Nitroalkanes Synthesis, Reactivity, and Applications

Discover a comprehensive exploration of recent progress in the preparation of nitroalkanes from two leading voices in the field

Nitroalkanes: Synthesis, Reactivity, and Applications delivers a thorough summary of the importance of nitroalkanes in organic synthesis. The book covers their preparation, transformation into other functional groups, like carbonyls and amines, and their use in the formation of single carbon-carbon or double carbon-carbon bonds. The distinguished authors have included chapters on acyclic and cyclic alpha-nitro ketones as well as the synthesis of cyclopropanes and spiro ketals.

The book provides treatments of the application of nitroalkanes for the synthesis of important heterocycles, poly-functionalized structures, natural products, and compounds of biological and pharmaceutical interest. A one-stop resource in a topic that hasn???t been fully addressed by any other book in decades, this book covers the most important synthetic routes toward nitroalkanes.

Readers will also benefit from the inclusion of:

Perfect for organic chemists, natural products chemists, and catalytic chemists, Nitroalkanes: Synthesis, Reactivity, and Applications will also earn a place in the libraries of medicinal chemists seeking a one-stop resource for the most recent developments in the preparation of nitroalkanes, their functionalization, and their applications.

About the Authors xiii

Acknowledgments xv

Introduction xvii

List of Abbreviations xix

1 Synthesis of Nitroalkanes 1

1.1 Synthesis of Nitroalkanes 1

1.1.1 Displacement of Alkyl Halides 1

1.2 Nitration of Mesylates and Tosylates 4

1.3 Oxidation of Nitrogen Derivatives 5

1.3.1 Oxidation of Amines 5

1.3.2 Oxidation of Oximes 7

1.3.3 Oxidation of Azides 8

1.4 Reduction of Conjugate Nitroalkenes 8

1.4.1 Reduction of Nitroalkenes into Nitroalkanes 8

1.4.2 Stereoselective Reduction of Conjugated Nitroalkenes 10

1.4.3 Aldehyde Reductive Nitromethylation 10

1.5 Nitration of Alkanes 11

1.6 Metal-Catalyzed Alkylation or Arylation of Nitroalkanes 11

1.6.1 Nitroalkylation of Aryl Halides 12

1.6.2 Nitroalkylation of Allylic Esters 13

1.6.3 Nitroalkylation of Allylic Alcohols 13

1.6.4 Two-Carbon Homologation of Vinyl Triflates and Bromides 15

References 16

2 Reduction of the Nitro Group into Amines 19

2.1 Representative Synthetic Applications of Nitroalkane Reductions 24

2.1.1 Reduction of Nitroalkanes Obtained via Nitroaldol Reaction 24

2.1.2 Reduction of Nitroalkanes Obtained via Michael Reaction 26

References 28

3 Nitro Group to Carbonyl (Nef Reaction) 31

3.1 Nef Reaction under Oxidative Conditions 31

3.1.1 Method Ox1 31

3.1.2 Method Ox2 31

3.1.3 Method Ox3 32

3.1.4 Method Ox4 33

3.1.5 Method Ox5 34

3.1.6 Method Ox6 34

3.1.7 Method Ox7 34

3.1.8 Method Ox8 35

3.1.9 Method Ox9 36

3.1.10 Method Ox10 37

3.1.11 Method Ox11 37

3.1.12 Method Ox12 38

3.1.13 Method Ox13 38

3.1.14 Method Ox14 38

3.1.15 Method Ox15 39

3.1.16 Method Ox16 40

3.1.17 Method Ox17 40

3.2 Nef Reaction Under Reductive Conditions 41

3.2.1 Method Red1 41

3.2.2 Method Red2 42

3.2.3 Method Red3 43

3.2.4 Method Red4 43

3.3 Nef Reaction Under Basic Conditions 44

3.3.1 Method Base1 44

3.3.2 Method Base2 45

3.4 Other Methods for the Nef Reaction 46

3.4.1 Method by NaNO₂ 46

3.4.2 Method by Me₃SiCl 47

3.4.3 Method by SiO₂/TBD 48

3.5 Synthetic Applications of the Nef Reaction (Representative Examples) 49

3.5.1 Solvolytic Methods 49

3.5.2 Oxidative Methods 50

