New Methods To Synthesize 1,3,4-Oxadiazole

1,3,4-Oxadiazoles have been introduced into drug development programs for several different purposes. In some cases, oxadiazoles have been used as replacements for carbonyl containing compounds such as esters, amides, carbamates, and hydroxamic esters. As an essential part of the pharmacophore,1,3,4-Oxadiazoles have demonstrated a broad spectrum of biological properties in both pharmaceutical and agrochemical fields.In this paper, two new synthetic methods for the preparation of 1,3,4-oxadiazole have been developed.One method involved oxidation of N-substituted benzyl-N’-substituted acylhydrazine which is as a new structure of synthetic intermediate. First of all, by the condition tests, the oxidizing agent, solvent and reaction temperature were screened. The optimum reaction condition has been determined:PhI (OAc) 2 as the oxidant, with the reaction substrate molar ratio:2.2:1; oxidation reaction solvent:acetonitrile; reaction temperature:40 ℃. Firstly, by the nitrogen alkylation and the nitrogen acylation reaction, sixteen N-substituted benzyl-N’-substituted acylhydrazine have been obtained. Fourteen have been successfully oxidized to the corresponding 2,5 - disubstituted-1,3,4-oxadiazole and the basic yield is between 35% to 75%. When the oxadiazole ring substituent is methyl, the yield of the product is generally lower than that of the substituent is phenyl, pyridyl and the methoxy group.The other method involved oxidation of N-substituted-benzyl-N’-substituted aromatic aldehyde hydrazone which is as another new structure of synthetic intermediate. Through the condition tests, the oxidizing agent, solvent and reaction temperature were screened. We determined the optimum reaction conditions:PhI (OCOCF3) 2 as the oxidant, with the reaction substrate molar ratio:3.2:1; oxidation reaction solvent:methyl tert-butyl ether; reaction temperature:40 ℃. First of all, by the nitrogen alkylation and carbonitride dehydrating condensing synthesis, twelve N-substituted-benzyl-N’-substituted aromatic aldehyde hydrazone have been prepared. Then we conducted a study of the oxidation reaction. Among them, ten N-substituted-benzyl-N’-substituted aromatic aldehyde hydrazone was successfully oxidized to 2,5-disubstituted-1,3,4-oxadiazole and the yield is 30% to 65%. When the oxadiazole ring substituent is an electron-donating group, the yield of the product is generally higher than that of the substituent is an electron-withdrawing group.In addition, by capturing the intermediate in the oxidation reaction process, the corresponding oxidation mechanisms have been proposed respectively. The structures of the oxidation reaction intermediates and oxidation products are confirmed by NMR, IR.