Organometallic Chemistry in Industry

Thomas J. Colacot is R&D Fellow and Director of Global Technology Innovation (Lab and Specialty Chemicals) at Millipore Sigma, USA. His expertise is in the areas of new product and technology development, process R&D, scale-up- tech transfers of organic, organometallic, and fine chemicals relevant for pharmaceutical, electronic, and biological applications with very strong interactions/partnership with customers. Carin C.C. Johansson Seechurn is Lead Scientist in Life Science Technologies division of Johnson Matthey in Cambridge, UK, where she is working on the development and scale-up of novel homogeneous metal catalysts.

• Foreword xiiiPreface xvii1 Industrial Milestones in Organometallic Chemistry 1Ben M. Gardner, Carin C.C. Johansson Seechurn, and Thomas J. Colacot1.1 Definition of Organometallic and Metal–Organic Compounds 11.1.1 Applications and Key Reactivity 11.1.1.1 Electronic Applications 11.1.1.2 Polymers 21.1.1.3 Organic Synthesis 21.2 Industrial Process Considerations 71.3 Brief Notes on the Historical Development of Organometallic Chemistry for Organic Synthesis Applications Pertaining to the Contents of this Book 81.3.1 Synthesis of Stoichiometric Organometallic Reagents 91.3.1.1 Conventional Batch Synthesis 91.3.1.2 Organometallics in Flow 101.3.2 Cross-coupling Reactions 101.3.2.1 C—H Bond Activation 121.3.2.2 Carbonylation 131.3.2.3 Catalysis in Water – Micellar Catalysis 131.3.3 Hydrogenation Reactions 141.3.4 Olefin Formation Reactions 151.3.4.1 Wittig Reaction 151.3.4.2 Metathesis Reactions 151.3.4.3 Dehydrative Decarbonylation 161.3.4.4 Olefins as Starting Materials 161.3.5 Poly- or Oligomerization Processes 171.3.6 Photoredox Catalysis for Organic Synthesis 171.4 Conclusion and Outlook 17Biography 18References 192 Design, Development, and Execution of a Continuous-flow-Enabled API Manufacturing Route 23Alison 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. Martinelli2.1 Continuous-flow-Enabled Synthetic Strategy 252.2 Design and Scale-up of Chan–Lam Coupling 282.2.1 Development of Homogeneous Conditions 312.2.2 Application of a Platform Technology to Aerobic Oxidation 322.2.3 Optimization of Reaction and Workup Parameters 352.2.4 Safety Considerations for Aerobic Oxidation on Scale 372.2.5 Continuous Scale-up and Manufacturing 382.3 Design and Scale-up of a Buchwald–Hartwig Cross-coupling 422.3.1 Initial Screening 432.3.2 Synthesis and Isolation of Pd(dba)DPEPhos Precatalyst 452.3.3 Workup Procedure, Metal Removal, and Crystallization 462.3.4 Scale-up and Manufacturing 482.4 Impurity Control 482.4.1 Solubility and Impurity Spiking Studies 502.5 Conclusions 54Biography 54References 583 Continuous Manufacturing as an Enabling Technology for Low-Temperature Organometallic Chemistry 61Andreas Hafner and Joerg Sedelmeier3.1 Introduction 613.2 Organo-Li and Mg Processes in Flow Mode 623.2.1 Technological Advantages of Flow Technology Compared to Traditional Batch Operation 623.2.2 Temperature Profile of Continuous Flow Reactions 643.2.3 Flash Chemistry: Functional Group Tolerance 653.2.4 Flash Chemistry: Selectivity 663.2.5 Flash Chemistry: Stoichiometry and Chemoselectivity 673.3 Continuous Flow Technology 693.3.1 Clogging as a Major Hurdle in Flow Chemistry 713.3.2 Start-up and Shutdown Operation 723.3.3 Material of Construction 723.3.4 Safety Concept and Emergency Strategies 733.4 Development