Synthesis and antimicrobial activity of some annelated quinazoline derivatives

Article abstract of DOI:10.1515/znb-2006-0814

A highly efficient and versatile synthetic approach to the synthesis of annelated quinazoline derivatives viz. 3,4,9,10a-tetraazaphenanthrenes 5-7, thiazolidinylquinazoline 9, 2,4,9,10a-tetraazaphenanthrene 11, quinazolino[4,3-b]quinazolin-8-one 12 and im

Full text of DOI:10.1515/znb-2006-0814

Synthesis and Antimicrobial Activity of Some Annelated Quinazoline
Derivatives
A. A. Aly
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
Reprint requests to Dr. A. A. Aly. E-mail: alymaboud@hotmail.com
Z. Naturforsch. 61b, 1012 – 1020 (2006); received October 10, 2005
A highly efficient and versatile synthetic approach to the synthesis of annelated quinazoline deriva-
tives viz. 3,4,9,10a-tetraazaphenanthrenes 5 – 7, thiazolidinylquinazoline 9, 2,4,9,10a-tetraazaphen-
anthrene 11, quinazolino[4,3-b]quinazolin-8-one 12 and imidazoquinazolines 14a,b, 15. Also, a va-
riety of pyrazolylquinazolines 19 – 21, 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 reagents. The new compounds were synthesized with the objective of
study their antimicrobial activity.
Key words: Tetraazaphenanthrene, Quinazolinoquinazoline, Pyrazolylquinazoline, Antimicrobial
Activity
Introduction
IR spectrum showed absorption bands at 3260 (νNH),
1745 (νCO) and 1440, 1370 cm−1 (νSO2). The 1H NMR
spectrum (CDCl3) showed signal (3H) at δ = 2.36 ppm
assigned for methyl protons, a multiplet signals (12H)
at (6.96– 8.11 ppm) assigned for the aromatic protons
and signal at 10.11 ppm assigned for NH which dis-
appeared upon addition of D2O to NMR sample and
its mass spectrum revealed a molecular ion peak at
m/z (%) = 392 (M+) corresponding to the molecu-
lar formula C21H16N2O4S. Fusion of benzoxazinone
derivative 1 with ammonium acetate in an oil bath
at 160– 170 ◦C afforded 4-methyl-N-[4-(4-oxo-3,4-di-
hydroquinazolin-2-yl)phenyl]benzenesulfonamide (2)
which is a promising intermediate for the synthesis
of a diverse annelated quinazoline derivatives. Re-
action of compound 2 with a mixture of phospho-
rus pentachloride/phosphorus oxychloride on a water
bath yielded 4-chloroquinazoline derivative 3 in fairly
good yield, which upon subsequent reaction with hy-
drazine hydrate in refluxing n-butanol furnished the
target compound, 4-hydrazinoquinazoline derivative 4
(Scheme 1).
Quinazoline derivatives and heterocyclic annelated
quinazolines are reported to be physiologically and
pharmacologically active [1], which exhibit a wide
rang of activities as anticonvulsant, anti-inflammatory,
antifungal, antimalarial and sedative [2 – 6]. Some of
these compounds are identifies as drugs [7], such as
quinethazone and metolazone are used in medicine
as diuretics while prazosin is a vasodilator which is
also used as antihypertensive drug. Moreover, sulfon-
amide derivatives have been widely used as bacterio-
static agents [8, 9]. Prompted us by above mentioned
facts and in conjunction with our ongoing program on
the utility of readily obtainable starting material for the
synthesis of heterocyclic systems of biological inter-
est [10 – 13]. We have decided to synthesis a series of
novel annelated quinazoline derivatives having sulfon-
amide moiety with potential wide spectrum of biologi-
cal responses.
Results and Discussion
The target compound, 4-methyl-N-[4-(4-oxo-4H-
As the preparation of novel tricyclic and tetracyclic
3,1-benzoxazin-2-yl)-phenyl]benzenesulfonamide (1) systems is the main goal of this synthetic program,
was readily obtained from cyclization of 2-[4-(toluene- hydrazinoquinazoline was used as a precursor for the
4-sulfonylamino)benzoylamino]benzoic acid by boil- synthesis of triazinoquinazoline derivatives of biologi-
ing in acetic anhydride [14]. The structure of the re- cal applications [15 – 17]. Thus, the cyclocondensation
action product 1 was supported by elemental anal- of compound 4 with α-haloketones (viz. chloroacetone
yses and compatible spectroscopic data. Thus, its and phenacyl bromide) in dry xylene gave tetraaza-
c
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A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
1013
Scheme 1.
