Dy(OTf)3 in ionic liquid: An efficient catalytic system for reactions of indole with aldehydes/ketones or imines

Article abstract of DOI:10.1016/j.tetlet.2004.04.039

Dy(OTf)₃ immobilized in ionic liquids was found to be an efficient catalytic system for the reactions of indole with aldehydes/ketones or imines. Enhanced activity was observed. The use of ionic liquids as the reaction media allows facile separ

Full text of DOI:10.1016/j.tetlet.2004.04.039

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4567–4570
Dy(OTf) in ionic liquid: an efficient catalytic system for reactions
3
of indole with aldehydes/ketones or imines
a
Xueling Mi, Sanzhong Luo, Jiaqi He and Jin-Pei Cheng
b
a
a,b,
*
a
Department of Chemistry and State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
b
Center for Molecular Science, Institute of Chemistry, CAS, Beijing 100080, China
Received 8 October 2003; revised 29 March 2004; accepted 1 April 2004
3
Abstract—Dy(OTf) immobilized in ionic liquids was found to be an efficient catalytic system for the reactions of indole with
aldehydes/ketones or imines. Enhanced activity was observed. The use of ionic liquids as the reaction media allows facile separation
and recycling of the catalyst.
Ó 2004 Elsevier Ltd. All rights reserved.
In recent years, considerable attention has been paid on
the synthetic methods leading to indole derivatives
because of their biological activities. Various indole
reaction time, complicated manipulations along with the
involving of environmentally toxic media. Wang’s
group, on the other hand, has demonstrated that a
1
10
derivatives, such as 3-substituted indoles, are common
components of drugs and are generally found to be of
pharmaceutical interest in a variety of therapeutic
areas. In addition, 3-substituted indole derivatives are
3
also versatile intermediates in organic synthesis, due to
‘green’ process of the reactions of indole with carbonyl
compounds can also be achieved by using lanthanide
triflate as the efficient and mild catalyst in aqueous
media.
2
the feasibility of their 3-position for electrophilic sub-
stitution. Acyl chlorides and acid anhydrates are often
used as the electrophilic reagents in such substitution
To expend our effort toward environmentally benign
11
synthesis, we have recently conducted a research on
room temperature reactions in ionic liquids, that is, a
salt with a melting point below ambient temperature.
Air- and moisture-stable room temperature ionic liquids
as novel solvent system for organic reactions have
4
with indoles. The reaction of indoles with aldehydes/
ketones or imines as electrophiles is, however, only
5
sparsely reported. Kamal and Qureshi reported the
reactions of indole and 2-methylindole with aldehydes
under controlled pH with reaction time as long as
12
attracted growing interest in recent years. In ionic
liquids, polar or ionic catalysts, such as lanthanide tri-
flates, can be immobilized so as to allow an easy sepa-
ration of the catalyst from the reagents and products. In
favorable cases, reactivity enhancement can also
6
7
1
0 days. Bergman et al. and Jackson et al. carried out
the similar reactions under acidic conditions in moder-
ate yields with the formation of cyclooligomeric com-
8
13
pounds. Recently, Penieres-Carrillo et al. showed a
observed.
significant improvement of the reaction by employing
infrared irradiation as the energy source and a bento-
nitic clay as the catalyst under solvent-free conditions,
though the reaction is applied only to aromatic alde-
hydes by far and the product yield still needs further
In the present work, we firstly screened the reactions of
indole with aldehydes and ketones in room temperature
ionic liquids using dysprosium triflate as the catalyst.
The reaction of indole with hexanal was chosen as
the model reaction. Upon mixing of indole and
hexanal in 1-butyl-3-methylimidazolium tetrafluoro-
1
5
9a
improvement. Other catalysts, including LiClO ,
4
9b
9c
In(OTf)
3
,
and I
reaction, but with various limitations such as long
2
were also found to promote the
4
borate ([BMIM]BF ) containing 10 mol % immobilized
Dy(OTf) , sudden color change to dark red was
3
observed in a few minutes, indicating a very fast cata-
lytic reaction. We then reduced the amount of catalyst
to 2 mol %. The reaction went to completion within 1 h
*
0
Corresponding author. Tel.: +86-22-23499174; fax: +86-10-685140-
4; e-mail: jpcheng@nankai.edu.cn
7
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.039

4568
X. Mi et al. / Tetrahedron Letters 45 (2004) 4567–4570
at room temperature in 95% of yield. In comparison, the
same reaction conducted in aqueous ethanol with
indolyl methane. The subsequent screening indicated
that different ionic liquids may influence the distribution
of the products (Table 2, entries 2–4). The reaction in
1
product in 84% yield after 24 h.
0 mol % Dy(OTf)3 afforded the desired bisindolyl
In the absence of
10a
4
[bupy]BF gave the best result in terms of the yield of the
Dy(OTf)
Table 1, entry 3). Among the ionic liquids tested, the
reaction in [BMIM]BF afforded the highest yield (95%,
3
, the reaction did not occur in ionic liquid
secondary indolyl amine. In a control experiment, no
reaction took place in the absence of Dy(OTf) (Table 2,
entry 5).
(
3
4
Table 1, entry 2). We next tested the reaction of acetone
and obtained similar result (Table 1, entry 10).
Other imines were also examined in the present work
3 4
using Dy(OTf) as catalyst in [bupy]BF . In all the cases
The reaction was then applied to a variety of aromatic
and aliphatic aldehydes and ketones, the results are all
collected in Table 1. As it reveals, both the reaction time
and yield are improved considerably in ionic liquids
compared to those of the same reactions in aqueous
media.
as shown in Table 2, the reaction afforded secondary
indolyl amines with moderate yields, along with signifi-
cant amount of bisindolyl methanes.
The by-product bisindolyl methane was initially thought
to result from decomposition of the corresponding imine
in ionic liquid. However, a separate experiment in the
absence of indole showed no imine decomposition after
24 h. In another experiment, benzoylhydrazone, a more
stable imine against decomposition, was tested under the
same conditions. The reaction afforded phenyl bisind-
olyl methane as the sole decomposed product. There-
fore, it is most likely that the byproduct bisindolyl
methane was derived from the indole–imine adduct; that
is, the secondary amine underwent elimination to gen-
erate a benzylidene–indole intermediate 4, which then
reacted with a second indole to yield 2b (Scheme 1). The
It is well known that imines can undergo electrophilic
reactions in a similar way as carbonyl compounds. We
next examined the reaction of indole with a variety of
imines in ionic liquids. In a preliminary experiment, the
reaction of indole with N-benzylidene aniline was car-
ried out in the presence of Dy(OTf)
[
3
(5 mol %) using
4
BMIM]BF as solvent. The reaction preceded smoothly
at room temperature to completion after 10 h, affording
a secondary amine, 3-(phenylamino benzylidene) indole
3h as the desired product, and phenyl bisindolyl meth-
ane 2b as the by-product (Table 2, entry 2). Compared
with the same reaction in aqueous media (Table 2, entry
3
weak association of Dy(OTf) with the indole–hydra-
zone adduct may further facilitate the elimination, and
thus only decomposition product was obtained in this
case (Scheme 1).
10b
1), the reaction in ionic liquid showed an enhanced
reactivity, but with the formation of a by-product, bis-
a
Table 1. Reactions of indole with aldehydes/ketones catalyzed by Dy(OTf)
3
R1
R2
O
Dy(OTf)3
+
R1
R2 solvent
r.t.
N
H
N
N
H
H
1
2
1
2
1
2
a: R = n-Hexyl, R = H;
b: R = Ph, R = H;
c: R = p-ClPh, R = H;
d: R = p-MeOPh, R =H
e: R = R = CH ;
3
1
2
1
2
f : R = R = -(CH ) -;
2 5
1
2
1
2
g: R = Ph, R = CH ;
3
1
2
b
Entry
Aldehyde/ketone
Dy(OTf)
3
(mol %)
Solvent
Time (h)
24
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1e
1f
10
2
EtOH/H
2
O (2:1)
2a
2a
84
95
[BMIM]BF
[BMIM]BF
4
1
1
––
2
4
No reaction
c
[BMIM]PF
d
6
1
2a
2a
2b
2c
2d
2e
2e
2e
2e
2f
88
89
98
96
99
76
96
94
98
96
88
2
[bupy]BF
4
1
2
[BMIM]BF
[BMIM]BF
[BMIM]BF
4
4
4
1
2
1
2
1
10
5
EtOH/H
[BMIM]BF
[BMIM]PF
[bupy]BF
2
O (2:1)
24
24
24
24
24
24
10
11
12
13
14
4
5
6
5
4
5
10
[BMIM]BF
[BMIM]BF
4
1g
4
2g
a
b
c
The reactions were carried out on 1 mmol scale in 2 mL solvent. Molar ratio of indole:aldehyde/ketone ¼ 2:1.
Isolated yield of pure product.
[
BMIM]PF
6
: 1-butyl-3-methylimidazolium hexafluorophosphate.
d
[
bupy]BF : 1-butylpyridinium tetrafluoroborate.
4

