LIST OF CONTRIBUTORS .......................................... xxi
PREFACE ....................................................... xxv
PART I ELECTROPHILIC AROMATIC SUBSTITUTION
1 Electrophilic Aromatic Substitution: Mechanism ............. 3
Douglas A. Klumpp
1.1 Introduction ............................................... 3
1.2 General Aspects ............................................ 4
1.3 Electrophiles .............................................. 4
1.4 Arene Nucleophiles ........................................ 12
1.5 π-Complex Intermediates ................................... 17
1.6 σ-Complex or Wheland Intermediates ....................... 22
1.7 Summary and Outlook ....................................... 27
Abbreviations ............................................. 27
References ................................................ 28
2 Friedel-Crafts Alkylation of Arenes in Total Synthesis
Gonzalo Blay, Marc Montesinos-Magraner and José R. Pedro
2.1 Introduction .............................................. 33
2.2 Total Synthesis Involving Intermolecular FC Alkylations ... 34
2.2.1 Synthesis of Coenzyme Q ........................... 34
2.2.2 Total Synthesis of (±)-Brasiliquinone B ............ 35
2.2.3 Synthesis of (-)-Podophyllotoxin ................... 35
2.2.4 Synthesis of Puupehenol and Related Compounds ...... 36
2.2.5 Synthesis of (-)-Talaumidin ........................ 36
2.2.6 Total Synthesis of (±)-Schefferine ................. 37
2.3 Total Synthesis Involving Intramolecular FC Alkylations ... 37
2.3.1 С-С Bond Formation Leading to Homocyclic Rings ..... 37
2.3.2 С-С Bond Formation Leading to Oxygen-Containing
Rings .............................................. 43
2.3.3 С-С Bond Formation Leading to Nitrogen-Containing
Rings .............................................. 44
2.4 Total Synthesis Through Tandem and Cascade Processes
Involving FC Reactions .................................... 46
2.4.1 С-С Bond Formation Leading to Homocyclic Rings ..... 46
2.4.2 С-С Bond Formation Leading to Oxygen-Containing
Rings .............................................. 49
2.4.3 С-С Bond Formation Leading to Nitrogen-Containing
Rings .............................................. 52
2.5 Total Synthesis Involving ipso-FC Reactions ............... 54
2.5.1 Synthesis of (S)-(-)-Xylopinine .................... 54
2.5.2 Synthesis of Garcibracteatone ...................... 55
2.6 Summary and Outlook ....................................... 56
2.7 Acknowledgment ............................................ 56
Abbreviations ............................................. 56
References ................................................ 57
3 Catalytic Friedel-Crafts Acylation Reactions .............. 59
Giovanni Sartori, Raimondo Maggi and Veronica Santacroce
3.1 Introduction and Historical Background .................... 59
3.2 Catalytic Homogeneous Acylations .......................... 60
3.2.1 Metal Halides ...................................... 60
3.2.2 Perfluoroalkanoic Acids Perfluorosulfonic Acids
and Their (Metal) Derivatives ...................... 62
3.2.3 Miscellaneous ...................................... 63
3.3 Catalytic Heterogeneous Acylations ........................ 64
3.3.1 Zeolites ........................................... 64
3.3.2 Clays .............................................. 69
3.3.3 Metal Oxides ....................................... 70
3.3.4 Acid-Treated Metal Oxides .......................... 70
3.3.5 Heteropoly Acids (HPAs) ............................ 71
3.3.6 Nation ............................................. 72
3.3.7 Miscellaneous ...................................... 73
3.4 Direct Phenol Acylation ................................... 73
3.5 Summary and Outlook ....................................... 77
Abbreviations ............................................. 78
References ................................................ 78
4 The Use of Quantum Chemistry for Mechanistic Analyses
of SEAr Reactions ......................................... 83
Tore Brinck and Magnus Liljenberg
4.1 Introduction .............................................. 83
4.1.1 Historical Overview of Early Quantum Chemistry
Work ............................................... 83
4.1.2 Current Mechanistic Understanding Based on
Kinetic and Spectroscopic Studies .................. 85
4.2 The SHAr Mechanism: Quantum Chemical Characterization in
Gas Phase and Solution .................................... 87
4.2.1 Nitration and Nitrosation .......................... 87
4.2.2 Halogenation ....................................... 93
4.2.3 Sulfonation ........................................ 96
4.2.4 Friedel-Crafts Alkylations and Acylations .......... 96
4.3 Prediction of Relative Reactivity and Regioselectivity
Based on Quantum Chemical Descriptors ..................... 97
4.4 Quantum Chemical Reactivity Prediction Based on Modeling
of Transition States and Intermediates ................... 100
4.4.1 Transition State Modeling ......................... 100
4.4.2 The Reaction Intermediate or Sigma-Complex
Approach .......................................... 101
4.5 Summary and Conclusions .................................. 102
Abbreviations ................................................. 103
References .................................................... 103
5 Catalytic Enantioselective Electrophilic Aromatic
Substitutions ............................................ 107
Marco Bandini
5.1 Introduction and Historical Background ................... 107
5.2 Metal-Catalyzed AFCA of Aromatic Hydrocarbons ............ 109
