Mechanistic studies and new methodologies relevant to palladium-catalyzed chemodivergent cross-coupling reactions

Abstract

Palladium-catalyzed cross-couplings are powerful methods for constructing new carbon-carbon bonds in organic molecules. While the mechanism of these reactions are generally well studied, complexities are introduced when the starting materials involved in the reaction contain several possible sites at which the new C-C bond can be made. It is often desirable for the palladium catalyst to facilitate (chemo)selective cross-coupling at just one of the reaction sites while leaving the other(s) intact. This can be challenging and often requires extensive tuning of the palladium catalyst and the reaction conditions. In this work, we describe efforts to better understand the properties causing palladium catalysts to react chemoselectively at aryl chloride (C-Cl) or triflate (C-OTf) reaction sites. Using a combined approach of computational and experimental chemistry, we demonstrate that solvent plays a critical role in the reaction selectivity by coordinating to the palladium catalyst and promoting reaction at C-OTf sites via formation of bisligated palladium. Anionic additives like inorganic bases play a complementary role in promoting reaction at C-OTf sites. We additionally describe efforts to develop new chemodivergent cross-coupling methodologies using palladium-N-heterocyclic carbene precatalysts. These catalysts demonstrate robust reactivity under mild conditions, allowing for a greatly expanded scope of chemoselective cross-coupling products, especially biaryl triflates.