Design, preparation and characterization of a new ionic liquid, 1,3-disulfonic acid benzimidazolium chloride, as an efficient and recyclable catalyst for the synthesis of tetrahydropyridine under solvent-free conditions

Article abstract of DOI:10.1039/c5ra10699k

In the present work, 1,3-disulfonic acid benzimidazolium chloride as a new ionic liquid, is synthesized, and characterized by studying its FT-IR, ¹H NMR, ¹³C NMR as well as mass spectra. This ionic liquid is used as an efficient, homogeneous and recyclable catalyst for synthesis of highly functionalized tetrahydropyridine via one-pot multi-component condensation of aromatic aldehydes, ethyl acetoacetate, and anilines under solvent-free conditions. The present synthetic route is a green protocol offering several advantages, such as high yield of products, shorter reaction time, mild reaction conditions, minimizing chemical waste and easy work-up procedures. Further, the catalyst could be reused and recovered at least four times without appreciable loss of activity.

Full text of DOI:10.1039/c5ra10699k

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Design, preparation and characterization of new ionic liquid 1,3-disulfonic acid
benzimidazolium chloride as an efficient and recyclable catalyst for the synthesis
of tetrahydropyridine under solvent-free conditions
Mohsen Abbasi
5
0
5
Department of Chemistry, Lamerd Branch, Islamic Azad University, Lamerd, Fars, Iran, E-mail: mohsen.abbasi90@gmail.com.
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
1
1
2
In the present work, 1,3ꢀdisulfonic acid benzimidazolium
chloride as a new ionic liquid, is synthesized, characterized by
of the most representative examples of multiꢀcomponent
reactions is preparation of tetrahydropyridines.
1
13
studying its FTꢀIR, H NMR, C NMR as well as mass spectra.
This ionic liquid is used as an efficient, homogeneous and
recyclable catalyst for synthesis of highly functionalized
tetrahydropyridine via oneꢀpot multiꢀcomponent condensation of
aromatic aldehydes, ethyl acetoacetate, and anilines under
solventꢀfree conditions. The present synthetic route is a green
protocol offering several advantages, such as high yield of
products, shorter reaction time, mild reaction conditions,
minimizing chemical waste and easy workꢀup procedures.
Further, the catalyst could be reused and recovered at least four
times without appreciable loss of activity.
Tetrahydropyridine derivatives are among the most important
classes of nitrogenꢀcontaining heterocycles, they are found in
many natural products, pharmaceutical agents, and functionalized
5
5
6
6
7
7
0
5
0
5
0
5
9ꢀ11
materials.
Tetrahydropyridines and compounds based on these
core templates exhibit a wide range of biological activities such
0
12
13
14
as antiꢀhypertensive, neurotoxic activity, antiꢀbacterial, antiꢀ
15
16
convulsant, antiꢀinflammatory activities, and antimalarial.
Although numerous methodologies have been for the synthesis of
1
7
functionalized tetrahydropyridines by using LaCl .7H O, Lꢀ
3
2
2
5
Introduction
16
proline/TFA , 1ꢀmethylꢀ2ꢀoxopyrrolidinium hydrogen sulfate
18
11
19
(
[Hpyro][HSO ]),
molecular iodine (I2),
ZrOCl .8H O,
2 2
4
Over the past decade academia and industry have been working
20
21
22
Bi(NO ) .5H O, SPINOLꢀphosphoric acids, BF .SiO , trityl
3
3
2
3
2
1
together in order to develop new greener alternative solvents.
23
24
chloride (Ph CCl), nanoꢀsphere silica sulfuric acid (NSꢀSSA),
3
The main aim is to reduce significantly the important drawbacks
and hazards associated with traditional solvents, replacing them
with safer and more efficient alternatives. In this regard, ionic
liquids have attracted significant research interest in the context
of green synthesis due to their adjustable physical and chemical
25
26
cerium ammonium nitrate (CAN), silica sulfuric acid (SSA),
27
28
29
citric acid, Lꢀproline nitrate, and acetic acid. Unfortunately,
most of the reported methods suffer from one or more of the
following drawbacks, such as longer reaction time, low product
yields, use hazardous solvents or nonꢀrecyclable catalysts, harsh
reaction conditions such as strong acids or elevated temperature
and poor compliance with the green chemistry protocols. Due to
these disadvantages of the existing methods, there have been
increasing demands for more efficient, reusability and
environmentallyꢀbenign methodologies for the synthesis of these
highꢀvalue compounds. In continuation of our research on the
3
3
4
4
0
5
0
5
2
properties. They have been introduced as an alternative green
reaction medium due to their exceptional features such as high
thermal and chemical stability, low vapor pressure, nonꢀ
flammability, nonꢀvolatile, large electrochemical window,
potential recyclability and the ability to dissolve many organic
3
,4
and inorganic materials.
Ionic liquids also have various
applications such as sensors, fuel cells, batteries, capacitors,
thermal fluids, plasticizers, lubricants, extractants, extractants,
development of eco� friendly and sustainable methodologies via
30ꢀ33
MCRs for the synthesis of tetrahydropyridines,
synthesis of
we report here
5
and solvents in analysis, synthesis, catalysis, and separation.
a
new ionic liquid, 1,3ꢀdisulfonic acid
Multiꢀcomponent reactions (MCRs), are excellent tools in
modern organic synthesis and medicinal chemistry due to the
product diversity, great efficiency, simple procedures,
benzimidazolium chloride ([Dsbim]Cl) as a highly efficient and
green catalyst for the preparation of tetrahydropyridines via the
oneꢀpot threeꢀcomponents (in situ five components) reaction of
anilines, ethyl acetoacetate and aromatic aldehydes under solventꢀ
6
ꢀ8
convergence, reduction in reaction steps and time savings. One
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free conditions (Scheme 1). To the best of our knowledge, there
seems to be no report on the synthesis of tetrahydropyridine
derivatives by using ([Dsbim]Cl) ionic liquid as an ecoꢀfriendly
catalyst. The homogeneous catalyst could be recovered easily and
reused five times without significant loss of its catalytic activity.
