Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed by Au–Co/TiO2

Article abstract of DOI:10.1007/s11164-020-04261-1

Abstract: The current work described a new and highly selective method for the synthesis of substituted 3-cyano-2-pyridones scaffolds using gold-cobalt supported on TiO₂ as a robust and recyclable catalyst. The products were successfully obtained by one-pot, multicomponent manner. This procedure generated the desired products 2-pyridones derivatives in good yields, from simple and available starting materials using heterogeneous and reusable catalyst. The diversity of 3-cyano-2-pyridones derivatives was prepared and characterized by IR, ¹H and ¹³C NMR data and confirmed by element analysis data. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-020-04261-1

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04261-1
Novel synthesis of 3‑cyano‑2‑pyridones derivatives
catalyzed by Au–Co/TiO2
Nawel Mehiaoui1 · Zahira Kibou1,2 · Amina Berrichi1,2 · Redouane Bachir1 ·
Noureddine Choukchou‑Braham1
Received: 2 July 2020 / Accepted: 26 August 2020
© Springer Nature B.V. 2020
Abstract
The current work described a new and highly selective method for the synthesis of
substituted 3-cyano-2-pyridones scafolds using gold-cobalt supported on TiO2 as a
robust and recyclable catalyst. The products were successfully obtained by one-pot,
multicomponent manner. This procedure generated the desired products 2-pyridones
derivatives in good yields, from simple and available starting materials using hetero-
geneous and reusable catalyst. The diversity of 3-cyano-2-pyridones derivatives was
prepared and characterized by IR, 1H and 13C NMR data and confrmed by element
analysis data.
Graphic abstract
Keywords 3-Cyano-2-pyridones · Au–Co/TiO2 · Nanocatalysts · Multicomponents
reactions · Nitrogen heterocyclic
*
Zahira Kibou
zahira_kibou@yahoo.fr
1
2
Laboratoire de Catalyse et Synthèse en Chimie Organique, Faculté des Sciences, Université de
Tlemcen, BP 119, 13000 Tlemcen, Algeria
Centre Universitaire Belhadj Bouchaib Ain Témouchent, Institut des Sciences, BP 284,
46000 Aïn Témouchent, Algeria
Vol.:(0123456789)
1 3

N. Mehiaoui et al.
Introduction
2-pyridones scafolds are an important class of nitrogen heterocyclic compounds
present in many natural compounds [1]. Moreover, these structures are incorporated
in many synthetic pharmaceuticals products [2–4].
3-cyano-2-pyridones derivatives have been found to be efective for treatment of
cancer [5], promising class of HIV-1 [6, 7], sedative [8], anti-microbial [9], as well
as modulators of the fbrillation of amyloid proteins, such as Alzheimer β-peptides
[10] and MEK-1 inhibitor [11]. Some biological 3-cyano-2-pyridones structures are
displayed in (Fig. 1). Also, these scafolds are used in manufacturing of dyes and
pigments [12–14], as ligands for the late 3d-metals [15], agrochemicals [16–19], and
functional materials [20].
The 2-pyridones moieties have not only a wide range of biological and pharma-
cological activities but there are also several protocols for the synthesis of this ring
over the last years [21–33]. The development of new and environmentally accept-
able synthetic methods is an important area of modern chemistry. Conventional
organic syntheses are generally based on homogeneous catalysts.
Recently, one of the most powerful tool pathway is the use of heterogeneous cata-
lysts [34, 35], is probably one of the most elegant method that respects the principles
of the so-called “green chemistry” for the following reasons: short reaction times,
cleaner reaction, readily available catalyst and easy isolation.
In last decades, synthesis and usage of nanoparticules catalysts have gained
important attention as a green and reusable catalyst, the use of TiO2 nanoparticules
as a support of multifunctional materials is very recommended due to their uni-
form pore size, high both stability and surface. From these reasons, nonocatalysts
have considered as efcient materials for the synthesis of heterocyclic compounds
[36–41].
Following our previous research on the synthesis and application of new hetero-
geneous catalysts, and in connection with our interest in the development of new and
environmental friendly methodologies to prepare heterocyclic compounds [42–47].
However, this work presents a new synthesis of derivatives of 3-cyano-2-pyri-
dones using new catalyst system Au–Co/TiO2, via three compounds. As fgured in
the following (Scheme 1).
Fig. 1 Some biologically active 2-pyridone moiety
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
Scheme 1 General synthesis of substituted 3-cyano-2-pyridones
On the other hand, to the best of our knowledge, the use of Au–Co/TiO2 in the
synthesis of nitrogen heterocyclic compounds is not reported. Herein, we present
a new practical application of Au–Co/TiO2 nanaoparticules as an efcient catalyst
for the synthesis of 3-cyano-2-pyridones derivatives via one-pot, multicomponent
manner by coupling α, β-unsaturated compounds, ethylacetoacetate with ammonium
acetate. We explain here an easy and efectual protocol to prepare various 3-cyano-
2-pyriodones, recycling experiments confrmed the good stability of the nanocata-
lyst for six times without observable losses in catalytic performance.
Experiment section
Melting points were determined with a Bank Kofer Hrizbank apparatus standard
WME 50–260 °C. IR spectra were recorded on Solid samples using a Fourier trans-
1
form Perkin Elmer spectrum with ATR accessory. H and 13C NMR spectra were
recorded on BRUKER BioSpin GmbH spectrometer at 400 and 100, 6 MHz/300.13
1
and 75.47 MHz, respectively. H and 13C NMR spectra were obtained on solution
in CDCl3 and DMSO using TMS as internal standard. Column chromatography
was performed with Merck silica gel 60, 230–400 mesh. The chemicals used in this
work were purchased from Fluka (Buchs, Switzerland) and were used without fur-
ther purifcation. Elemental analyses (C, H, and N) were performed on Perkin-Elmer
2400 analyzer (Perkin-Elmer, Norwalk).
