Harnessing regioselective aryl migration of pyridone-based aryl-λ3‑iodonium salts to access iodine-substituted aryloxypyridines

Abstract While 2- and 4-aryloxypyridines are ubiquitous in pharmaceutical molecules, efficient synthetic strategies—especially for synthesizing scaffolds with diverse multiple substituents on the pyridine core—remain limited. Here we report a hook-and-slide strategy for constructing these scaffolds, involving the in-situ generation of pyridonyl(aryl)iodonium salts from pyridones and Koser’s reagent (hook, C3 selectivity), followed by an iodine-to-oxygen aryl migration (slide, O selectivity). Such newly designed iodonium salts feature dual vicinal nucleophilic sites, and we demonstrate that using ionic liquids can exclusively transfer the aryl group to the strategic O site. This approach is transition-metal-free, scalable, and applicable to substrates with diverse electronic and steric properties or complex structures. Importantly, the resulting products retain − I and − NH₂ handles that are amenable to downstream derivatizations, enabling extensive exploration of previously inaccessible chemical space. The utility of this approach is further demonstrated through the concise synthesis of two pharmaceutical intermediates and a CRF₁ antagonist, CP-376395.