Shifting Lithium Amide Reactivity to the Radical Domain: Regioselective Radical C−H Functionalization of 3-Iodooxetane for the Synthesis of 1,5-Dioxaspiro[2.3]hexanes

Strained spiro-heterocycles (SSHs) have gained significant attention within the medicinal chemistry community as promising sp3-rich bioisosteres for their aromatic and non-spirocyclic counterparts. We herein report access to an unprecedented spiro-heterocycle—1,5-dioxaspiro[2.3]hexane. Our synthetic approach leverages a lithium-amide induced single-electron transfer to benzophenones generating an N-centered radical and a ketyl radical anion—reminiscent of a frustrated radical pair. This pair works synergistically to selectively abstract the β-hydrogen from 3-iodooxetane, initiating an exergonic radical-radical coupling reaction. This process enables the formation of the desired bond between the oxetane core and benzophenone derivatives, ultimately yielding the novel 1,5-dioxaspiro[2.3]hexane core. The stability and synthetic utility of the novel 1,5-dioxaspiro[2.3]hexane motif are showcased. An in-depth mechanistic investigation is presented, including cyclic voltammetry studies, as well as computational calculations and experiments to support the mechanism of this new single electron synthetic tactic.