Synthesis, characterization and quantum-chemical calculations of novel series of pyridones, quinazolinones and pyrazoles heterocyclic compounds

Article abstract of DOI:10.1007/s13738-015-0644-6

This paper presents a combined synthesis and computational study of novel series of pyridones, quinazolinones and pyrazoles heterocyclic compounds that were characterized by elemental analyses and spectral dada. Michael addition of substituted-2-methoxyca

Full text of DOI:10.1007/s13738-015-0644-6

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0644-6
ORIGINAL PAPER
Synthesis, characterization and quantum‑chemical calculations
of novel series of pyridones, quinazolinones and pyrazoles
heterocyclic compounds
M. A. Salem1,3 · M. H. Helal1,2 · Taha M. A. Eldebss4 · T. A. Abd‑elaziz1 ·
A. A. El‑Sherif2,4 · G. A. M. Mohamed1
Received: 15 January 2015 / Accepted: 5 April 2015
© Iranian Chemical Society 2015
Abstract This paper presents a combined synthesis and
computational study of novel series of pyridones, quina-
zolinones and pyrazoles heterocyclic compounds that
were characterized by elemental analyses and spectral
dada. Michael addition of substituted-2-methoxycarbon-
ylacetanilide 2a, b on the α-substituted cinnamonitriles
3a–d gave the corresponding pyridone and quinazolinone
derivatives 5, 6a–c, 7a–d, and 14a–e, respectively. Reac-
tion of ethyl-2-cyano3-ethoxyacrylate with 2a, b afforded
the corresponding pyridone 10a, b. Also, spiro pyridine
derivative 12 was synthesized through the reaction of 2a, b
with indandione malononitrile (11). Reaction of hydrazine
and phenyl hydrazine with acrylamido derivatives 15a–d
afforded the novel pyrazoles 16 and 17. The molecular
modeling of the synthesized compounds has been drawn
and their molecular parameters were calculated. Also,
valuable information is obtained from the calculation of
molecular parameters including electronegativity of the
coordination sites, net dipole moment of the compounds,
total energy, electronic energy, binding energy, HOMO and
LUMO energy.
Keywords Pyridones · Quinazolinones · Pyrazoles ·
Molecular modeling · Michael addition
Introduction
The importance of heterocyclic compounds has long been
recognized in the field of synthetic organic chemistry and
has been extensively studied due to their important prop-
erties and applications at present. It is well known that a
number of heterocyclic compounds containing nitrogen
exhibited a wide variety of biological activity. Also, in
recent years, the high therapeutic properties of the hetero-
cyclic compounds have attracted the attention of pharma-
ceutical chemists to synthesize a large number of novel
chemotherapeutic agents and many pharmaceuticals are
synthetic compounds and heterocyclic in nature. Among
these compounds, pyridines [1], quinazolinone derivatives
[2] and pyrazoles [3] have become especially noteworthy in
recent years.
Quinazoline and quinazolinone nuclei have drawn a great
attention due to their wide range of chemotherapeutic activi-
ties including antiviral [3], antibacterial [4], antifungal [5,
6], antimalarial [7], anticancer [8–10], antihypertensive [11],
diuretic [12, 13], inhibitors of derived growth factor recep-
tor phosphorylation [14], anticonvulsant [15], anti-inflamma-
tory and analgesic [16, 17]. Additionally, pyridones have a
wide range of biological activities like antitumor, cytotoxic
activities, anti-inflammatory and analgesic activities [18–22].
Also, pyrazoles act as an important class of compounds for
new drug development that attracted much attention due to
their broad spectrum of biological activities, such as anti-
inflammatory [23], antifungal [24], anticancer [25], antibac-
terial [26], antiviral [27], antidepressant [28], antidiabetic
[29] and antioxidant [30] activities. Computational chemistry
* Taha M. A. Eldebss
taha_eldebss@yahoo.com
1
Department of Chemistry, Faculty of Science, Al-Azhar
University, Nasr City, 11284 Cairo, Egypt
2
Department of Chemistry, Faculty of Arts and Science,
Northern Border University, Rafha, Kingdom of Saudi Arabia
3
Department of Chemistry, Faculty of Science and Arts, King
Khalid University, Mohail Assir, Kingdom of Saudi Arabia
4
Department of Chemistry, Faculty of Science, Cairo
University, Giza, Egypt
1 3

J IRAN CHEM SOC
has become of great importance, especially in recent years
[31]. It allows us to understand the probable behavior of the
compound during reactions and further to know an impor-
tant information about the compounds under investigations,
like total energy, binding energy, electronic energy, dipole
moment, bond lengths, HOMO, LUMO [32], and the value
of this information increases especially when it agrees with
the experimental data. The applicability of the semi-empir-
ical methods PM3 for the calculation of novel synthesized
compounds has been evaluated [33, 34].
In view of the above facts and in continuation of our
research program [35–43] directed to synthesize new com-
pounds, our current work highlights design, synthesis,
characterization and molecular modeling of various pyri-
dones, pyrazoles and quinazolinone derivatives.
ethanol in the presence of catalytic amount of piperidine
gave the corresponding pyridones of type 5 and 6a–c,
respectively. The structures of the synthesized products
were confirmed on the basis of their elemental analyses
and spectral data (see “Experimental” part). The formation
of pyridones 5 and 6 was assumed to be proceeded via the
Michael addition of active methylene group of compound
2a on the β-carbon atom of cinnamonitrile derivatives to
give the Michael adduct 4, intramolecular cyclization of 4
followed by elimination of HX or H2 molecule, afforded
pyridones 5 and 6, respectively, (Scheme 2).
Similarly, treatment of methyl 2-(3-ethoxy-3-oxopro-
panamido)benzoate 2b with α-substituted cinnamoni-
triles 3a–c in refluxing ethanol in the presence of catalytic
amount of piperidine afforded the corresponding pyridones
derivatives 7a–d via the intramolecular cyclization of the
Michael adduct 4a through addition–elimination reaction
on the carbonyl group followed by elimination of HX or
H2 molecule (Scheme 3). The structures of the latter prod-
ucts were established on the basis of their elemental analy-
ses and spectral data. For example, 13C NMR spectrum
(DMSO-d6) of compound 7a revealed signals at δ 13.91,
21.26, 52.29, 62.19, 115.67, 161.91, and 167.08 ppm attrib-
uted to ethoxy carbonyl, methyl, methoxy, cyano and car-
bonyl carbon atoms.
Results and discussion
Chemistry
The required starting material 2a, b [44] was synthesized in
good yield (80 %) through the reaction of methyl 2-amin-
obenzoate with diethylmalonate 1a or ethyl cyanoacetate
1b in refluxing xylene (Scheme 1).
Reaction of methyl 2-(2-cyanoacetamido)benzoate
(2a) with α-substituted cinnamonitriles 3a–c in refluxing
Also, 3, 4-dihydropyridone derivative 8 was obtained
via the reaction of acetanilide derivative 2a with 2-cyano-
3-(fuan-2-yl) acylamide 3d as shown in Scheme 4. 1HNMR
spectrum (DMSO-d6) of pyridone derivative 8 showed
two doublets at 3.70 and 3.86 ppm for pyridine-H3 and
H4, respectively, that was compatible with the proposed
structure.
Ternary condensation of 2a or 2b with acetaldehyde and
malononitrile in refluxing ethanol containing piperidine
as catalyst afforded 5-cyanopyridone derivative 9 through
releasing of HCN molecule. Also, reaction of 2a, b with
Scheme 1 Synthesis of acetanilide derivatives 2a, b
Scheme 2 Synthesis of 2-pyri-
dones derivatives 5 and 6
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J IRAN CHEM SOC
Scheme 3 Synthesis of 2-pyri-
dinone derivatives 7
Scheme 4 Synthesis of amido
pyridine derivative 8
diethoxy acrylonitrile furnished the pyridone types 10a, b
(Scheme 5). The structures of the synthesized compounds
9 and 10 were elucidated on the basis of their elemental
and spectral data. For example, the IR spectrum of com-
pound 9 showed bands at 3337, 3242 (NH2). 2200 (C≡N)
and 1670 cm−1 (C=O). The appearance of three singlet
On the other hand, quinazolines 14a–e were synthesized
via reaction of compound 2b with α-substituted cinnamoni-
triles 3 in refluxing DMF containing catalytic amounts of
piperidine. The structure of the isolated products was con-
firmed based on their elemental analyses and spectral data.
