. Protiva, Collect. Czech. Chem. Commun., 1981,46,2222. J. W. H.Watthey and M. Desai, J. Org. Chem., 1982, 47, 1755.
Five-MemberedRings: Thiophens and their Se and Te analogues
87
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 2iodothiophen 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 2iodothiophen. 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-bromothiophen 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.
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., Is'
1981, 22, 5319.
1s4bT.Kobayashi and M. Tanaka, J. Chem SOC.,Chem Commun., 1981, 333.
Heterocyclic Chemistry
88
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 0alkylated 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-5nitrothiophen 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-isopropyldithiocarbamate in quantitative yield. ‘60 Through the reaction of 2-thienyllithium with tellurium in THF, the tellurolate was obtained, which was converted 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
lS6
P. J . Newcombe and R. K. Norris, Aust. J. Chem., 1981, 34, 1879. B. C. Gilbert, R. 0. C. Norman, and P. S. Williams, J. Chem. Soc., Perkin Trans. 2 , 1981, 207.
151
Is* Is’
161
J. H. Lee and I. N. Tang, J. Chem. Phys., 1981, 7 5 , 137. R. S. Min, V. S. Aksenov, M. G . Vinogradov, and G. I. Nikishin, Izv. Akad. Nauk SSSR,Ser. Khim., 1981,2315. 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. L. Engman and M. P. Cava, Organometallics, 1982, 1,470.
Five-Membered Rings: Thiophens and their Se and Te analogues
89
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-amino5-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 cosolvent, 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-phenoxyand 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 2substituted 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
( 8 8 ) R = CH20H 163
164 165
(89)
K. Okuhara, Bull. Chem. SOC.Jpn., 1981, 54, 2045. A. Hassner, P. Munger, and B. A. Belinka, Jr., Tetrahedron Lett., 1982, 23,699. J . Bourguignon, C. BBcue, and G. QuCguiner, J. Chem. Res. ( S ) , 1981, 104. 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 .
90
Heterocyclic Chemistry
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 3,3dithienyl 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 3alkylthi~phens.'~~ Halogen-metal exchange between acetal-protected 5bromothiophen-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 benzaldehyde 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,
170
A. Kleemann, J. Heese, and J . Engel, Arzneim.-Forsch., 1981, 31, 1178. F. J. Stiefel, US P. 4 310674, 1982.
174
475.
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. T. Tanouchi, M. Kawamura, I. Ohyama, I. Kajiwara, Y. Iguchi, T. Okada, T. Miyamoto, K. Taniguchi, M. Hayashi, K. Iizuka, and M. Nakazawa, J. Med. Chem., 1981, 24, 1149.
Five-Membered Rings: Thiophens and their Se and Te analogues
91
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-methoxythiophens.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 3,4dibromothiophen 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 transformed 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 stereospecific synthesis of (102).143
(101) n = 1-4
( 1 0 2 ) n = 1-4
R2= CH2COOH or CH2Ph 175 176
A. Svensson and R. Hikansson, Chem. Scr., 1981, 18,202. 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.
Heterocyclic Chemistry
92
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 2thienylglyoxylate has been prepared by the addition of thiophen-2magnesium 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 investigated. 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.
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, 17'
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.
Five-Membered Rings: Thiophens and their Se and Te analogues
93
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 cyclometallation of 2(2-thienyl)- and 2-(3-thienyl)-pyridine with Pd", Rh" and Ru" complexes has been in~estigated.'~'The cleavage of (107) with iodine has been studied.'88 7
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.'"
J
3
Photochemistry of Monocyclic Thiophens. - The HCCS radical has been 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 . 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 .
187
Heterocyclic Chemistry
94
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 benzophenone 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-aryl2-isoxazolines, the 3-(2-thienyl) derivative was also studied. In the presence of thiophen, cycloaddition products such as (1 10) were formed.'" Photochemical 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
or
(111) a ; R = Ph
p- MeOOCC6H4
b ; R = Me
( 1 1 0 ) A r = p-NCC6H4
(112) a; R = Ph b ; R = Me
19* 193
194
19' 196
19'
Bra S
R. A. Bolivar, E. Cotte, C. Perez, and C. Rivas, Themzochim. Acta, 1981, 45, 125. C. Rivas, D. Pacheco, F. Vargas, and J. Ascanio, J. Heterocycl. Chem., 1981, 18, 1065.
T. Kumagai, K. Shimizu, Y. Kawamura, and T. Mukai, Tetrahedron, 1981, 37,3365. C. J. Moody, C. W. Rees, S. C. Tsoi, and D. J. Williams, J. Chem. SOC., Chem. Commun., 1981,927. S. Jeganathan and M. Srinivasan, Indian J. Chem., Sect. B y 1980, 19, 1028. J.-C. Gramain, Y. Troin, and D. Vallee, J. Chem. SOC., Chem. Commun., 1981, 832.
Five-Membered Rings: Thiophens and their Se and Te analogues
95
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 heterocycles 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-tetramethylphthalonitrile. 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 = b ; R1= R2= Me c ; R1= But, R2= H d ; R1= R 2 = (cH2)4
(123) a; R1= R2= Me b ; R1= H, R2= But 2 C ; R1= B u t , R = H
d; R1= R2= (CH2)4
M. Reinkhardt, V. G. Mitina, N. S. Pivnenko, and V. F. Lavrushin, Zh. Obshch. Khim., 1980,5 0 , 2770. R. Pratap, Y. Tominaga, M.L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981, 18,973. 200 R. F’ratap, M. L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981,18,1457. 201 V. N. Drozd and N. S. Zefirov, SulfurRep., 1981,1, 271. 201uK. Matsumoto, T. Uchida, and R M. Acheson, Heterocycles, 1981, 16, 1367. 19*
199
Heterocyclic Chemistry
96
(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 11014OoC, 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-Thienylthiones (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
"Y'
Me
CN
Me
CN
Me
Me ( 1 2 6 ) a ; R1= R2= M e = H
CN
( 1 2 7 ) a ; R1=
R2= Me
R2= H 1 2 t c; R = H , R = BU
b ; ql= B u t ,
202
R. H. Hall, H. J. den Hertog, Jr., and D. N. Reinhoudt, J. Org. Chem., 1982, 47, 967. 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. 203
Five-Membered Rings: Thiophens and their Se and Te analogues
97
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 ; b; c; d; e;
R1= R2= H R1= H, R2= Me R1= Me, R2= H R1= R 2= Me ='R H, R ~ =Et
and (137e), but the (E):(Z)ratios were 9:l and 3:2, respectively. Furthermore, the dihydrothiophens (1 39), prepared via electrochemical reduction of thiophen-2-carboxylic acids followed by reduction of the methyl ester with '08
'09
L. Chan and S. A. Matlin, Tetrahedron Lett., 1981, 22, 4025. P. C. Hayes, G. Jones, C. Keates, 1. Kladko, and P. Radley, J. Chem. Res. (S), 1980, 288.
Heterocyclic Chemistry
98
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-dialkylthiophens in good yields. Oxidation of these compounds to the 1,l-dioxides by MCPBA, followed by thermolysis, offers a convenient route to 1,3dienyl 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
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. Kumamoto, 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, 'lo
219
591.
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.,
221
P. Davidova and P. Kovacheva, Neftekhimiya, 1982, 22,93. 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. S. Gultekin, Chim. Acta Turc., 1981, 9, 257. T. W. Matheson and K. C. Pratt, React. Kinet. Cafal. Lett., 1981, 18, 21. F. E. Massoth and K. S. Chung, Stud. Surf. Sci. Catal., 1981, 7 , 629. A. V. Mashkina, V. N. Yakovleva, N. E. Buyanova, and Z. A. Dovbii, Kinet. Katal.,
1982, 73, 45. 222
223 214
22s 226
1982, 23, 58. 227
"* 229
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. I. Rajca, A. Borowski, and A. Marzec, Erdoel Kohle, Erdgas, Petrochem., 1982, 35, 36.
"O
231
R. Ramachandran and F. E. Massoth, Can. J. Chem. Eng., 1982, 60, 17. 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.
Five-Membered Rings: Thiophens and their Se and Te analogues
99
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 hydrosulphidehydrogen chloride .48 3-Hydroxy-4-anilinomethylthiophenexists in the stable tautomeric form (25).46 The allyl ether of dimethyl 3-hydroxythiophen2,5-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-3bromothiophen with sodium dimethylthiocarbamate or sodium t-butyltrithiocarbonate 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)bromobenzene 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 bacteriocida1,237,239 -241 or pesticidal activity.lz6*236 The reaction kinetics of substituted thiophen-2-sulphonyl chlorides and of thiophen-3-sulphonyl chloride
NO2
02N
(142) a; R = NMe2 b ; R = SBut
S
233
D. Binder, C. R. Noe, and B. C. Rager, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 751. 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.
234
100
Heterocyclic Chemistry
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-3carboxylic acid via isopropyl 3-thienylcarbamate. It was demonstrated that the instability of 3-aminothiophen was due to polymerization via di(3thieny1)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
243
244 245
A. Arcoria, F. P. Ballistreri, G. Musumarra, and G. A. Tomaselli, J. Chem. Soc.. Perkin Trans. 2, 1981,221. F. P. Ballistreri, k Cantone, E. Maccarone, G. A. Tomaselli, and M. Tripolone, J. Chem. SOC.,Perkin Trans. 2, 1981,438. F. P. Ballistrera and G. A. Tomaselli, J. Heterocycl. Chem., 1981, 18, 1229. D. Binder, C. R. Noe, F. Geissler, and F. Hillebrand, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 564.
246 141 248 249
J. D. Warren and J. B. Press, Synth. Commun., 1980, 10, 107. 'S. Rault, M. Cugnon de Servricourt, and M. Robba, Recl. Trav. Chim. Pays-Bas, 1982, 101, 205. D. Binder, B. C. Prager, and C. R. Noe, J. Chem. Res. (S), 1981, 140. 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.
Five-Membered Rings: Thiophens and their Se and Te analogues
101
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-aminothiophen2-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 (148) R = CN or COOEt
H (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 2acetylthiophen 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.259 251 252 253
254
255 256
251
”* 259
H. Wamhoff, G. Hendrikx, and M. Ertas, Liebigs Ann. Chem., 1982,489. I. G. C. Coutts, M. Edwards, and D. J. Richards, Synthesis, 1981,487. C. J. Moody, C. W. Rees, and S. C. Tsoi, J. Chem. SOC.,Chem. Commun., 1981,5 5 0 . R. Noto, S. Buscemi, G. Consiglio, and D. Spinelli, J. He&rucycZ. Chem., 1981, 18, 735. G. Consiglio, D. Spinelli, S. Gronowitz, A-B. Hornfeldt, and R. Noto, Chem. Scr., 1982,19,46. G. V. Rao, M. Balakrishnan, N. Venkatasubramanian, P. V. Subramanian, and V. Subramanian, Indian J. Chem, Sect B , 1981,20, 793. 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. E. Maccarone, A. Mamo, G. Perrini, and M. Torre, J. Heterocycl. Chem., 1981,18,735.
Heterocyclic Chernistry
102
Reactions of Thiophen Aldehydes, Ketones, and Carboxylic Acids. - Numerous 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-3pyridyl-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-(2thieny1)pyridines through the reaction with ma lo no nit rile^.^^^ 5-Nitrothiophen-2-carbaldehyde has been condensed with amides of carboxymethanesulphonic 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
"'
262 26 3 264 265
266 267 268 269 2 70
M. S. K. Youssef, Croat, C h e m Acta, 1980, 53,453. 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. W . D. Rudorf and M. Augustin, 2. Chem., 1982, 22, 255. M. S. K. Youssef, J. Chem Technol. Biotechnol., 1981, 31, 363. M. S. K. Youssef, Rev. R o u m C h i m , 1981, 26, 1005. A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28, 159. A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28,229. C. Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981, 234. M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron L e t t , 1981, 22, 4269.
T. Gungor, F. Marsais, and G. Queguiner, J. Organomef Chem., 1981, 215,139. 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,
271
1981, 120, 39. 273 274
275
276
E. Degny, S. Z. Zard, R. Pastor, and A. Cambon, Tetrahedron L e a , 1981, 22,2169. N. Latif, N. Mishriky, and N. S. Girgis, Indian J. Chem, Secf B y 1981, 20,147. 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. A. I. Pavlyuchenko, E. I. Kovshev, and V. V. Titov, K h i m GeterotsikL Soedin., 1981, 85.
Five-Membered Rings: Thiophens and their Se and Te analogues
103
(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(2thienyl)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 hydrochloride279 or with hydroxylamine hydrochloride and N-methylpyrrolidone.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 sidechain 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 thiosemicarbahave been studied. The reaction of ethyl thiophen-2-carboxylate with triphenylphosphineCC14 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 ArndtEistert reaction for the transformation of 2-thenoyl chloride into benzyl 2thienylacetate .288 Na'
-S
S- Na+
H OMe (157)
(155)
Me
(158) 277 278
2 79
280 281 282
283 284
28s 286 287
OE t (159)
V. P. Gul'tyai, L. M. Korotaeva, A. P. Rodionov, and A. M. Moiseenkov, Izv. Akad NaukSSSR, Ser. Khim., 1981, 1150. V. P. Gul'tyai, L. M. Korotaeva, A. S. Mendkovich, and I. V. Proskurovskaya, Izv. Akad. NaukSSSR, Ser. Khim., 1981, 834. D. Dauzonne, P. Demerseman, and R. Royer, Synthesis, 1981,739. P. Audoye, A. Gaset, and J. P. Gomchon, Chimia, 1982, 36,4. W.-D. Rudorf and M. Augustin, Phosphorus Sulfur, 1981,9,329. G.-I. Tsuchihashi, K. Kitajima, and S. Mitamura, Tefmhedron Lett., 1981, 22,4305. H. B. Singh, D. Singh, R K. Negi, and V. K. Gupta, J. Inorg. Nucl. Chem., 1981, 43, 1915. T . Odashima and H. Ishii, Nippon Kagaku Kaishi, 1982,425. C. G. R. Nair and K. K. Aravindakshan, J. Inst. Chem. (India), 1981, 53, 295. M. Suda and A. Fukushima, Tetrahedron Lett., 1981, 22, 759. 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-vinylthiophens 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(adimethylaminoviny1)thiophen gave (1 60).290 The synthesis of some substituted 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 corand of 2-acetoxymethy1thioresponding acetylthiophencarboxylic 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-acetylnaphthalene 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. 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, Tetrahedron 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. 291
Five-Membered Rings: Thiophens and their Se and Te analogues
105
Various Reactions in the Side-Chains of Thiophens. - The preparation of various N-substituted thieno [3,2-fl morphans from 2,5-dimethylthieno [3,2fl morphan has been de~cribed.~" Several thiophen isosteres of protoberberine alkaloids have been prepared, starting from amides between 3thienylacetic acid and substituted 0-phenylethylamine or /3-(3-thienyl)ethylamine, 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,wamino-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-dichloromethylthiophen 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
T
7-
S
6 b 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.
Heterocyclic Chemisw
106
with pent-4-ynyltriphenylphosphoniumylide gave (1 64), which by Glazer coupling was transformed into (165). It could not be conclusively established that prototropic rearrangement with potassium t-butoxide in t-butyl alcohol gave (166).305 ~
Melfs]MeJ I - (165)
7'); (CH =CH)
6
(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-dimethylaminofulvene 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 tetrachlorothiophen 1,l-dioxide with (172) led to (173), having an iceane
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.
'05
Five-Membered Rings: Thiophens and their Se and Te analogues
107
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 halogenmetal exchange occurs, followed by ring-opening to a vinyl sulphinate, which was trapped as (1 75) with benzyl br~mide.~"Nitration of 3,4-dimethylthiophen 1,l-dioxide with N204in chloroform gave 23% of the 2,5-dinitro-3,4dimethylthiophen 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 1oxides.312 The addition of dichlorocarbene to 2,Sdihydrothiophen 1,ldioxides has been used for the synthesis of (177), and further reactions of this system have been investigated.313 The photocycloaddition of 2,sdihydro-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
02NCH=CH-CH=
R1 1
I I
Me
M e f M eSOOCH 2Ph
2
(174) a; R = M e , R = Bu 2 b ; R1= Bu, R = M e
(177)
Me
(176)
(175)
(178)
CHN02
0
Me
(179) 310 31 1
D. P. G. Hamon and P. R. Spurr, J. Chem Soc., Chem. Commun., 1982,372.
J. 0.Karlsson, S. Gronowitz, and A. Hallberg, Actu Chem. Scund., Ser. B, 1982,
36, 341. 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.
' " ' M .
108
Heterocyclic Chemistry
treatment of 2,5dihydrothiophen 1-oxide and 2,s-dihydrothiophen 1,ldioxide 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-dihydrothiophen 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 cis2,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 dihydroand 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 315 316
R. L. Crumbieand D. D. Ridley, Aust. J. Chem., 1981, 34, 1017. 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
320
321 322
323
324
32s 326 327
328 329
S. E. Lauritzen, C. RQmmhg, and L. SkattebQl, Acta Chem. Scand., Ser. B , 1981, 35, 263. 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). P. I. Parkhomenko, Ukr. Khim. Zh. (Russ. E d ) , 1980,46, 1294. P. G. Dul'nev and T. E. Bezmenova, USSR P. 794012, 1981 (Otkrytiya, Izobret, Prom. Obmztsy, Tovamye Znaki, 1981, 95). 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).
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). L. N. Shkaraputa, L. A. Tishchenko, V. T. Sklydr, I. A. Manza, and A. G. Gordienko, Khim TekhnoL (Kiev), 1981, 32. F. Mauer, I. Hammann, and B. Homeyer, Ger. Offen. 3 003 019, 1981. G. Abe and J. M. Shreeve, J. Chem. Soc., Chem. Commun., 1981,242. T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20, 2432. T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20,2894.
Five-Membered Rings: Thiophens and their Se and Te analogues
109
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 othiophen, 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 ' , ~ ~the ~ reactive 1,3-dipole (193), formed in the reaction between diazomethane and thiobenzophenone, the di- and tetra-hydrothiophens (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)
(193)
( 194)
OH
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. H.-J. Liu and T. K. Ngooi, Can. J. Chem., 1982, 60,437. 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. 331
332
Heterocyclic Chemistry
110
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-ethoxycarbonylthiolate-3-ones has been carried out .M3 Sulphur analogues of prostaglandins that contain di- and tetra-hydrothiophen rings, such as the sulphur analogue of A6-PGIIm and (52)- and (5@-6,9thiapro~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 tetrahydrothiophens are discussed in refs. 347 - 350.
+
cdyJMe (199)
338
J. M. Bolster and R. M. Kellogg, J. Am. Chem. SOC., 1981, 103,2868. 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. 339
Five-Membered Rings: Thiophens and their Se and Te analogues
111
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 desulphurization of a degradation product with Raney nickel. From the simple phenylhydrazone 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 2,3diarylthi~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 2formyl-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)
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. 351
112
Heterocyclic Chemistry
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(5methoxycarbonylpyrrolyl)thiophen,formylation occurs both in the 5 -position of the thiophen ring and the 3-position of the pyrrole ring, and in the 2position 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 3amino-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 dithienyl-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 II S-C=CH-C NH-C=CH
I Ph
-C
II
0
Ph
( 2 1 2 ) X = 0 or S 358 359
360 36 1
362
363 364
J.-P. Boukou-Poba, M. Farnier, and R. Guilard, Can. J. Chem., 1981,59,2962. S. Rault, M. Cugnon de SBvricourt, N.-H.Dung, and M. Robba, J. HeterocycL Chem., 1981, 18,739. Y. Effi, M. Cugnon de S h i c o u r t , S. Rault, and M. Robba, Heterocycles, 1981, 16, 1519. T. E. Glotova, A. S. Nakhmanovish, G. G. Skvortsova, T. N. Komarova, I. D. Kalikhman, and M. G. Voronkov, Zh. Org. Khim., 1981, 17,749. T. Kauffmann and R. Otter, Chem. Ber., 1982, 115, 1825. V. G. Kharchenko, E. V. Burov, and V. A. Sedavkina, Khim. Geterotsikl. Soedin., 1981, 1604. k R. Katritzky, J. M. Lloyd, and R. C. Patel, Chem. Scr., 1981, 18,256.
Five-Membered Rings: Thiophens and their Se and Te analogues
113
2-(2-thienyl)hydroquinolines and related compounds.365 Several 2 -amino-3cyano-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 , respect i ~ e l y Some . ~ ~ ~2(2-thienyl)chromones have been prepared from hydroxyacet 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 2aroyl-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-2carboxylates 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 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. Geterotsikl. Soedin., 1981, 520. 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. 365
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, Neurophamacology, 1981, 20,461. 396 W. Sinenberg and 0. Spohn, Ger. Offen. 2 940 737, 1981.
Five-Membered Rings: Thiophens and their Se and Te analogues
115
and 2-phenylamino-2-imidazolinesas analgesic^;^'^ some thienopyridinopyrazines 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-hydroxythiophen-2-carboxylic acid,400 have been prepared 8 0 ' Basic dithienyl derivatives have been prepared as vasodilator^^^-^^^ and thienylpropanolamine 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-thenoylphenols?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. 422 Jpn. Kokai Tokkyo Koho 81 49 376,1981. 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.
116
Heterocyclic Chemistry
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 investigated?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
425 426
427 428
L. A. Koskenniska and R. A. Saxlund, Eur. Pat. Appl. 29 740, 1981. A. E. Sloboda, J. W. Hanifin, and D. N. Ridge, Austrian P. 363930, 1981. A. C. Goudie, R. W. Ward, and H. E. Rosenberg, Eur. Pat. Appl. 35 853, 1980. W. Opitz, M. Schwiertz, S. Raddatz, and P. R. Imberge, Arzneim.-Forsch., 1981, 31,402.
429 430
431 432
B. Lacaze, Fr. Demande 2 461 496, 1981. Jpn. Kokai Tokkyo Koho 82 02 294,1982. R. Boigegrain and J. P. Maffrand, Fr. Demande 2 478 640, 1981. W. Bartmann, G. Beck, 3. Knolle, and R. H. Rupp, Tetrahedron Lett., 1982, 23, 2947.
433 434
G. Beck, U. Lerch, B. Schoelkens, and R. H. Rupp, Ger. Offen. 2 946 116, 1981. E. W. Collington, P. Hallett, C. J. Wallis, and J. Bradshaw, Eur. Pat. Appl. 32 432, 1981.
T. Tamura, N. Inukai, H. Iwamoto, I. Yanagisawa, Y. Ishii, T. Takagi, K. Tomioka, and M. Murakami, YamunouchiSeiyuku Kenkyu Hokoku, 1980,4,16. 436 Jpn. Kokai Tokkyo Koho 81 131 579,1981. 4 3 7 Jpn. Kokai Tokkyo Koho 81 81 578,1981. 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.
435
2 946 810,1981. 442
443
R. Ziegler, B. Ho, and N. Castagnoli, Jr., J. Med. Chem., 1981, 24, 1133. Y. Kawamatsu, T. Sohda, and Y. Imai, Eur. J. Med Chem. - Chim. Ther., 1981, 16, 355.
Jpn. Kokai Tokkyo Koho 81 55 314,1981. 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. 4 4 7 Jpn. Kokai Tokkyo Koho 81 77 282,1981. 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, 444
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
454 45s
J. C. Vallejos and Y. Christidis, Fr. Demande 2 470 127, 1981. M. Foa and L. Cassar, US P. 4 287 352,1981. Jpn. Kokai Tokkyo Koho 81 23 429,1981.
Five-Membered Rings: Thiophens and their Se and Te analogues
117
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 antiparasitic activity, thiophencarbaldehyde thiosemicarbazones with antitubercular and many other structures with antibacterial activity have been s ~ r e e n e d ? ~ l - ~A’ ~large number of patents treat thieno484 and some pyrimidone and related compounds as antifungal other thiophen derivatives with a n t i f ~ n g a l ~ ~ ’and -~~~ antimolluscal
P. C. Harris and J. A. Wilcox, Eur. Pat. Appl. 21 645, 1981. 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. 4 6 5 Jpn. Kokai Tokkyo Koho 80 160 779,1980. 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 1 Jpn. Kokai Tokkyo Koho 81 95184,1981. 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. 476 Jpn. Kokai Tokkyo Koho 81 57 793,1981. 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. 4 7 8 Jpn. Kokai Tokkyo Koho 81 08389,1981. 479 Jpn. Kokai‘Tokkyo Koho 81 59 778,1981. 480 Jpn. Kokai Tokkyo Koho 81 53 681,1981. 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. 483 Jpn. Kokai Tokkyo Koho 81 34 683,1981. 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. 4 8 5 Jpn. Kokai Tokkyo Koho 81 79 604,1981. 486 Jpn. Kokai Tokkyo Koho 81 161 361,1981. 487 H. Boeshagen, K. H. Buechel, W. Draber, 1. Haller, and M. Plempel, Ger. Offen. 3 017 881, 1981. 456
457
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 intermediates for biotin can be noted.37:498-501Other biological aspects of thiophen derivatives have been treated.502-5'0 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. 490 Jpn. Kokai Tokkyo Koho 81 92 284,1981. 4 9 1 Jpn. Kokai Tokkyo Koho 81 92 285,1981. 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. 494 Jpn. Kokai Tokkyo Koho 81 133 282,1981. 4 9 5 Jpn. Kokai Tokkyo KohoSl 167 679,1981. 496 M. T. Clark, Br. P. 1 574429, 1980. 4 9 7 Jpn. Kokai Tokkyo Koho 82 35 579,1982. 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. 488
Five-Membered Rings: Thiophens and their Se and Te analogues
119
Thiophens of Technical Interest. - Many patents cover the synthesis of azodyes 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-methylthiophen-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 -diformylthiohen.'^^ 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 R. R. Giles and M. A. Weaver, US P. 4 301 068, 1981. 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. 5 1 5 Jpn. Kokai Tokkyo Koho 81 129 256,1981. S. Saito, S. Kashihara, and G. Takeshima, GS News Tech. Rep., 1981, 40, 8 2 . "'Jpn. Kokai Tokkyo Koho 82 13 670,1982. Jpn. Kokai Tokkyo Koho 82 34 677,1982. 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. 5 2 4 Jpn. Kokai Tokkyo Koho 81 47 421,1981. s 2 5 G. Kossmehl and G. Chatzitheodorou, Makromol. Chem., Rapid Commun., 1981, 'I1 'Iz
526
2, 551.
T. A. Starostina, V. L. Materikin, A. B. Gil'man, V. M. Vozzhennikov, and L. F. Rybakova, Vysokomol. Soedin., Ser. B , 1982, 24,269.
Heterocyclic Chemistry
120
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 4,7dihydro-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) 521 528
( 229)
R
= COOEt
or COPh
k M. van Leusen and J . W. Terpstra, Tetrahedron Lett., 1981, 22, 5097.
K. Gewald and H. Schafer, 2. Chem., 1981, 21, 183. 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. Karakhanov, 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. 52Y
Five-Membered Rings: Thiophens and their Se and Te analogues
121
presence of DMAD gave dimethyl 7-cyanobenzo [b] thiophen-2,3dicarboxylate in addition to mixtures of cis- and trans-substituted phenylthioalkene~.’~~’ 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-2,3dihydro-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 delocalization 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 2,3dichlorobenzo[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. 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. 539
122
Heterocyclic Chemistry
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 2and 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 7OAc derivatives, which sometimes react further to produce their dihydroderivatives. Alternatively, benzene can add across the double bond to give the 2- (for 6-OAc) or 3-phenyl-2,3-dihydrobenzo [ b ]thiophens (for 7OAC).”~Isomerization of 2- and 3-methylbenzo [b]thiophen on aluminosilicate 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-dihydrobenzothieno [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-ethoxycarbonylbenzo [b] thiophen with 2,s -dimethoxytetrahydrofurangave 3(1 -pyrrolyl)2-ethoxycarbonylbenzo [ b ]thiophen, which through Curtius reaction was
548
549
S. R. Ditto, P. D. Davis, and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 521. A. Buquet, A. Couture, A. Lablache-Combier, and A. Pollet, Tetrahedron, 1981, 37, 75.
552
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. P. D. Clark, L. K. k Rahman and R. M. Scrowston, J. Chem SOC.,Perkin Trans. I , 1982, 815.
553 554
555
M. V. Vagabov, Neftekhimiya, 1981, 21,658. k V. Anisimov, V. S. Babaitsev, S. Ya. Grobovenko, T. k Danilova, and E. A. Vik orova, Khim. GeterotsikL Soedin., 1981, 615. K. iindeldr, M. Ryska, J. Holubek, E. Svdtek, J. Metys‘ovd, J. Protiva, and M. Protiva, Collect. Czech. Chem Commun., 1981, 46, 118.
Five-MemberedRings: Thiophens and their Se and Te analogues
123
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-ene1,2-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 2,3dihydrobenzo [ 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 [b1thiophen 1-oxides led to different p h o t o d i m e r ~ .From ~ ~ ~ 3-chlorobenzo [ b ]thiophen-2 -carboxylic acid 1,l -dioxide, 1,3-0xazinones of biological interest were obtained through cyclization reactions with cyanamides and carbodii 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,lBenzo[c ] thiophens. - Compound (237), obtained by isomerization of 1methoxycarbonyl-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
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. 556
Heterocyclic Chemistry
124
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-lcarboxylic 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 trimethylsilyl 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 ~ ~ ~nitrogroup 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 photocyclization 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 polyhalophenyl 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 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. 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. 567
i::
Five-Membered Rings: Thiophens and their Se and Te analogues
125
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 2bromo-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-2naphthol 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 578 579
W. A. Lindley and D. W. H. MacDowell, J. Org. Chem., 1982, 47,705. 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.
Heterocyclic Chemistry
126
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 halogenmetal 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 5.34
R. D. Thompson, M. Iwao, M. L. Lee, and R. N. Castle, J. HeterocycL Chem., 1981, 18,981. 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.
Five-Membered Rings: Thiophens and their Se and Te analogues
127
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 diazoindenothiophens 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 ~
HN-
(257)
5 86
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. 588 589
590
R. Neidlein and G. Schafer, Chem.-Ztg., 1981, 105, 91. R. Neidlein and E. A. Varella, Chem. Chron., 1980, 9 , 79. S. Mataka, T. Ohshima, and M. Tashiro, J. Heterocycl. Chem., 1982, 19,65.
Heterocyclic Chemistry
128
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
H
591
K. Yamane, K. Fujimori, and T. Takeuchi, Bull. Chem. SOC.Jpn., 1981, 54,2537. 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, 592
23, 2859.
