FUSED PYRIMIDINES

E&ed by

I). J. Brown

Part I

QUINAZOLINES W. L. F. Armarego

Deparfment of Medcal Cbemis/ry, Tbs John Curiin School of Medcal Reiearch,

The Ausiralian National University, Canberra

With collaboration in part by GEORGE H. HITCHINGS and GERTRUDE B. ELION

WeLhome Researcb Labwatoritv, TrrcRaba, N. Y.

1967

INTERSCIENCE P U B L I S H E R S

a division of John Wiley & Sons New York - London - Sydney

This Page Intentionally Left Blank

FUSED PYRIMIDINES Part I: QUINAZOLINES

Tbis is rbc twen~+rtb wiume (Part r ) in tbs Icricr

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

T H E C H E M I S T R Y OF HETEROCYCLIC COMPOUNDS

A SERIES OF MONOGRAPHS

ARNOLD WEISSBERGER, Editor

FUSED PYRIMIDINES

E&ed by

I). J. Brown

Part I

QUINAZOLINES W. L. F. Armarego

Deparfment of Medcal Cbemis/ry, Tbs John Curiin School of Medcal Reiearch,

The Ausiralian National University, Canberra

With collaboration in part by GEORGE H. HITCHINGS and GERTRUDE B. ELION

WeLhome Researcb Labwatoritv, TrrcRaba, N. Y.

1967

INTERSCIENCE P U B L I S H E R S

a division of John Wiley & Sons New York - London - Sydney

First publiehed 1967 by John Wiley & Sons, Ltd.

All Righta Reserved

Library of Congress Catalog Card Number 67-27306

WILLzdyI DLOWEB AND SONS, LIICITW, WNDON ABD BECCLEB

The Chemistry of Heterocyclic Compounds

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

A field of such importance and i n t h i c di6culty should be made as readily accessible rn possible, and the lack of a modern detsiled and comprehensive presentation of heterocyolic chemistry is therefore keenly felt. It is the intention of the present series to fill this gap by expert presentations of the varioua branchea o f heterocyclic chemistry, The subdivieions 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 intereats of the authors.

ARNOLD WEISSSEEWER

Research Labord~es Eaatnaan H&k Cmpany Rochter, New Ymk

V

This Page Intentionally Left Blank

Foreword to The Fused Pyrimidines

OriginalXy it W ~ S intended to present aJ1 the fused pyrimidine systems in one volume of this series. Resurgence of interest in purines and quinazoolines, the development of pteridine chemistry, and the wide exploration of & great many new fused e y e t a m embracing the pyrimid- ine ring, have made the task impossible.

The fwed pyrimidines will now be covered in four parts, of whioh Dr. Armarego’s &uinazolines is the firat. Others, dealing with Purim, Pteridiw, and Mkwklanew Fwed Pyrimidines respectively, are in active preparation. Eventually, this braoket of volumes will bring to the WI%S the expertise of six enthusiastict authors with wide and diverse exprience in the field.

It is a privilege to assist Dr. Weissberger and the authors in organizing this projeat and in maintaining a memure of uniformity and balance in its parts.

D. J. BROWN

Vii

This Page Intentionally Left Blank

Preface

The presence of the benzene ring in quinazoline modifiea the chemistry of the pyrimidine ring in a number of ways. The modifies- tions are so diverse that a description of the chemistry of quinazolines merits a separate monograph. Quinazolines were originally prepared for academic interest, and a considerable variety were made because many synthetic approaches were possible. In the last two decades several naturally occurring quinazolines were discovered, and many quinazo- lines were synthesized for biologicd testing. The antimalarid activity of the alkaloid febrifugine, for example, led to the preparation of a large number of different quinazoline derivatives. The neurotoxic activity of the recently discovered tetrodotoxin, a perhydroiminoquinazoline, will undoubtedly stimulate research in this previously unknown claas of quinazolines.

This monograph is intended aa a, critical review of quinazoline chemistry &B well as a compilation of the melting pointa of quinazolines. Condensed quinazolines are excluded, with the exception of the thiazolo- quinazolines (thiopegenes) because the chemistry of these is closely related to that of the thioquinazolines. The literature is covered com- pletely from the preparation of the first quinrtzoline in 1869 to the middle of 1966, and incompletely until mid-1966,

I am grateful to the many people who helped me during the months of writing. Drs. G. H. Hitchings and G. B. Elion loaned me a preliminary account of the chemistry of quinazolines based essentially on synthetic methods. Dr. D. J. Brown has unselfishly guided and inspired me, particularly through the most difficult eections, and to him I owe a great debt of gratitude. Professor Adrien Albert carefully read several chapters and made constructive criticisms. The following were of considerable help in discussions, in making available to me information prior to publication, and in allowing me to reproduce some of their published dab: Professors R. D. Brown, A. R. Krttritzky, K. S. Nwang, Drs. 0. B. Barlin, T. J. Batterham, M. E. C. Biffin, J. W. Bunting, Gordon Catterall, M. L. Heffemn, D. D. Perrin, N. K. RaHmn, J. I. C. Smith, and Mr. H. Yamamoto. My wife (who is also an organic

1* ix

X Profme

chemist) assisted in making the tables, compiling the index, and in reading the whole manuscript. Finally, grateful thanks are due t o Miss P. Cope who canied out the tedious task of typing the manuscript and to Mre. D. McLeod for library facilities.

W. L. F. ARMAREQO

The Austpdian National University, Canberra June 1966

Contents

I. Introdmtion , 1.History . 2. Nomenclature . 3. The Dual Charaoter of Quinazolines. 4. General Summary of Quinazoline Chemistry

. .

A. Syntheses . a. F’rimary Synthesea . b. Secondary Syntheses .

B. The Heightened Reactivity of 2- and 4-Alkyl Croups C. Addition and Substitution Reactions, and Nucleophilic Meta-

. the& .

D. N-Oxides ,

E. Tautomerism . F. Oxidation and Reduction . G. Rearrtangementa . IX. Biological Activity in QuinazoIines

6. Tables . 6. References .

II. Qubaeoline . 1. $ynthesis of Quinazoline . 2. Physical Properties .

A. Theoretical Aspects . B. Spectra .

a. Ultraviolet Spectra . b. Phosphorescence Spectra . c. Infrared Spectra . d. Proton Magnetic Resonance Spectre e. MMS Spectra .

