Sulfuric acid-modified poly(ethylene glycol): An efficient, biodegradable, and reusable polymeric catalyst for synthesis of spiro oxindole derivatives in aqueous medium

Article abstract of DOI:10.1007/s11164-014-1627-4

A versatile, novel, and environmentally benign strategy has been successfully developed for synthesis of oxindoles, an important class of potentially bioactive compounds. Sulfonated poly(ethylene glycol) was used as inexpensive and recyclable acidic catal

Full text of DOI:10.1007/s11164-014-1627-4

Res Chem Intermed
DOI 10.1007/s11164-014-1627-4
Sulfuric acid-modified poly(ethylene glycol):
an efficient, biodegradable, and reusable polymeric
catalyst for synthesis of spiro oxindole derivatives
in aqueous medium
M. A. Nasseri B. Zakerinasab
•
Received: 25 January 2014 / Accepted: 18 March 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A versatile, novel, and environmentally benign strategy has been suc-
cessfully developed for synthesis of oxindoles, an important class of potentially
bioactive compounds. Sulfonated poly(ethylene glycol) was used as inexpensive
and recyclable acidic catalyst. The products were obtained in water, an excellent
solvent in terms of environmental impact, in high yield, by one-pot reaction of
malononitrile, 1,3-dicarbonylcoumarin or 4-hydroxycoumarin derivatives, and isa-
tins. This new method totally avoids the use of organic acids and toxic or expensive
solvents.
Keywords PEG-OSO H ꢀ Spirooxindole ꢀ Indoline ꢀ 4-Hydroxycoumarin ꢀ
3
Isatins
Introduction
Recent use of solid acidic catalysts as safer alternatives to mineral acids has
important advantages in organic synthesis, for example operational simplicity,
environmental compatibility, lack of toxicity, reusability, low cost, and ease of
isolation [1, 2]. Recently, soluble polymeric supports have been envisaged as
possible alternatives to their insoluble counterparts for catalyst immobilization,
Because they would secure higher chemical and stereochemical efficiency than
insoluble polymers. Poly(ethylene glycols) (PEGs) are highly favorable soluble
polymeric matrixes, and PEGs with molecular weight [2,000 Da have extensively
been used as inexpensive and easily functionalized supports for immobilization of
catalysts. PEGs are readily soluble in water and polar organic solvents (e.g.,
M. A. Nasseri (&) ꢀ B. Zakerinasab
Department of Chemistry, College of Sciences, University of Birjand, 97175-615 Birjand,
Islamic Republic of Iran
e-mail: manaseri@birjand.ac.ir
123

M. A. Nasseri, B. Zakerinasab
dichloromethane, acetonitrile, DMF, DMSO) and insoluble in less polar solvents
(
e.g., n-hexane, diethyl ether, tert-butyl methyl ether). Because of this solubility
profile, PEG-based supports combine high reactivity and analytical simplicity
advantageous features of homogeneous solution chemistry) with ready isolation
(
and purification of products (advantageous features of solid-phase methods).
Poly(ethylene glycol)-bound sulfonic acid (PEG-OSO H) is an interesting example
3
of PEG-supported catalysts that has emerged as an efficient Brønsted acid for
promotion of a variety of organic transformation, for example the synthesis of 3,4-
dihydro pyrimidones [3], quinolines [4, 5], a-amino phosphonates [6], b-amino
carbonyls [7], and acetamido carbonyls [8].
The indoline and oxindole structures are important components of a large number
of natural products and medicinal agents with good biological activity [9–18].
Oxindoles are known to have antibacterial, antiprotozoal, and anti-inflammatory
activity and are also patented as PR (progesterone receptor) agonists [19, 20].
Among oxygen-containing heterocycles fused to the spirooxindole ring system,
chromenes are of particular utility, because they are ‘‘privileged medicinal
scaffolds’’—molecular frameworks serving for the generation of ligands for
functionally and structurally discreet biological receptors. Functionally substituted
4
H-chromenes have attracted much attention because of their wide range of useful
biological properties, which include spasmolytic, diuretic, anticoagulant, anticancer,
and antianaphylactic activity [21, 22].
Organic solvents, which are used in huge amounts for many different
applications, have a negative impact on health and the environment. An important
aspect of green chemistry is elimination of solvents from chemical processes or
replacement of hazardous solvents with environmentally benign solvents. Water has
emerged as a useful alternative solvent for several organic reactions, owing to its
many advantages, for example safety and economy, and because it is environmen-
tally benign. Sometimes it results in greater reactivity and selectivity than
conventional organic solvents because of its strong hydrogen-bonding property
[
23, 24].
Because of the pharmacological properties of oxindoles, development of
synthetic methods enabling easy access to these compounds are desirable. In this
paper, we report the synthesis of spiro cyclic (5,6,7,8-tetrahydro-4H-chromene)-
0
4
,3 -oxindole and tetrahydro [pyrano [3,2-c]quinoline]-4,3-indoline derivatives by
coupling of malononitrile, 1,3-dicarbonylcoumarin or 4-hydroxycoumarin deriva-
tives, and isatins in the presence of sulfonated poly(ethylene glycol) in aqueous
medium.
Experimental
Malononitrile, isatin, and 1,3-dicarbonylcoumarin and 4-hydroxycoumarin deriva-
tives were purchased from Merck company. The purity of these compounds was
determined by TLC on Polygram SILG/UV 254 silica gel plates. Melting points
were measured by use of an Electrothermal 9100 apparatus. IR spectra were
acquired on a Perkin Elmer 781 spectrometer, as KBr pellets, and are reported in
1
23

