Synthesis of β-arylacyl / β-heteroarylacyl-β-alkylidene malonates and their application in substituted pyridone synthesis

Article abstract of DOI:10.1002/jhet.991

A novel approach has been developed for the synthesis of β-arylacyl/β-heteroarylacyl-β-alkylidine malonates in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β-chloroalkylidene malonates. The reaction involves conjugate

Full text of DOI:10.1002/jhet.991

January 2013
Synthesis of β-Arylacyl/β-Heteroarylacyl-β-alkylidene Malonates
49
and Their Application in Substituted Pyridone Synthesis
Manoj Balu Wagh,a R. Shankar,a K. Mini,a T. Krishnamohan,a
M. V. Madhubabu,a Abir K. Pal,a Sarva Jayaprakash,a T. Krishna,a
a
a
b
*
Vilas Dahanukar, U. K. Syam Kumar, and C. H. Gill
aTechnology Development centre, Custom Pharmaceutical Services, Dr. Reddys Laboratories Ltd.,
Miyapur, Hyderabad 500 049, India
bDepartment of Chemistry, Dr. Babasaheb Ambedkar University, Aurangabad, India
*
E-mail: syam_kmr@yahoo.com
Received August 22, 2010
DOI 10.1002/jhet.991
View this article online at wileyonlinelibrary.com.
A novel approach has been developed for the synthesis of β-arylacyl/β-heteroarylacyl-β-alkylidine malonates
in moderate to good yields by the reaction of Stork aryl and heteroaryl enamine with β-chloroalkylidene malo-
nates. The reaction involves conjugate (Michael) addition of Stork enamine on β-chloroalkylidene malonates
and elimination of chloride ion. These Michael adducts were utilized as intermediates for the synthesis of highly
substituted 1,4-dialkyl-2-oxo-6-aryl/hetreoaryl-1,2-dihydro-pyridine-3-carboxylic acid ethyl esters via 5 + 1
ring annulation protocol.
J. Heterocyclic Chem., 50, 49 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Enols and enolate equivalents are important intermediates
in organic synthesis and many exceptionally useful
reactions relay on their utilization. A particularly useful
strategy for the generation of enolate equivalents are via
Stork enamine intermediates [1]. Use of enamine for
electrophilic α-substitution of aldehydes [2] and ketones
[3] has resulted in formidable collection of literature.
Enamines are well utilized in the total syntheses of several
natural products [4] and also for the commercial manufacture
of active pharmaceutical ingredients [5]. Conjugate
addition (Michael) reaction of enamine on highly activated
Michael acceptors are also well reported [6]. Although
β-chloroalkylidene malonates 1 [7] and its derivatives
such as β-aryl alkylidene malonates 2[8, 9] are function-
ally enriched organic synthons, the literature precedence
for these class of compounds are rather very limited,
whereas β-arylacyl/β-heteroarylacyl-β-alkylidene malo-
nates 3 are totally unreported (Fig. 1). Herein, we report a
highly regioselective, mild, and practical approach for the
synthesis of hitherto unreported β-arylacyl/heteroarylacyl-
β-alkylidene malonates 3 by reaction of Stork aryl and
heteroaryl enamine 5 to β-chloroalkylidene malonates 1
and further their application in synthesis of 1,4,6-trisubstituted
pyridine -3-carboxylates 9 via 5 + 1 heterocycloannulation
protocol.
β-chloroalkylidene malonates (1a–c) required for the
study were prepared as per the literature procedure involving
initial treatment of diethyl malonate with acid chloride and
subsequent chlorination with phosphorous oxychloride
[10]. The Stork aryl and heteroaryl enamines (5a–g) were
synthesized by the reaction of appropriate ketones with
morpholine in presence of titanium tetrachloride
(Scheme 1) [11].
The reaction of enamine 5 with highly activated Michael
acceptors such as α, β-unsaturated ketones, esters, amides,
and nitrostyrenes are known to give 1,4-addition products
in varying yields [12]. However, in the product, the carbon
atoms of the newly formed carbon–carbon bond will be of
different oxidation state. The presence of a highly labile
leaving group at β-position of Michael acceptors will help
to retain the oxidation (hybridization) state of reactive
carbon atoms via elimination during the course of Michael
addition reaction. Having considered these assumptions,
we have studied the reactivity of enamine 5a with β-chlor-
oalkylidene malonate 1aunder various reaction conditions.
