Experimental Evidence for the Involvement of Dinuclear Alkynylcopper(I) Complexes in Alkyne–Azide Chemistry

Dinuclear alkynylcopper(I) ladderane complexes are prepared by a robust and simple protocol involving the reduction of Cu₂(OH)₃OAc or Cu(OAc)₂ by easily oxidised alcohols in the presence of terminal alkynes; they function as efficient catalysts in copper‐catalysed alkyne–azide cycloaddition reactions as predicted by the Ahlquist–Fokin calculations. The same copper(I) catalysts are formed during reactions by using the Sharpless–Fokin protocol. The experimental results also provide evidence that sodium ascorbate functions as a base to deprotonate terminal alkynes and additionally give a convincing alternative explanation for the fact that the Cu^I‐catalysed reactions of certain 1,3‐diazides with phenylacetylene give bis(triazoles) as the major products. The same dinuclear alkynylcopper(I) complexes also function as catalysts in cycloaddition reactions of azides with 1‐iodoalkynes.     

Key Non‐Metal Ingredients for Cu‐catalyzed “Click” Reactions in Glycerol: Nanoparticles as Efficient Forwarders

The effect of long‐alkyl‐chain amines in CuI‐assisted azide–alkyne cycloadditions of terminal alkynes with organic azides in glycerol and other environmentally benign solvents (water, ethanol) has been examined. The presence of these additives favors the in situ formation of Cu^I‐based nanoparticles and results in an increase of the catalytic reactivity. In glycerol, liquid‐phase transmission electron microscopy (TEM) analyses, enabled by the negligible vapor pressure of this solvent, proved that Cu^I nanoparticles are responsible for the observed catalytic activity. The wide variety of alkynes and azides of which this effect has been investigated (14 combinations) confirms the role played by these additives in Cu‐catalyzed Huisgen cycloadditions.     

A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

Efficient Cu(I) acetate‐catalyzed cycloaddition of multifunctional alkynes and azides: From solution to bulk polymerization

“Click” chemistry is an effective and commonly used technique in polymer chemistry for the synthesis and modification of polymers. In this study, the bulk polymerization of multifunctional alkynes and azides was achieved by the copper(I)‐catalyzed alkyne–azide 1,3‐dipolar cycloaddition. The influence of different catalyst systems on the polymerization kinetics of the “click”reaction were evaluated by differential scanning calorimetry. Surprisingly, Cu(I) acetate showed the most efficient catalytic behavior among the applied Cu(I) salts. The polymerization kinetics in solution were investigated by 1H NMR spectroscopy and size exclusion chromatography. According to the 1H NMR investigation the copper(I)‐catalyzed cycloaddition follows a second‐order kinetics with external catalysis. Additionally, the mechanical properties of the resulting polymers were investigated by depth sensing indentation. Thereby the polymerizations of the alkyne tripropargylamine with the azides 1,3‐bis(azidomethyl)benzene and 1,4‐bis(azidomethyl)benzene resulted in mechanical hard materials. Furthermore, the combination of the alkynes tripropargylamine and di(prop‐2‐yn‐1‐yl) isophorone dicarbamate and polymerization with 1,2‐bis(2‐azidoethoxy)ethane resulted in high indentation moduli. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 239–247     

Triazolyl‐Based Molecular Gels as Ligands for Autocatalytic ‘Click’ Reactions

The catalytic performance of triazolyl‐based molecular gels was investigated in the Huisgen 1,3‐dipolar cycloaddition of alkynes and azides. Low‐molecular‐weight gelators derived from l ‐valine were synthesized and functionalized with a triazole fragment. The resultant compounds formed gels either with or without copper, in a variety of solvents of different polarity. The gelators coordinated Cu^I and exhibited a high catalytic activity in the gel phase for the model reaction between phenylacetylene and benzylazide. Additionally, the gels were able to participate in autocatalytic synthesis and the influence of small structural changes on their performance was observed.     

