Knoevenagel condensation reaction using ionic liquid [ADPQ][CF3SO3] as green and reusable catalyst

Article abstract of DOI:10.14233/ajchem.2015.17821

Knoevenagel condensation reaction of aromatic aldehydes with some active methylene compounds proceeded efficiently without solvent using ionic liquids as catalyst. The experimental results show that these ionic liquids have good catalytic activities to th

Full text of DOI:10.14233/ajchem.2015.17821

Asian Journal of Chemistry; Vol. 27, No. 6 (2015), 2145-2148
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17821
Knoevenagel Condensation Reaction Using Ionic Liquid
[
ADPQ][CF
3
SO
3
] as Green and Reusable Catalyst
*
XIAOCHONG GAO, CAN GAO and RUICHANG GAO
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P.R. China
*
Corresponding author: Fax: +86 21 27400850 Tel: +86 13902186585; E-mail: pharmacy@tju.edu.cn
Received: 15 April 2014; Accepted: 1 July 2014; Published online: 17 March 2015;
AJC-16981
Knoevenagel condensation reaction of aromatic aldehydes with some active methylene compounds proceeded efficiently without solvent
using ionic liquids as catalyst. The experimental results show that these ionic liquids have good catalytic activities to the Knoevenagel
condensation with a wide range of reactant. The reactions are carried out in a few minutes with high yields. The ionic liquids can be
recycled and reused for 4 times without noticeably decreasing the catalytic activity.
Keywords: Ionic liquids, Knoevenagel condensation, Aromatic aldehydes, Active methylene compounds.
yield for some specific reaction, so the optimal ionic liquids
for Knoevenagel condensation need to be explored.
Encouraged by the use of ionic liquids above, we report
here in the development of a series of novel ionic liquids and
their use as catalysts for the Knoevenagel condensation of
various aromatic aldehydes and active methylene compounds.
INTRODUCTION
Since Knoevenagel condensation first discovered in
8961, it has become one of the most important synthesis
methods for the carbon-carbon double bonds formation. It has
been widely used for the preparation of important intermediates
1
2
-5
in chemical industry and pharmaceutical industry . Tradi-
tionally, Knoevenagel condensation is carried out in organic
EXPERIMENTAL
6
-8
9-10
solvents with acids , bases , acid-base bifunctional cata-
1
1-13
lysts . With special reaction instruments and conditions, this
reaction could also performed by microwave radiation or
supersonic wave . However, most of the methods have some
drawbacks such as long reaction time, harsh reaction condi-
tions, stoichiometric amount of catalysts, toxicity of the organic
solvents and unreusable for the catalysts .
All the chemicals were used as supplied without further
purification unless otherwise specified. Melting points were
1
4
15
1
13
taken on a Gallenkamp melting point apparatus. H and C
NMR spectra were recorded on a Bruker AM-400 MHz
spectrometer. HRMS values were measured by a JEOL JMS-
SX or JEOL JMS-SX 102A spectrometer. Flash column
chromatography was performed on silica gel (200-300 mesh)
(Qingdao Haiyang Chemical Co. Ltd, China) and TLC measu-
rements were performed on silica gel GF254 plates (Qingdao
Haiyang Chemical Co. Ltd, P.R. China).
Recently, ionic liquids (ILs) are receiving much interest
for application as innovative solvents or catalysts in a variety
of areas due to the advantages of ionic liquids, such as non
volatility, high thermal stability, versatile structures and
1
6
excellent reusability .Additionally, the water produced during
the reaction was absorbed by the ionic liquid and thus the
reaction getting a higher yield in a very short reaction time
compared with conventional methods in organic solvents. So
research about ionic liquids involved in Knoevenagel conden-
sation has experienced tremendous growth during the past
years. Until now, the ionic liquid systems for Knoevenagel
Synthesis of ionic liquids:A series of novel amino func-
tionalized ionic liquids was synthesized from commercially
available 4-amino quinuclidine and 3-chloro-1,2-propanediol,
followed by anion exchange through CF
CH COOK, KPF (Scheme-I).
