A simple and convenient synthesis of tautomeric (6 or 2)-hydroxy-4-methyl- (2 or 6)-oxo-1-(substituted phenyl)-(1,2 or 1,6)-dihydropyridine-3-carbonitriles

Article abstract of DOI:10.1007/s00706-012-0911-5

A simple and convenient synthesis of tautomeric (6 or 2)-hydroxy-4-methyl- (2 or 6)-oxo-1-(substituted phenyl)-(1,2 or 1,6)-dihydropyridine-3-carbonitriles from ethyl acetoacetate and 2-cyano-N-(substituted phenyl)ethanamides using microwave-assisted chemistry is presented. The structure of the obtained product was confirmed by the use of FT-IR, NMR, UV, and MS techniques. The presence of tautomeric forms (6-hydroxy-4-methyl-2-oxo-1-(substituted phenyl)-1,2- dihydropyridine-3-carbonitrile and 2-hydroxy-4-methyl-6-oxo-1-(substituted phenyl)-1,6-dihydropyridine-3-carbonitrile) and the state of equilibrium of the obtained product in DMSO-d ₆ was studied by ¹H and ¹³C NMR spectroscopy, as well as B3LYP/6-311++G(d,p) and GIAO/WP04/aug-cc-pVDZ theoretical calculations.

Full text of DOI:10.1007/s00706-012-0911-5

Monatsh Chem (2013) 144:665–675
DOI 10.1007/s00706-012-0911-5
ORIGINAL PAPER
A simple and convenient synthesis of tautomeric (6 or 2)-hydroxy-
4-methyl-(2 or 6)-oxo-1-(substituted phenyl)-(1,2 or 1,6)-
dihydropyridine-3-carbonitriles
•
Ismail Ajaj Dusan Mijin Veselin Maslak Danijela Brkovic
•
•
•
ˇ
Milos Milcic Nina Todorovic Aleksandar Marinkovic
´
•
•
ˇ
ˇ ´
´
´
Received: 26 May 2012 / Accepted: 25 December 2012 / Published online: 28 February 2013
Ó Springer-Verlag Wien 2013
Abstract A simple and convenient synthesis of tautomeric
(6 or 2)-hydroxy-4-methyl-(2 or 6)-oxo-1-(substituted phe-
nyl)-(1,2 or 1,6)-dihydropyridine-3-carbonitriles from ethyl
acetoacetate and 2-cyano-N-(substituted phenyl)ethana-
mides using microwave-assisted chemistry is presented. The
structure of the obtained product was confirmed by the use of
FT-IR, NMR, UV, and MS techniques. The presence of
tautomeric forms (6-hydroxy-4-methyl-2-oxo-1-(substituted
phenyl)-1,2-dihydropyridine-3-carbonitrile and 2-hydroxy-
4-methyl-6-oxo-1-(substituted phenyl)-1,6-dihydropyridine-
3-carbonitrile) and the state of equilibrium of the obtained
Introduction
Many naturally occurring and synthetic compounds con-
taining a 2-pyridone ring have a broad spectrum of
biological activity [1–3]. Some of them are cardiotonic
agents for the treatment of heart failure [4–7], whereas
others possess antitumor [8, 9], antibacterial [10], or some
other biological activities [1, 2, 11–15]. Many 3-cyano-2-
pyridone derivatives are used in the manufacture of dyes
and pigments, stabilizers for polymers and varnishes,
additives for fuels and lubricants, acid–base indicators, and
other practically important materials [2].
1
product in DMSO-d6 was studied by H and 13C NMR
spectroscopy, as well as B3LYP/6-311??G(d,p) and GIAO/
The 3-cyano-2-pyridones can be obtained by different pro-
cedures using various starting compounds [1, 2, 16, 17].
Microwave-assisted synthesis has also been used to obtain
2-pyridones and their derivatives [18–23]. 6-Hydroxy-4-
methyl-2-oxo-1-(substituted phenyl)-1,2-dihydro-pyridine-3-
carbonitriles are compounds which are mostly used as coupling
components in the synthesis of various pyridone azo dyes and
pigments as well as other pyridone dyes and pigments [24–35].
These 2-pyridones described in the literature were obtained
using different procedures. Matsui et al. [24] prepared
6-hydroxy-4-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-
carbonitrile from aniline, ethyl cyanoacetate, and ethyl
acetoacetate using the procedure described earlier by Chen
and Wang [36]. 6-Hydroxy-4-methyl-2-oxo-1-phenyl-1,2-
dihydropyridine-3-carbonitrile was also obtained by con-
densation of acetoacetanilide with methyl cyanoacetate or of
methyl acetoacetate with cyanoacetanilide in ethanol with
the addition of potassium hydroxide [28, 34]. This pyridone
was also prepared from ethyl 2-cyano-2-[1-methyl-3-oxo-3-
(phenylamino)-propylidine]acetate which was synthesized
by the reaction of ethyl cyanoacetate and acetoacetanilide
in the presence of sodium ethoxide [37]. 6-Hydroxy-4-
methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile
WP04/aug-cc-pVDZ theoretical calculations.
Keywords Microwave assisted synthesis ꢀ Heterocycles ꢀ
Cyclizations ꢀ Ab initio calculations ꢀ Tautomerism
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0911-5) contains supplementary
material, which is available to authorized users.
´
´
I. Ajaj ꢀ D. Mijin ꢀ D. Brkovic ꢀ A. Marinkovic (&)
Faculty of Technology and Metallurgy, University of Belgrade,
Karnegijeva 4, 11120 Belgrade, Serbia
e-mail: marinko@tmf.bg.ac.rs
ˇ ´
V. Maslak ꢀ M. Milcic
Faculty of Chemistry, University of Belgrade, Studentski trg 3-5,
11000 Belgrade, Serbia
´
N. Todorovic
Center for Chemistry, Institute of Chemistry, Technology
and Metallurgy, University of Belgrade, Studentski trg 12-16,
11000 Belgrade, Serbia
123

666
I. Ajaj et al.
and 1-(4-chlorophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile were in addition prepared from
ethyl 2-cyano-3-methyl-4-phenylcarbamoyl-2-butenoateorits
4-chlorophenyl derivative, respectively, and base [38]. 1-(4-
Ethoxycarbonylphenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile was prepared by the reaction of
ethyl 4-aminobenzoate and diketene, followed by condensa-
tion with ethyl cyanoacetate [33]. The ester was then
hydrolyzed to give the carboxy derivative.
reactant molar ratio, the reaction between 2-cyano-N-
phenylethanamide, ethyl acetoacetate, and freshly pow-
dered potassium hydroxide was used as a model reaction.
The optimized reactant ratios were found to be 1.0 equiv.
2-cyano-N-phenylethanamide, 3.9 equiv. ethyl acetoace-
tate, and 2.0 equiv. potassium hydroxide in the open vessel
reaction in a dedicated microwave reactor. Optimized
reaction time was found to be 10 min at 150 W. The iso-
lated yield of the product 1 is 78 %. All other products
were synthesized according to established optimized reac-
tion conditions and results are given in Table 1.
To our knowledge all of the known procedures suffer from
long reaction times, use of strong base, and/or require several
steps to produce the desired pyridine derivatives usually in
low to moderate yields. Herein, we report a simple, conve-
nient, and efficient microwave-assisted synthesis of products
consisting of the tautomeric pyridone 6-hydroxy-4-methyl-2-
oxo-1-(substituted phenyl)-1,2-dihydropyridine-3-carboni-
The obtained products were characterized by melting
point, FT-IR, NMR, UV, and MS data, as well as elemental
analysis (Supplementary Material). When reactions were
run in the closed vessel, ethanol was used as solvent.
Reactions were performed at 140 °C but the isolated yields
(20–25 %) were several times lower than in the open
vessel. Also reactions were run in an open vessel in the
domestic commercial microwave oven. These reactions
were run using the optimized reactant ratio obtained in the
dedicated microwave reactor and without stirring during
irradiation (10 min). The higher irradiation power (300 W)
than in the dedicated microwave reactor was needed to
obtain yields of 30–50 %. Although not much lower yields
were obtained in comparison to the dedicated microwave
reactor, synthesis in domestic commercial microwave
ovens cannot be advised owing to safety and reproduc-
ibility reasons [42]. In addition, conventional synthesis of
all pyridones was performed using optimal reactant ratio in
ethanol at reflux temperature. In comparison to the con-
ventional method, microwave synthesis gives products in
higher yields (e.g., compound 1: 78 % in the microwave
vs. 40 % in the conventional synthesis) and in a shorter
reaction time (10 min vs. 3 h). A similar trend was found
for other compounds, and results are given in Table S1.
