Heteroannulated quinazoline and quinazolinone derivatives from (Z)-2-[1-Benzamido-2-(3,4,5-trimethoxyphenyl)]vinyl-3,1-benzoxazin-4(3H)-one

Article abstract of DOI:10.1080/00397910903098722

The title compound 1 was prepared and allowed to react with a series of nitrogen nucleophiles to afford the quinazoline and quinazolinone derivatives 2-12 and tetrazole derivative 13. The IR, ¹HNMR, ¹³CNMR, and mass spectra of all th

Full text of DOI:10.1080/00397910903098722

This article was downloaded by: [North Carolina State University]
On: 11 March 2015, At: 04:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Heteroannulated Quinazoline and
Quinazolinone Derivatives from
(Z)-2-[1-Benzamido-2-(3,4,5-
trimethoxyphenyl)]vinyl-3,1-
benzoxazin-4(3H)-one
Mahmoud R. Mahmoud a & Hamed A. Y. Derbala a
a Chemistry Department, Faculty of Science , Ain Shams University ,
Abbassia, Cairo, Egypt
Published online: 23 Apr 2010.
To cite this article: Mahmoud R. Mahmoud & Hamed A. Y. Derbala (2010) Heteroannulated
Quinazoline and Quinazolinone Derivatives from (Z)-2-[1-Benzamido-2-(3,4,5-
trimethoxyphenyl)]vinyl-3,1-benzoxazin-4(3H)-one, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:10, 1516-1529, DOI:
10.1080/00397910903098722
To link to this article: http://dx.doi.org/10.1080/00397910903098722
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 40: 1516–1529, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903098722
HETEROANNULATED QUINAZOLINE AND
QUINAZOLINONE DERIVATIVES FROM (Z)-2-
[1-BENZAMIDO-2-(3,4,5-TRIMETHOXYPHENYL)]
VINYL-3,1-BENZOXAZIN-4(3H)-ONE
Mahmoud R. Mahmoud and Hamed A. Y. Derbala
Chemistry Department, Faculty of Science, Ain Shams University,
Abbassia, Cairo, Egypt
The title compound 1 was prepared and allowed to react with a series of nitrogen nucleo-
philes to afford the quinazoline and quinazolinone derivatives 2–12 and tetrazole derivative
13. The IR, 1H NMR, 13C NMR, and mass spectra of all the synthesized compounds were
discussed.
Keywords: Benzoxazin-4(3H)-one; imidazo-[1,5-b]-quinazolin-4(3H)-one derivatives; [1,2,5]-oxadiazino-
[3,2-b]-quinazolin-4(3H)-one derivatives; [1,2,4]-triazino-[6,1-b]-quinazolin-4(3H)-one derivatives; [1,2,4]-
triazolo-[1,5-c]-quinazolin-4(3H)-one derivatives
INTRODUCTION
One of the most important features of 4(3H)-3,1-benzoxazin-4(3H)-ones is
their use as key starting materials for synthesizing new heterocyclic ring systems,
including quinazoline and quinazolinone derivatives, which possess various synthetic
applications[1–15] and potential biological activity.[16–24] Of these compounds, for
example, allenic quinazolines are cell-growth inhibitors of Tarceva, 4-anilinoquina-
zolines are orally active inhibitors of erbB2 receptor tyrosine kinase, and 6,7,8-sub-
stituted quinazolines are potent and highly selective PDE5 inhibitors, which have
potential therapeutic uses for male erectile dysfunction.[23–25] Futhermore, several
quinazolinones were synthesized as potential antimicrobial,[26] anticancer,[16] and
antimalarial[27] agents. Moreover, 4(3H)-quinazolinone is a frequently encountered
unit in natural products; however, pyrido-[3,2-h]-quinazolines have been recently
discovered to have organic semiconductor properties.[28,29] These aforementioned
findings prompted us to synthesize quinazoline and quinazolinone derivatives via
the interaction of the benzoxazinone 1 with different nitrogen nucleophiles, which
could be more precise and interesting pharmaceutical compounds.
Received March 19, 2009.
Address correspondence to Hamed A. Y. Derbala, Chemistry Department, Faculty of Science,
Ain Shams University, Abbassia, Cairo, Egypt. E-mail: h_derbala@hotmail.com
1516

