Heterocyclic compounds from 4H-3,1-benzoxazin-4-one derivatives as anticancer agent

Article abstract of DOI:10.1002/jhet.5570420703

Behaviour of 2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzoic acid (1) towards nitrogen nucleophiles namely, hydrazine hydrate, in different solvents, ammonium acetate, and o-phenylenediamine has been investigated to give aminoquinazolin-4-one, benzotriazepi

Full text of DOI:10.1002/jhet.5570420703

Nov-Dec 2005
1257
Heterocyclic Compounds from 4H-3,1-Benzoxazin-4-one Derivatives
As Anticancer Agent
Taha M Abdel-Rahman
Faculty of Specific Education, Ain-Shams University, Abbassia , Cairo, Egypt
E-mail taha_mahmoud48@hotmail.com
Received November 9, 2004
Behaviour of 2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzoic acid (1) towards nitrogen nucleophiles
namely, hydrazine hydrate, in different solvents, ammonium acetate, and o-phenylenediamine has been
investigated to give aminoquinazolin-4-one, benzotriazepinone, spiro-type compound, and nitrogen bridge-
head compounds 3-5, respectively. Also, reactivity of the aminoquinazolin-4-one 2 towards carbon elec-
trophiles such as ethyl acetoacetate, ethyl phenylacetate, ethyl chloroacetate, and aromatic aldehydes has
been discussed. Reaction of Schiff's base 8 with sulfur nucleophiles namely o-aminothiophenol and/or thio-
glycolic acid afforded Michael type adducts. Structural assignments, of products 1-24 have been confirmed
1
13
by elemental analysis and spectral data ( H- and C –NMR and MS fragmentation). The bioassay indicates
that some of the target compounds obtained have good selective anticancer activity.
J. Heterocyclic Chem., 42, 1257 (2005).
Recently it was reported that 2-substituted (4H)-3,1-
benzoxazin-4-one acts as C1r serine protease inhibitors [1]
and the corresponding 4(3H)-quinazolin-4-ones acts as
non-steroidal anti-inflammatory agents [2], potent anti-
convulsant and enzyme initiators [3], and has been shown
to posses anti-mitotic, anti-cancer [4], anti-HIV-1 [5] and
anti-viral potency [6]. This led us to synthesize new iso-
lated and/or fused heterobicyclic systems starting from
compound (1) and the corresponding quinazolin-4-one 2 in
view of their anticancer activities.
Phthalic anhydride reacts with anthranilic acid in reflux-
ing 1-butanol to give 2-(4-oxo-4H-benzo[d][1,3]oxazin-2-
yl)-benzoic acid (1). Compound 1 was presented in two
conformer 1a and 1b. Conformer1b seems to be more sta-
ble than 1a due to it exhibits a decrease in steric hindrance
and the presence of carboxyl group in the same plane of
oxazinone nucleus and its ability to form hydrogen bond
with nitrogen atom.
Recently [7], it was reported that 4H-3,1-benzoxazin-4-
one derivatives bearing alkyl substituents at 2-position
undergo hetero ring opening by hydrazine hydrate. In this
investigation, the reactivity of 1 towards hydrazine hydrate
was studied. Thus, when compound 1 was allowed to react
with hydrazine hydrate in boiling ethanol compound 2 was
obtained (Scheme 1). On the other hand, when compound
1 was allowed to react with hydrazine hydrate in a high
boiling non-polar solvent, e.g., xylene, the reaction takes
place via hetero ring opening followed by cyclization and
accompanied by ring expansion leading to triazepinone
derivatives 3 (Scheme1).
was submitted to react with ammonium acetate at 150 °C
in an oil bath, hetero ring opening reaction occurs fol-
lowed by cyclization giving the spiro-type addition com-
pound 4 (Scheme1).
Interaction of the benzoxazin-4-one 1 with o-phenylene-
diamine under drastic conditions yielded the bridgehead
nitrogen compound 5 (this may be due to stability of the
oxazin-4-one nucleus or partly due to steric hindrance
which prevents approach of the nucleophile). Structure 5b
is more thermodynamically stable than 5a due to conjuga-
tion. The reaction possibly takes place via hetero ring
opening followed by recyclization, (Scheme1)
In this investigation reactivity of 2 towards carbon elec-
trophiles was also investigated. Thus when aminoquina-
zolin-4-one derivative 2 was allowed to react with ethyl
acetoacetate, ethyl phenylacetate and ethyl chloroacetate
in refluxing 1-butanol the condensed heterocyclic com-
pounds 6a-c were obtained, respectively (Scheme 2). The
reaction takes place via tetrahedral mechanism which
needs small energy of activation because such system
Table 1
13
C-NMR of Compound (6c)
During the last two decades El-hashash and cowork-
ers, [8-11] studied the reactivity of 2-substituted 4H-3,1-
benzoxazin-4-one derivatives towards ammonia and/or
formamide with the aim of conversion of benzoxazin-4-
one derivatives to the more stable quinazolin-4-one
derivatives by a facile one step process. The present
work deals with the reactivity of the benzoxazin-4-one
derivative 1 towards ammonia. Thus when compound 1
No.of
carbon
δ(ppm)
No.of
carbon
δ(ppm)
No.of
carbon
δ(ppm)
C-1
C-2
C-3
C-4
C-5
C-6
32.053
C-7
134.654 C-13
120.036 C-14
153.202 C-15
166.022 C-16
131.765 C-17
123.243
132.213
128.898
128.048
131.402
166.198
175.301 C-8
166.876 C-9
125.112 C-10
127.321 C-11
125.116 C-12

1258
T. M. Abdel-Rahman
Vol. 42
receive much of its "energy – payment" from formation of
the new bond (N-C) before having to pay its "energy debt"
for the breakage of the (C-OEt) bond.
