Direct -SF and -SFCF Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes.

In comparison to modern methods for carbon-SF bond formation, methods for are exceptionally scarce, rendering motifs such as "-SF" virtually unexplored in the context of organic and medicinal chemistry. Herein, we demonstrate that direct -SF bond formation can be accomplished through strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes (ABBs), using an easy-to-access solution of SFCl. To our surprise, the resultant -SF azetidines proved to be remarkably chemically stable and amenable to peripheral synthetic modifications (e.g., amination, cross-coupling, oxidation, dehalogenation, S1, and SAr reactions). The methodology also extends to direct -SFCF bond formation using -CFSFCl, enabling comparative studies throughout this work. From a mechanistic standpoint, DFT calculations, Hammett analyses, and radical trapping experiments support our proposed radical chain propagation mechanism. From a fundamental standpoint, considering -SF and -SFCF azetidines are heretofore unknown molecular motifs, this work analyzes their dynamic, spectroscopic, and crystallographic features, as well as computed properties (e.g., BDE and p values), to provide foundational knowledge and inform downstream applications. While the carbon-bound SF group has been employed as a bioisostere for a CF group, we posited the -SF motif could be a potential replacement for a small sulfonamide. Accordingly, we synthesized an -SF derivative of a spleen tyrosine kinase inhibitor reported in the patent literature for comparative ADME studies; results from profiling indicate that an -SF azetidine could indeed be an alternative for an -SOMe azetidine, in cases where enhanced lipophilicity is desirable.