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1517
RESULTS AND DISCUSSION
Compound 1 was prepared in a fairly good yield by treating 2-aminobenzoic
acid with 4-arylidene-5(4H)-oxazolone in boiling pyridine. Compelling evidence
for the structure of 1 was inferred from the infrared (IR) spectrum, which revealed
strong absorption bands at 3276, 1760, and 1676 cmꢀ1, attributable to NH, CO
1
(d-lactone), and CO (a,b-unsat. amide), respectively. H NMR and 13C NMR were
consistent with the assigned structure (see the Experimental section). Electron-
impact (EI) fragmentation of compound 1 showed the molecular ion peak at m=z
458 (30.74%) together with the base peak at m=z 105 (100%), corresponding to the
highly stable cation PhCꢁOþ.
When compound 1 was reacted with hydrazine hydrate (80%) or hydroxylamine
hydrochloride in the presence of fused sodium acetate in refluxing ethanol for 3 h, it
afforded (Z)-3-amino-, or (Z)-3-hydroxy-, 2-substituted quinazolin-4(3H)-ones 2
and 3, respectively. It was obvious that the reaction proceeded via hetero-ring-opening
followed by cyclization in situ. The IR spectra of compounds 2 and 3 showed the
carbonyl absorption frequencies of the six-membered lactam rings at 1688 and
1676 cmꢀ1, respectively, along with the absorption bands (CO, a,b-unsat. amide) at
1661 cmꢀ1(2) and 1656 cmꢀ1(3). In addition, 1H NMR spectra of compound 2
revealed a broad singlet at d 5.32 ppm (NH2, 2H); however, compound 3 showed a
singlet at d 10.37 ppm (1H, OH). Both bands were exchangeable with D2O.[30–34]
Prolonged heating of the former reaction mixture in n-butanol for 10 h and the
latter one in pyridine for 16 h yielded (Z)-2-phenyl-4(3,4,5-trimethoxybenzylidene)-
1H-[1,2,4]-triazino-[6,1-b]-, and [1,2,5]-oxdiazino-[3,2-b]-, quinazolin-10(4H)-ones 4
and 5, respectively (Scheme 1). The IR spectra of compounds 4 and 5 lack the
absorption frequencies of the open amide carbonyl groups; however, the carbonyl
absorptions of cyclic lactam rings were exhibited at 1681 and 1702 cmꢀ1, respect-
1
ively. H NMR spectrum of 4 displayed a singlet at d 8.93 ppm (1H, NH, triazine
ring, exchangeable with D2O); however, a similar spectrum of compound 5 lacks
the latter peak. Morever, the mass spectra of the former compound 4 showed the
molecular ion peak at m=z 454 (17.66%), and the latter one 5 showed the base peak
at m=z 455 (Mþ, 100%).
Treatment of compound 1 with cyanoacetic acid hydrazide in refluxing pyri-
dine resulted in the formation of annelated pyrazolo-[1,5-c]quinazoline derivative
(6) (Scheme 1). Furthermore, when compound 1 was reacted with semi- or thiosemi-
carbazide hydrochloride in the presence of anhydrous sodium acetate in the absence
of solvents at 160–170 ꢂC, it yielded the triazolo-[1,5-c]-quinazoline derivatives (7a)
and (7b), respectively.[35,36] The IR spectrum of 6 displayed the carbonyl absorption

1518
M. R. MAHMOUD AND H. A. Y. DERBALA
Scheme 1. Reactions of compound 1 with hydrazine hydrate, hydroxylamine hydrochloride, cyanoacetic
acid hydrazide, and semi- and thiosemicarbazide at different reaction conditions.
bands at 1692 cmꢀ1(CO, pyrazolone ring) and at 1652 cmꢀ1(CO, open amide), along
with the absorption at 2220 cmꢀ1(CꢁN). Compound 7a showed similar absorptions
at 1698 cmꢀ1 (pyraz. ring) and 1647 cmꢀ1(open amide). In turn, 7b lacks the carbonyl
absorption (pyraz. ring); however, it showed the frequencies 1672 cmꢀ1 (CO, open
amide) and 1286 cmꢀ1(C S). The EI fragmentation showed the molecular ion peaks
=
of compound 6 at m=z 416 (Mþ. – PhCO, 23.94%), 7a at m=z 497 (Mþ., 12.28%), and
7b at m=z 513 (Mþ., 23.26%).
With the aim of expanding the synthetic potential of the 4(3H)-benzoxazinone
1, it was allowed to react with o-phenylenediamine under different reaction con-
ditions. Thus, when conducted with the latter reagent in boiling dioxane, it afforded
Z-N-[1-(2-(1H-benzoimidazol-2-yl)phenylamino)-1-oxo-3-(3,4,5-trimethoxyphenyl)-
prop-2-en-yl]benzamide (8). The reaction took place via hetero-ring-opening fol-
lowed by 1,5-exo-trig cyclization in situ. The IR spectrum showed the disappearance
of the carbonyl absorption band of d-lactone, whereas two absorptions were dis-
played at 1671 (br.) and 1662 cmꢀ1(two CO, open amides). The mass spectrum
showed m=z 548 (17.22%; Mþ.). However, when the reaction was carried out in
boiling acetic acid, it yielded Z-3-(20-acetamidophenyl)-2-[10-benzamido-20-(3,4,5-
trimethoxyphenyl)vinyl]quinazolin-4(3H)-one (9). The IR spectrum revealed three

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1519
Scheme 2. Reactions of 1 with o-phenylenediamine under different reaction conditions. Formation of
compounds 8–10.
carbonyl absorptions at 1702 (CO, quinazolone ring), 1673, and 1661 cmꢀ1 (2 CO,
open amides). Upon treatment of 1 with the same diamine reagent in the absence of
solvents at 160 ꢂC in an oil bath, Z-3H,4H-2-[10-benzamido-20-(3,4,5-trimethoxy-
phenyl)vinyl]benzimidazo-[1,2-c]-quinazoline (10) was formed (Scheme 2). The
recorded peak in the mass spectrum of compound 10 at m=z 530 (14.75%) indicates
the removal of two molecules of water under the reaction conditions via ring open-
ing followed by double cyclizations in situ. The structure of compound 10 was
confirmed from the microanalytical and spectroscopic data. Thus, the IR spectrum
was devoid of carbonyl absorption bands for the quinazolone ring and retained
strong absorption bands at 1665 (amide CO) and1632 cmꢀ1 (2C N) (see the
=
Experimental section).
Interaction of the benzoxazinone 1 with N-(1-naphthyl)ethylenediamine
hydrochloride in refluxing pyridine for 6 h yielded 3-(N-1-naphthylamino)ethyl-2-
substituted quinazolin-4(3H)-one 11 (Scheme 3). The IR spectrum of the latter
compound displayed two broad absorptions at 3290 and 3178 cmꢀ1 (3NH) and
two absorption bands at 1683 (CO, quinazolone) and 1667 cmꢀ1(CO, open amide);
in addition, the mass spectrum showed a fragmentation peak at m=z 473
(Mþ. – C2H2, HN-C10H7) (see the Experimental section).
Refluxing the benzoxazinone 1 with excess formamide in an oil bath at 170 ꢂC
for 10 h afforded Z-3-(30,40,50-trimethoxybenzylidene)-1-phenylimidazo-[5,1-b]-
quinazolin-9(3H)-one, 12. The reaction presumably involved first the decomposition
of formamide under the influence of the employed temperature to produce ammonia,
which reacts with 1 to give the quinazolinone intermediate A. Afterwards, the
reaction went throuough internal nucleophilic addition followed by a loss of a water
molecule in situ from the intermediate B to yield the thermodynamically more stable
product 12.[37,38] The IR spectrum of 12 lacks the open amide carbonyl absorption
band; however, its quinazolone carbonyl absorption was displayed at 1684 cmꢀ1
.

