A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones from α-oxoketene-S,S-acetals

Article abstract of DOI:10.1016/j.tet.2011.08.066

A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones has been developed by the reaction of readily available α-oxoketene-S,S- acetals with malononitrile in the presence of sodium methoxide in methanol under reflux.

Full text of DOI:10.1016/j.tet.2011.08.066

Tetrahedron 67 (2011) 8343e8347
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A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones from
a-oxoketene-S,S-acetals
,
a
c
a
a
b
a
Xiuyun Yang a , Yanyan Cheng , Fei Zhao , Yunhui Li , Yuanli Ding , Yongjiu Liang , Fengjiao Gan ,
*
Dewen Dong b
,
*
a School of Chemistry and Environmental Engineering, Changchun University of Science and Technology, Changchun 130022, PR China
b Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China
c Department of Chemistry, Nankai University, Tianjin 300071, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2011
Received in revised form 23 August 2011
Accepted 23 August 2011
Available online 27 August 2011
A facile and efficient synthesis of fully substituted pyridin-2(1H)-ones has been developed by the re-
action of readily available
a-oxoketene-S,S-acetals with malononitrile in the presence of sodium meth-
oxide in methanol under reflux.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
In connection with our previous work and our continuing in-
terest in the synthesis of valuable heterocycles, we examined the
reaction of -oxoketene-S,S-acetals 1 with malononitrile. As a re-
sult, we achieved one-pot synthesis of fully substituted pyridin-
Pyridin-2(1H)-one motif makes up the core structure of nu-
merous biologically active natural products and synthetic com-
pounds, such as elfamycin and ilicolicin, that find a wide range of
applications in pharmaceutical and agrochemical industry.1,2 Pyr-
idin-2(1H)-ones and their benzo-/hetero-fused analogues are very
important in the area of natural product and pharmaceutical
chemistry, and widely used as versatile intermediates in the syn-
thesis of a variety of aza-heterocycles, such as pyridine, piperidine,
quinolizidine, and indolizidine alkaloids.3,4 Extensive work has
generated many approaches for the synthesis of pyridin-2(1H)-
ones involving pyridinium salt chemistry,5 GuareschieThorpe re-
action,6 Vilsmeier reaction,7 hetero DielseAlder reaction,8
Dieckmann-type condensation,9 and metal-mediated cycloaddi-
tion.10 In addition, some notable methods starting from polarized
ketene S,S- and N,N-acetals have been reported.2d,11
a
2(1H)-ones. Herein, we wish to report our results.
2. Results and discussion
The substrates,
prepared from commercially available
a
-acyl,
a
-carbamoyl ketene-S,S-acetals 1, were
-oxo amides in water in
b
excellent yields following the procedure described in our previous
work.21 With a series of condensation adducts 1aeh in hand, we
selected 2-[bis(ethylthio) methylene]-3-oxo-N-phenylbutanamide
1a as a model compound to examine its reaction behavior with
malononitrile 2. When 1a and 2 (1.0 equiv) was subjected to sodium
methoxide in methanol at room temperature for 5.0 h, the reaction
could be completed as monitored by TLC (Table 1, entry 1). The
resulting mixture was purified by silica column chromatography,
and three main products were obtained, which were characterized
as substituted pyridin-2(1H)-one 3a, methyl 3-oxo-3-(phenyl-
amino)propanoate 4a and pyridin-2(1H)-one 5a, respectively, on
the basis of their spectral and analytical data (Scheme 1).
The optimization of the reaction conditions, including the ratio
of malononitrile to 1a, the base, reaction medium and temperature
were then investigated and the results are summarized in Table 1.
