Construction Of Small Molecular Skeleton Of Containing-nitrogen Heterocyclic Drugs By Cyclization Of Substituted Benzamidines

Nitrogen-containing heterocycles are the most important motifs in drugs used widely,pesticides and bioactive natural products.Owing to inherent biological activity of these derivatives,the investigation and development of highly effective methods for the constructions of nitrogen-containing heterocyclic skeletons has become an significant topic in the research field of innovative new drugs.Notably,based on our reported results and in continuation of our interests in constructing the nitrogen-containing heterocycles,recently there has been potential drive in cycloaddition research of substituted benzamidine as a double nucleophilic reagent to access different nitrogen-containing heterocyclic derivatives.Thus,the following three nitrogen-containing heterocyclic compounds were designed and synthesized in this paper:1,2,5-triaryl-1H-imidazole derivatives,3,5-disubstituted-1,2,4-oxadiazole derivatives.and 2,5-disubstituted-4.6-diaminopyrimidine derivatives,respectively.The first part:A series of 1,2,5-triaryl-1H-imidazole derivatives were synthesized via the[3+2]cycloaddition reaction of substituted benzamidine and ?-nitrostyrene n the presence of DABCO as a promoter.Under optimal conditions,23 compounds were synthesized in 52-72%yield,and their structures were characterized by NMR spectroscopy,high-resolution mass spectrometry,and infrared spectroscopy.Additionally,the single-crystal structure of one product was determined by single-crystal X-ray diffraction.The second part:A two-step reaction of pyridine quaternary amine iodide salt and substituted benzamidine was investigated for the synthesis of a series of 1,2,4-oxadiazole derivatives.Firstly,the reaction of the substituted pyridinium iodidet and substituted benzamidine were carried out to form N-amide intermediates in the presence of NaHCO--₃.The N-amide intermediates were not purified further and used directly to the next step,then the 1,2,4-oxadiazole derivatives were obtained by intramolecular oxidative cyclization using the I₂/K₂CO₃/DMSO system.Under optimal reaction conditions,19 compounds were synthesized in 60-81%yield,and the structures of all products were characterized by NMR spectroscopy,high-resolution mass spectrometry,and infrared spectrometry.Moreover,the single-crystal structures of three compounds were confirmed by X-ray diffraction analysis.The third part:A series of 2,5-disubstituted-4,6-diaminopyrimidine derivatives were synthesized by the[3+3]cyclization reaction of substituted benzamidine and benzylidene malondinitrile.After optimization of the reaction conditions,212,5-disubstituted-4,6-diaminopyrimidines were synthesized by the cyclic reaction of substituted benzamidine and benzylidenemalononitrile in the presence of Na₂CO₃.4,6-Diaminopyrimidine derivatives were synthesized in 58-78%yield,and the structures of all synthesized compounds were characterized by NMR spectroscopy,high-resolution mass spectrometry,and infrared.While single-crystal X-ray diffraction analysis was performed,their stereostructures were determined.