A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines

Article abstract of DOI:10.1016/j.tet.2013.04.082

A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently synthesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)acrylamides and selected β-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a β-keto ester to 2-cyano-3,3-bis(methylthio) acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3- (methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine.

Full text of DOI:10.1016/j.tet.2013.04.082

Tetrahedron 69 (2013) 5112e5118
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple and general approach for the synthesis of highly
functionalized 6-oxo-1,6-dihydropyridines
*
Sukeerthi Kumar, Rajni R. Thakur, Sanjay R. Margal, Abraham Thomas
Medicinal Chemistry Division, Glenmark Research Centre, Glenmark Pharmaceuticals Ltd., Navi Mumbai 400709, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently syn-
thesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)ac-
Received 28 February 2013
Received in revised form 15 April 2013
Accepted 17 April 2013
rylamides and selected
conjugate addition of a
b
-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated
b-keto ester to 2-cyano-3,3-bis(methylthio)acrylamide followed by loss of methyl
Available online 22 April 2013
mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group.
The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3-
(methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-
dihydropyridine.
Keywords:
2-Cyanoacetamides
2-Cyanoacrylamides
Ketene dithioacetals
Ó 2013 Elsevier Ltd. All rights reserved.
b-Keto esters
Potassium hydrogen carbonate
6-Oxo-1,6-dihydropyridine-3-carboxylates
1. Introduction
ester is also reported to give pyridine-2(1H)-ones.17 However, this
approach has limited scope for the synthesis of N-alkyl and N-aryl
6-Oxo-1,6-dihydropyridine (synonymous with 2-oxo-1,2-
dihydropyridines and pyridine-2(1H)-ones) core structure fre-
quently occurs in pharmaceuticals and biologically active com-
pounds.1 This highly important heterocyclic system is found in both
natural products such as camptothecin, and its analogues,2 huperzine
A,3 and pharmaceutical products or preclinical lead molecules such as
milrinone,4 perampanel,5 pirfenidone,6 piridicillin,7 ciclopiroxol-
amine,8 amrinone,9 bimakalim,10 and trametinib.11 Therefore, de-
velopment of new methods for pyridine-2(1H)-ones synthesis with
broadscope andgeneralityisofhigh importance. Manymethods have
been reported for the synthesis of this class of compounds.12 One of
the most generally used approaches is the reaction of an appropriate
enamino ketone or aldehyde with 2-cyanoacetamide in the presence
of a base to give pyridine-2(1H)-ones.4,13 The condensation of 1,3-
dicarbonyl compounds with 2-cyanoacetamides is alsoknown to give
pyridine-2(1H)-ones.14 There are several reports on the preparation
pyridine-2(1H)-ones. The N-alkyl pyridine-2(1H)-ones are generally
prepared by N-alkylation of pyridine-2(1H)-ones, while the N-aryl
derivatives are prepared by copper-catalyzed arylation of pyridine-
2(1H)-ones.18
A direct method for the preparation of 2-
aminopyridine-2(1H)-one is reported by the reaction of the corre-
sponding carbamoyl ketene dithioacetal with cyanothioacetamide.19
A similar approach is also reported for 2-amino N-benzyl pyridine-
2(1H)-ones starting from 3,3-bis(methylthio)-2-cyano-N-phenyl-
acrylamide.20 An approach for the synthesis of 6-oxo-1,6-
dihydropyridine was discovered in the course of our experiments
designed toprepare an intermediaterequiredforoneofourmedicinal
chemistry projects.
2. Results and discussion
We required ethyl [5-amino-4-(methylcarbamoyl)-1,2-oxazol-
3-yl]acetate 4 as starting material for the synthesis of a lead mol-
ecule for one of our medicinal chemistry projects (Fig. 1). No such
fully functionalized isoxazole has been reported in the literature as
revealed by SciFinder and STN database searches. In 2011, we re-
ported the first synthesis of this intermediate using an alternative
novel approach.21 We envisioned that the molecule could be pre-
pared by the retrosynthetic approach given in Fig. 1. Thus, we
planned a base-catalyzed Michael addition of ethyl acetoacetate to
of pyridine-2(1H)-ones from ketene dithioacetals.15 The reaction of
acetyl- -carbamoyl ketene dithioacetals with Vilsmeier reagent un-
a-
a
der domino reaction conditions is also reported for the synthesis of
pyridine-2(1H)-ones.16 The reaction of ketene dithioacetals derived
from 2-cyanoacetamides with active methylene ketones and b-keto
* Corresponding author. Tel.: þ91 22 6772 0000; fax: þ91 22 2778 1206; e-mail
address: abraham_thomas@glenmarkpharma.com (A. Thomas).
2-cyano-N-methyl-3,3-bis(methylthio)acrylamide
1a22
with
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.082

S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
5113
Having failed in our efforts to prepare the intermediate 3 re-
quired for the synthesis of desired isoxazole 4 (Fig. 1), we reex-
amined this reaction with a view to develop a general approach for
the synthesis of pyridone esters 6 with an optional substitution at
its 2-position. In this paper, we describe an optimized simple,
general and highly flexible single-step procedure for the syntheses
of N-alkyl and N-aryl 6-oxo-1,6-dihydropyridine-3-carboxylates 6.
We decided to study the base-assisted conjugate addition of 5a
to carbamoyl ketene dithioacetals 1aed in more detail before
attempting optimization of a single-step procedure as shown
overleaf in Scheme 2. To check the generality of the reaction and to
confirm the intermediacy of ester 2 in the formation of pyridone 6,
we selected ketene dithioacetals 1aed bearing dissimilar sub-
stituents on the amide nitrogen. After a few trial experiments, so-
dium hydride (NaH) in N,N-dimethylacetamide (DMA) was selected
for this optimization study (Scheme 1). Thus, the reaction of ketene
dithioacetal 1a with 5a in the presence of NaH (1.2 equiv) in dry
DMA at 0 ꢀC followed by maintaining the mixture at ambient
temperature for 12 h resulted in the formation of a mixture of ester
2a (42%) and pyridone 6a (21%) along with small amounts of 1a
(4%). The reaction of 5a with the methoxypropyl derivative 1b also
showed a similar trend and ester 2b (32%) and pyridone 6b (20%)
were isolated from the reaction mixture along with small amounts
of starting material 1b (5%). The structures of 2b and 6b were fully
established by spectral and analytical data. Under identical condi-
tions, the cyclopropyl derivative 1c also yielded ester 2c (34%) and
pyridone 6c (20%) along with unreacted starting material 1c (7%).
The cyclohexyl derivative 1d yielded only the open chain ester 2d
(30%) and the pyridone 6d was not formed in the reaction mixture
even after 48 h at ambient temperature.
Fig. 1. Retrosynthetic approach for isoxazole 4.
concomitant elimination of methyl mercaptan to prepare adduct
2a. Acyl ester of the general formula 2a was expected to give the
deacylated intermediate 3 under appropriate basic reaction con-
ditions. The regioselective addition of hydroxylamine to 2a under
basic reaction conditions was expected to give the desired func-
tionalized isoxazole 4.
