Polyvinylpolypyrrolidone-supported triflic acid (PVPP·OTf) as a new, efficient, and recyclable heterogeneous catalyst for the synthesis of bis-indolyl methane derivatives

Article abstract of DOI:10.1016/j.crci.2013.07.014

A simple, inexpensive, environmentally friendly and efficient route for the synthesis of bis-indolyl methane derivatives by the reaction of indole or N-methyl indole with aldehydes using polyvinylpolypyrrolidone-supported triflic acid (PVPP·OTf) as a cata

Full text of DOI:10.1016/j.crci.2013.07.014

C. R. Chimie 17 (2014) 30–34
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Full paper/Memoire
Polyvinylpolypyrrolidone-supported triflic acid (PVPPÁOTf) as
a new, efficient, and recyclable heterogeneous catalyst for the
synthesis of bis-indolyl methane derivatives
b
a
Samad Khaksar a, , Mahmoud Tajbakhsh , Milad Gholami
*
a Chemistry Department, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
b Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar 47415, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, inexpensive, environmentally friendly and efficient route for the synthesis of bis-
indolyl methane derivatives by the reaction of indole or N-methyl indole with aldehydes
using polyvinylpolypyrrolidone-supported triflic acid (PVPPÁOTf) as a catalyst is described.
PVPPÁOTf catalyst is air-stable, heterogeneous, cost-effective, easy to handle, and easily
removed from the reaction mixtures.
Received 20 January 2013
Accepted after revision 25 July 2013
Available online 4 October 2013
Keywords:
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
PVPPÁOTf
Polymer
Indole
Bis-indolyl methane
Heterogeneous
1. Introduction
immobilization of triflic acid onto an inorganic material,
such as silica gel, affords solid acids that can be easily
Organic synthesis using heterogeneous catalysts in the
place of homogeneous reagents has received much
attention from the standpoint of green and sustainable
chemistry because of the possibility of performing
environmentally highly acceptable chemical processes
[1–4]. The use of heterogeneous catalysts in liquid phase
offers several advantages over homogeneous ones, includ-
ing the ease of recovery and recycling, atom utility, and
enhanced stability [5,6]. Triflic acid (TfOH) is widely used
as an acid catalyst due to its very strong Brønsted acidity,
structure, and properties. Because triflic acid is highly
corrosive and it is a fuming liquid, difficulties remain in its
storage, transportation, handling, and waste disposal,
which severely restricts its application in industry. The
handled, as they invariably are low-toxicity, non-corrosive,
free-flowing powders with superior thermal and mechan-
ical stability under catalytic conditions [7].
Different catalytic systems have been studied, in which
TFA is adsorbed on various solids, but they are all subject to
leaching [8]. Polyvinylpolypyrrolidone displays a strong
binding affinity toward small molecules. Furthermore, its
iodine complex, povidone–iodine, is widely used as an
anti-infective agent in clinical treatments [9]. In continu-
ing our studies on the application of new reagents or
systems for organic functional group transformations [10–
15], we decided to apply an appropriate method for the
synthesis of bis-indolyl methanes derivatives. In this light,
we have supported triflic acid on polyvinylpolypyrrolidone
to prepare an efficient and mild catalyst for the hetero-
geneous preparation of bis-indolyl methane derivatives.
Bis-indolyl methane derivatives (BIMs) are important
biologically active heterocycles. They show antibacterial,
anti-inflammatory and antiviral activities [16–20], and can
*
Corresponding author.
E-mail addresses: S.khaksar@iauamol.ac.ir,
samadkhaksar@yahoo.com (S. Khaksar).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.07.014

