Direct <i>N</i>–SF₅ and <i>N</i>–SF₄CF₃ Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes

Abstract

In comparison to modern methods for carbon-SF₅ bond formation, methods for <i>direct heteroatom-SF</i>₅ <i>bond formation</i> are exceptionally scarce, rendering motifs such as "<i>N</i>-SF₅" virtually unexplored in the context of organic and medicinal chemistry. Herein, we demonstrate that direct <i>N</i>-SF₅ bond formation can be accomplished through strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes (ABBs), using an easy-to-access solution of SF₅Cl. To our surprise, the resultant <i>N</i>-SF₅ azetidines proved to be remarkably chemically stable and amenable to peripheral synthetic modifications (e.g., amination, cross-coupling, oxidation, dehalogenation, S_N1, and S_NAr reactions). The methodology also extends to direct <i>N</i>-SF₄CF₃ bond formation using <i>trans</i>-CF₃SF₄Cl, 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 <i>N</i>-SF₅ and <i>N</i>-SF₄CF₃ 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<i>K</i>_b values), to provide foundational knowledge and inform downstream applications. While the carbon-bound SF₅ group has been employed as a bioisostere for a CF₃ group, we posited the <i>N</i>-SF₅ motif could be a potential replacement for a small sulfonamide. Accordingly, we synthesized an <i>N</i>-SF₅ derivative of a spleen tyrosine kinase inhibitor reported in the patent literature for comparative ADME studies; results from <i>in vitro</i> profiling indicate that an <i>N</i>-SF₅ azetidine could indeed be an alternative for an <i>N</i>-SO₂Me azetidine, in cases where enhanced lipophilicity is desirable.