HETEROCYCUC CHEMISTRY

TkirdedlPlov

J.A. Joule Department of Chemistry

University of Manchester, UK

K. Mills Glaxo Research and Development

Ware, Hertfordshire, UK

G.F. Smith Formerly Department of Chemistry

University of Manchester, UK

m CHAPMAN & HALL

University and Professional Division

London • Glasgow • Weinheim • New York • Tokyo • Melbourne - Madras

Contents

Preface xiii Introduction to the third edition xiii How to use this textbook xv

Definitions of abbreviations xvii

1 Structures and main physical properties of aromatic heterocycles 1 1.1 Carbocyclic aromatic Systems 1 1.2 Structure of six-membered heteroaromatic Systems 3 1.3 Structure of five-membered heteroaromatic Systems 6 1.4 Structures of bicyclic heteroaromatic Compounds 8 1.5 Tautomerism in heterocyclic Systems 8 1.6 Mesoionic Systems 9 1.7 Some spectroscopic properties of some heteroaromatic

Systems 10 References for chapter 1 16

2 Reactivity of aromatic heterocycles 18 2.1 Electrophilic addition at nitrogen 18 2.2 Electrophilic Substitution at carbon 19 2.3 Nucleophilic Substitution at carbon 24 2.4 Radical Substitution at carbon 25 2.5 Deprotonation of Af-hydrogen 29 2.6 Organometallic derivatives 30 2.7 Palladium-catalysed reactions 43 2.8 Oxidation and reduction of heterocyclic rings 49 References for chapter 2 50

3 Synthesis of aromatic heterocycles 56 3.1 Reaction types most frequently used in heterocyclic

ring synthesis 56 3.2 Typical reactant combinations 58

CONTENTS

3.3 Summary 60 3.4 Electrocyclic processes in heterocyclic ring synthesis 61l 3.5 Nitrenes in heterocyclic ring synthesis 62 References for chapter 3 63

4 Typical reactivity of pyridines, quinolines and isoquinolines 64

5 Pyridines: reactions and synthesis 72 5.1 Reactions with electrophilic reagents 73 5.2 Reactions with oxidising agents 79 5.3 Reactions with nucleophilic reagents 80 5.4 Reactions with bases 82 5.5 Reactions of C-metallated pyridines 83 5.6 Reactions with radical reagents 85 5.7 Reactions with reducing agents 86 5.8 Electrocyclic reactions (ground State) 87 5.9 Photochemical reactions 88 5.10 Oxy-and aminopyridines 89 5.11 Alkylpyridines 94 5.12 Pyridine aldehydes, ketones, carboxylic acids and esters 95 5.13 Quaternary pyridinium salts 95 5.14 Pyridine N-oxides 101 5.15 Synthesis of pyridines 104 References for chapter 5 111 Exercises for chapter 5 118

6 Quinolines and isoquinolines: reactions and synthesis 120 6.1 Reactions with electrophilic reagents 121 6.2 Reactions with oxidising agents 123 6.3 Reactions with nucleophilic reagents 123 6.4 Reactions with bases 125 6.5 Reactions of C-metallated quinolines and isoquinolines 126 6.6 Reactions with radical reagents 126 6.7 Reactions with reducing agents 126 6.8 Electrocyclic reactions (ground State) 127 6.9 Photochemical reactions 128 6.10 Oxyquinolines and-isoquinolines 128 6.11 Aminoquinolines and -isoquinolines 130 6.12 Alkylquinolines and-isoquinolines 130 6.13 Quinoline and isoquinoline carboxylic acids and esters 130 6.14 Quaternary quinolinium and isoquinolinium salts 131 6.15 Quinoline and isoquinoline TV-oxides 132 6.16 Synthesis of quinolines and isoquinolines 133

CONTENTS vii

References for chapter 6 141 Exercises for chapter 6 144

7 Typical reactivity of pyrylium and benzopyrylium ions, pyrones and benzopyrones 146

8 Pyryliums, 2- and 4-pyrones: reactions and synthesis 148 8.1 Reactions of pyrylium cations 148 8.2 oc-Pyrones and y-pyrones

(2//-pyran-2-ones and 4//-pyran-4-ones) 153 8.3 Synthesis of pyryliums 157 8.4 Synthesis of a-pyrones 159 8.5 Synthesis of y-pyrones 161 References for chapter 8 162 Exercises for chapter 8 165

