Huisgen 1,3-dipolar cycloaddition

In the 1,3-dipolar (3+2) cycloaddition reaction, also known as Huisgen cycloaddition, a 1,3-dipole (e.g. azides, nitriloxides or diazoalkanes) reacts with a dipolarophile (e.g. alkenes, alkynes or carbonyl) via a concerted mechanism to form a five-membered heterocycle. (1,2). The most important reaction within click chemistry is the cycloaddition between an azide and an alkyne producing a 1,2,3-triazole. This reaction gives poor regiospecificity which leads to a mixture of 1,4- and 1,5-substituted triazoles and may require elevated temperatures because alkynes are poor 1,3-dipolar acceptors (Scheme 1). (1,3)

Scheme 1. Formation of 1,4- and 1,5-disubstituted triazoles.

A modification of the Huisgen reaction was independently discovered, by Meldal et al. and Sharpless et al. in which addition of Cu(I) to the reaction mixture resulted in only 1,4-substituted triazoles. (4, 5) In recent years a method for synthesising 1,5-substituted triazoles utilising Ru (II) has also been developed.6 Different copper(I) sources can be used as catalyst such as CuI and CuOTf . Cu(I) can be generated in situ by using Cu(II)SO4 . 5H2O and sodium ascorbate as reducing agent. Cu(0), derived from copper turnings, has also resulted in regiospecific reactions. (5, 7)

Mechanism: The copper(I)-catalyzed cycloaddition between the azide and the alkyne proceeds through a stepwise mechanism as illustrated in Figure 1. The mechanism starts by coordination of the alkyne (6) to copper(I) (5), displacing one ligand and then re-coordination gives the copper acetylide (7). In the next step, the azide (8) replaces one of the ligands and the copper complex binds to the nitrogen adjacent to the carbon, forming intermediate 9. Attack by the terminal nitrogen in 9 on C-2 in the acetylide forms the unusual six-membered Cu(III) intermediate 10. Rearrangement of 10 gives the five-membered specie 11, which is transformed to 12 by proteolysis.


 
Figure 1. Copper(I)-catalysed formation of 1,4-disubstituted-1,2,3-triazole.

 

Mechanism:References: