The Principles of Heterocyclic Chemistry

Transcription

1 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 LANE LONDON EC4

2 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 Compounds 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 Monocyclic Nitrogen-Containing Compounds 12 (a) Nomenclature, 12. (b) Occurrence, 12. (c) Uses, Benzopyridines Monocyclic Oxygen- and Sulphur-Containing Compounds 14 (a) Nomenclature, 14. (b) Occurrence, Monobenzo-Pyrones and -Pyrylium Salts 15 (a) Nomenclature, 15. (b) Occurrence, Dibenzo-Pyrones and -Pyrylium Salts 16 II. RING SYNTHESES 17 A. General Survey 17 B. Preparation of Monocyclic Compounds (Pyridines, Pyridones, Pyrylium Salts, etc.) From Pentane-l,5-diones 19 (a) General, 19. (b) The Hantzsch Pyridine Synthesis, From Pent-2-ene-l,5-diones From Pentane-l,3,5-triones From Other 1,5-Disubstituted Pentanes Methods Involving C-C Bond Formation 22 C. Preparation of 2,3-Benzo Derivatives (Quinolines, Quinolones, Chromans, etc.) Ring Closure of o-substituted Anilines or Phenols 22 (a) o-substituted Cinnamoyl Derivatives, 22. (b) Other o-subsituted Benzenes, 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) Dibenzo Derivatives, 25 ix

3 x Contents 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 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, 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, 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, N-Oxides 32 (o) Electrophilic Reagents, 32. (b) Strong Nucleophiles, 33. (c) Weaker Nucleophilic Reagents, 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 Proton Acids 35 (a) Salt Formation, 35. {b) Substituent Effects, Metal Ions 36 ia) Simple Complexes, 36. (b) Chelate Complexes, Reactive Halides and Related Compounds 37 (a) Alkyl Halides, etc., 37. (b) Aryl Halides, 37. (c) Acid Chlorides, Halogens Peracids Other Lewis Acids 38 C. Electrophilic Attack at the Ring Carbon Atoms Nitration 38 (a) Pyridines, 38. {b) Pyridones, 39. (c) Pyridine l-oxides, Sulphonation Halogenation Nitrosation, Diazo-Coupling, and Reaction with Aldehydes Oxidation Acid-Catalyzed Hydrogen Exchange 41 D. Nucleophilic Attack at the Ring Carbon Atoms Hydroxide Ion 41 (a) Pyridine, 41. (ß) Alkyl-Pyridinium Ions, 41. (c) Other Pyridinium Ions, 42. {d) Pyrylium Salts, 42. (e) Pyrones, 43

4 Contents xi 2. Amines and Amide Ions 43 (o) Pyridines, 43. (b) Pyridinium Ions, 44. (c) Pyrylium Ions, Sulpiride Ions Chloride Ions Carbanions 45 (ß) Organometallic Compounds, 45. (6) Activated Methyl and Methylene Carbanions, 46. (c) Cyanide Ions, Chemical Reduction 47 E. Free Radical Attack at the Ring Carbon Atoms Halogen Atoms Aryl Radicals Dimerization Reactions 48 F. Miscellaneous Reactions Loss of a Proton from the Ring Nitrogen Atom Catalytic Hydrogenation Other Reactions 50 IV. THE REACTIONS OF SUBSTITUENTS ATTACHED TO AROMATIC RINGS 50 A. Substituents on Carbon 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 Heterocyclic Ring, Benzenoid Rings 53 (a) Fused Benzene Rings, 53. (ß) Aryl Groups, 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, Other Carbon-Containing Functional Groups 59 (a) Carboxylic Acids, 59. (6) Aldehydes and Ketones, 60. (c) Vinyl and Ethynyl Groups, Halogen Atoms Oxygen-Containing Functional Groups 62 (a) Alkoxyl Groups, 62. (b) Acyloxy Groups, 63. (c) Hydroxyl Groups, 63. (d) Pyridones, Pyrones, and Thiopyrones, 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, 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 Rearrangement Reactions Loss of N-Substituents Proton Loss from N-Substituents Reactions of N-Substituents with Electrophilic Reagents 71

