A novel method for the synthesis of 3-fluoro-4-aryl-2-pyridone via unprecedented denitration

Article abstract of DOI:10.1016/j.tet.2011.01.047

A simple and novel method to the synthesis of 3-fluoro-4-aryl-2-pyridone from a Michael-adduct of fluoronitroacetate and α,β-unsaturated ketone is reported. With (NH₄)₂CO₃ as the N-source and TsOH as the promoted acid, a s

Full text of DOI:10.1016/j.tet.2011.01.047

Tetrahedron 67 (2011) 2468e2473
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel method for the synthesis of 3-fluoro-4-aryl-2-pyridone via
unprecedented denitration
,
,
,
a,
*
Xiao-Wei Wang a b, Hai-Feng Cui a b, Hai-Feng Wang b, Ying-Quan Yang b, Gang Zhao b , Shi-Zheng Zhu
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Key Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and novel method to the synthesis of 3-fluoro-4-aryl-2-pyridone from a Michael-adduct of
fluoronitroacetate and -unsaturated ketone is reported. With (NH4)2CO3 as the N-source and TsOH as
the promoted acid, a series of fluorinated-pyridones was obtained with moderate to good yields.
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Received 24 November 2010
Received in revised form 13 January 2011
Accepted 18 January 2011
a,b
Available online 22 January 2011
Keywords:
Cyclization
Denitration
Fluorine-containing 2-pyridone
a,b-Unsaturated ketone
1. Introduction
Numerous methods for construction of cyclic compounds from
easily available starting materials have been developed.6 Generally,
Considerable attention has been given to the assembly of 2-pyr-
idone core structure for many years because these structural motifs,
which possess potent pharmacological and agrochemical activities
are found in a very large number of biologically active natural
products and related congeners,1 such as the Camptothecins,2 drug
candidates active against leukemia,2b Huperzine A,3 a potent acetyl-
choline esterase inhibitor,3b Lyconadin A, which was demonstrated to
possess modest anticanceractivity,4 and Merck’s L-697,661,5 anHIV-1
reverse transcriptase inhibitor (Fig. 1).
there are two mainly synthetic approaches to elaborate 2-pyridone
rings, one of which is conversion from other heterocyclics, such as
the oxidation of an N-substituted pyridinium salt,7 and the other is
condensation from acyclic compounds using Knovenagel-type re-
actions,8 such as cross-condensation of cyanoacetoamide with
b
-dicarbonyl compounds or 2-pyrones with amides. Recently,
Smith9 has reported an efficient protocol to annulate the 5,6-fused
2-pyridonering system, exploiting a tandem condensation of pro-
piolamide and cyclic
b
-keto methyl esters inwater, followed byacid-
O
O
Me
H
HN
H
H
O
N
H
N
O
H
O
N
OH
N
Me
H
H2N
Camptothecin
Huperzine A (HA)
Lyconadin A
Fig. 1. Some natural products with pyridone unit.
* Corresponding authors. Tel.: þ86 21 54925183; fax: þ86 21 64166128; e-mail
address: zhusz@mail.sioc.ac.cn (S.-Z. Zhu).
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.047

X.-W. Wang et al. / Tetrahedron 67 (2011) 2468e2473
2469
Table 2
or base-promoted intramolecular ring closure and decarboxylation.
a
Optimization of the cyclization conditions
This method could be employed in the syntheses of huperzine A and
analogues. However, the methods to synthesize fluorine-containing
2-pyridone core structure have been rarely reported. Schlosser10
reported a simple procotol to synthesis 3-fluoro-2-quinolones
from anilines and methyl 2-fluoro-3-methoxyprop-2-enoate via
a KnorreEffenberger-type reaction under stronglyacidic conditions.