With the retrosynthetic plan in place, we prepared the known
ketene dithioacetal 1a from 2-cyano-N-methylacetamide by using
a modified approach.23 The conjugate addition of ethyl acetoacetate
5a to 1a using excess (2.5 equiv) of anhydrous potassium carbonate
(K2CO3) in dry dimethyl sulfoxide (DMSO) at room temperature for
4 h resulted in the formation of two major products along with
a small amount of starting material 1a. The less polar product,
characterized as the required adduct 2a, was isolated in 55% yield as
a white solid by column chromatography. The more polar minor
product (15%) isolated from the reaction mixture was characterized
as pyridone 6a. Both the products were fully characterized by an-
alytical and spectroscopic data.
The next step in the retrosynthetic scheme is deacetylation of 2a
to the desired
b,g-unsaturated ester 3 using a suitable known
procedure. Thus, 2a was treated with catalytic amounts of sodium
ethanolate in ethanol at room temperature for 6 h, but the expected
deacetylated product was not detected in the reaction mixture.24 A
more polar product was isolated in small amounts, which was
identical in all respects with the pyridone 6a isolated from the
previous experiment. The deacetylation was then attempted as
reported using sodium acetate in a mixture of water and ethanol at
room temperature.25 A mixture of starting ester 2a and pyridone 6a
was detected after 96 h at ambient temperature along with un-
identifiable products. Heating the above reaction mixture at 80 ꢀC
for 6 h resulted in the conversion of 2a to 6a. The desired deace-
tylated product 3 was not detected in the mixture. Deacetylation
was then attempted using excess propylamine in chloroform at
ambient temperature for 12 h according to a published procedure,
which also did not give the expected deacetylated ester 3.26 The
reaction remained incomplete and both ester 2a and pyridone 6a
were detected in the reaction mixture. Finally, deacetylation27 was
attempted using triethylamine in water at 60 ꢀC, which resulted in
the conversion of 2a to pyridone 6a. These results strongly suggest
that the intermediate ethyl 2-acetyl-4-cyano-5-(methylamino)-3-
(methylthio)-5-oxopent-3-enoate 2a exists as its tautomer 5-
oxopent-2-enoate 2a0 under the described conditions, which is
not amenable to a deacetylation reaction (Fig. 2).
Scheme 1. Synthesis of esters 2aed and pyridones 6aed.
Scheme 2. KHCO3 mediated synthesis of pyridones 6aep.
It is interesting to note that all the four reactions remained in-
complete even after stirring for 12e48 h at room temperature.
Heating the reactions at 80 ꢀC resulted in a reddish brown mixture,
probably due to decomposition of unreacted ketene dithioacetal 1.
The sterically more demanding cyclohexyl derivative stopped at the
ester stage 2d and subsequent cyclization to pyridone 6d seemed
unviable. In a separate experiment, the ester 2d isolated was treated
Fig. 2. Tautomeric forms 2a and 2a0.

5114
S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
with p-toluenesulfonic acid (TsOH) in boiling 1,2-dichloroethane
(EDC) for 5 h. We were pleased to see that the desired 1-
cyclohexylpyridone 6d was formed quantitatively and was isolated
in 91% yield. Having understood the reaction pathway in more detail,
we explored the scope of this reaction for the exclusive synthesis of
N-substituted 6-oxo-1,6-dihydropyridines 6 in a one-pot operation.
Our initial objectives were: (i) to drive the conjugate addition
step to completion (ii) in situ conversion of the ester 2 to pyridone 6
and (iii) to minimize polymerization of ketene dithioacetal 1. We
used 1a derived from 2-cyano-N-methylacetamide and ethyl ace-
toacetate 5a as the model substrate for the optimization of reaction
conditions (Table 1). Thus, reaction of 1a with 5a using anhydrous
K2CO3 in dry DMSO at 100 ꢀC for 3 h (Table 1, entry 1) resulted in
a reddish brown oil and the pyridone 6a was isolated in poor 10%
yield after work-up and chromatographic purification. The reaction
was repeated in dry DMSO at 80 ꢀC with similar results (entry 2). In
general, ketene dithioacetal 1a was labile in the presence of strong
inorganic bases at elevated temperature (above 80 ꢀC). This was
confirmed by heating ketene dithioacetal 1a alone with K2CO3 in
DMSO at 100 ꢀC for 30 min, which resulted in significant polymer-
ization as indicated by the reddish brown colour of the reaction
mixture. A reaction mediated by stoichiometric amounts of sodium
ethoxide in ethanol at room temperature for 4 h gave a mixture of 2a
(17%) and 6a (15%) along with starting material 1a (5%). A reaction
With limited success in optimizing the reaction conditions, we
decided to try selected mild inorganic bases. To our delight, po-
tassium hydrogen carbonate (KHCO3) in dry DMF at 60 ꢀC for 6 h
resulted in complete consumption of starting material 1a and the
pyridone 6a was isolated in 50% yield (Table 1, entry 10). The re-
action in refluxing acetone was found to be very efficient and the
yield of the product increased to 75%. Polymerization of ketene
dithioacetal 1a was not observed under this condition. Sodium
hydrogen carbonate (NaHCO3) in refluxing acetone also worked
well, but with an increase in reaction time and slightly reduced
yield (entry 12). The reaction showed strong dependence on tem-
perature. The KHCO3 mediated reaction carried out in acetone at
room temperature for 12 h resulted in poor (<5%) conversion. A
reaction carried out at 50 ꢀC (bath temperature) for 5 h also
resulted in low (<20%) conversion. The reaction rate was consid-
erably accelerated in boiling acetone probably due to the favourable
entropy of the reaction by the irreversible removal of methyl
mercaptan from the reaction medium.