5
Fig.1. FTꢀIR spectra of benzimidazole (a) and 1,3ꢀdisulfonic acid
3
3
4
0
5
0
benzimidazolium chloride ([Dsbim]Cl) (b).
1
13
The H NMR and C NMR spectra of the ionic liquid obtained in
1
DMSOꢀd are displayed in Fig. 2 and 3. Here, we study H NMR
6
1
data of the catalyst. The important peak of H NMR spectrum of
ionic liquid were related to the acidic hydrogens (SO H) which
3
Scheme 1. General formulation for the preparation of 1,3ꢀdisulfonic acid
benzimidazolium chloride [Dsbim]Cl) and using it for the synthesis of
functionalized tetrahydropyridines.
observed in 13.64 ppm. To confirm that this peak (13.64 ppm) is
10
correctly related to the hydrogen of SO H in the compound, not
3
hydrogen of ClSO H (its unreacted starting material) in DMSOꢀ
3
1
Results and discussion
d , we ran the H NMR spectra of chlorosulfonic acid in DMSOꢀ
6
d6 presented in literature [4]. In these spectra, the peaks of the
15
Characterization of the catalyst
acidic hydrogens of [Dsbim]Cl and ClSO H were observed in
3
The structure of ionic liquid 1,3ꢀdisulfonic acid benzimidazolium
13.64 and 13.45 ppm, respectively. The difference between the
peaks of the acidic hydrogens in ([Dsbim]Cl) and its starting
1
13
chloride [Dsbim]Cl, was identified by FTꢀIR, H NMR,
C
NMR, as well as mass spectra. The corresponding FTꢀIR spectral
materials confirmed that the peak observed in 13.67 ppm of the
1
data of benzimidazole and 1,3ꢀdisulfonic acid benzimidazolium 45 H NMR spectra of [Dsbim]Cl is correctly related to the SO H
3
20
chloride [Dsbim]Cl ionic liquid are presented in Fig. 1. The FTꢀ
IR spectrum of [Dsbim]Cl showed a broad and strong bands at
group of this compound. Moreover, while benzimidazole and
ClSO H are readily soluble in CH Cl , ([Dsbim]Cl) ionic liquid is
3
2
2
ꢀ
1
34,35
2
536 to 3432 cm related to the OH of the SO H groups.
insoluble in CH Cl .
3
2
2
−1
−1
Moreover, the two peaks observed at 1189 cm and 1263 cm
correspond to the O–SO symmetric and asymmetric stretching,
2
−1
25
respectively and other band at 1063 cm is assigned to N–SO2
35
stretching. The symmetric N–S stretching vibration also
−1 36
appeared at 886 cm .
1
50
Fig. 2. H NMR spectrum of 1,3ꢀdisulfonic acid benzimidazolium
chloride ([Dsbim]Cl).
2
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Therefore, the model reaction was repeated in the presence of 5,
7.5, 10 and 15 mol% of 1,3ꢀdisulfonic acid benzimidazolium
chloride ([Dsbim]Cl). Using 10 mol% of the catalyst, the best
results regarding reaction time and yield was obtained (Table 1,
entry 4). Using lower amount of catalyst resulted in lower yield,
while higher amount did not affect the reaction time and yield. To
evaluate the influence of temperature, the model reaction was
performed in the range of 70–100 °C. It was found that 80 °C was
the optimal temperature and the reaction was incomplete at lower
2
5
30
temperature.
Table 1. Effect of different amounts of catalysts and temperature on the
condensation of benzaldehyde (2 mmol), 4ꢀchloroaniline (2 mmol) and
35
ethyl acetoacetate (1 mmol).
1
3
Fig. 3. The
C
NMR spectrum of 1,3ꢀdisulfonic acid
a
Entry
Catalyst
temp. (°C)
Time
(min)
150
70
Yield (%)
benzimidazolium chloride ([Dsbim]Cl).
(mol %)
5
The mass spectrum of the 1,3ꢀdisulfonic acid benzimidazolium
chloride ([Dsbim]Cl) ionic liquid is shown in Fig. 4. In this
spectrum the correct molecular ion peak appears at 314. Other ion
1
2
3
4
5
6
7
8
ꢀ
80
80
80
80
80
90
100
70
ꢀ
5
56
81
95
95
88
90
71
7.5
10
32
+
+
peaks are also observed at 279 (M ꢀCl), 198 (M ꢀSO H and Cl),
32
3
+
+
1
62 (2SO H), 154 (M ꢀ2SO H), 118 (M ꢀ2SO H and Cl) and 81
15
32
3
3
3
1
0
(SO H) as well.
10
35
3
10
35
10
55
a
Isolated yield.
In order to evaluate the effect of solvent, we investigated different
solvents, including CHCl , H O, THF, EtOAC, CH CN and
40
3
2
3
EtOH under refluxing conditions using 10 mol% of the catalyst.