H
N
F
O
F
Conditions
THF
O2N
Ph
COOEt
O
Ph
5a
3a
Entry
N-source (equiv)
Additive (equiv)
T (ꢀC)
Yield (%) b
2. Results and discussion
1
2
3
4
5
6
7
8
NH4OAc (10)
NH4OAc (10)
NH4OAc (10)
NH4OAc (5)
NH4OAc (15)
NH4Cl (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
(NH4)2CO3 (10)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
TsOH (0.2)
None
Et3N (0.2)
TsOH (1.0)
TsOH (2.0)
CF3COOH (2.0)
CF3SO3H (2.0)
p-NBA (2.0)
Reflux
60
40
56
55
45
52
55
NR
66
NR
NR
74
80
59
52
NR
Herein we developed a simple and novel method to synthesis of
3-fluoro-4-aryl-2-pyridone in moderate to good yields. Ketoesters
(3) can be prepared via Michael addition of fluoronitroacetates (1)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
with a,b-unsaturated methyl ketones (2) with good yields. Then,
with an ammonium salt and Brønsted acid, ketoesters (3) can be
easily converted to 3-fluoro-4-aryl-2-pyridones at 100 ꢀC.
Firstly, the Michael addition11 of ethyl 2-fluoro-2-nitroacetate
(1a) and (E)-4-phenylbut-3-en-2-one (2a) with some bases, such as
DBU, DABCO, Na2CO3 etc. was examined in CH2Cl2 at room tem-
perature. However, no product was observed fallaciously except
that using Et3N as catalyst at 40 ꢀC, which afforded the ketoester 3a
with about 40% yield. An advantageous method using N0,N0-dime-
thylethane-1,2-diamine (4) as catalyst and 4-nitrobenzoic acid as
cocatalyst could improve the yield to 85%, With this condition at
hand, a lot of ketoesters 3 with various substituents were prepared
with 75e85% yield (Table 1).
9
10
11
12
13
14
a
Unless otherwise noted, the reaction was carried out with 3 (0.1 mmol) in THF
ꢀ
(1.0 mL) and 50 mg of MS 4 A was used as additive.
b
Yield of the isolated product after column chromatography on silica gel.
Contrastively, if there was no additive or using Et3N as the additive,
no reaction was observed (Table 2, entries 8 and 9). When
reviewing the type and amount of Brønsted acid, we found that
2 equiv of TsOH was the optimal condition (Table 2, entries 10 and
11). Whenever CF3COOH, CF3SO3H or p-nitrobenzoic acid was used,
no better result was observered (Table 2, entries 12e14).
Table 1
Michael addition of fluoronitroacetates with a,b
-unsaturated methyl ketones a
Next, we examined the influence of solvent on the isolated yield.
Slightly lower yields were obtained with the use of chlorine-con-
taining solvents, such as CHCl3 and ClCH2CH2Cl (Table 3, entries 4
and 5). When CCl4 was used as solvent, no product was observed
(Table 3, entry 6). If we changed the solvent into ether, such as PhOMe
and1,4-dioxane, theyieldwerealsoaround60%(Table 3, entries2and
7). Fortunately, when toluene or xylene was used as solvent and the
reaction temperature was up to 100 ꢀC, the yield could increased to
more than 85% (Table 3, entries 8 and 9). However, DMF being
employed as solvent led to lower yield (Table 3, entry 10). Thus, the
optimum reaction condition for the transformation was that with
10 equiv of (NH4)2CO3 and 2 equiv of TsOH in xylene at 100 ꢀC.
With the optimized condition at hand, a series of 2-fluoro-2-
nitro-5-oxo-3-arylhexanote (3aem) for the cyclization reaction
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
C6H5
Et
Et
Et
Et
Et
Et
Et
3a
3b
3c
3d
3e
3f
85
81
80
82
77
80
78
4-BrC6H4
4-MeOC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
O
3g
8
Et
3h
79
O
Table 3
9
4-NO2C6H4
2-naphthyl
2-furan
n-C4H9
C6H5
Et
Et
Et
Et
3i
3j
3k
3l
3m
82
77
80
75
78
a
Screening of solvents for the cyclization conditions
10
11
12
13
i-Pr
a
Isolated yield of the product after column chromatography on silica gel.
