A Convenient Synthesis of 5-Amino-Substituted 1,2,4-Oxadiazole Derivatives via Reactions of Amidoximes with Carbodiimides

Abstract

5-Amino substituted 1,2,4-oxadiazole derivatives were easily prepared, in one step and in high yields, via reactions of a variety of aryl, benzyl, cycloalkyl and alkyl amidoximes with commercially available carbodiimides. Alkyl carbodiimides reacted with amidoximes in toluene to give 5-alkylamino-1,2,4oxadiazoles, whereas aromatic carbodiimide reacted in DMF to give initially the intermediate O-amidoxime adducts, which were further cyclized to the corresponding 5-arylamino-1,2,4-oxadiazoles.1,2,4-Oxadiazoles 1-3 and specifically their N-substituted (on the 3-, or 5-, or 3,5-positions) derivatives is a class of heterocyclic compounds evaluated in numerous therapeutic areas. They were found to be potent antiviral agents, 4 muscarinic receptor antagonists, 5,6 histamine H2 receptor antagonists, 7,8 hypocholesterolemic agents 9 and anti-inflammatories. 10,11 The variety of their biological activities was ascribed to the bioisosteric replacement 12,13 of an ester or amide functionality and the electronic effects of the main heterocyclic ring. The latter was interpreted in terms of the hydrogen bonding capacity of the pharmacophore. A number of structure-activity relationship studies revealed that the attachment of an additional amine functional group to the heterocyclic core increased the efficacy of the compound, by increasing the hydrogen bonding capacity of the pharmacophore. 5,6 Furthermore, changes in hydrophilicity by introduction of side chains on the nitrogen atom also affected the biological activity. 4-6,10,11 † Dedicated to Prof. Emeritus Demetrios N. Nicolaides on the occasion of his 70 th birthday

CAESAR models for developmental toxicity

“…Preparation of N -aryl- N -(3-aryl-1,2,4-oxadiazol-5-yl)amines 2 [8]. Reagents and conditions: (a) hydroxylamine hydrochloride (1 eq.…”

Discovery and SAR exploration of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines as potential therapeutic agents for prostate cancer

“…According to the literature [8], N -aryl- N -(3-aryl-1,2,4-oxadiazol-5-yl)amines 2 can be prepared in moderate yields by reaction of 2 eq. of carbodiimides with amidoximes ( 3 ).…”