Abstract
Despite the significant applications of fluorinated cyclobutanes in industrial and diagnostic fields, efficient methods for synthesizing these valuable fluorinated structures remain limited. Here, we report a new difluoroalkylating reagent, 2-(difluoromethylene)cyclobutyl sulfonium salts (CB-DFASs). This reagent can be readily synthesized on a gram scale in three steps from readily available cyclobutanone enol silyl ether. CB-DFASs exhibit high reactivity and enable chemodivergent synthesis of structurally diverse difluoroalkylated cyclobutenes using a wide array of nucleophiles, including those based on carbon, oxygen, nitrogen, and sulfur, under mild conditions. The resulting products serve as versatile linchpins for diverse transformations, thereby enabling the synthesis of a variety of difluoroalkylated cyclobutanes. The synthetic utility of CB-DFASs has been demonstrated through the late-stage modification of complex pharmaceuticals and the rapid synthesis of analogues of bioactive molecules, highlighting their potential in drug discovery.