Palladium catalyzed cross-coupling of esters and amides

Abstract

Over the last 40 years, great strides have been made in the use of palladium as both a catalyst and a reagent for a multitude of chemical transformations that have had tremendous impacts all walks of life from material science to the development and large-scale synthesis of new, novel pharmaceuticals. One such class of reactions is the palladium-catalyzed functionalization of the [alpha]-position of carbonyl compounds using aryl halides. When compared to palladium catalyzed C-N bond forming reactions, these reactions have been understudied and underutilized. Herein we report our efforts towards the development of the [alpha]-arylation of ethyl acetate by using a continuous flow reactor and a unique lithium amide base. Lessons learned from these studies lead to the development of a simple, one-pot protocol for the mono-[alpha]-arylation of amides under palladium catalysis. Previously reported palladium catalyzed [alpha]-arylations of amides with aryl halides required relatively high catalyst loadings, the use of a glove box, excess ligand, pyrophoric reagents, high temperatures or extended reaction times. This protocol affords the desired mono-[alpha]-arylated amide products in good to excellent yields using 1-2 mol % catalyst loading at ambient temperature in as little as two hours.