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Heterocyclic chemistry

Contents

Preface to Fourth Edition .................................................................................

xii

Introduction to the Fourth Edition ....................................................................

xiii

Definitions and Abbreviations ..........................................................................

xvi

1.

2.

Structures and Spectroscopic Properties of Aromatic
Heterocycles ...........................................................................................


1

1.1

Carbocyclic Aromatic Systems ......................................................................

1

1.2

Structure of Six-membered Heteroaromatic Systems ..................................

3

1.3

Structure of Five-membered Heteroaromatic Systems ................................

5

1.4

Structures of Bicyclic Heteroaromatic Compounds ......................................

7

1.5

Tautomerism in Heterocyclic Systems ..........................................................

7

1.6

Mesoionic Systems ........................................................................................

8

1.7


Some Spectroscopic Properties of Some Heteroaromatic Systems ............

8

References ...............................................................................................................

14

Reactivity of Aromatic Heterocycles .....................................................

16

2.1

Electrophilic Addition at Nitrogen ..................................................................

16

2.2

Electrophilic Substitution at Carbon ..............................................................

17

2.3

Nucleophilic Substitution at Carbon ..............................................................

20

2.4

Radical Substitution at Carbon ......................................................................

23

2.5

Deprotonation of N-hydrogen ........................................................................

26

2.6

Organometallic Derivatives ...........................................................................

26

2.7

Palladium-catalysed Reactions .....................................................................

40

2.8

Oxidation and Reduction of Heterocyclic Rings ............................................

46

2.9

Bioprocesses in Heterocyclic Chemistry .......................................................

46

References ...............................................................................................................

47

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v


vi

Contents

3.

Synthesis of Aromatic Heterocycles .....................................................
3.1

53

Reaction Types Most Frequently Used in Heterocyclic Ring
Synthesis .......................................................................................................

53

3.2

Typical Reactant Combinations ....................................................................

54

3.3

Summary .......................................................................................................

56

3.4

Electrocyclic Processes in Heterocyclic Ring Synthesis ..............................

57

3.5

Nitrenes in Heterocyclic Ring Synthesis .......................................................

58

3.6

ortho-Quinodimethanes in Heterocyclic Compound Synthesis ....................

59

References ...............................................................................................................

61

4.

Typical Reactivity of Pyridines, Quinolines and Isoquinolines ..........

63

5.

Pyridines: Reactions and Synthesis .....................................................

71

5.1

Reactions with Electrophilic Reagents ..........................................................

72

5.2

Reactions with Oxidising Agents ...................................................................

77

5.3

Reactions with Nucleophilic Reagents ..........................................................

78

5.4

Reactions with Bases ....................................................................................

80

5.5

Reactions of C-metallated Pyridines .............................................................

81

5.6

Reactions with Radical Reagents; Reactions of Pyridyl Radicals ................

84

5.7

Reactions with Reducing Agents ..................................................................

86

5.8

Electrocyclic Reactions (Ground State) ........................................................

86

5.9

Photochemical Reactions ..............................................................................

87

5.10 Oxy- and Aminopyridines ..............................................................................

88

5.11 Alkylpyridines .................................................................................................

93

5.12 Pyridine Aldehydes, Ketones, Carboxylic Acids and Esters .........................

94

5.13 Quaternary Pyridinium Salts ..........................................................................

95

5.14 Pyridine N-oxides ..........................................................................................

100

5.15 Synthesis of Pyridines ...................................................................................

103

Exercises for Chapter 5 ............................................................................................

110

References ...............................................................................................................

112

6.

Quinolines and Isoquinolines: Reactions and Synthesis ................... 121
6.1

Reactions with Electrophilic Reagents ..........................................................

122

6.2

Reactions with Oxidising Agents ...................................................................

123

6.3

Reactions with Nucleophilic Reagents ..........................................................

123

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Contents

vii

6.4

Reactions with Bases ....................................................................................

126

6.5

Reactions of C-metallated Quinolines and Isoquinolines .............................

126

6.6

Reactions with Radical Reagents .................................................................

127

6.7

Reactions with Reducing Agents ..................................................................

127

6.8

Electrocyclic Reactions (Ground State) ........................................................

128

6.9

Photochemical Reactions ..............................................................................

128

6.10 Oxyquinolines and -isoquinolines ..................................................................

128

6.11 Aminoquinolines and -isoquinolines ..............................................................

130

6.12 Alkylquinolines and -isoquinolines ................................................................

130

6.13 Quinoline and Isoquinoline Carboxylic Acids and Esters .............................

130

6.14 Quaternary Quinolinium and Isoquinolinium Salts ........................................

131

6.15 Quinoline and Isoquinoline N-oxides .............................................................

132

6.16 Synthesis of Quinolines and Isoquinolines ...................................................

133

Exercises for Chapter 6 ............................................................................................

142

References ...............................................................................................................

143

7.

Typical Reactivity of Pyrylium and Benzopyrylium Ions,
Pyrones and Benzopyrones ................................................................... 148

8.

