Huisgen reaction

Figure 17.9 A general Huisgen reaction involves the cycloaddition of an azide with an alkene or an azide with an alkyne. The products of these reactions are a triazoline ring or a triazole ring, respectively.

Esters of acetylenedicarboxylic acid 1023 are commercially readily available, are very reactive as dipolarophiles, and the carboxylic groups in products of their reactions can be easily converted to many other functionalities. Therefore, they are often the first choice as substrates for 1,3-dipolar cycloaddition to azides 1024 (Huisgen reaction). The reactions are carried out at room or elevated temperature, and the yields of 1,2,3-triazoles 1025 are usually high to quantitative (Equation 22). Several products obtained in this way are presented as structures 1026-1034. Some details about the reactions leading to these products are given in Table 10. 

Another theoretical investigation deals with the intramolecular [3+2] dipolar cycloaddition (Huisgen reaction) of azides and nitriles (Scheme 2) to form tetrazoles <2003JOC9076>. 

Following reports of efficient Cu(I)-catalyzed alkyne/azide cycloaddition on solid phase and in solution by Meldal [42] and Sharpless [43], respectively, the formerly obscure Huisgen reaction soared to prominence as a versatile tool for covalent chemical ligation. The so-called click reaction can be catalyzed by a number of copper sources in a variety of media (Equation 9.14). 

The iron-catalyzed [3 + 2]-cycloaddition (Huisgen reaction) of nitriles and carbonyl compounds as reported by Itoh et al. is one of the rare examples reported where an iron reagent can be utilized for the synthesis of 1,2,4-oxadiazoles (Scheme 9.35) [93]. In this reaction, methyl ketones are nitrated at the a-position by Fe(N03)3 to generate an a-nitro ketone. This intermediate rearranges to an acyl cyanate, which reacts further with the nitrile to give the heterocyclic product 48 in good to excellent yields (R1 = Ph, R2 = CH3 95% yield). 

Scheme 9.37 Asymmetric iron-catalyzed Huisgen reaction.

Acyltetrazoles in solution are subject to dediazoniation at room temperature. However, the acyl nitrilimines cyclize immediately to give 1,3,4-oxadiazoles (HuiSGEN reaction) ... 

Synthetic applications of tetrazoles are deoxygenation of phenols, preparation of nitrilimines and preparation of 1,3,4-oxadiazoles by the Huisgen reaction. All these have been previously... 

Angell and Burgess showed that click chemistry of copper-catalyzed Huisgen reaction between alk5mes and azides in the presence of a base resulted in the formation of C-C linked bitriazole atropisomers (169) (07AG3723). Several examples were reported but the barriers were not determined. 

PS-supported l,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was used as a polyvalent ligand for the Cu-catalyzed Huisgen reactions (Coelho et al., 2010) (Scheme 4.18). The three-component synthesis of 1,2,3-triazoles was successfully achieved under the same conditions. However, the catalytic system was less active, maybe due to its low catalyst loading. 

Azide-alkyne reaction has been known since 1893 when A. Michael reported the first synthesis of 1,2,3-triazoles from diethyl acetylenedicarboxylate and phenyl azide [32]. In the middle of the 20th century, Huisgen systematically studied the family of 1,3-dipolar cycloaddition reactions [33], and henceforth the reaction is known as Huisgen reaction. However, the non-catalyzed Huisgen reaction of azide-... 

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