ISBN: 3540652523
TITLE: Heterocyclic Chemistry II
AUTHOR: Gupta, Radha R.; Kumar, Mahendra; Gupta, Vandana
TOC:

Chapter 1. Introduction 1
Chapter 2. Five-Membered Heterocycles with One Heteroatom 3
Chapter 3. Benzo-Fused Five-Membered Heterocycles with One Heteroatom 181
Chapter 4. Five-Membered Heterocycles with Two Heteroatoms 357
Chapter 5. Five-Membered Heterocycles with More Than Two Heteroatoms 487
Chapter 6. Meso-Ionic Heterocycles 579
Subject Index 627
2 PYRROLES 33
2.1 General 33
2.1.1 Extraction 33
2.1.2 Ehrlich Test 34
2.2 Synthesis 34
2.2.1 Cyclization Reactions 34
2.2.1.1 (3 + 2) Cyclization Reactions 34
2.2.1.1.1 Reaction of alpha-Amino Ketones or alpha-Amino beta-Keto Esters with beta-Diketones or beta-Keto Esters (Knorr Pyrrole Synthesis) 34
2.2.1.1.2 Reaction of alpha-Amino Ketones with Alkynes 36
2.2.1.1.3 Reaction of beta-Amino-alpha,beta-unsaturated Esters with Nitroalkenes 37
2.2.1.1.4 Reaction of alpha-Diketones with Amines 37
2.2.1.2 (2 + 2 + 1) Cyclization Reactions 38
2.2.1.2.1 Reaction of beta-Keto Esters with alpha-Halo Ketones (Hantzsch Pyrrole Synthesis) 38
2.2.1.2.2 Reaction of Aldehydes or Ketones with Hydrazine (Piloty-Robinson Pyrrole Synthesis) 38
2.2.1.2.3 Reaction of Benzoin with Benzyl Aryl Ketones 38
2.2.1.2.4 Reaction of Aldehydes with Alkyl Isocyanoacetates 41
2.2.1.3 (4 + 1) Cyclization Reactions 41
2.2.1.3.1 Reaction of 1,4-Diketones with Ammonia or Ammonia Derivatives (Paal-Knorr Synthesis) 41
2.2.1.3.2 Reaction of 1,4-Dienes or Diynes with Amines 41
2.2.2 Ring Expansion Reactions 43
2.2.3 Extrusion Reactions 43
2.3 Structure 45
2.4 Basicity 46
2.5 Reactions 46
2.5.1 Protonation 46
2.5.2 Proton Exchange 47
2.5.3 Electrophilic Substitution Reactions 49
2.5.3.1 Orientation 50
2.5.3.2 Nitration 50
2.5.3.3 Halogenation 52
2.5.3.3.1 Chlorination 52
2.5.3.3.2 Bromination 52
2.5.3.3.3 Iodination 52
2.5.3.4 Sulfonation 54
2.5.3.5 Acylation 55
2.5.3.5.1 Houben-Hoesch Reaction 55
2.5.3.5.2 Gattermann Formylation 56
2.5.3.5.3 Vilsmeier-Haack Reaction 57
2.5.3.5.4 Friedel-Crafts Acylation 58
2.5.3.6 Alkylation 58
2.5.3.7 Hydroxymethylation (Mannich Reaction) 60
2.5.3.8 Reactions with Aldehydes and Ketones 60
2.5.3.9 Diazo Coupling 64
2.5.4 Reactions on Carbon and Nitrogen Anionic Species 65
2.5.4.1 Alkylation 66
2.5.4.2 Acylation 66
2.5.5 Nucleophilic Substitution Reactions 68
2.5.6 Oxidation 69
2.5.6.1 Autoxidation 69
2.5.6.2 Photo-oxidation 69
2.5.6.3 Oxidation with Chromium Trioxide 69
2.5.6.4 Oxidation with Hydrogen Peroxide 69
2.5.7 Reduction 71
2.5.7.1 Catalytic Hydrogenation 71
2.5.7.2 Reduction by Metal-Acid Systems (Chemical Reduction) 72
2.5.8 Reactions with Free Radicals 73
2.5.9 Reactions with Electron-Deficient Species 74
2.5.9.1 Reactions with Carbenes 74
2.5.9.2 Reactions with Nitrenes 77
2.5.10 Cycloaddition Reactions 77
2.5.10.1 (4pi + 2pi) Reactions 77
2.5.10.1.1 Reactions with DMAD 78
2.5.10.1.2 Reactions with Benzyne 79
2.5.10.1.3 Reaction with Hexafluorobicyclo- [2.2.0]hexa-2,5-diene 80
2.5.10.2 (2pi + 2x) Reactions 80
3 FURANS 82
3.1 General 82
3.2 Synthesis 83
3.2.1 Commercial Method (From Aldopentoses or Ketopentoses) 83
3.2.2 From 1,4-Diketones 83
3.2.3 Cyclization of Alkynes 84
3.2.3.1 Photochemical Cyclization 84
3.2.3.2 From Alkynyl Sulfonium Salts 84
3.2.4 Cyclization of Ylides 85
3.2.4.1 Sulfur Ylides 85
3.2.4.2 Phosphorus Ylides 86
3.2.5 From alpha-Halocarbonyl Compounds (Feist-Benary Synthesis) 87
3.2.6 Ring Expansion of Small Ring Heterocycles 88
3.2.6.1 Three-Membered Heterocycles 88
3.2.6.2 Four-Membered Heterocycles 89
3.2.7 Transformation of Five-Membered Heterocycles 89
3.2.8 Ring Contraction 90
3.3 Structure 91
3.4 Reactions 92
3.4.1 Reactions with Electrophiles 92
3.4.1.1 Reactivity and Orientation Effects 92
3.4.1.2 Directing Effects of Substituents 93
3.4.1.3 Protonation 94
3.4.1.4 Nitration 96
3.4.1.5 Sulfonation 97
3.4.1.6 Halogenation 98
3.4.1.7 Alkylation 100
3.4.1.8 Acylation 102
3.4.1.9 Reactions with Aldehydes and Ketones 104
3.4.1.10 Reactions with Diazonium Salts 105