phenanthrene derivatives 5a,b. Also, the reaction
Furthermore, chloroquinazoline 3 was also used
of compound 4 with ethyl chloroacetate yielded for construction of novel triazinoquinazoline deriva-
4-methyl-N-[4-(2-oxo-2,3-dihydro-1H-3,4, 9, 10a-
tive 11 via the reaction of compound 3 with ammo-
tetraazaphenanthren-10-yl)phenyl]benzenesulfon-
nium thiocyanate in dry acetone to afford the non-
amide (6). Moreover, tetraazaphenanthrene-1,2- isolable intermediate 10, which reacted in situ with
dione 7 was also obtained from the reaction of phenyl isocyanate to yield triazinoquinazoline deriva-
compound 4 with diethyl oxalate in absolute ethanol. tive 11 (Scheme 2).
Reaction of compound 4 with aromatic aldehydes
(viz. benzaldehyde and p-chlorobenzaldehyde) gave
quinazoline derivatives 8a,b. Cyclocondensation reac-
tion of 8b with 2-mercaptoacetic acid in presence of
catalytic amount of piperidine yielded thiazolidinone
derivative 9 via nucleophilic addition of sulfur atom to
activated C=N bond followed by cyclization to give 9
(Scheme 1).
The structure of compound 11 was confirmed by
its mass spectrum which showed a molecular ion
band at m/z (%) = 551 (M+) for molecular formula
C29H21N5O3S2, in addition to IR spectrum which
showed absorption band at 3320 (ν NH), 1680 (νCO
)
and at 1265 cm−1 (νCS). This contribution was
extended to study some nucleophilic substitution
reactions with chloroquinazoline 3 for construction
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1014
A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
Scheme 2.
a novel heteroaromatic systems. Thus, fusion of azolin-6-ylphenyl)-4-methylbenzenesulfonamide (15)
compound 3 with anthranilic acid in an oil bath at (Scheme 2).
165– 175 ◦C afforded 4-methyl-N-[4-(8-oxo-8H-quin-
The behavior of chloroquinazoline towards active
azolino[4,3-b]quinazolin-6-yl)-phenyl]benzenesulfon-
amide (12).
methylene compounds was also studied with respect
to the synthesis of highly substituted pyrazoles and
pyrimidines [19, 20]. Thus, the treatment of com-
pound 3 with active methylene compounds (viz. mal-
ononitrile, ethyl cyanoacetate, ethyl acetoacetate and
acetylacetone) afforded the corresponding quinazoline
derivatives 16 – 18, respectively (Scheme 3). The in-
frared spectrum of compound 16 showed the presence
of absorption peaks at 3310 due to (νNH) and 2225–
2215 cm−1 due to (2C≡N).
Treatment the chloroquinazoline 3 with the sodium
salt of various amino acids (viz. glycine and ala-
nine) under reflux, the corresponding quinazolin-
ylamino acids 13a,b were obtained. The amino
acid derivatives 13a,b were easily cyclized [18]
by boiling in acetic anhydride in presence of an-
hydrous sodium acetate to yield imidazoquinazo-
line derivatives 14a,b. Incorporation of imidazolyl
moiety in the quinazoline ring was also achieved
The condensation of compounds 16-18 with hy-
by fusion of compound 3 with o-phenylenedi- drazine hydrate in refluxing absolute ethanol yielded
amine to afford N-(4-[1,3]benzimidazo[1,2-c]quin- the pyrazolylquinazoline derivatives 19 – 21, respec-
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A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
1015
Table 1. The antimicrobial ac-
tivity of the tested compounds.
Diameters of inhibition zones
are measured in mm.
Comp. No.
Staphylococcus Bacillus Bacillus Pseudomonas Escherichia Aspergillus Penicillium
aureus
8
subtilis cereus aurignosa
coli
10
23
20
18
24
19
14
10
12
19
21
22
24
22
niger
7
italicum
6
2
5a
6
7
9
11
12
13a
14a
16
19
21
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
19
18
20
23
21
16
18
16
18
21
20
23
20
10
11
13
15
18
15
11
13
12
10
10
17
14
12
12
10
12
12
13
12
14
10
12
12
12
22b
Sulphadiazine
12
line derivatives 22a,b (Scheme 3). The structures of the
synthesized compounds were assigned on the basis of
elemental analysis and spectral data (cf. Experimental
Section).
