Rapid, efficient and eco-friendly procedure for the synthesis of quinoxalines under solvent-free conditions using sulfated polyborate as a recyclable catalyst

Article abstract of DOI:10.1007/s12039-017-1235-0

An efficient and inexpensive sulfated polyborate catalyst was applied for the rapid synthesis of quinoxaline derivatives from various substituted o-phenylenediamines and 1,2-diketones/α-hydroxy ketones using sulfated polyborate is described. The catalyst has the advantage of Lewis as well as Bronsted acidity and recyclability without significant loss in catalytic activity. The key advantages of the present method are high yields, short reaction times, solvent-free condition, easy workup, and ability to tolerate a variety of functional groups, which give economical as well as ecological rewards. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-017-1235-0

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-017-1235-0
RAPID COMMUNICATION
Rapid, efficient and eco-friendly procedure for the synthesis
of quinoxalines under solvent-free conditions using sulfated polyborate
as a recyclable catalyst
KRISHNA S INDALKAR, CHETAN K KHATRI and GANESH U CHATURBHUJ∗
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai,
Maharashtra 400 019, India
Email: gu.chaturbhuj@gmail.com
MS received 17 December 2016; revised 17 January 2017; accepted 17 January 2017
Abstract. An efficient and inexpensive sulfated polyborate catalyst was applied for the rapid synthesis of
quinoxaline derivatives from various substituted o-phenylenediamines and 1,2-diketones/α-hydroxy ketones
using sulfated polyborate is described. The catalyst has the advantage of Lewis as well as Bronsted acidity and
recyclability without significant loss in catalytic activity. The key advantages of the present method are high
yields, short reaction times, solvent-free condition, easy workup, and ability to tolerate a variety of functional
groups, which give economical as well as ecological rewards.
Keywords. Sulfated polyborate; o-phenylenediamines; 1,2-diketone; α-hydroxy ketones; quinoxaline.
heating,21 catalytic and reagent systems. Many catalysts
and reagents have also been reported such as sulfamic
acid,22 CuSO4.5H2O,23 amidosulfonic acid,24 polyani-
line sulfate,25 p-TSA,26 ionic liquid (Hbim)BF4,27 Mn
octahedral molecular sieves,28 Ga(OTf)3,29 Montmoril-
lonite K-10,30 Keggin-type heteropolyacids (H4SiW12
O40),31 Amberlyte-15,32 SnCl2,33 SnCl2/SiO2,34 Zr(DS)4,35
ZrO2 mixed metal oxide,36 iodine,37 silica bonded S-
sulfonic acid,38 silica supported SbCl3,39 Zn[(L)pro-
line,40 etc. Recently, many new improved methods were
also reported using silica gel,41 alumina,42 Sm(OTf)2,43
KHSO4,44 silica sulfuric acid in PEG,45 glycerol,46
CeCl3-7H2O in glycerin,47 triethylamine/O2,48 FeCl3/
morpholine,49 Ga(ClO4)3,50 p-TSA/H2O,51 graphite,52
sulfated TiO2,53 and PEG-400.54
Furthermore, many of these methods have some syn-
thetic advantages individually, but still suffer from one
or more limitations, such as the use of toxic organic
solvents, long reaction times, requiring anhydrous con-
ditions, use of expensive or corrosive reagents, strong
acids, strong oxidants, and toxic or expensive cata-
lysts, harsh reaction conditions, tedious workup and
most importantly unsatisfactory yields. Thus, develop-
ment of a safe, environmentally benign, mild, efficient,
and high yielding rapid reaction procedure using cost
effective and recyclable catalyst for the preparation of
quinoxalines is desirable.
1. Introduction
The importance of quinoxaline and its derivatives has
been reported in the literature.1 Quinoxaline deriva-
tives are valuable for their wide spectrum of biological
activities viz antiviral,2 anticancer,2 antibacterial,3 anti-
depressant,4 antiamoebic,5 anticonvulsant,6 antima-
larial,7 anti-inflammatory-antioxidant,8 antiprotozoal
activity,9 and activity as kinase inhibitors.10 They are
basic scaffolds for various insecticides, herbicides,
and fungicides.3 In addition, several antibiotics such
as actinomycin, echinomycin, levomycin and triostins
bear quinoxaline nucleus.11 Quinoxaline moiety is also
part of bioactive natural products like Izumiphenazine-
C.12 Other applications of quinoxaline as fluorescent
dyes,13 electroluminescent materials,14 organic semi-
conductors,15 cavitands,16 DNA cleaving agents1 have
been reported. Because of such a widespread applica-
tions of quinoxaline compounds in medicinal as well
as industrial fields, it remains an attractive target for an
organic chemist to develop new synthetic methods for
the preparation of quinoxaline derivatives.
The most common methods for the synthesis of
quinoxaline is condensation of aromatic 1,2-diamines
with 1,2-dicarbonyl compounds in refluxing ethanol or
acetic acid for 2–12 h with 34–85% yields.17 Over the
years, various improved methods have been developed
using grinding,18 microwave,19 sonication,20 ball mill
A literature search revealed that boric acid cat-
alyzes many important organic transformations at a
temperature above 100◦C.55 57 Boric acid dehydrates
∗For correspondence