The preliminary study of the 1H and 13C NMR spectra of
the obtained products indicated the existence of two com-
pounds that could not be separated using chromatographic
techniques. A detailed study on the assignments of the
triles
a
and 2-hydroxy-4-methyl-6-oxo-1-(substituted
phenyl)-1,6-dihydropyridine-3-carbonitriles b (Scheme 1).
Atom numbering in the corresponding pyridone tautomers
a and b has been defined arbitrarily and is given in Scheme 1.
Results and discussion
A series of 16 reaction products, consisting of a mixture of
tautomers a and b (Scheme 1), was synthesized using
microwave irradiation starting from ethyl acetoacetate and
corresponding 2-cyano-N-(substituted phenyl)ethanamides
in the presence of freshly powdered potassium hydroxide.
Starting 2-cyano-N-(substituted phenyl)ethanamides were
synthesized according to previously published methods
[39–41]. Microwave synthesis (MW) was performed in a
dedicated microwave reactor in an open vessel. An attempt
was made to perform synthesis in a closed vessel but much
lower yields were obtained. Reactions were also carried out
in a domestic commercial microwave oven as well. The
conventional synthesis was also performed.
In order to optimize reaction conditions irradiation
power (100–600 W), reaction time (1–30 min), and
Scheme 1
CH3
CH3
CN
O
CN
OH
CN
O
4
3
CH3
+
5
6
O
2
KOH
1
O
N
NH
X
HO
N
Microwave
O
θ b
θ a
O
1'
4'
a
2'
3'
6'
5'
CH2CH3
X
X
b
123

A simple and convenient synthesis of tautomeric substituted dihydropyridine-3-carbonitriles
667
Table 1 Yields and melting points of the obtained product
(MW synthesis)
Table 2 Percentage of tautomers a and b and equilibrium constant
KT
Compound
X
Yield/%a
M.p./°C
Compound
a/%
b/%
KTa
1
H
78
72
60
73
42
50
57
64
64
74
66
59
52
47
54
52
281–283
284–285
270–273
238–242
227–230
286–288
288–289
285–287
276–278
284–285
315–317
275–278
278–280
250–252
284–285
243–245
1
43
70
23
27
73
100
75
68
60
41
0
57
30
77
73
27
0
1.33
0.43
3.35
2.70
0.37
0.00
0.33
0.47
0.67
1.44
–
2
4-CH3
4-OCH3
4-NO2
4-COCH3
4-OH
4-I
2
3
3
4
4
5
5
6
6
7
7
25
32
40
59
100
55
46
20
70
57
8
4-Cl
8
9
4-Br
9
10
11
12
13
14
15
16
a
4-F
10
11
12
13
14
15
16
3-CF3
3-Cl
45
54
80
30
43
1.22
0.85
0.25
2.33
1.33
3-Br
3-OCH3
3-CH3
3-COCH3
Purification performed by chloroform washing
KaT = [b]/[a]; proportions are determined by ratio of integrated H5
signal in DMSO-d6
1
spectra with inverse-gated H decoupling were recorded.
1H and 13C NMR signals of the synthesized compounds
was undertaken using homonuclear correlated spectroscopy
(H,H-COSY), heteronuclear single quantum coherence
(1H–13C HSQC), and heteronuclear multiple bond corre-
lation (1H–13C HMBC) techniques. The results were used
for characterization and study of the state of equilibrium,
i.e., the state of tautomeric interconversion, of forms a and
b (Scheme 1) in DMSO-d6 solution. Most of the synthe-
sized compounds, according to our knowledge, are reported
for the first time, and for known compounds 2–4, 8, 12, 15,
and 17 corresponding NMR spectral data are not available
in the literature.
Analysis of the obtained results indicated that a good
agreement of the tautomer determination existed for the
methyl group proton at C4 and C2–C6 carbon atoms of the
pyridone ring (example given for compound 1; Fig. S1).
Results of density functional theory (DFT) calculations of
1H and 13C NMR chemical shifts (performed by GIAO/
WP04/aug-cc-pVDZ model and PCM-type calculation to
include DMSO solvation) are given in Tables S2 and S3.
The analysis of the 1H–13C correlated spectra provided
precise proton and carbon signal assignments. Examples
are given for compound 15: HMBC in Fig. S2, and HSQC
in Fig. S3. Connectivity found in the HMBC spectra helped
to distinguish the quaternary carbons of the pyridone core.
Results from Table 2 indicate the complex influence of
electronic substituent effects on the tautomeric equilibria.
Linear correlations of the negative logarithm value of the
equilibrium constant, pKT, with Hammett substituent con-
stant, rm/p [47], was found for electron-acceptor substituted
compounds (Fig. S4 and Table S4). The slopes of corre-
lation lines pKT versus rm/p are negative, and the
proportionality constants q indicate significant sensitivity
of pKT to substituent effects. The negative sign means
reverse behavior, i.e., the contribution of tautomer b in the
equilibrium increases, although the electron-withdrawing
ability of the substituents, measured by r, increases. A
non-linear relation of pKT versus rm/p, which includes
fluoro-substituted pyridone owing to its significant elec-
tron-donating character [47], was found for electron-donor
It was not a new notion that pyridones exist in solution
or in the solid state as an appropriate equilibrium of tau-
tomeric or dimeric forms [43, 44]. This equilibrium in
solution is mainly affected by substituent electronic effects
as well as solvent properties [45, 46]. Slow proton
exchange in the prototropic equilibrium allowed observa-
1
tion of separate signals in H and 13C NMR spectra which
was used for qualitative and quantitative determination of
each form in the tautomeric mixture. The integral of H5
NMR signal was the main indication and the parameter
used for determination of pyridone tautomer ratio in
DMSO-d6. In the 1H NMR spectra of compound 1 singlets
at 5.69 and 6.09 ppm are unequivocally assigned to H5 of
forms 1a and 1b, respectively. This methodology was
applied to the NMR data of the other compounds, and
results of tautomer percentages and KT determination are
given in Table 2. Additionally, quantitative 13C NMR
123

668
I. Ajaj et al.
endothermic nature of this process [48], which is in
accordance with the low temperature influence on the
equilibrium shift observed in the NMR spectra (Fig. S5).
The NMR spectra of compound 1 were recorded at 343 K
(Fig. S5) to confirm thermally induced tautomerization,
i.e., slow proton exchange in prototropic equilibrium of
compound 1. The prototropic interconversion could be
accomplished via [1,5]- [49] or less probably [1,7]-hydro-
gen transfer, as well as by intermolecular double proton
transfer, prototropic interconversion with cyclic associate
participation [50], supported by the high tendency of
pyridone to dimerize (self-association) [51].
The synthesized pyridones showed an interesting feature
(presented in case of pyridone 1): its diazotization
(Scheme 2) produced azo derivatives which are easily
rearranged to more stable hydrazone form [48].
Fig. 1 Optimized geometries of tautomers 1a and 1b
Spectral assignment of (Z)-6-hydroxy-4-methyl-5-[2-(4-
nitrophenyl)hydrazono]-2,6-dioxo-1-phenyl-1,2,5,6-tetra-
substituted compounds (Fig. S4). Transmission of the res-
onance substituent effect is significantly affected by the
non-planarity of the molecule (Table S5; angles ha and hb),
thereby influencing the p-electron delocalization and the
state of tautomeric equilibrium. Moreover, contributions of
the solvent effects (DMSO) could not be neglected: dipo-
larity, polarizability, and solute/solvent hydrogen bonding
interaction—hydrogen bond donor (HBD) and hydrogen
bond acceptor (HBA) interaction—significantly contribute
to the tautomer stability. Generally, it could be observed
that solvent HBA effect is more pronounced for compound
6 such that tautomer a predominates (Table 2) owing to the
presence of a proton-donating site, i.e., OH group. As the
contribution of solvent HBA effect decreases, owing to
decreasing substituent proton-donating capabilities (com-
pounds 2, 1, 10, 15, and 3, respectively; Fig. S4) KT
increases, i.e., contribution of tautomer b increases.
