Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

American Journal of Organic Chemistry 2015, 5(1): 14-56 DOI: 10.5923/j.ajoc.20150501.03

Ameen Ali Abu-Hashem1,2,*

1Photochemistry Department (Heterocyclic Unit), National Research Centre, Giza, Egypt 2Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia

Abstract The review deals with synthesis and reactions of quinoxaline derivatives as well as their diverse pharmacological and biological properties. Quinoxalines and fused ring systems show diverse pharmacological activities. Syntheses of quinoxaline derivatives via many different methods of synthetic strategies have been presented. Keywords Quinoxalines, o-phenylenediamine, Oxidation, Nitration, Diazotization, Alkylation, Addition, Condensation, Cyclization, Substitutions reactions

1. Introduction 2.1. Antimicrobial Activity Quinoxaline-1, 4-di-N-oxide derivatives, Quinoxaline derivatives have different pharamacological pyrazoloquinoxalines and 2-[4-arylidene hydrazinocarbonyl) activities such as bacteriocides and insecticides [1], aniline]-3-methyl quinoxalines (274, 275, 276, 277, 278) antibacterial [2-5], antifungal [2, 6], antitubercular [2, 7-9, respectively have been identified as antibacterial, Antifungal

10], analgesic [4, 11] and anti-inflammatory [11, 12]. The agents and antimicrobial activity [2, 52, 53, 54, 55] as shown importance of quinoxaline derivatives comes from its in (Figure 2). nitrogen contents (heterocyclic compounds). A structure of ring fused with quinoxalines, display 2.2. Anti-Amoebic, Anti-Proliferative Activity diverse pharmacological activities (antibacterial, anticancer 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1, 3-thiazolino and antiviral) [13, 14], antimalarial [15, 16] and anti- [5, 4-b] quinoxaline 279 was tested in vitro as anti-amoebic depressant activities [17]. Quinoxaline-diones derivatives activity against strain of (E. histolytica) [56]. Recently; use on treatment of epilepsy, pain and other 6-arylamino-2, 3-bis (pyridin-2-yl)-7-choloroquinoxaline-5, neurodegenerative disorders [1, 18]. 8- diones (280) have been as a potent anti-proliferative agent Quinoxalines were identified as antihypertensive agents [57]; as shown in (Figure 3). and animal growth promoters [19, 20]. It was found that several highly mutagenic and carcinogenic quinoxalines 2.3. Hypoglycemic, Anti-Glaucoma Activity have been identified in heated meat and fried fish [21]. (N-arylcarbamoyl and N- aryl thiocarbamoyl) Certain condensed quinoxalines exhibit antibacterial, hydrazinequinoxalin - 2 (1H) (281) have been informed as analgesic, tuberculostatic, antileukemic activities [22]. mild hypoglycaemic agents [58] and Brimonidin (282) Biologically active polypeptides such as levomycin and (Alphagan) is a drug used for the treatment of open - angle echinomycin have been shown to possess one or more glaucoma [59] shown in (Figure 4). quinoxalinyl residues [23]. 1, 4-di-N-oxide quinoxaline derivatives are heterocycles 2.4. Antiviral Activity that are often used in the synthesis of biologically active compounds, [24-51] as shown in (Figure 1). 2, 3-dimethyl-6-(dimethylaminoethyl)-6H-indolo-[2, 3-b] quinoxaline (283) shows highest activity against the herpes

virus with biological activity due to DNA binding properties 2. Biological and Pharmacological of these compounds [60]; shown in (Figure 5). Studies 2.5. Cytotoxic with Anticancer, Antitumor Activity A series of quinoxalines derivatives and substituted * Corresponding author: [email protected] (Ameen Ali Abu-Hashem) quinoxalines showed antitumor with remarkable cytotoxic Published online at http://journal.sapub.org/ajoc effect against different Sarcoma type. For examples: Copyright © 2015 Scientific & Academic Publishing. All Rights Reserved 2,3,7-trichloro-6- methylsulfamoylquinoxaline (284) [61];

American Journal of Organic Chemistry 2015, 5(1): 14-56 15

1H-quinoxalin-2-one (285), bromomethyl-5-chloro-3, quinoxalin-4-yl) hydrazide (290b) derivatives (290a), in 4-dihydro-1H-pyrido [2, 3-g] quinoxalin-2-one (286), 3- panel of cancer cell lines, a breast cancer cell and three colon Phenoxymethyl-1H-quinoxalin-2-one (287)] [62, 63]; 2, cancer cells [66] was moderately active against colon cancer 3-bis (bromomethyl) -5,10- benzo[g]quinoxaline-dione lines and highly active in all cells. The in vitro cytotoxic (tricyclic quinone) derivative (288). Some substituted activities of 7-dialkylaminomethyl benzo[g] - quinoxaline -5, quinoxaline 1, 4-di-N-oxides (289) and tested for tumour 10- dione derivatives (291a-e) was evaluated against panel inhibiting activity and highly active as a cytotoxic agent with of human cancer cell lines. These are ovarian carcinoma, highest hypoxic cytotoxicity [26, 64, 65] and colon cancer, breast cancer [67], shown in (Figure 6). pyridine-2-carboxylic acid N-(7-fluoro-pyrrolo[1,2-a]

O O O N O N O N H O N N N N N N N N N O H O O O S O O O HS O O O S S N N O H O O N N N N N O O N O N N N O O H N

300 301

Levomycin Echinomycin Figure 1. Levomycetin has a high level of activity and is only slightly toxic to man Echinomycin is a peptide anibintic

O O O H R R N N HC NNHCO2CH3 N

N N CH3 N OH O O O R1 / Ar

274 275 276

R=CH2OH, R=H, R1=4-OH-C6H4.C(CH3)3 R=CH3

O NHN Ar

N N Ar = 4- Br- C6H4 N N N NH R

N CH3

277 278

Figure 2. Quinoxaline derivatives as examples of antibacterial, antifungal and antimicrobial activity

R N O H N S N N R1 N N N N N Cl R2 N O R3

279 280

R = , R1=H,R2=OH,R3=H N H

Figure 3. Quinoxalines as examples of antiamoebic activity and antiproliferative

16 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

H CH3 N O Br H H H N N CH3 N N N N N N H N N X N R N

281 282 N CH3 H3C R = H, F X = O, S 283

Figure 4. Quinoxalines as hypoglycaemic and antiglaucom activity Figure 5. Quinoxalines as antiviral activity

Cl H3CHNO2S H N Cl R2 N R1 N N Br

Cl N Cl R3 N O N O H H

284 285 286

R1 = CH2Br ; R2= H ; R3 = CF3

R 2 O O N N F C N CN O Br 3 Br N N N O H N NH(CH2)3NMe3 O R1 O

287 288 289

R1= benzoyl ; R2 = 2-C( O)NH-phenyl

O O H N R1 N N N R3 H R N N O R2

290 291 N R = F , R = H , R = 1 2 3 a;R=-N(CH3)2 b;R=-N(CH2CH2OH)2 c;R=-N(CH2CH2)2 d;R=-N(CH CH ) CH N 2 2 2 2 e;R=-N(CH2CH2)2O R1 = H , R2 = F , R3 = N

Figure 6. Quinoxalinone derivatives and substituted ans cytotoxic with anticancer, antitumor activity

2.6. Antithrombotic Activity Quinoxalinone derivatives is a patented antithrombotic Activity [68] for examples (292); (293) and 3-{4-[5-(2, 6-dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3, 4-dihydro-quinoxalin-2-yl}-4-hydroxy-benzamidine (294) and 4-(4, 7-dimethyl- 3-oxo-3, 4-dihydroquinoxalin-2-ylmethyl)- benzamidine (295); shown in (Figure 7).

American Journal of Organic Chemistry 2015, 5(1): 14-56 17

CH3 O N OCH3 O R2 H3CO N O N N O N OCH3 R1 O H3CO N O

CH3 292

NH R2 N N 2 N X NH NH2 R1 N O N O N O

CH3 NH CH3

CH3 293 295 N

H3C

294 Figure 7. Quinoxalinone derivatives with antithrombotic activity

2.7. Anti-HIV Agents Quinoxalinone derivatives for examples[7-Chloro-2,2-dimethyl-3-thioxo-3,4-dihydro-2H-quinoxa line-1-carboxylic acid isopropenyl ester (296), 7-methoxy-2-methylsulfanyl methyl-3-thioxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester (297), 2-ethyl-7-fluoro-3-oxo-3,4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester (298), 3-cyclopropylethynyl-4,6-(sub)-3-trifluoro methyl-3,4-dihydro-1H-quinoxalin-2-one (299)] inhibitors of reverse transcriptase as potential anti-HIV Agents [69-71]; shown in (Figure 8).

H2C CH3 H3C CH3 H3C CH3

O O O O O O CH Cl N 3 H CO N CH 3 S 3 F N CH3 CH3

N S N S N O H H H

S - 2720 HBY- 097 GW - 420867X

296 297 298

F F R F X N

N O H

299 Figure 8. Quinoxalinone derivatives inhabitors of reverse transcriptase an potential anti-HIV Agents

2.8. Anti-Inflammatory and Analgesic Activity Compounds quinoxaline derivatives (200, 202, 206 and 211) exhibited potent anti-inflammatory and analgesic activities [72]; shown in (Figure 9).

18 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

O O Cl N N NH N N H2N S N N N S N

200 202

H3C O O N N N N N N N N N S N N N S N Ph

206 211

Figure 9. Quinoxalinone derive. As potential anti-inflammatory and analgesic activity

3. Synthesis of Quinoxaline derivatives via Different Methods 3.1. From Aromatic Diamines with Many of Organic Derivatives

3.1.1. Cyclocondensation of o-phenylenediamine with glyoxal Quinoxaline 3 itself [73] is prepared via reaction of o-phenylenediamine 1a and glyoxal 2 in acetonitrile; shown in (Scheme 1). O H NH2 acetonitrile N + NH - H2O 2 O H N

1a 2 3a

Scheme 1 3.1.2. Use Different Methods of Catalyst Systems and Reaction Conditions Quinoxalines derivatives 3a-d was prepared via stirring of glyoxal 2 and o- phenylenediamine derivatives 1a-d in acetonitrile in the presence of monodispersed and easily recyclable Ni-nanoparticles [73]. Shown in (Scheme 2).

NH2 R NH2 O H

1a-d O H R= H, NO , Cl, CF N 2 3 2 R N NH R.T,10 ml % Ni- nanoparticales, 2 o N2 atmosphere, 25 C, acetonitriles 3a-d NH2 47

NH2

N NH2

Pyridine-2,3-diamine

Scheme 2

American Journal of Organic Chemistry 2015, 5(1): 14-56 19

Furthermore, One -pot synthesis of quinoxaline derivatives were prepared via reacted o-phenylenediamine derivatives 1a, b, e with 1, 2-dicarbonyl compounds [oxalaldehyde, biacetyl, oxalyl difluoride and dimethyl oxalate] respectively at room temperature by using different catalysts [74-86] as CuSO4.5H2O, IBX, lead oxide (PbO), ZrO2, iodine, Palladium and Polyaniline sulphate, CuO nano particles, ZnO-β Zeolite, HClO4·SiO2, and ruthenium-charcoal (Ru/C) were reported. The procedure presented is operationally simple, practical and green, shown in (Scheme 3). O R NH N R 2 I2 ( 10 % Mol) R1 + R1 NH2 O R R.T, DMSO N R

1a,b,e 3a,e-g

R = H, NO , CH 1 2 3 R= H, Me, F, OCH3

Scheme 3

Some of different catalyst system (table 1) used for synthesis of quinoxaline derivatives and preparation of quinoxalines via microwave and room temperature (table 2) and some of these methods is one of the science of green chemistry.

Table 1. Synthesis of quinoxalines by different catalyst system

No. of References Names of Scientists Type of Catalyst used

In Aqueous Media

More SV et al.; Wan JP et al.; 1. Using ceric ammonium nitrate (CAN) [94-96] Kumar BSPA et al.; 2-Using trimethylsilyl chloride (TMSCl) 3. Using N-bromo succinimide

Table 2. Synthesis of quinoxalines via different reaction conditions

No. of References Names of Scientists Type of reaction conditions

Mohsenzadeh F et al.; Ashry El S H El et al.; Zhou [87-93] JF et al.; Zhou J F et al.; Zhou JF et al.; Using microwave energy Padmavathy K et al.; Zhang X Z et al.

Darabi HR et al.; Aghapoor K et al.; Meshram HM [97-101] At room temperature et al.; Hou JT et al.; Ghosh P et al.;

3.1.3. Oxidation of Aromatic Diamines with Many Organic Materials

Alkynes [102] 4 were oxidized efficiently using the catalytic amount of PdCl2 and CuCl2 in PEG-400 in the presence of H2O with o-phenylenediamine 1a.The optimized conditions were successfully utilized for the one-pot synthesis of 2,3- disubstituted quinoxaline derivatives, shown in (Scheme 4). N R NH2 PdCl2 / CuCl2 + R R1 N NH2 PEG / H2O (8;2) R1

1a 4 3h-K

h; R = Ph R1= 3-hydroxyphenyl i; R = Ph R1= P-tolyl j; R = Ph R1= 4-cyanophenyl k; R = Ph R1= 6-methoxy-2-naphthyl

Scheme 4 Furthermore, recyclable task-specific ionic liquid N, N, N-trimethyl -N- propane- sulfonic acid ammonium hydrogen sulfates [TMPSA]. H2SO4 was used as the catalyst [103] for the synthesis of quinoxaline 6. Thus; treatment of N-substituted aniline5 with o-phenylenediamine 1a in water in the presence of [TMPSA]. HSO4 afforded the 2, 3-disubstituted quinoxaline derivatives 6. The reaction could be accomplished in water as well as organic solvent, and the satisfactory results were obtained under the mild conditions, shown in (Scheme 5).

20 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

R1 O H [TMBSA ].H2SO4 N N H2N R + R H O,R.T N S 2 R1 N H H2N

5 1a 6

R= H, NO2, Cl, CF3

Scheme 5

Moreover, tetrahydroquinoxaline derivatives 9 was achieved from epoxides 7 and ene-1, 2-diamines 8 by a Bi-catalyzed oxidative coupling by using Bi (5 mol %) as catalyst in presence of DMSO solvent [104], shown in (Scheme 6).

H2N R N R 2 Bi ( 5 % Mol) 2 O + o R1 DMSO 100 C R1 N H2N R3 R3

7 8 9

R1,R2,R3= H

Scheme 6 Bi-catalyzed oxidative coupling of epoxides [104] 10 and o-phenylenediamine 1a afforded 2, 3-susbstituted quinoxaline derivatives 3, shown in (Scheme 7).

Bi o 5-10 mol % R 1 H2N + Additive = Cu (OTF)2,TFOH R1 N O 2.5 - 27 mol % H2N o R N R2 100 C, PO2 = 1 atm, DMSO 2

10 1a 3a

R1, R2 = H

Scheme 7

Condensation of p- tolylsulfone 29, [104] with o-phenylenediamine 1a in DMF yields 2-phenyl - quinoxaline 30, shown in (Scheme 8). O

NH2 N DMF + S Tol p NH2 N

1a 29 30

Scheme 8 O

NH2 Br N K2CO3 + NH2 TBAB N

1a 31 30

Scheme 9

American Journal of Organic Chemistry 2015, 5(1): 14-56 21

Moreover, reactions of α-bromo ketones (2-bromo-1-phenylethanone 31) with o-phenylenediamine 1a in presence of tetra-butyl ammonium bromide (TBAB) [117] in aqueous basic medium yield substituted quinoxalines 30. This method proved to be easy, economic safe, and time consuming, shown in (Scheme 9). Furthermore, phenylquinoxaline 30 has been prepared through refluxing of phenacyl chloride 32 with o-phenylenediamine 1a in ethanol followed by oxidation of the formed intermediate 33 [108, 118], shown in (Scheme 10). H

NH CH2Cl N N 2 C2H5OH [O] + -HCl N C6H5 C H NH2 O C6H5 H O N 6 5 - H2O 2 2 1a 32 33 30

Scheme 10

The enamine 11 was subjected to the N-hetero-annulation conditions consisting of Pd (dba)2 (0.07 mol %) and dppp (0.07 mol %) in DMF (w0.1 M) under 4 atm of carbon monoxide with the anticipation of a rapid enamine-imine tautomerization, followed by cyclization to give 1,2-dihydroquinoxaline 12 and 3,4-dihydroquinoxalin- one 13, [105] were isolated in place of the expected benzimidazole 171, shown in (Scheme 11). H N O Pd(dba)2,dppp,MeCN N + o CO (4atm),70 C N N H H H N 12 13 NO2

11 N X N H

171 Scheme 11

3.1.4. Condensation of Aromatic Diamines and Dicarbonyl Derivatives. Condensation of aromatic diamine and α-dicarbonyl compound is a very facile and widely used method for the synthesis of quinoxalines and alkyl substituted quinoxalines [106-108]. Thus, 2-methyl-quinoxaline 3L was prepared by the reaction o- phenylenediamine 1a and 2-oxopropionaldehyde 2 in DMF; these compounds have been identified as antibacterial activity, shown in (Scheme 12).