Thus, under an optimized reaction condition, a solution of
1a in dichloromethane was added to a freshly prepared
solution of 1-(2-phenyl vinyl) morpholine 5a in dichloro-
methane at room temperature. Reaction mixture was stirred
for nearly 14–18 h at room temperature (monitored by
© 2013 HeteroCorporation

50
M. B. Wagh, R. Shankar, K. Mini, T. Krishnamohan, M. V. Madhubabu, A. K. Pal,
S. Jayaprakash, T. Krishna, V. Dahanukar, U. K. S. Kumar, and C. H. Gill
Vol 50
Scheme 2
Figure 1. Structure of b-chloroalkylidene, b-aryl alkylidene and b-arylacyl/-
b-alkylidene malonates.
TLC), quenched in water, and extracted with dichloro-
methane. After work up and column chromatographic puri-
fication, product 1-(2-methyl-3-oxo-3-phenyl-propylidene)
malonic acid diethyl ester (7a) was isolated as brown vis-
cous liquid in 55% of yield (Scheme 2). The reaction also
resulted in the formation of β-morpholinoalkylidene malo-
nate (8) as byproduct around 12–14% of yield.
products tend to exist as a,γ-unsaturated esters, rather than
α,β-unsaturated esters (Fig. 2).
The interesting feature of the transformation reported
herein is the very high chemo and regio selectivity of the
Michael addition–elimination sequences in presence of
other reactive functional groups in β-chloroalkylidene mal-
onates (1a–c). Unlike other transition metal-catalyzed Mi-
chael-addition elimination reaction sequences, no
multiple addition products were observed in these reaction
conditions.
Encouraged by the finding that Stork enamine 5a under-
went the sequential conjugate addition–elimination reac-
tion with β-chloroethylidene malonate 1a, broader
applicability of reaction sequence for the synthesis of vari-
ety of β-arylacyl/heteroaryl β-acyl alkylidene malonates
was investigated further. Thus, several β-chloroalkylidene
malonates with β-methyl (1a), β-ethyl (1b), and β-propyl
(1c) substituents were synthesized. Vinyl amine derived
from acetophenone 5a, 4-methoxy acetophenone 5b, 4-
bromoacetophenone 5c, 4-nitroacetophenone 5d, 4-acetyl-
biphenyl 5e, 1-indanone 5f, and 2-acetyl thiophene 5g,
respectively, were then reacted with β-chloroalkylidene
malonates (1a–c) under the above reaction conditions
and the products 1-(2-alkyl-3-oxo-3-phenyl-propylidene)
malonic acid diethyl esters (7a–l) were isolated in satisfactory
yields (Table 1). The vinyl amine derived from 1-indanone 5f
also underwent smooth Michael addition–elimination
reaction, and the product 7j was isolated in 48% of yield.
All the reactions were completed within 18 h, and the
products were isolated by column chromatographic purifica-
tion. The electron-withdrawing substituent on the aryl
ring of enamine 1-{1-(4-nitrophenyl) vinyl} morpholine
(5d) has much influence on reactivity, as the product
diethyl-2-(5-(4-nitrophenyl)-5-oxopent-2-ene-3-yl) malonate
(7h) was isolated in considerably lower yield.
The β-arylacyl/heteroarylacyl-β-alkylidene malonates
synthesized by Michael addition–elimination of Stork aryl
and heteroarylenamine to β-chloroalkylidene malonates
provides an interesting 5-carbon synthon. To demonstrate
the utility of conjugate adducts (7a–i), we further investi-
gated its application in the synthesis of 4,6-disubstituted-
1,2-dihydro-2-oxo-3-pyridine carboxylic acid esters. Func-
tionalized 2(1H)-pyridones have been of long interest in
pharmaceutical and agrochemical research, and their bio-
logical activities have been attracted much attention [13].
β-Chloroalkylidene malonates (7a–i) obtained by conju-
gate addition reaction were used as intermediates for the
synthesis of substituted pyridones via 5 + 1 heteroannula-
tion [14]. In a typical experiment, to a solution of conjugate
adduct 7a in dimethyl sulphoxide, ammonium acetate and
molecular sieves were added, and reaction mixture was
stirred at 75–80°C for 4 h. The product was isolated as a
yellow crystalline solid after usual workup procedure and
column chromatographic purification and characterized as
4-ethyl-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carboxylic
acid ethyl ester (9b) based on the spectral and analytical
data (Scheme 3). Similarly, heterocyclization of 7b was
also attempted with methyl amine, and 1-N-methyl-4-
ethyl-2-oxo-6-phenyl-1,2-dihydro-pyridine-3-carboxylic acid
ethyl ester (9b) was isolated in 70% of yield as yellow crystal-
line solid after column chromatographic purification.
NMR spectral data of these Michael adducts indicate
that when the alkyl chain length in 1-(2-alkyl-3-oxo-3-
aryl-alkylidene)malonic acid diethyl ester increases,
Scheme 1
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis of β-Arylacyl/β-Heteroarylacyl-β-alkylidene Malonates
51
and Their Application in Substituted Pyridone Synthesis
Table 1
Table 1
Synthesis of β‐arylacyl alkylidene malonates.