For example, 1H NMR spectrum (DMSO-d6) of compound
14d revealed a triplet signal at δ 1.25 ppm for CH3 group
and a quartet signal at δ 4.38 ppm corresponding to CH2
group in addition to the presence of aromatic and OH pro-
tons at δ 7.54–8.12 and 9.53 ppm, respectively. The isolated
product 14 was assumed to proceed via the formation of
pyridine intermediate 13 followed by elimination of metha-
nol molecule (Scheme 6).
In this part of research the study was extended to syn-
thesis quinazoline derivatives containing pyrazole func-
tionalities. Thus, the reactivity of the substituted-2-meth-
oxycarbonyl acetanilide 2a, b towards some electrophiles
was investigated. Condensation of 2a, b with aromatic
aldehydes in ethanol in the presence of piperidine under
reflux gave the corresponding methyl 2-(substituted-3-ar-
ylacrylamido) benzoate 15a–d, (Scheme 7). The elemental
analyses and spectral data were in a complete accordance
with expected structures 15a–d. The reaction of hydrazine
hydrate with 15d and reaction of phenyl hydrazine with
1
signals in H NMR spectrum (DMSO-d6) at δ 2.18, 3.85
and 6.25 ppm attributed to CH3, CH3O and pyridine-H3
protons, respectively, in addition to aromatic protons with
NH2 in the region 7.20–8.30 ppm. Its mass spectrum exhib-
ited a peak at 283 due to molecular ion that confirmed the
assigned structure (Scheme 5).
In a similar manner, 2a, b was reacted with 1, 3-indan-
dione malononitrile (11) and gave the corresponding
spiro pyridine derivatives 12 (Scheme 5) whose structure
was established on the basis of its elemental analysis and
spectral data. For example, IR spectrum of compound 12
afforded bands at 3355, 3144 (NH2), 2202 (C≡N),1670
(C=O) cm−1 and its 1H NMR spectrum (DMSO-d6)
showed triplet and quartet signals at δ = 1.07, 4.03 ppm for
ethoxy protons, a singlet signal at δ 2.74 ppm for (CH2), a
singlet signal at δ 3.80 ppm (OCH3), and multiple signals
at δ 7.27–8.24 ppm (Ar–H + NH2) in addition to a singlet
signal at δ 12.19 ppm for hydroxyl group.
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J IRAN CHEM SOC
Scheme 5 Synthesis of
2-pyridones 9, 10 and pyridine
derivative 12
Scheme 6 Synthesis of
pyrido[1,2-a]quinazoline deriva-
tives 14a–e
15a, b, d in refluxing ethanol afforded the novel pyrazoles
16 and 17 a, b, d, respectively (Scheme 7). The structures
of the synthesized products were confirmed on the basis
of their elemental analyses and spectral data (see “Experi-
mental” part). On the other hand, 3-amino or hydroxy-5-
aryl-1H-pyrazol-4-yl) quinazolin-4(3H)-one derivatives
18a–c and 19a–d were formed through consumption of
2 mol of hydrazine hydrate or semicarbazide in reaction
with arylacrylamido derivatives 15 depending on elemen-
tal analyses and spectral data (see “Experimental” part)
(Scheme 7).
level provided by HyperChem 7.5 software. The most sta-
ble structures obtained were subsequently optimized to the
closest local minimum at the semiempirical level using
PM3 parameterizations. The calculated dipole moment
(µ), total energy (ET), binding energy (EB), and electronic
energy (EE) after geometrical optimization of the structures
of complexes are given in Table 1.
The values of the following parameters: the highest
occupied molecular orbital energy (EHOMO), the lowest
unoccupied molecular orbital energy (ELUMO), the dif-
ference between HOMO and LUMO energy levels (ΔE),
Mulliken electronegativity (χ), chemical potential (Pi),
global hardness (η), global softness (S), global electro-
philicity (ω) [45–49] and additional electronic charge
(ΔNmax) have been calculated [50] using semi-empirical
PM3 method as implemented in HyperChem [51]. In a
first step, the molecular geometries of all compounds
Molecular modeling and computational study
In the absence of a crystal structure, to obtain the molecular
conformation of a compound, energy minimization studies
were carried out on the basis of the semi-empirical PM3
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J IRAN CHEM SOC
Scheme 7 Synthesis of
pyrazoles 16, 17 in addition to
quinazolinones 18 and 19
were fully optimized in the gas phase to gradients of
0.01 kcal mol−1 Å−1 and afterwards the molecular descrip-
tors were determined.
The concepts of the parameters χ and Pi are related to
each other. The inverse of the global hardness is designated
as the absolute softness σ.
Equations (1)–(7) are used in calculations of molecular
parameters as given below:
Recently, quantum-chemical calculation methods have
become available to provide a powerful approach for crys-
tal structure prediction [52–57].
χ = −1/2(ELUMO − EHOMO
Pi = −χ
)
(1)
(2)
Molecular parameters
η = 1/2(ELUMO − EHOMO
S = 1/2η
)
(3)
(4)
(5)
According to the obtained data given in Table 2, we can
deduce each of the following:
(a) Absolute hardness (η) and softness (σ) are important
properties to measure the molecular stability and reac-
tivity. A hard molecule has a large energy gap and a
soft molecule has a small energy gap. Soft molecules
are more reactive than hard ones because they could
easily offer electrons to an acceptor.
ω = Pi2/2η
σ = 1/η
(6)
(7)
�N
max
= −Pi/ η
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J IRAN CHEM SOC
Dipole moment
Table 1 Some energetic properties of synthesized compounds calculated by PM3 method
Compound
Total energy (kcal mol−1
)
Binding energy (kcal mol−1
)
Electronic energy (kcal mol−1
)
5
−109,849.5
−111,066.0
−104,504.8
−108,546.0
−102,956.7
−99,505.7
−117,885.2
−87,323.4
−77,113.1
−113,912.3
−96,833.1
−127,334.5
−107,961.5
−101,012.4
−105,124.2
−110,646.0
−121,636.3
−954,149.2
−105,907.5
−95,800.3
−88,748.5
−96,863.2
−124,477.8
−117,394.2
−114,702.0
−97,150.0
−90,198.6
−94,475.7
−124,370.0
−117,389.6
−121,670.1
−114,724.6
−5568.3
−4789.2
−4893.9
−5630.1
−4657.2
−4374.2
−5217.9
−4165.8
−3796.1
−5169.3
−4437.9
−5937.0
−4551.3
−4569.4
−5376.3
−5130.7
−5848.8
−4556.1
−4913.7
−4186.8
−4102.2
−4344.2
−5659.2
−5542.8
−5587.0
−4171.3
−4187.2
−4233.3
−5043.7
−5030.6
−5080.1
−5101.9
−908,290.4
−894,354.1
−863,642.2
−944,900.8
−794,702.6
−733,827.6
−973,030.1
−650,543.1
−550,277.4
−915,394.6
−732,917.2
−1,120,130.6
−861,262.0
−812,342.0
−891,516.4
−924,543.8
−1,085,935.9
−729,224.8
−833,867.7
−672,873.6
−656,031.7
−710,672.2
−1,069,852.6
−1,003,366.0
−995,974.4
−770,606.0
−720,513.5
−767,778.7
−1,068,524.0
−1,025,429.3
−1,081,919.1
−1,046,102.2
3.45
4.68
5.72
6.40
2.95
4.74
2.77
2.65
3.76
3.36
6.47
11.58
4.52
5.85
8.42
6.52
5.65
6.90
4.24
4.98
4.05
7.62
4.71
5.81
6.30
7.31
7.93
7.91
6.55
6.06
6.16
6.96
6a
6b
6c
7a
7b
7c
7d
9
10a
10b
12
14a
14b
14c
14d
14e
15a
15b
15c
15d
16
17a
17b
17c
18a
18b
18c
19a
19b
19c
19d
(b) The reactivity index measures the stabilization in
energy when the system acquires an additional elec-
tronic charge (ΔNmax) from the environment. The elec-
trophilicity index is positive quantity and the direction
of the charge transfer is completely determined by
the electronic chemical potential (Pi) of the molecule
because an electrophile is a chemical species capa-
ble of accepting electrons from the environment and
its energy must decrease upon accepting electronic
charge. Therefore, the electronic chemical potential
must be negative, exactly as supported by the values in
Table 2.
lar orbitals are also called the frontier molecular orbit-
als (FMOs) and determine the way of interaction for
the molecule with other species. The FMOs are impor-
tant in molecular reactivity. HOMO energy is closely
related to reactivity to electrophilic attack (i.e., could
act as an electron donor), since it is the highest energy
orbital containing electrons while LUMO energy is
closely related to reactivity to nucleophilic attack (i.e.,
could act as the electron accepter), since it is the lowest
energy orbital that can accept electrons.
