CuF2/MeOH-Catalyzed N3-Selective Chan-Lam Coupling of Hydantoins: Method and Mechanistic Insight.

Abstract

An efficient and practical N-arylation of hydantoins with substituted aryl/heteroaryl boronic acids has been established, assisted by CuF2/MeOH under the base and ligand-free conditions at room temperature and open air. The protocol is general, and various N-arylated hydantoins have been prepared in excellent yields with exclusive regioselectivity. The CuF2/MeOH combination was explored further to furnish selective N3-arylation of 5-fluorouracil nucleosides. The efficiency of the protocol was also demonstrated with the gram-scale synthesis of the marketed drug, Nilutamide. A mechanistic study based on density functional theory calculations revealed that both hydantoin and MeOH are crucial for the generation of catalytically active copper species in the reaction process, in addition to their role as a reactant and solvent, respectively. The proposed reaction mechanism indicated that selective N3-arylation of hydantoin is favorable in MeOH, which helps initiate the catalytic cycle by forming a square-planner Cu(II) complex where strong hydrogen-bond interactions are observed. This study is expected to improve the understanding of Cu(II)-catalyzed oxidative N-arylation reactions and for the de novo design and development of Cu-catalyzed coupling reactions.