Synthesis Of Quinoxalines Research Articles

Aspects of green chemistry toward synthesis of benzazoles and quinoxalines: Bovine serum albumin-water system for C–N/C–S bond formation

In this report, a biocatalytic divergent approach of therapeutically important five-membered benzazole heterocyclic compounds such as benzothiazoles and benzimidazoles has been described wherein Bovine serum albumin (BSA) and water play cooperative role for oxidative cyclo-condensation reaction between 2-mercapto/amino anilines and aromatic aldehydes under air at room temperature. Further, this green strategy also extended for the synthesis of privileged and biologically important six membered quinoxalines, 2-phenylimidazo [1,2-a]pyridine and benzo[d]imidazo[2,1-b]thiazoles. Moreover, the present biocatalytic protocol for the synthesis of such five- and six-membered heterocyclic compounds also have the added benefits of high atom economy, operational simplicity, excellent yields, recyclability (up to four cycles), and gram scalability.

An overview of quinoxaline synthesis by green methods: recent reports

Abstract Quinoxalines and their derivatives belong to an important class of bicyclic aromatic heterocyclic system, also known as benzopyrazines, containing a benzene ring and a pyrazine ring. They have attracted considerable attention over the years due to their potential biological and pharmaceutical properties. A wide range of synthetic strategies is reported in this significant area of research. The present review showcases recent research advances in the synthesis of quinoxaline derivatives following environmentally benign approaches.

Synthesis of cinnamils and quinoxalines and their biological evaluation as anticancer agents.

We synthesized multiple cinnamils and quinoxalines to evaluate their anticancer activity. Cinnamils were used as precursors for quinoxalines via condensation with 1,2-diaminobenzene. Among the 26 synthesized compounds reported in this article, we found that cinnamil 3l exhibited its inhibitory effect with an IC50 value of 1.45 ± 0.98 μM, significantly higher than doxorubicin (8.5 ± 0.85 μM) against pancreatic cancer cells (PANC-1). Additionally, cinnamil 3l (IC50 10.98 ± 3.63 μM) showed less cytotoxicity than doxorubicin to Hs68 cells (0.92 ± 1.11 μM). The colony formation assay demonstrated that 3l obviously decreased the PANC-1 cell viability, and Western blot assays confirmed that 3l markedly induced apoptosis of PANC-1 cells through Bax, Bcl-2, and caspase 3 signaling cascades. These results demonstrate that cinnamil 3l has great potential to be further developed as a promising chemotherapeutic agent for pancreatic cancer.

A facile synthesis of quinoxalines by using SO4 2−/ZrO2-TiO2 as an efficient and recyclable heterogeneous catalyst

Quinoxaline derivatives have been synthesized in good to excellent yields by the cyclocondensation reaction of o-pheneylenediamine with substituted phenacyl bromides/benzil in the presence of SO4 2−/ZrO2-TiO2 as an efficient and heterogeneous catalyst. The catalyst can be recovered up to five catalytic cycles without significant loss in catalytic activity. The reported SO4 2−/ZrO2-TiO2 catalyst has been thoroughly characterized by using infrared spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and powder X-ray diffraction (XRD). Here, we have used ethanol as a green solvent in this cyclocondensation. This new method has several advantages, such as excellent yields, short reaction time, nontoxic, and easily recoverable catalyst.

Pyridine-2-yl Quinoxaline (2-CPQ) Derivative As a Novel Pink Fluorophore: Synthesis, and Chemiluminescence Characteristics.

Quinoxaline derivatives are well-known N-heterocycles with pharmacological and fluorescence activities. Almost all quinoxaline derivatives with extensive π-conjugation have been introduced as fluorophores which emit blue and green light. For the first time, we designed and synthesized 6-chloro-2,3 di(Pyridine-2yl) quinoxaline (2-CPQ) as a pink fluorophore in acetonitrile medium by simple route at room temperature whitin 30min. The synthesized quinoxaline was identified using 1H, 13C NMR, MS, and FT-IR spectroscopy. Our results showed that the iodine-catalyzed method for both oxidation and cyclization during the synthesis of quinoxaline from pyridine 2-carbaldehyde was straightforward, efficient, and clean. All of the mentioned characterization devices confirmed the synthesis of 2-CPQ.Moreover, we studied the photophysical properties of the synthesized fluorophore in which The UV-Vis absorption spectrum of 2-CPQ in DMF were three peaks at 451, 518 and 556nm. Based on photophysical properties investigation, 2-CPQ shows good fluorescence with maximum peaks 607 and 653nm in DMF as solvent (фF = 0.21). Hence, the fluorophore was applied in the peroxyoxalate chemiluminescence system. The reaction of imidazole, H2O2, and bis (2,4,6-trichlorophenyl) oxalate (TCPO) can transfer energy to a 6-chloro-2,3 di(pyridine-2yl) quinoxaline. In this process, dioxetane was synthesized, which chemically initiated the electron exchange luminescence (CIEEL) mechanism and led to pink light emission. We anticipate our synthesized fluorophores 2-CPQ will have great potential applications in imaging and medical markers.

Design, Synthesis, and Anti-Proliferative Activity of Quinoxaline Linked 1,2,4-Oxadiazole Hybrids

Design, Synthesis, and Anti-Proliferative Activity of Quinoxaline Linked 1,2,4-Oxadiazole Hybrids

Catalytic oxidative dehydrogenation of N-heterocycles with nitrogen/phosphorus co-doped porous carbon materials.

A metal-free oxidative dehydrogenation of N-heterocycles utilizing a nitrogen/phosphorus co-doped porous carbon (NPCH) catalyst is reported. The optimal material is robust against traditional poisoning agents and shows high antioxidant resistance. It exhibits good catalytic performance for the synthesis of various quinoline, indole, isoquinoline, and quinoxaline ‘on-water’ under air atmosphere. The active sites in the NPCH catalyst are proposed to be phosphorus and nitrogen centers within the porous carbon network.

Design and synthesis of antivirals benzimidazoles and quinoxalines

Background Chronic hepatitis C can cause serious, even deadly, health problems like cirrhosis and liver cancer. There is no vaccine for hepatitis C. The hepatitis C virus (HCV) NS5B gene encodes RNA-dependent RNA polymerase, which is a key player in viral replication and is a promising target for the development of antiviral drugs. Drugs having benzimidazole and quinoxaline scaffolds were described to selectively block the activity of NS5B polymerase. New antiviral drugs have to be developed to overcome drug resistance.Objective The main goal of this work was to develop new effective anti-bovine viral diarrhea virus (BVDV) and anti-HCV agents by designing and synthesizing benzimidazole and quinoxaline derivatives.Materials and methods Synthesis of target compounds based on benzimidazole and quinoxaline scaffolds according to reported methods was done. Antiviral activity against BVDV was studied. BVDV and Madin-Darby bovine kidney cells were obtained from the American Type Culture Collection. Antiviral activity against HCV infectious system was evaluated. Huh7.5.1 cells were cultured and treated with different concentrations of studied compounds. GOLD molecular docking study was evaluated. The crystal structures of the HCV polymerases in complex with its co-crystalized native ligand were retrieved from the Protein Data Bank. Acute toxicity studies were carried out on animals. Results and conclusion A rational design based on the previous work was performed to indicate new promising benzimidazole and quinoxaline derivatives to be synthesized and tested as anti-HCV compounds. New benzimidazole and quinoxaline derivatives were synthesized and tested for anti-BVDV activity. All of the compounds showed strong activity against BVDV, except 17, which exhibited moderate antiviral activity. Compounds 12 and 13 were the most promising. The anti-HCV activity of 12 and 13 was investigated after infection of Huh 7.5.1 cells with HCV (JFH1). The IC50 values of 12 and 13 were found to be 19.1 and 49.4 μM, respectively; their CC50 values were 752.25 and 1480 μM, respectively; and their SI were calculated to be 39.3 for 12 and 30.03 for 13. The assigned compounds were docked into the hepatitis-C virus polymerase enzyme (pdb: 3FRZ) using GOLD 5.2.2 docking program. They revealed GoldScore fitness activities of 69.78–80.71, which is comparable to the native ‘PF-00868554’ ligand as a potent HCV polymerase inhibitor. They are bound by up to three hydrogen bonds, mainly with aminoacids R422 and S476, as well as they were embedded into the two small hydrophobic pockets formed by amino acid residues including L419, M423, L482,and L497. The acute toxicity of compound 12 on rats was tested. No signs of toxicity, no deaths, and no significant changes were observed in the biochemical parameters of liver and kidneys.

