Copper-catalyzed click reaction

A one-pot, copper-catalyzed formation of fully decorated triazoles was recently demonstrated by Ackermann. In the first step, a copper-catalyzed click reaction produces triazoles from alkynes and azides. In the second step, a direct, copper-catalyzed... 

Tsarevsky has found that hypervalent iodine compounds can be used for the direct azidation of polystyrene and consecutive click-type functionalization [49]. In particular, polystyrene can be directly azidated in 1,2-dichloroethane or chlorobenzene using a combination of trimethylsilyl azide and (diacetoxyiodo)benzene. 2D NMR HMBC spectra indicate that the azido groups are attached to the polymer backbone and also possibly to the aryl pendant groups. Approximately one in every 11 styrene units can be modified by using a ratio of PhI(OAc)2 to trimethylsilyl azide to styrene units of 1 2.1 1 at 0 °C for 4 h followed by heating to 50 °C for 2 h in chlorobenzene. The azidated polymers have been further used as backbone precursors in the synthesis of polymeric brushes with hydrophilic side chains via a copper-catalyzed click reaction with poly(ethylene oxide) monomethyl ether 4-pentynoate [49],... 

Thorwith R, Stolle A, Ondruschka B, Wild A, Schubert US. Fast, ligand- and solvent-free copper-catalyzed click reactions in a ball mill. Chem Commun 2011 47 4370-2. 

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... 

Alkyne-modilied libraries containing 5-ethynyl-2 -deoxyuridine [12] (EdU, Fig. 4A) instead of thymidine are prepared. Functionalization of the library is achieved by copper-catalyzed click reaction with azide containing compounds. As a proof of principle, 3-(2-azidoethyl)indole was used and successful selection was performed against cycle 3 GFP [175]. The amplification step after selection is carried out in the presence of EdU to restore an enriched alkyne-modified library for subsequent rounds of selection. At this point, correct amplification of the functionalized template strand by DNA polymerases is stiU a requirement for successful selection, and can restrict the size of the azide-modified compounds used. 

Grafting-to Polymer Backbones via Copper-Catalyzed Click Reaction... 

The copper-catalyzed azide/alkyne click reaction has found the broadest application in the modification of ROMP polymers, with the first reported example in 2004 by Binder and Kluger [13]. Since then, the copper-catalyzed click reaction has been used for the preparation of block copolymers [24, 29, 37], stars [18, 26], cycles [23], networks [25], and graft copolymers [27, 28, 38, 56, 57], as well as for end- [16] and side-chain-functionalized polymers [13, 17, 19-22, 48]. The most often used catalysts and bases for the azide/alkyne click reaction include copper(l) iodide, copper(l) bromide, trisftriphenylphosphine) copper(l) bromide, or copperfll) sulfate/sodium ascorbate as catalyst and diisopropylethylamine (DIPEA), pentamethyldiethylenetriamine (PMDETA), or 2,2 -bipyridine (bPy) as base. 

Fig. 2 Ligation reactions used in two-step ABPP using the azide functionality as ligation handle (a) Staudinger-Bertozzi ligation, (b) Cu(I)-catalyzed click reaction, (c) copper-free click reaction, and (d) photoclick reaction...

Aldehyde 126 was converted to the terminal alkyne (142) in 61% yield by Seyferth-Gilbert homologation (Scheme 23) [60]. These basic conditions were well tolerated and no C-8 epimerization or C-2 deacetylation was observed. Alkyne 142 was coupled with various azides under copper(I)-catalyzed click reaction conditions to afford 1,4-disubstituted-l,2,3-triazoles (143-145) in 88% yield. Similar conditions were used to generate unsubstituted 1,2,3-triazoles. Alkyne 142 was coupled to azidomethyl pivalate under click reaction conditions to give the pivalyl triazole (146) in 88% yield. The pivalyl triazole was then treated with IN NaOH to remove both the pivalyl group and the C-2 acetyl group. These conditions also led to C-8 epimerization. Acetylation of the epimeric mixture under standard conditions (AC2O, pyridine) and preparative scale separation by TLC furnished the C-8 epimeric N-unsubstituted triazoles (147) in 54% yield over three steps in a ratio of 4 6 (C-8 epi-C-8). 

