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Edwin VedejsScott E. Denmark

Lewis Base Catalysis in Organic Synthesis

Edwin Vedejs and Scott E. Denmark

Lewis Base Catalysis in Organic Synthesis

Volume 1, 2 and 3

Editors

Dr. Edwin VedejsUniversity of MichiganDepartment of Chemistry930 N. University AvenueAnn Arbor, MI 48109-105USA

Prof. Scott E. DenmarkUniversity of IllinoisDepartment of Chemistry600, South Mathews AvenueUrbana, IL 61801USA

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Contents

Preface XXVIIIntroduction: Definitions of Catalysis XXXIII

Volume 1

1 From Catalysis to Lewis Base Catalysis with Highlights from 1806 to 1970 1Edwin Vedejs

1.1 Introduction 11.2 Catalysis 11.2.1 Berzelius Defines Catalysis 21.2.2 Early Proposals for Intermediates in Catalytic Reactions 21.3 Progress with Catalysis in Organic Chemistry 31.4 Ostwald’s Redefinition of Catalysis 51.4.1 The Evolution of Ostwald’s Views and Their Subsequent Refinement 51.4.2 Sabatier and “Temporary Compounds” in Heterogeneous Catalysis 61.4.3 A Curious Tangent: The Radiation Hypothesis for Catalysis 61.5 The First Example of Lewis Base Catalysis 71.6 The Road to Mechanistic Comprehension; Multistage Catalysis by Lewis Base 91.6.1 The Knoevenagel Condensation 91.6.2 Lapworth’s Breakthrough; Benzoin Revisited 111.7 An Uneven Path to a Unifying Concept 121.7.1 Halide Catalysis 121.7.2 Ambident Nucleophile Intermediates in Halide-Catalyzed Rearrangements 141.7.3 The First Recognition of Lewis Base Catalysis 141.8 Amine Catalysis 171.8.1 Amine-Catalyzed Decarboxylation 171.8.2 The Thiamine Story: Amine Catalysis Is Slower Than N-Heterocyclic Carbene Catalysis 181.8.3 Amine Activation of Anhydrides 201.8.3.1 Early Examples of Anhydride Activation 201.8.3.2 Gold and Jefferson: The First Mechanistic Study 201.8.4 Model Systems as Probes of Enzyme Function 211.8.4.1 Bender’s Summary of “Nucleophilic” Catalysis 211.8.4.2 Acetyl Phosphate Hydrolysis 23

V

1.8.5 Miscellaneous Examples of Lewis Base Catalysis 241.8.5.1 Dakin–West Reaction 241.8.5.2 Miscellaneous Catalytic Applications of Neutral and Anionic Lewis Bases 251.9 Summary 26

Acknowledgement 27References 27

Section I Principles 31

2 Principles, Definitions, Terminology, and Orbital Analysis of LewisBase–Lewis Acid Interactions Leading to Catalysis 33Scott E. Denmark and Gregory L. Beutner

2.1 Introduction 332.2 Lewis Definitions of Valence and the Chemical Bond 342.2.1 The “Rule of Two” 342.2.2 Electronic Theory of Acids and Bases 352.3 Extensions, Expansions of, and Objections to the Lewis Definitions 352.4 Interpretation of the Lewis Definitions in the Idiom of Molecular Orbital Theory and

Quantum Mechanics 382.4.1 The Mulliken Definition 382.4.2 The Lewis–Mulliken–Jensen Definition 392.5 Defining Lewis Base Catalysis 402.5.1 Why “Lewis Base Catalysis” and Not “Nucleophilic Catalysis” 422.5.2 Lewis Base Catalysis or Ligand-Accelerated Catalysis? 422.5.3 Classification of Interactions Involved in Lewis Base Catalysis 432.5.3.1 Catalysis by Nucleophilic Addition: n® π* Interactions 432.5.4 Catalysis by Polarization: n® σ* and n® n* Interactions 442.6 Theoretical Analysis of the Geometrical and Electronic Consequences of Lewis

Acid–Lewis Base Interactions 442.6.1 Valence Bond Analysis 442.6.2 Perturbation Molecular Orbital Theory Analysis 452.6.3 Gutmann Analysis 462.6.4 Hypervalent Bonding Analysis 492.6.5 Natural Bond Orbital (NBO) Analysis 512.7 Summary 51

References 52

3 Thermodynamic Treatments of Lewis Basicity 55Jean-François Gal

3.1 Introduction 553.2 Basic Thermodynamics for the Study of Lewis Acid–Base Interactions 563.3 Scales of Lewis Affinity and Basicity 583.3.1 Reference Lewis Acids: Experimental Considerations 583.3.2 Enthalpy (Affinity) versus Gibbs Energy (Basicity) as a Measure of Lewis Acid–Base

Interactions 613.4 Lewis Acidity and Lewis Basicity: Thermodynamic Scales 62

VI Contents

3.4.1 Solvents and Simple Functionalities 623.4.2 Methyl Cation Affinities 683.4.3 Lewis Base with Binding Sites Containing Heavier Pnictogen and Chalcogen Elements 723.5 Quantum Chemical Tools 743.6 Conclusion and Overview 753.7 Summary 76

List of Abbreviations 77Acknowledgment 78References 78

4 Quantitative Treatments of Nucleophilicity and Carbon Lewis Basicity 85Sami Lakhdar

4.1 Introduction 854.2 Nucleophilicity 854.2.1 The Swain–Scott and Edwards Approaches 854.2.2 The Ritchie Equation 874.2.3 The Mayr Equation 894.3 Lewis Basicity 914.4 Nucleofugality 934.5 Selected Applications 954.5.1 Pyridines and Derivatives 954.5.2 Tertiary Amines 994.5.3 Isothiourea Derivatives 1014.5.4 Phosphines and Phosphites 1024.5.5 N-Heterocyclic Carbenes 1044.5.6 Chiral Enamines 1074.6 Conclusion 1134.7 Summary 113

List of Abbreviations 113Acknowledgments 114References 114

Section II Mechanism and Lewis Base Catalysis: Nucleophilicity Is Only Part of the Story 119

5 Anhydride Activation by 4-Dialkylaminopyridines and Analogs (n®π*) 121Raman Tandon and Hendrik Zipse

5.1 Historical Background 1215.2 Mechanistic Considerations 1215.3 Catalyst Structure and Variation 1245.4 The Influence of Reaction Conditions 1305.5 The Influence of Acyl Donors 1325.6 The Influence of Substrate Structure 1365.7 Summary 141

