Synthesis and antibacterial activity of some new 4(3H)quinazolin-4-one derivatives

Article abstract of DOI:10.1080/10426500802243182

2-Phenylamino-6,8-dibromo-4H-3,1-benzoxazinone has been reacted with nitrogen nucleophiles, such as hydrazine hydrate, amines, and formamide, yielding 4(3H)quinazolinone derivatives; and with sulfur nucleophiles producing the corresponding thioesters. The

Full text of DOI:10.1080/10426500802243182

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Phosphorus, Sulfur, and Silicon
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Synthesis and Antibacterial
Activity of Some New
4(3H)Quinazolin-4-one
Derivatives
M. E. Azab a , E. A. Kassab b , M. A. El-Hashash a &
R. S. Ali b
a Organic Synthetic Laboratory, Chemistry
Department, Faculty of Science, Ain Shams
University, Cairo, Egypt
b Helwan University, Industrial Education College,
Ammeria, Cairo, Egypt
Version of record first published: 19 Feb 2009.
To cite this article: M. E. Azab , E. A. Kassab , M. A. El-Hashash & R. S. Ali (2009):
Synthesis and Antibacterial Activity of Some New 4(3H)Quinazolin-4-one Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:3, 610-625
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Phosphorus, Sulfur, and Silicon, 184:610–625, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802243182
Synthesis and Antibacterial Activity of Some New
4(3H)Quinazolin-4-one Derivatives
M. E. Azab,1 E. A. Kassab,2 M. A. El-Hashash,1
and R. S. Ali2
1Organic Synthetic Laboratory, Chemistry Department, Faculty of
Science, Ain Shams University, Cairo, Egypt
2Helwan University, Industrial Education College, Ammeria, Cairo,
Egypt
2-Phenylamino-6,8-dibromo-4H-3,1-benzoxazinone has been reacted with nitro-
gen nucleophiles, such as hydrazine hydrate, amines, and formamide, yielding
4(3H)quinazolinone derivatives; and with sulfur nucleophiles producing the corre-
sponding thioesters. The behavior of aminoquinazolinone and 4(3H)quinazolinone
towards some carbon electrophiles under different conditions has been studied.
Keywords Antibacterial; nitrogen nucleophiles; quinazoline
INTRODUCTION
Potent benzoxazinones are inhibitors for human leukocyte elastase
(HLE),1 human Cathepsin G, and bovine chymotrypsin.2 Also, the in-
hibition of chymotrypsin-like and elastase-like serine proteases by 4H-
3,1-benzoxazinones has been investigated.3
In addition, many fused pyrimidines such as quinazolines and
quinazolinones have been reported to exhibit anti-inflammatory,4
antimicrobial,5 anticancer,6 and antimalarial7 activities. 3H-
Quinazoline-4-one is a frequently encountered unit in natural
products such as L-vasicinone8 and chrysogine.9
For the above-mentioned findings and in continuation of our
program10–14 on the synthesis of novel heterocyclic systems exhibiting
biological activity, we synthesize a varieties of quinazolinone deriva-
tives via the interaction of the benzaxazinone derivative 1 with dif-
ferent nitrogen nucleophiles, with the aim of obtaining more precise
Received 31 August 2007; accepted 30 April 2008.
Address correspondence to M. E. Azab, Organic Synthetic Laboratory, Chem-
istry Department, Faculty of Science, Ain Shams University, Cairo, Egypt. E-mail:
meazab ali@yahoo.com
610

New 4(3H)Quinazolin-4-one Derivatives
611
information about the course of the reaction and some interesting phar-
maceutical compounds.
RESULTS AND DISCUSSION
The interaction of 3,5-dibromoanthranilic acid with phenyl iso-
cyanate in boiling toluene afforded 6,8-dibromo-2-(phenylamino)-4H-
benzo[d][1,3]oxazin-4-one (1). The structure of compound 1 was in-
ferred from its IR spectrum, which reveals strong absorption bands at
1646, 1749, and 3286 cm−1 attributable to νC N, νC O, and νNH respec-
1
tively. H-NMR (CDCl3) displayed the following peaks at δ: 7.28–8.31
(m, 7H, Ar-H) and 8.97 (br. s, 1H, NH, D2O exchangeable). Electron
impact fragmentation of compound 1 exhibits the molecular ion peak
m/e, M+ (394, 43.5%), M+2 (396, 78.2%), and M+4 (398, 41.8%).
When compound 1 was allowed to react with hydrazine hydrate
(in boiling EtOH), semicarbazide, and/or thiosemicarbazide (in boil-
ing pyridine), it yielded 3-amino-quinazolinone 2, 1,2,4-triazolo[5,1-
b]quinazolinone 3, and thiourea derivative 4, respectively (Scheme 1).
Alternatively, reaction of 1 with formamide and/or primary amines,
namely, 2-chloroaniline and isobutylamine, produced the quinazolinone
derivatives 5 and6a,b, respectively (Scheme 2). Formation of 6a,b takes
SCHEME 1

