A facile and divergent synthesis of substituted pyridine-2,4(1H,3H)-diones and 4H-thiopyran-4-ones from α-alkenoyl-α-carbamoyl ketene-S,S-acetals

Article abstract of DOI:10.1071/CH09489

A facile and divergent synthesis of substituted pyridine-2,4(1H,3H)-diones and 4H-thiopyran-4-ones from readily available α-alkenoyl-α- carbamoyl ketene-S,S-acetals has been developed. Subjected to N,N-dimethylformamide at 125°C, α-alkenoyl-α-carbamoyl ke

Full text of DOI:10.1071/CH09489

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2010, 63, 1267–1271
A Facile and Divergent Synthesis of Substituted Pyridine-
2,4(1H,3H)-diones and 4H-Thiopyran-4-ones from
α-Alkenoyl-α-carbamoyl Ketene-S,S-acetals
Jinying Liu,A Xiaolan Fu,A Yang Zhou,B Guangyuan Zhou,B Yongjiu Liang,B
and Dewen DongA,B,C
ADepartment of Chemistry, Northeast Normal University, Changchun, 130024, China.
BChangchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, 130022, China.
CCorresponding author. Email: dongdw663@nenu.edu.cn
A facile and divergent synthesis of substituted pyridine-2,4(1H,3H)-diones and 4H-thiopyran-4-ones from readily avail-
able α-alkenoyl-α-carbamoyl ketene-S,S-acetals has been developed. Subjected to N,N-dimethylformamide at 125◦C,
α-alkenoyl-α-carbamoyl ketene-S,S-acetals underwent an intramolecular aza-nucleophilic vinyl substitution reaction, a
formal [5C + 1N] annulation, to give the corresponding substituted pyridine-2,4(1H,3H)-diones in high yields, whereas
in the presence of Na2S·9H2O in DMF at 75◦C, tandem intermolecular and intramolecular thia-nucleophilic vinyl substi-
tution reactions, a formal [5C + 1S] annulation, occurred to produce the corresponding substituted 4H-thiopyran-4-ones
in good yields.
Manuscript received: 13 Sepetember 2009.
Manuscript accepted: 22 October 2009.
O
O
Introduction
O
O
DMFDMA
NHAr
SEt
The utility of α-oxo ketene-S,S-acetals as versatile intermediates
in organic synthesis has been recognized.[1] As three-carbon 1,3-
bielectrophilic synthons, they have been widely applied in the
synthesis of substituted and fused aromatic structural frame-
works by reacting with organometallic nucleophiles, such as
Reformatsky reagents,[2] Grignard reagents,[3] organolithium
reagents,[4] and organocuprate reagents,[5] and also in the con-
struction of five- and six-membered heterocycles by reacting
with heteronucleophiles, such as hydrazine, hydroxylamine,
guanidine, amidines, enamines, and diamines.[6]
NHAr
SEt
DMF, 60°C
EtS
Me2N
EtS
1
2
Scheme 1. Preparation of enaminones 2. DMFDMA, N,N-dimethyl-
formamide dimethyl acetal.
of substituted pyridine-2,4(1H,3H)-diones and 4H-thiopyran-4-
ones from readily available α-oxo ketene-S,S-acetals. Herein, we
wish to report our results.
During the course of our studies on the chemistry of α-oxo
ketene-S,S-acetals, we successfully developed novel strate-
gies for the synthesis of highly substituted six-membered
carbocycles[7] and heterocycles,[8] relying on the utilization
of α-alkenoyl ketene-S,S-acetals, derived from aldol conden-
sation of α-acyl ketene-S,S-acetals with aldehydes,[9] as a
five-carbon 1,5-bielectrophilic species in the formal [5 + 1]
annulation with various nucleophiles. Considering the syn-
thetic importance of α-alkenoyl ketene-S,S-acetals, we recently
investigated the aldol condensation reaction of 3-(1,3-dithiolan-
2-ylidene)pentane-2,4-dione in water and obtained both
mono- and double condensed products,[10] which were in turn
further used for the synthesis of thiopyrano[2,3-b]thiopyran-4,5-
diones via a double formal [5 + 1] annulation.[11] In connection
with our previous work and our continuing interest in the
synthesis of valuable heterocycles, we synthesized a series
of α-dimethylaminopropenoyl-α-carbamoyl ketene-S,S-acetals,
and examined their reaction behaviour under different condi-
tions. As a result, we achieved a facile and divergent synthesis
Results and Discussion
Synthesis of α-Dimethylaminopropenoyl-α-carbamoyl
Ketene-S,S-acetals 2
According to our published procedure,[12] α-dimethylamino-
propenoyl-α-carbamoyl ketene-S,S-acetals 2 were prepared from
α-acyl-α-carbamoyl ketene-S,S-acetals 1 with N,N-dimethyl
formamide dimethyl acetal (DMFDMA) at 60◦C in high yields
(Scheme 1). It should be noted that when α-oxo ketene-S,S-
acetals 1 were treated with DMFDMA at high temperature,
100◦C for example, a complex mixture was formed.With a series
of enaminones 2a–f in hand, we then selected 2-(1,3-dithiolan-
2-ylidene)-3-oxo-N-phenylbutanamide 2a as a model compound
to examine its behaviour under different conditions.
