Ionic liquid immobilized on γ-Fe2O3 nanoparticles: A new magnetically recyclable heterogeneous catalyst for one-pot three-component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines

Article abstract of DOI:10.1016/j.apcata.2013.08.006

2-Hydroxyethylammonium sulphonate immobilized on γ-Fe ₂O₃ nanoparticles (γ-Fe₂O ₃-2-HEAS) was synthesized as a new supported ionic liquid by the reaction of n-butylsulfonated γ-Fe₂O₃ with ethanolamine. It was used as a magnetically recyclable heterogeneous catalyst for the efficient one-pot, three-component synthesis of 2-amino-3,5- dicarbonitrile-6-thio-pyridines. The catalyst was easily isolated from the reaction mixture by magnetic decantation using an external magnet and reused at least five times without significant degradation in the activity.

Full text of DOI:10.1016/j.apcata.2013.08.006

Accepted Manuscript
Title: Ionic liquid immobilized on ␥-Fe2O3 nanoparticles: A
new magnetically recyclable heterogeneous catalyst for
one-pot three-component synthesis of
2-amino-3,5-dicarbonitrile-6-thio-pyridines
Author: Sara Sobhani Moones Honarmand
PII:
S0926-860X(13)00490-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2013.08.006
APCATA 14387
To appear in:
Applied Catalysis A: General
Received date:
Revised date:
Accepted date:
11-6-2013
20-7-2013
7-8-2013
Please cite this article as: S. Sobhani, M. Honarmand, Ionic liquid immobilized on
␥-Fe2O3 nanoparticles: A new magnetically recyclable heterogeneous catalyst for one-
pot three-component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines, Applied
Catalysis A, General (2013), http://dx.doi.org/10.1016/j.apcata.2013.08.006
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Ionic liquid immobilized on γ-Fe2O3 nanoparticles: A new magnetically recyclable
heterogeneous catalyst for one-pot three-component synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines
Sara Sobhani,* Moones Honarmand
Department of Chemistry, College of Sciences, University of Birjand, Birjand 414, Iran
*Corresponding author. Tel. +98 (561) 2502065; Fax: +98 (561) 2502065
E-mail address: ssobhani@birjand.ac.ir, sobhanisara@yahoo.com
Abstract
2-Hydroxyethylammonium sulphonate immobilized on γ-Fe2O3 nanoparticles (γ-
Fe2O3-2-HEAS) was synthesized as a new supported ionic liquid by the reaction of n-
butylsulfonated γ-Fe2O3 with ethanolamine. It was used as a magnetically recyclable
heterogeneous catalyst for the efficient one-pot, three-component synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines. The catalyst was easily isolated from the reaction mixture by
magnetic decantation using an external magnet and reused at least five times without
significant degradation in the activity.
Keywords: Magnetic nanoparticles, Ionic liquids, Heterogeneous catalyst, 2-Amino-3,5-
dicarbonitrile-6-thio-pyridines, One-pot
Page 1 of 36

1. Introduction
Heterocycles containing 2-amino-3,5-dicarbonitrile-6-thio-pyridine ring system are
known as interesting compounds in the pharmaceutical industry due to their various
therapeutic applications [1,2]. One of the most significant existing methods for the
synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines involves one-pot three-component
condensation of aldehyde, malononitrile and thiol. Acidic and basic catalysts were
reported for the promotion of this condensation reaction [3-17]. The reaction has also been
carried out in the presence of microporous molecular sieves [18] and nanocatalysts such as
ZnO [19], CuI [20], MgO [21] and SiO2 [22]. Moreover, ionic liquids including [bmIm]Br
[23] and [bmIm]OH [24] were found as efficient catalysts for the synthesis of
polysubstituted pyridines. However, the reported protocols suffer from one or more of the
following drawbacks such as prolonged reaction time, formation of inevitable side
products, harsh reaction conditions, low yields, tedious workup, time consuming methods
for catalyst recovery, and use of expensive, unrecyclable and environmentally toxic
catalysts and solvents. Therefore, in order to overwhelm these shortcomings, it is preferable
to introduce a new procedure that applies a reusable non-hazardous catalyst for the efficient
synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines.
Ionic liquids (ILs) have emerged as promising homogeneous catalysts [25] because
of their unique physicochemical properties including negligible vapour pressure, wide
liquid range, high ionic conductivity and excellent solubility [26]. Although ILs possess
some advantages but their practical applications have been restricted by some difficulties in
its recovery which lead to economical and environmental problems. On the other hand,
their high viscosity not only limits their mass transfer during catalytic reactions but also
makes their handling difficult. Moreover, the use of relatively large amounts of ILs is costly
Page 2 of 36

