Synthesis and antimicrobial activity of some annelated quinazoline derivatives

Article abstract of DOI:10.1002/jccs.200700061

A highly efficient and versatile synthetic approach to the synthesis of annelated quinazoline derivatives viz 1,2,4-triazino[4,3-c]quinazoline 5-7, 11, thiazolidinylquinazoline 9, quinazolino[4,3-b]quinazolin-8-one 12 and imidazoquinazolines 14a,b,15 is p

Full text of DOI:10.1002/jccs.200700061

Journal of the Chinese Chemical Society, 2007, 54, 437-446
437
Synthesis and Antimicrobial Activity of Some Annelated Quinazoline
Derivatives
A. A. Aly
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
A highly efficient and versatile synthetic approach to the synthesis of annelated quinazoline deriva-
tives viz 1,2,4-triazino[4,3-c]quinazoline 5-7, 11, thiazolidinylquinazoline 9, quinazolino[4,3-b]quin-
azolin-8-one 12 and imidazoquinazolines 14a,b,15 is presented. Also, a variety of pyrazolylquinazolines
19-21 and pyrimidinylquinazolines 22a,b were obtained via a sequence of heterocyclization reactions of
4-methyl-N-[4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl]benzene-sulfonamide (2) with different re-
agents. The new compounds were synthesized with the objective of studying their antimicrobial activity.
Keywords: Triazinoquinazoline; Quinazolinoquinazoline; Pyrazolylquinazoline; Antimicrobial
activity.
INTRODUCTION
Quinazoline derivatives and heterocyclic annelated
3260 (nNH), 1745 (nCO) and 1440, 1370 cm-1 (n SO ). The 1H
2
NMR spectrum (CDCl3) showed a signal (3H) at d 2.36
ppm assigned for methyl protons, multiplet signals (12H)
at (6.96-8.11 ppm) assigned for the aromatic protons and a
signal at 10.11 ppm assigned for NH which disappeared
upon addition of D2O to the NMR sample, and its mass
spectrum revealed a molecular ion peak at m/z = 392 (M+)
corresponding to the molecular formula C21H16N2O4S. Fu-
sion of benzoxazinone derivative 1 with ammonium ace-
tate in an oil bath at 160-170 °C afforded 4-methyl-N-[4-
(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl]-benzenesul-
fonamide (2) which is a promising intermediate for the syn-
thesis of diverse annelated quinazoline derivatives. Reac-
tion of compound 2 with a mixture of phosphorus penta-
chloride/phosphorus oxychloride on a water bath yielded
4-chloroquinazoline derivative 3, which upon subsequent
reaction with hydrazine hydrate in refluxing n-butanol fur-
nished the target compound, 4-hydrazinoquinazoline de-
rivative 4 (Scheme I).
quinazolines are reported to be physiologically and phar-
macologically active.1 They also exhibit a wide range of ac-
tivities such as anticonvulsant, anti-inflammatory, antifun-
gal, antimalarial and sedative.2-6 Some of these compounds
are identified as drugs7 used as diuretics, vasodilators and
antihypertensive agents. Moreover, sulfonamide deriva-
tives have been widely used as bacteriostatic agents.8,9
Prompted by the above mentioned facts and in conjunction
with our ongoing program on the utility of readily obtain-
able starting material for the synthesis of heterocyclic sys-
tems of biological interest,10-13 we have decided to synthe-
size a series of novel annelated quinazoline derivatives
having sulfonamide moiety with potentially wide spectrum
of biological responses.
RESULTS AND DISCUSSION
As the preparation of novel tricyclic and tetracyclic
systems is the main goal of this synthetic program, hydra-
zinoquinazoline was used as a precursor for the synthesis
of triazinoquinazoline derivatives of biological applica-
tions.15-17 Thus, the cyclo-condensation of compound 4
with a-haloketones (viz chloroacetone and phenacyl bro-
mide) in dry xylene takes place via condensation of a car-
bonyl group of haloketones with a hydrazino moiety of
compound 4 and afforded the fleeting corresponding hy-
The target compound, 4-methyl-N-[4-(4-oxo-4H-3,1-
benzoxazin-2-yl)phenyl]benzenesulfonamide (1) was read-
ily obtained from cyclization of 2-[4-(toluene-4-sulfonyl-
amino)benzoylamino]benzoic acid by boiling in acetic an-
hydride.14 The structure of the reaction product 1 was sup-
ported by elemental analyses and compatible spectroscopic
data. Thus, its IR spectrum showed absorption bands at
* Corresponding author. E-mail: alymaboud@hotmail.com

438 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Aly
Scheme I
drazone which undergoes 1,3-tautomerism followed by
ring closure to give 1,2,4-triazino[4,3-c]quinazoline deriv-
atives 5a,b. Also, the reaction of compound 4 with ethyl
chloroacetate yielded 3-oxo-2H-6-(toluene-4-sulfonylami-
no)phenyl]-[1,2,4]-triazino[4,3-c]quinazoline (6). Forma-
tion of compound 6 obtained firstly via nucleophilic attack
of NH2 of hydrazino moiety on carbonyl of the ester group
through tetrahedral mechanism yielded the fleeting acyl
derivative followed by 1,3-tautomerism and ring closure
via SN2 mechanism. Moreover, 1,2,4-triazino[4,3-c]quin-
azoline 7 was also obtained from the reaction of compound
4 with diethyl oxalate in absolute ethanol which takes place
via tetrahedral mechanism then undergoes 1,3-tautomerism
and ring closure through another tetrahedral mechanism.
