Azide Alkyne Huisgen Cycloaddition
One of the most popular reactions within the Click chemistry concept is the azide alkyne Huisgen cycloaddition using a Copper (Cu) catalyst at room temperature. It was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless at the Scripps Research Institute in California and Morten Meldal in the Carlsberg Laboratory, Denmark. Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of the reaction and did not make a connection with the click chemistry concept. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks."
Copper and ruthenium are the commonly used catalysts in the reaction. The use of copper as a catalyst results in the formation of 1,4-regioisomer, whereas ruthenium results in formation of the 1,5- regioisomer. Recently, silver was also used to carry out regioselective synthesis of 1,4 isomer. Silver catalysts had previously shown to be inactive for such transformation. A disadvantage of the Cu-catalysed Click reaction is that it does not work on internal alkynes. A mechanism for this reaction was originally proposed based on theoretical calculations.
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