Quinoxalines, Volume 61, Spplement 2

Desmond J. Brown is Professor of Chemistry at The Australian National University.

Chapter 1 Primary Syntheses 1

1.1 From a Single Benzene Substrate 1

1.1.1 By Formation of the N1,C8a Bond 1

1.1.2 By Formation of the N1,C2 Bond 4

1.1.2.1 Cyclization of o-(Ethylamino)aniline Derivatives 4

1.1.2.2 Direct Cyclization of o-(Ethylamino)nitrobenzene Derivatives 6

1.1.2.3 Reductive Cyclization of o-(Ethylamino)nitrobenzene Derivatives 8

1.1.3 By Formation of the C2,C3 Bond 12

1.2 From a Benzene Substrate with an Ancillary Synthon 13

1.2.1 When the Synthon Supplies N1 of the Quinoxaline 13

1.2.2 When the Synthon Supplies C2 of the Quinoxaline 14

1.2.3 When the Synthon Supplies C2 + C3 of the Quinoxaline 16

1.2.3.1 Using a Dialdehyde (Glyoxal) or Related Synthon 16

1.2.3.2 Using an Aldehydo Ketone or Related Synthon 18

1.2.3.3 Using an Aldehydo Acid or Related Synthon 22

1.2.3.4 Using an Aldehydo Ester or Related Synthon 23

1.2.3.5 Using an Aldehydo Amide, Nitrile, Acyl Halide, or Related Synthon 24

1.2.3.6 Using a Diketone or Related Synthon 24

1.2.3.7 Using a Keto Acid or Related Synthon 30

1.2.3.8 Using a Keto Ester or Related Synthon 31

1.2.3.9 Using a Keto Amide, Nitrile, Acyl Halide, or Related Synthon 34

1.2.3.10 Using a Diacid (Oxalic Acid) as Synthon 35

1.2.3.11 Using a Diester (a Dialkyl Oxalate) or Related Synthon 36

1.2.3.12 Using an Estero Amide, Nitrile, Acyl Halide, or Related Synthon 38

1.2.3.13 Using a Diamide (Oxamide), Amido Nitrile, or Related Synthon 40

1.2.3.14 Using a Diacyl Dihalide (Oxalyl Halide) or Related Synthon 40

1.2.4 When the Synthon Supplies N1 + C2 + C3 of the Quinoxaline 42

1.2.5 When the Synthon Supplies N1 + C2 + C3 + N4 of the Quinoxaline 42

1.3 From a Benzene Substrate with Two or More Synthons 44     

1.4 From a Pyrazine Substrate with or without Synthon(s) 45

1.5 From Other Heteromonocyclic Substrates/Synthons 46

1.5.1 Azirines as Substrates/Synthons 47

1.5.2 1,2,3-Dithiazol-1-iums as Substrates/Synthons 47

1.5.3 Furans as Substrates/Synthons 48

1.5.4 Isothiazoles as Substrates/Synthons 49

1.5.5 Isoxazoles as Substrates/Synthons 50

1.5.6 Oxazoles as Substrates/Synthons 51

1.5.7 Oxirenes as Substrates/Synthons 51

1.5.8 Pyrans as Substrates/Synthons 53

1.5.9 Pyridazines as Substrates/Synthons 53

1.5.10 Pyridines as Substrates/Synthons 54

1.5.11 Pyrimidines as Substrates/Synthons 54

1.5.12 Pyrroles as Substrates/Synthons 55

1.5.13 Thiophenes as Substrates/Synthons 55

1.5.14 1,2,4-Triazines as Substrates/Synthons 56

1.5.15 1,2,3-Triazoles as Substrates/Synthons 56

1.6 From Heterobicyclic Substrates/Synthons 57

1.6.1 7-Azabicyclo[4.1.0]heptanes as Substrates/Synthons 57

1.6.2 Benzimidazoles as Substrates/Synthons 57

1.6.3 1,4-Benzodiazepines as Substrates/Synthons 59