The “Click” Reaction Involving Metal Azides,Metal Alkynes,or Both: An Exploration into Multimetal Structures

Cu^I‐catalyzed 1,3‐cycloaddition of azides and alkynes (CuAAC) is one of the most powerful synthetic methodologies known. However, its use to prepare well‐defined multimetallic structures is underdeveloped. Apart from the applications of this reaction to anchor different organometallic reagents to surfaces, polymers, and dendrimers, only isolated examples of CuAAC with metal–η¹‐alkyne and metal–azide complexes to prepare multimetal entities have been reported. This concept sketches the potential of these reactions not only to prepare “a la carte” multimetal 1,2,3‐triazole derivatives, but also to discover new and unprecedented reactions.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

NHC copper complexes functionalized with sulfoxide and sulfone moieties

A series of N‐heterocyclic copper carbene complexes bearing sulfoxide and sulfone moieties have been prepared. In case of new copper compounds with sulfone ligand, the solid‐state structures were determined using X‐Ray crystallography. Obtained complexes were investigated as catalysts in such transformations as: 1,3‐dipolar cycloaddition of alkynes and azides (CuAAC), A³ coupling reaction and β‐hydroboration and compared with standard copper catalytic systems.     

Doped Nano‐Sized Copper(I) Oxide (Cu2O) on Melamine?Formaldehyde Resin: a Highly Efficient Heterogeneous Nano Catalyst for ‘Click’ Synthesis of Some Novel 1H‐1,2,3‐Triazole Derivatives Having Antibacterial Activity

A facile and simple protocol for the 1,3‐dipolar cycloaddition of organic azides with terminal alkynes catalyzed by doped nano‐sized Cu₂O on melamine? formaldehyde resin (nano‐Cu₂O? MFR) as a new and convenient heterogeneous catalyst is described. In this method, ‘click’ cycloaddition of various structurally diverse β‐azido alcohols and alkynes in the presence of nano‐Cu₂O? MFR in H₂O/THF 1 : 2 furnished the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazole adducts 1a – 1o in good to excellent yields at room temperature (Scheme and Table 3). The nano‐Cu₂O? MFR was characterized by scanning electron microscopy (SEM), X‐ray diffraction (XRD), inductively coupled plasma (ICP) analysis, and FT‐IR. The nano‐Cu₂O? MFR could be easily recovered and recycled from the reaction mixture and reused for many consecutive trials without significant decrease in activity (Table 4). The in vitro antibacterial activities of all synthesized compounds were tested on several Gram‐positive and/or Gram‐negative bacteria (Table 5). The results demonstrate the promising antibacterial activity for some of the synthesized compounds.     

Following the Azide‐Alkyne Cycloaddition at the Silica/Solvent Interface with Sum Frequency Generation

The Cu^I‐catalyzed 1,3‐dipolar azide‐alkyne cycloaddition (CuAAC) has arisen as one of the most useful chemical transformations for introducing complexity onto surfaces and materials owing to its functional‐group tolerance and high yield. However, methods for monitoring such reactions in situ at the widely used silica/solvent interface are hampered by challenges associated with probing such buried interfaces. Using the surface‐specific technique broadband sum frequency generation (SFG), we monitored the reaction of a benzyl azide monolayer in real time at the silica/methanol interface. A strong peak at 2096 cm^?1 assigned to the azides was observed for the first time by SFG. Using a cyano‐substituted alkyne, the decrease of the azide peak and the increase of the cyano peak (2234 cm^?1) were probed simultaneously. From the kinetic analysis, the reaction order with respect to copper was determined to be 2.1, suggesting that CuAAC on the surface follows a similar mechanism as in solution.     

Deactivation of Cu‐Exchanged Automotive‐Emission NH3‐SCR Catalysts Elucidated with Nanoscale Resolution Using Scanning Transmission X‐ray Microscopy

To gain insight into the underlying mechanisms of catalyst durability for the selective catalytic reduction (SCR) of NO_x with an ammonia reductant, we employed scanning transmission X‐ray microscopy (STXM) to study Cu‐exchanged zeolites with the CHA and MFI framework structures before and after simulated 135 000‐mile aging. X‐ray absorption near‐edge structure (XANES) measurements were performed at the Al K‐ and Cu L‐edges. The local environment of framework Al, the oxidation state of Cu, and geometric changes were analyzed, showing a multi‐factor‐induced catalytic deactivation. In Cu‐exchanged MFI, a transformation of Cu^II to Cu^I and Cu_xO_y was observed. We also found a spatial correlation between extra‐framework Al and deactivated Cu species near the surface of the zeolite as well as a weak positive correlation between the amount of Cu^I and tri‐coordinated Al. By inspecting both Al and Cu in fresh and aged Cu‐exchanged zeolites, we conclude that the importance of the preservation of isolated Cu^II sites trumps that of Brønsted acid sites for NH₃‐SCR activity.     

