Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate as an efficient, eco-friendly, and reusable catalyst for one-pot synthesis of highly functionalized tetrahydropyridines

Article abstract of DOI:10.1007/s11164-015-1934-4

Novel ionic liquid sulfonic acid pyridinium hydrogen sulfate ([Pyridine-SO₃H]HSO₄) is synthesized and characterized by various techniques such as FT-IR, ¹H NMR, ¹³C NMR, TG, DTG, as well as mass spectra. This ionic liquid is used as an efficient, homogeneous, and recyclable catalyst for one-pot synthesis of highly functionalized tetrahydropyridines from the three-component condensation of aromatic aldehydes, ethyl acetoacetate, and substituted anilines under solvent-free conditions. The main advantages of this protocol are the short reaction time, high yields, mild and clean conditions, and several reuse times without noticeably decreasing the catalytic activity.

Full text of DOI:10.1007/s11164-015-1934-4

Res Chem Intermed
DOI 10.1007/s11164-015-1934-4
Design of ionic liquid sulfonic acid pyridinium
hydrogen sulfate as an efficient, eco-friendly,
and reusable catalyst for one-pot synthesis of highly
functionalized tetrahydropyridines
•
Sedigheh Mohammadi Mohsen Abbasi
Received: 27 November 2014 / Accepted: 19 January 2015
ꢀ Springer Science+Business Media Dordrecht 2015
Abstract Novel ionic liquid sulfonic acid pyridinium hydrogen sulfate ([Pyridine-
SO3H]HSO4) is synthesized and characterized by various techniques such as FT-IR,
1H NMR, 13C NMR, TG, DTG, as well as mass spectra. This ionic liquid is used as
an efficient, homogeneous, and recyclable catalyst for one-pot synthesis of highly
functionalized tetrahydropyridines from the three-component condensation of aro-
matic aldehydes, ethyl acetoacetate, and substituted anilines under solvent-free
conditions. The main advantages of this protocol are the short reaction time, high
yields, mild and clean conditions, and several reuse times without noticeably de-
creasing the catalytic activity.
Keywords One-pot ꢀ Sulfonic acid pyridinium hydrogen sulfate ꢀ
Tetrahydropyridines ꢀ Solvent-free conditions ꢀ Multicomponent reaction
Introduction
Multicomponent reactions (MCRs) provide a variety of complex molecules through
one-step condensation of three or more starting materials. They reduce chemical
waste, are ease of separation and operation time, while being atom economic [1–3].
Among the different multicomponent reactions, the condensation of an aldehyde
(2 mmol), an amine (2 mmol), and a b-keto ester (1 mmol) is one of the best
examples, where tetrahydropyridines are produced as the main products. Tetrahy-
dropyridine derivatives are found in a wide spectrum of natural products (e.g.,
alkaloids), pharmaceuticals, biologically active, and synthetic compounds [4–6].
They have been shown to have a wide range of biological activities, such as anti-
S. Mohammadi ꢀ M. Abbasi (&)
Department of Chemistry, Lamerd Branch, Islamic Azad University, Lamerd, Fars, Iran
e-mail: mohsen.abbasi90@gmail.com
123

S. Mohammadi, M. Abbasi
hypertensive [7], anti-bacterial [8], anti-convulsant, anti-inflammatory activities [9]
and antimalarial activities [10].
