The Principles of Heterocyclic Chemistry

ALAN R. KATRITZKY M.A., D.PHIL., PH.D., SC.D.

Dean of the School of Chemical Sciences, University of East Anglia, Norwich, England

and J. M. LAGOWSKI

B.S., M.S., PH.D. Research Scientist, Genetics Foundation,

The University of Texas, Austin, Texas, U.S.A.

METHUEN & CO LTD 11 NEW FETTER L A N E • L O N D O N EC4

Contents

Preface vii 1. Introduction 1

1. Use of this Book by the Undergraduate Student 1 2. Fundamental Concepts of the Electronic Theory of Organic

Chemistry 2 3. Relationship of Heterocyclic and Carbocyclic Aromatic Com­

pounds 2 4. Arrangement of the Book 4 5. Conventions 5 6. Nomenclature 6 7. The Literature of Heterocyclic Chemistry 9

2. Six-Membered Rings with One Heteroatom 12 I. NOMENCLATURE AND IMPORTANT COMPOUNDS 12

1. Monocyclic Nitrogen-Containing Compounds 12 (a) Nomenclature, 12. (b) Occurrence, 12. (c) Uses, 13

2. Benzopyridines 13 3. Monocyclic Oxygen- and Sulphur-Containing Compounds 14

(a) Nomenclature, 14. (b) Occurrence, 15 4. Monobenzo-Pyrones and -Pyrylium Salts 15

(a) Nomenclature, 15. (b) Occurrence, 16 5. Dibenzo-Pyrones and -Pyrylium Salts 16

II. RING SYNTHESES 17

A. General Survey 17 B. Preparation of Monocyclic Compounds (Pyridines, Pyridones,

Pyrylium Salts, etc.) 19 1. From Pentane-l,5-diones 19

(a) General, 19. (b) The Hantzsch Pyridine Synthesis, 20 2. From Pent-2-ene-l,5-diones 20 3. From Pentane-l,3,5-triones 21 4. From Other 1,5-Disubstituted Pentanes 21 5. Methods Involving C-C Bond Formation 22

C. Preparation of 2,3-Benzo Derivatives (Quinolines, Quinolones, Chromans, etc.) 22 1. Ring Closure of o-Substituted Anilines or Phenols 22

(a) o-Substituted Cinnamoyl Derivatives, 22. (b) Other o-Subsituted Benzenes, 23

2. Formation of a C-C Bond by Reaction of a Carbonyl Group or Ethylenic Bond with a Benzene Ring 23 (a) Quinolones and Benzopyrones, 24. (b) Quinolines, 24. (c) Di-benzo Derivatives, 25

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D. Preparation of 3,4-Benzo Derivatives (Isoquinolines, etc.) 26 (a) Ring Closure of a Disubstituted Benzene, 26. (b) From a ß-Phenethylamine, 26. (c) From a Benzylamine, 27

III . REACTIONS OF THE AROMATIC NUCLEI 27

A. General Survey of Reactivity 27 1. Pyridines 27

(a) Reactions of Electrophilic Reagents at the Annular Nitrogen Atom, 27. (b) Reactions oj Electrophilic Reagents at a Ring Carbon, 28. (c) Reactions of Nucleophilic Reagents at Ring Carbon Atoms, 28. (d) Free Radical Attack at a Ring Carbon Atom, 29

2. Pyridinium, Pyrylium, and Thiopyrylium Cations 29 (a) Reaction with Electrophilic Reagents, 29. (b) Reactions with Nucleophiles at a Ring Carbon, 29. (c) Reaction of Nucleophiles at a Hydrogen Atom, 30. {d) Reaction of Nucleophiles at an Annular Sulphur Atom, 30

3. Pyridones, Pyrones, and Thiopyrones 30 (Ö) Electrophilic Reagents: Attack on a Ring Carbon Atom, 31. (6) Electrophilic Reagents: Attack on a Carbonyl Oxygen Atom, 31. (c) Nucleophilic Reagents: Removal of Proton from Ring Nitrogen Atom, 31. (d) Nucleophilic Reagents: Attack at a Ring Carbon Atom, 31. (e) Free Radical Reactions, 32. (f) a-Pyrones, 32

