FUSED PYRIMIDINES Part Three

PTERIDINES

D. J. Brown The Research School of Chemistry The Australian National University

Canberra

AN INTERSCIENCE@ PUBLICATION

JOHN WlLEY & SONS

NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

FUSED PYRIMIDINES

Part Three

This is a part ojrhe twenty-fourth volume in rhc series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

A SERIES OF MONOGRAPHS

EDWARD C. TAYLOR, Editor

ARNOLD WEISSBERGER, Founding Editor

FUSED PYRIMIDINES Part Three

PTERIDINES

D. J. Brown The Research School of Chemistry The Australian National University

Canberra

AN INTERSCIENCE@ PUBLICATION

JOHN WlLEY & SONS

NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

An Interscience@ Publication

Copyright @ 1988 by John Wiley Rr Sons. Inc.

All 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 Coogresa Cataloging-in-Publiitioa Data (Revised for volume 24, part 3)

Fused pyrimidines. (The Chemistry of heterocyclic compounds ; v. 24,

“An lnterscience publication.” Includes bibliographies. Contents: pt. 1. Quinazolines, by W. L. F.

PI. 3)

Armarego-pt. 2. Purines, by J. H. Lister- - pt. 3. Pteridines, D. J. Brown.

D. J., ed. 11. Series. I. Pyrimidines-Collected works. I. Brown,

QD401.F96 547.593 68-4274 ISBN 0-471-83041-0 (PI. 3) ISI3N 13: 978-0-471-83041-2

1 0 9 8 7 6 5 4 3 2 1

Dedicated to Four Greut Liviny Pteridine Chemists

Adrien Albert Wolfgang Pfleiderer

Edward C. Taylor Max Viscontini

This Page Intentionally Left Blank

Foreword to Fused Pyrimidines

Originally, it was intended to present all the fused pyrimidine systems in one book within this series. However, resurgence of interest in quinazolines and purines, the rapid development of pteridine chemistry, and ever widening exploration of a great many new fused systems embracing the pyrimidine ring, made such a task impossible.

Accordingly, the fused pyrimidine systems will now be covered as several distinct parts of the twenty-fourth volume of the series, Dr. Armarego’s Quin- azolines appeared as Part 1 in 1967; Dr. Lister’s Purines followed as Part 2 in 1971, with a supplementary work (to cover much subsequent research) in preparation; the current work on Preridines appears as Part 3 after a substantial delay resulting in a change of authorship as late as 1984; and Part 4, covering the more important of the remaining fused pyrimidine systems, is in active prep- aration.

It has been a privilege to assist the late Dr. Weissberger, Dr. Taylor, and individual authors in organizing this project on fused pyrimidines and in main- taining a measure of uniformity and balance within its parts.

DES BROWN The Australian National Unioersity Canberra, Australia

vii

This Page Intentionally Left Blank

The Chemistry of Heterocyclic Compounds Introduction to the Series

The chemistry of heterocyclic compounds is one of the most complex and intriguing branches of organic chemistry. It is of equal interest for its theoretical implications, for the diversity of its synthetic procedures, and for the physio- logical and industrial significance of heterocyclic compounds.

The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger's death in 1984, under our joint editorship, has attempted to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has dealt with syntheses, reactions, proper- ties, structure, physical chemistry and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, three- membered ring systems). This series has become the basic reference collection for information on heterocyclic compounds.

Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance which impinge on almost all aspects of modern organic and medicinal chemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes were intended to be of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry.

I t has become increasingly clear that this arbitrary distinction creates as many problems as it solves, and we have therefore elected to discontinue the more recently initiated series General Heterocyclic Chemistry, and to publish all forthcoming volumes in the general area of heterocyclic chemistry in The Chemistry of Heterocyclic Compounds series.

Departmrnl o/ Chemistry Princeton Unimrsity Princeton, New Jersey 08544

EDWARD C. TAYLOR

i X

This Page Intentionally Left Blank

Preface

This is the first attempt to present the detailed chemistry of pteridines as a book, although biochemical, biological, and even a few chemical aspects of pteridines have been well served in The Biochemistry of Folic Acid and Related Pteridines (R.L. Blakley: North-Holland, Amsterdam, 1969) and more recently in the several volumes of Folutes and Pterins, (R.L. Blakley and S.J. Benkovic, Eds. Wiley, New York, 1984).