The results of these experiments revealed that the use of a solvent
led to a significant reduction in the yield of the desired product 4l
in all cases compared with the yield obtained under solventꢀfree
conditions (Table 2, entries 1–7).
45
Table 2. Synthesis of compound 4l in the presence of [Dsbim]Cl (10
Fig. 4. Mass spectra of 1,3ꢀdisulfonic acid benzimidazolium
chloride ([Dsbim]Cl).
mol%) in different solvents.
o
Entry
Solvent
Temperature( C)
Time
Yield
(%)
trace
ꢀ
trace
32
60
78
95
b
(
min)
360
360
360
300
230
100
32
1
5
3.2. Synthesis of tetrahydropyridines catalyzed by [Dsbim]Cl
1
2
3
4
5
6
7
CHCl3
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
H O
2
THF
EtOAC
The condensation of 4ꢀchloroaniline (2 mmol), ethyl acetoacetate
(1 mmol) and benzaldehyde (2 mmol) was chosen as a model
CH CN
3
EtOH
Solventꢀfree
reaction for the optimization of parameters such as the amount of
catalyst, solvents and temperature of reaction. The results are
summarized in Table 1. Initially, the reaction was examined in
the absence of the catalyst at 80 °C; no desired product was
obtained under solventꢀfree conditions even after 2.5 h.
2
0
Reaction conditions: benzaldehyde (2 mmol), 4ꢀchloroaniline (2 mmol),
b
ethyl acetoacetate (1 mmol), [Dsbim]Cl (10 mol %), Isolated yield.
50
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After optimization of the reaction conditions, synthesis of a
variety of functionalized tetrahydropyridines was performed to
which indicated the presence of C–N stretching. The band at
–1
1604 and 1459 cm in the FTꢀIR spectrum of 4u was
explore the efficiency and the scope of the protocol. The 25 characteristic of a C=C stretching vibration, and the strong band
–
1
corresponding results are depicted in Table 3. Various aromatic
aldehydes containing electronꢀreleasing substituents, electronꢀ
withdrawing substituents and halogens on their aromatic ring
were utilized successfully react with various anilines and ethyl
at 1249 and 1075 cm confirmed the presence of CꢀO bond
1
5
0
5
0
stretching. The H NMR spectrum of 4u exhibited a triplet at δ=
1.47 ppm for the methyl protons of the carbethoxy group. The
methylene protons of the carbethoxy group, were observed as
acetoacetate to afford high to excellent yields of products and in 30 two doublets of quartets at δ= 4.32ꢀ4.37 and 4.44ꢀ4.50 ppm. A
short reaction times under solvent free.
doublet of doublets appeared at δ= 2.69 and 2.82 for the
methylene protons of the tetrahydropiperidines ring (H′ꢀ5, H′′ꢀ5).
One of the methine protons of the tetrahydropiperidines ring (Hꢀ
1
1
2
The structures of products (4a–p), were identified by comparison
of their spectroscopic data and melting points with those of
literature reports. Also, the structures of products (4q–v), were
6
) was observed as a multiplets at δ= 5.06 ppm, and another
1
confirmed by elemental analysis and spectral data (FTꢀIR,
H
35
methine proton (Hꢀ2) appeared as a singlet at δ= 6.26 ppm. The
aromatic proton signals were a mixture of doublets and multiplets
at δ = 6.37–7.24 ppm. The secondary amino group (NH) signal
shows their chemical shift in the higher frequency region at 10.29
ppm. The higher chemical shift is due to strong intramolecular
13
NMR, C NMR, mass spectroscopy). For example, the FTꢀIR
spectrum of 4u, as a representative example, contained broad
–1
peaks at 3234 cm , which were attributed to the stretching
vibrations of amine protons (NH groups). Furthermore, the bands
–
1
1
3
at 3069, 2956 and 2875 cm were attributed to the stretching
40
hydrogen bonding with ester carbonyl carbon. Furthermore,
C
vibrations of the CH, CH , and CH groups in the molecules,
2
3
NMR analysis of 4u revealed the presence of 28 distinct carbons,
which was in agreement with the proposed structure. The mass
spectrum of 4u showed a molecular ion signal at m/z 793
corresponding to the molecular formula C H Cl I N O .
–
1
whereas the strong bands at 1657 cm were attributed the
stretching vibrations of carbonyl groups (C=O stretching). The
–1
FTꢀIR spectrum of 4u also contained strong bands at 1375 cm ,
32
26 2 2
2
2
4
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Table 3. Synthesis of tetrahydropyridines catalyzed by [Dsbim]Cl.
