Conditional Copper-Catalyzed Azide–Alkyne Cycloaddition by Catalyst Encapsulation

Supramolecular encapsulation is known to alter chemical properties of guest molecules. We have applied this strategy of molecular encapsulation to temporally control the catalytic activity of a stable copper(I)–carbene catalyst. Encapsulation of the copper(I)–carbene catalyst by the supramolecular host cucurbit[7]uril (CB[7]) resulted in the complete inactivation of a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The addition of a chemical signal achieved the near instantaneous activation of the catalyst, by releasing the catalyst from the inhibited CB[7] catalyst complex. To broaden the scope of our on-demand CuAAC reaction, we demonstrated the protein labeling of vinculin with the copper(I)–carbene catalyst, to inhibit its activity by encapsulation with CB[7] and to initiate labeling at any moment by adding a specific signal molecule. Ultimately, this strategy allows for temporal control over copper-catalyzed click chemistry, on small molecules as well as protein targets.     

A Mechanochemically Triggered “Click” Catalyst

“Click” chemistry represents one of the most powerful approaches for linking molecules in chemistry and materials science. Triggering this reaction by mechanical force would enable site‐ and stress‐specific “click” reactions—a hitherto unreported observation. We introduce the design and realization of a homogeneous Cu catalyst able to activate through mechanical force when attached to suitable polymer chains, acting as a lever to transmit the force to the central catalytic system. Activation of the subsequent copper‐catalyzed “click” reaction (CuAAC) is achieved either by ultrasonication or mechanical pressing of a polymeric material, using a fluorogenic dye to detect the activation of the catalyst. Based on an N‐heterocyclic copper(I) carbene with attached polymeric chains of different flexibility, the force is transmitted to the central catalyst, thereby activating a CuAAC in solution and in the solid state.     

Copper‐Chelating Azides for Efficient Click Conjugation Reactions in Complex Media

The concept of chelation‐assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)‐catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper‐chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.     

Copper Catalysis in Living Systems and In Situ Drug Synthesis

The copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction has proven to be a pivotal advance in chemical ligation strategies with applications ranging from polymer fabrication to bioconjugation. However, application in vivo has been limited by the inherent toxicity of the copper catalyst. Herein, we report the application of heterogeneous copper catalysts in azide–alkyne cycloaddition processes in biological systems ranging from cells to zebrafish, with reactions spanning from fluorophore activation to the first reported in situ generation of a triazole‐containing anticancer agent from two benign components, opening up many new avenues of exploration for CuAAC chemistry.     

On the Mechanism of Copper(I)‐Catalyzed Azide–Alkyne Cycloaddition

The copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4‐disubstituted‐1,2,3‐triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring‐formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pK_a values and an inclination to engage in π‐backbonding with copper(I), azides with ancillary copper‐binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne‐involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.     

Sunlight‐Driven Copper‐Catalyst Activation Applied to Photolatent Click Chemistry

The synthesis, full characterization, photoreduction properties, and catalytic activity for the copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction of a copper(II)–DMEDA (N,N′‐dimethylethylendiamine) complex is reported. Spectroscopic studies (UV/Vis, EPR) demonstrated that under daylight illumination highly effective copper(II) to copper(I) reduction occurs in this complex. These findings are in agreement with a high photoreduction quantum yield value of 0.22 in MeOH, and a value approaching unity as determined in THF. The reduction process, which can also be conducted by irradiation at 365 nm by using a standard TLC (thin layer chromatography) lamp, is ascribed to a highly efficient photoinduced electron transfer (PET) process mediated by the benzophenone photosensitizer present in the carboxylate counterion. Having deaerated the reaction mixture, the photogenerated copper(I) species proved to be highly active for the CuAAC reaction, demonstrated by reactions conducted with low catalyst loading (0.5 mol %) on a range of clickable protected and non‐protected mono‐ and disaccharides. Once initiated, the reaction can be stopped at any time on introducing air into the reaction medium. Deoxygenation followed by irradiation restores the activity, making the copper(II)–DMEDA complex a switchable catalyst of practical value.     

A Biocompatible Heterogeneous MOF–Cu Catalyst for In Vivo Drug Synthesis in Targeted Subcellular Organelles

As a typical bioorthogonal reaction, the copper‐catalyzed azide–alkyne cycloaddition (CuAAC) has been used for drug design and synthesis. However, for localized drug synthesis, it is important to be able to determine where the CuAAC reaction occurs in living cells. In this study, we constructed a heterogeneous copper catalyst on a metal–organic framework that could preferentially accumulate in the mitochondria of living cells. Our system enabled the localized synthesis of drugs through a site‐specific CuAAC reaction in mitochondria with good biocompatibility. Importantly, the subcellular catalytic process for localized drug synthesis avoided the problems of the delivery and distribution of toxic molecules. In vivo tumor therapy experiments indicated that the localized synthesis of resveratrol‐derived drugs led to greater antitumor efficacy and minimized side effects usually associated with drug delivery and distribution.     