Knoevenagel condensation; typical procedure: Benzal-
dehyde (1 mmol) and ethyl cyanoacetate (1 mmol) were mixed
together in the presence of 20 mol % [ADPQ][CF SO ] and
3
SO
3
K, NaBF
4
,
3
6
1
7
condensation were ethylammonium nitrate , guanidinium
3
3
18
19,20
21,22
lactate , alkylammonium-based , imidazolium-based
.
then stirred at room temperature. Upon completion of the
reaction (monitored by TLC, solvent system: ethyl acetate and
petroleum ether), water (2 mL) was added to the mixture. The
Almost all the reported ionic liquids used in Knoevenagel
reaction are relatively narrow range for applications and low

2
146 Gao et al.
Asian J. Chem.
CH CH OH
3
2
OH
OH
H N
N + HO
H N
2
N
OH
2
Cl
+
8
0oC
Cl OH
CH OH
3
H N
N
2
CF SO K
H N
N
OH
3
3
2
o
Cl OH
65 C
CF SO3
3
OH
Scheme-I
product was filtered and the solid, was dried in vacuo at 60 °C
for 10 h. This gave the desired product in high purity that did
not need further purification. The ionic liquid was recovered
by removing the aqueous layer using a rotary evaporator.
All the products had the E-geometry exclusively and no
Z-geometrical isomers were detected in the NMR.
135.2, 132.5, 130.6, 129.5, 127.2, 126.3, 123.8, 121.9, 116.7,
105.8.
2-(Benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)acry-
1
lonitrile (Entry 2, Table-3): (Solid, m.p. 140-142 °C) H NMR
(400 MHz, CDCl
= 6.4 Hz), 7.51 (t, 2H), 7.01 (d, 2H, J = 6.8 Hz), 3.90 (s, 3H); C
NMR (100 MHz, CDCl ): δ 163.6, 153.8, 146.7, 135.0, 132.9,
27.0, 125.9, 123.5, 121.8, 117.3, 114.9, 102.5, 55.8.
-(1H-indol-2-yl)-3-phenylacrylonitrile (Entry 7,
3
): δ 8.18 (s, 1H), 8.04 (m, 3H), 7.89 (d, 1H, J
13
3
Spectral data of representative compounds
1
2
-Benzylidenemalononitrile (Entry 1, Table-2): (Solid,
2
1
m.p. 79-81 °C), H NMR (400 MHz, CDCl
3
): δ 7.92 (m, 2H),
1
Table-3): (Solid, m.p. 173-174 °C); H NMR (400 MHz,
CDCl ): δ 8.58 (s, 1H), 8.00 (d, 1H, J = 6.0 Hz), 7.88 (d, 2H,
J = 5.6 Hz), 7.61 (t, 2H), 7.40-7.49 (m, 4H), 7.29-7.34 (m,
13
7
.79 (s, 1H), 7.64 (m, 1H), 7.54 (m, 2H); C NMR (100 MHz,
CDCl ): δ 159.9, 134.6, 130.8, 129.6, 113.6, 112.5, 82.7.
Ethyl 2-cyano-3-phenylacrylate (Entry 2, Table-2):
Solid, m.p. 49-50 °C), H NMR (100 MHz, CDCl
s, 1H), 8.76 (m, 1H), 8.58 (d, 1H, J = 4.0 Hz), 8.27 (s, 1H),
3
3
13
2
1
1
H); C NMR (100 MHz, CDCl ): δ 138.2, 137.3, 134.9,
3
1
(
(
8
3
): δ 8.92
29.8, 129.1, 129.0, 125.8, 124.4, 123.6, 121.5, 120.0, 118.9,
13.1, 112.4, 106.5.
13
.48 (m, 1H), 4.41 (m, 2H), 1.41 (m, 3H); C NMR (400
): δ 162.4, 155.0, 133.3, 131.4, 131.0, 129.2,
15.4, 102.9, 62.7, 14.1.
