A microwave approach to the synthesis of certain 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones

Article abstract of DOI:10.2298/JSC130718145M

A study of the synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano- 2-pyridones from ethyl 2-cyano-3-(substituted phenyl) acrylates and acetophenone is presented. The 2-pyridones were obtained using conventional as well as microwave synthesis under solvent and solvent-free conditions in domestic and laboratory microwave ovens. The structure of the obtained pyridones was confirmed by m.p., FT-IR, NMR and UV data.

Full text of DOI:10.2298/JSC130718145M

J. Serb. Chem. Soc. 79 (7) 759–765 (2014)
JSCS–4624
UDC 537–962:547.391.1+547.551.43+
547.828:57–188
Original scientific paper
A microwave approach to the synthesis of certain 4-(substituted
phenyl)-6-phenyl-3-cyano-2-pyridones
1#
1
#
1#
*
ALEKSANDAR MARINKOVIĆ , DUŠAN MIJIN , JELENA MIRKOVIĆ ,
VESELIN MASLAK2 and C. OLIVER KAPPE3
1Faculty of Technology and Metallurgy, University of Belgrade, Karnegijeva 4, 11120
Belgrade, Serbia, 2Faculty of Chemistry, University of Belgrade, Studentski trg 12–16, 11000
Belgrade, Serbia and 3Christian Doppler Laboratory for Microwave Chemistry (CDLMC)
and Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstraße 28,
A-8010 Graz, Austria
(Received 18 July, accepted 27 November 2013)
Abstract: A study of the synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-
2-pyridones from ethyl 2-cyano-3-(substituted phenyl) acrylates and aceto-
phenone is presented. The 2-pyridones were obtained using conventional as
well as microwave synthesis under solvent and solvent-free conditions in
domestic and laboratory microwave ovens. The structure of the obtained
pyridones was confirmed by m.p., FT-IR, NMR and UV data.
Keywords: pyridone; acrylate; cyclocondensation reaction; microwave chemis-
try.
INTRODUCTION
It is well known that many naturally occurring and synthetic compounds
containing a 2-pyridone ring system have a broad spectrum of biological acti-
1–3
vity.
Some of them, such as milrinone, amrinone and their analogues are car-
4–7
diotonic agents for the treatment of heart failure.
antitumor, antibacterial and other biological activities.
Other 2-pyridones possess
8,9
10
1,2,11–15
In addition,
derivatives of 3-cyano-2-pyridones are used in the manufacture of dyes, pig-
ments, additives for fuels and lubricants, stabilizers for polymers and varnishes,
2
acid–base indicators and other practically important materials.
3-Cyano-2-pyridones can be obtained using different procedures starting
1,2,16,17
from various initial substrates.
Microwave-assisted chemistry has also
18–23
been used for the synthesis of 2-pyridones and their derivatives.
*Corresponding author. E-mail: kavur@tmf.bg.ac.rs
# Serbian Chemical Society member.
doi: 10.2298/JSC130718145M
759
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760
MARINKOVIĆ et al.
4,6-Diphenyl-3-cyano-2-pyridones (4,6-diaryl-2-oxo-1,2-dihydropyridine-3-
-carbonitriles) can be obtained by cyclization of ethyl cyanoacetate and ketones
24
by ammonium acetate, reaction between 1,3-diaryl-2-propen-1-one and cyano-
25
26
27
acetamide using MeONa, piperidine or DMSO–tert-BuOK, by the reaction
28
of β-aminoenones with substituted acetonitriles, by the reaction of malononit-
rile with acetylenic ketones, and by solid-phase and one-pot synthesis via
three-component cyclocondensation under solvent-free conditions. In addition,
29
30
31
4,6-diphenyl-3-cyano-2-pyridones were prepared by the reaction between 1,3-
-diaryl-2-propen-1-ones and cyanoacetamide using powdered KOH under micro-
32
wave irradiation.
One of the less explored synthesis of 4-(substituted phenyl)-6-phenyl-3-
-cyano-2-pyridones is their synthesis from ethyl 2-cyano-3-(substituted phenyl)
33,34
acrylates (Scheme 1).
