A groundbreaking book to offer a a comprehensive account of important reactions involving arynes
Modern Aryne Chemistry is the first book on the market to offer a conceptual framework to the reactions related to arynes. It also provides a systematic introduction to the cycloaddition reactions, insertion reactions and transition-metal-catalyzed transformations of arynes. The author, a noted expert on the topic, highlights a novel strategy for carbon-carbon and carbon-heteroatom bond construction using arynes.
The book reveiws the recent use of aryne chemistry for the development of new multicomponent reactions. New advances in this area has shown rapid emergence of a new class of reactions classified under rearrangement reactions. The author also includes information on aryne methods that have been employed for the synthesis of several natural products. The simplicity and sophistication of the synthetic strategy using arynes can serve as a springboard for organic chemists to explore new possibilities and imagine applications of the concept of arynes. This important book:
- Presents a one-of-kind comprehensive guide to arynes reactions
- Offers a proven approach to the synthesis of natural product and polymers
- Reviews the most recent developments in the carbon-carbon and carbon-heteroatom bond-forming reactions involving arynes
Written for organic, pharmaceutical, medicinal, natural products, and catalytic Chemists, Modern Aryne Chemistry offers a comprehensive review of the fundamentals of reactions related to arynes and the most recent developments in the field.
Table of Content
Foreword xv
Preface xix
1 Introduction to the Chemistry of Arynes 1
Tony Roy, Avishek Guin, and Akkattu T. Biju
1.1 Introduction 1
1.2 History of Arynes 1
1.3 Characterization of the Aryne Intermediates 3
1.4 Ortho-Arynes with Substitution 5
1.5 Ortho-Arynes of Heterocycles 6
1.6 Other Arynes 7
1.7 Methods of Aryne Generation 9
1.7.1 Selected Methods of Aryne Generation 9
1.7.1.1 Deprotonation of Aryl Halides 9
1.7.1.2 Metal–Halogen Exchange/Elimination 10
1.7.1.3 From Anthranilic Acids 10
1.7.1.4 Fragmentation of Amino Benzotriazoles 10
1.7.1.5 From Phenyl(2-(trimethylsilyl)phenyl)iodonium Triflate 10
1.7.1.6 Using Hexadehydro Diels–Alder (HDDA) Reaction 11
1.7.1.7 From ortho-Borylaryl Triflates 11
1.7.1.8 Pd(II)-Catalyzed C–H Activation Strategy Starting from Benzoic Acids 11
1.7.1.9 via Grob Fragmentation 12
1.7.2 Kobayashi’s Fluoride-Induced Aryne Generation 12
1.8 Possible Reactivity Modes of Arynes 13
1.8.1 Pericyclic Reactions 14
1.8.2 Arylation Reactions 17
1.8.3 Insertion Reactions 17
1.8.4 Transition-Metal-Catalyzed Reactions 18
1.8.5 Multicomponent Couplings (MCCs) 18
1.8.6 Molecular Rearrangements 18
1.9 Domino Aryne Generation 19
1.10 Arynes for the Synthesis of Large Polycyclic Aromatic Compounds 19
1.11 Arynes in Natural Product Synthesis 20
1.12 Concluding Remarks 21
References 21
2 Aryne Cycloadditions for the Synthesis of Functional Polyarenes 27
Fátima García, Diego Peña, Dolores Pérez, and Enrique Guitián
2.1 Introduction 27