129
Five-Membered Rings: Thiophens and their Se and Te analogues
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 [3,2b] 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
€tt--DFt;
J + S R1
‘d’
I
X
’
a s
‘R R2
(267)
r)
R1 R1
s
I
S R2 ( 2 6 6 ) X = H or C 1
l
(269)
(268)
R1=
R2= P h ; R1= R2= (CH=CH)2;
R1=
Ph, R2= H; R1= H, R = P h ;
or R1=
2
P h , R2= M e
Ph Ph
595 596 597 598 599
W. J. Archer and R. Taylor, J. Chem. Soc., Perkin Trans. 2 , 1982, 295. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1729. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1928. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1982, 315. 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.
Heterocyclic Chemistry
130
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 azidoacetylthiophen, 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-7MeOOC
"M2
I
COOBut (274)
(273)
H (275) MeHNHC
CHNHMe M
e
I O OI
C
w
)
COOMe
S Me
6oo 601
Me
G. Kumar, K. Rajagopalan, S. Swaminathan, and K. K. Balasubramanian, Indian J. Chem., Sect. B , 1981, 2 0 , 2 7 1 . E. A. Panfdova, I. Ya. Kvitko, A. D. Kuptsov, and k V. El'tsov, Zh. Om. Khim., 1981, 17,1564.
Five-Membered Rings: Thiophens and their Se and Te analogues
131
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-laza-azulene by annelating the thiophen ring by the Fiesselmann reaction.603 OH
rJyc:l2rfN) I
COOMe
CONHBu
H (279)
(280)
Thiophen Fused to Various Five-Membered Rings. The reaction of ethyl 3-cyano-5,S-diethoxy-2-oxopentanoatewith P4Sl0 gave thieno[2,3-c]isothiazole-3-carboxylic acid, and not, as previously claimed, thieno [3,4d] isothiazole-4-carboxylic acid. The parent compound was obtained by decarboxylation, and also by deamination of thieno [2,3c] isotkiazol-3amine.604 Alkylation of the product of the reaction between sodium 3iminobutyronitrile 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 [3,2d] isothiazole, which underwent bromination and nitration in the 5p~sition.~’’ Lithiation of 3-methylthieno[3,26] isothiazole and its S-bromoderivative 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-Diphenylthieno[3,4c] [ 1,231oxadiazole reacted with trinorbornene to give four stereoisomeric 1 :2 ad duct^.^'^ L
,& CN
Me
SCH2COOEt
SCH2COOEt
NH2
COOEt
s-
(2811
(282)
(283)
6 Thiophen Fused to Six-Membered Heteroaromatic Rings Thiophen Analogues of Quinoline. - Pyrolysis of 3-(2-thienyl)propenal 0methyloxime 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
‘03 604 605 606 607
608
A. Foucaud, Bull. SOC.Chim. Belg., 1981, 90,545. K. Yamane, K. Fujimori, and T. Takeuchi, Chem. Lett., 1981, 293. F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 385. F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 393. K. G. Jensen and E. B. Pedersen, 2. Naturforsch., Teil. B, 1981, 36, 1640. 0.Tsuge, T. Takata, and M. Noguchi, Heterocycles, 1981, 16, 789. C. L. Hickson and H. McNab, Synthesis, 1981,464.
Heterocyclic Chemistry
132
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 quinolinethiones 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 [2,341quinoline61 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 [2,3b] 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.
0.Piovesana, L. Sestili, and C. Troni, J. Inorg. Nucl. Chem., 1981, 43,2321. T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 1981, 29, 3173. 616 Belg. P. 886470. ‘14
615
Five-Membered Rings: Thiophens and their Se and Te analogues
133
from thiophen-2-carbaldehyde and N-aroylglycine, gave 4-arylthieno [3,2c] 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 3chloroisonico tinonitrile, 3 -amino-2-et hoxy carbonyl- and 3-amino-:! -phenylthieno [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' 1
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
618
619 620
621
622
N. F. Eweiss and A. A. Hosni, J. Univ. Kuwait, S c i , 1981, 8, 195. J.-P. Maffrand, R. Boigegrain, J. Courregelongue, G. Ferrand, and D. Frehel, J. Heterocycl. Chem., 1981, 18, 727. J. L. LaMattha and R. L. Taylor, J. Org. Chern., 1981, 46,4179. V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Gererotsikl. Soedin., 1981,1351.
T . Tsuchiya, H. Sawanishi, M. Enkaku, and T. Hirai, Chem. Pharrn. Bull., 1981, 29, 1539. M. A. Hernandez, F.-L.Chung, R. A. Earl, and L. B. Townsend, J. 0%.Chem., 1981, 46, 3941.
Heterocyclic Chemistry
134
of triethylamine gave (295), and with triethyl orthoformate, 3,6-dihydrothieno [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-amino3-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, 4oxo-(3H)-thieno [2,3-d] pyrimidines, and with benzyl isothiocyanate, 2mercapto-3-benzyl-4-oxothieno[2,3-d]pyrimidines, were obtained.624 NArylthieno [2,3-d] pyrimidin-4-amines have been prepared by heating 2acylaminothiophen-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 2acylaminothiophen-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
H
H
0
COOMe
623
H. K. Gakhar, S. Bharadwaj, A. Jain, and P. Baveja, J. Indian Chern. SOC., 1981, 58, 1017.
624
625
626 627
V. J. Ram, H. K. Pandey, and A. J. Vlietinck, J. Heterocycl. Chern., 1981, 18, 1277. K. E. Nielsen and E. B. Pedersen, Chem. Scr., 1981, 18,245. K. E. Nielsen and E. B. Pedersen, Chern. Scr., 1981, 18, 135. M. J. Kulshreshtha, S. m a t t , M. Pardasani, and N. M. Khanna, J. Indian Chern. SOC., 1981, 58, 982.
Five-Membered Rings: Thiophens and their Se and Te analogues
135
gave (300).628Photochemical ringclosure of (301) gave (302).629 Syntheses and reactions of 2-chloro-3,4-dihydrothieno-pyrimidinesand -quinazolines6309631and 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 [2,3d] 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-dicyano6-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) 628
629
bH
M. S%se and S. Johne, J. Prakt. Chem., 1981, 3 2 3 , 647. T. Itoh, H. Ogwa, K. A. Watanabe, and N. Kawahara, Chem. Pharm. Bull., 1981, 29, 1039.
630
"'
632 633
H. Yamaguchi and F. Ishikawa, J. Heterocycl. Chem., 1981, 18,67. H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 30,28. H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 3 0 , 326. P. €3 Talukdar, S. K. Sengupta, and A. K. Datta, Indian J. Chem., Sect. B y 1981, 20, 538.
634
635
S . K. Robev, Tetrahedron Lett., 1981, 2 2 , 345. E. C. Taylor and L. A. Reiter, J. Org. Chem., 1982, 47, 528.
Heterocyclic Chemistry
136
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.~~~ Benzothienothiazines 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 ringclosed.6 Thieno [2,3-~]coumarins have been re pa red.^^'? 641 Reactions of 5phenylthieno [3,2-b] pyran-7-one, 2-phenylbenzo [b] thieno [3,2-b] pyran-4one, 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
Y
NH P.
1
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-dicyanoselenophen.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-dibromoselenophen 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 selenophen636
637 638
P. I(rey and H. Dehne, 2. Chem., 1981, 21, 31. D. Achakzi, M. Ertas, R. Appel, and H. Wamhoff, Chem. Ber., 1981, 114, 3188. W. Offermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 168.
R. F'fiiter, Eur. Pat. Appl. 2 1 058, 1981. 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.
639 640
Five-Membered Rings: Thiophens and their Se and Te analogues
137
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 polymerization 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-benzyloxycarbonylglycine 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 it is given as the 3 - i s 0 m e r . ~The ~ 77Se n.m.r. spectra of 79 mono- or disubstituted 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 propionamide 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 3phenylthieno [3,4-b]ind01e.~’~Selenolo [3,4-b]thiophen, the last hitherto unknown ‘classical’ selenolothiophen, has been best synthesized via quaternization 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-3carbaldehyde, together with the 4- and 6-carbaldehydes in a ratio of 1 :4.654 V. P. Gultyai, T. G. Konstantinova, A. M. Moiseenkov, V. P. Litvinov, and A. Konar, Chem. Scr., 1982, 19,95. 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.
646
647
138
Heterocyclic Chemistry
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-dimethylbutadiene 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. 655 656
S. Gronowitz, A. Konar, and A.-B. Hornfeldt, Chem. Scr., 1982, 19, 5. 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
659 660 661
V. Z. Laishev, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 2064. W. Lohner and K. Praefcke, J. Organomet. Chem., 1981, 208,43. J. Bergman and L. Engman, J. Am. Chem. Soc., 1981, 103,2715. 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-CN 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-2phenylisothiaaolin-3-one (3)." 0
II
NcfiBr
PhCO(CH2)2CONHPh
Br
(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 C02 evolution gives 80% of isothiazole (5; R the same) (Scheme 1).12
'r + % '
Me00CCECCOOMe
COOMe
MeOOC 0
(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.
140
Heterocyclic Chemistry
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 (SCH2CHzCONHC6H3Me22,6)*.13 This latter compound is treated with S02C12 t o give 4-isothiazolin3-one (7). The oxidation of (7) with 3-C1C6H4CO3Hgives the corresponding 1,l -dioxide (8).
+
a,'
-
MeOOC RyN'ycOOMe
(6)
"/o
"/o ' cs'k O2
Me
0
Me 0
(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
sx
ArC=CHCH=NH
Synthesis of Isothiazoles by Ring-Cleavage of 3-Azidothiophens. 3-Azidothiophen-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 \[R
NC
(11)
= COOEt]
(12)
(13) l3
l4
Meiji Seika Kaisha Ltd., Jpn. P. 81 118 073,1981 (Chem. Abstr., 1982, 96,35 235). 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.
141
Five-Membered Rings: Systems containing Nand S, Se, or Te
Synthesis of Isothiazoles porn Substituted Enamines and Benzyl Isothiocyanate (Type C-C-N S-C). h i d e vinylogues (14; R' = PhCO, 4-C1C6H4C0, 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 isothiazoles is further confirmed by subjecting the intermediates (1 5 ) to oxidation by bromine, which also gives isothiazoles (Scheme 3). Similarly, the nitroenamine (14; R' = NO2) gives the intermediate R3NHCR2=C(N02)CSNHCOPh, then the isothiazole (17; R' = NO2), but no pyrimidinethiones.
+
R1CH=CR2NHR3
S
(14)
+
SCNCOPh
:' 6
,COPh
R3P
h
N
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
17
18
V. Aggarwal, H. Ila, and H. Junjappa, Synthesis, 1982, 65. G. Mille, J. C. Poite, M. Guliano, and J. Chouteau, Spectrosc. Lett., 1981, 14, 271. 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).
Heterocyclic Chemistry
142
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-alkylisothiazolium 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 3haloisothiazolium 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-3methylisothiazole-4-carboxylic acid (24), in benzene that contains pyridine, reacts with C1CH2COC1 and then with HNR2 to give 5-dialkylaminoacylamino-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 ( 2 4 ) R1= COOH
(26)
(23)
(27)
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, Heferocycles, 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). l9
Five-Membered Rings: Systems containing N and S,Se, or Te
143
A?-Isothiazolines.- Chemical Properties of Isothiazoline-5-thiones. By treatment 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-4isothiazolin-3-one 1,l-dioxide (30; R = octyl) is treated with diethyl dithiophosphate to give 4- or 5-(diethyldithiophosphoryl)-2-octylisothiazolidin-3-one 1,l -dioxide (3 1; R = octyl)?' -- - Chloro-5-methyl-4-phenyl-2isothiazolin-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 . ~ '
88t$ cf~$
(\&
0
O2
Et2PS
R3fs\c
R2
Me 0
0
0
(30)
(31)
0 (33)
(32) 0
PhCO[aO (34)
p
ceM;;
h
~
pho@
~
~
Ph
(35)
0
NPh
0
(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-
RENR2 (37)
24
2s
26 27
P. D. Clark and D. M. McKinnon., J. Heferocycl. Chem., 1981, 18,437. G. A. Miller and E. D. Weiler, U.S.P. 4302240, 1981 (Chem. Absfr., 1982, 96, 162 930). 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.
144
Heterocyclic Chemistry
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-benzisothiazole (38) (Scheme 4).29 Other compounds (39; R' = H, aliphatic, cycloaliphatic, 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 compounds (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
29
30
K. H. Albert, H. Duerr, S. H. Dos, and J. P. Zahra, Org. Mugn. Reson., 1980, 14, 209. H. Hagen, J . Markert, and H. Ziegler, Ger. Offen 3018108, 1981 (Chem. Absstr., 1982, 9 6 , 6 8 980). H. Boeshagen and W. Geiger, Liebigs Ann. Chem., 1982,14.
Five-Membered Rings: Systems containing N and S, Se, or Te
145
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
MeOOCC%COOMe
R\
MeOOCC =CHCOOMe
I
~
CN
hv
CN (46)
R
(47)
(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 2,3dihydro-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
32
33
T. Nihon and S. Noyaku, Jpn. P. 81 133 287,1981 (Chem. Abstr., 1982, 96, 759). M. Sindler-Kulyk and D. C. Neckers, Tetmhedron Lett., 1981, 22, 525 and 529. M. Sindler-Kulyk, D.C. Neckers, and J. R. Blount, Tetrahedron, 1981, 37, 3377.
146
Heterocyclic Chemistry
method for preparing 2-substituted 1,2-benzisothiazolin-3-ones (51 ; R = Et, Pr, But, C6Hll, PhCH2, Ph, or 4-MeC6H4), has been described (Scheme 6).% 0
C1-
?
Me
-
S-Me
[-HCl]
CNHR
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-Aminobenzonitriles and SO2. 2,6-o2N(Meo)C6H3CN is reduced and the 2,6NH2(MeO)C6H3CN is treated with NaNOz followed by SO2 to give 3-amino4-methoxy-l,2-benzisothiazole1,l-dioxide, which underwent demethylation followed by hydrolysis to give (53).36
bP’e OH
\
34
35 36
0
Y. Uchida and S. Kozuka, J. Chem. SOC., Chem. Commun., 1981, 510. Jpn. P. 81 6 5 882 (Chem. Abstr., 1982,96,20089). G. Trummlitz, W. Eberlein, W. Engel, and G. Schmidt, Ger. Offen. 3 01 5 113, 1981 (Chem. Abstr., 1982,96,104 222).
Five-Membered Rings: Systems containing Nand S, Se, or Te
147
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-, alkoxycarbonylalkanoyl-, carboxy-, carbamoyl-, acylamino-, alkylsulphonyl-, N,Ndialkylsulphamoyl-, trifluoromethoxy-, trifluoromethylthio-, trifluoromethylsulphonyl-, 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).
OCOR
-
SCH20COR
C'
II
It
'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.,
38
1981,95, 203 929). Y. Uchida, Y. Kobayashi, and S. Kozuka, Bull. Chem. SOC.Jpn., 1981,54,1781.
148
Heterocyclic Chemistry
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 40
41
42
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). I. K. Koslova, 0. A. Luk'yanov, and V. A. Tartakovskii, Izv. Akad. Nauk SSSR. Ser. Khim., 1981,2556 (Chem. Abstr., 1982, 96, 67902). Y. Imai, H. Okunoyama, K. Hirata, and M. Ueda, Nippon Kagaku Kaishi, 1982, 111 (Chem. A bstr., 1982, 96,104 134). K. G. Jensen and E. B. Pedersen, 2. Naturforsch., TeiZ. B , 1981, 36, 1640 (Chem. Abstr., 1982, 96, 122 677).
Five-Membered Rings: Systems containing N and S, Se, or Te
149
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
1,2-Benzisothiazoline-3-thione 1 ,l -Dioxides. - The sodium salt of 1,2-benzisothiazoline-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
44
4s 46
Jpn. P. 81 43 265,1981 (Chem. Abstr., 1981,95,97587). K. Inomata, H. Yamada, and H. Kotake, Chem. Lett., 1981, 1457. D. C. K. Chan, U.S.P. 4 253 865,1981 (Chern. Abstr., 1981,95,80935). R. Valters, D. Balode, R. Kampare, and S. Valtere, Khim. Geterotsikl. Soedin., 1981, 1209 (Chern. Abstr., 1981,95,203048).
Heterocyclic Chemistry
150
4 1,2-Benzisoselenazoles 1,2-Benzisoselenazolin-3-ones. - p-Toluidine, when treated with 2-ClSeC6H4COC1, 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 benzisothiazolyl benzoate (73) to benzoxazinone (74) were determined spectrophotometrically 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-tetrahydroquinoline, 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 benzisothiazolium iodide (76) reacts with Na+-CH(C02Et), to give the benzisothiazoline derivative (77).
Q""\( N= NR'
R2 (75)
mMj+ Uj \
\
C( COOE t )
1(76)
(77)
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.
47
Five-Membered Rings: Systems containing N and S, Se, or Te
151
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 ) (79)
(78)
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
52
Ya. L. Gol’dfarb, M. A. Kalik, and V. K. Zav’yalova, Izv. Akad. Nauk SSSR, Ser, Khim., 1981, 2771. B. R. Fishwick, and T. S. B. Sayer, Eur. Pat. Appl. 26596, 1981 (Chem. Abstr.,
53
P. Gregory and T. S. B. Sayer, Br. P. 2 0 7 4 598, 1981 (Chem. Abstr., 1982, 96,
5’
1981, 95, 82 388). 164 132). 54
K. Hirota, T. Asao, T. Fujioka, and S. Senda, Nippon Kagaku Kaishi, 1981, 721 (Chem. Abstr., 1981, 95,150 597).
Heterocyclic Chemistry
152
1,2-Dithiolo[4,3c]isothiazoles. - 3-Aroylamino-6-mercapto1,2-dithiolo [4,3c] 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: 2amino-4-(4-benzyloxyphenyl) thiazoles,” 2 -(2 -amino-5-hydroxythiazol-4-y1)1 -(4-chloro-3-methylpheny1)e thanone,58 2-benzylidenehydrazino-4-( 1,5-dime thyl-2-phenyl-3-pyrazolon-4-y1)-5-e t hylthiazoles, 59 2 -amino-4- [2 -(4-ace taH. 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 ”
’’
Five-Membered Rings: Systems containing N and S, Se, or Te
153
midophenylsulphonylamido)ethyl] thiaz~les,'~ 2-(2-aminothiazol-4-y1)-2hydroxyiminoacetic acids and substituted derivatives which are useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acids:' substituted 2-amino-4-phenylthiazole 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 thiazolyl-4-carboxylic ester and 4-isopropylthiazolyl-5-carboxylicester!7 242aminothiazo1-4-y1)-2-(syn)-methoxyiminoaceticester,68 substituted 2-anilino4-fluoroaryI-thia~oles,~~ 4-substituted 2-aminothia~oles,~~ and 2-amino-4aryl-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 2,4,5-triarylthiazole~.~~ From HC( S)NH2 and XCH2CO(CH2)30COMe(X = halo) are formed 5-(2-hydroxyethyl)-4-methylthiazoleas the major product and 4-(3-hydroxypropyl)thiazole as a by-pr~duct.'~Also noted are 2,46o
61
62
63 64
65
0. V. Isakova, A. M. Sipyagin, and V. G. Kartzev, Zh. Org. Khim., 1981, 17, 1522 (Chem. Abstr., 1982,96,6507). 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). Y. Kawamatsu, T. Sohda, and Y. Irnai, Eur. J. Med. Chem.-Chim. Ther., 1981, 16, 355. B. G. Khadse, S. R. Lokhande, and D. G. Kulkarni, Indian J. Chem., Sect. B , 1981, 20,683 (Chem. Abstr., 1981,95,187 140). D. G. Deng and S . X . Lu, Yao Hsueh Hsueh Puo, 1981, 16,14 (Chem. Abstr., 1981, 95, 132 756). R. K. Howe and L. F. Lee, Eur. Pat. Appl. 27108, 1981 (Chem. Abstr., 1981, 95, 115 528).
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, 66
217 829). 69
R. B. Pathak, B. Jahan, and S . C. Bakel, Bokin Bobai, 1981, 9 , 477 (Chem. Abstr., 1982, 96, 20 018).
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,
70
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).
Heterocyclic Chemistry
154
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-trifluoromethylthiazole-5-carboxylic esters and derivatives.80 Thioketens and 3dimethylamino-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)
(89)
(88)
Type F Syntheses of Thiazoles (C-N-C-S + C). Substituted N-thiocarbamolyformamidines R2CSN=CR"Me2 react with ally1 bromide to give an azavinamidinium salt, which, upon treatment with a base, gives an ethylideneA2-thiazoline (R1 = R2 = Me2N; R1 = H, R2 = morpholino). This last compound, upon heating or treatment with toluene-p-sulphonic acid, undergoes allylic rearrangement to the thiazole (90) with migration of the NN-dimethylamino-group (Scheme 8) .8s 2,4-Disubstit u t ed 5-benzoyldianilinothiazoles are NMe
I
Scheme 8 A. Corsaro, M. Tarantello, and G. P. Purrello, Tetrahedron Lett., 1981,22,3305. 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.
77 78
Five-Membered Rings: Systems containing Nand S, Se, or Te
155
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."
MeaR;y sl MeaHlyNl R
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
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. 86
Heterocyclic Chemistry
156
(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 waven ~ 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).~~
Me2S( + CH2)$HC
oj-jsyRclII
(99)
91
92
J. Lukasiewicz, D. hfisiuna, S. Bilinski, and L. Bielac; Chem. Anal. (Warsaw), 1981, 26, 207.
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 Nor 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 polymorphism of sulphathiazole and its crystallographic behaviour under pressure have also been rep0rted.9~
[syNR3R R1LyNso2Ar R1
R2
NH
R2
Reactions of Thiazoles. - 2-Bromothiazole is silylated to give compounds which undergo ipso-substitution with ketens to give, after hydrolysis, two 2acylthiazoles .loo 4,5-Disubstituted 2-chloro thiazoles are obtained by diazotization 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 reaction^,^'^'^^ 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. 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, 98
52 221). Io7
lo’ Io9 I10
I. M. Bazavova, R. G. Dubenko, and P. S. Pel’kis, Zh. Org. Khim., 1981, 17, 191 (Chem. Abstr., 1981, 95,7129). A. Medici, P. Pedrini, C. Venturoli, and A. Dondoni, J. Org. Chem., 1981,46,2790. R . B. Pathak and S. C. Bahel, Bokin Bobai, 1981, 9, 125 (Chem. Abstr., 1981, 95, 24 899). 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).
158
Heterocyclic Chemistry
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 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,
112
789.
R. Jain, S. Tyagi, and S. Agarwal, J. Indian Chem. SOC.,1981, 58, 1112. Z. Ma, B. Si, and L. Huang, Yaoxue Xuebao, 1981, 16, 793 (Chem. Abstr., 1982,
'I'
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
/
120
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). P. N. Bhargava, S. Prakash, and R. Lakhan; Indian J. Chem., Sect. B , 1981, 20,
927. 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. I21
159
Five-Membered Rings: Systems containing N and S,Se, or Te
r\
C1-
Me
NMeCOR
---
( CH2 i
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.
He terocycIic Chemistry
160
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; R' = H, R2 = R3 = Me), which with l-chloro-2,6-dinitro-4-trifluoromethyl-
H2cxT R2
N
SR1
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). 129
Five-Membered Rings: Systems containing Nand S, Se, or Te
161
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)
=fi
azavinamidinium salt Me2NCR1 -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 Compound (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)
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. 133
162
Heterocyclic Chemistry
+
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 nitrosothiazoline (123).138
fSIPh (S7.(T 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~' Mercaptoethylamine 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 tetrafluoroborates (127), the same scission of the C-S bond is observed under thermodynamic 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 electrondonor that is involved in the complexing of 2-aminothiazoline. 2-HydrazinoA2-thiazoline has been condensed with diethyl oxalate and oxamic acid esters.14 The reaction of 2-hydrazinothiazoline with diethyl oxalate gives
H. Vorbrueggen and K. KrolikieWicz, Tetrahedron Lett., 1981, 22,4471. 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, 13'
13*
1981, 56,41. 144
K. H. Ongania,Chem. Ber., 1981, 114, 1200.
Five-Membered Rings: Systems containing N and S, Se, or Te
163
the thiazolotriazinedione (129) as the only product, whereas with RNHCOC0,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.
G. A. Kraus and J. 0. Nagy, Tetrahedron Lett., 1981, 22,2727. 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, 14'
146
154
15'
96, 100 783). G. L.'abb&, G. Vermeulen, S. Toppet, G. S. D. King, J. Aerts, and L. Sengier, J. Heterocycl. Chem., 1981, 18, 1309. G.Gattow and W. Eul, 2.Anorg. Allg. Chem., 1981, 483, 121.
Heterocyclic Chemistry
164 9 A3-Thiazolines
2-(Alky1thio)alkyl-4,5-dialkyl-A3-thiazolines (135; R' , R2 = H or Me) are prepared by the iminolysis of MeSCHR2CH2CH0 followed by cyclocondensation 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
a
15'
Me (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). J. Gasteiger and U. Strauss, Chem. Ber., 1981, 114, 2336. J . Martins, H. Offermanns, and P. Scherberich, Angew. Chern., 1981, 93, 680.
Five-Membered Rings: Systems containing N and S,Se, or Te
165
(1 42).lS9 The 5-(arylmethylene)-2-piperidino(or morpholino)-2,4-diphenylA3-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-A2thiazolin-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
16' 16' 16' 163
R. Jorritsma, H. Steinberg, and T. J. De Boer, R e d . Trav. Chim. Pays-Bas, 1984, 100, 307. M.T.Omar, M. M . Habashi, M . E. Shabaan, and M . A. Kasem, Synthesis, 1981,318. C. Luethy and P. Winternitz, Eur. Pat. Appl., 39 520, 1981 ((Chem. Abstr., 1982,96, 104 226). S. Bilinski and B. Marcewicz-Rojewska, Ann. Univ. Mariae Curie-Sklodowska, Sect. D,1979, 34,383 (Chem. Abstr., 1981,95,24898). Neth. A D ~80 . 01 920,1980 (Ctern. Abstr., 1981,95,169174).
Heterocyclic Chemis@
166
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 prepared.'@ 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, bromomalonate, and bromocyanoacetate have been ~tudied.'~' Thus p-R1C6H4NHCSNHR2 (R1 = Me or H, R2 = Et) with MeCOCHClC0,Et gave Et2NHHCI, 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
164
'"
LYNPh NPh
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-substituted 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 compounds 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;
Me3C
R2
R2
('Y'
(165)
169
N
'CH~R~
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. S. P. Cornwell, P. T. Kaye, A. G. Kent, and G. D. Meakins, J. Chem. Soc., Perkin Trans. I , 1981,2340.
Heterocyclic Chemistry
168
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 independent 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 [ 1,2a ] benzimidazoles (168; R = H, Me, MeO, EtO, Br, or HO)."l 4-Aminothiazoline-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-2ylidenemalononitriles [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 2,4diaminothiazoles (1 71). The reaction of the thiazolinylacetates (1 72; R = C02Et or CN) with Me2S04 and then CH2(CN)2 gives the diaminopyrrolothiazoles (173).
CN
170
H2N
NCH2COOEt
H2N
COOE t
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).
Five-Membered Rings: Systems containing N and S, Se, or Te
169
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 homodimers. 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 cyN-N Me
HO
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 displacement 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
173 174
175 176
17' 178
N. Hadjiliadis and J. Markopoulos, J. Chem. SOC.,Dalton Trans., 1981,1635. D. Misiuna and S. Bilinski, Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 1979, 35,143 (Chem. Abstr., 1982, 96,134 799). E. Gentric, J. Lauransan, C. Roussel, and J. Metzger, Nouv. J. Chim., 1980, 4, 743. C. D'Hondt, D. bhrnann, and E. Neuenschwander, Eur. Pat. Appl. 25413, 1981 (Chem. Abstr., 1981, 95,110 182). 0. Ekhner and W. Stendel, Rorn. P. 66 113,1979 (Chem. Abstr., 1981,95,25050). Y. Osawa, M. Itoh, and S. Uchikuga, Ger. Offen. 3025461, 1981 (Chem. Abstr., 1981, 95,6489).
Heterocyclic Chemistry
170
.'"
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-methylene2-p-tolyliminothiazolidine (1 79). In the crystal, (1 79) is associated as a centrosymmetric dimer .lB2 The direct-current and differential-pulse polarographic 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). 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). 180
Five-Membered Rings: Systems containing N and S, Se, or Te
171
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 4C02Me, 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-4carboxylic 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-arylaminothiazolidines (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 Jpn. P. 80 81 869,1980 (Chem. Abstr., 1981,95,97781). Jpn. P. 80 167 280,1980 (Chem. Abstr., 1981,95,43090). 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). lB4
186
172
Heterocyclic Chemistry
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
'02
'03
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). 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). C. H. Li, Y. H. Yieh, Y. Lin, Y. J. Lu, A. H. Chi, and C. Y. Hsing, Tetrahedron Lett., 1981, 22,3467.
204
205 206
'07
'08
209
210
"I '12
Y. Nagao, T. Miyasaka, K. Seno, M. Yagi, and E. Fujita, Chem. Lett., 1981,463. F. A. Devillanova and G. Verani, Tetrahedron, 1981, 37, 1803. M. V. Andreocci, M. Bossa, F. A. Devillanova, C. Furlani, G. Mattogno, G. Verani, and R. Zanoni, J. Mol, Struct., 1981, 71,227. S. Y. Solov'eva, S. M. Ramsh, and A. I. Ginak, Khim. Geterotsikl. Soedin., 1981, 477 (Chem. Abstr., 1981, 95,80 900). A. M. Osman, M. A. Abbady, and F. M. Atta, Indian J. Chem., Sect. B , 1981, 20, 524 (Chem. Abstr., 1981,95,114964). S . S. Meher, S. Naik, R. K. Behera, and A. Nayak, J. Indian Chem. SOC., 1981, 58, 274 (Chem. Abstr., 1981, 95, 80 817). I. V. Smolanka, N. P. Mano, and T. A. Krasnitskaya, Khim. Geterotsikl. Soedin., 1981,627 (Chem. Abstr., 1981, 95,203 812). T. N. Rao, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 174 (Chem. Abstr., 1982, 96,68 886). 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).
'18
'19 220 221
222
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). M. A. Kaldrikyan and A. V. Khekoyan, Khim. Geterotsikl. Soedin., 1981,41 (Chem. Abstr., 1981, 95,150 520). N. Ben Mansour, W. D. Rudorf, and M. Augustin, 2. Chem., 1981, 21, 69 (Chem. Abstr., 1981, 95,62 071). R. Soliman, Pharmazie, 1981, 36,91 (Chem. Abstr., 1981, 95,62 100). A. J. Cowper, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 111 (Chem. Abstr., 1982, 96,20 01 7). 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).
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).
