Efficient one-pot synthesis of 1,3-disubstituted pyridin-2(1H)-ones from α-hydroxyketene S, S-acetals under Vilsmeier conditions

Article abstract of DOI:10.1055/s-0028-1083198

A facile and efficient one-pot synthesis of 1,3-disubstituted pyridin-2(1H)-ones is developed via a novel cascade reaction of readily available α-hydroxy-α-carbamoyl ketene S,S-acetals under Vilsmeier conditions (DMF/POCl₃), and a mechanism of this domino reaction is proposed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083198

PAPER
3633
Efficient One-Pot Synthesis of 1,3-Disubstituted Pyridin-2(1H)-ones from
a-Hydroxyketene S,S-Acetals under Vilsmeier Conditions
Synthesis
uof 1,3-Disub
n
stituted Pyridin-2(1
L
H
)-ones iu, Deqiang Liang, Mang Wang,* Qun Liu*
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax +86(431)85099759; E-mail: wangm452@nenu.edu.cn
Received 18 June 2008; revised 7 August 2008
droxyketene S,S-acetals have been successfully applied in
the synthesis of functionalized unsaturated d-lactones,13a
substituted 3,4-dihydro-2-pyridones,13b and 3,4-disubsti-
tuted dihydrocoumarins.13c As a part of our continuing in-
terest in further synthetic potential of a-hydroxyketene
S,S-acetals and the Vilsmeier–Haack reaction for the syn-
thesis of various heterocycles, in the present work, we ex-
amined the reactivity of a-hydroxyketene S,S-acetals
toward Vilsmeier reagent (VR). As a result, a facile and
alternative method for the one-pot synthesis of 1,3-disub-
stituted pyridin-2(1H)-ones of type 3 has been developed
via a new cascade reaction of readily available a-hydroxy-
a-carbamoyl ketene S,S-acetals 1 under Vilsmeier condi-
tions (DMF/POCl3). Herein, we wish to report our prelim-
inary results and the proposed mechanism of the
transformation from 1 into 3.
Abstract: A facile and efficient one-pot synthesis of 1,3-disubsti-
tuted pyridin-2(1H)-ones is developed via a novel cascade reaction
of readily available a-hydroxy-a-carbamoyl ketene S,S-acetals
under Vilsmeier conditions (DMF/POCl3), and a mechanism of this
domino reaction is proposed.
Key words: pyridin-2(1H)-ones, Vilsmeier reagent, a-hydroxy-
ketene S,S-acetals
Pyridin-2(1H)-ones are an important class of organic het-
erocycles due to their presence in numerous natural prod-
ucts and because of their use as synthetic organic
compounds with diverse bio-, physio-, and pharmacolog-
ical activities.1,2 A variety of synthetic approaches for ac-
cessing substituted pyridin-2(1H)-ones have been
developed,3 including modification of the preconstructed
heterocyclic ring by pyridinium salt chemistry4,5 and the
construction of the nitrogen heterocyclic skeleton from
appropriate acyclic precursors via Guareschi–Thorpe
reaction,6 Dieckmann-type condensation,7 hetero-Diels–
Alder reaction,8 or metal-mediated cycloaddition.9 How-
ever, these methods are generally limited in their use by
the lack of substrate scope, the harsh reaction conditions,
or the multistep procedure required. Recently, Dong et al.
reported an alternative method for the facile synthesis of
highly substituted pyridin-2(1H)-ones in one-pot from cy-
clopropyl amides,10a cyclic enaminones,10b and b-oxo
amides,10c respectively, under Vilsmeier conditions. Late-
ly, a novel synthesis of 3-thiocarbonothioyl-4-chloro/bro-
mo pyridin-2(1H)-ones via a domino reaction of a-acetyl-
a-carbamoyl ketene S,S-acetals with Vilsmeier reagents
has also been developed in our group.11 It is true that the
development of simple and efficient synthetic approaches
for the construction of pyridin-2(1H)-ones, especially
from readily available starting materials under mild reac-
tion conditions, are highly desired.
