Synthesis of new 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones and their antimicrobial and antifungal activity screening

Article abstract of DOI:10.14233/ajchem.2014.15880

Novel 2-[N'-(1,3-disubstituted-phenyl)allylidene]hydrazine-3-ethyl-3H- quinazolin-4-one (8) and 2-(3,5-disubstituted-phenyl-4,5-dihydropyrazol- 1-yl)-3-ethyl-3H-quinazolin-4-one (9) compounds have been prepared and tested for antibacterial and antifungal activities. ¹H NMR, ¹³C NMR, elemental analysis and mass spectroscopy methods have been used to identify molecular structures of the newly synthesized compounds. For screening antibacterial and antifungal activities of the new compounds, minimum inhibitory concentration (MIC) values were evaluated against the Staphylococcus aureus, Escherichia. coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans, Candida parapsilosis and Candida krusei using microdilution broth method. Compounds 8a-8h exhibited the best antibacterial activity against E. faecalis.

Full text of DOI:10.14233/ajchem.2014.15880

Asian Journal of Chemistry; Vol. 26, No. 11 (2014), 3197-3203
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15880
Synthesis of New 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-
quinazolinones and Their Antimicrobial and Antifungal Activity Screening
1,*
2
2
NEZIRE SAYGILI , MELIKE EKIZOGLU and CEREN ERDOGDU
1Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Hacettepe University, Sihhiye, 06100 Ankara, Turkey
2Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, Sihhiye, 06100 Ankara, Turkey
*Corresponding author: Fax: +90 312 3114777; Tel: +90 312 3054016-18; E-mail: nezires@hacettepe.edu.tr
Received: 7 June 2013;
Accepted: 5 September 2013;
Published online: 25 May 2014;
AJC-15212
Novel 2-[N'-(1,3-disubstituted-phenyl)allylidene]hydrazine-3-ethyl-3H-quinazolin-4-one (8) and 2-(3,5-disubstituted-phenyl-4,5-dihydro-
pyrazol-1-yl)-3-ethyl-3H-quinazolin-4-one (9) compounds have been prepared and tested for antibacterial and antifungal activities. 1H
NMR, 13C NMR, elemental analysis and mass spectroscopy methods have been used to identify molecular structures of the newly synthesized
compounds. For screening antibacterial and antifungal activities of the new compounds, minimum inhibitory concentration (MIC) values
were evaluated against the Staphylococcus aureus, Escherichia. coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida albicans,
Candida parapsilosis and Candida krusei using microdilution broth method. Compounds 8a-8h exhibited the best antibacterial activity
against E. faecalis.
Keywords: Activity, Antifungal, Antimicrobial, Pyrazoline, Quinazolinone, Synthesis.
Pyrazolyl-4(3H)quinazolinones were also synthesized and
screened for some biological activities17,18. 2-(1H-pyrazol-1-yl)-
4-(3H)quinazolinones possess antitubercular, antihistaminic,
platelet aggregation inhibitor and microbicidal activities (3)19.
INTRODUCTION
The 4-(3H)quinazolinone compounds are a class of hetero-
cyclic compounds that have wide variety of biological activities1-4.
The biological importance of these heterocyclics has lead synthetic
organic chemists to explore new synthetic routes and thus their
syntheses are available in literature5-7. A brief search on the
pharmaceutical activities of quinazolin-4(3H)-ones showed
antiinflammatory8, antitumor9, anti HIV10, antibacterial11, CNS
depressant12 and anticonvulsant12,13 activities. 3H-Quinazoline-
4-one framework is commonly found unit in natural product
alkaloids, such as L-vasicinone (1)14 and drugs such as diuretic
and antihypertensive metolazone (2)15. On the other hand, it
was found that not only quinazolinones showed diverse
biological activities, but also pyrazole moiety possesses some
important activities. Pyrazolines are five-membered hetero-
cyclics having two adjacent nitrogen atoms within the ring
and display a wide spectrum of pharmacological activities16.
R
N
N
N
NH
O
3
In view of the broad spectrum of pharmacological activity
of quinazolinone derivatives, we previously published certain
substituted quinazolinone derivatives18. In this work, we aimed to
synthesize some new 2-(N′-allylidene-hydrazino)quinazolinone
and 2-(4,5-dihydropyrazolyl)quinazolinone compounds and
investigate their antimicrobiological activities.
O
O
EXPERIMENTAL
H2NO2S
N
N
2-Thioxoquinazolinone molecule which was formed from
antranilic acid18,20, was used as starting material in this chemistry.
2-Thioxoquinazolinones could also be prepared from 2-amino-
benzoic acid methyl ester21,22 and isatoic anhydride23. In our
CH3
N
Cl
N
CH3
OH
1
2

3198 Saygili et al.
Asian J. Chem.
H
N
NH2
S
N
NHNH2
C2H5
NH2NH2 H2O
∆
+
CH3CH2NCS
N
N
∆
COOH
C2H5
4
O
O
5
6
Scheme-I: Synthesis of 3-ethyl-2-hydrazino-3H-quinazolin-4-one (6)
synthetic procedure 3-ethyl-2-thioxo-2,3-dihydro-1H-quinazolin-
4-one (5) was synthesized by refluxing anthranilic acid (4)
and ethyl isothiocyanate and then 5 was transformed to 3-ethyl-
2-hydrazino-3H-quinazolin-4-one (6) by refluxing with hydrazine
hydrate18,24 (Scheme-I).
The starting materials, 3-ethyl-2-thioxo-2,3-dihydro-1H-
quinazolin-4-one 525, 3-ethyl-2-hydrazino-3H-quinazolin-4-
one 626,27 and α,β-unsaturated ketone derivatives (chalcones)
7
28,29, were prepared according to the methods given in the
literature.
