Synthesis of new quinoxaline derivatives

Article abstract of DOI:10.1080/00397911.2010.519091

New quinoxaline derivatives were prepared by the reaction of 2-hydroxyquinoxaline 1 and alkyl or alkylaminoalkyl halides in dimethylformamide using potassium carbonate as a base. The hydroxyl group was readily converted into a thiol function by treatment with phosphorus pentasulfide and/or Lawesson's reagent in pyridine, and the subsequent alkylation of the thiol group was carried out under phase-transfer catalyst conditions. Chlorination of 1 was carried out with phosphorus oxychloride. Branching of alkylamino side chains to the 2-OH, 2-SH, and 2-Cl quinoxalines resulted in the synthesis of several compounds. Synthesis and alkylation of 2-hydroxy 7-nitroquinoxaline are also reported.

Full text of DOI:10.1080/00397911.2010.519091

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Synthesis of New Quinoxaline Derivatives
A. Makhloufi a , M. Baitiche a , M. Merbah a & D. Benachour a
a Faculté des sciences de l'ingénieur, Département de génie des
procédés, Laboratoire des matériaux polymériques multiphasiques,
Université Ferhat Abbas, Sétif, Algeria
Accepted author version posted online: 30 Jun 2011.Version of
record first published: 27 May 2011.
To cite this article: A. Makhloufi , M. Baitiche , M. Merbah & D. Benachour (2011): Synthesis
of New Quinoxaline Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:23, 3532-3540
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Synthetic Communications1, 41: 3532–3540, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.519091
SYNTHESIS OF NEW QUINOXALINE DERIVATIVES
A. Makhloufi, M. Baitiche, M. Merbah, and D. Benachour
´
Faculte des sciences de l’ingenieur, Departement de genie des procedes,
Laboratoire des materiaux polymeriques multiphasiques, Universite Ferhat
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Abbas, Setif, Algeria
GRAPHICAL ABSTRACT
Abstract New quinoxaline derivatives were prepared by the reaction of 2-hydroxyquinoxa-
line 1 and alkyl or alkylaminoalkyl halides in dimethylformamide using potassium carbon-
ate as a base. The hydroxyl group was readily converted into a thiol function by treatment
with phosphorus pentasulfide and=or Lawesson’s reagent in pyridine, and the subsequent
alkylation of the thiol group was carried out under phase-transfer catalyst conditions.
Chlorination of 1 was carried out with phosphorus oxychloride. Branching of alkylamino
side chains to the 2-OH, 2-SH, and 2-Cl quinoxalines resulted in the synthesis of several
compounds. Synthesis and alkylation of 2-hydroxy 7-nitroquinoxaline are also reported.
Keywords Alkylation; aminoalkylation; chlorination; quinoxalines; thiation
Received January 22, 2010.
Address correspondence to Milad Baitiche, Faculte des sciences de l’ingenieur, Departement de
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´
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´
´
genie des procedes, Laboratoire des materiaux polymeriques multiphasiques, Universite Ferhat Abbas,
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19000 Setif, Algeria. E-mail: baitiche_milad@yahoo.fr
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NEW QUINOXALINE DERIVATIVES
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INTRODUCTION
Nitrogen-containing heterocyclic compounds are desirable structural units for
both chemists and biochemists. Quinoxaline compounds have important pharmaco-
logical activities, such as the following: imidazoquinoxalines have been reported
as antiviral agents,[1] pyrazoloquinoxalines showed relatively high antibacterial
activity,[2] quinoxaline-1,4-di-N-oxides were used for treatment of tuberculosis,[3]
pyrimido[4,5-b]quinoxaline is known to be a antihypertensive and blood platelet
antiaggregating agent,[4] and some quinoxaline derivatives have cytotoxic effects on
human cancer cell lines,[5,6] and are commercially important as agrochemicals,[7]
herbicides,[8] and amebicides.[9] Different analogs of quinoxalines have been prepared
by alkylation. The presence of an alkyl group with nitrogen or sulfur atoms as a side
chain on an quinoxaline ring is an important factor for biological activities,[10] so
within the frame of our ongoing research in such chemosensitizers, we intended to
prepare new derivatives belonging to these series.
Alkylation reactions were carried out by nucleophilic substitution through
alkyl halides. It is well established that the 2-hydroxyquinoxaline exists in two
tautomeric forms, b1 and b2 (Fig. 1). This enolic equilibrium, which is a very slow
process in a neutral medium, can be catalyzed by bases or acids.[11] By considering
a reactional medium made of N,N-dimethylformamide (DMF)=potassium carbon-
ate (K2CO3), the enolic form b1 will prevail and consequently its reaction with the
alkylating agents will be favored, thus giving mainly alkoxy products compared to
the N-alkylated ones.[12] Previously, these conditions have shown to be very efficient
when using quinolines.[13]
According to previous works, chlorination of similar heterocycles is made by
acting thionyle chloride (SOCl2) on the hydroxylated form, but it seems that this
way of preparing chlorinated heterocyclic compounds usually gives poor yields. In this
situation, the reaction with phosphorus oxychloride (POCl3) was more effective.[14]
A large number of aromatic heterocyclic amines are prepared by direct reaction
of primary amines on the chlorinated compound. The conditions of the reaction
depend on the nucleophilic power of the amine and its volatility.[15]
The conversion of a carbonyl group into a thione is a classical reaction. It can
be carried out either under the effect of sulfur at high temperature or by an oxygen=
sulfur exchange under the action of phosphorus decasulfide or Lawesson’s reagent in
solvents such as pyridine, diglyme, or dioxane.[16] Greater yields were observed with
the latter method, which is why this was taken as the basis for the thiation reaction of
the initial product.
Sulfides are known for their biological properties,[17] and bringing more
modifications to the main skeleton by adding segments on the sulfur atom seems very
Figure 1. Tautomeric forms of 2-hydroxyquinoxaline.