The substrates, a-hydroxy-a-carbamoyl ketene S,S-ace-
tals 1, were prepared by the reduction of the correspond-
ing a-acetyl-a-carbamoyl ketene S,S-acetals using NaBH4
as reductive in excellent yields according to the procedure
described in our previous work.13b Initially, the reaction of
2-[bis(ethylthio)methylene]-3-hydroxy-N-phenylbutan-
amide (1a) with POCl3 (2.0 equiv) in DMF (10 mL) was
tried at room temperature for 4 hours, but no reaction oc-
curred. When the reaction was performed at 60 °C for 20
minutes, the reaction furnished a white solid after workup
and purification by column chromatography of the result-
ing reaction mixture. The product was characterized as 2-
[bis(ethylthio)methylene]-N-phenylbut-3-enamide (2a) in
90% yield based on their spectroscopic and analytical data
(Table 1, entry 1). Interestingly, on increasing the reaction
temperature to 90 °C for 60 minutes, 2a (50% yield) along
with a new cyclic product (25% yield), S-ethyl 2-oxo-1-
phenyl-1,2-dihydropyridine-3-carbothioate (3a), were ob-
tained (Table 1, entry 2) with the recovery of 1a in 10%
yield. Obviously, 2a is the precursor of 3a in this process.
Thus a transformation of 2a into 3a was tried by treatment
of 2a with POCl3 (5.0 equiv) in DMF at 90 °C for 30 min-
utes. As expected, the reaction afforded the desired prod-
uct 3a in 75% yield (Table 1). It is noteworthy that the
one-pot construction of 3a under such mild conditions
represents a novel and alternative route to substituted py-
ridin-2(1H)-ones from readily available starting materi-
als. Aiming to optimize this new cyclization, compound
1a was chosen as model substrate toward Vilsmeier re-
agent. From the results summarized in Table 1, it is clear
that the 1:4 ratio of 1a to POCl3 is enough to lead to a com-
plete conversion of 1a into 3a at 90 °C (entry 4) and high-
As a kind of important organic intermediates, a-hydroxy-
ketene S,S-acetals have been proved to possess high reac-
tivities toward nucleophiles under acidic conditions and
have found their applications in the synthesis of substitut-
ed pyridines,12a a,b-unsaturated dithioesters12b and conju-
gated polyene esters.12c During our ongoing research on
the chemistry of functionalized ketene S,S-acetals, a-hy-
SYNTHESIS 2008, No. 22, pp 3633–3638
x
x.
x
x
.
2
0
0
8
Advanced online publication: 23.10.2008
DOI: 10.1055/s-0028-1083198; Art ID: F13708SS
© Georg Thieme Verlag Stuttgart · New York

3634
J. Liu et al.
PAPER
er temperature did not show obvious improvement for this dimethylformimidamide (4)14 was obtained as the major
cyclization (entries 7 and 8). By comparison, the reaction product in 45 and 50% yield, respectively, when prolong-
performed at 90 °C with the 1:5 ratio of 1a to POCl3 was ing the reaction time to 5 hours (Scheme 1). All the 1,3-
superior, regarding both the yield and reaction time (entry disubstituted pyridin-2(1H)-ones 3 were well character-
5). Thus, these conditions were chosen for the following ized by the analytical and spectral data and the structure
investigations.
of them was further established by X-ray diffraction stud-
ies of 3a (Figure 1).15
Table 1 Optimization of Conditions for the Cyclization of 1a under
Vilsmeier Conditionsa
OH
S
( )n POCl3 (5.0 equiv)
DMF
S
N
S
Cl
N
90 °C
S
Cl
N
H
O
2a
OH
S
PhHN
O
1l: n = 1
1m: n = 2
4
POCl3 (5.0 equiv)
DMF
90 °C, 30 min
POCl3, DMF
S
+
Scheme 1 Reaction of 1l,m with Vilsmeier reagent
PhHN
O
O
1a
S
3a
N
O
Ph
Entry
1a:POCl3 Temp
Time
(min)
Yield of Yield of
(°C)
2ab
90
50
10
0
3ab
1
2c
3
4
5
6
7
8
1: 2
1: 2
1: 3
1: 4
1: 5
1: 6
1: 4
1: 4
60
90
20
60
60
50
45
42
40
38
0
25
67
78
80
81
80
78
90
90
90
0
90
0
100
120
0
Figure 1 ORTEP drawing of 3a
0
The mechanism of the Vilsmeier cyclization, on the basis
of all the obtained results combined with our previous
studies,11 most likely begins with dehydration of 1 to af-
ford 2, which can be converted into intermediate A upon
treatment with Vilsmeier reagent. Then, a nucleophilic at-
tack of the amide nitrogen at the positive carbon of the
methylene moiety leads to a cyclization of A into B with
elimination of HCl. The sequential removal of dimethyl-
amine from B results in the formation of intermediate C,
the hydrolysis of which produces 3-thiocarbonyl pyridin-
2(1H)-ones 3 during the workup. Different from our pre-
vious work11 on the study of the Vilsmeier cyclization of
a-acetyl-a-carbamoyl ketene S,S-acetals, the domino pro-
cess reported here was observed to be accompanied with
hydrolysis of ketene S,S-acetal moiety in all cases
(Scheme 2).