2.2 Aryne Cycloaddition Reactions: General Considerations 29
2.2.1 [4+2] Aryne Cycloadditions 29
2.2.2 [2+2] Aryne Cycloadditions 30
2.2.3 [2+2+2] Aryne Cycloadditions 31
2.3 Aryne-Mediated Synthesis of Functional Polyarenes 32
2.3.1 Synthesis of Acenes 32
2.3.2 Synthesis of Perylene Derivatives 43
2.3.3 Synthesis of Triptycenes 48
2.3.4 Synthesis of π-Extended Starphenes or Angular PAHs 48
2.3.5 Synthesis of Helicenes 54
2.3.6 Functionalization of Carbon Nanostructures 58
References 63
3 Dipolar Cycloaddition Reactions of Arynes and Related Chemistry 69
Pan Li, Jingjing Zhao, and Feng Shi
3.1 Introduction 69
3.2 1, 3-Dipolar Cycloaddition Reactions of Arynes 70
3.2.1 [3+2] Dipolar Cycloaddition Reactions of Arynes with Linear 1, 3-Dipoles 72
3.2.1.1 Reactions with Diazo Compounds 72
3.2.1.2 Reactions of Arynes with Azides 75
3.2.1.3 Reactions of Arynes with Nitrile Oxides 79
3.2.1.4 Reactions of Arynes with Nitrile Imines 80
3.2.1.5 Reactions of Arynes with Nitrones 80
3.2.1.6 Reactions of Arynes with Azomethine Imines and Ylides 83
3.2.1.7 Reactions of Arynes with Pyridinium N-Oxides 85
3.2.1.8 Reactions of Arynes with Pyridinium N-Imides 87
3.2.1.9 Reactions of Arynes with Pyridinium Ylides 89
3.2.2 [3+2] Dipolar Cycloaddition Reactions of Arynes with Cyclic 1, 3-Dipoles 90
3.2.2.1 Reactions of Arynes with Sydnones 90
3.2.2.2 Reactions of Arynes with Münchnones 92
3.3 Other [n+2] Dipolar Cycloaddition Reactions of Arynes 92
3.3.1 Cycloaddition with Other Dipoles 92
3.3.2 Cycloaddition of Extended Scope of Arynes 95
3.4 Formal Cycloaddition Reactions of Arynes 97
3.4.1 Formal Cycloaddition with N–C–C Systems Forming Indole/Indoline/Oxyindole Scaffolds 97
3.4.2 Formal Cycloaddition with Hydrazone-Derived N–N–C Systems 99
3.4.3 Formal Cycloaddition and with Sulfur-Containing Substrates 102
3.5 Summary 104
List of Abbreviations 104
References 104
4 Recent Insertion Reactions of Aryne Intermediates 111
Suguru Yoshida and Takamitsu Hosoya
4.1 Introduction 111
4.2 Amination and Related Transformations 111
4.2.1 Transformations Involving the Formation of C—N and C—H Bonds 111
4.2.2 Transformations Involving the Formation of C—N and C—Mg Bonds 115
4.2.3 Transformations Involving the Formation of C—N and C—C Bonds 116
4.2.4 Transformations Involving the Formation of C—N and C—S, C—P, C—Cl, or C—Si Bonds 118
4.3 Transformations Involving Bond Formation with Nucleophilic Carbons 121
4.3.1 Transformations Involving Carbometalation 121
4.3.2 Benzocyclobutene Synthesis by [2+2] Cycloaddition 122
4.3.3 Acylalkylations and Related Transformations 124
4.3.4 Transformations Involving C—C and C—H Bond Formations 128
4.4 Etherification and Related Transformations 129
4.5 Sulfanylation and Related Transformations 133
4.5.1 Hydrosulfanylation of Arynes 133
4.5.2 Transformations Involving C—S and C—C Bond Formations 135
4.5.3 Other Transformations Involving C—S and C—X Bond Formations 136
4.6 Transformations Involving Bond Formation with Other Heteroatom Nucleophiles 140
4.6.1 Transformations Involving C—P Bond Formation 140
4.6.2 Transformations Involving C—B, C—I, or C—Cl Bond Formations 142
