Heterocyclic Chemistry, 5th Edition

Heterocyclic Chemistry, Fifth Edition......Page 0
Contents......Page 6
Preface to the Fifth Edition......Page 20
P.2 How to Use This Textbook......Page 22
Web Site......Page 23
Biography......Page 24
Definitions of Abbreviations......Page 26
1: Heterocyclic Nomenclature......Page 30
2.1.1 Structures of Benzene and Naphthalene......Page 34
2.1.2 Aromatic Resonance Energy......Page 35
2.2.2 Structure of Diazines......Page 36
2.2.4 Structures of Pyridones and Pyrones......Page 37
2.3.1 Structure of Pyrrole......Page 38
2.3.3 Structures of Azoles......Page 39
2.4 Structures of Bicyclic Heteroaromatic Compounds......Page 40
2.6 Mesoionic Systems......Page 41
2.7.1 Ultraviolet/Visible (Electronic) Spectroscopy......Page 42
2.7.2 Nuclear Magnetic Resonance (NMR) Spectroscopy......Page 43
References......Page 46
3.1 Electrophilic Addition at Nitrogen......Page 48
3.2.1 Aromatic Electrophilic Substitution: Mechanism......Page 49
3.2.2 Six-Membered Heterocycles......Page 50
3.2.3 Five-Membered Heterocycles......Page 51
3.3.2 Six-Membered Heterocycles......Page 53
3.3.3 Vicarious Nucleophilic Substitution (VNS Substitution)......Page 55
3.4.1 Reactions of Heterocycles with Nucleophilic Radicals......Page 56
3.5 Deprotonation of N-Hydrogen......Page 59
3.7 ortho-Quinodimethanes in Heterocyclic Compound Synthesis......Page 60
References......Page 62
4.1.1 Lithium......Page 66
4.1.2 Magnesium......Page 74
4.1.3 Zinc......Page 76
4.1.5 Boron......Page 77
4.1.6 Silicon and Tin......Page 81
4.1.9 Side-Chain Metallation (‘Lateral Metallation’)......Page 83
4.2.1 Basic Palladium Processes......Page 85
4.2.2 Catalysts......Page 88
4.2.3 The Electrophilic Partner; The Halides/Leaving Groups......Page 90
4.2.4 Cross-Coupling Reactions......Page 93
4.2.5 The Nucleophilic (Organometallic) Partner......Page 94
4.2.6 Other Nucleophiles......Page 99
4.2.7 The Ring Systems in Cross-Coupling Reactions......Page 100
4.2.8 Organometallic Selectivity......Page 106
4.2.9 Direct C–H Arylation......Page 108
4.2.10 N-Arylation......Page 112
4.2.11 Heck Reactions......Page 116
4.2.12 Carbonylation Reactions......Page 118
References......Page 119
5.1.1 Solid-Phase Reactions......Page 126
5.1.2 Solid-Supported Reagents and Scavengers......Page 128
5.1.4 Soluble Polymer-Supported Reactions......Page 129
5.1.5 Phase Tags......Page 130
5.2 Microwave Heating......Page 132
5.3 Flow Reactors......Page 133
References......Page 134
6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis......Page 136
6.2.1 Typical Ring Synthesis of a Pyrrole Involving Only C–Heteroatom Bond Formation......Page 137
6.2.3 Typical Ring Syntheses Involving C–Heteroatom C–C Bond Formations......Page 138
6.3 Summary......Page 140
6.4 Electrocyclic Processes in Heterocyclic Ring Synthesis......Page 141
6.6 Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles......Page 142
References......Page 143
7: Typical Reactivity of Pyridines, Quinolines and Isoquinolines......Page 144
8.1.1 Addition to Nitrogen......Page 154
8.1.2 Substitution at Carbon......Page 157
8.2 Reactions with Oxidising Agents......Page 159
8.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer......Page 160
8.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups......Page 162
8.4.1 Direct Ring C–H Metallation......Page 163
8.4.2 Metal–Halogen Exchange......Page 166
8.5.3 Dimerisation......Page 167
8.6 Reactions with Reducing Agents......Page 168
8.8 Photochemical Reactions......Page 169
8.9.1 Structure......Page 170
8.9.2 Reactions of Pyridones......Page 171
8.9.3 Reactions of Amino-Pyridines......Page 173
8.10 Alkyl-Pyridines......Page 175
8.12.1 Reduction and Oxidation......Page 177
8.12.2 Organometallic and Other Nucleophilic Additions......Page 179
8.12.3 Nucleophilic Addition Followed by Ring Opening......Page 181
8.13 Pyridine N-oxides......Page 182
8.13.1 Electrophilic Addition and Substitution......Page 183
