Reaction between guanidine hydroehloride and chalcones: An efficient solvent-free synthesis of 2,4,6-triarylpyridines under microwave irradiation

Article abstract of DOI:10.1246/cl.2008.1048

A series of 2,4,6-triarylpyridines have been synthesized via an efficient solvent-free reaction between guanidine hydro-chloride and chalcones under microwave irradiation in excellent yields. Copyright

Full text of DOI:10.1246/cl.2008.1048

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1048
Chemistry Letters Vol.37, No.10 (2008)
Reaction between Guanidine Hydrochloride and Chalcones:
An Efficient Solvent-free Synthesis of 2,4,6-Triarylpyridines under Microwave Irradiation
Mehdi Adib,ꢀ1 Bagher Mohammadi,1 Sahar Rahbari,1 and Peiman Mirzaei2
1School of Chemistry, University College of Science, University of Tehran, P. O. Box 14155-6455, Tehran, Iran
2Department of Chemistry, Shahid Beheshti University, Tehran, Iran
(Received July 8, 2008; CL-080670; E-mail: madib@khayam.ut.ac.ir)
A series of 2,4,6-triarylpyridines have been synthesized
via an efficient solvent-free reaction between guanidine hydro-
chloride and chalcones under microwave irradiation in excellent
yields.
wave-assisted reaction between chalcones and urea derivatives
leads to TAPs. Thus, 1,3-diphenyl-2-propen-1-one, 1a, and urea
derivatives 2a–2c were converted to 2,4,6-triphenylpyridine
3a under microwave irradiation and solvent-free conditions in
56–96% yields (a cyclization from [3 þ 2 þ 1] atom fragments:
[C2C3C4 + C5C6 + N]) (Scheme 1).
The synthesis, reactions, and biological properties of pyri-
dines constitutes a significant part of modern heterocyclic chem-
istry.1 2,4,6-Triarylpyridines (TAPs)2 and substituted phenyl-
pyridines3 are useful intermediates in the synthesis of drugs, her-
bicides, insecticides, desiccants, and surfactants.4 Due to their ꢀ-
stacking ability, these pyridines are used in supramolecular
chemistry.5 Hence their synthesis has received much attention.
TAPs have been synthesized using various methods and pro-
cedures. Traditionally, these compounds have been synthesized
through the reaction of N-phenacylpyridinium salts with ꢁ,ꢂ-un-
saturated ketones in the presence of NH4OAc.2,6a More recently,
several new improved methods and procedures have been devel-
oped for the synthesis of these pyridines: reaction of N-phosphi-
nylethanimines with aldehydes,6b reaction of N-(diphenylphos-
phinyl)-1-azaallyl anions with ꢁ,ꢂ-unsaturated carbonyl com-
pounds,6c reaction of in situ generated ꢁ,ꢂ-unsaturated imines
with CH–nucleophiles,6d arylation of methylthiopyridines via
Ni-induced Grignard reactions,6e reaction of phenacylidenedi-
methylsulfurane with chalcones and NH4OAc,6f pyrolysis of 1-
vinyl-1,2-dihydropyridines,6g reaction of ꢁ-ketoketene dithio-
acetals with methyl ketones in the presence of NH4OAc,6h addi-
tion of lithiated ꢂ-enaminophosphonates to chalcones,6i reaction
of ꢁ-benzotriazolyl ketones with ꢁ,ꢂ-unsaturated ketones and
NH4OAc,6j and solvent-free reaction between acetophenones,
benzaldehydes, and NH4OAc in the presence of sodium hydrox-
ide,6k or without catalyst under microwave irradiation.6l Most
of these syntheses of TAPs are multistage, low to moderately
yielding laborious processes and involve harsh or environmen-
tally hazardous reaction conditions.
As part of our current studies on the design of efficient meth-
ods for the preparation of heterocyclic compounds from readily
available starting materials,7 we have recently described an
efficient synthesis of TAPs via a solvent-free reaction between
chalcones and NH4OAc and as most of the earlier syntheses of
TAPs, we employed ammonium acetate as the source of pyridine
N atom.8
There are so many reports concerning the reaction of ꢁ,ꢂ-
unsaturated ketones with urea derivatives producing functional-
ized pyrimidines.9 As far as we know there is only one report
concerning the reaction of ꢁ,ꢂ-unsaturated ketones with urea de-
rivatives leading to pyridine derivatives. Recently, Razdan et al.
reported a solid-supported synthesis of TAPs from chalcones and
urea derivatives using Bi(NO3)3–Al2O3.10 However, the reaction
yields were not very high. Herein we have found that micro-
Therefore, guanidine hydrochloride (2c) is the most effec-
tive urea derivative for the conversion of chalcones to the corre-
sponding TAPs under microwave irradiation. Thus, a range of
symmetrical TAPs 3a–3q were synthesized from the reaction
between 1,3-diaryl-2-propen-1-ones, 1a–1q, and guanidine hy-
drochloride in 90–98% yields (Table 1).12
All products were characterized by 1H and 13C NMR analy-
sis, and their melting points were compared with those of the
known compounds reported in the literature.
The mechanism of the reaction may be rationalized as
involving condensation and the Michael addition of guanidine
with chalcone leading to condensed product 4 and 1:1 adduct,
Ph
(2a-c)
(H2N)2CX
O
(X = O, S, NH2Cl)
Ph
Ph
MW, 180 OC, 5 min
Solvent-free
Ph
Ph
N
1a
3a
X = O, 56%; S, 64%; NH2Cl, 96%
Scheme 1.
Table 1. Solvent-free microwave-assisted synthesis of 2,4,6-
triarylpyridines
Ar'
O
(H2N)2C=NH2Cl(2c)
Ar'
MW, 180 OC, 5 min
Solvent-free
Ar
Ar
N
Ar
1a_1q
3a_3q
3
Ar
Ar0
% Yielda
mp/ꢁC (Lit.)
a
b
c
C6H5
4-CH3C6H4
C6H5
C6H5
C6H5
96
95
94
94
95
96
93
90
98
95
96
98
95
97
96
90
92
134–135 (137–138)2
157–158 (159–160)11a
123–124 (124.5–125)6b
178–179 (178–180)11b
100–103 (99–100)11a
155–157 (156.8–157.9)6l
139–140 (142–143)6b
195–197 (202–203)6b
125–127 (129–130)6b
113–114 (114–115)6b
199–201 (200.6–202)6l
115–116 (113.8–115)6l
135–136 (136–137)6l
164 (163.9–165)6l
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-(CH3)2NC6H4
4-O2NC6H4
4-ClC6H4
d
e
4-CH3C6H4
C6H5
f
4-CH3C6H4
C6H5
C6H5
g
h
i
C6H5
C6H5
4-CH3C6H4
j
2-ClC6H4
4-ClC6H4
k
l
4-CH3OC6H4 4-ClC6H4
4-CH3OC6H4 4-CH3OC6H4
4-CH3OC6H4 4-BrC6H4
m
n
o
p
q
C6H5
C6H5
C6H5
4-Pyridyl
2-Furyl
2-Thienyl
187–190
168–170
162–163 (165–166)6b
aIsolated yields.
Copyright Ó 2008 The Chemical Society of Japan