Reaction of compound 4 with aromatic aldehydes (viz
benzaldehyde and p-chlorobenzaldehyde) gave quinazo-
line derivatives 8a,b. Cyclocondensation reaction of 8b
with 2-mercaptoacetic acid in the presence of a catalytic
amount of piperidine yielded thiazolidinone derivative 9
via nucleophilic addition of sulfur atom to activated C=N
bond then yielded nonisolable adduct followed by cycliza-
tion to give 9 (Scheme I).
Furthermore, chloroquinazoline 3 was also used for
construction of novel triazinoquinazoline derivative 11 via
the reaction of compound 3 with ammonium thiocyanate
in dry acetone to afford the nonisolable intermediate 10,
which reacted in situ with phenyl isocyanate via 2+4 cyclo-
addition reaction to yield triazinoquinazoline derivative 11
(Scheme II).
The structure of compound 11 was confirmed by its

Synthesis of Some Annelated Quinazoline Derivatives
J. Chin. Chem. Soc., Vol. Vol. 54, No. 2, 2007 439
Scheme II
mass spectrum which showed a molecular ion peak at m/z =
551 (M+) for molecular formula C29H21N5O3S2, in addition
to IR spectrum which showed absorption bands at 3320
(nNH), 1680 (nCO) and at 1265 cm-1 (nCS). This contribution
was extended to study some nucleophilic substitution reac-
tions with chloroquinazoline 3 for construction novel het-
eroaromatic systems. Thus, fusion of compound 3 with
anthranilic acid in an oil bath at 165-175 °C afforded 4-
methyl-N-[4-(8-oxo-8H-quinazolino[4,3-b]quinazolin-6-
yl)-phenyl]benzenesulfonamide (12).
acetic anhydride in the presence of anhydrous sodium ace-
tate to yield imidazoquinazoline derivatives 14a,b. Incor-
poration of imidazolyl moiety in the quinazoline ring was
also achieved by fusion of compound 3 with o-phenyl-
enediamine to afford N-[4-([1,3]benzimidazo[1,2-c]quin-
azolin-6-yl)phenyl]-4-methylbenzenesulfonamide (15)
(Scheme II).
The behavior of chloroquinazoline towards active
methylene compounds was also studied with respect to the
synthesis of highly substituted pyrazoles and pyrimi-
dines.19,20 Thus, the treatment of compound 3 with active
methylene compounds (viz malononitrile, ethyl cyano-
acetate, ethyl acetoacetate and acetylacetone) afforded the
corresponding quinazoline derivatives 16-18, respectively
(Scheme III). The infrared spectrum of compound 16 showed
With treatment of chloroquinazoline 3 with the so-
dium salt of various amino acids (viz glycine and alanine)
under reflux, the corresponding quinazolinylamino acids
13a,b were obtained. The amino acid derivatives 13a,b
were easily cyclized18 via 1,3-tautomerism by boiling in

440 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Aly
Scheme III
N
N
N
NC
CN
N
H2N
NH2
Ar
N2H4.H2O
CH2(CN)2
Ar
N
N
16
19
NH
N
COOEt
N2H4.H2O
X
X
O
XCH2COOEt
N
N
Ar
Ar
N
N
20a,b
3
17a,b
17a,x = CN
NH
20a; x =
20b; x =
2
17b,x = COCH3
CH3
NH
N
COCH3
CH3CO
H3C
CH3
(CH3CO)2CH2
N2H4.H2O
N
N
Ar
Ar
N
N
X
18
21
N
HN
H3C
H2NCXNH2
CH3
N
Ar
N
22a,b
22a; X= O
22b; X = S
the presence of absorption bands at 3310 due to (nNH) and
2225-2220 cm-1 due to (2CºN).
signed on the basis of elemental analysis and spectral data
(cf. experimental).
The condensation of compounds 16-18 with hydra-
zine hydrate in refluxing absolute ethanol yielded the pyr-
azolylquinazoline derivatives 19-21, respectively. The in-
frared spectrum of compound 19 showed the absence of
nitrile functional group and the presence of only NH/NH2
groups.
Antimicrobial Activity
The antimicrobial activity of some of the synthesized
compounds were determined in vitro using hole plate and
filter paper disc methods.21 A variety of species of gram
positive and gram negative bacteria in addition to some
fungal plant pathogens were used. Also, a comparison be-
tween the activity of our synthesized compounds and sul-
phadiazine as standard drug was discussed. The tested
compounds were dissolved in 10% acetone (V/V), and dif-
ferent concentrations have been chosen (125, 250, 500
Moreover, the reaction of compound 18 with equi-
molar amounts of urea or thiourea, in refluxing ethanolic
sodium ethoxide solution, provided the corresponding
pyrimidinylquinazoline derivatives 22a,b (Scheme III).