On the other hand, treatment of compound 6c with ani-
line in an oil bath at 150 °C gave the nitrogen bridgehead
compound 6d (Scheme 1). Treatment of compound 2 with
chloroacetylchloride gives compound 6c which is identi-
fied via mp and mixed mp determination.
Recently[12], it was reported that 2-chloroacetyl
4(3H)quinazolin-4-one is easily replaced by nucleophiles.
This prompted us to investigate the reactivity of 6c
towards carbon nucleophiles. Thus when compound 6c
was allowed to react with active methylene compounds
namely, acetylacetone, ethyl acetoacetate and diethyl mal-
onate, in presence of sodium ethoxide yielded C-alkylated
derivatives 7a-c respectively (Scheme 1).
tivity of the 3-aminoquinazolinone 2 towards elec-
trophiles, we report here the reaction of 2 with aromatic
aldehydes namely, benzaldehyde, o-chlorobenzaldehyde
and p-methoxybenzaldehyde affording the Schiff's bases
8a–c respectively (Scheme 2). When compound 8a was
allowed to react with thioglycolic acid in ethanol 10 was
obtained (Scheme 2).
The Michael type adduct 9 was obtained by allowing
compound 8a to react with o-aminothiophenol. Compound
9 has been reacted with acetyl chloride and benzoyl chlo-
ride to give N-acetyl or benzoyl derivatives 11a and 11b
respectively. Acetylation and/or benzoylation of the sec-
ondary NH does not take place due to formation of an
intramolecular hydrogen bond. Also compound 9 has been
reacted with benzene sulphonylchloride and p-toulene
sulphonyl chloride to give N-sulphonyl derivatives 12a
and 12b, respectively (Scheme 2).
Moreover, as a part of our program on the chemical reac-

Nov-Dec 2005
Heterocyclic Compounds from 4H-3,1-Benzoxazin-4-one Derivatives
1259
On the other hand, treatment of compound 6c with
thiosemicarbazide [13] in methanol gave 13, which was
reacted with different aromatic aldehydes namely, ben-
zaldehyde, 4-methylbenzaldehyde and 3,4.5-trimethoxy
benzaldehyde in absolute ethanol and a few drops of
glacial acetic acid, which resulted in the formation of
compounds 14a-c. Compounds 14a-c on cyclo conden-
sation with thioglycolic acid in the presence of a pinch
of anhydrous zinc chloride furnished compounds 15a-c
(Scheme 3).
Treatment of compounds 7a-c with hydrazine hydrate in
boiling ethanol gave pyrazole derivatives 16-18 respec-
tively. However 7a-c reacts with urea and/or thiourea in
the presence of sodium ethoxide as a catalyst to afford
pyrimidine and thiopyrimidine derivatives 19a-b, 20a-b as
well as barbituric acid and thiobarbituric acid derivatives
21a-b respectively. On the other hand, treatment of com-
pounds 7a-c with hydroxyl amine hydrochloride in pyri-
dine gave isoxazole derivatives 22-24 respectively
(Scheme 4).

1260
T. M. Abdel-Rahman
Vol. 42
Table
2
Table 3
In vitro antitumor activity data of some selected new compounds.
Compds. cell line IC
13
C-NMRof Compound (21b)
50
DOX
DOX
3
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
0.7 µg/ml
0.8 µg/ml
9.32 µg/ml
8.97 µg/ml
9.32 µg/ml
9.88 µg/ml
5.16 ug/ml
8.67 µg/ml
5.96 µg/ml
9.02 µg/ml
2.36 µg/ml
4.03 µg/ml
5.65 µg/ml
9.43 µg/ml
5.39 µg/ml
9.24 µg/ml
3.65- µg/ml
3.43-µg/ml
6c
6d
11b
12b
15b
18
No.of
δ(ppm)
carbon
No.of
δ(ppm)
carbon
No.of
δ(ppm)
carbon
C-1
C-2
C-3
C-4
C-5
C-6
C-7
191.035 C-8
184.027 C-9
127.297 C-15
125.230 C-16
134.706 C-17
120.039 C-18
153.136 C-19
166.024 C-20
131.837 C-21
123.387
132.112
128.835
128.064
131.448
166.236
184.013
53.126
32.067
C-10
C-11
liver carcinoma cell line (Hepg 2)
brain tumor cell line (U251)
liver carcinoma cell line (Hepg 2)
21b
175.112 C-12
166.997 C-13
125.230 C-14
IC : Dose of the drug that reduces survival to 50%.
50

Nov-Dec 2005
Heterocyclic Compounds from 4H-3,1-Benzoxazin-4-one Derivatives
1261
Table 4
Characterization Data of Various Compounds Prepared
MP
°C
MolecularFormula(Mole
cularWeight)
Compd.