Pyryliums, 2- and 4-pyrones: Reactions and Synthesis ..................... 151

9.

8.1

Reactions of Pyrylium Cations ......................................................................

151

8.2

2-pyrones and 4-pyrones (2H-pyran-2-ones and 4H-pyran-4-ones; αpyrones and γ-pyrones) .................................................................................

156

8.3

Synthesis of Pyryliums ..................................................................................

160

8.4

Synthesis of 2-pyrones ..................................................................................

162

8.5

Synthesis of 4-pyrones ..................................................................................

164

Exercises for Chapter 8 ............................................................................................

165

References ...............................................................................................................

166

Benzopyryliums, Benzopyrones: Reactions and Synthesis ............... 170
9.1

Reactions of Benzopyryliums ........................................................................

170

9.2

Benzopyrones (Chromones, Coumarins, and Isocoumarins) ......................

173

9.3

Synthesis of Benzopyryliums, Chromones, Coumarins and
Isocoumarins .................................................................................................

179

Exercises for Chapter 9 ............................................................................................

186

References ...............................................................................................................

186

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viii

Contents

10. Typical Reactivity of the Diazines: Pyridazine, Pyrimidine and
Pyrazine ................................................................................................... 190
11. The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions
and Synthesis ......................................................................................... 194
11.1 Reactions with Electrophilic Reagents ..........................................................

196

11.2 Reactions with Oxidising Agents ...................................................................

198

11.3 Reactions with Nucleophilic Reagents ..........................................................

198

11.4 Reactions with Bases ....................................................................................

201

11.5 Reactions of C-metallated Diazines ..............................................................

202

11.6 Reactions with Reducing Agents ..................................................................

204

11.7 Reactions with Radical Reagents .................................................................

204

11.8 Electrocyclic Reactions ..................................................................................

204

11.9 Diazine N-oxides ............................................................................................

205

11.10 Oxydiazines ...................................................................................................

206

11.11 Aminodiazines ...............................................................................................

214

11.12 Alkyldiazines ..................................................................................................

215

11.13 Quaternary Azinium Salts ..............................................................................

215

11.14 Synthesis of Diazines ....................................................................................

216

11.15 Pteridines .......................................................................................................

224

Exercises for Chapter 11 ..........................................................................................

225

References ...............................................................................................................

226

12. Typical Reactivity of Pyrroles, Thiophenes, and Furans .................... 233
13. Pyrroles: Reactions and Synthesis ....................................................... 237
13.1 Reactions with Electrophilic Reagents ..........................................................

238

13.2 Reactions with Oxidising Agents ...................................................................

246

13.3 Reactions with Nucleophilic Reagents ..........................................................

246

13.4 Reactions with Bases ....................................................................................

246

13.5 Reactions of N-metallated Pyrroles ...............................................................

247

13.6 Reactions of C-metallated Pyrroles ...............................................................

248

13.7 Reactions with Radical Reagents .................................................................

249

13.8 Reactions with Reducing Agents ..................................................................

250

13.9 Electrocyclic Reactions (Ground State) ........................................................

250

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Contents

ix

13.10 Reactions with Carbenes and Carbenoids ...................................................

252

13.11 Photochemical Reactions ..............................................................................

252

13.12 Pyrryl-C-X Compounds .................................................................................

252

13.13 Pyrrole Aldehydes and Ketones ....................................................................

253

13.14 Pyrrole Carboxylic Acids ................................................................................

253

13.15 Pyrrole Carboxylic Acid Esters ......................................................................

254

13.16 Halopyrroles ...................................................................................................

254

13.17 Oxy- and Aminopyrroles ................................................................................

254

13.18 Synthesis of Pyrroles .....................................................................................

255

Exercises for Chapter 13 ..........................................................................................

265

References ...............................................................................................................

266

14. Thiophenes: Reactions and Synthesis ................................................. 273
14.1 Reactions with Electrophilic Reagents ..........................................................

273

14.2 Reactions with Oxidising Agents ...................................................................

278

14.3 Reactions with Nucleophilic Reagents ..........................................................

279

14.4 Reactions with Bases ....................................................................................

279

14.5 Reactions of C-metallated Thiophenes .........................................................

280

14.6 Reactions with Radical Reagents .................................................................

282

14.7 Reactions with Reducing Agents ..................................................................

283

14.8 Electrocyclic Reactions (Ground State) ........................................................

283

14.9 Photochemical Reactions ..............................................................................

284

14.10 Thiophene-C-X Compounds: Thenyl Derivatives .........................................

284

14.11 Thiophene Aldehydes and Ketones, and Carboxylic Acids and Esters .......

285

14.12 Oxy- and Aminothiophenes ...........................................................................

285

14.13 Synthesis of Thiophenes ...............................................................................

286

Exercises for Chapter 14 ..........................................................................................

290

References ...............................................................................................................

291

15. Furans: Reactions and Synthesis ......................................................... 296
15.1 Reactions with Electrophilic Reagents ..........................................................

