Task-specific ionic-liquid-catalyzed efficient synthesis of indole derivatives under solvent-free conditions

Article abstract of DOI:10.1139/V09-154

A sulfonic-acid-functionalized ionic liquid is used as a Bronsted acid catalyst for the efficient synthesis of indole derivatives in good-to-high yields at room temperature under solvent-free conditions. The catalyst can be reused for ten consecutive runs without significant loss of activity.

Full text of DOI:10.1139/V09-154

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Task-specific ionic-liquid-catalyzed efficient
synthesis of indole derivatives under solvent-free
conditions
Sudarshan Das, Matiur Rahman, Dhiman Kundu, Adinath Majee, and
Alakananda Hajra
Abstract: A sulfonic-acid-functionalized ionic liquid is used as a Brønsted acid catalyst for the efficient synthesis of in-
dole derivatives in good-to-high yields at room temperature under solvent-free conditions. The catalyst can be reused for
ten consecutive runs without significant loss of activity.
Key words: functionalized ionic liquid, indole derivatives, bis(indolyl)methanes, Michael adduct, recycling.
R e´ sum e´ : On a utilis e´ un liquide ionique a` base d’acide sulfonique fonctionnalis e´ comme catalyseur acide de Brønsted
pour d e´ velopper des synth e` ses efficaces de d e´ riv e´ s de l’indole obtenus avec des rendements allant de bons a` e´ leves, dans
des conditions sans solvant. Le catalyseur peut eˆ tre r e´ utilis e´ jusqu’ a` dix fois sans perte significative de son activit e´ .
Mots-cl e´ s : liquide ionique fonctionnalis e´ , d e´ riv e´ s de l’indole, bis(indolyl)m e´ thanes, adduit de Michael, recyclage.
[
Traduit par la R e´ daction]
Introduction
Scheme 1.
Michael reaction is one of the most important carbon–
1
carbon bond-forming reactions. The syntheses and the reac-
tions of indole derivatives have received much interest for
over a century because a number of their derivatives occur
2
in nature and show versatile biological activities. Since the
3
-position of indole is the preferred site for electrophilic
teristics of solid acids and mineral acids, TSILs have been
synthesized to replace traditional mineral liquid acids, such
as hydrochloric acid and sulfuric acid, in chemical reactions.
In view of green chemistry, the substitution of harmful
substitution reaction, 3-substituted indoles are versatile inter-
mediates for the synthesis of a wide range of indole com-
pounds. Till date, several catalysts were used to catalyze
the Michael addition of indoles to electron-deficient olefins;
however, most of them were Lewis acids.
acids are deactivated or sometimes decomposed by nitro-
gen-containing reactants. Even when the desired reactions
proceed, more than stoichiometric amounts of Lewis acids
are required because the acids are deactivated by the nitro-
gen atom of indoles. However, the acid-catalyzed conjugate
addition of indoles requires careful control of acidity to pre-
vent side reactions such as dimerization and polymerization.
For this reason, the need of a less expensive catalyst is de-
sirable to secure catalytic activity, low toxicity, moisture,
and air tolerance.
3
4
–20
liquid acids by reusable TSILs is the most promising cata-
Many Lewis
lytic system in chemistry.2
1–23
Some ‘‘greener’’ halogen-free
ionic liquids that involve phosphate or octyl sulfate anions
have been reported, and effects of the anion and toxicology
have been studied.2
4–26
The use of Brønsted acidic TSILs to
catalyze organic reactions is an area of ongoing activity and
TSILs have been successfully used for various chemical
27–29
transformations.
In continuation of our interest in ionic-
liquid-mediated reactions,30 we have explored the utility of a
functionalized ionic liquid,1-butane sulfonic acid-3-methyli-
midazolium tosylate, [BSMIM]Ts, as a catalyst for the con-
jugate addition of indoles with electron-deficient alkenes to
produce 3-substituted indole derivatives under solvent-free
conditions at room temperature (Scheme 1). To the best of
our knowledge, this is the first report of a functionalized
ionic liquid catalyzed Michael addition of various indoles to
electron-deficient alkenes.
The application of Brønsted acidic task-specific ionic
liquids (TSILs) as catalytic materials is growing continu-
ously in the field of catalysis. Combining the useful charac-
Received 23 July 2009. Accepted 5 October 2009. Published on
the NRC Research Press Web site at canjchem.nrc.ca on
2
9 January 2010.
Results and discussion
S. Das, M. Rahman, D. Kundu, A. Majee, and A. Hajra.1
Department of Chemistry, Visva-Bharati University,
Santiniketan 731235, India.
The experimental procedure is very simple. In a prelimi-
nary experiment, indole (2 mmol) was treated with methyl
vinyl ketone (2 mmol) in the presence of TSIL (5 mol%)
under solvent-free conditions at room temperature, providing
the corresponding Michael adduct, exclusively, within 5 min
1Corresponding author (e-mail:
alakananda.hajra@visva-bharati.ac.in).
Can. J. Chem. 88: 150–154 (2010)
doi:10.1139/V09-154
Published by NRC Research Press

