Study On Cu(?)-catalyzed Three-component Synthesis Of Pyrimidine Derivatives

Pyrimidine is one of important skeleton in organic compounds and heterocyclic compounds containing pyrimidine motifs have good biological activity and medicinal value.Therefore,it is of great significance to explore a synthetic method of pyrimidine derivatives which is simple,low cost and widely applicable.In this paper,we reviewed the research progress of pyrimidine derivatives,and developed Cu???-catalyzed three-component reaction for the synthesis of multi-substituted pyrimidine derivatives based on our previous work about the Cu-catalyzed synthesis of N-heterocyclic compounds.The details are as follows:Our study was initiated by choosing benzamidine hydrochloride,benzaldehyde,and phenylacetylene as the model substrates for the reaction optimization,which included catalyst,base,solvent,temperature,reaction time and atmosphere.The optimal conditions should be CuO as catalyst,KOH as base,in DMF at 140 oC refluxing for 24 h.Under the optimized reaction conditions,the scope of the substrates was investigated.It was found that the reaction substrates had good tolerance to different functional groups,the target product can be obtained in a higher yield with either electron donating groups or electron withdrawing groups on para-position of aromatic aldehydes except for OCH₃ and Br,however,the steric hindrance effect of aromatic aldehydes has a great influence on the reaction.The electron effect of the substituents on the amidine hydrochlorides has little influence on the reaction.The electron effect and steric hindrance effect of the substituents on the aromatic acetylenes also have little influence on the reaction.We further study on copper catalyzed the three-component synthesis of pyrimidine derivatives using amidine hydrochloride,primary alcohol and secondary alcohol.We optimized the reaction conditions such as catalyst,base,ligand,reaction solvent,reaction temperature and reaction time,We found that pyrimidine compounds could be obtained in the presence of Cu?OAc?₂ as catalyst potassium hydroxide as base,phenanthroline as ligand in toluene at 110 oC for 24 hours.Under the optimized condition,the applicability to the substrates was investigated.The aliphatic amidine hydrochlorides are also tolerated but gave the desired products in lower yields than that of aromatic amidine hydrochlorides.The electron effect of aromatic alcohol has a great influence on the reaction,but the steric hindrance effect of aromatic alcohols has a great influence on the reaction.In conclusion,we obtained a total of 24 multi-substituted pyrimidine compounds by the first method,and 15 multi-substituted pyrimidine compounds were obtained by the second method.The compound structures were characterized by 1^H NMR,13^C NMR and HRMS.The method has the advantages of easy to obtain raw materials,simple,efficient,wide applicability of the substrate,which suitable for large-scale industrial production.