Advanced Organic Chemistry PartB - Reaction and Synthesis by Francis A. Carey and Richard J. Sundberg
Advanced Organic Chemistry PartB - Reaction and Synthesis
EDITION
Part B: Reactions and Synthesis
Advanced Organic Chemistry
PART A: Structure and Mechanisms
PART B: Reactions and Synthesis
The focus of Part B is on the closely interrelated topics of reactions and synthesis. In
each of the first twelve chapters, we consider a group of related reactions that have
been chosen for discussion primarily on the basis of their usefulness in synthesis. For
each reaction we present an outline of the mechanism, its regio- and stereochemical
characteristics, and information on typical reaction conditions. For the more commonly
used reactions, the schemes contain several examples, which may include examples of
the reaction in relatively simple molecules and in more complex structures. The goal of
these chapters is to develop a fundamental base of knowledge about organic reactions
in the context of synthesis. We want to be able to answer questions such as: What
transformation does a reaction achieve? What is the mechanism of the reaction? What
reagents and reaction conditions are typically used? What substances can catalyze
the reaction? How sensitive is the reaction to other functional groups and the steric
environment? What factors control the stereoselectivity of the reaction? Under what
conditions is the reaction enantioselective?
Synthesis is the application of one or more reactions to the preparation of a
particular target compound, and can pertain to a single-step transformation or to a
number of sequential steps. The selection of a reaction or series of reactions for a
synthesis involves making a judgment about the most effective possibility among
the available options. There may be a number of possibilities for the synthesis of a
particular compound. For example, in the course of learning about the reactions in
Chapter 1 to 12, we will encounter a number of ways of making ketones, as outlined
in the scheme that follows.
Chapter 1. Alkylation of Enolates and Other Carbon Nucleophiles . . . . . . 1
Introduction........................................................................................................... 1
1.1. Generation and Properties of Enolates and Other Stabilized Carbanions... 2
1.1.1. Generation of Enolates by Deprotonation ........................................ 2
1.1.2. Regioselectivity and Stereoselectivity in Enolate Formation
from Ketones and Esters ................................................................... 5
1.1.3. Other Means of Generating Enolates................................................ 14
1.1.4. Solvent Effects on Enolate Structure and Reactivity ....................... 17
1.2. Alkylation of Enolates.................................................................................. 21
1.2.1. Alkylation of Highly Stabilized Enolates ......................................... 21
1.2.2. Alkylation of Ketone Enolates.......................................................... 24
1.2.3. Alkylation of Aldehydes, Esters, Carboxylic Acids, Amides,
and Nitriles ........................................................................................ 31
1.2.4. Generation and Alkylation of Dianions............................................ 36
1.2.5. Intramolecular Alkylation of Enolates.............................................. 36
1.2.6. Control of Enantioselectivity in Alkylation Reactions..................... 41
1.3. The Nitrogen Analogs of Enols and Enolates: Enamines
and Imine Anions ......................................................................................... 46
General References............................................................................................... 55
Problems ............................................................................................................... 56
Chapter 2. Reactions of Carbon Nucleophiles
with Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Introduction........................................................................................................... 63
2.1. Aldol Addition and Condensation Reactions............................................... 64
2.1.1. The General Mechanism ................................................................... 64
2.1.2. Control of Regio- and Stereoselectivity of Aldol Reactions
of Aldehydes and Ketones ................................................................ 65
2.1.3. Aldol Addition Reactions of Enolates of Esters
and Other Carbonyl Derivatives ....................................................... 78
2.1.4. The Mukaiyama Aldol Reaction....................................................... 82
2.1.5. Control of Facial Selectivity in Aldol and Mukaiyama Aldol
Reactions............................................................................................ 86
2.1.6. Intramolecular Aldol Reactions and the Robinson Annulation ....... 134
2.2. Addition Reactions of Imines and Iminium Ions ........................................ 139
2.2.1. The Mannich Reaction ...................................................................... 140
2.2.2. Additions to N-Acyl Iminium Ions ................................................... 145
2.2.3. Amine-Catalyzed Condensation Reactions....................................... 147
2.3. Acylation of Carbon Nucleophiles............................................................... 148
2.3.1. Claisen and Dieckmann Condensation Reactions ............................ 149
