Novel quinazolinone derivatives: Synthesis and antimicrobial activity

Article abstract of DOI:10.1007/s00044-012-0079-x

4-(4-Oxo-4H-3,1-benzoxazin-2-yl)phenyl-4-methylbenzenesulfonate (2) was prepared and reacted with some primary aromatic amines, e.g., aniline, p-chloro aniline, p-methoxy aniline, p-amino benzoic acid and p-amino acetophenone. It reacted also with some he

Full text of DOI:10.1007/s00044-012-0079-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:507–519
DOI 10.1007/s00044-012-0079-x
SYMPOSIUM PAPER
Novel quinazolinone derivatives: synthesis and antimicrobial
activity
•
Osman M. O. Habib Hussein M. Hassan
•
Ahmed El-Mekabaty
Received: 26 August 2011 / Accepted: 20 April 2012 / Published online: 4 May 2012
Ó Springer Science+Business Media, LLC 2012
Abstract 4-(4-Oxo-4H-3,1-benzoxazin-2-yl)phenyl-4-met-
hylbenzenesulfonate (2) was prepared and reacted with
some primary aromatic amines, e.g., aniline, p-chloro
aniline, p-methoxy aniline, p-amino benzoic acid and
p-amino acetophenone. It reacted also with some hetero-
cyclic amines, e.g., 2-aminothiazole, 2-aminobenzothia-
zole, 5-amino-4-phenylazo-2,4-dihydropyrazol-3-one and
3-amino-2-methylquinazolinone and with diamines; e.g.,
o-phenylenediamine, p-phenylenediamine, ethylenedia-
mine, semicarbazide hydrochloride and thiosemicarbazide
under different conditions. On the other hand, compound
(2) reacted with both sodium azide and active methylene
compounds, e.g., ethylcyanoacetate and ethylacetoacetate
to give (19) and (20), respectively. All new prepared
compounds were subjected to antimicrobial activity
evaluation.
antitubercular, antihypertensive, anticancer, anti-HIV,
antiviral, anti-inflammatory and antifungal activities
(Shirodkar and Vartak Meghana, 2000; Shah et al., 1995;
Parkanyi et al., 1992; Saxena et al., 1991; Pandey et al.,
1994). Besides, they were used as analgesics, inhibitors for
cathepsin G, Human leukocyte elastase, dual selective
serotonin reuptake and potent inactivators of CIr serine
protease (Bansal et al., 2002; Gutschow and Neumann,
1997; Krantz et al., 1990; Zhou et al., 2006; Hays et al.,
1998).
On the other hand, it has been stated that compounds
containing aromatic sulfonate or sulfonamide moieties
possess high acaricidal as well as insecticidal activity
(Habib et al., 1990; Kassem et al., 1982).
Results and discussion
Keywords Benzoxazinone Á Quinazolinone Á Tetrazole Á
Thiazolidinone Á Antimicrobial activity
As a part of our interest on the synthesis of biologically
active molecules, the present investigation aims to syn-
thesize a series of products bearing both aryl sulfonate,
benzoxazinone and quinazolone moieties in the same
molecule hoping that these new products might show high
biocide activity. It has been previously stated that, the
reaction of anthranilic acid with acyl or aroyl chlorides in
dry pyridine leads to the formation of 2-substituted-3,
1-(4H)-benzoxazin-4-one derivatives or a mixture of ben-
zoxazinone and N-substituted anthranilic acid derivatives
(Bain and Smalley, 1968). This study concerns with
the synthesis of 4-(4-oxo-4H-3,1-benzoxazin-2-yl)-phenyl-
4-methylbenzenesulfonate (2) and 2-(4-(tosyloxy)benz-
amido) benzoic acid (3). Thus, p-toluene sulfonyl chloride
was reacted with p-hydroxy benzoic acid and the resulting
ester was treated with excess thionyl chloride to give the
corresponding acid chloride (1) (Wesley and Henry, 1956).
Introduction
Substituted benzoxazinone and quinazolinone derivatives
have become great importance due to their wide range of
biological activity (Farghaly et al., 1990; Gilmore et al.,
1996). Previous studies have reported that, they exhibit
O. M. O. Habib Á H. M. Hassan Á A. El-Mekabaty (&)
Department of Chemistry, Faculty of Science,
Mansoura University, Mansoura 35516, Egypt
e-mail: a_el_m11@yahoo.com
123

508
Med Chem Res (2013) 22:507–519
with p-amino benzoic acid in glacial acetic acid and fused
sodium acetate to give 4-(4-oxo-2-(4-(tosyloxy) phenyl)
quinazolin-3(4H)-yl) benzoic acid (5). The infrared spec-
trum shows stretching frequencies at 3131–3188, 1685,
1,665 and 1,612 cm-1 corresponding for –OH, C=O, CON
and C=N groups, respectively. 1H-NMR showed singlet
signal at d 12.2 (s, 1H, COOH). Furthermore, compound
(2) reacted with p-amino acetophenone in glacial acetic
acid under reflux affording 4-(3-(4-acetylphenyl)-4-oxo-
3,4-dihydroquinazolin-2-yl)phenyl-4-methylbenzenesulfo-
nate (6) (Scheme 2). The infrared spectrum of (6) revealed
absorption bands at 1,678; 1,656; 1,593 and 1,373 cm-1
corresponding for CON, C=O, C=N and –SO3 groups,
respectively. 1H-NMR showed signals at d 2.4 (s, 3H,
–CH3) and d 2.62 (s, 3H, –COCH3) and the mass spectrum
showed the molecular ion peak at m/z 510 (M?) (32.18 %).
Compound (6) undergoes condensation with some aro-
matic aldehydes namely, benzaldehyde, p-methoxy benz-
aldehyde and p-methyl benzaldehyde in sodium hydroxide
to give the corresponding cinnamoyl phenyl derivatives
(7a–c). The infrared spectrum in general revealed stretch-
ing frequencies at 1,675; 1,645; 1,610 and 1,370 cm-1
attributable to the CON; C=O (Chalcone), –C=N and –SO3
O
C
O
O S
O
Cl
CH3
1
Treatment of 1 mol of anthranilic acid with 2 mol of the
acid chloride (1) in pyridine affords 4-(4-oxo-4H-3,
1-benzoxazin-2-yl)phenyl-4-methylbenzenesulfonate (2).
While, using 1 mol of the acid chloride (1), a mixture of (2)
and 2-(4-(tosyloxy) benzamido) benzoic acid (3) were
obtained (Scheme 1).
