Novel ring transformation of nitropyrimidinone; synthetic equivalent
of á-nitroformylacetic acid
Nagatoshi Nishiwaki, Hui-Ping Wang, Kengo Matsuo, Yasuo Tohda and
Masahiro Ariga *
Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara,
Osaka 582, Japan
O
3-M ethyl-5-nitropyrimidin-4(3H )-one reacts with ketones
O
O
O
O
in the presence of ammonium salts to afford disubstituted
pyrimidines and disubstituted 3-nitro-2-pyridones in a
novel ring transformation reaction; nitropyrimidinone
behaves as an activated diformylamine in the former case,
and as a synthetic equivalent of á-nitroformylacetic acid in
the latter case.
O2N
Me
N
H
N
H
H
H
OH
N
NO2
1
2
8
Fig. 1
Table 1 Reactions of pyrimidinone 2 with acetophenonea
Diformylamine (diformamide) 1 (see Fig. 1), the simplest
secondary amide, has not been extensively used in organic
synthesis due to its low reactivity. Since the carbonyl group
of 1 reveals carbamoyl properties rather than formyl proper-
ties, nucleophilic substitution predominantly occurs.1 A unique
example employing 1 as an aldehyde in an intramolecular
Wittig reaction leading to a pyrrole derivative has, however,
been reported.2
In our previous paper, we showed that 3-methyl-5-
nitropyrimidin-4(3H )-one 2 reacts with ketones in the presence
of NH3 to give disubstituted pyrimidines 3 (Scheme 1).3 In the
ring transformation, pyrimidinone 2 behaves as the activated
diformylamine. This reaction, however, requires severe condi-
tions,† and is applicable only to restricted substrates.
Yield (%)
Solvent
t/d
XϪ
3a
5a
Recovery (%)
MeOH
MeOH
EtOH
MeCN
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
1
AcOϪ
47
35
0
48
33
0
0
32
86
95
—
0
0
0
0
88
0
7b
1
AcOϪ
AcOϪ
1
1
3
3
AcOϪ
0
5
AcOϪ
trace
37
46
0
21
0
—
52
45
0
HCOOϪ
C6H4(COOϪ)2
(COOϪ)2
3
3c
3
CO3
52d
0
2Ϫ
ClϪ
Ϫ
3
BF4
0
0
a
2
Reaction conditions: 2 = 1 mmol; acetophenone = 2 mmol; NH4X =
2 mmol; solvent = 20 ml; T = 65 ЊC. b T = Room temperature. c T =
50 ЊC. d Crude yield.
O
NH3
RNH2
R2
the residue was column chromatographed to give 4-
phenylpyrimidine 3a and a second crop of pyridone 5a
(Scheme 2).
R1
O
R2
R1
N
O2N
Me
R2
N
H
R2
R1
NO2
O
N
RNH
2
+
+
NH4X
3
+
O
3
4
R1
N
H
Scheme 1
5
On the other hand, ring cleavage of pyrimidinone 2 with
amines, not in the presence of ketones, readily proceeds to yield
functionalized nitroenamines 4.4 This ring opening reaction
is considered to prevent the pyrimidine synthesis. To avoid
this aminolysis of 1, less nucleophilic ammonium salts were
employed as the nitrogen source for the ring transformation.
A solution of nitropyrimidinone 2 (155 mg, 1.0 mmol),
acetophenone (0.23 ml, 2.0 mmol) and NH4OAc (154 mg, 2.0
mmol) in MeOH (20 ml) was refluxed for 1 day. When the
contents were cooled to room temperature, yellow needles
precipitated. The collected crystalline product was identified
as 3-nitro-6-phenyl-2-pyridone 5a (R1 = Ph, R2 = H) from its
spectral and analytical data. The filtrate was concentrated, and
Scheme 2
Usage of NH4OAc instead of NH3† in the ring transform-
ation reaction afforded pyrimidine 3a under more mild condi-
tions and in a considerably improved yield. Pyridone derivative
5a was also isolated as the other product in moderate yield.
Since 3-nitro-2-pyridone derivatives have recently attracted
attention as anti-HIV drug intermediates, the present reaction
would be a useful method for construction of this skeleton.5
Although this transformation proceeded even at room temper-
ature, refluxing the mixture brought about almost complete
reaction after 1 day.
Several solvents and ammonium salts were also investigated.
In cases when the reaction mixture became a homogeneous
solution, both products 3a and 5a were obtained. Ammonium
salts (COONH4)2, NH4Cl and NH4BF4 were not effective owing
to their insolubility (Table 1).
† Pyrimidine 3a was obtained in only 6% yield in the reaction of
pyrimidinone 2 with acetophenone and NH3 even though severe
conditions (heating at 120 ЊC in a sealed tube for 3 h) were employed.3
J. Chem. Soc., Perkin Trans. 1, 1997
2261