Synthesis, characterization, and antibacterial activity of novel pyridones

Article abstract of DOI:10.1080/00397911.2013.845902

Novel ethyl 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carboxylate and 4,6-diaryl-3,4-dihydropyridine-2(1H)-one derivatives have been synthesized from the cyclization of adducts of diethylmalonate to chalcones with ammonium acetate. The structures were established on the basis of extensive spectroscopic methods and further confirmed by X-ray crystallographic analysis. Antibacterial activity of obtained pyridones was investigated against four human pathogen microorganisms and the compounds showed poor activity.

Full text of DOI:10.1080/00397911.2013.845902

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Synthesis, Characterization, and
Antibacterial Activity of Novel Pyridones
Hayreddin Gezegen a , Mustafa Ceylan a , İsa Karaman b & Ertan
Şahin c
a Department of Chemistry , Faculty of Arts and Sciences,
Gaziosmanpasa University , Tokat , Turkey
b Department of Biology , Faculty of Arts and Sciences,
Gaziosmanpasa University , Tokat , Turkey
c Department of Chemistry , Faculty of Science, Atatürk University ,
Erzurum , Turkey
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Hayreddin Gezegen , Mustafa Ceylan , İsa Karaman & Ertan Şahin (2014)
Synthesis, Characterization, and Antibacterial Activity of Novel Pyridones, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:8, 1084-1093,
DOI: 10.1080/00397911.2013.845902
To link to this article: http://dx.doi.org/10.1080/00397911.2013.845902
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Synthetic Communications®, 44: 1084–1093, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.845902
SYNTHESIS, CHARACTERIZATION, AND
ANTIBACTERIAL ACTIVITY OF NOVEL PYRIDONES
Hayreddin Gezegen,1 Mustafa Ceylan,1 İsa Karaman,2
and Ertan Şahin3
1Department of Chemistry, Faculty of Arts and Sciences, Gaziosmanpasa
University, Tokat, Turkey
2Department of Biology, Faculty of Arts and Sciences, Gaziosmanpasa
University, Tokat, Turkey
3Department of Chemistry, Faculty of Science, Atatürk University,
Erzurum, Turkey
GRAPHICAL ABSTRACT
Abstract Novel ethyl 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-3-carboxylate
and 4,6-diaryl-3,4-dihydropyridine-2(1H)-one derivatives have been synthesized
from the cyclization of adducts of diethylmalonate to chalcones with ammonium
acetate. The structures were established on the basis of extensive spectroscopic
methods and further confirmed by X-ray crystallographic analysis. Antibacterial
activity of obtained pyridones was investigated against four human pathogen
microorganisms and the compounds showed poor activity.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications® for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords: Antibacterial; chalcone; 1,5-dicarbonyl; pyridone
Received July 25, 2013.
Address correspondence to Mustafa Ceylan, Department of Chemistry, Faculty of Arts and
Sciences, Gaziosmanpasa University, 60250 Tokat, Turkey. E-mail mustafac.ceylan@gop.edu.tr
1084