C. Covalent Hydration . a, Covalent Hydration in Quinazoline. b. Effect of Substituents in the Pyrimidine Ring on Covalent

.

.

Hydration . (i) Effect of substituents in position 4

(ii) Effect of aubstituenta in position 2 . .

xi

6 7 7 8 8 9 9 10

11 11 13 14 14 14 15 15 10 18 19 19

27 27 28

xii Contents

c. Effeot of Substituenta in the Benzene Ring on Covalent Hydration .

D. Pohrography , .

A. Hydrolysie, Oxidstion, and Reduction B. Electrophilic end Nucleophilic Substitution, and Alkylation . C. Addition Reactions .

3. Chemical Reactivity of Quinazoline . .

4. References . III. C-Alkyl- and C-Arylquhzobes .

1. Methods of Preparation . A. Bischler’s Synthesie . B. Oxidation of 3,4-Dihydroquinazolis , C. Decarboxylation of Acids , D. From N’ToIuene-psulphonyly~razino Derivatives . E. From Imidoyl Chlorides and Nitriles . F. From Aryl Diazonium Salk and Nitriles G. From 4-chloro or 4-~anoquinazolines and Grignard Reagente H. From Chloro- or CyanoqUinazolines and Sub&mcee with sn

.

Active Methylene Group . I. Reidel’s Synthesis . J. Miscellaneous . A. ahysiceJ Properties . B. Chemical Properties .

2. Properties .

a. The Heightened Reactivity of 2- end 4-Methyl Groups b. Oxidation and Reduction . c. Eleotrophilic Substitution. . d. Alkylation . e. Reactivity of the Substituted Carbon Atoms Attached fo

.

29 32 33 33 34 35 36

39 39 39 41 42 42 42 43 44

46 48 48 49 49 60 50 54 56 66

%I, m d cw 3. Tables . 4. References .

IV. OxoquinosoJines and 5-, 6-, 7-, and 8-Hydmxyquixutzolines 1. 2-0x0quinaz01ines.

A. Prepwation . B. Properties . A. Preparation of 3,4-Dihydro-4-oxoquinszolinea .

2. 3,4- and 1,4-Dihydro-4-oxoquinasolines . a. Niementowski’s Synthesis . b. Cyclization of o-Amidobenzamides c. From o-Aminobenzonitriles . d. From Anthranilic Acid Derivatives and Nitriles

. 58

. 60

. 67

. 69

. 69

. 69

. 72

. 74

. 74

. 74

. 78

. 80

. 81 e. From 3,1,4-Benzoxazones (Acyhthranile) and Aminee . 83 f. From Isatoic Anhydrides . . 87 g. From Anthranilic Acids or Esters and Imidoyl ChIorides . 88 h. From Anthranilic Acids or Estere and Imidetes . . 91 i. Grimmel, Cuenther, and Morgan’s Synthesis . . 93 j. Sen and Ray’s Synthwis . . 94

Contents

k. Oxidation of Reduced Quinazolinea . 1. From hdoles and Related Compound6 .

m.MLdiscellaneous . B. Preparation of 1,4-Dihydro-4-oxoquinezoline~ . C. Properties of 4-Oxoquinazolines .

a. Physical Properties . b. ChemicalPropertiee .

(i) Akylation and Bcylation . (ii) The heightened reactivity of the 2-methyl group (iii) Oxidation, reduction, and hydrolysis fiv) Electrophilic subetitution . (v) Substitution reaatione involving ring opening . (vi) Reaction with cfrignard reagents

(vii) Mannich reactiom . (viii) Miscellaneous .

. .

.

3. 2 , 4 - D i o x o q u ~ o l i n ~ . A. Preparation of 1,2,3,4-Tetrahydro-2,4-dioxoq~oljnes .

a. From Anthranilic Acid (or Derivatives) and Cyan0 Com-

b. k o m Anthranilic Acid (or Derivatives) and Ureaa . c. Cyclization of 0-Ureidobenzoic Acids and Derivatives d. From o-Ethoxycarbonylsminobeneoic Esters or Amides e. From Phthalic Aoid Derivatives f. FromIaatina . g. From Anilines and Related Compouods . h.Miscekeous . a. PhysicalproPerties , b. ChemidProperties .

pounds . . .

.

B. Properties of 1,2,3,4-Tetrahydro-2,4-dioxo~uin~o~es .

4. Quinrtzoline~ with Hydroxy Groups in the Benzene Ring . A. Preptmttion . B. Properties .

5. Tables . 6. References .

V. Halogenoquinazolinee snd Quinazolinyl Ethers . A. Prepamtion of 2-Halogenoquinazolines . B. Preparation of 4 - H d o g e n o q ~ l i n e s . C. Preparetion of 2,4-Dihalogenoquinazoline~1 . D. Preparation of Quimmolines Substituted with Halogen in the

Benzene Ring or in the Side Chain . E. Properties of Halogenoquinazolinea .

a. PhysicalProprtiea . b. Chernimlhperties .

1. Balogenoquhzolines .

(i) Reactivity of halogens in the aide chain or in the benzene ring .

(ii) Reactivity of the 2- and 4-halogen atoms . (iii) Metatheah .

xiii

90 96 98 99

102 102 104 104 107 109 111 112 113 114 115 116 116

116 119 120 122 123 126 126 127 128 128 130 133 133 134 136 208

219 219 219 222 226

226 227 227 227

227 227 230

xiv Contents

(iv) Reduction . (v) Dehdogenation . (vi) Miscellaneous .

2. QuinazolinylEthers . A. Prepamtion of 2-Quinazolinyl Ethers . B. Preparetion of 4-Quinazolinyl Ethers .

8. Alkyhtion of 3,4-Dihydro-4.oxoquinazol~~ . b. Nucleophilic Displacement at Position 4 . c. From o-Aminobenzonitrile Derivatives . d.Miacellaneoue .

C. Preparation of 2,4-&uinazolinyl Diethers D. Preparation of Quinazolines with Alkoxy Groups in the Benzene

E. Properties of Quinaeolinyl Ethers

. Ring .

8. Physical Properties . b. ChemicdProperties .

(i) Hydrolysis . (ii) Alkylstion . (iii) Metathesis . (iv) Rearrangements .

.

3. Tables . 4. Referenw .

VI. Thio- M d Oxothiq-lhs . 1. 2-Thioquinazolines. .

A. 1,2-Dihydro-2-thioquinazolines . B. 3-Substituted 2,3-Dihydro- and 1,2,3,4-Tetrahydro- 2-Thio-

quinazolines . 2. 4-Thioquinazolines . .