8.13.3 Addition of Nucleophiles then Loss of Oxide......Page 184
8.14.1 Ring Synthesis......Page 185
8.14.2 Examples of Notable Syntheses of Pyridine Compounds 8.14.2.1 Fusarinic Acid......Page 194
Exercises......Page 195
References......Page 197
9.1.2 Substitution at Carbon......Page 206
9.3.1 Nucleophilic Substitution with ‘Hydride’ Transfer......Page 208
9.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups......Page 209
9.4.1 Direct Ring C–H Metallation......Page 210
9.5 Reactions with Radicals......Page 211
9.9 Oxy-Quinolines and Oxy-Isoquinolines......Page 212
9.12 Quinoline and Isoquinoline Carboxylic Acids and Esters......Page 214
9.13 Quaternary Quinolinium and Isoquinolinium Salts......Page 215
9.15.1 Ring Syntheses......Page 217
9.15.2 Examples of Notable Syntheses of Quinoline and Isoquinoline Compounds......Page 227
Exercises......Page 228
References......Page 229
10: Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones......Page 234
11.1.1 Reactions with Electrophilic Reagents......Page 238
11.1.2 Addition Reactions with Nucleophilic Reagents......Page 239
11.1.6 Photochemical Reactions......Page 241
11.1.8 Alkyl-Pyryliums......Page 242
11.2.2 Reactions of Pyrones......Page 243
11.3.1 From 1,5-Dicarbonyl Compounds......Page 247
11.3.2 Alkene Acylation......Page 248
11.4.1 From 1,3-Keto(aldehydo)-Acids and Carbonyl Compounds......Page 249
11.4.2 Other Methods......Page 250
11.5 Synthesis of 4-Pyrones......Page 251
Exercises......Page 253
References......Page 254
12.1.1 Reactions with Electrophilic Reagents......Page 258
12.1.3 Reactions with Nucleophilic Reagents......Page 259
12.1.5 Alkyl-Benzopyryliums......Page 260
12.2.2 Reactions with Oxidising Agents......Page 261
12.2.3 Reactions with Nucleophilic Reagents......Page 262
12.3.1 Ring Synthesis of 1-Benzopyryliums......Page 266
12.3.2 Ring Synthesis of Coumarins......Page 267
12.3.3 Ring Synthesis of Chromones......Page 269
12.3.4 Ring Synthesis of 2-Benzopyryliums......Page 271
12.3.6 Notable Examples of Benzopyrylium and Benzopyrone Syntheses......Page 272
Exercises......Page 273
References......Page 274
13: Typical Reactivity of the Diazines: Pyridazine, Pyrimidine and Pyrazine......Page 278
14.1.1 Addition at Nitrogen......Page 282
14.3 Reactions with Nucleophilic Reagents......Page 284
14.3.2 Nucleophilic Substitution with Displacement of Good Leaving Groups......Page 285
14.4.1 Direct Ring C–H Metallation......Page 288
14.4.2 Metal–Halogen Exchange......Page 289
14.7 Electrocyclic Reactions......Page 290
14.8 Diazine N-Oxides......Page 291
14.9.1 Structure of Oxy-Diazines......Page 292
14.9.2 Reactions of Oxy-Diazines......Page 293
14.10 Amino-Diazines......Page 300
14.11 Alkyl-Diazines......Page 301
14.13 Synthesis of Diazines......Page 302
14.13.1 Pyridazines......Page 303
14.13.2 Pyrimidines......Page 304
14.13.3 Pyrazines......Page 308
14.13.4 Notable Syntheses of Diazines......Page 310
14.14 Pteridines......Page 311
Exercises......Page 312
References......Page 313
15: Typical Reactivity of Pyrroles, Furans and Thiophenes......Page 318
16.1 Reactions with Electrophilic Reagents......Page 324
16.1.1 Substitution at Carbon......Page 325
16.3 Reactions with Nucleophilic Reagents......Page 332
16.4.2 Lithium, Sodium, Potassium and Magnesium Derivatives......Page 333
16.5.2 Metal–Halogen Exchange......Page 334
16.7 Reactions with Reducing Agents......Page 335
16.8 Electrocyclic Reactions (Ground State)......Page 336
16.10 Photochemical Reactions......Page 337
16.13 Pyrrole Carboxylic Acids......Page 338
16.15.1 2-Oxy-Pyrroles......Page 339
16.16.1 Ring Synthesis......Page 340
16.16.2 Some Notable Syntheses of Pyrroles......Page 346
Exercises......Page 348
References......Page 349
17.1.1 Substitution at Carbon......Page 354
17.1.2 Addition at Sulfur......Page 358
17.3 Reactions with Nucleophilic Reagents......Page 359
17.4.2 Metal–Halogen Exchange......Page 360
17.7 Electrocyclic Reactions (Ground State)......Page 362