1520
M. R. MAHMOUD AND H. A. Y. DERBALA
Scheme 3. Reactions of 1 with N-(1-naphthyl)ethylenediamine hydrochloride, formamide, and sodium
azide. Formation of compounds 11–13.
The EI fragmentation of compound 12 showed m=z 530 (22.3%), corresponding to
the molecular ion peak. Furthermore, 1H NMR and 13C NMR were consistent with
the proposed structure. This reaction is considered as a successful attempt to annu-
late a fused quinazolinone. It takes place via hetero-ring opening followed by cycliza-
tion to give the quinazolinone derivative, which was further cyclized via a
condensation reaction to create the imidazole nucleus.[39]
Scheme 4. Mechanistic pathway for the formation of compound 12.

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1521
Scheme 5. Mechanistic pathway for the formation of compound 13.
Recently, treatment of the oxazinone 1 with sodium azide in refluxing AcOH for
12 h afforded Z-2-[5-(10-benzamido-20-(3,4,5-trimethoxyphenyl)vinyl)-1H-tetrazolo-
1-yl]-benzoic acid 13. Adequate evidence for the structure 13 is forthcoming from
the study of its spectral data. The IR (t cmꢀ1) spectrum exhibited the absorption
bands at 3319 (br. NH, OH), 1708 (CO, acid), 1671 (CO, amide). 1H NMR
spectrum revealed a singlet at d 11.07 ppm (1H, COOH). In addition, the EI fragmen-
tation showed the molecular ion peak at m=z 501 (8.93%). Nevertheless, no evidence
was detected for the formation of the aroyl azide 14.[40–42]
Plausible mechanisms for the formation of compounds 12 and 13 are outlined
in Schemes 4 and 5, respectively.
EXPERIMENTAL
All melting points were taken on a Gallen Kamp electric melting-point appar-
atus. IR spectra were recorded in KBr and were determined on a Perkin-Elmer 2000
Fourier transform (FT)–IR system. NMR spectra were determined on Varian
1
Gemini instruments (200 MHz for H NMR and 50 MHz for 13C NMR) in CDCl3
or dimethylsulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as internal
standard; chemical shifts are reported in d (ppm). Mass spectra were measured on
VG Autospec QMS 30 and MS 9 (AEI) spectrometers with EI 70 eV. Elemental
analyses were measured using a Perkin-Elmer 2400 CHN Elemental Analyzer. The
monitoring of the progress of all reactions and the homogeneity of the synthesized
compounds were carried out by thin-layer chromatography (TLC).

1522
M. R. MAHMOUD AND H. A. Y. DERBALA
Z-2-[10-Benzamido-20-(3,4,5-trimethoxyphenyl)]vinyl-3,1-
benzoxazin-4(3H)-one (1)
A mixture of 2-aminobenzoic acid (1.4 g, 0.01 mol) and (3,4,5-trimethoxy-
benzylidene)-5(4H)-oxazolone (3.4 g, 0.01 mol) in pyridine (30 ml) was heated under
reflux for 6 h (TLC). After cooling, the reaction mixture was poured into ice-cold
hydrochloric acid. The solid separated was filtered off, stirred for 30 min with
50 ml sodium bicarbonate solution (10%), filtered, washed with water (4 ꢃ 50 ml),
and recrystallized from light petroleum ether (bp 100–120 ꢂC) to give 1 as yellow
crystals (3.19 g, yield 69.6%), mp 96–98 ꢂC. IR (n cmꢀ1): 3276 (NH), 1760 (COoxaz.),
1676 (COamide). 1H NMR (CDCl3, d ppm) 9.3 (s, 1H, NH, exchangeable with D2O),
8.26–7.74 (m, 9Harom.), 6.73 (s, 2Harom), 6.14 (s, 1H, olefinic proton), 3.85 (s, 6H,
2OMe), 3.82 (s, 3H, OMe). Ms m=z (%): 458 (30.74), 353 (60.27), 181 (22.34), 147
(32.92), 105 (100.0), 77 (67.86). Anal. calcd. C26H22N2O6 (458.44): C, 68.11; H,
4.83; N, 6.11. Found: C, 68.31; H, 5.09; N, 5.98. 13C NMR (CDCl3) is shown here:
Synthesis of Z-2-[10-Benzamido-20-(3,4,5-trimethoxyphenyl)]-
vinyl-3-amino-quinazolin-4 (3H)-one (2)
A solution of the benzoxazinone 1 (1.84 g, 0.004 mol) and hydrazine hydrate
(80%) (1.28 g, 0.025 mol) in ethanol (30 ml) was refluxed for 3 h (TLC). Evaporation
of the solvent in vacuo left an oily product, which triturated with methanol to give
a solid product recrystallized from dioxane as yellow crystals; mp 207–209 ꢂC (1.7g,
yield, 82.5%). IR (n cmꢀ1): 3416, 3321, 3279 (NH2), 1688 (COquinaz.), 1661
1
(COamide). H NMR (DMSO-d6, d ppm) 8.8 (s, 1H, NH, exchangeable with D2O),
8.42–7.26 (m, 9Harom.), 6.96 (s, 2Harom), 6.17 (s, 1H, CH ¼), 5.32 (br.s, 2H, NH2,
exchangeable with D2O), 3.92 (s, 6H, 2OMe), 3.81 (s, 3H, OMe). Ms m=z (%): 472
(9.35), 367 (15.0), 181 (23.79), 161 (72.32), 105 (100.0), 77 (66.36). Anal. calcd. for
C26H24N4O5 (472.49): C, 66.09; H, 5.13; N, 11.86. Found: C, 66.26; H, 4.96; N, 11.57.
Z-2-[1-Benzamido-2-(3,4,5-trimethoxyphenyl)vinyl]-3-
hydroxyquinazolin-4(3H)-one (3)
A mixture of 1 (1.84 g, 0.004 mol), hydroxylamine hydrochloride (1.04 g,
0.015 mol), and anhydrous sodium acetate (1.5 g) in absolute ethanol (50 ml) was

