Efficient FeIII-catalyzed synthesis of bis(indolyl)methanes in ionic liquids

Article abstract of DOI:10.1002/ejoc.200300719

An efficient synthesis of bis(indolyl)methanes through Fe ^III-catalyzed electrophilic substitution reactions of indoles with various aldehydes in ionic liquid is described. It was found that the ionic liquids involving FeCl₃·6H₂

Full text of DOI:10.1002/ejoc.200300719

FULL PAPER
Efficient FeIII-Catalyzed Synthesis of Bis(indolyl)methanes in Ionic Liquids
Shun-Jun Ji,*[a,b] Min-Feng Zhou,[a,b] Da-Gong Gu,[a,b] Zhao-Qin Jiang,[a,b] and
Teck-Peng Loh*[b,c]
Keywords: Bis(indolyl)methanes / Indoles / Ionic liquids / Iron
An efficient synthesis of bis(indolyl)methanes through FeIII-
catalyzed electrophilic substitution reactions of indoles with
various aldehydes in ionic liquid is described. It was found
that the ionic liquids involving FeCl3·6H2O were the most
efficient catalytic systems, and could be simply recycled
without significant loss of activity.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
prepared by the condensation of indoles with various alde-
hydes or ketones in the presence of either protic[8] or Lewis
[10]
acids[9] such as LiClO4
or I2.[11] More recently, ionic
Room-temperature ionic liquids have attracted steady at-
tention as green media in organic synthesis, mainly because
of their unique properties such as good solvating capability,
wide liquid range, negligible vapor pressure, and ease of re-
cycling. Moreover, their hydrophobicity/hydrophilicity can
be tuned by appropriate modification of the cation or
anion, which has earned them the sobriquet of ‘‘designer
solvents’’.[1] Studies of ionic liquids, especially those based
on the 1-(n-alkyl)-3-methylimidazolium cation (Scheme 1),
have had an important impact on organic reactions such as
FriedelϪCrafts reactions,[2] DielsϪAlder reactions,[3] Heck
reactions,[4] Mannich reactions,[5] bromination of alkynes,[6]
and so on.
liquids in conjunction with In(OTf)3 were employed for the
first time as novel and eco-friendly reaction media for this
transformation in our laboratory.[12] Not only is In(OTf)3
expensive, however, but some deactivation of In(OTf)3 also
obviously occurred during the recycling procedure. As a re-
sult, it was essential for us to continue our study into more
practical and efficient catalytic systems.
On the other hand, FeIII salts are well known to catalyze
many organic transformations, including oxidation of sulf-
ides,[13] the Michael reaction,[14] the thia-Fries rearrange-
ment,[15] and the synthesis of diphenylmethane[16] and 1,6-
anhydroglucopyranoses.[17] Recently, Suranna et al.[18] re-
ported that several metal complexes, including FeCl3·6H2O,
catalyzed the Michael addition of acetylacetone to methyl
vinyl ketone in ionic liquids and that their catalytic activity
was strongly dependent on the presence of halide impurities
of ionic liquids. In view of their commercial availability,
ease of handing, and remarkably low toxicity, we wish to
report here an efficient and recycling-friendly synthesis of
bis(indolyl)methanes with the aid of FeIII salts in ionic
liquids (Scheme 2). To the best of our knowledge, this is
the first report on the use of FeIII salts as catalysts for the
condensation of indoles with various aldehydes.
Scheme 1. The structure of ionic liquids
Since bis(indolyl)methanes possess a wide range of bio-
logical activity, their synthesis has received a considerable
amount of interest.[7] Generally, bis(indolyl)methanes are
[a]
College of Chemistry and Chemical Engineering, Suzhou
University,
Suzhou 215006, China
[b]
The Key Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou University
Suzhou 215006, China
Fax: (internat.) ϩ 86-512-65224873
E-mail: shunjun@suda.edu.cn
chemjsj@suda.edu.cn
[c]
Department of Chemistry, National University of Singapore,
3 Science Drive 3, Singapore 117543, China
E-mail: chmlohtp@nus.edu.sg
Scheme 2
1584
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300719
Eur. J. Org. Chem. 2004, 1584Ϫ1587

Efficient FeIII-Catalyzed Synthesis of Bis(indolyl)methanes in Ionic Liquids
FULL PAPER
(indolyl)methane, so the cause of this phenomenon may be
related to the specific water miscibility of [PF6Ϫ]-type ionic
liquids. This indicated that the choice of anion played an
important role in this transformation.