O CH3 NH N CH3 2 DMF + - H2O NH2 O H N

1a 2-oxopropanal 3 L Scheme 12

New derivatives of 3, 4‐dihydroquinoxaline‐2 (1H) ‐one 15 were synthesized and [109] characterized by reaction of o-phenylenediamine 1a and hexane-2, 3, 5-trione 14 in ethanol, shown in (Scheme 13). H NH O N O 2 O + O ethanol NH2 O N

1a 14 15

Scheme 13

22 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Reaction of 3-Bromo-2-oxo-3-phenyl-propionic acid ethyl ester derivatives 16 with o-phenylenediamine 1a in acetic acid afforded the quinoxalin-2(1H)-ones derivatives 17 which oxidized in DMSO to give the quinoxalin-2(1H)-one derivatives 18 [110], shown in (Scheme 14). Br O Br O H N 2 ACOH N DMSO N + Ar Ar Ar OEt H2N N O N O O H H 16 1a 17 18a-e Ar, (a) = Ph (b) = 4-BrC6H4 (c) = 2,4-Cl2C6H3 (d) = 3-O2NC6H4 (e) = 4-O2NC6H4

Scheme 14

o-phenylenediamine 1a and α-hydroxy ketones [111] in acetic acid via two methods: microwave irradiation and simple heating gave compounds 20a,b, shown in (Scheme 15). NH OH N Ar 2 ACOH + Ar `Ar NH Refluex N Ar` 2 O

1a 19 20a,b

a ; Ar , Ar` = Ph b: Ar = ph, Ar` = 4-OMeC6H4

Scheme 15 Condensation of mesoxalic acid derivatives (2-oxomalonic acid) and o-phenylenediamine 1a proceeds as expected whereas with sodium mesoxalate an anomalous reaction occurs [112] gave toutomerizem of 2-hydroxy quinoxaline-3-carboxylic acid or 3-oxo-3, 4-dihydroquinoxaline-2-carboxylic acid 21. Hydrogen transfer occurs even when a vigorous stream of oxygen is passed through the reaction mixture l, 2-dihydro benzimidazole- 2, 2-dicarboxylic acid 22 rather than its decarboxylation product 23 is thought to be the reducing agent. Condensation of o-phenyldiamine 1a with acetic acid [113] and form 2-tetrahydroxy butyl quinoxaline which further react with hydrogen peroxide and solid sodium hydroxide form quinoxaline-2-carboxylic acid 24. All compounds show highest biological activity, as in (Scheme 16). O HO O H NH N OH N O 2 O OH NH + COOH NH N COOH N COOH 2 NaOH N H COOH 1a 21 21 22 O 1) OH - CO2

2 ) NaOH/ H2O2 N O N N COOH OH H 23 N

24 Scheme: 16

American Journal of Organic Chemistry 2015, 5(1): 14-56 23

Quinoxaline-2-ones 25 were obtained in excellent yields by the condensation of n-butyl- oxo-acetate 2 and o-phenylenediamine 1a in DMF [114], shown in (Scheme 17). O OBU H N O NH2 DMF + - H2O NH2 O H N

1a 2 25

Scheme:17

Condensation of o-phenylenediamine 1a-c, f and 1, 2- dicarbonyl compounds 26 in the presence of a mild acidic reagent [115] lead to the synthesis of quinaxolines derivatives 27 in the presence of iodine as catalyst using microwave irradiation, shown in (Scheme 18). O R N R NH2 2 I2 / MWI 2 + O R1 NH2 EtOH / H2O (1:1) R1 N

1a-c,f 26 27

R1 = H,NO2, Cl, OMe, R2 = H, CH3,Ph

Scheme 18

Another approach for the synthesis of 2, 3-Bis (bromomethyl)quinoxaline derivatives 28 were synthesized by the condensation reaction of the corresponding o-phenylenediamine derivatives 1a with 1,4-dibromo-2,3-butanedione 2 [13, 116], shown in (Scheme 19). R O CH Br 1 NH2 2 MeOH R1 N CH2Br + CH Br NH R2 N 2 R2 2 O CH2Br

1a 2 28a,b

R1 ; R2 = H R1 = H R2= CH3

Scheme 19

Condensation of o-phenylenediamine 1a with pyruvic acid 34 in DMF afforded 3- methyl quinoxaline- 2-one 35 [118], shown in (Scheme 20) R NH O 2 O DMF N + NH2 R COOH Reflux N O H

1a 34 35

R = CH3 Scheme 20

Synthesis of potential chemotherapic quinoxalinones via biocatalysis, thus, reaction of o-phenylenediamine 1a,b,e and oxalic acid 36 [118-123] to give 1,4-dihydro quinoxaline-2,3-dione 37 which was reacted with ethane-1,2-diamine to yield 3-(2-amino-ethylimino)-3,4-dihydro-1H-quinoxalin-2-one 38, the latter compound 38 was reacted with aryl aldehyde derivatives gave 3-[2-(benzylidene-amino) -ethylimino]- 3,4- dihydro-1H-quinoxalin-2-one derivatives 39. Some of quinoxalinone derivatives was synthesized microwave assisted reaction between substituted aromatic diamine and α- keto-

24 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

glutric acid (2-oxopentanedioic acid) to yield 3-(3-oxo -3, 4-dihydroquinoxalin-2-yl) propionic acid 40 and then treated with hydrazine hydrate to yield its hydrazones derivatives 41, quinoxaline derivatives as potential anti-virus, shown in (Scheme 21).

O OH H N NH H 2 H 2 stirring 15 min N O NH2 N N NH + 2 R NH o 2 O OH heat 100 C N O Refulex 2h N O H H 1a,b,e 36 37a 38 R= H, NO2, CH3 ArCHO O MW COOH Ethanol

C2H5OH COOH H N N N Ar

H NH2NH2 N O N O H C H OH MW R N COOH 2 5 39 H 40 N N NH2

R N COOH

41 Scheme 21

Condensation of 1a with ethyl-2-oxo-propanoate 42 in methanol afforded quinoxalin-2(1H)-one 35, which condensed with aromatic aldehyde to give 3-substituted styryl- quinoxalin-2(1H)-ones 43a-d; [124] refluxing of 43a-d with POCl3 afforded the 2-chloro 44a-d, which reacted with 4-substituted piprazine to give 2-piperazinyl derivatives 45a-g. In addition, a series of 1-alkyl-3-substituted styryl- quinoxalin-2(1H)-ones 46a-d was also prepared via reaction of 43a-d with alkyl halide as show. These compounds have antimicrobial activity, shown in (Scheme 22). R O H NH2 N O OHC OC2H5 CH3OH + H3C NH2 O N CH3

1a 42 35a

N Cl R H N O N POCl3 R N 44 43

HN N R1 R2X

R1 2 N R H N N R N O R N N

45 R = H 46 R1 = H R2 =CH3 or C2H5; X = I Scheme 22

American Journal of Organic Chemistry 2015, 5(1): 14-56 25

Synthesis of quinoxalinone derivatives 48 via reacted of 2, 3- diamine- naphthalene 47 with a variety of α-ketoacids (2-oxopropanoic acid) through enzymatic catalysis or microwave irradiation [119], shown in (schemes 23). H NH2 HO O S. Cereviciae N O + NH2 R O MW irradiation N R 47 48

Scheme 23 R = CH3

Condensation reaction of o-phenylenediamine 1a, e with α-dicarbonyl derivatives in ethanol under microwave irradiation afforded quinoxalines 3a, m high yield [120], short reaction time; pure products without purification and using only ethanol instead of toxic and expensive solvents for isolation of the products are the advantages of this method, shown in (Scheme 24). R NH2 O 2 N R2 C H OH + 2 5 R NH2 O MW R1 N 1 R2 R2

1a,e 3a,m

R1 = H R2 = H R1 = CH3 R2 = CH3 Scheme 24

A readily available hypervalent iodine reagent was found to be highly effective in synthesis of quinoxaline derivatives 50; [125-128] thus, stirring of 1, 2-diketones 49 and o-phenylenediamines 1a at room temperature in acetic acid in presence of o-iodoxy benzoic acid (IBX) or in the presence of molybdophospho- vanadates (MOVP) as catalysts and toluene as solvent afforded 50, shown in (Scheme 25). IBX, HOAC

RT R R R O N 1 H2N R1 + N O H2N R R 50 49 1a

MoV P catalyst R,R1, = H

toluene , 25oC Scheme: 25 Various quinoxaline-2, 3-diones 51 [126] were synthesized by rotatory evaporation of 1, 2-diamino aromatic 1c in diethyl oxalate in chloroform at 50-80℃; compound 51 as NMDA receptor antagonists, shown in (Scheme 26).

R R O N O NH O CHCl3 + X N O NH Rot. evapor. X 2 O H O 50 - 80 oC 1c 51 Scheme 26 X = Cl , R = H

26 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Reaction of o-phenylenediamine 1a with 1, 2-dicarbonyl derivatives 119 in propan-1-ol in the presence of a catalytic amount of hydrochloric acid or p-toluene sulfonic acid [153] afforded quinoxalin-2-ones derivatives 120, shown in (Scheme 27).

R2 R2 R 2 H N R1 2 R O 2 N + N R R1 H 1 H2N O N R1

O N 119 1a 120 H R = H Scheme 27 1

Condensation of mixture o-phenylenediamine 1a, cyclohexyl isocyanide 52 and aromatic aldehydes 53 in the presence of (FeClO4)3 as a catalyst afforded the corresponding N-cyclohexyl-3-aryl-quinoxaline-2-amines 54, [129-131], shown in (Scheme 28).

CN R NH2 ( FeClO4)3 N + + R NH 2 Refluex N NH

1a 52 53 54

R = H, 3- NO2-C6H4, 4-Cl-C6H4 , 4- NO2- C6H4, 4-OCH3-C6H4

Scheme 28 Reaction of o-phenylenediamine 1a with 3, 4-dihydro-2H-1-benzopyran-2, 3-dione 55 gave 3-o-hydroxybenzyl-2(1H)-quinoxalinone 56; [132], shown in (Scheme 29). NH H 2 O O NaOH, 1000C, 15 min, N O + NH2 EtOH, reflux, 1 h O N CH2C6H4OH

1a 55 56

Scheme 29

Synthesis of aryl hydrazones, 2-oxo-6, 7-dichloro-1, 2-dihydro quinoxaline-3-carbaldehyde 60 occurred via refluxing [133] of dichlorophenylenediamine 57 with pyruvic acid followed by coupling with forming, as in (Scheme 30).

American Journal of Organic Chemistry 2015, 5(1): 14-56 27

Ar HN N

NH Cl 2 Cl N CH3 Cl N CH CH3COCOOH ArN N Cl NH Cl Cl 2 N O N O H H

57 58 59

ArN N

Ar HN N Ar = aniline, 4-Toluidine, 4-Anisidine, 4-Chloroaniline, 4-Bromoaniline, N C 2-Iodoaniline, 2-Toluidine, Cl N 2-Chloroaniline, 3-Toluidine Cl N O N Ar H

Scheme 30 60

Alkylation of o-phenylenediamine derivatives 1a with dimethyl sulphate or ethyl chloroacetate produced [134] the quinoxalinone 61 and 64 respectively. Hydrazinolysis of the ester derivative 61 with hydrazine hydrate afforded the hydrazide derivative (3-methyl-2-oxo-2H-quinoxalin-1-yl) - acetic acid hydrazide 62, which underwent condensation with aldehyde to give hydrazone derivative 63; these compounds have antimicrobial activity, shown in (Scheme 31).

CH COOEt 2 CH2CONHNH2

NH2 N O N O ClCH2COOEt NH2NH2 R R R NH2 CH N 3 N CH3

1a 61 62

ArCHO ( CH3)2SO4

CH 3 CH2CONHN CHAr N O N O R R N CH N 3 CH3

64 63

Scheme 31

Stirring of phenylenediamine 1a,b with maleic anhydride 65 in THF [135] in the presence of 10 mol% of butylated hydroxyl toluene (BHT) afforded a mixture from 3-oxo -1, 2, 3, 4-tetrahydroquinoxalin-2-yl)-acetic acid 66 and 3-(2-amino-phenyl carbamoyl)-acrylic acid 67. Decomposition of (3-oxo-1, 2, 3, 4-tetrahydro-quinoxalin-2-yl)-acetic acid) 66 and cyclized of 67 with basic medium afforded 3-methyl-1H-quinoxalin-2-one derivatives 35, shown in (Scheme 32).

28 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

O H H N O R NH2 10 mol % BHT R N O R + O + THF , rt CO2H CO2H NH2 N NH2 O H 1a,b 65 66 67 86 % R = H 4.7 % R = H ; NO 2 R = NO2 100 %

basic medium

or rt / air

H N O

N CH3 Scheme 32 35

Synthesis of 6-chloro-3-oxo-1, 2, 3, 4-tetrahydroquinoxaline-2-carboxylic acid ethyl ester 70, [136] via reduction and cyclization of 2-(2, 4-dinitro-phenylamino)-malonic acid diethyl ester 68 with (H2/Pd/C). Compound 69 was reacted with (CuCl2 + BuONO) to give 70; these compounds as Glycine /NMDA receptor antagonist, shown in (Scheme 33). H H H COOEt N N COOEt N COOEt a) H2/Pd/C (b) CuCl2, +-BuONO

COOEt H2N N O Cl N O O2N H NO2 H

68 69 70

Scheme: 33

Quinoxaline derivative 72 was also prepared via condensation of glucose 71 with o-phenylenediamine 1a [137, 138], shown in (Scheme 34). CHO NH N 2 NH2NH2 + (CHOH)4 ACOH N NH2 ( CHOH)3 CH2OH CH2OH 1a 71 72

Scheme 34

Reaction of hexulose 73 with o-phenylenediamines 1a under neutral conditions in presences of dichloromethane [139] afforded the quinoxaline derivatives 74; these compounds have cytotoxic activities, as in (Scheme 35).

H3CO OCH3 H3CO OCH3

O O NH CH CH Cl 2 O 3 2 2 CH + O 3 CH3 NH2 CH3 O N Cl

OH N

1a 73 74

Scheme 35

American Journal of Organic Chemistry 2015, 5(1): 14-56 29

Treatment of D-glucose 71 with o-phenylenediamine 1a in the presence of hydrazine hydrate and acetic acid [137, 140-143] gave the tetrahydroxybutyl- quinoxaline derivative 72 which oxidized with iodate to give quinoxaline-2-carboxaldehyde 75. Treatment of quinoxaline-2-carboxaldehyde 75 with excess of methyl magnesium iodide in ether gave 3-methyl-3, 4-dihydro-2- (hydroxyethyl) quinoxaline 76. Oxidation of 76 with CrO3 gave 12-acetyl-3 methylquinoxaline 77. Alkylation of Quinoxaline-2-carbaldehyde 75 by methyl magnesium yielded 1-Quinoxalin-2-yl-ethanol 78 which was oxidation by CrO3 to give 1-Quinoxalin-2-yl-ethanone 79, as shown in (Scheme 36).

CH2OH H2N O NH2NH2 N IO4 OH OH + ( CHOH) H2N ACOH / H2O N 3 OH OH CH2OH

71 1a 72

H H N N CH3 N CH3 CH3MgI CrO3 O O N Excess N OH N

H H CH3 CH3 75 76 77

CH3MgI ( 1 eqvt. )

N N CrO3 O N CHOH N CH3 CH3 78 79

Scheme: 36

One-pot condensation of D-glucose 71, o-phenylenediamine 1a or 57 with N,N-benzylphenylhydrazine hydrochloride in acidic medium [144] gave 3-(d-erythro-glycerol-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]quinoxaline 80. Compound 80 was also obtained by condensation of 2-(D-arabino-tetritol-1-yl) quinoxaline 72 and NNBPHH in acidic medium. These results indicate that 72 is an intermediate during the formation of 80, which reacts with NNBPHH in acidic medium to give N, N-benzyl- phenylhydrazone intermediate “A”. The unisolated intermediate “A” is then cyclized by the excess NNBPHH with elimination of the benzyl group in toluene to give 80. The cyclization of the intermediate “A” takes place by two possible routes 1) either by removal of the benzyl group. This compound 80 turns into product 82 via actylation, shown in (Scheme 37).

30 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

R R N NH2 NH2NH2.H2O D-Glucose + R R N CHOH NH2 ACOH,HCl CHOH 71 1a, 57 72 CHOH R = H R = Cl CH2OH

NH2.HCl

(NNBPHH) NPh CH2Ph

H R N N H2C N Ph R N H N Ph N R N N R N CH2OH CH2OH

CH2OH CH2OH

(A) (B)

-C6H6 -C6H5CH3

X 2) 1)

R N R N R N N CH2Ph N Ph N Ph N N N R N R N R N

CH2OH CH2OH CHOAC

CH OH 2 CH2OH CH2OAC

81 80 82 R = H

Scheme 37. Synthesis of 3-(D-erythro-glycerol-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]quinoxaline (3) and 6,7-dichloro-3-(D- erythro- glycerol-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]quinoxaline (B) by effect of phenylhydrazine hydrochloride and N,N- benzylphenyl- ydrazine hydrochloride.

3.2. Intramolecular Cyclisation of N-Substituted Aromatic O-Diamines Condensation of glycine 84 with o-Nitrohalogenobenzene 83 afforded 2-nitro-phenylamino)-acetic acid 89. Reductive cyclisation of 85 with Fe/HCl gave quinoxaline-2-one 25 [145], shown in (Scheme 38). H Cl N Fe / HCl N + NH CH COOH 2 2 CO2H NO2 NO2 N O H

83 84 85 25

Scheme: 38

1, 5-difluoro-2,4-dinitrobenzene derivatives 86 reacted with amino acid or amino acid ester [146] to give the glycine derivatives 87. Reductive cyclization of 87 with H2 in Raney Ni afforded the quinoxalinones 88, 89 and products of 91, 92, as shown in (Scheme 39). American Journal of Organic Chemistry 2015, 5(1): 14-56 31

O F H N H NH CH CO C H O R 2 2 2 2 5 CH3 H2 N R NO2 R or NH CH CO H 2 2 2 NO2 Raney Ni N O H

86 87 88

AgNO3 / NH4OH

1) Sn / HCl ; 2) H2O2 / OH ; 3) ACOH N R N OH

O H CH H F N 3 F N R F N R O Reduction - H2 R H2N H N O N NO N O 2 N OH 2 2 H

90 91 92

Scheme 39

6-chloro-1H-quinoxalin-2-one 99 was prepared by reaction of 5-chloro-2-nitro-phenylamine 93 with chloro acetyl chloride to yield 2-chloro-N-(4-chloro-2-nitro-phenyl)-acetamide 94. Reduction of 94 which reduced with H2/Pd-C to afford N-(2-amino-4-chloro-phenyl)-2-chloro acetamide 95 which further oxidized by H2O2 gave quinoxalin-2-one 96 [147], shown in (Scheme 40). Cl NO NO NH 2 Cl 2 H2 / Pd - C Cl 2 ClCH2COCl O O Cl Cl CH Cl NH2 NH 2 2 NH

93 94 95

[O]

H2O2

Cl N

N O H

96 Scheme 40

A series of quinoxalinones derivatives (97-106) were prepared via reaction of o-phenalindiamine derivatives with many reagents [α - ketone acid (or aldehyde) ester] derivatives [148], all compounds have been identified as antibacterial, antifungal and anti-cancer agents, shown in (Scheme 41).

