Practical Synthetic Organic Chemistry

This book is a hands-on guide for the organic chemist. Focusing on the most reliable and useful reactions, the chapter authors provide the information necessary for a chemist to strategically plan a synthesis, as well as repeat the procedures in the laboratory. Consolidates all the key advances/concepts in one book, covering the most important reactions in organic chemistry, including substitutions, additions, eliminations, rearrangements, oxidations, reductions Highlights the most important reactions, addressing basic principles, advantages/disadvantages of the methodology, mechanism, and techniques for achieving laboratory success Features new content on recent advances in CH activation, photoredox and electrochemistry, continuous chemistry, and application of biocatalysis in synthesis Revamps chapters to include new and additional examples of chemistry that have been demonstrated at a practical scale

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