Heterocyclic Chemistry At A Glance

Professor Emeritus John Joule, Chemistry Department, The University of Manchester, UKProfessor Joule worked for 41 years at the University of Manchester before 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 Therapeutics, and the University of Maryland, Baltimore County. He was William Evans Visiting Fellow at Otago University, New Zealand. He 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. He is co-author with Keith Mills of the leading textbook in the field, Heterocyclic Chemistry (Wiley, 5th Edition 2010).Dr Keith Mills, Independent Consultant, UKDr Mills worked in Medicinal Chemistry and Development Chemistry departments of GlaxoSmithKline for a total of 25 years. Since leaving GSK he has been an independent consultant to small pharmaceutical companies. Dr. Mills has worked in several areas of medicine and many areas of organic chemistry, but with particular emphasis on heterocyclic chemistry and the applications of transition metal-catalysed reactions. With John Joule he is co-author of the leading textbook in the field, Heterocyclic Chemistry (Wiley, 5th Edition 2010).

• Biography vAbbreviations xiiIntroduction to Second Edition xiv1. Heterocyclic Nomenclature 1Six-membered aromatic heterocycles 2Five-membered aromatic heterocycles 2Non-aromatic heterocycles 3Small-ring heterocycles 32. Structures of Heteroaromatic Compounds 4Structures of benzene and naphthalene 4Structures of pyridines and pyridiniums 5Structures of quinolines and isoquinolines 6Structures of diazines (illustrated using pyrimidine) 6Structures of pyrroles, thiophenes and furans 6Structure of indoles 8Structures of azoles (illustrated using imidazole) 83. Common Reaction Types in Heterocyclic Chemistry 9Introduction 9Acidity and basicity 9Electrophilic substitution of aromatic molecules 10Nucleophilic substitution of aromatic molecules 13Radical substitution of heterocycles 14C-Metallated heterocycles as nucleophiles 15Generation of C-metallated heterocycles 16Dimethylformamide dimethyl acetal (DMFDMA) 17Formation and hydrolysis of imine/enamine 18Common synthetic equivalents of carbonyl compounds in ring synthesis 19Cycloaddition reactions 194. Palladium in Heterocyclic Chemistry 21Palladium(0)-catalysed (and related) reactions 21Addition to alkenes: the Heck reaction 26Carbonylation reactions 26Cross-coupling reactions between heteroatom nucleophiles and halides – making carbon–heteroatom bonds 27Triflates as substrates for palladium-catalysed reactions 27Mechanisms of palladium(0)-catalysed processes 28Reactions involving electrophilic palladation 29Copper-catalysed amination 30Selectivity 315. Pyridines 33Electrophilic addition to nitrogen 33Electrophilic substitution at carbon 34Nucleophilic substitution 35Nucleophilic addition to pyridinium salts 36C-metallated pyridines 37Palladium(0)-catalysed reactions 39Oxidation and reduction 39Pericyclic reactions 40Alkyl and carboxylic acid substituents 40Oxygen substituents 41N-Oxides 42Amine substituents 43Ring synthesis – disconnections 43Synthesis of pyridines from 1,5-dicarbonyl compounds 44Synthesis of pyridines from an aldehyde, two equivalents of a 1,3-dicarbonyl compound and ammonia 45Synthesis of pyridines from 1,3-dicarbonyl compounds and a C2N unit 45Exercises 476. Diazines 48Electrophilic addition to nitrogen 49Electrophilic substitution at carbon 49Nucleophilic substitution 50Radical substitution 52C-Metallated diazines 52Palladium(0)-catalysed reactions 53Pericyclic reactions 54Oxygen substituents 55N-Oxides 57Amine substituents 57Ring synthesis – disconnections 58Synthesis of pyridazines from 1,4-dicarbonyl compounds 58Synthesis of pyrimidines from 1,3-dicarbonyl compounds 58Synthesis of pyrazines from 1,2-dicarbonyl compounds 59Synthesis of pyrazines from α-amino-carbonyl compounds 60Benzodiazines 60Exercises 617. Quinolines and Isoquinolines 62Electrophilic addition to nitrogen 62Electrophilic substitution at carbon 62Nucleophilic substitution 63Nucleophilic addition to quinolinium/isoquinolinium salts 64C-Metallated quinolines and isoquinolines 65Palladium(0)-catalysed reactions 65Oxidation and reduction 66Alkyl substituents 66Oxygen substituents 67N-Oxides 67Ring synthesis – disconnections 67Synthesis of quinolines from anilines 67Synthesis of quinolines from ortho-aminoaryl ketones or aldehydes 68Synthesis of isoquinolines from 2-arylethamines 69Synthesis of isoquinolines from aryl-aldehydes and an aminoacetaldehyde acetal 69Synthesis of isoquinolines from ortho-alkynyl aryl-aldehydes or corresponding imines 70Exercises 708. Pyryliums, Benzopyryliums, Pyrones and Benzopyrones 71Pyrylium salts 71Electrophiles 71Nucleophilic addition 71Ring-opening reactions of 2H-pyrans 71Oxygen substituents – pyrones and benzopyrones 73Ring synthesis of pyryliums from 1,5-diketones 74Ring synthesis of 4-pyrones from 1,3,5-triketones 75Ring synthesis of 2-pyrones from 1,3-keto-aldehydes 75Ring synthesis of 1-benzopyryliums, coumarins and chromones 76Exercises 779. Pyrroles 78Electrophilic substitution at carbon 78N-Deprotonation and N-metallated pyrroles 80C-Metallated pyrroles 80Palladium(0)-catalysed reactions 81Oxidation and reduction 81Pericyclic reactions 82Reactivity of side-chain substituents 82The ‘pigments of life’ 82Ring synthesis – disconnections 83Synthesis of pyrroles from 1,4-dicarbonyl compounds 83Synthesis of pyrroles from α-amino-ketones 83Synthesis of pyrroles using isocyanides 84Exercises 8510. Indoles 86Electrophilic substitution at carbon 86N-Deprotonation and N-metallated indoles 89C-Metallated indoles 90Palladium(0)-catalysed reactions 91Oxidation and reduction 92Pericyclic reactions 92Reactivity of side-chain substituents 93Oxygen substituents 94Ring synthesis – disconnections 94Synthesis of indoles from arylhydrazones 94Synthesis of indoles from ortho-nitrotoluenes 95Synthesis of indoles from ortho-aminoaryl alkynes 96Synthesis of indoles from ortho-alkylaryl isocyanides 96Synthesis of indoles from ortho-acyl anilides 96Synthesis of isatins from anilines 97Synthesis of oxindoles from anilines 97Synthesis of indoxyls from anthranilic acids 97Azaindoles 97Exercises 9811. Furans and Thiophenes 99Electrophilic substitution at carbon 99C-Metallated thiophenes and furans 101Palladium(0)-catalysed reactions 102Oxidation and reduction 102Pericyclic reactions 103Oxygen substituents 104Ring synthesis – disconnections 105Synthesis of furans and thiophenes from 1,4-dicarbonyl compounds 105Exercises 10612. 1,2-Azoles and 1,3-Azoles 107Introduction 107Electrophilic addition to N 107Electrophilic substitution at C 109Nucleophilic substitution of halogen 110N-Deprotonation and N-metallated imidazoles and pyrazoles 110C-Metallated N-substituted imidazoles and pyrazoles, and C-metallated thiazoles and isothiazoles 111C-Deprotonation of oxazoles and isoxazoles 112Palladium(0)-catalysed reactions 1131,3-Azolium ylides 113Reductions 114Pericyclic reactions 114Oxygen and amine substituents 1151,3-Azoles ring synthesis – disconnections 116Synthesis of thiazoles and imidazoles from α-halo-ketones 116Synthesis of 1,3-azoles from 1,4-dicarbonyl compounds 117Synthesis of 1,3-azoles using tosylmethyl isocyanide 118Synthesis of 1,3-azoles via dehydrogenation 1181,2-Azoles ring synthesis – disconnections 119Synthesis of pyrazoles and isoxazoles from 1,3-dicarbonyl compounds 119Synthesis of isoxazoles and pyrazoles from alkynes 120Synthesis of isothiazoles from α-amino α,β-unsaturated carbonyl compounds 121Exercises 12113. Purines 122Electrophilic addition to nitrogen 124Electrophilic substitution at carbon 125N-Deprotonation and N-metallated purines 125Oxidation 126Nucleophilic substitution 126C-Metallated purines by direct deprotonation or halogen–metal exchange 128Palladium(0)-catalysed reactions 128Purines with oxygen and amine substituents 128Ring synthesis – disconnections 130Synthesis of purines from 4,5-diaminopyrimidines 130Synthesis of purines from 5-aminoimidazole-4-carboxamide 131‘One-step syntheses’ 131Exercises 13114. Heterocycles with More than Two Heteroatoms: Higher Azoles (5-Membered) and Higher Azines (6-Membered) 132Higher Azoles 132Introduction 132Higher azoles containing nitrogen as the only ring heteroatom: triazoles, tetrazole and pentazole 132Benzotriazole 136Higher azoles also containing ring sulfur or oxygen: oxa- and thiadiazoles 137Higher azines 139Exercises 14215. Heterocycles with Ring-Junction Nitrogen (Bridgehead Nitrogen) 143Introduction 143Indolizine 144Azaindolizines 144Synthesis of indolizines and azaindolizines 146Quinoliziniums and quinolizinones 147Heteropyrrolizines (pyrrolizines containing additional heteroatoms) 148Cyclazines 148Exercises 14916. Non-Aromatic Heterocycles 150Introduction 150Three-membered rings 150Four-membered rings 153Five- and six-membered rings 153Ring synthesis 15517. Heterocycles in Nature 158Heterocyclic α-amino acids and related substances 158Heterocyclic vitamins – co-enzymes 159Porphobilinogen and the ‘Pigments of Life’ 162Deoxyribonucleic acid (DNA), the store of genetic information, and ribonucleic acid (RNA), its deliverer 163Heterocyclic secondary metabolites 16518. Heterocycles in Medicine 167Medicinal chemistry – how drugs function 167Drug discovery 168Drug development 169The neurotransmitters 169Histamine 170Acetylcholine (ACh) 171Anticholinesterase agents 1725-Hydroxytryptamine (5-HT) (serotonin) 172Adrenaline and noradrenaline 173Other significant cardiovascular drugs 173Drugs acting specifically on the CNS 173Other enzyme inhibitors 174Anti-infective agents 175Antiparasitic drugs 175Antibacterial drugs 176Antiviral drugs 177Anticancer drugs 177Photochemotherapy 17819. Applications and Occurrences of Heterocycles in Everyday Life 180Introduction 180Dyes and pigments 180Polymers 181Pesticides 182Explosives 184Food and drink 186Heterocyclic chemistry of cooking 187Natural and synthetic food colours 190Flavours and fragrances (F&F) 190Toxins 192Electrical and electronic 193Index 195

"Joule and Mills have succeeded here in condensing the essence of introductory undergraduate heterocyclic chemistry into a slim volume, presented (as is the way in this series) in an A4 page format and in a very easy-to-grasp style with many structures and reactions. All of the key areas are covered. ...the price and the concise nature of the text make it a feasible purchase and easy read for all those working in the area. I shall certainly be recommending it to my own classes." Chemistry World, June 2007 "The book delivers on its stated purpose to present the key concepts of heterocyclic chemistry to the nonspecialist and will likely find good application in the hands of molecular modelers, pharmacologists and undergraduates." Journal of Medicinal Chemistry, 2007, Vol.50, No.4, p6289