Cu–N3 Single-Atom Catalysts Enable High-Turnover C–N and C–O Cross-Coupling of Aryl Electrophiles

Transition-metal-catalyzed C–N cross-coupling is fundamental to the synthesis of pharmaceuticals, agrochemicals, and functional materials. However, many copper-based catalytic systems rely on exogenous molecular ligands to establish and tune the coordination environment around copper centers, which can increase catalyst-design complexity and complicate catalyst recovery and reuse. We report a copper single-atom catalyst (Cu–N3/OMC) that enables ligand-free C–N and C–O cross-coupling of aryl electrophiles, with isolated Cu sites embedded in a nitrogen-doped carbon framework that provides an intrinsic coordination environment. This system enables ligand-free copper-catalyzed C–N coupling of synthetically relevant aryl bromides and further extends the reaction to less-activated aryl chlorides. A broad range of substituted aryl and heteroaryl bromides─including electron-rich, electron-deficient, ortho-substituted, and fused substrates─undergo efficient coupling with diverse amines and alcohols, affording the corresponding products in moderate to excellent yields (up to 96%). Selected aryl chlorides are also compatible under KI-promoted conditions, albeit with reduced efficiency in some cases. The methodology is applicable to late-stage functionalization of complex pharmaceutical molecules and can be conducted on a preparative scale (5–100 mmol), affording yields of 90–95% and TONs of up to 84,000 under air. TON values were calculated based on the total Cu loading. More broadly, this work suggests that support-engineered coordination environments can influence the reactivity of isolated Cu sites, providing a strategy for ligand-free heteroatom cross-coupling.