1.6.4 1,5-Benzodiazepines as Substrates/Synthons 59

1.6.5 1-Benzopyrans (Chromenes) as Substrates/Synthons 61

1.6.6 2,1,3-Benzoselena(or thia)diazoles as Substrates/Synthons 61

1.6.7 2,1,3-Benzoxadiazoles as Substrates/Synthons 62

1.6.8 Cycloheptapyrazines as Substrates/Synthons 68

1.6.9 Indoles as Substrates/Synthons 68

1.6.10 Pyrrolo[3,4-b]pyrazines as Substrates/Synthons 69

1.7 From Heteropolycyclic Substrates/Synthons 70

1.7.1 Azeto- or Azirino[1,2-a]quinoxalines as Substrates/Synthons 70

1.7.2 Benz[g]indoles as Substrates/Synthons 71

1.7.3 Benzo[3,4]cyclobuta[1,2-b]quinoxalines as Substrates/Synthons 71

1.7.4 Benzo[g]pteridines as Substrates/Synthons 71

1.7.5 [1]Benzopyrano[2,3-b]quinoxalines as Substrates/Synthons 73

1.7.6 [1]Benzothiopyrano[4,3-b]pyrroles as Substrates/Synthons 73

1.7.7 Cyclobuta[b]quinoxalines as Substrates/Synthons 73

1.7.8 1,3-Dithiolo[4,5-b]quinoxalines as Substrates/Synthons 74

1.7.9 1,4-Ethanoquinoxalines as Substrates/Synthons 74

1.7.10 Furo[2,3-b]quinoxalines as Substrates/Synthons 75

1.7.11 Furo[3,4-b]quinoxalines as Substrates/Synthons 76

1.7.12 Indeno[1,2-b]pyrroles as Substrates/Synthons 76

1.7.13 Isoxazolo[2,3-d][1,4]benzodiazepines as Substrates/Synthons 77

1.7.14 Isoxazolo[2,3-a]quinoxalines as Substrates/Synthons 77

1.7.15 [1,3,4]Oxadiazino[5,6-b]quinoxalines as Substrates/Synthons 78

1.7.16 [1,2,4]Oxadiazolo[2,3-a]quinoxalines as Substrates/Synthons 78

1.7.17 [1,2,5]Oxadiazolo[3,4-f]quinoxalines as Substrates/Synthons 79

1.7.18 Phenazines as Substrates/Synthons 79

1.7.19 Pyrazolo[3,4-b]quinoxalines as Substrates/Synthons 79

1.7.20 Pyridazino[4,5-b]quinoxalines as Substrates/Synthons 80

1.7.21 Pyrrolo[3,4-b]quinoxalines as Substrates/Synthons 81

1.7.22 Quinoxalino[2,3-b]quinoxalines as Substrates/Synthons 82

1.7.23 Thiazolo[2,3-b]benzothiazoliums as Substrates/Synthons 82

1.7.24 Thiazolo[3,2-a]quinoxaliniums as Substrates/Synthons 82

1.8 From Spiro Heterocyclic Substrates 83

1.9 Glance Index to Typical Quinoxaline Derivatives Available by Primary Syntheses 84

Chapter 2 Quinoxaline, Alkylquinoxalines, And Arylquinoxalines 93

2.1 Quinoxaline 93

2.1.1 Preparation of Quinoxaline 93

2.1.2 Properties of Quinoxaline 94

2.1.3 Reactions of Quinoxaline 95

2.2 Alkyl- and Arylquinoxalines 100

2.2.1 Preparation of C-Alkyl- and C-Arylquinoxalines 101

2.2.1.1 By Direct Alkylation or Arylation 101

2.2.1.2 By Alkanelysis or Arenelysis of Halogenoquinoxalines 102

2.2.1.3 From C-Formyl-, C-Aroyl-, C-Cyano-, or Oxoquinoxalines 106

2.2.1.4 By Interconversion of Alkyl or Aryl Substituents 108

2.2.1.5 By Elimination of Functionality from Substituted-Alkyl Substituents 113

2.2.2 Preparation of N-Alkyl or N-Aryl Derivatives of Hydroquinoxalines 114

2.2.3 Properties of Alkyl- and Arylquinoxalines 115

