Development of Kilogram-Scale Electrochemical Ni-Catalyzed Cross Electrophile Coupling in Flow

Organic electrosynthesis opens novel routes for pharmaceutical production; however, limited knowledge and experience with the scale up of this technique have hindered its industrial implementation. In this work, we report a kilogram-scale flow electrochemical Ni-catalyzed cross-electrophile coupling (XEC) to prepare a key intermediate in the synthesis of the toll-like receptor (TLR) 7/8 inhibitor afimetoran. We successfully demonstrate scalability across 2 orders of magnitude while maintaining reaction performance. We also conduct a continuous 120 h reaction, highlighting compatibility with industrially relevant time scales. Key design aspects of our custom parallel-plate reactor are discussed that enabled kilogram-scale synthesis with a single electrode stack. This report showcases that with proper reaction engineering, electrochemical Ni-catalyzed XEC is a viable alternative to existing Pd-catalyzed cross-coupling methods.