Angell and Burgess showed that click chemistry of copper-catalyzed Huisgen reaction between alk5mes and azides in the presence of a base resulted in the formation of C-C linked bitriazole atropisomers (169) (07AG3723). Several examples were reported but the barriers were not determined. 

Copper vial and ball-catalyzed "click" reaction. 

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... 

Nanoparticles of Cu(0) powder that undergo oxidation in the presence of an amine hydrochloride lead to active Cu(I). The amine is presumed to play several roles reduction of Cu(II) to Cu(I) stabilization of Cu(I) as ligand and enhancement of solubility of copper in organic media. Nanosize clusters also catalyze click reactions, in this case in H2O//-BUOH at 25 °C without salts. A simplified route to copper nanoparticles (CuNPs) relies on CuC, lithium metal, and catalytic amounts of 4,4 -di-t-butylbiphenyl (DTBB) in THF at ambient temperatures.They exist as a range of nanospheres mainly between 1 and 6 nm, as analyzed by transmission electron microscopy (TEM). Terminal alkynes and a variety of azides can be cyclized in THF (88-98% isolated yields) between room and refluxing temperatures. Cycloadditions take place within 10-30 minutes, and simple filtration suffices to remove the catalyst. Recycling of CuNPs, however, is not an option. 

Fig. 3 Unnatural base pairs for enzymatic site-specific labeling of oligonucleotides using click chemistry, a DNA labeling using the unnatural d5SlCS-dNaM base pair [120]. PCR amplification was carried out with an alkyne-modified dfiSICS nucleoside that can be reacted with azide containing compounds, b RNA labeling via T7 in vitro transcription. The functionalized unnatural triphosphate is site-specifically incorporated into an RNA transcript in an in vitro transcription reaction and post-transcriptionally labeled via click chemistry. Triphosphates of the depicted unnatural bases for copper-catalyzed (Eth-C4-Pa [135]) and copper-free click reactions (N3-Pa [152] and Nor-UB [144]) have been developed...

A drawback of the copper(l)-catalyzed variant of this reaction is the presence of the transition metal, which is potentially toxic for hving cells. Therefore, ring-strained cyclooctyne derivatives have been introduced as substrates for the azide-alkyne cycloaddition whose reaction with the azide does not require a transition metal catalyst (Figure 16). The driving force of the corresponding copper-free click reaction stems for the release of ring strain associated with the conversion of the cyclooctyne s triple bond into a double bond. Fluorine substituents make the system even more reactive. ... 

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. 

Cu(0) catalyzes Click reactions indirectly via the formation of Cu(l) by compropor-tionation of Cu(II) and Cu(0). The essential Cu(ll) species can be added in the form of copper salts, but it is not mandatory due to the presence of traces of copper oxides and carbonates on the metal surface. Although this method benefits from very low copper contamination, high selectivity and the isolation of pure triazoles in high yields, the Cu(0)-catalyzed Click reaction is disadvantageous because of prolonged reaction times. 

One of the most prominent metal centred reactions of organoazides is the copper catalyzed click triazole synthesis.In a detailed computational study, Straub was able to elucidate the mechanism of this reaction dicopper(I) jU-acetylide complexes were identified as the central intermediates. ... 

In the first part of this review article, we have surveyed the click chemistry-based approaches to purely organic rotaxanes and discussed a few particularly efficient syntheses. Not too surprisingly, the copper(I)-catalyzed click reaction does not seem to be affected by the threaded nature of the precursors. In fact, since there is no interference between copper(I) and the functional groups borne by the organic fragments of the rotaxane precursor, rotaxane synthesis works as efficiently as classical click reactions with non-threaded precursors. 

SCHEME 25 Heterogeneous copper catalysts supported on chelate resins catalyzing Click reaction. 

A bis-cyclopeptide covalent capsule 154 for selective binding of sulfate dianion has been prepared in [116] using copper(I)-catalyzed click reaction-cycloaddition of the corresponding azide to alkyne ligand syntones by Scheme 2.103 and characterized using NMR and X-ray diffraction data. Thermodynamics and kinetics of the encapsulation reaction for this guest have been studied by ITC and temperature-depended H- H NOESY NMR methods, respectively. 

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. 

Azides react with Fischer alkynyl carbene complexes via copper-catalyzed or copper-free [3+2] cycloaddition ( click reaction) [19]. The copper-free click reaction... 

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