O-, N- and C-bicyclopentylation using thianthrenium reagents

Abstract Rigid 1,3-disubstituted bicyclo1.1.1pentanes (BCPs) are linear bioisosteres for para -substituted benzene rings in drug development and can lead to an improved pharmacokinetic profile. The construction of BCPs commonly requires the cumbersome use of labile 1.1.1propellane in solution, and more stable reagents do not show the versatile reactivity of propellane itself. Here we report stable thianthrenium-based BCP reagents for practical O -, N - and C -alkylation reactions that expand the scope of bicyclopentylation beyond that of any other reagent, including 1.1.1propellane. The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis of the BCP-thianthrenium reagents via strain release as well as their subsequent reactivity. The weak exocyclic C–S bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition metal-mediated C–O, C–N and C–C bond formations, even at a late stage of multistep reactions with a wide variety of functional groups present.