Regioselective C-alkylation in a series of functionalized 1,2,3-triazoles: An unexpected preference over O-alkylation

Abstract

International audienceA series of novel 1,2,3-triazole derivatives were synthesized via Cu(I)-catalyzed click chemistry, introducing structural diversity at positions 1 and 4 of the triazole ring, to explore their reactivity toward alkylation. Attempts to perform O-alkylation on hydroxymethyl-substituted triazoles unexpectedly led to unreported regioselective C-alkylation at the methylene adjacent to the triazole ring. The C-alkylation was optimized using DBU and choline acetate in acetonitrile and subsequently examined across a range of alkyl and benzyl bromides to establish its scope and generality. The resulting racemic C-alkylated products were fully characterized, including confirmation of the regioselectivity by X-ray crystallography, and their enantiomers were separated by supercritical fluid chromatography. This work reveals a novel and synthetically valuable C-alkylation pathway for 1,2,3-triazoles, offering new opportunities for the development of structurally diverse and potentially bioactive triazole derivatives