Phenoxythiazoline (FTz)–Cobalt(II) Precatalysts Enable C(sp2)–C(sp3) Bond– Formation for the Key Intermediate in the Synthesis of Afimetoran and Related Toll-like Receptor 7/8 (TLR7/8) Antagonists

Evaluation of the relative rates of the cobalt-catalyzed C(sp2)–C(sp3) Suzuki–Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4- bromopiperidine established that decreasing the size of the N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe•B(OiPr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise leads to demetallation of the FI chelate. Determination of the experimental rate law established a first- order dependence on the cobalt precatalyst and a saturation regime in heterogeneous potassium aryl boronate (apparent zeroth order), supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution. The optimized cobalt precatalyst and reaction conditions were applied to the multigram-scale synthesis of an intermediate used in both the discovery and process routes for toll-like receptor (TLR) 7/8 antagonist molecules.