Having established a good method for the synthesis of g-fluo-
Entry
Solvent
Yield(%)b
roketone 3, a further conversion of this product to other useful
compounds was investigated. As a test reaction, the cyclization of
ethyl-2-fluoro-2-nitro-5-oxo-3-phenylhexanote (3a) was initially
studied with several different ammonium salt and additives in THF
at varied temperatures (Table 2). When we used 10 equiv NH4OAc
as ammonium salt and 0.2 equiv TsOH as additives at different
temperatures, it was found that when the reaction temperature
was up to the bp, the desired product (5a) was provided in higher
yield (56%, Table 2, entries 1e3). While changing the amount of
NH4OAc to 5 or 15 equiv, the desired product was obtained in 52%
and 55% yield, respectively (Table 2, entries 4 and 5). No reaction
was observed when using NH4Cl as ammonium salt, but the yield
could increased to 66% with (NH4)2CO3 (Table 2, entries 6 and 7).
1
CH3CN
PhOMe
EtOH
CHCl3
DCE
55
62
69
49
56
NR
55
86
89
74
2c
3
4
5
6
CCl4
7c
8c
9c
10c
Dioxane
Toluene
Xylene
DMF
a
Unless otherwise noted, the reaction was carried out with 3 (0.1 mmol) in
ꢀ
solvent (1.0 mL) using 4 A MS (50 mg) as the additive.
b
Isolated yield of the product after column chromatography on silica gel.
The reaction was conducted at 100 ꢀC.
c

2470
X.-W. Wang et al. / Tetrahedron 67 (2011) 2468e2473
were examined (Table 4). Generally, most of the examined
substrates with different R1 group, including electron with-
drawing, electron donating or heterocycle substitution, partici-
pated in the reaction smoothly and the reaction completed in
1e2 days to provide the desired products with more than 80%
yields (Table 4, entries 1e7, 10, and 13). When the R1 group was
2-naphthyl or 4-nitrophenyl, the yield slightly declined to 69%
and 76%, respectively (Table 4, entries 8 and 9). Unfortunately,
when the R1 group was n-butyl, no reaction was observed (Table
4, entry 12).
Based on the experimental results, two plausible mechanisms
for the cyclization reaction of 3 were showed in Scheme 1. In path A,
Table 4
Scope of the cyclization reaction to synthesize 3-fluoro-4-aryl-2-pyridonea
H
F
N
O
F
COOR2
O
(NH4)2CO3 (10 equiv.)
TsOH (2 equiv.)
xylene 100 oC
O2N
R1
R1
5a-k
3a-m
b
Entry
1
Substrate
Product
Yield(%)
89
F
O
F
O2N
COOEt
O
HN
Ph
(5a)
(3a)
F
O
F
O2N
COOEt
O
2
3
4
5
86
82
85
83
HN
Br
(5b)
(5c)
Br
(3b)
F
O2N
COOEt
O
O
F
HN
OMe
MeO
(3c)
F
O
F
O2N
COOEt
O
HN
Cl
(5d)
Cl
F
(3d)
O2N
Cl
COOEt
O
O
F
HN
Cl
(5e)
(3e)
F
O
F
F
F
O2N
COOEt
O
6
7
8
82
84
85
HN
Cl
(5f)
(5g)
(5h)
Cl
F
(3f)
F
F
O
O2N
O2N
COOEt
O
HN
F
(3g)
O
COOEt
O
HN
O
O
O
O
(3h)
(3i)
F
O
F
O2N
COOEt
O
9
76
HN
NO2
(5i)
O2N

X.-W. Wang et al. / Tetrahedron 67 (2011) 2468e2473
2471
Table 4 (continued )
Entry
Substrate
Product
Yield(%) b
F
O
F
O2N
COOEt
O
10
69
81
HN
(5j)
(3j)
F
O
F
O2N
O
COOEt
O
O
11
12
HN
(5k)
(3k)
F
O2N
COOEt
O
NR
e
n-C4H9
(3l)
O
F
F
O2N
COOi-Pr
O
13
81
HN
Ph
Ph
(3m)
(5a)
a
ꢀ
Unless otherwise noted, the reaction was carried out with 3 (0.1 mmol) in THF (1.0 mL) using 4 A MS (50 mg) as the additive.
