Organic reactions in ionic liquids: Ionic liquids ethylammonium nitrate promoted Knoevenagel condensation of aromatic aldehydes with active methylene compounds

Article abstract of DOI:10.1081/SCC-200050380

The Knoevenagel condensation of aromatic aldehydes with active methylene compounds proceeded efficiently in a reusable ionic liquid, ethylammonium nitrate, at room temperature in the absence of any catalyst with high yields.

Full text of DOI:10.1081/SCC-200050380

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Organic Reactions in Ionic Liquids: Ionic
Liquids Ethylammonium Nitrate Promoted
Knoevenagel Condensation of Aromatic
Aldehydes with Active Methylene Compounds
Yi Hu a b , Jue Chen a , Zhang‐Gao Le a b c & Qin‐Guo Zheng d
a Ningbo Institute of Technology, Zhejiang University, Ningbo, P. R. China
b Department of Chemistry, Zhejiang University, (Xi Xi Campus), Hangzhou,
P. R. China
c Department of Applied Chemistry, East China Institute of Technology,
Fuzhou, P. R. China
d Pharmaceutical Science Reseach Institute, Aston University, Aston
Triangle, Birmingham, UK
Version of record first published: 20 Aug 2006.
To cite this article: Yi Hu , Jue Chen , Zhang‐Gao Le & Qin‐Guo Zheng (2005): Organic Reactions in
Ionic Liquids: Ionic Liquids Ethylammonium Nitrate Promoted Knoevenagel Condensation of Aromatic
Aldehydes with Active Methylene Compounds, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:5, 739-744
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Synthetic Communicationsw, 35: 739–744, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050380
Organic Reactions in Ionic Liquids: Ionic
Liquids Ethylammonium Nitrate Promoted
Knoevenagel Condensation of Aromatic
Aldehydes with Active Methylene
Compounds
Yi Hu
Ningbo Institute of Technology, Zhejiang University,
Ningbo, P. R. China and Department of Chemistry, Zhejiang University
(Xi Xi Campus) Hangzhou, P. R. China
Jue Chen
Ningbo Institute of Technology, Zhejiang University,
Ningbo, P. R. China
Zhang-Gao Le
Ningbo Institute of Technology, Zhejiang University, Ningbo,
P. R. China; Department of Chemistry, Zhejiang University
(Xi Xi Campus) Hangzhou, P. R. China and Department of Applied
Chemistry, East China Institute of Technology, Fuzhou, P. R. China
Qin-Guo Zheng
Pharmaceutical Science Reseach Institute, Aston University,
Aston Triangle, Birmingham, UK
Abstract: The Knoevenagel condensation of aromatic aldehydes with active
methylene compounds proceeded efficiently in a reusable ionic liquid, ethylammonium
nitrate, at room temperature in the absence of any catalyst with high yields.
Received in Japan 19 August 2004
Address correspondence to Jue Chen, Ningbo Institute of Technology, Zhejiang
University, Ningbo, P. R. China. E-mail: humi1@sohu.com