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Chemistry Letters Vol.37, No.10 (2008)
1049
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Ar'
Ar'
Ar'
Ar'
O
NH
..
(NH2)2CNH.HCl
(NH2)2CNH2Cl
N
NH2
H
..
_
_
H2O
HCl
N
OH
Ar
Ar
Ar
Ar
O
HN
NH2
6
a) F. Krohnke, W. Zecher, J. Curtze, D. Drechsler, K.
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4
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X
X
Heteroannulation
Ar
..
OH
Ar
O
Ar
HN
N
Ar
_
Ar
N
Ar
HN
NH
OH
HN
NH2
NH2
NH2
..
..
7
8
6
NH2
HN
Ar'
H
Ar'
NH
_
(NH2)2CO
_
Ar'CH2X
Ar
Oxidation
Ar
N
Ar
Ar
N
Ar
NH
9
3
N
H2N
X =
H
Scheme 2.
5, respectively, followed by the Michael addition of the enolized
adduct 5 to 4 from ꢂ carbon atom to form ꢃ-aminoketone inter-
mediate 6, which on heteroannulation may lead to formation
of tetrahydropyridine intermediate 7. Removal of a molecule
of urea may form dihydropyridine intermediate 9 through dihy-
dropyridinium hydroxide intermediate 8. Then oxidative aroma-
tization via disproportionation and removal of the benzyl side
chain would yield TAP 3. This oxidative dealkylation has been
previously observed.13 Similar reaction mechanisms have been
proposed for the reaction between N-(diphenylphosphinyl)-1-
ethanimine and aromatic aldehydes,6b by Kiselyov for the
reaction between azadienes and CH–nucleophiles6d and by
Razdan et al. for the Bi(NO3)3–Al2O3 promoted reaction be-
tween benzylideneacetophenones and urea derivatives.10 GC-
Mass analysis of the reaction mixture of 1a revealed presence
of C6H5CH2X by-product, which increased possibility of the
proposed mechanism (Scheme 2).
7
8
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In conclusion, we have developed a microwave-assisted
facile and efficient method for the preparation of 2,4,6-triaryl-
pyridines of potential synthetic and chemical interest. Solvent-
free conditions, excellent yields, a simplified purification
process, and short reaction times are the main advantages of
the presented method.
This research was supported by the Research Council of the
University of Tehran as a research project (No. 6102036/1/03).
10 A. Kumar, S. Koul, T. K. Razdan, K. K. Kapoor, Tetra-
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A mixture of 1 (2 mmol) and guanidine hydrochloride
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Published on the web (Advance View) September 6, 2008; doi:10.1246/cl.2008.1048