Structures (2) and (3) were based on correct analytical
data and spectroscopic measurements. The infrared spec-
trum of (2) revealed absorption bands at 1,766 and
1,627 cm-1 characteristic for the carbonyl of lactone and
1
–C=N groups, respectively. H-NMR, showed signals at
d 2.4 (s, 3H, –CH3) and the mass spectrum of (2) showed
the molecular ion peak at m/z 393 (M?) (29.24 %). On the
other hand, the infrared spectrum of (3) showed absorption
bands at 1,665; 3,132–3,230; and 1,613 cm-1 corre-
sponding for C=O, (NH, OH) and C=N groups, respec-
1
tively. H-NMR of (3), showed signals at d 12.2 (s, 1H,
–COOH), d 2.3 (s, 3H, –CH3) and d 8.7 (s, 1H, NH). The
mass spectrum showed the molecular ion peak at
m/z = 411 (M?) (24.8 %).
1
groups, respectively. H-NMR showed in general, signals
at d 4.2 (d, 1H, CH=) and d 4.6 (d, 1H, =CH). Compounds
(7a–c) were allowed to react with hydrazine hydrate
in boiling ethanol and yielded pyrazole derivatives
(8a–c) (Scheme 2).
Fusion of benzoxazinone (2) with some primary aro-
matic amines namely, aniline, p-anisidine and p-chloro-
aniline in the presence of anhydrous zinc chloride at
120–125 °C gave 4-{3-aryl-4-oxo-3,4-dihydroquinazolin-
2-yl}phenyl-4-methylbenzenesulfonates (4a–c). Structures
(4a–c) were confirmed by correct elemental analyses and
spectroscopic results. The infrared spectrum in general
showed stretching frequencies at 1,662; 1,606 and
1,379 cm-1 corresponding for, CON, C=N and –SO3
groups, respectively. Moreover, benzoxazinone (2) reacted
On the other hand, condensation of benzoxazinone (2)
with some heterocyclic amines namely, 2-aminothiazole,
2-aminobenzothiazole
and
5-amino-4-phenylazo-2,
4-dihydropyrazole-3-one in glacial acetic acid under reflux
yielded quinazolinone derivatives (9–11), respectively
(Schemes 2, 3). The structures of (9–11) were deduced
from correct analytical and spectroscopic results. The
O
O
1 : 2
N
Ar
2
O
C
O
O S
O
COOH
NH2
Cl
CH3
+
1
O
COOH
1 : 1
O
+
N C Ar
N
Ar
H
O
O
Ar =
2
O
S
CH
3
O
Scheme 1 Reaction of anthranilic acid with acid chloride 1
123

Med Chem Res (2013) 22:507–519
509
N
COOH
N
O
HOOC
NH2
O
N
H2N
S
S
N
N
AcOH
AcOH
Ar
N
Ar
5
9
O
N
O
COCH3
Ar
O
CH3
C
X
O
2
O
N
H2N
120-125°C
X
N
NH2
N
N
Ar
AcOH
Ar
6
4 ,
X=H
a
4b, X=OCH3
4c, X=Cl
Ar'-CHO
EtOH
O
Ar'
C
O
O
N
Ar'
NH
N
NH2NH2.H2O
EtOH
N
N
N
Ar
Ar
8a, Ar'= H
8b, Ar'=OCH3
7a, Ar'= H
7b, Ar'=OCH3
8c, Ar'=CH3
7c, Ar'=CH3
O
Ar =
O
S
CH3
O
Scheme 2 Reaction of benzoxazinone (2) with different amines
infrared spectrum in general, showed stretching frequen-
cies at 1,666; 1,610 and 1,380 cm-1 corresponding for
CON, C=N and –SO3 groups, respectively.
(13). On the other hand, fusion of compound (2) with
o-phenylenediamine in the presence of freshly fused
sodium acetate at 180 °C gives 4-(4-benzo[4,5]imidazo[1,
2-c]quinazolin-6-yl)phenyl-4-methylbenzenesulfonate (14)
(Scheme 3). The infrared spectrum of (14) revealed
absorption bands at 1,600 and 1,360 cm-1 attributable for
–C=N, –SO3 groups, respectively. The bands characteristic
for the C=O and –NH2 groups disappeared, and the mass
spectrum of (14) showed the molecular ion M??2 at
(m/z = 467) (30.96 %).
Fusion of benzoxazinone (2) with 3-amino-2-methyl
quinazolinone in an oil bath at 130–135 °C gives 4-(3-(2-
methyl-4-oxoquinazolin-3(4H)-yl)-4-oxo-3,4-dihydroqui-
nazolin-2-yl)phenyl-4-methylbenzenesulfonate (12). The
infrared spectrum of (12) revealed stretching frequencies at
1,665; 1,594 and 1,380 cm-1 corresponding for CON, C=N
and –SO3 groups, respectively, and the mass spectrum
showed the molecular ion M? at (m/z = 550) (15.93 %).
The behavior of benzoxazinone (2) towards o-phenyl-
enediamine under different conditions has been investigated.
Thus, reaction of benzoxazinone (2) with o-phenylenedi-
amine in glacial acetic acid under reflux in the presence of
fused sodium acetate gives 4-[(2-{1H-benzo[d]imidazol-2-
yl)phenyl}carbamoyl]phenyl-4-methylbenzenesulfonate
By analogy with the previously reported reactions of
2-substituted benzoxazinone derivatives with p-phenyl-
enediamine, compound (2) was heated under reflux with
p-phenylenediamine in glacial acetic acid containing
freshly fused sodium acetate and yielded 4-(3-(4-amino-
phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl-4-methyl-
benzenesulfonate of (15) (Scheme 3). Structure of (15) was
123

510
Med Chem Res (2013) 22:507–519
N
H2N
H2N
N
N
O
N
H
H2N
S
N
S
NH
AcOH
AcOH
N
Ar
O
C
Ar
10
13
N N Ph
H2N
H2N
H2N
N N Ph
O
N
O
N
O
O
N
O
NH
N
N
N
N
NH
AcOH
180°C
Ar
Ar
N
Ar
11
O
14
2
H2N
H3C
N
O
NH2
H2N
O
O
NH2
N
N
N
N
N
AcOH
130-135°C
N
Ar
CH3
N
Ar
O
12
15
Ar =
O
S
CH3
O
Scheme 3 Reaction of benzoxazinone (2) with o-phenylenediamine, p-phenylenediamine and heterocyclic amines
established from correct analytical data and infrared
spectrum which exhibits absorption bands at 3,221–3,331;
1,653; 1,600 and 1,360 cm-1 attributable to –NH2, –C=O,
–C=N and –SO3 groups, respectively, the mass spectrum
(m/z = 483) (33.74 %) and 1H-NMR shows signals at d 2.4
(s, 3H, –CH3) and d 3.38 (s, 2H, –NH2).
Moreover, when benzoxazinone (2) reacted with ethy-
lenediamine by fusion in an oil bath at 130 °C afforded
4-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)phenyl-4-
methylbenzenesulfonate (16). The infrared spectrum
revealed absorption bands at 1,593 and 1,380 cm-1
attributable for –C=N and –SO3 groups, respectively. The
bands characteristic for the C=O and –NH2 groups disap-
peared and the mass spectrum showed the molecular ion
peak at m/z 417 (M?) (47.71 %).
conjugated), C=N and (–SO3, C=S) groups, respec-
tively. The Mass spectrum: (m/z = 448) (M??1) (2.40 %).