2.3.2. Acylation of Enolates and Other Carbon Nucleophiles ................... 150
2.4. Olefination Reactions of Stabilized Carbon Nucleophiles .......................... 157
2.4.1. The Wittig and Related Reactions of Phosphorus-Stabilized
Carbon Nucleophiles ......................................................................... 157
2.4.2. Reactions of -Trimethylsilylcarbanions with Carbonyl
Compounds........................................................................................ 171
2.4.3. The Julia Olefination Reaction ......................................................... 174
2.5. Reactions Proceeding by Addition-Cyclization ........................................... 177
2.5.1. Sulfur Ylides and Related Nucleophiles........................................... 177
2.5.2. Nucleophilic Addition-Cyclization of -Haloesters......................... 182
2.6. Conjugate Addition by Carbon Nucleophiles .............................................. 183
2.6.1. Conjugate Addition of Enolates........................................................ 183
2.6.2. Conjugate Addition with Tandem Alkylation .................................. 189
2.6.3. Conjugate Addition by Enolate Equivalents..................................... 190
2.6.4. Control of Facial Selectivity in Conjugate
Addition Reactions ............................................................................ 193
2.6.5. Conjugate Addition of Organometallic Reagents............................. 197
2.6.6. Conjugate Addition of Cyanide Ion.................................................. 198
General References............................................................................................... 200
Problems ............................................................................................................... 200
Chapter 3. Functional Group Interconversion
by Substitution, Including Protection and Deprotection . . . . . . 215
Introduction........................................................................................................... 215
3.1. Conversion of Alcohols to Alkylating Agents............................................. 216
3.1.1. Sulfonate Esters ................................................................................. 216
3.1.2. Halides ............................................................................................... 217
3.2. Introduction of Functional Groups by Nucleophilic Substitution
at Saturated Carbon ...................................................................................... 223
3.2.1. General Solvent Effects..................................................................... 224
3.2.2. Nitriles ............................................................................................... 225
3.2.3. Oxygen Nucleophiles ........................................................................ 226
3.2.4. Nitrogen Nucleophiles....................................................................... 229
3.2.5. Sulfur Nucleophiles ........................................................................... 233
3.2.6. Phosphorus Nucleophiles .................................................................. 233
3.2.7. Summary of Nucleophilic Substitution at Saturated Carbon ........... 234
3.3. Cleavage of Carbon-Oxygen Bonds in Ethers and Esters........................... 238
3.4. Interconversion of Carboxylic Acid Derivatives ......................................... 242
3.4.1. Acylation of Alcohols ....................................................................... 243
3.4.2. Fischer Esterification......................................................................... 252
3.4.3. Preparation of Amides....................................................................... 252
3.5. Installation and Removal of Protective Groups........................................... 258
3.5.1. Hydroxy-Protecting Groups .............................................................. 258
3.5.2. Amino-Protecting Groups ................................................................. 267
3.5.3. Carbonyl-Protecting Groups.............................................................. 272
3.5.4. Carboxylic Acid–Protecting Groups ................................................. 275
Problems ............................................................................................................... 277
Chapter 4. Electrophilic Additions to Carbon-Carbon Multiple Bonds . . . 289
Introduction........................................................................................................... 289
4.1. Electrophilic Addition to Alkenes................................................................ 290
4.1.1. Addition of Hydrogen Halides.......................................................... 290
4.1.2. Hydration and Other Acid-Catalyzed Additions of Oxygen
Nucleophiles ...................................................................................... 293
4.1.3. Oxymercuration-Reduction ............................................................... 294
4.1.4. Addition of Halogens to Alkenes ..................................................... 298
4.1.5. Addition of Other Electrophilic Reagents ........................................ 305
4.1.6. Addition Reactions with Electrophilic Sulfur and Selenium
Reagents............................................................................................. 307
4.2. Electrophilic Cyclization .............................................................................. 310
