Synthesis of some quinazolines derived from 6,8-dibromo2-(2-carboxyphenyl)- 4h-3,1-benzoxazin-4-one as antimicrobial agents

Article abstract of DOI:10.1007/s10593-010-0459-4

The reactivity of 6,8-dibromo-2-(2-carboxyphenyl)-4H-3,1-benzoxazin-4-one towards the action of electrophilic and nucleophilic reagents led to the direct formation of heterobicyclic nitrogen compounds. The antimicrobial activity of some synthesized compou

Full text of DOI:10.1007/s10593-010-0459-4

Chemistry of Heterocyclic Compounds, Vol. 45, No. 12, 2009
SYNTHESIS OF SOME QUINAZOLINES
DERIVED FROM 6,8-DIBROMO-2-(2-CARBOXY-
PHENYL)-4H-3,1-BENZOXAZIN-4-ONE AS
ANTIMICROBIAL AGENTS
I. F. Nassar1*
The reactivity of 6,8-dibromo-2-(2-carboxyphenyl)-4H-3,1-benzoxazin-4-one towards the action of
electrophilic and nucleophilic reagents led to the direct formation of heterobicyclic nitrogen
compounds. The antimicrobial activity of some synthesized compounds was investigated.
Keywords: quinazolin-4-one, antimicrobial agents, electrophilic and nucleophilic reagents.
Some quinazoline derivatives are used in large scale in medicine as antitumor and antimicrobial agents.
This promted us to synthesize some new substituted quinazolines with potential biological activity. 4H-3,1-
Benzoxazin-4-ones substituted in position 2 with aliphatic groups such as methyl [1], n-propyl [2], isopropyl [3],
acetylmethyl [4], cyanomethyl [5], CH2CH2COOH [6], and benzyl [7] are among the more recently synthesized
heterocyclic compounds. The electron-deficient character of benzoxazine rings hinders the synthesis of
sufficiently stable derivatives. New organic substituents with special steric and electronic properties help to
solve this problem. In the last two decades the solution of this problem includes the use of bulk substituents with
strong conjugation power (the so-called static benzoxazinones) [8].
The required starting material 1 [9–11] was synthesized by the condensation of phthalic anhydride and
2-amino-3,5-dibromobenzoic acid in n-butanol under reflux for 20 h. The treatment of compound 1 with
hydrazine hydrate in ethanol under reflux afforded 3-aminoquinazolinone derivative 2 [12–14], which was used
as a key material for the synthesis of some interesting heterocyclic quinazolines. Thus, boiling compound 2 with
either acetyl chloride and/or benzoyl chloride afforded 5-acetoxy/benzoyloxy-substituted phthalazino-
[1,2-b]quinazoline derivatives 3a,b. Refluxing compound 2 with piperidine in ethanol in the presence of
formaldehyde gave the Mannich base 4. The treatment of compound 2 with phenyl isothiocyanate in dry
benzene produced 1-phenylthioureido-substituted phthalazinoquinazoline derivative 5.
Recently the chemistry of quinazolinones received much attention principally due to the novel synthesis
of some new oxazines with high potential biological activity. Thus, the treatment of compound 2 with
benzaldehyde or 4-chlorobenzaldehyde in ethanol under reflux afforded Schiff's bases 6a,b [15]. The reaction
took place via an addition/elimination reaction mechanism. Refluxing the Schiff's base 6a with o-amino-
thiophenol in the presence of a few drops of piperidine as a catalyst yielded the corresponding 2-amino-
_______
* To whom correspondence should be addressed, e-mail: tasneem_05nassar@yahoo.com.
1Faculty of Specific Education, Ain Shams University, Abbassia, Cairo, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1878-1887, December, 2009.
Original article received June 19, 2008. Revised version received December 4, 2009.
0009-3122/09/4512-1515©2009 Springer Science+Business Media, Inc.
1515

O
N
O
N
Br
Br
N
OCOR
O
N
Br
Br
HOOC
3a,b
N2H4
Br
1
RCOCl
EtOH
O
N
H
N
NH2
N
Ph–N=C=S
benzene
S
N
piperidine
CH2O
O
O
N
O
CH2
N
Br
O
N
Br
N
Br
N
HOOC
N
2
Br
Br
4
5
3 a R = Me, b R = Ph
phenylsulfanyl-substituted products 8, which on reaction with acetyl chloride or benzoyl chloride afforded
N-acyl-substituted quinazolines 9a,b. On the other hand, when the Schiff's base 6a was refluxed with
thioglycolic acid in the presence of a few drops of piperidine, 1,3-dihydro-4-thiazolone derivative 7 was
prepared. The reaction mechanism involves the addition of the thiolate anion derived from thioglycolic acid to
the azomethyne moiety followed by cyclization.