1H-NMR gave signals at d 2.4 (s, 3H, –CH3) and d 4.8 (s, 1H,
–NH). Benzoxazinone (2) reacted with sodium azide in the
presence of glacial acetic acid to gives 2-(5-(4-(tosyloxy)
phenyl)-1H-tetrazol-1-yl) benzoic acid (19) (Scheme 4).
The infrared spectrum of (19) showed stretching frequencies
at 1,665; 3,131; 1,613; 1,016 and 1,380 cm-1 attributable to
C=O, –OH (of the acid), C=N, tetrazole nucleus and –SO3
groups, respectively, and the mass spectrum showed the
molecular ion peak at m/z 438 (M? ?2) (46.79 %).
Treatment of the benzoxazinone (2) with ethyl-
cyanoacetate and/or ethylactoacetate in dry pyridine under
reflux afforded ethyl-4-oxo-2-(4-(tosyloxy)phenyl)-3,
4-dihydroquinoline-3-carboxylate (20) (Scheme 4). Struc-
ture of (20) was based upon correct analytical data and
infrared spectrum which showed stretching bands at 1,760;
1,665; 1,630 and 1,360 cm-1 attributable to the two C=O,
C=N and –SO3 groups, respectively. Its mass spectrum
showed molecular ion peak at m/z = 463 (3.34 %). The
reaction could be explained to proceed by fission of the
benzoxazinone ring as a result of the attack of the carb-
anion of the active methylene group on the carbonyl carbon
of the benzoxazinone (2) to give the intermediate (A). This
is followed by elimination of carbomethoxy or cyano group
and then condensation reaction takes place to form the final
product. This mechanism can be represented in the fol-
lowing scheme.
Cyclocondensation of semicarbazide and thiosemicar-
bazide with benzoxazinone (2) in pyridine afforded
4-(2-oxo-2,3-dihydro-[1,2,4]trizaolo [1,5-c]quinazolin-5-yl)
phenyl-4-methylbenzenesulfonate (17) and 4-(2-thioxo-2,3-
dihydro-[1,2,4] triazolo [1,5-c]quinazolin-5-yl)phenyl-4-
methylbenzenesulfonate (18), respectively. The infrared
spectrum of (17) showed stretching frequencies at 3,300;
1,700; 1,600 and 1,373 cm-1 corresponding for –NH, CON,
C=N and –SO3 groups, respectively, and the mass spectrum
showed the molecular ion M? ?1 as the base peak at (m/
z = 432) (40.66 %). On the other hand, infrared spectrum
of (18) revealed strong absorption bands at 3,421; 1,690;
1,597 and 1,369 cm-1 corresponding for –NH, C=N (not
123

Med Chem Res (2013) 22:507–519
511
R
O
C
O
C
C
H
C
O
OEt
H
C
O
O
O
OEt
O
C
O
R
R
C
H
OEt
+
N
C
Ar
N
Ar
N
Ar
O
2
H
H
O
O
O
C
O
O
O
C
H
H
C
C
R
C
OEt
C
R
C
OEt
C
C
R
OEt
HN
C
Ar
N
C
Ar
HN
C
Ar
O
OH
O
(A)
H
O
O
O
O
O
R
Ar
OH
O
O
OEt
OEt
OEt
-H
- ROH
R
Ar
20
+H
N
H
N
H
N
H
Ar
R= CN, COCH3
Pharmacology
Antimicrobial evaluation
Staphylococcus aureus (ATCC 25923) and Streptococcus
pyogenes (ATCC 19615) as examples of Gram-positive
bacteria and Pseudomonas phaseolicola (GSPB 2828) and
Pseudomonas fluorescens (S 97) as examples of Gram-
negative bacteria. They were also evaluated for their in
vitro antifungal potential against Fusarium oxysporum and
Twenty of the newly synthesized target compounds were
evaluated for their in vitro antibacterial activity against
O
H2N
N
OH
H2N
N
NaN3
N
N
AcOH
130°C
N
N
Ar
N
Ar
16
O
H2N
H2N
O
19
N
N
O
N
NH
NH
Ar
O
N
N
AcOH
Ar
17
2
S
H2N
H2N
S
O
O
N
OEt
NH
NH
Ethylcyanoacetate
Pyridine
Ar
N
AcOH
N
Ar
O
S
18
20
Ar =
O
CH3
O
Scheme 4 Reaction of benzoxazinone (2) with diamines, sodium azide and active methylene compounds
123

512
Med Chem Res (2013) 22:507–519
Aspergillus fumigatus fungal strains. Agar-diffusion
method was used for the determination of the preliminary
antibacterial and antifungal activity. Chloramphenicol,
cephalothin and cycloheximide were used as reference
drugs. The results were recorded for each tested compound
as the average diameter of inhibition zones (IZ) of bacterial
or fungal growth around the disks in millimeter. The
minimum inhibitory concentration (MIC) measurement
was determined for compounds showed significant growth
IZ ([12 mm) using twofold serial dilution method
(Shamroukh et al., 2007). The MIC (mg/mL) and inhibition
zone diameters values are recorded in Table 1. The results
depicted in Table 1 revealed that most of the tested com-
pounds displayed variable inhibitory effects on the growth
of the tested Gram-positive and Gram-negative bacterial
strains and also against antifungal strains. In general, most
of the tested compounds revealed better activity against the
Gram-positive rather than the Gram-negative bacteria. It
would be also noticed that, compounds belonging to the
thiazole, benzothiazole and pyrazole series (Schemes 2, 3)
exhibited high antibacterial potentials.
equipotent to chloramphenicol in inhibiting the growth of
S. aureus (MIC 3.125 mg/mL), while its activity was 50 %
lower than that of chloramphenicol against S. pyogenes.
Compounds 9 and 10 showed 50 % of the activity of
chloramphenicol (MIC 6.25 mg/mL), but they were equi-
potent to cephalothin in inhibiting the growth of S. aureus
and S. pyogenes (MIC 6.25 mg/mL). On the other hand,
compounds 11, 12, 13, 14, 16, 17 and 19 exhibited weak to
moderate growth inhibitory activity against Gram-positive
bacteria as revealed from their MIC values (25e100
mg/mL). Among these compounds 11 and 19 showed rel-
atively good growth inhibitory profiles against S. aureus
(MIC 12.5 mg/mL) which were about 25 % of the activity
of chloramphenicol and 50 % of cephalothin against the
same organism. Moreover, distinctive anti-Gram-positive
profile was displayed by compound 18 where it proved to
be equipotent as chloramphenicol against S. aureus (MIC
3.125 mg/mL) together with a significant activity against S.
pyogenes (MIC 6.25 mg/mL). Concerning the antibacterial
activity of the compounds 10, 12, 16 and 19 revealed weak
growth inhibitory against the tested Gram-negative bacteria
(MIC 50 mg/mL). On the other hand, compounds 14 and
17 showed equipotent activity as chloramphenicol and
cephalothin (MIC 6.25 mg/mL) against P. fluorescens and
P. phaseolicola. The substitution pattern was also crucial.
It is worth mentioning that incorporation of thiazole and
Regarding the structure–activity relationship of the thi-
azole, benzothiazole and pyrazole against Gram-positive
bacteria, the results revealed that compounds 9, 10 and
8a–c exhibited broad spectrum antibacterial profile against
the tested organisms. In this view, compounds 8a–c were
Table 1 MICs (mg/mL) and inhibition zone (mm) of some new synthesized compounds
Compound nos.
