Synthesis and spectral characterisation of novel 2,3-disubstituted quinazolin-4(3H)-one derivatives

Article abstract of DOI:10.3184/174751912X13274094865293

A new series of 2,3-disubstituted quinazolinones was synthesised via the reaction of readily obtainable 2-thioxo-3-phenylquinazolin-4(3H)-one 1 with ethyl chloroacetate followed by hydrazinolysis to afford the hydrazide 3. This was allowed to react with d

Full text of DOI:10.3184/174751912X13274094865293

66 RESEARCH PAPER
FEBRUARY, 66–71
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis and spectral characterisation of novel 2,3-disubstituted
quinazolin-4(3H)-one derivatives
Mahmoud R. Mahmoud, Wael S.I. Abou-Elmagd*, Salwa S. Abdelwahab and
El-Sayed A. Soliman
Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo 11566, Egypt
A new series of 2,3-disubstituted quinazolinones was synthesised via the reaction of readily obtainable 2-thioxo-3-
phenylquinazolin-4(3H)-one 1 with ethyl chloroacetate followed by hydrazinolysis to afford the hydrazide 3. This was
allowed to react with different electrophilic reagents such as carbon disulfide, phenyl isothiocyanate, β-diketones,
anhydrides, acrylonitrile, ethyl cinnamate, aldehydes, arylidene malononitrile and lauroyl chloride. Some of the
newly synthesised compounds showed promising anti-inflammatory activities.
Keywords: pyrazolyl-, 1,3,4-oxadiazolyl-quinazolinone, anti-inflammatory activity, Michael reaction
Several quinazolinone derivatives were synthesised as
potential antimicrobial,1,2 anticancer,3,4 anti-inflammatory,5,6
and antimalarial7 agents. Quinazolin-4(3H)-one is a frequently
encountered unit in natural products such as S-vasicinone,
chrysogine and drugs as methaqualone,8 i.e. molecules based
on quinazoline and quinazolinone which exhibit a multitude of
interesting pharmacological activities.9
by the reaction of anthranilic acid with phenyl isocyanate in
refluxing pyridine (Scheme 4).
Phenylisothiocyanate was added to the hydrazide 3 in
boiling ethanol and gave 1-[2-(4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-ylthio)acetyl]-4-phenylthiosemicarbazide 6. 3-
Phenyl-2-((4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)
methylthio)quinazolin-4(3H)-one 7 was achieved through the
reaction of compound 6 with alcoholic sodium hydroxide.
When the hydrazide 3 was allowed to react with phthalic
anhydride in refluxing dioxane it gave N-(1,3-dioxoisoindolin-
2-yl)-2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)
acetamide 8. The structure of 8 was confirmed from the correct
analytical and spectroscopic data. No evidence for the forma-
tion of the phthalazine derivative 9 was detected, since the
IR spectrum of the product shows the carbonyl vibrational
coupling bands at 1793 and 1738 cm−1 together with υC=O
(quinazolinone) at 1684 cm−1 which agrees well with the struc-
ture 8. The mass spectrum of 8 show the correct molecular ion
peak at m/z = 456 (4.04%) which upon loss of N-aminoph-
thalimide radical afforded the base peak at m/z = 295 (100%).
Refluxing compound 3 with acrylonitrile in dioxane afforded
2-[2-(5-iminopyrazolidin-1-yl)-2-oxoethylthio]-3-phenylquinazo-
lin-4(3H)-one 10. Fusion of 3 with methyl cinnamate on
oil bath at 180 °C gave a crude solid product which triturated
with ethanol to give 2-(2-oxo-3-(phenyl-2,5-dihydro pyrazol-
1-yl)ethylthio)-3-phenylquinazolin-4(3H)-one 11. The reac-
tion smoothly proceeds via Michael addition followed by
1,5-exo-trig cyclisation (Scheme 6).
