A ligand-free copper(II)-catalyzed three-component reaction in poly(ethylene glycol) medium: A versatile protocol for the preparation of selected 3-indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.09.008

An efficient and eco-friendly method has been developed for the synthesis of selected 3-indole derivatives via a copper-catalyzed condensation between indole, aldehydes, and malononitrile in polyethylene glycol. The reagent system (PEG solvent plus cataly

Full text of DOI:10.1016/j.tetlet.2012.09.008

Tetrahedron Letters 53 (2012) 6223–6225
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A ligand-free copper(II)-catalyzed three-component reaction
in poly(ethylene glycol) medium: a versatile protocol for the preparation
of selected 3-indole derivatives
Srivari Chandrasekhar a, , Vidyavathi Patro a, Gangireddy Pavan Kumar Reddy b, René Grée b,
⇑
⇑
a Division of Natural Products Chemistry, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Université de Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Général Leclerc, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Revised 31 August 2012
Accepted 4 September 2012
Available online 11 September 2012
An efficient and eco-friendly method has been developed for the synthesis of selected 3-indole deriva-
tives via a copper-catalyzed condensation between indole, aldehydes, and malononitrile in polyethylene
glycol. The reagent system (PEG solvent plus catalyst) could be recycled up to 5 times for reaction with
the same aldehyde and it was used also with at least three different aldehydes successively. This multi-
component reaction (MCR) occurs first through Knoevenagel condensation followed by Michael addition
of indole.
Keywords:
PEG
Ó 2012 Elsevier Ltd. All rights reserved.
Indole
Multicomponent reaction
Copper
Eco-friendly
Multi-component reactions (MCRs) are offering many advanta-
ges, as they allow more than two simple and flexible building
blocks to assemble in order to access archetypical molecules with
high variability.1 Indole structural motif represents a ‘privileged
scaffold’ in drug discovery.2 Indole alkaloids from medicinal plants
and its derivatives have taken on considerable pharmacological
importance.3 Multi-component reactions have emerged as an effi-
cient tool in the synthesis of structurally diverse indole derivatives
of high biological relevance.4 However, the development of simple
and efficient multi-component reactions for the synthesis of indole
3-derivatives still remains an active research area.
Recently poly(ethylene glycol) has received greater attention in
organic synthesis as an efficient and sustainable reaction media,5
including for MCRs.6 Due to the importance of eco-friendly systems
in organic synthesis, we have considered the development of se-
lected MCRs and tandem one-pot reactions in poly(ethylene glycol)
[PEG].7
component reaction of indole, aldehydes, and Meldrum’s acid to
give indole 3-derivatives, those were used as intermediates in
the synthesis of complex indole alkaloids.9,10
Usually this type of condensation has been carried out with or-
ganic bases but recently Curini et al. have exploited the Lewis acid
[Yb(OTf)3] catalyzed three-component reaction of indole, alde-
hydes, and dimethyl malonate under solvent-free conditions fur-
nishing the desired adducts in moderate to good yields.11 On the
other hand, Sapi and Gérard described the one-pot synthesis of in-
dole 3-derivatives by a TiCl4/Et3N promoted trimolecular conden-
sation,12 while Fontana and Re studied the mechanism of this
reaction.12c More recently, Zhou and co-workers have reported
the three component reaction of indole, aldehydes, and malononit-
rile in water, catalyzed by a copper(II) sulfonato Salen complex,
affording 3-indole derivatives in good to excellent yields.13 How-
ever, low yields were obtained in the absence of ligand and prepa-
ration of the disodium sulfonato Salen complex (ligand) required
several synthetic steps. We envisioned, based on our previous
work with PEG as the solvent medium,7 that the PEG may act as
an external ligand to perform this MCR reaction (Scheme 1).
To check our hypothesis, initially we attempted a three-compo-
nent coupling with indole, benzaldehyde, and malononitrile using
5 mol % Cu(OAc)2 as the catalyst and KH2PO4 as an additive in PEG-
400 at 70 °C. To our satisfaction, we observed a clean formation of
the desired product in excellent yield (90%) after simple work up
(Table 1, entry 1). To explore the scope of this methodology, a
number of aldehydes were used to perform this reaction under
Since 3-substituted indole derivatives have been widely found
in biologically active compounds, several research groups have
turned their attention to access those indole 3-derivatives by sim-
ple synthetic methods, both in racemic and optically pure forms.8
In 1978, Yonemitsu and co-workers have reported a new multi-
⇑
Corresponding authors. Tel.: +91 40 27193210; fax: +91 40 27160512 (S.C.);
tel.: +33 (0)2 23235715; fax: +33 (0)2 23236978 (R.G.).
E-mail addresses: srivaric@iict.res.in (S. Chandrasekhar), rene.gree@univ-re-
nnes1.fr (R. Grée).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.008