1
2
b
Entry
R
R
Product
4a
Time (min)
Yield (%)
Mp (°C)
156ꢀ158
229ꢀ230
Lit. Mp (°C) [ref]
5
1
2
4ꢀMe
4ꢀMe
4ꢀMe
H
38
34
86
89
169ꢀ171 [23]
4b
230ꢀ231 [25]
213ꢀ215 [30]
3
4ꢀMe
4ꢀNO2
4c
25
94
215ꢀ216
1
1
2
2
3
3
4
0
5
0
5
0
5
0
4
5
6
7
8
9
4ꢀMe
4ꢀOMe
H
4ꢀOMe
4ꢀCl
4ꢀBr
4ꢀCl
4ꢀOMe
H
4d
4e
4f
30
29
30
35
29
30
25
28
37
31
27
33
32
93
94
96
93
95
90
92
94
89
96
91
90
95
224ꢀ226
180ꢀ182
197ꢀ198
219ꢀ220
189ꢀ191
166ꢀ168
246ꢀ248
173ꢀ174
170ꢀ172
228ꢀ230
233ꢀ235
198ꢀ199
203ꢀ205
221ꢀ224 [25]
179ꢀ181 [28]
194ꢀ196 [30]
218ꢀ220 [23]
186ꢀ188 [30]
165ꢀ167 [28]
247ꢀ250 [25]
172ꢀ173 [25]
171ꢀ172 [28]
228ꢀ229 [30]
234ꢀ236 [23]
193ꢀ196 [23]
204ꢀ206 [28]
4ꢀMe
4ꢀCl
4ꢀOMe
4ꢀNO2
H
4g
4h
4i
1
1
1
1
1
1
1
0
1
2
3
4
5
6
H
4j
4ꢀOMe
H
4k
4l
H
4ꢀCl
4ꢀMe
H
H
4m
4n
4o
4p
4ꢀBr
4ꢀMe
4ꢀCl
H
1
1
7
8
H
3ꢀI
4q
4r
34
29
91
92
172ꢀ171
182ꢀ184
171ꢀ173 [31]
184ꢀ186 [30]
4ꢀOMe
4ꢀBr
1
9
4ꢀNO2
3ꢀI
4s
27
90
139ꢀ141
137ꢀ140 [31]
2
2
2
0
1
2
4ꢀMe
4ꢀCl
3ꢀI
3ꢀI
4t
4u
4v
30
33
38
89
90
90
209ꢀ207
189ꢀ187
182ꢀ180
208ꢀ209 [31]
189ꢀ190 [32]
181ꢀ182 [32]
b
45
3ꢀMe
4ꢀMe
Reaction conditions: benzaldehyde (2 mmol), 4ꢀchloroaniline (2 mmol), ethyl acetoacetate (1 mmol), [Dsbim]Cl (10 mol %), Isolated yield.
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A plausible mechanism for the formation of tetrahydropyridines
is proposed in Scheme 2 [11, 20, 25]. It was expected that
similar functionalized tetrahydropyridine derivatives. The results
of these catalysts, which perform the oneꢀpot multiꢀcomponent
arylamine (1) reacts with ethyl acetoacetate (2) to give enamine 25 condensation of benzaldehyde, ethyl acetoacetate and 4ꢀ
(
5) in the presence of 1,3ꢀdisulfonic acid benzimidazolium
chloride, which also reacts with arylaldehyde (5) to provide imine
6) with elimination of water. Next, the reaction between
enaminone (5) and activated imine (6) in the presence of
Dsbim]Cl as a Bronsted acid via intermolecular Mannichꢀtype
chloroaniline have tabulated in Table 4. As it is shown, our
catalyst has remarkably improved this in different terms {reaction
time, yield, turnꢀover number (TON) and turnꢀover frequency
(TOF)}.
5
0
5
(
[
30
reaction affords the intermediate (7). The reaction of the
intermediate (7) with the second arylaldehyde produces another
intermediate (8) by the loss of water. Intermediate (8)
tautomerizes to (9), which is stabilized by intramolecular
hydrogen bonding. Then, intramolecular Mannichꢀtype reaction
forms the intermediate (10). Deprotonation and tautomerization
of the intermediate (10) afford the desired tetrahydropyridine
derivatives (4).
1
35
1
Scheme 2. Possible reaction mechanism for the tetrahydropyridines
condensation 4.
20
To show the merit of the present work, we compared the results
of our catalyst with some reported catalysts for the synthesis of
40
6
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Table 4. Comparison of the results of the condensation of benzaldehyde, ethyl acetoacetate and 4ꢀchloroaniline in the presence of
Dsbim]Cl with those obtained using other catalysts.
[
a
b
ꢀ1
c
Catalyst/ Conditions
Catalyst
loading
Time (h)
Yield (%)
TON
(h ) TOF
Ref
2
5
LaCl .7H O/ MeOH, r.t
10 mol%
15 mol%
10 mol%
15 mol%
15 mol%
20 mol%
20 mol%
15 mol%
10 mol%
4
8
80
77
76
84
68
73
70
93
95
8
2
[17]
[18]
[20]
[23]
[25]
[26]
[27]
[32]
3
2
[
Hpyro][HSO ]/ EtOH, reflux
5.13
7.6
0.641
0.543
1.12
4
Bi(NO ) ·5H O/ EtOH, r.t
14
5
3
3
2
Ph CCl/ MeOH, 50 °C
3
5.6
CAN/ CH CN, r.t
35
14
6
4.53
3.65
3.5
0.13
3
SSA/ MeOH, 85 °C
citric acid/ MeOH, r.t
RuCl ·2H O / EtOH, r.t
0.26
30
0.583
1.55
4
6.2
3
2
o
d
[
Dsbim]Cl/ Solventꢀfree, 80 C
32 min
9.5
17.81
ꢀ
a
b
c
d
Isolated yield, Turnꢀover number, Turnꢀover frequency,
Experimental
5
This work.
3
4
4
5
0
5
General
All reagents were purchased from Merck and Aldrich companies,
and used without further purification. All known compounds
were identified by comparison of their melting points and spectral
data with those reported in the literature. Progress of the reactions
was monitored by thin layer chromatography (TLC) using silica
gel SIL G/UV 254 plates. Melting points were recorded on an
Electrothermal type 9100 apparatus without correction. FTꢀIR
spectra were recorded using KBr pellets on an Avatar 370 FTꢀIR
ThermoꢀNicolet spectrometer. NMR spectra were collected on a
Bruker Avanceꢀ400 MHz spectrometer (δ in ppm). Mass spectra
were obtained on a Varian Mat CHꢀ7 at 70 eV. Elemental
analysis was performed on a Thermo Finnigan Flash EA
microanalyser.
