Piperidinium Hydrogen Sulfate (PHS) as an Efficient Ionic Liquid Catalyst for the Synthesis of Imidazole Derivative under Solvent-Free Condition

Article abstract of DOI:10.1002/jhet.3525

Piperidinium hydrogen sulfate is used as a very important new catalyst for the synthesis of the biologically active compounds from a series of multi-substituted imidazole components by the simple reaction of benzyl with different aromatic aldehydes, ammonium acetate, and phenethylamine or butylamine as amine derivatives. The key merits of this method are very shorter reaction times, excellent yield, and ease of stabilization. Furthermore, the produced products can be purified by a non-chromatographic technique, and the catalyst is reusable. All of these new synthesized components have been characterized and checked from spectral data: IR, ¹H-NMR, and ¹³C-NMR spectra and elemental analyses.

Full text of DOI:10.1002/jhet.3525

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Month 2019 Piperidinium Hydrogen Sulfate (PHS) as an Efficient Ionic Liquid Catalyst
for the Synthesis of Imidazole Derivative under Solvent-Free Condition
a
b
c
*
Mustafa R. Albayati, Adel. A. Marzouk, and Antar A. Abdelhamid
aCollege of Education, Department of Chemistry, Kirkuk University, Kirkuk, Iraq
bPharmaceutical Chemistry Department, Faculty of Pharmacy, Al Azhar University, Cairo, Egypt
cDepartment of Chemistry, Faculty of Science, Sohag University, 82524 Sohag, Egypt
*E-mail: drantar25@yahoo.com
Received October 22, 2018
DOI 10.1002/jhet.3525
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Piperidinium hydrogen sulfate is used as a very important new catalyst for the synthesis of the biologi-
cally active compounds from a series of multi-substituted imidazole components by the simple reaction of
benzyl with different aromatic aldehydes, ammonium acetate, and phenethylamine or butylamine as amine
derivatives. The key merits of this method are very shorter reaction times, excellent yield, and ease of stabi-
lization. Furthermore, the produced products can be purified by a non-chromatographic technique, and the
catalyst is reusable. All of these new synthesized components have been characterized and checked from
1
spectral data: IR, H-NMR, and 13C-NMR spectra and elemental analyses.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
organic chemistry owing to their various uses in
convergent preparation of the organometallic complex
molecules from readily and simple available substrates in
a single vessel [10,11]. In this work, we are developing
the one-step construction of an important series of
imidazoles compounds by the reaction of benzil with
different aldehydes and ammonium acetate using
piperidinium hydrogen sulfate (PHS) as an efficient ionic
liquid catalyst. The reaction proceeded in a very short
time (10–25 min). The process illustrates significant
existing methods of imidazole synthesis. The most
important advantage of this protocol is that the ionic
liquid catalyst can be removed by being dissolved in
distilled water and by filtration and then reused again by
evaporating the water and washing with acetone. In
addition, the product of the reaction will be precipitated
with excellent purity.
Imidazoles are very significant scaffolds in numerous
biologically active components. Imidazole nucleus is
often used as a building block in the development of new
drugs [1,2]. They are a target for different bioactive
molecules showing anti-cancer, antibacterial, anti-
inflammatory, antiprotozoal, antihypertensive, and
antifungal activity. Imidazoles can be found in many
natural and artificial substances, which have variable
biological activities and are applicable in medicinal
chemistry. Additionally, imidazoles are used in material
science, catalysis, and the preparation of ionic liquids.
Numerous methods for the synthesis of imidazoles have
been designed, and several pertinent reviews have been
published [3–6]. Moreover, a photochemical one-pot
four-component synthesis of tetrasubstituted imidazole
derivatives has been reported [7–9].
Multicomponent reactions are a characteristic type of
synthetic organic methods in which complex compounds
are formed from the reaction of three or more simple
starting materials in one pot. This type of reactions has
advantages of smooth operation, atom economy,
structural diversity, and complexity of the molecules
that can be prepared in these reactions. Moreover,
multicomponent reactions have a high importance in
RESULTS AND DISCUSSION
Based on the corresponding literature review, it has been
found that 1,2,4,5-tetrasubstituted imidazoles have high
biological activity and pharmaceutical application. So it
was decided to study the ability of the PHS for synthesis
of multi-substituted 1,2,4,5-tetrasubstituted imidazoles
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M. R. Albayati, A. A. Marzouk, and A. A. Abdelhamid
Vol 000
Table 1
5a–t in an excellent yield, simple with expeditious and
environmentally friendly method. The reaction steps
include refluxing of benzil 1 with aromatic aldehyde
2a–k, ammonium acetate 3, and butylamine 4a or
phenethylamine 4b by adding the ionic liquid PHS as a
catalyst. The reaction was found to be more facile under
solvent-free conditions (Scheme 1, Table 1). All the new
compounds were investigated with the IR and NMR
analyses.