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1523
refluxed for 6 h. The reaction mixture was poured onto water, stirred for 30 min, and
then filtered off. The deposited product was dried and recrystallized from ethanol to
give 3 as pale yellow crystals (1.2 g, yield, 60.6%); mp 236–238 ꢂC. IR (n cmꢀ1): cen-
1
tered at 3432 (NH, OH), 1676 (CO), 1656 (COamide). H NMR (DMSO-d6, d ppm)
10.37 (s, 1H, OH, exchangeable with D2O), 8.79 (s, 1H, NH, exchangeable with
D2O), 8.3–7.4 (m, 9Harom.), 7.27 (s, 2Harom), 6.22 (s, 1H, CH¼), 3.93 (s, 6H,
2OMe), 3.82 (s, 3H, OMe). Ms m=z (%): 473 (11.36), 456 (17.88), 351 (30.38), 181
(8.31), 167 (17.62), 105 (100.0). Anal. calcd. for C26H23N3O6 (473.46): C, 65.95;
H, 4.91; N, 8.88. Found: C, 66.13; H, 4.62; N, 8.60.
(Z)-2-Phenyl-4-(3,4,5-trimethoxybenzylidene)-1H-[1,2,4]-triazino-
[6,1-b]-quinazolin-10(4H)-one (4)
A solution of the benzoxazinone 1 (1.84 g, 0.004 mol) and hydrazine hydrate
(80%) (1.0 g, 0.02 mol) in n-butanol (30 ml) was heated under reflux for 10 h. Evap-
oration of the solvent in vacuo left a solid product, which when treated with water. A
pale-yellow solid was deposited, filtered off, dried, and recrystallized from dimethyl-
formamide (DMF) to give the quinazolin-10(4H)-one derivative 3 as yellowish-white
crystals; mp 183–185 ꢂC (1.2 g, yield, 60.6%). IR (n cmꢀ1): 3310 (NH), 1681 (CO),
1
=
1632 (C N). H NMR (DMSO-d6, d ppm) 8.93 (s, 1H, NH, exchangeable with
D2O), 8.11–7.24 (m, 9Harom.), 6.81 (s, 2Harom), 6.34 (s, 1H, CH ¼), 3.92 (s, 6H,
2OMe), 3.81 (s, 3H, OMe). Ms m=z (%): 454 (17.66), 377 (24.95), 276 (40.36), 181
(38.28), 91 (27.64), 77 (56.68). Anal. calcd. for C26H22N4O4 (454.48): C, 68.71; H,
4.89; N, 12.33. Found: C, 68.82; H, 4.63; N, 12.08. 13C NMR (DMSO-d6) is shown
as follows:
(Z)-2-Phenyl-4-(3,4,5-trimethoxybenzylidene)-1H-[1,2,5]-
oxadiazino[3,2-b]quinazolin-10(4H)-one (5)
A solution of 1 (1.84 g, 0.004 mol) and hydroxylamine hydrochloride (1.04 g,
0.015 mol) in pyridine (30 ml) was refluxed for 16 h. The reaction mixture was cooled
and poured onto a crushed ice=HCl mixture. The solid that separated was filtered
off, washed with water, dried, and then recrystallized from dioxane to give 5 as
yellowish-white crystals; mp 177–179 ꢂC (0.8 g, yield 40%). IR (nc mꢀ1): 1702

1524
M. R. MAHMOUD AND H. A. Y. DERBALA
1
=
(CO), 1642 (C N). H NMR (DMSO-d6, d ppm) 8.61–7.25 (m, 9Harom.), 6.93 (s,
2Harom), 6.14 (s, 1H, CH ¼), 3.92 (s, 6H, 2OMe), 3.84 (s, 3H, OMe). Ms m=z (%):
455 (100.0), 378 (12.68), 276 (70.29), 181 (18.24), 91 (24.67), 65 (33.71). Anal. calcd.
for C26H21N3O5(455.47): C, 68.56; H, 4.66; N, 9.23. Found: C, 68.39; H, 4.41; N,
9.02. 13C NMR (DMSO-d6) is shown as follows:
Z-2H,3H-5-[10-Benzamido-20-(3,4,5-trimethoxyphenyl)]vinyl-2-
oxo-pyrazolo-[1,5-c]-quinazolin-1-carbonitrile (6)
Cyanoacetic acid hydrazide was added to a solution of 1 (4.58 g, 0.01 mol) in
pyridine (15 ml) and the solution mixture was stirred for 8 h (TLC). Evaporation of
solvent in vacuo left a semisolid product, which was neutralized using ice-cold 0.1 N
HCl (25 ml). The deposit was filtered off, dried, and recrystallized from dioxane to give
6 as pale-yellow crystals; mp 256–258 ꢂC (3.6 g, yield 69.1%). IR (n cmꢀ1): 3312 (NH),
1
2220 (CꢁN), 1692 (CO), 1652 (CO). H NMR (DMSO-d6, d ppm) 9.1 (s, 1H, NH,
exchangeable with D2O), 8.76 (s, 1H, NH, exchangeable with D2O), 8.40–7.32 (m,
9Harom.), 7.03 (s, 2Harom), 6.18 (s, 1H, CH ¼), 3.74 (s, 6H, 2OMe), 2.85 (s, 3H,
OMe). Ms m=z (%): 416 (M-PhCO, 23.94), 209 (34.16), 181 (17.25), 105 (100.0), 91
(8.46). Anal. calcd. for C29H23N5O5(521.53): C, 66.78; H, 4.45; N, 13.43. Found: C,
66.92; H, 4.58; N, 13.08.
Z-2H,3H-5-[10-Benzamido-20-(3,4,5-trimethoxyphenyl)vinyl]-2-
oxo-[1,2,4]-triazolo-[1,5-c]-quinazoline (7a) and
2-thioxo-[1,2,4]-triazolo-[1,5-c]-quinazoline (7b)
General procedure. A mixture of benzoxazinone 1 (1.38 g, 0.003 mol), semi-
or thiosemicarbazide hydrochloride (0.005 mol), and anhydrous sodium acetate
(0.8 g, 0.01 mol) was heated on an oil bath at 160–170 ꢂC for 1 h. The cooled mixture
was poured onto water (50 ml) and stirred for 15 min. The solid product was collected
by filteration, dried, and recrystallized from the proper solvent to give 7a and 7b.
Compound 7a. Recrystallized from benzene as light brown crystals; mp
312–314 ꢂC (0.7 g, yield 46.08%). IR (n cmꢀ1): 3317, 3212 (NH), 1698 (CO), 1647
1
(CO). H NMR (CDCl3, d ppm) 8.7 (br.s, 2H, exchangeable with D2O), 8.23–7.1