General procedure for the preparation of 2a–e
An equimolar mixture of aldehydes 1a–e (1 mmol) and (1 mmol) of ethyl cyanoac-
etate in the presence of ammonium acetate (1 mmol) was steered at room tempera-
ture for 25–60 min. After completion of reaction, a white crystalline precipitate was
formed, which then was extracted with chloroform (3×10 mL). The organic extracts
were combined and further washed with water and dried over MgSO4. Finally, evap-
orated under vacuum to give desired product.
2‑Cyano‑3‑phenyl‑acrylic acid ethyl ester 2a Using of benzaldehyde (1.20 g,
10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol) and ammonium acetate (0.77 g,
1 3

N. Mehiaoui et al.
10 mmol), it was obtained 2a. As white solid (1.40 g, 70%), Rf =0.31 (AcOEt/
1
Cyclohexane 75:25), mp 96 °C. H NMR (300.13 MHz, CDCl3, TMS) δH: 8.32
(s, 1H, C=C–H), 8.01–8.08 (m, 2H, Harom). 7.52–7.66 (m, 2H, Harom), 4.00 (q,
JH–H =7.1 Hz, 2H, CO2CH2CH3), 1.62 (t, JH–H =7.1 Hz, 3H, CO2CH2CH3); 13C
NMR (100.61 MHz, CDCl3, TMS) δC: 162.97 (C=C(CN)), 155.21 (C=O); 129.34–
133.46 (6×Carom); 115.49 (CN); 102.59 (C=C(CN)); 53.45 (OCH2–CH3); 11.87
(O–CH2–CH3); IR (νmax/cm−1): 1605 (C=C), 1726 (C=O), 2224 (CN).
3‑(3‑Chloro‑phenyl)‑2‑cyano‑acrylic acid ethyl ester 2b Using of 3′-chlorobenzal-
dehyde (1.40 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol) and ammonium
acetate (0.77 g, 10 mmol), it was obtained 2b. as white solid (2.02 g; 86%), Rf =0.37
(AcOEt/Cyclohexane 75:25), mp 90 °C. 1H NMR (400 MHz, DMSO, TMS)
δH: 8.41 (s, 1H, C=C–H). 7.47–8.14 (m, 4H, Harom). 4.34 (q, JH–H =7.1 Hz, 2H,
CO2CH2CH3); 1.33 (t, JH–H =7.1 Hz, 3H, CO2CH2CH3); 13C NMR (100.6 MHz,
DMSO, TMS) δC: 161.88 (C=C(CN)). 153.86 (C=O); 128.31–134.20 (6×Carom);
115.65 (CN); 104.86 (C=C(CN)); 63.01 (OCH2–CH3); 14.40 (O–CH2–CH3); IR
(νmax/cm−1): 1621 (C=C), 1708 (C=O), 2209 (CN).
2‑Cyano‑3‑(2, 4‑dichloro‑phenyl)‑acrylic acid ethyl ester 2c Using of 2, 4-dichlo-
robenzaldehyde (1.75 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol) and
ammonium acetate (0.77 g, 10 mmol), it was obtained 2b. as white solid (2.48 mg;
1
92%), Rf =0.35 (AcOEt/Cyclohexane 75:25), mp 120 °C. H NMR (400 MHz,
DMSO, TMS) δH: 8.47 (s, 1H, C=C–H). 8.12 (d, 1H, J=8.5 Hz, Harom). 7.90 (s,
1H, Harom), 7.70 (d, 1H, J=8.5 Hz, Harom); 4.35 (q, JH–H =7.1 Hz, 2H, CH2); 1.32
(t, JH–H =7.1 Hz, 3H, CO2CH2CH3); 13C NMR (100.6 MHz, DMSO, TMS) δC:
161.47 (C=C(CN)). 149.96(C=O); 128.74–138.46 (6×Carom); 114.96 (CN); 107.74
(C=C(CN)); 63.27 (OCH2–CH3); 14.38 (O–CH2–CH3); IR (νmax/cm−1): 1582
(C=C), 1723 (C=O), 2227 (CN).
2‑Cyano‑3‑(4‑fuoro‑phenyl)‑acrylic acid ethyl ester 2d Using of 4-fuorobenzalde-
hyde (1.24 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol) and ammonium ace-
tate (0.77 g, 10 mmol), it was obtained 2d. as white solid (1.62 mg; 74%), Rf =0.34
1
(AcOEt/Cyclohexane 75:25), mp 108 °C. H NMR (400 MHz, DMSO, TMS) δH:
8.41 (s, 1H, C=C–H). 8.14–8.17 (m, 2H, Harom). 7.44–7.48 (m, 2H, Harom), 4.33
(q, JH–H =7.2 Hz, 2H, CH2); 1.32 (t, JH–H =7.1 Hz, 3H, CO2CH2CH3); 13C NMR
(100.6 MHz, DMSO, TMS) δC: 166.40 (C=C(CN)). 163.88 (C=O); 128.56–134.20
(6×Carom); 116.01 (CN); 102.75 (C=C(CN)); 62.84 (OCH2–CH3); 14.43 (O–CH2–
CH3); IR (νmax/cm−1): 1585 (C=C), 1714 (C=O), 2226 (CN).
2‑Cyano‑3‑thiophen‑2‑yl‑acrylic acid ethyl ester 2e Using of thiophene-2-carbalde-
hyde (1.12 g, 10 mmol), ethyl cyanoacetate (1.13 g, 10 mmol) and ammonium ace-
tate (0.77 g, 10 mmol), it was obtained 2e. as white solid (1.75; 85%), Rf =0.32
1
(AcOEt/Cyclohexane 75:25), mp 1159 °C. H NMR (300.13 MHz, CDCl3, TMS)
δH: 8.33 (s, 1H, C=C–H). 7.77–7.83 (dd, 2H, JH–H =7.2 Hz, Harom); 7.20–7.25 (m,
1H, Harom), 4.30 (q, JH–H =7.1 Hz, 2H, CO2CH2CH3); 1.32 (t, JH–H =7.1 Hz, 3H,
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
CO2CH2CH3); 13C NMR (75.47 MHz, CDCl3, TMS) δC: 162.71 (C=C(CN)). 146.71
(C=O); 128.65–137.21 (6×Carom); 115.76 (CN); 99.35 (C=C(CN)); 62.59 (OCH2–
CH3); 14.23 (O–CH2–CH3); IR (νmax/cm−1): 1560 (C=C), 1625 (C=O), 2220 (CN).