Piperidinium hydrogen sulfate as catalyst for the synthesis of multi-
substituted imidazoles 5a–t.
Time
(min)
Yield
(%)
Comp no.
X
Mp (°C)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
4-Cl
4-OCH3
2,6-Cl2
111–113
102–103
135–137
123–125
127–129
124–125
151–152
132–135
108–110
107–109
131–135
142–145
109–111
141–143
129–130
124–125
135–136
103–105
126–128
140–142
10
12
13
14
15
15
14
14
15
24
23
20
18
25
19
17
16
21
17
21
89
91
92
94
91
94
95
85
84
89
92
92
84
93
89
92
95
89
90
93
4-CH3O,3-OH
4-(CH3)2N
4-NO2
4-Br
3,4-(CH3O)2
3-CH3O,4-OH
4-F
5j
5k
5l
4-Cl
4-OCH3
2,6-Cl2
5m
5n
5o
5p
5q
5r
5s
5t
3-CH3O,4-OH
4-(CH3)2N
4-NO2
The possible reaction mechanism of formation 1,2,4,5-
tetrasubstituted imidazoles via formation of hydrogen
bond between the carbonyl group of the used aromatic
aldehyde and the ionic liquid catalyst PHS creates the
carbonyl very predisposed to nucleophilic attack by an
ammonia produced from the ammonium acetate as starting
component. The produced intermediate willingly loses a
H2O molecule to give the romantic aldehyde imine I
(Scheme 2). In the same way, the catalyst encourages an
additional condensation reaction of one of the carbonyl
4-Br
3,4-(CH3O)2
4-CH3O,3-OH
groups from benzil with phenethylamine or butylamine
reactant to produce the iminobenzil II. PHS also catalyzes
nucleophilic attack by the imine I on another carbonyl
group in imine II followed by protonation to form the
Scheme 1. Synthesis of 1,2,4,5-tetrasubstituted imidazoles 5a–t.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Month 2019
Ionic Liquid Catalyst for the Synthesis of Imidazoles
Scheme 2. The possible mechanism of synthesized multi-substituted imidazoles 5a–r.
intermediate cation III. This in turn undertakes an
intramolecular cyclization to furnish the unstable cyclic
cation IV, which eradicates water and then loses a proton
to produce the objective products 5a–t. All of the products
were investigated by spectroscopic methods such as IR,
1H-NMR, and 13C-NMR.
2800 cmÀ1 vibrations of the aliphatic chain of CH2CH2
1
and 1610–1595 cmÀ1 correspond to the C═N group. H-
NMR spectrum of compound 5l–t showed significant two
triplet signals at 2.50 ppm, which belong to (Ph–CH2–
CH2–N) and significant signals at 4.00, which belong to
(Ph–CH2–CH2–N). In addition, multiplet signals at 6.60
to 8.00 corresponding to aromatic moiety were found.
13C-NMR of 5l–t showed two significant signals at 36.00
and 46.00, which belong to the carbon atoms of
Ph–CH2–CH2–N. All the carbon atoms of the aromatic
moiety appeared around 120–160.
All compounds 5a–k are colorless crystalline solids, and
their infrared spectra contained bands of 3050–3000
corresponding to three phenyl groups, 2999–2800 cmÀ1
vibrations of the aliphatic chain of (N–CH2–CH2–CH2–
CH3), while a strong band appeared in the region of C═N
1
bond vibration (1591–1610 cmÀ1). H-NMR spectra of
compound 5a–k showed a significant triplet signal at
3.9 ppm, which belongs to (CH3–CH2–CH2–CH2–N),
and two significant multiplet signals at 1.3 and 1.00 ppm
of (CH3–CH2–CH2–CH2–N). In addition, a triplet signal
at 0.50 corresponding to (CH3–CH2–CH2–CH2–N) group
of butyl moiety appeared. Also, an aromatic nucleus
appeared around 6.8 to 8.8 in multiplet signals. 13C-NMR
of 5a–k showed significant signals around 13.00 of
(CH3–CH2–CH2–CH2–N) and three characteristic
significant signals around 19.00, 32.000, and 44.000,
which belong to the carbon atoms of three CH2 groups
(CH3–CH2–CH2–CH2–N). All the carbon atoms of the
aromatic moiety appeared around 110–165.