Recycling of the catalyst is one of the most significant criteria of
green chemistry, hence the recovery and reuse of the IL catalyst
was examined. The recyclability of [Dsbim]Cl was investigated
for the reaction upon the condensation of benzaldehdye, ethyl
acetoacetate and 4ꢀchloroanilines. After completion of the
reaction had been confirmed by TLC, the reaction mixture was
extracted by warm EtOAc, and separated from the catalyst.
Afterward the reused catalyst was employed for another reaction.
We observed that the catalyst could be reused for the next cycle
without any appreciable loss of its activity (Fig 5).
1
0
1
5
Preparation of the ionic liquid
5
5
6
0
5
0
To a roundꢀbottomed flask (50 mL) containing benzimidazole
(
0.708 g, 6.0 mmol) in dry CH Cl2 (15 mL), was added
2
chlorosulfonic acid (1.40 g, 12 mmol) dropwise over a period of
min at room temperature. After the addition was completed, the
5
reaction mixture was stirred for 3 h under pressure of nitrogen (to
remove the produced HCl), stand for 5 min, and the CH Cl was
2
2
decanted. The residue was washed with dry CH Cl (3 × 50 mL)
2
2
Fig. 5. The condensation of benzaldehyde with 4ꢀchloroaniline,
and ethyl acetoacetate, in the presence of reused [Dsbim]Cl (10
mol%) under solventꢀfree conditions at 80 °C.
and dried under vacuum to give [Dsbim]Cl as a viscous pale
yellow oil in (1.97 g, 98% yield).
2
0
Spectral data: IR (Nujol): υ 574, 679, 750, 886, 1063, 1189, 1331,
ꢀ
1 1
1530, 1631, 2536ꢀ3432 cm ; H NMR (400 MHz, DMSOꢀd ): δ
6
8
5
.09 (t, J = 7.45 Hz, 2H), 8.43 (t, J = 7.81 Hz, 1H), 8.90 (d, J =
13
.76 Hz, 2H), 13.64 (s, 2H); C NMR (100 MHz, DMSOꢀd ): δ
6
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DOI: 10.1039/C5RA10699K
+
1
12.80, 125.61, 136.79, 143.24; MS: m/z= 315 (M +1), 314
White solid; m.p: 184ꢀ186 °C; IR (KBr): 3239, 3064, 2979, 2834,
+
+
+
+
ꢀ1 1
(
(
(
M ), 279 (M ꢀCl), 232 (M ꢀSO H), 198 (M ꢀSO H and Cl), 162
1647, 1603, 1462, 1370, 1248, 1068 cm : H NMR (400 MHz,
3
3
+
+
2SO H), 154 (M ꢀ2SO H), 118 (M ꢀ2SO H and Cl) and 81 45 CDCl ): δ 1.47 (3H, t, J = 8.0 Hz, CH ), 2.70 (1H, dd, J = 15.4,
3
3
3
3
3
SO H).
2.7 Hz, C ꢀH′), 2.83 (1H, dd, J = 15.4, 5.6Hz, C ꢀH′′), 3.79 (6H,
3
5
5
5
General procedure for the preparation of
s, OCH
3
), 4.27ꢀ4.35 (1H, m, OꢀCH
2
), 4.42ꢀ4.49 (1H, m, OꢀCH ),
2
5
6
.04 (1H, s, C ꢀH), 6.20 (2H, d, J=6.0, ArH), 6.29 (1H, s, C ꢀH),
6 2
functionalized tetrahydropyridines (4a-v)
.39 (2H, d, J = 6.80 Hz, ArH), 6.76ꢀ6.88 (5h, m, ArH), 7.04ꢀ7.24
In a 10 mL round bottom flask equipped with a condenser, a
mixture of the aromatic amine (2 mmol), ethyl acetoacetate (1
mmol), and [Dsbim]Cl (0.0312 g, 10 mol%) was stirred at 80 °C
for 10 min. After that, the aromatic aldehyde (2 mmol) was
added, and the resulting mixture was kept under stirring for the
specified time in Table 3, the progress of the reaction was
followed by TLC. After completion of the reaction, the reaction
mixture was cooled to room temperature, extracted by the warm
EtOAc (10 ml) to separate the catalyst. EtOAc was removed and
the crude product was recrystallized from aqueous ethanol (96%)
to afford the pure product which required no further purification.
The recovered catalyst was washed with EtOAc (2 × 10 mL),
dried and reused, without considerable catalytic activity decrease.
13
5
5
6
6
7
7
8
8
0
5
0
5
0
5
0
5
(7H, m, ArH), 10.26 (1H, s, NH); C NMR (100 MHz, CDCl ): δ
3
1
1
1
5.93, 34.73, 55.83, 56.4, 56.5, 58.8, 61.1, 100.2, 109.5, 114.9,
15.3, 115.8, 120.3, 128.3, 128.5, 128.7, 132.7, 133.1, 135.1,
36.2, 138.2, 147.1, 156.4, 159.4, 160.1, 169.3; MS (m/z): 692;
10
15
20
25
30
35
40
Elemental analysis for: C H Br N O : C, 58.97; H, 4.66; N,
34
32
2
2
4
4.05. Found: C, 59.16; H, 4.43; N, 3.89.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(4-
nitrophneyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4s).