In recent years, various methods have been developed for the synthesis of
functionalized piperidines in the presence of catalysts such as InCl3 [11], L-proline/
TFA [10], tetrabutylammonium tribromide (TBATB) [5], 1-methyl-2-oxopyrroli-
dinium hydrogen sulfate ([Hpyro][HSO4]) [12], ZrOCl2.8H2O [13], Bi(NO3)3.5H2O
[14], trityl chloride (Ph3CCl) [15], cerium ammonium nitrate (CAN) [16],
Ni(ClO4)2.6H2O [17], BF3.SiO2 [18], Al(H2PO4)3 [19], molecular iodine (I2) [20],
Ce(OTf)4 [21] and FeCl3/SiO2NPs [22]. However, most of these methods suffer
from various disadvantages such as long reaction times, use of toxic metals or of
volatile organic solvents, un-recyclable catalysts, low yields, tedious work-up
procedure, and harsh reaction conditions. Therefore, to overcome these limitations,
the development of a process without a solvent, efficient, mild and green is needed
for the synthesis of these valuable compounds. Recently, the use of ionic liquids
(ILs) as eco-friendly solvents, catalysts, and reagents in organic reactions has
attracted much attention from researchers due to their unique advantages such as
high thermal and chemical stability, low vapor pressure, lack of flammability,
ability to dissolve a wide range of materials, insolubility in nonpolar solvents, and
ease of recyclability [23–28].
In continuation of our interest in developing green protocols for the synthesis of
tetrahydropyridines [29, 30], we report herein from three-component coupling
reaction of aromatic aldehydes, aromatic amines, and ethyl acetoacetate by using
novel ionic liquid sulfonic acid pyridinium hydrogen sulfate ([Pyridine–SO3-
H]HSO4) as an eco-friendly solvent and as a reusable, efficient, and homogeneous
catalyst for the synthesis of highly tetrahydropyridines at 100 ꢁC under solvent-free
conditions (Scheme 1 and 2).
Experimental
General
All reagents were purchased from Merck and Aldrich companies, and used without
further purification. All yields refer to isolated products. 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. Fourier transform infrared (FT-IR) spectra were recorded on an
Avatar 370 FT-IR Thermo-Nicolet spectrometer using pressed KBr pellets. 1H
NMR and 13C NMR spectra were recorded on a Bruker DRX-400 spectrometer at
Scheme 1 The synthetic scheme of sulfonic acid pyridinium hydrogen sulfate preparation
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
Scheme 2 The three-component reaction of functionalized piperidines synthesis
400 and 100 MHz, respectively, and the chemical shifts are expressed in d parts per
million (ppm) relative to tetramethylsilane (TMS) as the internal standard. The
abbreviations used are: singlet (s), doublet (d), triplet (t), and multiplet (m). Thermal
gravimetry (TG) and differential thermal gravimetric (DTG) of the ionic liquid was
studied at the range of 25–600 ꢁC, with a temperature increase rate of 10 ꢁC min-1
in a argon atmosphere on a Bahr STA 503 apparatus. Mass spectra were obtained on
a Varian Mat CH-7 at 70 eV. The element analyses (C, H, N) were obtained from a
Thermo Finnigan Flash EA microanalyser.
Preparation of the ionic liquid
Chlorosulfonic acid (0.70 g, 6.0 mmol) was added dropwise to a stirred solution of
pyridine (0.474 g, 6.0 mmol in dry CH2Cl2 (20 ml) over a period of 5 min in an ice
bath. After the addition was completed, the reaction mixture was stirred for 60 min,
and then sulfuric acid (0.588 g, 98 %, 6.0 mmol) was added dropwise over a period
of 3 min at room temperature, followed by stirring for three more hours under
nitrogen to remove the produced HCl, and subsequent heating for 1 h at 50 ꢁC, and
CH2Cl2 was decanted. The residue was washed with dry CH2Cl2 (3 9 20 ml) [31],
and dried under vacuum to give sulfonic acid pyridinium hydrogen sulfate as a
1
viscous pale yellow oil (1.98 g, 97 % yield). H NMR (400 MHz, DMSO-d6): d
8.12 (t, J = 7.45 Hz, 2H), 8.64 (t, J = 7.81 Hz, 1H), 8.93 (d, J = 5.76 Hz, 2H),
11.61 (s, 1H), 13.86 (s, 1H); 13C NMR (100 MHz, DMSO-d6): d 128.79, 142.98,
148.21; IR (Nujol): 576, 886, 1,003, 1,069, 1,174, 1,329, 1,530, 1,631,
2,496–3,420 cm-1; MS (EI, 70 eV): m/z = 258 (M??1); 257 (M?); 160 (M?-
SO4H), 176 (M?-SO3H), and 79 (M?-SO3H and SO4H) as well.
