Novel synthesis of bihetaryl compounds

Article abstract of DOI:10.1055/s-2004-829195

The ring transformation of nitropyrimidinone 1 with acetophenone derivatives 2 affords two kinds of azaheterocyclic compounds, 4-phenylpyrimidines 3 and 3-nitro-6-phenyl-2-pyridones 4. On the basis of the relationship between electronic properties of the substituent and ratios of products, a plausible reaction mechanism is provided. Furthermore, the present reaction could be applied to heterocyclic ketones giving bihetaryl compounds.

Full text of DOI:10.1055/s-2004-829195

1996
PAPER
Novel Synthesis of Bihetaryl Compounds
N
ovel Synthesis of
a
Bihetaryl
C
g
ompounds atoshi Nishiwaki,* Keiko Yamashita, Mayumi Azuma, Tomoko Adachi, Mina Tamura, Masahiro Ariga*
Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
Fax +81(729)783398; E-mail: ariga@cc.osaka-kyoiku.ac.jp
Received 13 April 2004; revised 17 May 2004
O
O
Abstract: The ring transformation of nitropyrimidinone 1 with ace-
tophenone derivatives 2 affords two kinds of azaheterocyclic com-
pounds, 4-phenylpyrimidines 3 and 3-nitro-6-phenyl-2-pyridones
4. On the basis of the relationship between electronic properties of
the substituent and ratios of products, a plausible reaction mecha-
nism is provided. Furthermore, the present reaction could be applied
to heterocyclic ketones giving bihetaryl compounds.
R
O2N
Me
NH4OAc
N
+
G
MeOH
reflux, 2 d
N
1
2
R
R
NO2
N
+
Key words: ring transformation, nitropyridone, pyrimidine, bi-
hetaryl compounds
N
N
H
O
G
G
3
4
Scheme 1 Ring transformation affording two kinds of azahetero-
cyclic compounds 3 and 4.
The ring transformation has been employed as one of the
effective methodologies for preparation of functionalized
systems.1 Electron-deficient compounds having a good
leaving group are often used as the substrate for this reac-
tion, and we have studied ring transformations using
dinitropyridones2 and related nitro compounds.3 Among
them, 3-methyl-5-nitropyrimidin-4(3H)-one (1) is found
to be an excellent substrate leading to several kinds of
polyfunctionalized azaheterocyclic compounds. In reac-
tions of nitropyrimidinone 1 with 1,3-dicarbonyl com-
pounds under basic conditions, 2-pyridones,4 4-
pyridones5 and 4-aminopyridines6 can be readily pre-
pared. Furthermore, simple ketones are also usable in this
reaction. When pyrimidinone 1 is allowed to react with
ketones in the presence of ammonium acetate as the nitro-
gen source, two kinds of ring transformations competi-
tively proceed to give 4,5-disubstituted pyrimidines 3 and
5,6-disubstituted 3-nitro-2-pyridones 4 (Scheme 1).7 Pyri-
midinone 1 behaves as the synthetic equivalent of activat-
ed diformylamine in the former case, and behaves as that
of a-nitroformylacetic acid in the latter case. Since both
pyrimidine and 3-nitro-2-pyridone skeletons are often
found in biologically active compounds and synthetic in-
termediates of medicines,8 synthesis of either product on
demand provides a new methodology for this field.
When six p-substituted acetophenones 2b–g were used as
the substrate (runs 2–7), ring transformations effectively
proceeded except for the reaction using 2b, which was
somewhat complicated with side reactions caused by the
amino group. The ratios of 3:4 were markedly varied with
electronic properties of the substituent on the benzene
ring. While pyridones 4 were mainly produced in reac-
tions of 1 with electron-rich ketones 2b–e, the ratio of 3:4
was inverted in the case of electron-poor ketone 2g. 3-Ni-
troacetophenone (2h) showed similar reactivity to afford
pyrimidine 3h13 as the major product (run 8), however no
reaction was observed upon treatment of 1 with 2-nitro
derivative 2i because of steric hindrance besides strong
electron-withdrawing ability of the nitro group (run 9).
These results reveal that diminished electron density on
the carbonyl group is influential for the lower reactivity
and the formation of large amounts of 3. On the other
hand, all four methoxyacetophenones 2d and 2j–l effec-
tively caused the ring transformation to afford corre-
sponding products in good yields (runs 4 and 10–12). It is
noteworthy that the reactivity of these ketones is almost
the same, although 3-methoxy group only behaves as the
electron-withdrawing group for the carbonyl group.
Hence, the electron density on the benzene ring seems
more influential rather than that on the carbonyl group in
cases of electron-rich ketones.