32 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

O HO R N O CN 1

3-(4-Cyano-phenyl)-2-oxo-propionic acid R2 N O CN H 100

O O O R1 N H3C O O CH3 BrCH2COCO2Et Br O R1 N O CH3 R2 N O H R2 N O 2-Oxo-malonic acid diethyl ester H 99 101

CH R1 N 3 CH3CH2CH2COCO2Na

R2 N O H

102 R1 NH2

CH3 R2 NH2 R1 N (CH3)2CHCOCO2Et CH 1 3 R2 N O H

CF3COCO2Et 103

R N F PhCH2COCO2H 1 F R1 N F R2 N O H R2 N O H 104

CH3 97 ( CH3)CC(OH)=CHCOCO2Et R1 N OH CH3 R2 N O CH H 3 105

R1 N CH3 CH3COCO2Et R 2 N O R1 N H PhCOCO2H

R2 N O 98 2-oxo-2-phenylacetic acid H

106

Scheme: 41 : Keto acid ( or aldehyde ) ester method for the synthesis of quinoxalinone derivatives

Reaction of isatine 107 [123,149] with o-phenylenediamine 1a in the presence of hydro chloric acid give the quinoxaline derivatives 108 which was reacted with 4-amino-benzoic acid inter microwave to give 4-[(indolo[2,3-b]quinoxalin-6-ylmethyl)-amino]-benzoic acid 109. Condensation of quinoaxaline of 109 with o-phenylenediamine in the presence of hydrochloric acid gave [4-(1H-Benzoimidazol-2-yl)-phenyl]-indolo [2, 3-b] quinoxalin-6-ylmethyl-amine derivatives 110, most of compounds have been identified as Potential Anti-Virus, shown in (Scheme 42).

American Journal of Organic Chemistry 2015, 5(1): 14-56 33

H O N N NH2 NH2 O MW HO + N NH O N HCl MW 2 H HCHO 1a 107 108

NH2 O OH N N N NH2 HN N N N N HCl , MW N H NH

110 109

Scheme 42

Compound 1b could be selectively reacted with acetic anhydride to provide the mono-acylated adduct in 95% yield and coupling with the α-keto acid as thiophene-2-glyoxylic acid gave N- (2-acetylamino- 4- nitro- phenyl) - 2- oxo -2 -thiophen-2-yl-acetamide 111. Refluxing of compound 111 with methanol in presence hydrochloric acid to form 6-nitro-3-thiophen-2-yl-1H-quinoxalin-2-one 112 [150], shown in (Scheme 43). AcHN NO2 NO H2N 2 i,ii O N NO iii S 2 N O H2N S H N O H

1b 111 112

o Scheme 43. Reagents and conditions: (i) Ac2O, Et3N, CH2Cl2, 0 C to rt (95%); (ii) 2-thiophene-glyoxylic acid, EDCI, Et3N, CH2Cl2, rt; (iii)1 M HCl, MeOH, reflux (70% over two steps).

Condensation of 1, 3-cyclohexanedione 113 with 2-nitroaniline gave 3-(2-nitro-phenylamino)-cyclohex-2-enone 114 which was cyclized by catalyst (Pd(dba)2, dppp, phen) [105,151] in presences of DMF to produce phenazin-1-ol 115, shown in (Scheme 44). O H NH N N 2 Benzene Pd(dba)2,dppp,phen + NO H2SO4 CO(6atm),120oC,DMF 2 O NO2 N O OH 2-nitroaniline 113 114 115

Scheme 44

34 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Reaction of diaminomaleonitrile 116 with 2-hydroxy-1, 4-naphthoquinone 117 in acetic acid at room temperature for 24 h [152] afforded 6-hydroxy-benzo[f] - quinoxaline-2, 3-dicarbonitrile 118, shown in (Scheme 45). O NC NH2 ACOH NC N OH + OH rt , 24 h NC N NC NH 2 O

116 117 118

Scheme 45

Condensation of 1, 2-dicarbonyl derivatives 121 – 123 with o-phenylenediamine 1a,b,e at room temperature in the presence of magnesium sulfate heptahy- drate (MgSO4·7H2O) afforded phenazine and quinoxaline derivatives 124–126; [154-163] in excellent yields, shown in (Scheme 46). O F F F R O N

1,2-Bis-(4-fluoro-phenyl)-ethane- N 1,2-dione F 121 124

O O

R NH2 N R MgSO4 / H2O

NH2 Ethanol, rt Phenanthrene-9,10-dione N

122 1a, b, e 125

R= H, NO2, , Me O O

N R

Acenaphthylene-1,2-dione N

123 126

Scheme 46. The synthesis of quinoxaline and phenazine derivatives using MgSO4·7H2O as a catalyst.

Condensation of o-phenylenediamine 1a and 3-bromomethyl-4-methyl-2, 5-dihydro-2, 5-furandione (2-bromomethyl-3-methylmaleic anhydride) 127 in DMF gave 3-(1-carboxy vinyl) - 3-methyl-3, 4-dihydro-2(1H)-quinoxalinone 128 with loss of hydrogen bromide [132], as in (Scheme 47). H NH O O O N 2 DMF O + - HBr Me NH2 Me CH2Br N H C(=CH2)COOH

1a 127 128

Scheme 47

American Journal of Organic Chemistry 2015, 5(1): 14-56 35

Reaction of o-phenylenediamine 1a with 4-benzoyl-5-phenyl-2, 3-dihydro-2, 3-thiophenedione 129 in toluene [132] afforded 3-(α-benzoyl-β-mercaptostyryl)-2(1H)-quinoxalinone 130, as shown in (Scheme 48). Bz NH O S Bz 2 toluene N Ph + SH - H2O NH2 O Ph N O H 1a 129 130

Scheme 48 Condensation of o-phenylenediamine 1a with 3-hydroxy-4-oxo-cyclohexa-1, 5-diene-1, 2, 3-tri-carboxylic acid tributyl ester 131 in hot aqueous ethanolic sodium hydrogen carbonate gave tert-butyl 3-[3-(tert-butoxycarbonyl)-3-(tert-butoxy carbonylamino) propyl]-2-quinoxaline carboxylate 132 [132], shown in (Scheme 49). O NH2 N CO2Bu` C H OH + 2 5 HO NaHCO3 NH2 CO2Bu` N (CH ) CHCOBu` H 2 2 `UBO2C CO Bu` 2 NHCO2BU`

1a 131 132

Scheme 49 Reaction of 4, 5-dimethyl (o-phenylenediamine) with 1-Sub-pyrimidine-2, 4, 5, 6-tetraone 133 under acidic conditions [132] gave 6, 7-dimethyl-3-ureido carbonyl- 2(1H) - quinoxalinone 134, shown in (Scheme 50). O Me N CONRCONH NH O R H+ 2 2 N + N O NH O N O Me 2 H H

133 134

Scheme 50 Treatment of o-phenylenediamine 1a with 3, 4, 5, 6-tetrachloropyridazine 135 in N-methyl pyrrolidine at 115℃ for 17 h gave a separable mixture of prouducts one of which was 2, 3-bis (benzimidazol-2-yl) quinoxaline 136, [132] as shown in (Scheme 51).

H N Cl Refluex NH2 Cl N N N + N N NH Cl N-methyl pyrrolidine N 2 H Cl N H

1a 135 136

Scheme 51

36 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Treatment of o-phenylenediamine 1a with 3,3-bis(trifluoromethyl)-5-oxa- zolinone [132] 137 in ethyl acetate containing a trace of acetic acid afforded 2(1H)-quinoxalinone 35, shown in (Scheme 52).

H Refluex N H NH2 O CH COOC H N O O 3 2 5 + R NH2 F3C CH3COOH N R CF3

1a 137 35

R = CH3

Scheme 52

3.3. Ring Transformation of Aryl Aromatic Compounds 6-Amino-3-oxo-3, 4-dihydro-quinoxaline-2-carboxylic acid 139 is isolated from alkaline hydrolysis of a fused alloxazine (8-Amino-1H-benzo[g]pteridine-2, 4-dione) 138[164], shown in (Scheme 53). O COOH N N NH alkaline

N hydrolysis H2N N O H2N N O H H

138 139

Scheme 53 UV irradiation of 1, 5-benzodiazepine (2-Methyl-3H-benzo[b] [1, 4] diazepine) derivatives 140 in benzene undergoes oxidative ring contraction to 2-benzoyl-3-methylquinoxaline 141, [165] shown in (Scheme 54). R N hv N COR

N N Me Me 140 141

R= Ph, Me

Scheme 54 Reaction of 5-chloro-6-fluoro-benzo[1,2,5]oxadiazole-1-oxide 142a with 3 -oxo-3-N-diphenyl-propionamide 143, N-benzyl-3-oxo-3-phenyl-propionamide 144, 3 -oxo-N-phenethyl-3-phenyl-propionamide 145, N-ethyl-3-oxo-butyramide 146 afforded 1,4-di-N-oxide-quinoxaline-2-carboxylic acid aryl amide derivatives 147-150, thèse compounds have antimycobacterial activity [166], shown in (Scheme 55).

