TCT (2,4,6-trichloro-1,3,5-triazine) promoted single-step synthesis of 4,6-diarylpyrimidin-2(1H)-ones under microwave irradiation

Article abstract of DOI:10.3987/COM-05-10613

An efficient single-step procedure for the synthesis of 4,6-diarylpyrimidin-2(1H)-ones promoted by Zn(OTf)₂-TCT or Bi(OTf)₃-TCT under solvent-free microwave irradiation conditions has been developed.{A figure is presented}.

Full text of DOI:10.3987/COM-05-10613

HETEROCYCLES, Vol. 68, No. 8, 2006
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HETEROCYCLES, Vol. 68, No. 8, 2006, pp. 1551 - 1557. © The Japan Institute of Heterocyclic Chemistry
Received, 4th November, 2005, Accepted, 26th June, 2006, Published online, 27th June, 2006. COM-05-10613
TCT (2,4,6-TRICHLORO-1,3,5-TRIAZINE) PROMOTED SINGLE-STEP
SYNTHESIS
OF
4,6-DIARYLPYRIMIDIN-2(1H)-ONES
UNDER
MICROWAVE IRRADIATION
Ahmad R. Khosropour,*a Iraj Mohammadpoor-Baltork,*a Mohammad M.
Khodaei,b and Mahbubeh Jokar b
aDepartment of Chemistry, Faculty of Science, Isfahan University, Isfahan
81746-73441, Iran tel: +98-311-668-9732; fax: +98-311-668-9732; e-mail:
arkhosropour@razi.ac.ir
bDepartment of Chemistry, Faculty of Science, Razi University, Kermanshah
67149, Iran
Abstract – An efficient single-step procedure for the synthesis of
4,6-diarylpyrimidin-2(1H)-ones promoted by Zn(OTf)2-TCT or Bi(OTf)3-TCT
under solvent-free microwave irradiation conditions has been developed.
Pyrimidinone derivatives display various biological1-3 and pharmacological4-8 activities such as antitumor
action. Therefore, the synthesis of these heterocycles is interesting for both organic synthesis and
medicinal chemistry. Many procedures have been reported for the preparation of a variety of
pyrimidinone derivatives.9-14 But little attention has been paid to the synthesis of pyrimidin-2(1H)-ones
and there are only few methods for the preparation of these compounds.15 Thus the development of an
efficient and convenient method for this purpose is still in demand.
In recent years organic reactions assisted by microwave irradiation have gained special attention. The
chief features of the microwave reactions are the enhanced selectivity, much improved reaction rates and
milder reaction conditions.16 Several metal-catalyzed reactions for the synthesis of heterocyclic
compounds have been reported in the literature.17 Among them, multi-component reactions which
performed under solvent-free microwave irradiation conditions have received special attentions because
of their improved reaction rates and environmentally benign conditions.18 In the course of our ongoing
program to develop environmentally friendly methods using metal triflates under solvent-free microwave
irradiation conditions,19-21 we report a new protocol for the preparation of pyrimidin-2(1H)-one
derivatives.
Recently Sedova et al. reported a new method for the synthesis of pyrimidin-2(1H)-ones.15a However,

