Synthesis of Novel Heterocycles Derived from 4-Arylmethylene-2-phenyl-1,3-oxazole-5(4H)-ones

Article abstract of DOI:10.1002/jhet.2329

The acid hydrazide derivatives 2 were converted into pyrazolone, triazinone, and schiff bases. However, the reaction of Schiff base 12 with malononitrile or thioglycolic acid gives the pyrazolotriazinone or thiazolidinone derivative, respectively. The str

Full text of DOI:10.1002/jhet.2329

May 2016
Synthesis of Novel Heterocycles Derived from 4-Arylmethylene-2-phenyl-
809
1,3-oxazole-5(4H)-ones
*
Ahmed S. A. Youssef, Kamal A. Kandeel, Wael S. I. Abou-Elmagd, and David S. A. Haneen
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt
*
E-mail: waelmagd97@yahoo.com
Received May 12, 2014
DOI 10.1002/jhet.2329
Published online 11 June 2015 in Wiley Online Library (wileyonlinelibrary.com).
The acid hydrazide derivatives 2 were converted into pyrazolone, triazinone, and schiff bases. However,
the reaction of Schiff base 12 with malononitrile or thioglycolic acid gives the pyrazolotriazinone or
thiazolidinone derivative, respectively. The structures of the newly synthesized compounds were established
on the basis of IR, 1H-NMR, mass spectral data, and elemental analyses. The antimicrobial activities of the
synthesized compounds were examined against two types of bacteria and two types of fungi. Some of the
tested compounds showed promising activities.
J. Heterocyclic Chem., 53, 809 (2016).
INTRODUCTION
imidazolone. Further support for assigned structures is gained
1
from 1H-NMR and mass spectra. Inspection of the H-NMR
4-Arylmethylene-2-phenyl-1,3-oxazole-5(4H)-ones
(azlactones) are compounds that have synthetic and
technological applications [1–6]. Significant biological
potential as analgesic [7], anti-inflammatory [8], antide-
pressant [9], anticancer [10], antimicrobial, antidiabetic,
and antiobesity [11,12] were reported. The structures of these
compounds were investigated by several authors [13–17].
It has been found that the stable configuration is the Z-
isomer with respect to the exocyclic C¼C double bond.
The E- isomer, however, is metastable and the reverse
transformation to the Z-configuration occurs through the
photoactivation [18]. An extension of conjugation through
an exocyclic double bond present at C-4 of oxazolone
moiety and a phenyl ring at C-2 play a pivotal role in the
reactivity of these oxazolones [17,19,20].
spectra of compound 3 and 4 revealed the existence of extra
signals corresponding to protons of CH3CH2OCO, CH2
(pyrazolo), and NH groups, which is in consistence with the
existence of 3 as a mixture of E- and Z- stereoisomers in a ratio
of 2:1, respectively.
The appearance of extra signals for protons of CH3
CH2OCO (ester) for compounds 3 and 4 as well as CH2
(pyrazolo) of compound 3 can be rationalized on the basis
of the following facts:
1. When the pyrazolidinone ring is in plane of the molecule;
N1 atom of the hetero ring becomes in conjugation with
the exo C¼O group of the α, β- unsaturated system as
well as with the C¼O and C¼N groups of the hetero ring
of 3 or with the endo C¼O group of compound 4. This
leads to the higher δ values for the signals of protons of
CH3CH2OCO and CH2 groups, respectively.
2. In addition, the dipole–dipole interaction between the two
carbonyl groups exo- and endo- makes the pyrazolo ring
to come out of plane of the molecule. Accordingly, N1
atom of the hetero ring becomes in conjugation only with
the endo C¼O and C¼N groups of compound 3 or with
endo C¼O group of compound 4 that leads to lowering
the δ values of the above signals.
In the present work, we aimed to investigate the action of
different reagents on the acid hydrazide derivatives 2 to achieve
heterocyclic compounds of anticipated biological activity.
RESULTS AND DISCUSSION
The acid hydrazide derivatives 2 were previously prepared
by our research group upon hydrazinolysis of 4-arylmethy-
lene-2-phenyl-1,3-oxazole-5(4H)-one 1 [16,17,21–23]. Treat-
ment of the acid hydrazide derivatives 2 with diethyl
acetylene- dicarboxylate gave the imidazolone derivatives 3
and 4 (cf. Scheme 1). The structures of 3 and 4 are substanti-
ated from their spectral data. The IR spectrum is devoid of
any absorptions corresponding to NH2 group, instead the
appearance of an absorption of C¼O group for cyclic
Their MS spectra show the correct molecular ion peaks
beside some of abundant peaks (cf. Experimental part).
On the other hand, when the acid hydrazide derivatives 2
were treated with the arylidenemalononitrile in refluxing
ethanol, they afforded the N-substituted hydrazone deriva-
tives 5 and 6. The structure of 5 and 6 was established from
© 2015 HeteroCorporation

810
A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 53
Scheme 1
Scheme 2
their analytical and spectroscopic data. Recalling, the ap-
1
pearance of extra signals in the H-NMR spectra of com-
pounds 5a,b and 6a due to protons of OMe, Me, CH¼,
NH–N¼, and NHCOPh groups is a good evidence for their
existence as mixtures of Z/anti and E/syn stereoisomers in
a ratio of 2: 3 in case of 5a,b and 3:4 in case of 6a. Inspec-
Scheme 3
1
tion of the H-NMR spectrum of compound 6b reveals its
existence as the Z-configurated isomer.
