Dinesh Bharagava et al. / Journal of Pharmacy Research 2012,5(1),130-134 Review Article Available online through ISSN: 0974-6943 http://jprsolutions.info Recent trends in synthesis of quinoxaline and its derivatives *Dinesh Bharagava1 and Dr. Gopal Garg2 1Shekhawati College of Pharmacy, Dundlod, District-Jhunjhunu (Raj.) India 2VNS Institute of Pharmacy, Bhopal (M.P.) India Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011

ABSTRACT Quinoxaline is nitrogen containing heterocyclic nucleus made up of benzene ring and pyrazine ring. It is a wonderful nucleus which gives almost all type of biological activity. So due to diversity in biological activity, it attracts the researchers to find out more its biological activity. But its traditional synthesis suffers from variety of disadvantage such as pollution, high cost, low yield, tedious work-up and long reaction time. Recently different methods have been developed for synthesis of quinoxaline derivatives by use of microwave and catalyst. In present study, we provide a concise review on history, chemistry, different methods of quinoxaline synthesis and its biological activity.

Key words: Quinoxaline, o-Phenylenediamine, Diketones, Benzopyrazine, Quinoxalin-2-one

INTRODUCTION

1 2. HISTORY 8 N N Quinoxaline is heterocyclic compound containing benzene ring and pyrazine 8 a 2 7 ring. Pyrazine is water soluble and stable colourless compound. In quinoxaline, benzene ring is fused with diazines compounds. The pyrazine ring system is present in the fungal metabolite aspergillic acid and also in luciferin. Methoxy 6 3 4 a pyrazine are essential component of aroma of many fruits and vegetables such N N 5 4 as capsicum and peas [32]. Benzene Pyrazine Quinoxaline Nucleus 3. CHEMISTRY The melting point of quinoxaline is 29-300C and is soluble in water. It is basic Quinoxaline is important nitrogen containing heterocyclic compound containing in nature and form salt when react with acid. On oxidation of quinoxaline a ring complex made up of a benzene ring and a pyrazine ring in medicinal different types of products are formed depending upon oxidation in acidic and chemistry. For examples, quinoxaline is a part of various antibiotics such as basic medium. With paracid quinoxaline di-N-oxide is formed, while with echinomycin, levomycin and actinolutin that are known to inhibit growth of alkaline KMnO4 pyrazine 2,3-dicarboxylic acid is produced. gram positive bacteria [1-2]. Derivatives of quinoxaline have different type pharmacological activity like antibacterial [3-9], antifungal [10-11], antiviral O [12], antineoplastic [13-15], antidepressant [16-17], anticonvulsant [18], anti-inflammatory [19-20], antithrombotic [21], NMDA antagonistic activity N [22], antiglucoma activity [23], antimalarial activity [24], antituberculosis activity [25-26] and anti HIV activity etc [27]. In addition, quinoxaline compounds possess intrinsic diuretic, uterotonic, hypertensive and phosphodiesterase inhibitor activity. They are also used in agriculture field as H N OO herbicides, fungicides and insecticides. In addition, quinoxaline derivatives are CO H 3 also useful in formation of dyes, efficient electron luminescent materials, C O organic semiconductor, cavitands and dehydoannulenes [28-30]. N

Because of wide range of variety and applications associated with quinoxaline moieties, their synthesis has remained the goal of many research groups over the years. Several kinds of synthetic routes towards quinoxaline have been N developed, including condensation of aryl-1,2 diamines with a 1,2-diketones, N COOH Alk. KMnO4 bicatalyzed oxidative coupling of epoxides with ene-1,2-diamines, hetero- annulations of nitro ketene N,S-arylamino acetal with POCl3, cyclization of a-hydroxy ketone via a tandem oxidation process using Pd(OAc)2 or RuCl2- N COOH (PPh3)3-TEMPO as well as MnO2. But methods that have been established for preparation of quinoxaline derivatives are associated with one or more of the following drawbacks like low yield, long reaction time and harsh reaction It is worth to mention that the benzenoid moity in quinoxaline ring resistant conditions [31]. towards the usual electrophilic reagents employed in aromatic substitution.