a Reaction conditions: 1a (1.0 mmol), DMF (10 mL).
b Isolated yields after silica gel chromatography.
c Compound 1a was recovered in 10%.
Next, under the optimized conditions (Table 1, entry 5),
the scope of this Vilsmeier cyclization was studied by
treating various 1 with Vilsmeier reagent. As described in
Table 2, a wide scope of 1 bearing variable N-aryl- and N-
alkylamide groups can give the corresponding 1,3-disub-
stituted pyridin-2(1H)-ones 3 in good to high yields
(Table 2, entries 1–9). Especially, those substrates having
sterically hindered aryl amide also showed high reactivi-
ties in the cyclization (entries 5–8). The impact of varia-
tion at ketene S,S-acetal moieties of 1 on this procedure
was also investigated. Clearly, the reactions of 1j and 1k
with Vilsmeier reagent can yield the corresponding prod-
ucts 3j and 3k in good yields (entries 10 and 11). Differ-
ently, under the same conditions as above, the reactions of
a-hydroxy-a-carbamoyl cyclic ketene dithioacetals 1l and
1m with Vilsmeier reagent (DMF/POCl3) did not afford
the corresponding 1,3-disubstituted pyridin-2(1H)-ones in
shorter reaction time, while (E)-N¢-(4-chlorophenyl)-N,N-
To gain insight into the mechanism of the cyclization, the
reaction of 1n bearing N,N-disubstituents with 5.0 equiv-
alents of Vilsmeier reagent was performed under the iden-
tical conditions described above for 40 minutes, and then
quenched with aqueous NaOH. This led to the formation
of the acyclic dehydration–formylation product 5, (E)-2-
Synthesis 2008, No. 22, 3633–3638 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3-Disubstituted Pyridin-2(1H)-ones
3635
Table 2 Synthesis of Pyridin-2(1H)-ones 3a
[bis(ethylthio)methylene]-N,N-dimethyl-5-oxopent-3-
enamide, in 79% yield (Scheme 3).
OH
SR
O
O
POCl3 (5.0 equiv)
DMF
In conclusion, we have developed a facile and efficient
method for the preparation of 1,3-disubstituted pyridin-
2(1H)-ones via the Vilsmeier cyclization of a-hydroxy-a-
carbamoyl ketene S,S-acetals 1. The simple execution,
readily available substrates, mild conditions, and high
yields make this protocol very attractive. Further studies
on the details and potential of this new strategy and the
synthetic applications of 1,3-disubstituted pyridin-2(1H)-
ones are in progress.
SR
SR
90 °C
R'HN
N
O
R'
1a–k
3a–k
Entry
1
R
R¢
3
Time Yield
(min) (%)b
1
2
1a
1b
1c
1d
1e
1f
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Bn
Ph
3a
3b
3c
3d
3e
3f
45
40
45
40
60
50
45
60
35
40
50
80
76
69
73
70
64
87
65
70
75
70
4-ClC6H4
4-MeC6H4
4-MeOC6H4
2-ClC6H4
2-MeC6H4
2-MeOC6H4
2,4-Me2C6H3
Me
All reagents were purchased from commercial sources and used as
such, unless otherwise indicated. The products were purified by col-
umn chromatography over silica gel (300–400 mesh). All reactions
were monitored by TLC, which was performed on precoated alumi-
num sheets of silica gel 60 (F254). Melting points were uncorrected.