Having optimized conditions for the exclusive synthesis of 6-
oxo-1,6-dihydropyridine 6a in excellent isolated yield (75%), we
turned our attention towards the synthesis of a variety of pyr-
idones using the optimized conditions shown in Scheme 2. The
results of successful application of this methodology for the
synthesis of electronically and sterically diverse set of pyridones
are shown in Table 2. The methoxypropyl derivative 1b and
Table 1
cyclopropyl derivative 1c on reaction with b-keto ester 5a under
the optimized conditions gave 6b and 6c, respectively, in 70 and
Optimization of reaction conditions
Table 2
Synthesis of 6-oxo-1,6-dihydropyridines 6aep
Entry Dithioacetal R1
Ester R2
Pyridone Yielda
(%)
1
2
3
4
1a
1b
1c
1d
CH3
5a
5a
5a
5a
CH3
6a
6b
6c
6d
75
70
71
15
(70)b
73
56
76
73
72
73
76
79
78
74
78
56
CH3O(CH2)3e
Cyclopropyl
Cyclohexyl
CH3
CH3
CH3
Entry
Base, solvent
Conditions
Yielda (%) 1a/2a/6a
1
2
3
4
5
6
7
8
K2CO3, DMSO
K2CO3, DMSO
NaOEt, EtOH
NaOEt, EtOH
NaH, DMF
K2CO3, acetone
Et3N, EtOH
DBU, THF
100 ꢀC, 3 h
80 ꢀC, 3 h
rt, 4 h
rt, 24 h
0ꢀC to rt, 48 h
rt, 24 h
rt, 24 h
rt, 24 h
rt, 24 h
60 ꢀC, 6 h
Reflux, 5 h
Reflux, 9 h
0:0:10
0:0:12
5:17:15
0:0:18
0:0:20
0:0:13
30:0:26
92:0:0
90:0:0
0:0:50
0:0:75
0:0:68
5
6
7
8
1e
1f
CH2CH3
CH2CF3
C6H5
CH3
C6H5
5a
5a
5a
5b
5b
5c
5a
5a
5a
5d
5a
CH3
CH3
CH3
C6H5
C6H5
CH2CH3
CH3
CH3
CH3
6e
6f
6g
6h
6i
6j
6k
6l
1g
1a
1g
1g
1h
1i
1j
1k
1l
9
10
11
12
13
14
15
16
C6H5
4-FC6H4
4-ClC6H4
4-CH3OC6H4
3-CF3C6H4
4-(CH3)2CHC6H4
9
DIEA, THF
10
11
12
KHCO3, DMF
KHCO3, acetone
NaHCO3, acetone
6m
CH2CH2CH3 6n
CH3
CH3
6o
6p
a
1m
4-Methylthiazol-2-yl 5a
Yield of isolated products.
a
Yield of isolated pyridones.
Parenthetic yield refers to the yield after TsOH treatment of mixture of 2d and
b
6d.
under the same conditions for 24 h resulted in pyridone 6a (18%) as
the only isolated product (entry 4). A reaction mediated by NaH in
dry DMF at room temperature for prolonged time (48 h) resulted in
pyridone 6a (20%) as the only isolable product (entry 5). A reaction
using anhydrous K2CO3 in dry acetone for 24 h at room temperature
resulted in pyridone 6a in poor 13% yield (entry 6). As in the previous
cases, intermediate 2a was present in the reaction mixture (moni-
tored by TLC) up to 9 h. Similar yields were obtained when the above
reaction was carried out under reflux conditions for 2 h.
With some insight into the issues related to the reaction, we
screened a few selected organic bases for this transformation (Table
1, entries 7e9). Triethylamine as a base in ethanol at room tem-
perature for 48 h resulted in the formation of pyridone 6a in 26%
yield along with starting material 1a (30%). A reaction mediated by
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and diisopropyl-
ethylamine (DIEA) failed to give pyridone 6a. Heating the above
reactions also failed to give the desired pyridone 6a.
71% isolated yield (Table 2, entries 2 and 3). However, the reaction
of the cyclohexyl derivative 1d with 5a was sluggish and resulted
in an easily separable mixture of ester 2d (53%) and pyridone 6d
(15%) after refluxing in acetone for 24 h. In another experiment,
a crude mixture of ester 2d and pyridone 6d was treated with
TsOH in refluxing EDC. The ester 2d was quantitatively converted
to the desired pyridone 6d and was isolated in 70% yield (entry 4)
after chromatographic purification. It is worthy to note that 6d
was not formed under the original reaction conditions (NaH,
DMA, 24 h) described in Scheme 1. As expected, the N-ethyl de-
rivative 1e reacted smoothly with 5a to give 6e in 73% isolated
yield as viscous oil. The hitherto unknown N-trifluoroethyl de-
rivative 1f also reacted with 5a to give the 1-trifluoroethyl pyr-
idone 6f in moderate yield (56%). Based on the observation that
low yields were obtained in the case of N-cyclohexyl derivative

S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
5115
1d (entry 4), we attempted a reaction of N-phenyl ketene
dithioacetal 1g with the ester 5a to study the effect of N-phenyl
group in the condensation step. We were surprised to find that 1g
reacted smoothly with 5a and N-phenylpyridone 6g was formed
in 76% yield. Similarly, 1a also smoothly condensed with the
benzoyl ester 5b to give the 2-phenylpyridone 6h in 73% isolated
yield. To maximize steric crowding during the final condensation
step, we attempted reaction of 1g with 5b. It is gratifying to note
that 1g reacted with 5b smoothly under identical conditions and
the desired 1,6-diphenylpyridone 6i was isolated in 72% yield,
suggesting that the two phenyl groups adopted a coplanar con-
formation during the final condensation step. Various other 1,6-
disubstituted pyridones 6jeo were prepared in 73e79% yield
(entries 10e15). The N-(4-methylthiazol)-2-yl derivative 1m also
reacted with ester 5a to give 6p in 56% isolated yield.
followed by alkylation of the intermediate potassium dithiolate
with methyl iodide (13.70 mL, 220 mmol) in a one-pot reaction.
The spectral and analytical data of known carbamoyl ketene
dithioacetals 1a,22 1b,29 1d,30 1e,31 1g,15b 1h,32 1i,15b 1j15b were in
agreement with those reported in the literature.
4.2.1. 2-Cyano-N-cyclopropyl-3,3-bis(methylthio)acrylamide
1c. Yield 16.60 g (73%); white crystalline solid. Mp 118e119 ꢀC; IR
(KBr): 3012, 2203, 1645, 1526, 1422, 1296 cmꢁ1; 1H NMR (300 MHz,
CDCl3):
d
0.61 (br s, 2H), 0.82e0.88 (m, 2H), 2.60 (s, 3H), 2.68 (s, 3H),
6.0
2.75e2.79 (m, 1H), 6.29 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d
(2C), 18.9, 20.7, 23.2, 102.2, 117.4, 163.0, 176.0; HRMS (ESI): m/z
[MþH]þ calcd for C9H12N2OS2: 229.0463; found: 229.0460.