5.2.1 Introduction ...................................... 109
5.2.2 Metal-Catalyzed Condensation of Arenes with
Carbonyl Compounds and Their Nitrogen
Derivatives ....................................... 110
5.3 Organocatalyzed AFCA of Aromatic Hydrocarbons ............ 116
5.3.1 Introduction ...................................... 116
5.3.2 Asymmetric Organocatalyzed Condensation of
Arenes with Carbonyl Compounds and Their
Nitrogen Derivatives .............................. 117
5.3.3 Asymmetric Organocatalyzed Alkylations of Arenes
via Michael Additions ............................. 118
5.3.4 Organo-SOMO-Catalyzed Asymmetric Alkylations of
Arenes ............................................ 122
5.3.5 Miscellaneous in Asymmetric Organocatalyzed
Alkylations of Arenes ............................. 124
5.4 Merging Asymmetric Metal and Organocatalysis in
Friedel-Crafts Alkylations ............................... 125
5.5 Summary and Outlook ...................................... 126
Abbreviations ............................................ 127
References ............................................... 127
PART II NUCLEOPHILIC AROMATIC SUBSTITUTION ................... 131
6 Nucleophilic Aromatic Substitution: An Update Overview ... 133
Michael R. Crampton
6.1 Introduction ............................................. 133
6.2 The S Ar Mechanism ....................................... 135
6.2.1 Effects of Activating Groups ...................... 138
6.2.2 Leaving Group Effects ............................. 140
6.2.3 The Attacking Nucleophile ......................... 141
6.2.4 Solvent Effects ................................... 145
6.2.5 Intramolecular Rearrangements ..................... 146
6.3 Meisenheimer Adducts ..................................... 150
6.3.1 Spectroscopic and Crystallographic Studies ........ 150
6.3.2 Range and Variety of Substrates and Nucleophiles .. 153
6.3.3 Superelectrophilic Systems ........................ 158
6.4 The SN1 Mechanism ........................................ 159
6.4.1 Heterolytic and Homolytic Pathways ................ 159
6.5 Synthetic Applications ................................... 160
Abbreviations ............................................ 167
References ............................................... 167
7 Theoretical and Experimental Methods for the Analysis
of Reaction Mechanisms in SNAr Processes: Fugality
Philicity and Solvent Effects
Renato Contreras, Paola R. Campodónico and Rodrigo
Ormazábal-Toledo
7.1 Introduction ............................................. 175
7.2 Conceptual DFT: Global Regional and Nonlocal Reactivity
Indices .................................................. 176
7.3 Practical Applications of Conceptual DFT Descriptors ..... 179
7.3.1 Nucleophilicity and LG Scales ..................... 180
7.3.2 Activation Properties: Reactivity Indices
Profiles .......................................... 181
7.4 SNAr Reaction Mechanism .................................. 183
7.4.1 Kinetic Measurements .............................. 183
7.4.2 Nucleophilicity LG and PG Abilities ............... 185
7.5 Integrated Experimental and Theoretical Models ........... 187
7.5.1 Hydrogen Bonding Effects .......................... 187
7.6 Solvent Effects in Conventional Solvents and Ionic
Liquids .................................................. 188
7.6.1 Preferential Solvation ............................ 188
7.6.2 Ionic Liquids and Catalysis ....................... 189
7.7 Summary and Outlook ...................................... 189
Abbreviations ............................................ 190
References ............................................... 190
8 Asymmetric Nucleophilic Aromatic Substitution
Anne-Sophie Castanet, Anne Boussonnière and Jacques
Mortier
8.1 Introduction ............................................. 195
8.2 Auxiliary- and Substrate-Controlled Asymmetric
Nucleophilic Aromatic Substitution ....................... 198
8.2.1 Chiral Electron-Withdrawing Groups ................ 198
8.2.2 Chiral Leaving Groups ............................. 202
8.2.3 Planar Chiral Arenes .............................. 205
8.2.4 Chiral Tethered Arenes ............................ 207
8.2.5 Chiral Nucleophiles ............................... 209
8.3 Chiral Catalyzed Asymmetric Nucleophilic Aromatic
Substitution ............................................. 210
8.3.1 Chiral Ligands .................................... 211
8.3.2 Chiral Phase Transfer Catalysts ................... 211
8.4 Absolute Asymmetric Nucleophilic Aromatic Substitution ... 213
8.5 Summary and Outlook ...................................... 214
Abbreviations ............................................ 214
References ............................................... 215
9 Hemolytic Aromatic Substitution
Roberto A. Rossi, María E. Budén and Javier F. Guastavino
9.1 Introduction: Scope and Limitations ...................... 219
9.2 Radicals Generated by Homolytic Cleavage Processes:
Thermolysis and Photolysis ............................... 223
9.3 Reactions Mediated by Tin and Silicon Hydrides ........... 225
9.4 Radicals Generated by ET: Redox Reactions ................ 229
9.4.1 Reducing Metals ................................... 229
9.4.2 Other Reducing Agents ............................. 232
9.4.3 Oxidizing Metals .................................. 233
9.4.4 Base-Promoted Homolytic Aromatic Substitution
(BHAS) ............................................ 236
9.5 Summary and Outlook ...................................... 237
Abbreviations ............................................ 238
References ............................................... 238
