Heterocyclic Chemistry at a Glance Other Titles Available in the Chemistry at a Glance series: Steroid Chemistry at a Glance Daniel Lednicer ISBN: 978-0-470-66084-3 Chemical Thermodynamics at a Glance H. Donald Brooke Jenkins ISBN: 978-1-4051-3997-7 Environmental Chemistry at a Glance Ian Pulford, Hugh Flowers ISBN: 978-1-4051-3532-0 Natural Product Chemistry at a Glance Stephen P. Stanforth ISBN: 978-1-4051-4562-6 The Periodic Table at a Glance Mike Beckett, Andy Platt ISBN: 978-1-4051-3299-2 Chemical Calculations at a Glance Paul Yates ISBN: 978-1-4051-1871-2 Organic Chemistry at a Glance Laurence M. Harwood, John E. McKendrick, Roger Whitehead ISBN: 978-0-86542-782-2 Stereochemistry at a Glance Jason Eames, Josephine M Peach ISBN: 978-0-632-05375-9 Reaction Mechanisms at a Glance: A Stepwise Approach to Problem-Solving in Organic Chemistry Mark G. Moloney ISBN: 978-0-632-05002-4 Heterocyclic Chemistry at a Glance Second Edition JOHN A. JOULE The School of Chemistry, The University of Manchester, UK KEITH MILLS Independent Consultant, UK This edition fi rst published 2013 © 2013 John Wiley & Sons, Ltd Registered offi ce John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offi ces, 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 identifi ed as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. 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The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organiza- tion or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promo- tional 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 at a glance / John Joule, Keith Mills. – 2nd ed. p. cm. Includes index. ISBN 978-0-470-97122-2 (cloth) – ISBN 978-0-470-97121-5 (pbk.) 1. Heterocyclic chemistry–Textbooks 2. Chemistry–Textbooks. I. Mills, K. (Keith) II. Title. QD400.J594 2012 547'.59–dc23 2012016201 A catalogue record for this book is available from the British Library. Cloth ISBN: 9780470971222 Paper ISBN: 9780470971215 Set in 10/12.5pt Minion by Thomson Digital, Noida, India Answers to the exercises are available on the accompanying website http://booksupport.wiley.com Contents Biography v Abbreviations xii Introduction to Second Edition xiv 1. Heterocyclic Nomenclature 1 Six-membered aromatic heterocycles 2 Five-membered aromatic heterocycles 2 Non-aromatic heterocycles 3 Small-ring heterocycles 3 2. Structures of Heteroaromatic Compounds 4 Structures of benzene and naphthalene 4 Structures of pyridines and pyridiniums 5 Structures of quinolines and isoquinolines 6 Structures of diazines (illustrated using pyrimidine) 6 Structures of pyrroles, thiophenes and furans 6 Structure of indoles 8 Structures of azoles (illustrated using imidazole) 8 3. Common Reaction Types in Heterocyclic Chemistry 9 Introduction 9 Acidity and basicity 9 Electrophilic substitution of aromatic molecules 10 Nucleophilic substitution of aromatic molecules 13 Radical substitution of heterocycles 14 C-Metallated heterocycles as nucleophiles 15 Generation of C-metallated heterocycles 16 Dimethylformamide dimethyl acetal (DMFDMA) 17 Formation and hydrolysis of imine/enamine 18 Common synthetic equivalents of carbonyl compounds in ring synthesis 19 Cycloaddition reactions 19 4. Palladium in Heterocyclic Chemistry 21 Palladium(0)-catalysed (and related) reactions 21 Addition to alkenes: the Heck reaction 26 Carbonylation reactions 26 Cross-coupling reactions between heteroatom nucleophiles and halides – making carbon–heteroatom bonds 27 Trifl ates as substrates for palladium-catalysed reactions 27 Mechanisms of palladium(0)-catalysed processes 28 Reactions involving electrophilic palladation 29 Copper-catalysed amination 30 Selectivity 31 Contents vii 5. Pyridines 33 Electrophilic addition to nitrogen 33 Electrophilic substitution at carbon 34 Nucleophilic substitution 35 Nucleophilic addition to pyridinium salts 36 C-metallated pyridines 37 Palladium(0)-catalysed reactions 39 Oxidation and reduction 39 Pericyclic reactions 40 Alkyl and carboxylic acid substituents 40 Oxygen substituents 41 N-Oxides 42 Amine substituents 43 Ring synthesis – disconnections 43 Synthesis of pyridines from 1,5-dicarbonyl compounds 44 Synthesis of pyridines from an aldehyde, two equivalents of a 1,3-dicarbonyl compound and ammonia 45 Synthesis of pyridines from 1,3-dicarbonyl compounds and a C2N unit 45 Exercises 47 6. Diazines 48 Electrophilic addition to nitrogen 49 Electrophilic substitution at carbon 49 Nucleophilic substitution 50 Radical substitution 52 C-Metallated diazines 52 Palladium(0)-catalysed reactions 53 Pericyclic reactions 54 Oxygen substituents 55 N-Oxides 57 Amine substituents 57 Ring synthesis – disconnections 58 Synthesis of pyridazines from 1,4-dicarbonyl compounds 58 Synthesis of pyrimidines from 1,3-dicarbonyl compounds 58 Synthesis of pyrazines from 1,2-dicarbonyl compounds 59 Synthesis of pyrazines from ␣-amino-carbonyl compounds 60 Benzodiazines 60 Exercises 61 7. Quinolines and Isoquinolines 62 Electrophilic addition to nitrogen 62 Electrophilic substitution at carbon 62 Nucleophilic substitution 63 Nucleophilic addition to quinolinium/isoquinolinium salts 64 C-Metallated quinolines and isoquinolines 65 Palladium(0)-catalysed reactions 65 Oxidation and reduction 66 Alkyl substituents 66 Oxygen substituents 67 N-Oxides 67 Ring synthesis – disconnections 67 Synthesis of quinolines from anilines 67 Synthesis of quinolines from ortho-aminoaryl ketones or aldehydes 68 Synthesis of isoquinolines from 2-arylethamines 69 viii Contents Synthesis of isoquinolines from aryl-aldehydes and an aminoacetaldehyde acetal 69 Synthesis of isoquinolines from ortho-alkynyl aryl-aldehydes or corresponding imines 70 Exercises 70 8. Pyryliums, Benzopyryliums, Pyrones and Benzopyrones 71 Pyrylium salts 71 Electrophiles 71 Nucleophilic addition 71 Ring-opening reactions of 2H-pyrans 71 Oxygen substituents – pyrones and benzopyrones 73 Ring synthesis of pyryliums from 1,5-diketones 74 Ring synthesis of 4-pyrones from 1,3,5-triketones 75 Ring synthesis of 2-pyrones from 1,3-keto-aldehydes 75 Ring synthesis of 1-benzopyryliums, coumarins and chromones 76 Exercises 77 9. Pyrroles 78 Electrophilic substitution at carbon 78 N-Deprotonation and N-metallated pyrroles 80 C-Metallated pyrroles 80 Palladium(0)-catalysed reactions 81 Oxidation and reduction 81 Pericyclic reactions 82 Reactivity of side-chain substituents 82 The ‘pigments of life’ 82 Ring synthesis – disconnections 83 Synthesis of pyrroles from 1,4-dicarbonyl compounds 83 Synthesis of pyrroles from ␣-amino-ketones 83 Synthesis of pyrroles using isocyanides 84 Exercises 85 10. Indoles 86 Electrophilic substitution at carbon 86 N-Deprotonation and N-metallated indoles 89 C-Metallated indoles 90 Palladium(0)-catalysed reactions 91 Oxidation