No reaction occurred when 1a and 2 was treated with K2CO3 in
DMF at room temperature (Table 1, entry 2). It was observed that
the reaction of 1a and 2 (2.0 equiv) proceeded smoothly in the
presence of sodium methoxide (1.0 equiv) in methanol under reflux
to afford 3a in 67% yield (Table 1, entry 3). When the reaction was
conducted with sodium ethoxide (1.0 equiv) in ethanol under
Over the past decades, the utility of a-oxoketene-S,S-acetals as
versatile intermediates in organic synthesis has been recognized.12
During the course of our studies, we successfully achieved the
synthesis of
b
-lactams,13 pyridines,14 2H-pyrans,15 dihydropyr-
anones,16 tetronic acids,17 and isothiazoles18 from
a
-oxoketene-S,S-
acetals, also developed novel strategies for the synthesis of highly
substituted six-membered carbocycles19 and heterocycles,20 re-
lying upon the utilization of a-alkenoyl ketene-S,S-acetals, as a five-
carbon 1,5-bielectrophilic species in the formal [5þ1] annulation
with carbon, nitrogen, and sulfur nucleophiles, respectively.
* Corresponding authors. Tel.: þ86 431 85262190; fax: þ86 431 85693057
(D.D.); tel.: þ86 431 85582361; fax: þ86 431 86804621 (X.Y.); e-mail addresses:
yangxiuyun1@126.com (X. Yang), dwdong@ciac.jl.cn (D. Dong).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.066

8344
X. Yang et al. / Tetrahedron 67 (2011) 8343e8347
Ph
N
H2N
NC
O
CN
CN
3a
(26%)
SEt
O
O
O
O
CN
MeONa
NHPh
SEt
4a (43%)
5a (15%)
MeO
NHPh
MeOH
r.t.
CN
EtS
2
1a
Ph
N
H2N
NC
-oxoketene-S,S-acetal 1a and malononitrile 2.
O
Scheme 1. Reaction of
a
Fig. 1. The ORTEP drawing of 3h.
reflux, 3a was obtained in 64% yield (Table 1, entry 4). However,
with sodium hydroxide as base in the reaction system, the yield of
3a was decreased to 51% (Table 1, entry 5), whereas, product 4a was
obtained in 43% yield. The compound 4a should be derived from
nucleophilic vinylic substitution (SNV)22 and deacylation reactions
Table 2
Reactions of
a
-oxoketene-S,S-acetals 1 with malononitrile 2a
of
a-acyl, a-carbamoyl ketene-S,S-acetal 1a as reported in our
previous work.23 The result also suggested that the side reaction
might be attributed to the small amount of water within the re-
action system, which was from solvent and/or the one generated
from NaOH and methanol in situ. After a series of experiments, the
optimized reaction conditions were obtained when 1a and malo-
nonitrile (2.1 equiv) was performed in the presence of sodium
methoxide (1.1 equiv) in absolute methanol under reflux, whereby
the yield of 3a reached 85% (Table 1, entry 6).
Entry
1
Ar
R
3
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Bn
Bn
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
83
81
80
82
76
83
78
75
82
74
77
2-MeOC6H4
2-MeC6H4
2-ClC6H4
2,4-Me2C6H3
4-MeOC6H4
4-MeC6H4
4-ClC6H4
Ph
Table 1
9
Optimization of reaction conditions of 1a with malononitrile 2
10
11
12
1j
1k
1l
2-MeOC6H4
Ph
2-MeOC6H4
3j
3k
3l
a
Reagents and conditions: 1a (2.0 mmol), malononitrile 2 (4.2 mmol), MeONa
(2.2 mmol), absolute MeOH (10 mL), reflux, 3.0e4.0 h.
b
Isolated yields.
Entry Base (equiv) Ratio 2 to 1a Solvent Temp
Time (h) Yielda (%)
basic conditions. Therefore, we provided a facile and efficient
synthetic approach to fully substituted pyridin-2(1H)-ones of type
3. It should be noted that the richness of the functionality, e.g.,
amino, cyano, and methylenemalononitrile moiety on the pyridin-
2(1H)-one ring of 3, may render them versatile as synthons in
further synthetic transformations.
1
2
3
4
5
6
MeONa (1.0) 1.0:1.0
K2CO3 (3.0) 1.0:1.0
MeONa (1.0) 2.0:1.0
MeOH
DMF
MeOH
EtOH
rt
rt
5.0
5.0
26
0
Reflux 4.0
Reflux 4.0
Reflux 4.0
67
64
51
85
EtONa (1.0)
NaOH (1.0)
2.0:1.0
2.0:1.0
MeOH
MeONa (1.1) 2.1:1.0
MeOHb Reflux 3.0
a
On the basis of the obtained results and our previous studies,23
a plausible mechanism for the synthesis of substituted pyridin-
2(1H)-ones 3 is presented in Scheme 2. In the presence of sodium
Isolated yield for 3a.
