Green synthesis of novel quinoxaline sulfonamides with antibacterial activity

Article abstract of DOI:10.1007/s11164-017-2895-6

A facile and efficient method was investigated for the synthesis of different quinoxalines by the reaction of o-phenylene diamine and 2-bromoacetophenones. This procedure was carried out in ethanol under catalyst-free conditions. Several sulfonamides were synthesized from 2-(4-methoxyphenyl)-quinoxaline in two steps. At first chlorosulfonation of 2-(4-methoxyphenyl) quinoxaline was done using chlorosulfonic acid and led to 2-methoxy-5-quinoxalin-2-yl-benzenesulfonyl chloride. Then quinoxaline sulfonamides were synthesized by the reaction of quinoxaline sulfonyl chloride with different aromatic amines under solvent-free conditions. All the products were obtained in excellent yields after an easy work-up and were evaluated for antibacterial activities against Staphylococcus spp. and Escherichiacoli bacteria.

Full text of DOI:10.1007/s11164-017-2895-6

Res Chem Intermed
DOI 10.1007/s11164-017-2895-6
Green synthesis of novel quinoxaline sulfonamides
with antibacterial activity
1
,2
2
•
Sima Alavi
Razieh Mohebat
•
Mohammad Hossein Mosslemin
2
1
•
Ahmad Reza Massah
Received: 23 November 2016 / Accepted: 2 February 2017
Ó Springer Science+Business Media Dordrecht 2017
Abstract A facile and efficient method was investigated for the synthesis of different
quinoxalines by the reaction of o-phenylene diamine and 2-bromoacetophenones.
This procedure was carried out in ethanol under catalyst-free conditions. Several
sulfonamides were synthesized from 2-(4-methoxyphenyl)-quinoxaline in two steps.
At first chlorosulfonation of 2-(4-methoxyphenyl) quinoxaline was done using
chlorosulfonic acid and led to 2-methoxy-5-quinoxalin-2-yl-benzenesulfonyl chloride.
Then quinoxaline sulfonamides were synthesized by the reaction of quinoxaline
sulfonyl chloride with different aromatic amines under solvent-free conditions. All the
products were obtained in excellent yields after an easy work-up and were evaluated
for antibacterial activities against Staphylococcus spp. and Escherichia coli bacteria.
Keywords Quinoxaline Á Catalyst-free Á Sulfonamide Á Solvent-free Á Antibacterial
activity
Introduction
Quinoxalines (QXs) or benzopyrazines and their derivatives are the varied class of
nitrogen-containing heterocyclic compounds, which display various pharmacolog-
ical and biological activities, such as antiviral [1], antibacterial [2], antifungal [3],
anticancer [4], and antimalarial [5, 6]. Numerous methods have been reported for
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-2895-6)
contains supplementary material, which is available to authorized users.
&
Ahmad Reza Massah
massah@iaush.ac.ir
1
2
Department of Chemistry, Shahreza Branch, Islamic Azad University, Shahreza,
Isfahan 311-86145, Iran
Department of Chemistry, Yazd Branch, Islamic Azad University, Yazd 89195-155, Iran
123

S. Alavi et al.
preparing different QX derivatives, such as condensation of an aryl 1,2-diamine
with a-diketones [7–10], Suzuki–Miyaura coupling reaction, which lead to 2,3-
disubstituted QXs [11], 1,4-addition of 1,2-diamines to diazenyl butenes [12, 13],
oxidative coupling of epoxides with ene-1,2-diamines [14], and Ugi-based reactions
[
15]. A number of acidic reagents are shown to catalyze these reactions such as
acidic alumina [16], citric acid [17], heteropoly acids [18], and o-Iodoxybenzoic
acid (IBX) in HOAC [19]. Some metal catalyzed reactions have been recommended
for quinoxaline synthesis like nanoparticle-supported cobalt catalyst [20],
Ga(ClO ) [21], and Fe(ClO ) [22]. Most of these methods suffer from some
4
3
4 3
drawbacks such as harsh reaction conditions, tedious work-up, unsatisfactory
product yields, expensive and adverse catalytic reagents, and in some cases catalysts
are harmful to the environment and cannot be reused. Thus, a non-catalyst reaction
with mild reaction condition is still desired.