In‐situ Generated and Premade 1‐Copper(I) Alkynes in Cycloadditions

The copper(I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) was discovered in 2002, which has become the most remarkable example for “click chemistry” to date. In CuAAC reaction, 1‐copper(I) alkyne has been recognized to be a key intermediate. However, many contradictory experimental results for this intermediate were reported in literature. For example, only the in‐situ generated 1‐copper(I) alkyne was used, while the premade 1‐copper(I) alkyne proved to be inefficient under the standard conditions. The kinetic studies indicated that CuAAC reaction had a strict second‐order dependence on Cu(I) and the DFT studies demonstrated that 1‐copper(I) alkyne intermediate should be a dinuclear copper(I) complex. But these results were inconsistent with the structure of the premade 1‐copper(I) alkyne. Although hundreds of structurally different ligands were reported to significantly enhance the efficiency of CuAAC reaction, their functions were assigned to prevent the oxidation and the disproportionation of Cu(I) ion. Based on the investigation of the references and our works, we proposed that the in‐situ generated 1‐copper(I) alkyne in CuAAC reaction is not identical with the premade 1‐copper(I) alkyne. The ligands may play dual roles to activate the 1‐copper(I) alkyne by blocking the polymerization of the in‐situ formed 1‐copper(I) alkynes and dissociating the polymeric structures of the premade 1‐copper(I) alkynes. As a result, we first disclosed that carboxylic acids can function as such activators and a novel carboxylic acid‐catalyzed CuAAC strategy was developed, which has been proven to be the most convenient and highly efficient CuAAC method to date. Furthermore, highly efficient and regioselective methods for the syntheses of 1,4,5‐trisubstituted 1,2,3‐triazoles were developed by using the premade 1‐copper(I) alkynes as substrates, in which the novel function of the premade 1‐copper(I) alkynes as excellent dipolarophiles was first disclosed and applied. In this article, a series of works reported by our group for the in‐situ generated and the premade 1‐copper(I) alkynes in cycloadditions are reviewed.     

Star polymers by photoinduced copper‐catalyzed azide–alkyne cycloaddition click chemistry

Well‐defined star polymers consisting of tri‐, tetra‐, or octa‐arms have been prepared via coupling‐onto strategy using photoinduced copper(I)‐catalyzed 1,3‐dipolar cycloaddition click reaction. An azide end‐functionalized polystyrene and poly(methyl methacrylate), and an alkyne end‐functionalized poly(ε‐caprolactone) as the integrating arms of the star polymers are prepared by the combination of controlled polymerization and nucleophilic substitution reactions; whereas, multifunctional cores containing either azide or alkyne functionalities were synthesized in quantitatively via etherification and ring‐opening reactions. By using photoinduced copper‐catalyzed azide–alkyne cycloaddition (CuAAC) click reaction, reactive linear polymers are simply attached onto multifunctional cores to form corresponding star polymers via coupling‐onto methodology. The chromatographic, spectroscopic, and thermal analyses have clearly demonstrated that successful star formations can be obtained via photoinduced CuAAC click reaction. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1687–1695     

Copper‐Catalyzed Aminothiolation of 1,3‐Dienes via a Dihydrothiazine Intermediate

Heteroatom‐containing organic molecules are of particular interest to medicinal chemists and materials scientists. A strategy to reach these architectures via direct difunctionalization of abundant 1,3‐dienes is especially attractive. Herein, we describe the development of a regio‐ and diastereoselective 1,4‐aminothiolation of 1,3‐dienes with a sulfur diimide reagent, a copper catalyst, and alkyl Grignard reagents. This unique protocol provides remote nitrogen and sulfur functionalities with high levels of stereocontrol. The reaction proceeds via a tandem hetero‐Diels–Alder cycloaddition of N,N′‐bis(benzenesulfonyl)sulfur diimide with 1,3‐diene followed by copper‐catalyzed Grignard substitution. Mechanistic studies support a copper catalyzed formation of an unprecedented [10‐S‐4] sulfurane that reductively eliminates to afford a 3,6‐dihydrothiazine, which is selectively converted to 1,4‐aminothiols.     