X
O
CH3
O
OEt
CN
O
_
CN
+
NH4 CH3COO
X
N
H
EtOH
Scheme 1. Synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones from ethyl
2-cyano-3-(substituted phenyl) acrylates (X = H (1), 4-CH3 (2), 4-OCH3 (3), 4-Cl (4),
4-NO2 (5), 4-Br (6), 3-NO2 (7), 3-Cl (8), 2-NO2 (9)).
In this work, a microwave approach to the synthesis of known 4-(substituted
phenyl)-6-phenyl-3-cyano-2-pyridones from ethyl 2-cyano-3-(substituted phenyl)
acrylates and acetophenone was applied. Solvent and solvent-free reactions were
performed in a modified domestic microwave oven and laboratory microwave
ovens. Low to moderate yields were obtained in relatively short reaction time
using optimized procedures.
RESULTS AND DISCUSSION
In order to study the synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-
-pyridones by condensation of ethyl 2-cyano-3-(substituted phenyl) acrylates
with acetophenone, it was necessary to prepare ethyl 2-cyano-3-(substituted
phenyl) acrylates. These compounds can be easily prepared from substituted
33,34
benzaldehydes and ethyl cyanoacetate, as described elsewhere.
proceed relatively smoothly with good to excellent yields.
The reactions
In the first part of the pyridone synthesis, 4-(substituted phenyl)-6-phenyl-3-
33,34
-cyano-2-pyridones were prepared by conventional methods.
Ethyl 2-cyano-
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PYRIDONE MICROWAVE SYNTHESIS
761
-3-(substituted phenyl) acrylates, acetophenone and ammonium acetate were
heated in ethanol under reflux for 1 h and the obtained results are given in Table
I. The molar ratio of the reactants was ethyl 2-cyano-3-(substituted phenyl)
acrylates, acetophenone and ammonium acetate = 1:1:1.5.
TABLE I. Conventional and microwave synthesis of 4-(substituted phenyl)-6-phenyl-3-
cyano-2-pyridones
Microwave synthesisa
Modified domestic oven, % Microwave synthesis, %
Conventional
synthesis, %
No. Substituent
1
2
3
4
5
6
7
8
9
a
H
35
40
30
32
34
32
34
33
23
20
40
29
16
30b
14c
9c
4-CH3
4-OCH3
4-Cl
4-NO2
4-Br
3-NO2
3-Cl
2-NO2
32c
20c
29c
24c
15c
12c
No product
14
35
26
12
b
c
Biotage – yield of compound 1 = 29 %; 300 W, 5 min; 200 W, 2 min
As can be seen from Table I, the pyridones were obtained in low to moderate
yields, except for the 4-nitro derivative, which could not be obtained by this
procedure. At this moment of the work, it seemed that an improvement in the
isolated yield could be achieved if some other approach were used, such as mic-
rowave synthesis.
In the early days of microwave-assisted organic synthesis, the only possible
way to do the synthesis was to use domestic or modified domestic microwave
ovens. In this work, a microwave oven modified in such a manner to provide
stirring and refluxing of the reaction mixture as described in literature was
35
used. First, an optimization of the synthesis of 3-cyano-4,6-diphenyl-2-pyri-
done was performed. The reactant ratio, power of irradiation and reaction time
were varied. In addition, several solvents were used (ethanol, ethylene glycol and
DMF). The obtained results showed (optimization results not presented) that the
optimal reactant ratio was the same as in the conventional synthesis and that the
solvent-free reaction gave the best yield. It was established that the optimal reac-
tion time was 2 min (several times shorter than for the conventional method) and
using these parameters, the synthesis of the pyridones was performed (Table I).
The solvent-free synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyri-
dones in the modified domestic microwave oven led to similar or slightly better
yields in comparison to conventional procedure. Except for the shorter reaction
time, another advantage of the microwave synthesis was the synthesis of the
4-nitro derivative, which could not be obtained by the conventional approach. On
the other hand, the disadvantages of such a method are the non-uniform heating,
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762
MARINKOVIĆ et al.