296

15.2 Reactions with Oxidising Agents ...................................................................

300

15.3 Reactions with Nucleophilic Reagents ..........................................................

300

15.4 Reactions with Bases ....................................................................................

301

15.5 Reactions of C-metallated Furans .................................................................

302

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Contents
15.6 Reactions with Radical Reagents .................................................................

303

15.7 Reactions with Reducing Agents ..................................................................

303

15.9 Electrocyclic Reactions (Ground State) ........................................................

303

15.10 Photochemical Reactions ..............................................................................

305

15.11 Furyl-C-X compounds; Side-chain Properties ..............................................

305

15.12 Furan Carboxylic Acids and Esters ...............................................................

306

15.13 Oxy- and Aminofurans ...................................................................................

306

15.14 Synthesis of Furans .......................................................................................

308

Exercises for Chapter 15 ..........................................................................................

313

References ...............................................................................................................

314

16. Typical Reactivity of Indoles, Benzo[b]thiophenes,
Benzo[b]furans, Isoindoles, Benzo[c]thiophenes and
Isobenzofurans ....................................................................................... 319
17. Indoles: Reactions and Synthesis ......................................................... 324
17.1 Reactions with Electrophilic Reagents ..........................................................

325

17.2 Reactions with Oxidising Agents ...................................................................

336

17.3 Reactions with Nucleophilic Reagents (See Also Section 17.14.4) .............

337

17.4 Reactions with Bases ....................................................................................

337

17.5 Reactions of N-metallated Indoles ................................................................

338

17.6 Reactions of C-metallated Indoles ................................................................

339

17.7 Reactions with Radicals ................................................................................

341

17.8 Reactions with Reducing Agents ..................................................................

342

17.9 Reactions with Carbenes ..............................................................................

342

17.10 Electrocyclic and Photochemical Reactions .................................................

343

17.11 Alkylindoles ....................................................................................................

345

17.12 Reactions of Indolyl-C-X Compounds ...........................................................

345

17.13 Indole Carboxylic Acids .................................................................................

346

17.14 Oxyindoles .....................................................................................................

347

17.15 Aminoindoles .................................................................................................

350

17.16 Azaindoles .....................................................................................................

351

17.17 Synthesis of Indoles ......................................................................................

353

Exercises for Chapter 17 ..........................................................................................

370

References ...............................................................................................................

371

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Contents

xi

18. Benzo[b]thiophenes and Benzo[b]furans: Reactions and
Synthesis ................................................................................................. 380
18.1 Reactions with Electrophilic Reagents ..........................................................

380

18.2 Reactions with Nucleophilic Reagents ..........................................................

382

18.3 Reactions with Bases; Reactions of C-metallated Benzo[b]thiophenes
and Benzo[b]furans .......................................................................................

382

18.4 Reactions with Oxidising and Reducing Agents ...........................................

383

18.5 Electrocyclic Reactions ..................................................................................

384

18.6 Oxy- and Amino-benzothiophenes and -benzofurans ..................................

384

18.7 Synthesis of Benzo[b]thiophenes and Benzo[b]furans .................................

384

Exercises for Chapter 18 ..........................................................................................

389

References ...............................................................................................................

389

19. Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions
and Synthesis ......................................................................................... 392
19.1 Reactions with Electrophilic Reagents ..........................................................

392

19.2 Electrocyclic Reactions ..................................................................................

393

19.3 Phthalocyanines ............................................................................................

393

19.4 Synthesis of Isoindoles, Benzo[c]thiophenes, and Isobenzofurans .............

394

Exercises for Chapter 19 ..........................................................................................

397

References ...............................................................................................................

397

20. Typical Reactivity of 1,3- and 1,2-azoles .............................................. 399
21. 1,3-azoles: Imidazoles, Thiazoles, and Oxazoles: Reactions and
Synthesis ................................................................................................. 402
21.1 Reactions with Electrophilic Reagents ..........................................................

403

21.2 Reactions with Oxidising Agents ...................................................................

408

21.3 Reactions with Nucleophilic Reagents ..........................................................

408

21.4 Reactions with Bases ....................................................................................

409

21.5 Reactions of N-metallated Imidazoles ..........................................................

409

21.6 Reactions of C-metallated 1,3-azoles ...........................................................

410

21.7 Reactions with Radical Reagents .................................................................

412

21.8 Reactions with Reducing Agents ..................................................................

412

21.9 Electrocyclic Reactions ..................................................................................

412

21.10 Alkyl-1,3-azoles .............................................................................................

414

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xii

Contents
21.11 Quaternary 1,3-azolium Salts ........................................................................

414

21.12 Oxy- and Amino-1,3-azoles ...........................................................................

416

21.13 1,3-azole N-oxides .........................................................................................

418

21.14 Synthesis of 1,3-azoles .................................................................................

418

Exercises for Chapter 21 ..........................................................................................

424

References ...............................................................................................................