2
EtOH
ArCHO
O
N
O
N
O
Ar
S
Br
Br
N
N
CH
N
N
HSCH2COOH
Ph
6a
piperidine
Br
Br
HOOC
HOOC
6a,b
7
SH
NH2
Ph
6a
RCONH
S
H2N
O
O
Ph
Br
Br
N
N
C
H
N
N
H
C
H
S
H
N
N
RCOCl
Br
Br
HOOC
HOOC
8
9a,b
6 a Ar = Ph, b Ar = 4-ClC6H4; 9 a R = Me, b R = Ph
1516

The reaction of compound 2 with carbon electrophiles such as ethyl acetoacetate, ethyl phenylacetate, or
ethyl chloroacetate in n-butanol afforded N-(1-substituted acetyl)phthalazinoquinazoline derivatives 10a-c [16].
The reaction of compound 10c with active methylene compounds (acetyl acetone, diethyl malonate or ethyl
acetoacetate) in the presence of sodium ethoxide yielded the corresponding side-chain substituted
Me
N
O
O
N
COCH2NHPh
O
Br
N
O
Br
N
O
N
N
N
Br
Br
15
13
NH2
10c
NH2OH
10a
O
N
COCH2R
Br
N
O
RCH2COOEt
N
2
n-butanol
Br
10a–c
EtONa
10c
R1CH2R2
COCH2CHR1R2
N2H4
10a
HN
N
O
O
O
Me
Br
N
O
Br
N
N
N
N
N
Br
Br
14
11a–c
O
EtONa
HO
11b
H2N–C–NH2
Br
N
N
OH
O
COCH2
N
O
N
HO
N
Br
12
10 a R = COMe, b R = Ph, c R = Cl; 11 a R1 = R2 = MeCO, b R1 = R2 = COOEt,
c R1 = MeCO, R2 = COOEt
1517

phthalazinoquinazoline derivatives 11a-c [17]. The reaction took place via the SN2 mechanism. The treatment of
compound 11b with urea in the presence of boiling sodium ethoxide and ethanol afforded (2,4,6-trihydroxy-
pyrimidin-5-yl-acetyl)phthalazinoquinazoline 12, and reaction of compound 10c with aniline in an oil bath at
150oC afforded 1-phenylaminoacetylphthalazinoquinazoline (13). Refluxing compound 10a in either hydrazine
hydrate in ethanol or hydroxylamine hydrochloride in pyridine afforded 5-methyl-2H-pyrazolophthalazino-
quinazoline 14 or 3-methylisoxazol-5-yl-substituted phthalazinoquinazoline 15. The reaction took place via the
tetrahedral mechanism.
