Sodium bromate/sodium hydrogen sulfite: A new catalyst for the synthesis of quinoxaline derivatives

Article abstract of DOI:10.2174/1570178611666140304000936

Treatment of 1,2-phenylenediamine with benzil analogs in the presence of a mixture of sodium bromate/sodium hydrogen sulfite in water gave the corresponding quinoxalines in high yields. The method is eco-friendly due to use of water instead of other hazar

Full text of DOI:10.2174/1570178611666140304000936

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426
Letters in Organic Chemistry, 2014, 11, 426-431
Sodium Bromate/Sodium Hydrogen Sulfite: A New Catalyst for the
Synthesis of Quinoxaline Derivatives
Khalid M. Khana*, Shafqat Hussaina, Shahanaz Perveenb, Fazal Rahimac, Sammer Yousuf a and Ejaz
Hussaina
aH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of
b
Karachi, Karachi-75270, Pakistan; PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman, Karachi-75280,
Pakistan; cDepartment of Chemistry Hazara University, Mansehra, Pakistan
Received January 28, 2014: Revised February 24, 2014: Accepted February 26, 2014
Abstract: Treatment of 1,2-phenylenediamine with benzil analogs in the presence of a mixture of sodium bromate/
sodium hydrogen sulfite in water gave the corresponding quinoxalines in high yields. The method is eco-friendly due to
use of water instead of other hazardous organic solvents.
Keywords: Eco-friendly chemistry, high yield, quinoxaline, NaBrO3/NaHSO3 in water.
INTRODUCTION
RESULTS AND DISCUSSION
The significance of the NaBrO3/NaHSO3 reagent system
was extensively studied by our group in recent years [22-25].
Earlier, this reagent system efficiently used as bromohy-
droxylation agent for alkenes, alkynes and allylic alcohol
[26, 27]. This mixture system has also been used for the oxi-
dation of ethers and diols [28, 29], primary alcohols [30],
and the ꢀ-bromination of alkyl and allyl benzenes [31, 32].
The syntheses of ꢁ-lactones from corresponding o-
alkylbenzoic acids [25], disulfides from thiols [23], and es-
ters from aromatic carboxylic acids and substituted toluenes
by this reagent are also reported by our research group [24].
In addition, we have broadened the scope of this reagent in
our laboratory by developing various practical effective ap-
proaches in organic synthesis.
Quinoxaline is an important nitrogen-containing hetero-
cyclic class of compounds whose analogs exhibit a wide
spectrum of biological activities, this class of compounds
making a privileged structure for pharmaceutical use as anti-
fungal and antibacterial agents [1], a key structural compo-
nent for semiconductors [2], electrical and photochemical
material [3], anticancer and kinase inhibitors [4-7], pesticides
[8], herbicides [9], as part of other receptor antagonists [10],
antitumor agent [11]. Some quinoxaline analogs has been
reported as picomolar inhibitors of bc1 Qo sites [12].
Complexes of quinoxaline derivatives with indium and
europium have been found to enhance fluorescence proper-
ties through the transformation of ligand to metal and find
their use as imaging agents [13-15]. Functionalized quinox-
alines can be accessed by various synthetic methods such as
iodine catalysis [16], polyanilinesulfate salt [17], Bi/DMSO
[18], MnCl2 at room temperature [19], and iron catalysis
[20]. A stereospecific synthesis of tetrahydroquinoxaline has
been reported, starting from anhydro-sugars [21]. However,
all of these methodologies suffer from several limitations
such as, long multi-step route, low yields, tedious work-up,
long reaction times, limited or no selectivity, and the need to
use large amounts of a catalysts resulting in the production
of toxic waste. Considering these drawbacks, we have devel-
oped an eco-friendly and good yielding method for the syn-
thesis of quinoxalines.
In current study, we found that quinoxalines can easily be
prepared by reacting 1,2-phenylenediamines with benzils in
the presence of 10% catalytic amounts of the NaBrO3/
NaHSO3 reagent system in water at room temperature pro-
ducing derivatives 1-10 (Table 1). The main advantages of
this method are that neither toxic organic solvent nor high
temperatures are used. The products were obtained rapidly
and the method has overall eco-friendly profile. The struc-
tures of synthetic derivatives 1-10 were elucidated by using
1HNMR and mass spectroscopy. In addition, the assigned
structures of compounds 1-4 were further confirmed by sin-
gle crystal x-ray diffraction studies (Fig. 1). The experimen-
tal crystallographic data of compounds 1-4 is summarized in
(Table 2).