425

22. 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and
Synthesis ................................................................................................. 431
22.1 Reactions with Electrophilic Reagents ..........................................................

432

22.2 Reactions with Oxidising Agents ...................................................................

434

22.3 Reactions with Nucleophilic Reagents ..........................................................

434

22.4 Reactions with Bases ....................................................................................

434

22.5 Reactions of N-metallated Pyrazoles ............................................................

435

22.6 Reactions of C-metallated 1,2-azoles ...........................................................

435

22.7 Reactions with Radicals ................................................................................

436

22.8 Reactions with Reducing Agents ..................................................................

436

22.9 Electrocyclic Reactions ..................................................................................

437

22.10 Alkyl-1,2-azoles .............................................................................................

438

22.11 Quaternary 1,2-azolium Salts ........................................................................

438

22.12 Oxy- and Amino-1,2-azoles ...........................................................................

439

22.13 Synthesis of 1,2-azoles .................................................................................

440

Exercises for Chapter 22 ..........................................................................................

444

References ...............................................................................................................

445

23. Benzanellated Azoles: Reactions and Synthesis ................................. 449
23.1 Reactions with Electrophilic Reagents ..........................................................

449

23.2 Reactions with Nucleophilic Reagents ..........................................................

450

23.3 Reactions with Bases ....................................................................................

451

23.4 Reactions of C-metallated Derivatives ..........................................................

451

23.5 Reactions with Reducing Agents ..................................................................

452

23.6 Electrocyclic Reactions ..................................................................................

452

23.7 Quaternary Salts ............................................................................................

453

23.8 Oxy- and Amino-1,3-azoles ...........................................................................

453

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Contents

xiii

23.9 Synthesis .......................................................................................................

454

References ...............................................................................................................

458

24. Purines: Reactions and Synthesis ........................................................ 461
24.1 Nucleic Acids, Nucleosides, and Nucleotides ...............................................

463

24.2 Reactions with Electrophilic Reagents ..........................................................

464

24.3 Reactions with Radical Reagents .................................................................

469

24.4 Reactions with Oxidising Agents ...................................................................

469

24.5 Reactions with Reducing Agents ..................................................................

469

24.6 Reactions with Nucleophilic Reagents ..........................................................

470

24.7 Reactions with Bases ....................................................................................

472

24.8 Reactions of N-metallated Purines ................................................................

473

24.9 Reactions of C-metallated Purines ................................................................

473

24.10 Oxy- and Aminopurines .................................................................................

475

24.11 Alkylpurines ...................................................................................................

479

24.12 Purine Carboxylic Acids .................................................................................

479

24.13 Synthesis of Purines ......................................................................................

479

Exercises for Chapter 24 ..........................................................................................

485

References ...............................................................................................................

485

25. Heterocycles Containing a Ring-junction Nitrogen ............................. 489
25.1 Indolizines ......................................................................................................

489

25.2 Aza-indolizines ...............................................................................................

492

25.3 Quinoliziniums and Related Systems ...........................................................

498

25.4 Pyrrolizines and Related Systems ................................................................

499

25.5 Cyclazines .....................................................................................................

499

Exercises for chapter 25 ..........................................................................................

500

References ...............................................................................................................

501

26. Heterocycles Containing More Than Two Hetero Atoms .................... 504
26.1 Five-membered Rings ...................................................................................

504

26.2 Six-membered Rings .....................................................................................

516

26.3 Benzotriazoles ...............................................................................................

520

Exercises for Chapter 26 ..........................................................................................

522

References ...............................................................................................................

522

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xiv

Contents

27. Saturated and Partially Unsaturated Heterocyclic Compounds:
Reactions and Synthesis ....................................................................... 526
27.1 Five- and Six-membered Rings .....................................................................

527

27.2 Three-membered Rings ................................................................................

530

27.3 Four-membered Rings ..................................................................................

534

27.4 Metallation ......................................................................................................

535

27.5 Ring Synthesis ...............................................................................................

536

References ...............................................................................................................

540

28. Heterocycles at Work ............................................................................. 543
28.1 Solid Phase Reactions ..................................................................................

543

28.2 Heterocycles in the Pharmaceutical Industry: Large Scale
Heterocyclic Synthesis ..................................................................................

545

28.3 Electronic Applications ..................................................................................

546

References ...............................................................................................................

549

Appendix: Answers to Exercises ................................................................. 551
Chapter 5 ..................................................................................................................

551

Chapter 6 ..................................................................................................................

552

Chapter 8 ..................................................................................................................

552

Chapter 9 ..................................................................................................................

553

Chapter 11 ................................................................................................................

553

Chapter 13 ................................................................................................................

553

Chapter 14 ................................................................................................................

554

Chapter 15 ................................................................................................................

554

Chapter 17 ................................................................................................................

554

Chapter 18 ................................................................................................................

555

Chapter 19 ................................................................................................................

555

Chapter 21 ................................................................................................................

556

Chapter 22 ................................................................................................................

556

Chapter 24 ................................................................................................................

