Br?nsted acid hydrotrope combined catalyst for environmentally benign synthesis of quinoxalines and pyrido[2,3-b]pyrazines in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2012.03.097

A new Br?nsted acid hydrotrope combined catalyst (BAHC) has been developed and applied in acid catalyzed synthesis of pyrido[2,3-b]pyrazines and quinoxalines in an aqueous medium at ambient temperature with excellent yields. Interestingly, the catalyst ca

Full text of DOI:10.1016/j.tetlet.2012.03.097

Tetrahedron Letters 53 (2012) 2756–2760
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Brönsted acid hydrotrope combined catalyst for environmentally benign
synthesis of quinoxalines and pyrido[2,3-b]pyrazines in aqueous medium
⇑
Arjun Kumbhar, Santosh Kamble, Madhuri Barge, Gajanan Rashinkar, Rajashri Salunkhe
Department of Chemistry, Shivaji University, Kolhapur 416 004, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new Brönsted acid hydrotrope combined catalyst (BAHC) has been developed and applied in acid cat-
alyzed synthesis of pyrido[2,3-b]pyrazines and quinoxalines in an aqueous medium at ambient temper-
ature with excellent yields. Interestingly, the catalyst can be easily recovered after the reactions and
reused. Furthermore, BAHC catalyst worked well and avoids the use of organic solvents. We have
reported herein the synthetic pathway which has less disastrous effect in the atmosphere and human
survival.
Received 29 January 2012
Revised 23 March 2012
Accepted 25 March 2012
Available online 29 March 2012
Keywords:
Pyrido[2,3-b]pyrazines
Quinoxalines
Ó 2012 Elsevier Ltd. All rights reserved.
Brönsted acid hydrotrope combined catalyst
(BAHC)
Catalyst recycling
Aqueous medium
Annulated pyrazines, such as quinoxaline and pteridine deriva-
tives are very important nitrogen-containing heterocycles found in
biological systems and are widely used as pharmaceuticals.1 The
quinoxaline anticancer drugs CQS (chloroquinoxaline sulfonamide)
and XK469 were both found to have activity against solid tumors.
(2-Quinoxalinyloxy)phenoxypropanoic acid derivatives, such as
AssureÒ are well documented as herbicides and are used to control
annual and perennial grass weeds in broadleaf crops (Fig. 1).2 It is
noteworthy that, by virtue of their thermal stability, intense lumi-
nescence, and other desirable properties, they have been widely
used in organic semiconductors and electroluminescent materials.3
Generally, pyrido[2,3-b]pyrazines and quinoxalines are synthe-
sized by the condensation of aryl 1,2-diamines with 1,2-dicarbonyl
compounds in MeOH/AcOH4 and also by several modified proce-
dures using b-cyclodextrin (b-CD),5 ionic liquids,6 molecular io-
dine,7 heteropolyacid,8 cellulose sulfuric acid,9 TiO2,10 hypervalent
iodine(III) sulfonate in PEG,11 polyaniline-sulfate salt,12 DABCO,13
CAN,14 HClO4–SiO2,15 and MnO2.16 Although some of these methods
afford good to high yields of the corresponding quinoxalines, many
of them suffer from various disadvantages such as use of strong
acids, high temperatures, long reaction times, moisture sensitivity
as well as high cost, and toxicity of the reagents.
desirable to use water as a reaction solvent since it is safe, harm-
less, and environmentally benign.17 However, the limited aqueous
solubility of organic compounds poses a unique problem. The low
solubility of organic reactants in water can often be overcome by
using hydrotropes which are the class of compounds, though
amphiphilic in character, have hydrophobic regions and thus differ
from classical surfactants; yet they display substantial ability to
solubilize, non-polar compounds in water.18 The self aggregation
of hydrotropes has been considered to be a prerequisite for a huge
number of applications in various fields such as drug solubilization,
separation sciences, and nanocarriers for poorly soluble drugs.19
There is also growing interest for the use of hydrotropes as a reac-
tion media in organic synthesis.20 The key focus of the use of
Cl
NH2
O
COOH
N
N
N
N
O
S
O
XK469
Cl
N
O
H
Chloroquinoxaline
sulphonamide
N
( CQS)
O
O
Cl
O
Organic reactions in aqueous media have attracted increasing
interest offering many practical and economical advantages. From
a viewpoint of ecological advantage and greenness of water, it is
N
O
N
N
N
ASSURER
N
N
Quinoxaline
Pyrido[2,3-b]pyrazine
⇑
Corresponding author. Tel.: +91 231 260 9240; fax: +91 231 269 2333.
E-mail address: rss234@rediffmail.com (R. Salunkhe).
Figure 1. Pyrido[2,3-b]pyrazine and quinoxaline bicyclic heterocycles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.097

