Cu‐Catalyzed Chan–Evans–Lam Coupling Reactions of 2‐Nitroimidazole with Aryl Boronic Acids: An Effort toward New Bioactive Agents against S. pneumoniae

Abstract

The coupling of phenylboronic acids with poorly-activated imidazoles is studied as a model system to explore the use of copper-catalyzed Chan -Evans-Lam (CEL) coupling for targeted CÀ N bond forming reactions. Optimized CEL reaction conditions are reported for four phenanthroline-based ligand systems, where the ligand 4,5-diazafluoren-9-one (dafo, L2) with 1 molar equivalent of potassium carbonate yielded the highest reactivity. The substrate 2-nitroimidazole (also known as azomycin) has documented antimicrobial activity against a range of microbes. Here N-arylation of 2-nitroimidazole with a range of aryl boronic acids has been successfully developed by copper(II)-catalyzed CEL reactions. Azomycin and a range of newly arylated azomycin derivatives were screened against S. pneumoniae, where 1-(4-(benzyloxy)phenyl)-2-nitro-1H-imidazole (3d) was demonstrated to have a minimal inhibition concentration value of 3.3 μg/mL.

Copper complexes for the chemoselective N-arylation of arylamines and sulfanilamides via Chan–Evans–Lam cross-coupling

“…Based on the trials discussed in Table S1, † Cu 2+ BIM was further optimized using different additive bases as listed in Table 2. In a previous report, 45 it was noted that the addition of a slight excess of potassium carbonate improved the reactivity of CEL systems. We found that the addition of potassium carbonate to our reactions increased the conversion with the prepared catalyst Cu 2+ BIM when between 0.5 and 2.0 molar equivalents were added (Table 2, entries 1-3).…”

Recent advances in Chan–Lam coupling reaction

“…The reactivity of electronrich anilines was found to be higher than that of electrondeficient ones. The reaction of alkyl amines was similar to that of anilines, while secondary alkylamine, N-methyl hexylamine, and N-methyl aniline completely failed to give 40 The targeted C-N coupling was achieved by reacting 2-nitro imidazoles with aryl boronic acid in the presence of 8 mol% Cu(OTf) 2 , 1 equiv. of the ligand 4,5-diazafluoren-9-one (dafo), and 1 equiv.…”

“…Emerson et al successfully established the Chan–Evans–Lam coupling between inactive imidazoles and aryl boronic acids in 2022. 40 The targeted C–N coupling was achieved by reacting 2-nitro imidazoles with aryl boronic acid in the presence of 8 mol% Cu(OTf) 2 , 1 equiv. of the ligand 4,5-diazafluoren-9-one (dafo), and 1 equiv.…”

Aminoquinoline-Based Tridentate (NNN)-Copper Catalyst for C–N Bond-Forming Reactions from Aniline and Diazo Compounds

“…The organic motifs, framework, and donor atom set of these complexes all wield pivotal roles in their chemistry [8,9]. These coordination complexes have also found extensive utility in catalysis, with numerous research groups delving into their catalytic properties across a wide spectrum of processes, including oxidation reactions [10], atom transfer reactions [11,12], Chan-Evans-Lam reactions [13][14][15][16], Ullmann and Goldberg-type couplings [17], and click reactions [18,19].…”