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 CuF 2 /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 CuF 2 /MeOH combination was explored further to furnish selective N 3 -arylation of 5fluorouracil 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 N 3 -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.

Recent advances in Chan–Lam coupling reaction

“…In parallel, the same research team introduced regioselective ligands and base-free Chan–Lam coupling in hydantoins and 5-fluorouracil nucleosides. 45 Firstly, they analysed the N 3 -selective C–N coupling by reacting hydantoins with aryl/heteroarylboronic acids in the presence of 10 mol% CuF 2 in MeOH at room temperature for 4–20 h (Scheme 37). After that, they established the N 3 -selective coupling in 5-fluorouracil nucleosides under the same conditions for 3–12 h (Scheme 38).…”

7-Azaindole N-Oxide (7-AINO) Mediated Cu-Catalyzed N-Arylation: Mechanistic Investigation into the Role of Fluoride Ions

“…Recently, we reported two such coupling processes where the active involvement of base and solvent were discussed in the reaction pathway . In the case of CuOAc 2 /DBU-catalyzed N -arylation of 7-azaindole ( 1 ), a dimeric Cu­(II)-7-azaindole complex has been isolated, which in the presence of base (DBU) provides the active catalytic species, Cu­(II)-7-azaindole-DBU complex to facilitate the cross-coupling reaction (Scheme a) .…”

Preparation of 2,5‐Disubstituted Tetrazoles using a Copper‐Catalysed Regioselective Direct Coupling of Tetrazoles with Free NH Groups and Boronic Acid Derivatives

“…[1][2][3][4][5] Notably, they have the highest number of nitrogen atoms among the stable N-heterocycles and have been widely considered as a suitable precursor to various important scaffolds. [6][7][8][9][10] Recent studies have shown that there has been renewed interest in the preparation of tetrazoles as a substantial number of active pharmaceutical ingredients (API) contain the tetrazole ring. [11][12][13][14] For instance,numerous pharmacological applications of tetrazoles are anti-inflammatory, antihypertensive, anticancer, antiallergic, antibiotic, diuretics and receptor modulatory agents.…”

“…Several coordinating ligands, such as N,N'-dimethylethylenediamine (DMEDA)and N,N,N',N'-tetramethylethylenediamine (TMEDA), [33] pyridine N-oxide, [34] thiophene-2carboxylate (TC), [35] 1,10-phenanthroline (phen) [36] and 4-(Dimethylamino)pyridine (DMAP), [37][38][39] have been found promoting various copper catalysed CÀ N bond forming [40][41][42] reactions. These ligands help in preventing copper aggregation, enhancing solubility, stimulate milder conditions and stabilise active catalyst species during the catalysis process.…”

“…Amongst the various nitrogen‐containing heterocycles, scaffolds based on tetrazole offer a plethora of applications in the domain of medicinal chemistry, coordination chemistry, material sciences, high energy materials, biochemistry, pharmacology, and agriculture (as herbicides and fungicides) [1–5] . Notably, they have the highest number of nitrogen atoms among the stable N‐ heterocycle s and have been widely considered as a suitable precursor to various important scaffolds [6–10] . Recent studies have shown that there has been renewed interest in the preparation of tetrazoles as a substantial number of active pharmaceutical ingredients (API) contain the tetrazole ring [11–14] .…”