Synthesis And Fungicidal Activities Of 5,5-Disubstituted Pyrrolidine-2,4-Diones Incorporating Moiety Of Substituted Phenylhydrazine

The tetramic acid compounds, many of them, were isolated from natural products, usually exhibit remarkable biological activities including antiviral, antibacterial, antifungal cytotoxic, antitumour and herbicidal activity. These compounds contain the important heterocyclic building blocks pyrrolidine-2,4-dione. Many scholars used it as a key structural unit to design and synthesize a large number of tetramic acid derivatives and have found many biologically active compounds, it has attracted more and more attention. In this article,5-position of tetramic acid were modified by two alkyl groups in the same time to design three kinds of novel tetramic acid derivatives, one group is methyl,the other one is methyl, ethyl or benzyl, Then, substituted phenylhydrazine were introduced to 3-position of the tetramic acid to design and synthesize 38 novel tetramic acid derivatives, their fungicidal activities were also evaluated.Firstly, the intermediate a,a-disubstituted-a-amino acids were prepared by the reactions of esterification, amino protection by schiff base, alkylation, de-protection of amino and hydrolysis with L-alanine as a starting material. Then 3-(1-hydroxyethylidene)-5-disubstituted-pyrrolidine-2,4-diones 8 were prepared by the reactions of esterification, N-aceto-acetylation and cyclization. The compound 8 was reacted with substituted phenylhydrazine to give thirteen 5,5-dimethyl-3-(1-(2-(substituted phenyl)hydrazinyl)-ethylidene)pyrrolidine-2,4-diones, twelve 5-methyl-5-ethyl-3-(1-(2-(substituted phenyl)-hydrazinyl)ethylidene)pyrrolidine-2,4-diones and thirteen 5-methyl-5-benzyl-3-(1-(2-(substituted phenyl)hydrazinyl)ethylidene)pyrrolidine-2,4-diones.The structures of all target compounds were confirmed by IR,1H NMR, MS and elemental analysis. Two configurations, E-isomer and Z-isomer, of target compounds were revealed from 1H NMR.In addition,the three kinds of compounds 9,10,11 were screened for fungicidal activities in vitro against selected phytopathogenic fungi, Fusarium gramineaum,Botiytis cinerea, Rhizoctonia cerealis and Colletotrichum capsici at the concentration of 100 μg/mL and 10μg/mL. And the EC50 values of some selected compounds were determined. The results showed that the target compounds exhibited remarkable fungicidal activities against all tested fungi. The compound 9d showed the best activity against F. graminearum, its EC50 value was 0.5632 μg/mL. The compound 10h exhibited the best activity against B. cinerea, its EC50 value was 0.8035 μg/mL. The compound 9c gave the best activity against R. cerealis, its EC50 value 0.0533μg/mL was lower than 0.3541μg/mL of the control fungicide flutolanil.The compound 10g showed the hightest activity against C. capsici, its EC50 value 0.2252μg/mL was close to 0.2498 μg/mL of the control fungicide azoxystrobin.