Ultrasound-Promoted Copper-Catalyzed Azide−Alkyne Cycloaddition

The copper catalysis increase the reaction rate of 1,3-dipolar azide-alkine cycloaddition and results in regioselective formation of 1,4-disubstituted triazoles. The reaction is generally recognized as the most striking example of click chemistry. Microwave (MW) irradiation was efficiently applied to accelerate the azide-alkine click reaction. Catalytic activity of metallic copper was established early on, the final product was clean and the workup consisted of a simple removal of the copper turnings. Also ultrasound (US) has been efficiently used to promote this reaction. In this work is described a process in which metallic copper efficiently catalyzes Huisgen1,3-dipolar azide-alkine cicloadditions under US or simultaneous US/MW irradiation. We experimented with the tipical reaction of benzyl azide with phenylacetylene using metallic copper or Cu2O as catalyst. Results showed that an intense short sonication of the copper turnings in the solvent mixture sufficed to accelerate the reaction in comparison to mechanical stirring and conventional heating. The reaction rate increased further when US and MW irradiation was used simultaneously. The catalysis with metallic copper was applied to a series of other substrates among which was the 6-monoazido-beta-ciclodextrin both in the hydrophilic native form as well as in the lipophilic permethylated derivative. The reaction performs well in aqueous media, avoiding any pretreatments and the addition of ligands or amines. The use of copper turnings as a heterogeneous catalyst represents a much cleaner approach of click reactions.