MIC in (mg/mL), and zone of inhibition (mm)
Bacteria
Fungi
Gram-positive bacteria
Gram-negative bacteria
S. aureus
S. pyogenes
P. phaseolicola
P. fluorescens
F. oxysporum
A. fumigatus
8a
3.125(43)
3.125(43)
3.125(43)
6.25(38)
6.25(38)
12.5(32)
50(19)
6.25(38)
6.25(38)
6.25(38)
6.25(38)
6.25(37)
100(14)
100(15)
25(25)
50(19)
-ve
100(14)
100(14)
100(14)
100(15)
100(14)
12.5(31)
100(15)
100(15)
100(16)
6.25(37)
100(15)
50(19)
12.5(31)
12.5(31)
12.5(31)
50(19)
-ve
8b
50(19)
-ve
8c
50(19)
-ve
9
100(14)
50(19)
100(16)
50(20)
100(16)
50(19)
100(14)
6.25(37)
50(18)
50(19)
100(15)
50(19)
50(20)
10
11
50(20)
100(16)
6.25(38)
-ve
12
100(14)
50(19)
13
25(25)
14
25(26)
25(25)
100(14)
100(15)
25(26)
50(20)
25(26)
100(14)
100(15)
100(14)
-ve
15
100(14)
25(25)
100(15)
6.25(37)
100(15)
6.25(37)
6.25(38)
16
17
100(15)
3.125(44)
12.5(32)
6.25(38)
100(15)
100(14)
18
25(26)
19
50(19)
Reference drugs
Chloramphenicol
Cephalothin
Cycloheximide
3.125(42)
6.25(36)
3.125(44)
6.25(37)
6.25(37)
6.25(38)
Not tested
6.25(38)
6.25(37)
Not tested
Not tested
Not tested
3.125(43)
Not tested
Not tested
3.125(42)
Not tested
Not tested
123

Med Chem Res (2013) 22:507–519
513
Calcd.; C 64.11; H 3.84; N 3.56; S 8.15
Found; C 64.12; H 3.77; N 3.51; S 8.05
IR (KBr) mmax. cm-1: 1766 (CO of lactone), 1627
(C=N), 1370 (SO3).
MS: m/z (%), 393 (M?, 29.24), 354 (16.5), 221 (7.3),
196 (88.9), 105 (26.9), 65 (100).
benzothiazole to quinazolone nucleus produced a high
antimicrobial activity. Conversion of chalcones 7a–c to
pyrazoles 8a–c enhanced also the antimicrobial activity.
On the other hand, incorporation of quinazolone nucleus to
quinazolone derivative 2 at position 3 in compound 12
unfortunately produced weak antimicrobial activity. High
biological activity can be correlated with low electron
density of ring systems.
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 6.9–7.8 (m,
12H, Ar–H).
In conclusion, the objective of this study was to syn-
thesize and investigate the antimicrobial activities of some
new heterocyclic compounds incorporating sulfonate moi-
ety with the hope of discovering new structure leads
serving as potent antimicrobial agents. The obtained results
clearly revealed that, compounds derived from thiazole,
benzothiazole and pyrazoles exhibited better antimicrobial
activity than the others.
For compound (3)
Yellow crystals; Yield 45 %; m.p. 198–200 °C
Anal. For C21H17NO6S (411.4)
Calcd.; C 61.31; H 4.16; N 3.40; S 7.79
Found; C 61.24; H 4.16; N 3.36; S 7.59
IR (KBr) mmax. cm-1: 1655 (CO), 3132–3230 (NH,
OH), 1613 (C=N), 1380 (SO3).
MS: m/z (%), 411 (M?, 24.8), 343 (11.3), 265 (18.5),
176 (18.3), 145 (13.2), 91 (100), 55 (10).
Experimental
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 6.8–7.9 (m,
12H, Ar–H). 12.2 (s, 1H, –COOH) and 8.7 (s, 1H, NH).
General
All melting points (uncorrected) were determined on Gal-
lenkamp electric melting point apparatus, FTIR spectra
(KBr disk) were recorded on a Nicolet Magna. IR model
Preparation of 4-{3-aryl-4-oxo-3,4-dihydroquinazolin-2-
yl}phenyl-4-methylbenzenesulfonates (4a–c)
1
550 spectrophotometers, H-NMR spectra in DMSO, were
General procedure: A mixture of benzoxazinone (2)
(0.01 mol) and primary aromatic amines (0.01 mol) was
fused in a sand bath at 120–125 °C in the presence of
anhydrous ZnCl2 (1 g) for 5 h. The reaction mixture was
triturated with ice–HCl. The solid product was filtered off,
washed with water several times, dried and recrystallized
from methanol to give 4a–c.
determined on Brucker Wpsy 200 MHz spectrometer with
TMS as internal standard and the chemical shifts are in r
ppm. Mass spectra were recorded at 70 eV with a varian
MAT 311. Elemental analyses are satisfactory for all
synthesized compounds (2–20), all analyses were carried
out in Faculty of Science, Cairo University, Egypt.
Preparation of 4-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl-
4-methylbenzenesulfonate (2) and 2-(4-
(tosyloxy)benzamido) benzoic acid (3)
4-(3-Phenyl-4-oxo-3,4-dihydroquinazolin-2-yl)phenl-
4-methylbenzenesulfonate (4a)
Brown crystals; Yield 60 %; m.p. 144–145 °C
Anal. For C27H20N2O4S (468.52)
To a solution of anthranilic acid (0.01 mol) in dry pyridine
(30 mL), the acid chloride (1) (0.01 and/or 0.02 mol) was
added portion wise with stirring for 5 min. The reaction
mixture was stirred for further 1 h at room temperature.
The reaction mixture was poured onto cold water (100 mL)
and the precipitated solid was filtered off, washed with cold
water, dried and recrystallized from ethanol to give ben-
zoxazinone (2). The filtrate which was obtained on using
0.01 mol of acid chloride was acidified with dilute HCl, the
precipitated solid was filtered off, dried and recrystallized
from acetic acid to give (3).
Calcd.; C 69.22; H 4.30; N 5.98; S 6.84
Found; C 69.34; H 4.45; N 5.80; S 6.63
IR (KBr) mmax. cm-1: 1662 (CO amidic), 1606 (C=N),
1379 (SO3).