5 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, Six-Membered Rings with Two or More Heteroatoms 77 I. NOMENCLATURE AND IMPORTANT COMPOUNDS Diazines 77 (d) Monocydic Compounds, 11. (b) Benzo-Diazines, 19. (c) Other Fused Diazines, Other Compounds 80 (a) Triazines and Tetrazines, 80. (b) Oxazines and Thiazines, 80 II. RING SYNTHESES 81 A. Heteroatoms in the 1,2-Positions General Survey Methods Using Hydrazine or Hydroxylamine Other Methods 82 B. Heteroatoms in the 1,3-Positions General Survey Type C-C-C + Z-C-Z Type C-C-C-Z + C-Z Type Z-C-C-C-Z + C 84 C. Heteroatoms in the 1,4-Positions General Survey Type Z-C-C-Z + C-C Type C-C-Z + C-C-Z Type C-C-Z-C-C + Z 86 D. Compounds with Three or Four Heteroatoms 86 III. REACTIONS OF THE AROMATIC RINGS General Survey Electrophilic Attack on the Ring Nitrogen Atoms Electrophilic Attack on the Ring Carbon Atoms Nucleophilic Attack on the Ring Carbon Atoms 88 IV. REACTIONS OF SUBSTITUENTS ON AROMATIC RINGS General Survey Carbon-Containing Substituents 90 (a) Fused Benzene Rings, 90. {b) Aryl Groups, 91. (c) Alkyl Groups, 91. (d) Carboxylic Acids, Aldehydes, and Ketones, Halogen Atoms Oxygen-Containing Functional Groups 92 (a) Tautomerism, 92. (6) Diazinones, 92. (c) Alkoxyl Groups, 93

6 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 Reactions Involving 'Reversion to Type' Aromatization Other Reactions Five-Membered Rings with One Heteroatom 96 I. NOMENCLATURE AND IMPORTANT COMPOUNDS Aromatic Monocyclic Compounds 96 (a) Nomenclature, 96. (6) Thiophenes, 96. (c) Furans, 97. (d) Pyrroles, Non-Aromatic Monocyclic Compounds 98 (a) Nomenclature, 98. (6) Reduced Furans, 98. (c) Reduced Pyrroles, 98. (d) Reduced Thiophenes, ,3-Benzo Derivatives 99 (a) Nomenclature, 99. (6) Indoles, Other Compounds 100 (a) 3,4-5e«zo Derivatives, 100. (6) Dibenzo Derivatives, 101. (c) O/Aer Fused Ring Compounds, 101 II. RING SYNTHESES General Survey Formation of C-Z Bonds 102 (a) Saturated Compounds, 102. (6) jr/n^i vw/a One Ethylenic Linkage, 103. (c) Aromatic Compounds, Formation of the C3-C4 Bond 104 (a) T/ze Knorr Pyrrole Synthesis, 104. (6) 77ie Fischer lndole Synthesis, 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 Ease of Reaction Orientation Nitration Sulphonation Halogenation Acylation 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, Diazo-Coupling, Nitrosation, and Mercuration Reactions with Acids 115 (a) Cation Function, 115. (Z>) Ring Opening, 115. (c) Polymerization, 115. (rf) Picrates, 115

