Huisgen Reaction Research Articles

A New Route for the Synthesis of Trichloromethyl-1H-Benzo[d]imidazole and (1,2,3- Triazol)-1H-Benzo[d]imidazole Derivatives via Copper-Catalyzed N-Arylation and Huisgen Reactions

Abstract: In this study, functionalized 2-(trichloromethyl)-1H-benzo[d]imidazole derivative with good yields was synthesized using a copper-catalyzed N-arylation reaction of 2-iodoaniline and trichloroacetonitrile. This reaction was performed by employing the catalytic value of copper (I) and 1,10-phenanthroline as the ligand in tetrahydrofuran solvent at 23°C. In the following, the reaction of the final product with phenylacetylene and sodium azide (Huisgen reaction) using the copper catalyst in water solvent at 23°C led to the synthesis of new (1,2,3-triazol)-1H-benzo[d]imidazole derivatives with the principles of green chemistry and suitable efficiency. The availability of raw materials and suitable catalysts, mild reaction conditions, and easy purification are among the advantages of this method for the synthesis of various multi-substituted benzo[d]imidazole and 1,2,3-triazole derivatives.

A New Insight Into The Huisgen Reaction: Heterogeneous Copper Catalyzed Azide-Alkyne Cycloaddition for the Synthesis of 1,4-Disubstituted Triazole (From 2018-2023).

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.

Synthesis and Characterization of New Functionalized 1,2,3-Triazole-Based Acetaminophen Derivatives via Click Chemistry from Expired Commercial Acetaminophen Tablets

We hereby describe an efficient method for the preparation of a series of new 1-substituted 1,2,3-triazole-based acetaminophen derivatives through a clean, good-yielding, simple, and expeditious procedure based on the O-propargylation reaction of the acetaminophen (APAP) obtained from expired commercial tablets and the CuBr(PPh3)3-catalyzed Huisgen reaction between O-propargylated APAP and diverse organoazides prepared from commercially available anilines as available starting reagents. An interesting nitric oxide-releasing 1,2,3-triazole hybrid of APAP was also obtained easily using the developed method. The structures of the designed hybrid compounds, which are expected to be pharmacologically active, were characterized by FT-IR, 1H-, and 13C-NMR and are reported for the first time. According to the in-silico ADMET prediction studies performed in this work and literature analysis, these hybrids are interesting models in search of new pharmacological nontoxic agents endowed with anti-inflammatory and anticancer properties.

Synthesis of Functionalized 2′,5‐Oxo‐spiro[furan‐2,3′‐indoline]‐3‐carboxylate Derivatives as Antiproliferative Agents: ADMET Studies, and Molecular Docking against P2Y12 Inhibitors

AbstractHerein, we present a one‐pot, three‐component synthesis of spirooxindole‐oxofuran carboxylate derivatives (4 a–d) through the Huisgen reaction. The newly synthesized spirocyclic compounds were tested for in vitroantiproliferative efficacy against 60 human cancer cell lines at the National Cancer Institute (NCI) in the United States. The screening results indicated that two spirooxindole compounds, 4 b and4 c, possessed the strongest anti‐cancer efficacy in terms of percentage growth inhibition (% GI), with values of 34.17 and 38.19 at 10−5 M concentration against the CNS cancer panel‘s SNB‐75 cell line, respectively. Furthermore, molecular docking investigations demonstrated the binding affinity for the P2Y12 receptor. The compound 4 c which exhibited strong antiproliferative activity with high binding energies might therefore, serve as a potential lead molecule for the development of more effective anti‐cancer agents.

Synthesis of 1,2,3-triazole-fused N-heterocycles from N-alkynyl hydroxyisoindolinones and sodium azide via the Huisgen reaction.

An efficient methodology for the synthesis of dihydro[1,2,3]triazolo-pyrimidoisoindolones and dihydro[1,2,3]triazolo-diazepinoisoindolones has been developed using the Huisgen reaction from sodium azide and alkyne substituted amido alcohols in moderate to good yields. The reaction involves the in situ generation of the N-acyliminium ion intermediate, which undergoes a nucleophilic attack by the azide ion, followed by a [3 + 2]-intramolecular azide-alkyne cycloaddition reaction. Importantly, the reaction proceeds without the involvement of any transition metal catalyst. This methodology can be further utilized for the synthesis of dihydro[1,2,3]triazolo-pyrimidoisoindolthiones via thionation of amides.

Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions.

