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 cocatalysts 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 approximately 40% and
24 isolated examples. Importantly, this method was applied to prepare
a key intermediate in the synthesis of GSK3368715 on
multigram scale.