In the present paper, the control of these ring transforma-
tions is studied, in which electronic properties of ketones
are focused by use of substituted acetophenones 2
(R = H), and a plausible reaction mechanism is newly pro-
vided. Furthermore, a new preparative method for bihetar-
yl compounds is represented.
A plausible mechanism is reconsidered on the basis of
above experimental results, which is different from sup-
posed one in our previous paper (Scheme 2).7 The ring
transformation is initiated with addition of ketone 2 at the
6-position of pyrimidinone 1. Since electron-rich ketone
easily approaches to 1, the reaction effectively proceeds to
give ring-transformed products in a good total yield. Ad-
duct 5 is considered to be a key intermediate for the selec-
tion of reaction paths leading to 3 or 4. When the benzene
The ring transformation of pyrimidinone 1 with acetophe-
none 2a afforded equal amounts of pyrimidine 3a8d and
pyridone 4a9 in an excellent total yield (Table 1, run 1).
SYNTHESIS 2004, No. 12, pp 1996–2000
x
x.
x
x
.
2
0
0
4
Advanced online publication: 02.08.2004
DOI: 10.1055/s-2004-829195; Art ID: F04804SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of Bihetaryl Compounds
1997
Table 1 Ring Transformation of Pyrimidinone 1 with Substituted
Acetophenones 2
O
O
B
O2N
OH
Me
O2N
Me
N
N
Yield (%)
Ratio of
N
N
Ar
A
Run
1
G
3
4
3:4
1
5
2
Ar
O
H
a
b
c
d
e
f
498d
trace
7
519
47
61
63
75
41
10
25
0
49:51
<1:>99
10:90
24:76
25:75
47:53
77:23
60:40
-
NH4OAc
Me
NH4OAc
A
B
2
4-NH2
4-NHAc
4-OMe
4-Me
O
N
OH
Me
H2N
O2N
3
O2N
N
N
4
2010
2511
37
N
5
Ar
Ar
O
NH2
6
4-Cl
8
6
7
4-NO2
3-NO2
2-NO2
3-MeO
2-MeO
2,4-(MeO)2
g
h
i
5212
3813
0
8
NO2
Me
NH
NO2
HO
HN
9
N
Ar
O
Ar
N
N
10
11
12
j
27
54
52
58
34:66
37:63
25:75
N
HO
H
Me
k
l
30
7
3
9
4
19
ring is substituted with electron-withdrawing group, the
more electrophilic carbonyl group A is predominantly
aminated to give enamine 6. The following intramolecular
attack of the amino group occurs at the less hindered 2-po-
sition to furnish bicyclic intermediate 7 from which ni-
troacetamide is eliminated affording pyrimidine 3. On the
other hand, the carbonyl group B is more readily aminated
when electron-rich ketone is employed. The amino group
of 8 attacks the carbonyl A to yield pyridone 4 via the bi-
cyclic intermediate 9. In consideration of the result for the
reaction using 3-methoxyacetophenone 2j, attractive in-
teraction between two rings in adduct 5 might facilitate
the reaction of ammonium ion with two carbonyl groups
as shown in Figure 1 which results in predominant forma-
tion of pyridone 4.
Scheme 2 A plausible mechanism for two ring transformations.
erocyclic ones 2p–s. Although almost equal amounts of
3m11 and 4m were furnished in the reaction with 3-
acetylpyridine (2m) (Table 2, run 1), pyridylpyrimidines
3n14 and 3o15 were predominantly formed in cases of 2n
and 2o having a more electron-poor acetyl group (runs 2
and 3). When electron-sufficient heterocyclic ketones 2p–
s were employed as substrates, exclusive formation of py-
ridones 4p–r was realized to our expectation (runs 4–9).
In summary, the possibility to control two ring transfor-
mations was shown from the viewpoint of electronic prop-
erties of ketones. Pyridylpyrimidines 3m–o and pyridones
substituted with a five-membered ring 4p–s could be ac-
tually prepared as a result of application of tendency that
was observed in reactions using acetophenones 2a–l.
Hence, the present ring transformation provides a new
methodology in synthetic chemistry of polyfunctionalized
heterocyclic compounds, which are not easily prepared by
alternative procedures.
O
+
NH4
OMe
MeN
O
N
H
O2N
Figure 1 Adduct intermediate of 1 and 2j.