Solvent
Analysis % Calculated (Found)
C
(Yield)
H
Cl
N
S
1
2
A
E
M
P
155-6
(55)
176-7
(63)
188-190
(75)
162-3
55
180-1
(52)
186-8
(62)
296-8
44
183-5
(50)
C15H9 N O4
(267.24)
C15 H11 N3 03
(281.27)
C15 H11 N3 03
(281.27)
C15 H10N203
(266.25)
C21 H13 N3 O2
(339.35)
C19 H13 N3 O4
(347.32)
C23 H15 N3 O3
(381.38)
C17H10ClN3O3
(339.73)
67.42
67.61
64.05
64.29
64.05
64.32
67.67
67.94
74.33
74.52
65.70
65.96
72.43
72.62
60.10
59.88
69.69
69.45
65.50
65.33
63.74
63.98
62.20
62.04
71.54
71.33
65.43
65.19
69.17
69.39
68.00
67.77
65.00
64.79
67.15
66.92
70.22
69.98
64.34
64.57
64.80
65.03
54.81
55.05
62.23
61.97
62.89
63.14
58.73
58.97
58.26
58.53
58.93
59.18
55.72
55.98
66.16
66.40
62.84
62.59
59.56
59.78
3.39
3.46
3.94
4.00
3.94
4.01
3.79
3.85
3.86
3.92
3.77
3.84
3.96
3.89
2.97
2,91
4.07
3.99
4.25
4.17
4.42
4.35
4.57
4.49
4.09
4.02
3.49
3.41
4.29
4.21
4.48
4.41
3,86
3.79
4.51
4.45
4.38
4.32
4.13
4.07
4.35
4.28
3.58
3.65
3.76
3.69
4.06
3.99
4.22
4.17
3.62
3.55
3.89
3.96
4.05
3.97
4.29
4.20
3.77
3.69
3.25
3.18
5.24
5.19
14.94
15.09
14.94
14.79
10.52
10.63
12.38
12.51
12.10
12.01
11.02
11.13
12.37
12.25
14.13
13.98
10.42
10.31
9.70
3
4
5
B
B
A
E
E
E
B
E
E
M
M
A
E
P
6a
6b
6c
10.44
10.32
6d
7a
200-2
(55)
C23 H16 N4 O3
(396.40)
214-5
(48)
C22 H17 N3 O5
(403.39)
7b
7c
227-9
(73)
C23 H19N3O6
(433.41)
9.59
9.07
9.16
217-9
(55)
C24H21N3O7
(463.44)
8a
293-5
(56)
C22H15N3O3
(369.37)
11.38
11.26
10.41
10.30
10.52
10.64
11.33
11.23
9.48
8b
8c
216-8
(76)
C22H14ClN3O3
(403.82)
8.78
8.69
212-2
(59)
C 23H17N3 O4
(399.41)
9
219-221
(54)
C28H22N4O3 S
(494.57)
6.48
6.55
7.23
7.16
5.98
6.04
5.36
5.29
10.10
9.99
9.89
10.01
8.13
8.04
6.65
6.73
6.46
6.53
5.60
5.67
11.52
11.63
11.24
11.36
9.92
10.04
10
11a
11b
12a
12b
13
14a
14b
14c
15a
15b
15c
16
17
18
264-5
(49)
C24H17N3O4S
(443.48)
9.39
250-2
(66)
C30 H24 N4O4S
(536.60)
10.44
10.35
9.36
9.25
8.83
8.74
8.64
8.70
E
P
281-2
(73)
289-91 (73)
C35 H26 N4O4S
(598.67)
C34 H26 N4O5S2
(634.73)
P
291-3
(37)
C35 H28 N4O5S2
(648.75)
P
204-6
(45)
C18 H14N6O3S
(396.41)
21.31
21.19
17.42
17.27
16.93
17.09
14.68
14.80
15.10
14.97
14.73
14.62
13.00
12.89
17.53
17.38
17.45
17.30
17.36
17.50
B
B
B
E
M
E
A
E
E
227-9
(36)
C25 H18 N6O3S
(482.52)
228-6
(73)
C26 H20 N6O3S
(496.54)
277-9
(55)
C28 H24 N6O6S
(572.59)
272-4
(59)
C27 H20N6O4S2
(556.62)
275-7
(48)
289-91 (64)
C28 H22N6O4S2
(570.64)
C30 H26N6O7S2
(646.70)
201-3
(70)
C22H17N5O3
(399.40)
199-200
(59)
C21H15N5O4
(401.38)
206-8
(82)
C20H13N5O5
(403.35)

1262
T. M. Abdel-Rahman
Vol. 42
Table 4 (continued)
MP
°C
MolecularFormula(Mole
cularWeight)
Compd.