Das et al.
151
Table 1. Conjugate addition of indoles with electron-deficient olefins.
in 95% yield. The structure of the product was settled from
the spectral data. The crude product obtained after ether ex-
traction was found to be pure, as there was no detectable
duct in fairly good yield (Table 1, entry 10). By using sub-
stituted indoles, good-to-excellent yields were obtained. The
substituents did not affect the reactivity of indoles signifi-
cantly. The catalytic system also worked well with benzyli-
dene malonate to produce the corresponding product in 82%
yield (Table 1, entry 11). For benzylidene malononitrile, the
corresponding Michael adduct was obtained in low yield
under the same conditions even after a prolonged reaction
time (Table 1, entry 12). The present protocol could be
used on a 100 mmol scale using 2 mol% of the catalyst,
which could be reused several times.
1
amount of impurities or starting material in the H NMR of
the crude product. We next examined the generality of the
present reaction conditions to a series of substituted indoles
and electron-deficient alkenes. The results are summarized
in Table 1.
Electron-deficient olefins, such as chalcone, benzalace-
tone, cyclohexenone, and dibenzylidene acetone, afforded
the products in good-to-excellent yields. The reaction of di-
benzilidene with indole gave mono-addition product in 82%
yield. A hindered enone, mesityl oxide, which is difficult for
conjugate addition, is also reacted to produce Michael ad-
Generally, the reactions are clean, and the products are
obtained in high yields without the formation of any side
products, such as N-alkylation products. However, under the
Published by NRC Research Press