Synthesis of Substituted Pyridine-2,4(1H,3H)-diones 3
Thus, substrate 2a was first subjected to DMF at 100◦C; as moni-
toredbyTLC, thereactionproceededsmoothly.Withtheincrease
© CSIRO 2010
10.1071/CH09489
0004-9425/10/081267

1268
J. Liu et al.
Table 1. Synthesis of substituted pyridine-2,4(1H,3H)-diones
Table 2. Synthesis of substituted 4H-thiopyran-4-ones
SEt
O
O
O
O
O
O
O
Na2S·9H2O
DMF
NHAr
SEt
SEt
NHAr
SEt
NHAr
SEt
DMF, 75°C
125°C
EtS
Me2N
N
O
EtS
Me2N
S
2
4
Ar
2
3
YieldA [%]
Entry
2
Ar
Time [min]
4
YieldA [%]
Entry
2
Ar
Time [h]
3
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
C6H5
40
40
45
40
50
45
4a
4b
4c
4d
4e
4f
76
81
85
84
82
67
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
C6H5
3.0
2.5
2.5
2.5
2.0
2.0
3a
3b
3c
3d
3e
3f
86
92
89
94
88
90
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
AIsolated yields.
AIsolated yields.
of the reaction temperature to 125◦C, the reaction could be com-
pleted within 3 h to furnish a product (86% yield), which was
characterized as 3-[bis(ethylthio)methylene]-1-phenylpyridine-
2,4(1H,3H)-dione 3a on the basis of its spectral and analytical
data (Table 1, entry 1). Presumably, the formation of 3a involved
an intramolecular aza-nucleophilic vinyl substitution (SNV)
reaction,[13] which could be regarded as a formal [5C + 1N]
annulation.
analytical data. Obviously, the formation of 4a involved a
tandem thia-nucleophilic vinyl substitution (SNV) reaction,[13]
which could be regarded as a formal [5C + 1S] annulation.[8b,11]
Under identical conditions, a range of reactions between
enaminones 2b–f bearing various amide groups with
Na2S·9H2O was carried out in DMF at 75◦C, and some of the
results are summarized in Table 2. It was observed that all the
reactions of 2b–f proceeded smoothly to afford the correspond-
ing substituted 4H-thiopyran-4-ones 4b–f in good yields (up
to 85%). The results shown above demonstrate the efficiency
and the synthetic utility of the [5C + 1S] annulation reactions
with respect to α-dimethylaminopropenoyl-α-carbamoyl ketene-
S,S-acetals 2 (Table 2, entries 1–5).
In the past decades, thiopyrone derivatives including types
of thiin-4-ones, 4-thianones, and 2,3-dihydrothiopyran-4-ones
have gained increasing attention for both the interest of such het-
erocycles themselves and their importance as key units in medic-
inal chemistry, material chemistry, and versatile intermediates in
organic synthesis.[22–24] Therefore, extensive efforts have been
focussed on synthetic methodologies for 4H-thiopyran-4-ones.
So far, the most notable synthetic approaches to 4H-thiopyran-
4-ones are based on the addition of hydrogen sulfide to the
corresponding cross-conjugated dienones and subsequent oxi-
dization, but the oxidization conditions employed are usually
harsh and intolerant of substitution in some cases.[25] Gaudemar-
Bardone and other researchers reported mild methods for the
preparation of these heterocycles include sulfide dianion addi-
tion to crossconjugated diacetylenic ketones.[26] Boaz et al.
developed a novel synthesis of 4H-thiopyran-4-ones via two
sequential thio-Claisen condensations of a dialkyl ketone and
two dithioesters.[27] In the present work, we present a facile
and efficient alternative protocol for the synthesis of substituted
4H-thiopyran-4-ones without oxidation. It is worth noting that
the 4H-thiopyran-4-ones 4 possess very rich functionality, such
as amide, α,β-unsaturated carbonyl, and β-dicarbonyl groups,
and an α-oxo ketene-S,S-acetal moiety, which may render them
versatile intermediates for further synthetic transformations.