3534
A. MAKHLOUFI ET AL.
interesting. Alkylation reactions were carried out on previously prepared 2-thiol-
quinoxaline. We note that because of the poor yields of the alkylation reactions when
using the classical method of preparing 2-thioalkylatedquinoxalines, the phase-
transfer catalysis (PTC) procedure was adopted, which overcomes this deficiency.[18]
Based on the fact that the presence of a nitro group on an aromatic heterocyclic
compound may bring some new and interesting biological properties,[19] a nitration
reaction was at tempted on the initial product. For this, the nitration reaction was
carried out by the direct action of nitric acid in concentrated sulfric acid medium
onto the initial compound at 0 ꢀC,[11] and the resulting product was subjected to
alkylation reactions according to the classical method.
RESULTS AND DISCUSSION
At first, 2-hydroxyquinoxaline 1 was used as the starting material. With the
aim to obtain the O-alkyl derivatives 2, a mixture of 1 and alkyl or alkylaminoalkyl
halides was heated at 80 ꢀC in dimethylformamide (DMF) in the presence of potass-
ium carbonate for 5 h.
On the one hand, the 2-thioquinoxaline 3 was prepared by treating 1 with
phosphorus pentasulfide or with Lawesson’s reagent in pyridine. The yields were
respectively 75% and 60%. Alkylation of the thione gave 2-alkylthioquinoxaline
derivatives 4. The reaction was carried out under PTC conditions at 110 ꢀC for
24 h with tetrabutylammonium bromide (TBAB) as a dispersing agent.
Figure 2. Scheme showing the main chemical synthetic pathways.

