Preface .................................................... XV
List of Authors ........................................... XIX
List of Abbreviations ..................................... XXI
1 Structure, Properties, and Preparation Of Boronic Acid
Derivatives. Overview of Their Reactions and Applications ... 1
D.G. Hall
1.1 Introduction ................................................ 1
1.2 Structure and Properties of Boronic Acid Derivatives ........ 2
1.2.1 General Types and Nomenclature of Boronic Acid
Derivatives ........................................... 2
1.2.2 Boronic Acids ......................................... 3
1.2.2.1 Structure and Bonding ......................... 3
1.2.2.2 Physical Properties and Handling .............. 7
1.2.2.3 Safety Considerations ......................... 8
1.2.2.4 Acidic Character .............................. 8
1.2.2.5 Chemical Stability ........................... 13
1.2.3 Boronic Acid Derivatives ............................. 14
1.2.3.1 Boroxines .................................... 14
1.2.3.2 Boronic Esters ............................... 15
1.2.3.3 Dialkoxyboranes and other Heterocyclic
Boranes ...................................... 23
1.2.3.4 Diboronyl Esters ............................. 24
1.2.3.5 Azaborolidines and other Boron
Heterocycles ................................. 24
1.2.3.6 Dihaloboranes and Monoalkylboranes ........... 26
1.2.3.7 Trifluoroborate Salts ........................ 27
1.3 Synthesis of Boronic Acids and their Esters ................ 28
1.3.1 Arylboronic Acids .................................... 28
1.3.1.1 Electrophilic Trapping of Arylmetal
Intermediates with Borates ................... 28
1.3.1.2 Transmetallation of Aryl Silanes and
Stannanes .................................... 34
1.3.1.3 Coupling of Aryl Halides with Diboronyl
Reagents ..................................... 35
1.3.1.4 Direct Boronylation by Transition Metal-
catalyzed Aromatic C-H Functionalization ..... 35
1.3.1.5 Other Methods ................................ 36
1.3.2 Diboronic Acids ...................................... 36
1.3.3 Heterocyclic Boronic Acids ........................... 37
1.3.4 Alkenylboronic Acids ................................. 37
1.3.4.1 Electrophilic Trapping of Alkenymetal
Intermediates with Borates ................... 37
1.3.4.2 Transmetallation Methods ..................... 37
1.3.4.3 Transition-metal Catalyzed Coupling between
Alkenyl Halides/Triflates and Diboronyl
Reagents ..................................... 42
1.3.4.4 Hydroboration of Alkynes ..................... 43
1.3.4.5 Alkene Metathesis ............................ 46
1.3.4.6 Other Methods ................................ 46
1.3.5 Alkynylboronic Acids ................................. 48
1.3.6 Alkylboronic Acids ................................... 48
1.3.7 Allylic Boronic Acids ................................ 49
1.3.8 Chemoselective Transformations of Compounds
containing a Boronic Acid (Ester) Substituent ........ 49
1.3.8.1 Oxidative Methods ............................ 50
1.3.8.2 Reductive Methods ............................ 51
1.3.8.3 Generation and Reactions of α-Boronyl-
substituted Carbanions and Radicals .......... 51
1.3.8.4 Reactions of (α-Haloalkyl)boronic Esters ..... 54
1.3.8.5 Other Transformations ........................ 55
1.4 Isolation and Characterization ............................. 57
1.4.1 Chromatography and Recrystallization ................. 57
1.4.2 Solid Supports for Boronic Acid Immobilization and
Purification ......................................... 58
1.4.2.1 Diethanolaminomethyl Polystyrene ............. 59
1.4.2.2 Other Solid-supported Diol Resins ............ 60
1.4.2.3 Soluble Diol Approaches ...................... 60
1.4.3 Analytical and Spectroscopic Methods for Boronic
Acid Derivatives ..................................... 61
1.4.3.1 Melting Points and Combustion Analysis ....... 61
1.4.3.2 Mass Spectrometry ............................ 61
1.4.3.3 Nuclear Magnetic Resonance Spectroscopy ...... 61
1.4.3.4 Other Spectroscopic Methods .................. 62
1.5 Overview of the Reactions of Boronic Acid Derivatives ...... 62
1.5.1 Metallation and Metal-catalyzed Protodeboronation .... 62