2'4
Five-Membered Rings: Systems containing Nand S,Se, or Te
173
and thiazolidinethiazolidine-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
230
231
232
B. Buchmanand D. N. Hamilton, J. Agric. FoodChem., 1981, 29,1285. S . Satsumabayashi and J. Nakayama, Nippon Shika Daigaku Kiyo, Ippan Kyoikukei, 1981, 10,155 (Chem. Abstr., 1 9 8 1 , 9 5 , 8 0 797). H. Singh, P. Singh, and K. Deep, Chem. Ind. (London), 1981, 252. 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 2 34
235
236
13'
R. D. Khachikyan, S. M. Atashyan, and S. G. Agbalyan, Arm. Khim. Zh., 1981, 34, 775 (Chem. Abstr., 1982, 9 6 , 6 8 899). M. Valentiny, A. Martvon, and P. Kovac, Collect. Czech. Chem. Commun., 1981, 46, 2197.
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). 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). V. Machacek, V. Sterba, and H. Zahradnickova, Collect. Czech. Chem. Commun., 1981,46,3097.
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). 238
Heterocyclic Chemistry
174
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' =pMeOC6H4, 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 sulphurand 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-A2selenazolin-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 Sulphoalkylations of selenazoles were also rnenti~ned.~"
1SeYNHz Rcyse7(mz 0
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 24 1
0. P. Shvaika and V. F. Lipnitzkii, Zh. Obshch. Khim., 1981, 51, 1842 (Chem. Absfr., 1982, 96,20035). G . N. Jham, R. N. Hanson, R. W. Giese, and P. Vouros, J. Heferocycl. Chem., 1981, 18, 1335.
248
249 2 50
251
I. B. Levshin, A. A. Tsurkan, and K. A. V'yunov, Zh. Org. Khim., 1981, 17, 865 (Chem. A bsfr., 1981,95,132 761). 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). H. Kampfer, D. Wendisch, M. Hase, and M. Glass, Eur. Pat. Appl. 34 279, 1981 (Chem. Abstr., 1982, 96, 51 812). 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 this series.
the types A, B, etc. for benzothiazoles, see p. 133 of Volume 1 of
Five-Membered Rings: Systems containing N and S, Se, or Te
175
Type B Syntheses of Benzothiazoles (C6H5-N-C-S). Following a known method, arylthioureas were oxidized to give substituted 2-aminobenzot h i a ~ o l e sand ~ ~2~ [(2-thioxoimidazolidin)-3-yl] b e n z ~ t h i a z o l eby ~ ~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-2thiones2" were also described. The new picosecond laser photolysis system has also been used and gives well-resolved absorption ~pectra.~"The 13C and
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). 252
176
Heterocyclic Chemistry
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 constants ( 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-2y1azo)-NN-dimethylanilines with the substituent R at the 6-position of the benzothiazole system were measured and correlated with the Hammett 0constants for R = H, Me, MeO, EtO, H2N, C1, Br, and 02N.273 The substituent 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-aminobenzothiazole (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 thinlayer chromatography of some 1-(benzothiazol-2-yl)-3-methyl-4-arylhydrazonopyrazolin-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.
Five-Membered Rings: Systems containing N and S, Se, or Te
177
NO2, or OEt] .279 The best results were obtained with a 40: 15 hexaneethyl 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 6substituted 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 HammettJaffe 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 pronounced 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 solvolysis 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 benzothiazolecyanines (205; n = 1-5, R = Et, X = I) that was observed by gas chromato-
+
+
H
279
281
283
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). 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. G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2,1981,1051.
178
Heterocyclic Chemistry
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 photolysis. 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-NH2NHb 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
285
286
287
288
289 290
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). V. G. Khesin, M. A. Alperovich, and P. I. Abramenko, Khim. Geterotsikl. Soedin., 1981,1626 (Chem. Abstr., 1982,96,164115). D. Gaude, R. Gautron, R. Guglielmetti, and J. C. Duffy, Bull. SOC.Chim. Fr., Part 2, 1981,14. L. Fiser-Jakic and K. Jackopcic, Croat, Chem. Acta, 1981, 54, 245 (Chem. Abstr., 1981,95,219491). H. Knorr, R. Handte, L. Willms, and T. Tammer, Eur. Pat. Appl. 43 573, 1982 (Chem. Abstr., 1982,96, 142 845). T. Papenfuhs, Ger. Offen. 3 023 227,1982 (Chem. Abstr., 1982,96,104229). 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).
Five-Membered Rings: Systems containing N and S,Se, or Te
179
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).~'~Isocyanates give substituted derivatives of benzothiazolylurea (2 11; R1 = R1
H
H
(211)
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). 291
180
Heterocyclic Chemistry
CONHC6H4R3; R3 = H, o- or p-C1; R2 = H, OEt, or OMe);297 3-ClC6H4COCH2Br, 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 obenzothiazoles 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 2mercaptobenzothiazoles are substituted in alkaline solution with halo-
corn pound^.^^*^^^
Other Reactions of Benzothiuzoles. The regio- and stereo-specific photocycloaddition reaction (4h, under Nz, high- ressure Hg arc) or 2-phenylbenzothiazole with R1RC2=CR3R4 (R1= Rg = R4 = H, R3 = OEt; R' = R4 = H, R2 = R3 = Me; R1 = R3 = Me, R2 = R4 = H) gives the benzothiazepines (219,306 the structure of which was assigned by acidic ringM. 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. 297
Five-Membered Rings: Systems containing N and S, Se, or Te
181
cleavage followed by recyclization. The thermal cyclization of 2-(o-fluorobenzamido)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-2phenacyl-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 benzothiazolin2-ones (and -thiones) concerns N-alkylation and the modification of the Nalkylated 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 cycloadducts 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 benzothiazolium salts have also been d e ~ c r i b e d . ~ ' ~ - ~ l ~
+
Ft l I
"2
D. H. Kim, J. Heferocycl. Chem., 1981, 18, 801. 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.
307
308
182
Heterocyclic Chemistry
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[3,2d] tetrazol-4-ium perchlorates (2 18).318 R1 R2
(YN'i N-
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 hiadiazole 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-ylium2-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 dihydrothiazolotriazole (222; R = CONHPh).'* Compound (222; R = H) was also obtained by opening and re-cyclizing (223) with NaOH. Refluxing [224;
csy$o (221)
318 319
320
0
M. A. Eldawy, I. Chaaban, and A. S. Mehanna, Egypt. J . Pharm. Sci., 1978, 19, 185. A. F. Cameron, I. R. Cameron, and F. D. Duncanson, J. Chem. SOC.,Perkin Trans. 2 , 1981, 789. G. Jaeger and H. Heitzer, Synthesis, 1981, 704.
Five-Membered Rings: Systems containing Nand S, Se, or Te
183
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-dihydrothiazolotriazol5-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-oxothiazolidine2-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-ylidenecyanoacetate 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 cyclization of 3-aminoethyl-2-iminothiazolines gives 2,3,5,6-tetrahydroimidazo-
V. P. Upadhyaya and V. R. Srinivasan, Indian J. Chem., Sect. B y1981,20, 161. 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). 321
322
Heterocyclic Chemistry
184
[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 bromoacetate329 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 2,3,5,6tetrahydroimidazo [2 ,1411 thiazole derivative and of a 2,3-dihydroimidazothiazol-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 ringsystem (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
M. E. Menim, U.S.S.R. P. 847 915,1981 (Chem. Abstr., 1982,96,6727). S . Nielek and T. Lesiak, Chem. Ber., 1982, 115, 1247. 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.
325
326 327
Five-Membered Rings: Systems containing N and S, Se, or Te
185
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-3,4-2Hthiazolotriazinones (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-ami1-102,3-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] pyrimidine3-acetate, as previously reported by the authors.336 The cyclization of substi-
334
335 3 36
N. Matsui, K. Maeda, M. Kaeriyama, Y. Yasuda, A. Nakata, and M. Mizuno, Belg. P 889 390,1981 (Chem. Abstr., 1982,96,142898). K. Satoh and T. Miyasaka, Chem. Lett., 1981,1153. E. Campaigne, K. Folting, J. C. Huffman, and T. P. Selby, J. Heterocycl. Chem., 1981, 18,5 7 5 .
186
Heterocyclic Chemistry
tuted (2-pyrimidiny1thio)acetic acids in the presence of AcaO gives mesoionic 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)thiazolopyrimidinium 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-chloro3-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 diperchlorate with orthoesters RC(OEt), (R = H, Me, Et, or Ph) or with 1,1,3,3tetramethoxypropane 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
G. B. Foscolos, G. Tsatsas, and E. Costakis, Chem. Chron., 1980, 9 , 239 (Chem. Abstr., 1981,95,169054). 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).
337 338
Five-Membered Rings: Systems containing N and S, Se, or Te
187
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 [3,4a ] 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. Cyclocondensation 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 [4,5b ]pyrazine (246).
Pyrrolo(2,l -bJ benzothiazole [CflS-C&C, J. is obtained by following a similar method.333
This homologue of (23 1)
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
342
343
K. Tanaka, M. Ino, and Y. Murakami, Chem. Pharm. Bull., 1981, 29, 1876 (Chem. Abstr., 1981, 95, 220 004). 0. Tsuge, H. Shiraishi, and M. Noguchi, Chem. Lett., 1 9 8 1 , 2 13. Y . C. Tong, J. Heterocycl. Chem., 1981, 18, 751.
Heterocyclic Chemistry
188
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-3bromopropionic acids and esters gives acids (250) and lactones (25 1).346
344
345 346
M. D. Kazanis and P. E. Macheras, Chem. Chron., 1980, 9, 201 (Chem. Abstr., 1981,95, 115475). H.Boehme and J . P. Denis, Arch. Pharm. (Weinheim, Ger.), 1982, 315,227. G.Rovnyak, V. Shu, and J. Schwartz, J. Heterocycl. Chern., 1981, 18,327.
Five-Membered Rings: Systems containing N and S, Se, or Te
189
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)
347 348 349
( 254)
L. Mosti, G. Menozzi, and P. Schenone, J. Heferocycl. Chem., 1981, 18, 1069. H. Singhand S. C. Malhotra, Synfh. Commun., 1981, 11, 635. D. Farge, A. Jossin, G. Ponsinet, and D. Reisdorf, Eur. Pat. Appl. 30 198, 1981 (Chem. Abstr., 1982,96,6715).
Heterocyclic Chemistry
190
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-amino3-chloronaphthoquinone with Na2S and CS2.350
Other Condensed Systems incorporating Thiazole. - Dihydro- and tetrahydrocyclopropa [d] thiazole derivative^,^" cyclenothiazoles,352 hexahydrocycloocta[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.
Five-Membered Rings: Systems containing N and S,Se, or Te
191
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 thiadiazo1e .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 McConnellRobertson 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-methyl1,2,3-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-cisc 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 substituted Ph; R3 = CONH2, S02C6H4Me-4, or C02Et) cyclize with H2Se03 H. Ogura, H. Takahashi, and 0. Sato, Chem. Pharm. Bull., 1981, 29, 1843 (Chem. Abstr., 1981, 95, 187 574). 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.
359
360
192
Heterocyclic Chemistry
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-phenylselenadiazole 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-(5substituted 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-dehydrogenated 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 3alkyl(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
367 368
369 370
371
372 3 13
H. Meier, J. Zountsas, and 0.Zimmer, 2.Naturforsch., Teil. B, 1981, 36,1017. Y. V. Zachinyaev and D. S. Orlov, Khim. Promst., Ser. Reakt. Osobo Chist. Veshchestva, 1980,6,51 (Chem. Abstr., 1981,95,42 552). 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). M. N. Basyouni, A. M. A. El-Khamry, M. M. Habashy, M. E. Shaban, and M. M. ElAdly, Synthesis, 1981,232. R. F. Smith and T. P. Feltz, J. Heterocycl. Chem., 1981, 18,201. H. Kagami, T. Hanzawa, N. Suzuki, S. Yamaguchi, M. Saito, and S. Matoki, Bull. Chem. SOC.Jpn., 1980,53, 3658. P. V. Indukumariand C. P. Joshua, Indian J. Chem., Sect. B , 1981,2 0 , 651. F. Ogura, H. Yamaguchi, T. Otsubo, and H. Tanaka, Bull. Chem. SOC.Jpn., 1982, 55, 641.
Five-Membered Rings: Systems containing N and S, Se, or Te
193
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-thiadiazoline [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' =
MesK lJNHR
R~N-
S-
NR
2
s\N
N
N -
R2 = Ph, e t ~ . ) In . ~the ~ ~presence of base, (276) decomposes into R2NHCR'=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
375
376
A. F. Cuthbertson and C. Glidewell, Acra Crysrallogr., Sect. B , 1981, 37,141.9. A. Reiss, W. Walek, and S. Dietzel, J. Prakr. Chem., 1981, 3 2 3 , 279. G. L'abb6 and G. Vermeulen, Bull. SOC.Chim. Belg., 1981, 90, 89.
Heterocyclic Chemistry
194
(278)
(279)
1,3,4-Thiadiazoles. - Synthesis. 1,3,4-Thiadiazoles are obtained by cyclodehydration 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
(281)
(280)
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 0
N\N=C(
Me
SCH2CONHR
SMe)Me
(283)
(282)
0
1
RNH2
s
II It RNHCCH2SCNHN=C(SMe)Me
I]
-
t
[-MeSH]
0
N-
N
II
p 5 C N H R
II
M e l C \ S M e HS'
Scheme 11 The pyrazole-hydrazide (284) has been cyclized by P2S5 to give the 5pyrazolylthiadiazole (285).3&1 The thiadiazinone (286) undergoes thermal 377
378 379 380
382
383
384
D. L. Booth and R. M. Rodebaugh, U.S. P. 4283 543, 1981 (Chem. Abstr., 1981, 95, 187269). M. J. Lavanish, U.S. P. 4 269 983,1981 (Chem. Abstr., 1981,95,62229). S. Singh, L. D. S. Yadav, and H. Singh, Indian J. Chem., Sect. B , 1981, 2 0 , 518. 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. E. F. Rothgery, U.S. P. 4 252 962,1981 (Chem. Abstr., 1981,95,7295). E. K. Mikitenko, N. N. Romanov, and I. S. Shpileva, K h i m Geterofsikl. Soedin., 1981, 339 (Chem. Abstr., 1981,95,24940). J. C . Lancelot, D. Maume, and M. Robba, J. Heferocycl. Chem., 1981, 18, 1319.
Five-Membered Rings: Systems containing N and S, Se, or Te
195
fragmentation at 550°C and 0.08Torr, giving PhCN, MezNCN, and the thiadiazole (287).385 H
:
:
Me2N
’N HNCOMe
‘7’
( N N‘
Me2N
/ Ph
f ‘>Ph
-N
N
(287)
Physical Properties of 1,3,4-Thiadiazoles. Ultraviolet spectra of some 2benzylideneamino-5 -phenyl-1,3,4-thiadiazoles have been reported.386 The H n.m.r. spectral properties and conformational preferences of some openchain and cyclic aromatic sulphides that contain 1,3,4-thiadiazole spectroscopic data of metal (Mn, Fe, Co, Ni, Cu, or Zn) chelates of N-(5phenyl-l,3,4-thiadiazol-2-yl)dithiocarbamic conductometric and i.r. and Raman determinations on thirteen complexes of Zn, Cd, or Hg with 2methyl-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-phenyl1,3,4-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
386
387 388
389
390 391
392 393
394
395
A. E. Baydar, G. V. Boyd, and P. F. Lindley, J. Chem. Soc., Chem. Commun., 1981,1003. M. R. Mahmoud, R. Abdel Hamide, and F. Abdel Goad, 2. Phys. Chem. (Leipzig), 1981,262, 551 (Chem. Abstr., 1981,95,79479). F. Bottino and S. Papalardo, Org. Mugn. Reson., 1981, 16,l. H. Singh, L. D. S. Yadav, and S. B. S. Mishra, J. Inorg. Nucl. Chem., 1981, 43, 1701. A. C. Fabretti, G. C. Franchini, G. Peyronel, and M . Beller, Spectrochim. Actu, Part A , 1981, 37, 5 8 7 . K. N. Johri and B. S. Arora, Thermochim. Acta, 1982, 54,237. G. Bouchoux, Y. Hoppilliard, M . Golfier, and M. G. Guilleriez, Org. Mass.Spectrom., 1981, 16,29. H. Quast and F. Kees, Chem. Ber., 1981, 114,802. A. K. Ramrakhyani, R. S. Shukla, and P. Kumar, J. Indian Chem. Soc., 1981, 5 8 , 307. A. J. Cowper, G . S. Trivedi, R. R. Astik, and K. A. Thaker, J. Inst. Chem (India), 1981, 53,92,141. A. K. S. Gupta and K. Hajela, J. Indian Chem Soc., 1981,58, 690.
Heterocyclic Chemistry
196
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-thiadiazolo [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-5ones.4oo From 1-amino-4,6-diphenylpyridine-2-thione and Ph3P, the resulting iminophosphorane was treated with C 0 2 t o give the thiadiazolopyridiniumolate (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-Diethoxyand 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
396 397
398 399 400 40’
402
M. B. Ferrari, G . G. Fava, and C. Pelizzi, Inorg. Chim.Acta, 1981, 55, 167. H. Paul and G . Huschert, Z. Chem., 1981,21, 185. S. Herrling, U.S. P. 4281 120,1981 (Chem. Abstr., 1981,95,187294). D. Heydenhauss, G. Jaenecke, and B. Feuerstein, 2. Chem., 1981,21, 31. T. Tsuji and K. Takenaka, Bull. Chem. SOC.Jpn, 1982,5 5 , 637. P. Molina, M. Alajarin, A. Arques, and R. Benzal, J. Chem. SOC., Perkin Trans. 1 , 1982,351. 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\
fiRl
R211
(292)
PhNCO or CH2=CHC02Me?03 The reaction of N4S4 with various aryl and alkyl benzyl ketones, oxindole, benzyl a-pyridyl ketone, or a-phenacylS
' 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 RC6H4S02N3 gave the compounds (294; R = 4 M e 0 or 3-02N).408 NS02C6H4R c6Hll\N/
S I'\N/
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-74u3
404
40 5
406
407 408
409
S. Karady, J. S. Amato, D. Dortmund, R. A. Reamer, and L. M. Weinstock, Heterocycles, 1981, 16, 1565. A. A. Algieri, G. M. Luke, R. T. Standridge, M. Brown, R. A. Partyka, and R. R. Crenshaw, J. Med. Chem., 1982,25, 210. 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. 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). D. L. Boger and C. E. Brotherton, J. Heterocycl. Chem., 1981, 18, 1247. R. Neidlein and W. Lehr, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 650. I. A. Belen'kaya and G. P. Krokhina, Deposited Document, 1980, VINITI 384380 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 8 851).
198
Heterocyclic Chemistry
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 = 4CH2CHNH2C02H] 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 hydroxyand 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-benzoselenadiazole were measured and c.d. spectra reported for the 0-cyclodextrin compound with the heterocycle.413 The kinetics of formation and equilibrium 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
411
412 413
414 415
M. A. Kaldrikyan and L. A. Grigoryan, Khim. Gererotsikl. Soedin., 1981, 7 (Chem. Abstr., 1981, 95, 150 551). 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. V. V. Davydov, B. E. Zaitsev, V. G . Sheban, and A. K. Molodkin, Deposited Document, 1980, VINITI 2583-80, 75-83. H. Yamaguchi, A. Uchida, F. Yoneda, and H. Baumann, J. Chem. SOC., Furuduy Tram. 2, 1981, 947. C. Deicha and F. Terrier, J. Chem. Res. ( S ) , 1981, 312. R. Okazaki, K. Inoue, and N. Inamoto, Heterocycles, 1981, 15, 803.
Five-Membered Rings: Systems containing N and S, Se, or Te
199
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].
s L : A
HN
(298) H
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
417
418 419 4 20
R. Okazaki, K. Inoue, and N. Inamoto, Bull. Chem. SOC.Jpn., 1981,54,3541. R. Mayer, G . Domschke, S. Bleisch, and A. Bartl, 2. Chem., 1981,21, 324. J. R. Bews and C. Glidewell, Theo. Chem., 1982,3, 377. G.Wagner, D. Briel, and S. Lektner, 2. Chem., 1981,21, 261. A. W. Gal, J. W. Gosselink, and F. A. Vollenbroek, Inorg. Chim. Actu, 1980, 32, 235.
Heterocyclic Chemistly
200
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 decarboxylation of oxathiazolones (308; R2R3 = 0),undergo 1,3-dipolar cycloaddition
N-
421
S
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 CS3N2Br2 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 fivemembered 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
423
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. G. Wolmerschaeuser, C. JSrueger, and Y. M. Tsay, Chem. Ber., 1982, 115, 1126.
Heterocyclic Chemistry
202 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-carbaldehyde ,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 chargetransfer 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 dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related comp o u n d ~ .Other ~ ~ topics are synthetic applications of 1,3-dithiolium and 1,3oxathiolium 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 comand 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.
''
Five-Membered Rings: Other systems
203
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-tbutylfuran has been obtained by reductive desulphurization of compound (5).26 Photolysis of the (2)-diazo-ester N2CHCHT(CN)C02Et yields 3cyan0-2-ethoxyfuran.~~ The stabilized ylide PhCH2NMe2-cHCOAr (Ar = 4biphenylyl) reacts with dimethyl acetylenedicarboxylate to form the ester (6) with loss of benzyldimethylamine.28 The thermal isomerization of 1,ldiacetylcyclopropane 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 tetraphenylH :C=CH
\
0
Et Ph (10)
(11)
(12)
A. Cormier and M. D. Francis, Synth. Commun., 1981, 11, 365. Barba, M. D. Velasco, and A. Guirado, Synthesis, 1981,625. 26 Krebs, E. Franken, and S. Muller, Tetrahedron Lett., 1981,22, 1675. 27 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.
24 25
R. F. A. C.
Heterocyclic Chemistry
204
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 4ylidenebutenolides (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 cisbifuranylidenedione (17; Ar = 2,4,6-Me3C6H2) and the trans-isomer, which crystallize in a blue-black self-charge-transfer form and a scarlet non-chargetransfer 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
0
34
3s
36
no H2cTto
P. S. Bailey and T. M. Ferrell, J. Org. Chem., 1981, 46, 5028. H. Saimoto, T. Hiyama, and H. Nozaki, J. A m . Chem. SOC.,1981, 103,4975. M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron Lett., 1981, 22, 4269.
37 38 39 40
M. J . Begley, L. Crombie, G. L. Griffiths, R. C. F. Jones, and M. Rahrnani, J. Chem. SOC.,Chem. Commun., 1981,823. J. P. Marino and M. Neisser, J. A m . Chem. SOC., 1981, 103, 7687. J. R. Norton, Prepr. Div. Pet. Chem., A m . Chem. SOC.,1980, 2 5 , 368. Y. Inoue, T. Hibi, M. Sakate, Y. Kamashima, and H. Hashimoto, Nippon Kagaku Kaishi, 1982, 276 (Chem. Abstr., 1982, 96, 217 611).
Five-Membered Rings: Other systems
205
Reactions of Furans. Pyrolysis of the ester (21) yields a mixture of the cyclobutanone (22) and the dimeric compound (23)!l The lactone (25) is produced when octahydrodibenzofuran (24) is oxidized with m-chloroperoxybenzoic 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-2furoic acid with sulphur tetrafluoride in hydrogen fluoride yields the dihydrofuran (27).45 Bromo-furans are converted into aryl-furans by crosscoupling 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 phenylthiocompound (28) has been converted into a series of 4-substituted 2-methylfurans (29; R = alkyl, Me3Si, C02H, or RCHOH) by the sequence: bromination, 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.
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,
42
2636. 49
S. M. Nolan and T. Cohen, J. 0%.Chem., 1981,46,2473.
Heterocyclic Chemistry
206
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 2,5dimethyl-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. 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. " 51
Five-Membered Rings: Other systems
207
yellow fulgide (39) is suitable for chemical actinometry in near-ultraviolet and visible regions, being reversibly transformed into the deep red dihydrobenzofuran (40).55
Me
=
M
e
m
o
Me
Me
Me
0
Me Me
(39)
0
(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.”
*’
R (41)
COOMe
(43) 5
The synthesis of the diatropic [ 141annuleno [c]furan (45) has been described .58
II But
7I But
H. G. Heller and J . R. Langan, J. Chem. SOC.,Perkin Trans, 2, 1 9 8 1 , 341. 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 . ”
’‘ P. J.
208
Heterocyclic Chem istry
Other papers on the f ~ r r n a t i o n ’ ~and - ~ ~reaction^^'-'^ of furans should be noted. 59
R. Dams, M. Malinowski, I. Westdorp, and H. J. Geise, J. Org. Chem., 1981, 46, 2407 (Chem. Abstr., 1981, 95,693).
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, 6o
150 302). 65 66
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). 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. Bzhezovskii, 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, Tetrahedron 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).
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, 74
96, 122 540).
82
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). H. Kotsuki and H. Nishizawa, Heterocycles, 1981, 16, 1287 (Chem. Abstr., 1981, 95, 219 923).
83
84 85
S. Takano, Y. Oshima, F. Ito, and K. Ogasawara, Yukuguku Zusshi, 1980, 100, 1194 (Chem. Abstr., 1981, 95, 24 871). H. Hart and S. Shamouilian, J. Org. Chem., 1981, 46, 4874 (Chem. Abstr., 1981, 95, 203 613).
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).
Five-Membered Rings: Other systems
209
Benzofurans. - Treatment of a mixture of o-dichlorobenzene and cyclohexanone 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.(46)
Ph
,so2
(49)
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.
Heterocyclic Chemistry
210
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 CH=C=CH2
m M e F
-
F \
F
F (51)
(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)
@ c1
COOMe
-Me
a1c14-
c1 0
(58)
(59)
( 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.,
97
99
loo 101 102
1981,18, 507. A. L. J. Beckwith and G. F. Meijs, J. Chem. SOC.,Chem. Commun., 1981,136. G. Capozzi, V. Lucchini, F. Marcuzzi, and G. Modena, J. Chem. SOC.,Perkin Trans. 1, 1981,3106. 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.
Five-Membered Rings: Other systems
211
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 lo4
'05
P. Demerseman, S. Risse, and R. Royer, J. Heterocycl. Chem., 1981, 18, 695. J . K. Makrandi and S. K. Grover, J. Chin. Chem. SOC.(Taipei), 1981,28,65 (Chem. Absfr., 1981, 95, 80 609). R. Bloch and P. Orvane, Tetrahedron Lett., 1981, 22, 3597.
Heterocyclic Chemistry
212
(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
MeaT0
\
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. 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. lo'
Five-Membered Rings: Other systems
213
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-diphenylisobenzofuran (78).'17 The stable endo-peroxide (79) is produced by the action
9
Me0
0
(75)
'"
Me0
OMe
OMe
Ph
Ph
Me (76)
But
0
( 7 7 ) X = CMe2 (78) X = 0
(79)
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.
Heterocyclic Chem istr),
214
of singlet oxygen on 1,3-di-t-b~tylisobenzofuran.~~~ The isobenzofuran (78) 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 [2,1b ] 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 1,3anionic 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, ''I
'''
36, 632. R. F. C. Brown and F. W. Eastwood, J. Org. Chem., 1981,46,4588. 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-phenylpyrrole12’ and the reaction of buta-1,3-diene with ethylamine to give 1ethyl 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
JCNBJ
Me
M AcQcHAc2 e
NHPh
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-triphenylHOOC OHC N‘
Me
Me
Me
Me
Scheme 3 pyrrole.” The antibiotic pyrrolomycin B has been shown to have the structure (95).131
123 124
12’ 126
12’ 12*
131
c1
c1
H
OH
H. A. Houwing and A. M. Van Leusen, J. Heterocycl. Chem., 1981, 18,1127. J. Arct and L. Skatteboel, Tetrahedron Lett., 1982, 23, 113. K. Utimoto, H. Miwa, and H. Nozaki, Tetruhedron Lett., 1981, 22,4277. J . E. Baeckvall and J . E. Nystroem, J. Chem. SOC.,Chem. Commun., 1981, 59. 0. Attanasi, P. Bonifazi, E. Foresti, and G. hadella, J. Org. Chem., 1982, 47, 684. 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. M. Kaneda, S. Nakamura, N. Ezaki, and Y. Iitaka, J. Antibiot., 1981, 34, 1366.
Heterocyclic Chemistry
216
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 OH
Me
H
(96)
(97)
+
Treatment of the quaternary ammonium salt PhC=CCH2NMe2CH2C0Ph Br- with sodium hydroxide gives, inter alia, the betaine (98)." Controlledpotential 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.'~'
M:L)Ph COPh Me2
Me
I 0-
(98)
-pJ-==x pho I
Ph
I , ,
HO
0
E
( 100)
( E = COOEt)
(101)
(99)
132
R. E. Gawley, E. J. Termine, and K. D. Onan, J. Chem. SOC., Chem. Commun., 1981,568.
133 134
135
K. Shimizu and G. Tamura, J. Antibiot., 1981, 34, 654. S. Mageswaran, W. D. Ollis, D. A. Southam, I. 0. Sutherland, and Y. Thebtaranonth, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1969. 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-Benzoylpyrrole reacts with benzene in the presence of palladium(I1) acetate to yield a mixture of 1 -benzoyl-2,5-diphenylpyrrole:, the bipyrrolyl (107), and compound (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 hypochlorite, rearranges in methanol to a mixture of 2- and 3-chloropyrroles; 2,5dichloropyrrole 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) 138 139
140
141 142
143 144 145
146
R. Gassner, E. Krumbholz, and F. W. Steuber, Liebigs Ann. Chem., 1981, 789. M. Speranza, J. Chem. SOC.,Chem. Commun., 1981,1177. (a) R. X . Xu, H. J . Anderson, N. J . Gogan, C. E. Loader, and R. McDonald, Tetrahedron Lett., 1981, 2 2 , 4899; ( b ) J. Rokach, P. Hamel, M. Kakushima, and G . M. Smith, ibid., p. 4901. R. Miller and K. Olsson, Acta Chem. Scand., Ser. B, 1981, 35, 303. C. E. Loader, G. H. Barnett, and H. J . Anderson, Can. J. Chem., 1982, 60, 383. T. Itahara, J. Chem. SOC.,Chem. Commun., 1981, 254. T. Kauffmann and H. Lexy, Chem. Ber., 1981, 114,3674. A. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1981, 2 2 , 5319. M. De Rosa, J. Org. Chem., 1982, 47, 1008.
218
Heterocyclic Chernistv
product, which in hot methanol forms mainly 2-cyanomethyl-l,5-dimethylpyrr01e.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 ringexpanded product (1 18).lS0 E
1I ,1
I M e -
Me
NMe
(114)
E
17:- :uE Me
Me
(116)
(115) ( E = COOMe) 0
Whereas the reaction of 1 -methyl-2-vinylpyrrole with dimethyl acetylenedicarboxylate 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.
Five-Membered Rings: Other systems
219
(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 transpiperylene; 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. B. K. Rammash, C. M. Gladstone, and J. C. Wong, J. Org. Chern., 1981,46,3036.
