A Morita-Baylis-Hillman Inspired Cross-Coupling Strategy for the Direct alpha-Arylation of Cyclic Enones

Cyclic enone derivatives are important scaffolds in medicinal chemistry; methods that enable direct and selective Carylations of these compounds have the potential to enable the rapid evaluation of pharmaceutically relevant molecules. Herein, a method for the direct, selective Pd-catalyzed ??-arylation of cyclic enones with (hetero)aryl triflates is described. High-throughput screening identified the biaryl phosphines JohnPhos and CPhos as optimal ligands and DABCO as an essential additive, allowing for the formation of the regioisomer opposite to that obtained under traditional Mizoroki???Heck protocols. Preliminary mechanistic investigations suggest that the reaction proceeds by enone activation analogous to a Morita???Baylis???Hillman reaction followed by Pd-catalyzed enolate arylation. The palladium catalyst is hypothesized to serve a dual role: as a Lewis acid catalyst to facilitate 1,4 addition of the DABCO to the enone substrate and as a cross-coupling catalyst to enable C???C bond formation. Superscript/Subscript AvailableMore