The reactions of a series of enaminones 2 bearing various
substituted phenyl groups were carried out in DMF at 125◦C
and the results are summarized in Table 1. It was observed that
all the reactions of 2b–f proceeded smoothly to afford the corre-
sponding substituted pyridine-2,4(1H,3H)-diones 3b–f in high
yields (up to 94%). Actually, substituted pyridine-2,4(1H,3H)-
diones and their benzofused derivatives represent an important
class of aza-heterocycles that are widely distributed among a
large number of alkaloids with useful biological and pharmaco-
logical activities.[14,15] Recently, Chen and coworkers reported
the synthesis of 2(1H)-pyridinones via the Vilsmeier reaction
of α-acyl-α-carbamoyl ketene-S,S-acetals 1.[16] In the present
work, we provide a facile and efficient synthesis of substituted
pyridine-2,4(1H,3H)-diones 3 from readily available α-acyl-α-
carbamoyl ketene-S,S-acetals 1. It should be noted that the
pyridine-2,4(1H,3H)-diones of type 3 obtained possess very rich
functionality, such as α,β-unsaturated carbonyl and β-dicarbonyl
groups, and in particular, the α-oxo ketene-S,S-acetal moiety,
which may render them extremely versatile as valuable synthons
in other transformations.[17] For example, the characteristic 1,3-
dithiolan-2-ylidene group has the potential to be converted
to thioesters,[18] enamines,[19] 1,3-dithiolan-2-yl,[20] and aro-
matic rings[21] through hydrolysis, reduction, substitution, and
cycloaromatization reactions, respectively.
Synthesis of Substituted 4H-Thiopyran-4-ones 4
The formal [5 + 1] annulation reaction of enaminones 2 and
our previous results on the [5 + 1] annulation reaction of α-
alkenoyl ketene-S,S-acetals[8b,11] encouraged us to explore the
reaction of enaminones 2 with sulfur nucleophiles. Thus, the
reaction of enaminone 2a with Na2S·9H2O (1.1 equiv) was per-
formed in DMF at 75◦C. After stirring the reaction mixture for
40 min, the starting material 2a was consumed, as indicated
by TLC. Workup and column chromatography of the result-
ing mixture furnished a yellowish solid. The main product was
characterized as 2-(ethylthio)-4-oxo-N-phenyl-4H-thiopyran-3-
carboxamide 4a (76% yield) on the basis of its spectral and
Conclusions
In the present work, we described a facile and diver-
gent synthesis of substituted pyridine-2,4(1H,3H)-diones and
4H-thiopyran-4-ones based on formal [5 + 1] annulation
reactions of readily available α-alkenoyl-α-carbamoyl ketene-
S,S-acetals under varied reaction conditions. A series of α-
dimethylaminopropenoyl-α-carbamoyl ketene-S,S-acetals 2 was

Synthesis of Substituted Pyridine-2,4(1H,3H)-diones and 4H-Thiopyran-4-ones
1269
prepared from α-acyl-α-carbamoyl ketene-S,S-acetals 1 with
DMFDMA. Subjected to DMF at 125◦C, α-carbamoyl ketene-
S,S-acetals 2 underwent an intramolecular aza-nucleophilic
vinyl substitution reaction, a formal [5C + 1N] annulation, to
3-[Bis(ethylthio)methylene]-1-o-tolypyridine-
2,4(1H,3H)-dione 3c
White solid; mp 152–153◦C. δH (300 MHz, CDCl3) 1.29 (t,
7.5, 3H), 1.42 (t, 7.5, 3H), 2.17 (s, 3H), 2.90–2.99 (m, 4H), 6.39
(d, 7.5, 1H), 7.18 (d, 7.5, 1H), 7.26 (d, 7.5, 1H), 7.30–7.36 (m,
3H). δC (125 MHz, CDCl3) 191.1, 161.6, 159.6, 138.9, 138.3,
135.0, 131.1, 129.3, 127.1, 127.0, 120.6, 103.0, 26.3, 23.6, 17.6,
13.9, 12.8. νmax(KBr)/cm−1 2922, 1666, 1477, 1400, 1188, 925,
763. Anal. Calc. for C17H19NO2S2: C 61.23, H 5.74, N 4.20.
Found: C 61.04, H 5.80, N 4.12%.
give the corresponding substituted pyridine-2,4(1H,3H)-diones
in high yields, whereas in the presence of Na2S·9H2O in
DMF at 75◦C, tandem intermolecular and intramolecular thia-
nucleophilic vinyl substitution reactions, a formal [5C + 1S]
annulation, occurred to produce the corresponding substituted
4H-thiopyran-4-ones in good yields.The simple execution, read-
ily available substrates, mild conditions, good yields, and wide
range of synthetic potential of the products make this protocol
attractive.