10 Radical-Nucleophilic Aromatic Substitution ............... 243
Roberto A. Rossi, Javier F. Guastavino and María E. Budén
10.1 Introduction: Scope and Limitations-Background ........... 243
10.2 Mechanistic Considerations ............................... 245
10.2.1 Initiation Step ................................... 245
10.2.2 Propagation Steps ................................. 246
10.2.3 Termination Steps ................................. 248
10.3 Intermolecular SRN1 Reactions ............................ 248
10.3.1 Nucleophiles from Group 14: С and Sn .............. 248
10.3.2 Nucleophiles Derived from Group 15: N, P, As and
Sb ................................................ 254
10.3.3 Nucleophiles Derived from Group 16: O, S, Se and
Те ................................................ 256
10.4 Intramolecular SRNl Reactions ............................ 258
10.5 Miscellaneous Ring Closure Reactions ..................... 262
10.5.1 Exo or Endo Radical Cyclization Followed by an
SRN1 Reaction ..................................... 262
10.5.2 Intermolecular SRN1 Reaction Followed by
Intramolecular SRNl or BHAS Reaction .............. 263
10.6 Summary and Outlook ...................................... 264
Abbreviations ............................................ 265
References ............................................... 265
11 Nucleophilic Substitution of Hydrogen in Electron-
Deficient Arenes ......................................... 269
Mieczysław Mąkosza
11.1 Introduction ............................................. 269
11.2 Oxidative Nucleophilic Substitution of Hydrogen .......... 270
11.3 Conversion of the aH-Adducts of Nucleophiles to
Nitroarenes into Substituted Nitrosoarenes ............... 276
11.4 Vicarious Nucleophilic Substitution of Hydrogen .......... 278
11.4.1 Introduction ...................................... 278
11.4.2 Mechanism of VNS Reaction ......................... 279
11.4.3 Scope and Limitation of VNS ....................... 283
11.5 Other Ways of Conversion of the o-H-Adducts .............. 291
11.6 Concluding Remarks ....................................... 293
Abbreviations ............................................ 295
References ............................................... 295
PART III ARYNE CHEMISTRY ...................................... 299
12 The Chemistry of Arynes: An Overview ..................... 301
Roberto Sanz and Anisley Suárez
12.1 Introduction ............................................. 301
12.2 Structure and Representative Reactions of Arynes ......... 301
12.3 Aryne Generation ......................................... 303
12.3.1 Elimination Methods ............................... 303
12.3.2 By Hexadehydro-Diels-Alder Reaction ............... 306
12.3.1 12.4 Pericyclic Reactions ......................... 306
12.4.1 Diels-Alder Cycloadditions ........................ 306
12.4.2 [3+2] Cycloadditions .............................. 309
12.4.3 [2+2] Cycloadditions with Alkenes ................. 311
12.4.4 Ene Reactions ..................................... 313
12.5 Nucleophilic Addition Reactions to Arynes ................ 314
12.5.1 Regioselectivity Issues for Functionalized
Arynes ............................................ 314
12.5.2 Proton Abstraction: Monosubstitution of the Aryne . 315
12.5.3 Three-Component Reactions ......................... 317
12.5.4 Aryne Insertion Reactions into σ-Bonds ............ 321
12.5.5 Aryne Annulation .................................. 325
12.6 Transition Metal-Catalyzed Reactions of Arynes ........... 327
12.6.1 Cyclotrimerization of Arynes ...................... 327
12.6.2 Cocyclization of Arynes with Alkynes .............. 327
12.6.3 Cocyclization of Arynes with Alkenes .............. 327
12.6.4 Cocyclization of Arynes Alkenes and Alkynes ....... 329
12.6.5 Intermolecular Carbopalladation of Arynes ......... 329
12.6.6 Catalytic Insertion Reactions of Arynes into
σ-Bonds ........................................... 330
12.7 Conclusion ............................................... 332
Abbreviations ................................................. 332
References .................................................... 333
PART IV REDUCTION OXIDATION AND DEAROMATIZATION REACTIONS
13 Reduction/Hydrogenation of Aromatic Rings ................ 339
Francisco Foubelo and Miguel Yus
13.1 Introduction ............................................. 339
13.2 The Birch Reaction ....................................... 339
13.2.1 Dissolving Metals ................................. 340
13.2.2 Enzymatic Reactions ............................... 344
13.3 Metal-Catalyzed Hydrogenations ........................... 345
13.3.1 Homogeneous Conditions ............................ 345
13.3.2 Heterogeneous Conditions .......................... 351
13.4 Electrochemical Reductions ............................... 357
13.5 Other Methodologies ...................................... 359
13.6 Summary and Outlook ...................................... 361
Abbreviations ............................................ 361
References ............................................... 362
14 Selective Oxidation of Aromatic Rings .................... 365
Oxana A. Kholdeeva
14.1 Introduction ............................................. 365
14.2 Mechanistic Principles ................................... 367
14.2.1 Autoxidation ...................................... 367
14.2.2 Spin-Forbidden Reactions with Triplet Oxygen ...... 369
14.2.3 Radical Hydroxylation (Addition-Elimination) ...... 370
14.2.4 Electron Transfer Mechanisms ...................... 371
14.2.5 Electrophilic Hydroxylation via Oxygen Atom