A variety of 2,3-disubstituted quinazolinone derivatives
were synthesised from 2-thioxo-3-phenylquinazolin-4(3H)-
one 1.10
Results and discussion
In this investigation, ethyl 2-(4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-ylthio)acetate 2 was obtained in fairly good yield
by treatment of quinazolin-2-thione derivative 1 with ethyl
chloroacetate in the presence of fused sodium acetate in
refluxing ethanol. In previous work, the reaction of ethyl
S-(heteryl)thioglycollate with hydrazine in refluxing ethanol
involves the elimination of this group and substituted by the
hydrazine group. When compound 2 was allowed to react with
hydrazine hydrate to give the 2-(4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-ylthio)acetohydrazide 3. 3-Phenyl-2-[(5-thioxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl)methylthio]quinazolin-4(3H)-one
4 was obtained in fairly good yield upon refluxing the hydra-
zide 3 with carbon disulfide in pyridine on water bath for 8h
(Scheme 1).
Treatment of the hydrazide 3 with β-diketone such as, acetyl
acetone and/or benzoyl acetone in refluxing ethanol gave 2-[2-
(3,5-dimethylpyrazol-1-yl)-2-oxoethylthio]-3-phenylquinazolin-
4-(3H)-one 12a and 2-[2-(3-methyl-5-phenyl pyrazol-1-yl)-2-
oxoethylthio]-3-phenylquinazolin-4(3H)-one 12b respectively
(Scheme 6).
The reaction smoothly proceeds through a tetrahedral
pathway followed by 1,5-exo-trig cyclisation to give 4
(Scheme 2).
The hydrazide 3 easily condensed with aromatic aldehydes
such as salicylaldehyde, 2,6-dichlorobenzaldehyde and/or
p-anisaldehyde in refluxing dioxane for 24h to give N′-aryli-
dene-2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)
acetohydrazide 13a–c. Moreover, the 1H NMR spectra of com-
pounds 13a and 13b showed two singlets for NH amide proton
and two singlets for =CH olefinic proton, as well as, two
singlets for –OH in case of 13a. This showed that compounds
13a and 13b were formed as a mixture of two geometrical
(E- and Z-) isomers in which the E-isomers predominate.
The reaction of the hydrazide 3 with 3,4-dimethoxy α-cyano
cinnamonitrile in refluxing pyridine for 8 h followed by acidi-
fication with ice cold hydrochloric acid yielded the anil deriva-
tive 13d as a mixture of E- and Z- isomer and the pyrazolidine
derivative 14 was not isolated. The IR spectrum of the product
shows the stretching absorption bands for υNH at 3180 cm−1, υCO
When the hydrazide 3 was treated with carbon disulfide
in ethanolic potassium hydroxide, no reaction was detected
between the hydrazide 3 and the carbon disulfide and the solid
which separated was identified as the sulfur-free compound
3-phenylquinazolin-2,4(1H,3H)-dione 5. This may be due to
nucleophilic substitution reaction by the hydroxyl group at
C2 of the quinazolinone followed by eleimination of the
thiomethyl hydrazide group (Scheme 3).
The structure 5 was confirmed from the study of the IR and
mass spectrum together with chemical evidence and confirmed
by comparison with the reported m.p.11 A sample was prepared
* Correspondent. E-mail: waelmagd97@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 67
Scheme 1
Scheme 2
at 1681 cm−1 and lacks the absorption bands for υNH2 and υC≡N
which eliminate the assigned structure 14 and in accord with
the proposed structure 13d. H NMR spectrum (CDCl3) is
Experimental
Melting points are measured on an electrothermal melting point
apparatus. Elemental analyses were carried out at the microanalytical
unit, Cairo Univeristy. The IR spectra were measured on a Unicam
1
another indication for the structure 13d.
1
SP-1200 spectrometer using the KBr wafer technique. The H NMR
Acylation of the hydrazide 3 with lauroyl chloride in reflux-
ing pyridine yielded the N-acylated product 15. The structure
15 was confirmed from the analytical and spectroscopic data.
spectra were measured in DMSO-d6 on a Varian plus instrument
(300 MHz). Mass spectra were recorded on a Shimadzu GC-MS
QP- 1000EX instrument operating at 70 eV.