(d) The energies of the HOMO and LUMO are negative,
which indicate that the title molecules are stable [55].
(e) However, the LUMO energy presents the ability of a
molecule receiving an electron, thus the lower value of
ELUMO indicates that the high ability of the molecule
(c) The highest occupied molecular orbital (HOMO) and
lowest unoccupied molecular orbital (LUMO) are very
popular quantum-chemical parameters. These molecu-
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J IRAN CHEM SOC
Table 2 The calculated
quantum-chemical parameters
Compound
HOMO
LUMO
ΔE
x
η
σ
Pi
ω
ΔNmax
of the synthesized compounds
5
−8.72
−4.56
−8.99
−8.98
−9.22
−9.28
−9.24
−9
−0.82
−1.27
−1.28
−1.24
−0.95
−1.02
−1.09
−0.69
−0.76
−0.79
−1.04
−3.83
−2.19
−2.04
−1.75
−1.73
−1.31
−0.94
−1.17
−1.68
−2.32
−0.88
−2.64
−2.37
−2.46
−2.39
−2.48
−1.03
−2.36
−2.34
−2.36
7.9
4.77
2.915
5.135
5.11
5.39
0.1855
0.0962
0.0878
0.0807
0.0747
0.0695
0.0650
0.0610
0.0575
0.0544
0.0516
0.0490
0.0468
0.0447
0.0428
0.0410
0.0394
0.0379
0.0365
0.0352
0.0340
0.0329
0.0319
0.0309
0.0299
0.0291
0.0283
0.0275
0.0267
0.0260
0.0254
−4.77
−2.915
−5.135
−5.11
−5.085
−5.15
−5.165
−4.845
−4.755
−4.81
−4.985
−5.365
−5.195
−5.08
−5.37
−5.345
−4.56
−5.13
−5.15
−5
2.1107
0.4089
1.1575
1.0538
0.9655
0.9216
0.8667
0.7161
0.6501
0.6290
0.6408
0.7058
0.6309
0.5763
0.6164
0.5857
0.4095
0.4986
0.4842
0.4403
0.5307
0.4039
0.5239
0.4312
0.3781
0.3541
0.3603
0.2727
0.2613
0.2877
0.4102
0.8850
0.2806
0.4508
0.4124
0.3798
0.3579
0.3356
0.2956
0.2734
0.2616
0.2571
0.2631
0.2429
0.2269
0.2296
0.2191
0.1796
0.1944
0.1880
0.1761
0.1900
0.1630
0.1827
0.1632
0.1505
0.1435
0.1427
0.1224
0.1182
0.1224
0.1443
6a
3.29
7.71
7.74
8.27
8.26
8.15
8.31
7.99
8.04
7.89
3.07
6.01
6.08
7.24
7.23
6.5
10.39
11.39
12.39
13.39
14.39
15.39
16.39
17.39
18.39
19.39
20.39
21.39
22.39
23.39
24.39
25.39
26.39
27.39
28.39
29.39
30.39
31.39
32.39
33.39
34.39
35.39
36.39
37.39
38.39
39.39
6b
6c
7a
5.085
5.15
7b
7c
5.165
4.845
4.755
4.81
7d
9
−8.75
−8.83
−8.93
−6.9
10a
10b
12
4.985
5.365
5.195
5.08
14a
14b
14c
14d
15a
15b
15c
15d
16
−8.2
−8.12
−8.99
−8.96
−7.81
−9.32
−9.13
−8.32
−8.85
−9.03
−8.83
−8.2
5.37
5.345
4.56
8.38
7.96
6.64
6.53
8.15
6.19
5.83
5.13
5.09
5.14
6.85
4.12
4.72
6.65
5.13
5.15
5
5.585
4.955
5.735
5.285
5.025
4.935
5.05
−5.585
−4.955
−5.735
−5.285
−5.025
−4.935
−5.05
−4.455
−4.42
−4.7
17a
17b
17c
18a
18b
18c
19a
19b
19c
19d
−7.59
−7.48
−7.62
−7.88
−6.48
−7.06
−9.01
4.455
4.42
4.7
5.685
−5.685
is to accept electrons [56, 57]. The HOMO energy
implies that the molecule is a good electron donor so
the lower HOMO energy values show that the mol-
ecule donating electron ability is weaker.
large HOMO–LUMO gap automatically means high
excitation energies, good stability and a large chemical
hardness for the title compounds.
(f) The HOMO–LUMO energy gap, ΔE, which is an
important stability index, is applied to develop theoret-
ical models for explaining the structure and conforma-
tion barriers in many molecular systems. A molecule
with a small gap is more polarized and is known as soft
molecule. Soft molecules are more reactive than hard
ones because they easily offer electrons to an acceptor
[58, 59].
(g) The HOMO–LUMO energy separation has been used
as a simple indicator of kinetic stability and chemical
reactivity of the molecule. The values of the energy
separation between the HOMO and LUMO for the
synthesized compounds lie in the range 3.07–8.38. The
Bond length and bond angle calculations
Theoretical calculations have paid a considerable attention
to the characterization and inferences of geometrical opti-
mization of the prepared compounds; therefore, we could
obtain the optimized structure for the prepared compounds
by computing the theoretical physical parameters, such as
bond lengths and bond angles using the HyperChem 7.5
software. The optimized structures for the 5, 14a and 17a
with the atomic numbering scheme as a representative
example of pyridines, quinazolinones and pyrazoles hetero-
cyclic compounds, respectively, are shown in the Figs. 1, 2
and 3. The bond angles and bond lengths (Å) obtained from
1 3

J IRAN CHEM SOC
Fig. 1 The molecular structure of compound 5 along with the atom numbering scheme
the minimization of energy for the structure of 17a as a rep-
resentative example of the reported compounds are given in
the Table 3. In most of the cases, the actual bond lengths
and bond angles are close to the optimal values, and thus
the proposed structure of the compound is acceptable.
Chemistry
General procedure for preparation of 5 and 6a–c
A mixture of compounds either 2a (2.18 g) or 2b (2.65 g)
(0.01 mmol), α-cyanocinnamonitriles 3 (1.54 g, 0.01 mmol)
and piperidine (0.05 mL) in ethanol (30 mL) were refluxed
for 3 h; the solid product was receipted out on heating, then
collected and recrystallized from suitable solvent to give 5
and 6a–c.
Methyl-2-(6-amino-5-cyano-4-(furan-2-yl)-2-oxopyri-
din-1(2H)-yl) benzoate (5): Brown powder (MeOH); m.p.:
yield 60 %; 164–166 °C; IR (KBr, ν¯, cm−1): 3330, 3270,
(NH2), 2213(C≡N) and 1660 (C=O); 1H NMR (200 MHz,
DMSO-d6): δ 3.85 (s, 3H, OCH3),6.51 (s, 1H, pyridine-H),
7.14–8.33 (m, 7H, Ar–H), 9.50 (s, 2H, NH2); Anal. Calcd
for C18H13N3O4 (335): C, 64.47; H, 3.91; N, 12.53. Found:
C, 64.89; H, 3.39 N, 12.07 %.
Conclusion
We report a facile route for the formation of a novel series
of pyridones, quinazolinones and pyrazoles heterocy-
clic compounds. The compounds have been characterized
1
by elemental analyses and spectral like IR, H NMR, 13C
NMR and MS studies. Geometry optimization and con-
formational analysis have been performed and molecular
parameters were calculated. Further investigations on bio-
logical activities with these derivatives are still underway in
our laboratory.
Methyl-2-(6-amino-3,5-dicyano-4-(2,4-dichlorophenyl)-
2-oxopyridin-1(2H)-yl)benzoate (6a): White powder
(EtOH); yield 74 %; m.p.: 168–170 °C; IR (KBr, ν¯, cm−1):
34213, 3200 (NH2) 2218(C≡N) and 1697 (C=O). 1H NMR
(200 MHz, DMSO-d6): δ 3.89 (s, 3H, OCH3), 7.24–8.00
(m, 9H, Ar–H + NH2); Anal. Calcd for C21H12Cl2N4O3
(438): C, 57.42; H, 2.75; N, 12.76. Found: C, 57.22; H,
3.01 N, 13.27 %.
Methyl-2-(6-amino-4-(2-chlorophenyl)-3,5-dicyano-
2-oxopyridin-1(2H)-yl)benzoate (6b): Brown powder
(EtOH), yield 71 %; m.p.: 174–176 °C; IR (KBr, ν¯, cm−1):
3423, 3180 (NH2), 2218(C≡N) and 1693 (C=O); 1H
NMR (200 MHz, DMSO-d6): δ 3.91 (s, 3H, OCH3), 7.29–
8.15 (m, 8H, Ar–H),9.21 (s, 2H, NH2); MS: 405 (M + 1:
0.78 %); Anal. Calcd for C21 H13ClN4O3 (404): C, 62.31;
H, 3.24; N, 13.84. Found: C, 62.22; H, 3.21 N, 13.84 %.
