A simple, highly regioselective and efficient reaction of indole with epoxides under solvent-free conditions

Article abstract of DOI:10.1139/V06-063

Lithium perchlorate has been found to be an inexpensive and efficient catalyst for the ring opening of epoxides by indole and N-methylindole, which provides an environmentally friendly method for the synthesis of substituted indoles. A complete regioselec

Full text of DOI:10.1139/V06-063

8
00
A simple, highly regioselective and efficient
reaction of indole with epoxides under solvent-
free conditions
Najmedin Azizi, Shokopheh Mehrazma, and Mohammad R. Saidi
Abstract: Lithium perchlorate has been found to be an inexpensive and efficient catalyst for the ring opening of
epoxides by indole and N-methylindole, which provides an environmentally friendly method for the synthesis of substi-
tuted indoles. A complete regioselectivity in favor of nucleophilic attack at the benzylic carbon atom of aromatic
epoxides, such as styrene oxide, is observed. However, aliphatic unsymmetrical alkene oxides undergo selective
nucleophilic attack at the sterically less-hindered carbon atom. This catalyst offers several advantages, such as short re-
action time, high yields, lower catalytic loading, simple experimental procedure, and easy isolation of the products, un-
der solvent-free conditions.
Key words: indole, epoxide, regioselectivity, solvent-free.
Résumé : On a observé que le perchlorate de lithium est un catalyseur peu dispendieux et efficace pour l’ouverture
des cycles époxydes par l’indole et le N-méthylindole et la synthèse dans un environnement écologique d’indoles subs-
titués. Les réactions sont complètement régiosélectives en faveur d’une attaque nucléophile au niveau de l’atome de
carbone benzylique d’époxydes aromatiques tels que l’oxyde de styrène. Toutefois, avec les oxydes d’alcènes aliphati-
ques non symétriques, l’attaque nucléophile se fait sélectivement au niveau de l’atome de carbone le moins encombré.
Ce catalyseur présente plusieurs avantages, tel son court temps de réaction, des rendements élevés, une quantité plus
faible de catalyseur, une procédure expérimentale simple et une méthode facile d’isoler les produits dans des conditions
sans solvant.
Mots clés : indole, époxyde, régiosélectivité, sans solvant.
[
Traduit par la Rédaction] Azizi et al. 803
Introduction
were only reactive toward vinyl epoxides. Furthermore, all
of these reactions have been extensively investigated in toxic
organic solvents, and to the best of our knowledge, reactions
of indole with epoxides under solvent-free conditions have
not been reported. Thus, there is a need to develop a conve-
nient and efficient protocol for the regioselective ring opening
of epoxides with indole to produce 3-alkylindole derivatives
of biological importance.
Epoxides have been recognized as important and versatile
synthetic intermediates in organic synthesis (1) because they
are susceptible to attack by several nucleophiles and readily
accessible in pure form (2). Therefore, there is a significant
current interest in the ring opening of epoxides with a large
variety of reagents such as electrophiles, nucleophiles, acids,
bases, reducing agents, and some oxidizing agents. However,
the epoxide ring-opening reaction with certain nucleophiles
is generally performed with acid or base catalysis, with a
large excess of nucleophiles at elevated temperature, and of-
ten fails when poor nucleophiles such as indole and hindered
epoxides are used. Few procedures for the ring-opening re-
action of epoxides with indole are reported in the literature
by using high pressure or SiO (3), InCl (4), and InBr (5)
Results and discussion
As part of our research on organic synthesis under
solvent-free conditions (6), in this paper we describe a sim-
ple and practical method for the synthesis of indole deriva-
tives using a catalytic amount of lithium perchlorate. To find
out the best reaction conditions for the ring opening of epoxide
2
3
3
as catalysts. While the employment of high pressure requires
the use of special equipment, for a catalyst such as SiO , al-
though simple, several days were necessary to obtain good
yields of products. Indium salts are expensive and indoles
with indole in the presence of LiClO , styrene oxide was re-
4
2
acted with 1-methylindole in a common organic solvent and
under solvent-free conditions with a different amount of
solid lithium perchlorate. A series of experiments carried out
on epoxide and indole indicated that the best yields were ob-
tained in the presence of 20 mol% anhydr. LiClO4 and
Received 9 October 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 17 May 2006.
1
.0 equiv. of epoxide at 60 °C under neat conditions (Ta-
ble 1). In the absence of lithium perchlorate, only the start-
ing material was obtained after prolonged reaction times. As
was expected, conducting the same reaction with 20 mol%
of anhydrous lithium perchlorate in common organic sol-
vents such as THF, diethyl ether, petroleum ether, dichloro-
1
N. Azizi, S. Mehrazma, and M.R. Saidi. Department of
Chemistry, Sharif University of Technology, P.O. Box 11465-
9
516, Tehran, Iran.
1Corresponding author (email: saidi@sharif.edu).
Can. J. Chem. 84: 800–803 (2006)
doi:10.1139/V06-063
© 2006 NRC Canada

