American Journal of Organic Chemistry

p-ISSN: 2163-1271    e-ISSN: 2163-1301

2015;  5(1): 14-56


Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives

Ameen Ali Abu-Hashem1, 2

1Photochemistry Department (Heterocyclic Unit), National Research Centre, Giza, Egypt

2Chemistry Department, Faculty of Science, Jazan University, Saudi Arabia

Correspondence to: Ameen Ali Abu-Hashem, Photochemistry Department (Heterocyclic Unit), National Research Centre, Giza, Egypt.


Copyright © 2015 Scientific & Academic Publishing. All Rights Reserved.


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

Cite this paper: Ameen Ali Abu-Hashem, Synthesis, Reactions and Biological Activity of Quinoxaline Derivatives, American Journal of Organic Chemistry, Vol. 5 No. 1, 2015, pp. 14-56. doi: 10.5923/j.ajoc.20150501.03.

Article Outline

1. Introduction
2. Biological and Pharmacological Studies
    2.1. Antimicrobial Activity
    2.2. Anti-Amoebic, Anti-Proliferative Activity
    2.3. Hypoglycemic, Anti-Glaucoma Activity
    2.4. Antiviral Activity
    2.5. Cytotoxic with Anticancer, Antitumor Activity
    2.6. Antithrombotic Activity
    2.7. Anti-HIV Agents
    2.8. 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
        3.1.2. Use Different Methods of Catalyst Systems and Reaction Conditions
        3.1.3. Oxidation of Aromatic Diamines with Many Organic Materials
        3.1.4. Condensation of Aromatic Diamines and Dicarbonyl Derivatives.
    3.2. Intramolecular Cyclisation of N-Substituted Aromatic O-Diamines
    3.3. Ring Transformation of Aryl Aromatic Compounds
4. Reactions of Quinoxalines
    4.1. Diazotization Reactions
    4.2. Nitration Reactions
    4.3. Oxidation Reactions
    4.4. Substitutions Reactions
5. Reduction of Quinoxaline Derivatives
6. Condensation and Cyclization Reactions
7. Treatment of Quinoxalines with Many of Organic Reagents
    7.1. Quinoxalines with Several of Organic Derivatives
    7.2. Alkylation Reactions
    7.3. Addition Reactions (Spiro Compounds)
    7.4. Esterification Reactions
    7.5. Demethylation Reaction
8. Conclusions

1. Introduction

Quinoxaline derivatives have different pharamacological activities such as bacteriocides and insecticides [1], antibacterial [2-5], antifungal [2, 6], antitubercular [2, 7-9, 10], analgesic [4, 11] and anti-inflammatory [11, 12]. The importance of quinoxaline derivatives comes from its nitrogen contents (heterocyclic compounds).
A structure of ring fused with quinoxalines, display diverse pharmacological activities (antibacterial, anticancer and antiviral) [13, 14], antimalarial [15, 16] and anti- depressant activities [17]. Quinoxaline-diones derivatives use on treatment of epilepsy, pain and other neurodegenerative disorders [1, 18].
Quinoxalines were identified as antihypertensive agents and animal growth promoters [19, 20]. It was found that several highly mutagenic and carcinogenic quinoxalines have been identified in heated meat and fried fish [21]. Certain condensed quinoxalines exhibit antibacterial, analgesic, tuberculostatic, antileukemic activities [22]. Biologically active polypeptides such as levomycin and echinomycin have been shown to possess one or more quinoxalinyl residues [23].
1, 4-di-N-oxide quinoxaline derivatives are heterocycles that are often used in the synthesis of biologically active compounds, [24-51] as shown in (Figure 1).
Figure 1. Levomycetin has a high level of activity and is only slightly toxic to man Echinomycin is a peptide anibintic

2. Biological and Pharmacological Studies

2.1. Antimicrobial Activity

Quinoxaline-1, 4-di-N-oxide derivatives, pyrazoloquinoxalines and 2-[4-arylidene hydrazinocarbonyl) aniline]-3-methyl quinoxalines (274, 275, 276, 277, 278) respectively have been identified as antibacterial, Antifungal agents and antimicrobial activity [2, 52, 53, 54, 55] as shown in (Figure 2).
Figure 2. Quinoxaline derivatives as examples of antibacterial, antifungal and antimicrobial activity

2.2. Anti-Amoebic, Anti-Proliferative Activity

2-(5-substituted-3-phenyl-2-pyrazolinyl)-1, 3-thiazolino [5, 4-b] quinoxaline 279 was tested in vitro as anti-amoebic activity against strain of (E. histolytica) [56]. Recently; 6-arylamino-2, 3-bis (pyridin-2-yl)-7-choloroquinoxaline-5, 8- diones (280) have been as a potent anti-proliferative agent [57]; as shown in (Figure 3).
Figure 3. Quinoxalines as examples of antiamoebic activity and antiproliferative

2.3. Hypoglycemic, Anti-Glaucoma Activity

(N-arylcarbamoyl and N- aryl thiocarbamoyl) hydrazinequinoxalin - 2 (1H) (281) have been informed as mild hypoglycaemic agents [58] and Brimonidin (282) (Alphagan) is a drug used for the treatment of open - angle glaucoma [59] shown in (Figure 4).
Figure 4. Quinoxalines as hypoglycaemic and antiglaucom activity