The present work is intended as a critical review of pteridine chemistry with emphasis on practical rather than theoretical aspects. The literature from the earliest days until mid-I987 has been used to illustrate syntheses, properties, and reactions but no attempt has been made to include all relevant data, either in the text or in the interspersed tables, which simply serve to diversify the examples succinctly. However, it should be noted that Table XI is intended as a complete catalog of known pK, values for pteridines; likewise the Appendix Table represents an effort to list alphabetically all simple pteridines (as defined at the head of the table and described up to mid-1987), along with some indication of physical data available and a selection of references to such data and to preparation(s). The enormous gaps in our knowledge of pteridine chemistry will be all too evident to readers of this book: I t is hoped that some may be stimulated to remedy the situation.

The widespread appeal of pteridine chemistry is indicated by the following analysis of the origins of more than 17 hundred original publications quoted in this book:

Country

United States of America Germany (East and West) British Commonwealth Japan Switzerland Russia and Eastern Europe France Ten other countries

Percentage (YO) 26.9 20.7 19.1 11.5 8.3 3.5 3. I 6.9

I am greatly indebted to my academic colleagues, Adrien Albert, Wilf Armarego, and Gordon Barlin who have proved ready at all times to discuss matters of fact, interpretation, or presentation; to Margot Anderson and Jenny Rothschild who guided me through the minefield of biological nomenclature; to the library staff, Christine Bloem, Sheila Humphrey, Marie Humphries, and Jennefer Nicholson, for their kindly cooperation and assistance; to Barbara

xi

xii Preface

Cronin, Rosemary Enge, Abira Hassan, Betty Moore, and Akiko Ohnishi, each of whom assisted in some practical way(s) during the preparation of the manuscript; to Lew Mander and succeeding Deans of the Research School of Chemistry, who have provided me with office accommodation and facilities since my retirement from the John Curtin School of Medical Research in 1985; and finally to my wife, Jan, for her understanding, patience, and practical assistance during several years of concentrated writing.

The Aumalian Natronal University Canherra, Ausrrafia April I Y X X

DES BROWN

Contents

CHAPTER 1. INTRODUCTION TO THE PTERIDINES 1

1. History

2. Nomenclature

3. The Basis of Pteridine Chemistry

4. A General Summary of Pteridine Chemistry

A. Electrophilic Reactions B. Direct Nucleophilic Substitutions C. Nucleophilic Metatheses

( 1 ) Replacement of Halogeno Substituents (a) By Amino or Substituted-Amino Groups (b) By Hydroxy--0xo Substituents (c) By Alkoxy or Aryloxy Groups (d) By Mercapto--Thioxo Substituents (e) By Alkylthio or Arylthio Groups ( f ) By Sulfo Groups (g) By Other Groups

(2) Replacement of Alkoxy Groups (3) Replacement of Alkylthio Groups (4) Replacement of Sulfo Groups (5) Replacement of Alkylsulfonyl Groups

(1) Pteridinones to Chloropteridines (2) Pteridinones to Pteridinethiones (3) Pteridinethiones to Pteridinones (4) Pteridinones to Pteridinamines (5) Pteridinethiones to Pteridinamines or Pteridinimines (6) Pteridinamines or Pteridinimines to Pteridinones

(1) Covalent Hydration and Similar Additions (2) Addition of Phenyllithium

(1) Nuclear Oxidation (2) Formation of N-Oxides

D. Other Metatheses

E. Addition Reactions

F. Oxidative Reactions

... xi11

1

4

7

7

8 8 9 9 9

10 10 1 1 1 1 12 12 13 13 14 14 15 15 16 16 17 17 18 19 19 20 21 21 22

xiv Contents

(3) Oxidative Modification of Groups (a) C-Methyl to C-Formyl

(c) Alkyl to Carboxy (d) Hydroxyalkyl to Formyl (e) Hydroxyalkyl to Carboxy (f) C-Formyl to Carboxy (g) C-Acyl to Carboxy (h) Pteridinethiones to Dipteridinyl Disulfides (i) Thioxo to Sulfeno, Sulfino, or Sulfo ( j ) Alkylthio to Alkylsulfinyl or Alkylsulfonyl

(b) C-Alkyl to C-Acyl

G. Reductive Reactions (1) Nuclear Reduction (2) Reductivc Removal of Groups (3) Reductive Modification of Groups

(a) C-Formyl to Hydroxymethyl (b) (c) (d) Cyano to Aminomethyl (e)