Light yellow solid; m.p: 139ꢀ142 °C; IR (KBr): 3246, 3058,
ꢀ
1 1
2
979, 2872, 1652, 1593, 1448, 1372, 1253, 1070 cm ; HNMR
(400 MHz, CDCl ): δ 1.54 (3H, t, J = 7.5 Hz, CH ), 2.8 (2H, d, J
3
3
=
15.2Hz, C ꢀH′, H′′), 4.34ꢀ4.47 (2H, m, OꢀCH ), 5.25 (1H, m,
5 2
C ꢀH), 6.42ꢀ6.5 (2H, m, C ꢀH, ArH), 6.75ꢀ6.8 (1H, m, ArH),
6
6
7
8
.17(2H, m, ArH), 7.19 (2H, m, ArH), 7.48ꢀ7.63 (4H, m, ArH),
.07ꢀ8.35 (10H, m, ArH), 8.52 (2H, d, j=8.5, ArH), 10.28 (1H, s,
2
.3.1. Spectral data of the selected products
NH); Elemental analysis for: C H I N O : C, 47.08; H, 3.21; N,
32
26 2
4
6
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(phenyl)-
,2,5,6-tetrahydropyridine-3-carboxylate (4q).
White solid; m.p: 170ꢀ172 °C; IR (KBr): 3252, 3051, 2986, 2872,
6
.86; Found: C, 47.24; H, 3.35; N, 6.52.
1
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(4-tolyl)-
1,2,5,6-tetrahydropyridine-3-carboxylate (4t).
ꢀ
1 1
1
652, 1592, 1448, 1373, 1253, 1070 cm ; H NMR (400 MHz,
White solid; m.p: 203ꢀ204 °C; IR (KBr): 3239, 3080, 2978, 2859,
CDCl ): δ 1.53 (3H, t, J = 7.2 Hz, CH ), 2.72 (1H, dd, J = 14.4,
3
3
ꢀ
1
1
1647, 1603, 1454, 1371, 1255, 1068 cm ; HNMR (400 MHz,
CDCl ): δ 1.52 (3H, t, J = 7.6 Hz, CH ), 2.28 (3H, s, CH at
2
.2 Hz, C ꢀH′), 2.84 (1H, dd, J = 14.4, 5.4Hz, C ꢀH′′), 4.30ꢀ4.33
5 5
3
3
3
(
1H, m, OꢀCH ), 4.40ꢀ4.48 (1H, m, OꢀCH ), 5.08ꢀ5.18 (1h, m,
2
2
phenyl), 2.37 (3H, s, CH at phenyl), 2.68 (1H, dd, J = 15.5, 2.2
3
C ꢀH), 6.26ꢀ6.33 (1H, m, ArH), 6.37 (1H, s, C ꢀH), 6.49 (1H, m,
6
2
Hz, C ꢀH′), 2.81 (1H, dd, J = 15.5, 5.6Hz, C ꢀH′′), 4.34 (1H, dq, J
5
5
ArH), 6.63 (2H, t, J = 7.0 Hz, ArH), 6.76 (1H, t, J = 7.5 Hz,
ArH), 6.85 (2H, d, J = 7.2 Hz, ArH), 6.94 (1H, d, J = 6.0 Hz,
ArH), 7.15ꢀ7.29 (9H, m, ArH), 7.43 (1H, d, J = 6.8 Hz, ArH),
=
10.8, 7.2 Hz, OꢀCH ), 4.47 (1H, dq, J = 10.8, 7.0 Hz, OꢀCH ),
2 2
5.05 (1H, d, J = 2.5, C ꢀH), 6.23ꢀ6.83 (2H, m, ArH), 6.4 (1H, s,
6
1
3
C ꢀH), 6.47ꢀ6.51 (2H, m, ArH), 6.75ꢀ6.93 (4H, m, ArH), 7.03ꢀ
2
1
0.29 (1H, s, NH); C NMR (100 MHz, CDCl ): δ 16.0, 34.5,
3
7
.44 (8H, m, ArH), 10.28 (1H, s, NH); Elemental analysis for:
56.2, 59.2, 61.1, 95.1, 96.5, 99.8, 113.5, 122.7, 126.3, 126.5,
C H I N O : C, 54.13; H, 4.28; N, 3.71; Found: C, 54.19; H,
3
4
32 2
2
2
1
1
27.3, 127.3, 127.6, 127.8, 128.7, 129.6, 130.2, 131.5, 135.5,
36.1, 140.2, 142.9, 144.2, 149.3, 156.4, 169.2; MS (m/z): 726;
4
.35; N, 3.52.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(4-
chlorophenyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (4u).
White solid; m.p: 189ꢀ190 °C; IR (KBr): 3234, 3069, 2956,
Elemental analysis for: C H I N O : C, 52.91; H, 3.89; N, 3.86.
3
2
28 2
2
2
Found: C, 52.78; H, 3.65; N, 3.85.
Ethyl-(4-bromophenyl)-4-(4-bromophenylamino)-2,6-bis(4-
methoxyphenyl)-1,2,5,6-tetrahydropyridine-3carboxylate
ꢀ
1
1
2
875,1657, 1604, 1459, 1375, 1249, 1075 cm ; H NMR (400
MHz, CDCl ): δ 1.47 (3H, t, J = 7.5 Hz, CH ), 2.69 (1H, dd, J =
3
3
(4r).