2.4. Antiviral Activity

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 of these compounds [60]; shown in (Figure 5).
Figure 5. Quinoxalines as antiviral activity

2.5. Cytotoxic with Anticancer, Antitumor Activity

A series of quinoxalines derivatives and substituted quinoxalines showed antitumor with remarkable cytotoxic effect against different Sarcoma type. For examples: 2,3,7-trichloro-6- methylsulfamoylquinoxaline (284) [61]; 1H-quinoxalin-2-one (285), bromomethyl-5-chloro-3, 4-dihydro-1H-pyrido [2, 3-g] quinoxalin-2-one (286), 3- Phenoxymethyl-1H-quinoxalin-2-one (287)] [62, 63]; 2, 3-bis (bromo- methyl) -5,10- benzo[g]quinoxaline-dione (tricyclic quinone) derivative (288). Some substituted quinoxaline 1, 4-di-N-oxides (289) and tested for tumour inhibiting activity and highly active as a cytotoxic agent with highest hypoxic cytotoxicity [26, 64, 65] and pyridine-2-carboxylic acid N-(7-fluoro-pyrrolo[1,2-a] quinoxalin-4-yl) hydrazide (290b) derivatives (290a), in panel of cancer cell lines, a breast cancer cell and three colon cancer cells [66] was moderately active against colon cancer lines and highly active in all cells. The in vitro cytotoxic activities of 7-dialkylaminomethyl benzo[g] - quinoxaline -5, 10- dione derivatives (291a-e) was evaluated against panel of human cancer cell lines. These are ovarian carcinoma, colon cancer, breast cancer [67], shown in (Figure 6).
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).
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 iso- propyl 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-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (299)] inhibitors of reverse transcriptase as potential anti-HIV Agents [69-71]; shown in (Figure 8).
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).
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).
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).
Scheme 2
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).
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
Table 2. Synthesis of quinoxalines via different reaction conditions
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).
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).
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).
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).
Scheme 7
Condensation of p- tolylsulfone 29, [104] with o-phenylenediamine 1a in DMF yields 2-phenyl - quinoxaline 30, shown in (Scheme 8).
Scheme 8
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).
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).
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).
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).
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).
Scheme 13
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).
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).
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-dihydro- quinoxaline-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).
Scheme 16
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).
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).
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).
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)
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) -ethyl- imino]- 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- glutric acid (2-oxopentanedioic acid) to yield 3-(3-oxo -3, 4-dihydro- quinoxalin-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).
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).
Scheme 22
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).
Scheme 23
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).
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).
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).
Scheme 26
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).
Scheme 27
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).
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).
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).
Scheme 30
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).
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).
Scheme 32
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).
Scheme 33
Quinoxaline derivative 72 was also prepared via condensation of glucose 71 with o-phenylenediamine 1a [137, 138], shown in (Scheme 34).
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).
Scheme 35
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).
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).
Scheme 37

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).
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).
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).
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).
Scheme 41
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-phenylene- diamine 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).
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).
Scheme 43
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).
Scheme 44
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).
Scheme 45
Condensation of 1, 2-dicarbonyl derivatives 121 123 with o-phenylene- diamine 1a,b,e at room temperature in the presence of magnesium sulfate heptahy- drate (MgSO4·7H2O) afforded phenazine and quinoxaline derivatives 124126; [154-163] in excellent yields, shown in (Scheme 46).
Scheme 46
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).
Scheme 47
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).
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).
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).
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).
Scheme 51
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).
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).
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-methyl- quinoxaline 141, [165] shown in (Scheme 54).
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).
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).
Scheme 56
Scheme 57
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).
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).
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).
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).
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).
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).
Scheme 63

4.2. Nitration Reactions

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

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).
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).
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).
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).
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).
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. 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).
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).
Scheme 71
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).
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).
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).
Scheme 75
Compound 37 was added to a mixture of aniline and ethanol and few drops of glacial acetic acid stirred magnetically at 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).
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).
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).
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).
Scheme 79

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).
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).
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).
Scheme 82
1,3-bis(3-benzoyl-2-oxoquinoxalin-1-ylmethyl)- benzene 255 was 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).
Scheme 83
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).
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).
Scheme 85
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).
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).
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).
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).
Scheme 89

8. Conclusions

The last twenty years have witnessed an important growth in research that have an enormous synthetic methodologies lead to the synthesis of quinoxalines derivatives due to its applications in various fields such as organic and medicinal chemistry and material sciences. However, the classical methods for the synthesis of quinoxaline derivatives are common, environmentally benign protocols have been developed with the goal of increasing the yields or reducing reaction times as well as chemical pollution. All the methods that have been used in preparing these quinoxaline derivatives are mentioned through organic chemistry and the green chemical science. Further design and development of greener methodologies for the synthesis of quinoxalines will ensure the rapid growth of an active and important area of research in heterocyclic chemistry for the construction of a wider spectrum of biologically important quinoxaline scaffolds. This review contains all the biological studies to the quinoxalines derivatives; it shows its biological importance as well. More than 190 references have been mentioned to show the importance of these quinoxaline derivatives. Through the study of these compounds it shows the presence of many quinoxaline derivatives that are used to cure so many diseases; they are considered ultimate drugs that found in pharmacies, for example: Levomycin, Echinomycin and Brimonidin (Alphagan).


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