2-[N'-(1,3-diphenyl-allylidene)-hydrazino]-3-ethyl-3H-
Various α,β-unsaturated ketones (7) was further reacted
with 6 to give hydrazino-3-ethyl-4(3H)quinazolinone (8)
derivatives. In the last step 2-[3,5-bis-(substituted-phenyl)-4,5-
dihydro-pyrazol-1-yl]-3-ethyl-3H-quinazolin-4-one (9)
compounds were produced by refluxing hydrazone derivatives
in anhydrous acetic acid (Scheme-II).
quinazolin-4-ones (8): A mixture of 7 (1 mmol) and 3-ethyl-
2-hydrazino-3H-quinazolin-4-one (6) (204 mg, 1 mmol) and
2 mL of acetic acid in n-propanol (100 mL) was stirred under
reflux for 4-7 h. After the reaction was cooled to room tempe-
rature, the resulting residue was filtered, washed with n-propanol
and dried. Recrystallization of the crude product from ethanol
gave 8 as a yellow solid.
All reagents were of commercial quality and reagent
quality solvents were used without further purification. 1H and
13C NMR spectra were determined on a Bruker DPX 400 MHz
FT spectrometer. Mass spectra were obtained on an Agilent
5973 Network Mass Selective Detector via HPP7-M Direct
Insertion Probe. IR spectra (KBr) were recorded on a Shimadzu
FT-IR DR-8001 FT infrared spectrophotometer. The purity of
the compounds was assessed by thin layer chromatography
on silica gel 60 F254. Column chromatography was conducted
on silica gel 60 (mesh size 0.063-0.200 mm). Melting points
were measured on a Thomas Hoover Capillary Melting Point
Apparatus in an open capillary.
2-(3,5-Diphenyl-4,5-dihydro-pyrazol-1-yl)-3-ethyl-3H-
quinazolin-4-ones (9): A solution of 2-[N'-(1,3-diphenyl-
allylidene)hydrazino]-3-ethyl-3H-quinazolin-4-one (8) (0.5
mmol) in glacial acetic acid was stirred under reflux for 72 h.
The resulting solution was poured into ice-water, neutralized
with concentrated NaOH solution and extracted with ethyl
acetate. The organic phase was dried over magnesium sulphate,
filtered and evaporated to dryness to yield the oily residue.
The crude product was further purified by chromatography
R2
N
O
NH N C CH CH
R1
O
6
R2
C CH CH
R1
N
∆
7
C2H5
8
H+
∆
R1
R2
a: R1 = H, R2 = CH3
c: R1 = CH3, R2 = CH3
e: R1 = H, R2 = Cl
b: R1 = Cl, R2 = CH3
d: R1 = Br, R2 = CH3
f: R1 = Cl, R2 = Cl
h: R1 = Br, R2 = Cl
N
O
N N
g: R1 = CH3, R2 = Cl
N
C2H5
9
Scheme-II: Synthesis of new 2-(4,5-dihydropyrazolyl)quinazolinones

Vol. 26, No. 11 (2014)
Synthesis of New 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones 3199
on a silica gel column (elution with chloroform) followed by
crystallization from diethyl ether to give 9 as a white solid.
Antimicrobial activity: Minimum inhibitory concentra-
tions (MICs) were tested by microdilution broth method
recommended by Clinical and Laboratory Standards Institute
(CLSI)30,31.According to these procedure, antibacterial activity
was determined against following microorganisms:Staphylococcus
aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212),
Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa
(ATCC 27853). The following yeast-like fungi were used for
antifungal activity studies: Candida albicans (ATCC 90028),
Candida parapsilosis (ATCC 90018) and C. krusei (ATCC
6258).
the assigned structures. The first step involves the ring closure
reaction to form 2-thioxoquinazoline which in turn converted
to 2-hydrazinoquinazoline via nucleophilic addition and then
elimination reaction. Amino group of 6 gives 1,4-addition
reaction with α,β-unsaturated ketones (7) to afford hydrazone
(8) derivatives.Acid catalyzed pyrazole ring formation occurs
with subsequent addition of NH group on olefinic bond to
1
give 2-pyrazolylquinazolinones (9). In the H NMR spectra
of the compounds 5, olefinic protons (2′-CH and 3′-CH)
appeared as doublets at about 6.63-6.93 and 7.82-8.10 ppm,
respectively (Jtrans = 16.2-16.8 Hz). After the ring closure, ring
protons (4′-CHa and 4′-CHb) of the compounds 9 showed
double doublets at around 3.59-3.78 (Jdd = 11.2-11.4 and 16.8-
17.0 Hz) and 3.16-3.32 ppm (Jdd = 12.0 and 16.8-17.0 Hz)
and also 5′-CH gave triplet at about 5.79-5.96 ppm (Jt = 11.2-
12.0 Hz) due to vicinal coupling with the two magnetically
nonequivalent protons of the methylene group. The quinazo-
linone and phenyl protons were observed at the expected
chemical shifts and integral values. In the 13C NMR spectra of
the compound 8c, olefinic carbons (2′-C and 3′-C) appeared
at 138.69 and 119.84 ppm respectively. After the ring closure,
ring carbons (5′-C and 4′-C) of compound 9c gave signals at
62.88 and 40.85 ppm, respectively. In the ESI-MS spectra,
molecular ion [M]+ peaks, which were the base peaks, provided
the molecular formula of all synthesized compounds 8a-8h
and 9a-9h. Microanalysis results are within 0.4 % of the
theoretical values.
The stock solutions of the synthesized compounds were
prepared in dimethyl sulfoxide (DMSO). Test was performed
in Mueller-Hinton Broth (MHB) (BBL, MD, USA) for bacteria.
Fungi were cultivated in Sabouraud Dextrose Agar (SDA)
(Merck). RPMI-1640 medium (ICN-Flow,Aurora, OH-USA)
with L-glutamin, buffered with 3-(N-morpholino)propane
sulphonic acid (MOPS) (Buffer-ICN-Flow,Aurora, OH-USA)
at pH = 7.4 was used as the test medium. The final inoculum
densities were 5 × 105 cfu/mL for bacteria and 0.5-2.5 × 103
cfu/mL for fungi. The dilutions in the test medium were
prepared in the wells of the microtiter plates at the required
concentration of 1024-1.0 µg/mL and for reference compounds
at 64-0.0625 µg/mL. Fluconazole and ciprofloxacin were used
as the reference compounds for fungi and bacteria, respec-
tively. The microtiter plates were incubated at 35 °C for 18-
24 h for bacteria and 48 h for fungi. MICs were defined as the
lowest concentration of the compound that inhibited visible
growth of the microorganisms. It was established that dilution
of DMSO lacked antimicrobial activity against any of the test
microorganisms.
