The incorporation of the gem-difluoromethylene (CF 2 ) group into organic frameworks is highly sought due to the influence of this unit on the physicochemical and pharmacological properties of molecules. Herein we report an operationally simple, mild, and switchable protocol to access various gem-difluoro compounds that employs chlorodifloroacetic anhydride (CDFAA) as a low-cost and versatile fluoroalkylating reagent. Detailed mechanistic studies revealed that electron-transfer photocatalysis triggers mesolytic cleavage of a CÀ Cl bond generating a gemdifluoroalkyl radical. In the presence of alkene, this radical species acts as a unique intermediate that, under solventcontrolled reaction conditions, delivers a wide range of gem-difluorinated γ-lactams, γ-lactones, and promotes oxyperfluoroalkylation. These protocols are flow-and batch-scalable, possess excellent chemo-and regioselectivity, and can be used for the late-stage diversification of complex molecules.
Trifluoromethyl ketones are not only found in drug like substances, but
are also considered as key synthons for the preparation of various fluorinated
heterocyclic molecules. Access to such trifluoromethyl ketone derivatives typically
requires the incorporation of the trifluoromethyl group, or a surrogate moiety,
at the beginning of a multi-step synthetic sequence. However, direct trifluoroacylation
of alkenes could potentially provide a highly efficient and straightforward
method for the synthesis of a,b-unsaturated trifluoromethyl ketones. Here we report a mild and
operationally simple trifluoroacylation strategy of olefines, that utilizes trifluoroacetic
anhydride as a low-cost and readily available reagent. This light-mediated
process is fundamentally different from conventional methodologies and occurs
through an trifluoroacyl radical mechanism promoted by a photocatalyst. Beyond
simple alkenes, this method allows for chemo- and regioselective
functionalization of small-molecule drugs and common pharmacophores.
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.
The incorporation of the gem-difluoromethylene (CF 2 ) group into organic frameworks is highly sought due to the influence of this unit on the physicochemical and pharmacological properties of molecules. Herein we report an operationally simple, mild, and switchable protocol to access various gem-difluoro compounds that employs chlorodifloroacetic anhydride (CDFAA) as a low-cost and versatile fluoroalkylating reagent. Detailed mechanistic studies revealed that electron-transfer photocatalysis triggers mesolytic cleavage of a CÀ Cl bond generating a gemdifluoroalkyl radical. In the presence of alkene, this radical species acts as a unique intermediate that, under solventcontrolled reaction conditions, delivers a wide range of gem-difluorinated γ-lactams, γ-lactones, and promotes oxyperfluoroalkylation. These protocols are flow-and batch-scalable, possess excellent chemo-and regioselectivity, and can be used for the late-stage diversification of complex molecules.
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