General procedure for the preparation of functionalized piperidines (4a–r)
In a 10-ml round-bottom flask equipped with a condenser, a mixture of the aromatic
amine (2 mmol), ethyl acetoacetate (1 mmol), and [Pyridinium-SO3H]HSO4
(0.0,385 g, 15 mol %) was stirred at 100 ꢁC for 10 min. Afterwards, 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
123

S. Mohammadi, M. Abbasi
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 9 10 ml), dried, and reused, without
considerable catalytic activity decrease.
Spectral data of the selected products
Ethyl-(3-bromophenyl)-4-(3-bromophenylamino)-2,6-bis(4-chlorophenyl)-1,2,5,6
tetrahydropyridine-3-carboxylate (4n)
White solid; m.p: 183–185 ꢁC; IR (KBr): 3,237, 3,056, 2,966, 2,855,1,647, 1,604,
1,451, 1,372, 1,252, 1,071 cm-1 1HNMR (400 MHz, CDCl3): d 1.50 (3H, t,
;
J = 7.5 Hz, CH3), 2.71 (1H, dd, J = 14.6, 2.7 Hz, C5–H0), 2.79 (1H, dd, J = 14.6,
5.4 Hz, C5–H00), 4.32–4.37 (1H, m), 4.44–4.50 (1H, m), 5.09 (1H, m, C6–H), 6.30
(1H, s), 6.37–6.43 (4H, m), 6.61 (1H, s, C2–H), 6.78 (2H, d, J = 7.6 Hz), 6.90–7.30
(9H, m), 10.30 (1H, s, NH); 13C NMR (100 MHz, CDCl3): d 15.97, 34.58, 55.89,
58.59, 61.36, 99.61, 112.8, 116.75, 120.98, 123.64, 124.51, 125.42, 128.68, 128.99,
128.18, 129.46, 129.95, 130.31, 131.25, 131.79, 133.64, 134.51, 140.1, 142.22,
142.53, 148.88, 156.05, 168.4; MS (EI, 70 eV): m/z = 700 [M?]; Elemental
analysis for: C32H26Br2Cl2N2O2: C, 54.81; H, 3.74; N, 3.99. Found: C, 54.65; H,
4.15; N, 4.05 %.
Ethyl-(4-bromophenyl)-4-(4-bromophenylamino)-2,6-bis(4-methoxyphenyl)-1,2,5,6-
tetrahydropyridine-3carboxylate (4o)
White solid; m.p: 185 ꢁC; IR (KBr): 3,239, 3,064, 2,979, 2,834, 1,647, 1,603, 1,462,
1,370, 1,248, 1,068 cm-1: 1H NMR (400 MHz, CDCl3): d 1.47 (3H, t, J = 8.0 Hz,
CH3), 2.70 (1H, dd, J = 15.4, 2.7 Hz, C5–H0), 2.83 (1H, dd, J = 15.4, 5.6 Hz, C5–
H00), 3.79 (6H, s, OCH3), 4.27–4.35 (1H, m, O–CH2), 4.42–4.49 (1H, m, O–CH2),
5.04 (1H, s, C6–H), 6.20 (2H, d, J = 6.0, ArH), 6.29 (1H, s, C2–H), 6.39 (2H, d,
J = 6.80 Hz, ArH), 6.76–6.88 (5H, m, ArH), 7.04–7.24 (7H, m, ArH), 10.26 (1H, s,
NH); 13C NMR (100 MHz, CDCl3): d 15.93, 34.73, 55.83, 56.4, 56.5, 58.8, 61.1,
100.2, 109.5, 114.9, 115.3, 115.8, 120.3, 128.3, 128.5, 128.7, 132.7, 133.1, 135.1,
136.2, 138.2, 147.1, 156.4, 159.4, 160.1, 169.3; MS (EI, 70 eV): m/z = 692 [M?];
Elemental analysis for: C34H32Br2N2O4: C, 58.97; H, 4.66; N, 4.05. Found: C,
