Modern Aryne Chemistry

Akkattu T. Biju, PhD, is an Associate Professor in the Department of Organic Chemistry at the Indian Institute of Science, Bangalore, India.

• Foreword xvPreface xix1 Introduction to the Chemistry of Arynes 1Tony Roy, Avishek Guin, and Akkattu T. Biju1.1 Introduction 11.2 History of Arynes 11.3 Characterization of the Aryne Intermediates 31.4 Ortho-Arynes with Substitution 51.5 Ortho-Arynes of Heterocycles 61.6 Other Arynes 71.7 Methods of Aryne Generation 91.7.1 Selected Methods of Aryne Generation 91.7.1.1 Deprotonation of Aryl Halides 91.7.1.2 Metal–Halogen Exchange/Elimination 101.7.1.3 From Anthranilic Acids 101.7.1.4 Fragmentation of Amino Benzotriazoles 101.7.1.5 From Phenyl(2-(trimethylsilyl)phenyl)iodonium Triflate 101.7.1.6 Using Hexadehydro Diels–Alder (HDDA) Reaction 111.7.1.7 From ortho-Borylaryl Triflates 111.7.1.8 Pd(II)-Catalyzed C–H Activation Strategy Starting from Benzoic Acids 111.7.1.9 via Grob Fragmentation 121.7.2 Kobayashi’s Fluoride-Induced Aryne Generation 121.8 Possible Reactivity Modes of Arynes 131.8.1 Pericyclic Reactions 141.8.2 Arylation Reactions 171.8.3 Insertion Reactions 171.8.4 Transition-Metal-Catalyzed Reactions 181.8.5 Multicomponent Couplings (MCCs) 181.8.6 Molecular Rearrangements 181.9 Domino Aryne Generation 191.10 Arynes for the Synthesis of Large Polycyclic Aromatic Compounds 191.11 Arynes in Natural Product Synthesis 201.12 Concluding Remarks 21References 212 Aryne Cycloadditions for the Synthesis of Functional Polyarenes 27Fátima García, Diego Peña, Dolores Pérez, and Enrique Guitián2.1 Introduction 272.2 Aryne Cycloaddition Reactions: General Considerations 292.2.1 [4+2] Aryne Cycloadditions 292.2.2 [2+2] Aryne Cycloadditions 302.2.3 [2+2+2] Aryne Cycloadditions 312.3 Aryne-Mediated Synthesis of Functional Polyarenes 322.3.1 Synthesis of Acenes 322.3.2 Synthesis of Perylene Derivatives 432.3.3 Synthesis of Triptycenes 482.3.4 Synthesis of π-Extended Starphenes or Angular PAHs 482.3.5 Synthesis of Helicenes 542.3.6 Functionalization of Carbon Nanostructures 58References 633 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry 69Pan Li, Jingjing Zhao, and Feng Shi3.1 Introduction 693.2 1,3-Dipolar Cycloaddition Reactions of Arynes 703.2.1 [3+2] Dipolar Cycloaddition Reactions of Arynes with Linear 1,3-Dipoles 723.2.1.1 Reactions with Diazo Compounds 723.2.1.2 Reactions of Arynes with Azides 753.2.1.3 Reactions of Arynes with Nitrile Oxides 793.2.1.4 Reactions of Arynes with Nitrile Imines 803.2.1.5 Reactions of Arynes with Nitrones 803.2.1.6 Reactions of Arynes with Azomethine Imines and Ylides 833.2.1.7 Reactions of Arynes with Pyridinium N-Oxides 853.2.1.8 Reactions of Arynes with Pyridinium N-Imides 873.2.1.9 Reactions of Arynes with Pyridinium Ylides 893.2.2 [3+2] Dipolar Cycloaddition Reactions of Arynes with Cyclic 1,3-Dipoles 903.2.2.1 Reactions of Arynes with Sydnones 903.2.2.2 Reactions of Arynes with Münchnones 923.3 Other [n+2] Dipolar Cycloaddition Reactions of Arynes 923.3.1 Cycloaddition with Other Dipoles 923.3.2 Cycloaddition of Extended Scope of Arynes 953.4 Formal Cycloaddition Reactions of Arynes 973.4.1 Formal Cycloaddition with N–C–C Systems Forming Indole/Indoline/Oxyindole Scaffolds 973.4.2 Formal Cycloaddition with Hydrazone-Derived N–N–C Systems 993.4.3 Formal Cycloaddition and with Sulfur-Containing Substrates 1023.5 Summary 104List of Abbreviations 104References 1044 Recent Insertion Reactions of Aryne Intermediates 111Suguru Yoshida and Takamitsu Hosoya4.1 Introduction 1114.2 Amination and Related Transformations 1114.2.1 Transformations Involving the Formation of C—N and C—H Bonds 1114.2.2 Transformations Involving the Formation of C—N and C—Mg Bonds 1154.2.3 Transformations Involving the Formation of C—N and C—C Bonds 1164.2.4 Transformations Involving the Formation of C—N and C—S, C—P, C—Cl, or C—Si Bonds 1184.3 Transformations Involving Bond Formation with Nucleophilic Carbons 1214.3.1 Transformations Involving Carbometalation 1214.3.2 Benzocyclobutene Synthesis by [2+2] Cycloaddition 1224.3.3 Acylalkylations and Related Transformations 1244.3.4 Transformations Involving C—C and C—H Bond Formations 1284.4 Etherification and Related Transformations 1294.5 Sulfanylation and Related Transformations 1334.5.1 Hydrosulfanylation of Arynes 1334.5.2 Transformations Involving C—S and C—C Bond Formations 1354.5.3 Other Transformations Involving C—S and C—X Bond Formations 1364.6 Transformations Involving Bond Formation with Other Heteroatom Nucleophiles 1404.6.1 Transformations Involving C—P Bond Formation 1404.6.2 Transformations Involving C—B, C—I, or C—Cl Bond Formations 1424.7 Conclusions 142References 1445 Multicomponent Reactions Involving Arynes and Related Chemistry 149Hiroto Yoshida5.1 Introduction 1495.2 Classification of Multicomponent Reactions 1505.3 Carbon Nucleophile–Based Multicomponent Reactions 1505.3.1 Isocyanide 1505.3.2 Active Methylene Compounds 1535.4 Nitrogen Nucleophile–Based Multicomponent Reactions 1535.4.1 Amine 1535.4.2 Imine 1595.4.3 N-Heteroarene 1635.4.4 Diazene 1645.4.5 Nitrite 1655.5 Oxygen Nucleophile–Based Multicomponent Reactions 1655.5.1 Dimethylformamide 1655.5.2 Sulfoxide 1695.5.3 Cyclic Ether 1725.5.4 Trifluoromethoxide 1735.6 Phosphorus Nucleophile–Based Multicomponent Reactions 1745.7 Sulfur Nucleophile–Based Multicomponent Reactions 1765.8 Halogen Nucleophile–Based Multicomponent Reactions 1775.9 Miscellaneous 1795.10 Conclusive Remarks 179References 1806 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry 183Kanniyappan Parthasarathy, Jayachandran Jayakumar, Masilamani Jeganmohan, and Chien-Hong Cheng6.1 Introduction 1836.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes 1846.2.1 Palladium-Catalyzed Cyclotrimerization and Cocyclization with Arynes 1846.2.2 Ni-Catalyzed Cyclotrimerization and Cocyclization with Benzynes 1936.2.3 Au-Catalyzed Cyclotrimerization of Arynes 1976.2.4 Au-Catalyzed [4+2] Cycloaddition of o-Alkynyl(oxo)benzenes with Arynes 1986.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation 2016.3.1 Palladium-Catalyzed Carbocyclization Reaction by C–H Activation 2016.3.2 Palladium-Catalyzed Arynes in C–X Annulations (X = N, O) 2156.3.3 Ni-Catalyzed C–N Annulations by Denitrogenative Process 2226.3.4 Cu-Catalyzed C–H and N–H Annulations of Arynes 2246.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions 2256.4.1 Palladium-Catalyzed Three-Component Coupling in Arynes 2256.4.2 Nickel-Catalyzed Three-Component Coupling in Arynes 2306.4.3 Copper-Catalyzed Three-Component Coupling in Arynes 2306.4.4 Silver-Catalyzed Three-Component Coupling in Arynes 2396.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes 2406.5.1 Palladium-Catalyzed C—Sn Bond Addition to Arynes 2406.5.2 Palladium-Catalyzed Sn—Sn/Si—Si Bond Addition to Arynes 2416.5.3 Palladium-Catalyzed Ar—SCN Bond Addition to Arynes 2416.5.4 Platinum-Catalyzed Boron–Boron Bond Addition to Arynes 2436.5.5 Copper-Catalyzed B—B Bond Addition to Arynes 2446.5.6 Copper-Catalyzed Ar—Sn Bond Addition to Arynes 2446.5.7 Copper-Catalyzed sp C—H Bond Addition to Arynes 2476.5.8 Gold/Copper-Catalyzed sp C—H Bond Addition to Arynes 2476.5.9 Copper-Catalyzed C—Br Bond Addition to Arynes 2496.5.10 Copper-Mediated 1,2-Bis(trifluoromethylation) of Arynes 2496.5.11 Copper- and Silver-Catalyzed Hexadehydro-Diels–Alder-Cycloaddition of a Triyne (or) Tetrayne (HDDA Arynes) with Terminal Alkynes 2516.5.12 Copper-Catalyzed P—H Bond Addition to arynes 2536.6 Metal-Catalyzed CO Insertion Reactions of Arynes 2556.6.1 Cobalt-, Rhodium-, and Palladium-Catalyzed CO Insertion of Arynes 2556.7 Metal-Catalyzed [3+2] Cycloaddition of Arynes 2606.7.1 Silver-Catalyzed [3+2] Cycloaddition of Arynes 260Abbreviations 261References 2627 Molecular Rearrangements Triggered by Arynes 267Lu Han and Shi-Kai Tian7.1 Introduction 2677.2 Rearrangements Involved in the Monofunctionalization of Arynes 2687.2.1 Reactions of Arynes with Nitrogen Nucleophiles 2687.2.2 Reactions of Arynes with Sulfur Nucleophiles 2757.3 Rearrangements Involved in the 1,2-Difunctionalization of Arynes 2787.3.1 Formal Insertion of Arynes into Carbon–Carbon Bonds 2787.3.2 Formal Insertion of Arynes into Carbon–Heteroatom Bonds 2817.3.3 Formal Insertion of Arynes into Heteroatom–Heteroatom Bonds 2887.3.4 Vicinal Carbon–Carbon/Carbon–Carbon Bond-Forming Reactions of Arynes 2897.3.5 Vicinal Carbon–Carbon/Carbon–Heteroatom Bond-Forming Reactions of Arynes 2927.3.6 Vicinal Carbon–Heteroatom/Carbon–Heteroatom Bond-Forming Reactions of Arynes 3027.4 Rearrangements Involved in the 1,2,3-Trifunctionalization of Arynes 3037.5 Rearrangements Involved in the Multicomponent Reactions with Two or More Aryne Molecules 3057.5.1 Three-Component Reactions with Two Aryne Molecules 3057.5.2 Four-Component Reactions with Three Benzyne Molecules 3087.6 Conclusions 309References 3108 New Strategies in Recent Aryne Chemistry 315Yang Li8.1 Introduction 3158.2 New Aryne Generation Methods 3158.2.1 Revisiting ortho-Deprotonative Elimination Protocols 3168.2.2 Arynes from ortho-Difunctionalized Precursors 3208.2.3 Catalytic Aryne Generation Methods 3238.3 Aryne Regioselectivity 3268.3.1 Steric Effect 3278.3.2 Electronic Effect 3308.3.3 Regioselectivity on Small Ring-Fused Arynes 3358.4 Recent Advances in Aryne Multifunctionalization 3368.4.1 1,2-Benzdiyne 3368.4.2 1,3-Benzdiyne 3428.4.3 1,4-Benzdiyne 3458.4.4 1,3,5-Benztriyne 3498.4.5 Benzyne Insertion, C–H Functionalization Cascade 3518.5 Conclusions 354References 3549 Hetarynes, Cycloalkynes, and Related Intermediates 359Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju9.1 Introduction to Hetarynes 3599.2 Challenges in Hetarynes 3599.3 Different Types of Hetarynes 3619.4 Methods of Preparation 3629.4.1 2,3-Benzofuranyne Generation 3629.4.2 2,3-Indolyne Generation 3639.4.3 2,3-Benzothiophyne Generation 3639.4.4 3,4-Pyrrolyne Generation 3649.4.5 2,3-Thiophyne Generation 3649.4.6 3,4-Thiophyne Generation 3649.4.7 2,3-Pyridyne Generation 3659.4.7.1 2,3-Pyridyne from 3-Halopyridine 3659.4.7.2 2,3-Pyridyne from Dihalide Precursor 3669.4.7.3 From N-Aminotriazolo-Pyridine 3669.4.7.4 2,3-Pyridyne from 3-(Trimethylsilyl)pyridin-2-yl Trifluoromethanesulfonate 3679.4.8 3,4-Pyridyne Generation 3679.4.8.1 3,4-Pyridyne from Thermolysis of Diazonium Carboxylates 3679.4.8.2 From 3-Halopyridine 3679.4.8.3 From Oxidation of N-Aminotriazolo-pyridine 3689.4.8.4 From 3-Bromo-4-(phenylsulfinyl)pyridine 3689.4.8.5 From ortho-Trialkylsilyl Pyridyl Triflates 3689.4.9 4,5-Indolyne Generation 3699.4.9.1 From 5-Bromoindole 3699.4.9.2 From 4-Chloroindole Derivative 3699.4.9.3 From Dibromoindole 3699.4.9.4 From Silyltriflate Precursor 3709.4.10 5,6-Indolyne Generation 3709.4.11 6,7-Indolyne Generation 3719.4.11.1 From Dichloroindole Precursor 3719.4.11.2 Through Proton–lithium Exchange 3719.4.11.3 From 7-Bromoindole Derivative 3719.4.12 Quinolynes Generation 3729.4.12.1 3,4-Quinolyne from Halo Derivatives 3729.4.12.2 5,6- and 7,8-Quinolynes 3729.4.12.3 7,8-Quinolyne from Quinoline 4-Methylbenzenesulfonate Derivatives 3729.4.12.4 3,4-Isoquinolyne Generation 3739.4.13 3,4-Dehydro-1,5-Naphthyridine 3739.4.14 4,5-Pyrimidyne Generation 3739.4.15 Pyridyne-N-oxides Generation 3749.4.16 Indolinyne Generation 3759.5 Reactions of Hetarynes 3759.5.1 Cycloaddition Reactions 3759.5.2 Nucleophilic Addition Reaction 3779.5.3 Insertion Reaction 3799.6 Applications in Synthesis 3809.6.1 Application of Pyridyne 3819.6.2 Application of Indolyne 3829.7 Introduction to Cycloalkynes 3849.8 History of Cycloalkynes 3859.9 Different Types of Cycloalkynes 3879.10 Methods of Cycloalkyne Generation 3879.10.1 Traditional Methods of Cycloalkyne Generation 3889.10.1.1 Base-Induced 1,2-Elimination 3889.10.1.2 Metal–Halogen Exchange/Elimination 3899.10.1.3 Fragmentation of Aminotriazoles 3899.10.1.4 Fragmentation of Diazirine 3909.10.1.5 Oxidation of 1,2-Bis-hydrazones 3909.10.1.6 Rearrangement of Vinylidenecarbenes 3909.10.2 Fluoride-Induced Cycloalkyne Generation 3909.10.2.1 Generation of 3,4-Oxacyclohexyne 3919.10.2.2 Generation of 2,3-Piperidyne 3929.10.2.3 Generation of 3,4-Piperidyne 3929.10.2.4 Generation of Cyclohexenynone 3929.11 Reactions of Cycloalkynes 3939.11.1 Cycloaddition Reactions 3939.11.1.1 Diels–Alder Reaction 3939.11.1.2 [2+2] Cycloaddition 3939.11.1.3 1,3-Dipolar Cycloaddition 3949.11.2 Alkenylation Reactions 3959.11.3 Insertion Reactions 3959.12 Application in Synthesis 3969.13 Strained Cyclic Allenes 3969.13.1 Generation of 1,2-Cycloalkadienes 3969.13.1.1 Base-Induced 1,6-Elimination 3979.13.1.2 Rearrangement of Cyclopropylidenes 3989.13.1.3 Fluoride-Induced Elimination 3989.13.2 Reaction of 1,2-Cycloalkadienes 4009.13.2.1 Diels–Alder Addition 4009.13.2.2 [2+2] Cycloaddition 4019.13.2.3 1,3-Dipolar Cycloaddition 4019.14 Conclusions 402References 40210 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry 407Rachel N. Voss and Thomas R. Hoye10.1 Introduction 40710.2 History 40710.2.1 Overview of the Family of Dehydro-Diels–Alder Reactions 40710.2.2 First Example of a Tetradehydro-Diels–Alder (TDDA) Reaction 40810.2.3 Earliest Triyne to Benzyne Cycloisomerization (i.e., HDDA) Reactions 40910.2.4 First Minnesota Examples (and the Naming) of the “HDDA” Reaction 41110.3 Early Demonstration of New Modes of Aryne-Trapping Reactivity: Ag- and B-Promoted Carbene Chemistry 41210.4 De novo Construction of Arenes: A New Paradigm for Synthesis of Highly Substituted Benzenoid Natural Products 41310.5 Diradical Mechanism of the HDDA Cycloisomerization of Triyne to Benzyne 41410.6 Additional Contributions from the Lee Group (University of Illinois, Chicago (UIC)) 41610.7 Additional Notable Modes of Aryne Reactivity 41610.7.1 HDDA Benzynes as Dienophiles in Diels–Alder [4π+2π] Cycloaddition Reactions with Aromatic Dienes 41610.7.2 Trapping of Natural Products: Phenolics 41610.7.3 Trapping of Natural Products: Colchicine and Quinine 42010.8 New Reaction Modes and New Mechanistic Understanding 42110.8.1 Three-Component Reactions 42110.8.2 Dihydrogen Transfer Reactions 42210.8.3 Aromatic ene, Silyl Ether, Thioamide, and Diaziridine Reactions 42310.9 New Routes to Polycylic, Highly Fused Aromatic Products 42410.9.1 Naphthynes via Double-HDDA, Intramolecular-HDDA, and Highly Functionalized Naphthalenes 42410.9.2 Trapping with Perylene, Domino HDDA, and Tandem HDDA/TDDA 42610.10 One-Offs 42710.10.1 Enal, Formamide, Diselenide, and (N-heterocyclic carbene) NHC-Borane Trapping 42710.10.2 Cu(I)-Catalyzed Hydroalkynylation, Ether vs. Alcohol Competition, Photo-HDDA, and a Kobayashi Benzyne as an HDDA Diynophile 42810.11 Outgrowths from HDDA Chemistry 42810.11.1 Processes that Outcompete Aryne Formation in Potential HDDA Substrates 42810.11.2 Aza-HDDA Reaction 43010.12 Guidelines and Practical Issues: Strategic Considerations 43110.12.1 Complementarity of Classical vs. HDDA Benzyne Chemistries 43110.12.2 Regioselectivity Issues and the Nature of the Nucleophilic Trapping Agent 43210.12.3 Limitations Imposed by Trapping Agents 43310.12.4 Formal Equivalent of the Elusive Bimolecular HDDA Reaction 43310.12.5 Aspects of Substrate Design 43410.12.6 Limitations Imposed by Substituents on the Diynophile 43410.13 Guidelines and Practical Issues: Experimental Considerations 43510.13.1 Pristine Reaction Conditions (and Solvent Choices) 43510.13.2 Reaction Conditions: Tolerance for Water and Oxygen 43510.13.3 Reaction Conditions: Temperature, Pressure, and Alkyne Stability 43610.13.4 Reaction Conditions: Substrate Concentration 43710.13.5 The Value of Half-Life Measurements 437References 43811 Applications of Benzynes in Natural Product Synthesis 445Hiroshi Takikawa and Keisuke Suzuki11.1 Introduction 44511.2 General Reactivities of Benzynes 44511.3 Strategies Based on Nucleophilic Additions to Benzynes 44611.3.1 Additions of Nitrogen Nucleophiles 44711.3.2 Additions of Oxygen Nucleophiles 45011.3.3 Addition of Carbon Nucleophiles 45211.3.3.1 Carbanions 45211.3.3.2 π-Nucleophiles: Enamines and Enolates 45311.4 Addition–Fragmentation Reactions 45411.5 Strategies Based on [4+2] Cycloadditions 45711.6 Strategies Based on [2+2] Cycloadditions 46411.7 Strategies Based on Benzyne–Ene Reactions 47011.8 Recent Advances 47111.8.1 Strategies Based on Multiple Use of Benzyne 47111.8.2 Strategies Based on Transition-Metal-Catalyzed Reactions 47411.8.3 Benzyne Generation via Hexadehydro-Diels–Alder Reaction 477References 479Index 487