14.6, 2.7 Hz, C ꢀH′), 2.82 (1H, dd, J = 14.6, 5.4Hz, C ꢀH′′), 4.32ꢀ
5
5
8
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4
1
6
.37 (1H, dq, J = 10.5, 7.2 Hz, OꢀCH ), 4.44ꢀ4.50 (1H, dq, J =
Notes and references
2
4
5
5
6
5
0
5
0
0.5, 6.8 Hz, OꢀCH ), 5.06 (1H, m, C ꢀH), 6.26 (1H, s, C ꢀH),
2
6
2
1
P. Pollet, E. A. Davey, E. E. UrenaꢀBenavides, C. A. Ecker and
.37ꢀ6.46 (4H, m, ArH), 6.55 (1H, s, ArH), 6.74 (2H, d, J = 7.6
13
C. L. Liotta. Green Chem., 2014, 16, 1034.
Hz, ArH), 6.93ꢀ7.24 (9H, m, ArH), 10.29 (1H, s, NH); C NMR
2
3
V. I. Parvulescu and C. Hardacre, Chem. Rev., 2007, 107, 2615.
B. Xin and J. Hao, Chem. Soc. Rev., 2014, 43, 7171.
5
0
5
0
5
(100 MHz, CDCl ): δ 16.4, 33.9, 55.4, 59.1, 61.9, 99.2, 113.4,
3
1
1
1
17.4, 121.7, 123.8, 124.2, 125.4, 128.4, 128.8, 129.2, 129.6,
29.9, 130.2, 131.4, 131.7, 133.9, 134.7, 141.4, 142.5, 142.8,
4 M. A. Zolfigol, A. Khazaei, A. R. MoosaviꢀZare, A. Zare and
+
V. Khakyzadeh, Appl. Catal. A., 2011, 400, 70.
47.9, 155.8, 168.9; MS (EI, 70 eV): m/z= 793 [M ]; Elemental
5
S. Anvar, I. MohammadpoorꢀBaltork, S. Tangestaninejad, M.
analysis for: C H Cl I N O : C, 48.33; H, 3.30; N, 3.52. Found:
32
26 2 2
2
2
Moghadam, V. Mirkhani, A. R. Khosropour, A. Landarani
Isfahani and R. Kia, ACS. Comb. Sci., 2014, 16, 93.
6 S. Brauch, S. S. van Berkel and B. Westermann, Chem. Soc.
Rev., 2013, 42, 4948.
1
1
2
2
C, 48.39; H, 3.21; N, 3.69.
Ethyl 4-(p-tolylamino)-1,2,5,6-tetrahydro-1,2,6-trip-
tolylpyridine-3-carboxylate (4v).
White solid; m.p: 181ꢀ182 °C; IR (KBr): 3249, 3068, 2956, 2869,
ꢀ
1
1
7 X. He, Y. Shang, Z. Yu, M. Fang,Y. Zhou, G. Han and F. Wu,
J. Org. Chem., 2014, 79, 8882.
1
649, 1585, 1452, 1372, 1249, 1075 cm ; H NMR (400 MHz,
CDCl ): δ 1.46 (3H, t, J = 7.2 Hz, CH ), 2.17 (3H, s, CH , at
3
3
3
8
S. Shaabani, A. Shaabani and S. W. Ng, ACS Comb. Sci., 2014,
phenyl), 2.27 (3H, s, CH , at phenyl), 2.31ꢀ2.33 (6H, m, J = 8.5,
3
16, 176.
CH , at phenyl), 2.70 (1H, dd, J = 15.2, 2.2 Hz, C ꢀH′), 2.83 (1H,
3
5
9
S. Duttwyler, C. Lu, B. Q. Mercado, R. G. Bergman and J. A.
dd, J = 15.2, 5.4 Hz, C ꢀH′′), 4.33 (1H, dq, J = 10.8, 7.2 Hz, Oꢀ
5
Ellman, Angew. Chem. Int. Ed., 2014, 53, 3877.
CH ), 4.47 (1H, dq, J = 10.8, 7.0 Hz, OꢀCH ), 5.08 (1H, m, C ꢀ
2
2
6
1
0 A. R. Mohite, P. R. Sultane and R. G. Bhat, Tetrahedron
Lett., 2012, 53, 30.
65 11 A. T. Khan, M. M. Khan and K. K. Bannura, Tetrahedron,
H), 6.15 (2H, m, ArH), 6.37 (1H, s, C ꢀH), 6.45 (2H, m, ArH),
2
6
.89 (3H, d, 10.5 Hz), 6.95 (2H, d, 7.6 Hz), 7.03ꢀ7.26 (7H, m,
1
3
ArH), 10.19 (1H, s, NH); C NMR (100 MHz, CDCl ): δ 14.4,
3
2
1
010, 66, 7762.
2
1
0.5, 21.2, 21.7, 34.4, 56.2, 58.2, 60.1, 95.1, 113.5, 125.2, 125.5,
27.3, 127.6, 127.8, 128.7, 126.5, 127.2, 128.8, 129.3, 130.1,
2 S. Petit, J. P. Nallet, M. Guillard, J. Dreux, R. Chermat, M.
Poncelet, C. Bulach, P. Simon, C. Fontaine, M. Barthelmebs and
J. L. Imbs, Eur. J. Med. Chem., 1991, 26, 19.
135.2, 138.9, 139.4, 146.3, 154.4, 169.6; MS (m/z): 726;
Elemental analysis for: C H N O : C, 81.47; H, 7.22; N, 5.28.