612
M. E. Azab et al.
SCHEME 2
place via hetero-ring opening followed by cyclization, while the benzox-
azinone 1 undergoes hetero-ring opening upon treatment with piperi-
dine (secondary amine) in boiling ethanol to give the aniline derivative
7 (Scheme 2).
The behavior of the benzoxazinone 1 with aliphatic and aromatic
mercaptans was also investigated. Thus, when compound 1 was allowed
to react with 2-aminothiophenol and/or thioglycolic acid in dry toluene,
it underwent hetero-ring opening producing thiobenzoate derivatives
8 and 9, respectively (Scheme 3).
Also, in this investigation, we used 3-aminoquinazolinone deriva-
tive 2 as a key starting material for synthesis of 3-substituted quina-
zolinone derivatives and annulated fused quinazolinone compounds.
Thus, reactions of 2 with active methyl and methylene compounds were
studied, which afforded different compounds according to the pathway
of the reaction, wherein reaction with diethyl malonate gave the 2-
substituted quinazolinone derivative 10 as a result of losing ethanol
molecule.
Alternatively, refluxing 2 with acetylacetone furnished the bridge-
head nitrogen compound 11. Formation of the triazoloquinazolinone
11 takes place via condensation of acetylacetone with the amino group
followed by ring closure and deacetonylation, while treatment of the

New 4(3H)Quinazolin-4-one Derivatives
613
SCHEME 3
quinazolinone 2 with diacetyl in boiling ethanol yielded the triazino-
quinazolinone 12. Formation of 12 takes place via condensation fol-
lowed by elimination of the phenol molecule yielding the more thermo-
dynamically stable compound (Scheme 4).
SCHEME 4

614
M. E. Azab et al.
SCHEME 5
Treatment of the quinazolinone 2 with aromatic aldehydes,
namely cinnamaldehyde, 4-N,N-dimethylaminobenzaldehyde and/or
2-hydroxy-1-naphthaldehyde, afforded 5-aryl-triazoloquinazolinone
derivatives 13a–c. The reaction possibly takes place through non-
isolated intermediate arylidene amino derivative followed by cycliza-
tion, and dehydrogenation yielded the more thermodynamically stable
annulated quinazolinone.
Interaction of aminoquinazolinone derivative 2 with phenylisoth-
iocyanate in boiling ethanol provided 3-substitutedquinazolinone 14
(Scheme 5).
As an extension of this investigation, when quinazolinone 5 was
submitted to react with ethyl chloroacetate in refluxing dioxin, in the
presence of potassium carbonate, yielded the ester 15. Isolation of com-
pound 15 as a sole product suggests that the lactam form (ketoform) is
the predominant one15 (ketoform is more stable than the enol form by
about 10 kcal/mol). Hydrazinolysis of compound 15 in boiling ethanol
produced the hydrazide derivative 16 (Scheme 6).
SCHEME 6

New 4(3H)Quinazolin-4-one Derivatives
615
SCHEME 7
The hydrazide 16 was used as versatile starting material for prepar-
ing different quinazolinone derivatives. Thus, reaction of compound 16
with phenyl-isothiocyanate gives the thiourea derivative 17. Treatment
of compound 17 with sodium hydroxide yielded 1,2,4-triazole-4(3H)-
quinazolinone derivative 18 (Scheme 7).
On the other hand, reaction of the hydrazide16 with carbon disul-
fide in the presence of potassium hydroxide yielded the potassium salt
of dithioic acid 19, which reacts with methyl iodide to furnish the
dithioester 20 (Scheme 7).
Furthermore, when compound 16 was refluxed with potassium thio-
cyanate in the presence of hydrochloric acid, it afforded the thioamide
derivative 21.
Finally, reacting 16 with 4-methoxy-benzaldehyde and 2-hydroxy-
1-naphthaldehyde in boiling ethanol afforded 1,3,4-oxadiazole-
4(3H)quinazolinone derivatives 23a,b respectively. The reaction takes
place through the formation of the fleeting intermediate 22 followed by
cyclization via addition of enolic hydroxyl group to azaolefinic double
bond (Scheme 8).
ANTIBACTERIAL ACTIVITY
The behavior of the newly synthesized compounds as antibacterial has
been investigated at the Medical Mycology Lab, The Regional Center
for Mycology and Biotechnology, Alazhar University.
The new synthesized compounds were screened in vitro for their
antibacterial activities against four strains of bacteria Staphylococ-
cus aureus (NCTC-7447), Bacillus subtillis (NCTC 10400), Proteus
mirabilis (NCTC-289), and Escherichia coli (NCTC 10416) by the agar