3.4.2 Reactions with Nucleophiles 105
3.4.3 Reactions with Free Radicals 108
3.4.4 Reactions with Electron-Deficient Species 111
3.4.5 Cycloaddition Reactions 112
3.4.6 Photochemical Reactions 118
4 THIOPHENES 121
4.1 General 121
4.1.1 Isolation 122
4.2 Synthesis 122
4.2.1 Intramolecular Cyclization Reactions 122
4.2.1.1 From 4-Aralkylthiocrotononitriles 122
4.2.1.2 From 3-Methylenethiopropenals 123
4.2.2 (4 + 1) Cyclization Reactions 124
4.2.2.1 From Hydrocarbons 124
4.2.2.2 From 1,4-Diketones (Paal Synthesis) 125
4.2.3 (3 + 2) Cyclization Reactions 126
4.2.3.1 Reaction of alpha,beta-Unsaturated Carbonyl Compounds with Ethyl Mercaptoacetate 126
4.2.3.2 Reaction of Activated Alkynes with alpha-Mercapto Ketones or Esters 127
4.2.3.3 Reaction of Dimethyl Fumarate with Mercapto Esters 128
4.2.3.4 Reaction of alpha-Mercapto Ketones with Activated Methylene Nitriles (Gewald Synthesis) 129
4.2.3.5 Reaction of alpha-Diketones with Activated Methylene Compounds (Hinsberg Synthesis) 129
4.2.3.6 Reaction of Alkynes with Mesoionic Heterocycles 131
4.2.4 (2+2+1) Cyclization Reactions 131
4.3 Structure 132
4.4 Reactions 134
4.4.1 Reactions with Electrophiles 134
4.4.1.l Electrophilic Substitutions at Carbon 134
4.4.1.1.1 Orientation 134
4.4.1.1.2 Directing Effects of Substituents 135
4.4.1.1.2.1 Substituents at Carbon-2 135
4.4.1.1.2.2 Substituents at Carbon-3 136
4.4.1.1.3 Protonation 136
4.4.1.1.4 Nitration 137
4.4.1.1.5 Sulfonation 140
4.4.1.1.6 Halogenation 141
4.4.1.1.6.1 Chlorination 141
4.4.1.1.6.2 Bromination 142
4.4.1.1.6.3 Iodination 144
4.4.1.1.7 Alkylation 144
4.4.1.1.8 Acylation 145
4.4.1.1.9 Reactions with Aldehydes and Ketones 148
4.4.1.1.10 Mercuration 149
4.4.1.1.11 Reactions with Diazonium Salts 150
4.4.1.2 Electrophilic Attack on Su1fur 151
4.4.2 Reactions with Oxidizing Agents 152
4.4.2.1 Formation of Thiophene Sulfoxides and Sulfones 152
4.4.2.2 Oxidative Ring Cleavage 153
4.4.2.3 Oxidation by Metal Ions 153
4.4.3 Reactions with Nucleophiles 154
4.4.3.1 Nucleophilic Attack at Carbon 154
4.4.3.1.1 Nucleophilic Substitutions 154
4.4.3.1.2 Halogen-Metal Exchange 156
4.4.3.2 Nucleophilic Attack at Hydrogen 158
4.4.3.2.1 Lithiation 158
4.4.3.3 Nucleophilic Ring Opening Reactions 159
4.4.4 Reactions with Reducing Agents 160
4.4.4.1 Catalytic Reduction 160
4.4.4.2 Birch Reduction 161
4.4.4.3 Reductive Desulfurization 161
4.4.5 Reactions with Free Radicals 161
4.4.6 Reactions with Electron-Deficient Species 164
4.4.6.1 Reactions with Carbenes 164
4.4.6.2 Reactions with Nitrenes 165
4.4.7 Cycloaddition Reactions 165
4.4.7.1 Thermal [4 + 2] Cycloaddition Reactions 165
4.4.7.2 Thermal [2 + 2] Cycloaddition Reactions 167
4.4.7.3 Photocycloaddition Reactions 168
4.4.8 Photosubstitution 170
4.4.9 Photoisomerization 171
REFERENCES 171
CHAPTER 3
BENZO-FUSED FIVE-MEMBERED HETEROCYCLES WITH ONE HETEROATOM
CONTENTS
1 GENERAL 187
1.1 Reactivity 188
1.2 Orientation 188
1.3 Dibenzoheterocycles 189
2 BENZOPYRROLES 190
2.1 Indoles 191
2.1.1 General 191
2.1.2 Synthesis 194
2.1.2.1 Reaction of omicron-Nitrotoluene with Diethyl Oxalate (Reissert Indole Synthesis) 194
2.1.2.2 From omicron-Nitrophenylnitroethylene (omicron,omega-Dinitrostyrene) 195
2.1.2.3 Palladium Catalyzed Cyclization 196
2.1.2.4 Madelung Indole Synthesis 196
2.1.2.5 Isonitrile Cyclization 197
2.1.2.6 Bischler Indole Synthesis 198
2.1.2.7 Fischer Indole Synthesis 199
2.1.2.8 Gassman Indole Synthesis 203
2.1.2.9 Nenitzescu Indole Synthesis 203
2.1.2.10 From Pyrroles 206
2.1.2.11 From Azirines 207
2.1.3 Structure 208
2.1.4 Reactions 208
2.1.4.1 Reactions with Electrophiles 209
2.1.4.1.1 Protonation 210
2.1.4.1.1.1 Reaction with Proton Acids 210
2.1.4.1.1.2 Basicity 211
2.1.4.1.1.3 H <--> D Exchange 211
2.1.4.1.1.4 Dimerization and Trimerization 212
2.1.4.1.2 Nitration 212
2.1.4.1.3 Nitrosation 215
2.1.4.1.4 Halogenation 216
2.1.4.1.4.1 Chlorination 216
2.1.4.1.4.2 Bromination 218
2.1.4.1.4.3 Iodination 218
2.1.4.1.5 Sulfonation 220
2.1.4.1.6 Acylation 221
2.1.4.1.6.1 Friedel-Crafts Acylation 221