and may cause toxicological concerns. These problems can be overcome by immobilization
of ILs onto solid supports to obtain heterogeneous catalysts [27-29].
Among different catalyst supports, in recent years, magnetic nanoparticles (MNPs)
have attracted increasing attention because of their facile separation from the reaction
mixture by using an external magnet [30-32]. Magnetic separation of MNPs is easy,
economical, and saves time and energy. Moreover, MNPs such as γ-Fe2O3 have a high
surface area, excellent thermal and chemical stability, surface modification ability, ease of
synthesis and low toxicity and cost [33-36]. These attractive features have made γ-Fe2O3 as
a promising support for ILs [37-39].
In our ongoing work on the development of efficient and environmentally benign
procedures using ILs [40-43], we have recently synthesized silica supported 2-
hydroxyethylammonium acetate and used it as a recyclable catalyst for the synthesis of
phosphonate derivatives [44]. However, despite the high catalytic activity of silica
supported IL, its application was limited due to the inevitable loss of the catalyst during
recovery via filtration. To benefit the unique properties of ILs and the valuable applications
of MNPs, herein, we report the synthesis of 2-hydroxyethylammonium sulphonate
immobilized on γ-Fe2O3 (γ-Fe2O3-2-HEAS) as a new supported IL (Scheme 1). It is worthy
to note that there is not any report on the supporting of 2-hydroxyethylammonium
sulphonate on MNPs.
Scheme 1
To explore the catalytic activity of this catalyst in organic reactions, we have used
γ-Fe2O3-2-HEAS as a magnetically recyclable heterogeneous catalyst for one-pot three-
component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines (Scheme 2). By using
Page 3 of 36

an external magnet, the supported IL is readily separated from the reaction mixture. This
kind of separation eliminates the need of filtration and facilitates recycling of the catalyst.
Scheme 2
2. Experimental
2.1. Large scale synthesis of γ-Fe2O3 NMPs
γ-Fe2O3 nanoparticles were synthesized by a reported chemical co-precipitation
technique of ferric and ferrous ions in alkali solution with minor modification [45-47]. In
this procedure FeCl2.4H2O (9.25 g) and FeCl3.6H2O (15.8 g) were dissolved in deionized
water (200 mL) under Ar atmosphere at room temperature. Then a solution of NH4OH
(25%, 100 mL) was added dropwise (drop rate = 1 mL min-1) to the stirring mixture to
reach the reaction pH of 11. The resulting black dispersion was continuously stirred for 1 h
at room temperature and then refluxed for another 1 h to yield a brown dispersion. The
MNPs were then purified by a repeated centrifugation (1730-3461 ×g, 20 min) and
decantation followed by 3 times redispersion. The as-synthesized sample was heated in air
°
°
at 2 C min-1 up to 200 C and then kept in the furnace for 3 h to give a reddish-brown
powder.
2.2. Synthesis of n-butylsulfonated γ-Fe2O3 (γ-Fe2O3-n-BS)
In order to enrich the hydroxyl group on γ-Fe2O3 MNPs, ammonium hydroxide (100
ml, 25%, v/v aqueous solution) was added to a sonicated mixture of γ-Fe2O3 MNPs (6.2 g)
in ethanol and water (400 ml, 1:1 by volume). The resulting mixture was stirred vigorously
°
at 60 C for 24 h. γ-Fe2O3 MNPs were then isolated by magnetic decantation and washed
with copious amounts of deionized water, ethanol, and n-hexane. The resulting solid (6 g)
was suspended in 600 mL of 0.1 M toluene solution of 1,4-butanesultone. This colloidal
solution was refluxed for 48 h. The modified γ-Fe2O3 were isolated and purified by
Page 4 of 36

repeated washing (first in CH3CN and then in water) and centrifugation. The n-
butylsulfonated γ-Fe2O3 (γ-Fe2O3-n-BS) was obtained as reddish-brown powder. By
elemental analysis and TGA, the loading amount of n-butylsulfonated on γ-Fe2O3 was
determined and it was 0.19 mmol g-1.
2.3. Synthesis of 2-hydroxyethylammonium sulphonate immobilized on γ-Fe2O3 (γ-Fe2O3-2-
HEAS)
A mixture of γ-Fe2O3-n-BS (5.8 g) in dry CH2Cl2 (100 mL) was sonicated for 30
min. Ethanolamine (0.07 g) was added to the dispersed γ-Fe2O3-n-BS in dry CH2Cl2 and
stirred at room temperature for 8 h. The resulting solid was separated by an external magnet
and washed 3 times with CH2Cl2, ethanol and H2O. After drying at room temperature in
vacuum, γ-Fe2O3-2-HEAS was obtained as reddish-brown powder.
2.4. General procedure for the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines in
the presence of γ-Fe2O3-2-HEAS
γ-Fe2O3-2-HEAS (0.08 g) was added to a stirred mixture of aldehyde (1 mmol),
malononitrile (2 mmol) and thiol (1 mmol). The reaction mixture was stirred at 50 ˚C for
the appropriate time (Table 2). The progress of the reaction was monitored by TLC. After
completion of the reaction, EtOAc (10 mL) was added to the cooled reaction mixture. The
catalyst was separated by an external magnet, washed with EtOAc, dried and re-used for a
consecutive run under the same reaction conditions. Evaporation of the solvent of the
filtrate under reduced pressure gave the crude products. Pure product was obtained by
recrystallization in aqueous EtOH.
3. Results and Discussion
3.1. Characterization of γ-Fe2O3-2-HEAS
Page 5 of 36