Sulfonamides are a group of chemical compounds with a wide range of
pharmacological properties such as antibacterial [23], anti-inflammatory [24],
antitumor [25], and anti-thyroid [26, 27]. Because sulfonamides have a wide
applicability, various methods have been reported for the preparation of these
compounds, such as direct synthesis of sulfonamides in the presence of solid support
catalysts [28], direct synthesis from thiols and disulfides [29], and synthesis of aryl
sulfonamides via palladium-catalyzed chlorosulfonylation of arylboronic acids [30].
In continuing our research on the synthesis of and biological studies on
heterocyclic and sulfonamides compounds [31], herein we wish to investigate a
green method for the synthesis of quinoxaline derivatives under catalyst-free
conditions and then the synthesis and antibacterial studies of some new derivatives
of quinoxaline sulfonamides.
Experimental section
General
All materials were purchased from Merck Company. Purity of the compounds was
checked by TLC using silica gel-G plates and n-hexane/ethyl acetate. Melting points
were recorded on an electro-thermal apparatus and are uncorrected. NMR spectra
-
1
were determined with a BRUKER 400 spectrometer (DMSO-d ). IR spectra (cm
6
)
were measured with a Perkin-Elmer FT/IR-800 spectrometer. The elemental
analysis was done by a Costech ECS 4010 CHNS-O analyser. All yields referred to
isolated yields.
Preparation of 2-bromoacetophenones derivatives
To prepare the 2-bromoacetophenones derivatives, 3 mmol of acetophenone
derivatives and 6 mmol (1.338 g) of CuBr in EtOAc/CHCl (15:15 mL) were
2
3
refluxed for 18 h. After completion of the reaction (monitored by TLC), the white
CuBr powder was filtered, and the filtrate was evaporated. The product was washed
by cold EtOH for more purification.
1
23

Green synthesis of novel quinoxaline sulfonamides with…
Synthesis of quinoxaline derivatives
A mixture of o-phenylenediamine (5 mmol, 0.54 g) and 2-bromoacetophenones
(
5 mmol) was refluxed in 30 mL of EtOH for 24 h. The promotion of the reaction
was checked by TLC, using n-hexane/ethyl acetate (3:1) as eluent. After completion
of the reaction, more than half of the ethanol was evaporated, and then cold water
(
50 mL) was added and kept in the freezer for 10–15 min. The obtained solid was
filtered, washed with water, and dried in an oven. The product was obtained very
pure as a solid in 70–80% yield.
2
-(4-methoxyphenyl)quinoxaline
-
1
1
m.p. 87–89 °C; IR: (KBr, cm ) = 3052, 1606, 1491, 1250, 1028; H NMR
(
(
(
400 MHz, DMSO-d ) d (ppm) 9.55 (1H, s), 8.32 (2H, d, J = 8.9 Hz), 8.07–8.11
6
13
2H, m), 7.78–7.87 (2H, m), 7.15 (2H, d, J = 8.9 Hz), 3.86 (3H, s); C NMR
100 MHz, DMSO-d ) d (ppm) 161.2, 150.6, 143.3, 141.3, 140.6, 130.5, 129.3,
6
1
28.9, 128.9, 128.7, 128.3, 114.5, 55.3.
Synthesis of 2-methoxy-5-quinoxalin-2-yl-benzene-sulfonyl chloride (3)
To synthesize 2-methoxy-5-quinoxalin-2-yl-benzene-sulfonyl chloride, 1 mmol
0.236 g) of 2-(4-methoxyphenyl)-quinoxaline was stirred with 15 mmol (0.9 mL)
(
of chlorosulfonic acid in a round bottom flask in ice-bath for 30 min, 1 h at room
temperature, and 4 h at 40 °C. After completion of the reaction which was checked
by TLC, the solution was poured into crushed ice carefully and stirred for 15 min.