1.5.2 Oxidative Replacement of Boron ....................... 63
1.5.2.1 Oxygenation .................................. 63
1.5.2.2 Amination .................................... 65
1.5.2.3 Halogenation ................................. 66
1.5.3 Carbon-Carbon Bond forming Processes ................. 68
1.5.3.1 Palladium-catalyzed Cross-coupling with
Carbon Halides (Suzuki Coupling) .............. 69
1.5.3.2 Allylation of Carbonyl Compounds ............. 71
1.5.3.3 Uncatalyzed Additions to Imines and
Iminiums ..................................... 73
1.5.3.4 Rhodium-catalyzed Additions to Aldehydes
and Alkenes .................................. 73
1.5.3.5 Heck-type Coupling to Alkenes and Alkynes .... 73
1.5.4 Carbon-Heteroatom Bond forming Processes ............. 73
1.5.4.1 Copper-catalyzed Coupling with Nucleophilic
Oxygen and Nitrogen-containing Compounds ..... 73
1.5.5 Other Reactions ...................................... 74
1.6 Overview of other Applications of Boronic Acid
Derivatives ................................................ 76
1.6.1 Use as Reaction Promoters and Catalysts .............. 76
1.6.2 Use as Protecting Groups for Diols and Diamines ...... 78
1.6.3 Use as Supports for Derivatization and Affinity
Purification of Diols, Sugars, and Glycosylated
Proteins ............................................. 79
1.6.4 Use as Receptors and Sensors for Carbohydrates and
other Small Molecules ................................ 81
1.6.5 Use as Antimicrobial Agents and Enzyme Inhibitors .... 81
1.6.6 Use in Neutron Capture Therapy for Cancer ............ 82
1.6.7 Use in Transmembrane Transport ....................... 83
1.6.8 Use in Bioconjugation and Labeling of Proteins and
Cell Surface ......................................... 84
1.7 References ................................................. 85
2 Metal-catalyzed Borylation of Alkanes and Arenes via C-H
Activation for Synthesis of Boronic Esters ................ 101
T. Ishiyama and N. Miyaura
2.1 Introduction .............................................. 101
2.2 Borylation of Aromatic Halides and Triflates .............. 102
2.2.1 Cross-coupling Reaction of Diborons ................. 102
2.2.2 Cross-coupling Reaction of Pinacolborane ............ 104
2.3 Aliphatic C-H Borylation .................................. 105
2.3.1 Rhenium-catalyzed Photochemical Reaction ............ 106
2.3.2 Rhodium-catalyzed Reaction .......................... 107
2.4 Aromatic C-H Borylation ................................... 109
2.4.1 Rhenium-catalyzed Photochemical Reaction ............ 109
2.4.2 Rhodium-catalyzed Reactions ......................... 109
2.4.3 Iridium-catalyzed Reactions ......................... 110
2.4.4 Catalytic Cycle ..................................... 116
2.5 Benzylic C-H Borylation ................................... 118
Acknowledgments ........................................... 119
2.6 References ................................................ 119
3 Coupling Reactions of Areneboronic Acids or Esters with
Aromatic Electrophiles .................................... 123
A. Suzuki
3.1 Introduction .............................................. 123
3.2 Coupling Reactions of Areneboronic Acid Derivatives ....... 124
3.2.1 With Aryl Halides. Synthesis of Biaryls ............. 124
3.2.1.1 Aromatic-Aromatic Coupling .................. 124
3.2.1.2 Aromatic-Heteroaromatic and
Heteroaromatic-Heteroaromatic Couplings ..... 131
3.2.1.3 Coupling of Sterically Hindered
Arylboronic Acids or ones Possessing
Electron-attracting Substituents ............ 141
3.2.1.4 Modified Catalysts and Ligands .............. 144
3.2.1.5 Solid-phase Synthesis (Combinatorial
Methodology) ................................ 153
3.2.2 With Other Organic Halides, including Aryl
Chlorides and Electrophiles ......................... 156
3.2.3 Miscellaneous ....................................... 160
3.3 Conclusion ................................................ 166
3.4 References ................................................ 167
4 Rhodium-catalyzed Additions of Boronic Acids to Alkenes
and Carbonyl Compounds .................................... 171
K. Yoshida and T. Hayashi
