Continuous Flow Decarboxylative Monofluoroalkylation Enabled by Photoredox Catalysis

Abstract

Herein, we report a scalable and mild strategy for the monofluoroalkylation of a wide array of Giese acceptors via visible-light-mediated photoredox catalysis in continuous flow. The use of flow technology significantly enhances productivity and scalability, whereas mildness of conditions and functional group tolerance are ensured by leveraging 4CzIPN, a transition-metal-free organic photocatalyst. Structurally diverse secondary and tertiary monofluoroalkyl radicals can thus be accessed from readily available α-monofluorocarboxylic acids. Given the mild reaction conditions, this protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as menthol, amantadine, bepotastine, and estrone derivatives, rendering it suitable for application to drug discovery programs, for which the introduction of fluorinated fragments is highly sought after. This method was also extended to enable a reductive multicomponent radical-polar crossover transformation to rapidly increase the complexity of the assembled fluorinated architectures in a single synthetic operation.