Solvent
Analysis % Calculated (Found)
C
(Yield)
H
Cl
N
S
19a
19b
20a
20b
21a
21b
22
A
A
A
M
M
E
206-4
(63)
C23H17N5O4
(427.41)
64.63
4.01
3.94
3.86
3.79
3.52
3.45
3.39
3.46
3.04
3.12
2.93
3.01
4.03
4.11
3.51
3.44
2.99
3.07
16.39
16.55
15.79
15.64
16.31
16.18
15.72
15.58
16.24
16.09
15.65
15.49
13.99
14.14
13.92
14.07
13.86
14.00
64.86
62.29
62.50
61.54
61.31
59.32
59.10
58.47
58.69
56.37
56.58
65.99
66,23
62.69
62.91
59.41
59.63
215-3
(76)
C23H17N5O3S
(443.48)
7.23
7. 16
204-6
(71)
C22H15N5O5
(429.39)
207-9
(75)
C22H15N5O4S
(445.45)
7.20
7.13
215-7
(72)
C21H13N5O6
(431.36)
222-4
(74)
C21H13N5O5S
(447.42)
7.17
7.23
A
A
E
207-9
(34)
C22H16N4O4
(400.39)
23
211-4
(46)
C21H14N4O5
(402.36)
24
217-8
(53)
C20H12N4O6
(404.33)
B = benzene, E = Ethanol, A = Acetic acid , M = Methanol, P = Petroleum ether 60-80 °C.
was prepared following an reported procedure [7]. The physical
data of the synthesized compounds are given in Table 4
Some of the new compounds have been evaluated for in
vitro antitumor activity according to the described method
of Skehan and coworkers, [14] against brain tumor cell line
(U251) and liver carcinoma cell line (Hepg 2) at drug con-
centration between (1.00-10.00 µg/ml) using sulforho-
2-(4-Oxo-4H-benzo[d][1,3]oxazin-2-yl)-benzoic Acid (1).
To a solution of anthranilic acid (0.01 mol) in dry butanol (50
ml) was added phthalic anhydride (0.01 mol), and the reaction
mixture was heated under a reflux for 20 hrs. The product that
damine B (SRB) protein assay [14]. The IC percent con-
50
trol of infected and uninfected response values were calcu-
lated for the various active compounds are reported in Table
separated on cooling was recrystallized from benzene to give 1
-1
(Table 4). IR (KBr, ν
in cm ): 1701, 1681(C=O), 3475 (OH,
max
1
H-bridge); H NMR δ (DMSO-d ): 7.45-8.12 (m, 8H, Ar-H),
3. Compounds having IC
< 5 µg/ml. are considered
H
6
50
13
11.48 (s. 1H, OH) ppm; C NMR δ (DMSO-d ): 118.57,
potentially active and exposed to further in vivo studies.
The results obtained in Table 3 showed that: 1-The com-
pounds 12b and 21b possessed significant effect on both
cell lines [brain tumor (U251) and liver carcinoma (Hepg
2)], which might be due to the presence of N-Phenyl-ben-
zenesulfonamide and thiobarbituric acid moieties. 2-The
compounds 6d, 11b, 15b and 18 were moderately active
against brain tumor cell line (U251) and possess lethal activ-
ity against liver carcinoma (Hepg 2). 3-The compounds 3
and 6c possess lethal activity against both cell lines.
C
6
120.98, 128.64, 128.82, 129.41, 130.96, 132.09, 132.45, 132.82,
133.84, 135.87, 156.47, 158.56, 162.07, 172.64.
2-(3-Amino-4-oxo-3,4-dihydroquinazolin-2yl)-benzoic Acid (2).
A solution of 1 (0.01 mol) and hydrazine hydrate (0.015 mol)
in ethanol (40 ml) was heated under reflux for 3 hrs. The product
that separated on cooling was recrystallized from a suitable sol-
-1
vent to give 2 (Table 4). IR (KBr, ν
in cm ): 3482 (OH, H-
max
1
bridge) 3274, 3183 (NH ), 1705,1650(C=O). H-NMR δ
(DMSO-d ): 2.56 (s, 2H, NH ), 7.45-8.12 (m, 8H, Ar-H), 11.55
2
H
6
2
(s,1H, OH) ppm.; MS: m/z: (Int %): 281.05(0.04), 266.95 (0.08),
252.95 (0.10), 223(0.52), 179(20.15), 137 (54.53), 119(100),
91.95(42.61), 64.95 (26.49).
EXPERIMENTAL
2-(5-Oxo-4,5-dihydro-3H-benzo[e][1,2,4]triazepin-2-yl)-ben-
zoic Acid (3).
The reported mp's are uncorrected. Elemental analysis were
carried out in the Micro analytical center, Cairo university and
Anticancer activity "Doxirubsin was used as positive stander" in
the National center Institute, Cancer Biology Department,
Pharmacology Unit, Cairo University, Egypt. IR spectra (KBr)
were recorded on BRUKER VECTOR 22 FT spectrophotometer
A solution of compound (1) (0.01 mol) and hydrazine
hydrate (0.015 mole, 0.75 ml) in xylene (50 ml) was heated
under reflux for 3 hrs. The product that separated on cooling
was recrystallized from a suitable solvent to give 3 (Table 4);
-1
1
-1
(ν
in cm ), H-NMR spectra were recorded on a Varian
IR (KBr, ν
in cm ): 3487 (OH-H-bridge), 3186, 3165
max
max
1
Gemini 200 MHz (Germany) using DMSO as a solvent and TMS
as an internal reference δ (chemical shifts in ppm) and mass spec-
tra were recorded on a gas chromatographic GC/MS-HEWLETT
PACKARD 5988A GC/MS instrument at 70 eV. Compound 1
(NH), 1701, 1665(C=O), 1610(C=N); H-NMR δ (DMSO-
d ): 2.51 (s, H, NH), 7.47-8.10 (m, 8H, Ar-H),8.38 (s, 1H, NH-
H
6
C=O), 11.47(s, H, OH) ppm; MS: m/z: (Int %): 281.70(0.03),
262.95(0.04), 222.00(0.14), 221(0.50), 164.00(1.18), 163.00

Nov-Dec 2005
Heterocyclic Compounds from 4H-3,1-Benzoxazin-4-one Derivatives
1263
(12.61), 162.00 (99.73), 132.95 (4.65), 131.95(21.10), 118.05
(1.42), 105.05 (23.43), 103.95(100), 91.05(4.57),
676.95(30.14), 75.95 (37.74), 74.95 (11.87), 73.95(14.48),
72.95(3.81), 63.95(2.44), 62.95(4.27), 52.95(4.98),
51.95(6.71), 50.95(29.78).
