The Use of Ligands in Copper-Catalyzed [3+2] Azide-Alkyne Cycloaddition: Clicker than Click Chemistry?

Abstract

The last decade has witnessed a tremendous increase of the studies concerning [3+2] cycloaddition reactions of azides and alkynes. The recent discovery of copper(I) species as efficient catalysts for this transformation is at the origin of this true explosion. In contrast with classical thermal reactions, copper catalysis leads to the regioselective formation of 1,4-disubstituted 1,2,3-triazoles in high yields and under simple reaction conditions. This transformation has indeed become the most prominent example of the principles of Click chemistry, postulated in 2001 by Sharpless and co-workers.Despite the ever-increasing interest in this process, the use of ligands in this context remains minor when compared to ligandless systems. Nevertheless, besides overcoming the inherent limitations of ligandless systems, the use of ligands in this context has been shown to increase and, more importantly, modulate the catalytic activity of the metal center. Herein, the catalytic activities of ligated copper systems are reviewed in a way intended inspirational for future developments in this field.

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

“…The use of ligands in copper-catalyzed [3 + 2] azide–alkyne cycloadditions has recently been excellently reviewed [15–16]. Nonetheless, we will give a short outline of the reagent mixtures and copper(I) complexes commonly employed in order to understand the problems as to speciation and nuclearity faced by mechanistic studies.…”

“…Amine ligands are still very popular for CuAAC reactions with Cu(I) precursors [15–16]. Triethylamine can be used as ligand for copper(I) ions prepared in situ in aqueous media [88–89], and fulfil the twofold role of base and ligand in organic solvents [90–97].…”

“…It is essential for the discussion of the reaction’s mechanistic details to introduce some of the catalytically active reagent mixtures used in CuAAC, as the choice of reagents and especially the presence of ligands [15–16] does strongly influence speciation, nuclearity and solubility of the copper(I) species involved in the catalytic cycle.…”

Cationic Copper Iminophosphorane Complexes as CuAAC Catalysts: A Mechanistic Study

“…7 Alternatively, catalysis can be performed directly with a preformed Cu I complex ligated by, for example, carbenes, 8 amines, 9 or phosphines. 10 Several mechanistic studies have been performed on the CuAAC reaction. An early proposal made by Sharpless and coworkers suggested that catalysis proceeds via mononuclear Cu I intermediates.…”

“…The active CuAAC catalyst is often generated in situ by reduction of a Cu II precursor . Alternatively, catalysis can be performed directly with a preformed Cu I complex ligated by, for example, carbenes, amines, or phosphines …”