556

Chapter 25 ................................................................................................................

557

Chapter 26 ................................................................................................................

557

Index ............................................................................................................... 559

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Index

Individual compounds are listed by name when the text gives a ring synthesis, total synthesis, formation from another compound, or
where a particular aspect of reactivity is also noted. Metallated species are listed because of their importance in synthesis: products
derived from these intermediates are not listed. Some liberties have been taken with chemical names, with the aim of helping the
reader seeking chemical information, for example the Index gives: ‘Indole, 2-lithio-1-phenylsulfonyl-’ but also (incorrectly): ‘indole,
2-lithio-1-t-butoxycarbonyl’. Also, names emphasise the heterocyclic aspect: ‘furan, 2-ethoxycarbonyl’ is used rather than ‘ethyl
furan-2-carboxylate’. The (inorganic) counteranions to heterocyclic cations are omitted: ‘Pyrylium’ not ‘Pyrylium perchlorate’;
pyridinium salts are listed as ‘Pyridiniums’ etc.

Index terms

Links

A
Acenocoumarol

170

Acetaldehyde enolate

535

Acetazolamide

504

Acidity of side-chain alkyl

38

Acidity, pyrroles, azoles, etc.

26

Acyclovir

463

Addition of nucleophile, ring opening/ring closure

125

Adenine

461

ring opening

468

ring synthesis

483

of 2-methyl-

223

synthesis from 8-chloropurine

471

synthesis from uric acid

476

Adenine/thymine, hydrogen bonding

464

Adenosine

462

total synthesis

484

Adenosine-5’-diphosphate

462

Adenosine-5’-monophosphate

462

Adenosine-5’-triphosphate

462

ADP, see Adenosine-5’-diphosphate
Alcohol dehydrogenase

415

Alkaloids, biosynthesis

528

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559


560

Index terms

Links

N-Alkylation, see also under individual heterocycles

16

Allene, 1-bromo-1-methoxycarbonyl-

439

Allopurinol

463

Alosetron

325

Alprazolam

504

Amidines, in ring synthesis of pyrimidines

218

Amlodipine

72

AMP, see Adenosine-5’-monophosphate
Angelica lactone

307

Anomeric effect

529

ANRORC

125

Anthocyanidins

173

Anthocyanins

170

Antipyrine

439

Apigenin, total synthesis

185

Aristeromycin, total synthesis

483

Aromatic resonance energy

2

Anthranil see 2,1-Benzisoxazole
Antipyrine
4-Vilsmeier

439

Ascorbic acid

296

Aspergillic acid

195

Atorvasatin

238

ATP, see Adenosine-5’-triphosphate
Aureusin

380

Aurones

380

1-Azabicyclo[1.1.0]butane
ring opening to an azetidine

538

ring synthesis

538

2-Azabicyclo[2.2.0]hexadiene

87

2-Azabicyclo[2.2.0]hexenone

87

5-Azacytidine

504

4-Azaindole
nomenclature and basicity

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351

173


561

Index terms

Links

4-Azaindole (Continued)
5-methoxy, Vilsmeier formylation

369

ring synthesis
of 5-methoxy-

369

5-Azaindole, ring synthesis

82

nomenclature and basicity

351

4-chloro-, nucleophilic substitution ring synthesis
of 1-t-butoxycarbonyl-2-methyl-

369

6-Azaindole
nomenclature and basicity
bio-conversion to 6-aza-tryptophan
cyclohexano[h,i]-, ring synthesis

351
47
251

ring synthesis
of 1-(4-methylphenylsulfonyl)-5-ethoxycarbonyl-

370

of 2-ethoxycarbonyl-5-methoxy-

262

7-Azaindole
nomenclature and basicity

351

nitration

352

acetylation

352

bromination

352

Mannich reaction

352

N-methylation

352

4-chloro-, nucleophilic substitution

352

conversion to 4-amino-1-phenyl-5-azaindole

352

2-lithio-1-phenylsulfonyl-

353

2-trimethylstannyl-1-phenylsulfonyl-, Pd(0) coupling

353

ring synthesis
of 3-triethylsilyl-3-(2-hydroxyethyl)Azete

369
534

3,4-dihydro-

534

Azetidines

534

ring openings by nucleophilic attack

535

ring synthesis

536

Aziridine

530

basicity

530

rate of N-inversion

530

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538


562

Index terms

Links

Aziridines
ring opening with nucleophiles
to generate 1,3-dipoles
ring synthesis

532
532
537

of cis- and trans-1-(4-methylphenylsulfonyl)-2-(4-methylphenyl)-2dimethylaminocarbonyl-

537

of cis-1-(4-methylphenylsulfonyl)-2-methyl-3-phenyl-

537

of 2,2-spiro(cyclohexane)