In the XRD pattern of the synthesized γ-Fe2O3 MNPs (Figure 1), diffraction patterns
had a good agreement with the cubic structure of maghemite (JCPDS file No 04-0755), a
unit cell dimension of 8.35 Å and the space group of P4132 (213). The average crystallite
size was calculated to be 13.1 nm using Scherrer equation in which K = 0.9 and λ = 0.154
nm.
Figure 1
The synthesized γ-Fe2O3-2-HEAS was fully characterized by TEM, FT-IR, TGA,
elemental analysis, N2 adsorption–desorption and VSM. The particle size distribution of γ-
Fe2O3-2-HEAS was evaluated using transmission electron microscopy (TEM) (Figure 2)
and showed that the mean diameter of MNPs is 14 nm (Figure 2b).
Figure 2
FT-IR spectra of γ-Fe2O3 and γ-Fe2O3-2-HEAS (Figure 3) showed broad bands
around 450-600 cm-1, which were attributed to Fe-O vibration [48]. FT-IR spectrum of γ-
Fe2O3-2-HEAS showed the typical bands at 2960, 2933 and 2866 cm-1 attributed to C-H
stretching vibrations of alkyl chains. Moreover, the broad peak at 1111 cm-1 belonged to
S=O stretching vibrations in the sulphonate functional groups. Bands at 1600, 1502 cm-1
were related to N-H bending vibrations in the ammonium groups. These results indicated
that IL was successfully immobilized on γ-Fe2O3 MNPs.
Figure 3
The thermal behaviour of γ-Fe2O3-2-HEAS was investigated by thermogravimetric
analysis (TGA) (Figure 4). As shown in Figure 4, the weight loss around 180 °C was related
to the loss of adsorbed water molecules. The organic parts were decomposed completely at
487 °C. According to the TGA, the amount of IL supported on γ-Fe2O3 was evaluated to be
0.15 mmol g-1. The loading amount of IL on γ-Fe2O3 was also quantified via elemental
Page 6 of 36

analysis and it was 0.15 mmol g-1 based on nitrogen and sulfur determination (0.21% and
0.48%, respectively).
Figure 4
N2 adsorption–desorption isotherms of γ-Fe2O3-2-HEAS (Figure 5) showed a type
IV curve (IUPAC classification) and revealed that the adsorption–desorption process was
not reversible [49,50]. This is a result of the hysteresis loops due to capillary condensation.
Using BET method, values of 91 m2 g−1 and 14.3 nm were found for surface area and mean
pore diameter of γ-Fe2O3, respectively. Reducing surface area to 67 m2 g−1 and increasing
mean pore diameter to 18.2 nm for γ-Fe2O3-2-HEAS confirmed the immobilization of IL on
the surface of γ-Fe2O3.
Figure 5
The magnetic properties of γ-Fe2O3 and γ-Fe2O3-2-HEAS were characterized by
vibrating sample magetometer (VSM) at room temperature (Figure 6). γ-Fe2O3 and γ-
Fe2O3-2-HEAS displayed a superparamagnetic behaviour, as evidenced by a zero coercivity
on the magnetization loop. The saturation magnetizations of γ-Fe2O3 and γ-Fe2O3-2-HEAS
were 68.9 and 63.4 emu g-1, respectively. A slight decrease of the saturation magnetization
of γ-Fe2O3-2-HEAS was due to the immobilization of IL on the surface of γ-Fe2O3 MNPs.
Figure 6
3.2. Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines catalyzed by γ-Fe2O3-2-HEAS
At first, the reaction of benzaldehyde, malononitrile and thiophenol was chosen as a
model reaction to optimize the reaction conditions such as molar ratio of the catalyst,
temperature and solvent (Table 1). It was found that the best yield of the product was
obtained at 50 °C under solvent-free conditions in the presence of 1.2 mol% of γ-Fe2O3-2-
HEAS (Table 1, entry 2). Three separated reactions were examined in the absence of any
Page 7 of 36