General procedure for the preparation of 2f–j
An equimolar mixture of aldehydes 1a–e (1 mmol) and (1 mmol) of cyanoaceta-
mide in the presence of ethanol (10 ml) as a solvent was steered under refux for
1–2 h. After completion of reaction, a white crystalline precipitate was formed, then
was fltered and washed several times with diethyl ether and crystallized in absolute
ethanol to give pure product.
2‑Cyano‑3‑phenyl‑acrylamide 2f Using of benzaldehyde (1.20 g, 10 mmol) and
cyanoacetamide (0.84 g, 10 mmol), it was obtained 2f. Yield: (1.37 mg; 80%),
as white solid, Rf =0.41 (AcOEt/Cyclohexane 9.5:0.5), mp 141 °C. 1H NMR
(300.13 MHz, CDCl3, TMS) δH: 8.39 (s, 1H, C=C–H). 7.95–8.05 (m, 2H, Harom).
7.47–7.65 (m, 3H, Harom), 6.24 (d, 2H, NH2); 13C NMR (75.47 MHz, CDCl3, TMS)
δC: 162.17 (C=C(CN)). 154.09 (C=O); 129.34–133.14 (6×Carom); 117.06 (CN);
103.19 (C=C(CN)); IR (νmax/cm−1): 1575 (C=C), 1706 (C=O), 2221 (CN).
3‑(3‑Chloro‑phenyl)‑2‑cyano‑acrylamid 2g Using of 3′-chlorobenzaldehyde (1.40 g,
10 mmol) and cyanoacetamide (0.84 g, 10 mmol), it was obtained 2 g. As white
1
solid, mp (1.54 mg; 75%), Rf =0.39 (AcOEt/Cyclohexane 9.5:0.5), mp: 156 °C. H
NMR (400 MHz, DMSO, TMS) δH: 8.18 (s, 1H, C=C–H). 7.97 (s, 1H, Harom) 7.89
(d, 1H, JH–H =7.6 Hz, Harom); 7.88 (d, 2H, NH2); 7.59–7.66 (m, 2H, Harom), 13C
NMR (75.47 MHz, DMSO, TMS) δC: 162.75 (C=C(CN)). 149.45 (C=O); 128.87–
134.48 (6×Carom); 116.50 (CN); 108.85(C=C(CN)); IR (νmax/cm−1): 1589 (C=C),
1688 (C=O), 2210 (CN), 3472(NH2).
2‑Cyano‑3‑(2, 4‑dichloro‑phenyl)‑acrylamide 2h Using 3,4-dichlorobenzaldehyde
(1.75 g, 10 mmol) and cyanoacetamide (0.84 g, 10 mmol), it was obtained 2 h. as
white solid (1.97 mg, 82%), Rf =0.37 (AcOEt/Cyclohexane 9.5:0.5), mp 180 °C. 1H
NMR (400 MHz, DMSO, TMS) δH: 8.29 (s, 1H, C=C–H). 8.01 (d, J=8.5 Hz, 1H;
Harom); 7.95 (d, 2H, NH2);), 7.87 (d, 1H; J=8.5 Hz, Harom) 7.65–7.68 (m, 1H, Harom);
13C NMR (100.6 MHz, DMSO, TMS) δC: 162.06 (C=C(CN)). 146.32 (C=O);
128.56–137.42 (6×Carom); 115.80 (CN); 111.90 (C=C(CN)); IR (νmax/cm−1): 1605
(C=C), 1711 (C=O), 2229 (CN), 3392(NH2).
2‑Cyano‑3‑(4‑fuoro‑phenyl)‑acrylamide 2i Using 4-fuorobenzaldehyde (1.06 g,
10 mmol) and cyanoacetamide (0.84 g, 10 mmol), it was obtained 2i. as white solid
1
(1.71 mg; 90%), Rf =0.36 (AcOEt/Cyclohexane 9.5:0.5), mp 171 °C. H NMR
(400 MHz, DMSO, TMS) δH: 8.20 (s, 1H, C=C–H). 8.08–7.99 (m, 2H, Harom). 7.83
(d, 2H, NH2); 7.41–7.46 (m, 2H, Harom), 13C NMR (100.6 MHz, DMSO, TMS) δC:
165.75 (C=C(CN)). 163.24 (C=O); 129.07–149.83 (6×Carom); 116.81 (CN); 106.82
(C=C(CN)); IR (νmax/cm−1): 1589 (C=C), 1689 (C=O), 2210 (CN), 3389(NH2).
1 3

N. Mehiaoui et al.
2‑Cyano‑3‑thiophen‑2‑yl‑acrylamide 2j Using Thiophene-2-carbaldehyde (1.12 g,
10 mmol) and cyanoacetamide (0.84 g, 10 mmol), it was obtained 2j. as brown
solid (1.49 mg; 84%), Rf =0.34 (AcOEt/Cyclohexane 9.5:0.5), mp 159 °C. 1H NMR
(400 MHz, DMSO, TMS) δH: 8.94 (s, 1H, C=C–H). 8.61 (s, 1H, Harom); 8.10–8.13
(m, 1H, Harom), 7.52 (s, 1H, Harom); 6.99 (d, 2H, NH2); 13C NMR (100.6 MHz,
DMSO, TMS) δC: 125.07(C=C(CN)). 111.91 (C=O); 111.03–79.79 (6×Carom);
76.65 (CN); 61.98 (C=C(CN)); IR (νmax/cm−1): 1575 (C=C), 1696 (C=O), 2207
(CN), 3467 (NH2).
