Cycloaddition Of Azides Research Articles

3 + 3] Cycloaddition of Azides with in Situ Formed Azaoxyallyl Cations To Synthesize 1,2,3,4-Tetrazines.

A formal [3 + 3] cycloaddition reaction between azides and in situ formed azaoxyallyl cations has been realized. This reaction provided an efficient and practical pathway to synthesize 1,2,3,4-tetrazines in good yields under mild conditions. Biologically active molecules could also be well compatible, highlighting the potential value of this reaction.

An Insight into the Anionic Ring-Opening Polymerization with Tetrabutylammonium Azide for the Generation of Pure Cyclic Poly(glycidyl phenyl ether)

We evaluate the use of tetrabutylammonium azide (N3NBu4) as an anionic ring-opening polymerization initiator for synthesizing azide-terminated linear poly(glycidyl phenyl ether) and then generating monocyclic structures with high purity. In particular, we perform a detailed study on the end-group fidelity of polymers obtained by initiation with N3NBu4 in the presence and absence of trisisobutylaluminum (iBu3Al) and evaluate the purity of the cyclic structures obtained via copper-catalyzed alkyne–azide cycloaddition “click” reaction. We demonstrate that in contrast to the polymerization initiated by N3NBu4 alone, the polymerization performed in the presence of iBu3Al allows the formation of polymers with high end-group fidelity (azide groups at the α-position) for Mn < 20 kDa. The cyclic purity is evaluated by SEC with triple detection and dielectric spectroscopy. The latter technique, although not conventional for such a purpose, is shown to be very convenient to ensure cyclic purity in polymers showing a...

Copper-Free 'Click' Chemistry-Based Synthesis and Characterization of Carbonic Anhydrase-IX Anchored Albumin-Paclitaxel Nanoparticles for Targeting Tumor Hypoxia.

Triple negative breast cancer (TNBC) is a difficult to treat disease due to the absence of the three unique receptors estrogen, progesterone and herceptin-2 (HER-2). To improve the current therapy and overcome the resistance of TNBC, there is unmet need to develop an effective targeted therapy. In this regard, one of the logical and economical approaches is to develop a tumor hypoxia-targeting drug formulation platform for selective delivery of payload to the drug-resistant and invasive cell population of TNBC tumors. Toward this, we developed a Carbonic Anhydrase IX (CA IX) receptor targeting human serum albumin (HSA) carriers to deliver the potent anticancer drug, Paclitaxel (PTX). We used Acetazolamide (ATZ), a small molecule ligand of CA IX to selectively deliver HSA-PTX in TNBC cells. A novel method of synthesis involving copper free ‘click’ chemistry (Dibenzocyclooctyl, DBCO) moiety with an azide-labeled reaction partner, known as Strain-Promoted Alkyne Azide Cycloaddition (SPAAC) along with a desolvation method for PTX loading were used in the present study to arrive at the CA IX selective nano-carriers, HSA-PTX-ATZ. The anticancer effect of HSA-PTX-ATZ is higher compared to HSA, PTX and non-targeted HSA-PTX in MDA-MB-231 and MDA-MB-468 cells. The cell killing effect is associated with induction of early and late phases of apoptosis. Overall, our proof-of-concept study shows a promising avenue for hypoxia-targeted drug delivery that can be adapted to several types of cancers.

Cobalt‐Copper Ferrite Nanoparticles Catalyzed Click Reaction at Room‐Temperature: Green Access to 1,2,3‐Triazole Derivatives

AbstractA typical Cobalt‐Copper ferrite nanoparticles (CoCuFe2O4) was used as a catalyst for one‐pot [3+2] cycloaddition of alkyl azides with alkynes at room temperature in green media. These nanoparticles were synthesized by using co‐precipitation method and were fully characterized by physiochemical technique. By this catalyst system, various types of alkyl halides were coupled with alkynes efficiently to furnish 1,2,3 triazoles in excellent yields within short reaction time. The requirement on energy and time for the Click reaction extremely minimized in this method compared to previously reported reactions as an inevitable trend in development of green chemistry. Using green solvent, inexpensive catalyst, and ability to totally removal of catalyst from reaction media have made this protocol valuable from the green chemistry point of view.