3-[Bis(ethylthio)methylene]-1-(4-methoxyphenyl)
pyridine-2,4(1H,3H)-dione 3d
White solid; mp 116–118◦C. δH (500 MHz, CDCl3) 1.30 (t,
7.5, 3H), 1.41 (t, 7.5, 3H), 2.94 (q, 7.5, 4H), 3.84 (s, 3H), 6.36
(d, 7.5, 1H), 6.98 (d, 7.5, 2H), 7.28 (d, 7.5, 2H), 7.37 (d, 7.5,
1H). δC (125 MHz, CDCl3) 191.1, 161.3, 160.1, 159.6, 138.4,
132.4, 127.6, 120.6, 114.4, 103.0, 55.5, 26.2, 23.6, 13.9, 12.8.
Anal. Calc. for C17H19NO3S2: C 58.43, H 5.48, N 4.01. Found:
C 58.21, H 5.65, N 4.08%.
Experimental
General
All reagents were purchased from commercial sources and used
withouttreatment, unlessotherwiseindicated.Theproductswere
purified by column chromatography over silica gel. H NMR
1
and 13C NMR spectra were recorded at 500 MHz and 125 MHz,
respectively, with TMS as internal standard at 25◦C on a Varian
Inova-500 spectrometer. IR spectra (KBr) were recorded on a
Magna-560 Fourier-transform (FT)-IR spectrophotometer in the
range ∼400–4000 cm−1. Elemental analyses were conducted on
a PE-2400 analyzer (Perkin–Elmer). Light petroleum (PE) used
was the fraction boiling in the range 60–90◦C.
3-[Bis(ethylthio)methylene)-1-(2-methoxyphenyl)
pyridine-2,4(1H,3H)-dione 3e
White solid; mp 119–120◦C. δH (500 MHz, CDCl3) 1.29 (t,
7.5, 3H), 1.42 (t, 7.5, 3H), 2.94 (q, 7.5, 4H), 3.80 (s, 3H), 6.35 (d,
7.5, 1H), 7.03–7.05 (m, 2H), 7.25–7.28 (m, 1H), 7.29–7.30 (m,
1H), 7.41–7.42 (m, 1H). δC (125 MHz, CDCl3) 191.1, 161.6,
159.8, 154.0, 139.5, 130.5, 128.7, 128.0, 120.7, 120.5, 112.1,
102.6, 55.8, 26.2, 23.6, 13.9, 12.8. νmax(KBr)/cm−1 2970, 1648,
1612, 1509, 1254, 927, 765. Anal. Calc. for C17H19NO3S2:
C 58.43, H 5.48, N 4.01. Found: C 58.64, H 5.35, N 4.12%.
Typical Synthesis Procedure for Substituted
Pyridine-2,4(1H,3H)-diones 3 (3a as an Example)
A stirred solution of 2a (2.0 mmol) in DMF (15 mL) was heated
at 125◦C for 3 h. The resulting mixture was cooled to room tem-
peratureandsaturatedaqueousNaClsolution(20 mL)wasadded
under stirring. The mixture was extracted with dichloromethane
(3 × 20 mL) and the combined organic phase was washed with
water (3 × 20 mL), dried over MgSO4, filtered, and concentrated
under vacuum. The crude product was purified by chromato-
graphy (silica gel, PE/EtOAc, 3:1) to give 3a as a white solid,
yield: 86%.
3-[Bis(ethylthio)methylene]-1-(4-chlorophenyl)
pyridine-2,4(1H,3H)-dione 3f
White solid; mp 157–159◦C. δH (500 MHz, CDCl3) 1.30
(t, 7.5, 3H), 1.42 (t, 7.5, 3H), 2.95 (q, 7.5, 4H), 6.40 (d, 7.5,
1H) 7.33–7.35 (m, 3H), 7.46 (dd, 2.0, 7.5, 2H). δC (125 MHz,
CDCl3) 190.9, 161.6, 159.6, 137.9, 137.6, 134.7, 129.5, 127.9,
120.5, 103.5, 26.3, 23.7, 21.0, 13.9, 12.9. νmax(KBr)/cm−1
2971, 1642, 1478, 1418, 1321, 1194, 1089, 925. Anal. Calc.
for C16H16ClNO2S2: C 54.30, H 4.56, N 3.96. Found: C 54.46,
H 4.65, N 3.92%.
Selected Data for 3a–f
Typical Synthesis Procedure for Substituted
4H-Thiopyran-4-ones 4 (4a as an Example)
3-[Bis(ethylthio)methylene]-1-phenylpyridine-
2,4(1H,3H)-dione 3a
Na2S·9H2O (1.5 mmol) was added in one portion to a solution
of 2a (2.0 mmol) in DMF (15 mL) at room temperature. The
reaction mixture was heated to 75◦C and stirred for 40 min. The
resulting mixture was cooled to room temperature, and saturated
aqueous NH4Cl (20 mL) was added with stirring. The mixture
was extracted with dichloromethane (3 × 20 mL), and the com-
bined organic phase was washed with water (3 × 20 mL), dried
overMgSO4, filtered, andconcentratedundervacuum.Thecrude
product was purified by chromatography (silica gel, PE/EtOAc,
2:1) to give 4a as a white solid, yield: 76%.
