Strain‐Release Pentafluorosulfanylation of Carbonyl‐Containing Disubstituted Bicyclobutanes: A Fortuitous Path to SF ₅ ‐Containing Oxa[2.1.1]bicyclohexanes

The recent merger of pentafluorosulfanylation with strain‐release functionalization logic—largely enabled by an increase in SF 5 Cl accessibility—has begun to reshape the ways we can imagine incorporating the SF 5 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 SF 5 Cl addition across 1,3‐disubstituted ( viz . 3‐aryl‐1‐carbonyl‐substituted) bicyclobutanes (BCBs) to access a class of congested α‐SF 5 ‐carbonyl‐containing tetrasubstituted cyclobutanes (CBs). Synthetic, computational, and structural studies provide insight on the observed selectivity and reveal unusually close intramolecular SF 5 ⋯C═X (X = C, N, or O) contacts in several SF 5 ‐CBs by SC‐XRD. Beyond accessing compounds of fundamental interest, we describe a complementary telescoped protocol to facilitate isolation of SF 5 ‐CBs as alcohols, as well as a fortuitous observation that led to the synthesis of the first suite of SF 5 ‐substituted oxa[2.1.1]bicyclohexanes (OBHs). Finally, we examine the compatibility of SF 5 ‐CBs and SF 5 ‐OBHs with various reaction conditions to expand the scope of accessible building blocks and report the synthesis of an SF 5 ‐OBH‐containing drug derivative. Results from comparative in vitro ADME profiling indicate the SF 5 ‐OBH motif may serve as an attractive “hybrid bioisostere” for the meta ‐CF 3 ‐Ph motif.