New copper-containing catalysts based on modified amorphous silica and their use in flow azide—alkyne cycloaddition

Сopper-containing catalysts supported on amorphous silica modified by amines were prepared using the chemical reduction method. The morphology of copper particles and their chemi calstate depend on the type of the reducing agent used. The use of ascorbic acid results in the formation of monodisperse submicron Cu0 particles 200—300 nm in size, whereas Cu0 particles with a size ranging from 50 to 150 nm are formed when hydrazine hydrate was used. The morphology and chemical state of the copper particles reduced with sodium borohydride depend substantially on the amount of the reducing agent: Cu0 nanoparticles 10—15 nm in size are formed if the reducing agent is an excess, layered Cu2O plates are formed at the equimolar amount of sodium borohydride, and a decrease in the amount of sodium borohydride results in spherical Cu2O particles. All the catalysts synthesized in the flow regime showed higher activity in the catalytic cycloaddition of azides to alkynes than the commercially available copper catalysts.

Design, Synthesis, Antioxidant and Antibacterial Activities of Novel 2-((1-Benzyl-1H-1,2,3-Triazol-4-yl)methyl)-5-(2HChromen- 3-yl)-2H-Tetrazoles

1,4-Disubstituted 1,2,3-triazole derivatives of 2H-chromene-3-tetrazoles synthesized regioselectively by copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) click reaction were characterized by 1HNMR, 13C NMR, IR, and mass spectral data. These derivatives were screened for in vitro antioxidant activity using DPPH radical, H2O2 scavenging, and iron chelating activity methods and also evaluated for in vitro antibacterial activities against E. coli and S. aureus bacterial strains. The MIC and IC50 values for all these compounds were found to match the docking scores and relevant binding energies with the receptor active sites. These results allows one to consider the compounds as leads for a new generation of antioxidant and antibacterial agents.

L-Proline: An Efficient Organocatalyst for the Synthesis of 5-Substituted 1H-Tetrazoles via [3+2] Cycloaddition of Nitriles and Sodium Azide

A simple and efficient route for the synthesis of a series of 5-substituted 1H-tetrazoles using l-proline as a catalyst from structurally diverse organic nitriles and sodium azide is reported. The prominent features of this environmentally benign, cost effective, and high-yielding l-proline-catalyzed protocol includes simple experimental procedure, short reaction time, simple workup, and excellent yields making it a safer and economical alternative to hazardous Lewis acid catalyzed methods. The protocol was successfully applied to a broad range of substrates, including aliphatic and aryl nitriles, organic thiocyanates, and cyanamides.

Design and Synthesis of Novel 1,2,3‐triazolyl‐pyrimidinone Hybrids as Potential Anti‐HIV‐1 NNRT Inhibitors

A novel series of 2‐((1H‐1,2,3‐triazol‐4‐yl)methylthio)‐5‐chloro‐6‐phenylpyrimidin‐4 (3H)‐one derivatives has been synthesized and studied their molecular docking as well as vitro assay as an anti‐human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors. The synthetic approach was started from the reaction of aldehydes, ethylchloroacetate, and thiourea to give the 6‐aryl‐5‐chloro‐2‐thiouracils derivatives. Then, reaction of the later compounds with propargyl bromide followed by azide cycloaddition reaction (click reaction) led to the formation of the title compounds in good yields. The obtained derivatives were studied as anti‐human immunodeficiency virus type‐1 non‐nucleoside reverse transcriptase inhibitors. It was found that these compounds might have potent reverse transcriptase inhibition activity.

Higher-generation type III-B rotaxane dendrimers with controlling particle size in three-dimensional molecular switching

Type III-B rotaxane dendrimers (T3B-RDs) are hyperbranched macromolecules with mechanical bonds on every branching unit. Here we demonstrate the design, synthesis, and characterization of first to third (G1–G3), and up to the fourth (G4) generation (MW > 22,000 Da) of pure organic T3B-RDs and dendrons through the copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. By utilizing multiple molecular shuttling of the mechanical bonds within the sphere-like macromolecule, a collective three-dimensional contract-extend molecular motion is demonstrated by diffusion ordered spectroscopy (DOSY) and atomic force microscopy (AFM). The discrete T3B-RDs are further observed and characterized by AFM, dynamic light scattering (DLS), and mass spectrometry (MS). The binding of chlorambucil and pH-triggered switching of the T3B-RDs are also characterized by 1H-NMR spectroscopy.