537

of l-triphenylmethyl-2-benzyloxycarbonyl

537

Azirine

530

Azirines
removal of N – conversion to alkenes

532

ring opening with nucleophiles

532

ring synthesis
of 2-methyl-3-methoxycarbonyl-

537

Azlactones, ring synthesis of pyrroles

261

1,2-Azoles
electrophilic addition at N

399

432

electrophilic substitution

399

433

relative reactivity
regioselectivity

20
400

lithiation

400

434

nucleophilic substitution, regioselectivity

399

434

physical properties

431

structures

6

1,3-Azoles
alkyl-, deprotonation at side-chain

400

aza-dienes in Diels-Alder additions

399

electrophilic addition at N

399

403

399

406

electrophilic substitution
regioselectivity
relative reactivity
lithiation

20
31

nucleophilic substitution, regioselectivity

400

physical properties

402

structures

6
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410


563

Index terms

Links

AZT

195

Azulene, total synthesis

99

B
Baker-Venkataraman rearrangement

182

Banminth

273

Barbiturates

206

Barbituric acid

206

5-allyl-, replacement of O with halide

211

reaction with phosphoryl chloride

192

ring synthesis
of 5,5-di(allyl)-

220

Bartoli synthesis
Barton’s method for generation of radicals
Barton-Zard synthesis

24
259

Basicity, see also under individual
heterocycles

16

BEDT-TTF

547

Benzaldehyde, 4-dimethylamino-, see Ehrlich reaction
Benzene
aromaticity

1

orbitals

2

reactivity

1

structure

1

17

Benzimidazoles
bromination

450

2-halo-, nucleophilic displacements

450

2-iodo-1-benzyl-6-(2-dimethylaminoethyl)-, Pd(0) coupling

451

2-lithio-1-benzyl-6-(2-dimethylaminoethyl)-

451

numbering and nomenclature

449

ring synthesis

454

of 1-benzyl-5-methoxy-, via solid phase synthesis

544

of 2-ethyl-

454

of 2-ohexyl

456

of 2-thiol

455

This page has been reformatted by Knovel to provide easier navigation.

451

517


564

Index terms

Links

Benzimidazoles (Continued)
2-thiol, conversion to 2-bromo-

450

2-trimethylsilyl-1-methyl-, ipso acylation

450

1,2-benzisothiazole
nomenclature/numbering

449

ring synthesis
of 3-(pyrrolidin-1-yl)of 7-formyl-3-n-butyl- S,S-dioxide

456
458

2,1-Benzisothiazole
nomenclature/numbering

449

ring synthesis

458

of 3-ethyl-5-methyl-

457

of 3-methyl-

457

2,1-Benzisothiazoliums
as orthoaminoaraldehyde equivalents

453

ring cleavage

453

1,2-Benzisoxazole
nomenclature/numbering

449

ring synthesis
of 3-phenyl-

456

of 3-ethyl-

457

2,1-Benzisoxazole
nomenclature/numbering

449

ring synthesis
of 7-carboxy-3-methoxy-

458

of 3-styryl-

458

of 3-(2-pyridyl)-

458

of 5-chloro-

458

Benzo[l,2-b:4,3-b’]dipyrrole
ring synthesis

264

dihydro-, ring synthesis

257

Benzo[b]furan, see Benzofuran
Benzo[c]furan, see Isobenzofuran
3,4-Benzofuran, see Isobenzofuran

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565

Index terms

Links

Benzofuran
base-catalysed ring opening

382

C-deprotonation, regioselectivity

322

382

electrophilic substitution, regioselectivity

322

380

halogenation

380

2-lithio-

382

3-lithio-carboxylation ring opening

382

nitration

380

nomenclature/numbering

380

reduction

383

ring synthesis

386

Vilsmeier formylation

381

Benzofurans
amino-

384

2-lithio-

382

ring synthesis
of 4-acetoxy-6-i-propoxy-5-methyl-2-trimethylsilyl-

388

of 2-acetyl-

387

of 3-azidomethyl-

385

of 7-bromo-2-methyl-

386

of 4-r-butydimethylsilyloxy-6,7-bis(methoxycarbonyl)-

388

of 2,3-dihydro-2-iodomethyl-

389

of 6-hydroxy-3-carboxymethyl-

386

of 2-methyl-

387

of 2-tri-i-propylsilyl-3-phenyl-

387

of 2,3,4,5,7-pentamethyl-

385

oxy-

384

2H-l-Benzopyran-2-one, see Coumarin
1H-2-Benzopyran-1-one, see Isocoumarin
4H-Benzopyran-4-one, see Chromone
3,4-Benzopyrrole, see Isoindole
Benzo[b]pyrylium, see 1-Benzopyrylium
Benzo[c]pyrylium, see 2-Benzopyrylium
Benzopyryliums, reaction with ammonia

