Advancing BaseMetal Catalysis: Development and Executionof a Ni-catalyzed Borylation/Pd-catalyzed Suzuki Telescoped Process

The development and execution of a nickel-catalyzed borylation/palladium-catalyzed Suzuki telescoped process utilizing the inexpensive NiCl₂·6H₂O precatalyst for the borylation step are reported. The development of the borylation reaction was guided by a preliminary mechanistic investigation to understand the origin of the dehalogenated side product. The borylation stream was telescoped into a Suzuki coupling to form a bis-heteroaryl bond in the pentacyclic core of afimetoran, an antagonist of toll-like receptors 7/8 (TLR 7/8). The optimization of the Suzuki reaction and kilogram-scale demonstration of the telescoped process showcase the viability of utilizing nickel catalysis in the development of scalable routes to clinical APIs.