Furthermore, The EIMS of compounds 5 and 6 shows the
correct molecular ion peaks beside some of abundant peaks
(cf. experimental part). A strong evidence for the structure
of 5 and 6 was gained chemically by reacting 2 with 2, 5-
dimethoxy acetophenone and p-chlorobenzaldehyde, respec-
tively, under the same conditions. The products obtained
were identical in all respects (mp, mixed mp, TLC) with 5
and 6. On treating compounds 6 with HCl/AcOH mixture
afforded bis-(arylidene) hydrazine and triazinone derivatives
1
7 and 8, respectively (cf. Scheme 2). Inspection of the H-
afforded the pyrazolone derivative 9a (Scheme 4). The struc-
ture of compound 9a was substantiated from its analytical
and spectral data. IR spectrum has characteristic bands for
NH and C¼O (cyclic amide) groups at 3424, 3248, and
1644 cmꢀ1, respectively. Further evidence was ascertained
from its 1H-NMR spectrum (cf. experimental part).
NMR spectrum of compound 8 reveals the existence of a
broad singlet signal at δ 10.62 ppm, corresponding to OH
proton, which suggests the existence of compound 8 in the
lactim form 8a.
Similar treatment of 2b with ethyl acetoacetate in n-butanol
in the presence of drops of piperdine afforded a mixture of
pyrazolidinone derivative 9b, triazinone, and imidazolone
derivatives 10 and 11, respectively (cf. scheme 4). The struc-
tures of compounds 9b, 10, and 11 were elucidated from their
microanalytical and spectral data.
Their IR spectra show bands characteristic for NH and
C¼O groups. The 1H-NMR spectrum of compound 9b dis-
plays signals for protons of CH3, CH2, CH¼, and NH as well
as aromatic protons that corresponds very well with the sug-
An alcoholic solution of 8 gives a green color with aque-
ous FeCl3 solution. The mechanistic pathway for the for-
mation of 5 and 6 is represented in Scheme 3.
1
gested structure. The H-NMR spectrum of compound 10
exhibits a singlet signal for CH¼ proton, multiplet signals
Refluxing the acid hydrazide 2a with ethyl acetoacetate
in n-butanol solution in presence of drops of piperidine
for aromatic protons, one broad signal at δ 9.87 corresponding
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Novel Heterocycles Derived from 4-Arylmethylene-2-phenyl-1,
3-oxazole-5(4H)-ones
811
Scheme 4
to NHNHCO proton, and another broad signal in the down-
field region at δ 12.96 for OH proton. This suggests the exis-
tence of compound 10 in deuterated dimethylsulphoxide
solution as its lactim tautomer 10a.
olefinic proton, which is in a good agreement for its
existence as a mixture of E- and Z- stereoisomers in a ratio
of 2: 3, respectively (cf. Experimental part). The mass
spectrum of 12 shows the correct molecular ion peak.
Heating of compound 12 with acetic anhydride afforded
an adduct that was identical in all respects (mp, mmp, and
TLC) with compound 1b. The mechanistic pathway for the
formation of 1b from 12 is presented in Scheme 6.
On the other hand, refluxing 12 with hydrazine hydrate in
ethanol yielded an adduct that was identical in all respects
(mp, mmp, and TLC) with 2b. The mechanistic pathway
for the formation of 2b from 12 is presented in Scheme 7.
However, refluxing 12 with hydroxylamine hydrochloride
in presence of sodium acetate in ethanol gave the N-amino-
imidazolone derivative 11. The mechanistic pathway for
the formation of 11 from 12 is presented in Scheme 8.
The structure of the lactim tautomer 10a was supported
by the formation of an orange color on treatment of its
alcoholic solution with aq. FeCl3 solution.
The structure of compound 11 was further supported from
1
its H-NMR spectrum that shows signals for NH2, CH¼,
CH¼ (pyrazolo), and phenyl groups. Further support for
the structures of compounds 10 and 11 was gained from their
mass spectra, which exhibit their correct molecular ion peaks
beside other important peaks (cf. experimental part).
The hydrazide 2b easily condensed with aromatic aldehydes
such as p-anisaldehyde in refluxing ethanol to give the Schiff
base product N-((E,Z)-1-(1,3-diphenyl-1H-pyrazol-4-yl)-3-
((syn/anti)-2-(4-methoxybenzylidene) Hydrazinyl)-3-oxoprop-
1-en-2-yl) benzamide 12 (Scheme 5).
