Modular Access to N–SF₅ azetidines

Synthetically accessible novel scaffolds and chemical functional groups with drug-like properties offer an innovative approach to medicinal chemistry design. Replacement of N–alkyl substituents with the N–pentafluorosulfanyl (N–SF₅) group may help overcome the potential liabilities due to the SF5 group's larger steric volume, stronger electron-withdrawing effect, and increased lipophilicity. However, the lack of a general, operationally simple, and efficient synthetic strategy for N–SF₅ compounds has significantly hindered their evaluation as (bio)isosteres and in turn broader application. To address this, we developed a modular coupling approach using bench-stable, scalable SF₅-transfer reagents, enabling efficient access to N–SF₅-azetidines. This method provides a user-friendly protocol with mild reaction conditions and broad functional group tolerance, making it well-suited for the late-stage modification of commercial drugs and natural products. The resulting scaffolds demonstrate high aqueous stability and lipophilicity, staging them as a novel class of potential (bio)isosteres in medicinal chemistry.