A. Kumbhar et al. / Tetrahedron Letters 53 (2012) 2756–2760
2757
hydrotropes as a reaction media depends on the nature of hydro-
trope used and its minimum hydrotropic concentration (MHC)
above which there is maximum solubility of reactants. As hydro-
tropes increase the solubility of compounds in many fold excess,
this effect is attributed to a direct interaction between the reac-
tants which are practically insoluble in water. Secondly, the prod-
uct precipitates on dilution with water from hydrotropic solution,
which leads to the product formation in crystalline form with an
improved purity, and the mother liquor can be used to concentrate
the hydrotrope for recycling. This technique avoids the use of
highly inflammable and expensive organic solvents that are nor-
mally used in organic synthesis. These interactive properties of
hydrotropes and our ongoing efforts in the development of newer
methods for organic synthesis,21 rendered us to explore the use of
the Brönsted acid hydrotrope combined catalyst for the synthesis
of medicinally important pyrido[2,3-b]pyrazines and quinoxalines
in aqueous medium.
tained in 90% within 20 min (Table 1, entry 4). On the completion
of reaction as monitored by TLC, the reaction mixture was diluted
with cold water and product was separated out (Scheme 1). The fil-
tration of reaction mixture afforded the corresponding product of
high purity.23 From these observations, it was revealed that most
of the substrates and catalyst molecules were concentrated in
the hydrophobic reaction environment and enabled the rapid or-
ganic reaction in water.
With these results in hand, we have determined the hydro-
tropic concentration for maximum solubilization of the reactants
in water to give maximum yield of the product. Thus the model
reaction was carried out with various concentrations (% w/v) of
NaPTS in water at ambient temperature. By changing the con-
centration, a dramatic effect on the conversion rate of quinoxa-
line was observed. As shown in Table 1, a linear relationship
was observed with concentration. The yield of the product was
highest at 40% of hydrotropic concentration since this concentra-
tion was suitable for the maximum solubilization of organic
compounds (Table 1, entry 7). On the other hand, further in-
crease in concentration resulted in a decrease in the product
yield due to decreased solubility of substrates in solution (Table
1, entry 8).
After the optimization of hydrotropic concentration, various
hydrotropes such as, NaXS (sodium xylene sulfonate) and NaBS
(sodium benzene sulfonate) were used for model reaction with
5 mol % PTSA. Results revealed that PTSA is more active when com-
bined with NaPTS as compared to NaXS and NaBS (Table 1, entries
7, 9, and 10). The higher activity of NaPTS was rationalized on the
basis of an overall planar structure of hydrophobic and hydrophilic
regions giving rise to self associated configuration, offering a good
micro-environment of lower polarity and stabilizes the reactants
through a cooperative mechanism.18
In order to optimize the reaction conditions, initially, the con-
densation of o-phenylene diamine 1 and benzil 2 was studied as
a model reaction at room temperature (Scheme 1).
In the absence of any catalyst the product 3a was produced in
water with very low yield after 10 h (Table 1, entry 1), but, on addi-
tion of a catalytic amount (5 mol %) of p-toluene sulfonic acid
(PTSA) the yield increased to 70% in 3 h (Table 1, entry 2). On the
other hand, the hydrotrope aided acid catalysis was studied in
the model reaction using PTSA as Brönsted acid catalyst in aqueous
NaPTS (sodium p-toluene sulfonate) solution as a hydrotrope. The
reaction which proceeded sluggishly in the aqueous NaPTS (5 mL,
20% w/v) solution (Table 1, entry 3), showed a remarkable
enhancement of the reactivity when the reaction was carried out
in the presence of 5 mol % PTSA combined with aqueous NaPTS
(5 mL, 20% w/v) solution, and the corresponding product was ob-
Scheme 1. Synthesis of quinoxalines in aqueous hydrotropic solution.
Table 1
Screening of various reaction conditions for the synthesis of quinoxalinesa
Entry
Hydrotrope
Hydrotrope concentration (% w/v)
Catalyst (mol %)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
H2O
H2O
—
—
—
5
—
5
5
5
5
5
5
5
10 h
3.0 h
1.5 h
20
30
15
7
15
10
12
Trace
70
82
90
80
92
96
90
93
NaPTS
NaPTS
NaPTS
NaPTS
NaPTS
NaPTS
NaXS
NaBS
20
20
10
30
40
50
40
40
10
89
a
Reaction conditions: Benzil (1.0 mmol), o-phenylenediamine (1.0 mmol), PTSA (5 mol %), aqueous hydrotropic solution (5 mL), RT.
Isolated yields.
b