MS: m/z (%), 468 (M?, 34.2), 368 (22.1), 288 (41.5),
155 (100), 105 (8.2), 65 (21.0).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8–7.9
(m, 17H, Ar–H).
4-(3-(4-Methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-
2-yl)phenyl-4-methylbenzenesulfonate (4b)
For compound (2)
Brown crystals; Yield 80 %; m.p. 163–164 °C
Anal. For C28H22N2O5S (498.5)
Yellow crystals; Yield 50 %; m.p. 140–141 °C
Anal. For C21H15NO5S (393.41)
Calcd.; C 67.46; H 4.45; N 5.62; S 6.43
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Found; C 67.34; H 4.45; N 5.50; S 6.33
IR (KBr) mmax. cm-1: 1662 (CO amidic), 1606 (C=N)
and 1379 (SO3).
Brown crystals; Yield 53 %; m.p. 202–204 °C
Anal. For C29H22N2O5S (510.56)
Calcd.; C 68.22; H 4.34; N 5.49; S 6.28
Found; C 68.12; H 4.28; N 5.50; S 6.18
IR (KBr) mmax. cm-1: 1678 (CO amidic), 1656 (CO),
1593 (C=N) and 1373 (SO3).
MS: m/z (%), 498 (M?, 55.3), 412 (2.1), 348 (11.5), 218
(100), 145 (23.3), 106 (11.1).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 3.8 (s, 3H,
OCH3) and 6.8–7.9 (m, 16H, Ar–H).
MS: m/z (%), 510 (M?, 32.18), 485 (13.1), 348 (21.1),
238 (9.2), 165 (100), 93 (44.2).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 2.62 (s,
3H, –COCH3) and 6.8–7.9 (m, 16H, Ar–H).
4-(3-(4-Chlorophenyl)-4-oxo-3,4-dihydroquinazolin-
2-yl)phenyl-4-methylbenzenesulfonate (4c)
Brown crystals; Yield 50 %; m.p. 157–159 °C
Anal. For C27H19ClN2O4S (502.96)
Preparation of 4-(3-(4-(3-(aryl)acryloyl)-phenyl)-4-oxo-
3,4-dihydro quinazolin-2-yl)-phenyl-
4-methylbenzenesulfonate (7a–c)
Calcd.; C 64.47; H 3.81; N 5.57; S 6.38
Found; C 64.44; H 3.75; N 5.50; S 6.29
IR (KBr) mmax. cm-1: 1662 (CO amidic), 1606 (C=N)
and 1379 (SO3).
General procedure: A sodium hydroxide solution (10 %,
6 mL) was added to a mixture of compound (6) (0.03 mol)
and aromatic aldehydes (0.03 mol) in ethanol (40 mL).
The reaction mixture was stirred for 3 h at room temper-
ature, poured onto ice-cold water; the precipitated product
was filtered off and recrystallized from ethanol to give
(7a–c).
MS: m/z (%), 502 (M?, 4.2), 448 (12.1), 348 (21.1), 235
(100), 165 (34.2), 65 (11.2).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8–7.9
(m, 16H, Ar–H).
Preparation of 4-(4-oxo-2-(4-(tosyloxy)phenyl) quinazolin-
3(4H)-yl) benzoic acid (5)
(E)-4-(3-(4-cinnamoylphenyl)-4-oxo-3,4-dihydroquinazo-
lin-2-yl)phenyl-4-methylbenzenesulfonate (7a)
A mixture of (2) (0.002 mol) and p-amino benzoic acid
(0.002 mol) in glacial acetic acid (10 mL) was refluxed for
6 h. The reaction mixture was cooled; the precipitated solid
product was filtered off and recrystallized from acetic acid
to give (5).
Yellow crystals; Yield 32 %; m.p. 145–147 °C
Anal. For C36H26N2O5S (598.66)
Calcd.; C 72.22; H 4.38; N 4.68; S 5.36
Found; C 72.16; H 4.35; N 4.56; S 5.31
IR (KBr) mmax. cm-1: 1675 (CO amidic), 1645 (C=O,
Chalcone), 1610 (C=N), 1595 (C=C) and 1370 (SO3).
MS: m/z (%), 598 (M?, 11.3), 490 (3.3), 468 (12.3), 268
(19.1), 195 (23.2), 91 (100).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 4.2 (d, 1H,
CH=) and d 4.6 (d, 1H, =CH) and 6.8–8.3 (m, 21H,
Ar–H).
Yellow crystals; Yield 51 %; m.p. 192–194 °C
Anal. For C28H20N2O6S (512.53)
Calcd.; C 65.62; H 3.93; N 5.47; S 6.26
Found; C 65.48; H 3.83; N 5.40; S 6.16
IR (KBr) mmax. cm-1: 1665 (CO amidic), 1685 (CO),
1612 (C=N), 3131–3188 (OH) and 1380 (SO3).
MS: m/z (%), 512 (M?, 30), 466 (33.3), 338 (41.5), 258
(10.3), 145 (100), 88 (33.4).
(E)-4-(3-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)-4-oxo-
3,4-dihydroquinazolin-2-yl) phenyl 4-methylbenzenesulfo-
nate (7b)
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 12.2 (s,
1H, COOH) and 6.8–7.9 (m, 16H, Ar–H).
Yellow crystals; Yield 89 %; m.p. 193–195 °C
Anal. For C37H28N2O6S (628.69)
Preparation of 4-(3-(4-acetylphenyl)-4-oxo-3,
4-dihydroquinazolin-2-yl)phenyl-4-methylbenzenesulfonate
(6)
Calcd.; C 70.69; H 4.49; N 4.46; S 5.10
Found; C 70.66; H 4.32; N 4.48; S 5.11
IR (KBr) mmax. cm-1: 1675 (CO amidic), 1645 (C=O,
Chalcone), 1610 (C=N), 1595 (C=C) and 1370 (SO3).
MS: m/z (%), 628 (M?, 8.8), 550 (13.6), 488 (5.5), 338
(100), 185 (12.3), 65 (34.4).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 3.9 (s, 3H,
OCH3), 4.2 (d, 1H, CH=) and d 4.6 (d, 1H, =CH) and
6.8–8.3 (m, 20H, Ar–H).
A mixture of (2) (0.002 mol) and p-amino acetophenone
(0.002 mol) in glacial acetic acid (10 mL) was refluxed for
8 h. The reaction mixture was cooled and then poured over
ice–water. The separated solid was filtered off, washed
with water several times, dried and recrystallized from
methanol to give (6).
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515
(E)-4-(4-Oxo-3-(4-(3-(p-tolyl)acryloyl)phenyl)-3,4-dihydro-
quinazolin-2-yl)phenyl-4-methylbenzenesulfonate (7c)
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 3.9 (s, 3H,
OCH3) 1.9 (d, 2H, CH2) and d 4.1 (t, 1H, CH) and
6.8–8.4 (m, 20H, Ar–H).