Antimicrobial activity studies: Antifungal and antibac-
terial activities of the 2-thioxoquinazolinone (5), 2-hydrazino-
quinazolinone (6), 2-(N′-allylidene-hydrazino)quinazolinone
(8) and 2-(4,5-dihydropyrazolyl)quinazolinone (9) compounds
were tested by microdilution broth method as MIC values.
The MIC values of the compounds are presented in the Table-1.
These results indicate that compounds 8a through 8h showed
the best antibacterial activity against gram positive bacteria,
especially E. faecalis. However compounds 8d and 8h had no
significant activity against S. aureus. All compounds showed
similar antifungal activity. Their antifungal activity was not
RESULTS AND DISCUSSION
New quinazolinone compounds have been synthesized and
their structures were proven by 1H- and 13C NMR, mass spectra,
elemental analysis and all spectral data are in accordance with
TABLE-1
ANTIFUNGAL AND ANTIBACTERIAL ACTIVITIES OF 2-THIOXOQUINAZOLINONE (5), 2-HYDRAZINOQUINAZOLINONE (6), 2-(N′-
ALLYLIDENE-HYDRAZINO)-QUINAZOLINONES (8) AND 2-(4,5-DIHYDROPYRAZOLYL)-QUINAZOLINONES (9) (MIC in µg/mL)
Compound No.
S. aureus
ATCC 29213
256
E. faecalis
E. coli
ATCC 25922
P. aeruginosa
C. albicans
ATCC 90028
C. krusei
ATCC 6258
C. parapsilosis
ATCC 90018
ATCC 29212
ATCC 27853
256
5
256
128
32
256
256
256
256
256
1024
512
256
256
256
256
512
1024
512
0.015
-
32
ND
ND
ND
64
128
64
128
128
128
128
128
128
128
256
256
128
128
128
128
64
6
64
256
8a
128
512
128
128
128
256
128
128
128
128
128
128
128
256
-
8b
128
16
256
8c
128
16
256
8d
>1024
128
64
1024
256
256
128
128
128
128
128
1024
64
8e
256
32
8f
64
256
8g
256
32
256
8h
1024
512
64
512
9c
9d
512
>1024
>1024
128
2
512
512
>1024
1024
256
9e
512
9h
1024
0.5
32
Ciprofloxacin
Fluconazole
ND: not done
1
-
-
-
-
-
0.25
16
1

3200 Saygili et al.
Asian J. Chem.
promising, but compound 9h seem to possess activity with
the higher MIC values, except for C. krusei strain.
7.9 Hz, 5-CH), 8.06 (1H, d, J = 16.4 Hz, 3′-CH), 7.58 (2H, d,
J = 8.0 Hz, 2 × CH(Ar)), 7.53 (1H, t, J = 7.0 Hz, 7-CH), 7.44
(2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.32 (2H, d, J = 7.8 Hz, 2 ×
CH(Ar)), 7.22 (2H, d, J = 7.9 Hz, 2 × CH(Ar)), 7.13 (1H, t, J
= 7.4 Hz, 6-CH), 7.00 (1H, d, J = 8.1 Hz, 8-CH), 6.93 (1H, d,
J = 16.6, 2′-CH), 4.38 (2H, q, J = 7.0 Hz, NCH2CH3), 2.49
(3H, s, PhCH3), 2.41 (3H, s, PhCH3), 1.47 (3H, t, J = 7.0 Hz,
NCH2CH3); 13C NMR (100 MHz, CDCl3) δC 160.84 (4-C),
160.44 (1′-C), 148.80 (2-C), 138.69 (2′-C), 135.22, 134.68,
134.12, 129.56, 129.38, 128.96, 128.38, 127.36, 122.17 (Ar-
C), 119.84 (3′-C), 36.57 (NCH2CH3), 21.40 (PhCH3), 12.58
(NCH2CH3); MS (EI) m/z 422.2 (M+, 100 %);Anal. Calcd. for
C27H26N4O: C, 76.75; H, 6.20; N, 13.26. Found: C, 76.98; H,
6.51; N, 13.57 %.
A new series of 2-[N'-(1,3-diphenyl-allylidene)-
hydrazino]-3-ethyl-3H-quinazolin-4-one (8) and 2-(3,5-
diphenyl-4,5-dihydro-pyrazol-1-yl)-3-ethyl-3H-quinazolin-4-
one (9) compounds have been synthesized and screened for
their antibacterial [Staphylococcus aureus (ATCC 29213),
Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC
25922) and Pseudomonas aeruginosa (ATCC 27853)] and
antifungal [Candida albicans (ATCC 90028), Candida
parapsilosis (ATCC 90018) and C. krusei (ATCC 6258)]
activities. 8 compounds were found most effective on bacteria
E. faecalis with the higher MIC values whereas 9h was most
effective on C. albicans and C. parapsilosis fungies. With these
results in our hand, future work is aimed to be done for the
synthesis and activity studies of new quinazolinone compounds.