59.16; H, 4.43; N, 3.89 %.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(phenyl)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4p)
White solid; m.p: 171–173 ꢁC; IR (KBr): 3,252, 3,051, 2,986, 2,872, 1,652, 1,592,
1,448, 1,373, 1,253, 1,070 cm-1 1H NMR (400 MHz, CDCl3): d 1.53 (3H, t,
;
J = 7.2 Hz, CH3), 2.72 (1H, dd, J = 14.4, 2.2 Hz, C5–H0), 2.84 (1H, dd, J = 14.4,
5.4 Hz, C5–H00), 4.30–4.33 (1H, m, O–CH2), 4.40–4.48 (1H, m, O–CH2), 5.08–5.18
(1H, m, C6–H), 6.26–6.33 (1H, m, ArH), 6.37 (1H, s, C2–H), 6.49 (1H, m, ArH),
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
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), 7.15–7.29 (9H, m, ArH), 7.43
(1H, d, J = 6.8 Hz, ArH), 10.29 (1H, s, NH); 13C NMR (100 MHz, CDCl3): d 16.0,
34.5, 56.2, 59.2, 61.1, 95.1, 96.5, 99.8, 113.5, 122.7, 126.3, 126.5, 127.3, 127.3,
127.6, 127.8, 128.7, 129.6, 130.2, 131.5, 135.5, 136.1, 140.2, 142.9, 144.2, 149.3,
156.4, 169.2; MS (EI, 70 eV): m/z = 726 [M?]; Elemental analysis for: C32H28-
I2N2O2: C, 52.91; H, 3.89; N, 3.86. Found: C, 52.78; H, 3.65; N, 3.85 %.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-di(4-tolyl)-1,2,5,6-tetrahydropyridine-3-
carboxylate (4q)
White solid; m.p: 208–209 ꢁC; IR (KBr): 3,239, 3,080, 2,978, 2,859, 1,647, 1,603,
1,454, 1,371, 1,255, 1,068 cm-1 1HNMR (400 MHz, CDCl3): d 1.52 (3H, t,
;
J = 7.6 Hz, CH3), 2.28 (3H, s, CH3 at phenyl), 2.37 (3H, s, CH3 at phenyl), 2.68
(1H, dd, J = 15.5, 2.2 Hz, C5–H0), 2.81 (1H, dd, J = 15.5, 5.6 Hz, C5–H00), 4.34
(1H, m, O–CH2), 4.47 (1H, m, O–CH2), 5.05 (1H, d, J = 2.5, C6–H), 6.23-6.83 (2H,
m, ArH), 6.4 (1H, s, C2–H), 6.47–6.51 (2H, m, ArH), 6.75–6.93 (4H, m, ArH),
7.03–7.44 (8H, m, ArH), 10.28 (1H, s, NH); Elemental analysis for: C34H32I2N2O2:
C, 54.13; H, 4.28; N, 3.71; Found: C, 54.19; H, 4.35; N, 3.52 %.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(4-nitrophneyl)-1,2,5,6-
tetrahydropyridine-3-carboxylate (4r)
Light yellow solid; m.p: 137–140 ꢁC; IR (KBr): 3,246, 3,058, 2,979, 2,872, 1,652,
1,593, 1,448, 1,372, 1,253, 1,070 cm-1; 1HNMR (400 MHz, CDCl3): d 1.54 (3H, t,
J = 7.5 Hz, CH3), 2.8 (2H, d, J = 15.2 Hz, C5–H0, H00), 4.34–4.47 (2H, m, O–
CH2), 5.25 (1H, m, C6–H), 6.42–6.5 (2H, m, C6–H, ArH), 6.75–6.8 (1H, m, ArH),
7.17(2H, m, ArH), 7.19 (2H, m, ArH), 7.48–7.63 (4H, m, ArH), 8.07–8.35 (10H, m,
ArH), 8.52 (2H, d, J = 8.5, ArH), 10.28 (1H, s, NH); Elemental analysis for:
C32H26I2N4O6: C, 47.08; H, 3.21; N, 6.86; Found: C, 47.24; H, 3.35; N, 6.52 %.