X. Mi et al. / Tetrahedron Letters 45 (2004) 4567–4570
4569
a
Table 2. Dy(OTf)
3
catalyzed reactions of indole with imines in [bupy]BF
4
R1
Dy(OTf)3
+
N
H
N
R2
solvent, r.t.
R1
R1
1
2
R2
h: R =H, R =H
1
2
i: R =Cl, R =H
+
1
2
N
j: R =Cl, R =Cl
H
1
2
N
H
N
H
N
k: R =OCH , R =Cl
3
H
1
2
l: R =OCH , R =CH
3
3
3
2
1
2
b
Entry
R
R
Dy(OTf)
mol %)
3
Solvent
Time (h)
Product/yield (%)
(
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
10
5
EtOH/H
2
O (4:1)
24
10
10
10
10
10
10
10
10
3h
3h
3h
3h
57
30
30
47
2b
2b
2b
2b
12
45
55
45
H
[BMIM]BF
[BMIM]PF
6
4
H
5
H
5
[bupy]BF
[bupy]BF
[bupy]BF
[bupy]BF
[bupy]BF
[bupy]BF
4
4
4
4
4
4
H
––
5
No reaction
Cl
Cl
H
3i
3j
3k
3l
43
2c
2c
2d
2d
42
37
52
45
Cl
Cl
OCH
5
53
48
37
CH
CH
3
5
3
3
5
H
N
Ph
10
N
5
CH
2
Cl
2
/[bupy]BF
4
(10:1)
24
––
––
2h
61
O
Ph
a
The reactions were carried out on 1 mmol scale in 2 mL solvent. Molar ratio of indole/imine ¼ 1:1.
b
Isolated yield of pure product.
O
3+
Dy
H
NH
H
N
N
N
+
N
H
3
+
O
Dy
N
H
-BzNHNH2
H
indole
N
Dy3+
N
N
H
H
4
2b
Scheme 1. Proposed mechanism of reaction of indole with benzoylhydrazone.
Recycling of Dy(OTf)
3
was then tested using hexanal
catalytic system for the electrophilic substitution reac-
tions of indole with a variety of carbonyl compounds
and imines. Although ionic liquid itself cannot cata-
lyze the reaction, enhanced activity was observed in
1
5
and acetone as examples (Table 3). After each run, the
reaction mixture was readily extracted with diethyl ether
to separate the products. The ionic liquid phase contains
14
Dy(OTf)
runs. It was found that the Dy(OTf) catalyst can be
recycled for at least six times with no significant loss of
activity (Table 3).
3
, which was then reused directly for the next
3
ionic liquid using Dy(OTf) as catalyst. Furthermore,
the use of ionic liquid as solvent permits the product to
be easily separated from the catalyst. The recovered
catalyst could then be reused for several times with
little loss of catalytic activity, thus the current immobi-
lization strategy provides an efficient way toward the
recovery and reuse of this expensive catalyst. The simple
3
In summary, lanthanide triflate immobilized in ionic
liquid has been demonstrated to be a mild and efficient

4570
X. Mi et al. / Tetrahedron Letters 45 (2004) 4567–4570
a
Table 3. Recycling studies for the reaction of indole with hexanal and acetone
Number of cycles
1
2
3
4
5
6
b
c
Hexanal (2 mol %)
Acetone (5 mol %)
95%
96%
94%
94%
92%
94%
91%
93%
91%
93%
90%
92%
b
a
Isolated yield of pure products.
The numbers in the parentheses reference to the amount of catalyst.
b
procedure as well as easy recovery and reuse of this new
catalytic system merit further investigation for devel-
oping other electrophilic substitutions of indoles and the
like heterocyclic compounds, which are underway at this
laboratory.
5. Kamal, A.; Qureshi, A. Tetrahedron 1963, 19, 513–520.
6
7
8
. Bergman, J.; H o€ gberg, S.; Lindstr o€ m, J. Tetrahedron 1970,
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2
. Jackson, A. H.; Prasitpan, N.; Shannon, P. V.; Tinker, A.
C. J. Chem. Soc., Perkin Trans. 1 1987, 2543–2551.
. Penieres-Carrillo, G.; Garcia-Estrada, J. G.; Gutierrez-
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. (a) Yadav, J. S.; Subba Reddy, B. V.; Murthy, C. V. S. R.;
Kumar, G. M.; Mada, C. Synthesis 2001, 783–787; (b)
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We thank the National Natural Science Foundation of
China (NSFC) and the Ministry of Science and Tech-
nology (MoST) for financial support.
1
1
1
4
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2
3
3
14. During the course of this work, In(OTf) was shown to
. (a) Moore, R. E.; Cheuk, C.; Yang, X. Q.; Patterson, G.
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15. General procedure: To a 0.02 mmol dysprosium triflate
4
solution of [BMIM]BF (2 mL) was added indole (2 mmol)
1226–1229; (c) Moore, R. E.; Cheuk, C.; Patterson, G. M.
L. J. Am. Chem. Soc. 1984, 106, 6456–6457.
and aldehyde (1 mmol). The reaction mixture was sealed in
a vial and stirred for 1 h. After complete conversion, as
indicated by TLC, the product was extracted with diethyl
ether and purified by flash chromatography on silica gel.
Catalyst recycling study was conducted similarly. After
extraction with diethyl ether to separate the products, the
residue solvent was removed in vacuum and the resulting
ionic liquid layer was reused for the next run.
4
. (a) Yeung, K. S.; Farkas, M. E.; Qiu, Z. L.; Yang, Z.
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