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A. Kumbhar et al. / Tetrahedron Letters 53 (2012) 2756–2760
Table 2
Synthesis of quinoxaline and pyrido[2,3-b]pyrazine derivatives in BAHCa
Entry
1
1,2-Diamine
1,2-Diketone
Productb
Time (min)
Yieldc (%)
NH2
O
O
N
NH2
7
96
N
3a
NH2
NH2
Br
Br
Br
Br
2
3
4
O
O
N
N
20
10
7
91
91
93
3b
NH2
NH2
O
O
N
N
3c
NH2
NH2
O
O
N
N
3d
NH2
NH2
N
O
N
N
5
6
7
N
N
15
25
25
15
92
80
86
92
O
N
3e
NH2
O
O
N
N
NH2
N
N
N
N
3f
NH2
NH2
O
O
N
N
3g
Br
Br
NH2
NH2
8
9
O
O
Br
Br
N
N
N
N
3h
Br
Br
Br
Br
NH2
NH2
O
O
N
N
N
25
92
N
3i

A. Kumbhar et al. / Tetrahedron Letters 53 (2012) 2756–2760
2759
Table 2 (continued)
Entry
10
1,2-Diamine
1,2-Diketone
Productb
Time (min)
Yieldc (%)
Br
NH2
NH2
O
O
Br
N
N
N
10
93
N
3j
a
Reaction conditions: Diketone (1.0 mmol), diamine (1.0 mmol), PTSA (5 mol %), 40% aq NaPTS (5 mL), RT.
All products were analyzed by 1H NMR, 13C NMR, and mass spectroscopy.
Isolated yields.
b
c
X
X
NH2
NH2
N
N
O
O
PTSA (5 mol%)
X
N
H2N
H2N
+
40% aq. NaPTS, r t
X
X
2
N
X
4
6a-b
X = C, N
Scheme 2. Synthesis of quinoxalines 2,3,20,30-tetra aryl[6,60]biquinoxalinyl in BAHC.
quite easily recovered from the aqueous solution after the reac-
tion was completed. The reaction mixture was quenched with
water and the precipitated product was simply separated by fil-
tration. The BAHC was in the aqueous layer, and only removal
of water gave the catalyst which could be used in the next reac-
tion. To assess the reusability of BAHC, recycling experiments
were carried out with o-phenylenediamine and benzil as sub-
strates over the four reaction cycles. After each experiment, the
aqueous solution of BAHC was recovered by filtration, washed
thoroughly with diethyl ether, concentrated and then subjected
to a new run with fresh reactants under identical reaction condi-
tions. The results shown in Figure 2 indicated that BAHC could be
reused for at least five runs with a modest change in yield of the
product.
The plausible mechanism of the product formation is conceptu-
alized in Figure 3.22 The water molecules hydrate the hydrotrope
head groups decreasing the electrostatic interaction between these
groups. The two head groups move apart and displace the water
molecules interacting hydrophobic chains. This may be the driving
force for two hydrophobic chains to interact and force the diamine
to interact with diketone which is activated by acid. The eliminated
water molecules then get easily absorbed by the hydrophilic head
groups. As a result, of the overall effect there is a rate enhancement
of the reaction.
In conclusion, we have presented a simple, efficient, and green
protocol for the synthesis of quinoxaline and pyrido[2,3-b]pyrazine
derivatives in a novel Brönsted acid hydrotrope combined catalysts
(BAHC) in water at ambient temperature. The merits of the present
method are easy work-up, faster reactions, and satisfactory yields
which avoids hazardous organic solvents and toxic catalysts. The
BAHC could be reused for at least five runs with a modest change
in the product yield.
Figure 2. Recyclability of BAHC.
After the selection of an appropriate hydrotrope and optimized
conditions, a series of diketones were treated with various 1,2-dia-
mines in 40% aqueous NaPTS solution at ambient temperature with
5 mol % PTSA (Table 2). The reactions proceeded at room tempera-
ture within a short time to afford the desired products in excellent
yields.23
Next, we have extended this protocol for the tetra amines such
as 3,30,4,40-tetraamino-1,10-biphenyl 4. It underwent condensation
with diketones 2 in the presence of 5 mol % PTSA in 40% aq NaPTS
(5 mL) affording the sterically hindered product 2,3,20,30-tetra
aryl[6,60]biquinoxalinyl 6a–b in 83% and 81% yields, respectively
in 20 min (Scheme 2).
Acknowledgments
Another striking feature of BAHC catalyst was easy recovery
from the reaction mixture. As PTSA and hydrotrope are more sol-
uble in water than in organic solvents, almost 100% of BAHC was
We gratefully acknowledge the financial support from the
Department of Science Technology and University Grants Commis-
sion for FIST and SAP respectively. One of the authors, A.K. thanks