American Journal of Organic Chemistry 2015, 5(1): 14-56 37

O O

N OH O H F N N H 3-oxo-3,N-diphenyl-propionamide Cl N O 143

147 O O

N O O H F N N H N-benzyl-3-oxo-3-phenyl-propionamide Cl N

144 O O F N O 148 Cl N O O 142a N H O O F N N H 3-oxo-N-phenethyl-3-phenyl-propionamide Cl N O 145

149

O O O O F N R N N R H H N-ethyl-3-oxo-butyramide Cl N 146 O

150 Scheme 55

Claisen-schmidt condensation [167] these reactions, which consist in a condensation between aldehyde derivatives, afford the corresponding α, β-unsaturated ketone system derivative. A series of quinoxaline 1, 4-di-N-oxide analogues [168 -170] 151 -164 were synthesized by the classic Beirut reaction 142b, c-e, f with many reagents for examples β-diketone ester compounds, these compounds have been informed as antioxidant and anti-inflammatory agents, shown in (Schemes 56, 57).

38 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

O O O 4,4-dimethoxy-butan-2-one N R1 N R1 O O R R2 N R2 N 3 O R1= R2 = CH3 142b 151

butan-2-one HCl . MeOH, DCM extraction

O O O SeO . acetonitrile, 5 min, N 2 R1 R N 200 W (MW) 1 H R R N R 2 N 3 R2 3 O O DCM reflux, 5 . 6 h; (i) MeOH, 5 min, 25 W (MW).

152 153

O O R N 1 R3`

R3 R2 N R4` O R5` 154a R1=R2= CH3 ; R3 =CH3; R3', R4', R5' =OCH3 154b R1=R2= CH3 ; R3 =H; R3', R5' =H; R4' =OCH3 154

R = H, R = Me, O O O O 1 2 R2 R2 O R1 = H, R2 = Et, R = H, R = iPr, N O O N R2 1 2 X R = H, R = tBu, O 1 2 R1 = Me, R2 = Me, R1 N NaH / THF H R1 N R R1 = Me, R2 = Et, R1 = MeO, R2 = Me, O R = MeO, R = Et, 142c-e 155 1 2 R1 = MeO, R2 = iPr, 156 -158 R1 = MeO, R2 = tBu, R1 = H ,CH3, OCH3 R=OH, X=O

Scheme 56, Synthesis of quinoxaline 1,4-di-N-oxide analogues.

American Journal of Organic Chemistry 2015, 5(1): 14-56 39

O O O O R N a R N b R N H H O R N R N R N O

142 f 159 160

R = C2H5

NH2 N N O R N O N d R O R N O R N O O O 162 161

e f O NH2 S O

N NH N N R N O R N O

R N O R N O O O

163 164

Scheme 57: Synthesis of 159 -164. (a) Pentane-2,4-dione, triethylamine o (b) Na2S2O4, methanol, 70 C; (c) 3,4,5-trimethoxybenzaldehyde, 3% NaOH . methanol, r.t; (d) guanidine hydrochloride, 10% KOH . isopropanol reflux, 24 h; (e) NH2NH2, ethanol, r.t.; (f) 4-hydrazinobenzene-1-sulfonamide hydrochloride 97%, ethanol, 20 min, 50 W (MW).

On the other hand condensation of 142c with 4-Phenyl-but-3-en-2-one 165 in the presence of piperidine or butylamine [132] afforded 2-phenylquinoxaline 4-oxide 166 and 2-acetyl-3-phenylquinoxaline-4-oxide 167, shown in (Schemes 58).

40 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Piperidine N

O O N Ph Ph 166 N Me O N 4-Phenyl-but-3-en-2-one H O 165 144c BUNH2 N Ph Me N C O 167 Scheme 58 Reaction of 6-Phenyl- 5H-5,7(6H)-pyrrolo[3,4-b]pyrazine 168 underwent electrolytic reduction in the presence of chlorotrimethylsilane, [132] to give the intermediate 169 which reacted with methyl acrylate to afford 6-acetyl-8-(phenyl amino)-1,2-dihydroquinoxalin-5(4aH)-one 170, shown in (Scheme 59).

O CH2 O N H Ph MeO N N O CH Me N ClSIMe3 N 3 O O3MeSiO N H N 2-(methylperoxy)prop-1-ene O OSiMe NHPh

170 168 169

Scheme 59 Ring expansion[132] of benzimidazoles 171 with chloroform gave a separable 9:1 mixture of 2-chloro quinoxaline 172 and quinoxaline-2, 3-dicarbonitrile 173, shown in (Scheme: 60). H N N Cl N CN CHCl3 + N N N CN

171 172 173

Scheme 60

Refluxing of 3-Azido-3-methyl-2-indolinone 174 in xylene [132] gave 3-methyl-2(1H)-quinoxalinone 35, shown in (Scheme 61).

N3 Me xylene, 8 hr N Me NH - N2 N O O H 174 35

Scheme 61

Reaction of pyrrole-substituted anilines 175 and alkynes in presence of Au catalyst, toluene [171] afforded Substituted pyrrolo[1,2-a]quinoxalines 176, shown in (Scheme 62).

American Journal of Organic Chemistry 2015, 5(1): 14-56 41

R1 R 4 R2 R4 R1 R2 N N NH Au catalyst,toluene NH2 R3 R3 80 oC,1- 6 h

175 176

R1= aryl, alkyl; R2= H, aryl, alkyl; R3= H, Me, OMe,CN; R4= H,Me,Et,OMe,CN,F

Scheme 62

4. Reactions of Quinoxalines

4.1. Diazotization Reactions Diazotization [172] of 3-amino-2-ethoxycarbonylthieno[2,3-b]quinoxaline 177 gave the diazonium salt 178 which was reacted with SO2 / CuCl in acetic acid to give the sulphonyl derivative 179 which reacted with N-methylaniline to give sulfamoyl quinoxaline derivative 180. Hydrolysis of 180 with KOH afforded the corresponding acid 181, shown in (Scheme 63). O O N N NCl N S N NH2 SO / CuCl Cl HNO2 2 2 N N COOEt N COOEt S COOEt S ACOH S

177 178 179

CH3NHPh

O Me O O S N Me N O S Ph 1N.KOH N N Ph N S COOH COOEt N S 181 180 Scheme 63

4.2. Nitration Reactions ◦ Nitration of quinoxaline 3a occurs only under forcing conditions (Conc. HNO3, Oleum, 90 C) [108] to give 5-nitroquinoxaline (1.5%) 182 and 5, 7- dinitro quinoxaline (24%) 183, shown in (Scheme 64).

NO2 NO2 N N N Conc. HNO3, Oleum + N N N O2N 1.5 % 24%

3a 182 183

Scheme 64

42 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

4.3. Oxidation Reactions Oxidation of quinoxaline 3.With alkaline potassium permanganate [108, 173 -176] gave pyrazine 2, 3-dicarboxylic acid 184, while with peracid afforded the quinoxaline di-N-oxide 185, shown in (Scheme 65). N COOH alk.KMNO4

N COOH

N 184

N O 3a N CH3COOOH

185

Scheme 65

4.4. Substitutions Reactions Quinoxalines 3 are easily attacked by nucleophiles, for e.g. two molecules of Grignard reagent can be added across quinoxaline molecule to give 2, 3-dipropenyl-1, 2, 3, 4-tetrahydro-quinoxaline 186, [177] shown in (Scheme 66).

H H N N Me CH3CH CHMgBr

N N H Me H 3a 186

Scheme 66

2, 3-diphenyl-6-nitroquinoxaline 187 reacted with KCN in methanol [178] to gives 6-Methoxy-2, 3-diphenyl-quinoxaline-5-carbonitrile 188 which was reacted hydrazine hydrate to give 189, shown in (Scheme 67).

N Ph N Ph N Ph KCN NH2NH2

N H CO N N O2N Ph MeOH 3 Ph N Ph CN HN NH2

187 188 189

Scheme 67

Indoloquinoxalines 190 reacted with 2, 3-diphenyl-quinoxaline 50 to give comp. 191, [179] which condensed with methyl-chloroacetate in presence of K2CO3 to give 192. Aldol condensation of 192 with aromatic aldehyde in acetic acid afforded the chalcons 193, which condensed with benzoic acid hydrazide in acetic acid to give the pyrazol derivatives 194; these compounds show highest antimicrobial activity, shown in (Scheme 68).

American Journal of Organic Chemistry 2015, 5(1): 14-56 43

N MWI,HCHO, N N HCl , 35% N N N + H N N N H N

190 50 191

MWI, anhyd. K2CO3, ClCH2COCH3

N MWI N N N O ArCHO N Aq.NaOH H3C 192

N N N O

Ar 193 N

O NHNH N MWI 2 N N

N N Ar N Benzoic acid hydrazide O glicial ACOH

194 Scheme 68

5. Reduction of Quinoxaline Derivatives Catalytic reduction of 2-acetyl-3-methylquinoxaline 195 with sodium in THF at 20°C yields the 1, 4-dihydroquinoxaline 196, [180, 181] (Scheme 69).

CH H N 3 N CH3 Na O O N THF N H CH 3 CH3 195 196

Scheme 69

Reduction of 3a with LiAIH4 in ether, afforded I, 2, 3, 4-tetra-hydro quinoxaline, while Sodium borohydride in acetic acid [182,183] and hydrogen in the presence of Pt [184] have been used to reduce 1, 2, 3, 4-tetra-hydro compounds.