4.1 Introduction .............................................. 172
4.2 Addition of Organoboronic Acids to α, β-Unsaturated
Ketones ................................................... 172
4.3 Mechanism ................................................. 176
4.4 Addition of Organoboronic Acids to Other Alkenes .......... 181
4.5 Addition of Organoboronic Acids to Alkynes ................ 192
4.6 Addition of Organoboronic Acids to Aldehydes and Imines ... 195
4.7 Addition of Organoboronic Acids to Anhydrides ............. 200
4.8 Outlook ................................................... 201
4.9 References ................................................ 202
5 Recent Advances in Copper-promoted C-Heteroatom Bond
Cross-coupling Reactions with Boronic Acids and
Derivatives .............................................. 205
D.M.T. Chan and P.Y.S. Lam
5.1 General Introduction ..................................... 205
5.2 Copper-mediated Boronic Acid C-O and C-N Cross-
coupling - Historical Background ......................... 206
5.3 C(aryl)-O Cross-coupling ................................. 207
5.3.1 Intermolecular C-O Cross-coupling .................. 207
5.3.2 Intramolecular C-O Cross-coupling .................. 210
5.4 C-N Cross-coupling ....................................... 212
5.4.1 C-N (Non-heteroarene NH) Cross-coupling ............ 212
5.4.1.1 Application in Solid-phase Synthesis ....... 214
5.4.2 C-N (Heteroarene) Cross-coupling ................... 215
5.4.2.1 Factor Xa Inhibitors ....................... 217
5.4.2.2 Purines .................................... 229
5.4.2.3 Heteroarene-Heteroarene Cross-coupling ..... 220
5.5 C-O vs. C-N Cross-couplings .............................. 221
5.6 C-N and C-O Cross-coupling with Alkenylboronic Acids ..... 222
5.7 C-S Cross-coupling ....................................... 224
5.8 C-N and C-O Cross-coupling with Boronic Acid
Derivatives .............................................. 224
5.8.1 Boroxines, Boronic Esters and Trifluoroborate
Salts .............................................. 224
5.8.2 Alkylboronic Acids ................................. 227
5.9 Mechanistic Considerations ............................... 227
5.9.1 Electronic Effects ................................. 227
5.9.2 Solvent Effects .................................... 228
5.9.3 Ligand or Base Effects ............................. 229
5.9.4 Mechanism .......................................... 230
5.9.5 Side-products ...................................... 231
5.10 Other Organometalloids ................................... 233
5.11 Conclusion ............................................... 233
5.12 Appendix ................................................. 235
5.13 References ............................................... 238
6 Recent Advances in the Preparation of Allylboronates and
Their Use in Tandem Reactions with Carbonyl Compounds ..... 241
J.W.J. Kennedy and D.G. Hall
6.1 Introduction .............................................. 241
6.2 Preparation of Allylboronates ............................. 243
6.2.1 Direct Methods ...................................... 243
6.2.1.1 Allylboronates from Allylmetal
Intermediates ............................... 243
6.2.1.2 Allylboronates from Alkenylmetal
Intermediates ............................... 244
6.2.1.3 Allylboronates from the Hydroboration of
1,3-Butadienes and Allenes .................. 246
6.2.1.4 Allylboronates from the Transition-metal
Catalyzed Diboration and Silaboration of
Dienes and Allenes .......................... 247
6.2.1.5 Allylboronates from Palladium-catalyzed
Cross-coupling Reactions with Alkenyl
Fragments ................................... 249
6.2.1.6 Allylboronates from Palladium-catalyzed
Cross-coupling Reactions with Allyl
Electrophiles ............................... 249
6.2.2 Indirect Methods .................................... 250
6.2.2.1 Allylboronates from Alcoholysis of
Triallylboranes ............................. 250
6.2.2.2 Allylboronates from Homologation of
Alkenylboronates ............................ 250
6.2.2.3 Allylboronates from Allylic Rearrangement
of Alkenylboronates ......................... 251
6.2.2.4 Allylboronates from Isomerization of