Transfer .......................................... 373
14.2.6 Heterolytic Activation of Substrate ............... 374
14.3 Stoichiometric Oxidations ................................ 374
14.4 Catalytic Oxidations ..................................... 375
14.4.1 Benzene ........................................... 375
14.4.2 Polycyclic Arenes ................................. 379
14.4.3 Alkylarenes ....................................... 379
14.4.4 Electron-Poor Aromatic Compounds .................. 382
14.4.5 ortho-Hydroxylation Driven by Arene Functional
Group ............................................. 382
14.4.6 Phenol ............................................ 383
14.4.7 Alkylphenols and Alkoxyarenes ..................... 384
14.5 Photochemical Oxidations ................................. 386
14.6 Electrochemical Oxidations ............................... 387
14.7 Enzymatic Hydroxylation .................................. 389
14.8 Summary and Outlook ...................................... 390
Acknowledgments .......................................... 391
Abbreviations ............................................ 391
References ............................................... 392
15 Dearomatization Reactions: An Overview ................... 399
F. Christopher Pigge
15.1 Introduction ............................................. 399
15.2 Alkylative Dearomatization ............................... 400
15.2.1 C-Alkylation of Phenolate Anions .................. 400
15.2.2 Anionic Dearomatization ........................... 401
15.2.3 Radical Dearomatization ........................... 403
15.3 Photochemical and Thermal Dearomatization ................ 405
15.3.1 Dearomatization by Photocycloaddition ............. 405
15.3.2 Dearomatization by Thermally Induced
Rearrangement ..................................... 406
15.4 Oxidative Dearomatization ................................ 408
15.4.1 Oxidative Dearomatization with Formation of
Carbon-Heteroatom Bonds ........................... 408
15.4.2 Oxidative Dearomatization with Formation of
Carbon-Carbon Bonds ............................... 411
15.5 Transition Metal-Assisted Dearomatization ................ 413
15.5.1 Dearomatization Reactions of Metal Carbenoids ..... 413
15.5.2 Dearomatization Catalyzed by Palladium
Iridium and Related Complexes ..................... 413
15.5.3 Dearomatization of n2-Arene Metal Complexes ....... 416
15.5.4 Dearomatization of n6-Arene Metal Complexes ....... 417
15.6 Enzymatic Dearomatization ................................ 418
15.7 Conclusions and Future Directions ........................ 419
Abbreviations ............................................ 419
References ............................................... 420
PART V AROMATIC REARRANGEMENTS ................................ 425
16 Aromatic Compounds via Pericyclic Reactions .............. 427
Sethuraman Sankararaman
16.1 Introduction ............................................. 427
16.2 Electrocyclic Ring Closure Reaction ...................... 428
16.2.1 Application of Electrocyclic Ring Closure in
Aromatic Synthesis ................................ 429
16.3 Introduction to Cycloaddition Reactions .................. 433
16.3.1 Application of [4+2] Cycloaddition Method for
Synthesis of Aromatic Compounds ................... 434
16.4 Conclusions .............................................. 448
Abbreviations ............................................ 448
References ............................................... 448
17 Ring-Closing Metathesis: Synthetic Routes to
Carbocyclic Aromatic Compounds using Ring-Closing
Alkene and Enyne Metathesis .............................. 451
Charles B. de Koning and Willem A.L. van Otterlo
17.1 Introduction ............................................. 451
17.2 Alkene RCM for the Synthesis of Aromatic Compounds ....... 454
17.2.1 Synthesis of Substituted Benzenes ................. 454
17.2.2 Synthesis of Substituted Naphthalenes ............. 458
17.2.3 Synthesis of Substituted Phenanthrenes ............ 458
17.2.4 Synthesis of Anthraquinones and Benzo-Fused
Anthraquinones .................................... 459
17.2.5 Applications in the Synthesis of Polyarenes ....... 461
17.2.6 Applications in the Synthesis of Natural
Products .......................................... 462
17.3 Enyne Metathesis Followed by the Diels-Alder Reaction
for the Synthesis of Benzene Rings in Complex Aromatic
Compounds ................................................ 464
17.3.1 Synthesis of Substituted Benzenes ................. 464
17.3.2 Synthesis of Substituted Phenanthrenes ............ 466
17.3.3 Synthesis of Complex Naphthoquinones and
Anthraquinones .................................... 466
17.3.4 Applications to the Synthesis of Biologically
Active Products ................................... 470
17.4 Cyclotrimerization for the Synthesis of Aromatic
Compounds by Metathetic Processes ........................ 470
17.5 Strategies for the Synthesis of Aromatic Carbocycles
Fused to Heterocycles by the RCM Reaction ................ 472
17.5.1 Alkene RCM for the Synthesis of Benzene Rings in
Indoles Carbazoles Benzo-Fused Pyridines and
Pyridones and Benzo-Fused Imidazoles .............. 472
17.5.2 Enyne RCM for the Synthesis of Benzene Rings in
Tetrahydroisoquinolines Annulated 1,2-Oxaza- and
1,2-Bisazacycles and Indoles ...................... 479
17.6 Future Challenges ........................................ 481
17.7 Conclusions .............................................. 481
Abbreviations ............................................ 482
