12-Tungstophosphoric acid immobilized on γ-Fe2O 3@SiO2 coreshell nanoparticles: An effective solid acid catalyst for the synthesis of indole derivatives in water

Article abstract of DOI:10.1246/cl.2012.438

12-Tungstophosphoric acid immobilized on γ-Fe₂O ₃@SiO₂ coreshell nanoparticles was used as novel solid acid catalyst for the synthesis of various bis(indolyl)methanes and β-functionalized indoles in water. The catalyst can

Full text of DOI:10.1246/cl.2012.438

doi:10.1246/cl.2012.438
438
Published on the web April 4, 2012
12-Tungstophosphoric Acid Immobilized on £-Fe2O3@SiO2 Core-Shell Nanoparticles:
An Effective Solid Acid Catalyst for the Synthesis of Indole Derivatives in Water
Ezzat Rafiee,*1 Sara Eavani,1 and Bizhan Malaekeh-Nikouei2
1Faculty of Chemistry, Razi University, Kermanshah 67149, Iran
2Nanotechnology Research Centre, School of Pharmacy,
Mashhad University of Medical Sciences, Mashhad, Iran
(Received January 12, 2012; CL-120056; E-mail: e.rafiei@razi.ac.ir)
12-Tungstophosphoric acid immobilized on £-Fe2O3@SiO2
Fe(II)
+
2Fe(III)
NH4OH
Reflux
TEOS
PW
core-shell nanoparticles was used as novel solid acid catalyst for
the synthesis of various bis(indolyl)methanes and ¢-functional-
ized indoles in water. The catalyst can be recovered simply using
an external magnetic field and reused several times without
appreciable loss of its catalytic activity.
65.5 nm
Fe2O3
79.3 nm
94 nm
Fe2O3@SiO2 Fe2O3@SiO2-PW
Scheme 1. Design of the £-Fe2O3@SiO2-PW catalyst.2
Introducing of new, efficient, and strategically important
processes, which are environmentally benign and lead to greater
structural variation in a short period of time with high yields and
simple workup procedure is an important goal of synthetic
organic chemistry and one of the key paradigms of modern drug
discovery. Recent tendencies have been focused on the replace-
ment of homogeneous catalysts with heterogeneous analogs,
which can be easily recovered from the reaction mixture thereby
eliminating the need for separation through distillation or
extraction.
CHO
Catalyst
+
H2O (5mL), r.t.
N
H
N
H
N
H
Scheme 2. Model reaction.
possible the complete recovery of the catalyst by means of an
external magnetic field, which is an important advantage of the
use of a magnetically separable catalyst.5 Furthermore, nano-
scale supports have high surface area resulting in high catalyst
loading capacity, high dispersion, and outstanding stability.
Also, they do not suffer from porosity and other problems
associated with the transport of reactants and/or products to and
from the catalytic sites. As a result, the immobilization of HPAs
on the silica-coating magnetic core turned out to be beneficial,
giving rise to an invariant high activity and improved numbers
of recycle and reuse in comparison to immobilization on
conventional solid supports. These findings encourage us to
extend the catalytic application of £-Fe2O3@SiO2-PW for the
synthesis of useful building blocks and/or biologically active
compounds in water.
In the field of heterogeneous catalysis, solid-supported
Keggin type heteropolyacids (HPAs), such as 12-tungstophos-
phoric acid, H3PW12O40 (PW), arouse much attention for they
not only have strong Brønsted acidity, but they can also be
recovered from reaction media and reused. Among the supports
that can be used to immobilize HPAs, acidic or natural substance
like SiO2, TiO2, or active carbon is suitable and the Keggin
structure of HPAs is retained upon adsorption onto their surfaces
over a broad range of loading. However, although these solid-
supported HPAs can be recovered by filtration or precipitation,
lower activity or selectivity compared to homogeneous ones
are commonly detected due to steric and diffusion factors. In
addition, weak interaction between HPA and supports results in
its leaching from the support surface in polar reaction media.1
In the attempt to resolve such problems, nanomagnetically
recoverable HPA-based catalyst was first synthesized in our
laboratory and used as novel special heterogeneous HPAs in
Mannich type reactions in water.2 A simple ferric oxide, £-
Fe2O3, was used as the magnetic material for its low price,
simplicity, and nontoxicity. It was prepared through chemical
coprecipitation, and subsequently was coated with silica shell
by the Stöber process,3 that is the hydrolysis of tetraethyl