153
P. M. M. Nossin and W. N. Speckamp, Tetrahedron Lett., 1981,2 2 , 3289.
Heterocyclic Chemistry
220
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 1 e J . J (128)
1,1
’
EHE
2 r
-
‘CHZ/C\COPh ( 129) ( E = COOMe)
r2
I
C
EHC
‘CH<
‘COPh
(130)
Several other articles on the f o r r n a t i ~ n ~ ~ and ’ - ~ ~reactions ~ pyrroles have appeared.
169-186
of
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). l’’
Five-Membered Rings: Other systems
221
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 2methylind~le.'~'The enamino-ketone (1 35) cyclizes photochemically to 1,2dimethylindole (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). 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). K. Mohri, Y. Oikawa, K. Hirao, and 0. Yonernitsu, Heterocycles, 1982, 19, 515. 189 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. 179
222
Heterocyclic Chemistry
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
6
c1
QQR
COOMe
Ph
N3
m o
0
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 2t-butyl~arbazole.~~' Di-lithiation of the o-bromoaniline derivative (1 46), followed by addition of 2-chlorocyclohexanone, affords the hexahydrocarbazole ( 147).lg8
Et
(144) HO
(145) 193
(146)
(147)
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.
223
Five-Membered Rings: Other systems
Reactions of Indoles. 2-Arylindoles react with tosyl azide under phasetransfer conditions to give 3-diazo-compounds (1 48).’99The phenylazoindole (149; R = N2Ph) is converted into the nitroindole (149; R = NO2) by ipsonitration.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
Me m\
P
h
->
OOH
OH
Me
o\r..- 6:
Me \
HOH2C \
N
(153)
199
2oo 201
202
203 204
A. Gonzales and C. Galvez, Synthesis, 1981,741. M. Colonna, L. Greci, and M. Poloni, J. Chem. SOC., Perkin Trans. 2, 1981,6 2 8 . T. Ohnuma, H. Kasuya, Y. Kimura, and Y. Ban, Heterocycles, 1982, 17 (Spec. Issue), p. 377. C. Amsterdamsky and J. Rigaudy, Tetrahedron Lett., 1981,22, 1403. C. Bastianelli, A. Cipiciani, S. Clementi, and G. Giulietti, J. Heterocycl. Chem., 1981, 18, 1 2 7 5 . C. Berti, M. Colonna, L. Greci, L. Marchetti, and M. J. Perkins, J. Chem. SOC., Chem. Commun., 1981,694.
224
Heterocyclic Chemistry
3H-indole (157) results from the action of sodium hypochlorite on 2methylind~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-benzoyloxyor 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 spirocompound (163).212 i
& H
c1 02CPh
(161)
205
206 207
208
209 210 211 212
M. D. Rosa, L. Carbognani, and A. Febres, J. Org. Chem., 1981,46,2054.
T. Kaneko, M. Matsuo, and Y. Iitaka, Chem. Pharm. Bull., 1981,29, 3499. M. Colonna, L. Greci, and M. Poloni, Tetrahedron Lett., 1981, 22, 1143. (a) V. A. Budylin, M. S. Ermolenko, F. A. Chugtai, and A. N. Kost, Khim GeterotsikL Soedin., 1981, 1494;( b ) V. A. Budylin, M. S.'Ermolenko, F. A. Chugtai, P. A. Sharbatyan, and A. N. Kost, Ibid., p. 1503. T. Nagayoshi, S. Saeki, and M. Hamana, Chem. Pharm Bull., 1981, 29, 1920. T. Nagayoshi, S. Saeki, and M. Hamana, Chem Pharm. Bull., 1981,29,.1827. C. Berti and L. Greci, Synth. Commun., 1981, 1 1 , 681. M. K. Eberle, G. G. Kahle, and M. J. Shapiro, J. Org. Chem., 1982,47,2210.
Five-Membered Rings: Other systems
225
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
CH,Ph
H
(166) HQOOH
x0):
-
Me
Me
a (169)
COOMe __c
COPh
'I4 'Is 216
(170)
COPh /
COOMe
(171)
D. S. Johnston, Photochem. Photobiol., 1982, 35, 127. J. D. Lambert and Q. N. Porter, Aust. J. Chem., 1981, 34, 1483. R. M. Acheson, M. C. K. Choi, and R. M. Letcher, J. Chem. SOC.,Perkin Trans. I, 1981,3141. M. Ikeda, K. Ohno, M. Takahashi, T. Uno, Y. Tamura, and M. Kido, J. Chem. SOC., Perkin Trans. 1 , 1982,741.
Heterocyclic Chemistry
226
The azabenzofulvene (1 72) unexpectedly forms compound (1 73) by the action of a ~ e t y l a c e t o n e .The ~ ~ ~mechanism of the decomposition of 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
Me
Me
OOH
-
Ar '
N
~
'
H
A
ocoM
OH
I
+
\ -
N
NHCOAr
H
Attention is drawn to other articles on the formation220-226 and rea c t i o n ~ of ~ ~indoles. ~ - ~ ~ ~ 21 7 218 21 9
220
221
222
223 224
225
D. I. Bishop, I. K. ALKhawaja, and J. k Joule, J. Chem. Reg (S), 1981, 361. F. McCapra and P. V. Long, Tetrahedron Lett., 1981, 22, 3009. C. Berti, L. Greci, and M. Poloni, J. Chem. SOC., Perkin Trans. I , 1981, 1610. R. J. Olsen and 0. W. Cummings, J. Heterocycl. Chem., 1981, 18, 439. (Chem. Absfr., 1981, 95, 6 1 916). H. Galons, J. F. Girardeau, C. C. Farnoux, and M. Miocque, J. Heferocycl. Chem., 1981, 18, 561 (Chern Absfr., 1981, 95, 168014). W. J. Houlihan, V. A. Parrino, and Y. Uike, J. Org. Chem., 1981, 46, 4511 (Chem. Abstr., 1981, 95, 219 936). Y. Tamura, J. Uenishi, H. Maeda, H.-D. Choi, and H. Ishibashi, Synthesis, 1981, 534 (Chem Abstr., 1981, 95, 150 331). U. Kucklander and H. Toberich, Chem. Ber., 1981, 114, 2238 (Chem Absfr., 1981, 9 5 , 1 15 188). I. Erden and D. Kaufmann, Tetrahedron Lett., 1981, 22, 215 (Chem Absfr., 1981, 9 5 , 6 1 712).
226 227
K. H. Grellmann, W. Kuhnle, H. Weller, and T. Wolff, J. A m Chern Soc., 1981, 103,6889 (Chem. Absfr., 1981,95,202 921). G . W. Gribble and S. W. Wright, Heterocycles, 1982, 19, 229 (Chem Absfr., 1982, 96, 162482).
Five-Membered Rings: Other systems
227
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
Y. Kikugawa, Synthesis, 1981,460 (Chem. Abstr., 1981,95,80 644). 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. 228 229
Heterocyclic Chemistry
228
a mixture of N-methylisoindole and the chloride (182) yields the DielsAlder 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 transformed by the action of iodine trichloride into the 6n-iodolium cation (186), which has been isolated as a stable iodide, tetraphenylborate, and hexachlorostannate .259
G. Zoch, A. D. Schluter, and G. Szeimies, Tetrahedron Lett., 1981, 2 2 , 3839. R. Prewo, J. H. Bieri, U. Widmer, and H. Heimgartner, Helv. Chim. Acta, 1981,
l S oH. 251
64, 1515. 252
G. W. Gribble and C. S. LeHoullier, Tetrahedron Lett., 1981, 2 2 , 9 0 3 (Chem Abstr.,
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). F. G. Kathawala,. H. F. Schuster, and M. J. Shapiro, Tetrahedron Lett., 1981, 2 2 , 3703 (Chem Abstr., 1982,96, 52 120). L. Hoesch and B. Koeppel, Helv. Chim Acta, 1981, 64, 864 (Chem. Abstr., 1981,
1981, 95, 61 911). 254
255
257 258 259
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). L. Hoesch, Helv, Chim Acta, 1981, 64, 890 (Chem. Abstr., 1981, 95, 80 628). P. Sanna, F. Savelli, and G. Cignarella, J. HeterocycL Chem., 1981, 18, 475 (Chem Abstr., 1981, 95, 132 601). V. R. Sandel, G. R. Buske, S. G. Maroldo, D. K. Bates, D. Whitman, and G. Sypniewski, J. Org. Chem., 1981, 46, 4069.
229
Five-Membered Rings: Other systems 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'CHCH2CR2R302H.260Treatment of the ester Me2CHCH2CHC102CMewith antimony pentachloride affords the 1,3-dioxolanium salt (188) by way of a retropinacoline 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 1
Ph
R
I
Me
2
Et\O
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
H. Kropf and H. Von Wallis, Synthesis, 1981,237. 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. 260
"' G. N. Dorofeenko, S. V.
"'
Heterocyclic Chem istry
230
Other articles on dioxoles have a ~ p e a r e d . ~ ~ ~ - ~ ~ l
Dithioles and Related Systems. - Base-catalysed condensation of the 1,2dithiolium 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
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. 267
23 1
Five-Membered Rings: Other systems
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<-,
-
C2F5
(206) (207)
Ph
(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-CHC02Me.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 mesoionic 1,3-dithiolium 4-oxide (2 13) forms the intramolecular cyclo-adduct (2 14).285
gkg~ ~ L.+LOOEt Ph
COOMeM e i < T A P .
CH2CH I =CH2
Ph
(210)
(2091
(211)
NC
rA
R1
R2
;Me
- NC (212)
219
280
281
282 284 285
D. J . Burton and Y. Inouye, Chern. Lett., 1982,201. K. Takahashi, K. Takase, and Y. Noda, Chern. Lett., 1981,805. M. V. Iakshmikantham and M. P. Cava, J. 0%.Chem., 1981, 46, 3246. E. Vedejs and J. Eustache, J. Org.Chem., 1981, 46, 3353. I. Kalwinsch and R Huisgen, Tetrahedron Lett., 1981,22, 3941. F. Kato and T. Tanaka, Bull Chem SOC.Jpn., 1981,54, 1237. H. H. Gotthardt and M. Otmar, Liebigs Ann. Chem., 1981,347.
h
232
Heterocyclic Chemistry
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
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. 286
233
FiveMembered Rings: Other systems
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
S
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-
1
Te-
Te
I
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. R. Neidlein and H. Zeiner, Angew. Chem., Int. Ed, Engl., 1981, 2 0 , 1032. M. L. Petrov, V. Z. Laishev, and A. k Petrov, Zh. Org. Khim., 1981, 17, 667. M. V. Lakshmikantham, M. P. Cava, M. Albeck, L. Engman, F. Wudl, and E. AharonShalom, J. Chem. Soc., Chem. Commun., 1981, 829. D. J. Sandman, J. C. Stark, and B. M. Foxman, Organometallics (Washington, D.C.), 1982, 1,739 (Chem. Abstr., 1982, 96, 181 218).
294 295
296 297
Heterocyclic Chemistry
234
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-dihydro2,5-dimethoxyfuran, forms a 1 : 1 ion-radical salt with tetracyanotetrafluoro-
(231)
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. 298
Five-Membered Rings: Other systems
235
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
312 313
314 315 316
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. P. A. C. Gane, P. Kathirgamanathan, and D. R. Rosseinsky, J. Chem. SOC.,Chem. Commun., 198 1,378. 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). E. M. Engler, V. V. Patel, and R. R. Schumaker, Tetrahedron Lett., 1981, 2 2 , 2035. J. Nakayama, S. Maruyama, and M. Hoshino, BUZZ. Chern. SOC.Jpn., 1981, 54, 2845. R. Neidlein and H. Zeiner, Arch. Pharm. (Weinheim, Ger.), 1982, 315, 90.
236
Heterocyclic Chemistry
Deselenation of compound (239) with triethyl phosphite yields the syntetraselenafulvalene (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
CMe=CHCH2Ax
CH= CHCH 2Ph
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 BZ
Me N"
Et 2N Me
p
iBz "N
I
( B z = PhCO)
Me
(245
E. Fanghanel, G. Schukat, and J. Schutzendubel, 2.Chem., 1981,2 1,447. 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. 317
318
Five-Membered Rings: Other systems
237
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
CHAr
N’ Me2 (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
322 323 324
325 326 321
P. Imming, R. Mohr, E. Muller, W. Overheu, and G. Seitz, Angew. Chem., Int, Ed. Engl., 1 9 8 2 , 21, 284. Z. T. Fomum, S. R. Landor, P. D. Landor, and G. W. P. Mpango, J. Chem. SOC., Perkin Trans. I , 1981, 2997. P. S. Engel, and D. B. Gerth, J. A m . Chem. SOC.,1981, 103, 7689. E. Schaumann, H. Behr, G. Adiwidjaja, A. Tangerman, B. H. M. Lammerink, and B. Zwanenburg, Tetrahedron, 1981, 37, 217. R. Gompper and B. Kohl, Angew. Chem., Int. Ed. Engl., 1 9 8 2 , 2 1, 199. 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 . M . Poje and N. Bregant, Tetrahedron Lett., 1980, 21, 5 0 5 9 .
238
Heterocyclic Chemistry
The synthesis of iodo[ 'lC] antipyrine for positron emission of 13.7771.~~~ 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 octahydroindazole (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]
328 329
C. Y. Shiue and A. P. Wolf, J. Labelled Compd. Radiopharm., 1 9 8 1 , 18, 1059. 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).
330 331 332 333
334
B. Fouchet, M. Joucla, and J . Mamelin, Tetrahedron Lett., 1981, 2 2 , 1 3 3 3 . G. A. Olah, S. C. Narang, and A. P. Fung, J. Org. Chem., 1 9 8 1 , 4 6 , 2 7 0 6 . R. P. M. Berbee and C. L. Habraken, J. Heterocycl. Chem., 1 9 8 1 , 18, 559. 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 . G. Weber, G. Mann, H. Wilde, and S. Hauptmann, 2. Chem., 1980, 2 0 , 4 3 7 .
Five-Membered Rings: Other systems
239
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 spirocyclopropene (267) rearranges to the cyclopentafluorene (268) on Me
Me P
h
p
"
a
.
P
h
"Yke p
"
"
9-v //N
(2 N6 4 )
NEt2
(265)
-
N
( E = COOMe) 335
336 337
E
E
(268)
E'
G. Singh, D. Singh, and R. N. Ram, Tetrahedron Lett., 1 9 8 1 , 2 2 , 2 2 1 3 . H. Cardy and E. Poquet, Tetrahedron, 1981, 37, 2279. A. Padwa and T. Kumagai, Tetrahedron Lett., 1981, 22, 1199.
Heterocyclic Chemistry
240
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 have appeared.
reaction^^^-^'^
of pyrazoles
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. 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. 339
Five-Membered Rings: Other systems
241
3H-indazoles (273) and (274); thermolysis of either yields both the 3- and 4methyl 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
( 2 7 3 ) 3-Me ( 2 7 4 ) 4-Me
0
OH
II
Me
3
4
(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 3 54 355 356
K. Hirakawa, Y. Minami, and S. Hayashi, J. Chem. Soc., Perkin Trans. I , 1982, 577. P. C. Montevecchi and P. Spagnolo, J. Org. Chem., 1982,47, 1996. M. L. Mahati, R. Stradi, and E. Rivera, J. Heterocycl. Chem., 1981, 18, 921. G. Prasad, B. P. Giri, and K. N. Mehrotra, J. Org. Chem., 1982, 47, 2 3 5 3 .
Heterocyclic Chemistry
242
yield the irnidazoline N-oxide (282).357 Further studies by Butler on the formation of imidazolones from ureas have appeared; thus urea and 1,2diaminoethane 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 Copyrolysis of 2,4-dime thylimidazole and chloroform results in a complex mixture, containing imidazole and methyl-, dimethyl-, and chloromethylpyrimidines and - p y r a ~ i n e s .The ~ ~ ~confusion about the structures of Nmethyl 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
357
”*
R o N S P h
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, 363 364
Suppl., 1981,191. B. Iddon and B. L. Lim, J. Chem. SOC.,Chem. Commun., 1981,1095. M. A. Khan, J. Pharm. (Lahore), 1980,2 , 81 (Chem. Abstr., 1981,95,132 753). 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.
Five-Membered Rings: Other systems
243
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-benzoq ~ i n o n e .The ~~~ diazafulvene (293) is obtained by the action of benzylmagnesium 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 photoadduct (296) with ethylene.368*369Treatment of NN'-dimethylimidazoline-2thione with bromine and toluene-p-sulphonamide leads to the thione-Simide (297).370 The thione-thiol tautomerism of the nitroxides (298)+(299) has been studied by e.s.r. spectro~copy.~~'
Et (294)
G. Fukata, T. Itoh, and M. Tashiro, Heterocycles, 1 9 8 1 , 16, 549. 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 . 365
366
Heterocyclic Chemistry
244
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-2t h i ~ n e N-Phenylcarbimide .~~~ dichloride, PhN=CC12, reacts with the amidine
I 0( 300)
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, 372
Five-Membered Rings: Other systems
245
PhN(OH)CH=NBut to yield the benzimidazolidinone (303).392The cyclobutenedione derivative (305) is formed from o-phenylenediamine and the is0 thiocyanate (304). 393 CH= NBu
scNao
t
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
393 394
395
H. G. Schrecker and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 289. and H. Dietschmann, Liebigs Ann. Chem., 1981, 1003. 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. A. P. Davis and G. H. Whitham, J. Chem. Soc., Chem. Commun., 1981,741.
w. fied
246
Heterocyclic Chemistry
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 (312) is produced by the action of bromine trifluoride on the spiro-sulphuran (3 1 11.397
gD 0
But
Me
\
Me
Bu
t
Bu
t
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)
396
397 398
(314)
W. Y. Lam and J. C. Martin, J. Org. Chem., 1981,46,4468. R. S. Michalakand J . C. Martin, J . Am. Chem. SOC., 1982, 104,1683. K. Oka, A. Dobashi, and S. Hara, J. A m . Chem. Soc., 1981, 103,2757.
Five-Membered Rings: Other systems
247
compound (3 16) leads to the rearranged oxathiole (3 1 ' 3 , which undergoes an acid-catalysed ring-opening to give acetonyl vinyl sulphide, MeCOCH2SCH=CH2.399 Treatment of dimedone with the sulphur di-imide PhS02N= 0
C1H2C
K..
Me - H 3 c c A
(316 1
Me
: : h y , . , . h T e
(317)
Me
(318)
S=NS02Ph affords the spiro-oxathiole (3 18).4"0 A general synthesis of 1,3oxathiole-2-imines is exemplified in Scheme 6.401 MeCHC 1
I
MeACNO
S
(i) NaOMe [-HC1]
II
(ii) heat [-MeOH]
Me0"hHCOPh
+
*
M Mee a , A N C O P h
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
399 400
401
402 403 404
405
J . Mattay and H. D. Scharf, Tetrahedron Lett., 1982, 23,47. E. S. Levchenko, S. N. Gaidamaka, V. N. Kalinin, and L. V. Budnik, Zh. Org. Khim., 1981,17,990. M. Kulka, Can. J. Chem., 1981,59, 1557. A. M. Bernard, S. Cabiddu, P. P. Piras, and F. Sotgiu, J. Heterocycl. Chem., 1981, 18,639. R . Schulz and A. Schweig, Angew. Chem., Int. Ed. Engl., 1981,20, 571. W. Nakanishi, S. Murata, Y. Ikeda, T. Sugawara, Y. Kawada, and H. Iwamura, Tetruhedron Lett., 1981, 22,4241. W.Nakanishi, Y. Ikeda, and H. Iwamura, J. Org. Chem., 1982,47,2275.
248
Heterocyclic Chemistry
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 hydroxylamine .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-cycloaddition to olefins; thus sequential treatment of Me2CHN02 with trimethyl-
406 407
408
409
410 411
L. D. Sychkova, 0. L. Kalinkina, and Yu. D. Shabarov, Zh. Org. Khim., 1981, 17, 1435. G. L’Abbb, J . P. Dekerk, and P. Van Stappen, Bull. SOC. Chim. Belg., 1981, 90, 1073. F. Pochat, Tetrahedron Lett., 1980,21, 3755. C. J. Rao, K. M. Reddy, and A. Murthy, Indian J. Chem., Sect. B , 1981,20,282. H.Noda, M. Niwa, and S. Yamamura, Tetrahedron Lett., 1981,22, 3247. Ngan Sim Ooi and D. A. Wilson, J. Chem. Res. ( S ) , 1980,394.
Five-Membered Rings: Other systems
249
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-phenylhydroxylamine 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 rearrangement (336) (337) and those of the isoxazole oxazole transformation (338) +. (339) have been determined:l’ Palladium(I1) chloride-triphenylphosphine 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-dihydro5-hydroxyisoxazoles.418 -+
-+
H
412
413
414 415 416
417
418
S. K. Mukerji and K. B. G. Torssell, Acta Chern. Scand., Ser. B , 1981, 35, 643. K. Harada, E. Kaji, and S. Zen, Chem. Pharm. Bull., 1980,28, 3296. F. DeSarlo, A. Guarna, P. Mascagni, R. Carrie, and P. Guenot, J. Chem. SOC.,Perkin Trans. I , 1981,1367. J . D. Perez, R. G. De Diaz, and G. I. Yranzo, J. Org. Chem., 1981,46, 3505. H. Yamanaka, M. Shiraiwa, E. Yamamoto, and T. Sakamoto, Chem. Pharrn. Bull., 1981,29, 3543. D. J. Brunelle, Tetrahedron Lett., 1981,22, 3699. 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.
250
Heterocyclic Chemistry
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 1methyl-3,4-diphenylpyrrole(347) at room temperature.422
R4
( 344)
(345)
Other articles on the should be noted.
bH
(346)
and
Me (347)
reaction^^^'-^^^ of isoxazoles
Benzisoxazoles and Other Annelated Isoxazoles. - The sodium-me thoxideinduced cyclization of the nitro-ketone (348) furnishes 3-phenyl-2,lbenzisoxazole (349)429 5-Chloro-2,l-benzisoxazole adds dimethyl acetylenedicarboxylate to give the Diels-Alder product (350), while the parent com-
419 420 421
T. Kumagai, K. Shimizu, Y. Kawamura, and T. Mukai, Tetrahedron, 1981, 37, 3365. V. Jaeger, W. Schwab, and V. Buss, Angew. Chem., Int. Ed. Engl.. 1981, 20, 601. C. Baldoli, E. M. Beccalli, E. Licandro, and A. Marchesini, Guzz. Chim. Itul., 1981, 111, 347.
422 423
F. DeSarlo, A. Brandi, and P. Mascagni, Synthesis, 1981, 561. R. F. Cunico, J. Organomet. Chem., 1981, 212, C51 (Chem. Abstr., 1981, 95, 96 645).
424
425
426 427 428 429
B. J. Wakefield and D. J. Wright, J. Chem. Res.(S), 1981, 129 (Chem. Abstr., 1981, 95, 1 1 4 994). H. Yamanaka, M. Shiraiwa, T. Sakamoto, and S. Konno, Chem. Pharm. Bull., 1981, 29, 3548 (Chem. Abstr., 1982, 96, 122 673). Z. W. Wicks, Jr. and P. P. Patel, J. Org. Chem., 1981, 4 6 , 4 0 6 8 (Chem. Abstr., 1981, 95, 132 722). V. F. Rudchenko, V. G. Shtamburg, and R. G. Kostyanovskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1183 (Chem. Abstr., 1981, 95, 132 719). 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 ) . M. Jawdosiuk, I. Kmiotek-Skarzynska, and E. Czarnecka, Pol. J. Chem., 1981, 55, 379.
25 1
Five-Membered Rings: Other systems
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-
0
\ 0
+
0
'I
NH
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 HOCHPhCONH2.440 c104
(354) 430
(355)
( 356)
( 357 1
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.
Heterocyclic Chemistry
252
The reaction of the oxiran (358; Ar =p-N02C6H4) with methyl thiocyanate 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 Nbenzoylpropargylamine .443
8-.,o/#A
EtOOC
PhC
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=CMe02CCOC1, obtained by treating diacetylamine with oxalyl chloride, cyclizes to the oxazolidinedione (367) on heatingM8
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. 441
25 3
Five-Membered Rings: Other systems
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.,
450
J. E. Saavedra, J. Org. Chem., 1981, 46, 2610. W. J. Hammar and M. A. Rustad, J. Heterocycl. Chem., 1981, 18, 885. A. I. Meyers and J. P. Lawson, Tetrahedron Lett., 1981, 22, 3163. (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. M. Lheme, P. Le Perchec, J. Garapon, and B. Sillion, Tetrahedron Lett., 1982, 2 3 ,
1981, 38. 451 452 453
454
73. 455
K. Burger and H. Goth, J. Fluorine Chem., 1981, 17, 585.
254
Heterocyclic Chemistry
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-dihydrooxazoline 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 diastereoselectivity .461
Me
Me
456
457
458 459 460
461
T. Kopczynski and S. Goszczynski, Pol. J. Chem., 1981, 5 5 , 393. A. R. Colwell, L. R. Duckwall, R. Brooks, and S. P. McManus, J. Org. Chem., 1981, 46, 3097. S . Shibata, H. Matsushita, H. Kaneko, M. Noguchi, M. Saburi, and S. Yoshikawa, Chem. Lett., 1981,217. J . M. Wilson and D. J. Cram, J. A m . Chem. SOC.,1982, 104,881. A. I. Meyers and Y. Yamomoto, J. A m . Chem. SOC., 1981, 103,4278. (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.
25 5
Five-Membered Rings: Other systems
Photo-oxygenation of the oxazoles (387; n = 2 or 3) gives transient cycloadducts (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
(393)
( 394)
Me
(395)
A new reagent for activating carboxylic acids for amide formation is the phosphonate (39QM6 The azomethine imine (397), obtained from diphenylketen and diethyl azodicarboxylate, forms the 1,3-cyclo-adduct (398) with COOE t
Ph
Ph
462
463
OEt
H. H. Wasserman, J . E. Pickett, and F. S. Vinnick, Heterocycles, 1981, 15, 1069. H. H. Wasserman, R. J . Gambale, and M. J. hlwer, Tetrahedron Lett., 1981, 2 2 , 1737.
464 465 466
N. Saito, K. Hatakeda, S. Ito, T. Asano, and T. Toda, Heterocycles, 1981, 1 5 , 905. H. Laas, A. Nissen, and A. Niirrenbach, Synthesis, 1981,958. 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
RCH-NH2
I
ii
-*
COOH ( R = alkyl; A r
=
2,4,6-Me3C6H2) /
J
iii
CH CH CN
R RCOCHzCHzCN
c
N
1 COOH 0
H
A
Ar
Reagents: i, ArCOC1; ii, H,C=CHCN; iii, HO-; iv, Pb(OAc),
Scheme 7 467
46 0 469 470
411
E. Fahr, E. Buttner, K. H. Keil, J . Markert, F. Scheckenbach, R. Tiedemann, and J . Fontaine, Liebigs Ann. Chem., 1981, 1433. U . Niewohner and W. Steglich, Angew. Chem., Int. Ed. Engl., 1981, 20, 395. A. Padwa, M. Akiba, L. A. Cohen, and J . G. MacDonald, Tetrahedron Lett., 1 9 8 1 , 2 2 , 2435. A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. A m . Chem. Soc., 1982, 104, 286. H. Wegmann and W. Steglich, Chem. Ber., 1981, 1 1 4 , 2 5 8 0 .
Five-Membered Rings: Other systems
257
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 tetrachloroebenzoquinone 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 Ph
MeN
Ph CHPh
412
473 474
475
c1
Ph
c1
Ph
M. A. El-Hashash, A. A. Mify, A. M. Kaddah, and S. S. El-Kady, Synthesis, 1981, 798. W. Friedrichsen, I. Schwarz, B. Epe, and K. F. Hesse, 2.Naturforsch., Teil. B , 1981, 36, 622. (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. M. L. Deem, Org. Prep. Proced. Int., 1 9 8 1 , 1 3 , 4 1 4 .
258
Heterocyclic Chemistry
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 aminolyS ~ 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 1NHCOPh
\
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). 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 M. 1. El-Sheikh, A. Marks, and E. R. Biehl, J. Org. Chem., 1981,46,3256. 484 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. 417
25 9
Five-Membered Rings: Other systems
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 benzoxazole (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-methylbenzoxazole 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
E ( 4 2 7 ) E = COOMe
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. 487
Heterocyclic Chemistry
260
Benzoxaiodoles. - N.m.r. spectroscopy shows that diphenyliodonium-2carboxylate exists in the cyclic form (428).493 The stable periodonium salt (430) has been prepared from the benzoxaiodole (429).494
(428)
0
Y
CF..
C
F
3
CF3
I
-
CF3S03
c1
(430)
(429)
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 alkenyltriazolines (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*
R' (434 1
4y3
494 495 496
497
498
,NCH=CH2 N
RI (435)
D. Del Mazza, M. G. Reinecke, and W. B. Smith, Org. Magn. Reson., 1980, 14,540. (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. R. W. Saalfrank and E. Ackermann, Chem. Ber., 1981, 114,3456. N. Henning, T. Dassler, and W. Jugelt, 2.Chem., 1982,22, 25. A. Hassner, B. A. Belinka, Jr., M. Haber, and P. Munger, Tetrahedron Lett., 1981, 22, 1863. M. M. Ito, Y. Nomura, Y. Takeuchi, and S. Tomoda, Chem. Lett., 1981, 1519.
26 1
Five-Membered Rings: Other systems
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).
S l p 3 d NA r
\
N=N
(437)
/ NHAr
p! H
PhCCIZ
(438)
(4391
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 achlorobenzylidenecarbamoyl 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
(443)
s//c\R (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
501
502
504 505 ’06
J . Chem., Sect. B , 1981,2 0 , 898. F. Lubbe, K. P. Grosz, W. Hillebrand, and W. Sucrow, Tetrahedron Lett., 1981, 22, 227 (Chern. Abstr., 1981,95,61 647). 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). F. Risitano, G. Grassi, and F. Foti, J. Chem. Res. (S)., 1981, 65. P. Metra and J . Hamelin, Can. J. Chem., 1982,6 0 , 285. 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.
Heterocyclic Chernistry
262
The combined action of ethyl propiolate and triethylamine on the salt (445) results in the ester (447), which arises from the intermediate cycloadduct (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)
Ao:
0
Ph
(453)
509
511
512
'13
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. W. Bethauser, M. Regitz, and W. Theis, Tetrahedron Lett., 1 9 8 1 , 22, 2535. I. K. Korobitsyna, L. L. Rodina, and A. V. Lorkina, Zh. 0%. Khirn., 1 9 8 1 , 17, 2021. P. G. Gassmanand R. C. Hoye, J. Am. Chem. SOC., 1981, 1 0 3 , 2 4 9 8 .