Antimicrobial activity. The antimicrobial activity of some newly synthesized compounds was tested
using the hole plate and filter paper disk method [18]. Some selected compounds were tested against a variety
TABLE 1. Characteristics and Physical Data for the Synthesized Compounds
2-15
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, oC*
C
H
Br
N
S (Cl)
2
C15H9Br2N3O3
C17H9Br2N3O3
C22H11Br2N3O3
C21H18Br2N4O2
C22H12Br2N4O2S
C22H13Br2N3O3
C22H12Br2ClN3O3
C24H15Br2N3O4S
C28H20Br2N4O3S
C30H22Br2N4O4S
C35H24Br2N4O4S
C19H11Br2N3O4
C23H13Br2N3O3
C17H8Br2ClN3O3
C22H15Br2N3O5
C24H19Br2N3O7
C23H17Br2N3O6
C21H11Br2N5O6
C23H14Br2N4O3
C19H11Br2N5O2
C19H10Br2N4O3
41.00
41.03
44.10
44.09
50.33
50.32
48.66
48.67
47.50
47.51
50.11
50.12
47.00
47.05
48.00
47.94
51.50
51.52
51.90
51.90
55.54
55.57
45.23
45.18
51.34
51.24
41.45
41.46
47.12
47.09
46.45
46.40
2.10
2.07
2.00
1.96
2.11
2.11
3.52
3.50
2.18
2.17
2.50
2.49
2.30
2.15
2.45
2.51
3.10
3.09
3.09
3.19
3.10
3.20
2.09
2.19
2.44
2.43
1.67
1.64
2.89
2.70
3.24
3.08
36.40
36.39
34.53
34.51
30.42
30.43
30.76
30.84
28.74
28.73
30.33
30.31
28.34
28.46
26.54
26.58
24.50
24.49
22.04
23.01
21.10
21.13
31.66
31.64
29.55
29.64
32.45
32.45
28.56
28.48
25.72
25.72
9.58
9.57
9.00
9.07
8.00
8.00
6.16
6.17
10.08
10.07
8.00
7.97
7.50
7.48
6.97
6.99
8.60
8.59
7.99
8.07
7.23
7. 41
8.34
8.32
7.67
7.79
8.67
8.53
7.56
7.49
166-167
185-186
125-126
120-21
3a
3b
4
5
5.76
5.76
180-181
280-281
334-335
155-157
120-122
122-124
146-147
199-200
195-196
205-206
204-205
205-206
201-202
133-135
219-220
185-186
180-182
6a
6b
7
(6.43)
(6.31)
5.30
5.33
4.87
4.91
4.65
4.62
8
9a
9b
10a
10b
10c
11a
11b
11c
12
13
14
15
4.20
4.24
(7.23)
(7.20)
6.45
6.76
7.35
7.11
11.78
11.89
10.11
10.11
13.67
13.97
11.15
11.16
46.35
46.73
42.67
42.81
49.90
49.85
45.56
45.54
2.56
2.89
1.89
1.88
2.54
2.55
2.34
2.21
27.00
27.03
27.23
27.12
28.82
28.84
31.78
31.89
45.50
45.42
2.01
2.01
31.83
31.83
_______
Solvent: benzene (compounds 2, 3a,b, 8,9a,b,10a,b), ethanol
(compounds 4, 6a,b, 7, 10c, 11a−c,12−15), toluene (compound 5).
*
1518

of microorganisms, including Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, and
Micrococcus autea) (Table 2) and Gram-negative bacteria (Escherichia coli, Salmonella typhosa, and
Pseudomonas aeruginosa) (Table 3) using acetone as reference antimicrobial compounds. The extent of activity
was expressed in terms of the diameters of the inhibition zones.
The results showed that compounds 8,9 possess high activities against all tested bacteria (Gram-positive
and Gram-negative), but compounds 6, 10c, and 11c are inactive against all tested bacteria at all concentrations.
On the other hand, compounds 5, 12, and 14 exhibited a high activity towards all Gram-positive bacteria and are
inactive towards all Gram-negative bacteria at all concentrations, while compound 7 was found to be active only
against Gram-negative bacteria at all concentrations tested.
Regarding the structure-activity relationships we showed that the higher activity of compounds 8, 9 may
be due to the presence of N=C=S and quinazolin-4-one moieties in their structures.
EXPERIMENTAL
The reported mp's were recorded on an Electrothermal instrument. TLC was performed on plastic plates
Silica Gel 60 F254 (E. Merck, layer thickness 0.2 mm). IR spectra (KBr) were recorded on a Bruker Vector 22 FT
1
spectrophotometer, and H NMR spectra were recorded on a Varian Gemini 200MHz (Germany) and Varian-
Mercury-300 UH2 Oxford using DMSO-d6 as a solvent. The microanalyses were performed at the
Microanalytical unit, Cairo University, Egypt. The physical data of the synthesized compounds are given in
Table 1.
TABLE 2. Relative activity of some compounds against Gram-positive
expressed as diameters of inhibition zone
Inhibition zone, mm
Bacillus subtilis,
Atcc 7972
100
Micrococcus autea,
Staphylococcus aureus,
Com-
pound*
NCIB 196
Atcc 6538
50
200
50
100
200
50
100
200
µ/disc.
µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc.
5
10
12
11
15
12
11
12
12
17
13
12
13
13
20
14
10
10
12
11
10
11
11
14
11
11
11
12
15
13
12
10
11
14
12
11
12
12
15
12
11
13
14
17
15
12
8
9
12
14
_______
* Compounds 6, 7, 10c, and 11c are inactive.