The solid was filtered, washed with water, and dried in the oven at 70 °C. The pure
product was obtained as a light green solid in 85% yield.
-
1
1
m.p. 152–155 °C; IR: (KBr, cm ) = 3065, 1602, 1492, 1368, 1173; H NMR
(400 MHz, DMSO-d ) d (ppm) 9.50 (1H, s), 8.69 (1H, d, J = 2.4 Hz), 8.31 (1H, dd,
J = 8.6 Hz, J = 2.4 Hz), 8.08–8.14 (2H, m), 7.78–7.88 (2H, m), 7.17 (1H, d,
6
1
2
1
3
J = 8.6 Hz), 3.87 (3H, s); C NMR (100 MHz, DMSO-d ) d (ppm) 158.3, 150.6,
6
1
43.2, 141.4, 140.5, 136.1, 130.5, 129.7, 129.3, 128.9, 128.7, 127.7, 126.7, 112.1,
5.6.
5
Synthesis of quinoxaline sulfonamide derivatives
2
1
-Methoxy-5-quinoxalin-2-yl-benzenesulfonylchloride (1 mmol, 0.334 g) and
mmol of aromatic amine in the presence of NaHCO as the base was ground in
3
a mortar under solvent-free conditions at room temperature. Progress of the reaction
was monitored by TLC. When the reaction was completed, water was added and it
was stirred for 30 min. The product was filtered, washed with more water, and dried
in the oven at 80 °C. All of the products were obtained very pure without any
purification.
123

S. Alavi et al.
2
-methoxy-N-(4-methylphenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4a)
-
1
Cream solid; m.p. 186–187 °C; IR: (KBr, cm ) = 3271, 1602, 1510, 1488, 1340,
1
1
157, 819; H NMR (400 MHz, DMSO-d ) d (ppm) 9.96 (1H, s), 9.55 (1H, s), 8.70
6
(
1H, d, J = 2.0 Hz), 8.55 (1H, dd, J = 8.7 Hz, J = 2.1 Hz), 8.09–8.18 (2H, m),
1 2
7
.80–7.92 (2H, m), 7.38 (1H, d, J = 8.8 Hz), 6.98–7.09 (4H, m), 4.01 (3H, s), 2.13
1
3
(
3H, s); C NMR (100 MHz, DMSO-d ) d (ppm) 157.8, 149.2, 143.2, 141.2, 140.9,
6
1
34.8, 133.7, 133.2, 130.7, 129.8, 129.4, 129.1, 129.0, 128.8, 127.9, 127.4, 120.4,
13.3, 56.5, 20.2. Anal. calcd for C H N O S: C, 65.1; H, 4.7; N, 10.3; S, 7.9;
1
found: C, 64.8; H, 4.6; N, 10.0; S, 7.8%.
2
2 19 3 3
2
-methoxy-N-(4-methoxyphenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4b)
-
1
Cream solid; m.p. 187–188 °C; IR: (KBr, cm ) = 3266, 1601, 1512, 1489, 1337,
1
1
159, 829; H NMR: (400 MHz, DMSO-d ) d (ppm) 9.96 (1H, s), 9.55 (1H, s), 8.65
6
(1H, s), 8.57 (1H, d, J = 8.6 Hz), 8.08-8.19 (2H, m), 7.78–7.92 (2H, m), 7.41 (1H,
d, J = 8.6 Hz), 7.05 (2H, d, J = 8.6 Hz), 6.77 (2H, d, J = 8.6 Hz), 4.04 (3H, s),
1
3
3
1
1
.61 (3H, s); C NMR (100 MHz, DMSO-d ) d (ppm) 157.8, 156.4, 149.2, 143.2,
6
41.2, 140.8, 133.6, 130.6, 129.9, 129.8, 129.0, 128.8, 127.8, 127.5, 123.2, 114.1,
13.2, 56.5, 55.0. Anal. calcd for C H N O S: C, 62.6; H, 4.5; N, 9.9; S, 7.6;
2
2 19 3 4
found: C, 62.8; H, 4.6; N, 9.8; S, 7.7%.