of a Flow Process 733.4.1 Screening Phase: Feasibility Study 743.4.2 Process Development Phase: Extended Evaluations Including Technical Feasibility 753.5 Literature Examples: Flow Processes on Multi 100 g Scale 763.5.1 Manufacture of Verubecestat (MK-8931) 773.5.2 Manufacture of Edivoxetine 773.5.3 Scale-up of Highly Reactive Aryl Lithium Chemistry 803.5.4 Synthesis of Bromomethyltrifluoroborates in Continuous Flow Mode 813.5.5 Two-Step Synthesis Toward Boronic Acids 823.5.6 Reaction Sequence Toward a Highly Substituted Benzoxazole Building Block 843.6 Conclusion and Future Prospects 86Biography 86References 874 Development of a Nickel-Catalyzed Enantioselective Mizoroki–Heck Coupling 91Jean-Nicolas Desrosiers and Chris H. Senanayake4.1 Introduction 914.1.1 Nonprecious Metal Catalysis Advantages for Industry 914.1.2 Mizoroki–Heck Couplings in Industry with Palladium 924.1.3 Emergence of Nickel-Catalyzed Mizoroki–Heck Couplings 934.1.4 Enantioselective Nickel-Catalyzed Couplings 944.1.5 Synthesis of Oxindoles via Mizoroki–Heck Cyclizations 964.2 Development of a Nickel-Catalyzed Heck Cyclization to Generate Oxindoles with Quaternary Stereogenic Centers 974.2.1 Precedents and Challenges 974.2.2 Optimization of Reducing Agent and Base 974.2.3 Ligand Screening 984.2.4 Impact of Aryl Electrophile and of Stereochemistry of Alkene Moiety 1004.2.5 Exploration of the Substrate Scope 1024.2.6 Limitations of the Methodology 1044.2.7 Mechanistic Considerations 1044.3 Development of First Enantioselective Nickel-Catalyzed Heck Coupling 1074.3.1 Ligand Screening 1074.3.2 Impact of Alkene Stereochemistry 1074.3.3 Neutral vs Cationic Pathways 1084.3.4 Nickel Precatalyst Complex Synthesis 1094.3.5 Exploration of the Substrate Scope 1104.3.6 Mechanistic Studies 1104.4 Conclusions 113Biography 114References 1155 Development of Iron-Catalyzed Kumada Cross-coupling for the Large-Scale Production of Aliskiren Intermediate 121Srinivas Achanta, Debjit Basu, Uday K. Neelam, Rajeev R. Budhdev, Apurba Bhattacharya, and Rakeshwar Bandichhor5.1 Introduction 1215.2 Optimization of Grade and Equivalents of Mg Metal 1235.3 Optimization of Equivalents of 1,2-Dibromoethane 1235.4 Effect of Solvent Concentration on Preparation of Grignard Reagent and Kumada–Corriu Coupling 1245.5 Effect of Alkyl Chloride 3 Addition Time on the Grignard Reagent Preparation 1255.6 Stability of Grignard Reagent at 0–5 ∘C 1255.7 Iron-Catalyzed Cross-coupling Reaction 1275.8 Optimization of Equivalents of NMP and Fe(acac)3 1295.9 Optimization of Equivalents of Substrate 4 and Its Rate of Addition 1295.10 Execution at Pilot Scale and Scale-up Issues 1295.11 Agitated Thin Film Evaporator (ATFE) for Purification of 2 1315.12 Conclusion 132Acknowledgments 133Biography 133References 1356 Development and Scale-Up of a Palladium-Catalyzed Intramolecular Direct Arylation in the Commercial Synthesis of Beclabuvir 137Collin Chan, Albert J. DelMonte, Chao Hang, Yi Hsiao, and Eric M. Simmons6.1 Introduction 1376.2 KOAc/DMAc Process 1416.3 TMAOAc/DMF Process 1416.4 TMAOAc/DMAc Process 1496.4.1 Cyclization Reaction 1516.4.2 Mechanistic Understanding of the Cyclization Reaction and Impurity Formation 1596.4.3 Hydrolysis and Workup 1626.4.4 Crystallization and Drying 1646.5 Conclusion 167Biography 168References 1697 Ruthenium-Catalyzed C—H Activated C—C/N/O Bond Formation Reactions for the Practical Synthesis of Heterocycles