Quinoxaline as Ubiquitous Structural Fragment: An Update on the Recent Development of its Green Synthetic Approaches

Quinoxaline is a versatile heterocyclic moiety that possesses a wide range of biological activities. Therefore, many researchers have been performing the synthesis of quinoxaline derivatives on a daily basis. In addition, high demands for their synthesis often result in an increased generation of different waste chemicals. However, to minimize the utilization and generation of toxic organic substances, the present review focuses on the various green synthetic approaches for the synthesis of quinoxaline and its derivatives. Moreover, due to the quick manufacturing of novel medications using a quinoxaline scaffold, multiple study reports are published in a short period of time. Therefore, to fully comprehend the current state of the quinoxaline scaffold in medicinal chemistry, it is necessary to combine recent findings with previous understanding. Besides, compared to conventional methods, these green methods minimize the use and generation of harmful chemicals and improve reaction efficiency in terms of product yields, purity, energy consumption, and post-synthetic procedures. Therefore, in this review, we have attempted to shed light on various green synthetic strategies leading to the synthesis of quinoxaline scaffold and its derivatives, such as ultrasound irradiation, microwave irradiation, grindstone technique, environmentally benign solvents/catalysts based, and reactant immobilized on a solid support, etc.

Ionic‐Liquid‐Catalyzed Synthesis of Imines, Benzimidazoles, Benzothiazoles, Quinoxalines and Quinolines through C−N, C−S, and C−C Bond Formation

AbstractWe report the tetramethyl ammonium hydroxide catalyzed oxidative coupling of amines and alcohols for the synthesis of imines under metal‐free conditions by utilizing oxygen from air as the terminal oxidant. Under the same conditions, with ortho‐phenylene diamines and 2‐aminobenzenethiols the corresponding benzimidazoles and benzothiazoles were obtained. Quinoxalines were obtained from ortho‐phenylene diamines and 1‐phenylethane‐1,2‐diol, the conditions were then extended to the synthesis of quinoline building blocks by reaction of 2‐amino benzyl alcohols either with 1‐phenylethan‐1‐ol or acetophenone derivatives. The formation of C−N, C−S and C−C bonds was achieved under metal‐free conditions. A broad range of amines (aromatic, aliphatic, cyclic and heteroaromatic) as well as benzylic alcohols including heteroaryl alcohols reacted smoothly and provided the desired products. The mild reaction conditions, commercially available catalyst, metal‐free, good functional‐group tolerance, broad range of products (imines, benzimidazoles, benzothiazoles, quinoxalines and quinolines) and applicability at gram scale reactions are the advantages of the present strategy.

Tungstophosphoric acid/mesoporous silicas as suitable catalysts in quinoxaline synthesis

Quinoxalines and their derivatives are of great value in the chemical and biological sciences. These compounds are found in dyes, agrochemicals, and are used as building blocks of drugs for the treatment of different diseases. Quinoxalines and their derivatives are synthesized by a heterogeneous catalysis procedure that involves the condensation of 1,2-dicarbonyl compounds with aromatic 1,2-diamines in an aprotic organic solvent at low temperature, in the presence of an acid catalyst composed of tungstophosphoric acid immobilized on mesoporous silica nanoparticles. The reaction process is very simple and the catalyst, besides being very active and selective, can be easily isolated from the reaction medium and reused in subsequent reactions without considerable loss of activity. Quinoxalines are obtained in short reaction time with excellent yields and high purity.

Regioselective Synthesis of Trisubstituted Quinoxalines Mediated by Hypervalent Iodine Reagents.

A facile and regioselective synthesis of quinoxalines, an important motif in medicinal chemistry and materials sciences, was developed. Despite their prospective utility, the regioselective preparation of trisubstituted quinoxalines has not been previously established. In the reported system, hypervalent iodine reagents catalyzed the annulation between α-iminoethanones and o-phenylenediamines in a chemo/regioselective manner to afford trisubstituted quinoxalines. Excellent regioselectivities (6:1 to 1:0) were achieved using [bis(trifluoroacetoxy)iodo]benzene and [bis(trifluoroacetoxy)iodo]pentafluorobenzene as annulation catalysts.