Experimental
Materials and methods
All melting points (m.p.) are uncorrected. IR spectra were
recorded on “Buck scientific infrared spectroscopy M500
spectrophotometer” using KBr pellets. All the NMR spec-
tra were recorded on Gemini 200 MHz spectrometer using
TMS as internal standard; chemical shifts are reported as
(ppm), s = singlet, bs = broad singlet, d = doublet, t = tri-
plet, m = multiplet. The mass spectra (MS) were recorded
on GCMS/QP 1000 Ex mass spectrometer at 70 eV. Ele-
mental analyses were carried out at the Microanalytical
Center, Faculty of Science (Cairo University, Egypt).
1 3

J IRAN CHEM SOC
Fig. 2 The molecular structure of compound 14a along with the atom numbering scheme
Methyl-2-(6-amino-3,5-dicyano-4-(4-(dimethylamino)
phenyl)-2-oxopyri-din-1(2H)-yl)benzoate (6c): Yellow
solid (MeOH); yield 86 %; m.p.: 186–188 °C; IR (KBr, ν¯
, cm−1): 3423, 3180, (NH2), 2218(C≡N) and 1693 (C=O);
1H NMR (200 MHz, DMSO-d6): δ 3.09 (s, 6H, N(CH3)2),
3.92 (s, 3H, OCH3), 6.84–8.51(m, 8H, Ar–H), 11.40 (s,
2H, NH2); Anal. Calcd for C23H19N5O3 (413): C, 66.82; H,
4.63; N, 16.94. Found: C, 66.33; H, 4 0.15 N, 16.50 %.
1.13 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.94 (s, 3H, OCH3),
4.36(q, 2H, CH2), 7.25–8.36 (m, 8H, Ar–H), 10.89 (s, 1H,
OH); 13C NMR δ ppm 13.91, 21.26, 52.29, 62.19, 115.67,
118.50, 120.8 9, 120.93, 121.60, 123.60, 124.02, 124.15,
124.64, 128.60, 129.83, 130.54, 130.87, 132.89, 133.67,
138.82, 144.29, 154.79, 161.91, 167.09; Anal. Calcd for
C24H20N2O6 (432): C, 66.66; H, 4.66; N, 6.48. Found: C,
66.20; H, 4.10 N, 6.70 %.
Ethyl-5-cyano-6-hydroxy-1-(2-(methoxycarbonyl)
phenyl)-2-oxo-4-phenyl-1,2-dihydropyridine-3-carboxylate
(7b): Yellow crystal (Dioxane); yield 61 %; m.p.: 184–
186 °C; IR (KBr, ν¯, cm−1): 3425–3222 (brOH), 2214(C≡N)
General procedure for preparation of 7a–d
To a solution of either 2a (2.18 g) or 2b (2.65 g)
(0.01 mmol) in ethanol (30 mL), α-ethoxycarbonyl cinna-
monitriles 3 (2.01 g, 0.01 mmol) and piperidine (0.5 mL)
were added. The mixture was refluxed for 3 h, cooled and
poured into crushed ice acidified with drops of HCl where
the solid was filtered off and recrystallized from suitable
solvent to give 7a–d.
1
and 1710 (C=O); H NMR (200 MHz, DMSO-d6): δ 1.29
(t, 3H, CH3),3.86 (s, 3H, OCH3), 4.33(q, 2H, CH2), 7.13–
8.30 (m, 9H, Ar–H), 10.83(s, 1H, OH); Anal. Calcd for
C23H18N2O6 (418): C, 66.02; H, 4.34; N, 6.70. Found: C,
66.20; H, 4.01 N, 6.45 %.
Ethyl-5-cyano-4-(furan-2-yl)-6-hydroxy-1-(2-
(methoxycarbonyl)phenyl)-2-oxo-1,2-dihydropyridine-
3-carboxylate (7c): Beige crystal (AcOH); yield 61 %;
m.p.: 178–180 °C.; IR (KBr, ν¯, cm−1): 3316–3127 (OH),
2220 (C≡N) and 1716 (C=O). 1H NMR (200 MHz,
DMSO-d6): δ 1.09 (s, 3H, CH3), 3.90 (s, 3H, OCH3),
Ethyl-5-cyano-6-hydroxy-1-(2-(methoxycarbonyl)
phenyl)-2-oxo-4-p-tolyl-1,2-dihydropyridine-3-carboxylate
(7a): Beige powder (EtOH); yield 77 %; m.p.: 180–182 °C;
IR (KBr, ν¯, cm−1): 3400–3225 (br OH), 2177 (C≡N) and
1
1723, 1693 (C=O). H NMR (200 MHz, DMSO-d6): δ
1 3

J IRAN CHEM SOC
Fig. 3 The molecular structure of compound 17a along with the atom numbering scheme
4.37(q, 2H, CH2), 6.91–8.24 (m, 7H, Ar–H), 10.89 (s, 1H,
OH). Anal. Calcd for C21H16N2 O7 (408): C, 61.77; H,
3.95; N, 6.86. Found: C, 61.20; H, 4.10 N, 6.30 %.
Methyl-2-(5-cyano-4-(4-(dimethylamino)phenyl)-6-hy-
droxy-2-oxopyridin-1(2H)-yl)benzoate (7d): Yellow crystal
(MeOH); yield 84 %; m.p.: 176–178 °C; IR (KBr, ν¯, cm−1):