Carboxy or Alkoxycarbonyl to Hydroxymethyl C-Acyl to Hydroxyalkyl or Alkyl

Sulfo, Sulfino, or Sulfeno to Thioxo H. Other Substituent Modifications

( 1 ) Modification of Alkyl Groups (2) Modification of 0 x 0 Substituents (3) Modification of Thioxo Substituents (4) Modification of Amino Groups

(a) Amino to Acylamino (b) Amino to Alkylideneamino (c) Amino to Alkylamino (d) Transamination Modification of Carboxy and Related Groups (a) Carboxy to Related Groups (b) Alkoxycarbonyl to Related Groups (c) Carbamoyl to Related Groups (d) Cyano to Related Groups (e) C-Formyl to Related Groups (f) C-Acyl to Related Groups

( 5 )

I. Decarboxylation J. Homolytic C-Acylation K. Degradation to Pyrazines or Pyrimidines

( I ) Degradation of Pteridine (2) Degradation of Pteridinones (3) Degradation of Pteridinamines and Pteridinimines (4) Degradation of Pteridine N-Oxides

22 22 22 23 23 23 23 24 24 24 25 25 25 26 28 28 28 28 28 29 29 29 30 31 31 31 31 32 33 33 33 34 34 34 35 36 36 37 37 38 38 39 40

5. Physical Properties of Pteridines 40

Contents xv

CHAPTER 11. PRIMARY SYNTHESES FROM PYRIMIDINES 43

1. The Gabriel and Colman Synthesis from 4,5-Pyrimidinediarnines and a-Dicarbonyl Compounds A. B. Use of a-Aldehydoketones

Use of the a-Dialdehyde, Glyoxal

( I ) Simple Cases (2) Cases with One Functional Group (3) Cases with Two Functional Groups

(a) The 6- or 7-Alkyl-2-amino-4(3H)-pteridinones (b) The 6- or 7-Alkyl-2,4-pteridinediamines (c) The 6- or 7-Alkyl-2,4(1 H,3H)-pteridinediones (d) The Folic Acid-Type Synthesis (e) Use of Sugars as Pro-a-Aldehydoketones

C. Use of the a-Aldehydoester, Ethyl Glyoxylate, or an Equivalent ( 1 ) Simple Cases (2) Cases with a 2- or a 4-Functional Group (3) Cases with Both a 2- and a 4-Functional Group

( I ) Simple Cases without a Functional Group (2) Cases with a 2-Functional Group Only (3) Cases with a 4-Functional Group Only (4) Cases with Two Amino-Type Functional Groups (5) Cases with an Amino- and an 0x0-Type

Functional Group (6) Cases with Two 0x0-Type Functional Groups (7) Cases with Two Other Functional Groups

( I ) Simple Cases without a Functional Group in the Pyrimidine Ring

(2) Cases with One Functional Group in the Pyrimidine Ring

(3) Cases with Two Amino-Type Groups in the Pyrimidine Ring

(4) Cases with an Amino- and an 0x0-Type Group in the Pyrimidine Ring

(5) Cases with Two 0x0-Type Groups in the Pyrimidine Ring

F. Use of the a-Diester, Diethyl Oxalate, or Equivalent ( 1 ) Simple Cases without a Functional Group in the

Pyrimidine Ring (2) Cases with One Functional Group in the

Pyrimidine Ring (3) Cases with Two Functional Groups in the

Pyrimidine Ring

D. The Use of a-Diketones

E. The Use of a-Ketoesters

44 45 49 49 54 56 56 62 64 65 67

71 71 72 74 78 79 79 80 81

87 89 92 92

92

94

95

100

103 105

105

106

106

xvi Contents

2. The Timmis Synthesis from 5-Nitroso-4-pyrimidinamines with a-Carbonylmethylene or Related Compounds

A. Use of a-Methylenealdehydes B. Use of a-Methyleneketones C. D. Use of or-Methylenenitriles

3. The Boon Synthesis from 4-Chloro-S-nitro(or ary1azo)pyrimidines and a-Aminocarbonyl Compounds Via 7,8-Dihydropteridines

A. Complete Boon Syntheses

Use of a-Methylene esters and Related Compounds

( I ) From 4-Chloro-5-nitropyrimidines (2) From 4-Chloro-5-arylazopyrimidines (3)

B. Incomplete Boon Syntheses C. The Boonlike Synthesis of 5,6,7,8-Tetrahydropteridines

Minor Synthetic Routes from Pyrimidines to Pteridines

A. Minor Syntheses from 4,5-Pyrimidinediamines

From Nitrosopyrimidines and Related Compounds

4.

