International Journal of ChemTech Research
CODEN (USA): IJCRGG
ISSN: 0974-4290
Vol.2, No.1, pp 289-294,
Jan-Mar 2010
Ionic Liquid Mediated One Pot Synthesis of
Substituted 2,4,6-Triarylpyridines
Pravin G. Ingole, Sumit V. Jadhav and Hari C. Bajaj*
Discipline of Inorganic Material and Catalysis,
Central Salt and Marine Chemicals Research Institute,
Council of Scientific and Industrial Research (CSIR) G.B.Marg, Bhavnagar-364002,
Gujarat-India
*Corres. Author: ingolepravin@gmail.com
Tel: +91-278-2567760,Fax: +91-278-2567562
Abstract: A novel system for the synthesis of series of 2,4,6-triarylpyridines and their hydroxyl substituted analogues
using cheap and easy to synthesize ionic liquid, Ethyl ammonium nitrate (EAN) as a benign reaction medium is
demonstrated. The reaction of acetophenone or p-hydroxyacetophenone with aryl aldehydes in EAN, in the presence of
base, followed by treatment with ammonium acetate affords title compounds in significant yields using a 'one pot'
procedure. A sequential Aldol condensation and Michael addition reactions in ionic liquid, yields 1,5-diones, which can
be readily converted to expected triarylpyridines, via ring closure with ammonium acetate. The significance of our
findings relates to reducing the use of volatile organic solvents, simplicity of the process, as well as its good yields, mild
conditions and low costs.
Keywords: Triarylpyridine; Ionic liquid; Ethyl ammonium nitrate; Green chemistry.
Introduction
The N-heterocyclic compounds comprising Krohnke
type pyridines and other substituted pyridines such as
2,4,6-triarylpyridines are prominent synthons in
supramolecular chemistry, as a consequence of their πstacking ability along with directional H-bonding
capacity. Moreover this class of compound is
identified as very useful intermediate in the
development of molecules for pharmaceutical or
biological interest. Rich coordination properties of
these compounds have been greatly exploited for the
development of nanoscale metallosupramolecular
architectures [1]. Pyridines exhibit range of biological
activities as; antimalarial, anticonvulsant, anesthetic,
antioxidant, antibacterial and antiparasitic properties
[2,3]. In recent years these compounds are deeply
investigated as potential candidates for calcium
channel blockers and as antiviral agents [4]. Moreover,
pyridine derivatives have remarkable versatility in
synthetic organic chemistry as intermediates in the
preparation of natural products and as ligands to be
used in asymmetric synthesis [5]. Some analogues of
pyridines are also highlighted as useful intermediates
in the synthesis of pesticides, desiccants, surfactants
and so forth [6,7].
For the diverse range of potential applications, easy
access to differently functionalized Krohnke type
triarylpyridines on a large scale and high yields is a
prerequisite. Numbers of methods have been reported
for the synthesis of these compounds either involving
the condensation of 1, 5-diketones with formamideformic acid [8] or by other synthetic procedures such
as Chichibabin method [9,10]. Successful synthesis of
Krohnke type pyridines is also reported through the
reaction of N-phenacylpyridinium salts with α, βunsaturated ketones in the presence of ammonium
acetate [11] however, the pyridinium salts and the
unsaturated ketones have to be synthesized first,
turning this method
relatively expensive. More
recently many improved processes for synthesis of
Hari C. Bajaj et al /Int.J. ChemTech Res.2010,2(1)
Krohnke type pyridines have been established,
involving variety of precursors such as, α-ketoketene
dithioacetals [12], N-phosphinylethanimines [13] and
lithiated β-enaminophosphonates [14].