Scheme 6
The structure of compound 12 was established from an-
alytical and spectroscopic data. Its IR spectrum exhibits
1
bands for NH and C¼O groups. The H-NMR spectrum
of compound 12 shows two singlet signals for ¼CH
Scheme 5
Journal of Heterocyclic Chemistry
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812
A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 53
Scheme 7
Scheme 9
Scheme 8
Scheme 10
C¼N, and C¼C groups. Another support was gained from
The reactions of compound 12 with malononitrile and
thioglycolic acid have been investigated (Scheme 9). Thus,
treatment of compound 12 with malononitrile in piperidine
yielded the fused bicyclic compound, the cyano-amino-
pyrazolotriazinone derivative 13 (Scheme 9). The structure
of 13 was confirmed using the analytical and spectroscopic
data. The IR spectrum of 13 displayed νNH2 at 3288, 3227
cmꢀ1, νCN at 2198 cmꢀ1, and νC¼O at 1714 cmꢀ1. Further
evidence was gained from its 1H-NMR spectrum that shows
signals corresponding to OMe and NH2 as well as multiplet
signals for aromatic protons (cf. experimental part). The
mechanistic pathway for the formation of 13 from 12 is
represented in Scheme 10.
Refluxing compound 12 with thioglycolic acid in dry
benzene afforded the thiazolidinone derivative 14. The
structure of the thiazolidinone derivative 14 was substanti-
ated from its microanalytical and spectroscopic data. The
IR spectrum shows bands corresponding to CH2, C¼O,
1
its H-NMR spectrum that displays signals for protons of
CH2, OMe, CH, CH¼, and aromatic protons.
The appearance of two singlet signals for each of the
olefinic proton at δ 7.06 and 7.09 ppm and the pyrazolyl
proton at δ 9.31 and 9.33ppm is in a good agreement for
the existence of compound 14 as a mixture of E- and Z-
stereoisomers in a ratio of 2:1, respectively. The mechanis-
tic pathway for the formation of 14 from 12 is represented
in Scheme 11.
Antimicrobial Evaluation. Antimicrobial activity of the
tested samples was determined using a modified Kirby-
Bauer disc diffusion method [24]. Briefly, 100 μl of the test
bacteria/fungi were grown in 10 ml of fresh media until they
reached a count of approximately 108 cells/ml for bacteria
or 105 cells/ml for fungi [25]. One hundred microliter of
microbial suspension was spread onto agar plates
corresponding to the broth in which they were maintained.
Journal of Heterocyclic Chemistry
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May 2016
Synthesis of Novel Heterocycles Derived from 4-Arylmethylene-2-phenyl-1,
3-oxazole-5(4H)-ones
813
Scheme 11
and antifungal activities; compounds 1b, 3, and 4 exhibited
moderate antibacterial and antifungal activities compared
with the standard drugs, and compounds 9b, 11, and 14 ex-
hibited no antimicrobial activity.
EXPERIMENTAL
General. Melting points are uncorrected and were measured
on a Gallen Kamp electric melting point apparatus. The infrared
spectra were recorded using potassium bromide disks on FTIR
Thermo Electron Nicolet 7600 (USA) infrared spectrometer at the
Central Laboratory of Faculty of Science, Ain Shams University.
1
The H-NMR spectra were run at 300 MHz on a GEMINI 300
BB NMR spectrometer using tetramethylsilane (TMS) as internal
standard in deuterated dimethylsulphoxide (DMSO-d6) at the
main defense chemical laboratory. The mass spectra were
recorded on a Shimadzu GCMS-QP 1000EX mass spectrometer
operating at 70 eV at the Microanalytical Center of Cairo
University. The progress of all reactions was monitored by the
thin layer chromatography using Merck Kiesel gel 60 F254
aluminum backed plates. The spots were developed using UV lamp.
General procedure for reaction of 2a, b with diethyl acetylene
Plates inoculated with filamentous fungi as Aspergillus flavus at
25°C for 48 h, gram (+) bacteria as Staphylococcus aureus, and
gram (ꢀ) bacteria as Escherichia coli incubated at 35–37°C for
24–48 h and yeast as Candida albicans incubated at 30°C for
24–48 h, and then the diameters of the inhibition zones were
measured in millimeters [24].
Standard discs of Tetracycline (antibacterial agent) and
Amphotericin B (antifungal agent) served as positive con-
trols for antimicrobial activity, but filter discs impregnated
with 10 μl of solvent (distilled water, chloroform, DMSO)
were used as a negative control.
Preliminary screening of the synthetic derivatives and
standard drugs were performed and recorded by measuring
the diameter of the inhibition zone. On the basis of the re-
sults of the inhibition zoon, data in (Table 1) revealed that
compounds 6a, 6b, and 12 exhibited strong antibacterial
dicarboxylate.
To a solution of 2a (0.01 mol, 2.81 g) and 2b
(0.01 mol, 4.23 g) in ethanol (40 ml), diethyl acetylene
dicarboxylate (0.01 mol, 1.6 ml) was added. The reaction mixture
was refluxed for 4 h in case of 2a and 12h in case of 2b, and then
left to cool at room temperature. The solid obtained was filtered
off and washed with ethanol and recrystallized from a suitable
solvent to give compounds 3 and 4, respectively.
(E,Z)-ethyl 1-(2-benzamido-3-phenylacryloyl)-5-oxo-4,5-dihydro-1H-
pyrazole-3-carboxylate (3).