A. 1,4- and 3.4-Dihydro-4-thioqu~azolinos . B. 4-AIkylthio- and Arylthioquinazolinea . . C. 1,2,3,4-Totrahydro-4-thioquinazolines . D. Properties of 4-Thioquinazolines .

3. 2,4-Dithioquinazoli.nes . 4. 1,2,3,4-Tetrahydro-4-oxo-2-thioquinazolines . 5. Quinazolines Substituted with Thio Groups in the Benzene Ring. 6. Thiazoloquinazoiinea (“hiopegenes) . 7. Tables . 8. Referen- .

VII. Aminoquinaxolines (including Aminooxo- and Aminothioquinazo- lines) .

I. 2- and 4 -h ino - , and 2,4-Diaminoquinazolinnes A. Preprtration of 2-Aminoquinazolinee and 2-Amino-3,4-dihydro-

4-oxoquinazolinea . a. By NucleopMic Displacement with Amines . b. Syntheees involving Quanidinea, Cyanamides, Ureas, and

c. Miaceueneoue . RelstedCompounds .

23 1 233 234 236 236 236 230 237 238 239 238

240 241 24 1 241 241 242 243 243 245 264

270 270 270

27 1 277 277 280 28 1 282 284 285 287 288 292 317

322 322

322 322

324 327

Contenis xv

B. Preparation of 4-Aminoquinazolines, 4-h ino- 1,2-dihydro-2- 0x0- and 4-Amino- 1,2-dihydro-2-thioquhutzoEnes ,

a. By Nucleophilic Displacement with Aminea . b. From o-Aminobenzonitriles , c. Miscellaneous .

a. By Nucleophilic Displacement with Aminw . b.FromCluanidines . c. From o-Aminobenzonitriles

C. Preparation of .2,4-Diaminoquin~zolines .

D. Properties of 2- and 4-&&0-, and 2,4-Diaminoquinaxoiines. E. Reactions of 2- and 4-Amino-, and 2,4-Diaminoquinazolinea.

a. Hydrolysis . b. Aoylation, Methylation, and Chlorination c. Traneamination and Molecular Rearrangements d. Reaotions of Rydrazinoquinszolines .

2. 3-Ammooxo- and 3-Aminothioquinazoliea .

. ,

A. Preparation of 3-Amino-3,4-dihydr0-4-0~0- (and 4-thio-) and 3-Amino-l,2,3,4-tetr~hydro-2,4-dioxoquinazolinea , a. Syntheses from AnthraniIic Acid Derivatives . b. From 3,1,4-Benzoxazones and Related Thio Compounds . c. From 3,4-Dihydro-4-oxoquinrteolin~ and Hydrazinee . d. Miscellaneous .

B. Reaotions of 3-Aminooxoquinazolines . .

A. Preparation of 5-,6-,7-, and &Amino- and Aminooxoquina-

B. Properties of 5-,6-,7-, and &Amino- and Aminooxoquina-

3. AminoquboIines with Amino Groups in the Benzene Ring

EOlineS . aolines .

4. Tables . 5. References .

Vm. !€he Reduced Quinsz;oliner . 1. Preparation of 1,2-Dihydroquinazolines .

A. By the Reaction of o-Aminobenzaldehyde with Amines and

B. From Anthranihmides and Aldehydes, Ketones, or Related

C. B y Reduction of 3,4-Dihydro-4-oxoquinuinazolinee and Related

Formaldehyde .

Compounds . Compounds .

2. Preparation of 1,4-Dihydroquimzolinea . 3. Prepamtion of 2,3-DihydroquintwoIin~ . 4. prepctration of 3,4-Dihydroquinazohea .

A. From o-Aminobenzylamines or 0-AminobenzyI Alcohols B. From Anilinm and Formaldehyde . C. By NucleopUc Addition or DispIacement Reaction13 . D. By Reduction of Quinazohes . E. From 0-Aminobenzyl Chloride and Nitriles. F. Miecellaneous .

.

. 5. Preparation of 1,2,3,4-Tetxahydroquinazolinea .

327 327 328 330 330 330 33 1 332 332 333 333 334 335 336 337

337 337 338 339 339 340 340

340

34 1 342 384

391 381

391

392

393 394 396 396 396 396 398 398 399 400 400

Xvi Contents

A. From Aniline13 and Formaldehyde B, From 0-Aminobenzylsminea and AIdehydm C. By Reduction of 3,4-Dihydmquinazolinw (including their

. . 4-0x0 Derivatives) . a. Chemical Reductions . b. CataIytic and Electrolytic &uctions

6. Physical and Chemical Propertis of 1,2-, 1,4-, and 3,CDihydro-, and 1,2,3,4-Tetrahydroquinaeolins .

7. Trijger’s Base and Related Compounds . 8. 6,6,7.8-Tetrahydroqin~olines . A. Prepation of 6,6,7,8-Tetrahydroquinazolinee .

a. From Cyclohexanones . b. From 2-Ethoxycerbonylcyclohexssonee . . c. From S-Formyl-(or Acetyl-)cyclohexanones . . . d. F’romCyclohexenes .

B. Properties of 5,6,7,8-Tetrahydroquinazolin~ . 9. Miscellaneous Reduced Quinaeolines .

10. Tables . 11. References .

1. Quinazoline-1-oxidea . 2. Quinazoline-3-oxidea .

IX. Quinrzoline N-oxidea (including 1- end 3-Hydroxyqholinee) .

A. Preparation and Structure of Quinszoline-3-oxides B. Physical Properties of Quinazoline-3-oxidea . C. Reactions of Quinazoline-3-oxides .

.

3. 1,2-Dihydroquinazoline-3-oxidea .

6. Tablee . 6. Referenma .

1. Cyeno- and Carbmoylqubzohes . 2. Carboxyquinazolinea .

4. 1- a d 3-Hydro~y0~0q~in~~0hines .

X. Qubzoline Ctuboxylic 8nd Sulphonic Acids, and ReIated Compounds

A. ~ - C ~ W ~ O X Y ~ U ~ Z O ~ ~ E I . B. 4-Carboxyquinazolines . C. Quinazolines with Carboxy Groups in the Benzene Ring

3. Foll~~yl- and A~~t~lq~inezoi ines . 4. Sulphoquinazolines and Relstsd Compounds 6. Tables . 6. References .

. 1. Naturally Ocourring Quinazolines .