4.2.1. Halocyclization .................................................................................. 311
4.2.2. Sulfenylcyclization and Selenenylcyclization................................... 320
4.2.3. Cyclization by Mercuric Ion ............................................................. 324
4.3. Electrophilic Substitution to Carbonyl Groups........................................ 328
4.3.1. Halogenation to Carbonyl Groups ................................................ 328
4.3.2. Sulfenylation and Selenenylation to Carbonyl Groups ................ 331
4.4. Additions to Allenes and Alkynes ............................................................... 333
4.5. Addition at Double Bonds via Organoborane Intermediates ...................... 337
4.5.1. Hydroboration.................................................................................... 337
4.5.2. Reactions of Organoboranes ............................................................. 344
4.5.3. Enantioselective Hydroboration ........................................................ 347
4.5.4. Hydroboration of Alkynes................................................................. 352
4.6. Hydroalumination, Carboalumination, Hydrozirconation,
and Related Reactions .................................................................................. 353
Chapter 5. Reduction of Carbon-Carbon Multiple Bonds, Carbonyl
Groups, and Other Functional Groups . . . . . . . . . . . . . . . . . . . . . . 367
Introduction........................................................................................................... 367
5.1. Addition of Hydrogen at Carbon-Carbon Multiple Bonds.......................... 368
5.1.1. Hydrogenation Using Heterogeneous Catalysts ............................... 368
5.1.2. Hydrogenation Using Homogeneous Catalysts ................................ 374
5.1.3. Enantioselective Hydrogenation........................................................ 376
5.1.4. Partial Reduction of Alkynes ............................................................ 387
5.1.5. Hydrogen Transfer from Diimide ..................................................... 388
5.2. Catalytic Hydrogenation of Carbonyl and Other Functional Groups ......... 390
5.3. Group III Hydride-Donor Reagents ............................................................. 396
5.3.1. Comparative Reactivity of Common Hydride
Donor Reagents ................................................................................. 396
5.3.2. Stereoselectivity of Hydride Reduction ............................................ 407
5.3.3. Enantioselective Reduction of Carbonyl Compounds...................... 415
5.3.4. Reduction of Other Functional Groups by Hydride Donors............ 422
5.4. Group IV Hydride Donors ........................................................................... 425
5.4.1. Reactions Involving Silicon Hydrides .............................................. 425
5.4.2. Hydride Transfer from Carbon ......................................................... 429
5.5. Reduction Reactions Involving Hydrogen Atom Donors............................ 431
5.6. Dissolving-Metal Reductions ....................................................................... 434
5.6.1. Addition of Hydrogen ....................................................................... 435
5.6.2. Reductive Removal of Functional Groups ....................................... 439
5.6.3. Reductive Coupling of Carbonyl Compounds.................................. 444
5.7. Reductive Deoxygenation of Carbonyl Groups........................................... 452
5.7.1. Reductive Deoxygenation of Carbonyl Groups to Methylene ......... 452
5.7.2. Reduction of Carbonyl Compounds to Alkenes............................... 454
5.8. Reductive Elimination and Fragmentation................................................... 457
Problems ............................................................................................................... 462
Chapter 6. Concerted Cycloadditions, Unimolecular Rearrangements,
and Thermal Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Introduction........................................................................................................... 473
6.1. Diels-Alder Reactions................................................................................... 474
6.1.1. The Diels-Alder Reaction: General Features.................................... 474
6.1.2. Substituent Effects on the Diels-Alder Reaction.............................. 475
6.1.3. Lewis Acid Catalysis of the Diels-Alder Reaction .......................... 481
6.1.4. The Scope and Synthetic Applications
of the Diels-Alder Reaction .............................................................. 487
6.1.5. Diastereoselective Diels-Alder Reactions
Using Chiral Auxiliaries ................................................................... 499
6.1.6. Enantioselective Catalysts for Diels-Alder Reactions...................... 505
6.1.7. Intramolecular Diels-Alder Reactions............................................... 518
6.2. 1,3-Dipolar Cycloaddition Reactions ........................................................... 526
6.2.1. Regioselectivity and Stereochemistry ............................................... 528
6.2.2. Synthetic Applications of Dipolar Cycloadditions ........................... 531
6.2.3. Catalysis of 1,3-Dipolar Cycloaddition Reactions ........................... 535
6.3. [2 + 2] Cycloadditions and Related Reactions Leading
to Cyclobutanes ............................................................................................ 538
6.3.1. Cycloaddition Reactions of Ketenes and Alkenes............................ 539
6.3.2. Photochemical Cycloaddition Reactions........................................... 544
6.4. [3,3]-Sigmatropic Rearrangements............................................................... 552
6.4.1. Cope Rearrangements........................................................................ 552
6.4.2. Claisen and Modified Claisen Rearrangements................................ 560
6.5. [2,3]-Sigmatropic Rearrangements............................................................... 581
6.5.1. Rearrangement of Allylic Sulfoxides, Selenoxides,
and Amine Oxides............................................................................. 581
6.5.2. Rearrangement of Allylic Sulfonium and Ammonium Ylides......... 583
6.5.3. Anionic Wittig and Aza-Wittig Rearrangements ............................. 587
6.6. Unimolecular Thermal Elimination Reactions............................................. 590
6.6.1. Cheletropic Elimination..................................................................... 591
6.6.2. Decomposition of Cyclic Azo Compounds ...................................... 593
6.6.3. -Eliminations Involving Cyclic Transition Structures.................... 596
Problems ............................................................................................................... 604
Chapter 7. Organometallic Compounds of Group I and II Metals . . . . . . . 619
Introduction........................................................................................................... 619
7.1. Preparation and Properties of Organomagnesium
and Organolithium Reagents ........................................................................ 620
7.1.1. Preparation and Properties of Organomagnesium Reagents ............ 620
7.1.2. Preparation and Properties of Organolithium Compounds .............. 624
7.2. Reactions of Organomagnesium and Organolithium Compounds .............. 634
7.2.1. Reactions with Alkylating Agents .................................................... 634
7.2.2. Reactions with Carbonyl Compounds .............................................. 637
7.3. Organometallic Compounds of Group IIB and IIIB Metals ....................... 650
7.3.1. Organozinc Compounds .................................................................... 650
7.3.2. Organocadmium Compounds............................................................ 661
7.3.3. Organomercury Compounds ............................................................. 662
7.3.4. Organoindium Reagents .................................................................... 663
7.4. Organolanthanide Reagents.......................................................................... 664
General References............................................................................................... 666
Problems ............................................................................................................... 667
Chapter 8. Reactions Involving Transition Metals. . . . . . . . . . . . . . . . . . . . . . . 675
Introduction........................................................................................................... 675
8.1. Organocopper Intermediates......................................................................... 675
8.1.1. Preparation and Structure of Organocopper Reagents ..................... 675
8.1.2. Reactions Involving Organocopper Reagents
and Intermediates............................................................................... 680
8.2. Reactions Involving Organopalladium Intermediates.................................. 706
8.2.1. Palladium-Catalyzed Nucleophilic Addition
and Substitution ................................................................................. 709
8.2.2. The Heck Reaction............................................................................ 715
8.2.3. Palladium-Catalyzed Cross Coupling ............................................... 723
8.2.4. Carbonylation Reactions ................................................................... 748
8.3. Reactions Involving Other Transition Metals.............................................. 754
8.3.1. Organonickel Compounds................................................................. 754
8.3.2. Reactions Involving Rhodium and Cobalt........................................ 759
8.4. The Olefin Metathesis Reaction................................................................... 761
8.5. Organometallic Compounds with
-Bonding.............................................. 767
General References............................................................................................... 771
Problems ............................................................................................................... 771
Chapter 9. Carbon-Carbon Bond-Forming Reactions
of Compounds of Boron, Silicon, and Tin. . . . . . . . . . . . . . . . . . . . 783
Introduction........................................................................................................... 783
9.1. Organoboron Compounds............................................................................. 784
9.1.1. Synthesis of Organoboranes.............................................................. 784
9.1.2. Carbonylation and Other One-Carbon
Homologation Reactions ................................................................... 786