-(4-Methoxybenzylidene)malononitrile (Entry 9,
2
-(1H-indol-2-yl)-3-(p-tolyl)acrylonitrile (Entry 8,
MHz, CDCl
3
1
Table-3): (Solid, m.p. 192-194 °C); H NMR (400 MHz,
CDCl ): δ 8.46 (s, 1H), 8.00 (d, 1H, J = 6.0 Hz), 7.79 (d, 2H,
J = 6.4 Hz), 7.58 (t, 2H), 7.45 (d, 1H, J = 6.4 Hz), 7.27-7.33
m, 3H), 2.42 (s, 3H); C NMR (100 MHz, CDCl
38.5, 137.2, 132.1, 129.8, 128.9, 125.4, 124.4, 123.5, 121.4,
1
3
2
1
Table-2): (Solid, m.p. 113-114 °C), H NMR (400 MHz,
CDCl ): δ 7.91(d, 2H, J = 8.8 Hz), 7.66 (s, 1H), 7.02 (d, 2H, J
8.8 Hz), 3.92 (s, 3H); C NMR (100 MHz, CDCl
58.9, 133.4, 123.9, 115.1, 113.3, 55.8.
Ethyl 2-cyano-3-(4-methoxyphenyl)acrylate (Entry 10,
13
(
1
1
3
): δ 140.2,
3
13
=
1
3
): δ 164.8,
20.0, 119.1, 113.3, 112.3, 105.3, 21.8.
RESULTS AND DISCUSSION
1
Table-2): (Solid, m.p. 79-81 °C), H NMR (400 MHz, CDCl
3
):
For present investigations, four ionic liquids (ILs) were
prepared.
δ 8.17 (s, 1H), 8.00 (d, 2H, J = 6.8 Hz), 6.99 (d, 2H, J = 6.0
13
Hz), 4.36 (m, 2H), 3.89 (s, 3H), 1.39 (t, 3H); C NMR (100
MHz, CDCl ): δ 164.0, 163.3, 154.6, 133.9, 124.6, 116.5,
15.0, 99.5, 62.6, 55.9, 14.4.
-(2-Methoxybenzylidene)malononitrile (Entry 11,
3
1
H N
N
OH a: X=CF SO ; b: X=BF4;
3 3
2
2
X
c: X=CH COO; d: X=PF
OH
3 6.
1
Table-2): (Solid, m.p. 79-80 °C), H NMR (400 MHz, CDCl
3
):
a-d
ADPQ][X]
δ 8.31 (s, 1H), 8.18 (d, 1H, J = 7.6 Hz), 7.59 (m, 1H), 7.08 (m,
[
1
3
1
H), 6.99 (d, 1H, J = 8.8 Hz), 3.93 (s, 3H); C NMR (100
MHz, CDCl ): δ 158.9, 154.4, 136.5, 128.8, 121.1, 120.1,
14.3, 112.9, 111.4, 81.2, 55.9.
-(Thiophen-2-ylmethylene)malononitrile (Entry 15,
3
The reaction of benzaldehyde with ethyl cyanoacetate at
room temperature without any solvent was used as the model
to optimize the reaction conditions (Table-1). The reaction did
not proceed at all in absence of ionic liquid (entry 1, Table-1).
To our pleasure, the model reaction proceeded smoothly in
the presence of the novel ionic liquids a-d, leading to 76-89 %
yields of product (Table-1, entries 2-5).Among the four ionic
1
2
1
Table-2): (Solid, m.p. 96-97 °C), H NMR (400 MHz, CDCl
3
):
δ 7.89 (d, 2H, J = 4.0 Hz), 7.81 (d, 1H, J = 3.2 Hz), 7.28 (m,
13
1
1
H); C NMR (100 MHz, CDCl
29.0, 113.8, 112.9, 78.4.