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A. Kumbhar et al. / Tetrahedron Letters 53 (2012) 2756–2760
Figure 3. Conceptual picture of quinoxaline formation.
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the University Grants Commission, New Delhi, India for the award
of Teacher Fellowship under the F. I. P. of the XIth Plan.
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23. General procedure for the synthesis of quinoxaline and pyrido[2,3-b]pyrazine: In a
small Schlenk tube, 1,2-diamine (1 mmol), 1,2-diketone (1 mmol), PTSA
(5 mol %), and 40% aq NaPTS (5 ml) were taken and the reaction mixture was
stirred at room temperature. The reaction process was monitored by thin layer
chromatography (TLC). After completion of the reaction, the mixture was
diluted with water (20 mL). The filtrate was washed with water and dried
affording the corresponding products.
Spectral data of representative compounds: Compound 3d: Yellow solid; mp 228–
229 °C; 1H NMR (300 MHz, CDCl3, d ppm): 7.73–7.89 (6H, m), 8.31–8.37 (2H,
m), 8.59 (2H, d, J = 8.7 Hz), 9.42 (2H, dd, J = 7.8 Hz, 1.8 Hz); 13C NMR (75 MHz,
CDCl3, d ppm): 122.93, 126.27, 127.95, 129.44, 129.77, 130.32, 132.06, 142.19,
142.45; MS (ESI): m/z 280; elemental analysis (calcd C = 85.6, H = 4.3, N = 9.9:
observed C = 86.0, H = 4.2, N = 9.8).
Compound 3e: White solid; mp 178–179 °C; 1H NMR (300 MHz, CDCl3, d ppm):
7.21–7.25 (2H, m), 7.80–7.85 (4H, m), 8.00 (2H, d, J = 7.0 Hz), 8.22 (2H, dd,
J = 6.6 Hz, 3.3 Hz), 8.34 (2H, d, J = 4.2 Hz); 13C NMR (75 MHz, CDCl3, d ppm):
122.80, 124.20, 129.40, 130.28, 136.49, 141.14, 148.27, 152.41, 157.53; MS
(ESI): m/z 284; elemental analysis (calcd C = 76.0, H = 4.2, N = 19.7: observed
C = 76.2, H = 4.3, N = 19.4).
Compound 3g: Yellow solid; mp 217–219 °C; 1H NMR (300 MHz, CDCl3, d ppm):
7.71–7.85 (5H, m), 8.55 (2H, d, J = 7.8 Hz), 8.67 (1H, dd, J = 8.4 Hz, 1.8 Hz),
9.29–9.36 (2H, m) 9.54 (1H, dd, J = 7.8 Hz, 1.5 Hz); 13C NMR (75 MHz, CDCl3, d
ppm): 123.90, 126.21, 127.32, 129.50, 129.86, 130.82, 132.10, 132.50, 138.13,
145.09, 152.42, 154.31; MS (ESI): m/z 281; elemental analysis (calcd C = 81.1,
H = 3.9, N = 15.0: observed C = 81.1, H = 4.0, N = 14.9).
Compound 3i: White solid; mp 236–237 °C; 1H NMR (300 MHz, CDCl3, d ppm):
7.41–7.45 (2H, m), 7.53–7.56 (6H, m), 8.65 (1H, d, J = 2.4 Hz), 9.18 (1H, d,
J = 2.4 Hz); 13C NMR (75 MHz, CDCl3, d ppm): 121.34, 124.65, 124.91, 131.37,
131.66, 131.72, 131.84, 136.37, 136.64, 139.20, 148.10, 153.80, 154.86, 155.56;
MS (ESI): m/z 517; elemental analysis (calcd C = 43.8, H= 2.0, Br = 46.1, N = 8.0.
observed C = 43.7, H = 2.1, Br = 46.1, N = 8.1).
Compound 3j: White solid; mp 235–238 °C; 1H NMR (300 MHz, CDCl3, d ppm):
7.72–7.87 (4H, m), 8.56 (2H, d, J = 8.1 Hz), 8.81–8.83 (1H, m), 9.25–9.29 (2H,
m), 9.47 (1H, d, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3, d ppm): 120.64, 122.97,
123.10, 126.70, 127.31, 128.21, 128.32, 129.29, 129.54, 131.30, 131.47, 132.59,
137.49, 139.49, 144.22, 155.50; MS (ESI): m/z 359; elemental analysis (calcd
C = 63.3, H = 2.8, Br = 22.2, N = 11.6: observed, C = 63.5, H = 2.8, Br = 22.2,
N = 11.5).
Compound 6b: Yellow solid; mp >300 °C; 1H NMR (300 MHz, CDCl3, d ppm):
7.84–7.90 (4H, m) 8.07–8.10 (4H, m), 8.27–8.38 (8H, m), 8.65 (2H, d,
J = 1.8 Hz); MS (ESI): m/z 566; elemental analysis (calcd C = 76.3, H = 3.9,
N = 19.8: observed, C = 76.4, H = 3.8, N = 19.7).