4.2.2. 2-Cyano-3,3-bis(methylthio)-N-(2,2,2-trifluoroethyl)acrylam-
ide 1f. Yield: 22.10 g (82%); yellow crystalline solid. Mp 110e111 ꢀC;
IR (KBr): 3363, 2209,1658,1543,1251,1155 cmꢁ1; 1H NMR (300 MHz,
3. Conclusion
CDCl3):
d 2.58 (s, 3H), 2.71 (s, 3H), 3.93e4.04 (m, 2H), 6.52 (br s, 1H);
13C NMR (75 MHz, CDCl3):
d
19.2, 20.8, 41.0 (q, J¼34.3 Hz, CH2CF3),
In summary, we have developed a versatile synthetic method
for the preparation of a variety of poly-functional N-alkyl and N-
aryl 6-oxo-1,6-dihydropyridines using appropriate 2-cyano-3,3-
99.8, 117.1, 124.0 (q, J¼277 Hz, CF3), 161.8, 179.3; HRMS (ESI): m/z
[MþH]þ calcd for C8H9F3N2OS2: 271.0181; found: 271.0177.
bis(methylthio)acrylamides and a
b-keto ester in a single-step
4.2.3. 2-Cyano-3,3-bis(methylthio)-N-[3-(trifluoromethyl)phenyl]ac-
rylamide 1k. Yield: 25.30 g (76%); off-white solid. Mp 112e113 ꢀC;
IR (KBr): 3331, 2209,1660, 1548, 1448,1315,1120, 881, 697 cmꢁ1; 1H
using potassium hydrogen carbonate as the base in boiling ace-
tone. The method developed has potential applications for as-
sembling a variety of structurally diverse functionalized pyridones
from readily available starting materials. The use of inexpensive
starting materials, mild reaction conditions, relatively short re-
action time, a straightforward purification process and good yields
of products are the main attractions of the method. The present
method for the synthesis of dihydropyridones with two points of
structural diversity and bearing three functional groups for addi-
tional structural modification represents superiority over existing
methods and holds enormous potential in synthetic and medicinal
chemistry.
NMR (300 MHz, CDCl3):
1H), 7.47 (d, J¼7.8 Hz, 1H), 7.70 (d, J¼7.2 Hz, 1H), 7.93 (s, 1H), 7.99 (s,
1H); 13C NMR (75 MHz, CDCl3):
19.2, 21.0, 101.1, 117.1, 117.2, 121.6,
d
2.63 (s, 3H), 2.75 (s, 3H), 7.41 (d, J¼7.8 Hz,
d
123.4, 123.9 (q, J¼271.4 Hz, CF3), 129.7, 131.6 (q, J¼32.0 Hz, CCF3),
137.9, 160.0, 179.3; HRMS (ESI): m/z [MþH]þ calcd for
C13H11F3N2OS2: 333.0337; found: 333.0332.
4.2.4. 2-Cyano-N-(4-isopropylphenyl)-3,3-bis(methylthio)acrylam-
ide 1l. Yield: 22.70 g (74%); yellow crystalline solid. Mp 118e119 ꢀC;
IR (KBr): 3235, 2959, 2190, 1641, 1509, 1320, 842 cmꢁ1 1H NMR
;
(300 MHz, CDCl3):
2.84e2.91 (m, 1H), 7.20 (d, J¼8.4 Hz, 2H), 7.45 (d, J¼8.4 Hz, 2H), 7.80
(br s,1H); 13C NMR (75 MHz, CDCl3):
19.2, 20.8, 24.1 (2C), 33.7,102.3,
d
1.22 (d, J¼6.9 Hz, 6H), 2.60 (s, 3H), 2.71 (s, 3H),
4. Experimental
d
4.1. General information
117.4,120.4,120.5,127.1 (2C),134.8,145.9,159.6,177.1; HRMS (ESI): m/
z [MþH]þ calcd for C15H18N2OS2: 307.0933; found: 307.0930.
Melting points were determined on a Polmon digital melting
point apparatus model MP-96 and are uncorrected. 1H and 13C NMR
spectra were recorded on a Varian 300 MHz FT NMR spectrometer
in either CDCl3 or DMSO-d6 as specified using tetramethylsilane
(TMS) as an internal standard. Chemical shifts are expressed in
4.2.5. 2-Cyano-N-(4-methyl-1,3-thiazol-2-yl)-3,3-bis(methylthio)ac-
rylamide 1m. Yield: 17.70 g (62%); yellow crystalline solid. Mp
154e155 ꢀC; IR (KBr): 3260, 2192, 1647, 1541, 1420, 1268 cmꢁ1 1H
;
NMR (300 MHz, CDCl3): d 2.36 (s, 3H), 2.64 (s, 3H), 2.77 (s, 3H), 6.55
(s, 1H) 7.94 (br s, 1H); 13C NMR (75 MHz, CDCl3):
d 17.0, 19.3, 21.0,
parts per million (ppm) (
d) relative toTMS. IR spectra were obtained
99.5, 108.7,116.5, 146.7, 157.8, 159.8, 180.4; HRMS (ESI): m/z [MþH]þ
on PerkineElmer Spectrum One spectrophotometer. High-
a
resolution mass spectra (HRMS) of compounds were measured on
a Thermo Scientific LTQ Orbitrap Discovery MS system coupled
with an LQT Tune Plus (version 2.5.5 SPI) software. Compounds
were purified by flash silica gel (SRL, 100e200 mesh) chromatog-
raphy using an appropriate solvent mixture as given in the pro-
cedure. Petroleum ether (PE) refers to the fraction boiling in the
40e60 ꢀC range.
calcd for C10H11N3OS3: 286.0137; found: 286.0133.
4.3. NaH mediated synthesis of esters 2 and pyridones 6
Carbamoyl ketene dithioacetal 1aed (3.00 mmol) was added to
a stirred and cooled (0 ꢀC) suspension of 60% sodium hydride
(3.30 mmol)andethyl acetoacetate 5a (3.60mmol)indry DMA (6mL).
The cooling bath was removed and the mixture was further stirred at
ambient temperature for 12e48 h. The mixture was quenched with
ice-cold water (50 mL) and acidified till pH 6.0 using 1 N HCl. The
mixture was then extracted with EtOAc (2ꢂ100 mL). The combined
organic layers were washed with water (2ꢂ50 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum to af-
ford the crude mixture. Purification and separation of the mixture by
flash silica gel column chromatography using 20e30% EtOAc in pe-
troleum ether (PE) yielded esters 2aed and pyridones 6aec.
All b-keto esters used were from commercial sources and used
as received. The N-substituted cyanoacetamides were prepared by
known procedures by coupling appropriate amine with ethyl cya-
noacetate or cyanoacetic acid.28
4.2. Synthesis of carbamoyl ketene dithioacetals (1aem);
general procedure23
The carbamoyl ketene dithioacetals were prepared by reported
procedure by the reaction of 2-cyanoacetamides (100 mmol) with
carbon disulfide (7.22 mL, 120 mmol) in the presence of excess
potassium fluoride (116 g, 2000 mmol) in dry DMF (150 mL)
4.3.1. Ethyl 2-acetyl-4-cyano-5-(methylamino)-3-(methylthio)-5-
oxopent-3-enoate 2a. Off-white crystalline solid (42%). Mp

5116
S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
107e109 ꢀC; Rf 0.52 (EtOAc/PE, 1:1); IR (KBr): 3357, 2209, 1660,
1615, 1530, 1259, 1212, cmꢁ1; 1H NMR (300 MHz, CDCl3):
1.29 (t,
103.1,116.7,161.2, 169.3, 170.7, 175.2; HRMS (ESI): m/z [MꢁH]ꢁ calcd
d
for C17H23N2O4S: 351.1373; found: 351.1376.
