THE PYRAZINES

G. B. Badin THE AUSTRALIAN NATIONAL UNIVERSITY

CANBERRA

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY & SONS

NEW YORK * CHICHESTER * BRISBANE * TORONTO * SINGAPORE

THE PYRAZINES

This is the Forty-First Volume in the Series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

A SERIES OF MONOGRAPHS

ARNOLD WEISSBERGER AND EDWARD C. TAYLOR

Editors

THE PYRAZINES

G. B. Badin THE AUSTRALIAN NATIONAL UNIVERSITY

CANBERRA

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY & SONS

NEW YORK * CHICHESTER * BRISBANE * TORONTO * SINGAPORE

An Interscience@ Publication Copyright 0 1982 by John Wiley & Sons, Inc.

AU rights reserved. Published simultaneously in Canada.

Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc.

Library of Congress Cataloging in Publication Do&:

Barlin, G. B. The pyrazines.

(The Chemistry of heterocyclic compounds ; v. 41) “An Interscience publication.” Includes index. 1. Pyrazine. 1. Title. 11. Series: Chemistry

of heterocyclic compounds ; v. 41.

QD401.B2235 547’.593 81-7569 ISBN 0471-381 19-5 AACR2

10 9 8 7 6 5 4 3 2 1

The Chemistry of Heterocyclic Compounds

The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds.

A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and accommodate the specific interests of the authors.

In order to continue to make heterocyclic chemistry as readily accessible as possible new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwhelming progress. If, however, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edition.

ARNOLD WEISSBERCER Research Luboratories Eastman Kodak Company Rochester, New York

EDWARD C . TAYLOR Princeton University Princeton, New Jersey

This volume summarizes published pyrazine chemistry with emphasis on syntheses, properties, and reactions of pyrazines and pyrazine N-oxides (Chapters I-X). Treatment of theoretical aspects is minimal. Although not strictly relevant, Chapter XI is presented as a summary of earlier reviews and more recent literature of reduced pyrazines (including piperazines). The literature recorded in Beilstein to 1929 and Chemical Abstracts through 1978 (Volume89) has been covered together with selected references to 1980. Whereas every reasonable effort has been made to incorporate most significant material, no attempt has been made to include all relevant data. Tables have been incorporated in the text to extend the range of examples.

The tables in the Appendix provide access to the literature, melting points, and some other physical data for most known simple pyrazines and pyrazine N-oxides.

I have been helped greatly in the collection of the data and in the preparation of this manuscript over several years by many people. Dr. D. J. Brown has generously provided constant advice, assistance, and encouragement, and he has carefully read and advised on the entire text. Professor A. Albert advised in many ways and provided unpublished data. Mrs. Y. Yap, Mrs. Z. Pakulska, Mr. I. Brown, Mr. K. McAndrew, and the late Miss V. Richardson assisted with the collection of published data. Drs. K. Ienaga, T. Nagamatsu, Y. Iwai, and K. Shinozuka helped with trans- lations of Japanese, Dr. H. Stiinzi with German, and Mrs. 2. Pakulska and Professor L. Strqkowski with Polish papers. Drs. W. L. F. Armarego, W. V. Brown, M. D. Fenn, D. D. Perrin, E. Spinner, and Professor B. Stanovnik helped with the provision and interpretation of data. Mesdames S. Schenk, J. White, and D. Dick typed the manuscript and prepared the formulas. To these people, and others not mentioned, I express my gratitude and thanks for their assistance in so many ways.

G . B. BARLIN Canberra. Australia Januory 1982

Contents

I.

1. 2. 3. 4. 5.

11.

1 .

2.

3.

4.

5.

INTRODUCTION TO PYRAZINES

History Occurrence Structure Biological Activity and Uses Nomenclature

PRIMARY SYNTHESES OF PYRAZINES

Self-condensation of a-(Primary Amino) Carbonyl Compounds A. B. C. D. E. F.

C . H.

I.

J. K. L. M. N. 0. P.

Preformed &-Amino Carbonyl Compounds Reduction of a-Hydroxyimino Carbonyl Compounds Ammonolysis of a-Halogeno Carbonyl Compounds Oxidation of &-Amino Alcohols Reduction of &-Amino Acids Reaction of a-Hydroxy Carbonyl Compounds or Polyhydroxy Compounds with Ammonia, Ammonium Salts, or Formamide Reaction of a$-Dicarbonyl Compounds with Ammonia Bisulfite Compounds of a-Hydroxyimino Ketones with Potassium Cyanide Hydrolysis of Acetamidoacetone Derivatives Formed from a-Amino Acids, Acetic Anhydride, and Pyridine Rearrangement of Some Oximes Reduction of a-Azo, &-Diazo, or a-Azido Ketones Hydrolysis of 3-Imidazoiines (Isoxazoles and Oxazoles) 1,2-DicarbonyI Compounds with a-Amino Acids &-Amino Acids through Piperazine-2,5-diones Aldehyde Cyanohydrins Miscellaneous

1

1 4 7 8

10

11

11 12 12 15 18 18

18 20

20

21 22 23 24 25 25 26 27

Condensation of a,&Dicarbonyl Compounds with a,P-Diamino Compounds, etc. 28 Pyrazines from a,fl-Diamino or a$-Diimino Compounds and Reagents

Oxidation of Quinoxalines and Other Fused Pyrazines to Pyrazine-

Cleavage of Pteridines and Related Systems to Pyrazines

other than a,P-Dicarbonyl Compounds 35

carboxylic Acids 37 38

ix

X Con tents

6. 7.

8.

9.

10.

111.

1.

2.

3.

4.

5. 6.

N.

1.

2.

