Heterocyclic Chemistry At A Glance (2^nd Ed.) Chemistry At a Glance Series

This expanded second edition provides a concise overview of the main principles and reactions of heterocyclic chemistry for undergraduate students studying chemistry and related courses. Using a successful and student-friendly "at a glance" approach, this book helps the student grasp the essence of heterocyclic chemistry, ensuring that they can confidently use that knowledge when required. The chapters are thoroughly revised and updated with references to books and reviews; extra examples and student exercises with answers online; and color diagrams that emphasize exactly what is happening in the reaction chemistry depicted.

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

Triflates 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

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

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 and reduction 92

Pericyclic reactions 92

Reactivity of side-chain substituents 93

Oxygen substituents 94

Ring synthesis – disconnections 94

Synthesis of indoles from arylhydrazones 94

Synthesis of indoles from ortho-nitrotoluenes 95

Synthesis of indoles from ortho-aminoaryl alkynes 96

Synthesis of indoles from ortho-alkylaryl isocyanides 96

Synthesis of indoles from ortho-acyl anilides 96

Synthesis of isatins from anilines 97

Synthesis of oxindoles from anilines 97

Synthesis of indoxyls from anthranilic acids 97

Azaindoles 97

Exercises 98

11. Furans and Thiophenes 99

Electrophilic substitution at carbon 99

C-Metallated thiophenes and furans 101

Palladium(0)-catalysed reactions 102

Oxidation and reduction 102

Pericyclic reactions 103

Oxygen substituents 104

Ring synthesis – disconnections 105

Synthesis of furans and thiophenes from 1,4-dicarbonyl compounds 105

Exercises 106

12. 1,2-Azoles and 1,3-Azoles 107

Introduction 107

Electrophilic addition to N 107

Electrophilic substitution at C 109

Nucleophilic substitution of halogen 110

N-Deprotonation and N-metallated imidazoles and pyrazoles 110

C-Metallated N-substituted imidazoles and pyrazoles, and C-metallated thiazoles and isothiazoles 111

C-Deprotonation of oxazoles and isoxazoles 112

Palladium(0)-catalysed reactions 113

1,3-Azolium ylides 113

Reductions 114

Pericyclic reactions 114

Oxygen and amine substituents 115

1,3-Azoles ring synthesis – disconnections 116

Synthesis of thiazoles and imidazoles from -halo-ketones 116

Synthesis of 1,3-azoles from 1,4-dicarbonyl compounds 117

Synthesis of 1,3-azoles using tosylmethyl isocyanide 118

Synthesis of 1,3-azoles via dehydrogenation 118

1,2-Azoles ring synthesis – disconnections 119

Synthesis of pyrazoles and isoxazoles from 1,3-dicarbonyl compounds 119

Synthesis of isoxazoles and pyrazoles from alkynes 120

Synthesis of isothiazoles from -amino , -unsaturated carbonyl compounds 121

Exercises 121

13. Purines 122

Electrophilic addition to nitrogen 124

Electrophilic substitution at carbon 125

N-Deprotonation and N-metallated purines 125

Oxidation 126

Nucleophilic substitution 126

C-Metallated purines by direct deprotonation or halogen–metal exchange 128

Palladium(0)-catalysed reactions 128

Purines with oxygen and amine substituents 128

Ring synthesis – disconnections 130

Synthesis of purines from 4,5-diaminopyrimidines 130

Synthesis of purines from 5-aminoimidazole-4-carboxamide 131

‘One-step syntheses’ 131

Exercises 131

14. Heterocycles with More than Two Heteroatoms: Higher Azoles (5-Membered) and Higher Azines (6-Membered) 132

Higher Azoles 132

Introduction 132

Higher azoles containing nitrogen as the only ring heteroatom: triazoles, tetrazole and pentazole 132

Benzotriazole 136

Higher azoles also containing ring sulfur or oxygen: oxa- and thiadiazoles 137

Higher azines 139

Exercises 142

15. Heterocycles with Ring-Junction Nitrogen (Bridgehead Nitrogen) 143

Introduction 143

Indolizine 144

Azaindolizines 144

Synthesis of indolizines and azaindolizines 146

Quinoliziniums and quinolizinones 147

Heteropyrrolizines (pyrrolizines containing additional heteroatoms) 148

Cyclazines 148

Exercises 149

16. Non-Aromatic Heterocycles 150

Introduction 150

Three-membered rings 150

Four-membered rings 153

Five- and six-membered rings 153

Ring synthesis 155

17. Heterocycles in Nature 158

Heterocyclic -amino acids and related substances 158

Heterocyclic vitamins – co-enzymes 159

Porphobilinogen and the ‘Pigments of Life’ 162

Deoxyribonucleic acid (DNA), the store of genetic information, and ribonucleic acid (RNA), its deliverer 163

Heterocyclic secondary metabolites 165

18. Heterocycles in Medicine 167

Medicinal chemistry – how drugs function 167

Drug discovery 168

Drug development 169

The neurotransmitters 169

Histamine 170

Acetylcholine (ACh) 171

Anticholinesterase agents 172

5-Hydroxytryptamine (5-HT) (serotonin) 172

Adrenaline and noradrenaline 173

Other significant cardiovascular drugs 173

Drugs acting specifically on the CNS 173

Other enzyme inhibitors 174

Anti-infective agents 175

Antiparasitic drugs 175

Antibacterial drugs 176

Antiviral drugs 177

Anticancer drugs 177

Photochemotherapy 178

19. Applications and Occurrences of Heterocycles in Everyday Life 180

Introduction 180

Dyes and pigments 180

Polymers 181

Pesticides 182

Explosives 184

Food and drink 186

Heterocyclic chemistry of cooking 187

Natural and synthetic food colours 190

Flavours and fragrances (F&F) 190

Toxins 192

Electrical and electronic 193

Index 195

Professor Emeritus John Joule, Chemistry Department, The University of Manchester, UK
Professor 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, UK
Dr 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).