List of Abbreviations 142References 142

Contents VII

VIII Contents

6 Mechanistic Understanding of Proline Analogs and Related ProticLewis Bases (n®π*) 145Alan Armstrong and Paul Dingwall

6.1 Proline Catalysis: Overview 1456.1.1 The Limitations of Proline as a Catalyst 1466.2 Mechanism of the Proline-Catalyzed Aldol Reaction 1476.2.1 The Hajos–Parrish–Eder–Sauer–Wiechert (HPESW) Reaction 1486.2.2 The Houk–List Model 1506.2.2.1 A General Catalytic Cycle 1506.2.2.2 The Role of Enamine Intermediates 1526.2.2.3 Rationalizing the Origins of Stereoselectivity 1536.2.2.4 Advances in Computational Chemistry 1566.2.3 An Alternative to the Houk–List Model: The Seebach–Eschenmoser Model 1586.2.4 Water as an Additive 1596.2.4.1 Effect of Other Additives 1616.3 Mechanism of the Proline-Catalyzed α-Amination and α-Aminoxylation Reactions 1616.3.1 Protic Additives 1616.3.2 Basic Additives and Prolinate Salts 1666.4 The Proline-Mediated Conjugate Addition Reaction 1706.4.1 Peptidic Proline Analog 1746.5 Modified Proline Derivatives 1756.5.1 Proline Tetrazole 1766.5.2 The Houk–List Model and Proline Analogs 1796.5.2.1 Cyclopropane-Fused Proline 1796.5.2.2 β-Proline Analogs 1806.5.2.3 Constrained Bicycle Proline Analogs 1826.5.2.4 Pyrrolidine Ring Conformation and NCHδ+ ∙ ∙ ∙ Oδ Interactions 1826.5.2.5 Mannich Reaction: Designed Anti-Selective Catalyst 1826.5.3 Proline Analogs and Additives 1836.5.3.1 α-Methyl Proline and Triethylamine in the α-Alkylation Reaction 1836.5.3.2 (2S,5S)-Pyrrolidine-2,5-Dicarboxylic Acid and Triethylamine 1856.6 Concluding Remarks 186


7 Mechanistic Options for the Morita–Baylis–Hillman Reaction (n®π*) 191Marilia S. Santos, José Tiago M. Correia, Ana Paula L. Batista, Manoel T. Rodrigues Jr.,Ataualpa A. C. Braga, Marcos N. Eberlin, and Fernando Coelho

7.1 The Morita–Baylis–Hillman Reaction: An Overview 1917.2 Kinetic Studies Applied to aza-Morita–Baylis–Hillman Reaction 1957.2.1 Early Studies of Isaacs and Hill 1957.2.2 Bode and Kaye’s Kinetic Investigations 1977.2.3 McQuade Kinetic Investigations: Proposal of a More Complex MBH Mechanism in

Aprotic Solvents 1987.2.4 Aggarwal Kinetic Studies: Proposal of an Autocatalytic Mechanism 2017.2.5 Kinetic Studies Related to aza-Morita-Baylis-Hillman Reaction 203

IXContents

7.3 Theoretical Calculations Applied to MBH Reaction 2087.3.1 Theoretical Methodologies 2087.3.2 MBH Reactions 2107.3.3 aza-MBH Reactions 2127.3.4 Cocatalysts 2157.3.4.1 Thiourea 2157.3.4.2 Proline 2167.3.5 Summary 2177.4 Mass Spectrometry Aid the Understanding of the Morita–Baylis–Hillman Reaction 2177.4.1 Early Mass Spectrometry Studies of the MBH Reaction 2177.4.2 Dualistic Nature of the Mechanism of the MBH Reaction 2187.4.3 Cocatalyst Effect in the MBH Reaction 2197.4.4 aza-MBH – Mechanistic Investigations 2237.5 Classical and Nonclassical Methods for Mechanistic Studies Associated with the Morita–

Baylis–Hillman Reaction: Which Is the Correct Pathway of This Reaction? 226Acknowledgments 228List of Abbreviations 228References 229

8 Mechanism of C-Si Bond Cleavage Using Lewis Bases (n® σ*) 233Hans J. Reich

8.1 Introduction 2338.2 Mechanistic Issues 2358.2.1 Fluoride Initiation 2368.2.2 Chain-Carrying Species? 2378.2.3 Siliconate Intermediates? 2388.2.4 Hypervalent Silicon 2408.2.5 Siliconates as Lewis Acids 2448.2.6 Reactivity of Siliconates and Carbanions 2458.3 Alkylation 2478.3.1 Cleavage of Alkylsilanes Bearing S and Si Groups 2488.3.2 Cleavage of Alkylsilanes Bearing Halogens 2508.3.3 Trifluoromethylation 2518.4 Benzylation 2538.5 Allylation 2558.6 Allenylation/Propargylation 2608.7 Alkynylation 2618.8 Arylation 2628.9 Vinylation 2638.10 Cyanation 2648.10.1 Hydrogen Cyanide Reactions 2658.10.2 Cyanosiliconates 2658.10.3 Mechanism of Cyanosilylation Reactions 2688.10.4 Enantioselective Cyanosilylations 2708.10.5 Silylcyanation of Epoxides 2748.11 Summary 275


9 Bifunctional Lewis Base Catalysis with Dual Activation of X3Si-Nu and C��O (n®σ*) 281Jiping Fu, Shinji Fujimori, and Scott E. Denmark

9.1 Addition of Allyltrichlorosilanes to Aldehydes 2819.1.1 Introduction 2819.1.2 Lewis Base-Promoted Allylation Reactions 2829.1.3 Chiral Phosphoramide-Catalyzed Allylation Reactions 2839.1.4 Mechanistic Investigations 2839.1.5 Design and Optimization of Bisphosphoramide Catalysts 2869.1.6 Synthetic Applications 2929.2 Aldol Additions of Trichlorosilyl Enol Ethers Derived from Ketones, Aldehydes, and

Esters 2939.2.1 Background 2939.2.2 Mechanistic Investigations 2949.2.3 Substrate Scope 2979.2.3.1 Trichlorosilyl Ketene Acetals 2979.2.3.2 Trichlorosilyl Enol Ethers Derived from Aldehydes 3019.2.3.3 Aldol Addition of Methyl Ketone-Derived Enol Ethers 3069.2.3.4 Aldol Addition of Cyclic Enol Ethers, Acyclic Ethyl Ketone-Derived Enol Ethers 3139.2.3.5 Aldol Addition of Enol Ethers Derived from Chiral Methyl Ketones 3219.2.3.6 Aldol Additions of Enol Ethers Derived from Chiral Ethyl Ketones 3269.2.4 Recent Developments 3339.2.5 Summary 335


10 Bifunctional Lewis Base Catalysis with Dual Activation of R–M and C��O (n ® σ*) 339Manabu Hatano and Kazuaki Ishihara

10.1 Introduction 33910.2 Activation of C–Zn and Related C–Mg by a Simple Lewis Base 34010.2.1 Structures of R2Zn and R2Mg 34010.2.2 Simple Lewis Base Binding to R2Zn and R2Mg 34110.3 Lewis Base-Activated C–Zn + C��O Reactions 34210.3.1 Stoichiometric Activation of RLi, RMgX, and R2Zn with Chiral Ligands 34210.3.2 Chiral Amino Alcohol-Catalyzed, Enantioselective Diethylzinc Addition 34310.3.3 Noyori’s Chiral Amino Alcohol, (�)-DAIB 34410.4 Role of Dimeric Organozinc Species 34510.4.1 Origin of Catalyst Efficiency 34510.4.2 Amplification of Chirality 34610.4.3 Reaction Pathway and Transition States 34810.5 Scope of Carbonyl Substrates in Catalytic Asymmetric Organozinc Addition Reaction 35010.5.1 Organozinc Reagents and Titanium Isopropoxide 35010.5.2 Advances in Catalytic, Enantioselective Organozinc Addition to Aldehydes 35310.5.3 Advances in Catalytic, Enantioselective Organozinc Addition to Ketones 358

X Contents

10.5.4 Advances in Catalytic, Enantioselective Addition of Grignard Reagents 36710.6 Anionic Lewis Base Activation in Mg(II) and Zn(II) Ate Complexes 37210.6.1 Stoichiometric Alkyl Addition Reaction to Ketones with Mg(II) and Zn(II) Ate

Complexes 37210.6.2 Catalytic Alkyl Addition Reaction to Ketones with Zn(II) Ate Complexes 37510.7 Summary 382


