Action of Some Nitrogen and Carbon Nucleophils on 4-Arylidene-1,3-oxazolones

Article abstract of DOI:10.1002/jhet.2411

(Chemical Equation Presented) 1,3-Oxazolones 1 and 2 were reacted with hydrazine hydrate to afford the corresponding hydrazides 3 and 4. Treatment of the hydrazides withacetylacetone, acetonylacetone, ethyl acetoacetate and diethyl malonateyielded different heterocycles. However, oxazolones 1 and 2 reacted with methyl p-aminobenzoate to afford the imidazolones 5a,b which were converted into the hydrazide 3a or the triazinone derivative 6 upon treating with hydrazine hydrate. The structures of the newly synthesized compounds were established using IR, 1H-NMR, EIMS, and elemental analyses.

Full text of DOI:10.1002/jhet.2411

Month 2015
Action of Some Nitrogen and Carbon Nucleophils on 4-Arylidene-1,
3-oxazolones
,*
Ahmed S. A. Youssef, Kamal A. Kandeel, Wael S. I. Abou-Elmagd and David S. A. Haneen
Department of Chemistry, Faculty of Science, Ain Shams University, Abassia11566, Cairo, Egypt
*
E-mail: waelmagd97@yahoo.com
Received September 13, 2014
DOI 10.1002/jhet.2411
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
1,3-Oxazolones 1 and 2 were reacted with hydrazine hydrate to afford the corresponding hydrazides 3 and
4. Treatment of the hydrazides withacetylacetone, acetonylacetone, ethyl acetoacetate and diethyl
malonateyielded different heterocycles. However, oxazolones 1 and 2 reacted with methyl p-aminobenzoate
to afford the imidazolones 5a,b which were converted into the hydrazide 3a or the triazinone derivative 6
upon treating with hydrazine hydrate. The structures of the newly synthesized compounds were established
using IR, 1H-NMR, EIMS, and elemental analyses.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
yl)methylene)-2-phenyl-1,3-oxazole-5(4H)-one 2 and also
on the action of acetonylacetone, acetylacetone, ethyl
acetoacetate, and diethyl-malonate on the obtained acid hy-
drazide derivatives 3a and 4.
Oxazolones are considered as key starting materials for
the construction of many heterocycles of synthetic and bi-
ological importance as analgesic [1], anti-inflammatory [2],
antidepressant [3], anticancer [4], antimicrobial, antidia-
betic, and antiobesity [5,6].
The key step in these transformations is the formation of
the acid hydrazides that are formed by the action of hydra-
zine hydrate on the oxazolones, a reaction that occurs
smoothly and mostly at room temperature. An extension
of conjugation through an exocyclic double bond present
at C-4 position of oxazolone moiety and a phenyl ring pres-
ent at C-2 plays a pivotal role in the reactivity of these
oxazolones [7,8].
RESULTS AND DISCUSSION
The action of hydrazine hydrate on different oxazolones
in different conditions was previously studied [9–12], but
the stereochemistry of the product obtained was not
discussed. Thus, treatment of 1 with hydrazine hydrate in
refluxing ethanol afforded the E- configurated isomer hy-
drazide derivative (E) 3a (low yield). However, doing
the same reaction by stirring at room temperature gave
the Z- configurated isomer hydrazide derivative (Z) 3b in
a good yield.
In the present investigation, we aimed to make a compar-
ative study between the action of methyl-4-aminobenzoate,
hydrazine hydrate, on 4-phenylmethylene-2-phenyl-1,3-
oxazole-5(4H)-one 1 and 4-((1,3-diphenyl-1H-pyrazol-4-
Aforementioned findings prompted the authors to carry
out this reaction to show the effective factor (temperature
© 2015 HeteroCorporation

A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 000
Scheme 1
that the isolated isomer is the E- configurated one as it is
of lower steric interaction as compared with the Z-
counterpart.
Fusion of oxazolones
1 and 2 with methyl-4-
aminobenzoate on an oil bath gave the imidazolone deriv-
atives 5a and 5b, respectively. The structure of 5 is sub-
stantiated from its spectral data. The IR spectrum shows
disappearance of absorption of C¼O group of azlactone
and the appearance of an absorption of C¼O group for cy-
1
clic amide. The assigned structure is supported from H-
NMR and mass spectra. The MS spectrum shows the cor-
rect molecular ion peak beside some of abundant peaks
(cf. Experimental section). Refluxing 5a with hydrazine
hydrate in methanol for 3h gave the acid hydrazide deriv-
ative 3a, as E- configurated isomer with a better yield to-
gether and a compound that was identical in all respects
(m.p., mm.p., and TLC) with methyl-4-aminobenzoate
(Scheme 3), while the treatment of the imidazolone 5b with
hydrazine hydrate in dioxane for 20h gave the triazinone
derivative 6. The structure of 6 was illustrated from its an-
alytical, as well as, spectral data (cf. Experimental section).
The mechanistic pathway for the transformation of
imidazolone 5b to 6 is represented in (Scheme 4).
and/or nucleophile) on this isomerization (Scheme 1).
Thus, when Z- isomer 3b was heated under reflux in etha-
nol or in pyridine, the isomerization did not occur; how-
ever, the isomerization occurred upon heating an
ethanolic solution of 3b with prototype nucleophiles as hy-
drazine hydrate or piperidine. This can be explained on the
basis of the attack by a molecule of hydrazine hydrate or
piperidine at Cβ of the α,β-unsaturated carbonyl system to
give the saturated intermediate [A] not isolated. Rotation
around C–C single bond followed by removal of a hydra-
zine hydrate or a piperidine molecule gave the E-
configurated isomer (E)- 3a (Scheme 2).