Five-Membered Rings: Other systems
263
(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 norbornene (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
0
514
515
516 517
P. G. Gassman and R. C. Hoye, J. A m . Chem. SOC., 1981, 103,2496. R. L. Amey and B. E. Smart, J. Org. Chem., 1981,46,4090. W.Adam, 0. De Lucchi, and D. Scheutzow, J. Org. Chern., 1981,46,4130. W.Adam and 0. De Lucchi, Tetrahedron Lett., 1981,22,929. W.Adam, L. A. Arias, and 0. De Lucchi, Synthesis, 1981,543.
”’
Heterocyclic Chemistry
264
Several other papers on 1,2,4-triazoles should be noted.519-521
Other Systems. - Th,e trithiolan (464) has been prepared from the phosphonium 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
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. '19
Five-Membered Rings: Other systems
265
Electrolysis of 3-phenylsydnone in the presence of tetraethylammonium tosylate at a platinum anode results in formation of the 4t 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 = 2,6C12C6H3) unexpectedly leads to the 3-amino-oxadiazole (472).529 3-Azido5-phenyl-l,2,4-oxadiazole(473) reacts with dimethylformamide to form the imine (474);530 flash vacuum pyrolysis of the azide affords benzoyl
I
(473)
CN
(474)
(472) (471)
cyanide via the tetrazole ( 4 7 9 , which undergoes fission of the nitrogenoxygen 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
(4743) 525 526
527 528
529
531 532
- Ph
[-2N2]
‘c’
NC
II
0
(477)
Ph,
,CN
C
II
0
(478)
H. Gotthardt and F. Reiter, Chem. Ber., 1981, 114, 2450. H.-J. Tien, T. Nonaka, and M.-Y.Yeh, J. Chin. Chem. SOC. (Taipei), 1981, 28, 161 (Chem. Abstr., 1981, 95, 169 089). A. Padwa and R. Lim, Tetrahedron Lett., 1982, 23, 11. P. H. Benders, D. N. Reinhoudt, and D. M. W. Van den Ham, R e d : J. R. Neth. Chem. SOC., 1981, 100,330. M. J. Dimsdale, J. Heterocycl. Chem., 1981, 18, 37. P. Choi, C. W. Rees, and E. H. Smith, Tetrahedron Lett., 1982, 23, 125. P. Choi, C. W. Rees, and E. H. Smith, Tetruhedron Lett., 1982, 23, 121. G. Adembri, A. Camparini, F. Ponticelli, and P. Tedeschi, J. Chem. SOC., Perkin Trans. I , 1981, 1703.
266
Heterocyclic Chemistry
0
-
HN---f-
Ph
0
( 479 1
(4801
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
__t
0-
/ \Me Ph
-
Ph
N
/\ Ph
PhCON
Me 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 Me
N L O O N+ Lo-
-VNoH N\O
534
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). N. Vivona, G . Macaluso, G. Cusmano, and V. Frenna, J. Chem. SOC.,Perkin Trans. I ,
535
1982, 165. N. Suzuki, S . Wakatsuki, and H. Izawa, Heterocycles, 1981, 16, 1195.
533
Five-Membered Rings: Other systems
267
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
ATkre 02Nei \
\ + N’
Me
0
Me
I
0( 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 diazocompound as the key intermediates (see Scheme 9).%’ N-
Ph CN2
[-co 1 PhC
H
-
/ Me Ph \
I
C
w
Me
(491)
PhC :
.j, Me
(493)
Scheme 9 536
537 538
539 540
A. J . Boulton, D. E. Coe, and P. G . Tsounga, Gazz. Chim. Ital., 1981, 111, 167. R. A. Whitney and E. S. Nicholas, Tetrahedron Left., 1981, 2 2 , 3371. ( 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. M. Ekkhaziand J . Warkentin, J. A m . Chem. SOC.,1981, 103, 2 4 7 3 . A. Padwa, T. Caruso, S. Nahm, and A. Rodriguez, J. A m . Chem. SOC.,1 9 8 2 , 104, 2865.
268
Heterocyclic Chemistry
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-diazaphospholine (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
-Io\p/O
1
:o
Me-Me
OXp/O 0
O ‘Me (494 1
‘OSiMe3 (4951
(496)
p l y ! P h Ph Ph
Ph
ArN (498)
(499 )
OMe (500 1
G. Ronsisvalle, F. Guerrera, and M. A. Siracusa, Tetrahedron, 1981, 37, 1415 (Chem. Abstr.. 1981. 95. 115 363). 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 .
541 542
Five-Membered Rings: Other systems
269
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 HOCPh2CONHOH 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. 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.
560
Heterocyclic Chemistry
270
(507) is formed by the action of B4HI0 on NNN‘N’-tetramethyl-o-phenylenediarnir~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 (507 1
B3H8
(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 cyanotrinitr~methane.’~~ 5-Aryltetrazoles (51 2) are transformed into the oxadiazoles (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,
575
576
577
578 579
582
583
Chem. Ber., 1981, 114,3402. N. V. Vasilev, A. F. Kolomiets, and Z. Sokolskii, Zh. Vses. Khim. 0 - va , 1981,26, 350 (Chem. Abstr., 1981,95, 132 772). K. Nandi and J. Goerdeler, Chem. Ber., 1981, 114, 1972 (Chem. Abstr., 1981, 95, 42 968). J. L. Kice and S.-T. Liao, J. Org. Chem., 1981, 46, 2691 (Chem. Abstr., 1981, 95, 24 435). W. Weber and K. Niedenzu, J. Organomet. Chem., 1981, 2 0 5 , 147 (Chem. Abstr., 1981,95,62 078). 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. V. Grakauskas and A. H. Alber, J. Heterocycl. Chem., 1981, 18, 1477. M. Uher, J . Foltin, F. Povazanec, and J. Kovac, Collect. Czech. Chem. Commun., 1981,46,1492.
27 1
Five-Membered Rings: Other systems
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‘-dimethylcarbodi-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
MeNKNMe x
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 -0 584 585
586
J . Plenkiewicz and T. Zdrojewski, Bull. SOC.Chim. Belg., 1981,90, 193. I. D. Entwistle, B. J . Hussey, and R. A. W. Johnstone, Tetrahedron Lett., 1980, 21,4747. 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). D. Moderhack, Chem.-Ztg., 1981, 105,194 (Chem. Abstr., 1981,95,132 767). V. P. Shchipanov and N. A. Klyuev, Khim. Geterotsikl. Soedin., 1981, 694 (Chem. Abstr., 1981,95,132 762).
”’
’” s91 s92
(523)
Heterocyclic Chemi s t y
272
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,
c12
I
N ,
I
9 Compounds containing Two Fused Five-Membered Rings ( 5 3 ) Hypervalent Sulphur and Selenium Compounds. - Treatment of the aminothiatriazole (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
594 595 596
M. N. Martynova, M. S. Pevzner, N. A. Smorygo, and N. M. Serebryakova, Khim. Geterotsikl. Soedin., 1981, 1682. (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. G. L'abbi and G. Vermeulen, Bull. SOC. Chim. Belg., 1981, 90, 89. 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.
27 3
Five-Membered Rings: Other systems
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 dimerization to yield mainly compound (538).601 The pyrroloindoloquinone (540) is produced by irradiation of the benzoquinone derivative (539).602
0
H (535)
(534)
H
N
/
Ph
(537) E = COOMe 0 E
(539) 59a 599
6oo 601
602
( E = COOEt)
(5401
H. McNab, J. Org. Chem., 1981, 46, 2809. R. Neidlein and G. Jeromin, Chem. Ber., 1982, 115, 706. W. Verboom, G. W. Visser, W. P. Trompenaars, D. N. Reinhoudt, S. Harkema, and G. J. Van Hummel, Tetrahedron, 1981, 37,3525. K. Sumoto, S. Fujii, 0. Yamashita, T. Somehara, and S. Miyano, J. Heterocycl. Chern., 1981, 18,413. M. Akiba, S. Ikuta, and T. Takada, Heterocycles, 1981, 16, 1579.
274
Heterocyclic Chemistry
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
(543)
I
Me
(544)
(542 1
&,: N\N
(545)
( E = COOMe) (547)
A
603 ‘04
606
H. G. R. L.
mo
Kanety, H. Dodiuk, and E. M. Kosower, J. Org. Chem., 1982, 47,207. Zvilichovsky and M. David, J. Org.Chem., 1982,47,295. J . Sundberg and B. C. Pearce, J. Org. Chem., 1982, 47, 725. 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.
Five-Membered Rings: Other systems
27 5
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.
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). 608
Heterocyclic Chemistry
276
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 azaindolizine (557).625 The coupling product of the piperidino-enamine C5HI0NCH=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 hydroxyazaindolizine (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
Q=*:
(558) (559 1
(557)
Ph
623
0-
A. Kakehi, S. Ito, A. Hamaguchi, and T. Okano, Bull. Chem. SOC. Jpn., 1981, 54, 2833.
624 625
626 627
628
Y. Yamashita, D. Suzuki, and M. Masumura, Heterocycles, 1981, 16, 1697. W. C. Lumma, Jr., and J. P. Springer, J. Org. Chem., 1981, 46, 3735. C. B. Kanner and U. K. Pandit, Tetrahedron, 1981, 37, 3519. L. W. Deady and M. S. Stanborough, Aust, J. Chem., 1981, 34, 1295. 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.
Five-Membered Rings: Other systems
277
the perchlorate (562) yields the azetopyridinium salt (563), as shown by X ray crystallography.6m Ph
Q\ =1
N V " H 2
- QNTp
-- B r
\
c104
-
c104
Ph
(563)
(562)
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' = pNO2C6H4, Ar2 =p-MeC6H4) in the presence of pyridine and tetraethylammonium 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
(565)
(566 )
0 H
Ar (567)
(568)
obtained by the reaction of 2-aminobenzimidazole with diphenylcyclop r ~ p e n o n e . ~ Compound ~' (569), an analogue of isoindole, undergoes ringexpansion 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 COOE t
E
CN
H
(571)
CN
( E = COOEt)
bNqm
Drn CN
(574)
H
PhMeN
(575
CN
CN
(573)
(572)
/
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.
639 640
64 1 642
T. Kurihara, T. Tani, and K. Nasu, Chem. Pharm. Bull., 1981, 29, 1548. R. S. Hosmane, V. Bakthavachalam, and N. J . Leonard, J. A m . Chem. SOC., 1982, 104, 235. H. J . Timpe, R. Burggraf, and U. Lammel, J. Prakt. Chem., 1 9 8 1 , 323, 6 2 7 . E. Lippmann and E. Tober, 2. Chem., 1981, 21, 7 1 .
Five-Membered Rings: Other systems
279
For other work, see references 643-668.
Mixed Oxygen-Nitrogen Systems and a Diselenoloquinoxaline. - The 0methyloxime (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). 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). 644
Heterocyclic Chemistry
280
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
669 670 6 I2
0
C. L. Hickson and H. McNab, Synthesis, 1981,464. G . Fukata, T. Itoh, and M. Tashiro, Chem. Lett., 1981,1345. 0. Tsuge, K. Ueno, and I. Ueda, Heterocycles, 1981, 16, 1503. 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.
Five-Membered Rings: Other systems
281
urea (592) cyclizes to the betaine (593) under the influence of triphenylphosphine and carbon t e t r a ~ h l o r i d e . The ~ ~ furan analogue (594) of isatoic 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
(592
(593)
H ( 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 ,
6 14
J. B. Press, N. H. Eudy, and T. 0. Olagbemiro, J. Org. Chem., 1981, 46, 3853. G. Adembri, A. Camparini, D. Donati, F. Ponticelli, and P. Tedeschi, Tetrahedron Lett., 1981, 2 2 , 2 1 2 1 . B. R. Rao, G. Mohiuddin, and K. Ahmed, Indian J. Chem., Sect. B , 1 9 8 1 , 2 0 , 1 5 8 . T. K. Raja, J. Indian Chem. SOC., 1981, 5 8 , 1 7 4
615
676 671
1982, 351.
282
Heterocyclic Chemistry
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 Treatment of the pyrrolo-azepine (60 1) with benzoylmethylenetriphenylphosphorane, 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 diazomethane.687 Addition of dimethyl acetylenedicarboxylate to the cyclo-
E t OOC
Ph EtOOC (603)
(604)
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 ,
678
'*'
1981, 1132. 687
W. Flitsch and E. R. F. Gesing, Chem. Ber., 1981, 114, 3146. T. Kurihara, T. Tani, and K. Nasu, Heterocycles, 1981, 16, 1677.
Five-Membered Rings: Other systems
283
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
E
/
Me
Ph
For other articles on these systems, see references 690-701.
N. Abe and T. Nishiwaki, Bull. Chem. SOC.Jpn., 1981, 54, 1277. 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). 689
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 polyazaphena 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 isoquinolinediones,13 benzo[a]- and benzo[c]-quinolizinium ions,14 azachrysene preparation," 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). 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.
' A. F. Pozharskii and V. V . Dal'nikovskaya,
285
286
Heterocyclic Chernistry
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 photochemistry of nitrogen-containing hetero~ycles,2~phase-transfer h e t e r o - a r y n e ~and , ~ ~ the reactions of benzyne3' and of carbenes and nitrenes31 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
Is l9
Me
J . R. Jonesand S. E. Taylor, Chem. SOC.Rev., 1981, 10, 329. T. D. Miniker and M. N. Preobrazhenskaya, Chem. Heterocycl. Compd. (Engl. Trunsl.), 1981,17,97.
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. Heterocycl. Chem., 1981, 28, 127. 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, 2o
20, 521. 35
C. G. Chavdarian, E. B. Sanders, and R . L. Bassfield, J . Org. Chem., 1982, 47, 1069.
287
Six-Membered Rings: Systems containing nitrogen
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
(4)
(3)
(x =
0 or S)
Scheme 1 Di- and tri-acylated imines, formed by the reaction of aldehydo- or ketoesters with aza-Wittig reagents [Ph3P=NCOR], are moderately active dienophiles. Cycloaddition occurs with a good degree of regiospecificity, as illustrated by the example shown in Scheme 2.37 MegSiO
x+
benzene
N
IOMe
ref lux 15 h o u r s
COOBut
[ 84%]
Scheme 2 The sigma-complexes of cyclobutadienes and aluminium halides react with activated nitriles (e.g. Et0,CCN) to yield substituted pyridines. The sigmacomplexes are themselves formed by aluminium-bromide-promoted cyclodimerization of alkynes (Scheme 3).38In an extension of this work, DewarH
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 37 39
C. L. Hicken and H. M . McNab, Synthesis, 1981,464. 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. H.Hogeveen and D. M. Kok, J. Org. Chem., 1982,47,997.
288
Heterocyclic Chemistry
2
1;
Me
--
A1C13
+
MeNCO
Me
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 3,4dihydropyridones are formed by reactions of 1-azabutadienes with the lithium enolates of substituted acetates (Scheme 6).42
ih+
EtOOCU
Ph 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-azabutadienes 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.@ H. Hoberg and B. W.Oster, Synthesis, 1982,324. 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. 40 41
289
Six-Membered Rings: Systems containing nitrogen BufMe2SiOy
~
\9 COOMe
0
ii,iii
HNKR 0
/’ COOMe R
0s iMe2Bu
Reagents: i, CF,S020SiMe2But, Et,N; ii, MeOOCCSCOOMe; iii, HCI
Scheme 7
(7)
;lUt
Reagents: i, TsOH, PhH, at 200°C; ii, R’CH=CHNRZ,
Scheme 8
(6)
The use of 1,2,4-triazine in pyridine synthesis has been reported previouslyp5 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
46 47
48
49
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 . D. L. Boger, J. S. Panek, and M. M. Meier, J. Org. Chem., 1982, 4 7 , 895. 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 . 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. V. Agganval, G. Singh, H. Ila, and H. Junjappa, Synthesis, 1982, 214.
290
Heterocyclic Chemis try
qCN
NaOPr
R1
RfsMe
+
d C \ 0
HOPI-’
I
RYxcN R1
i
0
R5
R5
Scheme 10 It has also been found that the reaction of a-keto-ketene dithioacetals (8) with the carbanions derived from methyl ketones (9) gives unsaturated 1,5dicarbonyl 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
i
ArCH=C(CNI2
+
NCCH2CONHNH2
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 antagonists 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 acidcatalysed rearrangement of 1,2-0xazines (1 3).s3 51
52 53
K. T. Potts, M. J. Cipullo, P. Ralli, and G. Theodoridis, J . A m . Chem. Soc., 1981, 103, 3584. 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. F. Bossert, H. Meyer, and E. Wehinger, Angew. Chem., Int. Ed. Engl., 1981, 20, 762. T. L. Gilchrist, G. M. Iskander, and A. K. Yagoub, J. Chem. Soc., Chern. Commun., 1981,696.
MeoocorMe R:pNco 29 1
Six-Membered Rings: Systems containing nitrogen H
C6H4N02-0
R40H H+
Me
~
’0
i
R1O
H
(13)
0-
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.’~
X
(16)
(15)
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
S6
57 59
A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. A m . Chem. SOC.,1982, 104,286. R. Mommisse, E. Freyne, E. Esmans, J . Lepoivre, and F. Alderweireldt, Heterocycles, 1981, 16, 1893. 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. G. Koitz, W. Fabian, H.-W. Schmidt,and H. Junek, Monatsh. Chem., 1981, 112,973.
292
Heterocyclic Chemistry 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 cycloaddition was observed; instead the product of normal electrophilic substitution, 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-diazabiphenylene (19) with 2.5M sodium hydroxide at 150 "C gives the pyridylpyridone (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 previously 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 6position, respectively. With 4-substituted pyridines, substitution occurs preferentially at the 3 - p o ~ i t i o n The . ~ free-radical carbamoylation of 3-acylpyridines 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
S. A. T. Long and J . D. Memory, J. Magn. Reson., 1981,44,355. 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., 6o 61
1982,662.
ocoR/ocoRocH 293
Six-Membered Rings: Systems containing nitrogen i
ii a
HOOC
R1R2V-C
'
II
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-2chloropyridine (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 corresponding iodo-derivatives upon treatment with iodine. The trimethylstannyl compounds are themselves prepared by the reaction of the corresponding chloroor bromo-derivat ives with t rimethylst annylsodium8! The selective 3 -debromination 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
hl e
O
Me
C
E
C
H
'
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 indicated 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 68 69 70 71
72
73
T. Kato, M. Sato,and A. Wagai, J. Heterocycl. Chem., 1981, 1 8 , 603. Y. Yamamoto and A. Yanagi, Heterocycles, 1 9 8 1 , 1 6 , 1161. M. J . Robins, C. Kaneko, and M. Kaneko, Can. J . Chem., 1981, 59, 3356. J. L. LaMattina and R. L. Taylor, J. Org. Chem., 1981, 4 6 , 4179. B. Stanovnik, J . Zmitek, and M. Tigler, Heterocycles, 1981, 1 6 , 2173. E. S. Hand and W. W. Paudler, Tetrahedron, 1 9 8 2 , 3 2 , 4 9 . Z . T. Fomum, J . T. Mbafor, P. D. Landor, and S. R . Landor, Tetrahedron Lett., 1981, 22,4127.
294
bN
Heterocyclic Chemistry
+
RYR2 -
VYR2 NH
NC
The sequential addition of two Grignard reagents to 2-(N-methyl-Nformy1)aminopyridine (26) provides a high-yielding synthesis of unsymmetrical secondary alcohols (Scheme 15). The success of the method is attributable 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
75
76
D. L. Cominsand W. Dernell, Tetrahedron Lett., 1981, 2 2 , 1085. Y. Tamura, M . Fujita, L.-C. Chen, M . Inoue, and Y. Kita, J. Org. Chem., 1981, 46, 3564. E. C. Taylor, C.-P. Tseng, and J . B. Rampa1,J. Org. Chem., 1982,47, 552.
295
Six-Membered Rings: Systems containing nitrogen
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-alkoxypyridines by phase-transfer-catalysed alkylation of 2-amino-3-hydroxypyridines 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
0
Me (31
1
trans-anti (trans w.r.t. anti w.r.t. 77 78
79
d o u b l e bonds; amido functions)
M. J. Scanlan, I. H. Hillier, and R. H. Davies, J . Chem. SOC., Chem. Commun., 1982, 685. J . A. Bristol, I. Gross, and R. G. Lovey, Synthesis, 1981, 971. 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.
296
Heterocyclic Chemistry
+
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~.~~
+
C12C=CH2
-
0
H
0
Me
Me H
The pyridone (34) has been advocated for the protection of the aminogroup in primary amines and amino-acids (Scheme 1 8).84 0
0
R
(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 84'
K. Somekawa, R. Imai, R. Furukido, and S. Komamoto, Bull. Chem. SOC.Jpn., 1981, 54,1112. 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.
297
Six-Membered Rings: Systems containing nitrogen
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-(2,6dimethyl-4-oxopyridin-1-yl)pyridiniumsalts .93
R1
R1
R1
ii
i
___t
NH
I
R2
I R2
1
R2
Reagents: i, BunLi, THF, at - 78 to 0°C; ii, H,O
Scheme 20 81
89
90
92
93
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. K. Akiba, H.Matsuoka, and M. Wada, Tetrahedron Lett., 1981, 2 2 , 4093;K. Akiba, Y. Iseki, and M. Wada, ibid., 1982, 23, 429. 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. A. N. Kost, R. S. Sagitullin, and A. A. Fadda, Org. Prep. Proced. Int., 1981, 13,203. M. P. Sammes, C. M. Lee, and A. R. Katritzky, J. Chem. SOC.,Perkin Trans. I , 1981, 2476.
Heterocyclic Chemistry
298 ii ,iii
H2N-
I
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 deoxygenated 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 antimony pentachloride lose hydrogen chloride on heating; subsequent hydrolysis yields 2( 1H)-pyridones (Scheme 23).95 R
R
0I -
R
-& H2°
~ o s b c 1 4
H
0
OSbC15
Scheme 23 Phosphoryl chloride and triethylamine appears to be the reagent combination of choice for the conversion of 2-methylpyridine 1-oxide into 2-chl0romethylpyridine.~~ The mechanism of the acylamination and aminoarylation of the side-chain of 2- and 4-methylpyridine l-oxides (Scheme 24)
QMe - n
L T h
CH
I-
I
2
‘Ph
-
0
O Y N P h Ph
Reagents: i, PhClC=NPh, strong base
Scheme 24 94 95
%
NCOPh H
T. Morita, K. Kuroda, Y. Okamoto, and H. Sakurai, Chem. Lett., 1981,921. 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.
299
Six-Mem bered Rings: Systems containing nitrogen
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
I
c 1N02
SC6H4N02-p (37)
Scheme 26
The tetrafluoroborate from (37) serves as a source of 4-nitrophenylsulphenium ion (p-NO2C6H4S’), which can attack anisole to give a parasubstituted 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 (1,2and 1,4-dihydro) predicted to be either more or less stable than the three imino forms! lo’ 97
98 99
loo 101
R. A. Abramovitch, D. A. Abramovitch, and P. Tomasik, J . Chem. SOC.,Chem. Commun., 1 9 8 1 , 5 6 1 . A. Ohsawa, T. Kawaguchi, and H . Igeta, Chem. Lett., 1981, 1 7 3 7 . S . Mukaiyama, J . Inanaga, and M. Yamaguchi, Bull. Chem. SOC.Jpn., 1 9 8 1 , 5 4 , 2 2 2 1 . R. A. Abramovitch, A. L. Miller, and J . Pilski, J. Chem. SOC., Chern. Commun., 1 9 8 1 , 703. S. Bohm and J . Kuthan, Collect. Czech. Chem. Commun., 1 9 8 1 , 4 6 , 2 0 6 8 .
300
Heterocyclic Chemistry
'-
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 ,5dihydropyridine. At lower temperatures (- 60 "C), 2-fluoropyridine undergoes competitive 3-lithiation. 2,5-Dihydropyridines in general have poor stability, and must be stored in the cold and under nitrogen.lo3 Piperidine Nimides 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 methylpiperidine N-oxide (42), and with the benzyl analogue (44) a mixture of ringexpanded product (45) and benzyloxypiperidine (46) is obtained.
Ac (43) R = M e
( 4 0 ) X = N A c , R = Me
(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 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-0cycles, 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. lo'
301
Six-Mem bered Rings: Systems containing nitrogen CH )
H2N-(
i
hz,L-
H2N
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,
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. E. C. Taylor and J . S. Skotnicki, Synthesis, 1981, 606.
141.
'lo
Heterocyclic Chemistry
302
( 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-piperidines gave 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
+
CHC13
R
(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
i
+
phc\
Ph
Reagents: i, KOBU', DME, at 2 0 ° C for 24 hours
[72%1
Scheme 33 'I1 'I2
Y. Shvo and E. D. Kaufman, J . Org. Chem., 1981,46,2148. 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.
303
Six-Membered Rings: Systems containing nitrogen
__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 undergoes catalytic, palladium-assisted cyclization to 2-propylquinoline (Scheme 34);Il4 this is only one of a series of ring-closure reactions involving palladiumpromoted nucleophlic attack on an alkene. A tetrahydroquinoline (55) is produced by the action of trifluoroacetic acid on the hydroxylamine (54). This method has also been used to prepare 1,4-benzo~azines."~
or HN
I
Me
Me 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 'Is
L. S. Hegedus, P. M . Winton, and S. Varaprath, J . Org. Chem., 1981,46,2215.
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.
Heterocyclic Chemist?y
304
ap Ph
i
8\
-iii c
NHLi
Me
H
(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
i
0
" O O \ , l i r ,
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 prepared from cyclohexane-l,3-dione and ammonia."'
&-pm
i*
\
NH2
0
H
H
(57) (58)
(59)
Reagents: i, H,C=CHCO,H, at 140°C; ii, Pd/C, at 190°C
Scheme 38 Compilations of I3C n.m.r. data for 4 - q ~ i n o l o n e sand ' ~ ~ of "N n.m.r. data 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. A. R. Katritzky, J . Ellison, J . Frank, P. Rakdczy, L. Radics, and G. Gks-Baitz, Org.
12'
Magn. Reson., 1981, 16,2 8 0 . 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. 12'
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 MeO,CCl, at 0 ° C
- 78 "C;iii,
Scheme 39 2-, 3-, and 4-Methylquinolines are simply converted into the corresponding heating them with triethylammonium 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 dichlorocarbene. Hydrolysis of the cyclobuta[b]quinolines yields 2-methylquinoline3-carboxylic esters (62).'24
l-formyl-1,2,3,4-tetrahydroquinolinesby
Selective reduction (LiAlH4, THF, at - 70 "C) of 3,4-dicarbomethoxyquinoline at low temperatures unexpectedly affords 3-formyl4-carbometho ~ 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 conditions, 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 methoxysubstituted bicyclic azepines and benzodiazepines. Illustrative of these possibilities is the conversion of 5-azidoquinoline (63) into the pyridoazepine (64) (Scheme 40).12*
123
124 12s 126 127
M. Ferles and 0. Kocihn, Collect. Czech. Chem. Commun., 198 1 , 46, 15 18. Y. Hamada, M. Sugiura, and M. Hirota, Tetrahedron L e t t . , 1981, 22, 2893. A. Godard and G. Qukguiner, Tetrahedron L e t t . , 1981, 22, 4813. E. B. Pedersen and D. Carlsen, Chem. Scr., 1981, 18, 240. 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.
Heterocyclic Chemistry
306
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~'Tetrahydroquinoline is activated to deprotonation at the 2-position by conversion into the formamidine derivative (66). Subsequent reaction of the anion with electrophiles leads to 2-substituted derivatives (see also p. 31 1) (Scheme 42).131
- 80\
8\3 i-iii
iv-vi
H (66)
LJ
E H
Reagents: i, HCOOEt; ii, Et,O+ BF; ; iii, ButNH,; iv, ButLi, THF; v, electrophile; vi, hydrolysis
Scheme 42 12' 130 13'
K. Akiba, T. Kasai, and M. Wada, Tetrahedron Le t t . , 1 9 8 2 , 2 3 , 1709. S. Harusawa, Y. Hamada, and T. Shioira, Heterocycles, 1 9 8 1 , 1 5 , 981. A. I. Meyers and S. Hellring, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 5 119.
Six-Membered Rings: Systems containing nitrogen
307
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
Me
H
H
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 preparing the starting materials.' j3 ortho-Halogena t ed N-alkyl-N-acylbenzylamines (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 conditions, 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 cyclization of N-alkyl-N-(chloroacety1)benzylamines (69). The yield is best when R is t-b~ty1.l~' 132
133 134
13'
S. Kano, E. Sugino, S. Shibuya, and S . Hibino, J. Org. Chem., 1981,46,2979. J. R. Falck, S. Manna, and C. Mioskowski, J . Org. Chem., 1981,46, 3742. S. V. Kessar, P. Singh, R . Chawla, and P. Kumar, J . Chem. SOC., Chem. Comrnun., 1981,1074. T. Hamamada, Y. Okuno, M. Ohmori, T. Nishi, and 0. Yonemitsu, Chem. Pharm. Bull., 1981, 29, 128.
Heterocyclic Chemistry
308
R1w
R3
R3
I
R2
NMe
R2
( 6 7 ) X = C1 or B r
\
(68)
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
' 13' 137
H
M
Me
e
b\
e
R
d\ N
OH
H. A. Bates, J . Org. Chem., 1 9 8 1 , 4 6 , 4 9 3 1 . R. S. Mali, B. K. Kulkami, and K. Shankaran, Synthesis, 1982, 329.
/M R
e
Six-Mem bered Rings: Systems containing nitrogen 0
309 0
0-
I
+
R2CH=CR3
- dR hv
\
R3
R2
R’=
H or alkyl
R1= R2= H , R3= Me
X = Br or I
Scheme 46
90&1
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 advantageous 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.
Heterocyclic Chemistry
310
Phosphonate analogues of Reissert compounds (76) have been prepared and converted into 1-alkyl-isoquinolines (Scheme 49).14' Treatment of a number of N-methylisocarbostyrils with mercuric acetate gave rise to 4-mercuriated derivatives, which underwent insertion reactions with methyl acrylate and with styrenes in the presence of palladium chloride (Heck reaction).142
CH2R ( R = a l k y l or a r y l )
(76)
Reagents: i, BuLi, THF, at - 70°C; ii, RCHO; iii, HC1
Scheme 49 In an extension of earlier work on pyridones and quinolones, the photoinitiated 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
14' 143 144
K. Y. Akiba, Y. Negishi, K. Kurumaya, N. Ueyama, and N. Inamoto, Tetrahedron Lett., 1981,22,4977. S. F. Dyke and M. J . McCartney, Tetruhedron, 1981, 37,431. T. Naito and C. Kaneko, Tetrahedron Lett., 1981, 22,2671. M. Enkaku, J . Kunta, and T. Tsuchiya, Heterocycles, 1981,16, 1923.
