Heterocyclic Chemistry 5th Edition PDF

Heterocyclic Chemistry Fifth Edition John A. Joule School of Chemistry, The University of Manchester, UK Keith Mills Chemistry Consultant, Ware, UK A John Wiley & Sons, Ltd., Publication Heterocyclic Chemist...

Heterocyclic Chemistry Fifth Edition John A. Joule School of Chemistry, The University of Manchester, UK Keith Mills Chemistry Consultant, Ware, UK A John Wiley & Sons, Ltd., Publication Heterocyclic Chemistry Heterocyclic Chemistry Fifth Edition John A. Joule School of Chemistry, The University of Manchester, UK Keith Mills Chemistry Consultant, Ware, UK A John Wiley & Sons, Ltd., Publication This edition first published 2010 © 2010 Blackwell Publishing Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. 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No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Joule, J. A. (John Arthur) Heterocyclic chemistry / John A. Joule, Keith Mills. – 5th ed. p. cm. Includes bibliographical references and index. ISBN 978-1-4051-9365-8 (pbk.) – ISBN 978-1-4051-3300-5 (pbk.) 1. Heterocyclic chemistry. I. Mills, K. (Keith) II. Title. QD400.J59 2009 547′.59–dc22 2009028759 ISBN Cloth: 978-1-405-19365-8 ISBN Paper: 978-1-405-13300-5 A catalogue record for this book is available from the British Library. Set in 10 on 12 pt Times by Toppan Best-set Premedia Limited Printed and bound in Singapore by Fabulous Printers Pte Ltd  Contents Preface to the Fifth Edition xix P.1 Hazards xxi P.2 How to Use This Textbook xxi Acknowledgements xxii References xxii Web Site xxii Biography xxiii Definitions of Abbreviations xxv 1 Heterocyclic Nomenclature 1 2 Structures and Spectroscopic Properties of Aromatic Heterocycles 5 2.1 Carbocyclic Aromatic Systems 5 2.1.1 Structures of Benzene and Naphthalene 5 2.1.2 Aromatic Resonance Energy 6 2.2 Structure of Six-Membered Heteroaromatic Systems 7 2.2.1 Structure of Pyridine 7 2.2.2 Structure of Diazines 7 2.2.3 Structures of Pyridinium and Related Cations 8 2.2.4 Structures of Pyridones and Pyrones 8 2.3 Structure of Five-Membered Heteroaromatic Systems 9 2.3.1 Structure of Pyrrole 9 2.3.2 Structures of Thiophene and Furan 10 2.3.3 Structures of Azoles 10 2.3.4 Structures of Pyrryl and Related Anions 11 2.4 Structures of Bicyclic Heteroaromatic Compounds 11 2.5 Tautomerism in Heterocyclic Systems 12 2.6 Mesoionic Systems 12 2.7 Some Spectroscopic Properties of Some Heteroaromatic Systems 13 2.7.1 Ultraviolet/Visible (Electronic) Spectroscopy 13 2.7.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 14 References 17 3 Substitutions of Aromatic Heterocycles 19 3.1 Electrophilic Addition at Nitrogen 19 3.2 Electrophilic Substitution at Carbon 20 3.2.1 Aromatic Electrophilic Substitution: Mechanism 20 3.2.2 Six-Membered Heterocycles 21 3.2.3 Five-Membered Heterocycles 22 vi Contents 3.3 Nucleophilic Substitution at Carbon 24 3.3.1 Aromatic Nucleophilic Substitution: Mechanism 24 3.3.2 Six-Membered Heterocycles 24 3.3.3 Vicarious Nucleophilic Substitution (VNS Substitution) 26 3.4 Radical Substitution at Carbon 27 3.4.1 Reactions of Heterocycles with Nucleophilic Radicals 27 3.4.2 Reactions with Electrophilic Radicals 30 3.5 Deprotonation of N-Hydrogen 30 3.6 Oxidation and Reduction of Heterocyclic Rings 31 3.7 ortho-Quinodimethanes in Heterocyclic Compound Synthesis 31 References 33 4 Organometallic Heterocyclic Chemistry 37 4.1 Preparation and Reactions of Organometallic Compounds 37 4.1.1 Lithium 37 4.1.2 Magnesium 45 4.1.3 Zinc 47 4.1.4 Copper 48 4.1.5 Boron 48 4.1.6 Silicon and Tin 52 4.1.7 Mercury 54 4.1.8 Palladium 54 4.1.9 Side-Chain Metallation (‘Lateral Metallation’) 54 4.2 Transition Metal-Catalysed Reactions 56 4.2.1 Basic Palladium Processes 56 4.2.2 Catalysts 59 4.2.3 The Electrophilic Partner; The Halides/Leaving Groups 61 4.2.4 Cross-Coupling Reactions 64 4.2.5 The Nucleophilic (Organometallic) Partner 65 4.2.6 Other Nucleophiles 70 4.2.7 The Ring Systems in Cross-Coupling Reactions 71 4.2.8 Organometallic Selectivity 77 4.2.9 Direct C–H Arylation 79 4.2.10 N-Arylation 83 4.2.11 Heck Reactions 87 4.2.12 Carbonylation Reactions 89 References 90 5 Methods in Heterocyclic Chemistry 97 5.1 Solid-Phase Reactions and Related Methods 97 5.1.1 Solid-Phase Reactions 97 5.1.2 Solid-Supported Reagents and Scavengers 99 5.1.3 Solid-Phase Extraction (SPE) 100 5.1.4 Soluble Polymer-Supported Reactions 100 5.1.5 Phase Tags 101 5.2 Microwave Heating 103 5.3 Flow Reactors 104 5.4 Hazards: Explosions 105 References 105  Contents vii 6 Ring Synthesis of Aromatic Heterocycles 107 6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis 107 6.2 Typical Reactant Combinations 108 6.2.1 Typical Ring Synthesis of a Pyrrole Involving Only C–Heteroatom Bond Formation 108 6.2.2 Typical Ring Synthesis of a Pyridine Involving Only C–Heteroatom Bond Formation 109 6.2.3 Typical Ring Syntheses Involving C–Heteroatom C–C Bond Formations 109 6.3 Summary 111 6.4 Electrocyclic Processes in Heterocyclic Ring Synthesis 112 6.5 Nitrenes in Heterocyclic Ring Synthesis 113 6.6 Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles 113 References 114 7 Typical Reactivity of Pyridines, Quinolines and Isoquinolines 115 8 Pyridines: Reactions and Synthesis 125 8.1 Reactions with Electrophilic Reagents 125 8.1.1 Addition to Nitrogen 125 8.1.2 Substitution at Carbon 128 8.2 Reactions with Oxidising Agents 130 8.3 Reactions with Nucleophilic Reagents 131 8.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 131 8.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 133 8.4 Metallation and Reactions of C-Metallated-Pyridines 134 8.4.1 Direct Ring C–H Metallation 134 8.4.2 Metal–Halogen Exchange 137 8.5 Reactions with Radicals; Reactions of Pyridyl Radicals 138 8.5.1 Halogenation 138 8.5.2 Carbon Radicals 138 8.5.3 Dimerisation 138 8.5.4 Pyridinyl Radicals 139 8.6 Reactions with Reducing Agents 139 8.7 Electrocyclic Reactions (Ground State) 140 8.8 Photochemical Reactions 140 8.9 Oxy- and Amino-Pyridines 141 8.9.1 Structure 141 8.9.2 Reactions of Pyridones 142 8.9.3 Reactions of Amino-Pyridines 144 8.10 Alkyl-Pyridines 146 8.11 Pyridine Aldehydes, Ketones, Carboxylic Acids and Esters 148 8.12 Quaternary Pyridinium Salts 148 8.12.1 Reduction and Oxidation 148 8.12.2 Organometallic and Other Nucleophilic Additions 150 8.12.3 Nucleophilic Addition Followed by Ring Opening 152 8.12.4 Cyclisations Involving an α-Position or an α-Substituent 153 8.12.5 N-Dealkylation 153 8.13 Pyridine N-oxides 153 8.13.1 Electrophilic Addition and Substitution 154 8.13.2 Nucleophilic Addition and Substitution 155 8.13.3 Addition of Nucleophiles then Loss of Oxide 155 viii Contents 8.14 Synthesis of Pyridines 156 8.14.1 Ring Synthesis 156 8.14.2 Examples of Notable Syntheses of Pyridine Compounds 165 Exercises 166 References 168 9 Quinolines and Isoquinolines: Reactions and Synthesis 177 9.1 Reactions with Electrophilic Reagents 177 9.1.1 Addition to Nitrogen 177 9.1.2 Substitution at Carbon 177 9.2 Reactions with Oxidising Agents 179 9.3 Reactions with Nucleophilic Reagents 179 9.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 179 9.