(Continued)
Sl
No
Yield
(%)
Yield
(%)
Enamine
Vinyl Ester
Product
Sl No
Enamine
Vinyl Ester
Product
8
30
1
2
3
55
45
42
9
56
5a
5a
10
11
48
45
4
5
6
7
48
43
50
45
5b
12
5g
45
To establish the generality of the above methodology in
pyridone synthesis, several 4-alkyl-2-oxo-6-aryl/hetero-
aryl-1,2-dihydro-pyridine-3-carboxylic acid ethyl esters
(9c–j) were synthesized via 5 + 1 heteroannulation protocols
with Michael addition–elimination adducts (7a–k) and
5c
Figure 2. Structure of a, b and a, g 1-(2-alkyl-3-oxo-3-aryl-alkylidene)
malonic acid diethyl ester.
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

52
M. B. Wagh, R. Shankar, K. Mini, T. Krishnamohan, M. V. Madhubabu, A. K. Pal,
S. Jayaprakash, T. Krishna, V. Dahanukar, U. K. S. Kumar, and C. H. Gill
Vol 50
2
Table
Table 2
(Continued)
Synthesis of 4-alkyl-2-oxo-6-aryl/heteroaryl-1,2-dihydro-pyridine-3-
carboxylic acid ethyl esters.
Yield MP
(%) (°C)
Sl
No
Yield MP
(%) (°C)
Sl No
Reactant
Product
Reactant
Product
1
83 151
8
85 202
2
83 125
3
4
7b
70 112
9
78 133
75 149
10
70 Viscous
liquid
5
6
7
80 157
ammonium acetate in dimethyl sulphoxide at elevated
temperature (70–80°C). The products 1,4,6-trisubstituted
pyridine-3-carboxylates (9a–j) were isolated in good
yields (Table 2) and well characterized by means of spec-
tral and other analytical data.
82 132
CONCLUSION
In summary, an efficient protocol for the Michael addi-
tion–elimination strategy of Stork enamine to β-chloroalk-
ylidene malonates was developed for the first time in the
literature. Also, the synthetic utility of these Michael
adducts were demonstrated with an efficient synthesis of
diverse array of highly substituted pyridones in good yield
via 5 + 1 heterocycloannulation protocols with high func-
tional flexibility. The application of this methodology for
the synthesis of few alkaloids such as camptothecin and
luotonin is under progress.
80 167
(Continued)
Journal of Heterocyclic Chemistry
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Synthesis of β-Arylacyl/β-Heteroarylacyl-β-alkylidene Malonates
53
and Their Application in Substituted Pyridone Synthesis
Diethyl 2-(1-(4-methoxyphenyl)-1-oxohex-3-en-3-yl) malonate
(7e). Yield: 43%, viscous liquid,, IR (neat): 758, 1215, 1731, 2982,
3020 cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 0.97 (t, 3H, J = 7.2 Hz),
1.23 (t, 6H, J = 7.2), 2.13 (m, 2H), 3.84 (s, 2H), 3.85 (s, 3H), 4.15
(q, 4H), 4.55 (s, 1H), 5.51 (t, 1H, J = 6.8 Hz), 6.90 (m, 2H), 7.99 (d,
2H, J = 8.8 Hz). MS: m/z (%) 363.17 [M+H]+, Anal. Calcd for
C20H26O6 (362.17): C, 66.28; H, 7.23; Found: C, 66.21; H, 7.21.
Diethyl 2-(4-(4-bromophenyl)-4-oxobutan-2-ylidene) (7f).
Yield: 50%, viscous liquid, IR (neat): 757, 1047, 1241, 1373,
1741, 2985 cm−1. 1H-NMR (CDCl3, 400 MHz) δ: 1.21–1.32 (m,
6H), 2.07 (s, 3H), 4.15 (s, 2H), 4.21–4.3 (m, 4H), 7.62 (m, 2H),
7.85 (m, 2H) MS: m/z (%) 383 [M+H]+, 339, 291,183. Anal.
Calcd for C17H19BrO5 (382.04): C, 53.28; H, 5.00; Found: C,
53.20; H, 5.01.
EXPERIMENTAL
Experimental section. Solvents and reagents are obtained
from commercial sources and are not purified unless specified.
1H-NMR data was obtained on a Varian Gemini 400-MHz FT-
NMR spectrometer. Infrared spectra (IR) were recorded on a
Perkin-Elmer 1650 FTIR spectrometer. Mass spectra were
recorded on an HP-5989A quadrapole mass spectrometer.
Melting points were taken in open capillaries and are uncorrected.