Exploration of C-H Transformations of Aldehyde Hydrazones: Radical Strategies and Beyond.

The chemistry of hydrazones has gained great momentum due to their involvement throughout the evolution of organic synthesis. Herein, we discuss the tremendous developments in both the methodology and application of hydrazones. Hydrazones can be recognized not only as synthetic equivalents to aldehydes and ketones but also as versatile synthetic building blocks. Consequently, they can participate in a range of practical synthetic transformations. Furthermore, hydrazone derivatives display a broad array of biological activities and have been widely applied as pharmaceuticals. Owing to the weak directing group effect of simple aldehydes and ketones in C-H bond functionalizations, the C-H bond functionalizations of hydrazones that have been developed in the past five years represent a significant step forward. These novel transformations open a new door to a broader library of functionalized and complex small molecules. Moreover, a wide range of biologically important N-heterocycles (dihydropyrazoles, pyrazoles, indazoles, cinnolines, etc.) can be efficiently synthesized in an atom- and step-economical manner through single, double, or triple C-H bond functionalizations of hydrazones. Both radical C-H functionalizations and transition-metal-catalyzed directing-group strategies have enhanced the synthetic utility of hydrazones in the chemical community because these strategies solve the long-standing challenge of C-H functionalizations adjacent to aldehydes and ketones. We began this study based on our ongoing interest in visible-light photoredox catalysis. Visible-light photoredox catalysis has become a powerful tool in contemporary synthetic chemistry due to its remarkable advantages in sustainability and use of radical chemistry. By exploiting a photoredox-catalyzed aminyl radical polar crossover (ARPC) strategy, we successfully achieved visible-light-induced C(sp2)-H difluoroalkylation, trifluoromethylation, and perfluoroalkylation of aldehyde-derived hydrazones. This intriguing result was later applied in the C(sp2)-H amination of hydrazones and a cascade cyclization reaction for the synthesis of polycyclic compounds. Encouraged by this redox-neutral C-H functionalization of aldehyde hydrazones, we extended the oxidative C-H/P-H cross-coupling method, which represents a novel and efficient method for the synthesis of α-iminophosphine oxides. Furthermore, an elegant [3 + 2] cycloaddition of azides and aldehyde hydrazones for the synthesis of functionalized tetrazoles was advantageously developed during our investigation of the oxidative C(sp2)-H azidation of aldehyde hydrazones with TMSN3. The sequential C(sp2)-H/C(sp3)-H bond functionalization of aldehyde-derived hydrazones with simple 2,2-dibromo-1,3-dicarbonyls was achieved by employing relay photoredox catalysis, and it provides a novel method of accessing bioactive fused dihydropyrazole derivatives. The notable feature of this approach was further reflected in the formal [4 + 1] annulation of aldehyde-derived N-tetrahydroisoquinoline hydrazones with 2-bromo-1,3-dicarbonyls. To complement these radical C-H functionalization strategies, we recently applied a directing-group strategy in the Rh-catalyzed C(aldehyde)-H functionalization of aldehyde-derived hydrazones for the synthesis of distinctive and bioactive 1H-indazole scaffolds. In summary, this Account presents recent contributions to the exploration, development, mechanistic insights, and synthetic applications of C-H bond functionalizations of aldehyde hydrazones.

Investigation of Strain-Promoted Azide-Alkyne Cycloadditions in Aqueous Solutions by Capillary Electrophoresis.

