An efficient Friedel-Crafts alkylation of nitrogen heterocycles catalyzed by antimony trichloride/montmorillonite K-10

Article abstract of DOI:10.1016/j.tetlet.2008.12.022

It has been found that SbCl₃ supported on montmorillonite K-10 is an efficient and reusable catalyst for Friedel-Crafts alkylation of nitrogen heterocycles such as indoles and pyrroles with epoxides. The reaction gives the corresponding C-alkyl

Full text of DOI:10.1016/j.tetlet.2008.12.022

Tetrahedron Letters 50 (2009) 916–921
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Tetrahedron Letters
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An efficient Friedel–Crafts alkylation of nitrogen heterocycles catalyzed
by antimony trichloride/montmorillonite K-10
*
Yu-Heng Liu, Qiu-Shuang Liu, Zhan-Hui Zhang
The College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been found that SbCl3 supported on montmorillonite K-10 is an efficient and reusable catalyst for
Friedel–Crafts alkylation of nitrogen heterocycles such as indoles and pyrroles with epoxides. The reac-
Received 7 August 2008
Revised 2 December 2008
Accepted 5 December 2008
Available online 10 December 2008
tion gives the corresponding C-alkylated derivatives in good to excellent yields with
regioselectivity.
a high
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Epoxides
Ring opening
Friedel–Crafts alkylation
Nitrogen heterocycle
Indole
Pyrrole
Antimony trichloride
Montmorillonite K-10
Indole and pyrrole derivatives are important heterocyclic com-
pounds and have wide application in medicinal chemistry.1–4 In
particular, 3-alkylindole derivatives have significant biological
and pharmacological importance.5 Due to the nucleophilic nature
of indolyl and pyrrolyl compounds, various methods have been
developed for the alkylation of indoles and pyrroles.6–8,10 From
the synthetic point of view, the direct catalytic alkylation of indoles
and pyrroles with epoxides is an attractive reaction due to the fact
that this reaction is atom economic. Thus, some methodologies for
opening of epoxides with indoles or pyrroles have been developed.
This ring-opening reaction can be carried out in the presence of Le-
wis acids such as LiClO4,9 InBr3,10 Ln(OTf)3,11 RuCl3ÁnH2O,12 and
InCl3,13 and heterogeneous catalysts such as HBF4–SiO2,14 silica
gel,15 and nanocrystalline titanium(IV) oxide.16 Bis(cyclopentadi-
enyl)zirconium dichloride17 and chromium salen complexes18
have been used in alkylation of heteroaromatics with epoxides.
This reaction can also be performed under high pressure19 or in io-
nic liquids.20 However, these procedures are associated with one or
more disadvantages such as long reaction times,11 high tempera-
ture,9,11 and high pressure,15,19 and special efforts are needed to
prepare the catalyst,17 and the protocol for the Friedel–Crafts alkyl-
ation reaction of nitrogen heterocycles with epoxides is still
actively pursued.
In recent years, antimony trichloride has been used as a catalyst
for various types of organic transformations in organic synthesis
because this compound is not only commercially available and
inexpensive, but is also easier to handle than other metal halides
such as InCl3, GdCl3, and TiCl4.21,22 Clay-supported reagents have
been widely applied in organic synthesis mainly because of the
ease of separation of the products, simple work-up, mild reaction
conditions, high yield and selectivity, much improved reaction
rates, and recyclability of the catalyst.23 In continuation of our
work on the development of new synthetic methodologies,24 we
herein wish to report a simple, practical, and efficient method for
regioselective ring opening of aliphatic and aryl epoxides with
nitrogen heterocycle compounds using SbCl3/montmorillonite
K-10 as catalyst at room temperature under solvent-free condi-
tions (Scheme 1).25
Initially, we examined the Friedel–Crafts alkylation of indole
with the less-reactive glycidyl phenyl ether (Table 1, entry m).
There was no reaction in the presence of literature-reported cat-
alyst HBF4–SiO2,14 or in ionic liquid [bmin][OTf].20 It was re-
ported that this reaction was carried out in refluxing
acetonitrile in the presence of Yb(OTf)3 for 9 days to give the
product in less than 20% yield.11 This reaction could also be cat-
alyzed by SiO2 under high pressure for 3 days with poor yield
(16–29%).15 To our delight, the corresponding product 1-(1H-in-
dol-3-yl)-3-phenoxypropan-2-ol was obtained in 58% yield when
the reaction was performed in the presence of SbCl3/montmoril-
* Corresponding author. Tel.: +86 31186263124; fax: +86 311 85208792.
E-mail address: zhanhui@mail.nankai.edu.cn (Z.-H. Zhang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.022

