Simple methods to synthesize 2-pyridones: reactions of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and cyanoacetamide

Article abstract of DOI:10.1016/j.tet.2007.12.012

5-Aroyl-6-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles and 5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles are synthesized effectively by the reaction of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and cyanoacetamide un

Full text of DOI:10.1016/j.tet.2007.12.012

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1671e1675
www.elsevier.com/locate/tet
Simple methods to synthesize 2-pyridones: reactions of 2-aroyl-3,3-
bis(alkylsulfanyl)acrylaldehydes and cyanoacetamide
b
b
b
b
Annie Mathews a, , E.R. Anabha , K.A. Sasikala , K.C. Lathesh , K.U. Krishnaraj ,
*
K.N. Sreedevi b, M. Prasanth b, K.S. Devaky b, C.V. Asokan b
a Post Graduate Department of Chemistry, Baselius College, Kottayam, 686001 Kerala, India
b School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, 686560 Kerala, India
Received 27 September 2007; received in revised form 21 November 2007; accepted 6 December 2007
Available online 8 December 2007
Abstract
5-Aroyl-6-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles and 5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbo-
nitriles are synthesized effectively by the reaction of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and cyanoacetamide under two different
conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Heterocycles; Thermal cyclization; Acrylaldehydes; Dithioacetals; 2-Pyridones
1. Introduction
2. Results and discussion
The synthesis of a substituted 2-pyridone ring is an area of
continuing interest due to the number of biologically active
molecules containing this moiety.1 Over the last decade,
natural compounds with this structure have emerged as potent
anti-microbial and anti-viral agents and efforts to develop an
anti-HIV drug based on 2-pyridones are progressing world-
wide.2 Ketene dithioacetals have proved to be excellent pre-
cursors for the synthesis of alkylsulfanyl-substituted
pyridones in high yields.3 One of the most important methods
for the synthesis of 2-pyridones involves cyclocondensation of
ketene dithioacetals with compounds containing active methy-
lene group like cyanoacetamide and scope of such reactions is
well established.4 Recently Mathews and Asokan have utilized
2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes in the synthesis
of new heterocyclic compounds.5 In continuation of our exten-
sive work on 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes we
explored their synthetic utility in the synthesis of 2-pyridones
using cyanoacetamide.
Most of the earlier reported methods for the synthesis of
2-pyridones involving the condensation of 1,3-binucleophiles
with cyanoacetamide need strong bases like sodium hydride,
sodium hydroxide or alkoxides.6 In many reactions we encoun-
tered the deformylation of 2-aroyl-3,3-bis(alkylsulfanyl)acryl-
aldehydes with strong bases. Junjappa et al. used ammonium
acetate/acetic acid medium to cyclize polarized dienes, ob-
tained by the 1,2-addition of Reformatsky reagent to a-oxoke-
tene dithioacetals, leading to the synthesis of substituted
2-pyridones.7 So we used ammonium acetate/acetic acid me-
dium to synthesize 2-pyridones from 2-aroyl-3,3-bis(alkylsul-
fanyl)acrylaldehydes using cyanoacetamide.
When we attempted the reaction of 2-aroyl-3,3-bis(alkylsul-
fanyl)acrylaldehydes with cyanoacetamide in the presence of
ammonium acetate/acetic acid at 80 ꢀC, it afforded only the
Knoevenagel condensation adduct, 4-aroyl-2-cyano-5,5-bis-
(methylsulfanyl)-2,4-pentadienamides 2 in 80e90% yields
1
and no 2-pyridone was formed. H and 13C NMR, EIMS, IR
spectral data and CHN analysis supported the predicted struc-
ture. As the condensation product has the scope for cyclization
to produce 2-pyridones by the elimination of an alkylsulfanyl
* Corresponding author.
E-mail address: ocvengal@sify.com (A. Mathews).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.012

1672
A. Mathews et al. / Tetrahedron 64 (2008) 1671e1675
O
SMe
SMe
CONH2
CN
O
SMe
NH
O
SMe
SMe
CNCH2CONH2
Xylene,
130 °C
NH4Ac/AcOH,
80 °C, 2 h
CHO
R
R
O
R
CN
2
1
3
R = a, CH3; b, OCH3; c, Cl; d, Br; e, H
Yield (%) of 3.= a, 90; b, 80; c, 85; d, 76; e,
70.
