HETEROCYCLIC CHEMISTRY BOOK FREE PDF DOWNLOAD
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IN THIS BOOK THE MECHANISM IS EXPLAINED WITH COLOURED ARROW NOTATION.
THIS BOOK CONTAIN FOLLOWING CHAPTERS-
1 Heterocyclic Nomenclature 1
2 Structures and Spectroscopic Properties of Aromatic Heterocycles 5
2.1 Carbocyclic Aromatic Systems 5
2.1.1 Structures of Benzene and Naphthalene 5
2.1.2 Aromatic Resonance Energy 6
2.2 Structure of Six-Membered Heteroaromatic Systems 7
2.2.1 Structure of Pyridine 7
2.2.2 Structure of Diazines 7
2.2.3 Structures of Pyridinium and Related Cations 8
2.2.4 Structures of Pyridones and Pyrones 8
2.3 Structure of Five-Membered Heteroaromatic Systems 9
2.3.1 Structure of Pyrrole 9
2.3.2 Structures of Thiophene and Furan 10
2.3.3 Structures of Azoles 10
2.3.4 Structures of Pyrryl and Related Anions 11
2.4 Structures of Bicyclic Heteroaromatic Compounds 11
2.5 Tautomerism in Heterocyclic Systems 12
2.6 Mesoionic Systems 12
2.7 Some Spectroscopic Properties of Some Heteroaromatic Systems 13
2.7.1 Ultraviolet/Visible (Electronic) Spectroscopy 13
2.7.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 14
References 17
3 Substitutions of Aromatic Heterocycles 19
3.1 Electrophilic Addition at Nitrogen 19
3.2 Electrophilic Substitution at Carbon 20
3.2.1 Aromatic Electrophilic Substitution: Mechanism 20
3.2.2 Six-Membered Heterocycles 21
3.2.3 Five-Membered Heterocycles 22
vi Contents
3.3 Nucleophilic Substitution at Carbon 24
3.3.1 Aromatic Nucleophilic Substitution: Mechanism 24
3.3.2 Six-Membered Heterocycles 24
3.3.3 Vicarious Nucleophilic Substitution (VNS Substitution) 26
3.4 Radical Substitution at Carbon 27
3.4.1 Reactions of Heterocycles with Nucleophilic Radicals 27
3.4.2 Reactions with Electrophilic Radicals 30
3.5 Deprotonation of N-Hydrogen 30
3.6 Oxidation and Reduction of Heterocyclic Rings 31
3.7 ortho-Quinodimethanes in Heterocyclic Compound Synthesis 31
References 33
4 Organometallic Heterocyclic Chemistry 37
4.1 Preparation and Reactions of Organometallic Compounds 37
4.1.1 Lithium 37
4.1.2 Magnesium 45
4.1.3 Zinc 47
4.1.4 Copper 48
4.1.5 Boron 48
4.1.6 Silicon and Tin 52
4.1.7 Mercury 54
4.1.8 Palladium 54
4.1.9 Side-Chain Metallation (‘Lateral Metallation’) 54
4.2 Transition Metal-Catalysed Reactions 56
4.2.1 Basic Palladium Processes 56
4.2.2 Catalysts 59
4.2.3 The Electrophilic Partner; The Halides/Leaving Groups 61
4.2.4 Cross-Coupling Reactions 64
4.2.5 The Nucleophilic (Organometallic) Partner 65
4.2.6 Other Nucleophiles 70
4.2.7 The Ring Systems in Cross-Coupling Reactions 71
4.2.8 Organometallic Selectivity 77
4.2.9 Direct C–H Arylation 79
4.2.10 N-Arylation 83
4.2.11 Heck Reactions 87
4.2.12 Carbonylation Reactions 89
References 90
5 Methods in Heterocyclic Chemistry 97
5.1 Solid-Phase Reactions and Related Methods 97
5.1.1 Solid-Phase Reactions 97
5.1.2 Solid-Supported Reagents and Scavengers 99
5.1.3 Solid-Phase Extraction (SPE) 100
5.1.4 Soluble Polymer-Supported Reactions 100
5.1.5 Phase Tags 101
5.2 Microwave Heating 103
5.3 Flow Reactors 104
5.4 Hazards: Explosions 105
References 105
Contents vii
6 Ring Synthesis of Aromatic Heterocycles 107
6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis 107
6.2 Typical Reactant Combinations 108
6.2.1 Typical Ring Synthesis of a Pyrrole Involving Only C–Heteroatom Bond
Formation 108
6.2.2 Typical Ring Synthesis of a Pyridine Involving Only C–Heteroatom Bond
Formation 109
6.2.3 Typical Ring Syntheses Involving C–Heteroatom C–C Bond Formations 109
6.3 Summary 111
6.4 Electrocyclic Processes in Heterocyclic Ring Synthesis 112
6.5 Nitrenes in Heterocyclic Ring Synthesis 113
6.6 Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles 113
References 114
7 Typical Reactivity of Pyridines, Quinolines and Isoquinolines 115
8 Pyridines: Reactions and Synthesis 125
8.1 Reactions with Electrophilic Reagents 125
8.1.1 Addition to Nitrogen 125
8.1.2 Substitution at Carbon 128
8.2 Reactions with Oxidising Agents 130
8.3 Reactions with Nucleophilic Reagents 131
8.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 131
8.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 133
8.4 Metallation and Reactions of C-Metallated-Pyridines 134
8.4.1 Direct Ring C–H Metallation 134
8.4.2 Metal–Halogen Exchange 137
8.5 Reactions with Radicals; Reactions of Pyridyl Radicals 138
8.5.1 Halogenation 138
8.5.2 Carbon Radicals 138
8.5.3 Dimerisation 138
8.5.4 Pyridinyl Radicals 139
8.6 Reactions with Reducing Agents 139
8.7 Electrocyclic Reactions (Ground State) 140
8.8 Photochemical Reactions 140
8.9 Oxy- and Amino-Pyridines 141
8.9.1 Structure 141
8.9.2 Reactions of Pyridones 142
8.9.3 Reactions of Amino-Pyridines 144
8.10 Alkyl-Pyridines 146
8.11 Pyridine Aldehydes, Ketones, Carboxylic Acids and Esters 148
8.12 Quaternary Pyridinium Salts 148
8.12.1 Reduction and Oxidation 148
8.12.2 Organometallic and Other Nucleophilic Additions 150
8.12.3 Nucleophilic Addition Followed by Ring Opening 152
8.12.4 Cyclisations Involving an α-Position or an α-Substituent 153
8.12.5 N-Dealkylation 153
8.13 Pyridine N-oxides 153
8.13.1 Electrophilic Addition and Substitution 154
8.13.2 Nucleophilic Addition and Substitution 155
8.13.3 Addition of Nucleophiles then Loss of Oxide 155
viii Contents
8.14 Synthesis of Pyridines 156
8.14.1 Ring Synthesis 156
8.14.2 Examples of Notable Syntheses of Pyridine Compounds 165
Exercises 166
References 168
9 Quinolines and Isoquinolines: Reactions and Synthesis 177
9.1 Reactions with Electrophilic Reagents 177
9.1.1 Addition to Nitrogen 177
9.1.2 Substitution at Carbon 177
9.2 Reactions with Oxidising Agents 179
9.3 Reactions with Nucleophilic Reagents 179