Nitration of quinoxaline occurs only under condition like conc. HNO3, Conc. In present study, we provide a concise review on different types of synthesis H OS and 900C temperature to produce 5-nitro quinoxaline and 5,7-dinitro- methods of quinoxaline and its derivatives to select proper procedure and 2 4 eliminate above drawbacks. quinoxaline [33]. NO 2 NO2

N N *Corresponding author. Nitration O2N N Mr. Dinesh Bhargava Shekhawati College of Pharmacy, N Dundlod, Jhunjhunu, (Raj.) India N N

Minor Major

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 130-134 Dinesh Bharagava et al. / Journal of Pharmacy Research 2012,5(1),130-134

Electrophilic substitution of aromatic ring of quinoxaline usually occurs at H position 6. Thus saponification of quinoxaline 2,3-dione with fuming sulphuric R1 N R1 NH2 acid yield the sulphonic acid derivative. O Cl

N H O S NH O O D 3 Cl Cl R2 R2

H2SO4 HNO N NH O 3

Quinoxalin-2 one reacts with alkyl or aryl magnesium halides to yield the H H corresponding 3-substituted tetrahydro-quinoxalinones and gives nucleophilic R N R N 1 H 1 reactions. Cl 2 Cl

N N H O O O R2 NH2 R2 NO2 RMgX

O H N N R R= CH3, Ph X= B r, I H H R1 N O R1 N O O Reduction of quinoxaline was achieved by Raney nickel catalyst to 2 hydroquinoxaline. According to Harmer and Halliday methods quinoxaline is reduced to 1,4-di-N-hydroquinoxaline and 1,2,3,4-tetrahydroquinoxaline. R2 N R2 N H H N N Raney N ickel Scheme 5. The most of the important method to prepare 1H-quinoxalin-2- (z) ones was by oxidation of the corresponding 3,4-dihydro-1-H-quinoxalin-2- H 2 or LiA lH 4/ ether ones by using H O in acidic medium reported by Perkin et al [36]. N 2 2 N H

NH2 H H H N N N NaOH O2 ClCH2COOH

NH2 O N O N N a/ ethanol N H H H Scheme 6. Wageeh et al was used ethyl bromoacetate instead of chloroacetic 3. SYNTHESIS OF QUINOXALINE AND ITS DERIVATIVES acid in acetonitrial as solvent, triethylamine as catalyst and obtained directly 1H-quinoxalin-2-ones in addition to 3,4-dihydro-1-H-quinoxalin-2-ones [37]. Scheme 1. Quinoxaline is prepared by the reaction of o-phenylenediamine NH2 H H with glyoxal. N O N O O H N BrCH2COOEt NH 2 NH2 N N NH 2 -Water H N O H Scheme 7. Mohammad et al reported synthesis of quinoxalines using o-phe- nylenediamine and á-hydroxy ketones as reactants in acetic acid by micro- Scheme 2. 2-Phenyl quinoxaline has been prepared by reaction between wave irradiation and simple heating methods [38]. phenylacyl chlorides with o-phenylenediamine [33]. H

NH 2 Cl N NH 2 HO N N H2C AcOH or Reflux NH2 NH2 or microwave N C6H5 O N N O C6H5 H

Scheme 3. Pranab et al was synthesized quinoxaline derivative via condensation of aryl 1,2-diamine with 1,2-dicarbonyl compounds in MeOH at room Scheme 8. An efficient and simple method of 1,4-dihydro-quinoxaline-2,3- temperature in absence of acid, base or catalytic support. This is eco-friendly dione synthesis was reported by Harjyoti et al in 2006. In this method o- method and yield of product is more than 78% by this procedure [34]. phenylenediamine was react with oxalic acid dehydrate at room temperature by simple grinding in pestle mortar. This method is solvent free method which NH has advantage to prevent use of expensive and toxic solvent [39]. 2 N R R1 O 1 aq. MeOH H O OH N O NH2 RT, Grinding