The melting points were determined on a Yanaco micro-melting-
points apparatus, and are uncorrected. All the reagents and solvents
The ratio of 3:4 was influenced by electronic properties of
the substituent in a series of reactions of pyrimidinone 1
with acetophenones 2a–l. This observation prompted us to
study application of the present reaction to heterocyclic
ketones 2m–s. We considered pyrimidine derivatives
would be mainly formed in reactions using electron-defi-
cient heterocyclic ketones 2m–o, and pyridone derivative
would be obtained in those using electron-sufficient het-
were commercially available and used as received. 1H NMR and 13
C
NMR spectra were measured on a Bruker DPX-400 at 400 MHz and
at 100 MHz with TMS as an internal standard. 13C NMR assign-
ments (s, d and q) were made from DEPT experiments. IR spectra
were recorded on a Horiba FT-200 IR spectrometer. Elemental mi-
croanalyses were performed using a Yanaco MT-3 CHN recorder.
Since pyrimidines 3 are hygroscopic, it was difficult to obtain satis-
factory analytical data.
Synthesis 2004, No. 12, 1996–2000 © Thieme Stuttgart · New York

1998
N. Nishiwaki et al.
PAPER
1H NMR (CDCl3, 400 MHz): d = 2.23 (s, 3 H), 7.55 (br s, 2 H), 7.69
(d, J = 5.4 Hz, 1 H), 8.08 (d, J = 8.7 Hz, 2 H), 8.74 (d, J = 5.4 Hz, 1
H), 9.24 (s, 1 H).
Table 2 Synthesis of Bihetaryl Compounds
13C NMR (DMSO-d6, 100 MHz): d = 30.6 (q), 56.0 (s), 116.3 (d),
118.8 (d), 127.6 (d), 130.1 (s), 157.6 (d), 158.6 (d), 162.0 (s), 168.7
(s).
6-(4-Acetylaminophenyl)-3-nitro-2-pyridone (4c)
Yield (%)
Ratio of
Yellow powder; mp 260–268 °C (dec.).
IR (Nujol): 1678, 1556, 1377 cm–1.
Run
1
Het
Time (d)
3
4
3:4
3-pyridyl
4-pyridyl
2-pyridyl
2-pyrrolyl
2-pyrrolyl
3-pyrrolyl
3-pyrrolyl
2-thienyl
2-furyl
2
2
2
2
7
2
7
7
2
m
n
o
4411
4414
4915
0
38
9
54:46
84:16
98:2
1H NMR (DMSO-d6, 400 MHz): d = 2.09 (s, 3 H), 6.72 (br s, 1 H),
7.73 (d, J = 8.8 Hz, 2 H), 7.83 (d, J = 8.8 Hz, 2 H), 8.50 (d, J = 8.3
Hz, 1 H), 10.3 (s, 1 H), 12.9 (s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 24.1 (q), 102.0 (d), 118.7 (d),
123.8 (s), 128.2 (s), 128.6 (d), 138.3 (s), 140.3 (d), 142.4 (s), 155.1
(s), 168.9 (s).
2
3
1
4
p
24
47
34
68
72
60
0:100
0:100
0:100
0:100
0:100
18:82
5
0
Anal. Calcd for C13H11N3O4: C, 57.14; H, 4.06; N, 15.38. Found: C,
57.02; H, 4.18; N, 15.22.
6
q
0
6-(4-Methoxyphenyl)-3-nitro-2-pyridone (4d)
Yellow needles; mp 278–279 °C.
IR (Nujol): 1684, 1558, 1370 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 3.85 (s, 3 H), 6.73–6.75 (br s,
1 H), 7.10 (d, J = 8.9 Hz, 2 H), 7.85 (d, J = 8.9 Hz, 2 H), 8.48 (d,
J = 8.2 Hz, 1 H), 14.6–14.7 (br s, 1 H).
7
0
8
r
s
0
9
1316
13C NMR (DMSO-d6, 100 MHz): d = 55.6 (q), 102.4 (d), 114.5 (d),
3-Methyl-5-nitro-4(3H)-pyrimidinone (1)
Pyrimidin-4(3H)-one17 (2.00 g, 18.2 mmol) was gradually dis-
solved into cold 18 M H2SO4 (18 mL, 324 mmol), and then fuming
HNO3 (d = 1.52, 2.4 mL, 57.8 mmol) was added. After heating the
mixture at 100 °C for 7 h, it was poured onto ice. The pH of the mix-
ture was adjusted to 5, and it was extracted with CHCl3 (3 × 100
mL). The organic layer was dried (MgSO4), and concentrated under
reduced pressure giving crude nitropyrimidinone 1 (2.46 g) as a yel-
low solid. Further purification was performed with recrystallization
from EtOH to afford 1 (2.19 g, 78%) as yellow needles.