9.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 179
9.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 180
9.4 Metallation and Reactions of C-Metallated Quinolines and Isoquinolines 181
9.4.1 Direct Ring C–H Metallation 181
9.4.2 Metal–Halogen Exchange 182
9.5 Reactions with Radicals 182
9.6 Reactions with Reducing Agents 183
9.7 Electrocyclic Reactions (Ground State) 183
9.8 Photochemical Reactions 183
9.9 Oxy-Quinolines and Oxy-Isoquinolines 183
9.10 Amino-Quinolines and Amino-Isoquinolines 185
9.11 Alkyl-Quinolines and Alkyl-Isoquinolines 185
9.12 Quinoline and Isoquinoline Carboxylic Acids and Esters 185
9.13 Quaternary Quinolinium and Isoquinolinium Salts 186
9.14 Quinoline and Isoquinoline N-Oxides 188
9.15 Synthesis of Quinolines and Isoquinolines 188
9.15.1 Ring Syntheses 188
9.15.2 Examples of Notable Syntheses of Quinoline and Isoquinoline Compounds 198
Exercises 199
References 200
10 Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones 205
11 Pyryliums, 2- and 4-Pyrones: Reactions and Synthesis 209
11.1 Reactions of Pyrylium Cations 209
11.1.1 Reactions with Electrophilic Reagents 209
11.1.2 Addition Reactions with Nucleophilic Reagents 210
11.1.3 Substitution Reactions with Nucleophilic Reagents 212
11.1.4 Reactions with Radicals 212
11.1.5 Reactions with Reducing Agents 212
11.1.6 Photochemical Reactions 212
11.1.7 Reactions with Dipolarophiles; Cycloadditions 213
11.1.8 Alkyl-Pyryliums 213
11.2 2-Pyrones and 4-Pyrones (2H-Pyran-2-ones and 4H-Pyran-4-ones; α- and
γ-Pyrones) 214
11.2.1 Structure of Pyrones 214
11.2.2 Reactions of Pyrones 214
Contents ix
11.3 Synthesis of Pyryliums 218
11.3.1 From 1,5-Dicarbonyl Compounds 218
11.3.2 Alkene Acylation 219
11.3.3 From 1,3-Dicarbonyl Compounds and Ketones 220
11.4 Synthesis of 2-Pyrones 220
11.4.1 From 1,3-Keto(aldehydo)-Acids and Carbonyl Compounds 220
11.4.2 Other Methods 221
11.5 Synthesis of 4-Pyrones 222
Exercises 224
References 225
12 Benzopyryliums and Benzopyrones: Reactions and Synthesis 229
12.1 Reactions of Benzopyryliums 229
12.1.1 Reactions with Electrophilic Reagents 229
12.1.2 Reactions with Oxidising Agents 230
12.1.3 Reactions with Nucleophilic Reagents 230
12.1.4 Reactions with Reducing Agents 231
12.1.5 Alkyl-Benzopyryliums 231
12.2 Benzopyrones (Chromones, Coumarins and Isocoumarins) 232
12.2.1 Reactions with Electrophilic Reagents 232
12.2.2 Reactions with Oxidising Agents 232
12.2.3 Reactions with Nucleophilic Reagents 233
12.3 Synthesis of Benzopyryliums, Chromones, Coumarins and Isocoumarins 237
12.3.1 Ring Synthesis of 1-Benzopyryliums 237
12.3.2 Ring Synthesis of Coumarins 238
12.3.3 Ring Synthesis of Chromones 240
12.3.4 Ring Synthesis of 2-Benzopyryliums 242
12.3.5 Ring Synthesis of Isocoumarins 243
12.3.6 Notable Examples of Benzopyrylium and Benzopyrone Syntheses 243
Exercises 244
References 245
13 Typical Reactivity of the Diazine: Pyridazine, Pyrimidine and Pyrazine 249
14 The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions and Synthesis 253
14.1 Reactions with Electrophilic Reagents 253
14.1.1 Addition at Nitrogen 253
14.1.2 Substitution at Carbon 255
14.2 Reactions with Oxidising Agents 255
14.3 Reactions with Nucleophilic Reagents 255
14.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 256
14.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 256
14.4 Metallation and Reactions of C-Metallated Diazines 259
14.4.1 Direct Ring C–H Metallation 259
14.4.2 Metal–Halogen Exchange 260
14.5 Reactions with Reducing Agents 261
14.6 Reactions with Radicals 261
14.7 Electrocyclic Reactions 261
14.8 Diazine N-Oxides 262
x Contents
14.9 Oxy-Diazines 263
14.9.1 Structure of Oxy-Diazines 263
14.9.2 Reactions of Oxy-Diazines 264
14.10 Amino-Diazines 271
14.11 Alkyl-Diazines 272
14.12 Quaternary Diazinium Salts 273
14.13 Synthesis of Diazines 273
14.13.1 Pyridazines 274
14.13.2 Pyrimidines 275
14.13.3 Pyrazines 279
14.13.4 Notable Syntheses of Diazines 281
14.14 Pteridines 282
Exercises 283
References 284
15 Typical Reactivity of Pyrroles, Furans and Thiophenes 289
16 Pyrroles: Reactions and Synthesis 295
16.1 Reactions with Electrophilic Reagents 295
16.1.1 Substitution at Carbon 296
16.2 Reactions with Oxidising Agents 303
16.3 Reactions with Nucleophilic Reagents 303
16.4 Reactions with Bases 304
16.4.1 Deprotonation of N-Hydrogen and Reactions of Pyrryl Anions 304
16.4.2 Lithium, Sodium, Potassium and Magnesium Derivatives 304
16.5 C-Metallation and Reactions of C-Metallated Pyrroles 305
16.5.1 Direct Ring C–H Metallation 305
16.5.2 Metal–Halogen Exchange 305
16.6 Reactions with Radicals 306
16.7 Reactions with Reducing Agents 306
16.8 Electrocyclic Reactions (Ground State) 307
16.9 Reactions with Carbenes and Carbenoids 308
16.10 Photochemical Reactions 308
16.11 Pyrryl-C-X Compounds 309
16.12 Pyrrole Aldehydes and Ketones 309
16.13 Pyrrole Carboxylic Acids 309
16.14 Pyrrole Carboxylic Acid Esters 310
16.15 Oxy- and Amino-Pyrroles 310
16.15.1 2-Oxy-Pyrroles 310
16.15.2 3-Oxy-Pyrroles 311
16.15.3 Amino-Pyrroles 311
16.16 Synthesis of Pyrroles 311
16.16.1 Ring Synthesis 311
16.16.2 Some Notable Syntheses of Pyrroles 317
Exercises 319
References 320
17 Thiophenes: Reactions and Synthesis 325
17.1 Reactions with Electrophilic Reagents 325
17.1.1 Substitution at Carbon 325
17.1.2 Addition at Sulfur 329
Contents xi
17.2 Reactions with Oxidising Agents 330
17.3 Reactions with Nucleophilic Reagents 330
17.4 Metallation and Reactions of C-Metallated Thiophenes 331
17.4.1 Direct Ring C–H Metallation 331
17.4.2 Metal–Halogen Exchange 331
17.5 Reactions with Radicals 333
17.6 Reactions with Reducing Agents 333
17.7 Electrocyclic Reactions (Ground State) 333
17.8 Photochemical Reactions 334