White solid; mp 99–100◦C. δH (500 MHz, CDCl3) 1.30 (t,
7.5, 3H), 1.42 (t, 7.5, 3H), 2.95 (q, 7.5, 4H), 6.40 (d, 7.5, 1H),
7.36–7.45 (m, 3H), 7.46–7.52 (m, 3H). δC (125 MHz, CDCl3)
190.7, 161.2, 159.5, 139.4, 138.1, 128.9, 128.5, 126.3, 120.4,
103.1, 26.0, 23.4, 13.8, 12.7. Anal. Calc. for C16H17NO2S2:
C 60.16, H 5.36, N 4.38. Found: C 60.29, H 5.45, N 4.43%.
3-[Bis(ethylthio)methylene]-1-p-tolypyridine-
2,4(1H,3H)-dione 3b
White solid; mp 105–107◦C. δH (500 MHz, CDCl3) 1.29
(t, 7.5, 3H), 1.33 (t, 7.5, 3H), 2.40 (s, 3H), 2.94 (q, 7.5, 4H),
6.37 (d, 7.5, 1H), 7.24–7.29 (m, 4H), 7.37 (d, 7.5, 1H). δC
(125 MHz, CDCl3) 190.9, 161.2, 159.8, 138.7, 138.3, 136.9,
129.7, 126.1, 120.5, 103.0, 26.1, 23.6, 21.0, 13.9, 12.8. Anal.
Calc. for C17H19NO2S2: C 61.23, H 5.74, N 4.20. Found: C
61.10, H 5.61, N 4.29%.
Selected Data for 4a–f
2-(Ethylthio)-4-oxo-N-phenyl-4H-thiopyran-
3-carboxamide 4a
White solid; mp 146–147◦C. δH (500 MHz, CDCl3) 1.45 (t,
7.5, 3H), 3.04 (q, 7.5, 2H), 7. 10 (dd, 3.0, 8.0, 2H), 7.32–7.35
(m, 2H), 7.65–7.67 (d, 8.0, 1H), 7.71 (d, 8.0, 2H), 12.31 (s,

1270
J. Liu et al.
1H). δC (125 MHz, CDCl3) 178.7, 169.2, 163.2, 135.2, 129.9,
128.7, 124.9, 124.0, 122.6, 119.8, 28.6, 12.5. Anal. Calc. for
C14H13NO2S2: C 57.71, H 4.50, N 4.81. Found: C 57.46, H
4.64, N 4.76%.
References
[1] For reviews on the synthesis and application of α-oxo ketene-S,S-
acetals, see:
(a) R. K. Dieter, Tetrahedron 1986, 42, 3029.
(b) H. Junjappa, H. Ila, C.V. Asokan, Tetrahedron 1990, 46, 5423.
(c) H. Junjappa, H. Ila, P. K. Mohanta, in Progress in Heterocyclic
Chemistry (Eds G. H. Gribble, L. T. Gilchrist) 2001, Vol. 13, Ch. 1,
pp. 1–24 (Pergamon Press: Oxford).
2-(Ethylthio)-4-oxo-N-p-tolyl-4H-thiopyran-
3-carboxamide 4b
White solid; mp 172–174◦C. δH (500 MHz, CDCl3) 1.45 (t,
7.0, 3H), 2.32 (s, 3H), 3.04 (q, 7.0, 2H), 7.09 (d, 10, 1H), 7.13
(d, 8.0, 2H), 7.59–7.60 (d, 8.0, 2H), 7.66 (d, 10, 1H), 12.23 (s,
1H). δC (125 MHz, CDCl3) 178.7, 169.2, 163.0, 135.6, 134.9,
133.6, 130.2, 129.3, 124.9, 120.6, 28.6, 20.8, 12.6. Anal. Calc.
for C15H15NO2S2: C 58.99, H 4.95, N 4.59. Found: C 59.17,
H 5.03, N 4.46%.
(d) M. Kolb, Synthesis 1990, 171.