3
6
38
2
2
7
7
8
8
0
5
0
5
13 N. N. Mateeva, L. L. Winfield and K. K. Redda, Curr. Med.
Chem., 2005, 12, 551.
Found: C, 81.40; H, 7.43; N, 5.34.
1
4 Y. Zhou, V. E. Gregor, B. K. Ayida, G. C. Winters, Z. Sun, D.
Conclusion
Murphy, G. Haley, D. Bailey, J. M. Froelich and S. Fish, Bioorg.
Med. Chem., 2007, 17, 1206.
3
0
In summary, we have introduced an efficient, recyclable and
homogeneous Bronsted acidic ionic liquid, [Dsbim]Cl as a
catalyst and used it in the one‐pot multi‐component condensation
of aromatic aldehydes, anilines and ethyl acetoacetate for the
synthesis of tetrahydropyridines in excellent yields. Owing to its
operational simplicity, high yields, short reaction time, easy work
up, mild reaction condition as well as nonꢀcorrosive and nonꢀ
pollution aspects, this method will be better than many other
existing ones.
15 B. Ho, A. Michael Crider and J. P. Stables, Eur. J. Med.
Chem., 2001, 36, 265.
1
6 M. Misra, S. K. Pandey, V. P. Pandey, J. Pandey, R. Tripathi
and R. P. Tripathi, Bioorg. Med. Chem., 2009, 17. 625.
B. Umamahesh, V. Sathesh, G. Ramachandran, M.
Sathishkumar and K. Sathiyanarayanan, Cata. Lett., 2012, 142,
3
5
1
7
8
1
95.
8 S. S. Sajadikhah, N. Hazeri, M. T. Maghsoodlou, S. M.
HabibiꢀKhorassani, A. Beigbabaei and Lashkari, J. Chem. Res.,
012, 36, 463.
19 S. Mishra and R. Ghosh, Tetrahedron Lett., 2011, 52, 2857.
0 G. Brahmachari and S. Das, Tetrahedron Lett., 2012, 53, 1479
4
0
Acknowledgment
2
I gratefully acknowledge the Islamic Azad University of Lamerd
Research Councils for support of this work.
2
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Page 10 of 11
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DOI: 10.1039/C5RA10699K
2
2
2
2
1 X. Li, Y. Zhao, H. Qu, Z. Mao and X Lin, Chem. Commun.,
013, 49, 1401.
2 R. Ramachandran, S. Jayanthi and Y. T. Jeong, Tetrahedron,
012, 68, 363.
5
0
5
23 S. S. Sajadikhah, N. Hazeri, M. T. Maghsoodlou, S. M.
HabibiꢀKhorassani, A. C. Willis, Res. Chem. Intermed., 2014, 40,
7
2
23.
4 M. Daraei, M. A. Zolfigol, F. Derakhshan� Panah, M. Shiri, H.
G. Kruger and M. Mokhlesi, J. Iran. Chem. Soc., 2015, 12, 855.
25 H. J. Wang, L. P. Mo and Z. H. Zhang, ACS Comb. Sci., 2011,
1
1
3, 181.
2
6 W. M. Basyounia, K. A. M. ElꢀBayoukia, W. M. Tohamya
and S. Y. Abbas., Synth. Commun., 2015, 45, 1071
7 Z. Madanifar, M. T. Maghsoodlou, M. Kangani and N. Hazeri,
Res. Chem. Intermed., doi: 10.1007/s11164ꢀ015ꢀ1993ꢀ6
8 N. R. Agrawal, S. P. Bahekar, P. B. Sarode, S. S. Zadeb and
H. S. Chandak, RSC Adv., 2015, 5, 47053.
9 U. Balijapalli, S. Munusamy, K. N. Sundaramoorthy and S. K.
2
1
2
2
Iyer, Synth. Commun., 2014, 44, 943.
20
30 H. Eshghi, A. Khojastehnezhad, F. Moeinpour, M. Bakavoli,
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1
3
1 S. Mohammadi and M. Abbasi, Res. Chem. Intermed., doi:
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2 S. Mohammadi and M. Abbasi, J. Chem. Res., 2015, 39, 123
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33 M. Rahimizadeh, S. M. Seyedi, M. Abbasi, H. Eshghi, A.
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4 A. R. MoosaviꢀZarea, M. A. Zolfigol, M. Zarei, A. Zare, and
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35 F. Shirini, M. Abedini, M. Seddighi, O. Goli Jolodar, M.
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1
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Design, preparation and characterization of ionic liquid 1,3-disulfonic acid
benzimidazolium chloride as an efficient and recyclable catalyst for the
synthesis of tetrahydropyridine under solvent-free conditions
Mohsen Abbasi
Department of Chemistry, Lamerd Branch, Islamic Azad University, Lamerd, Fars, Iran, E-mail: mohsen.abbasi90@gmail.com.
Abstract
In the present work, 1,3-disulfonic acid benzimidazolium chloride as a new ionic liquid, is
1
13
synthesized, characterized by studying its FT-IR, H NMR, C NMR as well as mass spectra.
This ionic liquid is used as an efficient, homogeneous and recyclable catalyst for synthesis of
highly functionalized tetrahydropyridine via one-pot multi-component condensation of
aromatic aldehydes, ethyl acetoacetate, and anilines under solvent-free conditions. The
present synthetic route is a green protocol offering several advantages, such as high yield of
products, shorter reaction time, mild reaction conditions, minimizing chemical waste and
easy work-up procedures. Further, the catalyst could be reused and recovered at least four
times without appreciable loss of activity.