Sulfuric acid-modified poly(ethylene glycol)
13
-
1 1
cm . H NMR and C NMR spectra were acquired on a Bruker DPX-250 Avance
instrument at 250 MHz and 62.9 MHz in CDCl or DMSO-d ; chemical shifts are
given in ppm relative to TMS as internal standard.
3
6
Preparation of PEG-OSO H
3
Chlorosulfonic acid (1.16 g, 10 mmol) was added to a solution of PEG-6000 (6.0 g,
mmol) in CH Cl (10 mL) at 0 °C. The resulting solution was stirred at room
1
2
2
temperature overnight, then the solution was concentrated under vacuum. Diethyl
ether (10 mL) was added to the concentrated solution, and the precipitate formed
was isolated by filtration and washed with ether (3 9 30 mL) to afford PEG-
OSO H [3].
3
General procedure for preparation of oxindole derivatives
A mixture of malononitrile (1 mmol), isatin (1 mmol), dicarbonyl (1 mmol), PEG-
OSO H (0.1 mmol), and water (2 mL) was stirred under reflux for the appropriate
3
time (shown in Tables 3, 4). After completion of the reaction, the reaction mixture
was filtered and the residue was washed with ethanol. The crude solid product was
recrystallized from EtOH to afforded the pure products in high purity and yield.
1
13
Assignment of the structures of the products was based on their H NMR, C NMR,
and IR spectra.
Selected spectral data
0
0
2
-Amino-2 ,5-dioxo-5,6,7,8-tetrahydrospiro-[chromene-4,3 -indoline]-3-carbonitrile
Table 3, Compound 1)
(
1
White solid, mp[250 °C. H NMR (250 MHz, DMSO-d ) 1.91 (2H, m, CH ), 2.10
6
2
(
ArH), 7.10 (d, 1H, J 7.4 Hz, ArH), 7.22 (t, 1H, J 7.4 Hz, ArH), 7.35 (s, 2H, NH ),
2H, m, CH ), 2.62 (2H, m, CH ), 6.68 (d, 1H, J 7.4 Hz, ArH), 6.88 (t, 1H, J 7.4 Hz,
2 2
2
1
0.65 (s, 1H, NH). C NMR (62.9 MHz, DMSO-d ) 195.1, 178.2, 166.1, 158.7,
3
1
1
6
42.0, 134.6, 128.5, 123.3, 121.8, 117.4, 111.9, 109.2, 57.6, 46.9, 36.4, 26.8, 19.8.
1
IR (KBr, cm ) 3352, 3296, 3176, 2952, 2204, 1712, 1656, 1352, 1216, 1076. Anal.
Calcd for C H N O : C, 66.44; H, 4.26; N, 13.67 %. Found: C, 66.38; H, 4.32; N,
-
1
7 13 3 3
1
3.74 %.
0
0
2
-Amino-7,7-dimethyl-2 ,5-dioxo-5,6,7,8-tetrahydrospiro [chromene-4,3 -indoline]-
-carbonitrile (Table 3, Compound 6)
3
1
White solid, mp [250 °C. H NMR (250 MHz, DMSO-d ) 1.00 (3H, s, CH ), 1.1
6
3
(
ArH), 6.88 (t, 1H, J 7.4 Hz, ArH), 7.10 (d, 1H, J 7.4 Hz, ArH), 7.22 (t, 1H,
3H, s, CH ), 2.08–2.19 (2H, m, CH ), 2.56 (2H, m, CH ), 6.70 (d, 1H, J 7.4 Hz,
3 2 2
1
J 7.4 Hz, ArH), 7.35 (s, 2H, NH ), 10.65 (s, 1H, NH) . C NMR (62.9 MHz,
3
2
DMSO-d ) 195.3, 178.5, 166.58, 159.20, 152.4, 142.48, 134.83, 128.59, 123.4,
6
1
22.16, 117.76, 111.22, 109.7, 57.96, 50.45, 47.23, 32.35, 28.01, 27.1. IR (KBr,
123

