Direct Heterocycle C–H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation

One of the major challenges in developing catalytic methods for C–C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C–H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo)halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-¬tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr–H substrate classes undergoing C–H activation without the need for co-catalysts or stoichiometric silver bases (e.g. Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle, and the palladacycle effects C–H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested, with a hit-rate of approx. 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.