2.1.4.1.6.2 Vilsmeier-Haack Formylation 222
2.1.4.1.7 Alkylation 224
2.1.4.1.8 Reactions with Aldehydes and Ketones 224
2.1.4.1.8.1 Ehrlich Test 224
2.1.4.1.8.2 With Aromatic Aldehydes and Ketones 225

2.1.4.1.8.3 With Aliphatic Aldehydes and Ketones 225
2.1.4.1.8.4 With alpha,beta-Unsaturated Ketones 227
2.1.4.1.9 Mannich Reaction 227
2.1.4.2 Reactions on Carbon and Nitrogen Anionic Species 228
2.1.4.2.1 Alkylation 229
2.1.4.2.2 Acylation 231
2.1.4.3 Reactions with Nucleophiles 232
2.1.4.4 Oxidation 233
2.1.4.5 Reduction 234
2.1.4.6 Reactions with Electron-Deficient Species 237
2.1.4.7 Reactions with Free Radicals 238
2.1.4.8 Cycloaddition Reactions 239
2.2 Isoindoles (Benzo[c]pyrroles) 240

2.2.1 General 240
2.2.2 Synthesis 242
2.2.2.1 Cyclization Reactions 242
2.2.2.1.1 From alpha-Bromo-omicron-toluic Acid 242
2.2.2.1.2 From N-Cyanomethyl-N-methyl-o-chlorobenzylamine 243
2.2.2.1.3 From 1,4-Diketones 243
2.2.2.2 Extrusion Reaction 243
2.2.2.3 Ring Transformation Reactions 244
2.2.2.3.1 From Phthalimidines 244
2.2.2.3.2 From Isoindolines 245
2.2.2.3.3 From Pyrroles 247
2.2.3 Reactions 247
2.2.3.1 Reactions with Electrophiles 247
2.2.3.1.1 Protonation 248
2.2.3.1.2 Nitrosation 249
2.2.3.1.3 Acylation 249
2.2.3.1.4 Alkylation 249
2.2.3.1.5 Formylation 250
2.2.3.1.6 Reactions with Aldehydes and Ketones (Ehrlich Test) 250
2.2.3.2 Oxidation 251
2.2.3.3 Reduction 252
2.2.3.4 Cycloaddition Reactions 253
2.3 Indolizines (Pyrrocolines) 254
2.3.1 General 254
2.3.2 Synthesis 255
2.3.2.1 Reaction of Pyridines with alpha-Halocarbonyl Compounds (Tschitschibabin Reaction) 255
2.3.2.2 Reaction of Pyridine with Alkynic Compounds 257
2.3.2.3 Reaction of 2-Pyridyllithium with 2-Chloromethyloxirane 258
2.3.2.4 1,3-Dipolar Cycloaddition Reactions 258
2.3.3 Structure 259
2.3.4 Reactions 260
2.3.4.1 Reactions with Electrophiles 260
2.3.4.1.1 Protonation 261
2.3.4.1.2 Nitration 262
2.3.4.1.3 Nitrosation 262
2.3.4.1.4 Alkylation 263
2.3.4.1.5 Acylation 264
2.3.4.1.6 Reactions with Aldehydes and Ketones 264
2.3.4.2 Oxidation 264
2.3.4.3 Reduction 265
2.3.4.4 Cycloaddition Reactions 266
2.4 Carbazoles (Dibenzopyrroles) 267
2.4.1 General 267
2.4.2 Synthesis 268
2.4.2.1 From Cyclohexanone Phenylhydrazones (Borsche Synthesis or Modified Fischer Indole Synthesis) 268
2.4.2.2 Reaction of Anilines with alpha-Halocyclohexanones 268
2.4.2.3 From Diarylamines 269
2.4.2.3.1 Oxidative Cyclization 269
2.4.2.3.2 Photochemical Cyclization 270
2.4.2.4 Reductive Cyclization of omicron-Nitrobiphenyls 271
2.4.2.5 From omicron-Azidobiphenyls 271
2.4.2.6 From 1-Arylbenzotriazoles (Graebe-Ullnann Synthesis) 272
2.4.2.7 Nenitzescu Reaction 272
2.4.2.8 Annelation of Indoles 272
2.4.3 Structure 273
2.4.4 Reactions 274
2.4.4.1 Reactions with Electrophiles 274
2.4.4.1.1 Protonation 274
2.4.4.1.2 Nitration 275
2.4.4.1.3 Nitrosation 275
2.4.4.1.4 Chlorination 276
2.4.4.1.5 Bromination 276
2.4.4.1.6 Sulfonation 276
2.4.4.1.7 Acylation 277
2.4.4.2 Oxidation 278
2.4.4.3 Reduction 278
2.4.4.4 Reactions with Nucleophiles 279
3 BENZOFURANS 279
3.1 General 279
3.2 Benzo[b]furans 282
3.2.1 Synthesis 282
3.2.1.1 Intramolecular Cyclization of omicron-Substituted Phenols 282
3.2.1.2 Cyclodehydration of alpha-Aryloxyketones 283
3.2.1.3 Reaction of omicron-Acylphenols with alpha-Halo Ketones and Esters 284
3.2.1.4 Reaction of omicron-Acylphenols with Dimethylsulfoxonium Methylide 285
3.2.1.5 From p-Benzoquinones 286
3.2.1.6 Ring Contraction (From Coumarins) 287
3.2.2 Structure 287
3.2.3 Reactions 288
3.2.3.1 Reactions with Electrophiles 288
3.2.3.1.1 Reactivity and Orientation 288
3.2.3.1.2 Directing Effects of Substituents 289
3.2.3.1.3 Protonation 289
3.2.3.1.4 Nitration 289
3.2.3.1.5 Sulfonation 291
3.2.3.1.6 Halogenation 291
3.2.3.1.6.1 Bromination 292
3.2.3.1.6.2 Chlorination 293
3.2.3.1.7 Acylation 293
3.2.3.1.8 Alkylation 294
3.2.3.1.9 Reaction with Diazonium Salts 295
3.2.3.2 Reactions with Nucleophiles 295
3.2.3.3 Oxidation 297
3.2.3.4 Reduction 298
3.2.3.5 Reactions with Electron-Deficient Species 299
