Hydroxyalkylation of indole with cyclic carbonates catalyzed by ionic liquids

Article abstract of DOI:10.1016/S1872-2067(12)60571-3

A simple and eco-friendly procedure has been developed for the synthesis of hydroxyalkyl indoles from indole and cyclic carbonates in the presence of a catalytic amount of imidazolium based ionic liquids under solvent-free conditions. The effects of reaction time, the catalyst amount, temperature, and the ratio of the reactants were investigated to develop the optimum conditions for the transformation. Under the optimized reaction conditions, indole reacted with ethylene carbonate or propylene carbonate to give 1-(2-hydroxyethyl)indole or 1-(2-hydroxypropyl)indole, as well as the corresponding sequential derivatives, in high yields. The catalytic activity of the ionic liquids was affected by the anions of the ionic liquids in the order of BF₄ ^- < Br^- < Cl^- < OAc^-, which was consistent with the hydrogen bond basicity of the anions of the ionic liquids.

Full text of DOI:10.1016/S1872-2067(12)60571-3

Chinese Journal of Catalysis 34 (2013) 1187–1191
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
Article
Hydroxyalkylation of indole with cyclic carbonates catalyzed by
ionic liquids
GAO Guohua*, ZHANG Lifeng, WANG Binshen
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple and eco‐friendly procedure has been developed for the synthesis of hydroxyalkyl indoles
from indole and cyclic carbonates in the presence of a catalytic amount of imidazolium based ionic
liquids under solvent‐free conditions. The effects of reaction time, the catalyst amount, temperature,
and the ratio of the reactants were investigated to develop the optimum conditions for the trans‐
formation. Under the optimized reaction conditions, indole reacted with ethylene carbonate or
propylene carbonate to give 1‐(2‐hydroxyethyl)indole or 1‐(2‐hydroxypropyl)indole, as well as the
corresponding sequential derivatives, in high yields. The catalytic activity of the ionic liquids was
Received 20 December 2012
Accepted 12 March 2013
Published 20 June 2013
Keywords:
Ionic liquid
Indole
Cyclic carbonate
Hydroxyalkylation
–
affected by the anions of the ionic liquids in the order of BF4 < Br– < Cl– < OAc–, which was con‐
sistent with the hydrogen bond basicity of the anions of the ionic liquids.
© 2013, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
1. Introduction
functionalized alcohols [15–17]. Furthermore, ethylene car‐
bonate has a low melting point (35 °C) and a high boiling point
Hydroxyalkyl indoles are frequently used in a variety of dif‐
ferent areas of research, including medicine [1,2] and organic
synthesis [3–5], as well as the development of second‐order
nonlinear optical materials [6–8]. Hydroxyalkyl indoles are
traditionally synthesized from extremely toxic halohydrin
compounds in the presence of a stoichiometric amount of a
strong base [9,10]. They can also be synthesized from the reac‐
tion of indole with ethylene carbonate in the presence a stoi‐
chiometric amount of sodium hydride [11]. Although these
procedures can provide access to hydroxyalkyl indoles, they
are not environmentally benign and are limited by their re‐
quirement toxic starting materials and explosive reagents.
Cyclic carbonates are considered to be safe, nontoxic, and
eco‐friendly reagents [12–14], which can be used as electro‐
philes for the introduction of hydroxyalkyl moieties to generate
(248 °C), whereas propylene carbonate is a liquid at tempera‐
tures in the range of –49 to 242 °C. The wide temperature
ranges over which these compounds exist as liquids and their
high solvency means that these cyclic carbonates can be used
as stoichiometric reagents without the need for any other or‐
ganic solvents.
Ionic liquids have been applied to a wide variety of organic
reactions as novel solvents and catalysts [17–24]. For example,
ionic liquids have been used as catalysts in the reactions of
glycerol and ethylene carbonate to synthesize glycerol car‐
bonate [25], and in the reactions of aniline and ethylene car‐
bonate to synthesize bis‐N‐(2‐hydroxyethyl)aniline [17]. As a
part of our ongoing research towards the development of green
synthetic methodologies involving carbonates that are cata‐
lyzed by ionic liquids [26–29], we have previously reported
*Corresponding author. Tel/Fax: +86‐21‐62233323; E‐mail: ghgao@chem.ecnu.edu.cn
This work was supported by the National Natural Science Foundation of China (20873041, 21273078) and the Shanghai Leading Academic Discipline
Project (B409).
DOI: 10.1016/S1872‐2067(12)60571‐3 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 34, No. 6, June 2013

GAO Guohua et al. / Chinese Journal of Catalysis 34 (2013) 1187–1191
that imidazolium‐based ionic liquids are excellent catalysts for
1200
1000
800
600
400
200
0
solvent
the reaction of indole and dimethyl carbonate to synthesize
N‐based heterocycles carbamate [26], as well as the reaction of
aniline and ethylene carbonate to synthesize 2‐oxazolidinones
[27,28]. We have also reported that the acid‐base bifunctional
ionic liquid [PEmim]PbCl3 is an efficient catalyst for the reac‐
tion of aniline with dimethyl carbonate [29]. Herein, we report
a convenient and environmentally benign process for the syn‐
thesis of hydroxyalkyl indoles using cyclic carbonates as hy‐
droxyalkylating reagents in the presence of a catalytic amount
of an ionic liquid under solvent‐free conditions.
n-dodecane
1a
2a
indole
10
3a
0
5
15
20
t/min
2. Experimental
Fig. 1. GC spectrum of the reaction mixture containing 1a, 2a, and 3a.
2.1. General
liquid was recycled for the next reaction. The pure product was
obtained by chromatography on silica gel. The structure of the
products was characterized by 1H NMR analysis and mass
spectroscopy (MS).
Ethylene carbonate and propylene carbonate were pur‐
chased from Alfa Aesar (Tianjin, China). All of the other rea‐
gents used in the study were purchased as the analytical rea‐
gent grade and used without further purification. The ionic
liquids were synthesized according to procedures previously
described in the literature with minor modifications [30]. All of
3. Results and discussion
1
3.1. [Bmim]BF4 catalyzed reaction of indole and ethylene
carbonate
the ionic liquids and products were characterized by H NMR
1
spectroscopy. The H NMR spectra were recorded on a 400
MHz Bruker spectrometer (Switzerland) in deuterated solvent
with tetramethylsilane as an internal reference.
[Bmim]BF4 is one of the most commonly used ionic liquid,
and it has been applied as a catalyst for the reactions of
N‐based heterocycles with dimethyl carbonate [26], as well as
the reaction of aniline and ethylene carbonate [27]. On the ba‐
sis of these examples, it was envisaged that [Bmim]BF4 could
be used as a potential catalyst for the reactions of indole with
different cyclic carbonates. With this in mind, a preliminary
experiment was conducted to identify the products from this
reaction. The GC spectrum of the products is shown in Fig. 1.
Three products were detected in the reaction mixture, includ‐
ing 1‐(2‐hydroxyethyl)indole (1a), 1‐(2‐(2‐hydroxyl)‐ethoxy‐
ethyl)indole (2a), and 1‐(2‐(2‐(2‐hydroxyl)ethoxyethyl)oxy‐
ethyl)indole (3a) (Scheme 1).
To optimize reaction parameters, the effects of the reaction
time, catalyst amount, reaction temperature, and molar ratio of
reactants on the reaction profile were investigated. The results
are shown in Fig 2. As shown in Fig. 2(a), the conversion of the
indole reached a plateau at 86% following 9 h of the reaction
and remained at this level despite further increases in the reac‐
2.2. Typical procedure for the [Bmim]BF4 catalyzed reaction of
indole and ethylene carbonate
The reaction of indole with ethylene carbonate was con‐
ducted in a 5 ml round‐bottomed flask equipped with a mag‐
netic stirrer under nitrogen atmosphere. Indole (0.234 g, 2
mmol), ethylene carbonate (0.880 g, 10 mmol), and
1‐butyl‐3‐methyl‐imidazolium tetrafluoroborate ([Bmim]BF4)
(0.045 g, 0.2 mmol) were mixed together and heated to the
required temperature. Upon completion of the reaction (as
determined by TLC), chloroform (10 ml) was added and the
organic phase was extracted three times with water to remove
the ionic liquid. The organic phase was then analyzed using a
Shimadzu GC‐14B gas chromatograph (GC; Kyoto, Japan)
equipped with a CBP1‐M25‐025 capillary column (Shimadzu,
Kyoto, Japan) using n‐dodecane as the internal standard. The
aqueous phase was evaporated under vacuum, and the ionic
Scheme 1. Reaction of indole with ethylene carbonate.