SYNTHESIS OF NOVEL PYRIDONES
1085
INTRODUCTION
Synthesis of heterocyclic compounds holds an important place in synthetic
organic chemistry. Heterocycles plays leading roles in several organic syntheseis and
chemical processes such as synthesis of natural,[1,2] bioactive,[3] and polyfunctional
compounds.[4,5] Among the heterocyclic compounds containing nitrogen, pyridones
have attracted attention because of their biological activities and their potential appli-
cations as pharmacological agents. Several pyridone derivatives have been reported to
have potent HIV-RT inhibitors and antiviral,[6] cardiotonic,[7] antitumor,[8] analgesic[9]
and antimicrobial[10] activities. Furthermore, some pyridones are used for the treat-
ment of Parkinson’s disease.[11] In addition, there are numerous reports on the anti-
cancer,[12] phytotoxic,[13] antagonist,[14] MDR modulator[15] and anti-inflammatory[16]
effects of pyridone derivatives.
Therefore, synthesis of pyridones is valuable for organic and medicinal chemists,
and various reported methods for the synthesis of pyridones in the literature include
solid-supported aza-annulation,[17] regioselective cyclocondensation,[18] solvent-free
microwave irradiation,[19] tandem,[20,21] sonochemical,[22] and multicomponent[23] pyri-
done syntheses. Various types of pyridones have been reported in the literature.[24]
However, to our knowledge, there is no report on the synthesis of 1,2,3,4-tetrahydro-
pyridones (4a–e) and 3,4-dihydropyridone derivatives (5a–d).
In this study, we report the synthesis of novel ethyl 2-oxo-4,6-diaryl-1,2,3,4-
tetrahydropyridine-3-carboxylate derivatives (4a–e) and 4,6-diaryl-3,4-dihydropyr-
idine-2(1H)-one derivatives (5a–d) via Michael addition of diethylmalonate (2) to
chalcones (1a–e), followed by cyclization of obtained 1,5-dicarbonyl compounds
(3a–e) with ammonium acetate in two different solvent systems. We have also investi-
gated antibacterial activity of synthesized compounds against four human pathogen
microorganisms.
RESULTS AND DISCUSSION
Herein we have synthesized the 4,6-diaryl-1,2,3,4-tetrahydropyridones in three
steps in moderate to good yields.The 1,5-dicarbonyls (3) can be prepared via Michael
addition of diethylmalonate (2) to chalcones (1) and the 1,5-dicarbonyls (3) can be
easily converted to 4,6-diaryl-1,2,3,4-tetrahydropyridones with ammonium acetate.
Figure 1. Synthesis of chalcones (1a–e).

1086
H. GEZEGEN ET AL.
Table 1. Michael addition of diethylmalonate to chalcones
Entry
Ar
Ar′
Product
Yield (%)a
1
2
3
4
5
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
4-MeOC6H4
2-Furyl
2-Thiophenyl
4-MeC6H4
4-MeOC6H4
2-Thiophenyl
2-Thiophenyl
3a
3b
3c
3d
3e
82
84
82
86
79
aIsolated yield.
Initially, the chalcone derivatives (1a–e) were prepared by treatment of related
aromatic ketones and aromatic aldehydes with sodium hydroxide.[25] The synthetic
route of starting compounds is shown in Fig. 1.
Then, the Michael addition of diethylmalonate (2) to chalcones (1) with
KOt-Bu was examined in the presence of benzyltriethylammonium chloride as cata-
lyst in CH2Cl2 at room temperature. The best results were obtained using 5mol%
KOt-Bu and 10mol% benzyltriethylammonium chloride. With this condition at hand,
1,5-dicarbonyls (3a–e) were prepared in yields of 79–86% (Table 1).
The cyclization of diethyl 2-(3-oxo-1,3-di(thiophen-2-yl)propyl)malonate (3a)
with NH4OAc was studied in different solvents. No reaction was observed when using
CH2Cl2, tetrahydrofuran (THF), EtOH, and CH3CN as solvent in the presence of 10
equiv NH4OAc (Table 2, entries 1−4). Therefore, we used the solvents having higher
boiling points such as toluene, acetic acid, dimethylformamide (DMF) and their mix-
tures. The reaction in toluene and AcOH in the presence of 10 equiv NH4OAc gave the
product 4a in yields of 24% and 55%, respectively (Table 2, entries 5 and 6). The cycliza-
tion did not occur in DMF (Table 2, entry 7). While the cyclization in the AcOH/tolu-
ene mixture (1:1) gave only 4a (Table 2, entries 8, 10, and 12), the cyclization in AcOH/
DMF mixture (1:1) afforded only 5a (Table 2, entries 9, 11, and 13). We think that the
compound 4a easily converts to compound 5a, losing the ester group on structure by
effect of the reflux heat of AcOH/DMF system.The yields of products 4a and 5a were
not significantly changed by using various ratios of NH4OAc (10mol%, 8mol%, and
5mol%) and reaction times (24 and 16h.). The best yields were obtained using the 8
equiv NH4OAc and AcOH/toluene mixture (1:1) for 4a (yield, 85%; time, 16h) (Table 2,
entry 10), and the 8 equiv NH4OAc and AcOH/DMF mixture (1:1) for 5a (yield, 58%;
time, 16h) (Table 2, entry 11).
After the optimum conditions were determined, the cyclization of the other
1,5-dicarbonyls (3b–e) were performed in these conditions. While the products 4a–e
were obtained in yields of 75−91%, the products 5a–d were obtained in yields of
58−68%. The reaction of 3e with 8 equiv NH4OAc in AcOH/DMF mixture (1:1) gave
the polymeric products, and compound 5e was not isolated (Table 3).

