International Journal of Organic Chemistry, 2011, 1, 242-249
doi:10.4236/ijoc.2011.14035 Published Online December 2011 (http://www.SciRP.org/journal/ijoc)
A Simple and Efficient Procedure for a 2-Pyridones
Synthesis under Solvent-Free Conditions
Zahira Kibou1, Nawel Cheikh1,2, Didier Villemin2*, Noureddine Choukchou-Braham1,
Bachir Mostefa-Kara1, Mohamed Benabdallah1
1Laboratoire de Catalyse et Synthèse en Chimie Organique, Faculté des Sciences, Université Aboubekr Belkaïd,
Tlemcen, Algérie
2ENSICAEN, LCMT, Caen, France
Received June 7, 2011; revised July 21, 2011; accepted August 9, 2011
Abstract
A new series of 3-cyano-2-pyridones derivatives have been prepared by reaction of enaminonitriles with pri-
mary amine under solvent free condition. This procedure have the advantage of high yields and being environ-
mentally-friendly.
Keywords: 2-Pyridones, Solvent-Free, Enaminonitriles, Green Chemistry
1. Introduction
Nowadays, one powerful solution in the Green & Sus-
tainable Chemistry movement is the replacement of tra-
ditional synthetic methods, which use harmful stoichio-
metric reagents that produce vast amounts of wastes,
with clean and simple catalytic alternatives with high
atom efficiency [1,2]. Solvent-free and dominos reac-
tions represent very powerful green chemical technology
procedures from both the economical and synthetic point
of view and represent a possible instrument to perform a
near-ideal synthesis because they enhance the rate of
many organic reactions and afford quantitative yields
[3-8]. Heteroaromatic rings containing atoms frequently
play an important role as the scaffolds of bioactive sub-
stances [9]. It is well-known that the pyridone [9] and its
derivatives are among the most popular N-heteroaro-
matic compounds integrated into the structures of many
pharmaceutical compounds and the structural units occur
in various molecules exhibiting diverse biological activi-
ties [10-12]. This can easily be demonstrated using the
following examples (Figure 1) [13]. Pyridone L-697,661
[13] has been recognized as a specific non-nucleoside
reverse transcriptase inhibitor of human immunodefi-
ciency virus-1 (HIV-1) [13], Milrinone WIN 47203
[9,14], Amrinone WIN 40680 [9,14] and their analogues
are well time- honored positive inotropic and vasodilata-
tory agents, used in the clinical treatment of heart failure
[9,14]. Some others are reported to show antitumor [15],
antibacterial activity, evaluated as human rhinovirus (HRV)
3C-protease (3CP) inhibitors [15] and other biological
activities. Others, that share the 2-Pyridone and its deriva-
tives, illustrate a large class as ligands in coordination
chemistry [16,17].
The various research teams around the world were and
are still interested in the synthesis of 2-Pyridones (Pyri-
din-2(1H)-ones). The various synthetic approaches to 2-
pyridones of this type are described. Many literature
sources [18-26] describe more general approaches in-
volving the condensation of unsaturated ketones with
methylene active amides, using cyanoacetamide. A num-
ber of Milrinone (Figure 1) analogues have been ob-
tained [18-26]. Departing from the previous literature,
and as part of our continuing interest in the progress of
new synthetic methods in heterocyclic chemistry in our
laboratory [27-29], we started the development of a new
preparative procedure for this class of heterocyclic scaf-
fold compounds.
2. Results and Discussions
In our work, we developed a new method for an easier,
simpler and more universal synthesis to prepare this type
of heterocycles “2-pyridone”, while trying to respect the
criteria of the green chemistry, in which we employed, as
a key step, the synthesis of enaminonitrile and in the pre-
sence of a catalytic amount of NH4OAc (Scheme 1).
From Scheme 1, we found that the synthesis under
solvent-free of new nitrogen heterocyclic compounds of
“2-pyridone derivatives” can be obtained, by a simple,
effective, fast and cleaner method, using the three fol-
lowing steps:

243 Z. KIBOU ET AL.
N
NH
2
O
H
N
Amrinone WIN 40680
N
CN
O
H
Me
N
Milrinone WIN 47203
N O
H
N
Me
Me
O
N
Cl
Cl
H
Pyridone L-697,661
Figure 1. Structures of pyridones L697,661, Milrinone WIN 47203, Amrinone WIN 40680.
Ar CH
3
O
CO
2
EtNC
Ar CH
3
NC CO
2
Et
Ar
NC CO
2
Et
NR
O
Ar
NC
+i
iii
NMe
2
ii
1a-f 2a-f
3a-f
4a-f
Scheme 1. Synthesis of 3-cyano-2-pyridone derivatives. Reagents and conditions: (i) NH4OAc, AcOH, 100˚C, 3 hours, solvent-free,
65% - 80%; (ii) DMF-DMA (10 mmol), r.t., solvent-free, 24 hours, 75% - 90%; (iii) RNH2 solvent-free, 1 - 4 hours, 48% - 88%.
