Highly efficient method for synthesis of bis(indolyl)methanes catalyzed by FeCl3-based ionic liquid

Article abstract of DOI:10.1002/jccs.200900034

Asimple and highly efficient green protocol for synthesis of bis(indolyl)methanes was carried out by the reaction of indole with aldehydes and ketones in the presence of FeCl₃-based ionic liquid. These liquids serve as efficient media as well a

Full text of DOI:10.1002/jccs.200900034

240
Journal of the Chinese Chemical Society, 2009, 56, 240-245
Communication
Highly Efficient Method for Synthesis of Bis(indolyl)methanes Catalyzed
by FeCl3-based Ionic Liquid
Hojat Veisi,a,* Saba Hemmatib and Hamed Veisia
aDepartment of Chemistry, Payame Noor University, Songhor, Kermanshah, Iran
bDepartment of Chemistry, Islamic Azad University - Saveh Branch, P. O. 39187-366, Saveh, Iran
A simple and highly efficient green protocol for synthesis of bis(indolyl)methanes was carried out by
the reaction of indole with aldehydes and ketones in the presence of FeCl3-based ionic liquid. These liq-
uids serve as efficient media as well as Lewis acid catalysts.
Keywords: Bisindole; Carbonyl compounds; Ionic liquid; Lewis acid.
INTRODUCTION
vapour pressure, ability to dissolve a large range of organic
and inorganic compounds, increased reaction rate, selectiv-
ity and tendency to immobilize starting materials and cata-
lysts, make them an attractive substitute for various volatile
organic solvents.
Bis(indolyl)methanes, indole and their derivatives
are known as important intermediates in organic synthesis
and pharmaceutical chemistry and exhibit various physio-
logical properties.1 Bis(indolyl)methanes are found in cru-
ciferous plants and are known to promote beneficial estro-
gen metabolism2 and induce apoptosis in human cancer
cells. Therefore, there is great interest in the synthesis of
these compounds.3-5 Synthetically the reaction of indole
with aldehydes or ketones produces azafulvenium salts that
react further with a second indole molecule to form bis(in-
dol-3-yl)methanes.6 In recent years, synthesis of this class
of molecules under mild conditions have been reported,
with promoters such as Montmorillonite clay K-10,7 tri-
chloro-1,3,5-triazine,8 AlPW12O40,9 sodium dodecyl sul-
fate (SDS),10 ZrCl4,11 I2,12 In(OTf)3/ionic liquid,13 CuBr2,14
MW/Lewis acids (FeCl3, BiCl3, InCl3, ZnCl2, CoCl2),15
NaHSO4 and Amberlyst-15,16 silica sulfuric acid (SSA),17
metal hydrogen sulfates,18 NaHSO4/ionic liquid,19 CAN,20
NBS,21 and Ph3CCl.22 However, most of the existing meth-
ods involve toxic metal ions and solvents, have high costs,
use corrosive reagents and have cumbersome work-up pro-
cedures. Consequently, new procedures that that address
these drawbacks are desirable.
RESULTS AND DISCUSSION
Herein, we report the use of benzyl tributylammoni-
um chloride (BTBAC) at 60 °C as catalyst in the electro-
philic substitutions of indole with a variety of aldehydes
and ketones to afford bis(indolyl)methanes. The best result
based on yield and time of the reaction was obtained with
[BTBAC]Cl-FeCl3,24 N = 0.5 (Scheme I).
To investigate the scope and the generality of this new
protocol for various aldehydes and ketones under opti-
mized conditions, as shown in Table 1, a series of aromatic,
aliphatic aldehydes smoothly underwent electrophilic sub-
stitution reaction with indole to afford a wide range of sub-
stituted bis(indolyl)methanes in good to excellent yields.
The electron deficiency and nature of the substituents on
the aromatic ring affect the conversion rate; aromatic alde-
hydes having electron-withdrawing groups on the aromatic
ring (Table 1, entries 3, 4, 9) react faster than electron-do-
nating groups (Table 1, entries 2, 8). Furthermore, unsatu-
rated aldehydes, such as cinamaldehyde, give the corre-
sponding bis(indolyl)methanes without polymerization un-
der the above reaction conditions. Ketones required longer
reaction times, which is most probably due to the electron-
The design of solvent-free reactions and the use of
ionic liquids in organic synthesis have gained significant
interest.23 Some of the unique physical and chemical prop-
erties of ionic liquids, such as thermal stability, negligible
* Corresponding author. Fax: +98-08112523335; E-mail: h_organo2007@yahoo.com

Synthesis of Bis(indolyl)methanes
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 241
Scheme I
donating and steric effects of the methyl group.
in high yield (Scheme III).
This reaction was further explored for the synthesis
of tri-indolylmethane by the condensation of indol-3-carb-
aldehyde with two equivalents of indole under similar con-
ditions in high yields (Scheme II).
This method is also highly chemoselective for arylal-
dehydes in the presence of aliphatic aldehydes and ketones.
For example, when a 1:1 mixture of benzaldehyde and ace-
tophenone was allowed to react with indole in the presence
of [BTBAC]Cl-FeCl3, it was found that only phenyl-3,3-
bis(indolyl)methane was obtained, while acetophenone did
not give the corresponding product under these reaction
This reaction was further explored for the synthesis
of tri(bis-indolyl)methane e by the condensation of alde-
hyde d with 6 equivalents indole under similar conditions
Scheme II
Scheme III

242 J. Chin. Chem. Soc., Vol. 56, No. 2, 2009
Veisi et al.
Table 1. Synthesis of bis(indolyl)methanes by the reaction of indole with aldehydes and
ketones in the presence of FeCl3-based ionic liquid (N = 0.5)
Entry
Substrate
Product
Time (min) Yield (%)a Refs.
CHO
1
10
15
10
15
98
92
98
96
11
11
11
11
N
H
N
H
Me
Me
CHO
2
3
4
N
H
N
H
OMe
CHO
OMe
N
H
N
H
OMe
MeO
CHO
N
H
N
H
Br
Br
CHO
5
20
90
25
N
H
N
H
Cl
Cl
CHO
6
7
8
15
08
25
95
92
85
11
11
11
N
H
N
H
Cl
CHO
Cl
N
H
N
H
OH
HO
CHO
N
H
N
H
NO2
O2N
CHO
9
25
95
11
N
H
N
H

Synthesis of Bis(indolyl)methanes
J. Chin. Chem. Soc., Vol. 56, No. 2, 2009 243
CH O
10
11
15
20
90
70
11
11
N
H
N
H
CHO
3
N
H
N
H
O
12
13
30
30
85
80
11
11
N
H
N
H
O
N
H
N
H
H
N
H
N
OHC
CHO
14
10
90
11
N
H
N
H
a The products were characterized by comparison of their spectroscopic and physical data
with those of samples synthesized by reported procedures.
Scheme IV
conditions (Scheme IV). Also, in an equimolar mixture of
arylaldehyde and aliphatic aldehyde, it was found that the
arylaldehydes were chemoselectively converted to the cor-
responding bis(indolyl)methane but the aliphatic ones con-

244 J. Chin. Chem. Soc., Vol. 56, No. 2, 2009
Veisi et al.
verted only slightly (Scheme IV). The reaction was clean
and the products were obtained in high yields without the
formation of any side products.
Found: C, 84.46; H, 6.22; N, 6.28.
Analytical data for compound e
Light red solid, mp: 208-210 °C. IR (KBr): 3421,
2950, 2900, 1635, 1506, 1457, 1377, 1216, 1173, 1082,
742 cm-1. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 5.01
(s, CH2 benzylic, 6H), 5.72 (s, CH, 3H), 6.74-7.50 (m, CH
aromatic, 46H), 10.71 (s, NH, 6H). 13C NMR (75 MHz,
DMSO-d6): dc (ppm) 40.08, 69.48, 111.85, 114.67, 115.24,
118.54, 118.82, 119.58, 121.25, 123.87, 127.05, 129.66,
137.03, 137.73, 138.15, 156.91. Anal. Calcd for C78H60N6O3:
C, 82.97; H, 5.32; N, 7.44. Found: C, 83.23; H, 4.86; N,
7.02.
In conclusion, the best results are realized and the
utility of the FeCl3-based ionic liquid both as solvent and
catalyst is satisfactorily justified. The advantages of this
method using FeCl3-based ionic liquid are mild reaction
conditions, good to high yield, short reaction time, simple
work-up procedure, easy preparation of the catalyst and
chemoselectivity. This protocol provides a low cost proce-
dure for the synthesis of these compounds.
EXPERIMENTAL
Received October 16, 2008.
All commercially available chemicals were obtained
from Merck and Fluka companies, and used without further
purification unless otherwise stated. Nuclear magnetic res-
onance (NMR) spectra were recorded on a Bruker Avance
300 MHz and Jeol 90 MHz FT NMR spectrometer. Infrared
(IR) measurements were conducted on a Perkin Elmer GX
FT-IR spectrometer.
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