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1525
(m, 9Harom.), 6.81 (s, 2Harom), 6.27 (s, 1H, CH ¼), 3.94 (s, 6H, 2OMe), 3.84 (s, 3H,
OMe). Ms m=z (%): 497 (Mþ., 12.28), 312 (18.74), 186 (37.62), 181 (22.35), 105
(100.0), 91 (7.86), 77 (73.45). Anal. calcd. for C27H23N5O5(497.51): C, 65.18; H,
4.67; N, 14.08. Found: C, 65.51; H, 4.38; N, 13.97.
Compound 7b. Recrystallized from dioxane as brownish-red crystals;
mp > 300 ꢂC (0.9 g, yield 57.3%). IR (n cmꢀ1): 3304, 3250 (NH), 1672 (CO), 1286
(C S). 1H NMR (DMSO-d6, d ppm) 8.84 (br.s, 2H, NH, exchangeable with
=
D2O), 8.3–7.0 (m, 9Harom.), 6.93 (s, 2Harom), 6.48 (s, 1H, CH ¼), 3.92 (s, 6H,
2OMe), 3.82 (s, 3H, OMe). Ms m=z (%): 513 (Mþ., 23.26), 105 (100.0), 77 (40.43).
Anal. calcd. for C27H23N5O4S (513.57): C, 63.14; H, 4.52; N, 13.64; S, 6.24. Found:
C, 63.37; H, 4.42; N, 13.28; S, 6.36. 13C NMR (DMSO-d6) is shown as follows:
Z-N-[1-(2-(1H-Benzo[d]imidazol-2-yl)phenylamino)-1-oxo-
3-(3,4,5-trimethoxyphenyl)prop-2-en-yl]-benzamide (8)
Equimolar mixture of 1 (1.84 g, 0.004 mol) and o-phenylenediamine (0.54 g,
0.005 mol) in dioxane (30 ml) was heated under reflux for 10 h. The excess solvent
was removed in vacuo. The solid was filtered off, dried, and recrystallized from etha-
nol to give the benzimidazole derivative 8 as pale-yellow crystals; mp 280–283 ꢂC
(1.2 g, yield 50.2%). IR (n cmꢀ1): 3342, 3280, 3162 (NH), 1671 (CO), 1662 (CO).
1H NMR (DMSO-d6, d ppm) 8.93 (br.s, 2H, NH, exchangeable with D2O), 8.4 (s,
1H, NH, exchangeable with D2O), 8.0–7 (m, 13Harom.), 6.94 (s, 2Harom), 6.06 (s,
1H, CH ¼), 3.92 (s, 6H, 2OMe), 3.85 (s, 3H, OMe). Ms m=z (%): 548 (Mþ.,
17.22), 236 (32.76), 188 (12.38), 105 (100.0), 77 (70.69). Anal. calcd. for
C32H28N4O5(548.59): C, 70.06; H, 5.16; N, 10.21. Found: C, 70.24; H, 5.42; N, 10.07.
(Z)-3-(20-Acetamidophenyl)-2-[10-benzamido-20-(3,4,5-
trimethoxyphenyl)vinyl]quinazolin-4(3H)-one (9)
A mixture of compound 1 (1.84 g, 0.004 mol), o-phenylenediamine (0.5 g,
0.005 mol), and freshly fused sodium acetate (0.8 g, 0.01 mol) in glacial acetic acid
(20 ml) was refluxed for 3 h. After cooling, the reaction mixture was poured onto
water. The deposited was collected by filtration, dried, and recrystallized from toluene
to give 9 as yellow crystals; mp > 300 ꢂC (1.6 g, yield 62.2%). IR (n cmꢀ1): 3317, 3241