2.2.4 Reactions of Alkyl- and Arylquinoxalines 117

2.3 N-Alkylquinoxalinium Salts 129

2.3.1 Preparation of N-Alkylquinoxalinium Salts 129

2.3.2 Reactions of N-Alkylquinoxalinium Salts 131

Chapter 3 Halogenoquinoxalines 133

3.1 Preparation of Nuclear Halogenoquinoxalines 133

3.1.1 Nuclear Halogenoquinoxalines from Quinoxalinones 133

3.1.2 Nuclear Halogenoquinoxalines by Direct Halogenation 139

3.1.3 Nuclear Halogenoquinoxalines from Quinoxalinamines 141

3.1.4 Nuclear Halogenoquinoxalines by Transhalogenation 142

3.1.5 Nuclear Halogenoquinoxalines from Miscellaneous Substrates 144

3.2 Reactions of Nuclear Halogenoquinoxalines 146

3.2.1 Aminolysis of Nuclear Halogenoquinoxalines 146

3.2.2 Hydrolysis, Alcoholysis, or Phenolysis of Nuclear Halogenoquinoxalines 156

3.2.3 Thiolysis, Alkanethiolysis, Arenethiolysis, or Arenesulfinolysis of Nuclear Halogenoquinoxalines 161

3.2.4 Azidolysis of Nuclear Halogenoquinoxalines 164

3.2.5 Cyanolysis of Nuclear Halogenoquinoxalines 166

3.2.6 Hydrogenolysis of Nuclear Halogenoquinoxalines 167

3.2.7 Other Displacement Reactions of Nuclear Halogenoquinoxalines 168

3.2.8 Cyclization Reactions of Nuclear Halogenoquinoxalines 170

3.3 Preparation of Extranuclear Halogenoquinoxalines 174

3.4 Reactions of Extranuclear Halogenoquinoxalines 175

3.4.1 Aminolysis of Extranuclear Halogenoquinoxalines 175

3.4.2 Hydrolysis, Alcoholysis, or Phenolysis of Extranuclear Halogenoquinoxalines 179

3.4.3 Acyloxy Derivatives from Extranuclear Halogenoquinoxalines 181

3.4.4 Thiolysis, Alkanethiolysis, Arenethiolysis, or Arenesulfinolysis of Extranuclear Halogenoquinoxalines 183

3.4.5 Other Displacement Reactions of Extranuclear Halogenoquinoxalines 184

3.4.6 Cyclization Reactions of Extranuclear Halogenoquinoxalines 186

Chapter 4 Oxyquinoxalines 189

4.1 Tautomeric Quinoxalinones 189

4.1.1 Preparation of Tautomeric Quinoxalinones 190

4.1.2 Reactions of Tautomeric Quinoxalinones 194

4.1.2.1 Conversion into Quinoxalinethiones 195

4.1.2.2 Conversion into O- and/or N-Alkylated Derivatives 195

4.1.2.3 Miscellaneous Reactions 200

4.2 Quinoxalinequinones 206

4.2.1 Preparation of Quinoxalinequinones 206

4.2.2 Reactions of Quinoxalinequinones 208

4.3 Extranuclear Hydroxyquinoxalines 211

4.3.1 Preparation of Extranuclear Hydroxyquinoxalines 212

4.3.2 Reactions of Extranuclear Hydroxyquinoxalines 215

4.4 Alkoxy- and Aryloxyquinoxalines 219

4.4.1 Preparation of Alkoxy- and Aryloxyquinoxalines 219

4.4.2 Reactions of Alkoxy- and Aryloxyquinoxalines 221

4.5 Nontautomeric Quinoxalinones 223

4.5.1 Preparation of Nontautomeric Quinoxalinones 223

4.5.2 Reactions of Nontautomeric Quinoxalinones 224

4.6 Quinoxaline N-Oxides 225

4.6.1 Preparation of Quinoxaline N-Oxides 226

4.6.2 Reactions of Quinoxaline N-Oxides 230

