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The Huisgen cycloaddition, often referred to as 1,3-Dipolar cycloaddition, is a well-established method for synthesizing 1,4-disubstituted triazoles. Originally conducted under thermal conditions [3+2] cycloaddition reactions were limited by temperature, prolonged reaction time, and regioselectivity. The introduction of copper catalyzed azide-alkyne cycloaddition (CuAAC) revitalized interest, giving rise to the concept of "click chemistry". The CuAAC has emerged as a prominent method for producing 1,2,3-triazole with excellent yields and exceptional regioselectivity even in unfavorable conditions. Copper catalysts conventionally facilitate azide-alkyne cycloadditions, but challenges include instability and recycling issues. In recent years, there has been a growing demand for heterogeneous and porous catalysts in various chemical reactions. Chemists have been more interested in heterogenous catalysts as a result of the difficulties in separating homogenous catalysts from reaction products. These catalysts are favored for their abundant active sites, extensive surface area, easy separation from reaction mixtures, and the ability to be reused. Heterogeneous catalysts have garnered significant attention due to their broad industrial utility, characterized by cost-effectiveness, stability, resistance to thermal degradation, and ease of removal compared to their homogeneous counterparts. The present review covers recent advancements from year 2018 to 2023 in the field of click reactions for obtaining 1,2,3-triazoles through Cu catalyzed 1,3-dipolar azide-alkyne cycloaddition and the properties of the catalyst, reaction conditions such as solvent, temperature, reaction time, and the impact of different heterogeneous copper catalysts on product yield., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

There is considerable interest in using the metalloprotein cofactor vitamin B 12 as a vehicle to deliver drugs and diagnostic agents into mammalian or bacterial cells by exploiting the B 12 -specific active uptake pathways. Conjugation of the cargo via the β-axial site or the 5'-OH of the ribose of the nucleotide are the most desirable sites, to maximise intracellular uptake. Herein we show the potential of conjugation at the beta-azido ligand of the vitamin B 12 derivative azidocobalamin via a click-type azide-alkyne 1,3-dipolar cycloaddition (Huisgen cycloaddition) reaction. Reacting azidocobalamin with dimethyl acetylenedicarboxylate at 40 °C results in essentially stoichiometric conversion of azidocobalamin to the corresponding triazolato complex. The stability of the complex as a function of pH and in the presence of cyanide were investigated. The complex is stable in pD 7.0 phosphate buffer for 24 h. The rate of beta-axial ligand substitution was found to be one order of magnitude slower for the triazolatocobalamin complex compared with azidocobalamin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

An efficient method for the synthesis of DNA-conjugated 1,2,3-triazoles is copper (II) [Cu(II)-β-cyclodextrin]-mediated Huisgen cycloaddition ("click reaction") of DNA-conjugated alkynes with azides. However, a diverse array of building blocks is required to produce useful DNA encoded libraries, and the commercial availability of azides is limited. The method described herein generates azides in situ from aryl borates and TMSN 3 , which then further react with DNA-conjugated terminal alkynes. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Conjugation of PEG linker to DNA headpiece Basic Protocol 2: DNA conjugated terminal alkyne preparation Basic Protocol 3: DNA compatible one-pot click reaction Basic Protocol 4: LCMS monitoring., (© 2021 Wiley Periodicals LLC.)

RNAs with 5' functional groups have been gaining interest as molecular probes and reporter molecules. Copper-catalyzed azide-alkyne cycloaddition is one of the most straightforward methods to access such molecules; however, RNA functionalization with azide group has been posing a synthetic challenge. This article describes a simple and efficient protocol for azide functionalization of oligoribonucleotides 5'-end in solid-phase. An azide moiety is attached directly to the C5'-end in two steps: (i) -OH to -I conversion using methyltriphenoxyphosphonium iodide, and (ii) -I to -N 3 substitution using sodium azide. The reactivity of the resulting compounds is exemplified by fluorescent labeling using both copper(I)-catalyzed (CuAAC) and strain-promoted (SPAAC) azide-alkyne cycloaddition reactions, ligation of two RNA fragments, and cyclization of short bifunctionalized oligonucleotides. The protocol makes use of oligoribonucleotides synthesized by standard phosphoramidite approach on solid support, using commercially available 2'-O-PivOM-protected monomers. Such a protection strategy eliminates the interference between the iodination reagent and silyl protecting groups (TBDMS, TOM) commonly used in RNA synthesis by phosphoramidite approach. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Solid-phase synthesis of oligoribonucleotide 5'-azides Basic Protocol 2: CuAAC labeling of oligoribonucleotide 5'-azides in solution Alternate Protocol 1: CuAAC labeling of oligoribonucleotide 5'-azides on solid support Basic Protocol 3: SPAAC labeling of oligoribonucleotide 5'-azides Basic Protocol 4: CuAAC ligation of oligoribonucleotide 5'-azides Basic Protocol 5: CuAAC cyclization of oligoribonucleotide 5'-azides Support Protocol: HPLC Purification., (© 2020 Wiley Periodicals LLC.)

Binary polystyrene and poly(4-vinylpyridine) mixed grafted silica nanoparticles (PSt/P4VP-g-SNPs) are fabricated using Cu I -catalyzed azide-alkyne Huisgen cycloaddition (CuAAC) via grafting-to method. Azide-terminated PSt and P4VP are synthesized via post- and pre-atom transfer radical polymerization modification, respectively. Then, the polymers are simultaneously anchored onto alkyne-modified SNPs by CuAAC yielding mixed brushes as shown by Raman spectroscopy, dynamic light scattering, and thermogravimetric analysis. To the best of our knowledge, this is the first report of simultaneously grafting two distinct polymer chains to synthesize mixed grafted silica nanoparticles using CuAAC technique via grafting-to method., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A novel linker containing biotin, alkyne and benzophenone groups (1) was synthesized to identify target proteins using a small molecule probe. This small molecule probe contains an azide group (azide probe) that reacts with an alkyne in 1 via an azide-alkyne Huisgen cycloaddition. Cross-linking of benzophenone to the target protein formed a covalently bound complex consisting of the azide probe and the target protein via 1. The biotin was utilized via biotin-avidin binding to identify the cross-linked complex. To evaluate the effectiveness of 1, it was applied in a model system using an allene oxide synthase (AOS) from the model moss Physcomitrella patens (PpAOS1) and an AOS inhibitor that contained azide group (3). The cross-linked complex consisting of PpAOS1, 1 and 3 was resolved via SDS-PAGE and visualized using a chemiluminescent system. The method that was developed in this study enables the effective identification of target proteins.

Cellulose fibres have poor reactivity and limited potential for surface engineering with advanced chemical functionalization in water. In this work, cellulose fibres were decorated with azide functions by charge-directed self-assembly of a novel water-soluble multifunctional cellulose derivative yielding reactive fibres. Propargylamine and 1-ethynylpyrene were utilized as a proof of concept that alkyne molecules may react with the azide functions of the reactive fibres via copper(I)-catalyzed azide-alkyne Huisgen cycloaddition (CuAAc) reaction in mild conditions. Chemical characterization of the fibres was carried out using classical techniques such as Raman-, fluorescence-, and UV-vis spectroscopy. Among other techniques, time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray spectroscopy (XPS), two-photon microscopy (TPM), and inductively coupled plasma mass spectrometry (ICP-MS) were useful tools for additional characterization of the fibres decorated with amino- or photoactive groups. The information gathered in this work might contribute to the basis for the preparation of reactive cellulose-based interfaces with potential application in CuAAc reactions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The synthesis of an azide containing PNA monomer is described. The monomer was incorporated into two PNA sequences for the purpose of synthesizing an intercalating fluorophore-labeled PNA and a metal binding hairpin using a solid phase copper catalyzed azide-alkyne Huisgen cycloaddition (CuAAC). Click chemistry was performed using 2-ethynylfluorene or 1-ethynylpyrene to add a fluorophore to the PNA, which were tested for their ability to recognize an abasic site on a DNA target. A PNA hairpin possessing azide monomers at each termini was synthesized and reacted with 2-ethynylpyridine to form a hairpin that is stabilized by Ni²⁺.

A convenient method for the synthesis of 2-azido-3-arylpropanoic acids via the Meerwein halogenoarylation reaction of acrylic acid esters with diazonium salts, subsequent nucleophilic substitution of the halogen by an azide, and saponification is developed. The newly formed 2-azido-3-arylpropanoic acids react under the conditions of non-catalytic four-component Ugi reactions, leading to the formation of α-azidoamides in good yields. The use of propargylamine as the amine component allows the formation of Ugi adducts with azide and acetylene motifs ready for intramolecular 1,3-dipolar Huisgen cycloaddition to give the [1,2,3]triazolo[1,5- a ]pyrazine annulated system. The Ugi reaction is found to give 2-azido-3-aryl- N -(2-oxo-1,2-disubstituted ethyl)- N -(prop-2-yn-1-yl)propanamides at room temperature without azide–alkyne cycloaddition. These dipeptides are converted into 4,5-dihydro[1,2,3]triazolo[1,5- a ]pyrazin-6(7 H)-ones in near quantitative yields by heating in toluene. However, when the Ugi reaction is carried out by heating, it results in a one-pot Ugi–Huisgen tandem reaction leading to 4,5-dihydro[1,2,3]triazolo[1,5- a ]pyrazin-6(7 H)-ones in excellent yields. Moreover, the possibility of the incorporation of a bromovinyl fragment (the synthetic equivalent of an acetylene fragment) via the aldehyde component of the Ugi reaction is demonstrated in an alternative preparation of the [1,2,3]triazolo[1,5- a ]pyrazine system. [ABSTRACT FROM AUTHOR]

Metal‐catalyzed azide‐alkyne cycloaddition reactions represent the most convenient and atom‐economic way to construct robust 1,2,3‐triazole units. Remarkable copper‐ and ruthenium‐based catalytic systems have been well established for regioselective preparation of 1,4‐ and 1,5‐disubstituted 1,2,3‐triazoles, both of which have been widely utilized in various areas. In comparison, exploitation of efficient methods to promote the cycloaddition of azides with internal alkynes to afford 1,4,5‐trisubstituted 1,2,3‐triazole motifs with high regioselectivity is still challenging and attractive. This review provides a thorough summary of the developments in metal‐catalyzed cycloaddition of azides with internal alkynes. Besides discussions about mechanism and scope, applications of these strategies were also briefly overviewed. [ABSTRACT FROM AUTHOR]

ABSTRACT: The 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 [ABSTRACT FROM AUTHOR]

The mechanisms of three cascade reactions between N -methylindole and sulfonylazides via Huisgen cycloaddition were investigated using density functional theory, and the polarized continuum model (PCM) was applied to simulate the solvent effects. Fukui functions and dual descriptor have been employed to assess the atomic reactivity. With respect to these three reactions, each has two possible reaction pathways (I and II). The calculated results show that singlet O 2 plays a crucial role in the oxidative dehydrogenation process in the first reaction between 2-imine indole and p-tosylazide (TsN 3 ), when the reaction occurs without O 2 but with N 2 , two pathways via the processes of breaking two covalent bonds, followed by 1,2-H shift and N 2 removal (or by N 2 removal and 1,2-H shift) exist. Water molecule plays an important role in the H-shift process in the third reaction of the methyl substituted N -methylindole with TsN 3 . Our results demonstrated that these reactions can take place at certain condition, in good agreement with the experimental observation. The understanding of the competitive pathways for Huisgen cycloaddition of N -methylindole and sulfonylazides can provide valuable insights into related reactions. [ABSTRACT FROM AUTHOR]

The copper catalyzed azide-alkyne cycloaddition (CuAAC), known as “click reaction” is a well-known method used for the construction of complex molecular architectures. Due to its efficiency it has been applied in the porphyrin synthesis in order to prepare elaborated architectures and sophisticated molecules with various applications. Also, this strategy allows the installment of useful functionalities, in the form of polar and function-rich 1,2,3-triazole moieties, directly attached on the porphyrin ring. In this review we summarize the use of click reaction for the synthesis of porphyrin based compounds and the reaction conditions used in each example. All the examples presented herein concern the type and the place of the substrate present on the porphyrin ring. More specifically, this manuscript is divided in two sections where in the first part click reaction using alkynyl porphyrins and in the second part using azido porphyrins are discussed. These main sections are divided in subsections where alkynyl and azido groups are present on the meso -phenyl ring, on an aliphatic chain and on the β -position of the porphyrin ring. [ABSTRACT FROM AUTHOR]

The synthesis of α,γ-diazido-α,β-unsaturated esters is carried out via a Lewis acid-mediated 1,3-diazidation of α,α-dimethoxy-β,γ-unsaturated esters using two equivalents of trimethylsilyl azide. The reaction proceeds in a highly stereoselective manner to provide only the ( Z )-stereoisomers of the diazide products. The optimization and scope of the new method are discussed, and the utility of the products is demonstrated in the synthesis of bis-1,2,3-triazole derivatives. [ABSTRACT FROM AUTHOR]

The synthesis of an azide containing PNA monomer is described. The monomer was incorporated into two PNA sequences for the purpose of synthesizing an intercalating fluorophore-labeled PNA and a metal binding hairpin using a solid phase copper catalyzed azide-alkyne Huisgen cycloaddition (CuAAC). Click chemistry was performed using 2-ethynylfluorene or 1-ethynylpyrene to add a fluorophore to the PNA, which were tested for their ability to recognize an abasic site on a DNA target. A PNA hairpin possessing azide monomers at each termini was synthesized and reacted with 2-ethynylpyridine to form a hairpin that is stabilized by Ni2+. [ABSTRACT FROM AUTHOR]

1N-Alkyl-4-aryl-1,2,3-triazoles have been prepared through a multicomponent one-pot protocol from the corresponding (arylethynyl) trimethylsilanes and alkyl bromides. In situ alkyl azide formation and alkyne deprotection followed by copper(I)-catalyzed click cycloaddition afforded the desired 1,4-disubstituted 1,2,3-triazoles in generally good to excellent yield, with only minor observation of the undesired 1,5-regioisomeric cycloadduct. The protocol eliminates the need to use reactive organic azides and terminal alkynes. [ABSTRACT FROM AUTHOR]

Carboxymethyl glycoside lactones (CMGLs) are bicyclic synthons which open readily for accessing new types of pseudo-glycoconjugates, such as sugar-amino acid hybrids, neoglycolipids, pseudodisaccharides, and membrane imaging systems. After lactone opening, free OH-2 is available for further functionalization, leading to 1,2-bisfunctionalized derivatives. This strategy is illustrated herein with new polymerizable systems of the AB type bearing both azide and alkyne functions prepared from α or β gluco-CMGL synthons. After the reaction of lactones with propargylamine, an azido group was introduced by two different sequences leading to either the 2- manno-azido or the 6- gluco-azido products. The capability of these AB monomers to undergo step growth polymerization through copper(I) catalyzed alkyne-azide cycloaddition (CuAAC) and generate glycopolytriazoles was evidenced. [ABSTRACT FROM AUTHOR]

This article deal with the parallel synthesis of a 96 product-sized library using a polymer-based copper catalyst that we developed which can be easily separated from the products by simple filtration. This gave us the opportunity to use this catalyst in an automated chemical synthesis station (Chemspeed ASW-2000). Studies and results about the preparation of the catalyst, its use in different solvent systems, its recycling capabilities and its scope and limitations in the synthesis of this library will be addressed. The synthesis of the triazole library and the very good results obtained will finally be discussed. [ABSTRACT FROM AUTHOR]