Highly efficient, one-pot, solvent-free synthesis of 2,4,6-triarylpyridines using a bronsted-acidic ionic liquid as reusable catalyst

Article abstract of DOI:10.1007/s00706-010-0329-x

A simple, efficient, and green method for synthesis of 2,4,6- triarylpyridines by one-pot three-component reaction of acetophenones, aryl aldehydes, and ammonium acetate using 3-methyl-1-(4-sulfonylbutyl)imidazolium hydrogen sulfate [HO₃S(CH₂)₄MIM][HSO ₄], a Bronstedacidic ionic liquid, as an effective and reusable catalyst under solvent-free conditions is described. This method has several advantages, for example simple procedure with an easy work-up, shorter reaction times, and high yields. Springer-Verlag 2010.

Full text of DOI:10.1007/s00706-010-0329-x

Monatsh Chem (2010) 141:867–870
DOI 10.1007/s00706-010-0329-x
ORIGINAL PAPER
Highly efficient, one-pot, solvent-free synthesis of 2,4,6-
triarylpyridines using a Brønsted-acidic ionic liquid
as reusable catalyst
•
Abolghasem Davoodnia Mehdi Bakavoli
•
•
•
Raheleh Moloudi Niloofar Tavakoli-Hoseini
Maryam Khashi
Received: 2 February 2010 / Accepted: 11 May 2010 / Published online: 3 June 2010
Ó Springer-Verlag 2010
Abstract A simple, efficient, and green method for syn-
thesis of 2,4,6-triarylpyridines by one-pot three-component
reaction of acetophenones, aryl aldehydes, and ammonium
acetate using 3-methyl-1-(4-sulfonylbutyl)imidazolium
hydrogen sulfate [HO3S(CH2)4MIM][HSO4], a Brønsted-
acidic ionic liquid, as an effective and reusable catalyst
under solvent-free conditions is described. This method has
several advantages, for example simple procedure with an
easy work-up, shorter reaction times, and high yields.
The presence of the pyridine ring system in a number
of natural products, vitamins, and pharmacologically signifi-
cant molecules [4] has made it a prime target for scientific
research. Literature reports have already established pyri-
dines as antimalarials, vasodilators, anesthetics, anticovul-
sants, antiepileptics, and agrochemicals such as fungicides,
pesticides, and herbicides [5–8]. Also, because of their
p-stacking ability, some pyridines are used in supramolecular
chemistry [9].
¨
2,4,6-Triarylpyridines (Krohnke pyridines) are structur-
Keywords Brønsted-acidic ionic liquids ꢀ
Multi-component reactions ꢀ 2,4,6-Triarylpyridines ꢀ
Solvent-free conditions
ally related to symmetrical triaryl-thiopyrylium, triaryl-
selenopyrylium, and triaryl-telluropyrylium photosensitizers,
which have been recommended for photodynamic cell-
specific cancer therapy [10]. These compounds have
already been synthesized by reaction of N-phenacylpyrid-
inium salts with a,b-unsaturated ketones in the presence of
ammonium acetate [11, 12]. However, the pyridinium salts
and the unsaturated ketones have to be synthesized first, so
this method is relatively expensive. More recently, several
new improved methods and procedures for preparation of
2,4,6-triarylpyridines have been reported, for example
reaction of a-ketoketene dithioacetals with methyl ketones
in the presence of NH4OAc [13], reaction of N-phosph-
inylethanimines with aldehydes [14], solvent-free reaction
of chalcones with ammonium acetate [15], solvent-free
reaction between acetophenones, benzaldehydes, and
NH4OAc in the presence of various catalysts, for example
Preyssler type heteropolyacid [16], HClO4-SiO2 [17], and
I2 [18], and the one-pot reaction of acetophenones, benz-
aldehydes, and NH4OAc without catalyst under microwave
irradiation [19].
Introduction
Multicomponent reactions (MCRs) have recently received
the attention of organic chemists because of the many
advantages these reactions over conventional multi-step
synthesis and their potential applications in medicinal
chemistry for generation of diverse scaffolds and combi-
natorial libraries for drug development [1–3]. MCRs
contribute to the requirements of an environmentally
friendly process by reducing the number of synthetic steps,
energy consumption, and waste production. Therefore,
discovery for new MCRs and improving already known
MCRs are of substantial interest.
A. Davoodnia (&) ꢀ M. Bakavoli ꢀ R. Moloudi ꢀ
N. Tavakoli-Hoseini ꢀ M. Khashi
Ionic liquids (ILs) are salt-type compounds which are
liquid at room temperature and have low vapor pressure.
Because of the lack of evaporation, they are regarded as
promising ‘‘green solvents’’ for replacing the volatile––
Department of Chemistry, Faculty of Sciences,
Islamic Azad University, Mashhad Branch, Mashhad, Iran
e-mail: adavoodnia@yahoo.com; adavoodnia@mshdiau.ac.ir
123