2
-methoxy-N-(4-chlorophenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4c)
-
1
Cream solid; m.p. 167–169 °C; IR: (KBr, cm ) = 3288, 1602, 1541, 1488, 1368,
1
1
166, 824; H NMR (400 MHz, DMSO-d ) d (ppm) 10.35 (1H, s), 9.57 (1H, s), 8.75
6
(
d, J = 8.36 Hz), 7.25-7,27 (2H, d, J = 7.84 Hz), 7.15 (2H, d, J = 8.04 Hz), 3.98
1H, s), 8.58 (1H, d, J = 7.7 Hz), 8.06–8.22 (2H, m), 7.80–7.98 (2H, m), 7.39 (1H,
1
3
(
3H, s); C NMR (100 MHz, DMSO-d ) d (ppm) 157.8, 149.1, 143.2, 141.2, 140.9,
6
1
Anal. calcd for C H ClN O S: C, 59.2; H, 3.7; N, 9.8; S, 7.5; found: C, 59.1; H,
36.6, 134.0, 130.7, 129.8, 129.1, 129.0, 128.8, 128.02, 127.8, 121.2, 113.5, 56.6.
2
1
16
3 3
3
.8; N, 9.9; S, 7.6%.
2
-methoxy-N-(2,4-dimethylphenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4d)
-
1
Light yellow; m.p. 171–173 °C; IR: (KBr, cm ) = 3209, 1603, 1546, 1499, 1324,
1
1
dd, J = 8.7 Hz, J = 2.3 Hz), 8.56 (1H, d, J = 2.2 Hz), 8.08-8.14 (2H, m),
157; H NMR (400 MHz, DMSO-d ) d (ppm) 9.54 (1H, s), 9.35 (1H, s), 8.61 (1H,
6
1
2
7
.78–7.89 (2H, m), 7.46 (1H, d, J = 8.8 Hz), 6.95 (1H, s), 6.81–6.92 (2H, m), 4.06
3
1
(
3H, s), 2.15 (6H, s); C NMR (100 MHz, DMSO-d ) d (ppm) 157.9, 149.2, 143.1,
6
1
1
6
41.1, 140.8, 135.8, 134.5, 133.5, 132.1, 131.2, 130.7, 129.8, 129.1, 128.9, 128.7,
28.4, 127.6, 126.8, 126.7, 113.3, 56.6, 20.3, 17.5. Anal. calcd for C H N O S: C,
2
3 21 3 3
5.8; H, 5.0; N, 10.0; S, 7.6; found: C, 65.8; H, 5.1; N, 9.9; S, 7.7%.
1
23

Green synthesis of novel quinoxaline sulfonamides with…
2
-methoxy-N-(3-chlorophenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4e)
-
1
Cream solid; m.p. 176–178 °C; IR: (KBr, cm ) = 3240, 1598, 1490, 1339, 116,
1
8
72, 819, 730; H NMR (400 MHz, DMSO-d ) d (ppm) 10.48 (1H, s), 9.58 (1H, s),
6
8
.78 (1H, s), 8.59 (1H, d, J = 7.4 Hz), 8.05–8.25 (2H, m), 7.78–7.98 (2H, m), 7.41
1
3
(
1H, d, J = 8.6 Hz), 6.99–7.29 (4H, m), 3.98 (3H, s); C NMR (100 MHz, DMSO-
d6) d (ppm) 157.8, 149.1, 143.2, 141.2, 140.9, 139.2, 134.1, 133.2, 130.8, 129.8,
29.0, 128.7, 128.0, 127.0, 123.5, 118.9, 117.7, 113.5, 56.6. Anal. calcd for
C H ClN O S: C, 59.2; H, 3.7; N, 9.8; S, 7.5; found: C, 58.7; H, 3.9; N, 9.9; S,
1
2
1
16
3 3
7
.6%.