68 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 3
Scheme 4
Scheme 5

JOURNAL OF CHEMICAL RESEARCH 2012 69
Scheme 6
Synthesis of S-(heteryl)thioglycollate (2)
7 h. The cooled concentrated solution was poured onto ice-water
(50 mL) and acidified with acetic acid (2 mL). The mixture was
extracted twice with chloroform (75 mL). The organic layer was dried,
concentrated and left for slow evaporation. The crude precipitate
was crystallised from light petroleum to give the oxadiazolthione
derivative 4.
3-Phenyl-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methylthio]
quinazolin-4(3H)-one (4): Yellow crystals (67% yield); m.p. 210–
213 °C. IR: υmax 3444, 3130 (NH), 1665 (C=Oquinazolin), 1262 (C=S)
cm−1. 1H NMR (DMSO-d6): δ (ppm) 4.53 (s, 2H, CH2–S–), 7.26–8.11
(m, 10H, 9ArH + NH exchangeable). MS: m/z (%) 370 (M.+ +2, 4),
369 (3.5), 368 (M.+, 14), 266 (26), 264 (89), 253 (84), 230 (86), 221
(100), 167 (45), 144 (39), 143 (79), 119 (41), 91 (35), 77 (98), 63 (16).
Anal. Calcd for C17H12N4O2S2 (368): C, 55.42; H, 3.28; N, 15.21; S,
17.41. Found: C, 55.89; H, 3.41; N, 15.09; S, 17.67%.
Fused sodium acetate (0.8 g, 0.01 mol) was added to a solution of 1
(2.54 g, 0.01 mol) and ethylchloroacetate (1.23 g, 0.01 mol) in
(50 mL) ethanol. The whole mixture was refluxed for 6h, concentrated
and left to cool. The precipitated solid was filtered off, washed with
water, dried and recrystallised from ethanol to give S-(heteryl)
thioglycollate 2.
Ethyl-2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)acetate
(2): Colourless crystals (70% yield); m.p. 105–107 °C. IR: υmax 1739
1
(C=Oester), 1690 (C=Oquinazolin) cm−1. H NMR (CDCl3): δ (ppm) 1.31
(t, 3H, CH3–CH2, J=7.2 Hz), 3.91 (s, 2H, CH2–CO), 4.24 (q, 2H,
CH3–CH2, J=6.9 Hz), 7.27–8.26 (m, 9H, ArH). MS: m/z (%) 342
(M.+ +2, 3.1), 340 (M.+, 39), 295 (17), 294 (15), 267 (42), 266 (21),
253 (48), 165 (25), 221 (56), 119 (21), 90 (37), 77 (100), 63 (16).
Anal. Calcd for C18H16N2O3S (340): C, 63.51; H, 4.74; N, 8.23; S,
9.42. Found: C, 63.76; H, 4.95; N, 8.51; S, 9.79%.
Reaction of hydrazide 3 with carbon disulfide in ethanolic potassium
hydroxide; synthesis of quinazolindione derivative (5)
Hydrazinolysis of 2; synthesis of hydrazide 3
A mixture of 2 (2.5 g, 0.008 mol) and hydrazine hydrate (0.4 g, 0.008
mol) was stirred in (50 mL) ethanol for 10h. The precipitated solid
was filtered off and recrystallised from toluene to give the hydrazide
derivatives 3.
A solution of hydrazide 3 (0.65 g, 0.002 mol) in ethanol (50 mL),
potassium hydroxide (0.1 g, 0.002 mol) and excess of carbon disulfide
(1.5 mL, 0.02 mol) were refluxed on water bath for 7h. The cooled
concentrated solution was poured onto ice-water (50 mL) and acidi-
fied with acetic acid (2 mL). The crude product was filtered off, dried
and recrystallised from ethanol to give quinazolindione derivative 5.