( I )

(2)

Pteridine 5-Oxides Directly from 4-(Substituted amino)-5-nitropyrimidines Pteridines by Cyclization of 4-(Substituted amino)-5- unsubstituted pyrimidines

By Initial Acylation or Alkylation of the 5-Amino Group By Initial Conversion of the 5-Amino Group to a Schiff Base

B.

C.

D. Pteridines from Alloxan Derivatives E. Hydropteridines from 5-Halogenopyrimidines and

a-Diamines

CHAPTER 111. PRIMARY SYNTHESES FROM PYRAZINES OR OTHER HETEROCYCLES

1. Syntheses from Pyrazines

A. B. C. D. E. F. G.

By Addition of C-2 as in Skeletal Formula (1) By Addition of N-3 as in Skeletal Formula (2) By Addition of C-2 + N-3 as in Skeletal Formula (3) By Addition of N-l + C-2 + N-3 as in Skeletal Formula (4) By Completion of the 2,3-Bond as in Skeletal Formula (5) By Completion of the 1,2-Bond as in Skeletal Formula (6) By Completion of the 3,4-Bond as in Skeletal Formula (7)

2. Syntheses from Purines

3. Syntheses from Other Bi- and Tricyclic Systems

108

108 109 112 1 I3

120

120 121 124 127 128 131

132

132

132

133

136

137 139

140

143

143

1 44 150 151 154 155 158 158

159

161

Contents xvii

CHAPTER IV. PTERIDINE AND ITS ALKYL AND ARYL DERIVATIVES

1. Pteridine A. Preparation of Pteridine B. C. Reactions of Pteridine

2. Simple Alkyl- and Arylpteridines

Properties and Structure of Pteridine

A. Preparation of Alkyl- and Arylpteridines (1) By Primary Syntheses (2) By C-Alkylation or Arylation (3) From Derivatives Reactions of Alkyl- and Arylpteridines ( I ) Covalent Additions (2) Deuteration of Methyl Groups (3) Halogenation of Methyl Groups (4) Sulfonation of an Alkyl Group ( 5 ) Styryl from Methyl Groups (6) Oxidative Reactions of Alkyl Groups (7) Dimeric Methylpteridines and Related Compounds (8) Other Reactions

B.

3. The N-Alkylpteridinium Salts

CHAPTER V. HALOCENOPTERIDINES

1. Preparation of Nuclear Halogenopteridines

A. By Primary Syntheses B. From Pteridinones C. From Pteridine N-Oxides

2. Reactions of Nuclear Halogenopteridines

A.

B. Reductive Dehalogenation C. Aminolysis D. Hydrolysis and Alcoholysis E. Thiolysis, Alkanethiolysis, and Arenethiolysis F. Conversion into Sulfonic Acids

Formation of Covalent Adducts and Degradative Reactions

3. Preparation of Extranuclear Halogenopteridines

A. By Primary Syntheses B. By Direct Halogenation C. From Pteridinyl Alcohols D. By Derivatization with an Halogenated Reagent

165

165 165 166 1 69

172

172 172 173 1 74 175 175 176 177 178 178 179 181 183

184

187

187

187 188 191

192

192 194 195 200 20 1 203

203

203 204 205 206

xviii Contents

4. Reactions of Extranuclear Halogenopteridines

A. Reductive Dehalogenation B. Aminolysis C. Hydrolysis and Alcoholysis D. Other Reactions

CHAPTER VI. TAUTOMERIC PTERIDINONES AND EXTRANUCLEAR HYDROXYPTERIDINES

1. Preparation of Tautomeric Pteridinones

A. By Primary Syntheses B. By Oxidative Means C. From Pteridinamines

( 1 ) By Alkaline Hydrolysis (2) By Acidic Hydrolysis (3) By Treatment with Nitrous Acid

D. From Alkoxypteridines E. From Pteridinethiones or Alkylthiopteridines F. By Rearrangement of Pteridine N-Oxides

Properties and Reactions of Tautomeric Pteridioones

A. Degradation of Pteridinone Nuclei B. Formation of Covalent Adducts C. D. Conversion into Halogenopteridines E. Conversion into Pteridinamines F.