Krishna S Indalkar et al.
Scheme 1. Schematic representation of sulfated polyborate catalyzed quinoxaline synthesis.
above 100◦C and converts to its polymeric forms,
were accomplished by thin layer chromatography (TLC) on
Merck silica gel G F254 plates.
which presumably are the active species catalyzing
the reaction.58,59 Dehydrative polymerization liberates
water molecules which may hamper the progress of the
reactions. This inspired us to develop a polymeric boric
acid catalyst with mild Bronsted acidity. To accomplish
this, boric acid was dehydrated at 200◦C to convert it
into its polymeric Lewis acid form and then sulfonated
using chlorosulphonic acid to introduce the mild Bron-
sted acid character. Boron is an electron deficient
element and electron withdrawing effect of adjacent
sulfate enhances its Lewis acidity, hence, it has both
Lewis as well as Bronsted acid characters (Scheme 1).
The development of a novel methodology which
serves green chemistry purpose by maximizing effi-
ciency and minimizing waste is currently in demand.
To achieve these objectives, herein we report sulfated
2.2 Preparation of sulfated polyborate
Sulfated polyborate catalyst was prepared from boric acid as
reported in the literature.60
2.3 General procedure for the synthesis of quinoxaline
derivatives
To a mixture of substituted o-phenylenediamines derivative
(2.0 mmol) and 1,2-diketone / α-hydroxy ketone (2.0 mmol),
was added sulfated polyborate (10 wt%). The reaction mix-
ture was stirred at 100◦C in an oil bath. The reaction was
monitored by thin layer chromatography (TLC). After com-
pletion of the reaction, the mixture was cooled to room
temperature and quenched by water. The resultant product
polyborate as a mild, efficient and eco-friendly catalyst was filtered/extracted with EtOAc to get the product. Crude
products were either recrystallized from ethanol or purified
by column chromatography using silica as the stationary
phase and EtOAc: pet. ether as mobile phase. The products
obtained were known compounds and were identified by
melting point and 1H and 13C NMR spectroscopy. The
spectral data were compared with the literature values.
The catalyst was prepared and characterized by var-
ious analytical techniques such as potentiometric analy-
sis, Fourier transform infrared spectroscopy (FTIR), X-ray
diffraction (XRD), and scanning electron microscopy (SEM)
energy dispersive X-ray spectroscopy (EDAX).60
for synthesis of quinoxalines under solvent-free condi-
tion with high yields and short duration of times. The
catalyst was prepared from readily available boric acid,
as economic and non-toxic starting material. This is
the first report on the use of sulfated polyborate for
the synthesis of quinoxalines (Scheme 1). The catalyst
is environmentally benign due to its mild acidity and
non-toxic nature.
2. Experimental
2.1 Materials and methods
3. Results and Discussion
Melting points of all the compounds were recorded by
Analab ThermoCal melting point apparatus in the open cap-
illary tube and are uncorrected. The FTIR spectra (KBr) were
recorded on Shimadzu FTIR Affinity-1 Fourier Transform
Infrared spectrophotometer. 1H NMR spectra were recorded
on MR400 Agilent Technology NMR spectrometer using
tetramethylsilane (TMS) as an internal standard and DMSO-
d6 or CDCl3 as a solvent. Chemicals and solvents used were
of LR grade and purchased from SD fine, Avra Synthesis and
Spectrochem and used without purification. The purity deter-
The acidity of the catalyst was determined by potentio-
metric titration in a mixture of water and glycerine (2:1)
against standard 0.1 N NaOH solution and the total con-
centration of H+ was found to be 19.5 mmol/g which is
due to both SO3H as well as associated B–O–H.
FTIR spectrum of the catalyst showed the presence
of a band at 3221 cm−1 corresponding to O–H stretch-
ing of B–O–H and at 1469 cm−1 for B–O stretching, and
bands at 1294 cm−1 for O = S = O asym. stretching,
mination of the starting materials and reaction monitoring 1068 cm−1 for sym. stretching, 1004 cm−1 for S = O