J¼7.2 Hz, 3H), 2.04 (s, 3H), 2.15 (s, 3H), 2.92 (d, J¼4.8 Hz, 3H),
4.26e4.32 (q, J¼7.2 Hz, 2H), 6.20 (br s, 1H), 13.12 (br s, 1H); 13C
4.4. TsOH mediated cyclization of 2d to ethyl 5-cyano-1-
cyclohexyl-2-methyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-3-carboxylate 6d
NMR (75 MHz, CDCl3):
d 14.1, 16.3, 19.1, 26.4, 61.6, 99.7, 102.8,
116.6, 162.7, 169.2, 170.8, 175.2; HRMS (ESI): m/z [MꢁH]ꢁ calcd for
C12H15N2O4S: 283.0747; found: 283.0754.
A mixture of ester 2d (200 mg, 0.60 mmol) and TsOH (170 mg,
0.90 mmol) in 1,2-dichloroethane (2 mL) was refluxed with stirring
for 5 h. The mixture was cooled to ambient temperature and
quenched carefully with saturated aqueous NaHCO3 (2 mL). The
layers were separated. The organic layer was washed with water
(25 mL) and dried (Na2SO4). The residue obtained after evaporation
of the solvent was purified on a short length flash silica gel column
(20% EtOAc/PE) to afford 173 mg (91%) of 6d as a white solid. Mp
101e103 ꢀC; Rf 0.55 (EtOAc/PE, 1:1); IR (KBr): 2941, 2925, 2217, 1717,
4.3.2. Ethyl 5-cyano-1,2-dimethyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-3-carboxylate 6a. Off-white solid (21%). Mp
83e84 ꢀC; Rf 0.32 (EtOAc/PE, 1:1); IR (KBr): 2219, 1721, 1655, 1518,
1278, 1186 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.39 (t, J¼6.9 Hz, 3H),
2.41 (s, 3H), 2.74 (s, 3H), 3.56 (s, 3H), 4.37 (q, J¼6.9 Hz, 2H); 13C NMR
(75 MHz, CDCl3):
d 13.9, 18.6, 19.0, 32.1, 62.4, 102.4, 114.9, 116.9,
148.7, 157.5, 159.8, 165.4; HRMS (ESI): m/z [MþH]þ calcd for
C12H14N2O3S: 267.0797; found: 267.0794.
1670, 1509, 1269, 1052 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.28 (br
4.3.3. Ethyl
(methylthio)-5-oxopent-3-enoate 2b. Brown oil (32%); Rf 0.40
(EtOAc/PE, 1:1); IR (neat): 3019, 2207, 1651, 1525, 1262, 1215 cmꢁ1
1H NMR (300 MHz, CDCl3):
2-acetyl-4-cyano-5-[(3-methoxypropyl)-amino]-3-
s, 4H), 1.39 (t, J¼7.2 Hz, 3H), 1.62 (br s, 2H), 1.91 (br s, 2H), 2.39 (s,
3H), 2.72 (s, 3H), 2.73e2.81 (m, 2H), 3.98 (br s,1H), 4.37 (q, J¼7.2 Hz,
;
2H); 13C NMR (75 MHz, CDCl3):
d 13.9, 18.3, 19.2, 24.7, 26.2 (2C),
27.8, 32.7, 62.1, 62.4, 104.7, 114.9, 117.4, 147.5, 156.7, 160.1, 165.9;
HRMS (ESI): m/z [MþH]þ calcd for C17H22N2O3S: 335.1423; found:
335.1424.
d
1.30 (t, J¼6.9 Hz, 3H), 1.84 (t, J¼6.0 Hz,
2H), 2.04 (s, 3H), 2.14 (s, 3H), 3.37 (s, 3H), 3.45e3.55 (m, 4H), 4.29
(q, J¼6.9 Hz, 2H), 7.11 (br s, 1H), 13.11 (br s, 1H); 13C NMR (75 MHz,
CDCl3): d 14.1, 16.3, 19.1, 28.4, 39.0, 58.8, 61.6, 72.0, 99.8, 103.4, 116.5,
162.1, 169.3, 170.1, 175.2; HRMS (ESI): m/z [MꢁH]ꢁ calcd for
4.5. KHCO3 mediated synthesis of pyridines 6aep
C15H21N2O5S: 341.1165; found: 341.1172.
To a stirred solution of ketene dithioacetal 1aem (3.00 mmol)
4.3.4. Ethyl 5-cyano-1-(3-methoxypropyl)-2-methyl-4-(methylthio)-
6-oxo-1,6-dihydropyridine-3-carboxylate 6b. Brown oil (20%);
Rf 0.35 (EtOAc/PE, 1:1) IR (neat): 3019, 2224, 1724, 1654, 1648,
and b-keto ester 5aed (3.60 mmol) in dry acetone (5 mL) was
added KHCO3 (6.00 mmol) and the resultant heterogeneous mix-
ture was stirred under reflux for 5e9 h. CAUTION: Toxic methyl
mercaptan was liberated during this reaction. The reaction should
be carried out in an efficient fume hood. Most of the acetone was
evaporated under reduced pressure and the residue was taken up
in water (50 mL) and acidified till pH 6 using 1 N HCl. The mixture
was extracted with ethyl acetate (2ꢂ100 mL) and the combined
extracts were washed with water (25 mL) and dried (Na2SO4). The
solvent was evaporated and the crude product thus obtained was
purified by flash silica gel column chromatography using 30e40%
ethyl acetate in petroleum ether (PE) as eluent to yield pure
products 6aep.
1511, 1216 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.39 (t, J¼6.9 Hz,
3H), 1.97 (q, J¼6.6 Hz, 2H), 2.44 (s, 3H), 2.74 (s, 3H), 3.33 (s, 3H),
3.43 (t, J¼6.5 Hz, 2H), 4.14 (t, J¼6.9 Hz, 2H), 4.37 (q, J¼6.9 Hz,
2H); 13C NMR (75 MHz, CDCl3):
d 13.8, 18.1, 18.4, 28.0, 43.4, 58.6,
62.4, 69.3, 102.7, 114.8, 117.0, 148.3, 157.3, 159.6, 165.6; HRMS
(ESI): m/z [MþH]þ calcd for C15H20N2O4S: 325.1216; found:
325.1212.
4.3.5. Ethyl 2-acetyl-4-cyano-5-(cyclopropylamino)-3-(methylthio)-
5-oxopent-3-enoate 2c. White crystalline solid (34%). Mp
115e117 ꢀC; Rf 0.48 (EtOAc/PE, 1:1); IR (KBr): 3276, 3012, 2203,
1645, 1527, 1296 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
0.61 (br s, 2H),
4.5.1. Pyridone 6a. Reaction of 1a (500 mg, 2.47 mmol) with ethyl
acetoacetate 5a (0.37 mL, 2.96 mmol) for 5 h followed by chro-
matographic purification (EtOAc/PE, 3:7) afforded 494 mg (75%) of
6a as a white solid. The analytical and spectral data for the product
obtained by this method were identical to those obtained above by
NaH/DMA method.