Scheme 3
On the other hand, when the pyrazol-3-yl-methylene
oxazolone derivative 2 was treated with the hydrazine hy-
drate in refluxing ethanol, it afforded one isomer of the hy-
drazide derivative 4 in low yield. However, on doing the
same reaction by stirring at room temperature, the same
isomer was isolated but in a good yield, and the other iso-
mer did not, which may be due to the high steric effect of
the 1,3-diphenylpyrazolyl ring (Scheme 1). We suggest
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Action of Some Nitrogen and Carbon Nucleophils on 4-Arylidene-1,3-oxazolones
Scheme 4
Treatment of the acid hydrazide derivative 3a with
acetylacetone in refluxing ethanol gave the pyrazolyl deriv-
1
ative 8. The H-NMR spectrum of compound 8 showed
that it exists as a mixture of E- and Z- isomers in the ratio
of 48:52%, respectively (Scheme 5). The E- isomer is the
minor adduct due to the steric interaction between the
pyrazolyl and the phenyl group. Thus, the pyrazolyl group
becomes out of plane and the conjugation with the car-
bonyl group is no longer present, so the pyrazolyl hydro-
gen appears in the downfield region (as the ring becomes
more aromatic). However, in the Z- isomer (major), the
pyrazolyl moiety is in conjugation with the rest of the mol-
ecule, which leads to the upfield for the signal of the
pyrazolyl hydrogen. In addition, the extension of conjuga-
tion in the molecule leads to downfield for the signal of NH
proton. Both E- and Z- isomers will be planarized to a
greater or lesser extent by intramolecular H-bonding be-
tween the NH and the pyrazole N-2. In the E-isomer, steric
interaction between the (pyrazolyl-linked) carbonyl oxy-
gen and the Ph group will make the array less planar
resulting in weaker H-bonding (resulting in an upfield shift
of the NH proton – 8.37 ppm) compared with the Z- isomer
in which no such interaction is possible as reflected by the
deshielding of the NH to 9.03ppm. A quick look using
Chem3D does indicate the existence of intramolecular H-
bonding (cf. Experimental section).Similarly, treatment of
the acid hydrazide 4 with acetylacetone in refluxing etha-
N-Pyrrolo derivatives 7a,b were obtained upon treat-
ment of the acid hydrazide derivative 3a or 4 with
acetonylacetone in refluxing ethanol (Scheme 5). Inspec-
1
tion of the H-NMR spectrum of compound 7b revealed
its existence as a mixture of E,Z- stereoisomers in the ratio
of 2:3, respectively, based on the appearance of four sin-
glets for methyl groups (cf. Experimental section).
1
nol for 6 h gave a product that was proved by IR and H-
NMR spectra to be a mixture of oxazolone 2 and 3,5-
dimethylpyrazole. The appearance of absorption bands in
the IR spectrum at 1790cmꢀ1 (C¼O lactone) and at
3275, 3141cmꢀ1 (NH) is a good evidence for the existence
of oxazolone 2 and 3,5-dimethyl pyrazole. Further support
for the existence of the components mixture was gained
Scheme 5
1
from H-NMR spectrum that revealed signals for olefinic
protons, CH (pyrazolo), 2CH3, broad singlet signal for
NH proton and multiplet signals for aromatic protons (cf.
Experimental section). A chemical proof for the identity
of the mixture was ascertained by carrying TLC for the
mixture with oxazolone 2 and an authentic sample of 3,5-
dimethylpyrazole prepared from reacting hydrazine hy-
drate with acetylacetone in dioxane. However, the reaction
of 4 with acetylacetone in refluxing ethanol for 3 h gave the
open chain compound 9 (Scheme 5). The structure of com-
pound 9 was substantiated from its analytical and spectral
data. Thus, its IR spectrum revealed the appearance of
bands corresponding to NH and C¼O groups. Further evi-
dence was gained from its 1H-NMR that shows signals for
protons of NH, CH¼, CH2, CH3, and aromatic protons (cf.
Experimental section).The conversion of 4 to compounds 2
and 3,5-dimethylpyrazole could be visualized as shown in
Scheme 6. A good evidence for the suggested mechanism
was gained from the formation of the open chain adduct
9 on refluxing in ethanol for 3h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 000
Scheme 6
Scheme 7
A good explanation for the removal of the 3,5-
dimethylpyrazolyl group in case of the acid hydrazide 4
as compared with the acid hydrazide 3a is the higher steric
interaction between 1,3-diphenylpyrazolyl and 3,5-
dimethylpyrazolyl groups. This forces the 3,5-dimethyl-
pyrazolyl group to come out of plane of the molecule. So,
this prevents the conjugation between the C¼O group and
3,5-dimethylpyrazole moiety. This means that the N-
pyrazolyl group is singly bonded to C¼O group, which
makes the N-carbonyl bond easy to be broken. In addition,
the electrophilicity at the carbonyl carbon is high, which fa-
cilitates the nucleophilic attack by OH group followed by
the removal of 3,5-dimethylpyrazole molecule. This is a
good evidence for the existence of the acid hydrazide 4 as
the E- configurated isomer as mentioned before.
