Practical Synthetic Organic Chemistry

Stéphane Caron is an Executive Director in Chemical Research & Development at Pfizer Inc.

List of Contributors xxxi

Preface xxxiii

1 Aliphatic Nucleophilic Substitution 1
Jade D. Nelson

1.1 Introduction 1

1.2 Oxygen Nucleophiles 1

1.3 Phosphorus Nucleophiles 21

1.4 Sulfur Nucleophiles 21

1.5 Nitrogen Nucleophiles 26

1.6 Halogen Nucleophiles 38

1.7 Carbon Nucleophiles 47

1.8 Nucleophilic Substitution at a Sulfonyl Sulfur Atom 60

2 Addition to Carbon-Heteroatom Multiple Bonds 65
Prantik Maity and Rajappa Vaidyanathan

2.1 Introduction 66

2.2 Addition of Water to Aldehydes and Ketones: Formation of Hydrates 66

2.3 Addition of Bisulfite to Aldehydes and Ketones 67

2.4 The Addition of Alcohols to Aldehydes and Ketones: Acetal Formation 69

2.5 The Addition of Thiols to Aldehydes and Ketones: S,S-Acetal Formation 71

2.6 Reductive Etherification 72

2.7 Addition of NH3, RNH2, and R2NH 74

2.8 Formation of Hydrazones 79

2.9 Formation of Oximes 80

2.10 The Formation of gem-Dihalides from Aldehydes and Ketones 80

2.11 The Aldol Reaction 82

2.12 Allylorganometallics: Stannane, Borane, and Silane 92

2.13 The Nozaki–Hiyama–Kishi Reaction 97

2.14 Addition of Transition Metal Alkynylides to Carbonyl Compounds 99

2.15 Addition of Organometallic Reagents to Carbonyls 100

2.17 The Reformatsky Reaction 104

2.18 The Wittig Reaction 106

2.19 Horner–Wadsworth–Emmons Reaction 108

2.20 Peterson Olefination 109

2.21 Julia–Lythgoe Olefination 110

2.22 Tebbe Methylenation 112

2.23 The Mannich Reaction 113

2.24 The Strecker Reaction 115

2.25 Hydrolysis of Carbon–Nitrogen Double Bonds 117

2.26 Conversion of Carboxylic Acids to Acyl Chlorides 118

2.27 Synthesis of Acyl Fluorides from Carboxylic Acids 122

2.28 Formation of Amides from Carboxylic Acids 123

2.29 Formation of Amides from Esters 130

2.30 Hydrolysis of Acyl Halides 132

2.31 Conversion of Carboxylic Acids to Esters 132

2.32 Hydrolysis of Amides 136

2.33 Conversion of N-Acyloxazolidinones to Other Carboxyl Derivatives 139

2.34 Alcoholysis of Amides 140

2.35 Hydrolysis of Esters 141

2.36 Transesterification 143

2.37 Alkyl Thiol Addition to Esters 144

2.38 Addition of Organometallic Reagents to Carboxylic Acid Derivatives 145

2.39 The Kulinkovich Cyclopropanation 149

2.40 Synthesis of Acyl Cyanides 150

2.41 The Ritter Reaction 151

2.42 Thorpe Reaction 154

2.43 Addition of Organometallic Reagents to Nitriles 155

2.44 Conversion of Nitriles to Amides, Esters, and Carboxylic Acids 155

2.45 Conversion of Nitriles to Thioamides 158

2.46 The Addition of Ammonia or Amines to Nitriles 160

2.47 The Addition of Alcohol to Nitriles 161

2.48 Alkyl Thiol Addition to Nitriles 162

2.49 The Blaise Reaction 162

2.50 The Addition of Alcohols to Isocyanates 163

2.51 The Addition of Amines and Amides to Isocyanates 164

2.52 The Formation of Xanthates 165

2.53 The Addition of Amines to Carbon Dioxide 166

2.54 The Addition of Amines to Carbon Disulfide 167

2.55 Addition of Organometallic Reagents to Carbon Dioxide 167

3 Addition to Carbon–Carbon Multiple Bonds 169
John A. Ragan

3.1 Introduction 169

3.2 Hydrogen–Halogen Addition (Hydrohalogenation) 169

3.3 Hydrogen–Oxygen Addition 173

3.4 Hydrogen–Nitrogen Addition (Hydroamination) 178

3.5 Hydrogen–Carbon Addition (Hydroalkylation) 180

3.6 Halogen–Halogen Addition 191

3.7 Hydroxy–Halogen Addition 192

3.8 Amino–Halogen Addition 194

3.9 Carbon–Halogen Addition 194

3.10 Oxygen–Oxygen Addition 196

3.11 Oxygen–Nitrogen Addition 202

3.12 Nitrogen–Nitrogen Addition 204

3.13 Carbon–Oxygen Addition 206

3.14 Carbon–Nitrogen Addition 211

3.15 Carbon–Carbon Addition 212

4 Nucleophilic Aromatic Substitution 231
Stéphane Caron and Emma McInturff

4.1 Introduction 231

4.2 Oxygen Nucleophiles 232

4.3 Sulfur Nucleophiles 234

4.4 Nitrogen Nucleophiles 236

4.5 Halogen Nucleophiles 241

4.6 Carbon Nucleophiles 243

4.7 ortho-Arynes 245

5 Electrophilic Aromatic Substitution 247

Stéphane Caron and Emma McInturff

5.1 Introduction 247

5.2 Nitrogen Electrophiles 247

5.3 Sulfur Electrophiles 250

5.4 Halogenation 253

5.5 Carbon Electrophiles 257

6 Selected Catalytic Reactions 269
Sebastien Monfette, Adam R. Brown, Pascal Dubé, Nathan D. Ide, Chad A. Lewis, Jared L. Piper, Shashank Shekhar, and Shu Yu

6.1 Introduction 269

6.2 Organoboron Reagents:The Suzuki–Miyaura Coupling 270

6.3 Organomagnesium Reagents: Kumada–Corriu Coupling 282

6.4 Organozinc Reagents: Negishi Coupling 287

6.5 Cross-Electrophile Coupling 291

6.6 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction) 292

6.7 Cross-Coupling Reactions with Organosilicon Compounds 295

6.8 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling) 296

6.9 Metal-Catalyzed Coupling of Alkenes (Heck Coupling) 298

6.10 Enolate Arylations 303

6.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation 306

6.12 Pd- and Cu-Catalyzed Aryl C—O Bond Formation 320

6.13 Pd- and Cu-Catalyzed Aryl C—S Bond Formation 322

6.14 Aryl C—B Bond Formation 324

6.15 Pd-Catalyzed Aryl C—CN Bond Formation 327

6.16 Metal-Catalyzed Allylic Substitution 329

6.17 Catalytic Metal-Mediated Methods for Fluorination 337

6.18 Selected Metal-Mediated C—H Functionalization 347

6.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies 357

6.20 Alkene and Alkyne Metathesis Reactions 362

6.21 Organocatalysis 369

7 Rearrangements 377
David H. Brown Ripin and Chad A. Lewis

7.1 Introduction 377

7.2 [1,2]-Rearrangements 377

Other Rearrangements 402

7.3 Other Rearrangements 402

7.4 Miscellaneous Migrations 420

8 Eliminations 425
Sally Gut Ruggeri

8.1 Introduction 425

8.2 Formation of Alkenes 425

8.3 Formation of Dienes 438

8.4 Formation of Alkynes 442

8.5 Formation of C=N bonds 444

8.6 Formation of Nitriles 445

8.7 Formation of Ketenes and Related Compounds 447

8.8 Fragmentations 449

8.9 Dehydrating Reagents 451

9 Reductions 455
Sally Gut Ruggeri, Stéphane Caron, Pascal Dubé, Nathan D. Ide, Kristin E. Price Wiglesworth, John A. Ragan, and Shu Yu

9.1 Introduction 455

9.2 Reduction of C—C Bonds 455

9.3 Reduction of C—N Bonds 471

9.4 Reduction of C—O Bonds 479

9.5 Reduction of C—S Bonds 494

9.6 Reduction of C—X Bonds 500

9.7 Reduction of Heteroatom–Heteroatom Bonds 504

10 Oxidations 513
Eric C. Hansen, Robert Perkins, and David H. Brown Ripin

10.1 Introduction 513

10.2 Oxidation of C—C Single and Double Bonds 514

10.3 Oxidation of C—H Bonds 520

10.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent 536

10.5 Oxidation of Aldehydes to Carboxylic Acids and Derivatives 543

10.6 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent 546

10.7 Oxidation of Nitrogen Functionalities 548

10.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur 555

10.9 Oxidation of Other Functionality 561

11 Selected Free Radical Reactions 563
Christophe Allais, Eric C. Hansen, Nathan D. Ide, Robert J. Perkins, and Elizabeth C. Swift

11.1 Introduction 563

11.2 Radical Reactions via Chemical Initiation 563

11.3 Photoredox Catalysis 575

11.4 Electrochemical Methods 583

12 Synthesis of “Nucleophilic” Organometallic Reagents 591
David H. Brown Ripin and Adam R. Brown

12.1 Introduction 591

12.2 Synthesis of “Nucleophilic” Organometallic Reagents 592

12.3 Strategies for Metalating Heterocycles 615

12.4 Reactions of “Nucleophilic” Organometallic Reagents 618

13 Synthesis of Common Aromatic Heterocycles 621
Stéphane Caron

13.1 Introduction 621

13.2 Pyrroles 623

13.3 Indoles 624

13.4 2-Indolinones (Oxindoles) 626

13.5 Isatins (2,3-Indolindiones) 628

13.6 Carbazoles 628

13.7 Pyrazoles 629

13.8 Indazoles 630

13.9 Imidazoles and Benzimidazoles 631

13.10 1,2,3-Triazoles and Benzotriazole 633

13.11 1,2,4-Triazoles 635

13.12 Tetrazoles 635

13.13 Dihydropyridines 637

13.14 Pyridines 637

13.15 Quinolines 639

13.16 Quinolinones and 2-Hydroxyquinolines 641

13.17 Isoquinolines 642

13.18 Isoquinolinones 643

13.19 Quinolones (4-Hydroxyquinolines) 644

13.20 Pyrimidines and Pyrimidones 645

13.21 Quinazolines and Quinazolinones 647

13.22 Pyrazines and Quinoxalines 648

13.23 Pyridazines, Phtalazines, and Cinnolines 650

13.24 1,2,4-Triazines 651

13.25 Furans and Benzofurans 652

13.26 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone 653

13.27 Coumarins 655

13.28 Thiophenes and Benzothiophenes 656

13.29 Isoxazoles and Benzisoxazoles 657

13.30 Oxazoles and Benzoxazoles 659

13.31 Isothiazoles and Benzisothiazoles 660

13.32 Thiazoles and Benzothiazoles 661

13.33 1,2,4-Oxadiazoles 662

13.34 1,3,4-Oxadiazoles 663

14 Access to Chirality 665
Angela L. A. Puchlopek-Dermenci and Robert W. Dugger

14.1 Introduction 665

14.2 Using the Chiral Pool 665

14.3 Classical Resolutions 668

14.4 Dynamic Kinetic Resolutions 673

14.5 Desymmetrization of Meso Compounds 675

14.6 Chiral Chromatography 676

15 Biocatalysis 679
Carlos A. Martinez, Rajesh Kumar, and John Wong

15.1 Introduction 679

15.2 Group Transfer Reactions 682

15.3 Reductions 688

15.4 Oxidations 693

15.5 C—C Bond Forming Reactions 699

15.6 Future Developments 703

16 Green Chemistry 705
Juan Colberg, Jared L. Piper, and John Wong

16.1 Introduction 705

16.2 Green Chemistry Metrics 706

16.3 Solvent and Reagent Selection 710

16.4 Green Reactions/Reagents 716

16.5 Examples of Green Methods and Reagents for Common Reaction Types 716

16.6 Predictive Tools to Design for Green Chemistry 724

16.7 Green Chemistry Improvements in Process Development 725

17 Continuous Chemistry 729
David D. Ford, Robert J.Maguire, J. Christopher McWilliams, Bryan Li, and Jared L. Piper

17.1 Introduction 729

17.2 Aliphatic Nucleophilic Substitutions 731

17.3 Additions to C—Het Multiple Bonds 735

17.4 Addition to C—C Multiple Bonds 735

17.5 Nucleophilic Aromatic Substitutions 739

17.6 Electrophilic Aromatic Substitution 739

17.7 Catalysis 741

17.8 Rearrangements 743

17.9 Eliminations 746

17.10 Reductions 748

17.11 Oxidations 751

17.12 Free Radical Reactions 757

17.13 Syntheses of Organometallic Reagents 760

17.14 Synthesis of Aromatic Heterocycles 766

17.15 Access to Chirality 770

17.16 Biotransformations 771

18 General Solvent Properties 773
Stéphane Caron

18.1 Introduction 773

18.2 Definitions and Acronyms 774

18.3 Solvent Properties 775

18.4 Mutual Solubility of Water and Organic Solvents 778

18.5 Other Useful Information on Solvents 779

18.6 Solvent Safety 780

18.7 Risk Phrases Used in the Countries of EU 781

19 Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School 785
Sally Gut Ruggeri

19.1 Introduction 785

19.2 Reaction Execution 785

19.3 Solvents and Reagents 788

19.4 Isolation 793

19.5 Analysis 797

Subject Index 801

Combo Index 811