17.9 Thiophene-C–X Compounds: Thenyl Derivatives 334
17.10 Thiophene Aldehydes and Ketones, and Carboxylic Acids and Esters 335
17.11 Oxy- and Amino-Thiophenes 335
17.11.1 Oxy-Thiophenes 335
17.11.2 Amino-Thiophenes 336
17.12 Synthesis of Thiophenes 336
17.12.1 Ring Synthesis 336
17.12.2 Examples of Notable Syntheses of Thiophene Compounds 340
Exercises 342
References 342
18 Furans: Reactions and Synthesis 347
18.1 Reactions with Electrophilic Reagents 347
18.1.1 Substitution at Carbon 347
18.2 Reactions with Oxidising Agents 351
18.3 Reactions with Nucleophilic Reagents 352
18.4 Metallation and Reactions of C-Metallated Furans 352
18.4.1 Direct Ring C–H Metallation 352
18.4.2 Metal–Halogen Exchange 353
18.5 Reactions with Radicals 353
18.6 Reactions with Reducing Agents 353
18.7 Electrocyclic Reactions (Ground State) 353
18.8 Reactions with Carbenes and Carbenoids 356
18.9 Photochemical Reactions 356
18.10 Furyl-C–X Compounds; Side-Chain Properties 356
18.11 Furan Carboxylic Acids and Esters and Aldehydes 356
18.12 Oxy- and Amino-Furans 357
18.12.1 Oxy-Furans 357
18.12.2 Amino-Furans 358
18.13 Synthesis of Furans 358
18.13.1 Ring Syntheses 359
18.13.2 Examples of Notable Syntheses of Furans 363
Exercises 364
References 365
19 Typical Reactivity of Indoles, Benzo[b]thiophenes, Benzo[b]furans, Isoindoles,
Benzo[c]thiophenes and Isobenzofurans 369
20 Indoles: Reactions and Synthesis 373
20.1 Reactions with Electrophilic Reagents 373
20.1.1 Substitution at Carbon 373
xii Contents
20.2 Reactions with Oxidising Agents 385
20.3 Reactions with Nucleophilic Reagents 386
20.4 Reactions with Bases 386
20.4.1 Deprotonation of N-Hydrogen and Reactions of Indolyl Anions 386
20.5 C-Metallation and Reactions of C-Metallated Indoles 388
20.5.1 Direct Ring C–H Metallation 388
20.5.2 Metal–Halogen Exchange 390
20.6 Reactions with Radicals 391
20.7 Reactions with Reducing Agents 392
20.8 Reactions with Carbenes 392
20.9 Electrocyclic and Photochemical Reactions 393
20.10 Alkyl-Indoles 394
20.11 Reactions of Indolyl-C–X Compounds 395
20.12 Indole Carboxylic Acids 396
20.13 Oxy-Indoles 397
20.13.1 Oxindole 397
20.13.2 Indoxyl 398
20.13.3 Isatin 399
20.13.4 1-Hydroxyindole 399
20.14 Amino-Indoles 400
20.15 Aza-Indoles 400
20.15.1 Electrophilic Substitution 401
20.15.2 Nucleophilic Substitution 401
20.16 Synthesis of Indoles 402
20.16.1 Ring Synthesis of Indoles 402
20.16.2 Ring Synthesis of Oxindoles 416
20.16.3 Ring Synthesis of Indoxyls 417
20.16.4 Ring Synthesis of Isatins 418
20.16.5 Synthesis of 1-Hydroxy-Indoles 418
20.16.6 Examples of Notable Indole Syntheses 418
20.16.7 Synthesis of Aza-Indoles 421
Exercises 422
References 423
21 Benzo[b]thiophenes and Benzo[b]furans: Reactions and Synthesis 433
21.1 Reactions with Electrophilic Reagents 433
21.1.1 Substitution at Carbon 433
21.1.2 Addition to Sulfur in Benzothiophenes 434
21.2 Reactions with Nucleophilic Reagents 435
21.3 Metallation and Reactions of C-Metallated Benzothiophenes and Benzofurans 435
21.4 Reactions with Radicals 436
21.5 Reactions with Oxidising and Reducing Agents 436
21.6 Electrocyclic Reactions 436
21.7 Oxy- and Amino-Benzothiophenes and -Benzofurans 437
21.8 Synthesis of Benzothiophenes and Benzofurans 437
21.8.1 Ring Synthesis 437
Exercises 443
References 443
Contents xiii
22 Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions and Synthesis 447
22.1 Reactions with Electrophilic Reagents 447
22.2 Electrocyclic Reactions 448
22.3 Phthalocyanines 449
22.4 Synthesis of Isoindoles, Benzo[c]thiophenes and Isobenzofurans 449
22.4.1 Isoindoles 449
22.4.2 Benzo[c]thiophenes 450
22.4.3 Isobenzofurans 451
Exercises 452
References 452
23 Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and -1,2-Azoles 455
24 1,3-Azoles: Imidazoles, Thiazoles and Oxazoles: Reactions and Synthesis 461
24.1 Reactions with Electrophilic Reagents 461
24.1.1 Addition at Nitrogen 461
24.1.2 Substitution at Carbon 464
24.2 Reactions with Oxidising Agents 466
24.3 Reactions with Nucleophilic Reagents 466
24.3.1 With Replacement of Hydrogen 466
24.3.2 With Replacement of Halogen 466
24.4 Reactions with Bases 467
24.4.1 Deprotonation of Imidazole N-Hydrogen and Reactions of
Imidazolyl Anions 467
24.5 C-Metallation and Reactions of C-Metallated 1,3-Azoles 467
24.5.1 Direct Ring C–H Metallation 467
24.5.2 Metal–Halogen Exchange 468
24.6 Reactions with Radicals 468
24.7 Reactions with Reducing Agents 469
24.8 Electrocyclic Reactions 469
24.9 Alkyl-1,3-Azoles 470
24.10 Quaternary 1,3-Azolium Salts 470
24.11 Oxy- and Amino-1,3-Azoles 471
24.12 1,3-Azole N-Oxides 473
24.13 Synthesis of 1,3-Azoles 473
24.13.1 Ring Synthesis 473
24.13.2 Examples of Notable Syntheses Involving 1,3-Azoles 478
Exercises 479
References 480
25 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 485
25.1 Reactions with Electrophilic Reagents 486
25.1.1 Addition at Nitrogen 486
25.1.2 Substitution at Carbon 487
25.2 Reactions with Oxidising Agents 488
25.3 Reactions with Nucleophilic Reagents 488
25.4 Reactions with Bases 488
25.4.1 Deprotonation of Pyrazole N-Hydrogen and Reactions of
Pyrazolyl Anions 488
xiv Contents
25.5 C-Metallation and Reactions of C-Metallated 1,2-Azoles 489
25.5.1 Direct Ring C–H Metallation 489
25.5.2 Metal–Halogen Exchange 490
25.6 Reactions with Radicals 490
25.7 Reactions with Reducing Agents 490
25.8 Electrocyclic and Photochemical Reactions 491
25.9 Alkyl-1,2-Azoles 492
25.10 Quaternary 1,2-Azolium Salts 492
25.11 Oxy- and Amino-1,2-azoles 493
25.12 Synthesis of 1,2-Azoles 494
25.12.1 Ring Synthesis 494
Exercises 498
References 498
26 Benzanellated Azoles: Reactions and Synthesis 503
26.1 Reactions with Electrophilic Reagents 503