3535

3536

NEW QUINOXALINE DERIVATIVES
3537
Table 2. 13C NMR chemical shifts
13C NMR (solvent) d (ppm)
Compound
1
(DMSO) 154.876 (C2); 151.531 (C3); 131.978 (C5); 131.765 (C10); 130.689 (C7); 128.717
(C8); 123.198 (C9); 115.669 (C6);
2a
3
(CDCl3) 139.83, 130.028, 128.94, 127.16, 126.38, 62.32 (OCH2), 14.35 (OCH2CH3)
(CDCl3) 174.931 (C2¼S); 155.807 (C3); 131.651 (C5); 135.306 (C10); 131.365 (C7);
128.746 (C8); 125.705 (C9); 116.117 (C6);
4d
4e
5
(CDCl3) 152.55 (C2); 141.09 (C3); 139.75 (C10); 136.26 (C9); 131.54 (C5); 128.57 (C6);
126.12 (C7); 125.25 (C8); 64.62 (CH2O); 57.56 (CH2N); 53.24 (NCH2); 36.25 (SCH2);
(CDCl3) 153.94 (C2); 143.54 (C3); 141.45 (C10); 137.83 (C9); 131.21 (C5); 129.43 (C8);
127.28 (C6); 127.28 (C7); 56.35 [CH2N & N(CH3)2]; 43.31 (SCH2).
(CDCl3) 147.21 (C2); 145.22 (C3); 144.84 (C9); 144.80 (C10); 141.8 (C9); 140.8 (C5); 140.4
(C7); 128.11 (C8).
6d
(CDCl3) 151.75 (C2); 140.09 (C3); 139.48 (C10); 135.48 (C9); 130.73 (C5);
127.67 (C8); 125.09 (C7); 124.17 (C8); 63.72 (CH2O); 56.80 (CH2N); 52.16
(NCH2); 35.13 (CH2).
7
(DMSO) 160.04 (C2); 152.88 (C7); 148.86 (C9); 144.96 (C3); 129.01 (C10); 128.19 (C5);
122.69 (C8); 121.88 (C6).
On the other hand, chlorination of 1 with phosphorus oxychloride gave
2-chloroquinoxaline 5 in good yield. Because of its high reactivity, 5 reacts easily
with amino derivatives to form the 2-alkylaminoquinoxalines 6.
The 2-hydroxy 7-nitroquinoxaline 7 is obtained with good yield (75%) when
2-hydroxyquinoxaline 1 reacts with nitric acid in the sulfuric acid. Alkylation of 7
was realized under the same conditions as those used for 1.
Synthetic pathways are schematised in Fig. 2.
Chemical data of these compounds are gathered in Tables 1 and 2.
According to Table 1, the O-alkylated isolated products have different yields.
We note a raised value for the ethyl group (64%) as compared with that obtained
with the piperidinoethyl motive (30%). Large side chains are favorable for steric
hindrance. The aminoalkyl halides react less quickly with the 2-hydroxyquinoxaline
and require longer reaction times. The thioalkylation reaction yields are boarding
the 45% for the aminoalkyl halides series used. It would be interesting to use a simple
alkyl halide of smaller size to compare the reactivity as was done with O-alkylated
compounds. For amination reactions, the yields are increased. The chlorine atom
is mobile toward nucleophilic reagents such as amines. The yields of the alkylation
reaction of the nitrated product were different. We observed a bigger value for the
ethyl group than for the methyl one. Even there, the chain size plays an important
role in reactivity.
EXPERIMENTAL
Different techniques are used for spectroscopic characterization. Infrared (IR)
spectra were recorded on a Perkin-Elmer Spectrum 1000 spectrophotometer. NMR
spectra were recorded on a Brucker Advance 200 spectrometer with tetramethylsi-
¨
lane (TMS) used as internal standard. Melting points were determined on a Buchi
¨
B540 apparatus.

