Organometallic Chemistry in Industry A Practical Approach

Foreword xiii

Preface xvii

1 Industrial Milestones in Organometallic Chemistry 1
Ben M. Gardner, Carin C.C. Johansson Seechurn, and Thomas J. Colacot

1.1 Definition of Organometallic and Metal–Organic Compounds 1

1.1.1 Applications and Key Reactivity 1

1.1.1.1 Electronic Applications 1

1.1.1.2 Polymers 2

1.1.1.3 Organic Synthesis 2

1.2 Industrial Process Considerations 7

1.3 Brief Notes on the Historical Development of Organometallic Chemistry for Organic Synthesis Applications Pertaining to the Contents of this Book 8

1.3.1 Synthesis of Stoichiometric Organometallic Reagents 9

1.3.1.1 Conventional Batch Synthesis 9

1.3.1.2 Organometallics in Flow 10

1.3.2 Cross-coupling Reactions 10

1.3.2.1 C—H Bond Activation 12

1.3.2.2 Carbonylation 13

1.3.2.3 Catalysis in Water – Micellar Catalysis 13

1.3.3 Hydrogenation Reactions 14

1.3.4 Olefin Formation Reactions 15

1.3.4.1 Wittig Reaction 15

1.3.4.2 Metathesis Reactions 15

1.3.4.3 Dehydrative Decarbonylation 16

1.3.4.4 Olefins as Starting Materials 16

1.3.5 Poly- or Oligomerization Processes 17

1.3.6 Photoredox Catalysis for Organic Synthesis 17

1.4 Conclusion and Outlook 17

Biography 18

References 19

2 Design, Development, and Execution of a Continuous-flow-Enabled API Manufacturing Route 23
Alison C. Brewer, Philip C. Hoffman, Timothy D. White, Yu Lu, Laura McKee, Moussa Boukerche, Michael E. Kobierski, Nessa Mullane, Mark Pietz, Charles A. Alt, Jim R. Stout, Paul K. Milenbaugh, and Joseph R. Martinelli

2.1 Continuous-flow-Enabled Synthetic Strategy 25

2.2 Design and Scale-up of Chan–Lam Coupling 28

2.2.1 Development of Homogeneous Conditions 31

2.2.2 Application of a Platform Technology to Aerobic Oxidation 32

2.2.3 Optimization of Reaction and Workup Parameters 35

2.2.4 Safety Considerations for Aerobic Oxidation on Scale 37

2.2.5 Continuous Scale-up and Manufacturing 38

2.3 Design and Scale-up of a Buchwald–Hartwig Cross-coupling 42

2.3.1 Initial Screening 43

2.3.2 Synthesis and Isolation of Pd(dba)DPEPhos Precatalyst 45

2.3.3 Workup Procedure, Metal Removal, and Crystallization 46

2.3.4 Scale-up and Manufacturing 48

2.4 Impurity Control 48

2.4.1 Solubility and Impurity Spiking Studies 50

2.5 Conclusions 54

Biography 54

References 58

3 Continuous Manufacturing as an Enabling Technology for Low-Temperature Organometallic Chemistry 61
Andreas Hafner and Joerg Sedelmeier

3.1 Introduction 61

3.2 Organo-Li and Mg Processes in Flow Mode 62

3.2.1 Technological Advantages of Flow Technology Compared to Traditional Batch Operation 62

3.2.2 Temperature Profile of Continuous Flow Reactions 64

3.2.3 Flash Chemistry: Functional Group Tolerance 65

3.2.4 Flash Chemistry: Selectivity 66

3.2.5 Flash Chemistry: Stoichiometry and Chemoselectivity 67

3.3 Continuous Flow Technology 69

3.3.1 Clogging as a Major Hurdle in Flow Chemistry 71

3.3.2 Start-up and Shutdown Operation 72

3.3.3 Material of Construction 72

3.3.4 Safety Concept and Emergency Strategies 73

3.4 Development of a Flow Process 73

3.4.1 Screening Phase: Feasibility Study 74

3.4.2 Process Development Phase: Extended Evaluations Including Technical Feasibility 75

3.5 Literature Examples: Flow Processes on Multi 100 g Scale 76

3.5.1 Manufacture of Verubecestat (MK-8931) 77

3.5.2 Manufacture of Edivoxetine 77

3.5.3 Scale-up of Highly Reactive Aryl Lithium Chemistry 80

3.5.4 Synthesis of Bromomethyltrifluoroborates in Continuous Flow Mode 81

3.5.5 Two-Step Synthesis Toward Boronic Acids 82

3.5.6 Reaction Sequence Toward a Highly Substituted Benzoxazole Building Block 84

3.6 Conclusion and Future Prospects 86

Biography 86

References 87

4 Development of a Nickel-Catalyzed Enantioselective Mizoroki–Heck Coupling 91
Jean-Nicolas Desrosiers and Chris H. Senanayake