26.1.1 Addition at Nitrogen 503
26.1.2 Substitution at Carbon 504
26.2 Reactions with Nucleophilic Reagents 505
26.3 Reactions with Bases 505
26.3.1 Deprotonation of N-Hydrogen and Reactions of Benzimidazolyl
and Indazolyl Anions 505
26.4 Ring Metallation and Reactions of C-Metallated Derivatives 505
26.5 Reactions with Reducing Agents 506
26.6 Electrocyclic Reactions 506
26.7 Quaternary Salts 506
26.8 Oxy- and Amino-Benzo-1,3-Azoles 507
26.9 Synthesis 507
26.9.1 Ring Synthesis of Benzo-1,3-Azoles 507
26.9.2 Ring Synthesis of Benzo-1,2-Azoles 509
References 512
27 Purines: Reactions and Synthesis 515
27.1 Reactions with Electrophilic Reagents 516
27.1.1 Addition at Nitrogen 516
27.1.2 Substitution at Carbon 519
27.2 Reactions with Radicals 521
27.3 Reactions with Oxidising Agents 521
27.4 Reactions with Reducing Agents 521
27.5 Reactions with Nucleophilic Reagents 521
27.6 Reactions with Bases 524
27.6.1 Deprotonation of N-Hydrogen and Reactions of Purinyl Anions 524
27.7 C-Metallation and Reactions of C-Metallated Purines 524
27.7.1 Direct Ring C–H Metallation 524
27.7.2 Metal–Halogen Exchange 525
27.8 Oxy- and Amino-Purines 525
27.8.1 Oxy-Purines 526
27.8.2 Amino-Purines 527
27.8.3 Thio-Purines 529
Contents xv
27.9 Alkyl-Purines 530
27.10 Purine Carboxylic Acids 530
27.11 Synthesis of Purines 530
27.11.1 Ring Synthesis 530
27.11.2 Examples of Notable Syntheses Involving Purines 534
Exercises 535
References 536
28 Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 539
28.1 Indolizines 539
28.1.1 Reactions of Indolizines 540
28.1.2 Ring Synthesis of Indolizines 541
28.2 Aza-Indolizines 543
28.2.1 Imidazo[1,2-a]pyridines 543
28.2.2 Imidazo[1,5-a]pyridines 545
28.2.3 Pyrazolo[1,5-a]pyridines 546
28.2.4 Triazolo- and Tetrazolo-Pyridines 547
28.2.5 Compounds with an Additional Nitrogen in the Six-Membered Ring 549
28.3 Quinolizinium and Related Systems 551
28.4 Pyrrolizine and Related Systems 551
28.5 Cyclazines 552
Exercises 553
References 553
29 Heterocycles Containing More Than Two Heteroatoms 557
29.1 Five-Membered Rings 557
29.1.1 Azoles 557
29.1.2 Oxadiazoles and Thiadiazoles 569
29.1.3 Other Systems 574
29.2 Six-Membered Rings 574
29.2.1 Azines 574
29.3 Benzotriazoles 579
Exercises 581
References 581
30 Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis 587
30.1 Five- and Six-Membered Rings 588
30.1.1 Pyrrolidines and Piperidines 588
30.1.2 Piperideines and Pyrrolines 589
30.1.3 Pyrans and Reduced Furans 590
30.2 Three-Membered Rings 592
30.2.1 Three-Membered Rings with One Heteroatom 592
30.2.2 Three-Membered Rings with Two Heteroatoms 596
30.3 Four-Membered Rings 597
30.4 Metallation 598
30.5 Ring synthesis 599
30.5.1 Aziridines and Azirines 600
30.5.2 Azetidines and β-Lactams 602
30.5.3 Pyrrolidines 602
xvi Contents
30.5.4 Piperidines 603
30.5.5 Saturated Oxygen Heterocycles 604
30.5.6 Saturated Sulfur Heterocycles 605
References 606
31 Special Topics 609
31.1 Synthesis of Ring-Fluorinated Heterocycles 609
31.1.1 Electrophilic Fluorination 609
31.1.2 The Balz–Schiemann Reaction 611
31.1.3 Halogen Exchange (Halex) Reactions 612
31.1.4 Ring Synthesis Incorporating Fluorinated Starting Materials 612
31.2 Isotopically Labelled Heterocycles 616
31.2.1 Hazards Due to Radionuclides 616
31.2.2 Synthesis 616
31.2.3 PET (Positron Emission Tomography) 617
31.3 Bioprocesses in Heterocyclic Chemistry 619
31.4 Green Chemistry 620
31.5 Ionic Liquids 620
31.6 Applications and Occurrences of Heterocycles 621
31.6.1 Toxicity 622
31.6.2 Plastics and Polymers 622
31.6.3 Fungicides and Herbicides 623
31.6.4 Dyes and Pigments 623
31.6.5 Fluorescence-Based Applications 624
31.6.6 Electronic Applications 625
References 626
32 Heterocycles in Biochemistry; Heterocyclic Natural Products 629
32.1 Heterocyclic Amino Acids and Related Substances 629
32.2 Enzyme Co-Factors; Heterocyclic Vitamins; Co-Enzymes 630
32.2.1 Niacin (Vitamin B3) and Nicotinamide Adenine Dinucleotide
Phosphate (NADP+) 631
32.2.2 Pyridoxine (Vitamin B6) and Pyridoxal Phosphate (PLP) 631
32.2.3 Ribofl avin (Vitamin B2) 632
32.2.4 Thiamin (Vitamin B1) and Thiamine Pyrophosphate 632
32.3 Porphobilinogen and the ‘Pigments of Life’ 633
32.4 Ribonucleic Acid (RNA) and Deoxyribonucleic Acid (DNA); Genetic
Information; Purines and Pyrimidines 635
32.5 Heterocyclic Natural Products 637
32.5.1 Alkaloids 637
32.5.2 Marine Heterocycles 639
32.5.3 Halogenated Heterocycles 639
32.5.4 Macrocycles Containing Oxazoles and Thiazoles 640
32.5.5 Other Nitrogen-Containing Natural Products 640
32.5.6 Anthocyanins and Flavones 641
References 642
33 Heterocycles in Medicine 645
33.1 Mechanisms of Drug Actions 646
33.1.1 Mimicking or Opposing the Effects of Physiological Hormones or
Neurotransmitters 646
Contents xvii
33.1.2 Interaction with Enzymes 646
33.1.3 Physical Binding with, or Chemically Modifying,
Natural Macromolecules 646
33.2 The Neurotransmitters 647
33.3 Drug Discovery and Development 647
33.3.1 Stages in the Life of a Drug 647
33.3.2 Drug Discovery 649
33.3.3 Chemical Development 649
33.3.4 Good Manufacturing Practice (GMP) 650
33.4 Heterocyclic Drugs 650
33.4.1 Histamine 650
33.4.2 Acetylcholine (ACh) 652
33.4.3 5-Hydroxytryptamine (5-HT) 653
33.4.4 Adrenaline and Noradrenaline 654
33.4.5 Other Signifi cant Cardiovascular Drugs 654
33.4.6 Drugs Affecting Blood Clotting 655
33.4.7 Other Enzyme Inhibitors 656
33.4.8 Enzyme Induction 658
33.5 Drugs Acting on the CNS 658
33.6 Anti-Infective Agents 659
33.6.1 Anti-Parasitic Drugs 659
33.6.2 Anti-Bacterial Drugs 660
33.6.3 Anti-Viral Drugs 661
33.7 Anti-Cancer Drugs 661
33.8 Photochemotherapy 663
33.8.1 Psoralen plus UVA (PUVA) Treatment 663
33.8.2 Photodynamic Therapy (PDT) 664