References ............................................... 482
18 Aromatic Rearrangements in which the Migrating Group
Migrates to the Aromatic Nucleus: An Overview ............ 485
Timothy J. Snape
18.1 Introduction ............................................. 485
18.2 Mechanisms by Classification ............................. 486
18.2.1 Intramolecular Reactions: Nucleophilic Aromatic
Substitution ...................................... 486
18.2.2 Intramolecular: Sigmatropic Rearrangements ........ 494
18.2.3 Intermolecular Rearrangements ..................... 500
18.3 Summary and Outlook ...................................... 508
Abbreviations ............................................ 508
References ............................................... 508
PART VI. TRANSITION METAL-MEDIATED COUPLING ................... 511
19 Transition Metal-Catalyzed Carbon-Carbon Cross-Coupling .. 513
Anny Jutand and Guillaume Lefèvre
19.1 Introduction ............................................. 513
19.2 The Mizoroki-Heck Reaction ............................... 513
19.2.1 General Considerations and Mechanisms ............. 513
19.2.2 Scope of the Reaction ............................. 520
19.2.3 Synthetic Application ............................. 523
19.3 Cross-Coupling of Aryl Halides with Anionic
C-Nucleophiles ........................................... 523
19.3.1 The Kumada Reactions: Nickel-Catalyzed Cross-
Coupling with Grignard Reagents ................... 523
19.3.2 Palladium-Catalyzed Cross-Coupling with Grignard
Reagents .......................................... 524
19.3.3 The Negishi Reaction: Palladium-Catalyzed Cross-
Coupling with Organozinc Reagents ................. 525
19.3.4 Palladium-Catalyzed Cross-Coupling with
Organolithium Reagents ............................ 525
19.3.5 Mechanism of Palladium-Catalyzed Cross-Couplings
with Rm (m=Li,MgY,ZnY) ............................ 526
19.3.6 Nickel- and Palladium-Catalyzed Arylation of
Ketone Ester and Amide Enolates ................... 528
19.4 The Sonogashira Reaction ................................. 530
19.4.1 General Considerations and Mechanism .............. 530
19.4.2 Synthetic Applications ............................ 531
19.5 The Stille Reaction ...................................... 532
19.5.1 General Considerations and Mechanism .............. 532
19.5.2 Synthetic Application ............................. 533
19.6 The Suzuki-Miyaura Reaction .............................. 534
19.6.1 General Considerations and Mechanism .............. 534
19.6.2 Synthetic Application ............................. 539
19.7 The Hiyama Reaction ...................................... 539
19.7.1 General Considerations and Mechanism .............. 539
19.7.2 Synthetic Applications ............................ 541
19.8 Summary and Outlook ...................................... 541
Abbreviations ............................................ 541
References ............................................... 541
20 Transition Metal-Mediated Carbon-Heteroatom Cross-
Coupling (C-N, C-O, C-S, C-Se, C-Te, C-P, C-As, C-Sb and
C-B Bond Forming Reactions): An Overview ................. 547
Masanam Kannan, Mani Sengoden and Tharmalingam
Punniyamurthy
20.1 Introduction ............................................. 547
20.2 C-N Cross-Coupling ....................................... 550
20.2.1 Palladium-Catalyzed Reactions ..................... 550
20.2.2 Copper-Catalyzed Reactions ........................ 555
20.2.3 Other Transition Metal-Catalyzed Reactions ........ 559
20.2.4 Synthetic Applications ............................ 560
20.3 С-О Cross-Coupling ....................................... 561
20.3.1 Reactions with Aromatic Alcohols .................. 561
20.3.2 Reactions with Aliphatic Alcohols ................. 563
20.3.3 Synthesis of Phenols .............................. 566
20.3.4 Synthetic Applications ............................ 567
20.4 С-S Cross-Coupling ....................................... 569
20.4.1 Palladium-Catalyzed Reactions ..................... 569
20.4.2 Copper-Catalyzed Reactions ........................ 569
20.4.3 Other Transition Metal-Catalyzed Reactions ........ 570
20.5 C-Se Cross-Coupling ...................................... 571
20.6 С-Те Cross-Coupling ...................................... 571
20.7 C-P Cross-Coupling ....................................... 572
20.7.1 Palladium-Catalyzed Reactions ..................... 572
20.7.2 Copper-Catalyzed Reactions ........................ 576
20.7.3 Nickel-Catalyzed Reactions ........................ 577
20.8 C-As and C-Sb Cross-Coupling ............................. 578
20.9 С-В Cross-Coupling ....................................... 578
20.10 Summary and Outlook ..................................... 579
Abbreviations ............................................ 579
References ............................................... 579
21 Transition Metal-Mediated Aromatic Ring Construction
Ken Tanaka
21.1 Introduction ............................................. 587
21.2 [2+2+2] Cycloaddition .................................... 587
21.2.1 Mechanism ......................................... 588
21.2.2 [2+2+2] Cycloaddition of Monoynes ................. 589
21.2.3 [2+2+2] Cycloaddition of Diynes with Monoynes ..... 590
21.2.4 [2+2+2] Cycloaddition of Triynes .................. 598
21.3 [3+2+1] Cycloaddition .................................... 601
21.4 [4+2] Cycloaddition ...................................... 602
21.4.1 Diels-Alder Reactions ............................. 602
21.4.2 Reactions of Enynes with Alkynes .................. 603
