Copper I -catalyzed azide-alkyne cycloaddition

Copper(I)-catalyzed azide-alkyne cycloaddition as a selective bioconjugation technique... 

The turning point for the above mentioned 1,3-dipolar cycloaddition occurred with the independent discovery that copper(I) not only promotes the speed of the reaction (often referred to as click reaction), but also improves regioselectivity. The copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) of terminal alkenes with organic azides to yield 1,4-disubstituted 1,2,3-triazoles discovered by Meldal [51] and Sharpless [50] exhibits remarkably broad scope and exquisite selectivity [59,60]. The most prominent application of click reactions in recent years has been in drug research [61,62],... 

The alkynyl functionality of alkynones 1 is perfectly suited for subsequent copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) in the sense of an MCR (2015ASC(357)617). A microwave-assisted three-component reaction of aroyl chlorides 4, TMS-substituted acetylene (5a), and benzyl azide (10a) consisting of modified Sonogashira cross-coupling I, desilylation, and CuAAC furnishes 4-disubstituted 1,2,3-triazoles 11 in moderate to excellent yields (Scheme 5) (201 OOL(12)4936). 

Wang W, Hong SL, Tran A, Jiang H, Triano R, Liu Y, Chen X, Wu P (2011) Sulfated ligands for the copper(I)-catalyzed azide-alkyne cycloaddition. Chem-Asian J 6(10) 2796-2802. doi 10.1002/ asia.201100385... 

Fig. 1 Proposed intermediates of CuAAC with one or two copper atoms [41]. CuAAC copper(I)-catalyzed azide-alkyne cycloaddition...

Fig. 7 CuAAC reaction for studying protein lipidation and lipidation-induced protein-protein interactions. Schematic representation for studying (a) protein S-palmitoylation using an alkyne-tagged lipid probe alk-16 and the CuAAC reaction, and (b) S-palmitoylation-induced protein irotein interactions using a multifunctional lipid probe X-alk-16 [97, 98]. CuAAC copper(I)-catalyzed azide-alkyne cycloaddition, UV ultraviolet...

Describe the main criteria that should be satis ed for a reaction to be called a click reaction How would you justify the inclusion of the following reactions into the pantheon of click reactions (a) Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions (b) strain-promoted azide-alkyne coupling (SPAAC) reactions (c) Diels-Alder (DA) cycloaddition reactions (d) thiol-ene (TE) reactions and (e) thiol-yne (TY) reactions ... 

Although the azide-alkyne [3+2] cycloaddition (cf. Chapter 9) is known in carbohydrate chemistry for more than 50 years, its application for the preparation of glycoconjugates became particularly attractive with the development of the copper(I)-catalyzed variant by Meldal and Sharpless. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) enables the regioselective formation of 1,4-disubstituted 1,2,3-triazoles under very mild conditions even in a biological context. However, the cellular toxicity of the copper catalyst precludes applications wherein cells must remain viable. Therefore, as an alternative... 

Scheme 8.1 Examples of click reactions commonly employed in polymer synthesis and functionalization reactions, (a) Copper(I)-catalyzed azide alkyne cycloaddition reaction, (b) Diels-Alder [4 + 2] cycloaddition between anthracene derivatives and maleimides. (c) Hetero-Diels-Alder between a terminal electron-deficient thiocarbonylthio group of RAFT-generated polymers and an appropriate diene, (d) Ultrafast hetero-Diels-Alder reaction between a terminal electron-deficient thiocarbonylthio group of RAFT-generated polymers and a reactive cyclopentadiene. (e) Thiol-ene click chemistry.

Sinnwell, S., Inglis, A.J., Stenzel, M.H., and Bamer-KowoUik, C. (2008b) Access to three-arm star block copolymers by a consecutive combination of the copper(I)-catalyzed azide-alkyne cycloaddition and the RAFT hetero Diels-Alder concept. Macromolecular Rapid Communications, 29,1090. 

Geng J, Lindqvist J, Mantovani G, Haddleton DM (2008) Simultaneous copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and living radical polymerization. Angew Chem Int Ed 47(22) 4180 183... 

Fuchs M., Goessler W., Pilger C., Kappe C.O. Mechanistic insights into copper(I)-catalyzed azide-alkyne cycloadditions using continuous flow conditions. Adv. Synth. Catal. 2010 352(2-3) 323-328. 

Imidazoles carrying a long alkyl chain as a ligand for the copper(I)-catalyzed azide-alkyne cycloaddition are also very efficient. An alkyl chain can readily change its conformation in a host molecule to adjust its volume to the cavity size and may have an appreciable steric effect [15]. The copper(I) isonitrile complex prepared upon treatment of isonitriles with CuCl in THF in 95% yield as [CuLCl] units extended in a polymeric chain is stable in air or water for several months. This complex catalyzes the reaction of azides and acetylenes in water at room temperature in 0.5-5 mol% loading to give excellent yields in very short times. The catalyst may be recycled through five cycles [16-18]. 

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