NH RT, 2-6 hr 2 N R O R2 2 NH OH O N O 2 H Scheme 4. Xun et al has reported a synthetic method to prepare regioselective isomers of quinoxaline having different substitutes by synthesis of Scheme 9. The N-substituted quinoxalines can be formed from N-substituted dihydroquinoxalinones and its oxidation into the corresponding quinoxalinones phenylenediamine. Thus 1,4-di-N- (p-toluenesulphonyl)-2-methoxy carbo- [35]. Journal of Pharmacy Research Vol.5 Issue 1.January 2012 130-134 Dinesh Bharagava et al. / Journal of Pharmacy Research 2012,5(1),130-134 nyl 1,2,3,4-tetrahydro quinoxaline was obtained by reaction of 2,3-dimethyl O R2 acetylene carboxylate with N,N’-di-(p-toluenesulphonyl)-1,2-phenylenedi- H2N 1 mol % Ga(OTf) R2 N amine . 3 TS EtOH H N COOCH N 3 O R2 H2N R1 R2 N R1 TS H3CO 2C

TS CCO 2CH3 N N Scheme 15. Molecular iodine is also excellent catalyst for synthesis of H quinoxaline derivatives at room temperature from aliphatic or aromatic 1,2- TS diketones and aromatic 1,2-diamines [44].

Scheme 10. Quinoxaline-N-oxide was prepared from cyclization of a- Nitroacetanilide, obtained from o-Nitroaniline and substituted acetyl chlo- NH2 O N ride. I2

O Temp. 25°C R NH2 O N H NH2 N O NH

NaOC2H5 NO 4. DIFFERENT ACTIVITY OF QUINOXALINE NUCLEUS 2 C2H5OH N R NO2 4.1 Antifungal Activity O R=CH3COPhCN Lot of derivative of quinoxaline were found to exhibit significant fungicidal activity like trizolo or tetrazolo quinoxaline, imidazoquinoxaline fused to pyridine, pyrazoloquinoxalines and 3-phenyl-7-tri-fluromethyl-quinoxaline- Scheme 11. A microwave-assisted synthesis of quinoxaline derivative was N-oxide [10,11]. reported Gries et al. In this method o-phenylenediamine or 2,3- diaminenaphthahlene react with variety of a-keto acids in presence of micro- 4.2 Antineoplastic activity bial enzyme [40]. Substituted quinoxaline derivatives have been prepared and tested for antineoplastic activity. Some compound was found to be highly activity as a H NH2 HO O N O cytotoxic agent example quinoxaline-1,4- di-N-oxide derivatives. On other Microwave hand, a benzoquinoxaline derivative found remarkable cytotoxic effect against different sarcoma types [13-15]. S.cereviciae NH2 O R N R 4.3 Antidepressant activity Several [1,2,4]-triazolo quinoxaline derivatives have been synthesized and H found to possess potent selective adenosine antagonistic activity [16,17]. NH2 HO O N O Microwave 4.4 Anticonvulsant activity 6-chloro-1,4-dihydroquinoxaline-2,3-diones and N,N-dibenzyl-2,3 dioxo- S.cereviciae 1,2,3,4-tetrahydroquinoxaline-6-sulphonamide showed significant NH2 O R N R anticonvulsant activity. In addition, a series of 4-sstyryl-tetrazolo-[1,5- a]quinoxaline was synthesized and evaluated against anticonvulsant activity Scheme 12. Heravi et al has carried out the synthesis of quinoxalines and by PTZ animal model [18]. quinoxaline-2,3-diones as NMDA receptor antagonist in the presence of o- Iodoxybenzoic acid (IBX) at room temperature. IBX, a hypervalent iodine 4.5 Anti-inflammatory activity reagent, is very effective in synthesis of quinoxaline and its derivatives, from NSAID are used for treatment of acute or chronic pain and inflammation 1,2-diketones and o-phenylenediamine at room temperature with high yield including gout, arthritis, fever, headach and migranine. Some of quinoxaline [41]. derivatives have been synthesized and tested for anti inflammatory activity like 3-methyl-7-substituted-1{[5-(aryl)-1,3,4-oxadiazoles-2-yl]-methyl}- quinoxaline-2(1H)-ones. Some of the compounds exhibited potent anti inflammatory activity in carrageenan induced rat paw edema methods [20]. NH O N 2 IBX, AcOH 4.6 Antiglaucoma activity In glaucoma disease intraocular pressure is increased, which is reduce by of RT NH2 O N marketed quinoxaline derivatives Brimonidins (Alphagan) (5-bromo-N-(4,5- dihydro-1H-imidazol-2-yl)-6-quinoxaline amine and alleviating the symptoms of glaucoma [23].