Fluorinated heterocycles constitute an important group of organic compounds with a rapidly growing number of applications in such areas as medicinal chemistry, agrochemicals production, polymer chemistry, as well as chemistry of advanced materials. In the latter case, fluorinated thiophenes are considered as a lead class of compounds with numerous spectacular applications. On the other hand, cycloaddition reactions offer a superior methodology for stereo-chemically controlled synthesis of heterocycles with a diverse ring size and a variable number of heteroatoms. A comprehensive review of methods based on cycloaddition reactions and applied for construction of fluorinated and/or fluoroalkylated S-heterocycles has not yet been published. For this reason, the main goal of the presented review was to fill the existing gap and to summarize the results published over last six decades. In this context, the [3+2]- and [4+2]-cycloadditions (Huisgen reactions, and Diels–Alder reactions, respectively) are of special importance. Some questions related to the discussed mechanisms of cycloaddition processes observed in reactions with electron deficient, fluorinated substrates (dipolarophiles and dienophiles), and electron-rich sulfur containing counter partners, are of fundamental importance for the development of interpretations of organic reaction mechanisms.

Cyclobutane Formation by the Reaction of Ethenesulfonyl Fluoride with Dimethyl Diazomalonate

AbstractAttempts to synthesize fluorosulfonyl‐substituted pyrazolines by Huisgen reactions (1,3‐dipolar cycloadditions) of dimethyl diazomalonate with ethenesulfonyl fluoride led to the formation of dimethyl (2R*,3S*,4R*)‐2‐(1,3‐dimethoxy‐1,3‐dioxopropan‐2‐yl)‐3‐(fluorosulfonyl)‐4‐((fluorosulfonyl)methyl)cyclobutane‐1,1‐dicarboxylate, a highly substituted cyclobutane derivative, which was characterized by NMR spectroscopy and single crystal X‐ray crystallography. The mechanism of its formation was elucidated by carrying out the reaction at different temperatures and workup conditions. It is shown that an initial 1,3‐dipolar cycloaddition yields a pyrazoline which extrudes nitrogen with formation of 1‐fluorosulfonyl‐2,2‐bis(methoxycarbonyl)cyclopropane and dimethyl 2‐(2‐(fluorosulfonyl)ethylidene)malonate, the latter of which dimerized during chromatography on silica gel with formation of the isolated cyclobutane.

Synthesis of 2,5-disubstituted pyrazolyl-1,3,4-oxadiazoles by the Huisgen reaction

Synthesis of 2,5-disubstituted pyrazolyl-1,3,4-oxadiazoles by the Huisgen reaction

Diastereoselective Synthesis of Spiro[benzopyrrolothiazole-thioazlactone] Derivatives from Erlenmeyer Thioazlactones and Azomethine Ylides

AbstractErlenmeyer thioazlactones reacted with 3-(2-oxo-2-arylethyl)benzo[d]thiazol-3-ium bromides in the presence of Et3N in MeCN to afford 1-aryloyl-2′-(benzylthio)-2-aryl-2,3a-dihydro-1H,5′H-spiro[benzo[d]pyrrolo[2,1-b]thiazole-3,4′-thiazol]-5′-ones. Formally, this transformation can be regarded as a Huisgen reaction of the exocyclic carbon–carbon double bond of the Erlenmeyer thioazlactones and azomethine ylides generated in situ. Evidence for the structure of a product was obtained from single-crystal X-ray analyses. The important feature of this reaction is the fact it forms four stereogenic centers, one of which is quaternary, with excellent selectivity.

Highly Facile, Regio‐ and Stereoselective Synthesis of Spiropyrrolidine‐5‐aza‐2‐oxindole Derivatives through Multicomponent 1,3‐Dipolar Cycloaddition Reaction and Their In‐Vitro and In‐Silico Biological Studies

AbstractHighly facile one pot synthesis of an assortment of novel spiropyrrolidine 5‐aza‐2‐oxindole derivatives via 1, 3‐di polar cycloaddition reaction has been reported. The underlying concept of Huisgen reaction was applied wherein the azomethine ylides (1,3‐dipoles), generated in‐situ from isatin‐derived compounds and cyclic / acyclic α‐amino acids through the thermal decarboxylation, reacted with exo‐cyclic benzylidine derivatives (dipolarophiles) of 5‐aza‐2‐oxindole afforded plethora of spiropyrrolidine 5‐aza‐2‐oxindoles in excellent yield. High regio‐ and stereo selectivity were accomplished employing this methodology and optimum yield was obtained when reaction carried out under methanol reflux in presence of triethylamine. Furthermore, the compounds were tested for their in‐vitro biological potency as anti‐microbial and anti‐mycobacterial. Antibacterial screening result reveals that out of fifteen compounds four compounds emerged with moderate to reasonable activity against gram negative E. coli and P. aeruginosa. Antifungal screening resulted in identification of two compounds as moderate antifungal agents against A. niger. Antimycobacterial activity results revealed that the four compounds displayed good to moderate in‐vitro activity with MIC=12.5 μg/mL against H37Rv strain as compared to standard pyrazinamide (MIC=3.12 μg/mL). Additionally, molecular docking study was carried out to understand the possible binding modes of the synthesized derivatives within the active site of antibacterial (PDB ID : 3ACX), antifungal (PDB ID : 1IYL) and antimycobacterial (PDB ID : 4TZT) target proteins and were found to display good docking energies. Besides, ADMET properties of the synthesized compounds have shown drug likeness with good oral absorption and moderate BBB permeability.

Alkynyl-functionalization of carbon nanotubes to promote anchoring potential in glycidyl azide polymer-based binders via Huisgen reaction for solid propellant application

Triazole curing systems based on glycidyl azide polymer (GAP) have been widely used as the binders of solid propellant systems due to moisture insensitivity, high energy density, and room temperature curing. However, the low-flexible molecular structure of GAP usually causes low mechanical properties, and reinforcement fillers may not be suitable in the binder system of propellants because they probably diffuse into other parts of propellants. Thus, we anchored a strong nanomaterial, carbon nanotube (CNT), on GAP to prevent the CNT from diffusing uncontrollably. The anchoring process was based on the alkynylation reaction and the Huisgen reaction, which was confirmed by tests on chemical structure. The reaction process was further adjusted to introduce CNT into the triazole crosslinked network, leading to a 23.6% increase in the elongation at break of the binder. The high rigidity of CNT also improved the Young’s modulus and tensile strength of the binder increased by 107.7% and 199.0%, respectively. Furthermore, the high thermal conductivity of CNT could reduce the thermal resistance index of the binders from 160.4 °C to 151.2 °C, and decrease the carbon residue rate from 17.8% to 10.5%. Such an anchoring modification can thus target the reinforcement region in multi-component systems, which can be used not only in solid propellants, but also in ablative materials.

Synthesis of triethoxysilylated cyclen derivatives, grafting on magnetic mesoporous silica nanoparticles and application to metal ion adsorption.

The synthesis through click chemistry of triethoxysilylated cyclen derivative-based ligands is described. Different methods were used such as the copper catalyzed Huisgen's reaction, or thiol–ene reaction for the functionalization of the cyclen scaffold with azidopropyltriethoxysilane or mercaptopropyltriethoxysilane, respectively. These ligands were then grafted on magnetic mesoporous silica nanoparticles (MMSN) for extraction and separation of Ni(ii) and Co(ii) metal ions from model solutions. The bare and ligand-modified MMSN materials revealed high adsorption capacity (1.0–2.13 mmol g−1) and quick adsorption kinetics, achieving over 80% of the total capacity in 1–2 hours.

Synthesis and antimalarial activity of sulfonamide-attached coumarin-[1,2,3]-triazoles

Drug resistance in malaria parasites is one of the major stumbling blocks hindering the goal of malaria elimination. One of the major strategies to counter drug resistance is the development of new potent antimalarial drugs. In the present study, a series of novel sulfonamide based coumarin-[1,2,3]-triazole conjugates have been synthesized via Huisgen reaction between azidosulfonamides and 4-hydroxy- or 7-hydroxymethylcoumarinoalkynes. All the compounds have been characterized spectroscopically and screened for their in vitro antimalarial activity against P. falciparum 3D7 strain. Out of the twenty five synthesized compounds, four compounds displayed significant activity (IC50 <10 µM) with the most active compound having an IC50 of 3.64 µM.

1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides under "Non-Conventional" Conditions: Green Solvents, Irradiation, and Continuous Flow.

The 1,3-dipolar cycloaddition reactions (DCs) of nitrile oxides (NOs) to alkenes and alkynes are useful methods for the synthesis of 2-isoxazolines and isoxazoles respectively, which are important classes of heterocyclic compounds in organic and medicinal chemistry. Most of these reactions are carried out in organic solvents and under thermal activation. Nevertheless the use of supercritical carbon dioxide (scCO2 ) and ionic liquids (Ils) as alternative solvents and the application of microwave (MW) and ultrasound (US) as alternative activation procedures have evident advantages from the "Green Chemistry" point of view. The critical discussion on the applications of these "unconventional" activation methods and reaction conditions in the 1,3-DCs of NOs is the objective of the present Review.

Star‐Shaped Ferrocene‐Based 1,4‐Disubstituted‐1,2,3‐Triazole Derivatives: Synthesis, Characterization, and Investigation of Linear Optical and Electrochemical Properties

In this study, the star‐shaped ferrocene‐based 1,4‐disubstituted‐1,2,3‐triazole derivatives were designed and synthesized via Huisgen reaction. For this purpose, the [3 + 2] cycloaddition reaction between multi‐(4‐azidobutyl) substituted ferrocene derivatives and ethynylferrocene was carried out in the presence of CuSO4.5H2O as Cu (I) source and ascorbic acid as reluctant for convert the Cu (II) to Cu (I). The optical and electrochemical properties of the final dendrimer‐like ferrocenyl derivatives were evaluated using UV–vis spectroscopy (UV–vis) and cyclic voltammetry (CV) techniques, respectively. The linear relationship between the cathodic and anodic peak currents and the square root of the scan rate was indicated the diffusion‐limited mechanism for the redox process. Furthermore, ferrocene‐based 1,4‐disubstituted‐1,2,3‐triazole derivatives show good electrochemical behavior (the CV and DPV technique) when immobilized on glassy carbon electrode surface using Nafion. In addition, the quantum chemistry study was performed on the synthesized compounds with the DFT approach. The B3LYP/6‐31G(d) method was applied to do TD‐DFT calculations due to its good agreement with experimental data for prediction of UV–Vis spectra.

The Huisgen Reaction: Milestones of the 1,3-Dipolar Cycloaddition.

The concept of 1,3‐dipolar cycloadditions was presented by Rolf Huisgen 60 years ago. Previously unknown reactive intermediates, for example azomethine ylides, were introduced to organic chemistry and the (3+2) cycloadditions of 1,3‐dipoles to multiple‐bond systems (Huisgen reaction) developed into one of the most versatile synthetic methods in heterocyclic chemistry. In this Review, we present the history of this research area, highlight important older reports, and describe the evolution and further development of the concept. The most important mechanistic and synthetic results are discussed. Quantum‐mechanical calculations support the concerted mechanism always favored by R. Huisgen; however, in extreme cases intermediates may be involved. The impact of 1,3‐dipolar cycloadditions on the click chemistry concept of K. B. Sharpless will also be discussed.

Bioinspired All-Polyester Diblock Copolymers Made from Poly(pentadecalactone) and Poly(2-(2-hydroxyethoxy)benzoate): Synthesis and Polymer Film Properties.

The bioinspired diblock copolymers poly(pentadecalactone)-block-poly(2-(2-hydroxyethoxy)-benzoate) (PPDL-block-P2HEB) were synthesized from pentadecalactone and dihydro-5H-1,4-benzodioxepin-5-one (2,3-DHB). No transesterification between the blocks was observed. In a sequential approach, PPDL obtained by ring-opening polymerization (ROP) was used to initiate 2,3-DHB. Here, the molar mass Mn of the P2HEB block was limited. In a modular approach, end-functionalized PPDL and P2HEB were obtained separately by ROP with functional initiators, and connected by 1,3-dipolar Huisgen reaction ("click-chemistry"). Block copolymer compositions from 85:15 mass percent to 28:72 mass percent (PPDL:P2HEB) were synthesized, with Mn of from about 30,000-50,000 g mol-1. The structure of the block copolymer was confirmed by proton NMR, FTIR spectroscopy, and gel permeation chromatography. Morphological studies by atomic force microscopy (AFM) further confirmed the block copolymer structure, while quantitative nanomechanical AFM measurements revealed that the DMT moduli of the block copolymers ranged between 17.2 ± 1.8 MPa and 62.3 ± 5.7 MPa, i.e. between the values of the parent P2HEB and PPDL homopolymers (7.6 ± 1.4 MPa and 801 ± 42 MPa, respectively). Differential scanning calorimetry showed that the thermal properties of the homopolymers were retained by each of the copolymer blocks (melting temperature 90 °C, glass transition temperature 36 °C).

Predicting Absolute Rate Constants for Huisgen Reactions of Unsaturated Iminium Ions with Diazoalkanes.

The kinetics and stereochemistry of the reactions of iminium ions derived from cinnamaldehydes and MacMillan's imidazolidinones with diphenyldiazomethane and aryldiazomethanes were investigated experimentally and with DFT calculations. The reactions of diphenyldiazomethane with iminium ions derived from MacMillan's second‐generation catalysts gave 3‐aryl‐2,2‐diphenylcyclopropanecarbaldehydes with yields >90 % and enantiomeric ratios of ≥90:10. Predominantly 2:1 products were obtained from the corresponding reactions with monoaryldiazomethanes. The measured rate constants are in good agreement with the rate constants derived from the one‐center nucleophilicity parameters N and s N of diazomethanes and the one‐center electrophilicity parameters E of iminium ions as well as with quantum chemically calculated activation energies.

Bioinspired All-Polyester Diblock Copolymers Made from Poly(pentadecalactone) and Poly(3-hydroxycinnamate): Synthesis and Polymer Film Properties.

A bioinspired diblock copolymer was synthesized from pentadecalactone and 3-hydroxy cinnamic acid. Poly(pentadecalactone) (PPDL) with a molar mass of up to 43,000 g mol-1 was obtained by ring-opening polymerization initiated propargyl alcohol. Poly(3-hydroxy cinnamate) (P3HCA) was obtained by polycondensation and end-functionalized with 3-azido propanol. The two functionalized homopolymers were connected via 1,3-dipolar Huisgen addition to yield the block copolymer PPDL-triazole-P3HCA. The structure the block copolymer was confirmed by proton NMR, FTIR spectroscopy and GPC. By analyzing the morphology of polymer films made from the homopolymers, from a 1:1 homopolymer blend, and from the PPDL-triazole-P3HCA block copolymer, clearly distinct micro- and nanostructures were revealed. Quantitative nanomechanical measurements revealed that the block copolymer PPDL-triazole-P3HCA had a DMT modulus of 22.3 ± 2.7 MPa, which was lower than that of the PPDL homopolymer (801 ± 42 MPa), yet significantly higher than that of the P3HCA homopolymer (1.77 ± 0.63 MPa). Thermal analytics showed that the melting point of PPDL-triazole-P3HCA was similar to PPDL (89-90 °C), while it had a glass transition was similar to P3HCA (123-124 °C). Thus, the semicrystalline, potentially degradable all-polyester block copolymer PPDL-triazole-P3HCA combines the thermal properties of either homopolymer, and has an intermediate elastic modulus.

Unexpected Reactions of Terminal Alkynes in Targeted "Click Chemistry'' Coppercatalyzed Azide-alkyne Cycloadditions.

High efficiency in terms of reaction yield and purity has led to the extensive utilization of copper-catalyzed azide-alkyne cycloaddition (CuAAC) in various fields of chemistry. Its compatibility with low molecular weight alcohols promotes the application in surfactant synthesis to tackle the miscibility constraints of the reactants. For the tuning of surfactant properties, double click coupling of the antipode precursors was attempted. Failure of the CuAAC to provide the targeted product in combination with unexpected reaction outputs led to an investigation of the side reaction. The CuAAC-based coupling of sugar azide with propargyl building block in the presence of copper- (I) catalyst exclusively led to the mono-coupling product in a respectable yield of almost 80%. Besides the unexpected incomplete conversion, the loss of the remaining propargyl group, as indicated by both NMR and MS. On the other hand, application of substantial amounts of CuSO4 under reducing conditions in refluxing toluene/water furnished the alkyne dimer in a moderate yield of 43%, while no change of azide compound was noticed. The Cu(I)-catalyst applied for azide-alkyne cycloadditions enables the homo-coupling of certain terminal alkynes at a higher temperature. Moreover, aromatic propargyl ethers may be cleaved to furnish the corresponding phenol. The copper-catalyzed coupling appeared highly sensitive towards the alkyne compound. Only selected derivatives of propargyl alcohol were successfully dimerized. The observed failure of the Huisgen reaction for the synthesis of sugar-based surfactants may indicate non-recognized constrains of the reaction, which could affect its wide application in bioconjugation. The temperature requirement for the alternative dimerization of terminal alkynes renders this side reaction nonrelevant for typical click couplings, while narrow substrate diversity and moderate yield limit its synthetic application.