Efficient synthesis of quinoxalines in the ionic liquid 1-n-butylimidazolium tetrafluoroborate ([Hbim]BF4) at ambient temperature

Article abstract of DOI:10.1080/00397910802054271

Quinoxaline derivatives have been synthesized in excellent yields using an ionic liquid (IL) (viz., 1-n-butylimidazolium tetrafluoroborate) as a reaction medium as well as promoter from various 1,2-diketones and aryl-1,2-diamines. The process is general for the synthesis of quinoxaline derivatives from aromatic as well as aliphatic-1,2-diketones. The advantages of the present method are ambient reaction temperature, simplicity of operation, high yields of products, the recyclability of the IL, and ecofriendly nature of the reaction medium. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802054271

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Efficient Synthesis of
Quinoxalines in the Ionic
Liquid 1-n-Butylimidazolium
Tetrafluoroborate ([Hbim]BF4)
at Ambient Temperature
Taterao M. Potewar a , Sachin A. Ingale a & Kumar V.
Srinivasan a
a Division of Organic Chemistry, National Chemical
Laboratory , Pune, India
Published online: 14 Oct 2008.
To cite this article: Taterao M. Potewar , Sachin A. Ingale & Kumar V. Srinivasan
(2008) Efficient Synthesis of Quinoxalines in the Ionic Liquid 1-n-Butylimidazolium
Tetrafluoroborate ([Hbim]BF4) at Ambient Temperature, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:21, 3601-3612, DOI: 10.1080/00397910802054271
To link to this article: http://dx.doi.org/10.1080/00397910802054271
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Synthetic Communications1, 38: 3601–3612, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802054271
Efficient Synthesis of Quinoxalines in the Ionic
Liquid 1-n-Butylimidazolium Tetrafluoroborate
([Hbim]BF4) at Ambient Temperature
Taterao M. Potewar, Sachin A. Ingale, and Kumar V. Srinivasan
Division of Organic Chemistry, National Chemical Laboratory,
Pune, India
Abstract: Quinoxaline derivatives have been synthesized in excellent yields using
an ionic liquid (IL) (viz., 1-n-butylimidazolium tetrafluoroborate) as a reaction
medium as well as promoter from various 1,2-diketones and aryl-1,2-diamines.
The process is general for the synthesis of quinoxaline derivatives from aromatic
as well as aliphatic-1,2-diketones. The advantages of the present method are
ambient reaction temperature, simplicity of operation, high yields of products,
the recyclability of the IL, and ecofriendly nature of the reaction medium.
Keywords: Aryl-1,2-diamines, 1,2-diketones, ionic liquid (IL), quinoxalines
INTRODUCTION
Quinoxaline derivatives are an important class of nitrogen-containing
heterocycles and have shown a broad spectrum of biological activities.[1,2]
The quinoxaline ring moiety constitutes part of various antibiotics such
as echinomycin, levomycin, and actinoleutin,[3] which are known to inhi-
bit growth of Gram-positive bacteria. They have been reported for their
applications in pharmaceuticals[4,5] and have also been used as building
blocks for the synthesis of organic semiconductors.[6,7] They are also well
known for their applications in efficient electroluminescent materials[8]
Received February 15, 2008.
Address correspondence to Kumar V. Srinivasan, Division of Organic Chem-
istry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008,
India. E-mail: kumarv.srinivasan@gmail.com
3601