Yellow crystals; Yield 24 %; m.p. 164–166 °C
Anal. For C37H28N2O5S (612.69)
Calcd.; C 72.53; H 4.61; N 4.57; S 5.23
4-(4-Oxo-3-(4-(5-(p-tolyl)-4,5-dihydro-1H-pyrazol-
3-yl)phenyl)-3,4-dihydroquinazolin-2-yl)phenyl
4-methylbenzenesulfonate (8c)
Found; C 72.51; H 4.55; N 4.56; S 5.31
IR (KBr) mmax. cm-1: 1675 (CO amidic), 1645 (C=O,
Chalcone), 1610 (C=N), 1595 (C=C) and 1370 (SO3).
MS: m/z (%), 612 (M?, 5.7), 544 (8.8), 498 (15.5), 358
(15.5), 155 (100), 102 (14.1).
Yellow crystals; Yield 46 %; m.p. 187–189 °C
Anal. For C37H30N4O4S (626.72)
Calcd.; C 70.91; H 4.82; N 8.94; S 5.12
Found; C 70.82; H 4.75; N 8.84; S 5.10
IR (KBr) mmax. cm-1: 1685 (CO amidic), 1610 (C=N),
3222 (NH) and 1370 (SO3).
MS: m/z (%), 626 (M?, 9.9), 544 (13.5), 428 (11.2), 326
(14.4), 215 (100), 122 (33.4).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 2.8 (s, 3H,
CH3) 1.9 (d, 2H, CH2) and d 4.1 (t, 1H, CH) and 6.8–8.4
(m, 20H, Ar–H).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 2.9 (s, 3H,
CH3), 4.2 (d, 1H, CH=) and d 4.6 (d, 1H, =CH) and
6.8–8.3 (m, 20H, Ar–H).
Preparation of 4-(3-(4-(5-(aryl)-4,5-dihydro-1H-pyrazol-
3-yl)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pheny-4-
methylbenzenesulfonate (8a–c)
General procedure: A solution of (7a–c) (0.01 mol) in
absolute ethanol (30 mL) was heated under reflux with
hydrazine hydrate (0.01 mol) for 8 h. The solid that sepa-
rated after concentration and cooling of the reaction mix-
ture was filtered off, dried and recrystallized from ethanol
to give (8a–c).
Preparation of 4-(4-oxo-3-(thiazol-2-yl)-3,4-dihydro-
quinazolin-2-yl)phenyl-4-methylbenzenesulfonate (9)
A
mixture of (2) (0.002 mol) and 2-aminothiazole
(0.002 mol) in glacial acetic acid (20 mL) was refluxed for
4 h. The reaction mixture was concentrated and then
poured onto ice–water. The solid that was separated out
was filtered off, washed with water several times, dried and
then recrystallized from ethanol to afford (9).
4-(4-Oxo-3-(4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phe-
nyl)-3,4-dihydroquinazolin-2-yl) phenyl-4-methylbenzene-
sulfonate (8a)
Yellow crystals; Yield 76 %; m.p. 140–142 °C
Anal. For C36H28N4O4S (612.69)
Grey crystals; Yield 69 %; m.p. 200–202 °C
Anal. For C24H17N3O4S2 (475.54)
Calcd.; C 70.57; H 4.61; N 9.14; S 5.23
Calcd.; C 60.62; H 3.60; N 8.84; S 13.49
Found; C 59.77; H 3.63; N 8.82; S 13.39
IR (KBr) mmax. cm-1: 1666 (CO amidic), 1610 (C=N)
and 1380 (SO3).
MS: m/z (%), 475 (M?, 22.3), 418 (31.1), 276 (100), 185
(21.1), 152 (2.3), 112 (10.1).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 3.9 (d, 1H,
CH), 4.3 (d, 1H, CH) and 6.8–8.2 (m, 12H, Ar–H).
13C-NMR (400 MHz, DMSO-d6, d, ppm):160.6(C=O),
156.3(C=N), 21.3(CH3), 137.0, 112.1 (CH=CH of thia-
zole ring), 171.7 (C=N of thiazole), 128.2, 124.1, 135.2,
126.2, 146.1, 130.6, 116.0, 126.7, 130.3, 132.4, 138.2,
122.4, 152.5 (aromatic).
Found; C 70.52; H 4.55; N 9.14; S 5.20
IR (KBr) mmax. cm-1: 1685 (CO amidic), 1610 (C=N),
3222 (NH) and 1370 (SO3).
MS: m/z (%), 612 (M?, 15.1), 532 (12.3), 448 (22.1),
318 (100), 245 (10.3), 142 (5.2).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 1.9 (d, 2H,
CH2) and d 4.1 (t, 1H, CH) and 6.8–8.4 (m, 21H, Ar–H).
4-(3-(4-(5-(4-Methoxyphenyl)-4,5-dihydro-1H-pyrazol-
3-yl)phenyl)-4-oxo-3,4-dihydro quinazolin-2-yl)phenyl-
4-methylbenzenesulfonate (8b)
Yellow crystals; Yield 80 %; m.p. 170–172 °C
Anal. For C37H30N4O5S (642.72)
Calcd.; C 69.14; H 4.70; N 8.72; S 4.99
Found; C 69.11; H 4.55; N 8.64; S 4.89
IR (KBr) mmax. cm-1: 1685 (CO amidic), 1610 (C=N),
3222 (NH) and 1370 (SO3).
Preparation of 4-(3-(benzo[d] thiazol-2-yl)-4-oxo-3,
4-dihydroquinazolin-2-yl) phenyl-4-methylbenzensulfonate
(10)
MS: m/z (%), 642 (M?, 45.4), 555 (2.3), 478 (33.3), 356
A mixture of (2) (0.002 mol) and 2-aminobenzothiazole
(0.002 mol) in glacial acetic acid (20 mL) was refluxed for
(100), 265 (19.9), 162 (12.3).
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Brown crystals; Yield 56 %; m.p. 120–122 °C
Anal. For C30H22N4O5S (550.58)
5 h. The reaction mixture was concentrated and then poured
over ice–water. The solid that separated out was filtered off,
washed with water several times, dried and then recrystal-
lized from ethanol to afford quinazolinone (10).
Calcd.; C 65.44; H 4.03; N 10.18; S 5.82
Found; C 65.22; H 3.98; N 10.28; S 5.72
IR (KBr) mmax. cm-1: 1665, 1690 (2CO amidic), 1594
(C=N) and 1380 (SO3).
MS: m/z (%), 550 (M?, 15.93), 456 (11.3), 341 (100),
265 (7.8), 142 (14.1), 132 (15.3), 91 (44.6).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 2.1 (s, 3H,
CH3) and 6.8–8.2 (m, 16H, Ar–H).
13C-NMR (400 MHz, DMSO-d6, d, ppm):160.6(2C=O),
156.3(2C=N), 21.3(2CH3), 128.2, 124.1, 135.2, 126.2,
146.1, 130.6, 116.0, 126.7, 130.3, 132.4, 138.2,
122.4,133.4, 160.6, 152.5 (aromatic).