2,3,4,6‐Tetra‐O‐acetyl‐α‐d‐glucopyranosyl azide

The Cu^I‐catalysed 1,3‐dipolar cycloaddition of an azide and a terminal alkyne is becoming an increasingly popular tool for synthetic chemists. This is the most representative of the so‐called `click reactions' and it is used to generate 1,4‐disubstituted triazoles in high yield. During studies on such cycloaddition reactions, a reduced reactivity of an α‐glucosyl azide with respect to the corresponding β‐anomer was observed. With the aim of understanding this phenomenon, the structure of the title compound, C₁₄H₁₉N₃O₉, has been determined at 140 K. The glucopyranosyl ring appears in a regular ⁴C₁ chair conformation with all the substituents in equatorial positions, except for the anomeric azide group, which adopts an axial orientation. The observed bond lengths are consistent with a strong anomeric effect, which is reflected in a change in dipolar character and hence reduced reactivity of the α‐glucosyl azide.     

Cu‐Promoted Sydnone Cycloadditions of Alkynes: Scope and Mechanism Studies

Cu salts have been found to promote the cycloaddition reaction of sydnones and terminal alkynes, providing significant reduction in reaction times. Specifically, the use of Cu(OTf)₂ is found to provide 1,3‐disubstituted pyrazoles, whereas simply switching the promoter system to Cu(OAc)₂ allows the corresponding 1,4‐isomers to be produced. The mechanism of the Cu‐effect in each case has been investigated by experimental and theoretical studies, and they suggest that Cu(OTf)₂ functions by Lewis acid activation of the sydnone, whereas Cu(OAc)₂ promotes formation of reactive Cu^I acetylides.     

Tertiary Carbinamine Synthesis by Rhodium‐Catalyzed [3+2] Annulation of N‐Unsubstituted Aromatic Ketimines and Alkynes

A convenient and waste‐free synthesis of indene‐based tertiary carbinamines by rhodium‐catalyzed imine/alkyne [3+2] annulation is described. Under the optimized conditions of 0.5–2.5 mol % [{(cod)Rh(OH)}₂] (cod=1,5‐cyclooctadiene) catalyst, 1,3‐bis(diphenylphosphanyl)propane (DPPP) ligand, in toluene at 120 °C, N‐unsubstituted aromatic ketimines and internal alkynes were coupled in a 1:1 ratio to form tertiary 1H‐inden‐1‐amines in good yields and with high selectivities over isoquinoline products. A plausible catalytic cycle involves sequential imine‐directed aromatic C? H bond activation, alkyne insertion, and a rare example of intramolecular ketimine insertion into a Rh^I–alkenyl linkage.     

Copper Supported on the SiO2 Nanoparticle in Click Chemistry: An Alternative Catalytic System for Regioselective and One‐Pot Synthesis of 1,2,3‐Triazoles and β‐Hydroxytriazoles

In this work, readily prepared copper supported on the SiO₂ nanoparticles has been found to effectively catalyze the 1,3‐dipolar cycloaddition of a variety of azides, alkynes, epoxides and sodium azide, furnishing the corresponding 1,2,3‐triazoles and β‐hydroxytriazoles. Click reaction proceeds in short reaction times and under mild reaction conditions, and the resulting products are obtained in good yields at ambient temperature.     

