Benzyl Azide Research Articles

Synthesis of new 1,2,3-triazole-linked pyrimidines by click reaction

A mild and efficient synthesis of 1,4-disubstituted 1,2,3-triazole linked pyrimidines is reported using click reactions. These compounds were prepared by the reaction of 4-propargyl substituted 5-iodo-6-methyl-2(methylthio) pyrimidine with aryl and benzyl azides via copper-catalyzed azide-alkyne cycloaddition reactions in the presence of sodium ascorbate, as a reducing agent. Furthermore, the synthesized compounds were screened against the two bacterial strains pseudomonas aeruginosa and saphylococcus aureus.

Electron-withdrawing effect of polyoxometalates in Cu(I)-based metal–organic frameworks for enhanced azide-alkyne “click” reaction

Boosting the nucleophilicity of Cu(I) sites is an essential strategy to enhance the efficiency of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. In this work, a Lindquist-type polyoxometalate (POM)-based metal–organic framework, [CuI4(W6O19)2(L)]·2H2O (NEAU-1), was synthesized via an in-situ solvothermal method. Single-crystal X-ray diffraction results reveal that NEAU-1 exhibits a sandwich structure, with POMs intercalated between the two-dimensional layers formed by resorcin[4]arene ligands and Cu(I) ions. NEAU-1 possesses abundant Cu(I) active sites and high chemical stability, making it an effective heterogeneous catalyst for the CuAAC reaction. More importantly, the presence of POMs effectively reduces the electron cloud density around Cu(I) sites, significantly lowering the energy barrier for the formation of copper-acetylide compounds and facilitating subsequent nucleophilic reactions. The synergistic catalytic effect of POMs and Cu(I) can achieve a conversion rate of over 99 % for benzyl azide and phenylacetylene within 40 min. This work presents a sustainable molecular-level strategy to enhance the activity of the CuAAC reaction.

Pyrazoline Spiro-oxindole tethered 1,2,3-triazole hybrids: Design, synthesis, antimicrobial efficacy and molecular modelling studies.

Inspired from the important applications of spirocyclic compounds in medicinal chemistry, a new series of pyrazoline Spiro-oxindole tethered 1,2,3-triazole hybrids was reported via Cu(I)-catalyzed click reaction from isatin-pyrazoline linked terminal alkynes with in situ derived benzyl azides. Antimicrobial evaluation data showed that all hybrids exhibited promising efficacy towards the tested microbial strains. Antimicrobial screening as well as docking studies suggested that hybrid 6a was found to be most potent towards Aspergillus niger (MIC = 0.0122μmol/mL) and Escherichia coli (MIC = 0.0061μmol/mL). Molecular docking studies of 6a within the binding pockets of antibacterial and antifungal targets revealed good interactions with the binding energies of - 144.544kcal/mol and - 154.364kcal/mol against 1KZN (E. coli) and 3D3Z (A. niger), respectively. Further, MD simulations were performed to study the stability of the complexes formed at 300K. Based on the RMSD trajectories, it is evident that 3D3Z-6a complex exhibits minimal deviation, whereas the 1KZN-6a complex displayed little more deviation compared to the protein but, both are in acceptable range. Moreover, 3D3Z-6a and 1KZN-6a showed maximum number of hydrogen bonds at 50ns and 70ns, respectively, thereby complementing the stability of these complexes.

Unveiling Route for the Synthesis of Tröger's Bases Through Azide Rearrangement.

This study introduces a novel method for producing Tröger's bases by utilizing the rearrangement chemistry of benzyl azide. This method offers a convenient and adaptable pathway for synthesizing these important molecular structures with potential for further advancements. By reacting benzyl azide derivatives with TfOH under the presence of water, this process generates iminium ion, formaldehyde, and aniline intermediates in situ. Notably, this conversion is reversible under acidic conditions, allowing for the regeneration of the iminium ion and ultimately leading to the formation of the desired Tröger's base product. Additionally, this method could decrease the risk of exposure to an excess amount of formaldehyde.

Reactivity of Tetrel-Functionalized Heptaphosphane Clusters toward Azides.