Antimicrobial activity
The antimicrobial activities of some synthesized
compounds were determined in vitro using hole plate
and filter paper disc methods [21]. A variety species
of gram positive and gram negative bacteria in addi-
tion to some fungal plant pathogens were used. Also,
a comparison between the activity of our synthesized
compounds and sulphadiazine as standard drug was
discussed. The tested compounds were dissolved in
10% acetone (V/V), and different concentrations have
been chosen (125, 250, 500 µg/ml). A qualitative
screen was performed on all compounds while quan-
titative assays were done on active compounds only.
The results are summarized in Table 1.
It is apparent from the data listed in Table 1, the
antimicrobial activity of the most synthesized com-
pounds, 5a, 6, 7, 9, 11, 19, 21, 22b were highly ac-
tive against gram+ve and gram –ve bacteria but showed
moderate activity against the selected fungi as com-
pared by reference drug used. The high activity of the
tested compounds due to the incorporation of triazine,
thiazole, pyrazole and pyrimidine moieties to quinazo-
line ring in addition to sulfonamide moiety.
Scheme 3.
On the other hand, the compounds 12, 13a, 14a, 16
are moderately active towards bacteria and fungi as
compared with standard drug due to the introduction
of polynuclear nonmixed heterocyclic systems to the
quinazoline ring.
tively. The infrared spectrum of compound 19 showed
the absence of nitrile functional group and the pres-
ence of only NH/NH2 groups. Moreover, the reaction
of compound 18 with equimolar amounts of urea or
thiourea, in refluxing ethanolic sodium ethoxide solu-
In summary, the ability of quinazoline derivative 2
tion, provided the corresponding pyrimidinylquinazo- was demonstrated to undergo annelation reactions un-
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1016
A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
der rather mild conditions providing an efficient syn- N-[4-(4-Chloroquinazolin-2-yl)phenyl]-4-methylbenzene-
sulfonamide (3)
thetic methods for the preparation of various quinazo-
line derivatives of enhanced biological activity.
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 crystallized from ben-
zene to give 3. Yield, 73%; m. p. 163 – 5 ◦C; IR: ν = 3290
(NH), 1620 cm−1 (CN); MS: m/z: 409 (M+); 13C NMR:
δ = 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); Ana-
lysis for C21H16ClN3O2S (409.89): calcd. C 61.53, H 3.93,
N 10.25; found C 61.82, H 4.11, N 10.56.
Experimental Section
Melting points are uncorrected. IR spectra in KBr were
recorded on a Perkin-Elmer 298 spectrophotometer. 1H
and 13C NMR spectra were obtained on an Varian Gem-
ini 200 MHz and 50 MHz instrument using TMS as inter-
nal reference with chemical shifts expressed as δ ppm. Mass
spectra were recorded on a Schimadzu GCMS-QP 1000 EX
instrument (70 eV El mode). All reactions were monitored
by thin layer chromatography, carried out on 0.2 mm silica
gel 60 F254 (Merck) plates.
13C NMR values of 4-(toluene-4-sulfonylamino)phenyl–
moiety for the synthesized compounds are the same as in
compound 1 with δ 1 – 0.5 ppm.
N-[4-(4-Hydrazinoquinazolin-2-yl)phenyl]-4-methyl-
benzenesulfonamide (4)
A mixture of 3 (4.1 g, 10 mmol) and hydrazine hydrate
(0.5 g, 10 mmol) in 1-butanol (30 ml) was heated under re-
flux for 3 h. The reaction mixture was cooled, then poured
on cold water (30 ml) and the solid formed was collected
and crystallized from 1-butanol to give 4. Yield, 58%; m. p.
220 – 2 ◦C; IR: ν = 3400 – 3200 (multiple bands, NH2, NH),
1610 cm−1 (CN); 1H NMR (CDCl3): δ = 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+); Analysis
for C21H19N5O2S (405.47): calcd. C 62.20, H 4.72, N 17.27;
found C 62.58, H 4.94, N 17.10.
4-Methyl-N-[4-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)-
phenyl]benzenesulfonamide (1)
To a solution of 2-[4-(toluene-4-sulfonylamino)benzoyl-
amino]benzoic acid (8.2 g, 20 mmol) in acetic anhydride [14]
(25 ml) was heated under reflux for 3 h on a water bath, then
allowed to cool. The solid product was filtered off and re-
crystallized from benzene to give 1. Yield, 67%; m. p. 150 –
◦
2 C; IR: ν = 3260 (NH), 1745 (CO), 1440, 1370 cm−1
(SO2); 1H NMR (CDCl3): δ = 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: δ = 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); Analysis
for C21H16N2O4S (392.43): calcd. C 64.27, H 4.11, N 7.14;
found C 64.65, H 4.53, N 7.59.
