Copper-Catalyzed Disruption of a Cascade Reaction: Synthesis of γ-Ketoamides from Nitrones and Ynamides

A thermal dipolar cycloaddition and rearrangement reaction to form pyrrolines has been redirected towards the synthesis of γ-ketoamides from nitrones and ynamides with a Cu(II) catalyst. An iminium N,O-dialkenylhydroxylamine intermediate is proposed to initiate diastereoselective C–C bond formation and a combination of copper catalyst and nitrone protecting group balance the desired reactivity, diastereoselectivity, and sensitivity to hydrolysis. Reaction optimization is described in addition to scope, mechanistic studies, and conversion of γ-ketoamides to 1,4-diones. This catalytic method controls formation of the central C–C bond of 1,4-dicarbonyl compounds and showcases the unique reactivity of N-alkenylnitrones for accessing these molecules.