21.4.3 Reactions via Pyrylium Intermediates .............. 606
21.4.4 Reactions via АсуImetallacycles ................... 607
21.5 Intramolecular Cycloaromatization ........................ 608
21.5.1 Intramolecular Hydroarylation of Alkynes .......... 608
21.5.2 Cyclization via Transition Metal Vinylidenes ...... 610
21.6 Summary and Outlook ...................................... 612
References ............................................... 612
22 Ar-C Bond Formation by Aromatic Carbon-Carbon
ipso-Substitution Reaction
Maurizio Fagnoni and Sergio M. Bonesi
22.1 Introduction ............................................. 615
22.2 Formation of Ar-C(sp3) Bonds ............................. 616
22.2.1 Ni-Catalyzed Reactions ............................ 616
22.2.2 Rh-Catalyzed Reactions ............................ 617
22.2.3 Pd-Catalyzed Reactions ............................ 619
22.3 Formation of Ar-C(sp2) Bonds ............................. 620
22.3.1 Synthesis of Aryl Ketones and Amidines ............ 620
22.3.2 Formation of Ar-Vinyl Bonds ....................... 620
22.3.3 Formation of Ar-Ar Bonds .......................... 628
22.3.4 Formation of Benzocondensed Derivatives ........... 636
22.3.1 Formation of Ar-C(sp) Bonds ....................... 638
22.5 Summary and Outlook ...................................... 639
Abbreviations ............................................ 639
References ............................................... 640
PART VII С-H FUNCTIONALIZATION ............................... 645
23 Chelate-Assisted Arene C-H Bond Functionalization ........ 647
Marion H. Emmert and Christopher J. Legacy
23.1 Introduction ............................................. 647
23.1.1 Mechanisms of Chelate-Assisted C-H Bond
Functionalization and Activation .................. 648
23.1.2 Weakly and Strongly Coordinating Directing
Groups ............................................ 651
23.1.3 Common Directing Groups ........................... 651
23.1.4 Transformable and In Situ Generated Directing
Groups ............................................ 652
23.2 Carbon-Carbon (C-C) Bond Formations ...................... 654
23.2.1 C-CAryl Bond Formations ............................ 654
23.2.2 C-CAlkenyl Bond Formations .......................... 655
23.2.3 C-CAlkyl Bond Formations ........................... 656
23.2.4 C-CAcyl Bond Formations ............................ 657
23.2.5 C-CN Bond Formations .............................. 658
23.2.6 C-CF3 Bond Formations ............................. 659
23.3 Carbon-Heteroatom (C-X) Bond Formations .................. 660
23.3.1 C-B Bond Formations ............................... 660
23.3.2 C-Si Bond Formations .............................. 661
23.3.3 C-O Bond Formations ............................... 662
23.3.4 C-N Bond Formations ............................... 662
23.3.5 C-P Bond Formations ............................... 664
23.3.6 C-S Bond Formations ............................... 665
23.3.7 C-Halogen Bond Formations ......................... 666
23.3.8 C-D Bond Formations ............................... 667
23.4 Stereoselective C-H Functionalizations ................... 668
Abbreviations ............................................ 669
References ............................................... 669
24 Reactivity and Selectivity in Transition Metal-Catalyzed,
Nondirected Arene Functionalizations ..................... 675
Dipannita Kalyani and Elodie E. Marlier
24.1 Introduction ............................................. 675
24.2 Arylation ................................................ 676
24.2.1 Direct Arylations ................................. 677
24.2.2 Cross-Dehydrogenative Arylations .................. 684
24.3 Alkenylatjon ............................................. 693
24.4 Alkylation ............................................... 699
24.5 Carboxylation ............................................ 701
24.6 Oxygenation .............................................. 701
24.7 Thiolation ............................................... 704
24.8 Animation ................................................ 706
24.9 Miscellaneous ............................................ 708
24.9.1 Halogenation ...................................... 708
24.9.2 Silylation ........................................ 708
24.9.3 Borylation ........................................ 709
24.10 Summary and Outlook ..................................... 710
Abbreviations ............................................ 710
References ............................................... 710
25 Functionalization of Arenes via С-H Bond Activation
Catalysed by Transition Metal Complexes: Synergy
between Experiment and Theory ............................ 715
Amalia Isabel Poblador-Bahamonde
25.1 Introduction ............................................. 715
25.2 Mechanisms of C-H Bond Activation ........................ 716
25.3 Development of Stoichiometric C-H Bond Activation ........ 718
25.3.1 Mechanistic Ambiguity: The Power of Theory ........ 721
25.3.2 C-H Activation Assisted by Carboxylate or
Carbonate Bases ................................... 723
25.4 Catalytic C-H Activation and Functionalization ........... 730
25.4.1 Hydroarylation of Alkenes ......................... 730
25.4.2 Arene Functionalization via a Base-Assisted
Mechanism ......................................... 735
25.5 Summary .................................................. 738
Abbreviations ............................................ 738
References ............................................... 738
PART VIII. DIRECTED METALATION REACTIONS ...................... 741
