<i>gem</i>-Difluorobicyclo[2.1.1]hexanes via Photochemical [2π + 2σ] Cycloaddition Initiated by Oxidative Activation of <i>gem</i>-Difluorodienes

The incorporation of fluorine atoms into three-dimensional sp³-rich scaffolds represents an attractive tactic during bioisosteric evolution campaigns by endowing bioisosteric candidates with improved pharmacokinetic properties. Photo- or Lewis acid-mediated bicyclo[1.1.0]butane cycloaddition has offered an efficient approach for the construction of numerous regular bicyclo[<i>n</i>.1.1] scaffolds (<i>n</i> = 1-5) but remains a significant challenge to the synthesis of related 3D fluorinated scaffolds. Herein, we unveiled a photochemical single-electron oxidative strategy for <i>gem</i>-difluorodiene activation and subsequent [2π + 2σ] cycloaddition with bicyclo[1.1.0]butanes to provide a broad range of <i>gem</i>-difluorobicyclo[2.1.1]hexane scaffolds containing several post-transformable handles. A combination of experimental and computational mechanistic studies suggested that the conjugated π system of <i>gem</i>-difluorodiene plays important dual roles in promoting its preferential single-electron oxidation and stabilizing various radical-involved intermediates during the cyclization.