A. Arborine, Glycoemicine, Glycerine, and Glycosmhine . B. Vesicine and Related AlkaIoih . C. Febrifugine and Isofebrifugine . D. Evodismine, Rutwarpine, Xiortianhe, end Rhetainine E. Tetrodotoxin .

.

XI. NatmlIy Occurring end Biologically Active Quineeolines

2. Biologically Active Synthetic Quinazo)inae 3. Referemas .

. SubjeCtIndex .

400 40 1

40 1 40 1 402

402 406 409 409 409 410 410 411 412 413 4 16 440 446 446 460 450 462 466 456 467 46 1 47 1 473

. 473

. 476

. 475

. 478

. 479 . 480

. 480 . 481

. 488

. 490 . 490 . 490 . 492

. 496

. 500

. 503

. 608 . 518

. 619

Introduction . 11.1. Quinazoline and 3-Alkyl Derivatives . II.2. Electronic Effects and Hydra6ion in 2-Substituted Quinazoline

Cations . 11.3. Ionization and Covdent Hydration of &uinazolinea in Water at

20" . 11.4. Ionization Constants of Substituted Quinazohea in Water at 20'

111.1. 2-Alkyl- and Aryl- (including Heteroaryl-) quinazolinee . III.2. 4-AlkyL and Aryl- (including Heteroaryf-) quinazobea . III.4. Alkylquinazolinea Substituted in the Benzene Ring . 111.5. Alkyl- and Arylquinaeolinm Substituted in Both Rings . III.3, 2,4-Di~~b~tftuted Alky.1- and Arylquinazolines . .

III.6. M ~ ~ ~ ~ J W O U S Alkyl- a d ArylquinazOlinee ( in~ l~d ing Quina- zoriniumsdts) .

IV.1. 1,2-Dihydro-2-0~0q~inaeolines , N.2. 1 , 4 - D i h y d r o - 4 - 0 ~ 0 q ~ ~ 0 ~ ~ , N.3. 2-AIkyl-3,4-dydro-4-O~OquinezOlinee - W.4. t-Aryl.(and Hetemsryl-)3,4-dihydro-4-oxoq~olineii1 . IV.5. 3,4-Dihydro-4-oxoquinaeolinee with Alkoxy, Aryloxy, or chxoro

Substituents in Poaition 2 . IV.6. 3-Alkyl- (other than Oxygen-contehing Alkyl) 3,4-dihydro-4-

IV.7. 3-Alkyl- (with Oxygen-containing Side Chain other than Ace- tonyl) 3,4-dihydro-4-oxoquinszolines .

IV.8. 3-Acetonyl-3,4-dihydro-4-oxoquinazo~eii1 . IV.10. 3.4-Dihydr0-4-oxoqholines with e Heterocyclio Group in

IV.11. 3,4-Dihydm-4-oxoquinazoIine and Derivatives with Substituents

IV.12. 3--1- (other than Oxygen-containing Alkyl) 3,4-&ydro-

oxoquinazolines .

IV.9. 3-Aryl-3,4-dihydro-4-oxoquinazoline2a . Position 3 . intheBeneeneRing . 2 -methyl- 4-oxoquinezolines .

xvii

9 13

29

30 31

60 61 03 64 66

66

130 137 139 142

143

144

146 149 152

163

153

166

XViii Tables

IV.13. 3-Alkyl- (with Oxygen-containing Side Chain) 3,4-dihydro- 2-methyl-4-oxoquinmol.ines .

IV.14- 3-rkyl-3,4-dihydro-2-methyl-4-0~0q~i1~~~0lin0~ . IV.16. 3,4-Dihydro-2-methyl-P-oxoquinazolines with a Heterocyclic

IV.16. 3-Substituted 2-Ethyl-3,4-dihydro-4-oxoquinazolinea. . IV.17. 3-Substituted 3,4-Dihydro-4-0~0-2-propyL (and isopropyl-) quina-

IV. 18. 3-Substituted 2-Ethenyl-3,4-dihydro-4-oxoquinezolines . IV.19. 2-Alkyl- (other than Methyl, Ethyl, Propyl, or Ethenyl) 3-Substi-

IV.20. 3-Substituted 2-Aryl-3,4-dihydro-4-oxoquinazolines . IV.21. 3-Aryl-3,4-dihydro-4-oxoquinazolinea with a Heterocyclic Group

in Position 2 IV.22. 3-Substituted 3,4-Dihydro-4-oxoq~azolines with Halogeno,

A&oxy, or Aryloxy Substituents in Position 2 . IV.23. 3,4-Dihydro-2-methyl-4-oxoquinazolines Substituted in the Ben-

zene Ring . IV.24. 2-AlkyI- (other #an Methyl) 3,4-dihydro-4-oxoquinazolines with

Substituents in the Benzene Ring . IV.25. 2-Aryl-3,4-dihydro-4-oxoqujnazolinea with Substituents in the

BenzeneRing . IV.26. 3,4-Dihydro-3-methyl-4-oxoquinazolines with Substituents in the

Benzene Ring . N.27. 3-Alkyl- (other than Methyl) 3,4-dihydro-4-oxoquinazolines with

Subetituents in the Benzene Ring . IV.28. 3-Aryl-3,4-dihydro-4-oxoquinazolines with Substituents in the

BenzeneRing . IV.29. 3-Alkyl-3,4-dihydro-2-methyl-4-oxoquinamlines with Substi-

tuente in the Benzene Ring IV,90. 3-Aryl- (and Heteroarylr-) 3,4-dihydro-2-methyl-4-oxoqu~olinea

with Substituents in the Benzene Ring IV.31. 2-Ethyl-3,4-dihydro-d-oxoquinazolines with Substituents in the

Benzene Ring and in Position 3 IV.32. 2-Alkyl- (other than Methyl or Ethyl) 3,4-dihydro-4-oxoquinne-

zolfnas with Substituents in the Benzene Ring and in Position 3 . IV.33. 3,4-Dihydro-4-oxo-2-phenylquinazoline~ with Substituents in the

Benzene Ring and in Position 3 XV.34. 3,4-Dihydro-3-(3'-(3-hydroxy- 2 -piperidyl) - 2' - 0xo)propyl- 4 -0xo-

quinazolines with Substituents in the Benzene Ring . IV.36. 343'4 1-Ethoxycarbonyl-3-methoxy- 2 -piperidyl) - 2'-oxo)propyl-

~-0x0qUinrtzo~ines with Substituente in the Benzene Ring N.36. 3- (3'- (3 - Methoxy - 2 - piperidyl) - 2'. 0xo)propyl - 4 - oxoquinazoliines

with Substituents in the Benzene Ring IV.37. Miscellaneous 3.4-Dihydro-4-0x0-3- (2'-0x0 - 3'- (2-piperidy1))pro-

pylquinazolines . IV.38. 3,4-Dihydr0-4-0~0-3-(2'-0~0-3'- (pyrrolidin -2-y1))propylquinazo -

lines . IV.39. Quinazolinee with Hydroxy Groups in the Benzene Ring .