4. N-Oxides 32 (o) Electrophilic Reagents, 32. (b) Strong Nucleophiles, 33. (c) Weaker Nucleophilic Reagents, 33

5. Effects of Substituents 33 (a) Electrophilic Attack at Ring Nitrogen, 33. (b) Electrophilic Attack at a Ring Carbon Atom, 33. (c) Nucleophilic Attack at a Ring Carbon Atom, 34. (d) Free Radical Attack, 35

B. Electrophilic Attack at the Pyridine Nitrogen Atom 35 1. Proton Acids 35

(a) Salt Formation, 35. {b) Substituent Effects, 35 2. Metal Ions 36

ia) Simple Complexes, 36. (b) Chelate Complexes, 36 3. Reactive Halides and Related Compounds 37

(a) Alkyl Halides, etc., 37. (b) Aryl Halides, 37. (c) Acid Chlorides, 37

4. Halogens 37 5. Peracids 37 6. Other Lewis Acids 38

C. Electrophilic Attack at the Ring Carbon Atoms 38 1. Nitration 38

(a) Pyridines, 38. {b) Pyridones, 39. (c) Pyridine l-oxides, 39 2. Sulphonation 39 3. Halogenation 39 4. Nitrosation, Diazo-Coupling, and Reaction with Aldehydes 40 5. Oxidation 40 6. Acid-Catalyzed Hydrogen Exchange 41

D. Nucleophilic Attack at the Ring Carbon Atoms 41 1. Hydroxide Ion 41

(a) Pyridine, 41. (ß) Alkyl-Pyridinium Ions, 41. (c) Other Pyridinium Ions, 42. {d) Pyrylium Salts, 42. (e) Pyrones, 43

Contents xi 2. Amines and Amide Ions 43

(o) Pyridines, 43. (b) Pyridinium Ions, 44. (c) Pyrylium Ions, 44 3. Sulpiride Ions 44 4. Chloride Ions 44 5. Carbanions 45

(ß) Organometallic Compounds, 45. (6) Activated Methyl and Methylene Carbanions, 46. (c) Cyanide Ions, 46

6. Chemical Reduction 47

E. Free Radical Attack at the Ring Carbon Atoms 48 1. Halogen Atoms 48 2. Aryl Radicals 48 3. Dimerization Reactions 48

F. Miscellaneous Reactions 48 1. Loss of a Proton from the Ring Nitrogen Atom 48 2. Catalytic Hydrogenation 49 3. Other Reactions 50

IV. THE REACTIONS OF SUBSTITUENTS ATTACHED TO AROMATIC RINGS 50

A. Substituents on Carbon 50 1. General Survey 50

(a) Substituent Environment, 51. (b) The Carbonyl Analogy, 51. (c) The Effect of One Substituent on the Reactivity oj Another, 53. (d) Reactions of Substituents Not Directly Attached to the Hetero-cyclic Ring, 53

2. Benzenoid Rings 53 (a) Fused Benzene Rings, 53. (ß) Aryl Groups, 55

3. Alkyl Groups 55 (a) AlkylGroups Attachedto Heteroaromatic Systems, 55. (6) a-and y-Alkylpyridines, 55.(c) Alkyl-Pyridine 1-Oxidesand-Pyridones, 57. (d)Alkyl-Pyridiniumand-Pyrylium Compounds, 57. (e) Tautomerism ofAlkyl-Pyridines, 59

4. Other Carbon-Containing Functional Groups 59 (a) Carboxylic Acids, 59. (6) Aldehydes and Ketones, 60. (c) Vinyl and Ethynyl Groups, 60

5. Halogen Atoms 60 6. Oxygen-Containing Functional Groups 62

(a) Alkoxyl Groups, 62. (b) Acyloxy Groups, 63. (c) Hydroxyl Groups, 63. (d) Pyridones, Pyrones, and Thiopyrones, 64

7. Nitrogen-Containing Functional Groups 65 (a) Amino-Imino Tautomerism, 65. (b) a- and y-Amino Groups, 65. (c) ß-Amino Groups, 67. (d) Other Amino Groups, 67. (e) Mfro Groups, 67