311
Six-Mem bered Rings: Systems containing nitrogen
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 1lithation 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 arylamines 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 equimolecular amount of trifluoroacetic acid.'50
m""' 7 fJJ+Jc1 tJyJ 0
R
H
I
Regiospecific ring-closure of the 2-aminobiphenyl (83) to the phenanthridine (84) is achieved by sequential reaction with butyl-lithium and NNdimethylformamide. Conventional ring-closure procedures result in ringclosure at the alternative o r t h o - p ~ s i t i o n . Potent '~~ analgesic properties have
OMe (83) 146
14' 14' 149
Is'
OMe (84)
K. Yamada, M. Takeda, and T. Iwakuma, Tetrahedron L e t t . , 1981,22,3869. A. I. Meyers, S. Hellring, and W. T. Hoeve, Tetrahedron L e t t . , 1981,22, 5115. D. Seebach and M. Yoshifuji, Helv. Chim. Acta, 1981, 64, 643. J. Rosevear and J . F. K. Wiltshire, Aust. J. Chem., 1981,34,839. 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. Commun., 1982,453. N. S. Narasimhan, P. S. Chandrachood, and N. R. Shete, Tetrahedron, 1981,37, 825.
Heterocyclic Chemistry
312
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 dihydrodihydroxybenzacridines have been synthesized as possible carcinogenic metabolites 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-3ones 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 isomerization .l"
M. R . Johnson and G. M . Milne, J . Heterocycl. Chem., 1980,17, 1817. 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. lS2 lS3
313
Six-Membered Rings: Systems containing nitrogen
Coupling of terminal acetylenes with 3-chloropyridazines has been performed, 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-bromocinnoline and styrene .l 59 The pyridine (91) is known to possess potent and long-lasting antiPh
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. Alkylation 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 derivative (92).I6l
Ph
F0 1 NC
(92) lS9 160 16'
A. Ohsawa, Y. Abe, and H. Igeta, Chem. Pharm. Bull., 1980, 28, 3488. D. E. Ames and D. Bull, Tetrahedron, 1982, 38, 383. T.Yamada, Y. Nobuhara, H. Shimamaru, K. Yoshihara, A. Yamaguchi, and M . Ohki, Chem. Pharm. Bull., 1981, 29, 3433. T. Yamada and M. Ohki, Synthesis, 1981, 631.
314
Heterocyclic Chemistry
Attempts to prepare cinnoline-3,4-dicarboxylic acid (94) from 3,4dime 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 concentrated sulphuric acid results in nearly quantitative rearrangement to the pyrazole (96).'64
1,3-Diazines. - Heating 1-benzylpyrazoles with sodamide gives the corresponding 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-3H4-ones (99), none of the 1H-isomers being r e ~ 0 r t e d . lGood ~ ~ yields of 2Me
0
NMe2 (97)
R
-
c104
(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.
Six-Membered Rings: Systems containing nitrogen
315
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, trifluoroacetonitrile condenses with enamines to give the 2,4-bistrifluoromethylpyrimidines (104) (Scheme 55).I7l
(104)
Scheme 55 168
170
"'
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. 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.
Heterocyclic Chemistry
316
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 recommendation.’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 coupling, e.g. 3 decreases markedly across quaternized nitrogen, as shown with the two methylated derivatives (105) and (106).’73
I
1-
I-
1,le
(105)
(106)
3
Jc
3Jc -H = 5.8 Hz 2 6
-H
2
=
1 3 . 4 Hz
6
Trimethylsulphoxonium ylide dsplaces the chloro-group in 2-chloro-4,6dimethylpyrimidine to give the ylide (107); acylation of this product, followed by reduction with Raney nickel, gives the 2-acylmethyl derivatives (108) (Scheme 57). Similar sequences have been performed starting from 4chloropyrimidines, 4-chloroquinazoline, 2-chloro-5,6-diphenylpyrazine,and 3-chloro-6-phenylpyridazine; yields are generally good, but the initial step fails with less reactive substrates such as ch10ropyridines.l’~
rj i
Me \N
C1
c,L!Me0 Me
Me
Me
Me
-
(107)
M e
‘
CH~COR
(108)
Reagents: i, Me,$(O)CH,, THF, reflux; ii, RCOX; iii, Raney nickel
Scheme 57 172
173
174
A. L. Weis and V. Rosenbach, Tetrahedron Lett., 1981, 22, 1453. ( 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 . H. Yamanaka, S. Konno, T. Sakamoto, S. Niitsuma, and S. Noji, Chem. Pharm. Bull., 1981. 29.2837.
317
Six-Membered Rings: Systems containing nitrogen
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
OCl- CA+ i
R
ii
N M e 3 C1-
Reagents: i, Me,N, PhH; ii, Et,N+ CN-, CH,CI,
Scheme 58 good, 2- and 4-chloroquinazolines behave similarly, and 2-chloroquinoxalines can be directly converted into the nitrile by their reaction with tetraethylammonium cyanide.'77 4,5'-Bipyrimidines, e.g. (1 09), are obtained when 5bromopyrimidines are treated with b ~ t y l - l i t h i u m . Attempts '~~ at direct conversion 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), depending 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.
318
Heterocyclic Chemistry
Me2N
' R
(3N02
HN-N02
0
H2N RQNo2
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
[X 0
=
t
01
-
R3
' NAX N
R1
[x=S]
R3
fJ I NHR'
+ '
0-
[ 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-dialkylated 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 Treatment 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
lB5
H. Vorbruggen, K. Krolikiewicz, and B. Bennua, Chem. Ber., 1981, 114, 1234. M. Hedayatullah, J. Heterocycl. Chem., 1981, 18, 339. 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.
319
Six-Mem bered Rings: Systems containing nitrogen 0
HO
OH
(114)
Pyrimidine nucleosides have been chlorinated at the 5-position with m-chloroperoxybenzoic 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
M e
Scheme 60 g. Ph3PCHCONH2, eact with 5-hydrox Stabilized Wittig reagents 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 compound being less satisfactory." 0
R
0
0
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 61 189
E. K. Ryu and M. MacCoss,J. Org. Chem., 1 9 8 1 , 4 6 , 2 8 1 9 . 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 .
320
Heterocyclic Chemistry
Pyrimidinethiones have been converted into their oxygen analogues by the action of halogens in basic media;’” the reverse operation has been accomplished for certain nucleosides in a two-step process, as outlined in Scheme 62
S
0
ii
R [
(R
=
R
R 77%]
[ 85%]
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 tetrahydrofuran (Scheme 63); the generality of this reaction is limited in that the isomeric 4-thiouridine (1 18) merely gives a quantitative yield of d i ~ u l p h i d e . ’ ~ ~ X
0
R1
R’
[ 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-4ones (121) have been obtained from anthranilic acid and ketenimines R2C=C=NAr.19’ 19’
19’ 193 194
H. Singh, P. Singh, and N . Malhotra, J. Chem. SOC.,Perkin Trans. I , 1981, 2647. W. L. Sung, J . Chem. SOC.,Chem. Commun., 1982, 522.
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. J. Synth. Methods, 1981,7,75 814W. J . Sv6tlik and A. Martvdn, Collect. Czech. Chem. Commun., 1981,46,428.
32 1
Six-Membered Rings: Systems containing nitrogen 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 insensitive 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, isomeric 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)
'91 19' 19'
Scheme 65
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 . R. Kreher and U. Bergmann, Heterocycles, 1 9 8 1 , 16, 1693. A. Alemagna, P. Del Buttero, E. Licandro, and S. Maiorana, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 8 9 4 .
Heterocyclic Chemistry
322
1,4-Diazines. - Like phenylglyoxal, 2-furylglyoxal condenses with aminoacetamide 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 particular 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 .
323
Six-Memb ered Rings: Systems containing nitrogen
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
v,vi
[65%)
-
0
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 peroxymolybdenum complex, giving (1 36) (30%) (Scheme 69).203 201 '02
'03
K. Suzuki, Y. Sasaki, N. Endo, and Y. Mihara, Chem. Pharm. Bull,, 1981, 29, 233. T. Fukuyama, B. D. Robins, and R. A. Sachleben, Tetrahedron Lett., 1981, 2 2 , 4155. R. M . Williams, Tetrahedron Lert., 1981, 2 2 , 2341.
Heterocyclic Chemistry
324 0
0
0
0
(134)
(133)
(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-unsubstituted bicycle (1 37), (&)-NN',O-trimethylbicyclomycin (140) has been prepared (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--
Roil
(f)-( 138)
RO
(?)-(139) R = a c e t o n i d e
Scheme 70
(+)-(140) R
=
H
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 relative 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 treatment of the enaminones (141) with a base; the compounds (141) are them204
S . 4 . Nakatsuka, K. Yoshida, and T. Goto, Tetrahedron Lett., 1981,22,4973.
205
Y.Akita and A. Ohta, Heterocycles, 1981, 16, 1325. Y. Akita, Y. Shimazaki, and A. Ohta, Synthesis, 1981,974.
206
325
Six-Memb ered Rings :Systems containing nitrogen
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-phenyleneCOOH
diamine in ethanol to give an excellent yield of quinoxaline.2083,3-Dialkyl1,2,3,4-tetrahydroquinoxalin-2-ones (1 43) are formed when o-phenylenediamine is treated with ketones, chloroform, and strong base under phasetransfer 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-diaminobenzene 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 hexachlorodisilane 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-alkylquinoxalinium iodides in the presence of amine bases; the structure of one of these products was demonstrated by X-ray S. Miyano, N. Abe, K. Takeda, and K.Sumoto, Synthesis, 1981,60. 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. 207
208
Heterocyclic Chemistry
326
uNx alJ-Jc H I I
H
H N
Me
S
Me
Treatment of 2-chloroquinoxaline with the potassium enolate of 3,3dimethylbutan-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 equivalent 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 substitution, 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 tetraacetate, 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 c1
(148)
21 3
214 21 5
OEt
(149)
(150)
D. R. Carver, J . S. Hubbard, and J . F. Wolfe, J . Org. Chem., 1982,47, 1036. C. Herzig and J . Gasteiger, Chem. Bec., 1981, 114,2348. A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, J . Chem. SOC.,Chem. Commun., 1981, 1174.
Six-Membered Rings: Systems containing nitrogen
327 0
0
Reagents: i, sym-triazine, HOAc, Ac,O, BF, *Et,O, reflux
[ 58-95%]
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 particularly noteworthy is the 'one-pot' synthesis of 6-lactams that is shown in Scheme 74; the stereochemistry of the product is exclusively cis.218c
COOE t
6OOE t
Reagents: i, cyanuric chloride, Et,N, CH,Cl,
[ 58x1
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. F. Zilliken, and E. Breitmaier, Angew. Chem., Int. Ed. Engl., 1981, 20,
"' H. C. Jha, 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. Commun., 1982,225.
Heterocyclic Chemistry
32 8
OH
NBz
BzN
I I NH2 NH2
HN
i,ii
N f i N
iii,iv
I
I
I
-
I1
HNYNH""IfN
(154)
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
N& ' N
"1wN -
-
-N
R*NH2
I
It v
N
[OI
IJ
R1
NHR~ N
A
N
v
I
N
II N
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 acylpyridazines, 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 (157)
COOMe (158)
COOMe (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
"'
222
223
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. L. Birkofer and E. Hansel, Chern. Ber., 1981, 114, 3154. H. P. Figeys, A. Mathy, and A. Dralants,Synth. Comrnun., 1981, 11, 655.
Six-Membered Rings :System s containing nitrogen
R
=
2-pyridyl
F.
=
methyl
329
[7.5%1 [ 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 dinitropyrimidinone (1 66) (Scheme 8 1).226
224 225
226
H. P. Figeys and A. Mathy, Tetrahedron L e t t . , 1981, 22, 1393. G. Seitz and W. Overheu, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 3 7 6 . G. Tennant and C. W. Yacomeni, J. Chem. SOC.,Chem. Commun., 1982, 6 0 .
Heterocyclic Chemistry
330
(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
R1
H
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-acylglycinates, 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 trifluoromethanesulphonate [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 Me
33 1 Me
CN CN (174)
(173)
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 NH2
H2N (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 predominantly N-9-substituted adenine.233 Methylation of adenine under phasetransfer 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, ringclosure sequence.236 229
230
B. L. Booth and M. F. Proenca, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 7 8 8 . R. S. Hosmane, V. Bakthavachalam, and N. J. Leonard, J . Am. Chem. SOC., 1982, 104,235.
231
232
F. Yoneda and R. Koga, Heterocycles, 1981, 16, 2137. B. Stanovnik, M. TiBler, A. Hribar, G. B. Barlin, and D. J . Brown, Aust. J. Chem., 1981,34,1729.
235
M. Rasmussen and J. A. Hope, Aust. J . Chem., 1982, 3 5 , 535. M. Hedayatullah, J . Heterocycl. Chem., 1982, 19, 249. Y. Maki, M. Suzuki, K. Kameyama, M. Kawai, M . Suzuki, and M. Sako, Heterocycles,
236
R. F. Pratt and K. K. Kraus, Tetrahedron Lett., 1981, 2 2 , 2 4 3 1 .
233 234
1981,15,895.
332
Heterocyclic Chemistly
x%HF
xk;)
0
0
AJ -).
0
NH
0
0
Me
I
hie
CH 2NHA r
Me
CH=CHC02Et
(178)
(180) (179)
C1-
I
0
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 conditions has been utilized to introduce fluorine, chlorine, and bromine into the 2-position .241 The reaction of dimethyl acetylenedicarboxylate with the thiazolopyrimidine 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. 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.
239
Six-Membered Rings: Systems containing nitrogen
'A 5 N 0 2
i
Me
0
333
0
0
M
e
N
bR
0 AN Me
Me
OH
[42-52%1
(186)
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-Scarboxylic acids) (Scheme 87).244' 0
NA r
0
0
0
Me
Me (187)
H
(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 pyrazolopyrimidine N-oxides (1 91 ), these being readily prepared from bromomethyl-nitrouracil (190) (Scheme 88).245 0
NCH2R
-oMAk)R ii
HN 0
Me ( 190)
Me (191)
Me (192)
Reagents: i, RCH,NH,; ii, NaOEt, EtOH
Scheme 88 243 244 245
F. Yoneda, M. Motokura, and M. Otagiri, Chem. Lett., 1981, 1273. F. Yoneda and M. Higuchi, J. Heterocycl. Chem., 1980, 17, 1365. K. Hirota, Y. Yamada, T. Asao, and S. Senda, J. Chem. Soc., Perkin Trans. 1 , 1982, 277.
He terocy c lie Chemis try
334
Two modes of cyclization have been observed when the 6-(1’-alkylhydrazino)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 Fischertype ring-closure.2a
4
*<
H ~ \N N
N(R~)NH,
(193)
H2N H
(N
y
N’y R1
(194)
H2N H i %
N
R1 (195)
3,3-Dimethoxy-2-pyrrolidinopropene (196) has been shown to be a useful synthon for the synthesis of formylpterins and related compounds. Thus treatment of (196) with nitrosyl chloride, followed by hydrolysis, yields 1,ldime thoxy-3-oximino-2-propanone (1 97), which on treatment with aminomalononitrile gives a pyrazine (198) that is suitable for elaboration to a formylpterin (Scheme 89).247 Two nine-step syntheses, from pyrazine intermediates, of deoxyurothione (199) have been announced. A practical synthesis of the urinary thienopterin urothione (200) still remains a synthetic challenge .248
( 196) (197) Reagents: i, NOCl, THF; ii, H,O; iii, H,NCH(CN),, TsOH
(198)
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 phosphoryl chloride yields a triformylmethane derivative, which was condensed (in water) with 2,4-diaminopyrimidin-6( 1H)-one to give the pyridopyrimidine-6carbaldehyde (202). The latter compound was used as an intermediate for the synthesis of 5 -deazapt erin .251 246 247 2 48 249
*” 2s1
V. L. Styles and R . W. Morrison, J. Org. Chem., 1982, 47, 585. E. C. Taylor and D. J. Dumas, J. Org. Chem., 1981,46, 1394. E. C. Taylor and L. A. Reiter, J. Org. Chem., 1982, 47, 528. 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. C. Temple, R. D. Elliott, and J . A. Montgomery, J . Org. Chern., 1982, 47, 761.
Six-Membered Rings: Systems containing nitrogen
335 0
0
HN3(Nxxe G HNY? c "
H2N
H2N
H
YOH
CH~R
( 2 0 1 ) R = (1'~,2's)-cH--CHMe
(199) R = H
I
( 2 0 0 ) R = OH
OH
a
I
OH
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 autoEt
P h C H 2NH
X q&---(Eo (203)
Et
PhCH=NH
0
H
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.
336
Heterocyclic Chemistry HCOOH
Me
H
q z oA a x o Me
x
0 (204)
P h CH OH
PhCHO
Scheme 91
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 .
Six-Memb ered Rings: Systems containing nitrogen
337
Irradiatim of the 1,2-oxazines (208) affords a variety of products, depending 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
"
HO
DPh
(208)
formed reflect the relative ease of fission of C-0 and N - 0 bonds.256Depending 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 ringalkylated 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 The reaction of N-alkylof the diazo-ketones (211) with strong 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.260 256 257 258
259 260
H. Saiki and T. Mukai, Chem. L e t t . , 1981, 1561. R. Lidor and S. Shatzmiller, J. A m . Chem. SOC.,1981, 103, 5916. V. G. Kartser and A. M. Sipyagin, Chem. Heterocycl. Compd., (Engl. Transl.), 1980, 16, 1000. T. Kato, Chem. Pharm. Bull., 1981, 29,862. M. C. Venuti, Synthesis, 1 9 8 2 , 267.
338
Heterocyclic Chemistry
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-benzoxazinones (221); the intermediate imidophosphoranes (222) can be isolated.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. 263 164 265
I. Bitter, L. Szocs, and L. Toke, Acra Chim. Acad. Sci. Hung., 1981, 107, 5 7 . J. Synth. Methods, 1982, 8 , 7 5 327X. M. Byers, A. R. Forrester, I. L. John, and R . H . Thomson, J . Chem. SOC., Perkin Trans. 1 , 1981, 1092.
*
Six-Membered Rings: Systems containing nitrogen
339
0
\
Ar
0
/o /
N
II
/o /
HN
TMe
I
“l
m
M e
M e M e
M e
NMe
RF4
Thiazines. - Butadipes react with N-sulphinyldimethylammonium tetrafluoroborate (Me,N=S=O BFi) to give lY2-thazines,e.g. (228).266Thermolysis of the azides (229; R = Me or Ph) affords the cyclic sulphimides (230) in excellent these materials can be converted into the isomeric thiazines (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
R
S
-
/ COOEt
( 232)
COOE t
ii
S
SR
(233)
Reagents: i, toluene, reflux; ii, h v (350 nm), MeCN; iii, PhBr, reflux
Scheme 95 166 267
G. Kresze and M. Rossert, Liebigs Ann. Chem., 1 9 8 1 , 5 8 . ( 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.
Heterocyclic Chemistry
340
The oxazinium salts (234) react with hydrogen sulphide to give the corresponding 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
( 236)
(237)
-
c104 (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
Scheme 96
( 239 1
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
269
270 271 212
Y. Yamamoto, Y. Azuma, and S. Ohnishi, Heterocycles, 1981, 15, 851. J. Goerdeler, M.-L. Tiedt,and K. Nandi, Chem. Ber., 1981, 114, 2713. Y. Ohshiro, T. Hirao, N. Yamada, and T. Agawa, Synthesis, 1981,896. H. B, Hitchcock, R. W. McCabe, D. W. Young, and G . M . Davies, J. Chem. Soc., Chem, Commun., 1981,608. F. Asinger, M. Kaussen, I. Gold-Martin, and A. Saus, Monatsh. Chem., 1981, 112, 643.
Six-Memb ered Rings: Systems containing nitrogen 0
0-Mes
341
0
It
H
P h CH C -N
i
E to06
)2
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
H
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 273 274 275
G . H. Hakimelahi and A. Ugolini, Tetrahedron Lett., 1982, 2 3 , 9 1 3 . T. L. Gilchrist and G. M. Iskander, J . Chem. SOC.,Perkin Trans. I , 1982, 8 3 1 . ( 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.
342
Heterocyclic Chemistry
DSXR - a>R -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 I I Q , B 0
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
[91%1
[57%]
Ph
R2
H 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, Farmuco, 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 .
343
Six-Membered Rings: Systems containing nitrogen
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 sixmembered heterocycles from nitrilimines (PhN-NXR) and suitably heterosubstituted olefins; thus the selenate (256) gives a selenadiazine (257)279aand the phosphonite (258) affords a phosphadiazine (259)?79b Ph
Me2N
"'3
Se
Me2N
Se
Ph
COOE t
"'"a
( 257 1
( 256)
N\N
P( OEt )
[J
E t oHP*o
'gHqN02-P
(258) ( 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 (262)
( 263)
R = p-nitrobenzyl
Ar
=
2-benzothiazolyl
Reagents: i, AgOAc, PhH, reflux; ii, PPh,, MeCN, at room temperature
Scheme 102 278
279
280
281
A. E. Baydar, G. V. Boyd, and P. F. Lindley, J. Chem. SOC.,Chem. Commun., 1981, 1003. ( 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. K. Eger,Arch. Pharm. (Weinheim, Ger.), 1981,314, 176. G. Johnson and B. C. Ross,J. Chem. SOC.,Chem. Commun., 1981,1269.
He terocycZic Chemistry
344
The thioketen dimers (264) have been converted into dithiadiazines (265) by treatment with methanolic sodium azide followed by concentrated hydrochloric acid.282
Roocx RmcxcN S
S
I
S
" NCCO 'OR
I
COOR
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 . N. Latif, F. M. Assad, and N. S. Girgis, Indian J. Chem., Sect. B , 1 9 8 1 , 2 0 , 4 6 3 . 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 summarized 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.
346
Heterocyclic Chemistry
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 hydrogenolysis gave (2), which was hydrolysed to the acid.g A newly developed DielsH
A, '
--CHZCPC'
COO( CHz ) *COOMe
HOCHCHCH=CHCH~' MI e I 9 M e
O
H
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 separately 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 antibiotic) 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 biological 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
a
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. 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.
Six-Membered Rings: Systems containing oxygen or sulphur
347
Me
OH
0 Et
OH
H'
Me
(3)
COOH Mlru:H=CEt I
COOMe 1
MeCH
COEt
Me
,-.
(4)
Me
H
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-dihydro2H-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-2Hpyran to give the cyclopropa[c]pyran (1 1) and to 5,6-dihydro4-methylene2H-pyran to form the spiran (12) in high yields."
H
(13 1 17 18
Ph
(12)
D. H. Corbin, G . D. Hobbs, and J . D. Woodyard, J. HeterocycL Chem., 1981, 18, 643.
A. A. Gevorkyan, N. M . Khizantsyan, P. I. Kazaryan, and G . A. Panosyan, Khim. Geterotsikl. Soedin., 1981, 167 (Chem. Abstr., 1981, 9 5 , 6986).
348
Heterocyclic Chemistry
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 lowtemperature 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-pyrans on 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.”
phooH
ONOS03H
NC
/
Ph
CN
NC Ph
(r.. I
H
I NH2
[87%]
CN
(20)
l9 2o
21 22
H. A. Bates, J. Am. Chem. SOC.,1982,104,2490. T. Kitazume, K. Chino, and N. Ishikawa, J. Fluorine C h e m , 1981,18,213. G. W. Fischer, T. Zimmermann, and M. Weissenfels, 2. Chem., 1981, 21, 260, 282. 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-2methylprop-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 perchlorate 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 PhCCH=CHCOOH +
II
0
I
R1CCH2R2 II 0
(23)
0
0
COOH
+
MeoMe CH 2COOH
1 -
Me
so3
(22)
The less reactive pyrylium salts added on tributylphosphine (but not triphenylphosphine) to give a phosphonium salt (24), which, on heating with diisopropylethylamine, gave the bi-4H-pyran (25) in high yield. When the tertiary amine (with or without a catalytic amount of tributylphosphine) was
Ar
Ar
0 PBr3
Ar
Ar (25)
'.OAr (26)
23 l4 25
26
V. I. Dulenko and V. M. Golyak, Khim. Geterotsikl. Soedin., 1981, 844 (Chem. Abstr., 1 9 8 1 , 95, 150 339). 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). A. Dinculescu and A. T. Balaban, Org. Prep. Proced. In?., 1982, 14, 39. 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 ) .
Heterocyclic Chemistry
350
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 + /
\
BF4
O
O
E CMeOH t
'
Ac20 [86%];r Ph G
/
A
/
:
-
Ph
\
(28a)
(28)
0 +
P
o COOEt cA04:
h
C O OAc O Et
Ph
COOE t
0 +Ph
PhNH2
~
Ph
COOE t
-
[95%1
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
l8 29
30
G . A. Reynolds and C. H. Chen, J. Heterocycl. Chem., 1981, 18, 1235. G. Doddi, G. Illuminati, N. Insam, and F. Stegel, J. Om.C h e m , 1982,47,960. 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. A. R. Katritzky, P. Ballesteros, and A. T. Tomas, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1495.
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, 31
47,492. 34 35
A. R. Katritzky, P. Awartani, and R. C. Patel, J. Org. Chem., 1982,47,498. S . R. Baker, L. Crombie, and R. V . Dove, J. Chem. Soc.. Perkin Tmns. I , 1981, 165.
35 1
Six-Membered Rings: Systems containing oxygen or sulphur
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, further variations in the structures of xanthyrones have been developed, including 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
t4eOOC
MeOOC
/
+
MeOCH=yCOOMe
Ac
'C
CN
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 3hydroxy-aldehydes and titanium(l\r) chloride to form 5,6-dihydropyran-2ones?l Aroylarylacetylenes condense with either ethyl cyanoacetate or acetoacetate in the presence of a base to form 4,6-diarylpyran-2-ones (39).4* (Et0)2C=CHCCHC1Me
lLg,.CHIC
II
0
(36)
H+
Me
Et3N ____t
c1
+ C 1 2CHCOC1
EtO
C
-
Me l
OEt (37)
36
'*
40 41 42
C
v
c1 0
(38)
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.
39
H
S. R. Baker, M. J . Begley, and L. Crombie, J. Chem. Soc., Perkin Trans. 1, 1981, 182. S. R. Baker, M. J . Begley, and L. Crombie, J. Chem. Soc., Perkin Tram. I , 1981, 190. W. T. Brady and R. D. Watts, J. Org. Chem., 1981,46, 4047. G. Falsone and B. Spur, Liebllps Ann. Chem., 1981,565. F. A. Fouli and M. N. Basyouni, Acta Chim Acad. Sci Hung.,1981, 106,297.
Heterocyclic Chemistry
352 CN +
PhC=CCOAr ( A r = 4-H-,
4-Me0-,
4-C1-C6H4
I
CH2COOEt
/ CN
or
Ph (39)
)
H\C/Me
11
+
MeCH(COC1)2
E tOOCCH2C /C\Ml?,
(41)
(40) 0
(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 methylmalonyl 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 stereochemically 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 hydroborationoxidation 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 ozonolysis, is converted into the lactonic acid (47) in 85% yield.49 Fomannosin (53), isolated from a wood-rotting fungus, has been synthesized 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
44 45
4’ 49 50
H. N . Abramson and H. C. Wormser, J. HeterocycL C h e m , 1981,18,363. Ref. 29,p. 296. K. Matsuo, T. Kinuta, and K. Tanaka, Chem Pharm. BulL, 1981,29,3047. K. Matsuo and K. Tanaka, Chem. Pharm. Bull., 1981,18,3070. W.C.Still and K. R . Shaw, Tetrahedron Lett., 1981,22,3725. D.J. Morgans, Tetrahedron Lett., 1981, 22, 3721. K. Muruyama, Y. Ishihara, and Y. Yamamoto, Tetrahedron Lett., 1981, 22, 4235. M. F. Semmelhack and S. Tomoda, J. Am. Chem. SOC.,1981, 103,2427.
Six-Membered Rings: Systems containing oxygen or sulphur
-
Me But M e 2S iOCH 2/c *CH
Me.. /H But Me2S i O C H 2/c\c'--
I
H\
MeCH \CH2CMe=CH2
M/
(45)
We.
7
But Me 2S iOCH H
o
Mo e / c0
y
y
;
353
e
1
H
I O' H ,c'cH2CHCH20H rMe
H
Txo Me0
Me
(46)
(47)
ButMe2SiO(CH
) CMe
211
H2C=CHCH2CHCH
I
Me (48)
CH=CH2
1
MeOOC
MeHC
CHO Bu SnCH ,CH=CHMe ~
(47)
(49)
Me3Si0 "2'=r'O<
COOEt
+
COOMe
COOEt
-
4
h0ch2 /
(.5 2 ),
(53) HO
Heterocyclic Chemistry
354
~ynthesis.’~ An ingenious application of the diene-like properties of pyran-2ones 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-methoxypyran2-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
HO
k d ) a o M : & o oCOOMe ‘OOMe
/ 0
Me
Me
(60)
(61)
Me (59)
52
53 54 56
N. Y. Wang, C. T. HSU,and C. J. Sih, J. A m . C h e m Soc., 1981,103,6538. For a review, see I. R. Brown, Prog, Med. C h e m , 1978, 15, 165. M. E. Jung, M. Node, R. W. F’fluger, M. A. Lyster, and I . A. Lowe, J. Ow. Chem., 1982,47, 1152. 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. M. E. Jung and R. W. Brown, Tetrahedron Lett., 1981,22,3 3 5 5 .
Six-Membered Rings: Systems containing oxygen or sulphur
355
~ 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 amines with 5,6-dihydro-4-hydroxypyran-2-ones (65) are not 2-aminoderivatives, as originally believed, but 4-aminopyran-2-ones, e.g. (66)."'
Meu MeD
H
HOCHPhCH2
[ "!I I
PhNH2, MeOH
/
[76%1
OH
(64)
NHPh
(66)
(65)
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 5,6dihydropyran-3(4H)-ones. In an improved method, 3-methyleneheptane-2,6dione (67) has been converted, in three steps, into the 3-one (68), which on treatment with SeOz gave 2,6-dimethyl-3-hydroxypyran-4-one (69):'
MeuMe Me "'m)<, 0
(CH20H)
Me
NaBH4
0
[%%I
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-Diacetylpyran4-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
59
M. T. Ayub, M. Y. Shandala, G. M. G. Bashi, and A. Pelter, J. Chem SOC., Perkin Trans. 1, 1981, 697. 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.
Heterocyclic Chemistry
356
::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 secondary rather than a primary product of the photolysis of 2,3,6-trimethylpyran4-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-4ones ( ~ 1 . ~ ~ Me
..
Me
(74)
(73)
COOEt
RC
0 "
0
(75) 62
-
oQ
CmE
-
:H
0)
RCO 0 (76)
0
(77)
(a) Ref. 7 , p. 336; ref. 11, p. 289; ( b ) K. Mori, T. Ebata, and M. Sakakibara, Tetra-
hedron, 1981,37,709. 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.