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 180 9.4 Metallation and Reactions of C-Metallated Quinolines and Isoquinolines 181 9.4.1 Direct Ring C–H Metallation 181 9.4.2 Metal–Halogen Exchange 182 9.5 Reactions with Radicals 182 9.6 Reactions with Reducing Agents 183 9.7 Electrocyclic Reactions (Ground State) 183 9.8 Photochemical Reactions 183 9.9 Oxy-Quinolines and Oxy-Isoquinolines 183 9.10 Amino-Quinolines and Amino-Isoquinolines 185 9.11 Alkyl-Quinolines and Alkyl-Isoquinolines 185 9.12 Quinoline and Isoquinoline Carboxylic Acids and Esters 185 9.13 Quaternary Quinolinium and Isoquinolinium Salts 186 9.14 Quinoline and Isoquinoline N-Oxides 188 9.15 Synthesis of Quinolines and Isoquinolines 188 9.15.1 Ring Syntheses 188 9.15.2 Examples of Notable Syntheses of Quinoline and Isoquinoline Compounds 198 Exercises 199 References 200 10 Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones 205 11 Pyryliums, 2- and 4-Pyrones: Reactions and Synthesis 209 11.1 Reactions of Pyrylium Cations 209 11.1.1 Reactions with Electrophilic Reagents 209 11.1.2 Addition Reactions with Nucleophilic Reagents 210 11.1.3 Substitution Reactions with Nucleophilic Reagents 212 11.1.4 Reactions with Radicals 212 11.1.5 Reactions with Reducing Agents 212 11.1.6 Photochemical Reactions 212 11.1.7 Reactions with Dipolarophiles; Cycloadditions 213 11.1.8 Alkyl-Pyryliums 213 11.2 2-Pyrones and 4-Pyrones (2H-Pyran-2-ones and 4H-Pyran-4-ones; α- and γ-Pyrones) 214 11.2.1 Structure of Pyrones 214 11.2.2 Reactions of Pyrones 214  Contents ix 11.3 Synthesis of Pyryliums 218 11.3.1 From 1,5-Dicarbonyl Compounds 218 11.3.2 Alkene Acylation 219 11.3.3 From 1,3-Dicarbonyl Compounds and Ketones 220 11.4 Synthesis of 2-Pyrones 220 11.4.1 From 1,3-Keto(aldehydo)-Acids and Carbonyl Compounds 220 11.4.2 Other Methods 221 11.5 Synthesis of 4-Pyrones 222 Exercises 224 References 225 12 Benzopyryliums and Benzopyrones: Reactions and Synthesis 229 12.1 Reactions of Benzopyryliums 229 12.1.1 Reactions with Electrophilic Reagents 229 12.1.2 Reactions with Oxidising Agents 230 12.1.3 Reactions with Nucleophilic Reagents 230 12.1.4 Reactions with Reducing Agents 231 12.1.5 Alkyl-Benzopyryliums 231 12.2 Benzopyrones (Chromones, Coumarins and Isocoumarins) 232 12.2.1 Reactions with Electrophilic Reagents 232 12.2.2 Reactions with Oxidising Agents 232 12.2.3 Reactions with Nucleophilic Reagents 233 12.3 Synthesis of Benzopyryliums, Chromones, Coumarins and Isocoumarins 237 12.3.1 Ring Synthesis of 1-Benzopyryliums 237 12.3.2 Ring Synthesis of Coumarins 238 12.3.3 Ring Synthesis of Chromones 240 12.3.4 Ring Synthesis of 2-Benzopyryliums 242 12.3.5 Ring Synthesis of Isocoumarins 243 12.3.6 Notable Examples of Benzopyrylium and Benzopyrone Syntheses 243 Exercises 244 References 245 13 Typical Reactivity of the Diazine: Pyridazine, Pyrimidine and Pyrazine 249 14 The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions and Synthesis 253 14.1 Reactions with Electrophilic Reagents 253 14.1.1 Addition at Nitrogen 253 14.1.2 Substitution at Carbon 255 14.2 Reactions with Oxidising Agents 255 14.3 Reactions with Nucleophilic Reagents 255 14.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 256 14.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 256 14.4 Metallation and Reactions of C-Metallated Diazines 259 14.4.1 Direct Ring C–H Metallation 259 14.4.2 Metal–Halogen Exchange 260 14.5 Reactions with Reducing Agents 261 14.6 Reactions with Radicals 261 14.7 Electrocyclic Reactions 261 14.8 Diazine N-Oxides 262 x Contents 14.9 Oxy-Diazines 263 14.9.1 Structure of Oxy-Diazines 263 14.9.2 Reactions of Oxy-Diazines 264 14.10 Amino-Diazines 271 14.11 Alkyl-Diazines 272 14.12 Quaternary Diazinium Salts 273 14.13 Synthesis of Diazines 273 14.13.1 Pyridazines 274 14.13.2 Pyrimidines 275 14.13.3 Pyrazines 279 14.13.4 Notable Syntheses of Diazines 281 14.14 Pteridines 282 Exercises 283 References 284 15 Typical Reactivity of Pyrroles, Furans and Thiophenes 289 16 Pyrroles: Reactions and Synthesis 295 16.1 Reactions with Electrophilic Reagents 295 16.1.1 Substitution at Carbon 296 16.2 Reactions with Oxidising Agents 303 16.3 Reactions with Nucleophilic Reagents 303 16.4 Reactions with Bases 304 16.4.1 Deprotonation of N-Hydrogen and Reactions of Pyrryl Anions 304 16.4.2 Lithium, Sodium, Potassium and Magnesium Derivatives 304 16.5 C-Metallation and Reactions of C-Metallated Pyrroles 305 16.5.1 Direct Ring C–H Metallation 305 16.5.2 Metal–Halogen Exchange 305 16.6 Reactions with Radicals 306 16.7 Reactions with Reducing Agents 306 16.8 Electrocyclic Reactions (Ground State) 307 16.9 Reactions with Carbenes and Carbenoids 308 16.10 Photochemical Reactions 308 16.11 Pyrryl-C-X Compounds 309 16.12 Pyrrole Aldehydes and Ketones 309 16.13 Pyrrole Carboxylic Acids 309 16.14 Pyrrole Carboxylic Acid Esters 310 16.15 Oxy- and Amino-Pyrroles 310 16.15.1 2-Oxy-Pyrroles 310 16.15.2 3-Oxy-Pyrroles 311 16.15.3 Amino-Pyrroles 311 16.16 Synthesis of Pyrroles 311 16.16.1 Ring Synthesis 311 16.16.2 Some Notable Syntheses of Pyrroles 317 Exercises 319 References 320 17 Thiophenes: Reactions and Synthesis 325 17.1 Reactions with Electrophilic Reagents 325 17.1.1 Substitution at Carbon 325 17.1.2 Addition at Sulfur 329  Contents xi 17.2 Reactions with Oxidising Agents 330 17.3 Reactions with Nucleophilic Reagents 330 17.4 Metallation and Reactions of C-Metallated Thiophenes 331 17.4.1 Direct Ring C–H Metallation 331 17.4.2 Metal–Halogen Exchange 331 17.5 Reactions with Radicals 333 17.6 Reactions with Reducing Agents 333 17.7 Electrocyclic Reactions (Ground State) 333 17.8 Photochemical Reactions 334 17.9 Thiophene-C–X Compounds: Thenyl Derivatives 334 17.10 Thiophene Aldehydes and Ketones, and Carboxylic Acids and Esters 335 17.11 Oxy- and Amino-Thiophenes 335 17.11.1 Oxy-Thiophenes 335 17.11.2 Amino-Thiophenes 336 17.12 Synthesis of Thiophenes 336 17.12.1 Ring Synthesis 336 17.12.2 Examples of Notable Syntheses of Thiophene Compounds 340 Exercises 342 References 342 18 Furans: Reactions and Synthesis 347 18.1 Reactions with Electrophilic Reagents 347 18.1.1 Substitution at Carbon 347 18.2 Reactions with Oxidising Agents 351 18.3 Reactions with Nucleophilic Reagents 352 18.4 Metallation and Reactions of C-Metallated Furans 352 18.4.1 Direct Ring C–H Metallation 352 18.4.2 Metal–Halogen Exchange 353 18.5 Reactions with Radicals 353 18.6 Reactions with Reducing Agents 353 18.7 Electrocyclic Reactions (Ground State) 353 18.8 Reactions with Carbenes and Carbenoids 356 18.9 Photochemical Reactions 356 18.10 Furyl-C–X Compounds; Side-Chain Properties 356 18.11 Furan Carboxylic Acids and Esters and Aldehydes 356 18.12 Oxy- and Amino-Furans 357 18.12.1 Oxy-Furans 357 18.12.2 Amino-Furans 358 18.13 Synthesis of Furans 358 18.13.1 Ring Syntheses 359 18.13.2 Examples of Notable Syntheses of Furans 363 Exercises 364 References 365 19 Typical Reactivity of Indoles, Benzo[b]thiophenes, Benzo[b]furans, Isoindoles, Benzo[c]thiophenes and Isobenzofurans 369 20 Indoles: Reactions and Synthesis 373 20.1 Reactions with Electrophilic Reagents 373 20.1.1 Substitution at Carbon 373 xii Contents 20.2 Reactions with Oxidising Agents 385 20.3 Reactions with Nucleophilic Reagents 386 20.4 Reactions with Bases 386 20.4.1 Deprotonation of N-Hydrogen and Reactions of Indolyl Anions 386 20.5 C-Metallation and Reactions of C-Metallated Indoles 388 20.5.1 Direct Ring C–H Metallation 388 20.5.2 Metal–Halogen Exchange 390 20.6 Reactions with Radicals 391 20.7 Reactions with Reducing Agents 392 20.8 Reactions with Carbenes 392 20.9 Electrocyclic and Photochemical Reactions 393 20.10 Alkyl-Indoles 394 20.11 Reactions of Indolyl-C–X Compounds 395 20.12 Indole Carboxylic Acids 396 20.13 Oxy-Indoles 397 20.13.1 Oxindole 397 20.13.2 Indoxyl 398 20.13.3 Isatin 399 20.13.4 1-Hydroxyindole 399 20.14 Amino-Indoles 400 20.15 Aza-Indoles 400 20.15.1 Electrophilic Substitution 401 20.15.2 Nucleophilic Substitution 401 20.16 Synthesis of Indoles 402 20.16.1 Ring Synthesis of Indoles 402 20.16.2 Ring Synthesis of Oxindoles 416 20.16.3 Ring Synthesis of Indoxyls 417 20.16.4 Ring Synthesis of Isatins 418 20.16.5 Synthesis of 1-Hydroxy-Indoles 418 20.16.6 Examples of Notable Indole Syntheses 418 20.16.7 Synthesis of Aza-Indoles 421 Exercises 422 References 423 21 Benzo[b]thiophenes and Benzo[b]furans: Reactions and Synthesis 433 21.1 Reactions with Electrophilic