Tandem [3+1+1+1] Heterocyclization Of α-Acyl Ketene Dithioacetals With Ammonia And Methanol:Rapid Assembly Of Polysubstituted Pyrimidines

Nitrogen heterocyclic structures are commonly found in natural products with pharmacological value and biochemical activity.Among the many nitrogen heterocyclic compounds,pyrimidine derivatives are a kind of structural unit with wide application value.In medicine,pyrimidine derivatives can be used as antibacterial agents,anti-cancer agents and anti-AIDS drugs.Its wide range of biochemical activities has attracted the attention of many scholars and experts.However,there are still some limitations in the synthesis strategy of pyrimidine for a long time,such as the use of expensive catalysts,peroxides as oxidants,a narrow substrates range,and difficulties in downstream derivatization.We successfully obtained a series of C6-alkylthiopyrimidine derivatives using an easily preparedα-acyl ketene dithioacetals as the starting substrate,ammonium acetate as an economical nitrogen source,and methanol as the C1 unit and solvent.The easy preparation of substrates with abundant functional group,economically accessible nitrogen and C1sources,decent functional group tolerance and procedural simplicity demonstrate the promising application of this synthetic strategy in drug synthesis.This paper focuses on the optimization of the reaction conditions for the tandem[3+1+1+1]heterocyclization ofα-acyl ketene dithioacetals with ammonia and methanol,preparation of polysubstituted pyrimidine derivatives;proposal of a possible reaction mechanism based on the experimental exploration,transformation of application for C6-alkylthiopyrimidine products.The details are as follows:1.The tandem[3+1+1+1]heterocyclization reaction was successfully achieved usingα-acyl ketene dithioacetals,a unique polarized alkene,as the substrate,and ammonium acetate as the nitrogen source.This multicomponent reaction,which relies on the catalysis ofcopperchloride,undergoestheketoimination/C-S aminolysis/cyclocondensation/dehydroaromatization sequence in methanol solution.It provides an efficient synthetic route for functionalized pyrimidine derivatives.2.The optimal reaction conditions were explored by screening the model reaction catalyst,nitrogen source,additives,temperature and other reaction conditions:The substratesα-acyl ketene dithioacetals(1,0.3 mmol),ammonium acetate(1.8 mmol),copper chloride(0.03 mmol),and methanol(5 m L)were reacted in an oxygen atmosphere at 90 ~oC for 24 h.In the substrate generalization study,we successfully prepared 29 pyrimidine analogues containing different substituents,which to some extent met the requirement of different substituent pyrimidine backbones for a part of medicinal chemistry.3.Based on the results of multiple control experiments as well as intermediate capture experiments and extensive literature research,we propose a feasible reaction mechanism for this reaction.4.Based on the obtained C6-alkylthiopyrimidine products,we carried out further applied transformation studies.The condensation reaction with phenylhydrazine and Liebeskind-Srogl cross-coupling reaction with arylboronic acid were both realized.Furthermore,C6-alkylation and C6-amination were also accomplished by sequential thioether oxidation/nucleophilic substitution,respectively.The practicability of this method in organic synthesis was verified.