Dehydrogenation of Piperazines Ring Closures Involving the C-C-N-C-C, N-C-C-N-C-C, and N-C-C-N-C-C-N Systems Condensation of a-Bromopropionyl (or a-Bromophenylacetyl) Deriva- tives of Aminomethyl Ketones with Ammonia to Acylaminopyrazines Ring Transformations of Pyridazines and Other Heterocycles to Pyrazines Miscellaneous

PRJMARY SYNTHESES OF PYRAZINE N-OXIDES

2-Aminopyrazine 1Qxides from &-Amino Nitriles and a-Hydroxyimino Carbonyl Compounds 3-Substituted Pyrazine 1-Oxides from 2-Amino-2-deoxy-D-glucose (or Mannose) Oxime with Glyoxal 2-Hydroxypyrazine I-Oxides from a-Arninohydroxamic Acids and 1,2-Dicarbonyl Compounds or a$-Unsaturated a-Bromoaldehydes 2-Hydroxy-3,6-dimethylpyrazine 1-Oxide from the Bisulfite Derivative of Pyruvohydroxamic Acid and Aminoacetone Ring Closure of the C-C-N-C-C-N-O System Miscellaneous

PYRAZINE, ITS C-ALKYL, C-ARYL, ANDN-OXIDE DERIVATIVES

Pyrazine (Unsubstituted) A. Preparation of Pyrazine B. Properties of Pyrazine C. Reactions of Pyrazine C-Alkyl and C-Arylpyrazines A. Preparation of Alkyl- and Arylpyrazines

Alkylation at Nuclear Carbon, 73 Extranuclear C-Alkylation (and Acylation), 74 Decarboxylation of Alkyl Carboxy Pyrazines, 76 Replacement of Halogeno Substituents by Alkyl Groups, 76 Preparations of Particular Methyl-, Dimethyl-, and Vinyl- pyrazines, 76

(1) Primary Syntheses, 72 (2) (3) (4) ( 5 )

(6)

B. Properties of Alkylpyrazines C. Reactions of Alkylpyrazines

(1) Oxidation, 79 (2) Halogenation, 79 (3) Reduction, 80 (4) Alkylation, 8 1

(a) N-Alkylation, 8 1

48

49

53

53 57

59

59

62

63

64 64 66

68

68 68 69 70 72 72

77 79

Contents xi

(b) C-Alkylation, 8 1 (5) Aldol-Type Condensation, 81

(a) Dehydration of Carbinols from Aldol-Type Conden- sations, 82

(6) Mannich Reaction, 83 (7) Vilsmeier Reaction, 83 (8) (9) Ring Transformations, 84

Amination at Ring Carbon and Nitrogen, 83

( 10) Photoeliminations, 84 (1 1) Addition Reactions, 85 ( 1 2) (1 3)

Miscellaneous, 8 5 Reactions of Vinylpyrazine, 86

3. Pyrazine N-Oxides, their C-Alkyl and C'-Aryl Derivatives 86 A. Preparation of Alkyl- and Arylpyrazine N-Oxides by Oxidation 86 B. Properties of Pyrazine N-Oxides and their C-Alkyl Derivatives 86 C. Reactions of Alkylpyrazine N-Oxides 88

(1 ) Halogenation and Deoxygenation, 88 (2) Halogenation, 90 (3) (4) N-Amination, 91 (5) (6) Deoxygenation, 92 (7) Miscellaneous, 93

Rearrangement with Acetic Anhydride, 90

Methyl- to Styrylpyrazine N-Oxides, 92

V. HALOGENOPYRAZINES AND N-OXIDE DERIVATIVES 95

95 95

1. The Preparation of Nuclear Halogenopyrazines A. Direct Chlorination with Chlorine

(1) Simple Cases, 95 (2) (3) In Other Cases, 97

( 1 ) Simple Cases, 97 (2) (3) (4)

(1 ) Simple Cases, 99 (2) (3) (4) (5)

In the Presence of Amino Groups, 96

B. Direct Bromination with Bromine

In the Presence of Amino and Carboxy Groups, 97 In the Presence of Amino and Other Groups, 98 In the Presence of Hydroxy Groups, 98

C. Phosphoryl Chloride with Hydroxypyrazines

In the Presence of Amino Groups, 100 In the Presence of Carboxy Groups, 100 In the Presence of Nitro Groups, 101 From Amino Acid Anhydrides and Piperazinones, 101

D. Chlorinations with Phosphorus Pentachloride 102

F. Brominations with Phosphorus Bromides and Other Reagents 104

H. The Preparation of Fluoropyrazines 110 I. The Preparation of Iodopyrazines 111

E. Chlorinations with Sulfuryl Chloride and Thionyl Chloride 1 03

G . Pyrazine N-Oxides with Phosphoryl Chloride (and Other Acid Chlorides) 105

97

99

Xi i Con tents

J. Interconversion of Halogeno Substituents K. Conversion of Amino to Bromo Substituents L. Primary Syntheses M. Degradation N. Ring Transformations 0. Miscellaneous The Preparation of Extranuclear Halogenopyrazines A. By Direct Halogenation B. By Reaction of N-Oxides with Phosphoryl Chloride C. By Primary Synthesis D. Ring Transformations E. Miscellaneous

N-Oxides A. By N-Oxidation of Halogenopyrazines B. By Direct Synthesis C. By Halogenation D. By Reaction of Pyrazine 1,CDioxide with Phosphoryl Chloride

(and Other Acid Chlorides) 4. Properties of Halogenopyrazines 5 . Reactions of Nuclear Halogenopyrazines

2.

3. The Preparation of Nuclear and Extranuclear Halogenopyrazine

A. Removal of Halogeno Substituents (1 ) By Catalytic Hydrogenation, 121 (2) By Other Methods, 123 Replacement of Halogeno Substituents by Amino Groups ( 1 ) (2) (3) (4) (5 ) (6)

C. Replacement of Halogeno Substituents by Hydrazino, Azido, and Amido Groups

D. Replacement of Halogeno Substituents by Alkoxy Groups (1 ) With One Halogeno Substituent, 133 (2) With One Halogeno and Other Substituents, 134 (3) With Two Halogeno Substituents, 135 (4) With Two Halogeno and Other Substituents, 137 (5) With Three or Four Halogeno Substituents, 137

E. Replacement of Halogeno Substituents by Hydroxyl Groups F. Replacement of Halogeno Substituents by Alkylthio Groups G. Replacement of Halogeno Substituents by Mercapto Groups H. Replacement of Halogeno Substituents with the Formation of a

Carbon-Carbon Bond (except C-CN) I. Replacement of Halogeno Substituents by Cyano, Sulfo, and Silyl

Groups J. Other Reactions

B. With One Halogeno Substituent, 123 With One Halogeno and Other Substituents, 125 With Two Halogeno Substituents, 128 With Two Halogeno and Other Substituents, 128 With Three Halogeno Substituents, 130 With Four Halogeno Substituents, 131

111 112 113 113 113 113 114 114 114 115 115 115

116 116 116 116

119 119 121 121

123

132 133

138 139 141

142

144 145

Contents

Reactions of Extranuclear Halogenopyrazines A. Replacement of Halogeno Substituents by Alkoxy, Hydroxy, and

Alkylthio Groups B. Replacement of Halogeno Substituents by Amines C. Replacement of Halogeno Substituents by Other Groups Reactions of Halogenopyrazine N-Oxides A. Reactions of Nuclear Halogenopyrazine N-Oxides

(1)

(2)

(3)

(4)

(5) Other Reactions, 153 B. Reactions of Extranuclear Halogenopyrazine N-Oxides

( 1 ) Deoxygenation, 154 (2) Replacement of Halogeno Substituents by Triphenyl-

phosphine, 154 (3) Replacement of Halogeno Substituents by

Other Groups, 155

Replacement of Halogeno Substituents by Amino Groups, 149 Replacement of Halogeno Substituents by Hydroxy Groups, 150 Replacement of Halogeno Substituents by Other Groups, 151 Reactions Involving Removal of Halogeno Substituents and/ or the N-Oxide Function, 152

VI. HYDROXYPYRAZINES AND THEIR DERIVATIVES

1.

2.

3.

Preparation of Hydroxypyrazines A. By Primary Synthesis B. By Hydrolysis of Halogenopyrazines C. From Aminopyrazines D. From Alkoxypyrazines E. From Methylsulfonyl- and Methylsulfinylpyrazines F. By Hydrolysis of Acetoxypyrazines G. By Hydrolysis of Other Substituted Pyrazines H. By Other Reactions Preparation of Extranuclear Hydroxypyrazines A. By Primary Synthesis B. From Halogenopyrazines C. From Carboxylic Acid Derivatives D. From Alkylpyrazine N-Oxides with Acetic Anhydride Followed

by Hydrolysis E. From Alkylpyrazines with Aldehydes and Ketones F. By Other Reactions Preparation of Alkoxy- and Aryloxypyrazines A. From Halogenopyrazines B. By Alkylation of Hydroxypyrazines C. From Aminopyrazines

X i i i

145

145 147 148 149 149

156

156 156 157 158 160 161 162 162 163 164 1 64 165 165

166 166 167 168 168 168 169

xiv

4. 5 . 6.

7. 8. 9.

10.

11.

12. 13. 14.

Contents

D. By Dehydrogenation E. From Other Ring Systems F. By Other Reactions Preparation of Extranuclear Alkoxypyrazines Properties and Structure of Hydroxy- and Alkoxypyrazines Reactions of Hydroxypyrazines A. Conversion to Halogenopyrazines B. Conversion to Mercaptopyrazines C. Bromination of Hydroxypyrazines D. Alkylation of Hydroxypyrazines E. Nitration and Coupling With Diazonium Salts F. Other Reactions of Hydroxypyrazines Reactions of Extranuclear Hydroxypyrazines Reactions of Alkoxypyrazines N-Alkylated Oxodihydropyrazines A. Preparation

(1 ) By Primary Synthesis, 184 (2) (3) (4)

( 5 ) By Other Means, 185

By Alkylation of Hydroxypyrazines, 184 By Rearrangement of Alkoxypyrazines, 184 By Oxidation of N-Alkyl (or Aryl) piperazinones with Phosphorus Pentachloride, 1 84

B. Properties and Reactions Preparation of Hydroxypyrazine N-Oxides and Extranuclear Hydroxy- pyrazine N-Oxides A. By Primary Synthesis B. By N-Oxidation C. By Hydrolysis of Halogenopyrazine N-Oxides D. From Aminopyrazine N-Oxides E. From Alkoxypyrazine N-Oxides F. By Other Means Preparation of C- and N-Alkoxypyrazine N-Oxides A. From Halogenopyrazine N-Oxides B. By Oxidation C. By Alkylation D. By Other Means Preparation of 4-Alkyl-3-0~0-3,4-dihydropyrazine 1-Oxides Properties and Structure of Hydroxy- and Alkoxypyrazine N-Oxides Reactions of Hydroxypyrazine N-Oxides A. Chlorination and N-Deoxygenation with Phosphoryl Chloride B. Acetoxylation in Conjunction with N-Deoxygenation C. N-Deoxygenation D. Alkylation E. Other Reactions

15, Reactions of C- and N-Alkoxypyrazine N-Oxides

169 170 170 172 172 175 175 175 175 175 179 180 181 182 1 84 184

185

186 1 86 187 187 188 188 188 189 189 189 190 190 190 191 191 191 192 192 193 1 94 1 94

Contents

Vll. MERCAPTOPYRAZINES AND THEIR DERIVATIVES

xv

1 96

1. Preparation of Mercaptopyrazines A. From Halogenopyrazines B. From Hydroxypyrazines C. By Degradation Preparation of Alkylthio- and Arylthiopyrazines A. By Alkylation of Mercaptopyrazines B. From Halogenopyrazines C. D. By Other Reactions Structure and Properties of Mercapto- and Alkylthiopyrazines

2 .

