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

Abstract

Rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (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 [1.1.1]propellane 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 [1.1.1]propellane. 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. [Figure not available: see fulltext.]