1526
M. R. MAHMOUD AND H. A. Y. DERBALA
1
(NH), 1702, 1673, 1661. H NMR (DMSO-d6, d ppm) 9.04 (br.s, 2H, exchangeable
with D2O), 8.2–7.2 (m, 13Harom.), 7.08 (s, 2Harom), 6.54 (s, 1H, CH¼), 3.85 (s, 9H,
2OMe), 2.35 (s, 3H, COMe). Ms m=z (%): 457 (11.44), 351 (27.67), 181 (18.82), 135
(39.68), 105 (100.0), 77 (32.41). Anal. calcd. for C34H30N4O6(590.63): C, 69.14; H,
5.13; N, 9.48. Found: C, 69.32; H, 5.37; N, 9.18.
(Z)-3H,4H-2-[10-Benzamido-20-(3,4,5-trimethoxyphenyl)-
vinyl]benzimidazo-[1,2-c]-quinazoline (10)
A mixture of the benzoxazinone 1 (1.84 g, 0.004 mol) and o-phenylenediamine
(0.5 g, 0.005 mol) was stirred in an oil bath at 150 ꢂC for 2 h. After cooling, the reac-
tion mixture was poured onto sodium bicarbonate solution 10% (15 ml) and stirred
for 10 min. The residue was collected by filtration, washed several times with water,
dried, and recrystallized from methanol to give 10 as yellow crystals; mp 166–168 ꢂC
1
(0.86 g, yield 37.2%). IR (n cmꢀ1): 3215 (NH), 1665 (CO), 1632 (C N). H NMR
=
(DMSO-d6, d ppm) 8.7 (s, 1H, NH, exchangeable with D2O), 8.4–7.3 (m, 13Harom.),
7.07 (s, 1H, CH¼), 3.85 (s, 9H, 2OMe). Ms m=z (%): 530 (14.75), 313 (46.28), 171
(100.0), 105 (97.36), 77 (48.29). Anal. calcd. for C32H26N4O4(530.58): C, 72.44; H,
4.95; N, 10.56. Found: C, 72.75; H, 5.22; N, 10.46.
3-(N-1-Naphthyl)aminoethyl-2-[10-benzamido-20-
(3,4,5-trimethoxyphenyl)vinyl] quinazolin-4(3H)-one (11)
N-(1-Naphthyl)ethan-1,2-diamine hydrochloride (1.5 g, 0.006 mol) was added
to a solution of 1 (1.84 g, 0.004 mol) in dry pyridine (30 ml) with stirring for
15 min. The whole mixture was heated under reflux for 6 h. After cooling, the reac-
tion mixture was poured onto crushed ice=HCl. The solid was collected by fil-
tration, dried, and recrystallized from dioxane as light-brown crystals; mp
273–275 ꢂC (1.4 g, yield 51.8%). IR (n cmꢀ1): 3290, 3178 (NH), 1683, 1667 (CO).
1H NMR (DMSO-d6, d ppm) 8.9 (s, 1H, NH, exchangeable with D2O), 8.6–7.3
(m, 16Harom.), 6.86 (s, 2Harom), 6.15 (s, 1H, CH¼), 3.93 (s, 9H, 2OMe), 3.35 (t,
4H). Ms m=z (%): 473 [(Mþ. – C2H2, HN-C10H7), 29.36], 312 (22.37), 105
(100.0), 77 (62.40). Anal. calcd. for C38H35N4O5(641.73): C, 71.12; H, 5.51; N,
10.92. Found: C, 71.40; H, 5.28; N, 11.08.
(Z)-1-Phenyl-3-(30,40,50-trimethoxybenzylidene)imidazo-
[5,1-b]-quinazolin-9(3H)-one (12)
A mixture of compound 1 (1.84 g, 0.004 mol) and formamide (10 ml) was
stirred under reflux for 10 h (TLC). Evaporation of solvent in vacuo left a semisolid
product, which was stirred with water for 10 min. The solid deposited was filtered
off, dried, and recrystallized from methanol to give the imidazoquinazolinone deriva-
tive 12 as yellowish-white crystals; mp 243–245 ꢂC (1.1 g, yield 47.8%). IR (n cmꢀ1):
1
=
1684 (COquinaz.), 1632 (C N). H NMR (CDCl3, d ppm) 8.37–7.62 (m, 9Harom.),
7.28 (s, 2Harom), 6.19 (s, 1H, CH¼), 3.87 (s, 9H, 2OMe). Ms m=z (%): 530 (22.32),
352 (17.73), 181 (42.23), 91 (100.0), 77 (70.92), 65 (30.95). Anal. calcd. for

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1527
C26H21N3O4(439.46): C, 71.06; H, 4.83; N, 9.56. Found: C, 70.81; H, 5.12; N, 9.44.
13C NMR (CDCl3) is shown as follows:
(Z)-2-[5-(10-benzamido-20-(3,4,5-trimethoxyphenyl)vinyl)-
1H-tetrazol-1-yl]benzoic Acid (13)
Sodium azide (0.65 g, 0.01 mol) was added to a solution of compound 1 (1.84 g,
0.004 mol) in acetic acid (20 ml), and the mixture was heated under reflux for 12 h
(TLC). The reaction mixture after concentration was poured onto crushed ice.
The solid separated was filtered off, dried, and recrystallized from dioxane to give
the tetrazole derivative 13 as colorless crystals; mp 180–182 ꢂC (0.9 g, yield 42.8%).
1
IR (n cmꢀ1): br. centered at 3319 (NH, OH), 1708 (COacid), 1671 (COamide). H
NMR (CDCl3, d ppm) 11.07 (s, 1H, COOH, exchangeable with D2O), 8.86 (s, 1H,
NH, exchangeable with D2O), 8.63–7.14 (m, 9Harom.), 7.09 (s, 2Harom), 6.24 (s,
1H, CH¼), 3.94 (s, 9H, 2OMe). Ms m=z (%): 501 [Mþ.; 8.93], 457 (13.95), 381
(22.11), 181 (30.37), 105 (100.0), 91 (17.39), 77 (62.65). Anal. calcd. for
C26H23N5O6(501.48): C, 62.27; H, 4.63; N, 13.96. Found: C, 62.36; H, 4.36; N, 13.71.
REFERENCES
1. Dou, G.; Wang, M.; Shi, D. One-pot synthesis of quinazolinone derivatives. J. Comb.
Chem. 2009, 11, 151–154.
2. Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Highly efficient copper cascade synthesis of
quinazoline and quinazolinone derivatives. Chem. Commun. 2008, 6333–6335.
3. Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Synthesis of
4(3H)-quinazolines and quinazolinones. Tetrahedron 2005, 61, 10153.
4. Fray, J.; Mathias, J.; Nicholas, C.; Pa-Bo, Y.; Snow, H. Synthesis of substituted
2-amino-4-quinazolinones via ortho-flourobenzoyl guanidines. Tetrahedron Lett. 2006,
47, 6365.
5. Arumugam, N.; Srinivasan, P. C. A facile synthesis of indoloqinazolinones. Heterocycles
2003, 60, 1191.
6. Bhatti, H. S.; Seshadri, S. Facile synthesis of 12-ketoquinazo[2,1-b] quinazolines via
the Vilsmeier–Haack reaction of 6-nitro-2-methyl-3-aryl 4(3H)-quinazolones. Synth.
Commun. 2005, 35, 907.

