Substituent directed regioselective synthesis of 2-oxonicotonic acids and methyl nicotinates

Article abstract of DOI:10.1016/j.tetlet.2007.05.011

An innovative synthesis of aryl tethered 1,2-dihydro-2-oxopyridine-3-carboxylic acids has been developed through nucleophile induced ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates using either cyanamide or arylamidine

Full text of DOI:10.1016/j.tetlet.2007.05.011

Tetrahedron Letters 48 (2007) 4939–4942
Substituent directed regioselective synthesis of 2-oxonicotonic
I
acids and methyl nicotinates
a
a
a
Ramendra Pratap, Farahanullah, Resmi Raghunandan,
b
a,
*
P. R. Maulik and Vishnu Ji Ram
a
Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India
b
Molecular and Structural Biology, Central Drug Research Institute, Lucknow 226 001, India
Received 14 March 2007; revised 25 April 2007; accepted 2 May 2007
Available online 10 May 2007
Abstract—An innovative synthesis of aryl tethered 1,2-dihydro-2-oxopyridine-3-carboxylic acids has been developed through nucleo-
phile induced ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates using either cyanamide or
arylamidine in excellent yields. Further, the reaction of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylates with form-
amidine acetate under analogous reaction conditions did not follow the same course of reaction and produced methyl nicotinate,
regioselectively, in good yield. Decarboxylation of a 6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid has been
achieved by heating in PPA. The 4-methylsulfanyl substituent in 3 has also been oxidized to the corresponding methylsulfonyl group
with m-chloroperbenzoic acid.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Pyridine and 1,2-dihydro-2-oxopyridine ring systems are
present as substructures in a variety of naturally occur-
nions of b-ketoesters afforded 1,2-dihydro-4-hydroxy-
2-oxopyridine-3-carboxylic acids.
9
,10
1
2
ring alkaloids and pharmacologically active molecules
with wide synthetic potential for generating molecular
Acyl ketene dithioacetals have been found to be very
useful synthons for the preparation of congested 1,2-
dihydro-2-oxopyridine-3-carboxylic acids by base cata-
3
4
diversity by preparing quinolines, isoquinolines, indol-
5
5a
izidines and quinolizidines of therapeutic impor-
tance. The development of an efficient methodology
for the regiocontrolled synthesis of congested 1,2-dihy-
dro-2-oxopyridine-3-carboxylic acids and methyl nicoti-
nates is a major challenge in medicinal and heterocyclic
chemistry.
1
1
lyzed substitution–cyclization reactions.
Recently,
transition metal catalyzed synthesis of highly functional-
1
2
ized 2-oxopyridines has been reported by reaction of
azazircona cyclopentenones with alkynes in the presence
of NiCl (PPh ) .
2
3 2
6
The synthetic strategy for the preparation of 1,2-di-
The chemistry of 1,2-dihydro-2-oxopyridine-3-carbox-
ylic acids is poorly explored and suitable synthetic pro-
cedures are lacking. They have been obtained directly by
hydro-2-oxopyridine-3-carboxylic
oxidation, rearrangement and hydrolysis of various
,5-diarylpyridines. These are also prepared by the
hydrolysis of 3,5-diaryl-2-fluoropyridines in 1,4-diox-
ane in excellent yields. The synthesis of 5-alkoxycar-
bonyl-1,2-dihydro-2-oxopyridine-3-carboxylic acids has
been reported by nucleophilic addition of malonic esters
acids
involves
1
3
3
oxidation of quinoline
with dioxovanadium ions
7
þ
ðVO Þ as well as by oxidation of 8-quinolinol and 8-
2
1
4
quinolinamine using vanadium(V) in 5 M sulfuric
acid. Typically, this class of compounds has been syn-
1
5
thesized by the acid hydrolysis of 1,2-dihydro-2-oxo-
8
16
to alkynyl imines, and by coupling of a nitrile with a
pyridine-3-carbonitriles. Recently, Marcoux et al.
dienolate. A similar condensation of nitriles with dia-
have reported their synthesis from the reaction of
diethyl malonate with vinamidinium hexafluorophos-
phate salt and ammonium acetate in DMF.
