Synthesis Of Quinoxalines Research Articles

Efficient Synthesis of Quinoxalines by I2/AgNO3 Co‐Promoted One‐Pot Annulation of Alkynes with 1,2‐Arylenediamines

AbstractAn efficient I2/AgNO3 co‐promoted one‐pot annulation of alkynes with 1,2‐arylenediamines into quinoxalines is reported. The reaction proceeded smoothly under mild conditions and rapidly generated quinoxalines (37 examples) in good to excellent yields (up to 83 %) with a good tolerance of functional groups. Moreover, π‐conjugated polycyclic quinoxaline derivatives could also be successfully synthesized by this one‐pot strategy. Furthermore, a gram‐scale reaction of the one‐pot reaction is also investigated. Finally, a plausible mechanism for the one‐pot reaction is proposed.

MgxCu0.3Zn0.7-xLayFe2-yO4 Magnetic Mixed Metal Oxide Nanocatalyst: Synthesis, Characterization and Application for One-Pot N-Heterocycle Synthesis

The nano size Cu-Zn ferrite particles substituted to Mg2+ and La3+ having general chemical formula MgxCu0.3Zn0.7-xLayFe2-yO4 (x = 0.1, 0.2, 0.3, 0.4, 0.5; and y = 0.0, 0.025, 0.050, 0.075, 0.10) prepared through sol-gel method. The prepared mixed metal oxide nanoparticles were characterized employing techniques such as X-ray diffraction (XRD), scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM) analyses. The prepared MgxCu0.3Zn0.7-xLayFe2-yO4 magnetic nanoparticles were used as a efficient, recoverable and heterogeneous catalyst for the one-pot synthesis of quinoxalines 3(a–g) and 1,5-benzodiazepines 5(a–h) under mild reaction conditions in good yields. The recyclability of catalyst was tested for five times without significant decrease in the catalytic activity. Catalyst has been used for the synthesis of different derivatives of quinoxalines in short time (20 to 30 min) with 90 -97% yield. Also, different derivatives of 1,5-benzodiazepines have been synthesized in short time (15 to 30 min) with 89 -98% yield using the catalyst.

A rapid synthesis of quinoxalines by using Al2O3–ZrO2 as heterogeneous catalyst

In this study, we present a highly efficient and environmentally benign protocol for synthesizing biologically important quinoxaline derivatives. The synthesis involves the reaction of 1,2-diamines with substituted phenacyl bromides or benzil, taking place at room temperature in N,N-dimethylformamide (DMF) solvent. The reaction is facilitated by a bifunctional heterogeneous catalyst composed of Al2O3–ZrO2 binary metal oxide. Our method offers numerous advantages, including excellent product yield, renewable catalytic conditions, minimal catalyst usage, safer chemistry, short reaction time, and a simple work-up procedure. To determine the chemical structure of the synthesized derivatives, we employed characterization techniques such as nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Additionally, the Al2O3–ZrO2 catalyst was characterized using X-ray diffraction (XRD), scanning electron microscopy with energy-dispersive X-ray analysis (SEM-EDAX), and thermogravimetric analysis (TGA).

Synthesis of Quinoxalines through Cu-electrocatalytic Azidation/Annulation Cascade at Low Catalyst Loading.

A Cu-electrocatalytic azidation of N-aryl enamines and subsequent denitrogenative annulation for the construction of quinoxaline frameworks is reported. Only 0.5 mol % of copper(II) chloride was employed for this cascade transformation displaying excellent functional-group compatibility even with complex bioactive scaffolds. The efficient electro-oxidative protocol enables the use of NaN3 as the cheapest azide source. Detailed mechanistic experiments, cyclic voltammetry, and spectroscopic studies provided strong evidence for a dual role of the Cu catalyst in azidyl and iminyl radical generation steps.

Base-promoted facile synthesis of quinoxalines from β, β-dibrominated secondary enamides and o-phenylenediamines

Herein, we report a base-promoted reaction of β, β-dibrominated secondary enamides and o-phenylenediamines, thus providing facile access to quinoxaline scaffold, a prevalent structural motif in biologically active molecules. This reaction does not require metal catalysts or oxidants, and operates simply, and tolerates a wide array of functional groups.