General procedure for synthesis of β-chloroalkylidene
malonates. To a stirred solution of enamine 5a (2.5 gm, 0.013
mol, 1 equiv) in dichloromethane (25 mL, 10 volume), triethyl
amine (2.7 g, 0.026 mol, 2 equiv) was added at room
temperature (28–35°C). To this reaction mixture, β-
chloroalkylidene malonate 1 (3.2 g, 0.014, mol, 1.1 equiv) in
dichloromethane (12.5 mL, five volumes) was added drop wise
over a period of 45–50 min at room temperature. The reaction
mixture was then stirred at that temperature for 10–12 h
(monitored by TLC). It was then quenched in water (25 mL),
washed with 10% HCl solution (38 mL, 15 volumes) followed
by bicarbonate solution (10% solution, 20 mL), and water (25
mL × 3). The organic layer was then separated, dried over
sodium sulphate, and concentrated under vacuum. The crude
product was then purified by column chromatography over
silica gel (230–400 mesh) using hexane: ethyl acetate (10 : 1) as
eluent. The product 7awas isolated as a viscous liquid in 55% of yield.
Diethyl-2-(4-(4-nitrophenyl)-4-oxobutan-2-ylidine)
malonate
(7h). Yield: 30%, viscous liquid, IR (neat): 1047, 1240, 1374,
1
x1742, 2984 cm−1. H-NMR (CDCl3, 400 MHz) δ: 1.21–1.32 (m,
6H), 2.10 (s, 3H), 4.2 (m, 4H), 4,23 (s, 2H), 8.10 (m, 2H), 8.40 (m,
2H). MS: m/z (%) 364 [M+H]+, 323, 258. Anal. Calcd for
C18H21NO7 (382.04): C, 59.7; H, 5.83, N, 3.85; Found: C, 53.20;
H, 5.01.
Diethyl 2-[4-(biphenyl-4-yl)-4-oxobutan-2-ylidene] malonate
(7i). Yield: 56%. off white solid, MP: 202°C, IR (KBr): 650,
733, 908, 1686, 1719, 1793, 2253, 2984 cm−1 1H-NMR
.
(CDCl3, 400 MHz) δ: 1.2 (t, 3H, J = 7.2 Hz), 1.3 (t, 3H, J = 3.2
Hz), 2.13 (s, 3H), 4.16 (q, 2H, J = 7.2 Hz), 4.31 (s, 2H), 4.32
(m, 2H), 7.45 (m, 1H), 7.5 (m, 2H), 7.62 (m, 2H), 7.65 (m, 2H),
8.15 (d, 2H, J = 8.2 Hz). 13C-NMR (CDCl3, 50 MHz) δ: 14.0,
14.1, 23.1, 45.2, 60.9, 61.1, 127.2, 127.3, 128.2, 128.7, 128.9,
129.0, 135.2, 139.7, 145.9, 151.6, 164.3, 165.9, 194.9, 195 MS: m/z
(%) 381 [M+H]+, 380.5, 289, 181. Mass Calcd. for C23H24O5 C,
72.61; H, 6.36 found: C, 72.60; H: 6.34.
Diethyl 2-(4-oxo-4-phenylbutan-2-ylidene)malonate (7a).
Yield: 55%; viscous liquid, IR (neat): 1063, 1252, 1690, 1726, 1735,
2982; H-NMR (CDCl3, 400 MHz) δ: 1.05–1.30 (m, 6H), 2.07 (s,
3H), 3.91.(s, 2H), 3.93–4.05 (m, 4H), 7.52 (m, 2H), 7.61 (m, 1H),
7.96 (m, 2H). 13C-NMR (CDCl3, 50 MHz) δ: 13.6, 23.0, 43.8,
57.3, 120.1, 125.6, 133.1, 135.3, 136.2, 163.6, 167.1, 195.3, MS:
m/z (%) 305 [M+H]+, 273, 259, 213. Anal.Calcd for C17H20O5
(304.1): C, 67.09; H, 6.62; Found: C, 67.04; H, 6.60.
1
Diethyl
enyl]malonate (7j). Yield: 48%, viscous liquid, IR (neat):
634, 1049, 1238, 1374, 1459, 1749, 2874, 2959 cm−1
2-[1-(1-oxo-2,3-dihydro-1H-inden-2-yl)prop-1-
.
1H-NMR: (CDCl3, 400 MHz) δ: 1.26 (t, 3H, J = 6.8 Hz),
1.31 (t, 3H, J = 7.2 Hz), 1.73 (d, 3H, J = 6.8 Hz), 3.11 (dd, 1H,
J = 4.4 Hz, 17 Hz), 3.52 (m, 1H), 3.6 (dd, 1H, J = 4.4, 24 Hz ), 4.2
(m, 2H, ), 4.35 (m, 2H), 4.46 (s, 1H), 5.59 (q, 1H, J = 14 Hz ),
7.35 (m, 1H), 7.42 (m, 1H), 7.62 (m, 1H), 7.75 (m, 1H). 13C-NMR:
(CDCl3, 50 MHz) δ: 13.9, 14.0, 29.6, 35.5, 52.6, 52.9, 61.5, 61.7,
123.9, 126.3, 127.3, 129.1, 131.5, 134.5, 136.5, 153.4, 167.7, 168.1,
205. MS: m/z (%) 331 [M+H]+, 285, 239. Anal. Calcd for
C19H22O5 (330.37): C, 69.06; H, 6.71; Found: C, 69.04; H, 6.70.
Diethyl 2-[1-oxo-1-(thiophen-2-yl)butan-2-ylidene] malonate
(7k). Yield: 45%, viscous liquid, IR (neat): 727, 1064, 1251, 1415,
1666, 1721, 2982 cm−1. 1H-NMR (CDCl3, 400 MHz): 1.22 (t, 3H,
J = 6.7 Hz), 1.30 (t, 3H, J = 6.7 Hz), 2.14 (s, 3H), 4.15 (m, 2H),
4.21 (s, 2H), 4.31 (q, 2H, J = 11.8 Hz), 7.18 (m, 1H), 7.60 (m, 1H),
7.80 (m, 1H). MS: m/z (%) 311 [M+H]+, 265, 219, 149. Anal.
Calcd for C15H18O5 (310.3): C, 58.05; H, 5.85; Found: C, 58.01;
H, 5.80.
Diethyl 2-(5-oxo-5-phenylpent-2-en-3-yl)malonate (7b). Yield:
45%, viscous liquid, IR (neat): 757, 847, 1047, 1243, 1736, 2984
cm−1; 1H–NMR (CDCl3, 400 MHz) δ: 1.23 (t, 6H, J = 7.2 Hz), 1.75
(d, 3H, J = 6.8 Hz), 3.91 (s, 2H), 4.15 (q, 4H, J = 14 Hz), 4.58 (s,
1H), 5.63 (q, 1H, J = 13.6 Hz), 7.45 (m, 2H), 7.55 (m, 1H), 7.98 (m,
2H); 13C-NMR (CDCl3, 50 MHz) δ: 13.9, 43.9, 52.6, 61.6, 125.9,
128.0, 128.2, 128.4, 130.7, 132.8, 136.8, 167.8, 198.0. MS: m/z (%):
319 [M+H]+, 273, 227. Anal. Calcd for C18H22O5 (318.15): C,
67.91; H, 6.97; Found: C, 67.90; H, 6.91.
Diethyl 2-(1-oxo-1-phenylhex-3-en-3-yl)malonate (7c). Yield: 42%,
viscous liquid, IR (neat): 754, 1216, 1267, 1684, 1731, 2982, 3020
cm−1; 1H-NMR (CDCl3, 400 MHz) δ: 0.98 (t, 3H, J = 3.6 Hz), 1.23
(t, 6H, J = 7.2 Hz), 2.15 (m, 2H), 3.9 (s, 2H), 4.15 (q, 4H,
J = 14 Hz), 4.56 (s, 1H), 5.53 (t, 1H, J = 7.2 Hz), 7.48 (m,
3H), 7.99 (dd, 2H), 13C-NMR (CDCl3, 50 MHz) δ: 13.7,
13.9, 21.7, 43.8, 52.8, 61.6, 124.4, 128.3, 128.4, 132.8, 136.9,
138.2, 167.9, 198.1. MS: m/z (%) 333 [M+H]+, 287, 241, 161.
Anal. Calcd for C19H24O5 (332.16): C, 68.66; H, 7.28; Found: C,
68.60; H, 7.21.
Diethyl 2-(4-(4-methoxyphenyl)-4-oxobutan-2-ylidene)malonate
(7d). Yield: 48%, viscous liquid, IR (neat): 630, 1027, 1258, 1509,
1602, 1676, 2841 cm−1 1H-NMR (CDCl3, 400 MHz) δ: 1.23–1.38
(m, 6H), 2.1 (s, 3H), 3.9 (s, 2H), 4.2 (m, 7H), 6.98 (d, 2H, J =
6Hz), 7.9 (m, 2H), 13C-NMR (CDCl3, 50 MHz) δ: 13.7, 22.9, 44.9,
55.4, 61.7, 113.8, 123.5, 129.6, 130.4, 151.9, 165.9, 167.5, 190.1,
MS: m/z (%) 335 [M+H]+, 289, 243, 135. Anal.Calcd for
C18H22O6 (334.3): C, 64.60; H, 6.63, Found: C, 64.59; H, 6.61.