However, most of the established methodologies suffer
from several disadvantages, as multi-step procedures,
long reaction time, use of toxic reagents and volatile
organic compounds (VOC’s). As a consequence, for
the stringent and growing environmental regulations,
organic chemists are requested to develop
environmentally benign synthetic methods with
minimization of waste, a foremost requirement in
principles of green chemistry [15]. Among the
environment friendly approaches to synthesize
triarylpyridines; microwave assisted method using
polyethylene glycol (PEG) is been demonstrated by
Huang et al [16]. In a typical attempt to avoid solvent
media Heravia et al [17] have synthesized target
compounds in reasonable yields by using
heteropolyacids as a catalyst, whereas Wu et al [18]
have synthesized substituted triarylpyridines via
catalyst free Diels–alders reaction. To the date PEG
mediated synthesis of triarylpyridines via 1, 5-diketone
intermediate reported by Raston et al [19] is one of the
most prominent approach towards synthesis of
triarylpyridines, both in the context of green chemistry,
290
generality and simplicity of the procedure. In keeping
up with theme of green chemistry, we examined the
potential for using novel green reaction media for the
synthesis of triarylpyridines. One of the promising
approaches is to employ Ionic liquid (IL) media.
However, to the best of our knowledge, synthesis of
triarylpyridines in IL media has rarely been reported.
Herein, we have reported facile and clean synthesis of
series of substituted 2,4,6 triarylpyridines starting from
appropriate aromatic aldehydes and acetophenones
employing IL’s as reaction media. Ethyl ammonium
nitrate (EAN), a cheap and easy to synthesize IL was
chosen as solvent system and successfully employed to
synthesize target compounds under conventional
heating conditions.
Experimental
Materials
Acetophenone,
p-hydroxyacetophenone
and
corresponding aryl aldehydes were procured from
Sigma-Aldrich. Ethyl amine, nitric acid, ammonium
acetate, sodium hydroxide and common organic
solvents
were
obtained
from
S.D.fine
chemicals
Ltd. India. All
the
chemicals
were used as received, without further purification.
Scheme: Synthesis of triarylpyridines using IL solvent media
Hari C. Bajaj et al /Int.J. ChemTech Res.2010,2(1)
General
1
H and 13C NMR spectra were recorded on a Bruker
Avance-II spectrometer operating at 500 MHz and 125
MHz respectively, using DMSO-d6 as solvent and
TMS as an internal reference. GC-MS analyses were
performed on Shimadzu QP-2010 spectrometer.
Elemental analyses were determined by using a
Perkin-Elmer 2400 CHNS/O analyzer instrument.
Melting points were recorded with Metler-Toledo
melting point apparatus and are uncorrected.
Synthesis of EAN
EAN is synthesized via simple process reported
elsewhere [20]. Nitric acid (30%) was added dropwise
to an aqueous solution of ethyl amine, (70%, 50 ml)
under vigorous stirring maintaining the temperature
below 10°C, till the pH of the mixture reaches nearby
7.3, then addition was stopped and mixture further
stirred for 1 h. Most of the water from the mixture was
removed using rotary evaporator in a boiling water
bath at a pressure of 200 mm of Hg and final traces of
water were removed at 100°C in presence of high
vacuum of 1 mm Hg. The IL is obtained as viscous
colourless liquid and used as such for further
applications.
General Procedure for the Synthesis of 2,4,6Triarylpyridines
In a typical reaction, Acetophenone (2 mmol, 240 mg)
was added to a suspension of crushed NaOH (2 mmol,
80 mg) in EAN (3 cm3) at 80°C and stirred for few
minutes. Benzaldehyde (1mmol, 106 mg) was then
added along with ammonium acetate. (1.5 g, excess)
The reaction mixture was heated for 4 h at 110°C.
(Scheme 1) The progress of the reaction was
monitored by TLC. Upon completion of the reaction,
cold water was added to facilitate the precipitation of
product. If necessary some ethanol was added to
reaction mixture and further stirred for 30 minutes,
then solvent removed in vacuo and crude product was
subjected to column chromatography on silica gel.
Final product was collected in purified form with
recrystallization in hot acetone. (Yield 405 mg, 66%).
Characterized by 1H and 13C NMR spectroscopy.
Similar stoichiometric procedure and characterization
techniques were employed for other entries.
Results and Discussions
Synthesis of 2,4,6-triarylpyridines bearing various
functionalities, in simple one pot method is
demonstrated. Treatment of acetophenone or phydroxy acetophenone (2 mmol) with appropriately
substituted aromatic aldehydes (1 mmol) and
ammonium acetate (excess) in IL as reaction medium
afforded the triarylpyridines in single step reaction.