TABLE 3. Relative activity of some compounds against Gram-negative
bacteria expressed as diameters of inhibition zone
Inhibition zone, mm
Escherichia coli,
NCIB 9132
100
Salmonella typhosa,
Pseudomonas eruginosa,
Com-
pound*
NRRL.B.573
Atcc 77853
50
200
50
100
200
50
100
200
µ/disc.
µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc. µ/disc.
7
8
12
10
12
12
11
13
14
11
15
11
13
13
12
14
15
14
16
16
11
16
12
11
18
13
13
20
14
9
_______
* Compounds 5, 6, 10c, 11c, 12, and 14 are inactive.
1519

3-Amino-6,8-dibromo-2-(2-carboxyphenyl)-4(3H)-quinazolin-4-one (2). A mixture of compound 1
(4.25 g, 0.01 mol) and hydrazine hydrate (0.75 g, 0.015 mol) in ethanol (40 ml) was heated under reflux for 3 h.
The product separated on cooling was crystallized from benzene to give compound 2 (3.07 g, 70%). IR
1
spectrum, ν, cm–1: 3480 (OH), 3274–3183 (NH2), 1705 (C=O), 1670 (C=O). H NMR spectrum, δ, ppm: 7.85
(3H, m, Ar); 7.95 (1H, m, Ar); 8.11 (2H, s, Ar-Br); 9.75 (2H, s, NH2); 11.5 (1H, br. s, COOH).
Synthesis of 10,12-Dibromophthalazino[1,2-b]quinazolinones 3a,b (General Method). A solution of
compound 2 (4.39 g, 0.01 mol) in 20 cm3 acetyl chloride or benzoyl chloride was heated under reflux for 2 h.
The product that separated on cooling was crystallized from the proper solvent to give compound 3a (2.55 g,
55%) or 3b (2.78 g, 60%).
5-Acetoxy-10,12-dibromophthalazino[1,2-b]quinazolin-8-one (3a). IR spectrum, ν, cm–1: 1735
(C=O), 1670 (C=O). 1H NMR spectrum, δ, ppm: 1.83 (3H, s, CH3); 7.85 (3H, m, Ar); 8.11 (3H, m, Ar).
5-Benzoyloxy-10,12-dibromophthalazino[1,2-b]quinazolin-8-one (3b). IR spectrum, ν, cm–1: 1742
(C=O), 1672 (C=O).
10,12-Dibromo-6-(piperidinomethyl)phthalazino[1,2-b]quinazoline-5,8-dione (4).
A
mixture of
compound 2 (4.39 g, 0.01 mol), formaldehyde (1 ml, 0.33 mol), piperidine (0.85 g, 0.01 mol), and morpholine
(0.87 g, 0.01 mol) was heated under reflux for 1 h. The product that separated on cooling was crystallized from
ethanol to give compound 4 (2.8 g, 54%). IR spectrum, ν, cm–1: 1673 (C=O), 1625 (C=O).
10,12-Dibromo-6-(phenylthiocarbamoyl)phthalazino[1,2-b]quinazoline-5,8-dione (5). A solution of
compound 2 (4.39 g, 0.01 mol) and phenyl isothiocyanate (0.14 g, 0.01 mol) in dry benzene (30 ml) was
refluxed for 2 h. The product that separated on cooling was crystallized from the proper solvent to give
1
compound 5 (3.17 g, 57%). IR spectrum, ν, cm–1: 3200 (NH), 1668 (C=O), 1213 (C=S). H NMR spectrum, δ,
ppm: 7.20 (4H, m, Ar); 7.75 (2H, m, Ar); 8.18 (5H, s, Ar); 8.43 (1H, s, NH).
Synthesis of 3-Arylmethylideneamino-6,8-dibromoquinazolin-4-ones 6a,b (General Method). A
solution of compound 2 (4.39 g, 0.01 mol) and benzaldehyde or 4-chlorobenzaldehyde (0.01 mol) in ethanol
(30 ml) was refluxed for 3 h. The products that separated on cooling were crystallized from the suitable solvent
to give compound 6a (3.16 g, 60%) or 6b (3.31 g, 59%).
3-Benzylideneamino-6,8-dibromo-2-(2-carboxyphenyl)quinazolin-4-one (6a). IR spectrum, ν, cm–1:
3460 (OH), 1683 (C=O), 1675 (C=O), 1620 (C=N).
