Chalcogenide-Catalyzed Intermolecular Electrophilic Thio- and Halofunctionalization of gem-Difluoroalkenes: Construction of Diverse Difluoroalkyl Sulfides and Halides

Abstract

Thio- and halodifluoromethylated compounds are an important class of compounds in medicinal chemistry and organic synthesis. Herein, we report a facile method for the construction of these compounds via chalcogenide-catalyzed intermolecular electrophilic thio- and halofunctionalization of gem-difluoroalkenes. Simple treatment of gem-difluoroalkenes with electrophilic sulfur/halogen reagents and various O- or N-nucleophiles affords diverse multifunctionalized thio- and halodifluoromethylated compounds. This reaction features a relatively broad substrate scope, good functional group tolerance, and mild reaction conditions.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…An electrophilic thio-and halofunctionalization of gemdifluoroalkenes used a chalcogenide-based catalyst system (Scheme 16A). 45 Several strategies have been developed to rapidly quench the anionic intermediate 5 generated from nucleophilic addition into gem-difluoroalkenes (Scheme 1B). For example, the use of acid and base organocatalysts has enabled development of several functionalization reactions of gem-difluoroalkenes.…”

“…An electrophilic thio-and halofunctionalization of gemdifluoroalkenes used a chalcogenide-based catalyst system (Scheme 16A). 45 Mechanistically, this reaction operated by initial activation of a succinimide-based reagent 84 with SePh 2 or SPh 2 to generate ion pair 89 (Scheme 16B). This activated reagent 89 then formed a cation with the gem-difluoroalkene, and subsequent nucleophilic attack at the benzylic position afforded products 92.…”

Electrochemical bromofunctionalization of alkenes in a flow reactor

“…18 Halofunctionalizations of gem-difluoalkenes were demonstrated by Zhao and co-workers (2020). 19 Over the past decade, several electrochemical strategies for the bromination of alkenes using anodically generated bromine have been reported. Early examples include the bromohydroxylation of alkenes which were limited to a small number of substrates.…”

Synthesis of α-trifluoromethyl sulfides through fluorosulfuration ofgem-difluoroalkenes

“…This reaction required a Lewis acid and Lewis base to activate the relatively inert succinimide derived sulfur electrophile (Scheme 2a). 9 To test this hypothesis, we chose gem-difluoroalkene 1a and methyl benzenesulfonothioate 2a for a standard reaction to optimize conditions (Table 1). When the reaction was performed with CsF as the fluorine source in DMF solution at room temperature, the desired fluorosulfuration product 3a was obtained in 36% yield (entry 1).…”

“…This reaction required a Lewis acid and Lewis base to activate the relatively inert succinimide derived sulfur electrophile (Scheme 2a). 9…”