One-pot four component synthesis of 4, 6-disubstituted 3-cyano-2-pyridones in polyethylene glycol

Article abstract of DOI:10.2174/157017810791514832

The reaction of ketone, aldehyde, ethyl cyanoacetate and ammonium acetate in polyethylene glycol-600 is reported. The reaction proceeds smoothly in the absence of catalyst to yield 2-Pyridones.

Full text of DOI:10.2174/157017810791514832

406
Letters in Organic Chemistry, 2010, 7, 406-410
One-Pot Four Component Synthesis of 4, 6-Disubstituted 3-Cyano-2-
Pyridones in Polyethylene Glycol
Santosh V. Nalage1, Ajay P. Nikum2, Mohan B. Kalyankar1, Vijay S. Patil1, Umesh D. Patil1,
Kamlesh R. Desale2, Shamkant L. Patil*,2 and Sidhanath V. Bhosale*,1
1Department of Organic Chemistry, North Maharashtra University, Jalgaon-425001, India
2School of Chemical Sciences, North Maharashtra University, Jalgaon-425001, India
Received December 03, 2009: Revised March 25, 2010: Accepted March 25, 2010
Abstract: The reaction of ketone, aldehyde, ethyl cyanoacetate and ammonium acetate in polyethylene glycol-600 is
reported. The reaction proceeds smoothly in the absence of catalyst to yield 2-Pyridones.
Keywords: PEG, 2-pyridone, four components.
INTRODUCTION
product. Sakurai and co-workers reported the synthesis of 2-
pyridone in presence of benzene or without solvent under
reflux conditions for 8-12 hrs [11]. Rong et al. reported the
one-pot synthesis of 4,6-diaryl-2-oxo- 1, 2-dihydropyridine-
3-carbonitriles via three-component cyclocondensation in
presence of sodium hydroxide [16]. Despite the success of
available methods, there is always a need to develop newer
and simpler methods for the synthesis of 2-pyridone.
The interest of organic chemist increases in developing
green protocol for organic synthesis due to environmental
demands and sustainability. The development of uncatalysed
processes to replace stoichiometric reaction, which produces
large amount of waste byproducts, has made a significant
contribution to the reduction of environmental pollution.
Polyethylene glycol (PEG) hydrophilic, non-ionic polymer is
used in many biochemical and industrial applications. Due to
its nontoxic character PEG can be found in cosmetics, food
and pharmaceutical products. PEG is an environmentally
benign, cheap, and easily available, solvent which has been
successfully utilized in numerous reactions [1, 2].
RESULTS AND DISCUSSION
We report herein the One-pot four component synthesis
of 2-pyridone in PEG. A variety of substituted aromatic
ketones and aromatic as well as aliphatic aldehydes
underwent competitive formation of 2-pyridones. This
protocol is rapid and efficient to prepare a variety of
substituted 2-pyridone from both electron donating as well as
electron withdrawing aromatic ketones and aldehydes. It
follows from Table 1 that variety of functionalities (nitro,
halo, alkoxy) can be accommodated in 2-pyridone
derivatives. The structures of the products were confirmed
from melting point and spectroscopic data.
The synthesis of functionalized 3-cyano-2-pyridone
derivatives is a continuing area of interest due to the number
of biologically active molecules containing this moiety [3].
Natural compounds pyridone core has emerged during the
last ten years as a potent antitumor [4], antifungal [5],
antiviral [6] and psychotherapeutic [7], anti-HIV drugs [8].
Moreover, pyridones are key intermediates in the synthesis
of corresponding pyridines [9]. Several methods have been
reported for the synthesis of substituted 2-pyridones e.g.
metathesis-based approach to the synthesis of 2-pyridone
[10], cyclisation type reaction [11], one-pot synthesis of
pyridones by cross coupling of tributylstanlynallenes with
substituted iodopropan-2-enamides [12]. Reaction of ꢀ, ꢁ-
unsaturated carbonyl compounds with cyanoacetamide in the
presence of tBuOK [13], in such conventional methods for
synthesis of 2-pyridones, the time for completion of reaction
is very long ranging from 9-10 hr [14], low yield. Lam et.al
reported the synthesis of functionalized 2-pyridone with low
yield by using solid-phase synthesis method [15]. In this
strategy four components were involved to obtain the desired
We believe that the condensation between aryl aldehyde,
ketones, ethyl cyanoacetate and ammonium acetate leads to
substituted 2-pyriodnes via a knoevenagel reaction. The
reaction proceeds with the elimination of two moles of water
and one mole of alcohol (Scheme 2). These reactions were
completed via dehydrogenation under reflux condition. It is
important to mention that dehydrogenation takes place under
reflux condition has been described in literature [11]. This
mode of dehydrogenation suggests that reflux conditions are
essential to favour the formation of the 2-pyridone (Table 3).
Using PEG-600 as reaction medium, we next examined
the scope of the pyridone formation. The cyclic ketones
reacted smoothly with aldehydes, ethyl cyanoacetate and
ammonium acetate were examined to afford 2-pyridone (Vo
and Vp).
*Address correspondence to these authors at the School of Chemical
Sciences, North Maharashtra University, Jalgaon-425001, India; Tel: +91-
2572257433; Fax: +91-2572258403; E-mail: prof.slpatil@gmail.com
The effect of temperature was also studied at different
temperature. The reaction did proceed but the yield obtained
Department of Organic Chemistry, North Maharashtra University, Jalgaon-
425001, India; Tel: +91-2572257433; Fax: +91-2572258403;
E-mail: sidhanath2003@yahoo.co.in
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

