Bidirectional Alkene-Nucleophile Coupling at a Single Carbon Center Enabled by a Methylene-Bridged Thianthrenium Dication

Abstract The chemical space explored through synthesis is largely shaped by the availability of building blocks supplied by nature. Because biosynthesis follows defined metabolic logic, naturally occurring compounds are unevenly distributed across carbon count, creating intrinsic biases in synthetic accessibility. Consequently, molecules differing by only a single carbon atom can require markedly different synthetic effort. To overcome this longstanding challenge, we report a bidirectional coupling strategy that assembles alkenes and nucleophiles across an intervening methylene unit. In contrast to conventional alkene hydrofunctionalization, which joins these partners directly, this approach retains the modularity of the parent reaction while increasing product carbon count. We show that a designer methylene-bridged thianthrenium dication reagent exploits distinct redox properties and strain-release reactivity to differentiate two C–S bonds at a single carbon center. This design enables sequential alkene hydroalkylation and downstream nucleophile incorporation via substitution, cross-coupling or radical manifolds. This divergent reactivity accommodates diverse nucleophile classes (N, O, B, S, Se, C and halides), facilitates the hybridization of complex biorelevant fragments and expands retrosynthetic flexibility in the synthesis of marketed drugs. By rerouting two abundant substrate classes through a single-carbon linchpin, this platform opens one-carbon-shifted chemical space beyond the reach of conventional alkene hydrofunctionalization.