tallized from the proper solvent to give compounds 7a-c (Table 4).
-1
IR (KBr, ν
in cm ): (7a) 1705, 1708, 1697, 1673 and 1661
max
1
(C=O); H-NMR δ (DMSO-d ): (7b) 1.36 (t, 3H, CH CH ), 1.99
H
6
2
3
(s, 3H, COCH ), 2.72 (d, 2H, COCH CH), 3.53 (t, H, CH CHCO ),
3
2
2
2
4.14 (q, 2H, COOCH CH ), 7.61-8.00 (m, 8H, Ar-H) ppm.
2
3
2-[3-(Benzylideneamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-
benzoic Acid (8a), 2-[3-(2-Chloro-benzylidene)-amino}-4-oxo-
3,4-dihydro-quinazolin-2-yl) benzoic Acid (8b) and 2-{3-[4-
Methoxy-benzylidene)-amino]-4-oxo-3,4-dihydro-quinazolin-2-
yl}benzoic Acid (8c).
Formation of the Spiro Compound (4).
A mixture of compound 1 (1 g) and ammonium acetate (4 g)
was heated in an oil bath at 150 °C for 3 hrs., then cooled and
poured onto water. The product that separated was recrystallized
-
from a suitable solvent to give 4 (Table 4); IR (KBr, ν
in cm
max
1
1
A solution of compound 2 (0.01 mol) and aromatic aldehydes,
namely, benzaldehyde, o-chlorobenzaldehyde and p-methoxy-
benzaldehyde (0.01 mol) in ethanol (30 ml) was heated under
reflux for 3 hrs. The products that separated on cooling were
): 3243, 3197 (NH), 1775, 1731 and 1666 (C=O); H-NMR δ
H
(DMSO-d ): 4.09 (s, H, NH-Ar) ,6.71-7.97(m, 8H, Ar-H), 8.24
6
(s, H, NH-C=O), ppm.
Formation of Compound (5).
recrystallized from suitable solvents to give 8a-c (Table 4). IR
-1
(KBr, ν
in cm ): (8b) 3482 (OH, H-bridge), 1700, 1672
A mixture of compound 1 (0.01mol) and o-phenylenediamine
(0.01 mol) was fused in oil bath at 170 °C for 3 hrs. then poured
into water. The solid that separated on cooling was recrystallized
max
1
(C=O), 1618 (C=N).; H-NMR δ (DMSO-d ): (8c) 3.70 (s,
3H,OCH ), 7.04-8.18 (m, 13H, Ar-H and -N=CH-), 11.48 (s, H,
H
6
3
-
OH) ppm; MS: m/z: (Int %): (8a) 368.05(0.51), 366.45(0.56),
336.95(0.51), 310.15(0.56), 267.40(0.46), 223.05(2.41),
162(52.87), 104(95.65), 77(75.49), 76(100), 75.09(47.09),
74.00(77.15) (8c) 399.41(00.00), 344.20(2.37), 256.20 (2.37),
224.05 (10.21), 161.95(100), 162.95(11.07), 132(20.10),
121(10.64), 104(77), 77(18.05), 76(18.01), 73(12.73).
from a suitable solvent to give 5 (Table 4); IR(KBr, ν
in cm
max
1
1
): 3361 (NH), 1683,1645(C=O); H-NMR δ (DMSO-d ): 6.66-
H
6
7.97 (m, 12H, ArH), 8.18(brs, H, NH-C=O) ppm.
6-(3-Oxobutanoyl)-phalazino[1,2-b]quinazoline-5,8-dione (6a),
6-Phenylacetylphalazino[1,2-b]quinazoline-5,8-dione (6b) and
6-(2-Chloro-acetyl)-phalazino[1,2-b]quinazoline-5,8-dione (6c).
Formation of Michael Type Adducts.
A solution of compound 2 (0.01 mol) with ethyl esters
namely, ethyl acetoacetate, ethyl phenylacetate and ethyl
chloroacetate (0.01 mol) in 1-butanol (40 ml) was heated under
reflux 3 hrs. The products that separated after cooling were
2-(3-{[2-Amino-phenylsulfanyl)-phenyl-methyl]-amino}-4-oxo-
3,4-dihydro-quinazolin-2-yl)-benzoic Acid (9).