By Cleavage of Pteridines and Other Ring Systems

3. 4. Reactions of Mercaptopyrazines 5. Reactions of Alkylthiopyrazines

A. Oxidation of Alkylthiopyrazines B. Displacement of Alkylthio Substituents Dipyrazinyl Disulfides and Sulfides; Pyrazinesulfonic Acids

A. Preparation B. Properties C. Reactions

6. 7. Alkylsulfonyl- and Akylsulfinylpyrazines

8. Other Derivatives of Mercaptopyrazines

VIII. AMINOPYRAZINES, THEIR N-OXIDES, AND RELATED NITROGENOUS DERIVATIVES

196 196 196 196 197 197 198 198

198 200 200 200 201 202 202 202 203 203 204

205

205 205

1. Aminopyrazines A. Preparation of Aminopyrazines

(1) By Primary Synthesis, 205 (2) By Direct Amination, 207 (3) From Halogenopyrazines, 207 (4) From Mercapto-, Alkylthio-, Alkylsulfonyl-, and Alkyl-

(5) From Carbamoylpyrazines, 207 (6)

(7) (8) By Other Methods, 210

(1) By Reduction of a Nitrile, Imine, or Hydroxyamino Compound, 2 1 1

(2) By the Mannich Reaction, 2 12 (3) From Halogenopyrazines, 2 12 (4) From Amides by the Hofrnann Reaction, 2 12 (5 ) By Other Reactions, 2 12

sulfinylpyrazines, 207

From Acid Azides and Hydrazides and Urethanes (Alkoxy- carbonylarninopyrazines), 208 By Reduction of Nitro- and Phenylazopyrazines, 209

B. Preparation of Extranuclear Aminopyrazines 21 1

XVi Contents

C. Properties of Aminopyrazines D. Reactions of Aminopyrazines

( 1 )

(2) Replacement of Amino (and Hydrazino) by Halogeno

(3) (4)

Replacement of Amino by Hydroxy and Alkoxy Groups, 2 15

Substituents, 2 15 Formation of A d s (Schiff Bases), 21 5 Acyl Derivatives of Aminopyrazines, 2 15 (a) Acetylation, 2 15 (b) Formylation, 2 17 (c) (d) (e) Arylsulfonamidopyrazines, 2 18

Bicyclic Heterocycles from Aminopyrazines, 220

(a) Halogenation, 220 (b) Replacement of Hydrazino Substituents by Hydrogen, 232

Benzoylation and Other Acylations, 217 Deacylation of Acylaminopyrazines, 2 17

(5) Diazotization, 220 (6) (7) C-Substitution of Aminopyrazines, 220

Nuclear and Extranuclear C-Alkylation, 220 (8) (9) Other Reactions, 232

E. Urethanes (Alkoxycarbonylaminopyrazines) F. Ureidopyrazines G. Other Substituted Aminopyrazines

(1 ) Dirnethylaminomethyleneamines, Hy droxyiminomethylamines, and Alkoxymethyleneamines, 235

(2) Chloroamines, 236 (3) Extranuclear Quaternized Pyrazines, 236 (4) Guanidinopyrazines, 237

2. Nitro- and Phenylazopyrazines A. Preparation of Nitropyrazines B. Reactions of Nitropyrazines C. Preparation of Arylazopyrazines D. Reactions of Arylazopyrazines

A. Preparation of Aminopyrazine N-Oxides 3. Aminopyrazine N-Oxides

(1) By Primary Synthesis, 239 (2) (3) From Halogenopyrazine N-Oxides, 239 (4) (5 ) By Other Methods, 241

Cleavage of N-Oxides of Pteridines and Related Systems, 239

By Oxidation of Aminopyrazines, 241

B. Properties of Aminopyrazine N-Oxides C. Reactions of Aminopyrazine N-Oxides

(1) (2) Acetylation and Deacetylation, 242 (3) (4) Deoxygenation, 243 (5)

(6) Other Reactions, 245

Replacement of Amino by Hydroxy Groups, 242

Bicyclic Compounds from Aminopyrazine N-Oxides, 243

Deoxygenation with Formation of Chloro-, Acetoxy-, and Methoxypyrazines, 245

213 215

234 234 235

237 237 237 239 239 239 239

242 242

Contents

IX. THE PYRAZINECARBOXYLIC ACIDS AND RELATED DERIVATIVES

xvii

247

247 247

1. The Carboxypyrazines A. Preparation of Carboxypyrazines

(1) By Primary Synthesis, 247 (2) By Hydrolysis of Esters, Amides, and Nitriles, 247

(a) Pyrazine Esters, 247 (b) Pyrazine Amides, 248 (c) Pyrazine Nitriles, 249 By Oxidation of Alkyl-, Styryl-, Hydroxyalkyl-, and Fused Pyrazine Systems, 250

(3)

(4) By Other Methods, 252 B. Properties of Carboxypyrazines 252 C. Reactions of Carboxypyrazines 253

(1) Decarboxylation, 253 (2) Ekterification, 258 (3) (4) (5) Other Reactions, 262

2. Alkoxycarbonylpyrazines (Pyrazine Esters)

Formation of Acid Chlorides, 260 Formation of Anhydrides and Their Reactions, 260

A. Preparation of Esters (1 ) By Primary Synthesis, 264 (2) (3) (4) (5) From Halogenopyrazines, 265 (6) By Other Methods, 265

By Esterification of Carboxypyrazines, 264 From Acid Chlorides and Anhydrides, 264 By Hydrolysis of lminoethers (and Iminothioethers), 265