Grey crystals; Yield 72 %; m.p. 185–187 °C
Anal. For C28H19N3O4S2 (525.60)
Calcd.; C 63.98; H 3.64; N 7.99; S 12.20
Found; C 64.45; H 3.81; N 8.01; S 12.15
IR (KBr) mmax. cm-1: 1666 (CO amidic), 1610 (C=N)
and 1380 (SO3).
MS: m/z (%), 525 (M?, 12.8), 466 (11.6), 356 (100), 255
(41.4), 182 (6.3), 142 (15.5).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8–8.2
(m, 16H, Ar–H).
13C-NMR (400 MHz, DMSO-d6, d, ppm):160.6(C=O),
156.3(C=N), 21.3(CH3), 118.3, 125.3, 124.5, 139.4
(benzo thiazole ring), 160.7 (C=N of benzothiazole
ring), 128.2, 124.1, 135.2, 126.2, 146.1, 130.6, 116.0,
126.7, 130.3, 132.4, 138.2, 122.4, 152.5 (aromatic).
Preparation of 4-[(2-(1H-benzo[d]imidazol-
2-yl)phenyl)carbamoyl]phenyl-4-methylbenzenesulfonate
(13)
A mixture of benzoxazinone (2) (0.003 mol) and o-phen-
ylenediamine (0.003 mol) in glacial acetic acid (10 mL)
containing freshly fused sodium acetate (0.2 g) was heated
under reflux for 3 h. The reaction mixture was left to cool,
and then poured over ice; the solid that separated out was
filtered off, dried and recrystallized from mixture of ether-
ethanol to give (13).
Preparation of 4-[4-oxo-3-(5-oxo-4-phenylazo-4,
5-dihydro-1H-pyrazol-3-yl)-3,4-dihydroquinazolin-2-yl]-
phenyl-4methylbenzene sulfonate (11)
A mixture of (2) (0.002 mol) and 5-amino-4-phenylazo-
2,4-dihydropyrazol-3-one (0.002 mol) in glacial acetic acid
(20 mL) was refluxed for 8 h, then cooled. The reaction
mixture was poured onto ice–water; the precipitated
product was filtered off and recrystallized from acetic acid
yielding the product (11).
Yellow crystals; Yield 35 %; m.p. 160–162 °C
Anal. For C27H21N3O4S (483.54)
Calcd.; C 67.07; H 4.38; N 8.69; S 6.63
Found; C 67.12; H 4.37; N 8.78; S 6.53
IR (KBr) mmax. cm-1: 1680 (CO amidic), 1620 (C=N),
3260, 3280 (2NH) and 1360 (SO3).
MS: m/z (%), 483 (M?, 4.9), 426 (1.8), 332 (100), 225
(11.3), 142 (14.6), 102 (15.3).
Red crystals; Yield 84 %; m.p. 184–186 °C
Anal. For C30H22N6O5S (578.60)
Calcd.; C 62.27; H 3.83; N 14.52; S 5.54
Found; C 62.33; H 3.65; N 14.41; S 5.44
IR (KBr) mmax. cm-1: 1666, 1680 (2CO amidic), 1610
(C=N), 3230 (NH) and 1380 (SO3).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 9.7 (s, 1H,
NHCO) and 6.8–8.3 (m, 17H, Ar–H, NH).
MS: m/z (%), 578 (M?, 14.4), 486 (31.8), 388 (100), 295
(1.9), 162 (4.3), 122 (5.5).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 4.7 (s, 1H,
CH), 9.5 (s, 1H, NH) and 6.8–8.2 (m, 17H, Ar–H).
Preparation of 4-(4-benzo[4,5]imidazo[1,2-c]quinazoline-
6-yl)phenyl-4-methylbenzenesulfonate (14)
A mixture of benzoxazinone (2) (0.003 mol), o-phenyl-
enediamine (0.003 mol) and freshly fused sodium acetate
(0.2 g) was fused at 180 °C for 3 h, the reaction mixture
was cooled, washed with dil. HCl, and the separated solid
product was dried and recrystallized from methanol to give
(14).
Preparation of 4-(3-(2-methyl-4-oxoquinazolin-3(4H)-yl)-
4-oxo-3,4-dihydroquinazolin-2-yl)phenyl-4-
methylbenzenesulfonate (12)
A mixture of (2) (0.002 mol) and 3-amino-2-methyl-4H-
quinazolinone (0.002 mol) was fused in an oil bath at
130–135 °C for 6 h. The reaction mixture was triturated
with ice–HCl. The solid product was filtered off, washed
with water several times, dried and then recrystallized from
methanol affording the product (12).
Brown crystals; Yield 61 %; m.p. 291–292 °C
Anal. For C27H19N3O3S (465.52)
Calcd.; C 69.66; H 4.11; N 9.03; S 6.89
Found; C 69.33; H 4.00; N 9.12; S 6.78
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517
IR (KBr) mmax. cm-1: 1600 (C=N) and 1360 (SO3).
MS: m/z (%), 467 (M??2, 30.96), 416 (6.6), 372 (100),
245 (61.3), 112 (11.1), 93 (23.3).
Preparation of 4-(2-oxo-2,3-dihydro-[1,2,4] triazolo[1,5-
c] quinazolin-5-y1) pheny1-4-methylbenzenesulfonate (17)
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8-8.3
(m, 16H, Ar–H).
To a solution of benzoxazinone (2) (0.01 mol) in pyridine
(30 mL), semicarbazide hydrochloride (0.01 mol) was
added, and the reaction mixture was heated under reflux for
8 h, left to cool, poured onto water–HCl with stirring. The
solid product that separated out was filtered off, washed
with cold water, dried and recrystallized from ethanol to
give compound (17).
13C-NMR (400 MHz, DMSO-d6, d, ppm): 160.6(C=O),
156.3(C=N), 142.9(C=N), 21.3(CH3), 128.2, 123.0,
135.2, 126.2, 144.0, 130.6, 116.0, 126.7, 130.3, 132.4,
138.2, 122.4,133.4, 160.6, 152.5 (aromatic).
Brown crystals; Yield 55 %; m.p. 150–152 °C
Anal. For C22H16N4O4S (432.45)
Preparation of 4-(3-(4-amino phenyl)-4-oxo-3,4-
dihydroquinazolin-2-yl)phenyl-4-methylbenzenesulfonate
(15)
Calcd.; C 61.10; H 3.73; N 12.96; S 7.41
Found; C 61.23; H 3.81; N 12.81; S 7.34
IR (KBr) mmax. cm-1: 1700 (CO, amidic), 1600 (C=N),
3300 (NH) and 1373 (SO3).
MS: m/z (%), 432 (M??1, 40.66), 357 (6.5), 244 (100),
255 (41.4), 132 (22.3), 65 (22.5).