4.1 Introduction 91

4.1.1 Nonprecious Metal Catalysis Advantages for Industry 91

4.1.2 Mizoroki–Heck Couplings in Industry with Palladium 92

4.1.3 Emergence of Nickel-Catalyzed Mizoroki–Heck Couplings 93

4.1.4 Enantioselective Nickel-Catalyzed Couplings 94

4.1.5 Synthesis of Oxindoles via Mizoroki–Heck Cyclizations 96

4.2 Development of a Nickel-Catalyzed Heck Cyclization to Generate Oxindoles with Quaternary Stereogenic Centers 97

4.2.1 Precedents and Challenges 97

4.2.2 Optimization of Reducing Agent and Base 97

4.2.3 Ligand Screening 98

4.2.4 Impact of Aryl Electrophile and of Stereochemistry of Alkene Moiety 100

4.2.5 Exploration of the Substrate Scope 102

4.2.6 Limitations of the Methodology 104

4.2.7 Mechanistic Considerations 104

4.3 Development of First Enantioselective Nickel-Catalyzed Heck Coupling 107

4.3.1 Ligand Screening 107

4.3.2 Impact of Alkene Stereochemistry 107

4.3.3 Neutral vs Cationic Pathways 108

4.3.4 Nickel Precatalyst Complex Synthesis 109

4.3.5 Exploration of the Substrate Scope 110

4.3.6 Mechanistic Studies 110

4.4 Conclusions 113

Biography 114

References 115

5 Development of Iron-Catalyzed Kumada Cross-coupling for the Large-Scale Production of Aliskiren Intermediate 121
Srinivas Achanta, Debjit Basu, Uday K. Neelam, Rajeev R. Budhdev, Apurba Bhattacharya, and Rakeshwar Bandichhor

5.1 Introduction 121

5.2 Optimization of Grade and Equivalents of Mg Metal 123

5.3 Optimization of Equivalents of 1,2-Dibromoethane 123

5.4 Effect of Solvent Concentration on Preparation of Grignard Reagent and Kumada–Corriu Coupling 124

5.5 Effect of Alkyl Chloride 3 Addition Time on the Grignard Reagent Preparation 125

5.6 Stability of Grignard Reagent at 0–5 ^∘C 125

5.7 Iron-Catalyzed Cross-coupling Reaction 127

5.8 Optimization of Equivalents of NMP and Fe(acac)₃ 129

5.9 Optimization of Equivalents of Substrate 4 and Its Rate of Addition 129

5.10 Execution at Pilot Scale and Scale-up Issues 129

5.11 Agitated Thin Film Evaporator (ATFE) for Purification of 2 131

5.12 Conclusion 132

Acknowledgments 133

Biography 133

References 135

6 Development and Scale-Up of a Palladium-Catalyzed Intramolecular Direct Arylation in the Commercial Synthesis of Beclabuvir 137
Collin Chan, Albert J. DelMonte, Chao Hang, Yi Hsiao, and Eric M. Simmons

6.1 Introduction 137

6.2 KOAc/DMAc Process 141

6.3 TMAOAc/DMF Process 141

6.4 TMAOAc/DMAc Process 149

6.4.1 Cyclization Reaction 151

6.4.2 Mechanistic Understanding of the Cyclization Reaction and Impurity Formation 159

6.4.3 Hydrolysis and Workup 162

6.4.4 Crystallization and Drying 164

6.5 Conclusion 167

Biography 168

References 169

7 Ruthenium-Catalyzed C—H Activated C—C/N/O Bond Formation Reactions for the Practical Synthesis of Heterocycles and Pharmaceutical Agents 171
Anita Mehta, Naresh Kumar, and Biswajit Saha

