Magnetic nanoparticle supported amine: An efficient and environmental benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation

Article abstract of DOI:10.1016/j.crci.2014.05.012

Amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) were successfully prepared as a novel heterogeneous amine. The catalyst was characterized by XRD, FT-IR, TEM, magnetic measurement, elemental analysis and was found to be a magnetically separable and highly active catalyst for ambient Knoevenagel condensation of aromatic aldehydes and a-aromatic (heteroaromatic or polyaromatic)-substituted methylene compounds in water under ultrasonic irradiation to afford the corresponding products in good to excellent yields. Very interestingly, SiO2@MNP-A successfully catalyze the reaction of the non-cyano substituted compound with benzaldehyde to achieve a key intermediate for the preparation of Atorvastatin calcium in green and atom-economic manner. In addition, the catalyst SiO2@MNP-A can be reused for 8 times without any obvious loss of its activity. The role of ultrasonication in the Knoevenagel condensation was also discussed with the assistance of UV-vis spectrometry.

Full text of DOI:10.1016/j.crci.2014.05.012

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C. R. Chimie xxx (2014) xxx–xxx
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Full paper/Memoire
Magnetic nanoparticle supported amine: An efficient and
environmental benign catalyst for versatile Knoevenagel
condensation under ultrasound irradiation
Anguo Ying a, , Limin Wang a,b, Fangli Qiu a, Huanan Hu a, Jianguo Yang a,
*
*
a School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, China
b Collegel of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) were successfully
prepared as a novel heterogeneous amine. The catalyst was characterized by XRD, FT-IR,
TEM, magnetic measurement, elemental analysis and was found to be a magnetically
separable and highly active catalyst for ambient Knoevenagel condensation of aromatic
Received 20 March 2014
Accepted after revision 20 May 2014
Available online xxx
aldehydes and
a-aromatic (heteroaromatic or polyaromatic)-substituted methylene
Keywords:
compounds in water under ultrasonic irradiation to afford the corresponding products in
good to excellent yields. Very interestingly, SiO2@MNP-A successfully catalyze the
reaction of the non-cyano substituted compound with benzaldehyde to achieve a key
intermediate for the preparation of Atorvastatin calcium in green and atom-economic
manner. In addition, the catalyst SiO2@MNP-A can be reused for 8 times without any
obvious loss of its activity. The role of ultrasonication in the Knoevenagel condensation
was also discussed with the assistance of UV–vis spectrometry.
Magnetic nanoparticle
Immobilization
Ultrasonication
Knoevenagel condensation
Recyclability
ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
Recently, some heterogeneous Lewis acids [3], sulfate-ion
promoted Zirconia [4], layered double hydroxides [5],
The Knoevenagel condensation, one of the most
important reaction for the formation of C5C bond between
carbonyl functionality and active methylene compound,
has been widely used to prepare versatile fine chemical
intermediates, natural and therapeutic drugs, polymers,
cosmetics and perfumes [1]. Traditionally, it is catalyzed by
some acids, organic bases as well as their salts, including
dimethylamino pyridine, piperidine, guanidine, ethylene-
diamine [2]. However, the tedious recovery of these
catalysts reaction solutions imposed environmental bar-
rier upon their further application in industrial scale.
amine functionalized polyacrylonitrile fiber [6], Ni-SiO2
[7], Si-MCM-41 supported basic materials [8] and task-
specific ionic liquids [9] have been explored as catalysts for
the Knoevenagel condensation and more or less success
has been achieved. Unfortunately, the use of hazardous
and carcinogenic solvents and relatively lower catalytic
activities with regard to heterogeneous catalysts in the
above methodologies are incompatible with ‘‘green
chemistry’’. In accordance with the principles of ‘‘green
chemistry’’, the requirement of the design of catalysts for
Knoevenagel condensation with readily separation, highly
catalytic activity, low cost is still highly needed.
Magnetic nanoparticles (MNPs) supported catalysts,
exhibiting their intrinsically high surface area, readily
dispersion in reaction solution and paramagnetic proper-
ties, mimic their homogeneous counterparts and, at the
*
Corresponding authors.