Scheme 1. Synthesis of 5-aroyl-6-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles 3 via 4-aroyl-2-cyano-5,5-bis(methylsulfanyl)-2,4-pentadienamide 2.
O
SMe
O
SMe
N
CNCH2CONH2
K2CO3/CH3CN
O
SMe
SMe
CN
O
CN
OH
Reflux, 12 h.
R
R
R
N
CHO
H
4
a-d & f
1a-d & f
b & f
5
R = a, 4-CH3; b, 4- OCH3; c, 4-Cl; d, Br; f, 3-OCH3
a,= 70; b, 72; c, 64; d, 60; f, 70.
Yield (%) of 4
Scheme 2. Synthesis of 5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles 4.
group, we tried the thermal cyclization of the condensation
possible for the addition of amino group to the aldehyde, fol-
lowed by hydrolysis to produce the pyridones. Similar Michael
addition reaction products are reported by Hu et al. in the syn-
thesis of 2-pyridones using acetamidocyanoacetate and a,b-
unsaturated ketones.9
products 2 by heating in xylene at 130 ꢀC (Scheme 1). As
expected, the condensation products underwent thermal cycli-
zation to produce 5-aroyl-6-(methylsulfanyl)-2-oxo-1,2-dihy-
dro-3-pyridinecarbonitriles 3 in 83e90% yield. The products
were characterized by the 1H and 13C NMR, EIMS, IR spectral
data and CHN analysis.
2.1. Fluorescent study of 4-benzoyl-2-cyano-5,5-bis(methyl-
sulfanyl)-2,4-pentadienamide
One-pot reaction of acrylaldehydes 1 and cyanoacetamide
in the presence of ammonium acetate/acetic acid at 120 ꢀC
showed that the cyclization took place under these conditions
also but in this case the yield of the reaction was low.
As a continuation to this we treated 2-aroyl-3,3-bis(alkyl-
sulfanyl)acrylaldehydes 1 with cyanoacetamide in the pres-
ence of K2CO3 in acetonitrile and the reaction yielded new
pyridones, 5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-
pyridinecarbonitriles via a thermodynamically controlled reac-
tion (Scheme 2).
When acrylaldehyde 1a was treated with 1 equiv of cyano-
acetamide in the presence of potassium carbonate in acetonitrile
under reflux for 12 h, the reaction afforded pale yellow solid
having mp 200e202 ꢀC in good yields and it was characterized
on the basis of spectral data as 5-(4-methylbenzoyl)-4-(methyl-
sulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile 4a (the
nature and melting points of 3a and 4a are also different).
The reaction was also extended to other substituted acrylalde-
hydes as well in order to get corresponding 5-aroyl-4-(methyl-
sulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitriles in good
yields. It was observed that a mixture of tautomers 4 and 5
was obtained when the aryl part contains a methoxy substituent.
The formation of 5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-di-
hydro-3-pyridinecarbonitrile 4 is explained by a mechanism
reported by Junjappa et al.8 As the reaction is conducted in
the presence of mild base like K2CO3 in acetonitrile at reflux
temperature for 12 h, it facilitates thermodynamically con-
trolled conjugate addition of carbanion formed from the cya-
noacetamide to the ketene dithioacetal moiety. It is then
Recently number of ketene dithioacetal derivatives are
emerging as chemoluminescent labelling compounds especially
with peroxidase enzymes.10 Narasaka et al. made attempts to
synthesize ketene dithioacetal derivatives having fluorescent
character.11 The extensive conjugation of the 4-benzoyl-2-
cyano-5,5-bis(methylsulfanyl)-2,4-pentadienamide 2 having
a bright yellow colour spurred us to study the fluorescent nature
of these derivatives. For that their UVevis absorption and fluo-
rescence spectra were recorded. We noticed that in CHCl3
Figure 1. The UV spectrum and fluorescent spectrum (excited at 380 nm) of
the 4-benzoyl-2-cyano-5,5-bis(methylsulfanyl)-2,4-pentadienamide 2d.

A. Mathews et al. / Tetrahedron 64 (2008) 1671e1675
1673
4-benzoyl-2-cyano-5,5-bis(methylsulfanyl)-2,4-pentadienamide
4.2. General procedure for the synthesis of 4-aroyl-2-cyano-
showed two absorption maxima at 380 and 250 nm. Thus we
excited at 380 nm to study its fluorescent behaviour (Fig. 1).
The emission maxima were found to be at 460 nm when the ex-
citation was carried out at 380 nm. It clearly indicated that when
pentadienamide derivative was excited, it could emit radiation
in the visible region, thus showing the fluorescent nature of
the 4-benzoyl-2-cyano-5,5-bis(methylsulfanyl)-2,4-pentadiena-
mide fluorescent study on other pentadienamide derivatives also
gave the emission maxima in the higher wavelength region, con-
firming the above observation. Further detailed studies on the
quantumyieldofthefluorescenceandvariationinemissionmax-
ima with respect to different solvents have to be done in future.
5,5-bis(methylsulfanyl)-2,4-pentadienamide (2)
The appropriate 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehyde
(2 mmol) was added to a solution of cyanoacetamide (0.168 g,
2 mmol) in ammonium acetate (0.77 g, 10 mmol) and acetic acid
(5 mL). The solution mixture was heated at 80 ꢀC for 2 h. The
mixture was cooled and poured into ice-cold water and the solid
obtained was filtered, washed and recrystallized from methanol.
4.2.1. 2-Cyano-4-(4-methylbenzoyl)-5,5-bis(methyl-
sulfanyl)-2,4-pentadienamide 2a
Yellow solid; yield 80% (0.53 g); mp 202e204 ꢀC; IR (KBr,
nmax)¼3382, 3186, 2206, 1658, 1604, 1562, 1477 cmꢁ1; H
1
NMR (300 MHz, CDCl3) d¼2.27 (s, 3H, Me), 2.42 (s, 3H,
SCH3), 6.31(s, 2H, CONH2), 7.29(d, J¼9 Hz, 2H, ArH), 7.78(d,
J¼9 Hz, 2H, ArH), 8.64 (s, 1H, vinylic); 13C NMR (75 MHz,
CDCl3þDMSO-d6, 1:1) d¼18.2 (SMe), 21.6 (Me), 103.1
(]CeCONH2), 115.2 (CN), 129.2 (ArH), 129.5 (ArH), 134.2
[]C(SMe)2], 137.1 [C]C(SMe)2], 144.8 (ArH), 145.4 (ArH),
161.1 (vinylic), 162.3 (CONH2), 192.8 (CO); FABMS m/z
(%)¼333 (100). Anal. Calcd for C16H16N2O2S2 (332.44): C,
57.81; N, 8.43; H, 4.85. Found: C, 57.88; N, 8.46; H, 4.82.
3. Conclusions
In this paper we described the formation of two different
2-pyridones, 5-aroyl-6-(methylsulfanyl)-2-oxo-1,2-dihydro-
3-pyridinecarbonitrile 3 and 5-aroyl-4-(methylsulfanyl)-2-
oxo-1,2-dihydro-3-pyridinecarbonitrile 4 by the reaction of
2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and cyanoacet-
amide under different reaction conditions. The formation of
5-aroyl-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecar-
bonitrile 4 is explained by a conjugate addition reaction of the
cyanoacetamide in the presence of potassium carbonate fol-
lowed by cyclization while that of 5-aroyl-6-(methylsul-
fanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile 3 is by the
Knoevenagel condensation reaction of the aldehyde followed
by cyclization reaction. The analogues of these compounds
are important as drugs used in the clinical treatment of patients
with severe heart failure.12 Fluorescent study revealed the pos-
sibility of utilizing the 4-benzoyl-2-cyano-5,5-bis(methylsul-
fanyl)-2,4-pentadienamide derivatives 2 as a fluorescent
material.
4.2.2. 2-Cyano-4-(4-methoxybenzoyl)-5,5-bis(methyl-
sulfanyl)-2,4-pentadienamide 2b
Yellow solid; yield 63% (0.43 g); mp 198e200 ꢀC; IR (KBr,
nmax)¼3359, 3182, 2206, 1658, 1600, 1562, 1473 cmꢁ1; H
1
NMR (300 MHz, CDCl3) d¼2.48 (s, 3H, SMe), 3.88 (s, 3H,
OCH3), 6.43e6.56 (m, 2H, CONH2), 6.97 (d, J¼6 Hz, 2H,
ArH), 7.85 (d, J¼6 Hz, 2H, ArH), 8.64 (s, 1H, vinylic); 13C
NMR (75 MHz, CDCl3þDMSO-d6, 1:1) d¼18.1 (SMe), 55.3
(OMe), 103.0 (]CeCONH2), 114.0 (ArH), 115.1 (CN), 129.6
(ArH), 131.5 (ArH), 137.1 []C(SMe)2], 145.2 [C]C(SMe)2],
160.7 (vinylic), 162.3 (CONH2), 164.0 (ArH), 191.8 (CO);
FABMS m/z (%)¼349 (100). Anal. Calcd for C16H16N2O3S2
(348.44): C, 55.15; N, 8.04; H, 4.63. Found: C, 55.28; N, 8.01;
H, 4.62.