General procedure for synthesis of compounds (4a–j)
(a) Synthesis of compounds (4a–e) using ethylacetoacetate:
A mixture of 2a–j (10 mmol), ethylacetoacetate (10 mmol), and ammonium acetate
(10 mmol) with catalytic amount of Au (1%) Co (1%)/TiO2 in the presence of etha-
nol as a solvent was heated at refux for 30 min. After cooling, the reaction mixture
was diluted with dichloromethane (3×10 ml) and fltered to remove the catalyst.
Then 5 ml of water was added, the combined organic extracts were further washed
with water and dried over MgSO4. Finally, the solvent was removed under vac-
uum, and the resulting crude product was purifed by column chromatography over
60–120 mesh silica gel [ethyl acetate/hexane (1:1)].
(b) Synthesis of compounds (4a–e) using cyanoacetamide:
A mixture of 2a–e (10 mmol), cyanoacetamide (10 mmol) and ammonium acetate
(10 mmol) and catalytic amount of Au (1%) Co (1%)/TiO2 in the presence of ethanol
as a solvent were heated at refux for 30 min. After cooling, the reaction mixture was
diluted with dichloromethane (3×10 ml) and fltered to remove the catalyst. Then
5 ml of water was added, the combined organic extracts were further washed with
water and dried over MgSO4. Finally, the solvent was removed under vacuum, and
the resulting crude product was purifed by column chromatography over 60–120
mesh silica gel [ethyl acetate/hexane (1:1)].
5‑Cyano‑2‑methyl‑6‑oxo‑4‑phenyl‑1, 2, 3,6‑tetrahydro‑pyridine‑3‑carboxylic acid
ethyl ester 4a
•
•
Using 2-Cyano-3-phenyl-acrylamide (2a) yield of products 4a (47%)
Using 2-Cyano-3-phenyl-acrylic acid ethyl ester (2f) yield of products 4a (58%)
White solid, Rf =0.30 (AcOEt/Cyclohexane 7:3), mp 254 °C. 1H NMR (400.13 MHz,
DMSO, TMS) δH: 13.00 (s, 1H, NH). 7.44–7.52 (m, 3H, Harom); 7.33–7.40 (m, 2H,
Harom); 3.81 (q, JH–H =7.1 Hz, 2H, CH2–CH3); 2.41 (s, 3H, –C=C–CH3); 0.70 (t,
JH–H =7.1 Hz, 3H, CH2–CH3); 13C NMR (100.61 MHz, DMSO, TMS) δC: 165.37
(CO2Et). 160.27 (C=O); 159.12 (C=C(CN)); 153.62 ((CO2Et)C=C(CH3); 136.439
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
((CO2Et) C=C(CH3)); 115.86–129.86(6×Carom); 112.52 (CN); 101.09 (C=C(CN));
61.35 (OCH2–CH3); 18.67 (OCH2–CH3); 13.54 (C=C–CH3); IR (νmax/cm−1): 1580
(C=C), 1650 (C=O), 1706 (C=O), 2221 (CN). Anal. Calcd. for C16H16N2O3: C
68.07, H 5.00, N 9.92. Found: C 67.34, H 4.99, N 10.97.
4‑(3‑Chloro‑phenyl)‑5‑cyano‑2‑methyl‑6‑oxo‑1,2,3,6‑tetrahydro‑pyridine‑3‑carbox‑
ylic acid ethyl ester 4b
•
•
Using 3-(3-Chloro-phenyl)-2-cyano-acrylamide (2b) yield of products 4b (45%)
Using 3-(3-Chloro-phenyl)-2-cyano-acrylic acid ethyl ester (2 g) yield of prod-
ucts 4b (62%)
1
White solid, Rf =0.32 (AcOEt/Cyclohexane 7:3), mp 242 °C. H NMR (400 MHz,
DMSO, TMS) δH: 13.04 (s, 1H, NH). 7.51–7.57 (m, 2H, Harom); 7.41–7.42 (m, 1H,
Harom); 7.28–7.31 (m, 1H, Harom); 3.86 (q, JH–H =7.1 Hz, 2H, CH2–CH3); 2.42 (s, 3H,
–C=C–CH3); 0.77 (t, JH–H =7.1 Hz, 3H, CH2–CH3); 13C NMR (100.6 MHz, DMSO,
TMS) δC: 165.00 (CO2Et). 160.05 (C=O); 158.33 (C=C(CN)); 154.31 ((CO2Et)
C=C(CH3); 138.46 ((CO2Et)C=C(CH3)); 115.61–133.59 (6×Carom); 112.04 (CN);
101.46 (C=C(CN)); 61.38 (OCH2–CH3); 18.87 (OCH2–CH3); 13.60 (C=C–CH3);
IR nmax cm−1: 1590 (C=C); 1641(C=O); 1707(C=O); 2235(CN). Anal. Calcd. for
C16H15ClN2O3: C 60.67, H 4.14, N 8.84. Found: C 61.62, H 4.23, N 8.71.
5‑Cyano‑4‑(2,4‑dichloro‑phenyl)‑2‑methyl‑6‑oxo‑1,2,3,6‑tetrahydro‑pyridine‑3‑car‑
boxylic acid ethyl ester 4c
•
•
Using 2-Cyano-3-(2,4-dichloro-phenyl)-acrylamide (2c) yield of product 4c
(50%)
Using 2-Cyano-3-(2,4-dichloro-phenyl)-acrylic acid ethyl ester (2 h) yield of
product 4c (51%)
1
White solid, Rf =0.37 (AcOEt/Cyclohexane 7:3), mp 218 °C. H NMR (400 MHz,
CDCl3, TMS) δH: 13.57 (s, 1H, NH). 7.51–7.57 (m, 2H, Harom); 7.39–7.42 (m,
2H, Harom); 7.20–7.28 (m, 1H, Harom); 4.03 (q, JH–H =7.1 Hz, 2H, CH2CH3);
2.69 (s, 3H, –C=C–CH3); 0.96 (t, JH–H =7.1 Hz, 3H, CH2–CH3); 13C NMR
(100.6 MHz, CDCl3,TMS) δC: 163.79 (CO2Et). 162.09 (C=O); 158.21 (C=C(CN));
154.61((CO2Et)C=C(CH3); 136.38((CO2Et)C=C(CH3)); 113.61–133.59 (6×Carom);
113.47 (CN); 103.35(C=C(CN));); 61.77 (OCH2–CH3); 19.93 (OCH2–CH3), 13.42
(C=C–CH3); IR nmax cm−1: 1560 (C=C); 1635(C=O); 1707(C=O); 2225(CN); 3446
(NH). Anal. Calcd. for C16H14Cl2N2O2: C 54.41, H 4.23, N 7.93. Found: C 54.34, H
4.77, N 8.71.
