Copper-catalyzed Huisgen cycloaddition

H. Isobe, K. Cho, N. Solin, D. B. Werz, P. H. Seeberger, and E. Nakamura, Synthesis of fullerene glycoconjugates via a copper-catalyzed Huisgen cycloaddition reaction, Org. Lett., 9 (2007) 4611-4614. 

Selective and quantitative Af-phthaloylation of CS proceeds smoothly by the reaction of CS with phthalic anhydride in DMF at 130°C. Ifuka et al. [45] prepared N-(4-azidophthaloyl) CS by copper-catalyzed Huisgen cycloaddition. The derivative was prepared through chemoselective iV-bromophthaloylation of CS in acidic water and subsequent azidation. The M-(4-azidophthaloyl) CS was further converted with ethynyl derivatives having hydroxymethyl. 

A picket-fence zinc(ll) porphyrin bearing four halogen bond-donor iodotriazole groups has been synthesized by Beer and co-workers (Fig. 5) [47]. Halogen bond donor 9a and control 9b, which lacks the iodo substituent, were prepared from an azidoacetate-substituted Zn(II) porphyrin by copper-catalyzed Huisgen cycloadditions. Addition of anions to 9a and 9b was accompanied by a bathochromic shift of the Soret band in the UV-vis spectrum, probably signaling axial ligation to the Zn(ll) porphyrin. Association constants determined from the concentration... 

Fig. 41 Synthesis of cyclic PCL by click copper-catalyzed Huisgen s cycloaddition...

Scheme 33.1 The copper-catalyzed Huisgen 1,3-dipolar cycloaddition between azides and primary acetylenes to yield the 1,4-substituted 1,2,3-triazole.

In the last few years, click reactions, as termed by Sharpless et al. [280] received attention due to their high specificity, quantitative yields, and good fidelity in the presence of most functional groups. The click chemistry reaction includes a copper-catalyzed Huisgen dipolar cycloaddition reaction between an azide and an alkyne leading to 1,2,3-triazole. Recent publications on this click reaction indicate that it is a useful method for preparation of functional polymers [281]. 

Coelho, A., Diz, R, Caamano, O., and Sotelo, E. 2010. Polymer-supported 1,5,7-tiiazabicy-clo[4.4.0]dec-5-ene as polyvalent ligands in the copper-catalyzed Huisgen J,3-dipolar cycloaddition. A(iv. Synth. Catal. 352(7) 1179-1192. 

V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless, A stepwise Huisgen cycloaddition process Copper(I)-catalyzed regioselective ligation of azides and terminal alkynes, Angew. Chem. Int. Ed., 41 (2002) 2596-2599. 

Two recent publications feature metal vinylidenes functioning as 1,3-dipole equivalents, as in the Cu-catalyzed Huisgen cyclization (Section 9.4.5). Fiirstner and coworkers described intramolecular Diels-Alder reactions of unactivated die-nynes catalyzed via a proposed [4+3]-diene/copper vinylidene cycloaddition [59]. 

The reaction has been modified to a more regioselective, copper-catalyzed stepwise process by the Sharpless group, which is no longer a classic Huisgen Cycloaddition. Another approach prefers the use of a directing electron withdrawing group, which is removable later ... 

Figure 3.42 a General reaction scheme for the thermal Huisgen cycloaddition b the copper-catalyzed reaction between phenyl propargyl ether (phenyl 2-propynyl ether) and benzyl azide. The catalytic reaction is performed in the presence of a reductant (sodium ascorbate) and gives just one of the product isomers in high yield. 

Ruthenium catalysts were used as alternatives to the usual copper catalysts. Ynamides 102 reacted with various azides 103 in the ruthenium-catalyzed Huisgen [3+2] cycloaddition reaction to yield l-protected-5-amido 1,2,3-triazoles 104 <07T8094>. The formation of 1,5-... 

Rostovtsev, V.V., Green, L.G., Fokin, V.V., and Sharpless, K.B. (2002). A stepwise huisgen cycloaddition process copper(I)-catalyzed regioselective hgation of azides and terminal alkynes Angew Chem Int Ed 33 45. 

The utility of the Huisgen 1,3-dipolar cycloaddition was discovered when it was realized that copper not only catalyzes the reaction but also promotes the regiospecificity, with exclusive production of the 1,4-triazole regioisomer (Figure 14.8) [64]. The first publication by Meldal et al., in 2002, outlined the use of copper in the cycloaddition reaction for triazole synthesis on a solid phase [66]. This was an organic-solvent-based... 

A recent very flexible approach for the preparation of TSOS has been published by Liebscher [34], It relies on a two step procedure with one so-called click chemistry step, which is a regioselective copper catalyzed [3 + 2] Huisgen cycloaddition between an azide and a terminal alkyne, followed by quatemarisation of resulting triazoles. Both reagents can be functionalized prior to cyclisation and furthermore such triazolium synthesis can tolerate a large variety of substituents owing to its chemoselectivity (Fig. 14). 

The most popular click reaction is Huisgen 1,3-dipolar cycloaddition of azides to alkynes applicable to a very wide range of macro molecular architecture. It has been employed for the preparation of various polymer topologies including linear, star, hyperbranched, and H-shaped polymers. The general approach is illustrated in Scheme 70 for the preparation of linear block copolymer of EO with MMA and St. Anionically prepared PEO was functionalized with azide and used in copper-catalyzed click reaction with PMMA or PSt with alkyne moiety synthesized by using alkyne-flinctional ATRP initiator. It should be noted that alkyne functionality of hetero-functional ATRP initiator was protected with a trimethylsilyl... 

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. 

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