2.1. Knoevenagel Condensation of Acetophenone
Derivatives
The Kknoevenagel condensation is one of the basic nec-
essary reactions in organic chemistry. The research pro-
cess for this reaction was developed very rapidly. Consi-
dering the importance of this condensation, several syn-
thesis methods were carried out. Usually, it is carried out
in the presence of harmful organic solvents such as ben-
zene and the DMF [30], and catalysts such as Al2O3 [31] ,
silica gel [32], a basic ionic liquid [33], Na2CO3—MS 4
Å [34], Mn (III) salen [35], and NH4OAc-basic alumina
[36] .
From our side, as a first step, we have prepared a se-
ries of ethyl 2-cyano-3-arylbut-2-enoate (2a-f), α, β-un-
saturated compounds, according to the knoevenagel con-
densation of a sequence of aromatic ketones (1a-f), with
of the ethyl cyanoacetate catalyzed by ammonium ace-
tate at 100˚C, under solvent-free conditions (Scheme 1).
The ethyl 2-cyano-3-arylbut-2-enoate 2a-f was obtained
with a moderate to excellent yields. The results are re-
ported in Table 1.
2.2. Synthesis of Enaminonitriles
These olefins, α, β-unsaturated compounds, prepared by
Knoevenagel condensations are largely used as key pro-
ducts in organic syntheses. They found a major applica-
tion in medicine, biology, and agriculture; thanks to their
Michael acceptor properties [37,38]. Therefore, they are
attractive molecules; as they have an exploitable functio-
nal richness for organic chemistry, where we were inter-
ested in acid methylene, for synthesis of enaminonitriles.
For a long time, many strategies have been considered
for the enaminonitriles synthesis [10-12,39]. Promoted
by the literature, we prepared the ethyl 2-cyano-5-(dime-
thylamino)-3-arylpenta-2,4-dienoate 3a-f (enaminonitri-
les) using the reaction between 2a-b and N,N-dime-
thylformamide-dimethylacetal (DMF-DMA) under sol-
vent-free, at room temperature (Scheme 1). The yields
obtained are very satisfactory 75% - 90% (Table 2).
2.3. Synthesis of 3-Cyano-2-Pyridones
The enaminonitriles are “push-pull” dienes and a good
synthon for the organic synthesis, because they can react
with the nucleophilic and electrophilic agents. They are
used in the preparation of various heterocycles [39,40].
In this last step, well-known as the cyclization step,
and in order to study the reactivity of enaminonitriles, we
added various types of primary nucleophilic amines to
the ethyl 2-cyano-5-(dimethylamino)-3-arylpenta-2,4-di-
enoate 3a-f (enaminonitrile), under solvent-free (Sche-
me 1). The mixture was heated, for a few hours, to form
3-cyano-2-pyridone derivatives, with moderate to excel-
lent yields (Table 3).

Z. KIBOU ET AL.
244
Table 1. Solvent-free Knoevenagel condensation for the synthesis of 2a-f.
Entry Ar Product Yield (%)
1 C6H5-
CH
3
NC CO
2
Et
2a
70
2 p-ClC6H4-
CH
3
NC CO
2
Et
Cl
2
b
75
3 2,4-Cl2C6H3-
CH
3
NC CO
2
Et
ClCl
2c
68
4 m-CH3OC6H4-
CH
3
NC CO
2
Et
2
d
OMe
73
5 p-CH3OC6H4-
CH3
NC CO2Et
MeO
2e
O
e
80
6 p-CH3C6H4-
CH
3
NC CO
2
Et
Me
2f
65
Table 2. Synthesis of enaminonitrile (3a-f) without solvent.
Entry Ar Product Yield (%)
7 C6H5-
NC CO
2
Et
NMe
2
3a
88
8 p-ClC6H4-
NC CO
2
Et
Cl
NMe
2
3b
90
9 2,4-Cl2C6H3-
NC CO
2
Et
ClCl
NMe
2 3c
82
10 m-CH3OC6H4-
NC CO
2
Et
NMe
2
OMe
3d
75
11 p-CH3OC6H4-
NC CO
2
Et
MeO
NMe
2
O
M
e
3e
80
12 p-CH3C6H4-
NC CO
2
Et
Me
NMe
2
3f
77

245 Z. KIBOU ET AL.
Table 3. Synthesis of the 3-cyano-2-pyridones.
Entry Enaminonitrile R Product Yield (%)
13 CH3-
NC
4a
1
N
O
66
14 CH2=CH-CH2-
NC
4a
2
N
O
70
15 C6H5CH2-
NC
4a
3
N
O
73
16
3a
(CH3)2CH-
NC N
O
4a
4
48
17 CH3- 76
18 CH2=CH-CH2- 80
19 C6H5CH2- 85
20
3b
(CH3)2CH-
NC
NC
NC
NC
N
O
N
O
N
O
N
O
Cl
Cl
Cl
Cl
4b
1
4b
2
4b
3
4b
4
50
21 CH3- 75
22 CH2=CH-CH2- 80
23 C6H5CH2- 84
24
3c
(CH3)2CH-
NC
NC
NC
NC
N
O
N
O
N
O
N
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4c
1
4c
2
4c
3
4c
4
52
25 CH3- 73
26 CH2=CH-CH2- 79
27 C6H5CH2- 80
28
3d
(CH3)2CH-
NC
NC
NC
NC
4d
1
4d
2
4d
3
N
O
N
O
N
O
N
O
4d
4
OMe
OMe
OMe
O
M
e
53