Treatment of an ethanolic solution of the acid hydrazide
3a with ethyl acetoacetate afforded the open chain adduct
butanoate derivative 10 (Scheme 7). The structure of com-
pound 10 was substantiated from its spectral and microan-
alytical data. The IR spectrum exhibits bands that
correspond to NH at 3304, C¼O (ester) at 1736, and
C¼O (amide) at 1695 cmꢀ1. Further evidence was
ascertained from its 1H-NMR spectrum. Compound 10 ex-
ists in DMSO solution as a mixture of two tautomers in-
volving the NH hydrazono and the neighboring C¼O
group in the ratio of 1:1 (cf. Experimental section).
Compound 11 exists in deuterated dimethyl sulfoxide
(DMSO-d6) solution as the cyclic lactim form. This is evi-
denced from the higher δ value at 12.69ppm, which corre-
sponds to OH proton. Also, solution of 11 in alcohol with
aq. FeCl3 gives orange color (cf. Experimental section).
The structure of compound 12 was established from its in-
frared spectrum, which exhibits bands for NH2 at 3355,
1
3322, 3300 cmꢀ1 and C¼O at 1704cmꢀ1. The H-NMR
spectrum is in good agreement with the suggested structure
as it showed signals for protons of NH2, ¼CH, ¼CH
(pyrazolo), and aromatic protons.
Treatment of the acid hydrazide 3a with diethyl malonate
gave an adduct that may have one of the two possible struc-
tures: the trioxopiperidine 13 or the pyrazolidindione 14 (cf.
Scheme 7). The correct structure of the product was inferred
from its spectroscopic data. Its infrared spectrum displays
absorption bands corresponding to NH (3247cmꢀ1) and
C¼O (1643 cmꢀ1). The lower frequency of absorption for
C¼O group suggests its existence as structure 13 and not
1
14 [13–17]. The H-NMR spectrum supports structure 13
as it shows two broad singlet signals in the downfield region
for protons of 2NH as well as two doublets of doublets in
the upfield region corresponding to two CH2 groups, which
is in a good agreement with structure 13. Further evidence
for the structure of compound 13 was gained from its EIMS
spectrum. It does not show the molecular ion peak; instead,
it shows a peak at m/z =363 corresponding to (M+ ꢀCO).
The conversion of 3a to compound 13 could be visualized
as shown in Scheme 8.
On the other hand, ring closure of the acid hydrazide 4
occurred upon treatment of 4 with ethyl acetoacetate. The
six- and five-membered closed forms 11 and 12, respec-
tively, were obtained (Scheme 7). The separation of 11
and 12 was discussed in the Experimental section.
However, similar treatment of the hydrazide 4 with
diethyl malonate yielded a compound identical in all
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Action of Some Nitrogen and Carbon Nucleophils on 4-Arylidene-1,3-oxazolones
1H, pyrazolyl). EIMS, m/z (%): 392 (M+ + 1, 3.6), 391 (M+
Scheme 8
22.6), 105 (100), 104 (24), 77 (52.6), 60 (12.4), 52 (13). Anal.
Calcd for C25H17N3O2 (391): C, 76.71; H, 4.38; N, 10.74.
Found: C, 76.50; H, 4.43; N, 10.86.
General procedure for synthesis of N-(3-hydrazinyl-3-oxo-1-
phenylprop-1-en-2-yl)benzamide (3).
Method 1 from methyl
4-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydro-imidazol-1-yl)
benzoate (5a).A solution of 5a (0.001mol, 0.38g) and hydrazine
hydrate 80% 0.38mL in methanol (30 mL) was refluxed for 6 h
and then cooled. The reaction mixture was left to evaporate at
room temperature to give a yellowish white solid, which was
fractionally crystallized from benzene to give methyl p-
aminobenzoate, which was identified by m.p., mixed m.p., and
TLC. The insoluble part in benzene was recrystallized from
ethanol to give compound 3a; yield = 45%.
Method 2 from azlactone (1).A solution of 1 (0.001 mol,
0.249 g) and hydrazine hydrate 80% 0.2 mL in ethanol (30 mL)
was stirred at room temperature or refluxed for 3 h and then
cooled. The reaction mixture was left to evaporate at room tem-
perature to give a white solid that was recrystallized from ethanol
to give compounds 3b and 3a, respectively.
(E)-N-(3-Hydrazinyl-3-oxo-1-phenylprop-1-en-2-yl)benzamide
(3a). White crystals; m.p.: 198–200°C (ethanol), yield = 30%.
IR (KBr) (νmax, cmꢀ1): 3307, 3185 (NH), 3029, 3059 (aryl-H),
1663, 1631 (C¼O), 1579, 1530 (C¼C), 752, 696
(monosubstituted benzene). 1H-NMR (DMSO-d6): δH (ppm)
4.28 (br.s, 2H, NH2 exchangeable), 7.23 (s, 1H, ¼CH), 7.15–
7.80 (m, 10H, ArH), 8.62 (br.s, 1H, CONHNH2 exchangeable),
9.33 (br.s, 1H, NHCOPh exchangeable). EIMS, m/z (%): 281
(M+ 0.1), 252 (22.2), 253 (M+ ꢀ CO, 3.7), 224 (14.9), 225
(M+ ꢀ 2CO, 2.5), 104 (13.5), 105 (PhCO, 100), 91 (10.3), 77
(Ph, 44.5), 51 (13). Anal. Calcd for C16H15N3O2 (281): C,
68.31; H, 5.37; N, 14.94. Found: C, 67.99; H, 5.42; N, 15.08.
(Z)-N-(3-Hydrazinyl-3-oxo-1-phenylprop-1-en-2-yl)benzamide
(3b). White crystals; m.p.: 179–180°C (ethanol), yield = 85%.
