Efficient and Eco-Friendly Process for the Synthesis of Bis(1H-indol-3-yl)methanes using Ionic Liquids

Article abstract of DOI:10.1002/adsc.200390038

Indoles react smoothly with carbonyl compounds in 1-butyl-3- methylimidazolium tetrafluoroborate ([bmim]BF₄) or 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF₆) ionic liquids under mild reaction conditions to afford the corresponding bis-indolylmethanes in excellent yields. These ionic liquids can be recovered and recycled in subsequent reactions without any apparent loss of activity.

Full text of DOI:10.1002/adsc.200390038

COMMUNICATIONS
Efficient and Eco-Friendly Process for the Synthesis of
Bis(1H-indol-3-yl)methanes using Ionic Liquids
J. S. Yadav,* B. V. S. Reddy, S. Sunitha
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: ( ‡ 91)-40-7160512, e-mail: yadav@iict.ap.nic.in
Received: September 7, 2002; Accepted: November 11, 2002
as environmentally benign reaction media for catalytic
Abstract: Indoles react smoothly with carbonyl
compounds in 1-butyl-3-methylimidazolium tetra-
processes, much attention is currently being focused on
organic reactions promoted by ionic liquids.[ The
unique property of ionic liquids is that they have
essentially no vapor pressure, which makes them
optimal replacements for volatile organic solvents
9]
fluoroborate ([bmim]BF ) or 1-butyl-3-methylimida-
4
zolium hexafluorophosphate ([bmim]PF ) ionic liq-
6
uids under mild reaction conditions to afford the
corresponding bis-indolylmethanes in excellent
yields. These ionic liquids can be recovered and
recycled in subsequent reactions without any appa-
rent loss of activity.
[
10]
traditionally used as industrial solvents.
A nice
feature of ionic liquids is that yields can be optimized
by changing the anions or properties of the cation. In
addition, several ionic liquids show enhancement in
reaction rates and selectivity, compared to organic
solvents with the added advantages of ease of recovery
and reuse of these ionic solvents. Due to these advan-
tages, ionic liquids can make a significant contribution to
green chemistry.
Keywords: aldehydes; bis-indolylmethanes; ionic
liquids; ketones
In view of the emerging importance of ionic liquids as
novel reaction media, we herein report the synthesis of
The acid-catalyzed reaction of electron-rich heterocy- bis(1H-indol-3-yl)methanes from carbonyl compounds
clic compounds with p-dimethylaminobenzaldehyde is and indoles using ionic liquids as reaction media. The
known as the Ehrlich test for p-electron excessive treatment of indole with benzaldehyde in [bmim]BF4
[
1]
heterocycles such as pyrroles and indoles. The analo- ionic liquid afforded the corresponding bis-indolylme-
gous reaction of indoles with other aromatic or aliphatic thane in 90% yield (Scheme 1).
aldehydes and ketones produces azafulvenium salts. The
A variety of carbonyl compounds reacted smoothly
azafulvenium salts can undergo further addition with a with indoles to produce bis-indolylmethanes under
second indole molecule to afford bis(indolyl)me- these reaction conditions. The electron deficiency and
[
2]
[3,4]
thanes. Generally, Lewis acids
as well as protic the nature of the substituents on the aromatic ring show
acids[ are employed as catalysts to promote these some effects on this conversion. The nitro-substituted
reactions. However, many of these reagents are deacti- arylaldehydes took longer reaction times to produce
vated or sometimes decomposed by aqueous work-up comparable yields to those obtained with simple and
and, therefore, they cannot be recycled for further runs. electron-rich counterparts. Electron-rich aldehydes like
Recently, lanthanide triflates were reported to be veratraldehyde etc., reacted rapidly with indole and 2-
efficient for this transformation. Although metal methylindole to give the products in excellent yields
triflates are reusable, they are strongly acidic and highly within 4 h whereas aliphatic aldehydes such as hexanal,
expensive. Furthermore, there are no reports on the use and cyclohexanecarboxaldehyde afforded 80 ± 90%
5]
[
6]
of ionic liquids as reaction media for this conversion.
yields in 5 ± 6 h. Furthermore, the reaction of indole
One of the prime principles of green chemistry is to with ketones such as cyclohexanone and cyclopenta-
develop an alternative reaction medium, which is the none gave the products in good yields. The reaction of
basis for the development of many cleaner chemical ketones with indole took longer when compared to
technologies. Particularly, ionic liquids have recently
gained recognition as possible environmentally safe
alternatives to volatile organic solvents. Ionic liquids,
especially those based on the 1-n-alkyl-3-methylimida-
zolium cation, have shown great promise as novel
[
8]
reaction media for various catalytic processes. Due
to the great potential of room temperature ionic liquids Scheme 1.
Adv. Synth. Catal. 2003, 345, No. 3
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/34503-349 ± 352 $ 17.50+.50/0
349