4-Methyl-N-[4-(2-methyl-/phenyl-3H-3,4,9,10a-tetra-
azaphenanthren-10-yl)phenyl]benzenesulfonamide (5a,b)
A mixture of 4 (2.03 g, 5 mmol) and α-haloketones
(5 mmol) (viz. chloroacetone and phenacyl bromide) in dry
xylene (20 ml) was heated under reflux for 8 h. The solid
which separated upon cooling was filtered off and recrystal-
lized from proper solvent to give 5a,b.
4-Methyl-N-[4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl]-
benzenesulfonamide (2)
5a; Yield, 61%; m. p. 193 – 5 ◦C (benzene); IR: ν = 3295 –
3190 (NH), 1615 – 1605 (CN), 1440, 1360 cm−1 (SO2);
1H NMR (CDCl3): δ = 2.33, 2.41 (2s, 6H, 2CH3), 7.10 –
8.21 (m, 14H, ArH and NH of triazine), 10.12 (s, 1H,
NH, exchangeable); Analysis for C24H21N5O2S (443.52):
calcd. C 64.99, H 4.77, N 15.79; found C 64.63, H 4.32,
N 15.9.
A mixture of 1 (5.9 g, 15 mmol) and ammonium acetate
(1.4g, 18 mmol) was fused for 1 h in a fusion tube provided
◦
with an air condenser in an oil bath at 160 – 170 C, then
cooled and added to cold water (50 ml). The solid obtained
was filtered off and recrystallized from ethanol to give 2.
Yield, 69%; m. p. 187 – 9 ◦C; IR: ν = 3430 – 3250 (OH, NH),
5b; Yield, 57%, m. p. (201 – 3 ◦C (dioxane); IR: ν =
1680 (CO), 1610 cm−1 (CN); H NMR (CDCl3): δ = 2.31 3280 – 3200 (NH), 1612 – 1605 (CN), 1451, 1365 cm−1
(s, 3H, CH3), 6.97 – 8.12 (m, 13H, ArH and NH of quin- (SO2); MS: m/z: 505 (M+); 13C NMR: δ = 106.3 (C-1),
azolinone), 10.00 (s, 1H, NH, exchangeable); 13C NMR: 125.3 (C-8), 125.5 (C-5a), 128.3 (C-6), 129.1 (C-5), 130.3
δ = 127.1 (C-8), 128.3 (C-4a), 129.1 (C-6), 130.1 (C-5), (C-7), 132.3 (C-2), 153.1 (C-8a), 155.4 (C-4a), 160.1 (C-10),
131.3 (C-7), 147.3 (C-8a), 158.2 (C-2), 173.4 (CO); Analysis 122.1, 122.4, 123.3, 123.6, 128.6, 130.1 (C-phenyl group);
for C21H17N3O3S (391.44): calcd. C 64.43, H 4.38, N 10.73; Analysis for C29H23N5O2S (505.59): calcd. C 68.89, H 4.59,
1
found C 64.81, H 43.62, N 10.41.
N 13.85; found C 68.45, H 4.21, N 13.61.
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A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
1017
4-Methyl-N-[4-(2-oxo-2,3-dihydro-1H-3,4,9,10a-tetra-
azaphenanthren-10-yl)phenyl]-benzenesulfonamide (6)
N-(4-{4-[2-(4-Chlorophenyl)-4-oxothiazolidin-3-yl-
amino]quinazolin-2-yl}phenyl)-4-methylbenzenesulfon-
amide (9)
A mixture of 4 (2.03 g, 5 mmol) and ethyl chloroacetate
(0.61 g, 5 mmol) in absolute ethanol (25 ml) was heated un-
der reflux for 10 h. The solid separated after cooling and re-
crystallization from dioxane gave 6. Yield, 53%; m. p. 241 –
A mixture of 8b (2.6 g, 5 mmol) and 2-mercaptoacetic
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 dis-
tilled and the residue was recyrstallized from benzene to give
◦
3 C; IR: ν = 3310 (NH), 1675 (CO), 1618 cm−1 (CN);
1H NMR (CDCl3): δ = 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); Analysis for C23H19N5O3S (445.49):
calcd. C 62.01, H 4.30, N 15.72; found C 62.36, H 4.61,
N 15.36.