1H and 13C NMR spectra were determined at r.t. on a Varian spec-
trometer at 500 and 125 MHz, respectively, using TMS as internal
standard. All shifts were given in ppm. IR spectra (KBr) were re-
corded on a Magna-560 FTIR spectrophotometer in the range of
400–4000 cm–1. Mass spectra were measured on an Agilent 1100
LCMsD spectrometer. Elemental analyses were obtained on a
VarioEL analyzer. X-ray diffraction was measured on a Siemens P4
diffractometer. Compounds 1 were prepared according to our previ-
ous report.13b Petroleum ether used refers to the fraction boiling at
60–90 °C.
3
4
5
6
7
1g
1h
1i
3g
3h
3i
8
9
10
11
1j
4-ClC6H4
4-ClC6H4
3j
1k
3k
2-[Bis(ethylthio)methylene]-N-phenylbut-3-enamide (2a)
To a stirred solution of 1a (1.0 mmol, 311 mg) in DMF (10 mL) was
added POCl3 (2.0 mmol, 0.18 mL) in one portion at r.t. Then, the
mixture was heated to 60 °C for 20 min. After the consumption of
1a (monitored by TLC), the mixture was poured into H2O (50 mL),
neutralized with sat. aq NaHCO3 to pH 7, and extracted with
CH2Cl2 (2 × 10 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to yield the crude
product, which was purified by silica gel chromatography (eluent:
petroleum ether–Et2O, 8:1) to give 2a (264 mg, 90%) as colorless
crystals; mp 132–134 °C.
a Reaction conditions: 1 (1.0 mmol), POCl3 (5.0 mmol), DMF (10
mL), 90 °C.
b Isolated yields after silica gel chromatography.
+NMe2 Cl–
OH
O
O
NHR'
O
H+
VR
NHR'
NHR'
– H2O
RS
SR
RS
SR
+
RS
SR
IR (KBr): 1975, 1715, 1625, 1597, 1520, 967, 938 cm–1.
1
2
A
1H NMR (500 MHz, CDCl3): d = 1.25–1.30 (m, 6 H), 2.82–2.89 (m,
4 H), 5.33 (d, J = 11.0 Hz, 1 H), 5.44 (d, J = 17.5 Hz, 1 H), 7.13 (dd,
J = 11.0, 17.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.19 (s, 1 H), 7.36
(t, J = 7.5 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 166.1, 145.2, 138.0, 135.5, 132.4,
129.4 (2 C), 124.8, 120.1 (2 C), 118.5, 28.4, 28.2, 15.3, 15.3.
+
– HCl
NMe2
NR'
VR = [Me2N=CHOPOCl2] Cl–
H
NR'
NR'
H2O
O
O
O
quench
– NHMe2
ES-MS: m/z = 294 [(M + 1)]+.
+
SR
+
SR
O
SR
RS
RS
Anal. Calcd for C15H19NOS2: C, 61.39; H, 6.53; N, 4.77. Found: C,
61.50; H, 6.66; N, 4.67.
3
C
B
Scheme 2 Proposed mechanism for the formation of 3
Compounds 3; S-Ethyl 2-Oxo-1-phenyl-1,2-dihydropyridine-3-
carbothioate (3a); Typical Procedure
To a stirred solution of 1a (1.0 mmol, 311 mg) in DMF (10 mL) was
added POCl3 (5.0 mmol, 0.45 mL) in one portion at r.t. Then, the re-
action mixture was heated to 90 °C for 45 min. After the consump-
tion of 1a (monitored by TLC), the mixture was poured into H2O
(50 mL), neutralized with sat. aq NaHCO3 to pH 7, and extracted
with CH2Cl2 (2 × 10 mL). The combined organic extracts were
dried (MgSO4), filtered, and concentrated in vacuo to yield the
crude product, which was purified by silica gel chromatography
(eluent, petroleum ether–Et2O, 5:1) to give 3a (207 mg, 80%) as
colorless crystals; mp 146–148 °C.
