Fluoroboric acid adsorbed on silica gel catalyzed regioselective ring opening of epoxides with nitrogen heterocycles

Article abstract of DOI:10.1016/j.tetlet.2006.10.118

Aryl epoxides can be opened in a regioselective and efficient manner with nitrogen heterocycles such as indoles, pyrroles and imidazoles in the presence of a catalytic amount of HBF₄-SiO₂ under mild conditions to afford the correspon

Full text of DOI:10.1016/j.tetlet.2006.10.118

Tetrahedron Letters 48 (2007) 173–176
Fluoroboric acid adsorbed on silica gel catalyzed regioselective
ring opening of epoxides with nitrogen heterocycles
B. P. Bandgar* and Abasaheb V. Patil
Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand Teerth Marathwada University,
Nanded 431 606, Maharashtra, India
Received 30 March 2006; revised 10 October 2006; accepted 19 October 2006
Available online 17 November 2006
Abstract—Aryl epoxides can be opened in a regioselective and efficient manner with nitrogen heterocycles such as indoles, pyrroles
and imidazoles in the presence of a catalytic amount of HBF4–SiO2 under mild conditions to afford the corresponding C-alkylated
derivatives in good yields and with a high regioselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
Aromatic epoxides are an ideal source for diversity
because they can easily be opened with nucleophiles
furnishing functionally diverse compounds. They are
well-known carbon electrophiles and their ability to un-
dergo regioselective ring opening reactions contributes
to their synthetic value.1 The epoxide opening reaction
with nucleophiles is generally performed with acidic or
basic catalysis, and in the absence of such catalysts,
the reaction is moderately slow.2 Indole is a key struc-
tural motif in many pharmacologically and biologically
active compounds3 as well as in many natural products.4
While pyrrole derivatives are also important intermedi-
ates, not only for the synthesis of drugs, pigments and
pharmaceuticals, but also for the development of func-
tional organic materials.5
leaving scope for further synthetic studies to develop a
convenient and efficient protocol for the regioselective
ring opening of epoxides with indoles and pyrroles.
Here, we report HBF4–SiO2 as a supported catalyst for
the regioselective ring opening of oxiranes with indoles
and pyrroles at room temperature. Initially, a study
was carried out to evaluate HBF4–SiO2 as a catalyst
for the reaction of styrene oxide with indole in various
solvents (Table 1).
The reaction was slow in the absence of a catalyst (Table
1, entry 1) and inferior results were obtained in the
presence of solvents such as THF, CH3CN and CHCl3
(Table 1, entries 2–5). With respect to the amount of
catalyst, the yield depended on the catalyst loading.
We optimized the quantity of the catalyst at room
In the literature, the ring opening of epoxides with in-
doles and pyrroles have been described either by acid
catalysis6 or under high pressure conditions.7 In recent
years, lanthanide triflate8 and Lewis acid9 catalysts have
been reported. However, acid catalyzed alkylation reac-
tions of pyrrole are limited and require careful control of
the acidity to prevent side reactions.5 It is therefore nec-
essary to perform epoxide-based alkylation of pyrroles
under carefully controlled conditions.6 Furthermore,
there are only a limited number of reports on the alkyl-
ation of pyrroles and indoles under acidic conditions,
Table 1. Reactions of styrene oxide with indole under various
conditions
Entry Solvent
HBF4–SiO2 (mol %) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
Neat
THF
—
2
2
20
4
4
4
3.5
3.5
3.5
2.5
2.5
2.5
10
45
55
60
55
62
70
80
80
78
CH3CN
CHCl3
CH2Cl2 0.5
CH2Cl2 1.0
CH2Cl2 1.5
CH2Cl2
CH2Cl2 2.5
CH2Cl2 3.3
2
Keywords: Aryl epoxides; Nitrogen heterocycles; HBF4–SiO2;
Regioselectivity.
2
*
Corresponding author. Fax: +91 2462 229245; e-mail: bandgar_bp@
yahoo.com
10
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.118

174
B. P. Bandgar, A. V. Patil / Tetrahedron Letters 48 (2007) 173–176
Ph
OH
HBF4-SiO2 (2 mol%)
O
+
N
Ph
N
H
rt, CH2Cl2
H
1
2
3
Scheme 1.
Table 2. HBF4–SiO2 catalyzed ring opening of aryl epoxides with nitrogen heterocycles
Entry
Reactant
Substrate
Product
Time (h)
2.5
Yield (%)
807b
Ph
O
OH
OH
a
Ph
N
H
N
H
Ph
O
b
2.5
757b
CH3
N
H
Ph
N
H
CH3
Ph
H3C
OH
H3C
O
c
3.0
3.0
707a
N
H
Ph
N
H
Ph
H3CO
H3CO
OH
O
d
787a
N
H
Ph
N
H
Ph
O2N
Br
O2N
Br
OH
O
e
f
3.0
2.5
529a
N
H
Ph
N
H
Ph
OH
O
609a
N
Ph
N
H
H
Ph
OH
Ph
O
g
3.0
52
Ph
N
Ph
Ph
N
C2H5
C2H5
NC
NC
OH
O
h
i
2.5
3.5
509a
N
H
Ph
N
H
Ph
O
75:15a,7a
N
H
N
OH
Ph
H
Ph
O
j
N
3.5
3.0
3.0
50:15a,7a
N
Ph
OH
CH3
CH3
N
OH
O
707a
N
k
l
N
N
Ph
Ph
Ph
H
N
OH
N
O
N
637a
CH3
N
H
Ph
CH3
a Ratio of products 5:6.