616
M. E. Azab et al.
SCHEME 8
diffusion technique.16 1, 2.5, and 5 mg/mL solutions in dimethylfor-
mamide (DMF) were used. The bacteria were maintained on nutrient
agar media. DMF showed no inhibition zones. The agar media was in-
cubated with different microorganisms and culture tested. After 24 h
of incubation at 30◦C, the diameter of the inhibition zone was mea-
sured. Chloramphenicol was used as a reference of antibacterial activ-
ity. The minimal inhibitory concentration (MIC) of some of the tested
compounds was measured by a twofold serial dilution method.17 Most
of synthesized compounds exhibited antibacterial activity towards all
the microorganisms used. The results are presented in Table I.
EXPERIMENTAL
All melting points reported are uncorrected and were determined on
a Stuart electric melting point apparatus. The microanalyses were
within 0.4% of theoretical values and were measured at the Mi-
croanalytical Unit of the Faculty of Science, Cairo University. The IR
spectra were measured on a Shimadzu FT-IR 8101 PC using the KBr
wafer technique. The mass spectra were recorded on Shimadzu GCMS-
1
QP-1000EX mass spectrometer at 70 eV. The H-NMR spectra were
recorded on a Varian 300 MHz instrument in (CDCl3) or (DMSO-d6)
as solvents, using TMS as internal standard with chemical shifts (δ)
expressed in ppm. TLC was performed on ready-to-use silica gel plates
(Merck 60) to monitor the reactions and test the purity of the new
synthesized compounds. Physical data for the synthesized compounds
are given in (Table II).

617

618
M. E. Azab et al.
TABLE II Physical Data for the Synthesized Compounds
Analysis % Calc./Found
Compd.
No.
∗Solvent/
color
Formula
M. Wt.
Mp ◦
C
C
H
N
Br/Cl/S
1
276
252
222
196
Toluene
Yellow
Butanol
White
Toluene
Brown
Ethanol
White
C14H8N2O2Br2
(396)
42.42 2.02
42.13 1.83
40.98 2.44 13.66
41.26 2.61 13.41
41.38 2.07 16.09
41.66 2.30 15.79
7.07
6.81
40.40
40.12
39.02
38.78
36.78
36.41
2
C
14H10N4OBr2
(410)
3
C
15H9N5OBr2
(435)
4
C15H11N5OSBr2 38.38 2.35 14.93 34.12/—/6.82
(469)
14H9N3OBr2
(395)
38.04 2.56 15.21 33.74/—/6.55
42.53 2.28 10.63
42.31 2.09 10.25
5
Over Dioxan
300
224
C
40.51
40.17
31.65/7.02
31.41/6.79
35.47
35.70
33.26
32.97
Pale brown
Toluene
White
Toluene
White
Toluene
White
Pet. 8-100
White
Dioxan
White
Butanol
White
Toluene
Brown
6a
6b
7
C
20H12N3OBr2Cl 47.48 2.37
8.31
8.60
9.31
9.52
8.73
8.50
(505.5)
18H17N3OBr2
(451)
47.12 2.51
47.89 3.77
48.17 3.59
218
172
160
216
230
162
216
244
266
C
C
19H19N3O2Br2 47.40 3.95
(481) 47.64 4.17
20H15N3O2SBr2 46.07 2.88
(521) 45.78 2.61
16H12N2O4SBr2 39.34 2.46
(488) 39.05 2.60
8
C
C
8.06 30.71/—/6.14
7.81 30.34/—/6.31
5.74 32.79/—/6.56
5.99 33.00/—/6.72
9
10
11
12
13a
13b
13c
14
15
16
17
18
C
19H16N4O4Br2 43.51 3.05 10.68
30.53
30.22
36.87
37.15
41.67
41.92
30.75
31.04
29.68
29.42
28.47
28.18
29.36
29.09
33.26
33.52
34.26
34.54
(524)
16H10N4OBr2
(434)
43.12 2.87 10.44
44.24 2.30 12.90
44.45 2.52 13.16
37.50 2.08 14.58
37.24 1.92 14.75
52.87 2.68 10.73
53.13 2.55 10.92
51.21 3.15 12.99
50.89 3.34 13.26
C
Toluene
Brown
Toluene
Brick red
Butanol
Deep yellow
C
12H8N4OBr2
(384)
C
C
23H14N4OBr2
(522)
23H17N5OBr2
(539)
Over Dioxan
300
260
C
25H14N4O2Br2 53.38 2.49
(562) 53.56 2.63 10.11
21H15N5OBr2S 46.24 2.75 12.84
(545) 45.95 2.56 13.14
18H15N3O3Br2 44.91 3.12
(481) 45.18 2.99
9.96
Yellow
D.M.F
White
Benzen
White
C
C
C
176
8.73
9.01
Over Dioxan
300 White
Over Ethanol
300
224
16H13N5O2Br2 41.11 2.78 14.99
(467) 40.84 2.94 15.21
C
23H18N6O2SBr2 45.85 2.99 13.95 26.58/—/5.32
(602) 46.09 3.13 13.69 26.91/—/5.55
Pale yellow
Ethanol
C
23H18N6OSBr2 47.26 3.08 14.38 27.40/—/5.48
(Continued on next page)