Isolated yield of the product after column chromatography on silica gel.
b
O
COOR2
NH
F
F
O2N
R1
COOR2
NH2
F
O2N
R1
denitro group
(NH4)2CO3
H+
O2N
R1
NH
5
Path A
3
A'
B'
O
N
O
F
CONH2
O
F
F
O2N
(NH4)2CO3
H+
denitro group
O2N
R1
O2N
R1
NH
5
Path B
3
R1
A
B
Scheme 1. Two plausible mechanisms for the cyclization reaction of 3.
3 reacted with (NH4)2CO3 to give imine Aʹ, which was easily
isomerized to enamine. After an intramolecular amidation, the in-
termediate Bʹ was obtained and then converted to 5 with a denitro-
group step. In path B, an amide was obtained firstly and reacted
with ketone to give intermediate B. After an isomerization and
denitro-group reaction, the desired product was then obtained.
All solvents were distilled prior to use unless otherwise noted.
All reactions sensitive to moisture or oxygen were conducted under
an atmosphere of nitrogen or argon.
4.2. General procedure for the preparation of 3-fluoro-4-aryl-
2-pyridone (5)
3. Conclusion
Under an atmosphere of argon, a solution of compound (3)
(0.1 mmol), TsOH (0.2 mmol, 34 mg), (NH4)2CO3 (1 mmol, 96 mg),
and 4 A MS (40 mg) in xylene (1.0 mL) was heated at 100 ꢀC for
ꢀ
In summary, we have developed a novel and simple method to
synthesize a series of monofluorinated pyridones via intramolecular
cyclization/denitro-group reactions. By using commercial available
ammonium salt ((NH4)2CO3) and Brønsted acid (TsOH), the desired
products were obtained with up to 89% yields in xylene at 100 ꢀC.
Further application of this reaction is in progress in our laboratory.
appropriate times. When the reaction was completed (monitored
by TLC), the reaction system was cooled to room temperature. After
removal of the solvent under reduced pressure, the crude product
was purified directly by column chromatography on silica gel
(hexanes/EtOAc¼2/1) to afford the desired products.
4. Experimental
4.1. General
4.2.1. 3-Fluoro-6-methyl-4-phenylpyridin-2(1H)-one
89%; yellowish brown solid; mp: 198e199 ꢀC, IR (CH2Cl2, film):
3402, 2165, 1661, 1497, 1183, 1126, 1046, 749, 692 cmꢁ1 1H NMR
(5a). Yield:
;
(300 MHz, CDCl3):
d
¼13.23 (br s, 1H), 7.58 (d, J¼7.8 Hz, 2H),
1H and 13C NMR spectra were recorded at 300 and 100 MHz,
respectively, with TMS as the internal standard. 19F NMR spectra
were recorded at 282 MHz with CFCl3 as the external standard. IR
spectra were recorded in cmꢁ1. Melting points were uncorrected.
7.51e7.48 (m, 3H), 6.14 (d, J¼5.4 Hz, 1H), 2.42 (s, 3H); 13C NMR
(100 MHz, CDCl3/CD3OD): 157.9 (d, J¼27.1 Hz), 146.4 (d,
J¼244.2 Hz), 139.4 (d, J¼5.8 Hz), 136.3 (d, J¼9.0 Hz), 132.9,
129.2128.5, 128.4(d, J¼6.7 Hz), 106.4, 17.9; 19F NMR (CDCl3):

2472
X.-W. Wang et al. / Tetrahedron 67 (2011) 2468e2473
d
¼ꢁ146.0 (s, 1F); MS (ESI) (m/z): 226 (MþNaþ); HRMS calcd for
d
¼ꢁ145.0 (s, 1F), ꢁ111.8 (m, 1F); MS (ESI) (m/z): 244 (MþNaþ);
C12H10NFO: 203.0746, found: 203.0747.
HRMS calcd for C12H9NF2O: 221.0652, found: 221.0656.