3-Phenylquinazolin-2,4(1H, 3H)-dione (5): Yellow crystals (60%
yield); m.p. 260–261 °C. IR: υmax 3368 (NH), 1731, 1652 (C=O) cm−1.
MS: m/z (%) 240 (M.+ +2, 4.9), 238 (M.+, 100), 146 (42), 119 (77), 92
(12). Anal. Calcd for C14H10N2O2 (238): C, 70.58; H, 4.23; N, 11.76.
Found: C, 70.71; H, 4.40; N, 11.99%. Lit. m.p. 257–260 °C.11
2-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)acetohydrazide
(3): Colourless crystals (65% yield); m.p. 180–183 °C. IR: υmax 3303,
1
3250, 3220 (NH), 1693 (C=Oquinazolin), 1663 (C=Ohydrazide) cm−1. H
NMR (DMSO-d6): δ (ppm) 3.83 (s, 2H, CH2–CO), 4.25 (br.s, 2H,
NH2, exchangeable), 7.26–8.10 (m, 9H, ArH), 9.29 (br.s, 1H, NH–CO,
exchangeable). MS: m/z (%) 328 (M.+ +2, 0.49), 326 (M.+, 7), 296
(21), 295 (100), 254 (22), 253 (81), 221 (23), 132 (43), 90 (27), 77
(70), 63 (18). Anal. Calcd for C16H14N4O2S (326): C, 58.88; H, 4.32;
N, 17.17; S, 9.82. Found: C, 58.49; H, 4.10; N, 16.99; S, 9.60%.
Synthesis of phenyl isothiosemicarbazide derivative (6)
A mixture of hydrazide 3 (0.65 g, 0.002 mol) and phenyl isothiocya-
nate (0.2 mL, 0.002 mol) was refluxed in ethanol for 1h. The reaction
mixture was left to cool, the crude solid was filtered off, washed twice
with cold ethanol, dried and recrystallised from ethanol to give phenyl
isothiosemicarbazide derivative 6.
Reaction of the hydrazide 3 with carbon disulfide in pyridine;
synthesis of oxadiazolthione derivative 4
A solution of hydrazide 3 (0.65 g, 0.002 mol) in pyridine (50 mL) and
carbon disulfide (1.5 mL, 0.02 mol) was refluxed on water bath for

70 JOURNAL OF CHEMICAL RESEARCH 2012
1-(2-(4-Oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)acetyl)-
4-phenylthiosemicarbazide (6): Yellow crystals (70% yield); m.p.
210–212 °C. IR: υmax 3316, 3274, 3179 (NH), 1688 (C=Oquinazolin),
1657 (C=Oamide), 1617 (C=N), 1260 (C=S) cm−1. MS: m/z (%) 461
(M.+, 22), 420 (24), 367 (25), 312 (31), 295 (49), 294 (100), 293 (30),
260 (33), 253 (74), 239 (26), 180 (32), 150 (47), 134 (55), 94 (34).
Anal. Calcd for C23H19N5O2S2 (461): C, 59.85; H, 4.15; N, 15.17; S,
13.89. Found: C, 60.09; H, 4.31; N, 15.38; S, 13.57%.
Cyclisation of compound (6); synthesis of triazolthione derivative
(7): A solution of 6 (0.7 g, 0.0015 mol) in ethanolic sodium hydroxide
(0.25 g in 20 mL ethanol) was heated under reflux for 3h and then left
to cool. The solid obtained was filtered off, washed with water and
recrystallised from ethanol to give triazolthione derivative 7.