63
Six-Membered Rings: Systems containing oxygen or sulphur
357
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.~'
HC104
/
OEt (78)
mM Me8..'. Me
( MeO) 2P=0
+
AcO \ Me
(80)
(CH2)3COMe
I
Ar8-CH2
CH2SAr
_qC
I 0-
Ho \
Me
(81)
(82) I
t
( A r = 4-MeC6H4)
Me
(83)
Condensation of several dihydroxybenzoic acids with 2-methylbut-3-en2-01 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
67 68
F. Bigi, G. Casiraghi, G. Casnati, and G . Sartori, J. HeterocycL Chern., 1981, 18, 1325. J. A.Akkerman, H. De Koning, and H. 0. Huisman, Heterocycles, 1981,15,797. 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).
Heterocyclic Chemistry
358
R' 1 2 (84) R = R = H 1 ( 8 5 ) R = CH2CH=CMe2, ( 8 6 ) R1=
2 R = H
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 compounds 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. 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, 70
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.
Six-Membered Rings: Systems containing oxygen or sulphur H
359
H
Me
BuTMe2Si0
3 1 2 (91) R = R = OAc, R = H 1 3 (92) R = R = OH, R2= H
(93)
(95) R = -CH=C(CH2)20CII I Me 0
Me
Me
OH
Me Me 2 (97) R1= H , R = M e
Me Me
(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 synthesized 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-pentamethylchroman-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 3,4dihydroprecocene I 3,4-epoxide (1 02) in aqueous solvent^.^' The stretching 74
75 76
77
H. Etoh, K. Ina, and M. Iguchi, Agric, Biol. Chem., 1980,44,2871 (Chem. Abstr., 1981,95,24716). S. Carlsson and S. 0. Lawesson, Tetrahedron, 1980,36, 3585. S. Matsumoto, M. Matsuo, and Y. Iitaka, Tetrahedron Lett., 1981,22,3649. A. F. Hamnett, A. Pottridge, G . E. Pratt, R. C. Jennings, and K. M. Scott, Pestic. S c i , 1981,12,245.
360
Heterocyclic Chemistry
Mew Rmr: Me
Me
Me
0
CH2
Ho \
Me
(104)
(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 regioselective 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.
Six-Membered Rings: Systems containing oxygen or sulphur
361
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,
83
T. Kometani and E. Yoshii, J. Chem. SOC.,Perkin Trans I , 1981, 1191. 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 .
1197. 84
Heterocyclic Chemistry
362
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-benzylaminoisochroman (1 17) was formed, but, when this was heated at a higher temperature, it rearranged into 4-benzylisoquinoline (1 18) via the ring-opened intermediates.% 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
R
Ref. 29, p. 298. M . 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. 85
86
Six-Membered Rings: Systems containing oxygen or sulphur
363
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 Meom Ho \
+
H2C=CHCMez OH I
z:zCH=CMe2
( 1 2 11
Ho \
/
(120b)
When salicylaldehyde is heated with a 2-nitrovinylamine (1 22), 2-amino3-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)
92
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). 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 ) . L. Rene and R. Royer, Eur. J. Med. Chem., 1982, 17, 89 (Chem. Abstr., 1982,
93
96, 162 492). M. de la Torre, F. Garcia, and R. Cruz, J. Heterocycl. Chem., 1981, 18, 125 1.
91
Heterocyclic Chemistry
364
H \ Ho
: : :
O
W
/
/ 0 (125)
/
(126) R = H (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 trimethyl 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-halogenochromanone. When the latter is boiled with zinc and acetic acid, it is converted 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
(130)
0
(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.
% 97 98
J. Chem., 1981, 34, 587. G. I. Feutrill and M. L. Whitelaw, Aust. J. Chem., 1981,34, 1523. V. K.Ahluwalia and R. S. Jolly, Synthesis, 1982,74. J . D. Hepworth, T. K. Jones, and R. Livingstone, Tetrahedron, 1981, 37,2613.
Six-Membered Rings: Systems containing oxygen or sulphur
365
compounds .99 Another base-catalysed annelation of chromenes yields a 2pyridone (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 cyclization 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 Me0
:
\
r
~
~
~
~
2
: !h
-
c lo4
(135)
(134)
TIoMe
HOOCCHB Ar =
\
OMe
(136)
+
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 proportions, 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.
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, loo
863.
J.-P. Le ROUX,P.-L. Desbene, and J. C. Cherton, J. Heterocycl. Chem., 1981, 18,847.
Heterocyclic Chemistry
366
Ph
Ph
c lo4
-
13OoC
(139)
r 25%1 +
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 synthesis 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 examination 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.
Six-Membered Rings: Systems containing oxygen or sulphur
367
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 orthophosphoric 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 6oxatetracycline 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)
'
NM~R'
NHCSPh OH
CONH 0
g
o
OH 0
in moderate yield'" and the reaction has been applied to the synthesis of several chromones related to demethoxycapillarisin (1 48).'12 Thermal cyclization 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
'
E. Morera and G . Ortar, Tetrahedron Lett., 1 9 8 1 , 22, 1273. 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 . '06
lo'
368
Heterocyclic Chemistry
(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 biological activity. An Italian team has described a group of 2-cyclopropylchromone-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 chroman4-01s, 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 nonchromone heterocycles through its reactions with nucleophiles in a Michael reaction.'lg Reduction t o the amine and condensation with various unsaturated compounds, for example dimethyl acetylenedicarboxylate and diethyl ethoxymethylenemalonate, have led to new tricyclic compounds.12' Reduction of 3-nitro-2-styrylchromone with triethyl phosphite resulted in cyclization 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(cyanomethyl) chromone-2 $-dicarboxylate into the ditetrazolylmethyl ester regioselectively gave a single monotetrazole monocarboxamide, which was shown to be the 2-carboxamide (154).l14 G. M. Coppola and R. W. Dodsworth,Synthesis, 1981, 523. 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. '15 '16
m-ph
369
Six-Membered Rings: Systems containing oxygen or sulphur
i -”- o - i ~ c o N H 2 N\
0
n
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 distinguish 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-3carboxaldehyde (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
I
CHO
piperidine,
co
[77%]
0
(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
lZ4 125
’%
12’ lZ9
A. Fredenhagen, W. Ritter, U. Sequin, and M . Zehnder, Chimia, 1981, 36, 334 (Chem. Abstr., 1982,96,51 502). U. Sequin, Helv. Chim. Acta, 1981,64, 2654. 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. Ref. 1 1 , p . 301;ref.29,p. 301. W. D. Jones, J. Chem. SOC.,Perkin Trans. 1 , 1981, 344.
Heterocyclic Chemktry
37 0
W ANu 0QJ CH
0
-
0
R
CH=CCOOH OH I
(159)
(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 correlated, 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
133 134
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. F. M. Dean and R. S. Johnson, J. Chem. SOC.,Perkin Trans. I , 1981,224. J. I . Botha, D. A. Young, D. Ferreira, and D. G . ROUX,J. Chem. Soc., Perkin Trans. I , 1981,1213.
Six-Membered Rings: Systems containing oxygen or sulphur
37 1
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 flavan3,4-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’-methoxyflavanone (1 65) has been described.I3’ 3-Nitroflavanones have been synthesized 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) 135
13‘ 13’
140
0
J. H. van der Westhuizen, D. Ferreira, and D. G . ROUX, J. Chem. SOC., Perkin Trans. 1,1981,1220. H. K. L. Hundt and D. G . ROUX,J. Chem. SOC.,Perkin Trans. 1, 1981, 1227. 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. C. Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981,236.
372
Heterocyclic Chemistry
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-hydroxydibenzoylmethanes 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' 14* 143 144
14' 146 1 4 '
S. K. David, L. Main, and K. Bold, J. Chem. Soc., Perkin Trans. 2 , 1981,1367. M. A. Smith, L. E. Klebanoff, C. T. Morrow, and B. B. Sandel, J. Org. Chem., 1982, 47, 1702. V. K. Sharma, S. K. Garg, and S. R. Gupta, Indian J. Chern., Sect. B , 1981,20,991. P. K.Jain, J . K. Makrandi, and S. K. Grover, Curr. Sci., 1981,50,857. A. Pelter, R. S. Ward, R. Haensel, and F. Khaliefi, J. Chern. Soc., Perkin Trans. I , 1981,3182. B. Mendez, A. C. Rojas, A. Bahsas, R. Jaimes, and J . Triana, Acta Cient. Venez., 1980,31,394 (Chem. Abstr., 1981,95,149 388). 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.
Six-Membered Rings: Systems containing oxygen or sulphur
373
Isoflavones. - An interesting condensation of a benzyl cyanide with a salicylic ester (1 73) in boiling pyridine containing t-butoxide has given 2-aminoisoflavones (174).14' Robustigenin (1 76), which occurs in Dewis rubusta, has been synthesized from the deoxybenzoin (175).150 An earlier report that isoflavone may be synthesized via an enamine has been disputed and the procedure 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 trimethylsilyl ethers. Retention indices and the relative abundances of several ions enable the monitoring of selected ions to identify the isoflavones in submicrogram 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) trifluoroacetate-trifluoracetic acid (TTFA). The coumarin was accompanied by methyl 3-(2-hydroxyphenyl)propionate (178), which was formed by ring-
(177)
14'
150
lS2
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). 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. M. D. Woodward, Phytochemistry, 1981,20,532. S . Antus, A. Gottsegen, and M. Nogradi, Synthesis, 198 1 , 574.
Heterocyclic Chemistry
374
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 biosynthesis 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 isochroman (1 82)? Oxidation of alpinigenine (183), which is present in several species of poppies, gave the isochromanone (1 84).15'
HOOC
f A
il
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. 154
"'
Six-Membered Rings: Systems containing oxygen or sulphur
375
The spirodihydroisocoumarins (1 85) and (186) show promise in preventing 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
NCHZPh
(185)
73 N CH2Ph
(186)
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-3carbon it rile^.^^^ High yields of 3-phenylcoumarins were obtained when orthohydroxy-aldehydes or -ketones were treated with phenylacetyl chloridepotassium 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 disadvantage. The effect of substituents on the mode of cyclization has been investigated 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 triethyl 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
Heterocyclic Chemistry
3 steps
(190)
( 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
MeCHC=CH
I
CH2CH=CMe2 (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 'O
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). S. D. Samant and R. A. Kulkarni, Indian J. C h e m , Sect. B , 1981, 20,246.
oopo)/pe go ..J Six-Membered Rings: Systems containing oxygen or sulphur
377
\
\
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 benzylideneacetone t o give the ketone (197), which cyclized to the pyranobenzopyran (1 98) under acetylation conditions.172 Treatment of 3-amino-7hydroxycoumarin 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
P hCHCH 2A c
O
*
fJ& Ph
(197)
OAc Me
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.
173
V. K. Ahluwalia, K. Mukherjee, and N. Rani, Heterocycles, 1981,16, 1353. 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.
37 8
Heterocyclic Chemistry
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 oxidation, 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 ozonolysed 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 rearrangement 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 phosphoryl ~ h l 0 r i d e . l ~ ~ 114 1I1
F. D. Mills,J. Heterocycl. Chem., 1980,17, 1597. B. S. Kirkiacharian, J. D. Brion, M. Gomis, and P. Reynaud, Heterocycles, 1980, 14,
118
A. G. Gonzalez, Z . D. Jorge, H. L. Dorta, and F. R. Luis, Tetruhedron Lett., 1981,
1929. 22,335.
179 180
R. H. Carter, M. J. Garson, R. A. Hill,J. Staunton, and D. C. Sunter, J. Chem. SOC., Perkin Trans. I , 1981,471. K. Nozawa, M. Yamada, Y. Tsuda, and K. Kawai, Chem. Pharm. Bull., 1981, 29, 249 1.
181 182 183
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). J. R. Lewis and J . G . Paul, J. Chem. Soc., Perkin Trans. I , 1981,770. H. Obara, J. Onodera, T. Shibata, and K. Shibayama, Bull. Chem. SOC.J p n , 1981, 54, 1261.
Six-Membered Rings: Systems containing oxygen or sulphur
379
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 dichloridetin(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.
Heterocyclic Chemistry
380
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 triethylamine and hydrogen sulphide to give the dihydrothiopyran4one (21 6).'% When the sulphides (218; R' = H or Me, R2 = Me or H) were heated, a mixture of the thiopyran (219) and a dihydrothiophen (220) was formed, but not all vinyl sulphides react in this way.18' PhCH=CHCCH=CHOII 0 (215) *c201 [ 7 7 % ]
8
PhCH=CHCCH=CHOAc
phv -
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."'
But
I
-
c i s + trans
(B~~S),CHCH=CC=CC=CHCH(OM~)~
I
But 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.
Six-Membered Rings: Systems containing oxygen or sulphur
38 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 synthesis.lg3 The use of mass spectrometry in the identification of various isomers and analogues of trans-2,5-dimethyltetrahydropyran-4-one has been discussed.'94
wNoH
S
'R
Cl
(225) R = C1, R = H 2 (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
Y. Gaoni, J. Org. Chem., 1981,46,4502. 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. lg2
lg3
Heterocyclic Chemistry
382
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 2oxocyclohexanecarboxylate 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?"
( 2 3 6 ) R = NTs
( 235)
( 2 3 7 ) R = C(COOMe)2
Thiochromones and Thiocoumarins. - Thiochromone is converted into a mixture 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.201Thiochromones are not reduced by sodium borohydride alone, but the 4Hthiochromene is the main product in the presence of cerium(@) chloride."' Reduced 3-aryl-thiocoumarins have been synthesized from cyclohexane1,3-diones and 172-dithiolium iodides (239) via the thioxo-compound (240) .2m
(239) 19' 198 199
2oo 201
202
( 240)
I. W. J . Still and S. B. Abhyankar, Can. J . Chem., 1982,47,373. K. M. Bakre and J . R. Merchant,Zndian J. Chem., Sect. B , 1981,20, 346. 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. Y. Tamura, Y. Takebe, C. Mukai, and M. Ikeda,HeterocycZes, 1981,15,875. I. W.J . Still and T. S. Leong, Tetrahedron Lett., 1981, 22, 1183. M. Mosaddak, J . M. Catel, R . Pinel, and Y. Mollier, Bull. SOC. Chim. Fr., Part 2, 1981,125.
Six-Membered Rings: Systems containing oxygen or sulphur
383
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 compounds (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 (246b; thp = tetrahydropyranyl)?09
WCl WR1 a -
-
\
\
\
0
(241)
\
/
CH(CH212NMe2
HN( CH2I2NEt2
( 242
( ArCOOCH2) 2S02
NTs
\
Ik'
Me
(243)
-
( 244)
O2 (244a)
(246a) 203 204
(246b)
K. Sindelar, J . Jilek, J . Koerbl, F. Jancik, E. Svatek, J . Metysova, and M. Protiva, Collect. Czech. Chem. Commun., 1980,45, 3166. S . Archer, K. J . Miller, R. Rej, C. Periana, and L. Fricker, J. Med. Chem., 1982, 2 5 , 220.
'05 '06
'07
S. Archer and R. Rej, J . Med. Chem., 1982, 25, 328. Y. Tamura, C. Mukai, M . Ikeda, and M. Kido, Chem. Lett., 1981,619. V. Baliah, K. Ganapathy, and S. Ananthapadmanabhan, Indian J. Chem., Sect. B , 1981,20,334.
'09
M. Cavazza, G. Morganti, A. Guerriero, and P. Francesco, J. Chem. Soc., Perkin Trans. I , 1981,1868. E. Vedejs, D. M. Gapinski, and J . P. Hagen, J. Org. Chem., 1981,46, 5451.
384
Heterocyclic Chemistry
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 threoand eryth ro - 1-phenyl-2-(2-hydroxyphenoxy)propanols, for example the threo-isomer (247).210 A highly substituted dioxan (248) has been synthesized 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 synthesized 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 chloroa~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 equatorial 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. C . B. Chapleo and P. L. Myers, Tetrahedron Lett., 1981,22,4839. A. K. Willard, R. L. Smith, and E. J. Cragoe, J. Org. Chem., 1981,46,3846. C. A. Ramsden, J . Chem. SOC.,Perkin Trans. 1,1981,2456. L. F. Lapuka, E. A. Kantor, R. S. Musaviror, and D. L. Rakhmankulov, Zh. Obshch. Khim., 1981,51,934 (Chem. Abstr., 1981,95,96847).
213
'14 '14'
'15
Six-Membered Rings: Systems containing oxygen or sulphur
385
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 alkylation of 0-silylated enolates of carbonyl compounds to produce 1,3dicarbonyl derivatives, e.g. (259)?18 A wider variety of substituents in 1,3dithians is obtainable by allowing aromatic aldehydes t o react with the sulphone (260)?19 lY3-Dithianssuch as (261) are synthesized from 3(trimethylsilyl)propynal and propylene-l,3-dithiol, and are versatile intermediates?20
n
+ ArCHO
CH2[-iCH2COOEt] 2
0 ( 260)
E tOOC
Ar
(261)
1,4-Dithians.- A new synthesis of thianthrene and its symmetrically substituted derivatives has been described in which a lY2,3-benzothiadiazole(262) is heated in benzene that contains di-t-butyl peroxide.221 1-(3-Chloroethyl216
217
219 220
M. G. Voronkov, V. G. Komarov, A. I. Albanov, I. M. Korotaeva, and E. I. Dubinskaya, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1391 (Chem. Abstr., 1981, 95, 133 006). H. Jendralla and W. Pflaumbaum, Chem. Ber., 1982,115,229. I. Paterson and L. G. Price, Tetrahedron Lett., 1981,2 2 , 2829,2833. V. Balhh, S. Prema, C. B. Jawaharsingh, K. N. Chockalingam, and R. Jeyaraman, Synthesis, 1981,995. 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.
386
Heterocyclic Chemistry
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.
Six-Membered Rings: Systems containing oxygen or sulphur
387
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
Y. Ohfune, K. Takaki, H. Kameoka, and T. Sakai, Chem. Lett., 1982,209. 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.
228
229
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 pharmacological 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 disubstituted 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
Heterocyclic Chem istry
390
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
(5)
H
Ts
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
lo
R. Colman, E. F. V. Scriven, H. Suschitzky, and (the late) D. R. Thomas, Chem. Ind. (London), 1981,249. 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
6
RxoMe -
.y: XN
H
H+
R
XN
R
Me
\ 0 RQR
R
OR Me
/
\ The amino-substituted benzenium ion (13; X = Ts), prepared by the elimination 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)
l2
(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. H. Eckhardt, D. Hege, W. Massa, H. Perst, and R . Schmidt, Angew. Chem. Int. Ed. Engl., 1981, 2 0 , 699.
Heterocyclic Chemistry
392
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 CH2Ph R
m
R \
N
H
M
e
-
R
R \
OH
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 reduction (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
l4
H. P. Figeys and R. Jammar, Tetrahedron Lett., 1981, 2 2 , 637. 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 treatment with base.23
+)eo
-
&
&OR
0 ‘
0
R
(34)
-
R
R
0
H
(35)
(36)
l9
R . N. Carde, P. C. Hayes, G. Jones, and C. J . Cliff, J. Chem. SOC.,Perkin Trans. 1 ,
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.,
1981,1132.
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.
Heterocyclic Chemistry
394
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
(42)
(Ts = tosyl)
R-C=O
(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 25
26
27
28
29
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). M. Hanaoka, M. Inoue, K. Nagami, Y. Shimada, and S. Yasuda, Heterocycles, 1982, 19, 313. G. Jones and P. M. Radley, J. Chem. Soc., Perkin Trans. 1 , 1982, 1123. K. Hafner and H-P.Krimmer, Angew, Chem,, Inr. Ed. Engl., 1980, 19, 199. N. R. Ayyangar, A. K. Purohit, and B. D. Tilak, J. Chem. SOC., Chem. Commun., 1981,399. G . Jones and P. Rafferty, J. Org. Chem., 1982,47,2792.
Sev en-Membered Ring Systems
395 0
(44)
Br
(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
c14 (47)
( E = COOEt)
6-
6+
6-
6+
(48)
The reactions of l-alkoxycarbonyl-1H-azepineswith singlet oxygen had previously been reported to give only a [4 + 21 adduct, but in a reinvestigation 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
MeN- ( CH
I
I I
) 4C=CPh
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 elimination 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-1,2diazepines, e.g. (52), has been prepared by the reaction of cuP;uS -unsaturated ketones with a variety of monosubstituted hydrazines.% 30 31
K. Saito, S. Iida, and T. Mukai, Heterocycles, 1982, 19, 1197. T. Kumagai, A. Tokida, K. Kidoura, 0. Geshimoto, and T. Mukai, Tetrahedron Lett., 1982,23,873.
32 33 34
S. Wawzonek and J. M. Shradel, J, Org. Chem., 1981, 46,2410. K. Orito and T. Matsuzaki, Tetrahedron, 1980, 36,1017. P. N. Anderson, C. B. Argo, and J . T. Sharp, J. Chern. SOC., Perkin Trans. I , 1981, 2761.
396
Heterocyclic Chemistry
Me I
HC=C-CH=CH2
I
MeC=O
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 nondeuteriated 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 pyridine 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 isoquinoline 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 1,2and 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 1,2benzodiazepine 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-vinylpiperidine 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 dependent 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 acetic anhydride gives the 3-acetyl derivative (64).j6 However, a similar
c,:* c,: Ac20 ; .
\
\
R1 -N
(63)
R1
-
(64)
40
R. S. Atkinson, J . R. Malpass, and K. L. Woodthorpe, J. Chern. Soc., Chern. Cornmum, 1 9 8 1 , 1 6 0 . Y . Tamura, I. Morita, H. Tsubouchi, H . Ikeda, and M. Ikeda, Heterocycles, 1982,
4*
17, 163. T. Tsuchiya and M. Sashida, Chern. Pharrn. Bull., 1981 , 29, 1887.
39
398
Heterocyclic Chemistry
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 hydrochloride (69) or via dimerization of the short-lived dehydrochlorinated species (68).42
dimer
RCOCl
(65)
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 1,5sigmatropic hydrogen migration^.^^ R1
R1
MeCy 42
43
D. P. Munro and J. T. Sharp, Tetrahedron Lett., 1982, 2 3 , 345. C. B. Argo and J. T. Sharp, Tetrahedron Lett., 1981, 2 2 , 3 5 3 .
399
Seven-Membered Ring Systems
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 ___t
Ph
Ph
OH___)
Ar
Ph
(74)
(73)
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 alkaline 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 1H1,3-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 (82):’
R1
c.
R2
-N
W (77) 44 45 46 47
48 49
( E = COOEt)
(78)
(79)
P. Sohar, V. Z. Mekesfalvi, A. Neszmelyi, T. Lang, and J . Korosi, Kem. Kozl., 1980, 54,290 (Chem. Abstr., 1981,95,203162). W.Abraham, K. Buck, and D. Kreysig, Z.Chem., 1982,22,57. J. Kurita, M. Kojima, and T. Tsuchiya, Heterocycles, 1981, 16, 137. J. Kurita, H. Kojima, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 1981, 29, 3688. J. Kurita, H. Kojima, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 1981, 29, 3696. T. Tsuchiya, S. Okajima, M. Enkaku, and J . Kurita, J . Chem. Soc., Chem. Commun., 1981,211.
400
Heterocyclic Chemistry
(81)
(80)
(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 cycloalkyl) with a variety of ortho-esters. The 1H analogues (85) were also prepared from (84;R' = Me, R2 = MeCO or PhCO) by dehydration, using phosphorus pentachloride or thionyl ~ h l o r i d e . ~ ~ ~ ~ '
[R1= M e ]
Ph
Ph
(83)
(85)
(84)
The imidazo[ 1,2a][ 1,3]diazepine (87) has been prepared, by the hydrogenolytic ring-expansion of (86), and further converted into the fully unsaturated system (88).52 E
E
H
H
(87) ( E = COOEt)
(86)
(88)
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
MeNK9;Me 0
(89) 50
51
52
53
0
II C1CH2CCH2COOEt
NH2m2
*
(90)
0 (91)
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. 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. T. Kurihari, T. Tani, and K. Nasu, Heterocycles, 1981, 16, 1677. R. J. Breckenridge and C. J . Suckling,J. Chern. Res. (S), 1982, 166.
Seven-Mernbered Ring Systems
40 1
R
blkNH
R
R
R
H
(93)
R
H
(94)
( R = CF3)
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 photochemical 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 also investigated.37y38
Mex=)E NCHO H (95)
E (97)
(99) (E = C O O E t )
1,4-Diazepines.- Formation. The reaction between 1,2-diamines and conjugated 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 confirmed 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.
Heterocyclic Chemistry
402 H
Me Ph
NMe H
Ph
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 regiospecifically 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-Phosphoniovinamidinium salts have been similarly allowed to react with o-phenylenediamine to give (104).”
~ ~- q‘5 3 Me
0
0
i
u
l
yH
p
c104 h -3
c1 \
c1 \
H Ac (105)
(104) Reagents: i, Pd(0Ac)2, CO
NAC
0
(106)
A new synthesis of diazepam has been achieved, via the palladiumcatalysed 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
56 57
D. Lloyd, W. Scheibelein, and K. Hideg, J. Chern. Res. ( S ) , 1981,62. D. Lloyd, C. A. McCann, and D. R. Marshall, J. Chern. Res. (S),1981,356. 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-2ones." The new imidazo[2,1-c][ 1,4]benzodiazepine (1 11) has been synthesized by reduction of the nitro-aldehyde (1 /OEt RC=~-c
\\+
-
CR
i
BF~-
NH2
H
(112) Reagents : i, o-phenylenediamine
The 2-amino-4-phenyl-3H-1,5-benzodiazepines (1 13) can be produced conveniently, in a one-pot process, by the reaction of o-phenylenediamine with the imidates (1 12), using HMPA as the solvent .61 HCCOOMe
a;%-
a;> 0
H
II
C
II
HCCOOMe CH2COOMe (114)
(115)
H
f-"
MeOOC (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 0phenylenediamine, 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.,
6o
G. Stefancich, M. Artico, S. Massa, and F. Corelli, Synthesis, 1981, 321. P. Unangst, J. Heterocycl. Chem., 1981, 18,1257. J. Ackroyd and F. Scheinmann, J. Chem. SOC., Chem. Commun., 1981, 339; J. Chem. Res. ( S ) , 1982,89.
1981.18.963. 61
62
404 H
Heterocyclic Chemistry 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 equivalents of lithium di-isopropylamide (LDA) were required to produce an equilibrium concentration of (123) that was sufficiently high for synthetic use.% 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. 63
Seven-Membered Ring Systems
405
A similar base-induced alkylation of the chiral benzodiazepine (1 25) gave substituted 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 2,3dihydro- lY4-diazepiniumsalt s.68 Conformations and barriers to inversion in NN'-dialkylperhydro-l,4diazepine-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 temperature and substituents on the conformation of the 5-phenyl-l,5benzodiazepin1-one system has been studied by lanthanide-shift-assisted H n.m.r. spectro~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 E. Decorte, R. Toso, A. Sega, V. Sfinjib, Z. RuZik-ToroZ, B. Kojib-Prodid, N. BrescianiPahor, 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. 67
406
Heterocyclic Chem istly Me
H
MeOH
+
year's Report), has now appeared.76 Further work has shown that the 8nelectron 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 isomerization to dihydro-oxepins (1 35) under mild conditions. The analogous transisomers require a much higher temperature, and in addition they give 2-vinyl2,3-dihydrofurans,e.g. (136).78 Ph
76 77
78
Ph
W. Eberbach and U. Trostmann, Chern. Ber., 1981,114,2979. W. Eberbach, E. Hadicke, and U. Trostmann, Tetrahedron Lett., 1981, 22,4953. J-P. Beny, J-C. Pommelet, and J . Chuche, Bull. SOC.Chim. Fr., Part 2, 1981, 377.
Seven-Membered Ring Systems
G
R20
407
R1 Me
Me
R2d
The application of the new method of 1,2-carbonyl transposition in oxepins [e.g. (1 37) to (1 38)] that was mentioned in last year's Report to the synthesis 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 unsaturated 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 e.g. (144)' have been Several l-haloalkyl-1,3,4,5-tetrahydro-2-benzoxepins, synthesized via the electrophilic cyclization of mixed acetals, e.g. (143)?
CH ,,B r L d
(143) 79
8o
"
V. V. Kane and D. L. Doyle, Tetrahedron Lett., 1981, 2 2 , 3027. 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 84
(144)
C. K. Bradsher and D. C. Reames, J. Or%. Chem., 1981,46, 1384. R. E. TenBrink and J. M. McCal1,J. Heterocycl. Chem., 1981, 18, 821.
408
Heterocyclic Chemistry
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 lactones."
- Hm -2
RHN--
QCHOZ
H
The oxepin epoxide (148) is readily isomerized to (147) under protic conditions, but the epoxide ring can be opened by amine nucleophiles, e.g. to give (1 49), without significant ring-contraction.= RCO
H
0
0
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
86
''
R. F. C. Brown, F. W. Eastwood, N. Chaichit, B. M . Gatehouse, J . M. Pfeiffer, and D. Woodroffe, Aust. J. Chem., 1981, 34, 1467. 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 H I/(CH
R-C
I
1 H00-C'3
YH3 I
409
Pb(OAcI4
R
Ph
Ph
CH3
(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
~
N Me
Me
(155)
(156)
Further work on the acid-catalysed rearrangement of 4,5-dihydro-l,3dioxepins (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 thianorcara89
91 92
93 94
H. Kropf and H. van Wallis, Synthesis, 1981, 633. 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. I, Yavari, Org. Magn. Reson., 1980, 14, 511. 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). R. St-Amour and M . St-Jacques, Can. J. Chem., 1981, 59,2283. D. Menard and M. St-Jacques, Can. J. Chem., 1981, 5 9 , 1160.
410
Heterocyclic Chemistry
( 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 acting 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 thermolysis of (162). A P-elimination produces the sulphenic acid (163), which cyclizes to give ( 164).96 R R-CrC
\ (CH2>4
But-
/
s\\o
-
R-CEC
) \ p 2 ) , H\
0-0
I
- H'cT3 //s
0
(164)
(162)
(163)
In a new, general route to cyclic P-oxosulphonium salts, the 3-0x0thiepinium perchlorate (166) was prepared by adding the phenylthio-diazoketone (1 65) to perchloric acid in chloroform?' 0
ph-6 c lo,
HC10,
A high-yielding synthesis of thiepan has been achieved by allowing 1,6dibromohexane 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
96
97 98 99
K. Yamamoto, S. Yamazaki, Y. Kohashi, I. Murata, Y. Kai, N. Kanehisa, K. Miki, and N. Kasai, Tetrahedron Lett,, 1982, 2 3 , 3195. R. Bell, P. D. Cottam, J. Davies, and D. N. Jones, J. Chem. Soc., Perkin Trans. 1 , 1981,2106. W. T. Flowers, A. M . Freitas, G. Holt, and S. C. Purkiss, J. Chem. SOC.,Perkin Trans. I , 1981, 1119. A. Singh, A. Mehrotra, and S. L. Regen, Synth. Commun., 1981, 11,409. Y. Tamura, Y. Takebe, C. Mukai, and M . Ikeda, Heterocycles, 1981, 15, 875; J. Chem. Soc., Perkin Trans. 1 , 1981,2978.