Y.-H. Liu et al. / Tetrahedron Letters 50 (2009) 916–921
917
R1
OH
R1
OH
SbCl3/K-10
O
R
+
R
R
or
r.t., solvent-free
R1
N
N
H
N
H
H
O
SbCl3/K-10
+
N
r.t., solvent-free
Ph
N
H
OH
H
Ph
Scheme 1.
Table 1
SbCl3/K-10 catalyzed Friedel–Crafts alkylation of nitrogen heterocycles with epoxides
Entry
Indole
Epoxide
Product
Time (h)
0.25
Yielda (%)
Ph
O
OH
a
90
N
H
N
H
Ph
Me
O
O
O
Me
OH
b
c
0.70
0.40
0.50
70
80
70
N
H
N
H
Ph
OH
Me
Ph
N
H
N
H
Me
Ph
OH
d
N
H
N
H
Ph
Ph
Br
O
O
Br
OH
e
0.80
85
50
N
N
H
H
Ph
O2N
O N
2
OH
f
3.5
N
N
H
H
Me
O
OH
g
0.50
75
N
H
Me
N
H
(continued on next page)

918
Y.-H. Liu et al. / Tetrahedron Letters 50 (2009) 916–921
Table 1 (continued)
Entry
Indole
Epoxide
Product
Time (h)
Yielda (%)
OMe
O
MeO
OH
h
0.50
85
N
H
N
H
Cl
O
OH
i
0.65
90
N
H
Cl
N
H
Br
O
OH
j
0.65
80
N
H
Br
N
H
NC
O
OH
k
0.65
75
N
H
NC
N
H
O
OH
l
0.35
90
N
H
N
H
O
O
OPh
OPh
O
m
1.0
1.0
58
40
OH
OH
N
H
N
H
O
Me
n
N
H
N
H
Me

Y.-H. Liu et al. / Tetrahedron Letters 50 (2009) 916–921
919
Table 1 (continued)
Entry
Indole
Epoxide
Product
Time (h)
2.0
Yielda (%)
Br
Br
O
O
OPh
o
30
OH
Cl
N
N
H
H
O
p
q
r
0.80
70
86
72
OH
N
H
N
H
Cl
Ph
O
OH
Ph
Ph
1.5
N
H
Ph
N
H
1.5
O
N
H
OH
N
H
O
N
H
OH
OH
s
0.50
88
N
H
O
N
H
MeO
t
0.50
85
N
H
OMe
OH
N
H
O
O
u
0.25
90
N
H
Cl
Cl
OH
O
v
2.0
2.0
45
51
OPh
N
H
N
H
OH
O
w
Cl
N
H
N
H
Cl
a
Isolated yield.
lonite K-1026 at room temperature at solvent-free conditions.
Further studies showed that the catalyst loading of 10 mol %
was substantially efficient for this reaction (1 h, 58% yield). High-
er amount (20 mol %) of the catalyst did not improve the result.