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HETEROCYCLES, Vol. 68, No. 8, 2006
these methods suffer from drawbacks such as long reaction times, unsatisfactory yields and low
selectivity that limit these methods to small-scale synthesis. These results led us to develop a simple and
efficient procedure for the direct synthesis of 4,6-diarylpyrimidin-2(1H)-ones promoted by
2,4,6-trichloro-1,3,5-triazine (TCT) in the presence of Zn(OTf)2 or Bi(OTf)3 under microwave irradiation
(Scheme 1).
O
Cl
R4
R1
R4
R1
N
H
N
N
N
COCH3
CHO
(TCT)
Cl
N
Cl
(H2N)2CO
+
+
R2
R5
Y: Zn(OTf)2 or Bi(OTf)3
microwave
R2
R5
R3
R3
Scheme 1
3
1
2
Optimization of the various parameters resulted in two preferred methods. First we observed that when a
mixture of an aryl aldehydes (1), an aryl alkyl ketones (2) and urea in the presence of TCT and 10 mol%
of Zn(OTf)2 was irradiated by microwave at 450 W under solvent-free conditions, various
4,6-diarylpyrimidin-2(1H)-ones (3) were obtained efficiently (Method 1). The results in Table 1 show that
the products achieved in high yields with the exception of Entry 9 (64 %).
However, significant improvement in the yield was observed using Method 2. Many recent papers
describing the use of bismuth compounds in organic transformations pointed out that their use is
environmentally friendly.22 In addition, bismuth derivatives have been widely used in medicine.23 They
have attracted much attention because they are easy to handle, low cost and are relatively insensitive to
air and moisture.24 In the course of more investigation, we found that utilization of Bi(OTf)3 (only 1
mol%) instead of Zn(OTf)2 was also catalyzed this transformation at 300 W effectively (Table 1). As
shown in Table 1, a wide range of substituted and structurally divers aryl aldehydes and aryl alkyl ketones
were subjected to this procedure to synthesize the corresponding products in good to excellent yields
(Table 1).
We found that treatment of aryl aldehydes (1) or aryl methyl ketones (2), carrying either
electron-withdrawing or electron-donating groups, afforded the corresponding pyrimidinones (3) in high
to excellent yields in short reaction times (Table 1). Another important aspect is that various
functionalities such as ether, halide, nitro, etc., survived under the present reaction conditions. To the best
of our knowledge, this is the first example for the highly efficient single-step synthesis of
4,6-diarylpyrimidin-2(1H)-ones (3). These solvent-free single-step reactions which proceeded under
microwave irradiation are very fast and clean without the use of any harsh conditions. For comparison,

HETEROCYCLES, Vol. 68, No. 8, 2006
1553
a
b
Table 1. Synthesis of 4,6-diarylpyrimidin-2(1H)-ones promoted by Zn(OTf)2 -TCT or Bi(OTf)3 -TCT
under microwave irradiation
Product (3)c
Y
Entry
Time
(min)
Yield
(%)d
Aldehyde (1)
Ketone (2)
R1
R2
R3
R4
R5
1a
2a
2a
2b
3a
3b
3c
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
1
2
3
H
H
H
H
F
Br
H
H
H
H
H
H
H
H
Br
12
14
14
94
88
89
1b
1c
1d
1a
1d
1e
1f
2c
2d
2d
2e
2e
2b
2c
2d
2d
2d
2a
2a
2a
2b
2b
2b
2f
3d
3e
3f
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
4
5
6
7
8
9
H
H
H
H
CH3O
CH3
CH3
H
Cl
H
Cl
H
H
H
H
NO2
CH3O
H
H
H
H
H
H
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
NO2
CH3O
CH3O
Ph
Ph
Br
NO2
CH3O
CH3O
CH3O
H
H
H
Br
Br
Br
Cl
CH3
Ph
Ph
13
12
15
14
12
13
14
12
15
10
10
15
15
10
14
10
11
14
10
15
14
15
73
91
90
81
88
64
85
82
91
93
84
85
79
94
74
90
87
85
91
89
84
83
3g
3h
3i
H
1g
1g
1h
1d
1i
CH3
CH3
N(CH3)2
Cl
CH3
3j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3k
3f
H
H
3l
1j
3m
3n
3o
3p
3q
3r
3s
CH3O CH3O
1k
1c
1l
H
H
H
H
H
Br
Ph
F
1b
1j
CH3O CH3O
1j
H
H
H
H
CH3O
F
CH3
H
1b
1i
2g
2e
2e
2h
2h
3t
H
H
Br
H
H
3u
3v
3w
3x
1m
1j
CH3O CH3O
H
H
H
1b
F
F
COCH3
1l
2i
3y
Bi(OTf)3
86
26
H
Ph
H
H
10
COCH3
1d
2i
3z
Bi(OTf)3
85
27
H
Cl
15
aMethod A; bMethod B; cAll products were characterized by 1H-NMR,13C-NMR, IR and mass spectroscopy; dIsolated yields.
the reaction of 4-chlorobenzaldehyde and 4-methoxyacetophenone was performed by conventional
heating (stirring in an oil-bath at 140 °C) in the presence of Zn(OTf)2-TCT or Bi(OTf)3-TCT and the
product was formed in decreased yield (less than 12%) in prolonged reaction times (more than 18h)
showing that microwave irradiation plays a critical role in these reactions. It is important to note that in
the absence of the catalysts or promoter (TCT) the reaction did not proceed at all. Therefore, the
combination of Zn(OTf)2 or Bi(OTf)3 with TCT is essential in this process. According to these results we
propose a reaction mechanism for this transformation (Scheme 2).

