Unique role of 2-hydroxyethylammonium acetate as an ionic liquid in the synthesis of Fe3O4 magnetic nanoparticles and preparation of pyridine derivatives in the presence of a new magnetically recyclable heterogeneous catalyst

Article abstract of DOI:10.1007/s13738-018-1460-6

Abstract: In this paper, 2-hydroxyethylammonium acetate (2-HEAA) was used as the first functionalized ionic liquid for the facile, economical and environmentally friendly synthesis of Fe₃O₄ nanoparticles by a co-precipitation method. The synthesized Fe₃O₄ nanoparticles were used as solid material for supporting 2-HEAA (Fe₃O₄-2-HEAA). The newly prepared Fe₃O₄-2-HEAA was characterized by TEM, XRD, FT-IR, TGA and elemental analysis and successfully applied 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 separated by an external magnet and reused at least five times without significant degradation in the activity.

Full text of DOI:10.1007/s13738-018-1460-6

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1460-6
ORIGINAL PAPER
Unique role of 2-hydroxyethylammonium acetate as an ionic liquid
in the synthesis of Fe3O4 magnetic nanoparticles and preparation
of pyridine derivatives in the presence of a new magnetically
recyclable heterogeneous catalyst
Sara Sobhani1 · Fatemeh Nasseri1 · Farzaneh Zarifi1
Received: 16 April 2018 / Accepted: 26 July 2018
© Iranian Chemical Society 2018
Abstract
In this paper, 2-hydroxyethylammonium acetate (2-HEAA) was used as the first functionalized ionic liquid for the facile, eco-
nomical and environmentally friendly synthesis of Fe3O4 nanoparticles by a co-precipitation method. The synthesized Fe3O4
nanoparticles were used as solid material for supporting 2-HEAA (Fe3O4-2-HEAA). The newly prepared Fe3O4-2-HEAA
was characterized by TEM, XRD, FT-IR, TGA and elemental analysis and successfully applied 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 separated by an external magnet and reused at least five times without significant degradation in the
activity.
Graphical abstract
H2N
OAc
OH
Si
O
O
O
O
O
OAc
NH2
O
O
Fe3O4
Si
OH
O
O
HO
Si
OAc
H2N
Keywords Ionic liquids · Co-precipitation method · Fe3O4 nanoparticles · Heterogeneous catalyst · Pyridine derivatives
Introduction
* Sara Sobhani
Ionic liquids (ILs) possess unique physicochemical prop-
ssobhani@birjand.ac.ir; sobhanisara@yahoo.com
erties including negligible vapor pressure, intrinsic
1
ionic conductivity, supramolecular network acceptable
Department of Chemistry, College of Sciences, University
of Birjand, Birjand, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
electrochemical stability and tunable solubility for inorganic
and organic molecules [1–3]. They have aroused increasing
interest worldwide as new class of compounds for a poten-
tially effective green replacement of conventional organic
solvents [4, 5]. They have been used as a promising catalytic
media for the synthesis of organic compounds [6]. Moreover,
ILs have many advantages that make them useful media for
the synthesis of nanomaterials such as metals, alloys, oxides
and sulfides [7–10]. They act as nanosynthetic template to
stabilize, and control the size and shape of nanostructured
materials [11, 12]. In recent years, by introducing certain
functional groups into the cation or/and anion of traditional
ionic liquids a great number of functionalized ILs have been
designed for different purposes ranging from synthetic and
catalytic chemistry to biotechnology, electrochemistry, and
materials science [13–17]. However, the widespread use of
ILs is still troubled by the following practical shortcomings
such as isolation of the product; recovery of the catalyst
which leads to economical and environmental problems; dif-
ficult in handling and the use of relatively large amounts of
ILs which is costly and may cause toxicological concerns
[18]. To solve these problems, a concept of supported ILs
has recently been established to combine the advantages of
ILs with those of heterogeneous supporting materials. It was
also claimed that immobilized ILs can enhance the reactiv-
ity and selectivity when they are involved in catalytic reac-
tions [19]. Along this line, a variety of matrices have been
introduced for the immobilization of ILs [20]. Within these
supporting materials, magnetic nanoparticles (MNPs) have
attracted increasing attention because of their facile sepa-
ration from the reaction mixture using an external magnet
[21–23]. Magnetic separation of MNPs is easy, economical,
and saves time and energy. Furthermore, MNPs such as iron
oxide have excellent thermal and chemical stability, surface
modification ability, a high surface area, and low toxicity
and cost [24–26].
