Regiospecific de mayo reactions of enamino ketones

The de Mayo reaction is a powerful photochemical method for skeletal editing, enabling rapid synthesis of 1,5-dicarbonyl compounds through formal addition of 1,3-dicarbonyl units across olefins. However, its regio- and chemoselectivity remain limited. Distinct aryl groups cannot be selectively installed on 1,5-diketones; substituents in 1-aryl-5-alkyl diketones favor the α-position of the aryl ketone; and electron-withdrawing groups from deficient olefins are generally restricted to the 3-position. Such olefins also favor radical addition and formal redox pathways over the desired reaction. Here, we introduce de Mayo reactions of readily accessible enaminoketones that overcome these limitations and directly furnish valuable cyclohexenone derivatives. Tuning the N-protecting group and using a chiral Brønsted acid catalyst enables proof-of-concept kinetic resolution of the imine intermediate formed after [2 + 2] cycloaddition. This regiospecific platform expands precise access to 1,5-diketones and related motifs relevant to pharmaceutical discovery, while broadening the synthetic scope of this established photochemical transformation under practical conditions. The de Mayo reaction is a valuable photochemical method for skeletal editing, but longstanding regio- and chemoselectivity limitations restrict its synthetic scope. Here the authors report enaminoketone-enabled de Mayo reactions that overcome these constraints, providing regiospecific access to cyclohexenones and 1,5-diketone motifs.