Umpolung Synthesis of Pyridyl Ethers by Bi(V)‐Mediated O‑Arylation of Pyridones

Ruffell, Katie; Gallegos, Liliana; Ling, Kenneth; Paton, Robert S.; Ball, Liam T.

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.

Citation

Ruffell, K., Gallegos, L., Ling, K., Paton, R. S., & Ball, L. T. (2022). Umpolung Synthesis of Pyridyl Ethers by Bi(V)‐Mediated O‑Arylation of Pyridones. Angewandte Chemie International Edition, 61(51), Article e202212873. https://doi.org/10.1002/anie.202212873

• Journal Article Type: Article
• Acceptance Date: Oct 17, 2022
• Online Publication Date: Nov 17, 2022
• Publication Date: Dec 19, 2022
• Deposit Date: Oct 27, 2022
• Publicly Available Date: Nov 2, 2022
• Journal: Angewandte Chemie - International Edition
• Print ISSN: 1433-7851
• Electronic ISSN: 1521-3773
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 61
• Issue: 51
• Article Number: e202212873
• DOI: https://doi.org/10.1002/anie.202212873
• Public URL: https://nottingham-repository.worktribe.com/output/12898568
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/anie.202212873