The reaction conditions for our newly methodology were
optimized by varying the amount of catalyst (sodium
bromate/sodium bisulfite mixture). It was found that with
10% aqueous mixture of catalyst the reaction precedes
smoothly giving desired products in good yields. Increasing
*Address correspondence to this author at the H.E.J. Research Institute of
Chemistry, International Center for Chemical and Biological Sciences,
University of Karachi, Karachi-75270, Pakistan; Tel: 00922134824910;
Fax: 00922134819018; E-mails: hassaan2@super.net.pk and
khalid.khan@iccs.edu
1875-6255/14 $58.00+.00
© 2014 Bentham Science Publishers

Sodium Bromate/Sodium Hydrogen Sulfite: A New Catalyst for the Synthesis
Letters in Organic Chemistry, 2014, Vol. 11, No. 6 427
F
N
N
Me
Me
F
2,3-Bis(4-fluorophenyl)-6,7-dimethylquinoxaline (1)
F
F
N
N
Br
6-Bromo-2,3-Bis(4-fluorophenyl)quinoxaline (2)
N
Me
N
Me
6,7-Dimethyl-2,3-diphenylquinoxaline (3)
F
F
N
N
Cl
6-Chloro-2,3-bis(4-fluorophenyl)quinoxaline (4)
Fig. (1). ORTEP diagrams of compounds 1-4 along with their chemical structures.

428 Letters in Organic Chemistry, 2014, Vol. 11, No. 6
Khan et al.
R3
R3
R1
R2
NH2
NH2
R1
R2
N
N
O
O
NaBrO3, NaHSO3, H2O
r.t 1-2 h
+
R3
R3
R1 = Cl, Br, F, Me
R2 = H, Me
1-10
R3 = H, Me, F
Scheme 1.
Table 1. Synthesis of quinoxaline derivatives 1-10.
Entry
R1
R2
R3
Yield (%)
1
2
Me
Br
Me
Cl
F
Me
H
F
F
94
89
81
85
80
80
81
82
85
89
3
Me
H
H
4
F
5
H
H
6
Cl
F
H
H
7
H
Me
Me
Me
Me
8
Br
Me
Cl
H
9
H
10
H
Table 2. Crystal data for compounds 1-4.
Compound 1
Compound 2
Compound 3
Compound 4
Empirical formula
C22 H16 F2 N2
346.37
C21 H11Br F2 N2
397.22
C22 H18 N2
310.38
C20 H11Cl F2 N2
352.76
Formula weight
Temperature
273(2)
273(2)
273(2)
273(2)
Wavelength
0.71073 Å
Monoclinic
P21/c
0.71073 Å
Monoclinic
P21/n
0.71073 Å
Orthorhombic
Pbca
0.71073 Å
Monoclinic
P21/n
Crystal system
Space group
A
11.0017(7) Å
12.1567(12) Å
9.6409(7) Å
90°
13.7780(17) Å
7.6925(10) Å
16.303(2) Å
90°
8.0111(5) Å
19.9996(14) Å
20.8495(14) Å
90°
13.524(3) Å
7.7043(17) A
16.438(4) Å
90°
B
C
a
b
101.305(2)°
90°
105.501(3)°
90°
90°
105.456(4)°
90°
g
Volume
90°
1484.4(2) A3
1665.1(4) A3
3340.5(4) A3
1650.8(6) A3
Z
4
4
8
4
Calculated density
1.289 mg/m3
1.585 mg/m3
1.234 mg/m3
1.419 mg/m3

Sodium Bromate/Sodium Hydrogen Sulfite: A New Catalyst for the Synthesis
Letters in Organic Chemistry, 2014, Vol. 11, No. 6 429
Table 2. Contd…..
