Electrochemical Synthesis/Functionalization of 2-Oxabicyclo[2.1.1]hexanes by Anodic Oxidation-Cyclization Relay Strategy

A general electrosynthetic strategy for the preparation and direct functionalization of 2-oxa-bicyclo[2.1.1]hexanes (i.e. 2-oxa-BCHs) from hydroxymethyl-substituted bicyclo[1.1.0]butanes is reported. The method relies on the anodic generation of electrophilic heteroatom-centred species, including TEMPO-derived oxy-cations, halogen radicals, and thiyl radicals, rendering C(4) functionalized 2-oxa-BCHs selectively in good to excellent yields. The protocol operates under mild conditions, avoids stoichiometric oxidants, and displays broad substrate scope (41 examples). The synthetic utility of the resulting scaffolds is further demonstrated through late-stage functionalization, bio-conjugation, and telescoped synthesis from commercially available precursors. Mechanistic studies (cyclovoltammetry as well as DFT computations) support a pathway involving anodic oxidation for the formation of the electrophilic trigger followed by C–C bond capture and transannular intramolecular cyclization. Overall, this work establishes electrosynthesis as a powerful platform for the modular construction and diversification of 2-oxa-BCHs with potential relevance in drug discovery and expanding the chemical space of benzene bioisosteres.