Absolute MeOH was employed.
b
methoxide, Knoevenagel condensation24 between
a-oxoketene-
Under the optimized conditions as for the synthesis of 3a in
Table 1 (entry 6), a range of -acyl, -carbamoyl ketene-S,S-acetals
S,S-acetals 1 and malononitrile 225 occurs to give intermediate A,
which undergoes intramolecular cyclization reaction to afford in-
termediate B.26 Tandem addition of the anion of malononitrile 2 to
B and elimination of thiolate anion as a nucleophilic vinylic sub-
stitution (SNV) process22 leads to the formation of intermediate C,
which finally furnishes the pyridin-2(1H)-one of type 3.
a
a
1beh bearing varied arylamide groups (Ar) and malononitrile was
subjected to MeONa/MeOH, and the results are summarized in
Table 2. The efficiency of the cyclization proved to be suitable for
1beh to give the corresponding substituted pyridin-2(1H)-ones 3
in good yields (Table 2, entries 2e9). It is worth mentioning that the
structure of 3h was elucidated by means of the X-ray single crystal
analysis (Fig. 1), and further confirmed by its NMR spectra.
3. Conclusion
The versatility of this pyridin-2(1H)-one synthesis was further
evaluated by performing
a
-acyl,
a-carbamoyl ketene-S,S-acetals
In summary, we described a facile and efficient synthesis of fully
1iel bearing varied alkylthio groups (SR) under the identical con-
ditions (Table 2, entries 9e12). The results demonstrated the effi-
ciency and synthetic interest of the cyclization reactions of 1
bearing variable arylamide and alkylthio groups with respect to
substituted pyridin-2(1H)-ones 3 from readily available a-oxoke-
tene-S,S-acetals 1 and malononitrile 2 in the presence of sodium
methoxide in methanol under reflux, which involves consecutive
Knoevenagel condensation, intramolecular cyclization, and

X. Yang et al. / Tetrahedron 67 (2011) 8343e8347
8345
2.2 (s, 3H), 2.8 (m, 2H), 7.23 (d, J¼6.3, 1H), 7.32 (d, J¼7.5 Hz, 1H),
7.47e7.60(m, 5H); 13C NMR (100 MHz, DMSO-d6):
¼13.9,18.4, 27.9,
73.7, 78.7, 107.2, 112.3, 112.7, 116.1, 128.5, 128.5 (2C), 129.7, 130.3
(2C), 133.8, 151.5, 156.2, 156.8, 181.1. IR (KBr, cmꢀ1):
3220, 2970, 2218, 2198, 1660, 1662, 1522,1488, 723. Anal. Calcd for
C19H15N5OS: C, 63.14; H, 4.18; N, 19.38. Found: C, 63.34; H, 4.43; N,
19.20.
N
O
O
CN
d
ArHN
NaOMe/MeOH
-H2O
ArHN
R2S
NC
C N
+
O
n
¼3420, 3328,
S R 2
R2S
S R 2
A
1
2
Ar
Ar
N
4.3.2. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-1-(2-
methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3b). Yellow solid: mp 203e206 ꢁC. 1H NMR (300 MHz, DMSO-d6):
N
NH
C N
O
O
NH
-R S -
NC
+
NC
C N
H
R S
CN
B
d
¼1.18 (t, J¼7.5 Hz, 3H), 2.23 (s, 3H), 2.88 (m, 2H), 3.73(s, 3H), 7.1 (m,
1H), 7.23 (m, 2H), 7.49 (m, 3H); 13C NMR (100 MHz, DMSO-d6):
¼13.9, 18.4, 27.9, 55.7, 73.3, 78.8, 107.0, 113.0, 116.0, 121.4, 121.6,
121.7, 121.9, 129.8, 151.5, 154.4, 156.2, 181.1. IR (KBr, cmꢀ1):
NC
2
S R
C
S R
d
n
¼3420,
3324, 3215, 2221, 2202, 1660, 1623, 1527, 1499, 1462, 755. Anal.
