Polyethylene glycol (PEG-200)-promoted sustainable one-pot three-component synthesis of 3-indole derivatives in water

Article abstract of DOI:10.1016/j.apcata.2012.12.008

A sustainable three-component reaction of indoles, aldehydes, and malononitrile in water promoted by polyethylene glycol (PEG-200) afforded 3-indole derivatives in good to excellent yields.

Full text of DOI:10.1016/j.apcata.2012.12.008

Applied Catalysis A: General 454 (2013) 160–163
Contents lists available at SciVerse ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Polyethylene glycol (PEG-200)-promoted sustainable one-pot
three-component synthesis of 3-indole derivatives in water
Leilei Wang, Manna Huang, Xinhai Zhu, Yiqian Wan∗
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 October 2012
Received in revised form 6 December 2012
Accepted 7 December 2012
Available online 20 December 2012
A sustainable three-component reaction of indoles, aldehydes, and malononitrile in water promoted by
polyethylene glycol (PEG-200) afforded 3-indole derivatives in good to excellent yields.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Green chemistry
Multicomponent reaction
Aldol reaction
Michael addition
1. Introduction
We now wish to report a general route to 3-substituted indole
derivatives via the three-component reaction of indoles, malononi-
In addition to their occurrences in nature, indoles have found
wide applications in materials science, organic synthesis, medic-
inal chemistry and agricultural chemistry [1]. Thus, a number of
practical strategies based on multi-component reactions (MCRs)
for the synthesis of indoles have been established since Ugi et al.
reported the first four-component reactions in 1959 [1–4]. For
example, the three-component reactions of indoles, aldehydes, and
malononitrile are known to provide 3-substituted indole deriva-
tives [5], which are particularly useful for furnishing biologically
active chromenes [6–11].
MCRs, termed by Tsepalov in 1961 and possibly traceable to the
publication of the Strecker reaction [1,4,12], have attracted sig-
nificant attention in recent years due to their wide applications
in medicinal chemistry [2,4,12–20], organic synthesis (especially
asymmetric synthesis [21]) [22], and materials science with high
atom economy and good overall yields [23].
A variety of green MCR protocols have been documented in
recent years [5,7–11,24–32], utilizing unconventional solvents
(such as ionic liquid, water, and PEGs) or solvent-free conditions
[33]. However, it is still difficult to design “ideal” [34] MCR pro-
cesses, as motivated by increasing concern about strict legislation
aimed at improving the ‘greenness’ of synthetic pathways and
processes [35]. In addition, improving already known MCRs is an
interesting challenge for current organic synthesis [32,36,37].
trile and aldehydes in water promoted by PEG-200 without the use
of metal (such as Cu [5], Zn [38], and In [10]) or l-proline [26] as
catalysts.
2. Experimental
All starting materials and reagents are commercially available
and were used as received. All reactions were carried out in 10 mL
vials sealed with a septum. Flash column chromatography was per-
formed with silica gel (200–300 mesh). Thin-layer chromatography
was carried out with Merck silica gel GF254 plates. 1H NMR and 13
C
NMR spectra were recorded at r.t. on a Mercury-Plus 300 or a Bruker
AVANCE 400 instrument with TMS as an internal reference. LC/MS
was run on an LCMS-2010A or a LCQ DECA XP instrument. Element
analyses were carried out on an Elemental Analyzer vario EL cube.
Melting points were determined on a WRS-1B digital melting point
apparatus and are uncorrected. IR spectra were determined on an
EQUINOX 55 Fourier transformation infrared spectrometer coupled
with an infrared microscope.
2.1. General procedure A
KH2PO4 (136 mg, 1.0 mmol), PEG-200 (1.5 g), H2O (1.5 mL),
aldehyde (1.0 mmol), malononitrile (72.6 mg, 1.1 mmol), indole
(128 mg, 1.1 mmol), and a magnetic stir bar were added to a 10 mL
vial, which was then sealed. The reaction mixture was stirred at
room temperature. The precipitate was collected by filtration. The
∗
Corresponding author. Tel.: +86 2084113610; fax: +86 2084113610.
E-mail address: ceswyq@mail.sysu.edu.cn (Y. Wan).
0926-860X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.apcata.2012.12.008