11 The Corey–Bakshi–Shibata Reduction: Mechanistic and Synthetic Considerations –

Bifunctional Lewis Base Catalysis with Dual Activation 387Christopher J. Helal and Matthew P. Meyer

11.1 Introduction 38711.2 The Catalytic Cycle 38911.2.1 The Active Reductant 38911.2.2 Catalyst Regeneration 39011.2.3 Modes of Catalysis 39111.3 Mechanism 39311.3.1 Selectivity Studies 39511.3.1.1 Temperature Dependence of Enantioselectivity 39511.3.1.2 Solvent Effects upon Selectivity 39611.3.1.3 Stoichiometry of Catalyst–Reductant Complex versus Substrate 39711.3.2 Isotope Effect Studies 39811.3.2.1 Carbon-13 Isotope Effects 39811.3.2.2 Deuterium Isotope Effects 40211.3.3 Transition Structures 40911.3.3.1 Electrostatic Considerations 41011.3.3.2 Localization of Steric Repulsion 41111.3.3.3 A Conformationally Flexible Catalyst 41511.4 Applications of the CBS Reduction in Organic Synthesis 41611.4.1 Chiral Synthon Preparation 41711.4.1.1 Oxygen-Containing Ketones 41711.4.1.2 Sulfur-Containing Ketones 41911.4.1.3 Nitrogen-Containing Ketones 42111.4.1.4 Allenyl Ketones 42111.4.1.5 Trichloromethyl Ketones 42211.4.1.6 Organometallic Ketones 42411.4.2 Desymmetrization of meso-Dicarbonyl Substrates 42611.4.2.1 Imidazolone Desymmetrization 42611.4.2.2 Imide Desymmetrization: Biotin Synthesis 42811.4.2.3 meso-1,4-Cyclohexyl-Dione Desymmetrization 42911.4.2.4 Estrone Methyl Ether Synthesis 42911.4.3 Resolution of Racemic Carbonyl Substrates 43211.4.3.1 Biaryl Systems 43311.4.3.2 Oxazolidinones 43411.4.3.3 Nucleoside Analogs 436

Contents XI

11.4.4 Dicarbonyl Reductions 43711.4.4.1 Cyclic 1,3-Diketones 43811.4.4.2 Spiro-1,3-Diketones 43911.4.4.3 1,4-Diketones 44011.4.5 Bioactive Compound Synthesis 44111.4.5.1 Heteroaryl Alkyl Ketones 44111.4.5.2 Heteroaryl Aryl Ketones 44411.4.5.3 Piperidin-4-ene-3-one 44511.4.5.4 Silyl Ketones 44611.4.5.5 Natural Product Synthesis 44711.4.6 Large-Scale Synthesis 45011.4.7 Summary 452

References 453

Volume 2

Section III Applications: Lewis Base Catalysis Involving an n®π* Activation Step 457

12 Chiral Lewis Base Activation of Acyl and Related Donors in Enantioselective Transformations(n®π*) 459James I. Murray, Zsofia Heckenast, and Alan C. Spivey

12.1 Introduction 45912.2 Phosphine Catalysts 46012.2.1 Aryl/Alkyl Phosphine-Based 46012.2.1.1 Acylative Alcohol and Diol KR and Desymmetrization 46112.3 Amine Catalysts 46312.3.1 Pyrrole and 4-Dialkylaminopyridine Based 46412.3.1.1 Acylative Alcohol and Diol KR and Desymmetrization 46612.3.1.2 Steglich and Related O®C Acyl Reactions and Rearrangements 47112.3.1.3 C-Acylation of Silyl Ketene Acetals 47412.3.1.4 Acylative Amine KR 47512.3.2 Imidazole Based 48112.3.2.1 Acylative Alcohol and Diol KR and Desymmetrization 48112.3.2.2 Acylative Amine KR 48612.3.2.3 Phosphorylative Diol Desymmetrization 48612.3.2.4 Alcoholative Sulfinyl Chloride DKR and Sulfonylative Diol Desymmetrization 48912.3.2.5 Silylative Alcohol KR and Diol Desymmetrization 48912.3.3 Diamine Based 49112.3.3.1 Acylative Alcohol and Diol KR and Desymmetrization 49112.3.4 Cinchona Alkaloid Based 49412.3.4.1 meso-Anhydride Alcoholative Desymmetrization Ring Opening 49412.3.5 Amidine and Isothiourea Based 49912.3.5.1 Acylative Alcohol and Diol KR and Desymmetrization 49912.3.5.2 Alcoholative KR and DKR of α-Thioacids, Oxazolone, β-Lactams, and α-Substituted

Carboxylic Acids 502

XII Contents

12.3.5.3 Steglich and Related O®C Acyl Rearrangements 50212.3.5.4 Acylative Amine KR 50512.3.5.5 Silylative Alcohol KR 50512.4 N-Heterocyclic Carbene (NHC) Catalysts 50712.4.1 Thiazolium and Triazolium Based 50712.4.1.1 Acylative Alcohol and Diol KR and Desymmetrization 50812.4.1.2 Steglich and Related O®C Acyl Rearrangements 50912.5 Alcohol Catalysts 51112.5.1 sec-Alcohol Based 51112.5.1.1 Alcoholative KR of α-Substituted Ester KR 51112.5.2 Phenoxide Based 51112.5.2.1 Steglich Rearrangement 51112.5.3 Hydroxamic Acid Based 51212.5.3.1 Acylative Amine KR 51212.6 Concluding Remarks 516


13 Catalytic Generation of Ammonium Enolates and Related Tertiary Amine-DerivedIntermediates: Applications, Mechanism, and Stereochemical Models (n®π*) 527Khoi N. Van, Louis C. Morrill, Andrew D. Smith, and Daniel Romo

13.1 C(1)- and C(2)-Ammonium Enolates 52713.1.1 Enantioselective α-Protonation of Ketenes Following Nucleophilic Additions of Alcohols

and Amines Leading to Carboxylic Acid Derivatives 52713.1.1.1 Ketene Alcoholysis 52813.1.1.2 Ketene Aminolysis 53513.1.2 Aldol-Lactonization Cascades of Ammonium Enolates Leading to β-Lactones

Synthesis 53813.1.2.1 Borrmann/Wegler, Wynberg β-Lactone Synthesis 53913.1.2.2 In Situ Ketene Generation 54213.1.2.3 Development of Lewis Base-Catalyzed Methodologies toward β-Lactones Employing Less

Reactive Aldehydes 54413.1.2.4 Ketene Dimerization toward 4-Alkylidene-β-Lactones 55013.1.2.5 Romo’s Intramolecular Lewis Base-Catalyzed, Aldol-Lactonization toward Polycyclic

β-Lactones (NCAL) 55413.1.3 Enantioselective Mannich-Lactamization Cascades (Formal [2+ 2] Cycloadditions of

Ketenes and Imines) Delivering β-Lactams 56213.1.4 Other Enantioselective Formal [2+ 2] and [3+ 2] Cycloadditions 57313.1.5 Enantioselective [4+ 2] Cycloadditions of C(1)-Ammonium Enolates 57913.1.6 Enantioselective Michael Addition–Lactonization or Michael Addition–Lactamization

Providing Enol Lactones or Enol Lactams 58413.1.7 Enantioselective α-Halogenation of C(1)-Ammonium Enolates 59313.1.8 Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides 60313.1.9 C(2)-Ammonium Enolate 60413.2 α,β-Unsaturated Acylammonium Salts 61213.2.1 Fu’s Formal [3+ 2] Annulation 613