A solution of compound 8 (0.005 mol) and 2-aminothiophenol
(0.005 mol) in benzene (30 ml) containing 3 drops of piperidine
was left aside for 4 days at room temperature. The product was
crystallized from the proper solvents to give 6a-c (Table 4). IR
-1
(KBr, ν
in cm ): (6b) 3013 (CH-aromatic), 2914 (CH-
max
1
aliphatic), 1683, 1675 and 1660 (C=O); H NMR:(6b) 3.42
collected by filtration and recrystallized from the suitable solvent
1
-1
(s,2H,-COCH Ph), 7.09-7.90 (m,13H,ArH) ppm. H-NMR δ
to give the Michael adduct (9) (Table 4). IR(KBr, ν
in cm ):
2
H
max
(DMSO-d ):(6c), 4.27 (s,2H,COCH Cl),7.46-8.00 (m, 8H,Ar-
3444(OH,H-bridge), 3351, 3274 (NH ), 3182(NH), 1701, 1648
(C=O).; H-NMR δ (DMSO-d ): 2.51 (brs,1H, NH))
4.23(s,2H,NH -Ph ),4.95(s, H, N-CH-Ph), 6.48-8.18 (m, 17H,Ar-
6
2
2
1
H) ppm.; MS: m/z: (Int %): (6b) 385.45(21.92), 384.70
(15.07), 343.95(17.81), 292.40(15.07), 241.40(23.29),
204.30(20.55), 161.95(45.21), 127.40(19.18), 76.90 (39.73),
53(100).51.90(49.32), 51.00(73.97).
H
6
2
H). 11.53 (s, H,OH) ppm.; MS: m/z: (Int %): 494.57(0.00),
427.20 (9.32),394.20 (9.50), 320.05(40.43), 255.05(30.10),
211.05(100), 161.05 (45.81) ,103 (33.57).
6-(2-Phenylaminoacetyl)-phalazino[1,2-b]quinazoline-5,8-dione
(6d).
2-[4-Oxo-3,4-oxo-2-phenyl-thiazolidin-3-yl)-3,4-dihydro-quina-
zolin-2-yl}benzoic acid (10).
A mixture of compound 6c (0.01 mol) and aniline (0.01 mol) was
heated in an oil bath at 150 °C for 3 hrs. The reaction mixture after
cooling was treated with ice/conc. HCl. The solid that separated was
collected by filtration and recrystallized from the proper solvent to
A solution of compound 8a (0.01 mol) and thioglycolic acid
(0.01 mol) and piperidine 3 drops in ethanol (30 ml) was heated
under reflux for 3 hrs. The product separated on cooling was
-1
give 6d (Table 4). IR (KBr, ν in cm ): (6d); 3183(NH); 1684 and
recrystallized from a suitable solvent to give compound 10 (Table
max
1
-1
1662(C=O); H-NMR δ (DMSO-d ): (6d) 3.81(s, 2H,-CO CH NH
Ph), 4.22 (s, H, NH-Ar), 6.48-7.99 (m, 13H, Ar-H)ppm.
4); IR (KBr, ν
in cm ): 3475 (OH, H-bridge), 1743, 1693 and
H
6
2
max
1
1681(C=O); H-NMR δ (DMSO-d ): 3.28 (s, 2H, COCH -of
H
6
2
thiazolidinone ring), 5.5 (s, H, CH-of thiazolidinone ring), 7.09-
8.18 (m, 13H, Ar-H), 11.50 (s, H, OH) ppm; MS: m/z: (Int %):
443.49(0.00), 365.20(0.20), 313.30(0.22), 236.20(0.27),
161.85(100), 138(15.81), 104(3.00), 76(26), 51(14).
6-(3-Acetyl-4-oxo-pentanoyl)-phalazino[1,2-b]quinazoline-5,8-
dione (7a), 2-Oxo-[(5,8-dioxophalazino[1,2-b]quinazoline-6-
yl)-ethyl]-butyric Acid Ethyl Ester (7b) and 2-Oxo-[(5,8-diox-
ophalazino[1,2-b]quinazoline-6-yl)-ethyl]-Malonic Acid Diethyl
Ester (7c).
2-(3-{[2-Acetylamino-phenylsulfanyl)-phenylmethyl]amino-4-
oxo-3,4-dihydro-quinazolin-2-yl}benzoic Acid (11a) and 2-(3-
{[2-Benzoylamino-phenylsulfanyl)-phenylmethyl]amino-4-oxo-
3,4-dihydro-quinazolin-2-yl}benzoic Acid (11b).