2-amino-3,5-dicarbonitrile-6-thio-pyridine ring systems
are known as interesting compounds in the pharmaceuti-
cal industry due to their various therapeutic applications
[28, 30, 31]. One of the most significant routes for the
synthesis of these compounds involves the cyclocondensa-
tion of aldehyde, malononitrile and thiol. Generally, this
condensation has been carried out under acidic or basic
conditions [32, 33], microporous molecular sieves [34],
nanocatalysts such as ZnO [35], CuI [36], MgO [37] and
SiO2 [38], and ionic liquids including [bmIm]Br [39] and
[bmIm]OH [40]. However, the reported protocols suffer
from one or more of the following drawbacks such as low
yields, prolonged reaction time, harsh reaction conditions,
formation of inevitable side products, time consuming
methods for catalyst recovery, tedious workup, and use of
expensive, unrecyclable and environmentally toxic cata-
lysts and solvents. Therefore, introducing a simple syn-
thetic method for the preparation of a range of 2-amino-
3,5-dicarbonitrile-6-thio-pyridines using a recoverable
non-hazardous catalyst is highly desirable.
In continuation of our works towards the introduc-
tion of new heterogeneous catalysts, recently we have
focused our attention on the synthesis of new magneti-
cally heterogeneous catalysts [41–49]. Along this line
and to benefit the valuable applications of ILs in the syn-
thesis of MNPs, herein, at first part of our studies, we
report 2-hydroxyethylammonium acetate (2-HEAA) as a
cost-effective and the first functionalized ILs for the syn-
thesis of uniform Fe3O4 MNPs by the co-precipitation
of Fe2+ and Fe3+ ions. 2-HEAA has been reported as a
functionalized ILs for different types of reactions such
as Knoevenagel condensation reaction, and synthesis
of β-phosphonomalonates, 4-substituted 2-amino-4H-
chromenes and bis(pyrazolyl)methanes [50–52]. In the
second part of our studies, we have used the prepared
Fe3O4 for the immobilization of 2-HEAA to synthesis a
new supported IL (Scheme 1). We have also investigated
the applicability of this newly synthesized catalyst with
dual mode of activation as a magnetically heterogene-
ous catalyst for the one-pot three-component synthesis of
2-amino-3,5-dicarbonitrile-6-thio-pyridines.
Densely substituted pyridine derivatives are one
of the most important classes of compounds as they
widely occur as key structural subunits in numerous
natural products that exhibit many interesting biologi-
cal and physiological activities [27–29]. Among them,
Scheme 1 Synthesis of Fe3O4-2-HEAA
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Journal of the Iranian Chemical Society
Experimental section
General information
separated by an external magnet, washed with toluene, etha-
nol and methanol and dried in oven under vacuum.
Synthesis of 2‑hydroxyethylammonium acetate sup‑
ported on Fe3O4 (Fe3O4‑2‑HEAA)
Chemicals were purchased from Merck Chemical Compa-
nies. NMR spectra were recorded in ppm in DMSO on a
Bruker Avance DPX-400 instrument using TMS as internal
standard. Elemental analyses for C, H and N were obtained
using Elementar, Vario EL III. The purity of the products
and the progress of the reactions were accomplished by TLC
on silica gel polygram SILG/UV254 plates. TEM analysis
was performed using TEM microscope (Philips CM10).
FT-IR spectra were recorded on a Shimadzu Fourier Trans-
form Infrared Spectrophotometer (FT-IR-8300). IR spectra
were run on a Perkin Elmer 780 instrument. Thermogravi-
metric analysis (TGA) was performed using a Shimadzu
thermogravimetric analyser (TG-50). Power X-ray diffrac-
tion (XRD) was performed on a Bruker D8-advance X-ray
diffractometer with Cu Kα (λ=0.154 nm) radiation.
NaOAc (2 mmol) was added to a mixture of Fe3O4-2-HEAC
(1 g) in water (20 mL) and vigorously stirred at room tem-
perature for 24 h. Fe3O4-2-HEAA was separated from the
mixture by an external magnet. It was washed with water
until impurities of sodium chloride were removed (the
absence of chloride ions was tested by AgNO3 solution). It
was dried under reduced pressure to give Fe3O4-2-HEAA.