Reagents 433 21.1.1 Substitution at Carbon 433 21.1.2 Addition to Sulfur in Benzothiophenes 434 21.2 Reactions with Nucleophilic Reagents 435 21.3 Metallation and Reactions of C-Metallated Benzothiophenes and Benzofurans 435 21.4 Reactions with Radicals 436 21.5 Reactions with Oxidising and Reducing Agents 436 21.6 Electrocyclic Reactions 436 21.7 Oxy- and Amino-Benzothiophenes and -Benzofurans 437 21.8 Synthesis of Benzothiophenes and Benzofurans 437 21.8.1 Ring Synthesis 437 Exercises 443 References 443  Contents xiii 22 Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions and Synthesis 447 22.1 Reactions with Electrophilic Reagents 447 22.2 Electrocyclic Reactions 448 22.3 Phthalocyanines 449 22.4 Synthesis of Isoindoles, Benzo[c]thiophenes and Isobenzofurans 449 22.4.1 Isoindoles 449 22.4.2 Benzo[c]thiophenes 450 22.4.3 Isobenzofurans 451 Exercises 452 References 452 23 Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and -1,2-Azoles 455 24 1,3-Azoles: Imidazoles, Thiazoles and Oxazoles: Reactions and Synthesis 461 24.1 Reactions with Electrophilic Reagents 461 24.1.1 Addition at Nitrogen 461 24.1.2 Substitution at Carbon 464 24.2 Reactions with Oxidising Agents 466 24.3 Reactions with Nucleophilic Reagents 466 24.3.1 With Replacement of Hydrogen 466 24.3.2 With Replacement of Halogen 466 24.4 Reactions with Bases 467 24.4.1 Deprotonation of Imidazole N-Hydrogen and Reactions of Imidazolyl Anions 467 24.5 C-Metallation and Reactions of C-Metallated 1,3-Azoles 467 24.5.1 Direct Ring C–H Metallation 467 24.5.2 Metal–Halogen Exchange 468 24.6 Reactions with Radicals 468 24.7 Reactions with Reducing Agents 469 24.8 Electrocyclic Reactions 469 24.9 Alkyl-1,3-Azoles 470 24.10 Quaternary 1,3-Azolium Salts 470 24.11 Oxy- and Amino-1,3-Azoles 471 24.12 1,3-Azole N-Oxides 473 24.13 Synthesis of 1,3-Azoles 473 24.13.1 Ring Synthesis 473 24.13.2 Examples of Notable Syntheses Involving 1,3-Azoles 478 Exercises 479 References 480 25 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 485 25.1 Reactions with Electrophilic Reagents 486 25.1.1 Addition at Nitrogen 486 25.1.2 Substitution at Carbon 487 25.2 Reactions with Oxidising Agents 488 25.3 Reactions with Nucleophilic Reagents 488 25.4 Reactions with Bases 488 25.4.1 Deprotonation of Pyrazole N-Hydrogen and Reactions of Pyrazolyl Anions 488 xiv Contents 25.5 C-Metallation and Reactions of C-Metallated 1,2-Azoles 489 25.5.1 Direct Ring C–H Metallation 489 25.5.2 Metal–Halogen Exchange 490 25.6 Reactions with Radicals 490 25.7 Reactions with Reducing Agents 490 25.8 Electrocyclic and Photochemical Reactions 491 25.9 Alkyl-1,2-Azoles 492 25.10 Quaternary 1,2-Azolium Salts 492 25.11 Oxy- and Amino-1,2-azoles 493 25.12 Synthesis of 1,2-Azoles 494 25.12.1 Ring Synthesis 494 Exercises 498 References 498 26 Benzanellated Azoles: Reactions and Synthesis 503 26.1 Reactions with Electrophilic Reagents 503 26.1.1 Addition at Nitrogen 503 26.1.2 Substitution at Carbon 504 26.2 Reactions with Nucleophilic Reagents 505 26.3 Reactions with Bases 505 26.3.1 Deprotonation of N-Hydrogen and Reactions of Benzimidazolyl and Indazolyl Anions 505 26.4 Ring Metallation and Reactions of C-Metallated Derivatives 505 26.5 Reactions with Reducing Agents 506 26.6 Electrocyclic Reactions 506 26.7 Quaternary Salts 506 26.8 Oxy- and Amino-Benzo-1,3-Azoles 507 26.9 Synthesis 507 26.9.1 Ring Synthesis of Benzo-1,3-Azoles 507 26.9.2 Ring Synthesis of Benzo-1,2-Azoles 509 References 512 27 Purines: Reactions and Synthesis 515 27.1 Reactions with Electrophilic Reagents 516 27.1.1 Addition at Nitrogen 516 27.1.2 Substitution at Carbon 519 27.2 Reactions with Radicals 521 27.3 Reactions with Oxidising Agents 521 27.4 Reactions with Reducing Agents 521 27.5 Reactions with Nucleophilic Reagents 521 27.6 Reactions with Bases 524 27.6.1 Deprotonation of N-Hydrogen and Reactions of Purinyl Anions 524 27.7 C-Metallation and Reactions of C-Metallated Purines 524 27.7.1 Direct Ring C–H Metallation 524 27.7.2 Metal–Halogen Exchange 525 27.8 Oxy- and Amino-Purines 525 27.8.1 Oxy-Purines 526 27.8.2 Amino-Purines 527 27.8.3 Thio-Purines 529  Contents xv 27.9 Alkyl-Purines 530 27.10 Purine Carboxylic Acids 530 27.11 Synthesis of Purines 530 27.11.1 Ring Synthesis 530 27.11.2 Examples of Notable Syntheses Involving Purines 534 Exercises 535 References 536 28 Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 539 28.1 Indolizines 539 28.1.1 Reactions of Indolizines 540 28.1.2 Ring Synthesis of Indolizines 541 28.2 Aza-Indolizines 543 28.2.1 Imidazo[1,2-a]pyridines 543 28.2.2 Imidazo[1,5-a]pyridines 545 28.2.3 Pyrazolo[1,5-a]pyridines 546 28.2.4 Triazolo- and Tetrazolo-Pyridines 547 28.2.5 Compounds with an Additional Nitrogen in the Six-Membered Ring 549 28.3 Quinolizinium and Related Systems 551 28.4 Pyrrolizine and Related Systems 551 28.5 Cyclazines 552 Exercises 553 References 553 29 Heterocycles Containing More Than Two Heteroatoms 557 29.1 Five-Membered Rings 557 29.1.1 Azoles 557 29.1.2 Oxadiazoles and Thiadiazoles 569 29.1.3 Other Systems 574 29.2 Six-Membered Rings 574 29.2.1 Azines 574 29.3 Benzotriazoles 579 Exercises 581 References 581 30 Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis 587 30.1 Five- and Six-Membered Rings 588 30.1.1 Pyrrolidines and Piperidines 588 30.1.2 Piperideines and Pyrrolines 589 30.1.3 Pyrans and Reduced Furans 590 30.2 Three-Membered Rings 592 30.2.1 Three-Membered Rings with One Heteroatom 592 30.2.2 Three-Membered Rings with Two Heteroatoms 596 30.3 Four-Membered Rings 597 30.4 Metallation 598 30.5 Ring synthesis 599 30.5.1 Aziridines and Azirines 600 30.5.2 Azetidines and β-Lactams 602 30.5.3 Pyrrolidines 602 xvi Contents 30.5.4 Piperidines 603 30.5.5 Saturated Oxygen Heterocycles 604 30.5.6 Saturated Sulfur Heterocycles 605 References 606 31 Special Topics 609 31.1 Synthesis of Ring-Fluorinated Heterocycles 609 31.1.1 Electrophilic Fluorination 609 31.1.2 The Balz–Schiemann Reaction 611 31.1.3 Halogen Exchange (Halex) Reactions 612 31.1.4 Ring Synthesis Incorporating Fluorinated Starting Materials 612 31.2 Isotopically Labelled Heterocycles 616 31.2.1 Hazards Due to Radionuclides 616 31.2.2 Synthesis 616 31.2.3 PET (Positron Emission Tomography) 617 31.3 Bioprocesses in Heterocyclic Chemistry 619 31.4 Green Chemistry 620 31.5 Ionic Liquids 620 31.6 Applications and Occurrences of Heterocycles 621 31.6.1 Toxicity 622 31.6.2 Plastics and Polymers 622 31.6.3 Fungicides and Herbicides 623 31.6.4 Dyes and Pigments 623 31.6.5 Fluorescence-Based Applications 624 31.6.6 Electronic Applications 625 References 626 32 Heterocycles in Biochemistry; Heterocyclic Natural Products 629 32.1 Heterocyclic Amino Acids and Related Substances 629 32.2 Enzyme Co-Factors; Heterocyclic Vitamins; Co-Enzymes 630 32.2.1 Niacin (Vitamin B3) and Nicotinamide Adenine Dinucleotide Phosphate (NADP+) 631 32.2.2 Pyridoxine (Vitamin B6) and Pyridoxal Phosphate (PLP) 631 32.2.3 Riboflavin (Vitamin B2) 632 32.2.4 Thiamin (Vitamin B1) and Thiamine Pyrophosphate 632 32.3 Porphobilinogen and the ‘Pigments of Life’ 633 32.4 Ribonucleic Acid (RNA) and Deoxyribonucleic Acid (DNA); Genetic Information; Purines and Pyrimidines 635 32.5 Heterocyclic Natural Products 637 32.5.1 Alkaloids 637 32.5.2 Marine Heterocycles 639 32.5.3 Halogenated Heterocycles 639 32.5.4 Macrocycles Containing Oxazoles and Thiazoles 640 32.5.5 Other Nitrogen-Containing Natural Products 640 32.5.6 Anthocyanins and Flavones 641 References 642 33 Heterocycles in Medicine 645 33.1 Mechanisms of Drug Actions 646 33.1.1 Mimicking or Opposing the Effects of Physiological Hormones or Neurotransmitters 646  Contents xvii 33.1.2 Interaction with Enzymes 646 33.1.3 Physical Binding with, or Chemically Modifying, Natural Macromolecules 646 33.2 