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-keto- and γ-aldoamides from nitrones and ynamides with a Cu(II) catalyst. A copper-coordinated iminium intermediate is proposed to initiate a diastereoselective rearrangement for C–C bond formation and a combination of 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 showcases distinct copper-catalyzed reactivity of N-alkenylnitrones for the synthesis of 1,4-dicarbonyl compounds.