740
Y. Hu et al.
Keywords: Knoevenagel condensation, ionic liquids, reaction media
INTRODUCTION
Knoevenagel condensation is one of the elemental reactions in organic
chemistry. Traditionally, it was carried out in the presence of a base, acid,
or surfactant catalyst in organic solvents.[1] Additionally, Knoevenagel con-
densation could also be performed by infrared[2] or microwave irradiation[3]
under solvent-free conditions, but these techniques usually require the use
of catalysts, organic solvents for the extraction of product from the solid
supports and do not yield pure product so that further solvents are used for
purifying work-up.
In recent years ionic liquids (ILs) are emerging as potential “greener”
alternatives to volatile organic solvents[4] and they have been used as environ-
mentally benign media for many important organic reactions.[5] To date, some
reports have shown the Knoevenagel condensation could be performed more
efficiently in ionic liquids than the traditional methods. For example, Forbes
et al. reported glycine-promoted Knoevenagel condensation of benzaldehyde
with malononitrile in ionic liquid [6-mim]PF6 (1-hexyl-3-methyl imidazolium
hexafluorophosphate).[6] Meanwhile, Salunkhe et al. reported the reaction
.
conducted in Lewis acidic ionic liquids [Bmim]Cl xAlCl3 and
[7]
.
[Bpy]Cl xAlCl3. Most recently, Garcia et al. reported the reaction was
run in ionic liquid [Bmim]PF6 catalyzed by KOH,[8] and Khan et al.
reported this condensation reaction could be efficiently proceeded in
[Bmim]BF4 or [Bmim]PF6 using hydrotalcite as a heterogeneous catalyst.[9]
Previously, we also reported an effective Knoevenagel condensation
catalyzed by ethylenediammonium diacetate in ionic liquids [Bmim]BF4 or
[Bmim]PF6.[10] In continuation of our interest in using ionic liquids as a
recyclable, eco-friendly reaction medium in the Knoevenagel condensation,
we found that Knoevenagel reaction of aromatic aldehydes with active
methylene compounds could occur in ionic liquid ethylammonium nitrate
(EAN) without a catalyst.[11] Obviously, the new methods described here
are more convenient than are those reported in the literatures in which other
ionic liquids were used as reaction media.[6–10]
In fact, simple stirring of a mixture of p-nitrobenzaldehyde with malono-
nitrile in ethylammonium nitrate for three hours at room temperature gave,
after directly filtering, the corresponding condensation product in high yield
with practical purity (see Scheme 1).
Scheme 1.

Organic Reactions in Ionic Liquids
741
Table 1. Condensation of p-nitrobenzaldehyde with malononitrile in different
ionic liquids
Entrya
Ionic liquids
Time (h)
Yields (%)b
1
2
3
EAN
[Bmim]PF6
[Bmim]BF4
3
6
6
94
Trace
Trace
aAll reactions were run with p-nitrobenzaldehyde (2 mmol) and malononitrile
(2 mmol) in 2 mL ionic liquid at room temperature.
bIsolated yields.
We investigated the efficacy of EAN compared to the most commonly
used ionic liquids, [Bmim]PF6 and [Bmim]BF4 by the model condensation
between p-nitrobenzaldehyde and malononitrile. The experimental results
summarized in Table 1 showed the reaction could hardly take place in the
absence of catalyst in [Bmim]PF6 and [Bmim]BF4, which is different from
the results obtained by Khan et al.[12] The results showed that the ionic
liquid, EAN, plays a dual role as solvent and promoter in this reaction.
Next, the scope of the Knoevenagel condensation of a variety of aromatic
aldehydes 1 and different active methylene compounds 2 in ionic liquid EAN
was investigated (Scheme 2). The results are summarized in Table 2. The
products were characterized by 1H nuclear magnetic resonance (NMR),
infrared (IR), and melting points, that were consistent with the literature data.
As can be seen from Table 2, the reaction was found to be general and
applicable to the aromatic aldehydes bearing various substituents such as
nitro, chloro, methyl, methoxyl, hydroxyl, and N,N0-dimethylamino, etc.
The reaction of 2-furancarboxaldehyde (Entry 6, 20) and the aromatic a,
b-unsaturated aldehyde, cinnamic aldehyde (Entry 7, 15) also could proceed
smoothly under the reaction conditions. The experimental results show
aromatic aldehydes bearing electron-withdrawing groups reacted more
easily compared with those containing electron-donating groups. Besides, in
the case of 2-hydroxybenzaldehyde, the reaction led to the formation of
Scheme 2.