E-mail addresses: agying@tzc.edu.cn, yinganguo@163.com (A. Ying),
yjg@tzc.edu.cn (J. Yang).
http://dx.doi.org/10.1016/j.crci.2014.05.012
1631-0748/ß 2014 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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N
R
X
N
X
R
SiO2@MNP-A
Y
n
+
CHO
Ultrasonication, water
Y
n
1-60 min
X=C, N, S
Y=C, N
n=0,1
SiO2
O
Fe3O4
O Si
NH2
O
SiO2@MNP-A
Scheme 1. (Color online.) Knoevenagel condensation of aromatic aldehydes and
a-aromatic substituted methylene compounds catalyzed by amine
functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A).
same time, enable the trouble-free separation of the
catalyst from the reaction mixture simply using by an
external magnet [10]. Unmodified MNPs are reactive in
acid solution to lose their magnetic properties and tend to
aggregate into large clusters because of their anisotropic
attraction. In order to overcome these problems, silica was
used to coat the MNPs to form a core-shell structure
(Fe3O4), which also provided numerous surface Si-OH
groups for further versatile modifications [11]. Thus, many
silica coated MNPs (SiO2@Fe3O4) supported catalysts have
been developed and successfully explored in a range of
organic reactions, demonstrating the excellent catalytic
activities in Suzuki, Heck and Sonogashira coupling
reactions [12], enantioselective asymmetric hydrogena-
tion of aromatic ketones [13], one-pot synthesis of
benzoxanthenes [14], aerobic oxidation of alcohols [15],
2. Results and discussion
2.1. Preparation and characterization of the catalyst
(SiO2@MNP-A)
The magnetic nanoparticle supported amine catalyst
(SiO2@MNP-A) was prepared via the procedure depicted
on Scheme 2. The magnetic nanoparticles (MNPs) were
prepared by the chemical coprecipitation methods [20]. In
order to avoid the aggregation problem of naked nano-
Fe3O4, an outer silica shell, also providing the suitable sites
(Si-OH) for surface functionalization with amine, was
coated on the MNP through the ultrasound promoted
reaction of highly dispersing MNP with tetraethoxysilane
(TEOS) under basic conditions [21].
To guarantee the successful immobilization of amine on
the silica coated Fe3O4 nanoparticles, FT-IR was used to
investigate the blank MNP (SiO2@MNP) and the catalyst
SiO2@MNP-A. On Fig. 1, the bands at 579 cmÀ1 were
assigned to vibration of the Fe–O bonds, which show the
existence of the Fe3O4 ingredients in two samples. Two
peaks at 1099 cmÀ1, 964 cmÀ1 can be attributed the Si–O–
Si stretching vibration of silica shell. As shown on Fig. 1, the
two examples both have broad peak at 3447 cmÀ1, which
was the characteristic of the Si–OH stretching vibration. In
reduction of
a,b-epoxy ketones [16].
Ultrasonic irradiation has been frequently utilized in
various organic transformations [17]. Cativation process
that include the formation, growth, collapse of millions of
bubbles within very short time, which induces very high
local temperature and pressure, then strengthen the
mass transfer between the vapor bubble and ambient
liquid [18]. The distinctive behavior of ultrasonic
irradiation renders ultrasonic assisted reaction have
some advantages, such as short reaction time, improved
selectivity, high yield and clean reaction. Driven by the
unique properties of magnetic nanoparticles, their
successful utilization in organic transformations and
significant promotion of ultrasonic technique for organic
the curve of SiO2@MNP-A, two obvious bands 1211 cmÀ1
,
1153 cmÀ1 were verified as C–N bond vibration. At the
same time, there are two weak peaks at 2949 cmÀ1 and
2872 cmÀ1, which were assigned to the C–H stretching
vibration of alky chain of amine. No absorbance at these
wave numbers in the curve of SiO2@MNP was observed,
which demonstrating the successful immobilization of
amine on the surface of the silica coated Fe3O4 particles.
The crystalline structure of SiO2@MNP was character-
ized by X-ray diffraction (XRD). The diffraction pattern
gives characteristic peaks and relative intensity matched
well with the standard Fe3O4 nanoparticles (JCPDS file No.
reactions, herein we report
a simple silica coated
magnetic nanoparticle supported amine (SiO2@MNP-
A) catalyzed, ultrasound promoted, aqueous Knoevena-
gel condensation of aromatic aldehydes and
a-aromatic
(heteroaromatic or polyaromatic)-substituted methyl-
ene compounds (Scheme 1), in which the active carbon
exhibit relatively weak nucleophilicity because of the
steric hindrance of aryl group [19].