Calcd for C20H17N5O2S: C, 61.37; H, 4.38; N,17.89. Found: C, 61.37; H,
4.40; N, 17.60.
Ar
O
N
NH2
C N
CN
4.3.3. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-4-methyl-6-oxo-
NC
1-o-tolyl-1,6-dihydropyridine-3-carbonitrile(3c). Yellow solid: mp
S R
3
234e235 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼1.14e1.19 (m, 3H),
2.01 (s, 3H), 2.24 (s, 3H), 2.89 (m, 2H), 7.11e7.25 (m, 1H), 7.35e7.53
(m, 5H); 13C NMR (100 MHz, DMSO-d6):
¼14.0, 16.4, 18.5, 27.9,
73.5, 79.0, 107.2, 116.1, 116.1, 127.9, 128.5, 130.0, 131.5, 132.6, 132.9,
135.5, 151.5, 155.8, 156.3, 181.0. IR (KBr, cmꢀ1):
Scheme 2. Tentative mechanism of the reaction of
malononitrile 2.
a-oxoketene-S,S-acetals 1 with
d
n
¼3405, 3312, 3216,
nucleophilic vinylic substitution (SNV) reactions. This protocol is
associated with readily available starting materials, mild condi-
tions, good yields, and wide range of synthetic potential of the
products.
2206, 1670, 1626, 1577, 1527, 1460, 895, 739. Anal. Calcd for
C20H17N5OS: C, 63.98; H, 4.56; N, 18.65; S, 8.54. Found: C, 63.85; H,
4.97; N, 18.76.
4.3.4. 2-Amino-1-(2-chlorophenyl)-5-[2,2-dicyano-1-(ethylthio)vi-
nyl]-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3d). Yellow solid: mp 247e250 ꢁC. 1H NMR (300 MHz, DMSO-d6):
4. Experimental
4.1. General information
d
¼1.13e1.19 (m, 3H), 2.24 (d, 3H), 2.88 (m, 2H), 7.46e7.58 (m, 3H),
7.68e7.72 (m, 2H), 7.81 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
¼14.0, 18.4, 27.9, 73.6, 79.0, 107.0, 112.3, 112.6, 116.0, 129.3, 130.7,
131.0, 131.2, 131.5, 131.7, 151.9, 152.4, 156.0, 180.6. IR (KBr, cmꢀ1):
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
d
purified by column chromatography over silica gel. 1H NMR and 13
C
n
¼3405, 3315, 3220, 2208, 1675, 1628, 1574, 1532, 1476, 748. Anal.
NMR spectra were recorded at 300 MHz and 100 MHz, respectively,
with TMS as internal standard. IR spectra (KBr) were recorded on
Calcd for C19H14ClN5OS: C, 57.65; H, 3.56; Cl, 8.96; N, 17.69. Found:
C, 57.56; H, 3.65; Cl, 8.70; N, 17.55.
a
Magna-560 FTIR spectrophotometer in the range of
400e4000 cmꢀ1. Petroleum ether (PE) used was the fraction boiling
in the range 60e90 ꢁC. Elemental analyses were carried out on
a PerkineElmer PE-2400 analyzer.
4.3.5. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-1-(2,4-di-methyl-
phenyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3e). Yellow solid: mp 207e210 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼1.13e1.19 (m, 3H), 1.96 (s, 3H), 2.2 (s, 3H), 2.34 (s, 3H), 2.88 (m,
2H), 6.98e7.11 (m,1H) 7.18 (d, J¼8.1 Hz,1H), 7.24 (s,1H), 7.43 (s, 1H),
7.50 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
¼14.0, 16.3, 18.3, 20.7,
27.9, 73.4, 79.0, 107.2, 112.3, 112.6, 116.1, 128.4, 128.6, 130.2, 132.2,
135.1, 139.4, 151.4, 155.8, 156.4, 181.1. IR (KBr, cmꢀ1):
3203, 2218, 2202, 1664, 1614, 1591, 1525, 1496, 893, 823, 772, 694.