3602
T. M. Potewar, S. A. Ingale, and K. V. Srinivasan
and as building blocks for the synthesis of anion receptors,[9] cavi-
tands,[10] dehydroannulenes,[11] and DNA-cleaving agents.[12]
By far the most common method of synthesis relies on the condensa-
tion of an aryl 1,2-diamine with a 1,2-dicarbonyl compound in refluxing
ethanol or acetic acid for 2–12h, giving 34–85% yields.[13] Numerous meth-
ods are available in the literature for the synthesis of quinoxaline derivatives
including the Bi-catalyzed oxidative coupling of epoxides and ene-1,2-dia-
mines,[14] solid-phase synthesis on SynphaseTM lanterns,[15] cyclization of
a-arylimino oximes of a-dicarbonyl compounds under reflux in acetic
anhydride,[16] condensation of o-phenylenediamines and 1,2-dicarbonyl
compounds in MeOH=AcOH under microwave irradiation,[17] iodine-
catalyzed cyclocondensation of 1,2-dicarbonyl compounds and substituted
o-phenylenediamines in dimethyl sulfoxide (DMSO)[18] and CH3CN,[19]
and cerium ammonium nitrate (CAN)-catalyzed cyclocondensation reac-
tion between 1,2-dicarbomyl compounds and 1,2-diamines.[20] Recently,
Heravi et al. reported the synthesis of quinoxaline derivatives catalyzed
by CuSO4 ꢀ 5H2O in water and Zn[(L)proline] in HOAc.[21]
However, most of the existing methodologies suffer from disadvan-
tages such as use of volatile organic solvents, use of catalyst, use of
expensive and detrimental metal precursors, critical product isolation
procedures that limit their use under the aspect of environmentally
benign processes. Thus, to replace these critical reaction conditions and
limitations, the development of a new synthetic process for the synthesis
of quinoxaline derivatives would be highly desirable. In recent times,
room-temperature ionic liquids (RTILs) have shown great promise as
attractive alternatives to conventional solvents. They possess the unique
advantages of high thermal stability, negligible vapor pressure, immisci-
bility with a number of organic solvents, and recyclability.[22] As part
of our ongoing program to develop more efficient methods for the syn-
thesis of biologically active heterocycles[23] using environment friendly
solvents such as an ionic liquid (IL), we herein report the synthesis of
2,3-disubstituted quinoxaline derivatives from 1,2-diketone and aryl-
1,2-diamines in the IL, 1-n-butylimidazolium tetrafluoroborates as reac-
tion medium as well as promoter.
RESULTS AND DISCUSSION
In the beginning, a model reaction was carried out by condensing benzil
with 1,2-diaminobenzene in the IL, 1-n-butylimidazolium tetrafluorobo-
rate ([Hbim]BF4). When a mixture of benzil and 1,2-diaminobenzene was
stirred in [Hbim]BF4 at room temperature, it afforded the desired pro-
duct 2,3-diphenyl-quinoxaline 3a in 96% yield in just 20 min (Scheme 1).

Quinoxalines Synthesis
3603
Scheme 1. Synthesis of quinoxaline derivatives in [Hbim]BF4.
To optimize the reaction conditions, ILs based on 1-n -butylimidazolium
[Hbim] cations with varying anions were screened for this model reaction at
room temperature for 2 h to afford 2,3-diphenyl-quinoxaline 3a, and the
results are summarized in Table 1. It is evident from the result that among
the screened ILs, [Hbim]BF4 the best by virtue of its inherent Brønsted acid-
ity conferred by the most acidic –NH hydrogen [chemical shift d ppm ¼ 14.6].
Consequently, all further studies were carried out using [Hbim]BF4 as a
reaction medium as well as promoter for the synthesis of various quinoxa-
line derivatives. To investigate the scope and generality of this process, a ser-
ies of aryl-1,2-diketone 1 and substituted 1,2-diaminobenzene 2 was
subjected to condensation using IL as reaction media. The process tolerates
well both electron-donating as well as electron-withdrawing substituents on
1,2-diaminobenzene and afforded the quinoxaline derivatives in excellent
isolated yields. The applicability of the methodology is further successfully
extended for the synthesis of substituted quinoxalines by performing the
reaction with aliphatic-1,2-diketone and 1,2-diaminobenzene. When alipha-
tic-1,2-diketone such as 1,2-cyclohexandione and 3,4-hexanedione were sub-
jected to condensation with 1,2-diaminobenzene, reactions were smoothly
completed in short reaction times (10–15 min) and afforded the correspond-
ing 2,3-dialkyl-quinoxaline derivatives in good isolated yields. However, the
yields are relatively lower than 2,3-diaryl-quinoxalines. On reviewing the lit-
erature on quinoxaline synthesis, it was observed that very few methods
have been reported for the synthesis of 2,3-dialkyl-quinoxalines. It was
noteworthy that our process is equally applicable for both aromatic-1,2-
diketone as well as for aliphatic-1,2-diketone (Table 2, Entries 9–12).
Table 1. Synthesis of 2,3-diphenyl quinoxaline 3a in different ILs
Entry
ILs
pKaa
–NH proton d ppm
Yieldb (%)
1
2
3
4
[Hbim]ClO4
[Hbim]Br
[Hbim]Cl
ꢁ11
ꢁ9
ꢁ7
0.5
11.83
12.17
12.22
14.59
62
79
88
96
[Hbim]BF4
aThe pKa values of the parent acid of the anions.
bIsolated yield after column chromatography.