Compound 1
Compound 2
Compound 3
Compound 4
Absorption coefficient
F(000)
0.091 mm-1
720
2.493 mm-1
792
0.073 mm-1
1312
0.256 mm-1
720
Crystal size
0.59 x 0.22 x 0.07 mm
1.89 to 25.50°
10461
0.54 x 0.23 x 0.10 mm
1.72 to 25.50°
9457
0.46 x 0.20 x 0.13 mm
1.95 to 25.50°
18355
0.59 x 0.24 x 0.12 mm
1.74 to 25.50°
8857
qꢀrange
Reflections Collected
Reflections Unique
(Rint)
3313
3104
3097
3040
0.0294
0.0247
0.0357
0.0316
R1 with I > 2s(I)
R2 with I > 2s(I)
R1 for all data
0.0434
0.0386
1.041
0.0445
0.0996
0.1065
0.0432
0.0990
0.0718
0.0610
0.1015
0.0724
R2 for all data
0.1063
1186
0.0622
0.1118
Goodness of fit
1.030
1.043
0.1035
1.012
max / min r
ꢀ
0.133 and -0.151
948545
0.449 and -0.567
948547
0.109 and -0.174
948544
0.179 and -0.187
948546
CCDC numbers
Table 3. Impact of catalyst amount in overall yields and reac-
tion times.
bisulfate [24, 25]. Therefore, it was considered that the tolyl
or benzyl containing moieties may condense with diamine to
form secondary amine in the same reaction conditions in-
stead of quinoxaline formation. To eliminate this possibility,
sodium bromate/sodium bisulfite was used deliberately for
entries 7-10 which contain tolyl groups and it was observed
that it is quite selective in the presence of tolyl functionality
and methyl group remain intact even after the completion of
the reaction. No any side product was found in any reaction.
Entry
Amount of Catalyst % Reaction Time (h)
Yield %
1
2
3
4
5
6
7
8
5
2.10
2.10
2.15
2.40
3.00
3.00
3.00
3.00
70
94
74
73
69
00
00
00
10
15
20
CONCLUSION
25
Conclusively, we have developed a new method for the
synthesis of quinoxalines using a sodium bromate/sodium
hydrogen sulfite mixture as a catalyst in water. The reaction
is eco-benign, efficient, easy to handle and high yielding.
The newly developed method may be used as an alternative
method for the synthesis of quinoxalines.
Sodium Bromate
Sodium bisulfite
Without catalyst
the amount of catalyst from 10% to 25% had a negative yield
outcome and the reaction requires longer times for comple-
tion. This may be due to poising of reaction but actual reason
is unknown. To ensure the utility of sodium bromate/sodium
bisulfite as a catalyst for this reaction, we performed three
reactions. First, a blank reaction was carried out in same re-
action conditions without using sodium bromate or sodium
bisufite, however, no product was obtained. Second, using
only sodium bromate as a catalyst in same reaction condi-
tions but no product was observed. Third, only sodium bisul-
fite was used, however, it didn’t yield any product which
clearly indicates that combination of sodium bromate/sodium
bisulfite mixture behaves as catalyst for this reaction
(Table 3).
GENERAL EXPERIMENTAL
A Bruker Smart APEX II single-crystal X-ray diffracto-
meter fitted with a CCD detector was used to collect the data
[33]. Data was reduced and solved by was using the SAINT
program and direct methods, respectively [34]. Finally, the
structural atomic arrangement was solved using the
SHELXL97 program by using full-matrix least-square calcu-
lation on F2 [35,36]. The figures were plotted using the
ORTEP program. The crystallographic data is available free
of charge from the Cambridge crystallographic data centre
by using the CCDC numbers. (http://www.ccdc.cam.ac.uk/
Community/Requestastructure/Pages/Requestastructure.aspx).
Since the esterification of tolyl or benzyl group with car-
boxylic acids also takes place by sodium bromate/sodium
The experimental data of compounds 1-4 is summarized
in (Table 2).

430 Letters in Organic Chemistry, 2014, Vol. 11, No. 6
Khan et al.
General Synthetic Procedure for Quinoxaline Derivatives
1-10
J8,7 = 8.8 Hz, H-8), 7.91 (1H dd, 1H, J7,8 = 9.2, J7,5 = 2.4 Hz,
H-7), 7.46 (m 4H, 2 x H-2, H-6), 7.37 (m, 6H, 2 x H-3, 2 x
H-4, 2 x H-5); EI-MS m/z (rel. abund. %): 318 (M+2, 34),
317 (M+1, 44), 316 (M+, 100), 314.87 (71.5), 177 (24.1),
212.9 (21.7).