1
hydro-3-carbonitriles is given in the H NMR spectrum of
unpurified, as well as purified product (Figs. S6 and S7,
respectively). Additionally, the theoretical calculations
showed that the hydrazone form is 62.8 kJ/mol more stable
than azo/b form mainly because of the formation of an
intramolecular hydrogen bond (Scheme 2). On the other
hand, calculations have shown that azo/a tautomer is not a
minimum on the potential energy surface. All B3LYP/6-
311??G(d,p) optimizations, which started from azo/
a geometry, optimized to much more stable hydrazone
geometry. Theoretical calculations and NMR results
clearly indicate that if both tautomers (azo/a and azo/b;
Scheme 2) are obtained by diazotization of pyridone 1
subsequent hydrogen rearrangements drive the equilibrium
to the more stable hydrazone form. Diazotization of form
1b could take place either following path i and consecutive
tautomerization azo/b to azo/a or by prototropic equilib-
rium shifts to form 1a followed by diazotization (path ii)
(Scheme 2). Reactivity of the diazonium salt depends on
the substituent groups that are present on the starting
pyridone. From the kinetic point of view electrophilic
attack at C5 by para-nitrophenyldiazonium ion signifi-
cantly depends on charge density at this carbon. DFT
calculation showed higher negative charges at C5 for tau-
tomer a in all compounds (Tables S2 and S3), and thus, it
could be supposed that there is a higher probability that
reaction takes place at C5 of form a. Moreover, the results
of geometry optimization of pyridone showed that the
hydroxyl group at C6 and the pyridone ring are co-planar;
thus, the higher extent of overlapping (n,p-conjugation) of
oxygen lone pairs (p-orbitals) and p-electrons of the pyri-
done ring contributes to an increased electron density at C5
carbon. It is expected that the close vicinity of the electron-
donating hydroxyl group in form a at C6 could participate
in a stabilization of the activated complex, and more
Also, we carried out ab initio studies to calculate ener-
gies of both tautomers. The obtained results in the gas
phase indicate higher stability of tautomer b (0.5–11.4
kJ/mol) for all compounds owing to the existence of an
intramolecular hydrogen bond between hydroxy and cyano
groups. On the other hand, calculations of the solvation
free energy have shown that tautomers a are better solvated
in DMSO (difference in solvation free energy between
tautomer a and b is from 0.1 to 8.9 kJ/mol), thus indicating
a higher stability of form a in solution. Detailed experi-
mental and theoretical investigation on the solvent- and
temperature-dependent pyridone tautomeric equilibrium
and tautomerization mechanism is a matter of current
study. In Fig. 1 the optimized geometry of tautomers 1a
and 1b, obtained by the use of B3LYP method with
6-311G(d,p) basis set, is given. Also, some elements of
optimized geometries are given in Table S5.
The determination of thermodynamic parameters for the
keto–enol equilibrium of 1 in DMSO-d6 indicated the
123

A simple and convenient synthesis of tautomeric substituted dihydropyridine-3-carbonitriles
669
Scheme 2
CH3
CH3
O2N
CH3
H
HO
1a
H
CN
OH
CN
O
N
O
CN
O
N
H
N
O
N
N
Hydrazone
1b
+
ii
+
O2NPhN2
0-5 °C
O2NPhN2
i
0-5 °C
O2N
O2N
CH3
CH3
N
CN
N
O
CN
N
N
HO
N
O
N
OH
Azo/a
Azo/b
favorable reaction pathway ii could be operative in that
way. Studies of solvent and substituent intramolecular
charge transfer properties of pyridones and dyes, using UV
and time-dependent density functional theory (TD-DFT)
methods, will be the focus of forthcoming work. Generally
speaking, the dye synthesis gave a product containing
unreacted pyridone form b and azo dye product. The pure
pyridone azo dye absorbed at a higher wavelength (bato-
chromic shift; kmax = 430 nm) owing to larger mobility of
electronic densities (extended p-resonance) through the
overall p-electronic systems. The obtained dyes are red,
whereas the starting pyridone is white-yellowish. The high
commercial importance of such dyes as coloring materials
warrants intensive dye synthesis and further study of azo–
hydrazone tautomerism study, as well as their solvato-
chromic and substituent-dependent properties.
(substituted phenyl)ethanamides were synthesized accord-
ing to literature methods [39–41]. All NMR spectral
measurements were performed on a Bruker Avance III 500
1
spectrometer (500.26 MHz for H, 125.80 MHz for 13C)
equipped with broadband 5 mm probe (BBO). The spectra
were recorded at room temperature in deuterated dimethyl
sulfoxide (DMSO-d6). The chemical shifts were expressed
in ppm values referenced to dH = 2.5 and dC = 39.5 ppm
1
in H and 13C NMR spectra, respectively. Coupling con-
stants J were expressed in Hz. 1H NMR spectra of
compound 1 were recorded at 343 K. 2D COSY, HMBC,
and HSQC spectra were also recorded on a Bruker Avance
III 500 spectrometer. Standard pulse sequences were used
for 2D spectra. COSY spectra were recorded at spectral
widths of 5 kHz in both F2 and F1 domains; 1K 9 512
data points were acquired with 32 scans per increment and
relaxation delays of 2.0 s. Data processing was performed
on a 1K 9 1K data matrix. Inverse-detected 2D hetero-
nuclear correlated spectra were measured over 512
complex points in F2 and 256 increments in F1, collecting
128 (HSQC) or 256 (HMBC) scans per increment with
relaxation delays of 1.0 s. The HMBC experiments were
optimized for a coupling of 8 Hz. Fourier transform was
done on a 512 9 512 data matrix. p/2-shifted sine squared
window functions were used along F1 and F2 axes for all
2D spectra. UV data were obtained using a Shimadzu 1,700
UV–Vis spectrophotometer in ethanol as solvent at
In summary, this simple, convenient, and rapid one-pot
microwave procedure, which gives the title tautomeric
pyridones in good yield with high purity, can be useful in
the preparation of dyes and pigments as well as pharma-
ceutically important compounds.
Experimental
All commercially available chemicals were purchased from
Sigma-Aldrich (St. Louis, MO, USA). 2-Cyano-N-
123

670
I. Ajaj et al.
1
5 9 10-5 mol dm-3. Fourier transform infrared (FT-IR)
spectra were obtained using an FT-IR BOMEM MB 100 in
the form of KBr pellets. Elemental analysis (C, H, N, and
O) was performed using a VARIO EL III elemental ana-
lyzer, and F, Cl, Br, and I content was calculated by
subtraction; results agreed favorably with calculated val-
ues. The mass spectra were obtained on FinniganMAT
8230 (EI, 70 eV) and on Agilent technologies 6210 TOF
LC/MS (high resolution mass spectrometry, HRMS)
instruments (LC: series 1200). Microwave synthesis was
performed in a Milestone MycroSYNTH reactor.
2a: H NMR (500 MHz, DMSO-d6): d = 2.27 (s, 3H,
4-CH3), 2.35 (s, 3H, 40-CH3), 5.69 (s, 1H, 5-H), 7.07
(AA0XX0, J = 8.2 Hz, 2H, C6H4CH3), 7.27 (AA0XX0,
J = 8.6 Hz, 2H, C6H4CH3), 12.60 (bs, 1H, OH) ppm;
13C NMR (125 MHz, DMSO-d6): d = 20.9 (4-CH3), 21.0
(40-CH3), 88.6 (C3), 92.7 (C5), 117.8 (C:N), 128.4 (C20,
C60), 129.7 (C30, C50), 133.0 (C10), 138.0 (C40), 159.4 (C4),
161.1 (C2), 162.5 (C6) ppm.
1
2b: H NMR (500 MHz, DMSO-d6): d = 1.90 (s, 3H,
4-CH3), 2.36 (s, 3H, 40-CH3), 6.08 (s, 1H, 5-H), 7.14
(AA0XX0, J = 8.4 Hz, 2H, C6H4CH3), 7.31 (AA0XX0,
J = 8.4 Hz, 2H, C6H4CH3), 12.60 (bs, 1H, OH) ppm;
13C NMR (125 MHz, DMSO-d6): d = 21.0 (40-CH3), 21.9
(4-CH3), 83.6 (C3), 99.0 (C5), 115.5 (C:N), 128.3 (C20,
C60), 130.2 (C30, C50), 135.2 (C10), 138.6 (C40), 153.3 (C4),
161.2 (C6), 171.9 (C2) ppm.
