Fluorinated functional groups, specifically the difluorinated ketones, are important substituents for medicinal chemistry. Moreover, difluorinated ketones can interact with aspartyl proteases through noncovalent hydrogen-bonding networks, and with serine proteases through reversible covalent interactions. An alternate group, difluoroalkyl ethers display a wide range of applications in pharmaceuticals, agrochemicals, and material chemistry. Though compounds containing these two individual functional groups have notable applications in various fields, the preparation of compounds that contain both these groups together, specifically α,α-difluorinated-α-phenoxy ketones, are underexplored and only one method for accessing this potentially useful substructure exists. Therefore, new efficient and convergent synthetic strategies that provide facile access to this substructure would be valuable for medicinal chemistry and chemical biology. This presentation will discuss such a convergent strategy to generate α,α-difluorinated-α-phenoxy ketones involving the Cu-catalyzed difunctionalization of gem-difluoroalkenes by phenols and molecular oxygen. In ongoing research, our group has focused on the functionalization of gem-difluoroalkenes to construct diverse useful fluorinated compounds that retain both the fluorine atoms. Historically, reactions to functionalize gem-difluoroalkenes utilizing transition metal catalyzed reactions proceeded through β-fluoro anionic or β-fluoro metal intermediates that are both prone to undergo β-fluoride elimination and generate monofluoroalkenes. To overcome this elimination, the present reaction exploits a single-electron process that avoids anionic intermediates and generates difluorinated products. This reaction delivered a set of α,α-difluorinated-α-phenoxy ketones in good to excellent yield. Moreover, we demonstrate that α,α-difluorinated-α-phenoxy ketones can be further utilized as synthetic handles for accessing diverse functional groups.

Oxidation of gem-difluoroalkenes to α,α-difluorinated-α-phenoxy ketones

ACS Spring Meeting 2021

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