B. Properties of Esters C. Reactions of Esters

( 1 ) Hydrolysis, 266 (2) Formation of Amides and Related Compounds, 266

(a) Amides, 266 (b) Hydrazides, 269 (c) N-Hydroxamides (Hydroxamic Acids), 270 (d) N-Cyanamides, 270 (e) Guanidinocarbonylpyrazines, 270 (f) Guanidinocarbamoyl- and Amidinocarbonylguanidino-

carbonylpyrazines, 272 (9) Ureidocarbonylpyrazines, 2 72

(3) Reduction, 272 (4) Formation of Ketones, 274 (5) Other Reactions, 274

3. Carbamoylpyrazines (Amides) and Related Compounds (Hydrazides, Azides, etc.) 275 A. Preparation of Amides 275

(1) (2) By Primary Synthesis, 276 (3) (4) By Other Means, 278

From Esters, Acid Chlorides, and Acids, 275

By Partial Hydrolysis of Nitriles, 276

264 264

266 266

Xvi i i Contents

B. Properties of Carbamoylpyrazines C. Reactions of Amides

(1) (2) Transamination of Amides, 280 (3) Other Reactions, 281

D. Preparation and Reactions of Thioamides E. Hydrazides and Azides

(1) Preparation, 283

Dehydration of Amides to Nitriles, 279

(a) From Esters, 283 (b) From Amides, 283 (c) From Acids, 283 (d) From Nitriles, 284 Reactions of Hydrazides and Azides, 284 (2)

F. Preparation of Guanidinocarbonyl-, Guanidinocarbamoyl-, and Ureidocarbonylpyrazines 281

4. Pyrazine Nitriles 288 A. Preparation of Cyanopyrazines 288

( 1) (2) (3) From Halogenopyrazines, 289 (4) By Other Methods, 289

By Primary Synthesis, 288 By Dehydration of Amides, 289

B. Properties of Nitriles 289 C. Reactions of Cyanopyrazines 290

( I ) With Hydrazine, 290 (2) With Alcohols (and Thioalcohols) and Hydrogen

Chloride, 290 (3) With Amines, 292 (4) With Grignard Reagents, 293 (5) With Alkoxide Ions, 293 (6) Other Reactions, 294

Pyrazine Aldehydes and Their Acetals A. Preparation of Formylpyrazines

(1) By Primary Synthesis, 294 (2) By C-Formylation, 295 (3) By Oxidative Processes, 295 (4) By Reductive Processes, 295 (5) From Hydrazides, 295 (6) By Other Methods, 295

B. Reactions of Formylpyrazines (1) Oxidation and Reduction, 296 (2)

5.

Formation of the Usual Aldehyde Derivatives, 296 6. Pyrazine Ketones and Derivatives

A. Preparation of C-Acyl Derivatives ( I ) By Primary Synthesis, 297 (2) From Methylpyrazines, 298 (3) From Cyanopyrazines, 298 (4) By Oxidation, 298 (5) (6) By Other Methods, 299

From Acid Chlorides and Esters, 299

278 279

282 283

294 294

296

297 297

Contents

B. Properties of Acetylpyrazines C. Reactions of C-Acylpyrazines Isocyanato- and Thiocyanatopyrazines Carboxypyrazine N-Oxides A. Preparation of Carboxypyrazine N-Oxides

(1) By Primary Synthesis, 302 (2) (3) By Oxidation, 302

( 1 ) Decarboxylation, 303 (2) Esterification, 303 (3) Deoxygenation, 303 (4) Other Reactions, 303

Alkoxycarbonylpyrazine N-Oxides A. Preparation B. Reactions Carbamoylpyrazine N-Oxides and Related Compounds (Hydrazides, Guanidinocarbonyl Compounds, etc.) A. Preparation of Carbamoylpyrazine N-Oxides

By Primary Synthesis, 305

By Partial Hydrolysis of Nitriles, 305

B. Reactions of Carbamoylpyrazine N-Oxides C.

Cyanopyrazine N-Oxides A. Preparation B. Reactions C. Properties Formyl- and Acetylpyrazine N-Oxides and Derivatives A. Preparation B. Reactions

By Hydrolysis of Amides and Esters, 302

B. Reactions of Carboxypyrazine N-Oxides

( 1) (2) From Esters, 305 (3) (4) By Oxidation, 305

Preparation and Reactions of Hydrazinocarbonyl-, Guanidinocarbamoyl-, and Guanidinocarbonylpyrazine N-Oxides

xix

300 300 301 302 302

7. 8.

9.

10.

11.

12.

X.

1. 2. 3. 4.

XI.

1.

THE IONIZATION AND SPECTRA OF PY RAZINES

Ionization of Pyrazines Ultraviolet Spectra of Pyrazines Nuclear Magnetic Resonance Spectra of Pyrazines Infrared, Mass, and Other Spectra of Pyrazines

THE REDUCED PYRAZINES

Di- and Tetrahydropyrazines A. 1,2-Dihydropyrazines

303

3 03 303 304

3 05 3 05

306

3 07 308 308 308 308 3 08 308 3 09

3 10

310 3 14 328 338

344

344 344

xx Contents

(1) Preparation, 344 (2) Reactions, 347

B. 2,3-Dihydropyrazines ( I ) Preparation, 348 (2) Reactions, 349

C. 2,s-Dihydropyrazines (1) Preparation, 352 (2) Reactions, 354

D. 1,4-hhydropyrazines (1) Preparation, 355 (2 ) Reactions (and Properties), 357

E. Tetrahydropyrazines ( 1 ) Preparation, 358 (2) Reactions, 361

F. Dihydropyrazine N-Oxides ( 1 ) Preparation, 362 (2) Reactions, 363

2. Piperazinones A. Piperazin-?-ones

( 1 ) Preparation, 363 (2) Reactions, 365

B. Piperazine-2,3-diones C. Piperazine-2,s-diones

( 1 ) Preparation, 366 (2) Reactions, 367

D. Piperazine-2,6-diones (1) Preparation, 369 (2) Reactions, 371

E. Piperazine-2,3,5-triones and Piperazinetetraones F. Piperazinethiones

A. Preparation B. Properties C. Reactions

3. Piperazines

APPENDIX: SYSTEMATIC TABLES OF SIMPLE PYRAZINES

Introduction Pyrazines Excluded from the Tables Terms Used in the Tables Use of the Tables Table A. 1 Table A.2 Aminopyrazines Table A.3 Carboxypyrazines Table A.4 Halogenopyrazines Table A S

