Chelation-Assisted, Copper(II)-Acetate-Accelerated Azide−Alkyne Cycloaddition

Abstract

We described in a previous communication (ref. 13) a variant of the popular Cu I -catalyzed azidealkyne cycloaddition (AAC) process where 5 mol% Cu(OAc) 2 in the absence of any added reducing agent is sufficient to enable the reaction. 2-Picolylazide (1) and 2-azidomethylquinoline (2) were found to be by far the most reactive carbon azide substrates that convert to 1,2,3-triazoles in as short as a few minutes under the discovered conditions. We hypothesized that the abilities of 1 and 2 to chelate Cu II contribute significantly to the observed high reaction rates. The current work examines the effect of auxiliary ligands near the azido group other than pyridyl for Cu II on the efficiency of the Cu(OAc) 2 -accelerated AAC reaction. The carbon azides capable of binding to the catalytic copper center at the alkylated azido nitrogen in a chelatable fashion were indeed shown to be superior substrates under the reported conditions. The chelation between carbon azide 11 and Cu II was demonstrated in an X-ray single crystal structure. In a limited set of examples, the ligand tris (benzyltriazolylmethyl)amine (TBTA), developed by Fokin et al. for assisting the original Cu Icatalyzed AAC reactions (ref. 8), also dramatically enhances the Cu(OAc) 2 -accelerated AAC reactions involving non-chelating azides. This observation leads to the hypothesis of an additional effect of chelating azides on the efficiencies of Cu(OAc) 2 -accelerated AAC reactions, which is to facilitate the rapid reduction of Cu II to highly catalytic Cu I species. Mechanistic studies on the AAC reactions with particular emphasis on the role of carbon azide/copper interactions will be conducted based on the observations reported in this work. Finally, the immediate utility of the product 1,2,3-triazole molecules derived from chelating azides as multidentate metal coordination ligands is demonstrated. The resulting triazolyl-containing ligands are expected to bind with transition metal ions via the N(2) nitrogen of the 1,2,3-triazolyl group to form non-planar coordination rings. The Cu II complexes of bidentate T1 and tetradenetate T6, and the Zn II complex of T6 were characterized by X-ray crystallography. The structure of [Cu(T1) 2 (H 2 O) 2 ](ClO 4 ) 2 reveals the interesting synergistic effect of hydrogen bonding, π-π stacking interactions, and metal coordination in forming a one-dimensional supramolecular construct in the solid state. The tetradentate coordination mode of T6 may be incorporated into designs of new molecule sensors and organometallic catalysts.

New click-chemistry methods for 1,2,3-triazoles synthesis: recent advances and applications

“…Kuang et al reported non-reductive conditions using Cu(OAc) 2 and by chelating the azides with Ncontaining auxiliary ligands to increase significantly the rate of the reaction. 13 CuAAC one-pot synthesis of 5-iodo-1,2,3-triazoles was also described. 14,15 In the case of the regioselectivity towards 1,5-disubstituted-triazoles, ruthenium catalysts (RuACC) were the most commonly used for both thermal 7 or microwave 16 conditions, which also support internal alkynes.…”

Ligand‐Assisted, Copper(II) Acetate‐Accelerated Azide–Alkyne Cycloaddition

“…Those azides, which are termed "chelating azides," contain auxiliary ligands capable of assisting the azido group in binding the copper centre. [9] To expand the substrate scope of the Cu-A C H T U N G T R E N N U N G (OAc) 2 -mediated procedure to include nonchelating azides, we investigated conditions that employ an accelerating ligand.…”

“…[14][15][16][17][18][19] We recently found that TBTA also accelerates CuA C H T U N G T R E N N U N G (OAc) 2 -mediated AAC reactions that involve nonchelating azides. [9] In a number of reactions that proceed sluggishly under Cu-A C H T U N G T R E N N U N G (OAc) 2 -mediated conditions, yields of over 90 % were achieved in the presence of TBTA within 1 or 2 h. In this work, we investigated the acceleratory effects of other polytriazoles in CuA C H T U N G T R E N N U N G (OAc) 2 -mediated AAC reactions. The kinetic studies were also carried out to provide some insights on the mechanistic involvement of TBTA (as an example of polytriazole ligands) under the CuA C H T U N G T R E N N U N G (OAc) 2 -mediated conditions.…”

Well-defined copper(i) complexes for Click azide–alkyne cycloaddition reactions: one Click beyond

“…42 Pyridine containing azides were particularly reactive in CuAAC in the presence of Cu(OAc) 2 /t-BuOH, 43 although amine, carboxylic acid, ether and thioether groups also increased the reaction rates.…”