General procedure for pyridone synthesis
under microwave irradiation
A mixture of ethyl acetoacetate (4.9 mmol), 2-cyano-N-
(substituted phenyl)ethanamides (1.25 mmol), and freshly
powdered potassium hydroxide (2.5 mmol) was placed in a
glass vial, equipped with condenser, and irradiated with
stirring using the following method: ramp time 1 min at
150 W and hold time 10 min at 150 W. The obtained
product was suspended in hot water, acidified with diluted
HCl, filtrated, and washed with water and chloroform.
6-Hydroxy-1-(4-methoxyphenyl)-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (3a, C14H12N2O3) and
2-hydroxy-1-(4-methoxyphenyl)-4-methyl-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (3b, C14H12N2O3)
Yellowish crystalline solid; yield 60 %; m.p.: 270–273 °C;
HRMS: m/z (MH?) calcd for C14H13N2O3 255.0751, found
ꢀ
255.0762; IR (KBr): m = 551, 633, 770, 825, 1,036, 1,172,
1,255, 1,302, 1,410, 1,512, 1,665 (C=O), 2,218 (C:N),
2,514, 2,605, 2,835, 2,972, 3,074, 3,422 (O–H) cm-1; UV–
Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax (e) = 323
(18,460) nm (mol-1 dm3 cm-1).
General procedure for pyridone synthesis using
conventional method
A mixture of ethyl acetoacetate (30.0 mmol), 2-cyano-N-
(substituted phenyl)ethanamides (12.0 mmol), and freshly
powdered potassium hydroxide (20.0 mmol) was placed in
a three-necked flask, equipped with condenser, thermom-
eter, and magnetic stirrer, and heated for 3 h under reflux.
The obtained product was suspended in hot water, acidified
with diluted HCl, filtrated, and washed with water and
chloroform.
1
3a: H NMR (500 MHz, DMSO-d6): d = 2.28 (s, 3H,
CH3), 3.79 (s, 3H, OCH3), 5.69 (s, 1H, 5-H), 7.00
(AA0XX0, J = 7.2 Hz, 2H, C6H4OCH3), 7.12 (AA0XX0,
J = 7.2 Hz, 2H, C6H4OCH3), 12.73 (bs, 1H, OH) ppm; 13
C
NMR (125 MHz, DMSO-d6): d = 21.0 (CH3), 55.5
(OCH3), 89.0 (C3), 92.6 (C5), 114.4 (C30, C50), 1,17.8
(C:N), 128.0 (C10), 129.6 (C20, C60), 159.3 (C4), 159.4
(C40), 161.2 (C2), 162.7 (C6) ppm.
1
3b: H NMR (500 MHz, DMSO-d6): d = 1.91 (s, 3H,
CH3), 3.78 (s, 3H, OCH3), 6.07 (s, 1H, 5-H), 7.03
6-Hydroxy-4-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-
3-carbonitrile (1a, C13H10N2O2) and 2-hydroxy-4-methyl-
6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonitrile
(1b, C13H10N2O2)
(AA0XX0, J = 7.4 Hz, 2H, C6H4OCH3), 7.18 (AA0XX0,
J = 7.4 Hz, 2H, C6H4OCH3), 12.73 (bs, 1H, OH) ppm; 13
C
NMR (125 MHz, DMSO-d6): d = 22.0 (CH3), 55.6
(OCH3), 83.6 (C3), 99.0 (C5), 114.8 (C30, C50), 115.6
(C:N), 129.7 (C20, C60), 130.3 (C10), 153.6 (C4), 159.5
(C40), 161.5 (C6), 171.9 (C2) ppm.
White-yellowish crystalline solid; yield 78 %; m.p.:
281–283 °C (Ref. [52] 280–283 °C).
6-Hydroxy-4-methyl-1-(4-methylphenyl)-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (2a, C14H12N2O2)
6-Hydroxy-4-methyl-1-(4-nitrophenyl)-2-oxo-1,2-
dihydropyridine-3-carbonitrile (4a, C13H9N3O4)
and 2-hydroxy-4-methyl-1-(4-methylphenyl)-6-oxo-1,6-
dihydropyridine-3-carbonitrile (2b, C14H12N2O2)
White-yellowish crystalline solid; yield 72 %; m.p.: 284–
285 °C; HRMS: m/z (MH?) calcd for C14H13N2O2
and 2-hydroxy-4-methyl-1-(4-nitrophenyl)-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (4b, C13H9N3O4)
ꢀ
Yellow crystalline solid; yield 73 %; m.p.: 238–242 °C;
HRMS: m/z (MH?) calcd for C13H10N3O4 272.0691, found
272.0666; IR (KBr): ꢀm = 639, 751, 856, 1,112, 1,346,
1,411, 1,514, 1,575, 1,654 (C=O), 1,718, 2,221 (C:N),
2,501, 2,594, 3,085, 3,308, 3,426 (O–H) cm-1; UV–Vis
241.0996, found 241.0972; IR (KBr): m = 514, 655, 816,
1,036, 1,104, 1,131, 1,181, 1,232, 1,415, 1,538, 1,664
(C=O), 2,216 (C:N), 2,507, 2,608, 2,932, 3,078, 3,419
(O–H) cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3):
kmax (e) = 326 (16,420) nm (mol-1 dm3 cm-1).
123

A simple and convenient synthesis of tautomeric substituted dihydropyridine-3-carbonitriles
671
(ethanol, c = 5 9 10-5 mol dm-3): kmax (e) = 335
(500 MHz, DMSO-d6): d = 2.27 (s, 3H, CH3), 5.69 (s, 1H,
5-H), 6.82 (AA0XX0, J = 8.6 Hz, 2H, C6H4OH), 6.98
(AA0XX0, J = 8.8 Hz, 2H, C6H4OH) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 21.0 (CH3), 89.1 (C3), 92.5
(C5), 115.7 (C30, C50), 117.8 (C:N), 126.4 (C10), 129.5
(C20, C60), 157.6 (C40), 159.5 (C4), 161.3 (C2), 161.4 (C6)
ppm.
(15,760) nm (mol-1 dm3 cm-1).
1
4a: H NMR (500 MHz, DMSO-d6): d = 2.28 (s, 3H,
CH3), 5.69 (s, 1H, 5-H), 7.65 (AA0XX0, J = 10 Hz, 2H,
C6H4NO2), 8.32 (AA0XX0, J = 10 Hz, 2H, C6H4NO2),
12.10 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 20.9 (CH3), 88.1 (C3), 95.9 (C5), 118.0 (C:N), 124.1
(C30, C50), 130.3 (C20, C60), 141.0 (C40), 146.3 (C10), 159.0
(C4), 160.9 (C2), 161.3 (C6) ppm.
6-Hydroxy-1-(4-iodophenyl)-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (7a, C13H9IN2O2)
1
4b: H NMR (500 MHz, DMSO-d6): d = 1.93 (s, 3H,
and 2-hydroxy-1-(4-iodophenyl)-4-methyl-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (7b, C13H9IN2O2)
CH3), 6.13 (s, 1H, 5-H), 7.76 (AA0XX0, J = 10 Hz, 2H,
C6H4NO2), 8.36 (AA0XX0, J = 10 Hz, 2H, C6H4NO2),
12.10 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.5 (CH3), 83.4 (C3), 99.4 (C5), 114.9 (C:N), 124.7
(C30, C50), 130.4 (C20, C60), 143.2 (C40), 147.6 (C10), 152.1
(C4), 162.0 (C6), 172.1 (C2) ppm.
Grayish crystalline solid; yield 57 %; m.p.: 288–289 °C;
HRMS: m/z (MH?) calcd for C13H10IN2O2 352.9806,
ꢀ
found 352.9782; IR (KBr): m = 512, 590, 637, 760, 811,
1,009, 1,231, 1,269, 1,416, 1,524, 1,665 (C=O), 2,480,
2,223 (C:N), 2,664, 3,091, 3,426 (O–H) cm-1; UV–Vis
(ethanol, c = 5 9 10-5 mol dm-3): kmax (e) = 328
(6,720) nm (mol-1 dm3 cm-1).
