Cycloadditions azide-alkyne

Campidelli et al. have synthesized interesting linear and hyperbranched porphyrin polymers from CNTs via copper-catalyzed alkyne-azide cycloaddition (CuAAC) [122], Zinc porphyrin monomers containing an azide group and one or three alkyne groups were synthesized and chemically bound to alkyne functionalized SWCNTs via CuAAC. Depending upon the number of alkyne functionalities either linear (single alkyne) or dendrimer-like (triple alkyne) porphyrin polymers were produced (Fig. 5.9) [122],... 

CuAAC copper catalysed alkyne-azide cycloaddition... 

Akritopoulou-Zanze I, Gracias V, Djuric SW (2004) A versatile synthesis of fused triazolo derivatives by sequential Ugi/alkyne-azide cycloaddition reactions. Tetrahedron Lett 45 8439-8441... 

Further disadvantage of the alkyne-azide cycloaddition is the lack of regiospecificity. On the other hand, cycloadditions of azides to alkenes are, in most cases, regioselective and afford 1,5-disubstituted triazolines . Therefore, the regioselective cycloaddition of an azide to an alkene, followed by aromatization (see Section 4.01.5.3.1) is an alternative method for the synthesis of 1,2,3-triazoles. 

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). 

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

POC-click is formed by thermo-cross-linking the mixture of pre-POC-N (azide-containing POC prepolymer) and pre-POC-Al (alkyne-containing POC prepolymer) the process applies synchronous binary cross-link mechanism, esterification, and thermal click reaction, and the residual azide groups on the surface of POC-click film or scaffold paved the way of surface bioconjugation through strain-promoted alkyne-azide cycloaddition (SPAAC), another copper-free click reaction. 

A straightforward synthesis of fused dihydrotriazolo[l,5-Q ]pyrazinones and triazolobenzodiazepines by sequential Ugi/alkyne-azide cycloaddition reactions was recently demonstrated by Djuric et al. [55]. The couphng of the Ugi multi-component reaction with the intramolecular alkyne-azide cycloaddition provides access to highly functionaUzed heterocyclic ring systems in just two steps. 

Combined Cu-lalkyne-azide cycloaddition and fhran-maleimide Diels-Alder "click chemistry approach to thermorespon-sive dendrimers. Chem. Commun., 46, 1875-1877. 

For an example of such interaction in the TS of non-catalyzed alkyne/azide cycloaddition (click reaction), see Gold, B., Shevchenko, N. E., Bonus, N., Dudley, G. B., Alabugin, 1. V. (2012). Selective Transition State Stabihzation via Hyperconjugative and Conjugative Assistance Stereoelectronic Concept for Copper-Free Click Chemistry. The Journal of Organic Chemistry, 77(1), 75-89. 

We will illustrate the interplay between infra- and intermolecular effects in thermal (non-catalyzed) alkyne-azide cycloadditions. In this case, both infra- and intermolecular effects work in synergy and originate from the presence of the same acceptor group at the propargylic carbon. In this example, a single structural design element imbues more than one beneficial effect. The intramolecular effect involves stabilization of alkyne distortion and Jt-bond breaking, whereas the intermolecular effect involves assistance to bond formation (vide infra). 

Hetero Diels-Alder - intermolecular case - donor and acceptor are in different molecules (but interact via two orbital subsets) Intermolecular delocalization is not limited to the earlier discussed alkyne/ azide cycloadditions. It has been reported to provide significant contribution to the observed electronic effects in other cycloadditions. For example, Boger and coworkers reported that the Diels-Alder reaction of... 

Experimental protocol for Staudinger-Bertozzi, Cu(l)-catalyzed Huisgen alkyne-azide cycloaddition, and reverse-electron-demand Diels-Alder ligation to distinguish between pi, p2,and p5. 

Mechanistic investigations of copper(I)-catalysed alkyne—azide cycloaddition reactions to form 1,2,3-triazoles 12THC(28)1. 

Gold B, Dudley GB, Alabugin IV (2013) Moderating strain without sacrificing reactivity design of fast and tunable noncat-alyzed alkyne-azide cycloadditions via stereoelectronically controlled transition state stabilization. J Am Chem Soc 135(4) 1558-1569. doi 10.1021/ja3114196... 

Liang L, Astruc D (2011) The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction and its applications. An overview. Coord Chem Rev 255 2933-2945... 

Copper(I)-Catalyzed Alkyne-Azide Cycloaddition (CuAAC) on Nucleic Acids... 

The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction [1] (Fig. lA) has been extensively employed for the site-specific labeling of oligonucleotides with various reporter groups [3,4, 7, 9,12-16], ligating DNA strands [17, 18], cross-linking complementary strands [19], for surface functionalization [20] and for the formation of bimetallic Ag-Au nanowires from DNA templates [21], Selected examples are described in the following section. 

Shelbourne M, Chen X, Brown T, El-Sagheer AH (2011) Fast copper-free click DNA ligation by the ring-strain promoted alkyne-azide cycloaddition reaction. Chem Commun 47(22) 6257-6259. doi 10.1039/clccl0743g... 

Dendritic nanoreactor 1 was also employed as a recyclable micellar nanoreactor, stabilizer, and activator of Cu -catalyzed alkyne—azide cycloaddition click reaction, CuAAC reaction, in the presence of a very low amount (only 0.1%) of Cu (hexabenzyltren) Br (tren = triaminoethylantine) catalyst, 4, in aqueous media (Fig. 6.24) [60]. 

In an alternative route to gene synthesis, as opposed to that carried out by nature for billions of years, Birts et al. [67] in 2014 reported the use of the [3-1-2] alkyne/azide cycloaddition for the construction of a 1,2,3-triazole mimic of the phosphate group (Scheme 9.25). 

Currently, copper-catalyzed and copper-free alkyne-azide cycloadditions are the most widely applied cycloaddition reactions for the modification of biomolecules. We developed an approach based on the combination of CuAAC or strain-promoted copper-free variants with enzymatic tailing (and optional enzymatic hgation), which allows the convenient postsynthetic introduction of an azide into existing unmodified RNA strands (chemically or enzymatically synthesized or even isolated from biological sources) at a desired position, and the subsequent functionalization with a wide variety of commercially available or self-synthesized functional alkynes [16c]. 

SCHEME 10.3 Synthesis of Stoddart s rotaxane 3 templated using charge transfer donor-acceptor interactions and stoppered dioxynaphthalene using copper-catalyzed alkyne-azide cycloaddition (CuAAC). 

The Raines group published an elegant paper on the replacement of an amide bond with a 1,5-substituted [l,2,3]-triazole 22 and incorporation of this dipeptide into bovine pancreatic ribonuclease (RNase A) by semisynthetic methods and showed that the melting temperature (T ) and catalytic activity of the resulting RNase A variants were retained. The triazolyl dipeptide was prepared by a Ru(ll)-catalyzed alkyne-azide cycloaddition which afforded 1,5-substituted triazoles, selectively (see Scheme 10.6). 

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