Strain-Release Pentafluorosulfanylation of Carbonyl-Containing Disubstituted Bicyclobutanes: A Fortuitous Path to SF5-Containing Oxa[2.1.1]bicyclohexanes.

The recent merger of pentafluorosulfanylation with strain-release functionalization logic-largely enabled by an increase in SF5Cl accessibility-has begun to reshape the ways we can imagine incorporating the SF5 group into organic molecules. In this study, we first explore how both radical polarity matching and substituent effects, when employed synergistically, can be used to effect regio- and diastereoselective SF5Cl addition across 1,3-disubstituted (viz. 3-aryl-1-carbonyl-substituted) bicyclobutanes (BCBs) to access a class of congested α-SF5-carbonyl-containing tetrasubstituted cyclobutanes (CBs). Synthetic, computational, and structural studies provide insight on the observed selectivity and reveal unusually close intramolecular SF5⋯C═X (X = C, N, or O) contacts in several SF5-CBs by SC-XRD. Beyond accessing compounds of fundamental interest, we describe a complementary telescoped protocol to facilitate isolation of SF5-CBs as alcohols, as well as a fortuitous observation that led to the synthesis of the first suite of SF5-substituted oxa[2.1.1]bicyclohexanes (OBHs). Finally, we examine the compatibility of SF5-CBs and SF5-OBHs with various reaction conditions to expand the scope of accessible building blocks and report the synthesis of an SF5-OBH-containing drug derivative. Results from comparative in vitro ADME profiling indicate the SF5-OBH motif may serve as an attractive "hybrid bioisostere" for the meta-CF3-Ph motif.