IR (KBr) (νmax, cmꢀ1): 3423, 3230 (NH), 3030 (¼CH), 1654,
1647 (C¼O), 1606 (C¼C), 758, 697 (monosubstituted
respects (m.p., mm.p., and TLC) with the imidazolone de-
rivative 12 (Scheme 7).
EXPERIMENTAL
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 Fourier transform
infrared Thermo Electron Nicolet 7600 (Thermo Fisher Scientific
Inc., Waltham, MA, USA) spectrometer at the Central Laboratory
1
of the Faculty of Science, Ain Shams University. The H-NMR
spectra were run at 300 MHz on a GEMINI 300 BB NMR
spectrometer using tetramethylsilane as internal standard in
DMSO-d6 at the Main Defense Chemical Laboratory. The mass
spectra were recorded on a Shimadzu GC-MS QP-1000EX mass
spectrometer operating at 70eV at the Microanalytical Center of
Cairo University. The reactions and the purity of all the synthesized
compounds were monitored by thin layer chromatography using
Merck Kieselgel 60 F254 aluminum backed plates. Spots visualiza-
tion was carried out using a UV lamp.
1
benzene). H-NMR (DMSO-d6): δH (ppm) 4.38 (br.s, 2H, NH2
exchangeable), 7.17 (s, 1H, ¼CH), 7.07–8.08 (m, 10H, ArH),
9.5 (br.s, 1H, –CONHNH2 exchangeable), 9.84 (br.s, 1H,
NHCOPh exchangeable). EIMS, m/z (%): 281 (M+ 1), 263
(M+ ꢀ H2O, 6), 250 (11), 105 (100), 104 (64), 77 (60), 76 (27),
60 (91), 51 (22), 50 (12). Anal. Calcd for C16H15N3O2 (281):
C, 68.31; H, 5.37; N, 14.94. Found: C, 68.59; H, 5.45; N, 14.67.
General procedure for synthesis of N-(1-(1,3-diphenyl-1H-
General procedure for synthesis of 4-arylidene-2-
phenyloxazol-5-one (1 and 2). A mixture of N-benzoylglycine
[18] (22.5 g, 0.125 mol), aldehyde (0.125 mol), acetic anhydride
(36mL and 0.375mol), and anhydrous sodium acetate (11.0g,
0.125 mol) was refluxed for 2 h. The reaction mixture was cooled
to room temperature, and then 100mL of ethanol was added and
kept overnight at 6°C. The yellow precipitate was filtered off and
washed with 10mL of cold ethanol and 15mL of hot water twice
successively to give 1 and 2.
pyrazol-4-yl)-3-hydrazinyl-3-oxoprop-1-en-2-yl)
benzamide
(4). To a solution of 2 (0.001 mol, 0.38 g) in ethanol (30 mL),
hydrazine hydrate 80% (0.18 mL) was added. The reaction
mixture was refluxed for 3 h and cooled to room temperature. A
white solid was obtained, which was filtered off, washed with
ethanol, and recrystallized from ethanol to give compound 4;
white powder, yield = 63%. When the reaction mixture was
stirred at room temperature for 1 h, a white powder was
obtained while stirring, which was filtered off, washed with
dioxane, and recrystallized from dioxane to give compound 4;
white powder, yield = 84%.
4-Benzylidene-2-phenyloxazol-5-one (1).
Yellow crystals;
m.p.: 167–168°C (benzene), yield = 80% (Lit. [7] m.p. = 166–167°C).
4-((1,3-Diphenyl-H-pyrazol-4-yl)methylene)-2-phenyloxazol-
N-(1-(1,3-Diphenyl-1H-pyrazol-4-yl)-3-hydrazinyl-3-oxoprop-
5-one (2).
Yellow crystals; m.p.: 189–191°C (dioxane),
1-en-2-yl)benzamide (4).
White crystals; m.p.: 204–205°C,
yield = 60%. IR (KBr) (νmax, cmꢀ1) 3056 (aryl-H), 1789 (C¼O
oxazolone), 1652 (C¼N), 1595, 1556 (C¼N), 1556 (C¼C),
(dioxane) yield=84%, IR (KBr) (νmax, cmꢀ1): 3329, 3240, 3132
(NH), 1660, 1632 (C¼O), 1506 (C¼C), 756, 695
(monosubstituted benzene).1H-NMR (DMSO-d6): δH (ppm) 4.38
(br.s, 2H, NH2 exchangeable), 7.16 (s, 1H, ¼CH), 7.30–8.05 (m,
1
756, 694 (monosubstituted benzene). H-NMR (DMSO-d6): δH
(ppm) 7.15 (s, 1H, CH¼), 7.57–8.25 (m, 15H, ArH), 9.36 (1s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 000
15H, ArH), 8.50 (s, 1H, pyrazolyl proton), 9.50 (br.s, 1H, –
CONHNH2 exchangeable), 9.74 (br.s, 1H, Ph CONH
exchangeable). EIMS, m/z (%): 424 (M+ + 1, 1.2), 423 (M+ 1.4),
405 (M+ ꢀ H2O, 4.1), 392 (M+ ꢀ NHNH2, 10.5), 365 (2.0), 260
(2.0), 105 (PhCO, 100), 104 (26), 77 (47), 76 (13), 51 (15). Anal.
Calcd forC25H21N5O2 (423): C, 70.91; H, 5.00; N, 16.54. Found:
C, 70.64; H, 4.87; N, 16.12.