3604
T. M. Potewar, S. A. Ingale, and K. V. Srinivasan
Table 2. Synthesis of quinoxalines (3a–l) in [Hbim]BF4
Diketone 1,2-Diamine
1
Quinoxalines
3
TimeYielda
(min) (%)
Entry
1
2
Mp (ꢂC)
20 96
128–129
(126–127[21a]
)
)
2
3
15 95
117–118
(116–117[21a]
15 96
193–194
(193–194[21a]
)
4
20 94
194–195
5
25 92
185–186
6
25 89
188–190
(Continued )

Quinoxalines Synthesis
3605
Table 2. Continued
Diketone 1,2-Diamine
1
Quinoxalines
3
TimeYielda
(min) (%)
Entry
7
2
Mp (ꢂC)
20 91
40 96
10 78
152–153
(151–152[21a]
)
8
126–127
(125–127[21a]
)
9
51–52
10
11
15 69
94–95
41–42
15 75
12
10 71
84–85
aIsolated yield after column chromatography.

3606
T. M. Potewar, S. A. Ingale, and K. V. Srinivasan
The efficacy of the ILs to promote these heterocyclization reac-
tions was correlated with the basicity of the anions as well as –NH
proton chemical shifts of the ILs. It was assumed that the nature of
the anion would govern the electrophilicity of the imidazolium cation,
which in turn has a bearing on the acidity of the ILs. It was observed
that with increasing basicity of the anion (increasing pKa of the cor-
responding acid), there is a progressive increase in yield (Table 1).
This correlation was also evident when the yield of 3a was compared
with –NH proton chemical shifts of the ILs indicative of the Brønsted
acidities of the [Hbim] ILs (Table 1). The IL [Hbim]BF4 has most effi-
ciently promoted this heterocyclization reaction by virtue of its inher-
ent Brønsted acidity conferred by the most acidic –NH hydrogen
[chemical shift d ppm ¼ 14.6].
The reaction procedure is very simple and easy to carry out. A mix-
ture of 1,2-diketone and 1,2-diaminobenzenes in IL was stirred at ambient
temperature until completion of the reaction. On completion, the reaction
mixture was diluted with water, and the product was extracted using an
innocuous solvent such as ethyl acetate. The organic layer was separated
from the aqueous phase and evaporated under reduced pressure to afford
the crude quinoxalines, which were further purified by column chroma-
tography. All the products were characterized by their melting point,
1
IR, elemental analyses, and H and 13C NMR spectroscopy. For known
compounds, the values were in good agreement with those reported in the
literature. The aqueous layer containing the IL was subjected to distilla-
tion at 80 ꢂC under reduced pressure (10 mm Hg) for 4 h to remove water,
leaving behind the IL in almost complete recovery. The IL thus recovered
was further used three times for the typical reaction of benzil and 1,2-dia-
minobenzene without any loss in yield and purity.
Plausible Mechanism
Based on these observations, the following probable mechanism may be
postulated for this reaction as shown in Scheme 2. The role of the IL may
be postulated in terms of some Brønsted acidity of the –NH proton of the
imidazolium cation, leading to its interaction with the carbonyl oxygen
atom of 1,2-diketone, thereby increasing the polarization and promoting
the cyclocondensation reaction.
CONCLUSION
In conclusion, we have developed a simple, convenient, and efficient
method for the synthesis of quinoxaline derivatives from various

Quinoxalines Synthesis
3607
Scheme 2. Plausible mechanism for the synthesis of quinoxalines.
1,2-diketones and 1,2-diaminobenzene using the IL 1-n-butylimidazolium
tetrafluoroborate ([Hbim]BF4) as a reaction medium as well as promoter
under mild reaction conditions at room temperature. The process is gen-
eral for the synthesis of quinoxaline derivatives from aromatic as well as
aliphatic-1,2-diketones. The advantages of the present procedure are sim-
plicity of operation, short reaction times, high yields of products, and
complete recyclability of the reaction medium.
EXPERIMENTAL
General
1H NMR and 13C NMR spectra were recorded on a Bruker AV-200 spec-
trometer in CDCl3 using TMS as the internal standard. Infrared (IR)
spectra were recorded with ATI Mattson RS-1 FTIR spectrometer using
KBr pellets. Elemental analyses were obtained using a flash EA 1112
Thermofinnigan instrument. Melting points were recorded in an open
capillary on a Buchi Melting-Point B-540 apparatus. All solvents and
chemicals were of research grade and were used as obtained from Merck
and Lancaster. Column chromatography was performed using silica gel
(60 to 120-mesh size).
General Procedure for the Synthesis of Quinoxaline Derivatives
A mixture of 1,2-diketone 1 (1 mmol) and aryl-1,2-diamine 2 (1.1 mmol)
in [Hbim]BF4 (2 mL) was stirred at room temperature for the appropriate
time mentioned in Table 2. The progress of the reaction was monitored
by thin-layer chromatography (TLC). After completion of the reaction,
the reaction mixture was diluted with water and extracted using ethyl
acetate (3 ꢃ 10 mL). The combined organic layer was dried over