Colorless crystals; mp 138–140°C,
(ethanol) yield = 63%. IR (KBr) (νmax, cm1) 3322, 3183 (NH), 3084,
3030 (aryl-H), 2987, 2932, 2905 (alkyl-H), 1736 (C¼O ester), 1697
(C¼O amide), 1640 (C¼N), 1579, 1531 (C¼C), 758, 701
(monosubstituted benzene). 1H-NMR (CDCl3): δ 1.29, 1.34 (two
triplets, 6H, 2OCH2CH3, J= 6.9, 7.2 Hz), 3.27 (m,2H,CH2
pyrazole), 3.66 (m, 2H, CH2 pyrazole), 4.20, 4.39 (two quartets, 4H,
Table 1
Antibacterial and antifungal activity (as inhibition zone in mm diameter).
Inhibition zone diameter (mm/mg sample)
Escherichia coli
Staphylococcus aureus
Aspergillus flavus
Candida albicans
(fungus)
Sample
(Gꢀ)
(G+)
(fungus)
Control: DMSO
Tetracycline (Antibacterial
0.0
31
0.0
28
0.0
—
0.0
—
agent)
Amphotericin B (Antifungal
—
—
16
19
agent)
1b
3
4
6a
6b
9b
11
12
14
10
11
10
25
29
0.0
0.0
21
0.0
11
10
12
24
22
0.0
0.0
15
0.0
11
13
14
11
18
0.0
0.0
13
0.0
10
11
14
10
17
0.0
0.0
13
0.0
G = Gram reaction; 0.0 = no activity (inhibition zone less than 7 mm); 7–10 = weak activity; 11–15, moderate activity; more than 15 = strong activity.
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2CH3CH2O, J = 6.9, 7.2 Hz), 7.16–7.77 (m, 11H, ArH+¼CH), 12.13
(br. s, 1H, NH (for E- isomer, major); exchangeable), 12.06 (br. s,
1H,NH (for Z- isomer, minor); exchangeable). EIMS m/z (%): 405
(M+, missed), 388 (M+.–OH, 10), 338 (10), 144 (21), 119 (21),
118 (21), 116 (23), 105 (100), 104 (52), 92 (21), 91 (55), 89
(22), 77 (59), 76 (46), 65 (21), 64 (33), 63 (36), 61 (22), 60
(28), 58 (30), 55 (29), 51 (22), 50 (33). Anal. Calcd. For
C22H19N3O5 (405.39): C, 65.18; H, 4.72; N, 10.37. Found: C,
65.32; H, 4.59; N, 10.51%.
recrystallized from the suitable solvent to give the 6a and/or 6b,
respectively. After cooling the residual mother liquor gave the same
compound 6a and/or 6b, respectively.
N-(1-(E/Z)-3-(2-(syn/anti)-(4-chlorobenzylidene)hydrazinyl)-3-oxo-
1-phenylprop-1-en-2-yl)benzamide (6a).
Colorless crystals; mp
214–215°C, (ethanol-dioxane) yield = 92%. IR (KBr) (νmax, cmꢀ1
)
3282, 3239 (NH), 3060, 3030 (aryl-H), 1677 (C¼O), 1638, 1602
(C¼N), 1580, 1537 (C¼C), 825 (δ2H), 736, 697 cmꢀ1 (mono
1
substituted benzene). HNMR (DMSO-d6): δ 7.26–7.84 (m, 30H,
Ethyl 1-(2-benzamido-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl)-
5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (4). Yellow crystals;
mp 156–158°C, (benzene) yield = 49%. IR (KBr) (νmax, cmꢀ1) 3457,
3329, 3267, 3138 (NH), 3060 (aryl-H), 2981, 2934, 2905 (alkyl-H),
1736 (C¼O ester), 1704 (C¼O pyrazolo), 1669 (C¼O amide), 1599,
1540 (C¼C), 752, 694 (mono substituted benzene).1H-NMR (DMSO-
d6): δ 1.152 (m, 6H, 2 CH3), 3.56 (m, 2H, CH3CH2OCO), 4.11 (m,
2H, CH3CH2OCO), 7.40–8.05 (m, 17H, ArH + 2CH¼), 8.62 (s, 1H,
pyrazolyl), 10.26 (br. s, 1H, NHN, exchangeable), 12.98 (br. s, 1H,
NHCO exchangeable). EIMS m/z (%): 547 (M+., 5), 520, (35), 392 (93),
361 (22), 286 (25), 259 (57), 231 (42), 173 (22), 155 (53), 128 (43), 105
(100), 77 (95), 51 (63). Anal. Calcd. For C31H25N5O5 (547.56): C,
68.00; H, 4.60; N, 12.79. Found: C, 68.12; H, 4.49; N, 12.87%.
General procedure for reaction of 2a,b with 2, 5-dimethoxy
arylidene malononitrile. To a solution of 2a (0.01 mol, 2.81 g)
and 2b (0.01 mol, 4.23 g) in ethanol (40 ml), 2, 5-dimethoxy
arylidene malononitrile (0.01 mol, 2.25 g) was added. The reaction
mixture was refluxed for 8–12 h. The excess solvent was removed
under reduced pressure, the obtained solid was recrystallized from
suitable solvents to give compounds 5a and 5b, respectively.