7.1 Introduction 171

7.2 C–H Activation Followed by C—C Bond Formation 172

7.2.1 C–H Activation Followed by C—C Bond Formation: Biaryl/Heterobiaryl Synthesis in Organic Solvents 172

7.2.2 C–H Activation Followed by C—C Bond Formation: Biaryl/Heterobiaryl Synthesis in Green Solvents 181

7.3 Alkyl/Acyl/Alkenyl Substitution on Heterocycles 185

7.4 C–H Activation Followed by C—O/N Bond Formation: Heterocycle Synthesis 187

7.4.1 C–H Activation Followed by C—O/N Bond Formation: Heterocycle Synthesis in Organic Solvents 187

7.4.2 C–H Activation Followed by C—O and C—N Bond Formation: Heterocycle Synthesis in Green Solvents 189

7.5 Conclusion 196

Biography 197

References 198

8 Cross-couplings in Water – A Better Way to Assemble New Bonds 203
Tharique N. Ansari, Fabrice Gallou, and Sachin Handa

8.1 Introduction 203

8.2 Transition Metal Catalysis in Organic Solvents vs Micellar Catalysis 204

8.2.1 Micellization 205

8.2.2 Surfactant Solution – A Highly Organized Reaction Medium to Enhance Reaction Rate 206

8.2.3 Reaction Temperature 207

8.2.4 Size of Micelles 207

8.2.5 Nature of Catalyst 208

8.2.6 Increasing the Efficiency in Micellar Catalysis 209

8.2.7 Order of Addition 210

8.2.8 Product Precipitation or Extraction 211

8.2.9 Trace Metal in the Product 211

8.3 Highly Valuable Reactions in Water 212

8.3.1 Suzuki–Miyaura Couplings 212

8.3.2 Heck Couplings 217

8.3.3 Negishi Couplings 219

8.3.4 C–H Arylations 221

8.3.5 Aminations 225

8.3.6 Borylation 228

8.3.7 Arylation of Nitro Compounds 228

8.3.8 Adoption of Micellar Technology by Pharmaceutical Industry 229

8.4 Conclusions 234

Biography 234

References 235

9 Aspects of Homogeneous Hydrogenation from Industrial Research 239
Stephen Roseblade

9.1 Homogeneous Hydrogenation: A Brief Introduction 239

9.2 Catalyst Selection by Effective Screening Approaches 240

9.3 Considerations for Reaction Scale-up 244

9.4 Notes on Additive Effects 247

9.5 A Novel Approach to Aliskiren Using Asymmetric Hydrogenation as a Key Step 249

9.6 Efficient Chemoselective Aldehyde Hydrogenation 252

9.7 Closing Remarks/Summary 253

Biography 255

References 255

10 Latest Industrial Uses of Olefin Metathesis 259
John H. Phillips

10.1 Introduction 259

10.2 General Information 260

10.2.1 Non-ruthenium Catalysts 260

10.2.2 Ruthenium Catalysts 261

10.3 Industrial Uses 262

10.3.1 Ring-closing Metathesis (RCM) 262

10.3.2 Cross-metathesis (CM) 264

10.3.3 Ring-Opening Metathesis Polymerization (ROMP) 268

10.4 Reaction Considerations 270

10.4.1 Catalyst Choice 271

10.4.2 Catalyst Loading 273

10.4.3 Solvent 273

10.4.4 Reaction Concentration 273

10.4.5 Overall Handling 274

10.4.6 Application Guide and Availability 274

10.5 Troubleshooting 275

10.5.1 Catalyst Removal 275

10.5.2 Functional Group Tolerance 276

10.5.3 Substrate Purity 276

10.5.4 Catalyst Decomposition – Isomerization 277

10.6 Conclusion 277

Biography 277

References 278

11 Dehydrative Decarbonylation 283
Alex John

11.1 Introduction 283

11.2 Use of Sacrificial Anhydride and Catalytic Mechanism 285

11.3 Rh-, Pd-, and Ir-Catalysis 286

11.3.1 Early Studies 286

11.3.2 Recent Studies 289

11.4 Milder Temperatures 291

11.4.1 PdCl₂/XantPhos/(^tBu)₄biphenol System 291

11.4.2 Well-Defined Pd-bis(phosphine) Precatalysts 294

11.5 Nickel and Iron Catalysis 295

11.6 Ester Decarbonylation 297

11.7 Synthetic Utility: α-Vinyl Carbonyl Compounds 299

11.8 Conclusions and Future Prospects 300

Biography 300

References 301

Index 305

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