The Neurotransmitters 647 33.3 Drug Discovery and Development 647 33.3.1 Stages in the Life of a Drug 647 33.3.2 Drug Discovery 649 33.3.3 Chemical Development 649 33.3.4 Good Manufacturing Practice (GMP) 650 33.4 Heterocyclic Drugs 650 33.4.1 Histamine 650 33.4.2 Acetylcholine (ACh) 652 33.4.3 5-Hydroxytryptamine (5-HT) 653 33.4.4 Adrenaline and Noradrenaline 654 33.4.5 Other Significant Cardiovascular Drugs 654 33.4.6 Drugs Affecting Blood Clotting 655 33.4.7 Other Enzyme Inhibitors 656 33.4.8 Enzyme Induction 658 33.5 Drugs Acting on the CNS 658 33.6 Anti-Infective Agents 659 33.6.1 Anti-Parasitic Drugs 659 33.6.2 Anti-Bacterial Drugs 660 33.6.3 Anti-Viral Drugs 661 33.7 Anti-Cancer Drugs 661 33.8 Photochemotherapy 663 33.8.1 Psoralen plus UVA (PUVA) Treatment 663 33.8.2 Photodynamic Therapy (PDT) 664 References 664 Index 665  Preface to the Fifth Edition Heterocyclic compounds have a wide range of applications but are of particular interest in medicinal chem- istry, and this has catalysed the discovery and development of much heterocyclic chemistry and methods. The preparation of a fifth edition has allowed us to review thoroughly the material included in the earlier editions, to make amendments in the light of new knowledge, and to include recent work. Within the restrictions that space dictates, we believe that all of the most significant heterocyclic chemistry of the 20th century and important more recent developments, has been covered or referenced. We have maintained the principal aim of the earlier editions – to teach the fundamentals of heterocyclic reactivity and synthesis in a way that is understandable by undergraduate students. However, in recognition of the level at which much heterocyclic chemistry is now normally taught, we include more advanced and current material, which makes the book appropriate both for post-graduate level courses, and as a reference text for those involved in heterocyclic chemistry in the work place. New in this edition is the use of colour in the schemes. We have highlighted in red those parts of products (or intermediates) where a change in structure or bonding has taken place. We hope that this both facilitates comprehension and understanding of the chemical changes that are occurring and, especially for the under- graduate student, quickly focuses attention on just those parts of the molecules where structural change has occurred. For example, in the first reaction below, only changes at the pyridine nitrogen are involved; in the second example, the introduced bromine resulting from the substitution and its new bond to the het- erocycle, are highlighted. We also show all positive and negative charges in red. + H+ + N N H NBS Br S S In recognition of the enormous importance of organometallic chemistry in heterocyclic synthesis, we have introduced a new chapter dealing exclusively with this aspect. Chapter 4, ‘Organometallic Heterocyclic Chemistry’, has: (i) a general overview of heterocyclic organometallic chemistry, but most examples are to be found in the individual ring chapters, (ii) the use of transition metal-catalysed reactions that, as a consequence of a regularity and consistency that is to a substantial degree independent of the heterocyclic ring, is best treated as a whole, and therefore most examples are brought together here, with relatively few in the ring chapters. Other innovations in this fifth edition are discussions in Chapter 5 of the modern techniques of: (i) solid- phase chemistry, (ii) microwave heating and (iii) flow reactors in the heterocyclic context. Reflecting the large part that heterocyclic chemistry plays in the pharmaceutical industry, there are entirely new chapters that deal with ‘Heterocycles in Medicine’ (Chapter 33) and ‘Heterocycles in Biochemistry; Heterocyclic Natural Products’ (Chapter 32). xx Preface to the Fifth Edition We devote a new chapter (31) to some important topics: fluorinated heterocycles, isotopically labelled heterocycles, the use of bioprocesses in heterocyclic transformations, ‘green chemistry’ and the somewhat related topic of ionic liquids, and some the applications of heterocyclic compounds in every-day life. 1. The main body of factual material is to be found in chapters entitled ‘Reactions and synthesis of…’ a particular heterocyclic system. Didactic material is to be found partly in advanced general discussions of heterocyclic reactivity and synthesis (Chapters 3, 4 and 6), and partly in six short summary chapters (such as ‘Typical Reactivity of Pyridines, Quinolines and Isoquinolines’; Chapter 7), which aim to capture the essence of that typical reactivity in very concise resumés. These last are therefore suitable as an introduction to the chemistry of that heterocyclic system, but they are insufficient in themselves and should lead the reader to the fuller discussions in the ‘Reactions and Synthesis of …’ chapters. They will also serve the undergraduate student as a revision summary of the typical chemistry of that system. 2. More than 4000 references have been given throughout the text: the references to original work have been chosen as good leading references and are, therefore, not necessarily the first or last mention of that particular topic or method or compound; some others are included as benchmark papers and others for their historical interest. The extensive list of references is most relevant to post-graduate teaching and to research workers, however we believe that the inclusion of references does not interfere with the readability of the text for the undergraduate student. Many review references are also included: for these we give the title of the article; titles are also given for the books to which we refer. The majority of journals are available only on a subscription (personal or institutional) basis, but most of their web sites give free access to abstracts and a few, such as Arkivoc and Beilstein Journal of Organic Chemistry give free access to full papers. Free access to the full text of patents, with a search facility, is available via government web sites. Organic Syntheses, the ‘gold standard’ for practical organic chemistry, has totally free online access to full procedures. 3. Exercises are given at the ends of most of the substantive chapters. These are divided into straightfor- ward, revision exercises, such as will be relevant to an undergraduate course in heterocyclic chemistry. More advanced exercises, with solutions given on line at www.wiley.com/go/joule, are designed to help the reader to develop understanding and apply the principles of heterocyclic reactivity. References have not been given for the exercises, though all are real examples culled from the literature. 4. We largely avoid the use of ‘R’ and ‘Ar ’ for substituents in the structures in schemes, and instead give actual examples. We believe this makes the chemistry easier to assimilate, especially for the undergradu- ate reader. It also avoids implying a generality that may not be justified. 5. Structures and numbering for heterocyclic systems are given at the beginnings of chapters. Where the commonly used name differs from that used in Chemical Abstracts, the name given in square brackets is the official Chemical Abstracts name, thus: indole [1H-indole]. We believe that the systematic naming of heterocyclic substances is of importance, not least for use in computerised databases, but it serves little purpose in teaching or for the understanding of the subject and, accordingly, we have devoted only a little space to nomenclature. The reader is referred to an exposition on this topic1 and also to the Ring Index of Chemical Abstracts in combination with the Chemical Substances Index, from whence both standardised name and numbering can be obtained for all known systems. Readers with access to elec- tronic search facilities such as SciFinder and Crossfire can easily find the various names for substances via a search on a drawn structure. 