6224
S. Chandrasekhar et al. / Tetrahedron Letters 53 (2012) 6223–6225
Table 2
R'
R
KH2PO4
R2
Recyclability for the same substrate (synthesis of 4b)
Cu(OAc)2
R'
CN
2a-b
+
RCHO +
CN
R2
Aldehyde
Yielda (%)
N
R1
PEG-400
1
3
1st
2nd
90%
3rd
4th
5th
N
R1
4a-n
R1=R2=H (3a)
70 °C
1b
95%
88%
80%
75%
R1=Me;R2=H (3b)
R1=H;R2=2-Me (3c)
R' = CN (2a)
R' = CO2Et (2b)
a
Isolated yield after column chromatography.
R1=H;R2=5-OMe (3d)
Scheme 1. Synthesis of 3-indoles in PEG-400.
Table 3
Recyclability for different aldehydes
Table 1
Aldehyde
Product
Yielda (%)
Cu(OAc)2-catalyzed ligand-free synthesis of 3-indole derivatives
Entry Indole Aldehyde RCHO Reactant
Product
Time
(h)
Yieldb
(%)
1st Run
2nd Run
3rd Run
1b
1f
1a
4b
4f
4a
95
70
65
(R=)
(2)
(4)a
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
C6H5
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2a
2a
4a
4b
4b
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
15
15
24
24
15
15
15
15
15
15
15
24
24
40
40
40
90
98
51c
55d
82
79
70
88
86
68
48
62
95
63
70
78
a
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
3-NO2C6H4
2-BrC6H4
Isolated yield after column chromatography.
With regard to sustainable chemistry issues, the recyclability
was an important question. We were pleased to find that the entire
reagent [catalyst Cu(OAc)2 and KH2PO4 in PEG-400] could be suc-
cessfully recycled up to five runs with limited loss of activity (Yield
decreased from 95% to 75% after 5 runs, Table 2). Furthermore, it
has been demonstrated that the same system [PEG with Cu(OAc)2
and KH2PO4] can be recycled several times by using different alde-
hydes as substrates (Table 3). Therefore, this new catalytic process
does not require organic solvents, except those used for extraction
and purification of final products.
To the best of our knowledge, there are very few literature
precedents on the mechanism for this multicomponent reaction.12c
Initially, we hypothesized two possible pathways (path A and path
B in Scheme 2) to access the MCR product.
4-BrC6H4
4-FC6H4
9
10
11
12
13
14
15
16
4-OMeC6H4
2-OMeC6H4
(CH3)2CH
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4m
4n
All products were characterized by 1H, 13C, and mass spectroscopy.
Isolated yield.
The reaction was carried out in ethanol.
The reaction was carried out in ethylene glycol.
a
b
c
d
To reveal the mechanism of this reaction, we performed several
control experiments, under different conditions, in PEG-400.
previous conditions to yield the corresponding 3-substituted in-
doles (Table 1). 4-Nitrobenzaldehyde (entry 2) gave the product
4b in 98% yield, which was comparable to the reaction using cop-
per(II) sulfonato Salen complex as a catalyst. The 2- and 3-nitro-
benzaldehydes (entries 5 and 6) underwent a three-component
coupling reaction to afford the products 4c and 4d in 82% and
79% yields, respectively. The bromo and fluoro substituted benzal-
dehydes were also well compatible substrates for the MCR (entries
7, 8, and 9). In the case of 4-methoxybenzaldehyde (entry 10) the
product yield was slightly decreased (68%), while 2-methoxy also
reacted but gave adduct 4i in 48% yield only (entry 11). The ali-
phatic aldehyde isobutyraldehyde also provided the MCR product
in moderate yield (62%, entry 12), which is still better than using
[Yb(OTf)3].11 Then, to diversify this reaction malononitrile has been
replaced with ethyl 2-cyano acetate. Indole, 4-nitrobenzaldehyde