General procedure for synthesis of methyl 4-(4-arylidene-
5-oxo-2-phenyl-4,5-dihydroimidazol-1-yl)benzoate (5). An
equimolar mixture of azlactone (1 and/or 2) and methyl p-
aminobenzoate was heated on an oil bath at 140–150 or 160–
170°C, respectively, for 1 h. The jelly product obtained was
boiled with methanol. A yellow solid was separated out, filtered
off while hot, washed with cold methanol, and recrystallized
from the suitable solvent.
N-(3-(2,5-Dimethyl-1H-pyrrol-1-ylamino)-3-oxo-1-phenylprop-
1-en-2-yl)benzamide (7a). White crystals; m.p.: 229–231°C
(dimethylformamide (DMF)), yield = 78%, IR (KBr) (νmax
,
cmꢀ1): 3357, 3185 (NH), 3082, 3035 (aryl-H), 2933, 2901
(alkyl H), 1682, 1640 (C¼O), 1578 (C¼N), 1528 (C¼C), 752,
702 (monosubstituted benzene). EIMS, m/z (%): 362 (M+ + 3,
1.8), 361 (M+ + 2, 5.8), 360 (M+ + 1, 3.7), 105 (PhCO, 100),
104 (72.6), 94 (18.5), 93 (11.1), 90 (9.9), 77 (Ph, 47.6), 76
(19.4), 51 (16.2), 50 (11.8). Anal. Calcd for C22H21N3O2 (359):
C, 73.52; H, 5.89; N, 11.69. Found: C, 73.96; H, 5.80; N, 11.21.
(E,Z)N-(3-(2,5-Dimethyl-1H-pyrazol-1-ylamino)-1-(1,3-
diphenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-2-yl)benzamide
(7b).
Pale green crystals; m.p.: 244–246°C (DMF),
yield = 80%. IR (KBr) (νmax, cmꢀ1): 3219, 3171, 3114 (NH),
3056 (aryl-H), 2998, 2943, 2886 (alkyl-H), 1662, 1641 (C¼O),
1601 (C¼N), 1525 (C¼C), 756, 696 (monosubstituted
benzene).1H-NMR (DMSO-d6): δH (ppm) 1.78, 1.83, 1.87, 1.95
(four singlets, 12H, 4CH3), 7.08, 7.12 (two singlets, 2H, CH¼),
7.20–7.93 (m, 17H, ArH + 2H of pyrrolo protons), 8.36, 8.43
(two singlets, 2H, pyrazolyl), 9.77, 9.88 (two br.s, 2H, N–
NHCO exchangeable), 10.22, 10.33 (two br.s, 2H, 2NHPhCO,
exchangeable). EIMS, m/z (%): 501 (M+ 3.5), 406 (4), 405 (12),
391 (10.6), 378 (1.4), 275 (1.4), 243 (1.9), 195 (2.1), 172 (2.1),
119 (19), 106 (13.8), 105 (100), 104 (26), 95 (2.1), 91 (2.6), 81
(2.1), 77 (66), 76 (15.5), 51 (14.8). Anal. Calcd for
C31H27N5O2 (501): C, 74.23; H, 5.43; N, 13.96. Found: C,
73.99; H, 5.75; N, 13.73.
Methyl 4-(4-benzylidene-5-oxo-2-phenyl-4,5-dihydroimidazol-
1-yl)benzoate (5a).
White crystals; m.p.: 226–227°C
(dioxane), yield = 78% (Lit. [19] m.p. 181°C).
Methyl 4-(4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-5-oxo-
2-phenyl-4,5-dihydro-1H-imidazol-1-yl)benzoate (5b). Yellow
crystals; m.p.: 220–223°C (dioxane), yield = 65%. IR (KBr)
(νmax, cmꢀ1): 3052, 3029 (aryl-H), 2950, 2871 (alkyl-H), 1722,
1638 (C¼O), 1599 (C¼N), 1530 (C¼C), 826 (δ2H), 757, 696
(monosubstituted benzene). 1H-NMR (DMSO-d6): δH (ppm)
3.87 (s, 3H, OCH3), 7.18 (s, 1H, ¼CH), 7.39–8.04 (m, 19H,
ArH), 9.34 (s, 1H, pyrazolo). EIMS, m/z (%): 524 (M.+, 52), 510
(39), 271 (18), 238 (100), 224 (55), 179 (15), 105 (22), 77 (21),
65 (16), 51 (10). Anal. Calcd for C33H24N4O3 (524): C, 75.56;
H, 4.61; N, 10.68. Found: C, 75.98; H, 4.93; N, 10.73.
General procedure for the reaction of 3 with acetyl acetone
to give (E/Z)N-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxo-1-
General procedure for synthesis of 5-((1,3-diphenyl-1H-
phenylprop-1-en-2-yl)benzamide (8).
To a solution of 3
pyrazol-4-yl)methylene)-3-phenyl-1,2,4-triazin-6(5H)-one (6).
A
(0.01 mol, 2.81 g) in ethanol (30 mL), acetylacetone (0.01 mol,
1.03 mL) was added. The reaction mixture was refluxed for 10 h
and then left to cool at room temperature. The solid obtained
was filtered off, washed with ethanol, and recrystallized from
benzene to give the title compound (8).
solution of 5b (0.001 mol, 0.52 g) and hydrazine hydrate 80%
(0.52 mL) in dioxane (30 mL) was refluxed for 20 h and then
cooled; then, the reaction mixture was left to evaporate at room
temperature. The precipitated solid was boiled with ethanol,
filtered off while hot, and recrystallized from dioxane to give
compound 6. The residual mother liquor after separation of 6 was
investigated by TLC to show the presence of methyl p-
aminobenzoate.