5‑Cyano‑4‑(4‑fuoro‑phenyl)‑2‑methyl‑6‑oxo‑1,2,3,6‑tetrahydro‑pyridine‑3‑carbox‑
ylic acid ethyl ester 4d
•
Using 2-Cyano-3-(4-fuoro-phenyl)-acrylamide (2d) yield of product 4d (64%)
1 3

N. Mehiaoui et al.
•
Using 2-Cyano-3-(4-fuoro-phenyl)-acrylic acid ethyl ester (2i) yield of product
4d (49%)
White solid, Rf =0.33 (AcOEt/Cyclohexane 7:3),, mp 222–224 °C. 1H NMR
(400 MHz, DMSO, TMS) δH: 12.06 (s, 1H, NH), 7.35–7.39 (m, 4H, Harom);
3.86 (q, 2H, JH–H =7.1 Hz, CH2–CH3); 2.41 (s, 3H, –C=C–CH3); 0.79 (t, 3H,
JH–H =7.1 Hz,CH2–CH3); 13C NMR (100.6 MHz, DMSO, TMS) δC: 165.25
(CO2Et), 161.93 (C=O); 158.97 (C=C(CN)); 153.82 ((CO2Et)C=C(CH3); 132.78
((CO2Et) C=C(CH3)); 115.79–130.19 (6×Carom); 112.49 (CN); 101.38 (C=C(CN));
61.40 (OCH2–CH3); 18.75 (OCH2–CH3); 13.64 (C=C–CH3); IR (νmax/cm−1): 1557
(C=C); 1605(C=O); 1711(C=O); 2209(CN); Anal. Calcd. for C16H15FN2O3: C
64.00, H 4.36, N 9.3. Found: C 64.66, H 4.44, N 8.99.
5‑Cyano‑2‑methyl‑6‑oxo‑4‑thiophen‑2‑yl‑1,6‑dihydro‑pyridine‑3‑carboxylic acid
ethyl ester 4e
•
•
Using 2-Cyano-3-thiophen-2-yl-acrylamide (2e) yield of product 4e (62%)
Using 2-Cyano-3-thiophen-2-yl-acrylic acid ethyl ester (2j) yield of product
4e(43%)
White solid (1.78 mg, 62%-2e)/(1.23 mg, 43%-2j), Rf =0.33 (AcOEt/Cyclohex-
1
ane 7:3), mp 200 °C. H NMR (400 MHz, DMSO, TMS) δH: 9.39 (s, 1H, NH),
7.98 (s, 1H, Harom); 7.24 (s, 1H, Harom); 6.77 (s, 1H, Harom); 4.11 (q, JH–H =7.1 Hz,
2H, CH2–CH3); 2.35 (s, 3H, –C=C–CH3), 1.06 (t, JH–H =7.1 Hz, 3H, CH2–CH3);
13C NMR (100.6 MHz, DMSO, TMS) δC: 165.82 (CO2Et). 160.56 (C=O); 153.67
(C=C(CN));
153.28
((CO2Et)C=C(CH3);
132.78
((CO2Et)C=C(CH3));
116.06–146.81 (6×Carom); 113.10 (CN); 99.39(C=C(CN)); 61.88 (OCH2–CH3);
18.44 (OCH2–CH3); 14.22 (C=C–CH3); IR (νmax/cm−1): 1590 (C=C); 1605(C=O);
1635(C=O); 2220(CN); 3287 (NH). Anal. Calcd. for C14H14N2O4: C 61.31, H 5.14,
N 10.21. Found: C 60.03, H 4.99, N 10.09.
Results and discussion
In the present protocol as exhibited in Table 1 the synthesis of substituted 3-cyano-
2-pyridones derivatives started by the preparation of α, β-unsaturated compounds
(Michael acceptors) 2a–j from Knoevenagel condensation of aldehydes with actif
methylene compounds (cyanoacetamide or ethyl cyanoacetate), obtained in good
yields (Table 1). These intermediates 2a–j are useful starting materials in the con-
struction of a variety of polyfunctional heterocyclic compounds [42].
The second step to give 2-pyridones derivatives is a Michael addition of α,
β-unsaturated compounds with ethylacetoacetate consequent by an intramo-
lecular ring closure. Varieties of diferent reaction conditions were tested in an
attempt to optimize the yields, time of reaction. The study was initiated by using α,
β-unsaturated compounds 2a, ethylacetoacetate and ammonium acetate as models
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
Table 1 Synthesis of α, β-unsaturated compounds derivatives 2a–j
H
R
CN
Y
O
Y
AcONH4
EtOH, rt
R
H
CN
1
2a-j
2
Comp.
R
Y
Time (min)
Yields (%)
2a
2b
2c
2d
2e
2f
C6H5–
45
30
25
60
34
74
65
54
60
46
47
45
50
62
64
47
45
50
62
64
3-Cl–C6H4–
2,4-Cl–C6H3
4-F-C6H4–
C4H4O–
–CO2Et
C6H5–
2 g
2 h
2i
3-Cl–C6H4–
2,4-Cl–C6H3–
4-F-C6H4–
C4H4O–
–CONH2
2j
substrates and they were heated at 80 °C without any added of catalyst or solvent
(scheme 2). After 24 h only trace amount of the product 4a (10%).