3396–3141 (OH), 2209 (C≡N) and 1695 (C=O); 1H NMR
(200 MHz, DMSO-d6): δ 3.31 (s, 6H, N(CH3)2), 3.90 (s,
3H, OCH3), 6.86 (s, 1H, pyridine-H), 7.27–8.24 (m, 8H,
Ar–H), 10.88 (s, 1H, OH); Anal. Calcd for C22H19N3O4
(389): C, 67.86; H, 4.92; N, 10.79. Found: C, 67.80; H,
4.70 N, 11.00 %.
Ethyl-6-amino-5-carbamoyl-4-(furan-2-yl)-1-(2-
(methoxycarbonyl)phenyl)-2-oxo-1,2,3,4-tetrahydro-
pyridine-3-carboxylate (8): A mixture of compound 2a
(2.18 g, 0.01 mmol), (E)-2-cyano-3-(furan-2-yl)acrylamide
3 (1.62 g, 0.01 mmol) and piperidine (0.05 mL)in ethanol
(30 mL) were refluxed for 3 h; the solid product so formed
on heating was collected and recrystallized from suitable
solvent to give 8: White powder (EtOH); yield 57 %; m.p.:
178–180 °C; IR (KBr, ν¯, cm−1): 3422, 3262, (NH2), and
1693, 1686 (C=O); 1H NMR (200 MHz, DMSO-d6): δ 1.36
(t, 3H, CH3), 3.93 (s, 3H, OCH3),3.70 (d, 1H, pyridine-H3),
3.86 (d, 1H, pyridine-H4), 4.30 (q, 2H, CH2), 7.14–8.22
1 3

J IRAN CHEM SOC
Table 3 Selected bond
lengths and Angles (°) of 17a
compound
Atoms
Actual bond lengths (angles) (Å)
Optimal bond lengths (angles) (Å)
C(27)–H(49)
1.101
1.358
1.100
1.358
C(17)–N(18)
C(26)–H(45)
1.098
1.100
C(15)–O(33)
1.358
1.355
C(24)–H(44)
1.096
1.100
C(22)–H(42)
1.096
1.100
C(29)–C(30)
1.392
1.420
C(28)–H(46)
1.096
1.100
C(14)–C(17)
1.429
1.420
C(12)–O(13)
1.217
1.208
C(10)–H(35)
1.099
1.111
N(11)–H(50)
1.007
1.012
C(7)–O(8)
1.215
1.208
C(6)–H(41)
1.095
1.100
C(5)–H(37)
1.098
1.100
C(3)–H(40)
1.095
1.100
C(3)–C(6)
1.392
1.420
C(2)–H(38)
1.098
1.100
H(48)–C(30)–C(29)
H(48)–C(30)–C(27)
H(47)–C(29)–C(30)
H(47)–C(29)–C(28)
H(46)–C(28)–C(29)
H(46)–C(28)–C(26)
H(49)–C(27)–C(30)
H(49)–C(27)–C(25)
H(45)–C(26)–C(28)
C(27)–C(25)–C(26)
C(27)–C(25)–N(16)
C(26)–C(25)–N(16)
H(44)–C(24)–C(23)
H(44)–C(24)–C(21)
H(42)–C(22)–C(23)
H(42)–C(22)–C(20)
Cl(31)–C(21)–C(24)
C(24)–C(21)–C(19)
H(43)–C(20)–C(22)
H(43)–C(20)–C(19)
C(21)–C(19)–C(20)
C(14)–C(12)–O(13)
C(14)–C(12)–N(11)
O(13)–C(12)–N(11)
H(36)–C(10)–H(35)
H(41)–C(6)–C(5)
H(41)–C(6)–C(3)
H(37)–C(5)–C(6)
H(37)–C(5)–C(4)
N(11)–C(4)–C(5)
N(11)–C(4)–C(1)
C(5)–C(4)–C(1)
119.953
119.769
119.954
120.037
119.97
119.524
119.447
120.971
119.635
120.307
119.994
119.698
120.564
120.365
119.879
120.575
118.383
120.584
119.976
119.764
119.511
124.456
113.322
122.155
109.851
119.726
119.941
119.098
120.454
119.485
120.951
119.365
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
118.800
120.000
120.000
120.000
120.000
123.000
112.740
122.600
109.000
120.000
120.000
120.000
120.000
120.000
120.000
120.000
1 3

J IRAN CHEM SOC
Table 3 continued
Atoms
Actual bond lengths (angles) (Å)
Optimal bond lengths (angles) (Å)
H(40)–C(3)–C(6)
H(40)–C(3)–C(2)
H(38)–C(2)–C(3)
H(38)–C(2)–C(1)
C(4)–C(1)–C(2)
120.169
120.018
119.491
119.554
119.089
120.000
120.000
120.000
120.000
120.000
(m, 9H, Ar–H + NH2),10.88 (s, 2H, CONH2); MS: 353
(M–HCO2Et, 0.5 (40 %)); Anal. Calcd for C15H13N3O3
(427): C, 59.01; H, 4.95; N, 9.83. Found: C, 58.80; H, 4.75
N, 9.61 %.
Ethyl-2′-amino-3′-cyano-6′-hydroxy-1′-(2-
(methoxycarbonyl)phenyl)-3-oxo-2,3-dihydro-1′H-
spiro[indene-1,4′-pyridine]-5′-carboxylate (12): A mixture
of compound 2b (0.01 mmol), and 2-(3-oxo-2,3-dihy-
dro-1H-inden-1-ylidene) malononitrile (0.01 mmol) and
piperidine (0.05 mL) in ethanol (30 mL) were refluxed
for 3 h; the solid product so formed on heating was col-
lected and recrystallized from suitable solvent to give 12.
Brown powder (Dioxan); yield 65 %; m.p.: 184–186 °C;
IR (KBr, ν¯, cm−1): 3355–3144 (br NH2), 2202 (C≡N) and
Methyl-2-(6-amino-5-cyano-4-methyl-2-oxopyridin-
1(2H)-yl)benzoate (9): A mixture of compound either 2a or
2b (0.01 mmol), acetaldehyde (0.01 mmol), malononitrile
(0.01 mmol) and piperidine (0.05 mL) in ethanol (30 mL)
were refluxed for 3 h; the solid product so formed on heat-
ing was collected and recrystallized from suitable solvent
to give 9: Brown powder (EtOH); yield 77 %; m.p.: 180–
182 °C; IR (KBr, ν¯, cm−1): 3337, 3242 (NH2), 2200(C≡N)
1
1670 (C=O); H NMR (200 MHz, DMSO-d6): δ 1.07 (t,
3H, CH3) 2.74 (s, 2H, CH2) 3.80 (s, 3H, OCH3), 4.03 (q,
2H, CH2) 7.27–8.24 (m, 10H, Ar–H + NH2), 12.19 (s, 1H,
OH); Anal. Calcd for C25H21N3O6 (459): C, 65.35; H, 4.61;
N, 9.15. Found: C, 65.00; H, 4.77; N, 9.10 %.
1
and 1670 (C=O); H NMR (200 MHz, DMSO-d6): δ 2.18
(s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.25 (s, 1H, pyridine-
H3), 7.20–8.30 (m, 6H, Ar–H + NH2). MS: 283 (0.29 %).
Anal. Calcd for C15H13N3O3 (283): C, 63.60; H, 4.63; N,
14.83. Found: C, 63.20; H, 4.15 N, 14.60 %.
General procedure for preparation of 14a–e
General procedure for preparation of 10a, b
A mixture of compound 2b (0.01 mmol), α-substituted
cinnamonitriles 3 (0.01 mmol), and piperidine (0.05 mL)
in DMF (30 mL) were refluxed for 6 h, then cooled and
poured into crushed ice acidified with drops of HCl where
the solid was filtered off and recrystallized from suitable
solvent to give 14a–e.
A mixture of compound either 2a or 2b (0.01 mmol),
ethyl 2-cyano-3-ethoxyacrylate (0.01 mol) and piperidine
(0.05 mL) in ethanol (30 mL) were refluxed for 6 h; the
solid product was collected and recrystallized from suitable
solvent to give 10a, b.
2-cyano-3-(2,4-dichlorophenyl)-6-hydroxy-1-oxo-1H-
pyrido[1,2-a]quinazoline-4-carboxamide (14a): Yellow
crystals (EtOH); yield 71 %; m.p.: 158–160 °C; IR (KBr):
Vmax cm−1 3423–3352 (br NH2), 2219 (C≡N) and 1657
Diethyl-6-amino-1-(2-(methoxycarbonyl)phenyl)-
2-oxo-1,2-dihydropyridine-3,5-dicarboxylate (10a): Brown
powder (MeOH); yield 72 %; m.p.: 178–180 °C; IR (KBr,
ν¯, cm−1): 3402–3317 (br NH2) and 1690 (C=O); HNMR
(C=O); H NMR (200 MHz, DMSO-d6): δ 7.17–8.01 (m,
1
1
(200 MHz, DMSO-d6): δ 3.80 (s, 3H, OCH3), 1.10, 1.29
(2t, 6H, 2CH3), 4.20, 4.29 (2q, 4H, 2CH2), 7.20–8.45 (m,
5H, Ar–H + pyridine-H); MS: 388 (6.35 %); Anal. Calcd
for C19H20N2O7 (388): C, 58.76; H, 5.19; N, 7.21. Found:
C, 58.19; H, 4.80; N, 7.50 %.
9H, Ar–H + CONH2), 11.99 (s, 1H, OH); Anal. Calcd for
C20H10Cl2N4O3 (424): C, 56.49; H, 2.37; N, 13.18. Found:
C, 56.78; H, 2.07 N, 13.00 %.
3-(4-chlorophenyl)-2-cyano-6-hydroxy-1-oxo-1H-
pyrido[1,2-a]quinazoline-4-carboxamide (14b): Beige
crystals (EtOH); yield 63 %; m.p.: 156–158 °C; IR (KBr,
ν¯, cm−1): 3423–3111 (br NH2), 2219 (C≡N) and 1697
Ethyl-2-amino-5-cyano-1-(2-(methoxycarbonyl)
phenyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (10b):
Yellow crystals (EtOH); yield 77 %; m.p.: 162–164 °C.
IR (KBr, ν¯, cm−1): 3402–3317 (br NH2), 2229 (C≡N) and
1
(C=O); H NMR (200 MHz, DMSO-d6): δ 7.17–8.01 (m,
10H, Ar–H + CONH2), 11.40 (s, 1H, OH); Anal. Calcd for
C20H11ClN4O3 (390): C, 61.47; H, 2.84; N, 14.34; Found:
C, 61.30; H, 2.70; Cl, 8.90; N, 14.11 %.
1
1670 (C=O); HNMR (200 MHz, DMSO-d6): δ 1.10 (t,
3H, CH3), 4.29 (q, 2H, CH2), 3.80 (s, 3H, OCH3), 7.11–
8.57 (m, 5H, Ar–H + pyridine-H), 10.99 (s, 2H, NH2);
Anal. Calcd for C17H15N3O5 (341): C, 59.82; H, 4.43; N,
12.31. Found: C, 58.70; H, 4.27 N, 12.50 %.
2-cyano-3-(4-(dimethylamino)phenyl)-6-hydroxy-1-
oxo-1H-pyrido[1,2-a]quinazoline-4-carboxamide
(14c):
Brown crystals (MeOH); yield 65 %; m.p.: 170–172 °C.