17.9 Thiophene-C–X Compounds: Thenyl Derivatives......Page 363
17.11.1 Oxy-Thiophenes......Page 364
17.12.1 Ring Synthesis......Page 365
17.12.2 Examples of Notable Syntheses of Thiophene Compounds......Page 369
References......Page 371
18.1.1 Substitution at Carbon......Page 376
18.2 Reactions with Oxidising Agents......Page 380
18.4.1 Direct Ring C–H Metallation......Page 381
18.7 Electrocyclic Reactions (Ground State)......Page 382
18.11 Furan Carboxylic Acids and Esters and Aldehydes......Page 385
18.12.1 Oxy-Furans......Page 386
18.13 Synthesis of Furans......Page 387
18.13.1 Ring Syntheses......Page 388
18.13.2 Examples of Notable Syntheses of Furans......Page 392
Exercises......Page 393
References......Page 394
19: Typical Reactivity of Indoles, Benzo[b] thiophenes, Benzo[b]furans, Isoindoles, Benzo[c]thiophenes and Isobenzofurans......Page 398
20.1.1 Substitution at Carbon......Page 402
20.2 Reactions with Oxidising Agents......Page 414
20.4.1 Deprotonation of N-Hydrogen and Reactions of Indolyl Anions......Page 415
20.5.1 Direct Ring C–H Metallation......Page 417
20.5.2 Metal–Halogen Exchange......Page 419
20.6 Reactions with Radicals......Page 420
20.8 Reactions with Carbenes......Page 421
20.9 Electrocyclic and Photochemical Reactions......Page 422
20.10 Alkyl-Indoles......Page 423
20.11 Reactions of Indolyl-C–X Compounds......Page 424
20.12 Indole Carboxylic Acids......Page 425
20.13.1 Oxindole......Page 426
20.13.2 Indoxyl......Page 427
20.13.4 1-Hydroxyindole......Page 428
20.15 Aza-Indoles......Page 429
20.15.2 Nucleophilic Substitution......Page 430
20.16.1 Ring Synthesis of Indoles......Page 431
20.16.2 Ring Synthesis of Oxindoles......Page 445
20.16.3 Ring Synthesis of Indoxyls......Page 446
20.16.6 Examples of Notable Indole Syntheses......Page 447
20.16.7 Synthesis of Aza-Indoles......Page 450
Exercises......Page 451
References......Page 452
21.1.1 Substitution at Carbon......Page 462
21.1.2 Addition to Sulfur in Benzothiophenes......Page 463
21.3 Metallation and Reactions of C-Metallated Benzothiophenes and Benzofurans......Page 464
21.6 Electrocyclic Reactions......Page 465
21.8.1 Ring Synthesis......Page 466
References......Page 472
22.1 Reactions with Electrophilic Reagents......Page 476
22.2 Electrocyclic Reactions......Page 477
22.4.1 Isoindoles......Page 478
22.4.2 Benzo[c]thiophenes......Page 479
22.4.3 Isobenzofurans......Page 480
References......Page 481
23: Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and -1,2-Azoles......Page 484
24.1.1 Addition at Nitrogen......Page 490
24.1.2 Substitution at Carbon......Page 493
24.3.2 With Replacement of Halogen......Page 495
24.5.1 Direct Ring C–H Metallation......Page 496
24.6 Reactions with Radicals......Page 497
24.8 Electrocyclic Reactions......Page 498
24.10 Quaternary 1,3-Azolium Salts......Page 499
24.11 Oxy- and Amino-1,3-Azoles......Page 500
24.13.1 Ring Synthesis......Page 502
24.13.2 Examples of Notable Syntheses Involving 1,3-Azoles......Page 507
Exercises......Page 508
References......Page 509
25: 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis......Page 514
25.1.1 Addition at Nitrogen......Page 515
25.1.2 Substitution at Carbon......Page 516
25.4.1 Deprotonation of Pyrazole N-Hydrogen and Reactions of Pyrazolyl Anions......Page 517
25.5.1 Direct Ring C–H Metallation......Page 518
25.7 Reactions with Reducing Agents......Page 519
25.8 Electrocyclic and Photochemical Reactions......Page 520
25.10 Quaternary 1,2-Azolium Salts......Page 521
25.11 Oxy-and Amino-1,2-azoles......Page 522
25.12.1 Ring Synthesis......Page 523
References......Page 527
26.1.1 Addition at Nitrogen......Page 532
26.1.2 Substitution at Carbon......Page 533
26.4 Ring Metallation and Reactions of C-Metallated Derivatives......Page 534
26.7 Quaternary Salts......Page 535
26.9.1 Ring Synthesis of Benzo-1,3-Azoles......Page 536
26.9.2 Ring Synthesis of Benzo-1,2-Azoles......Page 538
References......Page 541
27: Purines: Reactions and Synthesis......Page 544