3.2.3.6 Cycloaddition Reactions 300
3.2.3.7 Photochemical Reactions 300
3.2.3.7.1 Photodimerization 300
3.2.3.7.2 Photosensitized Cycloaddition 301
3.2.3.7.3 Photooxygenation 301
3.3 Benzo[c]furans 302
3.3.1 General 302
3.3.2 Synthesis 302
3.3.2.1 Retro-Diels-Alder Reaction 302
3.3.2.2 Reductive Cyclization of o-Dibenzoylbenzenes 303
3.3.2.3 Reaction of Dibenzoylacetylene with Dienes 303
3.3.2.4 From Benzophenones 304
3.3.3 Reactions 305
3.3.3.1 Cycloaddition Reactions 305
3.3.3.2 Photochemical Reactions 307
3.3.3.2.1 Photodimerization 307
3.3.3.2.2 Photocycloaddition 307
3.3.3.2.2.1 With Cycloheptatriene 307
3.3.3.2.2.2 With Cyclohexadiene 308
3.3.3.2.3 Photooxygenation 308
3.3.3.3 Oxidation 309
3.3.3.4 Reduction 309
3.4 Dibenzofurans 309
3.4.1 General 309
3.4.2 Synthesis 310
3.4.2.1 From 2,2'-Dihydroxybiphenyls 310
3.4.2.2 From Diphenyl Ethers 310
3.4.2.3 From omicron-Aminodiphenyl Ethers (Pschorr Type Cyclization) 311
3.4.2.4 Wittig Reaction 312
3.4.3 Reactions 312
3.4.3.1 Reactions with Electrophiles 312
3.4.3.1.1 Bromination 313
3.4.3.1.2 Nitration 314
3.4.3.1.3 Formylation 316
3.4.3.1.4 Sulfonation 316
3.4.3.2 Metallation (Lithiation) 316
3.4.3.3 Reactions with Nucleophiles 318
3.4.3.4 Reduction 319
4 BENZOTHIOPHENES 320
4.1 General 320
4.2 Benzo[b]thiophenes 321
4.2.1 General 321
4.2.2 Synthesis 322
4.2.2.1 Oxidative Cyclization of Mercaptocinnamic Acids 322
4.2.2.2 Reaction of Cinnamic Acid with Thionyl Chloride 323
4.2.2.3 Dehydrative Cyclization 323
4.2.2.3.1 From Arylthioacetaldehyde Acetals 323
4.2.2.3.2 From Arylthio Methyl Ketones 324
4.2.2.4 Reaction of Mercaptoaldehyde or Acid with alpha-Halo Acids or Ketones 
324
4.2.2.5 From Benzenethiols (Thiophenols) 325
4.2.2.6 From Thiophene-2,3-dicarboxylic Anhydride 326
4.2.3 Reactions 327
4.2.3.1 Reactions with Electrophiles 327
4.2.3.1.1 Electrophilic Attack at Carbon 327
4.2.3.1.1.1 Orientation 327
4.2.3.1.1.2 Directing Effects of Substituents 328
4.2.3.1.1.3 Nitration 328
4.2.3.1.1.4 Halogenation 328
4.2.3.1.1.5 Sulfonation 329
4.2.3.1.1.6 Alkylation 330
4.2.3.1.1.7 Acylation 331
4.2.3.1.1.8 Diazo Coupling 331
4.2.3.1.2 Electrophilic Attack at Sulfur 332
4.2.3.2 Reactions with Oxidizing Agents 333
4.2.3.2.1 Formation of 1-Oxides and 1,l-Dioxides 333
4.2.3.2.2 Oxidative Ring Opening 334
4.2.3.3 Reactions with Nucleophiles 334
4.2.3.3.1 Metallation 334
4.2.3.3.2 Ring Opening by Nucleophiles 335
4.2.3.3.3 Addition of Nucleophiles 335
4.2.3.4 Reactions with Reducing Agents 335
4.2.3.5 Reactions with Carbenes 336
4.2.3.6 Cycloaddition Reactions 337
4.2.3.6.1 Thermal (2 + 2) Cycloaddition Reactions 337
4.2.3.6.2 Photochemical (2 + 2) Cycloaddition. Reactions 337
4.2.3.7 Photosubstitution 338
4.3 Benzo[c]thiophenes 339
4.3.1 General 339
4.3.2 Synthesis 339
4.3.2.1 From 1,4-Diketones 339
4.3.2.2 From omicron-Bis (chloromethyl)benzene 340
4.3.2.3 Ring Contraction of 1,2-Dithiins 341
4.3.2.4 Annelation of Thiophenes 341
4.3.3 Reactions 341
4.3.3.1 Cycloaddition Reactions 341
4.3.3.2 Oxidative Ring Opening Reactions 342
4.4 Dibenzothiophenes 343
4.4.1 General 343
4.4.2 Synthesis 344
4.4.2.1 Oxidative Cyclization of Diphenyl Sulfides 344
4.4.2.2 Reductive Cyclization of Diphenyl Sulfoxide 344
4.4.2.3 From Biphenyls 344
4.4.2.4 From Diphenyl sulfones 345
4.4.2.5 From 2-Allylbenzo[b]thiophenes 345
4.4.3 Reactions 346
4.4.3.1 Reactions with Electrophiles 346
4.4.3.2 Reactions with Nucleophiles 346
4.4.3.3 Oxidation 347
REFERENCES 347
CHAPTER 4
FIVE-MEMBERED HETEROCYCLES WITH TWO HETEROATOMS
CONTENTS
1 GENERAL 363
1.1 Structures 364
1.2 Basicity 365
1.3 Structure versus Chemical Reactivity (Consequences of Additional Nitrogen Atom) 367
1.3.1 Reactions with Electrophiles 367
1.3.1.1 Electrophilic Attack at Carbon 367
1.3.1.1.1 Orientation 367
1.3.1.1.1.1 1,3-Azoles 368
1.3.1.1.1.2 1,2-Azoles 369
1.3.1.2 Electrophilic Attack at Nitrogen-3 370
1.3.2 Reactions with Nucleophiles 371
1.3.2.1 Nucleophilic Attack at Carbon 371
1.3.2.2 Nucleophilic Attack at Hydrogen (Deprotonation) 372
2 1,3-AZOLES 374