1 3

J IRAN CHEM SOC
IR (KBr, ν¯, cm−1): 3423–3221 (br NH2), 2209 (C≡N) and
for C18H12Cl2N2O3 (374): C, 57.62; H, 3.22; N, 7.47.
Found: C, 57.13; H, 3.00 N, 7.10 %.
1
1650 (C=O); H NMR (200 MHz, DMSO-d6): δ 3.04 (s,
6H, N (CH3)2) 6.79–8.51 (m, 10H, Ar–H + CONH2), 11.70
(s, 1H, OH); Anal. Calcd for C22H17N5O3 (399): C, 66.16;
H, 4.29; N, 17.53. Found: C, 66.00; H, 4.10 N, 17.30 %.
(E)-Methyl-2-(3-(2-chlorophenyl)-2-cyanoacrylamido)
benzoate (15d): White powder (EtOH); yield 62 %; m.p.:
128–130 °C; IR (KBr, ν¯, cm−1): 3216 (NH), 2204 (C≡N)
1
Ethyl
3-(2-chlorophenyl)-2-cyano-6-hydroxy-1-oxo-
and 1693 (C=O); H NMR (200 MHz, DMSO-d6): δ 3.90
1H-pyrido[1,2-a] quinazoline-4-carboxylate (14d): Green
powder (EtOH); yield 51 %; m.p.: 182–184 °C; IR (KBr, ν¯,
cm−1): 3370–3237 (br OH), 2223 (C≡N) and 1728 (C=O).
1HNMR (200 MHz, DMSO-d6): δ 1.25 (t, 3H, CH3), 4.38
(q, 2H, CH2), 7.54–8.12 (m, 8H, Ar–H), 9.53 (s, 1H, OH);
11.70. Anal. Calcd for C22H14ClN3O4 (419): C, 62.94; H,
3.36; N, 10.01. Found: C, 62.75; H, 3.16 N, 9.85 %.
(s, 3H, OCH3), 7.29–8.61 (m, 9H, Ar–H + methine-H),
11.90 (s, 1H, NH); Anal. Calcd for C18H13ClN2O3 (340):
C, 63.44; H, 3.85; N, 8.22. Found: C, 63.11; H, 3.21; N,
8.00 %.
General procedure for preparation of 16, 17a, b, d
and 18a–c
Ethyl-2-cyano-3-(4-(dimethylamino)phenyl)-6-hydroxy-
1-oxo-1H-pyrido-[1,2-a]quinazoline-4-carboxylate (14e):
Yellow powder (EtOH); yield 59 %; m.p.: 176–178 °C;
IR (KBr, ν¯, cm−1): 3438–3312 (br OH), 2213 (C≡N) and
To a solution of 3a–d (0.01 mmol) in ethanol (30 mL), and
hydrazine hydrate or phenyl hydrazine (0.01 mmol) was
added. The mixture was refluxed for 3 h, cooled and fil-
tered off and recrystallized from suitable solvent to give 16,
17a, b, d and 18a–c.
Methyl 2-(3-amino-5-(2-chlorophenyl)-1H-pyrazole-4-
carboxamido)-benzoate (16): Brown powder (MeOH);
yield 76 %; m.p.: 178–180 °C; IR (KBr, ν¯, cm−1): 3424,
3312, 3122 (NH2, NH), and 1651 (C=O); 1H NMR
(200 MHz, DMSO-d6): δ 3.66 (s, 2H, NH2), 3.90 (s, 3H,
OCH3), 6.51–7.71 (m, 10H, Ar–H + 2NH); Anal. Calcd for
C18H15ClN4O3 (370): C, 58.31; H, 4.08; N, 15.11. Found:
C, 58.10; H, 4.00; N, 15.42 %.
1
1698 (C=O). H NMR (200 MHz, DMSO-d6): δ 1.24 (t,
3H, CH3), 427 (q, 2H, CH2), 3.05 (s, 6H, N(CH3)2) 6.76–
8.04 (m, 8H, Ar–H), 11.72 (s, 1H, OH); 13C NMR: δ 14.09,
40.33, 61.35, 86.31, 92.05, 111.56, 114.02, 115.12, 115.87,
117.34, 118.24, 120. 85, 121.88, 123.94, 133.54, 133.66,
139.62, 153.59, 154.00, 160.82, 163.38, 169.56; Anal.
Calcd for C24H20N4O4 (428): C, 67.28; H, 4.71; N, 13.08.
Found: C, 67.10; H, 4.50; N, 12.70 %.
General procedure for preparation of 15a–d
Methyl2-(3-(2,4-dichlorophenyl)-5-hydroxy-1-phe-
nyl-1H-pyrazole-4-carboxamido)benzoate (17a): Yel-
low powder (EtOH); yield 51 %; m.p.: 194–196 °C; IR
To a solution of either 2a (2.18 g) or 2b (2.65 g) (0.01 mmol)
in ethanol (30 mL), a mixture of aromatic aldehyde
(0.01 mmol) and piperidine (0.5 mL) were added. The mix-
ture was refluxed for 3 h, cooled and poured into crushed ice,
acidified with drops of HCl where the solid was filtered off
and recrystallized from suitable solvent to give 15a–d.
(Z)-Methyl-2-(3-(2,4-dichlorophenyl)-2-(ethoxycarbonyl)
acrylamido)-benzoate (15a): White powder (AcOH); yield
76 %; m.p.: 140–142 °C; IR (KBr, ν¯, cm−1): 3082 (NH) and
1651 (C=O);1H NMR (200 MHz, DMSO-d6): δ 1.29 (t, 3H,
CH3), 3.90 (s, 3H, OCH3), 4.35 (q, 2H, CH2), 6.70–8.23 (m,
8H,Ar–H + methine-H), 11.90 (s, 1H, NH); Anal. Calcd for
C20H17Cl2NO5 (421): C, 56.89; H, 4.06; N, 3.32. Found: C,
56.45; H, 4.00 N, 3.10 %.
(Z)-Methyl-2-(3-(2-chlorophenyl)-2-ethoxycarbonyl)
acrylamido)benzoate(15b): White powder (EtOH); yield
54 %; m.p.: 144–146 °C; IR (KBr, ν¯, cm−1): 3082 (NH),
and 1651 (C=O); MS: 387 (2.79 %); Anal. Calcd for
C20H18ClNO5 (387): C, 61.94; H, 4.68; N, 3.61. Found: C,
61.55; H, 4.50 N, 3.40 %.
1
(KBr, ν¯, cm−1): 3200 (br NH), and 1688 (C=O); H NMR
(200 MHz, DMSO-d6): δ 3.90 (s, 3H, OCH3), 6.78–8.23
(m, 13H, Ar–H + NH), 10.84 (s, 1H, OH); MS: 464 (M–
OH, 3.20 %). Anal. Calcd for C24H17Cl2N3O4 (481): C,
59.77; H, 3.55; Cl, 14.70; N, 8.71. Anal. Found: C, 59.50;
H, 3.30; N, 8.40 %.
Methyl2-(3-(2-chlorophenyl)-5-hydroxy-1-phenyl-1H-
pyrazole-4-carbox-amido)benzoate (17b): Brown pow-
der (Dioxan); yield 51 %; m.p.: 196–198 °C; IR (KBr, ν¯,
cm−1): 3298 (br NH), and 1692 (C=O); 1H NMR
(200 MHz, DMSO-d6): δ 3.75 (s, 3H, OCH3), 6.75–8.18
(m, 14H, Ar–H + NH), 10.72 (s, 1H, OH); Anal. Calcd for
C24H18ClN3O4 (447): C, 64.36; H, 4.05; N, 9.38. Found: C,
64.01; H, 4.00; N, 9.11 %.