New 4(3H)Quinazolin-4-one Derivatives
619
TABLE II Physical Data for the Synthesized Compounds (Continued)
Analysis % Calc./Found
Compd.
No.
∗Solvent/
color
Formula
M. Wt.
Mp ◦
—
C
C
H
N
Br/Cl/S
White
(584)
47.47 3.21 14.12 27.67/—/5.72
19
Salt
Pale yellow
C
17H12N5O2S2KBr2 35.11 2.07 12.05 27.54/—/11.02
(581) 34.80 1.91 11.87 27.75/—/10.79
18H15N5O2S2Br2 38.78 2.69 12.57 28.73/—/11.49
(557) 39.09 2.51 12.88 28.40/—/11.21
C17H14N6O2SBr2 38.78 2.66 15.97 30.42/–/6.08
20
238 Toluene
White
Over Methanol
300 White
Over Dioxan
300 Pink
C
21
(526)
24H19N5O3Br2
(585)
38.41 2.52 16.18 30.72/–/5.77
23a
23b
C
49.23 3.25 11.97
49.59 3.41 11.72
52.17 3.06 1127
52.51 3.21 10.93
27.35
27.70
25.76
25.41
Over D.M.F.
300 Deep yellow
C
27H19N5O3Br2
(621)
6,8-Dibromo-2-(phenylamino)-4H-benzo[d][1,3]oxazin-4-one
(1)
A mixture of 3,5-dibromoanthranilic acid (2.95 g, 0.01 mol) and phenyl
isocyanate (1.19 g, 0.01 mol) in dry toluene (30 mL) was refluxed for
2 h. The solid that separated after cooling was filtered off, dried, and
crystallized to afford the benzoxazine 1 (Table II).
3-Amino-6,8-dibromo-2-(phenylamino)quinazolin-4(3H)-one
(2)
A mixture of benzoxazinone (3.96 g, 0.01 mol) and hydrazine hydrate
(1 g, 0.02 mol) was heated under reflux in absolute ethanol (30 mL) for
3 h. The reaction mixture was concentrated. The solid that separated
out was filtered off, dried, and then recrystallized to afford the quina-
zolinone 2 (Table II). IR (ν/cm−1): 3436, 3305, 3203, 3170 (NH2, NH),
1
1666 (C=O), 1617 (C=N). H-NMR: 5.66 (s, 2H, NH2, D2O exchange-
able), 7.33–8.33 (m, 7H, Ar-H), 8.87 (s, 1H, NH, D2O exchangeable).
MS: (m/z, %): molecular ion peak at M+ (408, 32.4%), M+2 (410, 63.6%)
and M+4 (412, 31.2%).
2-Amino-5,7-dibromo-3-phenyl-[1,2,4]triazolo[5,1-
b]quinazolin-9(3H)-one (3) and 1-(6,8-Dibromo-4-oxo-2-
(phenylamino)quinazolin-3(4H)-yl)thiourea (4)
A mixture of benzoxazinone 1 (3.96 g, 0.01 mol), semicarbazide (0.75
g, 0.01 mol), and/or thiosemicarbazide (0.91 g, 0.01 mol) was boiled in