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J. S. Yadav et al.
aldehydes. All the products were characterized by
1
H NMR, IR and mass spectral analysis and also by
[
11]
comparison with authentic samples.
The reactions
were carried out in both hydrophilic [bmim]BF as well
4
as in hydrophobic [bmim]PF ionic liquids. [Bmim]BF
6
4
ionic liquid was found to be efficient in terms of
conversion and reaction rates. The advantage of the
use of ionic liquids as a novel reaction medium for this
transformation is that these ionic solvents can be easily
recovered and recycled in subsequent reactions. Since
the products were weakly soluble in the ionic phase, they
were easily separated by simple extraction with ether.
The rest of the oily ionic liquid was thoroughly washed
with ether and reused in subsequent reactions without
further purification. Although the products were ob-
tained in the same purity as in the first run, the yields
were gradually decreased in runs carried out using
recycled ionic liquid. For example, the reaction of
benzaldehyde afforded the corresponding bis-indolyl-
methane in 90%, 87%, 85%, and 81% yields over four
cycles. However, the activity of ionic liquid was con-
sistent in runs and no decrease in yield was obtained
when the recycled ionic liquid was activated at 80 8C
under vacuum in each cycle. The efficiency of various
quaternary ammonium salts was studied for the trans-
formation. The reaction did not proceed either in n-
tetrabutylammonium chloride (n-Bu NCl) or in 1-n-
4
butyl-3-methylimidazolium chloride (BMImCl) molten
salts. The reaction probably proceeds through the
activation of carbonyl group as well as the indole moiety
by ionic liquids as shown in Scheme 2.
However, in the absence of ionic liquids, the reaction
did not yield any product even after a long reaction
period (10 ± 15 h). Furthermore, we have performed the
reactions in polar organic solvents such as DMF and N-
methylpyrrolidine to compare the efficiency of ionic
liquids. The reactions did not proceed in these solvents liquids. The notable features of this procedure are mild
even under heating conditions (75 ± 80 8C). This clearly reaction conditions, improved yields, enhanced rates,
indicates the efficiency of ionic liquids in this trans- cleaner reaction profiles, ease of recovery and reuse of
formation. The scope and generality of this process is this novel reaction medium making this method simple,
illustrated with respect to various carbonyl compounds convenient, economic and environmentally friendly
and indoles and the results are presented in Table 1. The process for the synthesis of bis-indolylmethanes.
use of ionic liquids as promoters for this transformation
avoids the use of moisture-sensitive reagents and
tedious aqueous work-up to isolate the products. Thus
this method is preferable to either protic or Lewis acid
promoted procedures.
In summary, the paper describes a simple and highly
efficient procedure for the preparation of bis-indolyl-
methanes through the electrophilic substitution reac- spectra were recorded on a Nicolet-740 FTIR spectropho-
Experimental Section
Methods and Apparatus
Melting points were recorded on Buchi R-535 apparatus. IR
1
tions of indoles with aldehydes and ketones in ionic tometer. H NMR spectra were recorded on a Varian Gem-
Scheme 2.
350
Adv. Synth. Catal. 2003, 345, 349 ± 352

Eco-Friendly Synthesis of Bis(1H-indol-3-yl)methanes
COMMUNICATIONS
1
ini À 200 MHz spectrometer. Mass spectra were recorded on a
VG Micromass 7070 H (70 eV). CHN analysis was recorded on
a Vario EL analyzer. TLC was performed 0.25 mm E. Merck
precoated silica gel plates (60F-254). 1-Butyl-3-methylimida-
Table 1, entry g: Semisolid; H NMR (CDCl ): ˆ d 5.90 (s,
3
1H), 6.45 (d, 1H, J ˆ 16.6 Hz), 6.65 (d, 2H, J ˆ 2.3 Hz), 7.05 (t,
2H, J ˆ 8.1 Hz), 7.15 (t, 2H, J ˆ 8.1 Hz), 7.25 (m, 4H), 7.35 (m,
3H), 7.55 (m, 2H), 7.75 (d, 1H, J ˆ 16.6 Hz), 7.85 (brs, 2H, NH);
‡
zolium tetrafluoroborate ([bmim]BF ) and 1-butyl-3-methyl-
EIMS: m/z (%) ˆ 346 (20) M , 321 (100), 244 (80), 205 (30), 122
4
imidazolium hexafluorophosphate ([bmim]PF ) ionic liquids
(15), 77 (10); IR (KBr): n ˆ 3450, 3100, 2960, 1590, 1470, 1030,
6
À1
were prepared according to the procedures reported in the
970, 760 cm .
literature.[
9]
Table 1, entry h: Solid, mp 138 ± 140 8C; H NMR (CDCl ):
1
3
d ˆ 1.25 (m, 6H) 1.90 (m, 4H), 2.25 (m, 1H), 4.45 (m, 1H), 6.95
(
8
(
d, 2H, J ˆ 2.4 Hz), 7.05 (m, 2H), 7.15 (m, 2H), 7.25 (d, 2H, J ˆ
.0 Hz), 7.45 (d, 2H, J ˆ 8.0 Hz), 7.85 (brs, 2H, NH); EIMS: m/z
General Procedure
‡
%) ˆ 328 (30) M , 246 (80), 130 (25), 84 (60), 57 (90), 41 (100);
IR (KBr): n ˆ 3455, 3030, 2980, 1620, 1570, 1285, 1030,
A mixture of indole (2 mmol), aldehyde or ketone (1 mmol) in
À1
7
70 cm .
[
bmim]BF or [bmim]PF (2 mL) was stirred at room temper-
4
6
1
Table 1, entry i: Solid, mp 68 ± 70 8C; H NMR (CDCl ): d ˆ
ature for an appropriate time (Table 1). After completion of
the reaction, as indicated by TLC, the reaction mixture was
washed with diethyl ether (3 Â 10 mL). The combined ether
extracts were concentrated under vacuum and the resulting
product was directly charged on a small silica gel column and
eluted with a mixture of ethyl acetate:n-hexane (2:8) to afford
the pure bis-indole. The rest of the viscous ionic liquid was
further washed with ether and reused in subsequent reactions.
3
0
.8 (t, 3H, J ˆ 6.8 Hz), 1.25 (m, 6H), 2.25 (m, 2H), 4.60 (t, 1H,
J ˆ 6.8 Hz), 6.85 (d, 2H, J ˆ 2.3 Hz), 7.05 (t, 2H, J ˆ 8.0 Hz), 7.15
(
t, 2H, J ˆ 8.0 Hz), 7.35 (d, 2H, J ˆ 8.0 Hz), 7.50 (d, 2H, J ˆ 8.0
‡
Hz), 7.85 (brs, 2H, NH); EIMS: m/z (%) ˆ 316 (70) M , 245
(
100), 206 (5), 199 (40), 156 (60), 149 (35), 117 (30); IR (KBr):
À1
n ˆ 3500, 3100, 3030, 2950, 1610, 1580, 1250, 1060, 770 cm .
Acknowledgements
Recycling of Ionic Liquid
BVS thanks CSIR, New Delhi for the award of fellowship.
In case of a hydrophilic ionic liquid, i.e., [bmim]BF , the
4
reaction mixture was diluted water and extracted with ethyl
acetate (2 Â 10 mL). The combined organic extracts were
washed with water, dried over anhydrous Na SO , concen-
References and Notes
2
4
trated under vacuum and the resulting product was purified
either by column chromatography or by recrystallization to
afford pure product. Theionic liquid can berecoveredeither by
extracting the aqueous phase with ethyl acetate or by
evaporating the aqueous layer under vacuum. The ionic liquid
thus obtained was further dried at 80 8C under reduced
pressure for use in subsequent runs.
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Spectroscopic Data for Selected Products
1
Table 1 entry a: Solid, mp 89 ± 90 8C; H NMR (CDCl ): d ˆ
3
5
.90 (s, 1H, CH), 6.60 (d, 2H, J ˆ 2.4 Hz), 7.05 (t, 2H, J ˆ 8.2
Hz), 7.15 (t, 2H, J ˆ 8.2 Hz), 7.30 (m, 9H), 7.85 (brs, 2H, NH);
[
13
C NMR (proton decoupled): d ˆ 40.5, 110.8, 119.5, 119.8,
120.05, 121.7, 123.6, 126.7, 127.3, 128.5, 128.9, 136.6, 144.2;
‡
EIMS: m/z (%) ˆ 322 (100) M , 245 (60), 204 (45), 122 (35), 105
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6] a) D. Chen, L. Yu, P. G. Wang, Tetrahedron Lett. 1996,
(
7
20), 77 (10); IR (KBr): n ˆ 3450, 3020, 1600, 1490, 1220, 1070,
3
7, 4467; b) S. Kobayashi, M. Araki, M. Yasuda, Tetra-
À1
50 cm .
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1
Table 1, entry b: Solid, mp 199 ± 200 8C; H NMR (CDCl ):
3
d ˆ 3.70 (s, 3H), 3.80 (s, 3H), 5.75 (s, 1H), 6.70 (d, 2H, J ˆ 2.4
Hz), 6.80 (d, 2H, J ˆ 8.0 Hz), 6.85 (s, 1H), 6.90 (d, 2H, J ˆ 8.0
1
009.
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‡
2
(
H, NH); EIMS: m/z (%) ˆ 382 (100) M , 265 (10), 245 (50), 69
1
20); IR (KBr): n ˆ 3450, 3060, 2980, 1620, 1490, 1230, 1005,
À1
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760 cm .
1
Table 1, entry c: Solid, mp 153 ± 154 8C; H NMR (CDCl ):
3
[
d ˆ 5.85 (s, 1H), 6.75 (d, 2H, J ˆ 2.3 Hz), 6.85 (m, 1H), 6.90 (m,
2
H), 6.95 ± 7.05 (m, 4H), 7.2 (s, 1H), 7.25 (t, 2H, J ˆ 8.0 Hz), 7.35
‡
(
(
(
s, 1H), 7.75 (brs, 2H, NH); EIMS: m/z (%) ˆ 390 (100) M , 392
‡
60) (M ‡ 2) , 274 (80), 245 (50), 204 (20), 176 (5), 117 (10); IR
KBr): n ˆ 3480, 3050, 2970, 1600, 1470, 1250, 1020, 770.
Adv. Synth. Catal. 2003, 345, 349 ± 352
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Adv. Synth. Catal. 2003, 345, 349 ± 352