Diethyl 2-[1-oxo-1-(thiophen-2-yl)hex-3-en-3-yl] malonate
(7l). Yield: 45%, viscous liquid, IR (neat): 754., 1215, 1275,
1
1663, 1731, 3020 cm−1; H-NMR (CDCl3, 400 MHz) δ: 1.00 (t,
3H, J = 7.6 Hz). 1.21 (t, 6H, J = 7.3 Hz), 2.14 (q, 2H, J = 7.6 Hz),
3.83 (s, 2H), 4.16 (m, 4H), 4.55 (s, 1H), 5.61 (t, 1H, J = 7.2 Hz),
7.11 (m, 1H), 7.61 (m, 1H), 7.81 (m, IH).13C-NMR (CDCl3, 50
MHz) δ: 13.6, 13.9, 21.7, 44.3, 52.8, 61.6, 123.9, 128.0, 132.3,
133.4, 138.3, 144.1, 167.9, 190.7 MS: m/z (%) 339 [M+H]+, 293,
247. Anal.Calcd for C17H22O5S (338.42): C, 60.33; H, 6.55, Found:
C, 60.31; H, 6.54.
Journal of Heterocyclic Chemistry
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M. B. Wagh, R. Shankar, K. Mini, T. Krishnamohan, M. V. Madhubabu, A. K. Pal,
S. Jayaprakash, T. Krishna, V. Dahanukar, U. K. S. Kumar, and C. H. Gill
Vol 50
General procedure for synthesis of pyridones. To a stirred
114.4, 125.7, 128.0, 128.3, 148.5, 151.9, 161.4, 162.6, 167.2
MS: m/z (%) 288 [M+H]+, 219, 201, 162, 148. Anal.Calcd for
C16H17NO4 (287.0): C, 66.89; H, 5.96; N, 4.88, Found: C, 66.80;
H, 5.94; N, 4.87.
solution of β-arylacyl alkylidene malonates 7a(1 g, 0.0032 mol,
1 equiv) in dimethyl sulfoxide (10 mL, 10 volume), molecular
sieves (1 g) and ammonium acetate (0.76 g, 0.0096 mol, 3
equiv) were added at room temperature. The reaction mixture
was then stirred at 45–50°C for 3 h (monitored by TLC). The
molecular sieves were filtered-off, and the reaction mass was
then diluted with water (25 mL), extracted with dichloromethane
(3 × 15 mL), and washed with water (2 × 10 mL). The combined
organic layers was dried over sodium sulphate and concentrated
under vacuum. The crude product was then purified by column
chromatography over silica gel (230–400 mesh) using hexane: ethyl
acetate (10 : 2.5) as eluent. The product 9a was isolated as yellow
solid in 83% of yield.
Ethyl-4-methyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-
carboxylate (9a). Yield: 83%; MP: 151°C, yellow solid,
IR (KBr): 1123, 1259, 1637, 1728, 2925 cm−1. 1H-NMR
(CDCl3, 400 MHz) δ: 1.26 (t, 3H, J = 7.6 Hz), 2.19 (s, 3H),
4.26 (q, 2H, J = 7.6 Hz), 6.56 (s, 1H), 7.48 (m, 3H), 7.7 (m,
2H), 11.96 (brs, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 14.0,
19.1, 60.5, 107.0, 121.3, 126.8, 128.6, 129.9, 133.1, 147.2,
149.1, 160.1, 166. MS: m/z (%) 258 [M+H]+, 234, 212 Anal.
Calcd for C15H15NO3 (257. 3): C, 70.02; H, 5.88; N, 5.44;
Found: C, 70.00; H, 5.87; N, 5.4.
Ethyl-6-(4-methoxyphenyl)-2-oxo-4-propyl-1,2-dihydro
pyridine-3-carboxylate (9f). Yield: 82%, MP: 132°C;
yellow solid, IR (KBr): 787, 1047, 1241, 1373, 1742,
2985 cm−1. 1H-NMR (CDCl3, 400 MHz) δ: 1.00 (t, 3H,
J = 7.6 Hz), 1.36 (t, 3H, J = 7.2 Hz), 1.63 (m, 2H), 2.59 (m,
2H), 3.89 (s, 3H), 4.36 (q, 2H, J =14.4 Hz), 6.38 (s, 1H), 6.99
(d, 2H, J = 4.8 Hz), 7.74 (dd, 2H, J = 2, 6.8 Hz) 11.9 (brs,
1H). 13C-NMR (CDCl3, 50 MHz) δ: 14.0, 14.2, 23.3, 36.2,
55.4, 61.9, 106.1, 114.4, 120.0, 125.6, 128.3, 147.6, 155.6,
161.3, 162.5, 167.0 MS: m/z (%) 316 [M+H]+, 270; Anal.