9 Benzopyryliums and benzopyrones: reactions and synthesis 166 9.1 Reactions of benzopyryliums 167 9.2 Benzopyrones (chromones, coumarins and isocoumarins) 170 9.3 Synthesis of benzopyryliums, chromones,

coumarins and isocoumarins 176 References for chapter 9 181 Exercises for chapter 9 184

10 Typical reactivity of the diazines: pyridazine, pyrimidine and pyrazine 185

11 The diazines: pyridazine, pyrimidine and pyrazine: reactions and synthesis 189 11.1 Reactions with electrophilic reagents 191 11.2 Reactions with oxidising agents 193 11.3 Reactions with nucleophilic reagents 193 11.4 Reactions with bases 196 11.5 Reactions of C-metallated diazines 196 11.6 Reactions with reducing agents 198 11.7 Reactions with radical reagents 198 11.8 Electrocyclic and photochemical reactions 199 11.9 Diazine N-oxides 200 11.10 Oxydiazines 201 11.11 Aminodiazines 208 11.12 Alkyldiazines 209 11.13 Synthesis of diazines 210

V l l l CONTENTS

References for chapter 11 218 Exercises for chapter 11 223

12 Typical reactivity of pyrroles, thiophenes and furans 225

13 Pyrroles: reactions and synthesis 229 13.1 Reactions with electrophilic reagents 231 13.2 Reactions with oxidising agents 238 13.3 Reactions with nucleophilic reagents 239 13.4 Reactions with bases 239 13.5 Reactions of N-metallated pyrroles 240 13.6 Reactions of C-metallated pyrroles 240 13.7 Reactions with radical reagents 241 13.8 Reactions with reducing agents 241 13.9 Electrocyclic reactions (ground State) 242 13.10 Reactions with carbenes 243 13.11 Photochemical reactions 243 13.12 Pyrryl-C-X Compounds 244 13.13 Pyrrole aldehydes and ketones 244 13.14 Pyrrole carboxylic acids 244 13.15 Pyrrole carboxylic acid esters 245 13.16 Halopyrroles ' 245 13.17 Oxy-and aminopyrroles 246 13.18 Synthesis of pyrroles 247 References for chapter 13 253 Exercises for chapter 13 257

14 Thiophenes: reactions and synthesis 259 14.1 Reactions with electrophilic reagents 260 14.2 Reactions with oxidising agents 264 14.3 Reactions with nucleophilic reagents 264 14.4 Reactions with bases 265 14.5 Reactions of C-metallated thiophenes 265 14.6 Reactions with radical reagents 267 14.7 Reactions with reducing agents 267 14.8 Electrocyclic reactions (ground State) 268 14.9 Photochemical reactions 269 14.10 Thiophene-C-X Compounds: thenyl derivatives 269 14.11 Thiophene aldehydes and ketones, and carboxylic

acids and esters 269 14.12 Oxy- and aminothiophenes 270 14.13 Synthesis of thiophenes 271 References for chapter 14 274 Exercises for chapter 14 277

CONTENTS

15 Furans: reactions and synthesis 278 15.1 Reactions with electrophilic reagents 279 15.2 Reactions with oxidising agents 282 15.3 Reactions with nucleophilic reagents 283 15.4 Reactions with bases 283 15.5 Reactions of C-metallated furans 284 15.6 Reactions with radical reagents 285 15.7 Reactions with reducing agents 285 15.8 Electrocyclic reactions (ground State) 285 15.9 Photochemical reactions 287 15.10 Furyl-C-X Compounds; side-chain properties 287 15.11 Furan carboxylic acids and esters 287 15.12 Oxy-and aminofurans 288 15.13 Synthesis of furans 290 References for chapter 15 295 Exercises for chapter 15 299

16 Reactivity of indoles, benzo[6]thiophenes, benzo[6]furans, isoindoles, benzo[c]thiophenes and isobenzofurans 301

17 Indoles: reactions and synthesis 305 17.1 Reactions with electrophilic reagents 307 17.2 Reactions with oxidising agents 316 17.3 Reactions with nucleophilic reagents 317 17.4 Reactions with bases 318 17.5 Reactions of N-metallated indoles 319 17.6 Reactions of C-metallated indoles 320 17.7 Reactions with radicals 322 17.8 Reactions with reducing agents 322 17.9 Reactions with carbenes 323 17.10 Electrocyclic and photochemical reactions 324 17.11 Alkylindoles 325 17.12 Reactions of indolyl-C-X Compounds 326 17.13 Indole carboxylic acids 327 17.14 Oxyindoles 327 17.15 Aminoindoles 330 17.16 Synthesis of indoles 330 References for chapter 17 341 Exercises for chapter 17 348

18 Benzo[ft]thiophenes and benzo[6]furans: reactions and synthesis 350 18.1 Reactions with electrophilic reagents 350 18.2 Reactions with nucleophilic reagents 352

CONTENTS

18.3 Reactions with bases; reactions of C-metallated benz[b]thiophenes and benzo[ft]furans 352

18.4 Reactions with reducing agents 353 18.5 Oxy- and amino-benzothiophenes and -benzofurans 354 18.6 Synthesis of benzo[ö]thiophenes and benzo[fr]furans 354 References for chapter 18 357 Exercises for chapter 18 359

19 Isoindoles, benzo[c]thiophenes and isobenzofurans: reactions and synthesis 360 19.1 Reactions with electrophilic reagents 361 19.2 Electrocyclic reactions (ground State) 361 19.3 Phthalocyanines 362 19.4 Synthesis of isoindoles, benzo[c]fhiophenes

and isobenzofurans 362 References for chapter 19 365 Exercises for chapter 19 366

20 Typical reactivity of 1,3- and 1,2-azoles 367

21 1,3-Azoles: imidazoles, thiazoles and oxazoles: reactions and synthesis 370 21.1 Reactions with electrophilic reagents 371 21.2 Reactions with oxidising agents 375 21.3 Reactions with nucleophilic reagents 376 21.4 Reactions with bases 376 21.5 Reactions of N-metallated imidazoles 377 21.6 Reactions of C-metallated 1,3-azoles 377 21.7 Reactions with reducing agents 378 21.8 Electrocyclic and photochemical reactions 378 21.9 Alkyl-l,3-azoles 380 21.10 Quaternary 1,3-azolium salts 381 21.11 Oxy-and amino-l,3-azoles 382 21.12 Synthesis of 1,3-azoles 384 References for chapter 21 388 Exercises for chapter 21 392

22 1,2-AzoIes: pyrazoles, isothiazoles and isoxazoles: reactions and synthesis 394 22.1 Reactions with electrophilic reagents 395 22.2 Reactions with oxidising agents 396 22.3 Reactions with nucleophilic reagents 397 22.4 Reactions with bases 397

CONTENTS

22.5 Reactions of yV-metallated pyrazoles 398 22.6 Reactions of C-metallated 1,2-azoles 398 22.7 Reactions with reducing agents 399 22.8 Electrocyclic and photochemical reactions 399 22.9 Alkyl-1,2-azoles 400 22.10 Quaternary 1,2-azolium salts 400 22.11 Oxy- and amino- 1,2-azoles 401 22.12 Synthesisof 1,2-azoles 402 References for chapter 22 405 Exercises for chapter 22 407

23 Purines: reactions and synthesis 409 23.1 Nucleic acids, nucleosides and nucleotides 411 23.2 Reactions with electrophilic reagents 412 23.3 Reactions with radical reagents 416 23.4 Reactions with oxidising agents 417 23.5 Reactions with reducing agents 417 23.6 Reactions with nucleophilic reagents 417 23.7 Reactions with bases 419 23.8 Reactions of yV-metallated purines 420 23.9 Reactions of C-metallated purines 420 23.10 Oxy-and aminopurines 421 23.11 Alkylpurines 425 23.12 Purine carboxylic acids 425 23.13 Synthesis of purines 425 References for chapter 23 430 Exercises for chapter 23 433

24 Heterocycles containing a ring-junction nitrogen 434 24.1 Indolizines 435 24.2 Aza-indolizines 437 24.3 Quinoliziniums and related Systems 441 24.4 Pyrrolizines and related Systems 442 24.5 Cyclazines 443 References for chapter 24 444 Exercises for chapter 24 445

25 Heterocycles containing more than two hetero atoms 447 25.1 Five-membered rings 448 25.2 Six-membered rings 457 References for chapter 25 459 Exercises for chapter 25 462

XU CONTENTS

26 Saturated and partially unsaturated heterocyclic Compounds: reactions and synthesis 463 26.1 Five- and six-membered rings 464 26.2 Three-membered rings 468 26.3 Four-membered rings 471 26.4 Metallation 472 26.5 Ring synthesis 473 References for chapter 26 476

27 Appendix: answers to exercises 479

Index 485