General procedure for the synthesis
of 2‑amino‑3,5‑dicarbonitrile‑6‑thio‑pyridines
in the presence of Fe3O4‑2‑HEAA
Fe3O4-2-HEAA (1 mol%, 0.016 g) was added to a stirred
mixture of aldehyde (1 mmol), malononitrile (2 mmol) and
thiol (1 mmol). The reaction mixture was stirred at 70 °C for
the appropriate time (Table 2). EtOAc (10 mL) was added to
the cooled reaction mixture. The catalyst was separated by
an external magnet, washed with EtOAc, dried and reused
for a consecutive run under the same reaction conditions.
Evaporation of the solvent of the filtrate under reduced pres-
sure gave the crude products. Pure product was obtained by
recrystallization in aqueous EtOH.
Synthesis of Fe3O4 MNPs
In a typical procedure, aqueous solutions of FeCl2.4H2O
(5 mL, 0.4 M) and FeCl3 (7.5 mL, 0.4 M) were added drop
wise to 2-HEAA (32 mL) with vigorous stirring under N2
atmosphere at room temperature. A NaOH solution (1 M)
was then added drop wise to the stirring mixture at room
temperature to reach the reaction pH to 11. The resulting
black dispersion was refluxed for 1 h at 90 °C. After cool-
ing the black suspension to room temperature, MNPs were
separated by an external magnet and washed several times
with deionized water and ethanol. It was then dried under
vacuum at 50 °C overnight to furnish Fe3O4 MNPs.
Spectral data for 2‑amino‑3,5‑dicarboni‑
trile‑6‑thio‑pyridines
2-Amino-4-phenyl-6-phenylsulfanyl-pyridine-3,5
-dicarbonitrile (1)
1
White solid, H NMR: δH 7.84 (2H, br, NH2), 7.63–7.59
Synthesis of chloro‑functionalized Fe3O4
(7H, m, Ar), 7.53–7.51 (3H, m, Ar) ppm; IR (KBr) (νmax
/
cm−1): 3471 (NH), 3349 (NH), 2196 (CN).
The prepared Fe3O4 (1 g) was sonicated in dry toluene
(15 mL) for 30 min. 3-Chloropropyltrimethoxysilane (1 mL)
was added to the dispersed Fe3O4 in toluene, slowly heated
to 105 °C and stirred at this temperature for 24 h. The result-
ing chloro-functionalized Fe3O4 was separated by an exter-
nal magnet and washed with toluene, methanol and deion-
ized water in turn, and dried under vacuum.
2-Amino-4-(4-chloro-phenyl)-6-phenylsulfanyl-pyri-
dine-3,5-dicarbonitrile (2)
White solid, 1H NMR: δH 7.88 (2H, br, NH2), 7.68 (2H, d,
J=8.4 Hz, Ar), 7.61 (4H, d, J=8.4 Hz, Ar), 7.53–7.50 (3H,
m, Ar) ppm; IR (KBr) (νmax/cm−1): 3470 (NH), 3331 (NH),
2200 (CN).
Synthesis of Fe3O4 supported with 2‑hydroxyethyl‑
ammonium chloride (Fe3O4‑2‑HEAC)
2-Amino-4-(4-methyl-phenyl)-6-phenylsulfanyl-pyri-
dine-3,5-dicarbonitrile (3)
Ethanolamine (1 mL) was added to a magnetically stirred
mixture of chloro-functionalized Fe3O4 (1 g) in dry toluene
(15 mL). After refluxing for 24 h, the mixture was cooled
to room temperature. The resulting Fe3O4-2-HEAC was
1
White solid, H NMR: δH 7.81 (2H, br, NH2), 7.62–7.60
(2H, m, Ar), 7.52–7.50 (3H, m, Ar), 7.45 (2H, d, J=7.6 Hz,
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Journal of the Iranian Chemical Society
Ar), 7.39 (2H, d, J = 8.0 Hz, Ar), 2.42 (3H, s, CH3) ppm;
IR (KBr) (νmax/cm−1): 3460 (NH), 3318 (NH), 2200 (CN).
2-Amino-4-methyl-6-phenylsulfanyl-pyridine-3,5-dicarbo-
nitrile (10)
1
White solid, H NMR: δH 7.71 (2H, br, NH2), 7.58–7.56
2-Amino-6-(4-chloro-phenylsulfanyl)-4-phenyl-pyri-
dine-3,5-dicarbonitrile (4)
(2H, m, Ar), 7.50–7.47 (3H, m, Ar), 2.46 (3H, s, CH3) ppm;
IR (KBr) (νmax/cm−1): 3396 (NH), 3310 (NH), 2202 (CN).