Visible light-induced metal-free synthesis of quinoxalines
 using Rose Bengal as a photocatalyst

Visible light-induced metal-free synthesis of quinoxalines
 using Rose Bengal as a photocatalyst

Visible light-induced synthesis of biomass-derived quinoxaline by using Co phthalocyanine immobilized on pyridine-doped g-C3N4

Visible light-driven valorization of biomass has recently been a pioneering field for nitrogen-containing heterocyclics syntheses due to its sustainable features. Herein, various aromatic ring-doped g-C3N4 nanosheets (Ar-g-C3N4; Ar = Py, Pm, Ph) were precisely designed to modulate their intrinsic electronic and band structure, which involves pyridine (Py), pyrimidine (Pm), and benzene (Ph)-doped g-C3N4. Photocatalysts (CoPc/Ar-g-C3N4) of cobalt(II) phthalocyanine (CoPc)-fabricated Ar-g-C3N4 were then developed for oxidative cyclization of furoin with 1,2-phenylenediamines for syntheses of various biomass-derived quinoxalines under visible-light irradiation. The catalytic activity (in terms of TOFs) of serial CoPc/Ar-g-C3N4 samples increased with their transient photocurrents with CoPc/Py-g-C3N4 as the most active one. For CoPc/Py-g-C3N4, CoPc species functioned as both sensitizer and catalytic sites; while, doped Py led to a narrowed bandgap energy. Mechanism research further demonstrated that O2 was activated to superoxide radical (•O2−) by photoexcited high-level-energy electron (HLEE) transfer from Py-g-C3N4 to CoPc for the subsequent aerobic oxidation.

Synthesis, non-covalent interactions and chemical reactivity of 1-pentyl-3-phenylquinoxalin-2(1H)-one — Structural and computational studies

This contribution presents the synthesis of a new quinoxaline derivative, 1-pentyl-3-phenylquinoxalin-2(1H)-one with formula C19H20N2O, through an alkylation reaction, followed by a thorough structural characterization. X-ray crystallography revealed that π-stacking and unconventional CH…O/π hydrogen bonding play a significant role in the supramolecular solid-state framework. These interactions are further assisted by infrequent CO…π interactions and CH…HC dispersive contacts. These non-covalent interactions (NCIs) are analyzed in terms of geometrical criteria, and Hirshfeld surface analysis is used to demonstrate their individual contributions. The nature and strength of prevalent NCIs are thoroughly discussed via computational tools NCI, NBO, and QTAIM. Moreover, the application of Density Functional Theory (DFT) at the wB97X-D/cc-pVTZ level yields valuable insights into both the global and local chemical reactivity of studied compound, thereby enhancing our understanding of the chemistry involved in the synthesis of quinoxaline and its derivatives.

An ultrasound assisted green protocol for the synthesis of quinoxaline based bisspirooxindoles: Crystal structure analysis, enone umpolung, DFT calculations, anti-cancer activity, and molecular docking studies

A series of novel quinoxaline based bisspirooxindolo-pyrrolizidines were synthesized through 1,3-dipolar cycloaddition under ultrasonication with shorter reaction time and good yields. The compounds were well characterized by various spectroscopic methods and finally single crystal X-ray diffraction method (4c, 4d). DFT energy calculations confirm the regioselectivity due to enone umpolung effect. The in vitro anti-cancer activity of the synthesized compounds (4a–s) shows that the compounds 4g and 4q exhibited good anti-cancer activity with IC50 values14.51 ± 1.1 and 11.36 ± 0.23 µM against DU-145 prostate cancer cell line; and 16.78 ± 0.95 and 14.28 ± 0.64 µM against Hela cervical cancer cell lines when compared to the standard anti-cancer drug doxorubicin (1.75 ± 0.06 and 1.35 ± 0.09 µM). In silico molecular docking studies indicated that the synthesized compounds may serve as a potential lead for the further development of novel anti-cancer agents.

Glucose as an eco-friendly reducing agent for a one-pot multicomponent synthesis of quinoxalines

An efficient and scalable one-pot multicomponent process is developed for the synthesis of quinoxalines by using D-glucose as a clean, renewable and an eco-friendly reductant in an alkaline aqueous medium. This protocol eliminates the nitro reduction by using pyrophoric metal catalysts like Pd, Ni, Zn, etc., and cyclization as separate steps for the synthesis of quinoxalines. Gram scale experiments and further substrate scope of the reaction have also been well demonstrated.