4.7 Conclusions 142
References 144
5 Multicomponent Reactions Involving Arynes and Related Chemistry 149
Hiroto Yoshida
5.1 Introduction 149
5.2 Classification of Multicomponent Reactions 150
5.3 Carbon Nucleophile–Based Multicomponent Reactions 150
5.3.1 Isocyanide 150
5.3.2 Active Methylene Compounds 153
5.4 Nitrogen Nucleophile–Based Multicomponent Reactions 153
5.4.1 Amine 153
5.4.2 Imine 159
5.4.3 N-Heteroarene 163
5.4.4 Diazene 164
5.4.5 Nitrite 165
5.5 Oxygen Nucleophile–Based Multicomponent Reactions 165
5.5.1 Dimethylformamide 165
5.5.2 Sulfoxide 169
5.5.3 Cyclic Ether 172
5.5.4 Trifluoromethoxide 173
5.6 Phosphorus Nucleophile–Based Multicomponent Reactions 174
5.7 Sulfur Nucleophile–Based Multicomponent Reactions 176
5.8 Halogen Nucleophile–Based Multicomponent Reactions 177
5.9 Miscellaneous 179
5.10 Conclusive Remarks 179
References 180
6 Transition-Metal-Catalyzed Reactions Involving Arynes and Related Chemistry 183
Kanniyappan Parthasarathy, Jayachandran Jayakumar, Masilamani Jeganmohan, and Chien-Hong Cheng
6.1 Introduction 183
6.2 Metal-Catalyzed Cyclotrimerization and Cocyclization of Arynes 184
6.2.1 Palladium-Catalyzed Cyclotrimerization and Cocyclization with Arynes 184
6.2.2 Ni-Catalyzed Cyclotrimerization and Cocyclization with Benzynes 193
6.2.3 Au-Catalyzed Cyclotrimerization of Arynes 197
6.2.4 Au-Catalyzed [4+2] Cycloaddition of o-Alkynyl(oxo)benzenes with Arynes 198
6.3 Metal-Catalyzed Annulation with Arynes via C—H and N—H Bond Activation 201
6.3.1 Palladium-Catalyzed Carbocyclization Reaction by C–H Activation 201
6.3.2 Palladium-Catalyzed Arynes in C–X Annulations (X = N, O) 215
6.3.3 Ni-Catalyzed C–N Annulations by Denitrogenative Process 222
6.3.4 Cu-Catalyzed C–H and N–H Annulations of Arynes 224
6.4 Transition-Metal-Catalyzed Three-Component Coupling Reactions 225
6.4.1 Palladium-Catalyzed Three-Component Coupling in Arynes 225
6.4.2 Nickel-Catalyzed Three-Component Coupling in Arynes 230
6.4.3 Copper-Catalyzed Three-Component Coupling in Arynes 230
6.4.4 Silver-Catalyzed Three-Component Coupling in Arynes 239
6.5 Metal-Catalyzed Addition of Metal–Metal (or) Metal–Carbon and C—X bonds into Arynes 240
6.5.1 Palladium-Catalyzed C—Sn Bond Addition to Arynes 240
6.5.2 Palladium-Catalyzed Sn—Sn/Si—Si Bond Addition to Arynes 241
6.5.3 Palladium-Catalyzed Ar—SCN Bond Addition to Arynes 241
6.5.4 Platinum-Catalyzed Boron–Boron Bond Addition to Arynes 243
6.5.5 Copper-Catalyzed B—B Bond Addition to Arynes 244
6.5.6 Copper-Catalyzed Ar—Sn Bond Addition to Arynes 244
6.5.7 Copper-Catalyzed sp C—H Bond Addition to Arynes 247
6.5.8 Gold/Copper-Catalyzed sp C—H Bond Addition to Arynes 247
6.5.9 Copper-Catalyzed C—Br Bond Addition to Arynes 249
6.5.10 Copper-Mediated 1, 2-Bis(trifluoromethylation) of Arynes 249
6.5.11 Copper- and Silver-Catalyzed Hexadehydro-Diels–Alder-Cycloaddition of a Triyne (or) Tetrayne (HDDA Arynes) with Terminal Alkynes 251
6.5.12 Copper-Catalyzed P—H Bond Addition to arynes 253
6.6 Metal-Catalyzed CO Insertion Reactions of Arynes 255
6.6.1 Cobalt-, Rhodium-, and Palladium-Catalyzed CO Insertion of Arynes 255