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Can. J. Chem. Vol. 88, 2010
present reaction conditions, a,b-unsaturated aldehydes and
esters did not afford the corresponding Michael addition
products. Furthermore, the indole nitrogen did not require
prior protection, and the avoidance of strong bases for de-
protection permitted compatibility with a wide range of
functional groups. The procedure did not require any inert
atmospheric condition.
Scheme 2.
The efficacy and generality of the present protocol can be
realized by comparing some of the results presented here
with recently reported two ionic-liquid-based methods3
as shown in Table 2, which compares reaction time, yields,
and reaction conditions. Thus, it is clear from Table 2 that
the present protocol can act as an effective method with re-
spect to reaction times, yields, and reaction conditions.
We extended the utility of catalyst for Michael addition of
aniline and benzyl amine to methyl vinyl ketone under the
present reaction conditions (Scheme 2). Surprisingly, both
reactions proceeded very well in short times (25 min and
1,32
Scheme 3.
8
min, respectively), and the adducts were isolated in excel-
lent yields. The results indicate that the catalyst can catalyze
the Micheal addition of both aromatic and aliphatic amines.
This is a clear advantage over the recent reported ionic-
liquid-catalyzed conjugate addition of aliphatic amines to
2
8
electron-deficient alkenes.
Synthesis of bis(indolyl)methanes is a subject of continu-
ous interest to synthetic organic/medicinal chemists, as in-
doles and their derivatives have versatile biological
activities and are widely present in various biologically ac-
tive natural products. The catalyst is also effective for the
preparation of indole derivatives such as bis(indolyl)methane
from benzaldehyde under present reaction conditions
Experimental
The synthesis of the ionic liquid was carried out using a
method similar to the reported.
3
3
34
Typical procedure for the synthesis of 4-(1H-indol-3-yl)-
butan-2-one (Table 1, entry 1)
(Scheme 3).We found that 10 mg of the catalyst was suffi-
cient to obtain the desired bis(indolyl)methane in 96% yield
within 5 min at room temperature in neat conditions. Thus,
this acidic ionic liquid is a versatile catalyst for various
chemical transformations.
A mixture of indole (234 mg, 2 mmol) and MVK
(162 mL, 2 mmol) was stirred in presence of acidic ionic
liquid (39 mg, 5 mol%) at room temperature for 5 min
(TLC). After completion, the reaction mixture was extracted
with diethyl ether (3 Â 10 mL). Evaporation of solvent fur-
nished the addition product as a solid (355 mg, 95%) whose
The reusability of the catalyst is an important benefit, es-
pecially for commercial applications. Thus, the recovery and
reusability of the catalyst were investigated. After comple-
tion, the mixture was extracted with ether (3 Â 5 mL) to ob-
tain the desired products. The catalyst, left in the reaction
vessel, was dried under vacuum and was reused for subse-
quent reactions. It showed the same activity as a fresh cata-
lyst in term of yields. After ten recycles, the catalyst had a
high activity and gave the desired product in fairly good
yield (91%; Table 1, entry 1). Thus, this makes the process
more cost-effective.
In conclusion, we have developed a mild, simple,
environment-friendly, and cost-advantageous procedure for
the Michael addition of indoles to electron-deficient alkenes
using a recyclable task-specific acidic ionic liquid under
solvent-free conditions. We believe that this procedure will
provide a better and more practical alternative to the exist-
ing methodologies for the synthesis of 3-substituted indole
derivatives. The catalyst is also effective for Michael addi-
tion of both aromatic and aliphatic amines as well as the
synthesis of bis(indolyl)methane derivatives. Further proce-
dures to broaden the scope of this methodology towards
pharmaceuticals and biologically active compounds are
under investigation.
1
spectroscopic data (IR and H NMR) are in good agreement
5
with those reported. The catalyst left in the reaction vessel
was dried under vacuum and was reused for the subsequent
reaction. This procedure was followed for the synthesis of 3-
substituted indoles listed in Table 1. Small amount of etha-
nol (0.5 mL) was added to the reaction mixture when both
indoles and alkenes are solids. Analytically pure compound
was obtained by silica gel chromatography using n-hexane/
EtOAc as eluent. The spectral and elemental analyses of the
compound, which are not readily available, are provided
here.
The typical procedure for entry 1 (Table 1) was followed
for 100 mmol scale reaction, taking a mixture of indole
(11.7 g), MVK (8.1 mL), and acidic ionic liquid (780 mg).
The pure product was obtained in 96% yield (17.90 g).
3-(5-Methoxy-1H-indol-3-yl)-1,3-diphenylpropan-1-one
(Table 1, entry 6)
–1
Solid; mp 150–151 8C. IR (cm ) n: 3367, 1677, 1589,
1
1483, 1215. H NMR (400 MHz, CDCl ) d: 7.95 (d, J =
3
0.7 Hz, 2H), 7.93 (d, J = 1.4 Hz, 1H), 7.55–7.17 (m, 10H),
6.97 (d, J = 2.3 Hz, 1H), 6.85–6.80 (m, 1H), 5.03 (t, J =
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Das et al.
153
Table 2. Comparison of the present protocol with ionic-liquid-based reported methods.
7
1
1
.1 Hz, 1H), 3.84–3.80 (m, 1H), 3.78 (s, 3H), 3.75–3.69 (m,
(8) Zhan, Z. P.; Yang, R. F.; Lang, K. Tetrahedron Lett. 2005,
46 (22), 3859. doi:10.1016/j.tetlet.2005.03.174.
(9) Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli, L.;
Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem.
H). 13C NMR (100 MHz, CDCl ) d: 198.5, 153.8, 144.1,
3
37.1, 132.9, 131.7, 128.5, 128.4 (2C), 128.1 (2C), 127.8
(2C), 127.0 (2C), 126.3, 122.1, 119.1, 112.2, 111.7, 101.5,
2
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5.8, 45.1, 38.1. Anal. calcd. (%) for C H NO (355.4): C
24 21 2
1
5730329.
1.10, H 5.96, N 3.94; found: C 80.95, H 5.81, N 3.76.
(
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Acknowledgements
1
5685339.
A. H. is pleased to acknowledge the financial support
from the Department of Science and Technology (Grant No.
SR/FTP/CS-107/2006). A. M. is pleased to acknowledge the
financial support from the Council of Scientific and Indus-
trial Research (CSIR) (Grant No. 01(2251)/08/EMR-II).
D. K. thanks CSIR and M. R. thanks Visva-Bharati for their
fellowships.
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