8. Sulphur-Containing Functional Groups 68 (a) Mercapto-Thione Tautomerism, 68. (6) Thiones, 69. (c) Sulphonic Acid Groups, 69

B. Substituents on the Ring Nitrogen Atom 69 1. Rearrangement Reactions 70 2. Loss of N-Substituents 71 3. Proton Loss from N-Substituents 71 4. Reactions of N-Substituents with Electrophilic Reagents 71

xii Contents

C. Summary of Synthetic Routes to Substituted Pyridines 72 (a) 2-Position, 73. (b) 4-Position, 73. (c) 'i-Position, 74

V. REACTIONS OF NON-AROMATIC COMPOUNDS 74

A. Dihydro Compounds 74 (Ö) Tautomerism, 74. (b) Aromatization, 74. (c) OMer Reactions, 75

B. Tetra- and Hexa-hydro Compounds 75 (a) Aromatization, 75. (6) Ring Fission, IS. (c) OrAer Reactions, 76. (rf) Stereochemistry, 76

3. Six-Membered Rings with Two or More Heteroatoms 77

I. NOMENCLATURE AND IMPORTANT COMPOUNDS 77

1. Diazines 77 (d) Monocydic Compounds, 11. (b) Benzo-Diazines, 19. (c) Other Fused Diazines, 79

2. Other Compounds 80 (a) Triazines and Tetrazines, 80. (b) Oxazines and Thiazines, 80

II . RING SYNTHESES 81

A. Heteroatoms in the 1,2-Positions 81 1. General Survey 81 2. Methods Using Hydrazine or Hydroxylamine 82 3. Other Methods 82

B. Heteroatoms in the 1,3-Positions 82 1. General Survey 82 2. Type C-C-C + Z-C-Z 83 3. Type C-C-C-Z + C-Z 83 4. Type Z-C-C-C-Z + C 84

C. Heteroatoms in the 1,4-Positions 84 1. General Survey 84 2. Type Z-C-C-Z + C-C 84 3. Type C-C-Z + C-C-Z 85 4. Type C-C-Z-C-C + Z 86

D. Compounds with Three or Four Heteroatoms 86 III. REACTIONS OF THE AROMATIC RINGS 86

1. General Survey 86 2. Electrophilic Attack on the Ring Nitrogen Atoms 87 3. Electrophilic Attack on the Ring Carbon Atoms 87 4. Nucleophilic Attack on the Ring Carbon Atoms 88

IV. REACTIONS OF SUBSTITUENTS ON AROMATIC RINGS 89

1. General Survey 89 2. Carbon-Containing Substituents 90

(a) Fused Benzene Rings, 90. {b) Aryl Groups, 91. (c) Alkyl Groups, 91. (d) Carboxylic Acids, Aldehydes, and Ketones, 91

3. Halogen Atoms 91 4. Oxygen-Containing Functional Groups 92

(a) Tautomerism, 92. (6) Diazinones, 92. (c) Alkoxyl Groups, 93

Contents xiä 5. Nitrogen- and Sulphur-Containing Functional Groups 93

(a) Amino Groups, 93. ib) Nitro andNitroso Groups, 93. (c) Sulphur-Containing Groups, 93

V. REACTIONS OF NON-AROMATIC COMPOUNDS 94

1. Reactions Involving 'Reversion to Type' 94 2. Aromatization 94 3. Other Reactions 95

4. Five-Membered Rings with One Heteroatom 96 I. NOMENCLATURE AND IMPORTANT COMPOUNDS 96

1. Aromatic Monocyclic Compounds 96 (a) Nomenclature, 96. (6) Thiophenes, 96. (c) Furans, 97. (d) Pyr-roles, 97

2. Non-Aromatic Monocyclic Compounds 98 (a) Nomenclature, 98. (6) Reduced Furans, 98. (c) Reduced Pyr-roles, 98. (d) Reduced Thiophenes, 99