Calcd for C18H21NO4 (315.36): C, 68.55; H, 6.71; N, 4.44;
Found: C, 68.51; H, 6.73; N, 4.48.
Ethyl-6-(4-bromophenyl)-2-oxo-4-propyl-1,2-dihydro
pyridine-3-carboxylate (9g).
Yield: 80%, MP: 167°C; yellow
solid IR (KBr): 847, 1047, 1240, 1374, 1742, 2985 cm−1
.
1H-NMR (CDCl3, 400 MHz) δ: 0.97 (t, 3H, J = 7.2 Hz),
1.37 (t, 3H, J = 7.2 Hz), 1.63 (q, 2H, J = 14.8 Hz), 2.63
(m, 2H), 4.4 (q, 2H, J = 14.4Hz), 6.52 (s, 1H), 7.52–
7.67 (m, 4H), 12.2 (brs, 1H). 13C-NMR (CDCl3, 50
MHz) δ: 14.0, 14.2, 23.3, 36.1, 61.4, 107.5, 120.7,
124.8, 128.6, 132.1, 132.3, 147.3, 155.5, 162.9, 166.8;
MS: m/z (%) 365.1 [M+H]+, 318.0; C17H18BrNO3
(364.23): C, 56.06; H, 4.98; N, 3.85; Found: C, 56.01;
H, 4.91; N, 3.81.
Ethyl-4-ethyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylate
(9b). Yield: 83%, MP: 125°C; IR (KBr): 769, 921, 1095, 1240,
1
1622, 1730, 2934 cm−1; H-NMR (CDCl3, 400 MHz) δ: 1.26 (t,
3H J = 7.6 Hz), 1.35 (t, 3H, J = 7.2 Hz), 2.62 (q, 2H, J = 15
Hz), 4.38 (m, 2H), 6.65 (s, 1H), 7.46 (m, 3H), 7.80 (m, 2H),
12.21 (brs, 1H). 13C-NMR (CDCl3, 50 MHz) δ: 14.2, 14.5,
27.3, 61.2, 106.2, 121.0, 126.3, 128.9, 130.1, 133.1, 147.9,
156.7, 162.5, 166.7; MS: m/z (%) 272 [M+H]+, 226;
C16H17NO3 (271.3): C, 70.83; H, 6.32; N, 5.16; Found: C,
70.82; H, 6.30; N, 5.17.
Ethyl-6-(biphenyl-4-yl)-4-methyl-2-oxo-1,2-dihydro pyridine-
3-carboxylate (9h). Yield: 85%, MP: 202°C; White solid IR
1
(KBr): 650, 908, 1091, 1632, 2253, 2983, 3387 cm−1. H-NMR
(CDCl3, 400 MHz) δ: 1.37 (t, 3H, J = 7.2 Hz), 2.41 (s, 3H),
4.41 (q, 2H, J = 14.4 Hz), 6.6 (s, 1H), 7.37–7.72 (m, 7H), 7.86
(d, 2H, J = 8.4 Hz), 11.58 (brs, 1H). 13C-NMR (CDCl3, 50
MHz) δ: 14.2, 20.9, 61.4, 108.9, 118.0, 127.0, 127.3, 127.6,
127.8, 128.8, 132.3, 139.9, 143.1, 148.5, 151.9, 162.7, 167.2;
MS: m/z (%) 334 [M+H]+, 288; Anal.Calcd for C21H19NO3
(333.38): C, 75.66; H, 5.74; N, 4.20; Found: C, 75.69; H, 5.76;
N, 4.17.
Ehyl4-ethyl-1-methyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-
carboxylate (9c). Yield: 70%, yellow solid, MP 112 °C IR (KBr):
1
734, 908, 1138, 1642, 1725, 2252, 2979, 3608 cm−1. H-NMR
(CDCl3, 400 MHz) δ: 1.21 (t, 3H, J = 7.6 Hz), 1.40 (t, 3H,
J = 7.2 Hz), 2.52 (q, 2H, J = 14.8 Hz), 3.35 (s, 3H), 4.4 (q,
2H, J = 14.4 Hz), 6.02 (s, 1H), 7.32 (m, 2H), 7.47 (m, 3H)
13C-NMR (CDCl3, 50 MHz) δ: 14.0, 14.2, 26.0, 34.2, 61.3,
108.5, 122.0, 128.2, 128.7, 129.4, 135.1, 150.3, 153.2,
160.6, 166.7; MS: m/z (%) 286 [M+H]+, 242.3, 174;
C17H19NO3 (285.34): C, 71.56; H, 6.71; N, 4.91; Found: C,
71.55; H, 6.72; N, 4.83.
Ethyl-2-oxo-6-phenyl-4-propyl-1,2-dihydropyridine-3-
carboxylate (9d). Yield: 75%, MP: 149 °C; yellow solid;
IR (KBr): 847, 1047, 1243, 1374, 1740, 2985 cm−1; 1H-NMR
(CDCl3, 400 MHz) δ: 1.09 (t, 3H, J = 7.2 Hz), 1.35 (t, 3H, J =
7.2 Hz), 1.7 (m, 2H), 2.59 (m, 2H), 4.38 (q, 2H, J = 14 Hz),
6.44 (s, 1H), 7.46 (m, 3H), 7.74 (m, 2H) 11.8 (s, 1H). 13C-NMR
(CDCl3, 100 MHz) δ: 14.0, 14.2, 23.3, 36.1, 61.3, 107.1, 120.7,
126.7, 129.0, 130.3, 133.3, 147.8, 155.5, 162.3, 166.8 MS: m/z
(%) 286.2 [M+H]+, 240; Anal. Calcd for C17H19NO3 (285.34):
C, 71.56; H, 6.71; N, 4.91; Found: C, 71.55; H, 6.72; N, 4.83.
Ethyl-6-(4-methoxyphenyl)-4-methyl-2-oxo-1,2-dihydro
Ethyl 4-methyl-2-oxo-6-(thiophen-yl)-1,2-dihydropyridine-3-
carboxylate (9i). Yield: 78%, MP: 133°C; yellow solid; IR
(KBr): 1090, 1270, 1545, 1609, 1638, 1715, 2932, 2978 cm−1
.
1H-NMR (CDCl3, 400 MHz) δ: 1.42 (t, 3H, J = 7.8 Hz), 2.43
(s, 3H), 4.43 (q, 2H, J = 6.8 Hz), 6.65 (s, 1H), 7.11 (dd, 1H,
J = 4, 4.8 Hz), 7.43 (m, 1H), 7.92 (d, 1H, J = 4 Hz), 12.6 (brs,
1H); 13C-NMR (CDCl3, 50 MHz) δ: 14.3, 21.5, 61.5, 109.6,
127.8, 128.5, 128.6, 137.9, 146.2, 152.4, 156.0, 163.6, 167.9;
MS: m/z (%) 264 [M+H]+, 218, 192, 168, 110; Anal. Calcd for
C13H13NO3S (263.3): C, 59.37; H, 4.98; N, 5.32; Found: C,
59.37, H, 4.99, N, 4.97.
Ethyl-2-oxo-4-propyl-6-(thiophen-2-yl)-1,2-dihydro pyridine-
3-carboxylate (9J). Yield: 70%, yellow solid; IR (KBr): 847,
1047, 1243, 1374, 1740, 2985 cm−1 1H-NMR (CDCl3,
.
400 MHz) δ: 1.02 (t, 3H J = 7.3 Hz), 1.41 (t, 3H, J =7.2
Hz), 1.64 (q, 2H, J = 14.8 Hz), 2.64 (m, 2H), 4.43 (m,
2H), 6.6 (s, 1H), 7.26 (m, 1H), 7.4 (m, 1H), 7.9 (m, 1H),
12.27 (brs, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 14.0,
14.2, 23.5, 36.4, 61.4, 107.7, 124.5, 127.7, 128.3, 128.5,
137.2, 144.5, 156.1, 163.2, 167.5; Mass: m/z ratio (%)
292.1 [M+H]+, 246.1.; Anal. Calcd for C15H17NO3S
(291.37): C, 61.83; H, 5.88; N, 4.81. found: C, 61.83; H
5.89; N, 4.79.
pyridine-3-carboxylate (9e).
Yield: 80%, MP: 157; yellow
solid; IR (KBr): 1258, 1517, 1606, 1630, 1734, 2933, 2976
1
cm−1. H-NMR (CDCl3, 400 MHz) δ: 1.37 (t, 3H, J = 7.2 Hz),
2.35 (s, 3H), 3.85 (s, 3H), 4.39 (q, 2H, 6.8 Hz), 6.42 (s, 1H),
6.97 (t, 2H, J = 8.3 Hz), 7.7 (t, 2H, J = 8.3 Hz ), 12.09 (brs, 1H);
13C-NMR (CDCl3, 50 MHz) δ: 14.3, 20.8, 55.4, 61.2, 107.8,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Synthesis of β-Arylacyl/β-Heteroarylacyl-β-alkylidene Malonates
55
and Their Application in Substituted Pyridone Synthesis
Acknowledgments. The authors thank Dr. Reddy’s Laboratories
for the permission to carry out this work. They also thank for
analytical department, Dr. Reddy’s Laboratories, for providing
the analytical support.
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