Umpolung Synthesis of Pyridyl Ethers by BiV‐Mediated O‐Arylation of Pyridones

We report that O‐selective arylation of 2‐ and 4‐pyridones with arylboronic acids is affected by a modular, bismacycle‐based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on SNAr or cross‐coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5‐membered transition state. The kinetically‐controlled regioselectivity for O‐arylation—which is reversed relative to previous BiV‐mediated pyridone arylations—is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold. We demonstrate that sterically‐ and electronically‐diverse pyridyl ethers can be accessed via BiV‐mediated C−O coupling of 2‐ or 4‐pyridones with arylboronic acids. Use of a bismacyclic reagent not only confers modularity on our methodology, but also results in highly regioselective O‐arylation that is unprecedented for BiV.