(E/Z)N-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)-3-oxo-1-
phenylprop-1-en-2-yl)benzamide (8).
White crystals; m.p.:
184–185°C (benzene), yield = 53%. IR (KBr) (νmax, cmꢀ1):
3350, 3179 (NH), 3062, 3029 (aryl-H), 1680, 1641 (C¼O),
1580 (C¼N), 1529 (C¼C), 753, 697 (monosubstituted
benzene). 1H-NMR (DMSO-d6): δH (ppm) for (E- isomer): δ
1.85, 2.19 (two singlets, 6H, 2CH3), 5.82 (s, 1H, H pyrazolyl),
6.95–7.77 (m, 11H, ArH + ¼CH), 8.37 (br.s, 1H, NH
exchangeable). For (Z- isomer): δ 1.66, 2.05 (two singlets, 6H,
2CH3), 4.92 (s, 1H, H pyrazolyl), 6.95–7.77 (m, 11H, ArH + ¼
CH), 9.03 (br.s, 1H, NH exchangeable). EIMS, m/z (%): 347
(M+ + 2, 73), 346 (M+ + 1, 58), 345 (M+ 46), 240 (72), 225
(46), 145 (49), 129 (67), 116 (63), 80 (62), 77 (56), 60 (base),
58 (76), 52 (46). Anal. Calcd for C21H19N3O2 (345): C, 73.03;
H, 5.54; N, 12.17. Found: C, 73.12; H, 5.65; N, 12.53.
5-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-3-phenyl-1,2,4-
triazin-6(5H)-one (6).
Yellow crystals; m.p.: 210–212°
C,(ethanol–dioxane), yield = 20% IR (KBr) (νmax, cmꢀ1): 3056
(aryl-H), 1617 (C¼O), 1596 (C¼N), 1535 (C¼C), 760, 693
(monosubstituted benzene). 1H-NMR (DMSO-d6): δH (ppm)
7.34 (s, 1H, ¼CH), 7.37–8.68 (m, 15H, ArH), 8.81 (s, 1H,
pyrazolyl proton). EIMS, m/z (%): 405 (M+ + 2, 19), 403 (M+
15), 356 (22), 320 (23), 260 (28), 223 (23), 187 (25), 145 (25),
111 (31), 105 (25), 98 (30), 95 (34), 84 (44), 7 7(23), 71 (54),
57 (100), 55 (96). Anal. Calcd for C25H17N5O (403): C, 74.43;
H, 4.25; N, 17.36. Found: C, 75.01; H, 4.57; N, 17.18.
General procedure for synthesis of N-(3-(2,5-dimethyl-
1H-pyrrol-1-ylamino)-3-oxo-1-phenylprop-1-en-2-yl)benzamide
(7a) and (E,Z)N-(3-2,5-dimethyl-1H-pyrazol-1-ylamino)-1-
(1,3-diphenyl-1H-pyrazol-4-yl)-3-oxoprop-1-en-2-yl)benzamide
(7b). To a solution of 3 (0.01 mol, 2.81 g) and/or 4 (0.01 mol,
4.23 g) in ethanol (40 mL), acetonylacetone (0.01 mol,
1.72 mL) was added. The reaction mixture was refluxed for
1 h. A solid product was precipitated while hot, filtered off,
washed with ethanol, and recrystallized from the suitable
solvent to give the 7a and/or 7b, respectively. After cooling,
the residual mother liquor gave the same compounds 7a and/or
7b, respectively.
General procedure for the reaction of 4 with acetylacetone to
give
a
mixture of pyrazolidene oxazolone (2) and
3,5-dimethylpyrazole. To a solution of 4 (0.01 mol, 4.23 g) in
ethanol (30 mL), acetylacetone (0.01 mol, 1.03 mL) was added.
The reaction mixture was refluxed for 6 h. Yellow crystals were
formed while hot, which was filtered off, washed with cold
ethanol, and recrystallized from ethanol–dioxane to give a
product that was found to be a mixture of pyrazolidene
oxazolone (2) and 3,5-dimethyl pyrazole.
Pyrazolidene oxazolone (2) and 3,5-dimethyl pyrazole.
Yellow crystals; m.p.: 177–179°C (ethanol–dioxane), yield = 45%.
IR (KBr) (νmax, cmꢀ1): 3275, 3141 (NH), 3057 (aryl-H), 2957,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Action of Some Nitrogen and Carbon Nucleophils on 4-Arylidene-1,3-oxazolones
2886, 2851 (alkyl-H), 1790 (C¼O lactone), 1652 (C¼N), 1597,
1527 (C¼C), 758, 699 (monosubstituted benzene). 1H-NMR
(DMSO-d6): For 3,5-dimethylpyrazole: δ 1.31 (s, 3H, CH3a), 1.73
(s, 3H, CH3b), 5.61 (br.s, 1H, NH exchangeable), 6.64 (s, 1H,
pyrazolo). For pyrazolidene oxazolone: δ 7.15 (s, 1 H, CH¼),
7.16–8.26 (m, 15H, ArH), 9.36 (s, 1H, pyrazolo proton). EIMS,
m/z (%): For pyrazolidene oxazolone: 392 (M+ + 1, 8.3), 391
(M+ 9.7), 105 (100), 104 (26.9), 77 (64), 76 (14.9), 51 (15.6).
For 3,5-dimethyl pyrazole: 96 (M+, 0.8), 81 (M+ ꢀ CH3), 55
(M+ ꢀ CH3CN, 0.2).