Towards selective synthesis of quinoxalines by using transition metals-doped carbon aerogels

Transition metal (TM)-carbon aerogels, where TM = Mo, Fe, Co or Cu, were found to be active and selective catalysts for the synthesis of quinoxalines 1, from o-phenylenediamine 2 and α-hydroxy ketones 3, becoming an efficient and sustainable alternative to other carbon-based catalysts or even MOF.Doping metal phase consisting of the corresponding metal oxides but also as zero-valent metals depending on the metal and carbonization temperature, and metal loading at the surface of carbon aerogel are key factors conditioning both reactivity and selectivity. Although metal oxides are probably the predominant active catalytic species, zero-valent metals nanoparticles (Cu0 or Co0) could be implied in the last dehydrogenation step of the reaction. Moreover, the additional functionalization with oxygenated surface groups (Co-1000PO catalyst) resulted on an enhanced reactivity probably due to the cooperation between both functions. Remarkably, Mo-500 catalyst was the most efficient sample selectively leading to the quinoxaline 1a in high conversion.Finally, our results strongly suggest different operative pathways when using TM-doped carbon aerogels depending on the metallic phase at the carbon surface. While TM-doped carbon aerogels (where TM = Fe, Co, or Cu) probably act catalyzing a sequential acid-base steps and subsequent aromatization leading to the corresponding quinoxaline 1a, Mo-doped catalyst would work via the initial oxidation of α-hydroxy ketones followed by condensation-dehydration reactions.

Reusable nano-catalyzed green protocols for the synthesis of quinoxalines: an overview.

Heterocyclic compounds are very widely distributed in nature and are essential for life activities. They play a vital role in the metabolism of all living cells, for example, vitamins and co-enzyme precursors thiamine, riboflavin etc. Quinoxalines are a class of N-heterocycles that are present in a variety of natural and synthetic compounds. The distinct pharmacological activities of quinoxalines have attracted medicinal chemists considerably over the past few decades. Quinoxaline-based compounds possess extensive potential applications as medicinal drugs, presently; more than fifteen drugs are available for the treatment of different diseases. Diverse synthetic protocols have been developed via a one-pot approach using efficient catalysts, reagents, and nano-composites/nanocatalysts etc. But the use of homogeneous and transition metal-based catalysts suffers some demerits such as low atom economy, recovery of catalysts, harsh reaction conditions, extended reaction period, expensive catalysts, the formation of by-products, and unsatisfactory yield of products as well as toxic solvents. These drawbacks have shifted the attention of chemists/researchers to develop green and efficient protocols for synthesizing quinoxaline derivatives. In this context, many efficient methods have been developed for the synthesis of quinoxalines using nanocatalysts or nanostructures. In this review, we have summarized the recent progress (till 2023) in the nano-catalyzed synthesis of quinoxalines using condensation of o-phenylenediamine with diketone/other reagents with plausible mechanistic details. With this review, we hope that some more efficient ways of synthesizing quinoxalines can be developed by synthetic chemists.

Sustainable synthesis of azobenzenes, quinolines and quinoxalines via oxidative dehydrogenative couplings catalysed by reusable transition metal oxide–Bi(iii) cooperative catalysts

Heterogeneous catalytic oxidative dehydrogenative processes for N-heterocycles are presented, which enable waste-minimized (additive-, oxidant-, base-free), efficient cyclisations/couplings via transition metal oxide–Bi(iii) cooperative catalysis.

DMSO/tBuONa/O2-mediated efficient syntheses of diverse quinoxalines through α-imino radicals.

Herein, we describe an efficient method involving the synthesis of diverse quinoxalines using the DMSO/tBuONa/O2 system as a single-electron oxidant to form α-imino radicals and nitrogen radicals for the direct construction of C-N bonds. This methodology provides a novel approach to form α-imino radicals with good reactivity.

An electrochemical tandem oxidative azidation and intramolecular cyclization strategy for the synthesis of quinoxaline derivatives.

An electrochemical-oxidation-induced intramolecular annulation for the synthesis of quinoxalines was developed under undivided electrolytic conditions. N-Aryl enamines and TMSN3 as the starting materials could smoothly participate in the transformation to achieve the construction of two C-N bonds through tandem azidation and cyclic amination reactions. The reaction could be easily handled and avoided the use of transition metal catalysts as well as chemical oxidants, which makes it compatible with the sustainable development of green chemistry.

Carbon Microsphere Supported Copper Nanoparticles (Cu-NP/C): A Highly Efficient and Reusable Catalyst for the Synthesis of Quinoxalines

Carbon Microsphere Supported Copper Nanoparticles (Cu-NP/C): A Highly Efficient and Reusable Catalyst for the Synthesis of Quinoxalines

Ca(IO3)2 nanoparticles: fabrication and application as an eco-friendly and recyclable catalyst for the green synthesis of quinoxalines, pyridopyrazines, and 2,3-dicyano pyrazines