2.1 Imidazoles 375
2.1.1 General 375
2.1.2 Synthesis 377
2.1.2.1 Reaction of alpha-Hydroxy- or alpha-Halo Ketones with Amidines 377
2.1.2.2 Reaction of alpha-Amino Ketones with Cyanates, Thiocyanates or Isothiocyanates (Marckwald Synthesis) 378
2.1.2.3 Reaction of alpha-Diketones, alpha-Hydroxy-, alpha-Halo-or alpha-Amino Ketones with Formamide (Formamide Synthesis) 378
2.1.2.4 Reaction of Oxamide with Phosphorus Oxychloride (Wallach Synthesis) 379
2.1.2.5 Reaction of Arylaldoximes with Propiolate Ester 380
2.1.2.6 Reaction of 1,2-Diaminoalkanes with Carboxylic Acids and Aldehydes or Ketones 380
2.1.2.7 Ring Trasformation (From Oxazoles) 381
2.1.2.8 Ring Contraction (From Pyrazines) 381
2.1.3 Structure 382
2.1.3.1 Hydrogen Bonding 383
2.1.3.2 Tautomerism 383
2.1.4 Reactions 384
2.1.4.1 Reactivity 384
2.1.4.2 Reactions with Electrophiles 385
2.1.4.2.1 Electrophilic Attack at Nirtogen 385
2.1.4.2.1.1 Protonation (Basicity) 385
2.1.4.2.1.2 N-Alkylation 386
2.1.4.2.1.3 N-Acylation 387
2.1.4.2.2 Electrophilic Attack at Carbon 388
2.1.4.2.2.1 Orientation 388
2.1.4.2.2.2 Nitration 389
2.1.4.2.2.3 Sulfonation 390
2.1.4.2.2.4 Halogenation 390
2.1.4.2.2.5 Acylation 391
2.1.4.2.2.6 Diazo Coupling 392
2.1.4.2.2.7 Reactions with Aldehydes and Ketones 393
2.1.4.2.2.8 Oxidation 394
2.1.4.3 Reactions with Nucleophiles 394
2.1.4.3.1 Nucleophilic Attack at Carbon 394
2.1.4.3.2 Nucleophilic Attack at Hydrogen (Deprotonation) 396
2.1.4.3.2.1 Deprotonation of NH (Acidity) 396
2.1.4.3.2.2 Deprotonation of Carbon-2 396
2.1.4.3.2.2.1 H <--> D Exchange 397
2.1.4.3.2.2.2 Metallation 397
2.1.4.3.2.2.3 C-Acylation via Deprotonation 398
2.1.4.4 Reactions with Electron-Deficient Species 398
2.1.4.5 Reactions with Dienophiles 399
2.1.4.6 Photochemical Cycloaddition Reactions 399
2.2 Oxazoles 401
2.2.1 General 401
2.2.2 Synthesis 402
2.2.2.1 Cyclodehydration of alpha-Acylamino Ketones (Robinson-Gabriel Synthesis) 402
2.2.2.2 Reaction of alpha-Halo Ketones with Primary Amides (Blmlein-Lewy Synthesis) 402
2.2.2.3 Reaction of alpha-Hydroxyamino Ketones with Aldehydes 402
2.2.2.4 Reaction of Tosylmethyl Isocyanide with Aldehydes 403
2.2.2.5 Reaction of alpha-Metallated Isocyanides with Acid Derivatives 403
2.2.2.6 Ring Transformations 404
2.2.2.6.1 From C-Acylaziridines 404
2.2.2.6.2 From Isoxazoles (Isomerization) 405
2.2.3 Structure 405
2.2.4 Reactions 406
2.2.4.1 Reactivity 406
2.2.4.2 Reactions with Electrophiles 407
2.2.4.2.1 Electrophilic Attack at Nitrogen 407
2.2.4.2.1.1 Protonation (Basicity) 407
2.2.4.2.1.2 N-Alkylation 407
2.2.4.2.2 Electrophilic Attack at Carbon 408
2.2.4.2.2.1 Bromination 408
2.2.4.2.2.2 Mercuration 409
2.2.4.2.2.3 Vilsmeier-Haack Formylation 409
2.2.4.3 Reactions with Nucleophiles 410
2.2.4.3.1 Nucleophilic Attack at Carbon 410
2.2.4.3.2 Nucleophilic Attack at Hydrogen 411
2.2.4.3.2.1 Metallation 411
2.2.4.3.2.2 H <--> D Exchange 412
2.2.4.4 Thermal Reactions (Cornforth Rearrangement) 413
2.2.4.5 Photochemical Reactions 413
2.2.4.6 Cycloaddition Reactions 414
2.2.4.7 Photooxygenation 415
2.3 Thiazoles 416
2.3.1 General 416
2.3.2 Synthesis 417
2.3.2.1 Synthesis of Thiazoles 417
2.3.2.1.1 Reaction of alpha-halo Ketones with Thioamides (Hantzsch's Synthesis) 417
2.3.2.1.2 Reaction of alpha-Acylamino Ketones with Phosphorus Pentasulfide (Gabriel Synthesis) 418
2.3.2.1.3 From alpha-Aminonitriles (Cook-Heilborn's Synthesis) 418
2.3.2.1.4 From alpha-Thiocyano Ketones (Tcherniac's Synthesis) 419
2.3.2.1.5 Reaction of alpha-Mercapto Ketones or alpha-Mercapto Acids with Nitriles 419
2.3.2.2 Synthesis of Benzothiazoles 421
2.3.2.2.1 Synthesis from omicron-Aminothiophenols (2-Aminobenzenethiols) 421
2.3.2.2.1.1 Reaction with Aldehydes 421
2.3.2.2.1.2 Reaction with 1,2-Diketones 421
2.3.2.2.1.3 Reaction with Acids and Acid Derivatives 422
2.3.2.2.2 From Arylthioureas (Hugershoff's Method) 422
2.3.3 Structure 422
2.3.4 Reactions 423
2.3.4.1 Reactions with Electrophiles 423
2.3.4.1.1 Electrophilic Attack at Nitrogen 423
2.3.4.1.1.1 Basicity 424