The structures of the synthesized compounds were as-

Synthesis of Some Annelated Quinazoline Derivatives
Table 1. The antimicrobial activity of the tested compounds
J. Chin. Chem. Soc., Vol. Vol. 54, No. 2, 2007 441
Staphylococcus
aureus
Bacillus
subtilis
Bacillus Pseudomonas Escherichia Aspergillus
Penicillium
italicum
Comp. No.
cereus
aurignosa
coli
niger
2
08
19
18
20
23
21
16
18
16
18
21
20
23
20
10
21
19
23
21
22
17
19
18
17
22
21
22
23
12
18
16
21
19
19
21
18
19
18
23
18
24
23
11
20
23
18
20
21
18
15
18
19
21
20
20
20
10
23
20
18
24
19
14
10
12
19
21
22
24
22
07
10
11
13
15
18
15
11
13
12
10
10
17
14
06
12
12
10
12
12
13
12
14
10
12
12
12
12
5a
6
7
9
11
12
13a
14a
16
19
21
22b
Sulphadiazine
Diameter of inhibition zones in measured in mm.
mg/mL). A qualitative screen was performed on all com-
pounds while quantitative assays were done on active com-
pounds only. The results are summarized in Table 1.
It is apparent from the data listed in Table 1, the anti-
microbial activity of the most synthesized compounds, 5a,
6, 7, 9, 11, 19, 21, 22b were highly active against gram+ve
and gram–ve bacteria but showed moderate activity against
the selected fungi as compared with the reference drug
used.
by thin layer chromatography, carried out on 0.2 mm silica
gel 60 F254 (Merck) plates.
13C NMR values of 4-(toluene-4-sulfonylamino)phen-
yl-moiety for the synthesized compounds are the same as in
compound 1 with d ± 1-0.5 ppm.
4-Methyl-N-[4-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-
benzenesulfonamide (1)
A solution of 2-[4-(toluene-4-sulfonylamino)ben-
zoylamino]benzoic acid (8.2 g, 20 mmol) in acetic anhy-
dride14 (25 mL) was heated under reflux for 3 h on a water
bath, then allowed to cool. The solid product was filtered
off and recrystallized from benzene to give 1. Yield, 67%;
mp 150-2 °C; IR: n = 3260 (NH), 1745 (CO), 1440, 1370
cm-1 (SO2); 1H NMR (CDCl3): d = 2.36 (s, 3H, CH3), 6.96-
8.11 (m, 12H, ArH), 10.11 (s, 1H, NH, exchangeable); MS:
m/z: 392 (M+); 13C NMR: d = 28.2 (CH3), 126.2 (C-8),
128.3 (C-4a), 129.5 (C-6), 134.4 (C-5), 138.3 (C-7), 148.2
(C-8a), 158.3 (C-2), 176.3 (CO), 113.4, 118.3, 120.3, 124.2,
125.3, 130.3, 133.5, 142.6 (C-aromatics); Anal. Calcd for
C21H16N2O4S (392.43): C, 64.27; H, 4.11; N, 7.14%.
Found: C, 64.65; H, 4.53; N, 7.59%.
On the other hand, the compounds 12, 13a, 14a, 16
are moderately active towards bacteria and fungi as com-
pared with standard drugs.
In summary, the ability of quinazoline derivative 2
was demonstrated to undergo annelation reactions under
rather mild conditions providing an efficient synthetic
method for the preparation of various quinazoline deriva-
tives of enhanced biological activity. But it should be noted
that other pharmacological studies are still in progress.
EXPERIMENTAL
Melting points are uncorrected. IR spectra in KBr
were recorded on a Perkin-Elmer 298 spectrophotometer.
1H and 13C NMR spectra were obtained on a Varian Gemini
200 MHz and 50 MHz instrument using TMS as internal
reference with chemical shifts expressed as d ppm. Mass
spectra were recorded on a Shimadzu GCMS-QP 1000 EX
instrument (70 eV El mode). All reactions were monitored
4-Methyl-N-[4-(4-oxo-3,4-dihydroquinazolin-2-yl)phen-
yl]benzenesulfonamide (2)
A mixture of 1 (5.9 g, 15 mmol) and ammonium ace-
tate (1.4 g, 18 mmol) was fused for 1 h in a fusion tube pro-
vided with an air condenser in an oil bath at 160-170 °C,
then cooled and added to cold water (50 mL). The solid ob-

442 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Aly
tained was filtered off and recrystallized from ethanol to
give 2. Yield, 69%; mp 187-9 °C; IR: n = 3430-3250 (OH,
NH), 1680 (CO), 1610 cm-1 (CN); 1H NMR (CDCl3): d =
2.31 (s, 3H, CH3), 6.97-8.12 (m, 13H, ArH and NH of
quinazolinone), 10.00 (s, 1H, NH, exchangeable); 13C
NMR: d = 127.1 (C-8), 128.3 (C-4a), 129.1 (C-6), 130.1
(C-5), 131.3 (C-7), 147.3 (C-8a), 158.2 (C-2), 173.4 (CO);
Anal. Calcd for C21H17N3O3S (391.44): C, 64.43; H, 4.38;
N, 10.73%. Found: C, 64.81; H, 43.62; N, 10.41%.
which separated upon cooling was filtered off and recrys-
tallized from the proper solvent to give 5a,b.
