Cufe 2O 4 nanoparticles: A magnetically retrievable catalyst for green synthesis of novel 2-(3-(Dicyanomethyl)-2-Oxoindolin-3- Ylthio)acetic acids

Article abstract of DOI:10.1080/10426507.2013.788004

A highly efficient and green method for the synthesis of new 2-(3-(dicyanomethyl)-2-oxoindolin-3-ylthio)acetic acids is described using magnetically recoverable and reusable CuFe₂O₄ nanoparticles. A wide variety of aryl isatylidene malononitrils underwent Micheal addition with thioacids to afford novel 2-(3-(dicyanomethyl)-2- oxoindolin-3-ylthio)acetic acids in good to excellent yields. The reaction protocol is operationally simple and mild. Moreover, water as solvent makes the reaction procedure eco-friendly and economically viable. All products were characterized by NMR and IR spectroscopies.

Full text of DOI:10.1080/10426507.2013.788004

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Phosphorus, Sulfur, and Silicon and the
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Cufe2O4 Nanoparticles: A Magnetically
Retrievable Catalyst for Green Synthesis
of Novel 2-(3-(Dicyanomethyl)-2-
Oxoindolin-3-Ylthio)Acetic Acids
Ghazaleh Imani Shakibaei a , Ramin Ghahremanzadeh b & Ayoob
Bazgir a
a Department of Chemistry , Shahid Beheshti University , General
Campus, Tehran , 1983963113 , Iran
b Nanobiotechnology Research Center, Avicenna Research Institute,
Academic Center for Education, Culture and Research (ACECR) ,
Tehran , Iran
Accepted author version posted online: 02 Aug 2013.Published
online: 06 Sep 2013.
To cite this article: Ghazaleh Imani Shakibaei , Ramin Ghahremanzadeh & Ayoob Bazgir (2013)
Cufe2O4 Nanoparticles: A Magnetically Retrievable Catalyst for Green Synthesis of Novel 2-(3-
(Dicyanomethyl)-2-Oxoindolin-3-Ylthio)Acetic Acids, Phosphorus, Sulfur, and Silicon and the Related
Elements, 188:10, 1305-1311, DOI: 10.1080/10426507.2013.788004
To link to this article: http://dx.doi.org/10.1080/10426507.2013.788004
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Phosphorus, Sulfur, and Silicon, 188:1305–1311, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.788004
CUFE2O4 NANOPARTICLES: A MAGNETICALLY
RETRIEVABLE CATALYST FOR GREEN SYNTHESIS OF
NOVEL 2-(3-(DICYANOMETHYL)-2-OXOINDOLIN-3-
YLTHIO)ACETIC ACIDS
Ghazaleh Imani Shakibaei,1 Ramin Ghahremanzadeh,2
and Ayoob Bazgir1
1Department of Chemistry, Shahid Beheshti University, General Campus, Tehran
1983963113, Iran
2Nanobiotechnology Research Center, Avicenna Research Institute, Academic
Center for Education, Culture and Research (ACECR), Tehran, Iran
GRAPHICAL ABSTRACT
Abstract A highly efficient and green method for the synthesis of new 2-(3-(dicyanomethyl)-
2-oxoindolin-3-ylthio)acetic acids is described using magnetically recoverable and reusable
CuFe2O4 nanoparticles. A wide variety of aryl isatylidene malononitrils underwent Micheal
addition with thioacids to afford novel 2-(3-(dicyanomethyl)-2-oxoindolin-3-ylthio)acetic acids
in good to excellent yields. The reaction protocol is operationally simple and mild. Moreover,
water as solvent makes the reaction procedure eco-friendly and economically viable. All
products were characterized by NMR and IR spectroscopies.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the following free supple-
mental files: Additional figures]
Keywords Michael addition; oxindole; green chemistry; copper ferrite nanoparticles; magnetic
separation
INTRODUCTION
Over the past two decades, due to the increasing environmental concerns, research
efforts have remarkably focused on green methodologies, which diminish the use of
Received 27 January 2013; accepted 10 March 2013.
We are thankful to the Iran National Science Foundation (INSF) for supporting this project numbered
90002975, Research Council of Shahid Beheshti University, and Avicenna Research Institute.
Address correspondence to Dr. Ramin Ghahremanzadeh, Avicenna Research Institute, Tehran, Iran, Islamic
Republic of Iran 1936773493. E-mail: r.ghahremanzadeh@yahoo.com; r.ghahremanzadeh@avicenna.ac.ir
1305

