Direct <i>N</i> –SF <sub>5</sub> and <i>N</i> –SF <sub>4</sub> CF <sub>3</sub> Bond Formation through Strain-Release Functionalization of 3-Substituted [1.1.0]Azabicyclobutanes
Yannick Kraemer, Soojun Park, Wang‐Yeuk Kong, Yongxin Chen, Anthony J. Witt, Jón Atiba Buldt, Abbey N. Ragan, Lauren M. Holder, Dean J. Tantillo, Cody Ross Pitts
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.