SYNTHESIS OF NOVEL PYRIDONES
1087
Table 2. Optimization of the cyclization conditions
Entry
NH4OAc (Equiv)
Solvent
T (h)
Yield (%)a (product)
1
2
3
4
5
6
7
8
9
10
11
12
13
10
10
10
10
10
10
10
10
10
8
CH2Cl2
THF
EtOH
CH3CN
Toluene
24
24
24
24
24
24
24
24
24
16
16
16
16
NR
NR
NR
NR
24 (4a)
55 (4a)
NR
82 (4a)
58 (5a)
85 (4a)
58 (5a)
78 (4a)
54 (5a)
AcOH
DMF
AcOH/Toluene
AcOH/ DMF
AcOH/Toluene
AcOH/ DMF
AcOH/Toluene
AcOH/ DMF
8
5
5
aIsolated yield.
The structures of synthesized compounds were determined by spectroscopic
studies [1H and 13C NMR, infrared (IR), gas chromatography–mass spectrometry
1
(GC-MS), and elemental analysis]. In the H NMR spectrum of 4a–e, the proton
of amide gave a singlet at δ= 7.86–9.00ppm and olefinic proton gave a doublet at
δ= 5.51−5.78 (J= 2.8−4.0Hz) ppm. The CH-Ar proton of 4a–e gave a doublet of dou-
blets at δ= 4.32−4.69 (J= 10.6−9.0, 4.2−3.8Hz) ppm. Also, in the 1H NMR spectrum
of 5a–d, the proton of amide gave a singlet at δ= 7.41−8.46ppm and olefinic proton
gave a doublet at δ= 5.53−5.68 (J= 3.6−4.4Hz) ppm. The protons of -COCH2 gave an
AB system, while the Apart of the AB system is shown as a doublet of doublet in the
region δ= 2.87−2.98 (J= 16.3−16.0, 7.2−6.8Hz) and that of part B as a doublet of dou-
blet at δ= 2.70−2.83 (J= 16.3−16.0, 10.2−8.4Hz). The IR spectra of the compounds
4a–e and 5a–d showed a stretching band of -NH group in the region 3226−3097cm−1
and -C= O group in the region 1743−1673cm−1. The GC-MS spectra of compounds
4 and 5 gave the same molecular ion peak (M+). We assumed that the compounds 4
convert to compounds 5, losing the ester group on structure 4 as an effect of tempera-
ture in the GC oven.
1
The H and 13C NMR spectra indicated that 4b was a single diastromer.
The relative stereochemistry of the compound 4b was established by X-ray
diffractionanalysis. TheX-raydiffractionanalysisconfirmedtheproposedstructureof
Ethyl 2-oxo-6-(thiophen-2-yl)-4-p-tolyl-1,2,3,4-tetrahydropyridine-3-carboxylate (4b).

1088
H. GEZEGEN ET AL.
Table 3. Scope of the cyclization reaction to synthesize 4,6-diaryl-1,2,3,4-tetrahydropyridones
Solvent
(1:1)
Yield
(%)
Entry
1
Substrate
Product
AcOH/
Toluene
(3a)
(3b)
85
(4a)
AcOH/
Toluene
2
3
(4b)
88
91
AcOH/
Toluene
(3c)
(4c)
AcOH/
Toluene
4
5
(3d)
(4d)
89
75
AcOH/
Toluene
(3e)
(4e)
(Continued)