27.1.1 Addition at Nitrogen......Page 545
27.1.2 Substitution at Carbon......Page 548
27.5 Reactions with Nucleophilic Reagents......Page 550
27.7.1 Direct Ring C–H Metallation......Page 553
27.8 Oxy- and Amino-Purines......Page 554
27.8.1 Oxy-Purines......Page 555
27.8.2 Amino-Purines......Page 556
27.8.3 Thio-Purines......Page 558
27.11.1 Ring Synthesis......Page 559
27.11.2 Examples of Notable Syntheses Involving Purines......Page 563
Exercises......Page 564
References......Page 565
28.1 Indolizines......Page 568
28.1.1 Reactions of Indolizines......Page 569
28.1.2 Ring Synthesis of Indolizines......Page 570
28.2.1 Imidazo[1,2-a]pyridines......Page 572
28.2.2 Imidazo[1,5-a ]pyridines......Page 574
28.2.3 Pyrazolo[1,5-a ]pyridines......Page 575
28.2.4 Triazolo-and Tetrazolo-Pyridines......Page 576
28.2.5 Compounds with an Additional Nitrogen in the Six - Membered Ring......Page 578
28.4 Pyrrolizine and Related Systems......Page 580
28.5 Cyclazines......Page 581
References......Page 582
29.1.1 Azoles......Page 586
29.1.2 Oxadiazoles and Thiadiazoles......Page 598
29.2.1 Azines......Page 603
29.3 Benzotriazoles......Page 608
References......Page 610
30: Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis......Page 616
30.1.1 Pyrrolidines and Piperidines......Page 617
30.1.2 Piperideines and Pyrrolines......Page 618
30.1.3 Pyrans and Reduced Furans......Page 619
30.2.1 Three-Membered Rings with One Heteroatom......Page 621
30.2.2 Three-Membered Rings with Two Heteroatoms......Page 625
30.3 Four-Membered Rings......Page 626
30.4 Metallation......Page 627
30.5 Ring Synthesis......Page 628
30.5.1 Aziridines and Azirines......Page 629
30.5.3 Pyrrolidines......Page 631
30.5.4 Piperidines......Page 632
30.5.5 Saturated Oxygen Heterocycles......Page 633
30.5.6 Saturated Sulfur Heterocycles......Page 634
References......Page 635
31.1.1 Electrophilic Fluorination......Page 638
31.1.2 The Balz–Schiemann Reaction......Page 640
31.1.4 Ring Synthesis Incorporating Fluorinated Starting Materials......Page 641
31.2.2 Synthesis......Page 645
31.2.3 PET (Positron Emission Tomography)......Page 646
31.3 Bioprocesses in Heterocyclic Chemistry......Page 648
31.5 Ionic Liquids......Page 649
31.6 Applications and Occurrences of Heterocycles......Page 650
31.6.2 Plastics and Polymers......Page 651
31.6.4 Dyes and Pigments......Page 652
31.6.5 Fluorescence - Based Applications......Page 653
31.6.6 Electronic Applications......Page 654
References......Page 655
32.1 Heterocyclic Amino Acids and Related Substances......Page 658
32.2 Enzyme Co-Factors; Heterocyclic Vitamins; Co-Enzymes......Page 659
32.2.2 Pyridoxine (Vitamin B6) and Pyridoxal Phosphate (PLP)......Page 660
32.2.4 Thiamin (Vitamin B1) and Thiamine Pyrophosphate......Page 661
32.3 Porphobilinogen and the ‘Pigments of Life’......Page 662
32.4 Ribonucleic Acid (RNA ) and Deoxyribonucleic Acid (DNA); Genetic Information; Purines and Pyrimidines......Page 664
32.5.1 Alkaloids......Page 666
32.5.3 Halogenated Heterocycles......Page 668
32.5.5 Other Nitrogen-Containing Natural Products......Page 669
32.5.6 Anthocyanins and Flavones......Page 670
References......Page 671
33: Heterocycles in Medicine......Page 674
33.1.3 Physical Binding with, or Chemically Modifying, Natural Macromolecules......Page 675
33.3.1 Stages in the Life of a Drug......Page 676
33.3.3 Chemical Development......Page 678
33.4.1 Histamine......Page 679
33.4.2 Acetylcholine (ACh)......Page 681
33.4.3 5 - Hydroxytryptamine (5-HT)......Page 682
33.4.5 Other Signifi cant Cardiovascular Drugs......Page 683
33.4.6 Drugs Affecting Blood Clotting......Page 684
33.4.7 Other Enzyme Inhibitors......Page 685
33.5 Drugs Acting on the CNS......Page 687
33.6.1 Anti-Parasitic Drugs......Page 688
33.6.2 Anti-Bacterial Drugs......Page 689
33.7 Anti-Cancer Drugs......Page 690
33.8.1 Psoralen plus UVA (PUVA) Treatment......Page 692
References......Page 693
Index......Page 694