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

Abstract Strained spiro‐heterocycles (SSHs) have gained significant attention within the medicinal chemistry community as promising sp 3 ‐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.