6,8-Dibromo-2-(2-carboxyphenyl)-3-(4-chlorobenzylidene)aminoquinazolin-4-one (6b). IR spectrum, ν,
1
cm–1: 3465 (OH), 1685 (C=O), 1670 (C=O), 1617 (C=N). H NMR spectrum, δ, ppm: 6.32 (1H, s, CH); 7.20
(5H, m, Ar); 7.55 (3H, m, Ar); 8.18 (2H, s, Ar); 11.4–11.6 (1H, s, OH).
6,8-Dibromo-2-(2-carboxyphenyl)-3-(4-oxo-2-phenylthiazolidinyl)quinazolin-4-one (7). A mixture
of compound 6a (5.27 g, 0.01 mol) and thioglycolic acid (0.92 g, 0.01 mol) and 3 drops of piperidine in ethanol
(30 ml) was refluxed for 3 h. The products that separated on cooling were crystallized from ethanol to give
compound 7 (3.37 g, 56%). IR spectrum, ν, cm–1: 3480 (OH), 1690 (C=O), 1670 (C=O). 1H NMR spectrum, δ,
ppm: 3.27 (2H, s, CH2); 4.30 (1H, s, CH); 6.80 (5H, m, Ar); 7.65 (3H, m, Ar); 8.12 (3H, m, 2H ArBr + 1H
ArCOO); 11.24 (1H, s, OH).
3-[(2-Aminophenylsulfanyl)(phenyl)methylamino]-6,8-dibromo-2-(2-carboxyphenyl)quinazolin-4-one
(8). A solution of compound 6a (5.27 g, 0.01 mol), 2-aminothiophenol (1.25 g, 0.01 mol), and 3 drops of
piperidine in benzene (30 ml) was refluxed for 3 h. The products that separated on cooling were crystallized
from benzene to give compound 8 (2.48 g, 38%). IR spectrum, ν, cm–1: 3381 (OH), 3300–3100 (NH2), 1695
1
(C=O), 1680 (C=O). H NMR spectrum, δ, ppm: 2.51 (1H, s, CH); 4.29 (1H, s, NH); 5.40 (2H, s, NH2); 6.90
(5H, m, C6H5); 7.15 (5H, m, 3H ArCOO + 2H ArS); 7.50 (3H, m, 1H ArCOO + 2H ArN, ArS); 8.12 (2H, m,
ArBr); 11.3 (1H, s, OH).
Synthesis of 3-[(2-Acylaminophenylsulfanyl)(phenyl)methylamino]-6,8-dibromo-2-(2-carboxyphenyl)-
quinazolin-4-ones 9a,b (General Method). Compound 8 (6.52 g, 0.01 mol) was refluxed for 1 h in 20 ml of
acetyl chloride or benzoyl chloride. The products that separated after removing excess acid chloride were
crystallized from benzene to give compound 9a (3.33 g, 48%) or 9b (3.25 g, 43%).
1520

3-[(2-Acetylaminophenylsulfanyl)(phenyl)methylamino]-6,8-dibromo-2-(2-carboxyphenyl)quin-
azolin-4-one (9a). IR spectrum, ν, cm–1: 3460 (OH), 3272 (NH), 3190 (NH), 1718 (C=O), 1677 (C=O), 1636
(C=O). 1H NMR spectrum, δ, ppm: 1.83 (3H, s, CH3); 6.33 (1H, s, CH); 7.15 (5H, m, Ar); 7.20 (5H, m, 3H
ArCOO + 2H ArS); 7.55 (3H, m, 1H ArCOO + 2H ArN, ArS); 7.90 (2H, m, ArBr); 8.01 (1H, s, NH); 8.18 (1H,
s, NH); 10.70 (1H, s, OH).
3-[(2-Benzoylaminophenylsulfanyl)(phenyl)methylamino]-6,8-dibromo-2-(2-carboxyphenyl)quin-
azolin-4-one (9b). IR spectrum, ν, cm–1: 3480 (OH), 3072 (NH), 1675 (C=O), 1665 (C=O).
Synthesis of 6-Acyl-substituted 10,12-Dibromophthalazino[1,2-b]quinazoline-5,8-diones 10a,b (General
Method). A solution of compound 2 (4.39 g, 0.01 mol) and ethyl acetoacetate, ethyl phenylacetate, or ethyl
chloroacetate (0.01 mol) in n-butanol (40 ml) was refluxed for 3 h. The products that separated on cooling were
crystallized from the suitable solvent to give compound 10a (2.27 g, 45%), 10b (3.45 g, 64%), or 10c (2.96 g, 60%).