868
A. Davoodnia et al.
therefore flammable and harmful––conventional solvents.
ILs are also known as environmentally benign catalysts and
much attention has currently been focused on organic
reactions in the presence of these compounds as catalysts
or solvents [20–23]. The introduction of Brønsted-acidic
functional groups into the cations or anions of the ILs,
especially SO3H functional groups, obviously enhanced
their acidities and water solubilities [24–26]. Therefore,
Brønsted-acidic ILs can be used as highly efficient acid
catalysts and have been attracting extensive interest as
green substitute for H2SO4, HF, and AlCl3 catalysts in
chemical processes [27]. In fact, use of Brønsted-acidic
ILs as catalysts is an area of ongoing activity; however,
development and exploration of Brønsted-acidic ILs are
currently in a preliminary stage. To the best of our
knowledge, there are no examples of the use of Brønsted-
acidic ILs as catalysts for synthesis of 2,4,6-triaryl-
pyridines.
model reaction. Therefore, a mixture of acetophenone
(2 mmol), benzaldehyde (1 mmol), and NH4OAc (1.3 mmol)
was heated under various reaction conditions. The effi-
ciency of the reaction is mainly affected by the amount
of the catalyst (Table 1). In the absence of the catalyst,
4a was obtained in a trace amount after 4 h (entry 1),
whereas good results were obtained in the presence of
[HO3S(CH2)4MIM][HSO4] (entries 2–6). The optimum
amount of [HO3S(CH2)4MIM][HSO4] was 20 mol% (entry
5), a higher amount of the catalyst did not increase the
yield noticeably (entry 6).
Also, the reaction was carried out in various solvents
and under solvent-free conditions (Table 2). As shown in
Table 2, in comparison with conventional methods the
yields of the reaction under solvent-free conditions are
higher and the reaction time is shorter.
The effect of temperature was investigated by carrying
out the same model reaction at different temperatures under
solvent-free conditions. The yield increased as the reaction
temperature was raised and at 120 °C the product was
obtained in high yield. Higher temperatures did not
increase the yield noticeably (Table 3).
Because of the important pharmacological activity of
¨
the Krohnke pyridines, and in line with our research pro-
gram on synthesis of heterocycles [28–31] and using
Brønsted-acidic ILs as novel catalysts in organic reactions
[32–34], herein we would like to report an efficient pro-
cedure for preparation of 2,4,6-triarylpyridines by a one-
pot three-component reaction including acetophenones,
aryl aldehydes, and NH4OAc in the presence of 3-methyl-
1-(4-sulfonylbutyl)imidazolium hydrogen sulfate [HO3S(-
CH2)4MIM][HSO4] (Fig. 1), a Brønsted-acidic IL, under
solvent-free conditions (Scheme 1).
To evaluate the generality of this model reaction we
then prepared a range of 2,4,6-triarylpyridines under the
optimized reaction conditions. In all cases, aromatic alde-
hydes with substituents carrying either electron-donating or
electron-withdrawing groups reacted successfully and gave
the products in high yields. It was found that aromatic
aldehydes with electron-withdrawing groups reacted faster
than those with electron-donating groups, as would be
expected. The results are shown in Table 4.
Results and discussion
Reusability of the catalyst was also investigated. For this
purpose, the same model reaction was again studied under
the optimized conditions. After completion of the reaction,
the reaction mixture was cooled to room temperature and
then water was added. The precipitated solid was isolated
by filtration, the catalyst was recovered from the filtrate by
evaporation of the water, and reused for the similar reac-
tion. As shown in Fig. 2, the catalyst could be reused at
least three times with only slight reduction in catalytic
activity.
For our investigations, [HO3S(CH2)4MIM][HSO4] was
prepared according to the literature procedure [35]. Ini-
tially, in order to optimize the reaction conditions,
synthesis of 2,4,6-triphenylpyridine (4a) was used as a
SO3H
Me
N
N
In conclusion, we have developed a very simple and
efficient method for synthesis of 2,4,6-triarylpyridines
by one-pot three-component reaction of acetophenones,
aryl aldehydes, and NH4OAc in the presence of [HO3S-
(CH2)4MIM][HSO4], a Brønsted-acidic IL, as an efficient,
HSO4
[HO3S(CH2)4MIM][HSO4 ]
Fig. 1 Brønsted-acidic IL structure
Scheme 1
Ar'
O
O
[HO S(CH ) MIM][HSO ]
3
2 4
4
NH OAc
4
+
+
Ar
Ar'
H
Solvent-free at 120 °C
Ar
N
Ar
1
2
3
4a-4h
123