Initiation is done with generation of carbanion at the
acetophenone centre by treatment with strong base
291
such as sodium hydroxide, crushed within IL medium
by heating the reaction mixture at 80ºC. The reaction is
believed to proceed through previously reported 1, 5
dione intermediate. (See also ref. 19) Final ring closure
with insertion of nitrogen atom in the central pyridine
core is done with excess of ammonium acetate added.
This method to synthesize triarylpyridines is simple
and easy to operate, also applying the principles of
‘green chemistry’, notably the use of IL’s the results of
which are reported herein. IL’s are becoming
prominent, benign, alternative reaction medium in
synthetic chemistry as they have many fascinating
properties, with few of them are; no measurable vapor
pressure and hence can not emit VOC’s, nonflammability, high polarity, solubility for wide range
of materials including inorganic, organic and even
polymeric materials, with potential to be reused and
recycled.
To optimize the reaction temperature, a series of
reactions were carried out at temperatures ranging
from 100 to 150°C in an increment of 10°C each time.
The cleaner reaction conditions and better yields are
obtained at 110°C. Under these optimized reaction
conditions, we have synthesized a series of compounds
a-j in acceptable purity and yields. (Table 1). The
crude
product
was
subjected
to
column
chromatography on silica gel. Final product was
collected in purified form with recrystallization in hot
acetone. IL is water-soluble, thus goes to the aqueous
layer, which was distilled under vacuum using
rotavapor to remove water, living behind the IL. The
recovered EAN was recycled and reused several times
to carry out the same experiment (Table 2).
Conclusions
A new, convenient route for the synthesis of
substituted 2, 4, 6-triarylpyridines using IL has been
demonstrated. The ‘one pot’ base catalyzed reaction is
tolerant to various functionalities attached to the
aldehyde core, leading to the formation of libraries of
differently substituted triarylpyridine synthons for
wide range of potential applications. EAN has been
successfully employed as a benign reaction medium
proving its synthetic versatility over volatile organic
solvents. Good yields of products, accessible starting
compounds and relatively easy experimental procedure
feasible in single step is sufficient to attract green
chemists to open the new avenue in synthesis of
triarylpyridines in greener conditions.
a. δH (500 MHz, DMSO) 8.37 (d, 4H, Ar), 8.33 (s, 2H,
Pyr), 8.08 (m, 4H, Ar), 8.04 (d, 2H, Ar), 7.57 (m, 2H,
Ar), 7.53 (m, 2H, Ar), 7.29 (m, 1H, Ar). δC (125 MHz,
DMSO) 157.51, 150.59, 139.80, 138.73, 129.28,
128.35, 127.95, 126.84, 117.59. GCMS (EI): m/z (%)
307 (100) [M]+. Elemental analysis calcd.(%) for
C23H17N: C, 89.87; H, 5.57; N, 4.56; found C, 89.62;
H, 5.60; N, 4.43.
Hari C. Bajaj et al /Int.J. ChemTech Res.2010,2(1)
292
b. δH (500 MHz, DMSO) 8.25 (d, 4H, Ar), 8.24 (s, 2H,
Pyr), 8.08 (d, 2H, Ar), 8.01 (s, 1H, Ar), 7.99 (m, 4H,
Ar), 7.56 (m, 2H, Ar), 5.77 (s, 1H, OH), δC (125 MHz,
DMSO ) 156.56, 153.78, 152.61, 143.40, 142.74,
133.56, 133.14, 130.45, 128.95, 125.13, 125.11,
123.55, 118.61. GCMS (EI): m/z (%) 358 (100) [M]+.