1-(4-Acetylphenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (5a, C15H12N2O3) and
1-(4-acetylphenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (5b, C15H12N2O3)
1
7a: H NMR (500 MHz, DMSO-d6): d = 2.27 (s, 3H,
CH3), 5.66 (s, 1H, 5-H), 7.05 (AA0XX0, J = 10 Hz, 2H,
C6H4I), 7.82 (AA0XX0, J = 10 Hz, 2H, C6H4I), 8.65 (bs,
1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6): d = 20.8
(CH3), 88.0 (C3), 92.8 (C5), 94.6 (C40), 117.5 (C:N),
130.8 (C20, C60), 135.3 (C10), 137.8 (C30, C50), 159.2 (C4),
160.6 (C2), 160.8 (C6) ppm.
Brownish crystalline solid; yield 42 %; m.p.: 227–230 °C;
HRMS: m/z (MH?) calcd for C15H13N2O3 269.0927, found
ꢀ
269.0921; IR (KBr): m = 643, 822, 958, 1,010, 1,267,
1,450, 1,531, 1,666, 1,687 (C=O), 2,219 (C:N), 2,489,
2,593, 3,071, 3,433 (O–H) cm-1; UV–Vis (ethanol,
c = 5 9 10-5 mol dm-3): kmax (e) = 331 (24,040) nm
(mol-1 dm3 cm-1).
1
7b: H NMR (500 MHz, DMSO-d6): d = 1.91 (s, 3H,
CH3), 6.08 (s, 1H, 5-H), 7.11 (AA0XX0, J = 10 Hz, 2H,
C6H4I), 7.87 (AA0XX0, J = 10 Hz, 2H, C6H4I), 8.65 (bs,
1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6): d = 21.7
(CH3), 83.4 (C3), 99.0 (C5), 95.4 (C40), 115.1 (C:N),
130.7 (C20, C60), 137.3 (C10), 138.3 (C30, C50), 152.5 (C4),
162.1 (C6), 171.8 (C2) ppm.
1
5a: H NMR (500 MHz, DMSO-d6): d = 2.27 (s, 3H,
CH3), 2.62 (s, 3H, C(O)CH3), 5.66 (s, 1H, 5-H), 7.38
(AA0XX0, J = 8.5 Hz, 2H, C6H4C(O)CH3), 8.03 (AA0XX0,
J = 8.5 Hz, 2H, C6H4C(O)CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 20.8 (CH3), 26.9 (C(O)CH3),
87.3 (C3), 93.2 (C5), 117.8 (C:N), 128.8 (C30, C50), 129.0
(C20, C60), 136.5 (C40), 139.9 (C10), 158.9 (C4), 160.7
(C2), 161.0 (C6), 197.4 (C(O)CH3) ppm.
1-(4-Chlorophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (8a, C13H9ClN2O2) and 1-(4-
chlorophenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (8b, C13H9ClN2O2)
1
5b: H NMR (500 MHz, DMSO-d6): d = 1.92 (s, 3H,
CH3), 2.63 (s, 3H, C(O)CH3), 6.13 (s, 1H, 5-H), 7.47
(AA0XX0, J = 8.5 Hz, 2H, C6H4C(O)CH3), 8.08 (AA0XX0,
J = 8.5 Hz, 2H, C6H4C(O)CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 21.6 (CH3), 26.9 (C(O)CH3),
83.4 (C3), 99.1 (C5), 115.1 (C:N), 129.0 (C20, C60), 129.3
(C30, C50), 137.0 (C40), 141.5 (C10), 152.3 (C4), 162.0
(C6), 171.9 (C2), 197.4 (C(O)CH3) ppm.
White crystalline solid; yield 64 %; m.p.: 285–287 °C;
HRMS: m/z (MH?) calcd for C13H10ClN2O2 261.0450,
ꢀ
found 261.0425; IR (KBr): m = 515, 638, 738, 817, 1,021,
1,094, 1,232, 1,312, 1,416, 1,492, 1,536, 1,665 (C=O),
2,218 (C:N), 2,507, 2,612, 2,928, 3,074, 3,428 (O–H)
cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax
(e) = 328 (24,040) nm (mol-1 dm3 cm-1).
1
6-Hydroxy-1-(4-hydroxyphenyl)-4-methyl-2-oxo-
8a: H NMR (500 MHz, DMSO-d6): d = 2.27 (s, 3H,
1,2-dihydropyridine-3-carbonitrile (6a, C13H10N2O3)
Gray-brownish crystalline solid; yield 50 %; m.p.: 286–
288 °C; HRMS: m/z (MH-) calcd for C13H9N2O3
CH3), 5.66 (s, 1H, 5-H), 7.28 (AA0XX0, J = 8.6 Hz, 2H,
C6H4Cl), 7.53 (AA0XX0, J = 8.6 Hz, 2H, C6H4Cl) ppm;
13C NMR (125 MHz, DMSO-d6): d = 21.0 (CH3), 88.2
(C3), 93.1 (C5), 117.9 (C:N), 129.3 (C30, C50), 130.7
(C20, C60), 133.2 (C40), 134.7 (C10), 159.5 (C4), 161.0
(C2), 161.2 (C6) ppm.
ꢀ
241.0612, found 241.0618; IR (KBr): m = 543, 633, 768,
830, 1,030, 1,127, 1,168, 1,281, 1,407, 1,442, 1,511, 1,528,
1,665 (C=O), 2,220 (C:N), 2,513, 2,612, 3,060, 3,519 (O–
H) cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3):
1
8b: H NMR (500 MHz, DMSO-d6): d = 1.92 (s, 3H,
CH3), 6.10 (s, 1H, 5-H), 7.36 (AA0XX0, J = 8.8 Hz, 2H,
1
kmax (e) = 331 (23,080) nm (mol-1 dm3 cm-1); H NMR
123

672
I. Ajaj et al.
C6H4Cl), 7.55 (AA0XX0, J = 8.4 Hz, 2H, C6H4Cl) ppm;
13C NMR (125 MHz, DMSO-d6): d = 21.9 (CH3), 83.5
(C3), 99.3 (C5), 115.4 (C:N), 129.8 (C30, C50), 130.7
(C20, C60), 133.8 (C40), 136.6 (C10), 152.9 (C4), 162.5
(C6), 172.1 (C2) ppm.
(C30), 116.4 (C50), 130.5 (C20), 130.6 (C60), 133.7 (C10),
152.9 (C4), 160.8 (C6), 162.3 (C40), 171.7 (C2) ppm.
6-Hydroxy-4-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-
1,2-dihydropyridine-3-carbonitrile (11b, C14H9F3N2O2)
Grayish crystalline solid; yield 66 %; m.p.: 315–317 °C;
HRMS: m/z (MH-) calcd for C14H8F3N2O2 293.0519,
1-(4-Bromophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (9a, C13H9BrN2O2) and 1-(4-
bromophenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (9b, C13H9BrN2O2)
ꢀ
found 293.0543; IR (KBr): m = 570, 626, 657, 706, 807,
1,071, 1,133, 1,249, 1,330, 1,405, 1,461, 1,570, 1,645
(C=O), 2,229 (C:N), 2,610, 2,851, 3,077, 3,431 (O–H)
cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax
(e) = 303 (7,940) nm (mol-1 dm3 cm-1); 1H NMR
(500 MHz, DMSO-d6): d = 1.92 (s, 3H, CH3), 6.18 (s,
1H, 5-H), 7.67 (d, J = 7.6 Hz, 60-H), 7.76 (d, J = 7.4 Hz,
40-H), 7.82-7.89 (m, 2H, 20-H, 50-H), 12.81 (bs, 1H, OH)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 21.9 (CH3),
83.6 (C3), 99.5 (C5), 115.3 (C:N), 126.1 (C40), 126.7
(CF3), 130.2 (C20), 130.8 (C50), 131.0 (C60), 133.3 (C30),
138.5 (C10), 152.7 (C4), 162.5 (C6), 172.3 (C2) ppm.
White crystalline solid; yield 64 %; m.p.: 276–278 °C;
HRMS: m/z (MH?) calcd for C13H10BrN2O2 302.9750,
ꢀ
found 302.9762; IR (KBr): m = 513, 596, 633, 770, 812,
1017, 1,133, 1,246, 1,416, 1,488, 1,545, 1,663 (C=O), 2,219
(C:N), 2,616, 3,419 (O–H) cm-1; UV–Vis (ethanol,
c = 5 9 10-5 mol dm-3): kmax (e) = 323 (15,360) nm
(mol-1 dm3 cm-1).