CONCLUSIONS
In this study, we developed a safe method for
the synthesis of two series of new multi-substituted
imidazole derivatives using one-pot four-component
cyclocondensation reaction via the combination of benzil,
ammonium acetate, phenethylamine, or butylamine with
different aromatic aldehydes. This protocol has some
advantages of excellent yields, highly pure products,
simplicity of operation and easy work-up, enhanced rapid
reaction rates, and short reaction times. In this method,
we used a new ionic liquid as a novel catalyst for
synthesis of multi-substituted imidazoles under solvent-
free condition. All these new compounds have been
characterized by spectral data and are expected to be
effective pharmaceutical drugs.
Other derivatives of imidazoles that have (Ph–CH2–
CH2–) 5l–t are colorless crystalline solids with their
infrared spectra containing bands of 3060–3000
corresponding to the four phenyl groups; 2999–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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M. R. Albayati, A. A. Marzouk, and A. A. Abdelhamid
Vol 000
EXPERIMENTAL
3H, CH3–CH2–CH2–CH2N), 0.87–0.91 (m, 2H, CH3–
CH2–CH2–CH2–N), 1.25–1.29 (m, 2H, CH3–CH2–CH2–
CH2–N), 3.97–4.00 (t, 2H, CH3–CH2–CH2–CH2–N),
7.01–7.71 (m, 14H, Ar–H); 13C-NMR (400 MHz, CDCl3/
D2O): 13.25, 19.51, 32.37, 45.24, 117.48, 126.35,
127.91, 128.45, 129.11, 129.88, 129.85, 131.11, 131.26,
135.00, 148.15 ppm. Anal. Calcd for C25H23ClN2:
C, 77.61; H, 5.99; N, 7.24. Found: C, 77.60; H, 5.97;
All reagents are commercially available and were
purchased from Merck, Aldrich, and Fluka. All reactions
were checked by thin-layer chromatography using
percolated plates of silica gel G/UV-254 of 0.25-mm
thickness (Merck 60F254) using UV light (254 nm/
365 nm) for visualization. Melting points were measured
with a Kofler melting point apparatus and uncorrected. IR
spectra were recorded with an FTIR Alpha Bruker
Platinum ATR. 1H-NMR and 13C-NMR spectra were
recorded in DMSO-d6 or CDCl3 on a Bruker Bio Spin
AG spectrometer at 400 and 100 MHz, respectively.
Elemental analyses were obtained on a Perkin-Elmer
CHN-analyzer model.
N, 7.22.
2-(4-Methoxyphenyl)-4,5-diphenyl-1-butyl-1H-imidazole
(5c). Mp 135–137°C, yield = 92%, FTIR (KBr, cmÀ1):
3041 (C–H), 2975 (C–H), 2959, 2924, 1601 (C═N) 1529
(C═C), 1481, 1423, 1334, 1230, 1134, 1074, 849, 821,
1
774, 697; H-NMR (CHCl3/D2O, 400 MHz): 0.50–0.54
(t, 3H, CH3–CH2–CH2–CH2N), 0.88–0.90 (m, 2H, CH3–
CH2–CH2–CH2–N), 1.21–1.24 (m, 2H, CH3–CH2–CH2–
CH2–N), 3.76 (s, 3H, CH3–O), 3.76–3.83 (t, 2H, CH3–
CH2–CH2–CH2–N), 6.93–7.6 (m, 14H, Ar–H); 13C-NMR
(400 MHz, CDCl3/D2O): 13.28, 19.50, 32.37, 45.27,
55.57,114.42, 126.78, 127.17, 128.14, 129.00, 129.18,
129.43, 131.13, 131.26, 135.96, 147.04 ppm. Anal. Calcd
for C26H26N2O: C, 81.64; H, 6.84; N, 7.32. Found: C,
General procedure for the synthesis of the ionic liquid
(piperidinium hydrogen sulfate).
Piperidine (34.06 g,
0.40 mol) was added to a 150-mL three-necked flask with
a magnetic stirrer. Then concentrated sulfuric acid (98%)
(39.23 g, 0.40 mol) was added dropwise slowly. The
reaction mixture was then stirred at 100°C for 20 h,
washed with diethyl ether three times to remove nonionic
residues, and dried in vacuum on a rotary evaporator to
yield PHS as a clear brownish viscous liquid with yield
of 95% [12,13].
81.61; H, 6.81; N, 7.32.