3-Ethyl-2-[N'-(3-phenyl-1-p-tolyl-allylidene)hydra-
zino]-3H-quinazolin-4-one (8a): Obtained according to the
general procedure, by using 7a (222 mg, 1.0 mmol), as a white
solid (335 mg, 82 %); m.p. 163-164 °C; Rf 0.35 (CHCl3); 1H
NMR (400 MHz, CDCl3) δH 9.40 (1H, br-s, NH), 8.10 (1H, d,
J = 8.4 Hz, 5-CH), 8.00 (1H, d, J = 16.8 Hz, 3′-CH), 7.51 (2H,
d, J = 8.0 Hz, 2 × CH(Ar)), 7.48 (1H, t, J = 7.6 Hz, 7-CH),
7.30 (7H, m, 7 × CH(Ar)), 7.09 (1H, t, J = 7.6 Hz, 6-CH),
6.93 (1H, d, J = 8.0 Hz, 8-CH), 6.86 (1H, d, J = 16.4, 2′-CH),
4.37 (2H, q, J = 7.0 Hz, NCH2CH3), 2.50 (3H, s, PhCH3), 1.48
(3H, t, J = 7.0 Hz, NCH2CH3); ¹³C-NMR (100 MHz, CDCl3)
δC 160.85 (4-C), 160.17 (1′-C), 148.94 (2-C), 138.68 (2′-C),
136.91, 135.26, 134.70, 129.50, 129.34, 128.99, 128.91,
128.82, 128.39, 127.38, 127.16, 122.20 (Ar-C), 120.81 (3′-
C), 36.59 (NCH2CH3), 21.41 (PhCH3), 12.59 (NCH2CH3); MS
(EI) m/z 408.2 (M+, 100 %); Anal. calcd. for C26H24N4O:
C, 76.45; H, 5.92; N, 13.72. Found: C, 76.74; H, 6.28; N,
13.97 %.
2-{N'-[3-(4-Bromophenyl)-1-p-tolyl-allylidene]hydra-
zino}-3-ethyl-3H-quinazolin-4-one (8d): Obtained according
to the general procedure, by using 7d (301 mg, 1.0 mmol), as
a white solid (418 g, 86 %); m.p. 185-186 °C; Rf 0.36 (CHCl3);
1H NMR (400 MHz, CDCl3) δH 9.26 (1H, br-s, NH), 8.07 (1H,
d, J = 7.6 Hz, 5-CH), 8.00 (1H, d, J = 16.7 Hz, 3′-CH), 7.50
(1H, t, J = 7.2 Hz, 7-CH), 7.47 (4H, d, J = 8.3 Hz, 4 × CH(Ar)),
7.33 (2H, d, J = 8.4 Hz, 2 × CH(Ar)), 7.24 (2H, d, J = 8.0 Hz,
2 × CH(Ar)), 7.08 (1H, t, J = 7.6 Hz, 6-CH), 6.93 (1H, d, J =
8.1 Hz, 8-CH), 6.78 (1H, d, J = 16.7, 2′-CH), 4.31 (2H, q, J =
7.0 Hz, NCH2CH3), 2.44 (3H, s, PhCH3), 1.41 (3H, t, J = 7.0
Hz, NCH2CH3); 13C NMR (100 MHz, CDCl3) δC 160.42 (4-
C), 159.37 (1′-C), 149.11 (2-C), 138.69 (2′-C), 136.78, 135.90,
134.48, 132.15, 131.95, 129.67, 129.29, 129.22, 128.93, 128.65,
128.57, 122.77 (Ar-C), 122.14 (3′-C), 36.44 (NCH2CH3), 21.42
(PhCH3), 12.64 (NCH2CH3); MS (EI) m/z 486.1 (M+, 100 %),
488.1; Anal. Calcd. for C26H23N4OBr: C, 64.07; H, 4.76; N,
11,50. Found: C, 64.39; H, 5.12; N, 11.83 %.
2-{N'-[1-(4-Chlorophenyl)-3-phenyl-allylidene]-
hydrazino}-3-ethyl-3H-quinazolin-4-one (8e): Obtained
according to the general procedure, by using 7e (242 mg, 1.0
mmol), as a white solid (325 g, 76 %); m.p. 191-192 °C; Rf
0.38 (CHCl3); 1H NMR (400 MHz, CDCl3) δH 9.43 (1H, br-s,
NH), 8.14 (1H, d, J = 7.9 Hz, 5-CH), 8.10 (1H, d, J = 16.7 Hz,
3′-CH), 7.62 (2H, d, J = 8.5 Hz, 2 × CH(Ar)), 7.54 (3H, m, 7-
CH and 2 × CH(Ar)), 7.48 (2H, d, J = 8.5 Hz, 2 × CH(Ar)),
7.42 (2H, t, J = 6.9 Hz, 2 × CH(Ar)), 7.38 (1H, t, J = 7.0 Hz,
2 × CH(Ar)), 7.16 (1H, t, J = 8.0 Hz, 6-CH), 7.04 (1H, d, J =
8.0 Hz, 8-CH), 6.91 (1H, d, J = 16.8, 2′-CH), 4.37 (2H, q, J =
7.0 Hz, NCH2CH3), 1.45 (3H, t, J = 7.0 Hz, NCH2CH3); 13C
NMR (100 MHz, CDCl3) δC 160.13 (4-C), 159.23 (1′-C),
149.35 (2-C), 138.83 (2′-C), 136.65, 135.27, 134.41, 130.60,
129.56, 129.43, 129.31, 129.01, 128.80, 128.46, 128.38,
128.14, 127.92, 127.33, 122.13 (Ar-C), 120.42 (3′-C), 36.56
(NCH2CH3), 12.45 (NCH2CH3); MS (EI) m/z 428.1 (M+,
100 %), 430.1; Anal. Calcd. for C25H21N4OCl: C, 70.01; H,
4.93; N, 13.06. Found: C, 70.29; H, 5.27; N, 13.23 %.