OH
N
S
S
POCl3 (5.0 equiv)
DMF
OHC
S
S
90 °C
O
N
O
1n
5
Scheme 3 Reaction of 1n with Vilsmeier reagent
Synthesis 2008, No. 22, 3633–3638 © Thieme Stuttgart · New York

3636
J. Liu et al.
PAPER
IR (KBr): 2960, 1662, 1528, 1492, 1358, 1273, 1048, 937, 767
cm–1.
IR (KBr): 2931, 1662, 1536, 1444, 1255, 1221, 1028, 938, 768
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.31 (t, J = 7.5 Hz, 3 H), 2.98 (q,
J = 7.5 Hz, 2 H), 6.45 (t, J = 7.0 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 2 H),
7.47 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.59 (dd, J = 2.0,
7.0 Hz, 1 H), 8.33 (dd, J = 2.0, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.7, 160.4, 142.7, 142.7, 140.0,
129.4 (2 C), 129.1, 126.6 (2 C), 126.4, 105.7, 23.7, 13.9.
1H NMR (500 MHz, CDCl3): d = 1.30 (t, J = 7.5 Hz, 3 H), 2.98 (q,
J = 7.5 Hz, 2 H), 6.46 (t, J = 7.0 Hz, 1 H), 7.39–7.49 (m, 4 H), 7.57
(d, J = 7.0 Hz, 1 H), 8.35 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.4, 159.8, 143.0, 142.6, 137.4,
131.5, 130.7, 130.6, 129.1, 127.9, 126.7, 105.6, 23.6, 13.8.
ES-MS: m/z = 294 [(M + 1)]+.
ES-MS: m/z = 260 [(M + 1)]+.
Anal. Calcd for C14H12ClNO2S: C, 57.24; H, 4.12; N, 4.77. Found:
C, 57.06; H, 4.04; N, 4.81.
Anal. Calcd for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40. Found: C,
64.94; H, 4.75; N, 5.27.
S-Ethyl 2-Oxo-1-o-tolyl-1,2-dihydropyridine-3-carbothioate
(3f)
Colorless crystals; mp 99–101 °C.
S-Ethyl 1-(4-Chlorophenyl)-2-oxo-1,2-dihydropyridine-3-car-
bothioate (3b)
Colorless crystals; mp 101–103 °C.
IR (KBr): 2924, 1662, 1532, 1441, 1268, 1220, 1032, 934, 773
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.31 (t, J = 7.5 Hz, 3 H), 2.16 (s,
3 H), 2.98 (q, J = 7.5 Hz, 2 H), 6.44 (t, J = 7.0 Hz, 1 H), 7.20 (d,
J = 7.5 Hz, 1 H), 7.33–7.38 (m, 3 H), 7.51 (dd, J = 2.5, 7.0 Hz, 1
H), 8.35 (dd, J = 2.5, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 190.0, 160.2, 143.0, 142.8, 139.5,
135.1, 131.4, 129.8, 127.4, 127.3, 126.8, 105.7, 23.8, 17.8, 14.1.
ES-MS: m/z = 274 [(M + 1)]+.
IR (KBr): 2925, 1659, 1530, 1439, 1250, 1217, 1037, 938, 920, 775
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.29 (t, J = 7.5 Hz, 3 H), 2.97 (q,
J = 7.5 Hz, 2 H), 6.43 (t, J = 7.0 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 2 H),
7.46 (d, J = 8.5 Hz, 2 H), 7.58 (dd, J = 2.0, 7.0 Hz, 1 H), 8.29 (dd,
J = 2.0, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.8, 159.0, 142.6, 140.5, 138.8,
134.9, 129.6 (2 C), 128.0 (2 C), 126.5, 106.1, 32.3, 11.6.
ES-MS: m/z = 294 [(M + 1)]+.
Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53; N, 5.12. Found: C,
65.83; H, 5.45; N, 5.16.
Anal. Calcd for C14H12ClNO2S: C, 57.24; H, 4.12; N, 4.77. Found:
C, 57.20; H, 4.17; N, 4.85.
S-Ethyl 1-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-
carbothioate (3g)
Colorless crystals; mp 138–140 °C.
S-Ethyl 2-Oxo-1-p-tolyl-1,2-dihydropyridine-3-carbothioate
(3c)
Colorless crystals; mp 150–152 °C.