620
M. E. Azab et al.
pyridine (20 mL) for 4–6 h. After cooling, the reaction mixture was
poured into crushed ice/HCl. The solid that was deposited was filtered
off, dried, and crystallized to give 3 and 4, respectively (Table II).
3: IR (ν/cm−1): 3423, 3301, 3211, (NH2), 1670 (C=O), 1620 (C=N). The
1H-NMR: 5.78 (s, 2H, NH2, D2O exchangeable) and 7.35–8.29 (m, 7H,
ArH). MS, (m/z, %), M+ (435, 58.2%), M+2 (437, 100%), and M+4 (439,
58.7%).
4: IR (ν/cm−1): 3429, 3338, 3277, 3172 (NH2, NH), 1668 (C=O), 1370
(C=S). The 1H-NMR: and 7.41–8.39 (m, 7H, ArH), 8.82, 9.64, 10.73 (s,
4H, 2NH, NH2, D2O exchangeable).
6,8-Dibromo-2-(phenylamino)quinazolin-4(3H)-one (5)
A solution of benzoxazinone 1 (3.96 g, 0.01 mol) in formamide (15 mL)
was refluxed for 2 h. The reaction mixture after cooling was poured onto
ice/H2O. The solid that separated out was filtered, dried, and recrystal-
lized to give compound 5 (Table II). IR (ν/cm−1): 3274, 3169 (NH), 1681
1
(C=O). The H-NMR: and 7.22-8.31 (m, 7H, ArH), 8.85, 10.69 (s, 2H,
2NH, D2O exchangeable).
6,8-Dibromo-3-(2-chlorophenyl)-2-(phenylamino)quinazolin-
4(3H)-one (6a) and 6,8-Dibromo-3-isobutyl-2-(phenylamino)
quinazolin-4(3H)-one (6b)
A mixture of benzoxazinone 1 (3.96 g, 0.01 mol) and amines, namely
2-chloroaniline (1.28, 0.01 mol) and/or isobutylamine (0.73 g, 0.01 mol),
was refluxed in ethanol (30 mL) for 6–8 h. The reaction mixture was
concentrated. The solid that separated out was filtered off, dried, and
then recrystallized to afford the quinazolinone 6a,b (Table II).
6a: IR (ν/cm−1): 3274, 3211 (NH), 1678 (C O). The 1H-NMR: 7.35–8.29
(m, 7H, ArH) and 8.78 (s, 2H, NH2, D2O exchangeable). MS, (m/z, %),
M+ (503, 1.9%), M+2 (505, 4.2%), and M+4 (507, 1.7%).
6b: IR (ν/cm−1): 3277, 3207 (NH), 1676 (C O). MS, (m/z, %), M+ (449,
12.5%), M+2 (451, 23.2%), and M+4 (453, 11.7%).
1-(2,4-Dibromo-6-(piperidine-1-carbonyl)phenyl)-3-phenylurea
(7)
A solution of benzoxazinone 1 (3.96 g, 0.01 mol) and piperidine (0.85 g,
0.01 mol) in ethanol (30 mL) was heated under reflux for 4 h. The solid
separated on cooling was crystallized to provide 7 (Table II). IR (ν/cm−1):
1
3246, 3199 (NH), 1675 (C=O). The H-NMR: 1.61 (m, 6H, piperidine),

New 4(3H)Quinazolin-4-one Derivatives
621
3.88 (m, 4H, CH2-N-CH2), 7.24–8.32 (m, 7H, ArH) and 8.89, 9.12 (s,
2H, NH, D2O exchangeable).
2-Aminophenyl-3,5-dibromo-2-(3-phenylureido)benzothioate
(8) and 2-(3,5-Dibromo-2-(3-phenylureido)benzoylthio)acetic
acid (9)
A solution of benzoxazinone 1 (3.96, 0.01 mol), 2-aminothiophenol (1.88
g, 0.015 mol), and/or thioglicolic acid (1.38 g, 0.015 mol) in dry toluene
was stirred for 3–4 h. The solid separated was filtered off, washed by
dry toluene, dried, and crystallized to give 8 and9 (Table II).
8: IR (ν/cm−1): 3432, 3341, 3264, 3179 (NH2, NH), 1654, 1676 (C=O).
1
The H-NMR: 5.77 (br., 2H, NH2, D2O exchangeable), 7.22–8.41 (m,
11H, ArH) and 8.81, 9.08 (s, 2H, 2NH, D2O exchangeable). MS, (m/z,
%), M+ (519, 23.3%), M+2 (521, 41.2%), and M+4 (523, 21.7%).
9: IR (ν/cm−1): 2567–3488 (NH, OH acid) 1658, 1671 (C=O). The
1H-NMR: 4.12 (s, 2H, S-CH2-), 7.26–8.39 (m, 7H, ArH) and 8.91,
9.13 (s, 2H, NH, D2O exchangeable) and 12.34 (br.s, 1H, OH, D2O
exchangeable).
Ethyl 3-(6,8-dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-
ylamino)-3-oxopropanoate (10)
A mixture of quinazolinone 2 (4.1 g, 0.01 mol) and diethylmalonate
(10 mL) was refluxed for 4 hr. After cooling, the solid was filtered off,
washed with methanol, dried, and crystallized to give 10 (Table II).
1
IR (ν/cm−1): 3256, 3187 (NH), 1671, 1692, 1731 (C=O). The H-NMR:
1.32 (d, 3H, OCH2CH3, J = 6.1 Hz), 3.78 (s, 2H, CO-CH2-), 4.25 (t, 2H,
OCH2CH3, J = 8.3 Hz), 7.24–8.37 (m, 7H, ArH) and 8.86, 10.57 (s, 2H,
NH, D2O exchangeable).
5,7-Dibromo-2-methyl-3-phenyl-[1,2,4]triazolo[5,1-
b]quinazolin-9(3H)-one (11) and 6,8-Dibromo-2,3-
dimethyl-10H-[1,2,4] triazino[3,2-b]quinazolin-10-one (12)
A mixture of quinazolinone 2 (4.1 g, 0.01 mol), acetyl acetone (5 mL),
and/or diacetyl (0.86 g, 0.01 mol) in ethanol (30 mL) was refluxed for
2–3 h. After cooling, the precipitate was filtered off, washed with cold
ethanol, dried, and crystallized to produce 11 and 12 (Table II).
1
11: IR (ν/cm−1): 1688 (C O), 1621 (N N). The H-NMR: 2.33 (s, 3H,
CH3), 7.26–8.34 (m, 7H, ArH).