References 664
Index
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THIS BOOK CONTAIN FOLLOWING CHAPTERS-
1 Heterocyclic Nomenclature 1
2 Structures and Spectroscopic Properties of Aromatic Heterocycles 5
2.1 Carbocyclic Aromatic Systems 5
2.1.1 Structures of Benzene and Naphthalene 5
2.1.2 Aromatic Resonance Energy 6
2.2 Structure of Six-Membered Heteroaromatic Systems 7
2.2.1 Structure of Pyridine 7
2.2.2 Structure of Diazines 7
2.2.3 Structures of Pyridinium and Related Cations 8
2.2.4 Structures of Pyridones and Pyrones 8
2.3 Structure of Five-Membered Heteroaromatic Systems 9
2.3.1 Structure of Pyrrole 9
2.3.2 Structures of Thiophene and Furan 10
2.3.3 Structures of Azoles 10
2.3.4 Structures of Pyrryl and Related Anions 11
2.4 Structures of Bicyclic Heteroaromatic Compounds 11
2.5 Tautomerism in Heterocyclic Systems 12
2.6 Mesoionic Systems 12
2.7 Some Spectroscopic Properties of Some Heteroaromatic Systems 13
2.7.1 Ultraviolet/Visible (Electronic) Spectroscopy 13
2.7.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 14
References 17
3 Substitutions of Aromatic Heterocycles 19
3.1 Electrophilic Addition at Nitrogen 19
3.2 Electrophilic Substitution at Carbon 20
3.2.1 Aromatic Electrophilic Substitution: Mechanism 20
3.2.2 Six-Membered Heterocycles 21
3.2.3 Five-Membered Heterocycles 22
vi Contents
3.3 Nucleophilic Substitution at Carbon 24
3.3.1 Aromatic Nucleophilic Substitution: Mechanism 24
3.3.2 Six-Membered Heterocycles 24
3.3.3 Vicarious Nucleophilic Substitution (VNS Substitution) 26
3.4 Radical Substitution at Carbon 27
3.4.1 Reactions of Heterocycles with Nucleophilic Radicals 27
3.4.2 Reactions with Electrophilic Radicals 30
3.5 Deprotonation of N-Hydrogen 30
3.6 Oxidation and Reduction of Heterocyclic Rings 31
3.7 ortho-Quinodimethanes in Heterocyclic Compound Synthesis 31
References 33
4 Organometallic Heterocyclic Chemistry 37
4.1 Preparation and Reactions of Organometallic Compounds 37
4.1.1 Lithium 37
4.1.2 Magnesium 45
4.1.3 Zinc 47
4.1.4 Copper 48
4.1.5 Boron 48
4.1.6 Silicon and Tin 52
4.1.7 Mercury 54
4.1.8 Palladium 54
4.1.9 Side-Chain Metallation (‘Lateral Metallation’) 54
4.2 Transition Metal-Catalysed Reactions 56
4.2.1 Basic Palladium Processes 56
4.2.2 Catalysts 59
4.2.3 The Electrophilic Partner; The Halides/Leaving Groups 61
4.2.4 Cross-Coupling Reactions 64
4.2.5 The Nucleophilic (Organometallic) Partner 65
4.2.6 Other Nucleophiles 70
4.2.7 The Ring Systems in Cross-Coupling Reactions 71
4.2.8 Organometallic Selectivity 77
4.2.9 Direct C–H Arylation 79
4.2.10 N-Arylation 83
4.2.11 Heck Reactions 87
4.2.12 Carbonylation Reactions 89
References 90
5 Methods in Heterocyclic Chemistry 97
5.1 Solid-Phase Reactions and Related Methods 97
5.1.1 Solid-Phase Reactions 97
5.1.2 Solid-Supported Reagents and Scavengers 99
5.1.3 Solid-Phase Extraction (SPE) 100
5.1.4 Soluble Polymer-Supported Reactions 100
5.1.5 Phase Tags 101
5.2 Microwave Heating 103
5.3 Flow Reactors 104
5.4 Hazards: Explosions 105
References 105
Contents vii
6 Ring Synthesis of Aromatic Heterocycles 107
6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis 107
6.2 Typical Reactant Combinations 108
6.2.1 Typical Ring Synthesis of a Pyrrole Involving Only C–Heteroatom Bond
Formation 108
6.2.2 Typical Ring Synthesis of a Pyridine Involving Only C–Heteroatom Bond
Formation 109
6.2.3 Typical Ring Syntheses Involving C–Heteroatom C–C Bond Formations 109
6.3 Summary 111
6.4 Electrocyclic Processes in Heterocyclic Ring Synthesis 112
6.5 Nitrenes in Heterocyclic Ring Synthesis 113
6.6 Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles 113
References 114
7 Typical Reactivity of Pyridines, Quinolines and Isoquinolines 115
8 Pyridines: Reactions and Synthesis 125
8.1 Reactions with Electrophilic Reagents 125
8.1.1 Addition to Nitrogen 125
8.1.2 Substitution at Carbon 128
8.2 Reactions with Oxidising Agents 130
8.3 Reactions with Nucleophilic Reagents 131
8.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 131
8.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 133
8.4 Metallation and Reactions of C-Metallated-Pyridines 134
8.4.1 Direct Ring C–H Metallation 134
8.4.2 Metal–Halogen Exchange 137
8.5 Reactions with Radicals; Reactions of Pyridyl Radicals 138
8.5.1 Halogenation 138
8.5.2 Carbon Radicals 138
8.5.3 Dimerisation 138
8.5.4 Pyridinyl Radicals 139
8.6 Reactions with Reducing Agents 139
8.7 Electrocyclic Reactions (Ground State) 140
8.8 Photochemical Reactions 140
8.9 Oxy- and Amino-Pyridines 141
8.9.1 Structure 141
8.9.2 Reactions of Pyridones 142
8.9.3 Reactions of Amino-Pyridines 144
8.10 Alkyl-Pyridines 146
8.11 Pyridine Aldehydes, Ketones, Carboxylic Acids and Esters 148
8.12 Quaternary Pyridinium Salts 148
8.12.1 Reduction and Oxidation 148
8.12.2 Organometallic and Other Nucleophilic Additions 150
8.12.3 Nucleophilic Addition Followed by Ring Opening 152
8.12.4 Cyclisations Involving an α-Position or an α-Substituent 153
8.12.5 N-Dealkylation 153
8.13 Pyridine N-oxides 153
8.13.1 Electrophilic Addition and Substitution 154
8.13.2 Nucleophilic Addition and Substitution 155
8.13.3 Addition of Nucleophiles then Loss of Oxide 155
viii Contents
8.14 Synthesis of Pyridines 156
8.14.1 Ring Synthesis 156
8.14.2 Examples of Notable Syntheses of Pyridine Compounds 165
Exercises 166
References 168
9 Quinolines and Isoquinolines: Reactions and Synthesis 177
9.1 Reactions with Electrophilic Reagents 177
9.1.1 Addition to Nitrogen 177
9.1.2 Substitution at Carbon 177
9.2 Reactions with Oxidising Agents 179
9.3 Reactions with Nucleophilic Reagents 179
9.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 179
9.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 180
