Modern Organic Synthesis An Introduction

This book bridges the gap between sophomore and advanced / graduate level organic chemistry courses, providing students with a necessary background to begin research in either an industry or academic environment.

• Covers key concepts that include retrosynthesis, conformational analysis, and functional group transformations as well as presents the latest developments in organometallic chemistry and C–C bond formation
• Uses a concise and easy-to-read style, with many illustrated examples
• Updates material, examples, and references from the first edition
• Adds coverage of organocatalysts and organometallic reagents

GEORGE S. ZWEIFEL, PhD, is Professor Emeritus at the University of California, Davis.

MICHAEL H. NANTZ, PhD, is Professor of Chemistry and Distinguished University Scholar at the University of Louisville.

PETER SOMFAI, PhD, is Professor of Chemistry at Lund University.

About the Authors ix

Preface to the Second Edition xi

Preface to the First Edition xiii

SyntheticDesign 1

1.1 Retrosynthetic Analysis 1

1.2 Reversal of the Carbonyl Group Polarity (Umpolung) 6

1.3 Steps in Planning a Synthesis 11

1.4 Choice of SyntheticMethod 16

1.5 Domino Reactions (Cascade or Tandem Reactions) 18

1.6 Computer-Assisted Retrosynthetic Analysis 19

References 19

Stereochemical Considerations in Planning Syntheses 21

2.1 Conformational Analysis 21

2.2 Evaluation of Non-Bonded Interactions 25

2.3 Six-Membered Heterocyclic Systems 29

2.4 Polycyclic Ring Systems 30

2.5 Cyclohexyl Systems with sp2-Hybridized Atoms 33

2.6 Significant Energy Difference 35

2.7 Computer-Assisted Molecular Modeling 35

2.8 Reactivity and Product Determination as a Function of Conformation 36

References 42

The Concept of Protecting Functional Groups 45

3.1 Protection of N–H Groups 45

3.2 Protection of OH Groups 48

3.3 Protection of Diols as Acetals 55

3.4 Protection of Carbonyl Groups in Aldehydes and Ketones 56

3.5 Protection of the Carboxyl Group 62

3.6 Protection of Double Bonds 66

3.7 Protection of Triple Bonds 66

References 66

Functional Group Transformations 71

4.1 Oxidation of Alcohols to Aldehydes and Ketones 71

4.2 Reagents and Procedures for Alcohol Oxidation 72

4.3 Chemoselective Oxidizing Agents 76

4.4 Oxidation of Acyloins 79

4.5 Oxidation of Tertiary Allylic Alcohols 79

4.6 Oxidative Procedures to Carboxylic Acids 80

4.7 Allylic Oxidation of Alkenes 82

4.8 Terminology for Reduction of Carbonyl Compounds 85

4.9 Nucleophilic Reducing Agents 86

4.10 Electrophilic Reducing Agents 91

4.11 Regio- and Chemoselective Reductions 93

4.12 Diastereoselective Reductions of Cyclic Ketones 97

4.13 Inversion of Secondary Alcohol Stereochemistry 98

4.14 Diastereofacial Selectivity in Acyclic Systems 99

4.15 Enantioselective Reductions 104

References 108

Functional Group Transformations 115

5.1 Reactions of Carbon–Carbon Double Bonds 115

5.2 Reactions of Carbon–Carbon Triple Bonds 160

References 167

Formation of Carbon–Carbon Single Bonds via Enolate Anions 175

6.1 1,3-Dicarbonyl Compounds 175

6.2 Direct Alkylation of Enolates 185

6.3 Cyclization Reactions—Baldwin’s Rules for Ring Closure 193

6.4 Stereochemistry of Cyclic Ketone Alkylation 195

6.5 Imine and Hydrazone Anions 196

6.6 Enamines 197

6.7 The Aldol Reaction 199

6.8 Condensation Reactions of Enols and Enolates 213

6.9 Robinson Annulation 217

References 220

Formation of Carbon–Carbon Bonds via Organometallic Reagents 227

7.1 Organolithium Reagents 227

7.2 Organomagnesium Reagents 236

7.3 Organotitanium Reagents 239

7.4 Organocerium Reagents 240

7.5 Organocopper Reagents 241

7.6 Organochromium Reagents 251

7.7 Organozinc Reagents 252

7.8 Organoboron Reagents 256

7.9 Organosilicon Reagents 264

7.10 Organogold Chemistry 274

References 278

Palladium-Catalyzed Coupling Reactions 285

8.1 Palladium Oxidation State 285

8.2 Organic Synthesis with Palladium(0) Complexes 286

8.3 The Heck Reaction—Palladium(0)-Catalyzed Olefin Insertion Reactions 288

8.4 Palladium-Catalyzed Cross-Coupling with Organometallic Reagents 292

8.5 Cross-Coupling Reactions Involving sp-Carbons 301

8.6 The Trost–Tsuji Reaction 304

References 307

Formation of Carbon–Carbon ;;-Bonds 313

9.1 Formation of Carbon–Carbon Double Bonds 313

9.2 Formation of Carbon–Carbon Triple Bonds 343

References 350

Syntheses of Carbocyclic Systems 355

10.1 Intramolecular Free Radical Cyclizations 355

10.2 Cation–π Cyclizations 361

10.3 Pericyclic Reactions 364

10.4 Ring-Closing Olefin Metathesis 375

References 378

Index 383

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