◦
9. Yield, 71% (benzene), m. p. 216 – 8 C; IR: ν = 3320 –
3190 (NH), 1685 (CO), 1610 cm−1 (CN); 1H NMR (CDCl3):
δ = 2.31 (s, 3H, CH3), 3.72 (s, 1H, methine proton), 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+); 13C NMR:
δ = 41.1 (CH2 of thiazolidine), 61.3 (CH of thiazolidine),
112.2 (C-4a), 114.3 (C-5), 119.2 (C-6), 121.5 (C-8), 124.3
(C-7), 143.5 (C-8a), 153.6 (C-2), 156.1 (CO), 158.2 (C-2),
125.3, 127.7, 129.9, 131.2 (C- of phenyl group); Analysis for
C30H24ClN5O3S2 (602.13): calcd. C 59.84, H 4.02, N 11.63;
found C 59.53, H 4.31, N 11.32.
N-[4-(1,2-Dioxo-2,3-dihydro-1H-3,4,9,10a-tetraazaphen-
anthren-10-yl)phenyl]-4-methylbenzenesulfonamide (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 rec◦rystallized from ethanol to give 7.
Yield, 65%; m. p. 252 – 4 C; IR: ν = 3275 (NH), 1690 –
1680 cm−1 (CO); 1H NMR (CDCl3): δ = 2.35 (s, 3H, CH3),
7.12 – 8.10 (m, 13H, ArH and NH of triazine), 10.20 (s, 1H,
NH, exchangeable); Analysis for C23H17N5O4S (459.48):
calcd. C 60.12, H 3.73, N 15.24; found C 60.40, H 3.98,
N 15.01.
4-Methyl-N-[4-(1-oxo-2-phenyl-3-thioxo-2,3-dihydro-1H-
2,4,9,10a-tetraazaphenanthren-10-yl)phenyl]benzenesulfon-
amide (11)
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 r. t. Ammonium chloride was precip-
itated during the progress of the reaction. After filteration the
ammonium chloride, phenyl isocyanate (0.6 g, 5 mmol) was
added to the filterate. The reaction mixture was heated un-
der reflux for 30 min. The solid product which separated
after cooling, crystallized from ethanol to give 11. Yield,
53%; m. p. 241 – 3 ◦C; IR: ν = 3320 (NH), 1675 (CO), 1618
(CN), 1265 cm−1 (CS); 1H NMR (CDCl3): δ = 2.33 (s, 3H,
CH3), 7.15 – 8.12 (m, 17H, ArH), 9.95 (s, 1H, NH, exchange-
able); Analysis for C29H21N5O3S2 (551.64): calcd. C 63.14,
H 3.84, N 12.70; found C 63.36, H 3.97, N 12.48.
N-{4-[4-(N‘-Benzylidene-4-Chlorobenzylidenehydrazino)-
quinazolin-2-yl]phenyl}-4-methylbenzenesulfonamide
(8a,b)
A mixture of 4 (4.05 g, 10 mmol) and appropri-
ate aldehydes (10 mmol) namely benzaldehyde and/or
p-chlorobenzaldehyde in absolute ethanol (30 ml) was
heated under reflux for 4 h in presence of catalytic
amount of piperidine. The excess alcohol was distilled off
and the reaction solution was left to cool to obtain the
solid product which crystallized from suitable solvent to
give 8a,b.
8a; Yield, 61% (ethanol); m. p. 236 – 8 ◦C; IR: ν = 3360 –
3200 (NH), 1620 – 1610 cm−1 (CN); 1H NMR (CDCl3): δ =
2.33 (s, 3H, CH3), 7.11 – 8.21 (m, 18H, ArH and benzylidene
proton), 9.63, 10.00 (2s, 2H, 2NH, exchangeable); Analysis
for C28H23N5O2S (493.58): calcd. C 68.13, H 4.70, N 14.19;
found C 68.45, H 4.93, N 14.01.