[2] (a) S. Apparao, A. Datta, H. Ila, Synthesis 1985, 169. doi:10.1055/
S-1985-31142
(b) A. Datta, H. Ila, H. Junjappa, Tetrahedron Lett. 1988, 29, 497.
doi:10.1016/S0040-4039(00)80132-X
(c) A. Datta, H. Ila, H. Junjappa, J. Org. Chem. 1990, 55, 5589.
doi:10.1021/JO00308A015
[3] (a) G. Singh, M. L. Purkayastha, H. Ila, H. Junjappa, J. Chem. Soc.,
Perkin Trans. 1 1985, 1289. doi:10.1039/P19850001289
(b) P. K. Patra, J. R. Suresh, H. Ila, H. Junjappa, Tetrahedron 1998,
54, 10167. doi:10.1016/S0040-4020(98)00609-7
[4] (a) M. P. Balu, H. Ila, H. Junjappa, Tetrahedron Lett. 1987, 28, 3023.
doi:10.1016/S0040-4039(00)96275-0
(b) R. K. Dieter, J. R. Fishpaugh, J. Org. Chem. 1988, 53, 2031.
doi:10.1021/JO00244A035
[5] (a) R. K. Dieter, L. A. Silks, J. R. Fishpaugh, M. E. Kastner, J. Am.
Chem. Soc. 1985, 107, 4679. doi:10.1021/JA00302A014
(b) R. K. Dieter, J. R. Fishpaugh, L. A. Silks, Tetrahedron Lett. 1982,
23, 3751. doi:10.1016/S0040-4039(00)87697-2
2-(Ethylthio)-4-oxo-N-o-tolyl-4H-thiopyran-
3-carboxamide 4c
White solid; mp 159–161◦C. δH (500 MHz, CDCl3) 1.45 (t,
7.0, 3H), 2.41 (s, 3H), 3.04 (q, 7.0, 2H), 7.05–7.06 (m, 1H), 7.11
(d, 10, 1H), 7.20–7.23 (m, 2H), 7.67 (d, 10, 1H), 8.25 (d, 8.0,
1H), 12.22 (s, 1H). δC (125 MHz, CDCl3) 178.7, 169.8, 163.1,
136.6, 135.1, 130.0, 129.9, 128.2, 126.2, 124.4, 123.9, 121.7,
28.5, 18.3, 12.4. νmax(KBr)/cm−1 3048, 1655, 1513, 1456, 1378,
1161, 884, 820, 752. Anal. Calc. for C15H15NO2S2: C 58.99,
H 4.95, N 4.59. Found: C 58.78, H 4.83, N 4.70%.
[6] (a) P. K. Mahata, C. Venkatesh, U. K. S. Kumar, H. Ila, H. Junjappa,
J. Org. Chem. 2003, 68, 3966. doi:10.1021/JO034053L
(b) W.-D. Rudorf, Tetrahedron 1978, 34, 725. doi:10.1016/0040-
4020(78)88111-3
2-(Ethylthio)-N-(4-methoxyphenyl)-4-oxo-
4H-thiopyran-3-carboxamide 4d
White solid; mp 142–143◦C. δH (500 MHz, CDCl3) 1.45 (t,
7.0, 3H), 3.04 (q, 7.0, 2H), 3.80 (s, 3H), 6.87 (t, 8.5, 2H), 7.09
(d, 10, 1H), 7.62 (d, 8.5, 2H), 7.65 (d, 10, 1H), 12.16 (s, 1H).
δC (125 MHz, CDCl3) 178.8, 169.2, 163.0, 156.2, 134.9, 131.3,
130.2, 124.8, 122.2, 113.9, 55.4, 28.7, 12.6. νmax(KBr)/cm−1
3036, 2932, 1647, 1526, 1510, 1375, 1297, 1236, 825, 807.Anal.
Calc. for C15H15NO3S2: C 56.05, H 4.70, N 4.36. Found: C
56.28, H 4.63, N 4.23%.
(c) S. Apparao, A. Rahman, H. Ila, Synthesis 1982, 792.
doi:10.1055/S-1982-29950
(d) L. W. Singh,A. K. Gupta, H. Ila, H. Junjappa, Synthesis 1984, 516.
doi:10.1055/S-1984-30889
(e) O. Barun, H. Ila, H. Junjappa, J. Org. Chem. 2000, 65, 1583.
doi:10.1021/JO9916129
[7] X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao, B. Li, J. Am. Chem. Soc.
2005, 127, 4578. doi:10.1021/JA043023C
[8] (a) D. Dong, X. Bi, Q. Liu, F. Cong, Chem. Commun. 2005, 35802.
(b) X. Bi, D. Dong, Y. Li, Q. Liu, Q. Zhang, J. Org. Chem. 2005, 70,
10886. doi:10.1021/JO052032G
[9] (a) B. Myrboh, C. V. Asokan, H. Ila, H. Junjappa, Synthesis 1984, 50.
doi:10.1055/S-1984-30728
2-(Ethylthio)-N-(2-methoxyphenyl)-4-oxo-
4H-thiopyran-3-carboxamide 4e
White solid; mp 215–217◦C. δH (500 MHz, CDCl3) 1.45 (t,
7.0, 3H), 3.04 (q, 7.0, 2H), 3.96 (s, 1H), 6.91 (d, 8.0, 1H),
6.95–6.98 (m, 1H), 7.05–7.08 (m, 1H), 7.11 (d, 10, 1H), 7.64
(d, 10, 1H), 8.56 (d, 8.0, 1H), 12.38 (s, 1H). δC (125 MHz,
CDCl3) 178.7, 163.0, 149.1, 138.1, 134.8, 130.4, 128.1, 125.7,
123.9, 120.8, 120.8, 110.1, 55.9, 28.7, 12.7. Anal. Calc. for
C15H15NO3S2: C 56.05, H 4.70, N 4.36. Found: C 55.79, H
4.55, N 4.48%.