1306
G. IMANI SHAKIBAEI ET AL.
Figure 1 Structure of representative compounds containing the oxindole moiety.
hazardous substances and minimize generation of waste.1 In this regard, the use of be-
nign solvents, as well as effective and clean reusable catalysts, has a pivotal role.2 There is
a rapidly growing interest toward the replacement of traditional organic solvents by water,
because solvents are responsible for most of the waste generated in the chemical industries
and laboratories.3 Water has unique characteristics in terms of cost, availability, safety, and
environmental impact,4 which fit perfectly with the requirements of the Green Chemistry
principles.5 Furthermore, in some cases changing the reaction media to water can increase
the rate or change the selectivity of a given reaction.6 This can be attributed to strong
hydrogen bonding ability, hydrophobic effects, and high polarity of water.7
On the other hand, green catalysis is one of the key areas in Green Chemistry.
Although nanoparticle catalysts demonstrate numerous advantages over bulk catalysts,
their recovery from the reaction mixture is not possible via conventional techniques (such
as filtration) because of their nanosize. This limitation hampers the cost-efficiency and
sustainability of these nanocatalytic protocols. To overcome this problem, magnetically
active nanoparticles have appeared to be one logical solution.8 Owing to their insoluble and
paramagnetic nature, quantitative recovery of these catalysts will be easily achieved by the
use of an external magnet.9 This characteristic offers a promising option that can meet the
requirements for industrial applications.10
The Michael addition reaction is well known as one of the classic and fundamental
reactions in organic synthesis.11 This reaction, and its close variants, have been widely used
as a key step in many organic syntheses.12 Recently, our group13 along with others14 have
demonstrated that electron-deficient Isatylidene- malononitriles are readily available and
excellent Michael acceptors to construct a stereocenter at the 3-position of the oxindole
skeleton. The oxindole core is featured in many natural products as well as potential
pharmaceuticals.15 Incorporation of an asymmetric quaternary carbon into the 3-position
of oxindol accentuates its biological activity.16 This heterocyclic scaffold appears in many
pharmaceutically relevant compounds such as cardiovascular agents Indolidan 1,17 the
antiinflammatory Tenidap 2,18 and the anticancer drug Sunitinib 3.19(Figure 1).
RESULTS AND DISCUSSION
In view of our current studies on synthesis of novel oxindole dervaties,13,20 herein,
we wish to highlight our findings about the application of CuFe2O4, as an environmentally
friendly heterogeneous catalyst in Michael addition of 2-mercapto acetic acid to Isatyiliden

CUFE2O4 NANOPARTICLES: MAGNETICALLY RETRIEVABLE CATALYST
1307
Scheme 1
malononitriles (Scheme 1). To the best of our knowledge it is the first report for the synthesis
of dicyanomethyl-2-oxoindolin thioacids.
Our studies began with model reaction between 2-mercapto acetic acid 1a (1 mmol)
and isatylidenemalononitrile 2a (1 mmol) to furnish the Michael adduct (Table 1). Con-
sidering different variables affecting the reaction yield, we explored the effect of solvents,
Table 1 Optimization of reaction conditions
Entry
Catalyst
Solvent
T (◦C)
Catalyst loading (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MgO
TiO2
ZnO
Fe3O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
CuFe2O4
—
H2O
H2O
H2O
H2O
H2O
MeOH
EtOH
THF
CH2Cl2
H2O
H2O
H2O
H2O
H2O
90
90
90
90
90
50
70
50
50
r.t.
50
90
90
90
10
10
10
10
10
10
10
10
10
10
10
10
5
5
5
5
5
3
5
5
5
5
3
3
6
3
3
—
—
—
—
88
55
65
—
—
—
45
—
76
89
CuFe2O4
CuFe2O4
15
aIsolated yield.

1308
G. IMANI SHAKIBAEI ET AL.
temperatures, and different catalysts. The results have been summarized in Table 1. No sat-
isfactory result was obtained under a variety of catalytic conditions as indicated in Table 1
(Entries 1–4). The best result was obtained in the presence of catalytic amount of CuFe2O4
(30–40 nm) (Entry 5). We then repeated the reaction in different solvents such as MeOH,
THF, CH2Cl2, H2O, and EtOH in the presence of CuFe2O4 (Table 1, Entries 5–9). As far as
the solvent is concerned, H2O showed superiority over other solvents based on both reaction
time and product yield (Table 1, Entry 5). By varying the reaction temperature we found
out that only a trace amount of the desired product was obtained in lower temperatures
(Entries 10, 11, Table 1). In the absence of any catalyst, the reaction did not occur even
with prolonged reaction time (6 h, Entry 12).
In the next step, the effect of catalyst loading on the reaction was studied (Entries 5,
13, 14, Table 1). Higher catalyst loading neither shortened the reaction time, nor increased
the products yields obviously (Entry 14, Table 1). Thus, we chose 10 mol% amounts of
copper ferrite nanoparticles as the catalyst loading for this green protocol.
When this reaction was carried out with other thiol nucleophiles such as aromatic and
aliphatic thiols, TLC of the reaction mixture showed a combination of starting materials
and numerous products and the yield of the desired product was very poor.
To explore the scope and generality of the reaction, a range of dicyanomethyl-2-
oxoindolin thioacids were synthesized from a variety of substrates under the optimized
reaction condition. Pleasingly, all reactions gave excellent yields (63–90%, Table 2).
These results show that this method can be applied to both electron-donating and electron-
withdrawing Isatyiliden malononitriles, thus demonstrating the wide scope of this method-
ology.
The reusability of the inexpensive magnetically separable nano-copper ferrite catalyst
was examined (Table 3). After completion of the reaction, the catalyst was recovered by
with a magnet and washed with water. The catalyst was retrieved and reused for additional
cycles. There is no significant loss of yield even up to third run.
In conclusion we have developed copper ferrite nanoparticles as a nano catalyst for
the synthesis of novel 2-(3-(dicyanomethyl)-2-oxoindolin-3-ylthio)acetic acids which are
often encountered in biologically and pharmacologically active compounds. This protocol
avoids the use of expensive reagents and the reaction being performed in water and also
easy recyclability of the catalyst making it a green method.
EXPERIMENTAL
General
The chemicals used in this work were obtained from Fluka and Merck and were used
without purification. Melting points were measured on an Electrothermal 9200 apparatus.
IR spectra were recorded as KBr pellets on a Perkin-Elmer 781 spectrophotometer and
an Impact 400 Nicolet FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded
on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz, respectively.
1H and 13C NMR spectra were obtained on solutions in DMSO-d6 using tetramethylsilane
(TMS) as internal standard. The elemental analyses (C, H, N) were obtained from a Carlo
ERBA Model EA 1108 analyzer. XRD analysis was performed with an X-ray diffractometer
(PAnalytical X’Pert-Pro) using a Cu-Ka monochromatic radiation source and a Ni filter.
The purity determination of the substrates and reaction monitoring were accomplished by
TLC on silica-gel polygram SILG/UV 254 plates (from Merck Company).

CUFE2O4 NANOPARTICLES: MAGNETICALLY RETRIEVABLE CATALYST
1309
a
Table 2 Michael reaction of thioacids and various isatylidene malononitriles catalyzed by CuFe2O4
Entry
X
R1
R2
Yieldb
mp
a
b
c
d
e
f
g
h
i
H
Br
NO2
H
Me
H
H
Br
NO2
H
Me
H
H
H
H
H
H
H
H
H
Me
H
Bz
H
H
H
Me
H
Bz
88
85
90
79
76
68
63
70
89
68
71
67
267 (dec)
260 (dec)
260 (dec)
255–258
249–252
239 (dec)
245–248
262 (dec)
250 (dec)
232–235
237 (dec)
246 (dec)
H
Me
Me
Me
Me
Me
Me
j
k
l
aReaction conditions: Isatyiliden malononitriles (1 mmol), thioacid (1 mmol), CuFe2O4 (10 mol%) in H2O
(5 mL) at 90◦C.
bIsolated yield.
CuFe2O4 nanoparticles were prepared by co-precipitation of Cu(NO3)2 and Fe(NO3)3
in water in the presence of sodium hydroxide. Briefly, to a solution of Fe(NO3)3.9H2O
(0.05 mol) and Cu(NO3)2. 3H2O (0.025 mol) of distilled water (100 mL, NaOH (75 mL,
4 M) was added at room temperature over a period of 10 min to form reddish-black
precipitate. Then the reaction mixture was warmed to 90◦C and stirred. After 2 h, it
was cooled to room temperature and the formed magnetic particles were separated by a
magnetic separator. Then, the catalyst was washed with water and kept in air oven over night
at 80◦C. Then the catalyst was ground in a mortar-pestle and kept in a furnace at 800◦C
at a heating rate of (2◦C/min) and cooled to 100◦C at (5◦C/min) in air. The XRD patterns
of calcinated precipitate indicate that the powder is mainly composed of CuFe2O4 (Figure
Table 3 Recyclability of nano CuFe2O4 catalyst
Cycle
Product yield (%)
1
2
3
4
88
87
85
61

1310
G. IMANI SHAKIBAEI ET AL.
S1).21 Considering XRD pattern, the average diameter of nanoparticles was determined
30–40 nm.
Synthesis
As an example, the synthesis of 4a is described.22 Complete characterization infor-
1
mation for 4b–4l and some representative H and 13C NMR spectra are presented in the
Supplemental Materials (Figures S2–S5).
CONCLUSION
In conclusion we have developed copper ferrite nanoparticles as a nanocatalyst for
the synthesis of novel 2-(3-(dicyanomethyl)-2-oxoindolin-3-ylthio)acetic acids, which are
often encountered in biologically and pharmacologically active compounds. This protocol
avoids the use of expensive reagents and the reaction being performed in water and also
easy recyclability of the catalyst making it a green method.
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22. Typical procedure for the 2-(3-(dicyanomethyl)-2-oxoindolin-3-ylthio)acetic acids (4a): A mix-
ture of 2-(2-oxoindolin-3-ylidene) malononitrile (1 mmol, 0.195 g), 2-mercaptoacetic acid
(1 mmol, 0.070 mL), and CuFe2O4 (10 mol%, 0.024 g) in H2O (5 mL) was heated at 90◦C
for 3 h. After completion of the reaction (TLC), the catalyst was separated from mixture with the
aid of an external magnet and washed several times with water. Then the residue was filtered and
the precipitate washed with ether (2 × 5 mL) to afford pure product 4a. (253 g, 88%) as light pink
powder, mp 267◦C (dec); νmax (KBr) 3273, 3160, 2196, 1759, 1600 cm−1. 1H NMR (300 MHz,
DMSO-d6): δH 4.05–4.13 (2H, m, CH2), 4.81 (1H, s, CH), 6.85–7.27 (4H, m, H-Ar), 10.64 (1H,
s, NH), 12.15 (1H, s, COOH); 13C NMR (75 MHz, DMSO-d6): δC 34.0, 46.1, 77.6, 110.2, 117.7,
122.5, 125.1, 127.2, 129.3, 142.9, 157.9, 175.0, 175.7, Anal. Calcd. for C13H9N3O3S: C, 54.35;
H, 3.16; N, 14.63; Found: C, 54.40; H, 3.12; N, 14.68.