3.5.3 Reductive Methods 52

3.5.4 Basic Methods 54

3.5.5 NaNO₂ Methods 55

References 57

4 Nitroaldol (Henry) Reaction 59

4.1 General Catalysts and Promoters 60

4.1.1 Heterogeneous Catalysts and Promoters 60

4.1.2 Green Solvents 66

4.1.2.1 Nitroaldol Reaction inWater 67

4.1.2.2 Nitroaldol Reaction in Ionic Liquids 70

4.2 Nitroaldol Condensation 72

4.2.1 Application of General Henry Reaction 75

4.3 Asymmetric Henry Reaction 82

4.4 Aza-Henry Reaction 91

4.4.1 Aza-Henry Reaction via N-Protected Imines 92

4.4.2 Aza-Henry Reaction via α-Amidosulfones 96

References 102

5 Conjugate Addition of Nitroalkanes to Electron-Poor Alkenes (Michael Reaction) 107

5.1 General Homogeneous Procedures 107

5.2 Heterogeneous Procedures 109

5.3 Michael Reaction under Green Solvents 114

5.4 Asymmetric Michael Reaction 117

5.4.1 Asymmetric Michael Reaction with Enones 117

5.4.2 Asymmetric Michael Reaction with Enals 123

5.4.3 Asymmetric Michael Reaction with α,β-Unsaturated Esters 126

5.4.4 Asymmetric Michael Reaction with Conjugate Nitroalkenes 126

5.4.5 Asymmetric Michael Reaction with Vinyl Sulfones 128

5.5 Synthetic Applications of Michael Reaction 129

References 138

6 Formation of C—C Bond by Coupling Nitroalkanes with Aryl Halides 141

6.1 Main Procedures for Coupling Nitroalkanes with Aryl Halides 141

6.2 Application of C—C Coupling Nitroalkanes with Aryl Halides 144

6.3 Others 147

References 149

7 Synthesis and Reactivity of 1,3-Dinitroalkanes 151

7.1 Synthesis of 1,3-Dinitroalkanes 151

7.1.1 Asymmetric Synthesis of 1,3-Dinitroalkanes 152

7.1.2 Synthesis of Symmetric 1,3-Dinitroalkanes 154

7.2 Synthetic Applications of 1,3-Dinitroalkanes 156

7.2.1 Synthesis of 1,3-Diamines 156

7.2.2 Synthesis of Carbocycles 156

7.2.2.1 Synthesis of Dinitrocyclohexanols 156

7.2.2.2 Synthesis of Bicyclo[3.3.1]nonanes 157

7.2.3 Synthesis of Benzene Derivatives 159

7.2.3.1 Synthesis of Acetophenones and Benzoates 159

7.2.3.2 Synthesis of Arylamines 161

7.2.3.3 Synthesis of Polyfunctionalized Phenols 161

7.2.3.4 Synthesis of Nitrobenzenes 162

References 163

8 Formation of Carbon=Carbon Double Bonds via Nitrous Acid Elimination (NAE) 165

8.1 Synthesis of α,β-Unsaturated Carbonyl Derivatives 165

8.2 Nitroaldol Reaction, Nitrous Acid Elimination vs Water Elimination 170

8.3 Synthesis of Cyclic Compounds 171

8.3.1 Synthesis of Aromatic Rings 171

8.3.1.1 Synthesis of Benzene Ring 171

8.3.1.2 Synthesis of Furan Ring 174

8.3.1.3 Synthesis of Pyrrole Ring 176

8.3.1.4 Synthesis of Isoxazole Ring 176

8.3.2 Synthesis of Heterocyclic (Non-Aromatic) Rings 176

8.3.2.1 Synthesis of Dihydropyranol Ring 177

8.3.2.2 Synthesis of Butyrolactone Ring 177

8.3.2.3 Synthesis of Pyrrolidine Ring 178

8.3.2.4 Synthesis of Succinic Anhydride Ring 178

8.3.3 Synthesis of Cyclopentenone Ring 179

8.4 Synthesis of Polyenes 180

8.4.1 Asymmetric Synthesis of Electron-Poor Alkenes 183

References 185

9 𝛂-Nitrocycloalkanones, Synthesis, and Reactivity 187

9.1 Synthesis of Cyclic α-Nitro Ketones 187

9.2 Ring Cleavage of Cyclic α-Nitro Ketones 189

9.2.1 Cleavage to ω-Nitro Acids and ω-Nitro Esters 190

9.2.2 Cleavage to Methyl ω-Oxoalkanoate 192

9.2.3 Reductive Cleavage of α-Nitrocycloalkanones 193

9.2.4 Oxidative Cleavage of α-Nitrocycloalkanones 193

9.2.4.1 Cleavage into α,ω-Dicarboxylic Acids 193

9.2.4.2 Cleavage to α,ω-Dicarboxylic Acids Dialkyl Esters 195

9.2.4.3 Cleavage to α,ω-Dicarboxylic Acids Monomethyl Esters 195

9.2.4.4 Cleavage to Methyl ω,ω-Dihalo-ω-nitroalkanoates 196