6-Acetoacetyl-10,12-dibromophthalazino[1,2-b]quinazoline-5,8-dione (10a). IR spectrum, ν, cm–1:
1690 (C=O), 1685 (C=O), 1680 (C=O), 1640 (C=O).
10,12-Dibromo-6-phenylacetylphthalazino[1,2-b]quinazoline-5,8-dione (10b). IR spectrum, ν, cm–1:
1694 (C=O), 1685 (C=O), 1680 (C=O). 1H NMR spectrum, δ, ppm: 3.39 (2H, s, CH2); 7.49 (5H, m, C6H5); 7.88
(4H, m, Ar); 8.11 (2H, m, ArBr).
10,12-Dibromo-6-chloroacetylphthalazino[1,2-b]quinazoline-5,8-dione (10c). IR spectrum, ν, cm–1:
1
1690 (C=O), 1685 (C=O), 1675 (C=O). H NMR spectrum, δ, ppm: 4.27 (2H, s, CH2); 7.75 (4H, m, Ar); 8.00
(2H, m, ArBr).
Synthesis of 6-Acyl-substituted 10,12-Dibromophthalazino[1,2-b]quinazoline-5,8-diones 11a-c (General
Method). A mixture of compound 10c (4.93 g, 0.01 mol) and active methylene compounds, namely, acetyl acetone,
diethyl malonate, or ethyl acetoacetate (0.01 mol) was treated with sodium ethoxide obtained from sodium metal
(0.75 g, 0.033 mol) in 30 ml of ethanol under reflux for 3 h. The excess solvent was removed under reduced pressure.
The reaction mixtures were treated with ice/HCl, and the products that separated were crystallized from the suitable
solvent to give compound 11a (3.93 g, 70%), 11b (4.29 g, 69%), or 11c (2.90 g, 49%).
6-(3-Acetyl-4-oxopentanoyl)-10,12-dibromophthalazino[1,2-b]quinazoline-5,8-dione
(11a).
IR
spectrum, ν, cm–1: 1715 (C=O), 1695 (C=O), 1685 (C=O), 1670 (C=O). 1H NMR spectrum, δ, ppm: 2.03 (6H, s,
COCH3); 2.62 (2H, s, CH2); 6.32 (1H, s, CH); 7.85 (4H, m, Ar); 8.09 (2H, m, ArBr).
10,12-Dibromo-6-[3,3-di(ethoxycarbonyl)propionyl]phthalazino[1,2-b]quinazoline-5,8-dione (11b).
IR spectrum, ν, cm–1: 1745 (C=O), 1735 (C=O), 1680 (C=O), 1675 (C=O), 1670 (C=O).
10,12-Dibromo-6-(3-ethoxycarbonyl-4-oxopentanoyl)phthalazino[1,2-b]quinazoline-5,8-dione (11c).
IR spectrum, ν, cm–1: 1740 (C=O), 1683 (C=O), 1680 (C=O), 1670 (C=O), 1630 (C=O).
10,12-Dibromo-6-[(2,4,6-trihydroxypyrimidin-5-yl)acetyl]phthalazino[1,2-b]quinazoline-5,8-dione
(12). A solution of compound 11b (6.21 g, 0.01 mol) and urea (0.60 g, 0.01 mol) in sodium ethoxide solution
obtained from sodium metal (0.75 g, 0.033 mol) in 40 ml of ethanol was refluxed for 3 h, and the excess solvent
was removed under reduced pressure. The reaction mixture was treated with ice/HCl, and the products that
separated were crystallized from ethanol to give compound 12 (2.81 g, 47%). IR spectrum, ν, cm–1: 3444 (OH),
1
3350 (NH), 1681 (C=O), 1640 (C=N). H NMR spectrum, δ, ppm: 3.23 (2H, s, CH2C=O); 6.32 (1H, s, CH);
6.80 (3H, m, Ar); 7.99 (3H, m, Ar); 10.26 (1H, s, OH); 10.29 (1H, s, OH); 10.40 (1H, s, OH).
