Cu?OAc?₂-Catalyzed Synthesis Of Substituted 1,2,4-triazoles Via Addition-Oxidative Cyclization

1,2,4-Triazoles are predominant structural motifs in many functional molecules, natural products, agrochemicals, and pharmaceutical compounds for its biological activity such as antibacterial, anti-inflammatory, antifungal and anticancer activities. In addition, they have the characteristics of low toxicity and short residual. Therefore, developing a tandem method to synthesize 1,2,4-triazoles at mild conditions without strong base and additive is meaningful. In this thesis, we disclose a efficient Cu(OAc)2-catalyzed synthesis of 1,2,4-triazoles from amidines and nitriles through a N-H functionalization C-N/N-N bond-forming process that uses air as the oxidant and generates water as the only direct waste product.Bsed on our previous work on copper-catalyzed synthesis of heterocyclic compounds, we commenced our investigation on the Cu-catalyzed construction of 1,2,4-triazoles under air atmosphere. Initially, N-phenylbenzimidamide and benzonitrile were chosen as the model substrates to optimize reaction conditions. The results showed that Cu(OAc)2 could efficiently catalyze the reaction in the presence of phenanthroline, using Na2CO3 as base in toluene at 110 °C. Meanwhile, the substrates have good tolerance of different functional groups with electronic effects and steric effects. It is noted that no significant substitute effect was observed, good yields were obtained for N-arylbenzimidamide with both electron-donating and electron-withdrawing substituents. However, nitriles bearing electron-withdrawing groups gave the desired products in higher yields than those with electron-donating groups on the phenyl ring. It is worth mentioning that the influence of steric hindrance was observed in the reaction. Subsequently, the desired products 3,5-disubstituted-1H-1,2,4- triazoles could be obtained in good yields when benzamidine hydrochloride was used in this reaction. To our delight, we found that ligand is not essential and only 3 mol% of Cu(OAc)2 allowed for excellent activity toward the desired product rendering the process even more economic. Furthermore, triazolo[1,5-a]pyridines could be obtained via dehydrogenation coupling of o-aminopyridine and benzonitrile in moderate yields without ligand. In this paper, thirteen 1,3,5-tirsubstituted-1,2,4-triazoles, fourteen 3,5-disubstituted-1H-1,2,4-triazoles and five triazolo[1,5-a]pyridines were obtained and characterized by 1HNMR, 13 CNMR, HRMS and physical property. Moreover, reaction mechanism of the Cu(OAc)2-catalyzed aerobic oxidation intermolecular C-N/N-N bond formations of amidines and nitriles to 1,2,4-triazoles derivatives was proposed.In summary, we have developed an efficient Cu(OAc)2-catalyzed aerobic oxidation of amidines with nitriles for the synthesis of 1,2,4-triazoles in air atmosphere. This reaction conditions is mild and the substrate can be available readily. Furthermore, it can be applied to industry with potential economic significance.