2-{N'-[1,3-bis-(4-Chlorophenyl)allylidene]hydrazino}-
3-ethyl-3H-quinazolin-4-one (8f): Obtained according to the
general procedure, by using 7f (277 m, 1.0 mmol), as a white
solid (374 mg, 81 %); m.p. 206-207 °C; Rf 0.36 (CHCl3); 1H
NMR (400 MHz, CDCl3) δH 9.13 (1H, br-s, NH), 7.92 (1H, d,
J = 7.9 Hz, 5-CH), 7.82 (1H, d, J = 16.7 Hz, 3′-CH), 7.57 (1H,
t, J = 7.1 Hz, 7-CH), 7.39 (2H, d, J = 8.5 Hz, 2 × CH(Ar)),
2-{N'-[3-(4-Chlorophenyl)-1-p-tolyl-allylidene]hydra-
zino}-3-ethyl-3H-quinazolin-4-one (8b): Obtained according
to the general procedure, by using 7b (256 mg, 1.0 mmol), as
a white solid (349 g, 79 %); m.p. 178-179 °C; Rf 0.38 (CHCl3);
1H NMR (400 MHz, CDCl3) δH 9.44 (1H, br-s, NH), 8.15 (1H,
d, J = 8.0 Hz, 5-CH), 8.05 (1H, d, J = 16.6 Hz, 3′-CH), 7.56
(2H, d, J = 7.6 Hz, 2 × CH(Ar)), 7.55 (1H, t, J = 7.7 Hz, 7-
CH), 7.37 (2H, d, J = 7.8 Hz, 2 × CH(Ar)), 7.32 (2H, d, J = 8.1
Hz, 2 × CH(Ar)), 7.23 (2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.14
(1H, t, J = 7.6 Hz, 6-CH), 7.03 (1H, d, J = 8.1 Hz, 8-CH), 6.90
(1H, d, J = 16.6, 2′-CH), 4.36 (2H, q, J=6.8 Hz, NCH2CH3),
2.42 (3H, s, PhCH3), 1.45 (3H, t, J = 6.8 Hz, NCH2CH3); 13C
NMR (100 MHz, CDCl3) δC 160.51 (4-C), 159.85 (1′-C),
148.98 (2-C), 138.57 (2′-C), 135.30, 134.94, 134.77, 132.90,
129.38, 129.23, 129.06, 128.54, 128.49, 126.85, 122.84,
122.37 (Ar-C), 121.14 (3′-C), 36.75 (NCH2CH3), 21.42
(PhCH3), 12.58 (NCH2CH3); MS (EI) m/z 442.1 (M+, 100 %),
444.1; Anal. Calcd. for C26H23N4OCl: C, 70.50; H, 5.23; N,
12.65. Found: C, 70.85; H, 5.49; N, 12.93 %.
2-[N'-(1,3-Di-p-tolylallylidene)hydrazino]-3-ethyl-3H-
quinazolin-4-one (8c): Obtained according to the general
procedure, by using 7c (236 g, 1.0 mmol), as a white solid
(380 mg, 90 %); m.p. 172-173 °C; Rf 0.40 (CHCl3); 1H NMR
(400 MHz, CDCl3) δH 9.43 (1H, br-s, NH), 8.13 (1H, d, J =

Vol. 26, No. 11 (2014)
Synthesis of New 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones 3201
7.27 (2H, d, J = 8.5 Hz, 2 × CH(Ar)), 7.23 (2H, d, J = 8.7 Hz,
2 × CH(Ar)), 7.16 (2H, d, J = 8.4 Hz, 2 × CH(Ar)), 6.95 (1H,
t, J = 7.2 Hz, 6-CH), 6.81 (1H, d, J = 8.2 Hz, 8-CH), 6.63 (1H,
d, J = 16.7, 2′-CH), 4.15 (2H, q, J = 7.0 Hz, NCH2CH3), 1.23
(3H, t, J = 7.0 Hz, NCH2CH3); 13C NMR (100 MHz, CDCl3)
δC 160.36 (4-C), 158.20 (1′-C), 149.45 (2-C), 138.44 (2′-C),
136.78, 135.18, 134.80, 130.53, 129.84, 129.54, 129.29,
129.08, 128.94, 128.60, 128.48, 128.38, 128.00, 127.93,
122.34 (Ar-C), 120.99 (3′-C), 36.49 (NCH2CH3), 12.63
(NCH2CH3); MS (EI) m/z 462.1 (M+, 100 %), 464.1, 466.1;
Anal. Calcd. for C25H20N4OCl2: C, 64.80; H, 4.35; N, 12.09.
Found: C, 65.16; H, 4.72; N, 12.30 %.
5.94 (1H, t, J = 11.2 Hz, 5′-CH), 4.40 (2H, q, J = 7.0 Hz,
NCH2CH3), 3.75 (1H, dd, J = 11.2 and 17.0 Hz, 4′-CHa), 3.21
(1H, dd, J = 12.0 and 16.9 Hz, 4′-CHb), 2.35 (3H, s, PhCH3),
1.48 (3H, t, J = 7.0 Hz, NCH2CH3); 13C NMR (100 MHz,
CDCl3) δC 162.48 (4-C), 151.85 (2-C), 149.42 (3′-C), 136.91,
135.26, 134.70, 129.50, 129.34, 128.99, 128.91, 128.82,
128.39, 127.38, 127.16, 122.20 (Ar-C), 63.57 (5′-C), 40.43
(4′-C), 36.65 (NCH2CH3), 21.51 (PhCH3), 13.73 (NCH2CH3);
MS (EI) m/z 408.2 (M+, 100 %); Anal. Calcd. for C26H24N4O:
C, 76.45; H, 5.92; N, 13.72. Found: C, 76.79; H, 6.27; N,
14.05 %.
2-[5-(4-Chlorophenyl)-3-p-tolyl-4,5-dihydropyrazol-1-
yl]-3-ethyl-3H-quinazolin-4-one (9b): Obtained according
to the general procedure, by using 8b (221 mg, 0.5 mmol), as
a white solid (181 g, 82 %); m.p. 152-153 °C; Rf 0.42 (CHCl3);
1H NMR (400 MHz, CDCl3) δH 8.12 (1H, d, J = 8.1 Hz, 5-
CH), 7.64 (2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.59 (1H, t, J = 7.6
Hz, 7-CH), 7.45 (2H, d, J = 8.3 Hz, 2 × CH(Ar)), 7.39 (2H, d,
J = 7.8 Hz, 2 × CH(Ar)), 7.32 (2H, d, J = 8.1 Hz, 8-CH), 7.19
(1H, t, J = 7.6 Hz, 6-CH), 7.07 (2H, d, J = 8.1 Hz, 2 × CH(Ar)),
5.93 (1H, t, J = 11.2 Hz, 5′-CH), 4.36 (2H, q, J = 6.8 Hz,
NCH2CH3), 3.59 (1H, dd, J = 11.2 and 17.0 Hz, 4′-CHa), 3.29
(1H, dd, J = 12.0 and 16.8 Hz, 4′-CHb), 2.48 (3H, s, PhCH3),
1.45 (3H, t, J = 6.8 Hz, NCH2CH3); 13C NMR (100 MHz,
CDCl3) δC 163.04 (4-C), 152.43 (2-C), 148.56 (3′-C), 136.30,
135.94, 135.77, 131.90, 128.38, 128.23, 128.06, 127.54,
127.49, 125.85, 121.84, 121.37 (Ar-C), 62.63 (5′-C), 40.71
(4′-C), 36.23 (NCH2CH3), 20.98 (PhCH3), 13.08 (NCH2CH3);
MS (EI) m/z 442.1 (M+, 100 %), 444.1; Anal. Calcd. for
C26H23N4OCl: C, 70.50; H, 5.23; N, 12.65. Found: C, 70.83;
H, 5.58; N, 12.93 %.
