C-(β-d-Glucopyranosyl)formamidrazones, formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study

Synthesis of O-perbenzoylated 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, precursors of potent inhibitors of glycogen phosphorylase, was studied by ring closures of N1-acyl-carboxamidrazone type intermediates. Reactions of C-(β-d-glucopyranosyl)formimidate or C-(β-d-glucopyranosyl)formamidine with acid hydrazides as well as acylation of C-(β-d-glucopyranosyl)formamidrazone by acid chlorides unexpectedly gave the corresponding 1,3,4-oxadiazoles instead of 1,2,4-triazoles. The desired triazoles were obtained in reactions of C-(β-d-glucopyranosyl)formamidine or C-(β-d-glucopyranosyl)formyl chloride with arenecarboxamidrazones, and also in acylations of N1-tosyl-C-(β-d-glucopyranosyl)formamidrazone with acid chlorides. Theoretical calculations (B3LYP and M06-2X DFT with the standard 6-31G(d,p) basis set) on simple model compounds with methyl and phenyl substituents to understand the bifurcation of the ring closure of N1-acyl-carboxamidrazones indicated that in general the reaction led to 1,2,4-triazoles. However, the probability of the 1,3,4-oxadiazole forming pathway was shown to be significantly higher with N1-benzoyl-acetamidrazones, which were closest analogues of the intermediates resulting in C-glucosyl-1,3,4-oxadiazoles. It was thereby demonstrated that the substitution pattern of the N1-acyl-carboxamidrazones played a fundamental role in determining the direction of the ring closing reaction.