124.0 (s), 129.7 (d), 134.4 (s), 140.3 (d), 154.7 (s), 155.7 (s), 162.0
(s).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
58.65; H, 4.06; N, 11.23.
6-(4-Methylphenyl)-3-nitro-2-pyridone (4e)
Yellow needles; mp 195–196 °C.
IR (Nujol): 1680, 1516, 1350 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 2.38 (s, 3 H), 6.75 (d, J = 8.2
Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 8.49
(d, J = 8.2 Hz, 1 H), 13.0–13.1 (br s, 1 H).
Synthesis of Bihetaryl Compounds by Ring Transformation Re-
action; General Procedure
To a solution of pyrimidinone 1 (155 mg, 1.0 mmol) in MeOH (20
mL) were added acetophenone derivative 2 (2.0 mmol) and
NH4OAc (154 mg, 2.0 mmol) and the mixture was refluxed for 2 d.
During the reaction, 3-nitro-2-pyridone 4 precipitated, and the pre-
cipitates were collected by filtration. After concentration of the fil-
trate, the residue was extracted with benzene to give almost pure
pyrimidine 3, and further purification was performed on treatment
with column chromatography on silica gel.
13C NMR (DMSO-d6, 100 MHz): d = 21.0 (q), 102.9 (d), 127.7 (d),
129.0 (s), 129.6 (d), 135.2 (s), 140.2 (d), 141.8 (s), 154.6 (s), 155.4
(s).
Anal. Calcd for C12H10N2O3: C, 62.61; H, 4.38; N, 12.17. Found: C,
63.01; H, 4.30; N, 12.28.
4-(4-Chlorophenyl)pyrimidine (3f)
Yellow powder (eluted with CHCl3–EtOAc, 1:1); mp 84–90 °C
(dec.).
6-(4-Aminophenyl)-3-nitro-2-pyridone (4b)
IR (Nujol): 1599, 1558, 1093 cm–1.
Red powder; mp 234–240 °C (dec.).
IR (Nujol): 3471, 3375, 1680, 1524, 1380 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.13 (s, 2 H), 6.6-6.7 (br, 1 H),
6.64 (d, J = 8.7 Hz, 2 H), 7.67 (d, J = 8.7 Hz, 2 H), 8.43 (d, J = 8.5
Hz, 1 H), 12.5 (br s, 1 H).
1H NMR (DMSO-d6, 400 MHz): d = 7.63 (d, J = 8.5 Hz, 2 H), 8.12
(d, J = 5.4 Hz, 1 H), 8.24 (d, J = 8.5 Hz, 2 H), 8.89 (d, J = 5.4 Hz, 1
H), 9.26 (s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 117.1 (d), 128.7 (d), 129.0
(d), 134.7 (s), 136.1 (s), 158.1 (d), 158.7 (d), 161.3 (s).
13C NMR (DMSO-d6, 100 MHz): d = 101.1 (s), 114.0 (d), 117.2 (d),
130.1 (d), 132.6 (s), 141.1 (s), 153.5 (d), 155.8 (s), 155.9 (s).
Anal. Calcd for C10H7N2Cl: C, 63.01; H, 3.70; N, 14.70. Found: C,
62.80; H, 3.31; N, 14.84.
Anal. Calcd for C11H9N3O3: C, 57.14; H, 3.92; N, 18.17. Found: C,
57.06; H, 3.88; N, 18.35.
6-(4-Chlorophenyl)-3-nitro-2-pyridone (4f)
Yellow powder; mp 275–280 °C (dec.).
4-(4-Acetylaminophenyl)pyrimidine (3c)
IR (Nujol): 1687, 1558, 1353 cm–1.
Yellow powder (eluted with EtOH); mp 213–214 °C.
IR (Nujol): 3120, 1686 cm–1.
Synthesis 2004, No. 12, 1996–2000 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Bihetaryl Compounds
1999
1H NMR (DMSO-d6, 400 MHz): d = 6.81–6.83 (br s, 1 H), 7.62 (d,
J = 8.6 Hz, 2 H), 7.87 (d, J = 8.6 Hz, 2 H), 8.51 (d, J = 8.1 Hz, 1 H),
13.0–13.1 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 128.9 (d), 129.6 (d), 136.3 (s),
139.8 (d), 155.3 (s). The concentration of the sample was not
enough for observation of all of signals because of low solubility of
4f, and four signals were not detected.
6-(2-Methoxyphenyl)-3-nitro-2-pyridone (4k)
Yellow needles; mp 216–218 °C.