1528
M. R. MAHMOUD AND H. A. Y. DERBALA
7. Abdel-Razek, F.; Metwally, N. Synthesis of some new N-substituted pyrroles, pyrrolo[1,2-a]-
quinazoline, and diaza-as-indacenes derivatives. Synth. Commun. 2006, 36, 83.
8. Besson, T.; Chosson, E. Microwave-assisted synthesis of bioactive quinazolines and quin-
azolinones. Comb. Chem. and High-Thr. Scr. 2007, 10, 203.
9. Bashir, A.; Sahee, D. P. One-pot synthesis of 4(3H)-quinazolinones. Synth. Commun.
2004, 34, 2169.
10. Xie, C.; Xia, H.; Liu, M. G.; Ding, M. W. Efficient synthesis of 4(3H)-quinazolinones
using a soluble polymeric support. Chin. Chem. Lett. 2008, 19, 505.
11. Hemdan, M.; El-shahawy, M. Synthesis of 1,2,4-triazole, imidazoles, pyrimidines, quin-
azolines,
1,3,5-triazines,
and
1,3-thiazines
from
3-oxo-5,6-diphenyl-2,3-
dihydropyridazine-4-carbonyl isothiocyanate. J. Chem. Res. 2009, 2, 75.
12. Mahmoud, R. M.; El-Bordany, E. A.; Azab, M. E.; Soliman, E. A. Synthesis of new
thiadiazoles, 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles, and 1,2,4-triazolo[2,3-c] quinazoline
derivatives from 3,1-benzoxazine 4(3H)-one derivatives. Phosphorus, Sulfur Silicon Relat.
Elem. 2007, 181, 1275.
13. Mahmoud, R. M.; El-Bordany, E. A.; Hassan, N. F.; Abu El-Azm, F. S. M. New 2,3-
disubstituted quinazolin-4(3H)-ones from 2-undecyl-3,1-benzoxaziin-4-one. J. Chem.
Res. 2007, 541.
14. Derbala, H. A. Chemoselectivity of 6-bromo-2-methyl-3,1-benzoxazin-4-one towards
amines, Schiff bases, and azines. Monat. fur Chem. 1996, 127, 103.
15. Khajavi, M. S.; Rad-moghadam, K.; Hazarkhani, H. A facile synthesis of 6-substituted ben-
zimidazo[1,2-c] quinazolines under microwave irradiation. Synth. Commun. 1999, 29, 2617.
16. Srivastava, A. K.; Kumar, V.; Agarwal, S. K.; Makherjee, R.; Burman, A. C. Synthesis of
quinazolines as tyrosine kinase inhibitors. Anti-Cancer Age. Med. Chem. 2009, 9, 246.
17. Deeb, O.; Carle, B. QSAR of aromatic substances: EGFR inhibitory activity of quinazo-
line analogues. J. Enz. Inh. Med. Chem. 2008, 23, 763.
18. Nagase, I.; Mizutani, T.; Ishikawa, S.; Sekino, T.; Fujimura, T.; Ito, S.; Mitobe, Y.;
Sato, N. Quinazolinone derivatives as non-imidazole H3 receptor inverse agonists.
J. Med. Chem. 2008, 51, 4780–4789.
19. Lemoine, R. C.; Glinka, T. W.; Watkins, W. J.; Cho, A.; Yang, J.; Iqbal, N.; Singh, R.;
Madsen, D.; Lolans, K.; Lomovskaya, O.; Oza, U.; Dudly, M. Quinazolone-based fungal
efflux pump inhibitors: Activity in clinically relevant Candida spp. Bioorg. Med. Chem.
Lett. 2004, 14, 5127–5131.
20. Ye, Z.; Gao, Y.; Bakshi, R. K.; Rohrer, S. P. Quinazolinones as non-peptidic growth
hormone secretagogues. Bioorg. Med. Chem. Lett. 2000, 10, 3–8.
21. Refaei, F. M.; Esmat, A. Y.; Abdel Gawad, S. M.; Ibrahim, A. M.; Mohamed, M. A. The
antihyperlipidemic activities of 4(3H)-quinazolinones and two halogenated derivatives in
rats. Lip. Heal. Dis. 2005, 4, 22.
22. Balbaa, M.; Abdel Majeed, M.; Diab, T.; Mansour, H. Inhibition of mammalian
aspartate transcarbamylase by quinazolinone derivatives. Enz. Inh. Med. Chem. 2008,
23, 483.
23. Nakamura, H.; Onagi, S. Synthesis and biological evaluation of allenic quinazolines using
palladium-catalysed hydride-transfere reaction. Tetrahedron Lett. 2006, 47, 2539.
24. Bullard, P.; Bradburg, R. H.; Hennequin, L. F.; Hickinson, D. M.; Johson, P. D.; Kettle,
G. K.; Klinowska, T.; Margentin, R.; Ogilvie, D. J.; Olivier, A. 5-Substituted
4-anilinoquinazolines as potent, selective and orally active inhibitors of erbB2 receptor
tyrosine kinase. Bioorg. Med. Chem. Lett. 2005, 15, 4226.
25. Kim, Y. H.; Choi, H.; Lee, J.; Hwang, I. C.; Moon, S. K.; Kim, S. J.; Kim, S. J.; Lee,
H. W.; Im, S. D.; Lee, S. S.; Ahn, S. K.; Han, C. K.; Yoom, J. H.; Lee, K. J.; Choi,
N. S. Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutic
for male erectile dysfunction. Bioorg. Med. Chem. Lett. 2008, 18, 6279.

HETEROANNULATED QUINAZOLINES AND QUINAZOLINONES
1529
26. El-Azab, A. Synthesis of new substituted 2-mercaptoquinazoline analogs antimicrobial
agents. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 333.
27. Guan, J.; Zhang, Q.; O’Neil, M.; Obalidia, N.; Ager, A.; Gerena, L.; Lin, A. J. Antima-
larial activities of new pyrrolo[3,2-f] quinazoline-1,3-diamine derivatives. Antimic. Agents
Chemother. 2005, 49, 4928.
28. Leong, S. L.; Schnurer, J.; Broberg, A.; Verrucine, F. A quinazoline from Penicyllium
verrucosum. J. Nat. Prod. 2008, 71, 1455.
29. Saalbeck, J.; Kussler, M.; Lux, A. Pyrido[3,2-h] quinazolines as organic semiconductors
materials. J. Am. Chem. Soc. 2005, 127, 7227.
30. Tran, T. P.; Ellsworth, T. L.; Stier, M. A.; Domagala, J. M.; Showalter, H. D.;
Grancheck, S. J.; Shapiro, M. A.; Joannides, T. E.; Singh, R. Synthesis and structural–
activity relationship of 3-hydroxyquinazoline-2,4-dione antibacterial agents. Bioorg.
Med. Chem. 2004, 14, 4405.
31. Abdel-Mageed, M. F.; Saleh, M. A.; Abdo, M. A.; El-Hiti, G. A. Reaction of
6-substituted-3-amino-2-phenyl-4(3H)-quinazolinone with D-ribose and L-arabinose.
J. Coll. Czech. Chem. Commun. 1995, 60, 1016.
32. Smith, K.; El-Hiti, G. A.; Abdel-Mageed, M. F.; Abdo, M. A. Lithiation of 2-alkyl-
3-amino and 2-alkyl-3(methylamino)-4(3H)-quinazolinones. J. Org. Chem. 1996, 61, 656.
33. Nawrocka, W. P. Synthesis of new 4(3H)-quinazolinone derivatives by reaction of
3-amino-2-thioxo-4(3H)-quinazolinones with selected chloroformates: Ammonolysis of
3-ethoxycarbonylamino-2-ethoxycarbonylthio-4(3H)-quinazolinone, part 2. Phosphorus,
Sulfur Silicon Relat. Elem. 2009, 184, 261.
34. Nawrocka, W. P.; Stasko, J. J.; Liszkiewicz, H. Synthesis of new 4(3H)-quinazolinone
derivatives by reaction of 3-amino-2-thioxo-4(3H)-quinazolinones with selected substi-
tuted cinnamic acids and halogenoketones. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 1379.
35. Palmer, B. D.; Kallmeyer, S. T.; Fry, D. W.; Nelson, L. M.; Showalter, H. D.; Denny,
W. A. Tyrosine kinase inhibitors: Eleven soluble analogues of pyrrolo- and pyrazoloqui-
nazolines as epidermal growth factor receptor inhibitors: Synthesis of biological evalu-
ation and modeling of the mode of binding. J. Med. Chem. 1997, 40, 1519.
36. Kim, Y. C.; De Zewart, M.; Chang, L.; Moro, S.; Kunzel, J. K.; Melman, N.; Ilzerman, A.
P.; Jacobson, K. A. Derivatives of the triazoloquinazoline adenosine antagonist (CGS
15943) having high potency at the human A2B and A3 receptor subtypes. J. Med. Chem.
1998, 41, 2835.
37. Kostakis, I. K.; Elmori, A.; Seguin, E.; Ianneli, M.; Besson, T. Rapid synthesis of 2,3-di-
substituted quinazolin-4-ones enhanced by microwave-assisted decomposition of forma-
mide. Tetrahedron Lett. 2007, 48, 6609.
38. Nouria, I.; Chosson, E.; Dubouilh, C.; Kostakis, I. K.; Ianneli, M.; Besson, T. Decompo-
sition of formamide assisted by microwave, a tool for synthesis of nitrogen-containing
heterocycles. Tetrahedron Lett. 2008, 49, 7033.
39. Zhang, Y.; Xu, C.; Houghten, R. A.; Yu, Y. Scaffold approach for solid-phase synthesis
of 2,3-disubstituted 8-arylamino-3-imidazo[4,5-g]quinazolines. J. Comb. Chem. 2007, 9, 9.
40. Mosaad, S. M.; Mohammed, K. I.; Abdel-Hamide, S. G. New quinazoline related
derivatives with antimicrobial activity. J. Bio. Sci. 2004, 4, 504.
41. Himo, F.; Demko, Z. F.; Noodlman, L.; Sharpless, K. B. Mechanism of tetrazol forma-
tion by addition of azide to nitriles. J. Am. Chem. Soc. 2002, 124, 12210.
42. Amantini, D.; Fringuelli, F.; Piermattio, O.; Pizzo, F.; Zunino, E.; Vaccano, L. Sythesis of
2-aryl-1H-1,2,3-triazoles through TBAF-catalysed [3 þ 2] cycloaddition of 2-aryl-1-
nitroethanes with TMSN3 under solvent-free conditions. J. Org. Chem. 2005, 70, 6526.