4. Experimental section
4.1. General
4.2.3. 4-(4-Chlorobenzoyl)-2-cyano-5,5-bis(methylsulfanyl)-
2,4-pentadienamide 2c
Melting points were determined on Buchi 530 melting
point apparatus and were uncorrected. The IR spectra were
on KBr pellets on Schimadzu IR-470 spectrometer and the fre-
Yellow solid; yield 85% (0.59 g); mp 218e220 ꢀC; IR (KBr,
nmax)¼3379, 3182, 2206, 1658, 1585, 1562, 1477 cmꢁ1; H
1
1
quencies are reported in cmꢁ1. The H NMR spectra were re-
NMR (300 MHz, CDCl3) d¼2.43 (s, 6H, SCH3), 5.62 (s, 1H,
NH2), 6.01 (s, 1H, NH2), 7.48 (d, J¼9 Hz, 2H, ArH), 7.84 (d,
J¼9 Hz, 2H, ArH), 8.65 (s, 1H, vinylic); 13C NMR (75 MHz,
CDCl3þDMSO-d6, 1:1) d¼17.9 (SMe), 105.4 (]CeCONH2),
114.9(CN),129.1, 130.7(ArH),135.5(ArH),138.6[]C(SMe)2],
144.2 [C]C(SMe)2], 158.5 (vinylic), 162.41 (CONH2), 189.9
(CO);EIMS m/z(%)¼353(100). Anal. Calcdfor C15H13ClN2O2S2
(352.86): C, 51.06; N, 7.94; H, 3.71. Found: C, 51.26; N, 7.96;
H, 3.72.
corded on a Brucker WM (300 MHz) spectrometer using TMS
as internal standard and CDCl3, (CH3)2 C]O-d6 or DMSO-d6
as solvent. The 13C NMR spectra were recorded on a Brucker
WM 300 (75.47 MHz) spectrometer using CDCl3 or acetone-
d6 as solvent. The CHN analyses were done on an Elementar
VarioEL III Serial Number 11042022 instrument. The FAB
mass spectra were recorded on a JOEL SX 102/DA-6000
Mass Spectrometer/Data System using Argon as the FAB
gas. EIMS were recorded on a MICROMASS QUATTRO 11
triple quadrupole mass spectrometer.
4.2.4. 2-Cyano-4-(4-bromobenzoyl)-5,5-bis(methylsulfanyl)-
2,4-pentadienamide 2d
All commercially available reagents were purified before
use. The aroylketene dithioacetals and 2-aroyl-3,3-bis(alkyl-
sulfanyl)acrylaldehydes were prepared by the known
procedure.13
Yellow solid; yield 86% (0.68 g); mp 224e226 ꢀC; IR (KBr,
1
nmax)¼3363, 3182, 2206, 1658, 1562, 1477 cmꢁ1; H NMR
(300 MHz, CDCl3) d¼2.42 (s, 3H, SCH3), 5.60 (s, 1H, NH2),

1674
A. Mathews et al. / Tetrahedron 64 (2008) 1671e1675
6.09 (s, 1H, NH2), 7.65 (d, J¼9 Hz, 2H, ArH), 7.76 (d, J¼
9 Hz, 2H, ArH), 8.65 (s, 1H, vinylic); 13C NMR (75 MHz,
DMSO-d6) d¼17.8 (SMe), 106.9 (]CeCONH2), 115.9 (CN),
128.4, 130.2 (ArH), 134.9 (ArH), 138.6 []C(SMe)2], 142.9
[C]C(SMe)2], 161.2 (vinylic), 164.4 (CONH2), 192.5 (CO);
EIMS m/z (%)¼399 (98), 397 (100). Anal. Calcd for
C15H13BrN2O2S2 (397.31): C, 45.34; N, 7.05; H, 3.30. Found:
C, 45.44; N, 6.99; H, 3.32.