1
9a: H NMR (500 MHz, DMSO-d6): d = 2.26 (s, 3H,
CH3), 5.66 (s, 1H, 5-H), 7.24 (AA0XX0, J = 8.4 Hz, 2H,
C6H4Br), 7.66 (AA0XX0, J = 8.4 Hz, 2H, C6H4Br), 12.80
(bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.0 (CH3), 88.0 (C3), 93.1 (C5), 117.9 (C:N), 122.4
(C40), 131.1 (C30, C50), 132.7 (C20, C60), 135.2 (C10), 159.4
(C4), 160.9 (C2), 162.4 (C6) ppm.
1-(3-Chlorophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (12a, C13H9ClN2O2) and 1-(3-
chlorophenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (12b, C13H9ClN2O2)
Grayish crystalline solid; yield 59 %; m.p.: 275–278 °C;
HRMS: m/z (MH-) calcd for C13H8ClN2O2 259.0255,
1
9b: H NMR (500 MHz, DMSO-d6): d = 1.92 (s, 3H,
CH3), 6.09 (s, 1H, 5-H), 7.28 (AA0XX0, J = 8.4 Hz, 2H,
C6H4Br), 7.72 (AA0XX0, J = 8.6 Hz, 2H, C6H4Br), 12.80
(bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.9 (CH3), 83.6 (C3), 99.3 (C5), 115.4 (C:N), 121.7
(C40), 131.1 (C30, C50), 132.2 (C20, C60), 137.1 (C10), 152.9
(C4), 161.2 (C6), 172.1 (C2) ppm.
ꢀ
found 259.0279; IR (KBr): m = 581, 627, 690, 745, 789,
818, 1,078, 1,134, 1,297, 1,379, 1,406, 1,489, 1,546, 1,662
(C=O), 2,219 (C:N), 2,594, 3,073, 3,445 (O–H) cm-1
;
UV–Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax
(e) = 323 (12,080) nm (mol-1 dm3 cm-1).
1
12a: H NMR (500 MHz, DMSO-d6): d = 2.28 (s, 3H,
CH3), 5.67 (s, 1H, 5-H), 7.21–7.26 (m, 1H, 60-H), 7.42 (t,
J = 2.2 Hz, 1H, 40-H), 7.50–7.54 (m, 1H, 20-H), 7.55 (d,
J = 1.2 Hz, 1H, 50-H), 12.90 (bs, 1H, OH) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 21.0 (CH3), 88.6 (C3), 93.2
(C5), 117.9 (C:N), 127.7 (C60), 128.7 (C40), 130.7 (C50),
130.8 (C20), 133.3 (C30), 137.2 (C10), 159.4 (C4), 161.3
(C2), 162.4 (C6) ppm.
1-(4-Fluorophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (10a, C13H9FN2O2) and 1-(4-
fluorophenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (10b, C13H9FN2O2)
White-brownish crystalline solid; yield 74 %; m.p.: 284–
285 °C; HRMS: m/z (MH?) calcd. for C13H10FN2O2
1
ꢀ
245.0746, found 245.0721; IR (KBr): m = 537, 643, 655,
12b: H NMR (500 MHz, DMSO-d6): d = 1.94 (s, 3H,
CH3), 6.10 (s, 1H, 5-H), 7.28–7.34 (m, 1H, 60-H), 7.49 (t,
J = 2.2 Hz, 1H, 40-H), 7.50–7.54 (m, 1H, 20-H), 7.57 (d,
J = 1.2 Hz, 1H, 50-H), 12.90 (bs, 1H, OH) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 21.8 (CH3), 83.6 (C3), 99.3
(C5), 115.3 (C:N), 127.8 (C60), 129.0 (C40), 129.4 (C20),
131.3 (C50), 133.9 (C30), 139.1 (C10), 152.8 (C4), 161.0
(C6), 172.1 (C2) ppm.
797, 832, 1,132, 1,156, 1,224, 1,380, 1,408, 1,509, 1,572,
1,637, 1,663 (C=O), 1,637, 2,221 (C:N), 3,434 (O–H)
cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax
(e) = 321 (17,980) nm (mol-1 dm3 cm-1).
1
10a: H NMR (500 MHz, DMSO-d6): d = 2.27 (s, 3H,
CH3), 5.67 (1H, s, 5-H), 7.29 (t, J = 5 Hz, 4H, C6H4F),
12.70 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 20.8 (CH3), 87.8 (C3), 92.8 (C5), 115.7 (C30), 116.2
(C50), 117.6 (C:N), 130.7 (C60), 131.6 (C20), 133.6 (C10),
159.1 (C4), 160.6 (C2), 161.1 (C6), 162.8 (C40) ppm.
1-(3-Bromophenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (13a, C13H9BrN2O2) and 1-(3-
bromophenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (13b, C13H9BrN2O2)
1
10b: H NMR (500 MHz, DMSO-d6): d = 1.92 (s, 3H,
CH3), 6.09 (s, 1H, 5-H), 7.35 (t, J = 5 Hz, 4H, C6H4F),
12.70 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.7 (CH3), 83.4 (C3), 99.0 (C5), 115.0 (C:N), 115.9
Grayish crystalline solid; yield 52 %; m.p.: 278–280 °C;
HRMS: m/z (MH-) calcd for C13H8BrN2O2 302.9750,
123

A simple and convenient synthesis of tautomeric substituted dihydropyridine-3-carbonitriles
673
found 302.9775; IR (KBr): ꢀm = 676, 685, 730, 770, 786,
825, 1,036, 1,070, 1,134, 1,229, 1,246, 1,311, 1,408, 1,474,
1,545, 1,660 (C=O), 2,219 (C:N), 2,593, 2,924 (CH3),
6-Hydroxy-4-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (15a, C14H12N2O2) and
2-hydroxy-4-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (15b, C14H12N2O2)
Grayish crystalline solid; yield 54 %; m.p.: 284–285 °C
(Ref. [53] 278–281 °C).
3,066, 3,435 (O–H) cm-1
;
UV–Vis (ethanol,
c = 5 9 10-5 mol dm-3): kmax (e) = 323 (9,480) nm
(mol-1 dm3 cm-1).
1
13a: H NMR (500 MHz, DMSO-d6): d = 2.26 (s, 3H,
1-(3-Acetylphenyl)-6-hydroxy-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (16a, C15H12N2O3) and 1-(3-
acetylphenyl)-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyr-
idine-3-carbonitrile (16b, C15H12N2O3)
CH3), 5.65 (s, 1H, 5-H), 7.35 (d, J = 7.8 Hz, 1H, 60-H),
7.46–7.51(m, 1H, 40-H), 7.61–7.72 (m, 2H, 20-H, 50-H),
12.88 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.0 (CH3), 87.6 (C3), 93.3 (C5), 117.9 (C:N), 121.5
(C20), 128.2 (C60), 128.3 (C40), 131.5 (C50), 131.7 (C30),
137.4 (C10), 159.2 (C4), 161.1 (C2), 162.5 (C6) ppm.
Gray crystalline solid; yield 52 %; m.p.: 243–245 °C;
HRMS: m/z (M?CH3COO–H2O–H-) calcd for C17H11N2O4
ꢀ
267.0751, found 267.0775; IR (KBr): m = 589, 635, 698,
1
13b: H NMR (500 MHz, DMSO-d6): d = 1.93 (s, 3H,
757, 820, 1,037, 1,133, 1,239, 1,281, 1,412, 1,557, 1,662
(C=O), 2,216 (C:N), 2,356, 2,598, 3,446 (O–H),
3,537 cm-1; UV–Vis (ethanol, c = 5 9 10-5 mol dm-3):
CH3), 6.10 (s, 1H, 5-H), 7.27 (d, J = 6.8 Hz, 1H, 60-H),
7.40–7.45 (m, 1H, 40-H), 7.52–7.60 (m, 2H, 20-H, 50-H),
12.88 (bs, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 21.8 (CH3), 83.5 (C3), 99.3 (C5), 115.3 (C:N), 122.0
(C20), 128.1 (C60), 128.6 (C40), 131.0 (C50), 132.2 (C30),
139.2 (C10), 152.8 (C4), 161.3 (C6), 172.1 (C2) ppm.
k
max (e) = 324 (10,380) nm (mol-1 dm3 cm-1).
