Preparation Of 3-Substituted-1,2,4-Oxadiazole And Its Coupling Reaction Catalyzed By Palladium At The 5-position

Heterocyclic compounds are widely used in pharmaceuticals, food, dyes, etc. Among them,1,2,4-oxadiazole is of great importance due to their excellent chemical and thermal stability.To date, methods to prepare 1,2,4-oxadiazole compounds could be classified into six categories:cyclization of O-acylamidoximes, cyclization of N-acylamidoximes, condensation of amidoximes with specific reagent, oxidation of 4,5-dihydro-1,2,4-oxadiazoles,1,3-dipolar cycloaddition of nitrile oxides or hydroxamyl chlorides to nitriles and related compounds, and rearrangement from other heterocycles. In this paper, we focus on to explore the preparation of 3-aryl-substituted oxadiazole under mild conditions and its coupling reaction with aryl bromides.Aryl amidoximes, which were obtained from aromatic nitrile, were further cyclized with trimethyl orthoformate providing 3-substituted-1,2,4-oxadiazole in excellent yield at 40?.3,5-Disubstituted-1,2,4-oxadiazoles were synthesized from 3-substituted-1,2,4-oxadiazoles following a palladium catalyzed coupling reaction with aryl bromides. The reaction conditions were carefully optimized (base, reaction temperature, solvent, phosphorus ligands dosage, copper salts, catalyst Pd(OAc)2 and Cu salt ratio and catalyst dosage). The stabilities of the 3-substituted-1,2,4-oxadiazoles and the 3,5-disubstituted-1,2,4-oxadiazoles were investigated.Under optimized conditions, twelve 3,5-disubstituted-1,2,4-oxadiazoles were prepared in 43-63% yield.