Alkyl- and Arylpyrazines

Oxypyrazines without C- or N-Alkyl Groups

348

352

355

3 58

362

363 363

3 66 366

369

372 3 72 3 72 3 72 3 76 377

382

3 82 382 382 383 3 84 387 392 399 402

Table A.6 Table A.7 Table A.8 Table A.9 Table A.10 Table A.ll Table A.12 Table A. 1 3 Table A. 14 Table A. 1 5 Table A. 16 Table A. 17 Table A. 1 8

Table A. 19 Table A.20

Table A.2 1 Table A.22 Table A.23 Table A.24 Table A.25

Table A.26 Table A.27 Table A.28 Table A.29 Table A.30 Table A.3 1 Table A.32 Table A.33 Table A.34 Table A.35

Contents

Oxypyrazines with C- but without N-Alkyl Groups Oxypyrazines with Any N-Substituent Suifonylpy razines Thiopyrazines Aminocarboxyp yrazines Amino-halogenopyrazines Amino-oxypyrazines Amino-thiopyrazines Aminocarboxyl-halogenopyrazines Aminocar boxy -oxy py razines Aminocarboxy -sul fon ylp yrazines Amino-carboxy-thiopyrazines Amino-halogenopyrazines with Other Functional Groups Except Carboxy Amino-oxythiopyrazines Aminocarboxy-halogenopyrazines with Other Functional Groups Carboxy-halogenopyrazines Carboxy-oxypyrazines Carbox y -sul fon y Ip yrazines Carboxy-thiopyrazines Carboxy-halogenopyrazines with Other Functional Groups Except Amino Halogeno-nitro(and 0xy)pyrazines Halogeno-sulfonyl(and thio)pyrazines Nitro-oxy pyrazines Oxy -sulfonyl(and thio)pyrazines Alkyl- and Arylpyrazine N-Oxides Aminopyrazine N-Oxides Carboxypyrazine N-Oxides Halogenopyrazine N-Oxides Oxypyrazine N-Oxides Thiopyrazine N-Oxides

REFERENCES

AUTHOR INDEX

SUBJECT INDEX

xxi

404 408 409 409 410 420 422 423 424 43 5 436 436

436 437

437 438 440 442 442

443 443 446 446 447 447 448 45 1 452 453 456

457

509

577

CHAPTER I

Introduction to Pyrazines 1. HISTORY

The first recorded synthesis of a pyrazine (1) was that of tetraphenylpyrazine by Laurent ( 1 ) in 1855. In this preparation a-phenyla-(benzylideneamino)acetonitrile, PhCH=NCHPhCN (“benzoylazotid,” prepared from crude benzaldehyde, that is, benzaldehyde containing some hydrogen cyanide, by treatment with ammonia), was subjected to dry distillation to give(1, R’ = RZ = R3 = R4 = Ph), which Laurent called “amarone” [Table 1.1 lists the names assigned by early workers (1-14) to some simple pyrazines] . Tetraphenylpyrazine was also prepared by Erdmann (1 1) from the reaction of ammonia on benzoin, but on this occasion it was named “benzoinimide.”

TABLE 1.1 NAMES ASSIGNED TO SOME SIMPLE PYRAZINES BY EARLY WORKERS

Pyrazine Name Refs.

Unsubstituted Pyrazine Aldine Piazine Paradiazine

2,s-Dimethyl Ketine Glycolin

2,s-Diphenyl Isoindol Tetraphenyl Amarone

Benzoinimide Ditolanazotide Tetraphen ylazine Te traphenylpyrazine

293 4 5.6 5.6 7 , 8 9

10 1

11 12 13 14

2,5-Diphenylpyrazine (1, R’ = R3 = Ph, Rz = R4 = €3) was the second pyrazine synthesized, and it was prepared by Staedel and Rugheimer (10) in 1876 by the action of ammonia on w-chloroacetophenone and was named “isoindol.” These authors postulated the first structure for a pyrazine as an inner anhydride (2) of an amino ketone.

Alkylpyrazines were then described in a series of papers from Victor Meyer’s laboratory at Zurich. Gutknecht (15, 16) examined the reduction of the monoxime of diacetyl (then thought to be a true nitroso derivative of ethyl methyl ketone,

1

2 Introduction to Pyrazines

+VCH2 + H20

PhCOCH,NH, -Ph-C

(2) “Isoindol”

from which it was derived with nitrous acid) with tin and hydrochloric acid to give tetramethylpyrazine, which was also assigned the formula of an inner anhydride of the amino ketone. Treadwell (8) found from vapor density determinations on the analogous product from methyl propyl ketone that the molecular weight was about twice that which would be expected from an inner anhydride, and by analogy with the reduction of acetone to pinacol, Treadwell assigned the formula (3) to the product. He and Meyer (7,8) also proposed the name “ketine” for the product (2,5-dimethylpyrazine) derived from acetone, and dimethylketine and diethylketine for those derived from ethyl methyl ketone and methyl propyl ketone, respectively.

Meanwhile h a r d (9) in 188 1 found that 2,5-dimethylpyrazine (which he termed “glycolin”) could be isolated from the heating of a mixture of glycerol and an ammonium salt.

Meyer (17) in the following year then expressed the view that the products of the action of nitrous acid on the ketones were not true nitroso compounds (4) but isomeric oximes (S), and he considered their reduction to be analogous to the conversion of a nitro to amino group, rather than that of ketone to pinacol. There- after the Treadwell formulation of pyrazines was abandoned.

