Greener synthesis of spirooxindole in deep eutectic solvent

Article abstract of DOI:10.1016/j.molliq.2014.01.009

A simple and efficient synthesis of spirooxindole derivatives by one-pot, three-component reaction of isatins, malononitrile and different nucleophiles under catalyst-free condition in deep eutectic solvent is reported. A series of biological importance, spirooxindole derivatives were synthesized via a multicomponent reaction of isatin, or acenaphthoquinone, and malononitrile or cyanoacetic ester with 1,3-dicarbonyl compounds, naphtol and 4-hydroxycumarin in biodegradable choline chloride based deep eutectic solvent in good yields (50-95%). This green procedure has the advantages of higher yields, shorter reaction times, environmental friendliness, and easy work-up.

Full text of DOI:10.1016/j.molliq.2014.01.009

Journal of Molecular Liquids 194 (2014) 62–67
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Greener synthesis of spirooxindole in deep eutectic solvent
a,
b
c
Najmedin Azizi ⁎, Sahar Dezfooli , Mohammad Mahmoudi Hashemi
a
Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Young Researchers and Elites Club, Science and Research Branch, Islamic Azad University, Tehran, Iran
Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthesis of spirooxindole derivatives by one-pot, three-component reaction of isatins,
malononitrile and different nucleophiles under catalyst-free condition in deep eutectic solvent is reported. A
series of biological importance, spirooxindole derivatives were synthesized via a multicomponent reaction of
isatin, or acenaphthoquinone, and malononitrile or cyanoacetic ester with 1,3-dicarbonyl compounds, naphtol
and 4-hydroxycumarin in biodegradable choline chloride based deep eutectic solvent in good yields (50–95%).
This green procedure has the advantages of higher yields, shorter reaction times, environmental friendliness,
and easy work-up.
Received 30 October 2013
Received in revised form 4 January 2014
Accepted 12 January 2014
Available online 23 January 2014
Keywords:
Acenaphthoquinone
Cumarin
© 2014 Elsevier B.V. All rights reserved.
Green chemistry
Spirooxindole
Ionic liquid
Isatin
1
. Introduction
Volatile organic solvents are used daily in the chemical industry, in
of natural products such as phytochemicals either in alkaloids, lactones
or terpenoids [11]. Since the first report of spiran preparation by Bayer
in 1900 [12], there are a large number of classical and modern methods
for the synthesis and structural modification of the biologically active
spiro compounds [23-26]. Spiro-2-oxindole especially spiro fused to
other cyclic structures (Fig. 1) is subject of tremendous interest in syn-
thetic organic chemistry and medicinal chemistry due to its fascinating
medicinal properties such as anti-HIV [13], anticancer [14], antitubercu-
lar [15], antimalarial [16], progesterone receptor modulator [17] and
MDM2 inhibitor [18]. Architecture of spiro compounds due to their
steric strain has been a challenge for synthetic organic chemists
and recently several attempts have also been made for the formation
of spirooxindoles via one pot multicomponent in literature. Although
all reports have their own merits, continuing researches to find
green and economical methods under catalyst free condition seem
necessary.
large quantities as reaction media that contribute to the major source
of environmental pollution. Substitution of hazardous volatile solvents
with ones that show better environmental, health and safety properties,
such as increased biodegradability is a necessity in all industry. In syn-
thetic chemistry ecological pollution can be produced via side products
or unreacted starting materials and reaction media such as solvents and
catalysts. Thus development of green methodologies with high yields is
pioneer and in this context, ionic liquid (IL) has attracted much atten-
tion and utilized in many organic reactions. But despite all valuable
properties of ionic liquids [1–3], such as low vapor pressure, exceptional
chemical and thermal stability and recyclability, they are not as green as
expected [4]. At the beginning of this century a new generation of
solvents named deep eutectic solvent [5] was introduced by Abbott
group. DES has many advantages than IL such as simple preparation,
low price, chemical inertness with water, high atom economy, passing
purification problems and waste disposal encountered with common
ILs while their physico-chemical properties are very close [6]. So far
many organic reactions have performed in choline chloride based DES
2. Experimental section
2.1. Materials and methods
[
7–10]. In all reports short reaction time and easy isolation process
All starting materials and DES components were commercially avail-
able and purchased from Merck. Melting points were determined on
Buchi 535 and were uncorrected. IR spectra were recorded on nexus
make DES worthy to be considered as solvent and catalyst in other valu-
able organic reactions.
Spirooxindoles scaffold due to their quaternary carbon center
known as biological active compounds and are present in a wide variety
8
70 FTIR spectrometer (thermo Nicolet Madison WI). NMR spectra
were recorded on Brucker 400 and 500 MHz spectrometer using
DMSO as solvent and TMS as internal standard. All the reactions were
monitored with thin layer chromatography (TLC) and UV light as de-
tecting agent.
⁎
Corresponding author at: Chemistry & Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran.
0167-7322/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molliq.2014.01.009

N. Azizi et al. / Journal of Molecular Liquids 194 (2014) 62–67
63
O
Cl
F
NH O
NH
Et
N
Cl
H
O
N
Cl
H
Cl
MDM2-P53 interaction inhibitor
Antimalarial
O
O
S
N
F
O N
2
O
F
NC
N
N
O
N
H
F
Progesterone receptor agonist
M. tuberculosis inhibitor
Fig. 1. Selected biologically active compounds containing spiro-2-oxindole moiety.
1
2
.2. Deep eutectic solvent preparation
H NMR (500 MHz, DMSO-d
6
): δ H (ppm) 1.01 (s, 3H, CH
3
), 1.04
2
4
(
s, 3H, CH
3
), 2.16 (m, 2H, CH
2
2
), 2.57 (d, J = 15 Hz, 2H, CH ), 6.79 (d,
According to literature [19] 100 mmol choline chloride and the
second component were mixed according to Table 1, in a round flask
J = 10 Hz, 1H, ArH), 6.89 (t, J = 10 Hz, 1H, ArH), 6.98 (d, J = 5 Hz, 1H,
ArH), 7.16 (t, J = 10 Hz, 1H, ArH), 7.18 (brs, 2H, NH ), 10.36 (s, 1H, NH).
2
and were heated to obtain a clear liquid as DES called urea:ChCl (Fig. 2).
2-Amino-5-oxo-7,7-dimethyl-spiro [(4H)-5,6,7,8-tetrahydro-
chromene-4,30-(30H)-indol]-(10H)-20-one-3-carbonitrile (4b):
1
2
.3. General procedure for spiro-2-oxindole preparation
white powder, H NMR (400 MHz, DMSO-d
(
6
): 1.01 (s, 3H, CH
3
), 1.04
),
6.81 (d, J = 8 Hz, 1H, ArH), 6.90 (t, J = 8 Hz, 1H, ArH), 7.00
3 2
s, 3H, CH ), 2.16 (q, J = 16 Hz, 2H, CH), 2.57 (d, J = 4Hz, 2H, CH
In the test tube (0.5 mmol) isatin or acenaphthoquinone with 0.5
mmol active methylene and 0.5 mmol 1,3-dicarbonyl compounds/4H
cumarin/α naphtol and 0.5 mL urea:ChCl were added. The reaction
mixture was stirred and heated to 80 °C. The reaction completion was
monitored by TLC. After reaction completion about 5 mL water was
added to reaction mixture in the cases that the solid was obtained and
the solid was filtered, and in the cases that a viscose liquid was obtained
after water addition the ethyl acetate was added to extract the product
and the organic layer was removed under vacuum. The products were
recrystallized from ethanol to give pure corresponding compounds.
(d, J = 8 Hz, 1H, ArH), 7.15 (t, J = 8 Hz, 1H, ArH), 7.24 (s, 2H, NH
10.41 (s, 1H, NH).
2
),
2-Amino-2′-oxospiro[benzo[g]chromene-4,3′-indoline]-3-
1
6 2
carbonitrile (4h): H NMR (DMSO-d , 400 MHz): 5.42 (brs, 2H, NH ),
6.58 (d, J = 8Hz, 1H, ArH), 7.02 (t, J = 8Hz, 2H, ArH), 7.11 (d, J = 8Hz,
1H, ArH), 7.31 (t, J = 8Hz, 1H, ArH), 7.47 (s, 1H, ArH), 7.61 (m, 2H, ArH),
7.70 (t, J = 8Hz, 1H, ArH), 7.92 (d, J = 8Hz, 1H, ArH), 8.30 (d, J = 8Hz,
1H, ArH), 10.71 (s, 1H, NH).
Ethyl 2-amino-2,5-dioxo-5-H-spiro [indoline-3,4-pyrano [3,2-c]-
1
chromene]-3-carboxylate (4g): H NMR (400 MHz, DMSO-d6): δ
2
.3.1. Selected data
-Amino-7,7-dimethyl-2,5-dioxo-5,6,7,8-tetrahydrospiro
chromene-4,3-indoline]-3-carbonitrile (4a): pale yellow solid,
3 2
H (ppm) 0.84 (t, J = 8Hz, 3H, CH ), 3.76–3.79 (m, 2H, CH O),
6.77 (d, J = 8Hz, 1H, ArH), 6.81 (t, J = 8Hz, 1H, ArH), 7.04 (d, J = 8Hz,
1H, ArH), 7.13 (t, J = 8Hz, 1H, ArH), 7.47 (d, J = 8Hz, 1H, ArH), 7.53
2
[
Table 1
Comparing different DESs in optimizing the reaction.
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
Urea:ChCl (2:1)
Glycerin:ChCl (2:1)
95 (95, 88, 80)
45
30
35
20
0
2
LaCl3.6H O:ChCl (2:1)
Malonic acid:ChCl (1:1)
PTSA:ChCl (2:1)
Tartaric acid:ChCl (0.5:1)
a
NMR yields.

64
N. Azizi et al. / Journal of Molecular Liquids 194 (2014) 62–67
Fig. 2. Deep eutectic solvent preparation from urea and ChCl.
(
t, J = 8Hz, 1H, ArH), 7.75 (t, J = 8Hz, 1H, ArH), 8.05 (d, J = 8Hz, 1H,
), 10.44 (s, 1H, NH).
Methyl 2-amino-2′-oxospiro[benzo[g]chromene-4,3′-indoline]-
-carboxylate (4i): (400 MHz, DMSO-d6): δ H (ppm) 0.78 (t, J = 8Hz,
H, CH ), 3.74–3.79 (m, 2H, CH O), 6.70 (d, J = 8Hz, 1H, ArH), 6.85
3 2
t, J = 8Hz, 1H, ArH), 6.91 (t, J = 8Hz, 2H, ArH), 7.18 (t, J = 8Hz,
H, ArH), 7.54 (d, J = 8Hz, 1H, ArH), 7.60 (t, J = 8Hz, 1H, ArH),
.62 (t, J = 8Hz, 1H, ArH), 7.88 (d, J = 8Hz, 1H, ArH), 8.33 (d, J = 8Hz,
H, ArH), 10.53 (s, 1H, NH).
To optimize the reaction conditions, the three-component reaction
between isatin (0.5 mmol), malononitrile (0.5 mmol) and dimedone
(0.5 mmol) in urea–choline chloride was selected as the model reaction
to optimize reaction condition. The results have been shown in Table 1.
After carefully examining the effect of temperature of reaction, we
obtained an excellent result in the absence of any catalyst for the
model reaction in urea–choline chloride (0.5 mL) at 80 °C (entry 1,
Table 2). Next, the reactions were repeated with different DESs under
optimized temperature and only urea–choline chloride was found to
be the most effective reaction media and catalyst affording 95% yield
(Table 1). Other DESs were less effective and gave 60%, 38%, and 76%
yields, respectively. In the cases of PTSA:ChCl and malonic acid:ChCl
probably the DES components participate in the reaction but in the
tartaric acid:ChCl the high viscosity plays the most important role in de-
creasing the yield which leads to prohibition of the sufficient reaction
contacts between the starting materials.
ArH), 8.15 (br s, 2H, NH
2
3
3
(
1
7
1
Ethyl 2-amino-7, 7-dimethyl-2,5-dioxo-5, 6, 7, 8-tetrahydro-2H-
spiro [acenaphthylene-1,4-chromene]-3-carboxylate (4k): (400 MHz,
DMSO-d6): δ H (ppm) 0.44 (s, 3H, CH ), 1.40 (s,3H, CH ), 1.50 (s, 3H,
CH ), 2.55 (q, J = 16Hz, 2H, CH ), 3.09 (t, J = 16 Hz, 2H, CH ), 3.72–
.79 (m, 2H, CH ), 7.71 (d, J = 8Hz, 1H, ArH), 7.97–8.01 (m, 1H, ArH),
.17–8.27 (m, 3H, ArH), 8.40 (brs, 2H, NH ), 8.55–8.57 (m, 1H, ArH).
3
3
3
2
2
3
8
2
2
Encouraged by the remarkable results in hands and in order to study
the scope and limitations of the three-component reaction, a variety of
3
. Results and discussion
Due to our interest to develop multicomponent reaction in DESs as
1
,3-dicarbonyl compounds, malononitrile or cyanoacetic ester and
isatin were tested using these new and green reaction media. The results
summarized in Table 2 clearly demonstrate that DES is an excellent
catalyst and reaction media in terms of yields and time. Gratifyingly, it
was found that the one-pot reaction of isatin, and malononitrile, methyl
cyanoacetate or ethyl cyanoacetate with 1,3-dicarbonyl compounds such
as ethyl acetoacetate (2b), and dimedone (2c) to afford a variety of
green and efficient media and catalyst, [20–22] herein we wished to re-
port an efficient, simple, and green one pot, three component domino
reaction of isatin (1) or acenaphthoquinone, and malononitrile (2)
with active methylene compounds (3a–e) in urea–choline chloride
based deep eutectic solvent under catalyst free condition (Fig. 3).
H N
2
O
O
O
R
O
O
3
a-c
N
H
O
urea:ChCl (0.5 mL)
CN
O
o
N
H N
2
8
0 C
OH
H
R
O
1
a
2a-c
R
O
R:CN, CO Me, CO Et
2
2
O
O
O
1
1
1
a R': H
3
3
d
N
O
H
b R': Me
c R': Boc
OH
H N
2
O
R
e
N
H
O
Fig. 3. One pot, green synthesis of spiro-2-oxindole in DES.

N. Azizi et al. / Journal of Molecular Liquids 194 (2014) 62–67
65
Table 2
Synthesis of spiro-2-oxindole derivatives via three choline chloride based DES.
Entry
R
3
Product
4a
Time (h)
Yield (%)a
m.p
Found
291
Reported
1
2
3
Isatin
Isatin
Isatin
CN
1
2
2
95
80
72
288–28923
255–25624
256–25723
CO2Me
4b
282–285
258–264
CO
2
Et
4c
4
5
6
Isatin
Isatin
Isatin
CN
4d
4e
4f
1
3
4
98
77
65
N300
262
N30023
CO
2
Et
262–26323
284–28623
CN
294
7
8
9
Isatin
Isatin
Isatin
CO
2
Et
4g
4h
4i
4
2
4
60
95
82
248
252–25323
22225
CN
N300
CO
2
Et
285–288
22925
1
1
1
0
1
2
isatin
CN
4j
6
6
2
50
55
95
182–189
231–241
267–270
180–18325
261–26323
265–26626
Acenaphthoquinone
1-Methylindoline-2,3-dione
CO
2
Et
4k
4l
CN
1
1
3
4
1-Methylindoline-2,3-dione
CN
CN
4m
4n
2
3
60
65
275–278
N300
277–27826
N30026
Tert-butyl 2,3-dioxoindoline-1-carboxylate
15
Tert-butyl 2,3-dioxoindoline-1-carboxylate
CN
4o
3
62
N300
296–29726
a
NMR yields.
spirooxindole derivatives 4a–g in good yields (Table 2). However, the re-
action with ethyl cyanoacetate and acetoacetate offered a lower yield
than that with dimedone and malononitrile, which is probably due to
the lower reactivity of methyl acetoacetate and ethyl cyanoacetate.
On the basis of the above successful results to further expand the
scope of our protocol, we investigated one-pot reactions involving,
Apart from the mild and green conditions of the process and its good
results, the simplicity of product isolation and the possibility to recover
and recycle DES as catalyst and reaction medium offer a significant
advantage. Because DES is completely soluble in water and the
spirooxindole is less soluble in water, the products can be directly
separated by the addition of water and filtering after the reaction
was completed. The filtrate containing products can directly recrystal-
lize from ethanol to give analytically pure spirooxindole derivatives
with highly simple workup. In the cases that viscose liquid, ethyl acetate
was added to dissolve the product and participated insoluble DES and
the organic layer was evaporated via vacuum, and was recrystallized
from ethanol to afford pure products.
1
-hydroxynaphthalene and 2-hydroxynaphthalene or 4-hydroxy
coumarin (3d). Under the above optimized conditions, the one-pot
reactions proceeded smoothly and a variety of the desired spirooxindole
products were obtained in good yields albeit with long reaction time
(Table 2).
As a further application of this green protocol less reactive
acenaphthoquinone 5 was tested instead of isatin in one-pot reactions,
and provided moderated yields of desired products (Fig. 4).
The simple reusability is one of the important properties of this DES.
After the reaction was complete, water was added, and the mixture was

66
N. Azizi et al. / Journal of Molecular Liquids 194 (2014) 62–67
Fig. 4. One-pot, three component synthesis of spirochroman in DES.
filtered to isolate the product. The DES was recovered from the filtrate
by evaporating the water phase at 80 °C under vacuum. The recycled
DES was used directly with fresh substrates under identical conditions
without further purification. It was shown that the DES could be used
for three runs without noticeable drop in the product yield and its activity
isatin with hydrogen-bonding in the presence of urea with malononitrile
2 is proposed to give the Knoevenagel product (A) nucleophilic attack of
1,3-dicarbonyl compound to A and intramolecular cyclization to provide
the spiro compound.
(Table 1).
4. Conclusion
Although the detailed mechanism and the role of DES in the
present work have not been confirmed yet, the formation of com-
pound 5 could be explained by the reaction sequence in Fig. 5.
Weak acidic nature of choline chloride and hydrogen-bonding do-
nors of urea in DES is the main reason for the high catalytic activity
of the system. First, a Knoevenagel condensation reaction of activated
In summary, an efficient, simple one-pot synthesis of spiro-2-
oxindole via DES based choline chloride without the use of expensive
or sensitive catalyst and solvent is reported. The DES was found to
play a catalyst and reaction medium. The significant advantages offered
by this green protocol are the versatility of substrate, the experimentally
Fig. 5. Proposed mechanism for the synthesis of spiro-2-oxindole in urea:ChCl.

N. Azizi et al. / Journal of Molecular Liquids 194 (2014) 62–67
67
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7
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