Z. KIBOU ET AL.
246
29 CH3- 74
30 CH2=CH-CH2- 81
31 C6H5CH2- 88
32
3e
(CH3)2CH-
NC
NC
NC
NC
N
O
N
O
N
O
N
O
MeO
MeO
MeO
MeO
4e
1
4e
2
4e
3
4e
4
51
33 CH3- 80
34 CH2=CH-CH2- 83
35 C6H5CH2- 88
36
3f
(CH3)2CH-
NC
NC
NC
NC
N
O
N
O
N
O
N
O
Me
Me
Me
Me
4f
1
4f
2
4f
3
4f
4
49
3. Conclusions
In summary, we have developed a simple, efficient and
rapid method for the synthesis of 3-cyano-2-pyridones,
following three steps, i.e. the Knoevenagel condensation
catalyzed by NH4OAc, the enaminonitriles synthesis, and
finally the synthesis of the 3-cyano-2-pyridone under sol-
vent-free conditions. This procedure has the advantages
of being a mild conditions reaction, using a catalytic qua-
ntity of NH4OAc, with moderate to excellent yields, and
where we operate with simplicity while respecting the
criteria of Green Chemistry.
4. Experimental
The melting points were measured using a Bank Kofler
HEIZBANK apparatus standard WME 50-260˚C and
were uncorrected. IR spectra were obtained with solids
with a Fourier transform Perkin Elmer Spectrum One wi-
th ATR accessory. Only significant absorptions are listed.
The 1H NMR spectra were recorded at 400 MHz, on a
Brüker AC 400 spectrometers and 13C NMR spectra were
recorded in the same spectrometers at 100.6 MHz. Sam-
ples were registered in CDCl3 solutions using TMS as an
internal standard. The chemical shifts are expressed in 
units (ppm) and quoted downfield from TMS. The multi-
plicities are reported as: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet.
General procedure 1: Synthesis of ethyl 2-cyano-3-
(aryl) but- 2-enoate 2a-b
A mixture of acetophenone or substituted acetophe-
none (10 mmol), ethyl cyanoacetate (10 mmol), ammoni-
um acetate (10 mmol) and some drops of icy acetic acid
were stirred and heated at 100˚C during 3 hours. The re-
action mixture was cooled down to room temperature, di-
luted with 30 ml of CH2Cl2. The organic layer obtained
was washed with (3 × 20 ml) of water, (10 ml) of satura-
ted NaCl, dried on MgSO4, filtered then evaporated un-
der vacuum. The compounds 2a-f were obtained as col-
ourless oil.
Ethyl 2-cyano-3-phenylbut-2-enoate 2a. The general
procedure 1, using (1.20 g, 10 mmol) of acetophenone,
(1.13 g, 10 mmol) of ethyl cyanoacetate, (0.77 g, 10
mmol) of ammonium acetate and some drops of icy ace-
tic acid, gave 70% of 2a as burn oil. 1H NMR (400 MHz,
CDCl3): 7.53 - 7.14 (m, 5H), 4.20 (q, 2H, JH-H = 7.2 Hz),
2.57 (s, 3H), 1.26 (t, 3H, JH-H = 7.2 Hz). 13C NMR (100
MHz, CDCl3): 172.21, 162.12, 136.91 - 128.10, 116.01,
104.95, 61.83, 24.50, 13.75. IR (neat, cm–1): 2225, 1747,
1682.
Ethyl 3-(4-chlorophenyl)-2-cyanobut-2-enoate 2b. The
general procedure 1, using (1.54 g, 10 mmol) of 4-chlo-
roacetophenone, (1.13 g, 10 mmol) of ethyl cyanoacetate
and (0.77 g, 10 mmol) of ammonium acetate and some
drops of icy acetic acid, gave 75% of 2b as burn oil. 1H
NMR (400 MHz, CDCl3): 7.51 - 7.18 (m, 4H), 4.20 (q,
2H, JH-H = 7.2 Hz), 2.62 (s, 3H), 1.29 (t, 3H, JH-H = 7.2
Hz). 13C NMR (100 MHz, CDCl3): 174.81, 164.23,
136.75 - 128.60, 115.38, 102.00, 62.10, 24.50, 24.75. IR
(neat, cm–1): 2222, 1747, 1682.

247 Z. KIBOU ET AL.
General procedure 2: Synthesis of ethyl 2-cyano-5-
(dimethylamino)-3-arylpenta-2, 4-dienoate 3a-b
A mixture of ethyl 2-cyano-3-arylbut-2-enoate (10
mmol) 2a-b, N,N-dimethylformamide dimethyl acetal (10
mmol) were stirred at room temperature without solvent
during 24 hours. The solution takes a colouring increas-
ingly dark burn. The purple solid obtained was washed
several times with diethyl ether and crystallised in abso-
lute ethanol to provide products 3a-b.