5a; Yield, 61%; mp 193-5 °C (benzene); IR: n =
3295-3190 (NH), 1615-1605 (CN), 1440, 1360 cm-1 (SO2);
1H NMR (CDCl3): d = 2.33, 2.41 (2s, 6H, 2CH3), 7.10-8.21
(m, 14H, ArH and NH of triazine), 10.12 (s, 1H, NH, ex-
changeable); Anal. Calcd for C24H21N5O2S (443.52): C,
64.99; H, 4.77; N, 15.79%. Found: C, 64.63; H, 4.32; N,
15.9%.
5b; Yield, 57%, mp (201-3 °C (dioxane); IR: n =
3280-3200 (NH), 1612-1605 (CN), 1451, 1365 cm-1 (SO2);
1H NMR (CDCl3): d = 2.29 (s, 3H, CH3), 6.98-8.11 (m,
19H, ArH and NH of triazine), 10.16 (s, 1H, NH, exchange-
able); MS: m/z: 505 (M+); Anal. Calcd for C29H23N5O2S
(505.59): C, 68.89; H, 4.59; N, 13.85%. Found: C, 68.45;
H, 4.21; N, 13.61%.
N-[4-(4-Chloroquinazolin-2-yl)phenyl]-4-methylben-
zenesulfonamide (3)
A suspension of compound 2 (3.9 g, 10 mmol) and
PCl5 (0.5 g) in POCl3 (8 mL) was heated under reflux for 2
h on a water bath. The reaction mixture after cooling was
poured slowly on crushed ice (30 g) and the solid formed
was filtered off, washed with cold water, dried and crystal-
lized from benzene to give 3. Yield, 73%; mp 163-5 °C; IR:
n = 3290 (NH), 1620 cm-1 (CN); 1H NMR (CDCl3): d = 2.38
(s, 3H, CH3), 7.12-8.14 (m, 12H, ArH), 10.17 (s, 1H, NH,
exchangeable); MS: m/z: 409 (M+); 13C NMR: d = 118.3
(C-4a), 119.5 (C-5), 124.3 (C-6), 125.3 (C-8), 130.3 (C-7),
135.6 (C-8a), 145.3 (C-2), 146.4 (C-4); Anal. Calcd for
C21H16ClN3O2S (409.89): C, 61.53; H, 3.93; N, 10.25%.
Found: C, 61.82; H, 4.11; N, 10.56%.
3-Oxo-2H-6-(toluene-4-sulfonylamino)phenyl]-[1,2,4]-
triazino[4,3-c]quinazoline (6)
A mixture of 4 (2.03 g, 5 mmol) and ethyl chloro-
acetate (0.61 g, 5 mmol) in absolute ethanol (25 mL) was
heated under reflux for 10 h. The solid that separated after
cooling and recrystallization from dioxane gave 6. Yield,
53%; mp 241-3 °C; IR: n = 3310 (NH), 1675 (CO), 1618
cm-1 (CN); 1H NMR (CDCl3): d = 2.33 (s, 3H, CH3), 3.67 (s,
2H, CH2), 7.13-8.31 (m, 13H, ArH and NH of triazine), 9.96
(s, 1H, NH, exchangeable); Anal. Calcd for C23H19N5O3S
(445.49): C, 62.01; H, 4.30; N, 15.72%. Found: C, 62.36;
H, 4.61; N, 15.36%.
N-[4-(4-Hydrazinoquinazolin-2-yl)phenyl]-4-methyl-
benzenesulfonamide (4)
A mixture of 3 (4.1 g, 10 mmol) and hydrazine hy-
drate (0.5 g, 10 mmol) in n-butanol (30 mL) was heated un-
der reflux for 3 h. The reaction mixture was cooled, then
poured on cold water (30 mL) and the solid formed was col-
lected and crystallized from n-butanol to give 4. Yield,
58%; mp 220-2 °C; IR: n = 3400-3200 (multiple bands,
NH2, NH), 1610 cm-1 (CN); 1H NMR (CDCl3): d = 2.34 (s,
3H, CH3), 5.3 (br s, 2H, NH2), 7.11-8.23 (m, 12H, ArH),
9.51, 9.95 (2s, 2H, 2NH, exchangeable); MS: m/z: 405
(M+); 13C NMR: d = 121.2 (C-4a), 126.3 (C-5), 133.6 (C-6),
139.1 (C-8), 148.3 (C-7), 159.4 (C-8a), 167.3 (C-2), 179.3
(C-4); Anal. Calcd for C21H19N5O2S (405.47): C, 62.20; H,
4.72; N, 17.27%. Found: C, 62.58; H, 4.94; N, 17.10%.