9.2.5 Reaction of α-Nitrocycloalkanones with Organometallic Reagents 196

9.3 α-Nitrocycloalkanones and Michael Reaction 198

9.4 α-Nitrocycloalkanones and Henry Reaction 200

9.5 “Zip Reaction” 201

9.5.1 Synthesis of Bicyclic Macrolactones 202

9.5.2 Synthesis of 12-Oxotetradecan-14-lactam 202

9.5.3 Asymmetric Synthesis of Bicyclic Hemiketals 203

9.6 Arylation of Nitrocycloalkanones 203

9.6.1 Synthesis of Benzo- and Naphtho-fused Bicyclo[n.3.1]structures 204

9.6.2 α-Arylation of 2-Nitrocycloalkanones 205

References 206

10 Acyclic 𝛂-Nitro Ketones: Synthesis and Reactivity 209

10.1 Synthesis of α-Nitro Ketones 209

10.1.1 Synthesis of α-Nitro Ketones from Henry Reaction 209

10.1.2 Synthesis of α-Nitro Ketones from Carboxylic Acid Derivatives 211

10.1.3 Synthesis of α-Nitro Ketones from Alkenes 212

10.1.4 Synthesis of α-Nitro Ketones from Silyl Enol Ethers 212

10.2 Reactivity of Acyclic α-Nitro Ketones 213

10.2.1 Replacement of the Nitro Group of α-Nitro Ketones 213

10.2.1.1 Replacement of the Nitro Group with Hydrogen 213

10.2.1.2 Tandem Denitration–Deoxygenation 217

10.2.1.3 Replacement of the Nitro Group with Deuterium 220

10.2.1.4 Replacement of the Nitro Group with Phenylthio Group 221

10.2.2 α-Nitro Ketones to Conjugated Enones 221

10.2.3 α-Nitro Ketones into Nitroalkanols 224

10.2.4 Chemoselective Reduction of α-Nitro Ketones to Amino Ketones 226

10.2.5 Alkylation of α-Nitro Ketones 228

10.2.5.1 α1-Alkylation of α-Nitro Ketones 228

10.2.5.2 α-Allylation of α-Nitro Ketones 229

10.2.5.3 α-Alkylation of α-Nitro Ketones by Michael Reaction Followed by Nitrous Acid Elimination 232

10.2.5.4 α-Alkylation of α-Nitro Ketones by the Mannich (or Aza-Henry) Reaction 235

10.3 Other Reactions 235

10.3.1 Synthesis of Furoxans 235

10.3.2 Synthesis of α-Nitro-α-Diazocarbonyl Derivatives 236

10.3.3 Synthesis of Acylthioamides 236

References 237

11 Nitro Cyclopropanes: Synthesis and Applications 239

11.1 Synthesis of Nitro Cyclopropanes 239

11.1.1 Synthesis of Nitro Cyclopropanes from Bromine Derivatives 239

11.1.2 Synthesis of Nitro Cyclopropanes from Conjugate Nitroalkenes 247

11.1.3 Synthesis of Nitro Cyclopropanes from Alkenes 250

11.1.4 Intramolecular Synthesis of Nitro Cyclopropanes from γ-Nitro Alcohols (the Mitsunobu Displacement) 253

11.2 Applications of Nitrocyclopropanes 256

11.2.1 Nitrocyclopropanes and Henry Reaction: Synthesis of Novel HIV-1 Protease Inhibitor. 256

11.2.2 Cyclopropane Ring Expansion 257

References 261

12 Nitroalkanes as Source of Dicarbonyls 263

12.1 1,2-Dicarbonyl Derivatives 263

12.2 1,3-Dicarbonyl Derivatives 265

12.3 1,4-Dicarbonyl Derivatives 266

12.3.1 1,4-Diketones 266

12.3.2 γ-Ketoesters and γ-Ketoacids 272

12.4 1,5-Dicarbonyl Derivatives 275

References 276

13 Nitroalkanes as Source of Spiroketals 277

13.1 1,6-Dioxaspiro[4.4]nonanes 277

13.2 1,6-Dioxaspiro[4.5]undecanes 279

13.3 1,6-Dioxaspiro[4.6]undecanes 281

13.4 1,7-Dioxaspiro[5.5]undecanes and 1,7-Dioxaspiro[5.6]dodecanes 283

References 284

Index 285

Roberto Ballini is Professor of Organic Chemistry at the University of Camerino in Italy. His research focus is on organic synthesis, with a particular emphasis on aliphatic nitro compounds. He has published over 250 scientific articles and edited two books.

Alessandro Palmieri is Associate Professor at the University of Camerino in Italy. His research focus is on eco-friendly processes for the formation of C-C and C-X bonds and flow chemical protocols for the synthesis of fine chemicals. He has published over 100 scientific articles.