Group in Position 3 .

zoline43

tuted 3,4-Dihydra-4-oxoquinazol~es .

. .

.

.

.

167 168

163 164

166 166

168 170

171

172

173

174

176

177

177

180

180

182

186

188

189

190

192

193

196

196 197

Tables

IV.40. 3.4-Dihydro-4-oxoquinazolines with Hydroxy Gmupe in the

IV.41. 1-Substituted (and Unsubstituted) 1,2,3,4-Tetrehydro-2,4-dioxo-

IV.42. 3-Substituted 1,2,3,4-Tetrahydro-2,4-dioxoquinazoline6 . IV.43. 1,2,3,4-Tetrahydro-2,4-dioxoquinazolines with Substituents in the

BenzeneRing . IV.44. %-Substituted (and Unsubstituted) 1,2,3,4-Tetrahydro-2,4-dioxo-

quinazolinas with Halogens in the Benzene Ring IV.45. 3-Substituted (snd Unsubstituted) 1,2,3,4-Tetrahydro-2,4-dioxo-

quinszolines with Hydroxy or Alkoxy Groups in the Benzene Ring .

IV.46. 1.3-Dieubstituted 1,2,3,4-Tet~ydro-2,4-dioxoquinazolin~. . IV.47. 3- and 1,3-Substituted 1,2,3,4-Tetrahydro-2,4-dioxoq~zolines

BenzeneRmg . quiaezolines .

.

with Substituents in the Benzene Rmg

V.l. Replacement of Chlorine in 2- and 4-~orquinazo1ines by Piperi- dineinEthan01 .

V.2. QuineZohes Prepared from 4-N'-Toluene-p-sulphonyIbydrseino- qubazoline Derivatives in Ethylene Glycol-Water (7 : 3)

.

. v.3. 2-chl0roquinez0linea . v.4. 4-chloroquinszolines . V.5. 2 , 4 - D h h l o r o q ~ l i ~ ~ . V.6. Chloroquinazolines with Chloro Subetituents in the Benzene Ring V.7. Chloroquinazolines with Chloro Substituents in Both Rings . V.8. Miscellaneous Halogenoquin&zolines . V.9. 2-Quinazolinyl Ethers . V.10. 4 - Q u b o l i n y l Ethers . V.11. 4-Quir1&zobyl Ethers with a Subetituent in Position 2 V.12. 4 - Q u b a o h y l Ethers with Substituents in the Benzene Ring V.13. Q-Quinazohyl Ethers with Substituenta in Both Rings V.14. 2,d-Quinazolinyl Diethers . V.16. Quinmolinyl Ethers with Ether Groups in the Benzene Ring . V.16. Chloroquiuctzolinyl Ethers with Chloro and Ether Groups in the

V.17. Chloroquinazolinyl Ethers with Chloro and Ether Croups in

.

. .

PyrhidineRing ,

SeprateRings . VI.1.

vI.2. vI.3. vI.4. m.5. VI.6. vI.7.

vf.8. VI.9.

1,2- m d 2,3-Dihydro-2-thioquinazolines, and 2-Alkylthi0- rtnd 2-Arylthioquintazolinee . 1,2,3,4-Tetrahydro-2-thiquinazolinea . 4-Substituted 1,2,3,4-Tetrahydro-2-thioqu~azolines . 3,4-Dihydra-4-thioquinuinazolines without Substituents on Nc3, 3,4-Dihydro-4-thioquinszolines Substituted on Nc3, . 4-Alkylthio- and 4-Arylthioquinazolines . 4-Arylsulphonylquinazolin~ and 1,2- and 1,4-Dihydro.4-thio- quinazolines . 2,4-Dithioq~azolines . 2-Alkylthio-3,4-dihydro-4-oxoquinazolinea .

.

xix

198

199 199

202

202

204 204

206

228

235 246 247

249 251 262 263 264 256 258 268 269 280

263

263

2.48

292 293 294 296 297 298

301 302 303

xx Tables

VI.10. 3-Substituted 2-~ylthio-3,4-dihydm-4-oxoquin8zoEn~ . VI. 11. 3-Substituted (and 3-Umbstituted) 1,2,3,4-Tetr&ydm-4-0~0-

2-thioquinszolines . VI. 12. 1 - and 1,3-Substituted 1,2,3,4-Tetrahydro-4-oxo-2-thioqu~o-

lines . VI. 13. 3-Subetituted (end 3.Unsubetituted) 1,2,3,4-Tetrahydr0-4-0~0-

2-thioqujnazolines with Subatituents in the Benzene Ring . VI.14. 3,4-Dihydro-4-oxoquinazolines with Thio or Sulphonyl Group in

the Benzene Ring. . VI.15. Arninothioquinezolines . VI.16. Thiaeolo(2,3-b)qhzolin-5-ones . VI. 17. 2,3-Dihydrothiazolo( 2,3-b)quinazolin-5-ones . VI.18. Thi~.zolo(3,2-a)quinazolin-5-ones . VI.19. 3-H-1,3-Thiazino(3,2-e)quin~o~in~6-oneg . . VI.20. 11-H-Thiazolo(3,2-o)quinazolinea .