0.83 (br s, 2H), 1.29 (t, J¼6.8 Hz, 3H), 2.03 (s, 3H), 2.15 (s, 3H), 2.78
(br s, 1H), 4.29 (q, J¼6.8 Hz, 2H), 6.28 (br s, 1H), 13.12 (br s, 1H); 13C
NMR (75 MHz, CDCl3):
d 6.6, 10.6, 14.1, 16.4, 19.1, 23.0, 61.6, 99.7,
102.5, 116.6, 163.6, 169.2, 171.4, 175.2; HRMS (ESI): m/z [MþH]þ
calcd for C14H17N2O4S: 309.0903; found: 309.0908.
4.3.6. Ethyl 5-cyano-1-cyclopropyl-2-methyl-4-(methylthio)-6-oxo-
1,6-dihydropyridine-3-carboxylate 6c. Off-white crystalline solid
(20%). Mp 99e100 ꢀC; Rf 0.30 (EtOAc/PE, 1:1); IR (KBr): 2981, 2219,
4.5.2. Pyridone 6b. Reaction of 1b (500 mg, 1.92 mmol) with 5a
(0.29 mL, 2.30 mmol) for 6 h followed by chromatographic purifi-
cation (EtOAc/PE, 3:7) afforded 436 mg (70%) of 6b as a brown oil.
The analytical and spectral data for the product obtained by this
method were identical to those obtained above by NaH/DMA
method.
1711, 1668, 1500, 1214 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 0.90 (br s,
2H), 1.33 (br s, 2H), 1.38 (t, J¼6.9 Hz, 3H), 2.52 (s, 3H), 2.72 (s, 3H),
2.86 (br s, 1H), 4.37 (q, J¼6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
10.5 (2C), 13.9, 18.4, 18.8, 29.0, 62.3, 103.2, 114.7, 116.8, 150.9, 157.8,
160.6, 165.3; HRMS (ESI): m/z [MþH]þ calcd for C14H16N2O3S:
4.5.3. Pyridone 6c. Reaction of 1c (500 mg, 2.19 mmol) with 5a
(0.33 mL, 2.63 mmol) for 9 h followed by chromatographic purifi-
cation (EtOAc/PE, 3:7) afforded 454 mg (71%) of 6c as an off-white
crystalline solid. The analytical and spectral data for the product
obtained by this method were identical to those obtained above by
NaH/DMA method.
293.0954; found: 293.0950.
4.3.7. Ethyl 2-acetyl-4-cyano-5-(cyclohexylamino)-3-(methylthio)-
5-oxopent-3-enoate 2d. Off-white solid (30%). Mp 90e92 ꢀC; Rf 0.60
(EtOAc/PE, 1:1); IR (KBr): 3345, 2924, 2853, 2207, 1655, 1638, 1530,
1255 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.16e1.28 (m, 2H), 1.30 (t,
J¼7.0 Hz, 3H), 1.32e1.43 (m, 2H), 1.55e1.62 (m, 2H), 1.70e1.76 (m,
2H), 1.93e1.99 (m, 2H), 2.05 (s, 3H), 2.14 (s, 3H), 3.83 (br s, 1H), 4.31
(q, J¼7.0 Hz, 2H), 6.02 (br s, 1H), 13.12 (br s, 1H); 13C NMR (75 MHz,
4.5.4. Pyridone 6d. Reaction of 1d (500 mg, 1.85 mmol) with 5a
(0.28 mL, 2.22 mmol) for 24 h, resulted in a mixture of 2d and 6d
(78:22 by HPLC). Work-up of the reaction as described gave the
mixture as syrup. The mixture on treatment with TsOH (527 mg,
CDCl3):
d 14.1, 16.3, 19.1, 24.7 (2C), 25.3, 32.8 (2C), 48.9, 61.6, 99.8,

S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
5117
2.77 mmol) in boiling EDC for 5 h resulted in complete consump-
tion of 2d (TLC). Work-up and purification of the reaction mixture
as described earlier gave 433 mg (70%) of 6d as a white solid, which
was identical with the product prepared by TsOH assisted cycliza-
tion of pure ester 2d.
18.4, 62.0, 103.9, 114.6, 127.9 (2C), 128.5 (2C), 128.8 (2C), 128.9, 129.0
(2C), 129.6 (2C), 131.7, 136.5, 150.1, 159.2, 159.3, 164.4; HRMS (ESI):
m/z [MþH]þ calcd for C22H18N2O3S: 391.1110; found: 391.1113.
4.5.10. Ethyl 5-cyano-2-ethyl-4-(methylthio)-6-oxo-1-phenyl-1,6-
dihydropyridine-3-carboxylate 6j. Reaction of 1g (500 mg,
1.89 mmol) with ethyl propionylacetate 5c (0.32 mL, 2.27 mmol) for
6 h followed by chromatographic purification (EtOAc/PE, 3:7)
afforded 473 mg (73%) of 6j as an off-white crystalline solid. Mp
97e99 ꢀC; Rf 0.58 (EtOAc/PE, 1:1); IR (KBr): 2989, 2220, 1721, 1650,
4.5.5. Ethyl 5-cyano-1-ethyl-2-methyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-3-carboxylate 6e. Reaction of 1e (500 mg,
2.31 mmol) with 5a (0.35 mL, 2.77 mmol) for 6 h followed by
chromatographic purification (EtOAc/PE, 3:7) afforded 473 mg
(73%) of 6e as an amber oil. Rf 0.34 (EtOAc/PE, 1:1); IR (neat): 2983,
2935, 2222,1725,1651,1276,1050 cmꢁ1; 1H NMR (300 MHz, CDCl3):
1565, 1499, 1290 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 1.01 (t,
J¼7.5 Hz, 3H), 1.40 (t, J¼7.2 Hz, 3H), 2.40 (q, J¼7.2 Hz, 2H), 2.81 (s,
d
1.33 (t, J¼6.6 Hz, 3H), 1.39 (t, J¼6.9 Hz, 3H), 2.43 (s, 3H), 2.74 (s,
3H), 4.39 (q, J¼7.5 Hz, 2H), 7.19 (d, J¼5.7 Hz, 2H), 7.52e7.56 (m, 3H);
3H), 4.12 (q, J¼6.6 Hz, 2H), 4.37 (q, J¼6.9 Hz, 2H); 13C NMR (75 MHz,
13C NMR (75 MHz, CDCl3):
d 13.3, 13.9, 18.5, 25.4, 62.4, 103.2, 114.5,
CDCl3):
d
13.1, 13.9, 18.0, 18.4, 40.7, 62.3, 102.8, 114.8, 117.0, 147.8,
116.1, 127.8 (2C), 129.7 (2C), 129.8, 136.1, 153.5, 159.2, 159.9, 165.2;
HRMS (ESI): m/z [MþH]þ calcd for C18H18N2O3S: 343.1110; found:
343.1111.