Ethyl-(3-iodophenyl)-4-(3-iodophenylamino)-2,6-bis(4-chlorophenyl)-1,2,5,6-
tetrahydropyridine-3-carboxylate (4s)
White solid; m.p: 189–190 ꢁC; IR (KBr): 3,234, 3,069, 2,956, 2,875,1,657, 1,604,
1,459, 1,375, 1,249, 1,075 cm-1 1H NMR (400 MHz, CDCl3): d 1.47 (3H, t,
;
J = 7.5 Hz, CH3), 2.69 (1H, dd, J = 14.6, 2.7 Hz, C5–H0), 2.82 (1H, dd, J = 14.6,
5.4 Hz, C5–H00), 4.32–4.37(1H, m, O–CH2), 4.44–4.50 (1H, m, O–CH2), 5.06 (1H,
m, C6–H), 6.26 (1H, s, C2–H), 6.37–6.46 (4H, m, ArH), 6.55 (1H, s, ArH), 6.74 (2H,
d, J = 7.6 Hz, ArH), 6.93–7.24 (9H, m, ArH), 10.29 (1H, s, NH); 13C NMR
(100 MHz, CDCl3): d 16.4, 33.9, 55.4, 59.1, 61.9, 99.2, 113.4, 117.4, 121.7, 123.8,
124.2, 125.4, 128.4, 128.8, 129.2, 129.6, 129.9, 130.2, 131.4, 131.7, 133.9, 134.7,
141.4, 142.5, 142.8, 147.9, 155.8, 168.9; MS (EI, 70 eV): m/z = 793 [M?];
Elemental analysis for: C32H26Cl2I2N2O2: C, 48.33; H, 3.30; N, 3.52. Found: C,
48.39; H, 3.21; N, 3.69 %.
123

S. Mohammadi, M. Abbasi
Results and discussion
Characterization of the catalyst
After the preparation of sulfonic acid pyridinium hydrogen sulfate ionic liquid,
[Pyridine–SO3H]HSO4 via the reaction of [Pyridine–SO3H]Cl with sulfuric acid
1
(Scheme 2), its structure was identified by FT-IR, H NMR, 13C NMR as well as
mass spectra. The FT-IR vibrations at 1,329, 1,174, and 576 cm-1 are assigned to
the asymmetric stretching, symmetric stretching, and bending of S–O modes of
sulfonic acid and sulfate groups, respectively [28, 31]. The N–S stretching vibration
was also appeared at 886 cm-1. This specific infrared peak indicates the sulfonic
group-pyridine connection. In addition, the presence of the sulfur–nitrogen bond in
the ionic liquid increased the number of vibrational modes and changed the overall
shape of the IR spectrum in comparison with the pure pyridine and sulfuric acid.
The strong bands at 1,631 and 1,530 cm-1 arising from the pyridinium ring were
also present. By comparison with SOH bending frequencies in sulfuric acid and
other sulfonic acids, the bands at 1,003 and 1,069 cm-1 were assigned to SOH
bending modes [32]. The Broad and strong bands at 2,496 to 3,420 cm-1 can be
arisen by stretching the hydroxyl groups in the [Pyridine–SO3H]HSO4 ionic liquid
(Fig. 1).