(Z)-5-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-3-phenyl-
1,2-dihydro-1,2,4-triazin-6(5H)-one (11). Orange crystals;
m.p.: 225–228°C (benzene–methanol), yield = 40.3%. IR
(KBr) (νmax, cmꢀ1): 3272, 3171 (NH), 3056 (aryl-H), 1689
(C¼O), 1643 (C¼N), 1599, 1538 (C¼C), 756, 694
(monosubstituted benzene). 1H-NMR (DMSO-d6): δH (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): 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-
General procedure for the reaction of 4 with acetylacetone
for 3 h.
To a solution of 4 (0.01 mol, 4.23 g) in ethanol
(30 mL), acetylacetone (0.01 mol, 1.02 mL) was added. The
reaction mixture was refluxed for 3 h. The excess solvent was
removed under reduced pressure. The solid obtained was
recrystallized from ethanol to give compound 9.
2-phenyl-4,5-dihydro-1H-imidazol (12).
Orange crystals; m.
p.: 215–218°C (ethanol), yield = 45.7%. IR (KBr) (νmax, cmꢀ1):
3355, 3322, 3300, 3154 (NH2), 3051 (aryl H), 1704 (C¼O),
1632 (C¼N), 1597, 1528 (C¼C), 736, 692 (monosubstituted
(2Z,N’Z)-2-Benzamido-3-(1,3-diphenyl-1H-pyrazol-4-yl)-N′-
(4-oxopentan-2-ylidene)acrylohydrazide (9).
White crystals;
1
m.p.: 170–172°C (ethanol), yield = 58%. IR (KBr) (υmax
,
benzene). H-NMR (DMSO-d6): δH (ppm) 5.36 (br.s, 2H, NH2
cmꢀ1): 3526, 3233 (NH), 3113, 3061 (aryl-H), 2932, 3113
(alkyl-H), 1675 (C¼O), 1593 (C¼N), 1541, 1503 (C¼C),
760, 699 (δ5H). 1H-NMR (DMSO-d6): δH 1.78, 1.9 (two
singlets, 6H, 2CH3), 2.8 (dd, 2H, CH2, J = 18.3, 11.1 Hz),
6.19 (br.s, 1H, NH–N¼ exchangeable), 6.82 (s, 1H, CH¼),
7.33–7.94 (m, 15H, ArH), 8.79 (s, 1H, pyrazolyl hydrogen),
9.88 (br.s, 1H, NHCOPh exchangeable). Anal. Calcd for
C30H27N5O3 (505.57): C, 71.27; H, 5.38; N, 13.85. Found: C,
71.54; H, 5.50; N, 13.78.
exchangeable), 7.07 (s, 1H, ¼CH), 7.43–8.46 (m, 15H, ArH,
J = 7.5, 8.4, 8.1 Hz), 9.31 (s, 1H, pyrazolyl). 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): 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 3a with diethyl
malonate to give N-(3-oxo-1-phenyl-3-(2,4,6-trioxopiperidin-1-
ylamino)prop-1-en-2-yl)benzamide (13). To a solution of 3a
(0.01 mol, 2.81 g) in ethanol (30 mL), diethylmalonate
(0.01 mol, 1.52 mL) was added. The reaction mixture was
refluxed for 8 h. White crystals were formed while hot, filtered
off, washed with cold ethanol, and recrystallized from DMF to
give the title compound (13).
General procedure for the reaction of 3a with ethyl
acetoacetate to give ethyl 3-(2-(2-benzamido-3-phenylacryloyl)
hydrazono)butanoate (10).
To a solution of 3a (0.01 mol,
2.81 g) in ethanol (30 mL), ethyl acetoacetate (0.01 mol,
1.26 mL) was added. The reaction mixture was refluxed for 6 h
and then cooled at room temperature. A white solid was formed
that was filtered off, washed with ethanol, and then
recrystallized from ethanol to give the title compound (10).
(E)-N-(3-oxo-1-Phenyl-3-(2,4,6-trioxopiperidin-1-ylamino)
prop-1-en-2-yl)benzamide (13).
White crystals; m.p.: 232–
234°C (DMF), yield = 30%. IR (KBr) (νmax, cmꢀ1):3247
(NH), 3057, 3031 (aryl-H), 2922 (alkyl-H), 1643 (C¼O),
1578, 1527 (C¼C), 742, 700 (monosubstituted benzene)
Ethyl
3-(2-(2-benzamido-3-phenylacryloyl)hydrazono)
cmꢀ1 1H-NMR (DMSO-d6): δH (ppm) 3.01–3.05 (d-d, 2H,
.
butanoate (10).
White crystals; m.p.: 142–144°C (ethanol),
yield = 45%. IR (KBr) (νmax, cmꢀ1): 3304 (NH), 3062, 3031
(aryl-H), 2983, 2929 (alkyl-H), 1736 (C¼O ester), 1695 (C¼O
amide), 1631 (C¼N), 1577, 1527 (C¼C), 747, 699
(monosubstituted benzene). 1H-NMR (DMSO-d6): δH (ppm)
1.19 (two triplets, 6H, 2CH3CH2OCO, J = 6.6, 6.9 Hz), 1.91 (s,
3H, CH3), 1.96 (s, 3H, CH3), 3.00 (m, 4H, CH2), 4.11 (two
quartets, 4H, 2CH3CH2OCO, J = 6.9 Hz), 7.16–7.82 (m, 22H,
ArH + 2¼CH), 8.49 (br.s, 1H, OH exchangeable), 9.39 (br.s,
1H, NH exchangeable), 10.40, 10.45 (two br.s, 2H, 2NHCOPh,
exchangeable). Anal. Calcd for C22H23N3O4 (393): C, 67.16; H,
5.89;N, 10.68. Found: C, 66.97; H, 5.75; N, 10.43.