Synthesis of 2,4,6-triarylpyridines using a Brønsted-acidic ionic liquid
869
reusable, and eco-friendly homogeneous catalyst under
solvent-free conditions. The catalyst can be reused after
simple work-up, with a slight decline of its activity being
observed. Other advantages of this procedure are high
yields, short reaction times, easy work-up, and absence of
any volatile and hazardous organic solvents.
Table 1 Effect of the amount of [HO3S(CH2)4MIM][HSO4] on the
model reaction
Entry
Catalyst (mol%)
Time (h:min)
Yield (%)a
1
2
3
4
5
6
None
5
4:00
4:00
3:30
3:10
3:00
3:00
Trace
23
10
42
15
68
20
88
Experimental
25
89
All chemicals were commercially available and used
without further purification. The Brønsted-acidic ionic
liquid [HO3S(CH2)4MIM][HSO4] was synthesized accord-
ing to Ref. [35]. Melting points were recorded on an
Electrothermal type 9100 melting point apparatus. The IR
spectra were obtained on a 4300 Shimadzu spectropho-
2 mmol acetophenone, 1 mmol benzaldehyde, and 1.3 mmol
NH4OAc at 120 °C
a
Isolated yields
Table 2 Synthesis of 2,4,6-triphenylpyridine 4a in the presence of
[HO3S(CH2)4MIM][HSO4] (20 mol%) in different solvents
1
Entry Solvent
Temperature (°C) Time (h:min) Yield (%)a
tometer as KBr disks. The H NMR spectra (500 MHz)
were recorded on a Bruker DRX500 spectrometer.
1
2
3
4
5
a
EtOH
78
81
40
61
5:00
4:00
3:30
4:00
3:00
Trace
60
CH3CN
CH2Cl2
CHCl3
General procedure for synthesis of 2,4,
6-triarylpyridines 4a–4h
55
36
Solvent-free 120
Isolated yields
88
A mixture of 2 mmol acetophenone derivative 1, 1 mmol
aryl aldehyde 2, 100 mg NH4OAc (1.3 mmol), and 63 mg
[HO3S(CH2)4MIM][HSO4] (0.2 mmol, 20 mol% based on
aryl aldehyde) was heated on the oil bath at 120 °C for the
time indicated. The progress of the reaction was monitored
by TLC. After completion of the reaction, the reaction
mixture was cooled to room temperature and water was
added. The precipitated solid was isolated by filtration,
washed with water, and recrystallized from n-hexane to
give pure products 4a–4h. The structures of the products
were confirmed by 1H NMR and IR spectroscopy, and
comparison with authentic samples prepared by reported
methods [15–18].
Table 3 Synthesis of 2,4,6-triphenylpyridine 4a in the presence of
[HO3S(CH2)4MIM][HSO4] (20 mol%) at different temperatures
under solvent-free conditions
Entry
Temperature (°C)
Time (h:min)
Yield (%)a
1
2
3
4
a
50
100
120
150
5:00
4:00
3:00
3:30
Trace
62
88
89
Isolated yields
Table 4 Synthesis of 2,4,6-triphenylpyridines 4a–4h
Entry
Ar
Ar0
Productsa
Time (h:min)
Yieldb (%)
M.p. (°C)
Found
Reported
1
2
3
4
5
6
7
8
a
C6H5
C6H5
4a
4b
4c
4d
4e
4f
3:00
2:30
2:00
3:20
3:10
3:40
3:20
1:30
88
91
93
84
87
82
89
86
136–137
125–127
198–200
122–124
124–125
193–195
99–101
134–135 [15]
124–126 [18]
195–196 [18]
120–122 [15]
123–124 [15]
197 [16]
C6H5
4-ClC6H4
4-O2NC6H4
2-MeC6H4
4-MeC6H4
4-HOC6H4
4-MeOC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4g
4h
98 [16]
4-BrC6H4
103–105
101–102 [17]
All products were characterized by use of 1H NMR and IR spectral data, and comparison of their melting points with those of authentic
samples
b
Isolated yields
123

870
A. Davoodnia et al.
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80
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88
86
83
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