(16), 182 (10), 170 (15), 127 (20), 119 (14), 91 (13), 77 (12).
Anal. Calcd for C15H12N2O3S (300.33): C, 59.99; N, 9.33; H,
4.03. Found: C, 59.79; N, 9.45; H, 4.06.
4.3.3. 5-(4-Chlorobenzoyl)-6-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 3c
Colourless solid; yield 85% (0.25 g); mp 210e212 ꢀC; IR
(KBr, nmax)¼3405, 3054, 2896, 2226, 1727, 1656, 1485, 1187,
1
1092, 904 cmꢁ1; H NMR (300 MHz, CDCl3) d¼2.73 (s, 3H,
4.2.5. 4-Benzoyl-2-cyano-5,5-bis(methylsulfanyl)-2,4-
pentadienamide 2e
SCH3), 7.40 (d, J¼8 Hz, 2H, ArH), 7.46 (d, J¼8 Hz, 2H,
ArH), 8.32 (s, 1H, pyridone H-4); 13C NMR (75 MHz, CDCl3)
d¼12.1 (SCH3), 102.5, 114.7 (CN), 116.4, 127.8, 128.2, 130.1,
136.5, 146.6, 153.2, 159.8 (CO), 188.3 (CO); EIMS m/z (%)¼
304 (Mþ, 9), 288 (18), 273 (24), 257 (100), 232 (13), 222 (33),
194 (19), 174 (29), 138 (43), 111 (29), 75 (35). Anal. Calcd for
C14H9ClN2O2S (304.75): C, 55.18; N, 9.19; H, 2.98. Found: C,
54.92; N, 9.34; H, 2.89.
Yellow solid; yield 85% (0.5 g); mp 170e172 ꢀC; IR (KBr,
1
nmax)¼3375, 3182, 2210, 1650, 1554, 1469 cmꢁ1; H NMR
(300 MHz, CDCl3) d¼2.42 (s, 3H, SCH3), 5.65 (s, 1H, NH2),
6.12 (s, 1H, CONH2), 7.60e7.49 (m, 3H, ArH), 7.89e8.02 (m,
2H, ArH), 8.69 (s, 1H, vinylic); 13C NMR (75 MHz, DMSO-d6)
d¼16.8 (SMe), 105.9 (]CeCONH2), 115.9 (CN), 129.4, 130.5
(ArH), 135.9 (ArH), 137.6 []C(SMe)2], 143.2 [C]C(SMe)2],
160.8 (vinylic), 163.4 (CONH2), 190.8 (CO); FABMS m/z
(%)¼319 (100). Anal. Calcd for C15H14N2O2S2 (318.42): C,
56.58; N, 8.80; H, 4.43. Found: C, 56.63; N, 8.85; H, 4.42.
4.3.4. 5-(4-Bromobenzoyl)-6-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 3d
Pale yellow solid; yield 76% (0.26 g); mp 218e220 ꢀC; IR
1
(KBr, nmax)¼3055, 2233, 1658, 1631, 1593 cmꢁ1; H NMR
4.3. General procedure for the synthesis of 2-pyridones from
2-cyano-4-benzoyl-5,5-bis(methylsulfanyl)-2,4-
pentadienamide (3)
(300 MHz, acetone-d6) d¼2.64 (s, 3H, SMe), 7.38 (d, J¼9 Hz,
2H, ArH), 7.56 (d, J¼9 Hz, 2H, ArH), 8.31 (s, 1H, pyridone);
13C NMR (75 MHz, CDCl3) d¼12.1 (SCH3), 102.5, 114.7
(CN), 116.4, 127.8, 128.2, 130.1, 136.5, 146.6, 153.2, 159.8
(CO), 188.3 (CO); FABMS m/z (%)¼351 (80), 349 (80). Anal.
Calcd for C14H9BrN2O2S (349.20): C, 48.15; N, 8.02; H, 2.60.
Found: C, 48.54; N, 8.19; H, 2.34.
Xylene (10 mL) was added to 2-cyano-4-(4-methylbenzoyl)-
5,5-bis(methylsulfanyl)-2,4-pentadienamide (0.39 g, 1 mmol)
and refluxed at 130 ꢀC for 10 h. Hexane was added to the cooled
solution. The pale yellow solid obtained was filtered and recrys-
tallized from methanol.