Contents XIII

13.2.2 Other [3+ 2] Annulations 61513.2.3 Smith’s Michael-Proton Transfer-Enol Lactonization 61613.2.4 Vellalath/Romo’s Michael-Proton-Transfer Lactonization/Lactamization 62013.2.5 Liu/Romo’s Michael Aldol-Lactonization (NCMAL) 62013.2.6 Vellalath/Romo’s Michael Proton-Transfer Lactonization Process (NCMPL) Delivering

Polycyclic Enol Lactones 62413.2.7 Abbasov/Romo’s Diels–Alder Lactonization 62813.2.8 Rodriguez’s Michael-Proton Transfer–Lactamization 63213.2.9 Matsubara’s Thia-Michael Proton Transfer–Lactonization/Lactamization 63213.3 Ammonium Dienolates via Net [4+ 2] Cycloadditions 63713.3.1 Peters’ γ-Dienolate Delivering Dihydropyrones 63813.3.2 γ-Dienolate Functionalization Delivering Other Heterocycles 64113.3.3 α-Functionalization of Ammonium Dienolates 64513.4 Summary 647


14 Morita–Baylis–Hillman, Vinylogous Morita–Baylis–Hillman, and Rauhut–CurrierReactions 655Allison M. Wensley, Nolan T. McDougal, and Scott E. Schaus

14.1 Introduction 65514.1.1 Scope of the EWG Michael Acceptor 65614.1.1.1 Ketones 65614.1.1.2 Acrylates 65714.1.1.3 Thioacrylate Esters 65714.1.1.4 Acrolein 65814.1.1.5 Acrylamides 65914.1.1.6 Acrylonitrile 66014.1.1.7 Allenic Esters 66014.1.1.8 Vinyl Sulfones 66114.1.1.9 α-Silyl Enones 66114.1.2 Scope of the C��X Electrophile 66214.1.2.1 X = Oxygen 66214.1.2.2 X = Nitrogen 66514.2 Enantioselective Morita–Baylis–Hillman Reactions 66814.2.1 Chiral Lewis Basic Promoters as Bifunctional Catalysts in the Morita–Baylis–Hillman

Reaction 66814.2.1.1 Cinchona Alkaloids as Chiral Amine Promoters 66914.2.1.2 Binaphthol (BINOL)-Derived Chiral Promoters 67114.2.1.3 Thiourea-Derived Bifunctional Catalysts 67214.2.2 Chiral Cocatalysts in the Morita–Baylis–Hillman Reaction 67614.2.2.1 Chiral Lewis Acids 67614.2.2.2 Chiral Brønsted Acids 67814.2.3 Cooperative Catalysis in the Enantioselective Morita–Baylis–Hillman Reaction 680

XIV Contents

14.3 The Vinylogous Morita–Baylis–Hillman Reaction 68214.3.1 Examples of the Vinylogous Morita–Baylis–Hillman Reactions 68314.3.2 Tandem Vinylogous aza-Morita–Baylis–Hillman Reactions with Bis-Activated Dienes 68514.3.3 Vinylogous aza-Morita–Baylis–Hillman Reactions in Total Synthesis 68714.4 The Rauhut–Currier Reaction 68814.4.1 Rauhut–Currier Dimerization Reactions 68914.4.2 Mixed, Intermolecular Rauhut–Currier Reactions 69114.4.3 Intramolecular Rauhut–Currier Reactions 69714.4.4 Enantioselective Rauhut–Currier Reactions 69914.4.5 Rauhut–Currier Reactions in Total Synthesis 70314.5 Summary 707


15 Beyond the Morita–Baylis–Hilman Reaction (n®π*) 715Yi Chiao Fan and Ohyun Kwon

15.1 Introduction 71515.2 Phosphine-Catalyzed Reactions of Activated Alkenes/Allenes/Alkynes 71815.2.1 Phosphine-Catalyzed [3+ 2] Annulation 71915.2.2 Phosphine-Catalyzed [4+ 2] Annulation 73415.2.3 Phosphine-Catalyzed Annulations of Allenes and Aldehydes 74115.2.4 Phosphine-Catalyzed [3+ 3] Annulation 74315.2.5 Annulation of Alkynes and Aldehydes: Winterfeldt Reaction 74415.3 Phosphine-Catalyzed Generation of Brønsted Base: Michael Addition 74515.3.1 Michael Addition to Activated Alkenes/Alkynes 74615.3.2 Double-Michael Addition to Activated Alkynes/Allenes 75015.3.3 Tandem Michael–Heck Reaction 75415.4 Phosphine-Catalyzed Umpolung Additions 75415.4.1 γ-Umpolung Addition 75515.4.2 Tandem γ-Umpolung–Michael Reaction 75715.4.3 β´-Umpolung Addition 75815.4.4 Tandem γ-Umpolung–β´-Umpolung Reaction 75915.4.5 α-Umpolung Addition 76115.5 Brønsted Base-Assisted Phosphine Catalysis 76315.5.1 Allylic Substitution 76315.5.2 [3+ 2] Annulation 76515.6 Miscellaneous Phosphine-Catalyzed Processes 76915.6.1 Isomerization of Alkynes to Dienes 76915.6.2 Annulations of Activated Alkenes/Alkynes and Salicylaldehydes/Imines 77015.7 Chiral Phosphine Catalysis 77415.7.1 Enantioselective [3+ 2] Annulation 77515.7.2 Enantioselective [4+ 2] Annulation 78215.7.3 Enantioselective Michael Addition 78615.7.4 Enantioselective γ-Umpolung Addition 78715.7.5 Enantioselective Allylic Substitution 79115.7.6 Enantioselective Brønsted Base-Assisted [3+ 2] Annulation 792

Contents XV

15.7.7 Enantioselective [2+ 2] Annulation 79515.8 Application in Total Synthesis 79615.8.1 [3+ 2] Annulation in Total Syntheses 79615.8.2 [4+ 2] Annulation in Total Syntheses 79815.8.3 Michael–Heck Reaction in Total Syntheses 80015.9 Conclusion 800


16 Iminium Catalysis (n®π*) 805Aurélie Claraz, Juha H. Siitonen, and Petri M. Pihko

16.1 Introduction 80516.1.1 History of Iminium Catalysis 80616.2 Structural and Mechanistic Aspects of Iminium Catalysis 80616.2.1 Reactivity of Iminium Ions as Electrophiles 80716.2.2 Kinetic Studies 80816.2.3 Effect of the Acid Cocatalyst 81016.2.4 Solvent Effects 81316.3 Enantioselectivity: MacMillan Catalysts and Geometry Control 81416.3.1 First- and Second-Generation MacMillan Catalysts: Catalyst Design and Structural

Requirements 81416.3.2 Diels–Alder Reaction 82216.3.3 Friedel–Crafts Reaction with Electron-Rich Aromatics 82516.3.4 Mukaiyama–Michael Reactions with Enolsilanes and Other Silylated Nucleophiles 82916.4 Expanding the Diversity of Catalysts 83016.4.1 Jørgensen–Hayashi-Type Catalysts 83016.4.2 Other Pyrrolidine Catalysts 83616.5 Beyond Five-Membered Rings 83916.5.1 Morpholine 83916.5.2 Axially Chiral Secondary Amines 83916.5.3 Primary Amines 84016.6 Conclusions 850


