Copper-catalyzed cycloadditions

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

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. 

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>. 

Synthesis of p-lactams using the copper -catalyzed cycloaddition of a terminal alkyne and a nitrone, the Kinugasa reaction 07SL2321. 

A one-pot synthesis of macrocycles by a domino three-component reaction and [3+2] cycloaddition was investigated by Zhu et aL [99]. By combining three appropriately designed simple substrates, a programmed sequence involving an a-isocyano acetamide-based three-component reaction followed by a copper-catalyzed cycloaddition of alkyne and azide took place to afford macrocycles 119 in moderate to good yields (Scheme 26). 

Stabilized Cu(I) in the form of its iV-heterocyclic carbene (NHC) complex, e.g., (SIMes)CuBr (SIMes = iV,7V -f>is(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene), and the eyclohexyl analog [(ICy)2Cu]PF6, catalyzes click reactions very well in aqueous /-butanol, and even better in water alone. Low conversions were noted in nonaqueous solvents such as tetrahydrofuran (THF), /-BuOH, and dichloromethane (DCM). Starting from an alkyl bromide, triazoles could be smoothly generated by m situ conversion to the corresponding azide (aqueous NaNs) followed by copper-catalyzed cycloaddition. This is but one example of the potential for combining several steps in a single flask that culminates with a click reaction vide infra). The... 

General procedure for copper-catalyzed cycloadditions of aliphatic and aryl azides with alkynes to triazoles on water... 

Click chemistry, as introduced by Kolb and Sharpless in 2001 relates mainly to the Cu(i) eatalyzed [3+2] cycloaddition reaction of azides with alkynes. This copper catalyzed cycloaddition reaction is highly useful for attaching fluorescent or other markers to a wide variety of biomolecules. Although azides are often unstable at elevated temperatures, they are stable at physiological conditions, have no intrinsic toxicity and have extraordinary chemical selectivity. Proteins and glycans have already been labeled with azides in laboratory mice using enzyme inhibitors and sugar azides. 

SCHEME 3.142 Preparation of pyrazolines through copper-catalyzed cycloaddition reactions [151],... 

Scheme 17 Copper-catalyzed cycloaddition of organic azides and dimethylalkynylalumimuns...

Zhou Y, Lecourt T, Micouin L (2010) Direct synthesis of l,4-disubstituted-5-alumino-1,2,3-triazoles copper-catalyzed cycloaddition of organic azides and mixed aluminum acetylides. Angew Chem Int Ed 49 2607-2610... 

Click chemistry is now a popular concept, more specifically when it is used to indicate a copper-catalyzed cycloaddition reaction between alkyl or aryl azides and terminal alkynes. Due to the fact that Cu(I) catalysts dramatically accelerate the original Hiiisgen thermal reaction with perfect control of the mechanistic pathway to lead only to l,4-disubstituted-l,2,3-triazoles, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has become one of the most representative examples of click chemistry. It was proposed that this reaction proceeds first through the formation of a copper(l)-acetyhde from a copper(I) catalyst and a terminal alkyne, followed by cycloaddition with a copper(l)-bound azide to generate a triazolyl copper(I) complex, which is released by protonation of the Cu—C bond. 

The proposed mechanism for this transformation involves a transient vinylidene-like transition state B (Fig. 8, left). A closely related mechanism has also been proposed for the copper-catalyzed cycloaddition of azides on mixed organoaluminum compounds. 

J0rgensen and coworkers reported that copper-catalyzed cycloaddition of nitrone le with vinyl ether 5a in the presence of catalyst 7 predominantly afforded the cw-adduct with relatively high ee (Scheme 6.4) [8e]. The proposed transition state model C contrasts with transition state B, since copper in C coordinates with the oxygen atom of 5a as well as with oxygen atoms of nitrone le. 

One reason why the azo Diels-Alder has not yet been more popular for the stereoselective total synthesis of nitrogen-containing natural products may be because until recently the only asymmetric version relied on the use of chiral dienes. There were neither an azo dienophile bearing a chiral auxiliary able to induce a useful diastereoselectivity nor an enantioselective catalytic reaction until 2006. That year, Yamamoto and co-workers reported on a highly enantioselective copper-catalyzed cycloaddition of a... 

SCHEME 3 Copper catalyzed cycloaddition of unsbstituted Schiff base ligand. 

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