4.3.5. 5-Benzoyl-6-(methylsulfanyl)-2-oxo-1,2-dihydro-3-
pyridinecarbonitrile 3e
4.3.1. 5-(4-Methylbenzoyl)-6-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 3a
Colourless solid; yield 70% (0.2 g); mp 220e222 ꢀC; IR
(KBr, nmax)¼3178, 2364, 2227, 1680, 1643, 1546, 1191, 896,
Pale solid; yield 90% (0.26 g); mp 210e212 ꢀC; IR (KBr,
1
777, 702, 522 cmꢁ1; H NMR (300 MHz, CDCl3) d¼2.46 (s,
1
nmax)¼3182, 3056, 2231, 1677, 1645, 1534 cmꢁ1; H NMR
3H, SCH3), 7.25e7.58e7.75 (m, 5H, ArH), 8.45 (s, 1H, pyri-
done H-4), 13.15 (s, 1H, NH); 13C NMR (75 MHz, CDCl3) d¼
12.8 (SCH3), 102.6, 115.0 (CN), 127.9, 128.2, 130.7, 131.3,
148.6, 150.3, 154.3, 166.7 (CO), 188.6 (CO); EIMS m/z
(%)¼270 (Mþ, 6), 229 (15), 223 (100), 198 (8), 180 (22), 140
(38), 104 (52), 95 (51), 83 (76). Anal. Calcd for C14H10N2O2S
(270.31): C, 62.21; N, 10.36; H, 3.73. Found: C, 62.28; N,
10.25; H, 3.78.
(300 MHz, DMSO) d¼2.23 (s, 3H, CH3), 2.37 (s, 3H, SCH3),
7.27e7.35 (m, 4H, ArH), 8.4 (s, 1H, pyridone H-4), 13.07 (s,
1H, NH); 13C NMR (75 MHz, CDCl3) d¼11.9 (SCH3), 22.4
(CH3), 102.8, 115.3 (CN), 118.8, 126.7, 128.3, 129.8, 142.6,
147.4, 154.1, 160.1 (CO), 189.4 (CO); EIMS m/z (%)¼284
(Mþ, 5), 268 (16), 253 (18), 237 (100), 219 (2), 209 (9), 194 (10),
179 (13), 153 (16), 127 (8), 118 (20), 91 (34), 77 (8). Anal. Calcd
for C15H12N2O2S(284.33): C, 63.36; N, 9.85; H, 4.25. Found:C,
63.44; N, 9.89; H, 4.32.
4.4. General procedure for the synthesis of 5-aroyl-4-
4.3.2. 5-(4-Methoxybenzoyl)-6-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 3b
(methylsulfanyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (4)
Pale yellow solid; yield 80% (0.24 g); mp 194e196 ꢀC; IR
(KBr, nmax)¼2965, 2365, 2225, 1656, 1610, 1310, 1263, 1186,
The appropriate 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehyde
1 (2 mmol) was dissolved in acetonitrile (10 mL) at room tem-
perature. To the above solution cyanoacetamide (0.168 g,
2 mmol) followed by K2CO3 (0.55 g, 4 mmol) were added and
the reaction mixture was refluxed at 80 ꢀC for 12 h. The mixture
was then cooled, poured in to ice-cold water and acidified with
20% acetic acid. The resulting material was extracted with ethyl
acetate (3ꢂ25 mL), dried over anhydrous sodium sulfate and
purified by column chromatography on silica gel (60ꢂ120)
1
1025, 901 cmꢁ1; H NMR (300 MHz, CDCl3) d¼2.36 (s, 3H,
SCH3), 3.78 (s, 3H, OCH3), 7.24 (d, J¼9 Hz, 2H, ArH), 7.45 (d,
J¼9 Hz, 2H, ArH), 8.24 (s, 1H, pyridone H-4), 12.14 (s, 1H,
NH); 13C NMR (75 MHz, CDCl3) d¼12.8 (SCH3), 54.5
(OCH3), 101.0, 113.5 (CN), 117.7, 124.8, 129.5, 130.8, 147.6,
153.5, 162.3, 162.8 (CO/COH), 188.7 (CO); EIMS m/z
(%)¼301 (Mþ, 19), 284 (11), 269 (16), 253 (100), 238 (8), 210

A. Mathews et al. / Tetrahedron 64 (2008) 1671e1675
1675
using hexane/ethylacetate (1:1) as the eluent and then recrystal-
lized from methanol.
