Eutectic salts promote green synthesis of bis(indolyl) methanes

Article abstract of DOI:10.1007/s11164-011-0479-4

A convenient and rapid method for the electrophilic substitution reaction of indoles with carbonyl compounds has been developed by using deep eutectic solvent as green and reusable catalysts to afford the corresponding bis(indolyl) methanes in excellent y

Full text of DOI:10.1007/s11164-011-0479-4

Res Chem Intermed (2012) 38:1495–1500
DOI 10.1007/s11164-011-0479-4
Eutectic salts promote green synthesis of bis(indolyl)
methanes
•
Najmadin Azizi Zohreh Manocheri
Received: 3 December 2011 / Accepted: 28 December 2011 / Published online: 12 January 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A convenient and rapid method for the electrophilic substitution reac-
tion of indoles with carbonyl compounds has been developed by using deep eutectic
solvent as green and reusable catalysts to afford the corresponding bis(indolyl)
methanes in excellent yields at room temperature under mild reaction conditions.
Keywords Bis(indolyl) methanes Á Carbonyl compounds Á Deep eutectic solvent Á
Green chemistry Á Indole
Recent years have witnessed a major drive to increase the efficiency of organic
transformations while lowering the amount of waste materials. Solvents play a
central role in these efforts: solvents are often the largest sources of wastes in
chemical syntheses and processes. Eliminating the use of solvents can dramatically
reduce the amount of waste and volatile organic compound emissions that are
produced in a process. Recent endeavors have focused on limiting the use of organic
solvents and replacing them with new, environmentally benign media. Room-
temperature ionic liquids have attracted considerable attention as novel reaction
media over the last decade. By virtue of their nonflammability, chemical and
thermal stability, and outstanding solvation ability and negligible vapor pressure,
ionic liquids have been proposed as alternative solvents receiving serious
consideration with the promise of both environmental and technological benefits.
Unfortunately, cost, toxicity for some aquatic species, and high purity are the main
N. Azizi (&)
Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
e-mail: azizi@ccerci.ac.ir
Z. Manocheri
Department of Chemistry, Islamic Azad University, Shahr-e-Rey Branch, Tehran, Iran
123

1496
N. Azizi, Z. Manocheri
disadvantages of these green solvents, which has limited their use in the laboratory
and industry [1–3].
Deep eutectic solvents (DESs)—eutectic mixtures of an ammonium salt and a
hydrogen-bond donor compound such as urea, acid, amine, and salts, which were
developed by Abbott and co-workers, are alternatives to ionic liquids. These
eutectic mixtures are attractive alternatives to RTILs, as DESs can be less
expensive, more synthetically accessible, nontoxic, and biodegradable [4–7].
Certain indole derivatives were important class of nitrogen heterocycles in many
biological systems commonly found in nature [8] as well as in many compounds
that show pharmacological and biological activity [9]. The bis(indolyl)alkane
moiety is present in various natural products possessing important biological
activity [10]. Therefore, a number of synthetic methods for preparation of
bis(indolyl)alkane derivatives have been reported in the literature by reaction of
indole with various aldehydes and ketones in the presence of either a Lewis acid or a
protic acid [11–28].
As a part of our research, aimed at developing green chemistry by using water as
a reaction medium or by performing organic transformations under solvent-free
conditions [29–33], herein, we have described a clean, general, and safe protocol for
the synthesis of bis(indolyl)methane by electrophilic substitution reactions of indole
derivatives with various aldehydes in deep eutectic solvent (Scheme 1).
In a simple experimental procedure, equimolar amounts of indole 1 and
benzaldehyde 2 in five deep eutectic solvents were screened at different reaction
conditions (Scheme 1). The first findings indicated that simple mixing in of
benzaldehyde 1 (1 mmol), indole 2 (2 mmol), and choline chlorideÁ2SnCl2,
(0.1 mL) with stirring at room temperature for 20 min was a good reaction
condition and 3 was obtained in 80% yield after workup. The structure of 3 was
confirmed from spectroscopic data and by comparison with an authentic sample.
Further optimization of the reaction temperature and solvent for the condensation
reaction of 1 to 2 was examined to improve the yield of 3. By increasing the reaction
temperature, the viscosities of the mixture were improved greatly to produce 3 in a
90% yield. It was found that the amount of green solvent also affected the yields of
the reaction, and a better result was obtained by carrying out the reaction at room
temperature in the presence of 0.3 mL of polyethylene glycol (Scheme 1).
Ph
DES (0.1 mL)
PhCHO
+
rt, 60 min
N
1
N
H
N
H
H
3
2
DES
Ch/SnCl2 Ch/Urea Ch/ZnCl2 Ch/ZnCl2/SnCl2 Ch/Gly Ch/SnCl2/H2O Ch/SnCl2/PE
Molar ratio
Yields (%)
1:2
80
1:2
00
1:2
64
1:1:1
70
1:3
20
1:2:3
85
1:2:3
97
Scheme 1 Optimization of reaction condition in deep eutectic solvents
123

Eutectic salts promote green synthesis of bis(indolyl) methanes
1497
Under the optimized reaction conditions, a variety of aromatic aldehydes, including
electron-withdrawing and electron-donating groups, and indoles were tested using the
green reaction condition and the results are shown in Table 1. Generally, excellent
yields of bis(indolyl) methanes were obtained under optimized reaction conditions
with aromatic aldehydes as well as heterocyclic aldehydes. The reaction worked well
with a variety of aldehydes including those bearing an electron-withdrawing group,
Table 1 Green condensation of aldehydes and indoles in deep eutectic solvent
R
ChCl/SnCl2 (0.1 mL)
RCHO
+
N
N
H
N
H
1
PE (0.3 mL), rt, 60-200 min
3
2
H
2a = indole
2b = 1-methylindole
2c = 2-methylindole
2d = 5-bromoindole
64-97%
Entry
R
Indole
Yield (%)
M.p. (°C)
Ref.
Found
Reported
1
Ph
2a
2b
2c
2d
2a
2b
2c
2a
2a
2b
2a
2a
2a
2b
2b
2a
2b
2a
2b
2a
2a
2a
2a
2a
2a
2a
97
95
82
90
92
95
88
95
80
94
82
90
85
80
90
75
78
95
88
84
80
82
78
64
68
74
150–152
198–200
244–247
228–231
75–77
125
[24]
[23]
[24]
[10]
[25]
[25]
[14]
[27]
[25]
[25]
[26]
[27]
[16]
[25]
[23]
[23]
[26]
[24]
[25]
[27]
[24]
[23]
[23]
[28]
[27]
[27]
2
Ph
201–203
247–248
230–232
75–76
3
Ph
4
Ph
5
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-ClC6H4
3-ClC6H4
3-ClC6H4
3,4-Cl2C6H3
3-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OHC6H4
3-NO2C6H4
3-NO2C6H4
4-MeC6H4
4-MeC6H4
3,4-(OMe)2C6H3
2-Thienyl
2-Furyl
6
208–210
198–200
70–72
208–209
200–202
70–71
7
8
9
83–84
83–85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
164–166
156–158
186–188
184–186
215–217
122–124
260–264
156–158
90–92
167–168
154–156
188–189
185–187
218–219
124–126
264–265
157–159
93–94
196–198
155–157
144–147
318–322
250–253
67–69
197–198
154–156
150–153
321–323
252
1-Naphthyl
CH3CH2CH
CH3(CH2)4
(CH2)5
68–70
67–69
68–70
118–120
118–119
123

1498
N. Azizi, Z. Manocheri
and electron-donating group and the corresponding products were obtained with
excellent yields. Furthermore, aliphatic aldehydes as well as simple ketones are good
electrophilic partners for this green protocol and give the bis(indolyl) methanes in
good yields. The scope of our method was extended to indole derivatives, and all
commercial indoles such as indole, 1-methylindole, 2-methylindole, and 5-bromo-
indole to give the desired products in excellent yields.
Inaddition, thisgreenandsimpleprocedureissuperiorcomparedtotheliteraturedata
with respect to catalyst, solvent, ecofriendliness, and reaction time as shown in Table 2.
In summary, for the first time, a reusable deep eutectic solvent has been used for
the synthesis of symmetrical bis-indoles under green reaction media. The reaction is
experimentally simple, proceeding well without any organic solvent and harsh
conditions, requiring only commercially available starting materials, and generating
virtually no by-products in most cases.
Experimental
General
Reactions were monitored by TLC and GC. FT-IR spectra were recorded using KBr
disks on a Bruker Vector 22 FT-IR Spectrometer and 1H NMR spectra were
Table 2 Comparison of the catalytic efficiency of various catalysts reported in the literature
Entry
Catalyst
Condition
Yields
1
2
3
4
5
6
7
ZrCl4
CH3CN/rt
CH3CN/rt
CH3CN/rt
CH3CN/rt
Water
91
89
90
93
84
86
93
ZrOCl2
LiClO4
ILIS-SO2Cl
H3PW12O40
H3PMo12O40
Water
[bnmim] [HSO4] = 1-benzyl-3-methyl imidazolium
hydrogen sulphate
Neat/MW
8
AlPW12O40
Sb2(SO4)3
Al(HSO4)3
P2O5/SiO2
(CO2H)2/CTAB
LiClO4
CH3CN
MeOH
EtOH
Neat
92
96
92
94
98
92
98
98
94
93
92
97
9
10
11
12
14
15
16
17
18
19
20
H2O
Neat
Dy(OTf)3
NbCl5
IL
MeOH
Neat/rt
H2O-EtOH
H2O
HBF4-SiO2
CAS
Squaric acid
DES
PE
123

Eutectic salts promote green synthesis of bis(indolyl) methanes
1499
recorded on a 500-MHz NMR spectrometer and 13C NMR spectra were recorded on
a 125-MHz NMR spectrometer, respectively, using CDCl3 or DMSO, as a solvent
and chemical shifts have been expressed in ppm downfield from TMS. Melting
points were recorded on a Buchi 535 melting point apparatus and are uncorrected.
All starting materials are commercially available and were purchased and used
without further purification. Water and other solvents were distilled before being
used.
The general route for the synthesis of the ionic liquids was as follows: Choline
chloride (100 mmol) was mixed with tin chloride (200 mmol) and heated to ca.
100 °C in air with stirring until a clear colorless liquid was obtained [5].
General procedure
In the test tube equipped with a magnetic stirrer were added tin (II) chloride–choline
chloride (2:1) (0.1 mL), benzaldehyde (0.1 g, 1 mmol), and 0.3 mL of polyethylene
glycol 200. The indole (0.23 g, 2 mmol) was added in one portion and the test tube
was kept at room temperature under vigorous stirring for 60–200 min. After the
reaction was completed, diethyl ether or ethyl acetate (10 mL) was added and the
reaction mixture filtered off to extract the product from the deep eutectic solvent.
To the organic phase, water (10 mL) was added and after usual workup crude
bis(indolyl) methane were obtained. The crude product was analyzed by 1H and 13
C
NMR. Further purification was carried out by short-column chromatography on
silica gel (ethyl acetate/petroleum ether). All compounds were characterized on the
basis of their spectroscopic and physical (melting point) data (NMR) and by
comparison with those reported in the literature.
Acknowledgments Financial support of this work by the Chemistry and Chemical Research Center of
Iran is gratefully appreciated.
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