A mixture of 6c (0.01 mol) and active methylene compounds
namely, acetyl acetone, ethyl acetoacetate and diethyl malonate
(0.01 mol) was treated with ethanol (30 ml) containing sodium metal
(0.75 gm) and heated under reflux for 3 hrs. Excess of solvent was
removed under reduced pressure and the reaction mixture was
treated with ice/HCl solution. The solids that separated were recrys-
A solution of compound 9 (0.005 mol) and acetyl chloride and/or
benzoyl chloride (10 ml) was heated under reflux for 1 hr. The prod-
ucts separated after removing excess of acid chloride were recrys-

1264
T. M. Abdel-Rahman
Vol. 42
tallized from suitable solvents to give 11a,b (Table 4); IR (KBr,
cooled and poured into cold water. The separated solid was col-
lected by filtration and recrystallised from appropriate solvents to
-1
ν
in cm ): (11b) 3430 (OH, H-bridge), 3172, 3121 (NH), 1701,
max
1
-1
1673, and 1661 (C=O); H-NMR δ (DMSO-d ): (11a) 2.03 (s,
afford compounds 15a-b, (Table 4); IR (KBr, ν
in cm ):
H
6
max
3H, COCH ), 2.52 (s, 1H, NH), 4.84 (s, 1H, S-CH-Ph), 7.04-8.12
(15b) 3263, 3095 (NH), 2835 (CH ) 1766, 1675, 1667 and 1653
3
2
1
(m, 17H, Ar-H), 8.12 (brs, 1H, NH-COCH ), 11.55 (s, H, OH) ppm;
(C=O), 1586 (C=N), 1176 (C=S), 1142(C-S); H-NMR δ
3
H
MS: m/z: (Int %): (11b) 599(65), 505(60), 446(70), 399.70(55),
283(75), 229(70), 122.15(100), 105.15(95), 74.15(60), 54.90(70).
(DMSO-d ) (15a): 2.53, 2.61 (brs, 2H, 2NH), 3.25 (s, 2H, CH of
6
2
thiazolidinone ring), 3.65 (s, 2H, COCH ), 5.86 (s, H,CH-of thia-
2
zolidinone ring), 7.04-7.99 (complex m, 13H, Ar-H) ppm.
2-(3-{[2-Benzenesulfonylamino-phenylsulfanyl)-phenyl-
methyl]-amino}-4-oxo-3,4-dihydro-quinazolin-2-yl}benzoic
Acid (12a) and 2-[4-Oxo-3-({phenyl-[2-(toluene-4-sulfony-
lamino)-phenylsulfanyl]-methyl}-amino)-3,4-dihydro-quina-
zolin-2-yl}benzoic Acid (12b).
6-[2-(3,5-Dimethyl-4H-pyrazol-4-yl)-acetyl]-phalazino[1,2-b]-
quinazoline-5,8-dione (16), 6-[2-(3-Methyl-5-oxo-4,5-dihydro-
1H-pyrazol-4-yl)-acetyl]- phalazino[1,2-b]quinazoline-5,8-dione
(17) and 6-[2-(3,5-Dioxo-pyrazolidin-4-yl)-acetyl]-pha-
lazino[1,2-b]quinazoline-5,8-dione (18).
A solution of compound 9 (0.01 mol) and benzene sulphonyl
chloride and/or p-toluene sulphonyl chloride (10 ml) was heated
under reflux for 1 hr. The products that separated after removing
A solution of compounds 7a-c (0.01 mol) and hydrazine
hydrate (0.015 mol) in ethanol (40 ml) was heated under reflux
for 3 hrs. The product that separated on cooling was recrystal-
excess of acid chloride were recrystallized from suitable solvents
-1
to give 12a,b (Table 4); IR (KBr, ν
in cm ): (12b) 3429 (OH,
lized from a suitable solvent to give compounds 16-18 (Table 4);
max
-1
H-bridge), 3172, 3113 (NH), 1705 and 1663 (C=O), 1156(S=O);
H-NMR δ (DMSO-d ): (12a) 2.51 (brs, 1H, NH-Ph), 4.22 (s,
1H, NH-SO ), 4.84 (s, 1H, N-CH-Ph), 632-8.12 (m, 22H, Ar-H),
IR (KBr, ν
in cm ): (16) 1693, 1667 and 1656 (C=O), 1604
max
1
1
(C=N); H-NMR δ (DMSO-d ): (16) 1.85 (t, 1H, CH), 2.03,
H
6
H
6
2.04, (s, 6H, 2CH ), 2.52 (d, 2H, COCH ), 7.44-8.01 (m, 8H, Ar-
2
3
2
11.47 (s, H, OH) ppm.
H) ppm.
6-Acetylthiosemicarbazidophalazino[1,2-b]quinazoline-5,8-
dione (13).
6-[2-(4,6-Dimethyl-2-oxo-2,5-dihydro-pyrimidin-5-yl)-acetyl]-
phalazino[1,2-b]quinazoline-5,8-dione (19a), 6-[2-(4,6-
Dimethyl-2-thioxo-2,5-dihydro-pyrimidin-5-yl)-acetyl]-pha-
lazino[1,2-b]quinazoline-5,8-dione (19b), 6-[2-(4-Methyl-1-2,6-
dioxo-1,2,5,6-tetrahydro-pyrimidin-5-yl)-acetyl]-phalazino[1,2-
b]quinazoline-5,8-dione (20a), 6-[2-(4-Methyl-6-oxo-2-thioxo-
1,2,5,6-tetrahydro-pyrimidin-5-yl)-acetyl]-phalazino[1,2-
b]quinazoline-5,8-dione (20b), 5-[2-(5,7-Dioxo-5,7-dihydropha-
lazino[1,2-b]quinazoline-6-yl)-2-oxo-ethyl]-pyrimidine-2,4,6-
trione (21a) and 6-[2-(4,6-Dioxo-2-thioxo-hexahydro-pyrimidin-
5-yl)-acetyl]-phalazino[1,2-b]quinazoline-5,8-dione (21b).