IR (KBr): 2926, 1660, 1533, 1499, 1257, 1220, 1019, 936, 754
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.29 (t, J = 7.5 Hz, 3 H), 2.97 (q,
J = 7.5 Hz, 2 H), 3.80 (s, 3 H), 6.39 (t, J = 7.0 Hz, 1 H), 7.05 (t,
J = 8.0 Hz, 2 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.43 (t, J = 8.5 Hz, 1 H),
7.50 (dd, J = 1.5, 7.0 Hz, 1 H), 8.31 (dd, J = 1.5, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.8, 160.3, 154.0, 144.0, 142.7,
130.7, 128.6, 128.5, 126.3, 120.8, 112.2, 105.1, 55.8, 23.6, 13.9.
ES-MS: m/z = 290 [(M + 1)]+.
IR (KBr): 2924, 1663, 1536, 1509, 1273, 1220, 1019, 938, 762
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.30 (t, J = 7.0 Hz, 3 H), 2.42 (s,
3 H), 2.98 (q, J = 7.0 Hz, 2 H), 6.42 (t, J = 7.0 Hz, 1 H), 7.25 (d,
J = 8.5 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.62 (dd, J = 2.0, 7.0 Hz,
1 H), 8.31 (dd, J = 2.0, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.7, 160.5, 142.8, 142.5, 139.1,
137.5, 130.0 (2 C), 126.3, 126.3 (2 C), 105.5, 23.6, 21.2, 13.9.
ES-MS: m/z = 274 [(M + 1)]+.
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C,
62.45; H, 5.38; N, 4.90.
Anal. Calcd for C15H15NO2S: C, 65.91; H, 5.53; N, 5.12. Found: C,
66.09; H, 5.49; N, 5.21.
S-Ethyl 1-(2,4-Dimethylphenyl)-2-oxo-1,2-dihydropyridine-3-
carbothioate (3h)
Colorless crystals; mp 101–103 °C.
S-Ethyl 1-(4-Methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-
carbothioate (3d)
Colorless crystals; mp 143–145 °C.
IR (KBr): 2924, 1660, 1530, 1499, 1251, 1217, 1037, 939, 775
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.29 (t, J = 7.5 Hz, 3 H), 2.09 (s,
3 H), 2.36 (s, 3 H), 2.96 (q, J = 7.5 Hz, 2 H), 6.41 (t, J = 7.0 Hz, 1
H), 7.05 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 7.14 (s, 1
H), 7.49 (dd, J = 1.5, 7.0 Hz, 1 H), 8.32 (dd, J = 1.5, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 190.1, 160.4, 143.3, 142.8, 139.8,
137.0, 134.6, 132.1, 128.0, 127.0, 126.6, 105.7, 23.9, 21.4, 17.8,
14.2.
IR (KBr): 2978, 1672, 1528, 1509, 1258, 1174, 1023, 943, 758
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.30 (t, J = 7.0 Hz, 3 H), 2.98 (q,
J = 7.0 Hz, 2 H), 3.85 (s, 3 H), 6.41 (t, J = 7.0 Hz, 1 H), 7.00 (d,
J = 9.0 Hz, 2 H), 7.30 (d, J = 9.0 Hz, 2 H), 7.62 (dd, J = 2.0, 7.0 Hz,
1 H), 8.31 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.7, 160.6, 159.8, 142.9, 142.4,
132.8, 127.6 (2 C), 126.3, 114.5 (2 C), 105.4, 55.6, 23.6, 13.9.
ES-MS: m/z = 290 [(M + 1)]+.
ES-MS: m/z = 288 [(M + 1)]+.
Anal. Calcd for C15H15NO3S: C, 62.26; H, 5.23; N, 4.84. Found: C,
62.11; H, 5.20; N, 4.93.
Anal. Calcd for C16H17NO2S: C, 66.87; H, 5.96; N, 4.87. Found: C,
67.05; H, 6.14; N, 4.97.
S-Ethyl 1-(2-Chlorophenyl)-2-oxo-1,2-dihydropyridine-3-car-
bothioate (3e)
Colorless crystals; mp 146–148 °C.
S-Ethyl 1-Methyl-2-oxo-1,2-dihydropyridine-3-carbothioate
(3i)
Colorless oil.