4.2.2. 4-(4-Bromophenyl)-3-fluoro-6-methylpyridin-2(1H)-one
(5b). Yield: 86%; yellowish brown solid; mp: 238e239 ꢀC, IR
(CH2Cl2, film): 3411, 2853, 1670, 1477, 1182, 1144, 1049, 761,
4.2.8. 4-(Benzo[d][1,3]dioxol-5-yl)-3-fluoro-6-methylpyridin-2(1H)-
one (5h). Yield: 85%; yellowish brown solid; mp: 225e226 ꢀC, IR
(CH2Cl2, film): 3434, 2921, 1659, 1456, 1188, 1160, 1032, 761,
659 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼13.25 (br s, 1H), 7.53 (d,
662 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
¼7.08 (d, J¼8.1 Hz, 2H), 6.91
J¼7.8 Hz, 2H), 7.38 (d, J¼7.2 Hz, 2H), 6.02 (d, J¼4.8 Hz, 1H), 2.35 (s,
3H); 13C NMR (100 MHz, CDCl3): 158.7 (d, J¼24.6 Hz), 146.4 (d,
J¼244.7 Hz), 140.0 (d, J¼6.1 Hz), 135.1 (d, J¼8.7 Hz), 132.0, 130.2 (d,
(d, J¼7.8 Hz, 2H), 6.14 (d, J¼5.1 Hz, 1H), 6.04 (s, 2H), 2.35 (s, 3H); 13C
NMR(100 MHz, CDCl3): 157.9 (d, J¼25.4 Hz), 148.6, 148.0, 146.5 (d,
J¼242.9 Hz), 139.1 (d, J¼5.6 Hz), 135.9 (d, J¼8.9 Hz), 126.4, 122.8 (d,
J¼4.3 Hz), 108.9, 108.4, 106.3, 101.5, 18.2; 19F NMR (CDCl3):
J¼3.7 Hz),123.8, 106.4, 18.8; 19F NMR (CDCl3):
¼ꢁ145.0 (s, 1F); MS
d
(ESI) (m/z): 306 (MþNaþ); HRMS calcd for C12H9NBrFO: 280.9852,
d
¼ꢁ145.9 (s, 1F); MS (ESI) (m/z): 270 (MþNaþ); HRMS calcd for
found: 280.9857.
C13H10NFO3: 247.0645, found: 247.0642.
4.2.3. 3-Fluoro-4-(4-methoxyphenyl)-6-methylpyridin-2(1H)-one
(5c). Yield: 82%; yellowish brown solid; mp: 234e235 ꢀC, IR
(CH2Cl2, film): 3417, 2918, 1665, 1451, 1182, 1145, 1031, 762,
4.2.9. 3-Fluoro-6-methyl-4-(4-nitrophenyl)pyridin-2(1H)-one
(5i). Yield: 76%; yellowish brown solid; mp: 251e252 ꢀC, IR (CH2Cl2,
film): 3409, 2190, 1673, 1519, 1184, 1119, 1048, 749, 696 cmꢁ1 1H
;
664 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼13.11 (br s, 1H), 7.56 (d,
NMR (300 MHz, DMSO-d6):
d
¼12.29 (br s,1H), 8.34 (d, J¼6.0 Hz, 2H),
J¼6.0 Hz, 2H), 7.02 (d, J¼6.6 Hz, 2H), 6.15 (d, J¼4.8 Hz, 1H), 3.90 (s,
3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): 158.7 (d, J¼25.4 Hz),
146.4 (d, J¼228.8 Hz), 139.4 (d, J¼6.7 Hz), 135.6 (d, J¼8.1 Hz), 130.1,
7.85 (d, J¼8.4 Hz, 2H), 6.18 (d, J¼5.4 Hz, 1H), 2.22 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): 156.5 (d, J¼26.4 Hz), 146.4 (d, J¼243.0 Hz),
141.1, 140.0, 132.4 (d, J¼8.6 Hz),130.4 (d, J¼3.7 Hz),129.1,124.2,103.4,
130.1, 125.3, 114.2, 106.1, 55.4, 18.8; 19F NMR (CDCl3):
d
¼ꢁ146.3 (s,
18.7; 19F NMR (DMSO-d6):
d
¼ꢁ144.1 (s, 1F); MS (ESI) (m/z): 271
1F); MS (ESI) (m/z): 256 (MþNaþ); HRMS calcd for C13H12NFO2:
(MþNaþ); HRMS calcd for C12H9N2FO3: 248.0597, found: 248.0595.