Fig. 1 FT-IR spectra of pyridine (a), sulfonic acid pyridinium chloride ([Pyridine–SO3H]Cl) (b) and
sulfonic acid pyridinium hydrogen sulfate ([Pyridine–SO3H]HSO4) (c)
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
The 1H NMR and 13C NMR spectra of the ionic liquid obtained in DMSO-d6 are
displayed in Figs. 2 and 3, respectively. The peaks at 13.86 and 11.61 ppm, are
assigned to –SO3H and SO4H- protons, respectively. The assignment is based on
the comparison with 1H NMR spectra of, [Pyridine–SO3H]Cl, ClSO3H, H2SO4 and
pyridinium chloride in DMSO-d6 available in the literature [28]. The chemical shifts
of the acidic hydrogens of H2SO4, [Pyridine–SO3H]Cl, ClSO3H and pyridinium
chloride are at 14.32, 13.67, 13.45, and 11.37 ppm, respectively. The 1H NMR data
of the ionic liquid are different from those in pyridine, ClSO3H, H2SO4 and the
intermediate [Pyridine–SO3H]Cl. Moreover, while pyridine and ClSO3H are readily
soluble in CH2Cl2, [Pyridine–SO3H]Cl and [Pyridine–SO3H]HSO4 ILs are insoluble
in CH2Cl2.
The mass spectrum of the [Pyridine–SO3H]HSO4 ionic liquid showed the correct
molecular ion peak at 257. Other ion peaks are also observed at 258 (M??1), 160
(M?-SO4H), 176 (M?-SO3H), and 79 (M?-SO3H and SO4H) as well.
In order to obtain information on the thermal stability, thermogravimetry (TG)
and differential thermogravimetry analysis (DTA) of the ionic liquid is investigated
in 25–600 ꢁC range, with a temperature increase rate of 10 ꢁC min-1, under the
inert atmosphere of argon. The corresponding diagrams are depicted in Fig. 4. The
first strong loss weight was observed after 135 ꢁC and the second strong weight loss
appears after 320 ꢁC. Therefore, the molecular decomposition occurred for this
catalyst after 135 ꢁC.
Fig. 2 The 1H NMR spectrum of sulfonic acid pyridinium hydrogen sulfate
123

S. Mohammadi, M. Abbasi
Fig. 3 The 13C NMR spectrum of sulfonic acid pyridinium hydrogen sulfate
Fig. 4 The TG/DTG diagrams of [Pyridine–SO3H]HSO4
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
Application of [Pyridine–SO3H]HSO4 in the tetrahydropyridines synthesis
After characterization of the ionic liquid, we examined its efficacy to catalyze the
synthesis of tetrahydropyridines. To optimize the reaction conditions, the conden-
sation of 4-methyl benzaldehyde (2 mmol), aniline (2 mmol), and ethyl acetoacetate
(1 mmol) was studied in the presence of different amounts of [Pyridine–
SO3H]HSO4 and [Pyridine–SO3H]Cl at different temperatures ranging from
70–110 ꢁC, under solvent-free conditions. The results are summarized in Table 1.
The best results were obtained using 15 mol % of [Pyridine–SO3H]HSO4 at 100 ꢁC
(Table 1, entry 4). Increasing the amount of the catalyst, reaction time and
temperature did not improve the results (Table 1, entries 5, 6, and 10). A control
experiment was also done at 100 ꢁC in the absence of our catalyst, which did not
lead to noticeable product even after a long reaction time (Table 1, entry 1).
To investigate the effect of varying the solvent, the same reaction was carried out
in different solvents, including EtOH, CH3CN, THF, CHCl3, CH2Cl2, and H2O. As
shown in Table 2, it was found that the reaction in ethanol lead to the highest yield
compared to the other solvents. The non-occurrence of the reaction in other solvents
may be due to the poor solubility of the ionic liquid. In the case of H2O solvent,
[Pyridine-SO3H]HSO4 was soluble in water, but the starting materials were not.
Moreover, the catalyst hydrolyzes in the aqueous media.
After optimization of the reaction conditions, synthesis of a variety of
functionalized piperidines was performed to explore the efficiency and the scope
of the protocol. The corresponding results are depicted in Table 3. Various aromatic
aldehydes containing either electron-withdrawing or electron-donating substituents
successfully react with various anilines and ethyl acetoacetate to afford high to
excellent yields of products and short reaction times.