26 Directed Metalation of Arenes with Organolithiums
Lithium Amides, and Superbases ........................... 743
Frédéric R. Leroux and Jacques Mortier
26.1 Introduction ............................................. 743
26.2 Preparation and Reactivity of Organolithium Compounds .... 744
26.2.1 Bases and Complexing Agents ....................... 744
26.2.2 Solvents .......................................... 746
26.2.3 Electrophiles ..................................... 747
26.3 Directed or//io-Metalation (DoM) ......................... 748
26.3.1 Mechanisms: Complex-Induced Proximity Effect
Process Kinetically Enhanced Metalation and
Overriding Base Mechanism ......................... 748
26.3.2 Directing Metalation Groups (DMGs) ................ 750
26.3.3 Optional Site Selectivity: Selected Examples ...... 750
26.3.4 External and In Situ Quench Conditions ............ 754
26.3.5 Apparent Anomalies in the Reactivity of Certain
Electrophiles ..................................... 756
26.4 Directed remote Metalation (DreM) ........................ 757
26.5 Peri Lithiation of Substituted Naphthalenes .............. 759
26.6 Lithiation of Metal Arene Complexes ...................... 760
26.7 Lateral Lithiation ....................................... 761
26.8 Analytical Methods ....................................... 762
26.8.1 Quantitative Determination of Organolithiums ...... 762
26.8.2 Qualitative Determination of Organolithiums ....... 763
26.8.3 Crystallography ................................... 763
26.8.4 NMR Spectroscopy .................................. 765
26.9 Synthetic Applications ................................... 765
26.9.1 DoM and С-С Cross-Coupling ........................ 765
26.9.2 DoM, DreM, and Anionic Fries Rearrangement ........ 766
26.9.3 Industrial Scale-Up of Ortho Metalation
Reactions ......................................... 768
26.9.4 Lateral Lithiation ................................ 768
26.9.5 Superbase Metalation .............................. 769
26.10 Conclusion .............................................. 770
Abbreviations ............................................ 771
References ............................................... 771
27 Deprotonative Metalation Using Alkali Metal-Nonalkali
Metal Combinations ....................................... 777
Floris Chevallier, Florence Mongin, Ryo Takita and
Masanobu Uchiyama
27.1 Introduction ............................................. 777
27.2 Preparation of the Bimetallic Combinations and their
Structural Features ...................................... 778
27.2.1 Preparation of Alkali Metal-Nonalkali Metal
Basic Combinations ................................ 778
27.2.2 Ate Compounds ..................................... 778
27.2.3 Salt-Activated Compounds .......................... 779
27.2.4 Contacted and Solvent-Separated Ion Pairs ......... 779
27.3 Behavior of Alkali Metal-Nonalkali Metal Combinations .... 779
27.3.1 One-Electron and Two-Electron Transfers ........... 779
27.3.2 Base and Nucleophile Ligand Transfers ............. 780
27.4 Mechanistic Studies on the Deprotometalation Using
Alkali Metal-Nonalkali Metal Combinations ................ 780
27.4.1 Deprotometalation Using Alkali Metal-
Amidozincate Complexes ............................ 780
27.4.2 Deprotometalation Using Alkali Metal-
Amidoaluminate Complexes .......................... 783
27.4.3 Deprotometalation Using Alkali Metal-
Amidocuprate Complexes ............................ 786
27.4.4 Deprotometalation Using Alkali Metal-Amidocadmate
Complexes ......................................... 789
27.5 Scope and Applications of the Deprotometalation .......... 790
27.5.1 Using Lithium- or Sodium-Magnesium Mixed-Metal
Bases ............................................. 790
27.5.2 Using Lithium-Aluminum Mixed-Metal Bases .......... 793
27.5.3 Using Lithium-, Sodium- or Magnesium-Manganese
Mixed-Metal Bases ................................. 795
27.5.4 Using Lithium- Sodium- or Magnesium-Iron Mixed-
Metal Bases ....................................... 798
27.5.5 Using Lithium-Cobalt Mixed-Metal Bases ............ 799
27.5.6 Using Lithium-Copper Mixed-Metal Bases ............ 799
27.5.7 Using Lithium-Sodium- or Magnesium-Zinc
Mixed-Metal Bases ................................. 799
27.5.8 Using Lithium- or Magnesium-Zirconium Mixed-Metal
Bases ............................................. 804
27.5.9 Using Lithium-Cadmium Mixed-Metal Bases ........... 804
27.5.10 Using Lithium-or Magnesium-Lanthanum Mixed-
Metal Bases ....................................... 805
27.6 Conclusion and Perspectives .............................. 807
Acknowledgments .......................................... 807
Abbreviations ............................................ 807
References ............................................... 811
28 The Halogen/Metal Interconversion and Related
Processes (M=Li, Mg) ..................................... 813
Armen Panossian and Frederic R. Leroux
28.1 Introduction ............................................. 813
28.2 Generalities ............................................. 814
28.2.1 Monometallic Organolithium Reagents ............... 814
28.2.2 Monometallic Organomagnesium Reagents ............. 814
28.2.3 Bimetallic Organolithium/Magnesium Reagents ....... 814
28.3 Mechanism of the Halogen/Metal Interconversion ...... 815
28.3.1 Reactivity ........................................ 815
28.3.2 Mechanism ......................................... 816
28.4 Halogen Migration on Aromatic Compounds .................. 817
28.5 Selective Synthesis via Halogen/Metal Interconversion .... 818