6. There are several general reference works concerned with heterocyclic chemistry, which have been gathered together as a set at the end of this chapter, and to which the reader ’s attention is drawn. In order to save space, these vital sources are not repeated in particular chapters, however all the topics covered in this book are covered in them, and recourse to these sources should form the early basis of any literature search.  Preface to the Fifth Edition xxi 7. The literature of heterocyclic chemistry is so vast that the series of nine listings – ‘The Literature of Heterocyclic Chemistry’, Parts I–IX2 – is of considerable value at the start of a literature search. These listings appear in Advances in Heterocyclic Chemistry,3 itself a prime source for key reviews on hetero- cyclic topics; the journal, Heterocycles, also carries many useful reviews specifically in the heterocyclic area. Progress in Heterocyclic Chemistry4 published by the International Society of Heterocyclic Chem- istry5 also carries reviews, and monitors developments in heterocyclic chemistry over a calendar year. Essential at the beginning of a literature search is a consultation with the appropriate chapter(s) of Comprehensive Heterocyclic Chemistry, the original6a and its two updates,6b,6c or, for a useful introduc- tion and overview, the handbook7 to the series. It is important to realize that particular topics in the three parts of Comprehensive Heterocyclic Chemistry must be read together – the later parts update, but do not repeat, the earlier material. Finally, the Science of Synthesis series, published over the period 2000–2008, contains authoritative discussions of information organized in a hierarchical system.8 Volumes 9–17 discuss aromatic heterocycles. 8. There are three comprehensive compilations of heterocyclic facts: the early series9 edited by Elderfield, discusses pioneering work. The still-continuing and still-growing series of monographs10 dealing with particular heterocyclic systems, edited originally by Arnold Weissberger, and latterly by Edward C. Taylor and Peter Wipf, is a vital source of information and reviews for all those working with hetero- cyclic compounds. Finally, the heterocyclic volumes of Rodd’s Chemistry of Carbon Compounds11 contain a wealth of well-sifted information and data. P.1 Hazards This book is designed, in large part, for the working chemist. All chemistry is hazardous to some degree and the reactions described in this book should only be carried out by persons with an appropriate degree of skill, and after consulting the original papers and carrying out a proper risk assessment. Some major hazards are highlighted (Explosive: general discussion (5.4), sodium azide (29.1.1.5.3), tetrazoles: diazo- nium salts and others (29.1.1.3), perchlorates (5.4; 11 (introductory paragraph)), tosyl azide (5.4). Toxicity: general (31.6.1), fluoroacetate (31.1.1.4), chloromethylation (e.g. 14.9.2.1)),12 but this should not be taken to mean that every possible hazard is specifically pointed out. Certain topics are included only as informa- tion and are not suitable for general chemistry laboratories – this applies particularly to explosive compounds. P.2 How to Use This Textbook As indicated above, by comparison with earlier editions, this fifth edition of Heterocyclic Chemistry con- tains more material, including more that is appropriate to study at a higher level, than that generally taught in a first degree course. Nevertheless we believe that undergraduates will find the book of value and offer the following modus operandi as a means for undergraduate use of this text. The undergraduate student should first read Chapter 2, which will provide a structural basis for the chemistry that follows. We suggest that the material dealt with in Chapters 3 and 4 be left for study at later stages, and that the undergraduate student proceed next to those chapters (7, 10, 13, 15, 19 and 23) that explain heterocyclic principles in the simplest terms and which should be easily understandable by students who have a good grounding in elementary reaction chemistry, especially aromatic chemistry. The student could then proceed to the main chapters, dealing with ‘Reactions and Synthesis of…’ in which will be found full discussions of the chemistry of particular systems – pyridines, quinolines, etc. These utilise many cross references that seek to capitalise on that important didactical strategy – comparison and analogy with reactivity already learnt and understood. Chapters 3, 4 and 6 are advanced essays on heterocyclic chemistry. Sections can be sampled as required – ‘Electrophilic Substitution’ could be read at the point at which the student was studying electrophilic substitutions of, say, thiophene – or Chapter 3 can be read as a whole. We have devoted considerable space xxii Preface to the Fifth Edition in Chapter 3 to discussions of radical substitution, and Chapter 4, because of their great significance, is devoted entirely to metallation and the use of organometallic reagents, and to transition metal-catalysed reactions. These topics have grown enormously in importance since the earlier editions, and are of great relevance to heterocyclic chemistry. Acknowledgements We thank Richard Davies, Sarah Hall and Gemma Valler and their colleagues at Wiley, and earlier Paul Sayer at Blackwell, for their patience and support during the preparation of this fifth edition. We acknowl- edge many significant comments and corrections by Rob Young and Paul Beswick, and thank Mercedes Álvarez, Peter Quayle, Andrew Regan and Ian Watt for their views on the use of colour in schemes. We are greatly indebted to Jo Tyszka for her meticulous and constructive copy-editing. JAJ thanks his wife Stacy for her encouragement and patience during the writing of Heterocyclic Chemistry, Fifth Edition. References 1 ‘The nomenclature of heterocycles’, McNaught, A. D., Adv. Heterocycl. Chem., 1976, 20, 175. 2 Katritzky, A. R. and Weeds, S. M., Adv. Heterocycl. Chem., 1966, 7, 225; Katritzky, A. R. and Jones, P. M., ibid., 1979, 25, 303; Belen’kii, L. I., ibid., 1988, 44, 269; Belen’kii, L. I. and Kruchkovskaya, N. D., ibid., 1992, 55, 31; idem, ibid., 1998, 71, 291; Belen’kii, L. I., Kruchkovskaya, N. D., and Gramenitskaya, V. N., ibid., 1999, 73, 295; idem, ibid., 2001, 79, 201; Belen’kii, L. I. and Gramenitskaya, V. N., ibid., 2005, 88, 231; Belen’kii, L. I., Gramenitskaya, V. N., and Evdokimenkova, Yu. B., ibid., 2004, 92, 146. 3 Adv. Heterocycl. Chem., 1963–2007, 1–94. 4 Progr. Heterocycl. Chem., 1989–2009, 1–21. 5 http://euch6f.chem.emory.edu/ishc.html and the related Royal Society of Chemistry site: http://www.rsc.org/lap/rsccom/dab/perk003.htm 6 (a) ‘Comprehensive heterocyclic chemistry. The structure, reactions, synthesis, and uses of heterocyclic compounds’, Eds. Katritzky, A. R. and Rees, C. W., Vols 1–8, Pergamon Press, Oxford, 1984; (b) ‘Comprehensive heterocyclic chemistry II. A review of the literature 1982–1995’, Ed. Katritzky, A. R., Rees, C. W., and Scriven, E. F. V., Vols 1–11, Pergamon Press, 1996; (c) ‘Comprehensive heterocyclic chemistry III. A review of the literature 1995–2007’, Eds. Katritzky, A. R., Ramsden, C. A., and Scriven, E. F. V., and Taylor, R. J. K., Vols 1–15, Elsevier, 2008. 7 ‘Handbook of heterocyclic chemistry, 2nd edition 2000’, Katritzky, A. R. and Pozharskii, A. F., Pergamon Press, Oxford, 2000; ‘Handbook of het- erocyclic chemistry. Third edition 2010’, Katritzky, A. R., Ramsden, C. A., Joule, J. A., and Zhdankin, V. V., Elsevier, 2010. 