Solvent-Controlled Switchable Synthesis of gem-Difluoro Compounds from Anhydrides under Photoredox Catalysis



The outstanding impact of fluorine atom in drug discovery cannot be overestimated. Substantially, the incorporation of the gem-difluoro (CF2) group into organic frameworks is highly sought due to the influence of this unit on physicochemical and pharmacological properties of molecules. Yet, introduction of CF2 moiety into organic structures is a step-intensive preparation, and known approaches are often limited to certain classes of molecules. Development of strategies for a rapid incorporation of gem-difluoro synthon that utilizes inexpensive commercial reagents is highly desirable. In the context of divergency and applicability of such reagents, switchable synthesis can be beneficial to access a wide range of fluorinated compounds. Herein we report a mild and operationally simple protocols to access various gem-difluoro compounds that employs chlorodifloroacetic anhydride (CDFAA) as a low cost and versatile fluoroalkylating reagent. Detailed mechanistic investigations revealed that electron-transfer photocatalysis triggers mesolytic cleavage of a C−Cl bond generating a gem-difluoro carboxy radical. In the presence of alkene molecule, this radical species acts as an efficient and unique bifunctional reagent that, under solvent-controlled reaction conditions, delivers a wide range of gem-difluorinated γ-lactams, γ-lactones, as well as promotes oxy-perfluoroalkylation. These protocols are flow and batch scalable, possess excellent chemo- and regioselectivity, and can be used for the late-stage diversification of biorelevant molecules.

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Supplementary material

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Supplementary Infromation
The document includes synthetic procedures, NMR spectra, characterization for all new compounds, and further details of computational studies.