Synthesis of 2,5-Dialkyl-1,3,4-oxadiazoles Bearing Carboxymethylamino Groups

Abstract

A series of new symmetrical 2,5-dialkyl-1,3,4-oxadiazoles containing substituted alkyl groups at the terminal positions with substituents, such as bromine, isopropyloxycarbonylmethylamino, and carboxymethylamino, were successfully synthesized. The developed multistep method employed commercially available acid chlorides differing in alkyl chain length and terminal substituent, hydrazine hydrate, and phosphorus oxychloride. The intermediate bromine-containing 2,5-dialkyl-1,3,4-oxadiazoles were easily substituted with diisopropyl iminodiacetate, followed by hydrolysis in aqueous methanol solution giving the corresponding 1,3,4-oxadiazoles bearing carboxymethylamino substituents. The structure of all products was confirmed by conventional spectroscopic methods including 1H NMR, 13C NMR, and HRMS.

Microwave-Assisted Synthesis of Unsymmetrical 5-Phenyl-1,3,4-oxadiazoles Containing Bis(carboxymethyl)amino Group

“…In the next step, the benzhydrazide (2) formed was reacted with commercially available 4-bromomethylbenzoyl chloride (a) or alkanecarboxylic acid chlorides (b-e), which differed in the length of the alkyl chain and contained a bromine substituent in the terminal position (Scheme 1). We applied similar reaction conditions which were elaborated previously while working on the preparation of symmetrical N,N -diacylhydrazine derivatives [34]. The reaction was conducted at room temperature using diethyl ether as a solvent in which the benzhydrazide substrate was suspended.…”

“…Unfortunately, the reaction did not proceed even with the use of microwave irradiation. In our previous research on the synthesis of symmetrical 1,3,4-oxadiazole derivatives with carboxymethylamino groups, we used diisopropyl ester of iminodiacetic acid (6), which showed high reactivity towards oxadiazole derivatives [34]. The synthesis of such a reagent was carried out using iminodiacetic acid and isopropanol in the presence of an acidic catalyst such as concentrated sulfuric acid (Scheme 3).…”

“…It seems to be quite probable that these hybrids, unknown in the literature to date, could exhibit even stronger properties toward complexation due to the presence of ring oxygen and nitrogen heteroatoms with lone electron pairs. Previously, we elaborated the methodology for the construction of symmetrical derivatives of 2,5-dialkyl-1,3,4-oxadiazoles substituted with bis(carboxymethyl)amino groups at the terminal alkyl positions [34]. This study initiated a broad research program devoted to the synthesis and properties of new five-membered heterocyclic ligands, which may be of interest to researchers in agriculture who are still looking for new, effective micronutrient chelates.…”