Synthesis and antioxidant evaluation of some heterocyclic candidates from 3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propenonitrile

Article abstract of DOI:10.1080/00397911.2021.1879152

A new series of quinazoline derivatives bearing a 1,3-diphenylpyrazole core was synthesized starting from 3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2yl)propenonitrile (4) through reactions with some nitrogen nucleophiles. Hydrazinolysis of 4 furnished the biquinazoline and diheterylazine derivatives depending on the reaction conditions. Noteworthy, the benzimidazole derivatives were obtained via treatment with 2-aminoaniline under different reaction conditions. Inspect of the reactions of 4 with hydrazinecarbothioamide and hydrazinecarbothiohydrazide provided thiosemicarbazide, triazepinoquinazoline, and mercaptotetrazine derivatives. The antioxidant screening disclosed that some of these compounds such as 3, 5, 11, 12, and 13 exhibited significant potency.

Full text of DOI:10.1080/00397911.2021.1879152

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and antioxidant evaluation of some
heterocyclic candidates from 3-(1,3-diphenyl-1H-
pyrazol-4-yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2-
yl)propenonitrile
Sayed K. Ramadan, Ahmed K. El-Ziaty & Eman A. E. El-Helw
To cite this article: Sayed K. Ramadan, Ahmed K. El-Ziaty & Eman A. E. El-Helw (2021) Synthesis
and antioxidant evaluation of some heterocyclic candidates from 3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-
(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propenonitrile, Synthetic Communications, 51:8, 1272-1283,
DOI: 10.1080/00397911.2021.1879152
To link to this article: https://doi.org/10.1080/00397911.2021.1879152
Published online: 01 Feb 2021.
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2021, VOL. 51, NO. 8, 1272–1283
https://doi.org/10.1080/00397911.2021.1879152
Synthesis and antioxidant evaluation of some heterocyclic
candidates from 3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(4-oxo-
4H-benzo[d][1,3]oxazin-2-yl)propenonitrile
Sayed K. Ramadan , Ahmed K. El-Ziaty , and Eman A. E. El-Helw
Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received 28 November 2020
A new series of quinazoline derivatives bearing a 1,3-diphenylpyra-
zole core was synthesized starting from 3-(1,3-diphenyl-1H-pyrazol-4-
yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2yl)propenonitrile (4) through
reactions with some nitrogen nucleophiles. Hydrazinolysis of 4 fur-
nished the biquinazoline and diheterylazine derivatives depending
on the reaction conditions. Noteworthy, the benzimidazole deriva-
tives were obtained via treatment with 2-aminoaniline under differ-
KEYWORDS
Antioxidant; benzimidazole;
benzoxazinone; biquinazo-
line; propenylamide
ent reaction conditions. Inspect of the reactions of
4 with
hydrazinecarbothioamide and hydrazinecarbothiohydrazide provided
thiosemicarbazide, triazepinoquinazoline, and mercaptotetrazine
derivatives. The antioxidant screening disclosed that some of these
compounds such as 3, 5, 11, 12, and 13 exhibited significant
potency.
GRAPHICAL ABSTRACT
Introduction
The propenoyl chloride derivatives, prepared from hydrolysis of arylidine ethyl cyanoa-
cetate with sodium hydroxide and then acidification followed by treating with thionyl
chloride,[1–4] have been widely utilized for the synthesis of some valuable heterocyclic
systems e.g., benzoxazinones, quinazolinones, quinolones, benzimidazoles, benzoxazoles,
CONTACT Sayed K. Ramadan
sayed.karam2008@sci.asu.edu.eg
Chemistry Department, Faculty of Science, Ain
Shams University, Abassia, Cairo 11566, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Figure 1. Some pyrazole and quinazoline-based drugs.
oxadiazoles, pyridopyrimidines, and pyrazolones.[1–7] Pyrazoles possess robust biological
and pharmacological effects e.g., antiviral, anticancer, antimicrobial, antioxidant, and
insecticidal.[1,2,8–16] Hence, the synthesis of pyrazole-based heterocycles is an effective
synthetic strategy for the drug development process. Meanwhile, quinazolinone scaffolds
are found in both natural products and pharmaceuticals.[17–23] Some pyrazole and qui-
nazoline-based drugs are displayed in Figure 1. Enthused by these facts and as an exten-
sion of our study,[24–31] the present work aimed to combine both benzoxazinone and
pyrazole skeletons in one framework as an attempt to obtain novel pyrazole-based het-
erocycles of enhanced antioxidant activity through reactions with some mono and
bidentate nitrogen nucleophiles like ammonium acetate, benzylamine, 4-aminoacetophe-
none, 2-methylpropan-1-amine, dodecan-1-amine, 4-methylaniline, methyl 4-aminoben-
zoate, hydrazine hydrate, phenylhydrazine, 4-methylbenzenesulfonohydrazide,
thiophene-2-carbohydrazide, 1,2-diaminoethane, 2-aminoethanol, 2-aminoaniline,
hydrazinecarbothioamide, and hydrazinecarbothiohydrazide.
Results and discussion
Chemistry
Aiming to tribute a novel series of heterocyclic cores combining 1,3-diphenylpyrazole
and quinazoline moieties, 2-cyanopropenoyl chloride encompassing a pyrazole core 1[1]
was treated with anthranilic acid 2 at ambient temperature to afford propenylamide
derivative 3 which was successfully transformed into the benzoxazinone derivative 4 via
heating with acetic anhydride. IR spectrum of amide 3 lacked the carbonyl functionality
of the acid chloride moiety, conserved the nitrile functionality at ꢀ 2210 cmꢀ1, and

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S. K. RAMADAN ET AL.
Scheme 1. Synthesis and reactions of the benzoxazinone derivative 4.
disclosed bands for ꢀ NH at 3200 cmꢀ1, ꢀ C¼O of carboxylic acid and amide at 1702
and 1686 cmꢀ1, respectively. Further corroboration for the designated structure was
1
acquired from the H NMR spectrum that provided two exchangeable singlet signals
(COOH and NH protons) at d 13.40 and 12.29 ppm, respectively. Meanwhile, the IR
spectrum of benzoxazinone 4 exhibited a band for lactone C¼O moiety at ꢀ 1768 cmꢀ1
.
Full analysis of its 1H NMR spectrum supported the assigned structure (cf.
Experimental). The benzoxazinone 4 was utilized under different conditions following
different aspects for the construction of other heterocyclic systems. Initially, it under-
went aminolysis with monodentate and bidentate nucleophiles. The reaction involved a
nucleophilic attack of the co-reactant amine at position-4 of the benzoxazin-4-one ring.
Firstly, ammonolysis of benzoxazinone 4 was found to depend on the reaction circum-
stances. Indeed, a fusion of benzoxazinone 4 with ammonium acetate for 3 h afforded
the benzamide derivative 5. When the reaction time was extended for 8 h, the quinazoli-
none 6 was obtained as a sole product (cf. Scheme 1). Spectroscopically, IR spectra
1
lacked the lactone absorption band. H NMR spectrum of 5 disclosed two exchangeable
singlet signals, one of them is integrated to two protons for NH2 group at d 8.40 ppm
and the other is integrated to one proton of NH group at d 12.98 ppm. Otherwise, the
1H NMR spectrum of quinazolinone derivative 6 displayed NH proton as an exchange-
able singlet signal at d 12.77 ppm.
On the other hand, 4-aminoacetophenone reacted with benzoxazinone 4 under two
different conditions. Indeed, treating an equimolar mixture of them in boiling dioxane
acquired 2-(2-((4-acetylphenyl)amino)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-yl)-3-
(1,3-diphenylpyrazol-4-yl)acrylonitrile (7). This product could be demonstrated via