Table 1 The effect of different amounts of catalysts and temperature on the synthesis of 4ba
Entry
Catalyst amount
(mol %)
Temp. (ꢁC)
[Pyridine–SO3H]HSO4
[PyridineSO3H]Cl
Time (min)
Yieldb (%)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
a
–
5
100
100
100
100
100
100
70
480
36
36
36
36
36
36
36
36
36
Trace
36
480
54
54
54
54
54
54
54
54
54
Trace
25
10
15
20
25
15
15
15
15
71
53
93
80
93
79
91
77
62
45
80
75
63
90
80
70
110
79
71
Reaction conditions: 4-methylbenzaldehyde (2 mmol), aniline (2 mmol), and ethyl acetoacetate
(1 mmol)
b
Isolation yield
123

S. Mohammadi, M. Abbasi
Table 2 Synthesis of compound 4ba in the presence of [pyridine–SO3H]HSO4 (15 mol %) in different
solvents
Entry
Solvent
Temperature (ꢁC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
a
EtOH
78
82
180
260
480
420
460
600
36
78
CH3CN
THF
60
66
25
CHCl3
CH2Cl2
H2O
62
Trace
Trace
–
40
100
100
Solvent-free
93
Reaction conditions: 4-methylbenzaldehyde (2 mmol), aniline (2 mmol), ethyl acetoacetate (1 mmol),
[pyridine-SO3H]HSO4 (15 mol %)
b
Isolation yield
Table 3 Three-component reaction of various aldehyde, amines, and ethyl acetoacetate catalyzed by
[Pyridine-SO3H]HSO4 for one-pot synthesis of highly functionalized tetrahydropyridine
Entry
R1
R2
Product
Time (min)
Yielda (%)
Mp (ꢁC)
Lit. Mp (ꢁC) [ref]
1
4-Cl
4-Me
4-Me
4-OMe
4-Me
4-NO2
H
4-Me
H
4a
4b
4c
4d
4e
4f
39
36
43
35
39
46
34
41
36
38
41
36
35
49
42
46
42
45
41
92
93
94
90
86
88
91
84
89
92
88
93
92
89
94
87
90
89
87
231–232
230–232
226–227
176–177
219–220
249–251
194–195
178–179
237–239
198–199
159–160
199–201
169–171
183–185
185
227–229 [14]
230–231 [16]
221–224 [16]
180–181 [14]
218–220 [15]
247–250 [16]
193–196 [15]
175–176 [16]
234–236 [15]
193–196 [15]
155–157 [15]
201–202 [16]
172–173 [16]
183–185 [30]
184–186 [29]
170–172 [30]
205–207 [29]
142–140 [29]
…………
2
3
4-OMe
4-Cl
4-Cl
H
4
5
6
7
4-Br
H
4g
4h
4i
8
H
9
4-Me
H
4-Br
4-Me
H
10
11
12
13
14
15
16
17
18
19
a
4j
3-Me
H
4k
4l
4-Cl
4-OMe
3-Br
4-Br
3-I
H
4m
4n
4o
4p
4q
4r
4-Cl
4-OMe
H
171–173
208–209
137–140
189–190
4-Me
4-NO2
4-Cl
3-I
3-I
3-I
4s
Isolation yield
The structures of products (4a-r) were identified by comparison of their
spectroscopic data and melting points with those of literature reports. Also, the
structure of products (4n-s) was confirmed by elemental analysis and spectral data
1
(FT-IR, H NMR, 13C NMR, mass spectroscopy).
