The α-functionalization of carbonyl groups with nucleophiles is a long-standing issue in organic synthesis. It usually requires the pre-functionalization of the substrate with a leaving group such as an halogen. To tackle this problem, and based on its previous works, Maulide’s research group used an intermediate electrophilic enolonium species that can react with a broad range of heteroatom nucleophiles in an Umpolung event to achieve the direct and chemoselective α-functionalization of amides. The scope encompasses O-,S- and N-based nucleophiles as well as halides in a truly unified approach. Noteworthy, the methodology is selective for amides in the presence of esters, nitriles and ketones and is compatible with complex nucleophiles such as amino acids and sugars. Quantum chemical calculations helped shed some light on the reaction mechanism and uncovered an unexpected pathway where the α-OTf amide is an intermediate.
A very nice piece of work of Maulide and his team that will undoubtably find broad applications among the synthetic chemists community.

https://pubs.acs.org/doi/abs/10.1021/jacs.9b06956

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