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

Abstract

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 S_N Ar 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 Bi^V -mediated pyridone arylations-is attributed primarily to the geometric constraints imposed by the bismacyclic scaffold.

Keywords: Ambident Nucleophile; Arylation; Bismuth; Density-Functional Calculations; Synthetic Methods.