A facile synthesis of alkylated nitrogen heterocycles catalysed by 3D mesoporous aluminosilicates with cage type pores in aqueous medium

Article abstract of DOI:10.1039/b914628h

Friedel-Crafts alkylation of nitrogen heterocycles such as indoles and pyrroles with epoxides has been efficiently carried out using cage-type mesoporous aluminosilicates as recyclable catalysts in water under environmentally benign and mild conditions.

Full text of DOI:10.1039/b914628h

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A facile synthesis of alkylated nitrogen heterocycles catalysed by 3D
mesoporous aluminosilicates with cage type pores in aqueous medium†
a,b
a
a
a
a
Rajashree Chakravarti, Pranjal Kalita, S. Tamil Selvan, Hamid Oveisi, V. V. Balasubramanian,
b
a
M. Lakshmi Kantam and Ajayan Vinu*
Received 21st July 2009, Accepted 19th October 2009
First published as an Advance Article on the web 4th November 2009
DOI: 10.1039/b914628h
Friedel–Crafts alkylation of nitrogen heterocycles such as
indoles and pyrroles with epoxides has been efficiently
carried out using cage-type mesoporous aluminosilicates as
recyclable catalysts in water under environmentally benign
and mild conditions.
and a disordered porous structure which limit the efficiency of
these catalysts in the above transformation.
Ordered mesoporous materials with tunable pore size in the
range of 2–50 nm have attracted a great deal of attention owing
to their unique structures with organized porosity, high surface
area and pore volume, and potential applications, mainly in
the field of catalysis, adsorption, separation, sensors, and fuel
cells. Among the porous materials, mesoporous silica materials
consisting of an interconnected large-pore cage-type meso-
porous system with three-dimensional (3D) porous networks
are highly interesting and believed to be more advantageous
than porous materials having a hexagonal pore structure with a
one-dimensional array of pores. Very recently, Vinu et al. have
reported the preparation of 3D mesoporous cage-type alumi-
nosilicate materials (AlKIT-5) with different pore diameters,
Alkylated nitrogen heterocycles such as indoles and pyrroles
have been receiving much attention in modern pharmaceutical,
biological and synthetic chemistry because of their antibiotic
1,2
and anticancer activities. The alkylated nitrogen heterocycles
are generally prepared by the ring opening of various epoxides
with nitrogen heterocycles using highly corrosive acidic or
3
4
basic catalysts. Lewis acids such as lanthanide triflates and
indium salts have also been used as catalysts for the ring
5
opening of epoxides with nitrogen heterocycles. Recently, highly
13
enantioselective addition of indoles with aromatic epoxides has
aluminium contents and morphologies. AlKIT-5 materials
possess a highly-ordered cage-type mesoporous structure with
cubic Fm3m close packed symmetry, a high surface area, narrow
pore size distribution, a high specific pore volume and well-
distributed tetrahedral aluminium atoms in the silica framework
6
been carried out using chromium salen complexes as catalysts.
Although the catalysts are highly efficient, they cannot be
recovered and reused, which may create a large amount of
environmentally hazardous and toxic wastes.
13
Environmental and economic considerations have recently
raised a strong interest in redesigning commercially important
processes so that the use of harmful substances and the genera-
which provide a high acidity. It was also reported that the
activity of the AlKIT-5 catalysts in the acetylation of veratrole
and other organic transformations was superior to zeolites and
7
13
tion of toxic waste can be avoided. In this respect, heterogeneous
AlMCM-41 catalysts. These exciting catalytic properties of
catalytic processes are more favorable over their homogeneous
counterparts in the production of fine chemicals, owing to
their ease of handling, simple workup procedures and, most
importantly, their reusability. Heterogeneous catalysts such as
AlKIT-5 materials stimulated us to utilize them in various other
acid-catalyzed organic transformations for the production of
value-added products.
In this communication, we report, for the first time, the
catalytic performance of AlKIT-5 materials in the Friedel–
Crafts alkylation of nitrogen heterocycles such as indoles and
pyrroles with epoxides, which are important intermediates and
building blocks in organic synthesis and are readily decomposed
8
nanocrystalline titanium(IV) oxide, fluoroboric acid adsorbed
9
10
on silica gel and sulfated zirconia have been widely used in the
alkylation of nitrogen heterocycles with epoxides. Very recently,
Kantam et al. have reported the ionic liquid [bmim][OTf] as an
efficient promoter for the Friedel–Crafts alkylation of indoles
14
under acidic conditions in water. The reactions were conducted
in water at room temperature. The catalyst was found to be
highly active, affording the corresponding alkylated derivatives
of indoles and pyrroles in good yields (Scheme 1).