VII.1. 2-Amino- and 2-Substituted-aminoquinazolines +

VII.2. 2-Guanidinoquinszolines . M1.4. 4-Substituted-eminoquinazolines . VII.5. 4-Substituted-~inoquinezolines with a Substituent in Position 2 VII.6. 4-Substituted-aminoquinezolines with Substituents in the Benzene

Ring . VII.7. 4-Substituted.aminoquinazolines with Subatituents in Both

Riags. VII.8. 2,4-Diaminoquinazolinea with Substituente in the Benzene Ring. VII.9. 2,4-Bis Substituted-amhoquinazolines , VII.10. 4-Substituted-amino-2-p-ohIorottnilinoqu~~zol~~ . VII. 11. 2,4-Dhmho- (end Substituted-amino-) quinazolines with Subti-

VII.12. Quinazotines with an Amino or Substituted-amino Group in the

VIX. 13. 4-Alkylamino-2-p-chloroanilinoquina.lol with Substituents (in-

VII.14. 4-Amino- (and Substituted-amino-) quinazolinea with an Amino

VII.15. 2-Amino (and Substituted-amino)-3,4-dihydro-4-oxoquinaz0linea

VII.3. 4 -AminOqhOhM ,

tuenta in the Benzene Ring

Benzene Ring . cluding Amino Groups) in the Benzene Ring

(and Substituted-amino) Group in the Benzene Ring

(including its 3-Amino Derivatives). .

.

,

.

VII. 16. 4-AminO (and Substituted-amino)- I , ~ - ~ ~ ~ Y ~ ~ - ~ - O X O C ~ U ~ J Z L Z O ~ M . VII. 17. 4-Amino (and 8ubstituted-amino)- l,Z-dihydro-2-thiqublinea VII. IS. 3,4-Dihydro-4-oxoquinazolinea with Amino (and Substituted-

amino) Groups in Positions 6 or 6 . amino) Groups in Positions 7 or &? . tives . stituent in Position 2 . Substituted (and Umdmtituted) in the Benzene Ring

-1.19. 3,4-Dihydm-4-0~0q~~~0~es With Amino (and Substituted-

VII.20. 3-Amino-3,4-dihydro-4.oxoquinrtzoline and 2-Substituted Deriva-

VII.21. 3-Substituted-amino-3,4-dihydro-4-oxo~~zolin~ with e Sub-

VII.22. 3-Amino (and Subetituted-mr1ino)-3,4-dihydro-4-oxoquie~ .

304

306

308

309

310 310 311 314 315 316 317 342 343 344 345 348

36 1

353 364 365 359

361

362

362

363

364 366 367

367

369

37 1

372

374

Tablea xxi

VII.23, 3-Amino-3,4-dihydro-4-oxoquinazolinee with Substituenta in Position 2 and in the Benzene Ring

VII.24. 3.Substituted-emino.3,4-dihydro-4-oxoqholines With Subati- tuents in Poaition 2 and in the Benzene Ring .

VII.25. 3 - h i n o (and Substituted-amino)-3,4-dihydro-4-oxoqu~olinea Substituted (and Unsubetituted) in Position 2, with Amino (and Substituted-amino) Groups in the Benzene Ring

VII.26. 3 - h i n o (and Substituted-arnino)-3,4-dihydro-4-thioquinazolines VII.27. 3 - h h o (and Substitu~-amino)-1,2,3,4-tetr&ydm-2,4-dioxo-

Vn.28, 1,2,3,4-Tetrahydro-2,4-d~uina~lin~ with Amino (and Sub-

VIT.29. ~ ~ d r 8 2 ~ 0 ~ ~ W O l ~ M with Hydrazino cfmups in the Pyrimidine

.

.

quinazolines , . etituted-amino) Groups in the Benzene R b g

Ring . .

VIII.1. Ionization Constants of Reduaed Quinazolines in Water , VIII.2. 1,2-Dihydroquinctzolinea . VIII.3. I , Z , ~ , ~ - T ~ ~ ~ Y ~ ~ O - ~ - O X O ~ U ~ O ~ ~ . VIII.4. 1,4- and 2,3-Dihydroquina~olines . VIII.5. 3,8-Dihydroquinazol~ee Unmbatituted in Poeitiona 3 and 4 . VIII.6. 3-Substituted 3,4-Dihydroqu~lines . VIII.7. 4-Substituted 3,4-D~ydroquhazoKnes . VIII.8. 1,2,3,4-Tetrahydro-2-oxo-(snd thio-)quinwolinee . VlII.9. 1,2,3,4-Tetmhydroquinezolines (Umubstituted in Position 2) , v l l [ I . l O . 2-Substituted 1,2,3,4.Tetr~hydroqu~olines . Vm.11. 5,Il-Metheno-6H,12H-dibe~olb,f111,5]d~~in~ . VIII.12. 5,6,7,8-Tetrahydroquinazolinee . VIII. 14. 1,2-Disubatituted 1,4,5,0,7,8-Hexahyd-4-0~0- (and thio-)quina-

VIII. 15. 1,2.3,4,6,6,7,8-0atydro-2,4-~liox~linea . VIII. 16. 1,2,3,4,6,6,7,8-0ct&y&o- 2,4 - dithio - (and oxothio-)quimzohea Vm.17. Miecellaneow Reduced Quinazolines .

VIII.13. 3,4.6,6,7,8-He~ahydro-4-0~0q~~0lines . zolinee

fx.1. Ionization Con&mte of Quinwoline-3-oxide~ (H20. 20') . IX.2. Quintwoke-1-oxides . IX.3. Quinazoline-3-oxides . IX.4. 1,2-Dihydro-4-rnethylquinazoline-3-oxidee . IX.6. 3,4-Dihydro-4-oxoquinazoline-l-oxides . IX.7. 3,4-Dihydr0-3-hydro~-4-oxoq~lines . IX.8. 3,4-Dihydro-3-hydroxy-4-thioquinaao~inea .

IX. 10. N-Hydroxy- 1,2,3,4-tetrahydro-2,4-dioxoquinazolineS and Deriva-

IX.5. l - H y d r ~ ~ y - and 3-0x0- ~ , ~ - D ~ ~ Y & o - ~ - o x o ~ u ~ o ~ ~ .

IX.9. 3-AurO~y- and 3 - h l O ~ y - ~ , ~ - D ~ ~ Y ~ - ~ - o x o ~ u ~ I I ~ + z o ~ ~ u M . tivea .

x.1. C y F b n O q ~ o l i n ~ . X.2. Caxbamoyl- and Hydrazinocarbonylquinazolines . X.3. Quinazolines with Carboxy (and Ester) Groups in Positions 2 and 4

Carboxy (or Ester) Group in the pyrimidine Ring X.4. 3,4-Dihyh-4-0~0- and 1,2-Dihydro-2-0~0quinazolines with a

.