Ethyl 2-cyano-5-(dimethylamino)-3-phenylpenta-2,
4-dienoate 3a. The general procedure 2, using (2.15 g, 10
mmol) of 2a and (1.19 g, 10 mmol) of N, N-dime-
thylformamide dimethyl acetal, gave 85% of compound
3a as yellow solid, mp 142˚C. 1
H NMR (400 MHz,
CDCl3): 7.32 - 7.25 (m, 5H), 6.57 (d, 1H, JH-H = 12.8 Hz),
5.98 (d, 1H, JH-H = 12.8 Hz), 4.32 (q, 2H, JH-H = 7.2 Hz),
3.07 (s, 3H), 3.04 (s, 3H), 1,39 (t, 3H, JH-H = 7.2 Hz), 13C
NMR (100 MHz, CDCl3): 169.41, 165.56, 156.71,
137.80 - 127.70, 119.88, 99.75, 86.04, 60.07, 45.43,
37.48, 14.37. IR (neat, cm–1): 2191, 1674, 1609, 1508.
Ethyl 3-(4-chlorophenyl)-2-cyano-5-(dimethy-lami-
no) penta-2,4-dienoate 3b. The general procedure 2,
using (2.49 g, 10 mmol) of 2b, and (1.19 g,10 mmol) of
N,N-dimethylformamide dimethyl acetal, gave 90% of
compound 3b as yellow solid, mp 208˚C. 1H NMR (400
MHz, CDCl3): 7.35 - 7.20 (m, 4H), 6.48 (d, 1H, JH-H =
12.8 Hz), 5,90 (d, 1H, JH-H = 12.8 Hz), 4.26 (q, 2H, JH-H
= 7.2 Hz,), 3.01 (s, 3H), 2.99 (s, 3H), 1.33 (t, 3H, JH-H =
7.2 Hz). 13C NMR (100 MHz, CDCl3): 169.88, 158.38,
140.75, 137.20 - 128.75, 115.41, 107, 89.08, 60.01,
47.80, 38.77, 14.28. IR (neat, cm–1 ): 2199, 1680, 1604,
1507.
General procedure 3: Synthesis of 2-Pyridones 4ai-bi
A mixture of ethyl 2-cyano-5-(dimethylamino)-3-ar-
ylpenta-2,4-dienoate 3a-b (2 mmol) and primary amine
(2 mmol) were heated for a few hours. After cooling, the
solid obtained was washed several times with diethyl
ether to give 2-pyridone derivatives 4ai-bi.
1,2-dihydro-1-methyl-2-oxo-4-phenylpyridine-3-car
bonitrile 4a1. The general procedure 3, using (0.43 g, 2
mmol) of 3a and (0.06 g, 2 mmol) of methylamine, gave
66% of compound 4a1 as white solid, mp 174˚C. 1
H
NMR (400 MHz, CDCl3): 7.55 (d, 1H, JH-H = 6.7 Hz),
7.51 - 7.50 (m, 5H), 6.62 (d, 1H, JH-H = 6.4 Hz), 3.62 (s,
3H). 13C NMR (100 MHz, CDCl3): 159.82, 158.87,
134.46, 129.69 - 127.00, 114.57, 106.04, 101.42, 37.12.
IR (neat, cm–1): 2220, 1645, 1597.
1-allyl-1,2-dihydro-2-oxo-4-phenylpyridine-3-carbo
nitrile 4a2. The general procedure 3, using (0.43 g, 2
mmol) 3a and (0.11g, 2 mmol) of allylamine, gave 76%
of compound 4a2 as white solid, mp 99˚C - 100˚C. 1 H
NMR (400 MHz, CDCl3): 7.61 (d, 1H), 7.53 - 7.49 (m,
5H), 6.36 (d, 1H, JH-H = 6.7 Hz), 6.02 - 5.92 (m, 1H),
5.37 - 5.30 (m, 2H), 4.64-4.62 (m, 2H). 13C NMR (100
MHz, CDCl3): 160.2, 159.78, 140.41, 135.46, 131.29-
128.03, 120.29, 115.55, 107.26, 102.76, 51.26. IR (neat,
cm–1): 2216, 1634, 1591.