Methyl-2-(5-amino-3-(4-chlorophenyl)-1-phenyl-1H-
pyrazole-4-carbox-amido)benzoate (17d): White pow-
der (EtOH); yield 62 %; m.p.: 174–176 °C; IR (KBr, ν¯,
1
cm−1): 3400–3100 (br NH2, NH), 1690 (C=O); H NMR
(E)-Methyl-2-(2-cyano-3-(2,4-dichlorophenyl)acryla-
mido)benzoate (15c): White powder (EtOH); yield 76 %;
m.p.: 132–134 °C; IR (KBr, ν¯, cm−1): 3082 (NH), 2201
(C≡N) and 1693 (C=O); MS: 374 (22.39 %). Anal. Calcd
(200 MHz, DMSO-d6): δ 3.85 (s, 3H, OCH3), 7.18–8.14 (m,
15H, Ar–H + NH2), 11.40 (s, 1H, NH); MS: 446(2.20 %);
Anal. Calcd for C24H19ClN4O3 (446): C, 64.50; H, 4.29; N,
12.54. Found: C, 64.10; H, 4.20; N, 12.30 %.
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J IRAN CHEM SOC
3-Amino-2-(5-(2,4-dichlorophenyl)-3-hydroxy-1H-
pyrazol-4-yl)quinazolin-4(3H)-one (18a): White pow-
der (MeOH); yield 52 %; m.p.: 188–190 °C; IR (KBr, ν¯
, cm−1): 3400–3100 (br, NH2, NH), and 1648 (C=O);
1H NMR (200 MHz, DMSO-d6): δ 7.17–7.7.99 (m, 10H,
Ar–H + NH2 + NH), 11.38(s, 1H, OH); Anal. Calcd for
C17H11Cl2N5O2 (387): C, 52.60; H, 2.86; N, 18.04. Found:
C, 53.11; H, 2.62; N, 17.80 %.
3-Amino-2-(5-(2-chlorophenyl)-3-hydroxy-1H-pyrazol-
4-yl)quinazolin-4(3H)-one (18b): Yellow powder (EtOH);
yield 52 %; m.p.: 200–202 °C; IR (KBr, ν¯, cm−1): 3400–
3100 (br, NH2, NH), 1648 (C=O);1H NMR (200 MHz,
DMSO-d6): δ 7.23–8.17 (m, 10H, Ar–H + NH2), 8.97 (s,
1H, NH), 11.30 (s, 1H, OH); MS: (353, 0.60 %); Anal.
Calcd for C17H12ClN5O2 (353): C, 57.72; H, 3.42; N,
19.80. Found: C, 57.21; H, 3.10; N, 19.40 %.
166–68 °C; IR (KBr, ν¯, cm−1): 3400–3200 (br NH2,
1
NH), 1610 (C=O); H NMR (200 MHz, DMSO-d6): δ
1.60 (s, 1H, NH), 6.00 (s, 2H, NH2), 7.00–8.15 (m, 11H,
Ar–H + 2CONH2); Anal. Calcd for C19H14Cl2N8O3 (472):
C, 48.22; H, 2.98; Cl, 14.98; N, 23.68 Found: C, 48.00; H,
2.50; N, 23.40 %.
5-Amino-3-(2-chlorophenyl)-4-(4-oxo-3-ureido-3,4-di-
hydroquinazolin-2-yl)-1H-pyrazole-1-carboxamide (19d):
White powder (EtOH); yield 51 %; m.p.: 190–92 °C; IR
(KBr, ν¯, cm−1): 3400–3200 (br NH2, NH), 1727 (C=O);
1H NMR (200 MHz, DMSO-d6): δ 1.64 (s, 1H, NH), 6.55
(s, 2H, NH2) 7.33–8.23 (m, 12H, Ar–H + 2CONH2); Anal.
Calcd for C19H15ClN8O3 (438): C, 52.00; H, 3.45; N,
25.53. Found: C, 51.70; H, 3.20; N, 25.10 %.
Molecular modeling studies
3-Amino-2-(3-amino-5-(2,4-dichlorophenyl)-1H-
pyrazol-4-yl)quinazolin-4(3H)-one (18c): Yellow pow-
der (EtOH); yield 57 %; m.p.: 188–190 °C; IR (KBr, ν¯
, cm−1): 3400–3100(br, NH2, NH), 1614 (C=O); 1H
NMR (200 MHz, DMSO-d6): δ 7.368.16–8.17 (m, 11H,
Ar–H + 2NH2), 8.95 (s, H, NH); 13C NMR: δ ppm 120.70,
120.72, 120.74, 120.77, 120.83, 127.12, 127 0.67, 128.14,
128.61, 130.10, 130.46, 130.52, 131.57, 133.08, 134.59,
158.10; Anal. Calcd for C17H12Cl2N6O (386): C, 52.73;
H, 3.12; Cl, 18.31; N, 21.70. Found: C, 52.23; H, 3.00; N,
21.30 %.
An attempt to gain a better insight into the molecular struc-
ture of the synthesized compounds, geometric optimization
and conformation analysis were performed using semi-
empirical method PM3 as implemented in HyperChem 7.5
[51]. The structures of synthesized reported compounds
were optimized with semi-empirical method PM3 (Para-
metric Method-3). A gradient of 0.01 kcal Å−1 was set as
a convergence criterion in all the molecular mechanics and
quantum calculations. The lowest energy structure was used
for each molecule to calculate physicochemical properties.
General procedure for preparation of 19a–d
References
To a solution of 15a–d (0.01 mmol) in ethanol (30 mL),
semicarbazide (0.75 g, 0.01 mmol) was added. The mixture
was refluxed for 3 h, cooled, filtered off and recrystallized
from suitable solvent to give 19a–d.
3-(2,4-Dichlorophenyl)-5-hydroxy-4-(4-oxo-
3-ureido-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-
1-carboxamide(19a):White powder (AcOH); yield 51 %; m.p.:
198–200 °C; IR (KBr, ν¯, cm−1): 3400–3200 (br NH2, NH),
1711, 1646 (C=O); 1H NMR (200 MHz, DMSO-d6): δ 1.58 (s,
1H, NH),7.39–8.15 (m, 11H, Ar–H + 2CONH2), 10.50 (s, 1H,
OH); Anal. Calcd for C19H13Cl2N7O4 (473): C, 48.12; H, 2.76;
N, 20.67. Found: C, 48.10; H, 2.30; N, 20.23 %.
1. F.E. Silverstien, G. Faich, J.L. Goldstien, L.S. Simon, T. Pincus,
A. Whelton, R. Makuch, G. Eisen, N.M. Agrawal, W.F. Stenson,
A.M. Burr, W.W. Zhao, J.D. Kent, J.B. Lefkowith, K.M. Verburg,
G.S. Gies, J. Am. Med. Assoc. 284, 1247–1255 (2000)
2. S. Mark, E. Jan, A. Sabrina, L. Martina, A. Silke, R. Yeon, A.
Jodi, S. Gillian, R. William, M. Detlef, E. Stephen, K. Bert, S.
Thomas, M. Manfred, Antivir. Res. 79, 49–61 (2008)
3. H. Kumar, D. Saini, S. Jaina, N. Jain, Eur. J. Med. Chem. 70,
248–258 (2013)
4. J. Hanusek, Chem. Listy 95, 811–813 (2001)
5. H.J. Chan, J.S. Hong, L.F. Kuyper, D.P. Baccanari, S.S. Joyner,
R.L. Tansik, C.M. Boytos, S.K. Rudolph, J. Med. Chem. 38,
3608–3616 (1995)
6. R. Castaldo, D. Gump, M.J. Cormack, Antimicrob. Agents
Chemother. 15, 81–86 (1979)
7. K. Harushia, Y. Kiesuke, H. Seiko, H. Shingo, K. Ryota, H.
Norimitsu, M. Makoto, O. Yoshiteru, J. Med. Chem. 49, 4698–
4706 (2006)
3-(2-Chlorophenyl)-5-hydroxy-4-(4-oxo-3-ureido-
3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-carboxamide
(19b): Yellow powder (EtOH); yield 51 %; m.p.: 190–
92 °C; IR (KBr, ν¯, cm−1): 3400–3200 (br NH2, NH), 1637
8. T. Yasutaka, S. Takao, W. Nobuhisa, A. Hideyuki, S. Shigeru, S.
1
(C=O). H NMR (200 MHz, DMSO-d6): δ 1.60 (s, 1H,
Isao, J. Med. Chem. 37, 2106–2111 (1994)
NH), 6.65–8.20 (m, 12H, Ar–H + 2CONH2), 10.62 (s, 1H,
OH); Anal. Calcd for C19H14ClN7O4 (439): C, 51.89; H,
3.21; N, 22.29. Found: C, 51.60; H, 3.00; N, 22.00 %.
