CuAAC azide-alkyne cycloaddition

Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC)... 

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 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],... 

Among these reactions, the Cu(l)-catalyzed azide-alkyne cycloaddition (CuAAC) is the most widely used. This reaction has been implemented for the preparation of segmented block copolymers from polymerizable monomers by different mechanisms. For example, Opsteen and van Hest [22] successfully prepared poly(ethylene oxide)-b-poly(methyl methacrylate) (PEO-b-PMMA) and PEO-b-PSt by using azide and alkyne end-functionalized homopolymers as the click reaction components (Scheme 11.2). Here, PEO, PSt, and PMMA homopolymers were obtained via living anionic ring-opening polymerization (AROP), atom transfer radical polymerization (ATRP), and postmodification reactions. Several research groups have demonstrated the combination of different polymerization techniques via CuAAC click chemistry, in the synthesis of poly(e-caprolactone)-b-poly(vinyl alcohol) (PCL-b-PVA)... 

CuAAC Copper-catalyzed azide-alkyne cycloaddition... 

This chapter will serve to highlight recent advances in polymer science that have been aided by the use of click chemistry. The copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiol-ene reactions will be discussed first, after which the utilization of these chemical transformations in the construction and fimction-ahzation of a multitude of different polymeric materials will be outlined. Particular attention will be focused on the preparation of highly complex polymer architectures, such as dendrimers and star polymers, which exempHfy the essential role that chck chemistry has assumed in the polymer science community. 

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). 

The second step is the copper(l)-catalyzed azide-alkyne cycloaddition (CuAAC). CuAAC produces only 1,4-disubstituted-1,2,3-triazoles at room temperature in excellent yields. Formally, it is not a 1,3-dipolar cycloaddition and thus should not be termed a Huisgen cycloaddition. 

Hein, J. E. and Fokin, V. V. 2010. Copper-catalyzed azide-alkyne cycloaddition (CuAAC) and beyond New reactivity of copper(I)acetylides. Chem. Soc. Rev. 39(4) 1302-1315. 

Recent studies on the reaction mechanism provided the experimental evidence for a dinuclear Cu intermediate complex involved within the reaction steps [28]. Although the Huisgen s original reaction mechanism is considered to be concerted, where the old bonds break at the same time as the new bonds form, the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) is a stepwise process. Ever since the initial report, this reaction has found extensive applications in biotechnology [29-31], material sciences [32-34] and drug discovery [35, 36]. 

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

F e 2 Chelation-assisted CuAAC reaction, a Schematic illustration of the chelation model of picolyl azide-aUcyne cycloaddition. R group can be substituted by either the electron-withdrawing or electron-donating group It Selective labeling of neuron cell-surface proteins with an engineered picolyl azide li ase and chelation-assisted CuAAC [18, 58], CuAAC copper(l)-catalyzed azide-alkyne cycloaddition... 

Fig. 3 Coupling the residue-specific UAA incorporation with CuAAC reaction for labeling and visualization of newly synthesized proteins in situ [77, 78], UAA unnatural amino acid, CuAAC copperfl)-catalyzed azide-alkyne cycloaddition, AHA azidohomoalanine, HPG homopropargylglycine, TBTA tris-[(1-benzyl- IH-1,2,3-triazol-4-yl)methyl]amine...

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...

F. 10 Schematic representation for the photo-affinity-based ABPP strategy. The structure of HDAC photo-crosslinking probe (SAHA-BPyne) is shown in the middle [115]. ABPP activity-based protein profiling, HDAC histone deacetylase, SAHA suberoylanilide hydroxamic acid, CuAAC copper(l)-catalyzed azide-alkyne cycloaddition, LC-MS/MS liquid chromatography-tandem mass spectrometry... 

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