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
Our proposal for the condensation is shown in Scheme 3 [5, 12, 16]. Initially, the
dehydration arylamine (1) and ethyl acetoacetate (2) gives the b-enaminone (5) in
the presence of sulfonic acid pyridinium hydrogen sulfate, which also happens
between aryl-aldehyde (3) and arylamine (1) to form imine (6). Next, the reaction
between b-enaminone (5) and activated imine (6) in the presence of sulfonic acid
pyridinium hydrogen sulfate as a Lewis acid via intermolecular Mannich reaction
affords the intermediate (7). The reaction of the intermediate (7) with the second
aryl-aldehyde produces another intermediate (8) by the loss of water. Intermediate
Scheme 3 Possible reaction mechanism for the piperidines condensation 4
123

S. Mohammadi, M. Abbasi
Table 4 Comparison of the results of the condensation of benzaldehyde, ethyl acetoacetate and
4-chloroaniline in the presence of [Pyridine–SO3H][HSO4] with those obtained using other catalysts
Entry
Catalyst
Conditions
Time (h)
Yielda (%)
TOFb (h-1
)
Ref
1
2
3
4
5
6
7
8
9
10
a
CAN
CH3CN, r.t
EtOH, reflux
MeOH, r.t
23
78
80
78
85
80
70
71
80
81
93
0.129
0.666
0.975
0.425
0.666
0.777
0.591
0.666
0.450
10.333
[16]
[12]
[20]
[19]
[15]
[5]
[Hpyro][HSO4]
I2
8
8
Al(H2PO4)3
Ph3CCl
EtOH, r.t
10
MeOH, 50 ꢁC
EtOH, r.t
5.5
9
TBATB
BF3.SiO2
MeOH, 65 ꢁC
EtOH, r.t
8
[18]
[14]
[17]
Bi(NO3)3ꢀ5H2O
Ni(ClO4)2.6H2O
[Py–SO3H]HSO4
12
EtOH, r.t
18
c
Solvent-free, 100 ꢁC
36 min
–
Isolated yield
b
c
Turn-over frequency
This work
100
90
80
70
60
50
40
30
20
10
0
Time (min)
Yield (%)
1
2
3
4
5
Time (min)
Yield (%)
36
36
38
39
41
93
91
91
90
89
Run
Fig. 5 The condensation of 4-methylbenzaldehyde with aniline and ethyl acetoacetate in the presence of
reused [pyridine-SO3H]HSO4 (15 mol %) under solvent-free conditions at 100 ꢁC
(8) tautomerizes to (9), which is stabilized by intramolecular hydrogen bonding.
Then, intramolecular Mannich-type reaction forms the intermediate (10). Finally,
due to conjugation with the ester group, the intermediate (10) tautomerizes to afford
the final product (4).
To show the merit of the present work, we compared the results of our catalyst
with some reported catalysts for the synthesis of functionalized tetrahydropyridine
123

Design of ionic liquid sulfonic acid pyridinium hydrogen sulfate
derivatives. The results of these catalysts, which perform the one-pot multicom-
ponent condensation of 4-methylbenzaldehyde, ethyl acetoacetate, and aniline have
been tabulated in Table 4. As is shown, our catalyst has remarkably improved this in
different aspects, for example reaction conditions, time, yield, and turn-over
frequency (TOF). The present catalyst exhibited higher yields of products in shorter
times, not requiring the use of organic solvents, and the TOFs were higher compared
to the other reported system. Additionally, the present catalyst is more beneficial
from economical and accessibility points of view and is stable both in air and water.
Reusability is one of the important properties of this catalyst. The recyclability of
[Py–SO3H][HSO4] was investigated for the reaction upon the condensation of
4-methyl benzaldehyde, ethyl acetoacetate, and anilines. After completion of the
reaction, the reaction mixture was extracted by the warm EtOAc and separated from
the catalyst. We observed that the catalyst could be reused for the next cycle without
any appreciable loss of its activity (Fig. 5).
Conclusions
In summary, we have developed a simple, inexpensive methodology comprising
ionic liquid [Pyridine–SO3H]HSO4, as a green, highly efficient and homogeneous
catalyst for the one-pot multicomponent condensation of aromatic aldehydes,
aromatic amines, and ethyl acetoacetate for the synthesis of functionalized
piperidines. The present methodology offers several advantages, including short
reaction time, high yields, easy work-up procedures, mild reaction conditions,
avoiding hazardous organic solvents, as well as being reusable several times without
noticeably decreasing the catalytic activity.
Acknowledgments The authors acknowledge Islamic Azad University of Lamerd for support of this
work.
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