GAO Guohua et al. / Chinese Journal of Catalysis 34 (2013) 1187–1191
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
(a)
(b)
(c)
1a
2a
1a
2a
3a
2a
1a
3a
3a
0
2
4
6
8
10 12
0
2
4
6
8
10
120 130 140 150 160
Temperature (oC)
Amount of ionic liquid (mol%)
Time (h)
Fig. 2. Effects of reaction time (a), catalyst amount (b), and reaction temperature (c) on the [Bmim]BF4 catalyzed reaction of indole and ethylene car‐
bonate. Reaction conditions: indole 2 mmol, ethylene carbonate 10 mmol, 9 h (except (a)), [Bmim]BF4 0.2 mmol (except (b)), 140 °C (except (c)).
tion time. The yield of 1a increased at a similar rate to the yield
of 2a over the first 9 h and then decreased over an extended
reaction time. The yield of 3a was 2% following the first 9 h of
the reaction and increased to 4% following a 12 h reaction pe‐
riod.
carbonate was reduced. A molar ratio of 1/5 of the indole to the
ethylene carbonate gave the highest conversion of 96%.
3.2. Reaction of indole with cyclic carbonates catalyzed by
various ionic liquids
As shown in Fig. 2(b), the reaction of indole with ethylene
carbonate did not proceed in the absence of the catalyst. In the
presence of [Bmim]BF4, the reaction proceeded smoothly. In‐
creasing the amount of ionic liquid led to a gradual increase in
the yields of 1a and 2a. Any increase in the yield of 3a, howev‐
er, was slight. The indole conversion reached its highest level
(86%) when a 10% charge of the [Bmim]BF4 catalyst was used.
The [Bmim]BF4 catalyzed reaction of indole with ethylene
carbonate was investigated in the temperature range of
120−160 °C (Fig. 2(c)). The conversion of indole increased
gradually when the temperature was increased from 120 to
160 °C and reached a maximum of 96% at 150 °C. The yield of
1a increased when the temperature was below 140 °C and was
subsequently reduced by approximately 20% when the tem‐
perature was further increased from 140 to 160 °C. In contrast,
the yield of 2a increased remarkably when the temperature
was increased from 130 to 150 °C, and effectively reached a
plateau with further increases in the temperature. The yield of
3a was found to be in the range of 2%–10% when the temper‐
ature was in the range of 140–160 °C. It is noteworthy that the
reduction in the yield of 1a was consistent with an increase in
the yields of 2a and 3a. These results effectively confirmed that
2a and 3a were formed from the reaction of 1a with ethylene
carbonate (Scheme 1).
To evaluate the effect of different ionic liquids on the reac‐
tion, a series of ionic liquids with different anions and cations
were investigated for their ability to catalyze the reaction of
indole with ethylene carbonate. The results are listed in Table
2. In the presence of imidazolium based ionic liquids, the level
of indole conversion was generally very high and in the range
of 90%−100% with a variety of different anions. Although the
differences were only slight, the conversion of indole followed
the order of BF4– < Br– < Cl– < OAc–, which was consistent with
the hydrogen bond basicities of the anions in the ionic liquids
[31,32]. It is noteworthy that the combined yields of 1a, 2a, and
3a decreased as the conversion of indole increased (Table 2,
entries 1−4). This reduction in the combined yields was proba‐
bly caused by the sequential reactions of the hydroxyl group of
the product with ethylene carbonate to give indole substituted
polyethylene glycols in the presence of the highly active cata‐
lysts. In fact, the yield of 3a, which was considered to be the
sequential derivative of 1a and 2a, also followed the order of
Table 2
Reaction of indole and ethylene carbonate catalyzed by various ionic
liquids.
GC yield (%)
Conversion
(%)
96
Selectivity for
3a 1a+2a+3a (%)
Entry Ionic liquid
1a
41
27
9
2a
45
51
43
37
34
30
50
37
44
42
35
The reaction of indole with ethylene carbonate was per‐
formed at different molar ratios of indole to ethylene car‐
bonate, and the results are shown in Table 1. The level of indole
conversion increased as the molar ratio of indole to ethylene
1
2
[Bmim]BF4
[Bmim]Br
4
13
22
28
2
94
93
75
69
80
81
85
65
94
92
91
98
99
100
90
93
99
100
95
92
80
3
[Bmim]Cl
4
5
6
7
[Bmim]OAc
[Bmmim]BF4
[Bmmim]Br
[Bmmim]Cl
[Bmmim]OAc
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
4
36
41
18
2
41
40
35
Table 1
4
Effect of indole to ethylene carbonate (EC) molar ratio on reaction of
indole with ethylene carbonate.
17
26
4
8
9a
10b
11c
GC yield (%)
Conversion
n(indole)/n(EC)
(%)
62
91
96
1a
30
35
41
2a
9
30
45
3a
1
4
3
3
1/1
1/3
1/5
Reaction conditions: indole 2 mmol, ethylene carbonate 10 mmol, ionic
liquid 0.2 mmol, 150 °C, 9 h.
a The 2nd run. b The 3th run. c The 4th run.
4
Reaction conditions: 150 °C, 9 h, [Bmim]BF4 = 10 mol% based on indole.