Generally, to a stirring mixture of different substituted
1,2-phenylenedine (2 mmol) and substituted benzils (2
mmol) in water, sodium bromate and sodium hydrogen sul-
fite (10%) were added and stirred for 2-3 h. The progress of
reaction was monitored by TLC. After the completion of
reaction, 20 mL ethyl acetate was added to reaction mixture,
the organic layer was separated by a separating funnel. The
quinoxaline derivatives 1-10 were obtained in high yields.
Pure products were obtained by recrystallization from etha-
nol and in some cases through column chromatography (sil-
ica gel) using 2:8 ethyl acetate and n-hexane as eluent.
6-Fluoro-2,3-bis(4-methylphenyl)quinoxaline (7)
Yield: 0.49 g (75%); M.P: 248 °C, brown solid, 1H-NMR
(400 MHz, DMSO-d6): 8.20 (m, 1H, H-5), 8.18 (dd, J7,8 =
9.6, J7,5 = 2.8 Hz, H-7), 7.77 (m, 1H, H-8), 7.37 (m 4H, 2 x
H-2, H-6), 7.17 (m, 4H, 2 x H-3, 2 x H-5), 2.49 (s, 6H, 2 x
ArCH3); EI-MS m/z (rel. abund. %): 328 (M+, 100), 327.2
(73.6), 313.2 (94), 120.1 (19.4).
The structures of compounds were confirmed by using
1
6-Bromo-2,3-bis(4-methylphenyl)quinoxaline (8)
various spectroscopic techniques, including H NMR, EI
Yield: 0.56 g (73%); M.P: 256 °C, white solid, 1H-NMR
(400 MHz, DMSO-d6): ꢀ 8.35 (s, 1H, H-5), 8.04 (d, J 8,7 =
8.8 Hz, H-8), 7.96 (dd, 1H, J7,5 = 2.0 Hz, J 7,8 = 8.8 Hz, H-7),
7.36 (d, 4H, J 2,3 = 8.0 Hz, 2 x H-2, H-6), 7.17 (d 4H, J3,2 /
J5,6 = 8 .0 Hz, 2 x H-3, H-5), 7.17 (d, 4H, J 2,3/ J 6,5 = 6.8 Hz,
2 x H-2, H-6), 2.32 (s, 6H, 2 x ArCH3); EI-MS m/z (rel.
abund. %): 390 (M+2, 58), 388 (M+, 56), 192 (35), 90 (42).
mass, and X-ray spectroscopy.
2,3-Bis(4-fluorophenyl)-6,7-dimethylquinoxaline (1)
Yield: 0.57 g (90%); M.P: 221°C, white crystal, 1H-NMR
(400 MHz, Acetone): ꢀ 7.88 (s, 2H, H-5, H-8), 7.55 ((m, 4H,
2 x H-3, H-5), 7.55 (m, 4H, 2 x H-3, H-5), 7.14 (m, 4H, 2 x
H-2, H6 ), 2.53 (s, 6H, 2 x ArCH3 ); EI-MS m/z (rel. abund.
%): 446 (M+, 100), 445 (99), 103(48).
6-Methyl-2,3-bis(4-methylphenyl)quinoxaline (9)
6-Bromo-2,3-bis(4-fluorophenyl)quinoxaline (2)
Yield: 0.46 g (72%); M.P: 243 °C, yellow solid, 1H-NMR
(400 MHz, DMSO-d6): ꢀ 7.96 (d, 1H, J8,7 = 8.2 Hz, H-8),
7.87 (s, 1H, H-5), 7.85 (dd, 1H, J7,5 = 2.0 Hz, J7,8 = 11.2 Hz,
H-7), 7.43 (dd, 4H, J2,6 = 2.4 Hz, J2,3 = 10.8 Hz, 2 x H-2, H-
6), 7.16 (br d, 4H, J3',2'/5',6' = 10.4 Hz, 2 x H-3'/5'); 2.60 (s,
3H, ArCH3), 2.348 (s, 6H, 2 x ArCH3) EI-MS m/z (rel.
abund. %): 323 (M+, 100), 316 (32), 90(38).