16a: H NMR (500 MHz, DMSO-d6): d = 2.29 (s, 3H,
1
CH3), 2.61 (s, 3H, C(O)CH3), 5.70 (s, 1H, 5-H), 7.53 (d,
J = 8 Hz, 1H, 60-H), 7.64-7.62 (m, 1H, 20-H), 7.89 (t,
J = 2 Hz, 40-H), 8.03 (t, J = 7.7 Hz, 50-H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 21.1 (CH3), 27.1 (C(O)CH3),
88.2 (C3), 93.2 (C5), 117.9 (C:N), 128.4 (C20), 128.8
(C40), 130.2 (C60), 133.5 (C50), 136.3 (C10), 138.4 (C30),
159.6 (C4), 161.1 (C2), 162.6 (C6), 197.5 (C(O)CH3) ppm.
6-Hydroxy-1-(3-methoxyphenyl)-4-methyl-2-oxo-1,2-dihy-
dropyridine-3-carbonitrile (14a, C14H12N2O3) and
2-hydroxy-1-(3-methoxyphenyl)-4-methyl-6-oxo-1,6-dihy-
dropyridine-3-carbonitrile (14b, C14H12N2O3)
Gray crystalline solid; yield 47 %; m.p.: 250–252 °C;
HRMS: m/z (MH-) calcd for C14H11N2O3 255.0751, found
255.0775; IR (KBr): ꢀm = 513, 636, 701, 768, 821, 1,050,
1,120, 1,289, 1,412, 1,491, 1,539, 1,609, 1,663 (C=O),
2,218 (C:N), 3,072, 3,436 (O–H) cm-1; UV–Vis (etha-
1
16b: H NMR (500 MHz, DMSO-d6): d = 1.93 (s, 3H,
CH3), 2.59 (s, 3H, C(O)CH3), 6.13 (s, 1H, 5-H), 7.58 (d,
J = 8 Hz, 1H, 60-H), 7.64–7.62 (m, 1H, 20-H), 7.82 (t,
J = 2 Hz, 40-H), 8.03 (t, J = 7.7 Hz, 50-H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 22.0 (CH3), 27.0 (C(O)CH3),
83.7 (C3), 99.4 (C5), 115.4 (C:N), 128.5 (C20), 128.6
(C40), 129.7 (C60), 133.7 (C50), 138.0 (C10), 138.2 (C30),
153.0 (C4), 161.4 (C6), 172.2 (C2), 197.5 (C(O)CH3) ppm.
nol,
c = 5 9 10-5 mol dm-3):
kmax
(e) = 316
(10,580) nm (mol-1 dm3 cm-1).
1
14a: H NMR (500 MHz, DMSO-d6): d = 2.29 (s, 3H,
4-CH3), 3.75 (s, 3H, 30-OCH3), 5.70 (s, 1H, 5-H), 6.79 (dd,
J = 0.75 Hz, 7 Hz, 1H, 60-H), 6.84 (t, J = 2.2 Hz, 1H, 20-H),
7.00 (dd, J = 2 Hz, 6 Hz, 1H, 40-H), 7.38 (t, J = 8.2 Hz, 1H,
50-H), 12.70 (bs, 1H, OH) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 20.8 (4-CH3), 55.3 (30-OCH3), 88.9 (C3),
92.3 (C5), 114.1 (C20), 114.2 (C40), 117.4 (C:N), 120.5
(C60), 129.7 (C50), 136.4 (C10), 159.5 (C4), 159.8 (C30), 160.8
(C2), 162.1 (C6) ppm.
(Z)-4-Methyl-5-[2-(4-nitrophenyl)hydrazono]-2,6-dioxo-1-
phenyl-1,2,5,6-tetrahydropyridine-3-carbonitrile
(17, C19H13N5O4)
The azo dye was synthesized by the diazotization of
pyridone 1 with 4-nitrophenyldiazonium chloride [54]. The
obtained material was filtrated, washed with distilled water,
and recrystallized from methanol and finally purified by
flash chromatography. Dark red powder; yield 64 %; m.p.:
1
14b: H NMR (500 MHz, DMSO-d6): d = 1.94 (s, 3H,
4-CH3), 3.77 (s, 3H, 30-OCH3), 6.08 (s, 1H, 5-H), 6.82 (d,
J = 1 Hz, 1H, 60-H), 6.90 (t, J = 2.2 Hz, 1H, 20-H), 7.03
(dd, J = 2 Hz, 6.5 Hz, 1H, 40-H), 7.41 (t, J = 8.3 Hz, 1H,
50-H), 12.70 (bs, 1H, OH) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 21.5 (4-CH3), 55.4 (C30-OCH3), 83.4
(C3), 98.8 (C5), 1,14.1 (C20), 114.7 (C40), 115.2 (C:N),
120.4 (C60), 130.2 (C50), 138.6 (C10), 152.9 (C4), 160.1
(C30), 160.6 (C6), 171.7 (C2) ppm.
ꢀ
[300 °C; IR (KBr): m = 586, 632, 689, 700, 739, 749,
771, 796, 847, 872, 952, 1,110, 1,152, 1,167, 1,214, 1,260,
1,339, 1,407, 1,423, 1,507, 1,644, 1,697 (C=O), 2,221
(C:N), 2,852, 2,923, 3,082, 3,116, 3,444 (O–H) cm-1
;
UV–Vis (ethanol, c = 5 9 10-5 mol dm-3): kmax
(e) = 430 (24,560) nm (mol-1 dm3 cm-1); 1H NMR
(500 MHz, DMSO-d6): d = 2.63 (s, 3H, 4-CH3), 7.32-7.34
123

674
I. Ajaj et al.
(m, 2H, 50-H, 30-H), 7.46–7.49 (m, 1H, 40-H), 7.51–7.54
(m, 2H, 20-H, 60-H), 7.91 (AA0XX0, J = 9.0 Hz, 2H,
C6H4–NO2), 8.30 (AA0XX0, J = 9.5 Hz, 2H, C6H4–NO2),
14.26 (s, 1H, OH) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 16.6 (CH3), 103.4 (C5), 114.7 (C3), 117.6 (C:N),
125.5 (C6H4–NO2), 125.9 (C40), 128.8 (C6H4–NO2), 128.8
(C30, C50), 129.0 (C20, C60), 133.8 (C10), 144.4 (C6H4–
NO2), 146.5 (C6H4–NO2), 159.6 (C2), 159.9 (C4), 160.2
(C6) ppm.
9. Margolin SB (1999) Inhibition of tumor necrosis factor a by
N-substituted pyridones. US Patent 5,962,478, 5 Oct 1999; (1999)
Chem Abstr 131:267044
10. Li Q, Mitscher LA, Shen LL (2000) Med Res Rev 20:231
11. Dragovich PS, Prins TJ, Zhou R, Brown EL, Maldonado FC,
Fuhrman SA, Zalman LS, Tuntland T, Lee CA, Patick AK,
Matthews DA, Hendrickson TF, Kosa MB, Liu B, Batugo MR,
Gleeson J-PR, Sakata SK, Chen L, Guzman MC, Meador JWIII,
Ferre RA, Worland ST (2002) J Med Chem 45:1607
12. Dragovich PS, Prins TJ, Zhou R, Johnson TO, Brown EL,
Maldonado FC, Fuhrman SA, Zalman LS, Patick AK, Matthews
DA, Hou X, Meador JW, Ferre RA, Worland ST (2002) Bioorg
Med Chem Lett 12:733
13. Patankar SJ, Jurs PC (2002) J Chem Inf Comput Sci 42:1053
14. De Clercq E (1999) Farmaco 54:26
Ab initio theoretical calculation method
15. Parreira RLT, Abrahao O, Galembeck SE (2001) Tetrahedron
57:3243
The geometry optimizations were carried out by the
B3LYP method with the standard basis set 6-311G(d,p).
