Phase Transfer Catalysts Shift the Pathway to Transmetalation in Biphasic Suzuki-Miyaura Cross-Couplings

Abstract The Suzuki-Miyaura coupling (SMC) is arguably the most widely used C-C bond forming reaction. Numerous mechanistic studies of the SMC have enabled the use of exceptionally low catalyst loadings while significantly expanding its functional group tolerance. However, the dominant mode of transmetalation operative in SMCs remains controversial and likely depends on the particular conditions employed. Herein we report a detailed mechanistic study of a palladium catalyzed SMC under biphasic reaction conditions. The use of phase transfer catalysts (PTC) resulted in a remarkable 12-fold rate enhancement in the targeted system. Studying the speciation of the arylboron nucleophile and the palladium catalyst revealed that a shift from an oxo-palladium based transmetalation to a boronate based pathway lies at the root of this activity. Furthermore, the robustness of our monitoring platform enabled us to study the impact of different water loadings in biphasic settings. We found that increasing the proportion of the aqueous phase results in significant rate enhancements, contrary to the reaction conditions typically employed in the literature. This rate acceleration matched or surpassed those achieved by manipulating the nature of the organoboron nucleophile. The importance of these findings was highlighted by achieving an exceptionally broad substrate scope with benzylic electrophiles using a 10-fold reduction in catalyst loading relative to literature precedent.