44 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Hydrogenation of I, 2, 3, 4-tetra-hydroquinoxaline 197 over a 5% rhodium-onalumina catalyst at 100°C and 136 atmospheres pressure or over freshly prepared raney Ni gives meso (cis) - decahydro-quinoxaline 197, [185] shown in (Scheme 70). H N LiAIH4 N

ether N N H

3a 197

Scheme 70

6. Condensation and Cyclization Reactions Reaction of 6-aminothiouracil 198 and 2, 3-dichloroquinoxaline 199 in ethanol/ TEA [72] yielded 6-amino-2- (3-chloroquinoxalin-2-ylthio) pyrimidin-4(3H)-one 200, which was refluxed in dimethylformamide to give 2-aminopyrimidothiazolo [4, 5-b]- quinoxaline-4-one 201. Compound 201 was utilized as a key intermediate for the synthesis of a new pyrimidothiazoloquinoxaline 202 – 211 derivatives by the reaction with 2-chlorobenzaldehyde, 2-chlorocyclohex-1-enecarbaldehyde, 2-chloro benzoic acid, 2,4- dichlorobenzoic acid, 5-chloro-3-methyl-1-phenyl-1H- Pyrazole-4-carbaldehyde,2-chloro-4,6-dimethylnicotinonitrile,α,β-unsaturated ketones and isonicotinaldehyde, respectively, shown in (Scheme 71, 72). O O Cl N Cl N NH Ethanol NH + H N N TEA 2 SH Cl N H2N N S N

198 199 200

40h DMF 140oC COOH Cl O O O N N DMF N R N 200 30h,140oC H N N S N ACOH R N N S N 2 H

201 204, R= H 205, R= Cl

CHO CHO Cl ACOH ACOH Cl

O O N N N N

N N S N N N S N

202 203

Scheme 71

American Journal of Organic Chemistry 2015, 5(1): 14-56 45

N Ph N CH3 H3C O N Cl CHO N N ACOH N N N S N Ph 206 CH3 CN CH3 NH2 O H3C N Cl N N DMF / TEA H C N N N N O 3 S N N 207 O H2N N S N Ar O Ar Ar N 201 N

DMF / TEA N N S N

H Ar 208, Ar = Ph 209, Ar = p-C6H4-Cl 210, Ar = p-C6H4-OCH3

O N CHO N N N dioxane / pipridine N N S N 211 Scheme 72 Condensation between a 6-hydroxy-benzo[f] quinoxaline-2, 3-dicarbonitrile 212 with aromatic aldehyde 213, and Meldrum’s acid 214 in CH3CN/EtOH (2:1) in the presence of a catalytic amount of triethylamine [152] leading to expected products 215 and 216, shown in (Scheme 73).

R O

NC N O CH3CN / EtOH(2:1)

CHo NC N O NC N OH O Et N,rt 24 h + + 3 215 O O NC N R O O CH3CN / MeOH(2:1) R 212 213 214 NC N OH

NC N

216 Scheme 73 Furthermore, condensation between a 6-Hydroxy-benzo[f]quinoxaline-2, 3-dicarbonitrile 212with aldehyde 213, and malononitrile 217 in CH3CN/EtOH (2:1) in the presence of a catalytic amount of triethylamine [152] leading to expected products 218, shown in (Scheme 74).

46 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

CN R NH2 CHo NC N OH CN NC N O CH3CN / MeOH(2:1) + + CN NC N Et3N,rt 24 h NC N R

212 213 217 218

Scheme 74 Reaction of quinoxalin _2(1H) _ one hydrochloride 219 with ethyl acetoacetate 220 in boiling acetic acid for 15 h gave 2_(pyrrol_3_yl)benzimidazole 221 in 62% yield [186], shown in (Scheme 75).

Ph Ph N O O N NH NH2.HCl ACOH , NaHCO3 + Me OEt N O -2H O .- NaCl N H 2 H Me O OEt

219 220 221

Scheme 75

NH NH H 2 H 2 H N N O EtOH, ACOH N N 2 + + N O microwave 400 W N O H H 37 222 1a

EtOH, ACOH microwave 400 W

H DMF, ACOH, H N N M W 400 W, N N 45 seconds N N RCHO + N N H H N NH2

R 224 223

ClCH2COCl, 1,2-dioxan, Et3N M.w 400 W, 3 min thioglycolic acid, EtOH microwave 400 W,4 mins.

H H N N N N

N N N R N H H R Cl N N S O O

225 226

Scheme 76 Compound 37 was added to a mixture of aniline and ethanol and few drops of glacial acetic acid stirred magnetically at

American Journal of Organic Chemistry 2015, 5(1): 14-56 47

room temperature .Then, it was irradiated in microwave to yield of 3-((phenylimino)-3, 4-dihydro quinoxaline)-one 222. [187] To a stirred solution of compound 222 and o-phenylenediamine 1a in ethanol with few drops of glacial acetic acid. This mixture was irradiated with microwave to give N-((E)-3-(phenylimino) - 3, 4-dihydro- qunoxalin-2(1H)-ylidene) benzene-1, 2-diamine 223. Compound 223 was dissolved in ethanol and aromatic aldehyde derivatives with few drops of glacial acetic acid to produce corresponding schiff bases 224. The schiff base(s) 224 was dissolved in 1, 2-dioxan, followed by the addition of chloroacetyl- chloride and triethylamine. The reaction mixture was stirred for 1 h, and then, it was irradiated in a microwave to get 225. The residue was purified by silica gel column to yield respective azetidinones. A mixture of schiff base (s), 224 thioglycolic acid and ethanol were irradiated in microwave to afford 226, as in (Scheme 76). Ethyl quinoxaline-2-carboxylate 227 reacts with hydrazine [188] to form quinoxaline -2-carbohydrazide 228. This compound cyclised with CNBr to afforded 5-(quinoxalin- 3-yl) -1, 3, 4-oxadiazol-2-amine 229. Compound 229 then converted to N'-arylidene quinoxaline-2-carbohydrazides 230 via condensation with aromatic aldehyde. The hydrzides 230 are cyclised to form 3-aryl-5-(quinoxalin-3-yl)-1,3,4-oxadiazole-2(3H)-thiones 231 and 1-(2-aryl-5-(quinoxalin-3-yl)-1, 3, 4-oxadiazol 3(2H)-yl) ethanones 232 by reacting with KOH/CS2 and Ac2O respectively, shown in (Scheme 77). N N N N2H4 CNBr O N COOEt N CONHNH2 N NH2 N N 227 228 229

Ar-CHO

KOH, CS N Ac2O N 2 N

O O N Ar N CONHN N S Ar N N N N 232 230 231 COCH3 Ar

Scheme 77

Treatment of the 2-acetylquinoxaline thiosemicarbazone 233 with α-halogeno- ketones [189] gave the thiazoles 234 along thiazole synthesis. However, in the reaction mixture not only 234 was obtained, but along a redox process from the hydrazones 234 also the 1H-pyrazolo [3, 4-b]quinoxalines 235 could be obtained, shown in (Scheme 78). X R2 R2 HN Y X S R1 R1 H H H N NH N Hal N 2 HN Y N O HN O N N N N N

79 233 234

NHCl X= S,O Y = NH2, SCH3 ,OCH3 OH R2

S R H 1 N N N N N

235 Scheme 78

Coupling o-phenylenediamine 1a [190] with 3-benzoyl-1,2-dihydro-2-oxo- quinoxaline 236 in acetic acid give the phenyl-quinoxalinyl 238 and not to the expected quinoxalino benzodiazepine 237, but to its isomer, 2-benzimidazolyl-3-phenyl quinoxaline 238, shown in (Scheme 79).

48 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Ph N N x N N H H2N Ph 237

N H2N O N O 1a

236 HN N N

N Ph

238 Scheme 79

H N O H NH2NH2 N O (CH3CO)2O O Ar Ethanol N H SO 2 4 N 240 Ar 246 H N O N NH Br2, ACOH Ar ArCHO N Na-acetate

247 H PhCHO N O Ar = C6H5 = p-Cl-C6H4 CH3COOH N = m-NO2-C6H4 = p-F-C H 6 4 O

241

ArCHO H O N O CN ethylcyanoacetate HN

Ammonium acetate N Ar

H 242 N O O

N H NH N O CN Malononitril , ArCHO HN 239 Ammonium acetate N Ar

243

H N O HCHO, ACOH O

C2H5OH N

244

H ACOH , C2H5OH N O O piperidine N

N 245 Scheme 80

American Journal of Organic Chemistry 2015, 5(1): 14-56 49

7. Treatment of Quinoxalines with Many of Organic Reagents

7.1. Quinoxalines with Several of Organic Derivatives Reaction of 3 - (2-oxo-propyl)-1H-quinoxalin-2-one 239 with several reagents for examples [aromatic aldehydes derivatives, ethylcyanoacetate, malononitril, bromine, acetic anhydride and hydrazine hydrate] gave products 240 – 247 respectively [109], shown in (Scheme 80). Reaction of 2-(5,8- dihydroquinoxalino[2, 3-b]indol-5- yl) acetohydrazide 248 With benzofuran chalcones 249 in acetic acid afforded 1-[3-(5-hydroxybenzo[b] furan-2- yl)-5-substituted phenyl-4, 5-dihydro-1H-1-pyrazolyl]-2- (5H-indolo[2, 3-b] quinoxalin-5-yl)-1-ethanone derivatives 250, [191] shown in (Scheme 81). HO O HO

O R R

249 O CH3COOH + O N N 9h NHNH O N N 2 N N

N N

248 250

Scheme 81

7.2. Alkylation Reactions 3-(α-chlorobenzyl)quinoxalin- 2-one 251 reacts with benzylamine in DMSO at room temperature to give 3-(α-benzylamino-benzyl) - quinoxalin-2-one 252 which undergoes intramolecular ring closure to 1,3-diphenylimidazo[1,5-a]quinoxalin-4(5H)-one 253, [192] shown in (Scheme 82). Ph Ph Ph N N N N Ph Cl PhCH2NH2 N Ph DMSO H o o N O DMSO,20 C,48h N O 150 C, 2h N O H H H

251 252 253

Scheme 82

1,3-bis(3-benzoyl-2-oxoquinoxalin-1-ylmethyl)- benzene 255was achieved via alkylation of 3-Benzoyl-1H-quinoxalin-2-one 236 with 1,3-bis (dibromomethyl) benzene 254 in boiling dioxane in the presence of KOH [192], shown in (Scheme 83).

Ph Ph Ph Ph N N N N O O O O

N O O N N O O N H + H KOH , dioxane 236 236 Br Br

255 254 1,3-Bis-bromomethyl-benzene

Scheme 83

50 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

The basicity of the quinoxaline N atoms in 2, 3-di (pyridine-2-yl) quinoxaline 256, which is lower than that in pyridine, was responsible for quaternization [193] only in the pyridine part of the molecule. It should be noted that protons of benzene, pyridyl, and pyridine groups of 257a-c and 258a-c had the same resonances. This was indicative of the quaternization of the same N atom by methyliodide and dodecylbromide, these compounds show potential antimicrobial activity, as in (Scheme 84).

R N HN N N 2RX N N

N N (KOH+ C2H5OH) N N HN N R 256 258a-c

(KOH+ C2H5OH)

R N HN a, R = CH3 ; X= I N N b, R = C12H25 X= Cl N N C, R = CH2COOC2H5 X= Br N N

257a-c

Scheme 84 The N-quinoxalinylisoxazolones 259a-c was prepared by the reaction of the corresponding arylaminoisoxazolone with 2, 3-dichloroquinoxaline 199 in EtOH [194]. Products 259a-c were rearranged to imidazo[1,2-a]quinoxaline derivatives 260a-c by refluxing with triethylamine in THF, also when 2 equivalents of the isoxazolone were reacted with 2, 3- dichloroquinoxaline 199 under the above-described conditions in the absence of base, the rearranged bisimidazoquinoxaline product 261, shown in (Scheme 85).

HN O O HN CO2Et N Cl Ar N Cl O N Cl Ethanol, heat N N O 62-71% HN CO Et Ar 2 199 259a-c

HN O Et3N- THF O 2 equiv.1a heat - CO Ethanol , 2 HN heat ,10 % CO2Et 70- 76 % Ar

N Cl HN EtO2C Me N N N N EtO2C NH N N Me Ar

EtO2C HN

261 260a-c

a Ar = 3-MeC6H4 b Ar = 4-BrC6H4 c Ar = 4-O2NC6H4

Scheme 85

American Journal of Organic Chemistry 2015, 5(1): 14-56 51

Alkylation of 3-ethylquinoxalin- 2(1H)-one 262 by using of ethyl bromide in refluxing dioxane with presence of KOH gave 1, 3-diethyl-1H-quinoxalin-2-one 263. Bromination of compound 262 by using of bromine afforded α-bromoethyl derivative 264. Reaction of 264 with many reagent of nucleophiles as KSCN, NaN3, and PhNH2 in DMSO to give the corresponding 3-(α-x-ethyl) quinoxalines 265-267, [195] shown in (Scheme 86). N Et KOH, EtBr

dioxane , 6h N O Et 263 Me Me N N KSCN , DMSO SCN

N O N O H H 262 265

Br2, dioxane

Me Me N N Br NaN3,DMSO N3

N O N O H H

264 266

Me N PhNH2, DMSO NHPh

N O H

267 Scheme 86

7.3. Addition Reactions (Spiro Compounds) Reacted of 3-(2-aryl-2-oxoethylidene)- 3,4-dihydroquinoxalin-2(1H) - ones 236 with o-phenylenediamine 1a and hydrazine hydrate (and phenylhydrazine), in refluxing acetic acid [196] undergo new acid catalyzed rearrangement with the contraction of pyrazine ring of the quinoxaline system 268 to give form 2-benzo imidazoloquinoxalines derivatives 269, shown in (Scheme 87).

H R R R N N NH N H2N DMF O NH2NH2 H + N N - H O N N N O H2N - H2O H 2 H H N O H

236 268 269 R = Ph Scheme 87

7.4. Esterification Reactions Esterification of 2, 3- Bis-bromomethyl-quinoxaline- 6-carboxylic acid 270 with methanol or ethanol in the presence of a catalytic amount of sulfuric acid [116], afforded the methyl ester and ethyl ester of quinoxaline derivatives 271, as in (Scheme 88).

52 Ameen Ali Abu-Hashem: Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

HOOC N CH Br ROOC N CH2Br 2 H2SO4

N CH2Br ROH N CH2Br

270 271

R = CH3 (74%) = CH2CH3 (90%) Scheme 88

7.5. Demethylation Reaction The 6-hydroxyquinoxaline 273 was synthesized by treating the methoxy compound [2, 3-Bis-bromomethyl-6- methoxy-quinoxaline] 272 with boron tri- bromide. The demethylation reaction [116] proceeded without any side reaction to produce an exceptional yield of 2, 3-Bis- bromomethyl-quinoxalin-6-ol 273, as in (Scheme 89).

H3CO N CH Br HO N CH Br 2 BBr3 2

N CH2Br dry CH2Cl2 N CH2Br

272 273

Scheme 89 (94 %)

[2] Tandon, V. K.; Yadav, D. B.; Maurya, H. K.; Chaturvedi, A. 8. Conclusions K.; Shukla, P. K. Med. Chem. 2006, 14, 6120-6126. DOI: The last twenty years have witnessed an important growth 10.1016/j.bmc.2006.04.029 in research that have an enormous synthetic methodologies [3] Kotharkar, S. A.; Shinde, D.B. Bioorg. Med. Chem. Lett. lead to the synthesis of quinoxalines derivatives due to its 2006, 16, 6181-6184. applications in various fields such as organic and medicinal [4] Mashevskaya, I. V.; Makhmudov, R. R.; Aleksandrova, G. chemistry and material sciences. However, the classical A.; Golovnira, O. V.; Duvalov, A. V.; Maslivets. A. N. methods for the synthesis of quinoxaline derivatives are Pharm. Chem. J. 2001, 35,196 -198. common, environmentally benign protocols have been [5] Vyas, D. A.; Chauhan, N. A.; Parikh, A. R. Indian J. Chem. developed with the goal of increasing the yields or reducing 2007, 46B, 1699-1702. reaction times as well as chemical pollution. All the methods that have been used in preparing these quinoxaline [6] Carta, A.; Loriga, M.; Paglietti, G.; et al. Eur. J. Med. Chem. derivatives are mentioned through organic chemistry and the 2004, 39,195- 203. green chemical science. Further design and development of [7] Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. greener methodologies for the synthesis of quinoxalines will 2002, 45,5604-5606. ensure the rapid growth of an active and important area of [8] Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A. Bioorg. Med. research in heterocyclic chemistry for the construction of a Chem. 2003, 11, 2149-2156. wider spectrum of biologically important quinoxaline scaffolds. This review contains all the biological studies to [9] Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. J. Med. Chem. the quinoxalines derivatives; it shows its biological 2005, 48, 2019-2025. importance as well. More than 190 references have been [10] Jaso, A.; Zarranz, B.; Aldana, I.; Monge, A. Eur. J. Med. mentioned to show the importance of these quinoxaline Chem. 2003, 38,791-800. derivatives. Through the study of these compounds it shows [11] Burguete, A. ; Pontiki, E.; Litina, D. H.; et al. Bioorg. Med. the presence of many quinoxaline derivatives that are used to Chem. Lett. 2007, 17, 6439-6443. cure so many diseases; they are considered ultimate drugs that found in pharmacies, for example: Levomycin, [12] Wagle, S.; Adhikari, A. V.; Kumari, N. S. Indian J. Chem. Echinomycin and Brimonidin (Alphagan). 2008, 47B, 439-448. [13] Ishikawa, H.; Sugiyama, T.; Kurita, K.; Yokoyama, A. Bioorg.Chem.2012, 41-42, 1-5. [14] Loriga, M.; Piras, S.; Sanna, P.; Paglietti, G. Farmaco 1997, REFERENCES 52(3), 157-166. [1] Moloney, M. G. Nat. Prod. Rep.2002, 19, 597-616. DOI: [15] Crowther, A. F.; Curd, F.H.S.; Davey, D.G.; Stacey, G.J. J. 10.1039/B103777N, Review Article Chem. Soc. 1949, 1260-1262.

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