Practical Synthetic Organic Chemistry

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

• List of Contributors xxxiPreface xxxiii1 Aliphatic Nucleophilic Substitution 1Jade D. Nelson1.1 Introduction 11.2 Oxygen Nucleophiles 11.3 Phosphorus Nucleophiles 211.4 Sulfur Nucleophiles 211.5 Nitrogen Nucleophiles 261.6 Halogen Nucleophiles 381.7 Carbon Nucleophiles 471.8 Nucleophilic Substitution at a Sulfonyl Sulfur Atom 602 Addition to Carbon-Heteroatom Multiple Bonds 65Prantik Maity and Rajappa Vaidyanathan2.1 Introduction 662.2 Addition of Water to Aldehydes and Ketones: Formation of Hydrates 662.3 Addition of Bisulfite to Aldehydes and Ketones 672.4 The Addition of Alcohols to Aldehydes and Ketones: Acetal Formation 692.5 The Addition of Thiols to Aldehydes and Ketones: S,S-Acetal Formation 712.6 Reductive Etherification 722.7 Addition of NH3, RNH2, and R2NH 742.8 Formation of Hydrazones 792.9 Formation of Oximes 802.10 The Formation of gem-Dihalides from Aldehydes and Ketones 802.11 The Aldol Reaction 822.12 Allylorganometallics: Stannane, Borane, and Silane 922.13 The Nozaki–Hiyama–Kishi Reaction 972.14 Addition of Transition Metal Alkynylides to Carbonyl Compounds 992.15 Addition of Organometallic Reagents to Carbonyls 1002.17 The Reformatsky Reaction 1042.18 The Wittig Reaction 1062.19 Horner–Wadsworth–Emmons Reaction 1082.20 Peterson Olefination 1092.21 Julia–Lythgoe Olefination 1102.22 Tebbe Methylenation 1122.23 The Mannich Reaction 1132.24 The Strecker Reaction 1152.25 Hydrolysis of Carbon–Nitrogen Double Bonds 1172.26 Conversion of Carboxylic Acids to Acyl Chlorides 1182.27 Synthesis of Acyl Fluorides from Carboxylic Acids 1222.28 Formation of Amides from Carboxylic Acids 1232.29 Formation of Amides from Esters 1302.30 Hydrolysis of Acyl Halides 1322.31 Conversion of Carboxylic Acids to Esters 1322.32 Hydrolysis of Amides 1362.33 Conversion of N-Acyloxazolidinones to Other Carboxyl Derivatives 1392.34 Alcoholysis of Amides 1402.35 Hydrolysis of Esters 1412.36 Transesterification 1432.37 Alkyl Thiol Addition to Esters 1442.38 Addition of Organometallic Reagents to Carboxylic Acid Derivatives 1452.39 The Kulinkovich Cyclopropanation 1492.40 Synthesis of Acyl Cyanides 1502.41 The Ritter Reaction 1512.42 Thorpe Reaction 1542.43 Addition of Organometallic Reagents to Nitriles 1552.44 Conversion of Nitriles to Amides, Esters, and Carboxylic Acids 1552.45 Conversion of Nitriles to Thioamides 1582.46 The Addition of Ammonia or Amines to Nitriles 1602.47 The Addition of Alcohol to Nitriles 1612.48 Alkyl Thiol Addition to Nitriles 1622.49 The Blaise Reaction 1622.50 The Addition of Alcohols to Isocyanates 1632.51 The Addition of Amines and Amides to Isocyanates 1642.52 The Formation of Xanthates 1652.53 The Addition of Amines to Carbon Dioxide 1662.54 The Addition of Amines to Carbon Disulfide 1672.55 Addition of Organometallic Reagents to Carbon Dioxide 1673 Addition to Carbon–Carbon Multiple Bonds 169John A. Ragan3.1 Introduction 1693.2 Hydrogen–Halogen Addition (Hydrohalogenation) 1693.3 Hydrogen–Oxygen Addition 1733.4 Hydrogen–Nitrogen Addition (Hydroamination) 1783.5 Hydrogen–Carbon Addition (Hydroalkylation) 1803.6 Halogen–Halogen Addition 1913.7 Hydroxy–Halogen Addition 1923.8 Amino–Halogen Addition 1943.9 Carbon–Halogen Addition 1943.10 Oxygen–Oxygen Addition 1963.11 Oxygen–Nitrogen Addition 2023.12 Nitrogen–Nitrogen Addition 2043.13 Carbon–Oxygen