Cycloaddition copper catalyzed

Very recently, Wu et al. developed an eflhcient Fe/Cu relay-catalyzed domino protocol for the synthesis of pharmaceutically significant 2-phenylquinazoIin-4-amines 67 from commercially available ortlzo-halogenated benzonitriles, aldehydes, and sodium azide (Scheme 7.47) [115]. This elegant domino reaction involved consecutive iron-mediated [3 + 2] cycloaddition, copper-catalyzed SNAr, reduction, cyclization, oxidation, and copper-catalyzed denitrogenation sequences. The structure constructed by this protocol is the privileged core in drugs and bioactive molecules. 

Wu and co-workers presented an efficient domino reaction for the rapid synthesis of 5-phenyl-[l,2,3]triazolo[l,5-c]quinazolines derivatives (80) from simple and readily available (E)-l-bromo-2-(2-nitrovinyl)benzenes 79, aldehydes, and sodium azide (Scheme 7.56) [124]. This reaction cascade comprised [3 + 2] cycloaddition, copper-catalyzed SnAt, reduction, cyclization, and oxidation. It is noteworthy that sodium azide is used as a dual nitrogen source in the construction of these fascinating fused A-heterocycles. 

The enantioselective cycloaddition reaction catalyzed by chiral BOX-copper(II) complexes has been used for conjugated cyclic dienes, e.g. 1,3-cyclohexadiene 5c, as shown in Scheme 4.21 [9, 32]. This cycloaddition reaction is dependent on sol-... 

Gramlich PME, Wirges CT, Manetto A, Carell T (2008) Postsynthetic DNA modification through the copper-catalyzed azide-alkyne cycloaddition reaction. Angew Chem Int Ed... 

Owing to flexibility in the substrate, the TycATE was also used to synthesize a variety of novel cyclic structures. Inclusion of a propargylated amino acid into the linear substrate allowed the synthesis of over 247 macrocyclic glycopeptides, where azido-sugars were coupled onto the cyclized alkyne via copper-catalyzed 1,3-dipolar cycloaddition [44] (Figure 13.12). 

From the copper-catalyzed reaction of methyl 2-diazo-3-oxobutyrate 57 a with Z-3-methoxystyrene, dihydrofuran 59 (formed with retention of olefin configuration) and butadienol 60 result130). Such an acyclic by-product also occurs when benzofuran is the cycloaddition partner. In that case, however, regioisomers 61 and 62, arising from the connection of the former diazo carbon with either the 2- or 3-position of the heterocycle, are obtained similarly, two isomeric dihydrofurans 63 and 64 are formed under Cu(hfacac)2 catalysis130). 

Ethyl diazopyruvate, under copper catalysis, reacts with alkynes to give furane-2-carboxylates rather than cyclopropenes u3) (Scheme 30). What looks like a [3 + 2] cycloaddition product of a ketocarbenoid, may actually have arisen from a primarily formed cyclopropene by subsequent copper-catalyzed ring enlargement. Such a sequence has been established for the reaction of diazoacetic esters with acetylenes in the presence of certain copper catalysts, but metallic copper, in these cases, was not able to bring about the ring enlargement14). Conversely, no cyclopropene derivative was detected in the diazopyruvate reaction. 

Tandem azidination- and hydroazidination-Hiiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3-triazoles <06OBC2679>. A series of diversely l-substituted-4-amino-l,2,3-triazoles 132 were synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. 

An improved strategy using microwave-assisted synthesis, involving a gallic acid core and copper-catalyzed [3+2] cycloaddition (CuAAc), afforded a series of glyco-dendrons.329 The straightforward synthesis of this series of glycodendrons was... 

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. 

Disubstituted 1,2,3-triazoles are exclusive products of copper catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. A variety of substituents can be introduced in this way. Many examples of such reactions are discussed in Section 5.01.9. 

Another route involves a palladium-copper-catalyzed tandem carbon-carbon formation/cycloaddition sequence (Equation 12) <2005TL8531>. Notably, cycloadditions of azide to the internal alkynes failed under click chemistry reaction conditions <2003DDT1128>. Cyclization under oxidative conditions has been reported from dithioacetal 163 (Equation 13) <1996TL3925>. The formation of 164 as a single diastereoisomer has been explained by stereoelectronic effects. 

Jprgensen and co-workers (247) investigated the asymmetric 1,3-dipolar cycloaddition reaction catalyzed by bis(oxazoline)-copper(II) complexes. In the presence of 25 mol% 269c, nitrone (401) reacts with ethyl vinyl ether and methoxypropene to afford the [3 + 2] adducts in modest diastereoselectivity and high enantioselectivity, Eq. 217. Ethyl vinyl ether preferentially forms the exo adduct while methoxypropene prefers the endo mode for reasons that are unclear. 

Squaraines 17b and 17c have terminal acetylene residues, which allowed to convert the squaraine dyes and tetralactam macrocycles into permanently interlocked rotaxane structures using copper-catalyzed and copper-free cycloaddition reactions with bulky stopper groups [58]. 

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],... 

Figure 9 (a) Protein modification with PEG through a copper-catalyzed cycloaddition reaction, (b) Protein modification with fluorescein through Staudinger ligation. 

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

The success of copper-catalyzed cycloaddition reactions yielding products with up to 99% ee stimulated further investigations in this regard. Both of the key ligand structure types represented by C2-symmetric sulfoximine 60 and Q-symmetric 82 had a two-carbon distance between the two coordination nitrogens. 

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. 

Diaz, D.D., Punna, S., Holzer, P., Mcpherson, A.K., Sharpless, K.B., Fokin, V.V. and Finn, M.G. (2004) Click chemistry in materials synthesis. 1. Adhesive polymers from copper-catalyzed azide-alkyne cycloaddition. J. Polym. Sci. Polym. Chem., 42, 4392. 

Click chemistry has been used extensively since its introduction in organic chemistry, due to the high efficiency and technical simplicity of the reaction [40]. The most popular click reaction has been the copper-catalyzed dipolar cycloaddition of a terminal alkyne and an azide to form... 

A sequential process involving a copper catalyzed cycloaddition of the vinyl sulfone 34 to Af-methylpropargylamine (35), and a subsequent palladium meditated allylic substitution, provided a route to mixtures of the separable isomeric pyrrolines 36 and 37 <02EJO1493>. 

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