IR (Nujol): 1679, 1576, 1325, 1219, 1022 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 3.83 (s, 3 H), 6.50 (d, J = 8.0
Hz, 1 H), 7.10 (dd, J = 7.5, 7.5 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H),
7.45 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53 (ddd, J = 8.4, 7.5, 1.5 Hz), 8.48
(d, J = 8.0 Hz, 1 H), 12.8 (br s, 1 H).
Anal. Calcd for C11H7N2O3Cl: C, 52.71; H, 2.82; N, 11.18. Found:
C, 52.55; H, 2.90; N, 11.23.
13C NMR (DMSO-d6, 100 MHz): d = 55.7 (q), 104.9 (s), 111.9 (d),
120.5 (d), 121.0 (d), 130.2 (d), 132.6 (d), 135.8 (s), 139.9 (d), 152.5
(s), 154.5 (s), 156.6 (s).
3-Nitro-6-(4-nitrophenyl)-2-pyridone (4g)
Yellow powder; mp 272–285 °C (dec.).
1H NMR (DMSO-d6, 400 MHz): d = 6.8–7.1 (br s, 1 H), 8.1–8.2 (br
s, 2 H), 8.36 (d, J = 8.7 Hz, 2 H), 8.53 (d, J = 8.0 Hz, 1 H), 13.1–
13.2 (br s, 1 H).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
58.35; H, 4.01; N, 11.38.
4-(2,4-Dimethyoxyphenyl)pyrimidine (3l)
Yellow needles (eluted with CHCl3–EtOAc, 1:1); mp 100–102 °C.
Anal. Calcd for C11H7N3O5: C, 50.62; H, 2.70; N, 16.10. Found: C,
50.75; H, 2.72; N, 16.17.
IR (Neat): 1583, 1479, 1379 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 3.88 (s, 3 H), 3.91 (s, 3 H),
6.55 (d, J = 2.3 Hz, 1 H), 6.60 (dd, J = 8.6, 2.3 Hz, 1 H), 7.97 (d,
J = 5.4 Hz, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 8.64 (d, J = 5.4 Hz, 1 H),
9.20 (s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 55.7 (q), 56.0 (q), 98.9 (d),
106.3 (d), 117.7 (s), 120.9 (d), 131.8 (d), 156.9 (d), 158.6 (s), 159.7
(d), 161.4 (s), 162.9 (s).
3-Nitro-6-(3-nitrophenyl)-2-pyridone (4h)
Yellow powder; mp 241–242 °C.
1H NMR (DMSO-d6, 400 MHz): d = 7.05 (br s, 1 H), 7.85 (dd,
J = 8.0, 8.1 Hz, 1 H), 8.30 (d, J = 8.1 Hz, 1 H), 8.40 (dd, J = 8.0, 1.5
Hz, 1 H), 8.53 (J = 8,1 Hz, 1 H), 8.72 (s, 1 H), 13.2 (s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 112.4 (d), 122.9 (d), 125.8
(d), 129.6 (s), 130.8 (d), 134.4 (d), 139.6 (s), 142.2 (s), 145.5 (s),
148.2 (d), 155.5 (s).
6-(2,4-Dimethoxyphenyl)-3-nitro-2-pyridone (4l)
Yellow powder; mp 228–229 °C.
IR (Nujol): 1558, 1376 cm–1.
4-(3-Methyoxyphenyl)pyrimidine (3j)
1H NMR (DMSO-d6, 400 MHz): d = 3.85 (s, 6 H), 6.51 (d, J = 8.1
Hz, 1 H), 6.66 (dd, J = 8.5, 2.0 Hz, 1 H), 6.71 (d, J = 2.0 Hz, 1 H),
7.45 (d, J = 8.5 Hz, 1 H), 8.46 (d, J = 8.1 Hz, 1 H), 12.6 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 55.9 (q), 56.2 (q), 99.1 (d),
104.8 (d), 106.1 (d), 113.6 (s), 131.8 (d), 135.0 (s), 140.6 (d), 153.2
(s), 154.9 (s), 158.6 (s), 163.5 (s).
Yellow oil (eluted with CHCl3–EtOAc, 1:1).
IR (neat): 1473, 1232, 1039 cm–1.
1H NMR (CDCl3, 400 MHz): d = 3.91 (s, 3 H), 7.06 (d, J = 5.4 Hz,
1 H), 7.4–7.7 (m, 4 H), 8.76 (d, J = 5.4 Hz, 1 H), 9.26 (s, 1 H).
13C NMR (CDCl3, 100 MHz): d = 55.5 (q), 112.1 (d), 117.2 (d),
117.3 (d), 119.5 (d), 130.1 (d), 137.8 (s), 157.3 (d), 158.9 (d), 160.2
(s), 163.9 (s).