4.7 Antimalarial Activity Scheme 13. Various N-substituted quinoxaline-2,3-diones were synthesized by Many quinoxaline derivatives are reported for antimalarial activity such as rotatory evaporation of 1,2-diamino aromatic compounds in diethyl oxalate mono and di-oxide derivatives of quinoxalines. Vicente et al prepared a new 0 at 50-60 C [42]. series of 3-phenylquinoxaline-1,4-N,dioxide and screened for antimalarial R activity against chloroquine resistant strain of Plasmodium falciparum [24]. H N O O C2H5 Rotavapor N O R 4.8 Anti-tuberculosis activity In 2002, a series of 6,7-substituted-3-methyl-2-phenylthio-quinoxalin-1,4- di-N-oxide have been synthesized and tested against anti-tuberculosis activity. NH O O C2H5 Rifampicin is used as standard MIC 0.25 µ/ml. The anti tuberculosis activity of 2 N O the compounds was determined by Micro plate Blue Assay (MABA) method H against H37Rv strain of M.tuberculosis at a concentration 6.250 µg/ml and Scheme 14. Galium (III) triflate is very important catalyst for synthesis of DMSO is used as solvent. quinoxaline from phenylene-1,2-damine and 1,2 diketones. The yield of prod- uct is excellent in the presence of above catalyst. The reaction started with 1 In 2010, Ramalingam et al have been reported anti-tuberculosis activity of 1- mol% catalyst in C2H5OH at room temperature and after completing the substited quinoxaline-2,3(1H,4H)-diones. The anti-tuberculosis activity was reaction, the catalyst is again recovered [43]. performed by Alamer Blue Assay against M.tuberculosis H37Rv strain.

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 130-134 Dinesh Bharagava et al. / Journal of Pharmacy Research 2012,5(1),130-134 In addition, a series of ethyl-2-[(3-methyl-2-oxoquinoxalin-1(2H)yl)acetyl- 6. Badran, MM.; Abouzid, KAM.; Hussein, MHM., Synthesis of certain 3oxo-dihydro-1H-pyrozole-4-carboxylate derivatives were prepared and substitutedquinoxalines as anti-microbial agents, Part II., Arch. Pharm. Res., 26, 2003, 107–113. evaluated for their anti-tubercular activities. All compounds were screened for 7. Nasr, MNA., Synthesis and antibacterial activity of fused 1,2,4- triazolo[4,3- in vitro antiTB activity against M.tuberculosis H37Rv strain. The minimum a]quinoxaline and oxopyrimido[2',1':5,1]-1,2,4- triazolo[4,3-a]- quinoxaline inhibitory concentrations were determined and most active compound have derivatives, Arch. Pharm. Med.Chem., 8, 2002, 389-394. MIC 25 µg/ml and clogP value is -0.57 which less than is pyrazinamide and 8. El-Hawash, SA.; Habib, NS.; Fanaki, NH., Quinoxaline derivatives Part II: Synthesis streptomycin so this compound have drug like characters [25,26]. and antimicrobial testing of 1,2,4-triazolo[4,3-a]quinoxalines, 1,2,4-triazino[4,3-a]- quinoxalines and 2-pyrazolylquinoxalines, Pharmazie., 54, 1999, 808-815. 4.9 Antibacterial activity 9 . El-Gendy, AA.; El-Meligie, S.; El-Ansary, A; Ahmedy, AM., Synthesis of some quinoxaline derivatives containing indoline-2,3-dione or thiazolidine residue as Many quinoxaline derivatives have been described as antibacterial agents such potential antimicrobial agents, Arch. Pharm. Res., 18, 1995,44-47. as quinoxaline-1,4-di-N-oxide. Example carbadox is used as reference anti 10. Tandon, VK.; Yadav, DB.; Maurya, HK.; Chaturvedi, AK.; Shukla, PK., Design, bacterial agent. Quinoxaline derivatives containing oxadiazole moiety also synthesis and biological evaluation of 1,2,3-trisubstituted-1,4- dihydrobenzo [g] reported as antibacterial activity. 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Journal of Pharmacy Research Vol.5 Issue 1.January 2012 130-134