One-Pot Four Component Synthesis
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
407
O
O
R'
O
H
R
CH3
NC
CN
Ammonium Acetate
O
R'
II
IV
III
I
N
H
O
PEG 600, 110 ˚C
R
V(a-j)
Scheme 1.
Table 1. Synthesis of 2-Pyridones in Polyethylene Glycol-600a
Entry
R
R’
Time (h)
Product
Yield (%)b
Mp 0C
1
2
C6H5
C6H5
C6H5
3.0
3.5
4.0
4.0
5.0
4.0
4.0
4.5
4.0
4.0
3.0
3.5
3.0
3.0
Va
Vb
Vc
Vd
Ve
Vf
80
71
68
67
60
70
68
65
68
65
68
60
72
75
> 300
276-277
> 300
300
3,4-(OCH3)C6H3
3,4-(OCH3)C6H3
3,4-(OCH3)C6H3
3,4-(OCH3)C6H3
3,4-(OCH3)C6H3
C6H5
3
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-OMeC6H4
4-BrC6H4
4-NO2C6H4
C6H5
4
5
268
6
266
7
Vg
Vh
Vi
290
8
3,4-(OCH3)C6H3
4-NO2C6H4
250
9
> 300
> 300
156-158
188-190
142-144
208
10
11
12
13
14
C12H10O
C6H5
C6H5
Vj
n-Heptanal
Vk
Vl
C6H5
Isovaleraldehyde
Valeraldehyde
Propanal
C6H5
Vm
Vn
C6H5
aAll the reactions were performed with ethyl cyanoacetate and ammonium acetate.
bIsolated yield.
H3C
O
H
N
O
H
O
OEt
CN
CH3COONH4
CN
+
NC
O
H2N
O
Scheme 2. Proposed pathway for the reaction in Scheme 1.
remained low even after longer reaction time. Several
solvents like ethanol, H2O, PEG-H2O, were tested but very
low yield were obtained. However, an elevated temperature
(1100C) using PEG-600 gave better results in terms of yield
(summarized in Table 3).
product, which separated out, was filtered washed with water
and dried. The crude product was recrystallised from
ethanol/DMF mixture provided substituted 2-pyridone with
60-80% yield.
The generality of PEG was examined using PEG-400 and
PEG-600 as shown in Table 4. In presence of PEG-400 the
yield of product was slightly changed. All reactions
proceeded very smoothly and clearly were stirred at 1100C
condition in this method. This protocol is advantageous since
reaction was carried out in absence of catalyst, operational
In a typical experiment aromatic aldehydes (1mmol),
aromatic ketones (1mmol), ethyl cyano acetate (1mmol), and
ammonium acetate (8mmol) in PEG-600 were stirred at
1100C for appropriate time (mentioned in Tables 1, 2). After
the completion of reaction (monitored by TLC) the reaction
mass was poured in to cold water. The solid 2-pyridone