N-(1-(E/Z)-3-(2-(syn/anti)-(1-(2,5-dimethoxyphenyl) ethylidene)
hydrazinyl)-3-oxo-1-phenylprop-1-en-2-yl) benzamide (5a).White
ArH+2¼CH) For (Z/Anti) isomer: 8.25 (s, 1H, ¼CH), 8.68 (d, 1H,
NH–N¼ exchangeable), 11.73 (br. s, 1H, NHCOPh, exchangeable).
For (E/Syn) isomer: 8.01 (s, 1H, ¼CH), 8.80 (br. s, 1H, NH–N¼
exchangeable), 11.51 (br. s, 1H, NHCOPh, exchangeable).
EIMS m/z (%): 403 (M+, missed), 252 (13), 251 (8), 105 (100),
91 (13), 77 (37), 76 (22), 51 (10). Anal. Calcd. For
C23H18ClN3O2 (403.86): C, 68.40; H, 4.49; Cl, 8.78; N, 10.40.
Found: C, 68.59; H, 4.56; Cl, 8.89; N, 10.82%.
N-(1Z-3-(2-(4-chlorobenzylidene) hydrazinyl)-1-(1,3-diphenyl-1H-
pyrazol-4-yl)-3-oxoprop-1-en-2-yl) benzamide (6b). Colorless crystals;
mp 194–196°C, (ethanol-dioxane) yield = 73%. IR (KBr) (νmax, cmꢀ1
)
3228, 3186 (NH), 3054 (aryl-H) 1686, 1639 (C¼O), 1600, 1532 (C¼N
1
and/or C¼C), 703, 749 (monosubstituted benzene), 820 (δ2H ). H-
NMR (DMSO-d6): δ 7.14 (s, 1H, ¼CH), 7.33–8.08 (m, 19H, ArH),
8.40 (s, 1H, N¼CH), 8.63 (s, 1H, pyrazolo proton), 9.98 (br. s, 1H,
NH–N, exchangeable), 11.66 (br. s, 1H, NH Ph CO, exchangeable).
EIMS, m/z (%): 548 (M+ +2, 3), 546 (M+,15), 500 (89), 455 (76), 397
(80), 315 (90), 256 (100), 213 (78), 192 (87), 123 (83), 106 (58), 92
(60), 78 (33), 64 (59), 59 (56), 50 (51). Anal. Calcd. For
C32H24ClN5O2 (546.02): C, 70.39; H, 4.43; Cl, 6.49; N, 12.83.
Found: C, 71.00; H, 4.59; Cl, 6.60; N, 12.72%.
General procedure for synthesis of 1,2-bis(4-chlorobenzylidene)
hydrazine (7) and (Z)-4-benzoyl-3-(4-chlorophenyl)-5-((1,3-diphenyl-
1H-pyrazol-4-yl)methylene)-4,5-dihydro-1,2,4-triazin-6(1H)-
one (8). A solution of 6a (0.02 mol, 0.56 g) or 6b (0.02 mol,
0.84 g) in 20 ml of a mixture of HCl/CH3COOH (molar ratio 1:1)
was refluxed for 4 h. The reaction mixture was cooled and then
poured onto ice-water. The solid obtained was filtered off, washed
with cold water for several times, and crystallized from the
appropriate solvent to give compound 7 or 8, respectively.
1,2-Bis(4-chlorobenzylidene) hydrazine (7). Pale yellow crystals; mp
213–214°C (Lit. [26] mp = 210°C).
crystals; mp 130–132°C, (benzene) yield = 33%. IR (KBr) (νmax
,
cmꢀ1) 3296 (NH), 3059, 3030 (aryl-H), 2937, 2834 (alkyl-H), 1686
(C¼O), 1636 (C¼N), 1578, 1533 (C¼C), 747, 699 cmꢀ1 (mono
1
substituted benzene). H-NMR (DMSO-d6): δ 2.17, 2.22 (two s, 6H,
2CH3), 3.69, 3.72, 3.76, 3.77 (four s, 12H, 4OCH3), 6.99–7.83 (m,
28H, ArH+2¼CH), 8.53, 8.61 (two d, 2H, 2NHCO, exchangeable),
10.56, 10.62 (two broad s, 2H, 2NHCOPh, exchangeable). EIMS m/z
(%): 445 (M+ +2, 0.5), 444 (M+ +1, 0.5), 443 (M+, missed), 221 (17),
220 (14), 163 (38), 162 (32), 161 (16), 105 (100), 104 (86), 77 (41.4),
76 (36). Anal. Calcd. For C26H25N3O4 (443.49): C, 70.41; H, 5.68; N,
9.47. Found: C, 70.57; H, 5.81; N, 9.62%.
(Z)-4-benzoyl-3-(4-chlorophenyl)-5-((1,3-diphenyl-1H-pyrazol-4-
N-(3-(syn/anti)2-(1-(2,5-dimethoxy phenyl)ethylidene) hydrazinyl)-1
(1,3-diphenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-2-yl) benzamide
(5b). White crystals; mp 204–206°C, (dioxane) yield = 21%. IR
(KBr) (νmax, cmꢀ1) 3277, 3186 (NH), 3056 (aryl-H), 2992, 2941,
2910, 2833 (alkyl-H), 1647 (C¼O), 1616 (C¼N), 1660, 1503 (C¼C),
yl)methylene)-4,5-dihydro-1,2,4-triazin-6(1H)-one (8).