Anal. Calcd for C13H12N2O5: C, 56.52; H, 4.38; N, 10.14. Found: C,
56.23; H, 4.29; N, 10.12.
6-(3-Methoxyphenyl)-3-nitro-2-pyridone (4j)
Yellow powder; mp 252–253 °C.
IR (Nujol): 1695, 1560, 1377, 1219, 1047 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 3.85 (s, 3 H), 6.7–6.9 (br s, 1
H), 7.14 (dd, J = 7.1, 2.2 Hz, 1 H), 7.4–7.5 (m, 3 H), 8.50 (d, J = 8.1
Hz, 1 H), 13.0 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 55.3 (q), 112.5 (d), 117.6 (d),
117.6 (s), 120.0 (d), 125.3 (d), 130.1 (d), 132.8 (s), 140.1 (d), 153.9
(s), 155.1 (s), 159.4 (s).
3-Nitro-6-(3-pyridyl)-2-pyridone (4m)
Yellow powder; mp 270–276 °C (dec.).
IR (Nujol): 1678, 1510, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.90 (br s, 1 H), 7.58 (dd,
J = 7.9, 4.9 Hz, 1 H), 8.23 (d, J = 7.9 Hz, 1 H), 8.53 (d, J = 8.0 Hz,
1 H), 8.74 (d, J = 4.9 Hz, 1 H), 9.02 (s, 1 H), 13.2 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 123.6 (d), 135.4 (d), 138.7
(d), 148.4 (d), 151.7 (d), 155.2 (s). The concentration of the sample
was not enough for observation of all of signals because of low sol-
ubility of 4m, and four signals were not detected.
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
58.43; H, 4.06; N, 11.37.
Anal. Calcd for C10H7N3O3: C, 55.30; H, 3.25; N, 19.35. Found: C,
55.39; H, 2.94; N, 19.52.
4-(2-Methyoxyphenyl)pyrimidine (3k)
Yellow oil (eluted with CHCl3–EtOAc, 1:1).
IR (neat): 1458, 1024 cm–1.
3-Nitro-6-(4-pyridyl)-2-pyridone (4n)
Yellow solid; mp 280–285 °C (dec.).
IR (Nujol): 1678, 1560, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.96 (d, J = 7.9 Hz, 1 H), 7.85
(d, J = 5.5 Hz, 2 H), 8.46 (d, J = 7.9 Hz, 1 H), 8.74 (d, J = 5.5 Hz, 2
H).
1H NMR (CDCl3, 400 MHz): d = 3.91 (s, 3 H), 7.03 (d, J = 5.3 Hz,
1 H), 7.11 (dd, J = 7.5, 7.4 Hz, 1 H), 7.45 (ddd, J = 7.5, 5.4, 1.7 Hz,
1 H), 7.96 (d, J = 5.4 Hz, 1 H), 7.99 (dd, J = 7.4, 1.7 Hz, 1 H), 8.70
(J = 5.3 Hz, 1 H), 9.27 (s, 1 H).
13C NMR (CDCl3, 100 MHz): d = 55.5 (q), 111.4 (d), 121.1 (d),
121.9 (d), 125.8 (s), 130.9 (d), 131.9 (d), 156.2 (d), 157.8 (s), 158.6
(d), 162.6 (s).
13C NMR (DMSO-d6, 100 MHz): d = 104.8 (d), 121.5 (d), 136.3 (s),
138.9 (d), 140.2 (s), 150.2 (d), 152.5 (s), 156.3 (s).
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
70.75; H, 5.32; N, 14.81.
Synthesis 2004, No. 12, 1996–2000 © Thieme Stuttgart · New York

2000
N. Nishiwaki et al.
PAPER
3-Nitro-6-(2-pyridyl)-2-pyridone (4o)
The presence of small amount of 4o was confirmed by H NMR
spectroscopy.
1H NMR (DMSO-d6, 400 MHz): d = 7.2–7.5 (br s, 1 H), 7.61 (dd,
J = 7.5, 7.4 Hz, 1 H), 8.05 (dd, J = 7.8, 7.5 Hz, 1 H), 8.25 (d, J = 7.8
Hz, 1 H), 8.57 (d, J = 7.4 Hz, 1 H), 8.78 (d, J = 4.4 Hz, 1 H), 12.5
(br s, 1 H).
Chem. 1996, 33, 1003. (d) Rusinov, V. L.; Chupakhin, O.