B. P. Bandgar, A. V. Patil / Tetrahedron Letters 48 (2007) 173–176
175
temperature in CH2Cl2 as solvent and it was observed
that the use of just 2 mol % (Table 1, entry 8) was
sufficient to produce an excellent yield of the product.
Further studies showed that increasing the amount of
catalyst did not produce significantly better yields
(Table 1, entries 9–10).
the major isomer along with a minor amount of 6 (Table
2, entries i–j).
1
The structures of 5 and 6 were confirmed by H NMR
and 13C NMR spectroscopy. For compound 5, the pro-
tons on the pyrrole ring at 6.0 (dd, 1H, J = 5.3 and
3.7 Hz), 6.16 (dd, 1H, J = 5.3 and 2.4 Hz) and 6.69
(dd, 1H, J = 3.7 and 2.4 Hz) ppm and the carbons of
the pyrrole ring at 105.7, 108.1, 117.1 and 131.8 ppm
were indicative of the formation of the 2-substituted
pyrrole derivative. However, pyrrole ring protons of
compound 6 at 6.10 (dd, 1H, J = 3.7 and 2.5 Hz), 6.60
(dd, 1H, J = 3.7 and 2.0 Hz) and 6.74 (dd, 1H, J = 2.5
and 2.0 Hz) ppm and the carbons of the pyrrole ring
at 108, 115.9, 118.3 and 123.6 ppm indicated the forma-
tion of the 3-substituted isomer. This clearly indicates
that pyrrole attacks styrene oxide at the benzylic posi-
tion with the expected regioselectivity.
Indole on treatment with styrene oxide in the presence
of HBF4–SiO2 (2 mol %), afforded 2-(3-indolyl)-2-
phenylethanol in a 80% yield10 with preferential attack
at the benzylic position (Scheme 1).
The structure was confirmed by 1H and 13C NMR
spectroscopy. The methylene protons occurred at
1
4.18 ppm in the H NMR spectra and the methylene
carbon appeared at 66.38 ppm in the 13C NMR spectra
which indicated that indole reacted at the benzylic
position of styrene oxide resulting in the 3-substituted
indole derivative 3. Encouraged by these results, vari-
ous substituted indoles were treated with styrene oxide.
A single regioisomer 3 was formed in each reaction,
consistent with the 3-position of indole being the pre-
ferred site for the electrophilic substitution (Table 2,
entries a–h). The structures of all the products were
These results with indoles and pyrroles prompted us to
extend the generality of the protocol to imidazole, which
reacted with styrene oxide efficiently at room tempera-
ture under mild conditions (Scheme 3). Ring opening oc-
curred exclusively at the less hindered carbon of the
epoxide. This is consistent with SN2-type attack by the
imidazole nitrogen. The structure of the product was
1
confirmed by IR, H NMR, 13C NMR and mass spec-
troscopic data.
1
confirmed from its H NMR and 13C NMR spectral
We then treated styrene oxide with pyrrole in the pres-
ence of HBF4–SiO2 (Scheme 2). The reaction was highly
regioselective affording the corresponding product 5 as
data. The characteristics signals of the aliphatic protons
in the 1H NMR at 4.11 ppm (d, 2H, J = 5.7 Hz for
CH2N) and at 4.89 ppm (t, 1H, J = 5.7 Hz for CH(OH))
Ph
OH
O
HBF4-SiO2 (2 mol%)
rt, CH2Cl2
Ph
+
+
Ph
N
H
N
H
N
H
OH
1
4
5
6
Scheme 2.
N
OH
HBF4-SiO2 (2 mol%)
rt, CH2Cl2
O
N
+
N
N
H
Ph
Ph
1
7
8
Scheme 3.
Table 3. Comparative study of HBF4–SiO2 with recently reported literature methods for the ring opening reactions of aryl epoxides by nitrogen
heterocycles
Entry
Catalyst
Catalyst loading (mol %)
Yield (%)
Reaction conditions
1
2
3
4
5
6
High pressure technique
Yb(OTf)3
High pressure-silica gel
InCl3
InBr3
HBF4–SiO2
—
5
500 mg
10
10
2
13–90
19–66
19–88
70–85
24–84
50–80
10 K bar, 42 °C, 24 h
42 h to 9 d, reflux
10 K bar, 42 °C, 24 h to 7 d
2.5–5.5 h, rt
2–5 h, rt
2.5–3.5 h, rt

176
B. P. Bandgar, A. V. Patil / Tetrahedron Letters 48 (2007) 173–176
and signals in the 13C NMR at 52.1 ppm (CH2N) and at
70.3 ppm (CHOH) are in agreement with structure 8.
4. (a) The alkaloids: Specialist periodical reports; The
Chemical Society; London, 1971; (b) Saxton, J. E. Nat.
Prod. Rep. 1989, 6, 1; (c) Hesse, M. Alkaloid Chemistry;
Wiley: New York, 1978; (d) Cordell, G. A. Introduction to
Alkaloids: A Biogenetic Approach; Wiley: New York, 1981;
(e) Gilchrist, T. L. Heterocyclic Chemistry; Pitman:
London, 1981; (f) Pindur, A. R. J. Heterocycl. Chem.
1988, 25, 1; (g) Rainier, J. D.; Smith, A. B. Tetrahedron
Lett. 2000, 41, 9419; (h) Bennasar, M. L.; Vida, B.; Bosch,
J. J. Org. Chem. 1997, 62, 3597; (i) Amat, M.; Hadida, S.;
Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158.
5. (a) Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles;
Academic Press: London, 1977; (b) Lipshutz, B. H. Chem.
Rev. 1986, 86, 795; (c) Dirlam, J. P.; Clark, D. A.; Hecker,
S. J. J. Org. Chem. 1986, 51, 4920.
All of the reactions proceeded efficiently at an ambient
temperature with a high regioselectivity. No anhydrous
solvents or harsh reaction conditions were required.
All the reactions were clean and regioselective giving
good yields of products in short reaction times. The re-
sults shown in Table 2 clearly indicate the scope and
generality of this protocol. A comparison of the results
obtained using HBF4–SiO2 with other recently reported
methods indicated the superiority of the present proto-
col in terms of yield, catalyst loading (2 mol %) and
reaction conditions (Table 3). It is important to note
that no trace of the product was observed in the case
of aliphatic epoxides (e.g., epichlorohydrin) even after
stirring for a longer time (24 h) with various nitrogen
heterocycles. In each case the reactants were recovered
in almost quantitative amounts.
6. Tanis, S. P.; Raggon, J. W. J. Org. Chem. 1987, 52, 819.
7. (a) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.; Nishi-
zawa, H. J. Org. Chem. 1996, 61, 984; (b) Kotsuki, H.;
Nishiuchi, M.; Kobayashi, S.; Nishizawa, H. J. Org.
Chem. 1990, 55, 2969.
8. Kotsuki, H.; Teraguchi, M.; Shimomoto, N.; Ochi, M.
Tetrahedron Lett. 1996, 37, 3727.
9. (a) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Ronchi, A.
U. J. Org. Chem. 2002, 67, 5386; (b) Yadav, J. S.; Reddy,
B. V. S.; Araham, S.; Sabitha, G. Synlett 2002, 1550; (c)
Yadav, J. S.; Reddy, B. V. S.; Parimal, G. Synlett 2002,
1143.
In conclusion, this paper describes a simple and conve-
nient procedure for the alkylation of nitrogen hetero-
cycles with aryl epoxides using a supported catalyst.
10. General experimental procedure: To a stirred mixture of
indole (1 mmol) and styrene oxide (1 mmol) in CH2Cl2
(1 ml), HBF4–SiO2 (40 mg, 2 mol %) was added with
continuous stirring at room temperature. After comple-
tion of the reaction (TLC), the reaction mixture was
diluted with diethyl ether (15 ml). The catalyst was
separated by filtration. The filtrate was dried over anhy-
drous Na2SO4 and then evaporated under vacuum to
afford the crude product which on further purification by
column chromatography, gave 2-(1H-3-indolyl)-2-phenyl-
ethanol in a 80% yield.
References and notes
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1983, 39, 2323; (b) Smith, J. G. Synthesis 1984, 629; (c)
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cycles 2000, 53, 777.
2. March, J. Advanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992; p 376.
Spectral data for new compound 3g: 2-(1-Ethyl-2-phenyl-
3-indolyl)-2-phenylethanol (3g): White solid; mp 122 °C;
IR (KBr): 3549, 3400, 3060, 3030, 1610, 1600, 1470, 1360,
1335, 1020, 910, 735 cmÀ1; 1H NMR (200 MHz, CDCl3): d
1.50 (t, J = 6.8 Hz, 3H), 1.58 (br s, 1H), 3.78 (m, 2H),
4.16–4.25 (m, 2H), 4.50 (t, J = 6.8 Hz, 1H), 6.98–7.05 (s,
5H), 7.10–7.45 (m, 9H); EIMS: m/z 341 (M+); Anal Calcd
for C24H23NO: C, 84.42; H, 6.78; N, 4.10. Found: C,
84.51; H, 6.60; N, 4.28.
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