Three-components condensation catalyzed by molecular iodine for the synthesis of 2,4,6-triarylpyridines and 5-unsubstituted-3,4-dihydropyrimidin- 2(1H)-ones under solvent-free conditions

Article abstract of DOI:10.1007/s00706-008-0011-8

One-pot, three-components synthesis of 2,4,6-triarylpyridines and 5-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones was performed under solvent-free conditions using molecular iodine as the catalyst in moderate to good product yields.

Full text of DOI:10.1007/s00706-008-0011-8

Monatsh Chem (2009) 140:49–52
DOI 10.1007/s00706-008-0011-8
ORIGINAL PAPER
Three-components condensation catalyzed by molecular iodine
for the synthesis of 2,4,6-triarylpyridines and 5-unsubstituted-3,
4
-dihydropyrimidin-2(1H)-ones under solvent-free conditions
Yi-Ming Ren Æ Chun Cai
Received: 10 March 2008 / Accepted: 2 June 2008 / Published online: 13 August 2008
Ó Springer-Verlag 2008
Abstract One-pot, three-components synthesis of 2,4,6-
triarylpyridines and 5-unsubstituted-3,4-dihydropyrimidin-
presence of ammonium acetate [6, 7], but the pyridinium
salts and unsaturated ketones have to be synthesized first,
which has let this method appear to be relatively expensive.
The same compounds have also been synthesized by the
condensation of 1,5-diketones with formamide-ammonium
formate [8] and by other synthesis procedures [6]. How-
ever, most of the established methods suffer from some
disadvantages, such as multi-step procedures, long reaction
times, and use of toxic reagents and organic solvents. More
recently, one-pot syntheses of 2,4,6-triarylpyridines by
three-components condensation of aromatic ketones, alde-
hydes, and ammonium acetate have been reported [9–13].
The process consists of two or more synthesis steps, which
are carried out without isolation of any intermediate and,
thus, reduce time, saving money, energy, and raw materi-
als. In addition, via the Biginelli reaction, the synthesis of
3,4-dihydropyrimidin-2(1H)-ones has received renewed
interest, and several improved procedures have recently
been reported. However, the scope of substrates for the
Biginelli reaction is limited to aromatic aldehydes, aceto-
acetate (or acetylacetone) and urea or thiourea. The first
Biginelli-like reaction, reported by Wang et al. [14], was
2
(1H)-ones was performed under solvent-free conditions
using molecular iodine as the catalyst in moderate to good
product yields.
Keywords Molecular iodine Á Solvent-free Á
2
,4,6-Triarylpyridines Á
5
-Unsubstituted-3,4-dihydropyrimidin-2(1H)-ones
Introduction
The N-heterocyclic compounds, such as pyridines and di-
hydropyrimidinones, are very useful intermediates for the
development of molecules of pharmaceutical or biological
interest. Pyridines show variable biological activities, such
as antimalarial, anticonvulsant, anesthetic, antioxidant,
antibacterial, and antiparasitic properties [1–3]. In addition,
dihydropyrimidinones have also attracted much attention in
previous years due to the large range of biological activities
leading to calcium channel blockers, antiviral, antitumor,
and anti-inflammatory drugs [4, 5].
conducted in CH CN by condensation of aldehydes,
3
Owing to their wide range of pharmacological activity
and industrial and synthesis applications, a number of
methods have been reported for the synthesis of Kr o¨ hnke-
type pyridines [6]. Traditionally, Kr o¨ hnke-type pyridines
have been synthesized through the reaction of N-phen-
acylpyridinium salts with a,b-unsaturated ketones in the
ketones, and urea, using FeCl Á6H O and TMSCl as cata-
3
2
lysts, which remarkably broadened the Biginelli reaction.
Since then, the Biginelli-like reaction has been applied and
improved by several authors [15–17].
In recent years, the usage of molecular iodine has drawn
considerable attention as an inexpensive, nontoxic, readily
available catalyst for various organic transformations to
afford the corresponding products in excellent yields with
high selectivity. The mild Lewis acidity associated with
iodine enhances its usage in organic synthesis to realize
several organic transformations using stoichiometric levels
or even catalytic amounts [18–27]. As a part of our studies
Y.-M. Ren Á C. Cai (&)
Chemical Engineering College,
Nanjing University of Science and Technology,
Nanjing 210094, People’s Republic of China
e-mail: c.cai@mail.njust.edu.cn
123

