Development and Execution of an Ni(II)-Catalyzed Reductive Cross-Coupling of Substituted 2-Chloropyridine and Ethyl 3-Chloropropanoate

• DOI: 10.1021/acs.oprd.0c00134
• Publication Date: 2020-05-18T19:37:56Z
• Authors: Sri Krishna Nimma...; Satish Korapati; Debottam Dasgupta; Noormohamed Abdul...; Arun Vinodini; Aravind S. Gangu; Srinivas Kalidindi; Prantik Maity; Siva Sankar Bondi...; Alla Venu; William P. Gallagher; Selin Aytar; Francisco Gonzále...; Rajappa Vaidyanathan
• Keywords: Reductive elimination; Coupling reaction

We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between substituted 2-chloropyridine ethyl 3-chloropropanoate using manganese dust as terminal reductant. Several additives were screened for activation reductant in situ, chlorotriethylsilane (TESCl) was found to provide optimal conversion. A focused beam reflectance measurement (FBRM) probe utilized monitor particle attrition well during reaction. Modeling employed garner an understanding mixing requirements that would ensure effective suspension scale-up. The process successfully demonstrated on 7 kg scale afforded 2 64% yield.