17 Enamine-Mediated Catalysis (n®π*) 857John J. Murphy, Mattia Silvi, and Paolo Melchiorre

17.1 Introduction 85717.2 Mechanistic Considerations 85917.2.1 Enamine Reactivity 85917.2.1.1 HOMO-Raising Activating Effect 85917.2.1.2 Pyramidalization of the Enamine Nitrogen 85917.2.1.3 Enamine Formation and Reactivity: Primary versus Secondary Amines 86017.2.1.4 Effect of the Acidic Cocatalyst 86217.2.1.5 Reactivity of Enamines: A Case Study 86217.2.2 Origin of the Stereoselectivity 863

XVI Contents

17.2.2.1 Steric Control Approach 86417.2.2.2 Case Study I: Prolinol-Derived Catalysts 86417.2.2.3 Case Study II: Imidazolidinone Catalysts 86617.3 Michael Additions 86817.3.1 Early Examples 86817.3.2 Case Study: Enamine-Mediated Enantioselective Michael Additions to Nitro-Olefins 86917.3.2.1 The Seebach–Golin ́ski Topological Rule 87017.3.2.2 syn-Selective Additions 87117.3.2.3 anti-Selective Additions 87317.3.2.4 Applications in Cascade Reactions 87317.3.2.5 Reactive Intermediates and Mechanistic Implications 87417.4 Aldol Reactions 87617.5 Mannich Reactions 87717.6 Reactions of Heteroatomic Electrophiles 87817.6.1 α-Amination 87917.6.2 α-Oxidation 88017.6.3 α-Halogenation 88117.6.4 Other α-Heteroatomic Functionalizations 88417.7 α-Alkylation of Enamines 88517.7.1 SN2 Reactions 88517.7.2 SN1 Reactions 88617.7.3 Photoredox Catalysis and Enamine-Mediated Catalysis 88617.7.4 Photo-Organocatalytic Enantioselective Alkylation 88917.8 Cycloadditions 89017.9 Selected Applications 89217.9.1 Vinylogy in Enamine-Mediated Catalysis 89217.9.2 Enamines in Total Synthesis 89317.9.3 Combining Enamines with Transition Metal Catalysis 89517.10 Conclusions 896


Volume 3

Section IVa Applications: Enhanced Nucleophilicity by Lewis Base Activation(n®σ*, n®n*) 903

18 Si-C-X and Si-C-EWG as Carbanion Equivalents under Lewis BaseActivation (n®σ*) 905Ping Fang, Chang-Hua Ding, and Xue-Long Hou

18.1 Introduction 90518.2 Lewis Base-Induced Generation of Carbanion Equivalents with Si-C-EWG 90618.2.1 Enolate Generation from Si-C-Acyl Species 90618.2.1.1 Addition to C��O Using Enolates Generated from β-Ketosilanes 906

Contents XVII

18.2.1.2 Alkylation of Enolates Generated from β-Ketosilanes 90918.2.1.3 Michael Addition Using Enolates Generated from β-Ketosilanes 91018.2.2 Enolate Generation from Si-C–Carboxyl 91018.2.2.1 Addition to C��O Using Enolates Generated from α-Silylester 91018.2.2.2 Alkylation of Enolates Generated from α-Silylester 91318.2.2.3 Arylation of Enolates Generated from α-Silylester 91318.2.3 Carbanion Generation from Si-C-CN 91418.2.3.1 Addition to C��O Using Carbanions Generated from Si-C-CN 91418.2.3.2 Addition to C��N Using Carbanions Generated from Si-C-CN 91718.2.3.3 Arylation of Carbanions Generated from Si-C-CN 91718.2.4 Carbanion Generation from Si-C-S(O)R or Si-C-SO2R 91818.2.4.1 Addition to C��O Using Carbanions Generated from Si-C-S(O)R or Si-C-SO2R 91818.2.4.2 Reactions with Epoxides Using Carbanions Generated from Si-C-S(O)R or

Si-C-SO2R 91918.2.5 Carbanion Generation from Si-C-P(O)R2 92018.2.5.1 Addition to C��O Using Carbanions Generated from Si-C-P(O)R2 92018.2.5.2 Miscellaneous 92118.3 CF3SiMe3 and Related Reagents; Lewis Base-Induced Transfer of “CF3�” 92118.3.1 Addition to C��O Using Carbanions Generated from CF3SiMe3 and Related Reagents 92218.3.2 Addition to C��N Using Carbanions Generated from CF3CSiMe3 and Related Reagents 92718.3.3 Michael Reactions Using Carbanions Generated from CF3CSiMe3 and Related

Reagents 93018.3.4 Arylation, Vinylation, and Alkylation of Carbanions Generated from CF3SiMe3 and Related

Reagents 93218.3.5 Miscellaneous 93418.4 Potentially Catalytic Cases of Si-C-X Activation by Lewis Base; X = O, N, S, SMe2(+), and

Related Reagents 93618.4.1 Carbanion Equivalent Generation from Si-C-O 93618.4.1.1 Addition to C��O Using Carbanions Generated from Si-C-O 93618.4.1.2 Michael Addition Using Carbanion Equivalents Generated from Si-C-O 93718.4.1.3 1,3–Dipolar Cycloaddition with Carbonyl Ylides Generated from Si-C-O 93718.4.1.4 Arylation of Carbanions Generated from Si-C-O 93818.4.2 Carbanion Generation from Si-C-N 93818.4.2.1 Addition to C��O Using Carbanions Generated from Si-C-N 93818.4.2.2 1,3–Dipolar Cycloaddition with Azomethine Ylides Generated from Si-C-N 93918.4.2.3 Rearrangement of Ammonium Ylides R3N(+)CH2� Generated from Si-C-N 94318.4.3 Carbanion Generation from Si-C-S 94418.4.3.1 Addition to C��O Using Carbanions Generated from Si-C-S 94418.4.3.2 Addition to C��N Using Carbanions Generated from Si-C-S 94618.4.3.3 Alkylation of Carbanions Generated from Si-C-S 94718.4.3.4 Michael Addition Using Carbanion Generated from Si-C-S 94818.4.3.5 1,3–Dipolar Cycloaddition with Thiocarbonyl Ylides Generated from Si-C-S 94918.4.3.6 Addition to C��O Using Sulfonium Ylides Generated from Si-C-S 95018.4.3.7 [2,3]–Sigmatropic Rearrangement of Sulfonium Ylides Generated from Si-C-S 95118.4.3.8 Elimination of Sulfonium Ylides Generated from Si-C-S 95118.4.3.9 Dithiane Anion Relay Chemistry with Carbanions Generated from Si-C-S 954

XVIII Contents

18.5 Carbanion Generation from Selected Sn-C-X and Sn-C-EWG Analogs 95618.5.1 Addition to C��O Using Carbanions Generated from Sn-C-X and Sn-C-EWG

Analogs 95718.5.2 Alkylation, Arylation, and Vinylation of Carbanions Generated from Sn-C-X 95818.5.3 1,3–Dipolar Cycloaddition with Azomethine Ylides and 2-Azaallyl Anions Generated

from Sn-C-X 95818.5.4 Miscellaneous 96018.6 Conclusion 960


19 Activation of B-B and B-Si Bonds and Synthesis of Organoboron and OrganosiliconCompounds through Lewis Base-Catalyzed Transformations (n® n*) 967Amir H. Hoveyda, Hao Wu, Suttipol Radomkit, Jeannette M. Garcia, Fredrik Haeffner, andKang-sang Lee