Anal. Calcd for C21H19N5OS: C, 64.76; H, 4.92; N, 17.98. Found: C,
64.80; H, 4.80; N, 17.75.
4.2. Synthesis of substituted pyridin-2(1H)-ones 3
d
4.2.1. Typical procedure for the preparation of 3 (with 3a as an ex-
ample). To a solution of 1a (0.62 g, 2.0 mmol) in methanol (15 mL)
was added sodium methoxide (0.12 g, 2.2 mmol) under stirring at
room temperature. To the mixture was added a solution of malo-
nonitrile (0.28 g, 4.2 mmol) in absolute methanol (10 mL) within
10 min. The mixture was heated and stirred under reflux for 3.0 h,
then cooled down to room temperature. The resulting mixture was
slowly poured into saturated aqueous NaCl (50 mL), and extracted
with ethyl acetate (3ꢂ20 mL). The combined organic phase was
washed with water and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure, and the crude product was
purified by column chromatography (silica gel, petroleum ether/
ethyl acetate 2:1) to give 3a as a yellow solid, yield: 85%.
n
¼3445, 3335,
4.3.6. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-1-(4-
methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3f). Yellow solid: mp 212e214 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼1.13e1.18 (m, 3H), 2.21 (s, 3H), 2.88 (m, 2H), 3.81 (s, 3H),
7.08e7.25 (m, 5H), 7.46 (s, 2H); 13C NMR (100 MHz, DMSO-d6):
¼13.9, 18.4, 27.9, 55.4, 73.6, 78.7, 107.1, 112.3, 112.7, 115.4, 115.6,
116.1, 126.1, 129.6, 129.7, 151.3, 156.5, 157.0, 1601.0, 181.2. IR (KBr,
cmꢀ1):
d
n
¼3380, 3307, 3208, 2208, 1712, 1655, 1612, 1581, 1509, 828.
4.3. Selected data for 3
Anal. Calcd for C20H17N5O2S: C, 61.37; H, 4.38; N, 17.89. Found: C,
61.35; H, 4.22; N, 17.70.
4.3.1. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-4-methyl-6-oxo-
1-phenyl-1,6-dihydropyridine-3-carbonitrile (3a). Yellow solid; mp
4.3.7. 2-Amino-5-[2,2-dicyano-1-(ethylthio)vinyl]-4-methyl-6-oxo-
1-p-tolyl-1,6-dihydropyridine-3-carbonitrile (3g). Yellow solid: mp
236e238 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d¼1.17 (t, J¼7.5 Hz, 3H),

8346
X. Yang et al. / Tetrahedron 67 (2011) 8343e8347
226e227 ꢁC. H NMR (300 MHz, DMSO-d6):
d
¼1.16 (t, J¼7.5 Hz, 3H),
2215, 1663, 1619, 1574,1527,1496, 750. Anal. Calcd for C25H19N5O2S:
C, 66.21; H, 4.22; N, 15.44. Found: C, 66.53; H, 4.31; N, 15.75.
2.22 (s, 3H), 2.38 (s, 3H), 2.88 (m, 2H), 7.09 (d, J¼8.4 Hz, 1H), 7.18 (d,
J¼7.5 Hz, 1H), 7.32e7.43 (m, 4H); 13C NMR (100 MHz, DMSO-d6):
d
¼13.9, 18.4, 20.8, 27.9, 73.7, 78.5, 107.2, 112.3, 112.7, 116.1, 128.5,
Acknowledgements
128.2, 128.4, 130.6, 130.8, 131.1, 132.2, 139.2, 151.4, 156.3, 156.8,
181.8. IR (KBr, cmꢀ1):
n
¼3423, 3328, 3216, 2223, 2205, 1661, 1624,
Financial support of this research by the National Natural Sci-
ence Foundation of China (20872136) and Department of Science
and Technology of Jilin Province (20090535 and 201105051) is
greatly acknowledged.
