Enantioselective palladium-catalyzed α-arylation of primary alkylamines

Abstract

Chiral amines, particularly those bearing a stereocenter attached to nitrogen, are privileged and ubiquitous scaffolds in pharmaceuticals. The direct α-functionalization of alkylamines is synthetically attractive yet remains formidably challenging due to the inert nature of the α-C–H bond. To address this, the primary amines were masked with a 9-fluorenylidene moiety, which effectively enhances the acidity of the α-proton, facilitating deprotonation under basic conditions. The resulting aza-allyl anion intermediate, as a nucleophile, was then incorporated into palladium-catalyzed cross-coupling with bromoarenes. The employment of P-chiral monophosphorus ligands was essential for achieving both high regio- and enantioselectivities, allowing for unique access to chiral α-aryl amines in excellent enantioselectivities and moderate to good yields. The ease of installation and the subsequent removal of the 9-fluorenylidene moiety enhance the utility of this method in organic synthesis and medicinal chemistry.