SYNTHESIS OF NOVEL PYRIDONES
1089
Table 3. Continued
Solvent
Yield
Entry
6
Substrate
(1:1)
Product
(%)
AcOH/
DMF
(3a)
(5a)
58
AcOH/
DMF
7
8
(3b)
(5b)
65
68
AcOH/
DMF
(3c)
(5c)
AcOH/
DMF
(3d)
(5d)
9
62
AcOH/
DMF
10
(3e)
ND (5e)
−
The configurations of the new stereogenic centers C(7) and C(8) are determined as (S)
and (R), respectively (Fig. S1, Supplementary Material).
The formation mechanism of compounds 4 and 5 can be explained as shown
Fig. 2. The addition of ammonia to protonated intermediate i gave intermediate ii
followed by hydrogen transfer to hydroxyl group gave amine iii. The elimination of
H3O+ gave imine iv. The attack of N atom to ester group and leaving ethoxy group
gave intermediate v. Finally, loss of hydrogen atom of intermediate v gave compound 4.
In addition, the nucleophilic attack of ammonia to the carbonyl group of compound 4
gave the amide derivative vi and following ammonolysis gave compound 5.
Synthesized pyridone derivatives were screened in vitro for antibacterial activ-
ity against two Gram-positive bacteria (Staphylococcus aureus ATCC 29213 and
Hemolytic streptococcus) and two Gram-negative bacteria (Escherichia coli 111 and

1090
H. GEZEGEN ET AL.
Figure 2. Proposed formation mechanism of pyridones.
Salmonella enteritidis). The minimum inhibitory concentrations (MIC) of compounds
were determined by the serial dilution method,[26] and the results are given in Table S1.
Penicillin G and ceftriaxone were used as positive controls.
As seen in Table S1, while all compounds showed the same activity with penicil-
lin G against β-Hemolytic streptococcus ATCC 2957, all compounds showed lower
activity than penicillin G and ceftriaxoneagainst all tested bacteria. The most active
compound was 4e with 125µg/mL MIC value against Staphylococcus aureus ATCC
29213. Compounds 5a–d showed higher activity (MIC: 125µg/mL) against Escherichia
coli 111 than compounds 4a–e. Compounds 4e and 5a–d showed moderate activity
(MIC: 125µg/mL) against Salmonella enteritidis ATCC 13076.
Concerning SAR, among the series of 4a–e, compound 4e containing a
furan ring was found to be the most active compound according to theMIC values.
Compounds 5a–e showed the same activity.
CONCLUSIONS
In conclusion, the novel ethyl 2-oxo-4,6-diaryl-1,2,3,4-tetrahydropyridine-
3-carboxylate derivatives (4a–e) and 4,6-diaryl-3,4-dihydropyridine-2(1H)-one derivatives
(5a–d) have been synthesized from the 1,5-dicarbonyl compounds (3a–e) in good yields. The
structures were established on the basis of spectroscopic methods and further confirmed
by X-ray crystallographic analysis. Antibacterial activities were investigated against four
human pathogen microorganisms. All compounds showed lower activity than standards.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9100 apparatus. IR spec-
tra (KBr disc) were recorded on a Jasco FT/IR-430 spectrometer. 1H and 13C NMR
spectra were recorded on a Bruker Avance DPX-400 instrument. Internal standards

SYNTHESIS OF NOVEL PYRIDONES
1091
were tetramethylsilane (TMS) (δ 0.00) for 1H NMR and CDCl3 (δ 77.0) for 13C NMR
spectroscopy; J values are given in hertz (Hz). The multiplicities of the signals in the
1H NMR spectra are abbreviated by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), br (broad), and combinations thereof. Elemental analyses were obtained
from a Leco CHNS 932 elemental analyzer. GC-MS analyses were obtained from a
Perkin-Elmer Clarus 500 GC-MS. All column chromatography were performed on
silica gel (60–230 mesh, Merck). Anhydrous sodium sulfate was used as a drying agent
for the organic phase.
Synthesis of chalcone derivatives (1a–e) were carried out through Claisen–
Schmidt condensation of related ketones and aldehydes using sodium hydroxide as cat-
alyst in ethanol at room temperature.[27,28] The chalcones were obtained in good yields
(>90%).
General Procedure for the Synthesis of 3a–e
Catalyst (10mol%, benzyltriethylammonium chloride) and KOt-Bu (5mol%)
were added to a solution of chalcone (1 mmol) and diethylmalonate (1.2mmol) in
CH2Cl2 (5mL), and the mixture was stirred at room temperature for 4h. Then, the
mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the
solvent was removed under reduced pressure. The crude viscous product was purified
on asilica-gel column eluting with CHCl3/n-hexane (1:3) and crystallized in CHCl3/n-
hexane or EtOH/n-hexane.
General Procedure for the Synthesis of 4a–e
A solution of 3a–e (1mmol) and NH4OAc (8mmol) in AcOH/toluene mixture
(1:1, 20mL) was refluxed for 16h. Then, the mixture was extracted with CHCl3. The
organic layer was dried over Na2SO4, and the solvent was removed under reduced
pressure. The crude product was purified by filtration on silica-gel column eluting
with CHCl3/n-hexane (1:3) and crystallized in CHCl3/n-hexane or EtOH/n-hexane.
General Procedure for the Synthesis of 5a–d
A solution of 3a–d (1 mmol) and NH4OAc (8 mmol) in AcOH/DMF mixture
(1:1, 20 mL) was refluxed for 16 h. Then, the mixture was extracted with CHCl3.
The organic layer was dried over Na2SO4, and the solvent was removed under
reduced pressure. The crude product was purified by filtration on a silica-gel col-
umn eluting with CHCl3/n-hexane (1:3) and crystallized in CHCl3/n-hexane or
EtOH/n-hexane.
Crystallography
For the crystal structure determination, a single crystal of compound 4b was used
for data collection on a four-circle Rigaku R-AXIS Rapid-S diffractometer (equipped
with a two-dimensional-area image plate (IP) detector). Graphite-monochromated
Mo-Kα radiation (λ=0.71073 Å) and oscillation scans technique with ∆w= 5º for one

