InCl3-catalyzed alkylation of indoles with epoxides

Article abstract of DOI:10.1055/s-2002-33532

Indoles react smoothly with terminal epoxides in the presence of catalytic amount of InCl₃ under mild conditions to afford the corresponding 3-alkyl indole derivatives in high yields with high regioselectivity.

Full text of DOI:10.1055/s-2002-33532

1
550
LETTER
InCl -Catalyzed Alkylation of Indoles with Epoxides
3
I
J
nCl -Cata
.
lyze
d
A
lkyla
S
tion of Indole
.
s
Yadav,* B. V. S. Reddy, Sunny Abraham, G. Sabitha
3
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax 91(40)7160512; E-mail: yadav@iict.ap.nic.in
Received 15 July 2002
herein report another remarkable catalytic activity of
Abstract: Indoles react smoothly with terminal epoxides in the
InCl in the regioselective ring opening of oxiranes with
3
presence of catalytic amount of InCl under mild conditions to af-
3
indoles. Thus treatment of indole with styrene oxide in the
ford the corresponding 3-alkyl indole derivatives in high yields with
high regioselectivity.
presence of a catalytic amount of InCl under mild condi-
3
tions afforded 2-(3-indolyl)-2-phenylethanol in 85% yield
Key words: indium reagents, epoxides, indoles, tryptophol deriva-
tives
(
Scheme 1).
Epoxides are versatile building blocks for the synthesis of
1
many bioactive natural products. They are well known
carbon electrophiles capable of reacting with various nu-
cleophiles and their ability to undergo regioselective ring
opening reactions contributes largely to their synthetic
2
value. The epoxide ring opening with certain nucleo-
philes is generally carried out with acid or base catalysis
to produce ring opened products. In particular the epoxide
Scheme 1
ring opening with indoles has been reported using lan- Aryl epoxides underwent cleavage by indole with prefer-
3
4
thanide triflate catalysis or high pressure conditions.
ential attack at the benzylic position resulting in the for-
However these methods often involve the use of expen- mation of primary alcohol. Since 3-position of indole is
sive reagents, drastic conditions, longer reaction times, the preferred site for electrophilic substitution reactions 3-
unsatisfactory yields especially in case of aliphatic ep- alkyl indole derivatives were obtained exclusively in all
oxides and entail undesirable side reactions due to poly- reactions. In case of aryl epoxides, a single regio isomer 3
merization or rearrangement of oxiranes. Thus there is a was formed in each reaction, the structure of which was
1
need to develop a convenient and efficient protocol for the characterised by H NMR, IR and mass spectroscopic da-
regioselective ring opening of epoxides with indoles to ta. Similarly, glycidyl aryl ethers reacted smoothly with
produce 3-alkyl indole derivatives of biological impor- indole and methyl indole to afford the corresponding tryp-
5
tance. In recent years, indium reagents have emerged as tophol derivatives in high yields (Scheme 2).
mild and water-tolerant Lewis acids imparting high regio-
The reactions proceeded efficiently at ambient tempera-
ture with high regioselectivity. This method is even ef-
fective with aliphatic oxiranes, which is lacking in the
existing procedures. This method does not require anhy-
drous solvents or any stringent reaction conditions. No
and chemoselectivity in various chemical transforma-
8
6
tions. These reagents can be conveniently used either in
aqueous or in non-aqueous media and can be recovered
and reused in subsequent reactions.
In continuation of our interest in the use of indium halides precautions need to be taken to exclude moisture from the
7
as efficient Lewis acids in various transformations, we reaction media. The reactions are clean and highly regio-
Scheme 2
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1550,1552,ftx,en;D01602ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
InCl -Catalyzed Alkylation of Indoles
1551
3
selective affording high yields of products in a short peri- In summary this paper describes a simple, convenient and
od. The scope and generality of this process is illustrated efficient protocol for the alkylation of indoles with ep-
with respect to various epoxides and indoles and the re- oxides using a novel catalyst InCl . The notable features
3
sults are presented in the Table. Among various Lewis ac- of this procedure are mild reaction conditions, greater se-
ids such as YCl , YbCl , ZrCl , BiCl and CeCl studied lectivity, cleaner reaction profiles, improved yields, en-
3
3
4
3
3
for this transformation InCl was found to be more effec- hanced rates and simplicity in operation which make it a
3
tive in terms of yields and selectivity.
useful and attractive process for the synthesis of 3-alkyl
Table InCl -Catalyzed Alkylation of Indoles with Epoxides
3
a
b
Entry
Nucleohile
Epoxide
Time (h)
Yield (%)
85
Ratio (4:3)
a
3.0
–
b
c
2.5
80
87
–
4.0
–
d
e
f
4.5
5.0
3.5
80
70
82
–
–
85:15
g
2.5
3.5
84
72
85:15
78:22
h
i
3.0
4.0
3.5
78
82
76
90:10
92:8
j
k
89:11
l
5.5
4.0
80
74
90:10
95:5
m
n
o
3.5
3.0
73
75
91:9
93:7
a
Isolated and unoptimised yields.
Ratio of products resulting from terminal attack vs internal attack of nucleophile.
b
Synlett 2002, No. 9, 1550–1552 ISSN 0936-5214 © Thieme Stuttgart · New York

1
552
J. S. Yadav et al.
LETTER
indoles. This method also provides a useful procedure to
prepare tryptophol derivatives that are of interest as inter-
mediates towards the synthesis of antibiotics such as in-
dolmycin.
(7) (a) Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M. Synlett 2001,
1417. (b) Yadav, J. S.; Sunny, A.; Reddy, B. V. S.; Sabitha,
G. Synthesis 2001, 2165. (c) Yadav, J. S.; Sunny, A.; Reddy,
B. V. S.; Sabitha, G. Tetrahedron Lett. 2001, 42, 8063.
8) Experimental procedure: A mixture of epoxide (5 mmol),
(
indole (5 mmol) and InCl (10 mol%) in dichloromethane
3
(
15 mL) was stirred at ambient temperature for an
Acknowledgement
appropriate time (Table). After completion of the reaction,
as indicated by TLC, the reaction mixture was diluted with
water (2 10 mL) and extracted with dichloromethane (2
SA and BVS thanks CSIR, New Delhi for the award of fellowships.
1
5 mL). The aqueous layer was concentrated in vacuo to
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1
6
15
(
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(
(
–
1 1
3
5
(
br s, 1 H, OH), 3.10 (d, J = 6.4 Hz, 2 H), 3.90 (dd, J = 13.5,
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(
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1
7
17
2
(
6
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Synlett 2002, No. 9, 1550–1552 ISSN 0936-5214 © Thieme Stuttgart · New York