3. 2,3-Benzo Derivatives 99 (a) Nomenclature, 99. (6) Indoles, 99

4. Other Compounds 100 (a) 3,4-5e«zo Derivatives, 100. (6) Dibenzo Derivatives, 101. (c) O/Aer Fused Ring Compounds, 101

I I . RING SYNTHESES 101 1. General Survey 101 2. Formation of C-Z Bonds 102

(a) Saturated Compounds, 102. (6) jR/n i vw/A One Ethylenic Link-age, 103. (c) Aromatic Compounds, 104

3. Formation of the C3-C4 Bond 104 (a) T/ze Knorr Pyrrole Synthesis, 104. (6) 77ie Fischer lndole Syn-thesis, 105. (c) Cyclization oj a-Halogeno-Ketones to give Pyrroles, Furans, and Indoles, 105. (d) Other Cydizations onto a Benzene Ring, 106

III . REACTIONS OF THE AROMATIC NUCLEI 107 A. General Survey of Reactivity 107

(a) Comparison with Aliphatic Series, 107. {b) Aromaticity, 108

B. Reactions with Electrophilic Reagents 109 1. Ease of Reaction 109 2. Orientation 109 3. Nitration 110 4. Sulphonation 110 5. Halogenation 110 6. Acylation 111 7. Reactions with Aldehydes and Ketones 112

(o) Formation of Carbinols or Carbonium Ions, 112. (6) Further Reactions of Carbonium Ions, 112. (c) Chloromethylation, 113 (d) Mannich Reaction, 114

8. Diazo-Coupling, Nitrosation, and Mercuration 114 9. Reactions with Acids 115

(a) Cation Function, 115. (Z>) Ring Opening, 115. (c) Polymerization, 115. (rf) Picrates, 115

xiv Contents 10. Oxidation 116

(a) Pyrroles and Furans, 116. (b) Indoles, 116. (c) Thiophenes, 116

C. Other Reactions of the Aromatic Nuclei 117 1. Reactions Involving Deprotonation of Pyrroles 117

(a) Pyrroles as Acids, 117. (6) Pyrrole Grignard Reagents, 117. (c) Further Pyrrole Anion Intermediates, 118

2. Catalytic and Chemical Reductions 118 3. Other Reactions with Nucleophilic Reagents 119 4. Free Radical Reactions 119 5. Diels-Alder Reaction 120

IV. REACTIONS OF SUBSTITUENTS ON AROMATIC NUCLEI 1 2 0

1. General Survey ofReactivity 120 2. Fused Benzene Rings 121 3. Alkyl and Substituted-Alkyl Groups 121

(o) Alkyl Groups, 121. (b) Substituted-Alkyl Groups: General, 122. (c) Halogenomethyl Groups, 122. (d) Hydroxymethyl Groups, 122. (e) Aminomethyl Groups, 123

4. Carboxylic Acids 123 5. Formyl and Acyl Groups 124 6. Halogen 124 7. Nitro, Sulphonic Acid, and Mercuri Groups 125 8. N-Substituents on Pyrroles 126

V. REACTIONS OF H Y D R O X Y L , AMINO, A N D RELATED COMPOUNDS 126

1. Survey ofReactivity 126 (a) General, 126. (b) Tautomerism of Monocyclic Compounds, 126. (c) Tautomerism ofBenzo Derivatives, 127. (d) Interconversion and Reactivity of Tautomeric Forms, 127

2. Reactions with Electrophiles 129 (a) Hydroxy Compounds, 129. (b) Anions, 129

3. Reactions of Carbonyl Compounds with Nucleophiles 130 (Ö) Carbonyl Groups Adjacent to the Heteroatom, 130. (b) Carbonyl Groups Not Adjacent to the Heteroatom, 131

4. Reduction of Carbonyl and Hydroxyl Compounds 132 5. Reactions at Other Sites in the Ring 132 6. Amino and Imino Compounds 133

