CuAAC reaction

The synthesized CPMV-alkyne 42 was subjected to the CuAAC reaction with 38. Due to the strong fluorescence of the cycloaddition product 43 as low as 0.5 nM, it could be detected without the interference of starting materials. TMV was initially subjected to an electrophilic substitution reaction at the ortho-position of the phenol ring of tyrosine-139 residues with diazonium salts to insert the alkyne functionality, giving derivative 44 [100]. The sequential CuAAC reaction was achieved with greatest efficiency yielding compound 45, and it was found that the TMV remained intact and stable throughout the reaction. 

Numerous appUcations of the CuAAC reaction reported during the last several years have been regularly reviewed [7-13], and are continually enriched by investigators in many fields [14]. We focus here on the fundamental aspects of the CuAAC process and on its mechanism, with an emphasis on the qualities of copper that enable this unique mode of reactivity. 

Scheme 10.2 A Oxidative coupling byproducts in the CuAAC reactions catalyzed excess of the catalyst reactions with...

Whatever the details of the interactions of Cu with alkyne during the CuAAC reaction, it is clear that Cu-acetylide species are easily formed and are productive components of the reaction mechanism. Early indications that azide activation was rate-determining came from the CuAAC reaction of diazide 15, shown in Scheme 10.5, which afforded ditriazole 17 as the predominant product, even when 15 was used in excess [113]. The same phenomenon was observed for 1,1-, and 1,2-diazides, but not for 1,4-, 1,5-, and conformationally flexible 1,3-diazide analogues. The dialkyne 18, in contrast to its diazide analogue 15, gave statistical mixtures of mono- and di-triazoles 19 and 20 under similar conditions. Independent kinetics measurements showed that the CuAAC reaction of 16 was slightly slower than that of 15, ruling out the intermediacy of 16 in the efficient production of 17. The Cu-triazolyl precursor 21 is, therefore, likely to be converted to 17 very rapidly. 

Scheme 10.6 (A) Early proposed catalytic cycle for the CuAAC reaction based on DFT calculations. (B) Introduction of a second copper(l) atom favorably influences the energetic profile of the reaction (L-H2O in DFT calculations). At the bottom are shown the optimized structures for dinuclear Cu...

Sulfonyl azides participate in unique CuAAC reactions with terminal alkynes. Depending on the conditions and reagents, products other than the expected triazole 28 [119] can be obtained, as shown in Scheme 10.8. For example, N-sulfonyl azides are converted to N-sulfonyl amidines 29 when the reaction is conducted in the presence of amines [120]. In the aqueous conditions, N-acyl sulfonamides 30 are the major products [121, 122]. 

Scheme 10.8 (a) Products of CuAAC reactions with sulfonyl azides, (b) Possible pathways leading to ketenimine intermediates. 

In the mechanism of the CuAAC reaction described above, the metal catalyst activates terminal alkyne for reaction with a Cu-coordinated azide. This mode of reactivity operates with other dipolar reagents as well. In fact, the first example of a copper-catalzyed 1,3-dipolar cycloaddition reaction of alkynes was reported for nitriones by Kinugasa in 1972 [124]. An asymmetric version of the Kinugasa reaction was developed by Fu et al. in 2002 [125, 126]. 

The CuAAC reaction has been applied to a remarkable array of problems in synthetic chemistry, chemical biology, materials science, and other fields. A comprehensive or even representative list is beyond the scope of this chapter. Instead, we will highlight two examples involving metallic copper as the source of CuAAC catalyst. While decidedly not typical in the body of CuAAC applications in the literature, we believe that this most convenient form of this inexpensive metal should receive greater attention in azide-aUcyne ligation reactions. We also hope that these examples will give the reader some indication of the facility with which the CuAAC process can be applied. 

Cook TL, Walker JA, Mack J. Scratching the catalytic surface of mechanochemis-try a multi-component CuAAC reaction using a copper reaction vial. Green Chem 2013 15 617-9. 

Apart from the utilization of aryl- and vinyl-diazoacetates that can achieve the moderate to high chemo-, regio-, and enantioselectivity in intermolecular asymmetric C—H bond insertion reactions, Af-sulfonyl-l,2,3-triazole 11 was found to be able to function as an alternative carbene precursor for diverse transformations (Scheme 1.4). One advantage for using the N-sulfonyl-1,2,3-triazole is that it could be easily prepared by the Cu -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, and in some cases, delicately designed reactions can be conducted in a one-pot procedure starting from alkynes and sulfonyl azides. Moreover, since there exists an inherent equilibrium... 

The use of click chemistry has also influenced the construction of more sophisticated star polymers, such as those with block copolymer arms. Maty-jaszewski has eloquently demonstrated the preparation of three-arm star block copolymers by again combining ATRP with CuAAC click couphng [109]. In these studies the ATRP of styrene, starting from a trifunctional initiator, yielded the three-arm star homopolymer bearing bromide end groups that subsequently were transformed by substitution with sodium azide. CuAAC reaction with PEO-alkyne... 

Scheme 30.24 The click cyclization of heterotelechelic PS via an intramolecular CuAAC coupling reaction, (i) Substi. tution with sodium azide (ii) CuAAC reaction. Reproduced with permission from Ref [179] 2006, American Chemical Society.

Meldal, M. (2008) Polymer clicking by CuAAC reactions. Macromol. Rapid Commun., 29, 1016-1051. 

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