5
0
Y.-M. Ren, C. Cai
Ar1
N
Table 1 Studies on the synthesis of 2,4,6-triphenylpyridine using
iodine as catalyst
I2
1
2
a
Yield /%
Ar CHO + 2Ar COCH3 + NH4OAc
Entry
c(I )/mol%
2
Solvent
T/°C
solvent-free
Ar2
Ar2
1
2
3
4
5
6
7
8
9
10
0
–
120
120
120
120
120
120
80
Trace
35
Scheme 1
5
–
10
20
30
40
20
20
20
20
20
20
20
20
20
20
–
41
–
56
Ar1
–
51
O
I2
–
45
1
2
NH
Ar CHO + Ar COCH3 +
solvent-free
–
21
H2N
NH2
Ar2
N
H
O
–
110
130
140
78
37
–
52
Scheme 2
–
45
1
1
1
2
EtOH
22
CH
DMF
CH Cl
3
CN
82
17
to explore the utility of iodine-catalyzed reactions [28–30],
we proceeded to examine the synthesis of 2,4,6-triaryl-
13
14
15
16
140
40
9
2
2
10
pyridines
and
5-unsubstituted-3,4-dihydropyrimidin-
Et N
3
90
Trace
11
2
(1H)-ones in the presence of molecular iodine under
solvent-free conditions (Schemes 1, 2).
PhMe
110
Millimole ratio of benzaldehyde/acetophenone/NH
1
4
OAc was 5.0/
0.0/6.5. The reaction time was 6 h
a
Isolated yields
Results and discussion
Initially, we explored the synthesis of 2,4,6-triphenylpyri-
dine in order to identify optimal reaction conditions. The
reactions were carried out under solvent-free conditions
Table 2 I
2
-catalyzed solvent-free synthesis of 2,4,6-triarylpyridines
1
2
a
Entry Ar
Ar
Yield /% m.p./°C m.p./°C [Ref.]
(
Table 1, entries 1–10). Table 1 shows that the appreciable
1
2
3
4
5
6
7
8
C
6
H
5
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
5
5
5
5
5
56
61
57
52
48
52
54
57
133–134 134–135 [3]
195–196 195–197 [3]
124–126 125–127 [3]
119–120 123–124 [3]
182–184 184–185 [36]
126–128 126–127 [11]
156–157 157–158 [3]
264–265 269–270 [36]
amount of I for synthesis of 2,4,6-triphenylpyridine was
2
2 6 4
4-NO C H
2
0 mol% (referred to benzaldehyde) under solvent-free
6 4
4-ClC H
conditions. An increase in the amount of I did not lead to
2
6 4
4-MeC H
an improvement in yield. A reaction temperature of 120 °C
was found to be optimal (Table 1, entry 4). The reaction
medium had an influence on the reaction; the results
showed that solvent-free conditions provided better yield
than if solvents were used.
6 4
4-HOC H
C
6
H
H
5
5
4-ClC
4-MeC
4-ClC
6 4
H
C
6
6 4
H
4-Cl C
H
6 4
6 4
H
In order to explore the scope of our reagent system, we
synthesized a series of 2,4,6-triarylpyridines via three-
components condensation of aromatic ketones, aldehydes,
and ammonium acetate (Table 2). Table 2 shows that both
electron-deficient and electron-rich aromatic aldehydes
were converted to the corresponding 2,4,6-triarylpyridines
in moderate yields. Moreover, it is important to note that,
in all cases, 2,4,6-triarylpyridines were precipitated upon
dilution of the reaction mixture with EtOH and were iso-
lated by simple filtration. The products thus obtained
showed a single spot on TLC and were pure enough for all
practical purposes.
Millimole ratio of aldehyde/ketone/NH
The reaction was accomplished under solvent-free conditions at
4 2
OAc/I was 5.0/10.0/6.5/1.0.
1
a
20 °C in 6 h
Isolated yields
acetophenone/urea, we received, to our surprise, 3,4-dihy-
dro-4,6-diphenylpyrimidin-2(1H)-one in good yield by a
Biginelli-like reaction. Previously, molecular iodine had
been explored as a powerful catalyst for the Biginelli
reaction, in CH CN [32] and toluene [33], or under
3
microwave irradiation [34]. However, the scope of sub-
strates was limited to 1,3-dicarbonyl compounds in the
above-reported methods. We herein report the synthesis of
5-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones by one-
pot three-components condensation of aromatic aldehydes
According to Heravi et al. [9] and Razdanand colleagues
[
31], urea can also used as the ammonium source in the
synthesis of 2,4,6-triarylpyridines. However, if we applied
the established protocol of a 1/2/1.3 ratio of benzaldehyde/
1
23