8 ‘Science of Synthesis’, Vols. 9–17, ‘Hetarenes’, Thieme, 2000–2008. 9 ‘Heterocyclic compounds’, Ed. Elderfield, R. C., Vols. 1–9, Wiley, 1950–1967. 10 ‘The chemistry of heterocyclic compounds’, Series Eds. Weissberger, A., Wipf, P., and Taylor, E. C., Vols. 1–64, Wiley-Interscience, 1950–2005. 11 ‘Rodd’s chemistry of carbon compounds’, Eds., Coffey, S. then Ansell, M. F., Vols IVa–IVl, and Supplements, 1973–1994, Elsevier, Amsterdam. 12 United States Department of Labor, Occupational Safety & Health Administration Reports: Chloromethyl Methyl Ether (CMME) and Bis- Chloromethyl Ether (BCME); see also: Berliner, M. and Belecki, K., Org. Synth., 2007, 84, 102 (discussion). Web Site Power Point slides of all figures from this book, along with the solution to the exercises, can be found at http://www.wiley.com/go/joul.  Biography John Arthur Joule was born in Harrogate, Yorkshire, England, but grew up and attended school in Llan- dudno, North Wales, going on to study for BSc, MSc, and PhD (1961; with George F. Smith) degrees at The University of Manchester. Following post-doctoral periods in Princeton (Richard K. Hill) and Stanford (Carl Djerassi) he joined the academic staff of The University of Manchester where he served for 41 years, retiring and being appointed Professor Emeritus in 2004. Sabbatical periods were spent at the University of Ibadan, Nigeria, Johns Hopkins Medical School, Department of Pharmacology and Experimental Thera- peutics, and the University of Maryland, Baltimore County. He was William Evans Visiting Fellow at Otago University, New Zealand. Dr. Joule has taught many courses on heterocyclic chemistry to industry and academe in the UK and elsewhere. He is currently Associate Editor for Tetrahedron Letters, Scientific Editor for Arkivoc, and Co- Editor of the annual Progress in Heterocyclic Chemistry. Keith Mills was born in Barnsley, Yorkshire, England and attended Barnsley Grammar School, going on to study for BSc, MSc and PhD (1971; with John Joule) degrees at The University of Manchester. Following post-doctoral periods at Columbia (Gilbert Stork) and Imperial College (Derek Barton/ Philip Magnus), he joined Allen and Hanburys (part of the Glaxo Group) at Ware and later Stevenage (finally as part of GSK), working in Medicinal Chemistry and Development Chemistry departments for a total of 25 years. During this time he spent a secondment at Glaxo, Verona. Since leaving GSK he has been an inde- pendent consultant to small pharmaceutical companies. Dr. Mills has worked in several areas of medicine and many areas of organic chemistry, but with particu- lar emphasis on heterocyclic chemistry and the applications of transition metal-catalysed reactions. Heterocyclic Chemistry was first published in 1972, written by George Smith and John Joule, followed by a second edition in 1978. The third edition (Joule, Mills and Smith) was written in 1995 and, after the death of George Smith, a fourth edition (Joule and Mills) appeared in 2000; these authors also published Het- erocyclic Chemistry at a Glance in 2007.  Definitions of Abbreviations acac = acetylacetonato [MeCOCHCOMe–] adoc = adamantanyloxycarbonyl Aliquat® = tricaprylmethylammonium chloride [MeN(C8H17)3Cl] p-An = para-anisyl [4-MeOC6H4] aq. = aqueous atm = atmosphere 9-BBN = 9-borabicyclo[3.3.1]nonane [C8H15B] BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene [C44H32P2] BINOL = 1,1′-bi(2-naphthol) [C20H14O2] Bn = benzyl [PhCH2] Boc = tertiary-butoxycarbonyl [Me3COC=O] BOM = benzyloxymethyl [PhCH2OCH2] BOP = (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BSA = N,O-bis(trimethylsilyl)acetamide [MeC(OSiMe3)=NSiMe3] Bt = benzotriazol-1-yl [C6H4N3] i-Bu = iso-butyl [Me2CHCH2] n-Bu = normal-butyl [Me(CH2)3] s-Bu = secondary-butyl [MeCH2C(Me)H] t-Bu = tertiary-butyl [Me3C] Bus = tertiary-butylsulfonyl [Me3CSO2] c. = concentrated c = cyclo as in c-C5H9 = cyclopentyl [C5H9] CAN = cerium(IV) ammonium nitrate [Ce(NH4)2(NO3)6] Cbz = benzyloxycarbonyl (PhCH2OC=O) CDI = 1,1′-carbonyldiimidazole [(C3H3N2)2C=O] Chloramine T = N-chloro-4-methylbenzenesulfonamide sodium salt [TsN(Cl)Na] cod = cycloocta-1,5-diene [C8H12] coe = cyclooctene [C8H14] cp = cyclopentadienyl anion [c-C5H5–] cp* = pentamethylcyclopentadienyl anion [Me5-c-C5] m-CPBA = meta-chloroperbenzoic acid [3-ClC6H4CO3H] CSA = camphorsulfonic acid CuTC = thiophene-2-carboxylic acid copper(I) salt [C5H3CuO2S] Cy = cyclohexyl [C6H11] DABCO = 1,4-diazabicyclo[2.2.2]octane [C6H12N2] dba = trans,trans-dibenzylideneacetone [PhCH=CHCOCH=CHPh] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene [C9H16N2] DCC = N,N′-dicyclohexylcarbodiimide [c-C6H11N=C=N-c-C6H11] DCE = 1,2-dichloroethane [Cl(CH2)2Cl] DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone [C8Cl2N2O2] de = diastereomeric excess xxvi Definitions of Abbreviations DEAD = diethyl azodicarboxylate [EtO2CN=NCO2Et] DIAD = diisopropyl azodicarboxylate [i-PrO2CN=NCO2i-Pr] DIBALH = diisobutylaluminium hydride [(Me2CHCH2)2AlH] DMA = N,N-dimethylacetamide [MeCONMe2] DMAP = 4-dimethylaminopyridine [C7H10N2] DME = 1,2-dimethoxyethane [MeO(CH2)2OMe] DMF = N,N-dimethylformamide [Me2NCH=O] DMFDMA = dimethylformamide dimethyl acetal [Me2NCH(OMe)2] DMSO = dimethylsulfoxide [Me2S=O] DoM = directed ortho-metallation DPPA = diphenylphosphoryl azide [(PhO)2P(O)N3] dppb = 1,4-bis(diphenylphosphino)butane [Ph2P(CH2)4PPh2] dppf = 1,1′-bis(diphenylphosphino)ferrocene [C34H28FeP2] dppp = 1,3-bis(diphenylphosphino)propane [Ph2P(CH2)3PPh2] EDTA = ethylenediaminetetracetic acid [(HO2CCH2)2N(CH2)2N(CH2CO2H)2] ee = enantiomeric excess El+ = general electrophile eq = equivalent(s) ESR = electron spin resonance Et = ethyl [CH3CH2] f. = fuming Fur = furyl as in 2-Fur = 2-furyl (furan-2-yl) [C4H3O] FVP = flash vacuum pyrolysis Het = general designation for an aromatic heterocyclic nucleus HMDS = 1,1,1,3,3,3-hexamethyldisilazane [Me3SiNHSiMe3] hplc = high pressure liquid chromatography HOMO = highest occupied molecular orbital hν = ultraviolet or visible irradiation hy = high yield Kryptofix 2.2.2 = 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane [C18H36N2O6] LDA = lithium diisopropylamide [LiNi-Pr2] LiTMP = lithium 2,2,6,6-tetramethylpiperidide [LiN(CMe2(CH2)3CMe2)] liq. = liquid LR = Lawesson’s reagent [C14H14O2P2S4] LUMO = lowest unoccupied molecular orbital Me = methyl [CH3] MOM = methoxymethyl [CH3OCH2O] mp = melting point MS = molecular sieves MTBD = 1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyridine [C8H15N3] Ms = mesyl (methanesulfonyl) [MeSO2] MSH = O-(mesitylenesulfonyl)hydroxylamine [H2NOSO2C6H2-2,4,6-Me3] MW = reaction heated by microwave irradation NBS = N-bromosuccinimide [C4H4BrNO2] NDA = sodium diisopropylamide [NaNi-Pr2] NIS = N-iodosuccinimide [C4H4INO2] NMP = N-methylpyrrolidone [C4H9NO] NPE = 2-(4-nitrophenyl)ethyl [4-O2NC6H4CH2CH2]  Definitions of Abbreviations xxvii Nu– = general nucleophile n-Oct = normal-octyl[Me(CH2)7] OXONE® = potassium peroxymonosulfate [2KHSO5.KHSO4.K2SO4] Ph = phenyl [C6H5] PhH = benzene [C6H6] Phosphorus oxychloride (phosphoryl chloride ) = POCl3 Phth = phthaloyl [1,2-COC6H4CO] PIFA = phenyliodine(III) bis(trifluoroacetate) [PhI(OCOCF3)3] PMB = para-methoxybenzyl [4-MeOC6H4CH2] PMP = 1,2,2,6,6-pentamethylpiperidine [C10H21N] PP = pyrophosphate [OP(=O)(OH)OP(=O)OH] PPA = polyphosphoric acid i-Pr = iso-propyl [Me2CH] n-Pr = normal-propyl [CH3CH2CH2] proton sponge = 1,8-bis(dimethylamino)naphthalene [C14H18N2] PSSA = polystyrenesulfonic acid py = pyridine, usually as a solvent Py = pyridyl, as in 2-Py = 2-pyridinyl (pyridin-2-yl), 3-Py, 4-Py [C5H4N] Pybox = 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolin-2-yl]pyridine [C35H27N3O2] Rf = general designation of