1-benzyl-1,2-dihydro-2-oxo-4-phénylpyridine-3-car
bonitrile 4a3. The general procedure 3, using (0.43 g, 2
mmol) of 3a and (0.21 g, 2 mmol) of benzylamine, gave
73% of compound 4a3 as white solid, mp 134˚C. 1 H
NMR (400 MHz, CDCl3): 7.60 (d, 1H, JH-H = 7.2 Hz),
7.58 - 7.38 (m, 25H), 6.31 (d, 1H, JH-H = 7.2 Hz), 5.19
(s, 2H). 13C NMR (100 MHz, CDCl3): 160.55, 159.66,
140.44, 135.43, 134.96 - 128.71, 128.03, 115.98, 107.36,
52.69. IR (neat, cm–1): 2220, 1645, 1597.
1,2-dihydro- 1-isop ropy l-2-ox o-4 -pheny lpyridine-3-
carbonitrile 4a4. The general procedure 3, using (0.43 g,
2 mmol) of 3a and of (0.11 g, 2 mmol) isopropylamine
gave 48% of compound 4a4 as withe solid, mp 144˚C. 1H
NMR (400 MHz, CDCl3): 7.57 (d, 1H, JH-H = 6.8 Hz),
7.49 - 7.50 (m, 5H), 6.38 (d,1H, JH-H = 6.8 Hz), 5.24 - 5.31
(m, 1H), 1.42 (d, 6H, JH-H = 7.2 Hz). 13C NMR (100 MHz,
CDCl3): 160.274, 158.80, 136.85, 135.56 - 127.57,
115.86, 107.01, 102.34, 47.68, 21.78. IR (neat, cm–1):
2219, 1640, 1592, 1517.
4-(4-chlorophenyl)-1-methyl-2-oxo-1,2-dihydropyri
dine-3-carbonitrile 4b1. The general procedure 3, using
(0.60 g , 2 mmol) of 3b and (0.06 g, 2 mmol) of methy-
lamine, gave 76% of compound 4b1 as white solid, mp
184˚C. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H, JH-H =
6.7 Hz), 7.54 - 7.47 (m, 4H), 6.30 (d,1H, JH-H = 6.4 Hz),
3.64 (s, 3H). 13C NMR (100 MHz, CDCl3): 162.12,
157.66, 135.56, 127.33 - 129.88, 115.08, 107.80, 103.34,
34.20. IR (neat, cm–1): 2221, 1644, 1599.
1-allyl-4-(4-chlorophenyl) -2-oxo -1,2- dihydro pyridi
ne-3-carbonitrile 4b2. The general procedure 3, using
(0.60 g, 2 mmol) of 3b and (0.11 g, 2 mmol) of
allylamine, gave 80% of compound 4b2 as white solid,
mp 172˚C. 1H NMR (400 MHz, CDCl3): 7.62 (d, 1H),
7.56 - 7.41 (m, 4H), 6.44 (d, 1H, JH-H = 6.7 Hz), 5.93 -
5.58 (m, 1H), 5.34 - 5.28 (m, 2H), 4.76 - 4.68 (m, 2H).
13C NMR (100 MHz, CDCl3): 162.11, 160.22, 143.11,
136.80, 134.2 - 126.50, 122.18, 115.9, 107.80, 103.11,
48.02. IR (neat, cm–1): 2216, 1637, 1595.
4-(4-chlorophenyl)-1-ethyl-2-oxo-1,2-dihydropyridi
ne-3-carbonitrile 4b3. The general procedure 3, using
(0.60 g, 2 mmol) of 3b and (0.21 g, 2 mmol) of ben-
zylamine gave 85% of compound 4b3 as white solid, mp
214˚C. 1H NMR (400 MHz, CDCl3): 7.62 (d, 1H), 7.49-
7.30 (m, 4H), 7.29 - 7.19 (m, 5H), 6.20 (d, 1H), 5.12 (s,
2H). 13C NMR (100 MHz, CDCl3): 167.98, 156.50,
136.67, 135.10, 130.29 - 128.27, 119.84, 100.70, 45.63.
IR (neat, cm–1): 2219, 1656, 1597.
4-(4-chlorophenyl)-1-isopropyl-2-oxo-1,2-dihydrop
yridine-3-carbonitrile 4b4. The general procedure 3,

Z. KIBOU ET AL.
248
using (0.60g , 2 mmol) of 3b and (0.11 g, 2 mmol) of
isopropylamine, gave 50% of compound 4b4 as white
solid, mp 142˚C. 1H NMR (400 MHz, CDCl3): 7.52 (d,
1H, JH-H = 6.8 Hz), 7.50 - 7.40 (m, 4H), 6.27 (d, 1H, JH-H
= 6.8 Hz), 5.24 - 5.17 (m, 1H), 1.29 (d, 6H, JH-H = 7.2
Hz). 13C NMR (100 MHz, CDCl3): 163.32, 159.18,
134.88, 136.42 - 127.80, 115.9, 106.08, 101.54, 48.78,
21.26. IR (neat, cm–1): 2221, 1648, 1599, 1512.
5. References
[1] D. Blasco-Jiménez, A. J. Lopez-Peinado, R. M. Martin-
Aranda, M. Ziolek and I. Sobczak, “Sonocatalysis in
Solvent-Free Conditions: An Efficient Eco-Friendly Me-
thodology to Prepare N-Alkyl Imidazoles Using Amino-
Grafted NbMCM-41,” Catalysis Today, Vol. 142, No.
3-4, 2009, pp. 283-287.
doi:10.1016/j.cattod.2008.11.028
[2] D. Kumar, V. B. Reddy, B. G. Mishra, R. K. Ranna, M.
