Kraemer, Yannick, Soojun, Park, Wang-Yeuk, Kong, Chen, Yongxin, Witt, Anthony, Atiba Buldt, Jón, Ragan, Abbey, Holder, Lauren, Tantillo, Dean and Pitts, Cody (2025) Direct N–SF5 and N–SF4CF3 Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes. Journal of the American Chemical Society, 147 (31). pp. 27892-27904. ISSN 10.1021/jacs.5c07137

Abstract

In comparison to modern methods for carbon–SF5 bond formation, methods for direct heteroatom–SF5 bond formation are exceptionally scarce, rendering motifs such as “N–SF5” virtually unexplored in the context of organic and medici-nal chemistry. Herein, we demonstrate that direct N–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 N–SF5 azetidines proved to be remarkably chemically stable and amenable to peripheral syn-thetic modifications (e.g., amination, cross-coupling, oxidation, dehalogenation, SN1, and SNAr reactions). The meth-odology also extends to direct N–SF4CF3 bond formation using trans-CF3SF4Cl, enabling comparative studies through-out 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–SF5 and N–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 pKb values), to provide foundational knowledge and inform downstream applications. While the carbon-bound SF5 group has been employed as a bi-oisostere for a CF3 group, we posited the N–SF5 motif could be a potential replacement for a small sulfonamide. Ac-cordingly, we synthesized an N–SF5 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–SF5 azetidine could indeed be an al-ternative for an N–SO2Me azetidine, in instances where enhanced lipophilicity is desirable.

Item Type:	Article
Keywords:	Heteroatom–SF5 bond formation Strain-Release Functionalization
Date Deposited:	17 Sep 2025 00:45
Last Modified:	17 Sep 2025 00:45
URI:	https://oak.novartis.com/id/eprint/57306