M. A. Nasseri, B. Zakerinasab
-
1
-1
cm ): 3376, 3312, 3144, 2928, 2196, 1724, 1656, 1348, 1224, 1056 cm . Anal.
Calcd for C H N O : C, 68.05; H, 5.11; N, 12.53 %. Found: C, 67.94; H, 5.15; N,
1
9 17 3 3
1
2.64 %.
0 0
-Amino-2 ,5-dioxo-5,6-dihydro-spiro[pyrano[3,2-c]quinoline-4,3 -indoline]-3-
carbonitrile (Table 4, Compound 1)
2
White solid, mp[250 °C. 1H NMR (250 MHz, DMSO-d ): 6.83 (1H, d, J 7.6 Hz,
6
ArH), 6.92 (1H, t, J 7.6 Hz, ArH), 7.17 (1H, d, J 7.2 Hz, ArH), 7.32 (1H, d,
J 7.6 Hz, ArH), 7.44 (1H, t, J 7.6 Hz, ArH), 7.48 (1H, t, J 8.2 Hz, ArH), 7.52 (1H,
d, J 8.4 Hz, ArH), 7.53 (2H, s, NH ), 7.95 (1H, d, J 8.2 Hz, ArH), 10.65 (1H, s,
2
1
NH). C NMR (62.9 MHz, DMSO-d ) 177.4, 158.9, 155.7, 155.5, 152.4, 142.6,
3
6
1
1
34.1, 133.5, 129.38, 125.4, 124.5, 123.12, 122.52, 117.42, 117.09, 112.9, 109.9,
-
01.9, 70.2, 57.5. IR (KBr, cm ): 3415, 3241, 3260, 2218, 1719, 1679, 1623, 1581;
1
Anal. Calcd for C H N O : C, 67.23; H, 3.10; N, 11.76 %. Found: C, 67.35; H,
2
0 11 3 4
3
.12; N, 11.64 %.
Results and discussion
PEG-OSO H was prepared by anchoring chlorosulfonic acid on to poly(ethylene
3
glycol) by use of a simple and convenient procedure. This polymeric catalyst was
used as an efficient Brønsted acid catalyst for different organic functional group
transformations either as reagent or as catalyst under heterogeneous and homog-
enous conditions. Initially, we focused on the synthesis of oxindoles from isatins
and dicarbonyls. 1,3-Cyclohexadione (1), isatin (2), and malononitrile (3) were
selected as model substrates and reacted under different experimental conditions
(
Scheme 1).
In preliminary experiment, this reaction was performed in different solvents, with
PEG-OSO H (0.1 mmol) as a catalyst, under reflux conditions. The reaction
3
proceeded perfectly in polar solvents (Table 1, entries 1–6), but yields decreased
when the reaction was conducted in non-polar solvents (Table 1, entries 7–10). It
was very surprising that the model reaction proceeded in excellent yields (98 %) in
a short time (5 min) in aqueous medium (Table 1, entry 1). The reaction was
performed under solvent-free conditions and gave a low yield (Table 1, entry 11).
HN
O
O
O
O
CN
CN
O
CN
N
H
O
NH2
O
1
2
3
0 0
2-amino-2 ,5-dioxo-5,6,7,8-tetrahydrospiro-[chromene-4,3 -indoline]-3-
Scheme 1 Synthesis
carbonitrile
of
1
23

