Synthesis of some new pyrazoloquinazolinone and quinazolinone derivatives

Article abstract of DOI:10.1002/jhet.5570430509

The benzoxazinone derivative 2-(6,8-dibromo-4-oxo-4H-benzo[d]-1,3-oxazin-2- yl)-3-(4-methoxy-phenyl)acrylonitrile (1) has been used as a starting material for preparation of the hitherto unknown pyrazoloquinazolinone and quinazolinone derivatives. Under d

Full text of DOI:10.1002/jhet.5570430509

Sep-Oct 2006
1189
Synthesis of Some New Pyrazoloquinazolinone
and Quinazolinone Derivatives
A. A. El-Khamry, S. A. Shiba, A. A. Shalaby, and A. A. Abd alaha*
Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
e-mail: abdoelaal@yahoo.com
Received October 31, 2005
O
O
Br
Br
O
N2H4
N
NH
H
EtOH
N
C
C
N
Ar
NC
Ar
Br
Br
CN
(1)
(4)
Ar =
OMe
The benzoxazinone derivative 2-(6,8-dibromo-4-oxo-4H-benzo[d]-1,3-oxazin-2-yl)-3-(4-methoxy-
phenyl)acrylonitrile (1) has been used as a starting material for preparation of the hitherto unknown
pyrazoloquinazolinone and quinazolinone derivatives. Under different conditions the benzoxazinone (1)
was reacted with hydrazine hydrate to provide the pyrazolocarbonitrile derivative (2) and the azine
derivative (3) and/or the pyrazoloquinazoline derivative (4). When (4) was conducted to react either with
EAA (ethyl acetoacetate) or Ac2O/AcOH (acetic anhydride/acetic acid) mixture or phthalic
anhydride/acetic acid mixture, the pyrazoloquinazoline carbonitrile (5), pyrazolo-quinazoline acetic acid
(6) or the pyrazoloquinazolinone derivative (7) were formed respectively. When (1) was reacted with
phenylhydrazine, a mixture of the quinazolinone derivative (8) and the hydrazone derivative (9) were
obtained. The benzoxazinone derivative (1) was found also to react with benzylamine in ethanol or without
solvent to give the quinazolinone derivative (10) or the quinazolindione (11) respectively. Fusion of (1)
with ammonium acetate yielded the quinazolinone (12), which was methylated to give (13) and thiated to
the thioxyquinazoline derivative (14), while reaction of (1) with formamide gave the N-formylquinazoline
derivative (15).
J. Heterocyclic Chem., 43, 1189 (2006).
The pronounced biological and pharmacological
The following mechanism below summarizes their
formation.
activities as anticonvalsant [1,2], antihistaminic [3,4],
antihypertensive [5-8] of these classes of compounds have
stimulated the authors to synthesize these compounds.
Hydrazinolysis of [9] 2-(6,8-dibromo-4-oxo-4H-benzo[d]-
1,3-oxazin-2-yl)-3-(4-methoxyphenyl)acrylonitrile (1)
with hydrazine hydrate in 1-butanol provided a mixture of
3,5-bis-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (2)
and [10] N,N-bis-(4-methoxybenzylidene)hydrazine (3).
However, when the reaction was carried out in ethanol,
5,7-dibromo-2-(4-methoxyphenyl)-9-oxo-1,9-dihydropyra-
zolo[5,1-b]quinazolin-3-carbonitrile (4) was obtained in
fairly good yield. The structure of (4) was further supported
by the following chemical proofs. Reaction of (4) with
EAA (ethyl acetoacetate) yielded 5,7-dibromo-2-(4-
methoxyphenyl)-9-oxo-1-(1,3-dioxobutyryl)-1,9-dihydro-
O
O
O
Br
Br
..