N. Nadagouda and R. S. Varma, “Nanosized Magnesium
Oxide as Catalyst for the Rapid and Green Synthesis of
Substituted 2-Amino-2-Chromenes,” Tetrahedron, Vol.
63, No. 15, 2007, pp. 3093-3097.
doi:10.1016/j.tet.2007.02.019
[3] L. F. Teitze, “Domino Reactions in Organic Synthesis,”
Chemical Reviews, Vol. 96, No. 1, 1996, pp. 115-136.
doi:10.1021/cr950027e
[4] R. Maggi, R. Ballini and G. Sartori, “Basic Alumina
Catalysed Synthesis of Substituted 2-Amino-2-chromenes
via Three-Component Reaction,” Tetrahedron Letters,
Vol. 45, No. 11, 2004, pp.2297-2299.
doi:10.1016/j.tetlet.2004.01.115
[5] J. A. Wang, X. Bokhimi, O. Novaro, T. Lopez, F. Tzom-
pantzi, R. Gomez, J. Navarrete, M. E. Llanos and M. Lo-
pez-Salinas, “Effects of Structural Defects and Acid-Ba-
sic Properties on the Activity and Selectivity of Isopro-
panol Decomposition on Nanocrystallite Sol-Gel Alu-
mina Catalyst,” Journal of Molecular Catalysis A: Ch-
emical, Vol. 137, No. 1-3, 1999, pp. 239-256.
doi:10.1016/S1381-1169(98)00077-6
[6] S. Paul, P. Nanda, R. Gupta and A. Loupy, “Ac2O-Py/
Basic Alumina as a Versatile Reagent for Acetylations in
Solvent-Free Conditions under Microwave Irradiation,”
Tetrahedron Letters, Vol. 43, No. 23, 2002, pp. 4261-
4265. doi:10.1016/S0040-4039(02)00732-3
[7] C. M. Figueiredo, “Preparation of Aluminas from a Basic
Aluminium Carbonate,” Catalysis Today, Vol. 5, 1989,
pp. 433-442. doi:10.1016/0920-5861(89)80007-0
[8] S. Carre, B. Tapin, N. S. Gnep, R. Revel and P. Magnoux,
“Model Reactions as Probe of the Acid-Base Properties
of Aluminas: Nature and Strength of Active sites. Corre-
lation with Physicochemical Characterization,” Applied
Catalysis A: General, Vol. 372, No. 1, 2010, pp. 26-33.
doi:10.1016/j.apcata.2009.10.005
[9] M. T. Cocco, C. Congiu and V. Onnis, “Synthesis and
Antitumor Activity of 2-Hydroxy-2-pyridones Deriva-
tives,” European Journal of Medicinal Chemistry, Vol.
35, No. 5, 2000, pp. 545-552.
doi:10.1016/S0223-5234(00)00149-5
[10] F. Manna, F. Chimenti, A. Bolasco, A. Filippelli and E.
Lampa, “Antiinflammatory, Analgesic and Antipyfuztic
4,6-Disubstituted 3-Cyanopyridine-2-ones and 3-Cyano-
2-aminopyridines,” Pharmacological Research, Vol. 26,
Suppl. 1, 1992, pp. 267-277.
doi:10.1016/1043-6618(92)91243-A
[11] R. L. Parreira, O. Abrahão and S. E. Galembeck, “Con-
formational Preferences of Non-Nucleoside HIV-1 Re-
verse Transcriptase Inhibitors,” Tetrahedron, Vol. 57, No.
16, 2001, pp. 3243-3253.
doi:10.1016/S0040-4020(01)00193-4
[12] X. Fan, D. Feng, Y. Qu, X. Zhang, J. Wang, P. M.
Loiseau, G. Andrei, R. Snoeck, E. De Clercq, “Practical
and Efficient Synthesis of Pyrano[3,2-c]pyridone, Pyrano
[4,3-b]pyran and Their Hybrids with Nucleoside as Po-
tential Antiviraland Antileishmanial Agents,” Bioorganic
& Medicinal Chemistry Letters, Vol. 20, No. 3, 2010, pp.
809-813. doi:10.1016/j.bmcl.2009.12.102
[13] E. L. Presti, R. Boggia, A. Feltrin, G. Menozzi, P. Dorigo
and L. Mosti, “3-Acetyl-5-acylpyridin-2(1H)-ones and 3-
Acetyl-7,8-dihydro-2,5(1H,6H)-quinolinediones: Synthe-
sis, Cardiotonic Activity and Computational Studies,” II
Farmaco, Vol. 54, No. 7, 1999, pp. 465-447.
doi:10.1016/S0014-827X(99)00053-1
[14] W. K. Anderson, D. C. Dean and T. Endo, “Synthesis,
Chemistry, and Antineoplastic Activity of α-Halopyridi-
nium Salts: Potential Pyridone Prodrugs of Acylated Vi-
nylogous Carbinolamine Tumor Inhibitors,” Journal of
Medicinal Chemistry, Vol. 33, No. 6, 1990, pp. 1667-
1675. doi:10.1021/jm00168a021
[15] P. S. Dragovich, T. J Prins, Z. Ru, E. L. Brown, F. C.