S. Khaksar et al. / C. R. Chimie 17 (2014) 30–34
31
R1
PVPP.OTf (30 mg)
R1CHO
+
2
CH3CN, r.t, 0.5-4 h
N
N
N
R
2
1
R
R
3a- n
1a: R= H
1b: R= CH
*
3
n
*
-
N+
PVPP.OTf =
CF3SO3
O
H
Scheme 1. Synthesis of bis(indolyl)methanes 3 catalyzed by PVPPÁOTf.
also be useful in the treatment of fibromyalgia, chronic
fatigue and irritable bowel syndrome [21,22], and as
dietary supplements for promoting healthy estrogen
metabolism in humans [23]. As a result of their biological
and synthetic importance, a number of synthetic methods
for the preparation of bis(indolyl)alkane derivatives have
been reported in the literature by the reaction of indole
with various carbonyl compounds in the presence of a
catalyst [24–38]. However, some of these procedures have
certain limitations, such as high reaction temperatures,
prolonged reaction time, the use of toxic solvents, or low
yields. The recovery and reusability of the catalyst is also a
problem. Therefore, it is still desirable to seek a green and
ecofriendly protocol that uses a highly efficient and
reusable catalyst for the preparation of bis(indolyl)alkanes.
Herein, we found that PVPPÁOTf could be used for the
preparation of bis(indolyl)alkanes by the reaction of indole
or N-methyl indole with aldehydes in good to excellent
yields (Scheme 1).
in the presence of 30 mg of PVPPÁOTf afforded the product 3
in 97% yield (Table 1, entry 3). Either increasing the amount
of catalyst and/or prolonging the reaction time did not
improve the yield (Table 1, entry 9), while reducing these
factors led to a reduction in the product yield (Table 1, entry
2). Buildinguponthisresult,furtherstudieswereconducted,
and it was found that 30 mg of PVPPÁOTf were optimum for
this reaction and gave a product of 97% yield in just 0.5 h
(Table 1, entry 3). The reaction was also examined in
solvents, such as H2O, THF, CH2Cl2, ethanol, and diethyl
ether. In the presence of these solvents, the reaction was
sluggish and the formation of the by-products was observed
(Table 1, entries 4–8).
These results prompted us to investigate the scope and
the generality of this new protocol for various aldehydes
and ketones under optimized conditions (Table 2).
A series of aromatic, aliphatic aldehydes and simple
ketones underwent an electrophilic substitution reaction
with indole or N-methyl indole smoothly to afford a wide
range of substituted bis(indolyl)methanes in good to
excellent yields (Table 2). This method is equally effective
for aldehydes bearing electron-withdrawing or -donating
substituents in the aromatic rings. Furthermore, acid
sensitive aldehydes worked well without any decomposi-
tion or polymerization under these reaction conditions.
Also, tris-indolyl methane was produced in excellent yield
(Table 2, entry 10). As it is expected, N-methyl indole
provided better yields of the products in comparison with
indole under the same reaction conditions. This method is
even effective with aliphatic aldehydes, which normally
produce low yields due to their intrinsic lower reactivity.
The present method is also highly chemoselective for
2. Results and discussion
In order to optimize the reaction conditions, we chose
the condensation reaction of indole with 4-chlorobenzal-
dehyde catalyzed by PVPPÁOTf under different conditions,
both in the absence and in the presence of PVPPÁOTf; the
results are given in Table 1. It is noteworthy that, in the
absence of catalyst, the reaction failed to give the desired
product, even after long reaction times (24 h, Table 1, entry
1). Then, the effect of temperature, the amount of catalyst,
and the reaction time on the yield of the product was
examined. Reaction at room temperature (rt) in acetonitrile
aldehydes. For example, when
a 1:1 mixture of 4-
chlorobenzaldehyde and acetophenone was allowed to
react with indole in the presence of PVPPÁOTf in
acetonitrile, it was found that only 4-chlorophenyl-3,3-
bis(indolyl)methane (3a) was obtained, while acetophe-
none did not give the corresponding product under these
reaction conditions (Scheme 2).
The reactions were clean and the products were
obtained in high yields without the formation of any
side-products, such as N-alkylated ones.
The characterization of the Brønsted acid sites present
in the polymer was performed by recording the FT–IR
spectrum of PVPPÁOTf, which shows a strong broad
absorption at 3400 cmÀ1 for the O–H bond and a moderate
absorption at 1648 cmÀ1 that corresponds to the internal
Table 1
Effects of the amount of PVPPÁOTf catalyst used and of the solvent on the
formation of 4.
Entry PVPPÁOTf amount (mg) Condition/solvent Time (h)/yield
1
2
3
4
5
6
7
8
9
0
10
30
30
30
30
30
30
50
rt/CH3CN
rt/CH3CN
rt/CH3CN
rt/CH2Cl2
rt/THF
24/0
2/80
0.5/97
24/20
24/30
10/70
24/20
24/10
0.5/97
rt/ethanol
rt/H2O
rt/diethyl ether
rt/CH3CN
rt: room temperature.

32
S. Khaksar et al. / C. R. Chimie 17 (2014) 30–34
Table 2
PVPPÁOTf-catalyzed synthesis of BIMs.
Entry
1
Aldehyde/ketone
Indole
Time (h)
0.5
Product
Yield (%)
97
3a
CHO
N
Cl
H
2
3
3b
3c
3d
3e
3f
96
93
93
90
90
90
90
96
90
CHO
Cl
N
H
3
1
CHO
CHO
CHO
N
H
O2N
O2N
4
2
N
H
5
1.5
1
N
H
Br
6
CHO
N
H
7
1.5
2
3g
3h
3i
CHO
N
H
Me
MeO
O
8
CHO
N
H
9
1
CHO
CHO
N
H
10
1.5
3j
N
H
N
H
11
12
13
14
15
1
3k
3l
85
95
95
70
60
CHO
N
H
0.5
1
CHO
CHO
N
Cl
Br
Me
3k
3m
3n
N
Me
4
O
O
N
H
4
N
H
Cl
O
O
PVPP.OTf (30 mg)
CH3CN, r.t, 30 min
+
N
H
+
Cl
CHO
N
N
H
3a
97%
H
100 %
Scheme 2. Chemoselectivity of the aldehyde in the reaction with indole in the presence of ketone.

S. Khaksar et al. / C. R. Chimie 17 (2014) 30–34
33
Fig. 1. FT–IR spectrum of polyvinylpolypyrrolidone (PVPP) and (PVPPÁOTf) catalyst.
imine groups present in the pendant rings of the polymer
(Fig. 1). The loading capacity of the reagent was
determined by titration and was found to be 10 mmol/g,
ꢀ
bis-indolyl methanes derivatives are produced by an
environmentally benign process.
whereas its silica-supported analogue has
capacity of less than 1 mmol/g.
a loading
4. Experimental
As PVPPÁOTf is not soluble in acetonitrile, no PVPPÁOTf
leaching as well as no contribution of homogeneous
catalysis in the course of reaction was expected. To prove
this, after 3 h, the catalyst was removed from acetonitrile
by filtration and the supernatant was tested for activity.
No activity was observed, indicating that there was no
contribution of homogeneous catalysis in this reaction.
After the reaction, the catalyst can be easily separated (by
filtration) and reused after washing with dichloro-
methane, with gradual decrease in its activity. For
example, the reaction of indole with 4-chlorobenzalde-
hyde afforded the corresponding bis-indolyl methane
derivative in 97%, 95%, and 95% isolated yield over the
three cycles.
4.1. Preparation of the polyvinylpolypyrrolidone-supported
triflic acid (PVPPÁOTf)
To a suspension of polyvinylpolypyrrolidone (3.0 g) in
toluene (35 mL), TfOH (2.0 g, 13 mmol) was added. The
mixture was stirred magnetically for 60 min at rt. The
toluene was removed under reduced pressure and the
residue was dried at 110 8C for 2 h to afford PVPPÁOTf
as a white powder. The number of H+ sites PVPPÁOTf,
which was determined by acid–base titration, was
10 mequiv/g.
4.2. Typical experimental procedure
A mixture of aldehyde (1 mmol), indole (2 mmol)
dissolved in 4 mL acetonitrile, and PVPPÁOTf (30 mg) was
stirred for the appropriate reaction time. The reaction was
monitored by TLC. After completion of the reaction, the
mixture was washed with chloroform and filtered to
recover the catalyst. The filtrate was evaporated and dried.
The products were characterized by comparison of their
physical and spectral data with those of the authentic
samples [37]. Spectroscopic data for the selected examples
are shown below. Spectroscopic data for the selected
examples are as follows.
3. Conclusions
In conclusion, a simple and highly efficient method for
the synthesis of bis-indolyl methanes derivatives has been
developed via the condensation of indole with aldehydes
catalyzed by polyvinylpolypyrrolidoniume triflate in
acetonitrile at room temperature. In contrast to the
existing methods using potentially hazardous catalysts/
additives, the present method offers the following
competitive advantages:
ꢀ
PVPPÁOTf is easy to prepare from commercially available
polyvinylpolypyrrolidone and triflic acid;
short reaction time;
ease of product isolation/purification;
no side reactions;
4.2.1. Bis(3-indolyl)-tolylmethane
Pale–red solid, mp 96–97 8C; 1H NMR (400 MHz,
ꢀ
ꢀ
ꢀ
ꢀ
CDCl3): d = 2.31 (s, 3H), 5.84 (s, 1H), 6.65 (s, 2H), 6.99 (t,
2H, J = 7.2 Hz), 7.07 (d, 2H, J = 8.0 Hz), 7.15 (t, 2H, J = 7.6 Hz),
7.21 (d, 2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H,
J = 8.0 Hz),7.86 (br s, 2H); 13C NMR (100 MHz, CDCl3):
low costs and simplicity in the process and handling;

34
S. Khaksar et al. / C. R. Chimie 17 (2014) 30–34
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d
= 21.1, 39.8, 110.9, 119.2, 119.9, 120.0, 121.8, 123.5,
131 (2010) 106.
127.1, 128.5, 128.9, 135.4, 136.7, 141.0 (Table 1, entry 7).
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(2010) 1377.
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(2010) 2250.
4.3. Tris (3-indolyl)methane
Pale yellow solid; mp 160 8C. 1H NMR (400 MHz,
CDCl3):
d = 6.07 (s, 1 H), 6.87 (s, 3H), 6.85 (t, 3H,
J = 7.4 Hz), 7.03 (t, 3H, J = 7.2 Hz), 7.43 (d, 3H, J = 7.8 Hz),
7.55 (d, 3H, J = 7.8 Hz), 10.72 (s, 3H, –NH); 13C NMR
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(100 MHz, CDCl3):
120.5, 123.1, 126.5, 136.4 (Table 1, entry 10).
d = 30.8, 111.2, 117.8, 118.2, 119.4,
Acknowledgments
This research is supported by the Islamic Azad
University, Ayatollah Amoli Branch.
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