CH2, J = 11.2 Hz), 3.20–3.23, (d-d, 2H, CH2, J = 11.4 Hz),
7.24 (1H, C¼CH), 7.17–7.79 (m, 10H, ArH), 8.58 (d, 1H,
NH–N exchangeable), 10.29 (br.s, 1H, NHCOPh
exchangeable). EIMS, m/z (%): 363 (M+ ꢀ CO, 12), 248 (4),
223 (7), 177 (5), 146 (7), 105 (100), 77 (55). Anal. Calcd for
C21H17N3O5 (391): C, 64.45; H, 4.38; N, 10.74. Found: C,
64.79; H, 4.75; N, 10.56.
General procedure for the reaction of 4 with diethyl malonate
to give 1-amino-4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-5-
oxo-2-phenyl-4,5-dihydro-1H-imidazol (12). To a solution of
4
(0.01 mol, 4.23 g) in ethanol (30 mL), diethylmalonate
General procedure for the reaction of
4 with ethyl
(0.01 mol, 1.52 mL) was added. The reaction mixture was
refluxed for 10 h, poured onto ice-water, and acidified with conc.
HCl. The precipitated solid was filtered off and recrystallized
from ethanol to give compound 12 as yellow crystals.
acetoacetate to give a mixture of (Z)-5-((1,3-diphenyl-1H-pyrazol-
4-yl)methylene)-3-phenyl-1,2-dihydro-1,2,4-triazin-6(5H)-one (11)
major; and 1-amino-4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-
5-oxo-2-phenyl-4,5-dihydro-1H-imidazol (12) minor.
To a
solution of (0.01 mol, 4.23 g) in pyridine (20 mL),
4
ethylacetoacetate (0.01 mol, 1.25 mL) was added. The reaction
mixture was refluxed for 12 h, poured onto ice-water, and acidified
with conc. HCl, which gave a yellow-orange precipitate that was
fractionally crystallized from benzene to give compound 11. The
insoluble part in benzene was recrystallized from methanol to give
compound 12, which was filtered off and recrystallized from
benzene–methanol to give the title compounds 11 and 12.
REFERENCES AND NOTES
[1] Lesieur, D.; Aichaoui, H.; Lespagnol, C.; Bonnet, J. Eur Pat
Appl 1990, 390, 673, 03 OCT; Chem Abstr 1991, 114, 783.
[2] Ando, K.; Asai, N.; Ito, F.; Mano, T.; Nakane, M.; Satake, K.;
Shimada, K. Eur Pat Appl 1990, 385, 664, 05 SEPT; Chem Abstr 1991,
114, 783.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. S. A. Youssef, K. A. Kandeel, W. S. I. Abou-Elmagd, and D. S. A. Haneen
Vol 000
[3] Descas, P.; Panconi, E.; Jarry, C. Eur Pat Appl 1990, 392, 929,
17 OCT; Chem Abstr 1991, 114, 783.
[12] Gucky, T.; Frysova, I.; Slouka, J.; Hajduch, M.; Dzubak, P.
Eur J Med Chem 2009, 44, 891.
[4] Benedlt, D.; Daniel, V. J Med Chem 1994, 37, 710.
[5] Pereira, E. R.; Sancelme, M.; Voldoire, A.; Prudhomme, M.
Bio-org Med Chem Lett 1997, 7, 2503.
[6] Viti, G.; Namnicine, R.; Ricci, R.; Pestelline, V.; Abeli, L.;
Funo, M. Eur J Med Chem 1994, 29, 401.
[7] Abdel-Aty, A. S. World J Agric Sci 2009, 5, 105.
[8] Khan, K. M.; Mughal, U. R.; Khan, M. T. H.; Ullah, Z.;
Perveen, S.; Choudhary, M. I. Bioorg Med Chem 2006, 14, 6027.
[9] Youssef, A. S. A.; El-Mariah, F. A.; Abd-Elmottaleb, F. T.;
Hashem, H. E. J Heterocycl Chem 2014, DOI: 10.1002/jhet.2178.
[10] Madkour, H. M. F. Chem Pap 2002, 56, 313.
[11] Badr, M. Z. A.; Mahgoub, S. A. E. Indian J Chem 1989,
28B, 829.
[13] Patel, P. S.; Shah, R. A.; Trivedi, D. K.; Vyas, P. J. Orient J
Chem 2009, 25, 111.
[14] Patel, P. S.; Shah, R. A.; Trivedi, D. K.; Vyas, P. J. Orient J
Chem 2010, 26, 159.
[15] Patel, P. S.; Shah, R. A.; Trivedi, D. K.; Vyas, P. J. Der Pharma
Chem 2010, 2, 168.
[16] Kachroo, M.; Rao, G. K.; Rajasekaran, S.; Sanjay Pai, P. N.;
Hemalatha, Y. R. Der Pharma Chem 2011, 3, 241.
[17] Mamtha, P.; Devi, C. S. J Chem Pharm Res 2012, 4, 2767.
[18] Benson, F. R.; Hartizel, L. W.; Savell, W. L. J Am Chem Soc
1952, 74, 4719.
[19] Patel, A.; Bari, S.; Talele, G.; Patel, J.; Sarangapani, M. Iran J
Pharma Res 2006, 4, 249.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet