Direct Carbonylative Amidation of Benzylic Alcohols with Alkylamines via Palladium Catalyzed C-O Bond Activation

Abstract

A palladium-catalyzed direct carbonylative amidation that enables the efficient coupling of benzylic alcohols with alkylamines under mild conditions has been developed. Key to the success is the use of pentafluoropyridine as a activating group, which facilitates selective alcohol activation and suppresses undesired side reactions.Amide bond formation stands as a cornerstone-and a persistent challenge-in synthetic chemistry, particularly in the context of modern atom-and step-economical synthesis. 1 This is especially relevant for medicinally privileged structures such as the benzylamide motifs found in widely prescribed Z-drugs like zolpidem and alpidem, where efficient and modular access to this scaffold is highly desirable (Scheme 1, a). 2 While classical condensation methods relying on pre-activated carboxylic derivatives remain indispensable in both academic and industrial settings, their dependence on stoichiometric coupling agents and the concomitant generation of chemical waste imposes clear limitations in terms of sustainability and operational simplicity. Following the pioneering work on transition-metal-catalyzed carbonylative coupling by R. F. Heck, catalytic carbonylation has emerged as a powerful synthetic platform. 3 Among its most notable advances is the threecomponent coupling of aryl (pseudo)halides, carbon monoxide, and amines, which offers an efficient and direct route to amide bonds. 4 Despite substantial progress, these methods universally require pre-functionalized electrophilic partners, which introduces additional synthetic steps and constrains the modularity of the approach.