Yellow
crystals; mp 188–191°C, (PE 60–80/benzene) yield = 40%. IR (KBr)
(νmax, cmꢀ1) 3261 (NH), 3057 (aryl-H), 1746, 1683 (C¼O), 1596,
1535 (C¼N and/or C¼C), 831(δ2H ), 730, 694 (monosubstituted
benzene ).1H-NMR (DMSO-d6): δ 6.17 (s, 1H, ¼CH), 6.98–7.85
(m, 19H, ArH), 8.73 (s, 1H, pyrazolo proton), 10.62 (br. s, 1H,OH-
triazinone, exchangeable). EIMS, m/z (%): 543 (missed) 355
(100), 278 (70), 247 (90), 264 (77), 77 (95), 51 (48). Anal.
Calcd. For C32H22ClN5O2 (544.98): C, 70.65; H, 4.08; N, 12.87.
Found: C, 70.97; H, 4.22; N, 12.57%.
General procedure for the reaction of (2b) with ethyl
acetoacetate. To a solution of 2a (0.01 mol, 2.81g) or 2b (0.01
mol,4.23 g) in n-butanol (30 ml), ethyl acetoacetate (0.01
mol,1.27 ml) and drops of piperdine were added. The reaction
mixture was refluxed for 12 h; the excess solvent was removed
under reduced pressure. 9a was obtained in case of 2a. While in case
of 2b, the obtained solid was fractionally crystallized from benzene-
methanol to give compound 10. The insoluble part in benzene-
methanol was recrystallized from methanol to give compound 9b.
Leaving the mother liquor overnight at room temperature gives 11.
1
753, 708 (monosubstituted benzene). H-NMR (DMSO-d6): δ 2.15,
2.17 (two singlets, 6H, 2CH3);13.54, 3.57, 3.69, 3.75 (four singlets,
12H, 4OCH3); 7.17 (s, 1H, C¼CH), 6.69–8.39 (m, 38H, ArH), 8.67
(s, 1H, pyrazolo proton); 9.10, 9.83 (2br. s, 2H, 2NH–N¼
exchangeable), 9.96, 10.42 (2br. s, 2H, 2NHPhCO, exchangeable).
EIMS, m/z (%): 587 (M+ +2, 26), 586 (M+ +1, 21), 585 (M+, 34),
432 (38), 391 (40), 315 (36), 169 (33), 105 (100), 85 (40), 77
(83), 57 (53), 51 (28). Anal. Calcd. For C35H31N5O4 (585.65):C,
71.78; H, 5.34; N, 11.96. Found: C, 71.89; H, 5.49; N, 11.82%.
General procedure for reaction of 2a and/or 2b with p-chloro
benzylidene malononitrile. To a solution of 2a (0.01 mol, 2.81 g)
or 2b (0.01 mol, 4.23 g) in ethanol (40 ml), p-chloro benzylidene
malononitrile (0.01 mol, 1.87 ml and/or 1.74 ml; respectively) was
added. The reaction mixture was refluxed for 1 h. A solid product
was precipitated while hot, filtered off and washed with ethanol,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2016
Synthesis of Novel Heterocycles Derived from 4-Arylmethylene-2-phenyl-1,
3-oxazole-5(4H)-ones
815
Another method for synthesis of compound (11) by reaction of
(12) with hydroxyl aminehydrochloride. A solution of 12 (0.01
mol, 5.27 g) in ethanol (40 ml) and small amounts of Dioxane
(5 ml), hydroxyl amine hydrochloride (0.01 mol, 0.69 g) and
anhydrous sodium acetate (0.02 mol, 2.39 g) were added. The
reaction mixture was refluxed for 7 h. The solvent was removed
under reduced pressure, and the obtained solid was recrystallized
from (ethanol-dioxane = 4:1) to give compound 11.
(alkyl-H), 1635 (C¼O amide), 1601 (C¼N), 1537, 1507 (C¼C),
754, 696 (monosubstituted benzene). 1H-NMR (DMSO-d6): δ
3.57, 3.80 (two singlets, 6H, 2OCH3), 6.99–8.07 (m, 21H,
ArH + 2CH¼), 8.06, 8.08 (two singlets, 2H, 2N¼CH), 8.35, 9.61
(two singlets, 2H, 2 pyrazolo protons), 9.94 (br. s, 2H, 2CONH–N¼
exchangeable), 11.45 (br. s, 2H, 2NHCOPh exchangeable). EIMS,
m/z (%): 543 (M+ +2, 81), 542 (M+ +1, 51), 541 (M+, 47), 518 (75),
511 (71), 486 (100), 455 (88), 383 (76), 322 (88), 243 (61), 233
(77), 103 (49), 77 (25), 51 (20). Anal. Calcd. For C33H27N5O3
(541.60): C, 73.18; H, 5.02; N, 12.93. Found: C, 73.27; H,
5.05; N, 12.67%.
(Z)-N-(1-(3-methyl-5-oxo-4,5-dihydropyrazol-1-yl)-1-oxo-3-pheny
lprop-2-en-2-yl)benzamide (9a).
White crystals; mp 240–243°C,
(n-butanol) yield = 34%. IR (KBr) (νmax, cmꢀ1): 3424, 3248 (NH),
3057, 3028 (aryl-H), 2921, 2956 (alkyl-H), 1644 (C¼O amide) 1608
(C¼N), 1579 (C¼C), 743, 699 (monosubstituted benzene). 1H-NMR
(DMSO-d6): δ (ppm) 2.98–3.19 (m, 5H, CH3&CH2), 4.83 (s, 1H,
pyrazolo-H, for enol-form), 7.17–7.80 (m, 11H, ArH+¼CH), 10.27
(br. s, 1H, NH, exchangeable), 11.09 ( s, 1H, OH, enol-form). Anal.
Calcd. for C20H17N3O3 (347.37): C, 69.15; H, 4.93; N, 12.10.
Found: C, 69.35; H, 4.55; N, 12.15%.
General procedure for reaction of 12 with acetic anhydride.
A
solution of 12 (0.01 mol, 5.27 g) in acetic anhydride (40 ml) was
refluxed for 10 h and then poured onto ice-water to give a yellow-
orange precipitate which was filtered off, washed with cold water,
and crystallized from ethanol-dioxane to give compound 1b, which
was identical in all respects (IR,1H-NMR, mp, mmp, and TLC)
with an authentic sample [17].
N-(3-(1,3-diphenyl-1H-pyrazol-4-yl)-1-(3-methyl-5-oxo-4,5-dihydro
pyrazol-1-yl)-1-oxoprop-2-en-2-yl)benzamide (9b). Pale brown crystals;
mp 175–178°C, (ethanol) yield = 64%. IR (KBr) (νmax, cmꢀ1): 3248,
3151 (NH), 3063 (aryl-H), 2958, 2931, 2869 (alkyl-H), 1708 (C¼O
cyclic amide), 1643 (C¼O amide) 1600 (C¼N), 1579 (C¼C), 756,
689 (mono substituted benzene). 1H-NMR (DMSO-d6): δ (ppm) 2.09
(s, 3H, CH3), 3.17 (s, 2H, CH2), 7.33 (s, 1H,¼CH), 7.39–8.00
(m, 16H, ArH), 8.71 (s, 1H, pyrazolyl), 9.96 (br. s, 1H, NHCOPh,
exchangeable). Anal. Calcd. for C29H23N5O3 (489.52): C, 71.15; H,
4.74; N, 14.31. Found: C, 71.05; H, 4.87; N, 14.20%.
(Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-phenyl-1,2-dihy
dro-1,2,4-triazin-6(5H)-one (10). Orange crystals; mp 225–228°C,
(benzene - methanol) yield = 90.3%. IR (KBr) (νmax, cmꢀ1): 3272, 3171
(NH), 3056 (aryl-H), 1689 (C¼O), 1643 (C¼N), 1599, 1538 (C¼C),
756,694 (mono substituted benzene). 1H-NMR (DMSO-d6): δ
(ppm) 7.34 (s, 1H, ¼CH), 7.36–8.02 (m, 15H, ArH), 8.66 (s, 1H,
pyrazolyl), 9.87 (br. s, 1H, NH, exchangeable), 12.69 (br. s, 1H,
OH, exchangeable). EIMS, m/z (%):406 (M+ +1, 14), 405 (M+,
32), 394 (43), 388 (46), 351 (51), 337 (46), 306 (49), 288 (43),
257 (60), 236 (53), 219 (61), 145 (52), 115 (51), 105 (100), 77
(58). Anal. Calcd. for C25H19N5O (405.46): C, 74.06; H, 4.72; N,
17.27. Found: C, 73.99; H, 4.89; N, 17.43%.
1-Amino-4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-5-oxo-
2-phenyl-4,5-dihydro-1H-imidazole (11). Yellow crystals; mp
237–239°C, (ethanol-dioxane = 4:1) yield = 70%. IR (KBr)
(νmax, cmꢀ1) 3355, 3322, 3300, 3154 (NH2), 3051 (aryl-H),
1704 (C¼O), 1632 (C¼N), 1597, 1528 (C¼C), 736, 692
(monosubstituted benzene). 1H-NMR (DMSO-d6): δ (ppm) 5.36
(br. s, 2H, NH2, exchangeable), 7.07 (s, 1H, ¼CH), 7.43–8.46
(m, 15H, ArH), 9.31 (s, 1H, pyrazolo). EIMS, m/z (%):405
(M+, 100), 398 (13), 368 (13), 271 (15), 212 (20), 139 (28),
119 (93), 105 (15), 77 (53). Anal. Calcd. for C25H19N5O
(405.56): C, 74.06;H, 4.72; N, 17.27. Found: C, 73.97; H,
5.05; N, 17.42%.
General procedure for the reaction of 2b with p-anisaldehyde. To
a solution of 2b (0.01 mol, 4.23 g) in dioxane (30 ml), p-anisaldehyde
(0.01 mol, 1.23 ml) was added. The reaction mixture was refluxed
for 4 h and then left to cool at room temperature. The solid
obtained was filtered off and washed with ethanol and
recrystallized from dioxane to give the title compound 12.
N-((E, Z)-1-(1, 3-diphenyl-1H-pyrazol-4-yl)-3-((syn/anti)-2-(4-me
thoxy-benzylidene)hydrazinyl)-3-oxoprop-1-en-2-yl) benzamide) (12).
General procedure for reaction of 12 with hydrazine
hydrate. To a solution of 12 (0.001 mol, 0.53 g) in ethanol
(30 ml), hydrazine hydrate 80% (0.24 ml) was added. The reaction
mixture was refluxed for 1 h. The solid precipitated was filtered off
while hot, washed with cold ethanol and recrystallized from ethanol
to give compound 2b, which was identical in all respects
(IR,1H-NMR, MS, mp, mmp, and TLC) with an authentic sample
prepared from reacting of 1b with hydrazine hydrate [17].
General procedure for reaction of 13 with malononitrile.
A
solution of 12 (0.01 mol, 5.27 g) in ethanol (40 ml), malononitrile
(0.01 mol, 0.63 ml), and drops of piperdine were added. The
reaction mixture was refluxed for 7 h, and the excess solvent was
removed under reduced pressure. The obtained oil was triturated
with methanol, the deposited solid was collected by filtration and
crystallized from dioxane to give compound 13.
6-Amino-3-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-8-(4-methoxy-
phenyl)-4-oxo-1-phenyl-4,8-dihydro-3H-pyrazolo[1,2-a] [1,2,4] triazine-
7-carbonitrile (13).
Yellow crystals; mp 285–287°C, (dioxane)
yield = 20%, IR (KBr) (νmax, cm1): 3440, 3288, 3227, 3165 (NH),
3063 (aryl-H), 2198 (CN), 1714 (C¼O), 1664, 1607 (C¼N), 1565,
1
1509 (C¼C), 829 (δ2H), 757, 688 (monosubstituted benzene). H-
NMR(DMSO-d6):δ 3.83 (s, 3H, OCH3), 6.86 (s, 1H, ꢀCH–),
7.03–7.98 (m, 19H, ArH), 8.46 (br. s, 2H, NH2, exchangeable),
8.89 (s, 1H, ¼CH), 9.95 (s, 1H, pyrazolo). Anal. Calcd. for
C36H27N7O2 (589.65): C, 73.33; H, 4.62; N, 16.63. Found: C,
73.57; H, 4.54; N, 16.87%.
General procedure for reaction of 12 with thioglycolic
acid. To a solution of 12 (0.01 mol, 5.27 g) in dry benzene
(70 ml), thioglycolic acid (0.01 mol, 0.7 ml) was added. The
reaction mixture was refluxed for 8 h using water separator and
then left to cool at room temperature. The solid obtained was
filtered off and washed with dry benzene and recrystallized
from ethanol-dioxane = 4:1 to give compound 14.
E,Z-3-(4-(1,3-diphenyl-1H-pyrazol-4-yl)methylene-5-oxo-2-phenyl-
4,5-dihydro-1H-imidazol-1-yl)-2-(4-methoxyphenyl) thiazolidin-4-one
(14). Yellow crystals; mp 238–240°C, (ethanol-dioxane = 4:1)
yield = 76%, IR (KBr) (νmax, cmꢀ1):3051 (aryl-H), 2906, 2841
(alkyl-H), 1698, 1634 (C¼O), 1601 (C¼N), 1532, 1508 (C¼C), 829
1
(δ2H), 754, 687 (monosubstituted benzene). H-NMR (DMSO-d6): δ
3.57 (s, 2H, CH2), 3.83 (s, 3H, OCH3), 7.06, 7.09 (two singlets, 2H,
2¼CH), 7.16 (s, 1H, –CH–), 7.57–8.28 (m, 19H, ArH), 9.31,
9.33 (two singlets, 2H, 2 pyrazolo protons). EIMS, m/z (%): 597
(M+, 2), 525 (3), 523 (50), 391 (90), 346 (15), 268 (45), 243 (20),
161 (42), 134 (38), 105 (100), 77 (98), 51 (27). Anal. Calcd. for
White crystals; mp 215–217°C, (dioxane) yield = 94%. IR (KBr) (νmax
,
cm1) 3237, 3114 (NH), 3043, 3030 (aryl-H), 2943, 2914, 2847
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

816
A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 53
[13] Icli, S.; Doroshenko, A. O.; Alp, S.; Abmanova, N. A.;
Egorova, S. I.; Astley, S. T. Spectrosc Lett 1999, 32, 553.
[14] Ullman, E. F.; Baumann, N. J Am Chem Soc 1970,
92, 5892.
[15] Krasovitskii, B. M.; Surov, Y. N.; Lysova, I. V.; Afanasiadi, L. S.
Chem Heterocycl Compounds 1984, 20, 136.
C35H27N5O3S (597.68):C, 70.33; H, 4.55; N, 11.72; S, 5.36.
Found: C, 70.13; H, 4.25; N, 11.42; S, 5.59%.
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Journal of Heterocyclic Chemistry
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