3-Phenyl-2-((4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)
methylthio) quinazolin-4(3H)-one (7): Yellow crystals (79% yield);
m.p >300 °C. IR: υmax 3392 (NH), 1688 (C=Oquinazolin), 1247 (C=S)
cm−1. 1H NMR (DMSO-d6): δ (ppm) 3.90 (s, 2H, CH2–S–), 6.62–7.98
(m, 15H, 14ArH + NH exchangeable). MS: m/z (%) 445 (M.+ +2, 4.9),
443 (M.+, 14), 388 (21), 386 (100), 353 (24), 284 (41), 268 (40), 221
(69), 186 (46), 159 (43), 134 (72). Anal. Calcd for C23H17N5OS2 (443):
C, 62.28; H, 3.86; N, 15.79; S, 14.46. Found: C, 62.17; H, 3.93; N,
15.90; S, 14.80%.
ethanol (50 mL) for 7 h. The reaction mixture was left overnight for
slow evaporation. The solid product was collected, filtered off, dried
and recrystallised from light petroleum and chloroform to give
pyrazol derivatives 12a and 12b respectively.
2-(2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethylthio)-3-phenylquin-
azolin-4(3H)-one (12a): Bright yellow crystals (78% yield); m.p.
76–78 °C. IR: υmax 1688 (C=Oquinazolin), 1644 (C=Oamide) cm−1. 1H NMR
(CDCl3): δ (ppm) 1.82 (s, 3H, C5-Me), 2.08 (s, 3H, C3-Me), 4.13 (s,
2H, CH2–S) 7.2–7.6 (m, 9H, ArH), 8.2 (s, 1H, C4-Hpyrazole). MS: m/z
(%) 392 (M.++2, 0.57), 390 (M.+, 8), 296 (27), 295 (100), 294 (33), 255
(13), 253 (24), 221(24), 132 (12). Anal. Calcd for C21H18N4O2S (390):
C, 64.60; H, 4.65; N, 14.35; S, 8.25. Found: C, 64.97; H, 4.37; N,
14.72; S, 8.53%.
2-(2-(3-Methyl-5-phenyl-1H-pyrazol-1-yl)-2-oxoethylthio)-3-phen-
ylquinazolin-4(3H)-one (12b): Bright yellow crystals (55% yield);
m.p. 166–168 °C. IR: υmax 1689 (C=Oquinazolin), 1652 (C=Oamide) cm−1.
MS: m/z (%) 454 (M.++2, 0.49), 452 (M.+, 10), 439 (20), 411 (19), 403
(23), 340 (46), 328 (40), 307(52), 294 (42), 253 (100), 235 (65), 221
(66), 162 (64), 149 (80), 147(66), 132 (47), 104 (49), 97 (53). Anal.
Calcd for C26H20N4O2S (452): C, 69.01; H, 4.45; N, 12.38; S, 7.09.
Found: C, 69.30; H, 4.72; N, 12.19; S, 6.95%.
General procedure for the reaction of hydrazide 3 with aromatic
aldehydes
Reaction of hydrazide 3 with phthalic anhydride; synthesis of N-
substituted isoindolindione derivative 8
A mixture of hydrazide 3 (0.65 g, 0.002 mol) and phthalic anhydride
(0.2 g, 0.002 mol) was refluxed in dry dioxane (20 mL) for 5h. The
reaction mixture was left overnight for slow evaporation. The crude
product was recrystallised twice from light petroleum toluene mixture
to give N-substituted isoindolindione derivative 8.
N-(1,3-dioxoisoindolin-2-yl)-2-(4-oxo-3-phenyl-3,4-dihydroquin-
azolin-2-ylthio)acetamide (8): Yellowish white crystals (50% yield);
m.p. 250–252 °C. IR: υmax 3185 (NH), 1793, 1738, 1684 (C=O) cm−1.
1H NMR (DMSO-d6): δ (ppm) 3.99 (s, 2H, CH2–S–), 7.27–7.89 (m,
13H, ArH), 9.82 (s, 1H, NH, exchangeable). MS: m/z (%) 456 (M.+, 4),
296 (27), 295 (100), 253 (17), 221 (21), 132 (39), 104 (48), 89 (20).
Anal. Calcd for C24H16N4O4S (456): C, 63.15; H, 3.53; N, 12.27; S,
7.02. Found: C, 63.27; H, 3.68; N, 12.08; S, 6.90%.
A solution of hydrazide 3 (0.65 g, 0.002 mol) in dioxane (30 mL)
and salicylaldehyde (0.2 g, 0.002 mol) or 2,6-dichlorobenzaldehyde
(0.3 g, 0.002 mol) or p-anisaldehyde (0.12 g, 0.002 mol) was refluxed
in presence of (0.2 mL) triethylamine for 24h. The precipitate formed
was dried and recrystallised from light petroleum–toluene mixture to
give N′-arylidene-2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)
acetohydrazide 13a, 13b and 13c respectively.
N′-(2-hydroxybenzylidene)-2-(4-oxo-3-phenyl-3,4-dihydroquinazo-
lin-2-ylthio) acetohydrazide (13a): Yellow crystals (85% yield); m.p.
215–217 °C. IR: υmax 3444 (OH), 3177 (NH), 1678 (C=Oquinazolin), 1655
1
(C=Oamide) cm−1. H NMR (DMSO-d6): δ (ppm) (E-form, 55%) 4 (s,
2H, –CH2–S), 6.89–8.09 (m, 13H, ArH), 8.47 (s, 1H, =CH), 10.99 (s,
1H, -OH, exchangeable), 11.95 (s, 1H, NH, exchangeable); (Z-form,
45%) 8.34 (s, 1H, =CH), 10.08 (s, 1H, -OH, exchangeable), 11.60 (s,
1H, NH, exchangeable). MS: m/z (%) 432 (M.++2, 0.72), 430 (M.+, 8),
297 (10), 296 (21), 295 (100), 253 (30), 132 (40), 77(48). Anal. Calcd
for C23H18N4O3S (430): C, 64.17; H, 4.21; N, 13.01; S, 7.45. Found: C,
64.40; H, 4.45; N, 12.89; S, 7.67%.
Synthesis of iminopyrazolidin derivative 10
A mixture of hydrazide 3 (0.65 g, 0.002 mol), acrylonitrile (0.114 g,
0.002 mol) was refluxed for 3h. The reaction mixture was left over-
night for slow evaporation. The formed solid residue was recrystal-
lised from light petroleum–toluene mixture to give iminopyrazolidin
derivative 10.
2-(2-(5-Iminopyrazolidin-1-yl)-2-oxoethylthio)-3-phenylquinazo-
lin-4(3H)-one (10): Yellow crystals (70% yield); m.p. 224–226 °C.
IR: υmax 3190 (NH), 1687 (C=O) cm−1. MS: m/z (%) 380 (M.++1, 8),
379 (M.+, 14), 295 (31), 254 (49), 253 (90), 235 (30), 225 (16),
221(49), 181 (21), 167 (90), 166 (50), 162 (36), 145 (31), 144 (100),
134 (20), 132 (28), 119 (45), 92 (40), 90 (59), 77 (75). Anal. Calcd for
C19H17N5O2S (379): C, 60.14; H, 4.52; N, 18.46; S, 8.45. Found: C,
60.39; H, 4.87; N, 18.79; S, 8.20%.
N′-(2,6-dichlorobenzylidene)-2-(4-oxo-3-phenyl-3,4-dihydroquin-
azolin-2-ylthio) acetohydrazide (13b): Yellow crystals (80% yield);
m.p. 208–210 °C. IR: υmax 3189 (NH), 1684 (C=Oquinazolin), 1657
1
(C=Oamide) cm−1. H NMR (DMSO-d6): δ (ppm) (E-form, 82%) 4.43
(s, 2H, –CH2–S), 7.43–8.08 (m, 12H, ArH), 8.31 (s, 1H, =CH), 11.87
(s, 1H, NH, exchangeable); (Z-form, 18%) 8.45 (s, 1H, =CH), 12.02
(s, 1H, NH, exchangeable). MS: m/z (%) 482 (M.+, 0.86), 451 (15),
409 (10), 311 (17), 297 (43), 295 (100), 268(18), 264 (15), 221 (17),
132 (43), 91 (18), 90 (22), 77(47). Anal. Calcd for C23H16Cl2N4O2S
(482): C, 57.15; H, 3.34; N, 11.59; S, 6.63. Found: C, 57.40; H, 3.59;
N, 11.77; S, 6.39%.
(E)-N′-(4-methoxybenzylidene)-2-(4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-ylthio)acetohydrazide (13c): Yellow crystals (82%
yield); m.p. 217–219 °C. IR: υmax 3172 (NH), 1680 (C=Oquinazolin), 1645
(C=Oamide) cm−1. MS: m/z (%) 446 (M.++2, 0.9), 444 (M.+, 20), 296
(20), 295 (100), 253 (25), 221 (16), 144 (29), 132 (26), 120 (23), 104
(18), 91 (30), 77(38). Anal. Calcd for C24H20N4O3S (444): C, 64.85; H,
4.54; N, 12.60; S, 7.21. Found: C, 65.19; H, 4.80; N, 12.93; S,
7.09%.
Reaction of 3 with methyl cinnamate; synthesis of pyrazolidinone
derivative 11
A mixture of hydrazide 3 (0.65 g, 0.002 mol) and methyl cinnamate
(0.23 g, 0.002 mol) was fused in sand bath for 4h at 180–190 °C. The
residue was treated with hot light petroleum–toluene mixture (50 mL).
The formed crystals were collected, dried and crystallised from
toluene to give pyrazolidinone derivative 11.
2-(2-Oxo-3-(phenyl-2,5- dihydro pyrazol-1-yl)ethylthio)-3-phenyl-
quinazolin-4(3H)-one (11): Yellow crystals (56% yield); m.p. 258–
260 °C. IR: υmax 2220 (NH), 1690, 1641 (C=O) cm−1. 1H NMR
(DMSO-d6): δ (ppm) 3.78 (s, 2H, CH2–S–), 7.26–8.23 (m, 15H, ArH),
10.71 (br.s, 2H, NH, exchangeable). MS: m/z (%) 456 (M.++2, 3), 454
(M.+, 65), 253 (93), 231 (76), 221 (92), 145 (67), 143 (79), 134(68),
109 (67), 105 (67), 85 (67), 77 (83), 75 (91), 62 (75), 61 (100), 57
(72), 55 (65), 52 (71), 49 (89). Anal. Calcd for C25H18N4O3S (454):
C, 66.07; H, 3.99; N, 12.33; S, 7.05. Found: C, 66.29; H, 4.15; N,
12.70; S, 7.19%.
The reaction of hydrazide 3 with 2-(3,4-dimethoxybenzylidene)malon
onitrile
A solution of hydrazide 3 (0.65 g, 0.002 mol) and 2-(3,4-dimethoxy
benzylidene)malononitrile (0.2 g, 0.002 mol) in pyridine (10 mL) was
refluxed for 8h. The reaction mixture was acidified with ice cold
hydrochloric acid. The solid product obtained was filtered off
and recrystallised from ethanol to give 13d as a mixture of E and Z
isomers. The same product 13d was obtained when the hydrazide 3
refluxed with 3,4-dimethoxy benzaldehyde in pyridine.
