Efficient Synthesis of Bis(indolyl)methanes Catalyzed by Lewis Acids in Ionic Liquids

Article abstract of DOI:10.1055/s-2003-41464

Efficient electrophilic substitution reactions of indoles with various aldehydes proceed smoothly in ionic liquids using Lewis acids, In(OTf) ₃, YbCl₃, InCl₃, BiCl₃, and ZnCl₂, to afford the correspon

Full text of DOI:10.1055/s-2003-41464

LETTER
2077
Efficient Synthesis of Bis(indolyl)methanes Catalyzed by Lewis Acids in
Ionic Liquids
Synthesisof
B
h
is(indolyl)m
u
ethanesCata
n
lyzedbyLew
-
isAcid
J
s
in
I
onic
u
Liquids n Ji,*a Min-Feng Zhou,a Da-Gong Gu,a Shun-Yi Wang,a Teck-Peng Loh*a,b
a
College of Chemistry and Chemical Engineering of Suzhou University, Suzhou, China, 215006
b
Department of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543
Fax +86(512)65224873; E-mail: shunjun@suda.edu.cn; E-mail: chmlohtp@nus.edu.sg
Received 20 July 2003
Firstly, we studied the effect of different ionic liquids
on this reaction using In(OTf)3. Six different ionic liq-
uids were used in our investigation, i.e. butylmethylimi-
Abstract: Efficient electrophilic substitution reactions of indoles
with various aldehydes proceed smoothly in ionic liquids using
Lewis acids, In(OTf)3, YbCl3, InCl3, BiCl3, and ZnCl2, to afford
the corresponding bis(indolyl)methanes in high yields.
–
dazolium tetrafluoroborate ([bmim][BF4 ]), butylmethyl
–
imidazolium hexafluorophosphate ([bmim][PF6 ]), hexyl-
Key words: ionic liquids, In(OTf)3, Lewis acids, indoles,
bis(indolyl)methanes
methylimidazolium chloride ([hmim][Cl–]), hexyl meth-
–
ylimidazolium hexafluorophosphate ([hmim][PF6 ]), oct-
–
ylmethylimidazolium hexafluorophosphate ([omim][PF6 ])
and decylmethylimidazolium hexafluoro phosphate
The biologically active indoles and their derivatives have
long been of interest as pharmaceuticals.1 Bisindolylal-
kanes and their derivatives have received more attention
because of their existence in bioactive metabolites of
terrestrial and marine origin.2 The simple method for the
synthesis of this class of compounds involves the
electrophilic substitution of indoles with various alde-
hydes and ketones in the presence of either protic3 or
Lewis acids.4,5 However, more than stoichiometric
amounts of the Lewis acids are required because they are
–
([dmim][PF6 ]). The results are shown in Table 1. It was
–
–
found that in [BF4 ] or [PF6 ]-type ionic liquids the elec-
trophilic substitution reactions of indoles with 4-chlo-
robenzaldehyde proceeded smoothly in high yields. It is
interesting that no desired products were obtained ever af-
ter 48 hours when [hmim][Cl–] was used.
Table 1 In(OTf)3-Catalyzed Synthesis of 3,3¢-Bis(indolyl)-4-
chloro Phenylmethane in Various Ionic Liquids
Cl
8
9
trapped by nitrogen.6 Recently, LiClO4,7 In(OTf)3 and I2
were also found to catalyze these reactions. Although
these catalysts are very useful and efficient, the long
reaction time (4–10h) and complicated manipulation,
along with the use of environmentally harmful organic
solvents, (particularly their recovery and reuse) limited
their development from the viewpoint of green chemistry.
CHO
Ionic liquid
+
N
In(OTf)3
N
H
N
H
H
Cl
Entry
Ionic liquid
Time (min)
Yield (%)a
In recent years, owing to their interesting chemical and
physical properties, such as being non-flammable, non-
toxic, reusable, inexpensive, having no measurable vap-
our pressure and high thermal stability, ionic liquids are
attracting increasing interest as potential cleaner
solvents.10 Furthermore, utilization of ionic liquids,
particularly in metal-catalyzed reactions, allows easy
recovery and reuse of the catalysts.11 In addition to the
polar properties of ionic liquids, they are non-
coordinating, which avoids the undesired solvent binding
in the pre-transition states, and hence offers great
advantages for asymmetric synthesis. More recently, an
asymmetric Mannich-type reaction catalyzed by
immobilized In(III) complexes in ionic liquids has been
developed in our laboratory.12 As a result, we decided to
prepare the bis(indolyl)methanes catalyzed by Lewis
acids in ionic liquids.
–
1
2
3
4
5
6
[bmim][PF6 ]
15
15
89
95
96
82
81
0
–
[hmim][PF6 ]
–
[omim][PF6 ]
15
–
[dmim][PF6 ]
60
–
[bmim][BF4 ]
15
[hmim][Cl–]
720
a Isolated yields.
Prompted by these results, we then examined the catalytic
activity of different Lewis acids in [omim][PF6 ]. As
shown in Table 2, all catalysts examined were very
effective in this reaction in ionic liquid [omim][PF6 ].
Among the catalysts, In(OTf)3 showed the highest
catalytic activity, the reaction being completed in 15 min
(Table 2, entry 1). It was also found when a weaker Lewis
acid such as ZnCl2 (Table 2, entry 5) was utilized, it
always required longer reaction times and an increase of
–
–
SYNLETT 2003, No. 13, pp 2077–2079
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41464; Art ID: U14503ST
© Georg Thieme Verlag Stuttgart · New York

2078
S.-J. Ji et al.
LETTER
Table 3 In(OTf)3-Catalyzed Synthesis of Bis(indolyl)methanes
with Various Aldehydes Using [omim][PF6 ] (continued)
the amounts of catalyst. Moreover, study continued to be
done using [omim][PF6 ] with various aldehydes in
–
–
presence of In(OTf)3. Results shown in Table 3 indicated
both aliphatic and aromatic aldehydes underwent smooth
reaction with indoles giving high yields of products as
well as 3a (96%).
En- RCHO
try
Productsa
Time Yield
(min) (%)b
6
7
3f
30
75
95
86
O
Cl
H
Table 2 Synthesis of 3,3¢-Bis(indolyl)-4-chlorophenylmethane Us-
Cl
–
ing Lewis Acids in [omim][PF6 ]
N
N
H
H
Entry
Lewis acid (mol%)
In(OTf)3 (5)
YbCl3 (5)
Time (h)
Yield (%)a
3g
3h
O
Cl
1
2
3
4
5
0.25
4
96
87
93
71
79
Cl
H
OH
OH
N
H
N
H
BiCl3 (10)
1.5
1
InCl3 (10)
8
9
15
15
92
89
CHO
S
ZnCl2 (10)
7
S
a Isolated yields.
N
H
N
H
Table 3 In(OTf)3-Catalyzed Synthesis of Bis(indolyl)methanes
–
with Various Aldehydes Using [omim][PF6 ]
3i
Productsa
Time Yield
(min) (%)b
CHO
En- RCHO
try
1
3a
15
96
Cl
O
N
H
N
H
H
Cl
a All products were characterized by 1H NMR, IR, and HRMS spectra.
b Isolated yields.
N
H
N
H
2
3
3b
3c
15
20
90
73
–
O
Finally, the reuse of In(OTf)3 in [omim][PF6 ] was carried
H
out (Table 4). The catalytic activity of In(OTf)3 which
was immobilized in [omim][PF6 ] gradually decreased in
the second and third cycles (entries 2 and 3). In the fourth
cycle we did not gain the desired product. However, fol-
lowing the addition of another 0.05 equivalents of
–
N
H
N
H
O
–
H
In(OTf)3 in the recycled [omim][PF6 ], the reaction pro-
ceeded as in the first cycle.
H3C
Table 4 Synthesis of 3,3¢-Bis(indolyl)-4-chlorophenylmethane in
N
H
N
H
–
[omim][PF6 ] Using Recycled In(OTf)3
4
5
3d
3e
15
70
76
78
O
OCH3
Cycle
Time (h)
0.25
48
Yield (%)a
H
1
96
87
42
0
H3CO
2
N
H
N
H
3
48
O
NO2
4
48
H
a Isolated yields.
O2N
N
H
N
H
In conclusion, we have developed an efficient
electrophilic substitution reaction of indoles with various
aldehydes catalyzed by Lewis acids in ionic liquids.
In(OTf)3, YbCl3, InCl3, BiCl3, and ZnCl2 all exhibited
high catalytic activity in ionic liquids in this reaction.
Synlett 2003, No. 13, 2077–2079 © Thieme Stuttgart · New York

LETTER
Synthesis of Bis(indolyl)methanes Catalyzed by Lewis Acids in Ionic Liquids
2079
Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod. 1995, 58,
1254. (e) Bell, R.; Carmell, S.; Sar, N. J. Nat. Prod. 1994,
57, 1587. (f) Garbe, T. R.; Kobayashi, M.; Shimizu, N.;
Takesue, N.; Ozawa, M.; Yukawa, H. J. Nat. Prod. 2000, 63,
596.
Efforts to develop more active and available catalytic
system are currently in progress.
Typical Experimental Procedure: To a stirred solution of
In(OTf)3 (5 mol%) and 4-chlorobenzaldehyde (0.5 mmol) in the
ionic liquid (1 mL) at room temperature was added indole (1 mmol).
The mixture was stirred at room temperature for 15 min. After
completion of the reaction as indicated by TLC, the ionic liquid was
extracted with Et2O. The ether layer was dried (Na2SO4),
concentrated under vacuum and purified by column
chromatography (ethyl acetate:petroleum ether = 1:9) to afford the
pure product.
(3) (a) Roomi, M.; MacDonald, S. Can. J. Chem. 1970, 48, 139.
(b) Gregorovich, B.; Liang, K.; Clugston, D.; MacDonald, S.
Can. J. Chem. 1968, 46, 3291.
(4) (a) Woland, W.; Venkiteswaren, M.; Richards, C. J. Org.
Chem. 1961, 26, 4241. (b) Banerji, J.; Chatterjee, A.;
Manna, S.; Pascard, C.; Prange, T.; Shoolery, J.
Heterocycles 1981, 15, 325.
(5) (a) Chatterjee, A.; Manna, S.; Banerji, J.; Pascard, C.;
Prange, T.; Shoolery, J. J. Chem. Soc, Perkin Trans. 1 1980,
553. (b) Babu, G.; Sridhar, N.; Perumal, P. T. Synth.
Commun. 2000, 30, 1609.
(6) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett.
1995, 36, 5773.
3,3¢-Bis(indolyl)-4-chlorophenylmethane:
IR
(KBr):
u
1089,1455, 1487, 3054, 3410 cm–1. 1H NMR (400 MHz, CDCl3): d
= 5.86 (s, 1 H, Ar-CH), 6.66 (s, 2 H), 7.02 (t, 2 H, J = 8.3 Hz), 7.18
(d, 2 H, J = 7.9 Hz), 7.23–7.38 (m, 8 H), 7.4 (d, 2 H, J = 8.1 Hz),
7.85 (br, s, 2 H, NH).
(7) Yadav, J. S.; Subba Reddy, B. V.; Murthy, C. V. S. R.;
Kumar, G. M.; Madan, C. Synthesis 2001, 783.
(8) Nagarajan, R.; Perumal, P. T. Tetrahedron 2002, 58, 1229.
(9) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1959.
HRMS: m/z calcd for C23H17ClN2: 356.1080; found: 356.1005.
Acknowledgment
(10) (a) Wasserschied, P.; Keim, W. Angew. Chem., Int. Ed.
2000, 39, 3772. (b) Welton, T. Chem. Rev. 1999, 99, 2071.
(c) Seddon, K. R. J. Chem. Technol. Biotechnol. 1997, 68,
351.
We thank the National Natural Science Foundation of China (No.
20172039) and grants from the National University of Singapore.
References
(11) (a) Kamal, A.; Chouhan, G. Tetrahedron Lett. 2003, 44,
3337. (b) Lee, S.-g.; Park, J. H. J. Mol. Catal. 2003, 194, 49.
(c) Yadav, J. S.; Reddy, B. V. S.; Gayathri, K. U.; Prasad, A.
R. Synthesis 2002, 2537. (d) Yadav, J. S.; Reddy, B. V. S.;
Reddy, P. N.; Rao, M. S. Synthesis 2003, 1387.
(12) Chen, S.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2003, 44,
240.
(1) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970.
(2) (a) Porter, J. K.; Bacon, C. W.; Robins, J. D.; Himmelsbach,
D. S.; Higman, H. C. J. Agric. Food Chem. 1977, 25, 88.
(b) Osawa, T.; Namiki, M. Tetrahedron Lett. 1983, 24,
4719. (c) Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K.
J. Nat. Prod. 1991, 54, 564. (d) Bifulco, G.; Bruno, I.;
Synlett 2003, No. 13, 2077–2079 © Thieme Stuttgart · New York