A solution of (2) (0.003 mol) in glacial acetic acid (10 mL)
was added dropwise with stirring to a solution of p-phen-
ylenediamine (0.003 mol) in hot glacial acetic acid
(10 mL) containing (0.2 g) of freshly fused sodium acetate.
The precipitated solid product was filtered off, washed
several times with glacial acetic acid and recrystallized
from dimethylformamide affording (15).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8–8.4
(m, 13H, Ar–H, NH).
Preparation of 4-(2-thioxo-2,3-dihydro-
[1,2,4]triazolo[1,5-c]quinazolin-5-y1)pheny1-4-
methylbenzenesulfonate (18)
White crystals; Yield 49 %; m.p. 283–285 °C
Anal. For C27H21N3O4S (483.54)
Calcd.; C 67.07; H 4.38; N 8.69; S 6.63
Found; C 67.11; H 4.34; N 8.66; S 6.51
IR (KBr) mmax. cm-1: 1653 (CO, amidic), 1600 (C=N),
3221-3331 (NH2) and 1360 (SO3).
MS: m/z (%), 483 (M?, 33.74), 369 (16.2), 331 (100),
225 (1.7), 162 (14.4), 91 (53.5).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3) and 6.8–8.3
(m, 18H, Ar–H, NH2).
A solution of benzoxazinone (2) (0.01 mol) and thiosemi-
carbazide (0.01 mol) in dry pyridine (30 mL) was heated
under reflux for 8 h. The reaction mixture was left to cool,
and poured over ice–HCl. The solid that separated out was
filtered off, washed with water several times, dried and
then recrystallized from ethanol to give (18).
Brown crystals; Yield 60 %; m.p. 166–168 °C
Anal. For C22H16N4O3S2 (448.52)
Preparation of 4-(2,3-dihydroimidazo[1,2-c]quinazolin-
5-yl)phenyl-4-methylbenzenesulfonate (16)
Calcd.; C 58.91; H 3.60; N 12.49; S 14.30
Found; C 58.82; H 3.47; N 12.38; S 14.23
IR (KBr) mmax. cm-1: 1370 (CS), 1690 (C=N), 3421
(NH) and 1369 (SO3).
A
mixture of (2) (0.01 mol) and ethylenediamine
MS: m/z (%), 448 (M??1, 2.40), 374 (22.5), 274 (100),
225 (1.6), 192 (11.5), 112 (2.5).
(0.01 mol) was fused in an oil bath at 120–130°C for 5 h.
The reaction mixture was triturated with ice–HCl. The
precipitated solid product was filtered off, washed with
water several times, dried and then recrystallized from
acetic acid affording (16).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 10.5
(s, 1H, NH) and 6.8–8.4 (m, 12H, Ar–H).
Brown crystals; Yield 56 %; m.p. 270–272 °C
Anal. For C23H19N3O3S (417.48)
Preparation of 2-(5-(4-(tosyloxy)pheny1)-1H-tetrazol-l-yl)
benzoic acid (19)
Calcd.; C 66.17; H 4.59; N 10.07; S 7.68
Found; C 66.12; H 4.44; N 10.12; S 7.58
A mixture of benzoxozinone (2) (0.01 mol) and sodium
azide (0.015 mol) in glacial acetic acid (40 mL) was
refluxed for 5 h, and then the reaction mixture was con-
centrated and cooled to room temperature. The separated
solid product was filtered off and recrystallized from acetic
acid to give (19).
IR (KBr) mmax. cm-1: 1593 (C=N) and 1380 (SO3).
MS: m/z (%), 417 (M?, 47.71), 377 (21.1), 381 (14.4),
255 (21.2), 132 (16.7), 93 (100).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 3.7 (t, 2H,
CH2), 4.1 (t, 2H, CH2) and 6.8–8.1 (m, 12H, Ar–H).
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Med Chem Res (2013) 22:507–519
Yellow crystals; Yield 45 %; m.p. 194–151 °C
Anal. For C21H16N4O5S (436.44)
DMF alone was used as control at the same above-men-
tioned concentration. The plates were incubated at 37 °C
for 24 h for bacteria and for 48 days for fungi. Com-
pounds that showed significant growth IZ ([12 mm)
using the twofold serial dilution technique, were further
evaluated for their minimal inhibitory concentrations
(MICs).
Calcd.; C 57.79; H 3.70; N 12.84; S 7.35
Found; C 57.65; H 3.66; N 12.85; S 7.31
IR (KBr) mmax. cm-1: 1665 (CO), 1613 (C=N), 3131
(OH) and 1380 (SO3).
MS: m/z (%), 438 (M??2, 46.79), 384 (31.1), 292
(13.3), 245 (44.5), 122 (12.5), 65 (100).
1H-NMR (CDCl3) (d, ppm), 2.4 (s, 3H, CH3), 11.5 (s,
1H, COOH) and 6.8–8.2 (m, 12H, Ar–H).
13C-NMR (400 MHz, DMSO-d6, d, ppm):166.4(C=O),
163.5(C=N), 21.3(CH3), 128.2, 123.0, 135.2, 126.2,
144.0, 130.3, 132.4, 138.2, 122.4,133.4, 160.6, 152.5
(aromatic).
Minimal inhibitory concentration (MIC) measurement
The micro dilution susceptibility test in Mu¨ller–Hinton
Broth (Oxoid) and Sabouraud liquid medium (Oxoid) was
used for the determination of antibacterial and antifungal
activity, respectively. Stock solutions of the tested com-
pounds, streptomycin, chloramphenicol and treflucan were
prepared in DMF at concentration of 1000 mg/mL fol-
lowed by twofold dilution at concentrations of (500, 250
and 3.125 mg/mL). The microorganism suspensions at
106 CFU/mL (Colony Forming U/mL) concentrations were
inoculated to the corresponding wells. Plates were incu-
bated at 36 °C for 24–48 h and the MICs were determined.
Control experiments were also done.
Preparation of ethyl-4-oxo-2-(4-(tosyloxy)phenyl)-3,
4-dihydro quinoline-3-carboxylate (20)
A mixture of benzoxazinone (2) (0.01 mol) and ethyl
cyano acetate or ethyl aceto acetate (0.03 mol) in dry
pyridine (30 mL) was heated under reflux for 25 h. The
reaction mixture was left to cool then poured over ice–HCl,
the solid that separated out was filtered off, dried and re-
crystallized from ethanol to afforded (20).
Acknowledgments The authors are very grateful to Prof. Dr. F.
El-Hawary, Department of Microbiology, Faculty of Agriculture,
Mansoura University, Cairo, Egypt for performing the antimicrobial
evaluation.
Black crystals; Yield 48 %; m.p. 130–130 °C
Anal. For C25H21NO6S (463.50)
Calcd.; C 64.78; H 4.57; N 3.02; S 6.92
Found; C 64.59; H 4.43; N 3.12; S 6.82
IR (KBr) mmax. cm-1: 1760 (CO of ester), 1665 (CO),
1630 (C=N) and 1360 (SO3).
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