and ethyl 2-cyano acetate were coupled under optimized condi-
tions to provide the desired product 4k as inseparable diastereo-
meric mixture (1:1) in 95% yield (entry 13).
Next, the MCR was performed with substituted indoles provid-
ing the desired products in reasonably good yields. N-methyl in-
dole 3b, 2-methyl indole 3c, and 5-methoxy indole 3d (entries
14–16) were participating in the three component coupling reac-
tion with 4-nitrobenzaldehyde and malononitrile under optimized
reaction conditions to afford the desired products 4l–4n in 63%,
70%, and 78% yields, respectively.
Attempts to expedite this MCR in two related solvents, ethanol
and ethylene glycol, provided the desired product 4b however in
lower yields 51% and 55%, respectively (entry 3 and 4). This result
demonstrates that PEG plays a key role in this catalytic process but
complementary studies will be required to better understand this
mechanistic aspect.14
– In the first series of experiments, 4-nitro benzaldehyde treated
with malononitrile gave Knoevenagel adduct I in excellent yield.
The same reaction, carried out in the absence of catalyst
[Cu(OAc)2 and KH2PO4] in PEG at room temperature, provided
similar results. Therefore the copper catalyst has no key role in
this first step.
– In the second series of experiments, indole and Knoevenagel
adduct I treated with Cu(OAc)2 and KH2PO4 in PEG-400 at
70 °C for 15 h provided the MCR product in high yield.15
– In the third series of experiments, it was demonstrated that the
MCR could be performed with Cu(OAc)2 only affording 4b in 72%
yield. Alternatively, the use of KH2PO4 only also gave 4b in 88%
yield, but the combination of Cu(OAc)2 and KH2PO4 gave the
best yield (98%). However, there was no reaction between indole
and adduct-I in the absence of Cu(OAc)2 and KH2PO4.
– Finally, in the last series of experiments, it was demonstrated
that no reaction was taking place between indole and 4-nitro
benzaldehyde under the same reaction conditions. No evidence
could be found for adduct II in the scheme (path B).
Thus this MCR proceeds very likely via Knoevenagel condensa-
tion between aldehyde and malononitrile, followed by the Michael
addition of indole to adduct I catalyzed by Cu(OAc)2 and KH2PO4 in
PEG-400 (path A).
In conclusion, we have successfully demonstrated a MCR reac-
tion as an operationally simple and efficient method for the con-
densation of indole, aldehydes, and malononitrile using PEG as
the reaction medium in the presence of KH2PO4, and using Cu(OAc)2
as the catalyst under ligand-free conditions. Furthermore, in this

S. Chandrasekhar et al. / Tetrahedron Letters 53 (2012) 6223–6225
6225
CHO
CN
CN
+
+
N
H
O2N
Cu(OAc)2
KH2PO4
PEG-400
70 °C
path A
path B
OH
O2N
CN
NO2
O2N
NC
CN
CN
H
N
+
-H2O
+ H2O
N
H
N
Adduct I
Adduct II
O2N
CN
CN
N
H
Scheme 2. Proposed mechanism for MCR.
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Acknowledgments
This research has been performed as part of the Indo-French
‘Joint Laboratory for Sustainable Chemistry at Interfaces’. We thank
the CSIR, the CNRS, the University of Rennes 1 and the CEFIPRA/
IFCPAR for support of this research. V.P. thanks the CSIR, New Del-
hi, for financial assistance.
Supplementary data
Supplementary data (experimental procedures and compound
characterization) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.008.
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