3
): 151.0, 138.1, 136.8, 135.4,
Ethyl 2-cyano-3-(thiophen-2-yl)acrylate (Entry 16,
liquids tested, [ADPQ][CF
3
SO ] (a) was the most effective and
3
1
Table-2): (Solid, m.p. 89-91 °C), H NMR (400 MHz, CDCl
3
):
an excellent yield of 89 % was obtained. Then we optimized
the amount of a, the reaction was carried out in the presence
of 5, 10, 20 and 30 mol % a under solvent-free conditions at
room temperature (Table-1, entries 5-8). The best catalyst
loading was found to be 20 mol %. Then we added some organic
solvents, no significant change was found. Consequently, the
reaction conditions of 20 mol % of ionic liquid a as the catalyst
at room temperature without any organic solvent were subjec-
ted to further examination.
δ 8.34 (s, 1H), 7.80 (d, 2H, J = 7.6 Hz), 7.22 (m, 1H); 4.36 (m,
1
3
2
1
H), 1.38 (m, 3H); C NMR (100 MHz, CDCl
46.2, 137.1, 136.0, 135.1, 128.6, 115.7, 99.4, 77.0, 62.5, 14.2.
-(Benzo[d]thiazol-2-yl)-3-phenylacrylonitrile (Entry
3
): δ 162.7,
2
1
1
, Table-3): (Solid, m.p. 145-147 °C), H NMR (400 MHz,
): δ 8.26 (s, 1H), 8.09 (d, 1H, J = 6.4 Hz), 8.03 (d, 2H,
J = 4.0 Hz), 7.91 (d, 1H, J = 6.4 Hz), 7.53 (m, 4H), 7.44 (m,
CDCl
3
13
1
H); C NMR (100 MHz, CDCl ): δ 162.9, 153.8, 147.1,
3

Vol. 27, No. 6 (2015)
Knoevenagel Condensation Reaction Using Ionic Liquid [ADPQ][CF
3
SO ] 2147
3
TABLE-1
underwent favorable reaction at room temperature (entries
OPTIMIZATION OF CATALYST/ORGANIC SOLVENT
IN KNOEVENAGEL CONDENSATION REACTION
15, 16, Table-2).
a
Encouraged by the results, we continued to study the
CHO
COOEt
+ H O
CN Ionic liquid
reaction of aromatic aldehydes with other active methylene
compounds, such as benzimidazol-2-acetonitrile, benzo-
thiazole-2-acetonitrile and indole-2-acetonitrile. The reaction
smoothly proceeded to afford the corresponding products with
moderate to good yield. It is found that the acidic proton of
methylene group was the key factor influencing the reaction
rate. For example, malononitrile, which the acidic proton of
methylene was apparently stronger than those of others, results
in comparatively rapid reaction rates.
+
r. t.
2
CN
COOEt
b
Entry
IL (mol %)
blank
Solvent
Time (min) Yield (%)
1
2
3
4
5
6
7
8
9
-
-
-
-
-
-
-
-
60
30
30
30
30
30
30
30
30
30
30
-
b (10)
c (10)
d (10)
a (10)
a (5)
a (20)
a (30)
a (20)
a (20)
a (20)
79
76
86
89
83
91
91
90
91
92
TABLE-3
CH
CH
Toluene
OH
3
KNOEVENAGEL CONDENSATION REACTION OF OTHER
ACTIVE METHYLENE COMPOUNDS WITH FUNCTIONALIZED
1
1
0
1
2
Cl
2
a
AROMATIC ALDEHYDES
a
Reaction conditions: benzaldehyde (1 mmol) and ethyl cyanoacetate
1 eq), room temperature, reaction time = 0.5 h. Isolated yields
CN
X
Y
CHO
20% of IL
r.t.