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149


566

Index terms

Links

1-Benzopyrylium
ring synthesis
of 7-hydroxy-2,4-dimethyl-

180

of 7-hydroxy-2,4-diphenyl-

180

of 4-hydroxy-3-methyl-

182

of 8-methyl-

180

of 6-methyl-2-phenyl-

180

2-(4-methoxyphenyl)-, from coumarin

176

nomenclature/numbering

170

4-silyloxy, enol ether addition at C-2

172

2-Benzopyryliums
methyl-, reaction at methyl

173

nomenclature/numbering

170

a 3-oxido-, as 1,3-dipole in intramolecular cycloaddition

178

reaction with ammonia

149

172

ring synthesis
of 6,8-dimethoxy-1,3-dimethyl-

184

Benzothiazole
radical substitution

24

Benzothiazoles
2-lithio-

452

2-methylthio-, nucleophilic displacement

451

nomenclature/numbering

449

ring synthesis

454

of 2-(benzothiazol-2-ylamino)-

455

of 2-t-butyl-7-methyl-

456

of 2-(3-fluorophenyl)-

455

of 2-methylamino-

455

Reissert adduct

453

2-sulfonamide, nucleophilic displacement; amine protection

451

2-trimethylsilylipso hydroxyalkylation
ipso displacement with phosphorus
a 2-vinyl, as diene in cycloaddition

36
452
453

Benzothiazoliums
2-(1-hydroxyprop-1-yl)-3-methyl-, nucleophilic addition
This page has been reformatted by Knovel to provide easier navigation.

453

453


567

Index terms

Links

Benzothiazoliums (Continued)
ring synthesis
of 2-c-opropyl-3-methyl-

455

Benzothiophene
S-alkylation

381

C-deprotonation, regioselectivity

322

electrophilic substitution, regioselectivity

322

halogenation

381

nitration

380

nomenclature/numbering

380

S-oxidation

382

reduction

383

380

Benzothiophenes
amino-

384

3-azido-, with triphenylphosphine

384

bio-2,3-hydroxylation
2-t-butoxy-

46
384

2,3-dibromometal-Hal exchange, regioselectivity

383

nucleophilic substitution

382

2-dimethylamino-

384

S,S-dioxide, cycloadditions to the 2,3-bond

382

4-iodo-2-methoxycarbonyl-, ring synthesis

387

lithiation

31

2-lithio-

383

2-lithio-3-bromo-

383

3-lithio-, ring cleavage
3-lithio-2-allyl-

31
383

3-lithio-, ring opening
2-methyl-, ring synthesis
5-methyl, bio-2,3-dihydroxylation
oxy-

31
386
46
384

a 2,3-quinodimethane
ring synthesis

60
385

of 4- and 6-chloro-3-one

385

of 7-ethoxycarbonyl-4-phenyl-

388

This page has been reformatted by Knovel to provide easier navigation.

382

383


568

Index terms

Links

Benzothiophenes (Continued)
of 4-iodo-2-methoxycarbonyl-

387

of 2-methyl-

386

3,4-Benzothiophene, see Benzo[c]thiophene
Benzo[b]thiophene, see Benzothiophene
Benzo[c]thiophene
diene in Diels-Alder additions

322

nomenclature/numbering

392

synthesis from 1,3-dihydrobenzo[c]thiophene ;S-oxide

395

Benzo[c]thiophenes
ring synthesis
of 1,3-diphenyl-

395

of 1,3,4,7-tetramethyl-

395

Benzothiopheniums

381

Benzotriazole
N-alkylation

520

521

as leaving group

520

521

a 1-amino-, oxidation to a benzyne

521

1-hydroxymethyl-, as alkylating agent

520

7-lithio-1-t-butoxycarbonyl-

521

N-substituent lithiation

520

tris(benzotriazol-1-yl)methane, acidity

521

Benzoxazole
2-chloro-, nucleophilic displacement

451

2-lithio-

452

nomenclature/numbering

449

2-phenoxy-, nucleophilic displacement

451

ring synthesis

454

of 2-phenyl-

455

of 2-ethyl-

455

2-zincio-

452

Biotin

273

Bischler synthesis

360

Bischler-Napieralski synthesis

137

Bond fixation

2

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569

Index terms

Links

Boron reagents

34

Boronic acids
reactions

35

synthesis

34

Pd(0) couplings

44

Brassinin

325

Bromination, see under individual heterocycles
Butenolides

306

from furans

305

C
Caffeine

462

CarbaBVDU, total synthesis

223

Carbazole, ring synthesis

59

Carbazole
1,2,3,4-tetrahydro-, formation from 3-(4-hydroxybutyl)-indole
ring synthesis

330
59

of 2,2-dimethyl-4-oxo-

361

of 9-methyl-

355

4-oxo-

368

1-oxo-

329

2-oxo-1,2,3,4,4a,9a-hexahydro-4,4,4a,9-tetramethyl-

332

Carbenes
stable, from 1,3,4,5tetraphenylimidazolium

416

from 1,3-bis(adamantyl)-imidazolium

416

Carbocyclic bromovinyldeoxyuridine, see CarbaBVDU

α-Carboline
9-acetyl-3-ethoxycarbonyl-, ring synthesis

β-Carboline

205
351

3,4-dihydro-l-ethyl-

329

3-ethoxycarbonyl-l-methyl-

330

1,2,3,4-tetrahydro-1,1-dimethyl-

320

1-benzyl-

320

1-phenyl-

334

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570

Index terms

Links

γ-Carboline
ring synthesis

362

of cyclohexano[k,l]