41 1
Seven-Membered Ring Systems
I
E 2C-
E2k-
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 1,4dithiepan"' and on the dynamic behaviour of the l-methyl-l-benzothiepinium 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 prepared by a free-radical annelation technique. The reaction of (173) with tributyltin hydride generated (1 74), which cyclized predominantly via endoaddition 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
Io2 Io4
I. W. J. Still and G. W. Kutney, Tetrahedron L e t t . , 1981, 22, 1939. W. N. Setzer, G. S. Wilson, and R . S . Glass, Tetrahedron, 1981, 37, 2735. 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. 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.
Heterocyclic Chemistry
412
Following earlier work on the conversion of azidopyrans and azidochromenes into 1,3-oxazepines and 1,3-benzoxazepines, respectively, it has now been shown that the pyrolysis of 1-azidoisochromenes (177) gives 3,lbenzoxazepines (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 substituents on the carbanion; in some cases, attack at the 2-position leads to 1,4oxazepines, 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*
lo' 108
I-P. LeRoux, P-L.Desbene, and J-C. Cherton, J. Heterocycl. Chem., 1981, 18, 847. M. Dreme, P. LePerchec, J. Garapon, and B. Sillion, Tetrahedron Lett., 1 9 8 2 , 2 3 , 7 3 . S. Massa, F. Corelli, and G . Stefancich, J. Heterocycl. Chem., 1981, 829.
Seven-Membered Ring Systems
41 3
Thiazepines. - The full report has now appeared on the preparation of 1,2benzothiazepines 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 possible, 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 photost able.' l 2
Io9 'Io
'I1
'I2
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. M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 529. M . Sindler-Kulyk, D. C. Neckers, and J . R. Blount , Tetrahedron, 1981 , 37, 3377. M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 208 1.
Heterocyclic Chemistry
414 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
! kOOH
"COOH
(195)
(194)
( 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."' '14
'I5
M. Kaafarani, M. P. Crozet, and J-M. Suzur, Bull. SOC.Chim. Fr., Part 2 , 1981,449. L. Fodor, I. Szabo, G . Bernath, L. Phrkhnyi, and P. Sohhr, Tetrahedron Lett., 1981, 2 2 , 5077. 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.
Seven-Membered Ring Systems
415
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-benzotriazepine (199) in high yield, probably via (198)."'
1
Ph
L (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 subsequent 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 &oJmR*zl \ m2
a c - NH2 2
Jt)
(201)
The 1,3,4-benzoxadiazepine salt (204) has been simply prepared by treatment 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.
'''
Heterocyclic Chemistry
41 6
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-aminopenicillanic 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
E
Me
Me
(210)
(209) (208)
123
124
(E
=
COOR
2
)
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. 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.
Seven-Membered Ring Systems
417 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-benzoxathiazepine (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
127
M. Rai and B. Kaur, J. Chem. SOC.,Chem. Commun.,1981,971, 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 oxolactams, e.g. (4).2 There have been several reports of ring-expansions with a l k y n e ~ . ~Thus - ~ the tetrahydropyridine ( 5 ) reacts with methyl acetylenecarboxylate to give (6). The reaction is thought to occur via the cyclobutene intermediate .3 0
Me
7QCHPh( Y MOe N H 2
Me Me
(4)
’
01,. Me
(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
420
Heterocyclic Chemistry
The first eight-membered cyclic ketenimine (7) was synthesized as a mixture of two diastereoisomers, which interconvert through inversion.6 Tetraand 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 inactivated 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 1,4dichlorobutane 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 2Hbenzimidazole (1 9).13 The new 1,5-benzodiazocine ring system (20) was prepared 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-dimethyland 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 photoelectron spectroscopy and it was shown to occur in the chair-chair conformation. MNDO calculations on the compound indicate that, in the chairchair conformation, the N-N interaction is mainly through space.16 Proton affinities and ionization energies were determined, by photoelectron spectroscopy, 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 l3
G . Singh and K. N. Mehrotra, Hererocycles, 1981, 16, 1341. W. Friedrichsen, M . Roehe, and T. Debaerdemaeker, 2. Nururforsch., Teil. B , 1981, 36,632.
l4
Is l6
E. Aiello, G . Dattolo, G. Cirrincione, A. M. Almerico, and I. D'Asdia, J. Heterocycl. Chem., 1981,18,1153. J . W. Waluk, E. Vogel, and J . Michl, J. Org. Chem., 1981, 46, 3306. 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.
422
Heterocyclic Chemistry
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-dimethylbuta1,3-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 biochemical 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 boatchair 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.
, I . T. Doi and W. K. Musker, J. Am. Chem. SOC.,1981,103, 1159. 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, 'O
21
''
64,399. 25
E. Vedejs and D. W. Powell, J. Am. Chem. SOC.,1982,104,2046.
423
Eight-Membered and Larger Ring Systems
'NCOOEt
Me'
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.
P
n
5
HS
Me
Me
Me
(34) (33)
Treatment of Br(CH2),Br with Na2S under heterogeneous conditions yields the appropriate thia~ycloalkane.~'Similarly, the oxidative cyclization 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 mediumring 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+
+
Br(chain b)Br
CS+
DM??
FS> b)
(chain a)
(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; G. Shroder ibid., p. 248.
( b ) H. Rottele and
Heterocyclic Chemistry
424
n
macrocyclic lactams bearing three nitrogen atoms was reported in a synthesis of celacinnine alkaloids. The triamino-ester (37) reacted with tris(dimethy1amino)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 macrocyclic 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
u
N’
(37)
RN,
“H
,NR Si
Me2 OEt (39)
(38)
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 com31
” 33
H. Yamamoto and K. Maruoka, J. Am. Chem. SOC.,1981,103,6133. E. Schwartz and A. Shanzer, J. Chem. SOC.,Chem. Commun., 1981,634. E. Kimura, M. Kodama, and T. Yatsunami,J. Am. Chem. SOC., 1982,104,3182.
Eight-Membered and Larger Ring Systems
425
(41)
pounds also form ternary complexes with Mg2+- and Ca2+-nucleotide complexes. Some polyamino-macrocycles have the intriguing property of complexing 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 oxyhaemocyanin .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-azamacrocycles 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' cyclophanes as models for enzymes, schematically shown in (43). Thus (44) incorporates 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
3s
' 3
P. K. Coughlin and S. J . Lippard, J. Am. Chem. SOC.,1981, 103, 3228. 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 . 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 .,
39
J . E. Richman and R. B. Flay, J. A m . Chem. SOC., 1981, 103, 5265.
1981,22,2229.
Eight-Membered and Larger Ring Systems
427
Systems containing Sulphur as the only Heteroatom. - A variety of sulphurcontaining 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-(2,4dimethoxyphenyl) sulphide and S2C12 gave four macrocyclic systems, including (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 Macrocyclic Lactones. Macrolides have been synthesized, in good to excellent yields, from w-hydroxyalkanoic acids by tri-phase catalysis, using a 1% polystyrene 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 microemulsions 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 compounds 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 probably 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
41 42 43
44 45
S. Karbach, W. Lohr, and F. Vogtle, J. Chem. Res. ( S ) , 1981,314. F. Bottino and S. Pappalardo, J. Chem. SOC.,Perkin Trans. 1 , 1981,718. S. L. Regen and Y . Kimura, J. A m . Chem. SOC., 1982,104,2064. A. Gonzalez and S. L. Holt, J. Org. Chem., 1981,46,2594. W.H.Kruizinga and R. M. Kellogg, J. A m . Chem. SOC.,1981, 103,5183. U. Schmidt and M. Dietsche, Angew. Chem., Inr. Ed. Engl., 1981,2 0 , 771.
428
Heterocyclic Chemistry
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 propiolactones to form the macrocyclic lactones (52), using the cyclic tin-oxygen compound (53) as a template.48 OH
n
0
I R2Sn I 0 !302Ph (51)
0
I
SnR2
I
0
W
( 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. Compound (54) is cleaved by m-chloroperoxybenzoic acid to form the novel octaketone ( 5 5 ) , with a cis-enedione c o n f i g u r a t i ~ n .The ~ ~ endoperoxide (56) 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 . ’ ~ 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 , (a) H. H. Wasserman, R. 47 48 49
1737.
V . Bhat and R. C. Cookson, J. Chem. SOC.,Chem. Commun., 1981,1123. A. Shanzer, J. Libman, and F. Frolow, J. A m . Chem Soc., 1981, 103,7339. 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.
Eight-Membered and Larger Ring Systems
429 Me
Me
Me
Me
Me
Me
(54)
(55)
(57)
(56)
Other Macrocyclic Systems. The first synthesis of crown arsanes (58), which are air-stable, and which should prove useful in chelating transition metals, has been r e p ~ r t e d . ’The ~ novel fourteen-membered rings (59) are of interest 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 two-volume work by Patai.
including a
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 benzo52 53
’* 55
J. Ennen and T. Kauffmann, Angew. Chem., In?.Ed. Engl., 1981, 2 0 , 118. 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. 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 condensation 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 polymers and in linking crown ethers together; e.g., (66) was formed by condensation of the hydroxymethyl crown ether (65) with substituted malonic esters.62 A direct approach to 0x0-crown ethers has been devised [reaction 56 57 58
59
'*
61
62
G. Ercolani, L. Mandolini, and B. Masci, J. A m . Chem. SOC.,1981, 1 0 3 , 2 7 8 0 . B. Thulin and F. Vogtle, J. Chem. Res. ( S ) , 1981, 256. J . H. P. Tyman, J . Grundy, and G. R. Brown, J. Chem. SOC., Perkin Trans. I , 1981, 336. 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. G. S. Heo, R . A. Bartsch, L. L. Schlobohm, and J. G. Lee, J. Org. Chem., 1981, 46, 3574. 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.,
0
n
(CH2CH2)20 or (CH2)3
Et 0
/+0-"-s,"-**
U (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
+ N2CHCO( CH2)xCOCHN2
(2)
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 64 65
S. Kulkowit and M . A. McKervey, J. Chem. SOC.,Chem. Commun., 1981,616. H . Maeda, Y. Nakatsuji, and M. Okahara, J. Chem. SOC., Chem. Commun., 1981,471. ( 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 .
432
Heterocyclic Chemistry
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-dimethylfuran, which forms a hydroperoxide under similar conditions. 3,4Diaminobenzo-15-crown-5 reacts with EtOCH=CCHMe,CHO to form (70),
66 61
M. Eichner and A. Merz, Tetrahedron Lett., 1981, 22,1315. B. L. Ferringa, Tetrahedron Lett., 1981, 22, 1443.
Eigh t-Mem bered and Larger Ring Systems
433
n
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 photoinduced 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 aaintraNO,
(73) R 69
=
(CH2l3CH3
R. Kruse and E. Breitmaier, Chem. Ber., 1981, 114,832. S. Shinkai, T. Ogawa, Y. Kusano, 0. Manabe, K. Kikukawa, T. Goto, and T. Matsuda, J. Am. Chem. SOC.,1982,104,1960.
Heterocyclic Chem is try
434
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 inversion 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 possibility of a rotation mechanism.n
Applications of Crown Ethers in Organic Synthesis. - The first selective CHinsertion of aryl-halocarbenes has been reported.73 The free carbene, generated 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 tetrafluoroborates 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,
"
T. Asano, T. Okada, S. Shinkai, K. Shigematsu, Y. Kusano, and 0. Manabe, J. A m . Chem. SOC.,,1981,103,5161. H. Rauz and E. Luddecke, J. A m . Chem. SOC.,1982,104, 1616. K. Steinbeck and J. Klein, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 7 7 3 .
1967. 72
73
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 phosphonate 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 pathway. In dipolar aprotic solvents, the 18-crown-6 breaks up ion pairs by solvation 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 isoprenoids. 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. Commun., 1981,102, 554. 78 S . Akabori, M. Ohtomi, K. Shimada, and A. Takemura, Bull. Chem. SOC.Jpn., 1981, 54,1273. 79 80
A. M . Moiseenkov, E. V. Polunin, and A. V. Semenovsky, Angew. Chem., In?. Ed. Engl., 1981, 20, 1057. D. J . Cram and G . D. Y. Sogah, J. Chem. SOC.,Chem. Commun., 1981, 6 2 5 .
436
Heterocyclic Chemistry
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) 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.
W. H.
Eight-Membered and Larger Ring Systems
437
( 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 produced 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 prepare 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.
Heterocyclic Chemistry
43 8
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 host molecules through the aromatic ring." CH20CH2-18-crown-6
Meooc
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
89
90
R. Annunziata, F. Montanari, S. Quici, and M. T. Vitali, J. Chem. SOC., Chem. Commun., 1981,777. F. Montanari and P. Tundo,,J. Org. Chem., 1982, 47, 1298. 0. A. Gansow, A. R. Kausar, and K. B. Trippett, J. Heterocycl. Chem., 1981, 18,297. J . Gabard and A. Collet, J. Chem. SOC.,Chem. Commun., 1981, 11 37.
Eight-Membered and Larger Ring Systems
439
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 crystallography. 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 heating 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 correlation between the size of the ring and the cation that is bound is of less significance than in other systems. The binding constants reflect the total number 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. S. L. Baxter and J . S. Bradshaw, J. Hererocycl. Chem., 1981, 18,233. 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. 91 92
Heterocyclic Chemistry
440
n (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 electrostatic 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 dissociation of Ca[2.2.2I2' by a general acid is due to a rate-determining protontransfer 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 dissociation 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 separation of 22Naand 24Na, using [2.2.1], are promising."'
96 97
'*
H. M . Colquhoun, J . F. Stoddart, D. J. Williams, J . B. Wolstenholme, and R. Zarzycki, Angew. Chem., Inr. Ed. Engl., 1981, 20,1051. 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.
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. 99
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 compounds: 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., lo
l2 13 14 15
1981,103,2310. 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 . S. N. Whittleton, P. Seiler, a n d J. Dunitz, Helv. Chim. Act a, 1 9 8 1 , 64, 2 6 1 4 . M. J. Begley, J . P. Benner, and G. B. Gill, J . Chem. Soc., Perkin Trans. I , 1981, 11 12. T. Ota, S. Masuda, H. Tanaka, and M. Kido, Bull. Chem. SOC.Jpn., 1 9 8 2 , 5 5 , 171. 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
Heterocyclic Chemistry
442 COOE t 0
COOE t
F3C
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-bisethoxycarbonyl4-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 sixmembered 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
17
G. R. Newkome, D. C. Hager, and F. R. Fronczek, J. Chem. SOC.,Chem. Commun., 1981,858. 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, Tetruhedron 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 3silabicyclo[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 assignment 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]nonan2-onee3’ A barrier of 9.0kcal mol-’ t o inversion at nitrogen for the bicyclic n
B;
OH
R1
0
(16) R1,R2
=
alkyl, H
R3= H o r R3R3 = b o n d 22
23 24 25
26 27
29
30
(17)
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. Q . Shen, R. L. Hilderbrandt, C. S. Blankenship, a n d S. E. Cremer, J. Organornet. Chem., 1981,214,155. M. Perhsamy, Heterocycles, 1982, 18,127. P. H.Mazzochi, H. L. Ammon, L. Liu, E. Colicelli, P. Ravi, and E. Burrows, J . Org. Chern., 1981, 46,4530. 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. 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. F. 1. Carroll, M. L. Coleman, a n d A. H. Lewin, J. OR. Chem., 1982,47,13. G. L. Buchanan, J. Chem. Soc., Chem. Commun., 1981,814 ( c f . ref. 23 in last year’s Re port ).
Heterocyclic Chemistry
444
hydrazine (1 8) indicates that the positive nitrogen exerts only weak electronwithdrawal 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 carbony1 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 identified: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 (22b) X = N 31
32 33
34 35
36
37
(23)
S. F. Nelsen and P. M. Gannett, J. A m . Chem. SOC., 1 9 8 1 , 1 0 3 , 3300. R. J . Hunadi and G. K. Helmkamp, J. Org. Chem., 1 9 8 1 , 4 6 , 2 8 8 0 . H. Ogawa, N. Kariya, T. Imoto, H. Kato, and Y. Taniguchi, Croat. Chem. Acta, 1981, 5 3 , 637. F. Carnovale, T. H. Gran, J . B. Peel, and A. B. Holmes, J. Chern. SOC.,Perkin Trans. 2 , 1981,991. 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 Tetmhedron Lett., 1 9 8 2 , 2 3 , 4 1 8 1 for synthesis of (22b)l. (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 . G. Granozzi, A. Ajo, T. Boschi, and R . Roulet, J. Organomet. Chem., 1 9 8 1 , 224, 147.
445
Bridged Systems
(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 cyclohexa1,3-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-dimethylamino)-2,5-dimethylpyrrole, giving the pyrazole (29) as the ultimate product .41 Dienophiles such as N-phenylmaleimide add t o N-t-butyl-5-nitroisoi n d 0 1 e ~and ~ ~N-t-butylbenzisoindole?2b ka[3.1. llpropellanes, e.g. (3 l ) , are formed from N-methylisoindoles when they react with chlorobicyclobutanes, e.g. (30), in the presence of base43 and the addition of DMAD to 2,lbenzisoxazoles occurs straightforwardly.44 H N
(X (26)
(27a) Y = S (27b) Y = 0
=
CF3)
X (28a) Y = S (28b) Y = 0
Z
(29)
2
z
= COOM~
J . H. H. Hamerlinck, P. H. H. Hermkens, P. Schipper, and H. M. Buck, J. Chem. SOC., 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, '~3
1081.
Heterocyclic Chemistry
446
+
+
3;-
xONo
( X = rnorpholino)
Scheme 1 ‘Catalytic’ Diels-Alder addition of enamines (generated in situ) with 1,2,4triazines 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,forming 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)
‘*
‘’ 48
49
(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. P. Imming, R. Mohr, E. Miiller, W. Overheu, and G. Seitz, Angew. Chem., Int. Ed. Engl., 1982,21, 284. 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.
447
Bridged Sys terns Ph
I
I N0Ph (35)
(37)
H
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 photoaddition of chloroethylenes to 2-pyridones.” A detailed classification of two-electron cyclo-addends includes N-phenyltriazolinedione (PTAD).56 Enantiomerically pure unsaturated [4.4.2]propellanes have been isolated by means of Diels-Alder addition of (-)-endobornyltriazolinedione followed by separation of the resulting diastereoisomeric urazoles and re-formation of the propellanes.” The product (39) of 1,7dipolar cyclization of a conjugated carbonyl ylide has been intercepted by addition of PTAD across the diene moiety,58 as has the dimer of cyclo-octa1,5-dien-3-yne [yielding the adduct (40)].59 Similar [4 + 21 additions of PTAD have been reported with a variety of substituted cyclopentadienes,6’ 1
(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. (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. PaddonRow, 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. 51
’*
448
Heterocyclic Chemistry 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 preparation 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]octa2,6-diene (and derivatives) has been fully investigated by The formation 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 products6* Addition of triazolinediones across the central bond of bicyclobutanes 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
0
(45)
( 4 7 ) R = Me or Ph R 2 = Me, CN, COYH2,
or COOEt
(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. 61
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-aminocyclohexanone d e r i ~ a t i v e .Double ~~ Michael addition of (+)-a-methylbenzylamine 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 alkylation has been used in the synthesis of derivatives of the 2,6-methanobenzazepine ,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 Cl
R H (49)
H
pyoH
( 5 0 ) R = n-pentyl
A simple synthesis of 1-aza-adamantan-4-one has been de~cribed.~’7Chloro-l,7-dia~a-’~ and 1-aza-7-oxa-bicyclo[2.2.1] heptane~’~ have been prepared 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 R. F. Parcell and J. P. Sanchez, J. Org. Chem., 1981,46,5228. 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. 71
72
450
Heterocyclic Chemistry
0
1
( 5 2 a ) R = H , R2= ( 5 2 b ) R1R2=
bond
C1
(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]cyclazinesWare noted. Reactions of Nitrogen-containing Compounds. - Irradiation of cyclic nitrocompounds 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 80
J. T. Bailey, I. Berger, R. Friary, and M. S. Puar, J. Om. Chem., 1982,47, 857. J. Barluenga, J . Perez-Prieto, and G. Asensio, J. Chem. SOC.,Chem. Commun., 1982, 1181.
82
83 84
R. Richter, B. Tucker, and H. Ulrich, J. Otg. Chern., 1981, 46, 5 2 2 6 . J. M. MeUor, A. P. No t t , R. N. Pathirana, and J. H. A. Stibbard, Synthesis, 1982, 325. A. R. Butler, I. Hussain, and K. M. Peet,J. Chem. SOC.,Perkin Trans 2 , 1981, 320. J. W. Dick, W. K. Gibson, D. Leaver, and J. E. Roff, J. Chem. SOC., Perkin Trans. 1 , 1981,3150.
85
86 87
K. Yamada, T. Kanekiyo, S. Tanaka, K. Naruchi, and M. Yamamoto, J. Am. Chem. SOC.,1981,103,7003. K. Umano, J. Koura, and H. Inoue, Bull. Chem. SOC.Jpn., 1981, 54,2827. 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
R ( 5 7 ) R = COOMe o r CN
H
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).%
Ag+
A; /OH
H N
Y
O
H
Scheme 2
a9
90 91 92
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 . J . G . Henkel and W. C. Faith,J. Org. Chem., 1 9 8 1 , 4 6 , 4 9 5 3 . M. L. Durrant and J . R. Malpass, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 1 0 2 8 . A. Heesing and W. Herdering, Tetrahedron Lett., 1 9 8 1 , 2 2 , 4 6 7 5 .
45 2
Heterocyclic Chemistry
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 precursor 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 decomposition 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-tetrahydroaluminate-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
T. Fukuyama and Y. M. Yung, Tetrahedron Lett., 1981, 22,3759. 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 , 93 94
1981,1963.
lo' '02 103
Y.Shvo and E. D. Kaufman,J, Org. Chem., 1 9 8 2 , 4 7 , 2 1 9 0 . S. Sarel and E. Dykman, Heterocycles, 1981, 15,719. ( a ) R. Ashkenazi, R. Gleiter, W. von Philipsborn, P. Bigler, and D. Ginsburg, Tetruhedron, 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
0
(72) n = 1 or 2 m = O o r l x = O o r l
(73) R = I o r H
(74)
tives of azabenzvalene (75) has been invoked in the rearrangement of cyclopropenyl-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)
104
lo5
:
(77a) R = H (77b) RR = CMeZ
A. Padwa, M. Akiba, L. A. Cohen, H. L. Gingrich, and N. Kamigata, J. Am. Chem. SOC.,1982,104,286. (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.
Heterocyclic Chernisty
454
(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.
( 8 0 ) RR = 0 (81) R = H
n
( 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 congested 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=
108
M e , Ph
(86)
( 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. ( 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. 109
45 5
Bridged Systems
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 cycloadditions 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 isobenzofurans. The new dienophile ethyl (diethoxyphosphiny1)propynoate is highly
d2 c;B
cc1 l\
Ic1
c1
c1
'13
'14
'"
P. A. Jacobi and D. G. Walker,J. Am. Chem. SOC.,1981,103,4611. 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.
456
Heterocyclic Chernistry 0
R R O G II II ( 9 5 a ) XR = -COC( 9 5 h ) R = CN
Ph ( 9 6 ) R = II or CH
3 X = 0 or "Me2
(97)
reactive and regiospecific ,l l6a ethynedicarbonyl dichloride' l6 and but ynedinitrile116c 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 cyclopropenes,'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-tetrahydrobenzocyclobutene-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 discussed.' 26
(98)
(99)
0
(100)
( 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.
'16
"'
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 regioand 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
129
13'
132
D. Dopp, U. Langer, and H. Libera, Chem. Ber., 1982, 115, 346. E. Block and M. Aslam, Tetrahedron Lett., 1982,23,4203. 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. ( 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.
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, 135
'36
425 3. G. M. R. Tombo,
R. A. Pfund, and C. Canter, Helv. Chim. Actu, 1981,64,813. A. Nishinaga, K. Nakamura, and T. Matsuura,J. Org. Chem., 1982, 47, 1431.
458
Heterocyclic Chemistry
(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
Po HO
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 (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 accompanying 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. 13'
459
Bridged Systems
/
\ R2
(116) R 1 , R2= H , OMe (114) X = COOEt
(115)
to (24) is illustrated in the formation of (1 16);lWa investigations with halogeno- and methoxy-derivatives of (24) have been carried out.'44b The formation 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 monocyclic 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) 9!1 occurs 30 times faster than the retro-Diels-Alder reaction.
f
(1 24)
144
(a) J. Tamariz and P. Vogel, Helv. Chim. A ct a, 1981, 64, 188; ( b ) C. Mahaim and
146
Y.D. Xing and N. Z. Huang, J, OR. Chem., 1982,47,140. J. G. Smith and N. G. Chu, J. 0%.Chem., 1981,46,4083.
P. Vogel, ibid., 1982,65,866.
14' 148 149
R. A. Burt, Y. Chiang, H. K. Hall, Jr., and A. J . Kresge, J. A m . Chem. SOC., 1982, 104,3687. H.Duddeck, V. Wiskamp, and D. Rosebaum, J. Org. Chem., 1981,46,5332. J. P. Hagenbuch, B. Stampfli, and P. Vogel, J. A m . Chem. SOC.,1981, 103,3934.
Heterocyclic Chemistry
460
&
H+
OH
dH (121a) R = Me (121b) R = H
o$X
Brid ed Peroxides. - Discussions of the mechanism 0f,lSoa and solvent effects in,'' the reaction of singlet oxygen with conjugated dienes include examples of bicyclic peroxides. The photo-oxygenation of 1,4-disubstituted naphthalenes is thought to proceed partly via '02and partly via the 0;.radical anion.lSoc A hitherto unknown 1,4-adduct from singlet oxygen and cyclooctatetraene (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. Photosensitized oxygenation of (128) gives (129) or (130), depending on cond i t i o n ~addition ; ~ ~ ~ to a 1,4-diazepine gives the bicyclic peroxide (131).lM
4
(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 acidcatalysed decomposition of (129). lS4 V. T. Ramakrishnan and J. H. Boyer, Heterocycles, 1981, 16, 1345.
Bridged Systems
46 1
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. dissociation160b of endoperoxides that are derived from aromatic compounds have been investigated. (CH2In COOMe
";:>lk: R1
R R > b o
( 1 3 2 ) RR = b o n d , n (133) R = H, n = 1
=
2
0'
( 1 3 4 ) R1.
R2= Me, Ph
Me$ T j M e (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 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.
lS5
Heterocyclic Chernis try
462 I
Ar
0
Ar
K (138) (R1,
(137 1
( 1391
R2 = a l k y l , a r y l )
Ph
NNPh
(140)
(141) (R = alkyl)
(142)
primary products (1 38) from the reaction of maleic anhydride with enaminethiones 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 intermediate~.~~' 0
X
X
(144) X = O A c (143)
1 ( 1 4 5 a ) R = H , €IOAc 2=
( 1 4 5 b ) R1R2=
16'
164 165
0
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. T. Fukuyama, S-I.Nakatsuka, and Y . Kishi, Tetrahedron, 1981, 37,2045. T. M. Brown, W. Carruthers, and M . G. Pellatt, J. Chem. SOC.,Perkin Trans. 1 , 1982, 483.
16'
I. Lundt and B. Skelbaek-Pederson,Acta Chem. Scand., Ser. B , 1981, 35, 637. T. Miyashi, N. Suto, T. Yamaki, and T. Mukai, Tetrahedron L e t t . , 1 9 8 1 , 2 2 , 4 4 2 1 .
463
Bridged Systems Me,
,Me
Me
X ( 1 4 6 ) R1,
2
R = H , C1, o r Me
(147)
ye
'5i-0
' x Ph
( X = COOMe)
(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 irreversible 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
bond
(150a)
X = Si-Si
(151a)
X = 0 , SiMe2,
(150b)
( 1 4 9 ) X = H , D , or C1
CH2,
(151b)
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
168 169
170 171 172 1 73
114
(152) S. E. Cremer and C. Blankenship, J . Org. Chem., 1982,47, 1626. T. J . Barton, W. F. Goure, J . L. Witiak, and W. D. Wulff,J. Organomet. Ch e w. , 1982, 225, 87. G. Maier, G. Mihm, and H. P. Reisenauer, Angew. Chem., Int. Ed. Engl., 1981, 20, 597. J . D. Rich, T. J . Drahnak, R. West, and J . Michl, J. Organornet. Chem., 1981,212, C1. Y. Nakadaira, T. Otsuka, and H. Sakurai, Tetrahedron Let t ., 1981, 22 ( a ) p. 2417; ( b ) p. 242 1. A. Laporterie, G. Manuel, J . Dubac, P. Mazerolles, and H. Iloughmane, J. Organomet. Chern., 1981,210, C33. M. Schriewer and W. P. Neumann, Angew. Chem., Int. Ed. Engl., 1981,20, 1019.
Heterocyclic Chemistry
464
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' M e
Adducts, e.g. (1 5 9 , are formed when 1-phenylphospholes are heated with dienophiles such as diphenylethyne; they are the result of preferential trapping of the 2-phenylphosphole t a ~ t 0 m e r . l ~Interception ~ of the 1,4diphosphabenzene (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.,
177
Y. Kobayashi, S. Fujino, and I. Kumadaki, J. A m . Chem. SOC.,1981, 103,2465. G. Markl, G. Y. Jin, and E. Silbereisen, Angew. Chem., Int. Ed. Engl., 1982,21, 3 7 0 . 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-ulHaque, W. Horne, S. E. Cremer, and J . T. Most, J. Chem. SOC.,Perkin Trans. 2 , 1981,
1981,103,4595. 178
179
1000.
Bridged Systems
465
I
Ph (160) Z = 0 or "We2
\
Ph (161) ( + endo-isomer)
8 Boron-containing Compounds 1-Bora-adamantane (1 62)"la forms 1 : 1 complexes with carbonyl compounds; 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 hydroboration 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 stereoregulated 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 182
183
la4
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. H. C. Brown and J . C. Chen, J. Ow. Chem., 1981,46, 3978. B. Wrackmeyer and C. Bihlmayer, J. Chem. SOC.,Chem. Commun., 1981,1093. 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.
466
Heterocyclic Chemistry
lithium salt of 9-BBN catalyses the reduction of esters by LiBH,; B-methoxy9-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.