233.0852, found: 233.0853.
4.2.10. 3-Fluoro-6-methyl-4-(naphthalen-2-yl)pyridin-2(1H)-one
4.2.4. 4-(2-Chlorophenyl)-3-fluoro-6-methylpyridin-2(1H)-one
(5d). Yield: 85%; yellowish brown solid; mp: 213e214 ꢀC, IR
(CH2Cl2, film): 3420, 2852, 1654, 1468, 1183, 1148, 1048, 756,
(5j). Yield: 69%; yellowish brown solid; mp: 209e210 ꢀC, IR (CH2Cl2,
film): 3425, 2854, 1657, 1475, 1197, 1118, 1048, 762, 652 cmꢁ1 1H
;
NMR (300 MHz, CDCl3):
d
¼12.18 (br s,1H), 8.17 (s, 1H), 8.05e7.97 (m,
660 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼13.24 (br s, 1H), 7.50 (d,
3H), 7.69 (d, J¼8.4 Hz, 1H), 7.59 (t, J¼4.2 Hz, 2H), 6.25 (d, J¼5.7 Hz,
1H), 2.40 (s, 3H); 13C NMR(100 MHz, DMSO-d6): 161.4 (d, J¼26.4 Hz),
151.5 (d, J¼230.0 Hz), 145.2 (d, J¼6.0 Hz), 139.1 (d, J¼9.1 Hz), 138.0 (d,
J¼4.4 Hz), 135.7, 133.6, 133.4, 133.3, 132.8, 132.3, 131.9, 131.1, 131.1,
J¼8.7 Hz, 1H), 7.35 (t, J¼7.2 Hz, 3H), 5.99 (d, J¼4.2 Hz, 1H), 2.40 (s,
3H); 13C NMR (100 MHz, CDCl3): 157.4 (d, J¼24.6 Hz), 145.5 (d,
J¼245.5 Hz), 138.5 (d, J¼6.8 Hz), 133.8 (d, J¼11.6 Hz), 131.7, 131.4,
129.4, 129.2, 129.0, 125.8, 106.1, 17.7; 19F NMR (CDCl3):
d¼ꢁ139.9 (s,
109.0, 23.4; 19F NMR (CDCl3):
d¼ꢁ145.9 (s, 1F); MS (ESI) (m/z): 529
1F); MS (ESI) (m/z): 260 (MþNaþ); HRMS calcd for C12H9NClFO:
(2MþNaþ); HRMS calcd for C16H12NFO: 253.0903, found: 253.0906.
237.0357, found: 237.0353.
4.2.11. 3-Fluoro-4-(furan-2-yl)-6-methylpyridin-2(1H)-one
(5k). Yield: 81%; yellowish brown solid; mp: 209e210 ꢀC, IR
(CH2Cl2, film): 3435, 2925, 1666, 1490, 1203, 1145, 1049, 763,
4.2.5. 4-(3-Chlorophenyl)-3-fluoro-6-methylpyridin-2(1H)-one
(5e). Yield: 83%; yellowish brown solid; mp: 205e206 ꢀC, IR
(CH2Cl2, film): 3405, 2923, 1669, 1455, 1184, 1145, 1047, 759,
582 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
¼8.09 (s, 1H), 7.51 (t,
690 cmꢁ1; 1H NMR (300 MHz, DMSO-d6):
d
¼12.45 (br s,1H), 7.88 (s,
J¼3.0 Hz, 1H), 7.03 (d, J¼1.8 Hz, 1H), 6.96 (d, J¼5.1 Hz, 1H), 2.72 (s,
3H); 13C NMR(100 MHz, CDCl3/CD3OD): 161.4 (d, J¼24.7 Hz), 148.5
(d, J¼244.9 Hz), 143.7 (d, J¼5.9 Hz), 136.5, 129.4 (d, J¼8.1 Hz), 119.0,
1H), 7.80 (s, 3H), 6.41 (d, J¼5.4 Hz, 1H), 2.46 (s, 3H); 13C NMR
(100 MHz, CDCl3): 157.7 (d, J¼25.4 Hz), 146.4 (d, J¼245.8 Hz), 139.7
(d, J¼6.7 Hz), 134.8 (d, J¼8.6 Hz), 134.6 (d, J¼11.4 Hz), 129.9, 128.5,
128.5 (d, J¼3.6 Hz), 126.8, 126.7, 105.8, 18.0; 19F NMR (DMSO-d6):
129.2, 118.9,116.4,105.1, 17.9; 19F NMR (CDCl3):
d¼ꢁ141.7 (s, 1F); MS
(ESI) (m/z): 216 (MþNaþ); HRMS calcd for C10H8NFO2: 193.0539,
d
¼ꢁ145.1 (s, 1F); MS (ESI) (m/z): 260 (MþNaþ); HRMS calcd for
found: 193.0535.