157.2, 159.3, 165.5; HRMS (ESI): m/z [MþH]þ calcd for C13H16N2O3S:
281.0954; found: 281.0950.
4.5.6. Ethyl 5-cyano-2-methyl-4-(methylthio)-6-oxo-1-(2,2,2-
trifluoroethyl)-1,6-dihydropyridine-3-carboxylate 6f. Reaction of 1f
(500 mg, 1.85 mmol) with 5a (0.28 mL, 2.22 mmol) for 8 h followed
by chromatographic purification (EtOAc/PE, 3:7) afforded 346 mg
(56%) of 6f as an off-white solid. Mp 82e84 ꢀC; Rf 0.57 (EtOAc/PE,
4.5.11. Ethyl 5-cyano-1-(4-fluorophenyl)-2-methyl-4-(methylthio)-6-
oxo-1,6-dihydropyridine-3-carboxylate 6k. Reaction of 1h (500 mg,
1.77 mmol) with 5a (0.27 mL, 2.12 mmol) for 6 h followed by
chromatographic purification (EtOAc/PE, 3:7) afforded 466 mg
(76%) of 6k as a white crystalline solid. Rf 0.63 (EtOAc/PE, 1:1); Mp
163e164 ꢀC; IR (KBr): 2984, 2223, 1725, 1656, 1572, 1502, 1288,
1:1); IR (KBr): 2992, 2222, 1731, 1656, 1510, 1283, 1185, 1044 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.2 Hz, 3H), 2.44 (s, 3H), 2.81
1234, 845 cmꢁ1; 1H NMR (300 MHz, CDCl3):
2.03 (s, 3H), 2.81 (s, 3H), 4.39 (q, J¼7.2 Hz, 2H), 7.10e7.20 (m, 2H),
7.21e7.27 (m, 2H); 13C NMR (75 MHz, CDCl3):
13.9, 18.5, 19.8, 62.5,
d
1.40 (t, J¼7.2 Hz, 3H),
(s, 3H), 4.39 (q, J¼7.2 Hz, 2H), 4.78 (br s, 2H); 13C NMR (75 MHz,
CDCl3):
d
13.8, 18.4 (2C), 44.3 (q, J¼35.4 Hz, CH2CF3), 62.7, 102.2,
d
114.3, 117.5, 122.9 (q, J¼279.4 Hz, CH2CF3), 147.2, 159.1, 159.9, 164.9;
HRMS (ESI): m/z [MþH]þ calcd for C13H13F3N2O3S: 335.0671;
found: 335.0672.
103.1, 114.4, 116.6, 117.3 (d, J¼22.8 Hz, 2C), 129.4 (d, J¼9.0 Hz, 2C),
132.5 (d, J¼3.4 Hz), 148.4, 159.4, 159.7, 162.8 (d, J¼249.5 Hz, CF),
165.1; HRMS (ESI): m/z [MþH]þ calcd for C17H15FN2O3S: 347.0860;
found: 347.0856.
4.5.7. Ethyl 5-cyano-2-methyl-4-(methylthio)-6-oxo-1-phenyl-1,6-
dihydropyridine-3-carboxylate 6g. Reaction of 1g (500 mg,
1.89 mmol) with 5a (0.29 mL, 2.27 mmol) for 5 h followed by
chromatographic purification (EtOAc/PE, 3:7) afforded 472 mg
(76%) of 6g as an off-white crystalline solid. Mp 126e127 ꢀC; Rf 0.50
4.5.12. Ethyl 1-(4-chlorophenyl)-5-cyano-2-methyl-4-(methylthio)-
6-oxo-1,6-dihydropyridine-3-carboxylate 6l. Reaction of 1i (300 mg,
1.00 mmol) with 5a (0.15 mL, 1.20 mmol) for 6 h followed by
chromatographic purification (EtOAc/PE, 3:7) afforded 287 mg
(79%) of 6l as a white crystalline solid. Mp 197e198 ꢀC; Rf 0.69
(EtOAc/PE, 1:1); IR (KBr): 2983, 2223, 1723, 1651, 1573, 1504, 1489,
(EtOAc/PE, 1:1); IR (KBr): 2222, 1720, 1658, 1288, 1184, 1022 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
(s, 3H), 4.39 (q, J¼6.9 Hz, 2H), 7.16 (d, J¼6.9 Hz, 2H), 7.52e7.56 (m,
3H); 13C NMR (75 MHz, CDCl3):
14.0, 18.6, 19.9, 62.5, 103.6, 114.6,
d
1.40 (t, J¼6.9 Hz, 3H), 2.03 (s, 3H), 2.81
1230, 771 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.40 (t, J¼7.2 Hz, 3H),
d
2.03 (s, 3H), 2.81 (s, 3H), 4.39 (q, J¼7.2 Hz, 2H), 7.11 (d, J¼8.4 Hz, 2H),
116.5, 127.4 (2C), 129.8, 130.2 (2C), 136.7, 148.6, 159.1, 159.7, 165.3;
HRMS (ESI): m/z [MþH]þ calcd for C17H16N2O3S: 329.0954; found:
329.0951.
7.53 (d, J¼8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d 13.9, 18.6, 19.9,
62.6, 103.1, 114.4, 116.6, 128.9 (2C), 130.5 (2C), 135.0, 135.9, 148.1,
159.6 (2C),165.1; HRMS (ESI): m/z [MþH]þ calcd for C17H15ClN2O3S:
363.0564; found: 363.0560.
4.5.8. Ethyl 5-cyano-1-methyl-4-(methylthio)-6-oxo-2-phenyl-1,6-
dihydropyridine-3-carboxylate 6h. Reaction of 1a (300 mg,
1.48 mmol) with ethyl benzoylacetate 5b (0.31 mL, 1.78 mmol) for
7 h followed by chromatographic purification (EtOAc/PE, 2:3)
afforded 355 mg (73%) of 6h as a white crystalline solid. Mp
127e128 ꢀC; Rf 0.58 (EtOAc/PE, 1:1); IR (KBr): 2960, 2222, 1709,
4.5.13. Ethyl 5-cyano-1-(4-methoxyphenyl)-2-methyl-4-(methylthio)-
6-oxo-1,6-dihydropyridine-3-carboxylate 6m. Reaction of 1j (300 mg,
1.02 mmol) with 5a (0.15 mL, 1.22 mmol) for 6 h followed by
chromatographic purification (EtOAc/PE, 2:3) afforded 285 mg (78%)
of 6m as an off-white crystalline solid. Mp 131e132 ꢀC; Rf 0.47
(EtOAc/PE, 1:1); IR (KBr): 2975, 2223, 1714, 1666, 1509, 1252, 1169,
1664, 1544, 1485, 1185 cmꢁ1 1H NMR (300 MHz, CDCl3):
; d 0.90 (t,
J¼7.2 Hz, 3H), 2.79 (s, 3H), 3.26 (s, 3H), 3.91 (q, J¼7.2 Hz, 2H), 7.29
1022 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.39 (t, J¼7.2 Hz, 3H), 2.05
(d, J¼6.9 Hz, 3H), 7.49e7.53 (m, 3H); 13C NMR (75 MHz, CDCl3):
(s, 3H), 2.80 (s, 3H), 3.85 (s, 3H), 4.38 (q, J¼7.2 Hz, 2H), 7.01 (d,
d
13.3, 18.3, 34.7, 61.9, 103.4, 114.8, 117.4, 128.0 (2C), 129.0 (2C),
J¼7.5 Hz, 2H), 7.07 (d, J¼7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3):
130.5, 131.7, 150.5, 157.7, 159.7, 164.4; HRMS (ESI): m/z [MþH]þ
d 13.9, 18.5, 19.9, 55.5, 62.4, 103.2, 114.6, 115.3 (2C), 116.4, 128.4 (2C),
calcd for C17H16N2O3S: 329.0954; found: 329.0950.
