RESUMO
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.
RESUMO
Multiple spectroscopic techniques, along with single-crystal X-ray analysis, have been used to reveal the detailed structural and electronic information on reaction intermediates of a new copper(II)-DBU catalytic system for the N-arylation of 7-Azaindole. The reaction mixture of Chan-Lam cross-coupling yields two dimeric copper(II)-7-azaindole complexes, including one attached with DBU, prior to adding arylboronic acid and are confirmed structurally and spectroscopically. A suitable mechanism has been proposed using the dimeric copper(II) complex as a catalyst for the coupling reactions. The role of DBU as a base and also as an auxiliary ligand in the course of the reaction has been established. The transmetalated monomeric aryl-copper(II) species generated from the dimeric unit is oxidized by another equivalent of copper(II) to yield an aryl-copper(III) intermediate for facile N-arylation, which has been authenticated with UV-vis spectroscopy. The regeneration of the copper(II)-catalyst by aerial oxidation of colorless copper(I) species (generated via reductive elimination and disproportionation step) is confirmed by mass and absorption spectroscopy. Detailed DFT and TD-DFT calculations help to rationalize the proposed reaction intermediates and their corresponding electronic transitions. Moreover, the confirmation of copper(I)-7-azaindole intermediate via HRMS reaffirmed the involvement of Cu(II)/Cu(III)/Cu(I) species in the Chan-Lam type of coupling. A medicinally-important 7-azaindole-based SHP2 inhibitor has been synthesized via sequential arylation.
RESUMO
Transition-metal based carbon-heteroatom (C-X) bond formation has attracted the attention of synthetic chemists over the past few years because the resultant aryl/heteroaryl motifs are important substructures in many natural products, pharmaceuticals, etc. Several efficient protocols such as Buchwald-Hartwig amination, Ullmann coupling, Chan-Lam coupling and metal-free approaches have proved beneficial in C-X bond formation. Selective arylation of one hetero-centre over other centres without protection/deprotection thus allowing minimum synthetic manipulation has been achieved for several substrates using these protocols. Azoles are one such novel five-membered heterocyclic core with huge pharmaceutical applications. Though N-arylation on azole-bearing analogues has been extensively practised, selective N-arylation either on one N-centre or the exocyclic N-site of the azole ring in competition with other hetero-centres in the framework has been recently explored for azole-carrying systems. Thus, this review would focus on recent advances in chemo- and regio-selective N-arylation (either on one N-centre or the exocyclic N-site of the azole ring) on azole-containing frameworks.