perfluoroalkyl [CnF2n+1] RF = Rf(CH2)n rp = room (atmospheric) pressure rt = room temperature salcomine = N,N′-bis(salicylidene)ethylenediaminocobalt(II) [C16H14N2O2Co] SDS = sodium dodecylsulfate [C12H25SO3Na] SEM = trimethylsilylethoxymethyl [Me3Si(CH2)2OCH2] SES = 2-(trimethylsilyl)ethanesulfonyl [Me3Si(CH2)2SO2] SET = single electron transfer SOMO = singly occupied molecular orbital TASF = tris(dimethylamino)sulfur (trimethylsilyl)difluoride [(Me2N)3S(Me3SiF2)] TBAF = tetra-normal-butylammonium fluoride [n-Bu4N+ F–) TBAS = tetra-normal-butylammonium hydrogen sulfate [n-Bu4N+ HSO4–) TBDMS = tertiary-butyldimethylsilyl [Me3C(Me)2Si] TBTA = tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine TfO– = triflate [CF3SO3–] tfp = trifuran-2-ylphosphine [P(C4H3O)3] THF = tetrahydrofuran (2,3,4,5-tetrahydrofuran) [C4H8O] THP = tetrahydropyran-2-yl [C5H9O] TIPS = tri-iso-propylsilyl [i-Pr3Si] TMEDA = N,N,N′,N′-tetramethylethylenediamine [Me2N(CH2)2NMe2] TMP = 2,2,6,6-tetramethylpiperidine [C9H19N] TMS = trimethylsilyl [Me3Si] TMSOTf = trimethylsilyl triflate [Me3SiOSO2CF3] TolH = toluene [C6H5CH3] p-Tol = para-tolyl [4-MeC6H4] o-Tol = ortho-tolyl [2-MeC6H4] TosMIC = tosylmethyl isocyanide [4-MeC6H4SO2CH2NC] triflate = trifluoromethanesulfonate [CF3SO3–] xxviii Definitions of Abbreviations Ts = tosyl [4-MeC6H4SO2] dR = β-d-2-deoxyribofuranosyl R = β-d-ribofuranosyl S = a sugar, usually a derivative of ribose or deoxyribose, attached to heterocyclic nitrogen, in which the substituents have not altered during the reaction shown. = sonication  1 Heterocyclic Nomenclature A selection of the structures, names and standard numbering of the more common heteroaromatic systems and some common non-aromatic heterocycles are given here as a necessary prelude to the discussions which follow in subsequent chapters. The aromatic heterocycles have been grouped into those with six- membered rings and those with five-membered rings. The names of six-membered aromatic heterocycles that contain nitrogen generally end in ‘ine’, though note that ‘purine’ is the name for a very important bicyclic system which has both a six- and a five-membered nitrogen-containing heterocycle. Five- membered heterocycles containing nitrogen general end with ‘ole’. Note the use of italic ‘H’ in a name such as ‘9H-purine’ to designate the location of an N-hydrogen in a system in which, by tautomerism, the hydrogen could reside on another nitrogen (e.g. N-7 in the case of purine). Names such ‘pyridine’, ‘pyrrole’, ‘thiophene’, originally trivial, are now the standard, systematic names for these heterocycles; names such as ‘1,2,4-triazine’ for a six-membered ring with three nitrogens located as indicated by the numbers, are more logically systematic. A device that is useful, especially in discussions of reactivity, is the designation of positions as ‘α’, ‘β’, or ‘γ’. For example, the 2- and the 6-positions in pyridine are equivalent in reactivity terms, so to make discussion of such reactivity clearer, each of these positions is referred to as an ‘α-position’. Comparable use of α and β is made in describing reactivity in five-membered systems. These useful designations are shown on some of the structures. Note that carbons at angular positions do not have a separate number, but are designated using the number of the preceding atom followed by ‘a’ – as illustrated (only) for quino- line. For historical reasons purine does not follow this rule. Six-membered aromatic heterocycles Heterocyclic Chemistry 5th Edition John Joule and Keith Mills © 2010 Blackwell Publishing Ltd 2 Heterocyclic Chemistry Five-membered aromatic heterocycles A detailed discussion of the systematic rules for naming polycyclic systems in which several aromatic or heteroaromatic rings are fused together is beyond the scope of this book, however, a simple example will serve to illustrate the principle. In the name ‘pyrrolo[2,3-b]pyridine’, the numbers signify the positions of the first-named heterocycle, numbered as if it were a separate entity, which are the points of ring fusion; the italic letter, ‘b’ in this case, designates the side of the second-named heterocycle to which the other ring is fused, the lettering deriving from the numbering of that heterocycle as a separate entity, i.e. side a is between atoms 1 and 2, side b is between atoms 2 and 3, etc. Actually, this particular heterocycle is more often referred to as ‘7-azaindole’ – note the use of the prefix ‘aza’ to denote the replacement of a ring carbon by nitrogen, i.e. of C-7–H of indole by N.  Heterocyclic Nomenclature 3 The main thrust of this book concerns the aromatic heterocycles, exemplified above, however Chapter 30 explores briefly the chemistry of saturated or partially unsaturated systems, including three- and four- membered heterocycles. Non-aromatic heterocycles  2 Structures and Spectroscopic Properties of Aromatic Heterocycles This chapter describes the structures of aromatic heterocycles and gives a brief summary of some physical properties.1 The treatment we use is the valence-bond description, which we believe is appropriate for the understanding of all heterocyclic reactivity, perhaps save some very subtle effects, and is certainly sufficient for a general textbook on the subject. The more fundamental, molecular-orbital description of aromatic systems is less relevant to the day-to-day interpretation of heterocyclic reactivity, though it is necessary in some cases to utilise frontier orbital considerations,2 however such situations do not fall within the scope of this book. 2.1 Carbocyclic Aromatic Systems 2.1.1 Structures of Benzene and Naphthalene The concept of aromaticity as represented by benzene is a familiar and relatively simple one. The difference between benzene on the one hand and alkenes on the other is well known: the latter react with electrophiles, such as bromine, easily by addition, whereas benzene reacts only under much more forcing conditions and then typically by substitution. The difference is due to the cyclic arrangement of six π-electrons in benzene: this forms a conjugated molecular-orbital system which is thermodynamically much more stable than a corresponding non-cyclically conjugated system. The additional stabilisation results in a diminished ten- dency to react by addition and a greater tendency to react by substitution for, in the latter manner, survival of the original cyclic conjugated system of electrons is ensured in the product. A general rule proposed by Hückel in 1931 states that aromaticity is observed in cyclically conjugated systems of 4n + 2 electrons, that is with 2, 6, 10, 14, etc., π-electrons; by far the majority of monocyclic aromatic and heteroaromatic systems are those with six π-electrons. In this book we use the pictorial valence-bond resonance description of structure and reactivity. Even though this treatment is not rigorous, it is still the standard means for the understanding and learning of organic chemistry, which can at a more advanced level give way to the more complex, and mathematical, quantum-mechanical approach. We begin by recalling the structure of benzene in these terms. In benzene, the geometry of the ring, with angles of 120 °, precisely fits the geometry of a planar trigo- nally hybridised carbon atom, and allows the assembly of a σ-skeleton of six sp2 hybridised carbon atoms in a strainless planar ring. Each carbon then has one extra electron which occupies an atomic p orbital orthogonal to the plane of the ring. The p orbitals interact to generate π-molecular orbitals associated with the aromatic system. Benzene is described as a ‘resonance hybrid’ of the two extreme forms which correspond, in terms of orbital interactions, to the two possible