O
NH2NH2
:
H
NHNH2
H
C
Butanol
N
C
C
N
C
H
NC
Ar
Br
Br
CN Ar
(1)
- H+, +H+
Br
O
N
O
2 moles
- N2H4
Ar HC
N
NH2
Ar HC
N N CH Ar
+
CH2CN
(3)
Br

1190
A. A. El-Khamry, S. A. Shiba, A. A. Shalaby, and A. A. Abd alaha
Vol 43
O
N
O
N
CHAr
Br
Br
N
N
O
O
H
H2N
N CH Ar
H
H
H
C
C
C
C
NC
Ar
Br
Br
CN Ar
(1)
O
N
Br
N
N
O
+
Ar
Ar
CN
(2)
OMe
Ar =
Br
pyrazolo[5,1-b]quinazolin-3-carbonitrile (5). The pyrazolo-
quinazoline derivative (4) was reacted with Ac2O/AcOH
mixture to give 5,7-dibromo-3-cyano-2-(4-methoxy-
phenyl)-9-oxo-1,2,3,9-tetrahydropyrazolo[5,1-b]quinazolin-
benzylamine reacted with (1) to give the quinazolinone
derivative (10), while in excess of benzylamine, the dione
derivative (11) was obtained according to the following
mechanism:
O
O
Br
Br
O
NHCH Ph
..
PhCH2NH2
2
H
H
~ H+
N
C
C
N
C
O
C
C
H
NC
Ar
Br
Ar
Br
H
CN
(1)
- H+, +H+
Br
O
CH2Ph
O
N
H
C
C
+
N
H
NC
Ar
Ar =
OMe
Br
(11)
2-acetic acid (6). On the other hand (4) was conducted to
react with phthalic anhydride/AcOH to give 3-acetyl-5,7-
dibromo-2-(4-methoxyphenyl)-3H-pyrazolo[5,1-b]quin-
azolin-9-one (7).
Treatment of (1) with ethanolic solution of phenyl-
hydrazine gave a mixture of 6,8-dibromo-4-oxo-3-
phenylamino-3,4-dihydroquinazolin-2-yl) acetonitrile (8)
and p-anisaldehyde phenylhydrazone (9). In contrast to
Ismail [11] and our previous results [7,9] aminolysis of
benzoxazinone (1) with primary amines depends not only
on the type of amine but also on the conditions, beside the
nature of group in position-2, since in ethanolic solution,
Fusion of (1) with ammonium acetate gave the
quinazolinone derivative (12), whose structure was
confirmed by the following chemical proofs:
Methylation of (12) with dimethylsulphate furnished
2-(6,8-dibromo-3-methyl-4-oxo-3,4-dihydroquinazolin-
2-yl)-3-(4-methoxyphenyl)acrylonitrile (13). Thiation
of (12) with P2S5 gave 2-(6,8-dibromo-4-thioxo-3,4-
dihydroquinazolin-2-yl)-3-(4-methoxyphenyl)acryl-
onitrile (14). Formylation of (1) with excess
formamide, yielded the N-formylquinazolinone
derivative (15).

Sep-Oct 2006
Synthesis of Some New Pyrazoloquinazolinone and Quinazolinone Derivatives
1191
O
N
Br
N
C6H5
CN
Ar HC
N
NHPh
N
NH
Ar
+
Ar HC
(3)
N
(9)
+
2
Ar
Br
CN
(2)
(8)
PhNHNH2/EtOH
N2H4/butanol
Y
N
O
O
Br
PhCH2NH2/EtOH
Br
X
Br
X
Ph
N
N
N
H
H
C
C
N
N
Ar
C
C
NC
Ar
Br
NC
NH Ph
PhCH2NH2/
Br
Br
Y
(10)
(1) X = O, Y = O
(12) X = NH, Y = O
(13) X = NCH3, Y = O
(4) X = H, Y = CN
(5) X = COCH2COCH3, Y = CN
(7) X = H, Y = COCH3
O
(14) X = NH, Y = S
Br
(15) X = NCHO, Y = O
Ph
N
(4) + Ac2O/AcOH
N
O
H
Br
O
(11)
Br
H
N
N
OCOCH3
N
Ar
Ar =
OMe
Br
CN
(6)
Table 1
Characterization Data of Prepared Compounds
Analysis (Required/found)
M P °C
(colour)
Compd
No.
Yield %
(solvent)
Mol. For.