3608
T. M. Potewar, S. A. Ingale, and K. V. Srinivasan
anhydrous magnesium sulfate and evaporated under reduced pressure to
obtain the crude product, which was further purified by column chroma-
tography using petroleum ether–ethyl acetate (5:95 ratio) to obtain the
pure 2,3-disubstituted-quinoxaline derivatives 3.
Characterization Data for New Quinoxaline Derivatives
2,3-Bis(4-bromophenyl)quinoxaline (3d)
White solid; mp 194–195 ꢂC; IR (KBr): tmax 3019, 1589, 1343, 1216,
1
757 cmꢁ1; H NMR (CDCl3, 200 MHz): d 7.36–7.42 (m, 4H, ArH), 7.47–
7.53 (m, 4H, ArH), 7.76–7.81 (q, J ¼ 6.40 & 3.45 Hz, 2H, ArH), 8.12–8.17
(q, J ¼ 6.40 & 3.45 Hz, 2H, ArH); 13C NMR (CDCl3, 50 MHz): d 123.6,
129.1, 130.3, 131.3, 131.6, 137.5, 141.1, 151.8. Anal. calcd. for C20H12Br2N2
(440): C, 54.58; H, 2.75; N, 6.36. Found: C, 54.67; H, 2.84; N, 6.48.
2,3-Bis(4-bromophenyl)-6-methylquinoxaline (3e)
White solid; mp 185–186 ꢂC; IR (KBr): tmax 3019, 2974, 1619, 1589, 1484,
1
1342, 1215, 1073, 979, 833, 757, 669 cmꢁ1; H NMR (CDCl3, 200 MHz):
d 2.61 (s, 3H, CH3), 7.34–7.40 (m, 4H, ArH), 7.46–7.51 (m, 4H, ArH),
7.59–7.64 (dd, J ¼ 8.58 & 1.88 Hz, 1H, ArH), 7.91 (s, 1H, ArH), 8.01–
8.05 (d, J ¼ 8.58 Hz, 1H, ArH); 13C NMR (CDCl3, 50 MHz): d 21.9,
123.4, 123.5, 127.9, 128.6, 131.3, 131.5, 132.7, 137.7, 139.6, 141.0,
141.2, 150.9, 151.6. Anal. calcd. for C21H14Br2N2 (454): C, 55.54; H,
3.11; N, 6.17. Found: C, 55.41; H, 3.21; N, 6.32.
2,3-Bis(4-bromophenyl)-6-nitroquinoxaline (3f)
ꢂ
Faint yellow solid; mp 188–190 C; IR (KBr): tmax 3019, 1618, 1588,
1528, 1344, 1216, 1129, 1072, 758, 669 cmꢁ1
;
1H NMR (CDCl3,
200 MHz): d 7.39–7.45 (m, 4H, ArH), 7.49–7.54 (m, 4H, ArH), 8.22–
8.27 (d, J ¼ 9.14 Hz, 1H, ArH), 8.47–8.53 (dd, J ¼ 9.14 & 2.48 Hz, 1H,
ArH), 8.99–9.00 (d, J ¼ 2.48 Hz, 1H, ArH); 13C NMR (CDCl3,
200 MHz): d 123.6, 124.6, 124.7, 125.4, 130.7, 131.3, 131.8, 136.4,
136.5, 139.8, 143.3, 147.9, 154.0, 154.6. Anal. calcd. for C20H11Br2N3O2
(485): C, 49.52; H, 2.29; N, 8.66. Found: C, 49.41; H, 2.17; N, 8.81.
2,3-Diethylquinoxaline (3i)
ꢂ
White solid; mp 51–52 C; IR (KBr): tmax 3064, 2974, 2875, 1607, 1487,
1
1459, 1397, 1283, 1046, 757, 666 cmꢁ1; H NMR (CDCl3, 200 MHz): d