N.; van der Plas, H. C. Heterocycles 1995, 40, 441. (e) van
der Plas, H. C. Ring Transformations of Heterocycles, Vol.
1; Academic Press: London, 1973. (f) van der Plas, H. C.
Ring Transformations of Heterocycles, Vol. 2; Academic
Press: London, 1973.
1
(2) (a) Nishiwaki, N.; Matsushima, K.; Tamura, M.; Asaka, N.;
Hori, K.; Tohda, Y.; Ariga, M. Arkivoc 2002, x, 34; www.
arkat-usa.org. (b) Tohda, Y.; Kawahara, T.; Eiraku, M.;
Tani, K.; Nishiwaki, N.; Ariga, M. Bull. Chem. Soc. Jpn.
1994, 67, 2176.
(3) (a) Nishiwaki, N.; Nakanishi, M.; Hida, T.; Miwa, Y.;
Tamura, M.; Hori, K.; Tohda, Y.; Ariga, M. J. Org. Chem.
2001, 66, 7535. (b) Nishiwaki, N.; Ohtomo, H.; Tamura, M.;
Hori, K.; Tohda, Y.; Ariga, M. Heterocycles 2001, 55, 1581.
(c) Nishiwaki, N.; Nogami, T.; Kawamura, T.; Asaka, N.;
Tohda, Y.; Ariga, M. J. Org. Chem. 1999, 64, 6476.
(4) (a) Nishiwaki, N.; Matsushima, K.; Chatani, M.; Tamura,
M.; Ariga, M. Synlett 2004, 703. (b) Nishiwaki, N.;
Morimura, H.; Matsushima, K.; Tamura, M.; Ariga, M.
Heterocycles 2003, 61, 19.
3-Nitro-6-(2-pyrrolyl)-2-pyridone (4p)
Brown solid; mp 210–215 °C (dec.).
IR (Nujol): 3300, 1670, 1558, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.33 (br s, 1 H), 6.74 (d,
J = 8.5 Hz, 1 H), 7.29 (br s, 1 H), 7.39 (br s, 1 H), 8.49 (d, J = 8.5
Hz, 1 H), 12.0 (br s, 1 H), 12.5 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 98.5 (d), 111.4 (d), 115.3 (d),
122.8 (s), 126.6 (d), 131.4 (s), 141.0 (d), 146.8 (s), 155.0 (s).
Anal. Calcd for C9H7N3O3: C, 52.69; H, 3.44; N, 20.48. Found: C,
52.88; H, 3.21; N, 20.86.
3-Nitro-6-(3-pyrrolyl)-2-pyridone (4q)
Orange powder; mp 274–280 °C (dec.).
IR (Nujol): 3307, 1651, 1556, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.68 (d, J = 8.5 Hz, 1 H), 6.88
(br s, 1 H), 6.95 (br s, 1 H), 7.93 (d, J = 1.3 Hz, 1 H), 8.43 (d, J = 8.5
Hz, 1 H), 11.7 (br s, 1 H), 12.5 (br s, 1 H).
(5) Nishiwaki, N.; Tohda, Y.; Ariga, M. Synthesis 1997, 1277.
(6) Nishiwaki, N.; Azuma, M.; Tamura, M.; Hori, K.; Tohda,
Y.; Ariga, M. Chem. Commun. 2002, 2170.
(7) Nishiwaki, N.; Adachi, T.; Matsuo, K.; Wang, H.-P.;
Matsunaga, T.; Tohda, Y.; Ariga, M. J. Chem. Soc., Perkin
Trans. 1 2000, 27.
(8) (a) Konakahara, T.; Ogawa, R.; Tamura, S.; Kakehi, A.;
Sakai, N. Heterocycles 2001, 55, 1737. (b) Stadlbauer, W.;
Fiala, W.; Fischer, M.; Hojas, G. J. Heterocycl. Chem. 2000,
37, 1253. (c) Garg, R.; Gupta, S. P.; Gao, H.; Babu, M. S.;
Debnath, A. K.; Hansch, C. Chem. Rev. 1999, 99, 3525.
(d) Olejniczak, E. T.; Hajduk, P. J.; Marcotte, P. A.;
Nettesheim, D. G.; Meadows, R. P.; Edalji, R.; Holzman, T.
F.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 5828.
(e) Pomel, V.; Rovera, J. C.; Godard, A.; Marsais, F.;
Queguiner, G. J. Heterocycl. Chem. 1996, 33, 1995.
(f) Landquist, J. K. In Comprehensive Heterocyclic
Chemistry, Vol. 1; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon: Oxford, 1984, 144–183. (g) Brown, D. J. In
Comprehensive Heterocyclic Chemistry, Vol. 3; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, 142–155.