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 pro-
vided with an air condenser in an oil bath at 165 – 175 ◦C,
then cooled and added to cold water (40 ml). The solid prod-
8b; Yield, 67% (ethanol); m. p. 241 – 3 ◦C; IR: ν = 3340 – uct obtained was collected and recrystallized from benzene
3250 (NH), 1615 – 1605 cm−1 (CN); 13C NMR: δ = 117.1 to give 12. Yield, 65%; m. p. 193 – 5 ◦C; IR: ν = 3290 (NH),
(C-5), 118.3 (C-4a), 121.1 (C-6), 124.5 (C-8), 127.3 (C-7), 1675 (CO), 1605 (CN), 1435, 1360 cm−1 (SO2); H NMR
1
146.4 (CH=), 150.1 (C-2), 158.2 (C-7), 126.1, 129.2, 132.3, (CDCl3): δ = 2.33 (s, 3H, CH3), 6.97 – 7.89 (m, 16H, ArH),
134.3 (C-phenyl group); Analysis for C28H22ClN5O2S 9.98 (s, 1H, NH, exchangeable); Analysis for C28H20N4O3S
(528.03): calcd. C 63.69, H 4.20, N 13.26; found C 63.40, (492.55): calcd. C 68.28, H 4.09, N 11.37; found C 68.56,
H 4.01, N 13.62.
H 4.48, N 11.01.
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1018
A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
General procedure for the synthesis of quinazolinylamino Analysis for C24H20N4O3S (444.51): calcd. C 64.85, H 4.54,
acids (13a,b)
N 12.60; found C 64.27, H 4.24, N 12.93.
Amino acids (10 mmol) (viz. glycine and alanine) and
sodium carbonate (0.53 g, 5 mmol) were dissolved in wa-
ter (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 r. t., then treated with cold hydrochloric acid.
The solid product obtained was filtered off, washed with wa-
ter, and crystallized from proper solvent to give 13a,b.
N-(4-[1,3]Benzimidazo[1,2-c]quinazolin-6-ylphenyl]-4-
methylbenzenesulfonamide (15)
An equimolar amounts of compound 3 (2.0 g, 5 mmol)
and o-phenylenediamine (0.54 g, 5 mmol) was fused for 2 h
in an 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%; m. p. 206 – 8 ◦C; IR: ν = 3230 (NH), 1610 (CN), 1450,
{2-[4-(Toluene-4-sulfonylamino)phenyl]quinazolin-4-
ylamino}acetic acid (13a)
1
1360 cm−1 (SO2); H NMR (DMSO-d6): δ = 2.34 (s, 3H,
◦
Yield, 71% (dioxane); m. p. 246 – 8 C; IR: ν = 3420 –
CH3), 7.11 – 8.14 (m, 16H, ArH), 9.88 (s, 1H, NH, exchange-
able). Analysis for C27H20N4O2S (464.54): calcd. C 69.81,
H 4.34, N 12.06; found C 69.36, H 4.02, N 12.49.
3160 (OH, NH), 1700 (CO), 1610 cm−1 (CN); 1H NMR
(CDCl3): δ = 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); Analysis
for C23H20N4O4S (448.50): calcd. C 61.59, H 4.49, N 12.49;
found C 61.21, H 4.13, N 12.73.
General procedure for the synthesis of compounds (16 – 18)
An active methylene compounds (10 mmol) (viz. mal-
ononitrile, ethyl cyanoacetate, ethyl acetoacetate and acety-
lacetone) were added to an ethanolic sodium ethoxide solu-
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 ethanol)
and stirred for 2 h. The reaction mixture was heated under re-
flux for 5 h. The ethanol was removed under reduced pressure
and the residue was poured into cold water (100 ml) and ex-
tracted with ether. The extracted solvent was dried over anhy-
drous sodium sulphate and removed under reduced pressure
to give the compounds 16 – 18, respectively.
2-{2-[4-(Toluene-4-sulfonylamino)phenyl]quinazolin-4-
ylamino}propionic acid (13b)
◦
Yield, 66% (DMF-H2O, 3 : 1); m. p. 236 – 8 C; IR: ν =
3410 – 3220 (OH, NH), 1695 (CO), 1605 cm−1 (CN); Ana-
lysis for C24H22N4O4S (462.52): calcd. C 62.32, H 4.79,
N 12.11; found C 62.71, H 4.97, N 11.91.
General procedure for the synthesis of imidazoquinazolines
(14a,b)
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.
N-[4-(4-Dicyanomethylquinazolin-2-yl)phenyl]-4-methyl-
benzenesulfonamide (16)
Yield, 64% (ethanol); m. p. 173 – 5 ◦C; IR: ν = 3330
(NH), 2225 – 2215 (2 C≡N), 1620 cm−1 (CN); 1H NMR
(CDCl3): δ = 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+); 13C NMR: δ = 43.1 (CH), 113.2 (C-5),
115.1 (C-6), 117.2 (C-4a), 118.3 (C-8), 124.3 (C-7), 130.3
(CN), 143.5 (C-8a), 151.2 (C-2), 154.3 (C-4); Analysis for
C24H17N5O2S (439.49): calcd. C 65.59, H 3.90, N 15.94;
found C 65.23, H 3.61, N 15.72.
