Direct <i>N</i> –SF ₅ and <i>N</i> –SF ₄ CF ₃ Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes

Abstract

In comparison to modern methods for carbon–SF 5 bond formation, methods for direct heteroatom–SF 5 bond formation are exceptionally scarce, rendering motifs such as “ N –SF 5 ” virtually unexplored in the context of organic and medicinal chemistry. Herein, we demonstrate that direct N –SF 5 bond formation can be accomplished through strain-release pentafluorosulfanylation of 3-aryl [1.1.0]azabicyclobutanes (ABBs), using an easy-to-access solution of SF 5 Cl. To our surprise, the resultant N –SF 5 azetidines proved to be remarkably chemically stable and amenable to peripheral synthetic modifications (e.g., amination, cross-coupling, oxidation, dehalogenation, S N 1, and S N Ar reactions). The methodology also extends to direct N –SF 4 CF 3 bond formation using trans -CF 3 SF 4 Cl, 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 N –SF 5 and N –SF 4 CF 3 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 K b values), to provide foundational knowledge and inform downstream applications. While the carbon-bound SF 5 group has been employed as a bioisostere for a CF 3 group, we posited the N –SF 5 motif could be a potential replacement for a small sulfonamide. Accordingly, we synthesized an N –SF 5 derivative of a spleen tyrosine kinase inhibitor reported in the patent literature for comparative ADME studies; results from in vitro profiling indicate that an N –SF 5 azetidine could indeed be an alternative for an N –SO 2 Me azetidine, in cases where enhanced lipophilicity is desirable.