Keywords: 2H-Pyran-2-ones; Ring transformation.
q
Despite the numerous procedures for the construction
of 1,2-dihydro-2-oxopyridine-3-carboxylic acids, most
suffer from limitations such as lack of generality, harsh
CDRI Communication No. 7032.
*
Corresponding author. Tel.: +91 522 2212411; fax: +91 522
623405; e-mail: vjiram@yahoo.com
2
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.011

4940
R. Pratap et al. / Tetrahedron Letters 48 (2007) 4939–4942
reaction conditions, poor yields and the formation of
complex mixtures of side products. These difficulties
necessitate the development of an efficient novel proto-
col for the synthesis of 1,2-dihydro-2-oxopyridine-3-car-
boxylic acids.
Table 1. Comparative yields of the ring-transformed products using
cyanamide and arylamidinium salts
3
Ar
Yield (%) cyanamide Yield (%) arylamidine
a
b
c
d
e
f
C
6
H
5
73
72
76
79
80
73
77
75
70
76
87
85
90
94
89
92
88
79
86
80
4FÆC
4ClÆC
4BrÆC H
4CH
4CH
2-Thienyl
3-Pyridyl
1-Naphthyl
2-Naphthyl
6 4
H
6
H
4
Methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carb-
oxylates have been employed as precursors for the
construction of 6-aryl-4-methylsulfanyl-1,2-dihydro-2-
oxopyridine-3-carboxylic acids and methyl nicotinates
through base-catalyzed ring transformation using either
cyanamide or arylamidine and formamidine acetate.
The methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-
6
4
3
ÆC
6
H
4
3
OÆC
6
H
4
g
h
i
j
1
7
carboxylates were prepared from the reaction of an
aryl methyl ketone with methyl 2-carbomethoxy-3,3-
dimethylthioacrylate in the presence of KOH in DMSO.
transformed products were the same even though differ-
ent reaction pathways followed. A plausible mechanism
is depicted in Scheme 2.
Methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-car-
boxylate possesses three electrophilic centers at C-2,
C-4 and C-6 in which the latter is highly prone to nucleo-
philic attack due to extended conjugation and the pres-
ence of an electron-withdrawing substituent at C-3 of
the pyran ring. During ring transformation with cyana-
mide, the amino group attacks at C-6 of the pyran ring
with ring closure and concomitant loss of carbon
dioxide and hydrolysis of the imino and ester groups
to produce 6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxo-
pyridine-3-carboxylic acid 3. Intermediate A, formed
during the reaction, may yield either product 3 or 4 or
a mixture of both; however, only 3 was isolated. The
possibility for the formation of product 4 was ruled
out on the basis of intramolecular hydrogen bonding
which made the ester carbonyl carbon more electrophilic
and the imino nitrogen more nucleophilic in nature. This
situation favored ester hydrolysis and restricted tauto-
merization leading to an amino group. A plausible
mechanism is depicted in Scheme 1 and the compounds
prepared are listed in Table 1.
The possible initial step in this reaction is attack of the
nucleophile at position 6 of the 2H-pyran-2-one 1 with
ring opening followed by ring closure involving the ester
at C-3 and the amino group of the amidinium salt to
form intermediate B, which in the presence of a base
was transformed to 3 via intermediate C with elimina-
tion of arylamide as shown in Scheme 2.
When ring transformation of 1 was carried out with
formamidine acetate, the isolated product was charac-
terized as methyl 6-aryl-4-methylsulfanylnicotinate 6.
This reaction followed a different pathway as depicted
in Scheme 3. Possibly the reaction was initiated by at-
tack of the nitrogen nucleophile at C-6 of the pyran ring
followed by cyclization involving the amidine carbon
and C-3 of the pyran ring with elimination of carbon
dioxide and ammonia. The preference for the formation
of product 6 could be due to lack of p-electron contribu-
tion from the aryl ring, which makes the formamidine
carbon electrophilic and facilitates the intramolecular
cyclization.