2-{N'-[1,3-bis-(4-Chlorophenyl)allylidene]hydrazino}-
3-ethyl-3H-quinazolin-4-one (8g): Obtained according to the
general procedure, by using 7g (256 g, 1.0 mmol), as a white
solid (324 mg, 74 %); m.p. 182-183 °C; Rf 0.39 (CHCl3); 1H
NMR (400 MHz, CDCl3) δH 9.48 (1H, br-s, NH), 8.13 (1H, d,
J = 7.9 Hz, 5-CH), 7.83 (1H, d, J = 16.2 Hz, 3′-CH), 7.55 (1H,
t, J = 8.0 Hz, 7-CH), 7.57 (2H, d, J = 8.1 Hz, 2 × CH(Ar)),
7.43 (2H, d, J = 8.1 Hz, 2 × CH(Ar)), 7.26 (2H, d, J = 8.0 Hz,
2 × CH(Ar)), 7.22 (2H, d, J = 7.9 Hz, 2 × CH(Ar)), 7.15 (1H,
t, J = 8.0 Hz, 6-CH), 7.05 (1H, d, J = 8.2 Hz, 8-CH), 6.89 (1H,
d, J = 16.6, 2′-CH), 4.37 (2H, q, J = 7.0 Hz, NCH2CH3), 2.43
(3H, s, PhCH3), 1.45 (3H, t, J = 7.0 Hz, NCH2CH3); 13C NMR
(100 MHz, CDCl3) δC 160.41 (4-C), 158.86 (1′-C), 149.15 (2-
C), 138.96 (2′-C), 138.55, 138.41, 136.81, 134.82, 134.49,
133.95, 130.62, 129.54, 128.58, 128.40, 127.30, 122.19 (Ar-
C), 119.59 (3′-C), 36.48 (NCH2CH3), 21.63 (PhCH3), 12.68
(NCH2CH3); MS (EI) m/z 442.1 (M+, 100 %), 444.1; Anal.
Calcd. for C26H23N4OCl: C, 70,50; H, 5.23; N, 12.65. Found:
C, 70.84; H, 5.57; N, 13.01 %.
2-{N'-[3-(4-Bromophenyl)-1-(4-chlorophenyl)-
allylidene]-hydrazino}-3-ethyl-3H-quinazolin-4-one (8h):
Obtained according to the general procedure, by using 7h (321
mg, 1.0 mmol), as a white solid (430 mg, 85 %); m.p. 218-
219 °C; Rf 0.30 (CHCl3); 1H NMR (400 MHz, CDCl3) δH 9.24
(1H, br-s, NH), 8.07 (1H, d, J = 7.9 Hz, 5-CH), 8.00 (1H, d, J
= 16.7 Hz, 3′-CH), 7.52 (1H, t, J = 7.0 Hz, 7-CH), 7.44 (2H,
d, J = 8.4 Hz, 2 × CH(Ar)), 7.41 (2H, d, J = 8.4 Hz, 2 × CH(Ar)),
7.28 (2H, d, J = 8.3 Hz, 2 × CH(Ar)), 7.26 (2H, d, J = 8.4 Hz,
2 × CH(Ar)), 7.10 (1H, t, J = 7.6 Hz, 6-CH), 7.02 (1H, d, J =
8.1 Hz, 8-CH), 6.75 (1H, d, J = 16.8, 2′-CH), 4.32 (2H, q, J =
7.0 Hz, NCH2CH3), 1.41 (3H, t, J = 7.0 Hz, NCH2CH3); 13C
NMR (100 MHz, CDCl3) δC 160.21 (4-C), 159.81 (1′-C),
149.03 (2-C), 138.42 (2′-C), 135.50, 135.24, 134.57, 134.11,
132.04, 131.89, 130.75, 130.53, 130.27, 128.68, 128.49,
128.28, 127.94, 122.43 (Ar-C), 122.36 (3′-C), 36.32
(NCH2CH3), 12.47 (NCH2CH3); MS (EI) m/z 506.0 (M+, 100
%), 508.0;Anal. Calcd. for C25H20N4OClBr: C, 59.13; H, 3.97;
N, 11.03. Found: C, 59.42; H, 4.35; N, 11.38 %.
2-(3,5-Di-p-tolyl-4,5-dihydropyrazol-1-yl)-3-ethyl-3H-
quinazolin-4-one (9c): Obtained according to the general
procedure, by using 8c (211 mg, 0.5 mmol), as a white solid
(205 mg, 97 %); m.p. 136-137 °C; Rf 0.35 (CHCl3); 1H NMR
(400 MHz, CDCl3) δH 8.12 (1H, d, J = 7.9 Hz, 5-CH), 7.58
(2H, d, J = 8.1 Hz, 2 × CH(Ar)), 7.54 (1H, t, J = 8.0 Hz, 7-
CH), 7.38 (2H, d, J = 7.9 Hz, 2 × CH(Ar)), 7.37 (1H, m, 8-
CH), 7.21 (1H, m, 6-CH), 7.20 (1H, d, J = 8.1 Hz, 2 × CH(Ar)),
7.10 (1H, d, J = 7.9 Hz, 2 × CH(Ar)), 5.92 (1H, t, J = 11.6 Hz,
5′-CH), 4.46 (2H, q, J = 6.9 Hz, NCH2CH3), 3.68 (1H, dd, J =
11.2 and 17.0 Hz, 4′-CHa), 3.19 (1H, dd, J = 12.0 and 17.0
Hz, 4′-CHb), 2.40 (3H, s, PhCH3), 2.30 (3H, s, PhCH3), 1.54
(3H, t, J = 6.9 Hz, NCH2CH3); 13C NMR (100 MHz, CDCl3)
δC 162.47 (4-C), 151.81 (2-C), 148.43 (3′-C), 136.20, 132.65,
129.59, 128.53, 128.35, 128.27, 126.52, 126.08, 125.47,
125.05, 123.56, (Ar-C), 62.88 (5′-C), 40.85 (4′-C), 39.87
(NCH2CH3), 20.60 (PhCH3), 20.23 (PhCH3), 13.45
(NCH2CH3); MS (EI) m/z 422.2 (M+, 100 %);Anal. Calcd. for
C27H26N4O: C, 76.75; H, 6.20; N, 13.26. Found: C, 77.06; H,
6.51; N, 13.51 %.
3-Ethyl-2-(5-phenyl-3-p-tolyl-4,5-dihydropyrazol-1-
yl)-3H-quinazolin-4-one (9a): Obtained according to the
general procedure, by using 8a (102 mg, 0.5 mmol), as a white
2-[5-(4-Bromophenyl)-3-p-tolyl-4,5-dihydro-pyrazol-
1-yl]-3-ethyl-3H-quinazolin-4-one (9d): Obtained according
to the general procedure, by using 8d (243 mg, 0.5 mmol), as
a white solid (231 g, 95 %); m.p. 174-175 °C; Rf 0.42 (CHCl3);
1H NMR (400 MHz, CDCl3) δH 8.00 (1H, d, J = 8.0 Hz, 5-
CH), 7.58 (2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.55 (1H, t, J = 8.4
Hz, 7-CH), 7.44 (2H, d, J = 8.8 Hz, 2 × CH(Ar)), 7.39 (2H, d,
J = 8.8 Hz, 2 × CH(Ar)), 7.35 (1H, d, J = 8.0 Hz, 8-CH), 7.25
1
solid (173 g, 85 %); m.p. 125-126 °C; Rf 0.39 (CHCl3); H
NMR (400 MHz, CDCl3) δH 8.00 (1H, d, J = 8.0 Hz, 5-CH),
7.51 (2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.55 (1H, t, J = 8.4 Hz,
7-CH), 7.44 (2H, d, J = 8.8 Hz, 2 × CH(Ar)), 7.39 (2H, d, J =
8.8 Hz, 2 × CH(Ar)), 7.35 (1H, d, J = 8.0 Hz, 8-CH), 7.25
(1H, t, J = 7.6 Hz, 6-CH), 7.21 (2H, d, J = 8.0 Hz, 2 × CH(Ar)),

3202 Saygili et al.
Asian J. Chem.
(1H, t, J = 7.6 Hz, 6-CH), 7.21 (2H, d, J = 8.0 Hz, 2 × CH(Ar)),
5.94 (1H, t, J = 11.2 Hz, 5′-CH), 4.46 (2H, q, J = 6.8 Hz,
NCH2CH3), 3.70 (1H, dd, J = 11.2 and 17.0 Hz, 4′-CHa), 3.16
(1H, dd, J = 12.0 and 16.8 Hz, 4′-CHb), 2.41 (3H, s, PhCH3),
2.30 (3H, s, PhCH3), 1.55 (3H, t, J = 7.2 Hz, NCH2CH3); 13C
NMR (100 MHz, CDCl3) δC 162.24 (4-C), 151.73 (2-C),
149.31 (3′-C), 135.46, 133.90, 132.01, 131.80, 129.50, 129.43,
129.30, 129.18, 129.12, 128.96, 128.50, 126.98, 126.41,
125.79, 124.46, 122.36 (Ar-C), 63.38 (5′-C), 40.35 (4′-C),
36.95 (NCH2CH3), 21.42 (PhCH3), 13.92 (NCH2CH3); MS (EI)
m/z 486.1 (M+, 100 %), 488.1; Anal. Calcd. for C26H23N4OBr:
C, 64.07; H, 4.76; N, 11.50. Found: C, 64.36; H, 4.97; N,
11.83 %.
(1H, d, J = 8.0 Hz, 8-CH), 7.22 (1H, t, J = 7.4, 6-CH), 7.17
(1H, d, J = 8.1 Hz, 2 × CH(Ar)), 7.08 (1H, d, J = 7.9 Hz, 2 ×
CH(Ar)), 5.79 (1H, t, J = 11.6 Hz, 5′-CH), 4.58 (2H, q, J = 6.9
Hz, NCH2CH3), 3.74 (1H, dd, J = 11.4 and 17.0 Hz, 4′-CHa),
3.32 (1H, dd, J = 12.0 and 17.0 Hz, 4′-CHb), 2.37 (3H, s,
PhCH3), 1.63 (3H, t, J = 6.9 Hz, NCH2CH3); 13C NMR (100
MHz, CDCl3) δC 162.37 (4-C), 151.73 (2-C), 148.28 (3′-C),
135.46, 134.89, 134.65, 132.79, 129.56, 129.43, 129.26,
128.66, 128.43, 126.74, 122.65, 122.25 (Ar-C), 62.66 (5′-C),
40.34 (4′-C), 39.54 (NCH2CH3), 20.53 (PhCH3), 13.19
(NCH2CH3); MS (EI) m/z 442.1 (M+, 100 %), 444.1; Anal.
Calcd. for C26H23N4OCl: C, 70.50; H, 5.23; N, 12.65. Found:
C, 70.82; H, 5.51; N, 12.88 %.