19-0629, Fig. 2). The broad peak from 2u = 208 to 308 shows
Scheme 2. Synthesis of the magnetic nanoparticle supported amine catalyst.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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3
Fig. 1. (Color online.) FT-IR spectra of SiO2@MNP and amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A).
the typical properties of amorphous silica phase [22],
verifying the successful coat of SiO2 on the Fe3O4
particles. Moreover, transmission electron microscope
(TEM) analysis displays that the particle size of the
catalyst SiO2@MNP-A is similar to that of blank carrier
SiO2@MNP (Fig. 3), with the average size range of
20–30 nm for dark Fe3O4 core which is surrounded by
a grey silica shell about 4–6 nm thick. The loading
amount of amine was determined to be 0.75 mmol gÀ1 by
elemental analysis.
The magnetic behavior of the neat SiO2@MNP and the
catalyst SiO2@MNP-A was investigated using Magnetic
Properties Measurement System-5 (MPMS-5, Quantum
Design) magnetometer. As shown on Fig. 4, the field-
dependent magnetization curves at ambient temperature
reveal that SiO2@MNP and SiO2@MNP-A are both super-
paramagnetic with saturation magnetizations of 15.2 emu
gÀ1 and 6.1 emu gÀ1, respectively. No phenomenon of
hysteresis is detected from the two curves, further proving
their superparamagnetic characteristics.
2.2. SiO2@MNP-A catalyzed Knoevenagel condensation of
aromatic aldehydes and -aryl -substituted methylene
compounds in water under ultrasonic irradiation
a
In an initial screening of solvents under ultrasonic
irradiation (250 W), while dichloromethane (CH2Cl2),
toluene and chloroform (CHCl3) showed not to be effective
for the reaction of benzaldehyde and benzothiazole-2-
acetonitrile, methane (CH3OH), ethanol (C2H5OH) and
water provided the final product with promotional value of
yield (Table 1, entries 1–6). From the viewpoints of
environmental benign friendliness and cost efficiency,
water was the optimal choice of solvent for further
examinations. The influence of ultrasound power was also
investigated. As shown in Table 1, the best yield was
obtained by ultrasonic irradiation for 10 min at room
temperature and 200 W. Significantly, decreased yields
were detected when the power was decreased from 200 W
to 50 W (Table 1, entries 8–10). On the contrary, the
reaction times and yields did not change from 200 W to
[1.raw]
1500
1000
500
0
10
20
30
40
50
60
70
2-Theta(°)
Fig. 2. (Color online.) X-ray diffraction pattern of SiO2@MNP.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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Fig. 3. Transmission electron microscope images of SiO2@MNP (a) and amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) (b).
Table 1
The effect of solvent (20 mL) on the reaction of benzaldehyde (10 mmol) and benzothiazole-2-acetonitrile (10 mmol) in the presence of catalyst SiO2@MNP-
A at room temperature under ultrasonic irradiation.
N
S
N
S
Catalyst
+
CHO
Ultrasonication
CN
CN
Entry
Solvent
Power (W)
250
250
250
250
250
250
0
Time (min)
Yielda
90
1
Methanol
Ethanol
Water
CH2Cl2
Toluene
CHCl3
10
20
10
20
18
25
2 h
1 h
30
10
10
2
86
3
94
4
72
5
63
6
74
7
Water
Water
Water
Water
Water
35
8
50
58
9
150
200
300
68
10
11
94
93
SiO2@MNP-A: amine functionalized silica coated Fe3O4 nanoparticles.
a
Isolated yield based on benzaldehyde.
300 W. Thus, 200 W of ultrasonic irradiation was enough to
push the reaction forward (Table 1, entries, 3, 10, 11).
Without ultrasonic irradiation, only 35% yield of desired
product was obtained even if the reaction time was
prolonged to 2 h (Table 1, entry 7).
The same model reaction of benzaldehyde and ben-
zothiazole-2-acetonitrile under ultrasonic irradiation was
exploited to optimize the catalysts as well as their loading.
From the results provided in Table 2, it is obvious that the
catalyst SiO2@MNP-A worked well to give the desired
product within 40 min in 93% yield at room temperature
under ultrasonic irradiation (Table 2, entry 7). For
comparison, the support SiO2@MNP and silica supported
amine (SiO2@A) [23] were investigated as catalysts for the
model reaction and the corresponding product was
obtained in 15% and 63%, respectively (Table 2, entries
1–2). In addition, organic base propylamine gave the
product yield of 82%, which is lower than that catalyzed by
SiO2@MNP-A (Table 2, entries 3 and 7). These results
confirmed that SiO2@MNP-A performed more effectively as
catalyst than the homogeneous organic base, probably due to
the absorption of reaction substrates on the surface of the
nanoparticles, which lead to the increase in the local
concentration of reactants around the active site of the silica
coated Fe3O4 catalyst. To find an optimal loading amount of
catalyst loading, the model reaction was carried out in the
presence of the various amount of SiO2@MNP-A (Table 2,
entries5–8). Therational amountofthe catalyst was 2.0 mol %.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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5
Moreover, benzimidazolylacetonitrile is also an efficient
substrate to undergo with aromatic aldehydes to give the
corresponding products within 10 min in 85%–94% yields
(Table 3, entries 6–8). To our pleasure, the catalyst
SiO2@MNP-A was compatible with 2-indoleacetonitrile,
phenylacetonitrile and excellent desired product yields
of 85%–95% were obtained when the reaction times were
prolonged to 20–60 min (Table 3, entries 9–19). It is
noteworthy that all products obtained are E-geometry
exclusively and no subsequent Michael adduct is
detected because of steric hindrance effect (Scheme 3).
Encouraged by the exciting results of cyano sub-
stituted methylene compounds, we here also attempted
to conduct the condensation reaction between non-
cyano substituted ketone and benzaldehyde [Scheme 4,
eq. (1)]. Gratifying, the reaction of acetylacetone
furnished the product (I) in the yield of 79% in water
under ultrasonic irradiation at room temperature.
Atorvastatin calcium (IV) inhibits 3-hydroxy-3-methyl-
Fig. 4. (Color online.) Magnetic curves of SiO2@MNP and amine
functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A).
glutaryl-coenzyme
A (HMG-CoA) reductase, which
To evaluate the scope and limitations, as well as the
role of ultrasonic irradiation in this methodology, we
extended our studies to the reaction of benzothiazole-2-
acetonitrile and a variety of structurally diverse alde-
hydes in the presence of 2.0 mol % SiO2@MNP-A under
various conditions, including room temperature stirring
(rt), conventional heating (60 8C) and ultrasonic irradia-
tion (US). The results are summarized in Table 3. It is
notable that, under the same reaction conditions,
ultrasonic irradiated reactions furnished the corre-
sponding products in shorter reaction times with much
higher yields than both room temperature stirring
reaction condition and conventional heating condition.
In all cases with sonification (200 W), the reactions
proceeded smoothly to react with substituted aromatic
aldehydes to afford good to excellent yields. However,
aromatic aldehydes bearing with electron-withdrawing
groups (CF3 and Cl) reacted a little faster than aldehydes
bearing with electron-donating substituents (OMe).
catalyzes the rate-limiting step in cholesterol biosynth-
esis [24]. As a key intermediate for preparation of
Atorvastatin calcium salt (IV), 4-methyl-3-oxo-N-phe-
nyl-2-(phenylmethylene)pentanamide (III) was usually
synthesized via the condensation reaction of benzalde-
hyde and 4-methyl-3-oxo-N-phenylpentanamide (II) in
hexane in the presence of the catalytic amount of
b
-alanine and acetic acid at elevated temperature within
20 h [24c]. The utilization of harmful organic solvent,
notorious catalysts and long reaction time more or less
brought some problems to develop Atorvastatin calcium
in large scale. To our pleasure, SiO2@MNP-A smoothly
catalyzed the reaction between benzaldehyde and
4-methyl-3-oxo-N-phenylpentanamide (II) in water
under ultrasonic irradiation in 25 min and 87% yield of
4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)penta-
namide (III) could be obtained [Scheme 4, eq. (2)]. Thus,
this protocol may provide an environmentally friendly
alternative for the synthesis of Atorvastatin calcium in
industrial scale.
In many cases, the solubility of reagents and substrates
would determine the reaction efficiency in terms of
reaction rate and yield. In this method, the little solubility
of benzothiazole-2-acetonitrile in water hampered the
reaction proceed further. As demonstrated on Fig. 5, two
obvious bands at 217 nm, 254 nm in the three curves were
assigned to C5C bond vibration of benzene ring (Fig. 5).
The absorption magnitude of benzothiazole-2-acetonitrile
in water at 217 nm or 254 nm under ultrasonic irradiation is
much stronger than that under ambient stirring or that
under conventional heating, showing the better solubility of
benzothiazole-2-acetonitrile in water under ultrasonic
irradiation than that under the remained reaction condi-
tions. The reason for the interesting phenomena may
attribute the cavitation in sonochemistry. The chemical
and physical effects of ultrasound derive primarily from
acoustic cavitation, which includes formations, growth and
collapse of the cavity [18]. The implosive collapse of the
cavitation forms the bubbles in the liquid phase. Bubble
collapse results in high temperature and high pressure
within these bubbles, which lead to desired substrate
Table 2
Effect of catalyst and loading on the Knoevenagel condensation of
benzaldehyde (10 mmol) and benzothiazole-2-acetonitrile (10 mmol) in
water (20 mL) under ultrasonic irradiation (200 W) at room temperature.
Entry
Catalyst (mol %)
SiO2@MNP (0.4 g)
SiO2@A (3.0)
Time (min)
Yield (%)a
15
1
2b
3
4
5
6
7
8
20
20
20
30
10
10
5
63
Propylamine
82
–
Trace
58
SiO2@MNP-A (1.0)
SiO2@MNP-A (1.5)
SiO2@MNP-A (2.0)
SiO2@MNP-A (2.5)
81
93
10
94
SiO2@MNP-A: amine functionalized silica coated Fe3O4 nanoparticles.
a
Isolated yield based on benzaldehyde.
b
SiO2@A: 3-amino-propylated silica gel [21] and the loading amount
was 65 mmol gÀ1
.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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Table 3
SiO2@MNP-A catalyzed aqueous Knoevenagel condensation of aromatic aldehydes and
methylene compounds under various reaction conditions.
a-aromatic (heteroaromatic or polyaromatic)-substituted
CN
R
X
X
R
SiO2@MNP-A (2.0 mol %)
Water,1-240 min
CN
+
CHO
Y
n
Y
n
Entry
Methylene compound
Aldehyde
Time (min)
Yield (%)a
rt
Heat
20
US
rt
Heat
76
US
90
83
87
92
91
94
1
2
3
4
5
6
Benzothiazole-2-acetonitrile
Benzothiazole-2-acetonitrile
Benzothiazole-2-acetonitrile
Benzothiazole-2-acetonitrile
Benzothiazole-2-acetonitrile
4-CF3–C6H4–
2-Cl–C6H4–
30
40
40
50
60
40
1
2
63
75
72
53
64
72
15
72
4-Cl–C6H4–
20
2
70
4-MeO–C6H4–
2-MeO–C6H4–
4-MeO–C6H4–
30
8
68
35
10
10
73
Benzimidazolyl
acetonitrile
25
69
7
8
Benzimidazolyl
acetonitrile
3-MeO–C6H4–
3-Cl–C6H4–
60
50
30
30
8
6
48
53
66
58
85
85
Benzimidazolyl
acetonitrile
9
2-Indoleacetonitrile
2-Indoleacetonitrile
Phenylacetonitrile
C6H5–
120
100
180
180
150
280
180
180
180
240
240
60
60
20
20
30
30
40
50
40
35
35
60
60
36
42
59
63
63
65
63
58
69
61
66
61
59
66
61
71
68
73
78
81
67
65
95
93
95
88
86
90
92
92
95
85
88
10
11
12
13
14
15
16
17
18
19
4–Me–C6H4–
C6H5–
80
Phenylacetonitrile
4-HO–C6H4–
3-MeO–C6H4–
2-MeO–C6H4–
4-MeO–C6H4–
2-Furyl
80
Phenylacetonitrile
60
Phenylacetonitrile
90
Phenylacetonitrile
80
Phenylacetonitrile
60
Phenylacetonitrile
1-Naphthyl
4-MeO–C6H4–
C6H4–
50
3-Chloro-phenylacetonitrile
3-Chloro-phenylacetonitrile
100
100
SiO2@MNP-A: amine functionalized silica coated Fe3O4 nanoparticles; US: ultrasonic irradiation; rt: room temperature stirring.
a
Isolated yield based on aldehyde.
solubility in water as well as the acceleration of the followed
reaction rate. A plausible mechanism for the reaction
between benzaldehyde and benzothiazole-2-acetonitrile
catalyzed by SiO2@MNP-A under ultrasonic irradiation is
shown on Fig. 6. With the good aqueous solubility of
benzothiazole-2-acetonitrile in hand, the first step is the
condensation of the magnetic nanoparticle supported
propylamine with benzaldehyde to give imine with
+
CHO
NH
N
H
CN
N
H
CN
N
H
CN
Scheme 3. (Color online.) Amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) catalyzed aqueous Knoevenagel condensation of aromatic
aldehydes and -aromatic substituted methylene compounds.
a
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
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7
O
O
O
SiO2@MNP-A, Water
Ultrasonication, 35 min
+
CHO
O
(Eq.1)
I, 79 % yield
O
O
O
SiO2@MNP-A, Water
Ultrasonication, 25 min
O
HN
+
CHO
(Eq.2)
HN
II
III, 87 % yield
Ca2+
O
OH
O
OH
-
O
N
N
H
F
2
IV, Atorvastatin calcium
Scheme 4. (Color online.) Amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) catalyzed aqueous Knoevenagel condensation of non-
cyano substituted ketones with benzaldehyde.
good electrophilicity property (Fig. 6A) [25]. After the
proton was absorbed by propylamine [26], an activated
carbon anion of benzothiazole-2-acetonitrile react with
the imine to form the key intermediate B. B is subjected
to transfer the proton and electron on the surface of the
catalyst to finally afford the condensation product D the
recovered catalyst SiO2@MNP-A. The good solubility of
benzothiazole-2-acetonitrile in water stimulated by
ultrasonic irradiation, the excellent dispersibility of
MNPs in reaction solution (Fig. 7a) and high local
concentration of substrates around the catalytic sites
make the supported catalyst act as a ‘‘quasi-homo-
geneous’’ promoter which can facilitate the condensa-
tion reaction efficiently.
For practical applications of heterogeneous catalyst, the
recyclability of catalyst is a very important factor. To clarify
this issue, catalytic recycling experiments were carried out
using the reaction of benzothiazole-2-acetonitrile and
benzaldehyde as a model. Upon completion of the reaction,
the catalyst SiO2@MNP-A was readily recovered from the
reaction mixture with an external magnet (Fig. 7b) and
washed with ethanol, subsequently dried at 60 8C for
2 hours under vacuum. The recovered catalyst was reused
in the next run and the results are demonstrated on
Fig. 8. The results indicate that the catalyst could be simply
recovered and reused for 8 times without suffering any
significant drop in the catalytic efficiency in terms of
reaction yield.
Fig. 5. (Color online.) Absorption spectra of benzothiazole-2-acetonitrile
in water under various reaction conditions [a: room temperature stirring;
b: conventional heating condition (60 8C), c-ultrasonic irradiation
(200 W) at room temperature].
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

G Model
CRAS2C-3959; No. of Pages 10
8
A. Ying et al. / C. R. Chimie xxx (2014) xxx–xxx
Fig. 6. (Color online.) Plausible mechanism for the reaction between benzaldehyde and benzothiazole-2-acetonitrile catalyzed by amine functionalized
silica coated Fe3O4 nanoparticles (SiO2@MNP-A) under ultrasonic irradiation.
Fig. 7. a: amine functionalized silica coated Fe3O4 nanoparticles (SiO2@MNP-A) dispersion in the condensation reaction solution; b: catalyst separation
with an external magnet.
3. Conclusions
93
94
93
91 92
100
80
60
40
20
0
92
94 92
In conclusion, we have developed a simple magnetic
nanoparticle supported amine (SiO2@MNP-A) and used it
as catalyst for ambient Knoevenagel condensation of
aromatic aldehydes and
a-aromatic (heteroaromatic or
polyaromatic)-substituted methylene compounds in
water under ultrasonic irradiation. The reaction proceeds
smoothly to afford structurally diverse heterocyclic
products in good to excellent yields. Moreover, 87% yield
of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)penta-
namide, a key intermediate in the synthesis of Atorvastatin
calcium was achieved in the presence of SiO2@MNP-A in
water under ultrasonic irradiation at room temperature.
The MNP-supported catalyst with high activity because of
1
2
3
4
5
6
7
8
Runs
Fig. 8. The recyclability of amine functionalized silica coated Fe3O4
nanoparticles (SiO2@MNP-A) in the reaction of benzothiazole-2-acetonitrile
and benzaldehyde.
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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CRAS2C-3959; No. of Pages 10
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9
it ‘‘quasi-homogeneous’’ characteristics, could be readily
recovered from reaction mixture by an external magnet,
and reused at least 8 times without the significant loss of
the catalytic activity. Further preparation and applications
of MNP-supported catalysts in organic transformations are
underway in our lab.
the reaction mixture was refluxed for 12 h under N2
atmosphere. The supported catalyst was obtained by
magnetic force and rinsed with ethanol, dried in a vacuum
oven at 60 8C for 12 h. The loading of the catalyst was
determined to be 0.75 mmol gÀ1 by elemental analysis.
4.4. General procedure for the SiO2@MNP-A catalyzed
ambient Knoevenagel condensation in water under ultrasonic
irradiation
4. Experimental
4.1. General
A mixture of benzaldehyde (10 mmol),
a-aromatic
All chemicals were purchased from commercial sources
and were used without further purification. 1H and 13C NMR
were recorded on a Bruker Avance DPX 400 spectrometer at
400 MHz and 100 MHz in CDCl3, respectively. Chemical shifts
(heteroaromatic or polyaromatic)-substituted methylene
compound (10 mmol), water (20 mL) and SiO2@MNP-A
(270 mg) was stirred at room temperature under ultra-
sonic irradiation. Upon the completion of the reaction
(monitored by TLC), the catalyst, separated from the
reaction solution by magnet, washed with ethanol and
ethyl acetate, followed by drying under vacuum, was
reused for subsequent runs. The decanting solution was
directly filtrated and the remained residue was purified
with recrystallization using ethanol or column chromato-
graphy using petroleum ether/ethyl acetate as the eluent.
The products were characterized by 1H NMR, 13C NMR,
Mass spectra and elemental analysis.
were reported in parts per million (d), relative to the internal
standard of tetramethylsilane (TMS). IR spectra were
recorded on a Nicolet 5700 spectrometer using KBr pellets.
Mass spectra were obtained with an automated FININIGAN
TSQ Advantage mass spectrometer. Elemental analysis was
carried out on a Carlo Erba 1160. TEM was performed with a
Phlips Tecnai instrument operating at 40–100 kV. XRD
images were obtained a Bruker XRD D8 Advance instrument
with Cu Ka radiation. UV–vis concentration evaluation was
conducted on a SHIMADZU UV2401-PC spectrometer at
room temperature. All sonochemical synthesis were con-
ducted at the ultrasonic instrument (ACE, USA) with the set
up of operational frequency (22 kHz). All reactions were
monitored by thin layer chromatography (TLC). Flash
chromatography was performed on silica gel (100–200
mesh). All condensation products were purified through
column chromatography and were characterized by NMR
analysis, mass and elemental analysis.
4.4.1. 2-(Benzo[d]thiazol-2-yl)-3-(4-
methoxyphenyl)acrylonitrile (Table 2, entry 4)
1H NMR (400 MHz, CDCl3):
d
3.90 (s, 3H), 7.01 (d, 2H,
J = 6.4 Hz), 7.40–7.53 (m, 2H), 7.89 (d, 1H, J = 6.4 Hz), 8.02–
8.07 (m, 3H), 8.18 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
56.8, 102.5, 115.0, 117.3, 121.8, 123.6, 125.4, 125.9, 127.0,
133.0, 135.0, 146.7, 153.8, 163.1, 163.6; ESI-MS:
m/z = 293 [M + H]; Anal. Calc. for C17H12ON2S: C 69.85, H
4.13, O 5.47, N 9.58, S 10.97. Found: C 69.78, H 4.18, O 5.52,
N 9.53, S 10.99.
4.2. Preparation of silica coated magnetic nanoparticle
(SiO2@MNP)
Magnetic (Fe3O4) nanoparticles were prepared by the
coprecipitation [20]. FeCl3Á6H2O (8.1 g, 0.03 mmol) and
FeCl2Á4H2O (4.97 g, 0.025 mmol) were dissolved in distilled
water (100 mL). The resulting transparent solution was heated
at 85 8C with vigorous mechanically stirring under N2 atmo-
sphere for 1 h. The pH value was then adjusted to 9 using the
concentrated aqueous ammonia (25 wt %). After the color of
the bulk solution turned to back, the magnetic precipitates
were separated and washed several times with deionized
water until the pH value of the eluent decreased to 7. The
coating of alayer of silica on the surface of the naked Fe3O4 was
conducted through sol-gel method [21]. The naked Fe3O4
(1.0 g) was dispersed in ethanol (200 mL) by ultrasonic
irradiation. The concentrated NH3ÁH2O (6 mL) and TEOS
(2 mL) were successively added into the solution. With
continuous stirring for 24 hat room temperature. The resulting
SiO2@Fe3O4 was collected by an external magnet and washed
three times with ethanol, followed by drying in vacuum.
4.4.2. 2-(1H-indol-2-yl)-3-phenylacrylonitrile (Table 2 entry
9)
1H NMR (400 MHz, CDCl3):
d
7.26–7.33 (m, 2H), 7.40–
7.49 (m, 4H), 7.60–7.63 (m, 2H), 7.88 (d, 2H, J = 5.6 Hz), 8.00
(s, 1H), 8.58 (s, 1H); 13C NMR (100 MHz, CDCl3):
106.5,
d
112.4, 113.1, 118.9, 120.0, 121.5, 123.6, 124.4, 125.8, 128.9,
129.1, 129.8, 134.9, 137.3, 138.2; ESI-MS: m/z = 245 [M + H];
Anal. Calc. for C17H12N2: C 83.59, H 4.94, N 11.47. Found:
C 83.52, H 4.96, N 11.52.
4.4.3. 3-Benzylidene-2,4-pentanedione (Scheme 4, I)
1H NMR (400 MHz, CDCl3) (ppm): 7.47 (s, 1H, C = CH),
7.37 (m, 5H, ArH), 2.40 (s, 3H, CH3), 2.26 (s, 3H, CH3); 13C
NMR (100 MHz, CDCl3) (ppm): 200.6, 191.5, 137.8, 134.8,
127.8, 125.6, 124.6, 123.9, 26.6, 21.4.
4.4.4. 4-Methyl-3-oxo-N-phenyl-2-
(phenylmethylene)pentanamide (Scheme 4, III)
1H NMR (400 MHz, CDCl3):
d 1.21 (d, 6H, J = 6.4 Hz), 3.36
4.3. Synthesis of the catalyst SiO2@MNP-A
(m, 1H), 7.14–7.18 (m, 1H), 7.32–7.38 (m, 5H), 7.47 (d, 2H,
J = 7.6 Hz), 7.56–7.59 (m, 3H), 7.64 (s, 1H); 13C NMR
For 5 min, 0.5 g of Silica coated magnetic nanoparticles
was dispersed in dry toluene (30 mL) by ultrasonification.
(3-Aminopropyl)triethoxy silane (1.8 g) were added and
(100 MHz, CDCl3): d 19.1, 36.7, 120.3, 125.0, 129.0, 129.1,
130.0, 130.1, 133.0, 136.2, 137.4, 140.7, 165.5, 202.6; ESI-
MS: m/z = 294 [M + H]; Anal. Calc. for C19H19NO2: C 77.77,
Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012

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(d) N. Koukabi, E. Kolvari, A. Khazaei, M.A. Zolfigol, B. Shirmardi-Sha-
ghasemi, H.R. Khavas, Chem. Commun. 47 (2011) 9230;
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(2012) 441;
H 6.55, N 4.76, O 10.92. Found: C 77.79, H 6.53, N 4.77,
O 10.91.
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We are grateful for the financial supports for this
research by the National Natural Science Foundation of
China (Grant 21106090 and 21272169), Zhejiang Provin-
cial Natural Science Foundation of China (No. LY12B02004)
and we are also grateful for the financial supports for this
research by Key Disciplines of Applied Chemistry of
Zhejiang Province, Taizhou University.
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Please cite this article in press as: Ying A, et al. Magnetic nanoparticle supported amine: An efficient and environmental
benign catalyst for versatile Knoevenagel condensation under ultrasound irradiation. C. R. Chimie (2014), http://
dx.doi.org/10.1016/j.crci.2014.05.012