Swapping O for S: Converting Oxetanes into Thietanes and their Oxidized Derivatives

Thietanes, often considered as “oxetane analogs”, offer complementary physicochemical properties and, along with their oxidized derivatives, are attracting increasing interest in medicinal chemistry. Their exploration, however, remains limited, partly due to the restricted availability and structural diversity of appropriate building blocks. The variety of methods available for preparing oxetanes with diverse substitution patterns makes their conversion into thietanes an appealing strategy for both building-block synthesis and late-stage diversification. However, existing O-to-S exchange methods mostly rely on the sulfurization of a 1,3-diactivated intermediate, require forcing conditions, and, importantly, provide very limited access to C(2)-substituted thietanes. We report herein a one-pot, two-step sequence for the mild and efficient O-to-S exchange in oxetanes. The approach relies on an autoactivation via a group-transfer strategy that bypasses the need for diactivated intermediates and provides access to thietanes with unprecedented substitution patterns, thus expanding the range of building blocks available for molecular design. Extensions to the formal O-to-SO, O-to-SO 2 and O-to-S(O)NH exchanges are also reported.