156.6 (6C pyridone), 158.2 (4C pyridone), 163.6 (2C, CO),
186.2 (CO); EIMS m/z (%)¼351 (85), 349 (82), 304 (90), 232
(20), 222 (25), 194 (15), 174 (22), 138 (45), 111 (28), 75 (30).
Anal. Calcd for C14H9BrN2O2S (349.20): C, 48.15; N, 8.02;
H, 2.60. Found: C, 48.44; N, 8.19; H, 2.52.
4.4.1. 5-(4-Methylbenzoyl)-4-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 4a
Pale yellow solid; yield 70% (0.39 g); mp 200e202 ꢀC; IR
1
(KBr, nmax)¼3430, 3160, 2226, 1650, 1604 cmꢁ1; H NMR
4.4.5. 5-(3-Methoxybenzoyl)-4-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 4f
(300 MHz, CDCl3) d¼2.42 (s, 3H, Me), 3.06 (s, 3H, SCH3),
6.76 (br, NH/OH), 7.16 (m, 2H, ArH), 7.73e7.76 (m, 2H,
ArH), 8.57 (s, 1H, pyridone); 13C NMR (75 MHz, CDCl3)
d¼16.2 (SMe), 19.6 (Me), 103.4 (5C pyridone), 113.0 (CN),
127.2, 127.6, 132.5, 134.9 (ArH and 3C pyridone), 142.4 (6C
pyridone), 157.5 (4C pyridone), 160.6 (2C, CO), 190.7 (CO);
FABMS m/z (%)¼285 (80). Anal. Calcd for C15H12N2O2S
(284.33): C, 63.36; N, 9.85; H, 4.25. Found: C, 63.44; N, 9.95;
H, 4.32.
Pale yellow solid; yield 70% (0.42 g); mp 170e172 ꢀC; IR
1
(KBr, nmax)¼3420, 3160, 2220, 1660, 1605 cmꢁ1; H NMR
(300 MHz, DMSO-d6) d¼2.74 (s, 3H, SCH3), 3.86 (s, 3H,
OMe), 7.12e7.05 (m, 2H, C-5H, ArH and 1H, 4a), 7.54 (d, J¼
9 Hz, 1H, ArH), 7.77 (s, 1H, C-2H, ArH), 7.84 (d, J¼9 Hz, 1H,
ArH), 9.33 (s, 1H, 5a), 12.87 (br, NH/OH); 13C NMR (75 MHz,
CDCl3) d¼12.8 (SMe), 53.6 (OMe), 93.5 (3C pyridone), 115.0,
116.0 (CN), 119.2, 122.6, 129.2, 130.6, 132.5, 137.2 (ArH and
5C pyridone), 139.4 (6C pyridone), 167.9 (4C pyridone), 173.6
(2C, CO), 189.4 (CO); FABMS m/z (%)¼301 (85). Anal. Calcd
for C15H12N2O3S (300.33): C, 59.99; N, 9.33; H, 4.03. Found:
C, 60.14; N, 9.35; H, 4.32.
4.4.2. 5-(4-Methoxybenzoyl)-4-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 4b
Pale yellow solid; yield 72% (0.43 g); mp 184e186 ꢀC; IR
1
(KBr, nmax)¼3433, 3190, 2221, 1639, 1600 cmꢁ1; H NMR
(300 MHz, DMSO-d6) d¼2.50 (s, 3H, SCH3), 4.52 (s, 3H,
OMe), 7.36e7.29 (m, 2H, ArH), 7.62e7.53 (m, 3H, ArH and
proton of 4b), 9.34 (s, 1H, 5b), 13.15 (br, NH/OH); 13C NMR
(75 MHz, CDCl3) d¼13.2 (SMe), 55.6 (OMe), 90.5 (3C pyri-
done), 112.0, 117.0 (CN), 122.3, 129.2, 130.6, 132.5 (ArH and
5C pyridone), 138.4 (6C pyridone), 168.5 (4C pyridone),
170.6 (2C, CO), 189.7 (CO); FABMS m/z (%)¼301 (90).
Anal. Calcd for C15H12N2O3S (300.33): C, 59.99; N, 9.33; H,
4.03. Found: C, 59.34; N, 9.23; H, 4.12.
Acknowledgements
We thank CDRI, Lucknow and RRL, Trivandrum, India for
providing the spectral data. A.M. is grateful to UGC and the
management of Baselius college, Kottayam for sanctioning
the faculty improvement program to do the research.