19.1 Introduction 96719.2 Lewis Base Activation of B-B Bonds and Catalytic C-B Bond Forming Processes 96819.2.1 Initial Evidence Indicating the Possibility of B-B Bond Activation by a Lewis Base 96819.2.2 NHC-Catalyzed Boryl Conjugate Additions 96819.2.2.1 The Initial Hypothesis 96819.2.2.2 C-B Bond Formation Promoted by Achiral NHCs 96819.2.3 C-B Bond Formation with Chiral NHCs 97419.2.3.1 Enantioselective Formation of Tertiary C-B Bonds 97419.2.3.2 Enantioselective Formation of Quaternary C-B Bonds 97719.2.3.3 Comparison of Enantioselective Boryl Conjugate Additions Promoted by NHCs and

Cu-Based Complexes 97819.2.4 Phosphine-Catalyzed Boryl Conjugate Additions 98119.2.5 Phosphine-Catalyzed Boryl Additions to N-Tosylimines 98319.2.6 Diboron Additions to Alkenes and Alkynes Promoted by an Alkoxide 98519.2.7 Alkoxide-Promoted Conversion of Aryl Iodides to Organoboron Compounds 98919.2.8 Alkoxide-Promoted Conversion of Tosylhydrazones to Organoboron Compounds 98919.3 Lewis Base Activation of B-Si Bonds and Catalytic Silyl or Boryl Additions 99119.3.1 NHC-Catalyzed Silyl Conjugate Additions 99119.3.1.1 Previous Observations and the Initial Hypothesis 99119.3.1.2 C-Si Bond Formation with Chiral NHCs 99319.3.2 Alkoxide-Catalyzed Borosilyl Additions to Aryl Olefins 99519.3.3 Fluoride-Promoted Borosilyl Additions to Boc-Imines 99519.3.4 Alkoxide-Promoted Conversion of Aryl Bromides to Aryl–B (pin) Compounds 99819.4 Mechanistic Aspects of NHC-Catalyzed Boryl and Silyl Conjugate Additions 99919.4.1 X-Ray Crystallographic and Spectroscopic Studies 99919.4.2 NHC Association with the B-Based Reagent and Factors That Facilitate It 100119.4.3 Stereochemical Models for the Enantioselectivity Levels and Trends 100119.5 Conclusions and Outlook 1002


Contents XIX

XX Contents

Section IVb Applications: Enhanced Electrophilicity and Dual Activation by LewisBase Catalysis (n®σ*) 1011

20 Lewis Base-Catalyzed Reactions of SiX3-Based Reagents with C O, C N (n®σ*) 1013Andrei V. Malkov and Pavel Koc ̌ovský

20.1 Introduction 101320.2 Allylation of C O Substrates: Diastereoselection and Mechanistic Aspects 101320.3 Chiral Catalysts for Enantioselective Allylation 101620.3.1 Phosphoramides, Phosphinoxides, and Related Compounds as Catalysts 101720.3.2 Aromatic and Aliphatic N-Oxides as Catalysts 102120.3.3 Sulfoxides and Amides as Catalysts; Allylation of Aliphatic Aldehydes 102520.4 Functionalized Allyltrichlorosilanes and Synthetic Applications of Allylation 102720.5 Allylation of C N Substrates 103020.5.1 Addition to C N Bond 103020.6 Propargylation and Allenylation of Aldehydes, Imines, and Hydrazones 103120.7 Conclusion and Outlook 1033


21 Lewis Base-Catalyzed, Lewis Acid-Mediated Reactions (n®σ*) 1039Sergio Rossi and Scott E. Denmark

21.1 Introduction 103921.2 Allylation Reactions 104121.3 Aldol Reactions 104421.3.1 Aldol Reactions Involving Enoxysilane Derivatives of Aldehydes, Ketones and Esters as

Nucleophiles 104421.3.2 Spectroscopic and Mechanistic Investigations 104921.3.3 Aldol Additions with Other Nucleophiles 105421.3.4 Aldol Reactions Promoted by Phosphine Oxides 105721.4 Double-Aldol Additions 106421.5 Vinylogous Aldol Additions 106621.6 Passerini Reactions 107221.7 Outlook and Perspective 1074


22 Lewis Bases as Catalysts in the Reduction of Imines and Ketones with Silanes (n® σ*) 1077Pavel Koc ̌ovský and Andrei V. Malkov

22.1 Introduction: Activation of Silanes 107722.2 Reductive Amination of Aldehydes and Ketones with Trichlorosilane 107822.3 Enantioselective Reduction of Ketimines with Trichlorosilane 108322.3.1 Chiral Formamides as Catalysts for the Enantioselective Reduction of Ketimines 108322.3.2 Other Chiral Amides as Catalysts for the Enantioselective Reduction of

Ketimines 108822.3.3 Sulfinamides and Phosphoramides as Catalysts for the Enantioselective Reduction of

Ketimines 1091

XXIContents

22.3.4 (Pyridyl)oxazolines as Catalysts for the Enantioselective Reduction of Ketimines 109222.3.5 Computational Studies on the Enantioselective Reduction of Ketimines 109322.4 Enantioselective Reduction of Functionalized Ketimines with Trichlorosilane 109522.4.1 Lewis Base-Catalyzed Enantioselective Reduction of Vicinal Chloroimines 109522.4.2 Lewis Base-Catalyzed Enantioselective Reduction of α-Imino Esters 109622.4.3 Lewis Base-Catalyzed Enantioselective Reduction of Conjugated Enamines 109622.4.4 Enantioselective Reduction of Imines Utilizing Supported Lewis Base Catalysts 110322.5 Enantioselective Reduction of Ketimines with Trialkoxysilanes 110522.6 Enantioselective Reduction of Ketones with Trichlorosilane 110522.7 Selected Synthetic Applications of the Enantioselective Reduction of Imines with

Trichlorosilane 110622.8 Conclusion 1108


23 Reactions of Epoxides (n®σ*) 1113Tyler W. Wilson and Scott E. Denmark

23.1 Introduction 111323.1.1 Lewis Acid-Catalyzed, Enantioselective Epoxide Opening 111323.1.2 Opening of Epoxides with Halogen Nucleophiles 111423.1.3 Lewis Base Catalysis Applied to Epoxide Openings 111523.1.3.1 Modes of Activation for Lewis Base-Catalyzed Epoxide Openings 111523.2 Opening of Epoxides Catalyzed by Achiral Lewis Bases 111623.2.1 Introduction 111623.2.2 Lewis Base-Catalyzed Epoxide Opening with Chlorotrimethylsilane (TMSCl) 111623.2.3 Lewis Base-Catalyzed Epoxide Opening with SiCl4 112123.2.4 Lewis Base-Catalyzed Epoxide Openings with Organotin Halides 112223.3 Lewis Base-Catalyzed, Enantioselective Epoxide Opening 112223.3.1 Introduction 112223.3.2 Enantioselective Desymmetrization of meso-Epoxides 112323.3.2.1 Catalysis by Phosphoramide Lewis Bases 112323.3.2.2 Catalysis by N-Oxide-Derived Lewis Bases 112323.3.2.3 Catalysis by Phosphine Oxide Lewis Bases 112823.3.2.4 Catalysis by Lewis Bases with Unconventional Ligand Structures 113023.3.3 Kinetic Resolution of Epoxides with Lewis Bases 113323.3.3.1 Phosphoramide-Catalyzed Kinetic Resolution of Vinyl Epoxides 113423.4 Mechanistic Studies on Lewis Base-Catalyzed Epoxide Opening 113523.4.1 Introduction 113523.4.2 Mechanistic Studies on N-Oxide -Derived Lewis Bases 113623.4.2.1 Nonlinear Effects and Kinetic Studies 113623.4.2.2 Structure–Activity Relationship for N-Oxide Lewis Bases 113623.4.3 Mechanistic Studies on Phosphoramide-Derived Lewis Base Catalysts 113723.4.3.1 Stoichiometry and Catalyst Loading Studies 113723.4.3.2 Kinetic Studies and Nonlinear Effects 113823.4.3.3 NMR Studies on Reaction of HMPA with SiCl4 113923.4.3.4 Alternative Catalytic Cycle and Dimeric Catalyst Survey 1140

