Alkyne Cycloaddition Reaction Research Articles

Copper(I)–N-Heterocyclic Carbene Complexes as Efficient Catalysts for the Synthesis of 1,4-Disubstituted 1,2,3-Sulfonyltriazoles in Air

Bis-NHC and mixed NHC/PR3 copper(I) complexes (NHC = N-heterocyclic carbene) were found to be efficient catalysts enabling the azide–alkyne cycloaddition reaction leading to the formation of 1,2,3-sulfonyltriazoles under Click conditions. The mechanism of this transformation was probed and decoordination of the NHC ligand (even in the NHC/PR3 mixed ligand systems) during the catalytic transformation was observed.

Toward Orthogonal Preparation of Sequence-Defined Monodisperse Heteromultivalent Glycomacromolecules on Solid Support Using Staudinger Ligation and Copper-Catalyzed Click Reactions

The investigation of heteromultivalent interactions of complex glycoligands and proteins is critical for understanding important biological processes and developing carbohydrate-based pharmaceutics. Synthetic glycomimetics, derived by mimicking complex glycoligands on a variety of scaffolds, have become important tools for studying the role of carbohydrates in chemistry and biology. In this paper, we report on a new synthetic strategy for the preparation of monodisperse, sequence-defined glycooligomers or so-called precision glycomacromolecules based on solid phase oligomer synthesis and the Staudinger ligation. This strategy employs a solid-supported synthetic approach using a novel carboxy-functionalized building block which bears a functional handle required for Staudinger ligation on solid support. Furthermore, we combined Staudinger ligation and copper catalyzed azide alkyne cycloaddition (CuAAC) reactions to synthesize heteromultivalent glycooligomers on solid support for the first time, demonstrating the utility of this approach for the synthesis of heterofunctional glycomacromolecules.

Azide-alkyne cycloaddition en route to 4-aminoquinoline-ferrocenylchalcone conjugates: synthesis and anti-TB evaluation.

Tuberculosis is responsible for 9.6million infections and 1.5million deaths in 2015. The development of multidrug-resistant and extensively drug-resistant strains has impeded the development of effective antitubercular therapy. Results/methodology: The present manuscript describes the synthesis of a series of 4-aminoquinoline-ferrocenylchalcone conjugates via Cu-promoted Huisgen's azide-alkyne cycloaddition reaction and evaluation of their antitubercular activities against mc26230 strain of Mycobacterium tuberculosis. The conjugate 11j proved to be the most potent of the synthesized conjugates with a minimum inhibitory concentration (MIC99) value of 30μM and proved to be noncytotoxic against HeLa cells. The synthesized conjugates can act as starting point for the development of new antitubercular agents. Synthesis and antitubercular evaluation of 1H-1,2,3-triazole-tethered 4-aminoquinoline-ferrocenylchalcone conjugates. [Formula: see text].

“Onion peel” glycodendrimer syntheses using mixed triazine and cyclotriphosphazene scaffolds

An expeditious synthetic protocol for the construction of glycodendrimers is illustrated using the newly discovered “onion peel” strategy. The onion peel approach and orthogonal coupling strategies were accomplished with rationally design sequential modifications of cyanuric acid. Carefully chosen building blocks and their effective attachment by chemoselective atom economical click reactions, namely Cu (I) azide–alkyne cycloaddition reaction (CuAAC) and photocatalyzed thiol-ene reaction (TEC), allowed rapid build-up of glycodendrimers in contrast to traditional dendrimers syntheses that are based on the repetitive use of identical building blocks to form each layer. The newly formed glycodendrimers were evaluated for their capacity to cross-link carbohydrate-lectin interactions using dynamic light scattering (DLS). Rapid increase in particle size was observed as a function of time when compared to their monomer counterparts resulting from the multivalent lectin cross-linking ability of the new glycodendrimers.

Dual roles of substituted thiourea as reductant and ligand in CuAAC reaction

A highly efficient catalytic system, CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea, for the copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC) was discovered. In the above catalytic system, substituted thiourea acts both as a reductant and a ligand. CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea is both an economical and efficient catalyst for the CuAAC reaction. In addition, the new catalytic system has advantageous features including mild and green reaction conditions, and broad substrate compatibility. A variety of 1,4-disubstituted 1,2,3-triazoles have been prepared with good to excellent yields with the CuSO4·5H2O/1-(4-methoxyphenyl)-3-phenylthiourea catalytic system in aqueous solution.