9.4 Metallation and Reactions of C-Metallated Quinolines and Isoquinolines 181
9.4.1 Direct Ring C–H Metallation 181
9.4.2 Metal–Halogen Exchange 182
9.5 Reactions with Radicals 182
9.6 Reactions with Reducing Agents 183
9.7 Electrocyclic Reactions (Ground State) 183
9.8 Photochemical Reactions 183
9.9 Oxy-Quinolines and Oxy-Isoquinolines 183
9.10 Amino-Quinolines and Amino-Isoquinolines 185
9.11 Alkyl-Quinolines and Alkyl-Isoquinolines 185
9.12 Quinoline and Isoquinoline Carboxylic Acids and Esters 185
9.13 Quaternary Quinolinium and Isoquinolinium Salts 186
9.14 Quinoline and Isoquinoline N-Oxides 188
9.15 Synthesis of Quinolines and Isoquinolines 188
9.15.1 Ring Syntheses 188
9.15.2 Examples of Notable Syntheses of Quinoline and Isoquinoline Compounds 198
Exercises 199
References 200
10 Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones 205
11 Pyryliums, 2- and 4-Pyrones: Reactions and Synthesis 209
11.1 Reactions of Pyrylium Cations 209
11.1.1 Reactions with Electrophilic Reagents 209
11.1.2 Addition Reactions with Nucleophilic Reagents 210
11.1.3 Substitution Reactions with Nucleophilic Reagents 212
11.1.4 Reactions with Radicals 212
11.1.5 Reactions with Reducing Agents 212
11.1.6 Photochemical Reactions 212
11.1.7 Reactions with Dipolarophiles; Cycloadditions 213
11.1.8 Alkyl-Pyryliums 213
11.2 2-Pyrones and 4-Pyrones (2H-Pyran-2-ones and 4H-Pyran-4-ones; α- and
γ-Pyrones) 214
11.2.1 Structure of Pyrones 214
11.2.2 Reactions of Pyrones 214
Contents ix
11.3 Synthesis of Pyryliums 218
11.3.1 From 1,5-Dicarbonyl Compounds 218
11.3.2 Alkene Acylation 219
11.3.3 From 1,3-Dicarbonyl Compounds and Ketones 220
11.4 Synthesis of 2-Pyrones 220
11.4.1 From 1,3-Keto(aldehydo)-Acids and Carbonyl Compounds 220
11.4.2 Other Methods 221
11.5 Synthesis of 4-Pyrones 222
Exercises 224
References 225
12 Benzopyryliums and Benzopyrones: Reactions and Synthesis 229
12.1 Reactions of Benzopyryliums 229
12.1.1 Reactions with Electrophilic Reagents 229
12.1.2 Reactions with Oxidising Agents 230
12.1.3 Reactions with Nucleophilic Reagents 230
12.1.4 Reactions with Reducing Agents 231
12.1.5 Alkyl-Benzopyryliums 231
12.2 Benzopyrones (Chromones, Coumarins and Isocoumarins) 232
12.2.1 Reactions with Electrophilic Reagents 232
12.2.2 Reactions with Oxidising Agents 232
12.2.3 Reactions with Nucleophilic Reagents 233
12.3 Synthesis of Benzopyryliums, Chromones, Coumarins and Isocoumarins 237
12.3.1 Ring Synthesis of 1-Benzopyryliums 237
12.3.2 Ring Synthesis of Coumarins 238
12.3.3 Ring Synthesis of Chromones 240
12.3.4 Ring Synthesis of 2-Benzopyryliums 242
12.3.5 Ring Synthesis of Isocoumarins 243
12.3.6 Notable Examples of Benzopyrylium and Benzopyrone Syntheses 243
Exercises 244
References 245
13 Typical Reactivity of the Diazine: Pyridazine, Pyrimidine and Pyrazine 249
14 The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions and Synthesis 253
14.1 Reactions with Electrophilic Reagents 253
14.1.1 Addition at Nitrogen 253
14.1.2 Substitution at Carbon 255
14.2 Reactions with Oxidising Agents 255
14.3 Reactions with Nucleophilic Reagents 255
14.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer 256
14.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups 256
14.4 Metallation and Reactions of C-Metallated Diazines 259
14.4.1 Direct Ring C–H Metallation 259
14.4.2 Metal–Halogen Exchange 260
14.5 Reactions with Reducing Agents 261
14.6 Reactions with Radicals 261
14.7 Electrocyclic Reactions 261
14.8 Diazine N-Oxides 262
x Contents
14.9 Oxy-Diazines 263
14.9.1 Structure of Oxy-Diazines 263
14.9.2 Reactions of Oxy-Diazines 264
14.10 Amino-Diazines 271
14.11 Alkyl-Diazines 272
14.12 Quaternary Diazinium Salts 273
14.13 Synthesis of Diazines 273
14.13.1 Pyridazines 274
14.13.2 Pyrimidines 275
14.13.3 Pyrazines 279
14.13.4 Notable Syntheses of Diazines 281
14.14 Pteridines 282
Exercises 283
References 284
15 Typical Reactivity of Pyrroles, Furans and Thiophenes 289
16 Pyrroles: Reactions and Synthesis 295
16.1 Reactions with Electrophilic Reagents 295
16.1.1 Substitution at Carbon 296
16.2 Reactions with Oxidising Agents 303
16.3 Reactions with Nucleophilic Reagents 303
16.4 Reactions with Bases 304
16.4.1 Deprotonation of N-Hydrogen and Reactions of Pyrryl Anions 304
16.4.2 Lithium, Sodium, Potassium and Magnesium Derivatives 304
16.5 C-Metallation and Reactions of C-Metallated Pyrroles 305
16.5.1 Direct Ring C–H Metallation 305
16.5.2 Metal–Halogen Exchange 305
16.6 Reactions with Radicals 306
16.7 Reactions with Reducing Agents 306
16.8 Electrocyclic Reactions (Ground State) 307
16.9 Reactions with Carbenes and Carbenoids 308
16.10 Photochemical Reactions 308
16.11 Pyrryl-C-X Compounds 309
16.12 Pyrrole Aldehydes and Ketones 309
16.13 Pyrrole Carboxylic Acids 309
16.14 Pyrrole Carboxylic Acid Esters 310
16.15 Oxy- and Amino-Pyrroles 310
16.15.1 2-Oxy-Pyrroles 310
16.15.2 3-Oxy-Pyrroles 311
16.15.3 Amino-Pyrroles 311
16.16 Synthesis of Pyrroles 311
16.16.1 Ring Synthesis 311
16.16.2 Some Notable Syntheses of Pyrroles 317
Exercises 319
References 320
17 Thiophenes: Reactions and Synthesis 325
17.1 Reactions with Electrophilic Reagents 325
17.1.1 Substitution at Carbon 325
17.1.2 Addition at Sulfur 329
Contents xi
17.2 Reactions with Oxidising Agents 330
17.3 Reactions with Nucleophilic Reagents 330
17.4 Metallation and Reactions of C-Metallated Thiophenes 331
17.4.1 Direct Ring C–H Metallation 331
17.4.2 Metal–Halogen Exchange 331
17.5 Reactions with Radicals 333
17.6 Reactions with Reducing Agents 333
17.7 Electrocyclic Reactions (Ground State) 333
17.8 Photochemical Reactions 334
17.9 Thiophene-C–X Compounds: Thenyl Derivatives 334