1582, 1527, 841. Anal. Calcd for C20H17N5OS: C, 63.98; H, 4.56; N,
18.65. Found: C, 63.88; H, 4.55; N, 18.70.
4.3.8. 2-Amino-1-(4-chlorophenyl)-5-[2,2-dicyano-1-(ethyl-thio)vi-
nyl]-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3h). Yellow solid: mp 264e267 ꢁC. 1H NMR (300 MHz, DMSO-d6):
Supplementary data
d
¼1.16 (t, J¼7.5 Hz, 3H), 2.23 (s, 3H), 2.88 (m, 2H), 7.26e7.30 (m,1H),
7.37e7.41 (m, 1H), 7.57e7.64 (m, 4H); 13C NMR (100 MHz, DMSO-
d6):
¼14.0, 18.4, 27.9, 73.8, 78.8, 107.0, 112.7, 116.1, 130.1, 130.4,
130.6, 130.7, 130.8, 132.8, 134.5, 151.7, 156.2, 156.7, 180.9. IR (KBr,
cmꢀ1):
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.066.
d
References and notes
n
¼3454, 3416, 3323, 3225, 2226, 2205, 1668, 1626, 1513,
1491, 752. Anal. Calcd for C19H14ClN5OS: C, 57.65; H, 3.56; N, 17.69.
Found: C, 57.53; H, 3.44; N, 17.60.
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deposit@ccdc.cam.ac.uk.
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Grosser, R.; Michels, M.; Paulsen, H. J. Org. Chem. 2005, 70, 9463.
3. (a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757; (b) Angibaud, P.
R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.; Muller, P.; Poncelet, V. S.;
End, D. W. Eur. J. Org. Chem. 2004, 479.
4. (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107, 1691; (b) Cox, R. J.;
Ohagan, D. J. Chem. Soc., Perkin Trans. 1 1991, 2537.
5. (a) Decker, H. Chem. Ber. 1892, 25, 443; (b) Comins, D. L.; Saha, J. K. J. Org. Chem.
1996, 61, 9623; (c) Du, W. Tetrahedron 2003, 59, 8649; (d) Cristau, H.-J.; Cellier,
P. P.; Spindler, J.-F.; Taillefer, M. Chem.dEur. J. 2004, 10, 5607.
6. (a) Baron, H.; Remfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726; (b) Ag-
garwal, V.; Singh, G.; Ila, H.; Junjappa, H. Synthesis 1982, 214; (c) Gibson, K. R.;
Hitzel, L.; Mortishire-Smith, R. J.; Gerhard, U.; Jelley, R. A.; Reeve, A. J.; Rowley,
M.; Nadin, A.; Owens, A. P. J. Org. Chem. 2002, 67, 9354.
7. (a) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong, D. Org. Lett. 2008, 10, 345; (b)
Xiang, D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J.; Dong, D. J. Org. Chem.
2007, 72, 8593; (c) Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D. J.
Org. Chem. 2008, 73, 9504.
8. (a) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Tetrahedron Lett. 2004, 45,
9557; (b) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque, A. M.; Ghosez, L. J. Am.
Chem. Soc. 1982, 104, 1428.
oxo-1-phenyl-1,6-dihydropyridine-3-carbonitrile (3i). Yellow solid:
mp 260e262 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼2.23 (s, 3H), 2.40
(s, 3H), 7.22e7.25 (m, 2H), 7.33e7.36 (m, 1H), 7.46 (s, 1H), 7.53e7.55
(m, 3H); 13C NMR (100 MHz, DMSO-d6):
¼15.8, 18.4, 73.8, 78.4,
107.2, 112.3, 112.8, 128.6, 128.7, 129.3, 129.8, 130.0, 130.3, 133.8,
156.2, 156.6, 182.3; IR (KBr, cmꢀ1):
d
n
¼3420, 3324, 3219, 2207, 1666,
1624, 1600, 1576, 1498, 761. Anal. Calcd for C18H13N5OS: C, 62.23; H,
3.77; N, 20.16. Found: C, 62.04; H, 3.83; N, 19.98.
4.3.10. 2-Amino-5-[2,2-dicyano-1-(methylthio)vinyl]-1-(2-
methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3j). Yellow solid: mp 267e269 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼2.21 (s, 3H), 2.36 (s, 3H), 3.72 (s, 3H), 7.08e7.13 (m,1H), 7.21e7.28
(m, 2H), 7.45e7.47 (m, 1H), 7.51 (s, 2H); 13C NMR (100 MHz, DMSO-
d6):
¼15.3, 18.2, 55.7, 73.4, 78.3, 107.0, 112.8, 113.2, 116.1, 121.4,
121.6, 121.7, 121.9, 129.8, 131.5, 151.6, 154.4, 156.2, 182.4. IR (KBr,
cmꢀ1):
d
9. Chung, K. H.; Cho, K. Y.; Asami, Y.; Takahashi, N.; Yoshida, S. Heterocycles 1991,
32, 99.
10. (a) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787; (b) Yamamoto, Y.; Takagishi,
H.; Itoh, K. Org. Lett. 2001, 3, 2117; (c) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T.
J. Org. Chem. 2000, 65, 2368; (d) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org.
Chem. 1999, 64, 8648.
n
¼3414, 3311, 3216, 3164, 2219, 2200, 1669, 1623, 1578,
1526, 1489, 761. Anal. Calcd for C19H15N5O2S: C, 60.46; H, 4.01; N,
18.56. Found: C, 60.33; H, 4.21; N, 18.65.
11. (a) Anabha, E. R.; Asokan, C. V. Synthesis 2006, 151; (b) Chakrabarti, S.; Panda, K.;
Misara, N. C.; Ila, H.; Junjappa, H. Synlett 2005, 1437; (c) Mahata, P. K.; Syam, U.
K.; Kumar Sriram, V.; Ila, H.; Junjappa, H. Tetrahedron 2003, 59, 2631; (d)
Schirok, H.; Alonso-Alija, C.; Michels, M. Synthesis 2005, 3085; (e) Chen, L.;
Zhao, Y.; Liu, Q.; Cheng, C.; Piao, C. J. Org. Chem. 2007, 72, 9259.
4.3.11. 2-Amino-5-[1-(benzylthio)-2,2-dicyanovinyl]-4-methyl-6-
oxo-1-phenyl-1,6-dihydropyridine-3-carbonitrile (3k). Yellow solid:
mp 240e242 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼2.17 (s, 3H), 4.12
(s, 2H), 6.7 (s, 1H), 7.22e7.25 (m, 3H), 7.32e7.34 (m, 3H), 7.49e7.55
(m, 5H); 13C NMR (100 MHz, DMSO-d6):
12. For reviews on the synthesis and application of
a-oxoketene-S,S-acetals, see:
d
¼20.3, 37.2, 71.2, 81.3,
(a) Dieter, R. K. Tetrahedron 1986, 42, 3029; (b) Tominaga, Y. J. Heterocycl. Chem.
1989, 46, 143; (c) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423;
(d) Kolb, M. Synthesis 1990, 171; (e) Junjappa, H.; Ila, H. Phosphorous, Sulfur
Silicon 1994, 95, 35; (f) Junjappa, H.; Ila, H.; Mohanta, P. K. In Progress in Het-
erocyclic Chemistry; Gribble, G. H., Gilchrist, L. T., Eds.; Pergamon: Oxford, 2001;
Vol. 13; Chapter 1, pp 1e24.
107.0, 115.1, 115.9, 116.3, 128.5, 128.7, 128.9, 129.0, 129.1, 129.3, 129.7,
129.8, 130.0, 130.3, 133.8, 134.7, 155.8, 158.1, 158.8, 180.4. IR (KBr,
cmꢀ1):
n
¼3344, 3202, 2204, 1657, 1629, 1572, 1537, 1494, 1553, 753.
Anal. Calcd for C23H16N5OS: C, 67.30; H, 3.93; N, 17.06. Found: C,
67.46; H, 3.85; N, 17.21.
13. Yang, Y.; Xiang, D.; Zhao, X.; Liang, Y.; Huang, J.; Dong, D. Tetrahedron 2008, 64,
4959.
14. Sun, S.; Liu, Y.; Liu, Q.; Zhao, Y.; Dong, D. Synlett 2004, 1731.
15. Liu, Y.; Dong, D.; Liu, Q.; Qi, Y.; Wang, Z. Org. Biomol. Chem. 2004, 2, 28.
16. Ouyang, Y.; Huang, J.; Pan, W.; Liang, Y.; Yang, Y.; Dong, D. Eur. J. Org. Chem.
2009, 2003.
17. Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong, D. Synlett 2005, 49.
18. Huang, J.; Lu, Y.; Qiu, B.; Liang, Y.; Li, N.; Dong, D. Synthesis 2007, 2791.
19. Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578.
20. (a) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Commun. 2005, 3580; (b) Bi, X.; Dong,
D.; Li, Y.; Liu, Q.; Zhang, Q. J. Org. Chem. 2005, 70, 10886; (c) Pan, W.; Dong, D.;
Ouyang, Y.; Wu, R.; Yang, Y.; Liu, Q. Synthesis 2007, 2115.
4.3.12. 2-Amino-5-[1-(benzylthio)-2,2-dicyanovinyl]-1-(2-
methoxyphenyl)-4-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile
(3l). Yellow solid: mp 230e232 ꢁC. 1H NMR (300 MHz, DMSO-d6):
d
¼1.56 (s, 3H), 3.77 (s, 3H), 4.22 (s, 2H), 7.12e7.16 (m, 2H), 7.20e7.25
(m, 2H), 7.29e7.32 (m, 5H), 7.53e7.55 (m, 2H); 13C NMR (100 MHz,
DMSO-d6):
¼18.1, 36.6, 55.9, 73.7, 78.4, 107.2, 112.5, 115.8, 121.9,
127.5, 127.6, 128.4, 128.5, 128.8, 128.9, 129.8, 129.9, 131.5, 131.6,
136.1, 152.6, 154.6, 156.2, 180.9. IR (KBr, cmꢀ1):
¼3413, 3321, 3219,
d
n
21. Ouyang, Y.; Dong, D.; Yu, H.; Liang, Y.; Liu, Q. Adv. Synth. Catal. 2006, 348, 206.

X. Yang et al. / Tetrahedron 67 (2011) 8343e8347
8347
22. (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017; (b) Bernasconi, C. F.; Schuck, D.
F.; Ketner, R. J.; Eventova, I.; Rappoport, Z. J. Am. Chem. Soc. 1995, 117, 2719; (c)
Baldwin, J. E.; Adlington, R. M.; Aurelia, C.; Nageswara Rao, I.; Marquez, R.;
Pritchard, G. J. Org. Lett. 2002, 4, 2125; (d) Bernasconi, C. F.; Brown, S. D.; Ali, M.;
Rappoport, Z.; Yamataka, H.; Salim, H. J. Org. Chem. 2006, 71, 4795.
23. (a) Dong, D.; Yu, H.; Ouyang, Y.; Liu, Q.; Bi, X.; Lu, Y. Synlett 2006, 283; (b) Dong,
D.; Ouyang, Y.; Yu, H.; Liu, Q.; Liu, J.; Wang, M.; Zhu, J. J. Org. Chem. 2005, 70,
4535; (c) Yu, H.; Liu, Q.; Yin, Y.; Fang, Q.; Zhang, J.; Dong, D. Synlett 2004, 999;
(d) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong, D. J. Org. Chem.
2003, 68, 9148.
24. Jones, G. In The Knoevenagel Condensation; Adams, R., Ed.; Organic Reactions;
John Wiley: New York, N Y, 1967; Vol. 15, pp 204e599.
25. For the reactions of malononitrile, see: (a) Freeman, F. Chem. Rev. 1969, 69, 591;
(b) Freeman, F. Chem. Rev. 1980, 80, 329.
26. (a) Liang, F.; Cheng, X.; Liu, J.; Liu, Q. Chem. Commun. 2009, 3636; (b) Langer, P.;
Bose, G. Angew. Chem., Int. Ed. 2003, 42, 4033.