3,4-Dioxo-2H-6-[4-(toluene-4-sulfonylamino)phenyl]-
[1,2,4]triazino[4,3-c]quinazoline (7)
A mixture of 4 (2.03 g, 5 mmol) and diethyl oxalate
(0.73 g, 5 mmol) in absolute ethanol (20 mL) was heated
under reflux for 10 h. After cooling the separated solid pro-
duced was collected and recrystallized from ethanol to give
7. Yield, 65%; mp 252-4 °C; IR: n = 3275 (NH), 1690-1680
cm-1 (CO); 1H NMR (CDCl3): d = 2.35 (s, 3H, CH3), 7.12-
8.10 (m, 13H, ArH and NH of triazine), 10.20 (s, 1H, NH,
exchangeable); Anal. Calcd for C23H17N5O4S (459.48): C,
60.12; H, 3.73; N, 15.24%. Found: C, 60.40; H, 3.98; N,
15.01%.
3-Methyl-/phenyl-2H-6-[4-(toluene-4-sulfonylamino)-
phenyl]-[1,2,4]triazino[4,3-c]quinazolines (5a,b)
A mixture of 4 (2.03 g, 5 mmol) and a-haloketones (5
mmol) (viz chloroacetone and phenacyl bromide) in dry
xylene (20 mL) was heated under reflux for 8 h. The solid
N-{4-[4-(N¢-Benzylidene-/4-Chlorobenzylidenehydra-
zino)quinazolin-2-yl]phenyl}-4-methylbenzenesulfon-
amide (8a,b)
A mixture of 4 (4.05 g, 10 mmol) and appropriate al-

Synthesis of Some Annelated Quinazoline Derivatives
J. Chin. Chem. Soc., Vol. Vol. 54, No. 2, 2007 443
dehydes (10 mmol) namely benzaldehyde and/or p-chlo-
robenzaldehyde in absolute ethanol (30 mL) was heated
under reflux for 4 h in the presence of a catalytic amount of
piperidine. The excess alcohol was distilled off, and the re-
action solution was left to cool to obtain the solid product
which crystallized from a suitable solvent to give 8a,b.
8a; Yield, 61% (ethanol); mp 236-8 °C; IR: n =
3360-3200 (NH), 1620-1610 cm-1 (CN); 1H NMR (CDCl3):
d = 2.33 (s, 3H, CH3), 7.11-8.21 (m, 18H, ArH and benzyl-
idene proton), 9.63, 10.00 (2s, 2H, 2NH, exchangeable);
Anal. Calcd for C28H23N5O2S (493.58): C, 68.13; H, 4.70;
N, 14.19%. Found: C, 68.45; H, 4.93; N, 14.01%.
NMR (CDCl3): d = 2.33 (s, 3H, CH3), 7.15-8.12 (m, 17H,
ArH), 9.95 (s, 1H, NH, exchangeable); Anal. Calcd for
C29H21N5O3S2 (551.64): C, 63.14; H, 3.84; N, 12.70%.
Found: C, 63.36; H, 3.97; N, 12.48%.
4-Methyl-N-[4-(8-oxo-8H-quinazolino[4,3-b]quinazolin-
6-yl)phenyl]benzenesulfonamide (12)
A mixture of 3 (2.0 g, 5 mmol) and anthranilic acid
(0.69 g, 5 mmol) was fused for 2 h in a fusion tube provided
with an air condenser in an oil bath at 165-175 °C, then
cooled and added to cold water (40 mL). The solid product
obtained was collected and recrystallized from benzene to
give 12. Yield, 65%; mp 193-5 °C; IR: n = 3290 (NH), 1675
(CO), 1605 (CN), 1435, 1360 cm-1 (SO2); 1H NMR (CDCl3):
d = 2.33 (s, 3H, CH3), 6.97-7.89 (m, 16H, ArH), 9.98 (s,
1H, NH, exchangeable); Anal. Calcd for C28H20N4O3S
(492.55): C, 68.28; H, 4.09; N, 11.37%. Found: C, 68.56;
H, 4.48; N, 11.01%.
8b; Yield, 67% (ethanol); mp 241-3 °C; IR: n =
3340-3250 (NH), 1615-1605 cm-1 (CN); 1H NMR (CDCl3):
d = 2.22 (s, 3H, CH3), 7.20-8.13 (m, 17H, ArH and benzyl-
idene proton), 9.51, 10.11 (2s, 2H, 2NH, exchangeable);
Anal. Calcd for C28H22ClN5O2S (528.03): C, 63.69; H,
4.20; N, 13.26%. Found: C, 63.40; H, 4.01; N, 13.62%.
N-(4-{4-[2-(4-Chlorophenyl)-4-oxothiazolidin-3-ylami-
no]quinazolin-2-yl}phenyl)-4-methylbenzenesulfon-
amide (9)
General procedure for the synthesis of quinazolinyl-
amino acids (13a,b)
Amino acids (viz glycine and alanine, 10 mmol) and
sodium carbonate (0.53 g, 5 mmol) were dissolved in water
(15 mL), then adjusted to pH 9-9.5. Compound 3 (2.0 g, 5
mmol) was added and the reaction mixture was stirred at
100 °C for 8 h at controlled pH. The reaction mixture was
left overnight at room temperature, then treated with cold
hydrochloric acid. The solid product obtained was filtered
off, washed with water, and crystallized from the proper
solvent to give 13a,b.