and Pharmaceutical Agents 171Anita Mehta, Naresh Kumar, and Biswajit Saha7.1 Introduction 1717.2 C–H Activation Followed by C—C Bond Formation 1727.2.1 C–H Activation Followed by C—C Bond Formation: Biaryl/Heterobiaryl Synthesis in Organic Solvents 1727.2.2 C–H Activation Followed by C—C Bond Formation: Biaryl/Heterobiaryl Synthesis in Green Solvents 1817.3 Alkyl/Acyl/Alkenyl Substitution on Heterocycles 1857.4 C–H Activation Followed by C—O/N Bond Formation: Heterocycle Synthesis 1877.4.1 C–H Activation Followed by C—O/N Bond Formation: Heterocycle Synthesis in Organic Solvents 1877.4.2 C–H Activation Followed by C—O and C—N Bond Formation: Heterocycle Synthesis in Green Solvents 1897.5 Conclusion 196Biography 197References 1988 Cross-couplings in Water – A Better Way to Assemble New Bonds 203Tharique N. Ansari, Fabrice Gallou, and Sachin Handa8.1 Introduction 2038.2 Transition Metal Catalysis in Organic Solvents vs Micellar Catalysis 2048.2.1 Micellization 2058.2.2 Surfactant Solution – A Highly Organized Reaction Medium to Enhance Reaction Rate 2068.2.3 Reaction Temperature 2078.2.4 Size of Micelles 2078.2.5 Nature of Catalyst 2088.2.6 Increasing the Efficiency in Micellar Catalysis 2098.2.7 Order of Addition 2108.2.8 Product Precipitation or Extraction 2118.2.9 Trace Metal in the Product 2118.3 Highly Valuable Reactions in Water 2128.3.1 Suzuki–Miyaura Couplings 2128.3.2 Heck Couplings 2178.3.3 Negishi Couplings 2198.3.4 C–H Arylations 2218.3.5 Aminations 2258.3.6 Borylation 2288.3.7 Arylation of Nitro Compounds 2288.3.8 Adoption of Micellar Technology by Pharmaceutical Industry 2298.4 Conclusions 234Biography 234References 2359 Aspects of Homogeneous Hydrogenation from Industrial Research 239Stephen Roseblade9.1 Homogeneous Hydrogenation: A Brief Introduction 2399.2 Catalyst Selection by Effective Screening Approaches 2409.3 Considerations for Reaction Scale-up 2449.4 Notes on Additive Effects 2479.5 A Novel Approach to Aliskiren Using Asymmetric Hydrogenation as a Key Step 2499.6 Efficient Chemoselective Aldehyde Hydrogenation 2529.7 Closing Remarks/Summary 253Biography 255References 25510 Latest Industrial Uses of Olefin Metathesis 259John H. Phillips10.1 Introduction 25910.2 General Information 26010.2.1 Non-ruthenium Catalysts 26010.2.2 Ruthenium Catalysts 26110.3 Industrial Uses 26210.3.1 Ring-closing Metathesis (RCM) 26210.3.2 Cross-metathesis (CM) 26410.3.3 Ring-Opening Metathesis Polymerization (ROMP) 26810.4 Reaction Considerations 27010.4.1 Catalyst Choice 27110.4.2 Catalyst Loading 27310.4.3 Solvent 27310.4.4 Reaction Concentration 27310.4.5 Overall Handling 27410.4.6 Application Guide and Availability 27410.5 Troubleshooting 27510.5.1 Catalyst Removal 27510.5.2 Functional Group Tolerance 27610.5.3 Substrate Purity 27610.5.4 Catalyst Decomposition – Isomerization 27710.6 Conclusion 277Biography 277References 27811 Dehydrative Decarbonylation 283Alex John11.1 Introduction 28311.2 Use of Sacrificial Anhydride and Catalytic Mechanism 28511.3 Rh-, Pd-, and Ir-Catalysis 28611.3.1 Early Studies 28611.3.2 Recent Studies 28911.4 Milder Temperatures 29111.4.1 PdCl2/XantPhos/(tBu)4biphenol System 29111.4.2 Well-Defined Pd-bis(phosphine) Precatalysts 29411.5 Nickel and Iron Catalysis 29511.6 Ester Decarbonylation 29711.7 Synthetic Utility: α-Vinyl Carbonyl Compounds 29911.8 Conclusions and Future Prospects 300Biography 300References 301Index 305