Me Me

Wleugel (1 8), who examined the reduction of (iso) “nitrosoacetic acid” ester (from ethyl acetoacetate and nitrous acid) to the diethyl ester of dicarboxydi- methylpyrazine (“ketinedicarboxylic acid”), was the first to propose for the pyrazine nucleus a six-membered ring structure analogous to pyridine, in which one -CH= group para to the ring nitrogen was replaced by another ring nitrogen atom. However, the position of substituents assigned by Wleiigel was in error. Oeconomides (19) reported that Wleiigel’s product (7) did not form an anhydride, as would be expected for an o-dicarboxylic acid, and he claimed its identity by a synthesis from “iminoisonitrosobutyric ester” (6) by heating with fused zinc chloride. Hinsberg (20) had also recently shown that quinoxaline could be synthesized from o-phenylenediamine and glyoxal.

The reaction of ammonia on benzoin described by Erdmann was reinvestigated by Japp and Wilson (12) and Japp and Burton (13) and the product, tetraphenyl- pyrazine, renamed “ditolanazotide” and “tetraphenylazine,” respectively.

History 3

Me NCOOEt HON=C

Z”CI1 ‘c-NH

____) I + I C = NOH HN=C

EtOOC’ ‘Me

M e ~ ~ , c m E t + N, + 2H,O EtOOC Me

(7)

In 1887 two workers, Mason (2) and Wolff (3), independently suggested the name “pyrazine” for the nucleus to point out the analogy with pyridine, but the name had been used in the same year by Knorr (21) for pyrrole tetrahydride, and Braun and Meyer (4), in objecting(t0 pyrazine), proposed the name “aldine” because it would result from self-condensation of the hypothetical aminoacetaldehyde. Widman (5) then clarified the situation with a systematic nomenclature for azines. Compounds containing a six-membered ring consisting of two nitrogen and four carbon atoms were called diazines; these were further classified into o-diazines, m-diazines, and p-diazines according to whether the nitrogen atoms were ortho, meta, or para, respectively. These names were also condensed to oiazine, miazine, and piazine. Although the name “piazine” was promoted by Mason (6), it did not gain acceptance and the term pyrazine has since been employed.

Proof of the structure of the pyrazines was established in 1893 by Wolff (22) , who converted tetramethylpyrazine to piperazine (8) by the series of reactions shown. The conversion of a-amino ketones to pyrazines requires the loss of hydrogen as well as the loss of water. Gabriel and Pinkus (23) obtainedconsiderably higher yields when oxidizing agents were added to the reaction mixture after the condensation had been allowed to take place. Snape and Brooke (14) in 1897 established that “amarone” was identical with benzoinimide, ditolanazotide, tetraphenylazine, and tetraphenylpyrazine.

H

Q H

4 Introduction to Pyrazines

The bond structure of pyrazines had yet to be established. Kekule type ( 9 ) and Dewar type (10) formulas were each proposed and supported by various groups (24-28), but the Kekule structure was finally selected after a study of molecular refractions of a number of pyrazine derivatives by Bruhl(29).

The parent compound of this series, pyrazine, was first prepared in trace amounts by Wolff (30) by heating aminoacetaldehyde diethyl acetal [H2NCH2CH(OEt),] with anhydrous oxalic acid at 1 10-190°C, and later in better yield by heating the mercuric or platinic chloride double salts (of the aminoacetaldehyde acetal) with hydrochloric acid (3 1); it was also obtained from aminoacetaldehyde with mercuric chloride in sodium hydroxide (23). Wolff in 1893 (22) also prepared pyrazine by decarboxylation of the tetracarboxylic acid, obtained by oxidation of tetramethyl- pyrazine; and Stoehr (32) prepared it by the distillation of piperazine with lime and zinc dust. Brandes and Stoehr (33) in 1896 described the preparation of pyrazine by heating glucose with 25% aqueous ammonia at 100°C.

Significant reviews of pyrazine chemistry have been published by Newbold and Spring (34), Krems and Spoerri (39, Pratt (36), Ramage and Landquist (37), NovhEek et al. (38), Cheeseman and Werstiuk (39), and Sasaki (39a).

2. OCCURRENCE

Pyrazines occur in nature in relatively small quantities, and the introduction in the early 1960s of coupled gas-liquid chromatography - mass spectrometry assisted greatly in the isolation and identification of these compounds. Some sources are described below. Fuse1 oils contain 2,5-dimethyl-, 2,5-diethyl-, trimethyl-, tetramethyl-, and triethylmethylpyrazine (33, 40-44), and it is probable that these compounds are produced from proteins during the fermentation. Ammoniations of inverted molasses have been found to give 2,6-dimethylpyrazine, 2-hydroxymethyl- pyrazine, 5 -hydroxy -2-me t hylp yrazine, and 2-methyl-5 (and 6)-(~rabo-tet rahy droxy- buty1)pyrazines (45-47); and D-glucose with aqueous ammonia gives a complex mixture from whch 2-methyl-5[and 6(?)]-(arabo-tetrahydroxybutyl)pyrazine have been isolated and identified (48). Galbanum oil has been shown to contain various alkyl- and methoxyalkylpyrazines (49,50). Cocoa butter and cocoa beans contain 2,3dimethylpyrazine, 2-ethyl-5-methylpyrazine, trimethylpyrazine, 3-ethyl-2,5- dimethylpyrazine, 2-ethyl-3,5-dimethylpyrazine, and tetramethylpyrazine; the pyrazine content appeared to be greatest in samples from countries where beans were traditionally fermented (5 1,52). Tetramethylpyrazine was the only pyrazine detected in unroasted beans, and then only in fermented samples.