Modulating catalytic activity of polymer‐based cuAAC “click” reactions

The copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction is used to synthesize complex polymer architectures. In this work, we demonstrate the control of this reaction at 25 °C between polystyrene (PSTY) chains through modulating the catalytic activity by varying the combinations of copper source (i.e., Cu(I)Br or copper wire), ligand (PMDETA and/or triazole ligand), and solvent (toluene or DMF). The fastest rate of CuAAC was found using Cu(I)Br/PMDETA ligand in toluene, reaching near full conversion after 15 min at 25 °C. For the same catalysts system, DMF also gave fast rates of “click” (95% conversion in 25 min). Cu(0) wire in toluene gave a conversion of 98% after 600 min, a much higher rate than that observed for the same catalyst system used in DMF. When the PSTY had a chemically bound triazole ring close to the site of reaction, the rate of CuAAC in toluene increased significantly, 97% in 180 min at 25 °C, in agreement with our previously published results. This suggests that rapid rates can be obtained using copper wire and will have direct applications to the synthesis of compound where air, removal of copper, and reuse of the copper catalyst are required. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

A Fluxional Copper Acetylide Cluster in CuAAC Catalysis

A molecularly defined copper acetylide cluster with ancillary N‐heterocyclic carbene (NHC) ligands was prepared under acidic reaction conditions. This cluster is the first molecular copper acetylide complex that features high activity in copper‐catalyzed azide–alkyne cycloadditions (CuAAC) with added acetic acid even at ?5 °C. Ethyl propiolate protonates the acetate ligands of the dinuclear precursor complex to release acetic acid and replaces one out of four ancillary ligands. Two copper(I) ions are thereby liberated to form the core of a yellow dicationic C₂‐symmetric hexa‐NHC octacopper hexaacetylide cluster. Coalescence phenomena in low‐temperature NMR experiments reveal fluxionality that leads to the facile interconversion of all of the NHC and acetylide positions. Kinetic investigations provide insight into the influence of copper acetylide coordination modes and the acetic acid on catalytic activity. The interdependence of “click” activity and copper acetylide aggregation beyond dinuclear intermediates adds a new dimension of complexity to our mechanistic understanding of the CuAAC reaction.     

A Highly Active and Magnetically Recoverable Tris(triazolyl)–CuI Catalyst for Alkyne–Azide Cycloaddition Reactions

Nanoparticle‐supported tris(triazolyl)–CuBr, with a diameter of approximately 25 nm measured by TEM spectroscopy, has been easily prepared, and its catalytic activity was evaluated in the copper‐catalyzed azide–alkyne cycloaddition (CuAAC) reaction. In initial experiments, 0.5 mol % loading successfully promoted the CuAAC reaction between benzyl azide and phenylacetylene, in water at room temperature (25 °C). During this process, the iron oxide nanoparticle‐supported tris(triazolyl)–CuBr displayed good monodispersity, excellent recoverability, and outstanding reusability. Indeed, it was simply collected and separated from the reaction medium by using an external magnet, then used for another five catalytic cycles without significant loss of catalytic activity. Inductively coupled plasma (ICP) analysis for the first cycle revealed that the amount of copper leached from the catalyst into the reaction medium is negligible (1.5 ppm). The substrate scope has been examined, and it was found that the procedure can be successfully extended to various organic azides and alkynes and can also be applied to the one‐pot synthesis of triazoles, through a cascade reaction involving benzyl bromides, alkynes, and sodium azide. In addition, the catalyst was shown to be an efficient CuAAC catalyst for the synthesis of allyl‐ and TEG‐ended (TEG=triethylene glycol) 27‐branch dendrimers.     

Sulfinate and Carbene Co‐catalyzed Rauhut–Currier Reaction for Enantioselective Access to Azepino[1,2‐a]indoles

A carbene and sulfinate co‐catalyzed intermolecular Rauhut–Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co‐catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst‐bound intermediates. The dual catalytic reaction affords azepino[1,2‐a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron‐deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions.     

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.     

A reusable polymer‐supported copper(I) catalyst for triazole click reaction on water: An experimental and computational study

In the search for establishing a clickable copper‐catalysed (3 + 2) Huisgen azide–alkyne cycloaddition (CuAAC) reaction under strict conditions, in particular in terms of preventing the presence of copper particles/traces in reaction products and using an environmentally benign medium such as water, we describe here the synthesis of an aminomethyl polystyrene‐supported copper(I) catalyst (Cu(I)‐AMPS) and its characterization by means of Fourier transform infrared and energy‐dispersive X‐ray spectroscopies and scanning electron microscopy. Cu(I)‐AMPS was found to be highly active in the CuAAC reaction of various organic azides with alkynes affording the corresponding 1,4‐disubstituted 1,2,3‐triazoles in a regioselective manner in air at room temperature and using water as solvent. The insolubility and/or partial solubility of the organic azide and alkyne precursors as well as the heterogeneous Cu(I)‐AMPS catalytic system points to the occurrence of the cycloaddition at the organic–water interface ‘on water’ affording quantitative yields of water‐insoluble 1,2,3‐triazoles. A mechanistic study was performed using density functional theory aiming at explaining the observed reactivity and selectivity of the Cu (I)‐AMPS catalyst in CuAAC reactions.     

Kinetics of bulk azide/alkyne “click” polymerization

A bulk step‐growth polymerization of multifunctional azides and alkynes through the copper (I)‐catalyzed azide‐alkyne cycloaddition (CuAAC) reaction is described. The polymerization kinetics of two systems containing different diynes, bisphenol E diyne (BE‐diyne)/bisphenol A bisazide (BA‐bisazide) and tetraethylene glycol diyne (TeEG‐diyne)/BA‐bisazide, are evaluated by differential scanning calorimetry (DSC), shear rheology, and thermogravimetric analysis. The effects of catalyst concentration on reaction kinetics are investigated in detail, as are the thermal properties (glass transition and decomposition temperatures) of the formed polymers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 4093–4102, 2010     

Dirhodium(II)‐Catalyzed Annulation of Enoldiazoacetamides with α‐Diazoketones: An Efficient and Highly Selective Approach to Fused and Bridged Ring Systems

A dirhodium(II)‐catalyzed annulation reaction between two structurally different diazocarbonyl compounds furnishes the donor–acceptor cyclopropane‐fused benzoxa[3.2.1]octane scaffold with excellent chemo‐, regio‐, and diastereoselectivity under exceptionally mild conditions. The composite transformation occurs by [3+2]‐cycloaddition between donor–acceptor cyclopropenes generated from enoldiazoacetamides and carbonyl ylides formed from intramolecular carbene–carbonyl cyclization in one pot with one catalyst. The annulation products can be readily transformed into benzoxa[3.3.1]nonane and hexahydronaphthofuran derivatives with exact stereocontrol. This method allows the efficient construction of three fused and bridged ring systems, all of which are important skeletons of numerous biologically active natural products.     

Supramolecular Host‐Inhibited Excited‐State Proton Transfer and Fluorescence Switching of the Anti‐Cancer Drug,Topotecan

The effect of cucurbit[7]uril (CB[7]) nano‐caging on the photophysical properties, particularly excited‐state proton transfer (ESPT) reaction, of an eminent anti‐cancer drug, topotecan (TPT), is demonstrated through steady‐state and time‐resolved fluorescence measurements. TPT in water (pH 6) exists exclusively as the cationic form (C) in the ground state. However, the drug emission mainly comes from the excited‐state zwitterionic form (Z*) of TPT, and is attributed to water‐assisted ESPT between the 10‐hydroxyl group and water, which leads to the transformation of C* to Z* of TPT. In the presence of CB[7], it is found that selective encapsulation of the C form of TPT results in the formation of a 1:1 inclusion complex (CB[7]:TPT), and the ESPT process is inhibited by this encapsulation process. As a result, C* becomes the dominant emitting species in the presence of CB[7] rather than Z*, and fluorescence switching takes place from green to blue. Time‐resolved studies also support the existence of CB[7]‐encapsulated cationic species as the major emitting species in the presence of the macrocyclic host. Semi‐empirical quantum chemical calculations are employed to gain insight into the molecular picture of orientation of TPT in the inclusion complex. It is clearly seen from the optimised structure of 1:1 CB[7]:TPT inclusion complex that both 10‐hydroxyl and 9‐dimethylaminomethylene groups of TPT lie partly inside the cavity, and thereby inhibit the excited‐state transformation of C* to Z* by the ESPT process. Finally, controlled release of the drug is achieved by means of fluorescence switching by introducing NaCl, which is rich in cells, as an external stimulus.     

Synthesis of Lanthanide(III) Chelates by Using ‘Click’ Chemistry

The copper(I)‐catalyzed dipolar [2+3] cycloaddition reaction of an azide and a terminal alkyne is exploited in the preparation of various europium(III), terbium(III), and dysprosium(III) chelates (Schemes 1–3). By changing the nature of the alkyne and the azide, a wide range of chelates and biomolecule‐labeling reactants were obtained. The photophysical properties (Table) of the synthesized chelates are also discussed.