7 xiv Contents 10. Oxidation 116 (a) Pyrroles and Furans, 116. (b) Indoles, 116. (c) Thiophenes, 116 C. Other Reactions of the Aromatic Nuclei Reactions Involving Deprotonation of Pyrroles 117 (a) Pyrroles as Acids, 117. (6) Pyrrole Grignard Reagents, 117. (c) Further Pyrrole Anion Intermediates, Catalytic and Chemical Reductions Other Reactions with Nucleophilic Reagents Free Radical Reactions Diels-Alder Reaction 120 IV. REACTIONS OF SUBSTITUENTS ON AROMATIC NUCLEI General Survey ofreactivity Fused Benzene Rings 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, Carboxylic Acids Formyl and Acyl Groups Halogen Nitro, Sulphonic Acid, and Mercuri Groups N-Substituents on Pyrroles 126 V. REACTIONS OF HYDROXYL, AMINO, AND RELATED COMPOUNDS Survey ofreactivity 126 (a) General, 126. (b) Tautomerism of Monocyclic Compounds, 126. (c) Tautomerism ofbenzo Derivatives, 127. (d) Interconversion and Reactivity of Tautomeric Forms, Reactions with Electrophiles 129 (a) Hydroxy Compounds, 129. (b) Anions, Reactions of Carbonyl Compounds with Nucleophiles 130 (Ö) Carbonyl Groups Adjacent to the Heteroatom, 130. (b) Carbonyl Groups Not Adjacent to the Heteroatom, Reduction of Carbonyl and Hydroxyl Compounds Reactions at Other Sites in the Ring Amino and Imino Compounds 133 VI. REACTIONS OF OTHER NON-AROMATIC COMPOUNDS Pyrrolenines and Indolenines Thiophene Sulphones Dihydro Compounds Tetrahydro Compounds Five-Membered Rings Containing Two or More Heteroatoms 136 I. NOMENCLATURE AND IMPORTANT COMPOUNDS Monocyclic Compounds Containing Annular Nitrogen Atoms Only Monocyclic Compounds Containing Annular Nitrogen and Oxygen or Sulphur Atoms Polycyclic Derivatives 138

8 Contents xv II. RING SYNTHESES 139 A. Heteroatoms in the 1,2-Positions Monocyclic Compounds Benzo Derivatives 140 B. Heteroatoms in the 1,3-Positions Oxazoles, Thiazoles, and Imidazoles Other Monocyclic Derivatives Benzo Derivatives 142 C. Compounds Containing Three or More Heteroatoms Heteroatoms in the 1,2,3-Positions Heteroatoms in the 1,2,4-Positions Four or Five Heteroatoms 144 III. REACTIONS OF THE AROMATIC RINGS 144 A. General Survey Comparison with Other Heterocycles Tautomerism 145 B. Electrophilic Attack at a Multiply-Bonded Ring Nitrogen Atom Reaction Sequence Proton Acids Alkyl and Acyl Halides and Related Compounds 147 C. Electrophilic Attack at a Ring Carbon Atom Reactivity and Orientation 148 (a) Ease of Reaction, 148. (b) Orientation, 148. (c) Effect ofsubstituents, Nitration, Sulphonation, and Halogenation 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 General Survey 153 (a) Heteroatoms in the 1,3-Positions, 153. (b) Heteroatoms in the 1,2-Positions, Carbon-Containing Substituents 154 (a) Fused Benzene Rings, 154. (b) Aryl Groups, 154. (c) Alkyl Groups, 154. (d) Acyl Groups, Halogens Potential Hydroxy Compounds 155 (a) 2-Hydroxy, Heteroatoms-1,3, 155. (b) 3-Hydroxy, Heteroatoms-1,2, 156. (c) 4- and 5-Hydroxy, Heteroatoms-1,3 and 4- Hydroxy, Heteroatoms-1,2, 156. (d) 5-Hydroxy, Heteroatoms-1,2, Amino Groups 157

9 xvi Contents V. REACTIONS OF NON-AROMATIC COMPOUNDS 157 (a) Dihydro Compounds, 158. (6) Tetrahydro Compounds, 158. (c) Non-Aromatic Derivatives oj Azolinones, Heterocyclic Compounds with Three- and Four-Membered Rings 159 I. THREE-MEMBERED RINGS 159 A. Three-Membered Rings with One Heteroatom Nomenclature and Compounds Preparation Reactions 160 B. Three-Membered Rings Containing Two Heteroatoms 161 II. FOUR-MEMBERED RINGS 162 A. Four-Membered Rings Containing One Heteroatom Nomenclature and Compounds Preparation Reactions 163 (a) Saturated Rings, 163. (6) Carbonyl Derivatives, 163 B. Four-Membered Rings Containing Two Heteroatoms Physical Properties Melting Points and Boiling Points 165 (a) Unsubstituted Compounds, 165. (b) Effect oj Substituents, Refractive Indices, Specific Gravities, and Viscosities Dipole Moments pk Values Ultraviolet Spectra Infrared Spectra Nuclear Magnetic Resonance Spectra Mass Spectra 171 Index 173