VI. REACTIONS OF OTHER N O N - A R O M A T I C COMPOUNDS 133

1. Pyrrolenines and Indolenines 133 2. Thiophene Sulphones 134 3. Dihydro Compounds 135 4. Tetrahydro Compounds 135

5. Five-Membered Rings Containing Two or More Heteroatoms 136 I. NOMENCLATURE A N D IMPORTANT COMPOUNDS 136

1. Monocyclic Compounds Containing Annular Nitrogen Atoms Only 136

2. Monocyclic Compounds Containing Annular Nitrogen and Oxygen or Sulphur Atoms 137

3. Polycyclic Derivatives 138

Contents xv II . RING SYNTHESES 139

A. Heteroatoms in the 1,2-Positions 139 1. Monocyclic Compounds 139 2. Benzo Derivatives 140

B. Heteroatoms in the 1,3-Positions 141 1. Oxazoles, Thiazoles, and Imidazoles 141 2. Other Monocyclic Derivatives 142 3. Benzo Derivatives 142

C. Compounds Containing Three or More Heteroatoms 143 1. Heteroatoms in the 1,2,3-Positions 143 2. Heteroatoms in the 1,2,4-Positions 144 3. Four or Five Heteroatoms 144

III . REACTIONS OF THE AROMATIC RINGS 1 4 4

A. General Survey 144 1. Comparison with Other Heterocycles 144 2. Tautomerism 145

B. Electrophilic Attack at a Multiply-Bonded Ring Nitrogen Atom 145 1. Reaction Sequence 145 2. Proton Acids 146 3. Alkyl and Acyl Halides and Related Compounds 147

C. Electrophilic Attack at a Ring Carbon Atom 148 1. Reactivity and Orientation 148

(a) Ease of Reaction, 148. (b) Orientation, 148. (c) Effect ofSub-stituents, 149

2. Nitration, Sulphonation, and Halogenation 149 3. Other Electrophiles 150

D. Nucleophilic Attack at the Ring Carbon Atoms 151 (a) General, 151. (b) Hydroxide and Alkoxide Ions, 151. (c) Amines, 152. (d) Reducing Agents, 152. (e) Deprotonation, 152

E. Other Reactions of the Aromatic Nuclei 152 (a) Nucleophilic Attack on the Ring NH Groups, 152. (6) Loss of Nitrogen, 152

IV. REACTIONS OF SUBSTITUENTS ON AROMATIC NUCLEI 153

1. General Survey 153 (a) Heteroatoms in the 1,3-Positions, 153. (b) Heteroatoms in the 1,2-Positions, 153

2. Carbon-Containing Substituents 154 (a) Fused Benzene Rings, 154. (b) Aryl Groups, 154. (c) Alkyl Groups, 154. (d) Acyl Groups, 155

3. Halogens 155 4. Potential Hydroxy Compounds 155

(a) 2-Hydroxy, Heteroatoms-1,3, 155. (b) 3-Hydroxy, Hetero-atoms-1,2, 156. (c) 4- and 5-Hydroxy, Heteroatoms-1,3 and 4-Hydroxy, Heteroatoms-1,2, 156. (d) 5-Hydroxy, Heteroatoms-1,2, 157

5. Amino Groups 157

xvi Contents

V. REACTIONS OF NON-AROMATIC COMPOUNDS 157

(a) Dihydro Compounds, 158. (6) Tetrahydro Compounds, 158. (c) Non-Aromatic Derivatives oj Azolinones, 158

6. Heterocyclic Compounds with Three- and Four-Membered Rings 159

I . THREE-MEMBERED RINGS 159

A. Three-Membered Rings with One Heteroatom 159 1. Nomenclature and Compounds 159 2. Preparation . 159 3. Reactions 160

B. Three-Membered Rings Containing Two Heteroatoms 161

I I . FOUR-MEMBERED RINGS 162

A. Four-Membered Rings Containing One Heteroatom 162 1. Nomenclature and Compounds 162 2. Preparation 162 3. Reactions 163

(a) Saturated Rings, 163. (6) Carbonyl Derivatives, 163

B. Four-Membered Rings Containing Two Heteroatoms 163

7. Physical Properties 165

1. Melting Points and Boiling Points 165 (a) Unsubstituted Compounds, 165. (b) Effect oj Substituents, 165

2. Refractive Indices, Specific Gravities, and Viscosities 167 3. Dipole Moments 167 4. pK„ Values 168 5. Ultraviolet Spectra 169 6. Infrared Spectra 170 7. Nuclear Magnetic Resonance Spectra 170 8. Mass Spectra 171

Index 173