376

377

380 381

382

383

383 404 415 415 418 419 420 423 426 427 428 430 430 434

437

489 440

454 461 462 405 466 466 467 468 469

438

410

48 1 48 1 482

483

xxii Tables

X.6. 3,4-Dihydro-4-oxoquinazolinea with a Csrboxy (or Ester) Group in the Benzene Ring . . 484

X.0. 1,2,3,4-Tetrahydro-2,4-dioxoquinazolines with a Carboxy (or

X.7. Quinazolinea with Formyl or Acyl Substituents. . . 486 X.8. 3,4-Dihydro-4-oxoquin~ohes with a Sulpho (or Related) Group

in the Benzene Ring . . 486 X.9. Wnsubstituted Nitroquinazolines and 3,4-Dihydm-4-oxoquinazo-

Related) Group in the Benzene Ring . . 485

lines with an Arsono Group in the Benzene Ring . * 487

CHAPTER I

Introduction

1. History

In 1860 Griess' prepared the first quinazoline derivative, 2-cyano- 3,4-dihydro-4-oxoquinazoline, by the reaction of cyanogen with anthranilic acid. Griess apparently recognized the bicyclic nature of the product, which he called bicyanoamidobenzoyl and used this name until 188@ when the structure 1 was known with some certainty.

Weddige3** cmied out systematic quinazoline syntheses following the observation that the formyl and acetyl derivatives of anthranil- amide lost water on heating. He correctly interpreted this aa a cycliza- tion reaction and waa the first to realize the possibility of tautomeriam in the oxoquinazolines. The preparation of the parent quinazoline came many years later when Bischler and Lang6 obtained it by decarboxyla- tion of the 2-carboxy derivative. A more satisfactory synthesis of quinazoline was subsequently devised by Gabriele who studied its properties and those of ita derivatives in greater detail. A large number and variety of quinazolines were synthesized in an intensive research programme by Bogert and his collaborstors a t Columbia University, U.S.A. The earlier part of this reeectrch was reviewed in 1910.7 The published papers on quinazoline chemistry grew steadily until about 1939 when the annual output until about 1945 waa constant. After the second world war the number of papers rose rapidly for a few years, then was steady until about 1969, and has been increasing rapidly since then.

The discovery in 19S0,8 that quinazoline exists mainly as a hydrated molecule in aqueous acid and the confirmation of the struoture of the hydrated cation in 1961,9 has thrown much light on the under- standing of the properties and reactions of quinazolines. A knowledge of the effects of substituents on the hydration pattern in substituted quinazolinea is very useful in devising new experiments and in under- standing a l d y known properties. The chemistry of quinazolines WM

1

2 Chapter I

reviewed by Williamsonfo in 1957, then by hndquistll in 1959, and was brought up to date by Armaregola in 1963.

2. Nomenclature

Quinazoline hrts also been called phemiadne, benzyleneamidine, benzo-1 ,3-diazineY 5,6-benzopyrimidine, and 1,3-diazanaphthalene. The term phenmiazine was used by Widman13 and later by Bi~chler,~ and the positions in the pyrimidine ring were designated by a, 8, yI and 8 (2). A second system of numbering is shown in 3. The name quinazoline (German: chinamline), which is now universally adopted, was fist proposed by Weddige3 because he observed that his compounde were isomeric with the then known cinnoline and quinoxafine. It probably arose from the fact that it was an aza derivative of quinoline, hence quinazoline. The numbering shown in 4 was suggested by Paal and Buschf4 and is the one in current use.15 The above names and numbering must be remembered particularly when reading through the earlier literature.

The nomenclature used in this volume is essentially, though not entirely, in accordance with the Hundbook for Chemical Society A u t h P published by the Chemical Society of London in 1960. The nomenclature rules used are known as the I.U.P.A.C. I957 rules. The substitutive naming syatem is adopted because in this way it is much easier to find a particular compound from the index and the tables; e.g.

htroduotion 3

2-ethoxycarbonylquinazoIine and not ethyl 2-quinazolinylcarboxylate. The names of radiosla given in the handbook are used, with the exception of ureylene for the radical RNHCONH-, which is here referred to as an N’-substituted ureido radical. Radicals which are not liated, e.g. thioureido, were made up by analogy, or the respective literature naming WEN adopted. In polysubstituted quinazolines the substituents are written alphabetically irrespective of the position of substitution, e.g. 4-a;mino-2-chloroquina~line and not 2-chloro-4-aminoquinazoline. For branched alkyl group the following order is used: butyl, ethyl, isobutyl, methyl, neopentyl, pentyl, 8-butyl, t-butyl, although this is not universally accepted. Bisethylamino and dimethyl a m listed alphabetically under E and My respectively, if the substituents are directly attached to the quinazoline ring system, but not if they are part of a substituent, e.g. 4-dimethylamino is listed under D. These points must be borne in mind particularly when using the tables (see Sect. 6).

The naming of 0x0- and thioquinazolines is confusing, as it is indeed with most heterocyclic compounrb with 0x0 (hydroxy) or thio (thiol) groups a or y to the heterocyclic nitrogen atom. Throughout this work the 2- and 4-hydroxy-, and 2,4-dihydroxyquin~zolinee are named afbr their most likely tautomeric forms which require the dihydrooxo nomenclature after the related parent (hypothetical or not) hydro compound. Thus 4-hyciroxyquinazolinm are always referred to 8 8

3,4-dihydro-4-oxoq~nazolines. This becomes even more confusing when classifying reduced quinazolines where part of the molecule is reduoed and the other part is ‘derived’ (at least by name) from a reduced syatem; e.g. 3,4,6,6-tetrahydro-4-oxoq~n~zoline is a 6,8dihydro compound. This system of nomenclature, however, is used for con- venience and to avoid ambiguity. The names ‘quinazolinone’ and ‘ quinazolinthione ’ are avoided deliberately. Details of the nomenclature used in them compounds are given at the beginning of the relevant chapters (see Chs. IV, VI, and VIII).