Alkenylboronates ............................ 252
6.2.2.5 Allylboronates by Cycloadditions of
Dienylboronates ............................. 253
6.2.2.6 Allylboronates by Olefin Metathesis ......... 254
6.3 Reactions of Allylboronates ............................... 256
6.3.1 Additions to Aldehydes - Formation of Homoallylic
Alcohols ............................................ 256
6.3.1.1 Stereoselectivity and Mechanism of
Non-catalyzed Additions ..................... 256
6.3.1.2 Lewis Acid-catalyzed Additions .............. 257
6.3.1.3 Stereoselective Additions with Chiral
Allylboronates .............................. 259
6.3.2 Additions to Ketones ................................ 263
6.3.3 Additions to Imine Derivatives ...................... 264
6.4 Applications of Allylboronates in Tandem Reactions with
Carbonyl Compounds ........................................ 266
6.4.1 Allylboration as the Terminal Process ............... 266
6.4.1.1 Tandem [4+2] Cycloaddition/Allylation ....... 266
6.4.1.2 Tandem Hydroformylation/Intramolecular
Allylation .................................. 267
6.4.1.3 Tandem Alkene Cross-metathesis/Allylation ... 268
6.4.1.4 Tandem Diene Hydroboration/Allylation ....... 269
6.4.1.5 Tandem Diene Diborylation (Silaboration)/
Allylboration ............................... 270
6.4.1.6 Tandem Allylic Borylation/Intramolecular
Allylation .................................. 271
6.4.2 Allylboration as the Initiating Process ............. 271
6.4.2.1 Tandem Allylation/Allylation ................ 271
6.4.2.2 Tandem Allylation/Lactonization ............. 272
6.4.2.3 Tandem Allylation/Dioxene Thermolysis ....... 273
6.5 Conclusion ................................................ 274
6.6 References ................................................ 274
7 Nucleophilic Addition Reactions of Aryl and
Alkenylboronic Acids and Their Derivatives to Imines and
Iminium Ions .............................................. 279
R.A. Batey
7.1 Introduction .............................................. 279
7.2 Petasis Borono-Mannich Reaction: Iminium Ions Lacking
Neighboring Heteroatom Functionality ...................... 282
7.2.1 Discovery of the Reaction using Paraformaldehyde .... 281
7.2.2 Reactions of Iminium Ions Derived from Simple
Aldehydes ........................................... 281
7.3 Practicality, Scope and Reaction Mechanism ................ 282
7.3.1 Synthetic Benefits of the Petasis Borono-Mannich
Reaction ............................................ 282
7.3.2 Mechanistic Observations ............................ 283
7.3.3 Substrate Scope and the Effect of Neighboring
Heteroatoms ......................................... 284
7.4 Petasis Borono-Mannich Reaction: Iminium Ions Possessing
Neighboring Heteroatom Functionality ...................... 285
7.4.1 Reactions of Glyoxylic Acid-derived Iminium Ions .... 285
7.4.1.1 Diastereoselective Addition Reactions to
Iminium Ions Derived from Chiral Amines
and Glyoxylic Acid .......................... 289
7.4.1.2 Enantioselective Addition Reactions to
Glyoxylic Acid-derived Iminium Ions using
Chiral Boronic Esters ....................... 289
7.4.2 Reactions of Iminium Ions Bearing α-Heteroatom
Substituents ........................................ 290
7.4.2.1 Diastereoselective Addition Reactions ....... 290
7.4.3 Reactions of Iminium Ions Bearing β-Heteroatom
Substituents ........................................ 291
7.4.4 Addition Reactions using Iminium Ions Derived from
Hydrazines, Hydroxylamines and Sulfinamides ......... 293
7.5 Polymer-supported Petasis Borono-Mannich Reactions ........ 294
7.6 Other Types of Addition Reactions ......................... 297
7.6.1 Lewis Acid Promoted Additions: Addition Reactions
to N-Acyliminium Ions ............................... 297
7.6.2 Lewis Acid Promoted Additions of
Organotrifluoroborate Salts ......................... 298
7.6.3 Rhodium-catalyzed Additions of Boronic Acids to
N-Sulfonylimines .................................... 299
7.6.4 Dialkylzinc-promoted Additions of Alkenylboronic
Esters to Nitrones .................................. 301
7.6.5 Nickel-catalyzed Couplings of Boronic Acids with
Alkynes and Imines .................................. 301