G. Conversion into Pteridinethiones H. Formation of Dimers

2.

Removal of 0 x 0 Substituents from Pteridinones

Conversion into Alkoxypteridines or Trimethyl- silox ypteridines

3. Preparation of Extranuclear Hydroxypteridines

A. By Primary Syntheses B. By Reductive Processes C. D. By Other Means

By Hydrolytic or Alcoholytic Processes

4. Reactions of Extranuclear Hydroxypteridines

A. Conversion into Chloroalkylpteridines B. C. Acylation D. Other Reactions

Oxidation to Aldehydes or Carboxylic Acids

5. Pteridinones from Natural Sources

A. The Xanthopterin Group

206

207 207 209 21 1

213

213

213 214 217 218 220 22 1 222 223 225

227

228 232 233 234 234

236 240 24 1

242

242 243 246 246

248

248 248 250 25 1

252

253

Contents xix

(1) Xanthopterin (2) Dihydroxanthopterin (3) Chrysopterin (4) Ekapterin ( 5 ) Lepidopterin (6) Erythropterin (7) Pterorhodin

B. Leucopterin C. The Isoxanthopterin Group

(1) Isoxanthopterin (2) Asperopterin-B and Asperopterin-A (3) Ichthyopterin (4) Cyprino-purple-B, Cyprino-purple-CI, and

( 5 ) 2-Arnino-Qa-hydroxypropyl-8-methyl-4,7(3H,8H)- Cy prino-purple-C2

pteridinedione D. The Pterin Group

(1) Pterin (2) 6-Pterincarboxylic Acid (3) Ranachrome-3 (4) Biopterin, Siopterin Glucoside, and Ciliapterin (5) Neopterin, Bufochrome, and Monapterin (6) Euglenapterin (7) Sepiapterin (8) Deoxysepiapterin (9) Sepiapterin-C (10) 6-Aminopterin ( 1 1) Drosopterin, Isodrosopterin, Neodrosopterin, and

(12) Urothione

(1) Lumazine (2) 6-Hydroxymethyllumazine (3) Leucettidine (4) 6-Lumazinecarboxylic Acid (5) Dimethylribolumazine (6) Sepialumazine (7) Russupteridine-Yellow- 1

F. The Violapterin Group (1) Violapterin (2) Luciopterin (3) Photolumazine-C (4) Compound-V (5) Photolumazine-B and Photolumazine-A (6) Putidolumazine

Aurodrosopterin

E. The Lumazine Group

253 256 256 257 257 258 259 259 260 260 26 1 262

263

264 265 265 265 266 261 270 272 273 274 275 276

276 278 279 279 279 280 28 1 28 1 282 282 283 283 284 284 285 285 286

xx Contents

(7) 6-Indol-3'-yl-8-~-ri bityl-2,4,7( 1 H,3H,8H)-pteridinetrione 287 (8) R ussu pteridine-Yellow-4 287

G. Other Natural Pteridines 288 (1) Pteroylglutamic Acid and Related Molecules 288 (2) Riboflavine and Related Molecules 288 (3) Surugatoxin 288 (4) 2,4,6(1 H,3H,SH)-Pteridinetrione and Its 7,g-Dihydro

Derivative 289 (5) The Acrasin of a Cellular Slime Mould 289

CHAPTER VII. ALKOXY PTERIDINES, N-ALKYLPTERIDINONES, AND PTERIDINE N-OXIDES

1. Preparation of Alkoxy- and Aryloxypteridines

A. By Primary Syntheses B. By Covalent Addition of Alcohols C. From Halogenopteridines D. From Pteridinones and Extranuclear Hydroxypteridines E. Miscellaneous Methods

Reactions of Alkoxy- and Aryloxypteridines

A. Hydrolysis and Alcoholysis B. Aminolysis C. The Silyl Hilbert--Johnson Reaction

2.