Hoping to increase the yield of reaction. Initially, we focused systematic evalua-
tion of diferent catalysts for the model reaction of α, β-unsaturated compounds (2a)
and ethylacetoacetate (3) in the presence of AcONH4 at 80 °C (scheme 2). We have
applied a wide range of catalysts including: l-proline, Al2O3, CH3COOH, ZnCl2 and
Au (1%) Co (1%)/TiO2 as the catalysts in 25 mol % interesting result was obtained
with Au(1%)Co(1%)/TiO2 as the catalyst (Table 2).
We then tried to screen the reaction in the various organic solvents in order to
optimize the reaction conditions using Au (1%) Co (1%)/TiO2 as catalysts system.
We tested the efect of diferent solvents. The reaction carried out using EtOH,
dichloromethane, chloroform, DMF and acetonitrile. The synthesis of 4a, from
Scheme 2 Synthesis of pyridone 4a
1 3

N. Mehiaoui et al.
Table 2 Synthesis of 3-cyano-2-pyridones 4a
Ph
H
CN
Y
CO2Et
EtO2C
H3C
CN
+
catalyst
80°C
AcONH4
Ph
COCH3
N
H
O
3
2a
4a
Exp.
Catalyst
Y
Time (min)
Yields (%)
1
2
3
4
5
6
7
8
9
l-proline
Al2O3
CH3COOH
ZnCl2
Au (1%) Co (1%)/TiO2
l-proline
Al2O3
CH3COOH
ZnCl2
Au (1%) Co (1%)/TiO2
48
19
48
50
25
48
50
50
55
25
20
19
24
31
52
22
15
27
33
60
–CO2Et
–CONH2
10
α, β-unsaturated compounds 2a, ethylacetoacetate 3 and ammonium acetate were
heated at 80 °C. As shown in (Table 3), the best results in terms of yield were
obtained with ethanol as a suitable solvent for this reaction.
Based on the experimental results, a probable mechanism for the formation
of 3-cyano-2-pyridones was described in (Scheme 3). First, we assumed that our
catalyst is an efective catalyst to form the intermediate I from ethylacetoacetate
and ammounium acetate. Then, the condensation reaction between imine anion
and intermediate II with intercyclization was realized to form the 3-cyano-2-pyri-
done structure.
Then, we checked the role of the catalyst amount on the synthesis of 4a.
As can be seen in (Fig. 2). Our optimization studies revealed that the yield
increased smoothly with catalyst amount to 5 mol % and then was increased up
to 30 mol % after that the yield is decreased. So the best catalytic amount of this
reaction is 30 mol %.
Under the optimized reaction condition, the generality of reaction was tested by
the use of α, β-unsaturated compounds 2a–e. Two methods were found to be facile
to produce diferent 3-cyano-2-pyridones derivatives 4a–e in good yield (Table 4),
at the frst time using products 2a–e (Y=–CO2Et) and in another time using 2f–g
(Y=–CONH2), with equimolar amount of ethylacetoacetate and ammonium acetate
with 30% mol of Au (1%)Co(1%)/TiO2 in refux of ethanol for 30 min. This method-
ology converted the substrates to their corresponding products 4a–e in high yields,
simplicity of isolation of product and short reaction time.
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
Table 3 Solvent efect in the synthesis of pyridone 4a
Ph
H
CN
Y
CO2Et
EtO2C
CN
O
+
AcONH4
solvent
Ph
COCH3
Au(1%) Co(1%)/TiO2 H3C
N
H
80°C
3
2a
4a
Exp.
Catalyst
Y
Yields (%)
1
2
3
4
5
6
7
8
9
10
EtOH
CH2Cl2
CHCl3
DMF
Acetonitrile
EtOH
CH2Cl2
CHCl3
DMF
55
38
40
27
30
59
29
42
30
25
–CO2Et
–CONH2
Acetonitrile
Scheme 3 Proposed mechanism to prepare 3-cyano-2-pyridones
1 3

N. Mehiaoui et al.
Fig. 2 The efect of the catalyst
amount for the synthesis of
2-pyridones 4a
Catalyst amount (mol %)
Table 4 Synthesis of 3-cyano-2-pyridones 4a–e
R
H
R
CN
Y
CO2Et
EtO2C
H3C
CN
O
+
AcONH4
EtOH
COCH3
Au(1%) Co(1%)/TiO2
reflux,30 min
N
H
3
2a-e
4a-e
Entry
Ar
Y
Products
Yields (%)
1
2
3
4
5
6
7
8
9
C6H5–
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
47
45
50
64
62
58
62
51
49
43
3-Cl–C6H4–
2,4-Cl–C6H3–
4-F–C6H4–
C4H4O–
–CO2Et
C6H5–
3-Cl–C6H4–
2,4-Cl–C6H3–
4-F-C6H4–
C4H4O–
–CONH2
10
The Au (1%)Co(1%)/TiO2 as catalytic system was investigated for the synthesis
of 3-yano-2-pyridones 4d from a one-pot reaction of 2d with equimolar amount
of ethylacetoacetate and ammonium acetate with 30% mol of Au–Co/TiO2 in
refux of ethanol under the same previous reaction conditions for the synthesis
of pyridones 4a–e. the catalyst can be recycled many time without any change in
catalytic activity, can be active at least six recycle runs as shown, (scheme 4).
Herein, after the frst catalytic cycle, the reaction mixture was diluted with
chloroform then fltered and the catalyst was separated and washed with etha-
nol, dried at 120 °C for 1 h and used for the next process in the same reaction
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
F
NC
EtO2C
CN
O
CO2Et
EtOH
CO2Et
+
AcONH4
F
Au(1%) Co(1%)/TiO2
reflux
COCH3
H
H3C
N
H
3
4e
2e
Scheme 4 Synthesis of product 4a with reusability of catalyst
conditions. The catalyst was reused six times, without any signifcant loss of
activity (Fig. 3).
The catalyst Au (1%) Co(1%)/TiO2 was prepared by Deposition–Precipitation
with Urea (DPU). The DPU method was already described [48]. In the frst, the
catalyst 1%Au–1%Co/TiO2 was characterized by atomic absorption spectroscopy
analysis to identify the real metal content. The catalysts have a deposit amount of
gold and cobalt very close to the theoretical value with 0.9% and 0.8%, respectively,
which confrms that the DPU method is efective for the gold and cobalt deposition.
The sample was characterized by XRD. The catalyst Au–Co/TiO2 is compared with
the TiO2 in (Fig. 4) All the samples present peaks which correspond to the TiO2 dif-
fractions planes [49]. No difraction corresponding to gold or cobalt was observed
the catalyst. This may be attributed to the good dispersion of gold and cobalt on the
support.
The Fig. 5 shows UV visible spectra of catalyst and the TiO2 support. In sam-
ples, the catalyst present bands characteristic to TiO2 support at 212 nm, 269 nm and
350 nm. The frst characteristic to Ti4+ cations in tetrahedral environnement [50].
The second band attributed to Ti4+ cations in octahedral environment [50, 51]. The
anatas phase gives a band in the range of 350 nm [52].
Fig. 3 Recyclability study of
Au (1%) Co (1%)/TiO2 catalyst
(30 mol%) with 4d
Recyclability of catalyst
64
63
63
61
58
56
Number of Runs
1 3

N. Mehiaoui et al.
Fig. 4 XRD patterns of TiO2 (a), Au–Co/TiO2 and also in line 4
Fig. 5 DRUV–Vis spectra of Au–Co/TiO2
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
Fig. 6 The SEM image (a) and the EDS analysis (b) of Au–Co/TiO2
After deconvolution, in the visible party, the catalyst present a resonance plas-
mon band characteristic to metallic nanoparticle Au0 [53] at 560 nm and two
bands attributed to cobalt Co3+ and Co2+ species [54–56].
The energy-dispersive X-ray spectroscopy is presented in Fig. 4, the elemental
map images confrmed the presence of TiO2 of the support and picks characterized
of gold and cobalt metals (Fig. 4). The SEM image (Fig. 6) shows only the particles
of TiO2 support with homogenous morphologies.
The characterization by TEM of catalyst (Fig. 7) reveals the presence of separated
gold nanoparticles with dark particles and very small cobalt particles. The particles
were uniformly distributed on the TiO2 support. The particles size histogram indi-
cates the presence of gold particle sizes of 1–7 nm with an average size of 2.88 nm.
Conclusion
In summary, we have described an efcient procedure to prepare a series of 3-cyano-
2-pyridones derivatives using new nanocatalyst system in good yields. The proposed
strategy is simple with short reaction time, easy work-up and reusability of the nano-
catalyst. The last advantages will make this procedure useful. Spectral and analytical
data of the newly synthesized compounds were all in good agreement.
1 3

N. Mehiaoui et al.
Fig. 7 TEM image of Au (1%) Co(1%)/TiO2
Acknowledgments The authors wish to thank Directorate General for Scientifc Research and Techno-
logical Development (DGRSDT) and the University of Tlemcen for the fnancial support.
References
1. K. Hirano, M. Miura, Chem. Sci. 9, 22 (2018)
2. S. Hibi, K. Ueno, S. Nagato, K. Kawano, K. Ito, Y. Norimine, O. Takenaka, T. Hanada, M. Yonaga,
J. Med. Chem. 55, 10584 (2012)
3. T. Akihisa, S. Yokokawa, E. Ogihara, M. Matsumoto, J. Zhang, T. Kikuchi, K. Koike, M. Abe,
Chem. Biodivers. 8, 121 (2017)
4. P. Hajek, H. McRobbie, K. Myers, Thorax 68, 1037 (2013)
5. P. Storck, A. Aubertin, D.S. Grierson, Tetrahedron Lett. 46, 2919 (2005)
6. W. Chen, P. Zhan, D. Rai, E.D. Clercq, C. Pannecouque, Bioorg. Med. Chem. 6, 1863 (2014)
7. N.M. Khalifa, M.A. Al-Omar, A.E. Amr, M.E. Haiba, Int. J. Biol. Macromol. 54, 5 (2013)
8. I. Collins, C. Moyes, W. Davey, M. Rowley, E. Bromidge, I. Quirk, J. Atack, R. McKernan, S.A.
Thompson, K. Waford, G. Dawson, A. Pike, J. Med. Chem. 45, 1887 (2002)
9. N.M. Khalifa, M.E. Haiba, M.M. Taha, M.A. Al-Omar, Russ. J. Gen. Chem. 89, 319 (2019)
10. V. Aberg, F. Norman, E. Chorell, A. Westermark, A. Olofsson, A.E. Sauer-Eriksson, F. Almqvist,
Org. Biomol. Chem. 3, 2817 (2005)
11. J.A. Spicer, G.W. Rewcastle, M.D. Kaufman, S.L. Black, M.S. Plummer, W.A. Denny, J. Quin, A.B.
Shahripour, S.D. Barrett, C.E.W. Jared, J. Med. Chem. 21, 5090 (2007)