4-Methyl-N-[4-(3-oxo-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl)phenyl]benzenesulfonamide (14a)
Yield, 56% (DMF); m. p. 181 – 3 ◦C; IR: ν = 3260
(NH), 1680 (CO), 1610 cm−1 (CN); MS: m/z: 430 (M+);
13C NMR: δ = 63.5 (CH2), 119.2 (C-8), 121.2 (C-6),
123.1 (C-5), 124.9 (C-4a), 128.9 (C-7), 156.3 (C-4), 146.2
(C-8a), 158.3 (C-2), 176.3 (CO); Analysis for C23H18N4O3S
(430.48): calcd. C 64.17, H 4.21, N 13.01; found C 64.51,
H 4.62, N 13.43.
Cyano-{2-[4-(toluene-4-sulfonylamino)phenyl]quinazolin-
4-yl}acetic acid ethyl ester (17a)
4-Methyl-N-[4-(2-methyl-3-oxo-2,3-dihydroimidazo[1,2-c]-
quinazolin-5-yl)phenyl]benzenesulfonamide (14b)
Yield, 61% (1-butanol); m. p. 213 – 15 ◦C; IR: ν = 3290
◦
Yield, 61% (benzene); m. p. 175 – 7 C; IR: ν = 3280 (NH), 2230 (CN), 1735 (CO), 1615 cm−1 (CN); 1H NMR
(NH), 1675 (CO), 1605 cm−1 (CN); 1H NMR (CDCl3): (CDCl3): δ = 1.25 (t, 3H, CH3), 2.31 (s, 3H, CH3), 4.10
δ = 2.11, 2.35 (2s, 6H, 2CH3), 4.10 (s, 1H, methine proton), (s, 1H, CH), 4.31 (q, 2H, CH2), 6.91 – 7.98 (m, 12H, ArH),
7.12 – 8.13 (m, 12H, ArH), 9.95 (s, 1H, NH, exchangeable); 9.89 (s, 1H, NH, exchangeable). Analysis for C26H22N4O4S
Unauthenticated
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A. A. Aly · Synthesis and Antimicrobial Activity of Some Annelated Quinazoline Derivatives
1019
(486.54): calcd. C 64.18, H 4.56, N 11.52; found: C 64.43, 4-Methyl-N-{4-[4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-
H 4.76, N 11.21.
4-yl)quinazolin-2-yl]-phenyl}benzenesulfonamide (20b)
Yield, 65% (1-butanol); m. p. 251 – 3 ◦C; IR: ν = 3300 –
3120 (NH), 1675 (CO), 1610 cm−1 (CN); MS: m/z: 471
(M+); 13C NMR: δ = 26.1 (CH3), 96.2 (C-4 of pyra-
zole), 131.5 (C-5), 134.3 (C-4a), 139.6 (C-6), 140.2 (C-8),
143.5 (C-7), 154.3 (C-8a), 162.1 (C-3 of pyrazole), 164.2
(C-2), 169.4 (C-4), 178.9 (CO); Analysis for C25H21N5O3S
(471.53): calcd. C 63.68, H 4.49, N 14.85; found C 63.25,
H 4.12, N 14.99.
3-Oxo-2-{2-[4-(toluene-4-sulfonylamino)phenyl]quinazo-
lin-4-yl}butyric acid ethyl ester (17b)
◦
Yield, 65% (benzene); m. p. 183 – 5 C; IR: ν = 3310
(NH), 1735, 1710 (2CO), 1605 cm−1 (CN); 13C NMR: δ =
21.3 (CH3CH2), 29.8 (CH3), 62.3 (CH2), 118.2 (C-5), 120.1
(C-4a), 123.1 (C-6), 124.2 (C-8), 127.3 (C-7), 143.2 (C-8a),
151.2 (C-2), 153.2 (C-4), 161.3 (COCH3), 195.1 (COO);
Analysis for C27H25N3O5S (503.57): calcd. C 64.40, H 5.00,
N 8.34; found C 64.75, H 5.27, N 8.11.