Azizi et al.
801
Table 1. Reactions of 1-methylindole and styrene oxide under different conditions.
Ph
O
LiClO4
OH
+
N
Solvent (2 mL)
r.t, 1 h
N
Me
Me
Entry
Solvent
LiClO (g)
Yield (%)
4
1
2
CH Cl2
0.2
0.5
15
32
2
CH Cl2
2
3
4
5
THF
Diethyl ether
0.2
1
0.2
23
95
35
CH CN
3
6
7
8
Petroleum ether
Methanol
Water
0.2
0.2
0.2
0.1
20
0
0
a
9
—
95
a
Reaction run at 60 °C.
Scheme 1. Reactions of indole and styrene oxide in 5 mol/L LPDE and neat conditions.
Ph
5
mol/L LPDE
OH
N
95%
O
+
Me
Ph
N
Me
Neat
OH
2
0 mol% LiClO4
N
9
5%
Me
methane, acetonitrile, methanol, and water resulted, for the
most part, in the recovery of the starting materials.
This shows that the solvent-free conditions play an essen-
tial role in facilitating the desired epoxide ring-opening reac-
cleavage by indole and N-methylindole with the preferential
attack at the less-substituted carbon atom. On the other
hand, in the case of styrene oxide and other aromatic
oxiranes, the reaction likely proceeds partly through an at-
tack by the indole on the more stabilized “carbocation” with
tion in the presence of anhydr. LiClO . On the other hand,
4
participation of phenyl groups. The role of LiClO in cata-
our study shows that by increasing the amount of lithium
perchlorate to 200 mol% in diethyl ether (5 mol/L solution
of lithium perchlorate in diethyl ether, LPDE), the direct
nucleophilic addition of indole to styrene oxide is faster than
the rearrangement of the epoxide to the corresponding car-
bonyl compounds (Scheme 1). It also indicates that the
solvent-free condition is a superior method owing to low
loading of catalyst.
4
lyzing the opening of epoxide rings with indole may be real-
+
ized through the coordination of Li with epoxide oxygen
and rendering the epoxide more susceptible to nucleophilic
attack by indole, followed by hydrogen transfer to form the
indolyl alcohols. The comparison of the present methods
with respect to the amount of the catalyst used, reaction time
and requirement of solvent, products yield and regio-
selectivity with those reported in the literature, reveals that
this newly developed method is superior to the previous pro-
cedures.
Lithium perchlorate is an extraordinarily efficient catalyst
for the highly regioselective ring-opening reaction of epoxides.
To show the generality and scope of the LiClO -promoted
4
Reaction of 2-methylindole with 2,3-epoxypropyl phenyl
ether proceeds efficiently at 60 °C in the presence of
ring opening of epoxide with indole, the reaction was exam-
ined with various structurally diverse epoxides. The data in
Table 2 clearly show that all reactions proceed smoothly un-
der these reaction conditions to afford the desired indolyl al-
cohols in good yields with high regioselectivity. This method
is also effective with aliphatic oxiranes. No precaution is
needed to exclude moisture from the reaction media. The
regioselectivity in the reaction for unsymmetrical epoxides is
governed by both steric and electronic effects. The
2
0 mol% of anhydr. LiClO under neat conditions and gave
4
the corresponding 3-substituted 2-methylindole (4) in 60%
yield after 1.5 h.
OPh
OH
N
1
regioselectivity was determined by H NMR and by compar-
4
ison with the known samples. Aliphatic oxiranes underwent
H
©
2006 NRC Canada