References and notes
1. Peters, R.; Althaus, M.; Nagy, A.-L. Org. Biomol. Chem. 2006, 4, 498e
509.
4.4.3. 5-(4-Chloro)-4-(methylsulfanyl)-2-oxo-1,2-dihydro-3-
pyridinecarbonitrile 4c
2. (a) Fraley, A. W.; Chen, D.; Johnson, K.; McLaughlin, L. W. J. Am. Chem.
Soc. 2003, 125, 616e617; (b) Patick, A. K.; Brothers, M. A.; Maldonado,
F.; Binford, S.; Maldonado, O.; Fuhrman, S.; Petersen, A.; Smith, G. J.;
Zalman, L. S.; Burns-Naas, L. A.; Tran, J. Q. Antimicrob. Agents
Chemother. 2005, 49, 2267e2275.
Pale yellow solid; yield 64% (0.39 g); mp 198e200 ꢀC; IR
1
(KBr, nmax)¼3430, 3160, 2226, 1650, 1604 cmꢁ1; H NMR
(300 MHz, CDCl3) d¼2.89 (s, 3H, SCH3), 7.48 (d, J¼8.4 Hz,
2H, ArH), 7.60 (d, J¼8.9 Hz, 2H, ArH), 9.59 (s, 1H, pyridone);
13C NMR (75 MHz, CDCl3) d¼17.6 (SMe), 100.2 (5C pyri-
done), 111.7 (CN), 127.0, 130.0, 135.0 (ArH and 3C pyridone),
156.3 (6C pyridone), 157.9 (4C pyridone), 162.0 (2C, CO),
184.0 (CO); EIMS m/z (%)¼304 (Mþ, 9), 257 (100), 232 (15),
222 (23), 194 (19), 174 (29), 138 (43), 111 (29), 75 (35).
Anal. Calcd for C14H9ClN2O2S (304.75): C, 55.18; N, 9.19;
H, 2.98. Found: C, 55.34; N, 9.35; H, 2.89.
3. Rastogi, R. R.; Ila, H.; Junjappa, H. J. Chem. Soc., Chem. Commun. 1975,
645.
4. Litvinov, V. P. Russ. Chem. Rev. 1999, 68, 737e763.
5. Mathews, A.; Asokan, C. V. Tetrahedron 2007, 63, 7845e7849.
6. Nitta, M.; Sakakida, T.; Miyabara, H.; Yamamoto, H.; Naya, S. Org.
Biomol. Chem. 2005, 3, 638e644.
7. Datta, A.; Ila, H.; Junjappa, H. J. Org. Chem. 1990, 55, 5589e5594.
8. Rastogi, R. R.; Kumar, A.; Ila, H.; Junjappa, H. J. Chem. Soc., Perkin
Trans.1 1978, 549e553.
9. (a) Yu, G.; Wang, S.; Hu, Y.; Hu, H. Synthesis 2004, 1021e1028; (b) Yu,
G.; Wang, S.; Sun, J.; Hu, X.; Liu, J. O.; Hu, Y. Org. Biomol. Chem. 2004,
2, 1573e1574.
4.4.4. 5-(4-Bromobenzoyl)-4-(methylsulfanyl)-2-oxo-1,2-
dihydro-3-pyridinecarbonitrile 4d
10. Hashem, A. -T.; de Silva, R.; Wenhua, X. U.S. Patent 6,858,733, 2002.
11. Narasaka, K.; Shibata, T.; Hayashi, Y. Bull. Chem. Soc. Jpn. 1992, 65,
1392e1396.
Pale yellow solid; yield 60% (0.42 g); mp 210e212 ꢀC; IR
1
(KBr, nmax)¼3430, 3160, 2224, 1637, 1604 cmꢁ1; H NMR
12. Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A.
Synlett 2004, 2287e2290.
(300 MHz, DMSO-d6) d¼2.78 (s, 3H, SCH3), 7.57e7.62 (m,
4H, ArH), 7.68 (br, 1H, NH/OH), 9.40 (s, 1H, pyridone); 13C
NMR (75 MHz, CDCl3) d¼16.5 (SMe), 101.4 (5C pyridone),
112.5 (CN), 126.0, 129.2, 134.2 (ArH and 3C pyridone),
13. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423e
5506; (b) Kolb, M. Synthesis 1990, 171e177; (c) Anabha, E. R.; Asokan,
C. V. Synthesis 2006, 151e155.