In this work, the reactivity of tetrel-functionalized phosphorus clusters toward organoazides is probed. Clusters (Me3Si)3P7 (1) and (Me3Ge)3P7 (2) were reacted with benzyl azide, phenyl azide, and 4-bromophenyl azide, and it was found that the [RN] (R = benzyl, phenyl, and 4-bromophenyl) unit from the azide inserted into the phosphorus-tetrel bonds on the cluster, accompanied by N2 elimination. Through control of the azide stoichiometry, the mono-, bis-, and tris-inserted products could be observed, consistent with these insertions proceeding in a stepwise manner. The bonding between the amine moieties and clusters was further investigated by computational chemistry, and the findings were consistent with the phosphorus cluster having undergone a formal oxidation. These insertion reactions are a convenient means of accessing Zintl clusters functionalized with exo-nitrogen-bonded moieties, which, to the best of our knowledge, were previously unknown.

Fluoride Abstraction Induced by Tris(pentafluoroethyl)difluorophosphorane: A Convenient Way to Synthesize Cationic N-Heterocyclic Carbene- and Cyclic (Alkyl)(amino)carbene-Ligated Copper Alkyne and Arene Complexes.

We herein report the convenient synthesis of different N-heterocyclic carbene (NHC)- and cyclic (alkyl)(amino)carbene (cAAC)-ligated copper cations using the weakly coordinating tris(pentafluoroethyl)trifluorophosphate counterion (FAP anion, [(C2F5)3PF3]-). The reaction of the fluorido complexes [(carbene)CuF] (carbene = NHC, cAACMe) 2a-2f and the tris(pentafluoroethyl)difluorophosphorane (C2F5)3PF2 in the presence of alkynes or arenes led to fluoride transfer from Cu to the phosphorane with formation of the cationic transition metal complexes [(carbene)Cu(L)]+ and the weakly coordinating counteranion [(C2F5)3PF3]- (FAP). Using this method, the complexes [(IDipp)Cu(L)]+FAP- (IDipp = 1,3-bis(2,6-di-iso-propylphenyl)-imidazolin-2-ylidene; L = PhC≡CPh, 4d; PhC≡CMe, 5d), [(cAACMe)Cu(L)]+FAP- (cAACMe = 1-(2,6-di-iso-propylphenyl)-3,3,5,5-tetramethyl-pyrrolidin-2-ylidene; L = PhC≡CPh, 4f; PhC≡CMe, 5f), [(SIDipp)Cu(C6Me6)]+FAP- (6e), (SIDipp = 1,3-bis(2,6-di-iso-propylphenyl)-imidazolidine-2-ylidene), and [(cAACMe)Cu(C6Me6)]+FAP- (6f) have been synthesized and characterized. The complexes [(IDipp)Cu(C6Me6)]+FAP- (6d) and [(cAACMe)Cu(C6Me6)]+FAP- (6f) have been used as catalysts for the copper(I)-catalyzed cycloaddition of benzyl azide to terminal alkynes.

Exploiting Orthogonal C-C Cross-Coupling Reactions for Chemistry-on-the-Complex: Modular Assembly of 2,6-Di(quinolin-8-yl)pyridine Ruthenium(II) Photosensitizer Triads.

In this work, we present a concise modular assembly strategy using one universal heteroleptic 2,6-di(quinolin-8-yl)pyridine-based ruthenium(II) complex as a starting building block. Extending the concept from established ligand modifications and subsequent complexation (classical route), the later appearing chemistry-on-the-complex methodology was used for late-stage syntheses, i.e., assembling discrete building blocks to molecular architectures (here: dyad and triads). We focused on Suzuki-Miyaura and Sonogashira cross-couplings as two of the best-known C-C bond forming reactions. Both were performed on one building block complex bearing a bromine and TIPS-protected alkyne for functional group interconversion (bromine to TMS-protected alkyne, a benzyl azide, or a boronic acid pinacol ester moiety with ≥95% isolated yield and simple purification) as well as building block assemblies using both a triarylamine-based donor and a naphthalene diimide-based acceptor in up to 86% isolated yield. Additionally, the developed purification via automated flash chromatography is simple compared to tedious manual chromatography for ruthenium(II)-based substrates in the classical route. Based on the preliminary characterization by steady-state spectroscopy, the observed emission quenching in the triad (55%) serves as an entry to rationally optimize the modular units via chemistry-on-the-complex to elucidate energy and electron transfer.

Hydroquinone-treated Cu3(BTC)2: a mixed-valence Cu(I/II) MOF catalyst for efficient cycloadditions.