Synthesis 2008, No. 22, 3633–3638 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3-Disubstituted Pyridin-2(1H)-ones
3637
IR (KBr): 3024, 1674, 1540, 1516, 1465, 1295, 962, 848, 763 cm–1.
13C NMR (125 MHz, CDCl3): d = 193.7, 167.3, 146.5, 144.8, 140.5,
129.8, 37.5, 34.4, 29.1, 28.8, 15.4, 15.2.
1H NMR (500 MHz, CDCl3): d = 1.31 (t, J = 7.5 Hz, 3 H), 2.99 (q,
J = 7.5 Hz, 2 H), 3.64 (s, 3 H), 6.33 (t, J = 7.0 Hz, 1 H), 7.59 (d,
J = 7.0 Hz, 1 H), 8.22 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.6, 160.8, 143.0, 142.0, 125.5,
105.5, 38.2, 23.6, 14.0.
ES-MS: m/z = 274 [(M + 1)]+.
Anal. Calcd for C12H19NO2S2: C, 52.71; H, 7.00; N, 5.12. Found: C,
52.63; H, 6.98; N, 5.16.
ES-MS: m/z = 198 [(M + 1)]+.
Acknowledgment
Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found: C,
54.99; H, 5.77; N, 7.16.
Financial supports by the NNSFC (20672019), Science Foundation
for Young Teachers of Northeast Normal University (20070308),
and the NENU-STB07007 are gratefully acknowledged.
S-Methyl 1-(4-Chlorophenyl)-2-oxo-1,2-dihydropyridine-3-
carbothioate (3j)
Colorless crystals; mp 185–187 °C.
References and Notes
IR (KBr): 3091, 1654, 1621, 1580, 1533, 1250, 1222, 1016, 934,
767 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 6.45 (t, J = 7.0 Hz,
1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.59 (dd,
J = 2.0, 7.0 Hz, 1 H), 8.32 (dd, J = 2.0, 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 189.9, 160.2, 142.7, 142.2, 138.3,
135.1, 129.6 (2 C), 127.9 (2 C), 126.3, 105.9, 12.7.
(1) (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical
and Biological Perspectives, Vol. 5; Pelletier, S. W., Ed.;
Wiley: New York, 1981, 1. (b) Li, Q.; Mitscher, L. A.;
Shen, L. L. Med. Res. Rev. 2000, 20, 231. (c) Nagarajan,
M.; Xiao, X. S.; Antony, S.; Kohlhagen, G.; Pommier, Y.;
Cushman, M. J. Med. Chem. 2003, 46, 5712.
(2) (a) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985,
107, 1691. (b) Cox, R. J.; O’Hagan, D. J. Chem. Soc., Perkin
Trans. 1 1991, 2537.
(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. (c) Litvinov, V. P.
Russ. Chem. Rev. 2003, 72, 69.
(4) (a) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623.
(b) Du, W. Tetrahedron 2003, 59, 8649. (c) Comins, D. L.;
Gao, J. L. Tetrahedron Lett. 1994, 35, 2819. (d) Hu, T.; Li,
C. Org. Lett. 2005, 7, 2035. (e) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.
(5) (a) Decker, H. Ber. Dtsch. Chem. Ges. 1892, 25, 443.
(b) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61, 9623.
(6) (a) Baron, H.; Renfry, H.; Thorpe, J. J. Chem. Soc. 1904, 85,
1726. (b) Aggarwal, V.; Singh, G.; Ila, H.; Junjappa, H.
Synthesis 1982, 214.
ES-MS: m/z = 280 [(M + 1)]+.
Anal. Calcd for C13H10ClNO2S: C, 55.82; H, 3.60; N, 5.01. Found:
C, 55.62; H, 3.72; N, 5.11.
S-Benzyl 1-(4-Chlorophenyl)-2-oxo-1,2-dihydropyridine-3-car-
bothioate (3k)
Colorless crystals; mp 101–103 °C.
IR (KBr): 3061, 1619, 1535, 1515, 1449, 1238, 1210, 1024, 920,
759 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.22 (s, 2 H), 6.45 (t, J = 6.5 Hz,
1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.27–7.37 (m, 6 H), 7.47 (d, J = 8.0
Hz, 2 H), 7.59 (d, J = 6.5 Hz, 1 H), 8.33 (d, J = 6.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 188.7, 160.2, 143.0, 142.4, 138.2,
137.5, 135.1, 129.6 (2C), 129.1 (2C), 128.4 (2 C), 127.9 (2 C),
127.0, 126.2, 106.0, 34.0.
