Weiser, M. (2023, July 10). Continuous Enantioselective α-Alkylation of Ketones via Direct Enamine Photoexcitation [Poster Presentation]. 22nd European Symposium on Organic Chemistry 2023, Belgium.
The persistent difficulty of asymmetric catalytic direct intermolecular α-alkylation reactions of ketones with simple alkyl halides restricts access to many complex products in nature and explains its scarcity in photocatalytic processes. Inspired by the pioneering work of Melchiorre, we developed a new photo/organocatalytic strategy to achieve this synthetic task.
The highly abundant and natural-derived 9-amino(9-deoxy)-epi-cinchona alkaloids with a phenyl group in the 2-position acted as potent catalysts for the direct photo/organocatalytic asymmetric α-alkylation of ketones. After parameter optimization, diverse functionalized symmetric and cyclic ketones of different ring sizes could readily react with symmetric electron-deficient bromomalonates, and the related products could be obtained with good yield and enantioselectivity. Furthermore, this concept provided access to both enantiomeric antipodes. Mechanistic investigations revealed the proposed reaction mechanism, which proceeds via a self-propagating radical chain mechanism initiated by the direct excitation of the transiently formed secondary enamine upon 365 nm irradiation. Apart from an uncomplicated procedure optimized for batch, homogeneous conditions were found that enabled the photo-/organocatalytic synthesis of 1,3-diethyl-2-(2-oxocyclohexyl)propanedioate in continuous flow with good productivity and enantioselectivity.