12. A.S. Alimmari, A.D. Marinković, D. Mijin, N.V. Valentic, N. Todorović, G. Uscumlic, J. Serb.
Chem. Soc. 75, 1019 (2010)
13. F. Karcı, F. Karcı, Dyes Pigm. 76, 147 (2008)
1 3

Novel synthesis of 3-cyano-2-pyridones derivatives catalyzed…
14. D. Mijin, G. Uscumlic, N. Perisic-Janjic, I. Trkulja, M. Radetić, P. Jovancic, J. Serb. Chem. Soc. 71,
435 (2006)
15. J.M. Rawson, R.E.P. Winpenny, Coord. Chem. Rev. 139, 313 (1995)
16. P. Böger, J. Pestic. Sci. 21, 473 (1996)
17. V.A. Chebanov, S.M. Desenko, T.W. Gurley, Azaheterocycles Based on α, β-Unsaturated (Springer,
Berlin, 2008)
18. M. Furukawa, M. Makino, T. Uchiyama, K. Ishimi, Y. Ichinohe, Y. Fujimoto, Phytochemistry 59,
767 (2002)
19. S. Kagabu, H. Matsuno, J. Agric. Food Chem. 45, 276 (1997)
20. V. Litvinov, S. Krivokolysko, V. Dyachenko, Chem. Heterocycl. Compd. 35, 509 (1999)
21. S.A. Yermolayev, N.Y. Gorobets, S.M. Desenko, J. Comb. Chem. 11, 44 (2009)
22. T.J. Donohoe, L.P. Fishlock, P.A. Procopiou, Org. Lett. 10, 285 (2008)
23. M.I. Savchu, Y.K. Shtaitz, D.S. Kopchuk, Chem. Heterocycl. Comp. 55, 985 (2019)
24. T.K. Tanmay, S.K. Ajarul, M. Kundu, D. Tayde, U. Khamrai, D.K. Maitin, J. Organ. Chem. 13,
8563 (2020)
25. S. Babaee, M. Zarei, H. Sepehrmansourie, M.A. Zolfgo, S. Rostamnia, ACS Omega 12, 6240
(2020)
26. T.J. Donohoe, J.F. Bower, J.A. Basutto, L.P. Fishlock, P.A. Procopiou, C.K. Callens, Tetrahedron
65, 8969 (2009)
27. A.M. Serry, S. Luik, S. Laufer, A.H. Abadi, J. Comb. Chem. 12, 559 (2010)
28. P. Singh, P. Sharma, K. Bisetty, M.P. Mahajan, Tetrahedron 65, 8478 (2009)
29. I. Yavari, S. Souri, Synlett 19, 2969 (2007)
30. Y. Zhang, B.M. Loertscher, S.L. Castle, Tetrahedron 65, 6584 (2009)
31. N.Y. Gorobets, B.H. Yousef, F. Belaj, C.O. Kappe, Tetrahedron 60, 8633 (2004)
32. T. Kondo, M. Nomura, Y. Ura, K. Wada, T. Mitsudo, Tetrahedron Lett. 47, 7107 (2006)
33. I. Yavari, M.J. Bayat, Synlett 15, 2293 (2010)
34. N. Poomathi, P. Perumal, S. Ramakrishna, Green Chem. 19, 2524 (2017)
35. L. Ackermann, A.V. Lygin, N. Hofmann, Organ. Lett. 13, 3278 (2011)
36. R. Kaur, J. Bariwal, L.G. Voskressensky, Chem. Heterocycl. Compd. 54, 241 (2018)
37. G. Xaolong, W. Luyao, H. Ging, Z. Mengmeng, RSC Adv. 8, 22259 (2018)
38. S.F. Hojati, A. Amiri, S. Mohamadi, Res. Chem. Intermed. 44, 2275 (2018)
39. S. Jannati, A.A. Esmaeili, Res. Chem. Intermed. 43, 6817 (2017)
40. J. Safaei-Ghomi, M. Asgari-Keirabadi, B. Khojastehbakht-Koopaei, Res. Chem. Intermed. 42, 827
(2016)
41. A.G.A. Elagamey, F.M.A.A. El-Taweel, M.N.M. Khodeir, M.H. Elnagdi, Bull. Chem. Soc. Jpn. 66,
464 (1993)
42. F. Nouali, Z. Kibou, B. Boukoussa, Res. Chem. Intermed. 46, 3179 (2020)
43. Z. Kibou, N. Cheikh, D. Villemin, N. Choukchou-Braham, J. Mater. Environ. Sci. 7, 3061 (2016)
44. A. Hakiki, B. Boukoussa, Z. Kibou, I. Terrab, K. Ghomari, N. Choukchou-Braham, R. Hamacha, A.
Bengueddach, A. Azzouz, Thermochim. Acta 662, 108 (2019)
45. Z. Kibou, D. Villemin, J.-F. Lohier, N. Cheikh, N. Bar, N. Choukchou-Braham, Tetrahedron 72,
1653 (2016)
46. Z. Kibou, N. Cheikh, N. Choukchou-Braham, B. Mostefa-Kara, M. Benabdellah, D. Villemin, Sci.
Study Res. Chem. Chem. Eng. Biotechnol. Food Ind. 2, 121 (2011)
47. A. Medjdoub, F. Belhadj, A. Saidi-Merzouk, Y. Baba Hamed, Z. Kibou, N. Choukchou-Braham, H.
Merzouk, Chem. Pap. 74, 903 (2019)
48. A. Berrichi, R. Bachir, S. Bedrane, N. Choukchou-Braham, K. Belkacemi, Res. Chem. Intermed.
45, 3481 (2019)
49. N. Dragan, M. Crisan, M. Raileanu, D. Crişan, A. Ianculescu, P. Oancea, S. SomAcescu, L. Todan,
N. Stănică, B. Vasile, Ceram. Int. 40, 12273 (2014)
50. M. Cozzolino, M. Di Serio, R. Tesser, E. Santacesaria, Appl. Catal. A 325, 256 (2007)
51. N. Ameur, S. Bedrane, R. Bachir, A. Choukchou-Braham, J. Mol. Catal. A Chem. 374, 1 (2013)
52. E. Sacaliuc, A.M. Beale, B.M. Weckhuysen, T.A. Nijhuis, J. Catal. 248, 235 (2007)
53. H. Nur, Mater. Sci. Eng. B 133, 49 (2006)
54. K.R. Souza, A.F.F. De Lima, F.F. De Sousa, L.G. Appel, Appl. Catal. A 340, 133 (2008)
55. R. Zanella, S. Giorgio, C.H. Shin, C.R. Henry, C. Louis, J. Catal. 222, 357 (2004)
56. S.K. Ghosh, T. Pal, Chem. Rev. 107, 4797 (2007)
1 3

N. Mehiaoui et al.
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published
maps and institutional afliations.
1 3