2.3.4.1.1.2 N-Alkylation (Reaction with Alkyl Halides) 424
2.3.4.1.2 Electrophilic Attack at Carbon 425
2.3.4.1.2.1 Nitration 425
2.3.4.1.2.2 Sulfonation 425
2.3.4.1.2.3 Halogenation 426
2.3.4.1.2.4 Alkylation 427
2.3.4.1.2.5 Mercuration 427
2.3.4.1.2.6 Diazo Coupling 427
2.3.4.2 Condensation Reactions 428
2.3.4.3 Oxidation 429
2.3.4.4 Desulfurization 430
2.3.4.5 Reactions with Nucleophiles 430
2.3.4.5.1 Nucleophilic Attack at Carbon 430
2.3.4.5.1.1 Amination 430
2.3.4.5.1.2 Ring Cleavage 431
2.3.4.5.1.3 Displacement of Halide 431
2.3.4.5.1.4 Metal-Halogen Exchange 432
2.3.4.5.2 Nucleophilic Attack at Hydrogen 432
2.3.4.5.2.1 Metallation 432
2.3.4.5.2.2 H <--> D Exchange 433
2.3.4.6 Photochemical Rearrangements 434
3 1,2-AZOLES 435
3.1 Pyrazoles 435
3.1.1 General 435
3.1.2 Synthesis 436
3.1.2.1 (3 + 2) Cyclization Reactions 436
3.1.2.1.1 Reaction of beta-Diketones with Hydrazines 436
3.1.2.1.2 Reaction of alpha, beta-Unsaturated Carbonyl Compounds with Hydrazines 437
3.1.2.2 1,3-Dipolar Cycloadditions 439
3.1.3 Structure 440
3.1.3.1 Hydrogen bonding 441
3.1.3.2 Tautomerism 441
3.1.4 Reactions 442
3.1.4.1 Reactivity 442
3.1.4.2 Electrophilic Attack at Nitrogen 443
3.1.4.2.1 Basicity 443
3.1.4.2.2 Acidity 443
3.1.4.2.3 N-Alkylation 443
3.1.4.2.4 N-Acylation 443
3.1.4.2.5 Michael Addition 445
3.1.4.3 Electrophilic Attack at Carbon 445
3.1.4.3.1 Reactivity and Orientation 445
3.1.4.3.2 Nitration 447
3.1.4.3.3 Sulfonation 448
3.1.4.3.4 Halogenation 449
3.1.4.3.5 Mercuration 449
3.1.4.3.6 Diazo Coupling 450
3.1.4.4 Oxidation 450
3.1.4.5 Reduction 451
3.1.4.6 Reactions with Nucleophiles 451
3.1.4.6.1 Nucleophilic Attack at Carbon 451
3.1.4.6.2 Nucleophilic Attack at Hydrogen 452
3.1.4.6.2.1 Metallation 452
3.1.4.6.2.2 Ring Cleavage via Deprotonation 452
3.1.4.7 Reactions with Electron-Deficient Species 453
3.1.4.8 Cycloaddition Reactions 453
3.1.4.9 Photochemical Transformation 454
3.2 Isoxazoles 455
3.2.1 General 455
3.2.2 Synthesis 458
3.2.2.1 Reaction of beta-Diketones with Hydroxylamine 458
3.2.2.2 Reaction of Nitrile N-Oxides with Alkenes and Alkynes 459
3.2.3 Reactions 460
3.2.3.1 Reactivity 460
3.2.3.2 Reactions with Electrophiles 461
3.2.3.2.1 Electrophlic Attack at Nitrogen 461
3.2.3.2.1.1 Basicity 461
3.2.3.2.1.2 N-Alkylation 461
3.2.3.2.2 Electrophilic Attack at Carbon 461
3.2.3.2.2.1 H <--> D Exchange 462
3.2.3.2.2.2 Nitration 463
3.2.3.2.2.3 Sulfonation 464
3.2.3.2.2.4 Halogenation 465
3.2.3.2.2.5 Chloromethylation and Hydroxymethylation 466
3.2.3.2.2.6 Mercuration 466
3.2.3.3 Oxidation 467
3.2.3.4 Reactions with Nucleophiles 468
3.2.3.4.1 Nucleophilic Displacement 468
3.2.3.4.2 Ring Cleavage via C-Deprotonation 468
3.2.3.4.3 Reductive Ring Cleavage 471
3.2.3.5 Condensation Reactions 471
3.2.3.6 Rearrangement 472
3.2.3.7 Photochemical and Thermal Reactions 472
3.3 Isothiazoles 473
3.3.1 General 473
3.3.2 Synthesis 474
3.3.2.1 Oxidative Cyclization of gamma-Iminothiols 474
3.3.2.2 Ring Transformation 475
3.3.2.3 From Alkenes 476
3.3.2.4 From alpha,beta-Unsaturated Carbonyl Compounds 476
3.3.3 Structure 477
3.3.4 Reactions 478
3.3.4.1 Reactions with Electrophiles 478
3.3.4.1.1 Nitration 478
3.3.4.1.2 Sulfonation 479
3.3.4.1.3 N-Alkylation 479

3.3.4.2 Side Chain Reactivity 480
3.3.4.2.1 Reaction with Aromatic Aldehydes 480
3.3.4.2.2 Decarboxylation 480
3.3.4.3 Reactions with Nucleophiles 480
3.3.4.3.1 Nucleophilic Substitutions 480
3.3.4.3.2 Ring Transformation 481
3.3.4.3.3 Lithiation 482
3.3.4.3.4 Ring Cleavage 482
3.3.4.4 Photochemical Transformation 482
3.3.4.5 Oxidation 483
REFERENCES 483
CHAPTER 5
FIVE-MEMBERED HETEROCYCLES WITH MORE THAN TWO HETEROATOMS
CONTENTS
1 GENERAL 491
1.1 Effects of Additional Nitrogen Atoms 492
2 TRIAZOLES AND TETRAZOLES 492
2.1 1,2,3-Triazoles 492
2.1.1 General 492
2.1.2 Synthesis 493
2.1.2.1 Oxidative Cyclization of bis-Hydrazones of alpha-Diketones 493
2.1.2.2 Cycloaddition of Azides with Alkynes 494
2.1.3 Reactions 495
2.1.3.1 Amphoteric Nature 495
2.1.3.2 Electrophilic Substitutions 496
2.1.3.2.1 Alkylation 497
2.1.3.2.2 Acylation 498