10,12-Dibromo-6-(phenylaminoacetyl)phthalazino[1,2-b]quinazoline-5,8-dione (13). A mixture of
compound 10c (4.93 g, 0.01 mol) and aniline (0.93 g, 0.01 mol) was fused in an oil bath at 150°C for 3 h and
then cooled and poured on ice/HCl. The solid that separated was crystallized from ethanol to give compound 13
(2.77 g, 50%). IR spectrum, ν, cm–1: 3150 (NH), 1695 (C=O), 1685 (C=O), 1675 (C=O).
10,12-Dibromo-6-(5-methylpyrazol-3-yl)phthalazino[1,2-b]quinazoline-5,8-dione (14). A solution of
compound 10a (5.05 g, 0.01 mol) and hydrazine hydrate (0.75 g, 0.015 mol) in ethanol (50 ml) was refluxed for
4 h. The product that separated on cooling was crystallized from ethanol to give compound 14 (2.26 g, 45%). IR
1
spectrum, ν, cm–1: 3244 (NH), 1697 (C=O), 1651 (C=O). H NMR spectrum, δ, ppm: 1.82 (3H, s, CH3); 6.30
(1H, s, CH); 7.17 (3H, m, Ar); 8.01 (3H, m, Ar); 8.18 (1H, s, NH).
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10,12-Dibromo-6-(3-methylisoxazol-5-yl)phthalazino[1,2-b]quinazoline-5,8-dione (15). A solution of
compound 10a (5.05 g, 0.01 mol) and hydroxylamine hydrochloride (0.33 g, 0.01 mol) in pyridine (20 ml) was
heated under reflux for 3 h. The product that separated on cooling was crystallized from ethanol to give
compound 15 (2.0 g, 40%). IR spectrum, ν, cm–1: 1680 (C=O), 1670 (C=O), 1605 (C=N).
REFERENCES
1.
M. F. Ismail, A. A. El-Khamry, H. A. Abdel Hamid, and S. A. Emara, Acta Chim. Hung., 127, 35
(1990).
2.
3.
4.
5.
6.
M. M. Mahmoud, M. A. El-Hashash, A. Essawy, and M. E. Shabana, Indian J. Chem., 20B, 718 (1981).
A. Sammour, A. Rabie, M. A. El-Hashash, and M. A. Sayed, J. Chem. UAR, 19, 571 (1976).
A. M. Fahmy, M. A. El-Hashash, M. A. Habishy, and S. J. Nassar, Rev. Roum. Chim., 23, 1567 (1978).
M. A. El-Hashash, M. A. Hassan, and M. A. Sayed, Pakistan J. Sci. Ind. Res., 20, 336 (1977).
A. Essawy, M. A. El-Hashash, A. M. El-Gendy, and M. M. Hamad, Indian J. Chem., 21B, 593 (1982).
M. A. El-Hashash and M. A. Sayed, Egypt. J. Chem., 21, 115 (1978).
7.
8.
9.
10.
A. F. El-Farargy, M. M. Hamad, S. A. Said, and A. Haikal, Egypt. J. Chem., 33, 283 (1990).
S. El-Nagdy, M. A. El-Hashash, A. A. Afify, and F. El-Shahed F, Indian J. Chem., 28B, 126 (1989).
M. A. El-Hashash, A. A. El-Afify, M. A. Sayed, A. Y. Soliman, and M. Y. Amer, Oriental J. Chem.,
4,165 (1988).
11.
12.
13.
14.
15.
16.
17.
18.
M. A. El-Hashash, H. M. F. Madkour, and M. S. Amine, Pakistan J. Sci. Ind. Res., 34, 288 (1991).
M. I. Husain and S. Shukla, Indian J. Chem., 25B, 545 (1986).
M. M. Mohamed, A. A. El-Khamry, S. El-Nagdy, and S. W. Shoshaa, Indian J. Chem., 25B, 207 (1986).
M. S. Amine, M. A. El-Hashash, and I. A. Attia, Indian J. Chem., 32B, 577 (1993).
T. M. Abdel-Rahman, J. Heterocycl. Chem., 43, 1 (2006).
T. M. Abdel-Rahman, M. A. El-Hashash, and I. F. Nassar, Egypt. J. Chem., 4, 461 (2006).
C. Mitsos, A. Zografos, and O. Igglessi-Markopoulou, Heterocycles, 51, 1543 (1999).
A. A. Abu-Zeid and Y. M. Shehata, Indian J. Pharm., 31, 72 (1969).
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