17.10 Thiophene Aldehydes and Ketones, and Carboxylic Acids and Esters 335
17.11 Oxy- and Amino-Thiophenes 335
17.11.1 Oxy-Thiophenes 335
17.11.2 Amino-Thiophenes 336
17.12 Synthesis of Thiophenes 336
17.12.1 Ring Synthesis 336
17.12.2 Examples of Notable Syntheses of Thiophene Compounds 340
Exercises 342
References 342
18 Furans: Reactions and Synthesis 347
18.1 Reactions with Electrophilic Reagents 347
18.1.1 Substitution at Carbon 347
18.2 Reactions with Oxidising Agents 351
18.3 Reactions with Nucleophilic Reagents 352
18.4 Metallation and Reactions of C-Metallated Furans 352
18.4.1 Direct Ring C–H Metallation 352
18.4.2 Metal–Halogen Exchange 353
18.5 Reactions with Radicals 353
18.6 Reactions with Reducing Agents 353
18.7 Electrocyclic Reactions (Ground State) 353
18.8 Reactions with Carbenes and Carbenoids 356
18.9 Photochemical Reactions 356
18.10 Furyl-C–X Compounds; Side-Chain Properties 356
18.11 Furan Carboxylic Acids and Esters and Aldehydes 356
18.12 Oxy- and Amino-Furans 357
18.12.1 Oxy-Furans 357
18.12.2 Amino-Furans 358
18.13 Synthesis of Furans 358
18.13.1 Ring Syntheses 359
18.13.2 Examples of Notable Syntheses of Furans 363
Exercises 364
References 365
19 Typical Reactivity of Indoles, Benzo[b]thiophenes, Benzo[b]furans, Isoindoles,
Benzo[c]thiophenes and Isobenzofurans 369
20 Indoles: Reactions and Synthesis 373
20.1 Reactions with Electrophilic Reagents 373
20.1.1 Substitution at Carbon 373
xii Contents
20.2 Reactions with Oxidising Agents 385
20.3 Reactions with Nucleophilic Reagents 386
20.4 Reactions with Bases 386
20.4.1 Deprotonation of N-Hydrogen and Reactions of Indolyl Anions 386
20.5 C-Metallation and Reactions of C-Metallated Indoles 388
20.5.1 Direct Ring C–H Metallation 388
20.5.2 Metal–Halogen Exchange 390
20.6 Reactions with Radicals 391
20.7 Reactions with Reducing Agents 392
20.8 Reactions with Carbenes 392
20.9 Electrocyclic and Photochemical Reactions 393
20.10 Alkyl-Indoles 394
20.11 Reactions of Indolyl-C–X Compounds 395
20.12 Indole Carboxylic Acids 396
20.13 Oxy-Indoles 397
20.13.1 Oxindole 397
20.13.2 Indoxyl 398
20.13.3 Isatin 399
20.13.4 1-Hydroxyindole 399
20.14 Amino-Indoles 400
20.15 Aza-Indoles 400
20.15.1 Electrophilic Substitution 401
20.15.2 Nucleophilic Substitution 401
20.16 Synthesis of Indoles 402
20.16.1 Ring Synthesis of Indoles 402
20.16.2 Ring Synthesis of Oxindoles 416
20.16.3 Ring Synthesis of Indoxyls 417
20.16.4 Ring Synthesis of Isatins 418
20.16.5 Synthesis of 1-Hydroxy-Indoles 418
20.16.6 Examples of Notable Indole Syntheses 418
20.16.7 Synthesis of Aza-Indoles 421
Exercises 422
References 423
21 Benzo[b]thiophenes and Benzo[b]furans: Reactions and Synthesis 433
21.1 Reactions with Electrophilic Reagents 433
21.1.1 Substitution at Carbon 433
21.1.2 Addition to Sulfur in Benzothiophenes 434
21.2 Reactions with Nucleophilic Reagents 435
21.3 Metallation and Reactions of C-Metallated Benzothiophenes and Benzofurans 435
21.4 Reactions with Radicals 436
21.5 Reactions with Oxidising and Reducing Agents 436
21.6 Electrocyclic Reactions 436
21.7 Oxy- and Amino-Benzothiophenes and -Benzofurans 437
21.8 Synthesis of Benzothiophenes and Benzofurans 437
21.8.1 Ring Synthesis 437
Exercises 443
References 443
Contents xiii
22 Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions and Synthesis 447
22.1 Reactions with Electrophilic Reagents 447
22.2 Electrocyclic Reactions 448
22.3 Phthalocyanines 449
22.4 Synthesis of Isoindoles, Benzo[c]thiophenes and Isobenzofurans 449
22.4.1 Isoindoles 449
22.4.2 Benzo[c]thiophenes 450
22.4.3 Isobenzofurans 451
Exercises 452
References 452
23 Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and -1,2-Azoles 455
24 1,3-Azoles: Imidazoles, Thiazoles and Oxazoles: Reactions and Synthesis 461
24.1 Reactions with Electrophilic Reagents 461
24.1.1 Addition at Nitrogen 461
24.1.2 Substitution at Carbon 464
24.2 Reactions with Oxidising Agents 466
24.3 Reactions with Nucleophilic Reagents 466
24.3.1 With Replacement of Hydrogen 466
24.3.2 With Replacement of Halogen 466
24.4 Reactions with Bases 467
24.4.1 Deprotonation of Imidazole N-Hydrogen and Reactions of
Imidazolyl Anions 467
24.5 C-Metallation and Reactions of C-Metallated 1,3-Azoles 467
24.5.1 Direct Ring C–H Metallation 467
24.5.2 Metal–Halogen Exchange 468
24.6 Reactions with Radicals 468
24.7 Reactions with Reducing Agents 469
24.8 Electrocyclic Reactions 469
24.9 Alkyl-1,3-Azoles 470
24.10 Quaternary 1,3-Azolium Salts 470
24.11 Oxy- and Amino-1,3-Azoles 471
24.12 1,3-Azole N-Oxides 473
24.13 Synthesis of 1,3-Azoles 473
24.13.1 Ring Synthesis 473
24.13.2 Examples of Notable Syntheses Involving 1,3-Azoles 478
Exercises 479
References 480
25 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 485
25.1 Reactions with Electrophilic Reagents 486
25.1.1 Addition at Nitrogen 486
25.1.2 Substitution at Carbon 487
25.2 Reactions with Oxidising Agents 488
25.3 Reactions with Nucleophilic Reagents 488
25.4 Reactions with Bases 488
25.4.1 Deprotonation of Pyrazole N-Hydrogen and Reactions of
Pyrazolyl Anions 488
xiv Contents
25.5 C-Metallation and Reactions of C-Metallated 1,2-Azoles 489
25.5.1 Direct Ring C–H Metallation 489
25.5.2 Metal–Halogen Exchange 490
25.6 Reactions with Radicals 490
25.7 Reactions with Reducing Agents 490
25.8 Electrocyclic and Photochemical Reactions 491
25.9 Alkyl-1,2-Azoles 492
25.10 Quaternary 1,2-Azolium Salts 492
25.11 Oxy- and Amino-1,2-azoles 493
25.12 Synthesis of 1,2-Azoles 494
25.12.1 Ring Synthesis 494
Exercises 498
References 498
26 Benzanellated Azoles: Reactions and Synthesis 503
26.1 Reactions with Electrophilic Reagents 503
26.1.1 Addition at Nitrogen 503
26.1.2 Substitution at Carbon 504