920
Y.-H. Liu et al. / Tetrahedron Letters 50 (2009) 916–921
Lower catalyst loading (5 mol %) could be used with only a mar-
ginal drop in reaction rate. Reaction in organic solvents such as
CH3CN, CH2Cl2, THF, DMF, and ethyl acetate gave very low yield
of the desired product after prolonged reaction time.
The above experiment was carried out with 10 mol % of SbCl3
alone, and it was found that only 20% yield of product was obtained
after 2 h. There was no reaction in the presence of montmorillonite
K-10 alone, and the starting materials remained intact. Meanwhile,
the catalyst could be recycled five times for the reaction between
glycidyl phenyl ether and indole and gave the corresponding prod-
uct in 58%, 56%, 53%, 50%, and 49% yields.
References and notes
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To evaluate the scope of catalyst’s application, various structur-
ally divergent epoxides were tested with substituted indoles under
the optimized conditions and the results are presented in Table 1.
The reactions proceeded smoothly to afford the corresponding prod-
ucts in good yields with high regioselectivity. The regioselectivity
was determined by 1H NMR and also by comparison with known
samples.9,12,14 Aryl epoxides (Table 1, entries a–k) underwent cleav-
age by indoles with preferential attack at the benzylic position,
resulting in the formation of primary alcohols. On the other hand,
in the case of aliphatic oxiranes (Table 1, entries m–p), the reaction
likely occurred through an attack by the indole on the less-substi-
tuted carbon atom. Since the 3-position of indole is the preferred site
for electrophilic substitution reactions, 3-alkyl indole derivatives
were formedexclusivelyin all cases. In general, unsubstitutedindole
and electron-donating substituted indoles gave high to excellent
yields with short reaction time. The indole containing weakly elec-
tron-withdrawing group such as 5-bromoindole furnished the de-
sired product in good yield (85%, entry e), whereas a 50% yield for
5-nitroindole was obtained due to a strongly withdrawing group
in aromatic ring (entry f). 2-Anthracen-9-yl-oxirane reacted with in-
dole also to give an excellent yield (entry l). The aliphatic epoxides
(entries m–p) were converted into alkylated products in mediocre
yields. Likewise, 1,2-disubstituted epoxides such as trans-stilbene
oxide and cyclohexene oxide (entries q and r) also reacted with in-
dole under the same experimental conditions and provided the cor-
responding products in good yields.
Having successfully developed an efficient C3-alkylation of in-
doles with epoxides, we finally checked the possibility of applying
this method to the synthesis of alkylated pyrroles. Thus, the reac-
tion of pyrrole with aromatic epoxides, under SbCl3/montmorillon-
ite K-10 catalysis, afforded the corresponding pyrrole derivatives in
high yields (Table 1, entries s–u). Since the 2-position of pyrrole is
the preferred site for electrophilic substitution reactions, 2-alkyl
pyrrole derivatives were obtained in all reactions. We have also ob-
served that the presence of an electron-withdrawing group in the
epoxide reacted rapidly and gave higher yields (Table 1, entry s).
Furthermore, aliphatic epoxides such as glycidyl phenyl ether
and 2-chlorooxirane (Table 1, entries v and w) reacted with pyrrole
to give the expected products in satisfactory yields.
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Ganesh, K. N. Synth. Commun. 2008, 38, 1518–1526; (h) Liu, Y.-H.; Zhang, Z.-H.;
Li, T.-S. Synthesis 2008, 3314.
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Org. Prep. Proced. Int. 2008, 40, 1–65.
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Z.-H.; Lin, J. Synth. Commun. 2007, 37, 209–215; (e) Zhang, Z.-H.; Tao, X.-Y. Aust.
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25. General procedure for Friedel–Crafts alkylation of nitrogen heterocycles with
epoxides: To a mixture of indole (1.0 mmol) and styrene oxide (1.2 mmol),
SbCl3/montmorillonite K-10 (0.3 g, 10 mol % corresponding to the amount of
SbCl3) was added, and the mixture was stirred at room temperature. The
progress of the reaction was monitored by TLC. After completion of the
reaction, the catalyst was removed by filtration and the filtrate was diluted
with ethyl acetate (3 Â 10 mL), dried (MgSO4), and evaporated to give the
crude product. Further purification was achieved by silica gel chromatography
using ethyl acetate/cyclohexane as eluent to afford pure product. 1-(4-
In summary, we have demonstrated that SbCl3/montmorillonite
K-10 could efficiently promote Friedel–Crafts alkylation of nitrogen
heterocycles with epoxides at room temperature under solvent-
free conditions. The present procedure is endowed with some mer-
its, such as mild reaction conditions, relative short reaction times,
wide applicability, and recyclability of catalyst. Further study on
SbCl3-catalyzed reaction is currently underway in our laboratory.
Cyanophenyl)-2-(1H-indol-3-yl)ethanol (Table 1, entry k): IR (KBr):
m
.
= 3411,
2937, 2227, 1606, 1458, 1400, 1384, 1340, 1222, 1047, 835, 744 cmÀ1
1H NMR
(400 MHz, CDCl3): d = 1.89 (br s, 1H), 4.13–4.26 (m, 2H), 4.51 (t, J = 6.0 Hz, 1H),
7.04–7.09 (m, 2H), 7.18–7.22 (m, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.43 (d, J = 7.6 Hz,
2H), 7.53 (d, J = 7.6 Hz, 2H), 8.34 (br s, 1H). Anal. Calcd for C17H14N2O: C, 77.84;
H, 5.38; N, 10.68. Found: C, 77.76; H, 5.46; N, 10.75. 2-(3-Methoxyphenyl)-2-
Acknowledgments
(1H-pyrrol-2-yl)ethanol (Table 1, entry r): IR (KBr):
m = 3421, 2943, 1600, 1583,
1490, 1400, 1257, 1151, 1047, 729 cmÀ1 1H NMR (400 MHz, CDCl3): d = 1.94
.
We are grateful for financial support from National Natural Sci-
ence Foundation of China (20872025), Nature Science Foundation
of Hebei Province (B2008000149), Natural Science Foundation of
Hebei Education Department (2006318), and Research Foundation
for the Doctoral Program of Hebei Normal University (L20061314).
(br s, 1H), 3.78 (s, 3H), 4.02 (dd, J = 10.4, 5.6 Hz, 1H), 4.07–4.17 (m, 2H), 6.01
(dd, J = 5.6, 3.2 Hz, 1H), 6.17 (dd, J = 5.6, 2.8 Hz, 1H), 6.69 (dd, J = 4.0, 2.4 Hz,
1H), 6.78–6.83 (m, 3H), 7.23–7.27 (m, 1H), 8.44 (br s, 1H). Anal. Calcd for
C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.78; H, 7.05; N, 6.53. 1-
Phenoxy-3-(1H-pyrrol-2-yl)propan-2-ol (Table 1, entry t): IR (KBr):
m = 3385,

Y.-H. Liu et al. / Tetrahedron Letters 50 (2009) 916–921
921
2922, 2852, 1568, 1429, 1298, 1118, 1091, 885, 794, 725 cmÀ1
.
1H NMR
2.1 Hz, 1H), 6.64 (dd, J = 4.8, 3.9 Hz, 1H), 6.72 (dd, J = 4.8, 2.1 Hz, 1H), 6.89-6.96
(m, 3H), 7.22–7.29 (m, 2H), 8.21 (br s, 1H). Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96; N, 6.45. Found: C, 71.65; H, 7.10; N, 6.68.
(300 MHz, CDCl3): d = 2.22 (br s, 1H), 2.79 (d, J = 6.3 Hz, 2H), 3.53 (dd, J = 10.8,
6.3 Hz, 1H), 3.63 (dd, J = 10.8, 4.5 Hz, 1H), 3.95–4.02 (m, 1H), 6.12 (dd, J = 3.9,
2.4 Hz, 1H), 6.68 (dd, J = 4.8, 3.9 Hz, 1H), 6.76 (dd, J = 4.8, 2.4 Hz, 1H), 8.17 (br s,
1H). Anal. Calcd for C7H10ClNO: C, 52.67; H, 6.31; N, 8.78. Found: C, 52.80; H,
6.08; N, 8.96. 1-Chloro-3-(1H-pyrrol-2-yl)propan-2-ol (Table 1, entry u): IR
26. Preparation of SbCl3/montmorillonite K-10 catalyst: Antimony trichloride (2.28 g,
10 mmol) was added to a suspension of montmorillonite K-10 (27.8 g) in
ethanol (50.0 mL). The mixture was stirred at room temperature for 1 h. The
solvent was removed with rotary evaporator, and the residue was heated at
100 °C under vacuum for 5 h to furnish SbCl3/montmorillonite K-10 as a free
flowing powder.
(KBr):
754 cmÀ1
6.6 Hz, 1H), 3.98 (dd, J = 9.3, 3.9 Hz, 1H), 4.14–4.22 (m, 1H), 6.11 (dd, J = 3.9,
m
= 3413, 2956, 2871, 1618, 1598, 1458, 1400, 1292, 1244, 1076, 887,
.
1H NMR (300 MHz, CDCl3): d = 2.39 (br s, 1H), 3.91 (dd, J = 9.3,