Weiser, M., Pálvölgyi, Á. M., Weil, M., & Bica, K. (2024). Continuous Enantioselective α-Alkylation of Ketones via Direct Photoexcitation. Journal of Organic Chemistry, 89(12), 8906–8914. https://doi.org/10.1021/acs.joc.4c00759
Motivated by the scarcity of enantioselective direct intermolecular α-alkylation reactions of ketones with simple alkyl halides, we report a photo-organocatalytic process to access diethyl 2-(2-oxocyclohexyl)malonate and derivatives in good yield and enantioselectivity. The reaction design is based on highly abundant and nature-derived 9-amino-9-deoxy-epi-cinchona alkaloids to activate ketones as transient secondary enamines, which exist unfavorably in equilibrium with imines. These condensed species can serve as powerful photoinitiators via direct photoexcitation. This concept provides access to both enantiomeric antipodes. In addition to introducing an uncomplicated batch-optimized procedure, we investigated the feasibility and limitations of implementing the reaction in continuous flow, thus enabling to obtain diethyl 2-(2-oxocyclohexyl)malonate with a productivity of 47 μmol/h and 84% enantioselectivity.