XXII Contents

23.5 Enantioselective Opening of Epoxides with Fluoride 114223.5.1 Introduction 114223.5.2 Fluorination of Epoxides Using Cooperative Lewis Acid/Lewis Base Catalysis 114223.5.3 Mechanistic Studies on Cooperative Catalysis in the Fluorination of Epoxides 114523.6 Summary 1148


Section V Lewis Base-Catalyzed Generation of Electrophilic Intermediates 1153

24 Lewis Base Catalysis: A Platform for Enantioselective Addition to Alkenes Using Group 16and 17 Lewis Acids (n ® σ*) 1155Dipannita Kalyani, David J.-P. Kornfilt, Matthew T. Burk, and Scott E. Denmark

24.1 Introduction 115524.2 Selenofunctionalization 115624.2.1 Selenofunctionalization Reactions of Alkenes 115624.2.2 Enantioselective Selenofunctionalization of Alkenes Using Chiral Selenides or Substrates 115724.2.2.1 Intermolecular Reactions Using Chiral, Nonracemic Selenium Electrophiles 115724.2.2.2 Intramolecular Reactions Using Chiral Selenium Electrophiles 115924.2.3 Mechanistic Considerations for Lewis Base-Catalyzed Selenofunctionalizations 116024.2.3.1 Establishment of Lewis Base Catalysis 116124.2.3.2 Configurational Stability of Enantioenriched Seleniranium Ions 116324.2.4 Catalytic, Enantioselective Selenofunctionalization 116624.3 Sulfenofunctionalization 117024.3.1 Sulfenofunctionalization Reactions of Alkenes 117024.3.2 Enantioselective Alkene Sulfenofunctionalizations: Use of Chiral Substrates or

Stoichiometric Reagents 117124.3.2.1 Reactions Using Chiral Auxiliaries 117124.3.2.2 Reactions Using Chiral, Nonracemic Sulfenylating Reagents 117224.3.3 Mechanistic Considerations for Lewis Base-Catalyzed Enantioselective

Sulfenofunctionalization of Alkenes 117324.3.3.1 Enantiospecificity of Thiiranium Ion Opening in the Presence of Nucleophiles 117524.3.3.2 Racemization of Thiirianium ions by Lewis Bases 117524.3.3.3 Studies to Probe the Racemization via Olefin-to-Olefin Transfer 117624.3.4 Catalytic Enantioselective Sulfenofunctionalizations 117724.3.4.1 Sulfenoetherification 117724.3.4.2 Mechanistic Studies on the Sulfenoetherification Reaction 117924.3.4.3 Sulfenocarbocyclization 118524.3.4.4 Sulfenoamination 118924.4 Halofunctionalization 119124.4.1 Historical Background and Development of Mechanistic Understanding 119124.4.2 Mechanistic Considerations for Enantioselective Halofunctionalization 119224.4.2.1 Studies Probing the Racemization of Haliranium Ions by Olefin-to-Olefin Transfer 119224.4.2.2 Strategies for Maintaining Catalyst–Haliranium Association 119324.4.3 Enantioselective Halofunctionalization 1195

XXIIIContents

24.4.3.1 Halocarbocyclization 119524.4.3.2 Halolactonization 119624.4.3.3 Haloaminocyclization 120124.4.3.4 Haloetherification 120224.4.3.5 Dichlorination of Alkenes 120624.5 Summary 1206


Section VI Bifunctional (and Multifunctional) Catalysis 1213

25 Bifunctional and Synergistic Catalysis: Lewis Acid Catalysis and Lewis Base-Assisted BondPolarization (n ® σ*) 1215Won-jin Chung and Scott E. Denmark

25.1 Introduction 121525.2 Bifunctional Catalysis 121725.2.1 Silylcyanation of Aldehydes 121725.2.2 Silylcyanation of Ketones 122125.2.3 The Strecker and Reissert Reactions 122425.2.4 Desymmetrization of meso-N-Acyl Aziridines 122925.2.5 Conjugate Addition of Cyanide to α,β-Unsaturated Carbonyl Compounds 123025.3 Synergistic Catalysis 123225.3.1 Silylcyanation of Carbonyl Compounds 123225.3.2 Mukaiyama-Type Reactions 123525.4 Bifunctional/Synergistic Catalysis with Fluoride Activation 123625.4.1 Hosomi–Sakurai Allylation 123725.4.2 Mukaiyama-Type Aldol Reactions 124525.5 Conclusion 1253


26 Bifunctional Catalysis with Lewis Base and X-H Sites That Facilitate Proton Transfer orHydrogen Bonding (n®π*) 1259Curren T. Mbofana and Scott J. Miller

26.1 Introduction 125926.2 Group Transfer Reactions 125926.2.1 Acylation 125926.2.2 Phosphorylation 126226.2.3 Sulfonylation and Sulfinylation 126526.3 Addition Reactions to Electron-Deficient Alkenes 126926.3.1 Morita–Baylis–Hillman Reaction 126926.3.2 Rauhut–Currier Reaction 127126.3.3 Stetter/Umpolung Reactions 127626.4 Allenoate Reactions 127926.4.1 Allenoate Cycloaddition Reactions 1280

XXIV Contents

26.4.2 Allenoate Addition Reactions 128326.5 Summary 1286


Section VII Carbenes: Lewis Base Catalysis Triggers Multiple Activation Pathways 1289

27 Catalysis with Stable Carbenes (n®π*) 1291Darrin M. Flanigan, Nicholas A. White, Kevin M. Oberg, and Tomislav Rovis

27.1 Introduction 129127.2 N-Heterocyclic Carbenes as Lewis Base Catalysts: Structural and Electronic

Considerations 129227.2.1 pKa Measurements of N-Heterocyclic Carbenes 129327.2.2 Efforts toward Characterizing the Breslow Intermediate 129527.3 N-Heterocyclic Carbenes in Classical Lewis Base-Catalyzed Reactions 129727.3.1 The Benzoin Reaction 129727.3.1.1 Enantioselective Benzoin Reactions 129827.3.1.2 Cross-Benzoin Reactions 129927.3.2 The Stetter Reaction 130727.3.2.1 Intramolecular Stetter Reactions 130927.3.2.2 Intermolecular Stetter Reactions 131027.3.3 Hydroacylations of Unactivated Double Bonds 131227.3.4 Lewis and Brønsted Base Catalysis 131427.3.4.1 trans-Esterification and Amidation Reactions 131427.3.4.2 Mukaiyama Aldol and Reformatsky Reactions 131527.3.5 Catalysis via Initial Conjugate Addition 131627.3.5.1 Morita–Baylis–Hillman and Rauhut–Currier Reactions 131627.3.5.2 β-Functionalization of Acrylates 131827.4 N-Heterocyclic Carbenes in Nonclassical Lewis Base-Catalyzed Reactions 132027.4.1 α-Reducible Aldehydes as Substrates for Acylation Reactions 132027.4.1.1 Formation of Esters and Acids 132027.4.1.2 Aldehyde Oxidation Utilizing an External Oxidant 132427.4.2 β-Functionalization of Enals 132427.4.2.1 β-Protonation of Enals 132427.4.2.2 β-Addition to Electron-Deficient Electrophiles 132627.4.2.3 Oxidative Hydroxylation via Radical Cation Intermediates 132827.4.3 α-Functionalization of Enals 133027.4.3.1 Enantioselective α-Protonation 133027.4.3.2 Enantioselective α-Fluorination of Enals 133027.4.3.3 Aldol Reactions with Enol Azolium Intermediates 133027.4.4 Annulation Reactions 133127.4.4.1 Lactone and Lactam Formation via Homoenolate Equivalents 133227.4.4.2 Carbocycle Formation via Homoenolate Equivalents 133427.4.4.3 Lactone and Lactam Formation via Enol Azolium Intermediates 133527.4.4.4 Annulation Reactions of α,β-Unsaturated Acyl Azolium Intermediates 1337

