A Regioselective Synthesis of 2,4-Disubstituted 2H‑1,2,3-Triazoles by Coupling of N‑Tosylhydrazones and Anhydro-Aldose Tosylhydrazones with 4‑Substituted 1H‑1,2,3-Triazoles - Scope and Limitations.

In this paper we present the first investigation of the C-N coupling reaction between N-tosylhydrazones including O-peracylated 2,6-anhydro-aldose tosylhydrazones and 1H-1,2,3-triazoles under catalyst-free conditions. This transformation is characterized by relatively mild thermal conditions, high regioselectivity in favor of 2,4-disubstituted 2H-1,2,3-triazoles and broad functional group tolerance as well as applicability in medicinal chemistry due to the absence of transition metal residues. Tosylhydrazones of aldehydes showed better results in terms of yields (20-61%) than those of ketones (13-16%). From the 1,2,3-triazole side the reactions gave very good results in terms of regioselectivity with both electron-withdrawing and electron-donating groups in the 4-position aromatic substituents, while benzotriazoles proved unselective. The extension of the reaction to 2,6-anhydro-aldose tosylhydrazones retained the excellent regioselectivity with high yields, to provide a new synthetic pathway for 2-glycosylmethyl-4-substituted-2H-1,2,3-triazoles, a novel type of glycomimetics. The carbohydrate derivatives were evaluated as potential galectin-1 antagonists and glycogen phosphorylase enzyme inhibitors. In addition to classical 1H and 13C NMR characterizations, advanced 1H-15N multiple-bond correlation NMR experiments were also performed on some glycomimetics to get direct evidence for the regioisomer synthesized.