Maldonado, S. A. Fuhrman, L. S. Zalman, L. Iuniland, C.
A. Lee and S. T. Worland, “Structure-Based design,
Synthesis, and Biological Evaluation of Irreversible Hu-
man Rhinovirus 3C Protease Inhibitors. 6. Struc-ture-
Activity Studies of Orally Bioavailable, 2-Pyridone- Con-
taining Peptidomimetics,” Journal of Medicinal Chemis-
try, Vol. 45, No. 8, 2002, pp. 1607-1623.
doi:10.1021/jm010469k
[16] B. Kozlevcar, M. Radisek, Z. Jaglicic, F. Merzel, L.
Glazar, A. Golobic and P. Segedin, “Strong Antiferro-
magnetism in the Dinuclear 2-Pyridone Complex with
N-C-O Bridges: A Paddle-Wheel Analogue of the Dinu-
clear Tetracarboxylates,” Polyhedron, Vol. 26, 2007, pp.
5414-5419. doi:10.1016/j.poly.2007.08.019
[17] T. Mochida, M. Ueda, C. Aoki and H. Mori, “Structures
and Properties of Trans-Dichloro{Tetrakis (5-Chloro-2
(1H)-pyridone-O)}M(II) [M=Mn, Fe, Co, Ni, Cu]; For-
mation of Quasi-Macrocyclic Metal Complexes through
Hydrogen Bonding,” Inorganica Chimica Acta, Vol. 335,
No. 27, 2002, pp. 151-155.
doi:10.1016/S0020-1693(02)00817-4
[18] K. R. Gibson, L. Hitzel, R. J. Mortishire-Smith, U.
Gerhard, R.A. Jelley, A. J. Reeve, M. Rowley, A. Nadin
and A. P. Owens, “Synthesis and Conformational Dy-
namics of Tricyclic Pyridones Containing a Fused Seven-

249 Z. KIBOU ET AL.
Membered Ring,” Journal of Organic Chemistry, Vol. 67,
No. 26, 2002, pp. 9354-9360.
doi:10.1021/jo026411a
[19] I. Collins, C. Moyes, et al., “3-Heteroaryl-2-pyridones:
Benzodiazepine Site Ligands with Functional Delectivity
for Alpha 2/Alpha 3-Subtypes of Human GABA (A) Re-
ceptor-Ion Channels,” Journal of Medicinal Chemistry,
Vol. 45, No. 9, 2002, pp. 1887-1990.
doi:10.1021/jm0110789
[20] F. A. Abu-Shanab, A. D. Redhouse, J. R. Thompson and
B. J. Wakefield, “Synthesis of 2,3,5,6-Tetrasubtituted
Pyridines from Enamines Derived from N, N-Dimethyl-
formamide Dimethyl Acetal,” Synthesis, Vol. 5, 1995, pp.
557-560. doi:10.1055/s-1995-3954
[21] W. D. Jones, R. A. Schnettler and E. W. Huber, “A
Convenient Synthesis of 5-Acyl-6-substituted 3-cyano-2
(1H)-pyridinones,” Journal of Heterocyclic Chemistry,
Vol. 27, No. 3, 1990, pp. 511-518.
doi:10.1002/jhet.5570270307
[22] H. Fukatsu, Y. Kato, S. Murase and S. Nakagawa,
“Synthesis and Cardiotonic Activity of 5-(2-Substituted
thiazol-4-yl)-2-pyridones and Thiazolo[4,5-f] quinolino-
nes,” Heterocycles , Vol. 29, No. 8, 1989, pp. 1517-1528.
doi:10.3987/COM-89-4984
[23] I. Sircar, B. L. Duell, J. A. Bristol, R. E. Weishaar and D.
B. Evans, “Cardiotonic Agents. 5. 1,2-Dihydro-5-[4-
(1Himidazol-1-yl)phenyl]-6-methyl-2-oxo-3-pyridinecar-
bonitriles and Related Compounds. Synthesis and Ino-
tropic Activity,” Journal of Medicinal Chemistry, Vol. 30.
No. 6, 1987, pp. 1023-1029. doi:10.1021/jm00389a011
[24] D. W. Robertson, E. E. Beedle, J. K. Swartzendruber, N.
D. Jones, T. K. Elzey, R. F. Kauffman, H. Wilson and J.
S. Hayes, “Bipyridine Cardiotonics: The Three-Dimen-
sional Structures of Amrinone and Milrinone,” Journal of
Medicinal Chemistry, Vol. 29, No. 5, 1986, pp. 635-640.
doi:10.1021/jm00155a009
[25] J. J. Chen and I. J. Wang, “Synthesis and Colour Assess-
ment of Some 3-Cyano-4-pyrenyl-6-substituted-2-pyri-
done Derivatives,” Dyes and Pigments, Vol. 29, No. 4,
1995, pp. 305-313. doi:10.1016/0143-7208(95)00055-0
[26] A. H. Abadi, T. M. Ibrahim, K. M. Abouzid, J. Lehmann,
H. N. Tinsley, B. D. Gary and G. A. Piazza, “Design,
Synthesis and Biological Evaluation of Novel Pyridine
Derivatives as Anticancer Agents and Phosphodiesterase
3 Inhibitors,” Bioorganic & Medicinal Chemistry, Vol.
17, No. 16, 2009, pp. 5974-5982.
doi:10.1016/j.bmc.2009.06.063
[27] D. Villemin, B. Mostefa-Kara, N. Bar, N. Choukchou-
Braham, N. Cheikh, A. Benmeddah, H. Hazimeh and C.