(9) Shusherina, N. P.; Likhomanova, T. I. Chem. Heterocycl.
Compd. (Engl. Transl.) 1974, 1242; Khim. Geterotskl.
Soedin. 1972, 1374.
13C NMR (DMSO-d6, 100 MHz): d = 99.8 (d), 107.3 (d), 115.2 (s),
121.0 (d), 122.7 (d), 131.2 (d), 140.9 (d), 152.1 (s), 155.2 (s).
Anal. Calcd for C9H7N3O3: C, 52.69; H, 3.44; N, 20.48. Found: C,
52.29; H, 3.39; N, 20.08.
3-Nitro-6-(2-thienyl)-2-pyridone (4r)
Yellow needles; mp 250–256 °C (dec.).
IR (Nujol): 1672, 1560, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 7.28 (dd, J = 4.7, 4.1 Hz, 1 H),
7.7–7.8 (br s, 1 H), 7.93 (d, J = 4.7 Hz, 1 H), 8.07 (d, J = 4.1 Hz, 1
H), 8.45 (d, J = 8.3 Hz, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 125.3 (d), 126.4 (s), 128.3 (d),
129.1 (d), 130.1 (d), 132.3 (s), 139.7 (d), 145.2 (s), 155.3 (s).
Anal. Calcd for C9H6N3O3S: C, 48.64; H, 2.72; N, 12.61. Found: C,
48.88; H, 2.50; N, 12.54.
(10) (a) Balasubrahmanyam, S. N.; Jeyashri, B.; Namboothiri, I.
N. N. Tetrahedron 1994, 50, 8127. (b) Jones, H.; Fordice,
M. W.; Greenwald, R. B.; Hannah, J.; Jacobs, A.; Ruyle, W.
V.; Walford, G. L.; Shen, T. Y. J. Med. Chem. 1978, 21,
1100.
(11) Bredereck, H.; Gompper, R.; Herlinger, H. Chem. Ber. 1958,
91, 2832.
(12) Lynch, B. M.; Poon, L. Can. J. Chem. 1967, 45, 1431.
(13) Brown, D. J.; England, B. T. J. Chem. Soc. C 1971, 425.
(14) Bennett, G. B.; Mason, R. B.; Alden, L. J.; Roach, J. B. Jr. J.
Med. Chem. 1978, 21, 623.
(15) (a) Beauchamp, D. A.; Loeb, S. J. Chem. Commun. 2002,
2484. (b) Poson, M. I. J.; Lotoski, J. A.; Johansson, K. O.;
Taylor, N. J.; Hanan, G. S.; Hasenknopf, B.; Thouvenot, R.;
Loiseau, F.; Passalaqua, R.; Campagna, S. Eur. J. Inorg.
Chem. 2002, 2549. (c) Cuccia, L. A.; Ruiz, E.; Lehn, J.-M.;
Homo, J.-C.; Schmutz, M. Chem.–Eur. J. 2002, 8, 3448.
(16) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801.
(17) Bauer, L.; Wright, G. E.; Mikrut, B. A.; Bell, C. L. J.
Heterocycl. Chem. 1965, 2, 447.
6-(2-Furyl)-3-nitro-2-pyridone (4s)
Yellow powder; mp 241–245 °C (dec.).
IR (Nujol): 1664, 1560, 1377 cm–1.
1H NMR (DMSO-d6, 400 MHz): d = 6.76 (d, J = 8.2 Hz, 1 H), 6.79
(dd, J = 3.5, 1.8 Hz, 1 H), 7.70 (d, J = 3.5 Hz, 1 H), 8.07 (s, 1 H),
8.52 (d, J = 8.2 Hz, 1 H), 13.0 (br s, 1 H).
13C NMR (DMSO-d6, 100 MHz): d = 99.9 (d), 113.4 (d), 115.2 (d),
134.7 (s), 140.6 (d), 143.4 (s), 145.1 (s), 147.7 (d), 154.8 (s).
Anal. Calcd for C9H6N2O4: C, 52.43; H, 2.93; N, 13.59. Found: C,
52.04; H, 2.61; N, 13.68.
References
(1) Reviews for ring transformations: (a) Gromov, S. P.
Heterocycles 2000, 53, 1607. (b) van der Plas, H. C. Adv.
Heterocycl. Chem., Vol. 74; Academic Press: London,
1999. (c) Takagi, K.; Hubet-Habart, M. J. Heterocycl.
Synthesis 2004, No. 12, 1996–2000 © Thieme Stuttgart · New York