XXVContents

27.4.4.5 Ketenes and Other Direct Enol Azolium Precursors 133827.5 Selected Examples of N-Heterocyclic Carbenes in Synthesis 134027.6 Summary 1343


Summation 1351

Index 1355

XXVII

Preface

This three-volume book originates from a widely cited 2008 review with the same title, Lewis BaseCatalysis in Organic Synthesis, coauthored by Denmark and Beutner. Given the interest generatedby that article, as well as the explosion of related topics in the literature, a more comprehensivetreatment was desired by Wiley-VCH. Scott Denmark declined taking on the current project as soleeditor due to extensive prior commitments, but did agree to serve as coeditor in planning the project and determining scientific content. In addition, he edited Chapter 1, authored several of the laterchapters, and wrote the Introduction that traces definitions of catalysis from Ostwald to the currentera and presents an updated, broadly inclusive definition that is used in the current volumes.

After extensive discussion by both coeditors during the planning stages, the decision was made toemphasize mechanistic aspects of Lewis base catalysis where possible, and to provide broad coverageof the most important preparative advances with sufficient commentary and explanation to facilitategraduate instruction as well as to stimulate new research initiatives. Another important objectivewas to remind the current generation of the remarkable insight and contributions of G.N. Lewis. Hewas the first to recognize the possibility of catalysis by electron pair donors, and did so two decadesbefore independent attempts to classify this family of reactions resulted in the alternative terminology “nucleophilic catalysis.” For historical as well as heuristic and conceptual reasons, it is better andmore correct to regard this chemistry as Lewis base catalysis.

All of the examples of Lewis base catalysis in these volumes feature activation by a key bondingevent between a substrate acceptor orbital (classified as n*, π*, or σ* in chapter headings) and twoelectrons from a donor orbital in the Lewis base catalyst, but this donor–acceptor interaction is onlythe appetizer. The main course consists of the stages that follow the Lewis base activation step, andthe menu of mechanistic options can be incredibly rich. The options can be very simple, as in halidecatalysis (Chapter 1) where a single activation stage by the halide Lewis base is usually followed by asingle product-forming stage. However, such mechanistic simplicity is the exception. More often,the mechanisms are deceptively simple, multifaceted, and amazingly subtle. Even that familiarundergraduate-level example of Lewis base catalysis, the venerable benzoin condensation, can bechallenging for students who must confront multiple conceptual layers (reversible nucleophilic addition of cyanide; acid–base concepts; carbanion delocalization; leaving group ability) and decipherseveral steps following the activation stage. It is worth recalling that an earlier mechanism for thebenzoin condensation proposed the dimerization of “PhC(OH)” (yes, the hydroxyl carbene tautomerof benzaldehyde!) to the intermediate enediol PhC(OH) C(OH)Ph (Bredig, 1904). This suggestionwas perfectly logical, concise, and plausible at the time, but lasted only until the alternatives wereconsidered and the mechanism was studied. Perhaps a similar fate awaits other plausible mechanisms, a phrase that appears often in these volumes.

XXVIII Preface

By now, many of the fundamental principles underlying Lewis base catalysis have indeed beenstudied, and several of the most extensively investigated topics are featured in Volume 1. Chapter 1begins with a historical account tracing key highlights in the development of catalysis, includingimportant contributions by Berzelius, Liebig, Ostwald, and other major figures of nineteenth centurychemistry. This chapter also mentions milestones in Lewis base catalysis from 1834 to 1970, andbriefly comments on a few more recent developments that await detailed investigation.

Lewis was the first to recognize the electronic features that define Lewis base catalysis (Introduction and Chapter 2). An overview of his profound insight is presented in Chapter 2, which traces theevolution of Lewis’s landmark formulation of the electronic theory of structure and bonding to aclear assertion that his (Lewis’s) bases possess every property ascribed to Brønsted bases, includingtheir ability to act as catalysts. The Lewis concepts benefited greatly from refinement and popularization by Mulliken and Jensen, who helped to develop the unifying conceptual basis, a classificationscheme of reaction types according to relevant orbital interactions, and a generally applicable terminology that serves as the organizational framework for these volumes.

The next two chapters focus on the thermodynamic and kinetic aspects of Lewis base catalysis,respectively. Chapter 3 presents the classical methods that have been used to quantify Lewis basicityof the most important Lewis bases, and defines the concepts of Lewis Affinity and Basicity. Extensivediscussion and tables compare Lewis bases using representative affinity parameters, including thosefor various cations (proton, methyl, lithium) and neutral Lewis acids (BF3, iodine, 4-fluorophenol).Similarly, Chapter 4 quantifies the corresponding kinetic component (nucleophilicity) using theMayr Scale, introduces the related concepts of electrofugality and nucleofugality, and providesexamples of how these concepts are used by synthetic chemists.

The selection of topics for the subsequent chapters of Volume 1 was made according to severalcriteria: (i) extensive in-depth mechanistic study, (ii) preparative importance, and (iii) mechanisticdiversity following attack by the Lewis base. The first of these chapters (Chapter 5) takes on acyltransfer catalysis by pyridine derivatives, a topic that has been studied in sufficient depth to developa mechanism that is well understood and widely accepted. Perhaps the same can now be said formuch of Chapter 6, involving the mechanism for proline-catalyzed carbonyl activation in enantioselective synthesis, but this is complex, broadly applicable chemistry and the evaluation of models forenantioselection often depends on computational methods that are still undergoing refinement.Similar concerns regarding computations arise in reactions where complexity is associated with thetiming and nature of proton transfer events, or with the role of various additives. Those scenarioshave long confounded attempts to fully understand the mechanism of the Morita–Baylis–Hillmanreaction, a topic that is summarized in Chapter 7. Progress has been made using sophisticatedmechanistic tools based on kinetics, mass spectroscopy, computation, and acid–base relationships,but developing a generally applicable mechanism has proven to be difficult.

Some of the mechanistically most intriguing examples of Lewis base catalysis are featured inChapters 8–11 of Volume 1. These chapters describe reactions that begin with a bonding interactionbetween the Lewis base and the σ* or n* (unoccupied p) orbitals of the electrophile, reactions thatproceed with astonishing mechanistic diversification, even in the relatively simple context of Lewisbase activation of silicon nucleophiles (Chapter 8). One take-home message is that only by extensivemechanistic investigation of each substrate category is it possible to classify the reactive intermediates as carbon-bound siliconates or as free carbanions. This conclusion would not surprise authorsfrom an earlier era when physical organic chemistry was the central focus of organic chemistry, andit is underscored by the content of Chapters 9–11. Massive mechanistic study and correlation ofenantioselectivity data were required to reveal details of how a chiral Lewis base induces the

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