6.7 Metal-Catalyzed [3+2] Cycloaddition of Arynes 260
6.7.1 Silver-Catalyzed [3+2] Cycloaddition of Arynes 260
Abbreviations 261
References 262
7 Molecular Rearrangements Triggered by Arynes 267
Lu Han and Shi-Kai Tian
7.1 Introduction 267
7.2 Rearrangements Involved in the Monofunctionalization of Arynes 268
7.2.1 Reactions of Arynes with Nitrogen Nucleophiles 268
7.2.2 Reactions of Arynes with Sulfur Nucleophiles 275
7.3 Rearrangements Involved in the 1, 2-Difunctionalization of Arynes 278
7.3.1 Formal Insertion of Arynes into Carbon–Carbon Bonds 278
7.3.2 Formal Insertion of Arynes into Carbon–Heteroatom Bonds 281
7.3.3 Formal Insertion of Arynes into Heteroatom–Heteroatom Bonds 288
7.3.4 Vicinal Carbon–Carbon/Carbon–Carbon Bond-Forming Reactions of Arynes 289
7.3.5 Vicinal Carbon–Carbon/Carbon–Heteroatom Bond-Forming Reactions of Arynes 292
7.3.6 Vicinal Carbon–Heteroatom/Carbon–Heteroatom Bond-Forming Reactions of Arynes 302
7.4 Rearrangements Involved in the 1, 2, 3-Trifunctionalization of Arynes 303
7.5 Rearrangements Involved in the Multicomponent Reactions with Two or More Aryne Molecules 305
7.5.1 Three-Component Reactions with Two Aryne Molecules 305
7.5.2 Four-Component Reactions with Three Benzyne Molecules 308
7.6 Conclusions 309
References 310
8 New Strategies in Recent Aryne Chemistry 315
Yang Li
8.1 Introduction 315
8.2 New Aryne Generation Methods 315
8.2.1 Revisiting ortho-Deprotonative Elimination Protocols 316
8.2.2 Arynes from ortho-Difunctionalized Precursors 320
8.2.3 Catalytic Aryne Generation Methods 323
8.3 Aryne Regioselectivity 326
8.3.1 Steric Effect 327
8.3.2 Electronic Effect 330
8.3.3 Regioselectivity on Small Ring-Fused Arynes 335
8.4 Recent Advances in Aryne Multifunctionalization 336
8.4.1 1, 2-Benzdiyne 336
8.4.2 1, 3-Benzdiyne 342
8.4.3 1, 4-Benzdiyne 345
8.4.4 1, 3, 5-Benztriyne 349
8.4.5 Benzyne Insertion, C–H Functionalization Cascade 351
8.5 Conclusions 354
References 354
9 Hetarynes, Cycloalkynes, and Related Intermediates 359
Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju
9.1 Introduction to Hetarynes 359
9.2 Challenges in Hetarynes 359
9.3 Different Types of Hetarynes 361
9.4 Methods of Preparation 362
9.4.1 2, 3-Benzofuranyne Generation 362
9.4.2 2, 3-Indolyne Generation 363
9.4.3 2, 3-Benzothiophyne Generation 363
9.4.4 3, 4-Pyrrolyne Generation 364
9.4.5 2, 3-Thiophyne Generation 364
9.4.6 3, 4-Thiophyne Generation 364
9.4.7 2, 3-Pyridyne Generation 365
9.4.7.1 2, 3-Pyridyne from 3-Halopyridine 365
9.4.7.2 2, 3-Pyridyne from Dihalide Precursor 366
9.4.7.3 From N-Aminotriazolo-Pyridine 366
9.4.7.4 2, 3-Pyridyne from 3-(Trimethylsilyl)pyridin-2-yl Trifluoromethanesulfonate 367
9.4.8 3, 4-Pyridyne Generation 367
9.4.8.1 3, 4-Pyridyne from Thermolysis of Diazonium Carboxylates 367
9.4.8.2 From 3-Halopyridine 367
9.4.8.3 From Oxidation of N-Aminotriazolo-pyridine 368
9.4.8.4 From 3-Bromo-4-(phenylsulfinyl)pyridine 368
9.4.8.5 From ortho-Trialkylsilyl Pyridyl Triflates 368
9.4.9 4, 5-Indolyne Generation 369
9.4.9.1 From 5-Bromoindole 369
9.4.9.2 From 4-Chloroindole Derivative 369