9.1.3. Homologation via -Halo Enolates .................................................. 792
9.1.4. Stereoselective Alkene Synthesis...................................................... 793
9.1.5. Nucleophilic Addition of Allylic Groups from
Boron Compounds............................................................................. 797
9.2. Organosilicon Compounds ........................................................................... 809
9.2.1. Synthesis of Organosilanes ............................................................... 809
9.2.2. General Features of Carbon-Carbon Bond-Forming Reactions
of Organosilicon Compounds ........................................................... 814
9.2.3. Additions Reactions with Aldehydes and Ketones .......................... 815
9.2.4. Reaction with Iminium Ions.............................................................. 825
9.2.5. Acylation Reactions........................................................................... 826
9.2.6. Conjugate Addition Reactions .......................................................... 830
9.3. Organotin Compounds.................................................................................. 833
9.3.1. Synthesis of Organostannanes........................................................... 833
9.3.2. Carbon-Carbon Bond-Forming Reactions ........................................ 836
9.4. Summary of Stereoselectivity Patterns ........................................................ 851
General References............................................................................................... 852
Problems ............................................................................................................... 853
Chapter 10. Reactions Involving Carbocations, Carbenes,
and Radicals as Reactive Intermediates . . . . . . . . . . . . . . . . . . . . . 861
Introduction............................................................................................................. 861
10.1. Reactions and Rearrangement Involving Carbocation Intermediates ......... 862
10.1.1. Carbon-Carbon Bond Formation Involving Carbocations ............. 862
10.1.2. Rearrangement of Carbocations ...................................................... 883
10.1.3. Related Rearrangements.................................................................. 892
10.1.4. Fragmentation Reactions ................................................................. 897
10.2. Reactions Involving Carbenes and Related Intermediates .......................... 903
10.2.1. Reactivity of Carbenes .................................................................... 905
10.2.2. Generation of Carbenes................................................................... 909
10.2.3. Addition Reactions .......................................................................... 916
10.2.4. Insertion Reactions .......................................................................... 934
10.2.5. Generation and Reactions of Ylides
by Carbenoid Decomposition.......................................................... 938
10.2.6. Rearrangement Reactions................................................................ 940
10.2.7. Related Reactions ............................................................................ 941
10.2.8. Nitrenes and Related Intermediates ................................................ 944
10.2.9. Rearrangements to Electron-Deficient Nitrogen ............................ 947
10.3. Reactions Involving Free Radical Intermediates ......................................... 956
10.3.1. Sources of Radical Intermediates.................................................... 957
10.3.2. Addition Reactions of Radicals with Substituted Alkenes............. 959
10.3.3. Cyclization of Free Radical Intermediates ..................................... 967
10.3.4. Additions to C=N Double Bonds................................................... 973
10.3.5. Tandem Radical Cyclizations and Alkylations............................... 979
10.3.6. Fragmentation and Rearrangement Reactions ................................ 984
10.3.7. Intramolecular Functionalization by Radical Reactions................. 989
Problems ................................................................................................................. 992
Chapter 11. Aromatic Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Introduction............................................................................................................. 1003
11.1. Electrophilic Aromatic Substitution ............................................................. 1004
11.1.1. Nitration........................................................................................... 1004
11.1.2. Halogenation.................................................................................... 1008
11.1.3. Friedel-Crafts Alkylation................................................................. 1014
11.1.4. Friedel-Crafts Acylation.................................................................. 1017
11.1.5. Related Alkylation and Acylation Reactions.................................. 1023
11.1.6. Electrophilic Metallation ................................................................. 1026
11.2. Nucleophilic Aromatic Substitution ............................................................. 1027
11.2.1. Aryl Diazonium Ions as Synthetic Intermediates........................... 1027
