Dipolar Huisgen Cycloaddition Reactions

The authors have also elaborated a microwave-enhanced one-pot procedure [90] for the Huisgen 1,3-dipolar cycloaddition reaction. In a typical procedure, a pyrazinone with a triple bond connected to the core via C - O linkage, was reacted with a suitable benzylic bromide and NaNs in presence of the Cu(I) catalyst in a t Bu0H/H20 system under microwave irradiation (Scheme 26). The cycloaddition was found to proceed cleanly and with full regioselectivity. As the azide is generated in situ, this procedure avoids the isolation and purification of hazardous azides, which is especially important when handling the ahphatic ones, which are known to be toxic and explosive in nature. 

Studies of the Rab protein functional cycle require methods that allow for generating preparative amounts of prenylated Rab proteins with new functionalities, such as fluorophores. Two approaches have been developed in our laboratory, including EPL and Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction (click ligation). 

A variant of the Huisgen 1,3-dipolar cycloaddition reaction provides a new and convenient functionalization of fullerenes... 

Sharpless and coworkers pubhshed a paper in 2002 (Rostovtsev et al., 2002) where the formation of 1,23-triazoles by the Cu(l)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction between alkyl/aryl azides and non-activated alkynes was described as a chck reaction in contrast to the purely thermal (imcatalyzed) azide-alkyne chck reaction which refers to the 13-dipolar cycloaddition reaction between alkyl/aryl azides and strongly activated alkynes. The Cu(l)-catalyzed... 

Though tremendous success has been achieved with the development of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition reaction of azides and acetylenes as a robust and ef cient synthetic tool, it has several limitations which inclnde the need for a metal catalyst, an inability to photochemi-cally control the reaction or to conduct the reaction in the absence of solvent. In comparison, the century-old addition of thiols to alkene (the hydrothiolation of a C=C bond), which is currently called thiol-ene coupling (TEC), has many of the attributes of chck chemistry without, however, some of the aforesaid disadvantages of the CuAAC reaction. 

Among the chemical procedures listed above, click chemistry can be considered an efficient method that covers a wide range of different, requested functionalizations. The key reaction, called Sharpless-type click reaction , is a variant of the Huisgen 1,3-dipolar cycloaddition reaction between C—C triple bonds, C—N triple bonds, and alkyl-, aryl-, and sulfony 1-azides. 

The discovery of Cu(I) catalysis for the Huisgen 1,3-dipolar cycloaddition reaction has led to a tremendous number of synthetic developments [104, 143]. Even if the exact mechanism of the reaction is still debated, the process involves formation of a transient 5-cuprotriazole, which is protodemetalated to close the catalytic cycle. If stoichiometric or an excess of copper is used, one can conceive to trap this transient metalated intermediate by electrophiles (Fig. 7). 

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