622
M. E. Azab et al.
1
12: IR (ν/cm−1): 1682 (C O), 1619 (N N). The H-NMR: 2.29 (s, 6H,
2CH3), 8.21, 8.39 (s, 2H, ArH). MS, (m/z, %), M+ (382, 34.2%), M+2
(384, 63.8%), and M+4 (386, 31.7%).
5,7-Dibromo-3-phenyl-2-styryl-[1,2,4]triazolo[5,1-b]quinazolin-
9(3H)-one (13a), 5,7-Dibromo-2-(4-(dimethylamino)phenyl)-
3-phenyl-[1,2,4]triazolo[5,1-b]quinazolin-9(3H)-one (13b), and
5,7-Dibromo-2-(2-hydroxynaphthalen-1-yl)-3-phenyl-
[1,2,4]triazolo[5,1-b]-quinazolin-9(3H)-one (13c).
A mixture of the quinazolinone 2 (4.1 g, 0.01 mol) and aromatic alde-
hydes, namely cinnimaldehyde (1.6 g, 0.012 mol), 4-N,N-dimethyl-
aminobenzaldehyde (1.7 g, 0.012 mol), and/or 2-hydroxy-1-naphthal-
dehyde (2.07 g, 0.012 mol) was placed in absolute ethanol (50 mL) con-
taining (1 mL) pipridine and refluxed for 4–6 h. The crystalline solid
that was obtained after cooling was collected by filtration, dried, and
recrystallized to afford 13a–c, respectively (Table II).
13a: IR (ν/cm−1): 1671 (C O), 1612 (N N).
1
13b: IR (ν/cm−1): 1676 (C O), 1610 (N N). The H-NMR: 3.59 (s, 6H,
2CH3), 7.34–8.45 (s, 11H, ArH).
13c: IR (ν/cm−1): 1676 (C O), 1610 (N N). The 1H-NMR: 7.26–8.39 (s,
13H, ArH) and 10.84 (s, 1 H, OH, D2O exchangeable). MS, (m/z, %), M+
(560, 51.3%), M+2 (562, 100%), and M+4 (564, 46.7%).
1-(6,8-Dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-yl)-3-
phenylthiourea (14)
A mixture of quinazolinone 2 (4.1 g, 0.01 mol) and phenyl isothiocyanate
(1.35 g, 0.01 mol) in ethanol (30 mL) was refluxed for 2–3 h. After
cooling, the precipitate was filtered off, washed with cold ethanol, dried,
and crystallized to produce 14 (Table II). IR (ν/cm−1): 3288, 3245, 3191
(NH), 1676 (C O), 1614 (N N). The 1H-NMR: 7.28–8.32 (s, 12H, ArH)
and 8.87, 9.54, 10.61 (s, 3H, 3 NH, D2O exchangeable).
Ethyl 2-(6,8-dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-
yl)acetate (15)
A mixture of quinazolinone 5 (3.95 g, 0.01 mol), ethyl chloroacetate (4.9
g, 0.04 mol), and anhydrous potassium carbonate (5.5 g, 0.04 mol) in
dioxin (50 mL) was heated under reflux for 24 h. The reaction mixture
was concentrated, filtered off, dried, and recrystallized to afford quina-
zolinone 15 (Table II). IR (ν/cm−1): 3263, 3199 (NH), 1687, 1730(C O).