408 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Nalage et al.
Table 2. Synthesis of 2-Pyridones by Using Cyclic Ketones in Polyethylene Glycol-600a
Entry
Cyclic Ketone
Aldehyde
Product
Time (h)
Yield (%)b
Mp ˚C
O
CHO
Ph
1
3.0
74
>300
N
H
CN
O
Vo
O
CHO
H
CN
O
N
2
4.0
60
>300
Ph
Ph
Vp
aAll the reactions were performed with ethyl cyanoacetate and ammonium acetate.
bIsolated yield.
Table 3. Synthesis of 2-Pyridonea (Va) at Different Temperatures
Entry
Solvent
Temperature/0C
Time(h)
Yield (%)b
1
2
3
4
5
6
7
PEG-600
PEG-600
PEG-600
PEG-600
PEG+H2O(1:1)
H2O
250C
500C
750C
1100C
1000C
1000C
700C
24
12
12
3
05
24
45
80
20
04
18
8
8
Ethanol
12
aReaction was carried out with Benzaldehyde (1mmol), Acetophenone (1mmol), Ethyl cyanoacetate (1mmol), and ammonium acetate (8mmol).
bIsolated yield.
Table 4. Synthesis of 2-Pyridonesa in Polyethylene Glycol-600 and 400
Entry
Starting Material I
Starting Material II
Product
Solvent
Time (h)
Yield (%)b
O
CHO
PEG-600
PEG-400
4.0
4.0
71
67
1a
Vb
CH3
OMe
OMe
O
CHO
PEG-600
PEG-400
4.0
4.0
73
74
2b
Vo
aAll the reactions were performed with ethyl cyanoacetate and ammonium acetate.
bIsolated yield.
in absence of catalyst. The simple and mild reaction
conditions are an alternative to existing methods.
simplicity, good yields and purification simply by
crystallization.
CONCLUSION
ACKNOWLEDGEMENTS
In summary, we have reported a novel, eco-friendly,
efficient method for the synthesis of 2-pyridones from
various aromatic aldehydes, ketones, in polyethylene glycol
The authors are thankful to Dr. K. B. Patil, Vice-
Chancellor North Maharashtra University, Jalgaon, (India)

One-Pot Four Component Synthesis
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
409
[12]
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Cherry, K.; Abarbri, M.; Parrain, J-L.; Duchene, A. Regio- and
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(a) Abadi, A.; Al-Deeb, O.; Al-Afify, A.; El-Kashef, H. Synthesis
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for providing necessary facilities. SVB and SVN are
thankful to DST, New Delhi, for the financial assistance
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Letter No. SR/FTP/CS-82/2007].
EXPERIMENTAL SECTION
Melting points were uncorrected and IR Spectra were
recorded using Nujol for solids on a Perkin-Elmer-1710
1
spectrophotometer. H NMR spectra were recorded at 200
MHz and 300 MHz in CDCl3 and DMSO-d6 using TMS as
an internal standard. Mass spectra were recorded under ESI
mode, on Thermo Finnigan (Model-LCQ Advantage MAX)
mass spectrometer.
[15]
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Li, W.; Chen, Y.; Lam, Y. A facile solid-phase synthesis of 3, 4, 6-
trisubstituted-2-pyridones using sodium benzenesulfinate as
a
traceless linker. Tetrahedron Lett., 2004, 45, 6545.
Rong, L.; Han, H.; Jiang, H.; Shi, D.; Tu, S. One-Pot synthesis of 4,
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component cyclocondensation under solvent-free conditions. Synth.
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General Procedure for the Preparation of Substituted 2-
Pyridones
[17]
Spectral data for selected compound:
A mixture of aromatic ketone I (1mmol), aldehydes II
(1mmol), ethyl cyanoacetate III (1mmol), and ammonium
acetate IV (8mmol), in PEG-600(5-6ml) was stirred at 1100C
for appropriate time (mentioned in Tables 1, 2). After
completion of the reaction (monitored by TLC), the reaction
mass poured in to cold water. The solid 2-pyridone product,
which separated out, was filtered washed with water and
dried. The crude products were recrystallized from
ethanol/DMF mixture provided substituted 2-pyridone
(Scheme 1) with 60-80% yield.
1,2-dihydro-2-oxo-4,6-diphenylpyridine-3-carbonitrile
[Va]:
Yield - 80%, M.p.: >3000C. IR(Nujol): (NH) 3382, (CN) 2218,
(C=O) 1647 cm-1. 1H NMR (200 MHz,CDCl3+ DMSO-d6 )
ꢀ=12.60 (br, s, 1H, N-H), 7.53(m, 2H), 7.40 (m, 3H), 7.10-7.29 (m,
5H),6.80 ( s, 1H, pyridone C-H), MS (m/z): 273 (M+H) +, 272(M+).
1,2-dihydro-4-(3,4-dimethoxyphenyl)-2-oxo-6-phenylpyridine-
3-carbonitrile [Vb]: Yield- 71%, M.p.: 276-2770 C, IR(Nujol):
(NH) 3355, (CN) 2219, (C=O) 1651 cm-1 , 1H NMR (300 MHz,
DMSO-d6): ꢀ = 12.75 (br, s, 1H, NH), 7.88 (d, 2H), 7.53-7.55 (m,
3H), 7.34-7.36 (m, 2H), 7.12 (d, 1H), 6.83 (s, 1H, pyridone H),
3.83 (s, 6H, -OCH3), MS (m/z): 332 (M+).
6-(4-chlorophenyl)-1,2-dihydro-4-(3,4-dimethoxyphenyl)-2-oxo-
pyridine-3-Carbonitrile [Vc]: Yield
-
68%, M.p.: >3000C,
IR(Nujol): (N-H) 3305, (CN) 2221, (C=O) 1633 cm-1. 1H NMR
(300 MHz, DMSO-d6) ꢀ = 12.51 (br, s, 1H, NH), 7.92 (d, 2H), 7.60
(d, 2H), 7.33-7.36 (m, 2H), 7.12 (d, 1H), 6.89 (s, 1H), 3.83 (s, 6H, -
OCH3), MS (m/z): 366 (M+ ).
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1,2-dihydro-4-(3,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-2-
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2H), 7.32-7.34 (m, 2H), 7.12 (d, 1H), 7.07 (d, 2H), 6.78 (s, 1H,
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362(M+).
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bonitrile6 [Vg]: Yield-68%, M.p: 2900C, IR(Nujol): (N-H) 3300,
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7.61-7.63 (m, 2H), 7.30-7.47 (m, 3H), 6.54 (s, 1H, pyridone H),
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4-hexyl-1,2-dihydro-2-oxo-6-phenylpyridine-3-carbonitrile [Vk]:
Yield- 68%, M.p.: 156-1580C, IR (Nujol): (N-H) 3400, (CN) 2217,
(C=O) 1653 cm-1, 1H NMR (300 MHz DMSO-d6): ꢀ=12.52 (br, s,
1H, N-H), 7.79 (d, 2H), 7.52-7.54 (m, 3H), 6.75 (s, 1H), 2.67 (t,
2H), 1.63 (t, 2H), 1.30 (m, 6H), 0.85 (t, 3H) MS (m/z): 281 (M+).
1,2-dihydro-4-isobutyl-2-oxo-6-phenylpyridine-3-carbonitrile
[Vl]: Yield-60%, M.p.: 188-1900C, IR (Nujol): (N-H) 3390, (CN)
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2216, (C=O)1646 cm-1, H NMR (300 MHz DMSO-d6): ꢀ= 12.5
(br, s, 1H, N-H), 7.80 (d, 2H), 7.52-7.54 (m, 3H), 6.72 (s, 1H), 2.57
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4-butyl-1,2-dihydro-2-oxo-6-phenylpyridine-3-carbonitrile [Vm]:
Yield-72%, M.p.: 142-1440C, IR (Nujol): (N-H) 3400, (CN) 2219,
(C=O)1629 cm-1, 1H NMR (300 MHz DMSO-d6): ꢀ= 12.52 (br, s,

410 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Nalage et al.
1H, N-H), 7.86 (d, 2H), 7.58-7.60 (m, 3H), 6.81 (s, 1H), 2.75 (t,
2H), 1.64-1.74 (m, 2H), 1.35-1.48 (m, 2H), 0.94 (t, 3H), MS (m/z):
253 (M+).
1H, N-H), 7.80 (d, 2H), 7.53 (m, 3H), 6.75 (s, 1H), 2.65-2.70 (m,
2H), 1.23 (t, 3H), MS (m/z): 225 (M+).
1,2,5,6-tetrahydro-2-oxo-4-phenylbenzo[h]quinoline-3-carboni-
trile [Vo]: Yield-74%, M.p: >3000C, IR (Nujol): (N-H) 3356, (CN)
2221, (C=O) 1635 cm-1, 1H NMR (200 MHz DMSO-d6): ꢀ= 12.30
(br, s, 1H, N-H), 7.98-8.10 (m, 5H), 7.33-7.45 (m, 4H), 2.76 (t, 2H,
CH2), 2.38 (t, 2H, CH2), MS (m/z): 299 (M++H), 298 (M+).
4-ethyl-1,2-dihydro-2-oxo-6-phenylpyridine-3-carbonitrile [Vn]:
Yield-75%, M.p.: 2080C, IR (Nujol): (N-H) 3380, (CN) 2222,
1
(C=O) 1625 cm-1, H NMR (300 MHz DMSO-d6): ꢀ= 12.6 (br, s,