We present mixed-valence Cu(I)1Cu(II)2(BTC)2 [henceforth Cu(I/II)-HKUST-1], post-synthetically prepared via the hydroquinone (H2Q) treatment of Cu(II)3(BTC)2 (also referred to as HKUST-1) and its subsequent catalytic activity. This Cu(I/II)-HKUST-1 exhibits exceptional structural integrity and superior catalytic performance in the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between phenylacetylene and benzyl azide. These findings highlight the potential of mixed-valence Cu-based MOFs as effective and sustainable heterogeneous catalysts for organic transformations, paving the way for future advancements in MOF-based catalysis.

PCy3-assisted Ag(I)-catalyzed click reaction for regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature.

An approach towards Cu-free click chemistry has been developed in this work. Silver-catalyzed PCy3-ligand-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature has been developed. Regioselectivity of the reaction was confirmed from the results of single-crystal X-ray diffraction (SC-XRD) of one of the products. SC-XRD of ex situ-generated Ag-PCy3 complex helped us propose a plausible mechanism for the reaction. This reaction was indicated to exhibit a catalytic activity level similar to that for the in situ-generated complex. The methodology was found to work well with benzyl azides, phenyl azides, terminal alkynes and internal alkynes in aqueous medium. The one-pot three-component reaction leading to 1,2,3-triazole synthesis also proceeded well.

Angle-strained sila-cycloalkynes.

Second row elements in small- and medium-rings modulate strain. Herein we report the synthesis of two novel oligosilyl-containing cycloalkynes that exhibit angle-strain, as observed by X-ray crystallography. However, the angle-strained sila-cyclooctynes are sluggish participants in cycloadditions with benzyl azide. A distortion-interaction model analysis based on density functional theory calculations was performed.

Controllable synthesis of hollow mesoporous organosilica nanoparticles with pyridine-2,6-bis-imidazolium frameworks for CO2 conversion.

A series of hard-template-derived hollow mesoporous organosilica nanoparticles (HMONs) with pyridine-2,6-bis-imidazolium frameworks have been described for the first time. As a part of the investigation, to evaluate the effects of the hard template nature, the Si/CTAB and organosilica/TEOS molar ratios, and the stepwise addition of precursors, four reaction conditions denoted as methods A-D were designed. In the presence of polystyrene latex as a hard template, the HMONs that we wished to synthesize were not yielded with a Si/CTAB molar ratio of 3 (method A), but we could synthesize the desired HMONs with a Si/CTAB molar ratio of 9 and an organosilica : TEOS ratio of 1 : 99 (method B). The ratio of organosilica to TEOS could be improved up to 2.5 : 97.5 if the precursor additions are made in a stepwise manner rather than by simultaneous additions (method C). Using sSiO2 as a hard template, a yolk-shell morphology was observed by adopting a Si/CTAB molar ratio of 3 (method D). The HMONs were modified by iodide ions and their activity was explored toward the coupling of CO2 with epoxides. Among the catalysts, I-HMON-L-C-2.5 exhibited excellent results under mild reaction conditions. Well-oriented pore sizes and short channel length facilitated easy mass transfer from one side and the integration of the interior hollow regions of the catalyst particles from the other side improved the CO2 retention time around pores where the imidazolium organocatalysts were located, which made I-HMON-L-C-2.5 an effective catalyst for title CO2 utilization. The catalyst was reused at least six times without exhibiting any changes in its activity. HMONs can also be used as solid CNC ligands for the preparation of copper catalysts for the click reaction between phenyl acetylene and benzyl azide.

Hetero Diels-Alder reactions of isolable N-borylenamines.

A new strategy for N-borylenamines by reaction of 2-alkynyl benzyl azides with B(C6F5)3 was developed. This novel 1,3-carboboration reaction proceeded via a 5-exo-dig cyclization/formal 1,1-carboboration/B(C6F5)2 shift reaction sequence. Additionally, N-borylenamines can undergo hetero Diels-Alder (HDA) reactions with a variety of dienophiles. Our results are an attractive complement to HDA reactions.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Synthesis, X-ray crystallography, antimicrobial, molecular docking, and DFT study of bis-triazoles linked ampyrone

A new class of bis-triazoles linked with ampyrone molecules was synthesized from ampyrone-linked bis-alkyne with different benzyl azides under Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. All compounds were characterized by FTIR, 1H NMR, 13C NMR, and ESI-MS data. However, the structures of solid crystalline compounds 4a and 4h were finally supported by X-ray crystallographic data. In vitro, antimicrobial activity results of synthesized alkyne 2 and bis-1,2,3-triazoles 4a-4k showed that the incorporation of triazole units has augmented the antimicrobial activity of all compounds, except 4a for E. coli. Also, compound 4f was found potent against all bacterial strains (E. coli, S. aureus, and P. aeruginosa, each with MIC: 0.0178 µmol/mL) with superior efficacy to B. subtilis (MIC: 0.0089 µmol/mL) compared to standard antibacterial drug ciprofloxacin (MIC: 0.0094 µmol/m). Almost all synthesized triazoles showed superior potency to both fungal strains except 4a, 4g, and 4k against R. oryaze, C. albicans, and R. oryaze, respectively. Computational molecular docking and DFT results supported experimental antimicrobial results for improvement in the activity of all triazoles except 4a.

Technetium Complexes with an Isocyano-alkyne Ligand and Its Reaction Products.

The attachment of an ethyne substituent in the para position of phenylisocyanide, CNPhpC≡CH, enables the isocyanide to replace carbonyl ligands in the coordination sphere of common technetium(I) starting materials such as (NBu4)[Tc2(μ-Cl)3(CO)6]. The ligand exchange proceeds under thermal conditions and finally forms the corresponding hexakis(isocyanide)technetium(I) complex. The product undergoes a copper-catalyzed cycloaddition ("Click" reaction), e.g., with benzyl azide, which gives the [Tc(CNPhazole)6]+ cation. The free, uncoordinated "Click" product is obtained from a reaction of the corresponding tetrakis(CNPhazole)copper(I) complex and NaCN. It readily reacts with mer-[Tc(CO)3(tht)(PPh3)2](BF4) (tht = tetrahydrothiophene) under exchange of the thioether ligand. Alternatively, [Cu(CNPhazole)4]+ can be used as a transmetalation reagent for the synthesis of the hexakis(isocyanide)technetium(I) complex, which is the preferable approach for the synthesis of the technetium complex with the short-lived nuclear isomer 99mTc, and a corresponding protocol for [99mTc(CNPhazole)6]+ is reported. The 99Tc and copper complexes have been studied by single-crystal X-ray diffraction and/or spectroscopic methods including IR and multinuclear NMR spectroscopy.

Hybrid pyrazoline-triazole fluorescent dyes: Synthesis, photophysics, electrochemical, and antioxidative activity

A four-step reaction method to synthesize a new series of 1-benzyl-4-((2-(1,5-diaryl-4,5-dihydro-1H-pyrazol-3-yl)phenoxy)methyl)-1H-1,2,3-triazoles (5) and their photophysical and electrochemical evaluation is reported herein. The synthetic method comprises: (i) Michael condensation between 2-hydroxy-acetophenone and aryl aldehydes to obtain chalcones, (ii) a [3 + 2] cyclocondensation reaction involving chalcones and phenylhydrazine to reach the 2-pyrazolines (1), (iii) an O-alkylation reaction of 1 with propargyl bromide (2) to give O-propargylated 2-pyrazolines 3, and (iv) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving benzyl azide (4) and 2-pyrazolines 3 to furnish the desired triazole series (5) as a new hybrid polycyclic system at total yields of up to 51%. Steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, with varying values of fluorescence quantum yields (Φf) and Stokes Shift (SS), according to solvent polarity. In the solid state, the compounds showed similar behavior to the study of the absorption and emissive properties in solution. TD-DFT calculations revealed that all compounds had delocalized electron density along the pyrazoline unit and were not influenced by the attached substituent or change in solvent polarity. In addition, electrochemical and DPPH antioxidant analyses were performed.

Imine‐Linked Porous Organic Polymer Gel and Immobilization of Copper(II): Easy Synthesis and Excellent Catalyst for Huisgen [3+2] Cycloaddition Reactions

AbstractPorous organic polymeric gels (POP gels) were made by condensation of a newly synthesized C3‐symmetrical azobenzene‐based tri‐salicylaldehyde building block, 1,3,5‐tris(4‐((3‐formyl‐4‐hydroxyphenyl)diazenyl)phenyl)benzene (TAzo) with suitable aromatic tri‐ and di‐amines in N,N‐dimethylformamide (DMF) at ambient conditions. Here, we have furnished the pathway of an efficient, gentle, and simple one‐pot synthesis of imine‐linked porous organic polymers at room temperature without any acid catalysts. Detail rheological properties of the POP‐gels were studied and were also found to be stable for at least a year at room temperature. Nitrogen isotherm revealed the mesoporous nature of the gel‐powders with moderate surface area. Iminophenol moieties are known to provide binding sites to metallic species via the strong coordination interaction with hydroxy (−OH) and imine (−HC=N−) groups. We have successfully synthesized a copper‐metallated POP by immobilizing copper ions in one of the POP‐gels. The mesoporous POP material having 3 wt % copper loading was utilized for the solvent‐free Huisgen [3+2] cycloaddition reactions of various aryl, benzyl, and alkyl azides with terminal alkynes containing aromatic, heteroaromatic, and alkyl groups with excellent yield. The heterogeneous catalyst with low catalyst loading (1 mol %) was highly regioselective towards 1,4‐disubstituted 1,2,3‐triazoles, recyclable, and did not require the addition of a reducing agent.

Stereoselective Approach to Hydroxyalkyl-1,2,3-triazoles Containing Cyclooctane Core and Their Use for CuAAC Catalysis

1,2,3-Triazoles bearing additional functional groups have found applications as the ligands in catalysis of a broad scope of reactions, synthesis of transition metals complexes for various practicable purposes, and design of metal-based drugs. Triazolyl ligands accelerating CuAAC reactions, such as TBTA and TTTA, are nowadays commonly used in organic synthesis, and the search for novel ligands with a less complicated structure represents an important task. In the present work a series of hydroxyalkyltriazoles, containing a cyclooctane core, were synthesized via cycloaddition of readily available individual diastereomers of azidoalcohols or diazidodiols with phenylacetylene. The obtained hydroxyalkyltriazoles were probed as ligands for CuAAC reactions of benzyl azide with acetylenes, and 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol was demonstrated to act as an effective ligand for these processes. The complex salt of the abovementioned triazole and CuCl2 was readily obtained. According to X-ray diffraction analysis data, the complex contained two molecules of triazole, in which only N1-atoms of the triazole ring acted as coordination centers. Such a molecular structure correlates well with the efficiency of 1-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cyclooctanol as a ligand in CuAAC reactions: it is able to coordinate copper ions and, at the same time, it forms a sufficiently labile complex to not withdraw copper ions from the catalytic cycle.

New calix[4]resorcinol rccc diastereoisomer with terminal triple bonds: Synthesis, structural features and reactions

One-pot acid-catalyzed cyclocondensation of 2-methyl-resorcinol with 4-(propargyloxy)benzaldehyde in CHCl3/CF3CO2H media affords all-cis (rccc) and/or cis-trans-trans (rctt) calix[4]resorcinol diastereomers bearing four terminal alkyne groups at aromatic substituents, the isomer ratio and yield being dependent on the CHCl3/CF3CO2H ratio. The rctt isomer (kinetic control product) can be converted to thermodynamically more stable rccc isomer at prolonged refluxing in CHCl3/CF3CO2H mixture. The rccc diastereomer was subjected to additional propargylation followed by the click reactions with benzylic azides to afford new highly triazolated calix[4]resorcinols.

N-Heterocyclic Imine Supported Bimetallic Cu(II) Catalyst for Azide-alkyne cycloaddition: Solvent-free, Reductant free, ppm level catalysis to access 1,4-disubstituted triazoles.

In this article, we present a unique bimetallic paddle wheel copper (II) complex with the molecular formula [Cu2C42H54N6O8]. Several characterization tools have been employed to analyze this complex including, single-crystal X-ray diffraction, HRMS, FTIR, and UV-vis spectroscopy. This Copper (II) complex excels admirably as a catalytic system in Parts-per-million level (ppm) loading for the azide-alkene 'click' reaction under solvent-free conditions, allowing for the quantitative conversion of numerous 1,4-disubstituted 1,2,3-triazole. The specially designed coordinated ligand (perimidin-2-imine) in the Cu(II) complex accelerates the reaction rate significantly during the oxidative homocoupling reaction (OHC) and acts as a base for Cu-coordinated alkyne deprotonation. It has been demonstrated that the catalyst loading of 2.5 ppm is adequate to catalyze the cycloaddition of benzyl azide to phenylacetylene, leading to the extremely high turnover number of 120000 and a turnover frequency of 5000 h-1. Synergistic evidence from stoichiometric reactions and experimental results provides insights into the plausible mechanism for the reaction. Each copper atom contributes to the outcome of the proposed reaction, one by bonding to the acetylide and the other by activating the azide as part of a bimetallic synergistic pathway.