Harnessing Entropy for Switchable Radical Cyclization Cascades

Abstract Radical cyclizations are highly selective and useful transformations in complex molecule synthesis. However, the regioselectivity of radical cyclizations is often determined by substrate structure, and in most cases, selective for 5-exo cyclization products over the 6-endo regioisomer. Herein, we address this challenge using a reaction-condition engineering approach to afford selective access to both the 5-exo and 6-endo radical cyclization products from the same substrate. The approach utilizes temperature to control the kinetic favorability of the 5-exo radical intermediate to engage in either carbon–carbon bond formation through Giese addition to deliver 5-exo functionalized products, or a one-carbon ring expansion to deliver the 6-endo functionalized product. We display this switchable cyclization approach on heteroaryl radical intermediates generated from single-electron reductions of heteroaryl halides and on aryl radical intermediates generated via halogen atom transfer. Additionally, density functional theory supports the conclusion that the kinetically favorable pathway is determined by the reaction temperature.