orthosilicate (TEOS) in an ethanol solution containing water
and ammonia. After the surface coating by SiO2, magnetic
solid (designed as £-Fe2O3@SiO2) was used as support for
immobilization of PW. The obtained catalyst (designed as
£-Fe2O3@SiO2-PW) was collected by a permanent magnet
and dried (Scheme 1).2,4 Typically, a loading at ca. 31 wt %
PW (1.1 mmol g¹1) was obtained. It was found that the £-
Fe2O3@SiO2-PW catalyst exhibits several attractive features for
the synthesis of fine chemicals. The magnetic properties make
Among the different protocols for the synthesis of useful
building blocks, we selected the synthesis of 3-substituted
indoles, particularly 3-alkylindoles and bis(indolyl)methanes,
because of their very high impact as synthons for the preparation
of various bioactive compounds.6,7
Optimized experiments were carried out by using different
amounts of £-Fe2O3@SiO2-PW catalyst in the model reaction
(Scheme 2) and results were summarized in Table 1. Control
experiment showed that the substrates hardly reacted together
in the absence of catalyst (Table 1, Entry 1). £-Fe2O3@SiO2
showed poor effect on the yield of the product (Table 1,
Entry 2). When using the Fe2O3@SiO2-PW as catalyst, a
significant improvement was observed (Table 1, Entry 3). As
can be seen, by using of 0.05 g of Fe2O3@SiO2-PW as catalyst,
the product was obtained in excellent yield within short reaction
time while more than 0.05 g of the catalyst had no effect on
product yield (Table 1, Entries 3-7). Therefore, 0.05 g of
catalyst was selected as the best catalyst loading in further
Chem. Lett. 2012, 41, 438-440
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

439
Table 1. Catalytic activity of £-Fe2O3@SiO2-PW in the
reaction of benzaldehyde and indole as model substratesa
Time
/min
Yield
/%b
Entry
Catalyst
1
2
3
4
5
6
7
8
9
®
25
25
25
25
25
25
25
25
25
0
14
51
62
80
98
98
21
48
£-Fe2O3@SiO2 (0.01 g)
£-Fe2O3@SiO2-PW (0.01 g)
£-Fe2O3@SiO2-PW (0.02 g)
£-Fe2O3@SiO2-PW (0.03 g)
£-Fe2O3@SiO2-PW (0.05 g)
£-Fe2O3@SiO2-PW (0.1 g)
£-Fe2O3@SiO2 (0.05 g)
PW (0.05 g)
aReaction conditions: indole (2 mmol), benzaldehyde (1 mmol),
b
H2O (5 mL), room temperature. Isolated yields.
Figure 1. Reusability of £-Fe2O3@SiO2-PW (after 30 min).
CO2H
investigations. The catalytic activity of 0.05 g of Fe2O3@SiO2-
PW catalyst was compared with Fe2O3@SiO2 and unsupported
PW on unit weight basis (Table 1, Entries 8 and 9). The results
showed that Fe2O3@SiO2 was not efficient in the reaction and
the yield was much lower than that obtained using the
Fe2O3@SiO2-PW catalyst. However, when PW was used as
the catalyst, a moderate yield of the product was obtained
(Table 1, Entry 9). Nevertheless, the reaction proceeded in a
homogeneous system, which makes catalyst recovery very
difficult.
Me
N
H
N
H
1a
1b
N
H
1c
O
CHO
CHO
CHO
2d
2a
O
O
S
2c
2b
CHO
Formaldehyde 2g
2e
2f
NO2
O
O
O
O
O
O
OEt
OMe
3a
4a
3b
3c
In order to exam the reusability of the catalyst, the model
reaction was carried out by using 0.5 g of catalyst and the
experiments were properly scaled up. At the end of reaction,
bis(3-indolyl)phenylmethane was obtained as pinkish solid
product. The reaction mixture was centrifuged and water was
removed from the mixture to leave residue. The product was
dissolved in acetonitrile and the catalyst easily separated from
the product by attaching an external magnet onto the reaction
vessel, followed by decantation of the product solution. The
catalyst could be recovered and subsequently reused several
times without significant loss of activity (Figure 1). To check the
leaching of PW into the reaction mixture, the model reaction was
carried out for 1 h under selected reaction conditions. Then, the
reaction was stopped, catalyst and product were separated by
centrifugation, and the filtrate was added to a mixture of indole
and benzaldehyde as model substrates and stirred for 1 h. Only
15% of the corresponding product was obtained indicating
negligible PW leaching into the reaction mixture. This obser-
vation confirmed that the reaction was catalyzed heterogene-
ously. In addition, the content of PW into filtrate was evaluated
quantitatively by inductively coupled plasma atomic emission
spectroscopy (ICP-AES), which showed 12.2% of the initial
content was leached into reaction mixture. Nevertheless, the
yield of product was not substantially modified (10% difference)
after the fourth run.
Et NH
Et
NH
O
NH
4c
4b
Scheme 3. Various substrates.
R4
R3
R2
N
H
O
N
H
Catalyst (0.05g)
H2O (5mL), r.t.
R1R1
(a)
5a-g
+
R1
R3 R4
N
H
R2
R2
2a-e
1a-c
N
H
HN
5h
R3
R3
R4
R4
O
R5
O
O
O
R3 R4
Catalyst (0.05g)
H2O (5mL), r.t.
(b)
(c)
1a
1a
R5
+
+
COMe
2a, 2f
3a-c
N
H
6a-d
R6
N
Catalyst (0.1g)
H2O (5mL), r.t.
R7
7a-c
2g
+
R6R7NH
+
N
H
4a-c
Scheme 4. Various reactions for the synthesis of indole
derivatives.
To evaluate the scope and generality of this new protocol,
various aldehydes and ketones, as well as amines and ¢-
dicarbonyl compounds were tested as the substrates (Scheme 3).
At first, we investigated the electrophilic substitution of indole
with various aldehydes and ketones to probe their behavior
under the current catalytic conditions (Scheme 4a).8 The catalyst
has been applied successfully for the condensation of hetero-
aromatic aldehydes 2b and 2c to afford the corresponding
bis(indolyl)methanes in excellent yields (Table 2, Entries 2 and
3). It is also worth mentioning that the reaction is general and is
applicable to cyclic and aromatic ketones (Table 2, Entries 4 and
5) to afford the corresponding product in high yields, although
longer reaction times were required for their conversion. 2-
Methylindole (1b) reacted well with 2a and 2d to give the
Chem. Lett. 2012, 41, 438-440
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

440
References and Notes
Table 2. Synthesis of various indole derivatives in the presence
of £-Fe2O3@SiO2-PW
1
P. M. Rao, A. Wolfson, S. Kababya, S. Vega, M. V. Landau,
J. Catal. 2005, 232, 210.
Yield
/%b
Entry
Substrates
Producta
Time
2
3
4
E. Rafiee, S. Eavani, Green Chem. 2011, 13, 2116.
W. Stöber, A. Fink, E. Bohn, J. Colloid Interface Sci. 1968, 26, 62.
Preparation of the catalyst: FeCl2¢4H2O (2.0 g) and FeCl3¢6H2O
(5.4 g) were dissolved in water (20 mL) separately, followed by the
two iron salt solutions being mixed under vigorous stirring. An
NH4OH solution (0.6 M, 200 mL) was then added to the stirring
mixture at room temperature, immediately followed by the
addition of a concentrated NH4OH solution (25% w/w, 30 mL)
to maintain the reaction pH between 11 and 12. The resulting
black dispersion was continuously stirred for 1 h at room temper-
ature and then heated to reflux for 1 h to yield a brown dispersion.
It was then purified by a four times repeated centrifugation,
decantation, and redispersion cycle until a stable brown magnetic
dispersion (pH 9.2) was obtained. Coating of a layer of silica on
the surface of the nanoparticles was achieved by premixing a
dispersion of the purified nanoparticles (8.5% w/w, 20 mL)
obtained previously with ethanol (80 mL) for 1 h at 40 °C. A
concentrated ammonia solution was added and the resulting
mixture stirred at 40 °C for 30 min. Subsequently, TEOS (1.0 mL)
was charged to the reaction vessel and the mixture continuously
stirred at 40 °C for 24 h. It was collected using a permanent
magnet, followed by washing three times with ethanol, diethyl
ether, and drying under vacuum for 24 h. 0.7 g of PW was
dissolved in 5 mL of dry methanol. This solution was added
dropwise to a suspension of 1.0 g £-Fe2O3@SiO2 in methanol
(50 mL) while being dispersed by sonication. The mixture was
heated at 70 °C for 72 h under vacuum while being mechanically
stirred to obtain £-Fe2O3@SiO2-PW. The catalyst was collected
by a permanent magnet and dried under vacuum overnight.
M. Kotani, T. Koike, K. Yamaguchi, N. Mizuno, Green Chem.
2006, 8, 735.
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
15d
16c
17c
1a
1a
1a
1a
1a
1b
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2b
2c
2d
2e
2a
2d
2a
2a
2a
2a
2f
2g
2g
2g
2g
2g
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
7a
7a
7a
7b
7c
30 min
40 min
45 min
80 min
330 min
25 min
75 min
360 min
45 min
1 h
1 h
1 h
3 h
3 h
3 h
5 h
5 h
98
94
95
86
62
98
91
80
98
95
96
76
77
94
98
86
81
3a
3b
3c
3b
4a
4a
4a
4b
4c
aAll products were identified by comparing of their spectral
data with those of the authentic samples.9-14 bIsolated yields.
d
c0.1 g of the catalyst was used in this reaction. 0.2 g of the
catalyst was used in this reaction.
5
corresponding products 5f and 5g in excellent yields (Table 2,
Entries 6 and 7). Under these reaction conditions, indole-3-acetic
acid (1c) on reaction with 2a gave 5h in good yield (Table 2,
Entry 8).
Considering the synthetic utility of ¢-diketones and ¢-
ketoesters, their reactivity with indole and various aldehydes has
also been investigated (Scheme 4b).8 As expected, trimolecular
condensation reaction of 1a with 2a and ¢-dicarbonyl com-
pounds 3a-3c afforded the corresponding products 6a-6c in
excellent yields (Table 2, Entries 9-11). These experimental
conditions could successfully be extended to 2-nitrobenzalde-
hyde (2f) giving product 6d with satisfactory yield (Table 2,
Entry 12).
A Mannich-type reaction of secondary amine, formalde-
hyde, and indole was chosen as another way for the synthesis of
¢-functionalized indoles derivatives (Scheme 4c).8 As the first
case, the reaction of 1a, 4-methylpiperidine (4a), and formal-
dehyde (2g) was performed under optimized conditions
(Table 2, Entry 13). The corresponding product 7a was obtained
in good yield. Increasing the quantity of catalyst from 0.05 to
0.1 g improved the result to a greater extent while further
addition of catalyst had no noticeable effect on the yield or
reaction time (Table 2, Entries 13-15). Thus, 0.1 g of catalyst
was used for the synthesis of compounds 7b and 7c in good
yields (Table 2, Entries 16 and 17).
6
7
8
J.-i. Matsuo, Y. Tanaki, H. Ishibashi, Tetrahedron 2008, 64, 5262.
M. A. Zeligs, J. Med. Food 1998, 1, 67.
General procedure for the synthesis of products 5a-5h: A mixture
of aldehyde (1 mmol), indole (2 mmol), catalyst (0.05 g), and H2O
(5 mL) was stirred at room temperature. At the end of reaction,
water was removed from the mixture by centrifugation. The
product was dissolved in acetonitrile and the catalyst separated
from the product by an external magnet. The solvent was
evaporated in vacuum to give the product which was purified by
column chromatography on silica gel. General procedure for the
synthesis of products 6a-6d: A mixture of indole (1 mmol),
aldehyde (1 mmol), 1,3-dicarbonyl compound (1 mmol), and
catalyst (0.05 g) in H2O (5 mL) was stirred at room temperature.
Purification of products and recyclization of the catalyst are
similar to above procedure. General procedure for the synthesis of
products 7a-7c: A mixture of indole (1 mmol), amine (1.2 mmol),
formaldehyde (1.2 mmol), and catalyst (0.1 g) in H2O (5 mL) was
stirred at room temperature. At the end of reaction, CH2Cl2
(2 © 5 mL) was added and the reaction mixture was stirred. The
catalyst separated from the product by an external magnet onto the
reaction vessel, followed by decantation of the reaction mixture.
The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated. The residue was purified by column
chromatography on silica gel to afford the pure product.
9
J.-T. Li, S.-F. Sun, M.-X. Sun, Ultrason. Sonochem. 2011, 18, 42.
10 S.-J. Ji, S.-Y. Wang, Y. Zhang, T.-P. Loh, Tetrahedron 2004, 60,
2051.
11 J.-T. Li, H.-G. Dai, W.-Z. Xu, T.-S. Li, Ultrason. Sonochem. 2006,
13, 24.
12 G. V. M. Sharma, J. J. Reddy, P. S. Lakshmi, P. R. Krishna,
Tetrahedron Lett. 2004, 45, 7729.
13 S. Gérard, A. Renzetti, B. Lefevre, A. Fontana, P. de Maria, J.
Sapi, Tetrahedron 2010, 66, 3065.
Based on these results, it is expected that the £-
Fe2O3@SiO2-PW will be new promising catalysts in the
synthesis of biologically active indole derivatives.
14 B. B. Semenov, Y. I. Smushkevich, Russ. Chem. Bull. 2001, 50,
543.
We thank the Razi University Research Council and Iran
National Science Foundation (INSF) for support of this work.
Chem. Lett. 2012, 41, 438-440
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/