4.6.2.1 Deoxygenation 230

4.6.2.2 Deoxidative C-Substitutions 235

4.6.2.3 Other Reactions 237

Chapter 5 Thioquinoxalines 241

5.1 Quinoxalinethiones and Quinoxalinethiols 241

5.1.1 Preparation of Quinoxalinethiones and Quinoxalinethiols 241

5.1.2 Reactions of Quinoxalinethiones and Quinoxalinethiols 242

5.2 Alkylthioquinoxalines and Diquinoxalinyl Sulfides 246

5.2.1 Preparation of Alkylthioquinoxalines 246

5.2.2 Reactions of Alkylthioquinoxalines 248

5.3 Diquinoxalinyl Disulfides and Quinoxalinesulfonic Acid Derivatives 250

5.4 Quinoxaline Sulfoxides and Sulfones 251

Chapter 6 Nitro-, Amino-, and Related Quinoxalines 255

6.1 Nitroquinoxalines 255

6.1.1 Preparation of Nitroquinoxalines 255

6.1.1.1 By Direct Nitration 255

6.1.1.2 From Dimethylsulfimidoquinoxalines 260

6.1.2 Reactions of Nitroquinoxalines 260

6.1.2.1 Reduction to Quinoxalinamines 260

6.1.2.2 Displacement Reactions 265

6.2 Nitrosoquinoxalines 267

6.3 Regular Aminoquinoxalines 269

6.3.1 Preparation of Regular Aminoquinoxalines 269

6.3.2 Reactions of Regular Aminoquinoxalines 278

6.3.2.1 N-Acylation of Aminoquinoxalines or Reduced Quinoxalines 279

6.3.2.2 N-Alkylation or Alkylidenation of Aminoquinoxalines 283

6.3.2.3 Reactions Involving Initial Diazotization of Aminoquinoxalines 286

6.3.2.4 Miscellaneous Transformations of Aminoquinoxalines 288

6.3.2.5 Cyclization of Aminoquinoxalines 291

6.4 Hydrazino- and Hydrazonoquinoxalines 296

6.4.1 Preparation of Hydrazino- and Hydrazonoquinoxalines 297

6.4.2 Reactions of Hydrazino- and Hydrazonoquinoxalines 299

6.4.2.1 Noncyclization Reactions 300

6.4.2.2 Cyclization Reactions 305

6.5 Azidoquinoxalines 312

6.6 Arylazoquinoxalines 314

Chapter 7 Quinoxalinecarboxylic Acids And Related Derivatives 317

7.1 Quinoxalinecarboxylic Acids and Anhydrides 317

7.1.1 Preparation of Quinoxalinecarboxylic Acids 317

7.1.2 Reactions of Quinoxalinecarboxylic Acids 322

7.2 Quinoxalinecarboxylic Esters 327

7.2.1 Preparation of Quinoxalinecarboxylic Esters 327

7.2.2 Reactions of Quinoxalinecarboxylic Esters 329

7.3 Quinoxalinecarbonyl Halides 333

7.4 Quinoxalinecarboxamides and Related Derivatives 334

7.4.1 Preparation of Quinoxalinecarboxamides and the Like 335

7.4.2 Reactions of Quinoxalinecarboxamides and the Like 337

7.5 Quinoxalinecarbonitriles 342

7.5.1 Preparation of Quinoxalinecarbonitriles 342

7.5.2 Reactions of Quinoxalinecarbonitriles 343

7.6 Quinoxalinecarbaldehydes 345

7.6.1 Preparation of Quinoxalinecarbaldehydes 346

7.6.2 Reactions of Quinoxalinecarbaldehydes 348

7.7 Quinoxaline Ketones 352

7.7.1 Preparation of Quinoxaline Ketones 352

7.7.2 Reactions of Quinoxaline Ketones 353

7.8 Quinoxaline Cyanates, Isocyanates, Thiocyanates, Isothiocyanates, and Nitrones 356

Appendix: Table of Simple Quinoxalines 359

References 437

Index 471