Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles

Functionalization at the alpha-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C-X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the alpha-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate alpha-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.