7.7 Concluding Remarks ........................................ 302
7.8 References ................................................ 303
8 (α-Haloalkyl)boronic Esters in Asymmetric Synthesis ....... 305
D.S. Matteson
8.1 Introduction .............................................. 305
8.2 General Description of (α-Haloalkyl)boronic Ester
Chemistry ................................................. 305
8.2.1 A Brief History of Boronic Ester Chemistry .......... 305
8.2.2 C2-symmetrical Boronic Esters ....................... 306
8.3 Boronic Ester Intermediates in Synthesis .................. 311
8.3.1 Boronic Ester Intermediates without Functional
Substituents ........................................ 311
8.3.2 Halogen-substituted Boronic Esters .................. 315
8.3.3 Alkoxy-substituted Boronic Esters ................... 316
8.3.4 Carbonyl Substituents ............................... 323
8.3.5 Nitrile Substituents ................................ 325
8.3.6 Amino and Amido Substituents ........................ 328
8.3.7 Azido Substituents .................................. 331
8.3.8 Other Applications of (α-Haloalkyl)boronic Esters ... 333
8.4 Other Aspects of (α-Chloroalkyl)boronic Ester Chemistry ... 334
8.4.1 Replacement of Boronic Ester Groups ................. 334
8.4.2 Chain Extension with (Dialkoxymethyl)lithium ........ 336
8.4.3 (α-Iodoalkyl)boronic Esters via (Phenylthiomethyl)
boronic Esters ...................................... 336
8.4.4 Free Radicals from (α-Haloalkyl)boronic Esters ...... 337
8.4.5 Metal Substitutions of (α-Haloalkyl)boronic
Esters .............................................. 338
8.5 Conclusion ................................................ 340
8.6 References ................................................ 340
9 Cycloadditions and Other Additions to Alkenyl-, Alkynyl-
and Dienyl Boronic Esters ................................. 343
B. Carboni and F. Carreaux
9.1 Ionic Addition ............................................ 343
9.1.1 Halogenation and Hydrohalogenation .................. 343
9.1.2 Addition of Organometallics ......................... 345
9.2 Radical Additions ......................................... 347
9.3 Cycloaddition Reactions ................................... 350
9.3.1 Cyclopropanation .................................... 350
9.3.2 Diels-Alder Reactions ............................... 351
9.3.2.1 Alkenylboronates as Dienophiles ............. 351
9.3.2.2 Alkynylboronates as Dienophiles ............. 355
9.3.2.3 1,3-Dienyl-1-boronates as Dienes ............ 356
9.3.2.4 1,3-Dienyl-1-boronates as Heterodienes ...... 360
9.3.2.5 1,3-Dienyl-2-boronates as Dienes ............ 361
9.3.3 1,3-Dipolar Cycloadditions .......................... 363
9.3.3.1 Diazoalkanes ................................ 363
9.3.3.2 Nitrile Oxides .............................. 364
9.3.3.3 Nitrones .................................... 365
9.3.3.4 Azomethyne Ylides ........................... 366
9.3.4 Other Cycloadditions ................................ 367
9.4 Metathesis Reactions ...................................... 368
9.5 Miscellaneous Reactions ................................... 370
9.6 Conclusions ............................................... 372
9.7 References ................................................ 373
10 Organoboronic Acids and Organoborinic Acids as
Brønsted-Lewis Acid Catalysts in Organic Synthesis ....... 377
K. Ishihara
10.1 Introduction ............................................. 377
10.2 Diarylborinic Acids ...................................... 377
10.3 Arylboronic Acids ........................................ 381
10.4 Chiral Boronate Lewis Acids .............................. 389
10.4.1 Enantioselective Carbo Diels-Alder Reactions ...... 389
10.4.2 Enantioselective Hetero-Diels-Alder Reactions ..... 399
10.4.3 Enantioselective Mukaiyama Aldol Reactions ........ 400
10.4.4 Enantioselective Sakurai-Hosomi Allylation
Reactions ......................................... 405
10.4.5 Enantioselective Reduction ........................ 406
10.4.6 Enantioselective Cyclopropanation ................. 407
10.5 Conclusions .............................................. 407
10.6 References ............................................... 408
11 Oxazaborolidines as Asymmetric Inducers for
the Reduction of Ketones and Ketimines ................... 411
B.T. Cho
11.1 Introduction ............................................. 411
11.2 Oxazaborolidines ......................................... 413
11.3 Oxazaborolidine-catalyzed Asymmetric Reduction of
Ketones .................................................. 414
11.3.1 Mechanism of OAB-catalyzed Ketone Reduction ....... 415
11.3.2 Unfunctionalized Acyclic and Aryl Alkyl Ketones ... 416
11.3.3 Diaryl Ketones .................................... 416
11.3.4 Heterocyclic Ketones .............................. 417
11.3.5 Functionalized Ketones ............................ 418
11.3.5.1 α-Halo and α-Sulfonyloxy Ketones ......... 418
11.3.5.2 α-Hydroxy Ketones and Diketones .......... 421
11.3.5.3 α-Keto Acetals and Thioketals ............ 422
11.3.5.4 Keto Esters and meso-Imides .............. 423
11.3.5.5 α, β-Enones and Ynones ................... 424
11.3.5.6 α-Azido and Imino Ketones ................ 426
11.3.5.7 α-, β- and γ-Keto Phosphates ............. 427
11.3.5.8 β-Keto Sulfides and Sulfones ............. 428
11.3.6 Atropo-enantioselective Reduction ................. 429
11.3.7 Kinetic Resolution of Racemic Ketones and Biaryl
Lactones .......................................... 429
11.4 Asymmetric Reduction of Prochiral Ketimines .............. 430
11.4.1 Ketoxime Derivatives .............................. 430
11.4.2 N-Substituted Ketimines ........................... 433
11.5 Summary and Conclusions .................................. 434
Acknowledgments .......................................... 436
11.6 References ............................................... 436
12 Boronic Acid-based Receptors and Sensors for
Saccharides .............................................. 441
T.D. James
12.1 Introduction ............................................. 441
12.2 Fluorescence ............................................. 445
12.2.1 Internal Charge Transfer (ICT) .................... 445
12.2.2 Photoinduced Electron Transfer (PET) .............. 448
12.2.3 Other Fluorescent Sensors ......................... 458
12.3 Colorimetric Sensors ..................................... 461
12.4 Electrochemical Sensors .................................. 467
12.5 Assay Systems ............................................ 468
12.6 Polymer and Surface Bound Sensors ........................ 471
12.7 Conclusions .............................................. 474
12.8 References ............................................... 475
13 Biological and Medicinal Applications of Boronic Acids ... 481
W. Yang, X. Gao, and B. Wang
13.1 Introduction ............................................. 481
13.2 Boronic Acid Compounds as Enzyme Inhibitors .............. 484
13.2.1 Protease Inhibitors that Bind to One Side of
the Active Site ................................... 485
13.2.2 Boronic acid-Nucleophile Complex Formed in
the Enzyme Active Site as a way to Improve
Potency and Selectivity ........................... 488
13.2.3 Boronic Acids used for the Binding of the Non-
scissile Position ................................. 490
13.2.4 Boronic Esters as Enzyme Inhibitors ............... 493
13.2.5 Boronic Acids as Inhibitors of Glycosidases ....... 493
13.2.6 Boronic Acids as Agents Targeting the Human
Immunodeficiency Virus ............................ 494
13.2.7 Bortezomib as a Proteasome Inhibitor for Cancer
Therapy: A Successful Example ..................... 494
13.2.8 Others ............................................ 496
13.3 Boronic Acid Compounds as Boron Neutron Capture Therapy
(BNCT) Agents ............................................ 499
13.4 Boronic Acid Compounds as Drug (Insulin) Delivery
Devices and for In Vivo Glucose Imaging .................. 500
13.5 Cell Surface Carbohydrate Recognition by Artificial
Lectins-Boronolectins .................................... 503
13.6 Conclusions .............................................. 506
Acknowledgments .......................................... 506
13.7 References ............................................... 507
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