2.1.3.2.3 Bromination 498
2.1.3.3 Thermal and Photochemical Reactions 499
2.1.3.4 Dimroth Rearrangement 501
2.1.3.5 Ring Cleavage Reactions 502
2.2 1,2,4-Triazoles 503
2.2.1 General 503
2.2.2 Synthesis 504
2.2.2.1 From Hydrazine Derivatives 504
2.2.2.2 From Nitrilimines 505
2.2.3 Structure 506
2.2.4 Reactions 506
2.2.4.1 Acidity-Basicity 506
2.2.4.2 Reactivity 507
2.2.4.2.1 Reactions with Electrophiles 508
2.2.4.2.1.1 Electrophilic Attack at Nitrogen 508
2.2.4.2.1.2 Quaternization 509
2.2.4.2.1.3 Electrophilic Attack at Carbon 509
2.2.4.2.2 Reactions with Nucleophiles 510
2.2.4.2.3 Reactions with Electron-Deficient Species 511
2.2.4.2.3.1 Reactions with Nitrenes 511
2.2.4.2.3.2 Reactions with Carbenes 511
2.2.4.2.4 Oxidation 512
2.2.4.2.5 Thermal and Photochemical Reactions 512
2.3 Tetrazoles 513
2.3.1 General 513
2.3.2 Synthesis 513
2.3.2.1 From Imidoyl Chlorides 513
2.3.2.2 From Amidrazones 515
2.3.2.3 From Nitriles 516
2.3.2.4 From Nitrilium Salts 516
2.3.2.5 From Isonitriles 517
2.3.3 Structure 517
2.3.3.1 Hydrogen Bonding 518
2.3.4 Reactions 519
2.3.4.1 Reactions with Electrophiles 519
2.3.4.2 Reactions with Nucleophiles 520
2.3.4.2.1 Nucleophilic Attack at Hydrogen 520
2.3.4.2.1.1 Acidity 520
2.3.4.2.1.2 H <--> D Exchange 521
2.3.4.2.1.3 Metallation 521
2.3.4.2.2 Nucleophilic Attack at C-5 (Nucleophilic Substitutions) 522
2.3.4.3 Thermal and Photochemical Reactions 522
2.3.4.3.1 Reactions Involving Nitrilimine Intermediates 522
2.3.4.3.2 Reactions Involving Carbene Intermediates 524
2.3.4.3.3 Reactions involving Nitrene Intermediates 524
2.3.4.4 Rearrangements 525
3 OXADIAZOLES 525
3.1 1,2,3-Oxadiazoles 526
3.2 1,2,4-Oxadiazoles 527
3.2.1 General 527
3.2.2 Synthesis 528
3.2.2.1 Cyclization Reactions (From Amidoximes) 528
3.2.2.2 1,3-Dipolar Cycloadditions 528
3.2.3 Structure 529
3.2.4 Reactions 529
3.2.4.1 Electrophilic Substitution Reactions 529
3.2.4.2 Nucleophilic Substitution Reactions 530
3.2.4.3 Reactions of Substituents 530
3.2.4.4 Reduction 531
3.2.4.5 Ring Cleavage via C-Deprotonation 532
3.2.4.6 Photochemical Reactions 532
3.2.4.7 Rearrangements 533
3.3 1,2,5-Oxadiazoles 533
3.3.1 General 533
3.3.2 Synthesis 534
3.3.2.1 Furazans 534
3.3.2.1.1 Dehydration of alpha-Dioximes 534
3.3.2.1.2 Ring Transformations 534
3.3.2.2 Furoxans 535
3.3.2.2.1 Oxidation of alpha-Dioximes 535
3.3.2.2.2 Dehydration of alpha-Nitro Ketone Oximes 536
3.3.3 Structure 536
3.3.4 Reactions 537
3.3.4.1 Reactions with Electrophiles 537
3.3.4.2 Reactions with Nucleophiles 537
3.3.4.3 Ring Cleavage via C-Deprotonation 538
3.3.4.4 Rearrangements 539
3.3.4.5 Thermal and Photochemical Reactions 539
3.4 1,3,4-Oxadiazoles 540
3.4.1 General 540
3.4.2 Synthesis 541
3.4.2.1 From Diacylhydrazines 541
3.4.2.2 Ring Transformation 541
3.4.3 Structure 542
3.4.4 Reactions 543
3.4.4.1 Reactions with Electrophiles 543
3.4.4.2 Reactions with Nucleophiles 544
3.4.4.2.1 Nucleophilic Substitution Reactions 544
3.4.4.2.2 Nucleophilic Attack with Ring Cleavage 545
3.4.4.3 Thermal and Photochemical Reactions 546
4 THIADIAZOLES 547
4.1 1,2,3-Thiadiazoles 547
4.1.1 General 547
4.1.2 Synthesis 547
4.1.2.1 Pachmann and Nold Synthesis 547
4.1.2.2 Hurd-Mori's Classical Synthesis (From Hydrazones ) 548
4.1.3 Structure 549
4.1.4 Reactions 549
4.1.4.1 Reactions with Electrophiles 549
4.1.4.1.1 Electrophilic Attack at Nitrogen 549
4.1.4.2 Reactions with Nucleophiles 550
4.1.4.2.1 Nucleophilic Substitutions 550
4.1.4.2.2 Ring Cleavage via C-Deprotonation 550
4.1.4.2.3 Nucleophilic Attack at Sulfur 551
4.1.4.3 Oxidation 551
4.1.4.4 Thermal and Photochemical Reactions 552
4.1.4.4.1 Thermal Reactions 552
4.1.4.4.2 Photochemical Reactions 552
4.1.4.4.3 Rearrangements 553
4.2 1,2,4-Thiadiazoles 553
4.2.1 General 553
4.2.2 Synthesis 554
4.2.2.1 Oxidative Cyclization of Thioacylamidines 554
4.2.2.2 From Amidines 554
4.2.2.3 Heterocyclic Ring Transformations (Oxazole and Oxadiazole 
Rearrangements) 555
4.2.3 Structure 557
4.2.4 Reactions 557
4.2.4.1 Reactivity 557
4.2.4.2 Reactions with Electrophiles 557