Table 2. Knoevenagel condensation of aromatic aldehydes with active methylene compounds
Entry
Product
R
EWG1
EWG2
Time (h)
Yield (%)a
Mp 8C (lit.)
1
2
3a
3b
3c
3d
3e
3f
C6H5
p-CH3C6H4
p-ClC6H4
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
8
10
6
86
90
91
92
94
84
87
85
95
83
94
95b
93c
89
91
84
89
88
95
94
97
95
47–48(47–48)[10]
92–93(94–95)[3c]
91–92(91–92)[3c]
101–102(102–103)[13]
169–170(170–171)[10]
93–94(93–94)[10]
107–108(107–108)[3c]
134–135(134–136)[10]
179–180(185–185.5)[2a–2b]
114–115(114–115)[10]
160–161(159–160)[3b]
—
3
4
o-NO2C6H4
p-NO2C6H4
2-furfuraly
C6H5CH55CH
o-OHC6H4
p-Me2NC6H4
p-MeOC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
p-ClC6H4
5
5
4
6
8
7
3g
3h
3i
10
12
8
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3j
CN
CN
8
3k
3k
3k
3l
3
CN
CN
3
3
—
CN
CN
5
161–162(162–163)[3b]
127–128(126)[14]
83–84(82–84)[1b]
236–237(237–238)[3b]
213–214(214–215)[3b]
275–276(276–277)[2b]
261–262(264)[15]
163–164(162)[1b]
194–195(193)[1b]
3m
3n
3o
3p
3q
3r
3s
C6H5CH55CH
C6H5
8
CN
CONH2
CONH2
6
p-NO2C6H4
p-MeOC6H4
p-MeOC6H4
2-furfuraly
p-Me2NC6H4
p-OHC6H4
6
12
0.2
0.2
0.5
1.0
–(CONHCONHCO)–
–(CONHCONHCO)–
–(COOC(CH3)2OCO)–
–(COOC(CH3)2OCO)–
3t
aIsolated yields.
b–cSecond and third recycling of EAN.

Organic Reactions in Ionic Liquids
743
3-substituted coumarin derivatives in good yield (3h, Entry 8). Several active
methylene compounds such as malononitrile, ethyl cyanoacetate, cyanoaceta-
mide, bartituric acid, and meldrum’s acid, etc. were successfully reacted and
all unsymmetric active methylene compounds gave E-isomers as described in
the literature.[1,2,10] Disappointing, we did not obtain satisfactory result when
the same methods are applied to aliphatic aldehydes and ketones under the
same reaction conditions. In addition, the ionic liquid could be typically
recovered and reused with no appreciable decrease in yields and reaction
rates (Table 2, Entries 11–13).
In conclusion, we have demonstrated that the Knoevenagel condensation
between aromatic aldehydes with active methylene compounds can be effec-
tively performed at room temperature in the ionic liquid EAN. The present
method has many obvious advantages compared to previous methods,
including there is no need for the use of any catalyst, the method is
environmentally more benign, the ease of product isolation, the simplicity
of methodology, the high yield, the generality, the convenience of preparing
ionic liquid EAN using much cheaper starting material, and the potential
for recycling of ionic liquid. We have shown that the ionic liquid, EAN,
can replace the organic solvents, other ionic liquids, and the catalysts, and
is a simpler system—a good example of green chemistry.
EXPERIMENTAL
Melting points were determined on digital melting point apparatus and were
not corrected. Infrared spectra were recorded on a VECTOR-22 Infrared
Spectrophotometer. 1H NMR spectra were recorded on a BRUKER-
400MHz spectrometer using CDCl3 or DMSO-d6 (for 3o–3t) as the solvent
with tetramethylsilane (TMS) as an internal standard. The ionic liquids
[Bmim][PF6] and [Bmim][BF4] were synthesized as lit,[16] ethylammonium
nitrate was synthesized according to the literature.[17]
General Procedure for the Preparation of 3a–3t.
Aromatic aldehyde 1 (2 mmol), active methylene compound 2 (2 mmol) were
dissolved in ionic liquid EAN (2 mL). The reaction mixture was stirred at
room temperature for an appropriate time, reaction was monitored by thin
layer chromatography (TLC). Upon completion of the reaction, after
filtering the solid directly from the reaction mixture and washing with
water gave the desired products 3 in high yields with essential purity. After
isolation of the product, the remainder of the ionic liquids EAN was dried
for 4 h under vacuum at 508C. The next run was performed under identical
reaction conditions.

744
Y. Hu et al.
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