Sulfuric acid-modified poly(ethylene glycol)
Table 1 Effect of solvents on
Entry
a
Solvent
Time (min)
Yield (%)
the synthesis of oxindole
3
catalyzed by PEG-OSO H
1
2
3
4
5
6
7
8
9
1
1
H
2
O
5
10
10
20
45
40
45
60
60
60
60
98
93
91
89
80
78
62
60
54
46
35
EtOH
MeOH
EtOAc
DMSO
DMF
ClCH
2
2
CH Cl
THF
Reaction conditions: reagents
1 mmol), catalyst (0.1 mmol),
(
CHCl
3
solvent (2 mL) under reflux
conditions
0
1
CH
2
Cl
2
Solvent-free
a
Isolated yields
Table 2 One-pot three-
component synthesis of oxindole
in the presence of different
catalytic systems
a
Entry
Catalyst (mol%)
Yield (%)
1
2
3
4
5
6
7
8
9
SiO
Acidic Al
2 3
Basic Al O (10)
2
(10)
20
18
20
15
37
45
5
2
O
3
(10)
MgO (10)
CaO (10)
CdO (10)
NbCl
5
(10)
(10)
ZrCl
4
15
5
SnCl
2
ꢀ2H
2
O (10)
10
11
12
13
14
15
16
17
FeCl
3
(10)
5
PEG (1)
3
PEG (10)
PEG (20)
PEG (25)
PEG-OSO
PEG-OSO
PEG-OSO
PEG-OSO
PEG-OSO
None
8
15
25
98
38
78
99
99
15
3
3
3
3
3
H (10)
Reaction conditions: 1,3-
dicarbonyl compound (1 mmol),
isatin (1 mmol), malononitrile
H (1)
H (5)
(1 mmol), and H
2
O (2 mL)
18
H (20)
H (25)
stirred at 100 °C for 5 min
1
2
9
0
a
Isolated yields of pure
products
To optimize the reaction temperature, 1,3-cyclohexadione, isatin, and malono-
nitrile in the presence of 5 or 10 mol% PEG-OSO H in water were reacted at
3
different temperatures. Consequently, 10 mol% catalyst at 100 °C was selected as
the best conditions for synthesis of oxindole. With decreasing temperature, the
solubility of isatin and the catalyst decreased, therefore the rate of the reaction and
the yield of the product decreased.
123

M. A. Nasseri, B. Zakerinasab
Table 3 Preparation of oxindole derivatives
R2
N
O
O
R3
O
R1
R1
R3
O
CN
CN
CN
R1
R1
N
O
O
O
NH2
R2
a
Entry
Reactant
Dicarbonyl
Time (min)
Yield (%)
Isatin
R
1
R
2
R
3
1
2
3
4
5
6
7
8
9
H
H
H
5
5
98
95
89
89
91
90
93
91
93
93
88
88
76
78
83
86
88
90
85
88
H
H
5-NO
5-Br
5-Me
2
H
H
7
H
H
10
10
5
H
H
5-OMe
H
Me
Me
Me
Me
Me
H
H
H
5-NO
2
5
H
5-Br
5
H
5-Me
10
10
15
10
20
20
15
15
10
10
10
10
10
11
12
13
14
15
16
17
18
19
20
H
5-OMe
Et
5-NO
5-NO
H
2
Me
H
Et
2
PhCH
PhCH
PhCH
PhCH
H
2
2
2
2
Me
H
H
5-Br
5-Br
4-Me
4-Me
6-Me
6-Me
Me
H
Me
H
H
H
Me
H
Reaction conditions: dicarbonyl compound (1 mmol), isatin (1 mmol), malononitrile (1 mmol), catalyst
0.1 mmol), H
O (2 mL) at 100 °C
(
2
a
Isolated yields
To evaluate the catalytic activity of PEG-OSO H, the model reaction was
3
performed in water (2 mL) at 100 °C for 5 min in the presence of different
catalysts. The results are shown in Table 2, from which it is evident that PEG-
OSO H was the most effective catalyst in terms of yield of oxindole (98 %); with
3
other catalysts product yields were 3–45 % (Table 2, entries 1–14). To optimize the
reaction conditions, we also changed the amount of catalyst. Consequently, the
model condensation was best catalyzed by 0.1 mmol PEG-OSO H in water at
3
100 °C. Reaction with 5 mol% of catalyst required a longer reaction time and
reaction with 1 mol% catalyst was incomplete even after 3 h and only 50 % of the
1
23

Sulfuric acid-modified poly(ethylene glycol)
Table 4 Preparation of indoline derivatives
NH2
CN
OH
R2
O
O
O
0
CN
CN
O
N
R1
N
O
O
R1
O
R2
a
Entry
Reactant
Time (min)
Yield (%)
R
1
R
2
1
2
3
4
5
6
7
8
9
H
H
10
10
15
15
10
15
15
15
15
15
15
90
95
95
88
87
92
94
84
87
88
90
H
5-Br
5-NO
5-Me
H
H
2
H
Me
Et
5-NO
5-NO
H
2
2
Me
PhCH
PhCH
H
2
2
5-Br
4-Me
6-Me
1
1
0
1
H
Reaction conditions: 4-hydroxycoumarin (1.0 mmol), isatin (1.0 mmol), malononitrile (1.0 mmol), cat-
O (2 mL) at 100 °C
Isolated yields
alyst (0.1 mmol), H
a
2
product was obtained. Further increasing the amount of PEG-OSO H (20 mol%)
3
had no significant effect on product yield (Table 2, entries 15–19). Control
experiments indicated that in the absence of the catalyst, the reaction under the same
conditions gave the oxindole in rather low yield (15 %) (Table 2, entry 20).
To further investigate the scope and limitations of this procedure under the
optimized conditions (10 mol % catalyst in 2 mL H O at 100 °C), particularly with
2
regard to library construction, this reaction was evaluated using a variety of isatin
and 1,3-dicarbonyl compounds (Table 3). In all cases, the reaction proceeded
readily, affording the corresponding oxindoles in high to excellent yields (76–98 %)
in very short reaction times (5–20 min).
Reaction of dicarbonyl compounds with N-ethylisatin in the presence of
0 mol % PEG-OSO H proceeded well, giving the corresponding products in
3
1
excellent yields without formation by products (Table 3, entries 11, 12). Reaction of
dicarbonyls with N-benzylisatin required longer reaction times, however, and the
products were obtained in lower yields (Table 3, entries 13–16). Dimedone reacted
more quickly than 1,3-cyclohexadione analogues, possibly because of the presence
of electron-donating groups (Me).
These reactions also proceeded with 4-hydroxycoumarin (Table 4), but reaction
times were longer than for 1,3-diketones. This may be because 4-hydroxycoumarin
123

M. A. Nasseri, B. Zakerinasab
3
Table 5 Recyclability of PEG-OSO H as catalyst for synthesis of oxindoles
a
Entry
Cycle
Yield (%)
1
2
3
4
5
6
0
1
2
3
4
5
98
95
92
88
87
85
Reaction conditions: 1,3-cyclohexadione (1 mmol), isatin (1 mmol), malononitrile (1 mmol), and H
2
O
(
a
2 mL) stirred at 100 °C for 5 min
Isolated yield of the pure product
H
N
PEG-OSO3H
O
O
O
PEG-OSO3H
O
O
H
C
O
N
CN
H2C
N
NC
H
H
CN
H
O3SO-PEG
1
CN
2
H
3
O SO-PEG
H
N
HN
O
O
O
NH
C
NH2
CN
NC
O
CN
H
C
O
O
O
N
N
O
H
O
H
3
Scheme 2 Mechanism proposed for synthesis of spiro oxindoles in the presence of PEG-OSO H
is less active than dicarbonyl compounds. In all cases, the product obtained was
isolated by a simple filtration, washed with water, and purified by recrystallization
from ethanol. The applicability of the method was also studied for phenolic
compounds, for example phenol and resorcinol. We found that the reaction of
phenols with isatin in the presence of this catalyst was not a straightforward reaction
and after a prolonged reaction time (3 h) most of the starting materials remained
intact.
It is worth mentioning that the catalyst is recyclable and could be reused without
significant loss of activity. It could be recovered by filtration of the product,
evaporation of the solvent, and washing with diethyl ether. The recycled catalyst
could be used in another reaction. In the model reaction, yields from the first and
subsequent experiments were almost identical for 5 runs (Table 5).
1
23

Sulfuric acid-modified poly(ethylene glycol)
A reasonable pathway for the reaction of cyclohexadione, isatin, and malono-
nitrile conducted in the presence of PEG-OSO H is presented in Scheme 2. The first
3
step involves formation of activated isatin (1) followed by reaction of this with
malononitrile to generate compound 2. This subsequently undergoes elimination to
produce compound of Knoevenagel condensation. Intermediate undergoes addition
with cyclohexadione to afford the oxindole derivative. In this hypothesis, PEG-
OSO H might serve as a Brønsted-acid catalyst in several stages.
3
Conclusions
In summary, an efficient procedure with PEG-OSO H as green acidic catalyst in
3
water has been developed for preparation of spirocyclic(5,6,7,8-tetrahydro-4H-
0
chromene)-4,3 -oxindole and tetrahydro[pyrano[3,2-c]quinoline]-4,3-indoline deriv-
atives. The procedure has several advantages, including inexpensive and readily
available catalyst, mild reaction conditions, high yields of the products, and simple
experimental and isolation procedures. These make it a useful and an attractive
procedure for synthesis of oxindole and indoline derivatives.
Acknowledgments We gratefully acknowledge support of this work by the University of Birjand
research council.
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