The Cu-free 1,3-dipolar cycloaddition of cyclooctynes and azides is an up-and-coming method in bioorganic chemistry and other disciplines. However, broad application is still hampered by major drawbacks such as poor solubility of the reactants in aqueous media and low reaction rates. It is thus of high demand to devise a fast and user-friendly strategy for the optimization of reaction conditions and reagent design. We describe a capillary electrophoresis (CE) study of reaction kinetics in strain-promoted azide-alkyne cycloadditions (SPAAC) using substrates with acidic or basic functionalities. This study reveals that the pH value has a significant effect on reaction rates as a result of changes in the reactants' charge state via protonation or deprotonation, and the concomitant changes of electronic properties. This novel experimental setup also enables the study of even more challenging conditions such as reactions in micelles and we did indeed observe much faster SPAAC reactions in the presence of surfactants. Careful combination of the above-mentioned parameters resulted in the identification of conditions enabling remarkable rate enhancement by a factor of 80. This electrophoretic method may thus serve as a versatile, fast and reliable tool for screening purposes in all research areas applying SPAAC reactions.

Pincer Receptors for Anions Based on Triazolyl Bile Acids

Copper-catalyzed 1,3-dipolar cycloaddition of azides to acetylenes successfully afforded pincer bistriazolium receptor containing two lithocholic acid fragments and phenylphosphonic diamide bridge. The obtained receptor showed high complexing power toward fluoride ions and organic acid anions, which decreased in the series fluoride > succinate ≥ malonate > oxalate ≥ lithocholate > benzoate > acetate > hydrogen sulfate > bromide.

A copper-catalyzed three component reaction of aryl acetylene, sulfonyl azide and enaminone to form iminolactone via 6π electrocyclization.

We developed a copper-catalyzed three component reaction of aryl acetylene, enaminone and sulfonyl azide to construct iminolactone via a cascade process involving copper-catalyzed alkyne-azide cycloaddition (CuAAC), Michael addition of metalated ketenimine followed by elimination and 6π electrocyclization.

Fast functionalization of ultrasound microbubbles using strain promoted click chemistry.

Functionalization of microbubbles (MBs) is a difficult issue due to their unstable nature. Here we report a fast and versatile method using a strain promoted alkyne-azide cycloaddition (SPAAC) click reaction for microbubble functionalization. An azadibenzocyclooctyne (DBCO) group was first introduced onto the MB surface and then an azide group into the desired ligand. Without any initiators or catalysts, essential click ligation occurred within 1 min and a majority of the reaction completed in 5 min at 37 °C. This fast ligation shortens the microbubble reaction time and preserves essential amounts of microbubbles for further in situ imaging and delivery of therapeutics.

Phase behavior of main-chain liquid crystalline polymer networks synthesized by alkyne-azide cycloaddition chemistry.

Liquid crystalline polymer networks (LCNs) couple polymer chain organization to molecular ordering, the switching of which has been shown to impart stimuli-responsive properties, including actuation and one-way shape memory, to the networks. While LCNs have long been proposed as artificial muscles, recent reports have also suggested potential as dynamic biomaterial substrates. In contrast to many existing LCNs synthesized using hydrophobic spacers, this work investigates networks synthesized using more hydrophilic spacers to promote interaction with water. A challenge with such materials is liquid crystalline phases could be disrupted in hydrated networks. This work thus investigates the impact of polyether spacers and mesogen composition on the phase behavior of LCNs. Main-chain LCNs were synthesized using alkyne-azide cycloaddition ("click" chemistry), where two different mesogens (5yH and 5yMe) and a non-LC monomer (5yTe) were coupled with one of two different polyether spacers, poly(ethylene glycol) and poly(propylene glycol), and a crosslinker. The chemistry led to high gel fraction materials, the workup of which resulted in networks that displayed no difference in cellular toxicity due to leachable components compared to tissue culture plastic control. Calorimetric analysis, dynamic mechanical analysis, and X-ray scattering revealed the LC microstructure and temperature-responsive properties of the networks. The use of low molecular weight polyether spacers was found to prevent their crystallization within the LC network, and adjusting mesogen composition to enhance its LC phase stability allowed the use of spacers with larger molecular weights and pendant groups. Hydrated networks were found to rearrange their structure compared to dry networks, while maintaining their LC phases. Like other crosslinked LC materials, the networks display shape changes (actuation) that are tied to changes in LC ordering. The result is a new synthetic approach for polydomain networks that form stable LC phases that are tailorable using polyether spacers and may enable future application as hydrated, stimuli-responsive materials.

Controlled decoration of boron-doped diamond electrodes by electrochemical click reaction (e−CLICK)

Controlled surface functionalization of electrode materials is an important technique in various fields such as analytical chemistry, molecular electronics, and molecular recognition in biological systems. In this work, we report the control decoration of boron-doped diamond (BDD) electrodes by electrochemically driven copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition of alkyne and azide (e−CLICK) in which the catalyst is produced by electroreduction of copper(II) species. As the e−CLICK strategy enabled to tune the produced amount of the copper(I) catalyst electrochemically, the alkyne-terminated BDD electrodes were decorated with azide-terminated ferrocene in a controlled manner.

Imaging of a clickable anticancer iridium catalyst

Iridium-based anticancer reagents are receiving increasing attention for their high cytotoxicity. Herein, by activating CH bonds in the well-known antioxidant α-phenyl-N-tert-butylnitrone (PBN), we synthesized and characterized a series of new iridium complexes. Complex 1-AMP exhibited the best antiproliferation activity towards human ovarian cancer A2780 cells. The azide group in complex 1-AMP underwent the Cu(I)-catalysed azide−alkyne cycloaddition (CuAAC) reaction and the resulting fluorescent imaging in cells suggested it mainly accumulated in mitochondria. In comparison, to eliminate cytotoxicity of Cu(I) catalyst, we conducted a reaction between complex 1-AMP and a commercialized dye via strain-promoted alkyne–azide cycloaddition (SPAAC) reaction in live cells, confirming its targeting mainly in the mitochondria. Iridium-based anticancer complexes containing a nitrone ligand and azide group may offer a useful tool to probe the mechanism of metallodrugs.

Bonding and in‐channel microfluidic functionalization using the huisgen cyclization

ABSTRACTThe bonding of layers of silicone elastomers during the manufacturing of microfluidic devices is often accomplished using plasma oxidation. The process can be costly, may require a clean room and materials that ensure the flatness of the bonding layers and, as a consequence of hydrophobic recovery, can lead to high variability in the degree of adhesion. As importantly, the process precludes incorporation of chemical functionalities that work as anchors to immobilize biomolecules within the microfluidic channel. We hypothesized that it would be possible to fabricate microfluidic channels using the Huisgen 1,3‐dipolar cycloaddition of azides to alkynes to crosslink silicones and form PDMS elastomers and, in a subsequent step, bond one PDMS layer to another simply by heating, with the added advantage of producing microfluidic channels with embedded chemical functionalities. After thermal bonding, the microfluidic devices underwent cohesive failure (rupture of the elastomer layer) at ∼145 kPa during pressure tests, but did not exhibit adhesive failure (delamination), showing that the azide–alkyne reaction provides a strong bond between elastomer layers. Furthermore, the internal microfluidic channel surfaces retained alkyne and azide functionality during the process, as shown by the grafting of one or more fluorescent dyes, through Huisgen cyclization. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 589–597

3 + 2] Cycloaddition promoted by zinc oxide nanoparticles anchored on reduced graphene oxide using green solvent

ABSTRACTZnO anchored on RGO-catalyzed [3 + 2] cycloaddition of nitriles and sodium azide in the synthesis of 5-substituted 1H-tetrazoles in water is an efficient and simple protocol with low catalyst loading under reflux condition. It is applied to a wide range of substrates with an excellent yield, simple workup procedure, recovery, and reusability of catalyst with consistent activity and high turnover number. It is proposed that the functional groups present in RGO surface are effective for preventing the aggregation of catalytically active ZnO species during the reaction. Moreover, the excellent performance of ZnO–RGO nanocomposite is ascribed to the excellent dispersity of catalyst in water, hydrophilic nature of the RGO for the accumulation of organic substrates in water, and the “Breslow effect.”

Urea mediated 5-substituted-1H-tetrazole via [3 + 2] cycloaddition of nitriles and sodium azide

A simple, new and convenient metal free procedure for the synthesis of 5-substituted 1H-tetrazoles using various nitriles and sodium azide in the presence of urea and acetic acid with good to high yields is developed. The reaction plausibly proceeds through in situ formation of urea azide active complex without toxic and/or expensive metal catalysts.