Quinoxalines Synthesis
3609
1.37–1.44 (t, J ¼ 7.51 Hz, 6H, CH3), 2.99–3.10 (q, J ¼ 7.51 Hz, 4H, CH2),
7.62–7.67 (q, J ¼ 6.30 & 3.50 Hz, 2H, ArH), 7.97–8.02 (q, J ¼ 6.30 &
3.50 Hz, 2H, ArH); 13C NMR (CDCl3, 50 MHz): d 12.4, 28.2, 128.3,
128.5, 140.9, 157.1. Anal. calcd. for C12H14N2 (186): C, 77.38; H, 7.58;
N, 15.04. Found: C, 77.53; H, 7.67; N, 14.89.
1,2,3,4-Tetrahydrophenazine (3j)
ꢂ
Pale yellow solid; mp 94–95 C; IR (KBr): tmax 3019, 2948, 2868, 1592,
1565, 1487, 1340, 1215, 1213, 928, 826, 756, 669 cmꢁ1; 1H NMR (CDCl3,
200 MHz): d 2.03 (s, 4H, CH2), 3.15 (s, 4H, CH2), 7.62–7.67 (q, J ¼ 6.40
& 3.45 Hz, 2H, ArH), 7.93–7.98 (q, J ¼ 6.40 & 3.45 Hz, 2H, ArH); 13C
NMR (CDCl3, 50 MHz): d 22.6, 33.0, 128.1, 128.8, 141.0, 153.9; Anal.
calcd. for C12H12N2 (184): C, 78.23; H, 6.57; N, 15.21. Found: C,
78.11; H, 6.70; N, 15.29.
2,3-Diethyl-6-methylquinoxaline (3k)
White solid; mp 41–42 ꢂC; IR (KBr): tmax 2974, 2876, 1623, 1563, 1459,
1377, 1240, 1046, 964, 829, 755, 665 cmꢁ1 1H NMR (CDCl3, 200
;
MHz): d 1.35–1.43 (t, J ¼ 7.48 Hz, 6H, CH3), 2.54 (s, 3H, CH3), 2.96–
3.07 (q, J ¼ 7.48 Hz, 4H, CH2), 7.45–7.50 (dd, J ¼ 8.60 & 1.92 Hz, 1H,
ArH), 7.77 (s, 1H, ArH), 7.85–7.89 (d, J ¼ 8.52 Hz, 1H, ArH); 13C
NMR (CDCl3, 50 MHz): d 12.4, 12.5, 21.5, 28.1, 28.2, 127.3, 127.8,
130.7, 138.7, 139.3, 140.9, 156.1, 156.9. Anal. calcd. for C13H16N2
(200): C, 77.96; H, 8.05; N, 13.99. Found: C, 77.83; H, 7.93; N, 14.15.
1,2,3,4-Tetrahydro-7-methylphenazine (3l)
ꢂ
Brown solid; mp 84–85 C; IR (KBr): tmax 3018, 2947, 2867, 1622, 1495,
1
1454, 1215, 934, 817, 756, 667 cmꢁ1; H NMR (CDCl3, 200 MHz): d
1.98– 2.05 (m, 4H, CH2), 2.54 (s, 3H, CH3), 3.09–3.16 (m, 4H, CH2),
7.45–7.50 (dd, J ¼ 8.60 & 1.88 Hz, 1H, ArH), 7.72 (s, 1H, ArH), 7.81–
7.86 (d, J ¼ 8.60 Hz, 1H, ArH); 13C NMR (CDCl3, 50 MHz): d 21.6,
22.7, 32.9, 33.0, 127.0, 127.6, 131.0, 139.0, 139.4, 141.1, 152.9, 153.7.
Anal. calcd. for C13H14N2 (198): C, 78.75; H, 7.12; N, 14.13. Found:
C, 78.63; H, 7.33; N, 14.04.
ACKNOWLEDGMENTS
T. M. P. thanks the Council of Scientific and Industrial Research (CSIR),
New Delhi, for the award of a research fellowship.

3610
T. M. Potewar, S. A. Ingale, and K. V. Srinivasan
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