A large number of alkyl- and vinylpyrazines have been identified in coffee (53),

Occurrence 5

17 alklypyrazines have been identified in the products of pyrolysis of water-soluble components of fresh beef (54), and 33 pyrazines have been identified in flavor concentrates isolated from beef cooked superatmospherically at 162.7”C (55). Tetramethylpyrazine has been isolated from “natto,” obtained from fermented soy(a) bean (56), and the volatile compounds of Emmentaler and Gouda cheeses have been found to contain alkylpyrazines (57,58).

Three extremely odorous pyrazines, 3-isopropyl-2-methoxypyrazine, 2-s-butyl- 3-methoxypyrazine, and 2-isobutyl-3-methoxypyrazine have been shown to be present in green peas, and are likely t o be of major significance in the flavor of peas (59). The volatile oil of green bell peppers has been found to contain 2-isobutyl- 3-methoxypyrazine as a major component (60,6 1). The alkylpyrazines in potato chips (62,63) and roasted peanuts (63) have been examined. 2-Isopropyl-3- methoxypyrazine has been characterized in the vacuum steam volatile oil of potatoes (64), 2ethyl-3-methoxypyrazine in cooked potato (65), and 3ethyl-2,S- dimethylpyrazine and 2-ethyl-3,S-dimethylpyrazine as the components important t o the aroma of baked potato (66). A variety of alkylpyrazines have been identified in roasted sesame seeds (67); and 21 pyrazines have been identified in the aroma components isolated from roasted green tea (68).

A review listing the extensive occurrence of pyrazines (mostly alkylpyrazines) in foods and a discussion of the theories of pyrazine formation has been published by Maga and Sizer (69), and a review of the natural occurrence and mass spectra of pyrazines by Brophy and Cavil1 (69a).

3-Isopentyl-2,5-dimethylpyrazine, 2,5-dimethyl-3-propylpyrazine and the (2) and (a isomers of 2,5-dimethyl-3-styrylpyrazine have been characterized in the heads of Argentine ants (70,71). Mandibular gland secretions of the ponerine ants Odontomachus hastatus, 0. clarus, and 0. brunneus have been shown to contain alkylpyrazines; 3-isopentyl-2,5-dimethylpyrazine has been demonstrated in 0. hastatus and 0. clarus, and 3 ,S-dimethyl-2pentyl-, -butyl-, -propyl-, and -ethyl- pyrazines in 0. brunneus (72). 3-lsopentyl-2,5-dimethylpyrazine is also the main constituent in the mandibular gland secretions of workers of Hypoponera opucior and Ponera pennsylvunicu (73). See also reference (74a).

Metasternal gland secretions from the cerarnbycid beetle have been found to contain 3 -isopen tyl-2,s -dime th ylpyrazine (principally) and the 3-propy1, 3 -bu tyl, 3-penty1, and 3{2’-methylbutyl) analogues as major components in one genus, and as minor components in several other genera (74b).

Recent work has shown the presence of pyrazine and 2,6-dimethylpyrazine in leek ( 7 9 , pyrazine and alkylpyrazines in the volatile constituents of tamarind (76), five alkylpyrazines in soong-neung (extract of cooked and roasted rice) (77) and in shoyu (soy sauce) (78), and alkylpyrazines in white bread (79). Murray and Whitfield (80) have examined vegetable tissue for 2-isopropyl-, 2+butyl-, and 2-isobutyl-3methoxypyrazines and observed at least one of these compounds in 23 of the 27 samples studied. 2-Methylpyrazine and 2,5- and 2,6-dimethylpyrazines have been determined in black tobacco and in the smoke of nonfilter cigarettes made from these tobaccos (8 1).

Pyrazines are produced by certain molds. Thus White (82) and White and Hill

6 Introduction to Pyrazines

(83) first reported the isolation of the bactericidal antibiotic aspergillic acid from a strain of Aspergillus flavus, and after much work (84-93), its structure proved to be 6+butyl-2-hydroxy-3-isobutylpyrazine 1 -oxide (1 1). Hydroxyaspergillic acid was isolated also from cultures of A. flaws grown on a medium containing brown sugar (84) and its structure was established later as 2hydroxyd-(l '-hydroxy-1 '- methylpropyl)-3-isobutylpyrazine 1-oxide (12) (94); further work by Dunn et d. (95) led to the discovery of flavacol, 3-hydroxy-2,5-diisobutylpyrazine (13), in culture filtrates of A.flavus. Macdonald (96) has also studied the production of pyrazines by A. flavus. Neohydroxyaspergillic acid (97,98), 2-hydroxy-6- (1 '-hydroxy-2'-methylpropyl)-3-isobutylpyrazine 1 -oxide (14), and 2-hydroxy- 3,6diisobutylpyrazine 1-oxide (15) (98) have been isolated from cultures of A. sclerotiorum; and the pigment pulcherrimin, produced by the yeast OIndida pulchem'ma (Linder) Windisch, has been shown to be a polymeric ferric ion complex of pulcherriminic acid (16) or the tautomer (17) (99-101). Nakamura (102) isolated muta-aspergillic acid (a growth inhibitant against hiochi-bacilli) from culture filtrates of A. o y z a e and determined its structure as 2hydroxy-6- (l'-hydroxy-l'-methylethyl)-3-isobutylpyrazine 1-oxide (18) (103, 104); and A. otyzae A21 grown in media containing 0.05M valine and 0.01M isoleucine gave 3-s-butyI-2-hydroxy-6-isopropylpyrazine l-oxide (104a). Tetramethylpyrazine has been obtained from a strain of Bacillus subtifis (105) and from B. natto (106), and emimycin, 3-hydroxypyrazine 1-oxide (19), has been isolated from the broth of Sneptomyces No 2020-1 (107, 108).

EtMeCH t~cH2cme2 4 OH

0

(1 1)

Bu' Ax:H

0 t

HO Bu'

0 (16)

I

MeCH

Y q H 2CHMe2

2-7 OH 4

OH 0

(12)

OH

0 (14, R = CH Pr'OH)

(15, R = Bu')

OH I

HO Bu'