1,5-Regioselectivity in 1,2,3-triazoles from metal-catalyzed azide–alkyne cycloadditions: synthetic strategies and catalytic scope

Abstract

1,2,3-Triazoles constitute a prominent class of nitrogen-rich heterocycles with remarkable chemical stability and wide-ranging applications. Since the development of the copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction, the facile synthesis of 1,4-disubstituted 1,2,3-triazoles has become routine; however, selective access to the complementary 1,5-disubstituted regioisomers remained a long-standing synthetic challenge. This limitation was effectively addressed through the introduction of ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC), which enabled the direct and regioselective formation of 1,5-disubstituted 1,2,3-triazoles. The present review provides a comprehensive and critical overview of synthetic strategies developed for achieving 1,5-regioselectivity in 1,2,3-triazoles, with a primary focus on metal-catalyzed azide–alkyne cycloaddition reactions. The evolution of ruthenium-based catalytic systems is discussed in detail, encompassing Cp*Ru complexes, non-Cp ruthenium catalysts, mixed-ligand systems, heterogeneous and recyclable Ru-catalysts, and the mechanistic insights governing regioselectivity. In addition to ruthenium catalysis, the roles of alternative transition metals, such as nickel, iron, and zinc, in promoting 1,5-regioselective triazole formation are systematically examined. Furthermore, emerging strategies involving alkali and alkaline earth metals, as well as base-mediated synthesis, are highlighted as sustainable and economically attractive alternatives. By integrating diverse catalytic platforms, mechanistic perspectives, and synthetic methodologies, this review provides a unified and up-to-date account of the advances in 1,5-regioselective 1,2,3-triazole synthesis, serving as a valuable resource for researchers engaged in heterocyclic chemistry, catalysis, and drug discovery.