1
Yield: 0.53 g (89%); H-NMR (300 MHz, DMSO-d6):
ꢀ 8.15 (d, 1H, J5,7 = 2.4 Hz, H-5), 8.02 (d, 1H, J8,7 = 11.4
Hz, H-8), 7.96 (dd, 1H, J7,5 = 2.2 Hz, J7,8 =10.6 Hz, H-7),
8.16(m, 4H, H-3, H-5, 2 x H-3'/5'), 7.87 (m, 4H, H-2, H-6, 2
x H-2'/6'), EI-MS m/z (rel. abund.%): 398 (M++2, 92), 396
(M+, 100), 396 (65), 91(54).
2,3-Bis(4-methylphenyl)quinoxaline (3)
6-Chloro-2,3-bis(4-methylphenyl)quinoxaline (10)
1
Yield: 0.43 g (70%); M.P: 243 °C, white crystal, H-
Yield: 0.45 g (66%); M.P: 238 °C, white solid, 1H-NMR
(400 MHz, DMSO-d6): ꢀ 8.35 (d, 1H, J5,7 = 2.4 Hz, H-5),
8.06 (d, 1H, J8,7 = 12.0 Hz, H-8), 7.98 (dd, 1H, J7,5 = 2.8 Hz,
J7,8 = 12.0 Hz, H-7), 7.34 (br d, 4H, J2',3'/6',5' = 10.8 Hz, 2 x
H-2'/6'), 7.17 (d, 4H, J3',2'/5',6' = 10.4 Hz, 2 x H-3'/5'), 2.49 (s,
6H, 2 x ArCH3), EI-MS m/z (rel. abund. %): 346 (M+2, 26),
345 (M+1, 18), 344 (M+, 87), 301 (100), 91 (37).
NMR (400 MHz, DMSO-d6): ꢀ 8.14 (m, 2H, H-5, H-8), 7.84
( m, 2H, H-6, H-7 ), 7.37 (d, 4H, J3',2'/5',6' = 9.76 Hz, 2 x H-
3'/5'), 7.17 (br d, 4H, J2',3'/6',5' = 8.00 Hz, 2 x H-2'/6'), 2.49 (s,
6H, 2 x ArCH3 ); EI-MS m/z (rel. abund. %): 310 (M+, 78),
309 (32), 91(31).
6-Chloro-2,3-bis(4-fluorophenyl)quinoxaline (4)
1
Yield: 0.48 g (71%); M.P: 234 °C, white crystal, H-
NMR (400 MHz, DMSO-d6): ꢀ 8.65 (d, 1H, J5,7 =2.0 Hz, H-
5), 8.53 (d, 1H, J8,7 = 12.0 Hz, H-8), 8.61 (dd, 1H, J7,5 = 2.2
Hz, J7,8 = 10.2 Hz, H-7), 8.23 (m, 4H, 2 x H-3, 2 x H-5, 2 x
H-3'/5'), 7.76 (m, 4H, H-2, H-6, 2 x H-2'/6'), EI-MS m/z (rel.
abund.%): 354 (M+2, 24 ), 353 (M+1, 21), 352 (M+, 100),
21 225 (43), 123(96).
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
The authors are thankful to the Organization for Prohi-
bition of Chemical Weapons (OPCW), The Netherlands,
6-Fluoro-2,3-diphenylquinoxaline (5)
1
Yield: 0.43 g (70%); M.P: 226 °C, Yellowish solid, H-
for
their
financial
support
for
project
No.
NMR (400 MHz, DMSO-d6): ꢀ 8.24 (m, 1H, H-5), 7.96 (dd,
1H, J7,8 = 9.6 Hz, J7,5 = 2.8 Hz, H-7), 7.46 (m, 4H, 2 x H-2,
H-6), 7.83 (m, 6H, 2 x H-3, 2 x H-4, 2 x H-5); EI-MS m/z
(rel. abund. %): 299.2 (M+, 100), 197 (100), 150 (35.7), 103
(12.5).
L/ICA/ICB/173681/12.
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