L. Wang et al. / Applied Catalysis A: General 454 (2013) 160–163
161
solid was washed with water and dried in vacuo for 2 h at 50 ◦C to
afford the desired products.
presence of our previously reported Cu(OAc)2-sucrose-
PEG200 system. As expected, 2-((1H-indol-3-yl)(phenyl)
methyl)malononitrile, as
a desired product, was isolated in
90% yield (Table 1, entry 1). However, further control experiments
(Table 1, entries 2, 3) indicated that either the copper catalyst
or sucrose were not needed for the reaction. We then logically
optimized the conditions by exploring the effects of the base, time,
and temperature on the model reaction. As shown in Table 1,
the reaction proceeded smoothly at room temperature, although
it could be accelerated at higher temperature (Table 1, entries
3, 13). The weak acid KH2PO4 was beneficial to the reaction,
whereas stronger bases were obstructive (Table 1, entries 16,
17, 18). It was found that PEGs were essential to promoting the
model reaction, of which PEG-200 was the most effective as a
co-solvent and a phase transfer catalyst. The influence of the ratio
2.2. General procedure B
KH2PO4 (136 mg, 1.0 mmol), PEG-200 (1.5 g), H2O (1.5 mL),
aldehyde (1.0 mmol), malononitrile (72.6 mg, 1.1 mmol), indole
(128 mg, 1.1 mmol), and a magnetic stir bar were added to a 10 mL
vial, which was then sealed. The reaction mixture was stirred at
room temperature. The reaction mixture was extracted with water
(20 mL) and ethyl acetate (3× 20 mL). The combined organic phases
was washed with brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The crude product was purified by flash c.c. on silica
gel using dichloromethane/petroleum ether (1:1; 2:1) as an eluent
to afford the desired products.
3. Results and discussion
3-Indole derivatives have been efficiently obtained by Cu(II)-
sulfonato Salen catalyzed three-component reactions in water [5].
Moreover, PEGs, which are green and reusable solvents, have been
widely used to establish green systems for MCRs [25,28,29,39].
Hence, as part of our ongoing research interest in aqueous organic
reactions [40–43], we envisioned that our copper catalyst sys-
tem for C N coupling in water [40] might also be used in the
three-component reaction. Initially, we examined the reaction
of indole, benzaldehyde, and malononitrile in water in the
Table 1
Optimization of the model reaction.a
.
Entry
PEGs/H2O (g/g)b
Base (mol%)b
Time (h)
Yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
200 (1/2)
200 (1/2)
200 (1/2)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KH2PO4 (100)
KOH (100)
3
3
3
90d,f
91e,f
92f
83
95
90
85
80
68
60
11
40
75
81
10
15
Trace
Trace
70
100(1.5/1.5)
200(1.5/1.5)
300(1.5/1.5)
400 (1.5/1.5)
600(1.5/1.5)
800(1.5/1.5)
1000(1.5/1.5)
200 (0/3)
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
28
14
24
200 (0.5/2.5)
200 (1/2)
200 (2/1)
200 (3/0)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
200(1.5/1.5)
K3PO4 (100)
K2CO3 (100)
KF (100)
No addition
71
86
94
65
KH2PO4 (50)
KH2PO4 (200)
KH2PO4 (100)
KH2PO4 (100)
86
a
Reaction conditions: benzaldehyde (1.0 mmol), malononitrile (1.1 mmol),
indole (1.1 mmol), base, PEG, H2O, r.t.
b
Relative to benzaldehyde.
Isolated yield.
Cu(OAc)2 (0.05 mmol), sucrose (0.5 mmol).
c
d
e
Cu(OAc)2 (0.05 mmol).
Scheme 1. The products of the three-component reaction of aldehydes, indoles and
f
60 ◦C.
malononitrile. a 12 h, b 28 h, c 7 d, d 12 d.

162
L. Wang et al. / Applied Catalysis A: General 454 (2013) 160–163
between PEG-200 and water on the reaction was then further
studied (Table 1, Entries 5, 11–15). Notably, only approximately
10% isolated yield of the desired product was obtained in pure
PEG-200 or pure water (Table 1, Entries 11, 15). However, when
the mass ratio between water and PEG-200 was 1:1, the isolated
yield increased dramatically to 95% (Table 1, Entry 5). Overall, the
use of equivalent amounts (in mass ratio) of water and PEG-200
with KH2PO4 as an additive at room temperature was identified as
the optimum conditions for the present MCR (Table 1, entry 5).
To assess the application scope of this simple system, a variety of
aldehydes were tested under the optimized conditions. As shown in
Scheme 1, most of the electron-rich, electron-neutral, and electron-
poor aromatic aldehydes reacted with indole and malononitrile to
afford the desired 2-((1H-indol-3-yl)(aryl)methyl)malononitriles
in high yields. In contrast, slightly lower yields were obtained
from 4-methoxybenzaldehyde due to the strong electron-donating
nature of the methoxy group and 2-nitrobenzaldehyde due to side
reactions [44]. Notably, the steric hindrance of aldehydes seemed
to have very intriguing effects on the reaction outcomes: all the
ortho–para directors (such as methyl, methoxyl, chloro, and flu-
oro) in the ortho-position of benzaldehydes promoted the reactions
better than those on the para-position (Scheme 1, W1, W2, W4,
W16-W18). In terms of product purification, in most cases, the
operation was very simple and easy, without requiring special
purification techniques, such as column chromatography. The fil-
tration of the reaction mixture very straightforwardly afforded the
solid product (Scheme 1, W2-7, W11-19, W21, W24, W25). In addi-
tion, aliphatic aldehydes, such as pivalaldehyde and formaldehyde,
also provided the desired product in high yield (Scheme 1, W22,
W23).
proton of indole activates the nitrile moiety through hydrogen
bonding [45] to dramatically enhance the rates and yields of the
reactions.
It should be noted that the protocol easily and rapidly afforded
chromene when salicylaldehyde was used instead of benzaldehyde
(Scheme 1, W25; Scheme 2, W39).
Finally, the heterogeneous characteristic of the model reaction
encouraged us to further test the recyclability of the system. After
filtration and washing the solid products with cold water, the fil-
trate was combined and concentrated in vacuo to the original size
(3 mL). The model reaction was then run again to afford the desired
product with excellent yield. The reaction was run an additional
three times to afford the desired product with the same yields as
that (95%) in the first run.
4. Conclusions
In conclusion, we have established a recyclable, environ-
mentally benign synthesis of 3-indole derivatives by the three-
component reaction of indoles, malononitrile and aldehydes in
water, which was dramatically promoted by PEG-200. The simplic-
ity of the protocol will be beneficial to the sustainable synthesis of
3-indole derivatives in the laboratory and in industry.
Acknowledgments
This work was supported financially by grants from the National
Natural Science Foundation of China (20872182, 20802095).
Encouraged by these results, N-methyl indole and 2-methyl
indole were tested to extend the scope of the methodology. As
expected, 2-methyl indole readily reacted with various aldehydes
and malononitrile to produce the corresponding products in excel-
lent yields due to the electron-donating effect of 2-methyl group
(Scheme 2). In contrast, N-methyl indole did not afford the desired
product. In this regard, the presence of the acidic N H proton
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.
apcata.2012.12.008.
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