Microwave-assisted, solvent-free, three-component synthesis of 2,4,6-triarylpyridines from benign components

Article abstract of DOI:10.3184/174751912X13295721847185

2,4,6-Triarylpyridine derivatives were synthesised by the reaction of guanidine with an acetophenone and a chalcone. These reactions were carried out as economical one-pot reactions under green conditions: no catalyst and solvent free.

Full text of DOI:10.3184/174751912X13295721847185

138 RESEARCH PAPER
MARCH, 138–140
JOURNAL OF CHEMICAL RESEARCH 2012
Microwave-assisted, solvent-free, three-component synthesis of
2,4,6-triarylpyridines from benign components
Shahab Zomordbakhsha*, Hossein Anaraki-Ardakania, Mohsen Zeebb, Mahdi Sadeghib and
Manouchehr Mazraeh-Seffidc
aDepartment of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
bAgricultural, Medical and Industrial Research School, Nuclear Science andTechnology Research Institute, PO Box 31485/498, Karaj,
Iran PO Box 31485/498, Karaj, Iran
cDepartment of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
2,4,6-Triarylpyridine derivatives were synthesised by the reaction of guanidine with an acetophenone and a
chalcone. These reactions were carried out as economical one-pot reactions under green conditions: no catalyst and
solvent free.
Keywords: pyridine, one-pot synthesis, solvent-free conditions, microwave-assisted synthesis
One-pot multicomponent reactions (MCRs) have become a
practical tool for atom economic and benign synthesis by
virtue of their convergence, productivity, facile execution, and
generation of highly diverse and complex products from easily
available starting materials.1 Green chemistry emphasises the
need for environmentally clean synthesis, which involves
improvement in selectivity, high atom efficiency, elimination
of hazardous reagents, and easy separation with recovery and
reuse of reagents.2 Compared with conventional heating,
reactions promoted by microwave irradiation (MWI) have
shown an environmental friendly nature, greater selectivity,
and enhanced reaction rate. Therefore, the MWI-mediated
multicomponent reaction has constituted an especially
attractive synthetic strategy for rapid and efficient library
generation.3
highly step-economical reactions are particularly appealing in
the context of target-oriented synthesis. They also come with
the promise of novelty in terms of process and compound-
related intellectual property.13
In view of the chemical and pharmacological importance of
the Kröhnke pyridines, we have focused on introducing a new
facile and efficient synthesis of these pyridines. In this context,
and as a part of a research project dealing with the design
and synthesis of biologically active organic structures,14 we
report a simple one-pot, three-component reaction between a
guanidine, an acetophenone and a chalcone under microwave
irradiation and solvent free conditions leading to Kröhnke
pyridine derivatives 4 (Scheme 1). We have focused on
environmental-friendly features of the employed components
and feasibility of the reaction conditions.
Pyridines are common substructures in natural products,
pharmaceuticals, and functional materials.4 In particular, 2,4,6-
triarylpyridines represent an important class of biologically
active molecules and are prominent building blocks in
supramolecular chemistry.5
Results and discussion
A mixture of guanidine 1, various acetophenones 2 and
chalcones 3 were irradiated in a microwave oven at 600 W
for 4 minutes under solvent-free conditions to produce the
corresponding pyridines 4 in 92–98% yields (Table 1).
All the reactions went to completion within 4 min. 1H NMR
analysis of the reaction mixtures clearly indicated the forma-
tion of the corresponding 2,4,6-triarylpyridines 4a–m in good
to excellent yields. All products were characterised by 1H and
13C NMR spectroscopy and by comparison of their spectral
data and melting point values with those of the authentic
samples reported in the literature.
Although we have not yet established the mechanism of this
reaction in an experimental manner, a mechanistic rationalisa-
tion for this reaction is provided in Scheme 2. The first step
involves condensation of guanidine (1) and acetophenone (2)
to form enamine unit 5. Then the chalcone is attacked by inter-
mediate 5 leading to adduct 6, which in turn isomerises to
intermediate 7. Cyclisation of 7 leads, via 8, to intermediate 9,
which then tautomerises to dihydropyridine 10. This then
finally undergoes autoxidation under the reaction conditions to
afford the 2,4,6-triarylpyridines 4.
These significant prevalences of pyridine scaffolds with
diverse functionalities and substituents have stimulated the
need for elegant and efficient ways to make these heterocycles.
So far, the most common synthetic strategies for the prepara-
tion of pyridines with a 2,4,6-triaryl substitution pattern
(Kröhnke pyridines) include: (1) the reaction of N-phenacyl-
pyridinium salts with α,β-unsaturated ketones in the presence
of NH4OAc,6 (2) reaction of N-phosphinylethanimines with
aldehydes,7 (3) reaction of ketoketene dithioacetals with
methyl ketones in the presence of NH4OAc,8 (4) solvent-free
reaction between acetophenones, benzaldehydes, and NH4OAc
in the presence of sodium hydroxide,9 (5) addition of lithiated
β-enaminophosphonates to chalcones,10 and (6) the one-pot
reaction of acetophenones, benzaldehydes, and NH4OAc
without catalyst under microwave irradiation.11
In order to achieve this goal, MCRs are one of the first
choices, since their attractive attribute is the inherent forma-
tion of several bonds to construct complex molecules in one
operation, ideally without isolation of intermediates.12 These
Scheme 1
* Correspondent. E-mail: sh.zomorodbakhsh@mahshahriau.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2012 139
Table 1 One-pot three-component synthesis of 2,4,6-triarylpyridines 4a–m
4
Ar1
Ar2
Ar3
Yield/%a
98
M.p./°C (lit.)
a
135–136 (136–137)15
b
98
121–122 (122–123)7
c
d
e
f
95
96
97
93
91
96
92
97
93
98
94
100–102 (99–100)15
139–140 (138)16
126–127 (125–127)17
124 (124–125)18
g
h
i
177–179 (178–180)17
156–158 (156–157.5)15
119–21 (120–122)18
139–140 (140–142)19
153–155 (152–154)20
114–116 (113.8–115)21
143–145 (143.1–144.7)11
j
k
l
m
Scheme 2