3. Preparation of N-Alkylpteridinones

A. By Primary Syntheses B. By N-Alkylation of Pteridinones C. By Other Means

4. Reactions of N-Alkylpteridinones

A. Degradative Reactions B. Thiation C. Other Reactions

5. Preparation of Pteridine N-Oxides

A. By Primary Syntheses B. By Direct N-Oxidation C. By Other Means

6. Reactions of Pteridine N-Oxides

A. Deoxygenation B. Covalent Adduct Formation

29 1

292

292 293 293 294 294

295

295 295 296

291

297 298 304

305

305 307 307

-308

308 309 31 1

312

312 312

Contents xxi

C. Degradative Reactions D. Acylation E. Chlorination F. Dimroth-Type Rearrangements G. Transformation into Purines H. Amination

CHAPTER VIII. THE SULFUR-CONTAINING PTERIDINES

1. Preparation of Pteridinethiones

A. By Primary Syntheses B. By Covalent Addition C. From Chloropteridines D. By Thiation of Pteridinones E. By Thiolysis of Alkylthiopteridines F. By Reductive Processes

Properties and Reactions of Pteridinethiones A. Desulfurization B. Oxidative Reactions C. S-Alkylation D. Hydrolysis to Pteridinones E. Aminolysis F. Other Reactions

2.

3. Extranuclear Mercaptopteridines

4. The (Symmetrical) Dipteridinyl Sulfides and Disulfides

5. The Pteridine Sulfenic, Sulfinic, and Sulfonie Acids

6. Preparation of Alkylthio- and Arylthiopteridines

A. By Primary Syntheses B. By S-Alkylation C. By Nucleophilic Displacement D. By Covalent Addition

7. Reactions of Alkylthiopteridines

A. Desulfurization B. Hydrolysis to Pteridinones C. Aminolysis D. Other Reactions

8. Preparation of Pteridinyl Sulfoxides and Sulfooes

9. Reactions of Pteridinyl Sulfoxides and Sulfones

313 314 316 316 317 317

319

319

319 320 320 32 1 32 1 321

322 322 322 324 326 326 328

328

329

330

334

334 335 335 335

335

335 336 337 338

339

340

xxii Contents

CHAPTER IX. PTERIDINE AMINES AND IMINES

1. Preparation of Nuclear Aminopteridines

A. B. C. D. E. F. G. H.

By Primary Syntheses By Nucleophilic Displacement Reactions By Covalent Addition of Ammonia or Amines From Acylaminopteridines From Pteridinecarboxamides By the Dimroth Rearrangement From N-Oxides Formation of N- Aminopteridinones

2. Properties and Reactions of Nuclear Aminopteridines

A. Degradative Reactions B. Formation of Covalent Adducts C. Acylation Reactions D. Alkylation E. Conversion into Schiff Bases F. Transamination G. Hydrolysis to Pteridinones H. Pteridinamines as Drugs

( I ) Methotrexate (2) Triamterene

3. Preparation of Extranuclear Aminopteridines

A. By Primary Syntheses B. From Pteridinecarbonitriles C. From Pteridinecarbaldehydes D. By Aminolysis of Halogenoalkylpteridines E. By Deacylation Reactions F. By Covalent Addition