White solid, 1H NMR: δH 7.89 (2H, br, NH2), 7.63 (3H, d,
2-Amino-4-phenyl-6-(n-butylsulfanyl)-pyridine-3,5-dicar-
J=8.4 Hz, Ar), 7.60–7.56 (6H, m, Ar) ppm; IR (KBr) (νmax
/
cm−1): 3438 (NH), 3315 (NH), 2203 (CN).
bonitrile (11)
1
White solid, H NMR: δH (ppm) 8.04 (2H, br, NH2),
2-Amino-6-(4-methoxy-phenylsulfanyl)-4-phenyl-pyri-
dine-3,5-dicarbonitrile (5)
7.58–7.53 (5H, m, Ar), 3.25 (2H, t, J = 7.2 Hz, CH2),
1.69–1.62 (2H, m, CH2), 1.48–1.39 (2H, m, CH2), 0.93 (3H,
t, J=7.2 Hz, CH3) ppm; IR (KBr) (νmax/cm−1): 3452 (NH),
3313 (NH), 2200 (CN).
White solid, 1H NMR: δH 7.79 (2H, br, NH2), 7.59–7.55 (5H,
m, Ar), 7.52 (2H, d, J=8.4 Hz, Ar), 7.07 (2H, d, J=8.4 H,
Ar), 3.83 (3H, s, OCH3) ppm; IR (KBr) (νmax/cm−1): 3427
(NH), 3322 (NH), 2100 (CN).
1,4-bis(2-amino-6-phenylsufanyl-4-pyridyl-3,5-dicarboni-
trile)benzene (12)
2-Amino-6-(4-methyl-phenylsulfanyl)-4-phenyl-pyri-
dine-3,5-dicarbonitrile (6)
White solid, 1H NMR: δH 7.90 (4H, br, NH2), 7.80 (4H, s,
Ar), 7.64–7.62 (4H, m, Ar), 7.54–7.51 (6H, m, Ar) ppm;
IR (KBr) (νmax/cm−1): 3407 (NH), 3325 (NH), 2216 (CN).
13C NMR (100.6 MHz, DMSO-d6): δC (ppm) 166.8, 160.2,
158.2, 139.5, 136.1, 135.3, 129.9, 129.4, 127.5, 115.7,
115.4, 93.7, 87.5.
1
Light-yellow solid, H NMR: δH 7.84 (2H, br, NH2),
7.63–7.57 (6H, m, Ar), 7.52–7.50 (3H, m, Ar), 2.51 (3H, s,
CH3) ppm; IR (KBr) (νmax/cm−1): 3467 (NH), 3348 (NH),
2195 (CN).
2-Amino-4-(2-naphthyl)-6-phenylsulfanyl-pyridine-3,5-di-
carbonitrile (7)
Results and discussion
Characterization of Fe3O4‑2‑HEAA
Light-yellow solid, 1H NMR: δH 8.18 (1H, s, Ar), 8.13 (1H,
d, J = 8.8 Hz, Ar), 8.09–8.05 (2H, m, Ar), 7.89 (2H, br,
NH2), 7.71–7.64 (5H, m, Ar), 7.54–7.52 (3H, m, Ar) ppm;
IR (KBr) (νmax/cm−1): 3431 (NH), 3301 (NH), 2170 (CN).
At first, Fe3O4 MNPs were synthesized by a chemical co-
precipitation technique of ferric and ferrous ions in alkali
solution in the presence of 2-HEAA as a functionalized and
cost-effective ionic liquid. The size and structure of Fe3O4
MNPs were evaluated using transmission electron micros-
copy (TEM). TEM image demonstrated spherical-like shape
for Fe3O4 MNPs with a narrow size distribution (2–7 nm)
and an average diameter of about 5 nm (Fig. 1a). To show
the role of ILs in the synthesis of MNPs, a similar reaction
was studied in the absence of ILs. TEM image showed the
influence of ILs on the morphology of Fe3O4 MNPs. The
obtained MNPs were not uniform in shape and contain a
mixture of spherical and rod-like shapes (Fig. 1b). When
the reaction was performed in the presence of ethylammo-
nium acetate (EAA), Fe3O4 MNPs with uniform spherical-
like shape and sizes between 6 and 12 nm were obtained
(Fig. 1c). These results showed the role of hydroxyl group
in 2-HEAA on the size of MNPs and indicates that 2-HEAA
can act as a functionalized ionic liquid in this method. It is
worth to mention that this is the first report for the synthe-
sis of Fe3O4 MNPs via a co-precipitation method using a
functionalized ILs. Moreover, the most popular ILs which
2-Amino-4-(3-pyridinyl)-6-phenylsulfanyl-pyridine-3,5-di-
carbonitrile (8)
White solid, 1H NMR: δH 8.80–8.78 (2H, m, Ar), 8.07 (1H,
d, J = 7.6 Hz, Ar), 7.94 (2H, br, NH2), 7.67–7.61 (3H, m,
Ar), 7.53–7.52 (3H, m, Ar) ppm; IR (KBr) (νmax/cm−1):
3360 (NH), 3290 (NH), 2200 (CN).
2-Amino-4-phenethyl-6-phenylsulfanyl-pyridine-3,5-dicar-
bonitrile (9)
White solid, 1H NMR: δH 7.77 (2H, br, NH2), 7.59–7.57 (2H,
m, Ar), 7.50–7.47 (3H, m, Ar), 7.35 (2H, t, J=7.2 Hz, Ar),
7.28–7.22 (3H, m, Ar), 3.03–2.99 (2H, m, CH2), 2.92–2.89
(2H, m, CH2) ppm; IR (KBr) (νmax/cm−1): 3442 (NH), 3344
(NH), 2215 (CN). 13C NMR (100.6 MHz, DMSO-d6): δC
(ppm) 166.3, 160.4, 160.1, 139.9, 135.2, 130.1, 129.9, 129.1,
128.7, 127.6, 127.1, 115.4, 115.0, 93.9, 87.6, 36.1, 35.1.
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Journal of the Iranian Chemical Society
(b)
(a)
100
80
60
40
20
0
1
2
3
4
5
6
7
8
Particle size (nm)
(c)
100
80
60
40
20
0
5
6
7
8
9
10 11 12
Particle size (nm)
Fig. 1 a TEM image and particle size distribution histogram of Fe3O4 MNPs prepared in the presence of 2-HEAA, b TEM image of Fe3O4
MNPs prepared in the absence of ILs, c TEM image and particle size distribution histogram of Fe3O4 MNPs prepared in the presence EAA
have been used for the synthesis of Fe3O4 MNPs incorpo-
rate expensive cations, such as alkyl methyl imidazolium or
dialkyl imidazolium, and expensive anions, such as tetra-
fluoroborate or hexafluorophosphate [9, 53, 54]. The existing
methods also suffer from one or more of these drawbacks
such as requiring additives, microwave or co-solvents [9,
53–57].
the average particle size of Fe3O4 MNPs calculated using
Debye–Scherrer’s formula and was 10 nm.
Fe3O4 MNPs were then allowed to react with an appro-
priate concentration of 3-chloropropyl trimethoxysilane
to give chloro-functionalized Fe3O4. The obtained chloro-
functionalized Fe3O4 was reacted with ethanolamine to
produce Fe3O4 supported with 2-hydroxyethylammonium
chloride (Fe3O4-2-HEAC). To this end, the reaction of
Fe3O4-2-HEAC with NaOAc in water led to the formation
of 2-hydroxyethylammonium acetate supported on Fe3O4
MNPs (Fe3O4-2-HEAA) (Scheme 1).
The synthesized Fe3O4 MNPs mostly exist in cubic struc-
ture using XRD pattern (Fig. 2). All the diffraction peaks in
the XRD pattern were indexed to the structure known for the
Fe3O4 crystal and no other peaks were detected. In addition,
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Journal of the Iranian Chemical Society
Fig. 4 FT-IR spectra of Fe3O4 and Fe3O4-2-HEAA
Fig. 2 XRD pattern of Fe3O4
100
80
60
40
20
0
Fig. 5 TGA diagram of Fe3O4-2-HEAA
3
4
5
6
7
8
9 10
evidenced by the presence of bands at 1580 and 1615 cm−1
corresponding to stretching vibrations of C=O and C–N+
bonds which overlaps with OH vibration of adsorbed water
(1635 cm−1).
Particle size (nm)
Fig. 3 TEM image and particle size distribution histogram of
Fe3O4-2-HEAA
Thermogravimetric analysis (TGA) was used to study the
thermal behavior of the catalyst. TGA of Fe3O4-2-HEAA
showed two weight losses at different temperatures (Fig. 5).
The first weight loss observed below 207 °C was attributed
to adsorbed water and solvents from the catalyst. The second
and main weight loss was about 13.9 wt%, which could be
attributed to the loss of organic components attached to the
surface of Fe3O4 and verified the high thermal stability of
the Fe3O4-2-HEAA. According to the TGA, the amount of
organic components functionalized on Fe3O4 was calculated
to be 0.68 mmol g−1. These results are in good agreement
with the elemental analysis data (N=0.86% and C=3.56%).
In continuation of our recent research programs on
the development of novel methods for the synthesis of
TEM images of Fe3O4-2-HEAA (Fig. 3) demonstrated
that supporting of ILs leads to a small increase of the aver-
age particle size to ~6–7 nm, but the nanoparticles morphol-
ogy remain unchanged.
FT-IR spectra of Fe3O4 and Fe3O4-2-HEAA were shown
in Fig. 4. The band at around 557–690 cm−1 was assigned
to the stretching vibrations of Fe–O bond in these com-
pounds. The peaks positioned at 2910, 2930 and 1480 cm−1
in the FT-IR spectrum of Fe3O4-2-HEAA were related
to the stretching and bending of the CH2 bonds, respec-
tively. Si–O stretching bond was observed in the range of
1000–1110 cm−1. The anchoring of 2-HEAA on Fe3O4 was
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Journal of the Iranian Chemical Society
2-amino-3,5-dicarbonitrile-6-thio-pyridines [41, 42], in this
paper, we have studied the applicability of Fe3O4-2-HEAA
as a new magnetically recyclable catalyst for the one-pot
synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines
directly from aldehydes, malononitrile and thiols.
product was decreased (entries 2–4). The importance of the
catalyst was indicated by performing the reaction in the pres-
ence of Fe3O4 and in the absence of the catalyst. The results
of these studies showed that any quantity of the desired prod-
uct was not formed even after 24 h, and α, β-unsaturated
malonate was detected as the only product (entries 12, 13).
A similar reaction in the presence of 2-HEAA as a non-sup-
ported IL gave the desired product in moderate yield (41%)
due to the formation of by-products (entry 14). This result
indicated that the catalytic efficiency of IL was increased by
immobilization onto Fe3O4.
Catalytic activity of Fe3O4‑2‑HEAA in the synthesis
of 2‑amino‑3,5‑dicarbonitrile‑6‑thio‑pyridines
In the preliminary stage of investigation, one-pot reaction
of benzaldehyde, malononitrile and thiophenol was chosen
as a model reaction to optimize the reaction conditions. The
model reaction was studied in different conditions (Table 1).
We found that in the presence of 1 mol% of Fe3O4-2-HEAA,
the desired product 1 was obtained in the best yield at 70 °C
under solvent-free conditions (entry 1). When 0.5, 0.25 and
0.1 mol% of the catalyst was used, the yield of the desired
The reaction of different aldehydes and thiols with malon-
onitrile was then investigated to confirm the generality of the
present method (Table 2). As shown in Table 2, the reaction
of various aldehydes and thiols containing electron-donating
and electron-withdrawing groups with malononitrile in the
presence of Fe3O4-2-HEAA afforded the corresponding
Table 1 One-pot synthesis of 2-amino-4-phenyl-6-phenylsulfanyl-pyridine-3,5-dicarbonitrile under different conditions
Ph
SH
Catalyst
CHO
NC
CN
CN
+
+
2
CN
N
1
SPh
H2N
Entry
Catalyst
Solvent
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4-2-HEAA
Fe3O4
–
–
–
–
10
15
35
1 h
90
83b
41c
20d
75e
31
–
1 h
H2O
EtOH
MeOH
EtOAc
CH3CN
CHCl3
–
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
60
52
41
32
9
10
11
12
13
14
35
f
–
g
–
–
–
–
2-HEAA
41h
aIsolated yield, reaction conditions: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol (1 mmol), catalyst (1 mol%, except for entries
2,10,11), temperature 70 °C (except for entry 3)
bCatalyst (0.5 mol%)
cCatalyst (0.25 mol%)
dCatalyst (0.1 mol%)
eTemperature 50 °C
fCatalyst 0.016 g
gNo catalyst
hA mixture of by-products besides the desired product was formed
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Journal of the Iranian Chemical Society
_
Table 2 One-pot synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridine derivatives in the presence of Fe3O4 2-HEAA
Entry
R
R′
Product
Time (min)
Yielda (%)
MP (°C), found
219–220
MP (°C),
reported [refer-
ences]
1
2
1
2
10
5
90
81
216–218 [40]
222–223
222–224 [40]
3
4
3
4
10
5
82
84
212–213
228–229
208–211 [40]
228–230 [40]
5
6
5
6
15
5
80
83
228–229
238–239
228–229 [58]
238 [59]
7
7
5
5
5
5
82
80
81
85
238–240
305–306
218–220
224–225
236 [59]
305–306 [61]
–
8
8
9
9
10
Me
10
225–226 [61]
1 3

Journal of the Iranian Chemical Society
Table 2 (continued)
Entry
11
R
R′
Product
Time (min)
10
Yielda (%)
80
MP (°C), found
178–179
MP (°C),
reported [refer-
ences]
n-Bu
11
182–183 [62]
aIsolated yield, reaction conditions: aldehyde (1 mmol), malononitrile (2 mmol), thiol (1 mmol), catalyst (1 mol%), temperature=70 °C
Scheme 2 Synthesis of 1,4-bis(2-amino-6-phenylsulfanyl-4-pyridyl-3,5-dicarbonitrile)benzene
pyridines in good to high yields (entries 2–6). The reaction
of polyaromatic and heteroaromatic aldehydes underwent
the condensation reaction to produce the desired products in
good yields (entries 7 and 8). This method is also applicable
H2N
for the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyri-
OAc
OH
OH
dines using aliphatic aldehydes and thiols in 80–85% yields
(entries 9–11). Interestingly, Fe3O4-2-HEAA efficiently
catalyzed the reaction of both carbonyl groups in tereph-
thalaldehyde with malononitrile and thiophenol to give a
structurally complex pyridine derivative 12 in 93% yield
after 15 min (Scheme 2).
Si
O
O
O
O
O
OAc
NH2
O
O
Fe3O4
Si
O
O
HO
Si
OAc
H2N
The recyclability of Fe3O4-2-HEAA was investigated in
a model reaction of benzaldehyde, thiophenol and malo-
nonitrile under optimized reaction conditions. After the
reaction was completed, EtOAc was added to the reaction
mixture and the catalyst was separated using an external
magnet (Fig. 6), washed with EtOAc, dried 30 min at 100 °C
and reused in subsequent runs. The catalyst was found to
retain its activity for a minimum of five reaction cycles and
displayed almost high catalytic performance with over 85%
yields (Fig. 7).
Fig. 6 Separation of Fe3O4-2-HEAA from the reaction mixture by an
external magnet
the fresh catalyst showed the fact that the structure of
Fe3O4-2-HEAA remained intact after five recoveries.
We have proposed a mechanism for the synthesis of
2-amino-3,5-dicarbonitrile-6-thio-pyridine derivatives in
The recovered catalyst after five reaction cycle was
analyzed by TEM and FT-IR. The TEM image of used
Fe3O4-2-HEAA was illustrated a uniform and regular mor-
phology of the catalyst (Fig. 8). Moreover, the comparison
of FT-IR spectrum of used Fe3O4-2-HEAA (Fig. 9) with
_
the presence of Fe3O4 2-HEAA in Scheme 3. The first step
of the process involves the Knoevenagel condensation of
an aldehyde with malononitrile to form the corresponding
1 3

Journal of the Iranian Chemical Society
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
Run
Fig. 7 Recycling experiment of Fe3O4-2-HEAA
Fig. 9 FT-IR spectrum of recovered Fe3O4-2-HEAA after five runs
functional group (ammonium ion) activates the aldehyde and
nitrile of the Knoevenagel product.
Finally, the efficiency of Fe3O4-2-HEAA was com-
pared with reported reagents or catalysts in the syn-
thesis of 1 (Table 3). As demonstrated in Table 3,
Fe3O4-2-HEAA is the most efficient catalyst for the syn-
thesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines in
terms of turnover number (TON) and turnover frequency
(TOF).
Conclusion
In summary, we have reported a facile, economical and
environmentally friendly method for the synthesis of uni-
form Fe3O4 magnetic nanoparticles via a co-precipitation
method in the presence of 2-hydroxyethylammonium acetate
(2-HEAA) as a cost-effective ILs. This is the first report for
the synthesis of iron oxide using a functionalized ILs. The
synthesized nanoparticles were used as a solid material for
supporting 2-HEAA. The newly synthesized Fe3O4-2-HEAA
was then successfully applied as a magnetically recyclable
heterogeneous catalyst with dual mode of activation for the
one-pot synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyr-
idine derivatives. The catalyst was easily separated from the
reaction media by an external magnet and reused five times
without any obvious loss in activity. Using a cost-effective
and reusable catalyst with high TON and TOF, being ame-
nable for both aromatic and aliphatic aldehydes/thiols and
short reaction time (5–15 min) are the other advantages of
this protocol.
Fig. 8 TEM image of Fe3O4-2-HEAA after five time reuses
Knoevenagel product. The reaction proceeds through thi-
olate addition to nitrile of the Knoevenagel product followed
by Michael addition of the second molecule of malononi-
trile to the adduct and produces dihydropyridine. Aromatiza-
tion of dihydropyridine under the reaction conditions gives
pyridine 1–12. In this three-component reaction, it is sup-
posed that dual activation of substrates by Fe3O4-2-HEAA
has taken place. The Lewis base moiety of the catalyst
(OH) activates the malononitrile and thiol, and its acidic
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Journal of the Iranian Chemical Society
Scheme 3 A proposed mechanism for the synthesis of 2-amino-3,5-dicarbonitrile-6-thio-pyridines
Table 3 Comparison of the
catalytic activity of Fe3O4-2-
HEAA with reported reagents
or catalysts in the synthesis of 1
Entry Catalyst (mol%)
Reaction conditions
Yielda (%)
TON-TOF
[references]
1
2
DBU (5)
NH4OH (12)
10% H2O/EtOH, 35 °C, 15 min
MeOH, r.t., 360 min
MeOH, r.t., 180 min
CTAB (10 mol%), H2O, 80 °C, 35 min
EtOH, r.t, 300 min
80 [59]
85 [63]
92 [64]
86 [65]
80 [66]
86 [67]
92 [40]
85 [36]
80 [68]
91 [69]
16–64
7–1
18.4-6
43–74
4–0.8
43–86
1.8–1.5
8.5–4.6
8–5.3
4.5–18.2
5.8–17.5
8–8
3
4
5
Cs2CO3 (5), TBAB (5)
Phosphotungstic acid (2)
Diethylamine (20)
6
7
8
9
10
11
12
13
14
15
Zn(II) or Cd(II) MOFs (2) Solvent free, 70 °C, 30 min
[bmlm]OH (50)
CuI nanoparticles (10)
Iodoxybenzoic acid (10)
ZrOCl2·8H2O (20)
NaCl (15)
KOH (10)
TBAF (10)
EtOH, r.t, 70 min
H2O/EtOH/reflux, 110 min
H2O, 50 °C, 90 min
Ultrasound irradiation, r.t., 15 min
H2O, ultrasound irradiation, r.t., 20 min 88 [70]
EtOH/Reflux, 60 min
H2O, 80 °C, 50 min
H2O/EtOH/Reflux, 60 min
Solvent free, 70 °C, 10 min
80 [31]
92 [71]
80 [33]
90
9.2–11
4–4
90–542
K2CO3 (20)
_
Fe3O4 2-HEAAb (1)
TBAF, tetra-n-butyl ammonium fluoride, TON mole of the product/mole of the catalyst, TOF (h−1), TON/
reaction time
aIsolated yield, reaction conditions: benzaldehyde (1 mmol), malononitrile (2 mmol), thiophenol (1 mmol)
except for entries 2 (1:2.1:1), 8 (1:2.2:1) and 12 (3:6:3)
bThis work
1 3

Journal of the Iranian Chemical Society
35. M.A. Ghasemzadeh, Acta Chim. Slov. 59, 697 (2012)
Acknowledgements Financial support of this project by University of
36. J. Safaei-Ghomi, M.A. Ghasemzadeh, J. Sulfur Chem. 34, 233
(2013)
Birjand Research Council is appreciated.
37. M.L. Kantam, K. Mahendar, S. Bhargava, J. Chem. Sci. 122, 63
(2010)
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