Sulfated polyborate catalyzed quinoxaline synthesis
stretching of the SO3H group. Powder XRD pattern (Scheme 2). The effect of the catalyst loading on
showed significant peaks positioned at 2θ = 28.1◦ time and yields of the reaction was assessed (Table 1,
which confirms the presence of B–O bonds in the crys- entries 2–6). In the absence of the catalyst, the reaction
tal structure of the catalyst. EDAX shows boron: oxy- proceeded at 100◦C but it required longer time with
gen: sulfur signal ratio of 30.32: 68.73: 0.96 wt% over poor yield (Table 1, entry 1), while increased catalyst
different areas.
loading resulted in an increased product yield with sig-
Recently, we have reported the efficiency of sulfated nificant reduction in reaction time. (Table 1, entries 2–
polyborate as a catalyst for one-pot multicomponent 5). The catalyst loading beyond 10 wt% was not advan-
synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones tageous (Table 1, entries 6). Hence, a 10 wt% catalyst
via Biginelli60 reaction and synthesis of α-aminophos- loading was optimum for further study.
phinates via Kabachnik-Fields reaction61 both under
Temperature played a significant role in the synthe-
solvent-free conditions. Its ease of preparation, high sis of quinoxaline (Table 1, entries 5, 7 and 8). The
stability, mild acidity, and reusability prompted us for temperature effect was observed at ambient, 70◦C and
exploration of its potential to catalyze other useful 100◦C in presence of sulfated polyborate as a catalyst.
reaction transformations.
The reaction proceeded at 70◦C but took longer reaction
In continuation of the development of greener, eco- time with a lower yield (Table 1, entry 7). The reac-
friendly catalysts for the synthesis of various hetero- tion did not proceed at room temperature (Table 1, entry
cycles, herein, we report sulfated polyborate used as 8), while it proceeded at 100◦C with increased prod-
a catalyst for synthesis of quinoxalines from aromatic uct yield in a shorter reaction time (Table 1, entry 5).
1,2-diamines and 1,2-diketone/α-hydroxy ketone with Therefore, 100◦C was chosen as optimum temperature
good to excellent yields (Scheme 2).
for the reaction. The effect of different solvents on yield
Initially, we designed our study to investigate the and time of the reaction was assessed (Table 1, entries
suitability of sulfated polyborate as a catalyst at different 9–14). None of the solvents presented an advantage
reaction conditions for synthesis of the quinoxaline deri- over solvent-free condition. Therefore, the solvent-free
vatives. An equimolar mixture of o-phenylenediamines, condition was regarded as the best for the cost and
a representative substrate and benzil were used ecological benefits.
Scheme 2. Synthesis of quinoxaline from o-phenylenediamines and benzil.
Table 1. Catalyst loading, temperature and solvent optimization study.
Catalyst
(wt%)
Temperature
(◦C)
Yielda
(%)
Entry
Solvent
Time (min)
1.
2.
3.
4.
5.
6.
7.
8.
0
2.5
5.0
7.5
10.0
15.0
10
10
10
10
10
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
solvent-free
water
ACN
THF
Ethanol
Toluene
100
100
100
100
100
100
70
RT
Reflux
Reflux
Reflux
Reflux
Reflux
100
320
60
30
10
5
52
84
90
96
99
99
50
NRb
95
91
85
89
93
94
5
60
60
60
60
60
60
60
60
9.
10.
11.
12.
13.
14.
10
10
10
DMSO
aIsolated yield, bNo reaction.

