Solvent-free, ruthenium-catalyzed, regioselective ring-opening of epoxides, an efficient route to various 3-alkylated indoles

Article abstract of DOI:10.1016/j.tetlet.2008.01.001

Ruthenium-catalyzed regioselective ring-opening of aliphatic and aryl epoxides under solvent-free conditions is reported. It was found that RuCl₃·nH₂O catalyzes the Friedel-Crafts alkylation of indoles, providing 3-alkylated derivati

Full text of DOI:10.1016/j.tetlet.2008.01.001

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1450–1454
Solvent-free, ruthenium-catalyzed, regioselective ring-opening
of epoxides, an efficient route to various 3-alkylated indoles
K. Tabatabaeian *, M. Mamaghani, N. O. Mahmoodi, A. Khorshidi
Department of Chemistry, Faculty of Sciences, The University of Guilan, PO Box 41335-1914, Iran
Received 27 November 2007; revised 18 December 2007; accepted 3 January 2008
Available online 8 January 2008
Abstract
Ruthenium-catalyzed regioselective ring-opening of aliphatic and aryl epoxides under solvent-free conditions is reported. It was found
that RuCl3ÁnH2O catalyzes the Friedel–Crafts alkylation of indoles, providing 3-alkylated derivatives in good yields under mild reaction
conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ruthenium; Ring-opening; Epoxides; Indoles
1. Introduction
catalytic reactivity of ruthenium,22–24 we now describe our
study of the Friedel–Crafts alkylation reaction of indoles
using various epoxides.
Homogeneous transition metal catalysis is a gentle art.1
Many organic transformations which involve organometal-
lic ruthenium species as catalyst are known and well docu-
mented.2–4 RuIII salts are also known to catalyze a variety
of organic transformations,5–10 and the investigation of the
chemistry of ruthenium continues to be an active area of
organometallic chemistry. On the other hand, indole deriv-
atives occur in many pharmacologically and biologically
active compounds.11–13 In particular, 3-alkylindole deriva-
tives have significant medical importance,14–16 and can be
prepared by ring-opening of epoxides using indoles. In
the literature, this type of reaction has been reported using
different methods such as acid catalysis,17 high pressure
conditions,18 lanthanide triflates,19 nanocrystalline tita-
nium(IV) oxide20 and HBF4–SiO2.21 The drawbacks of
these methods are long reaction times, high temperatures,
a large excess of reagents, high pressure and unsatisfactory
yields, especially, with regard to aliphatic epoxides. In con-
tinuation of our recent work on indole derivatives and the
2. Results and discussion
Whilst the majority of synthetic methods for ring-open-
ing of epoxides using indoles have been focused on aryl
epoxides, little attention has been paid to the use of ali-
phatic analogues because of the lower reactivity of these
compounds. The ring-opening of phenyl glycidyl ether with
indole in a low yield under harsh reaction conditions has
been reported.18 We decided to evaluate the catalytic activ-
ity of RuIII as a mild Lewis acid in this reaction and during
the optimization process, we noticed that RuCl3ÁnH2O
freely dissolves in most epoxides (both aliphatic and aryl
epoxides), resulting in a homogeneous solvent-free process.
The optimized conditions are outlined in Scheme 1.
Typical results for the ruthenium-catalyzed ring-opening
of glycidyl and aryl epoxides with an array of substituted
indoles are shown in Table 1, indicating the generality
and scope of the reaction. Treatment of indole (1 mmol)
with 2,3-epoxypropyl phenyl ether (0.5 mL, 3.7 mmol) in
the presence of the RuCl3ÁnH2O catalyst (5 mol %) at rt
for 6 h gave 1-(3-indolyl)-3-phenoxy-2-propanol in a 67%
*
Corresponding author.
E-mail address: Taba@guilan.ac.ir (K. Tabatabaeian).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.001

K. Tabatabaeian et al. / Tetrahedron Letters 49 (2008) 1450–1454
1451
RuCl .nH O (5 mol %)
3
2
O
R
O
O
+
R
Solvent-free, rt
N
H
OH
HN
R= Ph, allyl,
n
-butyl
Scheme 1. RuIII-catalyzed Friedel–Crafts alkylation of indole using glycidyl ethers.
Table 1
RuIII-catalyzed alkylation of indoles with epoxides
Entrya
Epoxide
Indole
Product
Time (h)
6
Yieldb (%)
67c
O
O
O
O
1
N
O
H
OH
HN
CH3
2
3
4
6
73
60
O
N
H
OH
HN
Br
CH3
Br
O
O
N
O
H
OH
HN
NC
NC
O
O
O
O
4
5
8
8
56
52
N
O
O
H
OH
OH
HN
HN
COOH
N
H
COOH
OH
O
O
N
O
6
7
4
6
98
N
H
N
N
O
57d
O
O
O
N
H
OH
OH
HN
HN
O
CH3
8
9
6
6
61
O
N
H
CH3
52d
O
O
O
O
O
N
H
OH
HN
HN
CH3
O
10
11
6
3
59
N
H
OH
OH
CH3
O
82c
N
H
N
H
(continued on next page)

1452
K. Tabatabaeian et al. / Tetrahedron Letters 49 (2008) 1450–1454
Table 1 (continued)
Entrya
Epoxide
Indole
Product
Time (h)
3
Yieldb (%)
83c
OH
O
CH3
12
13
N
H
N
H
CH3
OH
Br
Br
O
O
4
4
72c
N
H
N
H
NC
OH
NC
14
60c
N
H
N
H
All products were characterized by 1H NMR, 13C NMR and IR data.
Isolated yields.
Identified by comparison with authentic samples.18,19
10 lL of CF3COOH was added as co-catalyst.
a
b
c
d
yield (entry 1). From the NMR spectral data, it was evident
that the reaction occurred exclusively at the less hindered
carbon of the epoxide ring. The reaction can be used for
substituted indoles with either electron-donating or elec-
tron-withdrawing groups (Table 1, entries 2–5), and the
same regioselectivity was observed in each case. Electron-
rich indoles, however, gave better yields and proceeded
with shorter reaction times. When 7-azaindole was treated
with 2,3-epoxypropyl phenyl ether, the reaction furnished
an excellent yield of the N-alkylation product, which was
insoluble in the reaction media. In this case, the white solid
precipitate was filtered and washed with methanol to pro-
vide a completely pure product (entry 6).
With regard to the epoxide moiety, the present protocol
is noteworthy because styrene epoxide as well as allyl- and
butyl-2,3-epoxypropyl ethers underwent ring-opening with
indoles. These results are also included in Table 1 and indi-
cate the scope of reaction. Electron-rich substituents on the
glycidyl ether, however, decreased the yield and rate of the
reaction, and in the case of entries 7 and 9, the reaction was
only promoted in the presence of CF3COOH as a co-cata-
lyst. Using styrene epoxide, however, better results in terms
of yield and reaction time were obtained in comparison
with previous reports. With regard to regioselectivity, pref-
erential attack at the benzylic position of styrene epoxide
gave primary alcohols (entries 11–14). It should be noted
that cyclohexene oxide resulted in no isolated product even
in the presence of CF3COOH at elevated temperatures.
Although the precise mechanism of the reaction awaits fur-
ther studies, a possible mechanistic pathway for the ring-
opening of glycidyl ethers, which rationalizes the formation
of products, is presented in Scheme 2.
R
O
R O
HO
O
N
H
[Ru]
R
O
[Ru]
[Ru]
O
H
O
O
R
N
H
[Ru]
O
O
R
..
N
H
N
H
Scheme 2. Proposed mechanism for the RuIII-catalyzed ring-opening of
epoxides.
diation. A mixture of indole (1 mmol), epoxide (0.5 mL)
and 5 mol % of catalyst was irradiated in a 450 W micro-
wave oven in an open vessel at 50 °C for the time specified
in Table 2, and the progress of the reaction was checked by
TLC.
These results reveal the potential of microwave irradia-
tion for promotion of the reaction. Generally, the products
were limited to 3-alkylated indoles; however, in some cases
lower yields were obtained.
Encouraged by these results, we decided to overcome the
problem of prolonged reaction times using microwave irra-

K. Tabatabaeian et al. / Tetrahedron Letters 49 (2008) 1450–1454
1453
Table 2
RuIII-catalyzed ring-opening of epoxides under microwave irradiation
Entrya
Epoxide
Indole
Product
Time (min)
5
Yieldb (%)
65c
O
O
O
O
1
N
O
H
OH
OH
HN
CH3
2
3
5
6
75
57
O
N
H
HN
Br
CH3
Br
O
O
N
O
H
OH
HN
OH
O
O
4
3
3
80c
N
H
N
H
OH
85c
CH3
5
N
H
N
H
CH3
a
All products were characterized by 1H NMR, 13C NMR and IR data.
Isolated yields.
Identified by comparison with authentic samples.18,19
b
c
In conclusion, we have developed a convenient method
(500 MHz, CDCl3, 25 °C): d = 2.23 (1H, br), 3.15 (1H,
dd, J = 14.5, 7.0 Hz), 3.20 (1H, dd, J = 14.5, 6.2 Hz),
4.01 (1H, dd, J = 9.3, 6.4 Hz), 4.07 (1H, dd, J = 9.3,
3.9 Hz), 4.41 (1H, m), 6.96 (2H, d, J = 8.3 Hz), 7.02 (1H,
t, J = 7.3 Hz), 7.15 (1H, s), 7.18 (1H, t, J = 7.8 Hz), 7.27
(1H, t, J = 7.6 Hz), 7.31–7.36 (2H, m), 7.42 (1H, d,
J = 8.2 Hz), 7.70 (1H, d, J = 7.9 Hz), 8.11 (1H, br) ppm.
13C NMR (125 MHz, CDCl3, 25 °C): d = 29.86, 70.57,
71.59, 111.66, 111.84, 115.06, 119.30, 120.06, 121.50,
122.69, 123.35, 128.03, 129.94, 136.77, 159.09 ppm. Anal.
Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found:
C, 76.40; H, 6.45; N, 5.23.
for the Friedel–Crafts alkylation of indoles with aryl- and
glycidyl epoxides. To the best of our knowledge, this is
the first report on the ring-opening of epoxides using RuIII
as a catalyst. The advantages of the present protocol
are the ease of work-up, the small amount of waste, the
solvent-free conditions and the regioselectivity.
3. General procedure for solvent-free ruthenium-catalyzed
ring-opening of glycidyl and aryl epoxides with indoles
A 3 mL screw-capped vial equipped with a magnetic stir-
ring bar was charged with indole (1 mmol) and 2,3-epoxy-
propyl phenyl ether (0.5 mL, 3.7 mmol). RuCl3ÁnH2O
(10.7 mg, 0.05 mmol) was added and the reaction mixture
was stirred at rt. After 6 h, the reaction mixture was purified
by preparative TLC (n-hexane/ethyl acetate 10/3), provid-
ing the product (179 mg, 67%). For microwave reactions,
irradiation was conducted in an open vessel at 50 °C in a
450 W microwave oven.
Acknowledgement
The authors are grateful to the Research Council of
Guilan University for the partial support of this study.
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