Et2NH‐Mediated 1,3‐Dipolar Cycloaddition: Synthesis of 1‐(2‐(Organylselanyl)pyridin‐3‐yl)‐1H‐1,2,3‐triazole‐4‐carboxylate Derivatives

AbstractThe use of Et2NH as organocatalyst for 1,3‐dipolar cycloadditions of 3‐azido‐2‐organylselanyl‐pyridines with 1,3‐dicarbonyl compounds is reported in this work. Reactions were conducted using DMSO as solvent at room temperature in air. All products were obtained in good to excellent yields. The reaction took place under very mild conditions and tolerated a range of functionalities. 1‐(2‐(Phenylselanyl)pyridin‐3‐yl)‐1H‐1,2,3‐triazole‐4‐carboxylate containing an alkyne substituent was selected as candidate for a Cu‐catalyzed azide alkyne cycloaddition reaction, affording the bis‐triazole in good yields.

Self-Accelerating Click Reaction in Step Polymerization

A self-accelerating double-strain-promoted azide–alkyne cycloaddition reaction (DSPAAC) was used in the step polymerization for the first time. This produced a novel stoichiometric imbalance-promoted homogeneous step polymerization method using sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DIBOD) and various bis-azide compounds (N3-R-N3) as respective monomers. Because of the self-accelerating property of DSPAAC reaction, the novel step polymerization method could prepare high molecular weight polymers under stoichiometry imbalance condition with excess molar amounts of DIBOD to N3-R-N3. Based on the click property of DSPAAC reaction, the novel step polymerization could be efficiently performed in very mild reaction conditions such as in air at room temperature without requiring any metal catalyst or chemical stimulus. Under the present polymerization condition, the preparation of high molecular weight polymers from this novel method was accompanied by the formation of cyclic oligomers with a weight content a...

An efficient (NHC) Copper (I)-catalyst for azide–alkyne cycloaddition reactions for the synthesis of 1,2,3-trisubstituted triazoles: Click chemistry

In this study a series of new benzimidazolium salts (2a–c) were synthesized from the reaction of 5,6-dimethyl-1-(alkylbenzyl)-1H-benzo[d]imidazole with various alkyl halides. These salts were used to synthesize cupper N-heterocyclic carbene (Cu-NHC) complexes 3–4. The obtained (NHC) Copper (I) complexes 3–4 were characterized by FT-IR, NMR (1H and 13C) spectroscopic methods, mass spectrometry (EI-MS and HRMS) and elemental analysis. These novel cupper complexes 3–4 were used as a catalyst for alkyne – azide cycloaddition (CuAAC) reaction. Several triazoles 7 have been synthesized. This catalytic system fulfils the requirements of “click chemistry” with its mild and convenient conditions, notably in water at room temperature with low catalyst loading and simple isolation with no purification step.

Claycop/hydrazine: A new and highly efficient recyclable/reusable catalytic system for 1,4‐disubstituted‐1,2,3‐triazole synthesis under solvent‐free conditions

Clay‐supported copper(II) nitrate (claycop) has been used as an efficient catalyst for azide–alkyne cycloaddition reactions leading to 1,4‐disubstituted 1,2,3‐triazoles. The highly efficient claycop/hydrazine hydrate catalytic system affords triazoles in a few minutes (1–20 min) at room temperature, under mild and solvent‐free conditions. High regioselectivity, excellent yields, ease of claycop synthesis and recyclability/reusability of the catalyst are considered as practical merits of the protocol.

Two new copper(II) complexes with chelating N,O-type bidentate ligands: Synthesis, characterization, crystal structure and catalytic activity in azide–alkyne cycloaddition reaction

Tetra-coordinated copper(II) complexes, [CuL2] and [Cu(phox)2], were synthesized by reaction of 1-((4-bromophenylimino)methyl)naphthalen-2-ol, HL, and 2-(2′-hydroxyphenyl)-2-oxazoline, Hphox, ligands with copper acetate, respectively. The complexes were characterized using FT-IR spectroscopy, elemental analyses, and their solid state structures were confirmed by single crystal X-ray diffraction. The catalytic activity of the complexes was evaluated in one-pot azide–alkyne cycloaddition (AAC) click reaction in water without need of any additional agent. The [CuL2] complex showed high catalytic activity in this reaction‌‌‌ and 1,2,3-triazole derivatives were produced in moderate to good yields.

Synthesis of RNA 5'-Azides from 2'-O-Pivaloyloxymethyl-Protected RNAs and Their Reactivity in Azide-Alkyne Cycloaddition Reactions.

Commercially available 2'-O-pivaloyloxymethyl (PivOM) phosphoramidites were employed in an SPS protocol for RNA 5' azides. The utility of the N3-RNAs in CuAAC and SPAAC was demonstrated by RNA 5' labeling, chemical ligation including fragment joining and cyclization, and bioconjugation. As a result, several new RNA conjugates that may be valuable tools for studies on biological events such as innate immune response (cyclic dinucleotides), post-transcriptional gene regulation (circular RNAs), or mRNA turnover (m7G capped RNAs) were obtained.

Copper-Catalyzed Sulfonyl Azide-Alkyne Cycloaddition Reactions: Simultaneous Generation and Trapping of Copper-Triazoles and -Ketenimines for the Synthesis of Triazolopyrimidines.

First simultaneous generation and utilization of both copper-triazole and -ketenimine intermediates in copper-catalyzed sulfonyl azide-alkyne cycloaddition reactions is achieved for the one-pot synthesis of triazolopyrimidines via a novel copper-catalyzed multicomponent cascade of sulfonyl azides, alkynes, and azirines. Significantly, the reaction proceeds under very mild conditions in good yields.

Synthesis, characterization, and pharmacological studies of ferrocene-1H-1,2,3-triazole hybrids

A series of ferrocene-1H-1,2,3-triazole hybrids namely 1-(4-nitrophenyl)-4-ferrocenyl-1H-1,2,3-triazole (1), 1-(4,4′-dinitro-2-biphenyl)-4-ferrocenyl-1H-1,2,3-triazole (2), 1-(3-chloro-4-fluorophenyl)-4-ferrocenyl-1H-1,2,3-triazole (3), 1-(4-bromophenyl)-4-ferrocenyl-1H-1,2,3-triazole (4) and 1-(2-nitrophenyl)-4-ferrocenyl-1H-1,2,3-triazole (5) were designed and synthesized by copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction. All the new hybrids were characterized by microanalyses, NMR (1H and 13C), UV–vis, IR, ESI-MS and electrochemical techniques. Crystal structure of the compound (3) was solved by single crystal X-ray diffraction method. The structural (single crystal) and spectroscopic (UV–Vis. and IR) properties of the compound 3 have been analyzed and compared by complementary quantum modeling. Hybrids 1–5 exhibited low toxicity and demonstrated neuroprotective effect.

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks.

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide–alkene building blocks coupled through copper catalyzed azide–alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

Study of the Hetero-[4+2]-Cycloaddition Reaction of Aldimines and Alkynes. Synthesis of 1,5-Naphthyridine and Isoindolone Derivatives.

Both experimental and computational studies for the cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes where 1,5-naphthyridines are obtained are reported. The reaction of benzaldimine with a methoxycarbonyl group in position 2 with phenyl acetylene, styrene, and indene afforded polycyclic isoindolone derivatives. The mechanism of reaction of N-(3-pyridyl)aldimines with olefins can be explained by an asynchronous [4+2] cycloaddition; in the case of acetylenes, the obtained results suggest a stepwise mechanism through a 3-azatriene.

Glycotriazole-peptides derived from the peptide HSP1: synergistic effect of triazole and saccharide rings on the antifungal activity.

This work proposes a strategy that uses solid-phase peptide synthesis associated with copper(I)-catalyzed azide alkyne cycloaddition reaction to promote the glycosylation of an antimicrobial peptide (HSP1) containing a carboxyamidated C-terminus (HSP1-NH2). Two glycotriazole-peptides, namely [p-Glc-trz-G1]HSP1-NH2 and [p-GlcNAc-trz-G1]HSP1-NH2, were prepared using per-O-acetylated azide derivatives of glucose and N-acetylglucosamine in the presence of copper(II) sulfate pentahydrate (CuSO4·5H2O) and sodium ascorbate as a reducing agent. In order to investigate the synergistic action of the carbohydrate motif linked to the triazole-peptide structure, a triazole derivative [trz-G1]HSP1-NH2 was also prepared. A set of biophysical approaches such as DLS, Zeta Potential, SPR and carboxyfluorescein leakage from phospholipid vesicles confirmed higher membrane disruption and lytic activities as well as stronger peptide-LUVs interactions for the glycotriazole-peptides when compared to HSP1-NH2 and to its triazole derivative, which is in accordance with the performed biological assays: whereas HSP1-NH2 presents relatively low and [trz-G1]HSP1-NH2 just moderate fungicidal activity, the glycotriazole-peptides are significantly more effective antifungal agents. In addition, the glycotriazole-peptides and the triazole derivative present strong inhibition effects on ergosterol biosynthesis in Candida albicans, when compared to HSP1-NH2 alone. In conclusion, the increased fungicidal activity of the glycotriazole-peptides seems to be the result of (A) more pronounced membrane-disruptive properties, which is related to the presence of a saccharide ring, together with (B) the inhibition of ergosterol biosynthesis, which seems to be related to the presence of both the monosaccharide and the triazole rings.

Immobilized polytriazole complexes of copper(I) onto graphene oxide as a recyclable nanocatalyst for synthesis of triazoles

An efficient solid‐supported catalyst for the Huisgen [3 + 2] cycloaddition reaction between azides and alkynes was prepared from copper(I) iodide and 1,2,3‐triazole‐functionalized graphene oxide. This catalyst was then used for the efficient synthesis of β‐hydroxy‐1,2,3‐triazoles giving access to these products in excellent yields. In this protocol, the catalyst was shown to have high activity, air‐stability and recyclability. The formation of copper triazolide is very straightforward and energetically desirable. The catalyst can be isolated from copper‐catalysed azide–alkyne cycloaddition reactions.

Electrochemical Imaging of Copper Contamination on Self-Assembled Organic Monolayer Modified Silicon Surfaces Following a ‘Click’ Reaction with Light-Addressable Potentiometric Sensors and Scanning Photo-Induced Impedance Microscopy

Light-addressable potentiometric sensors (LAPS)1 and scanning photo-induced impedance microscopy (SPIM)2, both of which are based on photocurrent measurements at electrolyte /insulator /semiconductor (EIS) field-effect structures can be used to detect local surface electrical potentials and impedance, respectively. While LAPS measures local potential changes by recording the shift of the photocurrent-voltage (I-V) curve along the voltage axis, SPIM records changes in the maximum photocurrent while the EIS structure is biased towards inversion. Both techniques have been extensively applied for chemical ion sensing, biosensing, and the investigation of cell metabolism, extracellular potentials, cell surface charge and impedance. Importantly, they have been reported to be highly sensitive to the surface contamination on self-assembled organic monolayers3. In this work, a copper (I) catalyzed azide alkyne cycloaddition (CuAAC) reaction, combined with microcontact printing was employed successfully to pattern alkyne-terminated self-assembled organic monolayer modified silicon surfaces (Figure 1a). Despite the absence of a copper peak in XPS spectra, copper contamination was found and visualized using LAPS and SPIM, after the ‘click’ modified silicon surfaces were rinsed with hydrochloric acid solution (Figure 1b), which has been frequently used to remove copper residues in the past. Different strategies for avoiding copper contamination, including the use of bulky chelators for the copper (I) catalyst and rinsing with different reagents, were tested. Only cleaning of the silicon surfaces with an ethylenediaminetetraacetic acid (EDTA) solution after the ‘click’ modification proved to be an effective method as confirmed by LAPS and SPIM results, which showed the desirable electrical properties (surface charge and impedance) of an organic monolayer (Figure 1c). 1. Hafeman, D. G.; Parce, J. W.; McConnell, H. M., LIGHT-ADDRESSABLE POTENTIOMETRIC SENSOR FOR BIOCHEMICAL SYSTEMS. Science 1988,240, (4856), 1182-1185. 2. Krause, S.; Talabani, H.; Xu, M.; Moritz, W.; Griffiths, J., Scanning photo-induced impedance microscopy - an impedance based imaging technique. Electrochim. Acta 2002,47, (13-14), 2143-2148. 3. Wang, J.; Wu, F.; Watkinson, M.; Zhu, J. Y.; Krause, S., "Click" Patterning of Self-Assembled Monolayers on Hydrogen-Terminated Silicon Surfaces and Their Characterization Using Light-Addressable Potentiometric Sensors. Langmuir 2015, 31, (35), 9646-9654. Figure 1

Silver(I)-Catalyzed Regioselective Synthesis of Triazole Fused-1,5-Benzoxazocinones.

An efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained from substituted 2-azido benzoic acid esters in a single step through a Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction using a CuI/NBS catalytic system. A carbon-carbon triple bond was installed through a Sonogashira coupling reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were cyclized by a AgOTf-mediated intramolecular cyclization to afford 8-endo-dig 1,2,3-triazole-fused-1,5-benzoxazocinones exclusively.

Homoconjugated and Spiro Push–Pull Systems: Cycloadditions of Naphtho- and Anthradiquinones with Electron-Rich Alkynes

We report the synthesis and characterization of three new classes of push–pull chromophores using [2+2]-cycloaddition reactions of electron-rich alkynes and electron-poor alkenes. Previous investigations have focused on the reactions of cyano-substituted electron acceptors. This study demonstrates that cyano-free electron acceptors, naphtho- and anthradiquinones, can also be used to access extended push–pull systems. The effects of the structural changes on the spectroscopic and electronic properties were investigated by UV/vis spectroscopy. Structures were confirmed by X-ray and NMR analysis in solution.