Three-components condensation catalyzed by molecular iodine
51
2
Table 3 I -catalyzed solvent-free synthesis of 5-unsubstituted-3,4-dihydropyrimidin-2(1H)-ones
1
2
a
Yield /%
Entry
Ar
Ar
Time/min
m.p./°C
m.p./°C [Ref.]
1
2
3
4
5
6
7
8
C
6
H
5
C
C
C
C
C
6
6
6
6
6
H
H
H
H
H
5
5
5
5
5
30
20
40
30
25
30
25
25
78
75
70
68
79
73
80
77
229–230
265–266
264–265
257–258
258–259
173–174
215–217
221–222
228–230 [35]
267–269 [17]
260–263 [17]
255–257 [17]
256–258 [17]
174–175 [15]
214–215 [15]
223–224 [15]
4-ClC
6
6
H
4
2-ClC
H
4
4-HOC
3-BrC
6
H
4
6
H
4
C
6
H
5
4-MeC
4-MeC
6
H
H
4
4
2 6 4
4-NO C H
6
C
6
H
5
6 4
4-ClC H
Millimole ratio of aldehyde/ketone/urea/I
a
Isolated yields
2
was 5.0/5.0/10.0/2.5. The reaction was accomplished under solvent-free conditions at 140 °C
Typical procedure for the synthesis
of 2,4,6-triphenylpyridine
O
O
O
O
I2
NH2 solvent-free
HN
N
H
+
CH3 + H N
2
R
To a mixture of 0.53 g benzaldehyde (5 mmol), 1.20 g
R
R = Me (yield: 76%), OMe (yield: 81%)
acetophenone (10 mmol), and 0.50 g NH OAc (6.5 mmol)
4
Scheme 3
were added 0.25 g I (1 mmol) at room temperature. Then,
2
the mixture was stirred at 120 °C. After 6 h, the mixture
obtained was treated with EtOH. A precipitate formed,
which was collected by filtration, washed with EtOH,
dried, and recrystallized from EtOH to afford the pure
product, 2,4,6-triphenylpyridine. M.p. 133–134 °C ([3]
with aromatic ketones and urea, using iodine as the cata-
lyst, under solvent-free conditions (Scheme 2). The results
are summarized in Table 3.
1
34–135 °C).
In a preliminary study, we had found that 50 mol% of
catalyst to aldehyde was sufficient to mediate the reaction
toward the formation of the corresponding 5-unsubstituted-
Typical procedure for 3,4-dihydro-4,6-
diphenylpyrimidin-2(1H)-one
3
,4-dihydropyrimidin-2(1H)-ones in good yields within the
given reaction time. Table 3 shows that various aromatic
aldehydes and several aromatic ketones were converted to
the corresponding products in good yields and in short
time. However, the dehydrogenated products were obtained
when aromatic aldehydes with electron-donating groups,
such as methoxy, methyl, were used (Scheme 3).
To a mixture of 0.53 g benzaldehyde (5 mmol), 0.60 g
acetophenone (5 mmol), and 0.60 g urea (10 mmol) were
added 0.63 g I (2.5 mmol) at room temperature. Then, the
2
mixture was stirred at 140 °C. After 30 min, the solid
produced was treated with EtOH. A precipitate was
formed, which was then filtered, washed with EtOH, dried,
and recrystallized from EtOH to afford the pure product,
In conclusion, the method of synthesis described here
represents a simple and inexpensive path to 2,4,6-triaryl-
pyridines and 5-unsubstituted-3,4-dihydropyrimidin-2(1H)-
ones. The advantages of our method are the avoidance of
metals, organic solvents, and toxic reagents and operational
simplicity. Further studies on the synthesis applications of
3
2
,4-dihydro-4,6-diphenylpyrimidin-2(1H)-one. M.p. 229–
30 °C ([35] 228–230 °C).
Acknowledgments We are grateful to Nanjing University of
Science and Technology for financial support.
2
,4,6-triarylpyridines and 5-unsubstituted-3,4-dihydropyr-
imidin-2(1H)-ones are now in progress.
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