GAO Guohua et al. / Chinese Journal of Catalysis 34 (2013) 1187–1191
4. Conclusions
Table 3
Reaction of indole with propylene carbonate catalyzed by ionic liquids.
We have developed a simple and eco‐friendly procedure for
the synthesis of hydroxyalkyl indoles from indole and cyclic
carbonates catalyzed by ionic liquids under solvent‐free condi‐
tions. The ionic liquids show high activity for the reaction of
indole with ethylene carbonate or propylene carbonate to give
1‐(2‐hydroxyethyl)indole (1a) and 1‐(2‐hydroxypropyl)indole
(1b), respectively, together with their sequential derivatives in
high yields. The indole conversion levels and the yields of 3a
were affected by the anions of the ionic liquids and followed the
order of BF4– < Br– < Cl– < OAc–, which was consistent with the
hydrogen bond basicity of the anions in the ionic liquids.
GC yield (%)
Temperature Conversion
Entry Ionic liquid
(oC)
140
150
160
150
140
(%)
48
87
85
88
95
1b
2b
0
5
4
5
3b
1
2
3
4a
5
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]OAc
35
70
73
73
30
0
0
0
0
7
29
Reaction conditions: indole 2 mmol, propylene carbonate 10 mmol,
ionic liquid 0.2 mmol, 9 h (a 12 h).
–
BF4 < Br– < Cl– < OAc–. When ionic liquids [Bmmim]BF4,
[Bmmim]Br, [Bmmim]Cl, and [Bmmim]OAc, in which the pro‐
ton at the 2‐position of the imidazolium ring was replaced with
a methyl group, were applied to catalyze the reaction, the in‐
dole conversion levels were also very high (90%−100%). The
indole conversion levels and the yields of 3a followed the order
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GAO Guohua et al. / Chinese Journal of Catalysis 34 (2013) 1187–1191
Graphical Abstract
Chin. J. Catal., 2013, 34: 1187–1191 doi: 10.1016/S1872‐2067(12)60571‐3
Hydroxyalkylation of indole with cyclic carbonates catalyzed by ionic
liquids
Ionic liquid
Catalytic activity
BF4 – ﹤Br – ﹤Cl – ﹤OAc –
GAO Guohua*, ZHANG Lifeng, WANG Binshen
East China Normal University
Cation Anion
O
O
N
O
N
O
O
O
O
O
O
Ionic Liquid
N
+
N
O
O
H
An eco‐friendly procedure is presented for the synthesis of hydroxyalkyl
indoles from indole and cyclic carbonates in the presence of a catalytic
amount of imidazolium based ionic liquids under solvent‐free conditions.
OH
O
HO
OH
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