(M.Wt)
C
H
N
287-90
(Brown)
178-80
(Pale yellow)
257-60
(Brown)
235-37
(Brown)
348-50
(Yellow)
350-52
(Colorless)
151-54
50
E
40
E
45
D
50
T
55
B
40
T/E
45
B
40
B
55
P
65
P
90
D
75
E
75
D
C18H15N3O2
(305.34)
C16H16N2O2
(268.32)
C18H10Br2N4O2
(474.11)
C22H14Br2N4O4
(558.19)
C20H14Br2N4O4
(534)
C19H13Br2N3O3
(491.17)
C16H10Br2N4O
(434.09)
C14H14N2O
(226.28)
C25H18Br2N4O
(549.25)
C15H10Br2N2O2
(410.07)
C18H11Br2N3O2
(461.13)
C19H13Br2N3O2
(475.13)
C18H11Br2N3OS
(477.18)
C19H11Br2N3O3
(489.13)
70.80
71.25
4.91
4.60
4.20
4.30
2
3
–
–
–
45.60
45.80
47.33
47.50
44.98
45.20
46.46
46.75
44.27
44.60
74.31
74.50
54.66
53.72
43.93
44.90
46.85
46.94
48.03
48.51
45.30
45.92
46.65
46.91
2.12
2.23
2.52
2.32
2.64
2.25
2.66
2.55
2.32
2.22
6.23
6.22
3.12
3.48
2.45
2.38
2.38
2.32
2.75
2.57
2.32
2.12
2.26
2.10
11.81
11.65
10.03
10.25
10.49
10.62
8.55
4
5
6
7
8.30
12.85
12.62
12.37
12.21
10.20
9.98
6.80
6.42
9.11
9.13
8.84
8.68
8.81
8.25
8.59
8.33
8
(Orange)
120-22
(Yellowish white)
218-20
9
10
11
12
13
14
15
(Colorless)
255-57
(Colorless)
340-43
(Yellow)
270-73
(Yellow)
> 360
(Green)
240-43
(Green)
80
B
B: Benzene; D: Dioxane; E : Ethanol; P: Petroleum ether (80-100°C); T: Toluene.

1192
A. A. El-Khamry, S. A. Shiba, A. A. Shalaby, and A. A. Abd alaha
Vol 43
Table 2
1H-NMR and MS Data of Prepared Compounds
IR cm-1
ꢁCꢂN
Compd
No.
1H-NMR (ꢀ in ppm)
MS (m/z %)
ꢁNH,OH
ꢁC=O
8.22 (broad, NH), 8.10 (d, 4H), 7.18 (d, 4H) and [M – 2]+. (303, 8%), 287 (100%), 259 (16%),
3380,
3181
2
3
4
5
2199
-
-
3.8 (s, 3H)
231 (19%) and 215 (15%)
8.65 (s, 2H), 7.85 (d, 4H), 7.08 (d, 4H) and 3.84 (s, [M+.] (268, 100%), 240 (23%), 162 (10%),
-
-
-
6H)
161 (94.5%) and 134 (30%)
8.24 (d, 1H), 8.01 (d, 1H), 8.25 (d, 2H), 7.13 (d, [M+.] (474, 100%), 444 (7%) and 431 (38%)
2H), 7.8 (broad, 1H) and 3.85 (s, 3H)
3303
3422
2199
2206
-
[M]+. (558, 27%), 557 (30%), 514 (24%),
394 (27%) and 234 (4%)
1683
8.29-8.33 (deformed, d, 2H), 7.97-8.01 (deformed, [M – 3]+. (531, 1.5%), 474 (100%), 473
d, 2H), 7.12-7.17 (deformed, 2H), 3.86 (s, 3H), (11%), 459 (3%) and 444 (4%)
1.93 (s, 3H) and 1.21 (s, 1H)
6
3425
2232
1728
[M]+. (491, 19%), 490 (37%) and 104
1723,
1699
7
8
––
3260
3430
3313
3274
3355
-
2209
-
(100%)
[M]+. (434, 8%), 395 (5%), 135 (97%) and
––
1685
-
92 (78%)
[M]+. (226, 100%), 211 (6%), 195 (1.5%)
9
–
and 90 (8%)
8.6-8.2 (broad, 3H), 7.85 (deformed 2H), 7.6-7.2 [M+2]+. (551, 0.5%), 158 (17%), 106
10
11
2207
-
1681
(broad, 9H) and 4.1 (s, 4H)
10.88 (broad, 1H), 8.05 (d, 1H), 8.2 (d, 1H), 7.3 [M]+. (410, 27%), 393 (8%), 303 (6%), 142
(m, 5H) and 5.1 (s, 2H) (2%) and 91 (100%)
(100%) and 91 (87%)
1718,
1661
11.8 (hump, 1H), 8.44 & 8.18 (broad 2H), 8.36 (s, [M+2]+. (463, 5%), 461 (60%), 460 (100%),