b
X
R
(
a
CN +
Y
R
With the optimal conditions in hand, we investigated the
Reaction time
Yield
Entry
R
H
X
Y
Knoevenagel reaction of various aromatic aldehydes with
malononitrile and ethyl cyanoacetate and the results are presen-
ted in Table-2. The reaction proceeded smoothly to afford the
corresponding products in good to excellent yields (83-98 %)
within 2 h.Among these cases, the electron-withdrawing group
substituted aromatic aldehydes with active methylene comp-
ounds converted smoothly to the corresponding products in
high yields (entries 3-8, Table-2). Electron-donating group
substituted aromatic aldehydes underwent Knoevenagel
condensation with malononitrile smoothly and obtained
good yield (entries 9-14, Table-2). In addition, Knoevenagel
condensation of hetero aromatic aldehydes such as 2-thio-
phene-carboxaldehyde with active methylene compounds also
(
min)
60
90
20
30
60
10
120
120
(%)
1
2
3
4
5
6
7
N
N
N
N
N
N
H
H
S
S
S
NH
NH
NH
NH
NH
94
92
91
93
90
92
73
68
4-OMe
2-Cl
H
2-Cl
4-OMe
H
8
Me
a
Reaction conditions: aldehyde (1 mmol) and active methylene
compound (1 mmol), 20 mol % a, room temperature
In order to demonstrate the industrial applicability of this
methodology, the reaction of ethyl cyanoacetate and benzal-
dehyde was carried out on a larger scale (100 mmol). The
reaction was completed in 0.5 h. A good yield of 91 % for the
product was achieved. On the same scale, the recyclability of
the catalytic system was investigated using the same reaction
as the model reaction. The ionic liquid (a) was recovered by
removing the aqueous layer using rotary evaporator. The reco-
vered a was reused in subsequent reactions.As shown in Fig. 1,
no significant decrease in yields was observed even after four
runs.
TABLE-2
KNOEVENAGEL CONDENSATION REACTION OF ACTIVE
METHYLENE COMPOUNDS WITH FUNCTIONALIZED
AROMATIC ALDEHYDESa
E1
E2
+ H O
CHO
2
0% of IL
a
+
R
R
2
r.t.
E1
E2
Reaction time
Yield
1
2
Entry
R
E
E
(
min)
5
(%)
96
91
97
96
95
93
98
94
94
86
92
87
96
83
85
79
1
2
3
4
5
6
7
8
9
H
H
3-NO2
3-NO2
2-Cl
2-Cl
4-Cl
4-Cl
4-OMe
4-OMe
2-OMe
2-OMe
3-OMe
3-OMe
2-Thienyl
2-Thienyl
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
CN
COOEt
100
30
3
20
5
80
30
20
30
15
60
30
60
15
60
45
120
6
0
0
9
1
89
89
87
86
4
1
0
1
2
3
4
5
6
1
1
1
1
1
1
20
0
1
2
3
4
SO
5
Number of runs
Fig. 1. Recyclability investigation of [ADPQ][CF
3
3
] used as a catalyst
for the Knoevenagel condensation of ethyl cyanoacetate and
benzaldehyde
a
Reaction conditions: aldehyde (1 mmol) and active methylene
compound (1 mmol), 20 mol % of ionic liquid a, room temperature

2
148 Gao et al.
Asian J. Chem.
6
7
8
.
.
.
.
N. Tavakoli-Hoseini, M.M. Heravi and F.F. Bamoharram, Asian J. Chem.,
Conclusion
In conclusion, a series of novel ionic liquids, namely,
ADPQ][CF SO ], [ADPQ][BF ], [ADPQ][CH COO] and
ADPQ][PF ] is developed. Among these functional ionic
SO ] showed the best catalytic activity for
Knoevenagel condensation of various aldehydes and different
active methylene compounds to afford E-geometry products
in good to excellent yields. The good catalytic effects and
2
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[
3
3
4
3
6
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3
3
9
1
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9
excellent recyclability of [ADPQ][CF
3
SO ] make this protocol
3
1
1
more useful. Investigations of these novel ionic liquids in
further application for other organic reactions are underway
in our laboratory.
1
1
1
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