140 JOURNAL OF CHEMICAL RESEARCH 2012
(4CH), 129.00 (C), 129.10 and 129.17 (2CH), 138.98 (C), 139.58
Conclusion
(CH), 150.20 and 157.39 (2C) MS, m/z (%): 307 (M+).
In summary, the reaction between guanidine, an acetophenone
and a chalcone provides a simple one-pot entry into the micro-
wave-assisted synthesis of 2,4,6-triarylpyridines of potential
synthetic and pharmaceutical interest. In this work, guanidine
was applied as an alternative and environmental friendly source
of ammonia. Solvent-free conditions, short reaction times,
excellent yields of the products and use of simple starting
materials are the key advantages of this method. The simplicity
of the present procedure makes it an interesting alternative to
complex multi-step approaches.
Received 6 January 2012; accepted 27 January 2012
Paper 1201083 doi: 10.3184/174751912X13295721847185
Published online: 22 March 2012
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Preparation of 2,4,6-triphenylpyridine (4a); general procedure
A mixture of 1,3-diphenyl-2-propen-1-one (0.21 g, 1 mmol), aceto-
phenone (0.12 g, 1 mmol), and guanidine (0.118 g, 2 mmol) was
irradiated in a microwave oven for four minutes at 600 W under
solvent-free conditions. TLC showed completion of the reaction.
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lised from absolute ethanol. The product 4a was obtained in 98%
yield as colourless crystals, m.p. 135–136 °C; IR (KBr) (νmax/cm–1):
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(500.1 MHz, CDCl3): δ 7.35–7.61 (9H, m, 9CH), 7.74 (2H, d,
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