Harmonic vibrational frequencies were evaluated at the
same level to confirm the nature of the stationary points
found (to confirm that optimized geometry corresponds to a
local minimum that has only real frequencies), and to
account for the zero point vibrational energy (ZPVE) cor-
rection. Global minima were found for every molecule
considering pyridone tautomeric forms a and b, and rota-
tional isomers of meta-substituted derivatives. Solvent
(DMSO) was simulated with the standard polarized con-
tinuum model (PCM). Theoretical calculation of chemical
shifts on optimized geometries can provide a good basis for
the estimation of experimental data. Quantum chemical
16. Brody F, Ruby PR (1960) In: Klinsberg E (ed) Pyridine and its
derivatives, part I. Interscience, New York, p 362
17. Ciufolini MA, Chan BK (2007) Heterocycles 74:101
18. Gorobets NY, Yousefi BH, Belaj F, Kappe CO (2004) Tetrahe-
dron 60:8633
19. Pemberton N, Aberg V, Almstedt H, Westermark A, Almqvist F
(2004) J Org Chem 69:7830
20. Pemberton N, Chorell E, Almqvist F (2006) Top Heterocycl
Chem 1:1
21. Pemberton N, Jakobsson L, Almqvist F (2006) Org Lett 8:935
22. Mijin D, Marinkovic A (2006) Synth Commun 36:193
23. Mijin DZ, Baghbanzadeh M, Reidlinger C, Kappe CO (2010)
Dyes Pigm 85:73
24. Matsui M, Joglekar B, Ishigure Y, Shibata K, Muramatsu H,
Murata Y (1993) Bull Chem Soc Jpn 66:1790
25. Toritsuka K, Ito A, Okaji M, Futaki K (1989) Electrophoto-
graphic photoreceptor containing hydroxypyridonylazo pigment.
JP Patent 1,234,856, 20 Sep 20 1989; (1990) Chem Abstr
113:31880
26. Adachi K, Inagaki Y, Jinbo Y (1988) Optical recording material
containing azomethine dye. JP Patent 63,247,092, 13 Oct 1988;
(1989) Chem Abstr 110:85706
1
calculation of H and 13C NMR chemical shifts (method
GIAO, WP04 functional and aug-cc-pVDZ basis set, and
PCM for inclusion of solvation effect) were done. Tauto-
mer electronic energies and atomic charges (ChelpG
method) were calculated on B3LYP/6-311G(d,p) opti-
mized geometries with the B3LYP/6-311??G(3df,3pd)
method. All calculations were done with the Gaussian03
program package [55].
27. Pedrazzi R (1986) Monoazo dyes. WO Patent 8,601,815, 27 Mar
1986; (1986) Chem Abstr 105:174399
28. Von Brachel H, Heinrich E, Grawinger O, Hintermeier K, Kin-
dler H (1981) Water-insoluble monoazo pyridone dye. US Patent
4,247,456, 27 Jan 1981; (1981) Chem Abstr 94:176681
29. Dattatraya IB, Dattatraya DA, Ramanuj AN (1980) Yellow to
violet azo-N-substituted pyridinone disperse dyes for synthetic
fibers. IN Patent 147,527, 29 Mar 1980; (1981) Chem Abstr
94:4943
Acknowledgments The authors are grateful to the Ministry of
Education, Science, and Technological development of the Republic
of Serbia for financial support (Project 172013).
30. Neeff R, Rolf M, Mueller W (1981) Anthraquinone-azomethines
and their use as dyes and pigments. DE Patent 2,931,710, 19 Feb
1981; (1981) Chem Abstr 94:210292
References
31. Harvey ED, Lewis JF (1980) Hydrophilic textiles colored with
azo dyes and a process for their coloration. GB Patent 1,559,001,
9 Jan 1980; (1980) Chem Abstr 92:182492
ˇ ´ ˇ ´
1. Misic-Vukovic M, Mijin D, Radojkovic-Velickovic M, Valentic
N, Krstic V (1998) J Serb Chem Soc 63:585
´
´
´
´
2. Litvinov VP, Krivokolysko D, Dayachenko VD (1999) Chem
Heterocyclic Compd 35:509
3. Rigby JH (2000) Synlett 1
32. Austin PW, Crabtree A (1973) 1- or 4-(Sulfoaryl)-6-hydroxy-2-
pyridinones. US Patent 3,763,170, 2 Oct 1973; (1973) Chem
Abstr 79:147434
4. Pastelin G, Mendez R, Kabela E, Farah A (1983) Life Sci
33:1787
5. Presti EL, Boggia R, Feltrin A, Menozzi G, Dorigo P, Mosti L
(1999) Farmaco 54:465
33. Kamosaki T, Kimura K, Ogiyama M (2000) Silver halide color
photographic photosensitive material and method for forming
image. EP Patent 1,037,101, 20 Sep 2000; (2000) Chem Abstr
133:259281
6. Dorigo P, Fraccarolo D, Gaion RM, Santostasi G, Borea PA,
Floreani M, Mosti L, Maragno I (1997) Gen Pharm 28:781
7. Altomare C, Cellamare S, Summo L, Fossa P, Mosti L, Carotti A
(2000) Bioorg Med Chem 8:909
34. Von Brachel H, Heinrich E, Graewinger O, Hintermeier K,
Kindler
1,813,385, 2 Jul 1970; (1970) Chem Abstr 73:99995
H
(1970) 5-(Phenylazo)-2-pyridones. DE Patent
35. Ohkawa A, Takizawa H, Ishikawa S-I, Yokokawa T (1998) Heat-
developable light-sensitive color imaging material and method of
8. Anderson WK, Dean DC, Endo T (1990) J Med Chem 33:1667
123

A simple and convenient synthesis of tautomeric substituted dihydropyridine-3-carbonitriles
675
forming color images. EI Patent 846,982, 10 Jun 1998; Chem
Abstr 129:74080
36. Chen CC, Wang IJ (1991) Dyes Pigm 15:69
37. Habashi A, Ibraheim NS, Sherif SM, Shams HZ, Mohareb RM
(1986) Heterocycles 24:2463
49. Khalili B, Tondro T, Hashemi MM (2009) Tetrahedron 65:6882
´
(2005) Chem Rev 1055:3561
¨
51. Limbach HH, Mannle F, Detering C, Denisov GS (2005) Chem
Phys 319:69
´
´
50. Raczynska ED, Kosinska W, Osmialowski B, Gawinecki R
38. Tsizin YuS, Kuklenkova OB, Lopatin BV, Bebris NK (1992)
Khim Geterotsikl Soedin 1636
52. Habashi A, Ibraheim NS, Mohareb RM, Fahmy SM (1986) Lie-
bigs Ann Chem 9:1632
39. Siedel MC, Viste KL, Yih RY (1973) N-Aryl-2-pyridones. US
Patent 3,761,240, 25 Sep 1973; (1970) Chem Abstr 72:21616
40. Sues O, Schaefer H (1970) Cyanoacetic acid amides as couplers
in diazotype process. GB Patent 1,284,608, 16 Feb 1970; (1970)
Chem Abstr 73:89164
41. Piccinini G, Delpiano A (1907) Chem Zentr 78:335
42. Glasnov TN, Kappe CO (2007) Macromol Rapid Comm 28:395
43. Szyc Ł, Guo J, Yang M, Dreyer J, Tolstoy PM, Nibbering ETJ,
Czarnik-Matusewicz B, Elsaesser T, Limbach HH (2010) J Phys
Chem A 114:7749
53. Mustroph H, Bartel R, Seele T (1990) Diazo copying material
with improved sensitivity. DD Patent 276,171, 14 Feb 1990;
(1990) Chem Abstr 113:162604
54. Ertan N, Gu¨rkan P (1997) Dyes Pigm 33:137
55. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Montgomery Jr JA, Vreven T, Kudin KN, Burant
JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B,
Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada
M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nak-
ajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE,
Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J,
Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R,
Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA,
Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels
AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghava-
chari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S,
Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P,
Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng
CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B,
Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03,
revision C.02. Gaussian, Inc, Wallingford, CT
44. Tsuchida N, Yamabe S (2005) J Phys Chem A 109:1974
´
45. Kolehmainen E, Osmialowski B, Krygowski TM, Kauppinen R,
Nissinen M, Gawinecki R (2000) J Chem Soc Perkin Trans
2:1259
´
46. Kolehmainen E, Osmialowski B, Nissinen M, Kauppinen R,
Gawinecki R (2000) J Chem Soc Perkin Trans 2:2185
47. Hansch C, Leo A, Hoekman D (1995) In: Exploring QSAR:
hydrophobic, electronic and steric constants. American Chemical
Society, Washington, DC
ˇ
48. Uscumlic GS, Mijin DZ, Valentic NV, Vals VV, Susic BM
ˇ´
(2004) Chem Phys Lett 397:148
´
´
ˇ ´
123