1092
H. GEZEGEN ET AL.
image were used for data collection. The lattice parameters were determined by the
least-squares methods on the basis of all reflections with F2 > 2σ(F2). Integration of
the intensities, correction for Lorentz and polarization effects, and cell refinement
were performed using CrystalClear (Rigaku/MSC Inc., 2005) software.[29] The struc-
tures were solved by direct methods using SHELXS-97[30] and refined by a full-matrix
least-squares procedure using the program SHELXL-97.[30] H atoms were positioned
geometrically and refined using a riding model. The final difference Fourier maps
showed no peaks of chemical significance. Crystal data for 4b: C19H19NO3S, crystal
system, space group: monoclinic, P21/n; (no: 14); unit cell dimensions: a= 13.7871(5),
b= 8.2816(4), c= 15.7044(4) Å, α=90, β= 92.94(2), γ=90 Å; volume: 1790.75(12) Å3;
Z= 4; calculated density: 1.266g/cm3; absorption coefficient: 0.196mm−1; F(000):
720; θ range for data collection 2.6–26.4º; refinement method: full matrix least-
square on F2; data/parameters: 3524/220; goodness of fit on F2: 0.997; final R indi-
ces [I> 2σ(I)]: R1 = 0.0701, wR2 = 0.164; largest diff. peak and hole: 0.209 and −0.259
e Å−3. Crystallographic data that were deposited in CSD under CCDC registration
number 892668 contain the supplementary crystallographic data. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre (CCDC)
via www.ccdc.cam.ac.uk/data_request/cif and upon request to CCDC, 12 Union
Road, Cambridge, UK (fax: +441223 336033, e-mail: deposit@ccdc.cam.ac.uk).
Microbiology
The minimum inhibitory concentration (MIC) values were determined by
the serial dilution technique in Mueller–Hinton broth. The inoculations of micro-
organisms were prepared from 24h broth cultures, and suspensions were adjusted
to 0.5Mc Farland standard turbidity. The test compounds dissolved in 12.5%
dimethylsulfoxide(DMSO)werefirstdilutedtothegreatestconcentration(500µg/mL)
to be tested. Then serial twofold dilution was made in concentration range from 0.98
to 500µg/mL in 5-mL sterile tubes containing nutrient broth. This process was also
repeated for the antibiotics. A prepared suspension of the standard microorganisms
was added to each dilution in a 1:1 ratio. Growth (or its lack) of microorganisms was
determined visually after incubation for 18h at 36°C. The lowest concentration at
which there was no visible growth (turbidity) was taken as the MIC. Penicillin G and
ceftriaxone were used as reference drugs.
SUPPORTING INFORMATION
Full spectral data, melting points, antibacterial activity tests, and X-ray crys-
tallographic materials can be found via the Supplementary Content section of this
article’s Web page.
FUNDING
The authors are indebted to the Gaziosmanpaşa University (Grant BAP-
2010/13) for financial support of this work.

SYNTHESIS OF NOVEL PYRIDONES
1093
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