Results and Discussion
Treatment of 4-chlorobenzaldehyde with indole in the
presence of FeCl3·6H2O in 1-methyl-3-octylimidazolium
hexafluorophosphate ([omim]PF6) afforded the correspond-
ing 4-chlorophenyl-3,3Ј-bis(indolyl)methane in 96% yield
(Table 1, Entry 1). The activity of FeCl3·6H2O was shown
to be no lower than that exerted by In(OTf)3 (Table 1, Entry
9). We also examined other FeIII salts such as
Fe(NO)3·9H2O and Fe2(SO4)3·xH2O. As shown in Table 1,
the reaction between indole and 4-chlorobenzaldehyde me-
diated by Fe(NO)3·9H2O was slow, but gave a high yield
(Entry 2). The catalytic reaction did not proceed on chang-
ing from FeCl3·6H2O to Fe2(SO4)3·xH2O. In addition, we
also tested the catalytic activity of different transition metal
chlorides, such as CoCl2·6H2O, NiCl2·6H2O, and
CuCl2·2H2O. A yield of only 55% was obtained when
FeCl3·6H2O was replaced with CoCl2·6H2O (Entry 4),
while the reaction was unsuccessful when the other Lewis
acids indicated in Table 1 were used (Entries 5Ϫ8).
Encouraged by these results, we studied various alde-
hydes under optimized conditions, and Table 3 summarizes
the results. In all cases, both aromatic and aliphatic alde-
hydes reacted smoothly with indoles in high yields when
catalyzed by FeCl3·6H2O in [omim]PF6, most of the reac-
tions proceeding nearly quantitatively. Moreover, this
method is highly chemoselective, as ketones do not partici-
pate in the reaction. For example, when a 1:1 mixture of 4-
chlorobenzaldehyde and acetophenone was allowed to react
with indole with catalysis by FeCl3·6H2O in [omim]PF6, it
was found that only 4-chlorophenyl-3,3Ј-bis(indolyl)me-
thane (3a) was obtained, while acetophenone did not give
the corresponding product 3j (Entry 10). This selectivity
might be useful to differentiate aldehydes from ketones
through the synthesis of bis(indolyl)methanes.
Table 3. FeCl3·6H2O-catalyzed synthesis of bis(indolyl)methanes
with various aldehydes with use of [omim]PF6
Table 1. Synthesis of 4-chlorophenyl-3,3Ј-bis(indolyl)methane by
use of FeIII and other Lewis acids in [omim]PF6
Entry[a]
R
RЈ
Product Time [h] Yield[b] [%]
Entry
Lewis acid (mol %)
Time [h]
Yield[a]
[%]
1
2
3
4
5
6
7
8
9
4-ClC6H4
C6H5
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
0.5
1.5
4
96
98
85
78
82
96
96
95
98
0
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
2-ClC6H4
(CH2)5CH
2-C4H3S
1
2
3
4
5
6
7
8
9
FeCl3·6H2O (5)
Fe(NO3)3·9H2O (5)
Fe2(SO4)3·xH2O (5)
CoCl2·6H2O (5)
NiCl2·6H2O (5)
CuCl2·2H2O (5)
SmCl3·5H2O (5)
LiCl (10)
0.5
6.5
48
48
48
48
48
48
0.25
96
95
0
55
0
0
0
5
2.5
0.25
1.25
4
0.75
10
CH3(CH2)5
C6H5
10
CH3 3j
0
96
In(OTf)3 (5)
[a]
All products were characterized by 1H NMR, IR, and HRMS
[b]
data. Isolated yields.
[a]
Isolated yields.
One of the main aims of our study was to investigate the
reuse and recycling of FeCl3·6H2O in the ionic liquid. The
products were easily separated by simple extraction with di-
ethyl ether. After removal of the diethyl ether fraction, the
To examine the influence of the nature of the ionic liquid,
we also carried out the reaction in various air-/moisture-
stable ionic liquids. The results are summarized in Table 2.
It was found that [omim]PF6 was a more effective medium
than other ionic liquids in terms of yield (Entry 3). How-
ever, the reaction did not proceed when some [BF4Ϫ]- or
[ClϪ]-type ionic liquids were used. The reaction mixture un-
avoidably produces water as well as the corresponding bis-
Table 2. FeCl3·6H2O-catalyzed synthesis of 4-chlorophenyl-3,3Ј-
bis(indolyl)methane in various ionic liquids
Entry
Ionic liquid
Time [h]
Yield[a]
[%]
1
2
3
4
5
6
7
[bmim]PF6
[hmim]PF6
[omim]PF6
[dmim]PF6
[hmim]BF4
[omim]BF4
[bmim]Cl
0.5
0.25
0.5
24.5
24
24
24
87
95
96
78
0
0
0
Figure 1. The recycle of the In(OTf)3 and FeCl3·6H2O in [om-
im]PF6
[a]
Isolated yields.
Eur. J. Org. Chem. 2004, 1584Ϫ1587
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S.-J. Ji, M.-F. Zhou, D.-G. Gu, Z.-Q. Jiang, T.-P. Loh
FULL PAPER
7.4 (d, J ϭ 7.2 Hz, 2 H), 7.93 (br. s, 2 H, NH) ppm. C24H20N2
(349.45): calcd. C 85.68, H 5.99, N 8.33; found C 85.37, H 5.95,
N 8.04.
rest of the viscous ionic liquid was directly recycled in sub-
sequent runs. As shown in Figure 1, treatment of 4-chlorob-
enzaldehyde with indole with catalysed by In(OTf)3 af-
forded 96, 87, 42, and 0% yields. Unlike the In(OTf)3-pro-
moted recycling, however, which resulted in a dramatic de-
crease in the yields of product, FeCl3·6H2O immobilized by
ionic liquid was reused for four cycles, and afforded yields
similar to those obtained in the first run, although increases
in reaction times were observed.
3,3Ј-Bis(indolyl)-4-methoxyphenylmethane
(3d):
Solid,
m.p.
187Ϫ189 °C, (68.7 mg, 78% yield). IR (KBr): ν˜ ϭ 1220, 1244, 1455,
1
1508, 1609, 2928, 3410 (NH) cmϪ1. H NMR (400 MHz, CDCl3):
δ ϭ 3.78 (s, 3 H, CH3), 5.84 (s, 1 H, Ar-CH), 6.66 (s, 2 H), 6.82
(d, J ϭ 8.3 Hz, 2 H), 7.00 (t, J ϭ 7.3 Hz, 2 H), 7.17 (t, J ϭ 7.3 Hz,
2 H), 7.19 (s, 2 H), 7.35Ϫ7.40 (m, 4 H), 7.94 (br. s, 2 H, NH) ppm.
C24H20N2O (352.43): calcd. C 81.79, H 5.72, N 7.95; found C
81.72, H 5.82, N 7.98.
Conclusion
3,3Ј-Bis(indolyl)-4-nitrophenylmethane (3e): Solid, m.p. 217Ϫ219
°C, (75.3 mg, 82% yield). IR (KBr): ν˜ ϭ 1340, 1456, 1507, 1592,
1
3052, 3422 (NH) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 6.00 (s,
In brief, we report that FeIII salts have been employed
for catalysis of electrophilic substitution reactions between
indoles and various aldehydes in ionic liquids to afford the
corresponding bis(indolyl)methanes. It is noteworthy that
the FeCl3·6H2O/[omim]PF6 catalytic system can be reused
at least four times without significant loss of activity. The
simple procedures as well as the easy reuse of this novel
catalytic system are expected to contribute to the develop-
ment of more benign syntheses of bis(indolyl)methanes.
1 H, Ar-CH), 6.70 (s, 2 H), 7.00Ϫ7.05 (m, 3 H), 7.35 (d, J ϭ 8.0 Hz,
3 H), 7.40 (d, J ϭ 8.0 Hz, 2 H), 7.52 (d, J ϭ 8.8 Hz, 2 H), 8.04 (br.
s, 2 H, NH), 8.15 (d, J ϭ 8.8 Hz, 2 H) ppm. C23H17N3O2 (367.40):
calcd. C 75.19, H 4.66, N 11.44; found C 75.28, H 4.51, N 11.60.
2-Chlorophenyl-3,3Ј-bis(indolyl)methane (3f): Solid, m.p. 72Ϫ74 °C.
(85.6 mg, 96% yield). IR (KBr): ν˜ ϭ 1010, 1037, 1093, 1337, 1417,
1
1455, 1616, 3052, 3412 (NH) cmϪ1. H NMR (400 MHz, CDCl3):
δ ϭ 6.34 (s, 1 H, Ar-CH), 6.66 (s, 2 H), 7.02 (t, J ϭ 8.0 Hz, 2 H),
7.11Ϫ7.23 (m, 6 H), 7.36Ϫ7.43 (m, 4 H), 7.96 (br. s, 2 H, NH)
ppm. HRMS: calcd. for C23H17ClN2 356.1080; found 356.1071.
Experimental Section
Cyclohexyl-3,3Ј-bis(indolyl)methane (3g): Solid, m.p. 184Ϫ186 °C.
(78.8 mg, 96% yield). IR (KBr): ν˜ ϭ 741, 1094, 1338, 1455, 1617,
3052, 3412 (NH) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 1.52 (m,
6 H), 1.83 (m, 4 H), 2.25 (m, 1 H), 4.27 (d J ϭ 9.6 Hz, 1 H),
7.03Ϫ7.18 (m, 6 H), 7.33 (d, J ϭ 5.6 Hz, 2 H), 7.54 (d, J ϭ 7.2 Hz,
2 H), 7.94 (br. s, 2 H, NH) ppm. C23H24N2 (328.19): calcd. C 84.11,
H 7.37, N 8.53; found C 84.17, H 7.77, N 8.03.
General Remarks: Ionic liquids were prepared as described pre-
viously.[19] Melting points were recorded with an Electrothermal
digital melting point apparatus and are uncorrected. IR spectra
were recorded with a Nicolet FT-IR500 spectrophotometer with
KBr optics. 1H NMR (400 MHz) spectra were recorded with a
Varian Mercury MHz spectrometer in CDCl3. CHN analyses were
recorded with a CarloϪErba EA1110 CNNO-S analyzer. High res-
olution mass spectra were obtained with a GCT-TOF instrument.
3,3Ј-Bis(indolyl)-2-thienylmethane (3h): Solid, m.p. 151Ϫ153 °C.
(78.0 mg, 95% yield). IR (KBr): ν˜ ϭ 1260, 1450, 1715, 3410 (NH)
cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 6.18 (s, 1 H, Ar-CH),
.
General Procedure: A mixture of indole (0.5 mmol), FeCl3·6H2O (5
mol %), and aldehyde (0.25 mmol) in the ionic liquid (0.5 mL) was
stirred at room temperature for the appropriate time (Table 2).
After completion of the reaction as indicated by TLC, the ionic
liquid was extracted with Et2O. The solvent was concentrated in
vacuo and purified by column chromatography (ethyl acetate/petro-
leum ether, 1:9) to afford the pure products.
6.87 (s, 2 H), 6.92Ϫ7.48 (m, 11 H), 7.98 (br. s, 2 H, NH) ppm.
C21H16N2S (328.10): calcd. C 76.80, H 4.91, N 8.53; found C 76.62,
H 5.04, N 8.54.
3,3Ј-Bis(indolyl)heptane (3i): Solid, m.p. 66Ϫ68 °C. (81.0 mg, 98%
yield). IR (KBr): ν˜ ϭ 799, 1092, 1337, 1455, 1618, 3052, 3414 (NH)
cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 0.83 (t, J ϭ 6.8 Hz, 3 H),
1.23Ϫ1.36 (m, 8 H), 2.19 (m,2 H), 4.66 (t, J ϭ 7.2 Hz, 1 H),
7.00Ϫ7.04 (m,4 H), 7.13 (t, J ϭ 8.0 Hz, 2 H), 7.31 (d, J ϭ 8.0 Hz,
2 H), 7.57 (d, J ϭ 7.2 Hz, 2 H), 7.90 (br. s, 2 H, NH) ppm.
C23H26N2 (330.47): calcd. C 83.39, H 7.93, N 8.48; found C 83.46,
H 8.17, N 8.06.
4-Chlorophenyl-3,3Ј-bis(indolyl)methane (3a): Solid, m.p. 76Ϫ77 °C
(85.6 mg, 96% yield). IR (KBr): ν˜ ϭ 1089, 1455, 1487, 3054, 3410
(NH) cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 5.86 (s, 1 H, Ar-
.
CH), 6.66 (s, 2 H), 7.02 (t, J ϭ 8.3 Hz, 2 H), 7.18 (t, J ϭ 7.9 Hz,
2 H), 7.26Ϫ7.38 (m, 8 H), 7.98 (br. s, 2 H, NH) ppm. HRMS:
calcd. C23H17ClN2 (356.11): 356.1080; found 356.1069.
Acknowledgments
We thank the National Natural Science Foundation of China (No.
20172039) and grants from the National University of Singapore.
3,3Ј-Bis(indolyl)phenylmethane (3b): Solid, m.p. 151Ϫ152 °C
(77.6 mg, 98% yield). IR (KBr): ν˜ ϭ 744, 1093, 455, 1600, 1618,
1
3055, 3412 (NH) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 5.89 (s,
1 H, Ar-CH), 6.67 (s, 2 H), 7.00 (t, J ϭ 6.8 Hz, 2 H), 7.19 (m, 3
H), 7.29 (m, 2 H), 7.35 (m, 6 H), 7.94 (br. s, 2 H, NH) ppm.
C23H18N2 (322.14): calcd. C 85.68, H 5.63, N 8.69; found C 85.75,
H 5.56, N 8.56.
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Efficient FeIII-Catalyzed Synthesis of Bis(indolyl)methanes in Ionic Liquids
FULL PAPER
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Received November 12. 2003
Eur. J. Org. Chem. 2004, 1584Ϫ1587
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