12-tungstosilicic acid supported on different carriers: Pronounced catalytic activity in the synthesis of bis(indolyl)methanes under solvent-free conditions

Article abstract of DOI:10.1080/00397911003590196

12-Tungstosilicic acid supported on different metal oxides was used as catalyst in the synthesis of bis(indolyl)methanes via electrophilic substitution reactions of indole with structurally diverse aldehydes and cyclohexanone. The effects of solvent, cata

Full text of DOI:10.1080/00397911003590196

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12-Tungstosilicic Acid Supported
on Different Carriers: Pronounced
Catalytic Activity in the Synthesis of
Bis(indolyl)methanes Under Solvent-Free
Conditions
Ezzat Rafiee a b , Zohre Zolfagharifar a , Mohammad Joshaghani a b
Sara Eavani a
&
a Faculty of Chemistry, Razi University, Kermanshah, Iran
b Kermanshah Oil Refining Company, Kermanshah, Iran
Version of record first published: 13 Jan 2011.
To cite this article: Ezzat Rafiee , Zohre Zolfagharifar , Mohammad Joshaghani & Sara Eavani (2011):
12-Tungstosilicic Acid Supported on Different Carriers: Pronounced Catalytic Activity in the Synthesis
of Bis(indolyl)methanes Under Solvent-Free Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:3, 459-467
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Synthetic Communications1, 41: 459–467, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003590196
12-TUNGSTOSILICIC ACID SUPPORTED ON DIFFERENT
CARRIERS: PRONOUNCED CATALYTIC ACTIVITY IN
THE SYNTHESIS OF BIS(INDOLYL)METHANES UNDER
SOLVENT-FREE CONDITIONS
Ezzat Rafiee,1,2 Zohre Zolfagharifar,1
Mohammad Joshaghani,1,2 and Sara Eavani1
1Faculty of Chemistry, Razi University, Kermanshah, Iran
2Kermanshah Oil Refining Company, Kermanshah, Iran
12-Tungstosilicic acid supported on different metal oxides was used as catalyst in the
synthesis of bis(indolyl)methanes via electrophilic substitution reactions of indole with
structurally diverse aldehydes and cyclohexanone. The effects of solvent, catalyst loading,
and the nature of substituents on the aromatic ring of aldehydes were investigated. The
workup of the reaction consists of simple filtration, followed by concentration of the crude
product, and purification. A mechanism for the catalytic activity is proposed, and corre-
sponding products were obtained in good to excellent yields in relatively short reaction
times. The catalysts were reusable without significant loss of activity.
Keywords: Bis(indolyl)methanes; indole; solvent-free conditions; supported catalysts; 12-tungstosilicic
acid
INTRODUCTION
The acid-catalyzed reaction of indoles with aldehydes or ketones affords
corresponding bis(indolyl)methanes (BIMs), which are effective in the prevention
of breast cancer.[1] They are the most active cruciferous substances for promoting
beneficial estrogen metabolism in humans.[2] Numerous methods for the preparation
of BIMs employing protic acids or Lewis acids as catalysts have been reported in the
literature, but there are still some drawbacks in these catalytic systems, such as
the requirement for a large quantity of catalyst, long reaction times, poor yield of
products, drastic conditions for catalyst preparation, or tedious workup that leads
to the generation of large amounts of toxic waste.[3–13] Recently, several reports have
been published on the use of solid acids as catalyst for BIM synthesis, but they need
high temperatures for reactivation or CH3CN as solvent.[14–18] Among various solid
acids, heteropoly acids (HPAs) have been pointed out lately as versatile green
catalysts for a variety of organic reactions. The green aspect of HPA catalysts has
been discussed in terms of fundamental properties of these compounds to develop
Received August 28, 2009.
Address correspondence to Ezzat Rafiee, Faculty of Chemistry Razi University, Kermanshah,
67149, Iran. E-mail: ezzat_rafiee@yahoo.com
459

460
E. RAFIEE ET AL.
sustainable chemistry.[19] As a part of our research program concerning the use of
HPAs in fine chemical preparation,[20–23] we investigated the catalytic performance
of commercially available 12-tungstosilicic acid on different carriers in the one-pot
synthesis of BIMs to overcome existing limitations.
RESULTS AND DISCUSSION
Initially, the reaction of indole with benzaldehyde was performed in the pres-
ence of H3PW12O40 (PW), H3PMo12O40 (PMo), and H4SiW12O40 (SiW) (Fig. 1). The
results show that tungsten HPAs (PW, SiW) are preferred over molybdenum ones as
acid catalysts, and SiW is particularly effective. Thus, the reaction of indole with
benzaldehyde in the presence of 0.12 g SiW was chosen as a model for comparison
of solvents. The results are shown in Fig. 2. Among the solvents examined, CH3CN
proved to be the most effective. The reaction proceeds equally well in H2O and tetra-
hydrofuran (THF), whereas in toluene the reaction proceeded slowly. It was found
that in a solventless system, the reaction time increased by 1 min in comparison with
CH3CN. However, solvent-free reactions are preferable not only for their efficiency
and simplicity but also as green and sustainable procedures. Thus, the reaction of
indole and benzaldehyde was carried out in the presence of 40 wt.% of SiW sup-
ported on different carriers in solvent-free conditions (Scheme 1). For comparison,
the same reaction was performed in the presence of supports only (Table 1). It
was found that K10 solely showed considerable activity. Therefore, this can mask
the effect of SiW (entries 2 and 8). In other cases, supported SiW shows higher
activity compared to the support on a unit weight basis. The best catalysts are
formed by supporting SiW on SiO2, TiO2, and KSF (entries 9, 11, and 12). The acid-
ity of the catalysts was measured by potentiometric titration with n-butylamine. The
n-butylamine is considered a strong base, so its adsorption could be expected on sites
of different acid strength. The total solid acidity without distinguishing the type of
Figure 1. Effect of the type of HPA catalysts in the reaction of indole with benzaldehyde.

SUPPORTED-SiW–CATALYZED SYNTHESIS OF BIMs
461
Figure 2. Effect of solvent and solventless conditions in the reaction of indole with benzaldehyde in the
presence of 0.12 g of SiW.
acidity is titrated. The potentiometric titration curves obtained for the supported
catalysts during the n-butylamine titration are shown in Fig. 3. This technique eval-
uated the total number of acid sites (meq amine=g solid) and their strength (Ei) on
the catalyst surface (Table 1). The strength of the acid sites can be classified accord-
ing to following scale: Ei > 100 mV (very strong sites), 0 < Ei < 100 mV (strong sites),
À100 < Ei < 0 mV (weak sites), and Ei < À100 mV (very weak sites).[24] All sup-
ported catalysts have stronger acid sites in comparison with support only, and
according to the mentioned scale all of them present very strong acid sites. It is
observed that SiW=c-Al2O3 is less acidic than the others. This may be due to the
interaction of the strongest protons of SiW with the most basic sites on the alumina
surface. This acid–base interaction induces a partial neutralization of the acid sites
that leads a to decrease in acidity and catalytic activity (Table 1, entry 10).
In this respect, the results in entries 9, 11, and 12 of Table 1 become parti-
cularly interesting. Hence, further investigations were performed by using various
SiW loading on SiO2, TiO2, and KSF as supports in the model reaction (Table 2).
With an increase in SiW loading from 20 to 40 wt.%, catalytic activity was increased.
The further increase in SiW content possibly leads to the aggregation of SiW on the
support surface, and thus all active sites are not available and there is a decrease
in the catalytic activity.
Scheme 1. Model reaction.

462
E. RAFIEE ET AL.
Table 1. Optimization of catalysts in the reaction of indole with benzaldehyde
Entry
Catalyst
Time (min)
Yield (%)a
Meq=g
Ei (mV)
1
2
Activated carbon
K10
KSF
15
10
15
15
15
15
8
10
81
0
0.35
0.16
0.16
0.12
0.04
0.08
0.70
0.50
0.50
0.20
0.30
0.80
24
360
3
426
4
c-Al2O3
TiO2
SiO2
7
21.8
À14.4
78.1
670
5
0
6
0
7
40 wt.% SiW=C
40 wt.% SiW=K10
40 wt.% SiW=KSF
40 wt.% SiW=c-Al2O3
40 wt.% SiW=TiO2
40 wt.% SiW=SiO2
92
98
98
78
98
95
8
5
578
521
9
3
10
11
12
8
308
615
5
2
652
aIsolated yields.
Figure 3. Potentiometric titration curves for supported catalysts.
Table 2. Optimization of SiW loading in the reaction of indole with benzaldehyde
Entry
Catalyst
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
20 wt.% SiW=KSF
40 wt.% SiW=KSF
60 wt.% SiW=KSF
20 wt.% SiW=TiO2
40 wt.% SiW=TiO2
60 wt.% SiW=TiO2
20 wt.% SiW=SiO2
40 wt.% SiW=SiO2
60 wt.% SiW=SiO2
3
3
3
5
5
5
2
2
2
70
98
85
75
98
90
60
95
80
aIsolated yields.

SUPPORTED-SiW–CATALYZED SYNTHESIS OF BIMs
463
Figure 4. Effect of catalyst loading in the reaction of indole with benzaldehyde.
Consequently, various amounts of 40 wt.% of SiW=SiO2, SiW=TiO2, and SiW=
KSF catalysts were used in the reaction of indole with benzaldehyde under
solvent-free conditions (Fig. 4). It indicates that as the catalyst loading is increased,
the product yield increases, which is due to the increase in the number of active sites.
At higher catalyst loading, there were more catalytic sites than required, and thus it
does not affect the rate. Therefore, there is no more increase in the rate. Thus, 0.3 g
of catalysts was chosen as an ideal amount. Afterward, the study was extended to a
variety of carbonyl compounds in the presence of SiW=SiO2, SiW=TiO2, and SiW=
KSF as catalysts, which were selected because of their greater activity (Scheme 2).
The results summarized in Table 3 clearly indicate the scope of the reaction with
respect to various substituted aldehydes on these supported catalysts. The chloro-
and nitro-substituted aryl aldehydes as well as their simple electron-rich counterparts
with indoles gave the corresponding BIMs in excellent yields (entries 2 and 3). As
shown in Scheme 3, reaction of terephthalaldehyde (entries 8 and 9) with indole gave
the corresponding products 1 and 2. It was found that the reaction of 2 mmol indole
with terephthalaldehyde gave the corresponding BIM with high selectivity (entry 8)
while by using 4 mmol of indole the corresponding products 1 and 2 were obtained
with comparable yields (entry 9). Finally, reaction of cyclohexanone with indole
afforded the corresponding BIM in an excellent yield (entry 10), while some previous
approaches gave poor yields for a similar reaction. The reusability of SiW=SiO2,
SiW=TiO2, and SiW=KSF catalysts was examined in the reaction of indole with
benzaldehyde under solvent-free conditions. All of these catalysts could be recovered
and subsequently reused several times (Fig. 5).
Scheme 2. Reaction of indole with various carbonyl compounds.

464
E. RAFIEE ET AL.
Table 3. Synthesis of various BIMs
Time (min)=Yield (%)a
Entry
R1
R2
SiW=TiO2
SiW=SiO2
SiW=KSF
1
2
H
H
H
H
H
H
H
H
H
C6H5
4-Cl-C6H4
5=98
10=94
10=98
5=52
2=95
7=95
3=98
15=96
15=93
3
4-NO2-C6H4
4-OH-C6H4
5=94
20=71
4
5=51
10=89
5
4-CH3-C6H5
4-OCH3-C6H5
3,4-(OCH3)2-C6H3
4-CHO-C6H4
4-CHO-C6H4
15=91
7=92
7=96
7=95
6
10=94
12=98
7
13=95
5=82
6=94
8b
9b,c
10
8=61 (30)
10=56 (44)
15=98
5=63 (19)
10=46 (45)
10=95
10=38 (62)
13=96
aIsolated yields.
bResults in parentheses show the yield of product 2.
c4 mmol of indole were used in this reaction.
Scheme 3. Reaction of indole with terephthalaldehyde.
Figure 5. Reusability of the catalysts in the reaction of indole with benzaldehyde after 5 min.

SUPPORTED-SiW–CATALYZED SYNTHESIS OF BIMs
465
Scheme 4. Reaction mechanism.
A proposed mechanism of the reaction is shown in Scheme 4. An aldehyde or
ketone is first protonated by the solid acid catalyst and an electrophilic substitution
reaction at the C-3 position of indole is carried out. After loss of water, an intermedi-
ate is generated, which is further activated by protons and serves as an electrophile to
attack a second molecule of indole to form the corresponding BIM.
CONCLUSION
SiW supported on TiO2, SiO2, and KFS shows comparable catalytic activity in
the synthesis of BIM. The catalytic activity of these catalysts is remarkable, and the
catalyst–substrate molar ratio required was very low. In addition, this procedure
offers several advantages such as easy catalyst separation from the reaction medium,
a simple workup procedure, catalyst reusability, short reaction time, and good to
excellent product yields. Moreover, the use of environmentally benign catalysts
and avoidance of hazardous organic solvents are important features of these
methodologies.
EXPERIMENTAL
Preparation of Supported SiW
Portions of 20, 40, and 60 wt.% of SiW=support catalysts were prepared by
impregnating the support with an aqueous solution of SiW (with concentration
depending upon the loading: 20, 40, and 60 wt.% SiW), followed by drying as
described in our previously published papers.[21,25,26]
Acidity Measurement
For the potentiometric titration, 0.05 g of the solid was suspended in aceto-
nitrile (90 mL) and stirred for 3 h. The suspension was titrated with a 0.05 N solution

466
E. RAFIEE ET AL.
of n-butylamine in acetonitrile. The potential variation was measured with a Hanna
302 pH meter using a double-junction electrode.
Catalytic Reaction
Aldehyde (1mmol) and indole (2 mmol) were mixed in the presence of an appro-
priate amount of catalyst at room temperature. The reaction was performed in solvent
(3 mL) and solvent-free conditions. After completion of the reaction as indicated by
thin-layer chromatography (TLC), the catalyst was filtered (in a solventless system,
the mixture was diluted with acetone, 5 mL). Evaporation of the solvent under vacuum
afforded a crude product, which was purified by column chromatography on silica gel
using EtOAc=petroleum ether as eluent. All products were identified by comparing of
their spectral data with those of the authentic samples.[26–28] Recovered catalyst was
washed with ether (3Â 10mL) and dried before reusing.
ACKNOWLEDGMENTS
The authors thank the Razi University Research Council and Kermanshah Oil
Refining Company for support of this work.
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