4.2.4.3 Reactions with Nucleophiles 559
4.2.4.3.1 Nucleophilic Substitution Reactions 559
4.2.4.3.2 Ring Cleavage 560
4.2.4.3.2.1 Nucleophilic Attack at Carbon 560
4.2.4.3.2.2 Nucleophilic Attack at Sulfur 560
4.2.4.3.3 Nucleophilic Attack at Hydrogen 560
4.2.4.4 Reduction 561
4.3 1,2,5 Thiadiazoles 561
4.3.1 General 561
4.3.2 Synthesis 562
4.3.2.1 From omicron-Diamines [(4 + 1) Cyclization] 562
4.3.3 Structure 563
4.3.4 Reactions 563
4.3.4.1 Stability 563
4.3.4.2 Reactions with Electrophiles 564
4.3.4.3 Reactions with Nucleophiles 564
4.4 1,3,4-Thiadiazoles 566
4.4.1 General 566
4.4.2 Synthesis 567
4.4.2.1 From Thiosemicarbazides 567
4.4.2.2 From Dimethylformamide 568
4.4.2.3 From Hydrazine 568
4.4.3 Structure 569
4.4.4 Reactions 569
4.4.4.1 Reactivity 569
4.4.4.2 Reactions with Electrophiles 569
4.4.4.2.1 Electrophilic Attack at Nitrogen (Quaternization) 569
4.4.4.2.2 Electrophilic Attack at Carbon 570
4.4.4.3 Reactions with Nucleophiles 570
4.4.4.3.1 H <--> D Exchange 570
4.4.4.3.2 Ring Cleavage via C-Deprotonation 570
4.4.4.3.3 Amination 571
4.4.4.3.4 Nucleophilic Substitutions 571
4.4.4.4 Reactions Involving Ring Formation 572
REFERENCES 573
CHAPTER 6
MESO-IONIC HETEROCYCLES
CONTENTS
1 GENERAL 581
2 CLASSIFICATION 583
3 CHEMISTRY OF MESO-IONIC HETEROCYCLES 584
3.1 Chemistry of Meso-Ionic Heterocycles of Type-A 584
3.1.1 1,3-Oxazolium-4-olates 585
3.1.1.1 Synthesis 585
3.1.1.1.1 From alpha-Diazoimides (Diazo Ketones) 585
3.1.1.1.2 From Imides 585
3.1.1.2 Reactions 585
3.1.2 1,3-Oxazolium-5-olates (Mnchnones) 587
3.1.2.1 Synthesis 587
3.1.2.1.1 From N-Acylamino Acids 587
3.1.2.2 Reactions 588
3.1.2.2.1 Cycloaddition Reactions 588
3.1.2.2.1.1 Reactions with Alkenes and Related Compounds 588
3.1.2.2.1.2 Reactions with Alkynes 592
3.1.2.2.1.3 Reactions with Carbonyl Compounds 593
3.1.2.2.1.4 Reaction with Carbon Disulfide 594
3.1.2.2.1.5 Reactions with Isothiocyanates and Isocyanates 594
3.1.2.2.2 Reactions with Nucleophiles 595
3.1.2.2.3 Reactions with Small Ring Heterocycles 596
3.1.2.2.4 Photochemical Reactions 596
3.1.3 1,3-Oxathiolium-4-olates 597
3.1.3.1 Synthesis 597

3.1.3.2 Reactions 598
3.1.4 1,3-Oxathiolium-5-olates 598
3.1.4.1 Synthesis 599
3.1.4.2 Reactions 599
3.1.5 1,3-Diazolium-4-olates 600
3.1.5.1 Synthesis 600
3.1.5.1.1 From Amino Amides 600
3.1.5.1.2 From Amidines 600
3.1.5.1.3 From 1,3-Oxazolium-5-olates 601
3.1.5.2 Reactions 601
3.1.6 1,3-Diazolium-4-aminides 601
3.1.6.1 Synthesis 602
3.1.6.2 Reactions 603
3.1.7 1,3-Dithiolium-4-olates 604
3.1.7.1 Synthesis 604
3.1.7.1.1 From Dithioglycolic Acids 604
3.1.7.1.2 From Dithiobenzoic Acids 605
3.1.7.2 Reactions 605
3.1.7.2.1 Cycloaddition with Alkynes 606
3.1.7.2.2 Cycloaddition with Alkenes 606
3.1.7.2.3 Cycloaddition with Compounds Containing Carbon-Heteroatom Double Bonds 607
3.1.7.2.4 Photochemical Cycloaddition 607
3.1.8 1,2,3-Oxadiazolium-5-olates (Sydnones) 609
3.1.8.1 Synthesis 609
3.1.8.1.1 From N-Nitroso-alpha-amino Acids 609
3.1.8.2 Reactions 609
3.1.8.2.1 Cycloadditions with Alkynes 610
3.1.8.2.2 Cycloadditions with Alkenes 611
3.1.8.2.3 Photochemical Reactions 612
3.2 Chemistry of Meso-Ionic Heterocycles of Type-B 614
3.2.1 1,2-Diazolium-4-aminides 614
3.2.1.1 Synthesis 614
3.2.1.2 Reactions 615
3.2.1.2.1 Thermal Isomerization 615
3.2.1.2.2 Reaction with DMAD 616
3.2.2 1,2-Dithiolium-4-olates 616
3.2.2.1 Synthesis 616
3.2.2.1.1 From Propane-1,3-dione Esters 616
3.2.2.1.2 From 1,3-Diarylpropane-1,2,3-triones 617
3.2.2.1.3 From 1,1,3,3-Tetrabromo-1,3-diarylpropan-Zones 617
3.2.2.2 Reactions 618
3.2.2.2.1 Desulfurization 618
3.2.2.2.2 Reactions with Ammonia and Its Derivatives 618
3.2.2.2.3 Thermal Reactions 620
3.2.3 1,2,3,4-Tetrazolium-5-thiolates 620
3.2.3.1 Synthesis 620
3.2.3.1.1 From Dithizone 620
3.2.3.1.2 From Diphenyhhiocarbazide 621
3.2.3.2 Reactions 621
3.2.3.2.1 Alkylation 621
3.2.3.2.2 Thermal Rearrangement 621
3.2.3.2.3 Cycloaddition Reactions 622
3.2.3.2.4 Reactions involving Dehydrodithizone as Acyclic Valence Tautomer 623
REFERENCES 624
END