N′-(3,4-dimethoxybenzylidene)-2-(4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-ylthio)acetohydrazide (13d): Yellow crystals (50%
yield); m.p. 220–222 °C. IR: υmax 3180 (NH), 1681 (C=Oquinazolin), 1645
General procedure for the reaction of hydrazide 3 with acetyl acetone
or benzoyl acetone; synthesis of pyrazol derivatives 12
A mixture of hydrazide 3 (0.65 g, 0.002 mol), acetyl acetone (0.2 mL,
0.002 mol) or benzoyl acetone (0.3 g, 0.002 mol) was refluxed in

JOURNAL OF CHEMICAL RESEARCH 2012 71
1
(C=Oamide) cm−1. H NMR (CDCl3): δ (ppm) (E-form, 75%) 3.88 (s,
Received 27 November 2011; accepted 12 January 2012
Paper 1101008 doi: 10.3184/174751912X13274094865293
Published online: 23 February 2012
3H, OCH3), 3.94 (s, 3H, OCH3), 4.5 (s, 2H, –CH2–S), 6.81–8.34
(m, 12H, ArH), 8.93 (s, 1H, =CH), 10.79 (s, 1H, NH, exchangeable);
(Z-form, 25%) 3.79 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 8.89 (s, 1H,
=CH), 10.75 (s, 1H, NH, exchangeable). Anal. Calcd for C25H22N4O4S
(474): C, 63.28; H, 4.67; N, 11.81; S, 6.76. Found: C, 63.51; H, 4.92;
N, 11.59; S, 6.55%.
References
1
2
3
4
5
S. El-Meligie, A.K. El-Ansary, M.M. Said and M.M. Hussein, Ind. J.
Chem., 2001, 32, 62.
A.M. Farghaly, R. Soliman, M.A.Khalil, A.A. Bekhite and A. El-Din, Boll.
Chem. Farm., 2002, 141, 372.
M.S. Amine, M.A. El-Hashash and I.A.Attia, Indian J. Chem., 1993, 32,
577.
D.R. Huron, M.E. Gorre, A.J. Kraker, C.L. Sawyers, N. Rosen and M.M.
Moasser, Clin. Cancer. Res., 2003, 9, 1267.
Acylation of 3 using lauroyl chloride
A mixture of hydrazide 3 (0.33 g, 0.001 mol) in dry pyridine (20 mL)
and lauroyl chloride (0.22 g, 0.001 mol) were refluxed for 4h. The
reaction mixture poured onto ice cold acetic acid. The solid product
was filtered off and recrystallised from petroleum ether/toluene mix-
ture to give N-acylated product 15.
E.A. Kassab, M.A. El-Hashash, F.M.A. Soliman and R.S. Ali, Egypt. J.
Chem., 2001, 44, 169.
6
7
C. Parkanyi and D.S. Schmidt, J. Heterocycl. Chem., 2000, 37, 725.
H. Kikuchi, H. Tasaka, S. Hirai, Y. Takaya, Y. Lwabuchi, H. Oie, S.
Hatakeyama, H.S. Kim,Y. Wataya andY. Oshima, J. Med. Chem., 2002, 45,
2563.
N′-(2-(4-oxo-3-phenyl-3,4-dihydroquinazolin-2-ylthio)acetyl)
dodecane hydrazide (15): Yellowish white crystals (65% yield);
m.p. 120–121 °C. IR: υmax 3210, 3195 (NH), 1701 (C=Oquinazolin), 1650
1
(C=Oamide) cm−1. H NMR (DMSO-d6): δ (ppm) 0.87 (t, 3H, CH3,
8
9
S. John, Rodd’s chemistry of carbon compounds, ed. M.F. Ansell, Elsevier:
Amsterdam, 1955, Vol. IXI, 223.
W.L.F. Armarego, Adv. Heterocycl. Chem., 1979, 25, 1.
J = 6.6 Hz), 1.24–1.48 (m, 18H, 9 CH2), 2.05–2.17 (m, 2H, CH2CO),
3.94 (s, 2H, CH2–S), 7.44–8.01 (m, 9H, ArH), 9.80 (s, 1H, NH,
exchangeable), 10.1 (s, 1H, NH exchangeable). Anal. Calcd for
C28H36N4O3S (508): C, 66.11; H, 7.13; N, 11.01; S, 6.30. Found: C,
66.40; H, 7.39; N, 11.21; S, 6.17%.
10 S.K. Pandey, A. Singh and A.S. Nizamuddin, Eur. J. Med. Chem., 2009, 44,
1188.
11 T.L. Cairns, D.D. Coffman and W.W. Gilbert, J. Am. Chem. Soc., 1957, 79,
4405.

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