New 4(3H)Quinazolin-4-one Derivatives
623
The 1H-NMR: 1.31 (d, 3H, OCH2CH3, J = 6.3 Hz), 4.06 (s, 2H, N-CH2-
CO), 4.28 (t, 2H, OCH2CH3, J = 8.2 Hz), 7.28–8.34 (m, 7H, ArH) and
8.91, (s, H, NH, D2O exchangeable).
2-(6,8-Dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-
yl)acetohydrazide (16)
A mixture of quinazolinone 15 (4.81 g, 0.01 mol) and hydrazine hydrate
(1.0 g, 0.02 mol) in absolute ethanol (30 mL) was heated under reflux
for 3 h. The reaction mixture was concentrated, filtered off, dried, and
crystallized to give 16 (Table II). IR (ν/cm−1): 3432, 3343, 3253, 3177
1
(NH2, NH), 1654, 1677 (C O). The H-NMR: 4.12 (s, 2H, N-CH2-CO),
5.31 (br., 2H, NH2, D2O exchangeable), 7.28–8.31 (m, 7H, ArH) and
8.89, 9.37 (s, 2H, 2NH, D2O exchangeable). MS, (m/z, %), M+ (465,
2.7%), M+2 (467, 4.5%), and M+4 (523, 2.1%).
2-(2-(6,8-Dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-
yl)acetyl)-N-phenylhydrazine-carbothioamide (17)
An equimolecular quantity of the acetohydrazide 16 (4.67, 0.01 mol) and
phenyl isothiocyanate (1.35 g, 0.01 mol) in dioxin (40 mL) was refluxed
for 6 h. The reaction mixture was cooled at room temperature, and the
fine crystals that was separated out were filtered off and recrystallized
to furnish 17 (Table II). IR (ν/cm−1): 3307, 3283, 3242, 3189 (NH), 1666,
1679 (C O). The 1H-NMR: 4.08 (s, 2H, N-CH2-CO), 7.27–8.32 (m, 12H,
ArH) and 8.86, 9.59, 10.77, 11.89 (s, 4H, 4NH, D2O exchangeable).
6,8-Dibromo-3-((4-phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl)methyl)-2-(phenyl-amino)quinazolin-4(3H)-one (18)
Carbothioamide 17 (6.02 g, 0.01 mol) was refluxed in sodium hydrox-
ide solution (4%, 25 mL) for 3 h. The resulting solution was treated
with charcoal, filtered, and cooled. The filtrate was acidified with hy-
drochloric acid to pH 5–6. The solid deposited was filtered, dried, and
recrystallized to give 18 (Table II). IR (ν/cm−1): 3238, 3178 (NH), 1676
1
(C=O). The H-NMR: 3.77 (s, 2H, N-CH2-), 7.30–8.35 (m, 12H, ArH)
and 8.91, 12.93 (s, 2H, 2NH, D2O exchangeable). MS, (m/z, %), M+ (582,
7.3%), M+2 (584, 12.7%), and M+4 (586, 6.5%).

624
M. E. Azab et al.
Potassium 2-(2-(6,8-Dibromo-4-oxo-2-(phenylamino)
quinazolin-3(4H)-yl)acetyl)hydrazine-carbodithioate (19)
Carbon disulfide (11.4 g, 0.15 mol) was added dropwise to an ice-cold
solution of 16 (4.67 g, 0.01 mol) in alc. KOH (5.6 g, 0.1 mol in 5 mL
C2H5OH). The whole mixture was stirred at room temperature for 2 h.
Dry ether (50 mL) was added, and the separated solid was filtered off
to give 19 (Table II).
Methyl 2-(2-(6,8-Dibromo-4-oxo-2-(phenylamino)quinazolin-
3(4H)-yl)acetyl)hydrazine-carbodithioate (20)
Methyl iodide (1.42 g, 0.01 mol) was added to a stirred solution of the
potassium salt 19 (5.81 g, 0.01 mol) in (50 mL) of water. After 1 h, the
white solid was filtered, washed with water, and recrystallized to give
20 (Table II). IR (ν/cm−1): 3332, 3247, 3184 (NH), 1655, 1679 (C=O).
1
The H-NMR: 2.87 (s, 3H, S-CH3), 4.16 (s, 2H, N-CH2-CO), 7.30–8.31
(m, 7H, ArH) and 8.89, 9.37, 11.01 (s, 3H, 3NH, D2O exchangeable). MS,
(m/z, %), M+ (555, 16.6%), M+2 (557, 30.5%), and M+4 (559, 15.1%).
2-(2-(6,8-Dibromo-4-oxo-2-(phenylamino)quinazolin-3(4H)-
yl)acetyl)hydrazinecarbothio-amide (21)
A suspension of 16 (4.67 g, 0.01 mol), potassium thiocyanate (1.94 g,
0.02 mol), hydrochloric acid (10 mL), and water (200 mL) was refluxed
for 3 h. The white solid that appeared upon cooling was filtered, dried,
and recrystallized to produce 21 (Table II). IR (ν/cm−1): 3443, 3337,
1
3261, 3191 (NH2, NH), 1667, 1684 (C=O). The H-NMR: 4.11 (s, 2H,
N-CH2-CO), 7.30–8.36 (m, 12H, ArH) and 8.88, 9.62, 10.84, 11.47 (s,
5H, 3NH, NH2, D2O exchangeable).
6,8-Dibromo-3-((5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)methyl)-2-(phenyl-amino)quinazolin-4(3H)-one
(23a) and 6,8-Dibromo-3-((5-(2-hydroxynaphthalen-1-yl)-4,5-
dihydro-1,3,4-oxadiazol-2-yl)methyl)-2-
(phenylamino)quinazolin-4(3H)-one (23b)
A mixture of quinazolinone 16 (4.67 g, 0.01 mol), p-anisaldehyde (1.63
g, 0.012 mol), and/or 2-hydroxy-1-naphthaldehyde (2.1 g, 0.012 mol) in
absolute ethanol (50 mL) containing (1 mL) piperidine was refluxed for
3–4 hr. The solid formed was filtered off and recrystallized to provide
23a,b, respectively (Table II).

