Synthesis Of1,2,4-triazolo[3,4-a]Isoquinolines Through Copper-Catalyzed Reactions Using Heterocyclic Ketene Aminals As New Ligands

1,2,4-Triazolo[3,4-a]isoquinolines scaffolds represent an important class of organic molecules that attract the interest of both synthetic and medicinal chemists. For example, they exhibit antiinflammatory activity, antiviral activity and they are valuable cardiovascular agents, in particular coronary dilating agents. They were also found to have potent monoamine oxidase inhibitor which almost equal to that of ipprniazid or nialamide. Traditional synthetic methods of1,2,4-Triazolo[3,4-a]isoquinolines derivatives have many disadvantages, for example, harsh reaction conditions, low yields, byproducts and low tolerance of functional groups. To the best of our knowledge, there has not been disclosed that using triazole, malononitrile, ethyl cyanoacetate as raw material to synthesize1,2,4-Triazolo[3,4-a]isoquinolines derivatives.As we all know, heterocyclic ketene aminals (HKAs) have proven to be important synthons in the construction of heterocyclic systems, but the use of HKAs as new ligands for the copper-catalyzed coupling reactions has not been disclosed.In recent years, many groups research on copper-catalyzed coupling reactions of aryl halides with nucleophiles came into renaissance and led to efficient formation of aryl C-C and C-heteroatom bonds. During the development of these progresses, Ligand identification has played an important role in improving both the efficiencies and scope. So there is still a high demand for exploring new ligands with broad application scope to further improve the efficiency and generality of copper-catalyzed coupling reactions.The new ligand HKAs have two possible kinds of coordination type:O,O-or N,O-. At last, We demonstrate that it is an efficient N,O-type ligand through experiments and calculations with density functional theory’s B3LYP methods, and the1,2,4-triazolo[3,4-a] isoquinoline derivatives were obtained in moderate to good yields under mild conditions.Herein we have revealed1,2,4-triazolo[3,4-a] isoquinoline derivatives can be easily prepared in good yields by the coupling reactions of triazole derivative with malononitrile, ethyl cyanoacetate, cyanoacetamide, benzoylacetonitrile or acetylacetonate using a combination of CuI and a HKA-type ligand, the reaction conditions is mild and post-processing is simple.The structures of all the target compounds were confirmed by IR,1H NMR,13C NMR and HRMS, and the plausible mechanism was also presented.