1H), 8.04-8.01 (d, 2H), 7.2 & 7.17 (d, 2H) and 3.8 380 (12%) and 277 (26%)
(s, 3H)
12
13
14
3240
-
2229
2218
2229
1679
1659
-
[M+2]+. (477, 17%), 476 (24%), 475 (23%),
––
460 (100%), 445 (12%) and 353 (6%)
[M+1]+. (478, 13%), 477 (16%), 445 (9%),
––
444 (17%), 380 (22%), 301 (13%), 184
(19%) and 170 (25%)
3320
9.04 (s, 1H), 8.35 & 8.18 (deformed 2H), 8.25 (s, [M]+. (489, 70%), 473 (100%), 448 (22%)
1H), 7.2 & 7.24 (d, 2H), 6.85 & 6.65 (d, 2H) and and 396 (18%)
3.75 (s, 3H)
1710,
1687
15
-
2206
EXPERIMENTAL
5,7-Dibromo-2-(4-methoxyphenyl)-9-oxo-1-(1,3-dioxobutyryl)-
1,9-dihydropyrazolo[5,1-b]quinazoline-3-carbonitrile (5).
Melting points were measured on an electrothermal melting
point apparatus and are uncorrected. Elemental analyses were
carried out at the Micro-Analytical unit, Cairo University, Giza.
A mixture of (4) (0.01 mol) and ethyl acetoacetate (0.01 mol) in
ethanol (50 mL) was refluxed for 3 h. The solid that formed after
concentration of the solvent was collected and crystallized to give (5).
Infrared spectra were measured on
a Unicam SP-1200
1
5,7-Dibromo-3-cyano-2-(4-methoxyphenyl)-9-oxo-1,2,3,9-tetra-
hydropyrazolo[5,1-b]quinazolin-2-acetic acid (6).
spectrometer using KBr wafer technique. H NMR spectra were
measured in DMSO-d6 on a Varian plus instrument (300 MHz).
The mass spectra were determined using HP model MS-5988 at
electron energy 70 eV.
A mixture of (4) (0.01 mol) and acetic anhydride (5 mL) in
acetic acid (30 mL) was refluxed for 3 h. The solid that formed
after concentration of the solvent was collected and crystallized
to give (6).
3,5-Bis-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (2) and
[10] N,N-Bis(4-methoxybenzylidene)hydrazine (3).
3-Acetyl-5,7-dibromo-2-(4-methoxyphenyl)-3H-pyrazolo[5,1-b]-
quinazolin-9-one (7).
A mixture of benzoxazinone (1) (0.01 mol) and hydrazine
hydrate (0.01 mol) in 1-butanol (30 mL) was refluxed for 6 h.
The solid that formed after concentration of the solvent was
collected and crystallized to give (2) and (3) which were
identified by mp and mixed mp with authentic sample.
A mixture of (4) (0.01 mol) and phthalic anhydride (0.01 mol)
in acetic acid (30 mL) was refluxed for 3 h. The solid that
formed after concentration of the solvent was collected and
crystallized to give (7).
5,7-Dibromo-2-(4-methoxyphenyl)-9-oxo-1,9-dihydropyrazolo-
[5,1-b]quinazoline-3-carbonitrile (4).
(6,8-Dibromo-4-oxo-3-phenylamino-3,4-dihydroquinazolin-2-
yl)acetonitrile (8) and p-Anisaldehyde phenyl hydrazone (9).
A mixture of (1) (0.01 mol) and hydrazine hydrate (0.01 mol)
in ethanol (30 mL) was refluxed for 5 h. The solid that formed
while heating was collected and crystallized to give (4).