36
mixing, and the precise determination of the reaction temperature. In order to
overcome the disadvantages of using modified domestic microwave ovens, syn-
theses in dedicated microwave reactors were performed (MicroSYNTH and Bio-
tage). The reactions were controlled by an IR thermometer. Solvent-free micro-
wave synthesis was used to enable comparison of the results with those obtained
using the domestic microwave oven. Optimization of the synthesis of 3-cyano-
-4,6-diphenyl-2-pyridone synthesis in the MicroSYNTH reactor was performed
by varying the irradiation power and reaction time using the previously estab-
lished ratio of reactants (1:1:1.5). It was found that 5 min and 300 W are optimal
for the reaction, since shorter or longer reaction times and lower or higher irra-
diation power decreased the yield of the pyridone. When these reaction para-
meters were applied to the synthesis of other pyridones, lower yields were
obtained in comparison with those obtained in the modified domestic microwave
oven (Table I).
To overcome all the disadvantages of solvent-free reactions, the synthesis of
3-cyano-4,6-diphenyl-2-pyridone in the Biotage reactor using ethanol as a sol-
vent was optimized. The influence of reactant ratio, temperature and reaction
time on the pyridone yield (HPLC) was studied. A higher concentration of reac-
tants was also used. Even here, low yields were obtained. The highest yield was
obtained at 150 °C after 15 min with the ratio of reactants being 1:1:3. The initial
3
amount of acrylate was 1 mmol and solvent volume was 1 cm . The yield was 29 %.
Moreover, the influence of the structure of the ammonium salt was studied.
Ammonium formate, carbonate and hydrogen carbonate were used. While
ammonium formate gave a slightly lower yield than ammonium acetate, ammo-
nium carbonate gave no yield at all. Ammonium hydrogen carbonate gave much
lower yield then ammonium acetate.
During optimization, it was observed that the starting acrylate was the com-
pound with the highest reactivity present in the reaction mixture. Acetophenone
was much less reactive. Since no influence of the initial concentration of aceto-
phenone was observed on the reaction and since no reaction between aceto-
phenone and ammonium acetate was observed, it seems that the reaction pro-
ceeds initially by ammonia attack on the acrylate followed by the reaction of the
37
formed amide with acetophenone. The low yields could be explained by a pos-
38
sible parallel reaction of the acrylate molecules that might lead to dimerization.
EXPERIMENTAL
Materials
All employed materials were obtained commercially, mostly from Sigma–Aldrich, and
were used without further purification.
Equipment
The IR spectra were recorded on a Bomem MB series FTIR spectrophotometer, in the
1
form of KBr pellets. The H-NMR spectra were recorded as solutions in DMSO-d6 using a
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PYRIDONE MICROWAVE SYNTHESIS
763
Varian Gemini-200 instrument, with tetramethylsilane as the internal standard. The UV
absorption spectra were taken using a Shimadzu 1700 UV–Vis spectrophotometer in 1.00 cm
cells at 25±0.1 °C in ethanol at a concentration of 5×10-5 mol dm-3. The spectral data of the
synthesized compounds together with their melting points are given in the Supplementary
material to this paper.
A Samsung domestic microwave oven was modified as given in the literature35 in order
to provide mixing and refluxing of the reaction mixture. A MicroSYNTH Milestone and a
Biotage Initiator 2.5 EXP were used for the microwave experiments. Analytical HPLC
analysis (Shimadzu LC20) was performed on a C 18 reversed-phase analytical column (150
mm×4.6 mm, particle size 3 mm) using the mobile phases A (water:acetonitrile 90:10 (V/V) +
0.1 % TFA) and B (acetonitrile + 0.1 % TFA) at a flow rate of 0.5 cm3 min-1. The following
gradient was applied: linear increase from 30 to 100 % B in 9 min, hold at 100 % solution B
for 5 min.