3538
A. MAKHLOUFI ET AL.
2-Alkoxyquinoxalines 2
In a round-bottomed flask, a mixture of 1 (5 mmol) and potassium carbonate
(5 mmol) was dissolved in 15 ml of DMF at 80 ꢀC under continuous stirring. Then,
the alkyl halide (5 mmol) was dropwise added to the solution and heated at 80 ꢀC
for 6 h. The obtained product 2 was poured into the water. The precipitated was
filtered and purified by recrystallization from ethanol.
2-Quinoxalinethiol 3
2-Hydroxyquinoxaline 1 (4 mmol) was added to a solution of phosphorus
pentasulfide (4.5 mmol) in pyridine (30 ml) under vigorous stirring under reflux at
80 ꢀC for 4 h. The precipitated product in water was filtered and purified by recrys-
tallization from ethanol.
2-Alkylthioquinoxalines 4
A mixture of 2-quinoxalinethiol (3 mmol), alkyl halide (3 mmol), tetrabutylam-
monium bromide (3 mmol) in toluene (30 ml), and 50% aqueous potassium hydrox-
ide (15 ml) were refluxed at 110 ꢀC for 24 h. The oily crude product was extracted
from the dried organic layer and purified by column chromatography in ethyl
acetate=methanol (7:3) system.
2-Alkylaminoquinoxalines 6
A mixture of 2-hydroxyquinoxaline (10 mmol) and phosphorus oxychloride
(30 ml) was heated at 80 ꢀC for 3 h to produce 2-chloroquinoxaline 5, which was
converted into 6 by addition of amine in the presence of MeOH (1.5 ml). The crude
product was precipitated in aqueous KOH (10%), filtered, and purified by column
chromatography using petroleum ether=ethyl acetate (1:1) system.
2-Hydroxy 7-Nitroquinoxaline 7
Nitric acid (0.6 ml) was added dropwise to a solution of 2-hydroxyquinoxaline
(5 mmol) in sulfuric acid (6 ml) with stirring at room temperature for 7 h. The crude
product was precipitated in crushed ice, filtered, and purified by recrystallization in
MeOH=water.
Alkylation of 7 was carried out in the same manner as for 1.
ACKNOWLEDGMENT
´
The authors are thankful to ANDRS (Agence Nationale pour le Developpement
´
de la Recherche en Sante) for supporting this work.
REFERENCES
1. Bhosale, R. S.; Sarda, S. R.; Ardhapure, S. S.; Jadhav, W. N.; Bhusare, S. R.; Pawar, R. P.
An efficient protocol for the synthesis of quinoxaline derivatives at room temperature
using molecular iodine as the catalyst. Tetrahedron Lett. 2005, 46, 7183–7186.

