Tricomponent α-Carbonyl Alkylation by a Cobalt-Catalyzed Polar-Radical and Radical-Polar Crossover Cascade

Regioselective introduction of functional groups at distal positions of carbonyl compounds remains a significant challenge, often necessitating inefficient stepwise routes to access synthetically and medicinally important targets such as 1,6-aminocarbonyls. Direct radical α-functionalization of carbonyls can unlock broad scope strategies for position-specific installation of diverse functionalities and can address the inherent limitations of enolate-based approaches. However, the development of radical α-functionalization has remained underexplored due to the scarcity of catalytic systems capable of efficiently promoting both the direct generation of α-carbonyl radicals and the regioselective construction of distally functionalized frameworks. We report herein the development of a tricomponent cobalt(salen)-catalyzed α-alkylation of carbonyl compounds, providing a direct approach to 1,6-aminocarbonyl frameworks from diverse unactivated carbonyls and aromatic amines. The reaction proceeds through a cobalt(salen)-catalyzed sequence involving polar-radical crossover (PRC), which enables direct formation of α-carbonyl radicals, and radical-polar crossover (RPC), which mediates regiospecific installation of the distal amino group. The method tolerates a wide range of carbonyl substrates, including α-substituted aldehydes that are typically prone to deleterious hydrogen atom transfer from the reactive carbonyl group. Mechanistic studies reveal the roles of cobalt(salen) O- and C-enolates in the PRC step and the involvement of α-carbonyl radicals in enabling the RPC process.