9.4.9.3 From Dibromoindole 369
9.4.9.4 From Silyltriflate Precursor 370
9.4.10 5, 6-Indolyne Generation 370
9.4.11 6, 7-Indolyne Generation 371
9.4.11.1 From Dichloroindole Precursor 371
9.4.11.2 Through Proton–lithium Exchange 371
9.4.11.3 From 7-Bromoindole Derivative 371
9.4.12 Quinolynes Generation 372
9.4.12.1 3, 4-Quinolyne from Halo Derivatives 372
9.4.12.2 5, 6- and 7, 8-Quinolynes 372
9.4.12.3 7, 8-Quinolyne from Quinoline 4-Methylbenzenesulfonate Derivatives 372
9.4.12.4 3, 4-Isoquinolyne Generation 373
9.4.13 3, 4-Dehydro-1, 5-Naphthyridine 373
9.4.14 4, 5-Pyrimidyne Generation 373
9.4.15 Pyridyne-N-oxides Generation 374
9.4.16 Indolinyne Generation 375
9.5 Reactions of Hetarynes 375
9.5.1 Cycloaddition Reactions 375
9.5.2 Nucleophilic Addition Reaction 377
9.5.3 Insertion Reaction 379
9.6 Applications in Synthesis 380
9.6.1 Application of Pyridyne 381
9.6.2 Application of Indolyne 382
9.7 Introduction to Cycloalkynes 384
9.8 History of Cycloalkynes 385
9.9 Different Types of Cycloalkynes 387
9.10 Methods of Cycloalkyne Generation 387
9.10.1 Traditional Methods of Cycloalkyne Generation 388
9.10.1.1 Base-Induced 1, 2-Elimination 388
9.10.1.2 Metal–Halogen Exchange/Elimination 389
9.10.1.3 Fragmentation of Aminotriazoles 389
9.10.1.4 Fragmentation of Diazirine 390
9.10.1.5 Oxidation of 1, 2-Bis-hydrazones 390
9.10.1.6 Rearrangement of Vinylidenecarbenes 390
9.10.2 Fluoride-Induced Cycloalkyne Generation 390
9.10.2.1 Generation of 3, 4-Oxacyclohexyne 391
9.10.2.2 Generation of 2, 3-Piperidyne 392
9.10.2.3 Generation of 3, 4-Piperidyne 392
9.10.2.4 Generation of Cyclohexenynone 392
9.11 Reactions of Cycloalkynes 393
9.11.1 Cycloaddition Reactions 393
9.11.1.1 Diels–Alder Reaction 393
9.11.1.2 [2+2] Cycloaddition 393
9.11.1.3 1, 3-Dipolar Cycloaddition 394
9.11.2 Alkenylation Reactions 395
9.11.3 Insertion Reactions 395
9.12 Application in Synthesis 396
9.13 Strained Cyclic Allenes 396
9.13.1 Generation of 1, 2-Cycloalkadienes 396
9.13.1.1 Base-Induced 1, 6-Elimination 397
9.13.1.2 Rearrangement of Cyclopropylidenes 398
9.13.1.3 Fluoride-Induced Elimination 398
9.13.2 Reaction of 1, 2-Cycloalkadienes 400
9.13.2.1 Diels–Alder Addition 400
9.13.2.2 [2+2] Cycloaddition 401
9.13.2.3 1, 3-Dipolar Cycloaddition 401
9.14 Conclusions 402
References 402
10 Hexadehydro Diels–Alder (HDDA) Route to Arynes and Related Chemistry 407
Rachel N. Voss and Thomas R. Hoye
10.1 Introduction 407
10.2 History 407
10.2.1 Overview of the Family of Dehydro-Diels–Alder Reactions 407
10.2.2 First Example of a Tetradehydro-Diels–Alder (TDDA) Reaction 408
10.2.3 Earliest Triyne to Benzyne Cycloisomerization (i.e., HDDA) Reactions 409
10.2.4 First Minnesota Examples (and the Naming) of the “HDDA” Reaction 411
10.3 Early Demonstration of New Modes of Aryne-Trapping Reactivity: Ag- and B-Promoted Carbene Chemistry 412
10.4 De novo Construction of Arenes: A New Paradigm for Synthesis of Highly Substituted Benzenoid Natural Products 413
10.5 Diradical Mechanism of the HDDA Cycloisomerization of Triyne to Benzyne 414