(b) C. V. Asokan, H. Ila, H. Junjappa, Synthesis 1985, 163.
doi:10.1055/S-1985-31140
(c) C. V. Asokan, M. P. Balu, H. Ila, H. Junjappa, Synthesis 1988, 727.
doi:10.1055/S-1988-27690
(d) E. B. Choi, I. K.Youn, C. S. Pak, Synthesis 1991, 15. doi:10.1055/
S-1991-26366
[10] Y. Ouyang, D. Dong, W. Pan, J. Zhang, Q. Liu, Tetrahedron 2006, 62,
10111. doi:10.1016/J.TET.2006.08.040
[11] W. Pan, D. Dong, Y. Ouyang, R. Wu, Y. Yang, Q. Liu, Synthesis 2007,
2115. doi:10.1055/S-2007-983749
N-(4-Chlorophenyl)-2-(ethylthio)4-oxo-
4H-thiopyran-3-carboxamide 4f
White solid; mp 169–170◦C. δH (500 MHz, CDCl3) 1.46 (t,
7.0, 3H), 3.04 (q, 7.0, 2H), 7.09 (d, 10.5, 1H), 7.27–7.30 (m,
2H), 7.66–7.68 (m, 3H), 12.45 (s, 1H). δC (125 MHz, CDCl3)
178.9, 170.2, 163.3, 136.8, 134.9, 130.3, 128.9, 128.8, 124.3,
121.9, 28.7, 12.6. νmax(KBr)/cm−1 3041, 1652, 1522, 1405,
1376, 1160, 1090, 884, 824. Anal. Calc. for C14H12ClNO2S2:
C 51.61, H 3.71, N 4.30. Found: C 51.78, H 3.79, N 4.31%.
[12] Y. Li, W. Li, R. Zhang, Y. Zhou, D. Dong, Synthesis 2008, 3411.
[13] (a) C. F. Bernasconi, D. F. Schuck, R. J. Ketner, I. Eventova,
Z. Rappoport, J. Am. Chem. Soc. 1995, 117, 2719. doi:10.1021/
JA00115A006
(b) C. F. Bernasconi,Tetrahedron 1989, 45, 4017. doi:10.1016/S0040-
4020(01)81304-1
(c) C. F. Bernasconi, R. J. Ketner, X. Chen, Z. Rappoport, J.Am. Chem.
Soc. 1998, 120, 7461. doi:10.1021/JA9743102
(d) J. E. Baldwin, R. M. Adlington, C. Aurelia, I. Nageswara Rao,
R. Marquez, G. J. Pritchard, Org. Lett. 2002, 4, 2125. doi:10.1021/
OL0200504
Acknowledgements
Financial support of this research by the National Natural Science Founda-
tion of China (grant no. 20572013 and grant no. 20872136), the Ministry
of Education of China (grant no. 105061) and the Department of Sci-
ence and Technology of Jilin Province (grant no. 20050309–2) is greatly
acknowledged.
[14] (a) A. L. Zografos, C. A. Mitsos, O. Igglessi-Markopoulou, Org. Lett.
1999, 1, 1953. doi:10.1021/OL9911021
(b) N. R. Irlapati, J. E. Baldwin, R. M. Adlington, G. J. Pritchard,
Org. Lett. 2003, 5, 2351. doi:10.1021/OL034736N

Synthesis of Substituted Pyridine-2,4(1H,3H)-diones and 4H-Thiopyran-4-ones
1271
(c) L. J. McCormick, C. T. McKee, J. Nat. Prod. 1996, 59, 469.
doi:10.1021/NP960250M
(c)H. Matsuyama,Y. Miyazawa,Y.Takei, M. Kobayashi, J. Org. Chem.
