Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(I) acetylides

Abstract

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(I) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science.

Scheme 1

Thermal cycloaddition of azides and alkynes usually requires prolonged heating and results in mixtures of both 1,4-and 1,5-regioisomers (A), whereas CuAAC produces only 1,4-disubstituted-1,2,3-triazoles at room temperature in excellent yields (B). The RuAAC reaction proceeds with both terminal and internal alkynes and gives 1,5-disubstituted and fully, 1,4,5-trisubstituted-1,2,3-triazoles.

Scheme 2

Simplified representation of the proposed C–N bond-making steps in the reaction of copper(i) acetylides with organic azides. [Cu] denotes either a single-metal center CuL_x or a di-/oligonuclear cluster Cu_xL_y.

Scheme 3

(A) Oxidative coupling byproducts in the CuAAC reactions catalyzed by copper(i) salts in the presence of oxygen; (B) CuAAC with immobilized alkyne avoids the formation of the oxidative byproducts but requires large excess of the catalyst; reactions with immobilized azide fail; (C) solution-phase CuAAC in the presence of sodium ascorbate.

Scheme 4

One-pot syntheses of triazoles from halides at (A,B) sp³ and (C) sp² carbon centers. Reaction B was performed in a flow reactor in 0.75 mm diameter Cu tubing with no added copper catalyst.

Scheme 5

CuAAC-accelerating ligands of choice: tris(1,2,3-triazolyl)methyl amine (TBTA, 10a) and its tert-butyl analog (TTTA, 10b), water-soluble analogs 11, sulfonated bathophenanthroline 12, and tris(benzimidazole)methyl amine (TBIA) 13.

Scheme 6

Common reactivity patterns of organic azides. Nucleophiles attack at the electrophilic terminal nitrogen, whereas the more electron-rich N1 can react with electrophiles and coordinate to transition metals.

Scheme 7

(A) Early proposed catalytic cycle for the CuAAC reaction based on DFT calculations. (B) Introduction of a second copper(i) atom favorably influences the energetic profile of the reaction (L = H₂O in DFT calculations). At the bottom is shown the optimized structures for dinuclear Cu forms of the starting acetylide (left, corresponding to 15), transition state for the key C–N bond-forming step (middle), and the metallacycle 17. The calculated structures are essentially identical when acetylide instead of chloride is used as the ancillary ligand on the second copper center (Cu^B).

Scheme 8

(A) Calorimetry trace of the reaction of benzyl azide and phenyl acetylene (0.1 M in tert-butanol/water, 1 : 1, the indicated amount of copper sulfate, and two equivalents of ascorbate with respect to copper. The multimodal kinetic profile is especially easy to see in the black and green traces: the reactions take 12 and 25 min, respectively, to reach maximum rate. All four reactions proceeded to completion. (B) Calorimetry trace of the reaction of benzyl azide with phenyl acetylene (0.1 M in THF, 5 mM CuX as a 1 : 1 complex with TTTA ligand 10b). The reaction is significantly faster when the iodide is removed with silver(i) tetrafluoroborate (red trace) than in the presence of the iodide (blue trace). Copper thiophene carboxylate (CuTC)-catalyzed trace, which shows intermediate behavior, is in green.

Scheme 9

Several key equilibria and irreversible off-cycle pathways affect the productive CuAAC catalytic cycle. For example, formation of oligomeric copper acetylides may become a key event under certain conditions: if most of the catalyst is occupied in the form of unproductive polymeric copper acetylides, the rate of the re-entry of reactive copper acetylide into the catalytic cycle (k₋₄) would determine the overall rate of the process.

Scheme 10

The iodoalkyne version of the CuAAC reaction (ⁱCuAAC).

Scheme 11

One-pot, two-step synthesis of 5-iodo-1,2,3-triazoles.

Scheme 12

One-pot, three-step synthesis of 1,4,5-triaryltriazoles. PMP = p-methoxyphenyl, p-Tol = p-methylphenyl.

Scheme 13

Proposed mechanistic pathways for the Cu(i)-catalyzed azide-iodoalkyne cycloaddition.

Scheme 14

(Right) Products of CuAAC reactions with sulfonyl azides. (Left) Possible pathways leading to ketenimine intermediates.

Scheme 15

Azavinyl carbenes from diazoimines.

Scheme 16

Synthesis of imidazoles via rhodium-catalyzed transannulation of 1-sulfonyl triazoles.

Scheme 17

Cyclopropanation of olefins using 1-sulfonyl 1,2,3-triazoles.