spin-coupled pairings of adjacent p electrons: structures 1 and 2. These are known as ‘resonance contributors’, or ‘mesomeric structures’, have no existence in their own right, but serve to illustrate two extremes which contribute to the ‘real’ structure of benzene. Note the standard use of a double-headed arrow to inter-relate resonance contributors. Such arrows must never be confused with the use of opposing straight ‘fish-hook’ arrows that are used to designate an equilibrium Heterocyclic Chemistry 5th Edition John Joule and Keith Mills © 2010 Blackwell Publishing Ltd 6 Heterocyclic Chemistry between two species. Resonance contributors have no separate existence; they are not in equilibrium one with the other. Structure of benzene; resonance contributors (mesomeric structures) Sometimes, benzenoid compounds (and also, occasionally six- and five-membered heterocyclic systems) are represented using a circle inside a hexagon (pentagon); although this emphasises their delocalised nature and the close similarity of the ring bond lengths (all exactly identical only in benzene itself), it is not helpful in interpreting reactions, or in writing ‘mechanisms’, and we do not use this method in this book. Treating naphthalene comparably reveals three resonance contributors, 3, 4 and 5. The valence-bond treatment predicts quite well the non-equivalence of the bond lengths in naphthalene: in two of the three contributing structures, C-1–C-2 is double and in one it is single, whereas C-2–C-3 is single in two and double in one. Statistically, then, the former may be looked on as 0.67 of a double bond and the latter as 0.33 of a double bond: the measured bond lengths confirm that there indeed is this degree of bond fixation, with values closely consistent with statistical prediction. Structure of naphthalene; resonance contributors (mesomeric structures) 2.1.2 Aromatic Resonance Energy3 The difference between the ground-state energy of benzene and that of hypothetical, non-aromatic, 1,3,5-cyclohexatriene corresponds to the degree of stabilisation conferred to benzene by the special cyclical interaction of the six π-electrons. This difference is known as aromatic resonance energy. Quantification depends on the assumptions made in estimating the energy of the ‘non-aromatic’ structure, and for this reason and others, a variety of values have been calculated for the various heteroaromatic systems; their absolute values are less important than their relative values. What one can say with certainty is that the resonance energy of bicyclic aromatic compounds, like naphthalene, is considerably less than twice that of the corresponding monocyclic system, implying a smaller loss of stabilisation energy on conversion to a reaction intermediate which still retains a complete benzene ring, for example during electrophilic substitu-  Structures and Spectroscopic Properties of Aromatic Heterocycles 7 tion (see 3.2). The resonance energy of pyridine is of the same order as that of benzene; that of thiophene is lower, with pyrrole and lastly furan of lower stabilisation energy still. Actual values for the stabilisations of these systems vary according to assumptions made, but are in the same relative order (kJ mol−1): benzene (150), pyridine (117), thiophene (122), pyrrole, (90), and furan (68). 2.2 Structure of Six-Membered Heteroaromatic Systems 2.2.1 Structure of Pyridine The structure of pyridine is completely analogous to that of benzene, being related by replacement of CH by N. The key differences are: (i) the departure from perfectly regular hexagonal geometry caused by the presence of the heteroatom, in particular the shorter carbon–nitrogen bonds, (ii) the replacement of a hydrogen in the plane of the ring with an unshared electron pair, likewise in the plane of the ring, located in an sp2 hybrid orbital and not at all involved in the aromatic π-electron sextet; it is this nitrogen lone pair which is responsible for the basic properties of pyridines, and (iii) a strong permanent dipole, traceable to the greater electronegativity of nitrogen compared with carbon. It is important to realise that the electronegative nitrogen causes inductive polarisation, mainly in the σ-bond framework, and additionally stabilises those polarised mesomeric contributors in which nitrogen is negatively charged – 8, 9, and 10 – which, together with contributors 6 and 7, which are strictly analogous to the Kekulé contributors to benzene, represent pyridine. The polarised contributors also imply a permanent polarisation of the π-electron system. Structure of pyridine; resonance contributors (mesomeric structures) The polarisations resulting from inductive and mesomeric effects are in the same direction in pyridine, resulting in a permanent dipole towards the nitrogen atom. This also means that there are fractional positive charges on the carbons of the ring, located mainly on the α- and γ-positions. It is because of this general electron-deficiency at carbon that pyridine and similar heterocycles are referred to as ‘electron-poor ’, or sometimes ‘π-deficient’. A comparison with the dipole moment of piperidine, which is due wholly to the induced polarisation of the σ-skeleton, gives an idea of the additional polarisation associated with distortion of the π-electron system. 2.2.2 Structure of Diazines The structures of the diazines (six-membered systems with two nitrogen atoms in the ring) are analogous, but now there are two nitrogen atoms and a corresponding two lone pairs; as an illustration, the main contributors (11–18) to pyrimidine are shown below. 8 Heterocyclic Chemistry Structure of pyrimidine; resonance contributors (mesomeric structures) 2.2.3 Structure of Pyridinium and Related Cations Electrophilic addition to the pyridine nitrogen generates pyridinium ions, the simplest being 1H-pyridinium formed by addition of a proton. 1H-Pyridinium is actually isoelectronic with benzene, the only difference being the nuclear charge of nitrogen, which makes the system, as a whole, positively charged. Thus pyri- dinium cations are still aromatic, the diagram making clear that the system of six p orbitals required to generate the aromatic molecular orbitals is still present, though the formal positive charge on the nitrogen atom severely distorts the π-system, making the α- and γ-carbons in these cations carry fractional positive charges which are higher than in pyridine, the consquence being increased reactivity towards nucleophiles. Electron density at the pyridinium β-carbons is also reduced relative to these carbons in pyridines. + + + + In the pyrylium cation, the positively charged oxygen also has an unshared electron pair, in an sp2 orbital in the plane of the ring, exactly as in pyridine. Once again, a set of resonance contributors, 19–23, makes clear that this ion is strongly positively charged at the 2-, 4- and 6-positions; in fact, because the more electronegative oxygen tolerates positive charge much less well than nitrogen, the pyrylium cation is cer- tainly a less stabilised system than a pyridinium cation. Structure of pyrylium cation; resonance contributors (mesomeric structures) 2.2.4 Structures of Pyridones and Pyrones Pyridines with an oxygen at either the 2- or 4-position exist predominantly as carbonyl tautomers, which are therefore known as ‘pyridones’4 (see also 2.5). In the analogous oxygen heterocycles, no alternative tautomer is possible; the systems are known as ‘pyrones’. The extent to which such molecules are aromatic has been a subject for considerable speculation and experimentation, and estimates have varied consider- ably. The degree of aromaticity depends on the contribution that dipolar structures, 25 and 27, with a ‘complete’ pyridinium (py