521

108

δ-Carboline
1,2,3,4-tetrahydro-1,4-ethano-, ring synthesis
Carbonyl diimidazole

362
405

Carbostyril, see 2-Quinolone
CC-1065

264

Celecoxib

431

Cephalosporins

526

Chalcones

180

Chelidonic acid, see 4-Pyrone-2,6-dicarboxylic acid
Chemiluminescence

195

Chichibabin reaction

79

Chichibabin synthesis of pyridines

109

Chichibabin synthesis of indolizines

491

Chlorination, see under individual heterocycles
Chlorophyll-α

237

Chloroquine

121

total synthesis

141

2H-Chromenes

172

4H-Chromenes

172

Chromone
bromination

174

epoxidation

174

Mannich reaction

174

nitration

174

nomenclature/numbering

170

protonation at carbonyl O

173

reaction with diethylamine

175

with dimethyldioxirane

174

Chromones
3-bromo-

183

Pd coupling

176

3-ethyl-2,7-dimethyl-, condensation at methyl
This page has been reformatted by Knovel to provide easier navigation.

178

535


571

Index terms

Links

Chromones (Continued)
3-iodo-, reaction with imidazole

175

2-methyl-, reaction with hydroxide

175

3-methoxycarbonyl-, as dienophile in Diels-Alder

177

2-(4-methoxyphenyl)-, iodination

174

ring synthesis
of 3-bromo

183

of 2-ethyl

182

of 2-dimethylamino-3-methyl-

183

of 3-ethoxycarbonyl-2-ethyl-

183

of 2-c-hexyl-8-methoxycarbonyl-3-methyl-

182

of 3-methyl-

182

of 2-methoxymethyl-

183

of 2-n-pentyl-

183

of 2-phenyl-

182

of 2-tetrahydropyran-2-ylmethylChromylium, see 1-benzopyrylium
Chuangxinmycin, total synthesis

369

Cimetidine

403

Cinnoline, nomenclature/numbering

194

Ciprofloxacin

121

Coelenterazine, total synthesis

223

Combes synthesis

133

Conrad-Limpach-Knorr synthesis

133

Corrin

238

Coumalic acid
decarboxylation

162

ring synthesis

162

Coumaranone

384

Coumaric acid

175

Coumarin
addition of bromine

174

alkylation at carbonyl O

173

2-arylation

176

chloromethylation

174

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572

Index terms

Links

Coumarin (Continued)
in cycloadditions

177

nomenclature/numbering

170

hv reactions
addition to cyclopentene

178

dimerisation

178

reaction with hydroxide, ring opening

175

with methyl magnesium iodide

176

reduction

177

Coumarinic acid

175

Coumarins
4-bromo-, Pd(0) coupling

170

4,7-dihydroxy-

181

a 4-methyl-, alkylation at side-chain

178

4-propanoic acid, acid-catalysed ring closure

171

ring synthesis

181

of a 4-c-oalkenyl-

181

of 6-bromo-4-hydroxy-3-methyl-

182

of 3-ethoxycarbonyl-

181

of 7-hydroxy-

181

of 7-hydroxy-4-methyl-

180

Coupling constants

11

Coupling reactions (Pd-catalysed), mechanism

40

Covalent hydrates

497

Cyanin chloride

173

2-Cyanoglycinamide; ring synthesis of pteridines

225

5-Cyano-1,2,6,7,12,12b-hexahydroindolo[2,3-a]quinolizine, total synthesis

443

Cyanuric acid

516

Cyclazines
nomenclature/numbering

500

ring synthesis

500

(3.2.2)Cyclazine, aromaticity

500

(3.3.3)Cyclazine, aromaticity

500

Cyclic AMP

462

Cyclohexene epoxide

531

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44


573

Index terms

Links

Cyclohexene oxide, see cyclohexene epoxide
Cyclopentadienyl anion
aromaticity

5

canonical structures

5

Cypridina luciferin

195

Cystothiazole A

402

Cytidine

195

Cytochromes

238

Cytosine

206

synthesis

199

D
Davicil

72

DDI, see Dideoxyinosine
Deboronation

37

π-Deficient heterocycle

3

Dehydracetic acid

165

Dehydrogenating agents; pyrylium ring synthesis

160

Dendrodoine

504

N-Deprotonation see also under individual
heterocycles

26

Dialkylaminoalkylation, see Mannich reaction under individual heterocycles
Diazines
alkyl-, deprotonation at alkyl

215

aminobasicity

214

diazotisation

214

electrophilic substitution

214

protonation

214

electrophilic addition at N

190

halorelative reactivity towards nucleophiles
relative reactivity in Pd(0) couplings

199
44

lithiation

201

nucleophilic additions

190

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463


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