2
-methoxy-N-(2-methoxyphenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4f)
-
1
Light cream solid; m.p. 181–182 °C; IR: (KBr, cm ) = 3304, 1601, 1541, 1498,
1
1
342, 1162, 756; H NMR (400 MHz, DMSO-d ) d (ppm) 9.55 (1H, s), 8.91 (1H, s),
6
8
.59–8.62 (2H, m), 8.05–8.22 (2H, m), 7.78–7.95 (2H, m), 7.38–7.48 (1H, m), 7.30
1
1H, d, J = 6.3 Hz) 6.78–7.12 (3H, m), 4.01 (3H, s), 3.64 (3H, s); C NMR
3
(
(
100 MHz, DMSO-d ) d (ppm)158.1, 151.8, 149.3, 143.2, 141.2, 140.84, 133.5,
6
1
30.7, 129.8, 129.0, 128.7, 128.2, 127.5, 126.1, 124.2, 120.4, 113.1, 111.5, 56.5,
5.6. Anal. calcd for C H N O S: C, 62.6; H, 4.5; N, 9.9; S, 7.6; found: C, 62.8;
5
H, 4.6; N, 9.8; S, 7.5%.
2
2 19 3 4
2
-methoxy-N-phenyl-5-quinoxaline-2-yl-benzenesulfonamide (4g)
-
1
Light cream solid; m.p. 228–230 °C; IR: (KBr, cm ) = 3262, 1602, 1541, 1489,
1
1
348, 1160, 765, 690; H NMR (400 MHz, DMSO-d ) d (ppm) 10.16 (1H, s), 9.56
6
(
1H, s), 8.74 (1H, s), 8.57 (1H, d, J = 7.8 Hz), 8.08–8.21 (2H, m), 7.80–7.95 (2H,
m), 7.39 (1H, d, J = 8.2 Hz), 7.10–7.27 (4H, m), 6.93–7.02 (1H, m), 4.00 (3H, s);
1
3
C NMR (100 MHz, DMSO-d ) d (ppm) 157.8, 149.1, 143.2, 141.2, 140.8, 137.6,
6
1
Anal. calcd for C H N O S: C, 64.4; H, 4.3; N, 10.7; S, 8.1; found: C, 64.3; H,
33.8, 130.7, 129.8, 129.0, 129.0, 128.7, 127.9, 127.4, 123.9, 119.9, 113.4, 56.5.
2
1 17 3 3
4
.3; N, 10.8; S, 8.1%.
N-ethyl-2-methoxy-N-phenyl-5-quinoxaline-2-yl-benzenesulfonamide (4h)
-
1
Light yellow; m.p. 118–120 °C; IR: (KBr, cm ) = 1600, 1540, 1490, 1333, 1169,
1
7
J = 7.6 Hz), 8.74 (1H, s), 8.20–8.40 (2H, m), 7.96–8.13 (2H, m), 7.68 (1H, d,
62, 696; H NMR (400 MHz, DMSO-d ) d (ppm) 9.73 (1H, s), 8.81 (1H, d,
6
J = 8.5 Hz), 7.30–7.61 (5H, m), 4.22 (3H, s), 3.99-4.11 (2H, m), 1.19–1.28 (3H,
1
3
m); C NMR (100 MHz, DMSO-d ) d (ppm) 158.0, 149.2, 143.2, 141.1, 140.8,
6
1
1
7
38.3, 133.7, 130.6, 129.8, 129.5, 129.0, 129.0, 128.7, 128.6, 128.1, 127.8, 127.5,
13.5, 56.5, 46.4, 14.6. Anal. calcd for C H N O S: C, 65.8; H, 5.0; N, 10.0; S,
2
3 21 3 3
.6; found: C, 65.7; H, 4.9; N, 9.4; S, 7.6%.