A mixture of thiosemicarbazide (0.01 mol) and (0.01 mol) of
compound 6c in methanol was refluxed on a steam bath for 6 hrs.
The excess solvent was distilled off and the reaction mixture was
poured into ice cold water, the solid collected by filtration and
recrystallized from an appropriate solvent to give compound (13)
-1
(Table 4). IR (KBr, ν
in cm ): 3342, 3274 (NH ), 3183, 3114
max
2
1
(NH), 1675, 1668, 1660 (C=O), 1190 (C=S); H-NMR δ
(DMSO-d ): 2.51-2.59 (complex m, 4H, NHNH CSNH ) 3.62 (s,
H
6
2
2H, COCH ), 7.41-7.86 (m, 8H, Ar-H) ppm.
2
A solution of compound 7a-c (0.01 mol) and urea and/or
thiourea (0.01 mol) in ethanol (40 ml) was treated with sodium
ethoxide (0.015 mol) and heated under reflux for 3 hrs. The reac-
tion mixture after concentration and cooling was treated with
ice/HCl solution. The solid product obtained was recrystallized
from a suitable solvent to give barbituric and thiobarbituric acid
6-Acetylthiosemicarbazido(substitudedarylidene)-phalazino[1,2-b]-
quinazoline-5,8-dione (14a-c).
A mixture of compound 13 (0.01 mol) in absolute ethanol (30
ml), a few drops of glacial acetic acid and aromatic aldehydes
(0.01 mol) namely, benzaldehyde, 4-methylbenzaldehyde and
3,4.5-trimethoxybenzaldehyde was refluxed on a steam bath for
6-8 hrs. The excess solvent was distilled off and the residue was
poured onto ice. The separated solids were collected by filtra-
derivatives 19a-b, 20a-b and 21a-b respectively, (Table 4);
-1
IR(KBr, ν
in cm ): (19a) 1679, 1675, 1660 and 1645 (C=O);
max
(20b) 3242 (NH), 1690, 1675, 1667 and 1647 (C=O), 1160
1
tion and recrystallized from appropriate solvents to give com-
(C=S), 1595 (C=N); H-NMR δ (DMSO-d ): (19a) 1.20 (s, 6H,
H
6
-1
pounds 14a-c, (Table 4); IR (KBr, ν
in cm ): (14a) 3282,
2CH ), 1.81 (t, 1H, CH-CH), 2.51 (d, 2H, COCH ), 7.37-8.01
max
3
2
1
3179 (NH), 1693, 1676 and 1658 (C=O), 1601 (C=N), 1180
(C=S); H-NMR δ (DMSO-d ): (14a) 2.53, 2.57 (bs, 2H,
2NH), 3.66 (s, 2H, CO CH ), 7.32- 8.12 (m, 14H, Ar-H and -
(m, 8H, Ar-H) ppm; H-NMR: (21a) 2.73 (d, 2H, COCH ), 3.68
2
1
(t, H, CH-CH ), 7.36-8.05 (m, 8H, Ar-H), 10.06 and 10.09(s, 2H,
H
6
2
2NH) ppm.
2
N=CH-Ph) ppm.
6-[2-(3,5-Dimethyl-isoxazol-4-yl)-acetyl]-phalazino[1,2-b]-
quinazoline-5,8-dione (22), 6-[2-(3-Methyl-5-oxo-4,5-dihydro-
isoxazol-4-yl)-acetyl]- phalazino[1,2-b]quinazoline-5,8-dione
(23) and 6-[2-(3,5-Dioxo-isoxazolidin-4-yl)-acetyl]-pha-
lazino[1,2-b]quinazoline-5,8-dione (24).
4-Oxo-2-phenyl-thiazolidine-3-carbathioic Acid N'-Phalazino-
[1,2-b]quinazoline-5,8-dione-6-yl)-2-oxo-ethyl]-hydrazide
(15a), 4-Oxo-2-p-tolyl-thiazolidine-3-carbathioic Acid N'-
Phalazino[1,2-b]quinazoline-5,8-dione-6-yl)-2-oxo-ethyl]-
hydrazide (15b) and 4-Oxo-2-(3,4,5-trimethoxy-phenyl)-thiazo-
lidine-3-carbathioic Acid N'-Phalazino[1,2-b]quinazoline-5,8-
dione-6-yl)-2-oxo-ethyl]-hydrazide (15c).
A solution of compound 7a-c (0.01 mol) and hydroxyl amine
hydrochloride (0.015 mol) in pyridine (30 ml) was refluxed for 3
hrs. The reaction mixture was cooled, then poured into crushed
ice/HCl solution. The solid that separated was collected by filtra-
tion and recrystallized from the proper solvent to give 22-24,
To a stirred solution of compound 14a-c (0.01 mol) in dry
DMF, containing a pinch of anhydrous ZnCl and thioglycolic
acid (0.02 mol), was heated under reflux for 8 hrs. then the excess
solvent was distilled off and the residual reaction mixture was
2
1
(Table 4); H-NMR δ (DMSO-d ) (22) 2.51(s, 6H, 2CH ), 3.49
H
6
3
(s, 2H, COCH ), 7.43-8.01 (m, 8H, Ar-H) ppm.
2

Nov-Dec 2005
Heterocyclic Compounds from 4H-3,1-Benzoxazin-4-one Derivatives
1265
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