Green  Synthesis of Quinoxaline derivatives

 

Jairaj K. Dawle¹*,  K. I. Momin⁴ , S R Mathapati², A. S. Bondge³, Suryawanshi V. B.⁴

¹Department of chemistry, Rajshri Shahu Mahavidhyalaya , Latur.

²Department of Chemistry, S. M. P. College, Murum, Omerga, Dist: Osmanabad.

³Department of chemistry, Shivneri Mahavidhyalaya, Shirur Anantpal Dist Latur.

⁴Department of Chemistry, K M C College , Khopoli Dist Raigad.

*Corresponding Author E-mail: amritkund_jk@rediffmail.com

 

The objective of present research work is to provide green technique for synthesis of 2,3-diphenyl quinoxaline. Quinoxaline derivatives are well known in the pharmaceutical industry. A simple, highly efficient and green procedure for the condensation of o-phenylenediamine with α-diketones in the presence of catalytic quantity of iodine. Thevery mild reaction conditions, the high yields of the products, and the use of water as solvent make this methodology an efficient and green route for synthesis of quinoxalines derivatives.

 

 

 

INTRODUCTION

Development of strategically important processes which are environmentally cleaner and more efficient which lead to greater structural variation, with simple work up, high yields, purity, and minimizes the formation of waste, is currently receiving considerable attention [1]. In this context, water played an important role in these processes. Water is an elegant solution with the ultimate goal of hazard-free, waste-free and energy efficient for the synthesis of biologically active compounds with potential application in the pharmaceutical or agrochemical industries [2-4]. Quinoxaline derivatives are ubiquitous in many biologically important compounds [5,6] such as antibiotics, which are known to inhibit the growth of Gram-positive bacteria and are also active against various transplantable tumors [7].

 

Furthermore, their synthesis on using zeolites [8,9], microwave [10] and solid phase synthesis [11] and zinc [12] catalyst, and CAN [13] have also been reported. Obviously, our goal was to develop highly efficient, green and preparative simple procedure for industrial large-scale production of quinoxaline with simple condensation of aromatic 1,2-diketones and 1,2-diamines with high purity and in excellent yield without catalyst in pure water.

 

Quinoxalines are a versatile class of nitrogen containing heterocyclic compounds and they constitute useful intermediates in organic synthesis and medicinal chemistry. Quinoxaline derivatives possess a broad spectrum of biological activities including anti-bacterial, anti-viral, anti-inflammatory, anticancer, and kinase inhibitors.[14] Conventionally, quinoxaline synthesis can be achieved by the reaction of 1,2- phenylenediamine with two-carbon synthones such as α-dicarbonyls,[15,16] α-halogeno carbonyls, α- hydroxycarbonyls, α-azocarbonyls, epoxides, and α, β-dihalides.[17,18]

 

 

The antibiotics amoxicillin, norfloxacilin and ciprofloxacin have been the therapeutic agents used to prevent their consequences [19], but these drugs have undesired secondary effects and increased chronic toxicity and microbes have developed resistance to most of them [20]. The mode of action for quinoxalines is based on MAO inhibitory activity, because the docked positions of these compounds reveal interactions with many residues that have an effect on the inhibition of the enzyme [21].

 

Some quinoxaline derivatives have been synthesized using microwave irradiation [22] but there is no systematic information about their spectroscopic attributes. It’s known that microwave conditions avoid the polymerization reactions due to the controlled hot spots formed during the heating by molecular friction of dipolar molecules [23].

 

The quinoxaline ring moiety is part of the chemical structure of various antibiotics such as echinomycine, levomycine and actinoleutine [24] that are known to inhibit growth of Gram-positive bacteria. Ionic liquid [25] have received considerable interest as Eco-friendly solvents, catalysts and reagents in organic synthesis because of their unique properties, such as low volatility, no flammability, high thermal stability negligible vapor pressure and ability to dissolve a wide range of material.

On the basis of literature survey, we have planned to synthesized quinoxalines derivatives using diamine and substituted benzil. In present work we had use green methodology for the synthesis of quinoxalines derivatives i.e. stirring method, because of its advantages over conventional method.Our interest in green chemistry led us to contemplate the possibility of using Iodine in water as highly potential solvent for quinoxaline synthesis.

 

RESULT AND DISCUSSION:

Our goal was to develop highly efficient, green and preparative simple procedure for industrial large-scale production of quinoxaline with simple condensation of aromatic 1,2-diketones and 1,2-diamines with high purity and in excellent yield with iodine catalyst in pure water. Reaction mixture was stirred at reflux conditions for the 60- 200 min. The compounds reported in this research work ie. Derivatives of quinoxaline. Final compounds are prepared due to its biological activity. The yield and malting point of synthesized compounds are given in Table. Present methodology gives excellent yield of products for the electron donating as well as electron withdrawing groups. Both substituted reactant i.e. diamine and diketones gives 100% transformation with good yield. The result shows water is the good green solvent for the quinolone synthesis.