(7) Chung, K. H.; Cho, K. Y.; Asami, Y.; Takahashi, N.;
Yoshida, S. Heterocycles 1991, 32, 4040.
(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.; Ghosez, L. J. Am. Chem.
Soc. 1982, 104, 1428.
(9) (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.; Sheehan, S. M.; Straub, C. S. J. Org.
Chem. 1999, 64, 8648. (d) Padwa, A.; Heidelbaugh, T. M.;
Kuethe, J. T. J. Org. Chem. 2000, 65, 2368.
(10) (a) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang,
D.; Liu, Q. Org. Lett. 2007, 9, 2421. (b) Xiang, D.; Yang,
Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J.; Dong, D. J.
Org. Chem. 2007, 72, 8593. (c) Xiang, D.; Wang, K.; Liang,
Y.; Zhou, G.; Dong, D. Org. Lett. 2008, 10, 345.
(11) Chen, L.; Zhao, Y.; Liu, Q.; Cheng, C.; Piao, C. J. Org.
Chem. 2007, 72, 9259.
(12) (a) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002,
43, 2273. (b) Nair, S. K.; Jose, A. M.; Asokan, C. V.
Synthesis 2005, 1261. (c) Asokan, C. V.; Ila, H.; Junjappa,
H. Synthesis 1985, 163.
(13) (a) Liu, J.; Wang, M.; Li, B.; Liu, Q.; Zhao, Y. J. Org. Chem.
2007, 72, 4401. (b) Liu, J.; Liang, F.; Liu, Q.; Li, B. Synlett
2007, 156. (c) Piao, C.-R.; Zhao, Y.-L.; Han, X.-D.; Liu, Q.
J. Org. Chem. 2008, 73, 2264.
ES-MS: m/z = 356 [(M + 1)]+.
Anal. Calcd for C19H14ClNO2S: C, 64.13; H, 3.97; N, 3.94. Found:
C, 64.30; H, 4.10; N, 3.98.
(E)-N¢-(4-Chlorophenyl)-N,N-dimethylformimidamide (4)
Colorless oil.
1H NMR (500 MHz, CDCl3): d = 3.01 (s, 6 H), 6.88 (d, J = 8.5 Hz,
2 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.48 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 153.7, 150.9, 129.2 (2 C), 127.7,
122.6 (2 C), 30.0 (2 C).
ES-MS: m/z = 183 [(M + 1)]+.
Anal. Calcd for C9H11ClN2: C, 59.18; H, 6.07; N, 15.34. Found: C,
59.33; H, 6.22; N, 15.40.
(E)-2-[Bis(ethylthio)methylene]-N,N-dimethyl-5-oxopent-3-
enamide (5)
Yellow oil.
IR (KBr): 2973, 1740, 1678, 1587, 1515, 1397, 1255, 1125, 969
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.25–1.35 (m, 6 H), 2.86–3.09 (m,
4 H), 2.89 (s, 3 H), 3.08 (s, 3 H), 6.04 (dd, J = 8.0, 15.5 Hz, 1 H),
7.91 (d, J = 15.5 Hz, 1 H), 9.66 (d, J = 8.0 Hz, 1 H).
Synthesis 2008, No. 22, 3633–3638 © Thieme Stuttgart · New York

3638
J. Liu et al.
PAPER
R1 = 0.0428, wR2 = 0.1077. CCDC 690433 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(14) Otto, M.-C.; Bramha, N.; Brian, T. J. Chem. Soc., Perkin
Trans.1 1981, 1520.
(15) Crystal data for 3a: C14H13NO2S, colorless crystal,
M = 259.31, monoclinic, space group P21, a = 5.6429(13),
b = 12.163(3), c = 9.504(2), Å, V = 652.3(3) Å3, a = 90.00,
b = 90.00, g = 90.00, Z = 2, T = 293 (2) K, F000 = 272,
Synthesis 2008, No. 22, 3633–3638 © Thieme Stuttgart · New York