In this paper, calcium iodate nanoparticles were first synthesized by the modified reaction of Ca(NO3)2 and KIO3 in an aqueous medium under ultrasonic irradiation. The structure of nanocatalyst was then characterized by FT-IR, FESEM, EDX, XRD, and BET techniques. Afterward, the fabricated Ca(IO3)2 was applied as a nanocatalyst in the facile synthesis of heterocycles including quinoxalines, 5,6-dicyano pyrazines, and pyrido[2,3-b]pyrazines. For this purpose, the feasibility of the reaction in the presence of different catalyst amounts, solvents, and temperatures was first investigated. Next, the target compounds were obtained by the condensation reaction of aryl-1,2-diamines or 2,3-diaminomaleonitrile with 1,2-diketones in the presence of a catalytic amount of Ca(IO3)2 in ethanol or acetic acid solvents at ambient temperature in good to excellent yields. One of the salient advantages of this work is the synthesis of calcium iodate nanoparticles by chemical precipitation method and its application as a heterogeneous nanocatalyst for the first time in the synthesis of organic compounds. The other important benefits of this process are the use of an inexpensive, safe, stable and recyclable catalyst, high product yields, short reaction times, and easy isolation of the product in pure form.

Anchoring of a nickel Schiff base complex with mixed ligands on MCM-41 as a heterogeneous catalyst for the synthesis of quinoxaline derivatives by various energies

A new class of heterogeneous catalyst, a nickel Schiff base complex of mixed ligands on MCM-41, has been synthesized. The Ni-MCM-41 catalyst has been characterized by FT-IR, PXRD analysis, N2 adsorption and desorption, elemental mapping-EDX, SEM and TEM microscopy, ICP-OES, TGA and 13C-CP-MAS-NMR. The catalyst was used for the green synthesis of quinoxaline derivatives via a simple condensation through thermal heating, ultrasonication and microwave irradiation. This environmentally benign method provides several advantages, such as mild reaction conditions, short reaction time, excellent yield of up to 99 %, operational simplicity, catalyst stability, heterogeneous nature and easy retrievability of the catalyst by filtration. The catalyst can be reused for up to four cycles without significant deterioration in the catalytic activity. The effectiveness of the energy sources for the synthesis of quinoxalines is as follows: microwave irradiation > ultrasonication > thermal heating. The efficiency of our catalyst is also compared against literature reports and the results are discussed.

Design, Synthesis, and Biological Evaluation of quinoxaline bearing tetrahydropyridine derivatives as anticancer, antioxidant, and anti-tubercular agents.

Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates. The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents. A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2. The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties. These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.

Synthesis, characterization of new heterocyclic compound: pyrazolyl hydrazino quinoxaline derivative: 3-[5-(hydroxy1methyl)-1-phenylpyrazol-3-yl]-2-[2, 4, 5-trimethoxybenzylidine] hydrazonyl-quinoxaline of potent antimicrobial, antioxidant, antiviral, and antitumor activity

Pyrazole and quinoxaline synthesis is gaining popularity due to its wide range of pharmacological qualities, including antiviral, antagonist, antibacterial, anticancer, anti-inflammatory, analgesic, anti-prostate cancer, herbicidal, acaricidal, and insecticidal effects. A novel and innovative heterocyclic biologically active compound, 3-[5-(hydroxy1methyl)-1-phenylpyrazol-3-yl]-2-[2, 4, 5-trimethoxybenzylidine] hydrazonyl-quinoxaline abbreviated as (TMPyrQu) is prepared by simple low-cost method. The chemical structure of the compound is assigned based on IR, 1H NMR, 13C NMR as well as elemental analysis. TMPyrQu showed potent antimicrobial activity: higher antibacterial activity against p. aeruginosa, E. coli, S. aureus, Streptomyces (inhibition zone (mm) 16, 14, 19, 18, 12), respectively, than the standard antibiotic ampicillin for bacteria with corresponding inhibition zone (mm) (12, 11, 9, 13).The antifungal activity of TMPyrQu is higher than ampicillin Fluconazole biocide (inhibition zone of 16 mm and 11 mm, respectively). It also demonstrated robust antiviral activity against the hepatitis B and good anticancer activity and cytotoxicity on the cell lines HepG-2 (liver carcinoma) and MCF-7 (breast carcinoma), with higher performance for breast cancer. The TMPyrQu molecule has the potential to be a powerful anticancer and immunosuppressive medication. TMPyrQu showed strong antioxidant activity that represented a first-line defense against free radical and reactive oxygen species (ROS), that target lipids, protein, and nucleic acid contributing to the progression of many chronic diseases. The novelty of this study is that it is the first time a multidisciplinary biologically active compound has been synthesized and evaluates its biological activity as well as its effectiveness against breast and liver tumor from a chemical, biochemical and medicinal perspective. The lack of adequate evaluation of such promising biocompatible biologically active compounds, despite the fact that the COVID-19 virus affects the entire world is the driving factor behind this work.