Conventional synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones33,34,37
A mixture of ethyl 2-cyano-3-(substituted phenyl) acrylate (0.1 mol), acetophenone (0.1
mol) and ammonium acetate (0.15 mol) in ethanol was heated under reflux for 1 h. After
cooling, the obtained crystals were removed by filtration, washed with diethyl ether and
purified by recrystallization (DMF/ethanol, 1:1).
Microwave synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones in a modified
domestic oven
A mixture of ethyl 2-cyano-3-(substituted phenyl) acrylate (0.1 mol), acetophenone (0.1
mol) and ammonium acetate (0.15 mol) was heated in a domestic microwave oven (100 or
200 W) for 2 minutes. Alternatively, a mixture in the chosen solvent was heated in the
modified domestic microwave oven. After cooling, the obtained crystals were removed by
filtration, washed with diethyl ether and purified by recrystallization (DMF/ethanol, 1:1).
Microwave synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones in the
MicroSYNTH reactor
A mixture of ethyl 2-cyano-3-(substituted phenyl) acrylate (2 mmol), acetophenone (2
mmol) and ammonium acetate (3 mmol) was heated in a microwave reactor in a glass tube (∅
29 mm) equipped with a condenser for 2 to 5 min. After cooling, the obtained crystals were
removed by filtration, washed with diethyl ether and purified by recrystallization (pyri-
dine/ethanol, 1:1).
Microwave synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones in the Biotage
reactor
A mixture of ethyl 2-cyano-3-(substituted phenyl) acrylate (1 mmol), acetophenone
(1 mmol) and ammonium acetate (3 mmol) in ethanol (1 cm3) was heated in a Biotage mic-
rowave reactor for a period of 15 min at 150 °C. The product yield was established by HPLC
analysis at 215 nm.
CONCLUSIONS
The synthesis of 4-(substituted phenyl)-6-phenyl-3-cyano-2-pyridones from
ethyl 2-cyano-3-(substituted phenyl) acrylates and acetophenone using mic-
rowave irradiation showed that the reaction time could be shortened from 60 to 2
min while the isolated yields remained constant. The 4-nitro derivative could be
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764
MARINKOVIĆ et al.
only prepared under microwave irradiation. Solvent-free reactions in comparison
to those run in solvents gave better results.
SUPPLEMENTARY MATERIAL
Melting points and spectral data of the synthesized pyridones are available electronically
from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgments. The authors are grateful to the Ministry of Education, Science and
Technological Development of the Republic of Serbia for financial support (Project No.
172013). D. M. thanks the Austrian Academic Exchange Service for a scholarship and Prof C.
O. Kappe for his support.
И З В О Д
МИКРОТАЛСНИ ПРИСТУП СИНТЕЗИ ОДРЕЂЕНИХ 4-(СУПСТИТУИСАНИХ
ФЕНИЛ)-6-ФЕНИЛ-3-ЦИЈАНО-2-ПИРИДОНА
АЛЕКСАНДАР МАРИНКОВИЋ1, ДУШАН МИЈИН1, ЈЕЛЕНА МИРКОВИЋ1, ВЕСЕЛИН МАСЛАК2
и C. OLIVER KAPPE3
1
Технолошко–металуршки факултет, Универзитет у Београду, Карнегијева 4, 11120 Београд,
2
3
Хемијски факултет, Универзитет у Београду, Студентски трг 3–5, 11000 Београд и Christian
Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens-
University Graz, Heinrichstraße 28, A-8010 Graz, Austria
У оквиру рада приказана је синтеза 4-(супституисаних фенил)-6-фенил-3-цијано-2-
-пиридона полазећи од етил-2-цијано-3-(супституисаних фенил) акрилата и ацетофе-
нона. 2-Пиридони су добијени како у присуству тако и у одсуству растварача користећи
класичну и микроталасну синтезу, у модификованој микроталасној пећници за дома-
ћинство као и у лабораторијском микроталасном реактору. Структура добијених пири-
дона потврђена је температурама топљења, IC, NMR и UV подацима.
(Примљено 18. јула, прихваћено 27 новембра 2013)
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