Nanostructured Mesoporous Zinc-Incorporated Copper Oxide (NMZI-CuO): An Efficient and Reusable Nanocatalyst for the Oxidant-Free Synthesis of Quinoxalines through a Tandem Oxidation Process

A nanostructured mesoporous zinc-incorporated copper oxide with different Cu/Zn molar ratios was prepared through a facile hydrothermal template-free route. Textural properties of prepared materials were studied with various techniques such as TEM, BET, XRD, FTIR, and XPS. The prepared mesoporous zinc-incorporated copper oxide was then successfully applied as a heterogeneous catalyst for the synthesis of quinoxaline derivatives from 1,2-diamines and α -hydroxy ketones through a tandem oxidation process (TOP) without any oxidant. Using this method all desired products were obtained with good to excellent yields in relatively short times under solvent-free conditions. The applied catalyst was simply isolated and reused several times without any detectable loss of catalytic activity.

BTP‐Rh@g‐C3N4 as an efficient recyclable catalyst for dehydrogenation and borrowing hydrogen reactions

AbstractHighly active catalysts play an important role in modern catalysis. A novel and efficient ligand benzotriazole‐pyrimidine (BTP) and the corresponding rhodium composite on C3N4 were successfully synthesized. The resulting rhodium composite was fully characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), x‐ray diffraction (XRD), thermogravimetric analysis (TGA), and x‐ray photoelectron spectroscopy (XPS). The obtained composite exhibited good catalytic activity and good recovery performance in the synthesis of quinoxaline from 2‐aminobenzyl alcohol and benzonitrile, and more than 20 quinoxalines were obtained in good yields. Additionally, it also showed that rhodium composite could achieved good catalytic performance in the synthesis of functionalized ketone through borrowing hydrogen strategy.

Recent Advances on the Synthesis, Reactions and Evaluation of the Pharmacological Properties of Quinoxaline, Quinoxaline-2-One and Quinoxaline-2,3-Dione

The review article attempts to give recent advances on quinoxaline and its derivatives. Some pathways to the synthesis of quinoxaline, quinoxaline-2-one and quinoxaline-2,3-dione were reported using simple reactive quinoxaline synthon. In addition, the reactions, biological and technological applications of derivatives of quinoxaline and related compounds were reported.

Exporting Metal‐Carbene Chemistry to Live Mammalian Cells: Copper‐Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N−H Carbene Insertions

AbstractImplementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha‐keto diazocarbenes with ortho‐amino arylamines, in a process that is initiated by an N‐H carbene insertion. The potential of this transformation is underscored by the in cellulo synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door to significantly expanding the repertoire of life‐compatible abiotic reactions.

Exporting Metal-Carbene Chemistry to Live Mammalian Cells: Copper-Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N-H Carbene Insertions.

Implementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha‐keto diazocarbenes with ortho‐amino arylamines, in a process that is initiated by an N‐H carbene insertion. The potential of this transformation is underscored by the in cellulo synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door to significantly expanding the repertoire of life‐compatible abiotic reactions.

Silica supported dodecatungstophosphoric acid (DTP/SiO2): An efficient and recyclable heterogeneous catalyst for rapid synthesis of quinoxalines

A facile synthesis of quinoxalines by the cyclocondensation of substituted phenacyl bromides with o-pheneylenediamines using silica-supported dodecatungstophosphoric acid (DTP/SiO2) as a recyclable heterogeneous catalyst is unveiled in this research work. This method is practicable due to environmentally benign, easy workup, high yield, less reaction time, low cost, mild reaction condition, and recyclable heterogeneous catalyst. The catalyst can be easily recovered from the reaction mixture only by filtration and reused up to five catalytic cycles without significant loss of catalytic activity and product yield. This leads to making the process more affordable.

Green Hydrothermal Synthesis of Fluorescent 2,3-Diarylquinoxalines and Large-Scale Computational Comparison to Existing Alternatives.

Invited for this month's cover is the group of Miriam Unterlass at the Technische Universität Wien and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. The image illustrates the synthesis of quinoxalines in "hot water" and the large-scale computational comparison of all existing syntheses of these quinoxalines. The Full Paper itself is available at 10.1002/cssc.202100433.

An efficient synthesis, characterization and docking studies of 2‐methoxy‐3‐(1‐substituted‐1H‐pyrazol‐3‐yl)quinoxalines

AbstractA basic, proficient and P‐TSA catalyzed synthesis of quinoxalines beginning from ethyl 3‐methoxyquinoxaline‐2‐carboxylate in great yields is introduced. All the compounds synthesized were analyzed by spectral analysis.