26.2 Reactions with Nucleophilic Reagents 505
26.3 Reactions with Bases 505
26.3.1 Deprotonation of N-Hydrogen and Reactions of Benzimidazolyl
and Indazolyl Anions 505
26.4 Ring Metallation and Reactions of C-Metallated Derivatives 505
26.5 Reactions with Reducing Agents 506
26.6 Electrocyclic Reactions 506
26.7 Quaternary Salts 506
26.8 Oxy- and Amino-Benzo-1,3-Azoles 507
26.9 Synthesis 507
26.9.1 Ring Synthesis of Benzo-1,3-Azoles 507
26.9.2 Ring Synthesis of Benzo-1,2-Azoles 509
References 512
27 Purines: Reactions and Synthesis 515
27.1 Reactions with Electrophilic Reagents 516
27.1.1 Addition at Nitrogen 516
27.1.2 Substitution at Carbon 519
27.2 Reactions with Radicals 521
27.3 Reactions with Oxidising Agents 521
27.4 Reactions with Reducing Agents 521
27.5 Reactions with Nucleophilic Reagents 521
27.6 Reactions with Bases 524
27.6.1 Deprotonation of N-Hydrogen and Reactions of Purinyl Anions 524
27.7 C-Metallation and Reactions of C-Metallated Purines 524
27.7.1 Direct Ring C–H Metallation 524
27.7.2 Metal–Halogen Exchange 525
27.8 Oxy- and Amino-Purines 525
27.8.1 Oxy-Purines 526
27.8.2 Amino-Purines 527
27.8.3 Thio-Purines 529
Contents xv
27.9 Alkyl-Purines 530
27.10 Purine Carboxylic Acids 530
27.11 Synthesis of Purines 530
27.11.1 Ring Synthesis 530
27.11.2 Examples of Notable Syntheses Involving Purines 534
Exercises 535
References 536
28 Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds) 539
28.1 Indolizines 539
28.1.1 Reactions of Indolizines 540
28.1.2 Ring Synthesis of Indolizines 541
28.2 Aza-Indolizines 543
28.2.1 Imidazo[1,2-a]pyridines 543
28.2.2 Imidazo[1,5-a]pyridines 545
28.2.3 Pyrazolo[1,5-a]pyridines 546
28.2.4 Triazolo- and Tetrazolo-Pyridines 547
28.2.5 Compounds with an Additional Nitrogen in the Six-Membered Ring 549
28.3 Quinolizinium and Related Systems 551
28.4 Pyrrolizine and Related Systems 551
28.5 Cyclazines 552
Exercises 553
References 553
29 Heterocycles Containing More Than Two Heteroatoms 557
29.1 Five-Membered Rings 557
29.1.1 Azoles 557
29.1.2 Oxadiazoles and Thiadiazoles 569
29.1.3 Other Systems 574
29.2 Six-Membered Rings 574
29.2.1 Azines 574
29.3 Benzotriazoles 579
Exercises 581
References 581
30 Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis 587
30.1 Five- and Six-Membered Rings 588
30.1.1 Pyrrolidines and Piperidines 588
30.1.2 Piperideines and Pyrrolines 589
30.1.3 Pyrans and Reduced Furans 590
30.2 Three-Membered Rings 592
30.2.1 Three-Membered Rings with One Heteroatom 592
30.2.2 Three-Membered Rings with Two Heteroatoms 596
30.3 Four-Membered Rings 597
30.4 Metallation 598
30.5 Ring synthesis 599
30.5.1 Aziridines and Azirines 600
30.5.2 Azetidines and β-Lactams 602
30.5.3 Pyrrolidines 602
xvi Contents
30.5.4 Piperidines 603
30.5.5 Saturated Oxygen Heterocycles 604
30.5.6 Saturated Sulfur Heterocycles 605
References 606
31 Special Topics 609
31.1 Synthesis of Ring-Fluorinated Heterocycles 609
31.1.1 Electrophilic Fluorination 609
31.1.2 The Balz–Schiemann Reaction 611
31.1.3 Halogen Exchange (Halex) Reactions 612
31.1.4 Ring Synthesis Incorporating Fluorinated Starting Materials 612
31.2 Isotopically Labelled Heterocycles 616
31.2.1 Hazards Due to Radionuclides 616
31.2.2 Synthesis 616
31.2.3 PET (Positron Emission Tomography) 617
31.3 Bioprocesses in Heterocyclic Chemistry 619
31.4 Green Chemistry 620
31.5 Ionic Liquids 620
31.6 Applications and Occurrences of Heterocycles 621
31.6.1 Toxicity 622
31.6.2 Plastics and Polymers 622
31.6.3 Fungicides and Herbicides 623
31.6.4 Dyes and Pigments 623
31.6.5 Fluorescence-Based Applications 624
31.6.6 Electronic Applications 625
References 626
32 Heterocycles in Biochemistry; Heterocyclic Natural Products 629
32.1 Heterocyclic Amino Acids and Related Substances 629
32.2 Enzyme Co-Factors; Heterocyclic Vitamins; Co-Enzymes 630
32.2.1 Niacin (Vitamin B3) and Nicotinamide Adenine Dinucleotide
Phosphate (NADP+) 631
32.2.2 Pyridoxine (Vitamin B6) and Pyridoxal Phosphate (PLP) 631
32.2.3 Ribofl avin (Vitamin B2) 632
32.2.4 Thiamin (Vitamin B1) and Thiamine Pyrophosphate 632
32.3 Porphobilinogen and the ‘Pigments of Life’ 633
32.4 Ribonucleic Acid (RNA) and Deoxyribonucleic Acid (DNA); Genetic
Information; Purines and Pyrimidines 635
32.5 Heterocyclic Natural Products 637
32.5.1 Alkaloids 637
32.5.2 Marine Heterocycles 639
32.5.3 Halogenated Heterocycles 639
32.5.4 Macrocycles Containing Oxazoles and Thiazoles 640
32.5.5 Other Nitrogen-Containing Natural Products 640
32.5.6 Anthocyanins and Flavones 641
References 642
33 Heterocycles in Medicine 645
33.1 Mechanisms of Drug Actions 646
33.1.1 Mimicking or Opposing the Effects of Physiological Hormones or
Neurotransmitters 646
Contents xvii
33.1.2 Interaction with Enzymes 646
33.1.3 Physical Binding with, or Chemically Modifying,
Natural Macromolecules 646
33.2 The Neurotransmitters 647
33.3 Drug Discovery and Development 647
33.3.1 Stages in the Life of a Drug 647
33.3.2 Drug Discovery 649
33.3.3 Chemical Development 649
33.3.4 Good Manufacturing Practice (GMP) 650
33.4 Heterocyclic Drugs 650
33.4.1 Histamine 650
33.4.2 Acetylcholine (ACh) 652
33.4.3 5-Hydroxytryptamine (5-HT) 653
33.4.4 Adrenaline and Noradrenaline 654
33.4.5 Other Signifi cant Cardiovascular Drugs 654
33.4.6 Drugs Affecting Blood Clotting 655
33.4.7 Other Enzyme Inhibitors 656
33.4.8 Enzyme Induction 658
33.5 Drugs Acting on the CNS 658
33.6 Anti-Infective Agents 659
33.6.1 Anti-Parasitic Drugs 659
33.6.2 Anti-Bacterial Drugs 660
33.6.3 Anti-Viral Drugs 661
33.7 Anti-Cancer Drugs 661
33.8 Photochemotherapy 663
33.8.1 Psoralen plus UVA (PUVA) Treatment 663
33.8.2 Photodynamic Therapy (PDT) 664
References 664
Index
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