N-{4-[4-(3,5-Dimethyl-1H-pyrazol-4-yl)quinazolin-2-
yl]phenyl}-4-methylbenzenesulfonamide (21)
N-{4-[4-(1-Acetyl-2-oxopropyl)quinazolin-2-yl]phenyl}-4-
methylbenzenesulfonamide (18)
◦
Yield, 60% (benzene); m. p. 201 – 3 C; IR: ν = 3320 –
3210 (NH), 1610 (CN); 1H NMR (CDCl3): δ = 2.31 (s, 3H,
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+); Analysis for C26H23N5O2S
(469.56): calcd. C 66.50, H 4.94, N 14.91; found C 66.86,
H 4.51, N 14.61.
◦
Yield, 64% (dioxane); m. p. 161 – 3 C; IR: ν = 3370
(NH), 1710 (CO), 1612 cm−1 (CN); 1H NMR (CDCl3):
δ = 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,
exchangeable). Analysis for C26H23N3O4S (473.54): calcd.
C 65.94, H 4.90, N 8.87; found C 65.63, H 4.71, N 8.99.
N-{4-[4-(4,6-Dimethyl-2-oxo-/thioxo-1,2-dihydropyrimidin-
5-yl)quinazolin-2-yl]-phenyl}-4-methylbenzenesulfonamide
(22a,b)
General procedure for the synthesis of pyrazolylquinazolines
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 proper solvent
to give the compounds 19 – 21, respectively.
To a solution of 18 (2.49 g, 5 mmol), in ethanolic sodium
ethoxide solution (0.12 g, 5 mmol) [prepared by dissolving
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 evaporated in vacuo,
and the residue was triturated with cold water 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)
22a; Yield, 59% (ethanol); m. p. 191 – 3 ◦C; IR: ν =
Yield, 62% (benzene); m. p. 211 – 13 ◦C; IR: ν = 3390 –
3200 (multiple bands, NH2, NH), 1615 – 1605 (CN), 1460,
1370 cm−1 (SO2); MS: m/z: 471 (M+); 13C NMR: δ =
90.1 (C-4 of pyrazole), 118.2 (C-5), 119.3 (C-4a), 121.3
(C-6), 123.1 (C-8), 129.3 (C-7), 139.5 (C-8a), 150.1 (C-2),
157.3 (C-4), 160.2 (C- 3,5 of pyrazole); Analysis for
C24H21N7O2S (471.54): calcd. C 61.13, H 4.49, N 20.79;
found C 61.48, H 4.83, N 20.34.
1
3300 – 3200 (NH), 1670 (CO), 1610 cm−1 (CN); H NMR
(CDCl3): δ = 2.32 (s, 3H, CH3), 2.51, 2.63 (2s, 6H, 2CH3 of
pyrimidine), 7.13 – 8.21 (m, 12H, ArH ), 9.95, 10.12 (2s, 2H,
2NH, exchangeable; Analysis for C27H23N5O3S (497.57):
calcd. C 65.17, H 4.66, N 14.08; found C 65.43, H 4.98,
N 14.49.
22b; Yield, 61% (ethanol); m. p. 206 – 8 ◦C; IR: ν =
3340 – 3210 (NH), 1605 (CN), 1250 cm−1 (CS); MS: m/z:
513 (M+); 13C NMR: δ = 22.3, 25.4 (2CH3), 110.2 (C-5 of
pyrimidine), 126.3 (C-4a), 129.2 (C-5), 131.2 (C-6), 134.2
(C-8), 141.3 (C-7), 151.1 (C-6 of pyrimidine), 153.4 (C-8a),
163.1 (C-2), 165.2 (C-4), 169.2 (C-4 of pyrimidine), 189.2
(CS); Analysis for C27H23N5O2S2 (513.64): calcd. C 63.14,
H 4.51, N 13.63; found C 63.51, H 4.92, N 13.31%.
N-{4-[4-(3-Amino-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)quin-
azolin-2-yl]phenyl}-4-methylbenzenesulfonamide (20a)
◦
Yield, 63% (AcOH); m. p. 241 – 3 C; IR: ν = 3420 –
3210 (multiple bands, NH2, NH), 1675 (CO), 1610 cm−1
(CN); 1H NMR (CDCl3): δ = 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 pyrazole), 9.96 (s, 1H, NH, exchangeable; Analysis
for C24H20N6O3S (472.52): calcd. C 61.00, H 4.27, N 17.79;
found C 61.48, H 4.63, N 17.31.
Acknowledgement
The author is grateful to Botany Department, Faculty of
Science, Benha University for biological screening.
Unauthenticated
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1020
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Unauthenticated
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