A mixture of 8b (2.6 g, 5 mmol) and 2-mercapto-
acetic acid (0.46 g, 5 mmol) was stirred in dry benzene (25
mL) for 15 min, then refluxed for 3 h. The yellow solution
was distilled and the residue was recyrstallized from ben-
zene to give 9. Yield, 71% (benzene), mp 216-8 °C; IR: n =
1
3320-3190 (NH), 1685 (CO), 1610 cm-1 (CN); H NMR
(CDCl3): d = 2.31 (s, 3H, CH3), 3.72 (s, 1H, methine pro-
ton), 4.80 (s, 2H, CH2), 7.01-8.12 (m, 16H, ArH), 9.21,
9.98 (2s, 2H, 2NH, exchangeable); MS: m/z: 602 (M+);
Anal. Calcd for C30H24ClN5O3S2 (602.13): C, 59.84; H,
4.02; N, 11.63%. Found: C, 59.53; H, 4.31; N, 11.32%.
{2-[4-(Toluene-4-sulfonylamino)phenyl]quinazolin-4-
ylamino}acetic acid (13a)
Yield, 71% (dioxane); mp 246-8 °C; IR: n = 3420-
1
4-Oxo-3-phenyl-2-thioxo-6-[4-(toluene-4-sulfonylami-
no)phenyl]-[1,2,4]triazino[4,3-c]-quinazoline (11)
3160 (OH, NH), 1700 (CO), 1610 cm-1 (CN); H NMR
(CDCl3): d = 2.36 (s, 3H, CH3), 3.51 (s, 2H, CH2), 7.11-
8.12 (m, 13H, ArH and NH), 9.78 (s, 1H, NHSO2, ex-
changeable); 10.61 (brs, 1H, OH, exchangeable); Anal.
Calcd for C23H20N4O4S (448.50): C, 61.59; H, 4.49; N,
12.49%. Found: C, 61.21; H, 4.13; N, 12.73%.
To a stirred solution of chloroquinazoline 3 (2.0 g, 5
mmol) in dry acetone, ammonium thiocyanate (0.38 g, 5
mmol) in dry acetone was added. The reaction mixture was
stirred for 1 h at room temperature. Ammonium chloride
was precipitated during the progress of the reaction. After
filtration of the ammonium chloride, phenyl isocyanate
(0.6 g, 5 mmol) was added to the filterate. The reaction
mixture was heated under reflux for 30 min. The solid
product which separated after cooling was crystallized
from ethanol to give 11. Yield, 53%; mp 241-3 °C; IR: n =
2-{2-[4-(Toluene-4-sulfonylamino)phenyl]quinazolin-4-
ylamino}propionic acid (13b)
Yield, 66% (DMF-H2O); mp 236-8 °C; IR: n = 3410-
3220 (OH, NH), 1695 (CO), 1605 cm-1 (CN); Anal. Calcd
for C24H22N4O4S (462.52): C, 62.32; H, 4.79; N, 12.11%.
Found: C, 62.71; H, 4.97; N, 11.91%.
1
3320 (NH), 1675 (CO), 1618 (CN), 1265 cm-1 (CS); H

444 J. Chin. Chem. Soc., Vol. 54, No. 2, 2007
Aly
General procedure for the synthesis of imidazoquin-
azolines (14a,b)
tion (0.56 g of sodium in 50 mL ethanol) and stirred for 2 h.
Compound 3 (4.1 g, 10 mmol) was added to an ethanolic
sodium ethoxide solution (0.56 g of sodium in 50 mL etha-
nol) and stirred for 2 h. The reaction mixture was heated
under reflux for 5 h. The ethanol was removed under re-
duced pressure, and the residue was poured into cold water
(100 mL) and extracted with ether. The extracted solvent
was dried over anhydrous sodium sulphate and removed
under reduced pressure to give the compounds 16-18, re-
spectively.
A mixture of 13a or 13b (5 mmol), acetic anhydride
(10 mL), and anhydrous sodium acetate (0.41 g, 5 mmol)
was heated under reflux for 3 h. The solvent was removed
under reduced pressure and the residue washed with water,
filtered, dried, and crystallized from proper solvent to give
14a,b.
4-Methyl-N-[4-(3-oxo-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-yl)phenyl]benzenesulfonamide (14a)
Yield, 56% (DMF); mp 181-3 °C; IR: n = 3260 (NH),
1680 (CO), 1610 cm-1 (CN); 1H NMR (CDCl3): d = 2.31 (s,
3H, CH3), 4.34 (s, 2H, CH2), 6.98-8.11 (m, 12H, ArH),
10.31 (s, 1H, NH, exchangeable); MS: m/z: 430 (M+); Anal.
Calcd for C23H18N4O3S (430.48): C, 64.17; H, 4.21; N,
13.01%. Found: C, 64.51; H, 4.62; N, 13.43%.
N-{4-[4-(Dicyanomethyl)quinazolin-2-yl]phenyl}-4-
methylbenzenesulfonamide (16)
Yield, 64% (ethanol); mp 173-5 °C; IR: n = 3330 (NH),
2225-2220 (2CºN), 1620 cm-1 (CN); 1H NMR (CDCl3): d =
2.31 (s, 3H, CH3), 4.57 (s, 1H, CH), 7.11-8.12 (m, 12H,
ArH), 10.01 (s, 1H, NH, exchangeable); MS: m/z: 439
(M+); Anal. Calcd for C24H17N5O2S (439.49): C, 65.59; H,
3.90; N, 15.94%. Found: C, 65.23; H, 3.61; N, 15.72%.
4-Methyl-N-[4-(2-methyl-3-oxo-2,3-dihydroimidazo-
[1,2-c]quinazolin-5-yl)phenyl]benzenesulfonamide
(14b)
Ethyl cyano-{2-[4-(toluene-4-sulfonylamino)phenyl]-
quinazolin-4-yl}acetate (17a)
Yield, 61% (benzene); mp 175-7 °C; IR: n = 3280
(NH), 1675 (CO), 1605 cm-1 (CN); 1H NMR (CDCl3): d =
2.11, 2.35 (2s, 6H, 2CH3), 4.10 (s, 1H, methine proton),
7.12-8.13 (m, 12H, ArH), 9.95 (s, 1H, NH, exchangeable);
Anal. Calcd for C24H20N4O3S (444.51): C, 64.85; H, 4.54;
N, 12.60%. Found: C, 64.27; H, 4.24; N, 12.93%.
Yield, 61% (1-butanol); mp 213-15 °C; IR: n = 3290
(NH), 2230 (CN), 1735 (CO), 1615 cm-1 (CN); 1H NMR
(CDCl3): d = 1.25 (t, 3H, CH3), 2.31 (s, 3H, CH3), 4.41 (s,
1H, CH), 4.31 (q, 2H, CH2), 6.91-7.98 (m, 12H, ArH), 9.89
(s, 1H, NH, exchangeable). Anal. Calcd for C26H22N4O4S
(486.54): C, 64.18; H, 4.56; N, 11.52%. Found: C, 64.43;
H, 4.76; N, 11.21%.
N-[4-([1,3]benzimidazo[1,2-c]quinazolin-6-yl)phenyl]-4-
methylbenzenesulfonamide (15)
A mixture of compound 3 (2.0 g, 5 mmol) and o-
phenylenediamine (0.54 g, 5 mmol) was fused for 2 h in a
fusion tube provided with an air condenser in an oil bath at
170-180 °C. After cooling the reaction mixture was poured
on cold water (40 mL), and the solid product which formed
was crystallized from n-butanol to give 15. Yield, 64%; mp
206-8 °C; IR: n = 3230 (NH), 1610 (CN), 1450, 1360 cm-1
(SO2); 1H NMR (DMSO-d6): d = 2.34 (s, 3H, CH3), 7.11-
8.14 (m, 16H, ArH), 9.88 (s, 1H, NH, exchangeable). Anal.
Calcd for C27H20N4O2S (464.54): C, 69.81; H, 4.34; N,
12.06%. Found: C, 69.36; H, 4.02; N, 12.49%.
Ethyl 3-oxo-2-{2-[4-(toluene-4-sulfonylamino)phenyl]-
quinazolin-4-yl}butyrate (17b)
Yield, 65% (benzene); mp 183-5 °C; IR: n = 3310
(NH), 1735, 1710 (2CO), 1605 cm-1 (CN); 1H NMR (CDCl3):
d = 1.31 (t, 3H, CH3CH2), 2.25 (s, 3H, CH3), 2.61 (s, 3H,
CH3CO), 4.11 (q, 2H, CH2CH3), 4.35 (s, 1H, CH), 7.10-
8.21 (m, 12H, ArH), 9.78 (s, 1H, NH, exchangeable); Anal.
Calcd for C27H25N3O5S (503.57): C, 64.40; H, 5.00; N,
8.34%. Found: C, 64.75; H, 5.27; N, 8.11%.
N-{4-[4-(1-Acetyl-2-oxopropyl)quinazolin-2-yl]phenyl}-
4-methylbenzenesulfonamide (18)
General procedure for the synthesis of compounds
(16-18)
Yield, 64% (dioxane); mp 161-3 °C; IR: n = 3370
(NH), 1710 (CO), 1612 cm-1 (CN); 1H NMR (CDCl3): d =
2.35 (s, 3H, CH3), 2.51 (br s, 6H, 2COCH3), 4.25 (s, 1H,
CH), 6.99-8.11 (m, 12H, ArH), 10.11 (s, 1H, NH, ex-
changeable). Anal. Calcd for C26H23N3O4S (473.54): C,
Active methylene compounds (viz malononitrile, eth-
yl cyanoacetate, ethyl acetoacetate and acetylacetone, 10
mmol) were added to an ethanolic sodium ethoxide solu-

Synthesis of Some Annelated Quinazoline Derivatives
J. Chin. Chem. Soc., Vol. Vol. 54, No. 2, 2007 445
65.94; H, 4.90; N, 8.87%. Found: C, 65.63; H, 4.71; N,
8.99%.
CH3), 2.53, 2.64 (2s, 6H, 2CH3 of pyrazole), 7.12-8.31 (m,
13H, ArH and NH of pyrazole), 10.01 (s, 1H, NH, exchange-
able); MS: m/z: 469 (M+); Anal. Calcd for C26H23N5O2S
(469.56): C, 66.50; H, 4.94; N, 14.91%. Found: C, 66.86;
H, 4.51; N, 14.61%.