Elemental analysis calcd.(%) for C23H16ClNO: C,
77.20; H, 4.51; N, 3.91; found C, 77.10; H, 4.75; N,
3.93.
c. δH (500 MHz, DMSO) 8.27 (d, 4H, Ar), 8.05 (s, 2H,
Pyr), 7.98 (s, 2H, Ar), 7.78 (s, 1H, Ar), 7.66 (m, 4H,
Ar), 7.56 (m, 2H, Ar). δC (125 MHz, DMSO) 158.35,
155.86, 147.05, 138.66, 133.75, 133.36, 129.40,
129.35, 129.22, 127.89, 126.79, 119.21. GCMS (EI):
m/z (%) 392 (100) [M]+. Elemental analysis calcd.(%)
for C23H15Cl2NO: C, 70.42; H, 3.85; N, 3.57; found C,
70.25; H, 3.76; N, 3.69.
d. δH (500 MHz, DMSO) 8.66 (d, 4H, Ar), 8.00 (s, 2H,
Pyr), 7.96 (m, 4H, Ar), 7.85 (d, 1H, Ar), 7.80 (m, 2H,
Ar), 7.79 (d, 1H, Ar), 7.67 (m, 1H, Ar), 6.31 (s, 1H,
OH). δC (125 MHz, DMSO) 153.78, 153.70, 133.65,
133.16, 130.43, 129.06, 128.99, 128.69, 128.65,
127.89, 124.00, 117.57, 114.91. GCMS (EI): m/z (%)
368 (100) [M]+. Elemental analysis calcd.(%) for
C23H16N2O3: C, 74.99; H, 4.38; N, 7.60; found C,
74.95; H, 4.30; N, 7.56.
e. δH (500 MHz, DMSO) 8.24 (s, 2H, Pyr), 8.14 (m,
4H, Ar), 7.97 (m, 2H, Ar), 7.56 (m, 2H, Ar), 7.37 (m,
1H, Ar), 7.11 (m, 4H, Ar), 5.65 (s, 2H, OH ). δC (125
MHz, DMSO) 156.50, 149.57, 138.70, 133.09, 129.27,
128.71, 127.34, 125.82, 122.01, 116.58. GCMS (EI):
m/z (%) 339 (100) [M]+. Elemental analysis calcd.(%)
for C23H17NO2: C, 81.40; H, 5.05; N, 4.13; found C,
81.52; H, 5.11; N, 4.06.
f. δH (500 MHz, DMSO) 8.30 (s, 2H, Pyr), 8.13 (m,
4H, Ar), 7.85 (m, 1H, Ar), 7.51 (m, 1H, Ar), 7.25 (m,
1H, Ar), 6.93 (m, 1H, Ar), 6.76 (d, 4H, Ar), 5.70 (s,
3H, OH). δC (125 MHz, DMSO ) 162.34, 154. 41,
136.27, 132.61, 131.39, 128.69, 119.20, 119.14,
118.63, 118.26, 117.82, 117.54, 116.02. GCMS (EI):
m/z (%) 355 (100) [M]+. Elemental analysis calcd.(%)
for C23H17NO3: C, 77.73; H, 4.82; N, 3.94; found C,
77.67; H, 4.78; N, 3.88.
Table 1: Structure yields and melting point of the synthesized triarylpyridines.
MP (°C)
Found
Reported
Time(h)
Yield(%)a
a
4
66
135
(137-138)10
b
5
52
112
--
c
4
54
165
--
6
69
122
--
e
5
59
151
--
f
5
76
109
--
g
6.5
80
116
(118-119)10
h
6
75
200
(202-203)13
i
5
82
199
(197)17
j
4.5
87
126
(129-130)13
Entry
Ar1
Ar2
d
Ar1: Aldehydes; Ar2: Acetophenone/p-hydroxyl acetophenone; aYields refer to isolated products.
Hari C. Bajaj et al /Int.J. ChemTech Res.2010,2(1)
293
Table 2: Recovery of ethylammonium nitrate [EtNH3] NO3 in the synthesis of 2, 4, 6triarylpyridines.
Yield (%) of [EtNH3]NO3
Entry
Recycle3
Recycle1
Recycle2
g
80
72
67
h
75
68
62
i
82
78
71
j
87
83
80
Acknowledgements
We gratefully acknowledge Council of Scientific and
Industrial Research (CSIR), New Delhi-India. We also
thank Analytical sciences discipline of the institute for
analysis facilities.
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