123

S. Alavi et al.
2
-methoxy-N-(2-methylphenyl)-5-quinoxaline-2-yl-benzenesulfonamide (4i)
-
1
Light cream solid; m.p. 212–215 °C; IR: (KBr, cm ) = 3325, 1600, 1539, 1498,
1
1
325, 1158, 755; H NMR (400 MHz, DMSO-d ) d (ppm) 9.63 (1H, s), 9.57 (1H, s),
6
8
J = 7.8 Hz), 7.00–7.32 (4H, m), 4.08 (3H, s), 2.27 (3H, s); C NMR (100 MHz,
.60–8.80 (2H, m), 8.10–8.30 (2H, m), 7.83–8.05 (2H, m), 7.54 (1H, d,
1
3
DMSO-d ) d (ppm) 157.9, 149.2, 143.2, 141.2, 140.8, 134.9, 134.3, 133.5, 130.6,
6
1
30.6, 129.7, 129.2, 129.0, 128.7, 128.3, 127.7, 126.4, 126.3, 126.2, 113.3, 56.4,
7.6. Anal. calcd for C H N O S: C, 65.1; H, 4.7; N, 10.3; S, 7.9; found: C, 65.1;
1
H, 4.7; N, 10.2; S, 7.9%.
2
2 19 3 3
2
-methoxy-N-naphthalene-5-quinoxaline-2-yl-benzenesulfonamide (4j)
-
1
Cream solid; m.p. 215–218 °C; IR: (KBr, cm ) = 3292, 1599, 1541, 1486, 1343,
1
1
8
7
1
1
159; H NMR (400 MHz, DMSO-d ) d (ppm) 10.22 (1H, s), 9.50 (1H, s),
6
.45–8.75 (2H, m), 8.20–8.36 (1H, m), 8.00–8.20 (2H, m), 7.75–8.00 (4H, m),
1
.25–7.62 (5H, m), 3.94 (3H, s). C NMR (100 MHz, DMSO-d ) d (ppm) 158.0,
49.1, 143.1, 141.1, 140.7, 133.7, 133.6, 130.74, 129.8, 129.5, 128.9, 128.7, 128.5,
27.8, 127.8, 126.2, 126.0, 125.5, 123.0, 113.3, 56.3. Anal. calcd for C H N O S:
3
6
2
5 19 3 3
C, 68.0; H, 4.3; N, 9.5; S, 7.2; found: C, 67.9; H, 4.2; N, 9.6; S, 7.3%.
Results and discussion
Chemistry
Synthesis of 2-phenylquinoxaline derivatives
Several 2-phenylquinoxalines were synthesized in two steps under catalyst-free
conditions (Scheme 1). Firstly, C bromination of acetophenones was carried out by
2
CuBr in a simple and effective method and led to the products in good yield and
2
purity. Synthesis of quinoxalines was carried out in an easy, ecofriendly, and non-
catalytic method by the reaction of o-phenylene diamine and 2-bromoacetophe-
nones in refluxed EtOH. 2-bromoacetophenones with different substituents were
subject to react with o-phenylendiamin under optimized conditions (Table 1). The
results show that both electron-donating and electron-withdrawing substituents on
O
O
N
N
NH
2
2
EtOAc/ CHCl
reflux
3
Br
EtOH
CH
3
+
2 CuBr2
+
reflux
NH
R
R
R
1
2
3 2 3
R= 4-OCH , 4- Cl, 4- Br, 4- NO , 3,4- OCH
Scheme 1 Catalyst-free synthesis of quinoxalines from 2-bromoacetophenone derivatives and o-
phenylenediamine
1
23

Green synthesis of novel quinoxaline sulfonamides with…
2
-bromoacetophenone undergo the reaction, and the corresponding 2-phenylquinox-
alines were obtained with good to excellent yield and purity. 2-(4-nitrophenyl)
quinoxaline derivative recrystallized in EtOH for more purification.
Synthesis of quinoxaline sulfonamides
Based on the pharmaceutical properties of quinoxalines and sulfonamides, several
quinoxaline compounds bearing a sulfonamide group were designed and synthe-
sized in the next part of this work (Scheme 2). 2-(4-methoxyphenyl) quinoxaline
was selected as the main structure because the sulfonation of this compound was
carried out under mild conditions and entirely on the ortho portion of the methoxy
group.
1
Comparison of HNMR of 2-(4-methoxyphenyl) quinoxaline with 2-methoxy-5-
1
quinoxalin-2-yl-benzenesulfonyl chloride proves this claim. In H NMR of 2-(4-
methoxyphenyl) quinoxaline the hydrogens of 4-methoxy phenyl ring appear as two
double 8.33 and 7.15 ppm with coupling constant of 8.9 Hz that was shown as
1
hydrogens a and b in Fig. 1. In comparison, the H NMR of 2-Methoxy-5-
quinoxalin-2-yl benzenesulfonyl chloride (3) showed only one hydrogen ortho to the
methoxy group (7.17 ppm, d, J = 8.6 Hz). Also, the meta hydrogens to the
methoxy group appeared as two separate peaks at 8.31 and 8.69 ppm (Fig. 1). The
NOESY spectrum of 2-Methoxy-5-quinoxalin-2-yl-benzenesulfonyl chloride (com-
pound 3) confirms the correlations between H (9.55 ppm) with two protons of H
e
c
(
8.31 ppm) and H (8.69 ppm) in other aromatic ring. The spectrum also shows a
d
Table 1 Catalyst free synthesis of 2-phenylquinoxaline derivatives
b
Entry 2-bromoacetophenone Product
Yield (%)
Mp (°C) Reported Mp (°C) [32, 33]
87–89 92
O
N
N
1
76
Br
H
3
CO
OCH3
2
a
O
O
N
N
2
85
83
70
75
132–135 138
129–131 135
180–182 185
110–111 105
Br
Br
Cl
Br
O
Cl
2b
N
N
3
4
5
Br
2c
O
N
Br
N
2
N
NO
2
2e
O
N
Br
OCH
3
3
N
H
3
CO
OCH
OCH
3
2f
a
Reaction conditions: 5 mmol o-phenylene diamine, 5 mmol 2-bromoacetophene refluxing in EtOH for
4 h
2
b
Isolated yields
123

S. Alavi et al.
N
N
N
N
Aromatic amines
solvent-free
N
N
3
ClSO H
O
S
NR
1 2
R
SO
2
Cl
O
NaHCO
3
OCH
3
OCH
3
OCH
3
2
a
4a-j
3
R
R
1
2
= H, C
= Aryl
2 5
H
Scheme 2 Synthesis of quinoxaline sulfonamide derivatives
1
Fig. 1 H NMR of 2-(4-methoxyphenyl) quinoxaline and 2-methoxy-5-quinoxalin-2-yl-benzenesulfonyl
chloride
strong vicinal coupling between H (7.1 ppm) and Hc (8.31 ppm) (see supporting
a
information).
In the next step 2-Methoxy-5-quinoxalin-2-yl benzenesulfonyl chloride was
reacted with different substituted aromatic amines in the presence of NaHCO at
3
room temperature under solvent-free conditions. The reactions proceeded in
3
7
-60 min and the corresponding quinoxaline sulfonamides were obtained in
4–92% in high purity. Aromatic amines with electron-donating group, such as
methyl and methoxy, reacted in 3–10 min and led to the products in higher yield in
comparison with aromatic amines with Cl group (Table 2). Aromatic amines with
strongly electron-withdrawing group such as NO did not react after a long time in
2
this condition.
Another advantage of this method is simplicity of work-up. After finishing the
reaction NaHCO can be easily separated by addition of water, and the desired solid
3
products can be easily filtered. All of the products obtained were very pure and
characterized by IR, NMR spectral data, and CHN analysis.
Antibacterial study
The antibacterial activities of all products have been tested against Escherichia coli
(
positive bacteria by agar well diffusion method. Test compounds of 4 mg mL
ATCC 35218) as gram-negative and Staphylococcus aureus (ATCC 6538) as gram-
-
1
1
23

Green synthesis of novel quinoxaline sulfonamides with…
Table 2 Synthesis of quinoxaline sulfonamide derivatives and the antibacterial activity
Entry
Amine
product
Time (min)
Yield (%)
S. aureus
(ATCC6538)
E. coli
(ATCC35218)
CH
3
NH
CH
2
3
N
N
1
NH
SO
6 / 89
3 / 92
17
20
10
9
2
OCH
OCH
3
4
a
3
NH
2
N
N
2
3
NH
SO
2
OCH
3
OCH
3
4
b
Cl
NH
Cl
2
N
N
NH
60 / 74
5 / 82
15
18
12
10
SO
OCH
CH
2
4
c
3
3
NH
2
3
CH
3
CH
3
N
4
NH
SO
2
CH
N
OCH
3
4d
Cl
NH
2
N
N
NH
SO
5
6
40 / 79
4 / 90
11
22
13
11
2
Cl
OCH
3
4e
NH
2
H
3
CO
N
N
OCH
3
NH
SO
2
OCH
3
4f
NH
2
N
N
NH
SO
7
8
9
5 / 91
35 / 85
7 / 90
5
5 >
12
8
2
OCH
3
4
g
H
3
C
NH
N
CH3
N
13
16
SO
2
N
OCH
3
4
h
NH
2
3
H C
N
N
CH
3
NH
SO
2
OCH
3
4i
NH
2
N
N
NH
SO
10
60 / 81
17
18
2
OCH
3
4j
1
1
1
2
-
-
Chloramphenicol
Ampicillin
-
-
19
28
22
15
a
Reaction conditions: 1 mmol aromatic amine and 1 mmol 2-Methoxy-5-quinoxalin-2-yl-benzenesul-
fonyl chloride, solvent- free in present of NaHCO
3
b
Isolated yield
123

S. Alavi et al.
concentrations prepared by dilution in dimethyl sulfoxide (DMSO). After culturing
the bacteria, dissolved products added to the holes on agar gel and incubated at
3
6 °C ± 1 °C for 24 h. The diameters of inhibition zones were measured in mm
and are shown in Table 2. The highest antibacterial activity against S. Aureus was
shown by 4b (2-methoxy-N-(4-methoxyphenyl)-5-quinoxaline-2-yl-benzenesulfon-
amide) and 4f (2-Methoxy-N-(2-methoxy phenyl)-5-quinoxaline-2-yl-benzenesul-
fonamide). At the same time, the most antibacterial activity against E. coli was
observed in 4j (2-methoxy -N-naphtalene-5-quinoxaline-2-yl benzenesulfonamide),
according to the resulting zones of inhibition, it is significant that the effect on
gram-negative bacteria for this quinoxaline sulfonamide is more than the gram-
positive one. As the results show electron rich groups on sulfonamides contributes
positively to increasing antibacterial activity, specially against S. aureus as a gram-
positive. These results were compared with chloramphenicol and ampicillin as
standard references. Solution reference drugs also were dissolved in DMSO to a
-
1
concentration of 4 mg mL
.
Conclusions
In conclusion, we have developed a catalyst-free method for the synthesis of several
quinoxalines. Also, a novel series of quinoxaline sulfonamide was synthesized from
quinoxaline sulfonylchloride and different amines in the presence of NaHCO as a
3
green base under solvent-free conditions. These protocols offer various advantages
such as simple procedure, mild reaction conditions, easy work-up, good to excellent
yields, and no need for further purification. Furthermore, the novel synthesized
quinoxaline sulfonamides were shown moderate to very good activity against
Escherichia coli and Staphylococcus spp. as gram-positive and gram-negative
bacteria.
Acknowledgements The Support from Islamic Azad University, Shahreza Branch (IAUSH) and Islamic
Azad University, Yazd Branch (IAUYAZD) Research Councils is gratefully acknowledged. Also we
appreciate Professor Babak Kaboudin (Institute for Advanced Studies in Basic Sciences) for helpful
comments on the manuscript.
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