10.6 Additional Contributions from the Lee Group (University of Illinois, Chicago (UIC)) 416
10.7 Additional Notable Modes of Aryne Reactivity 416
10.7.1 HDDA Benzynes as Dienophiles in Diels–Alder [4π+2π] Cycloaddition Reactions with Aromatic Dienes 416
10.7.2 Trapping of Natural Products: Phenolics 416
10.7.3 Trapping of Natural Products: Colchicine and Quinine 420
10.8 New Reaction Modes and New Mechanistic Understanding 421
10.8.1 Three-Component Reactions 421
10.8.2 Dihydrogen Transfer Reactions 422
10.8.3 Aromatic ene, Silyl Ether, Thioamide, and Diaziridine Reactions 423
10.9 New Routes to Polycylic, Highly Fused Aromatic Products 424
10.9.1 Naphthynes via Double-HDDA, Intramolecular-HDDA, and Highly Functionalized Naphthalenes 424
10.9.2 Trapping with Perylene, Domino HDDA, and Tandem HDDA/TDDA 426
10.10 One-Offs 427
10.10.1 Enal, Formamide, Diselenide, and (N-heterocyclic carbene) NHC-Borane Trapping 427
10.10.2 Cu(I)-Catalyzed Hydroalkynylation, Ether vs. Alcohol Competition, Photo-HDDA, and a Kobayashi Benzyne as an HDDA Diynophile 428
10.11 Outgrowths from HDDA Chemistry 428
10.11.1 Processes that Outcompete Aryne Formation in Potential HDDA Substrates 428
10.11.2 Aza-HDDA Reaction 430
10.12 Guidelines and Practical Issues: Strategic Considerations 431
10.12.1 Complementarity of Classical vs. HDDA Benzyne Chemistries 431
10.12.2 Regioselectivity Issues and the Nature of the Nucleophilic Trapping Agent 432
10.12.3 Limitations Imposed by Trapping Agents 433
10.12.4 Formal Equivalent of the Elusive Bimolecular HDDA Reaction 433
10.12.5 Aspects of Substrate Design 434
10.12.6 Limitations Imposed by Substituents on the Diynophile 434
10.13 Guidelines and Practical Issues: Experimental Considerations 435
10.13.1 Pristine Reaction Conditions (and Solvent Choices) 435
10.13.2 Reaction Conditions: Tolerance for Water and Oxygen 435
10.13.3 Reaction Conditions: Temperature, Pressure, and Alkyne Stability 436
10.13.4 Reaction Conditions: Substrate Concentration 437
10.13.5 The Value of Half-Life Measurements 437
References 438
11 Applications of Benzynes in Natural Product Synthesis 445
Hiroshi Takikawa and Keisuke Suzuki
11.1 Introduction 445
11.2 General Reactivities of Benzynes 445
11.3 Strategies Based on Nucleophilic Additions to Benzynes 446
11.3.1 Additions of Nitrogen Nucleophiles 447
11.3.2 Additions of Oxygen Nucleophiles 450
11.3.3 Addition of Carbon Nucleophiles 452
11.3.3.1 Carbanions 452
11.3.3.2 π-Nucleophiles: Enamines and Enolates 453
11.4 Addition–Fragmentation Reactions 454
11.5 Strategies Based on [4+2] Cycloadditions 457
11.6 Strategies Based on [2+2] Cycloadditions 464
11.7 Strategies Based on Benzyne–Ene Reactions 470
11.8 Recent Advances 471
11.8.1 Strategies Based on Multiple Use of Benzyne 471
11.8.2 Strategies Based on Transition-Metal-Catalyzed Reactions 474
11.8.3 Benzyne Generation via Hexadehydro-Diels–Alder Reaction 477
References 479
Index 487
About the author
Akkattu T. Biju, Ph D, is an Associate Professor in the Department of Organic Chemistry at the Indian Institute of Science, Bangalore, India.
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