28.5.1 Chemo and Regioselectivity of Halogen/Metal
Interconversions .................................. 818
28.5.2 Stereoselectivity of Halogen/Metal
Interconversions .................................. 821
28.6 The Sulfoxide/Metal and Phosphorus/Metal
Interconversions ......................................... 822
28.6.1 The Sulfoxide/Metal Interconversion ............... 822
28.6.2 The Phosphorus/Metal Interconversion .............. 826
28.7 Aryl-Aryl Coupling Through Halogen/Metal
Interconversion .......................................... 827
28.7.1 (Re)emerging Methods for Aryl-Aryl Coupling
Through Halogen/Metal Interconversion ............. 827
28.7.2 Aryne-Mediated Aryl-Aryl Coupling ................. 828
28.8 Summary and Outlook ...................................... 830
Abbreviations ............................................ 830
References ............................................... 830
PART IX PHOTOCHEMICAL REACTIONS
29 Aromatic Photochemical Reactions
Norbert Hoffmann and Emmanuel Riguet
29.1 Introduction ............................................. 837
29.2 Aromatic Compounds as Chromophores ....................... 838
29.2.1 Photocycloaddition and Photochemical
Electrocyclic Reactions Involving Aromatics ....... 838
29.2.2 Photoinduced Radical Reactions .................... 842
29.3 Photosensitized and Photocatalyzed Reactions ............. 849
29.3.1 Metal-Catalyzed Reactions ......................... 849
29.3.2 Metal-Free Reactions .............................. 856
29.4 Conclusion ............................................... 864
Abbreviation ............................................. 865
References ............................................... 865
30 Photochemical Bergman Cyclization and Related Reactions
Rana К. Mohamed, Kemal Kaya and Igor V. Alabugin
30.1 Introduction: The Diversity of Cycloaromatization
Reactions ................................................ 869
30.2 Electronic Factors in Photo-BC ........................... 870
30.2.1 Substituent Effects ............................... 872
30.2.2 Introducing Strain ................................ 872
30.3 Scope and Limitations of the Photo-BC ............... 876
30.3.1 Metal-Mediated Photochemistry ..................... 876
30.3.2 Diverting from ВС Pathway: Direct Excitation
and Photoinduced Electron Transfer ................ 881
30.4 Enediyne Photocyclizations: Tool for Cancer Therapy ...... 883
30.5 Conclusion ............................................... 883
Abbreviations ............................................ 885
References ............................................... 885
31 Photo-Fries Reaction and Related Processes ............... 889
Francisco Galindo, M. Consuelo Jimenez and Miguel
Angel Miranda
31.1 Introduction ............................................. 889
31.2 Mechanistic Aspects ...................................... 889
31.2.1 General Scheme .................................... 889
31.2.2 Experimental Evidence: Steady-State Photolysis .... 890
31.2.3 Experimental Evidence: Time-Resolved Studies ...... 891
31.2.4 Experimental Evidence: Spin Chemistry Techniques .. 894
31.2.5 Theoretical Studies ............................... 894
31.3 Scope of the Reaction .................................... 894
31.3.1 Esters ............................................ 894
31.3.2 Amides ............................................ 895
31.3.3 Other ............................................. 895
31.4 (Micro)Heterogeneous Systems as Reaction Media ........... 897
31.4.1 Cyclodextrins ..................................... 897
31.4.2 Micelles .......................................... 897
31.4.3 Zeolites .......................................... 897
31.4.4 Proteins .......................................... 897
31.4.5 Other Organized Media ............................. 897
31.5 Applications in Organic Synthesis ........................ 900
31.6 Biological and Industrial Applications ................... 902
31.6.1 Drugs ............................................. 902
31.6.2 Agrochemicals ..................................... 902
31.6.3 Polymers .......................................... 904
31.7 Summary and Outlook ...................................... 905
Abbreviations ............................................ 906
References ............................................... 906
PART X BIOTRANSFORMATIONS ..................................... 913
32 Biotransformations of Arenes: An Overview ................ 915
Simon E. Lewis
32.1 Introduction ............................................. 915
32.2 Dearomatizing Arene Dihydroxylation ...................... 915
32.3 Dearomatizing Arene Epoxidation .......................... 918
32.4 Arene Alkylation (Biocatalytic Friedel-Crafts) ........... 919
32.5 Arene Deacylation (Biocatalytic Retro Friedel-Crafts) .... 922
32.6 Arene Carboxylation (Biocatalytic Kolbe-Schmitt) ......... 923
32.7 Arene Halogenation (Halogenases) ......................... 925
32.8 Arene Oxidation with Laccases ............................ 925
32.9 Tetrahydroisoquinoline Synthesis (Biocatalytic Pictet-
Spengler) ................................................ 929
32.10 Arene Hydroxylation ..................................... 930
32.11 Arene Nitration ......................................... 932
32.12 Summary and Outlook ..................................... 933
Abbreviations ............................................ 934
References ............................................... 934
INDEX ......................................................... 939
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