2-[3-(4-Chlorophenyl)-5-phenyl-4,5-dihydro-pyrazol-
1-yl]-3-ethyl-3H-quinazolin-4-one (9e): Obtained according
to the general procedure, by using 8e (214 mg, 0.5 mmol), as
a white solid (199 mg, 93 %); m.p. 165-166 °C; Rf 0.43
(CHCl3); 1H NMR (400 MHz, CDCl3) δH 8.14 (1H, d, J = 8.0
Hz, 5-CH), 7.63 (2H, d, J = 8.8 Hz, 2 × CH(Ar)), 7.55 (1H, t,
J = 8.0 Hz, 7-CH), 7.49 (2H, d, J = 7.2 Hz, 2 × CH(Ar)), 7.40
(1H, m, 8-CH) 7.40 (2H, d, J = 8.8 Hz, 2 × CH(Ar)), 7.32
(2H, t, J = 7.6 Hz, 2 × CH(Ar)), 7.25 (1H, t, J = 8.0 Hz, 2 ×
CH(Ar)), 7.25 (1H, t, J = 8.0, 6-CH), 6.03 (1H, t, J = 11.4 Hz,
5′-CH), 4.46 (2H, q, J = 6.9 Hz, NCH2CH3), 3.71 (1H, dd, J =
11.3 and 16.9 Hz, 4′-CHa), 3.21 (1H, dd, J = 12.0 and 16.9
Hz, 4′-CHb), 1.54 (3H, t, J = 6.9 Hz, NCH2CH3); 13C NMR
(100 MHz, CDCl3) δC 162.89 (4-C), 151.95 (2-C), 148.96 (3′-
C), 136.12, 133.81, 130.49, 130.06, 129.65, 129.09, 128.83,
128.69, 127.87, 127.56, 127.34, 127.21, 127.02, 125.72,
124.86 (Ar-C), 64.27 (5′-C), 41.67 (4′-C), 40.89 (NCH2CH3),
14.37 (NCH2CH3); MS (EI) m/z 428.1 (M+, 100 %), 430.1;
Anal. Calcd. for C25H21N4OCl: C, 70.01; H, 4.93; N, 13.06.
Found: C, 70.29; H, 5.34; N, 13.32 %.
2-[5-(4-Bromophenyl)-3-(4-chloro-phenyl)-4,5-dihydro-
pyrazol-1-yl]-3-ethyl-3H-quinazolin-4-one (9h): Obtained
according to the general procedure, by using 8h (253 mg, 0.5
mmol), as a white solid (230 mg, 91 %); m.p. 210-211 °C; Rf
0.36 (CHCl3); 1H NMR (400 MHz, CDCl3) δH 8.15 (1H, d, J =
7.6 Hz, 5-CH), 7.63 (2H, d, J = 8.8 Hz, 2 × CH(Ar)), 7.57
(1H, t, J = 8.0 Hz, 7-CH), 7.45 (2H, d, J = 8.4 Hz, 2 × CH(Ar)),
7.40 (2H, d, J = 8.4 Hz, 2 × CH(Ar)), 7.39 (2H, d, J = 8.4 Hz,
2 × CH(Ar)), 7.35 (1H, d, J = 8.0 Hz, 8-CH), 7.27 (1H, t, J =
7.2, 6-CH), 5.95 (1H, t, J = 12.0 Hz, 5′-CH), 4.44 (2H, q, J =
7.2 Hz, NCH2CH3), 3.69 (1H, dd, J = 11.2 and 16.8 Hz, 4′-
CHa), 3.17 (1H, dd, J = 12.0 and 17.0 Hz, 4′-CHb), 1.52 (3H,
t, J = 7.1 Hz, NCH2CH3); 13C NMR (100 MHz, CDCl3) δC
163.10 (4-C), 152.21 (2-C), 149.10 (3′-C), 136.34, 133.91,
131.96, 131.73, 129.19, 129.00, 127.39, 126.95, 124.82,
122.03 (Ar-C), 63.91 (5′-C), 41.51 (4′-C), 40.58 (NCH2CH3),
14.23 (NCH2CH3); MS (EI) m/z 506.0 (M+, 100 %), 508.0;
Anal. Calcd. for C25H20N4OBrCl: C, 59.13; H, 3.97; N, 11.03.
Found: C, 59.41; H, 4.39; N, 11.37 %.
ACKNOWLEDGEMENTS
2-[3,5-bis-(4-Chlorophenyl)-4,5-dihydro-pyrazol-1-yl]-
3-ethyl-3H-quinazolin-4-one (9f): Obtained according to the
general procedure, by using 8f (231 mg, 0.5 mmol), as a white
solid (199 mg, 86 %); m.p. 189-190 °C; Rf 0.41 (CHCl3); 1H-
NMR (400 MHz, CDCl3) δH 8.25 (1H, d, J = 8.0 Hz, 5-CH),
7.54 (1H, t, J = 8.0 Hz, 7-CH), 7.44 (1H, m, 8-CH) 7.40 (2H,
d, J = 8.0 Hz, 2 × CH(Ar)), 7.35 (2H, d, J = 8.0 Hz, 2 × CH(Ar)),
7.31 (2H, d, J = 8.0 Hz, 2 × CH(Ar)), 7.28 (2H, d, J = 8.0 Hz,
2 × CH(Ar)), 7.20 (1H, t, J = 8.0, 6-CH), 6.12 (1H, t, J = 11.2
Hz, 5′-CH), 4.36 (2H, q, J = 7.0 Hz, NCH2CH3), 3.78 (1H, dd,
J = 11.2 and 17.0 Hz, 4′-CHa), 3.25 (1H, dd, J = 12.0 and 17.0
Hz, 4′-CHb), 1.63 (3H, t, J = 7.0 Hz, NCH2CH3). 13C NMR
(100 MHz, CDCl3) δC 161.78 (4-C), 152.43 (2-C), 149.11 (3′-
C), 136.78, 135.18, 134.80, 130.53, 129.84, 129.54, 129.29,
129.08, 128.94, 128.60, 128.48, 128.38, 128.00, 127.93,
122.34 (Ar-C), 64.36 (5′-C), 41.73 (4′-C), 40.76 (NCH2CH3),
13.89 (NCH2CH3); MS (EI) m/z 462.1 (M+, 100 %), 464.1,
466.1; Anal. Calcd. for C25H20N4OCl2: C, 64.80; H, 4.35; N,
12.09. Found: C, 65.16; H, 4.64; N, 12.33 %.
The authors gratefully acknowledged the partial financial
support from the Hacettepe University (BAB-03G046 and
BAB-2009, 08 D05 301 002).
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Synthesis of New 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones 3203
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