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Scheme 2. Proposed pathway for transformation of compound 7 into compound 9.
nucleophilic addition at position-2.[19] Whilst, using a double molar ratio of the amine,
propenylamide derivative 8 was obtained as a sole product (cf. Scheme 1). IR spectrum
of 7 conserved a lactone band at ꢀ 1767 cmꢀ1 which was disappeared in that of com-
1
pound 8. Compelling evidences for their structures were forthcoming from their H
NMR spectra (cf. Experimental). Treatment of benzoxazinone 4 with benzylamine in
boiling ethanol provided the N-benzylamide derivative 9. Meanwhile, benzylamine in
boiling dioxane induced transformation of compound 7 into the amide derivative 9
which can be demonstrated via (Scheme 2). IR spectrum of 9 disclosed NH band at ꢀ
1
3291 cmꢀ1, and the carbonyl absorption at ꢀ 1686 cmꢀ1. Moreover, H NMR spectrum
of 9 offered two NH protons as two exchangeable singlet signals at d 12.48
and 9.41 ppm.
In turn, treating the benzoxazinone 4 with 2-methylpropan-1-amine, dodecan-1-
amine, 4-methylaniline or methyl 4-aminobenzoate acquired the propenylamide deriva-
tives 10–13, respectively (Scheme 3). The IR spectra retained the nitrile functionality,
lacked lactone carbonyl absorption, and displayed the amide carbonyl absorption.
1
Furthermore, the inspection of their H NMR spectra was quite consistent with the pro-
posed structures.
On the other hand, to investigate the behavior of benzoxazinone 4 with versatile 1,2-
and 1,4-bidentate nucleophiles, compound 4 was submitted to react with hydrazine
hydrate, phenylhydrazine, 4-toluenesulfonohydrazide, 1,2-diaminoethane, 2-aminoetha-
nol, and 2-aminoaniline (cf. Schemes 3–5). Indeed, hydrazinolysis of 4 at ambient tem-
perature in an ethanolic solution was not successful but in N,N-dimethylformamide
solution, it furnished biquinazolinone derivative 15 (through a non-isolable intermediate
14). In contrast, heating the reaction mixture at 70–80 ꢁC in ethanol furnished the dihe-
teryl azine 16 which was congruent in all aspects (mp., mixed mp., TLC) to an ethnic
piece synthesized from treating pyrazole-4-carboxaldehyde 17 and hydrazine.[15]

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S. K. RAMADAN ET AL.
Scheme 3. Synthesis of compounds 10–16.
Conducting the benzoxazinone 4 with phenylhydrazine or 4-toluenesulfonohydrazide
in boiling dioxane produced quinazolinone derivatives 18 and 19, respectively.
Thiophene-2-carbohydrazide reacted with 4 in boiling dioxane to provide hydrazide
derivative 20 (Scheme 4). Otherwise, treating 1,2-diaminoethane with 4 achieved the
1
quinazolinone derivative 21. The H NMR spectrum of 21 exhibited only one exchange-
able singlet signal for NH2 protons at d 4.05 ppm in addition to CH2-CH2 protons as
two triplet signals. In contrast, 2-aminoethanol was reacted with benzoxazinone 4 in
1
boiling dioxane to provide the benzamide derivative 22. The H NMR spectrum of 22
displayed two NH and OH protons at d 12.51, 8.82, and 4.76 ppm (cf. Experimental).
Noteworthy, the reaction of 4 with 2-aminoaniline afforded products depending mainly
on the reaction aspects. Indeed, performing the reaction in boiling ethanol/glacial acetic acid
yielded the benzamide derivative 23 as a sole product. Meanwhile, a mixture of the benza-
mide derivative 23, benzimidazole derivative 24, and anthranilic acid 2 was obtained by con-
ducting the reaction mixture in boiling acetic acid/fused sodium acetate. In turn, when the
reaction was executed under fusion conditions, a mixture of benzimidazole 24 and anthra-
nilic acid 2 was obtained instead of the benzimidazoquinazoline derivative 26. Refluxing a
solution of the benzamide derivative 23 in n-butanol for 4 h achieved the benzimidazole

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Scheme 4. Synthesis of compounds 18–22.
derivative 25 as beige crystals (cf. Scheme 5). The IR spectrum of compound 23 retained the
nitrile functionality and displayed bands for NH, NH2 at ꢀ 3390 and 3283cmꢀ1, in addition
to C¼O group at ꢀ 1686cmꢀ1. Its 1H NMR spectrum revealed the existence of two NH pro-
tons at d 12.11 and 9.93ppm, and NH2 protons at d 4.90ppm. IR spectrum of 24 lacked car-
bonyl functionality, kept nitrile functionality at ꢀ 2216cmꢀ1, and showed a band for NH
group at ꢀ 3305cmꢀ1. A compulsory clue for the presented structure was acquired from its
1H NMR spectrum that offered the following signals: 13.07 (br.s, NH), 9.24 (s, C5-H pyra-
zole), 8.16 (s, CH¼), in addition to the aromatic protons. Meanwhile, 1H NMR spectrum of
25 acquired two NH protons of benzimidazole and amide groups at d 14.20 and 12.29ppm,
respectively.
A plausible explanation for the formation of compounds 23 and 24 can be outlined
in Scheme 6.[32,33] Evidently, the reaction involves the initial formation of benzamide
derivative 23 by nucleophilic attack at position-4. This benzamide derivative passes
through the intermediate (I) that possibly exists in equilibrium with its isomeric com-
pound (II) whose cyclization and then cleavage would afford benzimidazole derivative
24 and anthranilic acid 2.
Our work was expanded to inspect the reactions of benzoxazinone derivative 4 with
hydrazinecarbothioamide and hydrazinecarbothiohydrazide. Thus, when 4 reacted with
the former in boiling dioxane, the thiosemicarbazide derivative 27 was obtained.
Accordingly, formation of 27 can be viewed via the initial nucleophilic attack of the
free amino group of hydrazinecarbothioamide on the lactone carbonyl carbon atom fol-
lowed by oxazinone ring opening. On the other hand, execution of the reaction in

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S. K. RAMADAN ET AL.
Scheme 5. Synthesis of compounds 23–25.
higher boiling point solvent like n-butanol provided triazepinoquinazoline derivative 28.
Presumably, the formation of 28 can be visualized via cyclization of 27 by elimination
of water molecule followed by aza-Michael addition (which was enhanced by the higher
boiling point solvent)[34] on the b-carbon of the activated nitrile. Finally, hydrazinecar-
bothiohydrazide was conducted with benzoxazinone 4 in boiling dioxane to produce
mercaptotetrazine derivative 29 (Scheme 7).
Antioxidant screening
Some of the synthesized compounds were screened for their antioxidant activity using
ABTS assay.[35] Ascorbic acid was utilized as a reference antioxidant drug. Ascorbic
acid is protecting the double bonds and scavenging oxygen as the two free radicals
formed at 2- and 3-positions may be intermediates in scavenging oxygen and inhibiting
the radical formation at double bonds (cf. Figure 2). Absorption was recorded and the

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Scheme 6. Suggested pathways for compounds 23 and 24.
Scheme 7. Reactions of 4 with hydrazinecarbothioamide and hydrazinecarbothiohydrazide.

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S. K. RAMADAN ET AL.
Figure 2. Ascorbic acid (standard antioxidant drug).
Table 1. Results of antioxidant activity of the examined compounds.
Samples
Absorbance
% Inhibition
Control of ABTS
Ascorbic acid
3
4
5
6
8
9
10
11
12
13
15
0.500
0.058
0.108
0.201
0.105
0.152
0.141
0.138
0.131
0.110
0.098
0.103
0.291
0
88.4
78.4
59.8
79.0
69.6
71.8
72.4
73.8
78.0
80.4
79.5
41.8
alleviation in the color intensity was expressed as percent inhibition which can be calcu-
lated via the attached equation below:
ð
Þ
Abs control ꢀ AbsðtestÞ
% Inhibition ¼
ꢂ 100
AbsðcontrolÞ
The antioxidant results (cf. Table 1) disclosed that all tested compounds were potent.
Compounds 3, 5, 11, 12, and 13 were the most potent with % inhibition ¼ 78.4, 79.0,
and 78.0, 80.4 and 79.5%, respectively. Likewise, compounds 6, 8, 9, and 10 displayed
strong efficacy. Compounds 4 and 15 exhibited moderate activity. The antioxidant
results may comprise the subsidiary structure-activity relationship: (i) Existence of a
pyrazole moiety manifested to be pivotal for noteworthy inhibitory antioxidant activity.
(ii) the presence of OH, NH, and NH2 groups increased the capacity to scavenge free
radicals and thus enhanced the antioxidant activity.[36,37]
Conclusion
A novel series of pyrazole-based heterocyclic systems was prepared starting from the
benzoxazinone building block (4) through reactions with some mono and bidentate
nucleophiles. The reaction with ammonium acetate was mainly dependent upon the
heating period. In contrast, the reaction with 4-aminoacetophenone was dependent
upon whether equal or double molar ratios. Hydrazinolysis of 4 produced the

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biquinazoline derivative 15 and the diheterylazine 16 depending on the reaction
conditions. Noteworthy, the benzimidazole derivatives were obtained upon treatment
with 2-aminoaniline under different reaction conditions. Finally, thiosemicarbazide, tria-
zepinoquinazoline and mercaptotetrazine derivative 27–29 were achieved by conducting
benzoxazinone 4 with hydrazinecarbothioamide and hydrazinecarbothiohydrazide. The
antioxidant activity evaluation of some of the synthesized compounds revealed that
some of them exhibiting significant potency as compared with ascorbic acid.
Experimental
General
Chemicals and solvents obtained from Sigma Aldrich, Merck, Fluka, and El-Nasr
pharmaceutical chemicals companies were purified and dried by standard techniques.
All melting points were measured on a GALLENKAMP electric melting point apparatus
and are uncorrected. IR spectra (ꢀ, cmꢀ1) were run at the Department of Chemistry,
Faculty of Science, Ain Shams University utilizing KBr disks on FTIR Thermo Electron
Nicolet iS10 infrared spectrometer (Thermo Fisher Scientific Inc., Waltham, MA, USA).
1H NMR spectra (d, ppm) were run at 300 MHz on a GEMINI NMR spectrometer
(GEMINI, Manufacturing & Engineering Inc., Anaheim, CA, USA) utilizing tetrame-
thylsilane (TMS) as an internal standard in deuterated dimethyl sulfoxide. Elemental
analyses were run at Faculty of Science, Ain Shams University utilizing Perkin-Elmer
2400 CHN elemental analyzer. The starting 2-cyanopropenoyl chloride 1 was previously
reported by us.[1]
2-(2-Cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylamido)benzoic acid (3)
Anthranilic acid 2 (1.37 g, 0.01 mol) was added to a stirred solution of 2-cyanoprope-
noyl chloride derivative 1 (3.33 g, 0.01 mol) in dry dioxane (15 mL) containing triethyl-
amine (3-drops) and the reaction mixture was further stirred at ambient temperature
for 2 h. The precipitate was filtered off and then recrystallized from dioxane to produce
propenylamide derivative 3 as pale-yellow crystals, mp. 292–290 ꢁC, yield 88%. IR: 3426
1
(br.OH,NH), 2210 (CN), 1702 (CO acid), 1686 (CO amide). H NMR: 13.40 (br.s, 1H,
OH, exchangeable), 12.29 (br.s, 1H, NH, exchangeable), 9.22 (s, 1H, C5-H pyrazole),
8.62 (d, 1H, Ar-H, J ¼ 8.4 Hz), 8.25 (s, 1H, CH¼), 8.07–7.22 (m, 11H, Ar-H), 7.47 (t,
1H, Ar-H, J ¼ 7.28 Hz), 7.24 (t, 1H, Ar-H, J ¼ 7.52 Hz). Anal. Calcd. for C26H18N4O3
(434.46): C, 71.88; H, 4.18; N, 12.90. found: C, 71.73; H, 4.04; N, 12.87%.
3-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)propenoni-
trile (4)
A suspension of propenylamide derivative 3 (4.16 g, 0.01 mol) in acetic anhydride
(5 mL) was heated on water bath at 80 ꢁC for 3 h. A deposited solid after cooling was
filtered off and then recrystallized from benzene to furnish the benzoxazinone 4 as yel-
1
low crystals, mp. 290–292 ꢁC, yield 85%. IR: 2222 (CN), 1768 (CO). H NMR: 9.28 (s,
1H, C5-H pyrazole), 8.18 (s, 1H, CH¼), 8.13 (d, 1H, Ar-H, J ¼ 7.8 Hz), 7.99–7.61 (m,

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S. K. RAMADAN ET AL.
12H, Ar-H), 7.49 (t, 1H, Ar-H, J ¼ 7.32 Hz). Anal. Calcd. for C26H16N4O2 (416.44): C,
74.99; H, 3.87; N, 13.45. Found: C, 74.84; H, 3.75; N, 13.47%.
Full Experimental details, tables, and spectroscopic data can be found at supplemen-
tal files.
Acknowledgment
The authors received no funding for this work.
Disclosure statement
No potential conflict of interest was reported by the author(s).
ORCID
Sayed K. Ramadan
Ahmed K. El-Ziaty
Eman A. E. El-Helw
http://orcid.org/0000-0003-2743-6544
http://orcid.org/0000-0001-9121-9507
http://orcid.org/0000-0001-5104-6170
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