8
02
Can. J. Chem. Vol. 84, 2006
Table 2. Reactions of indoles with epoxide under solvent-free conditions.
R'
LiClO4
O
+
R'
OH
o
Neat 60 C
N
R
N
R
1
2
3
Entry
Epoxides
Time (min)
Yield (%)
O
3
a R = H
45
120
95
95
1
2
3b R = Me
O
O
O
3
c R = H
120
60
6
7
6
8
3
4
3dR = Me
O
3
e R = H
120
60
64
80
5
6
3f R = Me
OMe
O
O
3
g R = H
64
79
7
8
9
60
90
3h R = Me
3
i R = H
1
1
80
80
45
62
O
1
1
0
1
3j R = Me
In summary, we have described a new direct protocol for
the preparation of indolyl alcohol derivatives by ring-opening
sired products. All compounds were characterized on the ba-
sis of NMR spectroscopic data.
reactions of epoxides with indole and N-methylindole in the
presence of 20 mol% of anhydr. LiClO . The notable fea-
4
Selected spectroscopic data
tures of this procedure are the mild reaction conditions, high
conversions, short reaction times, economic viability of the
reagents, simple experimental procedure, and product isola-
tion. Although lithium perchlorate is normally responsible
for the rearrangement of aromatic epoxides to the corre-
sponding carbonyls, the mild reaction conditions allowed the
isolation of the desired compounds in high yields and with-
out rearrangement, when a 5 mol/L solution of LPDE was
used.
3
a
1
H NMR (CDCl , 500 MHz) δ : 2.28 (br s, 1 H, OH),
3
H
4.03–4.41 (m, 3H), 6.73–7.63 (m, 10H), 8.34 (br s, 1H, NH).
1
3
C NMR (CDCl , 500 MHz) δ : 45.7, 66.4, 111.2, 116.2,
3
C
119.4, 119.6, 121.9, 122.3, 126.7, 127.1, 128.3, 128.6,
136.6, 141.8.
3
b
1
H NMR (CDCl , 500 MHz) δ : 1.80 (br s, 1H, OH), 3.82
3
H
(
s, 3H), 4.23–4.53 (m, 3H), 7.02 (s, 1H), 7.11–7.53 (m, 9H).
Experimental
1
3
C NMR (CDCl , 500 MHz) δ : 33.1, 46.0, 66.9, 109.7,
3
C
1
1
14.9, 119.5, 119.9, 122.3, 126.6, 127.1, 127.9, 28.7, 128.8,
37.6, 142.3.
General procedure for the preparation of tryptophol
derivatives
To a mixture of indole (4 mmol) and epoxide (4 mmol),
anhydrous lithium perchlorate (0.1 mmol) was added and
stirred at 60 °C for 1–4 h. When the reaction was completed,
as indicated by TLC or GC, the reaction mixture was diluted
with diethyl ether or ethyl acetate and purified by flash col-
3
c
1
H NMR (CDCl , 500 MHz) δ : 1.17 (d, 3H, J = 6.3 Hz),
3
H
1.24 (d, 3H, J = 6 Hz), 2.19 (br s, 1H, OH), 3.01 (m, 2H),
3.43 (m, 1H), 3.53 (m, 1H), 3.65 (m, 1H), 4.18 (m, 1H),
6.57 (s, 1H), 6.87–7.71 (m, 4H), 8.56 (br s, 1H, NH).
umn chromatography (Et O–hexanes, 30:70) to give the de-
2
©
2006 NRC Canada

Azizi et al.
803
3
d
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(
1
Acknowledgments
6
We are grateful to the Research Council of Sharif Univer-
sity of Technology for financial support. We also thank
Volkswagen Stiftung, Germany, for financial support to-
wards the purchase of chemicals.
©
2006 NRC Canada