Ziani-Cherif, “Base Promoted Reaction in Ionic Liquid
Solvent: Synthesis of Butenolides,” Letters in Organic
Chemitry, Vol. 3, 2006, pp. 558-559.
doi:10.2174/157017806778341807
[28] D. Villemin, N. Cheikh, B.Mostefa-Kara, N. Bar, N.
Choukchou-Braham and M. A. Didi, “Solvent-Free Re-
action on KF-Alumina under Microwave: Serendipitous
One-Pot Domino Synthesis of New Isobenzofuran-1(3H)
-ones from Alpha-Hydroxyketones,” Tetrahedron Letters,
Vol. 47, No. 31, 2006, pp. 5519-5521.
doi:10.1016/j.tetlet.2006.05.137
[29] N. Cheikh, N. Bar, et al., “Efficient Synthesis of New
Butenolides by Subsequent Reactions: Application for the
Synthesis of Original Iminolactones, Bis-Iminolactones
and Bis-Lactones,” Tetrahedron, Vol. 67, No. 8, 2011, pp.
1540-1557. doi:10.1016/j.tet.2010.12.062
[30] Q. Shi, J. Chen, Q. Zhunag and X. Wang, “The Conden-
sation of Aromatic Aldehydes with Acidic Methylene
Compounds in Water,” Chinese Chemical Letters, Vol.
14, 2003, pp. 1242-1245.
[31] T. B. FranColse and F. Andre, “Knoevenagel Condensa-
tion Catalysed by Aluminium Oxide,” Tetrahedron Let-
ters, Vol. 23, No. 47, 1982, pp. 4927-4928.
doi:10.1016/S0040-4039(00)85749-4
[32] P. de la Cruz, E. Diez-Barra, A. Loupy and F. Langa,
“Silica Gel Catalysed Knoevenagel Condensation in Dry
Media under Microwave Irradiation,” Tetrahedron Let-
ters, Vol. 37, 1996, pp. 1113-1116.
doi:10.1016/0040-4039(95)02318-6
[33] G.-H. Gao, L. Lu, et al., “Basic Ionic Liquid: A Reusable
Catalyst for Knoevenagel Condensation in Aqueous Me-
dia,” Chemical Research in Chinese Universities, Vol. 23,
No. 2, 2007, pp. 169-172.
doi:10.1016/S1005-9040(07)60035-X
[34] B. Siebenhaar, B. Casagrande, M. Studer and H. U.
Blaser, “An Easy-to-Use Heterogeneous Catalyst for the
Knoevenagel Condensation,” Canadian Journal of Ch-
emistry, Vol. 79, No. 5-6, 2001, pp. 566-569.
doi:10.1139/v01-072
[35] M. L. Kantam and B. Bharathi, “Mn(III) Salen Catalyst
for Knoevenagel Condensation a Novel Heterogeneous
System,” Catalysis Letters, Vol. 55, No. 3-4, 1998, pp.
235-237. doi:10.1023/A:1019051416463
[36] S. Balalaie and N. Nemati, “Ammonium Acetate-Basic
Alumina Catalyzed Knoevenagel Condensation under
Microwave Irradiation under Solvent-Free Conditions,”
Synthetic Communications, Vol. 30, No. 5, 2000, pp. 869-
875. doi:10.1080/00397910008087099
[37] A. McCluskey, P. J. Robinson and T. Hill, “Green Che-
mistry Approaches to the Knoevenagel Condensation:
Comparison of Ethanol, Water and Solvent Free (Dry
Grind) Approaches,” Tetrahedron Letters, Vol. 43, No.
17, 2002, pp. 3117-3120.
doi:10.1016/S0040-4039(02)00480-X
[38] F. Freeman, “Properties and Reactions of Ylidenema-
lononitriles,” Chemical Reviews, Vol. 80, No. 4, 1980, pp.
329-350. doi:10.1021/cr60326a004
[39] A. W. Erian, S. M. Sherif, A. Alassar and Y. M. Elkholy,
“β-Enaminonitriles in Heterocyclic Synthesis: A Novel
Synthesis and Transformations of α-Substituted-β-enam-
inonitriles,” Tetrahedron, Vol. 50, No. 6, 1994, pp. 1877-
1884. doi:10.1016/S0040-4020(01)80859-0
[40] A. W. Erian, “The Chemistry of β-Enamino Nitriles as
Versatile Reagents in Heterocyclic Synthesis,” Chemical
Reviews, Vol. 93, No. 6, 1993, pp. 1991-2005.
doi:10.1021/cr00022a002