3. The Dud Charscter of Quinazobes

Quinazolines oan be divided into two main groups according to their characteristic properties. The firat group includes all the quinazo. lines in which the two rings are fully aromatic. These do not behave entirely as pyrimidines. The benzene ring has a profound effect on the properties of the pyrimidine ring: it delocalizes the w electrons of the 3,4-double bond making its reactivity like that of an isolated double

4 chapter I

bond. As a consequence of this, quinezoline is very reactive towards nucleophiles which readily add &cross the 3,Pdouble bond (Ch. 11, Sect. 3.C.). The cation in water has the structure 5,9+17 which makes it a cyclic carbinolamine. The energy required to form the hydrated cation is such that the electronic effects of substituents in position 218 and in the benzene ringle have a direct influence on the extent of hydration, and consequently the reactivity of the 3,4-double bond (Ch. 11, Sect. 2.C.). The quinazoline-3-oxides behave in a similar way (Ch. IX, Sect. 2.C.). The high polarization of the 3,4-double bond also shows up in the relative reactivity of substituents in positions 2 and 4. The hydrolysis of 4-substituted quinazolines, e.g. chloro and alkoxy (Ch. V, Sects. l.E.b.(ii) and 2.E.b.(i)), amino (Ch. VTI, Sect. LEA.), and apdiethoxycarbonylmetbyl (Ch. 111, Sect. 2.B.e.), to 3,4-dihydro-4- oxoquimzoline is thus more clearly understood.

The second group includes the quinazolines which lack the full complement of six rr electrons in either the pyrimidine or the benzene ring. These compounds can be divided into the quinazolines with tautomeric groups in the pyrimidine ring, and the reduoed quinazolines. The derivatives in this group show the charaoteristic reactions of pyrimidines and the following are a few examples to show the similarity. 2- and 4-Hydroxyquinazoline exist largely in the 0x0 form, they can be converted to chloroquinazolines (Ch. V, Sect. 1.) and are alkylated (Ch. IV, Sect. S.C.b.(i)) in the usual way. Rearrangements of the Dimroth type, which were studied in detail in the pyrimidine series,a0 are also known in aminooxo- and aminothioquinazolinea (Ch. VII, Sect. 1.E.c.). 5,6,7,8-Tetrahydroquinazolines are indeed 4,S-tetra- methylenepyrirnidines (Ch. VIII, Sect. 8.), and the dihydro- and 1,2,3,4-tetrahydroquinazolinea have reactivities of the type observed in reduced pyrimidines,21 although the fused benzene ring confers on them slightly greater stability, and certainly makes them more eaay to isolate.

4. General Summary of Quinazoline Chemistry A. Syntheses

The preparation of quinazolines can be divided into primary and secondary syntheses.

a. Primary Syntheses

In the primary syntheses use is made of the intact mrbocyclic ring and the quinazoline system is built up in many ways; e.g. 6,7, 8,9,10. 11, and 12. The primary syntheses described in this work am not

Introduction 6

classified according to this system but these seven types of ring closure can be easily recognized.

(121

The following are only a few examples for these types of ring closures. The first, 6, is exemplified by Niementowski’s synthesis in which o-aminobenzoic acids (or related compounds) yield 3,4-dihydro-4- oxoquinazolines with amidea (Ch. IV, Sect. 2.A.a.). Bischler’s synthesis is of the type 7 in which quinazolines are formed by reacting o-amido- benzaldehydes (or related compounds) with ammonia (Ch. 111, Sect. l.A.). The type 8 is disguised in several ways which include the forma- tion of 1,2,3,4-tetrahydroquinazolines from o-aminobenzylaminea and aldehydes (Ch. VIII, Sect. 5.B.) and the preparation of quinazoline-t- oxides from o-aminobenzaldehyde or o-aminophenyl ketone oximes and ethyl orthoformate (Ch. IX, Sect. 2.A.) among others. Reductive cyclization of bisamido-o-nitrobenzaldehydes (Riedel’s synthesis, Ch. 111, Sect. l.I.), and o-amidomethylnitrobenzenes (Ch. VIII, Sect. 4.A.) are examples of the type 9. The fifth type 10 is also commonly used, and the cyclization of o-midobermonitriles with alkaline hydrogen peroxide (Ch. IVY Sect. 2.A.c.) and o-amidoacetophenoneoximes by mineral acids (Ch. IX, Sect. 2.A.) to give, respectively, 3,4-dihydro-4- oxoquinazolines and quinazoline-3-oxides, are typical examples. The preparation of 1,2,3,4-tetrahydro-2-oxoquinazoline-s from o-ureido- benzyl alcohols (Ch. VIII, Sect. LA.) and 3,4-dihydroquinazolines from

6 Chapter I

anilines and formaldehyde (Ch. VIII, Sect. 4.B.), are examples of type 11 and IS, respectively.

b. SecondarySynthesea

In the secondary syntheses transformations on the intact skeleton 1% are made. Thus oxidation, reduction, metathesis, addition, and substitution reactions (also reactions involving side chains) which are performed on quinazohes are among the more important examples.

B. The Heightened aeoOtivity of 2- and 4-Alkyl Group

The electron-withdrawing property of the pyrimidine ring in quinazoline is reflected in an increase in the acidity of protons on the a-carbon atoms of 2- and 4-alkyl groups. Many examples are known in which the 2-methyl group (and to a smaller extent the 4-methyl group) react in much the same way as ‘active methylene’ groups adjacent to a strong electron-withdrawing group, e.g. carbonyl. For example, condensation products am formed by reaation with aldehydes and nucleophiles, e.g. - CHRCO,R, and they undergo Mannich reactions. The alkyl groups are not only reactive in alkylquinazolines in which the two rings of the quinazoline nucleus are aromatia (Ch. 111, Sect. 2.B.a.), but also in 2-alkyl-3,4-dihydro-Poxoquinazolines (Ch. IV, Sect. 2.C.b.(ii)); and the reactivity is enhanced by quaternization of the ring nitrogen atoms.

C. Addition and Substitution Reactions, and Nucleophilia M e t a t i d s

Addition of nucIeophilic reagents takes place readily acroas the 3,4-double bond of quinazolines in which the two rings are fully aromatic, and the nucleophile bonds with C,,,. Hence substituents on C,,, can easily hinder these reactions (Ch. 11, Sect. 3.C.). Quinazoline-3- oxides behave similarly (Ch. IX, Sect. 2.C.). Quinazoline is a r-electron deficient system,aa hence electrophilic substitution occurs with di8ticulty. Quinazoline (Ch. 11, Sect. 3.B.1, 3,4-dihydrO-4-0XO- (Ch. IV, Sect. 2.C.b.(iv)), and 1,2,3,4-tetra.hydro-2,4-dioxoquina~oline (Ch. IV,