11.2.2. Substitution by the Addition-Elimination Mechanism................... 1035
11.2.3. Substitution by the Elimination-Addition Mechanism................... 1039
11.3. Transition Metal–Catalyzed Aromatic Substitution Reactions.................... 1042
11.3.1. Copper-Catalyzed Reactions ........................................................... 1042
11.3.2. Palladium-Catalyzed Reactions....................................................... 1045
11.4. Aromatic Substitution Reactions Involving Radical Intermediates............. 1052
11.4.1. Aromatic Radical Substitution ........................................................ 1052
11.4.2. Substitution by the SRN 1 Mechanism ............................................. 1053
Problems ................................................................................................................. 1056
Chapter 12. Oxidations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Introduction............................................................................................................. 1063
12.1. Oxidation of Alcohols to Aldehydes, Ketones, or Carboxylic Acids ......... 1063
12.1.1. Transition Metal Oxidants............................................................... 1063
12.1.2. Other Oxidants................................................................................. 1070
Contents
12.2. Addition of Oxygen at Carbon-Carbon Double Bonds ............................... 1074
12.2.1. Transition Metal Oxidants............................................................... 1074
12.2.2. Epoxides from Alkenes and Peroxidic Reagents............................ 1091
12.2.3. Subsequent Transformations of Epoxides ...................................... 1104
12.3. Allylic Oxidation .......................................................................................... 1116
12.3.1. Transition Metal Oxidants............................................................... 1116
12.3.2. Reaction of Alkenes with Singlet Oxygen ..................................... 1117
12.3.3. Other Oxidants................................................................................. 1124
12.4. Oxidative Cleavage of Carbon-Carbon Double Bonds ............................... 1126
12.4.1. Transition Metal Oxidants............................................................... 1126
12.4.2. Ozonolysis ....................................................................................... 1129
12.5. Oxidation of Ketones and Aldehydes .......................................................... 1131
12.5.1. Transition Metal Oxidants............................................................... 1131
12.5.2. Oxidation of Ketones and Aldehydes by Oxygen
and Peroxidic Compounds .............................................................. 1134
12.5.3. Oxidation with Other Reagents....................................................... 1143
12.6. Selective Oxidative Cleavages at Functional Groups.................................. 1144
12.6.1. Cleavage of Glycols ........................................................................ 1144
12.6.2. Oxidative Decarboxylation.............................................................. 1145
12.7. Oxidations at Unfunctionalized Carbon....................................................... 1148
Problems ................................................................................................................. 1151
Chapter 13. Multistep Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Introduction............................................................................................................. 1163
13.1. Synthetic Analysis and Planning.................................................................. 1164
13.1.1. Retrosynthetic Analysis................................................................... 1164
13.1.2. Synthetic Equivalent Groups........................................................... 1166
13.1.3. Control of Stereochemistry ............................................................. 1171
13.2. Illustrative Syntheses.................................................................................... 1173
13.2.1. Juvabione ......................................................................................... 1174
13.2.2. Longifolene...................................................................................... 1186
13.2.3. Prelog-Djerassi Lactone .................................................................. 1196
13.2.4. Baccatin III and Taxol .................................................................... 1210
13.2.5. Epothilone A.................................................................................... 1220
13.2.6. Discodermolide................................................................................ 1231
13.3. Solid Phase Synthesis................................................................................... 1245
13.3.1. Solid Phase Polypeptide Synthesis ................................................. 1245
13.3.2. Solid Phase Synthesis of Oligonucleotides..................................... 1250
13.4. Combinatorial Synthesis............................................................................... 1252
General References................................................................................................. 1259
Problems ................................................................................................................. 1260
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