NEW QUINOXALINE DERIVATIVES
3539
2. Kotharkar, S. A.; Shinde, D. B. Synthesis of antimicrobial 2,9,10-trisubstituted-6-
oxo-7,12-dihydro-chromeno[3,4-b]quinoxalines. Bioorg. Med. Chem. Lett. 2006, 16,
6181–6184.
`
3. Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.; Thiolat, D.;
Massip, S.; Tabourier, A.; Leger, J. M.; Dufaure, B.; Haumont, G.; Jarry, C.; Mossalayi,
´
D. Synthesis, analytical behaviour and biological evaluation of new 4-substituted pyrro-
lo[1,2-a]quinoxalines as antileishmanial agents. Bioorg. Med. Chem. 2007, 15, 194–210.
4. Amin, K. M.; Ismail, M. M. F.; Noaman, E.; Soliman, D. H.; Ammar, Y. A. New quin-
oxaline 1,4-di-N-oxides. Part 1: Hypoxia-selective cytotoxins and anticancer agents
derived from quinoxaline 1,4-di-n-oxides. Bioorg. Med. Chem. 2006, 14, 6917–6923.
5. Tandon, V. K.; Yadav, D. B.; Maurya, H. K.; Chaturvedi, A. K.; Shukla, P. K. Design,
synthesis, and biological evaluation of 1,2,3-trisubstituted-1,4-dihydrobenzo[g]
quinoxaline-5,10-diones and related compounds as antifungal and antibacterial agents.
Bioorg. Med. Chem. 2006, 14, 6120–6126.
6. Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A. Synthesis and anticancer activity evaluation
of new 2-alkylcarbonyl and 2-benzoyl-3-trifluoromethyl-quinoxaline 1,4-di-n-oxide
derivatives. Bioorg. Med. Chem. 2004, 12, 3711–3721.
7. Piras, S.; Loriga, M.; Paglietti, G. Quinoxaline chemistry. Part XVII. Methyl [4-(substi-
tuted 2-quinoxalinyloxy) phenyl] acetates and ethyl N-f[4-(substituted 2-quinoxalinyloxy)
phenyl] acetylg glutamates analogs of methotrexate: Synthesis and evaluation of in vitro
anticancer activity. IL Farmaco. 2004, 59, 185–194.
8. Catarzi, D.; Colotta, V.; Varano, F.; Filacchioni, G.; Martini, C.; Trincavelli, L.;
Lucacchini, A. 1,2,4-Triazolo[1,5-a]quinoxaline derivatives: Synthesis and biological
evaluation as adenosine receptor antagonists. IL Farmaco. 2004, 59, 71–81.
9. Baitiche, M.; Mahamoud, A.; Benachour, D.; Merbah, M.; Barbe, J. Synthesis of new
quinazoline derivatives. Heterocycl. Commun. 2004, 10, 269–272.
10. Corona, P.; Carta, A.; Loriga, M.; Vitale, G.; Paglietti, G. Synthesis and in vitro antitu-
mor activity of new quinoxaline derivatives. Eur. J. Med. Chem. 2009, 44, 1579–1591.
11. Brown, D. J. Quinoxalines: Supplement II, Chemistry of heterocyclic compounds, 61; John
Wiley and Sons: Canberra, 2004.
12. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikwa, T. Structure-activity relation-ships
of antibacterial 6,7-and 7,8-disubstituted 1-alkyl-1,4 dihydro-4-oxoquinoline-3-carboxylic
acids. J. Med. Chem. 1980, 23, 1358–1363.
`
13. Gallo, S.; Chevalier, J.; Mahamoud, A.; Eyraud, A.; Pages, J. M.; Barbe, J. 4-alkoxy and
4-thioalkoxyquinoline derivatives as chemosensitizers for the chloramphenicol-resistant
clinical enterobacter aerogenes 27 strain. Int. J. Antimicrob. Agents. 2003, 22(3), 270–273.
14. Denny, W. A.; Atwell, G. J.; Roberts, P. B.; Anderson, R. F.; Boyd, M.; Lock, C. J. L.;
Wilson, W. R. Hypoxia-selective antitumor agents. 6. 4-(alkylamino)-nitro-quinolines: A
new class of hypoxia-selective toxins. J. Med. Chem. 1992, 35, 4832–4841.
15. Sharma, V. M.; Adi Seshu, K. V.; Sekhar, V. C.; Sachin, M.; Vishnu, B.; Babu, P. A.;
Krishna, C. V.; Sreenu, J.; Krishna, V. R.; Venkateswarlu, A.; Rajagopal, S.; Ajaykumar,
R.; Kumar, T. S. Synthesis and biological evaluation of [4-(2-phenylethenesulfonylmethyl)
phenyl]-quinazolin-4-yl-amines as orally active anti-cancer agents. Bioorg. Med. Chem.
Let. 2004, 14, 67–77.
16. Smolders, R. R.; Hanuise, J.; Coomans, R.; Projietto, V.; Voglet, N.; Waefelaer, A.
Thiation wih teteraphophorus decasulfide in hexamethyl phosphoric triamide: Synthesis
of thioacromycine and acridanethione. Synthesis 1982, 493–498.
17. Thornton, T. J.; Jones, T. R.; Jackman, A. L.; Flinn, A.; M.; O’Connor, B.; Warner, P.;
Calvert, A. H. Quinazoline antifolates inhibiting thymidylate synthase: 4-thio-substituted
analogs. J. Med. Chem. 1991, 34(3), 978–984.

3540
A. MAKHLOUFI ET AL.
18. Bsiri, N.; Johnson, C.; Kayirere, M.; Galy, A. M.; Galy, J. P.; Barbe, J.; Osuna, A.;
Mesa-valle, M. C.; Castilla Cavente, J. J.; Odriguez-Cabeza, M. N. Relations structure-
´
activite trypanocide chez les 9-thioalkylacridines. Ann. Pharm. 1996, 54, 27–33.
19. Tobe, M.; Isobe, Y.; Tomizawa, H.; Nagasaki, T.; Aoki, M.; Negishi, T.; Hayashi, H.
Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: Dual-acting compounds
with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha)
production and T cell proliferation. Chem. Pharm. Bull. 2003, 51, 1109–1112.