129.0, 149.1, 158.8, 159.9, 160.2, 165.3; HRMS (ESI): m/z [MþH]þ
calcd for C18H18N2O4S: 359.1060; found: 359.1055.
4.5.9. Ethyl 5-cyano-4-(methylthio)-6-oxo-1,2-diphenyl-1,6-
dihydropyridine-3-carboxylate 6i. Reaction of 1g (500 mg,
1.89 mmol) with 5b (0.39 mL, 2.27 mmol) for 7 h followed by
chromatographic purification (EtOAc/PE, 3:7) afforded 532 mg
(72%) of 6i as a yellow crystalline solid. Mp 157e158 ꢀC; Rf 0.70
(EtOAc/PE, 1:1); IR (KBr): 2999, 2220, 1714, 1666, 1552, 1484, 1226,
4.5.14. Ethyl 5-cyano-4-(methylthio)-6-oxo-2-propyl-1-[3-(trifluorom
ethyl)phenyl]-1,6-dihydropyridine-3-carboxylate 6n. Reaction of 1k
(300 mg, 0.90 mmol) with ethyl butyrylacetate 5d (0.17 mL,
1.08 mmol) for 5 h followed by chromatographic purification (EtOAc/
PE, 3:7) afforded 284 mg (74%) of 6n as a white crystalline solid. Mp
158e159 ꢀC; Rf 0.77 (EtOAc/PE, 1:1); IR (KBr): 2983, 2964, 2221, 1719,
1138 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
0.88 (t, J¼6.6 Hz, 3H), 2.87
(s, 3H), 3.93 (q, J¼6.6 Hz, 2H), 6.98 (d, J¼6.6 Hz, 2H), 7.06 (d,
1666, 1568, 1181, 1068, 660 cmꢁ1; 1H NMR (300 MHz, CDCl3):
(t, J¼7.2 Hz, 3H), 1.40 (t, J¼7.2 Hz, 3H), 1.40e1.45 (m, 2H), 2.25e2.31
d 0.69
J¼6.3 Hz, 2H), 7.16e7.24 (m, 6H); 13C NMR (75 MHz, CDCl3):
d 13.3,

5118
S. Kumar et al. / Tetrahedron 69 (2013) 5112e5118
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(m, 2H), 2.82 (s, 3H), 4.39 (q, J¼7.2 Hz, 2H), 7.42 (d, J¼8.4 Hz, 1H), 7.49
(s, 1H), 7.71 (t, J¼7.5 Hz, 1H), 7.80 (d, J¼7.8 Hz, 1H); 13C NMR (75 MHz,
4. Robertson, D. W.; Beedle, E. E.; Swartzendruber, J. K.; Jones, N. D.; Elzey, T. K.;
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CDCl3):
d 13.9 (2C), 18.5, 22.5, 33.8, 62.5, 103.1, 114.3, 116.5, 123.2 (q,
J¼271.4 Hz, CF3), 125.2, 126.7, 130.5,131.6,132.4 (q, J¼33.1 Hz, CeCF3),
136.7, 151.6, 159.6, 160.0, 164.9; HRMS (ESI): m/z [MþH]þ calcd for
C20H19F3N2O3S: 425.1141; found: 425.1143.
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(500 mg, 1.63 mmol) with 5a (0.25 mL, 1.96 mmol) for 5 h followed
by chromatographic purification (EtOAc/PE, 2:3) afforded 471 mg
(78%) of 6o as an off-white crystalline solid. Mp 197e198 ꢀC; Rf 0.72
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(EtOAc/PE, 1:1); IR (KBr): 2963, 2221, 1716, 1667, 1503, 1228 cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
1.28 (d, J¼6.6 Hz, 6H), 1.39 (t, J¼7.2 Hz,
3H), 2.04 (s, 3H), 2.80 (s, 3H), 2.98 (septet, J¼6.6 Hz, 1H), 4.38 (q,
J¼7.2 Hz, 2H), 7.06 (d, J¼8.4 Hz, 2H), 7.38 (d, J¼8.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d 13.9, 18.6, 19.9, 23.7 (2C), 33.8, 62.4, 103.2, 114.6,
116.4, 127.0 (2C), 128.1 (2C), 134.1, 148.9, 150.6, 158.8, 159.8, 165.3;
HRMS (ESI): m/z [MþH]þ calcd for C20H22N2O3S: 371.1423; found:
371.1419.
4.5.16. Ethyl 5-cyano-2-methyl-4-(methylthio)-1-(4-methyl-1,3-
thiazol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate 6p. Reaction
of 1m (500 mg, 1.75 mmol) with 5a (0.27 mL, 2.10 mmol) for 4 h
followed by chromatographic purification (EtOAc/PE, 1:4) afforded
343 mg (56%) of 6p as an off-white crystalline solid. Mp 118e120 ꢀC;
Rf 0.55 (EtOAc/PE, 1:1); IR (KBr): 2995, 2222, 1723, 1670, 1566, 1485,
1291 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
1.38 (t, J¼7.5 Hz, 3H), 2.15 (s,
3H), 2.48 (s, 3H), 2.82 (s, 3H), 4.38 (q, J¼7.5 Hz, 3H), 7.14 (s, 1H); 13C
NMR (75 MHz, CDCl3): d 13.9, 17.1, 18.6, 18.8, 62.5, 102.6, 114.0, 116.8,
117.6, 148.2, 151.5, 154.4, 159.3, 160.9, 164.6; HRMS (ESI): m/z
[MþH]þ calcd for C15H15N3O3S2: 350.0627; found: 350.0623.
Acknowledgements
We thank Dr. Rajesh Dwivedi and his team for analytical support
of this work. We also thank Dr. Nilanjana Biswas for recording high-
resolution mass spectra for the final products reported in this pa-
per. We also thank Ms. Aarti Sawant for technical support and for
the preparation of a few ketene dithioacetals reported in this paper.
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Supplementary data
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Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.04.082.
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