Adaptive Zinc-Amide Catalysis Enables C(sp²)-O Cross-Coupling of Aryl Fluorides with Alcohols

Developing sustainable and efficient catalytic strategies to construct aryl alkyl ethers from inexpensive feedstocks remains a central objective in modern synthetic chemistry. In this context, a ligand-centered redox-controlled zinc amide system is disclosed herein that enables highly selective defluoroetherification of aryl fluorides, irrespective of their electronic nature, with diverse alcohols under mild conditions (70-80 °C, 4-8 h), for the first time. Comprehensive mechanistic studies, including radical-trapping experiments, EPR spectroscopy, HRMS analysis, and various control experiments, support a radical-mediated C-(sp²)-O cross-coupling driven by unique intramolecular electron transfer within the Zn-(II)-amide framework. Intriguingly, the protocol could engage both electron-neutral and -rich aryl fluorides that are typically unreactive under conventional S _N Ar conditions and display excellent functional-group tolerance. Accordingly, selective C-F bond activation delivers F-containing aryl ethers of pharmaceutical relevance with high chemoselectivity over readily reducible, e.g., CN, NO₂, CO, and CC, functional groups. Moreover, many types of alcohols (primary, secondary, aliphatic, and benzylic) are efficiently transformed within a unified manifold. The mildness and breadth of the method further enable late-stage diversification of complex, bioactive molecules, providing streamlined access to structurally convoluted ether architectures including drug derivatives. Overall, this work establishes a mechanistically distinct, operationally simple, and sustainable platform for selective aryl C-F bond functionalization that expands the toolbox of C-O bond generation.