5-Amino-3-(2,4-dichlorophenyl)-4-(4-oxo-3-ureido-
3,4-dihydroquinazolin-2-yl)-1H-pyrazole-1-carboxam-
ide (19c): Yellow powder (MeOH); yield 55 %; m.p.:
9. D. Marianne, P. Fredric, C. Olivier, T. Jean-Claude, C. Jean-
Pierre, B. Yves, Chem. Pharm. Bull. 49, 1061–1065 (2001)
10. Mani Chandrica, P.; Yakaiah, T.; Raghu Ram Rao, A.; Narsaiah,
B.; Chakra Reddy, N.; Sridhar, V.; Venkateshwara Rao. J Eur. J.
Med. Chem. 43, 846–852 (2008)
11. M.H. Yen, J.R. Sheu, I.H. Peng, Y. Lee, M. Chern, J. Pharm.
Pharmacol. 48, 90–95 (1996)
1 3

J IRAN CHEM SOC
32. Y.D. Scherson, S.J. Aboud, J. Wilcox, B.J. Cantwell, J. Phys.
Chem. 115, 11036 (2011)
12. S. Hyao, M.J. Mvera, W. Strycker, T. Leipzi, R. Klup, H. Hart-
zler, J. Med. Chem. 8, 807–811 (1965)
33. J.J.P. Stewart, Comp. J. Chem. 10, 209 (1989)
34. J.J.P. Stewart, Comp. J. Chem. 16, 221 (1989)
35. M.H.M. Helal, N.S. Ahmed, M.S. Elwessaly, Y.A. Ammar, Arch.
Pharm. Chem. Life Sci. 346, 1–11 (2013)
13. E. Cohen, E. Klarberg, R. JamesVaughan, J. Am. Chem. Soc. 82,
2731–2735 (1960)
14. M. Kenji, U. Junko, S. Takashi, I. Michio, A.G. Neil, Y. Jin-
Chen, T. Shusuke, O. Shoji, N. Yuji, J. Med. Chem. 46, 4910–
4925 (2003)
36. M.H.M. Helal, M.A. Salem, M.S.A. El-Gaby, M. Aljahdali, Eur.
J. Med. Chem. 65, 517–526 (2013)
15. V.K. Archana, C. Srivastava, K. Ramesh, Indian J. Chem. 41,
2371–2375 (2002)
16. B. Atsuo, K. Noriaki, M. Haruhiko, O. Yoshikazu, T. Shigehisa,
S. Takashi, J. Med. Chem. 39, 5176–5182 (1996)
17. B.Y. Daniel, W.G. Jason, L.N. Stephanie, V.P. Arely, T.C. Mat-
thew, A.B. David, J. Dermatol. Sci. 42, 13–21 (2006)
18. J.L. Greene, A.M. Williams, J.A. Montgomery, J. Med. Chem. 7,
20 (1964)
19. M.J. Gil, M.A. Manu, C. Arteaga, M. Migliaccio, I. Encio, A.
Gonzalez, V. Martinez-Merino, Bioorg. Med. Chem. Lett. 9,
2321 (1999)
37. M.H.M. Helal, S.Y. Abbas, M.A. Salem, A.A. Farag, Y.A.
Ammar, Med. Chem. Res. 22, 5598–5609 (2013)
38. M.H. Helal, G.A.M. El-Hag Ali, A.A. Ali, Y.A. Ammar, J. Chem.
Res., 465 (2010)
39. A.A. El-Sherif, M.M. Shoukry, L.O. Abobakr, Spectrochim. Acta
(A) 112, 290–300 (2013)
40. A.A. El-Sherif, T.M.A. Eldebss, Spectrochim. Acta Part A 79,
1803–1814 (2011)
41. M. Aljahdali, A.A. EL-Sherif, Inorg. Chim. Acta 407, 58–68
(2013)
42. A.A. El-Sherif, Inorg. Chim. Acta 362, 4991–5000 (2009)
43. A.A. El-Sherif, B.J.A. Jeragh, Spectrochim. Acta (A) 68, 877
(2007)
44. R. Pal, R.N. Handa, H.K. Pujari, J. Indian Chem. Soc. 31B, 771
(1992)
45. R.G. Pearson, J. Org. Chem. 54, 1423 (1989)
46. R.G. Parr, R.G. Pearson, J. Am. Chem. Soc. 105, 7512 (1983)
47. P. Geerlings, F. De Proft, W. Langenaeker, Chem. Rev. 103, 1793
(2003)
48. R.G. Parr, J. Am. Chem. Soc. 1999, 121 (1922)
49. P.K. Chattaraj, S. Giri, J. Phys. Chem. A 111, 11116 (2007)
50. G. Speie, J. Csihony, A.M. Whalen, C.G. Pie-Pont, Inorg. Chem.
35, 3519 (1996)
20. A. Gangjee, Y. Zhu, S.F. Queener, J. Med. Chem. 4, 4533 (1998)
21. A.P. Krapcho, S.N. Haydar, S. Truong-Chiott, M.P. Hacker, E.
Menta, G. Beggiolin, Bioorg. Med. Chem. Lett. 10, 305 (2000)
22. F. Monna, F. Chimenti, A. Balasco, B. Bizzarri, W. Filippelli, A.
Filippelli, L. Gagliardi, Eur. J. Med. Chem. 34, 245 (1999)
23. G. Szabo, J. Fischer, A. Kis-Varga, K. Gyires, J. Med. Chem. 51,
142–147 (2008)
24. R. Sridhar, P.T. Perumal, S. Etti, G. Shanmugam, M.N. Pon-
nuswamy, V.R. Prabavathy, N. Mathivanan, Bioorg. Med. Chem.
Lett. 14, 6035 (2004)
25. M.A.F. Vera-DiVaio, A.C.C. Freitas, H.C.A. Castro, S. de Albu-
querque, L.M. Cabral, C.R. Rodrigues, M.G. Albuquerque,
R.C.A. Martins, M.G. Henriques, L.R.S. Dias, Bioorg. Med.
Chem. 17, 295 (2009)
26. A. Tanitame, Y. Oyamada, K. Ofuji, M. Fujimoto, N. Iwai, Y.
Hiyama, K. Suzuki, H. Ito, M. Wachi, J. Yamagishi, J. Med.
Chem. 47, 3693 (2004)
51. HyperChem version 7.5, Hypercube Inc., Gainesville (2003)
52. D.H. Brouwer, I.L. Moudrakovski, R.J. Darton, R.E. Morris,
Magn. Reson. Chem. 48, S113 (2010)
53. K.K. Baldridge, K.I. Hardcastle, T.J. Seiders, J.S. Siegel, Org.
Biomol. Chem. 8, 53 (2010)
54. V.D. Ghule, P.M. Jadhav, R.S. Patil, S. Radhakrishnan, T. Soman,
J. Phys. Chem. A 114, 498 (2010)
55. S.W. Xia, X. Xu, Y.L. Sun, Y.L. Fan, Y.H. Fan, C.F. Bi, D.M.
Zhang, L.R. Yang, Chin. J. Struct. Chem. 25, 200 (2006)
56. D.-Q. Zhang, L.-X. Gao, G.-D. Zhou, Corros. Sci. 46, 3031–
3040 (2004)
57. R.G. Parr, W. Yang (eds.), Density-Functional Theory of Atoms
and Molecules (Oxford, New York, 1989)
27. M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney, W.G.
Tarpley, Y. Yagi, D.L. Romero, J. Med. Chem. 43, 1034 (2000)
28. N. Gokhan-Kelekci, S. Koyunoglu, S. Yabanoglu, K. Yelekci, O.
Ozgen, G. Ucar, K. Erol, E. Kendi, A. Yesilada, Bioorg. Med.
Chem. 17, 675–689 (2009)
29. D.M. Shen, E.J. Brady, M.R. Candelore, Q. DallasYang, V.D.H.
Ding, W.P. Feeney, G. Jiang, M.E. McCann, S. Mock, S.A.
Qureshi, R. Saperstein, X. Shen, X. Tong, L.M. Tota, M.J.
Wright, X. Yang, S. Zheng, K.T. Chapman, B.B. Zhang, J.R.
Tata, E.R. Parmee, Bioorg. Med. Chem. Lett. 21, 76–81 (2011)
30. A. Padmaja, C. Rajasekhar, A. Muralikrishna, V. Padmavathi,
Eur. J. Med. Chem. 46, 5034–5038 (2011)
58. G. Gao, C. Liang, Electrochim. Acta 52, 4554–4559 (2007)
59. Y. Feng, S. Chen, W. Guo, Y. Zhang, G. Liu, J. Electroanal.
Chem. 602, 115–122 (2007)
31. F. Jensen, Introduction to Computational Chemistry (Wiley,
Chichester, 1999)
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