[(NHC)₂Cu]X Complexes as Efficient Catalysts for Azide-Alkyne Click Chemistry at Low Catalyst Loadings

In 2001, Sharpless and co-workers defined the concept of ‘Click Chemistry’ and the criteria for a transformation to be considered as ‘Click’. Since then, the copper-catalyzed reaction of azide and alkyne to produce 1,2,3-triazoles regioselectively (1,3dipolar Huisgen cycloaddition) has become the best Click reaction to date. Thanks to its mild conditions and high efficiency, this reaction has found a myriad of applications in biology and material science. Less attention has been focused on the development of novel copper(I)-based well-defined systems and to the amount of copper used. This last point is extremely important for future industrial applications and it might be one of the last challenges to overcome for this transformation. We recently reported the remarkable activity of [(NHC)CuX] complexes (NHC = N-heterocyclic carbene; X = Cl, Br) in this cycloaddition reaction and this catalytic system has already been applied to the preparation of triazole-containing carbanucleosides, porphyrins or platinum-based anticancer drugs. On the other hand, we have also studied a family of cationic NHC-containing complexes of general formulae [(NHC)2Cu]X (X = PF6, BF4). Interestingly, during the examination of their activity in the hydrosilylation of ketones we observed an enhanced reactivity of these complexes when compared to their neutral analogues [(NHC)CuCl]. This improved activity was rationalized via a more efficient activation pathway of the cationic pre-catalyst. Additionally, the second NHC ligand was found to have an active role in the catalytic cycle. Since under hydrosilylation conditions one NHC ligand is displaced by the base in the reaction mixture, we wondered if an alkyne could play a similar role to produce the active copper acetylide species, from [(NHC)2Cu]X species (Figure 1). Figure 1. Catalyst design