Synthesis Of 5,5-disubstituted Barbituric Acid Derivatives Via Amine-catalyzed [5+1] Cycloaddition And Air-oxidation

Barbituric acid derivatives are nitrogen-containing heterocyclic compounds with wide physiological activity and can be used as central nervous system depressants.Also as effective anxiolytics,hypnotics,and anticonvulsants,they play an important role in organic synthetic chemistry and pharmaceutical science.Most commonly used drugs in clinical practice are 5,5-disubstituted barbiturates.In this paper,two strategies for the cyclization and air-oxidation reactions of N,N?-disubstituted barbituric acid under amine as catalyst have been studied.Synthesis of different structures of 5,5-disubstituted barbituric acid derivatives in high yield.The formal[5+1]cyclization reaction of 1,3-dimethylbarbituric acid with 1,1-dicyano1,3-diene using amines as the catalysts have been studied.With screening of catalysts and solvents,the chemical selectivity of the reaction can be effectively controlled by changing different catalysts using tetrahydrofuran as a solvent.The barbituric acid-cyclohexene spiro compounds 2 were obtained with 99%or 97%yield under the catalysis of diisopropylamine or triethylamine respetively.The product containing Boc-protected barbituric acid-cyclohexadiene spiro compounds 4 were obtained up to 98%yield under the catalysis of 4-dimethylaminopyridine via one-pot reaction.In addition,the reaction mechanism was studied by designing a reasonable experiment,and the process of selectively generating two different products was proposed.Synthesis of 5-hydroxy-5-hydrocarbyl disubstituted barbituric acid derivatives via oxidation of 5-substituted 1,3-dimethylbarbituric acid derivatives using amines as catalysts with air as an oxidant have been studied.With screening of catalysts and solvents,we found that the hydroxylation reaction in?-C-H under optimized conditions can be realized produce with 5-aryl,benzyl and alkyl substituted barbituric acids as the substrates.Using DMF as solvent,the hydroxylations of different 5-aryl-substituted barbiturates were obtained up to 89%yield under the catalysis of 2 mol%HMTA at room temperture.Using THF as a solvent,the hydroxylations of different 5-benzyl or alkyl substituted barbiturates were obtained up to 96%yield under the catalysis of 10 mol%Et₃N at room temperture.