1987, 52, 1703. doi:10.1021/JO00385A011
[15] (a) S. Takahashi, N. Kakinuma, K. Uchida, R. Hashimoto,
T. Yanagishima, A. Nakagawa, J. Antibiot. 1998, 51, 596.
(b) S. Takahashi, N. Kakinuma, K. Uchida, R. Hashimoto,
T. Yanagishima, A. Nakagawa, J. Antibiot. 1998, 51, 1051.
[16] L. Chen, Y. Zhao, Q. Liu, C. Cheng, C. Piao, J. Org. Chem. 2007, 72,
9259. doi:10.1021/JO701742Q
(d) S. Lane, R. J. K. Taylor, Tetrahedron Lett. 1985, 26, 2821.
doi:10.1016/S0040-4039(00)94922-0
(e) J. J. Hollick, B. T. Golding, I. R. Hardcastle, N. Martin,
C. Richardson, L. J. M. Rigoreau, G. C. M. Smith, R. J. Griffin,
Bioorg. Med. Chem. Lett. 2003, 13, 3083. doi:10.1016/S0960-
894X(03)00652-8
[17] P. L. Donner, Q. Xie, J. K. Pratt, C. J. Maring, W. Kati, W. Jiang,Y. Liu,
G. Koev, S. Masse, D. Montgomery, A. Molla, D. J. Kempf, Bioorg.
Med. Chem. Lett. 2008, 18, 2735. doi:10.1016/J.BMCL.2008.02.064
[18] S. K. Nair, R. Samuel, C.V.Asokan, Synthesis 2001, 573. doi:10.1055/
S-2001-12356
[19] (a) J. M. Mellor, S. R. Schofield, S. R. Korn, Tetrahedron 1997, 53,
17151. doi:10.1016/S0040-4020(97)10136-3
(b) J. Kang, F. Liang, S. Sun, Q. Liu, X. Bi, Org. Lett. 2006, 8, 2547.
doi:10.1021/OL060763C
[20] F. Liang, J. Zhang, J. Tan, Q. Liu, Adv. Synth. Catal. 2006, 348, 1986.
doi:10.1002/ADSC.200606134
(f) L.-R. Wen, C. Ji, M. Li, H.-Y. Xie, Tetrahedron 2009, 65, 1287.
doi:10.1016/J.TET.2008.12.057
[24] (a) G. A. Reynolds, C. H. Chen, J. Org. Chem. 1980, 45, 2458.
doi:10.1021/JO01300A039
(b) C. H. Chen, J. J. Doney, G. A. Reynolds, J. Org. Chem. 1982, 47,
680. doi:10.1021/JO00343A015
(c) J. H. Perlstein, Angew. Chem. Int. Ed. Engl. 1977, 16, 519.
doi:10.1002/ANIE.197705191
(d)T. A. Johnson, T. Amagata, A. G. Oliver, K. Tenney, F. A. Valeriote,
P. Crews, J. Org. Chem. 2008, 73, 7255. doi:10.1021/JO801096M
[25] (a) I. E. El-Kholy, F. K. Rda, Tetrahedron Lett. 1965, 6, 1437.
doi:10.1016/S0040-4039(00)90085-6
[21] (a) P. J. Kocienski, A. Pontiroli, Q. Liu, J. Chem. Soc., Perkin Trans. 1
2001, 2356. doi:10.1039/B102961B
(b) C. H. Chen, G. A. Reynolds, J. A. Van Allan, J. Org. Chem. 1977,
42, 2777. doi:10.1021/JO00436A026
(c) C. H. Chen, Heterocycles 1977, 7, 231. doi:10.3987/S-1977-01-
0231
(d) M. Zupan, J. Fluor. Chem. 1976, 8, 305. doi:10.1016/S0022-
1139(00)81674-7
(b) S. Gill, P. J. Kocienski, A. Kohler, A. Pontiroli, Q. Liu, Chem.
Commun. 1996, 1743.
[22] (a) A. H. Ingall, in Comprehensive Hetrocyclic Chemistry II (Eds
A. R. Katritzky, C.W. Rees, E. F.W. Scriven) 1996,Vol. 5, pp. 501–617
(Pergamon: Oxford).
(b) E. Vedejs, G. A. Krafft, Tetrahedron 1982, 38, 2857. doi:10.1016/
0040-4020(82)85013-8
(c) L. W. Singh, H. Ila, H. Junjappa, Synthesis 1985, 531. doi:10.1055/
S-1985-31264
[26] (a) F. Gaudemar-Bardone, Ann. Chim. 1958, 3, 52.
(b) K. G. Migliorese, S. I. Miller, J. Org. Chem. 1974, 39, 843.
doi:10.1021/JO00920A024
(c) M. R. Detty, B. J. Murray, M. D. Seidler, J. Org. Chem. 1982, 47,
1968. doi:10.1021/JO00349A030
[27] N. W. Boaz, K. M. Fox, J. Org. Chem. 1993, 58, 3042. doi:10.1021/
JO00063A023
[23] (a) G. Casy, R. J. K. Taylor, Tetrahedron 1989, 45, 455.
doi:10.1016/0040-4020(89)80073-0
(b) G. Casy, R. J. K. Taylor, J. Chem. Soc. Chem. Commun. 1988, 454.
doi:10.1039/C39880000454