 

Experimental Work:

All the chemicals used for synthesis were of LR (Laboratory Reagent) grade. TLC (Thin Layer Chromatography) was performed on microscopic glass slides coated with silica gel-G, using benzene: ethyl acetate (9:1) as a solvent systems and the spots were visualized by exposure to iodine vapours. The IR spectrum of synthesized compounds was recorded on FT-IR Spectrophotometer using potassium bromide.

 

General procedure for Synthesis of quinoxaline catalyzed by iodine in water:

A mixture of o-phenylenediamine 3.24 gm and 1,2-dicarbonyl 6.30, catalytic amount of iodine in water (10 mL) were added and stirred at reflux conditions for the 60- 200 min. After the reaction was completed, pure products were isolated by filtration and washing with hot water. Aqueous mixture was extracted with 10 ml of ethyl acetate and dried over anhydrous Na₂SO₄, and solvent was removed under reduce pressure to give the desired products. The crude product was analyzed by 1H and 13C NMR. Further purification was carried out by crystallization.

 

 

 

 

 

 

Spectral analysis of synthesized compound.

2,3-Diphenylquinoxaline(3a): mp: 128–129 °C; I.R. (CH2Cl2): 3058, 1345, 697 cm−1; 1H-NMR: 8.18 (1H, d), 8.17 (1H, d), 7.77 (1H, d), 7.76 (1H, d), 7.51 (4H, m,), 7.34 (6H, m) ; 13C-NMR: 155.43 (C2, C3), 141.20 (C4a),139.05 (C1′), 129.90 (C5, C5′), 129.80 (C2′), 129.17 (C4′), 128.76 (C6, C6′), 128.22 (C3′); HR MS (m/z)282.1157 (calc.), 282.1156 (exp.).

 

2,3-(4-chloro-phenyl)quinoxaline 3b:Mp 150-151°C; 1HNMR (CDC13, 500 MHz)δ ppm: 8.08 (dd, 2H), 8.00 (dd, 2H), 7.94 (dd, 4H), 7.30-7.52 (m, 4H); 13C NMR (CDC13, 125MHz)δ ppm:152.7, 141.7, 140.6, 139.5 132.3 130.3, 129.5, 129.0, 128.8, 128.1; IR (KBr) νmax (cm-1): 3060, 1540, 1550, 1341, 1210, 845, 730.

 

6-Methyl-2,3-diphenylquinoxaline 3c:mp 117-119°C; 1H NMR (DMSO/d6, 500 MHz) δ ppm: 8.12 (d, 1H),7.92(s, 1H), 7.60 (dd,1H), 7.52 (m, 4H), 7.32 (m, 6H), 2.62 (s, 3H); 13C NMR (DMSO/d6, 125 MHz)δ ppm: 153.7, 153.0, 141.7, 140.8, 140.1, 139.7, 132.7, 130.3, 129.1,129.0128.6, 128.4, 22.3; IR (KBr)νmax (cm-1): 3060, 1662, 1590, 1212, 870, 711, 642.

 

6-nitro-2,3-diphenylquinoxaline 3d:Mp192-193°C; 1H NMR (CDC13, 125 MHz) δ ppm:9.12 (d, 1H), 8.50 (dd, 1H,), 8.38 (d, 1H), 7.58 (m, 4H), 7.42; (m, 6H); IR (KBr) νmax (cm-1): 3052,

2933, 1625, 1338, 1139.

 

CONCLUSIONS:

A gentle, efficient and environmentally benign method has been developed for the synthesis of quinoxalines that is established as more important in every respect in comparison to the previously reported method. The method is tested appropriately for aromatic diketones. The advantages of this method are efficiency, completeness, excellent yield, short reaction time, cleanest reaction profile, simplicity, easy work up.

 

 

 

Table: Analytical data of synthesized Quinoxalines derivatives.

 

 

 

REFERENCES:

[1].      Adams D. J., Dyson P. J., and Tavener S. J. (2005) Chemistry in alternative reaction media, Ed, John Wiley and Sons.

[2].      Leadbeater N. E. (2005) Fast, easy, clean chemistry by using water as a solvent and microwave heating: The suzuki coupling as an illustration. Chem. Commun., (23), 2881-2902.

[3].      Manabe K., Iimura S., Sun X.M., and Kobayashi S. (2002) Dehydration reactions in water. Brønsted acid-surfactant-combined catalyst for ester, ether, thioether, and dithioacetal formation in water. J. Am. Chem. Soc., 124(40), 11971-11978.

[4].      Chankeshwara S. V., and Chakraborti A. K. (2006) Catalyst-free chemoselective n-tertbutyloxycarbonylation of amines in water. Org. Lett., 8(15), 3259-3262.

 [5].     Sarges R., Howard H. R., Browne R. G., Lebel L. A., Seymour P. A., and Koe B. K. (1990) 4-amino [1, 2, 4] triazolo [4, 3-a] quinoxalines. A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. J. Med. Chem., 33(8), 2240-2254.

[6].      Gomtsyan A., Bayburt E. K., Schmidt R. G., Zheng G. Z., Perner R. J., Didomenico S., Koenig J. R., Turner S., Jinkerson T., and Drizin I. (2005) Novel transient receptor potential vanilloid receptor antagonists for the treatment of pain: Structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties. J. Med. Chem.,48 (3), 744-752.