11
and pyrrole derivatives. Friedel–Crafts alkylation of indole and
pyrrole derivatives has been reported with carbonyl compounds
12
and nitroalkenes in water. Unfortunately, however, these
heterogeneous catalysts suffer from poor textural characteristics
During the screening process of the catalysts for this reaction,
a major emphasis was laid on the zeolites and mesoporous
aluminosilicate catalysts due to their characteristic structural
and chemical features, which were synthesized by the procedures
a
International Centre for Materials Nanoarchitectonics, WPI Research
Centre, National Institute for Materials Science, 1-1 Namiki, Tsukuba,
15
reported in the literature. In order to find out the best
catalytic system suited to the synthesis of alkylated nitrogen
heterocycles, the reactions were carried out using various zeolite
catalysts such as MOR, BEA, MFI and FAU, and mesoporous
catalysts, namely AlSBA-15 and AlMCM-41. Recently, the ring-
opening reactions of epoxides or aziridines with various types of
3
05-0044, Japan. E-mail: vinu.ajayan@nims.go.jp;
Fax: +81-29-860-4667; Tel: +81-29-860-4563
b
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Uppal Road, Hyderabad, 500 607, India
†
Electronic supplementary information (ESI) available: HRTEM im-
ages, N adsorption–desorption isotherms and powder XRD patterns
2
of AlKIT-5 catalysts, before and after use. See DOI: 10.1039/b914628h
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Table 2 Screening of different solvents for the alkylation of indole with
a
styrene oxide
b
Entry
Solvent
Time/h
Yield (%)
1
2
3
4
5
6
H
2
O
Cl
2 2
1.5
1.5
1.5
1.5
1.5
1.5
88
65
42
42
—
—
CH
CHCl
CH CN
Toluene
Benzene
3
3
a
Reaction conditions: indole (1.2 mmol, 117 mg), styrene oxide (1 mmol,
1
20 mg), catalyst AlKIT-5(10) (50 mg), solvent (2 mL), stirred at room
b
temperature for 1.5 h. Isolated yields.
Scheme 1 Alkylation of indole and pyrrole with styrene oxide
16
nucleophiles have been studied. Several methods with different
catalysts employed water as the solvent, and it was believed that
having the highest number of active sites on the surface (Table 1,
entry 1).
17
water was essential for the success of the reactions. Therefore,
water and dichloromethane were used as solvents in the catalyst
screening experiments in order to understand the effect of
water. Comparatively better results were obtained when water
was used as the reaction medium. Finally the reaction results
were compared with the AlKIT-5 catalysts which are shown in
Table 1. Among the catalysts studied, as can be seen in Table 1,
the AlKIT-5 catalysts showed superior performance over the
zeolites and other mesoporous catalysts used in this study.
The higher activity of AlKIT-5 catalysts could be mainly
attributed to their excellent structural order with 3D pore
symmetry and highly dispersed active sites on the uniform pore
surface, which are easily accessible for the reactant molecules
Different solvents were used for the alkylation of indole with
styrene oxide. It was found that AlKIT-5 is very efficient in
water, affording an excellent yield of the corresponding product
in a shorter reaction time (Table 2, entry 1) compared to
other, organic solvents such as dichloromethane, chloroform,
acetonitrile, toluene and benzene (Table 2, entries 2–6). The
reaction was also carried out under solvent-free conditions but
the catalyst was not effective in the absence of any solvent. This
observation can be accounted for by the co-ordinating nature of
water as a solvent which may act as a tool for facile ring opening
of epoxides to form the corresponding products. The tendency
of epoxides to decompose under acidic water conditions also
provides an added advantage for the completion of the reaction
(
Fig. S1, ESI†). As the AlKIT-5 catalyst was found to be
14,18
the best catalyst used in this study, it was selected for use in
further studies. It should be pointed out that when the reaction
was carried out without any catalyst, no product was formed
in shorter times.
The reaction was also carried out using a wide variety of
structurally-diverse indoles and pyrroles, with several epoxides,
to form the corresponding alkylated products using AlKIT-
5(10) in water. The differences in the yields of the corresponding
alkylated products formed depend on the intrinsic properties of
the substituted indoles and pyrroles used.
It was evident from the NMR spectral data that the aryl
epoxides underwent cleavage at the benzylic position in the case
of indoles to selectively give the primary alcohol product. No
trace of the secondary alcohol product was detected. Moreover,
in the case of all the substituted indoles used, it was found that
the 3-alkylated indole products are formed selectively; no traces
of the 2-alkylated products were detected in the reaction mixture.
(
Table 1, entry 10) even after prolonged reaction times. The effect
of the Al content of the AlKIT-5 catalysts in the alkylation of
indoles was also studied. A series of AlKIT-5 catalysts having
different nSi/nAl ratios was used in this study. As expected, the
activity of the catalyst increases with increasing Al content in
the silica framework of AlKIT-5 (Table 1, entries 1–3). Of the
AlKIT-5 catalysts studied, AlKIT-5 with nSi/nAl = 10 showed
the best performance, affording a yield of ca. 88% thanks to
Table 1 Screening of different catalysts for the alkylation of indole by
a
styrene oxide
In all cases, the reactions proved to be faster than most of
b,c
5,8,9,10
Entry
Catalyst
Time/h
Yield (%)
those reported earlier in the literature,
and the yields of the
products were also found to be comparable. The regioselectivities
of the resulting products are in complete agreement with the
earlier reports.
The general trend noticed in case of these reactions is
that the indoles bearing electron-donating groups afforded the
corresponding alkylated products in good yields (Table 3, entries
3 & 4). On the other hand, electron withdrawing groups being
present on the indole moiety drastically decreases the rate of
the reaction and the yield of the product formed is also very
low, even after prolonged reaction times (Table 3, entries 8 &
1
2
3
4
5
6
7
8
9
AlKIT-5(10)
AlKIT-5(28)
AlKIT-5(44)
AlMCM-41
MOR
BEA
MFI
FAU
AlSBA-15
—
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
88, 65
85
80
42
35
25
20
20
—
8,9,11
1.5
1.5, 24
1
0
0, 2
a
Reaction conditions: indole (1.2 mmol, 140 mg), styrene oxide
1.0 mmol, 120 mg), catalyst (50 mg), solvent (2 mL) stirred at
(
9
) when 5-nitroindole was used in the reaction. It was observed
b
c
room temperature for 1.0 h. Yields determined by GC. Yield using
dichloromethane as solvent.
that in the case of 1-methylindole, the reaction proceeds in a
significantly more facile manner to afford the corresponding
5
0 | Green Chem., 2010, 12, 49–53
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a
Table 3 Alkylation of indoles and pyrroles with epoxides over AlKIT-5(10)
b
Entry
1
Nucleophile
Epoxide
Product
Time/h
1.5
Yield (%)
c
88, 85
2
1.5
85
3
4
5
1.0
1.0
1.0
88
88
90
6
1.0
80
7
8
2.5
24
78
18
9
24
10
78
1
0
1.5
1
1
1
2
No reaction
No reaction
24
24
—
—
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Table 3 (Contd.)
b
Entry
Nucleophile
Epoxide
Product
Time/h
2.5
Yield (%)
d
1
1
3
4
65, 15
d
2.5
60, 13
a
Reaction conditions: indole/pyrrole (1.2 mmol), epoxide (1 mmol), AlKIT-5(10) (50 mg), water (2 mL) stirred at room temperature for an appropriate
b
c
d
time. Isolated yield of the product. Yield after five cycles. Isolated yields of 2-alkyl and 3-alkyl pyrroles, respectively.
product in greater yield than in the reaction of unsubstituted
indole.
deterioration of the structure of the catalyst after the reaction
and the activation of the catalyst at higher temperature.
In contrast, in the case of pyrroles, the alkylation reaction
results in the corresponding product mixture of 2-alkylated and
In summary, a simple and an efficient protocol for a highly
regio- and chemoselective alkylation of indoles and pyrroles with
epoxides has been described. The reaction occurs in aqueous
media and requires only a catalytic amount of AlKIT-5 catalyst.
No other promoters or additives are required to obtain a good
yield of the product. The catalyst AlKIT-5 dispersed in water
forms a robust and recyclable catalytic system, which can be
reused several times without any regeneration, thus reducing the
amount of disposed waste considerably. Further, the recycling
of the heterogeneous catalyst makes the process of separation
simpler and cheaper. The reaction has also been extended to the
gram scale to prove its industrial usefulness, which could pave
the way to replace the existing toxic, corrosive and expensive
homogenous catalysts currently used in the industry.
3
one.
-alkylated pyrroles, in which the 2-alkylated pyrrole is the major
11
It was observed from the spectroscopic data that the epoxide
ring opens by the attack of the nucleophile at the benzylic
position, to afford the primary alcohol. In this case, the preferred
site for electrophilic attack being the 2-position of the pyrrole
ring, the reaction proceeds to yield mostly the 2-alkylated
product (Table 3, entry 10). This reveals that the reaction was
highly regioselective, affording only primary alcohols.
The aryl epoxides having an electron-withdrawing substituent
underwent the reaction comparatively faster (Table 3, entry 6)
than the unsubstituted ones. Later, the reaction was carried out
on a gram scale to test its effectiveness on a larger scale. In this
reaction, 1 g of styrene oxide was reacted with 1.2 g of indole in
the presence of AlKIT-5 in water. Interestingly, even in this case,
the reaction proceeds smoothly to give 85% yield of the product.
All the reactions proceeded smoothly at ambient temperature
and pressure in water with high regioselectivity to afford good
yields of the products in short periods. It should be pointed out
that N-alkylation of the indoles and pyrroles does not take place
under the optimized mild reaction conditions.
Experimental section
AlKIT-5 catalysts with different nSi/nAl ratios were synthesized
13
using the procedure reported in the literature. The various
13
zeolites used were also synthesized using reported procedures.
A typical experimental procedure
The use of water as a solvent is not only advantageous in
being the most ‘green’ solvent available but also allows a simple,
efficient and robust system for the recycling of the catalyst. In
fact, after the completion of the reaction, the aqueous solution
containing the catalyst and the products was extracted with
ethyl acetate. To the remaining aqueous solution containing the
dispersed AlKIT-5 catalyst, fresh substrates were added and the
process was repeated for five cycles. The catalyst was found to
be highly stable and the activity of the catalyst was not much
changed even after repeated cycles (Table 3, entry 1).
To a stirred solution of indole (1.2 mmol, 140 mg) and styrene
oxide (1 mmol, 120 mg) in water (2 mL), AlKIT-5 (50 mg) was
added. The reaction mixture was stirred at room temperature for
an appropriate time (Table 3). After completion of the reaction,
as monitored by TLC, the aqueous phase containing the catalyst
was recovered quantitatively via simple extraction of the product
with ethyl acetate (3 ¥ 10 mL). The organic extracts were then
dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The resulting product was then purified by
column chromatography on silica gel (100–200 mesh) with ethyl
acetate–n-hexane (1 : 4) as eluent to afford pure 2-(3-indolyl)-2-
In order to understand the influence of the aqueous media
and the reactants on the structural order of AlKIT-5, the
◦
catalyst was dried, calcined at 540 C, and subjected to nitrogen
phenylethanol (Table 3, entry 1). 1H NMR (300 MHz, CDCl ):
3
physisorption and X-ray diffraction (XRD) analysis after the
fifth cycle (Fig. S2 and S3, ESI†). Although the shape of
the nitrogen adsorption isotherm, the XRD pattern, and the
pore size of the AlKIT-5(10) catalyst used are similar to that
of the fresh catalyst, a slight reduction in the surface area
and pore volume was observed. This could be due to a slight
d = 1.60 (br, 1 H), 4.18–4.23 (m, 2 H), 4.50 (t, J = 6.7 Hz, 1 H),
7.01–7.45 (m, 10 H), 8.11 (br, 1 H) ppm. MS (EI): m/z = 237
(25), 206 (100), 178 (30), 128 (15), 102 (10), 77 (15), 63 (5), 51
(11).
Other known products were identified by comparison with
5,9,11
the data in the literature.
5
2 | Green Chem., 2010, 12, 49–53
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The aqueous phase containing the catalyst was recycled by
the addition of fresh substrates and by continuing the reaction
for appropriate times.
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Strategic Program for Building an Asian Science and Technology
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