New 4(3H)Quinazolin-4-one Derivatives
625
1
23a: IR (ν/cm−1): 3247, 3184 (NH), 1678 (C=O). The H-NMR: 3.71 (s,
2H, N-CH2-), 3.97 (s, 3H, O-CH3), 5.83 (s, 1H, oxadiazole), 7.27–8.33 (m,
11H, ArH) and 8.85, 9.42, 12.01 (s, 3H, 2NH, OH, D2O exchangeable).
23b: IR (ν/cm−1): 3453 (OH), 3252, 3196 (NH), 1681 (C=O). MS, (m/z,
%), M+ (619, 33.2%), M+2 (621, 60.4%), and M+4 (623, 30.5%).
REFERENCES
[1] A. Krantz, R. Spencer, T. Tam, T. Liak, L. Copp, E. Thomas, and S. Rafferty, J. Med.
Chem., 33, 464 (1990).
[2] M. Gu¨tschow and U. Neumann, Bioorg. Med. Chem., 5, 1935 (1997).
[3] U. Neumann, N. Schechter, and M. Gu¨tschow, Bioorg. Med. Chem., 9, 947 (2001).
[4] M. M. Gineinah, M. A. El-Sherbeny, M. N. Nasr, and A. R. Maarouf, Arch. Pharm.
Med. Chem., 335, 556 (2002).
[5] S. El-Meligie, A. El-Ansary, M. M. Said, and M. M. M. Hussein, Indian J. Chem.,
40B, 62 (2001).
[6] J. V. Partin, I. E. Anglin, and N. Kyprianou, J. Cancer, 88(10), 1615 (2003).
[7] H. Kikuchi, H. Tasaka, S. Hirai, Y. Takaya, Y. Lwabuchi, H. Ooi, S. Hatakeyama,
H.S. Kim, Y. Wataya, and Y. Oshima, J. Med. Chem., 45(12), 2563 (2002).
[8] S. Eguchi, T. Suzuzi, T. Okawa, Y. Matsushita, E. Yashima, and Y. Okamoto, J. Org.
Chem., 61, 7316 (1996).
[9] (a) J. Bergman and A. Brynolf, Tetrahedron, 46, 1295 (1990); (b) J. Bergman, J.
Chem. Res., 224 (S) (1997).
[10] M. R. Mahmoud, E. A. El-Bordany, M. E. Azab, and E. A. Soliman, Phosphorus,
Sulfur, and Silicon, 182, 1275 (2007).
[11] M. E. Azab, G. A. M. El-Hag Ali, and A. F. Abdel-Wahab, Acta Chemica Pharma-
ceutica, 53, 213 (2003).
[12] M. E. Azab, M. E. A. Ibraheem, and H. M. F. Madkour, Phosphorus, Sulfur, and
Silicon, 181, 1299 (2006).
[13] M. A. I. Salem, E. A. Soliman, M. B. Smith, M. R. Mahmoud, and M. E. Azab,
Phosphorus, Sulfur, and Silicon, 179, 61 (2004).
[14] A. S. Hamad and M E. Azab, Phosphorus, Sulfur, and Silicon, 173, 105 (2001).
[15] S. Eddy, B. C. Nuria, R. Jordi, and R. Enrique, Tetrahedron, 58, 2389 (2002).
[16] L. P. Carrod and F. D. Grady, Antibiotic and Chemotherapy, 3rd ed. (Churchill
Livingstone, Edinburgh, UK, 1972), p. 477.
[17] P. Courvalin, Am. Soc. Microbial News, 85, 368 (1992).