catalyst and in the presence of γ-Fe2O3 and γ-Fe2O3-n-BS. The results of these studies
showed that any amount of the desired product was not formed, and α,β-unsaturated
malonate was detected as the sole product of these reactions (Table 1, entries 15-17). A
similar reaction in the presence of 2-hydroxyethylammonium methansulfonate (2-HEAMS)
as a non-supported IL gave the desired product in moderate yield (69%) due to the
formation of by-products (Table 1, entry 18). This result indicated that the catalytic
efficiency of IL was increased by immobilization onto γ-Fe2O3.
In order to establish the generality of this method, the synthesis of various 2-amino-
3,5-dicarbonitrile-6-thio-pyridines was studied using different aldehydes and thiols under
optimized reaction conditions (Table 2).
Table 1
Synthesis of 2-amino-4-phenyl-6-phenylsulfanyl-pyridine-3,5-dicarbonitrile under different
conditions.
Entry
Catalyst
(mol %)
Temperature
(°C)
Solvent
Time
Yielda
(%)
1
2
3
4
5
γ-Fe2O3-2-HEAS (1.4)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1)
γ-Fe2O3-2-HEAS (0.8)
γ-Fe2O3-2-HEAS (1.2)
50
50
50
50
60
-
-
-
-
-
10 min
10 min
30 min
1 h
91
91
80
78
91
10 min
Page 8 of 36

6
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
γ-Fe2O3-2-HEAS (1.2)
-
40
30
25
50
50
50
50
50
50
50
50
50
50
-
1 h
84
82
81
40
50
10
40
10
0
7
-
3 h
8
-
4 h
9
EtOH
MeOH
CH3CN
CHCl3
EtOAc
H2O
-
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
10 min
10
11
12
13
14
15
16
17
18
0
γ-Fe2O3 (0.08 g)
-
0
γ-Fe2O3-n-BS (1.2)
2-HEAMS (1.2)
-
0
-
69b
b
aIsolated yields. Conditions: aldehyde/malononitrile/thiol: 1/2/1. The desired product plus a
mixture of by-products were obtained.
As the results of Table 2 indicate, 2-amino-3,5-dicarbonitrile-6-thio-pyridines 1a-g
were produced from the reaction of various substituted benzaldehyde and thiophenol in
good to high yields (Table 2, entries 1-7). 2-Naphthaldehyde as a polynuclear aldehyde and
pyridine-3-carbaldehyde as a heteroaromatic aldehyde underwent the condensation reaction
Page 9 of 36

to afford the corresponding pyridines in good yields (Table 2, entries 8 and 9).
Interestingly, γ-Fe2O3-2-HEAS efficiently promoted the synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines using aliphatic aldehydes and thiols (Table 2, entries 10-12).
The practical synthetic efficiency of this method was highlighted by the reaction of
both carbonyl groups in terephthalaldehyde with malononitrile and thiophenol to give a
structurally complex pyridine derivative 1m in 84% yield after 10 min (Scheme 3).
Scheme 3
Table 2
Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridine derivatives in the presence of γ-Fe2O3-2-
HEAS.
Entry
R
R′
Product
1a
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
Ph
Ph
10
10
20
10
10
5
91
81
79
84
81
87
80
79
89
88
Ph
4-ClC6H4
1b
1c
Ph
4-MeOC6H4
Ph
4-MeC6H4
1d
1e
4-MeC6H4
4-ClC6H4
4-ClC6H4
2-Naphthyl
3-Pyridinyl
3-Phenylpropanal
Ph
Ph
1f
4-MeC6H4
1g
10
10
5
Ph
Ph
Ph
1h
1i
1j
5
Page 10 of 36

11
12
Me
Ph
Ph
1k
1l
10
10
90
83
n-Bu
aYields refer to those of pure isolated products characterized by their spectral data (see
supplementary information). Conditions: aldehyde/malononitrile/thiophenol/γ-Fe2O3-2-HEAS:
1/2/1/0.012, 50 °C, solvent-free.
A plausible mechanism for the formation of 2-amino-3,5-dicarbonitrile-6-thio-
pyridines catalyzed by γ-Fe2O3-2-HEAS is shown in Scheme 4. The first step of the process
involves Knoevenagel condensation of aldehyde with malononitrile to form the
corresponding α,β-unsaturated malonate (A). The reaction proceeds through the addition of
thiolate to the nitrile of A followed by Michael addition of the second molecule of
malononitrile to the adduct. Aromatization and oxidation of dihydropyridines B by air
under the reaction conditions give pyridines 1a-m. It is supposed that dual activation of
substrates by γ-Fe2O3-2-HEAS has been taken place in this three-component reaction. The
hydroxyl group of the catalyst as a basic moiety has activated malononitrile and thiol, and
ammonium group as an acidic moiety has activated nitrile of α,β-unsaturated malonates
(A).
To show the role of the hydroxyl group in the synthesis of 2-amino-3,5-dicarbonitrile-6-
thio-pyridines 1a, the reaction of benzaldehyde, malononitrile and thiophenol in the presence
of γ-Fe2O3-2-HEAS and 2-ethylammonium sulphonate immobilized on γ-Fe2O3 (γ-Fe2O3-2-
EAS) was studied. The results showed that the reaction in the presence of γ-Fe2O3-2-EAS
proceeded in a longer reaction time (4 h) compared with γ-Fe2O3-2-HEAS (10 min) and
produced the desired product in 85% yield. These results depicted the specific role of
hydroxyl group of γ-Fe2O3-2-HEAS in imparting the catalytic property and indicated that γ-
Fe2O3-2-HEAS would take a part in the reaction as a functionalized ionic liquid.
Page 11 of 36

Scheme 4
The recovery and reuse of a catalyst is highly preferable for a catalytic process. In
this regard the recyclability of γ-Fe2O3-2-HEAS was investigated in a model reaction of
benzaldehyde, malononitrile and thiophenol under optimized reaction conditions. After the
reaction was completed, EtOAc was added to the reaction mixture and the whole amount of
γ-Fe2O3-2-HEAS simply separated from the product by an external magnet (Figure 7). The
recovered catalyst washed with ethylacetate, dried at room temperature and reused for a
similar reaction. It is worth to note that the magnetic property of γ-Fe2O3-2-HEAS
facilitates the efficient recovery of the catalyst from the reaction mixture during work-up
procedure so that the catalyst could be recycled and reused for five consecutive trials
without loss of its catalytic activity (Figure 8).
Figure 7
Figure 8
The recyclablity test was stopped after five runs. Comparison of TEM images
(Figure 9) and FT-IR spectra of used catalyst (Figure 10) with those of the fresh catalyst
(Figure 2b and 3) showed that the morphology and structure of γ-Fe2O3-2-HEAS remained
intact after five recoveries.
Figure 9
Figure 10
In order to show the merit of the present method for the synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines, we have compared our results obtained using γ-Fe2O3-2-
HEAS with some of those reported in the literature for the synthesis of 2-amino-3,5-
dicarbonitrile-6-thio-pyridines (Table 3). These results indicate well the superior activity of
γ-Fe2O3-2-HEAS than those of other promoters especially for the synthesis of 2-amino-3,5-
Page 12 of 36

dicarbonitrile-6-thio-pyridines from aliphatic aldehydes or thiols. Most of the reported
methods suffer from lack of generality for the synthesis of 2-amino-3,5-dicarbonitrile-6-
thio-pyridines
from
arylaldehydes/arylthiols,
alkylaldehydes/arylthiols
and
arylaldehydes/alkylthiols. Requiring a small amount of γ-Fe2O3-2-HEAS and short reaction
time are the other advantageous of this catalyst compared with the reported methods.
Table 3
Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines in the presence of reported reagents or
catalysts.
Entry Catalyst or
reagent
Aldehyde:malononitri Aldehyde/Thiol Time
le:thiol
Yield
(%)a [ref]
(mmol)/Catalyst or
reagent
1
2
H3BO3
ZnCl2
1:2:1/15 mol%
1:2:1/20 mol%
Aryl/Aryl
8-50 min
80-94 [3]
Aryl/Aryl
2 min-2.5 h
3 min-2.5 h
50-77 [4]
46 [4]
Alkyl/Aryl
3
ZrOCl2.8H2O
IBX
1:2:1/20 mol%
1:2:1/10 mol%
Aryl/Aryl
Aryl/Aryl
2-20 min
1.5-2.5 h
90-98 [5]
69-83 [6]
4
5
Et3N or
DABCO
1.5:3.1:1.6 or
1.5:2.25:0.75/10
mol%
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
2 h [7], 40-
90 min [8]
20-48 [7],
55-96 [8]
2 h [7], 40-
90 min [8]
20-29 [7],
39-55 [8]
2 h [7], 40-
90 min [8]
21-47 [7],
42-92 [8]
6
Piperidine or
TBAH
2:3:1/piperidine (30
mol%) or TBAH (50
mol%)
Aryl/Aryl
1-24 h
1-24 h
40-67 [9]
5-6 [9]
Alkyl/Aryl
Page 13 of 36

7
8
DBU
1:2:1/5 mol%
Aryl/Aryl
Aryl/Aryl
10-40 min
75-91
[10]
Basic alumina
1:2:1/10% aqueous
suspension of basic
alumina (2 mL)
50-100 min
79-90
[11]
9
KF/alumina
TBAF
1:2:1/10 mol%
Aryl/Aryl
5-70 min
56-93
[12]
10
1:2:1/10 mol%
Aryl/Aryl
45-120 min
87-96
[13]
Alkyl/Aryl
420-630
min
62-64
[13]
11
12
Sodium silicate 1:2:1/5 mol%
Aryl/Aryl
1 h
78-82b
[14]
K2CO3
1:2:1/20 mol%
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
40-180 min
90 min
70-89
[15]
80 [15]
75-90 min
60-61
[15]
13
KOH
3:6:3/10 mol%
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
30-60 min
90 min
71-90
[16]
76 [16]
30 min
82-89
[16]
14
15
1:2.1:1/12 mol%
1:2:1/200 mg
Aryl/Aryl
Aryl/Aryl
6 h
60-90
[17]
NH4OH
Microporous
molecular
sieves
30-120 min
78-91
[18]
16
17
Nano-ZnO
Nano-CuI
1:2.2:1/20 mol%
1:2.2:1/10 mol%
Aryl/Aryl
80-150 min
75-94
[19]
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
85-150 min
85-200 min
80-94
[20]
70-75
[20]
145-165
min
Page 14 of 36

min
78-82
[20]
18
19
Nano-MgO
Nano-SiO2
1:2.1:1.1/100 mg
Aryl/Aryl
2-9 h
4-8 h
48-69
[21]
Aryl/Alkyl
41-56
[21]
1:2:1/14 mg
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
2.5-3 h
6 h
70-85
[22]
60 [22]
6 h
60-65
[22]
20
21
22
[bmlm]Br
[bmlm]OH
2-HEAA
1:2:1/60 mol%
1:2:1/50 mol%
1:2:1/0.5 mL
Aryl/Aryl
Aryl/Aryl
4 -12 min
0.5-1.5 h
75-86
[23]
62-92
[24]
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
5 min
5 min
5 min
76-96
[42]
72-90
[42]
70 [42]
79-91c
88-90c
83c
23
γ-Fe2O3-2-
HEAS
1:2:1/1.2 mol%
Aryl/Aryl
Alkyl/Aryl
Aryl/Alkyl
5-20 min
5-10 min
10 min
aIsolated yield. bGC yield. cThis work.
4. Conclusions
In summary, in this paper, 2-hydroxyethylammonium sulphonate immobilized on γ-Fe2O3 (γ-
Fe2O3-2-HEAS) was successfully synthesized as a new supported IL from readily available
starting materials. It was applied as a magnetically recyclable heterogeneous catalyst for the
one-pot three-component synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines. This
Page 15 of 36

catalyst efficiently promoted the condensation of both aromatic and aliphatic aldehydes and
thiols with malononitrile leading to 2-amino-3,5-dicarbonitrile-6-thio-pyridines in good to
high yields under solvent-free conditions. Product separation and catalyst recycling are easy
and simple with the assistance of an external magnet. The catalyst can be recovered and
reused for five times without significant degradation in activity.
Acknowledgement
We are thankful to University of Birjand Research Council for their support on this
work.
References
[1] T.R.K. Reddy, R. Mutter, W. Heal, K. Guo, V.J. Gillet, S. Pratt, B. Chen, J. Med.
Chem. 49 (2006) 607-615.
[2] K, Guo, R. Mutter, W. Heal, T.R.K. Reddy, H. Cope, S. Pratt, M.J. Thompson, B.
Chen, Eur. J. Med. Chem. 43 (2008) 93-106.
[3]P.V. Shinde, S.S. Sonar, B.B. Shingate, M.S. Shingare, Tetrahedron Lett. 51 (2010)
1309-1312.
[4]M. Sridhar, B.C. Ramanaiah, C. Narsaiah, B. Mahesh, M. Kumaraswamy, K.K.R.
Mallu, V.M. Ankathi, P.S. Rao, Tetrahedron Lett. 50 (2009) 3897-3900.
[5]M.R. Poor Heravi, F. Fakhr, Tetrahedron Lett. 52 (2011) 6779-6782.
[6]S. Takale, J. Patil, V. Padalkar, R. Pisal, A. Chaskar, J. Braz. Chem. Soc. 23 (2012)
966-969.
[7]N.M. Evdokimov, A.S. Kireev, A.A. Yakovenko, M.Y. Antipin, I.V. Magedov, A.
Kornienko, J. Org. Chem. 72 (2007) 3443-3453.
Page 16 of 36

[8]N.M. Evdokimov, I.V. Magedov, A.S. Kireev, A. Kornienko, Org. Lett. 8 (2006)
899-902.
[9]K. Guo, M.J. Thompson, B. Chen, J. Org. Chem. 74 (2009) 6999-7006.
[10]R. Mamgain, R. Singh, D.S. Rawat, J. Heterocycl. Chem. 46 (2009) 69-73.
[11]P.V. Shinde, B.B. Shingate, M.S. Shingare, Bull. Korean Chem. Soc. 32 (2011)
459-462.
[12]K.N. Singh, S.K. Singh, ARKIVOC xiii (2009) 153-160.
[13]P.V. Shinde, B.B. Shingate, M.S. Shingare, Chin. J. Chem. 29 (2011) 1049-1054.
[14]M.M. Heravi, M. Khorshidi, Y.S. Beheshtia, B. Baghernejad, Bull. Korean Chem.
Soc. 31 (2010) 1343-1344.
[15]S. Mishra, R. Ghosh, Synth. Commun. 42 (2012) 2229-2244.
[16]M.N. Khan, S. Pal, T. Parvin, L.H. Choudhury, RSC Advances 2 (2012) 12305-
12314.
[17]Y.I. Shaikh, A.A. Shaikh, G.M. Nazeruddin, J. Chem. Pharm. Res. 4 (2012) 4953-
4956.
[18]P.V. Shinde, V.B. Labade, B.B. Shingate, M.S. Shingare, J. Mol. Catal. A: Chem.
336 (2011) 100-105.
[19]J. Safaei-Ghomi, M.A. Ghasemzadeh, Acta. Chim. Slov. 59 (2012) 697-702.
[20]J. Safaei-Ghomi, M.A. Ghasemzadeh, J. Sulfur. Chem. 34 (2013) 233-241.
[21]M.L. Kantam, K. Mahendar, S. Bhargava, J. Chem. Sci. 122 (2010) 63-69.
[22]S. Banerjee, G. Sereda, Tetrahedron Lett. 50 (2009) 6959-6962.
Page 17 of 36

[23]A. Davoodnia, P. Attar, H. Eshghi, A. Morsali, N. Tavakoli-Hoseini, A. Tavakoli-
Nishaburi, Asian. J. Chem. 23 (2011) 1273-1275.
[24]B.C. Ranu, R. Jana, S. Sowmiah, J. Org. Chem. 72 (2007) 3152-3156.
[25]P.J. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39 (2000) 3772-3789.
[26]T. Welton, Chem. Rev. 99 (1999) 2071-2084.
[27]T. Selvam, A. Machoke, W. Schwieger, Appl. Catal. A: Gen. 445–446 (2012) 92-
101.
[28]Y.H. Kim, S. Shin, H.J. Yoon, J.W. Kim, J.K. Cho, Y.S. Lee, Catal. Commun. 40
(2013) 18–22.
[29] J. Miao, H. Wan, Y. Shao, G. Guan, B. Xu, J. Mol. Cat. A: Chem. 348 (2011) 77-
82.
[30]P. Li, L. Wang, L. Zhang, G.W. Wang, Adv. Synth. Catal. 354 (2012) 1307-1318.
[31]M. Esmaeilpour, A.R. Sardariana, J. Javidi, Appl. Catal. A: Gen. 445-446 (2012)
359-367.
[32]C.O. Dalaigh, S.A. Corr, Y. Gun'ko, S.J. Connon, Angew. Chem. Int. Ed. 46 (2007)
4329-4332.
[33]N. Koukabi, E. Kolvari, M.A. Zolfigol, A. Khazaei, B. Shirmardi Shaghasemi, B.
Fasahati, Adv. Synth. Catal. 354 (2012) 2001–2008.
[34]E. Rafiee, S. Eavani, Green Chem. 13 (2011) 2116-2122.
[35]A. Dyal, K. Loos, M. Noto, S.W. Chang, C. Spagnoli, K.V.P.M. Shafi, A. Ulman,
M. Cowman, R.A. Gross. J. Am. Chem. Soc. 125 (2003) 1684-1685.
[36]Y.H. Liu, J. Deng, J.W. Gao, Z.H. Zhang, Adv. Synth. Catal. 354 (2012) 441-447.
[37]Y. Zhang, C. Xia, Appl. Catal. A: Gen. 366 (2009) 141-147.
Page 18 of 36

[38]Y. Zhang, Y. Zhao, C. Xia, J. Mol. Catal. A: Chem. 306 (2009) 107-112.
[39]F.P. Ma, P.H. Li, B.L. Li, L.P. Mo, N. Liu, H.J. Kang, Y.N. Liu, Z.H. Zhang, Appl.
Catal. A: Gen. 457 (2013) 34-41.
[40]S. Sobhani, M. Honarmand, J. Iran. Chem. Soc. 9 (2012) 661-669.
[41]S. Sobhani, M. Honarmand, Synlett 24 (2013) 236-240.
[42]S. Sobhani, M. Honarmand, C. R. Chimie 141 (2012) 557-560.
[43]S. Sobhani, R. Nasseri, M. Honarmand, Can. J. Chem. 90 (2012) 798-804.
[44]S. Sobhani, M. Honarmand, Catal. Lett. 143 (2013) 476-485.
[45]R. Massart, E. Dubois, V. Cabuil, E. Hasmonay, J. Magn. Magn. Mater. 149 (1995)
1-5.
[46]B.Z. Tang, Y. Geng, J.W.Y. Lam, B. Li, X. Jing, X. Wang, F. Wang, A.B.
Pakhomov, X.X. Zhang, Chem. Mater. 11 (1999)1581-1589.
[47]K.M. Ho, P. Li, Langmuir 24 (2008) 1801-1807.
[48] Z. Zhang, F. Zhang, Q. Zhou, W. Zhao, B. Ma, Y. Ding, J. Colloid Interface Sci.
360 (2011) 189-194.
[49] V.V. Balasubramanian , C. Anand , R.R. Pal, T. Mori, W. Böhlmann, K. Ariga,
A.K. Tyagi, A. Vinu, Micropor. Mesopor. Mater. 121 (2009) 18–25.
[50] V.V. Balasubramanian, P. Srinivasu, C. Anand, R.R. Pal, K. Ariga, S. Velmathi, S.
Alam, A. Vinu, Micropor. Mesopor. Mater. 114 (2008) 303-311.
Page 19 of 36

Figure captions
Figure 1. XRD spectra of γ-Fe2O3 MNPs.
Figure 2. (a) TEM images of γ-Fe2O3-2-HEAS and (b) γ-Fe2O3-2-HEAS particle size
distribution histogram.
Figure 3. FT-IR spectra of γ-Fe2O3 and γ-Fe2O3-2-HEAS.
Figure 4. Thermogravimetric analysis (TGA) of γ-Fe2O3-2-HEAS.
Figure 5. Nitrogen adsorption–desorption isotherms of γ-Fe2O3-2-HEAS.
Figure 6. Magnetization curves of γ-Fe2O3 and γ-Fe2O3-2-HEAS.
Figure 7. Separation of γ-Fe2O3-2-HEAS from the reaction mixture using an external
magnet.
Figure 8. Recycling experiment of γ-Fe2O3-2-HEAS.
Figure 9. TEM image of γ-Fe2O3-2-HEAS after five reuses.
Figure 10. FT-IR spectrum of recovered γ-Fe2O3-2-HEAS.
Page 20 of 36

OH
NH
3 SO3
H3N
SO3
HO
SO3H
O
SO3H
OH
OH
NH
3 O3S
O
SO
3H3N
HO3S
HO
O
SO3H
OH
O
O
O
O
O
O
HO
OH
γ-Fe2O3
ethanolamine
O
1,4-butanesultone
γ-Fe2O3
O
O
γ-Fe2O3
HO
HO
OH
OH
O
O
NH
HO
3O3S
O
HO3S
O
HO
SO
3 H3N
OH
SO3H
OH
NH
3O3S
O S
H3N
HO3S
n-BS γ-Fe2O3
3
HO3S
γ-Fe2O3-2-HEAS
Scheme 1. Synthesis of γ-Fe2O3-2-HEAS.
Page 21 of 36

R
N
NC
CN
SR'
CN
H2C
γ-Fe2O3-2-HEAS
R'SH
+
+
RCHO
CN
H2N
Scheme 2. Synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines catalyzed by γ-Fe2O3
MNPs.
Page 22 of 36

H2N
CN
CN
NC
NC
S
CN
H2C
CN
γ-Fe2O3-2-HEAS
50 oC, solvent-free
N
+
+
2
4
OHC
CHO
SH
S
NH2
1m
Scheme 3. Synthesis of 1,4-bis(2-amino-6-phenylsufanyl-4-pyridyl-3,5-
dicarbonitrile)benzene.
Page 23 of 36

R
R
N
R
CN
CN
O
NC
CN
SR'
NC
CN
SR'
NC
HN
CN
SR'
+
O
OH
air
H2N
γ-Fe2O3
SO3
R
H
H3N
H2N
N
N
H
H2O
1a-m
B
H
O
NC
NC
R
O
γ-Fe2O3
SO3
H3N
A
H
H
CN
N
C
R
N
C
H
N
H SR'
CN
HSR'
+
CN
O
OH
γ-Fe2O3
SO3
3 N
Scheme 4. Suggested mechanism for the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-
pyridines in the presence of γ-Fe2O3-2-HEAS.
Page 24 of 36

2200
2000
1800
1600
1400
1200
30
40
50
60
70
o
2 Theta ( )
Figure 1. XRD pattern of γ-Fe2O3 MNPs.
Page 25 of 36

30
25
20
15
10
5
(b)
(a)
0
6
10
14
18
Particle size (nm)
Figure 2. (a) TEM images of γ-Fe2O3-2-HEAS and (b) γ-Fe2O3-2-HEAS particle size
distribution histogram.
Page 26 of 36

Figure 3. FTIR spectra of γ-Fe2O3 and γ-Fe2O3-2-HEAS.
Page 27 of 36

Figure 4. Thermogravimetric analysis (TGA) of γ-Fe2O3-2-HEAS.
Page 28 of 36

Figure 5. Nitrogen adsorption–desorption isotherms of γ-Fe2O3-2-HEAS.
Page 29 of 36