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HETEROCYCLES, Vol. 68, No. 8, 2006
-
-
Y
Y
+
OH
+
H
O
O
O
+
Ar
H
Ar'
Ar'
Ar
Cl
Cl
Cl
N
N
-
Y
N
+
O
+
- Y, -Cl-
OH
O
OH
N
N
N
Cl
Ar'
Ar
Ar'
Ar
Cl
Cl
N
N
+
OH
O
N
Cl
Ar'
Ar
NH2CONH2
O
O
O
HN
NH2
Ar'
- H2O
HN
N
TCT
Ar'
HN
Ar
N
Ar
Ar'
Ar
+
O
-
Y
Scheme 2
In conclusion, we describe a new and highly efficient procedure for the solvent-free single-step synthesis
of 4,6-diarylpyrimidin-2(1H)-ones promoted by Zn(OTf)2-TCT or Bi(OTf)3-TCT under microwave
irradiation. In addition, short reaction times, absence of solvent and mild reaction conditions are
noteworthy advantages of this method.
ACKNOWLEDGEMENTS
We are thankful to the Isfahan University and Razi University Research Councils for partial support of
this work.
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25. Typical Procedure for the Synthesis of 4-(4-Chlorophenyl)-6-(4-methoxyphenyl)-1H-pyrimidin-2-one
promoted by Bi(OTf)3-TCT(Table 1, Entry 12): 4-Chlorobenzaldehyde (1d) (140.6 mg, 1 mmol),
4-methoxyacetophenone (2d) (150 mg, 1 mmol), urea (90 mg, 1.5 mmol), TCT (184 mg, 1 mmol)
and Bi(OTf)3 (7 mg, 0.01 mmol) were taken into a reaction tube and thoroughly mixed with a glass
rod. The resulting mixture was placed in the microwave cavity and irradiated for 15 min at 300 w.
After completion of the reaction, as indicated by TLC, the mixture was allowed to cool. The
precipitate was washed with cooled ethanol (10 ml) and recrystallized by ethyl acetate to give
pyrimidinone (3f) in 91% yield. mp 287-290 °C. IR (KBr) 3429, 3100, 2890, 1617, 1582, 810, 600

HETEROCYCLES, Vol. 68, No. 8, 2006
1557
1
cm-1; H NMR (CDCl3, 200MHz) δ 3.8 (s, 3H, OCH3), 7.09 (d, J =8.4 Hz, 2H, Ar), 7.53 (s,
13
1H,=CH-), 7.61 (d, J = 8.09 Hz, 2H, Ar), 8.17 (m, 4H, Ar), 12.0 (br, 1H, NH); C NMR(CDCl3,
50MHz) δ 100.4, 115.1, 115.4, 128.8, 129.7, 129.9, 130.2, 130.4, 130.7, 131.2, 137.1, 160.7, 163.0;
EIMS m/z 314 (M++2), 312 (M+), 311, 297, 270, 268, 205, 75.