A green method for the synthesis of bis-indolylmethanes and 3,3′-indolyloxindole derivatives using cellulose sulfuric acid under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2009.09.001

A highly efficient green protocol for the preparation of bis-indolylmethanes, bis-2-methylindolylmethanes, bis-1-methylindolylmethanes and 3,3′-diindolyloxindole derivatives from the reaction of indoles with various aldehydes and ketones in the presence o

Full text of DOI:10.1016/j.cclet.2009.09.001

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Chinese Chemical Letters 21 (2010) 183–186
www.elsevier.com/locate/cclet
A green method for the synthesis of bis-indolylmethanes and
3,30-indolyloxindole derivatives using cellulose sulfuric acid
under solvent-free conditions
*
Heshmatollah Alinezhad , Asefeh Hagh Haghighi, Fatemeh Salehian
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
Received 8 July 2009
Abstract
A highly efficient green protocol for the preparation of bis-indolylmethanes, bis-2-methylindolylmethanes, bis-1-methylindo-
lylmethanes and 3,30-diindolyloxindole derivatives from the reaction of indoles with various aldehydes and ketones in the presence
of cellulose sulfuric acid under solvent-free conditions is reported. The significant features of this procedure are high yields of the
products, mild reaction, solvent-free condition and non-toxicity of the catalyst.
# 2009 Heshmatollah Alinezhad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Aldehydes; Ketones; Cellulose sulfuric acid; Bis-indolylmethanes; 3,30-Diindolyloxindole derivatives
Bis-indolylmethanes (DIMS) that contain two indoles or substituted indole units in a molecule feature widely in
pharmacology, medicinal and biochemistry [1]. These compounds can be prepared from the reaction of indoles with
various aldehydes and ketones. Therefore, several synthetic methods for the synthesis of these compounds have been
reported using either protic or Lewis acid catalysts such as I2 [2], hexamethylenetetramine–bromine [3], ZrOCl2 [4], p-
toluenesulfonic acid [5], [bnmim] [HSO4] [6], NH4Cl [7], AlPW12O40 [8], TPA-ZrO2 [9], Zr(DS)4 [10], sulfamic acid
[11], ZrCl4 [12], trichloro-1,3,5-triazine [13] and ZrOCl2ꢀ8H2O–silica gel [14].
One of the ultimate goals for organic reactions is to reduce the use of harmful organic solvents. For this reason, over
the last few years enormous advances have been made to achieve the environmentally friendly chemical processes.
One way for this purpose is carrying out the reactions in solvent-free conditions.
Cellulose sulfuric acid (CSA) is non-explosive, easy handling, eco-friendly, stable and recoverable solid acid
catalyst [15].
Recently, Shingare and coworkers reported synthesis of few derivatives of bis-indolylmethanes using cellulose
sulfuric acid [16].
In the present article, we report a facile route using cellulose sulfuric acid as an efficient catalyst for the synthesis of
widespread range of bis-indolylmethanes, bis-2-methylindolylmethanes, bis-1-methylindolyl methanes and 3,30-
diindolyloxindoles derivatives under solvent-free conditions (Schemes 1 and 2).
* Corresponding author.
E-mail address: heshmat@umz.ac.ir (H. Alinezhad).
1001-8417/$ – see front matter # 2009 Heshmatollah Alinezhad. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.09.001

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H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 183–186
Scheme 1. Reaction of carbonyl compounds with indoles in the presence of CSA.
Scheme 2. Reaction of isatin with indoles in the presence of CSA.
1. Experimental
Materials were purchased from Merck. The reactions were monitored by TLC using silica gel plates and the
products were purified by flash column chromatography on silica gel (Merck, 230–400 mesh) and were identified by
1
comparison of their spectra (1H NMR and FTIR) and physical data with those of the authentic samples. H NMR
spectra were recorded with Brucker DRX-500 AVANCE (500 MHz) and Brucker DRX-300 AVANCE (300 MHz)
spectrometers, using CDCl3 as solvent. IR spectra were recorded on a Pye-unicam SP 1100 spectrophotometer. The
catalyst cellulose sulfuric acid was prepared by an established procedure [15].
To the mixture of indole (2.0 mmol), an aldehyde or a ketone (1 mmol) and cellulose sulfuric acid (0.1 g, 5 mol.%)
was added and the mixture was ground at room temperature until the disappearance of the starting materials. After
completion of the reaction as indicated by TLC, EtOH was added to the reaction mixture and then filtered. The filtrate
was evaporated under reduced pressure to afford crude product which was then purified by column chromatography
and eluted with ethyl acetate and petroleum ether mixture (1:9) to afford the pure product (73–98%, Table 2). The
1
products were identified by melting point, IR and H NMR data.
2. Results and discussion
At the first stage, we examined the reaction of benzaldehyde (1 mmol) with indole (2 mmol) for the synthesis of
3,30-diindolylphenylmethane from the viewpoint of time, temperature and the molar ratio of catalyst. We found that
CSA is an effective catalyst for this reaction in terms of the amount of catalyst and reaction time in compare with
recently reported solid acid catalysts (Table 1). 0.1 g (5 mol.%) of CSA was required to give the most satisfactory
result (96% yield) within 15 min at room temperature under solvent-free condition (Table 2, entry 1).
To prove the generality of this protocol, the reaction was then extended towards a variety of aldehydes and ketones
with indoles and our observations are recorded in Table 2. As shown in Table 2, a variety of aliphatic, aromatic and
heterocyclic aldehydes and ketones underwent smooth transformation to the corresponding bis-indolylmethanes in
high to excellent yields. It is important that after completion of the reaction, the catalyst can be separated by simple
filtration and recovered cellulose sulfuric acid can be reused in subsequent reactions without significant decrease in
activity.
In this category of reactions, 2-methylindole was found to be more reactive than indole, giving the corresponding
products in excellent yields. As shown in Table 2, the required reaction time for the reaction of aldehydes and ketones
with 2-methylindole is shorter in compare with indole under the same reaction condition. As it is expected, due to the

H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 183–186
185
Table 1
Reaction of indole with benzaldehyde in the presence of different catalysts.
Entry
Catalyst
Condition
Catalyst (mol.%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
ZrOCl2ꢀ8H2O
AlPW12O40
15-ZTPA
NH4Cl
Solvent free, 50 8C
CH3CN, r.t.
5
2
40
15
84
92
90
96
94
91
96
Solvent free, 60 8C
Solvent free, 90 8C
H2O, r.t.
0.25
50
10
10
5
30
120
25
Zr(DS)4
ZrCl4
CH3CN, r.t.
30
CSA
Solvent free, r.t.
15
Table 2
Synthesis of bis-indolylmethanes and 3,30-diindolyloxindole derivatives by the condensation of indoles and carbonyl compounds catalyzed by
cellulose sulfuric acida.
Entry
Carbonyl compounds
Indoles
Time (min)
Yield (%)b
Ref.
1
2
H
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
C
C
C
A
A
A
A
A
A
B
B
B
B
B
C
A
B
15
35
15
20
35
20
30
15
60
5
96
98
92
93
96
93
95
96
96
82
97
94
92
93
90
96
98
96
98
87
98
85
97
94
73
80
98
95
98
91
82
91
88
85
[9]
4-OH
[8]
3
4-Cl
[9]
4
2-Cl
[7]
5
3-Cl
[5]
6
4-Me
[9]
7
4-OMe
[9]
8
4-Br
[17]
[9]
9
4-CN
10c
11
12
13
14
15
16
17
18d
19d
20c
21
22
23
24
25
26
27
28
29
30
31
32
33
34
4-CHO
[10]
[9]
H
5
4-OH
20
5
[8]
4-Cl
[9]
4-Me
5
[9]
4-OMe
7
[9]
4-Br
5
[17]
[9]
4-CN
10
20
20
5
4-Br
[17]
[17]
[10]
[18]
[18]
[17]
[7]
4-Cl
4-CHO
Furan-2-carbaldehyde
Pyrrole-2-carbaldehyde
Thiophene-2-carbaldehyde
Butanal
35
30
40
15
50
40
5
Acetophenone
Cyclohexanone
Thiophene-2-carbaldehyde
Pyrrole-3-carbaldehyde
Furan-2-carbaldehyde
Pyridine-4-carbaldehyde
Cyclohexanone
Thiophene-2-carbaldehyde
Isatin
[17]
[17]
[17]
[10]
[10]
[10]
[17]
[17]
[19]
[19]
2
5
10
20
15
120
10
Isatin
aAll products were characterized by IR and 1H NMR.
b
All yields refer to isolated yield.
c
The molar ratio of aldehyde:indole was 1:4.
d
These reactions were carried out at 50 8C.

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H. Alinezhad et al. / Chinese Chemical Letters 21 (2010) 183–186
Scheme 3. Chemoselectivity of aldehyde in reaction with indole in the presence of a ketone.
steric crowding in corresponding DIMS, aliphatic and aromatic ketones (Table 2, entries 25, 26 and 31) reacted with
longer reaction times and their yields of products was lower. The outstanding feature of this procedure is the synthesis
of diindolyl methanes of pyrrole, furan, thiophen and pyridine in good to excellent yields. By controlling the molar
ratio of indole, condensation of a dialdehyde i.e. terephthaldialdehyde to the corresponding DIMS (Table 2, entries 10
and 20) was achieved.
As shown in Table 2, entries 33 and 34, we have also prepared 3,30-diindolyloxindole derivatives by the reaction
between isatin and indoles using this procedure.
This method is also highly chemoselective for aldehydes. For example, when a 1:1 mixture of benzaldehyde and
cyclohexanone reacted with indole in the presence of CSA, only phenyl-3,30-bis-indolylmethane was obtained, while
cyclohexanone did not give the corresponding product under this reaction conditions (Scheme 3).
3. Conclusion
In conclusion, we have provided a powerful and convenient procedure for the preparation of bis-indolylmethanes
and 3,30-diindolyloxindole derivatives. Mild reaction condition, improvement of yields of the products, using friendly
process and easy work up procedure are the merits of this procedure.
Acknowledgment
Financial support of this work from the Research Council of Mazandaran University is gratefully acknowledged.
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