A mixture of (1) (0.01 mol) and phenyl hydrazine (0.01 mol)
in ethanol (30 mL) was refluxed for 3 h. The solid that formed

Sep-Oct 2006
Synthesis of Some New Pyrazoloquinazolinone and Quinazolinone Derivatives
1193
after concentration of the solvent was collected and crystallized
to give (8) and (9).
that formed after cooling was triturated with boiling water,
collected and crystallized to give (14).
2-(3-Benzyl-6,8-dibromo-4-oxo-3,4-dihydroquinazolin-2-yl)-
3-(benzylamino)acrylonitrile (10).
2-(6,8-Dibromo-3-formyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-
(4-methoxy phenyl) acrylonitrile (15).
A mixture of (1) (0.01 mol) and benzyl amine (0.01 mol) in
ethanol (50 mL) was refluxed for 5 h. The solid that formed after
concentration of the solvent was collected and crystallized to
give (10).
A mixture of (1) (0.01 mol) and formamide (30 mL) was
refluxed for 3 h. After cooling, the reaction mixture was poured
into water, and the solid that formed was collected and
crystallized to give (15).
3-Benzyl-6,8-dibromo-1H-quinazoline-2,4-dione (11).
REFERENCES
A mixture of (1) (0.01 mol) and benzylamine (20 mL) was
refluxed for 3 h. After cooling, the reaction mixture was poured
onto ice cold HCl, the solid that formed was collected and
crystallized to give (11).
[1] J. Erusalimsky and R. Franklin, Experimental Hematology,
30, 625-626 (2002).
[2] A. M. Farghaly, R. Soliman, M. A. Khalil, A. A. Bekhit, and
A. El-Din, Bollettino Chimico Farmaceutico, 141, 372-378 (2002).
[3] D. Bebbington, J. D. Charrier, R. Davies, S. Everitt, and D.
Kay, PCT Int. Appl. WO 02 50, 065 (Cl. C07D 403/12), 27 Jun 2002,
US Appl. PV 286, 949, 27 Apr 2001; 342 pp; Chem. Abstr., 137, 47221k
(2002).
[4] M. Okano and K. Mori, PCT Int. Appl. WO 01 72, 710 (Cl.
C07 D 215/42), 4 Oct 2001, JP Appl. 2000/336, 464, 2 Nov 2000; 75 pp;
Chem. Abstr., 135, 288787p (2001).
[5] A. S. Alyaa, A. E. Abdel Momen, A. S. Sayed, and A. A.
Abd elaal, Archiv. Der Pharmazie, 333, 355 (2000).
[6] A. A. El-Helby, Egypt Phar,. Sci., 36, 287 (1995).
[7] A. A. El-Khamry, S. El-Nagdy, M. M. Habashy, and F. A.
El-Bassiouny, F Pharmazie, 44, 312 (1989).
[8] A. E. Ossman and S. E. Barakat, Sauidi Pharm. J., 2, 21
(1994).
[9] H. M. Madkour, S. A. Shiba, H. M. Sayed and A. A. Hamed,
Sulfur Letters, 24, 151 (2001).
[10] J. B. Shoesmith and J. Slater, J. Chem. Soc., 127, 1490
(1925).
2-(6,8-Dibromo-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(4-methoxy-
phenyl)acrylonitrile (12).
A mixture of (1) (0.01 mol) and ammonium acetate (0.04
mol) was heated in oil bath at 180-190 °C for 3 h. The residue
was triturated with warm water, then collected and crystallized
to give (12).
2-(6,8-Dibromo-3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-3-
(4-methoxy phenyl)acrylonitrile (13).
A mixture of (12) (0.01 mol) and dimethylsulphate (0.01 mol)
in sodium hydroxide (50 mL) was refluxed for 5 h. After
cooling, the reaction mixture was poured in ice cold
hydrochloric acid, the solid formed was collected and
crystallized to give (13).
2-(6,8-Dibromo-4-thioxo-3,4-dihydroquinazolin-2-yl)-3-(4-
methoxyphenyl)acrylonitrile (14).
A mixture of (12) (0.01 mol) and phosphorous pentasulphide
(0.02 mol) was heated in a sand bath at 250 °C for 5 h. The solid
[11] M. F. Ismail, N. A. Shams, M. R. Salem S. A. and Emara, J.
Org. Chem., 84, 4172 (1983).