Addition 2063.14 Carbon–Nitrogen Addition 2113.15 Carbon–Carbon Addition 2124 Nucleophilic Aromatic Substitution 231Stéphane Caron and Emma McInturff4.1 Introduction 2314.2 Oxygen Nucleophiles 2324.3 Sulfur Nucleophiles 2344.4 Nitrogen Nucleophiles 2364.5 Halogen Nucleophiles 2414.6 Carbon Nucleophiles 2434.7 ortho-Arynes 2455 Electrophilic Aromatic Substitution 247Stéphane Caron and Emma McInturff5.1 Introduction 2475.2 Nitrogen Electrophiles 2475.3 Sulfur Electrophiles 2505.4 Halogenation 2535.5 Carbon Electrophiles 2576 Selected Catalytic Reactions 269Sebastien Monfette, Adam R. Brown, Pascal Dubé, Nathan D. Ide, Chad A. Lewis, Jared L. Piper, Shashank Shekhar, and Shu Yu6.1 Introduction 2696.2 Organoboron Reagents:The Suzuki–Miyaura Coupling 2706.3 Organomagnesium Reagents: Kumada–Corriu Coupling 2826.4 Organozinc Reagents: Negishi Coupling 2876.5 Cross-Electrophile Coupling 2916.6 Organotin Reagents: The Stille Coupling (Migita-Stille Reaction) 2926.7 Cross-Coupling Reactions with Organosilicon Compounds 2956.8 Metal-catalyzed Coupling of Alkynes (Sonogashira Coupling) 2966.9 Metal-Catalyzed Coupling of Alkenes (Heck Coupling) 2986.10 Enolate Arylations 3036.11 Pd- and Cu-Catalyzed Aryl C—N Bond Formation 3066.12 Pd- and Cu-Catalyzed Aryl C—O Bond Formation 3206.13 Pd- and Cu-Catalyzed Aryl C—S Bond Formation 3226.14 Aryl C—B Bond Formation 3246.15 Pd-Catalyzed Aryl C—CN Bond Formation 3276.16 Metal-Catalyzed Allylic Substitution 3296.17 Catalytic Metal-Mediated Methods for Fluorination 3376.18 Selected Metal-Mediated C—H Functionalization 3476.19 C—X Bond Forming Reactions via Borrowed Hydrogen Methodologies 3576.20 Alkene and Alkyne Metathesis Reactions 3626.21 Organocatalysis 3697 Rearrangements 377David H. Brown Ripin and Chad A. Lewis7.1 Introduction 3777.2 [1,2]-Rearrangements 377Other Rearrangements 4027.3 Other Rearrangements 4027.4 Miscellaneous Migrations 4208 Eliminations 425Sally Gut Ruggeri8.1 Introduction 4258.2 Formation of Alkenes 4258.3 Formation of Dienes 4388.4 Formation of Alkynes 4428.5 Formation of C=N bonds 4448.6 Formation of Nitriles 4458.7 Formation of Ketenes and Related Compounds 4478.8 Fragmentations 4498.9 Dehydrating Reagents 4519 Reductions 455Sally Gut Ruggeri, Stéphane Caron, Pascal Dubé, Nathan D. Ide, Kristin E. Price Wiglesworth, John A. Ragan, and Shu Yu9.1 Introduction 4559.2 Reduction of C—C Bonds 4559.3 Reduction of C—N Bonds 4719.4 Reduction of C—O Bonds 4799.5 Reduction of C—S Bonds 4949.6 Reduction of C—X Bonds 5009.7 Reduction of Heteroatom–Heteroatom Bonds 50410 Oxidations 513Eric C. Hansen, Robert Perkins, and David H. Brown Ripin10.1 Introduction 51310.2 Oxidation of C—C Single and Double Bonds 51410.3 Oxidation of C—H Bonds 52010.4 Oxidation of Carbon–Oxygen Bonds and at Carbon Bearing an Oxygen Substituent 53610.5 Oxidation of Aldehydes to Carboxylic Acids and Derivatives 54310.6 Oxidation of Carbon–Nitrogen Bonds and at Carbon Bearing a Nitrogen Substituent 54610.7 Oxidation of Nitrogen Functionalities 54810.8 Oxidation of Sulfur and at Carbon Adjacent to Sulfur 55510.9 Oxidation of Other Functionality 56111 Selected Free Radical Reactions 563Christophe Allais, Eric C. Hansen, Nathan D. Ide, Robert J. Perkins, and Elizabeth C. Swift11.1 Introduction 56311.2 Radical Reactions via Chemical Initiation 56311.3 Photoredox Catalysis 57511.4 Electrochemical Methods 58312 Synthesis of “Nucleophilic” Organometallic Reagents 591David H. Brown Ripin and Adam R. Brown12.1 Introduction 59112.2 Synthesis of “Nucleophilic” Organometallic Reagents 59212.3 Strategies for Metalating Heterocycles 61512.4 Reactions of “Nucleophilic” Organometallic Reagents 61813 Synthesis of Common Aromatic Heterocycles 621Stéphane Caron13.1 Introduction 62113.2 Pyrroles 62313.3 Indoles 62413.4 2-Indolinones (Oxindoles) 62613.5 Isatins (2,3-Indolindiones) 62813.6 Carbazoles 62813.7 Pyrazoles 62913.8 Indazoles 63013.9 Imidazoles and Benzimidazoles 63113.10 1,2,3-Triazoles and Benzotriazole 63313.11 1,2,4-Triazoles 63513.12 Tetrazoles 63513.13 Dihydropyridines 63713.14 Pyridines 63713.15 Quinolines 63913.16 Quinolinones and 2-Hydroxyquinolines 64113.17 Isoquinolines 64213.18 Isoquinolinones 64313.19 Quinolones (4-Hydroxyquinolines) 64413.20 Pyrimidines and Pyrimidones 64513.21 Quinazolines and Quinazolinones 64713.22 Pyrazines and Quinoxalines 64813.23 Pyridazines, Phtalazines, and Cinnolines 65013.24 1,2,4-Triazines 65113.25 Furans and Benzofurans 65213.26 Benzopyran-4-One (Chromen-4-One, Flavone) and Xanthone 65313.27 Coumarins 65513.28 Thiophenes and Benzothiophenes 65613.29 Isoxazoles and Benzisoxazoles 65713.30 Oxazoles and Benzoxazoles 65913.31 Isothiazoles and Benzisothiazoles 66013.32 Thiazoles and Benzothiazoles 66113.33 1,2,4-Oxadiazoles 66213.34 1,3,4-Oxadiazoles 66314 Access to Chirality 665Angela L. A. Puchlopek-Dermenci and Robert W. Dugger14.1 Introduction 66514.2 Using the Chiral Pool 66514.3 Classical Resolutions 66814.4 Dynamic Kinetic Resolutions 67314.5 Desymmetrization of Meso Compounds 67514.6 Chiral Chromatography 67615 Biocatalysis 679Carlos A. Martinez, Rajesh Kumar, and John Wong15.1 Introduction 67915.2 Group Transfer Reactions 68215.3 Reductions 68815.4 Oxidations 69315.5 C—C Bond Forming Reactions 69915.6 Future Developments 70316 Green Chemistry 705Juan Colberg, Jared L. Piper, and John Wong16.1 Introduction 70516.2 Green Chemistry Metrics 70616.3 Solvent and Reagent Selection 71016.4 Green Reactions/Reagents 71616.5 Examples of Green Methods and Reagents for Common Reaction Types 71616.6 Predictive Tools to Design for Green Chemistry 72416.7 Green Chemistry Improvements in Process Development 72517 Continuous Chemistry 729David D. Ford, Robert J.Maguire, J. Christopher McWilliams, Bryan Li, and Jared L. Piper17.1 Introduction 72917.2 Aliphatic Nucleophilic Substitutions 73117.3 Additions to C—Het Multiple Bonds 73517.4 Addition to C—C Multiple Bonds 73517.5 Nucleophilic Aromatic Substitutions 73917.6 Electrophilic Aromatic Substitution 73917.7 Catalysis 74117.8 Rearrangements 74317.9 Eliminations 74617.10 Reductions 74817.11 Oxidations 75117.12 Free Radical Reactions 75717.13 Syntheses of Organometallic Reagents 76017.14 Synthesis of Aromatic Heterocycles 76617.15 Access to Chirality 77017.16 Biotransformations 77118 General Solvent Properties 773Stéphane Caron18.1 Introduction 77318.2 Definitions and Acronyms 77418.3 Solvent Properties 77518.4 Mutual Solubility of Water and Organic Solvents 77818.5 Other Useful Information on Solvents 77918.6 Solvent Safety 78018.7 Risk Phrases Used in the Countries of EU 78119 Practical Chemistry Concepts Tips for the Practicing Chemist or Things They Don’t Teach You in School 785Sally Gut Ruggeri19.1 Introduction 78519.2 Reaction Execution 78519.3 Solvents and Reagents 78819.4 Isolation 79319.5 Analysis 797Subject Index 801Combo Index 811