4. Reactions of Extranuclear Arninopteridines

5. Preparation of (Fixed) Pteridinimines

6. Reactions of (Fixed) Pteridinimines

A. Hydrolysis and/or Degradation B. Dimroth Rearrangement

7. The Quinonoid Dihydropterins

CHAPTER X. PTERIDINECARBOXYLIC ACIDS AND RELATED COMPOUNDS

1. Preparation of Pteridinecarboxylic Acids

343

343

343 345 345 347 348 348 348 348

349

350 35 1 352 3 54 355 356 357 357 358 359

360

360 36 1 362 364 364 364

365

366

368

368 370

372

377

377

Contents xxiii

A. By Primary Syntheses B. By Oxidative Means C. By Hydrolytic Means D. Miscellaneous Methods.

2. Reactions of Pteridinecarboxylic Acids

A. Decarboxylation B. Reduction to an Alcohol C. Esterification D. Conversion into Carboxamides

3. Preparation of Pteridinecarboxylic Esters

A. By Primary Syntheses B. By Esterification or Transesterification C. By Covalent Addition D. By Other Routes

4. Reactions of Pteridinecarboxylic Esters

A. Formation of Covalent Adducts B. Reduction C. Hydrolysis D. Transesterification E. Aminolysis

5. Preparation of Pteridimarboxamides

A. By Primary Syntheses B. By Covalent Addition C. By Hydration of Nitriles D. By Aminolytic Reactions E. By Other Means

6. Reactions of Pteridinecarboxamides

7. Preparation of Pteridinecarbonitriles

A. By Primary Syntheses B. By Covalent Addition C. By Other Means

8. Reactions of Pteridinecarbonitriles

9. Preparation of Pteridinecarbaldehydes

A. By Primary Syntheses B. By Oxidative Means C. D. From Dibromomethylpteridines E.

By Cleavage of Pteroylglutamic Acid, and so on

From Acetals or Other Derivatives

377 378 380 383

384

384 386 3 86 387

389

389 390 39 1 392

392

392 393 394 394 394

3%

395 396 396 396 396

397

397

397 398 399

400

400

400 401 403 403 403

xxiv Contents

10. Reactions of Pteridinecarbaldehydes

A. Oxidation and Reduction B. Conversion into Styryl-Type Compounds C. Conversion into Schiff Bases D. Formation of Other Functional Derivatives

11 . Preparation of Pteridine Ketones

A. By Primary Syntheses B. By Covalent Addition C. By Direct C-Acylation D. By Oxidative Means E. From Acetals

12. Reactions of Pteridine Ketones

A. Oxidation B. Reductive Reactions C. Other Reactions

CHAPTER XI. THE HYDROPTERIDINES

1. Preparation of Dihydropteridines

A. By Primary Syntheses B. By Reductive Processes

(1) Reduction to 3,4-Dihydropteridines (2) Reduction to 5,6-Dihydropteridines (3) Reduction to 5,8-Dihydropteridines (4) Reduction to 7,8-Dihydropteridines

C. By Oxidation of Tetrahydropteridines D. By Covalent Addition E. By Prototropic Rearrangement

2. Reactions of Dihydropteridines

A. Oxidation (Aromatization) B. Reduction to 5,6,7,8-Tetrahydropteridines C. Alkylation or Acylation at a Ring Nitrogen

3. Preparation of Tetrahydropteridines

A. By Primary Syntheses B. By Nuclear Reduction C. By Covalent Addition

4. Reactions of Tetrahydropteridines

A. Oxidative Reactions B. N-Acylation and N-Alkylation

404

404 404 405 405

406

406 407 408 410 41 1

41 1

412 412 41 3

415

416

416 418 418 420 42 1 42 1 424 425 426

421

427 428 429

430

430 43 1 436

431

437 438

Contents xxv

C . Other Reactions

5. Mono- and Trihydropteridine Radicals

CHAPTER XII. IONIZATION AND SPECTRA

1. Ionization Constants

2. Ultraviolet Spectra

3. Proton Nuclear Magnetic Resonance Spectra

4. Infrared Spectra

5. Massspectra

6. Fluorescence Spectra

7.

8. Polarographic Data

13C Nuclear Magnetic Resonance Spectra

APPENDIX. TABLE OF SIMPLE PTERIDINES

442

. 442

445

445

486

501

502

508

508

508

509

51 1

REFERENCES 591

INDEX 637

This Page Intentionally Left Blank

List of Tables

Table I Table I1

Table 111

Table IV

Table V

Table VI

Table VII Table VIlI Table IX

Table X

Table XI Table XI1

Table XI11

Table XIV

Appendix Table

Trivial Names for Some Pteridine Derivatives Additional Examples of the Gabriel and Colman Syn- thesis with the Dialdehyde, Glyoxal Additional Examples of the Gabriel and Colman Syn- thesis with Aldehydo Ketones Additional Examples of the Gabriel and Colman Syn- thesis with the Aldehydo Ester, Ethyl Glyoxylate Ethyl Hemiacetal Additional Examples of the Gabriel and Colman Syn- thesis with a-Diketones Additional Examples of the Gabriel and Colman Syn- thesis with a-Keto Esfers Additional Examples of the Timmis Synthesis Additional Examples of the Boon Synthesis Additional Examples of the Preparation of Pteridines from Pyrazines Decomposition Temperatures and Solubilities in Water for Simple Pteridinones Measured pK, Values for Pteridines in Water The Ultraviolet Spectra of Representative Simple Pteri- dines The Proton Nuclear Magnetic Resonance Spectra of Some Simple Pteridines References to the Infrared, Mass, Fluorescence, and ' 3C Nuclear Magnetic Resonance Spectra and to Polaro- graphic Data for Some Simple Pteridines Simple Pteridines

5

50

59

75

83

96 114 125

147

227 446

487

503

506 513

xxvii

FUSED PYRIMIDINES

Part Three

This is o part of the twenty-fourth volume in the series

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS