Highly efficient friedel-crafts alkylation of indoles and pyrrole catalyzed by mesoporous 3D aluminosilicate catalyst with electron-deficient olefins

Article abstract of DOI:10.1055/s-0030-1258801

The C3-selective Friedel-Crafts alkylation of indoles with electron-deficient olefins has been achieved using a mesoporous aluminosilicate catalyst with 3D cage-type porous structure to furnish the 3-alkylindole derivatives in excellent yields due to its

Full text of DOI:10.1055/s-0030-1258801

LETTER
2813
Highly Efficient Friedel–Crafts Alkylation of Indoles and Pyrrole Catalyzed
by Mesoporous 3D Aluminosilicate Catalyst with Electron-Deficient Olefins
ins lu Naidu, V. V. Balasubramanian, M. A. Chari, T. Mori, S. M. J. Zaidi, Salem S. Al-Deyab,d
a
b
b
a,b,e
c
E
T
fficient
F
riede
.
l–Crafts
Alk
S
ylation of Indo
i
les
w
it
d
hElectron-D
d
eficient
O
le
f
u
b,e
a,b,e
B. V. Subba Reddy,* A. Vinu*
a
Ionics Materials Chemistry Group, Department of Chemistry, Hokkaido University, E-mail: Sapporo 060-0810, Japan
International Center for Materials Nanoarchitectonics, WPI Research Center, National Institute for Materials Science,
b
1-1 Namiki, Tsukuba, 305-0044, Japan
Fax +81(29)8604706; E-mail: vinu.ajayan@nims.go.jp
Department of Chemical Engineering, King Fahd University of Petroleum & Minerals, Dhahran 31261, Saudi Arabia
Department of Chemistry, Petrochemicals Research Chair, Faculty of Science, King Saud University,
P.O. Box 2455 Riyadh 11451, Kingdom of Saudi Arabia
NIMS-IICT Materials Research Center, Indian Institute of Chemical Technology, Hyderabad 500007, India
c
d
e
Received 6 August 2010
catalyzed addition of indoles on olefin often requires care-
ful control of the acidity to prevent side reactions such as
dimerization of indoles or polymerization of pyrroles.
Abstract: The C3-selective Friedel–Crafts alkylation of indoles
with electron-deficient olefins has been achieved using a mesopo-
rous aluminosilicate catalyst with 3D cage-type porous structure to
furnish the 3-alkylindole derivatives in excellent yields due to its Thus, the development of an effective catalyst for the
high surface area, large pore volume and high acidity. Pyrrole also preparation of the alkyl derivatives of indole or pyrrole is
reacted efficiently under similar reaction conditions to give the cor-
responding 2-alkylated pyrrole derivatives in good yields.
highly critical as they have become increasingly useful
and important in the field of drugs and pharmaceuticals.
Key words: nanoporous aluminosilicate, conjugate addition, elec- Recently we have found that the mesoporous aluminosili-
tron-deficient olefins, C3-alkylation of indoles, C2-alkylation of
pyrrole
cate catalyst with 3D mesoporous cage-type porous struc-
ture, high surface area and large pore volume (AlKIT-5)
has been highly active and efficient for various acid-cata-
lyzed multicomponent organic transformations due to its
The C3-selective Friedel–Crafts alkylation of indoles is excellent structural order and high acidity.8
,9
one of the most important organic transformations and
In continuation of our research on the application of Al-
plays a key role in the total synthesis of complex natural
KIT-5 catalyst in various organic transformations, we
1
2
products such as diolmycins and hapalindole. The hapal-
indole alkaloids are mostly obtained from the blue-green
herein report a simple and efficient method for the C3-
alkylation of indoles with electron-deficient olefins using
a highly acidic 3D mesoporous aluminosilicate nanocage
catalyst. In a test experiment, 1 mmol of indole was treat-
ed with 1 mmol of chalcone in 1,2-dichloroethane at room
temperature in the presence of 100 mg of AlKIT-5(10)
2
algae Hapalosiphon fontinalis and exhibit potent antibac-
terial and antimycotic activity. Therefore, the synthesis
3
of 3-substituted indoles has been receiving significant in-
terest in medicinal chemistry. The 3-alkylated indoles are
generally prepared by the simple conjugate addition of in-
doles with electron-deficient olefins in the presence of ei-
where the number in the parenthesis indicates the n /n
Si Al
ratio of the final product. Even though the reaction pro-
ceeded at room temperature, the yield of the desired prod-
uct 3a was low even after 12 hours. However, the reaction
was completed within 8.5 hours under reflux conditions
and the final product 3a was obtained in 87% yield
4
5–7
ther protic or Lewis acids. Recently, some Lewis acids
also became known to be effective in promoting this reac-
7
tion under mild reaction conditions. Asymmetric version
of conjugate addition of indole has also been reported us-
ing proline-derived chiral amines to produce enantiomer-
(
Scheme 1).
6
ically enriched indole derivatives. However, the acid-
O
O
AlKIT-5
+
DCE, reflux
N
H
N
H
1
2
3a
Scheme 1 C3-Alkylation of indole with chalcone
SYNLETT 2010, No. 18, pp 2813–2817
x
x
.x
x
.2
0
1
0
Advanced online publication: 01.10.2010
DOI: 10.1055/s-0030-1258801; Art ID: U07310ST
©
Georg Thieme Verlag Stuttgart · New York

2
814
T. S. Naidu et al.
LETTER
The effect of n /n ratio of the AlKIT-5 catalyst on the corresponding C2-alkylated pyrrole derivatives in good
Si Al
alkylation of indole has also been investigated. It has been yields (entries k–m, Table 1). It should be noted that no
found that the catalytic activity of the materials increases by-products arising from 1,2-addition or bisaddition were
with increasing the Al content of the sample as each Al observed. The reaction was also carried out with a,b-un-
atom in the aluminosilicate matrix of the catalyst offers an saturated esters and nitriles using AlKIT-5 which failed to
active site. Among the catalysts with different n /n ratio undergo Michael addition with indoles or pyrroles under
Si Al
studied, AlKIT-5(10) was found to be the best, affording identical conditions. In order to confirm the effectiveness
a high yield of the final product. The high activity of the of the AlKIT-5 catalyst, the reaction was carried out at
AlKIT-5(10) catalyst is mainly due to the fact that the room temperature or reflux conditions without catalyst.
acidity, surface area, pore diameter and pore volume of Unsurprisingly, no product was formed even after long re-
the catalyst are higher as compared to those of other cata- action times (10–20 h) in the absence of a catalyst, reveal-
8
,9
lysts used in the study. These factors are highly critical ing the effectiveness of the AlKIT-5 catalyst for this
for the adsorption, diffusion, and the activation of the re- particular reaction. It is noteworthy to highlight that this
actant molecules in the pore channels of the catalyst.
method is useful for the alkylation of both pyrrole and in-
doles. Various electron-deficient olefins have been used
with similar success to provide the corresponding C3-
alkylated indoles in high yields, which are also of much
interest with respect to biological activity. In all the cases,
the corresponding products were obtained in high yields
Inspired by the results obtained from indole and chalcone,
we turned our attention to various indoles. Substituted in-
doles such as 2-methyl, 5-methoxy, 5-bromo, and N-me-
thyl derivatives participated well in this reaction (entries
b–e, Table 1). In addition, various electron-deficient ole-
fins such as 1,3-diphenyl-2-propen-1-one, 4-chlorochal-
cone, trans-b-nitrostyrene, 1-cyclohex-2-enone and 1-
cyclopent-2-enone were examined for this transforma-
(
60–91%). The structure of the products was determined
from their spectral data (NMR, IR, and MS) and also by
comparison with authentic samples.5
,7
tion. In all the cases, the reactions were highly selective Mechanistically, the reaction proceeds via the activation
and the catalyst afforded the corresponding Michael ad- of enone by AlKIT-5 followed by indole addition on ole-
ducts in excellent yields (entries a–i, Table 1). Next, we fin. The resulting intermediate undergoes subsequent tau-
have attempted the Friedel–Crafts alkylation of pyrrole tomerization to give the C3-alkylated product as shown in
with various electron-deficient olefins. To our surprise, Scheme 3. The catalyst was easily separated by filtration
the reaction of pyrrole with chalcone (Scheme 2) under and reused after activation at 500 °C for three to four
similar reaction conditions underwent smoothly to furnish hours. The efficiency of the recovered catalyst was veri-
the C2-alkylated pyrrole in 65% yield (entry j, Table 1).
fied in the alkylation of indole with chalcone (entry a,
Table 1). Using the fresh catalyst, the yield of product 3a
was 87%, while the recovered catalyst gave the yield of
To explore the generality and scope of the pyrrole alkyla-
tion catalyzed by AlKIT-5(10), the reaction was carried
out with various electron-deficient olefins. It has been
found that the pyrrole reacted well with cyclopentenone,
8
7%, 85% and 82% over three cycles, respectively. The
scope and generality of this process is illustrated with re-
spect to various electron-deficient olefins and indoles and
the results are summarized in Table 1.10
4
-chlorochalcone, and trans-b-nitrostyrene to afford the
O
AlKIT-5
+
DCE, reflux
N
N
H
H
Ph
O
3
j
Scheme 2 C2-Alkylation of pyrrole with chalcone
..
NH
HO
Ph
O
AlKIT
Ph
O
Ph
H
AlKIT-5
Ph
N
O
Ph
Ph
N
H
Scheme 3 A plausible reaction mechanism
Synlett 2010, No. 18, 2813–2817 © Thieme Stuttgart · New York

LETTER
Efficient Friedel–Crafts Alkylation of Indoles with Electron-Deficient Olefins
2815
Table 1 AlKIT-5-Catalyzed Conjugate Addition of Indoles and Pyrrole with Electron-Deficient Olefins
Entry
Indole 1
Enone 2
Product 3a
Time (h) Yield (%)b
Ph
Ph
O
O
O
O
O
a
8.5
9.5
8.0
9.0
87
85
91
82
Ph
Ph
N
H
N
H
O
b
c
N
H
N
H
Ph
O
MeO
MeO
Ph
N
H
N
H
Ph
O
Br
Br
d
Ph
N
H
N
H
Ph
Cl
O
O
Ph
e
f
10.0
80
89
N
N
Me
Me
O
O
9.0
N
H
Ph
Cl
N
H
Ph
NO2
NO2
g
8.0
91
82
N
H
N
H
O
O
h
11.0
N
H
N
H
O
O
i
10.5
10.0
85
65
N
H
N
H
O
j
Ph
N
N
H
H
Ph
O
Synlett 2010, No. 18, 2813–2817 © Thieme Stuttgart · New York

2
816
T. S. Naidu et al.
LETTER
Table 1 AlKIT-5-Catalyzed Conjugate Addition of Indoles and Pyrrole with Electron-Deficient Olefins (continued)
Entry
Indole 1
Enone 2
Product 3a
Time (h) Yield (%)b
Cl
O
N
H
k
10.0
62
N
H
O
Cl
O
Ph
l
10.5
9.5
60
70
N
N
H
O
H
NO2
m
N
NO2
N
H
H
Ph
a
1
All products were characterized by H NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
In summary, we have demonstrated for the first time the
Friedel–Crafts alkylation of indoles and pyrrole with elec-
tron-deficient olefins using a highly acidic 3D mesopo-
rous aluminosilicate nanocage as the novel catalyst. The
catalyst was highly active and selective, affording the
alkylated indoles and pyrroles in a good to excellent
yields. The high activity of the AlKIT-5 catalyst on the
Friedel–Crafts alkylation is due to its high surface area,
large pore volume, and high acidity. In addition, the cata-
lyst is highly stable and can be recycled several number of
times without much affecting the activity of the catalyst
which makes this process simple, convenient and practical
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Acknowledgment
This work was financially supported by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) under the Strate-
gic Program for Building an Asian Science and Technology Com-
munity Scheme and the World Premier International Research
Center (WPI) Initiative on Materials Nanoarchitectonics, MEXT,
Japan. B.V.S. thanks CSIR and NIMS for the award and the finan-
cial assistance.
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References and Notes
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Synlett 2010, No. 18, 2813–2817 © Thieme Stuttgart · New York

LETTER
Efficient Friedel–Crafts Alkylation of Indoles with Electron-Deficient Olefins
2817
(
9) (a) Chakravarti, R.; Oveisi, H.; Kalita, P.; Pal, R. R.;
chromatography using EtOAc–n-hexane (1:9) as eluent to
afford the pure 3-alkylindole or 2-alkylpyrrole. The spectral
data are in full agreement with the data reported in the
Halligudi, S. B.; Kantam, M. L.; Vinu, A. Micropor.
Mesopor. Mater. 2009, 123, 338. (b) Balasubramanian,
V. V.; Srinivasu, P.; Anand, C.; Pal, R. R.; Ariga, K.;
Velmathi, S.; Alam, S.; Vinu, A. Micropor. Mesopor. Mater.
5
literature. Spectral data for the selected products: 2-Phenyl-
1
3-indolyl-1-nitroethane(3g): H NMR (300 MHz, CDCl ):
3
2
008, 114, 303. (c) Shobha, D.; Chari, M. A.; Selvan, S. T.;
d = 4.91–5.12 (m, 2 H), 5.22 (t, J = 7.0 Hz, 1 H), 7.01 (d, J
Oveisi, H.; Mano, A.; Mukkanti, K.; Vinu, A. Micropor.
Mesopor. Mater. 2010, 129, 112. (d) Chari, M. A.;
Karthikeyan, G.; Pandurangan, A.; Naidu, T. S.;
= 2.2 Hz, 1 H), 7.07–7.37 (m, 8 H), 7.47 (d, 1 H, J = 8.0 Hz,
1
3
1 H), 8.06 (br s, 1 H, NH). C NMR (75 MHz, CDCl ): d =
3
40.9, 78.4, 110.6, 118.7, 120.2, 121.9, 123.0, 126.3, 127.9,
128.2, 129.1, 135.8, 140.2. EIMS: m/z (%) = 266 (100) [M ].
+
Sathyaseelan, B.; Zaidi, S. M. J.; Vinu, A. Tetrahedron Lett.
1
2010, 51, 2629.
2-Phenyl-2-pyrrolyl-1-nitroethane (3m): H NMR (300
(
10) General Procedure. A mixture of activated olefin (1.0
mmol), indole or pyrrole (1.0 mmol) and AlKIT-5 (100 mg)
in DCE (5 mL) was stirred at reflux temperature for the
appropriate time (Table 1). After completion of the reaction,
as monitored by TLC, the reaction mixture was diluted with
EtOAc (20 mL) and the catalyst was separated by filtration.
The organic layer was concentrated under reduced pressure
and the crude product was purified by silica gel column
MHz, CDCl ): d = 4.76 (dd, J = 11.6, 7.4 Hz, 1 H), 4.86 (dd,
3
J = 7.4, 7.1 Hz, 1 H), 4.96 (dd, J = 11.6, 7.1 Hz, 1 H), 6.03–
6.05 (m, 1 H), 6.14 (dd, J = 6.0, 2.7 Hz, 1 H), 6.40 (dd, J =
13
4.0, 2.5 Hz, 1 H), 7.20–7.31 (m, 5 H), 7.85 (s, 1 H). C NMR
(75 MHz, CDCl ): d = 137.9, 129.2, 128.9, 128.0, 127.9,
3
118.2, 108.6, 105.8, 79.2, 42.9. EIMS: m/z (%) = 216 (30)
+
[M ], 169 (100).
Synlett 2010, No. 18, 2813–2817 © Thieme Stuttgart · New York

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