Telescoped Nickel-Catalyzed Borylation-(Phenoxyimine)Nickel-Catalyzed C(sp ² )–C(sp ³ ) Suzuki–Miyaura Coupling for Afimetoran Core Synthesis

The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp 2 )–C(sp 3 ) Suzuki–Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.