C12H9NClFO: 237.0357, found: 237.0350.
4.3. General procedure for the preparation of ketoester (3)
4.2.6. 4-(4-Chlorophenyl)-3-fluoro-6-methylpyridin-2(1H)-one
(5f). Yield: 82%; yellowish brown solid; mp: 212e214 ꢀC, IR
(CH2Cl2, film): 3405, 2173, 1665, 1493, 1183, 1110, 1048, 768,
A solution of a,b-unsaturated methyl ketones (2) (0.1 mmol),
fluoronitroacetates (1) (0.15 mmol), N0,N0-dimethylethane-1,2-di-
amine (4) (20 mol %) and 4-nitrobenzoic acid (20 mol %) in CH2Cl2
(1.0 mL) was reacted at room temperture for appropriate times.
After removal of the solvent under reduced pressure, the crude
product was purified directly by column chromatography on silica
gel (hexanes/EtOAc¼5/1) to afford the desired products.
678 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d
¼12.18 (br s, 1H),
7.62e7.55 (m, 4H), 6.12 (d, J¼5.7 Hz, 1H), 2.20 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): 156.6 (d, J¼26.4 Hz), 146.6 (d, J¼223.7 Hz),
140.6 (d, J¼3.4 Hz), 134.5, 133.2 (d, J¼9.0 Hz), 132.3, 130.8 (d,
J¼3.8 Hz), 129.3, 129.2, 103.7, 18.6; 19F NMR (DMSO-d6):
¼ꢁ145.6
d
(s, 1F); MS (ESI) (m/z): 260 (MþNaþ); HRMS calcd for C12H9NClFO:
237.0357, found: 237.0352.
Acknowledgements
4.2.7. 3-Fluoro-4-(4-fluorophenyl)-6-methylpyridin-2(1H)-one
(5g). Yield: 84%; yellowish brown solid; mp: 189e190 ꢀC, IR
(CH2Cl2, film): 3398, 2924, 1665, 1465, 1199, 1147, 1041, 769,
This research was supported by the National Natural Science
Foundation of China (No.21032006, 20172064), the QT Program,
Shanghai Natural Science Council.
682 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6):
d
¼12.16 (br s, 1H),
7.66e7.62 (m, 2H), 7.37e7.32 (m, 2H), 6.12 (d, J¼5.1 Hz, 1H), 2.20 (s,
3H); 13C NMR (100 MHz, DMSO-d6): 163.3 (d, J¼245.6 Hz), 156.6 (d,
J¼25.3 Hz), 146.5 (d, J¼242.1 Hz), 140.5, 133.4 (d, J¼8.8 Hz), 131.3 (d,
J¼3.7 Hz), 116.1 (d, J¼21.6 Hz), 104.0, 18.6; 19F NMR (DMSO-d6):
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.01.047. These data

X.-W. Wang et al. / Tetrahedron 67 (2011) 2468e2473
2473
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include MOL files and InChiKeys of the most important compounds
described in this article.
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