Ring transformation of 1 by arylamidinium chlorides 5
under analogous reaction conditions regioselectively
provided 6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxopyr-
idine-3-carboxylic acids in excellent yields. The ring-
O
SCH3
COOCH3
O
NH.HCl
NH2
H CS
3
DMF/KOH
COOCH3
Ar'
NH
+
Ar'
Ar
O
O
O
1
5
SCH3
Ar
NH
COOCH3
Ar' = C6H5, C6H4N
H3CS
O
DMF/KOH
RT
COOCH3
+
NH2CN
N
C
Ar
O
1
O
SCH3
H
HOOC
H3CS
N
H
HOOC
2
Ar
COOH
O
O
H3CS
OCH3
Ar'
OCH3
Ar'
Ar
HN
N
H3CO
O
O
O
N
H
N
C
H
Ar
H3CS
Ar
COOCH3
Ar'
N
H3CS
O
C
NH
NH
C
NH
OH
B
Ar
N
H
Ar
N
H
A
SCH3
SCH3
H2O
COOH
O
-
Ar'CONH2
COOH
SCH3
SCH3
Ar
H2N
N
COOH
O
COOCH3
NH2
Ar
N
H
O
Ar'
O
3
Ar
N
H
3
Ar
N
H
4
C
Scheme 1.
Scheme 2.

R. Pratap et al. / Tetrahedron Letters 48 (2007) 4939–4942
4941
O
The therapeutic importance and lack of efficient syn-
thetic procedures for the construction of aryl tethered
SCH3
COOCH3
O
NH.CH3COOH DMF/KOH
NH2
H3CS
COOCH3
1,2-dihydro-2-oxopyridine-3-carboxylic
acids
and
+
H
methyl 6-aryl-4-methylsulfanylnicotinate inspired us to
develop a simple and economical procedure for their
preparation. This methodology provides an easy access
to the regioselective synthesis of highly functionalized
6-aryl-4-methylsulfanyl-1,2-dihydro-2-oxopyridine-3-carb-
oxylic acids and methyl 6-aryl-4-methylsulfanylnicoti-
nate in excellent yields.
Ar
O
1
O
H
NH
Ar
NH
O
6
Ar
Yield (%)
SCH3
COOCH3
H
a
b
4
4
Cl.C6H4
Br.C6H4
65
59
COOCH3
H3CS
O
Ar
N
NH2
N
Ar
6
H
Scheme 3.
Acknowledgements
The authors are thankful to CSIR, New Delhi, for finan-
cial support and Sophisticated Analytical Instrument
Facility, CDRI, Lucknow for providing spectroscopic
data.
The structure of 3a was confirmed by single crystal
X-ray diffraction analysis and its ORTEP diagram
1
8
is shown in Figure 1.
The oxidation of 6-(naphthalen-2-yl)-4-methylsulfanyl-
,2-dihydro-2-oxopyridine-3-carboxylic acid with m-
chloroperbenzoic acid at room temperature afforded
-(naphthalen-2-yl)-4-methylsulfonyl-1,2-dihydro-2-oxo-
1
References and notes
6
pyridine-3-carboxylic acid 7 in very good yield. Com-
pound 3 was decarboxylated in hot PPA at 90 ꢁC for
1
. (a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1983; Vol. 1, pp 33–84; (b) Fodor, G. B.; Colasanti,
B. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, pp 1–
8
h to yield 4-methylsulfanyl-6-phenyl-1,2-dihydro-2-
oxopyridine 8 (Scheme 4).
All the compounds synthesized were characterized by
spectroscopic analysis. Data of some representative
compounds are given in the reference section.
9
0; (c) Strunz, G. M.; Findlay, J. A. In The Alkaloids;
Brossi, A., Ed.; Academic Press: Orlando, 1985; Vol. 26, p
89; (d) Daly, J. W. J. Nat. Prod. 1998, 61, 162; (e) Plunkett,
A. O. Nat. Prod. Rep. 1994, 11, 581; (f) Balasubramanian,
M.; Deay, J. G. In Comprehensive Heterocyclic Chemistry
II; Katrizky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: New York, 1996; Vol. 5, p 245; (g)
Rubiralta, M.; Giralt, E.; Diez, A. In Piperidine: Structure,
Preparation, Reactivity, and Synthetic Applications of
Piperidine and its Derivatives; Elsevier: Amsterdam, 1991.
. Paulvannan, K.; Chen, T. J. Org. Chem. 2000, 65, 6160–
1
9
2
3
4
5
6
166.
. Fujita, R.; Watanabe, K.; Ikeura, W.; Ohtake, Y.; Hongo,
H. Heterocycles 2000, 53, 2607–2610.
. Casamitjana, N.; L o´ pez, V.; Jorge, A.; Bosch, J.; Molins,
E.; Roig, A. Tetrahedron 2000, 56, 4027–4042.
. (a) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 523; (b)
Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1981; Vol. 5, pp 1–54.
Figure 1. ORTEP diagram of 3a.
6. Tagat, J. R.; McCombie, S. W.; Barton, B. E.; Jackson, J.;
Shortall, J. Bioorg. Med. Chem. Lett. 1995, 5, 2143–2146.
7
8
9
. Sutherland, A.; Gallagher, T. J. Org. Chem. 2003, 68,
3352–3355.
. Hachiya, I.; Ogura, K.; Shimizu, M. Org. Lett. 2002, 4,
SCH
3
COOH
O
2
755–2757.
. Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343–
351; Also, b-enamino ketone dianions: Bartoli, G.;
Ar
N
H
3
1
PPA /
8
Bosco, M.; Cimarelli, C.; Dalpozzo, R.; De Munno, G.;
Guercio, G.; Palmieri, G. J. Org. Chem. 1992, 57, 6020–
6025.
m-CPBA
Ar = 2-Naphthyl
Ar = Phenyl
h, 90 o
C
SO CH3
SCH
3
2
COOH
10. Brun, E. M.; Gil, S.; Mestres, R.; Parra, M. Synlett 1999,
088–1090.
1
N
H
7
O
N
H
8
O
1
1. (a) Rastogi, R. R.; Ila, H.; Junjappa, H. J. Chem. Soc.,
Chem. Commun. 1975, 645–646; (b) Rastogi, R. R.;
Kumar, A.; Ila, H.; Junjappa, H. J. Chem. Soc., Perkin
Trans. 1 1978, 549–553; (c) Vogel, G. J. Org. Chem. 1965,
30, 203–207.
84%
80%
Scheme 4.

4942
R. Pratap et al. / Tetrahedron Letters 48 (2007) 4939–4942
1
2. Takahashi, T.; Tsai, Fu-Yu.; Li, Y.; Wang, H.; Kondo,
and purified by column chromatography using 1% meth-
anol in chloroform as eluent. Procedure B (Scheme 2): the
product was obtained by stirring an equimolar mixture of
methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbox-
ylate (1 mmol), arylamidininium salt (1.2 mmol) and
KOH (1.5 mmol) in DMF (3.0 mL) for 2–3 h. After usual
work-up, the crude product was purified through column
chromatography using 1% methanol in chloroform as
eluent. Compound 3e: Cream coloured solid; yield: 80%
(NH CN), 89% (ArCÆNHÆNH ); mp >250 ꢁC; IR (KBr)
Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am.
Chem. Soc. 2002, 124, 5059–5067.
3. Assamoi, A.; Hamon, M.; Chastagnier, M.; Chaigneau,
M. Talanta 1987, 24, 1015–1020.
4. Assamoi, A.; Hamon, M. Anal. Chim. Acta 1988, 204, 77–
1
1
1
1
86.
5. Radojkovic-Velickovic, M.; Valentic, N. V.; Misic-Vuko-
vic, M. J. Serbian Chem. Soc. 1994, 59, 921–927.
6. Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.; Dormer, P. G.;
Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem.
2
2
3424, 3119, 3044, 2979, 2919, 2369, 1702, 1611, 1519, 1469,
1382, 1334, 1314, 1268, 1200, 1170, 1131, 1069, 980, 918,
2001, 66, 4194–4199.
ꢁ1
1
1
7. (a) Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. J.
Chem. Res. (S) 1991, 98–99; (b) Ram, V. J.; Verma, M.;
Hussaini, F. A.; Shoeb, A. Liebigs Ann. Chem. 1991, 1229–
876, 845, 815, 716 cm
2.38 (s, 3H, CH ), 2.54 (s, 3H, SCH ), 6.74 (s, 1H, ArH),
; H NMR (CDCl , 300 MHz):
3
3
3
7.36 (d, J = 7.44 Hz, 2H, ArH), 7.77 (d, J = 7.44 Hz, 2H,
1
3
1231; (c) Ram, V. J.; Srivastava, P.; Goel, A. Tetrahedron
ArH), 13.08 (br s, 1H, NH), 15.66 (s, 1H, COOH);
NMR (CDCl , 75 MHz): d 15.53, 21.15, 103.97, 107.30,
127.96, 128.81, 129.56, 141.55, 147.66, 165.20, 165.91 and
C
2003, 59, 7141–7146.
3
1
8. The ORTEP diagram, Figure 1, shows the crystal struc-
ture of 3a and its conformation. The molecule contains a
planar pyridone ring (X1A) that consists of a phenyl ring
+
3
166.12; MS (ESI): 276 (M +1); C14H13NO S (275.32)
calcd: C, 61.07; H, 4.76; N, 5.09. Found: C, 61.23; H, 4.92;
N, 4.91.
(
X1B) substituted at C5, a carboxylic acid at C2 and a
methylsulfanyl group at C3. The twisting angle between
the least-square mean plane of the phenyl and pyridone
ring is 46.3ꢁ. The structural analysis shows the presence of
an intermolecular pꢀ ꢀ ꢀp interaction (centroid separation
General procedure for the synthesis of methyl 6-aryl-4-
methylsulfanylnicotinates (6a): An equimolar mixture of
methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carbox-
ylate (1 mmol), formamidine acetate (1.2 mmol) and KOH
(1.5 mmol) in DMF (3.0 mL) was stirred for 2–3 h. After
usual work-up and column chromatography purification
using 40% hexane in chloroform as eluent, the desired
compound was isolated as a white amorphous solid; yield:
191 mg (65%); mp 158–160 ꢁC; IR (KBr): 2996, 2922,
2849, 2364, 1706, 1584, 1510, 1464, 1437, 1344, 1293, 1228,
˚
X1Aꢀ ꢀ ꢀX1A = 3.932, X1Bꢀ ꢀ ꢀX1B = 3.748 A); (symmetry
codes: 2 ꢁ x, 1 ꢁ y, 1 ꢁ z; 2 ꢁ x, 1 ꢁ y, ꢁz). The crystal
packing further reveals the formation of intermolecular
˚
C–Hꢀ ꢀ ꢀO [H13Bꢀ ꢀ ꢀO3 = 2.48 A, \C13–H13B–O3 = 171ꢁ,
˚
C13–O3 = 3.4326 A]
and
N–Hꢀ ꢀ ꢀO
interactions
N1–O2 =
˚
[
2
H1ꢀ ꢀ ꢀO2 = 1.98 A,
\N1–H1–O2 = 175ꢁ,
˚
ꢁ1
1
.8385 A], (symmetry codes: 1 ꢁ x, 2 ꢁ y, 1 ꢁ z; 2 ꢁ x,
1183, 1131, 1089, 1068, 1009, 963, 830, 784, 720 cm ; H
ꢁ
y, 1 ꢁ z) and intramolecular O–Hꢀ ꢀ ꢀO interaction
NMR (300 MHz, CDCl ): d 2.53 (s, 3H, CH ), 3.95 (s, 3H,
3
3
˚
[
H4ꢀ ꢀ ꢀO2 = 1.74 A,
\O4–H4–O2 = 154ꢁ,
O4–O2 =
3
OCH ), 7.45 (d, J = 8.44 Hz, 2H, ArH), 7.48 (s, 1H, ArH),
˚
2
.5038 A]. Crystal data of 3a: C13
H11NO
3
S
,
M = 261.29,
7.95 (d, J = 8.44 Hz, 2H, ArH), 9.09 (s, 1H, ArH); MS m/z
˚
˚
+
triclinic, P(ꢁ1), a = 6.995(1) A, b = 7.655(1) A, c =
294 (M +1); HRMS: (EI, 70 eV) calcd for C H ClNO S
1
4
12
2
˚
+
1
1.964(1) A, a = 75.82(1)ꢁ, b = 83.63(1)ꢁ, c = 76.64(1)ꢁ,
293.02773 (M ), found m/z 293.02719. Synthesis of 4-
methanesulfonyl-6-naphthalen-2-yl-2-oxo-1,2-dihydropyri-
dine-3-carboxylic acid (7): The product was obtained by
stirring a mixture of 4-methylsulfanyl-6-naphthalen-2-yl-
2-oxo-1,2-dihydro-pyridine-3-carboxylic acid and m-
chloroperbenzoic acid in dichloromethane at room tem-
perature for 10 h. The solvent was removed under reduced
pressure and the crude product obtained was purified by
silica gel column chromatography to afford a yellow
powder using chloroform/methanol (19:1) as eluent; yield:
84%; mp >250 ꢁC; IR (KBr): 3430, 2928, 2862, 2367, 2340,
1700, 1621, 1586, 1533, 1452, 1353, 1266, 1089, 1020, 971,
˚
3
ꢁ3
V = 603.3(13) A , Z = 2,
D
c
= 1.438 g cm ,
l(Mo-
ꢁ
1
Ka) = 0.267 mm , F(000) = 272, rectangular block, col-
ourless, size = 0.3 · 0.25 · 0.075 mm, 2672 reflections
2
measured (Rint = 0.0232), 2109 unique, wR = 0.0994 for
all data, conventional R = 0.0376 [(D/r)max = 000)] on F-
values of 1642 reflections with I > 2r(I), S = 1.032 for all
data and 165 parameters. Unit cell determination and
intensity data collection (2h = 50ꢁ) were performed on a
Bruker P4 diffractometer at 293(2) K. Structure solutions
were performed by direct methods and refinements by full-
2
matrix least-squares methods on F . Programs: XSCANS
ꢁ
1 1
[Siemens Analytical X-ray Instrument Inc.: Madison,
823, 764 cm ; H NMR (DMSO-d
6 3
/CDCl , 200 MHz): d
Wisconsin, USA 1996], SHELXTL-NT [Bruker AXS Inc.:
Madison, Wisconsin, USA 1997]. CCDC (deposit No:
2.89 (s, 3H, SCH ), 7.59 (s, 1H, ArH), 7.64–7.68 (m, 2H,
ArH), 7.94–8.13 (m, 4H, ArH), 8.53 (s, 1H, ArH), 13.40
3
6
18376) contains the supplementary crystallographic data.
(br s, 1H, NH), 15.82 (s, 1H, COOH); MS (ESI): 344
+
These data can be obtained free of charge from
www.ccdc.cam.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, CB2 1EZ, UK. Fax: (internat.) +44
(M +1); C17
H13NO
5
S (343.35) calcd: C, 59.47; H, 3.82; N,
4.08. Found: C, 59.55; H, 3.76; N, 4.14. Synthesis of 4-
methylsulfanyl-6-phenyl-2-oxo-1,2-dihydropyridine (8): The
product was obtained by heating 4-methylsulfanyl-2-oxo-
6-phenyl-1,2-dihydro-pyridine-3-carboxylic acid in poly-
phosphoric acid (PPA) at 90 ꢁC for 8 h. The reaction
mixture was diluted with distilled water and the precipitate
obtained was filtered and purified by silica gel column
chromatography to afford a white solid using hexane/ethyl
acetate (4:1) as eluent; yield: 80%; mp >250 ꢁC; IR (KBr):
3435, 2928, 2862, 2367, 2340, 1658, 1630, 1586, 1533, 1452,
1223/336 033. E-mail: deposit@ccdc.cam.ac.uk.
1
9. General procedure for the synthesis of 6-aryl-4-meth-
ylsulfanyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid 3:
Procedure A (Scheme 1): an equimolar mixture of methyl
6
-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylate
(
1 mmol) and cyanamide (50 mg, 1.2 mmol) in the pres-
ence of KOH (84 mg, 1.5 mmol) in DMF (5.0 mL) was
stirred under a nitrogen atmosphere for 8 h. Consumption
of starting material was monitored by TLC. Excess DMF
was removed under reduced pressure, and the reaction
mixture poured onto crushed ice with vigorous stirring
and finally neutralized with 10% HCl (5.0 mL). The
precipitate obtained was filtered, washed with water, dried
ꢁ
1
1
1353, 1266, 1089, 1020, 971, 823, 764 cm
; H NMR
(CDCl , 200 MHz): d 2.46 (s, 3H, SCH ), 6.22 (s, 1H,
3
3
ArH), 6.32 (s, 1H, ArH), 7.48–7.54 (m, 3H, ArH), 7.61–
7.64 (m, 2H, ArH), 10.34 (br s, 1H, NH); MS (ESI): 218
+
(M +1); C12
H
11NOS (217.28) calcd: C, 66.33; H, 5.10; N,
6.45. Found: C, 66.25; H, 5.16; N, 6.51.