 [7].     Dell A., Williams D. H., Morris H. R., Smith G. A., Feeney J., and Roberts G. C. (1975) Structure revision of the antibiotic echinomycin. J. Am. Chem. Soc., 97(9), 2497-2502.

 [8].     Antoniotti S., and Duñach E. (2002) Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1, 2-diamines. Tetrahedron Lett.,43(22), 3971-3973.

[9].      Raw S. A., Wilfred C. D., and Taylor R. J. (2003) Preparation of quinoxalines, dihydropyrazines, pyrazines and piperazines using tandem oxidation processes. Chem. Commun.,(18)., 2286-2287.

 [10].   Zhou J. F., Gong G. X., Shi K. B andZhi S. J (2009) Montmorillonite K-10: an efficient and reusable catalyst for the synthesis of quinoxaline derivatives in water. Chin. Chem. Lett., 20, 672.

 [11].   Wu Z., and Ede N. J. (2001) Solid-phase synthesis of quinoxalines on synphase™ lanterns. Tetrahedron Lett.,42(45), 8115-8118.

[12].    Heravi M. M., Tehrani M. H., Bakhtiari K., and Oskooie H. A. (2007) Zn [(l) proline]: A powerful catalyst for the very fast synthesis of quinoxaline derivatives at room temperature. Catal. Commun., 8(9), 1341-1344.

[13].    Heravi M. M., Bakhtiari K., Bamoharram F. F., and Tehrani M. H. (2007) Wells-dawson type heteropolyacid catalyzed synthesis of quinoxaline derivatives at room temperature. Monatsh Chem., 138(5), 465-467.

 [14].   More S. V., Sastry M., and Yao C.-F. (2006) Cerium (iv) ammonium nitrate (can) as a catalyst in tap water: A simple, proficient and green approach for the synthesis of quinoxalines. Green Chem., 8(1), 91-95.

[15]     Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. Synthesis of new quinoxaline-2-Carboxylate 1,4-dioxide derivatives as anti-Mycobacterium tuberculosis agents. J. Med. Chem. 2005, 48, 2019-2025.

[16]     More, S. V.; Sastry, M. N. V.; Wang, C. C.; Yao, C. F. Molecular iodine: a powerful catalyst for the easy and efficient synthesis of Quinoxalines. Tetrahedron Lett. 2005, 46, 6345-6348.

[17]     Driller, K. M.; Libnow, S.; Hein, M.; Harms, M.; Wende, K.; Lalk, M.; Michalik, D.;Reinke, H.; Langer, P. Synthesis of 6H-indolo[2,3b]quinoxaline-N-glycosides and their cytotoxic activity against human ceratinocytes (HaCaT). Org. Biomol. Chem. 2008, 6, 4218-4223.

[18]     Antoniotti, S.; Dunach, E. Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1,2-diamines. Tetrahedron Lett. 2002, 43, 3971-3971.

[19]     Das, B.; Venkateswarlu, K.; Suneel, K.; Majhi, A. An efficient and convenient protocol for the synthesis of quinoxalinesanddihydropyrazinesvia cyclization-oxidation processes using HClO4.SiO2 as a heterogeneous recyclable catalyst. Tetrahedron Lett. 2007, 48, 5371-5374.

[20].    Sur, D.M.; Dutta, P.; Nair, G.B.; Bhattacharya, S.K. Severe cholera outbreak following floods in a northern district of West Bengal. Indian J. Med. Res. 2000, 112, 178–182.

[21].    Rezaee, M.A.; Sheikhalizadeh, V.; Hasani, A. Detection of integrons among multi-drug resistant (MDR) Escherichia coli strains isolated from clinical specimens in Northern West of Iran. Br. J. Microbiol. 2011, 42, 1308–1313.

[22].    Sherine, N.K.; Seham, Y.H.; Adnan, A.B.; Abdel, M.E.; Vratislav, L.; Adel, A. Synthesis of new series of quinoxaline based MAO-inhibitors and docking studies. Eur. J. Med. Chem. 2010, 45, 4479–4489.

[23].    Jian, F.Z.; Giu, X.G.; Li, T.A.; Yu, L.; Feng, X.Z.; Shun, J.J. An efficient synthesis of quinoxalines under catalyst-free and microwave irradiation conditions. Synlett2008, 20, 3163–3166.

[24].    Zhang, X.Z.; Wang, J.X.; Bai, L. Microwave-assisted synthesis of quinoxalines in PEG-400 Synth. Commun. 2011, 41, 2053–2063.

[25].    Cheeseman, G.W.; Cookson, R.F. Condensed pyrazines. In The Chemistry of the Heterocyclic Compounds; Weissberger, A., Taylor, E.C., Eds.; John Wiley and Sons: New York, NY, USA, 1979; pp. 1–27, 35–38.

 

 

 

 

Received on 15.11.2016         Modified on 24.11.2016

Accepted on 30.11.2016         © AJRC All right reserved