General procedure for the synthesis of pyrazolylquin-
azolines 19-21
A mixture of 16, 17a, 17b, 18 (5 mmol) and hydrazine
hydrate (0.25 g, 5 mmol) in absolute ethanol (20 mL) was
heated under reflux for 6 h, then allowed to cool. The solid
product was collected and recrystallized from the proper
solvent to give the compounds 19-21, respectively.
N-{4-[4-(4,6-Dimethyl-2-oxo-/thioxo-1,2-dihydropyr-
imidin-5-yl)quinazolin-2-yl]phenyl}-4-methylbenzene-
sulfonamide (22a,b)
To a solution of 18 (2.49 g, 5 mmol), in ethanolic so-
dium ethoxide solution (0.12 g, 5 mmol) [prepared by dis-
solving sodium metal (0.12 g, 5 mmol) in absolute ethanol
(50 mL)] urea or thiourea was added. The reaction mixture
was heated under reflux for 8 h. The solvent was evapo-
rated in vacuo, and the residue was triturated with cold wa-
ter whereupon the solid that formed was collected and
recrystallized from proper solvent to give 22a,b.
N-{4-[4-(3,5-Diamino-4H-pyrazol-4-yl)quinazolin-2-yl]-
phenyl}-4-methylbenzenesulfonamide (19)
Yield, 62% (benzene); mp 211-13 °C; IR: n = 3390-
3200 (multiple bands, NH2, NH), 1615-1605 (CN), 1460,
1370 cm-1 (SO2); 1H NMR (CDCl3): d = 2.30 (s, 3H, CH3),
4.11 (s, 1H, CH), 5.10-5.40 (br s, 4H, 2NH2), 7.15-8.12 (m,
12H, ArH), 9.69 (s, 1H, NH, exchangeable); MS: m/z: 471
(M+); Anal. Calcd for C24H21N7O2S (471.54): C, 61.13; H,
4.49; N, 20.79%. Found: C, 61.48; H, 4.83; N, 20.34%.
22a; Yield, 59% (ethanol); mp 191-3 °C; IR: n =
1
3300-3200 (NH), 1670 (CO), 1610 cm-1 (CN); H NMR
(CDCl3): d = 2.32 (s, 3H, CH3), 2.51, 2.63 (2s, 6H, 2CH3 of
pyrimidine), 7.13-8.21 (m, 13H, ArH and NH of pyrimi-
dine), 10.12 (s, 1H, NH, exchangeable; Anal. Calcd for
C27H23N5O3S (497.57): C, 65.17; H, 4.66; N, 14.08%.
Found: C, 65.43; H, 4.98; N, 14.49%.
N-{4-[4-(3-Amino-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)-
quinazolin-2-yl]phenyl}-4-methylbenzenesulfonamide
(20a)
Yield, 63% (AcOH); mp 241-3 °C; IR: n = 3420-3210
(multiple bands, NH2, NH), 1675 (CO), 1610 cm-1 (CN); 1H
NMR (CDCl3): d = 2.45 (s, 3H, CH3), 4.21 (s, 1H, CH),
4.40 (br s, 2H, NH2), 6.81-7.83 (m, 13H, ArH + NH of pyr-
azole), 9.96 (s, 1H, NH, exchangeable; Anal. Calcd for
C24H20N6O3S (472.52): C, 61.00; H, 4.27; N, 17.79%.
Found: C, 61.48; H, 4.63; N, 17.31%.
22b; Yield, 61% (ethanol); mp 206-8 °C; IR: n =
1
3340-3210 (NH), 1605 (CN), 1250 cm-1 (CS); H NMR
(CDCl3): d = 2.21 (s, 3H, CH3), 2.45, 2.53 (2s, 6H, 2CH3 of
pyrimidine), 6.95-8.10 (m, 13H, ArH and NH of pyrimi-
dine), 10.10 (s, 1H, NH, exchangeable); MS: m/z: 513
(M+); Anal. Calcd for C27H23N5O2S2 (513.64): C, 63.14; H,
4.51; N, 13.63%. Found: C, 63.51; H, 4.92; N, 13.31%.
4-Methyl-N-{4-[4-(3-methyl-5-oxo-4,5-dihydro-1H-pyr-
azol-4-yl)quinazolin-2-yl]phenyl}benzenesulfonamide
(20b)
ACKNOWLEDGEMENT
Yield, 65% (n-butanol); mp 251-3 °C; IR: n = 3300-
3120 (NH), 1675 (CO), 1610 cm-1 (CN); 1H NMR (CDCl3):
d = 2.12, 2.23 (2s, 6H, 2CH3), 4.13 (s, 1H, CH), 6.98-8.11
(m, 13H, ArH and NH of pyrazole), 9.70 (s, 1H, NH, ex-
changeable); MS: m/z: 471 (M+); Anal. Calcd for C25H21N5O3S
(471.53): C, 63.68; H, 4.49; N, 14.85%. Found: C, 63.25;
H, 4.12; N, 14.99%.
The author is grateful to the Botany Department, Fac-
ulty of Science, Benha University for biological screening.
Received October 24, 2005.
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