5‐(1,2,3‐Triazol‐1‐yl)tetrazole Derivatives of an Azidotetrazole via Click Chemistry

N? C bonded (non‐bridged) 5‐(1,2,3‐triazol‐1‐yl)tetrazoles were synthesized by the Cu^I‐catalyzed 1,3‐dipolar azide–alkyne cycloaddition click reaction using 5‐azido‐N‐(propan‐2‐ylidene)‐1H‐tetrazole ( 1 ). For example, the click reaction of 1 in the presence of CuSO₄?5 H₂O and Na ascorbate at 65–70 °C for 48 h in CH₃CN/H₂O co‐solvent was found to be limited to only terminal alkynes that have electron‐withdrawing groups, CF₃C?CH ( 2 a ) and SF₅C?CH ( 2 b ), giving rise to isopropylidene‐[5‐(4‐trifluoromethyl‐1,2,3‐triazol‐1‐yl)tetrazol‐1‐yl]amine ( 3 a ) and isopropylidene‐[5‐(4‐pentafluorosulfanyl‐1,2,3‐triazol‐1‐yl)tetrazol‐1‐yl]amine ( 3 b ) in 47 % and 66 % yields, respectively. When carried out under conditions using CuI and 2,6‐lutidine as catalysts at 0 °C for 13 h in CHCl₃, the click reaction was versatile toward alkynes even those having electron‐donating groups. Properties of new products were determined and compared with those of 1 . Heats of formation, detonation pressures, detonation velocities and impact sensitivities are reported for these new 5‐(1,2,3‐triazol‐1‐yl)tetrazoles.     

One‐pot synthesis of precise polyisoxazoles by click polymerization: Copper (I)‐catalyzed 1,3‐dipolar cycloaddition of nitrile oxides with alkynes

This article reports a new one‐pot method for polymer preparation, which involves double click chemistry. In one pot, two click reactions take place sequentially by adding the reactants step by step. The first click reaction is to produce the monomer for the second click reaction for polymerization. The click polymerization differs from the general click polymerization with the reaction of diazides and dialkynes. Nitrile oxides, produced in situ by the first click reaction of the formation of aldoxime, instead azides, avoiding the poisonousness and explosiveness of azides and being much safer and easy to operate. And 3,5‐disubstitute polyisoxazoles are produced by the copper(I)‐catalyzed the 1,3‐dipolar cycloaddition of nitrile oxides with alkynes in high yields by our one‐pot method. The resulting polyisoxazoles agree well with the structural assignment obtained by the ¹H NMR and IR analyses, with high molecular weights, narrow molecular weight distribution (M_w/M_n < 1.2) and high regioregularity. The poor solubility of these polymers is found to be caused by their crystallization. Improvement of solubility is achieved by modifying the structures of alkyne monomers. All the polymers are thermally stable, losing little of their weights when heated to ～350 °C. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Alkenyl Arenes as Dipolarophiles in Catalytic Asymmetric 1,3‐Dipolar Cycloaddition Reactions of Azomethine Ylides

The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3‐dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a Cu^I or Ag^I catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4‐aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3‐dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.     

Synthesis of New Hybrid Heterocyclic Compounds Having 1,2,3‐Triazole and Isoxazole via Click Chemistry

A simple and highly efficient method for the regioselective synthesis of isoxazolyl‐1,4‐disubstituted‐1,2,3‐triazoles 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k , 6l in good to excellent yields from terminal alkynes having isoxazole scaffold 4a , 4b , 4c and various azides through Cu(I)‐catalyzed 1,3‐dipolar cycloaddition is described. The reaction proceeds smoothly in 1:1 mixture of t‐BuOH and water at RT. The structures of all newly synthesized hybrid heterocycles are established on the basis of spectral data ir, ¹H nmr, mass, and elemental analysis.     

Reaction of Alkynes and Azides: Not Triazoles Through Copper–Acetylides but Oxazoles Through Copper–Nitrene Intermediates

Well‐defined copper(I) complexes of composition [Tpm*^,BrCu(NCMe)]BF₄ (Tpm*^,Br=tris(3,5‐dimethyl‐4‐bromo‐pyrazolyl)methane) or [Tpa^*Cu]PF₆ (Tpa^*=tris(3,5‐dimethyl‐pyrazolylmethyl)amine) catalyze the formation of 2,5‐disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5‐isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper–acyl nitrene species, in contrast to the well‐known mechanism for the copper‐catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper–acetylide complex.