Krishna S Indalkar et al.
Table 2. Efficiency of sulfated polyborate in comparison with polyborate and boric
acid.
Entry
Catalyst
Conditions
Time (min)
Yielda (%)
1.
2.
3.
Sulfated polyborate
Polyborate
solvent-free/100◦C
solvent-free/100◦C
solvent-free/100◦C
5
30
40
99
97
96
Boric acid
aIsolated yield.
Table 3. Substrate scope for quinoxaline synthesis.
Melting point (◦C)
Entry 1,2-Diamine (R) Diketone (R1) Time (min) Yielda (%) Obtained
Literature
1.
2.
3.
4.
5.
6.
7.
8.
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
H
5
5
5
7
5
10
3
3
3
3
3
7
3
3
3
3
3
5
99
98
97
97
96
95
99
98
98
97
96
96
99
98
98
97
97
96
126–128
113–115
118–120
80–82
122–124
187–189
111–113
93–95
74–76
liquid
94–96
132–134
31–33
128–12952
112–11452
120–12162
8363
6-CH3
5-CH3
6-C4H9
6-Cl
6-NO2
H
6-CH3
5-CH3
6-C4H9
6-Cl
6-NO2
H
124–12662
188–19052
109–11062
94–9562
76–7762
NAb
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
92–9362
130–13264
29–3067
liquid67
18–2068
NAb
6-CH3
5-CH3
6-C4H9
6-Cl
H
H
H
H
liquid
liquid
liquid
64–66
63–6465
17466
6-NO2
H
172–173
aIsolated yields, bNot Available in literature.
Herein, the comparison of sulfated polyborate with the substrates and reaction yields of products were
polyborate and boric acid is shown in Table 2, which highly dependent on the substituent. It was observed
revealed that sulfated polyborate showed advantages that o-phenylenediamines with either electron donating
over its precursors with respect to time and yields groups or electron withdrawing groups gave the corre-
(Table 2).
sponding products in good to excellent yields. The dif-
To study the scope and generality of the present pro- ferences in the yields were very small but substrates
tocol, the optimized reaction conditions were applied having electron-withdrawing groups gave lower yields
for the synthesis of a variety of quinoxaline deriva- in increased reaction times compared to substrates hav-
tives from substituted o-phenylenediamines and 1,2- ing electron-donating groups (Table 3, entries 1–18).
diketones in the presence of a sulfated polyborate On the other hand, structurally diverse 1,2-diketone had
catalyst (Table 3, entries 1–18, Table 4, entries 1– no significant effect on the yields and the reaction times.
6). All the substrates gave excellent yields in short
The optimized protocol was also applied to the reac-
reaction times. All reactions proceeded very cleanly tion of α-hydroxy ketone, benzoin with substituted o-
and no undesirable side reactions were observed, phenylenediamines for the synthesis of quinoxalines
while the reaction time for a 100% conversion of derivatives. The reaction gave lower yield with longer

Sulfated polyborate catalyzed quinoxaline synthesis
Table 4. Quinoxaline synthesis using benzoin under solvent-free condition.
Time
(min)
Melting point (◦C)
Entry
1,2-Diamine (R)
Yielda (%)
Obtained
Literature
1.
2.
3.
4.
5.
6.
H
20
20
20
20
20
30
96
95
93
94
92
89
126–128
113–115
118–120
80–82
122–124
187–189
128–12952
112–11452
120–12162
8363
6-CH3
5-CH3
6-C4H9
6-Cl
124–12652
188–19052
6-NO2
aIsolated yields.
catalyst and environment-friendliness are the key fea-
tures of the present protocol. Moreover, this method has
the ability to tolerate a wide variety of substituents.
Supplementary Information (SI)
Full experimental details, 1H and 13C NMR spectra of com-
pounds are available in Supplementary Information at www.
ias.ac.in/chemsci.
Acknowledgements
The authors are grateful to University Grants Commission
(UGC), New Delhi, India for their financial support.
Figure 1. Reusability of the catalyst.
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