2-(2,6-Dichlorophenyl)-4,5-diphenyl-1-butyl-1H-imidazole
(5d). Mp 123–125°C, yield = 94%, FTIR (KBr, cmÀ1):
3045 (C–H), 2961 (C–H), 2929, 2864, 1603 (C═N) 1520
(C═C), 1483, 1337, 1023, 969, 937, 841, 772, 691, 565;
1H-NMR (CDCl3/D2O, 400 MHz): 0.51–0.54 (t, 3H,
CH3–CH2–CH2–CH2N), 0.87–0.90 (m, 2H, CH3–
CH2–CH2–CH2–N), 1.20–1.23 (m, 2H, CH3–CH2–CH2–
CH2–N), 3.78–3.86 (t, 2H, CH3–CH2–CH2–CH2–N),
6.90–7.6 (m, 13H, Ar–H); 13C-NMR (400 MHz, CDCl3/
D2O): 13.15, 19.18, 32.89, 45.27, 114.45, 126.14,
127.33, 128.27, 129.47, 129.76, 129.91, 131.45, 131.95,
135.17, 145.14, 146.18 ppm. Anal. Calcd for
C25H22Cl2N2: C, 71.26; H, 5.26; N, 6.65. Found: C,
General procedure for the synthesis of tetrasubstituted
imidazole derivatives 5a–n.
In a 50-mL rounded flask
with a magnetic stirrer, add benzil (4.20 g, 0.02 mol), an
equivalent amount of the aromatic aldehyde (0.02 mol),
ammonium acetate (1.54 g, 0.02 mol), amine (0.02 mol),
and PHS catalyst (1.21 g, 0.007 mol). The mixture was
refluxed in an oil bath with stirring at 100°C for 10–25
min, following up the reaction with thin-layer
chromatography till reaction completed. The reaction
mixture was poured on an iced water, and the resulting
precipitate was filtered off, washed with water, and dried.
The crude product was crystallized from ethanol.
71.23; H, 5.24; N, 6.54.
2-(3-Hydroxy-4-methoxyphenyl)-4,5-diphenyl-1-butyl-1H-
imidazole (5e). Mp 127–129°C, yield = 91%, FTIR (KBr,
1-Butyl-2,4,5-triphenyl-1H-imidazole (5a).
Mp 111–
113°C, yield = 89%, FTIR (KBr, cmÀ1): 3045, 3033
cmÀ1): 3250 (OH), 3061 (C–H) aromatic, 2941–2725 (C–
H) aliphatic, 1601 (C═N); 1H-NMR (CHCl3/D2O,
400 MHz): 0.48–0.52 (t, 3H, CH3–CH2–CH2–CH2N),
0.84–0.89 (m, 2H, CH3–CH2–CH2–CH2–N), 1.19–1.23
(m, 2H, CH3–CH2–CH2–CH2–N), 3.66 (s, 3H, CH3–O),
3.87–3.91 (t, 2H, CH3–CH2–CH2–CH2–N), 6.67–7.47
(m, 13H, Ar–H + 1H, ArOH); 13C-NMR (400 MHz,
CDCl3/D2O): 13.23, 19.48, 32.45, 44.71, 56.13, 112.65,
114.67, 122.11, 126.45, 127.01, 128.05, 128.76, 129.05,
129.39, 131.06, 147.00, 147.55 ppm. Anal. Calcd for
C26H26N2O2: C, 78.36; H, 6.58; N, 7.03. Found: C,
(C–H), 2924, 2911 (C–H), 2840, 1596 (C═N), 1550
1
(C═C); H-NMR (DMSO-d6/D2O, 400 MHz): 0.52–0.56
(t, 3H, CH3–CH2–CH2–CH2), 0.89–0.94 (m, 2H, CH3–
CH2–CH2–CH2), 1.24–1.27 (m, 3H, CH3–CH2CH2CH2),
3.84–3.87 (t, 2H, CH3–CH2CH2CH2), 6.93–7.54 (m,
15H, Ar–H); 13C-NMR (400 MHz, DMSO-d6): 13.46,
19.31, 32.12, 44.27, 115.87, 122.38, 126.38, 126.49,
128.44, 129.17, 129.55, 129.65, 130.62, 131.31, 131.79,
135.35, 147.58, 158.47 ppm. Anal. Calcd for C25H24N2:
C, 85.19; H, 6.86; N, 7.95. Found: C, 85.18; H, 6.84;
N, 7.93.
78.36; H, 6.57; N, 7.02.
2-(4-Chlorophenyl)-4,5-diphenyl-1-butyl-1H-imidazole
N,N-Dimethyl-4-(1-butyl-4,5-diphenyl-1H-imidazol-2-yl)
(5b). Mp 102–103°C, yield = 91%, FTIR (KBr, cmÀ1):
aniline (5f ).
Mp 124–125°C, yield = 94%, FTIR
(KBr, cmÀ1): 3010, 3001 (C–H) aromatic, 2996–2722
(C–H) aliphatic, 1602 (C═N); 1H-NMR (CHCl3/D2O,
3011 (C–H), 2953 (C–H), 2885, 1610 (C═N) 1541
(C═C); H-NMR (CHCl3/D2O, 400 MHz): 0.49–0.53 (t,
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet